Abstract

INTRODUCTION

Psoriasis is an immune-mediated, chronic inflammatory disease of genetic basis, which affects mainly the skin, although it has systemic pathological effects. The most severe forms have been associated with several diseases that have similar pathogenic factors. Comorbidities classically associated with psoriasis are psoriatic arthritis (PsA), Crohn's disease (CD), psychological/psychiatric disorders (DPP) and uveitis. In recent years, the metabolic syndrome as a whole and its individual components have been associated with psoriasis.¹1 Henseler T, Christophers E. Disease concomitance in psoriasis. J Am Acad Dermatol. 1995;32:982-6.

2 Christophers E. Comorbidities in psoriasis. Clin Dermatol. 2007;25:529-34.^-33 Naldi L, Mercury SR. Epidemiology of comorbidities in psoriasis. Dermatol Ther. 2010;23:114-8. Gelfand et al. were the first to consider psoriasis as an independent factor of cardiovascular risk aggravation.⁴4 Gelfand JM, Troxel AB, Lewis JD, Kurd SK, Shin DB, Wang X, et al. The risk of mortality in patients with psoriasis: results from a population-based study. Arch Dermatol. 2007 ;143:1493-9. Recent studies also showed an increased prevalence of celiac disease, nonalcoholic fatty liver disease (NAFLD), and erectile dysfunction in patients suffering from psoriasis.⁵5 Birkenfeld S, Dreiher J, Weitzman D, Cohen AD. Celiac disease associated with psoriasis. Br J Dermatol. 2009;161:1331-4.

6 Gisondi P, Targher G, Zoppini G, Girolomoni G. Non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. J Hepatol. 2009;51:758-64.

7 Miele L, Vallone S, Cefalo C, La Torre G, Di Stasi C, Vecchio FM, et al. Prevalence, characteristics and severity of non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. J Hepatol. 2009;51:778-86.^-88 Goulding JM, Price CL, Defty CL, Hulangamuwa CS, Bader E, Ahmed I. Erectile dysfunction in patients with psoriasis: increased prevalence, an unmet need, and a chance to intervene. Br J Dermatol. 2011;164:103-9. Preliminary epidemiological data suggest that adequate treatment of psoriasis could reduce the incidence of these comorbidities.

In a simplified way, the comorbidities associated with psoriasis may be classified as classic, emerging, related to lifestyle or related to disease treatments (Chart 1). With the aim of understanding this group of often underdiagnosed conditions, this article summarizes the current evidence on the knowledge of classical and emerging comorbidities in patients with psoriasis.

CLASSIC COMORBIDITIES

Psoriatic arthritis. PsA is a quite heterogeneous, usually seronegative, chronic inflammatory spondyloarthritis associated with psoriasis.⁹9 Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum. 1973;3:55-78. The exact prevalence of PsA is unknown, but estimates range from 20 to 420 cases per 100,000 in the western countries and 1 per 100,000 in Japan.¹⁰10 Hukuda S, Minami M, Saito T, Mitsui H, Matsui N, Komatsubara Y, et al. Spondyloarthropathies in Japan: nationwide questionnaire survey performed by the Japan Ankylosing Spondylitis Society J Rheumatol. 2001;28:554-9.

The wide variability in its prevalence rates reflects the different populations studied (ranging from communities to hospitalized patients), and the existence of five different diagnostic criteria with considerable variations in sensitivity and specificity: (1) Moll and Wright (2) Bennet, (3) Vasey and Espinoza (4) Fournié and (4) CASPAR (Classification Criteria for Psoriatic Arthritis).⁹9 Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum. 1973;3:55-78.^,1111 Ruderman EM, Tambar S. Psoriatic arthritis: prevalence, diagnosis, and review of therapy for the dermatologist. Dermatol Clin. 2004;22:477-86, x.

12 Bennet RM. Psoriatic arthritis. In: McCarty DJ, editor. Arthritis and related conditions. Philadelphia: Lea & Febiger; 1979. p. 645.

13 Vasey FB, Espinoza LR. Psoriatic arthropathy. In: Calin A, editor. Spondyloarthropathies. Orlando: Grune & Stratton, Inc.; 1984. p. 151-85.

14 Fournie B, Crognier L, Arnaud C, Zabraniecki L, Lascaux-Lefebvre V, Marc V, et al. Proposed classification criteria of psoriatic arthritis. A preliminary study in 260 patients. Rev Rhum Engl Ed. 1999;66:446-56.^-1515 Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H, et al. Classification criteria for psoriatic arthritis. Development of new criteria from a large international study. Arthritis Rheum. 2006;54:2665-73. PsA prevalence varies from 6 to 42% among patients with psoriasis.

Pathogenesis. With regard to genetic factors, in contrast to psoriasis, association with specific HLA antigens is less clear; most of them coincide with HLA associated with early-onset psoriasis.¹⁶16 Gladman DD, Farewell VT, Kopciuk KA, Cook RJ. HLA markers and progression in psoriatic arthritis. J Rheumatol. 1998;25:730-3. Single nucleotide polymorphisms in the IL-13 gene have been recently associated with specific risk of PsA, without correlation with psoriasis.¹⁷17 Bowes J, Eyre S, Flynn E, Ho P, Salah S, Warren RB, et al. Evidence to support IL- 13 as a risk locus for psoriatic arthritis but not psoriasis vulgaris. Ann Rheum Dis. 2011;70:1016-9. The rate of concordance between monozygotic twins is 70%, whereas among dizygotic twins it is up to 20%.¹⁸18 Mease P, Goffe BS. Diagnosis and treatment of psoriatic arthritis. J Am Acad Dermatol. 2005;52:1-19.

Environmental factors are: infection (Grampositive bacteria such as Streptococcus or retroviruses such as HIV), drugs and joint trauma (especially in children); emotional stress plays an important role as a trigger for both skin and joint psoriasis, however, the neuro-immuno-endocrine mechanisms involved in this process still need to be elucidated.¹⁶16 Gladman DD, Farewell VT, Kopciuk KA, Cook RJ. HLA markers and progression in psoriatic arthritis. J Rheumatol. 1998;25:730-3.^,1818 Mease P, Goffe BS. Diagnosis and treatment of psoriatic arthritis. J Am Acad Dermatol. 2005;52:1-19.^,1919 Finzi AF, Gibelli E. Psoriatic arthritis. Int J Dermatol. 1991;30:1-7. Zhang et al. identified a higher frequency of PsA in obese or overweight patients (7.81%) than in normal weight patients (5.17%, p <0.01).²⁰20 Zhang C, Zhu KJ, Zheng HF, Cui Y, Zhou FS, Chen YL, et al. The effect of overweight and obesity on psoriasis patients in Chinese Han population: a hospital-based study. J Eur Acad Dermatol Venereol. 2011;25:87-91.

From the immunological point of view, changes are observed both in humoral and cellular immunity.¹⁸18 Mease P, Goffe BS. Diagnosis and treatment of psoriatic arthritis. J Am Acad Dermatol. 2005;52:1-19.^,1919 Finzi AF, Gibelli E. Psoriatic arthritis. Int J Dermatol. 1991;30:1-7. Most lymphocytes are of type CD4+, whose CD4+/CD8+ ratio reaches 2:1 in the synovial fluid compartment. CD8+ cells are most commonly found in the entheses.²¹21 Gottlieb A, Korman NJ, Gordon KB, Feldman SR, Lebwohl M, Koo JY, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008;58:851-64.

Clinical manifestations. The peak incidence of PsA occurs between ages 30 and 50 years of age.²¹21 Gottlieb A, Korman NJ, Gordon KB, Feldman SR, Lebwohl M, Koo JY, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008;58:851-64. Clinically it is characterized by edema, pain and stiffness of the joints, ligaments and tendons (enthesitis and dactylitis). The association between synovitis and enthesitis of tendons and ligaments of a single fin-ger/toe is called dactylitis or "sausage digit", and it is identified in 30% of patients with PsA.¹⁸18 Mease P, Goffe BS. Diagnosis and treatment of psoriatic arthritis. J Am Acad Dermatol. 2005;52:1-19.^,2222 Gladman DD, Brockbank J. Psoriatic arthritis. Expert Opin Investig Drugs. 2000;9:1511-22. Up to 20% of affected patients suffer from severely destructive and mutilating forms of the disease.²³23 Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis. 2005;64:ii14-7.

Arthritis is characterized by periods of worsening and remissions. However, it may lead to persistent inflammation if left untreated. The onset of arthritis may precede, succeed or be concomitant with cutaneous lesions. Skin involvement usually precedes arthritis in 75% of cases, and occurs concomitantly in 10%. In the other 15%, arthritis may precede the skin lesion. A correlation between the type or severity of skin lesions and the presence, type or extent of joint affection is not common.²⁴24 Espinoza LR, Cuellar ML. Psoriatic arthritis and spondylitis: a clinical approach. In: Calin A, Taurog JD, editors. Spondylarthritides. Oxford: Oxford University Press; 1998. p. 97-111.

Most patients with PsA present vulgar psoriasis.²⁵25 Torre Alonso JC, Rodriguez Perez A, Arribas Castrillo JM, Ballina Garcia J, Riestra Noriega JL, Lopez Larrea C. Psoriatic arthritis (PA): a clinical, immunological and radiological study of 180 patients. Br J Rheumatol. 1991;30:245-50. When lesions appear after articular affection, eventually after 10 to 15 years, it is called "PsA sine psoriasis".²⁶26 Slobodin G, Rosner I, Rozenbaum M, Boulman N, Kessel A, Toubi E. Psoriatic arthropathy: where now? Isr Med Assoc J. 2009;11:430-4.

Nail changes are seen in up to 90% of individuals with PsA, but only in 45% of patients with psoriasis.¹¹11 Ruderman EM, Tambar S. Psoriatic arthritis: prevalence, diagnosis, and review of therapy for the dermatologist. Dermatol Clin. 2004;22:477-86, x.^,2727 Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826-50.

Classification. The classification of PsA is a controversial topic. Although used, the five subgroups described by Moll and Wright frequently overlap each other, and one patient may move from one subgroup classification to the other over time (Chart 2).¹¹11 Ruderman EM, Tambar S. Psoriatic arthritis: prevalence, diagnosis, and review of therapy for the dermatologist. Dermatol Clin. 2004;22:477-86, x.^,2828 Kyle S, Chandler D, Griffiths CE, Helliwell P, Lewis J, McInnes I, et al. Guideline for anti-TNF-alpha therapy in psoriatic arthritis. Rheumatology (Oxford). 2005;44:390-7.

Although less frequent, isolated synovitis of the distal interphalangeal joint and mutilating arthritis are the most specific findings of PsA.¹¹11 Ruderman EM, Tambar S. Psoriatic arthritis: prevalence, diagnosis, and review of therapy for the dermatologist. Dermatol Clin. 2004;22:477-86, x.

Diagnostic criteria. In 2006, the Classification of Psoriatic Arthritis (CASPAR) Study group set up a highly sensitive (91-100%) and specific (97-99%) set of criteria that allows for the diagnosis of PsA even in cases of PsA sine psoriasis and in patients with positive rheumatoid factor (Chart 3).¹⁵15 Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H, et al. Classification criteria for psoriatic arthritis. Development of new criteria from a large international study. Arthritis Rheum. 2006;54:2665-73.^,2626 Slobodin G, Rosner I, Rozenbaum M, Boulman N, Kessel A, Toubi E. Psoriatic arthropathy: where now? Isr Med Assoc J. 2009;11:430-4.

The Psoriatic Arthritis Screening and Evaluation (PASE) is a screening tool that has been developed to increase detection of PsA by dermatologists. It is a self-administered questionnaire whose score greater than or equal to 47 has a sensitivity of 82% and a specificity of 73% for symptoms of PsA.²⁹29 Husni ME, Meyer KH, Cohen DS, Mody E, Qureshi AA. The PASE questionnaire: pilot-testing a psoriatic arthritis screening and evaluation tool. J Am Acad Dermatol. 2007;57:581-7.

Radiological findings. Radiographic features of peripheral PsA are: asymmetric distribution, involvement of the distal interphalangeal joint, periostitis, bone density preservation and pencil-in-cup deformity in advanced cases of the disease. The most characteristic radiographic finding of PsA is bone proliferation.¹²12 Bennet RM. Psoriatic arthritis. In: McCarty DJ, editor. Arthritis and related conditions. Philadelphia: Lea & Febiger; 1979. p. 645.

Ultrasonography (US) is a reliable method to detect signs of subclinical enthesopathy of the Achilles tendon and confirm diagnosis in patients with symptoms.³⁰30 De Simone C, Guerriero C, Giampetruzzi AR, Costantini M, Di Gregorio F, Amerio P. Achilles tendinitis in psoriasis: Clinical and sonographic findings. J Am Acad Dermatol. 2003;49:217-22.

The use of nuclear magnetic resonance (NMR) has led to an increased understanding of PsA. It has helped to identify the fact that synovial inflammation is usually a secondary phenomenon to extrasynovial inflammation (primary affection), which aids to differentiate it from rheumatoid arthritis.³¹31 Schwenzer NF, Kotter I, Henes JC, Schraml C, Fritz J, Claussen CD, et al. The role of dynamic contrast-enhanced MRI in the differential diagnosis of psoriatic and rheumatoid arthritis. AJR Am J Roentgenol. 2010;194:715-20.

Thus, radiography detects more erosions and osteoproliferation, but is less sensitive in the detection of changes in general. Effusions and synovitis are often detected by NMR and US. Features found in radiographic studies of PsA are listed in Chart 4.

Differential diagnoses. The main differential diagnoses of PsA are reactive arthritis, rheumatoid arthritis (RA), ankylosing spondylitis and erosive osteoarthritis of hands.³²32 Gladman DD, Christopher R. Clinical manifestations and diagnosis of psoriatic arthritis. Uptodate.com [Internet]. 2010 [cited in 2013 Jul 26]; 18.1. Available from: http://www.uptodate.com/contents/clinical-manifestations-and-diagnosisof-psoriatic-arthritis.
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Treatment. All patients with PsA should receive counseling regarding their illness, psychological support and physiotherapy. Mild forms of the disease may respond to non-steroidal anti-inflammatory drugs with or without intra-articular infiltration with glucocorticoid.³³33 Nash P, Clegg DO. Psoriatic arthritis therapy: NSAIDs and traditional DMARDs. Ann Rheum Dis. 2005;64:ii74-7. Moderate to severe forms of PsA should initially be treated like the mild form of the disease, associated with the use of disease-modifying antirheumatic drugs (DMARD).³⁴34 Gelfand JM, Kimball AB, Mostow EN, Chiou CF, Patel V, Xia HA, et al. Patient-reported outcomes and health-care resource utilization in patients with psoriasis treated with etanercept: continuous versus interrupted treatment. Value Health. 2008;11:400-7. Refractory cases are defined as cases in which there is a non-response to one or a combination of DMARDs after at least three months of use. Anti-TNFα agents (adalimumab, etanercept and infliximab) are recommended in these cases. All these drugs have IA level of efficacy evidence. Apparently, there is no superiority of cost-effectiveness among the three agents.³⁵35 Rodgers M, Epstein D, Bojke L, Yang H, Craig D, Fonseca T, et al. Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis: a systematic review and economic evaluation. Health Technol Assess. 2011;15:i-xxi, 1-329.

Prognosis. PsA, once considered a benign arthritis, compromises the quality of life of patients and causes significant functional impairment.³⁶36 Husted JA, Gladman DD, Farewell VT, Cook RJ. Health related quality of life of patients with psoriatic arthritis: a comparison with patients with rheumatoid arthritis. Arthritis Rheum. 2001;45:151-8.

In a study, patients with PsA were followed up for more than 10 years. In 55% of cases, patients had five or more joint deformities.³⁷37 Kane D, Stafford L, Bresnihan B, FitzGerald O. A prospective, clinical and radiological study of early psoriatic arthritis: an early synovitis clinic experience. Rheumatology (Oxford). 2003;42:1460-8. It is possible that patients with initial presentation of five or more affected joints exhibit worse prognosis in relation to erosion and deformity.³⁸38 Queiro-Silva R, Torre-Alonso JC, Tinture-Eguren T, Lopez-Lagunas I. A polyarticular onset predicts erosive and deforming disease in psoriatic arthritis. Ann Rheum Dis. 2003;62:68-70. On the other hand, male gender, beginning in "early " age, small number of inflamed joints and improved functional class are associated with a higher chance of remission.²⁴24 Espinoza LR, Cuellar ML. Psoriatic arthritis and spondylitis: a clinical approach. In: Calin A, Taurog JD, editors. Spondylarthritides. Oxford: Oxford University Press; 1998. p. 97-111.^,3636 Husted JA, Gladman DD, Farewell VT, Cook RJ. Health related quality of life of patients with psoriatic arthritis: a comparison with patients with rheumatoid arthritis. Arthritis Rheum. 2001;45:151-8.

Wong et al. identified increased rates of mortality among patients with PsA (59 % and 65 % in women and men, respectively), when compared to the healthy population.³⁹39 Wong K, Gladman DD, Husted J, Long JA, Farewell VT. Mortality studies in psoriatic arthritis: results from a single outpatient clinic. I. Causes and risk of death. Arthritis Rheum. 1997;40:1868-72. Jamnitski et al. found a higher prevalence of risk factors and cardiovascular disease in patients with PsA, when compared with the general population. However, these authors stress that it is not possible to say yet that changes in lifestyle and suppression of inflammation would have the same clinical effect observed in patients without psoriasis.⁴⁰40 Jamnitski A, Symmons D, Peters MJ, Sattar N, McInnes I, Nurmohamed MT. Cardiovascular comorbidities in patients with psoriatic arthritis: a systematic review. Ann Rheum Dis. 2013;72:211-6.

The primary goals in the management of patients with PsA are, therefore, improve the quality of life, reducing progression of structural joint damage, parameters of inflammatory activity, risk of deformities, and morbidity and mortality among patients with this condition.

Inflammatory Bowel Disease (IBD). Patients with CD have a 7-times higher risk of developing psoriasis, and psoriasis patients have a 2.9-times higher risk of developing CD, when compared with the general population.⁴¹41 Christophers E. Psoriasis: epidemiology and clinical spectrum. Clin Exp Dermatol. 2001;26:314-20.^,4242 Gulliver W. Long-term prognosis in patients with psoriasis. Br J Dermatol. 2008;159:2-9. Binus et al. reported that patients with psoriasis and concomitant IBD have a higher rate of comorbidities (seronegative arthritis, thyroiditis, diabetes and lymphoma) than patients with psoriasis only, which could be explained by common inflammatory pathways and shared genetic risks.⁴³43 Binus AM, Han J, Qamar AA, Mody EA, Holt EW, Qureshi AA. Associated comorbidities in psoriasis and inflammatory bowel disease. J Eur Acad Dermatol Venereol. 2012;26:644-50. Although individual susceptibility to psoriasis, DC and ulcerative colitis has been located in close chromosomal loci,⁴⁴44 Nair RP, Henseler T, Jenisch S, Stuart P, Bichakjian CK, Lenk W, et al. Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan. Hum Mol Genet. 1997;6:1349-56. several other genetic loci are also found in each of these conditions. In a recent study, seven susceptibility loci shared by psoriasis and DC were identified.⁴⁵45 Ellinghaus D, Ellinghaus E, Nair RP, Stuart PE, Esko T, Metspalu A, et al. Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. Am J Hum Genet. 2012;90:636-47.

Psychological and Psychiatric Disorders. The physical, emotional and social impact of psoriasis on quality of life is similar and sometimes even worse than that observed in patients with ischemic heart disease, cancer, arthritis and diabetes mellitus.⁴⁶46 Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999;41:401-7.^,4747 Tejada CS, Mendoza-Sassi RA, Almeida HL Jr, Figueiredo PN, Tejada VF. Impact on the quality of life of dermatological patients in southern Brazil. An Bras Dermatol. 2011;86:1113-21.

Psoriasis is associated with low self-esteem and prevalence of anxiety and depressive disorders (30% and 60%, respectively). Recently, a high prevalence of alexithymia was observed.⁴⁸48 Masmoudi J, Maalej I, Masmoudi A, Rached H, Rebai A, Turki H, et al. Alexithymia and psoriasis: a case-control study of 53 patients. Encephale. 2009;35:10-7. About 10% of patients with psoriasis consider the possibility of suicide.⁴⁹49 Krueger G, Koo J, Lebwohl M, Menter A, Stern RS, Rolstad T. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patientmembership survey. Arch Dermatol. 2001;137:280-4.

50 Esposito M, Saraceno R, Giunta A, Maccarone M, Chimenti S. An Italian study on psoriasis and depression. Dermatology. 2006;212:123-7.^-5151 Gupta MA, Gupta AK. Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis. Br J Dermatol. 1998;139:846-50. Recent data shows that depression and anxiety are mainly found in women with family problems.⁵²52 Campolmi E, Zanieri F, Santosuosso U, D'Erme AM, Betti S, Lotti T, et al. The importance of stressful family events in psoriatic patients: a retrospective study. J Eur Acad Dermatol Venereol. 2012;26:1236-9.

Psychological and emotional impact is not always related to the extent/severity of the cutaneous disease, although disease control may affect the course of depression. One study revealed that patients with psoriasis who were treated with etanercept showed significant decrease in severity/frequency of depressive episodes in parallel to decreased lesions.⁵³53 Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, et al. Etanercepte and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomized phase III trial. Lancet. 2006;367:29-35.

Cases of depression may bear direct resemblance to the pathophysiology of psoriasis, although they are more related to behavioral disorders that lead to seclusion and are imposed by skin lesions. Thus, the treatment of psoriasis may promote improvement of depression both due to psychodynamic issues and to the decreased TNFα production. It is therefore essential that psychosocial aspects are taken in to consideration during therapeutic decision-making processes.

Uveitis. Although psoriasis is associated with intraocular inflammatory disease, especially uveitis, only few studies have assessed the ophthalmic pathologies that accompany vulgar psoriasis. Its prevalence is around 2% in patients with cutaneous psoriasis.⁵⁴54 Fraga NA, Oliveira MF, Follador I, Rocha BO, Rego VR. Psoriasis and uveitis: a literature review. An Bras Dermatol. 2012;87:877-83.

Most publications available emphasizes its higher prevalence in males and patients with late onset of the disease. It is still associated with pustular psoriasis, PsA (especially axial PsA), and HLA-B27. Uveitis associated with psoriasis is generally insidious and, if left untreated, often leads to complications such as hypopyon, posterior synechiae and retinal vasculitis. Thus, although this ophthalmologic manifestation is not as frequent as others, it represents a significant problem due to its potential complications.⁵⁴54 Fraga NA, Oliveira MF, Follador I, Rocha BO, Rego VR. Psoriasis and uveitis: a literature review. An Bras Dermatol. 2012;87:877-83.^,5555 Oliveira MFSP, Rocha BO, Boeira VLSV, Fraga NAA Follador I, et al. Ophthalmic manifestations in psoriatic patients in a Brazilian referral center. In: 3rd World Psoriasis & Psoriatic Arthritis Conference 2012, Stockholm. New York: Springer Healthcare, 2012. v. 2. p. S24-S25. It is recommended, therefore, that physicians pay attention to ocular symptoms, and perform routine eye examination in these patients.⁵⁵55 Oliveira MFSP, Rocha BO, Boeira VLSV, Fraga NAA Follador I, et al. Ophthalmic manifestations in psoriatic patients in a Brazilian referral center. In: 3rd World Psoriasis & Psoriatic Arthritis Conference 2012, Stockholm. New York: Springer Healthcare, 2012. v. 2. p. S24-S25.

EMERGING COMORBIDITIES

Metabolic syndrome (MS). MS comprises a group of risk factors, including central obesity, dyslipidemia, hypertension and insulin resistance. A population-based study conducted in the UK has confirmed the association between psoriasis and MS. The greater the severity of psoriasis, the stronger this association is shown. In addition, associations with obesity, hypertriglyceridemia and hyperglycemia also increase with the severity of psoriasis, independently from other components of MS.⁵⁶56 Langan SM, Seminara NM, Shin DB, Troxel AB, Kimmel SE, Mehta NN, et al. Prevalence of metabolic syndrome in patients with psoriasis: A population-based study in the United Kingdom. J Invest Dermatol. 2012;132:556-62. The presence of MS is a strong predictor for the development of cardiovascular disease (CVD). Some studies have shown that cardiovascular comorbidities are more common in patients with psoriasis, and more exuberant in individuals with severe cutaneous involvement than in those with PsA.⁵⁷57 Tablazon IL, Al-Dabagh A, Davis SA, Feldman SR. Risk of cardiovascular disorders in psoriasis patients: current and future. Am J Clin Dermatol. 2013;14:1-7.

58 Arumugam R, McHugh NJ. Mortality and causes of death in psoriatic arthritis. J Rheumatol Suppl. 2012;89:32-5.^-5959 Mehta NN, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database. Eur Heart J. 2010;31:1000-6. Suppression of systemic inflammation with biological agents seems to positively affect risk factors for CVD.⁵⁸58 Arumugam R, McHugh NJ. Mortality and causes of death in psoriatic arthritis. J Rheumatol Suppl. 2012;89:32-5. Patients with severe psoriasis have a higher risk of CV mortality, independent of traditionally considered risk factors.⁶⁰60 Mehta NN, Yu Y, Pinnelas R, Krishnamoorthy P, Shin DB, Troxel AB, et al. Attributable risk estimate of severe psoriasis on major cardiovascular events. Am J Med. 2011;124:775.e1-6.

In a retrospective cohort of 3,603 patients with psoriasis who were using systemic therapy and 14,330 patients without psoriasis, severe psoriasis showed a hazard ratio of 1.53 after adjustments for age, sex, presence of diabetes, hypertension, dyslipidemia and smoking habits. This represents an attributable risk of 6.2% for the development of major cardiovascular events in 10 years. This finding is extremely important for the proper management of patients, since the risk predicted by the Framingham score, which only considers traditional risk factors, does not take into account emerging factors such as psoriasis.⁶¹61 Xue K, Liu H, Jian Q, Liu B, Zhu D, Zhang M, et al. Leptin induces secretion of proinflammatory cytokines by human keratinocytes in vitro - a possible reason for increased severity of psoriasis in patients with a high body mass index. Exp Dermatol. 2013;22:406-10.

Subsequently, another study used this attributable risk value, and recalculated the Framingham score in 138 patients with psoriasis. Initially, due to the low average age of the sample, the scores were relatively low (risk <10 %, mean of 7.4 in men and 5.9 in women), despite the high frequency of alcohol consumption, high smoking rates, body mass index (BMI) and dyslipidemia rates. However, they were reclassified as intermediate and high risk when the estimated attributable risk of 6.2% was considered (>10% in 10 years; mean of 13.9 in men and 12.4 in women).⁶⁰60 Mehta NN, Yu Y, Pinnelas R, Krishnamoorthy P, Shin DB, Troxel AB, et al. Attributable risk estimate of severe psoriasis on major cardiovascular events. Am J Med. 2011;124:775.e1-6.

In psoriasis, chronic inflammatory response with production of Th1 and Th17 cytokines promotes systemic inflammation. Proinflammatory cytokines such as TNFα and IL-6 may stimulate the hypothalamic-pituitary axis, which is admittedly associated with central obesity, hypertension and insulin resistance. Thus, psoriasis may aggravate obesity, diabetes, thrombosis and atherosclerosis. Likewise, these same conditions with production of inflammatory molecules such as IL-6, TNFα, plasminogen activation inhibitor (PAI -1) and some adipokines (leptin and resistin) induce a chronic pro-inflammatory state, contributing to the onset and/or worsening of psoriasis.⁶²62 Davidovici BB, Sattar N, Prinz J, Puig L, Emery P, Barker JN, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol. 2010;130:1785-96. PAI-1 levels (an antifibrinolytic protein produced in the liver and visceral fat) are related to CVD.⁶³63 Armstrong AW, Harskamp CT, Ledo L, Rogers JH, Armstrong EJ. Coronary artery disease in patients with psoriasis referred for coronary angiography. Am J Cardiol. 2012;109:976-80. Thus, these findings suggest that obesity could potentiate inflammatory pathways mediated by TNFα and IL-6 observed in psoriasis, leading to further decrease in glucose homeostasis, dyslipidemia, endothelial dysfunction and hypertension, with consequent increased cardiovascular risk due to the psoriatic inflammation. Patients with psoriasis for more than 8 years have a higher prevalence of coronary heart disease.⁶⁴64 Li WQ, Han JL, Manson JE, Rimm EB, Rexrode KM, Curhan GC, et al. Psoriasis and risk of nonfatal cardiovascular disease in U.S. women: a cohort study. Br J Dermatol. 2012;166:811-8.

Psoriasis is also a risk factor for CVD in women with long-standing disease and concomitant arthritis.⁶⁵65 Cohen AD, Gilutz H, Henkin Y, Zahger D, Shapiro J, Bonneh DY, et al. Psoriasis and the metabolic syndrome. Acta Derm Venereol. 2007;87:506-9. The link between psoriasis and its comorbidities is a state of chronic inflammation, common to these pathologies. Even after adjusting for risk factors for heart disease, such as smoking, diabetes, obesity, hypertension and hyperlipidemia, the probability of acute myocardial infarction factors is higher in patients with psoriasis than in the general population. Relative risk is especially higher in younger patients and in patients with more severe psoriasis.⁴4 Gelfand JM, Troxel AB, Lewis JD, Kurd SK, Shin DB, Wang X, et al. The risk of mortality in patients with psoriasis: results from a population-based study. Arch Dermatol. 2007 ;143:1493-9.

Obesity and production of proinflammatory cytokines are associated with clinical forms and severity of psoriasis. Although there is speculation about the actual role of obesity in the pathogenesis of psoriasis, there is evidence that adipokines, such as leptin, adiponectin and ghrelin are related to pathogenic mechanisms of obesity, since they are among the most important in the irregular deposit of fat and development of peripheral insulin resistance.⁶⁶66 Gisondi P, Tessari G, Conti A, Piaserico S, Schianchi S, Peserico A, et al. Prevalence of metabolic syndrome in patients with psoriasis: a hospital-based case-control study. Br J Dermatol. 2007;157:68-73.

In this sense, obesity could play some role in triggering psoriasis (based on the chronic proinflammatory state that it produces) or it could be a consequence of psoriasis, arising from metabolic disorders, added to the loss of quality of life and eating habits of individuals with this disease. The Nurses Health II study, with prospective data from 78,626 women followed for 14 years, identified obesity and weight gain as important risk factors for the development of psoriasis. Multivariate analysis showed that the relative risk would be higher in women with higher BMI.⁶⁷67 Setty AR, Curhan G, Choi HK. Obesity, waist circumference, weight change, and the risk of psoriasis in women: NURSES' health study II. Arch Intern Med. 2007;167:1670-5.

A study conducted at the Psoriasis Outpatient Clinic of the Federal University of Bahia demonstrated, like many other studies around the world, the association between obesity and psoriasis. In this study, the correlation among PASI (Psoriasis Area Severity Index) values, measures of BMI (R = 0.0154, p = 0.01), waist circumference (R = 0.207, p = 0.001), and waist-hip ratio (R = 0.164 , p = 0.007 ), as well as severe forms of psoriasis, PsA and facial involvement was observed.⁶⁸68 Duarte GV, Oliveira MF, Cardoso TM, Follador I, Silva TS, Cavalheiro CM, et al. Association between obesity measured by different parameters and severity of psoriasis. Int J Dermatol. 2013;52:177-81.

Some studies suggest that weight loss may improve or cause remission of psoriasis. However, weight loss alone may not be sufficient to control the disease.⁶⁹69 de Menezes Ettinger JE, Azaro E, de Souza CA, dos Santos Filho PV, Mello CA, Neves M Jr, et al. Remission of psoriasis after open gastric bypass. Obes Surg. 2006;16:94-7.

70 Farias MM, Achurra P, Boza C, Vega A, de la Cruz C. Psoriasis following bariatric surgery: clinical evolution and impact on quality of life on 10 patients. Obes Surg. 2012;22:877-80.

71 Del Giglio M, Gisondi P, Tessari G, Girolomoni G. Weight reduction alone may not be sufficient to maintain disease remission in obese patients with psoriasis: a randomized, investigator-blinded study. Dermatology. 2012;224:31-7.^-7272 Gisondi P, Targher G, Zoppini G, Girolomoni G. Non-alcoholic fatty liver disease in patients with chronic plaques psoriasis. J Hepatol. 2009;51:758-64. Many aspects of the association between obesity and psoriasis, such as the impact of obesity on response to treatment of psoriasis and the impact of anti-psoriatic drugs on metabolic syndrome, still need to be better elucidated by prospective, longitudinal studies. The first prospective, randomized study on the topic revealed a trend in the reduction of PASI and DLQI (Dermatology Life Quality Index) values of overweight patients with psoriasis after the adoption of a reduced-calorie diet. However, only the impact on the DLQI was statistically significant.⁷³73 Jensen P, Zachariae C, Christensen R, Geiker NR, Schaadt BK, Stender S, et al. Effect of weight loss on the severity of psoriasis: a randomized clinical study. JAMA Dermatol. 2013;149:795-801.

Non-Alcoholic Fat Liver Disease (NAFLD). Prevalence of NAFLD in patients with psoriasis ranges from 17-60%,⁷⁴74 Miele L, Vallone S, Cefalo C, La Torre G, Di Stasi C, Vecchio FM, et al. Prevalence, characteristics, and severity of non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. J Hepatol. 2009;51:778-86.

75 Madanagobalane S, Anandan S. The increased prevalence of non-alcoholic fatty liver disease in psoriatic patients: a study from South India. Australas J Dermatol. 2012;53:190-7.^-7676 Paschos P, Paletas K. Nonalcoholic fatty liver disease and metabolic syndrome. Hippokratia. 2009;13:9-19. and is even greater in patients with severe psoriasis and PsA.⁷⁴74 Miele L, Vallone S, Cefalo C, La Torre G, Di Stasi C, Vecchio FM, et al. Prevalence, characteristics, and severity of non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. J Hepatol. 2009;51:778-86. Similarly, Gisondi et al. speculated that NAFLD may contribute to the severity of psoriasis through the release of inflammatory mediators from the liver, including reactive oxygen species, CRP and IL-6, which also act as mediators of atherogenesis.⁷²72 Gisondi P, Targher G, Zoppini G, Girolomoni G. Non-alcoholic fatty liver disease in patients with chronic plaques psoriasis. J Hepatol. 2009;51:758-64.

Moreover, patients with psoriasis and NAFLD have higher risk of developing non-alcoholic steatohepatitis (NASH) and cirrhosis than patients with NAFLD without psoriasis.⁷⁴74 Miele L, Vallone S, Cefalo C, La Torre G, Di Stasi C, Vecchio FM, et al. Prevalence, characteristics, and severity of non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. J Hepatol. 2009;51:778-86.^,7777 Wenk KS, Arrington KC, Ehrlich A. Psoriasis and non-alcoholic fatty liver disease. J Eur Acad Dermatol Venereol. 2011;25:383-91. At least in part, progression of NAFLD to NASH is associated with an increase in the TNFα/adiponectin ratio.⁷⁴74 Miele L, Vallone S, Cefalo C, La Torre G, Di Stasi C, Vecchio FM, et al. Prevalence, characteristics, and severity of non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. J Hepatol. 2009;51:778-86.^,7878 Sanz LP. Psoriasis, a Systemic Disease? Actas Dermosifiliogr. 2007;98:396-402.

Lymphomas and other neoplasms. Although the majority of studies indicate a similar incidence of lymphoma among patients with psoriasis and the general population, more recent studies suggest a slightly more elevated risk in the first group.⁷⁹79 Kim N, Thrash B, Menter A. Comorbidities in psoriasis patients. Semin Cutan Med Surg. 2010;29:10-5.^,8080 Gelfand JM, Berlin J, Van Voorhees A, Margolis DJ. Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom. Arch Dermatol. 2003;139:1425-9. Gelfand et al. demonstrated that patients with psoriasis are three times more likely to develop lymphomas.⁸¹81 Gelfand JM, Shin DB, Neimann AL, Wang X, Margolis DJ, Troxel AB. The risk of lymphoma in patients with psoriasis. J Invest Dermatol. 2006;126:2194-201. However, we should point out that this study only included patients older than 65 years. Additionally, a small percentage of these individuals was receiving treatment with drugs that are known to elevate the risk of lymphoproliferative malignancies.⁸⁰80 Gelfand JM, Berlin J, Van Voorhees A, Margolis DJ. Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom. Arch Dermatol. 2003;139:1425-9.

Subsequently, a cohort of over 153,000 psoriasis patients of all age groups corroborated this association, although the relative risk found was much lower than previously thought (RR = 1.34). On the other hand, when various subtypes of the disease were considered, there was a high incidence of T-cell lymphomas and Hodgkin's lymphoma (RR = 10.75 and 3.18, respectively).⁸²82 Stern RS. Lymphoma risk in psoriasis: results of the PUVA follow-up study. Arch Dermatol. 2006;142:1132-5. The significance of these data is even enhanced in case of treatment with TNFα inhibitors⁸⁰80 Gelfand JM, Berlin J, Van Voorhees A, Margolis DJ. Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom. Arch Dermatol. 2003;139:1425-9. or high cumulative doses of methotrexate, as well as in patients with severe psoriasis.⁸³83 Hannuksela-Svahn A, Pukkala E, Laara E, Poikolainen K, Karvonen J. Psoriasis, its treatment, and cancer in a cohort of Finnish patients. J Invest Dermatol. 2000;114:587-90.^,8484 Lunder EJ, Stern RS. Merkel-cell carcinomas in patients treated with methoxsalen and ultraviolet A radiation. N Engl J Med. 1998;339:1247-8.

Brauchli et al., in a population-based study, found that patients with psoriasis have a higher risk of developing cancer of the hematopoietic system and pancreatic cancer than the general population. In addition, patients with long-standing diseases seem to have increased risk of developing colon, bladder and kidney cancer. This increased risk may be due to immunological mechanisms that are involved in the pathogenesis of psoriasis.⁸⁵85 Brauchli YB, Jick SS, Miret M, Meier CR. Psoriasis and risk of incident cancer: an inception cohort study with a nested case-control analysis. J Invest Dermatol. 2009;129:2604-12. Increased risk of skin cancer (melanoma and nonmelanoma) was not demonstrated. However, there are subpopulations with definitely increased risk of skin cancer, such as: white individuals who received more than 250 PUVA sessions. These individuals have a fourteen times greater risk of developing squamous-cell carcinoma than patients who received fewer sessions.⁸⁶86 Stern RS, Laird N. The carcinogenic risk of treatments for severe psoriasis. Photochemotherapy Follow-up Study. Cancer. 1994;73:2759-64.^,8787 Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet. 2007;370:263-71. Treatments like PUVA, methotrexate and cyclosporine in high doses may also be associated with carcinogenesis.⁸⁸88 Herrinton LJ, Liu L, Chen L, Harrold LR, Raebel MA, Curtis JR, et al. Association between anti-TNF-α therapy and all-cause mortality. Pharmacoepidemiol Drug Saf. 2012;21:1311-20.

Obstructive Sleep Apnea/Hypopnea (OSAHS) syndrome. Information in the literature on the relationship between OSAHS and psoriasis is scarce and inconsistent. Available data suggest a higher prevalence in relation to the general population.⁸⁹89 Buslau M, Benotmane K. Cardiovascular complications of psoriasis: Does obstructive sleep apnoea play a role? Acta Derm Venereol. 1999;79:234. In comparison with patients with other dermatoses and individuals with chronic bronchitis, individuals with psoriasis have a higher prevalence of OSAHS.⁸⁹89 Buslau M, Benotmane K. Cardiovascular complications of psoriasis: Does obstructive sleep apnoea play a role? Acta Derm Venereol. 1999;79:234.^,9090 Larsson LG, Lundback B, Jonsson AC, Lindstrom M, Jonsson E. Symptoms related to snoring and sleep apnoea in subjects with chronic bronchitis: Report from the obstructive lung disease in Northern Sweden study. Respir Med. 1997;91:5-12. It is believed that this association is due to the increased prevalence of obesity in these individuals, although the participation of inflammatory mediators cannot be excluded.⁹⁰90 Larsson LG, Lundback B, Jonsson AC, Lindstrom M, Jonsson E. Symptoms related to snoring and sleep apnoea in subjects with chronic bronchitis: Report from the obstructive lung disease in Northern Sweden study. Respir Med. 1997;91:5-12.

Chronic Obstructive Pulmonary Disease (COPD). In an Israeli study, prevalence of COPD in patients with psoriasis was 5.7%, whereas in the control group it was estimated to be 3.7% (p <0.001).⁹¹91 Dreiher J, Weitzman D, Shapiro J, Davidovici B, Cohen AD. Psoriasis and chronic obstructive pulmonary disease: A case-control study. Br J Dermatol. 2008;159:956-60. Similar results were also obtained in the Chinese population.⁹²92 Chiang YY, Lin HW. Association between psoriasis and chronic obstructive pulmonary disease: a population-based study in Taiwan. J Eur Acad Dermatol Venereol. 2012;26:59-65. Nevertheless, although these studies controlled for confounding variables such as smoking, age, gender, obesity, they are still only a small number of studies conducted in restricted populations.

Osteoporosis. Not only TNFα but also IL-6 acts by stimulating bone reabsorption. Elevated levels of these cytokines are found in menopausal women and in children with idiopathic osteoporosis.⁹³93 Kastelan D, Kastelan M, Massari LP, Korsic M. Possible association of psoriasis and reduced bone mineral density due to increased TNF-alpha and IL-6 concentrations. Med Hypotheses. 2006;67:1403-5. Millard et al. observed no statistically significant difference between the Z-score of lumbar vertebrae of individuals with and without psoriasis. However, among psoriatic patients, those with arthropathy showed lower bone density.⁹⁴94 Millard TP, Antoniades L, Evans AV, Smith HR, Spector TD, Barker JN. Bone mineral density of patients with chronic plaque psoriasis. Clin Exp Dermatol. 2001;26:446-8.

In the casuistry of Hofbauer et al., One third of patients with PsA had reduced bone density, and osteoporosis was about 6 times more frequent in men.⁹⁵95 Hofbauer LC, Schoppet M, Christ M, Teichmann J, Lange U. Tumour necrosis factor- related apoptosis-inducing ligand and osteoprotegerin serum levels in psoriatic arthritis. Rheumatology (Oxford). 2006;45:1218-22. This discovery is similar to the findings of a subsequent study, which identified increased prevalence of osteoporosis in both genders. This, however, is statistically significant only for men.⁹⁶96 Dreiher J, Weitzman D, Cohen AD. Psoriasis and osteoporosis: a sex-specific association? J Invest Dermatol. 2009;129:1643-9. Bone mass loss in PsA still seems to be related to the duration of the disease, its severity (measured by PASI) and the number of joints affected.⁹⁷97 Attia EA, Khafagy A, Abdel-Raheem S, Fathi S, Saad AA. Assessment of osteoporosis in psoriasis with and without arthritis: correlation with disease severity. Int J Dermatol. 2011;50:30-5.

In a study with post/menopausal women, Pedreira et al. observed similarity in bone density among healthy controls, individuals with psoriasis and individuals with PsA. However, osteoporotic fractures were more common in patients with psoriasis and PsA.⁹⁸98 Pedreira PG, Pinheiro MM, Szejnfeld VL. Bone mineral density and body composition in postmenopausal women with psoriasis and psoriatic arthritis. Arthritis Res Ther. 2011;13:R16.

It is clear, therefore, that the data in the literature are controversial, because some authors still advocate that there is no association between psoriasis and osteoporosis.⁹⁹99 Grazio S, Cvijetić S, Vlak T, Grubišić F, Matijević V, Nemčić T, et al. Osteoporosis in psoriatic arthritis: is there any? Wien Klin Wochenschr. 2011;123:743-50.

Erectile Dysfunction. Current evidence suggests there is a higher prevalence of sexual dysfunction in individuals with psoriasis and, as expected, those with genital lesions suffer an even greater negative impact.⁸8 Goulding JM, Price CL, Defty CL, Hulangamuwa CS, Bader E, Ahmed I. Erectile dysfunction in patients with psoriasis: increased prevalence, an unmet need, and a chance to intervene. Br J Dermatol. 2011;164:103-9.^,100100 Turel Ermertcan A, Temeltaş G, Deveci A, Dinc G, Guler HB, Ozturkcan S. Sexual dysfunction in patients with psoriasis. J Dermatol. 2006;33:772-8.

Psoriasis has a deleterious effect on the overall quality of life and on the sexual life of individuals, although there is no consensus whether it constitutes an independent risk factor for erectile dysfunction.⁸8 Goulding JM, Price CL, Defty CL, Hulangamuwa CS, Bader E, Ahmed I. Erectile dysfunction in patients with psoriasis: increased prevalence, an unmet need, and a chance to intervene. Br J Dermatol. 2011;164:103-9.^,101101 Meeuwis KA, de Hullu JA, van de Nieuwenhof HP, Evers AW, Massuger LF, van de Kerkhof PC, et al. Quality of life and sexual health in patients with genital psoriasis. Br J Dermatol. 2011;164:1247-55. Its association is probably due to incipient pelvic atherosclerosis, and it is, thus, an early predictor of cardiovascular disease that is notably frequent in patients with psoriasis.⁸8 Goulding JM, Price CL, Defty CL, Hulangamuwa CS, Bader E, Ahmed I. Erectile dysfunction in patients with psoriasis: increased prevalence, an unmet need, and a chance to intervene. Br J Dermatol. 2011;164:103-9.^,102102 Reynolds OD. Erectile dysfunction in etretinate treatment. Arch Dermatol. 1991;127:425-6. Depression does not seem to have an additional negative effect on the sexual dysfunction of men with psoriasis.⁹⁵95 Hofbauer LC, Schoppet M, Christ M, Teichmann J, Lange U. Tumour necrosis factor- related apoptosis-inducing ligand and osteoprotegerin serum levels in psoriatic arthritis. Rheumatology (Oxford). 2006;45:1218-22. Decreased libido and erectile dysfunction have been reported during use of methotrexate.¹⁰³103 Wylie G, Evans CD, Gupta G. Reduced libido and erectile dysfunction: rarely reported side-effects of methotrexate. Clin Exp Dermatol. 2009;34:e234. Retinoids are related to sexual dysfunctions both in humans and in animals.¹⁰²102 Reynolds OD. Erectile dysfunction in etretinate treatment. Arch Dermatol. 1991;127:425-6.^,104104 Rossi M, Pellegrino M. Acitretin-associated erectile dysfunction: a case report. Cases J. 2009;2:210. At present, it is recommended that the cardiovascular risk of patients with documented erectile dysfunction should be evaluated more carefully.

Parkinson's Disease. Recently, it was observed that patients with psoriasis are more likely to develop Parkinson's disease. However, the influence of psoriasis severity, lifestyle habits and individual factors on the risk of developing the disease has not yet been established.¹⁰⁵105 Sheu JJ, Wang KH, Lin HC, Huang CC. Psoriasis is associated with an increased risk of parkinsonism: a population-based 5-year follow-up study. J Am Acad Dermatol. 2013;68:992-9.

COMORBIDITIES RELATED TO LIFESTYLE AND TREATMENTS

Patients with psoriasis have a higher frequency of smoking and drinking habits, which also contributes to an increased risk of cardiovascular disease.¹⁰⁶106 Higgins E. Alcohol, smoking and psoriasis. Clin Exp Dermatol. 2000;25:107-10.

107 Poikolainen K, Reunala T, Karvonen J, Lauharanta J, Karkkainen P. Alcohol intake: a risk factor for psoriasis in young and middle aged men? BMJ. 1990;300:780-3.

108 Poikolainen K, Karvonen J, Pukkala E. Excess mortality related to alcohol and smoking among hospital-treated patients with psoriasis. Arch Dermatol. 1999;135:1490-3.^-109109 Naldi L, Chatenoud L, Linder D, Belloni Fortina A, Peserico A, Virgili AR, et al. Cigarette smoking, body mass index, and stressful life events as risk factors for psoriasis: results from an Italian case-control study. J Invest Dermatol. 2005;125:61-7. Smoking habits are strongly associated with pustular forms of psoriasis. The risk of developing the disease is 70% higher in smokers compared to nonsmokers.¹⁰³103 Wylie G, Evans CD, Gupta G. Reduced libido and erectile dysfunction: rarely reported side-effects of methotrexate. Clin Exp Dermatol. 2009;34:e234.^,110110 Fortes C, Mastroeni S, Leffondre K, Sampogna F, Melchi F, Mazzotti E, et al. Relationship between smoking and the clinical severity of psoriasis. Arch Dermatol. 2005;141:1580-4. The effect of tobacco would only be nullified after twenty years of abstinence.⁸⁶86 Stern RS, Laird N. The carcinogenic risk of treatments for severe psoriasis. Photochemotherapy Follow-up Study. Cancer. 1994;73:2759-64. The prevalence of psoriasis is increased among patients who abuse alcohol, and alcohol consumption is associated with increased risk of hepatic steatosis, cirrhosis, depression and anxiety, and decreased response to psoriasis treatments.⁶6 Gisondi P, Targher G, Zoppini G, Girolomoni G. Non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. J Hepatol. 2009;51:758-64.^,8888 Herrinton LJ, Liu L, Chen L, Harrold LR, Raebel MA, Curtis JR, et al. Association between anti-TNF-α therapy and all-cause mortality. Pharmacoepidemiol Drug Saf. 2012;21:1311-20.^,111111 Wolk K, Mallbris L, Larsson P, Rosenblad A, Vingard E, Stahle M. Excessive Body Weight and Smoking Associates with a High Risk of Onset of Plaque Psoriasis. Acta Derm Venereol. 2009;89:492-7.^,112112 Mrowietz U, Elder JT, Barker J. The importance of disease associations and concomitant therapy for the long-term management of psoriasis patients. Arch Dermatol Res. 2006;298:309-19. Studies have associated alcohol consumption with worsening of psoriasis.⁸⁵85 Brauchli YB, Jick SS, Miret M, Meier CR. Psoriasis and risk of incident cancer: an inception cohort study with a nested case-control analysis. J Invest Dermatol. 2009;129:2604-12.^,107107 Poikolainen K, Reunala T, Karvonen J, Lauharanta J, Karkkainen P. Alcohol intake: a risk factor for psoriasis in young and middle aged men? BMJ. 1990;300:780-3.

It must be said that the classical systemic drugs used in the treatment of psoriasis may worsen comorbidities in these patients and often disable their use.¹¹³113 Gupta MA, Schork NJ, Gupta AK, Kirkby S, Ellis CN. Suicidal ideation in psoriasis. Int J Dermatol. 1993;32:188-90.

114 Vena GA, Vestita M, Cassano N. Psoriasis and cardiovascular disease. Dermatol Ther. 2010;23:144-51.^-115115 Barker J, Horn EJ, Lebwohl M, Warren RB, Nast A, Rosenberg W, et al. Assessment and management of methotrexate hepatotoxicity in psoriasis patients: report from a consensus conference to evaluate current practice and identify key questions toward optimizing methotrexate use in the clinic. J Eur Acad Dermatol Venereol. 2011;25:758-64. Cyclosporine is nephrotoxic and may cause hypertension and dyslipidemia. Conditions associated with obesity (such as NAFLD) are contraindications to the use of methotrexate. Diabetics, alcoholics and obese patients have a higher risk of developing liver fibrosis. Acitretin may cause dyslipidemia and hepatotoxici-ty.¹¹⁴114 Vena GA, Vestita M, Cassano N. Psoriasis and cardiovascular disease. Dermatol Ther. 2010;23:144-51. On the other hand, some drugs used to treat these conditions have a recognized potential to worsen psoriasis.¹¹⁵115 Barker J, Horn EJ, Lebwohl M, Warren RB, Nast A, Rosenberg W, et al. Assessment and management of methotrexate hepatotoxicity in psoriasis patients: report from a consensus conference to evaluate current practice and identify key questions toward optimizing methotrexate use in the clinic. J Eur Acad Dermatol Venereol. 2011;25:758-64.

PRACTICAL CONSIDERATIONS

When dealing with a patient with psoriasis and especially before choosing a systemic therapy, it is important to make a checklist to detect comorbidities and lifestyle factors (e.g.: smoking habits and alcoholism); to make a clinical examination (body weight, height, BMI, waist circumference) and an ophthalmologic examination; to assess the severity of psoriasis (PASI and DLQI); and to request laboratory tests (blood glucose, lipidogram, liver profile and renal function). The physician should also encourage healthy lifestyles. We suggest the application of scales to assess anxiety and depression, and the questioning about sexual dysfunction during history-taking.¹¹⁶116 Dauden E, Castaneda S, Suarez C, Garcia-Campayo J, Blasco AJ, Aguilar MD, et al. Clinical practice guideline for an integrated approach to comorbidity in patients with psoriasis. J Eur Acad Dermatol Venereol. 2013;27:1387-404.^,117117 Ladizinski B, Federman DG. Approaching erectile dysfunction in dermatology patients. JAMA Dermatol. 2013;149:783-4.

Therapeutic decision should be discussed with the patient, taking into account his/her comorbidities and lifestyle. Regardless of the treatment chosen, it is important to remember that, since emotional stress is a triggering and exacerbating factor for psoriasis, activities such as yoga, meditation and relaxation exercises are recommended.¹¹⁸118 Basavaraj KH, Navya MA, Rashmi R. Stress and quality of life in psoriasis: an update. Int J Dermatol. 2011;50:783-92. Patients should not only receive individualized drug therapy, but also nutritional guidance.¹¹⁹119 Duarte GV, Follador I, Cavalheiro CM, Silva TS, Oliveira MF. Psoriasis and obesity: literature review and recommendations for management. An Bras Dermatol. 2010;85:355-60. General recommendations include a hypocaloric diet with low-glycemic index foods and rich in polyunsaturated fatty acids. Some studies have shown benefit in the adoption of a vegetarian diet rich in omega-3, vitamin C, flavonoids, carotenoids and tocopherols. Gluten should only be removed from the diet of positive anti-gliadin/transglutaminase antibodies subjects, specially if symptomatic. Supplementation of specific nutrients should be evaluated case by case.¹²⁰120 Duarte G, Barbosa LO, Rosa ME. The management of psoriasis through diet. Psoriasis: Targets and Therapy. 2012:2 45-53.

CONCLUSION

Evidence increasingly suggest that there is a relation between psoriasis and several comorbidities. Affected patients show higher mortality and hospitalization rates, which indicates the need for a multidisciplinary approach in the management of these patients.

Finally, the integral approach of psoriasis should include the identification of cardiovascular risk factors and metabolic diseases, the adaption of treatments to the existing comorbidities, as well as the evaluation of existing psychological/psychiatric disorders, in order to achieve a long-term control of the disease and improve the cumulative quality of life. Early and aggressive treatment of severe psoriasis, PsA and associated comorbidities may influence the well-being and probably the longevity of patients.

QUESTIONS

a) NMR.

b) Anti-CCP antibody test.

c) Ultrasonography.

d) Scintigraphy.

a) More severe forms of psoriasis and higher PASI scores.

b) Psoriasis of early onset, with a peak in the second decade of life.

c) Higher mortality than expected for healthy population.

d) Negative rheumatoid factor in nearly 100% of cases.

a) Lower frequency in obese subjects, in contrast to osteoarthritis.

b) Change in the cellular immunity mechanism, without association to humoral immunity factors.

c) Nail forms are the most commonly associated with arthritis, followed by plaque forms.

d) Arthritis may precede cutaneous manifestations in 15% of cases.

a) Methotrexate and leflunomide represent excellent value for money in axial forms, as well as in other spondyloarthropathies

b) Superiority of infliximab over other anti-TNFα agents was confirmed in the treatment of peripheral forms.

c) Intra-articular injections and NSAIDs are not part of the treatment due to low efficacy and significant potential side effects.

d) Arthritis is called refractory only after treatment with one or more DMARDs over a period of 3 months.

a) Patients with psoriasis and Crohn's disease are more likely to develop lymphomas than patients with psoriasis alone.

b) There is no evidence of a genetic basis that justify this association.

c) Ulcerative colitis is not associated with psoriasis.

d) Patients with psoriasis have the same risks of developing Crohn's disease as the general population, although with more severe forms of the disease.

a) The observed disorders are predominantly psychotic.

b) Suicidal ideation is uncommon.

c) Women with family problems are more affected.

d) It is proportional to the severity of cutaneous disease.

a) Psychodynamic aspects fully explain this association.

b) Elevation of TNFα is observed in depressed patients, even without psoriasis.

c) Control of the skin disease does not seem to affect the course of depression.

d) None of the above.

a) Arthropathic and pustular psoriasis (particularly with axial involvement).

b) Male gender.

c) HLA-B27.

d) All of the above.

a) Its onset is sudden, and there is no need for routine ophthalmologic examination in these patients.

b) Early-onset and long-term illness is a risk factor.

c) Although relatively rare, it presents potential complications if left untreated.

d) It occurs in approximately 10% of patients at some point in life.

a) Traditional risk factors are sufficient.

b) Psoriasis is an independent risk factor for cardiovascular events.

c) There is no established correlation between the severity of cutaneous/joint clinical picture and cardiovascular comorbidities.

d) There is greater cardiovascular morbidity when compared to the general population, although mortality is practically the same.

a) is higher in elderly with prevalence of joint disease.

b) is higher in young people with early onset of the skin disease.

c) is equivalent among subjects with and without arthritis.

d) is slightly increased when compared to the general population, but has no statistical significance.

a) May show improvement or remission of disease with weight loss.

b) Are as frequently affected by arthritis as non-obese patients.

c) Achieve the same benefits as nonobese patients in the systemic treatment of psoriasis with standard doses as nonobese.

d) None of the above.

a) Occurs with similar frequency among patients with and without psoriasis, although with different severity and evolution.

b) Occurs equally among psoriatic patients with and without arthritis.

c) May cause an increase in the inflammatory status, although it is insignificant in individuals with severe psoriasis.

d) May contribute to the severity of psoriasis.

a) Increase in the TNFα/adiponectin ratio.

b) Erythrodermic psoriasis.

c) Pustular psoriasis.

d) All of the above.

a) It seem to be slightly increased when compared to the healthy population.

b) There is an increase in its incidence with the use of high cumulative doses of methotrexate.

c) There is a decrease in incidence with the use of immunobiologicals.

d) It is more likely in severe psoriasis.

a) may be increased due to treatment.

b) is only relevant for squamous cell carcinoma, given the hyper-proliferation of keratinocytes in the psoriatic plaque.

c) is significant for lymphomas and cutaneous neoplasias (melanoma e non-melanoma)

d) None of the above.

a) The sleep apnea/hypopnea syndrome (SAHS) can be fully explained by the high frequency of obesity in these individuals.

b) Chronic obstructive pulmonary disease occurs in about 6% of patients in the case series in the literature.

c) It is likely that inflammatory mediators have a contribution in the occurrence of SAHS.

d) The large number of studies in the literature on the topic makes it possible to give details on this association.

a) Osteoporotic fractures are as common in individuals with arthritis as in individuals without arthritis.

b) There seems to be a predilection for males.

c) The severity of the skin disease does not seem to influence the occurrence of osteoporosis.

d) Prophylaxis with vitamin D and calcium should be instituted for all patients with arthropathic psoriasis.

a) is dramatically affected by mood disorders such as depression.

b) is an early predictor of cardiovascular disease.

c) is independent of the treatment used for the skin disease.

d) is more frequent in the presence of visible lesions, in patients with seclusion behavior and depressed mood.

a) They worsen psoriasis lesions but do not interfere with the efficiency of classic treatments.

b) Smokers have a 70% higher risk of developing psoriasis than the general population.

c) Smoking habit is equally associated with all forms of psoriasis.

d) None of the above.

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