JUVENILE IDIOPATHIC ARTHRITIS

Juvenile idiopathic arthritis (JIA), previously known as juvenile rheumatoid arthtritis, is the leading cause of chronic arthropathy in children with intermittent exacer­bations and residual deformities.

Rather than a single disease, JIA is a heterogeneous group of chronic arthritides and clear distinction between various subtypes is difficult. While there is no universal agreement on nomenclature and classification of JIA, one of the most acceptable one is the International League of Associations for Rheumatology (ILAR) classification (Table 24.2).

Recently, Pediatric Rheumatology International Trials Organizations (PRINTO), 2019, has classified JIA in four homogenous clinical groups—(1) systemic JIA, (2) RF positive JIA, (3) enthesitis/spondylitis related JIA, and (4) early-onset ANA positive JIA.

Etiopathogenesis of JIA is complex and poorly under­stood, though definitely involves:

• An autoimmune reaction to external triggering factors, e.g. viral infections or joint trauma, and

• An inherent susceptibility to these reactions with specific HLA types - HLA-DR4 in polyarticular disease, and HLA-DR8/5 in pauciarticular disease. Non-HLA candidate loci are also associated with JIA, including polymorphisms in various genes encoding protein tyrosine phosphatise nonreceptor 22 (PTPN22), tumor necrosis factor (TNF)-#945;, macrophage inhibitory factor (MIF), interleukin (IL)-6, and IL-1.

Eventually, abnormal immune response provokes chronic inflammation in target organs, responsible for tissue injury. T lymphocytes play a central role, releasing pro-inflammatory cytokines to favor Th-1 response. B cell activation, immune complex formation and complement activation also promote inflammation.

Pathologically, tissue injury is characterized by—(a) hyperemia and edema of sub-synovial tissues, (b) pannus formation over articular cartilage with destruction in late stages, and (c) chronic inflammatory infiltration.

Clinically, Arthritis is the hallmark of JIA, though the spectrum may vary from a solitary joint involvement

TABLE 24.2: ILAR classification* of JIA

Systemic arthritis

Polyarticular (Rheumatoid factor -ve) Polyarticular (Rheumatoid factor +ve) Oligoarthritis

Enthesitis-related arthritis

Psoriatic arthritis

Undifferentiated arthritis

*abridged to a systemic-onset disease where other systemic involvement precedes arthritis.

Arthritis in JIA, irrespective of sub-types, is characterized by—(a) early morning stiffness, (b) joint swelling and restricted movements, disproportionate to local pain and other signs, (c) chronic course with intermittent exacerbations and residual deformity. Residual deformities are common after multiple attacks (Fig. 24.1A) and present as contractures, abnormal joint shapes, asymmetric limb length with postural abnormalities, e.g. scoliosis, and undergrowth of affected joints, e.g. micrognathia due to temporomandibular joint involvement.

Extra-articular manifestations are more common in systemic-onset or polyarticular disease and include: (a) anterior uveitis, with red-eye, posterior synechiae, glaucoma and blindness in untreated cases, (b) serositis, e.g. pericardial/pleural effusion, (c) chronic renal disease, and (d) rare cardiovascular, pulmonary or neurological complications.

Of various sub-types of JIA discussed below (Table 24.3), All are 3-10 times more common in females,

Fig. 24.1A and B: Juvenile idiopathic arthritis: (A) Finger deformities; (B) Rheumatoid nodule

except systemic JIA with equal sex ratio. Cases with oligoarthritis have earlier onset (3-4 years) than others.

• Oligoarticular JIA is the commonest and mildest subtype (40-50%). Clinically, it affects four or less joints during first 6 months of disease, as asymmetrical involvement of large joints of legs, e.g. knees and ankles. Small joints are usually spared.

Two clinical variants of oligoarthritis include - Persistent oligoarticular JIA limited to four or less joints even after 6 months; and Extended oligoarticular JIA with involvement of gt;4 joints after 6 months period with poorer prognosis.

Extra-articular manifestations are rare except asymptomatic or symptomatic uveitis in ~25%, more common in ANA-positive girls.

• Polyarticular JIA occurs in 25-30% cases, characterized by inflammation of 5 or more joints within 6 months of the onset of disease. Unlike oligoarthritis, Pain is more prominent than swelling. Clinical course differs in RF-ve and RF+ve cases of polyarticular disease.

RF-ve cases are less severe and usually involve larger joints of knee, wrist, ankle and hips. Small joints are less commonly affected and Rheumatoid nodules are not seen.

RF+ve cases have more aggressive disease resemb­ling symmetric arthropathy of adult rheumatoid arthritis, typically involving small joints, cervical spine and temporomandibular joint.

Rheumatoid nodules are seen almost exclusively in RF-positive individuals over extensor surfaces of the elbows, spine and scalp and indicate more severe course (Fig. 24.1B). These nodules arise from synovial sheaths and tend to be better palpable than visible (d/d rheumatic nodules, which are subcutaneous and better visible than palpable).

TABLE 24.3: Important differences between various sub-types of JIA

• Systemic-onset JIA is the most severe sub-type, which presents with: (a) quotidian fever with daily spikes, more in evenings, for gt;2 weeks, (b) typical macular rash over trunk and proximal extremities that comes and goes with fever spikes, (c) arthritis, usually polyarticular, after 2-6 months of systemic features (though arthralgia and myalgia may be present on onset), and (d) early extra-articular manifestations, e.g.

Macrophage activation syndrome (MAS) is a rare but potentially fatal complication of systemic­onset JIA, which can develop any time during the course of disease. MAS presents with acute spiking fevers, lymphadenopathy, hepatosplenomegaly, and encephalopathy. ESR falls and helps to diffe­rentiate MAS from acute flare of systemic JIA. Thrombocytopenia with high ferritin levels is common and bone marrow shows macrophage hemophagocytosis.

Diagnosis of MAS rests on a combination of clinical and laboratory criteria, in a febrile child with known or suspected JIA as follows—(a) serum ferritin gt;684ng/ml, and (b) any two or more of the following - platelet cunt lt;181/109/L, Aspartate Aminotransferase (AST) gt;48 U/L, Triglycerides gt;156 mg/dl or fibrinogen 360 mg/dl. (PRINTO criteria 2016).

Emergency treatment includes high-dose steroids (IV Methylprednisolone) or IVIG, while other options include cyclosporine and biological agents, e.g. Anakinra in severe cases.

• Psoriatic arthritis is an asymmetrical oligoarthritis of large or small joints, associated with—(a) psoriasis, or (b) any two of the following features - dactylitis, nail pitting (onycholysis) or history of psoriasis in a first-degree relative. ANA is frequently positive and spinal involvement is seen only in cases with HLA-B27 association. Arthritis may precede, accompany or succeed psoriasis.

• Enthesitis-related arthritis is more common in older boys (9-10 years) with asymmetrical involvement of the large joints of lower limbs and Enthesitis, i.e. inflammation at the site of attachment of ligaments, presenting as localized tenderness around the foot and knee. Many of these cases are HLA-B27 positive and develop ankylosing spondylitis after adolescence. Acute self-limiting iritis may develop in 25% but chronic iridocyclitis is rare.

• Undifferentiated JIA refers to those cases which fit no other category or fit more than one category.

Diagnosis of JIA is mainly clinical, as no laboratory investigation is pathognomonic.

Clinical diagnosis as well as sub-typing of JIA is based on a clinical criteria (Table 24.4) and may not always be accurate in early stages due to gradual evolution of signs, e.g. polyarticular change from early pauciarticular

TABLE 24.4: ILAR diagnostic criteria for JIA

Age of onset lt;16 years, Arthritis for gt;6 weeks, with

• Joint swelling/effusion or

• Any two of the following:

- Restricted active movements

- Painful/tender movements

- Increased joint temperature (hot joints)

Pattern of joint involvement

• Oligoarthritis* (Persistent or extended)

• RF-negative polyarthritis

• RF positive polyarthritis

• Systemic arthritis

• Psoriatic arthritis

• Enthesitis-related

• Undifferentiated

Exclusion of other causes of arthritis

*Oligoarthritis is further classified as:

- Persistent: #8804; 4 joints are involved throughout course of disease

- Extended: gt; 4 joints are involved after first 6 months

disease or absence of joint involvement in early systemic disease. It is prudent to wait for ~6 months before final sub­typing the JIA.

Laboratory diagnosis is largely supportive and includes:

• Indicators of chronic inflammation, i.e. elevated ESR, CRP, leukocytosis help in monitoring the activity of disease. Serum ferritin is elevated though markedly high values suggests possibility of MAS.

• Indicators of immunological reactions, e.g. ANA and Rh factor have diagnostic as well as prognostic value. ANA is positive in gt;50-70% cases, except systemic­onset disease. RF is positive in only lt;10% cases, usually with polyarticular disease and poor functional prognosis.

• Radiological abnormalities in involved joints appear only after few weeks and include—(a) soft tissue swelling and increased joint space due to effusion and osteopenia in early stages, followed by (b) subchondral erosion on articular surface (pannus formation) with decreased joint space, and (c) bony destruction or ankylosis in later stages.

• USG or MRI of involved joints is useful for early diagnosis of JIA before appearance of X-ray abnor­malities and detect minor inflammatory changes, e.g. synovial thickening, joint effusion, etc.

• Synovial fluid aspiration for microscopy and culture is indicated in cases with monoarthritis to exclude other causes, e.g. septic or tubercular arthritis.

D/D of JIA depends on the clinical sub-types and includes various causes of chronic arthritis (Table

24.5).

• D/D of Polyarticular JIA includes rheumatic fever (Table

24.6), SLE (butterfly rash), vasculitis syndromes, e.g. Kawasaki disease or Henoch-Schonlein purpura (typical rash) and leukemia.

TABLE 24.5: Causes of chronic arthritis in children

• Juvenile idiopathic arthritis

• Spondyloarthropathies

- Juvenile ankylosing spondylitis

- Psoriatic arthritis

- Chronic reactive arthritis

- Arthritis with inflammatory bowel disease

• Connective tissue disorders

- Systemic lupus erythematosus

- Juvenile dermatomyositis

- Scleroderma

• Vascular: Legg-Calve-Perthes disease

• Infections: Tubercular arthritis

• Hematologic: Hemophilia

• Metabolic: Gout, sarcoidosis

• Others: Post-traumatic degeneration

TABLE 24.6: D/D juvenile idiopathic arthritis vs rheumatic arthritis

• D/D of Oligoarticular JIA includes other causes of acute joint pain, e.g. septic arthritis, tubercular arthritis, joint trauma and Lyme disease.

Lyme disease, rare in India, is a vector-borne disease due to spirochete - Borrelia burgdorferi, with typical skin lesion (erythema chronicum migrans) and recurrent large-joint arthritis.

• D/D of systemic JIA includes reactive arthritis, vasculitis syndromes, e.g. Kawasaki disease and leukemia.

Management of JIA aims for—(a) control of acute joint and systemic symptoms, (b) prevention of exacerbations and long-term deformities, and (c) physical rehabilitation.

a. Anti-inflammatory therapy is the cornerstone of management, though the choice of drugs depends on severity of disease and response to therapy.

• Non-steroidal anti-inflammatory drugs, e.g. Naproxen (PO 10-20 mg/kg/day q12hr), Ibuprofen (30-40 mg/kg/day q8hr) or Diclofenac (2-3 mg/kg/ day q8hr) are first-line agents in acute phase of JIA, though clinical response may vary and treatment should continue for at least 6 weeks before changing the drug. Despite symptomatic relief, these agents do not affect progression of disease. Aspirin is no longer used due to potential risk of Reye syndrome, while safety of selective COX-2 inhibitors, e.g. rofecoxib, is not established in children.

• Disease modifying anti-rheumatoid drugs (DMARDs), e.g. Methotrexate is the safest and most-effective drug for long-term treatment of JIA, given as PO/ SC 15-20 mg/m² weekly (max 25 mg/m² week), till remission is achieved, followed by gradual tapering to the minimum effective dose for at least 1-2 years.

Adverse effects are rare, though periodic liver function tests and complete blood counts are advised due to potential risk of hepatic fibrosis and marrow suppression on prolonged use.

Other DMARDs in use include sulfasalazine, Leflunomide, etc. Old-generation drugs, e.g., penicillamine and gold salts are no longer used at present routinely due to adverse effects.

• Biological agents, which inhibit pro-inflammatory cytokines, e.g. TNF-#945;, IL-1, and IL-6 are used as second-line drugs in cases with poor response to DMARDs. TNF-#945; antagonists (e.g., etanercept, adalimumab) are preferred over other agents except systemic JIA, in whom systemic steroids followed by the IL-1 or IL-6 antagonist therapy (with Canakinmab or Tocilizumab respectively), often induces more rapid response.

• Steroids: With advent of newer DMARDs, the systemic steroids are recommended only for severe systemic illness, or as bridge therapy till the response to DMARDs, or for control of uveitis. Topical steroids are also used as intra-articular injections in non­responding pauciarticular lesions.

• Other Interventions, e.g., plasmapheresis, gene therapy, and stem-cell transplant have been approved in adults with severe refractory cases, but not yet in children.

b. Supportive therapy in JIA includes—(a) occupational and physical therapy, (b) nutritional support, specially to ensure adequate iron and calcium intake, (c) psychosocial support, (d) surgical/orthopaedic correction of defor­mities, and (e) regular follow-up, specially with periodic slit-lamp examination to exclude asymptomatic uveitis. Outcome of JIA depends on clinical type with best prognosis in persistent oligoarticular JIA and worst in systemic JIA or RF+ve polyarticular disease. About half

of JIA cases enter adulthood with active disease and functional limitations of variable severity, though outlook has improved with recent advances in management.

Late complications of JIA include—(a) joint contractures and deformities, (b) growth abnormalities with limb­length discrepancies, and (c) very rarely, amyloidosis.

24.3