Management of Moderate-to-Severe Psoriasis in Patients With Metabolic Comorbidities

Introduction

Psoriasis (plaque psoriasis) is an immune-mediated, chronic inflammatory skin disease. It affects approximately 2–3% of the world's population. Psoriasis can develop at any age, although most cases begin before the age of 40. This condition is uncommon in children. Psoriasis is a complex disease influenced by genetic factors (1). It is estimated that approximately 20 chromosomal regions may harbor genes associated with susceptibility to psoriasis, mainly affecting the innate and adaptive immune responses. The major risk locus is located within the major histocompatibility complex (MHC) class I antigen cluster region, which includes the human leukocyte antigen Cw6 gene associated with early-onset psoriasis (2). Current understanding of the molecular pathogenesis of psoriasis focuses on the interaction between adaptive and innate immunity (3).

Chronic plaque psoriasis is the most common form of the disease (4). The skin may be covered with scales, plaques, or patches in only a few areas, most commonly on the extensor surfaces of the elbows, knees, legs, and arms, or the lesions may spread over the entire body surface. Moderate to severe psoriasis is diagnosed when >10% of the body's skin surface is affected. Psoriasis significantly impairs the quality of life of those affected (5).

Chronic Psoriasis and Associated Metabolic Disorders

Several epidemiological studies have confirmed a strong association between moderate to severe psoriasis and cardiovascular and metabolic diseases, including hypertension, obesity, type 2 diabetes (T2D), elevated blood cholesterol levels (dyslipidemia), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome (MS), and chronic kidney disease (CKD) (6).

Patients with psoriasis are often overweight or obese, and disease severity correlates with body mass index (BMI) (7, 8). An association between obesity and psoriasis in the pediatric population has recently been confirmed (9). Obesity develops before the onset of psoriasis. Several measures of obesity—BMI, waist and hip circumference, and their ratio—are considered independent risk factors that are significant in the development of psoriasis and psoriatic arthritis (PA) (10).

The association between psoriasis and obesity is explained by the complex properties of adipose tissue. Adipose tissue is not only a site of fat storage but also an active endocrine organ with numerous secretory products, such as free fatty acids, adipose-derived hormones, and anti-inflammatory adipokines (chemerin, resistin, visfatin, interleukin-6, and tumor necrosis factor α [TNF-α]) (11). A recent meta-analysis showed that psoriasis is a risk factor for T2D (12, 13).

Visceral obesity and T2D are key components of MS. MS is a collection of metabolic disorders, also known as insulin resistance syndrome, that increases the risk of inflammation and thrombosis. The diagnosis of MS is confirmed by the presence of 3 or more of the following: abdominal obesity (waist circumference >102 cm in men and >88 cm in women), elevated serum triglycerides (>1.7 mmol/l) or treatment to reduce them, low HDL cholesterol concentration (men <1.04 mmol/l, women <1.3 mmol/l) or treatment to increase it, high blood pressure (>130/85 mm Hg or treatment for hypertension), and hyperglycemia (>5.55 mmol/l or treatment for it) (14).

A cross-sectional study found that patients with psoriasis were more likely to have MS than those with other inflammatory skin diseases (30.1% compared with 20.6%; risk ratio [RR] 1.65, 95% CI 1.16–2.35) (14). The association between psoriasis and MS was recently confirmed in a meta-analysis, which showed a combined RR of 2.26 (95% CI 1.70–3.01) (15).

NAFLD encompasses a spectrum of progressive liver diseases, including simple steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. NAFLD is considered a hepatic manifestation of MS, as these conditions share insulin resistance as a common pathophysiological mechanism (16). The prevalence of NAFLD among patients with chronic plaque psoriasis is significantly higher than in the control group (47% and 28%, respectively; p<0.0001) (17). A study conducted in the Netherlands found that NAFLD was diagnosed in 46.2% of patients with psoriasis compared with 33.3% of patients in the control group without psoriasis (p=0.005) (18). Psoriasis has been found to be associated with NAFLD regardless of alcohol consumption, smoking, MS, and serum alanine aminotransferase concentration (adjusted OR 1.7, 95% CI 1.1–2.6) (18).

NAFLD is a risk factor for the development of cardiovascular diseases (CVD) (19). There is no consensus on whether psoriasis is associated with an increased risk of CVD. Patients with psoriasis have more cardiovascular risk factors, such as smoking, a sedentary lifestyle, and dyslipidemia, which make them more likely to develop and die from CVD, particularly younger patients with more severe skin disease (20, 21). Several studies have shown that patients with severe psoriasis are more likely to experience acute myocardial infarction and stroke and to die from CVD (22). In fact, it is not yet clear whether the increased risk of CVD in patients with psoriasis is directly attributable to psoriasis or to a combination of interacting risk factors (23).

An association between psoriasis and NAFLD has recently been identified (24). A retrospective cohort study found that, regardless of traditional risk factors, moderate to severe psoriasis is associated with NAFLD: 5% of patients with psoriasis had NAFLD compared with 2% of patients in the control group. Such an association was not found in patients with mild (

The relationship between psoriasis and comorbidities can be explained by genetics, the body's response to chronic inflammation, insulin resistance, and unhealthy lifestyle habits, including alcohol and smoking abuse, overeating, and a sedentary lifestyle, which are common among patients with psoriasis. A meta-analysis of 4 different studies showed that polymorphisms in 10 metabolic genes, including those related to CARD14, are closely correlated with both psoriasis and MS (CVD, dyslipidemia, hypertension) (25).

The inflammatory states associated with psoriasis and obesity can interact. Indeed, cytokines released from psoriatic keratinocytes or inflammatory cells infiltrating psoriatic skin can lead to insulin resistance, thereby creating conditions for the development of type 2 CVD (11). It is also likely that comorbid metabolic diseases can directly contribute to the exacerbation of psoriatic inflammation by releasing several pro-inflammatory mediators from the liver or visceral adipose tissue, such as reactive oxygen species, C-reactive protein (CRP), IL-6, and other adipokines (26).

Treatment of Patients With Moderate to Severe Psoriasis and Comorbid Metabolic Diseases

The relationship between psoriasis and cardiometabolic disorders has important clinical significance. First, systemic treatment of psoriasis can negatively affect comorbid metabolic diseases, especially when medications are used for prolonged periods (Table 1).

Table 1. Systemic Treatment of Psoriasis May Negatively Affect Components of Metabolic Syndrome

If a patient is obese, has IBD, IBS, or consumes alcohol, methotrexate should be prescribed with extreme caution because of the increased risk of liver fibrosis (27). Transient elastography and FibroTest are effective non-invasive methods for monitoring the liver in patients with psoriasis treated with methotrexate (28). It is important to remember that in elderly patients, renal elimination of methotrexate may decrease due to impaired renal function, increasing the risk of toxicity (29).

Cyclosporine may induce arterial hypertension or worsen its course, increase insulin resistance, and impair fatty acid metabolism, thereby promoting dyslipidemia and hyperuricemia (30). The interaction between cyclosporine and statins used to treat dyslipidemia may lead to rhabdomyolysis (31). Therefore, cyclosporine should be used cautiously in patients with psoriasis and metabolic syndrome, and if renal function is impaired, cyclosporine should not be used. Acitretin can also promote the development of hypertriglyceridemia and/or hypercholesterolemia, although severe cases are rare (30).

Photochemotherapy (PUVA) and narrowband UVB therapy do not significantly affect metabolic parameters (32), but they are not suitable for many patients.

Biological therapies do not negatively affect metabolic parameters compared with conventional treatments. However, clinically significant dyslipidemia may occasionally occur in patients treated with TNF-α inhibitors, although this is rare in clinical practice (33). Weight gain is possible during treatment with TNF-α inhibitors (34, 35). This is due to an increase in fat mass in patients with psoriasis (34). In contrast, ustekinumab does not increase body weight in patients with chronic psoriasis (36).

The impact of anti-TNF-α therapy on insulin resistance remains debated (37, 38). The effects of this treatment on glycemic indices and insulin resistance in patients with psoriasis have been investigated in small studies using HOMA and QUICKI tests. A randomized, double-blind study involving 12 patients with psoriasis and a high risk of developing type 2 diabetes showed no significant effect of etanercept on insulin secretion or sensitivity after 2 weeks of treatment (39). A 24-week study involving 9 patients with stable active psoriasis treated with etanercept showed a significant decrease in blood insulin concentration and insulin resistance (40). In another study, 18 patients with psoriasis were treated with adalimumab for 12 weeks, but no significant changes in insulin sensitivity or blood glucose levels were observed (41). Solomon and colleagues noted that patients with rheumatoid arthritis or psoriasis treated with TNF-α inhibitors were less likely to develop diabetes than those treated with other drugs (42).

Biological agents targeting the IL-12/23 pathway are particularly effective in treating psoriasis, but their safety regarding the risk of IBD remains a subject of debate. In fact, the clinical trial program for briakinumab was halted at an early stage because of an increased frequency of IBD events compared with the control group (43). Similar concerns arose regarding the safety of ustekinumab, but data from an international registry collected after the drug had entered the market did not show any risk (44). To date, the FDA has not changed the information regarding the possible association between ustekinumab and IBD risk.

It is also important to consider that commonly used drugs for the treatment of arterial hypertension (beta-blockers and ACE inhibitors) may worsen the course of psoriasis in some patients (45). Patients with moderate to severe psoriasis should follow a low-calorie diet, exercise regularly, and quit smoking to reduce the risk of IBD. A low-calorie diet results in moderate weight loss (approximately 5–10%) and improves the effectiveness of systemic treatment in obese patients (46–48). Smoking is associated with the development and exacerbation of psoriasis; quitting smoking improves the course of the disease (49). It is speculated that patients with psoriasis are less physically active for psychological and physiological reasons (50). Regular physical activity can reduce the risk of developing psoriasis and have a positive effect on the natural course and severity of the disease, as well as on potential metabolic disorders (51). When conducting studies, it is important to understand that treatment should be tailored to the individual needs of the patient, taking comorbidities into account.

Prepared by Aurelija Dautartienė

Source: Internistas