Over the past two decades, the treatment of juvenile idiopathic arthritis (JIA) has undergone significant changes, with an increasing number of new, effective, and relatively safe therapeutics promoting early remission of the disease. At present, more and more attention has been paid to the study of the optimal time and method of drug discontinuation for children with JIA to achieve sustained clinical remission. In this context, foreign scholars summarize the current evidence and discuss the treatment of non-systemic JIA, including oligoarticular JIA, polyarticular JIA, enthesitis-associated arthritis, and psoriatic arthritis. The editor excerpts some of them for compilation, hoping to provide some help for your clinical diagnosis and treatment.
General principles
According to the 2019 and 2021 ACR guidelines, the following treatment strategies can be used to treat non-systemic JIA with different clinical phenotypes.
Non-steroidal anti-inflammatory drugs and intra-articular glucocorticoid injections
Nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular glucocorticoid injections are recommended as first-line treatment for oligoarticular JIA, sacroiliitis, and enthesitis, and as an adjunct to polyarticular JIA.
- Non-steroidal anti-inflammatory drugs: reduce pain and joint stiffness, improve joint function, but do not have disease-modifying effects. Although there are many options for NSAIDs, naproxen (15 to 20 mg/kg/day), which is administered twice daily, is usually the drug of choice for the treatment of nonsystemic JIA.
- Intra-articular glucocorticoid injections: hexatriamcinolone acetonide is preferred because of its longer-lasting efficacy. Repeated injections can be given as needed. While there are no established guidelines outlining the following practices, most rheumologists generally limit the frequency of repeated injections to three times per year, with at least 3 months between injections. Intra-articular injections in young children carry risks of general anesthesia.
csDMARDs
Traditional synthetic DMARDs (csDMARDs): oligoarticular JIA is started in the setting of poor first-line treatment and as an initial treatment for polyarticular JIA. Methotrexate (MTX) is the preferred csDMARD and can be injected subcutaneously or orally. For patients with enthesitis-related arthritis, particularly in the setting of sacroiliitis, sulfasalazine is usually the preferred csDMARD.
bDMARDs
Typically TNF inhibitors recommended for patients who do not respond well to (or are intolerant) to csDMARDs, or as part of an initial regimen for patients with high disease activity who have polyarticular JIA and have specific risk factors. These patients include those with certain risk factors (positive for rheumatoid factor and/or anticyclic citrullinated peptide antibodies), joint injury, involvement of axial joints, sacroiliac joints, or other high-risk joints (e.g., cervical, wrist, or hip) and/or enthesitis despite treatment with nonsteroidal anti-inflammatory drugs and/or those who are judged by physicians to be at high risk of disability from joint injury. However, due to the emergence of anti-drug antibodies in vivo, the effectiveness of bDMARDs decreases over time, and preventing this phenomenon is an important area of future research.
JAK inhibitors
Although the efficacy and safety of some Janus kinase (JAK) inhibitors have been demonstrated in randomized controlled trials conducted over the past 3 years, and some of these inhibitors have been approved or are awaiting approval for the treatment of JIA, formal guidelines or recommendations do not clarify the place of targeted synthetic DMARDs in the treatment of JIA.
Oral glucocorticoids
It should be used with caution due to its poor safety profile. When these drugs are used for rapid control of severe symptoms (e.g., when intra-articular glucocorticoid injections are not available or appropriate, or as bridging therapy prior to dDMARD, or when disease flares up), they should be limited to the lowest effective dose and for the shortest possible duration.
Target treatment
Attainment therapy has been identified as a possible approach to improve the prognosis of chronic arthritis. This strategy promotes shared decision-making around specific goals (ideally clinical remission, but low disease activity may be present in some patients). Assessment modalities include JIA clinical inactive disease or minimal disease activity criteria, juvenile arthritis disease activity score (JADAS) cut-off value. At each visit, determine whether the patient is meeting the target, and then adjust the treatment to achieve the goal as needed for the condition.
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Oligoarticular JIA
According to the ACR 2021 guidelines for the treatment of oligoarticular JIA, NSAIDs have potential adverse effects and limited efficacy, so it is recommended to use NSAIDs for a short time during initial treatment. Intra-articular glucocorticoid injections are highly recommended as part of the initial treatment of active oligoarthritis. A randomized, open-label trial suggests that concomitant oral MTX may prolong and, to a lesser extent, increase the effectiveness of intra-articular glucocorticoid injections in the treatment of oligoarticular form.
Treatment with csDMARDs is recommended in cases of poor response to non-steroidal anti-inflammatory drugs or intra-articular glucocorticoid injections. Treatment decisions can be guided by a variety of risk factors associated with poor outcomes, including involvement of the ankle, wrist, hip, sacroiliac joint, and/or temporomandibular joints, joint erosion or enthesitis, delayed diagnosis, elevated levels of inflammatory markers, and symmetrical disease.
NSAIDs or intra-articular glucocorticoid injections are sufficient to treat temporomandibular arthritis in some patients, but given the destructive power of arthritis in these joints, rapid escalation to bDMARDs (possibly in combination with csDMARDs) is often necessary, although evidence is limited. In the 2022 consensus-based interdisciplinary recommendations for the treatment of oral-facial manifestations of JIA, intra-articular glucocorticoid injections are not recommended as a first-line treatment for temporomandibular arthritis in patients with osteoimmature bones, nor are repeated glucocorticoid injections recommended.
- In a retrospective analysis of 370 patients with persistent oligoarticular disease who received MTX for the first time using the German BIKER database, 44% and 33% of patients achieved JADAS minimal disease activity (JADAS-10≤2) and JADAS remission (JADAS-10≤1), respectively, after 24 months of treatment. The proportion of optimal disease control seen in the BIKER study was lower than expected, suggesting that a significant proportion of children with oligoarticular disease may require early introduction of bDMARDs to achieve complete disease quiescence.
- An open-label, multicenter, phase III trial evaluating the efficacy of abatacept in patients with recently onset localized JIA is ongoing, administered subcutaneously once a week, to determine whether weekly abatacept injections (for 24 weeks) compared with usual care prevent patients from progressing to polyarticular disease, developing uveitis, or requiring other systemic medications.
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Polyarticular JIA
In the 2019 guidelines, the ACR made various recommendations for the treatment of polyarticular JIA.
In all patients with polyarticular JIA, initial treatment is recommended with DMARDs rather than NSAIDs monotherapy. Patients without risk factors should be started on DMARD therapy alone.
The addition of bDMARDs to the initial approach to therapy may be preferred for patients with comorbid risk factors, high-risk joints, and/or those who are judged by physicians to be at high risk of disability from joint injury.
MTX is recommended as the preferred DMARD. If MTX is inadequate or intolerant, other csDMARDs, such as leflunomide or sulfasalazine, may be considered on a case-by-case basis. Currently, there is limited evidence on the efficacy of triple therapy for JIA. For patients whose disease remains active after initial therapy, subsequent treatment should be individualized based on the level of disease activity. The JIA clinical disease activity assessment > 2.5 was moderate and high disease activity, the JIA clinical disease activity assessment was ≤ 2.5, and ≤ one active arthritis was low disease activity.
- Although an increasing number of bDMARDs with different targets can be used to treat polyarticular JIA, there are no trials evaluating these drugs head-to-head to guide clinicians on which drug is preferable in which clinical situation. A meta-analysis of randomized withdrawal trials of five bDMARDs (abatacept, adalimumab, anakinra, etanercept, and tocilizumab) for the treatment of polyarticular JIA showed no difference in efficacy or safety.
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Enthesitis-related arthritis
The 2019 ACR guidelines for children with JIA provide some guidance for the treatment of sacroiliitis and enthesitis, but the level of evidence is low.
Most children with enthesitis-associated arthritis usually have less joint involvement, and treatment is similar to that of oligoarticular arthritis. Hip disease and sacroiliitis are risk factors for poor prognosis.
NSAIDs provide good pain relief and disease control in 20 to 30% of patients (with or without enthesitis-related arthritis), and patients with active disease who have a small number of peripheral joint involvement may benefit from intra-articular glucocorticoid injections.
Patients with peripheral arthritis should be given adequate doses of csDMARDs, such as sulfasalazine or MTX. TNF inhibitor therapy is recommended if peripheral arthritis does not respond to csDMARD therapy, or if the patient still has active sacroiliitis despite NSAID therapy.
- IL-17 inhibitors and JAK inhibitors have achieved encouraging results in clinical trials for enthesitis-associated arthritis, which will expand treatment options for enthesitis-associated arthritis. Future studies will determine whether these drugs should be used after TNF inhibitor failure, or as an alternative to first-line biologic therapy.
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Psoriatic arthritis
The concept and classification of PsA in childhood remain controversial. Current ILAR criteria define juvenile PsA as arthritis and psoriasis occurring together, or, in the absence of a psoriasis rash, arthritis with at least two of the following: dactylitis, nail depression or nail detachment, or psoriasis in a first-degree relative. Therefore, children with features of spondyloarthropathy are excluded. However, there is evidence that in childhood, arthritis with psoriasis includes at least two separate groups of patients: the first group has the same features as early-onset ANA-positive JIA, with the main features of increased frequency of dactylitis and facet joint involvement, and arthritis is more rapidly involved than early-onset ANA-positive JIA, and the other group is very similar to adult PsA and is part of the spondyloarthropathy spectrum.
Randomised controlled trials of bDMARDs in juvenile PsA are ongoing. Current recommendations for the management of juvenile PsA are based on extrapolation of the results of RCTs of polyarticular JIA and adult PsA, as well as reports of experience with psoriasis, adult PsA, and other types of JIA. As with other JIA categories, the treatment of adolescent PsA should take into account the clinical heterogeneity of JIA and develop an individualized approach to the unique disease phenotype.
It is uncertain whether local corticosteroids should be injected or MTX or bDMARDs should be used for dactylitis. Although evidence is lacking, clinical experience suggests that ultrasound-guided injection of glucocorticoids into the flexor finger sheath usually results in resolution of extra-articular inflammation.
For the treatment of juvenile PsA with TNF inhibitors, most evidence suggests that etanercept can be used for juvenile PsA. A extrapolated analysis of golimumab therapy supported intravenous golimumab for juvenile PsA, prompting the FDA to approve intravenous golimumab for juvenile PsA ≥ 2 years of age.
When concomitant treatment of coexisting psoriasis is being considered, selective IL-17 inhibitors may be a better option. Currently, secukinumab has been approved by the FDA for the treatment of PsA in adolescents ≥ 2 years of age, and by the European Medicines Agency for the treatment of refractory PsA and ankylosing spondylitis in adults. In addition, a multicenter, open-label trial is ongoing on the efficacy and safety of ixekizumab, another IL-17 inhibitor, in juvenile PsA. Ustekinumab, an inhibitor targeting IL-12 and IL-23, was approved by the FDA in 2022 for the treatment of juvenile PsA ≥ 6 years of age.
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Withdrawal
Currently, there is no consensus on whether or how to try discontinuation in patients who achieve remission. The trial designs of JIA discontinuation studies varied widely, and in addition, most studies were observational, retrospective, and/or involved only one study center. Maintenance of disease remission after discontinuation requires better assessment to detect mild disease activity and ensure that the patient is in true clinical remission.
A prospective study based on a biomarker-guided JIA discontinuation strategy (the PREVENT-JIA trial) found that stratification through the use of biomarkers, such as high-sensitivity C-reactive protein and S100A12, may improve the prediction and success of discontinuation compared to traditional discontinuation methods. Patients in the biomarker risk stratification group discontinued the drug earlier and had a longer interval between first episodes after discontinuation compared with the traditional approach (hazard ratio 0.62, 95% CI 0.38-0.99). Although this biomarker-guided withdrawal strategy shows promise and feasibility, the factors associated with subclinical status that promote disease activity need to be further explored.
Therefore, caution should be exercised when attempting to discontinue and/or discontinue the drug in patients with polyarticular JIA, particularly those who are rheumatoid factor-positive. A review of recurrence rates after discontinuation of bDMARDs in patients with non-systemic JIA revealed a 12-month recurrence rate of 60% to 78%, with a median time to recurrence of 3 to 10 months. HOWEVER, IN THE RECAPTURE CARRA STUDY, THE RECURRENCE RATE AT 12 MONTHS AFTER DISCONTINUATION WAS ONLY 50% IN RHEUMATOID FACTOR-POSITIVE POLYARTICULAR PATIENTS AND 59% IN RHEUMATOID FACTOR-NEGATIVE POLYARTICULAR OR EXTENDED OLIGOARTHRITIS.
Bibliography:
Shenoi S, Horneff G, Aggarwal A, Ravelli A. Treatment of non-systemic juvenile idiopathic arthritis. Nat Rev Rheumatol. 2024 Mar; 20(3):170-181. doi: 10.1038/s41584-024-01079-8.
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