Table 41Overall tolerability in patients with rheumatoid arthritis treated with oral DMARDs

StudyStudy Design
Study PopulationDrugResultsQuality Rating
Cannon et al., 2004229Retrospective cohort
2 years (claims database)
RA ptsLEF, MTX, other DMARDAE rates in LEF and LEF+MTX were lower than or similar to AE rates for MTX and other DMARDsFair
Emery et al., 2000105RCT
1 year with optional 2nd year
RA 4 months to 10 yearsLEF, MTXFrequency of SAEs similar between groupsFair
Maetzel et al., 2000230Meta-analysis (RCT and observational)
159 studies MTX=2,875 SSZ=1,418
5 years
RA pt studies including withdrawal informationMTX, SSZ, HCQ (and gold)Withdrawals due to toxicity for 5 years: MTX 35%, SSZ 52%
Pts treated with SSZ were 1.68 times more likely to fail therapy due to toxicity than MTX (RR, 1.68; P<0.0001)
*Osiri et al., 200955Systematic review and meta-analysis
6 studies
1,220 patients
Mixed duration
Active RALEF, MTX, SSZWithdrawals due to adverse events were 10% (95%CI: 6–15%) greater with leflunomide than placebo.
NNH: 10 (7 to 17)
Adverse events and withdrawal rates simiar for LEF, SSZ, and MTX
Smolen et al., 1999107, 108RCT
24 weeks
Active RALEF, SSZWithdrawal due to AEs 14% vs. 19%Fair
Strand, et al., 199956, 104RCT
12 months (1 year continuation)
RA for at least 6 months, MTX-naiveLEF, MTXAEs constant over time for LEF and MTX
12 months:
Higher discontinuation rate for LEF (22% vs. 10.4%, P=NR)
Oral DMARD Combinations
Boer et al., 199795
COBRA study
56 weeks
Early RA, DMARD naivePNL taper+MTX+SSZ vs. SSZLower withdrawal rate due to AEs (2.6% vs. 7.6%, P=NR)Fair
Capell et al., 200659RCT
165 (Phase 1 run-in: 687)
6 months (18 months for those with DAS ≥2.4 at 6 months)
Active RASSZ+MTX vs. SSZ or MTXSimilar withdrawal rate due to AEsFair
Dougados et al., 199957RCT
209 (146)
52 weeks (5-year followup)
DMARD naive, early RASSZ +MTX vs. SSZ or MTXDiscontinuation rate due to AEs similar among groups
AEs higher in SSZ+MTX vs. SSZ vs. MTX (91% vs. 75% vs. 75%, P=0.025)
*Goekoop-Ruiterman et al., 2005100102, 196
BeSt study
12 months
Early RASequential monotherapy (starting with MTX) vs. step-up combination therapy (MTX, then SSZ, then HCQ, then PRED) vs. combination (MTX, SSZ, tapered high-dose PRED) vs. combination with INF (3 mg/kg – could be titrated to 10 mg/kg based on DAS)No significant differences in serious AEs in all groupsGood
Haagsma et al., 199758RCT
52 weeks
DMARD naive, early RASSZ+MTX vs. SSZ or MTXNo significant difference in number of withdrawals due to AEsFair
Korpela et al., 199998
FIN-RACo study
24 months
Early RAMTX+HCQ+SSZ+PNL vs. DMARD ± PNLFrequency of serious AEs similar in both groups
Discontinuation due to AEs similar in both groups
*Malysheva et al., 2008233Retrospective cohort
2–62 months
RA PtsMTX vs. MTX +glucocorticoids vs. HCQ vs. HCQ+glucocorticoidsUse of GC significantly increased the time until withdrawal of DMARD therapy due to AE (18.6 ± 2.3 months; P<0.05) compared with no use of GC (12.5 ± 1.4 months)Fair
O’Dell et al., 2006231Prospective cohort
48 weeks
Active RA, previous use of DMARDsETA +SSZ vs. ETA+HCQSimilar discontinuation rates due to AEsFair
O’Dell et al., 200261RCT
2 years
RA pts not previously treated with combination drugsMTX+SSZ+HCQ vs. MTX+HCQ vs. MTX+SSZ
Similar withdrawal rate due to AEs across groupsGood
O’Dell et al., 199662RCT
2 years
RA and poor response to at least 1 DMARDMTX+SSZ+ HCQ vs. MTX vs. SSZ+HCQ
Similar withdrawal rate due to AEs across groupsGood
*Osiri et al., 200955Systematic review and meta-analysis
6 studies
1,220 patients
Mixed duration
Active RALEF+ MTX, MTXAdverse events reported more frequently for LEF+ MTX than MTX. Withdrawal rates similar with LEF+MTX vs. MTXGood
*Schipper et al., 2009232Systematic review
24 to 52 weeks
Ra pts with insufficient response to SSZ or MTX and SSZ naiveMTX+SSZ vs. MTX vs. SSZPts naïve to MTZ or SSZ on combination therapy experienced significantly more nausea. Those on MTX+SSZ who previously failed SSZ had comparable tolerabilityFair
*Schipper et al., 2009110Nonrandomized inception cohort
52 weeks
RA pts that had failed SSZ treatmentSSZ+MTX vs. MTX switchRate of discontinuation significantly lower in MTX vs. SSZ+MTX group (P=0.01)
Relative hazard to stop DMARD within 1 year in SSZ+MTX group vs. MTX group: 1.7 (95% CI, 1.11 to 2.46, P<0.01)
Svensson et al., 200565Open-label RCT
2 years
Early RADMARD+PNL vs. DMARDSimilar number of discontinuations between groupsFair
Svensson et al., 2003318Open-label RCT
2 years
Lower withdrawal rate due to AEs or inefficacy for PRED+MTX group vs. PRED+SSZ group (11.5% vs. 33.3%, P=0.0005)Fair

New study added since last review.

AEs = adverse events; CI = confidence interval; DMARD = disease-modifying antirheumatic drug; GC = glucocorticoids; hydroxychloroquine; HR = hazard ratio; LEF = leflunomide; MTX = methotrexate; OR = odds ratio; PNL = prednisolone; PRED = prednisone; Pts = patients; RA = rheumatoid arthritis; RCT = randomized controlled trial; RR = relative risk; SAEs = serious adverse events; SSZ = sulfasalazine

From: Results

Cover of Drug Therapy for Rheumatoid Arthritis in Adults: An Update
Drug Therapy for Rheumatoid Arthritis in Adults: An Update [Internet].
Comparative Effectiveness Reviews, No. 55.
Donahue KE, Jonas DE, Hansen RA, et al.

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