In recent years, even with remarkable scientific advancements and a significant increase of global research and development spending, drugs are frequently withdrawn from markets. This is primarily due to their side effects or toxicities. Drug molecules often interact with multiple targets, coined as polypharmacology, and the unintended drug-target interactions could cause side effects. Polypharmacology remains one of the major challenges in drug development, and it opens novel avenues to rationally design the next generation of more effective, but less toxic, therapeutic agents. This review outlines the latest progress and challenges in polypharmacology studies.

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Polypharmacology: drug discovery for the future.

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 methods
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.

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.

Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis).

Relief of symptoms in patients with chronic rheumatoid arthritis is difficult. Conventional analgesics such as aspirin, paracetamol, and phenylbutazone have limited efficacy and are not free from toxic effects. Any alternative which was more effective, safer, or both would be welcome, but most new remedies owe such success as they achieve to therapeutic optimism which is a powerful but transient potentiator of pharmacological effects. The accurate assessment of new drugs by properly controlled trials is indispensable. Two drugs which have shown promise in laboratory studies and early clinical trials are mefenamic and flufenamic acids (Winder, Wax, Scotti, Scherrer, Jones, and Short, 1962; Goodley, 1963; Young, 1962), derivatives of xylylanthranilic acid with actions broadly resembling those of aspirin. We have submitted these drugs to a controlled trial, which has already been briefly reported (Barnardo, Currey, Mason, Fox, and Weatherall, 1966). Since our trial began, several other trials have been reported. Flufenamic acid (600 mg./day) has been found to be less effective than prednisone (Fearnley and Masheter, 1966), and comparable in effect to aspirin (2,700 mg./day) over periods up to 6 months (Simpson, Simpson, and Masheter, 1966) and also comparable with phenylbutazone (300 mg./day) over shorter periods (Rajan, Hill, Barr, and Whitwell, 1967). Mefenamic acid (1,500 mg./day) has been found effective also in osteo-arthritis (Cahill, Hill, Jessop, and Hume Kendall, 1965). The methods of clinical trials are still capable of much improvement. Particularly in trials on outpatients, the opportunities for undetected errors are very great. Problems of measurement are also considerable, at least in rheumatoid arthritis, in which all of the many measurements which can be made appear to vary somewhat independently of each other (American Rheumatism Association, 1965), so that confidence in any one is limited. One cannot decide which is the best of a number of alternative procedures without testing all of them in parallel. The present trial has been extended considerably beyond the needs of a simple comparison of drugs in order also to be informative about problems of method.

https://ard.bmj.com/content/annrheumdis/26/5/373.full.pdf

Assessment of drugs in out-patients with rheumatoid arthritis. Evaluation of methods and a comparison of mefenamic and flufenamic acids with phenylbutazone and aspirin.

The antipyretic activity of three N-aryl-anthranilic acid derivatives, mefenamic acid, tolfenamic acid and flufenamic acid, was compared and their optimal antipyretic dose determined in a trial in 87 children (aged 5 months to 15 years), who suffered from infections and fever exceeding 38.5°C. Tolfenamic acid proved to be the most potent antipyretic agent of the three drugs; it was eight times more powerful than mefenamic acid and three times more powerful than flufenamic acid. The optimal antipyretic doses were: mefenamic acid 4 mg/kg, tolfenamic acid 0.5 mg/kg and flufenamic acid 1.5 mg/kg. It is evident that the antipyretic activity of these anthranilic acid derivatives is even greater than their antirheumatic effect, the difference being most noticeable in the case of tolfenamic acid.

Oral antipyretic therapy: evaluation of the N-aryl-anthranilic acid derivatives mefenamic acid, tolfenamic acid and flufenamic acid.

SummaryA double-blind crossover study was carried out in 18 patients with classical rheumatoid arthritis to assess the effectiveness of mefenamic acid (500 mg t.d.s.) compared with placebo or indomethacin (25 mg q.d.s.). Each treatment was given for 1 week and subjective and objective assessments were carried out at the end of each period. Results showed that both mefenamic acid and indomethacin were significantly better than placebo in most parameters. Although duration of morning stiffness and patient preference favoured indomethacin it was considered that there was no demonstrable difference of any clinical significance between the two active medications.

H. C. Masheter

Papers

Flufenamic acid in rheumatoid arthritis comparison with aspirin and the results of extended treatment

A controlled study of flufenamic acid in ankylosing spondylitis. A final report and follow-up study

Flufenamic acid in rheumatoid arthritis. The second six months of treatment.