Causality or Confounding by Indication: Do Statins Promote Development of Rheumatoid Arthritis? Comment on the Article by de Jong et al.
We read with interest the retrospective case-control study by de Jong et al.(1) The authors found an intriguing association between statin use and development of rheumatoid arthritis (RA). Some comments regarding the methodology and authors statements, may be appropriate.
Evaluating treatment effects in observational studies can be problematic as prognostic factors influencing treatment decisions can cause so-called "confounding by indication". The baseline characteristics show that the prevalence of cardiovascular co-morbidity is considerably higher in cases versus controls. Since statin therapy is standard care in people with a high cardiovascular risk, this could explain more statin use in the RA group. Moreover, one study showed that the lipid profile of subjects who later developed RA is more atherogenic than of subjects who did not develop RA.(2) As the authors have correctly mentioned in the discussion, data on hyperlipidemia is limited. We therefore disagree with the statement that statins may promote the development of RA. To our opinion, this association could be based on the underlying predisposition to develop hyperlipidemia and cardiovascular disease, which is already present long before individuals develop RA.
Another point of concern is the selection of the study population. The investigators selected all patients with the ICPC code L88 (arthritis) if they were referred to a rheumatologist or had had a prescription of at least one DMARD or two or more prescriptions of corticosteroids.
In the Netherlands many patients are referred to the rheumatologist and only 10-20% has indeed RA. Furthermore, corticosteroids and DMARDs are prescribed for many (rheumatic) diseases other than RA. This could mean that patients with polymyalgia rheumatica, psoriatic arthritis or even systemic lupus erythematosis (SLE) are included in the cases group. In part, this problem could have been solved by verification of the diagnosis in the medical record. Furthermore, the controls do not seem to be matched for general practitioner (GP). Some GP's are more keen on cardiovascular risk management and prescribe statins more frequently. Would multilevel logistic regression analyses not have been more appropriate to correct for this sampling bias?
As to the underlying mechanisms behind the association, the authors suggest that statins increase the production of autoantibodies by promoting a shift in the TH1/TH2 balance. However, Kanda et al. demonstrated a reduction of the Th1/Th2 and CD4/CD8 ratios, rheumatoid factor, erythrocyte sedimentation rate and C-reactive protein levels after statin use, implying an anti-inflammatory effect and down-regulation of T-cell mediated immune responses(3). To date there are more studies showing an anti-inflammatory (4) and beneficial effect on onset and activity of Th1 mediated diseases like RA(5) and multiple sclerosis(6) than case reports showing a possible triggering effect of statins on auto-immune diseases like autoimmune hepatitis(7) and SLE(8).
Despite the possibility of confounding by indication, this study raises important questions regarding the role of statins in the development of RA. We definitely concur more evidence is needed to confirm this association before statins are withheld, since cardiovascular disease is a prominent health problem especially among individuals with prodromal RA.
1. de Jong HJI, Klungel OH, van Dijk L, et al. Use of statins is associated with an increased risk of rheumatoid arthritis. Ann Rheum Dis 2011 Oct 6. epub ahead of print.
2. van Halm VP, Nielen MM, Nurmohamed MT, et al. Lipids and inflammation: serial measurements of the lipid profile of blood donors who later developed rheumatoid arthritis. Ann Rheum Dis 2007;66:184-8.
3. Kanda H, Yokota K, Kohno C, et al. Effects of low-dosage simvastatin on rheumatoid arthritis through reduction of Th1/Th2 and CD4/CD8 ratios. Mod Rheumatol 2007;17:364-8.
4. McCarey DW, Sattar N, McInnes IB. Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases? Art Res Ther 2005;7:55-61.
5. Jick SS, Choi H, Li L et al. Hyperlipidaemia, statin use and the risk of developing rheumatoid arthritis. Ann Rheum Dis 2008;68:546-551.
6. Willey JZ, Elkind MSV. 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the treatment of central nervous system diseases. Arch Neurol 2010;67(9):1062-1067.
7. Alla V, Abraham J, Siddiqui J, et al. Autoimmune hepatitis triggered by statins. J Clin Gastroenterol 2006;40(80):757-61.
8. Noel B. Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review. J Eur Acad Dermatol Venereol 2007;21:17-24.
Conflict of Interest: