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JCR: Journal of Clinical Rheumatology:
doi: 10.1097/RHU.0b013e31827cdda7
Concise Reports

Interleukin 6 Blockade–Associated Weight Gain With Abdominal Enlargement in a Patient With Rheumatoid Arthritis

Younis, Said MD*; Rosner, Itzhak MD*†; Rimar, Doron MD*†; Boulman, Nina MD*†; Rozenbaum, Michael MD*†; Odeh, Majed MD†‡; Slobodin, Gleb MD†‡

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From the *Rheumatology, Bnai Zion Medical Center; †Ruth & Bruce Rappaport Faculty of Medicine, Technion; and ‡Internal Medicine A, Bnai Zion Medical Center, Haifa, Israel.

The authors declare no conflict of interest.

Correspondence: Gleb Slobodin, MD, Internal Medicine A, Bnai Zion Medical Center, PO Box 4940, Haifa 31048, Israel. E-mail: gslobodin@yahoo.com.

Tocilizumab (TCZ) is a humanized monoclonal antibody to the interleukin 6 (IL-6) receptor used primarily in the treatment of rheumatoid arthritis (RA). The efficacy of TCZ in patients with RA has been well established both in terms of clinical response as well as inhibition of structural joint damage.1,2 Adverse effects of TCZ include intravenous infusion and hypersensitivity reactions, infections, possible gastrointestinal perforations, and laboratory test abnormalities, particularly hepatic transaminase elevations, altered lipid profile, and neutropenia.3 Weight gain, although discussed as a potential adverse effect of IL-6 blockade,4 has not been reported as yet in TCZ-treated patients. Although a mild weight increase in RA patients treated with anti–tumor necrosis factor α (TNF-α) agents has been previously shown, presumably as a result of decreased inflammation and/or improved well-being,5 we observed and report herein an RA patient with anomalous weight gain during TCZ treatment.

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CASE REPORT

A 56-year-old woman with seropositive RA and Sjögren syndrome initiated TCZ treatment in November 2010 after a long course of the disease and failure—due to inefficacy or unacceptable adverse effects—of numerous synthetic disease-modifying antirheumatic drugs, 3 anti-TNF agents, and rituximab. Her hemoglobin at that time was 10 g/dL, serum albumin level was 3.8 g/dL, and serum C-reactive protein was 1.9 mg/L (reference, up to 5 mg/L). Her weight was 43 kg (16.8 body mass index [BMI] units), and the dose of TCZ she received was 320 mg. Prednisone 10 mg/d, which had been part of her long-term background regimen, was also continued. In February 2011, she started complaining of persistent abdominal distention and pain. Abdominal ultrasonography, computed tomography, gastroscopy, and colonoscopy did not reveal diagnostic findings explaining the pain. She reported no change in her appetite or eating habits. Her weight at that time was 52 kg (20.3 BMI units). There was moderate improvement in RA activity, and TCZ treatment was continued. In May 2011, she presented with worsening of diffuse abdominal pain. Her appearance had changed dramatically, with prominent trunk fat deposition now apparent in this usually slim woman (Fig.). The anterior abdominal wall was tender to palpation, and the skin was distended. Ultrasonography of the abdominal wall revealed significant diffuse fat deposition in the subcutaneous area. Biopsy of the subcutaneous fat revealed normal fat tissue with no evidence of inflammation or amyloidosis. Her body weight at that point was 56 kg (21.9 BMI units). Laboratory studies were unrevealing, with normal levels of serum glucose, as well as normal lipid profile. Overnight dexamethasone suppression test and level of thyroid-stimulating hormone were within reference range. She denied the use of other new medications and had not changed the dose of glucocorticosteroids. At this point, TCZ was stopped. In August 2011, 3 months after cessation of TCZ, the patient noted significant improvement in her abdominal pain and distention, and her weight had decreased by 5 kg. She required, however, an increase in her daily intake of prednisone to a dose of 20 mg daily to control the RA. Because of worsening joint disease, the patient agreed to receive another infusion of TCZ in November 2011. Two weeks after the treatment, she presented again with abdominal pain and new weight gain of 3 kg. She refused further TCZ treatment and was maintained on prednisone 10 mg daily. During follow-up, the patient’s abdominal distension gradually diminished, and pain disappeared. Her weight, however, did not decrease significantly, remaining at 52 kg (20.3 BMI units) in September 2012. She was still being treated with only prednisone 10 mg daily, and her joint disease was mildly active.

FIGURE. Trunkal obes...
FIGURE. Trunkal obes...
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DISCUSSION

Weight gain is a well-known adverse effect of some medications, such as glucocorticosteroids, antipsychotics, and others. Biologic drugs used in rheumatology have not been implicated in abnormal weight gain, and yet a mild increase in weight with anti–TNF-α agents has been reported.5 We observed and report herein significant weight gain, from 43 to 56 kg—a gain of more than 30% of initial weight—in a patient with RA during TCZ treatment. After cessation of the drug, her weight decreased by 5 kg within 3 months, whereas rechallenge led again to weight gain, consistent with a causative role for TCZ. Although improvement of nutritional status during effective treatment of any inflammatory disorder, including RA, has always been one of the goals of treatment, the excessive weight gain in our patient treated with TCZ was clearly disproportional to that expected. Our patient also did not have evidence of metabolic disorder; thus, the mechanisms underlying the potential relationship between pharmacological IL-6 blockade and weight gain observed herein are unclear and may include multiple metabolic pathways.4 Although weight gain has not been reported in the context of large clinical trials, at least 1 cohort study mentioned that “weight gain was in fact often seen” in TCZ-treated patients.6 Patients with Castleman disease treated with TCZ also reportedly gained weight, presumably due to general recovery from intense chronic inflammation.7 Our patient, however, did not have laboratory signs of significant systemic inflammation before treatment with TCZ had been started. Of relevance, laboratory studies using the IL-6−/− mice model, which develops spontaneous obesity, have demonstrated that administered IL-6 prevented fat accumulation, presumably by increasing energy expenditure and via effects of IL-6 on the hypothalamus.8 In humans, metabolic effects of IL-6 and IL-6 blockade have not been elaborated in depth. Although a normally functioning blood-brain barrier would presumably prevent the central effects of TCZ,9 the state of the blood-brain barrier in the patient presented herein is unknown, and direct hypothalamic effects of TCZ cannot be excluded. On the other hand, the peripheral action of anti–IL-6 treatment on the synthesis of triacylglycerol in adipocytes is also possible as one potential mechanism leading to weight gain. Studies targeting the metabolic changes in patients treated with IL-6 blockade in humans are urgently needed to expand our appreciation of the variety of potential effects resulting from the inhibition of IL-6.

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REFERENCES

1. Tanaka T, Ogata A, Narazaki M. Tocilizumab for the treatment of rheumatoid arthritis. Expert Rev Clin Immunol. 2010; 6: 843–854.

2. Kremer JM, Blanco R, Brzosko M, et al.. 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. 2011; 63: 609–621.

3. Bannwarth B, Richez C. Clinical safety of tocilizumab in rheumatoid arthritis. Expert Opin Drug Saf. 2011; 10: 123–131.

4. Febbraio MA, Rose-John S, Pedersen BK. Is interleukin-6 receptor blockade the Holy Grail for inflammatory diseases? Clin Pharmacol Ther. 2010; 87: 396–398.

5. Brown RA, Spina D, Butt S, et al.. Long-term effects of anti-tumor necrosis factor therapy on weight in patients with rheumatoid arthritis. Clin Rheumatol. 2012; 31: 455–461.

6. Hirabayashi Y, Ishii T, Harigae H. Clinical efficacy of tocilizumab in patients with active rheumatoid arthritis in real clinical practice. Rheumatol Int. 2010; 30: 1041–1048.

7. Nishimoto N, Kanakura Y, Aozasa K, et al.. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005; 106: 2627–2632.

8. Jansson JO, Wallenius K, Wernstedt I, et al.. On the site and mechanism of action of the anti-obesity effects of interleukin-6. Growth Horm IGF Res. 2003; 13 (suppl A): S28–S32.

9. Lampson LA. Monoclonal antibodies in neuro-oncology. Getting past the blood-brain barrier. MABs. 2011; 3: 153–160.

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© 2013 Lippincott Williams & Wilkins, Inc.

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