An Update on Juvenile Idiopathic Arthritis

Juvenile Idiopathic Arthritis (JIA) refers to a group of inflammatory arthritides of unknown cause that begin before 16 years of age and persists for at least 6 weeks. It is the most common chronic paediatric rheumatological condition affecting approximately 1 in 1000 children and young people less than 16 years of age with an overall female predominance.

It is important that other causes of arthritis, including infection and malignancy, are excluded before the diagnosis is made. The key features of JIA include joint pain, stiffness, swelling and loss of movement or reduced function. Chronic anterior uveitis is strongly associated with JIA and can occur in up to 30% depending on the subtype of JIA. It can be asymptomatic and potentially lead to irreversible sight loss including blindness. All children with a diagnosis of JIA should be referred to ophthalmology for uveitis screening (within 6 weeks of referral) with subsequent regular uveitis monitoring by slit lamp examination. Duration of uveitis monitoring will depend on the age of the child at diagnosis and subtype of JIA, however is typically up until the age of 11-12 years (RCO/BSPAR Guidelines).

The International League Against Rheumatism (ILAR) classification criteria characterise JIA into 7 different subtypes as shown in Table 1. Oligoarticular JIA is the commonest subtype accounting for up to 60% of all cases with the knee being the most commonly affected joint.

The heterogeneous nature of JIA adds to the complexity of fully understanding the underlying pathophysiology. It is likely a number of different risk factors, including genetic (HLA associated) and environmental (infectious triggers), are involved resulting in an auto-immune driven disease process with the production of pro-inflammatory cytokines causing synovial inflammation.

Clinical Assessment, Investigations & Diagnosis

Whilst investigations can be helpful to exclude other pathologies, JIA remains a clinical diagnosis without a single diagnostic investigation. If there is clinical concern of JIA then a paediatric rheumatology referral should not be delayed even if investigations are normal.

Careful clinical assessment therefore remains essential with a detailed history and a basic musculoskeletal assessment, as a minimum, such as the paediatric Gait, Arms, Legs, Spine (pGALS). Particular focus to changes of the child’s activities, new limitations, developmental regression in addition to exploration of key features including joint pain, stiffness and swelling are important. If an abnormality is detected on pGALS assessment, then a more detailed joint assessment should be performed such as the paediatric Regional Examination of the Musculoskeletal System (pREMS). Further information on clinical assessment and these examination methods can be found in the recommended further reading.

Elevated inflammatory markers including erythrocyte sedimentation rate, C-reactive protein and ferritin are likely to be elevated in Systemic JIA, however can be entirely normal in the other JIA subtypes. Autoantibodies can aid with prognosis and subtyping of JIA but are not diagnostic. Positive antinuclear antibodies (ANAs) in the presence of JIA can be associated with an increased risk of chronic anterior uveitis, however also occurs in other paediatric rheumatological diseases (e.g. childhood Systemic Lupus Erythematosus), non-rheumatological paediatric disorders (e.g. auto-immune hepatitis) and in healthy children.

Rheumatoid factor is rarely positive, less than 5% of all JIA patients, and more likely to be present in adolescent females with polyarticular disease predicting a more aggressive disease course and similar disease pattern to adult onset rheumatoid arthritis. Therefore, JIA should still be considered in a child presenting with joint symptoms with a negative rheumatoid factor. HLA B27 positivity is associated with enthesitis related JIA, however is found in approximately 20% of healthy children and can also be found in other paediatric inflammatory diseases including chronic recurrent multifocal osteomyelitis (CRMO) and inflammatory bowel disease. It is important to note that up to approximately 30% of those with enthesitis related JIA can be HLA B27 negative.

Further investigations are considered case by case and in particular to exclude alternative diagnoses such as infection (e.g. synovial fluid aspiration in presence of single hot swollen joint in febrile child to exclude septic arthritis) and malignancy (e.g. bone marrow aspirate in a child with joint pain and/or swelling, malaise, fever and pancytopenia).

Imaging can be helpful as part of the diagnostic work-up and later during the disease course for monitoring of disease activity and potential complications. X-Rays are likely to be normal initially, however can be helpful in detecting bony erosions and considering alternative causes for a child’s pain (e.g. presence of osteochondral defect). Ultrasonography (US) can detect early or longstanding inflammatory changes within the joint and is useful in monitoring of disease activity. MSK US is well tolerated by children, can be performed rapidly at the bedside and is likely to be used in greater frequency in the next number of years. Magnetic Resonance Imaging (MRI) ideally performed with gadolinium contrast is helpful for those where diagnostic uncertainty exists, in the presence of a normal ultrasound or monitoring for further complications. Availability can however be limited with delays in younger children requiring general anaesthetic.

Management

Principles of management include early referral to the paediatric rheumatology specialist multidisciplinary team (MDT), initiation of early treatment and monitoring for complications. Complications (such as joint damage, sight impairment, growth disturbance) are fortunately less frequently seen due to earlier diagnosis and mostly due to recent advancements in the development of biological agents to treat JIA and chronic anterior uveitis.

The MDT including physiotherapy, occupational therapy, clinical nurse specialists and psychology are all essential in the optimal management of a child with JIA. Preparing the young person with JIA for transition to adolescent services is particularly important to ensure timely transition at an appropriate timepoint for the young person with regards to their disease control and education. The diagnosis of JIA does not change and therefore should not be relabelled as rheumatoid arthritis as the patient moves to adult services.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are 1st line treatments for JIA. NSAIDs in isolation are unlikely to be sufficient to control the arthritis. Intra-articular corticosteroid injections (IACIs) are used for the treatment of Oligoarticular JIA and in those with polyarticular joint involvement waiting for further systemic treatment to take full effect. This lessens the potential use of high dose systemic steroids and their multiple side effects and toxicity in a growing child. In cases of severe JIA, such as systemic JIA or aggressive polyarticular JIA involving multiple joints – pulsed intravenous methylprednisolone is likely to be needed in order to establish rapid disease control followed by a weaning course of oral prednisolone.

Methotrexate is the most frequently used Disease Modifying Anti-Rheumatic Drug (DMARD) either in weekly subcutaneous or oral form. It is used in cases such as extended oligoarticular JIA, polyarticular JIA or psoriatic JIA where isolated IACIs are unlikely to provide sufficient control of disease.

The development of biological agents to selectively inhibit the effects of pro-inflammatory cytokines have transformed the management of JIA where additional immunosuppression, to DMARD therapy, is required. Biological agents are also becoming increasingly used as 1st line treatments in some subtypes of JIA (e.g. enthesitis related JIA) or where there is intolerance to standard DMARD therapy. Screening for infection (namely tuberculosis) before commencing and blood monitoring before and during biologic therapy is important in addition to contraception counselling and awareness of infection risk (including the avoidance of live vaccinations and recommendation of annual inactivated influenza vaccination).

Table 2 summarises the main biological agents used in the treatment of JIA. Anti-TNF therapy is typically used as a 1st line biological agent, except in systemic JIA where an anti – IL-1 or IL-6 receptor antagonist is used. T cell blockage and Janus Kinase (JAK) inhibitors are reserved typically for cases that have not responded to anti-TNF therapy. Anti CD-20 therapy, such as rituximab, is less frequently used but can be considered in cases of refractory rheumatoid factor positive polyarticular JIA. Advancements in research and ongoing clinical trials are promising with the development of additional biological agents. With the continued use of biological agents, the need for autologous haemopoietic stem cell transplant has reduced and is reserved for severe, refractory cases of JIA.

A separate article focusing on Systemic JIA and Macrophage Activation Syndrome will be discussed in May’s edition

Written by Dr Orla Killeen, Consultant Paediatric Rheumatologist and Dr Diarmuid McLaughlin, Paediatric Rheumatology Clinical Fellow, Children’s Health Ireland @ Crumlin

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