Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (axSpA)

In this Cochrane review of the effect of NSAIDs for people with axSpA (including ankylosing spondylitis and non-radiographic (nr-)axSpA), we included 39 studies with 4356 people (search up to 18 June 2014). One study looked at people with nr-axSpA.

In people with axSpA:

Traditional and COX-2 NSAIDs improve pain, disease activity and functioning (high quality evidence) and probably do not result in more withdrawals due to adverse events or serious adverse events compared with placebo in the short term (moderate quality evidence, as some outcomes suffered potential imprecision). We often do not have precise information about side effects, particularly for rare but serious side effects. Possible side effects may include gastrointestinal complaints. Rare complications may include gastrointestinal bleeding or problems with heart or blood vessels.

What is axSpA and what are NSAIDs?

AxSpA is a form of arthritis involving the joints of the pelvis or spine or both. It causes pain and stiffness in those regions and can result in deformities of the spine and poor functioning.

NSAIDs are commonly used to reduce pain and inflammation and are considered first-line treatment for people with axSpA. COX-2 NSAIDs are a subgroup of NSAIDs that potentially lead to less gastrointestinal complaints than traditional NSAIDs, although there is evidence that they may lead to other complications, like a higher risk of cardiovascular events.

What happens to people with axSpA taking NSAIDs after six weeks:

People who used a traditional NSAID rated their pain to be 16.5 points lower on a scale of 0 to 100 (lower score means less pain) (17% absolute improvement).

- People using a traditional NSAID rated their pain to be 44 points; people using placebo 60.5 points.

People who used a traditional NSAID rated their disease activity to be 17.5 points lower on a scale of 0 to 100 (lower score means less disease activity) (18% absolute improvement).

- People using a traditional NSAID rated their disease activity to be 37.2 points; people using placebo 54.7 points.

People who used a traditional NSAID rated their functioning to be 9.1 points lower on a scale of 0 to 100 (lower score means better functioning) (9% absolute improvement).

- People using a traditional NSAID rated their functioning to be 40.9 points; people using placebo 50.0 points.

Thirteen people less out of 1,000 stopped taking a traditional NSAID before the end of the study because of side effects (0% absolute difference).

- 39 people out of 1,000 receiving a traditional NSAID stopped, compared to 52 out of 1,000 receiving placebo.

One more person out of 1,000 had a serious adverse event while taking a traditional NSAID during the study (0% absolute difference).

- 3 people out of 1,000 receiving a traditional NSAID had a serious adverse event during the study, compared to 2 out of 1,000 receiving placebo.

People who used a COX-2 NSAID rated their pain to be 21.7 points lower on a scale of 0 to 100 (22% absolute improvement).

- People using a COX-2 NSAID rated their pain to be 42.3 points; people using placebo 64 points.

People who used a COX-2 NSAID rated their disease activity to be 22 points lower on a scale of 0 to 100 (22% absolute improvement).

- People using a COX-2 NSAID rated their disease activity to be 32.7 points; people using placebo 54.7 points.

People who used a selective COX-2 NSAID rated their functioning to be 13.4 points lower on a scale of 0 to 100 (13% absolute improvement).

- People using a COX-2 NSAID rated their functioning to be 36.6 points; people using placebo 50.0 points.

Thirteen people more out of 1,000 stopped taking a COX-2 NSAID before the end of the study because of side effects (2% absolute difference).

- 24 people out of 1,000 receiving a COX-2 NSAID stopped, compared to 11 out of 1,000 receiving placebo.

The same number of people had a serious adverse event while taking a COX-2 NSAID or placebo during the study (0% absolute difference).

- 2 people out of 1,000 receiving a COX-2 NSAID had a serious adverse event during the study, compared to 2 out of 1,000 receiving placebo.

Authors' conclusions: 

High to moderate quality evidence indicates that both traditional and COX-2 NSAIDs are efficacious for treating axSpA, and moderate to low quality evidence indicates harms may not differ from placebo in the short term. Various NSAIDs are equally effective. Continuous NSAID use may reduce radiographic spinal progression, but this requires confirmation.

Read the full abstract...
Background: 

Axial spondyloarthritis (axSpA) comprises ankylosing spondylitis (radiographic axSpA) and non-radiographic (nr-)axSpA and is associated with psoriasis, uveitis and inflammatory bowel disease. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line drug treatment.

Objectives: 

To determine the benefits and harms of NSAIDs in axSpA.

Search strategy: 

We searched CENTRAL, MEDLINE and EMBASE to 18 June 2014.

Selection criteria: 

Randomised controlled trials (RCTs) or quasi-RCTs of NSAIDs versus placebo or any comparator in adults with axSpA and observational cohort studies studying the long term effect (≥ six months) of NSAIDs on radiographic progression or adverse events (AEs). The main comparions were traditional or COX-2 NSAIDs versus placebo. The major outcomes were pain, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), radiographic progression, number of withdrawals due to AEs and number of serious AEs

Data collection and analysis: 

Two review authors independently selected trials for inclusion, assessed the risk of bias, extracted data and assessed the quality of evidence for major outcomes using GRADE.

Main results: 

We included 39 studies (35 RCTs, two quasi-RCTs and two cohort studies); and 29 RCTs and two quasi-RCTs (n = 4356) in quantitative analyses for the comparisons: traditional NSAIDs versus placebo, cyclo-oxygenase-2 (COX-2) versus placebo, COX-2 versus traditional NSAIDs, NSAIDs versus NSAIDs, naproxen versus other NSAIDs, low versus high dose. Most trials were at unclear risk of selection bias (n = 29), although blinding of participants and personnel was adequate in 24 trials. Twenty-five trials had low risk of attrition bias and 29 trials had low risk of reporting bias. Risk of bias in both cohort studies was high for study participation, and low or unclear for all other criteria. No trials in the meta-analyses assessed patients with nr-axSpA.

Traditional NSAIDs were more beneficial than placebo at six weeks. High quality evidence (four trials, N=850) indicates better pain relief with NSAIDs (pain in control group ranged from 57 to 64 on a 100mm visual analogue scale (VAS) and was 16.5 points lower in the NSAID group (95% confidence interval (CI) -20.8 to -12.2), lower scores indicate less pain, NNT 4 (3 to 6)); moderate quality evidence (one trial, n = 190) indicates improved disease activity with NSAIDs (BASDAI in control group was 54.7 on a 100-point scale and was 17.5 points lower in the NSAID group, 95% CI -23.1 to -11.8), lower scores indicate less disease activity, NNT 3 (2 to 4)); and high quality evidence (two trials, n = 356) indicates improved function with NSAIDs (BASFI in control group was 50.0 on a 100-point scale and was 9.1 points lower in the NSAID group (95% CI -13.0 to -5.1), lower scores indicate better functioning, NNT 5 (3 to 8)). High (five trials, n = 1165) and moderate (three trials, n = 671) quality evidence (downgraded due to potential imprecision) indicates that withdrawals due to AEs and number of serious AEs did not differ significantly between placebo (52/1000 and 2/1000) and NSAID (39/1000 and 3/1000) groups after 12 weeks (risk ratio (RR) 0.75, 95% CI 0.46 to 1.21; and RR 1.69, 95% CI 0.36 to 7.97, respectively). BASMI and radiographic progression were not reported.

COX-2 NSAIDS were also more efficacious than placebo at six weeks. High quality evidence (two trials, n = 349) indicates better pain relief with COX-2 (pain in control group was 64 points and was 21.7 points lower in the COX-2 group (95% CI -35.9 to -7.4), NNT 3 (2 to 24)); moderate quality evidence (one trial, n = 193) indicates improved disease activity with COX-2 (BASDAI in control groups was 54.7 points and was 22 points lower in the COX-2 group (95% CI -27.4 to -16.6), NNT 2 (1 to 3)); and high quality evidence (two trials, n = 349) showed improved function with COX-2 (BASFI in control group was 50.0 points and was 13.4 points lower in the COX-2 group (95% CI -17.4 to -9.5), NNT 3 (2 to 4)). Low and moderate quality evidence (three trials, n = 669) (downgraded due to potential imprecision and heterogeneity) indicates that withdrawals due to AEs and number of serious AEs did not differ significantly between placebo (11/1000 and 2/1000) and COX-2 (24/1000 and 2/1000) groups after 12 weeks (RR 2.14, 95% CI 0.36 to 12.56; and RR 0.92, 95% CI 0.14 to 6.21, respectively). BASMI and radiographic progression were not reported.

There were no significant differences in benefits (pain on VAS: MD -2.62, 95% CI -10.99 to 5.75; three trials, n = 669) or harms (withdrawals due to AEs: RR 1.04, 95% CI 0.60 to 1.82; four trials, n = 995) between NSAID classes. While indomethacin use resulted in significantly more AEs (RR 1.25, 95% CI 1.06 to 1.48; 11 studies, n = 1135), and neurological AEs (RR 2.34, 95% CI 1.32 to 4.14; nine trials, n = 963) than other NSAIDs, these findings were not robust to sensitivity analyses. We found no important differences in harms between naproxen and other NSAIDs (three trials, n = 646), although other NSAIDs appeared more effective for relieving pain (MD 6.80, 95% CI 3.72 to 9.88; two trials, n = 232). We found no clear dose-response effect on benefits or harms (five studies, n = 1136). Single studies suggest NSAIDs may be effective in retarding radiographic progression, especially in certain subgroups of patients, e.g. patients with high CRP, and that this may be best achieved by continuous rather than on-demand use of NSAIDs.

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