Persistence with statins and onset of rheumatoid arthritis: a population-based cohort study.

BACKGROUND: The beneficial effects of statins in rheumatoid arthritis (RA) have been suggested previously, but it is unclear whether statins may prevent its development. The aim of this retrospective cohort study was to explore whether persistent use of statins is associated with onset of RA. METHODS AND FINDINGS: The computerized medical databases of a large health organization in Israel were used to identify diagnosed RA cases among adults who began statin therapy between 1998 and 2007. Persistence with statins was assessed by calculating the mean proportion of follow-up days covered (PDC) with statins for every study participant. To assess the possible effects of healthy user bias, we also examined the risk of osteoarthritis (OA), a common degenerative joint disease that is unlikely to be affected by use of statins. A total of 211,627 and 193,770 individuals were eligible for the RA and OA cohort analyses, respectively. During the study follow-up period, there were 2,578 incident RA cases (3.07 per 1,000 person-years) and 17,878 incident OA cases (24.34 per 1,000 person-years). The crude incidence density rate of RA among nonpersistent patients (PDC level of <20%) was 51% higher (3.89 per 1,000 person-years) compared to highly persistent patients who were covered with statins for at least 80% of the follow-up period. After adjustment for potential confounders, highly persistent patients had a hazard ratio of 0.58 (95% confidence interval 0.52-0.65) for RA compared with nonpersistent patients. Larger differences were observed in younger patients and in patients initiating treatment with high efficacy statins. In the OA cohort analysis, high persistence with statins was associated only with a modest decrement in risk ratio (hazard ratio = 0.85; 0.81-0.88) compared to nonadherent patients. CONCLUSIONS: The present study demonstrates an association between persistence with statin therapy and reduced risk of developing RA. The relationship between continuation of statin use and OA onset was weak and limited to patients with short-term follow-up.

Lipopolysaccharide induced protection against sulfur mustard cytotoxicity in RAW264.7 cells through generation of TNF-alpha.

Sulfur mustard (HD), a very potent alkylating agent and lipopolysacchride (LPS), are both well characterized inflammatory factors. We have found that concomitant exposure of murine macrophage cells (RAW264.7) to LPS and HD induced protection against HD induced cytotoxicity. Both HD and LPS induce release of inflammatory markers in RAW264.7 cells. However, there are marked differences in the repertoire of inflammatory factors released by the two toxins: While exposure to HD, induced a dose-dependant death of these cells, no significant change in survival rate was observed following LPS (1-100 ng/ml) exposure. Additionally, LPS elicited a robust nitric oxide (NO) and TNF-alpha secretion whereas HD was practically ineffective. Both toxins increased PGE(2) secretion in a concentration dependent manner. Treatment of HD-exposed RAW264.7 cells with anti-inflammatory drugs such as dexamethazone (5 muM), voltaren (diclofenac) (8 muM) or doxycycline (5 muM), decreased the release of cytokines but had no effect on cell viability. Simultaneous application of LPS (100 ng/ml) and HD (20-100 muM) resulted in an amelioration of HD cytotoxicity. Adding the NO generator S-nitrosoglutathione (GSNO) or inhibiting NO production using L-N(G)-monomethyl Arginine, had no effect on cell viability. Moreover, addition of PGE(2) (20 ng/ml) failed to induce any changes in cell viability under basal or HD-induced toxicity. In contrast, TNF-alpha (20 ng/ml) provided remarkable protection against HD-induced cell death. These findings strongly suggest that LPS exerts its protective action against HD toxicity through the generation of TNF-alpha and may provide better understanding of the mechanism of cytoprotection.