Juvenile arthritis

---

Reference: June 2024 | Issue 6 | Vol 10 | Page 40

---

Juvenile arthritis (JA) refers to a group of chronic inflammatory diseases affecting individuals under the age of 16, characterised by persistent joint inflammation, pain, stiffness, and potential joint damage. JA incorporates several subtypes including: Juvenile idiopathic arthritis (JIA); juvenile psoriatic arthritis; juvenile systemic lupus erythematosus; juvenile dermatomyositis; and juvenile spondyloarthritis, among others.

Although JA is relatively rare compared to adult-onset rheumatic diseases, it represents a significant cause of disability and impairment in children and adolescents worldwide. The exact prevalence of JA varies depending on the geographic region and population studied.^1,2

According to Arthritis Ireland, about one-in-10,000 children in Ireland are diagnosed with JIA annually. It is estimated that there are 1,200-to-1,400 under-16s with the condition in Ireland.³

JIA is the most common rheumatic disease reported in children in the western world. It is further classified into several subtypes based on clinical and laboratory criteria, including oligoarticular, polyarticular, systemic, enthesitis-related, psoriatic, and undifferentiated subtypes.

While the prevalence of JIA subtypes varies, oligoarticular JIA accounts for most cases, particularly in younger children. Females are more commonly affected than males, although the prevalence differs among subtypes. The disease course of JIA is highly unpredictable. While some individuals experience a self-limiting course of the disease, others face relentless progression marked by a heightened risk of joint deterioration.^1,2,3

Aetiology and pathophysiology

The aetiology of JA is multifactorial, involving a complex interplay of genetic susceptibility, environmental triggers, and dysregulated immune responses. Genetic predisposition plays a significant role in the development of JA, with certain human leukocyte antigen (HLA) alleles, such as HLA-DRB1, associated with increased susceptibility to the disease.

Environmental factors, including infections, trauma, and hormonal influences, may trigger the onset of JA in genetically susceptible individuals. Dysregulation of the immune system – particularly involving pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1 – contributes to the chronic inflammation and tissue damage observed in JA. Aberrant activation of innate and adaptive immune pathways, including the involvement of T-cells, B-cells, and antigen-presenting cells, sustain the inflammatory cascade within the joints, leading to synovial hyperplasia, cartilage degradation, and bone erosions.^1,4,5

Clinical presentation

The clinical presentation of JA can vary widely depending on the subtype and disease activity. Common symptoms include joint pain, swelling, stiffness, and decreased range of motion, which may fluctuate over time.

Children with systemic-onset JIA often present with systemic features, including fever, rash, lymphadenopathy, and serositis, in addition to joint involvement. Enthesitis-related arthritis typically manifests as inflammation at the sites of tendon or ligament insertion into bone, such as the heels, knees, or hips.

Psoriatic arthritis may be associated with skin psoriasis, nail changes, and uveitis. Chronic inflammation in JA can lead to long-term complications, including joint deformities, growth disturbances, uveitis, osteoporosis, and functional impairment. Early recognition and prompt intervention are important to minimise disease-related morbidity and optimise outcomes for affected individuals.^6,7

Diagnosis

Diagnosis of JA relies on a combination of clinical evaluation, laboratory tests, and imaging studies. Thorough history-taking and clinical examination are important. There is no single diagnostic test for JA, and diagnosis is often one of exclusion, ruling out other causes of joint inflammation and systemic symptoms in children.

Blood tests can be used to exclude other diseases, assist with understanding the subtype of JIA, or to help guide future treatment and management. Laboratory investigations may reveal nonspecific markers of inflammation, such as elevated erythrocyte sedimentation rate and C-reactive protein levels.

Certain autoantibodies, including rheumatoid factor and anti-cyclic citrullinated peptide antibodies, may be present in some JIA subtypes. Imaging modalities, such as plain radiographs, ultrasound, and magnetic resonance imaging (MRI), may help assess disease activity, joint damage, and complications such as uveitis. Collaboration with rheumatologists and other specialists is important for accurate diagnosis and timely initiation of treatment.^7,8,9

Differential diagnosis includes crystalline arthropathies such as gout and pseudogout; infection-related arthritis; connective tissue diseases; bone and joint disorders; traumatic and mechanical causes; inflammatory arthritis like rheumatoid arthritis, and seronegative spondyloarthropathies such as psoriatic arthritis and reactive arthritis.

Malignancy, such as leukaemia, is the single most important disease that is mistaken for JIA. The early presentation of JIA and malignancy can be very similar; therefore, if malignancy is suspected, early investigations to exclude this differential such as bone marrow biopsy or further imaging are important.¹⁰

Complications

The most common complications of JIA are leg-length discrepancy and joint contracture. Other complications are growth retardation, low bone mineral density for chronologic age, severe hip involvement with the need for hip prosthesis, and amyloidosis.^1,11

Treatment and management

The treatment and management of JA is aimed at controlling inflammation, alleviating symptoms, preventing joint damage, and optimising functional outcomes. Treatment strategies may vary depending on disease severity, subtype, and individual patient factors.¹ Non-pharmacological interventions, including physical therapy, occupational therapy, and patient education, play an important role in maintaining joint mobility, muscle strength, and overall well-being.^{1, 11}

Pharmacotherapy remains the cornerstone of treatment for JA, with nonsteroidal anti-inflammatory drugs (NSAIDs) being commonly used to alleviate pain and inflammation. NSAIDs can control inflammation if used regularly at optimised doses but will not induce remission in the long term.

Disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, sulfasalazine, and leflunomide, are often prescribed to suppress disease activity and prevent joint damage. DMARDs alleviate pain, swelling, and stiffness while also reducing inflammation and safeguarding joints from arthritis-induced damage. Methotrexate, sulfasalazine (usually administered to older children), and hydroxychloroquine (usually reserved for older children) are typically the initial prescriptions upon diagnosis.

DMARDs mitigate immune system attacks but require a considerable time to take effect (weeks to months). They offer a means of managing the condition long-term, depending upon the specific type of JIA. Sulfasalazine and hydroxychloroquine are available solely in tablet form, while methotrexate is obtainable in tablets, liquid formulation, or subcutaneous injection. While side-effects are uncommon, regular blood tests are necessary for monitoring. Leflunomide, administered in tablet form, serves as a less common DMARD, reserved for occasional use.^1,3,11

Biologic therapies function by selectively targeting specific chemicals or cells within the body’s immune system. Like DMARDs, biologic drugs not only alleviate pain, stiffness, and swelling but also impede the progression of arthritis. Biologic medications offer enhanced management for children and adolescents who exhibit inadequate responses to DMARDs.³

Biologic agents, including TNF-α inhibitors, IL-6 inhibitors, and other targeted therapies, have revolutionised the management of JA, particularly in cases refractory to conventional therapies. These biologic agents target specific immune pathways involved in the pathogenesis of JA, offering improved disease control and quality-of-life for affected individuals.

However, their use requires careful monitoring for potential adverse effects, including infections and infusion reactions. Commonly employed biologics for JIA include etanercept, adalimumab, infliximab, tocilizumab, abatacept, anakinra, and canakinumab (used sparingly). They may be prescribed in conjunction with a standard DMARD. Etanercept and adalimumab are administered via subcutaneous injection, while tocilizumab and abatacept are administered intravenously.^1,3,11

Patients and their families should be given clear advice about the risks of infection when starting any immunomodulating therapy. This should include advice about what to do if they develop or are in contact with infectious diseases; advice around live and non-live vaccines; travel advice; general advice about simple hygiene measures to reduce infection, such as hand washing; and they should be given a contact number for their specialist team.^1,11 

In cases of refractory or severe disease, corticosteroids may be used as adjunctive therapy to achieve rapid symptom control, although their long-term use is limited by side-effects. Surgical interventions, such as synovectomy, joint replacement, and correction of deformities, may be necessary in selected cases to alleviate pain and improve joint function. The treatment approach should be individualised based on disease activity.^1,10

Eye care

In children and adolescents diagnosed with JIA, inflammation can affect not only their joints but also their eyes, causing uveitis. Approximately 10-to-30 per cent of children and young individuals with JIA experience uveitis.

During the initial phases, uveitis may manifest without noticeable symptoms; however, if present, symptoms typically include eye pain, redness, and blurred vision. Left untreated, uveitis can progressively impair vision and, in rare instances, lead to blindness. It is important that all children and young individuals diagnosed with JIA undergo assessment by an ophthalmologist.³

Prognosis and outlook

The prognosis for JA varies widely depending on several factors, including the subtype of JA, disease severity, response to treatment, and the presence of complications. Overall, advancements in medical understanding and treatment options have significantly improved outcomes for children and adolescents with the disease in recent years. However, the long-term prognosis can still vary from individual to individual.

Children who receive timely and effective treatment are more likely to achieve disease remission, experience fewer flares, and have better long-term functional outcomes. While some individuals may achieve remission with conventional DMARDs or biologic therapies, others may experience persistent disease activity despite treatment. Close monitoring and adjustment of treatment regimens are necessary to achieve and maintain disease control.¹²

Despite the challenges posed by JA, many children and adolescents can lead active and fulfilling lives with appropriate treatment and support. Physical therapy, occupational therapy, and psychosocial interventions play important roles in improving quality-of-life and promoting independence in daily activities. As children with JA transition into adulthood, ongoing medical care and support are necessary to address the evolving needs of young adults living with a chronic rheumatic condition.^1,3

Several new and novel therapies are currently being studied for JA with the aim of improving disease management, achieving better outcomes, and reducing treatment-related adverse effects. Some of these therapies include:

Janus kinase (JAK) inhibitors are oral medications that target the Janus kinase enzymes involved in the signalling pathways of inflammatory cytokines. These drugs have shown promise in the treatment of rheumatoid arthritis and other autoimmune diseases and are now being investigated for use in JA. Tofacitinib is one JAK inhibitor that has demonstrated efficacy in adult rheumatoid arthritis and is being studied in paediatric populations with JA.¹²

IL-6 plays a key role in the pathogenesis of inflammatory arthritis by promoting the production of inflammatory cytokines. Biologic agents targeting IL-6, such as tocilizumab, have been approved for use in adults with rheumatoid arthritis and JIA. Ongoing research is exploring the efficacy and safety of IL-6 inhibitors in paediatric patients with JA.¹³

Bruton’s tyrosine kinase (BTK) inhibitors are a novel class of medications that block BTK, a key enzyme involved in B-cell signalling. BTK inhibitors have shown efficacy in the treatment of adult rheumatoid arthritis and are now being investigated as potential therapies for JA. Studies are underway to evaluate the safety and efficacy of BTK inhibitors in children and adolescents with JIA.¹⁴

Selective costimulation modulators are small molecule drugs that target specific immune cell signalling pathways involved in the pathogenesis of autoimmune diseases. These drugs aim to selectively modulate the immune response while minimising off-target effects. Several selective costimulation modulators are currently in preclinical and clinical development for the treatment of JA.¹²

Cell-based therapies, including mesenchymal stem cell (MSC) therapy and chimeric antigen receptor (CAR) T-cell therapy, are emerging as potential treatments for autoimmune diseases, including JA. MSCs have immunomodulatory properties and have shown promise in preclinical studies for the treatment of inflammatory arthritis. CAR T-cell therapy involves genetically modifying T-cells to target and eliminate autoreactive immune cells. Clinical trials are ongoing to evaluate the safety and efficacy of cell-based therapies in children and adolescents with JA.¹⁵

Gene therapy holds great potential for JIA treatment by introducing new or modified genes into the body to correct or replace defective genes involved in the disease. In JIA, gene therapy aims to reduce cytokine production and joint inflammation, improving symptoms and slowing down disease progression. Although significant advancements in gene-based therapy for JIA are yet to be achieved, alternative delivery methods have been explored to facilitate targeted therapy.¹²

3D-printing technology holds promise for assessing disease progression and facilitating joint regeneration in JIA. Advancements in 3D printing have made it a feasible and high-quality modelling tool. 3D bioprinting technology has facilitated the development of sophisticated scaffolding models that can be implanted into joints, containing biomaterials capable of promoting joint regeneration.^12,16

The use of artificial intelligence (AI) models for treatment monitoring in JIA holds promise in optimising drug efficacy and management. AI and machine learning techniques can filter an abundance of information and identify clinically relevant details. This could have implications for their use in diagnosis, management, monitoring, and disease risk estimation of a multitude of disorders, including those seen in rheumatology.^12,16

New and novel therapies hold promise for improving the management of JA and may offer additional treatment options for patients who do not respond adequately to current therapies. However, further research is needed to establish their safety and efficacy in paediatric populations and to determine their long-term effects on disease outcomes.