Copyright. "It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.

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1 154 UNIVERSITÁ DEGLI STUDI DI VERONA FACOLTÁ DI MEDICINA E CHIRURGIA Dipartimento di Medicina Sezione di Dermatologia e Venereologia AZIENDA OSPEDALIERA UIVERSITARIA INTEGRATA DI VERONA Unità Operativa di Dermatologia Comorbidities, Systemic nature of disease metabolic & cardiovascular impact Paolo Gisondi The «moisaicism» of treatment success Content flow Patient centered medicine Patient s satisfaction Achievement of treatment goalsin the context of comorbidities Fingerprint of psoriasis Screen and management of comorbidities A. Gaudì "It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has. OslerW

2 157..The growingdemands for quality and safety in health care have refocused attentionon patientoutcomes, even if efforts to ensure more consistently positive outcomes sometimesreduce the physician s prized autonomy The fingerprint of psoriasis I.B.D. Comorbidities Gisondi P et al. J Hepatol 29;51:758-64; Gisondi P et al. Br J Dermatol27;157:68-73; Gisondi P et al. Eur J Dermatol 25;15:279-83; Esposito M. Dermatology 26;212:123-7; De Simone C et al. G Ital Dermatol Venereol 213;148: Skin Liver Rheumatic involvement Metabolic syndrome Depression/anxiety Phenotype of a patient with psoriasis and metabolic syndrome Co-morbidity Treatment Arterial hypertension Ramipril and hydrochlorothiazide Type II diabetes Insulin Hypercholesterolemia, hypertriglyceridemia Statin Obesity - COPD - Liver steatosis - Picture courtesy of Dr Gisondi. 53

3 Increased prevalence of metabolic syndrome in patients with psoriasis 16 Cases Controls P No Sex, M/F 16/178 15/184.8 Age at enrollment; year, mean ± SD 62.1 ± ± BMI, mean ± SD 27.7 ± ± Smoker, n (%) 121 (36.2) 72 (21.).1 Metabolic syndrome, n (%) 12 (3.1) 69 (2.6).5 Waist circumference >12 cm (M) or >88 (F), n (%) 193 (57.1) 159 (47.6).1 Triglyceridemia >1.7 mmol/l, n (%) 128 (37.8) 78 (23.3).1 HDL cholesterol <1. mmol/l (M) or <1.3 (F), n (%) 61 (18.) 72 (21.5).2 Blood pressure >135/85 mm Hg, n (%) 138 (4.8) 132 (39.5).7 Fasting plasma glucose >6.1 mmol/l, n (%) 65 (19.2) 7 (2.9).6 According to the National Cholesterol Education Programme s Adult Treatment Panel III (ATP III), 21. Gisondi P, et al. Br J Dermatol. 27;157: Meta-analysis of the prevalence of MetSin patients with psoriasis Study Sommer 26 Gisondi 27 Chen 28 Chen 29 Al-Mutairi 21 Augustin 21 Bongiorno 21 Nisa 21 Takahashi 21 Love 211 Mebazaa 211 Langan 212 Overall Year of publication NOTE: Weights are from random effects analysis Pooled odds ratio was 2.26 (95% CI: ) Dose response relationship between psoriasis severity and prevalence of MetS Armstrong AW, et al. J Am Acad Dermatol 213 (Epubahead of print) OR (95% CI) 4.22 (2.6, 8.65) 6.86 % weight 1.65 (1.16, 2.35) (.31, 2.27) (.67, 8.59) (2.16, 3.36) (2.21, 3.71) (2.22, 5.21) (2.84, 13.6) (.99, 3.5) (1.2, 3.77) (1.6, 2.82) (1.31, 1.51) (1.7, 3.1) 1. Non-alcoholic fatty liver disease (NAFLD) is associated with the metabolic syndrome Normal liver Pure steatosis Cirrhosis (HCC) Adams LA et al. CMAJ. 25;172: Angulo P. New Eng J Med. 22;346: Steatohepatitis (NASH) Inflammation Fibrosis 54

4 NAFLD is more frequent in patients with psoriasis than in BMI-matched controls NAFLD prevalence (%) % 25% NAFLD prevalence (%) Controls PASI <1 PASI 1 Controls P Gisondi P, et al. J Hepatol. 29;51: Number Sex (M/F) 89/41 18/8 NS Age 51± ±8 NS BMI (kg/m 2 ) 27.5± ±3.2 NS Metabolic syndrome 28% 26% Nutrient overload activates inflammatory responses in adipose tissue, liver, skeletal muscle, pancreas and the hypothalamus, contributing to systemic insulin resistance and glucose intolerance OsbornO et al. Nat Med. 212;18(3): Is inflammation only in the skin in patients psoriasis? with Obesityleads to systemic inflammation 55

5 is associated with an increased serum CRP ± 7.9 CRP levels (mg/l) ± 2.4 Controls patients Gisondi P, et al. Int J Immunopathol Pharmacol.21;23(4): ; Strober B. et al. Br J Dermatol 28;159(2):322 3; Isha J. et al. Indian J Clin Biochem. 211;26(3):39 11; Sergeant A. et al. Br J Dermatol 28;158(2):417 9; Ohtsuka T. et al. Br J Dermatol 28;158(5): Patients with psoriasis and NAFLD have higher IL-6 and lower adiponectin serum levels Serum IL-6 and adiponectin were measured in 21 patients with NAFLD and 22 patients without NAFLD, respectively IL-6 (ng/ml) with NAFLD Gisondi P, et al. J Hepatol. 29;51: p=.2 without NAFLD Adiponectin (µg/ml) with NAFLD p=.3 without NAFLD Adipokines and CRP are increased in psoriasis patients (n=4) than in age-, sex- and BMImatched controls Chemerin (ng/ml) p<.1 p<.1 4 Controls Resistin (ng/ml) Controls p<.3 NS 1 CRP (ng/ml) Visfatin (ng/ml) Controls Controls Gisondi P et al. Br J Dermatol. 212; [Epub ahead of print] 56

6 Systemic and Vascular Inflammation in Patients With Moderate to Severe as Measured by [18F]-FluorodeoxyglucosePositron Emission Tomography Computed Tomography (FDG-PET/CT) 169 FDG-PET/CT identified numerous foci of inflammation in 6 patients with psoriasis within the skin, liver, joints, tendons, and aorta. These findings persisted after adjustment for traditional cardiovascular risk factors in multivariate Mehta NN et al. Arch Dermatol211;147: Inflammatory mediators released from psoriatic lesions may have systemic effects Homocysteine CRP fibrinogen From Paolo Gisondi, Verona (Italy) Liver Endothelial dysfunction TNF-α, INF-α, INF-γ, IL-1, IL-6, IL-17 Adipose tissue Chemerin leptin resistin adiponectin TG LDL HDL Skeletal muscle Insulin resistance glucose Atherosclerosis Pulse Wave Velocity (carotid femoral) was significantly higher in patients with psoriasis than in controls Difference was still significant after adjustment for age, gender, smoking status, hypertension and body mass index 57

7 172 The psoriatic march Cardiovascular diseases Metabolic syndrome Diabetes Genes Environmental triggers Obesity NAFLD Hypertension Dyslipidaemia Smoking Psoriatic arthritis GisondiP, et al. SeminThrombHaemost29;35(3): Gisondi P, et al. Actas Dermosifiliogr 29;1(Suppl. 2):14 21 Framingham risk estimation of developing hard CHD (myocardial infarction and cardiac death) and stroke in patients with psoriasis and controls patients Controls P value Number (male/female) 234 (134/1) 144 (78/66).5 Age, mean ±SD 54.9 ± ± Smokers, n (%) 98 (41) 32 (22).6 BMI, mean ± SD 26.4 ± ± Hypertension, n (%) 18 (46) 22 (15). Systolic blood pressure, mean ± SD 131 ± ± 13.6 Diabetes, n (%) 42 (17) 9 (6).1 Total cholesterol 26 ± ± 35. HDL cholesterol 55 ± 1 61 ± 13. Framingham 5-year estimate, mean ± SD 5.3 ± ± 3.1 Framingham 1-year estimate, mean ± SD 11.2 ± ± 6.1 PASI, mean ± SD (range 1.2 4) 9.9 ± 7.9 BSA, mean ±SD (range 1) 23.2 ±31.3 duration, mean ± SD 17.6 ± 13.6 Framingham risk factors; BMI, body mass index; BSA, body surface area; CHD, coronary heart disease. Gisondi P, et al. Am J Cardiol 21;16: Framingham estimate of risk for hard coronary heart disease and stroke: increased in psoriasis patients 5 years Framingham 5-y estimate Year Risk Framingham 1-y estimate Year Risk Age range Age range Control P <.1 Gisondi P, et al. Am J Cardiol. 21;16:

8 175 is associated with increased cardiovascular mortality Increased risk for cardiovascular mortality in patients hospitalized for psoriasis Risk higher in young patients 1 Severe psoriasis is associated with increased risk of death Patients die years younger than patients without psoriasis 2 Severe psoriasis is associated with an increased risk of cardiovascular death (HR 1.57; 95%CI ) and is independent of traditional CV risk factors 3,4 Severe psoriasis (and PsA) is associated with an increased risk of cardiovascular mortality (RR 1.58; 95%CI ) and is independent of traditional CV risk factors 5 1. Mallbris L, et al. Eur J Epidemiol 24;19:225 3; 2. Gelfand J, et al. Arch Dermatol 27;143:1493 9; 3. Abuabara K, et al. Br J Dermatol 21;163:586 92; 4. Mehta NN, et al. Eur Heart J 21;31:1 6; 5. Ahlehoff O, et al. J Intern Med 211 Why psoriasis is associated to metabolic comorbidities? Wedo not know Common genetic background Enviromental factors By chance Why psoriasis is associated to metabolic comorbidities? Systemic effects of chronic inflammation 1 Insulin resistance 2 Unhealthy lifestyle 3 Common genetic background 4 1. Roifman I, et al. Can J Cardiol 211;27: Ucak S, et al. J Eur Acad Dermatol Venereol26; 2(5): EmreS, et al. J Eur Acad Dermatol Venereol212(Epubahead of print) 4. Suarez-Farinas M, et al. J Invest Dermatol 212;132:

9 178 Mounting evidence Changing clinical practice Screen and Manage comorbidities Boehncke WH Nature 212;492:S55 and obesity: a two-compartment model of inflammation DavidoviciBB, et al. J Invest Dermatol 21;13: therapy in obese patients GG High BMI is associated with a reduced short-term clinical response to all systemic treatments 1. Obesity is associated with reduced long-term retention of all systemic treatments for psoriasis 2. Biologicalswith a fixed-dose regimen (etanercept, adalimumab, alefacept, ustekinumab) may have compromised efficacy in heavier individuals 3,4. Obesity increases the risk of liver and renal toxicity to methotrexate(mtx) and cyclosporine (CsA), respectively 5,6. Weight loss improves the response of obese patients with psoriasis to low-dose CsAtherapy NaldiL, et al. Dermatology28;217: GisondiP, et al. Clinical Derm213 (In press) 3. Clark L, et al. J Am Acad Dermatol 28;58: PuigL. J Eur Acad Dermatol Venereol211;25: RosembergP, et al. J Hepatol27;46: ThaçiD, et al. Dermatology22;25: GisondiP, et al. Am J ClinNutr28; 88:

10 181 Do systemic treatments for psoriasis affect metabolic parameters? Gisondi P, et al. J Eur Acad Dermatol Venereol. 212 Feb 7. [Epub ahead of print] 182 New diagnoses of hypertension, diabetes and dyslipidemia initiation of systemic treatment for psoriasis 183 The relative risk of developing hypertension(or 3.31) and diabetes(or 2.88) at week 52 was higher for patients receiving cyclosporine(n=184) Acitretinwas associated with the risk of developing hypercholesterolaemia(or 1.51) and hypertriglyceridemia(or 1.43) Methotrexateand infliximabwere associated with the risk of developing an increase 2 times of AST(OR 2.6 and 1.87) and ALT(OR 2.38 and 1.74) Gisondi P, et al. J Eur Acad Dermatol Venereol. 212 Feb 7. [Epub ahead of print] 61

11 Anti-TNF-alpha drugs increase body weight in patients with psoriasis 184 A relevant increase (4 1 kg) in body weight was observed in about 25% of patients treated with etanercept or infliximab. Gisondi P, et al. J Eur Acad Dermatol Venereol. 28;22(3): patients? 185 Body mass index and Response rate for 75% improvement in psoriasis area and severity index at months 1 and 7. Blacksquares represent infliximab and open squares Gisondi P, et al. Br J Dermatol. 213 Jan 16 ustekinumab. 186 Is weight reduction helpful in the management of psoriasis in obese 62

12 187 Weight loss and treatment response (I) Weightloss improves the response of obese patients with moderate-to-severe chronic plaque psoriasis to low-dose CsA therapy A randomised, controlled, investigator-blinded, clinical trial investigated: CsA2.5 mg/kg/day plus low-calorie diet CsA 2.5 mg/kg/day alone Diet regimen Carbohydrates 6% Lipids 25% Proteins 15% Moderate physical activity ( 4 min x4/w) Monthly controls BMI (kg/m 2 ) Females (kcal/day) Males (kcal/day) GisondiP, et al. Am J ClinNutr28;88: Weight loss and treatment response (II) Body weight (kg; mean ± SD) Study to investigate whether moderate weight loss increases the therapeutic response to low (suboptimal)-dose CsA in obese patients with moderate-to-severe chronic plaque psoriasis Months Mean (±SD) reductions in body weight Intervention group: 7. ±3.5 kg Control group:.2 ±.9 kg GisondiP, et al. Am J ClinNutr28;88: p<.1 (Cochran-Mantel-Haenszelanalysis) PASI (mean ±SD) Months CsA2.5 mg/kg/day + calorie-controlled diet CsA2.5 mg/kg/day p<.1 (Cochran-Mantel-Haenszelanalysis) 188 Are there any adverse effects of systemic drugs on the components of metabolic syndrome? 189 MTX CSA Retinoids Anti-TNF-α Ustekinumab Dyslipidemia + + Hypertension + Abdominal obesity Diabetes/reduced glucose tolerance + Liver steatosis + Decreased renal function - + No adverse effects Occasionally significant adverse effects Adverseeffects From Paolo Gisondi, Verona (Italy) 63

13 19 Summary -associated immune responses and inflammation, when protracted and severe enough, may have systemic consequences Therapy of psoriasis is influenced by and may affect other organ systems and co-morbid diseases Patients with severe psoriasis are candidate for early cardiovascular risk factor modification including diet and physical exercise UNIVERSITÁ DEGLI STUDI DI VERONA Dipartimento di Medicina Sezione di Dermatologia e Venereologia Expert considerations in selecting therapies for patients with moderate to severe psoriasis Giampiero Girolomoni University of Verona REGIONE DEL VENETO A.O.U.I. Verona U.O. du Clinica Dermatologica IPC psoriasis preceptorship Verona, 13 June 213 Treatment of Moderate-to-Severe is a life-long disease requiring long-term treatment Patients with moderate-to-severe disease may require phototherapy or systemic therapy + Topical Therapy MTX ADA CSA ETN RET FAE INF PHOTO UST Moderate-to-Severe Plaque Conventional Systemic Therapy Biologic Systemic Therapy Despite a multitude of treatment options, many patients do not receive optimal treatment Adapted from Nast A, et al. J Dtsch Dermatol Ges. 212;1(suppl 2):S1 S95. ADA: adalimumab; CSA: cyclosporine; ETN: etanercept; FAE: fumaric acid ester; INF: infliximab; MTX: methotrexate; PHOTO: phototherapy; RET: retinoids; UST: ustekinumab. 64