Safe Stopping of Tocilizumab in RA: MTX Helps

Janis C. Kelly

June 13, 2018

Second-year data from the SURPRISE rheumatoid arthritis (RA) trial support the finding that many patients who achieve remission can safely stop ­— or at least interrupt ­— biologic treatment with tocilizumab. Such interruptions might reduce both costs and risks for side effects.

The SURPRISE investigators suggest a three-part treatment strategy: adding tocilizumab for patients for whom methotrexate (MTX) is tolerable but inadequate; stopping tocilizumab but continuing MTX after the patient attains remission lasting several months; and restarting tocilizumab if flare occurs.

"It was surprising that more than half of patients would remain in remission after discontinuing tocilizumab with continued methotrexate. Tocilizumab has been believed to be difficult to stop (without conventional DMARDs [disease-modifying antirheumatic drugs]). What kinds of patients can stop tocilizumab and then remain in remission still remains to be investigated," senior author Tsutomu Takeuchi, MD, professor of rheumatology at Keio University School of Medicine in Tokyo, Japan, told Medscape Medical News.

Yuko Kaneko, MD, from the Division of Rheumatology at the Keio University School of Medicine, and colleagues report the results of the 104-week prospective, randomized, controlled study in an article published online May 31 in Annals of the Rheumatic Diseases.

The SURPRISE (Success of Tocilizumab for RA Patients with Remission Induction and Sustained Efficacy After Discontinuation) study was designed to determine whether patients with inadequate RA control after initial treatment with MTX would be more likely to eventually be "tocilizumab-free" while maintaining remission or low disease activity if they had added tocilizumab to MTX (the add-on group) for 52 weeks or if they were switched from MTX to tocilizumab (the switch group) for 52 weeks. Eligible patients had active disease despite receiving stable doses of at least 6 mg of methotrexate per week for at least 8 weeks and had not previously been treated with a biologic agent.

At week 52, 105 patients who achieved remission, defined as a disease activity score for 28-joints based on erythrocyte sedimentation rate (DAS28-ESR) score below 2.6, stopped tocilizumab and were observed for 52 more weeks while continuing MTX (the add-on group, n = 51) or receiving no DMARDs (the switch group, n = 54).

The researchers found no statistically significant differences at week 104 between those who had been randomly assigned to the add-on or the switch group for sustained remission rates (24% vs 14%) or for radiologic progression (modified total Sharp score, 0.37 vs 0.64). 

However, twice as many patients in the add-on group had sustained low disease activity (defined as DAS28-ESR score ≤ 3.2) as did those in the switch group (55% vs 27%; P = .005).

Tocilizumab was reinstituted in 16 patients in the add-on group and in 18 patients in the switch group because of disease flare between weeks 52 and 104. Other patients in the switch group also restarted MTX (n = 12) or a combination of both drugs (n = 5).

"Overall, the restart of tocilizumab induced remission in 91.3% of patients and its efficacy was independent of concomitant methotrexate," the authors write.

Takeuchi said, "Our study has proved that discontinuation of tocilizumab with continued

methotrexate was successful for maintaining low disease activity in more than half of patients; however, that means a part of patients would flare and suffer from pain and impaired activity of daily life. Discontinuation of biologic agents, including tocilizumab, should be decided based on a shared decision between the patient and the rheumatologist."

Robert B.M. Landewé, MD, from the Amsterdam Rheumatology & Clinical Immunology Center, the Netherlands, told Medscape Medical News that these results support the approach described in the recent European League Against Rheumatism (EULAR) recommendations for the management of RA. The recommendations indicated that MTX is a good "anchor drug" and that patients adding tocilizumab to MTX do better when discontinuing tocilizumab than those not continuing MTX. Landewé is coauthor of the EULAR recommendations and was not involved in Kaneko and colleagues' study.

Landewé said, "Stopping tocilizumab in this way is something physicians should consider in clinical practice. There is a considerable chance that patients will do well. And they do better if they continue MTX — maybe not if 'remission' is the outcome, but certainly if low disease activity is considered. Since tocilizumab is an expensive drug, and the likelihood of remission upon restarting tocilizumab is high, this is definitely something to consider in the discussion with the patient, fully in accordance with 'shared decision making.'"

The length of time the patient with RA should be in remission before being a candidate for stopping tocilizumab is uncertain. Thomas W.J. Huizinga, MD, head of rheumatology at Leiden University in the Netherlands, told Medscape Medical News that he would like to see the patient in stable remission for 6 months before stopping tocilizumab. Huizinga was not involved in Kaneko and colleagues' study but has worked on other tocilizumab research.

Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy at the University of California, San Diego, told Medscape Medical News, "Kaneko et al did a very nice job of tackling a complex problem; namely, trying to taper effective therapies when patients are in remission. Quite a few physicians already do this in ordinary clinical practice. Reasons seem to include economic considerations, concern about adverse effects, and the idea to use fewer medicines. It is always important for patients and doctors to work together to find the optimal regimen."

Kavanaugh, who was not involved in the study, added, "The main potential down side to tapering or stopping effective treatment is that some patients may not achieve the kind of disease control they had had before they tried, or it may take a while for them to do so."

Multiple authors reported receiving grant support, lecture fees, and consulting fees from numerous companies. For the full disclosure, please see the journal website. Landewé has received honoraria and/or research grants from AbbVie, Ablynx, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Janssen, Galapagos, GlaxoSmithKline, Novartis, Novo-Nordisk, Merck, Pfizer, Roche, Schering-Plough, TiGenix, and UCB. Huizinga has been a consultant for Abbott, Axis Shield Diagnostics, Biotest AG, BMS, Crescendo Bioscience, Roche, Novartis, Schering-Plough, UCB, Wyeth, and Pfizer. Kavanaugh has received compensation for consultancy work, or has been involved in the conduct of clinical research studies, for AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB and has consulted for Galapagos NV.   

Ann Rheum Dis. Published online May 31, 2018. Full text    

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