Background Nuclear factor kappa B (NF-κB) as a transcription factor plays an important integrating role in the intracellular regulation of immune response, inflammation and cell cycle regulation.1 NF-κB is one of the most important regulators of proinflammatory cytokines involved in the chronic inflammatory processes that often aggravate bone loss, such as RA.2 NF-κB-targeting anti-inflammatory agents that are specific, efficacious, and cost-effective may therefore complement current therapies. Here we have investigated the effect of spironolactone (SPIR) on proinflammatory cytokines, inflammatory disease activity and cardiovascular surrogates in rheumatoid arthritis (RA)
Objectives A randomized, placebo-controlled, parallel study to investigate anticytokine effect of spironolactone in RA
Methods Sixty four patients with RA were included and randomly assigned to either SPIR (2 mg/kg/day) or matched placebo in addition to combination of csDMARDs for 24 weeks. Inflammatory biomarkers (ESR, CRP) and Disease Activity Score in 28 joints (DAS28), simple disease activity index (SDAI) and ACR response criteria were measured at baseline and after 24 weeks therapy. Pro inflammatory cytokines (TNF-α, IL-6 and IL-1) and assessment of endothelial function by brachial artery flow-mediated dilatation (FMD), CIMT, ankle brachial index (ABI) and nitric oxide level were made. Endothelial progenitor cells (EPCs) (CD34+/CD133+) were quantified by flow cytometry. Quality of life was measured with HAQ-DI and the Short Form Health Survey (SF-36), Questionnaire.
Results The SPIR and placebo groups were well matched at baseline. Of the 64 randomized patients, 58 completed the study, 30 in the SPIR group and 28 in the placebo group. Two patients were excluded in the SPIR group (one due to hyperkalemia and other to less than 80% compliance) and four in the placebo group due to compliance less than 80%. At 24 wks; proinflammatory cytokines TNF-α, IL-6 and IL-1 were significantly reduced p<0.001, p=0.001, p=0.002 respectively in SPIR group compared with placebo. In the SPIR group, biomarkers of inflammation (ESR and CRP), disease activity measures (DAS-28 and SDAI) significantly reduced (all p<0.001) compared with placebo group. After 24 wks treatment; the ACR improvement response rates of >20% (SPIR 66% versus placebo 28%), >50% (SPIR 43% versus placebo 17%), and >70% (SPIR 20% versus placebo 7%) were observed in both the active treatment groups. Surrogates of vascular function including FMD, CIMT, ABI, nitrite and EPCs (CD34+/CD133+) significantly improved p<0.001, p=0.01, p=0.006, p<0.01 and p<0.001 respectively in SPIR arm compared with placebo. SPIR group QoL improved significantly more than placebo HAQ as well as SF-36 scales (All p=0.01) after 24 wks treatment.
Conclusions Spironolactone is a potent anti-inflammatory and cardio-protective agent that significantly reduces inflammatory disease activity and improves quality of life by simultaneously inhibiting the production of several proinflammatory cytokines.
Brown KD et al. Arthritis Res Ther. 2008; 10(4):212
D Acquiosto et al. Mol Interv. 2002; 2(1):22-35
Acknowledgements We are very thankful to University Grant Commission, New Delhi (Govt. of India) for providing the research fellowship (No. F.10–15/2007 [SA-I]).
We are very thankful 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