0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Research Letter |

Effects of Anti–Tumor Necrosis Factor Therapy on Body Composition and Insulin Sensitivity in Patients With Psoriasis FREE

Kristian Kofoed, MD, PhD; Anders Clemmensen, MD, PhD; Ulla R. Mikkelsen, MSc, PhD; Lene Simonsen, MD, DMSc; Ove Andersen, MD, PhD; Robert Gniadecki, MD, DMSc
[+] Author Affiliations

Author Affiliations: Department of Dermatology (Drs Kofoed, Clemmensen, and Gniadecki), Institute of Sports Medicine, Department of Orthopedic Surgery (Dr Mikkelsen), and Department of Clinical Physiology (Dr Simonsen), Copenhagen University Hospital, Bispebjerg, Denmark; Center for Health Aging (Dr Mikkelsen), Faculty of Health Sciences (Drs Mikkelsen and Gniadecki), University of Copenhagen, Copenhagen, Denmark; and Clinical Research Center, Copenhagen University Hospital, Hvidovre, Denmark (Dr Andersen).


Arch Dermatol. 2012;148(9):1089-1091. doi:10.1001/archdermatol.2012.1753.
Text Size: A A A
Published online

Epidemiologic studies have shown an association between psoriasis and cardiovascular diseases. An interesting but unproven hypothesis ascribes this association to the psoriatic march, the process by which inflammatory mediators released in the course of the psoriatic autoimmune reaction cause insulin resistance, which ultimately leads to atherosclerosis.1

Tumor necrosis factor (TNF) is a proinflammatory cytokine that impairs response to insulin in adipocytes and muscle cells via inhibition of tyrosine kinase activity of the insulin receptor, activation of peroxisome proliferator–activated receptor-δ, and changes in secretion of adipokines.2 For the present study, we investigated the effect of anti-TNF treatment on insulin resistance and body composition in patients with psoriasis.

Eligible participants were anti-TNF–naïve male patients with psoriasis recalcitrant to other systemic treatments and UV-B therapy. They also had a PASI (Psoriasis Area and Severity Index) or a DLQI (Dermatology Life Quality Index) of 10 or higher. The selection of the TNF agent was left to the treating dermatologist. Patients were asked to maintain their usual physical activity and to stay on their usual diet during the 12-week study period. Approval was granted by the scientific ethical committee (approval No. H-D-2009-040).

Insulin sensitivity was determined by a 2-hour hyperinsulinemic euglycemic clamp. Body composition was estimated by dual-energy x-ray absorptiometry. Peak oxygen uptake was assessed during a progressive exercise test. Patients completed the International Physical Activity Questionnaire. A sample size of 18 was required to detect an increase of 15% or more in insulin sensitivity (1-sided α = .05 and power = 0.91). An interim analysis after 9 completed patients was performed to indicate a trend for a difference. A P < .20 was needed to justify study continuation. A more detailed description of methods is available in the eAppendix.

The interim analysis did not indicate a trend; therefore, the study was terminated. Baseline patient characteristics are summarized in Table 1. Truncal fat percentage was negatively correlated with insulin sensitivity (r = −0.78; P = .01) and positively correlated plasma leptin (r = 0.88, P = .002). After 12 weeks of therapy (infliximab = 5, adalimumab = 4), there were no significant changes in insulin sensitivity or levels of fasting glucose, hemoglobin A1c, or C-peptide. Body fat increased by 6.5%, and truncal fat increased by 11.4%. Leptin concentrations significantly decreased after anti-TNF treatment (Table 2).

Table Graphic Jump LocationTable 1. Patient Characteristics, Treatment Before and During Study, and Changes in PASI and DLQI After Anti-TNF Treatment
Table Graphic Jump LocationTable 2. Disease Severity, Physical Activity, Peak Oxygen Uptake, Insulin Sensitivity, Leptin Concentration, and Body Composition at Baseline and After Anti-TNF Treatmenta

It is known that anti-TNF therapy increases body weight in patients with psoriasis. In line with our results, Renzo et al3 observed a gain in the body fat of 8.6% in patients with psoriasis after 24 weeks of anti-TNF therapy. It is known that TNF stimulates lipolysis in human adipocytes4; thus, anti-TNF may reduce lipolysis and thereby accumulation of fat in adipocytes.

We confirmed an inverse correlation between truncal fat percentage and insulin sensitivity, but anti-TNF therapy had no significant influence on insulin sensitivity. Martínez-Abundis et al5 reported no effect on insulin sensitivity measured using a hyperinsulinemic clamp during 2 weeks of etanercept treatment, but Marra et al6 reported a decrease in insulin resistance assessed by homeostatic model assessment after 24 weeks of etanercept treatment. The clamp primarily measures insulin-mediated glucose disposal by skeletal muscles. To investigate insulin sensitivity in adipose tissue, other methods should have been used.

Epidemiologic evidence indicates a lower risk of developing diabetes mellitus for patients with psoriasis who are treated with a TNF inhibitor compared with several other drugs.7 Leptin is a fat-tissue hormone. Reduction in plasma leptin is associated with suppression of metabolic rate and stimulation of appetite in lean subjects.8 Plasma leptin level is increased in patients with psoriasis.9 Tumor necrosis factor is capable of inducing leptin production, and infusion of infliximab decreases leptin levels in rodents.8 Thus, the observed decrease in plasma leptin level is in line with experimental data. On the other hand, the increase in fat should have resulted in an increase in leptin levels, and clinical studies on other autoimmune diseases have found unchanged or even increased leptin levels after anti-TNF treatment.10 An interesting note is that plasma leptin level is an independent risk factor for cardiovascular disease and an indirect measure of insulin sensitivity. Thus, the decrease in leptin level indicates that anti-TNF treatment reduces the risk of cardiovascular disease.

Weaknesses of the present study include the limited number of patients, the fact that only men were included, the uncontrolled study design, and the use of 2 different anti-TNF antibodies. Using the gold-standard methods, we found that the increase in body weight in patients with psoriasis treated with anti-TNF is due to an increase in the amount of truncal fat, but we were unable to demonstrate any significant effect of anti-TNF therapy on insulin sensitivity. Future studies should investigate the mechanism behind the increase in body fat.

ARTICLE INFORMATION

Correspondence: Dr Kofoed, Department of Dermatology, Copenhagen University Hospital, Bispebjerg, Bispebjerg Bakke 23, DK2400 Copenhagen NV, Denmark (kkofoed@hotmail.com).

Accepted for Publication: April 27, 2012.

Author Contributions: Drs Kofoed, Clemmensen, and Gniadecki had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kofoed and Gniadecki. Acquisition of data: Kofoed, Clemmensen, Mikkelsen, Simonsen, and Andersen. Analysis and interpretation of data: Kofoed and Gniadecki. Drafting of the manuscript: Kofoed and Gniadecki. Critical revision of the manuscript for important intellectual content: Kofoed, Clemmensen, Mikkelsen, Simonsen, Andersen, and Gniadecki. Statistical analysis: Kofoed. Obtained funding: Kofoed. Administrative, technical, and material support: Kofoed, Mikkelsen, Simonsen, and Andersen. Study supervision: Kofoed, Clemmensen, and Gniadecki.

Financial Disclosure: Drs Kofoed has received fees as a speaker from Abbott, Janssen-Cilag, and Pfizer and has served as an advisory board member for Abbott. Dr Gniadecki has obtained research grants from Abbott and lecture fees from Abbott, Janssen-Cilag, Merck Sharp & Dohme, and Pfizer.

Funding/Support: This study was supported by unrestricted research grants from Abbott and Serono Nordic and by the Danish Psoriasis Research Foundation.

Previous Presentations: This study was presented in part, at the Third International Congress on Psoriasis; July 2, 2010; Paris, France; and at 41st Annual Meeting of the European Society for Dermatology Research; September 7-10, 2011; Barcelona, Spain.

Boehncke WH, Boehncke S, Schön MP. Managing comorbid disease in patients with psoriasis.  BMJ. 2010;340:b5666
PubMed   |  Link to Article
Gustafson B, Hammarstedt A, Andersson CX, Smith U. Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis.  Arterioscler Thromb Vasc Biol. 2007;27(11):2276-2283
PubMed   |  Link to Article
Renzo LD, Saraceno R, Schipani C,  et al.  Prospective assessment of body weight and body composition changes in patients with psoriasis receiving anti-TNF-α treatment.  Dermatol Ther. 2011;24(4):446-451
PubMed   |  Link to Article
Ryden M, Dicker A, van Harmelen V,  et al.  Mapping of early signaling events in tumor necrosis factor-alpha–mediated lipolysis in human fat cells.  J Biol Chem. 2002;277(2):1085-1091
PubMed   |  Link to Article
Martínez-Abundis E, Reynoso-von Drateln C, Hernández-Salazar E, González-Ortiz M. Effect of etanercept on insulin secretion and insulin sensitivity in a randomized trial with psoriatic patients at risk for developing type 2 diabetes mellitus.  Arch Dermatol Res. 2007;299(9):461-465
PubMed   |  Link to Article
Marra M, Campanati A, Testa R,  et al.  Effect of etanercept on insulin sensitivity in nine patients with psoriasis.  Int J Immunopathol Pharmacol. 2007;20(4):731-736
PubMed
Solomon DH, Massarotti E, Garg R, Liu J, Canning C, Schneeweiss S. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis.  JAMA. 2011;305(24):2525-2531
PubMed   |  Link to Article
La Cava A, Matarese G. The weight of leptin in immunity.  Nat Rev Immunol. 2004;4(5):371-379
PubMed   |  Link to Article
Chen YJ, Wu CY, Shen JL,  et al.  Psoriasis independently associated with hyperleptinemia contributing to metabolic syndrome.  Arch Dermatol. 2008;144(12):1571-1575
PubMed   |  Link to Article
Engvall IL, Tengstrand B, Brismar K, Hafström I. Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomised study over 21 months.  Arthritis Res Ther. 2010;12(5):R197
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Patient Characteristics, Treatment Before and During Study, and Changes in PASI and DLQI After Anti-TNF Treatment
Table Graphic Jump LocationTable 2. Disease Severity, Physical Activity, Peak Oxygen Uptake, Insulin Sensitivity, Leptin Concentration, and Body Composition at Baseline and After Anti-TNF Treatmenta

References

Boehncke WH, Boehncke S, Schön MP. Managing comorbid disease in patients with psoriasis.  BMJ. 2010;340:b5666
PubMed   |  Link to Article
Gustafson B, Hammarstedt A, Andersson CX, Smith U. Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis.  Arterioscler Thromb Vasc Biol. 2007;27(11):2276-2283
PubMed   |  Link to Article
Renzo LD, Saraceno R, Schipani C,  et al.  Prospective assessment of body weight and body composition changes in patients with psoriasis receiving anti-TNF-α treatment.  Dermatol Ther. 2011;24(4):446-451
PubMed   |  Link to Article
Ryden M, Dicker A, van Harmelen V,  et al.  Mapping of early signaling events in tumor necrosis factor-alpha–mediated lipolysis in human fat cells.  J Biol Chem. 2002;277(2):1085-1091
PubMed   |  Link to Article
Martínez-Abundis E, Reynoso-von Drateln C, Hernández-Salazar E, González-Ortiz M. Effect of etanercept on insulin secretion and insulin sensitivity in a randomized trial with psoriatic patients at risk for developing type 2 diabetes mellitus.  Arch Dermatol Res. 2007;299(9):461-465
PubMed   |  Link to Article
Marra M, Campanati A, Testa R,  et al.  Effect of etanercept on insulin sensitivity in nine patients with psoriasis.  Int J Immunopathol Pharmacol. 2007;20(4):731-736
PubMed
Solomon DH, Massarotti E, Garg R, Liu J, Canning C, Schneeweiss S. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis.  JAMA. 2011;305(24):2525-2531
PubMed   |  Link to Article
La Cava A, Matarese G. The weight of leptin in immunity.  Nat Rev Immunol. 2004;4(5):371-379
PubMed   |  Link to Article
Chen YJ, Wu CY, Shen JL,  et al.  Psoriasis independently associated with hyperleptinemia contributing to metabolic syndrome.  Arch Dermatol. 2008;144(12):1571-1575
PubMed   |  Link to Article
Engvall IL, Tengstrand B, Brismar K, Hafström I. Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomised study over 21 months.  Arthritis Res Ther. 2010;12(5):R197
PubMed   |  Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Supplemental Content

Kofoed K, Clemmensen A, Mikkelsen UR, Simonsen L, Andersen O, Gniadecki R. Effects of anti–tumor necrosis factor therapy on body composition and insulin sensitivity in patients with psoriasis. Arch Dermatol.. 10.1001/archdermatol.2012.1753.

eAppendix. Expanded Methods Section.

Supplemental Content

Some tools below are only available to our subscribers or users with an online account.

1,048 Views
2 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs