Current Diagnosis & Treatment of Pain, 1st Edition

14. Osteoarthritis & Rheumatoid Arthritis

Daniel J. Mazanec MD

Russell C. DeMicco DO

Edwin L. Capulong MD


Essentials of Diagnosis

  • A monoarticular or oligoarticular disorder that is asymmetric with minimal inflammatory findings.
  • No systemic manifestations.
  • Morning stiffness lasting less than 1 hour; pain relieved by rest.
  • Radiographic changes showing joint space narrowing, osteophytes, bony cysts, and subchondral sclerosis.
  • Laboratory findings are normal.

General Considerations

Osteoarthritis (OA) is one of the most common musculoskeletal disorders and has a significant impact on functional activities. In the absence of a congenital joint deformity or serious trauma, OA is rare before 40 years of age. Prevalence increases with advanced age. Current data suggest that there are approximately 41 million Americans suffering from symptomatic OA. Men have a higher incidence and prevalence under the age of 50. This difference diminishes after the age of menopause. African Americans have a higher incidence of OA than whites.


OA is a multifactorial disorder resulting from a complex interplay of age, genetic, and environmental factors. Risk factors range from nonmodifiable to modifiable. Nonmodifiable risk factors include age, genetic predisposition, and congenital joint anomalies. Modifiable risk factors include diet, physical activity, obesity, and some metabolic disorders.

Joint trauma increases the risk of OA, particularly in the presence of joint malalignment, such as knee valgus deformity, leg length discrepancy, and joint instability brought about by quadriceps weakness or atrophy. In addition, strenuous physical activity and repetitive or mechanical stress (dystonia or spasticity) may hasten the development of arthritic changes in affected joints.

In the case of spasticity or dystonia, arthritic changes depend on the sites of involvement. In the neck, dystonia may produce cervical spondylosis, and in the hip, it may increase the risk of hip OA. In both cases, dystonia may develop at a younger than expected age because of persistent mechanical stress. In patients with prior trauma (eg, meniscal tear or hip injury), the risk of knee OA increases by five to six times, and hip OA by four times, respectively.

Age-related changes in the musculoskeletal tissues include calcification of joint cartilage, increased joint laxity due to muscle weakness and diminished joint proprioception. Overall, these factors may lead to increase propensity to arthritic changes and increase risk of falls in the elderly.

Increased concordance rates of clinical OA between monozygotic versus dizygotic twins support the notion of genetic predisposition to the disease. Clinical manifestations that may be suggestive of genetic predisposition include early age of onset, location (hands and hips) and family history.


Primary prevention of OA entails risk factor modification. Weight reduction, work environment modification for occupation-related disorders (cumulative trauma or repetitive stress disorders), and appropriate physical activity may reduce the risk of OA. Proper training, warm-ups, stretching exercises prior to physical activity, and maintenance of muscle strength may diminish trauma to the knees or hips, reducing the risk of OA.

Oxygen radicals have been associated with aging and variety of disorders, including OA, coronary artery disease, cataracts, and cancer. Nutritional factors play a major role in modulating oxygen radicals. In the joint, free oxygen radicals can cause damage to cartilage. Vitamin C, a potent antioxidant, may reduce the cartilage loss and retard progression of degenerative disease. In the Framingham study, persons with lower consumption of


vitamin C had an increased fourfold risk of OA. Other antioxidants, including vitamins A and E did not show the same efficacy as vitamin C. In fact, in recent studies, vitamin E did not demonstrate any effect on pain modulation. Vitamin A supplementation may increase risk of fragility fracture among males by a factor of seven.

Vitamin D may have a favorable effect on chondrocytes and may play a role in preventing arthritic changes, particularly in the knees. Suboptimal levels of vitamin D affect calcium metabolism and osteoblast activity affecting bone mineral density. Risk of knee OA may be increased as much as threefold in vitamin D-deficient patients.

Estrogen deficiency may play a role in progression of OA via stiffening of the bone, transmitting force to the overlying cartilage. In the Framingham study, estrogen replacement therapy has a moderate protective effect against worsening radiographic knee OA, although not statistically significant.

Secondary prevention is defined as limiting the progression of established degenerative joint disease and requires specific and prompt rehabilitation of injured joints with proper use of therapeutic exercise for rehabilitation. Education regarding activity modification in workplace or recreational activities may be helpful in retarding progression of degenerative joint disease.

Clinical Findings

  1. Symptoms and Signs

OA is readily distinguished from rheumatoid arthritis (RA) and other inflammatory joint disorders by the pattern of joint involvement and the absence of systemic manifestations. In OA, pain is typically worse in the morning, with stiffness lasting a few minutes to less than 1 hour. Joint involvement is frequently asymmetric in a monoarticular to oligoarticular pattern, without evidence of systemic inflammation or extra-articular features (eg, fever, weight loss, rash, and presence of nodules).

In the hands, OA classically affects distal interphalangeal joints and less commonly the proximal interphalangeal joints or metacarpophalangeal joints. Other commonly affected joints include hips and knees as well as the cervical and lumbar spine. In the absence of trauma, elbows, wrists, and shoulders are less often affected (Table 14-1). On physical examination, bony enlargement of the affected joints is noted. Joint effusion may be present, and crepitus may be felt with joint motion.

Table 14-1. Characteristic Findings in Osteoarthritis, Rheumatoid Arthritis, Gout, and Pseudogout.



Rheumatoid arthritis



Sites of predilection

Knees and hips

Polyarticular wrist, MCP, PIP
Extraskeletal sites

Usually asymmetric
MTP joint, ankles, knees, and feet
Tophaceous deposits in ears, elbow joint, hands, knees, feet

Usually polyarticular
Knees, wrists,
MTPs, hips, and shoulders

Synovial fluid


>2000 WBC/mcL

Positive urate crystals

Positive calcium pyrophosphate crystals

Laboratory findings


Positive rheumatoid factor
Presence of anti-CCP antibody

Serum uric acid level >7.0

Serum uric acid level normal

Radiographic findings

Joint space narrowing
Subchondral sclerosis

Juxta-articular osteoporosis
Joint erosions

Normal in early disease
Joint space narrowing and erosions with overhanging edge

Punctate and linear densities in the articular hyaline or fibrocartilaginous tissues

Table 14-2. Characteristics of Synovial Fluid in Noninflammatory, Inflammatory, and Septic Arthritis Compared with Normal Findings.



Noninflammatory arthritis

Inflammatory arthritis

Septic arthritis


<3 mL

<3 mL

>3.5 mL

>3.5 mL


Clear to light



Greenish yellow


< 200/mcL




Polymorphonuclear leukocytes

< 25%

< 25%

50% or more

75% or more

Culture and Gram

No growth

No growth

Usually no growth

Usually positive

Glucose (md/dL)

Equal to serum

Equal to serum

Lower than serum

Lower than serum



  1. Laboratory Findings

Laboratory findings in OA are usually normal and are performed to exclude other arthropathies. Laboratory studies indicated in selected patients include measuring uric acid levels, erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibodies (ANA), and synovial fluid analysis. Synovial fluid analysis is helpful if infectious or crystalline arthritis must be excluded. In OA, synovial fluid is characteristically noninflammatory. White blood cell count and differential analysis of synovial fluid is used to differentiate inflammatory versus noninflammatory arthritis. Synovial fluid Gram stain and bacterial culture is helpful when infection is suspected (Table 14-2). Light polarizing microscopy can distinguish monosodium urate crystals, which appear as negatively birefringent versus calcium pyrophosphate crystals, noted as positively birefringent.

  1. Imaging Studies

The clinical suspicion of OA is confirmed with plain radiographs of the affected joint. Typical findings include asymmetric joint space narrowing, osteophyte formation, degenerative cysts, and subchondral bone sclerosis. These radiographic changes can help classify the grade of OA (Table 14-3).

Severity of radiographic degenerative changes correlates imperfectly with clinical symptoms. OA is frequently asymptomatic and may coexist with other rheumatic disorders. Careful assessment for other causes of joint pain is required before attributing symptoms to osteoarthritic changes.

Magnetic resonance imaging (MRI) is more sensitive than plain radiographs for demonstrating cartilage loss, subchondral cyst formation, and osteophytes. In addition, MRI is more sensitive in identifying soft tissue injuries, including meniscal and ligamentous abnormalities.

Differential Diagnosis

In most cases, OA is easily distinguished from RA and other inflammatory arthritides by the absence of inflammation and laboratory abnormalities, by the pattern of joint involvement, and by radiographic changes. In contrast to RA and other inflammatory arthritides, OA is characterized by minimal articular inflammation without systemic manifestations. In contrast to OA, joint distribution in RA involves the wrist, proximal interphalangeal joint and metacarpophalangeal joint, sparing the distal interphalangeal joints.

Gouty arthritis is characterized by elevated serum uric acid levels, sudden onset of pain, erythema, and swelling most commonly affecting metatarsophalangeal joint of the big toe (podagra). Other joints may also be affected, including knees, ankles, and feet. Involvement is usually asymmetric (see Table 14-1). On physical examination, there is exquisite tenderness overlying an erythematous and swollen joint. In severe cases, tophaceous deposits can be seen in the ears, elbow joint, hands, knees, and feet. Synovial fluid examination for monosodium urate crystals is the definitive diagnostic test for suspected gouty arthritis. Another crystalline osteopathy, pseudogout (also called calcium pyrophosphate dihydrate deposition


[CPPD] disease) may also be identified by examination of synovial fluid. In addition to CPPD, a radiograph may show punctuate or linear densities in the articular hyaline or fibrocartilaginous tissues (see Table 14-1).

Table 14-3. Kellgren-Lawrence Classification of Radiographic Changes in Osteoarthritis.



Grade 1 OA

Joint space narrowing
Densification of underlying bone

Grade 2 OA

Further aggravation of grade 1.

Grade 3 OA

Grade 1 and 2 plus loss of joint space
Start of osteophyte formation

Grade 4 OA

Grade 1, 2, 3 plus bone cysts


The treatment of OA emphasizes a multidisciplinary approach, encompassing nonpharmacologic and pharmacologic treatment. The most important nonpharmacologic treatment for OA is exercise. Other options include weight loss, lifestyle modification, use of assistive devices, patient education, and occupational rehabilitation. The following medications may be helpful in treating OA: topical creams, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol, opioids, and intra-articular injections.

The primary objectives of treatment are reduction of pain, improvement of function, and preservation of joint structure. Nonpharmacologic and pharmacologic interventions should be exhausted before considering surgical therapy.


In general, it is better to rest an acutely painful joint for a few days before starting an active physical therapy or exercise program. The duration of a supervised therapeutic exercise is variable, but the emphasis should be the transition to a long-term home-based exercise maintenance program.

The goals of exercise may be specific to the affected joints. In the knees, for example, isometric strengthening of the quadriceps femoris muscles reduces joint instability and prevents disuse atrophy.

For short-term rehabilitation of the knee, closed kinetic chain exercises (feet are in contact with the floor or a solid surface) produce less stress at the knee joint and simulate functional movements; examples include walking, knee bending, seated leg presses, stair climbing, and stationary bicycling. Open kinetic chain exercises, on the other hand, involve exercises where the feet are not in contact with a solid surface, producing more tension in the soft tissues surrounding the knee joint; examples include knee extension, straight leg raising, and leg adduction in lateral decubitus position.

For short-term rehabilitation of knee OA pain, closed kinetic chain exercises are beneficial, but for long-term therapy (more than 3 months), open kinetic chain exercises may be more effective for pain control.

The use of aquatic therapy is beneficial for patients with lower extremity OA in whom weight-bearing exercise may be difficult.

Studies in people with knee OA have clearly demonstrated clinical benefit to a supervised fitness walking program. In one trial, supervised walking plus light stretching and strengthening exercises as well as patient education for up to 30 minutes three times weekly reduced knee osteoarthritic pain by 27% and increased the functional walking distance by 18% compared with baseline. At 1-year follow-up, patients who did not maintain an exercise program showed loss of functional benefits.

Table 14-4. Physical Activity Recommendations by the ACR for Persons with OA

Aerobic Exercise for People with Hip or Knee OA

· Accumulate 30 minutes of moderate intensity (50-70% maximal HR) physical activity on at least 3 days a week.

· Tailor the type of aerobic activity and venue to individual needs.

· If overweight, combine physical activity with diet modifications.

· Incorporate self-management education into exercise recommendations and programs.

Neuromuscular Rehabilitation for People with Knee OA

· A lower extremity exercise program should combine strengthening, endurance, coordination, balance, and functional exercise.

· Recommended programs will progress in duration, intensity, and complexity; be tailored to the individual needs, abilities, and preferences; move from clinical supervision to self-directed community setting; and be periodically reviewed, revised, and reinforced.

OA, osteoarthritis; ACR, American College of Rheumatology; HR, heart rate.

Overall, weight loss and a moderate intensity exercise program prove to be beneficial not only in terms of increased cardiovascular endurance but also improving pain perception as reported in the Fitness Arthritis and Senior Trial (FAST). The American College of Rheumatology and American Geriatrics Society have developed guidelines for exercise in OA (Tables 14-4 and 14-5).

Topical Analgesics

Capsaicin is a topical medication available without prescription. It stimulates unmyelinated C fiber afferent neurons causing a release of substance P. With prolonged use, capsaicin reversibly depletes stores of substance P from sensory nerve endings reducing the transmission of painful stimuli from the peripheral nerve fibers to the higher centers. Capsaicin can be an effective treatment of


acute exacerbations of osteoarthritic pain. For maximum benefit, it should be applied to the affected joint three or four times daily. Patients must be instructed to wash their hands carefully after each application as the drug may be very irritating if accidentally brushed into the eyes.

Table 14-5. Exercise Recommendations by the American Geriatric Society for Persons with Osteoarthritis.a

· Warm up: 5 minutes

· Exercise:
- Isometric strength training: daily
- Isotonic strength training: 2-3 times per week
- Flexibility training: daily
- Aerobic training (endurance): 3-5 times per week

· Cool down: 5 minutes

aMany patients need to concentrate on strength and flexibility training first before considering aerobic training. The exercise program should be adapted to the patient's age and functional ability.


The American College of Rheumatology has recommended the use of acetaminophen as the first-line agent for mild symptomatic OA. Clinical trials have demonstrated significant improvement in pain and functional scores of patients with knee and hip OA treated with approximately 4 g of acetaminophen daily, comparable to treatment with naproxen 750 mg daily. In contrast, lower doses of acetaminophen are inadequate and generally inferior to treatment with NSAIDs in OA patients. A major advantage of acetaminophen versus NSAIDs is an excellent safety profile in doses less than 4 g daily. However, side effects may include liver enzyme elevation and drug sensitivity. In patients without underlying liver disease, dosages up to 4 g daily are well tolerated.

Nonsteroidal Anti-Inflammatory Drugs

Nonselective NSAIDs (cyclooxygenase [COX]-1 and COX-2) have been the mainstay in treating moderate to severe OA for many years because of their combined analgesic and anti-inflammatory actions. Risk factor assessment should be done in patients who are being considered for long-term therapy. A need for a gastro-protective agent should be considered in patients at high risk for gastrointestinal toxicity (Table 14-6).

COX-2 selective NSAIDs have been the medication of choice in OA patients at risk for gastrointestinal tox-icity. However, recent trials suggest a 1.5 to 2.0 times increased risk of cardiovascular events in patients receiving COX-2 selective NSAIDs, particularly rofecoxib and valdecoxib (both now withdrawn from the market), compared with nonselective COX inhibitors (see Chapter 3).

Table 14-6. Risk Factors for NSAID Toxicity.


Age >65 years old

Use of oral corticosteroids

History of abdominal pain and ulcer disease

Use of antiplatelet and anticoagulation drugs


Age >65 years old

Renal insufficiency


Congestive heart failure

Use of diuretics

Use of angiotensin-converting enzyme inhibitors


Tramadol is a weak opioid receptor agent and nore-pinephrine and serotonin reuptake inhibitor. Tramadol is used for moderate to severe OA pain and should be considered in patients who do not respond to acetaminophen or NSAIDs. Tramadol is also used as an adjunctive therapy with NSAIDs. Maximum dosing for younger patients (younger than 65 years of age) is 400 mg/d in four divided doses, and for older patients (older than 65 years of age) is 300 mg/d in four divided doses. Side effects include drowsiness, constipation, and gastrointestinal symptoms (see Chapter 3). Tramadol is rarely associated with seizures but should be used with caution in high-risk patients or patients taking antidepressants. Low risk exists for abuse potential and withdrawal symptoms (see Table 3-2).


For patients with significant pain and functional impairment despite maximal nonpharmacologic treatment and nonopioid analgesic or NSAIDs, opioids should be considered. Advantages of opioids include superior analgesic effect for nociceptive pain and lack of significant end organ toxicity. Fears of tolerance and diversion have proved unfounded in recent studies of opioid therapy of


nonmalignant musculoskeletal disease. In patients at very high risk for NSAID-related gastrointestinal or renal adverse effects, opioid agents may offer a superior risk benefit profile.

Intra-Articular Injections

  1. Corticosteroid Injections

Intra-articular corticosteroid injections are indicated in some patients with symptomatic OA; it is especially effective as adjunct treatment in patients in whom oral therapy is contraindicated or inadequate. In general, a large weight-bearing joint, such as the knee or hip, should not be injected more than 3 or 4 times per year. The agents most commonly used are methylprednisolone (80 to 120 mg per dose) and triamcinolone (20 to 40 mg per dose). These are usually combined with an anesthetic agent such as lidocaine (0.5 to 1%) or bupivacaine (0.25 to 0.5%). The volume and dose injected varies depending on the size of the joint.

Aseptic technique should be observed for all procedures. Before injecting, aspiration of synovial fluid for gross fluid examination may be performed if infection is a concern. If the fluid appears turbid or greenish-yellowish in color, injection should be aborted and synovial fluid analysis and culture should be performed.

If fewer than four injections are done per year, cartilage damage, pseudo-Charcot arthropathy, and avascular necrosis are rare complications. Patients should be warned of the more common complications, including infection, hemarthrosis, and corticosteroid-induced hyperglycemia in a diabetic patient.

  1. Viscosupplementation

Hyaluronan is a glycosaminoglycan responsible for synovial fluid viscoelasticity, which is reduced in OA joints by catalytic enzymes. Viscosupplementation therapy involves intra-articular injection of a hyaluronan derivative. Preparations available include hylan G-F 20 (administered weekly for 3 consecutive weeks) and sodium hyaluroniate (given as a weekly intra-articular injection for 5 weeks).

Clinical trials have produced conflicting results, but in a recent study, hylan G-F 20 showed significant analgesic effect compared with placebo as early as the third week continuing up to the eighth week following treatment. Previous uncontrolled cohort studies have demonstrated up to 1 year of symptomatic relief.

Experience with viscosupplementation in hip OA is limited, but recent reports suggest symptomatic relief and improvement of function at 3 months following injection. Adverse reactions include acute joint pain with effusion (particularly with hylan G-F 20 preparation), bleeding, and infection.


Older patients who have not responded to nonoperative treatment and are suffering from a moderate to severe disability due to pain should be considered for surgery. In younger patients in whom the risk of long-term failure or complication for artificial joints is high, delaying total joint arthroplasty, if possible, is the rule. Appropriate, “lesser” alternative procedures, such as arthroscopic debridement meniscectomy or high tibial meniscectomy for knee OA, should be considered.

Total hip and knee arthroplasty provide significant pain relief that usually translates to functional improvement. Perioperative mortality is below 1%. Early complications include deep venous thrombosis, pulmonary embolism, and infection. Late complications include aseptic loosening brought about by deterioration of cement (methylmethacrylate). Revision arthroplasty may be indicated in such patients.

Alternative Therapy

  1. Glucosamine

The most popular alternative treatment for OA is glucosamine sulfate, which is derived from oyster or crab shells. Glucosamine has been proposed as both a preventive modality and treatment for mild OA. A proposed mechanism of action is stimulation of proteoglycan synthesis, which may either prevent or retard the clinical progression of OA. Preliminary studies suggest a significant analgesic effect in about two-thirds of patients, comparable to NSAID therapy. In addition, a small placebo-controlled trial found reduced progression of radiographic knee OA in persons treated with glucosamine. The recommended therapeutic dose is 1500 mg of glucosamine daily. Glucosamine is well tolerated with few side effects. A combination of glucosamine and chondroitin has not been shown to have significant benefit versus glucosamine alone.

  1. S Adenosylmethionine

S adenosylmethionine (SAMe) is reported to increase production of proteoglycans, potentially benefiting patients with OA. Randomized trials demonstrating efficacy in OA have not been reported. SAMe is claimed to be as effective as NSAIDs in terms of symptom relief, with fewer side effects. SAMe (800 mg/d orally in two doses) is primarily advocated for mild OA. SAMe may take up to 1 week to produce clinical effects. Side effects include nausea and skin irritation. Other proposed potential indications include fibromyalgia and depression.

  1. Acupuncture

In a recent randomized, controlled trial, acupuncture was demonstrated to be efficacious in treating osteoarthritic knee pain. The basis for the analgesic effect of


acupuncture is postulated to be either release of endogenous opioids or, alternatively an interference with pain transmission based on the gate theory of pain. In addition, absence of known side effects makes acupuncture an attractive treatment option for patients unresponsive to or intolerant of more traditional therapy, including NSAIDs.

Baldwin CT et al. Absence of linkage or association for osteoarthritis with the vitamin D receptor/type II collagen locus: The Framingham Osteoarthritis Study. J Rheumato l. 2002;29:161.

Berman BM et al. Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial. Ann Intern Med.2004;141:901.

Cicuttini FM et al. Effect of estrogen replacement therapy on patella cartilage in healthy women. Clin Exp Rheumatol. 2003;21:79.

Conrozier T et al. Intra-articular injections of hylan G-F 20 in patients with symptomatic hip osteoarthritis: an open-label, multicentre, pilot study. Clin Exp Rheumatol. 2003;21:605.

Cubukcu D et al. Hylan G-F 20 efficacy on articular cartilage quality in patients with knee osteoarthritis: clinical and MRI assessment. Clin Rheumatol.2005;24:336.

Emkey R et al. Efficacy and safety of tramadol/acetaminophen tablets (Ultracet) as add-on therapy for osteoarthritis pain in subjects receiving a COX-2 nonsteroidal antiinflammatory drug: a multicenter, randomized, double-blind, placebo-controlled trial. J Rheumatol. 2004;31:150.

Hannan MT et al. Estrogen use and radiographic osteoarthritis of the knee in women. The Framingham Osteoarthritis Study. Arthritis Rheum. 1990;33:525.

Malonne H et al. Efficacy and tolerability of sustained-release tramadol in the treatment of symptomatic osteoarthritis of the hip or knee: a multicenter, randomized, double-blind, placebo-controlled study. Clin Ther. 2004;26:1774.

McAlindon T et al. Effectiveness of glucosamine for symptoms of knee osteoarthritis: results from an internet-based randomized double-blind controlled trial. Am J Med. 2004; 117:643.

McAlindon TE et al. Efficacy of glucosamine and chondroitin for treatment of osteoarthritis. JAMA. 2000;284:1241.

Messier SP et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial. Arthritis Rheum. 2004;50:1501.

Michaelsson K et al. Serum retinol levels and the risk of fracture. N Engl J Med. 2003;348:287.

Opotowsky AR et al; NHANES I follow-up study. Serum vitamin A concentration and the risk of hip fracture among women 50 to 74 years old in the United States: a prospective analysis of the NHANES I follow-up study. Am J Med. 2004; 117:169.

Raynauld JP et al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2003;48: 370.

Richy F et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med.2003;163:1514.

Roddy E et al. Evidence-based recommendations for the role of exercise in the management of osteoarthritis of the hip or knee-the MOVE consensus. Rheumatology (Oxford). 2005;44:67.

Solomon DH et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation. 2004; 109:2068.

Sowers M. Epidemiology of risk factors for osteoarthritis: systemic factors. Curr Opin Rheumatol. 2001;13:447.

White WB et al. Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal antiinflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis. Am J Ther. 2004; 11:244.

Witvrouw E et al. Open versus closed kinetic chain exercises in patellofemoral pain: a 5-year prospective randomized study. Am J Sports Med. 2004;32:1122.

Witvrouw E et al. Open versus closed kinetic chain exercises for patellofemoral pain. A prospective, randomized study. Am J Sports Med. 2000;28:687.

Wluka AE et al. Supplementary vitamin E does not affect the loss of cartilage volume in knee osteoarthritis: a 2 year double blind randomized placebo controlled study. J Rheumatol. 2002;29:2585.

Ytterberg SR et al. Codeine and oxycodone use in patients with chronic rheumatic disease pain. Arthritis Rheum. 1998;41:1603.

Rheumatoid Arthritis

Essentials of Diagnosis

  • RA remains a clinical diagnosis that requires the presence of symmetric, polyarticular, inflammatory arthritis for at least 4 to 6 weeks.
  • The presence of at least four of the criteria established by The American College of Rheumatology. Criteria 1 through 4 must be present for at least 6 weeks.

General Considerations

RA is a chronic progressive autoimmune disease with varying systemic features that affects 2.1 million people in the United States. RA causes pain, progressive joint destruction, fatigue, loss of mobility, and inability to perform activities of daily living. The primary pathology is a hypertrophied inflammatory synovium ultimately leading to erosive joint disease with pain, loss of function, and progressive disability. RA might be better termed “rheumatoid disease” because of its multiple extra-articular manifestations, including pleuritis, pericarditis, vasculitis, and pulmonary nodules among others (Table 14-7).

RA accounts for more than 9 million physician visits per year and at least 250,000 hospitalizations. The


substantial economic burden of RA is associated with both treatment costs and lost productivity and employment. Furthermore, RA significantly reduces life expectancy; age-adjusted mortality rates are increased by about 50%.

Table 14-7. Extra-articular Manifestations of Rheumatoid Arthritis.

System affected



Weight loss


Coronary vasculitis


Interstitial lung disease
Bronchiolitis obliterans


Entrapment neuropathy
Peripheral neuropathy
Mononeuritis multiplex


Subcutaneous nodules


Keratoconjunctivitis sicca
Choroid and retinal nodules


Felty syndrome

Epidemiologic studies indicate that the prevalence of RA is 0.5 to 1% of the adult populations in the United States and Europe. Certain Native American tribes show prevalence up to 5.3%. Prevalence increases with age and peaks between the ages of 40 and 60 years.

Joint pain and stiffness significantly impact quality of life in people with RA. Many people experience pain that impairs physical and psychological function despite receiving appropriate and aggressive treatment for underlying disease. Pain is sometimes viewed as an indication of disease activity even though disease activity and severity do not predict intensity of pain or level of function of the individual.

Most commonly, RA follows a progressive course punctuated by disease flares. Spontaneous lasting remission is rare, occurring in less than 5% of patients. Specific criteria for defining clinical remission include the following:

  1. Duration of morning stiffness lasting 15 minutes or longer
  2. No fatigue or joint pain by history
  3. No joint pain or tenderness or range of motion
  4. No soft tissue swelling in joints or tendon sheaths
  5. Erythrocyte sedimentation rate less than 30 mm/h for females or less than 20 mm/h for males
  6. C-reactive protein less than 10 mg/L

Early diagnosis and treatment of RA are crucial to maintaining optimal functional status in most patients. Recent studies describe development of erosive disease within the first few months of disease. Early and aggressive treatment may limit joint damage, preserving movement and ability to work while reducing medical costs and potential surgery.


RA is a disease of an aberrant immune response in a genetically predisposed host that leads to chronic progressive synovial inflammation and destruction of the joint architecture. The hallmark of RA is the proliferation of inflamed synovium, which spreads over the articular surface as a pannus and damages cartilage, bone, and joint capsule. Although research continues to broaden the understanding of the pathophysiologic mechanisms involved in the development and progression of RA, no clear triggering agent has been identified.

Although the precise cause of RA is unknown, hormonal, genetic, and environmental risk factors have been identified. The incidence of RA increases with age. However, incidence begins to decline when people reach their mid-70s. Females are 2 to 3 times more likely to develop rheumatoid arthritis than males. Genetic factors also play a role in some patients. There is a well-established association between RA and HLA-DR4 with an increased relative risk of in 4 to 5 patients with this allele. Recent research has demonstrated an association between RA and Runt-related transcription factor 1 (RUNX1), organic cation transporter gene SLC22A, and peptidylarginine deiminases citrullinating enzyme 4 (PADI4). Of lifestyle factors, only smoking has been associated with an increased risk of developing RA.


Since the precise etiology of RA has not been identified, preventing the disease is not possible. However, the destructive capacity, pain and stiffness, and resultant disability of RA may be reduced with appropriate recognition and early treatment.

Many nonspecific approaches have been suggested to prevent or minimize recurrences or flares. These include proper nutrition, relaxation, low-impact exercise,


flexibility exercises, yoga, tai chi, counseling, meditation, hydrotherapy, and stress reduction.

Clinical Findings

  1. Symptoms and Signs
  2. ACR Criteria

-The 1987 revised criteria of the American College of Rheumatology for RA were developed to aid with clinical assessment and performance of clinical trials. RA is diagnosed in patients who meet at least four of the following criteria (criteria 1 through 4 must be present for at least 6 weeks):

  1. Morning stiffness lasting at least 1 hour or longer
  2. Presence of 3 or more arthritic joint areas (of 14 possible areas)
  3. Arthritis of the hands
  4. Symmetric arthritis
  5. Rheumatoid (subcutaneous) nodules over bony prominences, extensor surfaces, or juxta-articular regions
  6. Serum rheumatoid factor
  7. Radiographic changes typical of RA (Table 14-8)

RA manifestations may be articular (joint pain, swelling, and stiffness) or nonarticular (see Table 14-7). Nonarticular findings may be classified as systemic (fever, fatigue) or nonsystemic (pleuritis, vasculitis, Felty syndrome, and Sjögren syndrome).

Articular RA can start in any joint, but it most commonly begins in the smaller joints of the fingers, hands, and wrists. Joint involvement is usually symmetric. Joints typically involved include the metacarpophalangeal, proximal interphalangeal, and wrists with sparing of the distal interphalangeal joints. Carpal tunnel syndrome may be an early manifestation of RA. The temporomandibular joint may also be involved. Joints are painful and typically swollen and warm. Prolonged stiffness in the joints in the morning or after prolonged inactivity is characteristic of inflammatory arthritis such asRA.

Table 14-8. Diagnostic Criteria for RA Established by the American College of Rheumatology.

· Morning stiffness or stiffness after rest lasting >1 hour

· Polyarthritis of at least 3 joints in 14 areas

· Arthritis of the hand joints

· Symmetric arthritis

· Rheumatoid nodules

· Serum rheumatoid factor

· Radiographic changes

RA, rheumatoid arthritis.

  1. Physical Examination

-Actively inflamed joints are swollen, warm, and tender to palpation. On palpation of the joint, a boggy sensation results from the combination of synovial proliferation and fluid. Synovial proliferation in the flexor tendons of the fingers fills the palm, giving it a flat appearance. Joint range of motion is initially limited by pain and later by contractures. Grip strength is reduced. Carpal tunnel syndrome and synovitis at the elbow manifested as inability to fully extend may be early indications of presence of RA. Ulnar deviation of the fingers at the metacarpophalangeal joint is a common deformity in established disease that results from radial deviation of the wrist and slippage of the extensor tendons to the ulnar side of the metacarpophalangeal joints. Another deformity of the hand that develops in chronic disease is the swan-neck deformity, which results from the flexion of the distal interphalangeal joint and metacarpophalangeal joint with hyperextension of the proximal interphalangeal joint. The boutonniere deformity is caused by avulsion of the extensor hood over the proximal interphalangeal joint. In advanced disease, subluxation and flexion deformities are common and involve the knees, ankles, elbows, wrists, shoulders, hands, and feet.

  1. Laboratory Studies
  2. Rheumatoid Factor

-Rheumatoid factor is found in the serum of about 85% of persons with RA. In the individual patient, rheumatoid factor titer is of limited prognostic value, and serial titers are of no value in following the disease process. Higher rheumatoid factor titers tend to correlate with more severe and unremitting disease, more radiologic abnormalities, nodules, extra-articular lesions, and worse functional ability. Conversely, seronegative patients generally have less destructive disease. Rheumatoid factor may be negative in early stages of disease and is not specific for RA. Rheumatoid factor may be present in other connective tissue disorders such as systemic lupus erythematosus (SLE), Raynaud disease, scleroderma, Sjögren syndrome as well as autoimmune thyroid disease and chronic infections such as tuberculosis and endocarditis.

  1. Anticyclic Citrullinated Peptides

-Many patients with RA have IgG antibodies to citrullinated peptides (anti-CCP antibody). Such anti-CCP antibodies appear relatively early in RA, are highly specific for the disease (98%), and can be measured by quite reproducible, readily available assay systems. Several experimental observations suggest that the immune responses to citrulline could play a significant role in the pathogenesis of RA


inflammation. In contrast to RF, anti-CCP antibodies fluctuate with activity of the disease.

  1. Acute Phase Reactants

-Acute-phase reactants such as the erythrocyte sedimentation rate and C-reactive protein measure the inflammatory response and correlate well with the degree of synovial inflammation. They are useful for following the course of inflammatory activity in an individual patient or monitoring response to treatment. Erythrocyte sedimentation rate is an indirect measure of inflammatory proteins and is not reliable in patients with significant anemia.

Thrombocytosis and eosinophilia occur more often in patients with severe disease, high rheumatoid factor titer, rheumatoid nodules, and extra-articular manifestations. Normochromic normocytic anemia of chronic disease is frequently seen in active RA.

  1. Diagnostic Imaging
  2. Radiography

-Early radiographic changes in RA include swelling of the soft tissues and periarticular osteopenia. With progressive disease, erosive changes appear. Baseline radiographs of hands or feet should be obtained within 3 months of diagnosis of RA and every 12 to 24 months thereafter to assess development or progression of destructive erosive change.

Since tenosynovitis of the transverse ligament of C1, which stabilizes the odontoid process of C2, may produce significant C1-2 instability, patients with RA planning surgery with general anesthesia (intubation) should be evaluated with a set of lateral flexion and extension views of the cervical spine.

  1. Magnetic Resonance Imaging

-New RA lesions may be detected 1 to 5 years earlier with MRI than with conventional radiography. MRI is particularly useful in identifying synovitis.

  1. Special Tests

It is important to assess functional status and monitor clinical disease activity during treatment. Traditional historical measures of rheumatoid disease activity include duration of morning stiffness (decreases in response to treatment) and time of onset of systemic fatigue (occurring later with response to treatment). Patient self-assessed pain level using a Visual Analogue Scale is very useful in monitoring disease activity and response to treatment. However, pain levels may be significant due to residual joint destruction even without active disease. Less specific historical indicators include need for supplemental or “rescue” analgesics and lost work days. Clinical measures of disease activity include counting the number of swollen joints or in the absence of fixed deformity, range of motion of involved joints. Several well-validated self-administered instruments are available to monitor functional status in RA patients. These include the Health Assessment Questionnaire and the Arthritis Impact Measurement Scale.

Differential Diagnosis

Table 14-9 outlines the key distinguishing features of the seven conditions discussed in this section, including OA, systemic lupus erythematosus (SLE), polymyalgia rheumatica (PMR), infectious arthritis, crystalline arthritides, seronegative spondyloarthropathies, and


fibromyalgia. Table 14-10 lists a more detailed differential diagnosis that is divided into acute and chronic inflammatory disorders.

Table 14-9. Key Distinguishing Features.




Late age at onset
Lack of inflammation and constitutional symptoms
DIP and PIP involvement

Systemic lupus erythematosus

Positive antinuclear antibody
Typically not erosive

Polymyalgia rheumatica

Predominant hip and shoulder involvement
Temporal arteritis symptoms

Infectious arthritis

Duration is key

Crystalline arthritides

Synovial fluid analysis is usually definitive

Seronegative spondyloarthropathies

Back pain
Affects more men than women


Absence of swelling, rheumatoid factor, and ESR/CRP elevation

DIP, distal interphalangeal; PIP, proximal interphalangeal; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.

Table 14-10. Differential Diagnosis of Rheumatoid Arthritis.

Acute Inflammatory Disorders

Crystal-induced arthropathy



Infectious arthritis



Connective tissue disease-associated arthritis

  Systemic lupus erythematosus




Seronegative spondyloarthropathies

  Reiter syndrome

  Psoriatic arthritis

Chronic Inflammatory Disorders


Connective tissue disease-associated arthritis

  Systemic lupus erythematosus




Seronegative spondyloarthropathies

  Ankylosing spondylitis

  Reiter syndrome

  Psoriatic arthritis

  Enteropathic arthropathies

Chronic regional pain syndrome

  1. Osteoarthritis

OA is differentiated from RA by onset later in life, pattern of joint involvement (proximal interphalangeal, distal interphalangeal, monoarticular involvement of hip or knee, propensity for neck and low back), and absence of inflammatory signs and symptoms. OA is rarely erosive and lacks the morning gelling and systemic features associated with RA.

  1. Systemic Lupus Erythematosus

SLE and other connective tissue diseases may mimic RA with symmetric joint inflammation. SLE is not typically erosive. Clinical manifestations of SLE (eg, fever, serositis, dermatitis, nephritis) and serologic findings (eg, cytopenia, ANA seropositivity, anti-DNA seropositivity) assist with making the correct diagnosis.

  1. Polymyalgia Rheumatica

PMR and giant cell arteritis may present with symmetric polyarthritis. RA in the elderly may mimic PMR. The presence of arteritic signs or symptoms such as headache, joint claudication, or visual change with predominant shoulder and hip girdle stiffness support the diagnosis of PMR.

  1. Infectious Arthritis

Infectious arthropathies are an important consideration in the setting of fever and polyarthritis. Joint aspiration as well as synovial fluid cultures and blood cultures are often helpful in establishing the diagnosis of bacterial arthritis. Lyme disease may present with myalgias and arthralgias in the setting of erythema chronicum migrans and history of tick bite. Viral arthritides (parvovirus B19, rubella infection, or immunization) often distinguish themselves by history of exposure, accompanying rash, and self-limited course.

  1. Crystal Deposition Arthritis

Polyarticular crystal arthropathies, such as gout and pseudogout, may mimic RA. Synovial fluid analysis is usually definitive in crystalline arthritis if performed early during an acute attack. Erosions may be seen in gouty arthritis but they differ from the marginal erosive changes of RA. Chondrocalcinosis may be apparent with pseudogout.

  1. Seronegative Spondyloarthropathies

The seronegative spondyloarthropathies include enteropathic arthritides, psoriatic arthritis, ankylosing spondylitis, and reactive arthritis. Seronegative spondyloarthropathies characteristically present with asymmetric inflammatory disease of the large joints. Involvement of the lumbosacral spine, absence of small-joint disease, and sausaging of the digits support the diagnosis of seronegative spondyloarthropathies. Coexisting uveitis, urethritis, psoriasis, or inflammatory bowel disease also favor a diagnosis of seronegative spondyloarthropathies.

  1. Fibromyalgia

Although noninflammatory, fibromyalgia may present with diffuse symmetric arthralgias and stiffness at rest. Normal laboratory and imaging studies with the absence of synovitis help differentiate fibromyalgia from RA. Fibromyalgia coexists in 10 to 15% of the patients in whom rheumatic diseases such as RA and SLE are diagnosed.


Medications used in the treatment of RA may be categorized as analgesics, anti-inflammatory agents, or disease-modifying antirheumatic drugs (DMARDs)


(Table 14-11). In general, analgesics and anti-inflammatory drugs relieve symptoms but do not retard joint damage. Typically, they are more rapidly acting in providing symptomatic benefit in comparison to DMARDs, though newer anti-tumor necrosis factor (TNF) agents also often provide prompt relief of pain and stiffness.

Table 14-11. Pharmacologic Treatment for Rheumatoid Arthritis




Anti-inflammatory Agents





Disease-modifying Antirheumatic Drugs



Immunosuppressive Agents




Anticytokine Therapy

  Anti-TNF agents




Interleukin receptor antagonists


Other Agents



NSAIDs, nonsteroidal anti-inflammatory drugs; TNF, tumor necrosis factor.

Most patients are initially treated with a combination of an anti-inflammatory agent and one or more DMARDs. Pure analgesics have an important role in supplementing symptom control, particularly pain, and as substitutes for NSAIDs in patients who are intolerant or who are at high-risk for adverse effects. Intra-articular administration of a corticosteroid is important adjunctive therapy in some patients with active disease in an isolated joint. In patients with a polyarticular flare, systemic corticosteroids, either orally or parenterally may provide acute symptom control.

Immediate therapy with DMARDS not only improves symptom control but more importantly retards the progression of erosive, destructive joint disease at an earlier stage. The American College of Rheumatology currently recommends DMARD therapy within 3 months of disease onset. Hopefully, this more aggressive approach will result in preservation of joint structure and function, reduced long-term disability, reduced health care costs and preservation of economic productivity.

In the management of RA, nonpharmacologic treatment must not be neglected. Patient education, physical and occupational therapy, activity modification, and psychosocial support also play important roles in optimizing patient outcome.

Surgical treatment, particularly joint replacement, has dramatically improved the quality of life of many patients with RA over the past 30 years.

  1. Nonsteroidal Anti-Inflammatory Drugs

NSAIDs have long been used as initial therapeutic agents in RA for rapid symptom control. These agents inhibit to some degree one or both COX enzymes (COX-1 and COX-2). The traditional NSAID adverse effects gastropathy and nephrotoxicity are primarily associated with inhibition of COX-1 synthesis. Older, nonselective NSAIDs affect both enzymes, resulting in greater risk of COX-1 adverse effects.

Gastric or duodenal ulcers that can be seen endoscopically develop in 15 to 20% of persons taking nonselective NSAIDs. More significant symptomatic lesions develop in 2 to 4% with 1 to 2% noting ulcer complications of bleeding or perforation. Risk factors for NSAID gastropathy include older age, higher dose NSAID, previous history of peptic ulcer disease, previous use of antacids or H2-antagonists, concomitant use of corticosteroids, and more severe inflammatory disease.

Selective COX-2 inhibitors are associated with an approximate 50% reduction in prostaglandin-mediated clinical gastrointestinal toxicity in comparison to nonselective agents. However, accumulating evidence suggests therapy with newer selective COX-2 agents (ie, rofecoxib and valdecoxib, which are no longer available) is associated with a significant increase in cardiovascular adverse events including myocardial infarction and stroke, particularly at higher doses and in higher risk patients. No difference in efficacy between COX-2 inhibitors and nonselective drugs has been demonstrated. In addition, no difference in renal toxicity between the two classes of NSAIDs has been shown.

Based on currently available data, patients with rheumatoid disease who require NSAID therapy but who are at high risk for gastrointestinal adverse effects and who have no history or risk factors for cardiovascular events may be treated with celecoxib. Alternatively,


a nonselective NSAID may be combined with a proton pump inhibitor such as omeprazole for gastric protection. In patients with significant cardiovascular risk factors or history, selective COX-2 NSAIDs should be avoided.

Unfortunately, co-therapy with low-dose aspirin for cardiovascular prophylaxis in such patients negates the COX-2 inhibitor's beneficial reduction of gastrointestinal toxicity. Low-dose (<10 mg prednisone equivalent) corticosteroid therapy combined with a pure analgesic such as acetaminophen represents a reasonable alternative to an NSAID for management of inflammatory symptoms.

  1. Corticosteroids

Corticosteroids may be administered systemically or locally for treatment of RA. Low-dose (<10 mg prednisone equivalent) corticosteroids taken orally are typically combined with other medications in initial management of RA. Corticosteroids provide prompt suppression of inflammation and may be viewed as “bridging therapy” while treatment with more slowly acting DMARDs is being initiated. Many patients remain on long-term corticosteroid therapy, however, posing risk of long-term corticosteroid toxicity, particularly cataracts and bone loss (osteoporosis). In persons in whom longer term use of corticosteroid therapy is anticipated, baseline bone density measurement is recommended and prophylactic treatment with calcium supplementation, vitamin D, and antiresorptive therapy such as diphosphonates should be considered.

For patients experiencing generalized “flares” of disease activity, a short, rapidly tapering course of an oral corticosteroid may provide prompt, short-term relief of severe polyarticular and systemic symptoms. Alternatively, intramuscular injection of a “depo” corticosteroid may provide similar benefit. Use of such “pulse” treatment should be reserved for episodic treatment of severe flares and probably limited to 2 to 3 times yearly. Excessive administration of intramuscular or pulse corticosteroids is associated with risk of iatrogenic Cushing syndrome as well as the full range of corticosteroid toxicity and should prompt reevaluation of the patient's regular rheumatoid therapy.

Intra-articular injection of corticosteroid may effectively reduce inflammatory pain and swelling in joints refractory to systemic therapy. Injection into any single joint should be limited to three or four times within 1 year. Systemic absorption of corticosteroid occurs and diabetic patients should be warned about the possibility of transient hyperglycemia.

  1. Disease-Modifying Antirheumatic Drugs

The defining characteristic of a DMARD is the ability to retard erosive joint damage by controlling synovial inflammation. For most older DMARDs, the precise mechanism of action is unknown.

The American College of Rheumatology currently recommends starting DMARD therapy within 3 months of disease onset. Most patients should be started on DMARD therapy at the time of initial diagnosis. DMARDs may be used as monotherapy or in combinations depending on the disease severity, prognostic features, costs, and comorbidity. In addition to slowing radiographic progression of disease, DMARDs are more effective than NSAIDs in reducing systemic symptoms such as fever or fatigue.

  1. Antimalarials

-These agents, including hydroxychloroquine and chloroquine, are less potent DMARDs often used to treat early or mild RA in combination with an NSAID. Hydroxychloroquine is well tolerated but slow-acting, which is a characteristic feature of most older DMARDs. Patients may not notice therapeutic effect for 3 to 6 months. If total daily dose is limited to 5.5 mg/kg/d and never exceeds 400 mg/d, serious retinal toxicity is rare. Annual ophthalmologic examination is required in all patients, however, to detect retinopathy.

  1. Methotrexate

-Methotrexate is a folate analog that blocks DNA synthesis, though its antirheumatic effect may be related to other anti-inflammatory properties of the drug.

For most patients with active RA, methotrexate remains the first-line choice because of its established and sustained efficacy with manageable toxicity as well as a substantial cost advantage over newer biologic agents. Approximately 60% of patients with RA respond to methotrexate, which is comparable to the results seen with newer biologic agents, such as etanercept.

Methotrexate is typically administered in a once weekly oral dose of 7.5 to 15 mg. Escalation of dose by 2.5 to 5.0 mg increments based on clinical response should be considered at 4- to 6-week intervals. In the absence of significant toxicity, the dose of methotrexate may be increased to 20 to 25 mg weekly based on the clinical response. Clinical response to the drug occurs with 4-12 weeks. Clinical indicators of response include reduced morning stiffness and systemic fatigue as well as the number of swollen, tender joints. A significant proportion of patients with early RA can achieve disease control for at least 1 year by taking methotrexate alone.

Methotrexate is excreted by the kidneys and is contraindicated in patients with creatinine levels over 2.0 to 2.5 mg/dL. Patients who consume significant amounts of alcohol on a regular basis should not be treated with methotrexate because of risk of hepatic toxicity. In general, limiting alcohol intake to the equivalent of a glass of wine once or twice weekly is reasonable advice for patients taking methotrexate. Regular monitoring of liver function tests (complete blood count, aspartate


aminotransferase, and alanine aminotransferase) is appropriate, but hepatic fibrosis may occur in the face of normal enzymes. Regular liver biopsy to monitor for fibrosis is not routinely recommended at antirheumatic doses of methotrexate.

In patients in whom methotrexate is contraindicated, initial therapeutic alternatives include sulfasalazine, hydroxychloraquine, or even etanercept or adalimumab, depending on the severity of the disease.

Methotrexate may be combined with anti-TNF drug therapy (etanercept, infliximab, or adalimumab). Recent trials suggest combined methotrexate and anti-TNF therapy is more efficacious than monotherapy with either agent. However, long-term toxicity of combined therapy is unknown, (ie, is the risk of lymphoma increased?). Also, cost-benefit analysis of combined versus monotherapy needs further study. Patients with active rheumatoid disease who do not respond to anti-TNF therapy alone or in combination with methotrexate should be considered for treatment with anakinra (see below).

  1. Leflunomide

-Leflunomide is a pyrimidine synthesis inhibitor with a clinical profile very similar to methotrexate. Efficacy that is similar to methotrexate, including reduction in radiographic erosive disease, has been demonstrated. Like methotrexate, hepatic toxicity occurs, elevating liver enzymes. Diarrhea is a common side effect of the drug, which may require discontinuation of treatment. Leflunomide therapy is initiated with a 3-day loading dose (100 mg/d) and then continued in a single 20-mg daily dose. Like methotrexate, improvement in signs and symptoms occurs within about 6 weeks. Regular monitoring for thrombocytopenia and liver enzyme elevation should be performed.

  1. Sulfasalazine

-Though initially developed as an anti-inflammatory antirheumatic drug in the precorticosteroid era more than 60 years ago, sulfasalazine has been more widely used to treat inflammatory bowel disease. Sulfasalazine demonstrates modest DMARD qualities including reduction in radiographic erosive disease and improvement in articular inflammatory signs and symptoms. The mechanism of action of the drug in RA is not known, but the metabolites of the drug-sulfapyridine and 5-ASA-have a variety of effects on cellular immune function.

Sulfasalazine is best administered in an enteric-coated form to reduce the risk of gastrointestinal toxicity. Therapy is initiated at a dose of 500 mg/d with escalation over 1 to 2 months to the full antirheumatic dose of 2000 mg/d. Sulfasalazine is slow acting with approximately 3 months of therapy required before clinical improvement occurs. Toxicity of sulfasalazine includes gastrointestinal distress (minimized by the enteric-coated preparation) and, rarely, agranulocytosis. Complete blood count should be performed regularly to monitor for toxicity.

  1. Immunosuppressive Agents

Azathioprine, cyclophosphamide, and cyclosporine have largely been replaced as treatment for severe, active RA by newer biologic therapies including anti-TNF agents (etanercept, infliximab, adalimumab) and interleukin receptor antagonists (anakinra). In general, use of these older immunosuppressives is limited primarily by significant toxicity. Cyclosporine commonly causes hypertension and renal impairment, complicating its use with methotrexate in RA. Cyclophosphamide is an alkylating agent with significant toxicity. Hemorrhagic cystitis, bone marrow suppression, and risk of lymphoma are major concerns. Azathioprine is the most commonly used drug in this group, often in combination with methotrexate. Bone marrow suppression and concerns regarding oncogenicity limit its usefulness.

  1. Anticytokine Therapy

The newest agents available for treatment of RA are targeted at proinflammatory cytokines, which are central to the pathogenesis of the disease. Sometimes referred to as “biologics” for “biologic response modifiers,” these presently include three drugs targeted at TNFα and one interleukin-1b antagonist. TNFα and interleukin-1b are secreted by synovial macrophages and T helper lymphocytes and play a major role in pannus development and joint destruction. They stimulate proliferation of synovial cells and production of collagenase, which degrades cartilage contributing to erosive joint damage.

TNFα also promotes recruitment of other inflammatory cells and increased secretion of interleukins, perpetuating the inflammatory process. By specifically interfering with this inflammatory cascade, the biologics produce prompt and significant clinical effects in patients with RA. The cost of anticytokine therapy is substantial, exceeding $12,000 annually. This represents a significant consideration in choice of first-line therapy for many patients.

  1. Etanercept

-Etanercept is a TNFα receptor fusion protein that binds soluble TNFα, inhibiting its ability to bind to cellular surface receptors and exert its proinflammatory effects. Etanercept produces comparable clinical improvement to methotrexate (20 mg weekly) in the signs and symptoms of RA but does so much more rapidly, often within 2 weeks of the first dose. Long-term studies comparing methotrexate and etanercept suggest comparable benefits in reducing radiographic damage to joints. Combined therapy with etanercept and methotrexate is more effective than either drug alone. Long-term follow-up studies now beyond 6 years suggest


continued efficacy and safety of combined methotrexate and etanercept.

Etanercept is administered by subcutaneous injection, either in a single 50-mg weekly dose or in two 25-mg split weekly doses with comparable efficacy. Mild injection site reactions occur in about one-third of patients, particularly during early therapy. Opportunistic infections, which may be life-threatening rarely occur in patients treated with etanercept.

Reactivation of tuberculosis is a particular concern and patients should be screened for tuberculosis by history and with a purified protein derivative (PPD) skin test before starting therapy. Demyelinating disease and non-Hodgkins lymphomas have rarely been reported in patients using etanercept. The incidence of non-Hodgkins lymphomas in etanercept-treated patients is comparable to the RA population in general. Cytopenias have rarely been reported.

  1. Infliximab

-Infliximab is a chimeric (murine/human) IgG monoclonal antibody to TNFα which in combination with methotrexate has comparable efficacy to etanercept in the treatment of RA. The drug is administered by intravenous infusion at a dose of 3 to 5 mg/kg at intervals of 4 to 8 weeks. Clinical response is rapid. Antibodies to the drug develop in about 40% of patients but do not appear to affect efficacy or safety.

Infusion reactions characterized by headache, rash, nausea, or hypotension may occur and are usually mild. As with etanercept, serious infections, particularly tuberculosis, have been reported with infliximab therapy. Most cases represent reactivation of dormant disease and occur within 6 months of starting infliximab therapy. Ex-trapulmonary disease is common. Screening as discussed with etanercept is mandatory in patients before initiating treatment. Anticytokine treatment should be suspended in patients in whom a serious infection is developing. Vaccination with a live vaccine is contraindicated during treatment with all TNF inhibitors. Higher doses of infliximab (10 mg/kg) in patients with heart failure have caused worsening of the failure. As with etanercept therapy, infliximab treatment has been associated with development of autoantibodies, including anti-double-stranded DNA. Rarely, a lupus-like reaction has been seen with either infliximab or etanercept. Since all patients receiving infliximab are also treated with methotrexate, appropriate monitoring for methotrexate adverse effects, as discussed earlier, is required.

  1. Adalimumab

-Adalimumab is a fully human recombinant IgG antibody to TNFα with similar efficacy and toxicity to etanercept and infliximab. Adalimumab is effective as monotherapy or in combination with methotrexate. Adalimumab provides additional benefit to patients taking a stable dose of methotrexate alone. Adalimumab is administered by subcutaneous injection in a recommended dose of 40 mg every other week.

  1. Anakinra

-Interleukin-1 receptor antagonist protein (IL-1Ra) is a naturally occurring IL-1 inhibitor that binds to the IL-1 receptor without producing cellular activation, effectively blocking the proinflammatory effects of IL-1. Anakinra is a human recombinant IL-1 receptor antagonist that has demonstrated efficacy in patients with RA. Clinical benefits and radiographic effects are generally fewer than those with anti-TNFα agents. Anakinra is administered daily by subcutaneous injection.

A significantly increased risk of serious infection has been seen when anakinra is combined with anti-TNFα drugs such as etanercept. Combination with older DMARDs such as methotrexate or sulfasalazine appears safe.

  1. Analgesics

Pure analgesics play an important role in arthritis pain management. In patients with active RA, inflammatory pain is best managed with NSAIDs, corticosteroids (systemic or intra-articular) and ultimately with control of disease by a DMARD such as methotrexate. The presence of active inflammation is suggested by prolonged morning stiffness, systemic fatigue, and palpable joint swelling (synovitis) and warmth. However, some patients with active disease require additional analgesic treatment during initiation of DMARD therapy or because of toxicity or intolerance to NSAIDs or corticosteroids. For some patients, full dose acetaminophen is adequate adjunctive treatment but many require at least transient or supplemental treatment with an opioid analgesic.

Some patients with RA who have responded well to DMARD therapy still experience significant pain as a consequence of significant joint damage from quiescent prior synovitis. In these patients, inflammatory signs and indicators are absent. These symptoms do not require escalation of anti-inflammatory or DMARD therapy.

Treatment of pain in persons with controlled or “burnt-out” RA is similar to pain management discussed for OA and involves local (topical or intra-articular) modalities, assistive devices, as well as nonopioid and opioid analgesics.

  1. Other Therapies

Gold compounds administered parenterally or orally have demonstrated efficacy and a long history of use in RA but are rarely used at this time. Less than 10% of patients continue taking gold 5 years after starting therapy in contrast to much higher rates of patients treated with methotrexate or anticytokine drugs. For similar reasons, D-penicillamine use for RA has declined precipitously as well.

Minocycline is an antibiotic that has been shown to favorably affect signs and symptoms of RA. Its mechanism


of action is unknown but the drug has anti-inflammatory properties. No disease-modifying effect has ever been demonstrated.

  1. Nonpharmacologic Therapies

A comprehensive approach to treatment of rheumatoid arthritis is required to ensure the efficacy of the management plan, ultimately providing decreased pain, increased mobility, and improved patient satisfaction and quality of life.

  1. Education

-Patient education is essential early in the disease course and on an ongoing basis. Because RA may make a patient prone to fatigue and muscle weakness, energy conservation and joint protection techniques are important in limiting pain while maintaining function. Education is directed at patients and family members.

  1. Exercise

-Muscle strengthening or aerobic exercise programs also play an important role in maintenance of function and optimizing outcome. All individuals should be encouraged and supported to participate in the minimum level of physical activity recommended by the US Surgeon General-at least 30 minutes of moderate physical activity on most days of the week. Persons with OA and RA who have difficulty in maintaining minimum levels of physical activity may be referred to physical or occupational therapy to evaluate and reduce impairments in range of motion, flexibility, strength, and endurance as well as receive instruction in joint protection strategies. Therapists will properly prepare an individual for successful participation in a community-based or self-directed exercise program. In addition, modalities such as splinting, ice, heat, paraffin baths (see Chapter 6), and massage have been shown to be useful for pain management in adults with RA. Transcutaneous electrical nerve stimulation (TENS) has been shown to improve wrist function while reducing pain with minimal adverse effects in RA patients.

  1. Self-Management Techniques

-A patient's thoughts, feelings, emotions, and behavior, and his or her family's response, can influence the arthritis pain experience. Therefore, education about pain, pain management options, and self-management programs should be communicated to the patient and family as an integral and cost-effective part of treatment. The degree to which RA affects daily activities depends in part on how well the patient can cope with the disease. Cognitive-behavioral therapy may be used to reduce pain and psychological disability and to enhance self-efficacy and pain coping. Use of assistive equipment or devices (Table 14-12) is another adjunctive treatment to help maintain function while minimizing or reducing pain.

  1. Alternative Therapies

-People with arthritis should be advised to maintain an ideal body weight and ad here to a balanced diet containing adequate amounts of protein, fat, vitamins, and minerals. Adults should lose weight if their body mass index is greater than 30 and follow a weight management program. Fish oil supplements, fasting, and a vegetarian diet may reduce pain in some patients with RA. Evidence from double-blind, placebo-controlled randomized clinical trials supports dietary omega-3 polyunsaturated fatty acids in reducing morning stiffness and joint tenderness in RA. However, the clinical application of fish oil in the treatment of RA is not well-defined in terms of dose and duration of therapy. Fish oil has not been shown to benefit patients with OA.

Table 14-12. Assistive and Adaptive Equipment to Help Patients with Rheumatoid Arthritis.

Aimed at Improving Movement or Positioning

Compression gloves

Elastic wrist extensor orthoses

Resting hand splints

Thumb post splints

Dynamic splints

Ankle and foot orthoses

Knee braces

Spinal orthoses

Aimed at Improving Activities of Daily Living

Custom shoes






Built-up handles on brushes (tooth and hair) and eating

Button/zipper hook

Velcro fasteners on clothing

Elastic shoe laces

Sock aids

Long handle shoe horn

Jar openers

Fasting has been shown to reduce pain and stiffness associated with RA. However, most persons relapse as food is reintroduced. Fasting followed by a vegetarian diet for 1 year has shown a reduction in the number of tender joints and duration of morning stiffness. Reduction of


joint inflammation and pain was sustained if vegetarian diet was followed. There is insufficient evidence of the benefits of electromagnetic field therapy to recommend its use in the management of pain related to arthritis. Prayer and spirituality may also play a role in reduction of pain in patients with RA.

  1. Surgery

Indications for surgery in RA include loss of function and pain that is refractory to medical management. For optimal functional results, people with disabling arthritis should be referred for surgical care prior to the onset of joint contracture, severe deformity, advanced muscular wasting, and deconditioning rather than as a last resort. If the patient has severe pain in the hips and knees that significantly limits activities despite any drug or nondrug therapies, with significant radiographic damage, orthopedic referral should be considered.

  1. Arthroplasty

-Joint replacement surgery restores the integrity and functional power of a joint. For many people with RA whose joints are severely damaged, joint replacement surgery can restore joint function, reduce pain, or correct a deformity. Hip and knee total joint arthroplasty provide major improvement in musculoskeletal function and improved quality of life with benefit of complete pain relief in most cases. Because of their documented effectiveness, these procedures should be offered to patients when nonsurgical management becomes less effective and preferably before deconditioning becomes severe and difficult to reverse.

  1. Arthrodesis

-Arthrodesis is the surgical removal of the articular surface and fixation of the two bones to pro mote bone fusion at the prior joint. Joints treated with total joint arthroplasty (hip, knee, shoulder, and less frequently the elbow) are rarely treated with arthrodesis because of the likelihood of functional deficit. The most successful arthrodesis is performed on joints where replacement is not an option, such as the subtalar, calcaneocuboid, talonavicular, midfoot joints of the feet, and the lesser joints of the hands and feet.

  1. Synovectomy

-Synovectomy is sometimes performed to remove inflammatory tissue and retard joint destruction. Synovectomy of selected joints may transiently alleviate symptoms and improve function in the first year after operation. Long-term benefits of synovectomy are less clear and concurrent medical therapy must be maintained. Removal of synovial tissue from the wrist and dorsal tendon sheath and resection of the ulnar head might prevent rupture of extensor tendons in patients at risk.

Table 14-13. Poor Prognostic Indicators for Patients with Rheumatoid Arthritis

More than 10-20 joints involved

Extra-articular manifestations (especially nodules and vasculitis)

Rheumatoid factor-positive

Erosionson radiographs within 2 years of disease on set

HLA-DR4 genetic marker

Education level lower than 11th grade


The course of the disease varies considerably among individuals. Poor prognosis is suggested by earlier age at disease onset, high titer of rheumatoid factor, elevated erythrocyte sedimentation rate, and swelling of more than 20 joints. Extra-articular manifestations of RA, such as rheumatoid nodules, Sjögren syndrome, episcleritis and scleritis, interstitial lung disease, pericardial involvement, systemic vasculitis, and Felty syndrome, may also indicate a worse prognosis (Table 14-13).

Studies have shown that patients with active, polyarticular, rheumatoid factor-positive RA have a greater than 70% probability of joint damage or erosions developing within 2 years of the onset of disease. Since studies have demonstrated that DMARDs may alter the disease course in patients with recent-onset RA, particularly those with unfavorable prognostic factors, aggressive treatment should be initiated as soon as the diagnosis has been established. Frequently, the disease can be controlled with a combination of treatments. Treatment may vary depending on the severity of the symptoms.

Remission is most likely to occur in the first year and the probability decreases as time progresses. About 20% of persons will have experienced remission by 10 to 15 years from diagnosis.

Between 50 and 70% of patients with RA will remain capable of full-time employment. After 15 to 20 years, only 10% of patients are severely disabled, and unable to perform simple activities of daily living (washing, toileting, dressing, eating). The average life expectancy of patients with RA may be shortened by 3 to 7 years. Patients with severe forms of RA may die 10 to 15 years earlier than expected.

American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: Arthritis Rheum.2002;46:328.

Borchers AT et al. The use of methotrexate in rheumatoid arthritis. Semin Arthritis Rheum. 2004;34:465.

Bukhari MA et al. Influence of disease-modifying therapy on radiographic outcome in inflammatory polyarthritis at five years:



Results from a large observational inception study. Arthritis Rheum. 2003;48:46.

Choi HK. Diet and rheumatoid arthritis: Red meat and beyond. Arthritis Rheum. 2004;50:3745.

Ejbjerg B et al. Low cost, low field dedicated extremity MRI is highly specific and sensitive for synovitis and bone erosions in rheumatoid arthritis wrist and finger joints: A comparison with conventional high-field MRI and radiography. Ann Rheum Dis. 2005;64:1280.

Haraoui B. The anti-tumor necrosis factor agents are a major advance in the treatment of rheumatoid arthritis. J Rheumatol Suppl. 2005;72:46.

Herman CJ et al. Use of complementary therapies among primary care clinic patients with arthritis. Prev Chronic Dis. 2004;1:A12.

Kuritzky L et al. Advances in rheumatology: Coxibs and beyond. J Pain Symptom Manage. 2003;25:S6.

Li LC. What else can I do but take drugs? The future of research in nonpharmacological treatment in early inflammatory arthritis. J Rheumatol Suppl.2005;72:21.

Maddison P et al. Leflunomide in rheumatoid arthritis: Recommendations through a process of consensus. Rheumatology (Oxford). 2005;44:280.

Maetzel A. Cost-effectiveness estimates reported for tumor necrosis factor blocking agents in rheumatoid arthritis refractory to methotrexate-a brief summary. J Rheumatol Suppl. 2005;72:51.

O'dell J. Rheumatoid arthritis initial therapy: Unanswered questions. J Rheumatol Suppl. 2005;72:14.

Osiri M et al. Leflunomide for treating rheumatoid arthritis. J Rheumatol. 2003;6:1182.

Pincus T et al. Methotrexate as the “anchor drug” for the treatment of early rheumatoid arthritis. Clin Exp Rheumatol. 2003;21 (Suppl 31):S179.

Quinn MA et al. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: Results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52:27.

Rantapaa-Dahlqvist S et al. Antibodies against citrullinated pep-tide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48:2741.

Sander O. Long-term use of combination DMARDs did not sustain disease remissions, but delayed joint damage in early rheumatoid arthritis. ACP J Club. 2005; 142:9.

Saraux A et al. Value of antibodies to citrulline-containing pep-tides for diagnosing early rheumatoid arthritis. J Rheumatol. 2003;30:2535.

Schooff M et al. Is leflunomide as safe and effective in the treatment of rheumatoid arthritis as other DMARDs? Am Fam Physician. 2003;68:849.

Stephensen CB. Fish oil and inflammatory disease: Is asthma the next target for n-3 fatty acid supplements? Nutr Rev. 2004;62:486.