Juvenile Arthritis: Pattern of Drug Withdrawal Affects Flare

Veronica Hackethal, MD

October 06, 2014

Children with juvenile idiopathic arthritis (JIA) or juvenile enthesitis-related arthritis (ERA) who attain remission while receiving combination therapy are less likely to flare when withdrawing methotrexate (MTX) first compared with withdrawing tumor necrosis factor inhibitors (TNFis) first, according to a study published online September 12 in Arthritis Care & Research.

"This is the first study in JIA examining the impact of therapy withdrawal methods on long-term outcome in children on MTX and TNFi [combination therapy]," write Caroline Chang, MD, a physician in Hawaii, and colleagues.

"Despite early initiation and continuation of TNFi for long periods after achieving inactive disease, relapse rates of all patients requiring TNFi remain high, suggesting that TNFi therapy, while effective, does not change the underlying disease process."

Combination therapy for JIA with TNFi and MTX is well-established, although concerns exist regarding the long-term safety, efficacy, cost, and toxicity of TNFis. MTX is generally well-tolerated, but it also has adverse effects, the authors write. These concerns have led to interest in determining the appropriate method of withdrawal for these medications. No current guidelines exist for tapering medications in JIA after remission, and limited data exist on long-term outcomes.

The retrospective observational study included 335 patients with JIA or ERA, defined according to 2001 International League of Associations for Rheumatology JIA classification criteria. The study took place at Children's Hospital in Los Angeles, California, from January 2000 through December 2011. At this institution, children with inadequate response at 1 to 3 months are usually started on MTX plus TNFi. Children with advanced disease at diagnosis usually receive TNFi immediately. Methods vary for the withdrawal of medications on remission.

Researchers extracted information from patient charts and analyzed patients according to four withdrawal groups: group 1, TNFi plus MTX, with MTX withdrawn first; group 2, TNFi plus MTX, with TNFi withdrawn first; group 3, withdrawal of MTX monotherapy; and group 4, withdrawal of TNFi monotherapy.

Patients had a mean age of 11 years and a mean follow-up of about 4 years and were 68% female and 54% Hispanic. Sixty-four percent of patients achieved remission during a mean of 21.5 months.

Among those receiving combination therapy, 89% of those who withdrew TNFis first flared within 12 months, even though they continued receiving MTX. Only 12% of those who withdrew MTX first and continued TNFi flared within 12 months (P < .0005). This was significant in both rheumatoid factor–positive and rheumatoid factor–negative JIA (P < .005 and P < .012, respectively) and "seemed grossly true in ERA," the authors note.

Among those who discontinued TNFi monotherapy, 78% flared within 12 months. Among those who withdrew MTX monotherapy, 50% flared within 12 months. These results could have been influenced by less severe disease among those receiving MTX monotherapy, the authors note.

Twenty-seven percent of patients were able to withdraw all medications. Of these, 63% of these flared within 12 months, and only 49% of them were able to regain remission within 12 months of restarting therapy.

"Once all medications were discontinued, there was no difference in [flare-free survival] between the [combination therapy] groups," the authors add.

Disease subtype, rheumatoid factor status, initial erythrocyte sedimentation rate, initial joint count, corticosteroid exposure, time in remission, and method of medication discontinuation did not significantly affect flare-free survival.

The authors offer several recommendations that may contrast with those for adult rheumatoid arthritis:

  • Patients with JIA who are in remission while receiving combination therapy should discontinue MTX first, rather than TNFis.

  • Depending on tolerability, consider tapering the TNFi by decreasing injection frequency.

  • Maintain remission for at least 6 months before attempting to taper the TNFi.

  • Use a low threshold for restarting TNFis after discontinuation.

Because of high rates of relapse, "it may be prudent to maintain patients on lower doses and/or frequency of medications rather than completely discontinuing them, as these periods of disease flare often affect long-term outcome and quality of life," the authors advise.

"There is no most accepted way to take children off [rheumatoid arthritis] drugs," Andrew White, MD, told Medscape Medical News. Dr White is associate professor of pediatrics and director of rheumatology services at Shriner's Hospital, Washington University School of Medicine in St. Louis, Missouri.

"[This study suggests that] patients often flare when anti-[tumor necrosis factor] medication is withdrawn first, compared to withdrawing MTX first, for those on both medications," Dr White commented. "This is a bit of a tricky point, because the lesson may in fact be that anti-[tumor necrosis factor] medications are simply better at keeping these patients in clinical remission than MTX alone."

Once all medications are discontinued, however, the order of medication withdrawal makes "no difference," in terms of flare-free survival, Dr White added.

"Anti-[tumor necrosis factor] medications may not alter the underlying disease process, unlike [MTX]," Dr White emphasized. "This study suggests that a prospective trial needs to be undertaken to determine the correct way to discontinue these medications when a child is in clinical remission."

One coauthor reports working as a consultant/speaker for Abbott and Amgen. The other authors and Dr White have disclosed no relevant financial relationships.

Arthritis Care Res. Published online September 12, 2014. Abstract

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