Juvenile idiopathic arthritis

• Juvenile idiopathic arthritis is arthritis of unknown cause that begins before the age of 16 and lasts at least 6 weeks; diagnosis requires other causes of joint inflammation to be excluded. ^[2]
• It is not one disease: the International League of Associations for Rheumatology recognises seven subtypes, of which the five classic ones are oligoarticular, polyarticular (rheumatoid factor negative or positive), systemic-onset Still disease, enthesitis-related and psoriatic JIA.
• A single swollen knee in a young girl with a positive antinuclear antibody needs the eyes examined, not the joints, because chronic anterior uveitis is silent and can threaten sight.
• Systemic JIA behaves like an autoinflammatory illness: quotidian fevers to 39.5 °C ^[1], a salmon-pink rash, and possible macrophage activation syndrome, which is life-threatening. ^[2][3]
• Treatment runs from a short trial of NSAIDs and joint injection with triamcinolone hexacetonide, through methotrexate, to biologic IL-1 or IL-6 blockade; goal is inactive disease without long-term steroids.

By the end of this page you should be able to:

1. State the ILAR definition of JIA and classify a patient into the correct subtype using joint count, systemic features and serology.
2. Recognise the phenotype of each subtype: who is affected, which joints, what the eyes and skin show.
3. Explain ANA-related risk of uveitis and the need for regular ophthalmology review. ^[2]
4. Distinguish JIA from septic arthritis, reactive arthritis, leukaemia and Lyme disease.
5. Manage oligoarticular, polyarticular and systemic JIA step by step, with drugs, doses, routes and monitoring.
6. Recognise and escalate macrophage activation syndrome.
7. State realistic expectations for remission, flares and long-term damage.

The word "idiopathic" is important: JIA is a diagnosis made after septic, malignant, post-infectious and traumatic causes have been ruled out. JIA is an umbrella term. The International League of Associations for Rheumatology (ILAR) groups childhood arthritis by the findings during the first 6 months (joint count, systemic features, serology and genetics) and then by the final phenotype. Seven ILAR subtypes exist, including undifferentiated JIA when a patient does not fit, or fits more than one, of the categories. The five subtypes in common clinical use are listed in the table.

Clinical points that follow from the table:

• Oligoarticular is the commonest subtype in high-income settings. It is subdivided into persistent (no more than 4 joints ever) and extended (more than 4 joints after the first 6 months), because extended disease carries higher risk of joint damage.
• Polyarticular disease is split by rheumatoid factor, and the RF-positive form is the one most like adult rheumatoid arthritis: symmetric small joints, erosive, with rheumatoid nodules possible.
• Systemic JIA (Still disease) is considered by many to be an autoinflammatory condition rather than autoimmune disease. It is the subtype most likely to produce high ferritin and to progress to macrophage activation syndrome.
• ERA sits between JIA and the juvenile spondyloarthropathies and may be accompanied by subclinical gut inflammation.
• Psoriatic JIA is heterogeneous: young children often present with ANA positivity and uveitis, whereas older children present more like ERA.
• The 2019 Pediatric Rheumatology International Trials Organization consensus proposed newer labels (early-onset ANA-positive JIA, RF-positive JIA, enthesitis/spondylitis-related JIA, sJIA). These are still being validated and are not yet in universal use, so both vocabularies appear in the literature.

Collective population studies report a JIA incidence of 1 to 22 cases per 100,000 children and a prevalence of 7 to 150 cases per 100,000 children, with wide variation by region, case definition and diagnostic access. ^[1] Oligoarticular JIA is the most common subtype in most European and North American series. Overall JIA is more common in girls, largely because oligoarticular and polyarticular disease predominate. Systemic JIA and ERA are the exceptions: systemic disease affects boys and girls equally, and ERA is seen most in boys. Figures quoted here come from reviews and are approximate; local rheumatology registers should be used for service planning.

No single cause of JIA has been found. Non-systemic subtypes behave as autoimmune disorders with associations to HLA class II alleles and autoantibodies. Systemic JIA behaves as an autoinflammatory disorder driven by innate immunity (see pathophysiology), with little HLA association.

Environmental factors proposed as risk factors include certain infections (Epstein-Barr virus, parvovirus B, Salmonella, Shigella, Campylobacter and others), gut microbiome disruption, maternal smoking during pregnancy, and stress. Protective associations reported include breastfeeding and having siblings in the household. Genetic contributions are subtype specific: HLA-B27 for ERA, HLA class II alleles for oligoarticular and polyarticular disease, and polymorphisms in cytokine genes such as IL1, IL6 and IL10 for systemic JIA. No modifiable risk factor has been proven, so routine "prevention" means early recognition and uveitis screening rather than avoiding an exposure.

In non-systemic JIA, tolerance to self breaks down. Autoreactive T-cells (Th1 and Th17 subsets) and B-cells accumulate in the synovium and produce TNF-alpha, IL-17 and IFN-gamma. The synovial lining thickens into an invasive, hypervascular "pannus" that releases matrix metalloproteinases and aggrecanases, which digest cartilage, while receptor activator of nuclear factor-kappa B (RANK) signalling activates osteoclasts and erodes bone. ANA and rheumatoid factor are serological reflections of this adaptive immune activity. Cytokine profiles differ enough between subtypes that IL-18, for example, predicts systemic disease and macrophage activation syndrome with about 93% accuracy in review data ^[2].

In systemic JIA the innate immune system is the main driver. Monocytes, macrophages, neutrophils and immature myelomonocytic precursors overproduce IL-1 beta, IL-6, IL-18 and phagocyte-specific S100 proteins. This produces the fever, rash, serositis and visceral involvement and explains why biologic blockade of IL-1 or IL-6 is the targeted treatment. The mechanism also explains why conventional DMARDs (such as methotrexate) that act on adaptive immunity do not control the systemic features.

Macrophage activation syndrome is the dangerous end of this process. A trigger such as infection or a drug produces uncontrolled expansion of cytotoxic CD8-positive T-cells, which release pro-inflammatory cytokines and activate haemophagocytic macrophages. These infiltrate bone marrow, liver and spleen and consume host tissues and blood cells. The result is pancytopenia, coagulopathy and liver injury, and the syndrome can be fatal without rapid treatment.

The synovium in JIA shows marked lining-cell hyperplasia, dense lymphocyte and plasma-cell infiltrate, pathological angiogenesis and pannus formation. Cartilage degradation and subchondral bone erosion follow in aggressive subtypes. Histology is not used to make the diagnosis of JIA itself, which is clinical; biopsy is reserved for excluding malignancy or infection in atypical cases.

General pattern. Symptoms are often intermittent for months before diagnosis. Morning stiffness is common: the child is slow to get going, the leg is stiff after sitting, or there is a limp that improves as the day goes on. Pain is often mild relative to the swelling, which is why JIA can be mistaken for normal childhood aching.

Oligoarticular. The parent notices a swollen knee or ankle, often with no pain. The child limps after rest or on cold mornings. No fever, no weight loss, no rash. Early-morning stiffness can be the presenting complaint.

Polyarticular. Stiffness of several joints on waking, symmetric or asymmetric, involving wrists, fingers, knees and ankles. The child struggles with buttons, stairs and writing. Mild fever, weight loss and anaemia are described by parents as "tiredness and pale".

Systemic (Still) disease. Parents describe high spiking fevers, typically once or twice daily, with temperatures up to 39.5 °C ^[1], peaking in the late afternoon or evening and settling by morning. The fever is accompanied by a salmon-pink, evanescent rash (best seen on trunk and proximal limbs, appearing with fever and fading as temperature falls), and often by abdominal pain, chest pain and profound malaise. Arthritis may be absent initially; arthralgia often precedes obvious swelling by weeks. Weight loss and night-time waking are common.

ERA. Boys after age six with heel pain or knee/ankle swelling, especially asymmetric. Parents report foot pain on running and "bad posture". Low back pain and gluteal pain suggest sacroiliac involvement. Occasional acute red eye from anterior uveitis.

Psoriatic JIA. Psoriatic rash, nail pitting or onycholysis, dactylitis (sausage-like swelling of a whole digit). Joint pattern varies.

Inspect for joint swelling, warmth and limited range, with tenderness often modest. Measure leg lengths: limb overgrowth can occur beneath an inflamed knee. Examine for fixed flexion deformity, especially of the knees and elbows. Palpate entheses (Achilles insertion, plantar fascia, tibial tubercle) in ERA. Examine skin (psoriasis, eczema), nails and oral mucosa. Examine the eye for injected sclera or anisocoria, although most uveitis is silent. Palpate for lymphadenopathy and hepatosplenomegaly in systemic disease. Assess growth (height velocity, Tanner stage) and test gait.

A swollen joint in a child is not JIA until infection, malignancy and trauma are excluded. The history and the speed of onset do most of the separating: JIA is chronic (more than 6 weeks) with modest pain; infection is acute, hot and very painful.

A swollen joint that follows a minor injury is often not trauma: in a child, JIA can become symptomatic after trivial trauma, so do not close the diagnosis too quickly. Request joint aspiration whenever septic arthritis is plausible. Raised acute-phase markers are common to most of these conditions, so they distinguish inflammatory arthritis from non-inflammatory causes but not JIA from infection.

No single test confirms JIA. Investigations are used to subtype, to support the diagnosis, and to exclude infection, malignancy and other inflammatory diseases.

Blood tests. Full blood count (may show anaemia and thrombocytosis), ESR and CRP, ferritin, liver function and muscle enzymes. Rheumatoid factor and anti-CCP (usually in older children with polyarticular disease), ANA (request in all, because it predicts uveitis), and HLA-B27 when ERA is suspected. Myeloid-related proteins (S100A8/9, S100A12) and IL-18 are research or specialist biomarkers for systemic disease and macrophage activation syndrome. In suspected systemic JIA, also order triglycerides, fibrinogen and LDH to exclude macrophage activation syndrome at the outset.

Joint fluid. Aspirate whenever infection is suspected; also useful to confirm non-inflammatory (haemorrhagic, crystal) disease.

Imaging. Ultrasound with power Doppler shows active synovitis and tenosynovitis and guides injection. Plain radiographs of hands, wrists and affected joints look for erosions, joint-space narrowing and leg-length discrepancy in established disease. Magnetic resonance imaging detects early erosions, TMJ and sacroiliac disease, and subclinical gut inflammation in ERA.

Eye assessment. Slit-lamp examination by an ophthalmologist, repeated at intervals; see screening below. This is not optional, because the uveitis is silent and the child may not complain of redness.

ILAR criteria remain the working standard:

• arthritis starting before age 16;
• arthritis of at least one joint for at least 6 weeks;
• no other recognised cause (e.g., infection, malignancy);
• classification into the most appropriate subtype using the findings of the first 6 months, with the final subtype declared after follow-up.

Uveitis screening recommendations used in practice:

• ANA is common in oligoarticular, polyarticular and psoriatic subtypes and is associated with risk of chronic non-granulomatous anterior uveitis. The younger, ANA-positive, early-onset girl is at highest risk. ^[2]
• In one review series, 15 to 67% of children with JIA in European regions had uveitis by region ^[1], 13.1% of 1081 cases had uveitis overall ^[1], and ANA-positive oligoarticular girls with early-onset disease should have ophthalmological examination every 3 months ^[1]. Polyarticular disease carries uveitis in 5 to 10% of cases ^[1]
• Most JIA uveitis is chronic anterior (68.3% ^[1]), then acute anterior (16.2%), recurrent anterior (12%) and panuveitis (3.5%). HLA-B27-positive children are more prone to acute anterior uveitis (often symptomatic with red painful eye).
• Uveitis is typically asymptomatic. It becomes a cause of band keratopathy, cataract, glaucoma and visual impairment, which is why eyes, not joints, are the main disability factor in oligoarticular disease.

For treatment decisions, clinicians use validated composite scores (Juvenile Arthritis Disease Activity Score, clinical JADAS, Wallace criteria for remission, American College of Rheumatology provisional criteria for inactive disease) to run treat-to-target care. Strong recommendation exists for formal disease-activity assessment; no single instrument is mandated.

Diagnosis should be confirmed and treatment plan agreed with a paediatric rheumatologist where available. The broad aims are to achieve inactive disease, minimise joint damage and growth disturbance, protect the eyes, and avoid prolonged systemic steroids. Treatment is adjusted to the phenotype: oligoarticular disease is articular and local; systemic disease is an autoinflammatory emergency of the whole body.

• Physiotherapy and occupational therapy to maintain range, strength, posture and function; home exercise programmes.
• Splints at night for wrists/knees to prevent contracture; serial casting or orthoses for fixed deformity.
• Activity and sport at a level the joint tolerates; school trips and normal childhood are to be protected.
• Psychological support for chronic disease, steroid-related body change and school absence.
• Nutrition and bone health: calcium and vitamin D, and weight-bearing activity, are sensible precautions in a child on steroids.

Current American College of Rheumatology guidance (2021, published 2022) recommends phenotypic treatment. Evidence overall is low or very low quality, so many recommendations are conditional rather than strong.

Oligoarticular (4 or fewer joints).

• A trial of scheduled NSAIDs is conditionally recommended as initial therapy ^[3]. Response is judged over a few days; escalate if inactive disease is not achieved, as many clinicians now prefer to avoid prolonged NSAID monotherapy.
• Intra-articular glucocorticoids are strongly recommended as initial therapy ^[3], with triamcinolone hexacetonide strongly recommended as the preferred agent ^[3]; triamcinolone acetonide is less durable. Inject under sedation/anaesthesia in younger children. Intra-articular injection can suppress a single joint for months.
• Oral glucocorticoids are conditionally recommended against as initial therapy ^[3]; if given for severe symptoms before a DMARD acts, use the lowest effective dose for the shortest time.
• Conventional synthetic DMARDs (methotrexate first) are strongly recommended for inadequate response to NSAIDs and/or intra-articular steroids ^[3]. Methotrexate is conditionally preferred over leflunomide, sulfasalazine and hydroxychloroquine in that order ^[3].
• bDMARDs are strongly recommended for inadequate response to or intolerance of NSAIDs and/or intra-articular steroids plus at least one conventional DMARD ^[3]. There is no preferred biologic in oligoarticular disease.

Polyarticular (5 or more joints). Guidance from the complementary ACR 2019 recommendations starts with NSAIDs plus intra-articular injection where feasible, moving promptly to methotrexate (oral or subcutaneous) for active disease, then biologic escalation for inadequate response. Polyarticular disease causes the most cumulative damage, so treat-to-target escalation is justified.

Systemic JIA without macrophage activation syndrome.

• NSAIDs are conditionally recommended as initial monotherapy in the 2021 ACR guideline (some children respond fully) ^[3]. Newer ACR and EULAR/PReS recommendations favour IL-1 or IL-6 inhibitors first, so check the current local guideline.
• Oral glucocorticoids are conditionally recommended against as initial monotherapy ^[3].
• Conventional synthetic DMARDs are strongly recommended against as initial monotherapy (they do not control systemic features) ^[3].
• Biologic DMARDs (IL-1 and IL-6 inhibitors) are conditionally recommended as initial monotherapy in the 2021 guideline (newer guidance makes them first-line), and are strongly preferred over conventional DMARDs after inadequate response to NSAIDs and/or glucocorticoids ^[3]. No preferred agent is named. Both anakinra/canakinumab (IL-1 pathway) and tocilizumab (IL-6 pathway) are used; switching between and within classes is reasonable according to response and tolerability. Rapid escalation matters because glucocorticoid exposure in childhood impairs growth and bone health.
• Residual arthritis after cytokine blockade is treated with methotrexate or another DMARD or biologic rather than long-term steroids.

Systemic JIA with macrophage activation syndrome.

• IL-1 and IL-6 inhibitors are conditionally recommended over calcineurin inhibitors alone to achieve inactive disease and resolution of MAS ^[3].
• Glucocorticoids are conditionally recommended as part of initial treatment of systemic JIA with MAS ^[3].
• Non-response or partial response can prompt calcineurin inhibitor (cyclosporin), etoposide, intravenous immunoglobulin or other approaches; ACR deferred a formal recommendation here, so this is a specialist decision.
• MAS is an emergency; treat in a centre with paediatric rheumatology and haematology input.

Table 2 gives the agent class, typical paediatric dose and practical notes. Doses are those reported in major reviews; confirm with your local formulary, adjust for body surface area, renal/hepatic function and infection status, and verify against current product labelling.

Also remember that oral or intravenous glucocorticoids do not change long-term outcome in JIA; they give short-term control. Intra-articular steroid plus physiotherapy is what protects a single joint.

The 2021 ACR monitoring recommendations (also 2022) include:

• NSAIDs: blood count, liver function and renal function every 6 to 12 months ^[4].
• Methotrexate: blood count, liver function and renal function within the first 1 to 2 months and every 3 to 4 months thereafter; give folic or folinic acid with methotrexate ^[4].
• Take tuberculosis and hepatitis B screening and vaccination status into account before starting biologics; screen for latent tuberculosis.
• Keep a documented disease-activity assessment (JADAS or similar) and revisit treatment targets.
• Reassess immunisations: live vaccines avoided while on biologics or high-dose steroids; inactivated vaccines can be given and should be kept up to date.

A child with inactive disease for a sustained period can be considered for step-down. The ACR advises that tapering and discontinuing glucocorticoids is strongly recommended once inactive disease is attained; tapering and discontinuing biologic DMARDs is conditionally recommended ^[3]. In practice, clinicians taper steroids first, then DMARDs or biologics one drug at a time, with sustained clinically inactive disease off treatment being the target. Tapering runs over many months; a child in remission may flare years later, so long-term follow-up with examination of eyes and joints continues.

• Uveitis and visual impairment (see screening).
• Growth disturbance and limb-length discrepancy from chronic inflammation and steroids; TMJ involvement disturbs mandibular growth.
• Joint damage and contracture: erosions, joint-space narrowing, ankylosis; hip and wrist damage is associated with poor outcome.
• Osteopenia and osteoporosis from both disease and glucocorticoids.
• Systemic JIA extras: pericarditis/myocarditis, serositis, hepatitis, splenomegaly, growth failure; rare fatal pulmonary disease (systemic JIA-associated interstitial lung disease) reported particularly in younger children with macrophage activation syndrome, with clubbing as a warning sign.
• Macrophage activation syndrome (5 to 8% ^[1] in one review, approximately 10% ^[2] in another, and "up to 40%" ^[3] in ACR guidance, depending on whether subclinical disease is counted). It carries serious morbidity and mortality.
• Amyloidosis can complicate long-standing, poorly controlled inflammation, although it is now uncommon.
• Psychosocial impact: school absence, body image on steroids, chronic pain.

Prognosis has improved markedly with early aggressive therapy, intra-articular steroids and biologics, but it remains subtype specific.

• Oligoarticular JIA has a benign course in most children, and many achieve remission, yet some (especially extended disease) continue into adulthood; flares can occur many years after apparent remission. Uveitis, rather than arthritis, drives disability in this group.
• Polyarticular JIA is more likely to persist. Rheumatoid factor positivity and anti-CCP are the strongest predictors of significant joint damage. About 5% of all children with JIA are rheumatoid factor positive ^[2].
• Systemic JIA has a variable course; many have a monocyclic pattern in which systemic features resolve. However, articular involvement often persists even after systemic features improve. Macrophage activation syndrome is the major cause of death.
• ERA and psoriatic JIA can progress towards adult spondyloarthritis or psoriatic arthritis; early ankle/hip involvement and more joints at onset predict worse outcome.

Overall, many children have some active disease or need medication into adulthood; set expectations accordingly and emphasise adherence, monitoring and early treatment of flares.

There is no primary prevention. Screening means:

• Uveitis: regular slit-lamp examination following the intervals above, more frequent (every 3 months) for high-risk (ANA-positive, early-onset, female, oligoarticular) patients, and at intervals advised by ophthalmology for lower-risk groups. Because uveitis is asymptomatic, this is the most important screening in JIA. ^[1]
• Growth: height velocity and puberty at every visit.
• Bone health: steroid-sparing and calcium/vitamin D.
• Infection screening before biologics, including latent tuberculosis.
• Disease activity and joint damage on interval imaging and blood tests.

JIA affects children, so the special-group considerations centre on the child's life stages rather than pregnancy or old age.

• Adolescents and transition to adult care require planned handover, assessment of adherence, and discussion of sexual health and contraception, because methotrexate, leflunomide and many biologics are teratogenic or have limited pregnancy data.
• Pregnancy planning should involve rheumatology before conception to adjust DMARDs; methotrexate must be stopped. This is a consultative, individualised decision.
• Immunocompromised or infected children: active infection, uncontrolled tuberculosis or hepatitis B may contraindicate biologic therapy; treat first.
• Low-resource settings are addressed below.

• Confirm the diagnosis clinically: a child under 16 with at least 6 weeks of arthritis, exclusion of infection, is JIA until proven otherwise.
• A basic examination and slit-lamp, wherever available, are worth more than advanced imaging. If slit-lamp is unavailable, organise periodic ophthalmology referral for high-risk children.
• Treat in escalation: NSAIDs first, intra-articular triamcinolone or triamcinolone acetonide if hexacetonide is unavailable (one practical alternative), then methotrexate (widely available and inexpensive), then sulfasalazine for ERA.
• Biologics are often unavailable; methotrexate doses and combination DMARD strategies remain the backbone, with referral to tertiary centres when possible.
• If macrophage activation syndrome is suspected, treat as an emergency with high-dose steroids and arrange urgent transfer; even without advanced tests, the clinical picture warrants action.
• Encourage physiotherapy, splinting and family education; these are cheap and prevent deformity.

Chronic anterior uveitis and its screening, reactive arthritis, septic arthritis, acute lymphoblastic leukaemia, Lyme disease, Kawasaki disease and the juvenile spondyloarthropathies (clinical articles are being developed for several of these).