Obesity is a serious illness in our society because it plays a major role in several chronic diseases and in premature death (15, 16). Furthermore, obesity is becoming more and more prevalent (17). The percentage of obese RA patients has been shown to reflect the trends of the general population, thus suggesting that patients with RA should be treated accordingly, considering the risk of comorbidities associated with adiposity (18, 19). Obesity was considered among the risk factors for developing RA (6, 7), but more recently, a group from Leiden, The Netherlands, did not confirm the BMI values as a risk factor of evolving into RA in patients with undifferentiated arthritis (20). Second, even more stringent, some studies showed that a BMI of >30 kg/m2 was associated with less erosions over time in an early arthritis cohort in Leiden (20), and was associated with a lower prevalence of mortality among RA patients in Texas (21). These data are very difficult to match with other data, showing that, in longstanding RA, obesity determines higher grades of arthritis-attributable physical limitations (22) and is associated with more disease activity and functional disability (6, 10, 23). In a large community practice database (Quantitative Standardized Monitoring of Patients with Rheumatoid Arthritis) that collected data from 5,161 patients in 25 countries, it was noted that BMI was similar between sexes, but it also transpired that the DAS28 scores among female subjects increased with increasing BMI from normal weight to overweight and obese (24). Of interest, in that study, the association between BMI and disease activity values was not explained by any single component of the DAS28. Our data are different from all of these reports because we focused on patients who were taking anti-TNFα drugs due to persistent unresponsiveness to MTX and who did not change their standard therapy. The findings imply that, besides being patients with longstanding RA, the disease was already persistent, stable, and active. In these patients, the possible positive effect of obesity as seen in other studies in the first years of the disease had already been lost. The patients considered in our study had a persistently active disease and mild to moderate disability, i.e., the worst situation in the long run in terms of future disability and future cardiovascular morbidity. In this setting, we have seen that obesity determines a lower chance of successful response to anti-TNFα therapy and that this occurs more with infliximab and less with adalimumab and etanercept. This result was confirmed in the subanalysis of the BeST (Behandelstrategieën voor Reumatoide Artritis) trial, in which overweight and obese patients responded less than normal weight patients (25) to the combination of MTX and infliximab, whereas in an abstract presented at the American College of Rheumatology Annual Scientific Meeting in Chicago, Illinois in 2011, even etanercept plus MTX in RA patients with moderate disease activity led to a lower clinical response in the 52-week PRESERVE trial (26). The reason that obesity affects the RA outcome in patients treated with infliximab much more than in those treated with etanercept and adalimumab needs to be clarified. In fact, these findings do not seem to be the result of pharmacokinetic factors, as discussed in the study by Klaasen et al (11), and to our knowledge, there are no data about a possible infliximab compartmentalization in the adipose tissue. On the other hand, it is well known that adipose tissue is a source of specific adipocytokines (e.g., leptin, resistin, adiponectin, and visfatin) that are increased in RA patients and are able to increase the expression of inflammatory cytokines, such as TNF and interleukin-6. Therefore, it could be speculated that the adipose tissue might play a role in creating a more inflammatory and therapy-resistant state. In this regard, however, studies testing the effect of TNF blockade on adipokine plasma levels in patients with RA are not conclusive, and the majority of the studies show that anti-TNF drugs have no influence on the levels of adipocytokines (27). However, the adipose tissue may be associated with an induction of resistance to all of the anti-TNF drugs, and understanding its role requires further research.
Our data obtained from a large cohort of patients provide more insight into the findings of Klaasen et al (11). In that study, after 16 weeks of treatment with infliximab, 89 patients observed a highly significant negative association between BMI and the absolute decrease in DAS28. From a clinical point of view, this appears to be extremely important because the persistence of inflammation already represents a high risk of cardiovascular disease and RA is considered at the same risk level as type 2 diabetes mellitus (1, 2, 28, 29). In this setting, obesity may represent a further challenge in terms of treatment of inflammatory conditions such as RA, either because it represents per se a mild inflammatory condition (1, 30) or because it can reduce the response to therapy, especially in patients who need to be treated with TNFα blockers, and then add to the conventional risk factors for cardiovascular morbidity. Indeed, even in our cohort, despite a great overall improvement, the nonremitters still had high inflammatory parameters, albeit in a minority of patients. Certainly, inflammation and disability represent the first target of any therapy in patients who are incomplete responders to MTX, yet there are no algorithms for choosing among the TNFα blockers as a rescue therapy in obese patients with RA. We have provided data obtained from a real-life setting that can be of help in clinical practice. The data should be further confirmed in other registry databases, so that all possible confounders existing in the general RA population can be normalized. After checking for possible confounders (steroids, DMARDs alternative to MTX, etc.), we have reached some practical conclusions.
The first conclusion is that a high DAS28 in the therapeutic protocol certainly plays the most relevant role in determining a lower chance of remission. Obesity represents a further additional risk of not reaching remission. In this setting, the highest chance of putting RA into remission is provided by 2 TNFα blockers (etanercept and adalimumab), with the lowest chance provided by another TNFα blocker (infliximab). The findings appear relevant when one considers the need of a personalized therapy (31). Moreover, the results indicate importance in terms of pharmacoeconomics, which means achieving the best possible results by making the right choice at any phase of the disease in a patient with a poor response to MTX.