Aditya K. Gupta, MD, PhD

Psoriasis, a chronic inflammatory, autoimmune skin disorder that is associated with both genetic (concordance rate of about 60% in monozygotic and 20% in dizygotic twins) and environmental factors, affects about 2% to 4% of the population worldwide.

 Initially considered a primary dermatological disorder, psoriasis is now considered by many to be a systemic disorder of immune regulation that is mediated by T cells and dendritic cells (DCs). Common triggers for psoriasis include infection (streptococcal throat infection, HIV infection), physical trauma (Koebner phenomenon), medications (eg, Î²-blockers, lithium, NSAIDs, antimalarials), and psychological stress (associated with both onset and exacerbation of psoriasis).

The most common form presents as symmetrical, sharply demarcated, erythematous, dry, scaling, pruritic plaques, with a predilection for the scalp, extensor surfaces of the limbs, hands and feet, and sacral and genital regions. The total body surface area affected can vary. Pruritus is one of the most bothersome symptoms of psoriasis. Painful nail changes are also seen in some patients, and many patients have psoriatic arthritis that commonly affects the distal interphalangeal joints. Psoriasis can occur at any age from infancy to the eighth decade of life; the age of onset is before 40 years in most patients. Psoriatic plaques may persist for months to years, and periods of complete remission are possible.

The genetics and immunology of psoriasis have direct implications in the management of the psychiatric patient with psoriasis. The presence of the histocompatibility antigen HLA-Cw6 is the major genetic risk factor for psoriasis and is associated with an early age of onset (age 40 or younger) and positive family history for psoriasis; early-onset psoriasis has been associated with greater severity as well as being more reactive to psychological stress.

 Genome-wide association studies have identified other genetic association signals for psoriasis outside the major histocompatibility complex (MHC)1 that fall into 4 areas that may be interrelated:

• Interferon-Î³ (IFN-Î³)/interleukin (IL)-23)/IL-17 signaling: supported by the efficacy of biologics targeting these cytokines.

• Nuclear factor Îº-light-chain-enhancer of activated B cells (NF-ÎºB) signaling: NF-ÎºB, a transcription factor, is widely implicated in inflammatory and autoimmune diseases. Tumor necrosis factor-Î± (TNF-Î±) is a major activator of NF-ÎºB signaling; this is clinically emphasized by the therapeutic response of psoriasis to the anti– TNF-Î± biologics.

• Inflammatory DC function: inflammatory DCs produce TNF-Î± and nitric oxide in addition to their major function in antigen presentation.

• Keratinocyte differentiation: hyperproliferation and altered differentiation of keratinocytes are prominent features of psoriasis.

Immune regulation, which is mediated by T cells and DCs, plays a primary role in the pathophysiology of psoriasis. Psoriasis is characterized by activation of antigen-presenting DCs and activation and expansion of T-helper (T

17 inflammatory cytokines are elevated in the skin and blood of patients with psoriasis. These inflammatory mediators promote angiogenesis and epidermal hyperplasia and affect diverse processes, such as insulin signaling, lipid metabolism, and adipogenesis. Thus, the metabolic aspects of the chronic T

17 inflammation in psoriasis can affect conditions such as obesity, diabetes, and atherosclerosis.

Medical comorbidities have important treatment implications for patients with psoriasis who have psychiatric disorders (eg, adverse effects of medications) and who may already be at a greater risk for obesity, diabetes, and cardiovascular complications (

). The heightened proinflammatory state associated with psoriasis as well as the patient’s emotional reaction to the effects of psoriasis on quality of life may also contribute to psychiatric comorbidity (eg, PTSD, MDD).

Sleep-related symptoms, such as insomnia, are a core feature of psychiatric disorders. One night of sleep deprivation can inhibit recovery of skin barrier function in humans. Skin barrier function recovery was assessed by measuring transepidermal water loss immediately before and at 2 time points following the stripping of the forearm skin with repeated applications of cellophane tape.

Sleep restriction of 25% to 50% of the normal 8-hour sleep period is associated with an elevation of mediators of inflammation such as IL-1Î² and TNF-Î±. In a mouse model of psoriasis, 48 hours of selective paradoxical sleep deprivation was associated with significant increases in proinflammatory cytokines (IL-1Î², IL-6, and IL-12) and decreases in the anti-inflammatory cytokine IL-10.

 The cytokine levels normalized after 48 hours of sleep rebound, which suggests that sleep loss is a risk factor for psoriasis.

Psoriasis is also associated with a higher prevalence of obstructive sleep apnea, which is possibly related to the heightened proinflammatory state as well as the risk factors for obstructive sleep apnea, such as hypertension and obesity. Obstructive sleep apnea is more commonly encountered in psychiatric disorders such as MDD and PTSD-conditions that are also more frequently associated with psoriasis.

Most studies of neuroendocrine response to stress in psoriasis have demonstrated a blunted hypothalamic-pituitary-adrenal (HPA) axis cortisol response and a heightened sympathetic response to stressors. During a standardized stressor exposure test (eg, forced mental arithmetic), patients with psoriasis reported higher levels of strain than did healthy controls; the patients also had higher levels of urinary adrenalin and lower levels of plasma cortisol.

 Similar findings were seen in patients with psoriasis during a social performance stressor (version of the Trier paradigm).

A 6-month prospective study of 62 patients with psoriasis examined serum cortisol levels (between 9 and 11 am).

 Peak levels of daily stressors predicted an increase in disease severity a month later (

 = 0.28; P < .05); however, they were associated with a lower cortisol level (

 = −0.28; P < .05). The dysregulation of the HPA axis with decreased release of cortisol, along with a heightened sympathetic response, is assumed to be involved in the stress-induced exacerbation of chronic inflammatory diseases by leading to up-regulation of proinflammatory cytokines.

A study of 5604 randomly selected patients with psoriasis and psoriatic arthritis from the National Psoriasis Foundation database (2003-2011) revealed that 52.3% of patients with psoriasis and 45.5% of patients with psoriatic arthritis were dissatisfied with their overall treatment.

 After controlling for clinical characteristics of psoriasis (psoriasis type, disease severity, and location), patients who received biologic therapy were most satisfied and patients who received topical therapy were least satisfied.

 It is possible that some biologics improve mood and other psychological symptoms independent of the clinical improvement in psoriasis, which, in turn, may reflect as a greater satisfaction with treatment.

More than 50% of patients with psoriasis report that psychological stress exacerbated their psoriasis.

 The physical and psychosocial impact of psoriasis on quality of life has been rated as the same as or worse than the impact of conditions such as cancer, ischemic heart disease, arthritis, and diabetes.

 Stress-reactive psoriasis tends to manifest consequent to greater psoriasis- related stress or the daily hassles associated with the cosmetic disfigurement and the associated social stigma. Disfiguring psoriasis or psoriasis in “emotionally charged” body regions, such as the socially visible and genital regions, had a greater impact on the patient’s quality of life and psoriasis-related stress.

The social impact of psoriasis has been studied using functional MRI in 13 men with psoriasis, by employing a covert recognition of faces task.

 Compared with healthy controls, patients with psoriasis had significantly (

 < .005) smaller signal responses to disgusted faces bilaterally in the insular cortex. Both feelings of disgust and observation of disgust in others are known to activate the insular cortex. This apparently contradictory response may be an indication that patients with psoriasis develop a coping mechanism to protect themselves from stressful emotional responses by blocking the processing of disgusted facial expressions.

An increased frequency of psoriasis has been reported with PTSD (DSM-III criteria; 

). PTSD has been associated with higher circulating levels of T lymphocytes and lower cortisol levels with concurrent higher catecholamine levels, a physiological state (similar to that observed in patients with stress exacerbated psoriasis) that increases the risk of autoimmune diseases.

 Baseline depression, measured using the 5-item Mental Health Index of the Short Form 36 health status survey, was associated with a higher incidence of psoriasis.

 Men who had a lifetime history of DSM-IV-TR–diagnosed anxiety disorders also had an increased rate of psoriasis.

 An increased frequency of psoriasis was also seen in patients with schizophrenia.

 However, neither study controlled for psoriasis risk factors, such as cigarette smoking, alcohol use, and body mass index.

Psoriasis has been consistently associated with an increased frequency of suicidal ideation in several studies, including a recently published multicenter study.

 Among individuals with a wide range of dermatological diagnoses, only psoriasis had a significant association with suicidal ideation (adjusted odds ratio [OR] = 1.94; 95% confidence interval [CI], 1.33-2.82). In a UK database of Hospital Episode Statistics for 1999-2011, individuals with both psychiatric and medical disorders were examined for hospital episodes of self-harm. The relative risk of self-harm was greater for all years in patients with psoriasis (1.6; 95% CI, 1.5-1.7) than in those in the reference group.

Effective management of psychiatric factors in psoriasis requires an integrated, multidisciplinary approach that treats both cutaneous and systemic inflammation (which in part involves treatment of the psychiatric disorder in which psoriasis may be more frequent, such as MDD or PTSD). Because patients with psoriasis (independent of psychiatric morbidity) tend to experience a greater frequency of suicidal ideation and self-harm, carefully evaluate suicide risk in these patients.

Even mild psoriasis that affects a small percentage of total body surface in socially visible body regions or the genital area can carry a significant psychosocial burden. In such cases, the psoriasis should be treated aggressively because the psoriasis-related stress can adversely affect the course of the disorder.

Obesity, diabetes, metabolic syndrome, and greater cardiovascular morbidity (stroke, hypertension, myocardial infarction) are often present in patients with psychiatric disorders such as MDD and PTSD. Comorbidity with psoriasis, especially severe psoriasis, may further increase the prevalence and risk of these comorbidities in the psychiatric patient. Take such comorbidities into consideration when choosing psychotropics based on their adverse-effect profiles.

Educate patients about the effects of tobacco and alcohol on psoriasis. Tobacco smoking is associated with a 70% increase in the risk of developing psoriasis.

 In addition, the use of alcohol and tobacco is associated with worsening symptoms and less treatment-related improvement.

Obstructive sleep apnea and insomnia are prevalent in patients with psoriasis and psychiatric disorders such as MDD and PTSD (conditions that are also more frequently associated with psoriasis). Remember to screen for sleep disorders because they can heighten the proinflammatory state. Pruritus in psoriasis can be associated with insomnia, which may have to be managed in conjunction with the psoriasis.

Lithium can precipitate or exacerbate psoriasis; lithium-induced psoriasis usually occurs within the first few years of treatment but it can occur within a few months, and it is typically resistant to standard antipsoriatic treatments. If psoriasis becomes intractable, discontinue lithium; psoriasis symptoms will usually remit within a few months. Î²-Blockers such as propranolol that are used to treat lithium-induced tremors may also be associated with psoriasis.

Cyclosporine, an immunosuppressant that is used to treat psoriasis, can interact with psychiatric medications by its action on cytochrome P-450 3A4 (CYP3A4), of which it is both a substrate and an inhibitor. Cyclosporine can dramatically increase blood levels of drugs that are CYP3A4 substrates, such as carbamazepine, antidepressants (doxepin, amitriptyline, and imipramine), benzodiazepines (alprazolam, triazolam, and diazepam), and the antipsychotic pimozide. There are no significant drug-drug interactions reported between psychiatric medications and the biologics used in psoriasis.

Psoriasis is a systemic autoimmune disorder in which immune regulation by T cells and DCs plays a primary role. The comorbidity of psoriasis with certain psychiatric disorders (such as anxiety disorders, including PTSD, and depressive illness) most likely has a multifactorial basis that includes a heightened proinflammatory state underlying both disorders and the impact of a chronic, cosmetically disfiguring condition (eg, psoriasis) on the patient’s quality of life and the resultant stress, mainly as a result of the social stigma associated with psoriasis.

Several studies have reported a blunted HPA axis cortisol response in conjunction with a heightened sympathetic response to psychological stressors in psoriasis; this may be the basis for the stress-induced up-regulation of proinflammatory cytokines. Patients with HLA-Cw6, which is a major genetic risk factor for psoriasis, generally present with early onset (40 years or younger) and with psoriasis that is more reactive to psychological stress.

The proinflammatory state in psoriasis is associated with a higher prevalence of metabolic syndrome, obesity, diabetes, and cardiovascular morbidity. This has important treatment implications for certain patients with psychiatric disorders who may already be at increased risk for comorbidities and more serious adverse effects. Sleep disorders as well as tobacco and alcohol use, which are more common in certain psychiatric populations, have been associated with onset and treatment resistance. Psoriasis is independently associated with increased suicidal ideation and self-harm.

Dr M A Gupta is Professor in the department of psychiatry, Schulich School of Medicine and Dentistry at Western University in London, Ontario, where she is also in private practice. Dr A K Gupta is Professor in the division of dermatology, department of medicine, at the University of Toronto; he is also in private practice (dermatology) in London and Toronto, Ontario. They report no conflicts of interest concerning the subject matter of this article.

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Psoriasis, a chronic inflammatory, autoimmune skin disorder, is associated with both genetic and environmental factors. It has important treatment implications for patients who have psychiatric disorders. 

Aditya K. Gupta, MD, PhD

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