Modern management of juvenile idiopathic arthritis
Many children with juvenile idiopathic arthritis (JIA) experience delays in diagnosis, but evidence suggests that treating early and aggressively leads to better long-term outcomes. This article discusses the recommended treatment options, including both traditional therapies and the newer biological agents.
Juvenile idiopathic arthritis (JIA) is the most common rheuma-tological disease of childhood, with a prevalence estimated at 1 in 1000 children. It is characterised by arthritis with onset before the 16th birthday, lasting for more than six weeks, with no other cause identified. JIA is a different entity to rheumatoid arthritis, with distinct phenotypes and disease course. The current international classification identifies seven JIA subtypes based on phenotype, serology and associated features (see Table 1).1
Table 1. Juvenile idiopathic arthritis (JIA) subtypes (International League of Associations for Rheumatology)1
Arthritis is a clinical diagnosis based on history and exami-nation. However, many paediatricians lack confidence and train-ing in paediatric musculoskeletal assessment.2 Given this, it is not surprising that children with JIA often experience protracted delays in diagnosis – nearly six months on average but many years in some.3 These delays are worrisome as they may lead to complications such as erosions, limb-length discrepancy and bony overgrowth.
Children with arthritis often present with joint pain, swelling and morning stiffness. However, presenting symptoms may also be subtle including limp, unusual posturing (such as torticollis) or overt limb preference. Diagnosis may be particularly chal-lenging in the preverbal child, where apparent developmental regression (such as reverting from walking to crawling) may be the only sign; therefore, a high index of suspicion is warranted. The paediatric Gait Arms Legs Spine (pGALS) musculoskeletal screening tool is quick to learn and implement, and is available on the Arthritis Research UK website.4
The most serious extra-articular complication of JIA is ante-rior uveitis – ocular inflammation that is often asymptomatic but may be sight-threatening. Uveitis occurs in nearly 10 per cent of children with JIA overall,5 but in the oligoarticular subtype the cumulative prevalence is much higher, approaching one in three.6 Risk is greatest in those who are antinuclear antibody (ANA) positive and have early disease onset. There is also a slight female preponderance. Consequently, regular ophthalmology review with slit-lamp examination represents part of the routine care of children with JIA.7
Principles of management
The management of JIA needs to be provided by a multidisciplinary team (MDT), including specialist doctors, nurses, physiotherapists, podiatrists and psychologists, working closely with paediatricians, community nurses and GPs.8 Two major trends have emerged in the drug treatment of inflammatory conditions over recent years, including in the treatment of JIA. The first is the concept of a treatment ‘window of opportunity’: literature suggests that treating inflammatory disease early and aggressively to ‘switch off’ the immune process leads to better longterm outcomes.9-12 This is supported by evidence that children who achieve a state of inactive disease within the first five years following diagnosis accrue less disease-related damage.13 This has encouraged a trend towards early aggressive therapy – such as high-dose ‘pulse’ intravenous corticosteroids – instead of a slower ‘step-up’ pyramid approach.
The second important treatment principle is ‘treat-to-target’. This concept has arisen in the era of biological agents, when treatment goals have become more ambitious and patient outcomes vastly improved. The treat-to-target approach states that tighter disease control can be achieved by formally measuring and tracking patient outcomes, with low tolerance for persistent disease activity, so that incremental gains continue to be made and patient care optimised.14,15 A parallel concept is that of clinical versus immunological remission: that there may be ongoing activity within the immune system, measurable by increasingly sensitive biochemical and radiological markers, even in the absence of clinically apparent disease. Extinguishing even this subclinical immune activity is becoming the new treatment goal.16,17
Long-term outcomes for children with JIA are variable and difficult to predict. In some children, the disease resolves spontaneously, often around the time of puberty. In others, JIA represents a chronic condition requiring lifelong immunosuppression and eventual transition to an adult rheumatology service.
Specific therapeutic agents
NSAIDs have been used in the treatment of JIA for decades, and continue to have important anti-inflammatory and analgesic roles. They are an excellent first-line therapy in the primary care setting as they are well-tolerated, provide reasonable symptom relief and will not mask other diagnoses such as infection or malignancy.18 Naproxen (7.5mg/kg orally twice daily) is often advised first-line because it has the convenience of twice daily dosing, and also comes in a liquid formulation.
Ibuprofen is more readily available than naproxen, but when used as an anti-inflammatory agent in the treatment of JIA it should be given at higher doses than when used for antipyretic purposes. In rheumatic disease, ibuprofen should be dosed at 30–40mg/kg daily in three to four divided doses (max 2.4g per day). Alternative NSAIDs that are in common usage include piroxicam, diclofenac and indometacin.19 When used in the treatment of arthritis, NSAIDs should be given regularly to maximise the anti-inflammatory effect. All patients on regular NSAIDs should be prescribed a gastroprotective agent such as a proton-pump inhibitor or H2-receptor antagonist.
Intra-articular steroid injections
Joint injections are safe and effective therapy for the management of JIA. The procedure is well tolerated, and usually performed under general anaesthetic for younger children, or sedation (such as nitrous oxide) for older children. The agent of choice is triamcinolone hexacetonide, which is longer acting than alternative preparations, with mean duration of response just over 12 months.20,21 Joint injections are used frequently for the treatment of oligoarticular disease, where they may suffice as monotherapy, thus sparing the need for regular systemic medication. They may also be used for children whose disease has a polyarticular course, to ‘mop up’ residual or flaring joints in children who have had an otherwise good response to systemic therapies. Important adverse effects include cutaneous atrophy at the injection site, and septic arthritis. When performed under sterile conditions, the risk of septic arthritis is small.22
Disease-modifying antirheumatic drugs
The disease-modifying antirheumatic drug (DMARD) methotrexate has been used in the treatment of JIA for decades and, when dosed and monitored appropriately, remains a safe and effective mainstay of treatment.23 It is used in children with multiple active joints, or those who have activity in joints that are not readily injectable – especially the cervical spine and temperomandibular joint. It also has a major role in the treatment of uveitis not adequately controlled by topical steroid drops. Methotrexate is dosed by body surface area at 15mg/m2 and is given once per week via the subcutaneous or oral routes.
Methotrexate use in JIA is limited by two major factors. The first is efficacy – a significant minority of children show inadequate response to methotrexate, especially in the era of tight disease control.24 The other is tolerability – especially nausea and vomiting, which can be debilitating and requires careful management (see Table 2). Methotrexate may also cause liver dysfunction and cytopenias. These abnormalities are usually mild and self-resolving upon temporary cessation of the drug, but its safe use requires regular blood monitoring.25 The cumulative effect of these short treatment interruptions can limit the utility of the drug, especially if the child begins to flare in between.
Table 2. Strategies for the management of methotrexate-associated nausea
The mechanism of action of methotrexate in arthritis is poorly understood, but is postulated to work by modulating lymphocyte function or by modifying adenosine levels.26 It is known to disrupt folate metabolism so is usually co-administered with folic acid to reduce side-effects. Folic acid may be given daily, or weekly, but is traditionally not administered on the same day as methotrexate due to a theoretical risk of reducing methotrexate efficacy.
Other DMARDs used in the treatment of JIA include sulfasalazine (especially for enthesitis-related arthritis, the juvenile spondyloarthropathy), leflunomide, ciclosporin and hydroxychloroquine. While it was standard in the past for children to switch between DMARDs, most children who fail methotrexate therapy now escalate directly to a biological agent.27 In fact, as safety data grows, some children with severe disease are beginning biological therapy as first-line.28
As with methotrexate, all DMARDs require routine blood tests, monitoring for cytopenias, hepatic and renal dysfunction. Many DMARDS are teratogenic and should be prescribed cautiously in females of childbearing age. Adolescent patients should be warned to avoid alcohol while on most DMARDs, given the potential for hepatotoxicity. National British Society for Paediatric and Adolescent Rheumatology (BSPAR) guidelines exist to direct safe prescribing of many DMARDS, including methotrexate. These are freely available on the BSPAR website.29
Biological agents, or ‘biologics’, have revolutionised the treatment of JIA and JIA-uveitis, vastly improving patient outcomes and raising the bar on disease control. These represent a new class of drug that uses monoclonal antibodies or other recombinant proteins to specifically target cells and cytokines that are driving the inflammatory process. Biologics are a great triumph of ‘bench-to-bedside’ medicine, where laboratory understanding of disease pathogenesis has allowed the development of targeted effective therapies. A number of biological DMARDs (bDMARDs) have now entered the market, each with slightly different indications and utility (see Table 3). In clinical trials, many show efficacy in over 50 per cent of children, but longer-term efficacy data are awaited. NICE guidelines now exist to direct the safe prescribing of several biological agents in JIA, including their indications, safety data and dosing guidance.30
Table 3. Biological agents used in the treatment of juvenile idiopathic arthritis (JIA) (NB. Doses listed here are provided as a guide only; these medications should only be prescribed through a specialist paediatric rheumatology service. Please refer to NICE guidelines for further guidance on dosing30)
Etanercept was the first biological agent to be approved for use in JIA. It is a soluble receptor protein that targets tumour necrosis factor (TNF) alpha, a critical proinflammatory cytokine. Subcutaneous therapy with etanercept (given twice weekly at 0.4mg/kg, or weekly at 0.8mg/kg body weight) may be administered via prefilled pens, prefilled syringes or vials, depending on the drug and the dose required. Parents should receive education and support for these injections from specialist nursing teams.
Biologics are new therapies with limited long-term safety data. There is some evidence that they may increase the risk of malignancy, especially lymphoproliferative malignancy.31 Concerns have also been raised regarding an increased risk of demyelinating disease.32 Biologic registries have been developed to gather answers to these important questions. Nonetheless, it is undeniable that biologics have opened up entirely new treatment pathways for JIA, and in doing so have improved patient and disease outcomes.
Antidrug antibodies (ADAs) are a well-recognised complication of biologic use. These occur when the patient mounts an immune response to the drug itself, and may result in reduced treatment efficacy and infusion reactions.33 Co-administration of methotrexate or another DMARD appears to reduce ADA development,34 hence many children may be prescribed a DMARD and a bDMARD simultaneously.
Systemic corticosteroid therapy
Corticosteroids continue to play an important role in the management of JIA, despite their significant side-effect profile (see Table 4). They are powerful and fast-acting anti-inflammatory agents, and are often used in JIA induction therapy or in the management of disease flares. Systemic corticosteroids (often given as a high-dose ‘pulse‘ of 30mg/kg daily intravenous methylprednisolone for three days followed by a weaning course of oral prednisolone starting between 1–2mg/kg daily) are primarily used in the treatment of children with polyarticular or systemic disease; oligoarticular disease can usually be managed with targeted joint injections.
Table 4. Corticosteroid side-effects in children
Corticosteroids provide rapid relief of symptoms and control of inflammation, hence their role is largely as a temporising measure while awaiting the effect of a DMARD or bDMARD. Biological therapies have had a dramatic role as steroid-sparing agents and steroids are now rarely used as maintenance therapy. Long-term steroids should not be stopped abruptly due to the risk of adrenal suppression.
GPs and community paediatricians have a key role in monitoring the growth, wellbeing and disease sequelae of JIA and its treatment, including drug-related side-effects. There are a number of other medications that are commonly prescribed in children with JIA; many are employed to reduce treatment adverse effects (see Table 5).
Table 5. Other medications commonly used in juvenile idiopathic arthritis (JIA)
Managing the immunosuppressed child
JIA is an autoimmune disease, hence most therapeutics used in its management are immunosuppressive. This places children being treated for JIA at increased risk of infection, including disseminated infection or infection with unusual organisms.
Children who are immunosuppressed and develop fever or signs of infection must be seen by a doctor as a matter of urgency, and close physical examination undertaken. Importantly, some immunosuppressive agents prevent a child from developing a fever, or raised inflammatory markers, even in the presence of significant or overwhelming infection. Hence the absence of pyrexia is not always reassuring. If there is any clinical doubt, the child should be referred to their local emergency department and consideration given to admission.
Chickenpox infection is of particular note in the management of immunosuppressed children. Management of varicella exposures varies depending on the level of immunosuppression and the child’s pre-existing varicella immunity. It may involve close observation, passive immunisation with varicella immunoglobulin, or hospital admission for antiviral therapy.
Tuberculosis exposures in children on biological therapies are also potentially high risk, especially in children who are on antiTNF therapy. TNF alpha has an important role in granuloma formation, and therefore in the immune response to tuberculosis.35 All children should be screened for tuberculosis before commencing biological therapy36,37 and the treating team should be notified of any significant tuberculosis exposure as a matter of urgency.
Clinicians involved in the care of children with JIA should also be vigilant to the possibility of malignancy, especially in children who have been on a DMARD or biological agent.31,38,39
School and social life
Modern management aims to keep children with JIA out of hospital, attending full-time school and participating in sport and peer activities, wherever possible. Visits to hospital may mean missed school time and require the understanding and co-operation of school staff to ensure children are not excluded from activities due to their JIA. Good communication between all MDT members, school and primary care providers ensures smooth arrangements for drug prescribing and monitoring as well as full integration into school life.
Therapeutics in the treatment of JIA have progressed rapidly over the last decade, and so too have our expectations of disease control. Treatment now aims for minimal disease activity and quality of life approaching that of any other child. While biological therapies have largely been responsible for these gains, we are also using traditional therapies in more effective ways. In particular, there has been a movement to early aggressive therapy and closer disease monitoring as we ‘treat-to-target’. With the shift to personalised, targeted therapies we can expect biomarkers and pharmacogenomics to play an increasing role in JIA treatment choices in the future.
Helpful online resources
Arthritis Research UK. http://www.arthritisresearchuk.org/arthritis-information/young-people.aspx
British Society for Paediatric and Adolescent Rheumatology. http://www.bspar.org.uk/
Pediatric Rheumatology INternational Trials Organisation (PRINTO). https://www.printo.it/
Arthritis Care. https://www.arthritiscare.org.uk/what-is-arthritis/types-of-arthritis/656-juvenile-idiopathic-arthritis-jia
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Declaration of interests
Dr James is supported by educational research grants funded by the Australian Rheumatology Association, Arthritis Australia and the Asia-Pacific League of Associations for Rheumatology. Professor Wedderburn is supported by grants from Arthritis Research UK (ref. 20164) and the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and UCL Institute of Child Health, University College London.
Dr James is a clinical fellow in the Department of Rheumatology, Great Ormond Street Hospital NHS Foundation Trust; and Professor Wedderburn is professor and consultant of paediatric rheumatology and director, Arthritis Research UK Centre for Adolescent Rheumatology at University College London, University College London Hospital and Great Ormond Street Hospital, and deputy lead, Infection, Immunity, Inflammation Programme, UCL Institute of Child Health.