In the patient with arthritis, the two clinical clues most helpful for diagnosis are the joint pattern and the presence or absence of extra-articular manifestations. The joint pattern is defined by the answers to three questions: (1) Is inflammation present? (2) How many joints are involved? and (3) What joints are affected? Joint inflammation manifests as redness, warmth, swelling, and morning stiffness of at least 30 minutes’ duration. Both the number of affected joints and the specific sites of involvement affect the differential diagnosis (Table 20–1). Some diseases—gout, for example—are characteristically monarticular, whereas other diseases, such as rheumatoid arthritis, are usually polyarticular. The location of joint involvement can also be distinctive. Only two diseases frequently cause prominent involvement of the distal interphalangeal (DIP) joint: osteoarthritis and psoriatic arthritis. Extra-articular manifestations such as fever (eg, gout, Still disease, endocarditis), rash (eg, systemic lupus erythematosus [SLE], psoriatic arthritis, Still disease), nodules (eg, rheumatoid arthritis, gout), or neuropathy (eg, polyarteritis nodosa, granulomatosis with polyangiitis [formerly Wegener granulomatosis]) narrow the differential diagnosis further.
Table 20–1. Diagnostic value of the joint pattern.
If the diagnosis is uncertain, synovial fluid should be examined whenever possible (Table 20–2). Most large joints are easily aspirated, and contraindications to arthrocentesis are few. The aspirating needle should never be passed through an overlying cellulitis or psoriatic plaque because of the risk of introducing infection. For patients who are receiving long-term anticoagulation therapy with warfarin, joints can be aspirated with a small-gauge needle (eg, 22F) if the international normalized ratio (INR) is < 3.0.
Table 20–2. Examination of joint fluid.
1. Types of studies
A. GROSS EXAMINATION—Clarity is an approximate guide to the degree of inflammation. Noninflammatory fluid is transparent, mild inflammation produces translucent fluid, and purulent effusions are opaque. Bleeding disorders, trauma, and traumatic taps are the most common causes of bloody effusions.
B. CELL COUNT—The synovial fluid white cell count discriminates between noninflammatory (< 2000 white cells/mcL [2.0 × 109/L]), inflammatory (2000–75,000 white cells/mcL [2.0 × 109/L–75.0 × 109/L]), and purulent (> 100,000 white cells/mcL [> 100 × 109/L]) joint effusions. Synovial fluid glucose and protein levels add little information and should not be ordered.
C. MICROSCOPIC EXAMINATION—Compensated polarized light microscopy identifies and distinguishes monosodium urate (gout, negatively birefringent) and calcium pyrophosphate (pseudogout, positive birefringent) crystals. Gram stain has specificity but limited sensitivity (50%) for septic arthritis.
D. CULTURE—Bacterial cultures as well as special studies for gonococci, tubercle bacilli, or fungi are ordered as appropriate.
2. Interpretation—Synovial fluid analysis is diagnostic in infectious or microcrystalline arthritis. Although the severity of inflammation in synovial fluid can overlap among various conditions, the synovial fluid white cell count is a helpful guide to diagnosis (Table 20–3).
Table 20–3. Differential diagnosis by joint fluid groups.
ESSENTIALS OF DIAGNOSIS
A degenerative disorder with minimal articular inflammation.
No systemic symptoms.
Pain relieved by rest; morning stiffness brief.
Radiographic findings: narrowed joint space, osteophytes, increased density of subchondral bone, bony cysts.
Osteoarthritis, the most common form of joint disease, is chiefly a disease of aging. Ninety percent of all people have radiographic features of osteoarthritis in weight-bearing joints by age 40. Symptomatic disease also increases with age. Gender is also a risk factor, because osteoarthritis develops in women more frequently than in men.
This arthropathy is characterized by degeneration of cartilage and by hypertrophy of bone at the articular margins. Inflammation is usually minimal. Hereditary and mechanical factors may be involved in the pathogenesis.
Obesity is a risk factor for osteoarthritis of the knee, hand, and probably of the hip. Recreational running does not increase the incidence of osteoarthritis, but participation in competitive contact sports does. Jobs requiring frequent bending and carrying increase the risk of knee osteoarthritis (see Chapter 41).
Degenerative joint disease is divided into two types: (1) primary, which most commonly affects some or all of the following: the DIP and the proximal interphalangeal (PIP) joints of the fingers, the carpometacarpal joint of the thumb, the hip, the knee, the metatarsophalangeal (MTP) joint of the big toe, and the cervical and lumbar spine; and (2) secondary, which may occur in any joint as a sequela to articular injury resulting from either intra-articular (including rheumatoid arthritis) or extra-articular causes. The injury may be acute, as in a fracture; or chronic, as that due to occupational overuse of a joint, metabolic disease (eg, hyperparathyroidism, hemochromatosis, ochronosis), or neurologic disorders (syringomyelia; see below).
The onset is insidious. Initially, there is articular stiffness, seldom lasting more than 15 minutes; this develops later into pain on motion of the affected joint and is made worse by activity or weight bearing and relieved by rest. Flexion contracture or varus deformity of the knee is not unusual, and bony enlargements of the DIP (Heberden nodes) and PIP (Bouchard nodes) are occasionally prominent (Figure 20–1). There is no ankylosis, but limitation of motion of the affected joint or joints is common. Crepitus may often be felt over the knee. Joint effusion and other articular signs of inflammation are mild. There are no systemic manifestations.
Figure 20–1. Osteoarthritis with bony enlargement of the distal interphalangeal (DIP) joints (Heberden nodes) and proximal interphalangeal (PIP) joints (Bouchard nodes). (Reproduced with permission, from Richard P. Usatine, MD.)
Osteoarthritis does not cause elevation of the erythrocyte sedimentation rate (ESR) or other laboratory signs of inflammation. Synovial fluid is noninflammatory.
Radiographs may reveal narrowing of the joint space; osteophyte formation and lipping of marginal bone; and thickened, dense subchondral bone. Bone cysts may also be present.
Because articular inflammation is minimal and systemic manifestations are absent, degenerative joint disease should seldom be confused with other arthritides. The distribution of joint involvement in the hands also helps distinguish osteoarthritis from rheumatoid arthritis. Osteoarthritis chiefly affects the DIP and PIP joints and spares the wrist and metacarpophalangeal (MCP) joints; rheumatoid arthritis involves the wrists and MCP joints and spares the DIP joints. Furthermore, the joint enlargement is bony-hard and cool in osteoarthritis but spongy and warm in rheumatoid arthritis. Skeletal symptoms due to degenerative changes in joints—especially in the spine—may cause coexistent metastatic neoplasia, osteoporosis, multiple myeloma, or other bone disease to be overlooked.
Weight reduction reduces the risk of developing symptomatic knee osteoarthritis. Correcting leg length discrepancy of > 1 cm with shoe modification may prevent knee osteoarthritis from developing in the shorter leg. Maintaining normal vitamin D levels may reduce the occurrence and progression of osteoarthritis, in addition to being important for bone health.
Patients with osteoarthritis of the hand may benefit from assistive devices and instruction on techniques for joint protection; splinting is beneficial for those with symptomatic osteoarthritis of the first carpometacarpal joint. Patients with mild to moderate osteoarthritis of the knee or hip should participate in a regular exercise program (eg, a supervised walking program, hydrotherapy classes) and, if overweight, should lose weight. The use of assistive devices (eg, a cane on the contralateral side) can improve functional status.
1. Acetaminophen—First-line therapy for patients with mild osteoarthritis is acetaminophen (2.6–4 g/d orally).
2. Nonsteroidal anti-inflammatory drugs—NSAIDs (see Table 5–2) are more effective than acetaminophen for osteoarthritis but have greater toxicity. NSAIDs inhibit cyclooxygenase (COX), the enzyme that converts arachidonic acid to prostaglandins. Although prostaglandins play important roles in promoting inflammation and pain, they also help maintain homeostasis in several organs—especially the stomach, where prostaglandin E serves as a local hormone responsible for gastric mucosal cytoprotection. COX exists in two isomers—COX-1, which is expressed continuously in many cells and is responsible for the homeostatic effects of prostaglandins, and COX-2, which is induced by cytokines and expressed in inflammatory tissues. Most NSAIDs inhibit both isomers. Celecoxib is the only selective COX-2 inhibitor currently available in the United States.
Gastrointestinal toxicity, such as gastric ulceration, perforation, and gastrointestinal hemorrhage, are the most common serious side effects of NSAIDs. NSAIDs can also affect the lower intestinal tract, causing perforation or aggravating inflammatory bowel disease. The overall rate of bleeding with NSAID use in the general population is low (≤ 1:6000 users) but is increased by the risk factors of long-term use, higher NSAID dose, concomitant corticosteroids or anticoagulants, the presence of rheumatoid arthritis, history of peptic ulcer disease or alcoholism, and age over 70. Proton pump inhibitors (eg, omeprazole 20 mg orally daily) reduce the incidence of serious gastrointestinal toxicity and should be used for patients with risk factors for NSAID-induced gastrointestinal toxicity. Patients who have recently recovered from an NSAID-induced bleeding gastric ulcer appear to be at high risk for rebleeding (about 5% in 6 months) when an NSAID is reintroduced, even if prophylactic measures (such as proton pump inhibitors) are used. Compared with nonselective NSAIDs, celecoxib may be less likely in some circumstances to cause upper gastrointestinal tract adverse events. However, long-term use of COX-2 inhibitors, particularly in the absence of concomitant aspirin use, has been associated with an increased risk of cardiovascular events.
All of the NSAIDs, including aspirin and celecoxib, can produce renal toxicity, including interstitial nephritis, nephrotic syndrome, prerenal azotemia, and aggravation of hypertension. Hyperkalemia due to hyporeninemic hypoaldosteronism may also be seen rarely. The risk of renal toxicity is low but is increased by the following risk factors: age over 60, a history of kidney disease, heart failure, ascites, and diuretic use.
All NSAIDs, except the nonacetylated salicylates and the COX-2 inhibitor celecoxib, interfere with platelet function and prolong bleeding time. Aspirin irreversibly inhibits platelet function, so the bleeding time effect resolves only as new platelets are made. In contrast, the effect of nonselective NSAIDs on platelet function is reversible and resolves as the drug is cleared. Concomitant administration of a nonselective NSAID can interfere with the ability of aspirin to acetylate platelets and thus may interfere with the cardioprotective effects of low-dose aspirin.
Topical NSAIDs (eg, 4 g of diclofenac gel 1% applied to the affected joint four times daily) appear more effective than placebo for knee and hand osteoarthritis and have lower rates of systemic side effects than with oral NSAIDs. Few studies have compared the efficacy of oral and topical NSAIDs.
Topical capsaicin may be of benefit for osteoarthritis of the hand but is not recommended for osteoarthritis of the knee or hip.
Chondroitin sulfate and glucosamine, alone or in combination, are no better than placebo in reducing pain in patients with knee or hip osteoarthritis.
3. Intra-articular injections—Intra-articular injections of triamcinolone (20–40 mg) for patients with osteoarthritis of the knee or hip may reduce the need for analgesics or NSAIDs and can be repeated up to four times a year. The American College of Rheumatology does not recommend corticosteroid injections for osteoarthritis of the hand.
Intra-articular injections of sodium hyaluronate produce moderate reduction in symptoms in some patients with osteoarthritis of the knee.
Total hip and knee replacements provide excellent symptomatic and functional improvement when involvement of that joint severely restricts walking or causes pain at rest, particularly at night. Arthroscopic surgery for knee osteoarthritis is ineffective.
Marked disability is less common in patients with osteoarthritis than in those with rheumatoid arthritis, but symptoms may be quite severe and limit activity considerably (especially with involvement of the hips, knees, and cervical spine).
Refer patients to an orthopedic surgeon when recalcitrant symptoms or functional impairment, or both, warrant consideration of joint replacement surgery of the hip or knee.
Fernandes L et al. EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis. Ann Rheum Dis. 2013 Jul;72(7):1125–35. [PMID: 23595142]
Hochberg MC et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012 Apr;64(4):465–74. [PMID: 22563589]
Katz JN et al. Surgery versus physical therapy for a meniscal tear and osteoarthritis. N Engl J Med. 2013 May 2;368(18):1675–84. [PMID: 23506518]
Uthman OA et al. Exercise for lower limb osteoarthritis: systematic review incorporating trial sequential analysis and network meta-analysis. BMJ. 2013 Sep 20;347:f5555. [PMID: 24055922]
ESSENTIALS OF DIAGNOSIS
Acute onset, usually monarticular, recurring attacks, often involving the first MTP joint.
Polyarticular involvement more common in patients with long-standing disease.
Identification of urate crystals in joint fluid or tophi is diagnostic.
Dramatic therapeutic response to NSAIDs.
With chronicity, urate deposits in subcutaneous tissue, bone, cartilage, joints, and other tissues.
Gout is a metabolic disease of a heterogeneous nature, often familial, associated with abnormal amounts of urates in the body and characterized early by a recurring acute arthritis, usually monarticular, and later by chronic deforming arthritis. The associated hyperuricemia (serum uric acid level > 6.8 mg/dL [> 404.5 mcmol/L]) is due to overproduction or underexcretion of uric acid—sometimes both. The disease is especially common in Pacific islanders, eg, Filipinos and Samoans. Primary gout has a heritable component, and genome-wide surveys have linked risk of gout to several genes whose products regulate urate handling by the kidney. Secondary gout, which may have a heritable component, is related to acquired causes of hyperuricemia, eg, medication use (especially diuretics, low-dose aspirin, cyclosporine, and niacin), myeloproliferative disorders, multiple myeloma, hemoglobinopathies, chronic kidney disease, hypothyroidism, psoriasis, sarcoidosis, and lead poisoning (Table 20–4). Alcohol ingestion promotes hyperuricemia by increasing urate production and decreasing the renal excretion of uric acid. Finally, hospitalized patients frequently suffer attacks of gout because of changes in diet, fluid intake, or medications that lead either to rapid reductions or increases in the serum urate level.
Table 20–4. Origin of hyperuricemia.
About 90% of patients with primary gout are men, usually over 30 years of age. In women, the onset is typically postmenopausal. The characteristic lesion is the tophus, a nodular deposit of monosodium urate monohydrate crystals with an associated foreign body reaction. Tophi are found in cartilage, subcutaneous and periarticular tissues, tendon, bone, the kidneys, and elsewhere. Urates have been demonstrated in the synovial tissues (and fluid) during acute arthritis; indeed, the acute inflammation of gout is believed to be initiated by the ingestion of uncoated urate crystals by monocytes and synoviocytes. Once inside the cells, the gout crystals are processed through Toll-like receptors and activate NALP-3 inflammasomes that in turn release a variety of chemotactic agents and cytokines capable of mediating inflammation. The precise relationship of hyperuricemia to gouty arthritis is still obscure, since chronic hyperuricemia is found in people who never develop gout or uric acid stones. Rapid fluctuations in serum urate levels, either increasing or decreasing, are important factors in precipitating acute gout. The mechanism of the late, chronic stage of gouty arthritis is better understood. This is characterized pathologically by tophaceous invasion of the articular and periarticular tissues, with structural derangement and secondary degeneration (osteoarthritis).
Uric acid kidney stones are present in 5–10% of patients with gouty arthritis. Hyperuricemia correlates highly with the likelihood of developing stones, with the risk of stone formation reaching 50% in patients with a serum urate level > 13 mg/dL. Chronic urate nephropathy is caused by the deposition of monosodium urate crystals in the renal medulla and pyramids. Although progressive chronic kidney disease occurs in a substantial percentage of patients with chronic gout, the role of hyperuricemia in causing this outcome is controversial, because many patients with gout have numerous confounding risk factors for chronic kidney disease (eg, hypertension, alcohol use, lead exposure, and other risk factors for vascular disease).
Acute gouty arthritis is sudden in onset and frequently nocturnal. It may develop without apparent precipitating cause or may follow rapid increases or decreases in serum urate levels. Common precipitants are alcohol excess (particularly beer), changes in medications that affect urate metabolism, and, in the hospitalized patient, fasting before medical procedures. The MTP joint of the great toe is the most susceptible joint (“podagra”), although others, especially those of the feet, ankles, and knees, are commonly affected. Gouty attacks may develop in periarticular soft tissues such as the arch of the foot. Hips and shoulders are rarely affected. More than one joint may occasionally be affected during the same attack; in such cases, the distribution of the arthritis is usually asymmetric. As the attack progresses, the pain becomes intense. The involved joints are swollen and exquisitely tender and the overlying skin tense, warm, and dusky red. Fever is common and may reach 39°C. Local desquamation and pruritus during recovery from the acute arthritis are characteristic of gout but are not always present. Tophi may be found in the external ears, feet, olecranon and prepatellar bursae, and hands (Figure 20–2). They usually develop years after the initial attack of gout.
Figure 20–2. Acute gouty arthritis superimposed on tophaceous gout. (Reproduced with permission from Geiderman JM. West J Med. 2000;172 (1):51-52.)
Asymptomatic periods of months or years commonly follow the initial acute attack. After years of recurrent severe monarthritis attacks of the lower extremities and untreated hyperuricemia, gout can evolve into a chronic, deforming polyarthritis of upper and lower extremities that mimics rheumatoid arthritis.
Although serial measurements of the serum uric acid detect hyperuricemia in 95% of patients, a single uric acid determination during an acute flare of gout is normal in up to 25% of cases. A normal serum uric acid level, therefore, does not exclude gout, especially in patients taking urate-lowering drugs. During an acute attack, the peripheral blood white cell count is frequently elevated. Identification of sodium urate crystals in joint fluid or material aspirated from a tophus establishes the diagnosis. The crystals, which may be extracellular or found within neutrophils, are needle-like and negatively birefringent when examined by polarized light microscopy.
Early in the disease, radiographs show no changes. Later, punched-out erosions with an overhanging rim of cortical bone (“rat bite”) develop. When these are adjacent to a soft tissue tophus, they are diagnostic of gout.
Acute gout is often confused with cellulitis. Bacteriologic studies usually exclude acute pyogenic arthritis. Pseudogout is distinguished by the identification of calcium pyrophosphate crystals (positive birefringence) in the joint fluid, usually normal serum uric acid, and the radiographic appearance of chondrocalcinosis.
Chronic tophaceous arthritis may resemble chronic rheumatoid arthritis; gout is suggested by an earlier history of monarthritis and is established by the demonstration of urate crystals in a suspected tophus. Likewise, hips and shoulders are generally spared in tophaceous gout. Biopsy may be necessary to distinguish tophi from rheumatoid nodules. A radiographic appearance similar to that of gout may be found in rheumatoid arthritis, sarcoidosis, multiple myeloma, hyperparathyroidism, or Hand-Schüller-Christian disease. Chronic lead intoxication may result in attacks of gouty arthritis (saturnine gout).
Asymptomatic hyperuricemia should not be treated; uric acid–lowering drugs need not be instituted until arthritis, renal calculi, or tophi become apparent.
Arthritis is treated first and hyperuricemia weeks or months later, if at all. Sudden reduction of serum uric acid often precipitates further episodes of gouty arthritis.
1. NSAIDs—Oral NSAIDs in full dose (eg, naproxen 500 mg twice daily or indomethacin 25–50 mg every 8 hours; see Table 5–2) are effective treatment for acute gout and should be continued until the symptoms have resolved (usually 5–10 days). Contraindications include active peptic ulcer disease, impaired kidney function, and a history of allergic reaction to NSAIDs.
2. Colchicine—Oral colchicine is an appropriate treatment option for acute gout, provided the duration of the attack is less than 36 hours. For acute gout, colchicine should be administered orally as follows: a loading dose of 1.2 mg followed by a dose of 0.6 mg 1 hour later and then dosing for prophylaxis (0.6 mg once or twice daily) beginning 12 hours later. Patients who are already taking prophylactic doses of colchicine and have an acute flare of gout may receive the full loading dose (1.2 mg) followed by 0.6 mg 1 hour later (before resuming the usual 0.6 mg once or twice daily) provided they have not received this regimen within the preceding 14 days (in which case, NSAIDs or corticosteroids should be used). The use of oral colchicine during the intercritical period to prevent gout attacks is discussed below.
3. Corticosteroids—Corticosteroids often give dramatic symptomatic relief in acute episodes of gout and will control most attacks. They are most useful in patients with contraindications to the use of NSAIDs. Corticosteroids may be given intravenously (eg, methylprednisolone, 40 mg/d) or orally (eg, prednisone, 40–60 mg/d). These corticosteroids can be given at the suggested dose for 5–10 days and then simply discontinued or given at the suggested initial dose for 2–5 days and then tapered over 7–10 days. If the patient’s gout is monarticular or oligoarticular, intra-articular administration of the corticosteroid (eg, triamcinolone, 10–40 mg depending on the size of the joint) is very effective. Because gouty and septic arthritis can coexist, albeit rarely, joint aspiration and Gram stain with culture of synovial fluid should be performed when intra-articular corticosteroids are given.
4. Interleukin-1 inhibitors—Anakinra (an interleukin-1 receptor antagonist), canakinumab (a monoclonal antibody against interleukin-1 beta), and rilonacept (a chimera composed of IgG constant domains and the extracellular components of the interleukin-1 receptor) have efficacy for the management of acute gout but these drugs have not been approved by the US Food and Drug Administration (FDA) for this indication.
Treatment during symptom-free periods is intended to minimize urate deposition in tissues, which causes chronic tophaceous arthritis, and to reduce the frequency and severity of recurrences. Potentially reversible causes of hyperuricemia are a high-purine diet, obesity, alcohol consumption, and use of certain medications (see below). Patients with a single episode of gout who are willing to lose weight and stop drinking alcohol are at low risk for another attack and may not require long-term medical therapy. In contrast, individuals with mild chronic kidney disease or with a history of multiple attacks of gout are likely to benefit from pharmacologic treatment. In general, the higher the uric acid level and the more frequent the attacks, the more likely that long-term medical therapy will be beneficial. All patients with tophaceous gout should receive urate-lowering therapy.
1. Diet—Excessive alcohol consumption can precipitate attacks and should be avoided. Beer consumption appears to confer a higher risk of gout than does whiskey or wine. Although dietary purines usually contribute only 1 mg/dL to the serum uric acid level, moderation in eating foods with high purine content is advisable (Table 20–5). Patients should avoid organ meats and beverages sweetened with high fructose corn syrup. A high liquid intake and, more importantly, a daily urinary output of 2 L or more will aid urate excretion and minimize urate precipitation in the urinary tract.
Table 20–5. The purine content of foods.1
2. Avoidance of hyperuricemic medications—Thiazide and loop diuretics inhibit renal excretion of uric acid and, if possible, should be avoided in patients with gout. Similarly, niacin can raise serum uric acid levels and should be discontinued if there are therapeutic alternatives. Low doses of aspirin also aggravate hyperuricemia but, in general, should be continued due to their overriding benefits in cardiovascular prophylaxis.
3. Colchicine prophylaxis—There are two indications for daily colchicine administration. First, colchicine can be used to prevent future attacks for the individual who has mild hyperuricemia and only occasional attacks of gouty arthritis. Second, colchicine can be used when urate-lowering therapy (see below) is started, to suppress attacks precipitated by abrupt changes in the serum uric acid level. For either indication, the usual dose is 0.6 mg either once or twice a day. Colchicine is renally cleared. Patients who have coexisting moderate chronic kidney disease should take colchicine only once a day or once every other day in order to avoid peripheral neuromyopathy and other complications of colchicine toxicity.
4. Reduction of serum uric acid—Indications for a urate-lowering therapy in a person with gout include frequent acute arthritis (two or more episodes per year), tophaceous deposits, or chronic kidney disease (stage 2 or worse). If instituted, the minimum goal of urate-lowering therapy is to maintain the serum uric acid at or below 6 mg/dL or 357 mcmol/L (ie, below the level at which serum is supersaturated with uric acid, thereby allowing urate crystals to solubilize); in some cases, control of gout may require lowering serum uric acid to less than 5 mg/dL or 297.4 mcmol/L. Lowering serum uric acid levels is not of benefit for the treatment of an acute gout flare. Asymptomatic hyperuricemia should not be treated.
Three classes of agents may be used to lower the serum uric acid—xanthine oxidase inhibitors (allopurinol or febuxostat), uricosuric agents, and uricase (pegloticase). Xanthine oxidase inhibitors are the preferred first- line agents for urate lowering. The uricosuric agent, probenecid, is an acceptable alternative, provided the serum creatinine clearance is > 50 mL/minute and there is no history of nephrolithiasis. The uricase, pegloticase, requires intravenous administration and is indicated only in patients with chronic gout refractory to other treatments.
A. XANTHINE OXIDASE INHIBITORS—The xanthine oxidase inhibitors, allopurinol and febuxostat, lower plasma uric acid levels by blocking the final enzymatic steps in the production of uric acid. Allopurinol and febuxostat should not to be used together but they can be tried sequentially if the initial agent fails to lower serum uric acid to the target level or if it is not tolerated. The most frequent adverse effect with either medication is the precipitation of an acute gouty attack; thus, patients generally should be receiving prophylactic doses of colchicine.
Hypersensitivity to allopurinol occurs in 2% of cases, usually within the first few months of therapy, and it can be life-threatening. The most common sign of hypersensitivity is a pruritic rash that may progress to toxic epidermal necrolysis, particularly if allopurinol is continued; vasculitis and hepatitis are other manifestations. Patients should be instructed to stop allopurinol immediately if a rash develops. Chronic kidney disease and concomitant thiazide therapy are risk factors. In certain ethnic groups, there is a strong association between HLA-B*5801 and allopurinol hypersensitivity. Current recommendations are to screen for HLA-B*5801 prior to initiating allopurinol in Han Chinese, those of Thai descent, and Koreans with stage 3 or worse chronic kidney disease.
The initial daily dose of allopurinol is 100 mg/d orally (50 mg/d for those with stage 4 or worse chronic kidney disease); the dose of allopurinol should be titrated upward every 2–5 weeks to achieve the target serum uric acid level (either ≤ 6.0 mg/dL [357 mcmol/L] or ≤ 5.0 mg/dL [297.4 mcmol/L]). Successful treatment usually requires a dose of at least 300 mg of allopurinol daily. The maximum daily dose is 800 mg.
Allopurinol interacts with other drugs. The combined use of allopurinol and ampicillin causes a drug rash in 20% of patients. Allopurinol can increase the half-life of probenecid, while probenecid increases the excretion of allopurinol. Thus, a patient taking both drugs may need to use slightly higher than usual doses of allopurinol and lower doses of probenecid.
Febuxostat does not cause the hypersensitivity reactions seen with allopurinol and can be given without dose adjustment to patients with mild to moderate kidney disease. However, abnormal liver tests may develop in 2–3% of patients taking febuxostat. In addition, one clinical study showed that febuxostat was associated with a slightly higher rate of fatal and nonfatal cardiovascular events than allopurinol (0.97 vs 0.58 per 100 patient-years). The initial dose of febuxostat is 40 mg/d orally. If the target serum uric acid is not reached, the dose of febuxostat can be increased to 80 mg/d and then to the maximum dose of 120 mg/d.
B. URICOSURIC DRUGS—Uricosuric drugs lower serum uric acid levels by blocking the tubular reabsorption of filtered urate, thereby increasing uric acid excretion by the kidney. Probenecid (0.5 g/d orally) is the uricosuric of choice in the United States. It is an acceptable alternative when xanthine oxidase inhibitors cannot be used and can be added when monotherapy with a xanthine oxidase inhibitor fails to reach the target serum uric acid. Probenecid should not be used in patients with a creatinine clearance of < 50 mL/min due to limited efficacy; contraindications include a history of nephrolithiasis (uric acid or calcium stones) and evidence of overproduction of uric acid (ie, > 800 mg of uric acid in a 24-hour urine collection). To reduce the development of uric acid stones (which occur in up to 11%), patients should be advised to increase their fluid intake and clinicians should consider prescribing an alkalinizing agent (eg, potassium citrate, 30–80 mEq/d orally) to maintain a urine pH of > 6.0.
C. URICASE—Pegloticase, a recombinant uricase that must be administered intravenously (8 mg every 2 weeks), is indicated for the rare patient with refractory chronic tophaceous gout. Pegloticase carries a “Black Box Warning,” which advises administering the drug only in health care settings and by health care professionals prepared to manage anaphylactic and other serious infusion reactions.
With rigorous medical compliance, allopurinol or febuxostat or pegloticase shrinks tophi and in time can lead to their disappearance. Resorption of extensive tophi requires maintaining a serum uric acid below 6 mg/dL. Surgical excision of large tophi offers mechanical improvement in selected deformities.
Hyperuricemia and gout commonly develop in many transplant patients because they have decreased kidney function and require drugs that inhibit uric acid excretion (especially cyclosporine and diuretics). Treating acute gout in these patients is challenging. Often the best approach for monarticular gout—after excluding infection—is injecting corticosteroids into the joint (see above). For polyarticular gout, increasing the dose of systemic corticosteroid may be the only alternative. Since transplant patients often have multiple attacks of gout, long-term relief requires lowering the serum uric acid with allopurinol or febuxostat. (Kidney dysfunction seen in many transplant patients makes uricosuric agents ineffective.) Both allopurinol and febuxostat inhibit the metabolism of azathioprine and should be avoided in patients who must take azathioprine.
Without treatment, the acute attack may last from a few days to several weeks. The intervals between acute attacks vary up to years, but the asymptomatic periods often become shorter if the disease progresses. Chronic gouty arthritis occurs after repeated attacks of acute gout, but only after inadequate treatment. The younger the patient at the onset of disease, the greater the tendency to a progressive course. Destructive arthropathy is rarely seen in patients whose first attack is after age 50.
Patients with gout are anecdotally thought to have an increased incidence of hypertension, kidney disease (eg, nephrosclerosis, interstitial nephritis, pyelonephritis), diabetes mellitus, hypertriglyceridemia, and atherosclerosis.
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Calcium pyrophosphate deposition (CPPD) in fibrocartilage and hyaline cartilage (chondrocalcinosis) can cause an acute crystal-induced arthritis (“pseudogout”), a degenerative arthropathy, and a chronic inflammatory polyarthritis (“pseudorheumatoid arthritis”). CPPD also can be an asymptomatic condition detected as incidental chondrocalcinosis on radiographs. The prevalence of CPPD increases with age. Hyperparathyroidism, hemochromatosis, and hypomagnesemia confer risk of CPPD, but most cases have no associated condition.
Pseudogout is most often seen in persons age 60 or older, is characterized by acute, recurrent and rarely chronic arthritis involving large joints (most commonly the knees and the wrists) and is almost always accompanied by radiographic chondrocalcinosis of the affected joints. Pseudogout, like gout, frequently develops 24–48 hours after major surgery. Identification of calcium pyrophosphate crystals in joint aspirates is diagnostic. NSAIDs are helpful in the treatment of acute episodes. Colchicine, 0.6 mg orally once or twice daily, is more effective for prophylaxis than for acute attacks. Aspiration of the inflamed joint and intra-articular injection of triamcinolone, 10–40 mg, depending on the size of the joint, are also of value in resistant cases.
The degenerative arthropathy associated with CPPD can involve joints not usually affected by osteoarthritis (eg, glenohumeral joint, wrist, patellofemoral compartment of the knee). The “pseudorheumatoid arthritis” of CPPD affects the metacarpophalangeal joints and wrists. In both conditions, radiographs demonstrate chondrocalcinosis and degenerative changes such as asymmetric joint space narrowing and osteophyte formation.
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ESSENTIALS OF DIAGNOSIS
Usually insidious onset with morning stiffness and pain in affected joints.
Symmetric polyarthritis with predilection for small joints of the hands and feet; deformities common with progressive disease.
Radiographic findings: juxta-articular osteoporosis, joint erosions, and joint space narrowing.
Rheumatoid factor and antibodies to cyclic citrullinated peptides (anti-CCP) are present in 70–80%.
Extra-articular manifestations: subcutaneous nodules, interstitial lung disease, pleural effusion, pericarditis, splenomegaly with leukopenia, and vasculitis.
Rheumatoid arthritis is a chronic systemic inflammatory disease whose major manifestation is synovitis of multiple joints. It has a prevalence of 1% and is more common in women than men (female:male ratio of 3:1). Rheumatoid arthritis can begin at any age, but the peak onset is in the fourth or fifth decade for women and the sixth to eighth decades for men. The cause is not known. Susceptibility to rheumatoid arthritis is genetically determined with multiple genes contributing. Inheritance of HLA DRB1 alleles encoding a distinctive five-amino-acid sequence known as the “shared epitope” is the best characterized genetic risk factor. Untreated, rheumatoid arthritis causes joint destruction with consequent disability and shortens life expectancy. Early, aggressive treatment is the standard of care.
The pathologic findings in the joint include chronic synovitis with formation of a pannus, which erodes cartilage, bone, ligaments, and tendons. In the acute phase, effusion and other manifestations of inflammation are common. In the late stage, organization may result in fibrous ankylosis; true bony ankylosis is rare.
1. Joint symptoms—The clinical manifestations of rheumatoid disease are highly variable, but joint symptoms usually predominate. Although acute presentations may occur, the onset of articular signs of inflammation is usually insidious, with prodromal symptoms of vague periarticular pain or stiffness. Symmetric swelling of multiple joints with tenderness and pain is characteristic. Monarticular disease is occasionally seen initially. Stiffness persisting for > 30 minutes (and usually many hours) is prominent in the morning. Stiffness may recur after daytime inactivity and be much more severe after strenuousactivity. Although any diarthrodial joint may be affected, PIP joints of the fingers, MCP joints (Figure 20–3), wrists, knees, ankles, and MTP joints are most often involved. Synovial cysts and rupture of tendons may occur. Entrapment syndromes are not unusual—particularly of the median nerve at the carpal tunnel of the wrist. Rheumatoid arthritis can affect the neck but spares the other components of the spine and does not involve the sacroiliac joints. In advanced disease, atlantoaxial (C1–C2) subluxation can lead to myelopathy.
Figure 20–3. Rheumatoid arthritis with ulnar deviation at the metacarpophalangeal (MCP) joints. (Reproduced with permission, from Richard P. Usatine, MD.)
2. Rheumatoid nodules—Twenty percent of patients have subcutaneous rheumatoid nodules, most commonly situated over bony prominences but also observed in the bursae and tendon sheaths (Figure 20–4). Nodules are occasionally seen in the lungs, the sclerae, and other tissues. Nodules correlate with the presence of rheumatoid factor in serum (“seropositivity”), as do most other extra-articular manifestations.
Figure 20–4. Rheumatoid nodules over the extensor surface of the forearm (Reproduced with permission, from Richard P. Usatine, MD).
3. Ocular symptoms—Dryness of the eyes, mouth, and other mucous membranes is found especially in advanced disease (see Sjögren syndrome). Other ocular manifestations include episcleritis, scleritis, and scleromalacia due to scleral nodules.
4. Other symptoms—Interstitial lung disease is not uncommon (estimates of prevalence vary widely according to method of detection) and manifests clinically as cough and progressive dyspnea. Pericarditis and pleural disease, when present, are usually silent clinically. Patients with active joint disease often have palmar erythema. Occasionally, a small vessel vasculitis develops and manifests as tiny hemorrhagic infarcts in the nail folds or finger pulps. Although necrotizing arteritis is well reported, it is rare. A small subset of patients with rheumatoid arthritis have Felty syndrome, the occurrence of splenomegaly and neutropenia, usually in the setting of severe, destructive arthritis. Felty syndrome must be distinguished from the large granular lymphocyte syndrome, with which it shares many features.
Aortitis is a rare late complication that can result in aortic regurgitation or rupture and is usually associated with evidence of rheumatoid vasculitis elsewhere in the body.
Anti-CCP antibodies and rheumatoid factor, an IgM antibody directed against the Fc fragment of IgG, are present in 70–80% of patients with established rheumatoid arthritis. Rheumatoid factor has a sensitivity of only 50% in early disease. Anti-CCP antibodies are the most specific blood test for rheumatoid arthritis (specificity ~95%). Rheumatoid factor can occur in other autoimmune disease and in chronic infections, including hepatitis C, syphilis, subacute bacterial endocarditis, and tuberculosis. The prevalence of rheumatoid factor positivity also rises with age in healthy individuals. Approximately 20% of rheumatoid patients have antinuclear antibodies.
The ESR and levels of C-reactive protein are typically elevated in proportion to disease activity. A moderate hypochromic normocytic anemia is common. The white cell count is normal or slightly elevated, but leukopenia may occur, often in the presence of splenomegaly (eg, Felty syndrome). The platelet count is often elevated, roughly in proportion to the severity of overall joint inflammation. Initial joint fluid examination confirms the inflammatory nature of the arthritis (see Table 20–2). Arthrocentesis is needed to diagnose superimposed septic arthritis, which is a common complication of rheumatoid arthritis and should be considered whenever a patient with rheumatoid arthritis has one joint inflamed out of proportion to the rest.
Of all the laboratory tests, radiographic changes are the most specific for rheumatoid arthritis. Radiographs obtained during the first 6 months of symptoms, however, are usually normal. The earliest changes occur in the hands or feet and consist of soft tissue swelling and juxta-articular demineralization. Later, diagnostic changes of uniform joint space narrowing and erosions develop. The erosions are often first evident at the ulnar styloid and at the juxta-articular margin where the bony surface is not protected by cartilage. Characteristic changes also occur in the cervical spine, with C1–2 subluxation, but these changes usually take many years to develop. Although both MRI and ultrasonography are more sensitive than radiographs in detecting bony and soft tissue changes in rheumatoid arthritis, their value in early diagnosis relative to that of plain radiographs has not been established.
The differentiation of rheumatoid arthritis from other joint conditions and immune-mediated disorders can be difficult. In 2010, the American College of Rheumatology updated their classification criteria for rheumatoid arthritis. In contrast to rheumatoid arthritis, osteoarthritis spares the wrist and the MCP joints. Osteoarthritis is not associated with constitutional manifestations, and the joint pain is characteristically relieved by rest, unlike the morning stiffness of rheumatoid arthritis. Signs of articular inflammation, prominent in rheumatoid arthritis, are usually minimal in degenerative joint disease. CPPD disease can cause a degenerative arthropathy of the MCPs and wrists; radiographs are usually diagnostic. Although gouty arthritis is almost always intermittent and monarticular in the early years, it may evolve with time into a chronic polyarticular process that mimics rheumatoid arthritis. Gouty tophi can resemble rheumatoid nodules both in typical location and appearance. The early history of intermittent monarthritis and the presence of synovial urate crystals are distinctive features of gout. Spondyloarthropathies, particularly earlier in their course, can be a source of diagnostic uncertainty; predilection for lower extremities and involvement of the spine and sacroiliac joints point to the correct diagnosis. Chronic Lyme arthritis typically involves only one joint, most commonly the knee, and is associated with positive serologic tests (see Chapter 34). Human parvovirus B19 infection in adults can mimic early rheumatoid arthritis. However, arthralgias are more prominent than arthritis, fever is common, IgM antibodies to parvovirus B19 are present, and the arthritis usually resolves within weeks. Infection with hepatitis C can cause a chronic nonerosive polyarthritis associated with rheumatoid factor; tests for anti-CCP antibodies are negative.
Malar rash, photosensitivity, discoid skin lesions, alopecia, high titer antibodies to double-stranded DNA, glomerulonephritis, and central nervous system abnormalities point to the diagnosis of SLE. Polymyalgia rheumatica occasionally causes polyarthralgias in patients over age 50, but these patients remain rheumatoid factor–negative and have chiefly proximal muscle pain and stiffness, centered on the shoulder and hip girdles. Joint pain that can be confused with rheumatoid arthritis presents in a substantial minority of patients with granulomatosis with polyangiitis (formerly Wegener granulomatosis). This diagnostic error can be avoided by recognizing that, in contrast to rheumatoid arthritis, the arthritis of granulomatosis with polyangiitis preferentially involves large joints (eg, hips, ankles, wrists) and usually spares the small joints of the hand. Rheumatic fever is characterized by the migratory nature of the arthritis, an elevated antistreptolysin titer, and a more dramatic and prompt response to aspirin; carditis and erythema marginatum may occur in adults, but chorea and subcutaneous nodules virtually never do. Finally, a variety of cancers produce paraneoplastic syndromes, including polyarthritis. One form is hypertrophic pulmonary osteoarthropathy most often produced by lung and gastrointestinal carcinomas, characterized by a rheumatoid-like arthritis associated with clubbing, periosteal new bone formation, and a negative rheumatoid factor. Diffuse swelling of the hands with palmar fasciitis occurs in a variety of cancers, especially ovarian carcinoma.
The primary objectives in treating rheumatoid arthritis are reduction of inflammation and pain, preservation of function, and prevention of deformity. Success requires early, effective pharmacologic intervention. Disease-modifying antirheumatic drugs (DMARDs) should be started as soon as the diagnosis of rheumatoid disease is certain and then adjusted with the aim of suppressing disease activity. NSAIDs provide some symptomatic relief in rheumatoid arthritis but do not prevent erosions or alter disease progression. They are not appropriate for monotherapy and should only be used in conjunction with DMARDs, if at all. The American College of Rheumatology recommends using standardized assessments, such as the Disease Activity Score 28 Joints (DAS28), to gauge therapeutic responses, with the target of mild disease activity or remission by these measures. In advanced disease, surgical intervention may help improve function of damaged joints and to relieve pain.
Low-dose corticosteroids (eg, oral prednisone 5–10 mg daily) produce a prompt anti-inflammatory effect in rheumatoid arthritis and slow the rate of articular erosion. These often are used as a “bridge” to reduce disease activity until the slower acting DMARDs take effect or as adjunctive therapy for active disease that persists despite treatment with DMARDs. No more than 10 mg of prednisone or equivalent per day is appropriate for articular disease. Many patients do reasonably well on 5–7.5 mg daily. (The use of 1 mg tablets, to facilitate doses of < 5 mg/d, is encouraged.) Higher doses are used to manage serious extra-articular manifestations (eg, pericarditis, necrotizing scleritis). When the corticosteroids are to be discontinued, they should be tapered gradually on a planned schedule appropriate to the duration of treatment. All patients receiving long-term corticosteroid therapy should take measures to prevent osteoporosis.
Intra-articular corticosteroids may be helpful if one or two joints are the chief source of difficulty. Intra-articular triamcinolone, 10–40 mg depending on the size of the joint to be injected, may be given for symptomatic relief but not more than four times a year.
1. Methotrexate—Methotrexate is usually the initial synthetic DMARD of choice for patients with rheumatoid arthritis. It is generally well tolerated and often produces a beneficial effect in 2–6 weeks. The usual initial dose is 7.5 mg of methotrexate orally once weekly. If the patient has tolerated methotrexate but has not responded in 1 month, the dose can be increased to 15 mg orally once per week. The maximal dose is usually 20–25 mg/wk. The most frequent side effects are gastric irritation and stomatitis. Cytopenia, most commonly leukopenia or thrombocytopenia but rarely pancytopenia, due to bone marrow suppression is another important potential problem. The risk of developing pancytopenia is much higher in patients with elevation of the serum creatinine (≥ 2 mg/dL or ≥ 176.8 mcmol/L). Hepatotoxicity with fibrosis and cirrhosis is an important toxic effect that correlates with cumulative dose and is uncommon with appropriate monitoring of liver function tests. Methotrexate is contraindicated in a patient with any form of chronic hepatitis. Heavy alcohol use increases the hepatotoxicity, so patients should be advised to drink alcohol in extreme moderation, if at all. Diabetes mellitus, obesity, and kidney disease also increase the risk of hepatotoxicity. Liver function tests should be monitored at least every 12 weeks, along with a complete blood count. The dose of methotrexate should be reduced if aminotransferase levels are elevated, and the drug should be discontinued if abnormalities persist despite dosage reduction. Gastric irritation, stomatitis, cytopenias, and hepatotoxicity are reduced by prescribing either daily folate (1 mg orally) or weekly leucovorin calcium (2.5–5 mg taken orally 24 hours after the dose of methotrexate). Hypersensitivity to methotrexate can cause an acute or subacute interstitial pneumonitis that can be life-threatening but which usually responds to cessation of the drug and institution of corticosteroids. Because methotrexate is teratogenic, women of child bearing age as well as men must use effective contraception while taking the medication. Methotrexate is associated with an increased risk of B cell lymphomas, some of which resolve following the discontinuation of the medication. The combination of methotrexate and other folate antagonists, such as trimethoprim-sulfamethoxazole, should be used cautiously since pancytopenia can result. Amoxicillin can decrease renal clearance of methotrexate, leading to toxicity. Probenecid also increases methotrexate drug levels and toxicity and should be avoided.
2. Sulfasalazine—This drug is a second-line agent for rheumatoid arthritis. It is usually introduced at a dosage of 0.5 g orally twice daily and then increased each week by 0.5 g until the patient improves or the daily dose reaches 3 g. Side effects, particularly neutropenia and thrombocytopenia, occur in 10–25% and are serious in 2–5%. Sulfasalazine also causes hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, so a G6PD level should be checked before initiating sulfasalazine. Patients with aspirin sensitivity should not be given sulfasalazine. Patients taking sulfasalazine should have complete blood counts monitored every 2–4 weeks for the first 3 months, then every 3 months.
3. Leflunomide—Leflunomide, a pyrimidine synthesis inhibitor, is also FDA-approved for treatment of rheumatoid arthritis and is administered as a single oral daily dose of 20 mg. The most frequent side effects are diarrhea, rash, reversible alopecia, and hepatotoxicity. Some patients experience dramatic unexplained weight loss. The drug is carcinogenic, teratogenic, and has a half-life of 2 weeks. Thus, it is contraindicated in premenopausal women or in men who wish to father children.
4. Antimalarials—Hydroxychloroquine sulfate is the antimalarial agent most often used against rheumatoid arthritis. Monotherapy with hydroxychloroquine should be reserved for patients with mild disease because only a small percentage will respond and in some of those cases only after 3–6 months of therapy. Hydroxychloroquine is often used in combination with other conventional DMARDs, particularly methotrexate and sulfasalazine. The advantage of hydroxychloroquine is its comparatively low toxicity, especially at a dosage of 200–400 mg/d orally (not to exceed 6.5 mg/kg/d). The most important reaction, pigmentary retinitis causing visual loss, is rare at this dose. Ophthalmologic examinations every 12 months are required when this drug is used for long-term therapy. Other reactions include neuropathies and myopathies of both skeletal and cardiac muscle, which usually improve when the drug is withdrawn.
5. Minocycline—Minocycline is more effective than placebo for rheumatoid arthritis. It is reserved for early, mild cases, since its efficacy is modest, and it works better during the first year of rheumatoid arthritis. The mechanism of action is not clear, but tetracyclines do have anti-inflammatory properties, including the ability to inhibit destructive enzymes such as collagenase. The dosage of minocycline is 200 mg orally daily. Adverse effects are uncommon except for dizziness, which occurs in about 10%.
6. Tofacitinib—Tofacitinib, an inhibitor of Janus kinase 3, was approved in 2012 by the FDA for use in severe rheumatoid arthritis that is refractory to methotrexate. It is administered orally in a dose of 5 mg twice daily and can be used either as monotherapy or in combination with methotrexate. Tofacitinib increases the risk of opportunistic and other serious infections; patients should be screened and treated for latent tuberculosis prior to receiving the drug.
1. Tumor necrosis factor inhibitors—Inhibitors of tumor necrosis factor (TNF)—a pro-inflammatory cytokine—are fulfilling the aim of targeted therapy for rheumatoid arthritis. These medications are frequently added to the treatment of patients who have not responded adequately to methotrexate and are increasingly used as initial therapy in combination with methotrexate for patients with poor prognostic factors.
Five inhibitors are in use: etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. Etanercept, a soluble recombinant TNF receptor:Fc fusion protein, is usually administered at a dosage of 50 mg subcutaneously once per week. Infliximab, a chimeric monoclonal antibody, is administered at a dosage of 3–10 mg/kg intravenously; infusions are repeated after 2, 6, 10, and 14 weeks and then are administered every 8 weeks. Adalimumab, a human monoclonal antibody that binds to TNF, is given at a dosage of 40 mg subcutaneously every other week. The dose for golimumab, a human anti-TNF monoclonal antibody, is 50 mg subcutaneously once monthly. Certolizumab pegol is a PEGylated monoclonal antibody TNF inhibitor; the dose is 200–400 mg subcutaneously every 2 to 4 weeks. Each drug produces substantial improvement in more than 60% of patients. Each is usually very well tolerated. Minor irritation at injection sites is the most common side effect of etanercept and adalimumab. Rarely, nonrecurrent leukopenia develops in patients. TNF plays a physiologic role in combating many types of infection; TNF inhibitors have been associated with a several-fold increased risk of serious bacterial infections and a striking increase in granulomatous infections, particularly reactivation of tuberculosis. Screening for latent tuberculosis (see Chapter 9) is mandatory before the initiation of TNF blockers. It is prudent to suspend TNF blockers when a fever or other manifestations of a clinically important infection develops in a patient. Demyelinating neurologic complications that resemble multiple sclerosis have been reported rarely in patients taking etanercept, but the true magnitude of this risk—likely quite small—has not been determined with precision. While there are conflicting data with respect to increased risk of malignancy, in 2009, the FDA issued a safety alert about case reports of malignancies, including leukemias, in patients treated with TNF inhibitors. Contrary to expectation, TNF inhibitors were not effective in the treatment of heart failure. The use of infliximab, in fact, was associated with increased morbidity in a heart failure trial. Consequently, TNF inhibitors should be used with extreme caution in patients with heart failure. Infliximab can rarely cause anaphylaxis and induce anti-DNA antibodies (but rarely clinically evident SLE). A final concern about TNF inhibitors is the expense, which is more than $10,000 per year.
2. Abatacept—Abatacept, a recombinant protein made by fusing a fragment of the Fc domain of human IgG with the extracellular domain of a T-cell inhibitory receptor (CTLA4), blocks T-cell costimulation. It is approved by the FDA for use in rheumatoid arthritis and produces clinically meaningful responses in approximately 50% of individuals whose disease is active despite the combination of methotrexate and a TNF inhibitor.
3. Rituximab—Rituximab is a humanized mouse monoclonal antibody that depletes B cells. It is approved by the FDA to be used in combination with methotrexate for patients whose disease has been refractory to treatment with a TNF inhibitor.
4. Tocilizumab—Tocilizumab is a monoclonal antibody that blocks the receptor for IL-6, an inflammatory cytokine involved in the pathogenesis of rheumatoid arthritis. It also is approved by the FDA to be used in combination with methotrexate for patients whose disease has been refractory to treatment with a TNF inhibitor.
As a general rule, DMARDs have greater efficacy when administered in combination than when used individually. Currently, the most commonly used combination is that of methotrexate with one of the TNF inhibitors, which clearly is superior to methotrexate alone. The combination of methotrexate, sulfasalazine, and hydroxychloroquine is also effective. The American College of Rheumatology has published detailed recommendations on the initiation of DMARD combinations.
After months or years, deformities may occur; the most common are ulnar deviation of the fingers, boutonnière deformity (hyperextension of the DIP joint with flexion of the PIP joint), “swan-neck” deformity (flexion of the DIP joint with extension of the PIP joint), valgus deformity of the knee, and volar subluxation of the MTP joints. The excess mortality associated with rheumatoid arthritis is largely due to cardiovascular disease that is unexplained by traditional risk factors and that appears to be a result of deleterious effects of chronic systemic inflammation on the vascular system.
Early referral to a rheumatologist is essential for appropriate diagnosis and the timely introduction of effective therapy.
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Still disease is a systemic form of juvenile chronic arthritis in which high spiking fevers are much more prominent, especially at the outset, than arthritis. This syndrome also occurs in adults. Most adults are in their 20s or 30s; onset after age 60 is rare. The fever is dramatic, often with daily spikes to 40°C, associated with sweats and chills, and then plunging to normal or several degrees below normal in the absence of antipyretics. Many patients initially complain of sore throat. An evanescent salmon-colored nonpruritic rash, chiefly on the chest and abdomen, is a characteristic feature. The rash can easily be missed since it often appears only with the fever spike. Many patients also have lymphadenopathy and pericardial effusions. Joint symptoms are mild or absent in the beginning, but a destructive arthritis, especially of the wrists, may develop months later. Anemia and leukocytosis, with white blood counts sometimes exceeding 40,000/mcL, are the rule. Although there must be exclusion of other causes of fever, the diagnosis of adult Still disease is strongly suggested by the quotidian fever pattern, sore throat, and the classic rash. About half of the patients respond to high-dose aspirin (eg, 1 g three times orally daily) or other NSAIDs, and half require prednisone, sometimes in doses > 60 mg/d orally. For patients with refractory adult Still disease, the IL-1 receptor antagonist, anakinra, and the IL-6 receptor inhibitor, tocilizumab, appear to be more effective than anti-TNF agents.
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ESSENTIALS OF DIAGNOSIS
Occurs mainly in young women.
Rash over areas exposed to sunlight.
Joint symptoms in 90% of patients. Multiple system involvement.
Anemia, leukopenia, thrombocytopenia.
Glomerulonephritis, central nervous system disease, and complications of antiphospholipid antibodies are major sources of disease morbidity.
Serologic findings: antinuclear antibodies (100%), anti–double-stranded DNA antibodies (approximately two-thirds), and low serum complement levels (particularly during disease flares).
SLE is an inflammatory autoimmune disorder characterized by autoantibodies to nuclear antigens. It can affect multiple organ systems. Many of its clinical manifestations are secondary to the trapping of antigen-antibody complexes in capillaries of visceral structures or to autoantibody-mediated destruction of host cells (eg, thrombocytopenia). The clinical course is marked by spontaneous remission and relapses. The severity may vary from a mild episodic disorder to a rapidly fulminant, life-threatening illness.
The incidence of SLE is influenced by many factors, including gender, race, and genetic inheritance. About 85% of patients are women. Sex hormones appear to play some role; most cases develop after menarche and before menopause. Among older individuals, the gender distribution is more equal. Race is also a factor, as SLE occurs in 1:1000 white women but in 1:250 black women. Familial occurrence of SLE has been repeatedly documented, and the disorder is concordant in 25–70% of identical twins. If a mother has SLE, her daughters’ risks of developing the disease are 1:40 and her sons’ risks are 1:250. Aggregation of serologic abnormalities (positive antinuclear antibody) is seen in asymptomatic family members, and the prevalence of other rheumatic diseases is increased among close relatives of patients. The importance of specific genes in SLE is emphasized by the high frequency of certain HLA haplotypes, especially DR2 and DR3, and null complement alleles.
Before making a diagnosis of SLE, it is imperative to ascertain that the condition has not been induced by a drug (Table 20–6). Procainamide, hydralazine, and isoniazid are the best-studied drugs. While antinuclear antibody tests and other serologic findings become positive in many persons receiving these agents, clinical manifestations occur in only a few.
Table 20–6. Drugs associated with lupus erythematosus.
Four features of drug-induced lupus separate it from SLE: (1) the sex ratio is nearly equal; (2) nephritis and central nervous system features are not ordinarily present; (3) hypocomplementemia and antibodies to double-stranded DNA are absent; and (4) the clinical features and most laboratory abnormalities usually revert toward normal when the offending drug is withdrawn.
The diagnosis of SLE should be suspected in patients having a multisystem disease with a positive test for antinuclear antibodies. Differential diagnosis includes rheumatoid arthritis, systemic vasculitis, scleroderma, inflammatory myopathies, viral hepatitis, sarcoidosis, acute drug reactions, and drug-induced lupus.
The diagnosis of SLE can be made with reasonable probability if 4 of the 11 criteria set forth in Table 20–7 are met. These criteria, developed as guidelines for the inclusion of patients in research studies, do not supplant clinical judgment in the diagnosis of SLE.
Table 20–7. Criteria for the classification of SLE. (A patient is classified as having SLE if any 4 or more of 11 criteria are met.)
The systemic features include fever, anorexia, malaise, and weight loss. Most patients have skin lesions at some time; the characteristic “butterfly” (malar) rash affects less than half of patients. Other cutaneous manifestations are panniculitis (lupus profundus), discoid lupus, typical fingertip lesions, periungual erythema, nail fold infarcts, and splinter hemorrhages. Alopecia is common. Mucous membrane lesions tend to occur during periods of exacerbation. Raynaud phenomenon, present in about 20% of patients, often antedates other features of the disease.
Joint symptoms, with or without active synovitis, occur in over 90% of patients and are often the earliest manifestation. The arthritis can lead to reversible swan neck deformities, but erosive changes are almost never noted on radiographs. Subcutaneous nodules are rare.
Ocular manifestations include conjunctivitis, photophobia, transient or permanent monocular blindness, and blurring of vision. Cotton-wool spots on the retina (cytoid bodies) represent degeneration of nerve fibers due to occlusion of retinal blood vessels.
Pleurisy, pleural effusion, bronchopneumonia, and pneumonitis are frequent. Restrictive lung disease can develop. Alveolar hemorrhage is uncommon but life-threatening. Interstitial lung disease is rare.
The pericardium is affected in the majority of patients. Heart failure may result from myocarditis and hypertension. Cardiac arrhythmias are common. Atypical verrucous endocarditis of Libman-Sacks is usually clinically silent but occasionally can produce acute or chronic valvular regurgitation—most commonly mitral regurgitation.
Mesenteric vasculitis occasionally occurs in SLE and may closely resemble polyarteritis nodosa, including the presence of aneurysms in medium-sized blood vessels. Abdominal pain (particularly postprandial), ileus, peritonitis, and perforation may result.
Neurologic complications of SLE include psychosis, cognitive impairment, seizures, peripheral and cranial neuropathies, transverse myelitis, and strokes. Severe depression and psychosis are sometimes exacerbated by the administration of large doses of corticosteroids.
Several forms of glomerulonephritis may occur, including mesangial, focal proliferative, diffuse proliferative, and membranous (see Chapter 22). Some patients may also have interstitial nephritis. With appropriate therapy, the survival rate even for patients with serious chronic kidney disease (proliferative glomerulonephritis) is favorable, albeit a substantial portion of patients with severe lupus nephritis still eventually require renal replacement therapy.
(Tables 20–8 and 20–9.) SLE is characterized by the production of many different autoantibodies. Antinuclear antibody tests based on immunofluorescence assays are sensitive but not specific for SLE—ie, they are positive in virtually all patients with lupus but are positive also in many patients with nonlupus conditions such as rheumatoid arthritis, autoimmune thyroid disease, scleroderma, and Sjögren syndrome. False-negative results can occur with tests for antinuclear antibodies based on enzyme-linked immunosorbent assays (ELISA). Therefore, SLE should not be excluded on the basis of a negative ELISA for antinuclear antibodies. Antibodies to double-stranded DNA and to Sm are specific for SLE but not sensitive, since they are present in only 60% and 30% of patients, respectively. Depressed serum complement—a finding suggestive of disease activity—often returns toward normal in remission. Anti-double-stranded DNA antibody levels also correlate with disease activity in some patients; anti-Sm levels do not.
Table 20–8. Frequency (%) of autoantibodies in rheumatic diseases.1
Table 20–9. Frequency (%) of laboratory abnormalities in systemic lupus erythematosus.
Three types of antiphospholipid antibodies occur (Table 20–9). The first causes the biologic false-positive tests for syphilis; the second is the lupus anticoagulant, which despite its name is a risk factor for venous and arterial thrombosis and for miscarriage. The lupus anticoagulant often causes prolongation of the activated partial thromboplastin time, and its presence is confirmed by an abnormal Russell viper venom time (RVVT) that corrects with the addition of phospholipid but not normal plasma. Anti-cardiolipin antibodies are the third type of antiphospholipid antibodies. In many cases, the “antiphospholipid antibody” appears to be directed at a serum cofactor (beta-2-glycoprotein-I) rather than at phospholipid itself. Abnormality of urinary sediment is almost always found in association with renal lesions. Showers of red blood cells, with or without casts, and proteinuria (varying from mild to nephrotic range) are frequent during exacerbation of the disease.
Patient education and emotional support are especially important for patients with lupus. Since the various manifestations of SLE affect prognosis differently and since SLE activity often waxes and wanes, drug therapy—both the choice of agents and the intensity of their use—must be tailored to match disease severity. Patients should be cautioned against sun exposure and should apply a protective lotion to the skin while out of doors. Skin lesions often respond to the local administration of corticosteroids. Minor joint symptoms can usually be alleviated by rest and NSAIDs.
Antimalarials (hydroxychloroquine) may be helpful in treating lupus rashes or joint symptoms and appear to reduce the incidence of severe disease flares. The dose of hydroxychloroquine is 200 or 400 mg/d orally and should not exceed 6.5 mg/kg/d; annual monitoring for retinal changes is recommended. Drug-induced neuropathy and myopathy may be erroneously ascribed to the underlying disease.
Corticosteroids are required for the control of certain complications. (Systemic corticosteroids are not usually given for minor arthritis, skin rash, leukopenia, or the anemia associated with chronic disease.) Glomerulonephritis, hemolytic anemia, pericarditis or myocarditis, alveolar hemorrhage, central nervous system involvement, and thrombotic thrombocytopenic purpura all require corticosteroid treatment and often other interventions as well. Forty to 60 mg of oral prednisone is often needed initially; however, the lowest dose of corticosteroid that controls the condition should be used. Central nervous system lupus may require higher doses of corticosteroids than are usually given; however, corticosteroid psychosis may mimic lupus cerebritis, in which case reduced doses are appropriate. Immunosuppressive agents such as cyclophosphamide, mycophenolate mofetil, and azathioprine are used in cases resistant to corticosteroids. Treatment of severe lupus nephritis includes an induction phase and a maintenance phase. Cyclophosphamide, which improves renal survival but not patient survival, has been for many years the standard treatment for both phases of lupus nephritis, but mycophenolate mofetil appears to be an equally effective alternative treatment for many patients with lupus nephritis. Very close follow-up is needed to watch for potential side effects when immunosuppressants are given; these agents should be administered by clinicians experienced in their use. When cyclophosphamide is required, gonadotropin-releasing hormone analogs can be given to protect a woman against the risk of premature ovarian failure. Belimumab, a monoclonal antibody that inhibits the activity of a B cell growth factor, has received FDA approval for treating antibody-positive SLE patients with active disease who have not responded to standard therapies (eg, NSAIDs, antimalarials, or immunosuppressive therapies). However, the precise indications for its use have not been defined, and its efficacy in severe disease activity is unknown. Belimumab appears less effective in blacks. While observations studies suggested that rituximab was effective in SLE, one large randomized-controlled trial demonstrated it was no more effective than placebo. For patients with the antiphospholipid syndrome—the presence of antiphospholipid antibodies and compatible clinical events—anticoagulation is the treatment of choice (see Antiphospholipid Antibody Syndrome, below). Moderate intensive anticoagulation with warfarin to achieve an INR of 2.0–3.0 is as effective as more intensive regimens. Pregnant patients with recurrent fetal loss associated with antiphospholipid antibodies should be treated with low-molecular-weight heparin plus aspirin.
Ten-year survival rates exceeding 85% are routine. In most patients, the illness pursues a relapsing and remitting course. Prednisone, often needed in doses of 40 mg/d orally or more during severe flares, can usually be tapered to low doses (5–10 mg/d) when the disease is inactive. However, there are some in whom the disease pursues a virulent course, leading to serious impairment of vital structures such as lung, heart, brain, or kidneys, and the disease may lead to death. With improved control of lupus activity and with increasing use of corticosteroids and immunosuppressive drugs, the mortality and morbidity patterns in lupus have changed. Mortality in SLE shows a bimodal pattern. In the early years after diagnosis, infections—especially with opportunistic organisms—are the leading cause of death, followed by active SLE, chiefly due to kidney or central nervous system disease. In later years, accelerated atherosclerosis, linked to chronic inflammation, becomes a major cause of death. Indeed, the incidence of myocardial infarction is five times higher in persons with SLE than in the general population. Therefore, it is especially important for SLE patients to avoid smoking and to minimize other conventional risk factors for atherosclerosis (eg, hypercholesterolemia, hypertension, obesity, and inactivity). Patients with SLE should receive influenza vaccination every year and pneumococcal vaccination every 5 years. Since SLE patients have a higher risk of developing malignancy (especially lymphoma, lung cancer, and cervical cancer), preventive cancer screening recommendations should be followed assiduously. With more patients living longer, it has become evident that avascular necrosis of bone, affecting most commonly the hips and knees, is responsible for substantial morbidity. Nonetheless, the outlook for most patients with SLE has become increasingly favorable.
• Appropriate diagnosis and management of SLE requires the active participation of a rheumatologist.
• The severity of organ involvement dictates referral to other subspecialists, such as nephrologists and pulmonologists.
• Rapidly progressive glomerulonephritis, pulmonary hemorrhage, transverse myelitis, and other severe organ-threatening manifestations of lupus usually require in-patient assessment and management.
• Severe infections, particularly in the setting of immunosuppressant therapy, should prompt admission.
Dooley MA et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011 Nov 17;365(20):1886–95. [PMID: 22087680]
Murphy et al. Systemic lupus erythematosus and other autoimmune rheumatic diseases: challenges to treatment. Lancet. 2013 Aug 31;382(9894):809–18. [PMID: 23972423]
Navarra SV et al; BLISS-52 Study Group. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011 Feb 26;377(9767):721–31. [PMID: 21296403]
Ramos-Casals M et al. B-cell-depleting therapy in systemic lupus erythematosus. Am J Med. 2012 Apr;125(4):327–36. [PMID: 22444096]
Skaggs BJ et al. Accelerated atherosclerosis in patients with SLE—mechanisms and management. Nat Rev Rheumatol. 2012 Feb 14;8(4):214–23. [PMID: 22331061]
Walsh M et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis with poor kidney function: a subgroup analysis of the Aspreva Lupus Management Study. Am J Kidney Dis. 2013 May;61(5):710–5. [PMID: 23375819]
ESSENTIALS OF DIAGNOSIS
Hypercoagulability, with recurrent thromboses in either the venous or arterial circulation.
Thrombocytopenia is common.
Pregnancy complications, specifically pregnancy losses after the first trimester.
Lifelong anticoagulation with warfarin is recommended currently for patients with serious complications of this syndrome because recurrent events are common.
A primary antiphospholipid syndrome (APS) is diagnosed in patients who have venous or arterial occlusions or recurrent fetal loss in the presence of persistent (≥ 12 weeks), high-titer, diagnostic antiphospholipid antibodies but no other features of SLE. Diagnostic antiphospholipid antibodies are IgG or IgM anticardiolipin, or IgG or IgM antibodies to beta-2-glycoprotein I, and lupus anticoagulant. In < 1% of patients with antiphospholipid antibodies, a potentially devastating syndrome known as the “catastrophic antiphospholipid syndrome” occurs, leading to diffuse thromboses, thrombotic microangiopathy, and multiorgan system failure.
Patients are often asymptomatic until suffering a thrombotic complication of this syndrome or a pregnancy loss. Thrombotic events may occur in either the arterial or venous circulations. Thus, deep venous thromboses, pulmonary emboli, cerebrovascular accidents are typical clinical events among patients with the APS. In case-control studies, 3.1% of patients in the general population who experienced a venous thrombotic event (in the absence of cancer) tested positive for the lupus anticoagulant (versus 0.9% of controls, yielding an odds ratio of 3.6). For women younger than 50 years in whom stroke developed, the odds ratio for having the lupus anticoagulant is 43.1. Budd-Chiari syndrome, cerebral sinus vein thrombosis, myocardial or digital infarctions, and other thrombotic events also occur. A variety of other symptoms and signs are often attributed to the APS, including thrombocytopenia, mental status changes, livedo reticularis, skin ulcers, microangiopathic nephropathy, adrenal insufficiency (from infarction/hemorrhage), and cardiac valvular dysfunction—typically mitral regurgitation due to Libman-Sacks endocarditis. Livedo reticularis is strongly associated with the subset of patients with APS in whom arterial ischemic events develop. Pregnancy losses that are associated with APS include unexplained fetal death after the first trimester, one or more premature births before 34 weeks because of eclampsia or preeclampsia, or three or more unexplained miscarriages during the first trimester.
As noted in the discussion of SLE, three types of antiphospholipid antibody are believed to contribute to this syndrome: (1) anti-cardiolipin antibodies; (2) antibodies to beta-2 glycoprotein; and (3) a “lupus anticoagulant” that prolongs certain phospholipid-dependent coagulation tests (see below). Antibodies to cardiolipin and to beta-2 glycoprotein are typically measured with enzyme immunoassays. Anti-cardiolipin antibodies can produce a biologic false-positive test for syphilis (ie, a positive rapid plasma reagin but negative specific anti-treponemal assay). In general, IgG anti-cardiolipin antibodies are believed to be more pathologic than IgM. Presence of the lupus anticoagulant is a stronger risk factor for thrombosis or pregnancy loss than is the presence of antibodies to either beta-2-glycoprotein I or anticardiolipin. A clue to the presence of a lupus anticoagulant, which may occur in individuals who do not have SLE, may be detected by a prolongation of the partial thromboplastin time (which, paradoxically, is associated with a thrombotic tendency rather than a bleeding risk). Testing for the lupus anticoagulant involves phospholipid-dependent functional assays of coagulation, such as the Russell viper venom time (RVVT). In the presence of a lupus anticoagulant, the RVVT is prolonged and does not correct with mixing studies but does with the addition of excess phospholipid.
The exclusion of other autoimmune disorders, particularly those in the SLE spectrum, is essential because such disorders may be associated with additional complications requiring alternative treatments. Other genetic or acquired conditions associated with hypercoagulability such as protein C, protein S, or antithrombin deficiency and factor V Leiden should be excluded. Catastrophic APS has a broad differential, including sepsis, pulmonary-renal syndromes, systemic vasculitis, disseminated intravascular coagulation, and thrombotic thrombocytopenic purpura.
Present recommendations for anticoagulation are to treat patients with warfarin to maintain an INR of 2.0–3.0. Patients who have recurrent thrombotic events on this level of anticoagulation may require higher INRs (> 3.0), but the bleeding risk increases substantially with this degree of anticoagulation. Guidelines indicate that patients with APS should be treated with anticoagulation for life. Because of the teratogenic effects of warfarin, subcutaneous heparin and low-dose aspirin (81 mg) is the usual approach to prevent pregnancy complications in women with APS. In patients with catastrophic APS, a three-pronged approach is taken in the acute setting: intravenous heparin, high doses of corticosteroids, and either intravenous immune globulin or plasmapheresis.
Arachchillage DJ et al. Use of new oral anticoagulants in antiphospholipid syndrome. Curr Rheumatol Rep. 2013 Jun;15(6):331. [PMID: 23649961]
Clark CA et al. The lupus anticoagulant: results from 2257 patients attending a high-risk pregnancy clinic. Blood. 2013 Jul 18;122(3):341–7. [PMID: 23649468]
Giannakopoulos B et al. The pathogenesis of the antiphospholipid syndrome. N Engl J Med. 2013 Mar 14;368(11):1033–44. [PMID: 23484830]
Lockshin MD. Pregnancy and antiphospholipid syndrome. Am J Reprod Immunol. 2013 Jun;69(6):585–7. [PMID: 23279134]
Mok CC et al. Prevalence of the antiphospholipid syndrome and its effect on survival in 679 Chinese patients with systemic lupus erythematosus: a cohort study. Medicine (Baltimore). 2013 Jul;92(4):217–22. [PMID: 23793109]
ESSENTIALS OF DIAGNOSIS
Paroxysmal bilateral digital pallor and cyanosis followed by rubor.
Precipitated by cold or emotional stress; relieved by warmth.
Primary form of Raynaud phenomenon is benign and usually affects young women.
Secondary form can cause digital ulceration or gangrene.
Raynaud phenomenon (RP) is a syndrome of paroxysmal digital ischemia, most commonly caused by an exaggerated response of digital arterioles to cold or emotional stress. The initial phase of RP, mediated by excessive vasoconstriction, consists of well-demarcated digital pallor or cyanosis; the subsequent (recovery) phase of RP, caused by vasodilation, leads to intense hyperemia and rubor. Although RP chiefly affects fingers, it can also affect toes and other acral areas such as the nose and ears. RP is classified as primary (idiopathic or Raynaud disease) or secondary. Nearly one-third of the population reports being “sensitive to the cold” but does not experience the paroxysms of digital pallor, cyanosis, and erythema characteristic of RP. Primary RP occurs in 2–6% of adults, is especially common in young women, and poses more of a nuisance than a threat to good health. In contrast, secondary RP is less common, is chiefly associated with rheumatic diseases (especially scleroderma), and is frequently severe enough to cause digital ulceration or gangrene.
In early attacks of RP, only one or two fingertips may be affected; as it progresses, all fingers down to the distal palm may be involved. The thumbs are rarely affected. During recovery there may be intense rubor, throbbing, paresthesia, pain, and slight swelling. Attacks usually terminate spontaneously or upon returning to a warm room or putting the extremity in warm water. The patient is usually asymptomatic between attacks. Sensory changes that often accompany vasomotor manifestations include numbness, stiffness, diminished sensation, and aching pain.
Primary RP appears first between ages 15 and 30, almost always in women. It tends to be mildly progressive and, unlike secondary RP (which may be unilateral and may involve only one or two fingers), symmetric involvement of the fingers of both hands is the rule. Spasm becomes more frequent and prolonged. Unlike secondary RP, primary RP does not cause digital pitting, ulceration, or gangrene.
Nailfold capillary abnormalities are among the earliest clues that a person has secondary rather than primary RP. The nailfold capillary pattern can be visualized by placing a drop of grade B immersion oil at the patient’s cuticle and then viewing the area with an ophthalmoscope set to 20–40 diopters. Dilation or dropout of the capillary loops indicates the patient has a secondary form of RP, most commonly scleroderma (Table 20–10). While highly specific for secondary RP, nailfold capillary changes have a low sensitivity. Digital pitting or ulceration or other abnormal physical findings (eg, skin tightening, loss of extremity pulse, rash, swollen joints) can also provide evidence of secondary RP.
Table 20–10. Causes of secondary Raynaud phenomenon.
Primary RP must be differentiated from the numerous causes of secondary RP (Table 20–10). The history and examination may suggest the diagnosis of systemic sclerosis (including its CREST variant), SLE, and mixed connective tissue disease; RP is occasionally the first manifestation of these disorders. The diagnosis of many of these rheumatic diseases can be confirmed with specific serologic tests (seeTable 20–8).
RP may occur in patients with the thoracic outlet syndromes. In these disorders, involvement is generally unilateral, and symptoms referable to brachial plexus compression tend to dominate the clinical picture. Carpal tunnel syndrome should also be considered, and nerve conduction tests are appropriate in selected cases.
A particularly severe form of RP occurs in up to one-third of patients receiving bleomycin and vincristine in combination, often for testicular cancer. Treatment is unsuccessful, and the problem persists even with discontinuation of the drugs.
The differentiation from Buerger disease (thromboangiitis obliterans) is usually not difficult, since thromboangiitis obliterans is generally a disease of men, particularly smokers; peripheral pulses are often diminished or absent; and, when RP occurs in association with thromboangiitis obliterans, it is usually in only one or two digits.
In acrocyanosis, cyanosis of the hands is permanent and diffuse; the sharp and paroxysmal line of demarcation with pallor does not occur with acrocyanosis. Frostbite may lead to chronic RP. Ergot poisoning, particularly due to prolonged or excessive use of ergotamine, must also be considered but is unusual.
RP may be mimicked by type I cryoglobulinemia, in which a monoclonal antibody cryoprecipitates in the cooler distal circulation. Type I cryoglobulinemia is usually associated with multiple myeloma or with lymphoproliferative disorders.
Erythromelalgia can mimic the rubor phase of RP; exacerbation by heat and relief with cold readily distinguish erythromelalgia from RP.
Patients should wear gloves or mittens whenever outside in temperatures that precipitate attacks. Keeping the body warm is also a cornerstone of initial therapy. Wearing warm shirts, coats, and hats will help prevent the exaggerated vasospasm that causes RP and that is not prevented by warming only the hands. The hands should be protected from injury at all times; wounds heal slowly, and infections are consequently hard to control. Softening and lubricating lotion to control the fissured dry skin should be applied to the hands frequently. Smoking should be stopped and sympathomimetic drugs (eg, decongestants, diet pills, and amphetamines) should be avoided. For most patients with primary RP, general measures alone are sufficient to control symptoms. Medical or surgical therapy should be considered in patients who have severe symptoms or are experiencing tissue injury from digital ischemia.
Calcium channel blockers are first-line therapy for RP. Calcium channel blockers produce a modest benefit and are more effective in primary RP than secondary RP. Slow release nifedipine (30–180 mg/d orally), amlodipine (5–20 mg/d orally), felodipine, isradipine, or nisoldipine are popular and more effective than verapamil, nicardipine and diltiazem. Other medications that are sometimes effective in treating RP include angiotensin-converting enzyme inhibitors, sympatholytic agents (eg, prazosin), topical nitrates, phosphodiesterase inhibitors (eg, sildenafil, tadalafil, and vardenafil), selective serotonin reuptake inhibitors (fluoxetine), endothelin-receptor inhibitors (ie, bosentan), statins, parenteral prostaglandins (prostaglandin E1), and oral prostaglandins (misoprostol).
Sympathectomy may be indicated when attacks have become frequent and severe, when they interfere with work and well being, and particularly when trophic changes have developed and medical measures have failed. Cervical sympathectomy is modestly effective for primary but not secondary RP. Digital sympathectomy may improve secondary RP.
Primary RP is benign and largely a nuisance for affected individuals who are exposed to cold winters or excessive air conditioning. The prognosis of secondary RP depends on the severity of the underlying disease. Unfortunately, severe pain from ulceration and gangrene are not rare with scleroderma, especially the CREST variant.
Appropriate management of patients with secondary RP often requires consultation with a rheumatologist.
Patients with severe digital ischemia as evidenced by demarcation should be admitted for intensive therapy.
Goundry B et al. Diagnosis and management of Raynaud’s phenomenon. BMJ. 2012 Feb 7;344:e289. [PMID: 22315243]
Herrick AL. Contemporary management of Raynaud’s phenomenon and digital ischaemic complications. Curr Opin Rheumatol. 2011 Nov;23(6):555–61. [PMID: 21885977]
Landry GJ. Current medical and surgical management of Raynaud’s syndrome. J Vasc Surg. 2013 Jun;57(6):1710–6. [PMID: 23618525]
Pavlov-Dolijanovic S et al. Late appearance and exacerbation of primary Raynaud’s phenomenon attacks can predict future development of connective tissue disease: a retrospective chart review of 3,035 patients. Rheumatol Int. 2013 Apr;33(4):921–6. [PMID: 22821334]
ESSENTIALS OF DIAGNOSIS
Limited disease (80% of patients): thickening of skin confined to the face, neck, and distal extremities.
Diffuse disease (20%): widespread thickening of skin, including truncal involvement, with areas of increased pigmentation and depigmentation.
Raynaud phenomenon and antinuclear antibodies are present in virtually all patients.
Systemic features of gastroesophageal reflux, hypomotility of gastrointestinal tract, pulmonary fibrosis, pulmonary hypertension, and renal involvement.
Scleroderma (systemic sclerosis) is a rare chronic disorder characterized by diffuse fibrosis of the skin and internal organs. Symptoms usually appear in the third to fifth decades, and women are affected two to three times as frequently as men.
Two forms of scleroderma are generally recognized: limited (80% of patients) and diffuse (20%). In limited scleroderma, which is also known as the CREST syndrome (representing calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia), the hardening of the skin (scleroderma) is limited to the face and hands. In contrast, in diffuse scleroderma, the skin changes also involve the trunk and proximal extremities. Tendon friction rubs over the forearms and shins occur uniquely (but not universally) in diffuse scleroderma. In general, patients with limited scleroderma have better outcomes than those with diffuse disease, largely because kidney disease or interstitial lung disease rarely develops in patients with limited disease. Cardiac disease is also more characteristic of diffuse scleroderma. Patients with limited disease, however, are more susceptible to digital ischemia, leading to finger loss, and to life-threatening pulmonary hypertension. Small and large bowel hypomotility, which may occur in either form of scleroderma, can cause constipation alternating with diarrhea, malabsorption due to bacterial overgrowth, pseudoobstruction, and severe bowel distension with rupture.
Raynaud phenomenon is usually the initial manifestation and can precede other signs and symptoms by years in cases of limited scleroderma. Polyarthralgia, weight loss, and malaise are common early features of diffuse scleroderma but are infrequent in limited scleroderma. Cutaneous disease usually, but not always, develops before visceral involvement and can manifest initially as non-pitting subcutaneous edema associated with pruritus. With time the skin becomes thickened and hidebound, with loss of normal folds. Telangiectasia, pigmentation, and depigmentation are characteristic. Ulceration about the fingertips and subcutaneous calcification are seen. Dysphagia and symptoms of reflux due to esophageal dysfunction are common and result from abnormalities in motility and later from fibrosis. Fibrosis and atrophy of the gastrointestinal tract cause hypomotility. Large-mouthed diverticuli occur in the jejunum, ileum, and colon. Diffuse pulmonary fibrosis and pulmonary vascular disease are reflected in restrictive lung physiology and low diffusing capacities. Cardiac abnormalities include pericarditis, heart block, myocardial fibrosis, and right heart failure secondary to pulmonary hypertension. Scleroderma renal crisis, resulting from intimal proliferation of smaller renal arteries and usually associated with hypertension, is a marker for a poor outcome even though many cases can be treated effectively with angiotensin-converting enzyme inhibitors.
Mild anemia is often present. In scleroderma renal crisis, the peripheral blood smear shows findings consistent with a microangiopathic hemolytic anemia (due to mechanical damage to red cells from diseased small vessels). Elevation of the ESR is unusual. Proteinuria appears in association with renal involvement. Antinuclear antibody tests are nearly always positive, frequently in high titers (Table 20–8). The scleroderma antibody (anti-SCL-70), directed against topoisomerase III, is found in one-third of patients with diffuse systemic sclerosis and in 20% of those with CREST syndrome. Although present in only a small number of patients with diffuse scleroderma, anti-SCL-70 antibodies may portend a poor prognosis, with a high likelihood of serious internal organ involvement (eg, interstitial lung disease). Anticentromere antibodies are seen in 50% of those with CREST syndrome and in 1% of individuals with diffuse scleroderma (Table 20–8). Anticentromere antibodies are highly specific for limited scleroderma, but they also occur occasionally in overlap syndromes. Anti-RNA polymerase III antibodies develop in 10–20% of scleroderma patients overall and correlate with the development of diffuse skin disease and renal hypertensive crisis.
Early in its course, scleroderma can cause diagnostic confusion with other causes of Raynaud phenomenon, particularly SLE, mixed connective tissue disease, and the inflammatory myopathies. Scleroderma can be mistaken for other disorders characterized by skin hardening. Eosinophilic fasciitis is a rare disorder presenting with skin changes that resemble diffuse scleroderma. The inflammatory abnormalities, however, are limited to the fascia rather than the dermis and epidermis. Moreover, patients with eosinophilic fasciitis are distinguished from those with scleroderma by the presence of peripheral blood eosinophilia, the absence of Raynaud phenomenon, the good response to prednisone, and an association (in some cases) with paraproteinemias. Diffuse skin thickening and visceral involvement are features of scleromyxedema; the presence of a paraprotein, the absence of Raynaud phenomenon, and distinct skin histology point to scleromyxedema. Diabetic cheiropathy typically develops in long-standing, poorly controlled diabetes and can mimic sclerodactyly. Nephrogenic fibrosing dermopathy produces thickening and hardening of the skin of the trunk and extremities in patients with chronic kidney disease; exposure to gadolinium may play a pathogenic role. Morphea and linear scleroderma cause sclerodermatous changes limited to circumscribed areas of the skin and usually have excellent outcomes.
Treatment of scleroderma is symptomatic and supportive and focuses on the organ systems involved. There is no effective therapy for the underlying disease process. However, interventions for management of specific organ manifestations of this disease have improved substantially. Severe Raynaud syndrome may respond to calcium channel blockers, eg, long-acting nifedipine, 30–120 mg/d orally, or to losartan, 50 mg/d orally, or to sildenafil 50 mg orally twice daily. Patients with esophageal disease should take medications in liquid or crushed form. Esophageal reflux can be reduced and the risk of scarring diminished by avoidance of late-night meals and by the use of proton pump inhibitors (eg, omeprazole, 20–40 mg/d orally), which achieve near-complete inhibition of gastric acid production and are remarkably effective for refractory esophagitis. Patients with delayed gastric emptying maintain their weight better if they eat small, frequent meals and remain upright for at least 2 hours after eating. Malabsorption due to bacterial overgrowth also responds to antibiotics, eg, tetracycline, 500 mg four times orally daily, often prescribed cyclically. The hypertensive crises associated with systemic sclerosis renal crisis must be treated early and aggressively (in the hospital) with angiotensin-converting enzyme inhibitors, eg, captopril, initiated at 25 mg orally every 6 hours and titrated up as tolerated to a maximum of 100 mg every 6 hours. Apart from the patient with myositis, prednisone has little or no role in the treatment of scleroderma; high doses (> 15 mg daily) have been associated with scleroderma renal crisis. Cyclophosphamide improves dyspnea and pulmonary function tests modestly in patients with severe interstitial lung disease; this highly toxic drug should only be administered by physicians familiar with its use. Mycophenolate mofetil, 1 g twice daily, stabilized lung function in small, uncontrolled studies of patients with interstitial lung disease. Bosentan, an endothelin receptor antagonist, improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension and helps prevent digital ulceration. Sildenafil or prostaglandins (delivered by continuous intravenous infusion or intermittent inhalation) may also be useful in treating pulmonary hypertension. At an experimental level, immunoablative therapy with or without stem cell rescue has achieved promising results for some patients with severe, rapidly progressive diffuse scleroderma.
The 9-year survival rate in scleroderma averages approximately 40%. The prognosis tends to be worse in those with diffuse scleroderma, in blacks, in males, and in older patients. Lung disease—in the form of pulmonary fibrosis or pulmonary arterial hypertension—is now the number one cause of mortality. Death from advanced heart failure or chronic kidney disease is also common. Those persons in whom severe internal organ involvement does not develop in the first 3 years have a substantially better prognosis, with 72% surviving at least 9 years. Breast and lung cancer may be more common in patients with scleroderma.
• Appropriate management of scleroderma requires frequent consultations with a rheumatologist.
• Severity of organ involvement dictates referral to other subspecialists, such as pulmonologists or gastroenterologists.
Gelber AC et al. Race and association with disease manifestations and mortality in scleroderma: a 20-year experience at the Johns Hopkins Scleroderma Center and review of the literature. Medicine (Baltimore). 2013 Jul;92(4):191–205. [PMID: 23793108]
Guillevin L et al. Scleroderma renal crisis: a retrospective multicentre study on 91 patients and 427 controls. Rheumatology (Oxford). 2012 Mar;51(3):460–7. [PMID: 22087012]
Onishi A et al. Cancer incidence in systemic sclerosis: meta-analysis of population-based cohort studies. Arthritis Rheum. 2013 Jul;65(7):1913–21. [PMID: 23576072]
ESSENTIALS OF DIAGNOSIS
Bilateral proximal muscle weakness.
Characteristic cutaneous manifestations in dermatomyositis (Gottron papules, heliotrope rash).
Diagnostic tests: elevated creatine kinase, muscle biopsy, electromyography, MRI.
Increased risk of malignancy, particularly in dermatomyositis.
Inclusion body myositis can mimic polymyositis but is less responsive to treatment.
Polymyositis and dermatomyositis are systemic disorders of unknown cause whose principal manifestation is muscle weakness. Although their clinical presentations (aside from the presence of certain skin findings in dermatomyositis, some of which are pathognomonic) and treatments are similar, the two diseases are pathologically quite distinct. They affect persons of any age group, but the peak incidence is in the fifth and sixth decades of life. Women are affected twice as commonly as men, and the diseases (particularly polymyositis) also occur more often among blacks than whites. There is an increased risk of malignancy in adult patients with dermatomyositis. Indeed, up to one patient in four with dermatomyositis has an occult malignancy. Malignancies may be evident at the time of presentation with the muscle disease but may not be detected until months afterward in some cases. Rare patients with dermatomyositis have skin disease without overt muscle involvement, a condition termed “dermatomyositis sine myositis.” Myositis may also be associated with other connective tissue diseases, especially scleroderma, lupus, mixed connective tissue disease, and Sjögren syndrome.
Polymyositis may begin abruptly, but the usual presentation is one of progressive muscle weakness over weeks to months. The weakness chiefly involves proximal muscle groups of the upper and lower extremities as well as the neck. Leg weakness (eg, difficulty in rising from a chair or climbing stairs) typically precedes arm symptoms. In contrast to myasthenia gravis, polymyositis and dermatomyositis do not cause facial or ocular muscle weakness. Pain and tenderness of affected muscles occur in one-fourth of cases, but these are rarely the chief complaints. About one-fourth of patients have dysphagia. In contrast to scleroderma, which affects the smooth muscle of the lower esophagus and can cause a “sticking” sensation below the sternum, polymyositis or dermatomyositis involves the striated muscles of the upper pharynx and can make initiation of swallowing difficult. Muscle atrophy and contractures occur as late complications of advanced disease. Clinically significant myocarditis is uncommon even though there is often creatine kinase-MB elevation. Patients who are bed-bound from myositis should be screened for respiratory muscle weakness that can be severe enough to cause CO2 retention and can progress to require mechanical ventilation.
The characteristic rash of dermatomyositis is dusky red and may appear in a malar distribution mimicking the classic rash of SLE. Facial erythema beyond the malar distribution is also characteristic of dermatomyositis. Erythema also occurs over other areas of the face, neck, shoulders, and upper chest and back (“shawl sign”). Periorbital edema and a purplish (heliotrope) suffusion over the eyelids are typical signs (Figure 20–5). Coloration of the heliotrope and other rashes of dermatomyositis can be affected by skin tone. In blacks, the rashes may appear more hyperpigmented than erythematous or violaceous. Periungual erythema, dilations of nailbed capillaries, and scaly patches over the dorsum of PIP and MCP joints (Gottron sign) are highly suggestive. Scalp involvement by dermatomyositis may mimic psoriasis. Infrequently, the cutaneous findings of this disease precede the muscle inflammation by weeks or months. Diagnosing polymyositis in patients over age 70 years can be difficult because weakness may be overlooked or attributed erroneously to idiopathic frailty. Polymyositis can remain undiagnosed or will be misdiagnosed as hepatitis because of elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. A subset of patients with polymyositis and dermatomyositis develop the “antisynthetase syndrome,” a group of findings including inflammatory arthritis, fever, Raynaud phenomenon, “mechanic’s hands” (hyperkeratosis along the radial and palmar aspects of the fingers), interstitial lung disease, and often severe muscle disease associated with certain autoantibodies (eg, anti-Jo -1 antibodies).
Figure 20–5. Heliotrope (violaceous) rash around the eyes in a patient with dermatomyositis (Reproduced with permission, from Richard P. Usatine, MD).
Measurement of serum levels of muscle enzymes, especially creatine kinase and aldolase, is most useful in diagnosis and in assessment of disease activity. Anemia is uncommon. The ESR and C-reactive protein are often normal and are not reliable indicators of disease activity. Rheumatoid factor is found in a minority of patients. Antinuclear antibodies are present in many patients, especially those who have an associated connective tissue disease. A number of autoantibodies are seen exclusively in patients with myositis and are associated with distinctive clinical features (Table 20–11). The most common myositis-specific antibody, anti-Jo-1 antibody, is seen in the subset of patients who have associated interstitial lung disease, nonerosive polyarthritis, fever, and “mechanic’s hands.” The other myositis-specific autoantibodies are anti-Mi-2, associated with dermatomyositis; anti-SRP (anti-signal recognition particle), associated with rapidly progressive, severe polymyositis, and dysphagia; and anti-155/140, strongly associated with dermatomyositis with malignancy (malignancy in 71% with versus 11% without this antibody). In the absence of the anti-synthetase syndrome, chest radiographs are usually normal. Electromyographic abnormalities consisting of polyphasic potentials, fibrillations, and high-frequency action potentials point toward a myopathic, rather than a neurogenic, cause of weakness. MRI can detect early and patchy muscle involvement, can guide biopsies, and often is more useful than electromyography. The malignancies most commonly associated with dermatomyositis in descending order of frequency are ovarian, lung, pancreatic, stomach, colorectal, and non-Hodgkin lymphoma. The search for an occult malignancy should begin with a history and physical examination, supplemented with a complete blood count, comprehensive biochemical panel, serum protein electrophoresis, and urinalysis, and should include age- and risk-appropriate cancer screening tests. Given the especially strong association of ovarian carcinoma and dermatomyositis, transvaginal ultrasonography, CT scanning, and CA-125 levels may be useful in women. No matter how extensive the initial screening, some malignancies will not become evident for months after the initial presentation.
Table 20–11. Myositis-specific antibodies.
Biopsy of clinically involved muscle is the only specific diagnostic test. The pathology findings in polymyositis and dermatomyositis are distinct. Although both include lymphoid inflammatory infiltrates, the findings in dermatomyositis are localized to perivascular regions and there is evidence of humoral and complement-mediated destruction of microvasculature associated with the muscle. In addition to its vascular orientation, the inflammatory infiltrate in dermatomyositis centers on the interfascicular septa and is located around, rather than in, muscle fascicles. A pathologic hallmark of dermatomyositis is perifascicular atrophy. In contrast, the pathology of polymyositis characteristically includes endomysial infiltration of the inflammatory infiltrate. Owing to the sometimes patchy distribution of pathologic abnormalities, however, false-negative biopsies sometimes occur in both disorders.
Muscle inflammation may occur as a component of SLE, scleroderma, Sjögren syndrome, and overlap syndromes. In those cases, associated findings usually permit the precise diagnosis of the primary condition.
Inclusion body myositis, because of its tendency to mimic polymyositis, is a common cause of “treatment-resistant polymyositis.” In contrast to the epidemiologic features of polymyositis, however, the typical inclusion body myositis patient is white, male, and over the age of 50. The onset of inclusion body myositis is more insidious than that of polymyositis or dermatomyositis (eg, occurring over years rather than months), and asymmetric distal motor weakness is common in inclusion body myositis. Creatine kinase levels in inclusion body myositis are often minimally elevated and are normal in 25%. Electromyography may show a mixed picture of myopathic and neurogenic abnormalities. Muscle biopsy shows characteristic intracellular vacuoles by light microscopy and either tubular or filamentous inclusions in the nucleus or cytoplasm by electron microscopy. Inclusion body myositis is less likely to respond to therapy.
Hypothyroidism is a common cause of proximal muscle weakness associated with elevations of serum creatine kinase. Hyperthyroidism and Cushing disease may both be associated with proximal muscle weakness with normal levels of creatine kinase. Patients with polymyalgia rheumatica are over the age of 50 and—in contrast to patients with polymyositis—have pain but no objective weakness; creatine kinase levels are normal. Disorders of the peripheral and central nervous systems (eg, chronic inflammatory polyneuropathy, multiple sclerosis, myasthenia gravis, Eaton-Lambert disease, and amyotrophic lateral sclerosis) can produce weakness but are distinguished by characteristic symptoms and neurologic signs and often by distinctive electromyographic abnormalities. A number of systemic vasculitides (polyarteritis nodosa, microscopic polyangiitis, the Churg-Strauss syndrome, granulomatosis with polyangiitis, and mixed cryoglobulinemia) can produce profound weakness through vasculitic neuropathy. The muscle weakness associated with these disorders, however, is typically distal and asymmetric, at least in the early stages.
Limb-girdle muscular dystrophy can present in early adulthood with a clinical picture that mimics polymyositis: proximal muscle weakness, elevations in serum levels of creatine kinase, and inflammatory changes on muscle biopsy. Failure to respond to treatment for polymyositis or the presence of atypical clinical features such as scapular winging or weakness of ankle plantar flexors should prompt genetic testing for limb-girdle muscular dystrophy.
Many drugs, including corticosteroids, alcohol, clofibrate, penicillamine, tryptophan, and hydroxychloroquine, can produce proximal muscle weakness. Long-term use of colchicine at doses as low as 0.6 mg twice a day in patients with moderate chronic kidney disease can produce a mixed neuropathy-myopathy that mimics polymyositis. The weakness and muscle enzyme elevation reverse with cessation of the drug. Polymyositis can occur as a complication of HIV or HTLV-1 infection and with zidovudine therapy as well.
HMG-CoA reductase inhibitors can cause myopathy and rhabdomyolysis. Although only about 0.1% of patients taking a statin drug alone develop myopathy, concomitant administration of other drugs (especially gemfibrozil, cyclosporine, niacin, macrolide antibiotics, azole antifungals, and protease inhibitors) increases the risk. Statin use has also been linked to the development of an autoimmune-mediated necrotizing myositis, which persists after the statin has been discontinued and is associated with autoantibodies to HMG-CoA reductase.
Most patients respond to corticosteroids. Often a daily dose of 40–60 mg or more of oral prednisone is required initially. The dose is then adjusted downward while monitoring muscle strength and serum levels of muscle enzymes. Long-term use of corticosteroids is often needed, and the disease may recur or reemerge when they are withdrawn. Patients with an associated neoplasm have a poor prognosis, although remission may follow treatment of the tumor; corticosteroids may or may not be effective in these patients. In patients resistant or intolerant to corticosteroids, therapy with methotrexate or azathioprine may be helpful. Intravenous immune globulin is effective for dermatomyositis resistant to prednisone. Mycophenolate mofetil (1–1.5 g orally twice daily) may be useful as a steroid-sparing agent. Rituximab has achieved encouraging results in some patients with inflammatory myositis unresponsive to prednisone. Since the rash of dermatomyositis is often photosensitive, patients should limit sun exposure. Hydroxychloroquine (200–400 mg/d orally not to exceed 6.5 mg/kg) can also help ameliorate the skin disease.
• Appropriate management of myositis usually requires frequent consultations with a rheumatologist or neurologist.
• Severe lung disease may require consultation with a pulmonologist.
• Signs of rhabdomyolysis.
• New onset of dysphagia.
• Respiratory insufficiency with hypoxia or carbon dioxide retention.
Ernste FC et al. Idiopathic inflammatory myopathies: current trends in pathogenesis, clinical features, and up-to-date treatment recommendations. Mayo Clin Proc. 2013 Jan;88(1):83–105. [PMID: 23274022]
Mammen AL. Autoimmune myopathies: autoantibodies, phenotypes and pathogenesis. Nat Rev Neurol. 2011 Jun 8;7(6):343–54. [PMID: 21654717]
ESSENTIALS OF DIAGNOSIS
Women are 90% of patients; the average age is 50 years.
Dryness of eyes and dry mouth (sicca components) are the most common features; they occur alone or in association with rheumatoid arthritis or other connective tissue disease.
Rheumatoid factor and antinuclear antibodies are common.
Increased incidence of lymphoma.
Sjögren syndrome is a systemic autoimmune disorder whose clinical presentation is usually dominated by dryness of the eyes and mouth due to immune-mediated dysfunction of the lacrimal and salivary glands. The disorder is predominantly seen in women, with a ratio of 9:1; most cases develop between the ages of 40 and 60 years. Sjögren syndrome can occur in isolation (“primary” Sjögren syndrome) or in association with another rheumatic disease. Sjögren syndrome is most frequently associated with rheumatoid arthritis but also occurs with SLE, primary biliary cirrhosis, scleroderma, polymyositis, Hashimoto thyroiditis, polyarteritis, and interstitial pulmonary fibrosis.
Keratoconjunctivitis sicca results from inadequate tear production caused by lymphocyte and plasma cell infiltration of the lacrimal glands. Ocular symptoms are usually mild. Burning, itching, and the sensation of having a foreign body or a grain of sand in the eye occur commonly. For some patients, the initial manifestation is the inability to tolerate wearing contact lenses. Many patients with more severe ocular dryness notice ropy secretions across their eyes, especially in the morning. Photophobia may signal corneal ulceration resulting from severe dryness. For most patients, symptoms of dryness of the mouth (xerostomia) dominate those of dry eyes. Patients frequently complain of a “cotton mouth” sensation and difficulty swallowing foods, especially dry foods like crackers, unless they are washed down with liquids. The persistent oral dryness causes most patients to carry water bottles or other liquid dispensers from which they sip constantly. A few patients have such severe xerostomia that they have difficulty speaking. Persistent xerostomia results often in rampant dental caries; caries at the gum line strongly suggest Sjögren syndrome. Some patients are most troubled by loss of taste and smell. Parotid enlargement, which may be chronic or relapsing, develops in one-third of patients. Desiccation may involve the nose, throat, larynx, bronchi, vagina, and skin.
Systemic manifestations include dysphagia, small vessel vasculitis, pleuritis, obstructive airways disease and interstitial lung disease (in the absence of smoking), neuropsychiatric dysfunction (most commonly peripheral neuropathies), and pancreatitis; they may be related to the associated diseases noted above. Renal tubular acidosis (type I, distal) occurs in 20% of patients. Chronic interstitial nephritis, which may result in impaired kidney function, may be seen.
Laboratory findings include mild anemia, leukopenia, and eosinophilia. Polyclonal hypergammaglobulinemia, rheumatoid factor positivity (70%), and antinuclear antibodies (95%) are all common findings. Antibodies against SS-A and SS-B (also called Ro and La, respectively) are often present in primary Sjögren syndrome and tend to correlate with the presence of extra-glandular manifestations (Table 20–8). Thyroid-associated autoimmunity is a common finding among patients with Sjögren syndrome.
Useful ocular diagnostic tests include the Schirmer test, which measures the quantity of tears secreted. Lip biopsy, a simple procedure, reveals characteristic lymphoid foci in accessory salivary glands. Biopsy of the parotid gland should be reserved for patients with atypical presentations such as unilateral gland enlargement that suggest a neoplastic process.
Isolated complaints of dry mouth are most commonly due to medication side effects. Chronic hepatic C can cause sicca symptoms and rheumatoid factor positivity. Minor salivary gland biopsies reveal lymphocytic infiltrates but not to the extent of Sjögren syndrome, and tests for anti-SS-A and anti-SS-B are negative. Involvement of the lacrimal or salivary glands, or both in sarcoidosis can mimic Sjögren syndrome; biopsies reveal noncaseating granulomas. Rarely, amyloid deposits in the lacrimal and salivary glands produce sicca symptoms. IgG4-related systemic disease (characterized by high serum IgG4 levels and infiltration of tissues with IgG4+ plasma cells) can result in lacrimal and salivary gland enlargement that mimics Sjögren syndrome.
Treatment of sicca symptoms is symptomatic and supportive. Artificial tears applied frequently will relieve ocular symptoms and avert further desiccation. Topical ocular 0.05% cyclosporine also improves ocular symptoms and signs of dryness. The mouth should be kept well lubricated. Sipping water frequently or using sugar-free gums and hard candies usually relieves dry mouth symptoms. Pilocarpine (5 mg orally four times daily) and the acetylcholine derivative cevimeline (30 mg orally three times daily) may improve xerostomia symptoms. Atropinic drugs and decongestants decrease salivary secretions and should be avoided. A program of oral hygiene, including fluoride treatment, is essential in order to preserve dentition. If there is an associated rheumatic disease, its systemic treatment is not altered by the presence of Sjögren syndrome.
Although Sjögren syndrome may compromise patients’ quality of life significantly, the disease is usually consistent with a normal life span. Poor prognoses are influenced mainly by the presence of systemic features associated with underlying disorders, the development in some patients of lymphocytic vasculitis, the occurrence of a painful peripheral neuropathy, and the complication (in a minority of patients) of lymphoma. Severe systemic inflammatory manifestations are treated with prednisone or various immunosuppressive medications. The patients (3–10% of the total Sjögren population) at greatest risk for developing lymphoma are those with severe exocrine dysfunction, marked parotid gland enlargement, splenomegaly, vasculitis, peripheral neuropathy, anemia, and mixed monoclonal cryoglobulinemia.
• Presence of systemic symptoms or signs.
• Symptoms or signs of ocular dryness not responsive to artificial tears.
Presence of severe systemic signs such as vasculitis unresponsive to outpatient management.
Ramos-Casals M et al. Primary Sjögren syndrome. BMJ. 2012 Jun 14;344:e3281. [PMID: 22700787]
Shiboski SC et al. American College of Rheumatology classification criteria for Sjögren’s syndrome: a data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken). 2012 Apr;64(4):475–87. [PMID: 22563590]
St Clair EW et al; Autoimmunity Centers of Excellence. Rituximab therapy for primary Sjögren’s syndrome: an open-label clinical trial and mechanistic analysis. Arthritis Rheum. 2013 Apr;65(4):1097–106. [PMID: 23334994]
ESSENTIALS OF DIAGNOSIS
Predominantly affects men (75% of patients); average age > 50 years.
Protean manifestations caused by lymphoplasmacytic infiltrates in any organ or tissue, especially the pancreas, lacrimal glands, biliary tract, and retroperitoneum.
Subacute onset; fever, constitutional symptoms rare.
Diagnosis rests on specific histopathological findings that include presence of IgG4-bearing plasma cells.
IgG4-related disease is a systemic disorder of unknown cause, first recognized in 2003, marked by highly characteristic fibroinflammatory changes that can affect virtually any organ. Elevations of serum IgG4 levels occur often but are not diagnostic. The disorder chiefly affects men over the age of 50 years.
IgG4-related disease has been compared with sarcoidosis: both disorders can affect any organ of the body, can be localized or generalized, demonstrate the same distinctive histopathology at all sites of involvement, produce protean manifestations depending on location and extent of involvement, and cause disease that ranges in severity from asymptomatic to organ- or life-threatening. The inflammatory infiltration in IgG4-related disease frequently produces tumefactive masses that can be seen on physical examination or on imaging. Some of the common presenting manifestations include enlargement of submandibular glands, proptosis from periorbital infiltration, retroperitoneal fibrosis, mediastinal fibrosis, inflammatory aortic aneurysm, and pancreatic mass with autoimmune pancreatitis. IgG4-related disease can also affect the thyroid, kidney, meninges, sinuses, lung, prostate, breast, and bone. Most symptomatic patients with IgG4-related disease present subacutely; fever and constitutional symptoms are usually absent. Nearly half of the patients with IgG4-related disease also have allergic disorders such as sinusitis or asthma.
The infiltrating lesions in IgG4-related disease often produce tumors or fibrotic changes that are evident on CT or MRI imaging. However, the cornerstone of diagnosis is the histopathology. The key pathological findings are a dense lymphoplasmacytic infiltrate rich in IgG4 plasma cells, storiform (matted and irregularly whorled) fibrosis, and obliterative phlebitis. Serum IgG4 levels are usually, but not invariably, elevated so this finding cannot be used as a diagnostic criterion.
IgG4-related disease can mimic many disorders including Sjögren syndrome (lacrimal gland enlargement), pancreatic cancer (pancreatic mass), and granulomatosis with polyangiitis (proptosis). It is now recognized that some cases of retroperitoneal fibrosis and mediastinal fibrosis are caused by IgG4-related disease. Lymphoma can mimic some of the histopathologic features of IgG4-related disease.
Patients who are asymptomatic and have no organ-threatening disease can be monitored carefully. Spontaneous resolution can occur. The optimal therapy for symptomatic patients has not been defined, but initial therapy is usually oral prednisone 0.6 mg/kg/d, tapered over weeks or months depending on response. Patients who do not respond to prednisone or respond only to sustained high doses of prednisone can be treated with rituximab, mycophenolate mofetil, or azathioprine. The degree of fibrosis in affected organs determines the patient’s responsiveness to treatment.
• Presence of systemic symptoms or signs.
• Symptoms or signs not responsive to prednisone.
• Presence of severe systemic signs unresponsive to outpatient management.
Stone JH et al. IgG4-related disease. N Engl J Med. 2012 Feb 9;366(6):539–51. [PMID: 22316447]
ESSENTIALS OF DIAGNOSIS
Associated with crush injuries to muscle, prolonged immobility, drug toxicities, hypothermia, and other causes.
Massive acute elevations of muscle enzymes that peak quickly and usually resolve within days once the inciting injury has been identified and removed.
Rhabdomyolysis is a syndrome of acute necrosis of skeletal muscle associated with myoglobinuria and markedly elevated creatine kinase levels. Acute tubular necrosis is a common complication of rhabdomyolysis and is due to the toxic effects of filtering excessive quantities of myoglobin in the setting of hypovolemia (See Acute Tubular Necrosis in Chapter 22). Many patients in whom rhabdomyolysis develops are volume-contracted and, therefore, oliguric renal failure is encountered routinely.
Rhabdomyolysis was first recognized as a complication of crush injuries to muscle among victims of the London Blitz during the World War II. Cocaine use and alcohol intoxication, particularly in the setting of prolonged immobility and exposure hypothermia, are leading causes of admissions due to rhabdomyolysis on the medical services of inner city hospitals. Use of statins is another important cause of rhabdomyolysis. The presence of compromised kidney and liver function, diabetes mellitus, and hypothyroidism as well as concomitant use of other medications increase the risk of rhabdomyolysis in patients taking statins. The cytochrome P450 liver enzymes metabolize all statins except for pravastatin and rosuvastatin. Drugs that block the action of cytochrome P450 include protease inhibitors, erythromycin, itraconazole, clarithromycin, diltiazem, and verapamil. Use of these drugs concomitantly with the statins (but not pravastatin or rosuvastatin) can increase the risk of development of rhabdomyolysis. The likelihood of rhabdomyolysis also increases when statins are used with niacin and fibric acids (gemfibrozil, clofibrate, and fenofibrate). Rhabdomyolysis is an uncommon complication of polymyositis, dermatomyositis, and the myopathy of hypothyroidism, despite the high levels of creatine kinase often seen in these conditions.
Often there is little evidence for muscle injury on clinical assessment of the patients with rhabdomyolysis—specifically, myalgias and weakness are usually absent. The first clue to muscle necrosis in such individuals may be a urinary dipstick testing positive for “blood” (actually myoglobin) in the absence of red cells in the sediment. This positive finding is due to myoglobinuria, which results in a false-positive reading for hemoglobin. Such an abnormality should prompt determination of the serum creatine kinase level, which invariably is elevated (usually markedly so). Other commonly encountered laboratory abnormalities in rhabdomyolysis include elevated serum levels of AST ALT and lactate dehydrogenase due to release of these enzymes from skeletal muscle.
Vigorous fluid resuscitation (4–6 L/d, with careful monitoring for volume overload) is indicated. Infusion of mannitol (100 mg/d) and urine alkalinization (to minimize precipitation of myoglobin within tubules) have been recommended as measures to reduce kidney injury, but definitive evidence for the efficacy of these measures is lacking. Myopathic complications of statins usually resolve within several weeks of discontinuing the drug.
Landau ME et al. Exertional rhabdomyolysis: a clinical review with a focus on genetic influences. J Clin Neuromuscul Dis. 2012 Mar;13(3):122–36. [PMID: 22538307]
Scharman EJ et al. Prevention of kidney injury following rhabdomyolysis: a systematic review. Ann Pharmacother. 2013 Jan;47(1):90–105. [PMID: 23324509]
“Vasculitis” is a heterogeneous group of disorders characterized by inflammation within the walls of affected blood vessels. The major forms of primary systemic vasculitis are listed in Table 20–12. The first consideration in classifying cases of vasculitis is the size of the major vessels involved: large, medium, or small. The presence of the clinical signs and symptoms shown in Table 20–13 help distinguish among these three groups. After determining the size of the major vessels involved, other issues that contribute to the classification include the following:
Table 20–12. Classification scheme of primary vasculitides according to size of predominant blood vessels involved.
Table 20–13. Typical clinical manifestations of large-, medium-, and small-vessel involvement by vasculitis.
• Does the process involve arteries, veins, or both?
• What are the patient’s demographic characteristics (age, gender, ethnicity, smoking status)?
• Which organs are involved?
• Is there hypocomplementemia or other evidence of immune complex deposition?
• Is there granulomatous inflammation on tissue biopsy?
• Are antineutrophil cytoplasmic antibodies (ANCA) present?
In addition to the disorders considered to be primary vasculitides, there are also multiple forms of vasculitis that are associated with other known underlying conditions. These “secondary” forms of vasculitis occur in the setting of chronic infections (eg, hepatitis B or C, subacute bacterial endocarditis), connective tissue disorders, inflammatory bowel disease, malignancies, and reactions to medications. Only the major primary forms of vasculitis are discussed here.
Jennette JC et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013 Jan;65(1):1–11. [PMID: 23045170]
ESSENTIALS OF DIAGNOSIS
Age over 50 years.
Giant cell (temporal) arteritis is characterized by headache, jaw claudication, polymyalgia rheumatica, visual abnormalities, and a markedly elevated ESR.
The hallmark of polymyalgia rheumatica is pain and stiffness in shoulders and hips lasting for several weeks without other explanation.
Polymyalgia rheumatica and giant cell arteritis probably represent a spectrum of one disease: Both affect the same population (patients over the age of 50), show preference for the same HLA haplotypes, and show similar patterns of cytokines in blood and arteries. Polymyalgia rheumatica and giant cell arteritis also frequently coexist. The important differences between the two conditions are that polymyalgia rheumatica alone does not cause blindness and responds to low-dose (10–20 mg/d orally) prednisone therapy, whereas giant cell arteritis can cause blindness and large artery complications and requires high-dose (40–60 mg/d) prednisone.
Polymyalgia rheumatica is a clinical diagnosis based on pain and stiffness of the shoulder and pelvic girdle areas, frequently in association with fever, malaise, and weight loss. In approximately two-thirds of cases, polymyalgia occurs in the absence of giant cell arteritis. Because of the stiffness and pain in the shoulders, hips, and lower back, patients have trouble combing their hair, putting on a coat, or rising from a chair. In contrast to polymyositis and polyarteritis nodosa, polymyalgia rheumatica does not cause muscular weakness either through primary muscle inflammation or secondary to nerve infarction. A few patients have joint swelling, particularly of the knees, wrists, and sternoclavicular joints.
Giant cell arteritis is a systemic panarteritis affecting medium-sized and large vessels in patients over the age of 50. The incidence of this disease increases with each decade of life. The mean age at onset is approximately 79 years. Giant cell arteritis is also called temporal arteritis because that artery is frequently involved, as are other extracranial branches of the carotid artery. About 50% of patients with giant cell arteritis also have polymyalgia rheumatica. The classic symptoms suggesting that a patient has arteritis are headache, scalp tenderness, visual symptoms (particularly amaurosis fugax or diplopia), jaw claudication, or throat pain. Of these symptoms, jaw claudication has the highest positive predictive value. The temporal artery is usually normal on physical examination but may be nodular, enlarged, tender, or pulseless. Blindness usually results from the syndrome of anterior ischemic optic neuropathy, caused by occlusive arteritis of the posterior ciliary branch of the ophthalmic artery. The ischemic optic neuropathy of giant cell arteritis may produce no funduscopic findings for the first 24–48 hours after the onset of blindness.
Asymmetry of pulses in the arms, a murmur of aortic regurgitation, or bruits heard near the clavicle resulting from subclavian artery stenoses identify patients in whom giant cell arteritis has affected the aorta or its major branches. Clinically evident large vessel involvement—characterized chiefly by aneurysm of the thoracic aorta or stenosis of the subclavian, vertebral, carotid, and basilar arteries—occurs in approximately 25% of patients with giant cell arteritis, sometimes years after the diagnosis. Subclinical large artery disease is the rule: positron emission tomography scans reveal inflammation in the aorta and its major branches in nearly 85% of untreated patients. Forty percent of patients with giant cell arteritis have nonclassic symptoms at presentation, chiefly respiratory tract problems (most frequently dry cough), mononeuritis multiplex (most frequently with painful paralysis of a shoulder), or fever of unknown origin. Giant cell arteritis accounts for 15% of all cases of fever of unknown origin in patients over the age of 65. The fever can be as high as 40°C and is frequently associated with rigors and sweats. In contrast to patients with infection, patients with giant cell arteritis and fever usually have normal white blood cell counts (before prednisone is started). Thus, in an older patient with fever of unknown origin, marked elevations of acute phase reactants, and a normal white blood count, giant cell arteritis must be considered even in the absence of specific features such as headache or jaw claudication. In some cases, instead of having the well-known symptom of jaw claudication, patients complain of vague pain affecting other locations, including the tongue, nose, or ears. Indeed, unexplained head or neck pain in an older patient may signal the presence of giant cell arteritis.
1. Polymyalgia rheumatica—Anemia and elevated acute phase reactants (often markedly elevated ESRs, for example) are present in the most cases, but cases of polymyalgia rheumatica occurring with normal acute phase reactants are well documented.
2. Giant cell arteritis—Nearly 90% of patients with giant cell arteritis have ESRs > 50 mm/h. The ESR in this disorder is often > 100 mm/h, but cases in which the ESR is lower or even normal do occur. In one series, 5% of patients with biopsy-proven giant cell arteritis had ESRs < 40 mm/h. Although the C-reactive protein is slightly more sensitive, patients with biopsy-proven giant cell arteritis with normal C-reactive proteins have also been described. Most patients also have a mild normochromic, normocytic anemia and thrombocytosis. The alkaline phosphatase (liver source) is elevated in 20% of patients with giant cell arteritis.
The differential diagnosis of malaise, anemia, and striking acute phase reactant elevations includes rheumatic diseases (such as rheumatoid arthritis, other systemic vasculitides, multiple myeloma, and other malignant disorders) and chronic infections (such as bacterial endocarditis and osteomyelitis).
Patients with isolated polymyalgia rheumatica (ie, those not having “above the neck” symptoms of headache, jaw claudication, scalp tenderness, or visual symptoms) are treated with prednisone, 10–20 mg/d orally. If the patient does not experience a dramatic improvement within 72 hours, the diagnosis should be revisited. Usually after 2–4 weeks of treatment, slow tapering of the prednisone can be attempted. Most patients require some dose of prednisone for a minimum of approximately 1 year; 6 months is too short in most cases. Disease flares are common (50% or more) as prednisone is tapered. The addition of weekly methotrexate may increase the chance of successfully tapering prednisone in some patients.
The urgency of early diagnosis and treatment in giant cell arteritis relates to the prevention of blindness. Once blindness develops, it is usually permanent. Therefore, when a patient has symptoms and findings suggestive of temporal arteritis, therapy with prednisone (60 mg/d orally) should be initiated immediately and a temporal artery biopsy performed promptly. For patients who seek medical attention for visual loss, intravenous pulse methylprednisolone (eg, 1 g daily for 3 days) has been advocated; unfortunately, few patients recover vision no matter what the initial treatment. One study—too small and too preliminary to change the standard therapy recommendations mentioned above—suggested that initiating treatment with intravenous pulse methylprednisolone may increase the chance that a patient with giant cell arteritis will achieve remission and be able to taper off of prednisone. Retrospective studies suggest that low-dose aspirin (~81 mg/d orally) may reduce the chance of visual loss or stroke in patients with giant cell arteritis and should be added to prednisone in the initial treatment. Although it is prudent to obtain a temporal artery biopsy as soon as possible after instituting treatment, diagnostic findings of giant cell arteritis may still be present 2 weeks (or even considerably longer) after starting corticosteroids. Typically, a positive biopsy shows inflammatory infiltrate in the media and adventitia with lymphocytes, histiocytes, plasma cells, and giant cells. An adequate biopsy specimen is essential (at least 2 cm in length is ideal), because the disease may be segmental. Unilateral temporal artery biopsies are positive in approximately 80–85% of patients, but bilateral biopsies add incrementally to the yield (10–15% in some studies, less in others). Ultrasonography can detect abnormalities in inflamed temporal arteries, but it has not displaced temporal artery biopsy as the gold standard for diagnosis in most cases because results are highly operator dependent. Temporal artery biopsy is abnormal in only 50% of patients with large artery disease (eg, arm claudication and unequal upper extremity blood pressures). In these patients, magnetic resonance angiography or CT angiography will establish the diagnosis by demonstrating long stretches of narrowing of the subclavian and axillary arteries. Prednisone should be continued in a dosage of 60 mg/d orally for about 1 month before tapering. When only the symptoms of polymyalgia rheumatica are present, temporal artery biopsy is not necessary.
After 1 month of high-dose prednisone, almost all patients will have a normal ESR. When tapering and adjusting the dosage of prednisone, the ESR (or C-reactive protein) is a useful but not absolute guide to disease activity. A common error is treating the ESR rather than the patient. The ESR often rises slightly as the prednisone is tapered, even as the disease remains quiescent. Because elderly individuals often have baseline ESRs that are above the normal range, mild ESR elevations should not be an occasion for renewed treatment with prednisone in patients who are asymptomatic. Unfortunately, no highly effective prednisone-sparing therapy has been identified. Methotrexate was modestly effective in one double-blind, placebo-controlled treatment trial but ineffective in another. Anti-TNF therapies do not work in giant cell arteritis. Thoracic aortic aneurysms occur 17 times more frequently in patients with giant cell arteritis than in normal individuals and can result in aortic regurgitation, dissection, or rupture. The aneurysms can develop at any time but typically occur 7 years after the diagnosis of giant cell arteritis is made.
Ghinoi A et al. Large-vessel involvement in recent-onset giant cell arteritis: a case-control colour-Doppler sonography study. Rheumatology (Oxford). 2012 Apr;51(4):730–4. [PMID: 22179725]
Kermani TA et al. Polymyalgia rheumatica. Lancet. 2013 Jan 5;381(9860):63–72. [PMID: 23051717]
Scheurer RA et al. Treatment of vision loss in giant cell arteritis. Curr Treat Options Neurol. 2012 Feb;14(1):84–92. [PMID: 22037998]
Takayasu arteritis is a granulomatous vasculitis of the aorta and its major branches. Rare in North American but more prevalent in the Far East, it primarily affects women and typically has its onset in early adulthood. Takayasu arteritis can present with nonspecific constitutional symptoms of malaise, fever, and weight loss or with manifestations of vascular damage (diminished pulses, unequal blood pressures in the arms, bruits over carotids and subclavian arteries, limb claudication, and hypertension). There are no specific laboratory abnormalities; the ESR and the C-reactive protein level are elevated in most cases. The diagnosis is established by imaging studies, usually MRI, which can detect inflammatory thickening of the walls of affected vessels, or CT angiography, which can provide images of the stenoses, occlusions, and dilations characteristic of arteritis. Corticosteroids (eg, oral prednisone 1 mg/kg for 1 month, followed by a taper over several months to 10 mg daily) are the mainstays of treatment. The addition of methotrexate or mycophenolate mofetil to the prednisone may be more effective than the prednisone alone. Takayasu arteritis has a chronic relapsing and remitting course that requires ongoing monitoring and adjustment of therapy.
Clifford A et al. Recent advances in the medical management of Takayasu arteritis: an update on use of biological therapies. Curr Opin Rheumatol. 2014 Jan;26(1):7–15. [PMID: 24225487]
ESSENTIALS OF DIAGNOSIS
Medium-sized arteries are always affected; smaller arterioles are sometimes involved; lung is spared but kidney often affected, causing renin-mediated hypertension.
Clinical findings depend on the arteries involved.
Common features include fever, abdominal pain, extremity pain, livedo reticularis, mononeuritis multiplex, anemia, and elevated acute phase reactants (ESR or C-reactive protein or both).
Associated with hepatitis B (10% of cases).
Polyarteritis nodosa, described in 1866, is acknowledged widely as the first form of vasculitis reported in the medical literature. For many years, all forms of inflammatory vascular disease were termed “polyarteritis nodosa.” In recent decades, numerous subtypes of vasculitis have been recognized, greatly narrowing the spectrum of vasculitis called polyarteritis nodosa. Currently, the term is reserved for necrotizing arteritis of medium-sized vessels that has a predilection for involving the skin, peripheral nerves, mesenteric vessels (including renal arteries), heart, and brain, but polyarteritis nodosa can actually involve almost any organ. Polyarteritis nodosa is relatively rare, with a prevalence of about 30 per 1 million people. Approximately 10% of cases of polyarteritis nodosa are caused by hepatitis B. Most cases of hepatitis B–associated disease occur within 6 months of hepatitis B infection.
The clinical onset is usually insidious, with fever, malaise, weight loss, and other symptoms developing over weeks to months. Pain in the extremities is often a prominent early feature caused by arthralgia, myalgia (particularly affecting the calves), or neuropathy. The combination of mononeuritis multiplex (with the most common finding being foot-drop) and features of a systemic illness is one of the earliest specific clues to the presence of an underlying vasculitis. Polyarteritis nodosa is among the forms of vasculitis most commonly associated with vasculitic neuropathy.
In polyarteritis nodosa, the typical skin findings—livedo reticularis, subcutaneous nodules, and skin ulcers—reflect the involvement of deeper, medium-sized blood vessels. Digital gangrene is not an unusual occurrence. The most common cutaneous presentation is lower extremity ulcerations, usually occurring near the malleoli. Involvement of the renal arteries leads to a renin-mediated hypertension (much less characteristic of vasculitides involving smaller blood vessels). For unclear reasons, classic polyarteritis nodosa seldom (if ever) involves the lung, with the occasional exception of the bronchial arteries.
Abdominal pain—particularly diffuse periumbilical pain precipitated by eating—is common but often difficult to attribute to mesenteric vasculitis in the early stages. Nausea and vomiting are common symptoms. Infarction compromises the function of major viscera and may lead to acalculous cholecystitis or appendicitis. Some patients present dramatically with an acute abdomen caused by mesenteric vasculitis and gut perforation or with hypotension resulting from rupture of a microaneurysm in the liver, kidney, or bowel.
Subclinical cardiac involvement is common in polyarteritis nodosa, and overt cardiac dysfunction occasionally occurs (eg, myocardial infarction secondary to coronary vasculitis, or myocarditis).
Most patients with polyarteritis nodosa have a slight anemia, and leukocytosis is common. Acute phase reactants are often (but not always) strikingly elevated. A major challenge in making the diagnosis of polyarteritis nodosa, however, is the absence of a disease-specific serologic test (eg, an autoantibody). Patients with classic polyarteritis nodosa are ANCA-negative and may have low titers of rheumatoid factor or antinuclear antibodies, both of which are nonspecific findings. In patients with polyarteritis nodosa, appropriate serologic tests for active hepatitis B infection must be performed.
The diagnosis of polyarteritis nodosa requires confirmation with either a tissue biopsy or an angiogram. Biopsies of symptomatic sites such as skin (from the edge of an ulcer or the center of a nodule), nerve, or muscle have sensitivities of approximately 70%. The least invasive tests should usually be obtained first, but biopsy of an involved organ is essential. If performed by experienced clinicians, tissue biopsies normally have high benefit-risk ratios because of the importance of establishing the diagnosis. Patients in whom polyarteritis nodosa is suspected—eg, on the basis of mesenteric ischemia or new-onset hypertension occurring in the setting of a systemic illness—may be diagnosed by the angiographic finding of aneurysmal dilations in the renal, mesenteric, or hepatic arteries. Angiography must be performed cautiously in patients with baseline renal dysfunction.
For polyarteritis nodosa, corticosteroids in high doses (up to 60 mg of oral prednisone daily) may control fever and constitutional symptoms and heal vascular lesions. Pulse methylprednisolone (eg, 1 g intravenously daily for 3 days) may be necessary for patients who are critically ill at presentation. Immunosuppressive agents, especially cyclophosphamide, lower the risk of disease-related death and morbidity among patients who have severe disease. For patients with polyarteritis nodosa associated with hepatitis B, the preferred treatment regimen is a short course of prednisone accompanied by anti-HBV therapy and plasmapheresis (three times a week for up to 6 weeks).
Without treatment, the 5-year survival rate in these disorders is poor—on the order of 10%. With appropriate therapy, remissions are possible in many cases and the 5-year survival rate has improved to 60–90%. Poor prognostic factors are chronic kidney disease with serum creatinine > 1.6 mg/dL (> 141 mcmol/L), proteinuria > 1 g/d, gastrointestinal ischemia, central nervous system disease, and cardiac involvement. In the absence of any of these five factors, 5-year survival is nearly 90%. Survival at 5 years drops to 75% with one poor prognostic factor present and to about 50% with two or more factors. Substantial morbidity and even death may result from adverse effects of cyclophosphamide and corticosteroids. Consequently, these therapies require careful monitoring and expert management. In contrast to many other forms of systemic vasculitis, disease relapses in polyarteritis following the successful induction of remission are the exception rather than the rule, occurring in only about 20% of cases.
de Menthon M et al. Treating polyarteritis nodosa: current state of the art. Clin Exp Rheumatol. 2011 Jan–Feb;29(1 Suppl 64):S110–6. [PMID: 21586205]
Diamantopoulos AP et al. Polyarteritis nodosa. J Rheumatol. 2013 Jan;40(1):87–8. [PMID: 23280163]
ESSENTIALS OF DIAGNOSIS
Classic triad of upper and lower respiratory tract disease and glomerulonephritis.
Suspect if mild respiratory symptoms (eg, nasal congestion, sinusitis) are refractory to usual treatment.
Pathology defined by the triad of small vessel vasculitis, granulomatous inflammation, and necrosis.
ANCAs (90% of patients), usually directed against proteinase-3 (less commonly against myeloperoxidase present in severe, active disease).
Kidney disease often rapidly progressive without treatment.
Granulomatosis with polyangiitis, which has an estimated incidence of approximately 12 cases per million individuals per year, is the prototype of diseases associated with antineutrophil cytoplasmic antibodies (ANCA). (Other “ANCA-associated vasculitides” include microscopic polyangiitis and the Churg-Strauss syndrome.) Granulomatosis with polyangiitis is characterized in its full expression by vasculitis of small arteries, arterioles, and capillaries, necrotizing granulomatous lesions of both upper and lower respiratory tract, glomerulonephritis, and other organ manifestations. Without treatment, generalized disease is invariably fatal, with most patients surviving < 1 year after diagnosis. It occurs most commonly in the fourth and fifth decades of life and affects men and women with equal frequency.
The disorder usually develops over 4–12 months. Upper respiratory tract symptoms develop in 90% of patients and lower respiratory tract symptoms develop in 60% of patients; some patients may have both upper and lower respiratory tract symptoms. Upper respiratory tract symptoms can include nasal congestion, sinusitis, otitis media, mastoiditis, inflammation of the gums, or stridor due to subglottic stenosis. Since many of these symptoms are common, the underlying disease is not often suspected until the patient develops systemic symptoms or the original problem is refractory to treatment. The lungs are affected initially in 40% and eventually in 80%, with symptoms including cough, dyspnea, and hemoptysis. Other early symptoms can include a migratory oligoarthritis with a predilection for large joints; a variety of symptoms related to ocular disease (unilateral proptosis from orbital pseudotumor; red eye from scleritis [Figure 20–6], episcleritis, anterior uveitis, or peripheral ulcerative keratitis); purpura or other skin lesions; and dysesthesia due to neuropathy. Renal involvement, which develops in three-fourths of the cases, may be subclinical until kidney disease is advanced. Fever, malaise, and weight loss are common.
Figure 20–6. Scleritis in a patient with granulomatosis with polyangiitis (formerly Wegener granulomatosis). (From Everett Allen, MD; reproduced with permission from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)
Physical examination can be remarkable for congestion, crusting, ulceration, bleeding, and even perforation of the nasal septum. Destruction of the nasal cartilage with “saddle nose” deformity occurs late. Otitis media, proptosis, scleritis, episcleritis, and conjunctivitis are other common findings. Newly acquired hypertension, a frequent feature of polyarteritis nodosa, is rare in granulomatosis with polyangiitis. Venous thrombotic events (eg, deep venous thrombosis and pulmonary embolism) are a common occurrence in granulomatosis with polyangiitis, at least in part because of the tendency of the disease to involve veins as well as arteries. Although limited forms of granulomatosis with polyangiitis have been described in which the kidney is spared initially, kidney disease will develop in the majority of untreated patients.
1. Serum tests and urinalysis—Most patients have slight anemia, mild leukocytosis, and elevated acute phase reactants. If there is renal involvement, there is proteinuria and the urinary sediment contains red cells, with or without white cells, and often has red cell casts.
Serum tests for ANCA help in the diagnosis of granulomatosis with polyangiitis and related forms of vasculitis (Table 20–8). Several different types of ANCA are recognized, but the two subtypes relevant to systemic vasculitis are those directed against proteinase-3 (PR3) and myeloperoxidase (MPO). Antibodies to these two antigens are termed “PR3-ANCA” and “MPO-ANCA,” respectively. The cytoplasmic pattern of immunofluorescence (c-ANCA) caused by PR3-ANCA has a high specificity (> 90%) for either granulomatosis with polyangiitis or a closely related disease, microscopic polyangiitis (or, less commonly, the Churg-Strauss syndrome). In the setting of active disease, particularly cases in which the disease is severe and generalized to multiple organ systems, the sensitivity of PR3-ANCA is > 95%. A substantial percentage of patients with “limited” granulomatosis with polyangiitis—disease that does not pose an immediate threat to life and is often confined to the respiratory tract—are ANCA-negative. Although ANCA testing may be very helpful when used properly, it does not eliminate the need in most cases for confirmation of the diagnosis by tissue biopsy. Furthermore, ANCA levels correlate erratically with disease activity, and changes in titer should not dictate changes in therapy in the absence of supporting clinical data. The perinuclear (p-ANCA) pattern, caused by MPO-ANCA, is more likely to occur in microscopic polyangiitis or Churg-Strauss but may also be found in granulomatosis with polyangiitis. Approximately 10–25% of patients with classic granulomatosis with polyangiitis have MPO-ANCA. All positive immunofluorescence assays for ANCA should be confirmed by enzyme immunoassays for the specific autoantibodies directed against PR3 or MPO.
2. Histologic findings—Histologic features of granulomatosis with polyangiitis include vasculitis, granulomatous inflammation, geographic necrosis, and acute and chronic inflammation. The full range of pathologic changes is usually evident only on thoracoscopic lung biopsy. Granulomas, observed only rarely in renal biopsy specimens, are found much more commonly on lung biopsy specimens. Nasal biopsies often do not show vasculitis but may show chronic inflammation and other changes which, interpreted by an experienced pathologist, can serve as convincing evidence of the diagnosis. Renal biopsy discloses a segmental necrotizing glomerulonephritis with multiple crescents; this is characteristic but not diagnostic. Pathologists characterize the renal lesion of granulomatosis with polyangiitis (and other forms of “ANCA-associated vasculitis”) as a pauci-immune glomerulonephritis because of the relative absence (compared with immune complex–mediated disorders) of immunoreactants—IgG, IgM, IgA, and complement proteins—within glomeruli.
Chest CT is more sensitive than chest radiography; lesions include infiltrates, nodules, masses, and cavities. Pleural effusions are uncommon. Often the radiographs prompt concern about lung cancer. Hilar adenopathy is unusual in granulomatosis with polyangiitis; if present, sarcoidosis, tumor, or infection is more likely. Other common radiographic abnormalities include extensive sinusitis and even bony sinus erosions.
In most patients with granulomatosis with polyangiitis, refractory sinusitis or otitis media is initially suspected. When upper respiratory tract inflammation persists and is accompanied by additional systemic inflammatory signs (eg, red eye from scleritis, joint pain, and swelling), the diagnosis of granulomatosis with polyangiitis should be considered. Rheumatoid arthritis will wrongly be suspected in a substantial minority of patients who chiefly complain of joint pain. Arriving at the correct diagnosis is aided by awareness that rheumatoid arthritis typically involves small joints of the hand, whereas granulomatosis with polyangiitis favors large joints, such as the hip, knee, elbow, and shoulder. Lung cancer may be the first diagnostic consideration for some middle-aged patients in whom cough, hemoptysis, and lung masses are presenting symptoms and signs; typically, evidence of glomerulonephritis, a positive ANCA or, ultimately, the lung biopsy findings will point to the proper diagnosis. Granulomatosis with polyangiitis shares with SLE, anti–glomerular basement membrane disease, and microscopic polyangiitis the ability to cause an acute pulmonary-renal syndrome. Approximately 10–25% of patients with classic granulomatosis with polyangiitis have MPO-ANCA. Owing to involvement of the same types of blood vessels, similar patterns of organ involvement, and the possibility of failing to identify granulomatous pathology on tissue biopsies because of sampling error, granulomatosis with polyangiitis is often difficult to differentiate from microscopic polyangiitis. The crucial distinctions between the two disorders are the tendencies for granulomatosis with polyangiitis to involve the upper respiratory tract (including the ears) and to cause granulomatous inflammation. Cocaine use can cause destruction of midline tissues—the nose and palate—that mimics granulomatosis with polyangiitis. Indeed, distinguishing between the two conditions can be challenging because patients with cocaine-mediated midline destructive disease frequently have positive tests for PR-3-ANCA and lesional biopsies that demonstrate vasculitis. In contrast to granulomatosis with polyangiitis, cocaine-mediated midline destructive disease does not cause pulmonary or renal disease.
Early treatment is crucial in preventing the devastating end-organ complications of this disease, and often in preserving life. While granulomatosis with polyangiitis may involve the sinuses or lung for months, once proteinuria or hematuria develops, progression to advanced chronic kidney disease can be rapid (over several weeks). For patients with severe disease, there are now two treatment options for inducing remission: cyclophosphamide plus corticosteroids or rituximab plus corticosteroids. For several decades, the combination of cyclophosphamide and prednisone had been the standard of care for patients with severe disease. Remissions can be induced in more than 90% of patients treated with prednisone (1 mg/kg daily) plus cyclophosphamide (2 mg/kg/d orally with adjustments required for acute or chronic kidney disease and age >70 years old). Cyclophosphamide is best given daily by mouth; intermittent high-dose intravenous cyclophosphamide is less effective. Whenever cyclophosphamide is used, Pneumocystis jirovecii prophylaxis with either single-strength oral trimethoprim-sulfamethoxazole or dapsone 100 mg/d is essential. The current approach to remission induction is to use cyclophosphamide for 3–6 months, and then switch the patient to a regimen more likely to be tolerated well. Unfortunately, disease relapses occur in a substantial proportion of those patients who achieve remission. In patients with remission induced by 3–6 months of cyclophosphamide and corticosteroids, azathioprine (up to 2 mg/kg/d orally) has been shown to be as effective as cyclophosphamide in maintaining disease remissions (at least for up to 12–15 months). Before the institution of azathioprine, patients should be tested (through a commercially available blood test) for deficiencies in the level of thiopurine methyltransferase, an enzyme essential to the metabolism of azathioprine. Another option for remission maintenance is methotrexate, 20–25 mg/wk (administered either orally or intramuscularly). The other option for treating severe granulomatosis with polyangiitis is rituximab, a B-cell depleting antibody. The FDA has approved rituximab in combination with corticosteroids for the treatment of granulomatosis with polyangiitis and microscopic polyangiitis. Studies demonstrate that rituximab is not less effective for remission-induction in these conditions. Indeed, post-hoc analysis of one clinical trial demonstrates that rituximab is more effective than cyclophosphamide for treating relapses of granulomatosis with polyangiitis and microscopic polyangiitis. Both rituximab and cyclophosphamide increase the risk of developing life-threatening opportunistic infections (including progressive multifocal leukoencephalopathy [PML]). Owing to rituximab’s high cost, its unknown long-term health effects, and its undefined use for maintaining remission, its precise role in treating ANCA-associated vasculitis is being studied. Because of its superior side-effect profile, methotrexate is viewed as an appropriate substitute for cyclophosphamide or rituximab for initial treatment in patients who do not have significant renal dysfunction (of any cause) or immediately life-threatening disease. Treatment with TNF inhibitors, particularly etanercept, is not effective.
Lyons PA et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012 Jul 19;367(3):214–23. [PMID: 22808956]
Roubaud-Baudron C et al; French Vasculitis Study Group. Rituximab maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis. J Rheumatol. 2012 Jan;39(1):125–30. [PMID: 22089465]
ESSENTIALS OF DIAGNOSIS
Necrotizing vasculitis of small- and medium-sized arteries and veins.
Most common cause of pulmonary-renal syndrome: diffuse alveolar hemorrhage and glomerulo-nephritis.
Associated with ANCA in 75% of cases, usually anti-myeloperoxidase antibodies (MPO-ANCA) that cause a p-ANCA pattern on immunofluorescence testing. ANCA directed against proteinase-3 (PR3-ANCA) can also be observed.
Microscopic polyangiitis is a pauci-immune nongranulomatous necrotizing vasculitis that (1) affects small blood vessels (capillaries, venules, or arterioles), (2) often causes glomerulonephritis and pulmonary capillaritis, and (3) is often associated with ANCA on immunofluorescence testing (directed against MPO, a constituent of neutrophil granules). Because microscopic polyangiitis may involve medium-sized as well as small blood vessels and because it tends to affect capillaries within the lungs and kidneys, its spectrum overlaps those of both polyarteritis nodosa and granulomatosis with polyangiitis.
In rare instances, medications, particularly propylthiouracil, hydralazine, allopurinol, penicillamine, minocycline, and sulfasalazine, induce a systemic vasculitis associated with high titers of MPO-ANCA and features of microscopic polyangiitis.
A wide variety of findings suggesting vasculitis of small blood vessels may develop in microscopic polyangiitis. These include “palpable” (or “raised”) purpura and other signs of cutaneous vasculitis (ulcers, splinter hemorrhages, vesiculobullous lesions).
Microscopic polyangiitis is the most common cause of pulmonary-renal syndromes, being several times more common than anti–glomerular basement membrane disease. Interstitial lung fibrosis that mimics usual interstitial pneumonitis is the presenting condition. Pulmonary hemorrhage may occur. The pathologic findings in the lung are typically those of capillaritis.
Vasculitic neuropathy (mononeuritis multiplex) is also common in microscopic polyangiitis.
As noted, three-fourths of patients with microscopic polyangiitis are ANCA-positive. Elevated acute phase reactants are also typical of active disease. Microscopic hematuria, proteinuria, and red blood cell casts in the urine may occur. The renal lesion is a segmental, necrotizing glomerulonephritis, often with localized intravascular coagulation and the observation of intraglomerular thrombi upon renal biopsy.
Distinguishing this disease from granulomatosis with polyangiitis may be challenging in some cases. Microscopic polyangiitis is not associated with the chronic destructive upper respiratory tract disease often found in granulomatosis with polyangiitis. Moreover, as noted, a critical difference between the two diseases is the absence of granulomatous inflammation in microscopic polyangiitis. Because their treatments may differ, microscopic polyangiitis must also be differentiated from polyarteritis nodosa.
Microscopic polyangiitis is usually treated in the same way as granulomatosis with polyangiitis: patients with severe disease, typically involving pulmonary hemorrhage and glomerulonephritis, require urgent induction treatment with corticosteroids and either cyclophosphamide or rituximab. If cyclophosphamide is chosen, it may be administered either in an oral daily regimen or via intermittent (usually monthly) intravenous pulses; following induction of remission, cyclophosphamide may be replaced with azathioprine. In cases of drug-induced MPO-ANCA–associated vasculitis, the offending medication should be discontinued; significant organ involvement (eg, pulmonary hemorrhage, glomerulonephritis) requires immunosuppressive therapy.
The key to effecting good outcomes is early diagnosis. Compared with patients who have granulomatosis with polyangiitis, those who have microscopic polyangiitis are more likely to have significant fibrosis on renal biopsy because of later diagnosis. The likelihood of disease recurrence following remission in microscopic polyangiitis is about 33%.
Corral-Gudino L et al. Overall survival, renal survival and relapse in patients with microscopic polyangiitis: a systematic review of current evidence. Rheumatology (Oxford). 2011 Aug;50(8):1414–23. [PMID: 21406467]
Suppiah R et al. Peripheral neuropathy in ANCA-associated vasculitis: outcomes from the European Vasculitis Study Group trials. Rheumatology (Oxford). 2011 Dec;50(12):2214–22. [PMID: 21890618]
Walsh M et al. Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2012 Feb;64(2):542–8. [PMID: 21953279]
Exposure to levamisole, a prevalent adulterant of illicit cocaine in North America, can induce a distinctive clinical syndrome of retiform purpura and cutaneous necrosis affecting the extremities, ears, and skin overlying the zygomatic arch. Biopsies reveal widespread thrombosis of small cutaneous vessels with varying degrees of vasculitis. The syndrome is associated with the lupus anticoagulant, IgM antibodies to cardiolipin, and very high titers of p-ANCAs (due to autoantibodies to elastase, lactoferrin, cathepsin-G, and other neutrophil components rather than to myeloperoxidase alone). There is no consensus on treatment of levamisole-induced purpura, but early lesions can resolve with abstinence. Use of levamisole-adulterated cocaine also has been linked to neutropenia, agranulocytosis, and pauci-immune glomerulonephritis.
Graf J et al. Purpura, cutaneous necrosis, and anti-neutrophil cytoplasmic antibodies associated with levamisole-adulterated cocaine. Arthritis Rheum. 2011 Dec;63(12):3998–4001. [PMID: 22127712]
Cryoglobulinemia can be associated with an immune-complex mediated, small-vessel vasculitis. Chronic infection with hepatitis C is the most common underlying condition; cryoglobulinemic vasculitis also can occur in the setting of other chronic infections, such as subacute bacterial endocarditis and osteomyelitis, and with connective tissues diseases, especially Sjögren syndrome. The cryoglobulins associated with vasculitis are cold-precipitable immune complexes consisting of rheumatoid factor and IgG (rheumatoid factor is an autoantibody to the constant region of IgG). The rheumatoid factor component can be monoclonal (type II cryoglobulins) or polyclonal (type III cryoglobulins). (Type I cryoglobulins are cryoprecipitable monoclonal proteins that lack rheumatoid factor activity; these cause cold-induced hyperviscosity syndromes, not vasculitis, and are associated with lymphoproliferative disease.)
Cryoglobulinemic vasculitis typically manifests as recurrent palpable purpura and peripheral neuropathy. A proliferative glomerulonephritis can develop and can manifest as rapidly progressive glomerulonephritis. Abnormal liver function tests, abdominal pain, and pulmonary disease may also occur. The diagnosis is based on a compatible clinical picture and a positive serum test for cryoglobulins. The presence of a disproportionately low C4 level can be a diagnostic clue to the presence of cryoglobulinemia.
Treatment depends on the cause and the severity of the vasculitis. Asymptomatic cryoglobulinemia is common in hepatitis C–infected individuals and does not in itself warrant treatment. Patients with mild to moderate vasculitis associated with hepatitis C are treated with viral suppression with pegylated forms of interferon-alpha and ribavirin; the protease inhibitor, telaprevir, should be added to provide triple therapy for patients with genotype 1 hepatitis C infection. Since interferon can augment the immune response, it is not used in patients with severe, life-threatening vasculitis. Rather, these patients are usually treated initially with immune suppression with plasmapheresis, corticosteroids, and cyclophosphamide. B cell depletion using rituximab appears to be a promising alternative avenue of immunosuppressive therapy. Once improved, patients with severe vasculitis from hepatitis C can then be given antiviral therapy.
Dammacco F et al. Therapy for hepatitis C virus-related cryoglobulinemic vasculitis. N Engl J Med. 2013 Sep 12;369(11):1035–45. [PMID: 24024840]
De Vita S et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum. 2012 Mar;64(3):843–53. [PMID: 22147661]
Henoch-Schönlein purpura, the most common systemic vasculitis in children, occurs in adults as well. Typical features are palpable purpura (Figure 20–7), arthritis, and hematuria. Abdominal pain occurs less frequently in adults than in children. Pathologic features include leukocytoclastic vasculitis with IgA deposition. The cause is not known.
Figure 20–7. Palpable purpura in a woman with leukocytoclastic vasculitis. (From Eric Krauss, MD; reproduced with permission from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)
The purpuric skin lesions are typically located on the lower extremities but may also be seen on the hands, arms, trunk, and buttocks. Joint symptoms are present in the majority of patients, the knees and ankles being most commonly involved. Abdominal pain secondary to vasculitis of the intestinal tract is often associated with gastrointestinal bleeding. Hematuria signals the presence of a renal lesion that is usually reversible, although it occasionally may progress to chronic kidney disease. Children tend to have more frequent and more serious gastrointestinal vasculitis, whereas adults more often suffer from chronic kidney disease. Biopsy of the kidney reveals segmental glomerulonephritis with crescents and mesangial deposition of IgA.
Chronic courses with persistent or intermittent skin disease are more likely to occur in adults than in children. The value of corticosteroids has been controversial. In children or adults, prednisone (1 mg/kg/d orally) may benefit those with severe extrarenal manifestations and with evidence of kidney disease. The incremental efficacy of steroid-sparing drugs such as azathioprine and mycophenolate mofetil—often used in the setting of kidney disease—is not known.
Jithpratuck W et al. The clinical implications of adult-onset Henoch-Schönlein purpura. Clin Mol Allergy. 2011 May 27;9(1):9. [PMID: 21619657]
This disease is characterized by inflammatory destructive lesions of cartilaginous structures, principally the ears, nose, trachea, and larynx. Nearly 40% of cases are associated with another disease, especially either other immunologic disorders (such as SLE, rheumatoid arthritis, or Hashimoto thyroiditis) or cancers (such as multiple myeloma) or hematologic disorders (such as myelodysplastic syndrome). The disease, which is usually episodic, affects males and females equally. The cartilage is painful, swollen, and tender during an attack and subsequently becomes atrophic, resulting in permanent deformity. Biopsy of the involved cartilage shows inflammation and chondrolysis. Noncartilaginous manifestations of the disease include fever, episcleritis, uveitis, deafness, aortic regurgitation, and rarely glomerulonephritis. In 85% of patients, a migratory, asymmetric, and seronegative arthropathy occurs, affecting both large and small joints and the costochondral junctions. Diagnosing this uncommon disease is especially difficult since the signs of cartilage inflammation (such as red ears or nasal pain) may be more subtle than the fever, arthritis, rash, or other systemic manifestations.
Prednisone, 0.5–1 mg/kg/d orally, is often effective. Dapsone (100–200 mg/d orally) or methotrexate (7.5–20 mg orally per week) may also have efficacy, sparing the need for long-term high-dose corticosteroid treatment. Involvement of the tracheobronchial tree, leading to tracheomalacia, may lead to difficult management issues.
Kemta Lekpa F et al. Biologics in relapsing polychondritis: a literature review. Semin Arthritis Rheum. 2012 Apr;41(5):712–9. [PMID: 22071463]
Yoo JH et al. Relapsing polychondritis: systemic and ocular manifestations, differential diagnosis, management, and prognosis. Semin Ophthalmol. 2011 Jul–Sep;26(4–5):261–9. [PMID: 21958172]
ESSENTIALS OF DIAGNOSIS
Most commonly occurs among persons of Asian, Turkish, or Middle Eastern background, but may affect persons of any demographic profile.
Recurrent, painful aphthous ulcers of the mouth and genitals.
Erythema nodosum–like lesions; a follicular rash; and the pathergy phenomenon (formation of a sterile pustule at the site of a needle stick).
Either anterior or posterior uveitis. Posterior uveitis may be asymptomatic until significant damage to the retina has occurred.
Variety of neurologic lesions that can mimic multiple sclerosis, particularly through involvement of the white matter of the brainstem.
Named after the Turkish dermatologist who first described it, this disease is of unknown cause. Its protean manifestations are believed to result from vasculitis that may involve all types of blood vessels: small, medium, and large, on both the arterial and venous side of the circulation.
The hallmark of Behçet disease is painful aphthous ulcerations in the mouth (see Figure 8–7). These lesions, which usually occur multiply, may be found on the tongue, gums, and inner surfaces of the oral cavity. Genital lesions, similar in appearance, are also common but do not occur in all patients. Other cutaneous lesions of Behçet disease include tender, erythematous, papular lesions that resemble erythema nodosum. (On biopsy, however, many of these lesions are shown to be secondary to vasculitis rather than septal panniculitis.) These erythema nodosum–like lesions have a tendency to ulcerate, a major difference between the lesions of Behçet disease and the erythema nodosum seen in cases of sarcoidosis and inflammatory bowel disease. An erythematous follicular rash that occurs frequently on the upper extremities may be a subtle feature of the disease. The pathergy phenomenon is frequently underappreciated (unless the patient is asked); in this phenomenon, sterile pustules develop at sites where needles have been inserted into the skin (eg, for phlebotomy) in some patients.
A nonerosive arthritis occurs in about two-thirds of patients, most commonly affecting the knees and ankles. Eye involvement may be one of the most devastating complications of Behçet disease. Posterior uveitis, in essence a retinal venulitis, may lead to the insidious destruction of large areas of the retina before the patient becomes aware of visual problems. Anterior uveitis, associated with photophobia and a red eye, is intensely symptomatic. This complication may lead to a hypopyon, the accumulation of pus in the anterior chamber. If not treated properly with mydriatic agents to dilate the pupil and corticosteroid eyedrops to diminish inflammation, the anterior uveitis may lead to synechial formation between the iris and lens, resulting in permanent pupillary distortion.
Central nervous system involvement is another cause of major potential morbidity. The central nervous system lesions that may mimic multiple sclerosis radiologically often result in serious disability or death. Findings include sterile meningitis (recurrent meningeal headaches associated with a lymphocytic pleocytosis), cranial nerve palsies, seizures, encephalitis, mental disturbances, and spinal cord lesions. Aphthous ulcerations of the ileum and cecum and other forms of gastrointestinal involvement develop in approximately a quarter of patients. Large vessel vasculitis can lead to pulmonary artery aneurysms and life-threatening pulmonary hemorrhage. Finally, patients have a hypercoagulable tendency that may lead to complicated venous thrombotic events, particularly multiple deep venous thrombosis, pulmonary emboli, cerebral sinus thrombosis, and other problems associated with clotting.
The clinical course may be chronic but is often characterized by remissions and exacerbations.
There are no pathognomonic laboratory features of Behçet disease. Although acute phase reactants are often elevated, there is no autoantibody or other assay that is distinctive. No markers of hypercoagulability specific to Behçet have been identified.
Both colchicine (0.6 mg once to three times daily orally) and thalidomide (100 mg/d orally) help ameliorate the mucocutaneous findings. Corticosteroids (1 mg/kg/d of oral prednisone) are a mainstay of initial therapy for severe disease manifestations. Azathioprine (2 mg/kg/d orally) may be an effective steroid-sparing agent. Infliximab, cyclosporine, or cyclophosphamide is indicated for severe ocular and central nervous system complications of Behçet disease.
Geri G et al. Spectrum of cardiac lesions in Behçet disease: a series of 52 patients and review of the literature. Medicine (Baltimore). 2012 Jan;91(1):25–34. [PMID: 22198500]
Mohammad A et al. Incidence, prevalence and clinical characteristics of Behcet’s disease in southern Sweden. Rheumatology (Oxford). 2013 Feb;52(2):304–10. [PMID: 23012468]
Primary angiitis of the central nervous system is a syndrome with several possible causes that produces small and medium-sized vasculitis limited to the brain and spinal cord. Biopsy-proved cases have predominated in men who have a history of weeks to months of headaches, encephalopathy, and multifocal strokes. Systemic signs and symptoms are absent, and routine laboratory tests are usually normal. MRI of the brain is almost always abnormal, and the spinal fluid often reveals a mild lymphocytosis and a modest increase in protein level. Angiograms classically reveal a “string of beads” pattern produced by alternating segments of arterial narrowing and dilation. However, neither the MRI nor the angiogram appearance is specific for vasculitis. Indeed, in one study, none of the patients who had biopsy-proved central nervous system vasculitis had an angiogram showing “the string of beads,” and none of the patients with the classic angiographic findings had a positive brain biopsy for vasculitis. Review of many studies suggests that the sensitivity of angiography varies greatly (from 40% to 90%) and the specificity is only approximately 30%. Many conditions, including vasospasm, can produce the same angiographic pattern as vasculitis. Definitive diagnosis requires a compatible clinical picture; exclusion of infection, neoplasm, or metabolic disorder or drug exposure (eg, cocaine) that can mimic primary angiitis of the central nervous system; and a positive brain biopsy. In contrast to biopsy-proved cases, patients with angiographically defined central nervous system vasculopathy are chiefly women who have had an abrupt onset of headaches and stroke (often in the absence of encephalopathy) with normal spinal fluid findings. Many patients who fit this clinical profile may have reversible cerebral vasoconstriction rather than true vasculitis. Such cases may best be treated with calcium channel blockers (such as nimodipine or verapamil) and possibly a short course of corticosteroids. Biopsy-proved cases usually improve with prednisone therapy and often require cyclophosphamide. In recent years, cases of central nervous system vasculitis associated with cerebral amyloid angiopathy have been reported. These cases often respond well to corticosteroids, albeit the long-term natural history remains poorly defined.
Salvarani C et al. Adult primary central nervous system vasculitis. Lancet. 2012 Aug 25;380(9843):767–77. [PMID: 22575778]
Livedo reticularis produces a mottled, purplish discoloration of the skin with reticulated cyanotic areas surrounding paler central cores. This distinctive “fishnet” pattern is caused by spasm or obstruction of perpendicular arterioles, combined with pooling of blood in surrounding venous plexuses. Livedo reticularis can be idiopathic or a manifestation of a serious underlying condition.
Idiopathic livedo reticularis is a benign condition that worsens with cold exposure, improves with warming, and primarily affects the extremities. Apart from cosmetic concerns, it is usually asymptomatic. Systemic symptoms or the development of cutaneous ulcerations point to the presence of an underlying disease.
Secondary livedo reticularis occurs in association with a variety of diseases that cause vascular obstruction or inflammation. Of particular importance is the link with antiphospholipid antibody syndrome. Livedo reticularis is the presenting manifestation of 25% of patients with antiphospholipid antibody syndrome and is strongly associated with the subgroup that has arterial thromboses, including those with Sneddon syndrome (livedo reticularis and cerebrovascular events). Other underlying causes of livedo reticularis include the vasculitides (particularly polyarteritis nodosa), cholesterol emboli syndrome, thrombocythemia, cryoglobulinemia, cold agglutinin disease, primary hyperoxaluria (due to vascular deposits of calcium oxalate), and disseminated intravascular coagulation.
Dean SM. Livedo reticularis and related disorders. Curr Treat Options Cardiovasc Med. 2011 Apr;13(2):179–91. [PMID: 21287303]
The seronegative spondyloarthropathies are ankylosing spondylitis, psoriatic arthritis, reactive arthritis, the arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthropathy. These disorders are noted for male predominance, onset usually before age 40, inflammatory arthritis of the spine and sacroiliac joints, asymmetric oligoarthritis of large peripheral joints, enthesopathy (inflammation of where ligaments, tendons, and joint capsule insert into bone), uveitis in a significant minority, the absence of autoantibodies in the serum, and a striking association with HLA-B27. HLA-B27 is positive in up to 90% of patients with ankylosing spondylitis and 75% with reactive arthritis. HLA-B27 also occurs in 50% of the psoriatic and inflammatory bowel disease patients who have sacroiliitis. Patients with only peripheral arthritis in these latter two syndromes do not show an increase in HLA-B27.
ESSENTIALS OF DIAGNOSIS
Chronic low backache in young adults, generally worst in the morning.
Progressive limitation of back motion and of chest expansion.
Transient (50%) or persistent (25%) peripheral arthritis.
Anterior uveitis in 20–25%.
Diagnostic radiographic changes in sacroiliac joints.
Negative serologic tests for rheumatoid factor and anti-CCP antibodies.
HLA-B27 testing is most helpful when there is an intermediate probability of disease.
Ankylosing spondylitis is a chronic inflammatory disease of the joints of the axial skeleton, manifested clinically by pain and progressive stiffening of the spine. The age at onset is usually in the late teens or early 20s. The incidence is greater in males than in females, and symptoms are more prominent in men, with ascending involvement of the spine more likely to occur.
The onset is usually gradual, with intermittent bouts of back pain that may radiate into the buttocks. The back pain is worse in the morning and usually associated with stiffness that lasts hours. The pain and stiffness improve with activity, in contrast to back pain due to mechanical causes and degenerative disease, which improves with rest and worsens with activity. As the disease advances, symptoms progress in a cephalad direction, and back motion becomes limited, with the normal lumbar curve flattened and the thoracic curvature exaggerated. Chest expansion is often limited as a consequence of costovertebral joint involvement. In advanced cases, the entire spine becomes fused, allowing no motion in any direction. Transient acute arthritis of the peripheral joints occurs in about 50% of cases, and permanent changes in the peripheral joints—most commonly the hips, shoulders, and knees—are seen in about 25%. Enthesopathy, a hallmark of the spondyloarthropathies, can manifest as swelling of the Achilles tendon at its insertion, plantar fasciitis (producing heel pain), or “sausage” swelling of a finger or toe (less common in ankylosing spondylitis than in psoriatic arthritis).
Anterior uveitis is associated in as many as 25% of cases and may be a presenting feature. Spondylitic heart disease, characterized chiefly by atrioventricular conduction defects and aortic regurgitation occurs in 3–5% of patients with long-standing severe disease Constitutional symptoms similar to those of rheumatoid arthritis are absent in most patients.
The ESR is elevated in 85% of cases, but serologic tests for rheumatoid factor and anti-CCP antibodies are negative. Anemia may be present but is often mild. HLA-B27 is found in 90% of white patients and 50% of black patients with ankylosing spondylitis. Because this antigen occurs in 8% of the healthy white population (and 2% of healthy blacks), it is not a specific diagnostic test.
The earliest radiographic changes are usually in the sacroiliac joints. In the first 2 years of the disease process, the sacroiliac changes may be detectable only by MRI. Later, erosion and sclerosis of these joints are evident on plain radiographs; the sacroiliitis of ankylosing spondylitis is bilateral and symmetric. Inflammation where the annulus fibrosus attaches to the vertebral bodies initially causes sclerosis (“the shiny corner sign”) and then characteristic squaring of the vertebral bodies. The term “bamboo spine” describes the late radiographic appearance of the spinal column in which the vertebral bodies are fused by vertically oriented, bridging syndesmophytes formed by the ossification of the annulus fibrosus and calcification of the anterior and lateral spinal ligaments. Fusion of the posterior facet joints of the spine is also common.
Additional radiographic findings include periosteal new bone formation on the iliac crest, ischial tuberosities and calcanei, and alterations of the pubic symphysis and sternomanubrial joint similar to those of the sacroiliacs. Radiologic changes in peripheral joints, when present, tend to be asymmetric and lack the demineralization and erosions seen in rheumatoid arthritis.
Low back pain due to mechanical causes, disk disease, and degenerative arthritis is very common. Onset of back pain prior to age 30 and an “inflammatory” quality of the back pain (ie, morning stiffness and pain that improve with activity) should raise the possibility of ankylosing spondylitis. In contrast to ankylosing spondylitis, rheumatoid arthritis predominantly affects multiple, small, peripheral joints of the hands and feet. Rheumatoid arthritis spares the sacroiliac joints and only affects the cervical component of the spine. Bilateral sacroiliitis indistinguishable from ankylosing spondylitis is seen with the spondylitis associated with inflammatory bowel disease. Sacroiliitis associated with reactive arthritis and psoriasis, on the other hand, is often asymmetric or even unilateral. Osteitis condensans ilii (sclerosis on the iliac side of the sacroiliac joint) is an asymptomatic, postpartum radiographic finding that is occasionally mistaken for sacroiliitis. Diffuse idiopathic skeletal hyperostosis (DISH) causes exuberant osteophytes (“enthesophytes”) of the spine that occasionally are difficult to distinguish from the syndesmophytes of ankylosing spondylitis. The enthesophytes of DISH are thicker and more anterior than the syndesmophytes of ankylosing spondylitis, and the sacroiliac joints are normal in DISH.
NSAIDs remain first-line treatment of ankylosing spondylitis and may slow radiographic progression of spinal disease. Because individual patients differ in their response to particular NSAIDs, empiric trials of several different NSAIDs are warranted if the response to any given NSAID is not satisfactory. TNF inhibitors have established efficacy for NSAID-resistant axial disease; responses are often substantial and durable. Etanercept (50 mg subcutaneously once a week), adalimumab (40 mg subcutaneously every other week), infliximab (5 mg/kg every other month by intravenous infusion), or golimumab (50 mg subcutaneously once a month) is reasonable for patients whose symptoms are refractory to NSAIDs. Sulfasalazine (1000 mg orally twice daily) is sometimes useful for peripheral arthritis but lacks effectiveness for spinal and sacroiliac joint disease. Corticosteroids have minimal impact on the arthritis—particularly the spondylitis—of ankylosing spondylitis and can worsen osteopenia. All patients should be referred to a physical therapist for instruction in postural exercises.
Almost all patients have persistent symptoms over decades; rare individuals experience long-term remissions. The severity of disease varies greatly, with about 10% of patients having work disability after 10 years. Developing hip disease within the first 2 years of disease onset presages a worse prognosis. The availability of TNF inhibitors has provided symptomatic relief and improved quality of life for many patients with ankylosing spondylitis.
Reveille JD et al. The epidemiology of back pain, axial spondyloarthritis and HLA-B27 in the United States. Am J Med Sci. 2013 Jun;345(6):431–6. [PMID: 23841117]
Smith ME et al. Treatment recommendations for the management of axial spondyloarthritis. Am J Med Sci. 2013 Jun;345(6):426–30. [PMID: 23841116]
ESSENTIALS OF DIAGNOSIS
Psoriasis precedes onset of arthritis in 80% of cases.
Arthritis usually asymmetric, with “sausage” appearance of fingers and toes but a polyarthritis that resembles rheumatoid arthritis also occurs.
Sacroiliac joint involvement common; ankylosis of the sacroiliac joints may occur.
Radiographic findings: osteolysis; pencil-in-cup deformity; relative lack of osteoporosis; bony ankylosis; asymmetric sacroiliitis and atypical syndesmophytes.
Although psoriasis usually precedes the onset of arthritis, arthritis precedes (by up to 2 years) or occurs simultaneously with the skin disease in approximately 20% of cases.
The patterns or subsets of psoriatic arthritis include the following:
1. A symmetric polyarthritis that resembles rheumatoid arthritis. Usually, fewer joints are involved than in rheumatoid arthritis.
2. An oligoarticular form that may lead to considerable destruction of the affected joints.
3. A pattern of disease in which the DIP joints are primarily affected. Early, this may be monarticular, and often the joint involvement is asymmetric. Pitting of the nails and onycholysis frequently accompany DIP involvement.
4. A severe deforming arthritis (arthritis mutilans) in which osteolysis is marked.
5. A spondylitic form in which sacroiliitis and spinal involvement predominate; 50% of these patients are HLA-B27-positive.
Arthritis is at least five times more common in patients with severe skin disease than in those with only mild skin findings. Occasionally, however, patients may have a single patch of psoriasis (typically hidden in the scalp, gluteal cleft, or umbilicus) and are unaware of its presence. Thus, a detailed search for cutaneous lesions is essential in patients with arthritis of new onset. Also, the psoriatic lesions may have cleared when arthritis appears—in such cases, the history is most useful in diagnosing previously unexplained cases of mono- or oligoarthritis. Nail pitting is sometimes a clue. “Sausage” swelling of one or more digits is a common manifestation of enthesopathy in psoriatic arthritis.
Laboratory studies show an elevation of the ESR, but rheumatoid factor is not present. Uric acid levels may be high, reflecting the active turnover of skin affected by psoriasis. There is a correlation between the extent of psoriatic involvement and the level of uric acid, but gout is no more common than in patients without psoriasis. Desquamation of the skin may also reduce iron stores.
Radiographic findings are most helpful in distinguishing the disease from other forms of arthritis. There are marginal erosions of bone and irregular destruction of joint and bone, which, in the phalanx, may give the appearance of a sharpened pencil. Fluffy periosteal new bone may be marked, especially at the insertion of muscles and ligaments into bone. Such changes will also be seen along the shafts of metacarpals, metatarsals, and phalanges. Psoriatic spondylitis causes asymmetric sacroiliitis and syndesmophytes, which are coarser than those seen in ankylosing spondylitis.
NSAIDs are usually sufficient for mild cases. Methotrexate (7.5–20 mg orally once a week) is generally considered the drug of choice for patients who have not responded to NSAIDs; methotrexate can improve both the cutaneous and arthritic manifestations. For cases with disease that is refractory to methotrexate, the addition of TNF inhibitors (at doses similar to the treatment of ankylosing spondylitis) is usually effective for both arthritis and psoriatic skin disease. Corticosteroids are less effective in psoriatic arthritis than in other forms of inflammatory arthritis and may precipitate pustular psoriasis during tapers. Antimalarials may also exacerbate psoriasis. Successful treatment directed at the skin lesions alone (eg, by PUVA therapy) occasionally is accompanied by an improvement in peripheral articular symptoms.
McInnes IB et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013 Aug 31;382(9894):780–9. [PMID: 23769296]
Russolillo A et al. Obesity and psoriatic arthritis: from pathogenesis to clinical outcome and management. Rheumatology (Oxford). 2013 Jan;52(1):62–7. [PMID: 22989426]
ESSENTIALS OF DIAGNOSIS
Fifty to eighty percent of patients are HLA-B27-positive.
Oligoarthritis, conjunctivitis, urethritis, and mouth ulcers most common features.
Usually follows dysentery or a sexually transmitted infection.
Reactive arthritis is precipitated by antecedent gastrointestinal and genitourinary infections and manifests as an asymmetric sterile oligoarthritis, typically of the lower extremities. It is frequently associated with enthesitis. Extra-articular manifestations are common and include urethritis, conjunctivitis, uveitis, and mucocutaneous lesions. Reactive arthritis occurs most commonly in young men and is associated with HLA-B27 in 80% of white patients and 50–60% of blacks.
Most cases of reactive arthritis develop within 1–4 weeks after either a gastrointestinal infection (with Shigella, Salmonella, Yersinia, Campylobacter) or a sexually transmitted infection (with Chlamydia trachomatis or perhaps Ureaplasma urealyticum). Whether the inciting infection is sexually transmitted or dysenteric does not affect the subsequent manifestations but does influence the gender ratio: The ratio is 1:1 after enteric infections but 9:1 with male predominance after sexually transmitted infections. Synovial fluid from affected joints is culture-negative. A clinically indistinguishable syndrome can occur without an apparent antecedent infection, suggesting that subclinical infection can precipitate reactive arthritis or that there are other, as yet unrecognized, triggers.
The arthritis is most commonly asymmetric and frequently involves the large weight-bearing joints (chiefly the knee and ankle); sacroiliitis or ankylosing spondylitis is observed in at least 20% of patients, especially after frequent recurrences. Systemic symptoms including fever and weight loss are common at the onset of disease. The mucocutaneous lesions may include balanitis (Figure 20–8), stomatitis, and keratoderma blennorrhagicum (Figure 20–9), indistinguishable from pustular psoriasis. Involvement of the fingernails in reactive arthritis also mimics psoriatic changes. When present, conjunctivitis is mild and occurs early in the disease course. Anterior uveitis, which can develop at any time in HLA-B27-positive patients, is a more clinically significant ocular complication. Carditis and aortic regurgitation may occur. While most signs of the disease disappear within days or weeks, the arthritis may persist for several months or become chronic. Recurrences involving any combination of the clinical manifestations are common and are sometimes followed by permanent sequelae, especially in the joints (eg, articular destruction).
Figure 20–8. Circinate balanitis due to reactive arthritis (Reiter syndrome). (From Susan Lindsley, Dr. M. F. Rein, Public Health Image Library, CDC.)
Figure 20–9. Keratoderma blennorrhagica of the soles due to reactive arthritis (Reiter syndrome). (From Susan Lindsley, Public Health Image Library, CDC.)
Radiographic signs of permanent or progressive joint disease may be seen in the sacroiliac as well as the peripheral joints.
Gonococcal arthritis can initially mimic reactive arthritis, but the marked improvement after 24–48 hours of antibiotic administration and the culture results distinguish the two disorders. Rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis must also be considered. By causing similar oral, ocular, and joint lesions, Behçet disease may also mimic reactive arthritis. The oral lesions of reactive arthritis, however, are typically painless, in contrast to those of Behçet disease.
The association of reactive arthritis and HIV has been debated, but evidence now indicates that it is equally common in sexually active men regardless of HIV status.
NSAIDs have been the mainstay of therapy. Antibiotics given at the time of a nongonococcal sexually transmitted infection reduce the chance that the individual will develop this disorder. For chronic reactive arthritis associated with chlamydial infection, combination antibiotics taken for 6 months are more effective than placebo. Patients who do not respond to NSAIDs may respond to sulfasalazine, 1000 mg orally twice daily, or to methotrexate, 7.5–20 mg orally per week. For those patients with recent-onset disease that is refractory to NSAIDs and these DMARDs, anti-TNF agents, which are effective in the other spondyloarthropathies, may be effective.
Morris D et al. Reactive arthritis: developments and challenges in diagnosis and treatment. Curr Rheumatol Rep. 2012 Oct;14(5):390–4. [PMID: 22821199]
One-fifth of patients with inflammatory bowel disease have arthritis, which complicates Crohn disease somewhat more frequently than it does ulcerative colitis. In both diseases, two distinct forms of arthritis occur. The first is peripheral arthritis—usually a nondeforming asymmetric oligoarthritis of large joints—in which the activity of the joint disease parallels that of the bowel disease. The arthritis usually begins months to years after the bowel disease, but occasionally the joint symptoms develop earlier and may be prominent enough to cause the patient to overlook intestinal symptoms. The second form of arthritis is a spondylitis that is indistinguishable by symptoms or radiographs from ankylosing spondylitis and follows a course independent of the bowel disease. About 50% of these patients are HLA-B27-positive.
Controlling the intestinal inflammation usually eliminates the peripheral arthritis. The spondylitis often requires NSAIDs, which need to be used cautiously since these agents may activate the bowel disease in a few patients. Range-of-motion exercises as prescribed for ankylosing spondylitis can be helpful.
About two-thirds of patients with Whipple disease experience arthralgia or arthritis, most often an episodic, large-joint polyarthritis. The arthritis usually precedes the gastrointestinal manifestations by years. In fact, the arthritis resolves as the diarrhea develops. Thus, Whipple disease should be considered in the differential diagnosis of unexplained episodic arthritis.
Papamichael K et al. Low prevalence of antibodies to cyclic citrullinated peptide in patients with inflammatory bowel disease regardless of the presence of arthritis. Eur J Gastroenterol Hepatol. 2010 Jun;22(6):705–9. [PMID: 19525851]
ESSENTIALS OF DIAGNOSIS
Acute onset of inflammatory monoarticular arthritis, most often in large weight-bearing joints and wrists.
Common risk factors include previous joint damage and injection drug use.
Infection with causative organisms commonly found elsewhere in body.
Joint effusions are usually large, with white blood counts commonly >50,000/mcL.
Nongonococcal acute bacterial arthritis is often a disease that occurs when there is an underlying abnormality. The key risk factors are bacteremia (eg, injection drug use, endocarditis, infection at other sites), damaged or prosthetic joints (eg, rheumatoid arthritis), compromised immunity (eg, diabetes, advanced chronic kidney disease, alcoholism, cirrhosis, and immunosuppressive therapy), and loss of skin integrity (eg, cutaneous ulcer or psoriasis). Staphylococcus aureus is the most common cause of nongonococcal septic arthritis, accounting for about 50% of all cases. Methicillin-resistant S aureus(MRSA) and group B streptococcus have become increasing frequent and important causes of septic arthritis. Gram-negative septic arthritis causes about 10% of cases and is especially common in injection drug users and in immunocompromised persons. Escherichia coli and Pseudomonas aeruginosa are the most common gram-negative isolates in adults. Pathologic changes include varying degrees of acute inflammation, with synovitis, effusion, abscess formation in synovial or subchondral tissues, and, if treatment is not adequate, articular destruction.
The onset is usually acute, with pain, swelling, and heat of the affected joint worsening over hours. The knee is most frequently involved; other commonly affected sites are the hip, wrist, shoulder, and ankle. Unusual sites, such as the sternoclavicular or sacroiliac joint, can be involved in injection drug users. Chills and fever are common but are absent in up to 20% of patients. Infection of the hip usually does not produce apparent swelling but results in groin pain greatly aggravated by walking. More than one joint is involved in 15% of cases of septic arthritis; risk factors for multiple joint involvement include rheumatoid arthritis, associated endocarditis, and infection with group B streptococci.
Synovial fluid analysis is critical for diagnosis. The leukocyte count of the synovial fluid usually exceeds 50,000/mcL and often is > 100,000/mcL, with 90% or more polymorphonuclear cells (Table 20–2). Gram stain of the synovial fluid is positive in 75% of staphylococcal infections and in 50% of gram-negative infections. Synovial fluid cultures are positive in 70–90% of cases; administration of antibiotics prior to arthrocentesis reduces the likelihood of a positive culture result. Blood cultures are positive in approximately 50% of patients.
Imaging tests generally add little to the diagnosis of septic arthritis. Indeed, other than demonstrating joint effusion, radiographs are usually normal early in the disease; however, evidence of demineralization may develop within days of onset. MRI and CT are more sensitive in detecting fluid in joints that are not accessible to physical examination (eg, the hip). Bony erosions and narrowing of the joint space followed by osteomyelitis and periostitis may be seen within 2 weeks.
Gout and pseudogout can cause acute, very inflammatory monoarticular arthritis and high-grade fever; the failure to find crystals on synovial fluid analysis excludes these diagnoses. A well-recognized but uncommon initial presentation of rheumatoid arthritis is an acute inflammatory monoarthritis (“pseudoseptic”). Acute rheumatic fever commonly involves several joints; Still disease may mimic septic arthritis, but laboratory evidence of infection is absent. Pyogenic arthritis may be superimposed on other types of joint disease, notably rheumatoid arthritis. Indeed, septic arthritis must be excluded (by joint fluid examination) in any patient with rheumatoid arthritis who has a joint strikingly more inflamed than the other joints.
There is no evidence that patients with prosthetic joints undergoing procedures should receive antibiotic prophylaxis to prevent joint infection unless the patient has a prosthetic heart valve or the procedure requires antibiotics to prevent a surgical site infection. However, the topic remains controversial. The American Academy of Orthopedic Surgeons advocates prescribing antibiotic prophylaxis for any patient with a prosthetic joint replacement undergoing a procedure that can cause bacteremia.
The effective treatment of septic arthritis requires appropriate antibiotic therapy together with drainage of the infected joint. Hospitalization is always necessary. If the likely causative organism cannot be determined clinically or from the synovial fluid Gram stain, treatment should be started with broad-spectrum antibiotic coverage effective against staphylococci, streptococci, and gram-negative organisms.The recommendation for initial treatment is to give vancomycin (1 g intravenously every 12 hours, adjusted for age, weight, and renal function) plus a third-generation cephalosporin: ceftriaxone, 1 g intravenously daily (or every 12 hours if concomitant meningitis or endocarditis is suspected); or cefotaxime, 1 g intravenously every 8 hours; or ceftazidime, 1 g intravenously every 8 hours. Antibiotic therapy should be adjusted when culture results become available; the duration of antibiotic therapy is usually 4–6 weeks.
Early orthopedic consultation is essential. Effective drainage is usually achieved through early arthroscopic lavage and debridement together with drain placement. Open surgical drainage should be performed when conservative treatment fails, when there is concomitant osteomyelitis requiring debridement, or when the involved joint (eg, hip, shoulder, sacroiliac joint) cannot be drained by more conservative means. Immobilization with a splint and elevation are used at the onset of treatment. Early active motion exercises within the limits of tolerance will hasten recovery.
The outcome of septic arthritis depends largely on the antecedent health of the patient, the causative organism (eg, S aureus bacterial arthritis is associated with a poor functional outcome in about 40% of cases), and the promptness of treatment. Five to 10 percent of patients with an infected joint die of respiratory complications of sepsis. The mortality rate is 30% for patients with polyarticular sepsis. Bony ankylosis and articular destruction commonly also occur if treatment is delayed or inadequate.
Cipriano CA et al. Serum and synovial fluid analysis for diagnosing chronic periprosthetic infection in patients with inflammatory arthritis. J Bone Joint Surg Am. 2012 Apr 4;94(7):594–600. [PMID: 22488615]
Mathews CJ et al. Bacterial septic arthritis in adults. Lancet. 2010 Mar 6;375(9717):846–55. [PMID: 20206778]
ESSENTIALS OF DIAGNOSIS
Prodromal migratory polyarthralgias.
Tenosynovitis is the most common sign.
Purulent monarthritis in 50%.
Characteristic skin lesions.
Most common in young women during menses or pregnancy.
Symptoms of urethritis frequently absent.
Dramatic response to antibiotics.
In contrast to nongonococcal bacterial arthritis, gonococcal arthritis usually occurs in otherwise healthy individuals. Host factors, however, influence the expression of the disease: gonococcal arthritis is two to three times more common in women than in men, is especially common during menses and pregnancy, and is rare after age 40. Gonococcal arthritis is also common in men who have sex with men, whose high incidence of asymptomatic gonococcal pharyngitis and proctitis predisposes them to disseminated gonococcal infection. Recurrent disseminated gonococcal infection should prompt testing of the patient’s CH50 level to evaluate for a congenital deficiency of a terminal complement component (C5, C6, C7, or C8).
One to 4 days of migratory polyarthralgias involving the wrist, knee, ankle, or elbow are common at the outset. Thereafter, two patterns emerge. The first pattern is characterized by tenosynovitis that most often affects wrists, fingers, ankles, or toes and is seen in 60% of patients. The second pattern is purulent monarthritis that most frequently involves the knee, wrist, ankle, or elbow and is seen in 40% of patients. Less than half of patients have fever, and less than one-fourth have any genitourinary symptoms. Most patients will have asymptomatic but highly characteristic skin lesions that usually consist of two to ten small necrotic pustules distributed over the extremities, especially the palms and soles.
The peripheral blood leukocyte count averages about 10,000 cells/mcL and is elevated in less than one-third of patients. The synovial fluid white blood cell count usually ranges from 30,000 to 60,000 cells/mcL. The synovial fluid Gram stain is positive in one-fourth of cases and culture in less than half. Positive blood cultures are uncommon. Urethral, throat, cervical, and rectal cultures should be done in all patients, since they are often positive in the absence of local symptoms. Urinary nucleic acid amplification tests have excellent sensitivity and specificity for the detection of Neisseria gonorrhoeae in genitourinary sites.
Radiographs are usually normal or show only soft tissue swelling.
Reactive arthritis can produce acute monarthritis, urethritis, and fever in a young person but is distinguished by negative cultures and failure to respond to antibiotics. Lyme disease involving the knee is less acute, does not show positive cultures, and may be preceded by known tick exposure and characteristic rash. The synovial fluid analysis will exclude gout, pseudogout, and nongonococcal bacterial arthritis. Rheumatic fever and sarcoidosis can produce migratory tenosynovitis but have other distinguishing features. Infective endocarditis with septic arthritis can mimic disseminated gonococcal infection. Meningococcemia occasionally presents with a clinical picture that resembles disseminated gonococcal infection; blood cultures establish the correct diagnosis. Early hepatitis B infection is associated with circulating immune complexes that can cause a rash and polyarthralgias. In contrast to disseminated gonococcal infection, the rash in hepatitis B is urticarial.
In most cases, patients in whom gonococcal arthritis is suspected should be admitted to the hospital to confirm the diagnosis, to exclude endocarditis, and to start treatment. While outpatient treatment has been recommended in the past, the rapid rise in gonococci resistant to penicillin makes initial inpatient treatment advisable. The recommendation for initial treatment is to give azithromycin (1 g orally as a single dose) and a third-generation cephalosporin: ceftriaxone, 1 g intravenously daily (or every 12 hours if concomitant meningitis or endocarditis is suspected); or cefotaxime, 1 g intravenously every 8 hours; or ceftizoxime, 1 g intravenously every 8 hours. Azithromycin enhances eradication of gonorrhea and covers potential coinfection with Chlamydia. Because of the increasing prevalence of resistant strains of gonococci, step-down treatment from parenteral to oral antibiotics is no longer recommended. Indeed, once improvement has been achieved for 24–48 hours, patients must receive ceftriaxone 250 mg intramuscularly every 24 hours to complete a 7–14 day course.
Generally, gonococcal arthritis responds dramatically in 24–48 hours after initiation of antibiotics, and drainage of the infected joint(s) is required infrequently. Complete recovery is the rule.
Bolan GA et al. The emerging threat of untreatable gonococcal infection. N Engl J Med. 2012 Feb 9;366(6):485–7.
Infection with HIV has been associated with various rheumatic disorders, most commonly arthralgias and arthritis. HIV painful articular syndrome causes severe arthralgias in an oligoarticular, asymmetric pattern that resolve within 24 hours; the joint examination is normal. HIV-associated arthritis is an asymmetric oligoarticular process with objective findings of arthritis and a self-limited course that ranges from weeks to months. Psoriatic arthritis and reactive arthritis occur in HIV-infected individuals and can be severe; it remains uncertain whether the incidence of these disorders is increased in HIV-infected populations. These spondyloarthropathies can respond to NSAIDs, though many cases are unresponsive. In the era of highly active antiretroviral therapies, immunosuppressive medications can be used if necessary in HIV patients, though with caution. Muscle weakness associated with an elevated creatine kinase can be due to nucleoside reverse transcriptase inhibitor-associated myopathy or HIV-associated myopathy; the clinical presentations of each resemble idiopathic polymyositis but the muscle biopsies show minimal inflammation. Less commonly, an inflammatory myositis indistinguishable from idiopathic polymyositis occurs.
Kaddu-Mukasa M et al. Rheumatic manifestations among HIV positive adults attending the Infectious Disease Clinic at Mulago Hospital. Afr Health Sci. 2011 Mar;11(1):24–9. [PMID: 21572853]
Morar N et al. HIV-associated psoriasis: pathogenesis, clinical features, and management. Lancet Infect Dis. 2010 Jul;10(7):470–8. [PMID: 20610329]
Arthralgias occur frequently in the course of acute infections with many viruses, but frank arthritis is uncommon. A notable exception is acute parvovirus B19 infection, which leads to acute polyarthritis in 50–60% of adult cases (infected children develop the febrile exanthem known as “slapped cheek fever”). The arthritis can mimic rheumatoid arthritis but is almost always self-limited and resolves within several weeks. The diagnosis is established by the presence of IgM antibodies specific for parvovirus B19. Self-limited polyarthritis is also common in acute hepatitis B infection and typically occurs before the onset of jaundice. Urticaria or other types of skin rash may be present. Indeed, the clinical picture resembles that of serum sickness (see Atopic Disease below). Serum transaminase levels are elevated, and tests for hepatitis B surface antigen are positive. Serum complement levels are often low during active arthritis and become normal after remission of arthritis. The incidence of hepatitis B–associated polyarthritis has fallen substantially with the introduction of hepatitis B vaccination. Effective vaccination programs in the United States have eliminated acute rubella infections, formerly a common cause of virally induced polyarthritis. Changes in the rubella vaccine (an attenuated live vaccine) have greatly reduced the incidence of rubella vaccine–induced polyarthritis as well.
Chronic infection with hepatitis C is associated with chronic polyarthralgia in up to 20% of cases and with chronic polyarthritis in 3–5%. Both can mimic rheumatoid arthritis, and the presence of rheumatoid factor in most hepatitis C–infected individuals leads to further diagnostic confusion. Indeed, hepatitis C–associated arthritis is frequently misdiagnosed as rheumatoid arthritis. Distinguishing hepatitis C–associated arthritis/arthralgias from the co-occurrence of hepatitis C and rheumatoid arthritis can be difficult. Rheumatoid arthritis always causes objective arthritis (not just arthralgias) and can be erosive (hepatitis C–associated arthritis is nonerosive). The presence of anti-CCP antibodies points to the diagnosis of rheumatoid arthritis.
Varache S et al. Is routine viral screening useful in patients with recent-onset polyarthritis of a duration of at least 6 weeks? Results from a nationwide longitudinal prospective cohort study. Arthritis Care Res (Hoboken). 2011 Nov;63(11):1565–70. [PMID: 21954118]
ESSENTIALS OF DIAGNOSIS
Fever and chills associated with pain and tenderness of involved bone.
Diagnosis usually requires culture of bone biopsy.
ESR often extremely high (eg, <100 mm/h).
Radiographs early in the course are typically negative.
Osteomyelitis is a serious infection that is often difficult to diagnose and treat. Infection of bone occurs as a consequence of (1) hematogenous dissemination of bacteria, (2) invasion from a contiguous focus of infection, and (3) skin breakdown in the setting of vascular insufficiency.
1. Hematogenous osteomyelitis—Osteomyelitis resulting from bacteremia is a disease associated with sickle cell disease, injection drug users, diabetes mellitus, or the elderly. Patients with this form of osteomyelitis often present with sudden onset of high fever, chills, and pain and tenderness of the involved bone. The site of osteomyelitis and the causative organism depend on the host. Among patients with hemoglobinopathies such as sickle cell anemia, osteomyelitis is caused most often by salmonellae; S aureus is the second most common cause. Osteomyelitis in injection drug users develops most commonly in the spine. Although in this setting S aureus is most common, gram-negative infections, especially P aeruginosa and Serratia species, are also frequent pathogens. Rapid progression to epidural abscess causing fever, pain, and sensory and motor loss is not uncommon. In older patients with hematogenous osteomyelitis, the most common sites are the thoracic and lumbar vertebral bodies. Risk factors for these patients include diabetes, intravenous catheters, and indwelling urinary catheters. These patients often have more subtle presentations, with low-grade fever and gradually increasing bone pain.
2. Osteomyelitis from a contiguous focus of infection—Prosthetic joint replacement, pressure ulcer, neurosurgery, and trauma most frequently cause soft tissue infections that can spread to bone. S aureusand Staphylococcus epidermidis are the most common organisms. Polymicrobial infections, rare in hematogenously spread osteomyelitis, is more common in osteomyelitis due to contiguous spread. Localized signs of inflammation are usually evident, but high fever and other signs of toxicity are usually absent. Septic arthritis and cellulitis can also spread to contiguous bone.
3. Osteomyelitis associated with vascular insufficiency—Patients with diabetes and vascular insufficiency are susceptible to developing a very challenging form of osteomyelitis. The foot and ankle are the most commonly affected sites. Infection originates from an ulcer or other break in the skin that is usually still present when the patient presents but may appear disarmingly unimpressive. Bone pain is often absent or muted by the associated neuropathy. Fever is also commonly absent. Two of the best bedside clues that the patient has osteomyelitis are the ability to easily advance a sterile probe through a skin ulcer to bone and an ulcer area > 2 cm2.
The plain film is the most readily available imaging procedure to establish the diagnosis of osteomyelitis, but it can be falsely negative early. Early radiographic findings may include soft tissue swelling, loss of tissue planes, and periarticular demineralization of bone. About 2 weeks after onset of symptoms, erosion of bone and alteration of cancellous bone appear, followed by periostitis.
MRI, CT, and nuclear medicine bone scanning are more sensitive than conventional radiography. MRI is the most sensitive and is particularly helpful in demonstrating the extent of soft tissue involvement. Radionuclide bone scanning is most valuable when osteomyelitis is suspected but no site is obvious. Nuclear medicine studies may also detect multifocal sites of infection. Ultrasound is useful in diagnosing the presence of effusions within joints and extra-articular soft tissue fluid collections but not in detecting bone infections.
Identifying the offending organism is a crucial step in selection of antibiotic therapy. Bone biopsy for culture is required except in those with hematogenous osteomyelitis, who have positive blood cultures. Cultures from overlying ulcers, wounds, or fistulas are unreliable.
Acute hematogenous osteomyelitis should be distinguished from suppurative arthritis, rheumatic fever, and cellulitis. More subacute forms must be differentiated from tuberculosis or mycotic infections of bone and Ewing sarcoma or, in the case of vertebral osteomyelitis, from metastatic tumor. When osteomyelitis involves the vertebrae, it commonly traverses the disk—a finding not observed in tumor.
Inadequate treatment of bone infections results in chronicity of infection, and this possibility is increased by delaying diagnosis and treatment. Extension to adjacent bone or joints may complicate acute osteomyelitis. Recurrence of bone infections often results in anemia, a markedly elevated ESR, weight loss, weakness and, rarely, amyloidosis or nephrotic syndrome. Pseudoepitheliomatous hyperplasia, squamous cell carcinoma, or fibrosarcoma may occasionally arise in persistently infected tissues.
Most patients require both debridement of necrotic bone and prolonged administration of antibiotics. Patients with vertebral body osteomyelitis and epidural abscess may require urgent neurosurgical decompression. Depending on the site and extent of debridement, surgical procedures to stabilize, fill in, cover, or revascularize may be needed. Oral therapy with quinolones (eg, ciprofloxacin, 750 mg twice daily) for 6–8 weeks has been shown to be as effective as standard parenteral antibiotic therapy for chronic osteomyelitis with susceptible organisms. When treating osteomyelitis caused by S aureus, quinolones are usually combined with rifampin, 300 mg orally twice daily.
If sterility of the lesion is achieved within 2–4 days, a good result can be expected in most cases if there is no compromise of the patient’s immune system. However, progression of the disease to a chronic form may occur. It is especially common in the lower extremities and in patients in whom circulation is impaired (eg, diabetics).
Spellberg B et al. Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin Infect Dis. 2012 Feb 1;54(3):393–407. [PMID: 22157324]
Zimmerli W. Clinical practice. Vertebral osteomyelitis. N Engl J Med. 2010 Mar 18;362(11):1022–9. [PMID: 20237348]
ESSENTIALS OF DIAGNOSIS
Seen primarily in immigrants from developing countries or immunocompromised patients.
Back pain and gibbus deformity.
Radiographic evidence of vertebral involvement.
Evidence of Mycobacterium tuberculosis in aspirate or biopsies of spinal lesions.
In the developing world, children primarily bear the burden of musculoskeletal tuberculosis. In the United States, however, musculoskeletal infection is more often seen in adult immigrants from countries where tuberculosis is prevalent, or it develops in the setting of immunosuppression (eg, HIV infection, therapy with TNF inhibitors). Spinal tuberculosis (Pott disease) accounts for about 50% of musculoskeletal infection due to M tuberculosis (see Chapter 9). Seeding of the vertebrae may occur through hematogenous spread from the respiratory tract at the time of primary infection, with clinical disease developing years later as a consequence of reactivation. The thoracic and lumbar vertebrae are the most common sites of spinal involvement; vertebral infection is associated with paravertebral cold abscesses in 75% of cases.
Patients complain of back pain, often present for months and sometimes associated with radicular pain and lower extremity weakness. Constitutional symptoms are usually absent, and < 20% have active pulmonary disease. Destruction of the anterior aspect of the vertebral body can produce the characteristic gibbus deformity.
Most patients have a positive reaction to purified protein derivative (PPD) or a positive interferon-gamma release assay. Cultures of paravertebral abscesses and biopsies of vertebral lesions are positive in up to 70–90%. Biopsies reveal characteristic caseating granulomas in most cases. Isolation of M tuberculosis from an extraspinal site is sufficient to establish the diagnosis in the proper clinical setting.
Radiographs can reveal lytic and sclerotic lesions and bony destruction of vertebrae but are normal early in the disease course. CT scanning can demonstrate paraspinal soft tissue extensions of the infection; MRI is the imaging technique of choice to detect compression of the spinal cord or cauda equina.
Spinal tuberculosis must be differentiated from subacute and chronic spinal infections due to pyogenic organisms, Brucella, and fungi as well as from malignancy.
Paraplegia due to compression of the spinal cord or cauda equina is the most serious complication of spinal tuberculosis.
Antimicrobial therapy should be administered for 6–9 months, usually in the form of isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months followed by isoniazid and rifampin for an additional 4–7 months (see also Chapter 9). Medical management alone is often sufficient. Surgical intervention, however, may be indicated when there is neurologic compromise or severe spinal instability.
Fuentes Ferrer M et al. Tuberculosis of the spine. A systematic review of case series. Int Orthop. 2012 Feb;36(2):221–31. [PMID: 22116392]
Trecarichi EM et al. Tuberculous spondylodiscitis: epidemiology, clinical features, treatment, and outcome. Eur Rev Med Pharmacol Sci. 2012 Apr;16(Suppl 2):58–72. [PMID: 22655484]
Infection of peripheral joints by M tuberculosis usually presents as a monoarticular arthritis lasting for weeks to months (or longer), but less often, it can have an acute presentation that mimics septic arthritis. Any joint can be involved; the hip and knee are most commonly affected. Constitutional symptoms and fever are present in only a small number of cases. Tuberculosis also can cause a chronic tenosynovitis of the hand and wrist. Joint destruction occurs far more slowly than in septic arthritis due to pyogenic organisms. Synovial fluid is inflammatory but not to the degree seen in pyogenic infections, with synovial white cell counts in the range of 10,000–20,000 cells/mcL. Smears of synovial fluid are positive for acid-fast bacilli in a minority of cases; synovial fluid cultures, however, are positive in 80% of cases. Because culture results may take weeks, the diagnostic procedure of choice usually is synovial biopsy, which yields characteristic pathologic findings and positive cultures in > 90%. Antimicrobial therapy is the mainstay of treatment. Rarely, a reactive, sterile polyarthritis associated with erythema nodosum (Poncet disease) develops in patients with active pulmonary tuberculosis.
Kim SJ et al. Total hip replacement for patients with active tuberculosis of the hip: a systematic review and pooled analysis. Bone Joint J. 2013 May;95-B(5):578–82. [PMID: 23632665]
The frequency of arthritis among patients with sarcoidosis is variously reported between 10% and 35%. It is usually acute in onset, but articular symptoms may appear insidiously and often antedate other manifestations of the disease. Knees and ankles are most commonly involved, but any joint may be affected. Distribution of joint involvement is usually polyarticular and symmetric. The arthritis is commonly self-limited, resolving after several weeks or months and rarely resulting in chronic arthritis, joint destruction, or significant deformity. Sarcoid arthropathy is often associated with erythema nodosum, but the diagnosis is contingent on the demonstration of other extra-articular manifestations of sarcoidosis and, notably, biopsy evidence of noncaseating granulomas. Despite the clinical appearance of an inflammatory arthritis, synovial fluid often is noninflammatory (ie, < 2000 leukocytes/mcL). In chronic arthritis, radiographs show typical changes in the bones of the extremities with intact cortex and cystic changes.
Treatment of arthritis in sarcoidosis is usually symptomatic and supportive. Colchicine may be of value. A short course of corticosteroids may be effective in patients with severe and progressive joint disease.
Sweiss NJ et al. Rheumatologic manifestations of sarcoidosis. Semin Respir Crit Care Med. 2010 Aug;31(4):463–73. [PMID: 20665396]
Thoracic outlet syndromes result from compression of the neurovascular structures supplying the upper extremity. Symptoms and signs arise from intermittent or continuous pressure on elements of the brachial plexus (> 90% of cases) or the subclavian or axillary vessels (veins or arteries) by a variety of anatomic structures of the shoulder girdle region. The neurovascular bundle can be compressed between the anterior or middle scalene muscles and a normal first thoracic rib or a cervical rib. Most commonly thoracic outlet syndromes are caused by scarred scalene neck muscle secondary to neck trauma or sagging of the shoulder girdle resulting from aging, obesity, or pendulous breasts. Faulty posture, occupation, or thoracic muscle hypertrophy from physical activity (eg, weight-lifting, baseball pitching) may be other predisposing factors.
Thoracic outlet syndromes present in most patients with some combination of four symptoms involving the upper extremity, namely pain, numbness, weakness, and swelling. The predominant symptoms depend on whether the compression chiefly affects neural or vascular structures. The onset of symptoms is usually gradual but can be sudden. Some patients spontaneously notice aggravation of symptoms with specific positioning of the arm. Pain radiates from the point of compression to the base of the neck, the axilla, the shoulder girdle region, arm, forearm, and hand. Paresthesias are common and distributed to the volar aspect of the fourth and fifth digits. Sensory symptoms may be aggravated at night or by prolonged use of the extremities. Weakness and muscle atrophy are the principal motor abnormalities. Vascular symptoms consist of arterial ischemia characterized by pallor of the fingers on elevation of the extremity, sensitivity to cold and, rarely, gangrene of the digits or venous obstruction marked by edema, cyanosis, and engorgement.
The symptoms of thoracic outlet syndromes can be provoked within 60 seconds over 90% of the time by having a patient elevate the arms in a “stick-em-up” position (ie, abducted 90 degrees in external rotation). Reflexes are usually not altered. Obliteration of the radial pulse with certain maneuvers of the arm or neck, once considered a highly sensitive sign of thoracic outlet obstruction, does not occur in most cases.
Chest radiography will identify patients with cervical rib (although most patients with cervical ribs are asymptomatic). MRI with the arms held in different positions is useful in identifying sites of impaired blood flow. Intra-arterial or venous obstruction is confirmed by angiography. Determination of conduction velocities of the ulnar and other peripheral nerves of the upper extremity may help localize the site of their compression.
Thoracic outlet syndrome must be differentiated from osteoarthritis of the cervical spine, tumors of the superior pulmonary sulcus, cervical spinal cord, or nerve roots, and periarthritis of the shoulder.
Treatment is directed toward relief of compression of the neurovascular bundle. Greater than 95% of patients can be treated successfully with conservative therapy consisting of physical therapy and avoiding postures or activities that compress the neurovascular bundle. Some women will benefit from a support bra. Operative treatment, required by < 5% of patients, is more likely to relieve the neurologic rather than the vascular component that causes symptoms.
Brooke BS et al. Contemporary management of thoracic outlet syndrome. Curr Opin Cardiol. 2010 Nov;25(6):535–40. [PMID: 20838336]
Ferrante MA. The thoracic outlet syndromes. Muscle Nerve. 2012 Jun;45(6):780–95. [PMID: 22581530]
Povlsen B et al. Treatment for thoracic outlet syndrome. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD007218. [PMID: 20091624]
ESSENTIALS OF DIAGNOSIS
Most frequent in women aged 20–50.
Chronic widespread musculoskeletal pain syndrome with multiple tender points.
Fatigue, headaches, numbness common.
Objective signs of inflammation absent; laboratory studies normal.
Fibromyalgia is a common syndrome, affecting 3–10% of the general population. It shares many features with the chronic fatigue syndrome, namely, an increased frequency among women aged 20–50, absence of objective findings, and absence of diagnostic laboratory test results. While many of the clinical features of the two conditions overlap, musculoskeletal pain predominates in fibromyalgia whereas lassitude dominates the chronic fatigue syndrome.
The cause is unknown, but aberrant perception of painful stimuli, sleep disorders, depression, and viral infections have all been proposed. Fibromyalgia can be a rare complication of hypothyroidism, rheumatoid arthritis or, in men, sleep apnea.
The patient complains of chronic aching pain and stiffness, frequently involving the entire body but with prominence of pain around the neck, shoulders, low back, and hips. Fatigue, sleep disorders, subjective numbness, chronic headaches, and irritable bowel symptoms are common. Even minor exertion aggravates pain and increases fatigue. Physical examination is normal except for “trigger points” of pain produced by palpation of various areas such as the trapezius, the medial fat pad of the knee, and the lateral epicondyle of the elbow.
Fibromyalgia is a diagnosis of exclusion. A detailed history and repeated physical examination can obviate the need for extensive laboratory testing. Rheumatoid arthritis and SLE present with objective physical findings or abnormalities on routine testing. Thyroid function tests are useful, since hypothyroidism can produce a secondary fibromyalgia syndrome. Polymyositis produces weakness rather than pain. The diagnosis of fibromyalgia probably should be made hesitantly in a patient over age 50 and should never be invoked to explain fever, weight loss, or any other objective signs. Polymyalgia rheumatica produces shoulder and pelvic girdle pain, is associated with anemia and an elevated ESR, and occurs after age 50. Hypophosphatemic states, such as oncogenic osteomalacia, should also be included in the differential diagnosis of musculoskeletal pain unassociated with physical findings. In contrast to fibromyalgia, oncogenic osteomalacia usually produces pain in only a few areas and is associated with a low serum phosphate level.
A multidisciplinary approach is most effective. Patient education is essential. Patients can be comforted that they have a diagnosable syndrome treatable by specific though imperfect therapies and that the course is not progressive. Cognitive behavioral therapy, including programs that emphasize mindfulness meditation, is often helpful. There is modest efficacy of amitriptyline, fluoxetine, duloxetine, milnacipran, chlorpromazine, cyclobenzaprine, pregabalin, or gabapentin. Amitriptyline is initiated at a dosage of 10 mg orally at bedtime and gradually increased to 40–50 mg depending on efficacy and toxicity. Less than 50% of the patients experience a sustained improvement. Exercise programs are also beneficial. NSAIDs are generally ineffective. Tramadol and acetaminophen combinations have ameliorated symptoms modestly in short-term trials. Opioids and corticosteroids are ineffective and should not be used to treat fibromyalgia. Acupuncture is also ineffective.
All patients have chronic symptoms. With treatment, however, many do eventually resume increased activities. Progressive or objective findings do not develop.
Dieppe P. Chronic musculoskeletal pain. BMJ. 2013 May 16;346:f3146. [PMID: 23709528]
Younger J et al. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013 Feb;65(2):529–38. [PMID: 23359310]
Complex regional pain syndrome (formerly called reflex sympathetic dystrophy) is a rare disorder of the extremities characterized by autonomic and vasomotor instability. The cardinal symptoms and signs are pain localized to an arm or leg, swelling of the involved extremity, disturbances of color and temperature in the affected limb, dystrophic changes in the overlying skin and nails, and limited range of motion. Strikingly, the findings are not limited to the distribution of a single peripheral nerve. Most cases are preceded by direct physical trauma, often of relatively minor nature, to the soft tissues, bone, or nerve. Early mobilization after injury or surgery reduces the likelihood of developing the syndrome. Vitamin C, 500 mg/d orally, is effective in reducing the risk of complex regional pain syndrome following wrist fracture and may be effective following lower extremity fractures as well. Any extremity can be involved, but the syndrome most commonly occurs in the hand and is associated with ipsilateral restriction of shoulder motion (“shoulder-hand” syndrome). This syndrome proceeds through phases: pain, swelling, and skin color and temperature changes develop early and, if untreated, lead to atrophy and dystrophy. The swelling in complex regional pain syndrome is diffuse (“catcher’s mitt hand”) and not restricted to joints. Pain is often burning in quality, intense, and often greatly worsened by minimal stimuli such as light touch. The shoulder-hand variant of this disorder sometimes complicates myocardial infarction or injuries to the neck or shoulder. Complex regional pain syndrome may occur after a knee injury or after arthroscopic knee surgery. There are no systemic symptoms. In the early phases of the syndrome, bone scans are sensitive, showing diffuse increased uptake in the affected extremity. Radiographs eventually reveal severe generalized osteopenia. In the posttraumatic variant, this is known as Sudeck atrophy. Symptoms and findings are bilateral in some. This syndrome should be differentiated from other cervicobrachial pain syndromes, rheumatoid arthritis, thoracic outlet obstruction, and scleroderma, among others.
Early treatment offers the best prognosis for recovery. For mild cases, NSAIDs (eg, naproxen 250–500 mg twice daily orally) can be effective. For more severe cases associated with edema, prednisone, 30–60 mg/d orally for 2 weeks and then tapered over 2 weeks, can be effective. Pain management is important and facilitates physical therapy, which plays a critical role in efforts to restore function. Some patients will also benefit from antidepressant agents (eg, nortriptyline initiated at a dosage of 10 mg orally at bedtime and gradually increased to 40–75 mg at bedtime) or from anticonvulsants (eg, gabapentin 300 mg three times daily orally). Bisphosphonates, calcitonin, intravenous immunoglobulin, regional nerve blocks, and dorsal-column stimulation have also been demonstrated to be helpful. Patients who have restricted shoulder motion may benefit from the treatment described for scapulohumeral periarthritis. The prognosis partly depends on the stage in which the lesions are encountered and the extent and severity of associated organic disease.
Marinus J et al. Clinical features and pathophysiology of complex regional pain syndrome. Lancet Neurol. 2011 Jul;10(7):637–48. [PMID: 21683929]
Parkitny L et al. Inflammation in complex regional pain syndrome: a systematic review and meta-analysis. Neurology. 2013 Jan 1;80(1):106–17. [PMID: 23267031]
Rheumatologic syndromes may be the presenting manifestations for a variety of cancers. Dermatomyositis in adults, for example, is often associated with cancer (see Table 39–2). Hypertrophic pulmonary osteoarthropathy, which is characterized by the triad of polyarthritis, new onset of clubbing, and periosteal new bone formation, is associated with both malignant diseases (eg, lung and intrathoracic cancers) and nonmalignant ones (eg, cyanotic heart disease, cirrhosis, and lung abscess). Cancer-associated polyarthritis is rare, has both oligoarticular and polyarticular forms, and should be considered when “seronegative rheumatoid arthritis” develops abruptly in an elderly patient. Palmar fasciitis manifests as bilateral palmar swelling with finger contractures and may be the first indication of cancer, particularly ovarian carcinoma. Remitting seronegative synovitis with non-pitting edema (“RS3PE”) presents with a symmetric small joint polyarthritis associated with non-pitting edema of the hands; it can be idiopathic or associated with malignancy. Palpable purpura due to leukocytoclastic vasculitis may be the presenting complaint in myeloproliferative disorders. Hairy cell leukemia can be associated with medium-sized vessel vasculitis such as polyarteritis nodosa. Acute leukemia can produce joint pains that are disproportionately severe in comparison to the minimal swelling and heat that are present. Leukemic arthritis complicates approximately 5% of cases. Rheumatic manifestations of myelodysplastic syndromes include cutaneous vasculitis, lupus-like syndromes, neuropathy, and episodic intense arthritis. Erythromelalgia, a painful warmth and redness of the extremities that (unlike Raynaud) improves with cold exposure or with elevation of the extremity, is often associated with myeloproliferative diseases, particularly essential thrombocythemia.
Ashouri JF et al. Rheumatic manifestations of cancer. Rheum Dis Clin North Am. 2011 Nov;37(4):489–505. [PMID: 22075194]
Ravindran V et al. Rheumatologic manifestations of benign and malignant haematological disorders. Clin Rheumatol. 2011 Sep;30(9):1143–9. [PMID: 21698399]
Neurogenic arthropathy is joint destruction resulting from loss or diminution of proprioception, pain, and temperature perception. Although initially described in the knees of patients with tabes dorsalis, it is more frequently seen in association with diabetic neuropathy (foot and ankle) or syringomyelia (shoulder). As normal muscle tone and protective reflexes are lost, secondary degenerative joint disease ensues, resulting in an enlarged, boggy, relatively painless joint with extensive cartilage erosion, osteophyte formation, and multiple loose joint bodies. Radiographs can reveal striking osteolysis that mimics osteomyelitis or dramatic destruction of the joint with subluxation, fragmentation of bone, and bony sclerosis.
Treatment is directed toward the primary disease; mechanical devices are used to assist in weight bearing and prevention of further trauma. In some instances, amputation becomes unavoidable.
Richard JL et al. Treatment of acute Charcot foot with bisphosphonates: a systematic review of the literature. Diabetologia. 2012 May;55(5):1258–64. [PMID: 22361982]
Palindromic rheumatism is a disease of unknown cause characterized by frequent recurring attacks (at irregular intervals) of acutely inflamed joints. Periarticular pain with swelling and transient subcutaneous nodules may also occur. The attacks cease within several hours to several days. The knee and finger joints are most commonly affected, but any peripheral joint may be involved. Systemicmanifestations other than fever do not occur. Although hundreds of attacks may take place over a period of years, there is no permanent articular damage. Laboratory findings are usually normal. Palindromic rheumatism must be distinguished from acute gouty arthritis and an atypical acute onset of rheumatoid arthritis. In some patients, palindromic rheumatism is a prodrome of rheumatoid arthritis.
Symptomatic treatment with NSAIDs is usually all that is required during the attacks. Hydroxychloroquine may be of value in preventing recurrences.
Osteonecrosis is a complication of corticosteroid use, alcoholism, trauma, SLE, pancreatitis, gout, sickle cell disease, dysbaric syndromes (eg, “the bends”), knee menisectomy, and infiltrative diseases (eg, Gaucher disease). The most commonly affected sites are the proximal and distal femoral heads, leading to hip or knee pain. Other commonly affected sites include the ankle, shoulder, and elbow. Osteonecrosis of the jaw has been rarely associated with use of bisphosphonate therapy, almost always when the bisphosphonate is used for treating metastatic cancer or multiple myeloma rather than osteoporosis. Initially, radiographs are often normal; MRI, CT scan, and bone scan are all more sensitive techniques. Treatment involves avoidance of weight bearing on the affected joint for at least several weeks. The value of surgical core decompression is controversial. For osteonecrosis of the hip, a variety of procedures designed to preserve the femoral head have been developed for early disease, including vascularized and nonvascularized bone grafting procedures. These procedures are most effective in avoiding or forestalling the need for total hip arthroplasty in young patients who do not have advanced disease. Without a successful intervention of this nature, the natural history of avascular necrosis is usually progression of the bony infarction to cortical collapse, resulting in significant joint dysfunction. Total hip replacement is the usual outcome for all patients who are candidates for that procedure.
Fessel J. There are many potential medical therapies for atraumatic osteonecrosis. Rheumatology (Oxford). 2013 Feb;52(2):235–41. [PMID: 23041599]
Weinstein RS. Glucocorticoid-induced osteonecrosis. Endocrine. 2012 Apr;41(2):183–90. [PMID: 22169965]
Allergy is an immunologically mediated hypersensitivity reaction to a foreign antigen manifested by tissue inflammation and organ dysfunction. These responses have a genetic basis, but the clinical expression of disease depends on both immunologic responsiveness and antigen exposure. Allergic disorders may be local or systemic. Because the allergen is foreign (ie, environmental), the skin and respiratory tract are the organs most frequently involved in allergic disease. Allergic reactions may also localize to the vasculature, gastrointestinal tract, or other visceral organs. Anaphylaxis is the most extreme form of systemic allergy.
An immunologic classification for hypersensitivity reactions serves as a rational basis for diagnosis and treatment. The classification follows.
IgE antibodies occupy receptor sites on mast cells. Within minutes after exposure to the allergen, a multivalent antigen links adjacent IgE molecules, activating and degranulating mast cells. Clinical manifestations depend on the effects of released mediators on target end organs. Both preformed and newly generated mediators cause vasodilation, visceral smooth muscle contraction, mucous secretory gland stimulation, vascular permeability, and tissue inflammation. Arachidonic acid metabolites, cytokines, and other mediators induce a late-phase inflammatory response that appears several hours later. There are two clinical subgroups of IgE-mediated allergy: atopy and anaphylaxis.
1. Atopy—The term “atopy” is applied to a group of diseases (allergic rhinitis, allergic asthma, atopic dermatitis, and allergic gastroenteropathy) occurring in persons with an inherited tendency to develop antigen-specific IgE reaction to environmental allergens or food antigens. Aeroallergens such as pollens, mold spores, animal danders, and house dust mite antigen are common triggers for allergic conjunctivitis, allergic rhinitis, and allergic asthma. The allergic origin of atopic dermatitis is less well understood, but some patients’ symptoms can be triggered by exposure to dust mite antigen and ingestion of certain foods. There is a strong familial tendency toward the development of atopy.
2. Anaphylaxis—Certain allergens—especially drugs, insect venoms, latex, and foods—may induce an IgE antibody response, causing a generalized release of mediators from mast cells and resulting in systemic anaphylaxis. This is characterized by (1) hypotension or shock from widespread vasodilation, (2) bronchospasm, (3) gastrointestinal and uterine muscle contraction, and (4) urticaria or angioedema. The condition is potentially fatal and can affect both nonatopic and atopic persons. Isolated urticaria and angioedema are cutaneous forms of anaphylaxis, are much more common, and have a better prognosis.
Cytotoxic reactions involve the specific reaction of either IgG or IgM antibody to cell-bound antigens. This results in activation of the complement cascade and the destruction of the cell to which the antigen is bound. Examples include immune hemolytic anemia and Rh hemolytic disease in the newborn.
Immune complex-mediated reactions occur when antigen and IgG or IgM antibodies form circulating immune complexes. Deposition of these complexes in tissues or in vascular endothelium can produce immune complex-mediated tissue injury through activation of the complement cascade, anaphylatoxin generation, and chemotaxis of polymorphonuclear leukocytes. Serum sickness is the classic example of type III hypersensitivity. Immune complex disease also can develop in the setting of acute infection with hepatitis B or chronic infections such as subacute bacterial endocarditis, osteomyelitis, and hepatitis C.
Type IV delayed hypersensitivity is mediated by activated T cells, which accumulate in areas of antigen deposition. The most common expression of delayed hypersensitivity is allergic contact dermatitis, which develops when a low-molecular-weight sensitizing substance haptenates with dermal proteins, becoming a complete antigen. Sensitized T cells release cytokines, activating macrophages and promoting the subsequent dermal inflammation; this occurs 1–2 days after the time of contact. Common topical agents associated with allergic contact dermatitis include nickel, formaldehyde, potassium dichromate, thiurams, mercaptos, parabens, quaternium-15, and ethylenediamine. Rhus (poison oak and ivy) contact dermatitis is caused by cutaneous exposure to oils from the toxicodendron plants. Acute contact dermatitis is characterized by erythema and induration with vesicle formation, often with pruritus, with exudation and crusting in more severe cases. Chronic allergic contact dermatitis may be associated with fissuring, lichenification, or dyspigmentation and may be mistaken for other forms of dermatitis. To diagnose allergic contact dermatitis, patch testing can be performed.
Activated cytotoxic CD8 T lymphocytes play a key role in the pathogenesis of toxic epidermal necrolysis and other serious, drug-induced adverse cutaneous reactions. There are striking, medication-specific associations between inheritance of particular HLA-B alleles and risk of these hypersensitivity reactions. Most notably, B*57:01 confers risk for reactions to abacavir; B*15:02, for carbamazepine; B*58:01, for allopurinol; and B*13:01, for dapsone. The most likely mechanism is a direct interaction between the drug and the antigen-binding cleft of the HLA-B molecule, such that many “self” antigens subsequently bound by the HLA-B molecule are perceived as “foreign,” eliciting massive CD8 T cell activation. Current guidelines call for testing for the relevant HLA-B allele prior to initiating therapy with abacavir, carbamazepine, allopurinol, or dapsone in at-risk patients.
Schwartz RA et al. Toxic epidermal necrolysis. Part I. Introduction, history, classification, clinical diagnosis, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol. 2013 Aug;69(2):173.e1–13. [PMID: 23866878]
ESSENTIALS OF DIAGNOSIS
Fever, pruritic rash, arthralgias, and arthritis; nephritis in severe cases.
Occurs 7–10 days following administration of an exogenous antigen (eg, heterologous gamma globulin) when specific IgG antibodies develop against the antigen.
Immune complex–mediated small vessel vasculitis and tissue injury.
Serum sickness occurs when an antibody response to exogenously administered antigens results in the formation of immune complexes. Deposition of these complexes in vascular endothelium and tissues produces immune complex–mediated small vessel vasculitis and tissue injury through activation of complement, generation of anaphylatoxins, and chemoattraction of polymorphonuclear leukocytes. The skin, joints, and kidneys are commonly affected. It is self-limited and resolves after the antigen is cleared. First observed in the preantibiotic era when heterologous serum preparations were used for passive immunization, serum sickness is now less common but still occurs with the use of heterologous anti-thymocyte globulin for transplant rejection and, infrequently, after the administration of murine monoclonal antibodies or even non-protein drugs.
Sustained high fever (> 101°F) is typical. The earliest manifestation is often a maculopapular or urticarial pruritic rash. Angioedema can occur. Polyarthralgias, frank polyarthritis, and lymphadenopathy are common. Nephritis is usually mild but can progress to acute renal failure.
The ESR is increased, and leukocytosis is common. Other nonspecific laboratory findings include elevated hepatic aminotransferases. When nephritis is present, the urinalysis reveals proteinuria, hematuria, and red cell casts. Hypocomplementemia (low serum levels of C3 and C4) is usually present in cases due to administration of heterologous gamma globulin but not in milder cases precipitated by non-protein drugs.
This disease is self-limited, and treatment is usually conservative for mild cases. NSAIDs help relieve the arthralgias, and antihistamines and topical corticosteroids can be of benefit for the skin manifestation. A high-dose course of corticosteroids is administered for serious reactions, especially those complicated by glomerulonephritis and other manifestations of vasculitis. Plasma exchange may be of benefit for cases refractory to corticosteroids.
These reactions resemble immediate hypersensitivity reactions but are not mediated by allergen-IgE interaction. Instead, direct mast cell activation occurs. Examples of pseudoallergic or “anaphylactoid” reactions include radiocontrast reactions, direct mast cell activation by opioids, and the now rare “red man syndrome” from rapid infusion of vancomycin. In contrast to IgE-mediated reactions, these can often be prevented by prophylactic medical regimens.
Reactions to radiocontrast media do not appear to be mediated by IgE antibodies, yet clinically they are similar to anaphylaxis. If a patient has had an anaphylactoid reaction to conventional radiocontrast media, the risk for a second reaction upon reexposure may be as high as 30%. Patients with asthma or those being treated with beta-adrenergic blocking medications may be at increased risk. The management of patients at risk for radiocontrast medium reactions includes use of the low-osmolality contrast preparations and prophylactic administration of prednisone (50 mg orally every 6 hours beginning 18 hours before the procedure) and diphenhydramine (25–50 mg intramuscularly 60 minutes before the procedure). The use of the lower-osmolality radiocontrast media in combination with the pretreatment regimen decreases the incidence of reactions to < 1%.
Brockow K. Immediate and delayed cutaneous reactions to radiocontrast media. Chem Immunol Allergy. 2012;97:180–90. [PMID: 22613862]
Brockow K et al. Anaphylaxis to radiographic contrast media. Curr Opin Allergy Clin Immunol. 2011 Aug;11(4):326–31. [PMID: 21659863]
Most primary immunologic deficiency diseases are rare and, because they are genetically determined, usually present in childhood. Nonetheless, several important immunodeficiency disorders can present in adulthood, most notably selective IgA deficiency, common variable immunodeficiency, and deficiencies in the terminal components of the complement pathway, which confer susceptibility to Neisseriainfections. Autoantibodies that neutralize cytokines are a recently recognized mechanism of acquired immunodeficiency in adulthood. For example, neutralizing autoantibodies against interferon-gamma can lead to severe opportunistic infections with nontuberculous mycobacteria, and antibodies to granulocyte macrophage-colony stimulating factor are associated with cryptococcal meningitis in otherwise immunocompetent individuals.
Selective IgA deficiency is the most common primary immunodeficiency disorder and is characterized by serum IgA levels < 15 mg/dL (< 0.15 g/L) with normal levels of IgG and IgM; its prevalence is about 1:500 individuals. Most persons are asymptomatic because of compensatory increases in secreted IgG and IgM. Some affected patients have frequent and recurrent infections, such as sinusitis, otitis, and bronchitis. Some cases of IgA deficiency may spontaneously remit. When IgG2 subclass deficiency occurs in combination with IgA deficiency, affected patients are more susceptible to encapsulated bacteria and the degree of immune impairment can be more severe. Patients with a combined IgA and IgG subclass deficiency should be assessed for functional antibody responses to glycoprotein antigen immunization.
Atopic disease and autoimmune disorders can be associated with IgA deficiency. Occasionally, a sprue-like syndrome with steatorrhea has been associated with an isolated IgA deficit. Treatment with commercial immune globulin is ineffective, since IgA and IgM are present only in trace quantities in these preparations.
Individuals with selective IgA deficiency may have high titers of anti-IgA antibodies and are at risk for anaphylactic reactions following exposure to IgA through infusions of plasma (or blood transfusions). These anti-IgA antibodies develop in the absence of prior exposure to human plasma or blood, possibly due to crossreactivity to bovine IgA in cow’s milk or prior sensitization to maternal IgA in breast milk.
Wang N et al. IgA deficiency: what is new? Curr Opin Allergy Clin Immunol. 2012 Dec;12(6):602–8. [PMID: 23026772]
1 Lyme disease is discussed in Chapter 34.