Cholesterol-lowering statin drugs may also reduce the risk of developing rheumatoid arthritis by over 40%, the Daily Mail reported.

The news is based on a large Israeli study, which looked at how the regularity of patients’ use of statins related to their chances of developing the painful joint problem. It found that the most infrequent users of statins had around double the risk of rheumatoid arthritis compared with those taking the most statins. The research was well conducted and generally well reported, but its design has some limitations. An important shortcoming is its failure to take into account some medical and lifestyle factors that could have influenced its results. Controlled trials are now necessary to establish whether statins do reduce the risk of arthritis.

People who have not been recommended or prescribed statins should not take them to attempt to prevent rheumatoid arthritis. Equally, people who have been prescribed or recommended statins by their GP should take their medication as instructed for cholesterol lowering.

Where did the story come from?

The study was carried out by researchers from Tel Aviv University and other medical and academic centres in Israel. The authors report that no funding was required for the study, which was published in PLoS Medicine, the peer-reviewed medical journal of the Public Library of Science.

There are some potentially misleading points in the news articles. Firstly, the Daily Mirror’s claim that people taking the drugs had a “42% reduced risk of the disease, compared with those not taking the drugs” is incorrect. All the people in this study took statins for at least part of the study period, and there was no analysis of the effects of not taking the drugs.

Some news sources also suggested that the study sample included 1.8 million participants, which is incorrect. The research only looked at a subset of that total, who had taken statins and had other necessary data available for analysis. The study analysed data on 211,627 people in the rheumatoid arthritis calculations and 193,770 in the osteoarthritis calculations.

What kind of research was this?

This was a retrospective cohort study of people who were taking statins. The study followed them up for about five years on average to determine the rate of new cases of rheumatoid arthritis and osteoarthritis in relation to the participants’ levels of statin use.

What did the research involve?

The researchers recruited adults aged over 18 who registered with a particular Israeli health insurance organisation between 1995 and 1998. Those recruited to the study had been prescribed at least one statin (simvastatin, fluvastatin, pravastatin, cerivastatin or lovastatin) for the first time between January 1998 and July 2007. This cohort population, which was identified through the health insurer’s database, was followed up until one of the following outcomes: a diagnosis of rheumatoid arthritis or osteoarthritis, death, leaving the insurance organisation or the end of the study in December 2007. People with rheumatoid arthritis, osteoarthritis or rheumatic fever at the start of the study were excluded.

For each participant, the researchers calculated the “proportion of days covered”, a measure of the amount of time they had spent taking statins during the study period. They grouped the participants into the following proportions of statin coverage: <20%, 20-39%, 40-59%, 60-79% and ≥80% of the study period. They compared each category with the people who used statins for less than 20% of the time (considered to be “non-adherent patients”) to see whether greater statin use was associated with a different incidence of rheumatoid arthritis or osteoarthritis.

The researchers adjusted their analysis model to account for the influence a number of other factors, including age, gender, socioeconomic level, nationality, marital status, other health conditions, use of health services, LDL cholesterol levels and how effective the statin therapy had been (in terms of how well it lowered LDL cholesterol levels). The analysis only included people who had taken statins and for whom information on the potential confounders was available. This left 211,627 people for inclusion in the rheumatoid arthritis analysis and 193,770 people in the osteoarthritis analysis.

The researchers compared the risk of onset of rheumatoid arthritis and osteoarthritis across the different levels of statin use during the follow-up period. Patients were followed up for an average of about five years.

What were the basic results?

During the follow-up period, there were 2,578 cases of rheumatoid arthritis across the 211,627 people in this analysis. There were 17,878 cases of osteoarthritis in the 193,770 people included for this analysis. As expected, the type of arthritis that occurred differed across the age groups, with new cases of osteoarthritis peaking in women aged 65 to 74.

After adjusting for the influence of health and lifestyle factors, the study found that those taking statins for 80% or more of the time were almost half as likely (0.58 times) to develop rheumatoid arthritis than people taking statins for less than 20% of the study time (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.52 to 0.65).

In a separate analysis, it seems that the reduction in risk of rheumatoid arthritis was associated with the effectiveness of the statin treatment. Patients with the greatest reduction in cholesterol levels showed a greater reduction in rheumatoid arthritis risk than those with less effective anti-cholesterol treatments. Also, the effects seemed more pronounced in younger age groups.

A reduced risk of osteoarthritis was also associated with greater statin use, but not to the same degree as with rheumatoid arthritis (HR 0.85, 95% CI 0.81 to 0.88).

How did the researchers interpret the results?

The researchers concluded that their study demonstrates a link between persistence with statin therapy and a reduced risk of developing rheumatoid arthritis.

Conclusion

This large cohort study has established a link between longer use of statins and a reduced risk of rheumatoid arthritis and osteoarthritis. It should be noted that the study compared the incidence of rheumatoid arthritis in people taking different amounts of statins, but did not assess arthritis risk in people who did not use statins. Therefore, this study cannot tell us whether taking the drugs is better at preventing rheumatoid arthritis than taking no statins at all.

The study’s design had a number of potential limitations:

• It is not clear whether the study took into account all possible confounding factors (those linked to the exposure and outcome).
• One important potential confounder is the cholesterol-lowering action of statin drugs. Lower rates of rheumatoid arthritis were associated with greater reductions in cholesterol levels, but the study does not show whether any potential arthritis-preventing effect might be due to the properties of the statin drugs or the lower cholesterol levels.
• The researchers also note that the “proportion of days covered with statins” may be a surrogate for other unmeasured variables, such as higher quality of care or more aggressive treatment strategies.
• Mild muscle pains are one of the frequent side effects of statins, which the researchers say are documented in 5% to 10% of outpatients on statins. If the pain of early rheumatoid arthritis was mistaken for this side effect and made people stop their statin therapy, this could account for some of the association seen.
• Another important problem is a bias called “healthy adherer effect”. This describes the fact that people who adhere to treatments, even placebos, have better outcomes. To investigate this, the researchers assessed the incidence of osteoarthritis in a similar sample to the rheumatoid arthritis group. They found a small but significant reduction in risk of this condition too. However, they say that because this was small compared to the reduction in rheumatoid arthritis risk, the finding supports the notion that most of the reduction in rheumatoid arthritis risk is due to a real biological effect.

The researchers call for further study in this area, saying that “larger, systematic, controlled, prospective studies with high efficacy statins, particularly in younger adults who are at increased risk for rheumatoid arthritis” are needed to confirm their findings. The most appropriate way to test a drug for a new use is with randomised controlled trials.

Links To The Headlines

Patients on statins to lower cholesterol 'at less risk of arthritis' study finds. Daily Mail, September 8 2010

Cholesterol drugs help in arthritis. Daily Mirror, September 8 2010

Statins may cut arthritis risk, study suggests. BBC News, September 8 2010

Links To Science

Chodick G, Amital H, Shalem Y et al. Persistence with Statins and Onset of Rheumatoid Arthritis: A Population-Based Cohort Study. PLoS Medicine 7(9)