Anti-tumour necrosis factor-α treatment and weight gain in psoriasis: the ‘pudgy blanching’ conundrum
Authors: L. Puig
Journal: British Journal of Dermatology (2013)

The article by Gisondi et al.1 in this issue of BJD provides further confirmation that body weight gain on long-term treatment of patients with psoriasis is a class effect of antitumor necrosis factor (anti-TNF)-α agents, which appears not to be shared by ustekinumab,1 methotrexate2, 3 or efalizumab.3 This multicentric prospective study included two cohorts of patients with moderate to severe psoriasis without psoriatic arthritis that were treated with infliximab or ustekinumab for 7 months. There were no significant differences between both groups with regard to sex distribution, age, prevalence of diabetes, baseline body weight and Psoriasis Area and Severity Index (PASI) or eventual PASI 75 response rates (58% vs. 69%, respectively). Baseline body mass index (BMI) did not influence the risk of weight gain in patients treated with infliximab, who put on a mean of 2·5 kg, with a mean BMI increase of 2·1%. The authors suggest that this differential effect could be taken into account in the selection of biologics for treating patients with psoriasis. Weight gain associated with the treatment of psoriasis with anti-TNF-α agents was initially reported in 2008 by two Italian groups,2, 3 and may be more persistent in patients treated with etanercept.3, 4 Up to one-fourth of patients may experience a 4–10-kg weight gain,2 and 32% of patients on etanercept and 25% on adalimumab had an increase in weight of more than 10% in a 48-week evaluation.3 According to one study, the percentage change in body weight associated with infliximab treatment of psoriasis is larger in patients with normal weight at baseline than in their overweight/obese counterparts,5 but this finding has not been confirmed.1, 6 Normal weight participants in recent open prospective studies showed a greater increase in fat mass than lean mass compared with obese participants,7 and weight changes correlated with fat mass gain in patients with psoriasis and with fat and lean mass gain in patients with psoriatic arthritis.8 A recently published multicentric French study included 191 patients who had received infliximab for at least 1 year.6 Nearly 50% of them suffered from weight gain (> 2% above baseline); their mean weight change was 7·8%, and in 10% the weight increment was 10% or more.6 Male sex, psoriasis severity and low baseline BMI were associated with greater weight increment on univariate analysis, whereas dietary management during infliximab treatment and simultaneous methotrexate intake provided protection against weight gain on multivariate analysis.6 The association of anti-TNF-α treatment with weight gain is now well established in psoriasis1-9 and psoriatic arthritis,3, 4, 7, 8, 10, 11 and has also been observed in patients with spondyloarthropathy,10, 11 rheumatoid arthritis12, 13 and Crohn disease.14 Little is known about the mechanisms leading to weight gain in those patients, but changes in physical activity, smoking habits or diet have not been reported to affect the outcome.8 Pro-inflammatory cytokines such as TNF-α, interleukin (IL)-1, IL-6 and interferon-γ have been involved in wasting associated with cachexia, and their activities are closely interrelated.15 Interestingly, IL-6 blockade with tocilizumab leads to a significant weight gain after only 16 weeks of treatment in patients with inflammatory rheumatic disorders, which appears not to be the case following infliximab treatment.16 TNF-α blockade may lead to an increase in leptinaemia14 and a return to true baseline weight in the absence of inflammation.6 The association between weight gain and baseline levels of biomarkers of inflammation (such as IL-6), which has been found in some studies,7, 8, 10, 11 is consistent with this hypothesis. TNF-α is produced by infiltrating macrophages in adipose tissue, and functions as a paracrine and/or autocrine factor contributing to the insulin resistance of overall obesity,17 which would be expected to be eventually reversed by TNF-α blockade. Lean patients would not be subject to this effect, and this might provide an explanation for the greater relative increase in weight in patients with normal BMI as opposed to obese/overweight patients,5 but the opposite has also been reported.9 Body weight increment in patients treated with anti-TNF-α agents has several consequences, including undesired changes in body appearance and the implications of metabolic syndrome, from increased cardiovascular risk or abnormal glucose tolerance to sleep apnoea. A statistically significant reverse correlation between BMI and PASI improvement has not been detected,3, 4 even in obese patients treated with etanercept,18 but optimal responses to biological agents prescribed at fixed doses are less frequent in patients with increasing weight.19 In the BELIEVE study, body weight at baseline has been shown to be an important predictor of response to treatment with adalimumab in patients with psoriasis20 and psoriatic arthritis.21 Even though the efficacy of infliximab treatment does not seem to depend on patient weight, in 10% of patients treated with infliximab, the weight gain may lead to at least a 10% increase in the cost of treatment.22 All these factors must be taken into account when a therapeutic decision has to be made in patients with psoriasis and/or psoriatic arthritis, and diet and nutrition advice should be recommended systematically in patients treated with anti-TNF-α agents, even in normal weight subjects. Prevention of weight increase might also be a bonus when combination treatment with methotrexate is taken into consideration to increase the efficacy and decrease the immunogenicity of anti-TNF-α agents. Further research should be done on the mechanisms and characteristics of weight gain associated with anti-TNF-α treatment, with special emphasis on body composition and fat distribution in these patients, and special consideration should be given to the assessment of this potential effect of new therapeutic agents for psoriasis and immune-mediated inflammatory diseases in clinical trials and open label extension studies. No external funding. I have received honoraria as advisor and/or speaker from Abbott, Janssen, Merck, and Pfizer, and participated in clinical trials sponsored by Abbott, Janssen, Merck and Pfizer.