Approach

Patients with JIA, or suspected JIA, should be managed by a specialist paediatric rheumatology multidisciplinary team.[57] 

The goals of treatment are:

  • Achieving clinically inactive disease

  • Excellent symptom control

  • Prevention and minimisation of of joint damage

  • Prevention and minimisation of treatment side effects

  • Promotion of good physical and mental health.

Prompt initiation of disease-modifying therapy is essential, because active, uncontrolled JIA can cause permanent joint damage.[58]

Specific therapy is indicated by disease phenotype, disease activity, and presence/absence of risk factors.

Phenotypic groups

The treatment of JIA varies according to the predominant clinical features. American College of Rheumatology (ACR) guidelines define treatment groups by clinical phenotype rather than International League of Associations for Rheumatology categories. The patient groups are:[58][59]

  • Oligoarticular arthritis (history of arthritis of 4 or fewer joints)

  • Polyarticular arthritis (history of arthritis of 5 or more joints)

  • Active sacroiliitis

  • Active enthesitis

  • Systemic-onset JIA.

Patients with psoriatic arthritis may belong to the polyarticular JIA, sacroiliitis, or enthesitis phenotypic group.[58]

Assessing disease activity

Disease activity is assessed by:

  • Patient (or parent) ratings

  • Physician ratings

  • Measurement of inflammatory markers

  • Number of active joints.

Each of these four factors is a component of the Juvenile Arthritis Disease Activity Score.[60] Disease activity scores can help the clinician select an appropriate initial treatment, and recognise a need to escalate treatment. 

Physician and patient global assessment of disease activity is performed using a Likert scale. The physician rates the disease activity from 0 (no activity) to 10 (maximum activity). The patient (or parent) rates patient wellbeing from 0 (very good) to 10 (very poor).[61] 

A joint is considered active if it is swollen or has limited motion with pain/tenderness.

Low disease activity is not the same as disease remission, and should prompt a re-evaluation of therapy.

Supportive care

All aspects of the child’s physical and psychological health should be evaluated and addressed by the multidisciplinary team.[57] Physiotherapy and occupational therapy are recommended for children with, or at risk of, functional limitations.[58]

Patients should be encouraged to participate in interests, sport, and community life.[57] Inactivity leads to deconditioning and disability.[62] Weight-bearing activity may reduce the risk of low bone mineral density.[63] One Cochrane review found that exercise therapy does not appear to increase quality of life, exercise capacity, functional ability, or pain in patients with JIA; neither is it associated with any adverse effects or exacerbation of arthritis. However, heterogeneous outcome measures were used in the included trials, and the authors suggest that more standardised outcome measures are needed to evaluate the long-term effect of exercise therapy.[64] 

Foot orthoses may reduce pain and improve quality of life in children with JIA.[65][66] 

Patients with JIA have an increased risk of psychiatric morbidity.[67] Support and strategies for managing any difficulties should be provided.[57]

Polyarticular JIA

Conventional synthetic disease-modifying antirheumatic drugs (DMARDs) include methotrexate, sulfasalazine, and leflunomide.

Methotrexate is first-line initial therapy for children with polyarticular JIA.[58] Randomised controlled trials have demonstrated improvement in joint symptoms and a reduction in disease activity with methotrexate.[68][69] Folic acid is usually given concomitantly to decrease the side effects of methotrexate, and anti-emetics may be used to reduce nausea. Patients should be counselled to avoid alcohol and pregnancy while taking methotrexate. 

Full blood count, serum creatinine, and liver enzymes should be checked before starting methotrexate, and every 3 to 4 months during treatment.[70] Patients at risk of hepatitis B or hepatitis C infection should have a screening antibody test before starting methotrexate.[59] Elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) above 2 times the upper limit justifies temporary suspension of methotrexate, which can be re-started following normalisation of serum liver enzyme levels.[59]

Some trials have demonstrated the safety and efficacy of leflunomide as a second-line conventional synthetic DMARD in paediatric patients who are intolerant or unresponsive to methotrexate. Most of the paediatric patients responsive to leflunomide maintained their response in a 2-year open-label extension study.[71] Sulfasalazine may also be used as a second-line option.[58]

Biological therapies that block the action of inflammatory cytokines, including tumour necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6, are highly effective and have revolutionised the treatment of JIA. These therapies are typically given in addition to a DMARD. They may be given as part of initial therapy in patients with risk factors for a poor prognosis, or started after an inadequate response to a conventional synthetic DMARD.[58] 

Risk factors for poor prognosis include:[58]  

  • Presence of anti-cyclic citrullinated peptide antibodies

  • Presence of rheumatoid factor

  • Joint damage at presentation

  • High-risk joint involvement (cervical spine, wrist, or hip)

  • High disease activity

  • Patient judged by physician to be at high risk of disabling joint damage.

A TNF-alpha inhibitor is first-line.[58] Treatment with etanercept or adalimumab is preferred to treatment with infliximab. Infliximab is given by intravenous infusion and carries a risk of infusion-associated reactions and is not approved for the treatment of any form of JIA. 

Etanercept is a soluble TNF-alpha receptor antagonist. It is approved for polyarticular disease in children 2 years of age and over.[72] An open-label extension trial has demonstrated safety and efficacy for up to 8 years of use.[73]

Adalimumab is a recombinant humanised TNF-alpha inhibitor that is approved for polyarticular disease in children 2 years of age and over.[74] Over 70% of children receiving adalimumab in combination with methotrexate had a 70% improvement in at least three of the ACR core set variables after 16 weeks of therapy.[74] It is also effective in patients with enthesitis.[75] The long-term tolerability and efficacy of adalimumab in JIA has been demonstrated.[76][77]

Infliximab is a monoclonal, chimeric TNF-alpha inhibitor.[78] Monoclonal antibodies have analogies to murine proteins, meaning pre-medication with antihistamines, paracetamol, and corticosteroids is advised to minimise infusion-associated reactions.[79][80]

TNF-alpha inhibitors should be used with caution in patients with recurrent infections, conditions predisposing to infections, pre-existing demyelinating disorders, or haematological diseases, due to the immunosuppressive nature of these medicines.[81] A study evaluating etanercept and adalimumab showed an increase in number of infections but no clear evidence that the overall malignancy risk was increased.[76] Chronic carriers of tuberculosis and hepatitis B are susceptible to disease reactivation. Tuberculosis skin tests, and viral hepatitis screening for patients with risk factors for infection, are recommended prior to treatment.[59][81] Live vaccines should be avoided during treatment.[82]

Tocilizumab (an IL-6 inhibitor) or abatacept (a fusion protein) are used if the patient does not respond to a TNF-alpha inhibitor.

Tocilizumab can be used as monotherapy or in combination with methotrexate for children with polyarticular JIA. Tocilizumab is relatively well tolerated and has proven efficacy for up to 52 weeks.[83] It is approved in children 2 years of age and older. 

Serious hepatotoxicity (including acute liver failure, hepatitis, and jaundice) has been identified in eight patients treated with tocilizumab worldwide. Two patients required liver transplantation. Serious liver injury has been reported from 2 weeks to more than 5 years after starting treatment. While liver toxicity occurs rarely and the risk-benefit profile still supports the use of tocilizumab, the ACR recommends monitoring ALT or AST at initiation of treatment, within 4 to 8 weeks of treatment and every 3 to 4 months thereafter.[70] Be cautious when considering starting tocilizumab treatment in patients with ALT or AST levels higher than 1.5 times the upper limit of normal. Tocilizumab is not recommended if ALT or AST levels are higher than 5 times the upper limit of normal. If liver enzyme abnormalities are identified, consider a dose modification (reduction, interruption, or discontinuation) according to the manufacturer’s recommendations. Advise patients to seek medical help immediately if they experience signs and symptoms of hepatic injury.[84]

Abatacept is a recombinant, fully humanised fusion protein composed of the extracellular domain of human CTLA-4 and a portion of the Fc-domain of human immunoglobulin G-1. It is used in children aged 2 years and older with polyarticular JIA who have had an inadequate response to previous conventional synthetic DMARDs, and has proven efficacy and long-term safety.[85][86][87] Improvements in health-related quality of life were observed during a phase 3, double-blind, placebo controlled trial with abatacept, providing real-life, tangible benefits to children with JIA and their parents or carers.[88]

Non-steroidal anti-inflammatory drugs (NSAIDs) are used as adjunctive therapy to treat pain and stiffness in children with polyarticular JIA while systemic therapies take effect.

Specific NSAIDs are approved for children with JIA (e.g., ibuprofen, naproxen, meloxicam). Others are commonly used off-label. No specific NSAID is superior to another.[89] Sequential trials of different NSAIDs are used to identify the most effective medicine for individual patients.

Possible adverse effects include renal impairment, gastrointestinal symptoms (nausea, constipation, diarrhoea, abdominal pain), headache, and rash.[89]

Low-dose oral corticosteroid therapy can be used for up to 3 months to improve symptoms while systemic therapies take effect. This treatment is particularly helpful for children with polyarticular JIA with high or moderate disease activity.[46]

Intra-articular corticosteroid injections can be used alone or as part of a treatment plan involving other systemic treatments. Radiographical assistance may be necessary for injecting some joints. The procedure can be undertaken with the administration of entonox or general anaesthetic to the child.

Relief is expected to last for at least 4 months.[59] Injections can be repeated every 4 months as needed. Adverse effects from intra-articular injections are uncommon.

Intra-articular corticosteroid injections may not be a suitable treatment for large numbers of joints that have been injected multiple times. Escalation of systemic therapy may be more appropriate.[58] Duration of relief <4 months may also imply a need to escalate systemic therapy.[59]

Oligoarticular JIA

Corticosteroid injections are first-line treatment for most patients.[59] 

Initial NSAID monotherapy may be given for 2 months if the child has low disease activity, no contractures, and no poor prognostic features, to relieve joint pain and swelling.[59] 

Poor prognostic features are:[59] 

  • Arthritis of the hip or cervical spine

  • Arthritis of the ankle or wrist plus prolonged or marked inflammatory marker elevation

  • Radiographic evidence of erosions or joint space narrowing.

If there is any residual disease activity after 2 months’ treatment, therapy should be escalated to intra-articular corticosteroid injections.[59] 

Methotrexate is used if a patient has not responded to intra-articular corticosteroids, or as initial treatment for children with high disease activity and adverse prognostic features.[59] 

TNF-alpha inhibitors are rarely needed for patients with oligoarticular JIA, but they should be considered in patients with ongoing active disease despite treatment with intra-articular corticosteroids and methotrexate.[59] When treatment with a TNF-alpha inhibitor is needed, etanercept or adalimumab are preferred to infliximab. Infliximab is given by intravenous infusion and carries a risk of infusion-associated reactions and is not approved for the treatment of any form of JIA. 

Sacroiliitis

First-line treatment is NSAID monotherapy. Oral corticosteroids may be used to relieve symptoms for up to 3 months during initiation or escalation of systemic therapy.[58]

Treatment should be escalated to a TNF-alpha inhibitor if disease activity is not controlled by NSAID monotherapy. Use of TNF-alpha inhibitors is associated with decreased disease activity, compared with placebo.[90][91][92] Treatment with etanercept or adalimumab is preferred to treatment with infliximab. Infliximab is given by intravenous infusion and carries a risk of infusion-associated reactions and is not approved for the treatment of any form of JIA.

Sulfasalazine may be used instead of a TNF-alpha inhibitor, particularly for children in whom TNF-alpha inhibitors are contraindicated or not tolerated.[58]

Enthesitis

First-line treatment is NSAID monotherapy. Oral corticosteroids may be used to relieve symptoms for up to 3 months during initiation or escalation of systemic therapy.[58]

Treatment should be escalated if there is active enthesitis despite NSAID monotherapy.[58] 

Typically methotrexate or sulfasalazine are used first, with escalation to a TNF-alpha inhibitor if the child doesn’t respond.[93] When treatment with a TNF-alpha inhibitor is required, etanercept or adalimumab are preferred to infliximab. Infliximab is given by intravenous infusion and carries a risk of infusion-associated reactions and is not approved for the treatment of any form of JIA.

However, the ACR guidelines recommend that children with active enthesitis despite NSAID monotherapy should escalate to TNF-alpha inhibitors, rather than methotrexate or sulfasalazine, and noted that the level of evidence for this recommendation was low.[58] One observational study reported a greater improvement in pain and disease activity after 12 months in children with enthesitis who received a TNF-alpha inhibitor, compared with those who received a DMARD alone.[94]

Systemic-onset JIA

The ACR recommends that the management of systemic JIA is based on a confirmed diagnosis of JIA and whether it has features of macrophage activation syndrome (MAS).[95]

MAS is a life-threatening complication of systemic-onset JIA. Signs and symptoms include:[96]

  • Persistent fever

  • Elevated and/or rising ferritin or other markers of inflammation/damage

  • Inappropriately low or declining haemoglobin, platelet counts or white blood cells (neutrophils and lymphocytes)

  • Hepatic dysfunction

  • Coagulopathy

  • Splenomegaly

  • Central nervous system dysfunction

About 10% to 15% of patients with systemic-onset JIA develop life-threatening overt MAS.[97] MAS is present if the following criteria are met in a febrile patient with known or suspected systemic-onset JIA: ferritin >684 micrograms/L (>684 ng/mL) and any two of platelet count ≤181 x 10⁹/L, aspartate aminotransferase >48 U/L, triglycerides >1.76 mmol/L (>156 mg/dL), or fibrinogen ≤3.6 g/L (≤360 mg/dL).[98] If a patient has a normal ferritin level, but there is ongoing clinical suspicion of MAS, serial ferritin testing should be considered.[96]

Consult a paediatric rheumatology specialist urgently if features of MAS are present. Patients with MAS can deteriorate rapidly and may require intensive care admission. For patients with suspected MAS, initiating treatment while diagnostic testing is in progress should be considered.[96]

Monitoring initial treatment response by assessing clinical and laboratory markers of organ involvement should be assessed at least daily, and markers of systemic inflammation at least twice weekly. Worsening or lack of improvement in laboratory parameters of systemic inflammation, particularly ferritin, may indicate disease progression and a need to reassess diagnosis and/or treatment.[96]

The ACR recommends early use of biological agents in children with systemic JIA due to their proven effectiveness, moving away from former recommendations that focused on corticosteroids and conventional synthetic DMARDs.

Systemic JIA without MAS

Initial treatment is with a biological agent (i.e., IL-1 or IL-6 inhibitor) and/or an NSAID.[95]

There is some evidence that those with systemic JIA without MAS will respond to NSAIDs alone and even have clinically inactive disease.[95] Patients who undergo an initial trial of NSAID monotherapy should be followed up within 2 weeks for evaluation of a possible need for drug escalation.[99] If a response occurs and inactive disease occurs, then NSAIDs should be tapered and discontinued. If clinical response is not rapid and complete, rapid escalation of therapy is recommended. Several NSAIDs are approved for children with JIA (e.g., ibuprofen, naproxen, meloxicam). Others are commonly used off-label. No specific NSAID is superior to another.[89] Sequential trials of different NSAIDs are used to identify the most effective drug for individual patients. Possible adverse effects include renal impairment, gastrointestinal symptoms, headache, and rash.[89]

Biological agents can be given in combination with an NSAID for initial treatment or after a trial period of an NSAID. The ACR does not recommend any one preferred agent, but indicates that IL-1 inhibitors (e.g., anakinra, canakinumab) and IL-6 inhibitors (e.g., tocilizumab) are extremely effective and well-tolerated options. The choice should be based on discussions between the practitioner and patient as routes of administration and frequency vary. The ACR recommends switching between IL-1 and IL-6 inhibitors when needed due to a lack of efficacy or poor tolerability as individual response varies significantly.[95][100][101][102]

Biological agents used in systemic JIA appear safe and comparable with respect to adverse effect risk in the short term.[100] Anakinra has a short half-life, meaning its dose can be adjusted or it can be withdrawn quickly. One randomised controlled trial reported a response rate of 66% to 1 month's treatment with anakinra, compared with 8% to placebo, in children with systemic JIA. After 1 month, 83% of the children receiving placebo were switched to anakinra; 90% of children who switched from placebo responded to anakinra.[103] Canakinumab is effective for treating active systemic JIA.[101][104] Treatment with canakinumab significantly reduces fever and disease activity, compared with placebo.[101] One randomised trial showed a significant reduction in fever and active arthritis in children with systemic JIA refractory to corticosteroids and NSAIDs who were treated with tocilizumab, compared with placebo.[105] Meta-analysis has shown similar efficacy between tocilizumab, canakinumab, and anakinra.[100] One meta analysis of randomised controlled trials found that canakinumab had the highest probability of being the best treatment, in terms of the modified ACR Pediatric 30 (ACRpedi30) response rate, followed by anakinra and tocilizumab.[106]

Serious hepatotoxicity (including acute liver failure, hepatitis, and jaundice) has been identified with tocilizumab. The ACR recommends monitoring ALT or AST at initiation of treatment, within 4 to 8 weeks of treatment and every 3 to 4 months thereafter.[70] Be cautious when considering starting tocilizumab treatment in patients with ALT or AST levels higher than 1.5 times the upper limit of normal. Tocilizumab is not recommended if ALT or AST levels are higher than 5 times the upper limit of normal. If liver enzyme abnormalities are identified, consider a dose modification (reduction, interruption, or discontinuation) according to the manufacturer’s recommendations.[84]

A range of small-scale trials demonstrated resolution of systemic signs following the use of biological agents.[103][105][107][108] With prolonged use, some patients suffered from adverse effects (e.g., infection, neutropenia, and increased aminotransferase levels).[105] The ACR recommends considering tapering and discontinuing biological therapies when the disease is deemed inactive.[95]

Conventional synthetic DMARDs in combination with biological agents can be considered in people with an inadequate response.

Systemic JIA with MAS

Initial treatment includes a biological agent and/or corticosteroid.[95] Biological agent monotherapy may not be sufficient for severely ill patients. Biological agents combined with a corticosteroid and a conventional synthetic DMARD may be necessary to control MAS in some patients.[95] If a combination is used, then it is typically continued until disease control is established. If a patient is receiving both a biological agent or conventional synthetic DMARD and a corticosteroid, the corticosteroid should be tapered and discontinued first before attempting to taper the biological agent or the conventional synthetic DMARD. It is unclear how soon or rapidly these can be safely discontinued in patients with inactive systemic JIA.[95]

Although there are potential effects on bone health and growth, corticosteroids are conditionally recommended by the ACR as part of the initial treatment of acute systemic JIA with MAS.[95][109] Glucocorticoid therapy should be limited to the lowest effective dose for the shortest duration possible, although treatment with high-dose corticosteroids may be required for initial disease control.[95] Long-term corticosteroid therapy in children is not appropriate because of its potential side effects on bone health and growth.[109]

Treatment with biological agents may mask some MAS features and lead to limitations in diagnosis.[110] In children with systemic JIA whose disease is inactive, it may be possible to maintain this inactive disease state with lower doses of, or discontinuation of, biological agents.[111][112] 

Conventional synthetic DMARDs are strongly recommended over long-term corticosteroids for residual arthritis and incomplete response to IL-1 and/or IL-6 inhibitors.[95] There is no preferred agent.[95] The primary conventional synthetic DMARD used for the treatment of systemic JIA is methotrexate. Methotrexate has been commonly used in children with systemic JIA due to its corticosteroid-sparing effect.[113] Although it is used less frequently, it can be given alone or alongside a biological agent to control symptoms. Leflunomide is another conventional synthetic DMARD that can be used in JIA to manage the inflammatory response when methotrexate is not tolerated.[71][114] Tacrolimus, ciclosporin, cyclophosphamide, etoposide, chlorambucil, and azathioprine have been used in the treatment of systemic JIA, but are used less frequently due to the introduction of biological agents.

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