The quality of evidence is downgraded by study limitations (unclear allocation concealment and lack of blinding) and by imprecise results (few patients and outcome events).
A Cochrane review included 17 studies (3 RCTs, 4 controlled before and after studies, 7 cohort studies, 3 case-control studies) with a total of 1 809 subjects with rheumatoid arthritis using various non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin. No studies for paracetamol were indentified. Two of these studies reported no evidence for increased risk of methotrexate-induced pulmonary disease; 1 study assessed the effect of concurrent NSAIDs on renal function and found no adverse effect; 1 study identified no adverse effect on liver function; 3 studies demonstrated no increase in methotrexate withdrawal; and 1 study showed no increase in all adverse events, including major toxic reactions. However, transient thrombocytopenia was demonstrated in 1 study, specifically when NSAIDs were taken on the same week day as methotrexate. This study was a retrospective review that involved small numbers only and was of moderate quality; these finding have not been replicated since.
Four studies looked at specific NSAIDs (etodolac, piroxicam, celecoxib and etoricoxib). The studies were primarily pharmacokinetic studies but also reported adverse events as secondary outcomes. There were no clinically significant adverse effects with concomitant piroxicam or etodolac; and only mild adverse events with celecoxib or etoricoxib, such as nausea and vomiting, and headaches. For aspirin, 7 studies provided data on adverse events with the use of aspirin and methotrexate. Two of the studies reported no evidence for increased risk of methotrexate-induced pulmonary disease and two studies showed no increase in all adverse events including major toxic reactions; however, none of these studies specified the dose of aspirin that was used. One study demonstrated that concurrent aspirin adversely affected liver function at a mean dose of 6.84 tablets of aspirin per day, which is a possible daily dose of 2.1 g presuming that 300 mg aspirin tablets were given. A further study described a partially reversible decline in renal function with 2 g daily of aspirin. One study reported no increase in adverse events with 975 g aspirin daily, however the study duration was only one week.
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