Date Published: February 23, 2018
Publisher: Public Library of Science
Author(s): Hilda J. I. de Jong, Jan Willem Cohen Tervaert, Arief Lalmohamed, Frank de Vries, Rob J. Vandebriel, Henk van Loveren, Olaf H. Klungel, Tjeerd P. van Staa, Ying-Ju Lin.
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 (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are widely prescribed drugs to reduce the risk of cardiovascular morbidity and mortality . Statins exert, next to their well-known cholesterol-lowering activity, anti-inflammatory and immunomodulatory effects, and may be beneficial in the treatment of immune-mediated disorders other than atherosclerosis. Indeed, beneficial effects of statins were observed in clinical trials and experimental models of RA [2–4]. The anti-inflammatory effects of statins have been studied in several clinical trials by measuring C-reactive protein (CRP) [5,6]. In these clinical trials it has been shown that statins decrease levels of CRP [5,6]. Since statin therapy reduces the incidence of acute and chronic rejection in heart and renal transplant patients [7,8], the immunomodulating effects have been further studied. Statins have been reported to suppress interferon-γ (IFN-γ)-inducible expression of major histocompatibility complex (MHC) class II proteins in endothelial cells, monocytes/macrophages and T cells [9,10]. Another beneficial effect of statins is the effect on the T helper cells (Th1)/Th2 balance by inducing the secretion of Th2 cytokines (IL-4, IL-5 and IL-10) and transforming factor β (TGF-β), or by suppressing secretion of Th1 cytokines (IL-2, IL-12, IFN-γ and TNF-α) [11,12]. Recently, it has been suggested that statins skew T cell differentiation towards regulatory T cell (T reg) and away from pro-inflammatory Th17 cells via geranylgeranylation of proteins, resulting in promoting Treg differentiation in the periphery, while blocking Th17 cell differentiation . Statins can also down-regulate expression of the co-stimulatory molecule CD40 in various cell types, e.g., endothelial cells, smooth muscle cells and macrophages . Interestingly, certain types of statins selectively block the β-2 integrin, leukocyte function antigen-1 (LFA-1), thereby blocking binding to intercellular adhesion molecule-1 (ICAM-1) and thus reducing T cell activation .
The study population included 1,107,988 patients. After excluding 40,320 patients who were younger than 40 years, 31,460 patients with a medical history of RA and 12,968 patients with prescriptions of DMARDs before the index date, 511,620 statin users and 511,620 non-users were enrolled in the study (Fig 1).
This study demonstrated a 1.3-fold increased risk of developing RA during the first year of statin use. The risk of developing RA was increased shortly after the first prescription of statins and then gradually decreased to baseline level. In recent users, statin use was associated with incident RA whereas in past users no such effect was found.
To our knowledge, this is the first study evaluating risks of RA in statin users over time. In patients who use statins, the risk of RA is substantially increased in the first year after initiation of statins and then diminishes to baseline, suggesting an association between statin use and an increased risk of RA in the first year after initiating statin treatment. Our finding may suggest that statins can accelerate disease onset in patients susceptible to develop RA, but in other patients, statins are probably safe and well tolerated, even after prolonged use. Another explanation for this increased risk of RA shortly after starting statins is ascertainment bias with increased diagnostic monitoring around the time of initiation of statin therapy. Although more research is needed, this study supports our previous finding showing an increased risk of developing RA shortly after starting statin treatment.