Do Tumor Necrosis Factor α Inhibitors Cause Weight Gain ?

John J. Cush, Kathryn H. Dao, Catalina Orozco Chronic systemic inflammation yields a notable and proportional risk for myocardial infarction, coronary artery disease, heart failure and cardiovascular (CV) death. The role of tumor necrosis factor (TNF) in the pathogenesis of cardiovascular events and congestive heart failure (CHF) in rheumatoid arthritis (RA) has been well documented (1-4). TNFα mediates anorexia, cardiac cachexia and endotoxic shock, and also induces left ventricular hypertrophy (LVH), LV dysfunction/remodeling/dilation and has negative inotropic effects on the myocardium. Many studies have shown increased circulating levels of TNF in heart failure, especially in those with New York Heart Association (NYHA) class III and IV disease, which correlates with the morbidity and mortality of CHF. Finally, transgenic mice that over express TNFα tend to die prematurely from dilated cardiomyopathy. The vascular and myotoxic effects of TNF have led to the hypothesis that TNF inhibition may benefit patients with CHF, improving both myocardial function and overall survival. Two large trials examined the use of etanercept and 1 trial studied infliximab in patients with NYHA class III and IV CHF (without any history of RA). Surprisingly, and paradoxically, these trials failed showing both a lack of CV benefit and poorer outcomes – especially for those treated with higher doses (5). Etanercept has been tested in 2,048 CHF patients followed for less than two years and failed to show any improvement in survival, hospitalizations or NYHA class. Trials were suspended and no further use was planned. Infliximab was also tested in a 150 patient-controlled trial performed in patients with NYHA Class III/IV disease. An interim analysis at 24 weeks resulted in this trial being prematurely discontinued for a dose-related increase in hospitalizations and deaths (5, 6). Reasons for these failed results are thus far inexplicable. Prescribing guidelines suggest that TNF inhibitors (TNFi) may cause worsening or new onset CHF and that clinicians should exercise caution when using TNFi in patients with CHF. Such patients should be monitored closely and the TNFi use suspended with the onset or worsening of CHF. In the early registration trials, the risk of new-onset CHF was 0.06%, 0.2% and 0.26% for etanercept, infliximab and adalimumab respectively (7). In 2003, Kwon reported 47 RA cases with new onset or worsening CHF reported to the FDA; 38 with new-onset CHF and 9 with CHF worsening (8). Half had no identifiable risk factors, and 10 patients were younger than 50 years of age when they developed newonset heart failure. Although there have been several reports of new onset CHF in patients initiating TNFi therapy, this appears to be a rare event. Most have recommended the avoidance of TNFi in patients with NYHA Class III or IV heart disease. Nevertheless, there is a growing body of literature supporting the cardiac safety or benefits of TNF targeted therapies in patients with RA. Recognizing that patients with CHF and cardiac disease are usually excluded from clinical trials, the early trials of etanercept, infliximab and adalimumab showed more de novo CHF events in those on placebo than the TNFi comparator (6). Numerous studies and registries of RA patients have demonstrated a cardioprotective effect of TNF inhibition on myocardial infarction and new cardiac events (9,10). Wolfe and Michaud studied 13,171 RA patients in the National Databank for Rheumatic Disease, noting more cases of CHF in RA (compared with osteoarthritis), however this was not higher in patients receiving TNFi (11). A retrospective cohort study of 303 Veterans Administration RA patients failed to show a higher rate of CHF admissions or mortality amongst those treated with TNF blockers(12). Listing examined 4,248 RA patients on TNFi and DMARDs in the RABBIT registry over 3 years and found that CHF was 5 times more likely in those with CV disease compared to those without (2.2% vs. 0.4%). When TNFi was given to patients with or without prior CHF, CHF rates were not higher in those receiving DMARDs (13). Factors most predictive of new onset CHF included age, prior CHF, DAS activity, male sex and higher BMI. Effective reduction of inflammatory activity in RA with TNFi therapy was more likely to be beneficial than harmful with regard to the risk of heart failure – especially if there is no concomitant therapy with glucocorticoids or cyclooxygenase-2 inhibitors. Using administrative claims from a large U.S. health care organization and studying individuals under the age of age 50, Curtis focused on 4,018 RA and Crohn’s disease (CD) patients and identified 9 new cases of CHF (0.2%). The relative risk of incident CHF among TNFi-treated RA and CD patients was elevated