Jennifer B. Soep, MD
JUVENILE IDIOPATHIC ARTHRITIS
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Arthritis, involving pain, swelling, warmth, tenderness, morning stiffness, and/or decreased range of motion of one or more joints, lasting at least 6 weeks.
May have associated systemic manifestations, including fever, rash, uveitis, serositis, anemia, and fatigue.
Juvenile idiopathic arthritis (JIA) is characterized by chronic arthritis in one or more joints for at least 6 weeks. There are four main subtypes of JIA: (1) oligoarticular, (2) polyarticular, (3) systemic, and (4) enthesitis-associated. The exact cause of JIA is not known, but there is substantial evidence that it is an autoimmune process with genetic susceptibility factors.
A. Symptoms and Signs
The most common type of JIA is the oligoarticular form, which constitutes approximately 30%–40% of patients and is characterized by arthritis of four or fewer joints. This type of JIA often affects medium to large joints. Because the arthritis is often asymmetrical, children may develop a leg-length discrepancy in which the involved leg grows longer due to increased blood flow and growth factors. The synovitis is usually mild and may be painless. Systemic features are uncommon except for inflammation in the eye. Up to 20% of children with this type of JIA develop insidious, asymptomatic uveitis, which may cause blindness if untreated. The activity of the eye disease does not correlate with that of the arthritis. Therefore, routine ophthalmologic screening with slit-lamp examination must be performed at 3-month intervals if the antinuclear antibody (ANA) test is positive, and at 6-month intervals if the ANA test is negative, for at least 4 years after the onset of arthritis, as this is the period of highest risk.
Polyarticular disease is defined as arthritis involving five or more joints. This type of JIA affects 25% of patients. Both large and small joints are involved, typically in a symmetrical pattern. Systemic features are not prominent, although low-grade fever, fatigue, rheumatoid nodules, and anemia may be present. This group is further divided into rheumatoid factor (RF)-positive and RF-negative disease. The former resembles adult rheumatoid arthritis with more chronic, destructive arthritis.
The systemic form, previously known as Still disease, comprises 5%–10% of patients with JIA. The arthritis can involve any number of joints and affects both large and small joints, but may be absent at disease onset. One of the classic features is a high fever, often as high as 39°C–40°C, typically occurring one to two times per day. In between fever spikes, the temperature usually returns to normal or subnormal. Ninety percent of patients have a characteristic evanescent, salmon-pink macular rash that is most prominent on pressure areas and when fever is present. Other systemic features that may be present, but are not specific for JIA, include hepatosplenomegaly, lymphadenopathy, leukocytosis, and serositis.
Enthesitis-associated arthritis is most common in males, older than 10 years of age, and is typically associated with lower extremity, large joint arthritis. The hallmark of this form is inflammation of tendinous insertions (enthesopathy), such as the tibial tubercle or the heel. Low back pain and sacroiliitis are also commonly seen in this form of arthritis which comprises approximately 10%–20% of patients with JIA.
There are two additional subtypes of JIA. Children with psoriatic arthritis may have typical psoriasis, but may also present prior to the onset of the classic thick scaly plaques and have more subtle changes such as nail pitting (see Chapter 15). Patients with psoriatic arthritis may also present with dactylitis or “sausage digit,” which is painful swelling of an entire finger or toe. Undifferentiated JIA, comprising 10% of patients, includes children with chronic arthritis that do not meet criteria for any of the other subgroups or meet more than one criterion and therefore could be classified into multiple subgroups.
B. Laboratory Findings
There is no diagnostic test for JIA. A normal erythrocyte sedimentation rate (ESR) does not exclude the diagnosis of JIA. However, patients with systemic JIA typically have significantly elevated markers of inflammation, including ESR, C-reactive protein (CRP), white blood cell count, and platelets. RF is positive in about 5% of patients, usually when the onset of polyarticular disease occurs after age 8 years. A newer test, anti-cyclic citrullinated peptide (anti-CCP) antibody, has a very high specificity for rheumatoid arthritis and may be detectable prior to the RF. ANAs are associated with an increased risk of iridocyclitis in patients with oligoarticular disease. A positive ANA test is also fairly common in patients with the late-onset RF-positive form of the disease. Carriage of HLAB27 antigen is associated with an increased risk of developing enthesitis-associated arthritis.
Table 29–1 lists the general characteristics of joint fluid in various conditions. The main indication for joint aspiration and synovial fluid analysis is to rule out infection. A positive Gram stain or culture is the only definitive test for infection. A leukocyte count over 2000/μL suggests inflammation; this may be due to infection, rheumatologic diseases, leukemia, or reactive arthritis. A very low glucose concentration (< 40 mg/dL) or very high polymorphonuclear leukocyte count (> 60,000/μL) is highly suggestive of bacterial arthritis.
Table 29–1. Joint fluid analysis.
C. Imaging Studies
In the early stages of the disease, only soft tissue swelling and possibly periarticular osteoporosis may be seen. Magnetic resonance imaging (MRI) of involved joints may show early joint damage and, if obtained with gadolinium, can confirm the presence of synovitis. Later in the course of the disease, particularly in patients with RF-positive disease, plain films may demonstrate joint space narrowing due to cartilage thinning and erosive changes of the bone related to chronic inflammation.
Table 29–2 lists the most common causes of limb pain in childhood. JIA is a diagnosis of exclusion; therefore, it is important to rule out other causes of the clinical signs and symptoms prior to settling on this diagnosis. The differential diagnosis is often quite broad, including orthopedic conditions, infectious diseases, and malignancies. A few key features can help distinguish these different entities, including the timing of the pain and associated signs and symptoms. In inflammatory conditions, patients frequently have increased symptoms in the morning with associated stiffness. In contrast, patients with an orthopedic abnormality typically have increased symptoms later in the day and with activity. Growing pains, a common cause of leg pain in childhood, are characterized by poorly localized pain at night, which frequently wakes the child from sleep; no objective signs of inflammation; and no daytime symptoms. Patients with growing pains often ask to be massaged, which is not typical of those with arthritis.
Table 29–2. Differential diagnosis of limb pain in children.
It is particularly important to establish the diagnosis in the case of monoarticular arthritis. Bacterial arthritis is usually acute and monoarticular except for arthritis associated with gonorrhea, which may be associated with a migratory pattern and hemorrhagic pustules, usually on the distal extremities. Fever, leukocytosis, and increased ESR with an acute process in a single joint demand synovial fluid examination and culture to identify the pathogen. Pain in the hip or lower extremity is a frequent symptom of childhood cancer, especially leukemia, neuroblastoma, and rhabdomyosarcoma. Infiltration of bone by tumor and a joint effusion may be seen. Radiographs of the affected site and examination of the blood smear for unusual cells and thrombocytopenia are necessary. An elevated lactate dehydrogenase value should also raise concern about an underlying neoplastic process. In doubtful cases, bone marrow examination is indicated.
Reactive arthritis is joint pain and swelling triggered by an infection. The infection is nonarticular and can be either viral or bacterial. A preceding illness is identified in approximately half of cases. Patients often have acute onset of arthritis, and there may be a migratory pattern. The duration of symptoms is a very important distinction between reactive arthritides and JIA. Symptoms associated with reactive arthritis typically resolve within 4–6 weeks. In contrast, to meet criteria for chronic arthritis, symptoms must be present for at least 6 weeks.
The arthritis of rheumatic fever is migratory, transient, and often more painful than that of JIA. Rheumatic fever is very rare in children younger than 5 years of age (see Chapter 20). In suspected cases, evidence of rheumatic carditis should be sought based on examination and electrocardiographic findings. Evidence of recent streptococcal infection is essential to the diagnosis. The fever pattern in rheumatic fever is low grade and persistent compared with the spiking fever that characterizes the systemic form of JIA. Lyme arthritis resembles oligoarticular JIA, but the former usually occurs as discrete, recurrent episodes of arthritis lasting 2–6 weeks and children should have a history of being in an endemic area. The typical bull’s-eye rash is called erythema chronicum migrans. Approximately 70%–80% of patients have a history of a compatible rash, although it is usually resolved by the time the arthritis appears. For children suspected of having Lyme disease, testing for antibodies against Borrelia burgdorferi should be performed, with confirmatory testing by Western blot (see Chapter 42).
The objectives of therapy are to restore function, relieve pain, maintain joint motion, and prevent damage to cartilage and bone.
A. Nonsteroidal Anti-Inflammatory Medications
First-line therapy is nonsteroidal anti-inflammatory drugs (NSAIDs). A wide range of agents is available but only a few are approved for use in children, including naproxen (10 mg/kg per dose twice daily), ibuprofen (10 mg/kg per dose three to four times daily), and meloxicam (0.125 mg/kg once daily). NSAIDs are generally well tolerated in children, as long as they are taken with food. The average time to symptomatic improvement is 1 month, but in some patients a response is not seen for 8–12 weeks.
B. Disease-Modifying and Biologic Agents
For patients with JIA who fail to respond to NSAIDs, weekly methotrexate is the second-line medication of choice. Symptomatic response usually begins within 3–4 weeks. The low dosages used (5–10 mg/m2/wk or 1 mg/kg/wk as a single dose) are generally well tolerated. Potential side effects include nausea, vomiting, hair thinning, stomatitis, leucopenia, immunosuppression, and hepatotoxicity. A complete blood count and liver function tests should be obtained every 2–3 months. Several additional disease-modifying agents are available for use in patients with persistently active disease or those intolerant to methotrexate. Leflunomide is an antipyrimidine medication that is administered orally. Side effects may include diarrhea and alopecia. Biological modifying medications that inhibit tumor necrosis factor, a cytokine known to play an important role in the pathogenesis of JIA, include etanercept, infliximab, and adalimumab. These drugs are generally quite effective in controlling disease and preventing cartilage and bone damage, and have been associated with healing based on radiologic changes. However, their potential long-term effects are unknown, they are very expensive, and require parenteral administration. Newer biologic agents, including anakinra, rituximab, abatacept, and tocilizumab, have demonstrated some efficacy in patients who have not responded to other treatments.
Local steroid joint injections may be helpful in patients who have arthritis in one or a few joints. Triamcinolone hexacetonide is a long-acting steroid that can be used for injections and is often associated with at least several months of disease control. Oral or parenteral steroids are reserved for children with severe involvement, primarily patients with systemic disease.
Iridocyclitis should be closely monitored by an ophthalmologist (see Chapter 16). Typically treatment is initiated with corticosteroid eye drops and dilating agents to prevent scarring between the iris and the lens. In patients who fail topical treatments, methotrexate, cyclosporine, and/or a tumor-necrosis factor inhibitor such as infliximab or adalimumab may be used.
Physical and occupational therapies are important to focus on range of motion, stretching, and strengthening. These exercises, as well as other modalities such as heat, water therapy, and ultrasound, can help control pain, maintain and restore function, and prevent deformity and disability. Young children with oligoarticular disease affecting asymmetrical lower extremity joints can develop a leg-length discrepancy, which may require treatment with a shoe lift on the unaffected side.
The course and prognosis for JIA is variable, depending on the subtype of disease. Children with persistent oligoarticular JIA have the highest rate of clinical remission, while patients with RF-positive disease are the least likely to achieve this status and are at highest risk for chronic, erosive arthritis that may continue into adulthood. The systemic features associated with systemic arthritis tend to remit within months to years. The prognosis in systemic disease is worse in patients with persistent systemic disease after 6 months, thrombocytosis, and more extensive arthritis.
Beukelman T et al: 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res 2011;63:465–482 [PMID: 21452260]. http://emedicine.medscape.com/article/1007276-overview.
Perry DC, Bruce C: Evaluating the child who presents with an acute limp. BMJ 2010;341:c4250 [PMID: 20729271].
Prakken B, Albani S, Martini A: Juvenile idiopathic arthritis. Lancet 2011;377:2138–2149 [PMID: 21684384]. www.arthritis.org.
SYSTEMIC LUPUS ERYTHEMATOSUS
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Multisystem inflammatory disease of the joints, serosal linings, skin, kidneys, blood, and central nervous system.
Autoantibodies such as ANA, double-stranded DNA, and anti-Smith antibodies are present and related to the pathogenesis of disease.
Systemic lupus erythematosus (SLE) is the prototype of immune complex diseases; its pathogenesis is related to the formation of antibody-antigen complexes that exist in the circulation and deposit in the involved tissues. The spectrum of symptoms is due to tissue-specific autoantibodies as well as damage to the tissue by lymphocytes, neutrophils, and complement evoked by the deposition of immune complexes. Autoreactive T lymphocytes that have escaped clonal deletion and unregulated B-lymphocyte production of autoantibodies may initiate the disease.
A. Symptoms and Signs
The onset of pediatric SLE is most common in girls between the ages of 9 and 15 years. Signs and symptoms depend on the organs affected by immune complex deposition. The American College of Rheumatology has established criteria to aid in the diagnosis of SLE; four of the following 11 criteria are necessary to establish the diagnosis:
1. Malar rash—photosensitive, so-called butterfly rash on the cheeks and nasal bridge
2. Discoid rash—annular, scaly rash on the scalp, face, and extremities that can lead to scarring
3. Photosensitivity—increased rash or other disease symptoms in response to sunlight exposure
4. Mucous membrane ulcers—painless ulcers on the hard palate and/or nasal septum
5. Arthritis—nonerosive arthritis of large and small joints, typically in a symmetrical distribution
6. Serositis—pericarditis and/or pleuritis, often associated with chest pain and difficulty breathing
7. Renal abnormalities—proteinuria (> 0.5 g/d) and/or cellular casts
8. Neurologic abnormalities—seizures and/or psychosis
9. Blood count abnormalities—low white blood cell count (< 4000/mm3), Coombs test–positive anemia, and/or thrombocytopenia (< 100,000/mm3)
10. Positive ANA—seen in almost 100% of patients with SLE
11. Autoantibodies—positive double-stranded DNA antibody, anti-Smith antibody, anticardiolipin antibodies, lupus anticoagulant, and/or false-positive blood test for syphilis
Other common signs and symptoms include fever, fatigue, weight loss, anorexia, Raynaud phenomenon, myositis, vasculitis, chorea, neuropathies, depression, and cognitive changes.
B. Laboratory Findings
Complete blood count abnormalities are common, including leukopenia, anemia, and thrombocytopenia. Approximately 15% of patients are Coombs test–positive, but many patients develop anemia due to other causes, including chronic disease and blood loss. Patients with significant renal involvement may have electrolyte disturbances, elevated kidney function tests, and hypoalbuminemia. The ESR is frequently elevated during active disease. In contrast, many patients with active SLE have a normal CRP. When the CRP is elevated, it is important to investigate possible infectious causes, particularly bacterial infections. It is critical to monitor the urinalysis in patients with SLE for proteinuria and hematuria, as the renal disease may be otherwise clinically silent. In immune complex diseases, complement is consumed; therefore, levels of C3 and C4 are depressed with active disease.
The ANA test is positive in almost 100% of patients, usually at titers of 1:320 or above. In patients with suspected SLE, it is important to obtain a full ANA profile—including antibodies directed against double-stranded DNA, Smith, ribonucleic protein, and Sjogren’s specific antibody A and B to better characterize their serologic markers of disease. Because approximately 50%–60% of pediatric SLE patients have antiphospholipid antibodies and are therefore at increased risk of thrombosis, it is important to screen all patients with SLE for anticardiolipin antibodies and lupus anticoagulant.
Because there is such a wide spectrum of disease with SLE, the differential diagnosis is quite broad, including systemic JIA, mixed connective tissue disease (MCTD), rheumatic fever, vasculitis, malignancies, and bacterial and viral infections. A negative ANA test essentially excludes the diagnosis of SLE. Anti–double-stranded DNA and Smith antibodies are very specific for SLE. The preceding diagnostic criteria, which are very helpful in establishing the diagnosis of SLE, have a specificity and sensitivity of 96%.
MCTD, an overlap syndrome with features of several collagen-vascular diseases, shares many features with SLE. The symptom complex is diverse and often includes arthritis, fever, skin tightening, Raynaud phenomenon, muscle weakness, and rash. The ANA test is typically positive in very high titers. The ANA profile is negative except for antibodies directed against ribonucleic protein.
The treatment of SLE should be tailored to the organ system involved so that toxicities may be minimized. Prednisone is the mainstay of treatment and has significantly lowered the mortality rate in SLE. Patients with severe, life-threatening, or organ-threatening disease are typically treated with intravenous pulse methylprednisolone, 30 mg/kg per dose (maximum of 1000 mg) daily for 3 days, and then switched to 2 mg/kg/d of prednisone. The dosage should be adjusted using clinical and laboratory parameters of disease activity, and the minimum amount of corticosteroid to control the disease should be used. Skin manifestations, arthritis, and fatigue may be treated with antimalarials such as hydroxychloroquine, 5–7 mg/kg/d orally. Pleuritic pain or arthritis can often be managed with NSAIDs.
If disease control is inadequate with prednisone or if the dose required produces intolerable side effects, a steroid-sparing agent, such as mycophenolate mofetil, azathioprine, and cyclophosphamide, should be added. More recently, rituximab, a monoclonal antibody directed against the B-cell surface marker CD20, has been used for persistent active disease, particularly in patients with hematologic manifestations. Patients who have evidence of antiphospholipid antibodies should be treated with a baby aspirin every day to help prevent thrombosis. Thrombotic events due to these antibodies require long-term anticoagulation.
The toxicities of the regimens must be carefully considered. Growth failure, osteoporosis, Cushing syndrome, adrenal suppression, and aseptic necrosis are serious side effects of chronic use of prednisone. When high doses of corticosteroids are used (> 2 mg/kg/d), there is a high risk of infection. Cyclophosphamide can cause bone marrow suppression, bladder epithelial dysplasia, hemorrhagic cystitis, and sterility. Azathioprine has been associated with liver damage and bone marrow suppression. Immunosuppressant treatment should be withheld if the total white blood cell count falls below 3000/μL or the neutrophil count falls below 1000/μL. Retinal damage from hydroxychloroquine is generally not observed with recommended dosages, but patients are typically instructed to have visual field testing every 6–12 months to screen for retinal toxicity.
The prognosis in SLE relates to the presence of renal involvement or infectious complications of treatment. Nonetheless, the survival rate has improved from 51% at 5 years in 1954 to 90% today. The disease has a natural waxing and waning cycle; the disease may flare at any time and spontaneous remission may rarely occur.
Brunner HI, Huggins J, Klein-Gitelman MS: Pediatric SLE—towards a comprehensive management plan. Nat Rev Rheumatol 2011;7:225–233 [PMID: 21386795].
Marks SD, Tullus K: Modern therapeutic strategies for paediatric systemic lupus erythematosus and lupus nephritis. Acta Paediatr 2010;99:967–974 [PMID: 20222881].
Watson L et al: Disease activity, severity, and damage in the UK Juvenile-Onset Systemic Lupus Erythematosus Cohort. Arthritis Rheum 2012;64:2356–2365 [PMID: 22294381].
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Pathognomonic skin rashes.
Weakness of proximal muscles and occasionally of pharyngeal and laryngeal groups.
Pathogenesis related to vasculitis.
A. Symptoms and Signs
The predominant symptom is proximal muscle weakness, particularly affecting pelvic and shoulder girdle muscles. Tenderness, stiffness, and swelling may be found. Pharyngeal involvement, manifested as voice changes and difficulty swallowing, is associated with an increased risk of aspiration. Intestinal vasculitis can be associated with ulceration and perforation of involved areas. Flexion contractures and muscle atrophy may produce significant residual deformities. Calcinosis may follow the inflammation in muscle and skin.
Several characteristic rashes are seen in dermatomyositis. Patients often have a heliotrope rash with a reddish-purple hue on the upper eyelids, along with a malar rash that may be accompanied by edema of the eyelids and face. Gottron papules are shiny, erythematous, scaly plaques on the extensor surfaces of the knuckles, elbows, and knees. Dilated nailbed vessels are commonly seen with active disease. Thrombosis and dropout of periungual capillaries may identify patients with a more severe, chronic disease course.
B. Laboratory Findings/Imaging Studies/Special Tests
Determination of muscle enzyme levels, including aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine phosphokinase, and aldolase, is helpful in confirming the diagnosis, assessing disease activity, and monitoring the response to treatment. Even in the face of extensive muscle inflammation, the ESR and CRP are frequently normal. An MRI scan of the quadriceps muscle can be used in equivocal cases to confirm the presence of inflammatory myositis. Electromyography is useful to distinguish myopathic from neuropathic causes of muscle weakness. Muscle biopsy is indicated in cases of myositis without the pathognomonic rash.
Treatment is aimed at suppression of the inflammatory response and prevention of the loss of muscle function and joint range of motion. Acutely, it is very important to assess the adequacy of the ventilatory effort and swallowing and to rule out intestinal vasculitis. Corticosteroids are the initial therapy of choice. Treatment is usually initiated with prednisone, 2 mg/kg/d, and continued until signs and symptoms of active disease are controlled; the dosage is then gradually tapered. In severe cases, intravenous pulse methylprednisolone for 3 days is indicated. Therapy is guided by the physical examination findings and muscle enzyme values. Methotrexate is often used concomitantly to achieve better control of the disease and minimize the steroid side effects. If patients continue to have active disease, additional steroid-sparing agents, such as cyclosporine, intravenous immunoglobulin, and, in severe cases, cyclophosphamide should be started.
Hydroxychloroquine and intravenous immunoglobulin may be particularly helpful in managing the skin manifestations. As the rashes are photosensitive, sun protection is very important. Physical and occupational therapy should be initiated early in the course of disease. Initially, passive range-of-motion exercises are performed to prevent loss of motion. Later, once the muscle enzymes have normalized, a graduated program of stretching and strengthening exercises is introduced to restore normal strength and function.
Most patients have a monocyclic course; 10%–20% of patients have more chronic or recurrent symptoms. Factors that influence the outcome include the rapidity of symptom onset, extent of weakness, presence of cutaneous or gastrointestinal vasculitis, timeliness of diagnosis, initiation of therapy, and response to treatment. Dermatomyositis in children is not associated with cancer as it is in adults.
Huber AM et al: Protocols for the initial treatment of moderately severe juvenile dermatomyositis: results of a Children’s Arthritis and Rheumatology Research Alliance Consensus Conference. Arthritis Care Res 2010;62:219–225 [PMID: 20191521].
Ravelli A et al: Long-term outcome and prognostic factors of juvenile dermatomyositis: a multinational, multicenter study of 490 patients. Arthritis Care Res 2010;62:63–72 [PMID: 20191492].
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Cutaneous involvement with nonblanching, tender skin lesions.
Frequently with systemic inflammation, particularly in the lungs and kidneys.
Gold-standard for diagnosis is demonstration of vasculitis on biopsy.
The vasculitides are a group of conditions that involve inflammation of blood vessels. They are classified by the size of the blood vessels affected (Table 29–3). The two most common forms of vasculitis in childhood—Henoch-Schonlein Purpura (HSP) (see Chapter 30) and Kawasaki Disease (see Chapter 20)—are acute, self-limited forms of vasculitis. In contrast, there are idiopathic, chronic forms of vasculitis, such as granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), which are rare in childhood.
Table 29–3. Classification of vasculitides by vessel size involved.
A. Symptoms and Signs
Signs and symptoms vary by disease, but most children with chronic forms of vasculitis have persistent fever, fatigue, weight loss, and signs of pulmonary, renal, musculoskeletal, gastrointestinal, and/or skin inflammation.
Granulomatosis with polyangiitis (previously called Wegener granulomatosis) often causes nephritis and involves the lungs, manifesting as chronic cough, hemorrhage, and/or cavitating lesions. This form of vasculitis also frequently affects the upper respiratory tract, causing chronic otitis media, sinusitis, and/or inflammation of the trachea; saddle nose deformity may occur.
Children with polyarteritis nodosa (PAN) often present with skin lesions such as purpura, nodules or ulcers, and evidence of organ involvement with abdominal pain, testicular pain, hypertension, hematuria and/or neurologic symptoms. MPA typically presents with pulmonary-renal syndrome with features of pulmonary hemorrhage and rapidly progressive kidney inflammation.
B. Laboratory Findings/Imaging Studies/Special Tests
Patients with vasculitis often have elevated inflammatory markers. If they have significant renal involvement, they may have elevated renal function tests and abnormal urinary sediment. Anemia is common, due to chronic disease and/or renal insufficiency. A low hemoglobin may also be an indicator of pulmonary hemorrhage in a patient with cough, hemoptysis, respiratory distress, and/or infiltrates on chest x-ray.
Antineutrophil cytoplasmic antibodies (ANCA) may be present in patients with small vessel vasculitis. Cytoplasmic ANCA (c-ANCA), which is usually directed against proteinase 3 and is quite sensitive and specific for GPA, is positive in 80%–95% of patients with active disease. Perinuclear ANCA (p-ANCA) is typically directed against myeloperoxidase and is associated with MPA and can also be seen in HSP, Churg-Strauss, and inflammatory bowel disease.
The diagnosis is made based on a typical clinical presentation and laboratory findings. If the diagnosis remains uncertain, then attempting to definitively establish the diagnosis with a biopsy of involved tissue is warranted. A biopsy in patients with GPA typically demonstrates necrotizing granulomatous vasculitis. Biopsies of involved areas will confirm the presence of vasculitis in small vessels in patients with MPA and small and medium arteries in PAN. If a biopsy is not feasible, additional imaging studies such as an angiogram, which can demonstrate characteristic patterns of inflammation in affected blood vessels, should be considered.
The treatment of the various forms of chronic vasculitis is based on the severity of illness and the organs involved. Typically, corticosteroids are the initial therapy. Patients with severe disease are usually treated with intravenous pulse methylprednisolone, 30 mg/kg per dose (maximum of 1000 mg) daily for 3 days, and then switched to 2 mg/kg/d of prednisone. The dosage is then gradually tapered as tolerated based on clinical and laboratory markers of disease activity. Patients are usually treated with other immunosuppressant medications to gain and maintain control of the disease and minimize the steroid side effects. Standard treatment has included cyclophosphamide for induction, followed by maintenance with methotrexate, azathioprine, or mycophenolate. More recent studies in patients with GPA suggest that rituximab can be used for induction therapy with potentially fewer side effects and risks than cyclophosphamide.
Immunosuppressive medications have improved survival and remission rates for patients with chronic vasculitis. Conditions such as GPA had almost always been fatal; since introducing the regimen of high-dose steroids and cyclophosphamide (or other cytotoxic agents), patients with vasculitides have greatly improved outcomes, with 5-year survival ranging from 50% to 100%. Because relapses are common when therapy is weaned or stopped, maintenance immunosuppression is commonly used in these disorders.
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Guerry MJ et al: Recommendations for the use of rituximab in anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology 2012;51:634–643 [PMID: 21613248].
O’Neil K: Progress in pediatric vasculitis. Curr Opin Rheumatol 2009;21:538–546 [PMID: 19568171].
Raynaud phenomenon is an intermittent vasospastic disorder of the extremities. As much as 10% of the adult population has this disorder, and onset in childhood is not uncommon. The classic triphasic presentation is cold-induced pallor, then cyanosis, followed by hyperemia, but incomplete forms are frequent. In adults older than 35 years who are ANA-positive, Raynaud phenomenon may be a harbinger of rheumatic disease. This progression is rarely seen in childhood. Evaluation should include a detailed history with review of systems relevant to rheumatic disease. Examination of the cuticle edge, using an otoscope or a special microscope called a capillaroscope, is important to screen for dilated and/or tortuous capillaries that may suggest an underlying rheumatic disease such as lupus or scleroderma. In the absence of positive findings, Raynaud phenomenon is likely to be idiopathic.
Treatment involves education about keeping the extremities and core body warm and the role of stress, which may be a precipitant. In very symptomatic patients, treatment with calcium channel blockers such as nifedipine can be effective.
Pope JE: Raynaud’s phenomenon (primary). Clin Evid (Online) 2011;03:1119 [PMID: 21401971].
NONINFLAMMATORY PAIN SYNDROMES
1. Complex Regional Pain Syndrome
Complex regional pain syndrome, previously known as reflex sympathetic dystrophy, is a painful condition that is frequently confused with arthritis. Prevalence and recognition of the condition appear to be increasing. Severe extremity pain leading to nearly complete loss of function is the hallmark of the condition. Evidence of autonomic dysfunction is demonstrated by pallor or cyanosis, temperature differences (with the affected extremity cooler than surrounding areas), and generalized swelling. On examination, allodynia, which is marked cutaneous hyperesthesia to even the slightest touch, is often evident. Results of laboratory tests are normal, without evidence of systemic inflammation. Radiographic findings are normal except for late development of osteoporosis. Bone scans may be helpful and may demonstrate either increased or decreased blood flow to the painful extremity.
The cause of this condition remains elusive. Treatment includes physical therapy to focus on restoration of function, maintenance of range of motion, and pain relief. NSAIDs can be helpful for pain control, and in patients with more chronic disease, gabapentin or pregabalin are frequently effective. Persistent disease may respond to local nerve blocks. Counseling is helpful to identify potential psychosocial stressors and to assist with pain management. Long-term prognosis is good if recovery is rapid; recurrent episodes imply a less favorable prognosis.
Tan EC et al: Complex regional pain syndrome type I in children. Acta Paediatr 2008;97:848 [PMID: 18410465]. http://childhoodrnd.org/index.php.
Fibromyalgia is a chronic pain syndrome characterized by diffuse musculoskeletal pain, fatigue, sleep disturbance, and chronic headaches. Weather changes, fatigue, and stress exacerbate symptoms. Patients have a normal examination except for characteristic trigger points at the insertion of muscles, especially along the neck, spine, and pelvis.
Treatment centers on physical therapy, nonnarcotic pain medications, improving sleep, and counseling. Low-dose amitriptyline or trazodone can help with sleep and may produce remarkable reduction in pain. Physical therapy should emphasize a graded rehabilitative approach to stretching and exercise and promote regular aerobic exercise. Pregabalin recently became the first medication to be approved by the Food and Drug Administration for the treatment of fibromyalgia. Use of the drug is associated with decreased pain in adults with fibromyalgia, and studies are planned to test the safety and efficacy of its use in children with the condition. The prognosis for children with fibromyalgia is not clear, and long-term strategies may be necessary to enable them to cope with the condition.
Buskila D: Pediatric fibromyalgia. Rheum Dis Clin North Am 2009;35:253 [PMID: 19647140]. www.myalgia.com.
Wolfe F et al: The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res 2010;62:600–610 [PMID: 20461783].
3. Hypermobility Syndrome
Ligamentous laxity, which previously was thought to occur only in Ehlers-Danlos syndrome or Down syndrome, is now recognized as a common cause of joint pain. Patients with hypermobility present with episodic joint pain and occasionally with swelling that lasts a few days after increased physical activity. Depending on the activity, almost any joint may be affected. Five criteria have been established: (1) passive opposition of the thumb to the flexor surface of the forearm, (2) passive hyperextension of the fingers so that they are parallel to the extensor surface of the forearm, (3) hyperextension of the elbow, (4) hyperextension of the knee, and (5) palms on floor with knees extended. Results of laboratory tests are normal. The pain associated with the syndrome is produced by improper joint alignment caused by the laxity during exercise. Treatment consists of a graded conditioning program designed to provide muscular support of the joints to compensate for the loose ligaments and to train patients to protect their joints from hyperextension.
Tofts LJ et al: The differential diagnosis of children with joint hypermobility: a review of the literature. Pediatr Rheumatol Online J 2009;7:1 [PMID: 19123951].