A nationwide prospective cohort study in Korea found that metabolically unhealthy non-obese subjects and metabolically unhealthy obese subjects had a higher risk of psoriasis compared to metabolically healthy non-obese subjects (35).

A meta-analysis including seven prospective studies concluded that adiposity as measured by BMI, WC, waist-to-hip ratio, and weight gain was associated with increased risk of psoriasis (29). WC measuring central adiposity is a specific factor affecting psoriatic risk (36), after adjustment for confounders and BMI (37). Two Mendelian randomization analyses using genetic variants as instrumental variables confirmed that higher BMI causally increased the risk of psoriasis (38, 39).

A systematic review and network meta-analysis including six studies concluded that compared with conventional systemic treatments, tumor necrosis factor (TNF) α inhibitors were associated with a significant increase in body weight, while anti-IL-12/23 or anti-IL-17 biologics had no effect on an increase of body weight or BMI (33).

The prevalence of MetS in patients with psoriasis ranges from 14.3% to 50% (31, 40, 41). The strength of these associations between psoriasis and MetS has been repeatedly confirmed by several observational studies (40, 42–44), and psoriatic patients had at least a double risk of MetS compared with non psoriatic individuals (41). The psoriasis risk tended to increase with the number increase of MetS components, and this trend was evident in obese subjects (44). A systematic review and meta-analysis of 14 observational studies found that a greater risk for MetS was reported in Middle Eastern than European patients (31). However, in Thailand, no significant association was found between MetS and psoriasis severity using PASI (45).

Significant differences were found in relation to the prevalence of cardiovascular risk factors, MetS, and major cardiovascular events in patients with psoriasis compared to non-psoriatic population, however, differences were not seen among psoriasis severity groups (43). After adjusting for all other MetS factors, WC and blood pressure remained significantly associated with noncalcified coronary burden (46).

Women with MetS have a higher chance of being psoriatic (47). Prevalence of MetS (32) and insulin resistance (48) was significantly higher in children with psoriasis. In most studies included in a meta-analysis conducted by Pietrzak et al. (32), a significantly decrease of high-density lipoprotein cholesterol level was found in children with psoriasis.

The increase in expression of surviving and heat shock protein 27, heat shock protein 60, and heat shock protein 90, and the decrease in cyclin D1 expression may be an important molecular mechanism involved in the development of MetS in psoriasis (49). Selenoprotein P was increased in psoriasis and significantly decreased after psoriatic treatment (50).

IL-17A monoclonal antibody treatment cannot only ameliorate psoriatic lesions but also restore dysregulation of lipid metabolism in psoriasis patients (51). MetS negatively affects psoriasis severity and treatment outcomes (45).

A systematic review including 26 clinical studies concluded that the available literature does not unequivocally support the association between psoriasis and type 2 diabetes because the low quality of studies included (30). However psoriasis was reported to be associated with type 2 diabetes, independent of visceral fat (52), and psoriasis severity is an independent risk factor of the homeostatic model assessment of insulin resistance (53). Lee et al. (54) firstly confirmed the association between psoriasis and diabetic complications including diabetic retinopathy and end-stage renal disease (ESRD). The effect of age seemed to differ between psoriasis sexes, men from 35 to 49 years old were at a lower risk of type 2 diabetes compared to their peers of 75 years of age and older, whereas women of 50 to 64 years old were at an increased risk of type 2 diabetes (55).

Psoriasis was significantly associated with hypercholesterolemia, hospital-diagnosed hypertension (56), and hyperlipidemia (57). The accumulating evidence of the nature of psoriasis and the risk of cardiovascular comorbidities is potentially due to an acquired hypercoagulability (58). Psoriasis significantly increased the risk of CKD, and so did hyperlipidemia. Statin treatment for hyperlipidemia reduced the CKD risk in psoriasis patients compared to treatment without statins (57).

A meta-analysis including 11 studies demonstrated that psoriasis patients had higher levels of visfatin (SMD, 0.90; 95% CI, 0.52-1.28), which was associated with ethnicity, PASI, and BMI (34). Visceral fat was associated with psoriasis, hyper-triglyceridemia, low high-density lipoprotein, and type 2 diabetes, and these associations were linked to serum IL-6, adiponectin, tumor necrosis factor, and insulin resistance (52).

A meta-analysis suggests that thyroid peroxidase antibody positivity (pooled OR, 1.71, 95% CI: 1.27-2.31), hypothyroidism, and hyperthyroidism (pooled OR, 1.17, 95% CI: 1.03-1.32) might be associated with prevalent psoriatic disease (59). Patients with thyroid dysfunction have significantly higher PASI scores and elevated serum C-reactive protein levels than those without thyroid dysfunction (60). In Taiwan, the psoriasis group had an increased risk for incident hyperthyroidism, Graves’ disease, hypothyroidism, and Hashimoto thyroiditis compared with controls (61), and a high prevalence of Hashimoto’s thyroiditis is especially observed in women with psoriasis (62).

A nationwide population-based cross-sectional study in Taiwan found gout was associated with psoriasis (adjusted OR, 1.30, 95% CI:1.20-1.42) (63), and a positive correlation was found between PASI scores and serum uric acid levels in psoriasis patients (64).

Psoriasis and depression might have a bidirectional association (74). The prevalence of anxiety/depression among psoriasis patients was 11.52%-27.00% (75–77). Psoriasis patients were at an increased risk for depression (78–81), anxiety disorders (79–81), anxiety and depression co-occurrence (81), and somatoform disorders (79) compared with the referent cohort. Risk factors in psoriasis patients associated with depression were: 20-50 years (77), female sex (77, 82), major comorbid diseases (77, 82), and low income (77, 81). Patients with moderate-to-severe psoriasis had a significant risk of depression and somatoform disorders compared to patients with mild disease (79), and the highest risk was observed among patients with severe psoriasis aged 40-50 years (78). However a HUNT3 study found depressive symptoms do not seem to be a major concern among individuals with psoriasis (83).

Major depressive disorder is a risk factor for the development of psoriasis (84, 85), especially in the male sex (85). Somatic and anxiety symptoms, as well as BMI, are closely linked to dermatology-related quality of life (86).

A unique study conducted in a South East Asian population determined that Indian ethnicity was a predictor of depression (P = 0.024) (87), and it provided invaluable insight into predictive factors of adverse effects of psoriasis on distress in a special population.

A systematic review described that the prevalence of anxiety in patients with psoriasis was significantly higher than healthy controls (OR: 2.91, 95% CI: 2.01-4.21), and an improvement in anxiety symptoms with therapy of psoriasis was demonstrated (Table 3) (88).

For moderate-to-severe psoriasis, unadjusted incremental all-cause healthcare costs associated with anxiety/depression were $8,077. Psoriasis treatments that improve psychiatric symptoms may reduce their economic burden (76). Therefore, screening for depressive/anxiety can lead to an increase of utilization of mental health care and improvement of psoriasis.

Two systematic reviews and meta-analyses found more suicidal ideation and acts with psoriasis (Table 3) (89, 90), and severe psoriasis and younger age were risk factors (89). However, another systematic review and meta-analysis with five population-based cohort studies found no increase in the risk of suicide, suicide attempt, or suicidality among people with psoriasis (Table 3) (91).

Because the systematic review and meta-analyses from Pompili et al. (90) analyzed the association between suicidal risks with not only psoriasis but also atopic dermatitis, Matterne et al. (97) compared the two systematic reviews and meta-analyses with opposite conclusions (89, 91) focusing on suicidal risks with psoriasis, and found that the differences mainly came from the data source. Chi et al. (91) only included cohort studies while Singh et al. (89) included cross-sectional, case-control, and cohort studies. Chi et al. (91) included five high quality studies according to the Newcastle-Ottawa Scale. Singh et al. (89) included 18 studies that were defined as to be medium quality to high quality.

The results of the association between suicides and psoriasis in later studies are still contradictory: the risk of suicidal behavior in individuals with psoriasis was confirmed in Canada (97), but not in Taiwan (98).

A systematic review and meta-analysis identified no increased risk for depression, anxiety, or suicidality with treatment of secukinumab in a pooled data analysis from 10 studies in patients with moderate-to-severe plaque psoriasis (99).

Two systematic review and meta-analyses summarized the association between dementia and psoriatic disease (Table 3) (92, 93), however two population-based studies in Taiwan found contradictory results on the association between psoriasis and dementia (100, 101). Phototherapy and systemic treatment might not have a protective effect against dementia in psoriatic patients (100).

Psychological stress plays an important role in the development of psoriasis, but the details of this association remain to be clearly defined. A systematic review demonstrates a temporal relationship between stress and psoriasis (Table 3) (95). A tertiary level of education was an independent risk factor while a higher monthly income was a protective factor for psoriasis populations (87). However, another systematic review and meta-analysis including 39 studies concluded there is no convincing evidence that preceding stress is significantly associated with exacerbation/onset of psoriasis because data are primarily based on retrospective studies with nonnegligible limitations (Table 3) (94).

Cohort studies from the UK and Denmark observed no evidence supporting increased long-term risk of psoriasis following bereavement (102).

A systematic review observed an overall 36% to 81.8% prevalence of obstructive sleep apnea in psoriasis (96), and psoriasis is also associated with restless legs syndrome, which is a possible sign of autonomic activation in psoriasis (103).

Psoriasis was associated with an elevated risk of chronic fatigue syndrome, which is differentiated by sex and age (104). Fatigue severity was associated with smoking, pain, and depression, but not with psoriasis severity (105).

An increased risk of Parkinson disease (106) and migraine, especially migraine with aura (107) was reported in patients with psoriasis; while a higher risk of psoriasis was found in patients with schizophrenia, and Th17 and pro-inflammatory cytokines may act as a link between these two diseases (108). There is a relationship between psoriasis and alexithymia (109) and dental fear (110), and impulse control proved to be the strongest predictor to psoriasis disability (111).

A meta-analysis showed significant, small-to-medium effects of psychosocial interventions on quality of life (0.28, 0.04-0.51) and anxiety (0.36, 0.15-0.57), but a not significant effect on depression (0.37, -0.05-0.80) (112).

IBDs include two chronic idiopathic inflammatory diseases: ulcerative colitis (UC) and Crohn’s disease (CD), which are the main gastrointestinal comorbidities of psoriasis. Two meta-analyses found significant bidirectional associations between psoriasis and IBDs, presence of CD (OR 2.0, 95% CI 1.4-2.9) and UC (OR 1.5, 95% CI 1.2-2.0) was significantly associated with psoriasis (119), and psoriasis had an increased risk of CD (RR= 2.53; 95% CI, 1.65-3.89) and UC (RR=1.71; 95% CI, 1.55-1.89) (120). Psoriasis patients were reported to have a higher prevalence of gastrointestinal signs and symptoms (feeling full/bloated, belly pain, diarrhea, mucus/blood in stool, and unintentional weight loss) (121), and sex and PsA were particular risk factors (122). Psoriasis-UC patients may have a higher BMI and milder skin symptoms than those with psoriasis alone (123), while psoriasis-CD patients have a mild (early-onset) psoriasis but a severe CD phenotype (124). While a cohort study in Denmark found a limited incremental effect of IBDs on risk of comorbidities in patients with psoriasis (125).

Association of psoriasis/PsA with IBD influences management strategy (126), and young patients and those with severe psoriasis may require comprehensive management (127). Time to CD, but not UC, diagnosis was significantly longer for patients with psoriasis compared with the general controls, and patients with systemic treatment had the longest time to CD and UC (122). A systematic review on 132 randomized, controlled, double-blinded studies concluded that infliximab and adalimumab had demonstrated efficacy in psoriasis, PsA, UC, and CD (128).

The prevalence of NAFLD in psoriasis patients is high and related to a higher prevalence of MetS, bacterial translocation, and a higher pro-inflammatory state (TNF-α, TGF-β level, and bacterial translocation) (129). Early onset of psoriasis was independently associated with greater odds of NAFLD, hypertriglyceridemia, hyperuricemia, and smaller odds of diabetes compared to late onset (130). The NAFLD fibrosis score proved a high significant correlation (P<0.0001) with fibrosis histological lesions in psoriatic patients (131). Enhanced liver fibrosis score and procollagen-3 N-terminal peptide are elevated in psoriasis and PsA, and enhanced liver fibrosis score may be superior to procollagen-3 N-terminal peptide alone (132).

A two-way meta-analysis including 18 studies found bidirectional associations between celiac disease and psoriasis; the OR is 2.16 (95% CI, 1.74-2.69) for celiac disease in patients with psoriasis and 1.8 (95% CI, 1.36-2.38) for psoriasis in patients with CD (133). The prevalence of gallstones was higher in the psoriasis patients (adjusted OR is 1.18, 95% CI: 1.14-1.23) (134). Patients with psoriasis may have an elevated risk for diverticulitis, not appendicitis or cholecystitis, compared to the general population (135). Psoriasis is associated with cirrhosis, even among patients without systemic therapy (136).

COVID‐19 is the worst epidemic in the last 2 years, and psoriasis patients might discontinue treatment without consulting a dermatologist due to fear of SARS-CoV-2 infections, especially patients who require systemic therapy. However, a Danish study reported that most patients felt to a great extent well treated (67.0%) and safe about their treatment in general (76.4%) (152). A retrospective cohort study in Brazil suggested that systemic therapy did not worsen COVID-19 in psoriasis (150). It is not necessarily concluded that TNFi is safer than biologics targeting IL-17 and IL-23 or not, with respect to risk of respiratory tract and SARS-CoV-2 infections (153). In patients with moderate-to-severe psoriasis, nonbiologic systemic therapies were associated with a higher risk of COVID-19-related hospitalization than with biologic use, and established risk factors included older age, male sex, non-white ethnicity, and having comorbidities (154). A so-called “cytokine storm syndrome” may increase the risk of mortality in COVID-19 patients (155). Although, there are no obvious contraindications to the use of inactivated vaccines, evaluating the risk-benefit ratio of maintaining ongoing immunosuppressive therapy before performing the vaccine is mandatory (156).

A large US population study reported the prevalence of chronic hepatitis B/C in psoriasis and non-psoriasis patients was 0.5%/0.8% and 1.3/1.6%, respectively, and there was no significant difference between the populations with and without psoriasis in terms of prevalence of hepatitis B or C (157). A higher prevalence of hepatitis C virus was demonstrated in adults with psoriasis and a higher rate of hepatic decompensation in hepatitis C virus+ individuals with moderate-severe psoriasis (158). Long-term use of methotrexate may not be associated with a liver cirrhosis risk among psoriatic patients with chronic viral hepatitis (159). Upregulation of inflammatory cytokines in patients with hepatitis viral infection possibly increases susceptibility to developing psoriasis (160).

Infection of HIV was an independent risk factor for development of psoriasis (adjusted HR, 1.80; 95%CI: 1.38-2.36) (161), and severe psoriasis was an independent risk factor for steatosis in patients with HIV infection (OR, 12; 95% CI, 1.2-120) (162). Treatment of psoriasis patients with HIV is a challenge as immunosuppressive agents may reactivate or induce infection in such patients, so biologics become a possible effective choice in psoriatic patients with a stable HIV infection, and it is also mandatory to monitor CD4 count and HIV viral load, in order to avoid possible causes of infection (163).

Single nucleotide polymorphism of rs1465788 in the zinc finger protein 36 ring finger protein-like 1 gene was identified as an early-onset psoriasis risk gene which demonstrates opposite associations with leprosy and psoriasis in a Chinese Han population (164).

Detection of latent Mycobacterium tuberculosis infection is mandatory before biotherapy in psoriasis as biotherapy may reactivate the infection. The national investigation of latent tuberculosis infection in Italian patients with psoriasis reported a prevalence of 8.5%, and independent risk factors included male sex, age over 55 years, and being entered into conventional treatment (165). The heparin-binding hemagglutinin, a higher sensitivity marker in response to a mycobacterial antigen, may help to prioritize patients who receive prophylactic interventions of Mycobacterium tuberculosis before starting biotherapies (166).

A systematic review and meta-analysis found that psoriatic patients faced an increased risk for colonization of staphylococci compared to healthy controls, and the pooled prevalence was 39.2% (95% CI 33.7-44.8) vs. 35.3% (95% CI 25.0-45.6) (167). A 4.5-fold increase of Staphylococcal aureus colonization was found on the patients’ skin compared to healthy controls, and 60% was in the nares (167).

A Taiwanese cohort study confirmed psoriasis was associated with an increased risk of HZ (adjusted HR of 1.29, 95% CI= 1.07-1.56), which involved differences in sex and age (168). The risk of HZ was significantly increased among the moderate to severe psoriasis group and was associated with immunosuppressive therapy (151). Although systemic therapy may play an important role in the risk of HZ, the intrinsic factors of psoriasis should be considered.

Almost 1/3 of patients with psoriasis develop PsA, which showed strong associations with psoriasis (adjusted OR:10.08; 95% CI: 7.97-12.74) (169). A meta-analysis including 266 studies found that the overall pooled proportion of PsA among adult psoriatic patients was 19.7%, and was 3.3% (95% CI, 2.1%-4.9%) in adolescents <18 years. The PsA prevalence was 22.7% (95% CI, 20.6%-25.0%), 21.5% (95% CI, 15.4%-28.2%), 19.5% (95% CI, 17.1%-22.1%), 15.5% (95% CI, 0.009%-51.5%), and 14.0% (95% CI, 11.7%-16.3%) in psoriasis from European, South American, North American, African, and Asian patients respectively (170). However, the high heterogeneity of studies included may have affected the estimates.

Incidence of PsA was 1.48, 3.00, and 5.49 per 100 patient-years in mild, moderate, and severe psoriasis patients, respectively (171). Risk of PsA increases steadily with duration of cutaneous symptoms following psoriasis onset (172, 173). PsA patients have a larger clinical burden, characterized by higher comorbidity rates, than those with psoriasis. Ratios of psoriasis-PsA comorbidity rates relative to psoriasis-only ranged from 1.1 for allergies and infections to 1.7 for fatigue, diabetes, and obesity (174).

Main factors that contribute to the delay in the diagnosis of PsA are lack of awareness among patients of the relationship between skin disease and joint symptoms and the absence of a specific diagnostic marker. Improved PsA screening is suggested in patients with psoriasis because the validated psoriasis epidemiology screening tool identified more than 10% of registry patients who could have had undiagnosed PsA (175). Recent consensus guidelines for managing psoriasis recommend using questionnaires to screen for the presence of PsA, and Salaff et al. (176) developed a self-administered questionnaire, called Simple Psoriatic Arthritis Screening (SiPAS), which screens psoriasis patients for signs and symptoms of PsA with compared high sensibility and specificity. In a systematic review, 259 possible markers associated with the development or presence of PsA in patients with psoriasis were identified in 119 studies (177). Laboratory markers related to inflammation and bone metabolism showed a strong association (not prediction) of PsA in psoriasis, however only C-X-C motif ligand 10 reached a strong level of evidence for a positive predictive value (177), but whether these indicators are clinically useful remains to be further investigated.

Active enthesitis and synovitis could be useful to identify subclinical PsA (178). Fluorescence optical imaging may be a helpful novel tool to analyze microcirculation in psoriasis/PsA patients (179).

Studies have yielded inconclusive results on the association between psoriatic/PsA and bone loss (180–182), a systematic review and meta-analysis including 12 studies concluded that patients with psoriasis/PsA have an increased risk of fractures (psoriasis: OR = 1.29, 95%CI = 1.02-1.63; PsA: OR = 2.88, 95%CI = 1.51-5.48). However there is little evidence supporting the association between psoriasis and osteoporosis/osteopenia (osteoporosis, psoriasis: OR, 1.28, 95%CI 0.86-1.90; PsA: OR, 1.32, 95%CI: 0.79-2.19; osteopenia, psoriasis: OR, 1.50, 95%CI: 0.75-3.02; PsA: OR, 1.61, 95%CI: 0.67-3.85) (183). Psoriasis increased the risk of osteoporosis in patients aged ≥ 40 years in Korea (182).

A meta-analysis including 10 case-control and cross-sectional studies found psoriasis and vitiligo are bidirectionally associated with each other: increased odds for psoriasis in vitiligo patients (summary OR: 3.43, 95% CI: 1.86-6.33) as well as elevated odds for vitiligo in psoriatic patients (summary OR: 2.29, 95% CI: 1.56-3.37) (116) (Table 4).

A systematic review and meta-analysis of 12 observational studies found that the overall pooled prevalence of psoriasis was 2.4% (95% CI, 1.0-4.4) among pemphigus patients (186). Pemphigus patients face an increased risk of psoriasis (187).

Psoriasis was independently associated with an increased risk of bullous pemphigoid (188, 189), with an important risk factor of younger age, and over one-third of bullous pemphigoid cases were diagnosed in the first year after incident psoriasis (188).

Higher itch intensity was associated with women, lower educational level, pustular psoriasis, lesions on visible or sensitive areas, palmoplantar areas, severe disease, disease duration <15 years, and no or few prior systemic treatments (190). Reszke et al. (191) firstly reported the possible associations between psoriatic pruritus and drugs administrated in various systemic conditions, including antacids, beta-blockers, angiotensin enzyme converting inhibitors, and xerosis intensity angiotensin receptor blockers.

Three large population-based cohorts reported that the prevalence of psoriasis was between 14.2% and 61.3% in patients with palmoplantar pustulosis, and patients both with palmoplantar pustulosis and psoriasis had a higher PsA prevalence and antipsoriatic drug use (192).

A positive association was reported between psoriasis and contact allergy (193), while an inverse association was reported in psoriasis and atopic diseases (194). The polarization of the activated immune response by allergens may affect the occurrence and significance of allergies in underlying immune-mediated diseases, even beyond the skin (193).

Two comprehensive meta-analyses summarized that psoriasis was associated with an increased risk of erectile dysfunction (OR, 1.22; 95% CI 1.08-1.37; P = 0.002 (195); OR, 1.62, 95%CI: 1.37-1.91, P < 0.001 (196)), especially in men with mild psoriasis (1.13; 1.09-1.20) and severe psoriasis (1.17; 1.04-1.32) (197). A pilot study supported a correlation between hypogonadism and obesity in male psoriasis patients, while no psoriasis-specific reduction of testosterone can be assumed (198).

A comprehensive literature review and meta-analysis including 28 studies found that the prevalence of sexual dysfunction (SD) ranged from 40.0% to 55.6% in psoriasis patients (199). Physical and psychological comorbidities are risk factors for SD, and the strongest association with SD is anxiety and depression, PsA, and genital psoriasis. Biologic drugs have benefits for the improvement of SD (199).

A meta-analysis including 16 studies found that pregnant women with psoriasis had a significantly higher risk of adverse maternal outcomes [preterm birth: 1.32 (1.15, 1.52); caesarean delivery: 1.33 (1.17, 1.52); (pre)eclampsia: 1.28 (1.14, 1.43); gestational hypertension: 1.30 (1.18, 1.44); gestational diabetes: 1.19 (1.10, 1.30)], but not adverse neonatal events (200).

GT has been described as a predictor of psoriasis, however, reports are inconclusive. A systematic review and meta-analysis including 11 case-control studies found that the frequency of GT was statistically associated with psoriasis (pooled OR was 3.53, 95% CI: 2.56-4.86) (204), however prevalence rates vary from 0.51% to 11.43% and data for Europe are sparse (205). A hospital-based cross-sectional study in Saudi Arabia found a positive association of both GT and fissured tongue in adult patients with psoriasis compared with those without (206). The PASI score was statistically higher in patients affected by GT, and exhibited less improvement after treatment (204). However a prospective case-control study in an Austrian cohort found that psoriasis was associated with fissured tongue but not with GT (207), and the severity of the disease evaluated by the PASI scale did not influence mucosal involvement (208).

A meta-analysis including two cohort studies and three case-control studies found that patients with periodontitis had a significantly elevated risk of psoriasis (pooled RR is 1.55, 95% CI, 1.35-1.77) (209). Vice versa, studies confirmed a significant psoriasis-associated increased risk of periodontitis (210–212), which was highest in patients with severe psoriasis and PsA (210). Severity of psoriasis also presented a strong relationship with periodontal clinical parameters (211). A link was identify between the inverse type of psoriasis and periodontitis (212).