Weight change during pharmacological blockade of interleukin-6 or tumor necrosis factor-α in patients with inflammatory rheumatic disorders: A 16-week comparative study

doi:10.1016/j.cyto.2012.11.007

Cytokine

Volume 61, Issue 2, February 2013, Pages 353-355

https://doi.org/10.1016/j.cyto.2012.11.007 Get rights and content

Abstract

Background

Interleukin (IL)-6 −/− mice develop spontaneous mature onset obesity, while the influence of the pharmacological blockade of IL-6 on body weight in humans has not been previously reported. The aim of the present study was to observe weight change in patients treated with tocilizumab (TCZ).

Methods

Twenty-one consecutive patients who started new treatment with TCZ were enrolled in the study. Sixteen consecutive patients who started treatment with infliximab (IFX) formed the control group. Height and weight of all patients were registered and Body Mass Index (BMI) calculated before the first treatment and at week 16. The Mann–Whitney or paired Wilcoxon test were used for comparisons between or within groups, respectively.

Results

The study demonstrated that treatment with TCZ was accompanied with significant weight gain and BMI increase (p = 0.04), while IFX treatment did not result in any significant weight change during the 16-week period.

Conclusions

Weight gain can be seen in some patients during the pharmacological blockade of IL-6. The phenomenon and metabolic pathways involved should be further investigated.

Highlights

► Weight gain in the course of pharmacological IL-6 blockade is possible. ► IL-6 blockade-related weight gain is not dependent on the activity of RA. ► Risk factors for IL-6 blockade-related weight gain to be elucidated.

Introduction

Tocilizumab (TCZ) is a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor in use primarily for the treatment of rheumatoid arthritis (RA). The efficacy of TCZ in patients with RA has been well established in terms of both clinical response as well as inhibition of structural joint damage [1], [2]. Adverse effects of TCZ involve intravenous infusion and hyper-sensitivity reactions, infections – including opportunistic infections, gastrointestinal perforation, and laboratory test abnormalities, especially hepatic transaminase elevations, altered lipid profile and neutropenia [3]. While IL-6 KO mice develop spontaneous mature onset obesity [4], weight change has never been reported as one of outcomes of large clinical trials, involving patients treated with TCZ. Recently we have observed several patients with excessive otherwise unexplained weight gain after starting TCZ treatment and decided to perform a controlled trial examining weight change in patients treated with TCZ in comparison to those treated with infliximab (IFX).

Section snippets

Methods

The study was approved by the local Helsinki committee and conducted in the Bnai Zion Medical Center, Haifa, Israel. Twenty-one consecutive patients who started new treatment with TCZ were enrolled in the study. Sixteen consecutive patients who started treatment with IFX formed the control group. Inclusion criteria included age ⩾18 years, absence of other significant chronic inflammatory disorders, normal liver and renal function, and otherwise stable regimen of medicines. Height and weight of

Patients

The characteristics of the patients enrolled in the study are shown in Table 1 The age of the patients, baseline BMI and levels of serum hemoglobin (Hgb) were not different between the groups, while pre-treatment erythrocyte sedimentation rate (ESR) was higher in TCZ group. Of importance, all but one patient receiving TCZ suffered from RA, while in IFX group the majority of patients have been diagnosed with one of spondyloarthritides (SpA). The prevalence of diabetes mellitus and hyperlipidemia

Discussion

Improvement of the nutritional status during effective treatment of any inflammatory disorder has been always one of the goals of treatment; and mild weight gain in RA patients during efficacious treatment with anti-TNF-α therapies has been recently shown [6]. This study is the first to compare weight change in patients with inflammatory rheumatic diseases, treated with biologic medicines targeting different cytokines. We found that the large proportion of patients in both groups, treated with

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Obesity and hypertension are major risk factors for cardiovascular diseases that affect millions of people worldwide. Both conditions are associated with chronic low-grade inflammation, which is mediated by cytokines such as interleukin-6 (IL-6). IL-6 is a multifunctional cytokine that can have pro-inflammatory or anti-inflammatory effects depending on the context. The exact role of IL-6 in obesity-associated hypertension is unclear.
To investigate how IL-6 affects blood pressure, inflammation, and metabolic function in obesity-hypertension using a Chinese adult case-control study.
A total of 153 participants were sorted into four subgroups according to their body mass index (BMI) and blood pressure (BP): normal healthy group (NH), just obesity group (JO), just-hypertension group (JH), and obesity-hypertension group (OH). Serum IL-6 concentrations were measured by Enzyme-linked Immunosorbent Assay (ELISA) and their correlations with anthropometric and laboratory parameters and their differences across the subgroups were examined. Multiple linear regression analysis was performed to identify the predictors of serum IL-6 concentrations in each group.
Serum IL-6 concentrations were higher in NH group than in JO group and correlated positively with diastolic blood pressure in NH and JO groups, but not in JH and OH groups. Serum IL-6 concentrations also correlated with albumin in NH group, alkaline phosphatase in JO group, serum creatinine and fasting blood glucose in JH group. The influencing factors of serum IL-6 concentrations varied among the four groups, with gender, diastolic blood pressure and albumin being significant predictors in NH group, alkaline phosphatase in JO group, age and serum creatinine in JH group, and none in OH group.
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Schizophrenia is a debilitating psychiatric illness that remains poorly understood. While the bulk of symptomatology has classically been associated with disrupted brain functioning, accumulating evidence demonstrates that schizophrenia is characterized by systemic inflammation and disturbances in metabolism. Indeed, metabolic disease is a major determinant of the high mortality rate associated with schizophrenia. Antipsychotic drugs (APDs) have revolutionized management of psychosis, making it possible to rapidly control psychotic symptoms. This has ultimately reduced relapse rates of psychotic episodes and improved overall quality of life for people with schizophrenia. However, long-term APD use has also been associated with significant metabolic disturbances including weight gain, dysglycemia, and worsening of the underlying cardiometabolic disease intrinsic to schizophrenia. While the mechanisms for these intrinsic and medication-induced metabolic effects remain unclear, inflammation appears to play a key role. Here, we review the evidence for roles of inflammatory mechanisms in the disease features of schizophrenia and how these mechanisms interact with APD treatment. We also discuss the effects of common inflammatory mediators on metabolic disease. Then, we review the evidence of intrinsic and APD-mediated effects on systemic inflammation in schizophrenia. Finally, we speculate about possible treatment strategies. Developing an improved understanding of inflammatory processes in schizophrenia may therefore introduce new, more effective options for treating not only schizophrenia but also primary metabolic disorders.
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Brown and beige adipocytes contribute significantly to the regulation of whole body energy expenditure and systemic metabolic homeostasis not exclusively by thermogenesis through mitochondrial uncoupling. Several studies have provided evidence in rodents that brown and beige adipocytes produce a set of adipokines („batokines”) which regulate local tissue homeostasis and have beneficial effects on physiological functions of the entire body. We observed elevated secretion of Interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1, but not tumor necrosis factor alpha (TNFα) or IL-1β pro-inflammatory cytokines, by ex vivo differentiating human beige adipocytes (induced by either PPARγ agonist or irisin) compared to white. Higher levels of IL-6, IL-8 and MCP-1 were released from human deep neck adipose tissue biopsies (enriched in browning cells) than from subcutaneous ones. IL-6 was produced in a sustained manner and mostly by the adipocytes and not by the undifferentiated progenitors. Continuous blocking of IL-6 receptor by specific antibody during beige differentiation resulted in downregulation of brown marker genes and increased morphological changes that are characteristic of white adipocytes. The data suggest that beige adipocytes adjust their production of IL-6 to reach an optimal level for differentiation in the medium enhancing browning in an autocrine manner.
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Despite this evidence, the role of this adipokine in development of obesity and related diseases remains controversial, as studies in mouse models deficient in IL-6 have shown inconsistent results on the development of spontaneous obesity (Di Gregorio et al., 2004; Wallenius et al., 2002b). Intriguingly, an anti-IL-6 antibody therapy (e.g., tocilizumab), which was recently introduced in the treatment of rheumatoid arthritis, was shown to induce weight gain (Younis et al., 2013). Resistin is another adipokine with pro-inflammatory features belonging to the family of resistin-like molecules.
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IL-6 knockout mice develop spontaneous mature onset obesity and weight gain has been seen in patients with inflammatory rheumatic disease treated with tocilizumab. Younis et al. found treatment with it was accompanied with significant weight gain and BMI increase, while Infliximab treatment did not result in any significant weight change during the 16-week period [63]. 24% of patients treated with tocilizumab had a BMI increase of more than 2 units, with some of these patients going from a healthy weight (as defined by BMI) to being overweight.
Interleukin 6 (IL-6) plays a significant role in many rheumatological diseases and has been described as both a pro- and anti-inflammatory cytokine. IL-6 blockade has been investigated in various rheumatic diseases and a humanised anti-IL-6 receptor antibody has been licensed for use in rheumatoid arthritis, systemic and polyarticular juvenile idiopathic arthritis. The increasing clinical experience of IL-6 blockade in rheumatic diseases adds to the existing knowledge regarding the physiological and pathological roles of IL-6.

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Short CommunicationWeight change during pharmacological blockade of interleukin-6 or tumor necrosis factor-α in patients with inflammatory rheumatic disorders: A 16-week comparative study

Abstract

Background

Methods

Results

Conclusions

Highlights

Introduction

Section snippets

Methods

Patients

Discussion

Growth Horm IGF Res

Tocilizumab for the treatment of rheumatoid arthritis

Expert Rev Clin Immunol

Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year

Arthritis Rheum

Clinical safety of tocilizumab in rheumatoid arthritis

Expert Opin Drug Saf

Interleukin-6-defficient mice develop mature-onset obesity

Nat Med

Short Communication
Weight change during pharmacological blockade of interleukin-6 or tumor necrosis factor-α in patients with inflammatory rheumatic disorders: A 16-week comparative study