Juvenile Idiopathic Arthritis Treatment & Management

The ultimate goals in managing rheumatoid arthritis are to prevent or control joint damage, to prevent loss of function, and to decrease pain. ^[1] These goals are particularly important in juvenile idiopathic arthritis (JIA), in which the rate of progression and the onset of debility can be rapid. JIA is a chronic disease characterized by periods of remission and flare. Treatment is aimed at inducing remission with the least toxicity from medications with hopes of inducing a permanent remission.

The success of therapy is monitored best with repeated physical examinations and history. The number of joints involved and the duration of morning stiffness should demonstrate continued decrease, with elimination reflecting success. Surgery may be indicated in patients who are unresponsive to medical therapy.

A team-based approach can be helpful. Management may include one or all of the following areas:

• Pharmacologic management consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), biologic agents, ^[30] and intra-articular and oral steroids

• Psychosocial factors, including counseling for patients and parents

• School performance, such as academic counseling, school-life adjustments, and physical education adjustments

• Nutrition, particularly to address anemia and generalized osteoporosis; often microcytic, anemia is refractive to treatment with iron

• Physical therapy to relieve pain and to address range of motion, muscle strengthening, activities of daily living, and conditioning exercises

• Occupational therapy, including joint protection, a program to relieve pain, range of motion, and attention to activities of daily living

American College of Rheumatology (ACR) criteria for complete remission are as follows ^[1] :

• No inflammatory joint pain

• No morning stiffness

• No fatigue

• No synovitis

• No progression of damage, as determined in sequential radiographic examinations

• No elevation of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels

The ACR issued recommendations for the treatment of JIA on the basis of the following 5 treatment groups ^[2] :

• History of arthritis in 4 or fewer joints

• History of arthritis in 5 or more joints

• Active sacroiliac arthritis

• Systemic arthritis without active arthritis

• Systemic arthritis with active arthritis

Within each treatment group, choice of therapy is guided by the severity of disease activity and the presence or absence of features indicating a poor prognosis.

The ACR released updated guidelines for the treatment of systemic JIA, which included the medications canakinumab, rilonacept, and tocilizumab. ^[31] These guidelines include the following treatment recommendations:

• For systemic JIA with active systemic features and varying degrees of synovitis, initial treatment for most patients should consist of anakinra with systemic glucocorticoids

• For systemic JIA without active systemic features and with varying degrees of active synovitis, initial treatment should be methotrexate or leflunomide for an active joint count higher than 4, with a change to abatacept, anakinra, a tumor necrosis factor (TNF)-α inhibitor, or tocilizumab if disease activity continues after 3 months; for patients with 4 or fewer active joints, NSAID monotherapy or intra-articular glucocorticoid injections should be initial treatment

• For systemic JIA with features suggesting macrophage activation syndrome (MAS), initial treatment should include anakinra, a calcineurin inhibitor, or systemic glucocorticoid monotherapy for up to 2 weeks

According to ACR guidelines, the treatment group that comprises patients who have developed active arthritis in only 4 or fewer joints total throughout their disease course includes patients in the International League of Associations for Rheumatology (ILAR) categories of persistent oligoarthritis, as well as patients with psoriatic arthritis, enthesitis-related arthritis, and undifferentiated arthritis. ^[2]

In this treatment group, escalation of therapy typically proceeds from NSAIDs to intra-articular glucocorticoid injections to methotrexate to TNF-α inhibitors.

NSAIDs alone may be adequate for patients with involvement of a single joint and other indications of low disease activity (eg, normal inflammatory marker levels); response should be evident within 2 months. For other patients, NSAIDs may be used as adjunctive treatment, as needed.

Intra-articular injections of triamcinolone can be used for any joint involved with active arthritis, and should provide clinical relief for at least 4 months. If so, the injections can be repeated as needed.

Methotrexate can be instituted in patients who fail to show adequate response to NSAIDs and/or joint injections. Alternatively, methotrexate is recommended as initial treatment for patients in this treatment group who have high disease activity and features indicating poor prognosis. In patients with enthesitis-related JIA, sulfasalazine rather than methotrexate is recommended for patients who have an inadequate response to joint injection or an adequate trial of NSAIDs.

Patients in this treatment group who fail to respond adequately to joint injections and to 3-6 months (depending on disease characteristics and severity) of methotrexate are candidates for TNF-α treatment. The same is true of patients with enthesitis-related JIA who receive sulfasalazine.

This group comprises patients who have developed active arthritis in 5 or more joints total throughout throughout their disease course. Patients need not currently have active involvement in 5 or more joints. According to ACR guidelines, this group includes patients with the ILAR categories of extended oligoarthritis, rheumatoid factor (RF) negative and RF-positive polyarthritis, psoriatic arthritis, enthesitis-related arthritis, and undifferentiated arthritis. ^[2]

Treatment in this group places less emphasis on initial NSAIDs. After 1 month of NSAID treatment in patients with low disease activity, or 1-2 months in those with moderate disease activity but without poor prognostic features (ie, hip or cervical spine involvement, positive RF or anti-cyclic citrullinated peptide antibodies (CCP), radiographic signs of joint damage), it is appropriate to escalate to methotrexate, plus adjunctive NSAIDs and joint injection as needed.

In patients with moderate disease activity and poor prognostic features, as well as in patients with high disease activity, treatment may start with methotrexate.

Several immunomodulating drugs (eg, TNF blockers, interleukin inhibitors, Janus kinase inhibitors) have been approved by the US Food and Drug Administration (FDA) for JIA. 

Leflunomide may be used as an alternative to methotrexate, after a failed NSAID trial, or as initial treatment in patients with high disease activity and poor prognostic features.

The FDA has approved the interleukin (IL)-6 inhibitor tocilizumab for the treatment of polyarticular JIA in children 2 years of age and older with active disease. Tocilizumab can be used alone or in combination with methotrexate. ^[32]

Escalation to a TNF-α inhibitor follows if 3-6 months (depending on disease characteristics and severity) of methotrexate or leflunomide provides inadequate control. Patients who show inadequate response after 3-4 months (depending on disease characteristics and severity) of TNF-α inhibitor treatment can be switched to a different TNF-α inhibitor or to abatacept. If these agents prove inadequate, patients may be started on rituximab; this agent may be most appropriate in patients with RF-positive polyarticular JIA.

A study confirmed the acceptable long-term tolerability of etanercept and adalimumab treatment in polyarticular juvenile idiopathic arthritis. However, the authors also add that whether the onset of inflammatory bowel disease and uveitis during etanercept monotherapy is a paradoxical effect or an inadequate response to therapy remains unclear and requires further investigation in this growing cohort. ^{[33, 34]}

Another study by Horneff et al that included 577 pediatric patients reported a similar safety profile of adalimumab in pediatric patients with polyarticular juvenile idiopathic arthritis, enthesitis-related arthritis, psoriasis, and Crohn disease. The most common adverse events were infections which occurred in 82% of patients with JIA. ^[35]

Tofacitinib, a Janus kinase inhibitor, is indicated for active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients aged 2 years and older. The phase 3 trial (n = 225) was a 44-week, 2-part study (consisting of an 18-week, open-label, run-in phase, followed by a 26-week double-blind, placebo-controlled, randomized withdrawal phase). Of the 225 patients, 173 (76.9%) patients achieved JIA ACR30 response at week 18 and were randomized into the double-blind phase to either active tofacitinib tablets or oral solution (n = 88) or placebo (n = 85). At the conclusion of the 18-week, open-label, run-in phase, pediatric ACR 30/50/70 responses were 77%, 70%, and 49%, respectively. Disease flare was significantly less at week 44 with tofacitinib compared with placebo (P = .0007). ^[36]

This group includes all patients with clinical and imaging evidence of active sacroiliac arthritis. It may include patients from any of the ILAR JIA categories. ^[2]

Use of a TNF-α inhibitor is recommended more readily for patients in this group. A TNF-α inhibitor may be started after failure of an adequate trial of NSAIDs or after 3-6 months (depending on disease characteristics and severity) of methotrexate or sulfasalazine proves inadequate.

This group includes all patients who fulfill the ILAR criteria for systemic arthritis and who have active fever of systemic JIA with or without other systemic features, but without active arthritis. ^[2] A 2-week trials of NSAIDs may be used in patients who have fever and less severe disease, and have had significant active systemic disease for less than 6 months; after that, patients should be started on systemic glucocorticoids, with adjunct NSAIDs as needed.

Patients with high systemic disease activity (eg, significant serositis) may be started on steroids as a first step. There is virtually no published evidence regarding steroid doses or administration routes in this setting.

Patients who sustain or develop active fever while on systemic steroid therapy can be started on anakinra. This agent may be a first choice in patients who have had significant active systemic disease for at least 6 months.

The FDA has approved tocilizumab for the treatment of systemic JIA. Clinical trials in children with JIA showed significantly fewer disease flares when treated with tocilizumab compared with placebo (26% vs 48%). Additionally, a higher success rate of steroid reduction/discontinuance was achieved in the tocilizumab group (24%) compared with placebo (3%). ^[37]

The phase III TENDER study demonstrated that tocilizumab was effective in improving the signs and symptoms of systemic JIA. After 3 months of treatment, 85% of participants who took tocilizumab had a 30% improvement (JIA ACR30+) in the signs and symptoms of systemic JIA and absence of fever, compared with 24% of patients who received placebo.

Further data showed 70% of patients on tocilizumab achieved JIA ACR70+ and 37% achieved JIA ACR90+, compared with 8% and 5% of patients who received placebo, respectively. Additionally, nearly two-thirds of patients in the study were free of rash after 3 months. In this study, the safety profile similar to adults treated with tocilizumab for rheumatoid arthritis. ^[38]

The interleukin-1 β inhibitor canakinumab has also been FDA-approved for systemic JIA. ^[39] In the beta-SPECIFIC 1 trial, 84% of patients with SJIA treated with canakinumab experienced at least a 30% improvement in symptoms compared with 10% in the placebo group after 15 days of treatment (P< 0.001). ^[40]

In the open-label beta-SPECIFIC 2 trial, 45% of canakinumab-treated patients who were prescribed corticosteroids were able to reduce steroid use, and one-third of patients completely discontinued corticosteroids. Additionally, the canakinumab-treated patients were nearly 3 times less likely to experience a new flare, with 74% remaining flare-free compared to 25% with placebo (P = 0.003). ^[40]

This category includes all patients who fulfill the ILAR criteria for systemic arthritis and who have active arthritis, but who do not have active systemic features. ^[2] Most of these patients are started on NSAIDs while their diagnostic assessment progresses.

NSAID therapy, with intra-articular joint injections as needed, may be adequate for patients with low disease activity who do not have hip involvement or radiographic signs of joint damage. After up to 1 month, however, methotrexate can be added for patients with any degree of disease severity who continue to have active arthritis.

After 3 months of methotrexate therapy, the next step in escalation is to anakinra or a TNF-α inhibitor, although etanercept is less effective in systemic arthritis than in other forms of JIA. ^[41] Patients who show inadequate response to TNF-α inhibitor treatment can be started on abatacept.

Inpatient care is required for persisting fevers of unknown origin or when children with known JIA have severe exacerbation of disease.

Admit for evaluation any child who loses the ability to walk for unknown reasons.

The development of pericarditis in children with systemic-onset JIA is usually an indication for admission.

Exercise preserves joint range of motion and muscular strength, and it protects joint integrity by providing better shock absorption. Types of exercises that may be advised include a muscle-strengthening program, range-of-motion activity, stretching of deformities, and endurance and recreational exercises. Hydrotherapy is a good form of exercise that helps achieve the aforementioned objectives.

Rarely, children require splinting or serial casting to help decrease contractures in joints unresponsive to medical treatment.

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 contralateral side.

In a single-blind, randomized, controlled trial involving 60 children with JIA, Coda and colleagues found that the use of inexpensive prefabricated fitted foot orthoses reduced pain and improved quality of life compared with use of sham orthoses. Changes in pain were measured with a visual analogue scale and quality of life was measured with the Pediatric Quality of Life questionnaire. The study included 60 children with lower joint involvement beginning at age 5-18 years, previous failure of orthotic management with no use of orthoses for at least 3 months, the ability to walk 15 meters without assistive devices, and a 6-month history of disease-modifying antirheumatic drugs. At 3- and 6-month follow-ups, children in the fitted orthoses group experienced significantly greater pain reduction and improvements in quality of life than controls. ^[42]

Advances in medical treatment have reduced the need for surgical intervention in JIA. Possible procedures include synovectomy, osteotomy and arthrodesis, and hip and knee replacement.

Synovectomy

Synovectomy is rarely needed, and long-term outcome is poor; however, it may be used in children in whom a single joint or just a few joints are involved and who have very active, proliferative synovitis.

Osteotomy and arthrodesis

Osteotomy and arthrodesis are salvage procedures for patients whose JIA is associated with severe joint destruction or deformity.

Arthrodesis is superior to arthroplasty for children who have rheumatic disease in the wrist and fingers and in the ankle.

Total hip and total knee replacements

Total hip and knee replacements provide excellent relief of pain and restore function in a functionally disabled child with debilitating disease.

The role of total hip replacement and total knee replacement in JIA is fraught with problems, however. Joint replacement is usually delayed until bone growth has completed, as indicated by epiphyseal closure.

MAS) is a rare but important complication of systemic-onset JIA in which numbers of all 3 bloodlines become rapidly decreased. Hypofibrinogenemia, thrombocytopenia, and elevated aspartate aminotransferase levels are hallmarks.

MAS often responds to cyclosporine, and some case reports have detailed a response to anakinra. Treatment of MAS is a medical emergency and should be performed by physicians familiar with this complication.

Uveitis is often asymptomatic. Patients are typically young girls who have positive levels of ANA.

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 cyclosporine, may help control chronic uveitis. Infliximab can be effective in some patients who are resistant to immunosuppressive agents. ^[43]

A multicenter, double-blind, randomized, placebo-controlled trial by Ramanan et al reported that adalimumab plus methotrexate therapy controlled inflammation and was associated with a lower rate of treatment failure than placebo among children and adolescents with active JIA-associated uveitis. The study observed 16 treatment failures out of 60 patients (27%) in the adalimumab group compared to 18 treatment failures in 30 patients (60%) in the placebo group (hazard ratio, 0.25; 95% confidence interval [CI], 0.12 to 0.49; P< 0.0001). The study also reported a higher rate of adverse events (eg, oropharyngeal pain, cough, arthralgia) in the adalimumab group (10.07 events per patient-year vs. 6.51 events per patient-year) as well as a higher rate of serious adverse events (eg, infections or infestations [0.29 events per patient-year vs. 0.19 events per patient-year]). ^[44]

No specific diet helps in the treatment of JIA. However, because active JIA 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 supplementation when poor calcium intake persists. Rarely, overall caloric intake is poor and supplementation is required. TMJ disease may also compromise the child’s diet.

Encourage patients to be as active as possible. Bed rest is not a part of the treatment. In fact, the more active the patient, the better the long-term prognosis. 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.

Referral to a pediatric rheumatologist may be indicated when the diagnosis is unclear, when information on diagnostic evaluation and long-term management is needed, or because the family requires information from a subspecialist to cope with the patient's disease process, to accept the treatment plan, to allay anxiety, and/or to receive education. ^[45]

In addition to a pediatric rheumatologist (when available), the subspecialty team may include a nurse, physical and occupational therapists, social worker, ophthalmologist, and orthopedic surgeon. A nurse may provide patient education through nursing care.

Although at presentation, arthritis may be so active as to preclude the use of an aggressive program of muscle strengthening, physical and occupational therapists are an important part of treatment. The use of pain modalities during this period may permit the gradual introduction of an active program of exercises and stretching.

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 that helps children maintain healthy relationships within their families and at school. Transition programs for adolescents with arthritis can help to prepare them for higher education and vocation.

A pediatric ophthalmologist provides slit-lamp examinations to exclude uveitis, and a pediatric orthopedic surgeon is essential when orthopedic diagnoses are being considered.

The spectrum of specialists may be required such as pediatric hematologist for evaluation for malignancy or a pediatric gastroenterologist if inflammatory bowel disease is suspected.

A complete blood cell count and measurement of liver enzymes and serum creatinine should be part of routine follow-up in JIA patients. For JIA patients receiving NSAIDs on a long-term daily basis, these tests, plus urinalysis, should be done twice yearly; in patients taking these agents 3-4 days per week, testing should be repeated annually.

In JIA patients taking methotrexate, these tests should be conducted approximately 1 month after initiation of routine use and approximately 1-2 months after any increase in dose. If prior results were normal and the patient is on a stable dose, the tests can be repeated approximately every 3-4 months.

In JIA patients taking TNF inhibitors, these tests should be repeated approximately every 3-6 months. Tuberculosis screening should be repeated approximately once yearly.