Juvenile Idiopathic Arthritis (JIA) is a heterogeneous subset of idiopathic inflammatory arthritis that often affects children under 16 years old and lasts for a minimum of six weeks or longer. This article explains the aetiology, treatment and prognosis of this condition. 

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Juvenile Idiopathic Arthritis (JIA)

Juvenile Idiopathic Arthritis (JIA) is the most common chronic rheumatological condition in children and has been subdivided into seven different categories with distinct phenotypes, genetic predispositions, pathophysiology, laboratory findings, disease course, and prognosis as per the International League of Associations for Rheumatology (ILAR).

In a US and Canada study, the incidence of JIA is 0.041 to 0.061 per 1000 children, respectively, however, there is a paucity of epidemiological studies from our country.

According to the consensus conference of the ILAR, there are seven JIA categories:

1. Oligoarthritis: Arthritis affecting four joints or less during the first six months of the disease.
2. Rheumatoid Factor (RF) positive polyarthritis: Affecting five joints or more during the first six months of disease with a positive IgM RF on at least two tests three months apart.
3. RF-negative polyarthritis: arthritis affecting five joints or more during the first six months of disease with a negative IgM RF.
4. Systemic arthritis is defined as arthritis that has at least one of the following symptoms in addition to a fever lasting at least two weeks: Evanescent erythematous rash, generalised lymph node enlargement, hepatomegaly and/or splenomegaly, or serositis (pericarditis, pleuritis, or peritonitis).
5. Psoriatic arthritis: Chronic arthritis with psoriasis or chronic arthritis with at least 2 of the following: dactylitis, nail pitting, onycholysis, or psoriasis in a first-degree relative.
6. Enthesitis-related arthritis (ERA): Arthritis with enthesitis, or arthritis or enthesitis with at least 2 of the following: SI joint tenderness and/or inflammatory lumbosacral pain, a positive HLA-B27, the onset of arthritis in a male over six years of age, acute anterior uveitis, history of ankylosing spondylitis, ERA, sacroiliitis with inflammatory bowel disease, reactive arthritis or acute anterior uveitis in a first-degree relative.
7. Undifferentiated arthritis: Chronic arthritis, which does not fulfil criteria in any subtype or fulfils two or more subtypes.

Given the heterogeneity in these categories, a new system of classification of JIA was proposed by the Pediatric Rheumatology International Trials Organisation (PRINTO) which proposes the following categories of JIA:

1. Systemic arthritis: The new definition allows the inclusion of patients with fever but without arthritis, as in the adult equivalent, adult-onset still disease.
2. The definition of RF-positive arthritis now includes anti-CCP antibodies.
3.  The definition and nomenclature for JIA related to enthesitis/spondylitis have been adjusted to more closely resemble those of the adult counterpart.
4. Early onset ANA+: A separate criterion has been established as it has been seen that this represents a homogeneous form of chronic arthritis, which is typical of children.
5. Other JIA: Doesn't match the conditions a. to d. Arthritis >= 6 weeks.
6.  JIA that is not classified: Fits multiple disorders a. to d. Arthritis >= 6 weeks.

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Aetiology

It's still unclear what exactly causes and triggers chronic arthritis in JIA patients. The primary element in the pathophysiology of JIA is abnormal immune responses that are set off by the interplay of environmental factors in a genetically vulnerable individual. Some environmental factors such as antibiotic exposure and C-section deliveries are potential risks; however, breastfeeding has a protective role.

The roles of microorganisms such as Parvovirus B19, Epstein-Barr virus, enteric bacteria, Chlamydophila pneumonia, and streptococcal infections are still not clear. The imbalance of regulatory T cells, Th1 (IFN-gamma secreting T cells), and Th17 (interleukin -17 secreting T cells) of adaptive immunity is the feature of most subtypes of JIA.

In oligoarthritis, polyarthritis, and psoriatic arthritis, proinflammatory cytokines and matrix metalloproteinases are induced by IL-17, which results in joint destruction. Among the key cytokines in ERA, IL-23 promotes inflammation via IL-17 and tumour necrosis factor (TNF).

Genetic factors play a significant role with a 25% to 40% concordance rate in monozygotic twins. Certain JIA subtypes and uveitis may be associated with specific HLA alleles and non-HLA genes. HLA-A2, HLA-DRB1:11, and HLA-DRB1:08 are linked to both RF-negative polyarticular JIA and oligoarticular JIA. HLADRB1:01 and HLADRB1:04 are associated with RF-positive polyarthritis. HLADRB1:04 and DRB1:11 are associated with systemic JIA.

HLA-B27:05 and HLA-B27:04 are the most common HLA-B27 subtypes associated with ERA. HLADRB1:01 and DQA1:01 are related to psoriatic JIA. HLADRB1:11 and HLADRB1:13 are associated with uveitis. The higher number of the HLA-DR risk alleles predisposes to the earlier development of JIA.

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Evaluation

1. Any child under 16 years old who has had arthritis for at least six weeks and has had all other possible causes of chronic arthritis ruled out will be examined for a JIA diagnosis.
2. The joint inflammatory arthritis (JIA) pattern includes synovitis, joint effusion, soft tissue swelling, osteopenia, bone oedema, and erosions.
3. It also includes some developmental age-related characteristics like limb length inequality, premature epiphyseal fusion, and abnormalities in epiphyseal growth.
4. Early in the course of sJIA, arthritis is frequently experienced, albeit it is not always evident. 
5. Disease in the wrists, knees, and ankles is most typical. Unlike the oligoarticular and polyarticular subtypes of JIA, it can also occasionally affect the hands, hips, cervical spine, and temporomandibular joints.
6. A thorough history taking, including the age of onset, the affected joints, the duration of arthritis, the associated symptoms or diseases, and physical and musculoskeletal examinations are essential for diagnosis and classification of JIA.
7. For JIA, there is no particular test for diagnosing or predicting disease activity.

Laboratory

HLA-B27, CBC, ESR, CRP, ANA, RF, and anti-cyclic citrullinated peptide antibodies (anti-CCP) should all be performed as part of the initial laboratory testing. A positive RF or anti-CCP provides little value for the diagnosis but may indicate a poorer disease course and outcome. Ferritin, fibrinogen, AST, and triglyceride are recommended when there is a concern about macrophage activation syndrome (MAS).

Imaging

1. Imaging helps to assess joint degeneration, reduce the differential diagnosis, and increase the certainty of a JIA diagnosis.
2. Radiography remains the initial imaging used for symptomatic joints; however, the radiographic changes are undetectable in the early stage of JIA. Soft tissue oedema, a rise in soft tissue density, and the displacement of fat folds are indirect indicators of arthritis in radiography.
3. Other features are periarticular osteoporosis, joint space narrowing, bone erosion and deformity, and joint subluxation or ankyloses in an advanced stage.
4. Ultrasound also plays a significant role in the imaging of JIA. It can assess synovial thickening, joint effusion, tenosynovitis, enthesitis, and bone erosions.
5. In addition to detecting synovitis, the USG accurately guides intra-articular corticosteroid injections. Magnetic resonance imaging (MRI) is the gold standard for the study of JIA.
6. All joints affected by pathological inflammatory phenomena can be easily examined in all possible plans and with an excellent contrast resolution of bone and soft tissues.
7. It's the most accurate imaging method for identifying synovitis. MRI is the only modality able to objectively detect bone marrow oedema and the most sensitive to detect bone erosions.

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Differential diagnosis

Chronic arthritis has a wide differential diagnosis based on the JIA subtypes and clinical presentation.

The following differential diagnosis should be considered:

• Infections such as post-streptococcal reactive arthritis, Lyme arthritis, acute rheumatic fever, septic arthritis, osteomyelitis
• Steroid-induced osteonecrosis
• Sickle cell disease, haemophilia, scurvy
• Osteoid osteoma, bone tumours, neuroblastoma, leukaemia, and lymphoma
• Systemic lupus erythematosus (SLE), Mixed connective tissue disease (MCTD), Sjögren syndrome, scleroderma, sarcoidosis, Blau syndrome, arthritis associated with inflammatory bowel diseases, Farber disease, autoinflammatory syndromes, systemic vasculitis (polyarteritis nodosa, Kawasaki disease), inflammatory bowel disease

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Treatment

Treatment of JIA requires anti-inflammatory and immunomodulatory drugs, physical therapy, and eventually, surgery, nutritional support, and psychosocial support. The disease subtypes, damage and severity of the condition, related diseases, and family acceptance all influence the pharmacological therapy option.

For all subtypes, nonsteroidal anti-inflammatory medications (NSAIDs) are the cornerstone of the first line of treatment for symptoms. With the advent of more aggressive modern treatments like methotrexate and biologics, the usage of NSAIDs in JIA has gradually declined.

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Prognosis

1. The most common complications of JIA are leg-length discrepancy and joint contracture.
2. Growth retardation, low bone mineral density for chronological age, severe hip involvement requiring a hip prosthesis, and amyloidosis are other major complications.
3. An extremely serious complication is macrophage activation syndrome, due to the uncontrolled activation and proliferation of T lymphocytes and macrophages.
4. The frequency of this syndrome in patients with JIA is unknown, but some studies report that it occurs in up to 10% of cases.
5. The availability of novel medications that selectively inhibit the molecular pathways causing persistent inflammation has resulted in a remarkable shift in the prognosis of juvenile inflammatory arthritis (JIA).
6. To avoid irreversible joint injury and maintain joint functionality, prompt and precise diagnosis and therapy are crucial.

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Vernika Tyagi is a consultant paediatrician from Delhi.