From the Journals

Opinions vary considerably on withdrawing drugs in clinically inactive JIA


A wide range of attitudes and practices for the process of withdrawing medications in pediatric patients with clinically inactive juvenile idiopathic arthritis (JIA) exist among clinician members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA), according to findings from an anonymous survey.

The cross-sectional, electronic survey found that respondents varied in the amount of time they thought was necessary to spend in clinically inactive disease before beginning withdrawal of medications and in the amount of time to spend during tapering or stopping medications, for both methotrexate and biologics.

Dr. Daniel Horton

Dr. Daniel Horton

Many studies of discontinuing therapy after achieving clinically inactive disease have been small and retrospective and have been unable to identify predictors of successful withdrawal of medications, according to the authors of the survey study, led by Daniel B. Horton, MD, of the division of pediatric rheumatology at Rutgers Biomedical and Health Sciences, New Brunswick, N.J. Some of these studies found that discontinuation of biologics with or without methotrexate led to disease flare in one-half to two-thirds of patients within 1 year. Results from one of these smaller retrospective studies found that better outcomes were associated with longer durations of medicated remission and medication taper instead of immediate discontinuation, but the results were not supported by the only published randomized trial on medication discontinuation in JIA, which involved methotrexate. However, two single-center observational studies have shown improved outcomes with the use of medication reduction, rather than discontinuation, using low-dose etanercept, or by continuing biologics after withdrawing methotrexate.

To better understand how clinicians care for patients with clinically inactive disease, the investigators emailed the survey to 388 clinician members of the CARRA in the United States and Canada over a 4-week period during November-December 2015 (J Rheumatol. 2017 Feb 1. doi: 10.3899/jrheum.161078).

The survey, which the investigators thought to be “the first comprehensive evaluation of influential factors and approaches for the clinical management of children with clinically inactive JIA,” did not include questions about systemic JIA, inflammatory bowel disease, psoriasis, and uveitis in order “to simplify responses and encourage participation, because in practice, the manifestations and outcomes of these diseases could substantially influence treatment decisions for children with JIA.”

They received complete responses from 124 of the 132 clinicians who responded to the survey email. Of the 121 respondents who reported taking clinical care of patients with JIA, 87% were physicians, and the same number reported taking care of pediatric patients only. About three-quarters spent half of their professional time in clinical care, and about half had more than 10 years of post-training clinical experience.

When deciding about withdrawing JIA medications, more than one-half of respondents said that the time that a patient spent in clinically inactive disease and a history of drug toxicity are very important factors. Most participants ranked those two factors most highly and most often among their top five factors for decision making.

Respondents also commonly ranked these factors as important:

  • JIA duration before attaining clinically inactive disease.
  • Patient/family preferences.
  • Presence of JIA-related damage.
  • JIA category.

The factors that consistently appeared in responses fit into three clusters that included JIA features and time spent in clinically inactive disease (JIA category and total disease duration), JIA severity and resistance to treatment (disease duration before clinically inactive disease, number of drugs needed to attain inactivity, joint damage, and a history of sacroiliac or temporomandibular disease), and the patient’s experience (drug toxicity and family preference).

The respondents indicated that they would be least likely to stop medications for children with rheumatoid factor (RF)–positive polyarthritis (85%), which is “consistent with prior studies showing that RF-positive polyarthritis is associated with higher rates of flares than other JIA categories,” the investigators wrote. However, respondents said they would be most likely to stop medications for children with persistent oligoarthritis (87%) “even though rates of flares in this category appear similar to other JIA types. This method may reflect a belief that flares in children with persistent oligoarticular JIA will be less severe and easier to control.”

When patients met all criteria for clinically inactive disease for a “sufficient amount of time” and families were interested in stopping medications, some factors continued to make respondents reluctant to withdraw medications. These factors were most often a history of erosions (81%), asymptomatic joint abnormalities on ultrasound or MRI (72%), and failure of multiple prior disease-modifying antirheumatic drugs or biologics to control disease (64%). The definition of clinically inactive disease is a composite of no active arthritis, uveitis, or systemic JIA symptoms; the best possible clinical global assessment; inflammatory markers normal or elevated for reasons other than JIA; and no more than 15 minutes of joint stiffness.

A little over half of respondents said they would wait until clinically inactive disease had lasted 12 months before considering stopping or tapering methotrexate or biologic monotherapy, but a substantial minority said they would wait for only 6 months for methotrexate (31%) or biologic monotherapy (23%). A smaller number would wait for 18 months for methotrexate (13%) or biologics (18%), and another 3%-5% said they could not give a time frame.

The strategies varied for how actual withdrawing of medications occurred. Most methotrexate monotherapy withdrawals involved tapering over 2-6 months, one-third over longer periods, and the fewest reported tapering for less than 2 months (7%) or immediate withdrawal (17%).

Withdrawal of biologics was generally said to occur more gradually than with methotrexate, with one-third of respondents citing over 2-6 months, a quarter more slowly, and another 29% in less than 2 months or immediately. Some wrote that they preferred spacing out the interval between doses, but none decreased the dose. When children took combination therapy with methotrexate plus a biologic, 63% said that they began tapering or stopping methotrexate first, but a quarter said that the order was strongly context dependent, and the most commonly cited reason for deciding was history of toxicity or intolerance.

Imaging played a role in less than half of the decisions to withdraw medications, with it being used often by 9% and sometimes by 36%. And while it’s assumed that patients and family consideration played an important role in decision making, only 25% of respondents reported using specific patient-reported outcomes in deciding to withdraw medications.

The study was funded by grants from Rutgers Biomedical and Health Sciences and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

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