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Impact of Infliximab on Serum Leptin Levels in Patients with Crohn’s Disease

Laboratory of Experimental Gastroenterology and Department of Gastroenterology (D.F., S.R., T.G., E.Q., M.-C.G., J.D., A.V.G.), Erasme University Hospital, Brussels 1070, Belgium; and Division of Gastroenterology (D.F., Y.T.), Montreal General Hospital, McGill University, Montreal, Quebec, Canada H3A 1A4

Address all correspondence and requests for reprints to: Denis Franchimont, M.D., Ph.D., Division of Gastroenterology, Montreal General Hospital, McGill University, 1650 Cedar Avenue, D7.102, Montreal, Quebec, Canada H3A 1A4. E-mail: denis.franchimont{at}mcgill.ca.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Objectives: In mice, body weight is regulated by adipocyte-derived leptin. TNF is a critical mediator of inflammation-induced cachexia in Crohn’s disease (CD). The regulation of leptin by TNF is poorly understood in CD. Pharmacological neutralization of TNF with infliximab offers a unique opportunity to study TNF-mediated regulation of leptin in CD patients.

Methods: We prospectively followed up CD patients treated with infliximab (n = 20). Body composition was assessed before and after treatment at 1 and 4 wk. Serum leptin, IL-6, soluble TNF receptor type II, and soluble intercellular antiadhesion molecule-1 levels were measured as well as cholesterol levels and free urinary cortisol. Because methylprednisolone (MP) increases leptin production in vivo, CD patients treated with MP (n = 9) were studied separately as a positive control group.

Results: Infliximab induced clinical remission and a significant decrease in C-reactive protein (P < 0.01) and IL-6 (P < 0.05) levels in all CD patients and increased body weight (P = 0.013) at 4 wk. Leptinemia was significantly increased after infliximab administration at 1 wk (P = 0.014) and 4 wk (P < 0.001). This increase in serum leptin occurred early at 1 wk, when no significant weight and fat mass changes could be observed and was associated with the down-regulation of TNF-regulated mediators, soluble TNF receptor type II (P = 0.015), and soluble intercellular antiadhesion molecule-1 (P = 0.007). Moreover, infliximab increased cholesterol levels at 1 wk (P = 0.001). Twenty-four-hour cortisol secretion was not altered by infliximab. Leptinemia increased at 1 wk after MP administration (P = 0.028).

Conclusion: Infliximab increases leptinemia in CD. This study suggests that TNF exerts major inhibitory actions on leptin production in CD patients.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
SIGNIFICANT WEIGHT LOSS is frequently observed in patients with active Crohn’s disease (CD). TNF (previously named cachectin-) is a critical mediator of inflammation-related cachexia (1, 2). TNF induces anorexia and increases resting energy expenditure. The discovery of leptin has provided additional insight regarding the regulation of body weight. Leptin is primarily secreted by adipocytes and plays an integral role in the regulation of food behavior and energy homeostasis (3). Indeed, leptin (ob/ob)-deficient mice demonstrate hyperphagia, decreased energy expenditure, and severe obesity, and exogenous administration of leptin reverses this phenotype (4). Leptin reflects adipose tissue mass and its plasma level serves as a signal of energy sufficiency to the hypothalamus resulting in anorexia and increased energy expenditure when fat stores are exceeded (5). Interestingly, increased release of leptin has been observed after in vivo administration of TNF in mice (6). In addition, the rapid increase in leptin and the severe weight loss observed in trinitrobenzene sulfonic acid-induced colitis in mice may be mediated by inflammatory mediators such as TNF (7). During inflammation, leptin may falsely signal an excess of fat mass to the hypothalamus and drive an inappropriate physiological response and induce anorexia. Taken together, these findings provided the centerpiece to examine leptin regulation in human inflammatory diseases. A dramatic increase in leptin production was first reported in patients with septic shock (8). Similarly, iv TNF therapy given to cancer patients, which mimics critical and acute illnesses, confirmed the increased leptinemia observed in patients in septic shock (9). Thus, both TNF and leptin appeared to participate either sequentially or independently to modulate weight loss during acute inflammatory diseases.

Recently, a number of studies conducted both in mice and humans suggested that whereas TNF transiently induces acute release of intracellular pools of leptin, it decreases leptin synthesis during more chronic inflammation (6, 10, 11). Indeed, longer exposure to TNF appeared to diminish leptin production (6, 10, 11). TNF suppresses in vitro leptin expression and release from human adipocytes within 48 h (10, 11). This may explain why leptin levels remained surprisingly similar in patients with either active or quiescent CD (12, 13). Additional evidence came from the description of reduced levels of leptin in patients with long-lasting tuberculosis, a TNF-mediated disease (14). These patients exhibited dramatically enhanced leptin production after antituberculous treatment, suggesting that leptin was released from the inhibitory effect of TNF. Unfortunately, understanding TNF-mediated leptin regulation during chronic inflammatory diseases remains challenging and difficult to explore. Infliximab is a chimeric IgG1 monoclonal antibody that neutralizes both soluble and membrane-bound TNF in humans. Several clinical trials have provided compelling data regarding the safety and clinical efficacy of infliximab in both induction and maintenance of remission in CD (15, 16, 17, 18). The inhibition of TNF activity with this molecule offers a unique opportunity to understand TNF-mediated leptin regulation and delineate the in vivo metabolic actions of TNF in CD. In the present study, we sought to prospectively examine serum leptin levels in CD patients treated with infliximab and simultaneously monitor their body weight and composition.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients and study protocol

CD patients were recruited from a single center (Erasme University Hospital, Brussels, Belgium). CD was diagnosed according to clinical, radiological, endoscopic, and pathological criteria as previously described (19). Twenty-nine CD patients with active disease [CD activity index (CDAI) > 150] were treated with either infliximab (group I, n = 20) or corticosteroids (group II, n = 9) according to standard recommendations (20, 21) and were prospectively followed up for 4 wk. Because corticosteroids are known to induce leptin secretion, group II was studied as a positive control group (22, 23). Briefly, infliximab (5 mg/kg) was given to patients with luminal disease relapsing despite receiving appropriate doses of concomitant immunosuppressants, patients suffering from active corticosteroid-dependent/resistant disease, or patients with fistulizing disease. Corticosteroids (methylprednisolone, 0.5 mg/kg) were given to patients presenting with moderate active luminal disease. The clinical characteristics of CD patients are shown in Table 1. In group I, patients received either a three-dose induction regimen (0, 2, and 6 wk) (n = 14) or a single-dose induction (n = 6). All patients who received infliximab were infliximab naïve. In group I, patients were either corticosteroid free (n = 12) or receiving prednisolone (n = 8) before being treated with infliximab (Table 1). The eight patients who were receiving prednisolone were on stable doses (<16 mg) for at least 4 wk. The following clinical characteristics were analyzed in patients from groups I and II: age at diagnosis, sex, familial/sporadic, surgery, extraintestinal manifestations, and concomitant medications. CD location (ileal, ileocolonic, colonic, and anal) and behavior (fibrostenotic, inflammatory, and fistulizing) were assessed according to the Vienna classification (24).

Immunoassays

Serum leptin, IL-6, soluble TNF receptor type II (sTNFRII) and soluble intercellular antiadhesion molecule (sICAM)-I levels were measured using specific enzyme-linked immunoassays, according to the manufacturer’s protocol (Quantikine, R&D Systems, Abingdon, UK).

Bioimpedance

A single clinical investigator (Karine Buedts, nutritionist) measured height and body weight and performed bioimpedance analysis. The latter measure was performed to determine extracellular water, total body water, and percentage of lean and fat mass, as previously described (25). Briefly, body resistance is measured using a four-terminal portable analyzer (BIA-101/S; RJL, Detroit, MI). Current injector electrodes were placed while the subjects were supine. Resistance to the flow of administered current at multiple frequencies was measured on a 0–1000 n scale and reactance was measured on a 0–200 n scale. Body composition was then assessed using the BODYCOMP software (RJL).

Statistical analyses

Statistical comparisons were performed using either parametric (paired t test or ANOVA) or nonparametric tests (paired Wilcoxon test or Kruskal-Wallis). Significance level was defined with P < 0.05. The Spearman test was used for correlation analysis. All statistical analyses were performed using SPSS software (version 10, SPSS, Chicago, IL).

A multivariate adjustment was performed to identify clinical characteristics that could be associated with a higher percentage of change in leptin level using a linear regression model. Briefly, the mean percentage of change in leptin level at T2 (leptin 2) and T0 (leptin 0) was calculated among patients (group I) treated with infliximab according to the following calculation.

Any association between the percentage of change of leptin and other variables, such as age, sex, BMI (T0), fat mass (T0), and CRP level (T0), was assessed in univariate analyses. Variables with P < 0.20 on univariate analyses were entered in the multivariate model. Because of the limited number of data, the final model included only two variables, and its selection was based on R². Results were reported in differences in percent changes and 95% confidence intervals (CIs). The analyses were done using the software SAS8.2 (SAS Institute Inc., Cary, NC).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
The demographics of patient clinical characteristics are listed in Table 1.

Infliximab increased serum leptin levels in CD patients

We sought to examine the influence of infliximab on leptin production in patients with CD (group I). Infliximab significantly induced clinical remission in all patients at 4 wk (mean CDAI ± SEM: 268 ± 26 vs. 135 ± 17, P = 0.003) (Fig. 1A). CRP levels were significantly decreased at 1 wk (mean ± SEM: 5.3 ± 1.2 vs. 1.2 ± 0.4 mg/dl, P < 0.001) and 4 wk (mean ± SEM: 5.3 ± 1.2 vs. 1.68 ± 0.6 mg/dl, P < 0.01) (Fig. 1B). Leptin levels increased after infusion of infliximab (Fig. 2). Leptin levels were significantly higher after infliximab administration at 1 wk [median (range): 4,921 (825–100,000) vs. 4334 (600–59,500) pg/ml, P = 0.014] and 4 wk [5702 (715–72,500) vs. 4334 (600–59,500) pg/ml, P < 0.001] than at baseline (Fig. 2A). This increase in serum leptin was negatively correlated with the decrease in CRP at 1 wk ( = –0.540, P = 0.025). Figure 2B shows the relative mean fold change in serum leptin levels at 1 and 4 wk after infliximab infusion. Subgroup analysis of group I revealed a trend toward a higher baseline serum leptin level in patients treated with prednisolone, compared with corticosteroid-free patients [11,200 (3,253–30,700) vs. 3,440 (649–9,491) pg/ml, P = 0.069]. However, whereas leptin levels increased at 1 wk [5,152 (1,000–17,628) vs. 3,440 (649–9,491) pg/ml, P = 0.033] and 4 wk [4,502 (715–25,321) vs. 3,440 (649–9,491) pg/ml, P = 0.004] in corticosteroid-free patients, they did not significantly increase at 1 wk [13,700 (3,973–35,000) vs. 11,200 (3,253–30,700) pg/ml, P = 0.176] and 4 wk [17,700 (3,939–27,631) vs. 11,200 (3,253–30,700) pg/ml, P = 0.091] in the eight patients who received prednisone before infliximab treatment. Multivariate adjustment with a linear regression model revealed that men had a lower percentage of leptin change at 4 wk, compared with women [–0.87 (95% CI –1.65, –0.09), P = 0.03]. The model also showed that a higher leptin level at baseline was associated with a lower percentage of change at 4 wk, although not significant [–0.24 (95% CI –0.57, 0.09), P = 0.14]. Thus, leptin levels increased in patients treated with infliximab who were entering into clinical and biological remission.

View larger version (12K): [in this window] [in a new window]   FIG. 1. Infliximab induced clinical remission and biological response in CD patients. CD patients (group I, n = 20) were treated with infliximab. CDAI was calculated at baseline and at 4 wk, and serum CRP levels were measured at baseline and 1 and 4 wk after infliximab administration. A, Infliximab induced clinical remission (CDAI < 150) in patients with CD (P = 0.003). B, Serum CRP levels were significantly decreased by infliximab (P < 0.01).

View larger version (17K): [in this window] [in a new window]   FIG. 2. Infliximab increased serum leptin levels in CD patients. CD patients (group I, n = 20) were treated with infliximab. Serum leptin concentration was measured at 1 and 4 wk after infliximab administration. A, Serum leptin levels were significantly higher after infliximab at 1 (P = 0.014) and 4 wk (P < 0.001) than at baseline. B, The mean fold change of serum leptin level was 1.47 and 1.68 at 1 and 4 wk, respectively.

Infliximab decreased TNF-regulated inflammatory mediators, decreased IL-6 levels, and increased serum cholesterol levels

The inflammatory mediators, regulated by TNF, were examined to assess the negative regulation of these mediators by infliximab. Membrane or sICAM-1 and type II TNF receptor are positively regulated by TNF. Both sICAM-1 [median (range): 331 (213–732) vs. 387 (213–801) ng/ml, P = 0.007] and soluble type II TNF receptor [median (range): 1917 (593–7287) vs. 2351 (656–6726) pg/ml, P = 0.015] were significantly decreased in CD patients 1 wk after infliximab administration (Fig. 3, A and B). IL-6 serum levels decreased significantly at 1 [6.2 (0–42) vs. 24.3 (3.8–69) pg/ml; P < 0.05] and 4 wk [4.5 (0–49.9) vs. 24.3 (3.8–69) pg/ml; P < 0.05] after infliximab administration. TNF drastically decreases cholesterol production (26). Therefore, we tested whether infliximab could increase cholesterol levels. Indeed, infliximab dramatically increased cholesterol levels at 1 wk [median (range): 194 (132–254) vs. 170 (97–234) mg/dl, P = 0.001] (Fig. 3C). Thus, the increase in leptin, whereas sICAM-1, sTNFRII, and IL-6 decreased and cholesterol increased, supports the positive regulation of infliximab on leptin production.

View larger version (28K): [in this window] [in a new window]   FIG. 3. Infliximab decreased TNF-regulated inflammatory mediators and increased serum cholesterol level. CD patients (group I, n = 20) were treated with infliximab. sICAM-1, sTNFRII, and serum cholesterol concentrations were measured at 1 wk after infliximab administration. A and B, sICAM-1 (P = 0.007) and sTNFRII (P = 0.015) were significantly decreased in CD patients after infliximab administration at 1 wk. C, Serum cholesterol levels significantly increased at 1 wk after infliximab administration (P = 0.001).

TNF is known to induce weight loss (2). Therefore, we prospectively assessed body weight, BMI, and body composition after infliximab infusion in CD patients. Infliximab significantly induced weight gain at 4 wk (mean ± SEM: 64.4 ± 3.5 vs. 63.6 ± 3.6 kg, P = 0.013) (Fig. 4A). Because leptin level is correlated with fat mass and represents the magnitude of fat mass (27), the hyperleptinemia observed after infliximab administration could therefore reflect only positive actions of infliximab on fat mass. We first examined whether infliximab could influence the magnitude of fat mass. Fat mass was not significantly altered by infliximab at 1 wk [median (range): 11.6 (6.1–29.2) vs. 11.2 (3.1–20.5) kg, P = 0.46] and 4 wk [median (range): 11.3 (6.3–15.2) vs. 11.2 (3.1–20.5) kg, P = 0.38] (Fig. 4B). The percentage of fat mass at 4 wk did not change as compared with the percentage of fat mass at baseline [median (range): 18.0 (10.7–27.4) vs. 18.8 (7.8–29.6%), P = 0.58]. Thus, the increase in leptin after infliximab seemed to be independent of fat mass. Furthermore, whereas leptin concentration was correlated with fat mass ( = 0.585, P = 0.014), the percentage of increase of leptin was not correlated with the percentage of increase of fat mass at 1 wk ( = –0.150, P = 0.57) and 4 wk ( = 0.244, P = 0.4). Similarly, whereas leptin levels were significantly correlated with BMI before infliximab ( = 0.468, P = 0.038), the percentage of increase in leptin did not correlate with the percentage of increase in BMI at 4 wk ( = 0.247, P = 0.32) (Fig. 5, A and B). Moreover, the leptin to fat mass ratio was significantly increased at 4 wk, compared with the ratio at baseline (mean ± SEM: 908 ± 218 vs. 579 ± 171 pg/ml·kg, P = 0.02) (Fig. 5C). Thus, the leptin increase after infliximab administration in CD patients was independent of fat mass.

View larger version (24K): [in this window] [in a new window]   FIG. 4. Infliximab induced weight gain without altering body composition. CD patients (group I) were treated with infliximab. Body weight (kilograms) and fat mass (kilograms) were measured at 4 wk after infliximab administration. A, Body weight significantly increased at 4 wk in CD patients (n = 20) after infliximab administration (P = 0.013). B, The fat mass was not significantly altered after infliximab administration (n = 17) at 1 and 4 wk.

View larger version (9K): [in this window] [in a new window]   FIG. 5. Infliximab increased serum leptin level in CD patients independently of fat mass. Body weight (kilograms) and serum leptin levels were measured at 1 and 4 wk after infliximab administration. A and B, Serum leptin level was significantly correlated with BMI before infliximab ( = 0.468, P = 0.038). The increase of leptinemia was not correlated with the increase of BMI at 4 wk ( = 0.247, P = 0.32). C, Leptin to fat mass was significantly increased after 4 wk (P = 0.02).

Corticosteroids up-regulate leptin expression in vitro and enhance leptin production in vivo in mice and humans (22, 23). Thus, treatment with corticosteroids was a relevant positive control for our observation in CD patients treated with infliximab. We tested whether methylprednisolone induced hyperleptinemia in CD patients (group II, n = 9) (Fig. 6). In this instance, leptin concentration increased at 1 wk after methylprednisolone injection [median (range): 7,500 (740–31,629) vs. 5,215 (950–19,951) pg/ml, P = 0.028]. Thus, methylprednisolone induced hyperleptinemia in CD patients and confirmed the direct positive action of corticosteroids on leptin production.

View larger version (12K): [in this window] [in a new window]   FIG. 6. Infliximab increased serum leptin level to the same extent as corticosteroids. CD patients (group II, n = 9) were treated with methylprednisolone (MP). Serum leptin concentration was measured at 1 wk after MP administration. Serum leptin levels were significantly higher after MP at 1 wk than at baseline (P = 0.028).

The hypothalamo-pituitary-adrenal (HPA) axis is tightly controlled by inflammatory mediators during systemic inflammation (28). TNF demonstrates selective actions on different components of the HPA axis (28). Whereas TNF can stimulate the hypothalamus, it can also suppress pituitary or adrenal activation. Therefore, infliximab could block the inhibitory actions of TNF on the HPA axis, thereby increasing cortisolemia that in turn would enhance leptin production. We examined 24-h free urinary cortisol in CD patients (group I) at baseline and 1 wk after infliximab. Cortisol production was altered by infliximab administration in each individual. However, infliximab did not significantly alter cortisol production in these patients in a uniform fashion [median (range): 29 (5–93) vs. 27.5 (6–83) µg/dl, P = 0.46]. Subgroup analysis of CD patients (group I) demonstrated that 24-h free urinary cortisol was similar in corticosteroid-free patients as compared with patients treated with prednisolone at baseline [median (range): 28.5 (6–83) vs. 24.5 (6–71) µg/dl, P = 0.76]. Moreover, infliximab did not influence cortisol production in both corticosteroid-free patients [median (range): 30.4 (5–93) vs. 28.5 (6–83) µg/dl, P = 0.53] and patients treated with prednisolone [median (range): 28 (8–93) vs. 24.5 (6–71) µg/dl, P = 0.74]. Thus, the increased leptinemia did not appear to be influenced by cortisol production in CD patients treated with infliximab.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The investigation of CD patients treated with infliximab provides a unique opportunity to analyze the in vivo physiological role of TNF on leptin regulation during chronic inflammation. In this study, infliximab induced an increase in serum leptin levels in CD patients. This increase occurred early, at a time when body weight was not yet altered by treatment with infliximab, and was not correlated with a change in fat mass. Importantly, the rise in leptin levels was associated, early on, with a clinical and biological response to infliximab and the decreased plasma concentrations of other TNF-regulated mediators such as sTNFRII and sICAM-1. Finally, adrenal corticosteroids did not influence the infliximab-mediated increase in leptin. These observations demonstrate a selective action of infliximab on leptin production and suggest that long exposure to TNF during chronic inflammatory diseases, such as CD, suppresses leptin expression and secretion. The neutralization of TNF by infliximab appears to alleviate the inhibitory action of endogenous TNF on leptin production.

The impaired T-cell immune response observed in leptin-deficient (ob/ob) and resistant (db/db) mice is restored with exogenous administration of recombinant leptin (29). Administration of leptin reverts T-cell hyporesponsiveness and cytokine secretion in genetically leptin-deficient obese children who are immunodeficient (30, 31). The immunosuppression associated with leptin-deficient states, such as in malnutrition or starvation, is restored with leptin administration in humans (32). Thus, the increased leptinemia in CD patients after infliximab infusion underscores the potentially beneficial immuno-enhancing action of leptin in the shaping and resolution of the immune response in this clinical setting (29, 31).

The increase in leptin, which induces anorexia in mice, after infliximab appears counterintuitive because most CD patients regain appetite when entering into remission. However, a number of studies indicate that leptin does not seem to influence food behavior in humans to the same extent as in mice. Obese patients demonstrate high levels of leptin and still exhibit hyperphagia (27). Even patients with anorexia nervosa demonstrate persistent hypophagia with very low leptin levels (33, 34). Importantly, further elevation of leptin levels above the normal threshold does not appear to influence food intake (35). In fact, leptin acts more as an emergency signal of energy depletion in humans (35, 36). If leptin is a static indicator of the magnitude of fat mass, leptin becomes a sensor of energy balance during acute caloric changes, independently of fat stores (37, 38, 39). Indeed, infliximab enhanced leptinemia in CD patients without altering the percentage of fat mass, suggesting a fat mass-independent physiological mechanism of leptin regulation. In lean and obese individuals, leptin declines with fasting and signals a negative energy balance that is translated into compensatory physiological changes. Inversely, leptin returns to normal blood levels with refeeding (37). Interestingly, infliximab corrects the TNF-driven increase of energy expenditure related to systemic inflammation and restores a positive energy balance (40). Reversing the energy balance could therefore be paralleled by an increase of leptin in these patients. The increased serum leptin levels in CD patients treated with infliximab may therefore represent biological evidence of the correction of energy imbalance in these patients.

In conclusion, infliximab increases leptinemia in CD patients, independently of fat mass. Our findings suggest a framework to further examine the precise metabolic and immune actions of leptin in CD. Dissection of hormone and cytokine signaling by targeting cytokines with monoclonal antibodies may provide an integrative approach to understand the perturbations in the homeostasis of weight regulation during inflammation.

	Acknowledgments

 
We are indebted to Karine Buedts (nutritionist, Division of Gastroenterology, Erasme Hospital) for her help.

	Footnotes

 
D.F. is the recipient of a Canada Research Chair in Inflammatory Bowel Disease.

First Published Online March 22, 2005

Abbreviations: BMI, Body mass index; CD, Crohn’s disease; CDAI, CD activity index; CI, confidence interval; CRP, C-reactive protein; HPA, hypothalamo-pituitary-adrenal; sICAM, soluble intercellular antiadhesion molecule; sTNFRII, soluble TNF receptor type II; T0, baseline; T1, 1 wk after infliximab administration; T2, 4 wk after infliximab administration.

Received June 28, 2004.

Accepted March 14, 2005.

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