Juvenile Rheumatoid Arthritis: Follow-up

Juvenile Rheumatoid Arthritis: Follow-up
Author: C Egla Rabinovich, MD, MPH, Associate Professor and Co-Division Chief, Department of Pediatrics, Division of Pediatric Rheumatology, Duke University Medical Center
Contributor Information and Disclosures
Updated: Apr 7, 2010

Follow-up
Further Inpatient Care
Further inpatient care is required for persisting fevers of unknown origin or when children with known juvenile idiopathic arthritis (JIA) have severe exacerbation of disease. Admit for evaluation any child who loses the ability to walk for unknown reasons. Development of pericarditis in children with systemic juvenile idiopathic arthritis is usually an indication for admission.
Further Outpatient Care
Patients may have a gradually responsive disease (particularly those with pauciarticular juvenile idiopathic arthritis).
A small number of patients with pauciarticular juvenile idiopathic arthritis develop aggressive arthritis confined to a single joint; such patients may require more intensive medical treatment and physical therapy.
Some patients with polyarticular juvenile idiopathic arthritis demonstrate rapid response to treatment; however, most have prolonged courses, requiring frequent adjustments in medical and nonmedical therapy. Some have sufficient problems with activities of daily living, and they may benefit from courses of outpatient (and sometimes inpatient) rehabilitation.
Inpatient & Outpatient Medications
See Medication.
Transfer
Consider outpatient evaluation in a pediatric rheumatology center for all patients with known and suspected disease. Inpatient care for individuals with intercurrent illnesses may best be carried out at local hospitals; complications from juvenile idiopathic arthritis usually indicate transfer to a hospital with a pediatric rheumatology center.
Treatment of macrophage activation syndrome (MAS) is a medical emergency and should be done by physicians familiar with this complication.
Deterrence/Prevention
No prevention methods are known. The best means of deterrence is compliance with recommended treatment. As many as one half of patients may not comply with every detail of recommended treatment. Persisting noncompliance is a problem that increases risk of morbidity. Parents of such patients often admit noncompliance only to the child's primary care physician, rather than to a pediatric subspecialty team. The continued monitoring of compliance by the primary care physician, together with continuing communication between the pediatric subspecialist and primary physician, is an important part of the treatment of children with juvenile idiopathic arthritis and any chronic illness.
Complications
The following complications may occur:
• Systemic-onset juvenile idiopathic arthritis
o Pericarditis (patients often presenting with orthopnea and responsive to intravenous corticosteroid treatment)
o Hemolytic anemia
o Disseminated intravascular coagulopathy (DIC), often present at a low level of activity: The levels of D-dimer and fibrinogen may be elevated; their return to reference range levels is observed with successful treatment.
o MAS
 This is a rare, but important, complication, in which numbers of all 3 bloodlines become rapidly decreased. Hypofibrinogenemia, thrombocytopenia, and elevated aspartate aminotransferase levels are hallmarks.
 Hypotension, CNS disease, and marked hepatosplenomegaly may be noted as complications of a release of massive amounts of cytokines.
 Bone marrow aspiration may reveal histiocytic consumption of bone marrow precursors, which confirms the diagnosis and excludes malignancy. One does not need to see the histiocytic consumption for diagnosis of MAS.
 MAS often responds to cyclosporin A, and some case reports have detailed response to anakinra.
o Endarteritis resulting in circulatory compromise of the digits with threatened autoamputation
 This complication is even more rare than MAS.
 Central administration of prostaglandin E1 may be of potential benefit, similar to its use for patients with scleroderma and endarteritis.
• Pauciarticular juvenile idiopathic arthritis
o Knee flexion contractures: This complication requires splinting at night, in addition to medical treatment, to restore range of motion, allow recovery of muscle strength, and avoid subluxation of the joint. Intra-articular corticosteroid injection should be strongly considered.
o Uveitis
 Often asymptomatic, patients are typically young girls who have positive levels of antinuclear antibody (ANA).
 In such patients, evaluation using a slit-lamp examination by a pediatric ophthalmologist every 4 months can detect early disease.
 Treatment with topical corticosteroid medication and with mydriatic agents (to prevent closed-angle glaucoma) often can prevent progression of disease to development of calcium deposition in the lens (band keratopathy) and adhesions of the iris to the lens (posterior synechiae), in which an irregular pupillary margin develops.
 Such complications may herald a chronic active disease, in which vision is threatened; immunosuppressive agents, such as methotrexate or cyclosporin, may help to control chronic uveitis. Infliximab can be effective in some patients who are resistant to immunosuppressive agents.
o Leg length discrepancy (can result from neovascularization of growth plates of an affected knee)
 The problem may not be detected in patients with a knee flexion contracture until the contracture is corrected.
 Treatment consists of a shoe lift on the nonaffected side.
• Polyarticular juvenile idiopathic arthritis
o Skeletal abnormalities - Increased size of epiphyses, accelerated bone age, narrowed joint spaces, swan-neck and/or boutonniere deformities, and joint subluxation
o Cervical spine involvement
 Difficulty flexing the spine may create a problem for intubation prior to surgery; inform anesthesiologists of the patient's diagnosis. Screening cervical spine radiography (in both flexion and extension) may help screen for potential difficulties during induction of anesthesia.
 High-level subluxation is a potential complication.
Prognosis
Some studies suggest that many children with juvenile idiopathic arthritis can lead productive lives. However, other studies suggest many patients, particularly those with polyarticular disease, may have problems with active disease throughout adulthood, with sustained remission attained in a minority of patients. Early hip or wrist involvement, symmetric disease (even in pauciarticular patients), presence of rheumatoid factor, and prolonged active disease have been associated with poor long-term outcomes.
Children with systemic disease tend to have either complete responsiveness to medical therapy or development of a polyarticular course that tends to be refractive to medical treatment, with disease persisting into adulthood.
Most children with pauciarticular disease demonstrate eventual permanent remission; a small number progress to persisting polyarticular disease.
Patient Education
Educating the patient, family, and school personnel (eg, classroom teachers, physical education teachers, nurses) about juvenile idiopathic arthritis and its presentation, treatment, and potential effects is continually necessary. Members of the pediatric rheumatology team in pediatric rheumatology clinics are the best educators about juvenile idiopathic arthritis. Another important source of information is the American Juvenile Arthritis Organization, a council of the Arthritis Foundation.
For excellent patient education resources, visit eMedicine's Arthritis Center. Also, see eMedicine's patient education articles Juvenile Rheumatoid Arthritis and Understanding Rheumatoid Arthritis Medications.
Miscellaneous
Medicolegal Pitfalls
The major medicolegal pitfall lies in diagnosing juvenile idiopathic arthritis (JIA) when another problem exists (eg, infection, malignancy, orthopedic problem). Whenever possible, referral to a pediatric rheumatologist can help address this issue. Careful attention to presenting history and initial physical examination findings can lower the likelihood of such a pitfall. However, the chance of such a pitfall can never be eliminated completely.
At the time of diagnosis, inform parents and/or caregivers of the possible need to revise the diagnosis of juvenile idiopathic arthritis should new symptoms, physical findings, or unusual laboratory results develop.
Special Concerns
Chronic illness imposes burdens on families, who may vary in their abilities to cope. Social workers can help provide assessment and assist families in finding resources (including counseling). Remind parents and/or caregivers to bring all questions to the pediatric rheumatology team, who can often help. Any unusual symptom may signal a new complication of disease or adverse effect of medication. In the current health care environment, managed care can result in initial denial of services (eg, physical therapy), resulting in delays in treatment with subsequent morbidity. Advocacy by the primary care physician and pediatric rheumatologist can help point out the need for such services.

Acknowledgments
The authors and editors of eMedicine gratefully acknowledge Michael L Miller, MD, to the original writing and development of this article.

Juvenile Rheumatoid Arthritis: Treatment & Medication

Author: C Egla Rabinovich, MD, MPH, Associate Professor and Co-Division Chief, Department of Pediatrics, Division of Pediatric Rheumatology, Duke University Medical Center
Contributor Information and Disclosures

Updated: Apr 7, 2010

Treatment

Medical Care

Medical care of children with juvenile rheumatoid arthritis (JRA) must be provided in the context of a team-based approach, considering all aspects of their illness (eg, physical functioning in school, psychological adjustment to disease). Using medications in the absence of an appropriate physical therapy program and attention to problematic social issues of the family is not successful. Success of medications is monitored best with repeated physical examinations and history. Both the number of joints involved and the duration of morning stiffness should demonstrate continued decrease, with elimination reflecting success.

Surgical Care

Surgery is not usually needed; however, some children with persisting pauciarticular juvenile rheumatoid arthritis, despite medical treatment, may benefit from intra-articular steroid injection. Such injections may also be effective in treating temporomandibular arthritis in children with polyarticular juvenile rheumatoid arthritis. Usually, delay joint replacement (often of the hips, in patients with polyarticular juvenile rheumatoid arthritis) until bone growth has completed, which is reflected by epiphyseal closure. The consistent effective use of medical treatment has consigned synovectomy to a rarely used intervention. Large leg length discrepancies may need surgical treatment.

Consultations

The subspecialty team includes the following:

• Pediatric rheumatologist (when available)
• Nurses (who help with education)
• Physical and occupational therapists: Nonmedical approaches (eg, physical and occupational therapy) are an important part of treatment. At presentation, arthritis may be so active as to preclude the use of an aggressive program of muscle strengthening. Nevertheless, the use of pain modalities during this period may permit the gradual introduction of an active program of exercises and stretching.
• Social workers: Social work evaluation helps to determine how well each family is coping with their child's disease in terms of emotional and financial resources. Social workers can offer invaluable guidance for helping children to maintain healthy relationships both within their families and at school. Transition programs for adolescents with arthritis can help prepare them for higher education and future vocations.

Pediatric ophthalmologists help provide slit-lamp examinations to exclude uveitis. Pediatric orthopedic surgeons can offer consultation when orthopedic diagnoses are being considered. The development of profound anemia or a drop in 2 or more cell lines may require the help of a pediatric hematologist. A pediatric gastroenterologist may help with hepatic abnormalities or symptoms suggesting inflammatory bowel disease.

Diet

No specific diet helps in the treatment of juvenile rheumatoid arthritis. However, because active juvenile rheumatoid arthritis has been associated with decreased osteoblastic activity and a risk of osteopenia, encourage the inclusion of at least 3 servings of calcium-rich foods each day. Consider behavioral intervention when poor calcium intake persists.

Activity

Encourage patients to be as active as possible. Except in individuals with severe systemic disease, bed rest is not a part of the treatment. In fact, the more active the patient the better the long-term prognosis is. Children may experience increased pain during routine physical activities. As a result, these children must be allowed to self-limit their activities, particularly during physical education classes. A consistent physical therapy program, with attention to stretching exercises, pain modalities, joint protection, and home exercises, can help ensure that patients are as active as possible.

Medication

Classes of medications are suggested below, and specific drugs are covered in detail by category. See the therapeutic algorithm below

One set of suggested algorithms for the treatment of patients with juvenile arthritis. This should not be considered dogmatic because treatment is not standardized and remains empiric and, at times, controversial.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat all subtypes of juvenile rheumatoid arthritis (JRA). They may help with pain and decrease swelling. They are often used in conjunction with second-line agents. These medications are effective because of inhibition of prostaglandin synthesis. Naproxen is listed below as an example of an NSAID used in treatment; other NSAIDs commonly used include ibuprofen, tolmetin, diclofenac, and indomethacin. In addition, sulfasalazine is sometimes used as a second anti-inflammatory drug in some children with persisting pauciarticular and polyarticular disease. Its use may be considered as an intermediate step prior to adding a second-line drug such as methotrexate (MTX).

Aspirin is no longer the drug of first choice because of the increased frequency of gastric toxicity and hepatotoxicity when compared to other NSAID medications, along with its association with Reye syndrome. The discovery that cyclooxygenase (COX) in gastric and intestinal endothelium (ie, COX-1) is different in structure from that in leukocytes (ie, COX-2) has led to the development of anti-inflammatory drugs specific for COX-2. COX-2 inhibitors have been found to be effective in treatment of adults with rheumatoid arthritis. Studies of COX-2 inhibitors in persons with juvenile idiopathic arthritis are underway. Besides the benefit of greatly reducing gastric toxicity (although hepatotoxicity remains a possible adverse event), COX-2 inhibitors do not inhibit platelet aggregation. Thus, these agents may find a role in the treatment of inflammatory conditions in which a bleeding diathesis is a potential problem, such as in the postoperative setting.

NSAIDs alone are usually adequate for treatment of pauciarticular disease. However, an aggressive arthritis sometimes develops in this subtype, requiring the need to add a second-line drug. Various second-line drugs have been used in addition to first-line NSAIDs. Gold salt injections were used until approximately 15 years ago, when studies by the Pediatric Rheumatology Collaborative Study Group demonstrated the efficacy of oral (PO) MTX; these injections are not currently used for most children. Subsequent studies have demonstrated that some children with polyarticular arthritis unresponsive to PO MTX benefit from subcutaneous (SC) or intramuscular (IM) administration. The use of high-dose intravenous (IV) steroids as a therapeutic bridge in selected patients has been beneficial in some patients, particularly during an early period before MTX may have a full therapeutic effect.

Etanercept, a biologic agent administered SC twice weekly and containing a receptor to tumor necrosis factor (TNF) ligated to an Fc portion of immunoglobulin, has been found to be effective in controlling polyarticular arthritis not controlled by conventional medical treatment. Adalimumab is another anti-TNF agent now approved for use in juvenile idiopathic arthritis. These medications are for those children treated by pediatric rheumatology centers who are unresponsive to treatment including conventional second-line drugs.

Abatacept is a biological immune modulator with a delayed onset of action (4 mo) that may be useful in polyarticular disease.

Finally, the treatment of systemic juvenile idiopathic arthritis may require, in addition to treatment with NSAIDs, the careful use of either PO or high-dose pulse IV corticosteroids. Such treatment is best reserved for patients in whom definite arthritis has developed to avoid premature treatment in a patient who may prove to have a disease other than juvenile rheumatoid arthritis. Corticosteroids may be avoided with the use of anakinra, which is relatively new, inhibits interleukin (IL)-1 activity, and appears to have unique efficacy on the systemic signs and symptoms of systemic juvenile idiopathic arthritis. Rilonacept (anti-IL-1) may be an alternative treatment that is being studied, as is tocilizumab, which is anti-IL-6. Thalidomide has also been reported to be useful in these children.

Juvenile Rheumatoid Arthritis: Differential Diagnoses & Workup

Author: C Egla Rabinovich, MD, MPH, Associate Professor and Co-Division Chief, Department of Pediatrics, Division of Pediatric Rheumatology, Duke University Medical Center
Contributor Information and Disclosures

Differential Diagnoses

Acute Lymphoblastic Leukemia	Neuroblastoma
Autoimmune Chronic Active Hepatitis	Osteomyelitis
Behcet Syndrome	Pericarditis, Viral
Celiac Disease	Rheumatic Fever
Crohn Disease	Sarcoidosis
Endocarditis, Bacterial	Serum Sickness
Fever in the Toddler	Somatoform Disorder: Pain
Infectious Mononucleosis	Systemic Lupus Erythematosus
Kawasaki Disease	Tularemia
Lyme Disease	Ulcerative Colitis

Other Problems to Be Considered

Many conditions may manifest with arthritis of brief duration. Postinfectious arthritis typically affects large joints. This syndrome is clinically indistinguishable from the early phase of juvenile idiopathic arthritis (JIA), particularly because onset of juvenile idiopathic arthritis may be triggered by viral infections; a duration longer than 6 weeks eventually differentiates juvenile idiopathic arthritis. Patients with acute lymphocytic leukemia can present with joint pain and arthritis. Expansion of lymphoblasts in bone metaphyses results in pain, which is typically severe and may awaken a child from sleep.

Thrombocytopenia is rare in persons with juvenile idiopathic arthritis; its presence also suggests the possibility of leukemia. The differential count in juvenile idiopathic arthritis often demonstrates a relative lymphopenia, presumably because of egress of activated lymphocytes from circulation into synovium. Lymphocytosis is uncharacteristic of juvenile rheumatoid arthritis and raises the possibility of leukemia, particularly when a neutropenia is present.

Enthesitis-related arthritis, or spondyloarthropathy, is a chronic disease characterized by periods of inflammation of tendons and ligaments, particularly at the area of insertion into bone (entheses). Often, children and adolescents with spondyloarthropathy present with arthritis, making the distinction between subtypes difficult. Furthermore, some children occasionally develop a disease that appears to be a combination of the 2 diseases. Nevertheless, although enthesitis can be observed in persons with pauciarticular and polyarticular juvenile rheumatoid arthritis, the eventual evolution of arthritis to a predominant enthesitis is more characteristic of spondyloarthropathy. The presence of the human leukocyte antigen (HLA) B27 is helpful in suggesting the diagnosis. However, radiographic changes observed in adults (eg, sclerosis of the sacroiliac joints, bamboo spine) are rare in childhood and adolescence.

Workup

Laboratory Studies

No laboratory studies are diagnostic for juvenile idiopathic arthritis (JIA).

• All laboratory study findings may be normal in children with juvenile idiopathic arthritis. Diagnosis is based on the physical finding of arthritis. Laboratory studies help exclude other underlying diagnosis, classify the type of arthritis, and help evaluate for extra-articular manifestations of juvenile idiopathic arthritis. Initial evaluation should include the following:
• Inflammatory markers
• Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) are usually elevated in children with systemic juvenile rheumatoid arthritis (JRA) and may be elevated or normal in those with polyarticular disease; however, it is often within the reference range in those with pauciarticular disease.
• When elevated, inflammatory markers may be used to monitor success of medical treatment.
• CBC count with differential and platelet count
• Lymphopenia is not uncommon because of emigration of activated lymphocytes out of the circulation into synovium.
• Neutropenia is uncommon and, particularly with lymphocytosis or thrombocytopenia, raises the possibility of acute lymphocytic leukemia.
• Thrombocytopenia may also be observed in persons with systemic lupus erythematosus (SLE) presenting with arthritis, as well as marrow occupying malignancies. Thrombocytosis reflects inflammatory state and often mirrors inflammatory markers in juvenile idiopathic arthritis.
• Anemia may result from chronic active juvenile rheumatoid arthritis; often microcytic, anemia is usually refractive to treatment with iron.
• Alanine aminotransferase (ALT) test: Obtain ALT levels to exclude the possibility of hepatitis (viral or autoimmune) prior to initiating treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or methotrexate (MTX), which can cause hepatotoxicity.
• Urinalysis with microscopic examination: Perform a urinalysis to exclude the possibility of infection (as a trigger of juvenile rheumatoid arthritis or transient postinfectious arthritis) and nephritis (observed in individuals with SLE). Urinalysis should be monitored in children on chronic NSAIDs. Serum creatinine levels should be obtained prior to initiation of treatment with NSAIDs.
• Antinuclear antibody (ANA)
• ANA is observed in as many as 50% of children with juvenile idiopathic arthritis, particularly in those with oligoarticular or polyarticular rheumatoid factor–negative subtypes.
• A positive ANA is a marker for increased risk of anterior uveitis. Children younger than 6 years at arthritis onset with a positive ANA finding are in the highest risk category for development of uveitis and need slit lamp screening every 3-4 months.
• Very high titers may sometimes be associated with evolution to other rheumatic disease (eg, SLE).
• Titers otherwise do not correlate with disease activity.
• Rheumatoid factor
• Rheumatoid factor is found to be present in less than 10% of children with juvenile idiopathic arthritis. It is very rarely found in those with systemic juvenile idiopathic arthritis. Rheumatoid factor is a marker for early erosive disease and persistence of arthritis into adulthood.
• Rheumatoid nodules may be seen in those with rheumatoid factor–positive disease
• Compared with adults who have rheumatoid factor, children are at less risk for rheumatoid lung involvement and vasculitis.
• Other laboratory tests for systemic juvenile rheumatoid arthritis include the following:
• Total protein and albumin levels are often decreased during active disease.
• Fibrinogen and D-dimer levels are often elevated in individuals with active disease.
• A falling sedimentation rate, along with normalization or falling WBC, low platelets, elevated liver function test findings, increased ferritin and triglycerides with low fibrinogen and associated erratic fevers, hemorrhages (disseminated intravascular coagulation–like pattern) are indicative of development of macrophage activating syndrome (MAS) in particularly in those with systemic onset juvenile idiopathic arthritis.
• Other laboratory tests to consider include the following:
• ACE elevation may be indicative of sarcoidosis.
• Antistreptolysin 0 (AS0) and anti-DNAse B elevations may indicate acute rheumatic fever or poststreptococcal arthritis.

Imaging Studies

The following imaging studies are indicated:

• Radiography of affected joints: When only a single joint is affected, radiography is important to exclude other diseases, such as osteomyelitis or septic arthritis.
• Bone scanning: When physical findings do not document definite arthritis, consider bone scanning as a means of identifying a potential focus of osteomyelitis or other abnormality.
• MRI
• Perform MRI of the affected joint, with gadolinium injection to enhance inflamed synovium.
• MRI is helpful when considering trauma in the differential diagnosis.
• MRI of the temporal-mandibular joint (TMJ) is useful in diagnosing TMJ inflammatory arthritis.
• CT scanning of long bones: Perform when considering osteoid osteoma in a child with lower extremity pain (often at night) and unremarkable findings on physical examination.
• Echocardiography
• This is performed in a child with possible systemic juvenile rheumatoid arthritis and with fevers.
• Perform echocardiography in an individual who has orthopnea by history or a rub to exclude pericarditis.
• In a person who has nonspecific rash, adenopathy, and possible mucocutaneous changes, perform echocardiography to exclude coronary arterial dilation resulting from (possibly atypical) Kawasaki disease.
• In an individual who has findings suggestive of SLE (eg, nephritis, pleuritic chest pain, thrombocytopenia), perform echocardiography to exclude valvular disease, although mild dilation may be seen in some patients with systemic juvenile rheumatoid arthritis.

Other Tests

Perform dual-energy radiograph absorptiometry (DXA) scanning to document osteopenia in children with polyarticular juvenile rheumatoid arthritis.

Procedures

The following procedures are indicated:

• Arthrocentesis: Perform arthrocentesis to exclude septic arthritis in a child with monoarticular swelling.
• Synovial biopsy: This procedure may be helpful to exclude other diagnoses, particularly when the knee is affected (eg, villonodular synovitis, granulomatous arthritis).
• Pericardiocentesis: Perform this in an ICU setting to treat severe pericarditis.

Histologic Findings

Synovial biopsy may reveal synovial infiltration with plasma cells, mature B lymphocytes, and T lymphocytes, with areas of synovial thickening and fibrosis.