In the september issue of PloS Medicine, a study showing the association between the use of statins and incidence of Rheumatoid Arthritis has been published.
A retrospective cohort study was done to explore whether persistent use of statins is associated with onset of Rheumatoid Arthritis (RA).
Rheumatoid Arthritis is a chronic systemic inflammatory condition characterized by leukocyte recruitment into synovial tissue. There is growing evidence that statins have anti-inflammatory and immunumodulatory properties, demonstrated by reducing the level of C-reactive protein (CRP) that may play an important role in RA, independent of their cholesterol lowering effects. Some small studies have demonstrated a modest beneficial effect of statins in RA.
In contrast, a large US study showed no beneficial effect for statins among 31,451 RA patients as measured by initiation and cessation of oral steroids.
A large study (more than 200,000 patients) with a long follow-up period (average of 10 years) was conducted to discover whether there was any kind of association between persistent use of statins and the onset of rheumatoid arthritis. This was conducted among the members of Maccabi Healthcare Services in Israel. The cohort covered the period 1998–2007 and included members who were continuously enrolled in the HMO from 1995 to 1998.
New users of statins were identified among all MHS enrollees aged 18 y or older, who from January 1, 1998 to July 1, 2007 had at least one dispensed prescription of 3-hydroxy-3-methylgluraryl coenzyme A (HMG-CoA) reductase inhibitors (e.g., lovastatin, pravastatin, simvastatin, atorvastatin).
Then the incidence of newly diagnosed rheumatoid arthritis was analyzed, recording the date of first diagnostic codes (International Classification of Diseases, 9th revision [ICD-9]) associated with rheumatoid arthritis during the study follow-up period.
To assess any potential effects of “healthy adherer” bias (good adherence to medication in patients with a chronic illness may be more likely to lead to better health and improved survival), the researchers also examined any possible association between persistent statin use and the development of osteoarthritis (OA), a common degenerative joint disease that is unlikely to be affected by statin use
The mean proportion of days covered (PDC) were calculated.
During the study follow-up period, there were 2,578 incident cases of rheumatoid arthritis and 17,878 incident cases of osteoarthritis. The crude incidence density rate of rheumatoid arthritis among patients who did not persistently take statins was 51% higher than that of patients who used statins for at least 80% of the follow-up period.
Furthermore, patients who persistently used statins had a risk ratio of 0.58 for rheumatoid arthritis compared with patients who did not persistently use statins. In the osteoarthritis cohort analysis, high persistence with statin use was associated with a modest decrement in risk ratio (0.85) compared to patients who did not persist with statins.
The authors have themselves compared the strengths and limitations of the study.
Strengths of this study include prospective data collection, the use of administrative databases to avoid the problem of differential recall bias, the systematic and comprehensive collection of personal socio-demographic data, medical history, and utilization of health services prior to the index date, which reduces the possibility for bias due to study outcomes. The present retrospective cohort is one of the largest undertaken to date on the relationship between statin therapy and RA, with respect to the length of follow-up and the size of the study population.
The authors have highlighted the following limitations. The analysis was retrospective in nature and allocation of statin therapy was not randomized. Despite adjustment for baseline differences and an abundance of poor prognostic factors, a higher proportion of days covered with statins could still be a surrogate for other unmeasured variables that reflect a higher quality of care and more aggressive treatment strategies. In the analysis the different temporal variations in patients' use of statins over the study period were not addressed. However, a majority of RA patients (79%) purchased statins at least 3 mo prior to diagnosis. Also, the similarity in study results when limiting the analysis to patients with at least 5 y of follow-up reduces the possible effect of this potential limitation.
The most important methodological limitation in estimating effectiveness in observational studies is the potential for “healthy adherer” bias. In order to evaluate this potentially important bias in the study, a analysis with OA as an outcome was conducted. Results indicated that persistent use of statins was associated with a 15% lower OA risk, a relatively small difference compared to RA risk, but one that needs to be noted when considering the results of the study overall. In addition, the reduced risk for OA in patients with high PDC with statins was limited to patients with short follow-up periods and was not found in patients with a follow-up of 5 y or more. This finding supports the notion that most of the RA risk reduction is due to a real biological effect.
In conclusion, this study showed that persistence with statin treatment was associated with an ongoing decrement in the risk for contracting RA. The observed associations were greater than those that would be expected from methodological biases alone. Larger, systematic, controlled, prospective studies with high efficacy statins, particularly in younger adults who are at increased risk for RA, are needed to confirm the findings, and to elucidate the possible biological relationship between adherence to statin therapy and RA onset.
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000336
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