Juvenile Idiopathic Arthritis

• Oligoarticular — the commonest, affecting four or fewer joints, typically large joints (knee) in young girls. ANA positivity carries a high risk of chronic anterior uveitis, which is asymptomatic and painless — so these children need regular slit-lamp screening regardless of joint activity. This is the highest-yield fact in the topic.
• Polyarticular — five or more joints, symmetrical, small and large. Rheumatoid factor–positive disease behaves like adult rheumatoid arthritis with worse erosive potential.
• Systemic (Still disease) — daily quotidian fevers with a transient salmon-pink evanescent rash appearing at fever peaks, hepatosplenomegaly, lymphadenopathy and serositis. Markedly raised inflammatory markers, ferritin, and neutrophilia. Macrophage activation syndrome is the feared complication: falling cell counts and ESR with a rising ferritin and triglycerides.
• Other subtypes include enthesitis-related (HLA-B27, older boys) and psoriatic.
• Management: NSAIDs, intra-articular and systemic corticosteroids, methotrexate, and biologics — TNF inhibitors, and IL-1 or IL-6 blockade for systemic disease.

Autoimmune (adaptive-immune) subtypes

• Oligoarticular and RF-negative polyarticular: HLA class II associations (*HLA-DRB1\*08*, *DRB1\*11*) and class I (HLA-A2 in early-onset ANA-positive girls) point to aberrant presentation of joint-derived self-peptide to CD4+ T cells.
• RF-positive polyarticular: shares the HLA-DRB1 shared-epitope biology and anti-CCP seropositivity of adult rheumatoid arthritis; it is essentially adult RA of childhood onset.
• Enthesitis-related arthritis: *HLA-B27*-linked, mechanistically an axial spondyloarthropathy with IL-23/IL-17 skewing at the enthesis.

Autoinflammatory subtype

• **Systemic JIA (Still disease)**: weak HLA linkage; driven by innate effectors — IL-1β, IL-6 and IL-18 released by monocytes and neutrophils. This explains the fever, rash and acute-phase response rather than antibody-mediated joint injury, and explains why IL-1/IL-6 blockade works.

Non-modifiable risk factors examiners plant

• Age under 16 by definition, with peaks in toddlers/preschoolers (oligoarticular, ANA-positive) and late childhood/adolescence (RF-positive poly, ERA).
• Female sex for oligoarticular and polyarticular disease; male sex plus late childhood for enthesitis-related disease. Systemic JIA has no sex predilection and no age peak.
• Family history of psoriasis, inflammatory bowel disease, uveitis or spondyloarthropathy in a first-degree relative (supports psoriatic or enthesitis-related subtype).
• ANA positivity — not a cause, but the dominant risk marker for chronic anterior uveitis.

Modifiable / environmental (associations only, none proven causal)

• Preceding infection, altered gut microbiome, maternal smoking, caesarean delivery and antibiotic exposure in infancy have all been reported as associations; none is a testable exposure on a stem and none changes management.
• Note the negatives: JIA is not post-streptococcal, not Lyme, and not caused by trauma — those are the differential, not the etiology.

Autoimmune subtypes — synovitis first

• Antigen presentation to CD4+ T cells in a genetically susceptible synovium initiates a Th1/Th17 response. Activated T cells and macrophages release TNF-α, IL-6 and IL-17, which drive fibroblast-like synoviocyte proliferation.
• Pannus formation: the hypertrophied, neovascularised synovium behaves as an invasive tissue at the cartilage margin. Matrix metalloproteinases degrade cartilage and RANKL-driven osteoclastogenesis erodes subchondral bone — the reason RF/anti-CCP-positive polyarticular disease is the most erosive subtype.
• Effusion and warmth without redness: the exudate and vasodilation produce a boggy, warm, swollen joint; overlying erythema is uncommon and should raise suspicion of septic arthritis instead.
• Morning stiffness and gelling reflect overnight accumulation of oedema and inflammatory mediators in a joint at rest, improving with movement — the opposite pattern to mechanical pain.
• Growth disturbance is local and paradoxical: hyperaemia adjacent to an inflamed epiphysis accelerates growth, so a chronically inflamed knee produces a longer ipsilateral leg early on; late premature physeal closure can then shorten it. TMJ involvement stunts mandibular growth → micrognathia.

Uveitis

• The ciliary body and iris share antigenic and immunologic features with synovium; ANA-positive young girls develop a non-granulomatous chronic anterior uveitis in which the inflamed eye is white and painless because the process is indolent and largely spares the conjunctival vasculature and corneal nerves. Silence is precisely why screening — not symptoms — detects it.

Systemic JIA

• Inflammasome-driven IL-1β produces the quotidian fever spikes; IL-6 drives the acute-phase response (ESR/CRP, thrombocytosis, anaemia of inflammation via hepcidin) and growth failure; neutrophil-attracting chemokines produce the fleeting salmon-pink rash at fever peaks, often Koebnerised by scratching or warmth.
• Macrophage activation syndrome is the extreme: defective NK/cytotoxic-T killing fails to terminate macrophage activation → hyperferritinaemia, consumptive cytopenias, hypofibrinogenaemia from plasmin activation, and hepatic dysfunction. A falling ESR with rising ferritin signals fibrinogen consumption, not improvement.

Articular findings (all subtypes)

• Joint swelling, warmth and limited range of motion from synovial hypertrophy and effusion. Marked erythema is atypical — it points to septic arthritis.
• Morning stiffness / gelling after inactivity, relieved by movement; the inflammatory pattern.
• Pain is often mild or denied in young children, who instead present with limp, regression of motor milestones, or refusal to use a limb. Absence of complaint does not exclude active synovitis.
• Oligoarticular: ≤4 joints, asymmetric, large joints (knee > ankle > wrist); hips and small joints are rarely first.
• Polyarticular: ≥5 joints, symmetric, small joints of hands with wrists and cervical spine; RF-positive adolescents may have nodules and early erosions.
• Enthesitis-related: adolescent boy with heel/Achilles or plantar fascia insertional tenderness, sacroiliac tenderness, inflammatory back pain, and possible acute painful, red, photophobic uveitis — the mirror image of oligoarticular uveitis.

Systemic JIA (Still disease)

• Quotidian fever — one or two daily spikes with return to or below baseline, the child appearing miserable at the peak and remarkably well between spikes.
• Evanescent salmon-pink macular rash on trunk and proximal limbs, appearing with fever and vanishing between spikes; may Koebnerise.
• Hepatosplenomegaly, generalised lymphadenopathy, serositis (pericardial rub, pleural effusion) from systemic cytokine drive. Arthritis may lag the fever by weeks.

Extra-articular red flags

• Chronic anterior uveitis in ANA-positive young girls is asymptomatic — the eye looks normal; irregular pupil, band keratopathy or reduced acuity are late.
• Micrognathia and leg-length discrepancy reflect long-standing untreated disease.

Step 1 — exclude the emergencies before anything else

• Septic arthritis / osteomyelitis: a hot, exquisitely tender, monoarticular joint with fever demands arthrocentesis with Gram stain, culture and cell count before steroids. Synovial fluid in JIA is inflammatory but sterile, typically in the tens of thousands of WBC/µL with neutrophil predominance; septic fluid is usually far higher.
• Leukaemia: night pain out of proportion, bone pain away from joints, cytopenias, or a high ESR with a low or falling platelet count. Obtain CBC with differential, peripheral smear and LDH/uric acid; bone marrow biopsy before starting corticosteroids if suspicion exists — steroids can partially treat and obscure leukaemia.
• Also exclude Lyme arthritis (endemic exposure, serology with confirmatory immunoblot), acute rheumatic fever, reactive/post-infectious arthritis, and non-accidental trauma.

Step 2 — subtype and risk stratification

• ANA: prognostic, not diagnostic — positivity identifies the child needing intensive slit-lamp screening.
• RF and anti-CCP (repeat RF at least 3 months apart to call RF-positive polyarthritis) and HLA-B27 for suspected enthesitis-related disease.
• ESR, CRP, CBC: normal or mildly raised in oligoarticular disease; markedly raised with neutrophilia, thrombocytosis and microcytic anaemia in systemic JIA. Ferritin is markedly elevated in systemic JIA.
• Imaging: plain films are usually normal early (soft-tissue swelling, periarticular osteopenia) and serve mainly to exclude fracture or tumour; ultrasound or contrast MRI confirms synovitis, effusion and erosions, and MRI is preferred for sacroiliac and TMJ disease.

Step 3 — mandatory ophthalmology

• Slit-lamp examination detects the asymptomatic anterior chamber cell and flare. Per the AAP and ACR/Arthritis Foundation, ANA-positive children with oligoarticular or polyarticular disease and young age at onset need screening roughly every 3 months, with less frequent intervals for lower-risk groups; systemic JIA carries the lowest uveitis risk.

Oligoarticular disease

• Intra-articular glucocorticoid (triamcinolone hexacetonide preferred over acetonide) is the ACR-recommended first-line intervention for a limited number of active joints — high local efficacy, no systemic exposure.
• NSAIDs (naproxen, ibuprofen) as adjuncts for pain and stiffness; NSAID monotherapy alone is not adequate long-term control.
• Escalate to a conventional DMARD — methotrexate (weekly, with folic acid) — for inadequate response, then a TNF inhibitor.

Polyarticular disease

• Methotrexate is the anchor DMARD; bridge with intra-articular or short-course oral glucocorticoids.
• Escalate to a biologic DMARD: TNF inhibitor (adalimumab, etanercept), or abatacept or tocilizumab if TNF blockade fails. The ACR recommends against chronic systemic glucocorticoids as maintenance.

Systemic JIA

• IL-1 blockade (anakinra, canakinumab) or IL-6 blockade (tocilizumab) is favoured, including as initial monotherapy, precisely because the disease is cytokine- rather than autoantibody-driven. The ACR 2021 guideline recommends against prolonged glucocorticoid monotherapy given growth suppression and osteoporosis.
• Macrophage activation syndrome is an emergency: hospitalise, give high-dose IV glucocorticoids (methylprednisolone pulse) with anakinra and/or cyclosporine; refractory cases move to HLH-directed therapy including etoposide.

Ocular — the classic tested complication

• Chronic anterior uveitis progressing to posterior synechiae (irregular pupil), band keratopathy (calcium in Bowman layer), cataract, secondary glaucoma and permanent vision loss. Because it is painless, the signalling finding is a slit-lamp abnormality or a late irregular pupil — not a symptom. Vision-threatening flares warrant urgent ophthalmology referral.

Emergencies

• Macrophage activation syndrome: unremitting fever, cytopenias, hepatosplenomegaly, encephalopathy, bleeding from DIC-like coagulopathy. The tell is a falling ESR and platelet count with a soaring ferritin in a systemic JIA patient — deterioration masquerading as improvement.
• Pericardial effusion with tamponade from systemic JIA serositis: muffled heart sounds, pulsus paradoxus, jugular venous distension.
• Septic arthritis superimposed on a treated joint, especially after intra-articular injection or on a biologic.
• Cervical spine involvement with apophyseal fusion or atlantoaxial instability — a difficult-airway and cord-compression risk during intubation.

Structural and growth complications

• Leg-length discrepancy from hyperaemic epiphyseal overgrowth adjacent to a chronically inflamed knee; micrognathia from TMJ arthritis; joint contractures, erosions and joint destruction in RF-positive polyarthritis.
• Growth failure, delayed puberty and osteoporosis from IL-6 excess plus chronic glucocorticoid exposure.
• AA (secondary) amyloidosis from sustained serum amyloid A production — now rare with cytokine blockade; suspect with proteinuria.

Treatment-related

• Methotrexate: hepatotoxicity, cytopenias, oral ulcers and nausea (mitigated by folic acid); pneumonitis is rare. Monitor LFTs and CBC.
• TNF inhibitors: reactivation of latent tuberculosis and other granulomatous infection, demyelinating events, and a boxed warning for malignancy in children — screen for TB before starting.
• Tocilizumab: neutropenia, transaminitis, hyperlipidaemia and GI perforation; it blunts fever and CRP, so infection can present silently.
• Anakinra/canakinumab: injection-site reactions and infection risk.
• NSAIDs: gastropathy, renal injury, pseudoporphyria. Systemic glucocorticoids: growth suppression, adrenal suppression, avascular necrosis.

• The single most tested association: ANA-positive oligoarticular JIA in a young girl → chronic anterior uveitis that is asymptomatic. The eye is white and quiet. The best next step is slit-lamp examination, not "reassure and follow symptoms."
• Contrast the two uveitides: oligoarticular JIA gives painless, insidious anterior uveitis found only on screening; HLA-B27 enthesitis-related arthritis in an adolescent boy gives acute, painful, red, photophobic uveitis that the patient reports himself.
• Etanercept does not treat uveitis. Use a monoclonal TNF inhibitor (adalimumab) after methotrexate — a classic distractor answer.
• Systemic JIA buzzwords: quotidian fever with a transient salmon-pink rash appearing only at fever spikes, hepatosplenomegaly, serositis, markedly elevated ferritin and neutrophilia — with a negative ANA and negative RF. Arthritis can appear weeks after the fever.
• MAS is the trap: in a systemic JIA patient, a falling ESR, falling platelets and falling WBC with a rising ferritin and triglycerides plus low fibrinogen means deterioration, not remission. It is an emergency — pulse glucocorticoids plus anakinra ± cyclosporine.
• Always exclude leukaemia before giving steroids to a child with joint pain: night pain, bone pain between joints, cytopenias, or a high ESR with a low platelet count should prompt smear and marrow examination.
• A single hot, red, exquisitely tender joint with fever is septic arthritis until arthrocentesis proves otherwise — JIA joints are swollen and warm but usually not erythematous or exquisitely tender.
• First-line for a limited number of active joints is an intra-articular glucocorticoid (ACR/Arthritis Foundation), with methotrexate as the anchor DMARD for polyarticular disease and IL-1 or IL-6 blockade for systemic disease. Give live vaccines before starting biologics, and screen for latent TB first.