|Year : 2015 | Volume
| Issue : 2 | Page : 266-271
Psoriasis: Not just skin deep
Malcolm Pinto, Manjunath Mala Shenoy, Spandana Prakash Hegde, Vishal B Amin
Department of Dermatology, Yenepoya Medical College Hospital, Mangalore, Karnataka, India
|Date of Web Publication||16-Dec-2015|
Manjunath Mala Shenoy
Department of Dermatology, Yenepoya Medical College Hospital, Deralakatte, Mangalore - 575 018, Karnataka
Source of Support: None, Conflict of Interest: None
Psoriasis is a multisystem, chronic, and incapacitating inflammatory disease, which can be associated with comorbidities of varying severity. These comorbidities can have a notable influence on the quality of life and result in mortality in rare instances. Although the disorders represent separate entities, the underlying chronic inflammatory nature of psoriasis and overlapping pathogenic pathways explain most of these associations. These disorders often present years after the initiation of psoriasis and are usually associated with extensive disease. In this review article, we discuss the various comorbidities associated with psoriasis as their early recognition will enable timely intervention, influence management options, and go a long way in improving the quality of life and life expectancy of these patients.
Keywords: Psoriasis, comorbidities, metabolic syndrome
|How to cite this article:|
Pinto M, Shenoy MM, Hegde SP, Amin VB. Psoriasis: Not just skin deep. Arch Med Health Sci 2015;3:266-71
| Introduction|| |
Psoriasis is a chronic, relapsing, autoinflammatory, heterogeneous disease with a complex multifactorial pathogenesis resulting from the interaction between genetic and environmental factors.  Skin is not the only organ, which is clinically affected by psoriasis. There is robust evidence that psoriatic patients have an increased relative risk of developing comorbidities such as psoriatic arthritis, metabolic syndrome, coronary heart disease, cancer, chronic obstructive pulmonary disease, cardiovascular disease, inflammatory bowel disease, depression, and osteoporosis.  It is yet to be established whether this spectrum of comorbidities occur as a direct result of the systemic inflammation associated with psoriasis or as a consequence of genetically determined selection or whether other factors are involved. Severe psoriasis has been associated with excess mortality compared with the general population in a number of studies, whereas the evidence is more mixed for mild disease.  Detecting and treating these comorbid conditions in the preliminary phase improves life expectancy and ensures comprehensive management of a patient with psoriasis. 
| Psoriatic Arthritis|| |
Psoriatic arthritis (PsA) is a systemic, polymorphic, inflammatory arthritis affecting 14-30% of psoriatic patients, and can lead to significant joint damage and disability.  It is characterized by varying admixture of dactylitis, peripheral arthritis, spondyloarthropathy, and enthesitis. Cutaneous involvement can be variable. PsA is more common among those with predominantly nail involvement. Patients can develop remarkable morbidity and mortality if not treated early. Up to 50% of PsA patients develop advanced erosive disease.  The presence of inflammatory arthritis in a patient with past or current psoriasis is the basis of diagnosis for PsA. In patients with no history of obvious skin involvement by psoriasis, careful examination of the scalp, retroauricular region, umbilicus and nail for nail pitting, onycholysis, and total nail dystrophy assumes prime importance. 
Moll and Wright classified PsA into five subgroups: Asymmetrical oligoarticular with dactylitis; symmetrical polyarticular similar to rheumatoid arthritis; classical form, primarily involving the distal interphalangeal joints; spondyloarthropathic variant; and arthritis mutilans.  A multicenter study Classification Criteria for Psoriatic Arthritis (CASPAR) developed new criteria with better sensitivity (91.4%) and high specificity (98.7%). 
Pharmacologic therapy of PsA includes symptomatic treatment and the use of disease-modifying antirheumatic drugs (DMARDs). Biologics constitute the only treatment modality targeting all pathological changes in psoriasis. Mild skin disease is controlled by the usage of topical corticosteroids in combination with phototherapy. Extensive and refractory cases of psoriasis are treated with systemic therapy and biologics. Nonsteroidal anti-inflammatory drugs (NSAIDs), DMARDs, and when necessary, antitumor necrosis factor (TNF) alpha agents are recommended in PsA. The presence of axial disease, enthesitis, and recalcitrant dactylitis also necessitates the use of anti-TNF agents. For peripheral arthritis, Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommends the usage of DMARDs as monotherapy or in combination for at least 3 months.  The utility of physical therapy in every phase of the treatment cannot be overemphasized.
| Psoriasis and Metabolic Syndrome|| |
Metabolic syndrome is defined as the presence of at least three of the five following criteria: Increased waist circumference or abdominal obesity; hypertension; hypertriglyceridemia; reduced high-density lipoprotein (HDL) levels, and insulin resistance. 
Genetically, the most important susceptibility locus for psoriasis, human leukocyte antigen (HLA)-CW6, is associated with obesity.  Regarded as the largest endocrine organ, adipose tissue synthesizes and secretes peptides such as adipokines, which play a role in regulating homeostasis, nutrition, blood pressure, carbohydrate and lipid metabolism, coagulation, insulin resistance, atherosclerosis, and inflammatory or immunological processes. 
Adiponectin is clearly associated with obesity and metabolic syndrome, which contributes to the increased risk of psoriasis and its exacerbation. Decreased adiponectin levels are found in obesity, insulin resistance, type 2 diabetes, and dyslipidemia. Reduced adiponectin levels serve as a risk factor for hypertension and diabetes mellitus. 
Leptin acts contrary to adiponectin in numerous physiological functions. Elevated levels of leptin are observed in obesity, type 2 diabetes, metabolic syndrome, chronic renal failure, and atherosclerosis. Leptin stimulates a Th1 immune response and inhibits Th2 response.  This confirms the role of leptin in the pathogenesis of diseases such as diabetes and psoriasis.  Metabolic syndrome shows an increased prevalence rate with the severity of psoriasis. A case-control-based study from Germany revealed an increased association of psoriasis with diabetes, dyslipidemia, hypertension, and coronary artery disease.  Hence, a multidisciplinary approach may result in adequate treatment of psoriasis and the associated comorbidity. 
| Psoriasis and Cardiovascular Disease|| |
Atherosclerosis results from chronic low-grade inflammation due to an interaction between immune mechanisms and metabolic abnormalities within the vessel wall. Population-based studies have found an increased association of premature atherosclerosis and cardiovascular disease in patients with psoriasis and PsA. This risk is higher with the severity of psoriasis and musculoskeletal inflammation.  According to a study, highly sensitive C-reactive protein (CRP) positively correlated with and independently predicted arterial stiffness in patients with psoriasis. 
It has been studied that psoriasis is an independent risk factor for calcification of coronary arteries as evident by the severity and frequency of coronary artery calcification in the epicardial vessels.  The prevalence of dilated cardiomyopathy is reported to be about tenfold greater among psoriatic patients. The existing chronic recurrent inflammatory process accompanying cytokine levels and oxidative stress may trigger arrhythmias in psoriatic patients. ,
Su YS et al. provide additional insights to the two types of systemic inflammatory marches present in psoriasis: Patients with metabolic disorder prior to the onset of psoriasis (psoriasis serves as the disease amplifier) have a greater risk of developing severe vascular disease in contrast to those who develop metabolic disorder developed after the onset of psoriasis (psoriasis acts as the disease initiator).  The relative risk of developing myocardial infarction is higher in young patients with severe psoriatic disease. 
| Psoriasis and Nonalcoholic Fatty Liver Disease|| |
Nonalcoholic fatty liver disease (NAFLD) is defined as the excessive deposition of triglycerides in the hepatocytes of patients who lack the history of excessive intake of alcohol.  There is an increased risk of metabolic syndrome and cardiovascular disease in patients with NAFLD and psoriasis. NAFLD represents the hepatic manifestation of metabolic syndrome, with visceral obesity being a vital component.  Mortality has also been observed to be higher in patients with NAFLD.  NAFLD can rarely progress to nonalcoholic steatohepatitis (NASH).
The mechanisms by which adipokines contribute to NAFLD include TNF-a triggered increase in insulin resistance and loss of adiponectin's protective effect on steatosis. The levels of adipokines including adiponectin, leptin, and resistin have been found to correlate with psoriasis disease severity.  Interleukin (IL)-6 is a key cytokine involved in the inflammatory response by keratinocytes in psoriasis and also has an effect on insulin resistance and development of fatty liver. Patients with NAFLD and psoriasis tend to have extensive cutaneous disease and are at a higher risk of hepatic involvement.
It is a great diagnostic challenge to identify patients with NASH and NAFLD as they are generally asymptomatic. Liver biopsy is currently the most optimal investigation to diagnose and stage NASH as clinical features and radiological imaging are unreliable. It is observed that NAFLD is more commoner in psoriasis patients and significantly correlates with metabolic syndrome and PsA. , Early detection of NAFLD warrantees avoidance of systemic therapy with liver toxicity such as methotrexate in psoriasis patients.
| Psoriasis and Gastrointestinal Tract|| |
Systemic inflammation links psoriasis with inflammatory bowel disease. Th17 cells produce IL-23, which plays a vital role in the inflammatory process involving the intestinal mucosa. Polymorphisms in IL-23 and IL-12B receptor genes also contribute to the disease process.  The inflammatory bowel disease 3 (IBD3) locus lined to inflammatory bowel disease and the PSORS1 locus of psoriasis lie in the 6p21 locus, which encompasses the major histocompatibility complex.  Cohen et al. found a higher prevalence of inflammatory bowel disease in patients with psoriasis.  Women with concomitant PsA showed increased risk of developing Crohn's disease. 
Early and accurate diagnosis of inflammatory bowel disease is essential as systemic therapy used in psoriasis such as methotrexate, acitretin, cyclosporine, and biologics such as infliximab and adalimumab are known to produce gastrointestinal side effects. 
Celiac disease is an autoimmune disorder seen in people with genetic predisposition with gluten rich diet as an inducing factor, associated with cutaneous and systemic manifestations. Celiac disease-associated antibodies such as antigliadin, antireticuline, antitransglutaminase, and antismooth muscle endomysium have been demonstrated in the serum of patients with psoriasis and correlate with the disease severity. A case-control study from Israel found an increased prevalence of celiac disease among patients with psoriasis. 
Dermatitis herpetiformis, chronic plaque psoriasis, and PsA show high frequency of the immunoglobin (Ig) heavy-chain DNase hypersensitive region enhancer 2 allele, thus suggesting a common genetic predisposition. 
Patients with inflammatory dermatosis such as psoriasis may develop steatorrhea. This results due to the cutaneous inflammation and resolves on treatment of the underlying condition. This condition is referred to as dermatogenic enteropathy and is not accompanied by histopathological changes in the intestinal mucosa. 
| Psoriasis and Eye Disease|| |
Ten percent of the patients with PsA may develop ocular changes. The ocular involvement could be due to the direct disease process or may result as a complication of the treatment. Apart from conjunctivitis, the other ocular diseases that have been reported include blepharitis, keratoconjunctivitis sicca, uveitis, keratitis, cataract, orbital myositis, symblepharon, cicatricial ectropion, and madarosis.  Typically a psoriasis patient may present with conjunctivitis, uveitis, or scleritis, which may precede cutaneous findings. Ocular findings may correlate with severe cutaneous lesions but are generally independent of articular findings. Although corneal involvement occurs less commonly, they may be of severe intensity. Thickening of the epithelium with erosions, infiltration with vascularization below the Bowman layer, and the presence of a deep stromal opacity are a few corneal findings that have been described. Early detection of ocular involvement is important as catastrophic complications such as the loss of vision could be prevented. Up to 5% of psoriasis patients may show inflammatory ocular changes.  Among HLA-B27-positive patients, uveitis is the most common extraarticular feature. Uveitis can also be independently associated with psoriasis without psoriatic arthropathy and HLA-B27. 
| Psoriasis and Psychiatric Comorbidities|| |
Psoriasis can be accompanied by psychosocial effects that can have a negative impact on the quality of life. High stress levels, social stigmatization, and physical limitations are often reported by such patients.  In a vicious cycle, psoriasis causes stress and stress exacerbates psoriasis. 
Psoriasis is a risk factor for depression. Depression may also trigger or exacerbate psoriasis. Depression is considered to have a strong inflammatory component, with mechanisms involving many of the same inflammatory mediators as those implicated in psoriasis, e.g., IL-2, IL-6, IL-12, and TNF-a.  Jensen et al. in a nationwide population-based study observed that the severity of psoriasis determined the increased risk of depression but this risk was mediated by the impact of comorbid conditions.  Brain-derived neurotrophic factor (BDNF) is a neurotrophin-associated with synaptic strength, neuronal growth, and neuroplasticity. It is involved in important functions such as memory and learning. Levels of BDNF have been found to be decreased in depression. Brunoni et al. in their study found decreased BDNF plasma levels in psoriasis, thus strengthening the concept of a relationship between the central nervous system and the skin in psoriasis.  Significant psychosocial and psychological comorbidities lead to worsening or precipitation of disease and poor response to therapy. Psychological and behavior therapy addresses this facet of the disease.
| Psoriasis and Chronic Obstructive Pulmonary Disease|| |
Increased rates of chronic obstructive pulmonary disease (COPD) have been detected in patients with psoriasis.  Chiang et al. observed that patients with psoriasis had a higher risk of developing COPD with significantly lower COPD-free survival rates than the comparison group.  Dreiher et al. in a case-control study found that the prevalence of COPD was significantly higher in patients with psoriasis. In view of this association, it is recommended that psoriasis patients should stop smoking and reduce additional risk factors for COPD. 
| Psoriasis and Cancer|| |
The data investigating the association of psoriasis with cancer have been inconsistent. It has been proposed that neoplasia may be induced by the presence of the chronic systemic inflammatory state triggered by psoriasis.  The pathophysiology of Th1-mediated diseases such as psoriasis and rheumatoid arthritis is associated with an increased risk of lymphoma.  Malignancies have been reported with psoralen plus ultraviolet A (PUVA) therapy, methotrexate, and cyclosporine. Increasing prevalence of substance abuse and predisposing factors for malignancy have been observed in psoriasis. A study observed that the long duration of psoriasis was associated with an increased risk of solid organ malignancies and lymphohematopoietic cancers.  A cohort study conducted in Taiwan found that psoriasis patients were more prone to nonmelanoma skin cancer and lymphoma.  A PUVA follow-up study over a period of 30 years observed that there was a dose-dependent increase in the risk of squamous cell carcinoma (SCC) and a moderate increase in the risk of developing basal cell carcinoma. 
| Psoriasis and Osteoporosis|| |
D'Epiro et al. suggested the need of an early diagnostic evaluation of bone metabolism in those with a long duration of psoriasis.  The proposed mechanisms that link psoriasis and osteoporosis include systemic inflammation, intake of antipsoriatic drugs, and joint involvement for PsA.
| Psoriasis and Systemic Autoimmune Inflammatory Diseases|| |
The coexistence of psoriasis with various autoimmune disorders is gaining importance but has been systematically reviewed by only a few studies until now. A retrospective study evaluated 25 psoriatic patients with various systemic autoimmune diseases. The coexistence of psoriasis and autoimmune diseases resulted in the worsening of clinical outcome of the autoimmune diseases. This was evident by the higher frequency and dosages of glucocorticoid use, need for biologicals, and also the presence of other comorbidities. These also suggest a common environmental and genetic background as well as therapeutic possibilities in the future. 
| Conclusion|| |
The presence of moderate to severe degree of psoriasis is accompanied by concomitant diseases that may have a significant impact on patients. The presence of comorbid diseases is associated with an increase in concomitant medication, some of which may worsen psoriasis; conversely, treating psoriasis with systemic drugs could impact the comorbid conditions. Being primary health care providers for psoriasis, dermatologists should adopt a multidisciplinary approach to screen patients to detect the existence of comorbid conditions such as PsA, metabolic syndrome, and cardiovascular (CV) disease, which may enable timely intervention and initiation of appropriate therapy. This will lead to a comprehensive improvement in the overall standards of care of patients with psoriasis.  Future studies need to be taken up to determine the utility of BDNF levels in psoriasis and also its role as a potential biomarker in psoriasis.
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