Background Synthetic disease-modifying antirheumatic drugs (DMARDs) though effective have limitations often requiring use of expensive parenteral biologic DMARDs in ankylosing spondylitis. Hence there is a need for safe, efficacious economical therapies for management of disease and its co-morbidities. Anticytokine therapy with Biologic DMARDs is efficacious but has limitations. Given the anti-inflammatory and immunomodulatory potential of spironolactone (SPIR)^1,2, we investigated the anti-inflammatory potential of SPIR in AS in randomized, placebo-controlled open label study.

Objectives To investigate the anti-inflammatory effects of spironolactone in AS

Methods Fifty ankylosing spondylitis patients fulfilling the 1984 Modified New York Criteria were randomized to receive 24 weeks of treatment with spironolactone (n=25, 2 mg/kg/day) or placebo (n=25) as an adjunct to existing stable antirheumatic drugs. Therapy results were evaluated by assessment of inflammatory measures BASDAI, ASDAS, BASFI, ESR and CRP and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1) at baseline and after 24 weeks treatment. Assessment of endothelial function by brachial artery flow-mediated dilatation (FMD) and ultrasound assessment of carotid intima-media thickness (CIMT), ankle brachial index (ABI) and nitrite level was made. Circulating EPCs (CD34⁺ CD133⁺) were quantified by flow cytometry. Quality of life (QoL) was assessed using HAQ-DI

Results The SPIR and placebo groups were well matched at baseline. Of the 50 randomized patients, 45 completed the study, 23 in the SPIR group and 22 in the placebo group. Two patients were excluded in the SPIR group (one due to protocol violation and other lost to follow-up) and three in the placebo group were lost to follow-up. After 24 weeks: inflammatory measures BASDAI, ASDAS, BASFI, ESR and CRP (All p<0.001) were significantly reduced after treatment with spironolactone but did not show significant change with placebo (p>0.05). Proinflammatory cytokines, TNF-α and IL-6, significantly reduced after treatment (Both p<0.001) in SPIR arm. After 24 weeks treatment, surrogates of vascular function including FMD, CIMT and nitrite level significantly improved p<0.001, p<0.001 and p=0.01 respectively in SPIR arm compared with placebo. EPCs significantly increased 0.027±0.009 to 0.033±0.005, p<0.001 after treatment with SPIR compared with Placebo 0.025±0.006 to 0.027±0.010, p=0.27. The effect of SPIR on IL-1 and ABI is less clear (p=0.063 and 0.065 respectively), though it showed a trend towards significance. QoL improved significantly in SPIR group as compared to placebo. A significant correlation was observed between clinical response, reflected by changes in BASDAI and the degree of increase in EPCs

Conclusions First study to show that spironolactone significantly improves inflammatory disease activity, EPC biology and endothelial dysfunction in AS possibly through its anti-inflammatory effect via inhibition of proinflammatory cytokines. This anti-inflammatory and immunomodulatory effect of spironolactone may help to reduce disease activity as well as associated cardiovascular risk in AS.

References

1. Bendtzen K et al. Clin Exp Immunol. 2003;134:151–158.

2. Syngle A et al. Arthritis Rheum. 2014;66 (11). S639.

Acknowledgements We are very grateful to University Grant Commission, New Delhi (Govt. of India) for providing the research fellowship [No. F.10-15/2007 (SA-I)].

Disclosure of Interest None declared