Pattern of risks of rheumatoid arthritis among patients using statins: A cohort study with the clinical practice research datalink

Abstract

We examined the association between statin use and the risk of rheumatoid arthritis (RA), with special focus on describing the patterns of risks of RA during statin exposure in a large population-based cohort in the United Kingdom. In the Clinical Practice Research Datalink, patients aged ≥40 years with at least one prescription of statins (1995–2009) were selected, and matched by age (+/-5 years), sex, practice and date of first prescription of statins to non-users. The follow-up period of statin use was divided into periods of current, recent and past exposure, with patients moving between these three exposure categories over time. Time-dependent Cox models were used to derive hazard ratios (HRs) of RA, adjusted for disease history and previous drug use. The study population included 1,023,240 patients, of whom 511,620 were statin users. No associations were found between RA and current (HRadj,1.06;99%CI:0.88–1.27) or past statin users (HRadj,1.18;99%CI:0.88–1.57). However, in patients who currently used statins, hazard rates were increased shortly after the first prescription of statins and then gradually decreased to baseline level. The risk of developing RA was increased in recent statin users, as compared to non-users (HRadj,1.39;99%CI:1.01–1.90). The risk of RA is substantially increased in the first year after the start of statins and then diminishes to baseline level. These findings may suggest that statins might accelerate disease onset in patients susceptible to develop RA, but in other patients, statins are probably safe and well tolerated, even after prolonged use. Alternatively, we cannot rule out that confounding by cardiovascular risk factors and ascertainment bias may have influenced the findings.

Statins and autoimmunity: State-of-the-art

“…These observations show that statins trigger immunomodulatory effects that mitigate acute and chronic rejection of transplanted kidneys and hearts. These observations prompted studies investigating the anti-inflammatory and immunomodulatory effects of statins (de Jong et al, 2018) (Fig. 2).…”

“…Simvastatin has been shown to inhibit the production of pro-inflammatory mediators by altering the gene expression of cyclooxygenase-2 (COX2) and IFN-γ (C. S. Lee et al, 2009). Numerous clinical trials have reported statin-mediated reductions in C-reactive protein (CRP), as well as inhibiting the production of MMP1 and MMP3, which are involved in connective tissue degradation (Crouse, et al, 2007;de Jong et al, 2018;Ridker et al, 2009).…”

“…More than 30 years ago, lovastatin was introduced as the first pharmacological agent able to reduce Low-Density Lipoprotein (LDL)-cholesterol to unprecedented levels, without serious side effects. By inhibiting 3-hydroxy-3-methyl-glutarylcoenzyme A (HMG-CoA) reductase, the first step of the L-mevalonate pathway is competitively inhibited (de Jong et al, 2018;Salvo & Franchini, 2019;Ulivieri & Baldari, 2014). Although debate continues as to whether the observed cardiovascular disease (CVD) benefits can be explained solely by the LDL-cholesterol-lowering properties or the combination of cholesterol reducing and non-cholesterol effects, numerous studies have pointed out that statins can influence anti-inflammatory, immunomodulatory, and anti-thrombotic properties, as well as endothelial function (Chruściel et al, 2016;Hashemi et al, 2017;Parizadeh et al, 2011;A.…”

Cardiac and vascular complications in rheumatoid arthritis

“…A meta-analysis on the use of statins in patients with RA indicated that they may have an anti-inflammatory effect as well as a lipid-lowering property [ 54 , 55 ], with atorvastatin reducing the disease activity score more than simvastatin, although there are conflicting reports where statins are associated with increased risk of developing RA in the first year of use [ 56 ]. Taking into account that some specific RA medications also affect the lipid profile of patients, it is advocated that lipid screening should be performed on all patients with RA as soon as they have achieved low disease activity [ 2 , 57 ].…”

Biocatalyzed Synthesis of Statins: A Sustainable Strategy for the Preparation of Valuable Drugs

“…Thus, as a consequence of the inhibition of GTPases prenylation, statin-based therapy can be a potential alternative for the treatment of autoimmune diseases [44,47,48]. In fact, positive effects of statin treatment have been reported in numerous autoimmune diseases such as multiple sclerosis [49,50], systemic lupus erythematosus [51][52][53], autoimmune myocarditis [54][55][56], or rheumatoid arthritis [44,[57][58][59].…”