1. Dr. Pravin R. Bharatia M. D. KEM Hospital, Pune.

3. Metabolic syndrome  A clustering of certain risk factors, if occur together are strong predictors for CVD, Diabetes and stroke.  -Central (visceral) obesity  -Glucose intolerance  -Hypertension  -Atherogenic dyslipidemia

5. Metabolic Syndrome: Clustering of Interconnected Metabolic Risk Factors Obesity Insulin Resistance + Hyperglycemia Hypertension Atherogenic Dyslipidemia

6. Diagnosis of Metabolic syndrome  SAM NCEP ATP Panel III Criteria: 3 of 5 of following:  1. Waist circumference for Asian patients: ≥90 cm for men, ≥ 80 cm for women.  2. Fasting BSL ≥ 100 mg/dL  3. Blood pressure: ≥ 130/ ≥ 85 mm Hg  4.Serum Triglycerides ≥ 150 mg/dL  5. HDL ≤ 40 mg/dL in men, ≤ 50mg/dL in women

9. Common links between Psoriasis & Metabolic Syndrome Chronic inflammation:  Th1, 17 cytokines:ICAM-1, TNF α, IL-1, IL-6, IL-12, Inflammation markers like CRP predominate in psoriatic and atherosclerotic plaques.  Proinflammatory glycoproteins like osteopontin, peptide hormones like leptin and other markers like homocysteine –implicated in bringing both conditions together.  VGEF induced angiogenesis: found both in psoriasis and atherosclerosis. Genetic:  Psoriasis and Metabolic syndrome share susceptibility loci including CDKAL1, PSORS 2-4, ApoE4.

10. Back Visceral AT Subcutaneous AT Front Intra-abdominal (Visceral) Fat The dangerous inner fat!

11. Central (Visceral) obesity  Obesity favours psoriasis : proinflammatory state & release of inflammatory mediators – adipocytokines.  Intra-abdominal fat: An endocrine organ  -secreting proteins such as adiponectin, leptin, resistin, visfatin  -promoting inflammation, altered glucose metabolism & endothelial biology.  Leptin: Hypothalamus modulator of food intake, body weight and fat stores, Modulates balance between helper T cell types 1 & 2.It activates macrophages & potentiates proinflammatory cytokines.

12.  Adiponectin:  -30 kDa adipocyte secreted polypeptide hormone.  -Stimulates glucose utilization & fatty acid oxidation liver & muscles.  -Plays principal role in suppression of metabolic derangements that may result in insulin resistance, Type 2 diabetes, Met S and CVDs.  -Anti-inflammatory-Suppresses TNFα and IL 6 production by keratinocytes & macrophages.  - Found to be lower in psoriasis patients.  -TNFα inhibits adiponectin production.

14. Study and year Study period Outcome ascertainme nt No. of Met S in Control group No. Of Met S in psoriasis group Odds Ratio Sommer et al, 2006 1996- 2002 Manual chart view 11(1.1)25(4.3)4.22(2.06-8.65) Gisondi et al, 2007 NRClinical assessment, NCEP ATP III 69(20.6)102(30.1)1.65(1.16-2.35) Chen et al, 2008 2006-07Clinical assessment 13(16.3)10(14.1)0.84(0.31-2.26) Al Mutairi et al, 2010 2003-07Manual chart review 124(6.8)Mild ps 265(16), Sev 34(26.4) Mild 2.6(2.09- 3.28), Sev 4.93(3.21-7.60) Augustin et al, 2010 2005ICD-10786(0.1)61(0.2)2.86(2.21-3.71) Bongiorno et al, 2010 NRClinical assessment, NCEP ATP III 32(9.2)103(25.8)3.4(2.23-5.24) Takahashi et al, 2010 2006-08Manual chart view 25(16.2)38(25.2)1.74(0.99-3.05) Love et al, 2011 2003-06Clinical assessment, NCEP ATP III 560(23.5)28(38.9)2.16(1.02-3.77) Mebazza et al, 2011 2008-10Clinical assessment, NCEP ATP III 67(31.0)67(40.9)1.39(0.88-2.18) Langan et al, 2012 NRRead Codes THIN database 10,515(25.9)1389(34.2)1.50(1.40-1.61) Insulin resistance & Diabetes  Chronically raised FFA, TNF α,IL-6 in psoriasis  - glucose production in liver  - glucose uptake in muscle.  - Pancreatic insulin secretion-Insulin resistance Genetic: Shared genetic risk loci  -Type I Diabetes and psoriasis:PTPN22  -Type II Diabetes and psoriasis:CDKAL1

15. Hypertension & Dyslipidemia  Psoriasis patients have altered Renin- angiotensin-aldosterone system, Increased Renin and ACE activity-hypertension.  Angiotensinogen from adipose tissue: salt retention, vasoconstrictor-Hypertension  IL-1, IL-6, TNFα increase lipid levels and affect arterial smooth muscle cells giving rise to Dyslipidemia and hypertension.

17. Prevalence of individual metabolic abnormalities of Met S according to NHANES 2003-3006 % (95% CI) VariablesPsoriasisNo PsoriasisOR Abdominal obesity62.9 [51.3- 74.5] 47.9 [45.3- 50.5] 1.75 [1.03- 2.86] Hypertryglyceridemia44 [33.8-54.2]27.2 [24.9- 29.6] 2.08 [1.39- 3.11] Low HDL Cholesterol33.9 [23.7- 44.1] 23.9 [21.3- 26.4] 1.63 [0.98- 2.71] High blood pressure28.4 [14.8- 41.9] 22.2 [20.4- 24] 1.33 [0.63- 2.79] High fasting glucose (original) 8.4 [1.4-15.4]8.0 [6.5-9.4]1.01 [0.44- 2.36] High blood glucose (modified) 30.5 [16.9- 44.1] 28.5 [25-32]1.06 [0.56- 1.99] Love et al, Arch Dermatol. 2011 April; 147 (4): 419-424.

18. Study and year Study period Outcome ascertainmen t No. of Met S in Control group No. Of Met S in psoriasis group Odds Ratio (95% CI) Sommer et al, 2006 1996- 2002 Manual chart view11(1.1)25(4.3)4.22(2.06-8.65) Gisondi et al, 2007 NRClinical, NCEP ATP III 69(20.6)102(30.1)1.65(1.16-2.35) Chen et al, 20082006-07Clinical assessment 13(16.3)10(14.1)0.84(0.31-2.26) Al Mutairi et al, 2010 2003-07Manual chart review 124(6.8)Mild ps 265(16), Sev 34(26.4) Mild 2.6(2.09- 3.28), Sev 4.93(3.21-7.60) Augustin et al, 2010 2005ICD-10786(0.1)61(0.2)2.86(2.21-3.71) Bongiorno et al, 2010 NRClinical, NCEP ATP III 32(9.2)103(25.8)3.4(2.23-5.24) Takahashi et al, 2010 2006-08Manual chart view25(16.2)38(25.2)1.74(0.99-3.05) Love et al, 20112003-06Clinical, NCEP ATP III 560(23.5)28(38.9)2.16(1.02-3.77) Mebazza et al, 2011 2008-10Clinical, NCEP ATP III 67(31.0)67(40.9)1.39(0.88-2.18) Langan et al, 2012 NRRead Codes THIN database 10,515(25.9)1389(34.2)1.50(1.40-1.61)

19. Outcome of Indian Studies Author and yearAreaJourna l Type of study No. of patients Psoriasis/con trol Significant associatio n Nisa, Quazi et al, 2010 Srinagar, J & K IJDVLCase-control150/150Yes Pereira, Amladi, 2011 MumbaiIJDCase-control, cross- sectional 77/92No Madanagobalane Anandan et al, 2012 ChennaiIJDHospital based, case- conrol 118/120Yes Khunger et al, 2013 New DehliIJDCase-control50/50Yes Ali, Kuruvilla, 2014Mangalore, Karnataka IJDVLCase-controlNAYes Lakshmi, Nath et al, 2014 PuducherryIDOJHospital based, comparative 40/40No

20.  TG and  HDL cholesterol  ß cell function  BG Adipocytokines & FFA Insulin resistance CVS and renal complications Metabolic Syndrome - A Unifying Hypothesis Aging Family history (Genetics or shared environment) Psychosocial stress Visceral fat  GH and IGF-1  Testosterone (M)  Testosterone (F)  Cortisol  SNS  RAAS  BP Activated immunity Adapted from Björntorp P. Obes Res 1993; 1: 206-22 and Chan JCN et al. Diabetes Care 1995; 18: 1013-6. Luk A and Chan JCN Diabetes Res Clin Pract 2008: 82 Suppl 1:S15-20

21. Interesting observations  Individual components of Met S :proved beyond doubt comorbidities in psoriasis.  Psoriatics have 2-3 fold high risk of Met S.  Incidence of Met S – in Psoriasis after age 40.  Psoriatics with high PASI : more likely to develop Met S.  Psoriatics with Met S : longer disease duration  Even in children, association of diabetes, hyperlipidemia and obesity is found.  Few Asian studies have found no link.

22. Impact of Treatment  MTX reduces risk of major CV events in psoriasis, Ps A, RA probably by its vascular effects.  Cyclosprin: May induce or aggravate hypertension, dyslipidemia, increase insulin resistance, interact with statins-rhabdomyolysis.  Acitretin may cause hyperlipidemia.  Beta blockers may aggravate psoriasis.  TNFα antagonists reduce CRP levels esp in obese patients and improve insulin sensitivity in diabetes; weight gain, but no effect on S. Lipids.  Poor response to fixed dose biologicals in Obese patients.  Clearing of psoriasis after gastrectomy.

23. Systemic psoriasis treatments affecting components of Met s MTXCys-AAcitretinAnti-TNF alpha Ustekinum ab HyperlipidemiaNoYes No HypertensionNoYesNo ObesityNo YesNo DiabetesNoYesNo NAFLDYesNo Decreased Renal function Yes No

24. Management of Metabolic syndrome Lifestyle modifications  -Dietary restrictions  -Regular physical activity  -Weight reduction  -Cessation of smoking Medical  - Metformin, OHA, AHA, LLAs Surgical  - Gastrectomy/ Bariatric surgery for morbid obesity

25. Summary Points A patient of Psoriasis  -Long duration  -Moderate or severe type  -Known Diabetes/ FH  -Overtly overweight/obese Do look for - AN, Check weight, abdominal girth  -Take Blood pressure  -Advise BSL, Lipid profile  -Discuss Met S, its implications and suggest Lifestyle changes – to prevent adverse CV events.

26. Thank you

28. StudyStudy setting Study design Total control no. Total psoriasis patients Mean age control [yrs] Mean age psoriasis [yrs] Sommer et al 2006Germany, IPDCross sectional 104458158.554.4 Gissondi et al, 2007 Italy, OPDCross- sectional 33433863.862.1 Chen et al, 2008Taiwan, OPDCase control817755.657.4 Al Mutairi et al, 2010 Kuwait, OPDCase control1835 52.752.3 Augustin et al, 2010 Germany, Insurance database Cross- sectional 131009033981NR Bongiorno et al, 2010 Italy, OPDCross- sectional 34840047.6 Nisa and Quazi, 2010 India, OPD records Case-control150 36.337.3 Takahashi et al, 2010 Japan, OPDCase control15415157.253.1 Love et al, 2011USA, OPDCross- sectional 23857138.641.7 Mebazza et al 2011Tunisia OPDCase-control21616448.646.3 Langan et al, 2012UK, OPDCase-control406504065NR

32. Metabolic Syndrome – A Multifaceted Syndrome High blood glucose High blood pressure Abnormal lipid levels Obesity Heart disease Stroke Kidney failure Depression? Cancer? Urine protein Inflammatory markers

33.  TG and  HDL cholesterol  ß cell function  BG Adipocytokines & FFA Insulin resistance CVS and renal complications Metabolic Syndrome - A Unifying Hypothesis Aging Family history (Genetics or shared environment) Psychosocial stress Visceral fat  GH and IGF-1  Testosterone (M)  Testosterone (F)  Cortisol  SNS  RAAS  BP Activated immunity Adapted from Björntorp P. Obes Res 1993; 1: 206-22 and Chan JCN et al. Diabetes Care 1995; 18: 1013-6. Luk A and Chan JCN Diabetes Res Clin Pract 2008: 82 Suppl 1:S15-20