Psoriasis patients with obesity and type 2 biabetes: the effect of glucagon-like peptide 1 (GLP-1) receptor agonists

2014/2015 Paula Cristina Cardoso Teixeira Psoriasis patients with obesity and type 2 diabetes: the effect of glucagon-like peptide-1 (GLP-1) receptor agonists março, 2015 Mestrado Integrado em Medicina Área: Dermatologia Trabalho efetuado sob a Orientação de: Doutora Sofia Magina Trabalho organizado de acordo com as normas da revista: Journal of the European Academy of Dermatology and Venereology Paula Cristina Cardoso Teixeira Psoriasis patients with obesity and type 2 diabetes: the effect of glucagon-like peptide-1 (GLP-1) receptor agonists março, 2015 Projeto de Opção do 6º ano - DECLARAÇÃO DE INTEGRIDADE Eu, Paula Cristina Cardoso Teixeira, abaixo assinado, nº mecanográfico 200907067, estudante do 6º ano do Ciclo de Estudos Integrado em Medicina, na Faculdade de Medicina da Universidade do Porto, declaro ter atuado com absoluta integridade na elaboração deste projeto de opção. Neste sentido, confirmo que NÃO incorri em plágio (ato pelo qual um indivíduo, mesmo por omissão, assume a autoria de um determinado trabalho intelectual, ou partes dele). Mais declaro que todas as frases que retirei de trabalhos anteriores pertencentes a outros autores, foram referenciadas, ou redigidas com novas palavras, tendo colocado, neste caso, a citação da fonte bibliográfica. Faculdade de Medicina da Universidade do Porto, 15 /_03 /_2015_ Assinatura conforme cartão de identificação: Projecto de Opção do 6º ano – DECLARAÇÃO DE REPRODUÇÃO NOME Paula Cristina Cardoso Teixeira CARTÃO DE CIDADÃO OU PASSAPORTE (se estrangeiro) E-MAIL TELEFONE OU TELEMÓVEL 13942107 [email protected] 919249651 NÚMERO DE ESTUDANTE DATA DE CONCLUSÃO 200907067 23 de Março de 2015 DESIGNAÇÃO DA ÁREA DO PROJECTO Dermatologia TÍTULO DISSERTAÇÃO/MONOGRAFIA (riscar o que não interessa) Psoriasis patients with obesity and type 2 diabetes: the effect of glucagon-like peptide-1 (GLP-1) receptor agonists ORIENTADOR Prof. Dra. Sofia Magina COORIENTADOR (se aplicável) É autorizada a reprodução integral desta Dissertação/Monografia (riscar o que não interessa) para efeitos de investigação e de divulgação pedagógica, em programas e projectos coordenados pela FMUP. Faculdade de Medicina da Universidade do Porto, _03 /_03_/_2015_ Assinatura conforme cartão de identificação: DEDICATÓRIA “If you focus on the problem, you can't see the solution. Never focus on the problem! See what no one else sees. See what everyone chooses not to see... out of fear, conformity or laziness. See the whole world as new each day “ Patch Adams MONOGRAFIA Psoriasis patients with obesity and type 2 diabetes: the effect of glucagon-like peptide-1 (glp-1) receptor agonists Redigida de acordo com as normas da revista Journal of the European Academy of Dermatology and Venereology Review Article 1 PSORIASIS PATIENTS WITH OBESITY AND TYPE 2 DIABETES: THE EFFECT OF GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS 2800 words 2 tables 2 figures Author information P. Teixeira1,3, S. Magina1,2,3 1Faculdade de Medicina da Universidade do Porto, Porto, Portugal; 2Department of Dermatology; 3Department of Pharmacology and Therapeutics, Hospital de São João, Porto, Portugal Correspondence P. Teixeira Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200 - 319 Porto, Portugal Telf 220426700 Fax 225513643 Email: paula.cardoso.te[email protected] Funding Sources None Conflict of interest All authors declare no conflicts of interest 2 ABSTRACT Patients with psoriasis have a high prevalence of diabetes mellitus (DM), obesity and cardiovascular diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonists is a recent therapy used in obese patients with type 2 diabetes. This new drugs improve glycaemic control and reduce weight. Besides, GLP-1R is present on some cells of the immune system. Recent studies suggested that GLP-1R agonists may improve psoriasis. We reviewed the literature to examine the efficacy of GLP-1R agonists on clinical severity of psoriasis patients with obesity and type 2 diabetes and to evaluate the mechanism by which GLP-1R agonists exert their effects. Psoriasis patients, with type 2 diabetes and obesity, seem to have a significant improvement in psoriasis severity and quality of life, after GLP-1R agonist therapy. They also showed a decreased in weight and cholesterol levels and an improvement in glycaemic control. The effects on psoriatic lesions occur after a few weeks of treatment, even before the metabolic improvement occurs. GLP-1R agonists appear to have an added beneficial effect on psoriasis patients, possibly due to its immunomodulatory effects. Furthermore, this treatment can also improve other comorbidities that may be associated, such as diabetes and obesity. In conclusion, GLP-1R agonists may be a useful adjunctive therapy for the treatment of psoriasis in diabetics and obese patients. 3 INTRODUCTION Psoriasis is a chronic inflammatory disease that affects 2-3% of world’s population. Histopathologically is characterized by hiperproliferation of epidermal keratinocytes and hyperkeratosis, dermal inflammatory infiltrate and angiogenesis. The inflammatory infiltrate consists mainly of dendritic cells, macrophages, and T cells in the dermis and neutrophils, with some T cells in the epidermis (1, 2). Psoriasis is considered an immune-mediated inflammatory skin disorder (3), in which Th17 pathway plays an important role (1), supported by the good results with IL-17 based therapies (4). Psoriasis was considered a disease confined to the skin (5), but recent findings have shown that patients with psoriasis also have an increased risk of cardiovascular disease and mortality, as well as metabolic syndrome and its components (6-8). Several studies have shown that patients with psoriasis have a high prevalence of DM, hypertension, obesity, hyperlipidaemia and smoking (9-11). So, it is important to approach psoriasis as a systemic disorder. Psoriasis patients have a higher risk of developing impaired glucose tolerance and type 2 diabetes (12-14). Obesity seems to be more common in psoriasis patients when compared with the general population (15) and is considered a risk factor for the development of psoriasis (6). The reason behind this association remains unknown, but different studies suggest that obesity, as a chronic inflammatory state, may contribute to the development and aggravation of psoriatic lesions (16, 17). Two new drug classes based on the actions of the incretin hormones have been approved for therapy of type 2 diabetes - incretin enhancers and incretin mimetics (18). Inhibitors of dipeptidyl peptidase 4 (DPP4 - the enzyme responsible for the rapid degradation of GLP-1), increase incretins levels and enhance GLP-1 action. It is known that DPP4 is also expressed on T cells surface, having an important role in activating T cells (19). However, only two cases reports showed that DPP4 inhibitors have positive effects in the treatment of psoriasis patients with diabetes (19, 20). Glucagon-like peptide-1 receptor (GLP-1R) agonists (incretin mimetics – liraglutide and exenatide) have been used in obese patients with type 2 diabetes. This therapy improves glycaemic control and reduces weight. Several studies suggest that psoriasis patients with obesity and DM2, treated with GLP-1R agonists, exhibited a significant improvement of psoriasis lesions, possibly due to its anti-inflammatory effect (21). 10 skin from psoriasis patients (31). Cameron et al demonstrated that cells expressing NK markers and NK-T cell markers are present in psoriasis lesions (32). Recent data, reported by T. Ahern et al and Hogan et al, show that circulating iNKT cells increased and plaque iNKT cells decreased after liraglutide treatment in psoriasis patients with type 2 diabetes and obesity(22, 25). These results suggest that GLP-1R agonists may have a role in psoriasis treatment, since they seem to have direct and indirect effects on immune cells involved in psoriasis pathogenesis. Other studies have shown that GLP-1 levels also increased after gastric bypass surgery. Some case reports have described that psoriasis improves immediately after this procedure in obese patients (33). Changes on psoriasis manifestations occur before any weight loss and coincide with a significant increase in GLP-1 levels (34-36). Faurschou et al suggested that GLP-1 is responsible for this effect. The changes on GLP-1 levels are presumed to be caused by the surgically-introduced rerouting of ingested nutrients directly to the distal part of jejunum, where GLP-1 releasing L cells are abundant (figure 2). GLP-1 is secreted to the blood stream upon food ingestion when luminal nutritional components contact with the apical part of the L cells. These data support the hypothesis that GLP-1 is responsible for the positive effect observed in psoriasis and obese patients with type 2 diabetes (37). Most of the studies were limited by small sample size, short duration, lack of comparative groups and placebo effect. Further studies are obviously needed, including randomised clinical trials. GLP-1R agonists appear to have an added beneficial effect on psoriasis patients, possibly due to its immunomodulatory effects. Besides, this treatment can also improve other comorbidities that may be associated, such as diabetes and obesity. In conclusion, GLP-1R agonists seem to have a positive effect on psoriasis severity and quality of life. It appears to act by an immune mechanism, through a reduction of IL-17 expression and dermal γδ T-cells. These results suggest that GLP-1R agonists may be a useful adjunctive therapy for the treatment of psoriasis in diabetics and obese patients. 11 ACKNOWLEDGMENTS I would like to express my gratitude to my supervisor, Prof. Doctor Sofia Magina, for her help through the course of this work. REFERENCES 1. Nestle FO, Kaplan DH, Barker J. Psoriasis. The New England journal of medicine. 2009;361(5):496-509. 2. Schon MP, Boehncke WH. Psoriasis. The New England journal of medicine. 2005;352(18):1899-912. 3. Jadali Z, Eslami MB. T cell immune responses in psoriasis. Iranian journal of allergy, asthma, and immunology. 2014;13(4):220-30. 4. Lonnberg AS, Zachariae C, Skov L. Targeting of interleukin-17 in the treatment of psoriasis. 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Buysschaert M, Tennstedt D, Preumont V. Improvement of psoriasis during exenatide treatment in a patient with diabetes. Diabetes & metabolism. 2012;38(1):86-8. 29. Reid CT, Tobin AM, Ahern T, O'Shea D, Kirby B. Liraglutide in combination with acitretin for severe recalcitrant psoriasis. The British journal of dermatology. 2013;169(1):230-1. 30. Cai Y, Fleming C, Yan J. Dermal gammadelta T cells--a new player in the pathogenesis of psoriasis. International immunopharmacology. 2013;16(3):388-91. 31. Peternel S, Kastelan M. Immunopathogenesis of psoriasis: focus on natural killer T cells. Journal of the European Academy of Dermatology and Venereology : JEADV. 2009;23(10):1123-7. 32. Cameron AL, Kirby B, Fei W, Griffiths CE. Natural killer and natural killer-T cells in psoriasis. Archives of dermatological research. 2002;294(8):363-9. 33. Hossler EW, Maroon MS, Mowad CM. Gastric bypass surgery improves psoriasis. Journal of the American Academy of Dermatology. 2011;65(1):198-200. 14 34. Hossler EW, Wood GC, Still CD, Mowad CM, Maroon MS. The effect of weight loss surgery on the severity of psoriasis. The British journal of dermatology. 2013;168(3):660-1. 35. Laferrere B. Effect of gastric bypass surgery on the incretins. Diabetes & metabolism. 2009;35(6 Pt 2):513-7. 36. Mingrone G. Role of the incretin system in the remission of type 2 diabetes following bariatric surgery. Nutrition, metabolism, and cardiovascular diseases : NMCD. 2008;18(8):574-9. 37. Faurschou A, Zachariae C, Skov L, Vilsboll T, Knop FK. Gastric bypass surgery: improving psoriasis through a GLP-1-dependent mechanism? Medical hypotheses. 2011;77(6):1098-101. 15 FIGURES AND TABLES Literature search Total number of abstracts identified from database search (MEDLINE, SCOPUS, Web of SCIENCE) n = 84 Duplicated articles (excluded n = 17) Total number of articles n = 67 Articles screened on basis of title and abstracts (excluded 55) Included n = 12 Manuscript review and application of inclusion criteria Included n = 8 Excluded n = 4 3 reviews 1 french article 16 Diabetes and Obesity Psoriasis GLP-1 GLP-1 receptor agonists Liraglutide and Exenatide - prolongs and enhances the effect of GLP-1 - they are resistant to inactivation by DPP4 Gastric Bypass Surgery - Roux-en-Y gastic bypass procedure: a small part of the stomach is used to create a new stomach pouch; the smaller stomach is connected directly to the middle portion of the small intestine (jejunum), bypassing the rest of the stomach and the upper portion of the small intestine (duodenum). - reduces body weight - improves glycaemic control - improves PASI and DLQI - decreases number of dermal γδ Tcells and IL-17 mRNA expression in psoriatic lesions - increases circulating iNKT cells decreases and plaque iNKT cells - Increases GLP-1 levels - Immediately improvement of psoriasis before any weight loss Figure 2. Effects of GLP-1 receptor agonists and gastric bypass surgery in psoriatic patients with diabetes and obesity 17 Table 1 Study outcomes Study Study design Intervention Participants Variables Results T. Ahern et al, 2013 Prospective cohort study 10 weeks of liraglutide therapy: self-administered by subcutaneous injection; 0.6mg daily for 2 weeks and 1.2mg daily for 8 weeks Psoriasis patients with diabetes and obesity (median age 48 years, median BMI 48.2 Kg/m2) n = 7 - PASI - DLQI - Circulating iNKT number - Monocyte cytokine production At week 10 - median PASI dropped from 4.8 (2.6–11.4) to 3.0 (1.9–7.9, P = 0.03) - median DLQI dropped from 6 (3.5–8.9) to 2 (1– 6.1, P = 0.03) - median circulating iNKT cell percentage increased 37.9% (18.5–234.6, P = 0.03) - PBMC TNFα production decreased by a median of 53% A.Faurschou et al, 2014 Randomized placebocontrolled trial Once-daily subcutaneous injections with liraglutide or placebo, for 8 weeks; 0.6mg for 1 week, 1.2mg the following week and then 1.8mg Glucose-tolerant and obese patients (BMI > 25 Kg/m2) with plaque psoriasis Placebo n = 9 Liraglutide n = 11 - PASI - DLQI - Weight - hsCRP - Adverse events At week 8 - mean PASI decrease 2.6 ± 2.1 (mean ± SD, P=0.026) in the liraglutide group; non-significant change in PASI in the placebo group (-1.3 ± 2.4, P=0.141) - no significant differences were observed in the DLQI - the liraglutide group had a significant loss in bodyweight compared with the placebo group - no significant changes in hsCRP occurred in both groups - no major adverse events were observed M.Buysschaert et al, 2014 Prospective case-series Patients self-administered subcutaneous injections with exenatide (5µg twice daily) or liraglutide (0.6mg once a day for 1 week and then 1.2mg once a day). The variables were measured at baseline (T0) and 7±1 (T1) and 18±2 (T2) weeks after treatment with liraglutide/exenatide. Patients with type 2 diabetes and chronic psoriasis plaques (mean age 56 ± 8 years, mean BMI 32.0 ± 10.1 Kg/m2) n = 7 - PASI - BMI - HbA1c - dermal γδ T-cell percentage - IL-17 expression - Psoriasis severity improved with liraglutide/exenatide treatment (12.0±5.9 (T0), 9.2±6.2 (T1) and 9.2±6.4 (T2)) - BMI decreased after 4-5 months of treatment (from 32.0±10.1(T0) to 30.6±9.1 (T2) Kg/m2, P=0.05) - Glycaemic control improved at T2 (HbA1c decreased from 7.5±1.2 (T0) to 6.5±0.8 (T2), P=0.014) - Dermal γδ T-cell percentage was higher in psoriatic lesions compared with unaffected skin and a decreased of 4.0±0.7% (P=0.05) occurred in the patients with improved (n=5) or unchanged (n=1) PASI scores during the treatment. 18 - No significance difference was seen during the treatment in IL-17 expression. Hogan et al, 2011 Prospective study Index patient: underwent treatment with exenatide for 2 months and then with liraglutide. Other patients: two additional patients started liraglutide for 6 weeks, after the improvement of psoriatic lesions in the index patient Patients with type 2 diabetes and psoriasis (n=2) - PASI - circulatory and plaques levels of iNKT cell - GLP-1 receptor expression on iNKT cells - PASI improved from 13.2 to 10.8 (patient 1) and from 4.8 to 3.8 (patient 2) - circulatory iNKT cell number increased after the treatment and plaque iNKT cell decreased - iNKT cells express GLP-1R, which respond to GLP-1 activating a signalling pathway Faurschou et al, 2013 Crosssectional study A skin biopsy was made every healthy volunteer and two skin biopsies every psoriasis patients (from affected and unaffected skin). They collected a blood sample from all participants and cultured human keratinocytes were stimulated or unstimulated. Health volunteers (n=6) vs Psoriasis patients (n=6) - Expression of GLP-1 receptors in skin biopsies, blood samples and cultured human keratinocytes - GLP-1 receptors were expressed in five of six skin biopsies from psoriasis plaques, in one of six biopsies from unaffected psoriatic skin and in one of six biopsies from healthy skin. - GLP-1 receptors were expressed in the blood of all participants. - GLP-1 receptors expression were not found in stimulated or unstimulated cultured human keratinocytes. 19 Table 2. Case reports Study Patient Medical History Physical examination Treatment Results A.Faurschou et al, 2014 59 years Man - Type 2 diabetes (inadequate glycaemic control) - Hypertension - Hypercholesterolemia - Acute myocardial infarction - Plaque psoriasis (diagnosed 15 years ago) - BMI 29.3 kg/m2 - HbA1c 8.9% (74mmol/mol) - Psoriasis was located on the elbows, knees, scalp, buttocks and dorsal parts of the hands - Physician’s global assessment (PGA) score 3 - Liraglutide: 0.6mg once daily for 1 week and then 1.2 mg once daily the following 5 weeks and then 1.8mg. - Metformin: 1g twice a day - Insulin?? After 3 months of treatment: - HbA1c reduced (5.9%) - BMI 26.81 kg/m2 - Adverse events - nausea and headache, intermittent constipation and diarrhoea. No episodes of hypoglycaemia were reported - Psoriasis symptoms improved - PGA reduced (score 1) M.Buysschaert et al, 2012 61 years Man - Type 2 diabetes for 14 years - Hypertension - Dyslipidaemia - Psoriasis (since 1980) - BMI 25.5 kg/m2 - HbA1c 8.1% (65mmol/mol) - CRP 0.22 mg/dL - PASI score 11 - Exenatide 2x5µg/day (initiated on September 2008) - Metformin and sulphonylureas - Perindopril (5mg/day) - Moxonidine (0.4mg/day) - Simvastatin (20mg/day) After 12 months of treatment: - BMI 24.07 kg/m2 - HbA1c 7.3% (56mmol/mol) - CRP 0.03 md/dL - PASI score 3-4 (he stopped all topical treatments) Exenatide treatment interrupted in September 2009: - PASI score (after 6 months) >10 - weight gain and worsening of glycaemic control (HbA1c 9.2%) April 2010, started exenatide treatment again: - weight loss - HbA1c 8.1% (65mmol/mol) - PASI score 3.1 Reid et al, 2013 54 years Man - Extensive plaque psoriasis - Malignant melanoma (without metastatic disease) - No diabetes - BMI 42.1 kg/m2 - PASI 14.2 - DLQI 25 - Acitretin 50mg daily - Liraglutide (0.6mg daily for one week and then 3mg daily) After one year: - PASI 7.6 - DLQI 12 - Weight decreased 10kg to the studies being reported should be included in all manuscripts in the Materials and Methods section. 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Please therefore sign up for author services if you would like to access your article PDF offprint and enjoy the many other benefits the service offers. Additional offprints can be ordered on the offprint order form, which accompanies the proofs. Disclaimer. The Publisher, the European Academy of Dermatology and Venereology (EADV) and Editors cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed do not necessarily reflect those of the Publisher, the EADV and Editors or the products advertised.