Methods
Literature search strategy
Efficacy
Literature on the following nonbiologic DMARDs, given in monotherapy and in combination, was examined: methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, intramuscular gold, Auranofin, azathioprine, cyclosporine, minocycline, D-penicillamin, cyclophosphamide, chlorambucil, mycophenolate, tacrolimus. We also searched ACR/EULAR meeting abstracts of the past two years. In addition, reference lists of the papers initially detected were hand searched to identify additional relevant reports.
The trials were initially selected on the basis of their titles and abstract, then on the full texts. The inclusion criteria were all RCTs reporting the efficacy on signs and symptoms, disability and/or structure of synthetic DMARDs versus placebo (except for methotrexate) or other nonbiologic DMARDs, in patients with RA. Articles reporting no interpretable results (data needed to include means and a measure of variability such as standard deviation, SD) for any of the 3 outcome measures were not analysed.
One investigator (CGV) selected the articles and collected the data, using a predetermined form. The following methodological features were collected: blinding, intent-to-treat-analysis or not, number of participants who completed the follow-up. For each trial, demographic characteristics (sex, mean age), RA duration, type of DMARD (with doses), type of comparator and duration of follow-up were collected. Signs and symptoms were extracted from the studies, as available, by swollen joint count (SJC), Disease Activity Score (DAS/DAS28), ACR 20, 50, 70 response rates, pain, patient global assessment, erythrocyte sedimentation rate (ESR), C reactive protein; disability was extracted, as available, by the health assessment questionnaire (HAQ or MHAQ); structure was assessed by different scores according to different studies (total Sharp score, Sharp modified by Van der Heijde, Larsen score...).
Safety
In addition, reference lists of the papers initially detected were hand searched to identify additional relevant reports. Safety was assessed regarding infections and cancers only in longitudinal prospective cohorts (not trials, not case reports), only if the safety was reported separately for each treatment, which was not frequent, and only if there was a control group or standardised incidences.
Statistical analysis
The ES is calculated as the ratio of the treatment effect (mean differences in treatment group or group 1 minus differences in control group or group 2) to the pooled baseline standard deviation. Improvement, e.g. lower pain VAS was considered as a positive change. Thus a positive ES was in favour of group 1 and negative ES in favour of group 2. This calculation entails the use of means, for both baseline and final data with a measure of variability such as SD. Every effort was made to calculate the ES in all studies. However if no measure of variability was given the ES could not be extrapolated and we calculated the SRM (mean change in treatment group minus mean change in control group divided by pooled SD of the change) when available. By convention, an ES <0.2 is usually considered as trivial; 0.2-0.5 as small; 0.5-0.8 as moderate; 0.8-1.2 as important and >1.2 as very important (1). A SRM >0.8 is considered as large.
Results
Efficacy of synthetic DMARD monotherapy versus placebo
Leflunomide
Leflunomide was more efficacious than placebo on SJC (4 studies, 987 patients, SRM= 0.50 [0.37, 0.62]) (2-5) (Figure C), on pain (4 studies, 987 patients, SRM= 1.60 [0.41, 2.80]) (2-5), on disability (4 studies, 987 patients, SRM= 0.50 [0.27, 0.72]) (2-5), on ACR 20 response criteria (3 studies, 784 patients, OR= 3.22 [2.36, 4.39]) (3-5), on ACR 50 response criteria (3 studies, 784 patients, OR= 3.88 [2.54, 5.91]) (3-5), on ACR 70 response criteria (2 studies, 563 patients, OR= 5.30 [2.45, 11.47]) (4,5) and on structure (2 studies, 365 patients, SRM= 0.25 [0.04, 0.46]) (3-4) (Table A).
Sulfasalazine
Sulfasalazine was more efficacious than placebo on SJC (4 studies, 519 patients, SRM=0.40 [0.22, 0.57] (3,6-8); 2 studies, 141 patients, ES= 0.32 [-0.33, 0.96] (8,9)) (Figure D), on pain (3 studies, 467 patients, SRM= 0.47 [0.28, 0.65] (3,7,8); 3 studies, 180 patients, ES= 0.47 [0.28, 0.65] (8-10)) and on ACR 20 response criteria (2 studies, 390 patients, OR= 1.92 [0.94, 3.90]) (3,7). Results on structure indicated some efficacy: sulfasalazine was more efficacious than placebo in 2 studies (3,11) but the difference was statistically significant in only one study with 117 patients: ES=6.26 [5.37, 7.16] (11). Results on disability and ACR 50 response criteria were not significant (Table B).
Intramuscular Gold
As regard injectable gold, results were in favour of the efficacy of gold on SJC ( 3 studies, 368 patients, ES= 0.34 [0.13, 0.55] (8,12,13); 3 studies, 248 patients, SRM= 0.74 [0.01, 1.46] (8,13,14)) (Figure E), on pain (2 studies, 183 patients, ES= 0.46 [0.16, 0.76] (8,13); 3 studies, 248 patients, SRM= 0.70 [0.43, 0.96] (8,13,14)) and on disability (1 study, 63 patients, SRM= 2.64 [1.96, 3.32]) (14) (Table D).
Hydroxychloroquine
Hydroxychloroquine was more efficacious than placebo on SJC (2 studies, 362 patients, ES= 0.30 [0.09, 0.50] (15,16); 1 study, 120 patients, SRM= 0.42 [0.06, 0.78] (16)), on pain (2 studies, 362 patients, ES= 0.20 [-0.01, 0.40]) (15,16) and on ACR 20 response criteria (1 study, 122 patients, OR=2.56 [1.16, 5.69]) (17) but not on disability (Table C).
Auranofin
For auranofin, there were data showing that this drug was not really efficacious on SJC (2 studies, 250 patients, ES= 0.20 [-0.06, 0.45] (13,18); 2 studies, 421 patients, SRM= 0.21 [0.02, 0.40] (13,19)) and on pain (2 studies, 421 patients, SRM= 1.51 [-0.35, 3.37]) (13,19). A trivial effect on disability was possible (SRM= 0.25 [0.02, 0.48]) but results were only from one study (19) (Table E).
Cyclosporine
Cyclosporine seemed efficacious on SJC (ES was calculated in 2 studies, 213 patients, ES= 0.27 [-0.31, 0.85] (20,21); SRM in 3 studies, 414 patients, SRM= 1.57 [-0.03, 3.17] (22-24)) (Figure F) and on pain (SRM in 2 studies, 292 patients, SRM= 1.90 [-1.17, 4.98] (23,24); ES in one study , 59 patients, ES= 0.12 [-0.39, 0.63] (21)), but the results did not reach statistical significance. Cyclosporine was efficacious on disability (1 study, 148 patients, SRM= 0.60 [0.27, 0.93]) (24) and on ACR20 response criteria (4 studies, 401 patients, OR= 3.19 [2.00, 5.09]) (20,21,24,25) (Table F).
Tetracyclins
Minocycline had shown some efficacy on SJC (3 studies, 345 patients, SRM= 0.40 [0.19, 0.62]) (26-28) (Figure G) but not on disability (2 studies, 299 patients, SRM= 0.06 [-0.17, 0.29]) (26,28) nor on structure (1 study, 64 patients, ES= -0.13 [-0.62, 0.36]) (28) (Table G).
D-penicillamine
D-penicillamine was not efficacious on SJC (SRM= 0.09 [-0.31, 0.49]) (29) and on function (SRM= 0.14 [-0.32, 0.59]) (30) but these were results of only one study for each of these outcomes (Table H).
Azathioprine
For azathioprine the number of patients was very low but the result was in favour of some efficacy on SJC (SRM in 1 study, 28 patients, SRM= 2.67 [1.61, 3.73] (31); ES in 2 studies, total 32 patients, ES=1.99 [1.07, 2.91] (32,33)) (Table I).
Tacrolimus
Tacrolimus was efficacious on SJC (3 studies, 567 patients, SRM=0.43 [0.26, 0.60]) (34-36)(Figure H), on pain (2 studies, 257 patients, SRM= 0.48 [0.23, 0.73]) (34,35) and on disability (SRM= 0.50 [0.15, 0.84]) (34) (Table J).
Cyclophosphamide, Chlorambucil and Mycophenolate
There was no appropriate data on Cyclophosphamide, Chlorambucil and Mycophenolate.
Synthetic DMARD monotherapy versus other synthetic DMARD combination therapy
Hydroxychloroquine monotherapy versus hydroxychloroquine combination
One study showed better efficacy on SJC of the combination hydroxychloroquine+sulfasalazine: ES= -0.75 [-1.36, -0.14] (37).
IM gold monotherapy versus IM gold combination
One study showed better efficacy of the combination IM gold+hydroxychloroquine on SJC: -0.69 [-1.33, -0.05] but not on disability: -0.25 [-0.87, 0.38] (38). There was no difference on pain between gold monotherapy and gold+hydroxychloroquine combination: ES= -0.42 [-1.60, 0.75] (39,40).
Auranofin monotherapy versus auranofin combination
The combination auranofin+MTX 7.5 mg/week was less efficacious on pain than auranofin monotherapy: ES= 0.50 [0.15, 0.84] but not on SJC in one study: ES = 0.00 [-0.34, 0.34] (41).
Cyclosporine monotherapy versus cyclosporine combination
Cyclosporine+hydroxychloroquine or cyclosporine+chloroquine combination therapy provide similar results on pain, SJC, disability, ACR 20, 50 and 70 response criteria and structure than cyclosporine monotherapy in 2 studies (42,43). The combination of cyclosporine + MTX or leflunomide was more efficacious on SJC than cyclosporine monotherapy: SRM= -0.42 [-0.78, -0.06], on ACR 50 response criteria: OR=0.28 [0.16, 0.49] and on ACR 70 response criteria: OR= 0.37 [0.20, 0.70] but not on pain, nor on disability, structure and ACR 20 response criteria (42,44,45) (Table L).
Azathioprine monotherapy versus azathioprine combination
One study showed better efficacy on SJC of the combination azathioprine+MTX on SJC: SRM= -2.60 [-3.05, -2.15] (46).
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