What Causes Juvenile Rheumatoid Arthritis?

Although a specific trigger has not been identified, T lymphocytes of genetically predisposed children are chronically activated to recruit other inflammatory cells, leading to synovitis. The prevalence of juvenile rheumatoid arthritis (JRA) is about 1.3 in 1000 children in the general population.

What Is the Typical Clinical Presentation of Juvenile Rheumatoid Arthritis?

All cases of JRA are characterized by chronic arthritis (joint pain, limitation of range of motion, joint swelling, and/or warmth) for at least 6 weeks without another etiology such as Lyme disease. Morning stiffness is common, but severe pain, especially at night, should raise concerns about another diagnosis such as leukemia. There are three general presentations for JRA based on clinical findings during the first 6 months of disease.

What Laboratory Tests Should I Order?

Complete blood count (CBC) may reveal anemia of chronic disease or iron-deficiency anemia from gastrointestinal blood loss caused by nonsteroidal antiinflammatory drugs (NSAIDs). The erythrocyte sedimentation rate (ESR) is often elevated. Antinuclear antibody (ANA) and the rheumatoid factor (RF) may be variably positive, as indicated in Table 70-1. Patients on NSAIDs are monitored for liver toxicity by checking liver enzymes and for renal dysfunction by periodically checking a urinalysis.

Do Laboratory Test Results Predict Disease and Prognosis?

In general, patients with positive ANA have a better prognosis than those with positive RF. Overall, however, clinical signs and symptoms are the best indicators of prognosis and disease control rather than lab tests. Joint destruction and unremitting disease progressing into adulthood are most common in patients who are positive for RF.

How Is Rheumatoid Arthritis Treated?

The mainstays of treatment are the NSAIDs. Disease-modifying drugs such as methotrexate and biologic therapies are reserved for those with persistent symptoms and radiologic evidence of erosions. Etanercept, a recombinant anti-TNF, has proven efficacy for patients with moderate to severe polyarticular JRA unresponsive to NSAIDs or methotrexate but is associated with an increased risk of infection. Sulfasalazine is also being used to treat patients with unresponsive JRA but has been associated with a risk of severe hypersensitivity reactions, such as Stevens-Johnson syndrome. Corticosteroids may be used systemically to quiet the inflammation seen in systemic-onset JRA. Chronic use of steroids should be minimized to avoid side effects. Steroids are also used in joint injections or topically as ophthalmic drops to treat uveitis. One of the primary concerns with long-term steroid use is poor bone mineralization during treatment. Various agents such as alendronate are being studying to help ameliorate osteopenia resulting from long-term steroid use, but their role in management of JRA is not yet clear.

What Is the Cause of Systemic Lupus Erythematosus?

A single etiologic agent cannot explain systemic lupus erythematosus (SLE), a complex autoimmune disorder involving autoantibodies to a variety of tissues throughout the body. It is thought that a combination of hormones and environmental stimuli activate B lymphocytes in genetically predisposed individuals, triggering production of autoantibodies. Disease prevalence varies between 4 and 250 cases per 100,000 children, depending on gender and ethnicity. SLE is more common among Native American, Asian, Latino, and African-American children than in white patients. Girls are four times more likely to develop SLE than are boys before puberty and eight times more likely afterward.

How Do Patients with Systemic Lupus Erythematosus Present?

Most of the physical findings in SLE result from vasculitis. SLE can present at any age from the newborn period into adult life. The typical patient with SLE is an African-American adolescent girl with weight loss, fatigue, arthralgias, and rash, all of which often are induced by sun exposure. Over the course of the illness, 80% develop glomerulonephritis. Neonatal lupus manifests as rash and heart block in a newborn infant, resulting from placental transfer of autoantibodies from a mother with the disease. Outside of the neonatal period, SLE is uncommon in males and in children younger than 10 years. SLE should be considered in the differential diagnosis when children or adolescents present acutely with unusual findings, such as thrombosis, psychosis, or pericardial or pleural effusions (serositis). Table 70-2 depicts the most common multiorgan system findings in SLE. Diagnosis is based on the combination of clinical findings plus laboratory test results. To categorize patients as having SLE for clinical research studies, 4 of the 11 findings in Table 70-2 must be present. In clinical practice, the diagnosis is often made with fewer than four findings.

Table 70-2 1982 Revised Criteria for Diagnosis of Systemic Lupus Erythematosus

ANA, Antinuclear antibody; ECG, electrocardiogram; LE, lupus erythematosus; RBC, red blood cell; Sm, Smith antigen; WBC, white blood cell.

From Tan EM et al: The 1982 revised criteria for the diagnosis of systemic lupus erythematosus, Arthritis Rheum 25:1271, 1982, with permission.

What Laboratory Tests Help to Diagnose and Monitor Systemic Lupus Erythematosus?

No single laboratory test can be used to diagnose SLE. In addition to nonspecific findings of inflammation, such as an elevated ESR, several autoantibodies may be found. The ANA has high sensitivity but low specificity for SLE. Anti-SSA and anti-SSB antibodies occur more often with Sjögren’s syndrome than with SLE. Anti-Smith antibody is specific for SLE but is not an indicator of disease activity. Anti–double-stranded DNA is specific for SLE and reflects disease activity, although decreased levels of complement (CH50, C3, C4) are better markers of disease activity. Autoantibodies can cause a range of laboratory and clinical abnormalities, depending on the organ system affected. All of the cell lines on the CBC can be depressed because of antibodies produced against white blood cells (ANA), red blood cells (Coombs’), or platelets. Other autoantibodies can be associated with hypothyroidism (antithyroid antibodies), cerebritis (antiribosomal P antibody), and coagulopathy or thrombosis (lupus anticoagulant/antiphospholipid antibodies). Elevations in transaminases reflect autoimmune hepatitis. Hematuria and proteinuria as seen on urinalysis reflect renal disease.

How Is Systemic Lupus Erythematosus Treated?

Specific treatment may vary, depending on the organ system involved. NSAIDs can be used to treat arthritis, but creatinine and liver transaminases should be monitored closely because patients with SLE are more susceptible to NSAID-related renal and hepatic damage. Hydroxychloroquine may also be used to treat arthritis, arthralgia, skin rash, and fatigue. Patients should be advised to use sunscreen liberally because SLE is exacerbated by exposure to ultraviolet (UV) light. Patients presenting with signs of vasculitis such as thrombosis from antiphospholipid antibody should be treated with anticoagulant medications until the disease is under control. Systemic corticosteroids are often used both in low doses to control disease and in high doses to treat renal, central nervous system, or pulmonary complications. Cytotoxic agents, such as cyclophosphamide and azathioprine, are standard treatment for the patient with renal disease.

Does Treatment Affect the Long-Term Prognosis?

Lupus is a lifelong illness that requires meticulous clinical and laboratory follow-up. Signs of increasing disease activity may be identified from clinical findings such as fatigue, rash, and weight loss, and from laboratory tests including proteinuria and decreased complement. Any increase in disease activity affecting organ function must be treated promptly with appropriate immunosuppressive medications. Clinicians must have a low threshold for suspecting and treating potential infectious complications such as pneumonia or sepsis. Signs of infection such as fever, elevated white blood cell (WBC) count, and elevated ESR will be unreliable indicators of bacterial infection because of the ongoing immunosuppression caused by both the disease and treatment.

What Causes Juvenile Dermatomyositis?

The factors that trigger autoimmune activation in this disease are unknown, but some epidemiologic studies point to infectious triggers such as enteroviruses. Disease prevalence is about 3 per 1 million children. It is twice as common in girls as in boys. The mean age of onset is 6 years, with two peaks between preschool and 9 years and between 10 and 14 years. Younger children generally have a better prognosis than adolescents.

What Is the Clinical Presentation of Juvenile Dermatomyositis?

As the name implies, the two primary features of the disease are skin and muscle inflammation. Fatigue, weight loss, fever, and weakness may precede the rash. A few patients have only the skin manifestations and little to no myositis.

What Is the Characteristic Rash?

The characteristic “heliotrope” rash is purplish in color and noted over the eyelids, often with facial edema. The purple rash may also occur on the trunk, the extensor surfaces of the arms and legs, the ankles, and the buttocks. Sun exposure can be a trigger, so the rash may initially appear during the summer.

Are There Other Skin Findings?

Other skin findings include Gottron’s papules, which are violaceous papules over the metacarpal and proximal interphalangeal joints. Patients with long-standing disease may also develop nail-bed telangiectases, infarction of areas of the oral epithelium, and calcinosis and ulceration involving the extensor surfaces of the hands and extremities, resulting in areas of hyperpigmentation or vitiligo.

Besides Rash, What Other Findings Are Likely?

Skeletal muscle weakness is the most common finding other than rash. Weakness is greatest in the proximal muscles and is noted with activities such as climbing stairs but may be insidious until severe. The involved muscles are often painful to palpation. Smooth muscle weakness of the pharynx and the gastrointestinal tract may cause hoarseness, dysphagia, and constipation. Cardiomyopathy and/or conduction defects can also occur. Central nervous system, liver, and kidney can be involved. Retinitis or iritis may also occur.

What Laboratory Tests Are Useful for Diagnosis and Management?

Elevations in muscle enzymes such as creatine phosphokinase, aldolase, serum glutamic-oxaloacetic transaminase, and lactic acid dehydrogenase reflect myositis. The ANA is positive and has a speckled pattern in most patients at the time of diagnosis. In primary dermatomyositis without other associated connective tissue disease, antibodies to rheumatoid factor, SSA, SSB, Sm, RNP, and DNA are negative. ESR may be increased. CBC may reveal anemia of chronic disease. Myositis is confirmed as the etiology for weakness by electromyography, magnetic resonance imaging (MRI), and muscle biopsy. MRI can be used to guide muscle biopsy to confirm the diagnosis. Electrocardiography may reveal conduction defects and often shows myocardial contraction dysfunction.

What Treatment Is Recommended for Dermatomyositis?

A child with dermatomyositis must use sunscreen assiduously to prevent sun exposure–induced flare-ups of disease. If skin manifestations are the only disease manifestation, a patient may be managed with hydroxychloroquine and relatively low doses of oral prednisone. Those with myositis require higher doses of systemic steroids to control disease. Intravenous steroids are required if there is dysphagia or other evidence of gastrointestinal smooth muscle involvement. Steroid doses are titrated to alleviate symptoms and to normalize muscle enzymes. Methotrexate may also be added if muscle enzymes fail to decline to acceptable levels with steroids or if the steroid dose cannot be tapered to acceptable levels. Occasionally, other immunosuppressive drugs, intravenous immunoglobulin (IVIG), and biologic therapies are required to control disease.

What Is the Prognosis?

With aggressive management, the period of active inflammation can be reduced substantially and repair of muscle damage may occur. Meticulous follow-up will allow prompt treatment when laboratory or clinical evidence demonstrates disease exacerbation. Complete recovery is possible, but prognosis is poor with active severe muscle disease, calcinosis, and lipodystrophy. Careful assessment of swallowing ability is important, because aspiration pneumonia can be a complication of dysphagia. Calcinosis can lead to draining skin lesions, which may become secondarily infected. A high index of suspicion should be maintained for secondary bacterial infection because treatment renders patients immunocompromised. Lipodystrophy, or loss of subcutaneous fat, can occur in a few patients and persist into adulthood.

KEY POINTS

Distinguish between arthritis and arthralgia

This patient has arthritis, because there is objective evidence of inflammation: joint swelling accompanied by decreased range of motion and warmth. Although pain and erythema are not noted in this patient, arthritis often causes both. Arthralgia is the subjective complaint of joint pain, without any objective evidence of inflammation.

Differentiate inflammatory arthritis from arthritis caused by trauma or other mechanical causes

The child has no history of trauma. Overuse injuries of the knee (patellar-femoral syndromes) do not occur in prepubertal children. Without significant trauma, the knee swelling and the decreased range of motion indicate an inflammatory rather than a mechanical problem. Infection usually has a more acute onset, with high fever and obvious redness, swelling, and pain. The chronicity of this patient’s problem is evident from the history and from the quadriceps atrophy and leg-length discrepancy. Chronic noninfectious joint inflammation causes overgrowth of the affected limb in children younger than 9 years and physeal arrest with limb shortening after age 9 years.

List causes of arthritis in childhood

Because this child has no evidence of trauma and nothing to suggest an acute bacterial infection, you should consider JRA and reactive arthritis, such as Lyme disease, in your differential diagnosis.

Differentiate among the various types of JRA

Pauciarticular JRA affects young children, has few joints involved (usually the knee), and is associated with uveitis. Systemic-onset JRA is also rheumatoid factor negative but has high fever and other systemic involvement, including carditis, hepatitis, lymphadenopathy, and rash. Polyarticular JRA may be either rheumatoid factor positive or negative. If positive, the patient has a high risk for a chronic, relapsing course.

Discuss the systemic effects of JRA

Pauciarticular JRA has a strong association with uveitis, which is often asymptomatic. An ophthalmologic examination must be done at the time of diagnosis, and yearly thereafter.

Identify systemic lupus erythematosus using the history and physical examination

The combination of fever, arthritis, and malar rash should make you consider SLE. SLE is more common among African-American adolescents. Although other rheumatologic disorders may also have some of the same clinical findings, the specific constellation in this patient points to SLE.

Select laboratory tests to identify SLE

You should order the tests and would expect the results shown in the following table.

Discuss the organ system involvement and the progression of the disease process in a patient with SLE

Multiple organ systems are involved by SLE. Renal disease is most common and often progresses to end-stage renal disease. Central nervous system involvement occurs less commonly but has the worst prognosis.

Discuss how monitoring of physical findings and laboratory test results aids in long-term management of SLE

Clinical symptoms may reflect increasing activity of SLE: weight loss, decreased activity level, declining school performance, and mental status changes. Similarly, evidence of new rash, arthritis, signs of peripheral vascular insufficiency, and serositis (cardiomyopathy, pleural effusion, and hepatomegaly) should be sought on physical examination. Laboratory tests used to follow disease include complete blood count, erythrocyte sedimentation rate, complement levels, urinalysis, serum creatinine, liver enzymes, and anti–double-stranded DNA.

Recognize the infectious risks of the immunosuppression caused by SLE

Serious bacterial illnesses are one of the major risks because SLE is a severe autoimmune disease. Patients with SLE have decreased ability to mount an appropriate immune response to infection. In addition, treatment with immune modulators, such as corticosteroids, further impedes the patient’s ability to mount an appropriate immune response, which makes the usual signs of infection unreliable and impairs a patient’s ability to localize infection.

Identify dermatomyositis using history and physical examination

The history suggests extensive muscle involvement, including weakness of skeletal muscles and smooth muscle of the gastrointestinal tract. Physical examination confirms the skeletal muscle involvement and demonstrates that this child also has involvement of skin. The most likely diagnosis is dermatomyositis. You should examine the heart carefully, because cardiac involvement is common.

Discuss the life-threatening complications of dermatomyositis

Cardiomyopathy or arrhythmias may lead to cardiac failure; weakness of the diaphragm and pharyngeal muscles can cause respiratory failure. Smooth muscle involvement of the gastrointestinal tract can cause perforation.

List the options for treatment of dermatomyositis and understand the complications of therapy

Steroids are the main therapy for dermatomyositis and can cause growth failure, diabetes, cataracts, Cushing’s syndrome, and pathologic fractures.