Can we better strategize our choice of pharmacotherapy for patients with co-morbid psoriasis and obesity?

KEYWORDS:

• Biologics
• comorbidity
• dyslipidemia
• metabolic syndrome
• obesity
• psoriasis
• therapy

1. Introduction

Psoriasis, which affects approximately 2–4% of the population worldwide, represents a chronic, complex, systemic, immune-mediated inflammatory dermatopathy with expanded Th-1, Th-17 and Th-22 cell populations, characterized by skin or joint manifestations or both [1]. Equally prevalent in both genders, psoriasis is considered a multifarious disease where two thirds of patients present mild forms that can be treated with topical therapies. However, psoriasis presents many challenges comprising significant prevalence, disfiguration, chronicity, complexity, disability, psychological burden and associated comorbidities [2]. Besides psoriatic arthritis (PsA), these comorbidities include among others obesity, cardiovascular disease (CVD), diabetes mellitus (DM) type 2, metabolic syndrome (Mets), hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD) and obstructive sleep apnea [3]. Interestingly, psoriasis is usually treated with drugs that could interfere with comorbidities via their side effects [2–5].

2. The bidirectional relationship between psoriasis and obesity

There is strong evidence supporting an important relationship between psoriasis and obesity, considered a chronic, low-grade subclinical inflammatory state. Indeed, the association between the two conditions is potentially bidirectional, with psoriasis favoring obesity, and obesity predisposing to moderate-to-severe psoriasis [2–7]. The same Janus-faced association is observed also between PsA and obesity as well as between childhood psoriasis and obesity. A meta-analysis of 16 observational epidemiologic studies including 2.1 million individuals has shown that psoriatic patients present elevated incidence and prevalence of obesity, with an important correlation between psoriasis severity and obesity (pooled Odds Ratio of 1.46 for mild psoriasis versus 2.23 for severe psoriasis) [5]. From the opposite side, prospective studies have shown that obesity represents an independent risk factor for psoriasis onset risk, with a positive graded association between Body Mass Index (BMI) and psoriasis [1,6]. Additionally, measures of central obesity such as higher waist circumference and waist-hip ratio as well as weight gain from early adulthood were all associated with increased psoriasis risk [6]. Interestingly, obesity-associated conditions such as Mets and DM present the same bidirectional relationship with psoriasis as evidenced by meta-analyses and few prospective studies [1–5]. It is important to emphasize that BMI as a diagnostic criterion of obesity is inaccurate to distinguish body components such as fat mass and fat-free mass, and therefore assess obesity in fat subjects in the normal-range of BMI [8]. Psoriasis has also been associated with a high fat mass as assessed by bioelectrical impedance analysis (BIA) [8]. Therefore, screening for body fat distribution in patients with psoriasis may be useful to detect early obesity-related disease [8].

3. The crucial role of adipose tissue, adipocytokines and inflammatory molecules

Both obesity/Mets and psoriasis, considered chronic inflammatory states, share an underlying pathophysiology with common genetic predisposition and risk factors including high caloric intake, physical inactivity and psychological stress [2]. Whatever is the etiologic sequence of these states, once obesity and psoriasis are developed, they enhance each other in a vicious cycle. Adipose tissue is considered a genuine endocrine organ secreting a variety of adipocytokines and cytokines, participating in several physiologic and pathologic processes, including metabolism, insulin sensitivity, immunity and inflammation. Excessive adiposity, particularly visceral fat, and its activated macrophages are associated with low-grade, chronic inflammation leading to overproduction of pro-inflammatory cytokines and adipocytokines [1,9,10], and the reduction of beneficial adipocytokines such as adiponectin and omentin [2,11]. Adipocytokines may represent a missing link in the association between psoriasis and obesity. A recent meta-analysis and many cross-sectional studies have shown that, generally, psoriatic and obese patients present higher serum concentrations of leptin, resistin, visfatin and chemerin, and lower levels of adiponectin [2,11].

Moreover, elevated fat mass despite a normal BMI could also perpetuate a chronic inflammatory state [8]. However, an increase in subcutaneous adiposity, in contrast to an increase in visceral fat, may prevent Mets and systemic inflammation [12]. Indeed, subcutaneous adipocytes treated with UVB-irradiated keratinocytes and fibroblasts may induce chemokines or cytokines impairing fat homeostasis, exerting the secretion of pro-inflammatory adipokines and exacerbating associated comorbidities such as obesity [12,13]. Further studies are needed to clarify the role of subcutaneous adipose tissue in psoriatic inflammation.

4. Strategy of pharmacotherapy in patients with co-morbid psoriasis and obesity

Weight loss is the cornerstone of the therapeutic approach in obese psoriatic patients with or without PsA in order to: 1) achieve psoriasis and PsA remission; 2) decrease psoriasis severity; 3) enhance pharmacological response to conventional and biologic treatment; 4) minimize the risk of side treatment effects with conventional systemic drugs; 5) lower the cardiometabolic risk profile of patients and the obesity-related inflammation and insulin resistance; and 6) reduce the treatment cost when weight-adjusted doses of prescription treatment are applied [3,14–17].

Education on healthy diet, weight loss and physical activity is pivotal in the holistic strategic therapeutic management of co-morbid psoriasis and obesity affecting psoriasis prognosis (Figure 1). Indeed, low-caloric diet leading to weight loss was associated with increased efficacy of biologics amid obese psoriatic and PsA patients on etanercept, adalimumab, infliximab or ustekinumab [1,5,14]. Overall, weight loss interventions such as low-calorie diet and/or physical exercise were associated with higher improvements in Psoriasis Area and Severity Index (PASI) scores though the clinical significance was modest [1,18]. Furthermore, bariatric surgery for morbidly obese psoriatic patients was associated with significant improvements of psoriasis severity due to postoperative weight loss [1,19]. Also, the type of diet may modulate the systemic inflammatory response of both conditions. Adherence to a healthy diet such as the traditional Mediterranean with beneficial anti-oxidant and anti-inflammatory compounds may reduce long-term inflammation, psoriasis severity and C-Reactive Protein (CRP) levels [15].

Figure 1. Flowchart of practical issues in the holistic strategic management of comorbid obesity (BMI>30 kg/m²) and psoriasis.

The management of co-morbid psoriasis and obesity should include screening for the most important obesity-associated metabolic disorders, and involve structured collaboration with other relevant specialties (e.g. endocrinology, rheumatology, cardiology, hepatology) if a co-morbid disease is identified. Screening for metabolic comorbidities and PsA is important for the therapeutic choice, management and follow-up of patients (Table 1). Interestingly, some anti-diabetic drugs and simvastatin for co-morbid states may decrease psoriasis severity [1,20].

Table 1. Screening recommendations and therapeutic issues for co-morbid obesity/associated metabolic disorders and psoriasis.

Somatometric Indicators for Obesity
Indicators	Classifications	Remarks
WC (cm)	M: >102 W: >88	These cut-offs represent increased CVD risk WC is associated better with abdominal fat than BMI Great ethnic and inter-ethnic variability
WHR	M: >0.90 W: >0.85	WHR is associated more strongly with abdominal fat than BMI; WHR better reflects weight changes in men WC and WHR are surrogates of visceral obesity but they may not distinguish VAT and SAT at the waist level Both WC and WHR are strongly associated with atherosclerosis risk
Fat distribution	Abdominal adiposity as SAT and VAT	CT and MRI are the standard methods for quantification of VAT, which is closely related to CVD risk. Bioelectrical impedance analysis is a non-invasive, simple and quick method to measure body composition, mainly body fat.
Neck circumference (cm)	M: ≥ 37^‡ W: ≥ 34	Simple and time-saving screening measure for overweight/obesity NC may indicate cardiometabolic risk NC may be useful for sleep-apnea which is associated with obesity and psoriasis
Laboratory biomarkers and other tests for obesity/associated disorders
Other Associated Comorbidities	Markers and referral criteria of patients with no previous diagnosis	Remarks
Dyslipidemia	Fasting blood lipids: – Triglycerides ≥250 mg/dL, – Total Cholesterol ≥200 mg/dL, – LDL-C: 1) ≥160 mg/dL if there is low CVD risk, 2) ≥100 mg/dL if DM, kidney disease and multiple CVD risk) and 3) ≥70 mg/dL if cerebrovascular disease, ischemic heart disease or peripheral arteriopathy.	Retinoids and cyclosporine may worsen dyslipidemia associated with obesity and Mets
Metabolic syndrome	– Fasting plasma glucose – Fasting blood lipids (TG and HDL-C)	Diagnostic criteria for Mets (European people) if three or more of the following: WC: M: >94; W: >80 TG ≥150 mg/dL or treatment HDL-C: M: <40 mg/dL and W: <50 mg/dL or treatment BP ≥130/85 mmHg or treatment for HT Fasting plasma glucose >100 mg/dL Cyclosporine may aggravate Mets associated with obesity
Diabetes Mellitus	– Fasting plasma glucose – HbA1c – 2h OGTT	Based on the ADA criteria, DM and prediabetes are suspected if any of the following is present: Fasting plasma glucose ≥126 mg/dL for DM and ≥100 mg/dL for prediabetes HbA1c ≥ 6.5% for DM and between 5.7% and 6.5% for prediabetes Symptoms of hyperglycemia such as polydipsia, polyphagia, polyouria or weight loss AND one random plasma glucose measure independently of intake: ≥200 mg/dL for DM 2-hour glucose tolerance test after ingesting the standardized 75 Gm glucose solution, plasma glucose level of 140 to 199 mg/dL for prediabetes, plasma glucose ≥ 200 mg/dL for DM
NAFLD	– Liver enzymes: AST, ALT, γ-GT If moderate-to-severe psoriasis and Mets risk factors: – Abdominal US for detection of liver steatosis – Follow-up every 3–5 years with abdominal US and liver enzymes if liver steatosis is absent in US and liver enzymes are within reference range	– Methotrexate may increase serum liver enzymes and aggravate liver steatosis associated with obesity and Mets – Oral folic acid supplements may reduce liver enzyme levels in patients on low-dose and long-term methotrexate treatment
Hypertension	Two consecutive BP measurements: Systolic BP ≥140 mmHg and/or Diastolic BP≥ 90 mmHg	Cyclosporine may worsen hypertension associated with obesity and Mets
CVD risk	– Screening for Mets components – Smoking, family history of CVD
Kidney Disease	– Serum creatinine and urea – GFR – Albuminuria in a urine test – Urine albumin-to-creatinine ratio(mg/g)	Cyclosporine may increase nephrotoxicity risk in obesity
OSAH	– Epworth Sleepiness Scale questionnaire	– Confirmation with nocturnal polysomnography – CPAP treatment
Psoriatic Arthritis	– Screening questionnaires (e.g, DAPSA, PASE, PEST, ToPAS) – Tender or swollen joints – Inflammatory back pain – Enthesitis (especially in plantar fascia or Achilles tendon) – Dactylitis – Elevated markers of inflammation such as ESR and CRP attributable to PsA	Referral to rheumatologist or combined dermatologic/rheumatologic clinic

‡ not officially defined

ADA: American Diabetes Association; ALT: Alanine transaminase; AST: Aspartate transaminase; BMI, body mass index; BP: Blood pressure; CPAP: Continuous Positive Airway Pressure; CRP: C-Reactive Protein; CT: Computed Tomography; CVD: Cardiovascular Disease; DAPSA: Disease Activity in Psoriatic Arthritis; DM: Diabetes Mellitus; ESR: Erythrocyte Sedimentation Rate; GFR: Glomerular Filtration Rate; γ-GT: γ-glutamyltransferase; HbA1c: glycated hemoglobin; HC, hip circumference; HDL-C: High-density lipoprotein Cholesterol; HT: hypertension; LDL-C: Low-density Lipoprotein cholesterol; M, men; Mets: Metabolic syndrome; MRI: Magnetic Resonance Imaging; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OGTT: Oral Glucose Tolerance Test; OSAH: Obstructive Sleep Apnea-Hypopnea; PASE: Psoriatic Arthritis Screening and Evaluation; PEST: Psoriasis Epidemiology Screening Tool; PsA: Psoriatic Arthritis; SAT, subcutaneous adipose tissue; ToPAS: Toronto Psoriatic Arthritis Screening questionnaire; TG: Triglycerides; US: Ultrasound; VAT, visceral adipose tissue; W, women; WC, waist circumference; WHR, waist/hip ratio.

Systemic conventional drugs such as methotrexate, cysclosporine and acitretin do not affect body weight. Nevertheless, dermatologists should be aware about methotrexate long term courses in patients with co-morbid obesity and associated Mets, DM type 2, NAFLD and excessive alcohol intake due to the elevated risk of liver fibrosis. A cautious monitoring of liver toxicity (liver enzymes, abdominal ultrasound, liver elastography, liver biopsy when reaching a cumulative dose of 1.5 g) in patients with co-morbid obesity is mandatory. Acitretin may worsen dyslipidemia causing hypercholesterolemia and/or hypertriglyceridemia in co-morbid obesity [20]. Cyclosporine may aggravate arterial hypertension, dyslipidemia, Mets and DM, and increase nephrotoxicity risk in co-morbid obesity [1,3,20].

Over the last decade, the therapy of moderate-to-severe psoriasis has been revolutionized, especially for patients with refractory disease. Approved biologic treatment for psoriasis can be classified in: Tumor Necrosis Factor (TNF)-α inhibitors (etanercept, infliximab, adalimumab); IL-12/23 inhibitors (ustekinumab); IL-17 inhibitors (ixekizumab, secukinumab, brodalumab); and IL-23 inhibitors (guselkumab) [21]. However, the presence of co-morbid obesity modifies the clinical and therapeutic approach of psoriasis as obesity is generally considered a negative predictor of efficacy for both systemic conventional and biologic drugs, particularly for the fixed-dosed drugs, due to altered pharmacokinetics and clearance of drugs [14]. Additionally, obesity has been linked to a higher withdrawal rate on long term therapeutic period of biologics. Dosing regimens of biologics do not account for weight with the exception of infliximab and ustekinumab, where the dose of the latter is doubled in patients weighing more than 100 kg. Based on recent literature, off-label dose escalation with adalimunab, etanercept and ustekinumab led to increased efficacy than standard approved dosing regimens amid non-responders [22]. Dermatologists should be aware that TNF-α inhibitors may be associated with a small increase in body weight of approximately 1.5 kg due mainly to appetite increase [23]. However, anti-TNF-α treatment may improve insulin sensitivity causing hypoglycemia particularly in patients receiving insulin [20,23].

Recent network meta-analyses have shown that newer biologics targeting the IL-12/23 (ustekinumab) and IL-17 axes appear more effective in skin clearing comparing to oral agents and other biologics [21]. These biologics, including also the IL-23 inhibitor guselkumab, were not reported to affect body weight, glucose and lipid metabolism [24]. Ustekinumab may also present beneficial effects on cellular integrity as assessed by BIA [25]. Interestingly, recent data has shown that ixekizumab was efficacious in the treatment of moderate-to-severe psoriasis despite patient’s body weight. However, more studies are needed to support this observation. The therapeutic response rate of secukinumab was higher in patients weighting less than 90 kg than those weighting above 90 kg [24]. Data regarding brodalumab across different body weight categories are not available yet; however, non-obese patients presented higher rates of PASI 90 and PASI 75 (a 90% and 75% reduction in PASI scores from baseline respectively) than obese patients [24]. Body weight may interfere with guselkumab pharmacokinetics.

Finally, apremilast, an oral, small-molecule phosphodiesterase (PDE) 4 inhibitor, has been shown to slightly decrease body weight, particularly in individuals with higher glycated hemoglobin (HbA1c) levels. As a PDE 4 inhibitor, apremilast may promote: 1) lipolysis of white adipose tissue; 2) energy expenditure; 3) insulin sensitivity; 4) metformin activity; and 5) attenuation of fat accumulation in the liver [26].

5. Expert opinion

Current evidence supports a bidirectional relationship between psoriasis and obesity which share an underlying chronic inflammatory state. The present goal in psoriasis therapeutics aiming at reducing skin manifestations and symptoms must shift to a holistic management approach comprising screening and integration of co-morbid disorders, particularly obesity. Collectively, all the evidence highlights the strategic importance of weight loss in obese psoriatic patients, which is essential on both psoriasis severity and therapeutic response. Indeed, obesity is generally considered a negative predictor of efficacy for both systemic conventional and biologic drugs, particularly for the fixed-dosed drugs. Moreover, methotrexate, acitretin and cyclosporine may aggravate hypertension, liver steatosis and dyslipidemia associated with obesity. Because infliximab and ustekinumab are the only weight-dosed drugs, they may be ideal in the treatment of obese psoriatic patients. Despite the paucity of weight data, IL-17 and IL-23 inhibitors are very efficacious anti-psoriatic drugs showing, however, better results in nonobese patients. Apremilast may present potential favorable effects in psoriatic patients with co-morbid obesity because weight loss is one of its noted adverse effects.

Obese psoriatic patients have frequently associated metabolic comorbidities (i.e. DM type 2, Mets, hyperlipidemia) that must be treated with other drugs (polypharmacy), which can complicate treatment [20,27] or present favorable effects on psoriasis severity [27,28]. Indeed, several hypoglycemic agents used in the treatment of DM type 2, including metformin, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors and thiazolidinediones, display simultaneous favorable glycemic and anti-psoriatic effects through targeting skin inflammation networks and keratinocyte proliferation [28]. Moreover, statins, particularly simvastatin and atorvastatin, which are commonly used to lower serum cholesterol and CVD risk, may decrease psoriasis severity due to their effects on lipid metabolism as well as their immunomodulatory and anti-inflammatory actions [20,27]. However, atorvastatin and pravastatin were reported to worsen psoriasis [27].

More mechanistic, translational and epidemiologic studies, and well-conducted randomized controlled trials will be pivotal to provide evidenced-based specific recommendations for psoriasis and co-morbid obesity management and screening. Additional studies will be necessary to answer the critical question of whether targeting obesity and associated insulin resistance may be an effective approach to treat psoriatic symptoms and decrease the CVD risk of patients. Omics-driven drug repurposing strategies may be used to spot effectively the potential of drugs in treating psoriasis with co-morbid obesity providing guidance for precision medicine. Novel therapeutic strategies adjusting levels of pro- and anti-inflammatory adipokines and cytokines in obese psoriatic patients may exert beneficial actions in the prevention and treatment of obesity-related metabolic disorders. Other challenges and opportunities comprise the deciphering of mechanistic links between psoriasis and obesity, the prevention of psoriasis, adipocytokine-oriented and personalized treatment approaches as well as unmet clinical needs of current treatments.

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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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