The excess of adipose tissue in obese individuals may have immunomodulating properties and pharmacokinetics consequences [2
]. In this study, we investigated retrospectively whether the BMI could influence the response to IFX in AS patients. Of most interest, although the baseline BASDAI was found to be similar in the three BMI categories of AS individuals (that is, normal, overweight, and obese), multivariate analysis, including gender, identified the BMI as an independent risk factor for a poor response at M6, whatever the response criteria considered (BASDAI50, VAS50, CRP50, or NSAID50). In good agreement with this finding, when BASDAI20, 50, and 70 responses were queried according to the three WHO BMI categories, a higher BMI resulted in a decrease of clinical response to IFX in the whole AS population (Figure ). However, when analyses were performed according to gender, similar results were observed in both male and female populations, reaching statistical significance only in AS male patients. Nevertheless, the multivariate analysis, including gender as covariate, provides evidence for an independent role of BMI in the IFX response, ruling out a residual confounding by gender.
Both lower BMI and high CRP level at baseline were found to be associated with a good response to IFX. Interestingly, a recent study reported that a high CRP level was associated with a good outcome in AS [10
]. Nonetheless, in these studies, the BMI was not assessed [10
]. In addition, and to strengthen the independent role of BMI as a predictive marker of the IFX response, it is of note that, in our study, baseline CRP was not different among the three BMI categories (Table ).
To our knowledge, this is the first reported study investigating the influence of BMI on the response to IFX in AS. Of most interest, similar results were observed in RA patients treated with IFX, as a significant association between a low BMI and the decrease in the DAS28 after 16 weeks was observed [7
]. Additionally, it is now well established that obesity is associated with psoriasis [12
]. Interestingly, a previous cohort study reported a decrease of response to systemic agents in psoriasis [13
]. A negative impact of weight was also found with ustekinumab and etanercept [14
]. However, other studies revealed that BMI did not influence the response to IFX in psoriasis [14
]. If IFX therapy was found to be associated with a gain of weight, in Crohn disease (CD), to date, no study designed to investigate the role of BMI in modulating the response to IFX is available [16
]. Most interestingly, a recent study found that CD patients with a low baseline BMI (< 18.5) and those with small-bowel involvement achieved a higher increase in BMI as compared with patients with BMI ≥18.5 or patients without small-bowel involvement [17
]. These findings suggest that fat-tissue excess could play a role in modulating the response to anti-TNF-α in RA, AS, psoriasis, and CD.
The rate of response in our study was found to be 49.6% for BASDAI50, which is in line with previous reports [18
]. Of the most interest, 77.6% of AS patients who were of normal weight achieved the BASDAI50 response compared with 26.5% of obese patients. Hence, obesity should be considered a predictor factor of low-rate response to IFX in AS, leading to a threefold decrease of the response rate.
Although IFX had a dose fixed according to the patient's weight, huge variations of interindividual serum concentration have been widely reported in different inflammatory diseases [20
]. Unlike that observed in RA [20
], treatment failure was not associated with a low circulation concentration of IFX in AS [21
]. Further pharmacokinetic findings could explain the negative influence of a high BMI on the IFX response. The volume of distribution, Vd
, of a drug provides an estimate of the extent to which a drug is distributed into extravascular tissues. A wide variation exists in the effect on the Vd
, because the affinity of each drug for the excess adipose tissue is unique. Hence, a nonlipophilic drug, such as IFX, whose distribution into the excess adipose tissue is limited, could alter the Vd
]. In addition, tissue blood flow influences drug distribution. Tissue perfusion and cardiac function may be reduced in obese individuals, leading to a decrease of IFX distribution [22
A direct role of the fat tissue excess through the release of adipocytokines may also contribute to predicting drug response. Nonetheless, the putative influence of IFX therapy on adipocytokines production in AS remains unclear. IFX therapy was reported to increase weight and fat mass in the first 6 months of treatment in AS patients [6
]. Conversely, another study failed to detect any association between IFX therapy and leptin serum-level variation [23
]. Taking into account that (a) TNF-α induces cachexia and (b) a lower weight is correlated with active RA [5
], it could be hypothesized that IFX good responders are more likely to have a TNF-α-driven disease, leading to a lower BMI. Nonetheless, caution should be taken with the hypothesis about a direct role of fat tissue-related mediators in AS, as to date, this remains speculative, and robust data are lacking.
Taking into account the increasing number of obese patients worldwide, investigation of the consequences of an excess of fat mass on drug metabolism is not trivial. Further studies have shown a direct influence of obesity on drug pharmacokinetics, notably regarding chemotherapy [24
] and antihypertensive drugs [25
]. Consequently, clearly a need exists for further work in elucidating the complex mechanisms involved in the development of obesity-associated resistance to IFX.
This study has some limitations. The design of our study was retrospective, which can lead to different biases, notably, the lack of pharmacokinetics analyses including correlation study between the IFX clearance and BMI. Additionally, we did not have detailed data on concurrent drugs that could be related to the overweight/obese status, and, therefore, are unable to assess the impact of the therapies on the results. However, regarding the BMI, similar findings were recently reported in a study in RA, and preliminary prospective data, not yet published, support our conclusions [27
]. BMI is an indirect measure of body composition. Hence, a direct quantification of the body fat mass and fat-free mass should be assessed by using skinfold measurement, bioelectrical impedance analysis, or dual-energy x-ray absorptiometry to understand better the effect of each tissue in pharmacokinetics and adipocytokine production.