In the recent years, treatment options and outcomes for patients with juvenile idiopathic arthritis (JIA) have improved considerably. These changes have been attributed to the availability of biologic therapies and the increasing efforts to move toward a treat-to-target approach in JIA management. In addition, with a greater clarity regarding criteria, clinical remission and minimally active disease have become more achievable for patients. Also, clinical trial results now have greater reproducibility.1

However, the lack of treatment response in a significant number of patients with JIA has resulted in poor disease outcomes for this population. A “[percentage] of patients with polyarticular disease are still refractory to multiple treatments, and, more recently, some patients with systemic JIA are developing a form of interstitial lung disease, which is a cause for concern,” said Professor A.V. Ramanan, FRCPCH, FRCP, consultant pediatric rheumatologist at the Bristol Royal Hospital for Children & Royal National Hospital for Rheumatic Diseases, and professor of pediatric rheumatology at the University of Bristol, UK. 

“It is important to understand the reasonably good evidence base for therapies currently available, as the appropriate use of biologics and timely intervention in refractory patients are key to effective management of JIA,” he told us in an interview.


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Murray, Sen, and Ramanan published a review, in April 2021 in Lancet Rheumatology,1 in which they described the latest treatment updates, emerging therapies, and ongoing needs in the realm of JIA.

Polyarticular-Course JIA

For patients with polyarticular-course JIA, methotrexate is often used in combination with biologics “to potentiate their effect and to reduce the likelihood of developing antidrug antibodies that can impact drug efficacy,” the authors of the review wrote.1 Among children and adolescents with JIA and polyarthritis initiating treatment with a biologic (etanercept, adalimumab, golimumab, abatacept, or tocilizumab), the American College of Rheumatology (ACR) 2019 guidelines recommend combination therapy with a disease-modifying antirheumatic drug (DMARD) over biologic monotherapy.2

In September 2020, the US Food and Drug Administration (FDA) announced the approval of intravenous golimumab for the treatment of polyarticular and psoriatic JIA.3

An ongoing trial (PASCAL study; ClinicalTrials.gov Identifier: NCT01550003) is investigating the use of certolizumab pegol, a pegylated antitumor necrosis factor (TNF) α inhibitor, for the treatment of polyarticular JIA. Studies have found that pegylation enhances the half-life of the drug and allows for a 2- to 4-week dosing schedule.1,4

In a 2019 study, researchers pooled safety and tolerability data from 21 randomized controlled trials of the anti-interleukin (IL)-17A biologic secukinumab in more than 7000 adults with psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis. Results demonstrated a favorable long-term safety profile of secukinumab in psoriasis, PsA, and AS.5

An ongoing phase 3 trial (ClinicalTrials.gov Identifier: NCT03031782) is investigating the effect of secukinumab on time to flare in pediatric patients with PsA and enthesitis-related arthritis.6

In September 2020, the Janus kinase (JAK) inhibitor tofacitinib received FDA approval for the treatment of active polyarticular-course JIA.7 Findings from a phase 3 trial showed that improvements in Childhood Health Assessment Questionnaire scores were greater than the minimal clinically important difference in 48.4% of children with polyarticular-course JIA receiving tofacitinib, and physical wellbeing scores increased to a healthy, normative range.8

An open-label trial (ClinicalTrials.gov Identifier: NCT03725007) is currently underway to investigate the pharmacokinetics, safety, and tolerability of the JAK inhibitor upadacitinib in pediatric patients with polyarticular-course JIA.9

Systemic JIA

The IL-1 receptor antagonist anakinra has been approved by the European Medicines Agency (EMA) as a first-line monotherapy for the treatment of systemic JIA.1 In a 2019 review of 27 studies (N=446 patients), 23% to 88% of patients showed a clinically meaningful response to anakinra. Glucocorticoid tapering and discontinuation were achieved in 29% to 67% of patients and 5% to 71% of patients, respectively.10

The IL-1β inhibitor canakinumab and the IL-6 inhibitor tocilizumab have received EMA and FDA approval for systemic JIA treatment,1 and a trial (ClinicalTrials.gov Identifier: NCT02776735) investigating the IL-6 inhibitor sarilumab for this indication is ongoing in children and adolescents aged between 2 and 17 years.11

Compared with TNF inhibitors, anakinra, canakinumab, and tocilizumab were all linked to more favorable JIA-ACR pediatric (Pedi) 30/50/70/90 responses over a period of 24 months, according to results of a German registry study.12

Serum IL-18 levels may be correlated to disease activity in systemic JIA. An ongoing trial (ESTIS study; EudraCT Number: 2015-004393-16) is evaluating IL-18 levels in the facilitation of clinical decisions regarding the timing of anakinra discontinuation in patients with systemic JIA.13

Emerging reports have also suggested the potential benefits of the exogenous IL-18 binding protein in the treatment of refractory systemic JIA. Therapies targeting the Th17 pathway represent another possible focus of research for this population.1

Ongoing trials are examining the efficacy of tofacitinib and baricitinib for patients with systemic JIA.1

In addition, a phase 2 open-label, single-arm trial (ClinicalTrials.gov Identifier: NCT03311854) is currently investigating the use of emapalumab in pediatric patients with systemic JIA and macrophage activation syndrome. Preliminary findings showed that patients had a rapid reduction in CXCL9 levels, weaning of corticosteroids, and a complete clinical response by week 8.14

JIA-Associated Uveitis

Ramanan and colleagues conducted a study15 in which adalimumab combined with methotrexate demonstrated positive effects in patients with JIA-associated uveitis; 57% of patients who received this combination therapy (vs 17% of those who received placebo) showed a response in the post-hoc analysis of the SYCAMORE trial (EudraCT Number: 2010-021141-41).

In another trial of 25 patients, tocilizumab was associated with improved uveitis activity in 68% of patients at 3 months and 88.2% of patients at 12 months, with significant reductions in the dose of daily median prednisolone. Two patients discontinued tocilizumab use due to adverse events, including thrombocytopenia.16

Results of several small studies of abatacept for refractory JIA-associated uveitis have been mixed.

A small case series indicated positive results with JAK inhibitors among patients with JIA-associated uveitis. A trial (ClinicalTrials.gov Identifier: NCT04088409) is underway to compare the effects of baricitinib vs subcutaneous adalimumab in children with JIA-associated uveitis.17

“There are many additional research needs in this area,” Prof Ramanan noted. “The ‘holy grail’ remains personalized medicine to help use the right drug for the right patient at the right time,” he added. “We need effective biomarkers to classify patients, identify those at greatest risk [for] disease progression and damage, and target the most appropriate drug for each patient.”

Disclosures: Prof Ramanan declared affiliations with the pharmaceutical industry.

References

  1. Murray GM, Sen ES, Ramanan AV. Advancing the treatment of juvenile idiopathic arthritis. Lancet Rheumatol. 2021;3(4):294-305. doi:10.1016/s26659913(20)30426-4
  2. Ringold S, Angeles-Han ST, Beukelman T, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the treatment of juvenile idiopathic arthritis: therapeutic approaches for non-systemic polyarthritis, sacroiliitis, and enthesitis. Arthritis Care Res (Hoboken). 2019;71(6):717-734. doi:10.1002/acr.23870
  3. SIMPONI ARIA® (golimumab) approved by the U.S. Food and Drug Administration for active polyarticular juvenile idiopathic arthritis and extension of its active psoriatic arthritis indication in patients 2 years of age and older. News Release. PR Newswire. Published September 30, 2020. Accessed April 29, 2021. https://www.prnewswire.com/news-releases/simponi-aria-golimumab-approved-by-the-us-food-and-drug-administration-for-active-polyarticular-juvenile-idiopathic-arthritis-and-extension-of-its-active-psoriatic-arthritis-indication-in-patients-2-years-of-age-and-older-301141976.html
  4. Pediatric Arthritis study of certolizumab pegol (PASCAL). ClinicalTrials.gov Identifier: NCT01550003. Updated February 21, 2021. Accessed April 29, 2021. https://clinicaltrials.gov/ct2/show/NCT01550003
  5. Deodhar A, Mease PJ, McInnes IB, et al. Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data. Arthritis Res Ther. 2019;21:111. doi:10.1186/s13075-019-1882-2
  6. Secukinumab safety and efficacy in juvenile psoriatic arthritis (JPsA) and enthesitis-related arthritis (ERA). ClinicalTrials.gov Identifier: NCT03031782. Updated April 9, 2021. Accessed April 29, 2021. https://clinicaltrials.gov/ct2/show/NCT03031782
  7. FDA approves Pfizer’s XELJANZ® (tofacitinib) for the treatment of active polyarticular course juvenile idiopathic arthritis. News release. Business Wire US. Published September 28, 2020. Accessed April 29, 2021. https://www.businesswire.com/news/home/20200928005729/en/
  8. Brunner H, Synoverska O, Ting T, et al. Tofacitinib for the treatment of polyarticular course juvenile idiopathic arthritis: results of a phase 3 randomized, double-blind, placebo-controlled withdrawal study [abstract]. Arthritis Rheumatol. 2019;71(suppl 10).
  9. A study to evaluate the pharmacokinetics, safety, and tolerability of upadacitinib in pediatric subjects with polyarticular course juvenile idiopathic arthritis. ClinicalTrials.gov Identifier: NCT03725007. Updated January 6, 2021. Accessed April 29, 2021. https://clinicaltrials.gov/ct2/show/NCT03725007
  10. Vastert SJ, Jamilloux Y, Quartier P, et al. Anakinra in children and adults with Still’s disease. Rheumatology (Oxford). 2019;58(suppl 6):9-22. doi:10.1093/rheumatology/kez350
  11. An open-label, ascending, repeated dose-finding study of sarilumab in children and adolescents with polyarticular-course juvenile idiopathic arthritis (pcJIA) (SKYPP). ClinicalTrials.gov Identifier: NCT02776735. Updated February 9, 2021. Accessed April 30, 2021. https://www.clinicaltrials.gov/ct2/show/NCT02776735
  12. Horneff G, Schulz AC, Klotsche J, et al. Experience with etanercept, tocilizumab and interleukin-1 inhibitors in systemic onset juvenile idiopathic arthritis patients from the BIKER registry. Arthritis Res Ther. 2017;19:256. doi:10.1186/s13075-017-1462-2
  13. ESTIS trial: early stop of targeted treatment in children with systemic JIA. EU Clinical Trials Register. EudraCT Number: 2015-004393-16. Accessed April 30, 2021. https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-004393-16/NL
  14. A study to investigate the safety and efficacy of an anti-IFN-gamma mab in children with systemic juvenile idiopathic arthritis (sJIA) developing macrophage activation syndrome/secondary hemophagocytic lymphohistiocytosis (MAS/sHLH). ClinicalTrials.gov Identifier: NCT03311854. Updated January 6, 2021. Accessed April 30, 2021. https://clinicaltrials.gov/ct2/show/NCT03311854
  15. Ramanan AV, Dick AD, Jones AP, et al; for the SYCAMORE Study Group. Adalimumab plus methotrexate for uveitis in juvenile idiopathic arthritis. N Engl J Med. 2017;376:1637-1646. doi:10.1056/NEJMoa1614160
  16. Calvo-Río V, Santos-Gómez M, Calvo I, et al. Anti-interleukin-6 receptor tocilizumab for severe juvenile idiopathic arthritis-associated uveitis refractory to anti-tumor necrosis factor therapy: a multicenter study of twenty-five patients. Arthritis Rheumatol. 2017;69:668-675. doi:10.1002/art.39940
  17. A study of baricitinib (LY3009104) in participants from 2 years to less than 18 years old with active JIA-associated uveitis or chronic anterior antinuclear antibody-positive uveitis. ClinicalTrials.gov Identifier: NCT04088409. Updated April 19, 2021. Accessed April 29, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04088409