Rationale in Discontinuing DMARDS

• Currently, the risks and benefits of stopping DMARD monotherapy in good responders remain uncertain and the evidence for stopping or continuing DMARDs is currently incomplete.

DMARDs Retention

• azici et al. quantified the low risk of discontinu­ing methotrexate; in 1007 person-years of observation the probability of con­tinuing methotrexate for five years was 79%
• Low retention rates are com­moner in patients receiving combina­tion DMARDs and in those with high disease activity
• low retention rates of patients starting DMARDs mean it is crucial to consider carefully the benefits and risks of discontinuing DMARDs in patients in whom therapy is controlling RA and is not causing adverse effects

Stepping Down from Combination

• There is strong evidence from RCTs that treating active RA with step-down DMARD combinations is effective and, in early RA, achieves sustained responses.

COBRA early RA Trial

• trial Its in­tensive treatment comprised high-dose reducing prednisolone for 28 weeks, low-dose methotrexate for 40 weeks with sulfasalazine as maintenance therapy. Controls received sulfasala­zine monotherapy.
• Both disease activ­ity and erosive progression were better controlled by combination DMARDs.
• Subsequent follow-up in routine prac­tice settings over 4-5 years showed that the benefits of intensive initial treat­ment on radiological progression were maintained after tapering

The FIN-RACo Trial

• evaluated com­bination therapy with sulphasalazine, methotrexate, hydroxychloroquine and prednisolone. Treatment was tapered in patients achieving remission during the first year; prednisolone and metho­trexate were discontinued. Controls re­ceived monotherapy with sulfasalazine followed by methotrexate for patients with adverse effects or non-responders.
• More patients had good clinical re­sponses and achieved remission with intensive treatment.
• The radiological benefits were maintained long-term with a subsequent 11-year follow-up report showing less radiologic dam­age in patients receiving initial com­bination DMARDs compared to those receiving monotherapy.

BeSt study

• compared four differ­ent treatment strategies in 508 patients with recent-onset RA. These com­prised DMARD monotherapy, step-up DMARD combinations, step-down DMARD combinations (based on the COBRA regimen) and methotrexate combined with infliximab.
• When patients achieved remission DMARDs were tapered and stopped. Five-year follow-up data evaluated the frequency and impact of DMARD tapering
• During this period, 23% of patients had drug-free remissions. Subsequently, 46% restarted treatment for increasing disease activity and 51% had drug-free remissions.
• frequencies of drug-free remissions were similar across initial treatment groups . The evidence suggests sustained drug-free remission is uncommon and tapering DMARDs in patients in remission has questionable benefits.

Overall Evidence & International Guidelines

• RCTs in early and estab­lished RA show that step-down combi­nation therapy is effective and has sus­tained benefits.
•  To reduce subsequent flares at least one anchor DMARD should be retained.
• The optimal main­tenance DMARD regimen was not de­fined in these RCTs.
• NICE recommend that if RA is stable, DMARD doses should be cau­tiously reduced, returning promptly to disease controlling doses if there are any indications of a flare
• EULAR guidelines are more guarded about DMARD tapering. They recom­mend that in sustained long-term re­mission cautious titration of synthetic DMARD dose may be considered.
• By contrast American College of Rheuma­tology guidelines do not comment on DMARD withdrawal

Discontinuation Regimen

• generally avoid discontinuing all DMARD treatment, and there are insufficient data to prospectively identify which patients will be able to successfully reduce or discontinue therapy without clinical recurrence or radiographic progression.
• Although some patients may tolerate a reduced dose of medications, the decision to discontinue DMARDs in patients in remission remains controversial

Prednisolone

• in a patient in clinical remission being treated with prednisone (7 mg/day), methotrexate (MTX; 20 mg/week), and etanercept (ETN; 50 mg/week), we would first try to reduce prednisone because of the risk of long-term adverse effects with glucocorticoids. In such a patient, we would lower the glucocorticoid dose slowly (no faster than 1 mg every two to four weeks), as long as there was no recurrence of disease activity
• If prednisone can be discontinued or if it cannot be completely eliminated but can be lowered to a dose no greater than 5 mg/day, we would then reduce the dosing of the tumor necrosis factor (TNF) inhibitors

MTX

• In patients who are able to discontinue a biologic and who then remain in remission for at least a year, we next decrease MTX. We reduce the MTX dose in 2.5 mg increments every two to three months as tolerated but generally to no lower than 10 mg/week. 
• In patients who are tolerating MTX more poorly, reduction in the MTX dose can be implemented before reduction in the dose of the TNF antagonist

Conclusion:

• There is strong evidence from RCTs that treating active RA with step-down DMARD combinations is effective and, in early RA, achieves sustained responses.
• There is also good evidence that drug-free remission is achievable in a small minority of cases
• Many if not most patients who achieve sus­tained remissions on DMARDs some­times flare, and the risks of flaring are increased when DMARDs are discon­tinued, though restarting DMARDs usually reverses these flares.
• Currently, the risks and benefits of stopping DMARD monotherapy in good responders remain uncertain and the evidence for stopping or continuing DMARDs is currently incomplete

References:

1.  Can we discontinue synthetic disease-modifying anti-rheumatic drugs in rheumatoid arthritis. Clin Exp Rheumatol 2013; 31 (Suppl. 78): S4-S8.
2. www.uptodate.com