Table 1 Methotrexate combination therapy.
Combination / Number of trials / Disease duration(months) / Follow-up periods
(weeks) / Outcomes / Adverse events
Methotrexate + sulphasalazine / 4 / Early and established
3–69 / 24–104 / Conflicting: combination more effective than each monotherapy in 1 trial; an effective step-up from either monotherapy in another trial / No increase
Methotrexate + antimalarial / 3 / Established
69–75 / 26–104 / More effective than methotrexate monotherapy / Hydroxychloroquine may potentiate methotrexate toxicity
Methotrexate + cyclosporin / 3 / Early and established
3–134 / 24–104 / Conflicting: combination more effective than methotrexate monotherapy in 1 trial; equivalent in another; slower slower radiological progression in another / Similar rate to cyclosporin monotherapy; slight increase in serum creatinine levels, hypertension and hirsuitism
Methotrexate+ leflunomide / 1 / Established
126 / 24–48 / More effective than methotrexate monotherapy / Similar overall rate; but increased levels of transaminases
Methotrexate+ gold / 2 / Early
3–6 / 48 / IM gold more effective than methotrexate monotherapy. Auranofin + methotrexate combination similar efficacy to each monotherapy.
Radiological progression was slower in both methotrexate groups / Increased mucocutaneous adverse events from IM-gold; nonsignificant increase from methotrexate + auranofin (oral gold)
Methotrexate+ azathioprine / 1 / Early
8 / 24–48 / No more effective than each monotherapy; methotrexate alone results in slower radiological progression / Increased incidence of serious adverse events
Methotrexate+ tacrolimus / 1 / Early
9 / 26 / More effective than methotrexate monotherapy / Similar rate to low and high-dose methotrexate monotherapy;
no placebo control
Methotrexate+ doxycycline / 1 / Early
5 / 104 / More effective than methotrexate monotherapy / No significant increase increase in photosensitivity
Abbreviation: IM, intramuscular
Table 2 Sulphasalazine combination therapy.
Combination / Number of trials / Disease duration(months) / Follow-up periods
(weeks) / Outcomes / Adverse events
Sulphasalazine+ leflunomide / 1 / Established
72 / 48 / More effective than sulphasalazine monotherapy / Higher incidence
Sulphasalazine+ hydroxychloroquine / 1 / Established
75 / 24 / Marginally better than hydroxychloroquine monotherapy, similar efficacy to sulphasalazine monotherapy / No significant increase; gastrointestinal problems most common
Sulphasalazine+ cyclosporin / 1
(open, nonrandomized) / Early
8 / 52 / More effective than each monotherapy, improvement in all parameters but trial uncontrolled / 11% stopped owing to gastrointestinal problems
Sulphasalazine+ penicillamine / 1
(open, uncontrolled) / Early
2 / 24 / More effective than sulphasalazine monotherapy / No significant increase, but more rashes
Table 3 Triple therapy
Combination / Number of trials / Disease duration(months) / Follow-up periods
(weeks) / Outcomes / Adverse Events
Methotrexate +sulphasalazine + cyclosporin / 1
(open) / Early
14 / 156 / Significantly more effective than sulphasalazine monotherapy / Similar frequency in all groups
Methotrexate + sulphasalazine + hydroxychloroquine / 3 / Early and established
15–120 / 104 / Significantly more effective than methotrexate + sulphasalazine and sulphasalazine + hydroxychloroquine; marginally more effective than methotrexate + hydroxychloroquine / Similar frequency in all groups