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Methotrexate for ankylosing spondylitis

  • Review
  • Intervention


  • J Chen,

  • C Liu

Dr Junmin Chen, WHO Fellow, Australasian Cochrane Centre, Monash University, Level 1, Block E, Locked Bag 29, Monash Medical Centre, Clayton, Victoria, 3168, AUSTRALIA.



Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown cause, characterized by sacroiliitis and spondylitis. To date, treatment of AS has been limited to the alleviation of symptoms, mainly using non-steroidal anti-inflammatory drugs (NSAIDs). For patients refractory or intolerant to NSAIDs, the disease modifying antirheumatic drugs (DMARDs) have been used as a second line approach. Methotrexate (MTX) is currently one of the most widely used DMARDs and its efficacy in rheumatoid arthritis (RA) has been confirmed (Suarez-Almazor 2003). There is uncertainty whether MTX works in the treatment of AS.


To evaluate the efficacy and toxicity of methotrexate in the treatment of ankylosing spondylitis.

Search strategy

Relevant randomised and quasi-randomised trials in any language were sought using the following sources: CENTRAL (Cochrane Central Register of Controlled Trials, Issue 2, 2003), MEDLINE (1966 to June Week 4 2003), EMBASE (1980 to 2003 Week 26), CINAHL (1982 to June Week 3 2003) and the reference section of retrieved articles.

Selection criteria

We evaluated randomised and quasi-randomised trials examining the efficacy of methotrexate on AS.

Data collection and analysis

Unblinded trial reports were reviewed independently by two reviewers according to the selection criteria. Disagreements on the inclusion of the studies were resolved, where necessary, by recourse to a third reviewer. The methodological quality of included trials were independently assessed by the same reviewers on randomization, concealment, blindness (participants, care providers and outcome investigators), description of withdrawals and drop-outs and intention-to-treat analysis. The same reviewers independently entered the data extracted from the included trials, using RevMan's double entry facility. In the absence of significant heterogeneity, results were combined using weighted mean difference or standardised mean difference for continuous data, and relative risk for dichotomous data.

Main results

Two trials met the inclusion criteria. Altan 2001compared naproxen plus MTX (7.5 mg/week orally) with naproxen alone and Roychowdhury 2002 compared MTX (10 mg/week orally) with placebo. The duration of the trials were 12 months and 24 weeks, respectively. They assessed different outcomes except for C-reactive protein (CRP). The included trials treated a total of 81 patients and assessed more than 10 outcomes relevant to the review, covering function, pain, peripheral arthritis/enthesitis, morning stiffness, patient and physician global assessment, CRP and erythrocyte sedimentation rate (ESR). No significant difference between intervention groups was found favouring MTX over no MTX. No serious side effect was reported in either trial.

Authors' conclusions

There was no statistically significant benefit of MTX in the examined outcomes for AS patients. High quality, larger sample and longer period of randomized controlled trials (possibly with higher dosage of MTX) are needed to verify the uncertainty about the efficacy and toxicity of MTX for the treatment of AS.

Plain language summary

Plain language summary

Does methotrexate work to treat ankylosing spondylitis and is it safe?

To answer this question, scientists found and analyzed 2 high quality studies testing 81 people (mostly men) who had ankylosing spondylitis. In the one study, people took either 10 mg of methotrexate pills or a sugar pill (placebo) for 6 months. In the other study, people took either 7.5 mg of methotrexate pills with naproxen or just naproxen alone for 12 months. These studies provide the best evidence we have today.

What is ankylosing spondylitis and how can methotrexate help?
Ankylosing spondylitis (AS) is a type of arthritis, usually in the joints and ligaments of the spine. It may also affect the shoulders, hips, or other joints. Pain and stiffness occurs and limits movement in the back and in other joints that are affected. It can come and go, last for long periods, and be quite severe. Non steroidal anti-inflammatory drugs (NSAIDs) are usually prescribed to stop the pain and stiffness. When people do not do well with NSAIDs, disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate, are sometimes prescribed. It is not known whether methotrexate controls pain and stiffness in AS, slows its progress or stops damage.

Does methotrexate work?
In the 6 month study, people improved about the same amount for pain, stiffness, swelling and disease activity whether they took methotrexate or the sugar pill (placebo).

In the 12 month study, people improved about the same amount with naproxen plus methotrexate or with naproxen alone. Some people improved more with naproxen alone than with naproxen plus the methotrexate.

What side effects occurred with methotrexate?
No serious side effects were reported in the two studies. But in the 12 month study, 31 out of 100 people taking methotrexate with naproxen had nausea which went away but no one taking naproxen alone had nausea.

What is the bottom line?
There is "Silver" level evidence that in patients with ankylosing spondylitis, taking methotrexate does not appear to improve symptoms, such as pain, stiffness, swelling and disease activity more than taking a sugar pill or naproxen alone.

Serious side effects with methotrexate did not occur with methotrexate, but nausea did.

Based on Chen J and Liu C. Methotrexate for ankylosing spondylitis. In The Cochrane Library, Issue3, 2004 (in press).