Juvenile idiopathic arthritis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nehal Eid, M.D.[2]

Overview

The treatment of JIA is best undertaken by an experienced team of health professionals, including paediatric rheumatologists, nurse specialists, physiotherapists, occupational therapists, chiropractors and psychologists. Many others in the wider health and school communities also have valuable roles to play, such as ophthalmologists, dentists, orthopaedic surgeons, school nurses and teachers, careers advisors and, of course local general practitioners, paediatricians and rheumatologists. It is essential that every effort is made to involve the affected child and their family in disease education and balanced treatment decisions.

Management involves recognition and treatment of specific childhood arthritis issues as well as effective transition to adult care as patients mature.

Medical Therapy

Medical treatment of juvenile idiopathic arthritis (JIA) is individualized according to subtype, number of joints involved, presence of systemic features, risk of complications (e.g., uveitis), and response to initial therapy. Contemporary reviews emphasize early control of inflammation and the increasing use of targeted biologic therapies, particularly for systemic JIA and refractory disease. Advances in the treatment of JIA have resulted in meaningful disease control for up to 70% of patients.

General Principles

• Use a treat-to-target approach aimed at inactive disease or low disease activity
• Traditionally, a step-up approach was adopted when response is inadequate to prevent joint damage and disability such as sequential addition of a conventional synthetic DMARD, followed by a biologic DMARD. Modern approaches that involve initiation of biologic DMARD, with or without conventional synthetic DMARD, are more common nowadays. Two studies of these novel approaches have shown improved outcomes.
• In a single group, single-center study involving patients with systemic JIA who received early treatment with an interleukin-1 inhibitor, more than 70% of the patients had medication-free remission at 5 years, indicating a possible window of opportunity early in the disease course for preventing the development of chronic systemic JIA.
• In STOP-JIA study, patients treated early with a combination of conventional synthetic DMARDs and biologic DMARDs had better out comes at 3 years than treatment with traditional step-up approach. The group that recieved the combination DMARD therapy had longer inactive disease periods. Additionally, administeration of biologic DMARD within 2 months after diagnosis lead to 3 times more likely rapid improvement and sustained disease inactivity periods.
• BeST-for-Kids trial compared 3 initial treatment combinations and treat-to-target strategy. Its outcomes are consistent with STOP-JIA study. showing clinical remission at years in 70% of study population regardless of intial assignment. However, early combination group had the most rapid improvement and were most likely to have sustained responses.
• The STARS trial compares step-up treatment intensification coupled with a treat-to-target framework to early combination therapy without a treat-to-target framework in patients with oligoarticular or polyarticular JIA.
• After reducing disease activity, ongoing disease control can be refined with modifying therapy at defined intervals to achieve clinical targets, a strategy named treat-to-target strategy.
• Coordinate care with ophthalmology for uveitis screening and management
• Use physical and occupational therapy to preserve range of motion and function
• As the patients get older, transition from pediatric to adult care should be facillitated to improve long-term outcomes.
• Common barriers to disease control during patient's lifetime are limited global access to rheumatologic care and to advanced treatments.
• Flare rates after treatment discontinuation is between 30 to 100%.

Symptomatic and Bridging Therapy

• Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Often used as initial therapy for mild disease
• Glucocorticoids
  • Intra-articular glucocorticoid injections for active synovitis in one or a few joints
  • Systemic glucocorticoids may be used as short-term bridging therapy or for severe systemic features; prolonged use is avoided due to toxicity (e.g., growth suppression, osteoporosis)

Conventional Synthetic DMARDs

• Methotrexate
  • Common first-line disease-modifying therapy for persistent active arthritis (oligoarticular extended disease, polyarticular disease, and some cases of enthesitis-related or psoriatic JIA)
  • Used to reduce disease activity and allow glucocorticoid-sparing therapy

Biologic DMARDs and Targeted Therapy

Biologic therapy is used for moderate-to-severe disease, poor prognostic features, inadequate response to methotrexate, or specific subtype-driven indications.

• Tumor necrosis factor (TNF) inhibitors
  • Commonly used for polyarticular JIA and enthesitis-related arthritis; may also be used for psoriatic JIA
• Interleukin-6 (IL-6) inhibition
  • Used in systemic JIA and polyarticular JIA
• Interleukin-1 (IL-1) inhibition
  • Central to systemic JIA management, particularly with prominent systemic features. In a single group, single-center study involving patients with systemic JIA who received early treatment with an IL-1 inhibitor, more than 70% of the patients had medication-free remission at 5 years.

Over the past decade, therapeutic management of JIA has witnessed the development and approval of novel targeted biologic DMARDs such as inhibitors of IL-12, IL-17, IL-23 and interferon-γ.

Interleukin-17 (IL-17) inhibitors

• Used primarily for enthesitis-related arthritis particularly fter TNF failure.
• Other biologics
  • Agents such as abatacept may be used in selected refractory cases depending on subtype and prior therapy

Targeted synthetic DMARDs (e.g., Janus kinase inhibitors) may be considered in selected refractory cases under specialist guidance.

Treatment algorithm for oligoarthritis

Systemic JIA–Specific Therapy

Systemic JIA is biologically distinct and is irresponsive to commonly used medications. It is managed with early cytokine-targeted therapy.

• Methotrexate and TNF inhibitors are ineffective in early systemic JIA.
• IL-1 or IL-6 inhibitors are commonly preferred early, often with limited-duration systemic glucocorticoids for severe systemic inflammation

Macrophage Activation Syndrome (MAS)

MAS is a life-threatening complication most often associated with systemic JIA and requires urgent therapy.

• High-dose systemic glucocorticoids are commonly used as initial therapy
• IL-1 or IL-6 inhibitors are conditionally recommended over calcineurin inhibitors alone to achieve inactive disease and MAS resolution (specialist-guided)

• 

  Treatment algorithm for sJIA

Common medications used for JIA

Medication Category	Examples	Potential side effects
NSAIDs	Ibuprofen, Naproxen, Meloxicam, Celecoxib, Indomethacin	Gastritis and interstitial nephritis
Systemic glucocorticoids	Prednisone, Prednisolone, Methylprednisolone	Long-term therapy is not recommended as it can lead to: Growth failure Osteoporosis Avascular necrosis Hypertension Weight gain Diabetes Mellitus Cushingoid Features Immunosuppression
Topical glucocorticoids	Prednisolone eye drops	Increased intraocular pressure, glaucoma and cataracts
Intraarticular glucocorticoids	Triamcinolone hexacetonide (preferred), Triamcinolone acetonide	Repeated TMJ injections is not recommended due to questionable efficacy and potential effects on bone growth.
Conventional synthetic DMARD	Methotrexate (most common), sulfasalazine, leflunomide	Methotrexate: Nausea, Aphthous ulcers, liver injury, and teratogenicity Leflunomide: Liver injury and teratogenicity. Contraindicated in patients using alcohol Sulfasalazine: Gastrointestinal symptoms
Biologic DMARD	Cytokine inhibitors: TNF (etanercept, adalimumab, golimumab and certolizumab pegol), IL-6 (tocilizumab and sarilumab), IL-1 (canakinumab and anakinra (approved in Europe not in the US)), IL-17(secukinumab), IL-12 and IL-23 (ustekinumab) and interferon-γ inhibitors (emapalumab). T or B cell modulating agents: abatacept and rutiximab	Opportunistic infections and demyelinating CNS lesions (specific to TNF inhibitors); increased risk of cancer not confirmed, events are very rare
Targeted specific DMARD	Janus kinase inhibitors: tofacitinib,upadacitinib (US) and baricitinib (Europe)	Serious infections, major adverse cardiovascular events, thromboembolic disease, and increased cancer rates reported among adults with rheumatoid arthritis using these agents