PRSYM—The treatment of juvenile idiopathic arthritis (JIA) requires consideration of two competing yet equally important aspects: how to aggressively treat and prevent morbidity of disease, and how to appropriately withdraw treatment to avoid side effects while maintaining disease remission. During the virtual 2021 Pediatric Rheumatology Symposium (PRSYM), a series of speakers covered these topics in detail.
Factors in Treatment
Richard Fuhlbrigge, MD, PhD, professor and section head of pediatric rheumatology, Children’s Hospital Colorado, Aurora, began the session by describing an evidence-based approach to the care of patients with JIA. He noted that, in 2019, the ACR and Arthritis Foundation jointly published a guideline for the treatment of JIA in patients with polyarthritis, sacroiliitis and enthesitis.1
According to the guideline, untreated JIA with active polyarthritis refers to patients with five or more joints involved and can include patients with and without positive rheumatoid factor; patients with extended oligoarthritis, enthesitis-related arthritis or psoriatic arthritis; and patients with undifferentiated disease. In patients with untreated JIA with active polyarthritis, initial treatment should include a single disease-modifying anti-rheumatic drug (DMARD) over non-steroidal anti-inflammatory drug (NSAID) monotherapy. Methotrexate is the preferred first-line DMARD. Adjunctive therapies may include NSAIDs, intra-articular glucocorticoids, physical and/or occupational therapy, and bridging therapy with a limited course of oral glucocorticoids lasting less than three months. Each of these recommendations was given a “very low” grade by the guideline developers in terms of strength of evidence.
Dr. Fuhlbrigge also discussed variables that influence treatment options: clinical features, laboratory and imaging parameters, and medication characteristics.
When assessing a patient, rheumatologists must first consider the clinical features, such as the presence or absence of systemic symptoms, the number and distribution of joints involved, and the patient’s age, pubertal status and comorbidities. Second, rheumatologists should consider laboratory and imaging parameters, including autoantibodies, acute phase reactants, genetic markers and the presence or absence of synovitis, enthesitis and erosive joint disease. Third, rheumatologists must evaluate the characteristics of medications, including weighing the risks and benefits of corticosteroids—whether systemic or intra-articular—conventional DMARDs, biologic DMARDs and combination therapies.
When choosing DMARD therapy, rheumatologists must apply best practices in medication selection, and optimal use of these medications must take into account dosing, route of administration, timing and pharmacogenomics. Although not always available, data on comparative effectiveness can help indicate if individual or combination therapies are warranted and may allow for comparisons between generic and biosimilar treatments with brand-name medications. The long-term safety and biologic effect of individual, sequential and combination therapies must also be examined, as well as the potential for loss of efficacy and the ability to plan for medication withdrawal.
With regard to tracking disease activity, the Clinical Juvenile Arthritis Disease Activity Score-10 (cJADAS-10) includes a physician global assessment, parent/guardian or patient global assessment and number of joints with active arthritis up to a maximum of 10. Dr. Fuhlbrigge explained that the cJADAS-10 can be used to determine if a patient has low, moderate or high disease activity, allowing for treat-to-target approaches that may help improve patients’ quality of life and prevent damage from their disease.
Dosing Optimization
Ruud Verstegen, MD, PhD, assistant professor and clinical investigator in the Division of Clinical Pharmacology and Toxicology, Division of Rheumatology, The Hospital for Sick Children, Toronto, discussed treatment optimization. He noted that although many treatment options exist for patients with JIA, 33% of patients won’t respond to a given treatment and 5–10% of patients will have loss of response over the course of a year. Response and lack or loss of response are dictated by the interplay between the characteristics of the patient, the disease and the pharmacotherapeutic elements of the medication in question.
An important difference in the dosing of medications, such as adalimumab and etanercept, for pediatric vs. adult patients is the use of weight-based dosing. For adalimumab and similar medications, a specific dose is given every other week for patients who fall into a range of weights. Thus, a patient at the lower end of the weight range will receive a higher mg/kg dose of adalimumab than a patient at the upper end of the weight range who is getting the same absolute dose.
Dr. Verstegen has studied real-world dosing variations and evaluated for correlation with treatment response. In patients studied from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, Dr. Verstegen and his team found that, for each mg/kg dose increase with adalimumab or etanercept, there was no change in the odds ratio for achieving low disease activity via cJADAS-10. (Note: This study has not been published.)
With respect to therapeutic drug monitoring, Dr. Verstegen showed a schematic that may be helpful to clinicians. In cases of treatment failure (i.e., non-response or loss of response), the first step is to measure a trough serum drug concentration. If this trough is detectable, then the best next step would be to switch the class of the medication. If the trough is undetectable, then anti-drug antibodies can be measured. If anti-drug antibodies are negative, then this finding may mean the issue is treatment adherence or an inappropriately low dose for that patient. This factor can be corrected by encouraging adherence or increasing the dose. If anti-drug antibodies are positive, then it may be worthwhile to switch to a treatment within the same class of medication.
Treatment Withdrawal
Finally, medication withdrawal was discussed by Daniel Horton, MD, MSCE, assistant professor of pediatrics and epidemiology, Rutgers Robert Wood Johnson Medical School and Rutgers School of Public Health, New Brunswick, N.J. Dr. Horton provided a conceptual model to consider regarding medication withdrawal after achieving disease inactivity in patients with JIA. This model is based on four elements:
- Factors associated with flare after withdrawal;
- Strategies for treatment withdrawal;
- Timing of withdrawal and use of biomarkers; and
- Shared decision making with patients and their families.
Factors associated with flare after withdrawal may include anti-nuclear antibody positivity, older age at uveitis diagnosis, delay of initiation of biologic therapy, delay in achieving inactive disease and the need for biologic therapy. Dr. Horton noted many methods may be used to withdraw treatment, including stopping treatment immediately, tapering and changing the interval of dosing. Evidence indicates fewer flares occur in patients on combination therapy if methotrexate is stopped before discontinuing treatment with a tumor necrosis factor-α inhibitor.2,3
With respect to when to initiate withdrawal, Dr. Horton predicted biomarkers will become available in the not-too-distant future to help predict which patients would do well with treatment withdrawal. He concluded by advocating for patients and their families to be actively involved in all treatment withdrawal decisions.
In Sum
On the whole, the session focused on important issues in the management of JIA. As the field continues to evolve, new evidence may become available to help rheumatologists optimize treatment and guide tapering decisions.
Jason Liebowitz, MD, completed his fellowship in rheumatology at Johns Hopkins University, Baltimore, where he also earned his medical degree. He is currently in practice with Skylands Medical Group, N.J.
References
- 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 Rheumatol. 2019 Jun;71(6):846–863. Epub 2019 Apr 25.
- Chang CY, Meyer RM, Reiff AO. Impact of medication withdrawal method on flare-free survival in patients with juvenile idiopathic arthritis on combination therapy. Arthritis Care Res (Hoboken). 2015 May;67(5):658–666.
- Horton DB, Onel KB, Beukelman T, et al. Attitudes and approaches for withdrawing drugs for children with clinically inactive nonsystemic JIA: A survey of the Childhood Arthritis and Rheumatology Research Alliance. J Rheumatol. 2017 Mar;44(3):352–360. Epub 2017 Feb 1.
