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The contribution of perceptions of stigmatisation to disability in patients with psoriasis.

OBJECTIVE: The aim of the present study was to assess the significance of general and psoriasis specific psychological variables in patients with psoriasis and to examine the relative importance of disease status and these psychological variables in predicting psoriasis-related disability. METHOD: A total of 115 patients with psoriasis underwent clinical assessment and completed a number of psychological and psoriasis specific questionnaires. RESULTS: High levels of self-reported distress were identified with 43% and 10% of patients scoring as probable cases on the Hospital Anxiety and Depression Scale (HADS) subscales of anxiety (mean 9.3+/-4.9) and depression (mean 4.8+/-3.7), respectively. Multiple regression analysis indicated that clinical severity of psoriasis and anatomical area of involvement had no impact on psychological distress and disability. Perceptions of stigmatisation were significantly related to both psychological distress and degree of disability (P's<.001) and accounted for a significant amount of the variance in disability over and above general psychological distress (F change=11.03; P<.001). CONCLUSION: Psychological factors were much stronger determinants of disability in patients with psoriasis than disease severity, location or duration. This has important implications in relation to the clinical management of psoriasis.

Adolescent↗

[Severe psoriasis: 160 cases].

INTRODUCTION: Psoriasis is a frequent dermatosis, its prevalence is estimated of between 1 and 3 p. 100. The severe forms may threaten the functional and life prognosis of patients. PATIENTS AND METHODS: We conducted a retrospective study on 160 cases of severe psoriasis collected between 1990 and 2001. We included patients exhibiting severe psoriasis: pustular, erythrodermic or arthropathic psoriasis, the generalized forms that had developed for more than 6 months, without positive response to treatment and the forms with a PASI greater than 50. RESULTS: The patients' ages ranged from 6 to 85 years with a clear male predominance (96 men, 64 women). Nine familial cases were collected. Erythroderma was noted in 87 cases, pustular psoriasis in 31, generalized psoriasis in 31 and psoriatic rheumatism in 15 (4 of which were associated with pustular psoriasis). Local treatment with topical corticosteroids or a Vitamin D derivative was recommended in respectively 41.8 and 13.75 p. 100 of cases. The administration of general treated relied on methotrexate and was required in 68.75 p. 100 of cases. Progression was usually good, relapses were often noted when treatment was stopped. Four patients died. DISCUSSION: Although the diagnosis of psoriasis is often easy, the severe forms are still difficult to treat. Treatment is complicated, sometimes disappointing and often necessitates heavy and aggressive treatments that require strict surveillance.

Administration, Topical↗

Immunofluorescence in psoriasis: a clinical study of sixty patients.

Direct immunofluorescent microscopy was positive on skin biopsy specimens in thirty-one of sixty patients with various forms of psoriasis. Patients with positive immunofluorescence were classified into five main clinical subgroups: (1) psoriasis vulgaris with decreased tolerance to sunlight or ultraviolet light B (eight patients), (2) psoriatic arthritis (seven patients), (3) guttate psoriasis (five patients), (4) pustular psoriasis (four patients), and (5) "uncomplicated" psoriasis vulgaris (seven patients). Various patterns of deposition of immunoglobulins, complement, and fibrin were seen in the five subgroups, the most consistent being granular C3 at the basement membrane zone in specimens from five of the seven patients with guttate psoriasis. Direct immunofluorescent microscopy was usually negative in psoriasis vulgaris, but positive results may be anticipated in special forms of psoriasis.

Biopsy↗

Vitiligo and psoriasis.

The concurrence of vitiligo and psoriasis in a single patient has previously been considered unusual. The clustering of seven such patients at our institution over the past 3 years prompted a literature review. Only eighteen well-documented cases could be found, although the incidence of psoriasis in larger series of vitiligo patients seems greater than the isolated case reports would indicate. The occasional tendency of psoriasis to start in, or remain confined to, areas of vitiligo, as well as a purported resistance of dark skin to psoriasis, has tempted some to conclude that depigmented skin may be predisposed to psoriasis. This tendency, however, was not observed in our seven cases or in the majority of previously reported cases. Immunologic phenomena abound in both vitiligo and psoriasis, and the incidence of immunologic phenomena may be increased in patients with both diseases. These phenomena, however, are too dissimilar to draw any conclusions regarding pathogenetic links between vitiligo and psoriasis. The workup of our seven cases, including complete blood cell count and differential, platelet count, VDRL, SMA 18, antinuclear antibodies, thyroid function studies, antithyroid antibodies, urinalysis, eye examination, and skin biopsies, did not further elucidate any possible relationship between vitiligo and psoriasis.

Adult↗

Human in vivo phosphorus 31 magnetic resonance spectroscopy of psoriasis. A noninvasive tool to monitor response to treatment and to study pathophysiology of the disease.

BACKGROUND: There is no objective laboratory technique to measure and to monitor disease activity in psoriasis. OBJECTIVE: We assessed the effectiveness of using phosphorus 31 (31P) magnetic resonance spectroscopy (MRS) to noninvasively monitor metabolism in psoriasis and to compare these spectroscopic data with chromatographic analysis. METHODS: Fourteen persons were enrolled in the study. 31P magnetic resonance spectra were obtained from skin of persons without skin disease, uninvolved psoriatic skin, nonpsoriatic erythroderma, and from skin of patients with psoriasis. In three patients with psoriasis 31P magnetic resonance spectra were repeated after treatment with methotrexate, UVB, etretinate, and topical steroids. Finally, shave biopsy specimens were obtained from two patients with psoriasis and submitted for chromatographic evaluation. RESULTS: In patients with severe psoriasis, in comparison with the control group, elevations in phosphomonoester concentrations and in the phosphomonoester/phosphodiester ratio were observed. These appear to be useful markers to monitor treatment response in patients with psoriasis. Finally, 31P MRS data in conjunction with chromatographic analysis indicated a defect in phosphometabolism in psoriatic skin. However, it is unclear whether this defect is a cause or an epiphenomenon of the disease. CONCLUSION: 31P MRS appears to be a sensitive, noninvasive technique to monitor disease activity in psoriasis. Further studies to characterize the defect in phosphometabolism in psoriatic skin are warranted.

Adenosine Triphosphate↗

Are lipoprotein profile and lipoprotein (a) levels altered in men with psoriasis?

BACKGROUND: Previous studies have demonstrated that patients with psoriasis may have an increased risk of a variety of noncutaneous diseases, including arterial and venous occlusive diseases. Changes in plasma lipid and lipoprotein composition in patients with psoriasis may be the reason for the increased risk of atherosclerosis in these patients. Lipoprotein (a) (Lp(a)) is a genetically determined lipoprotein associated with an increased prevalence of atherosclerotic and thrombotic cardiovascular diseases. OBJECTIVE: The aim of this prospective study was to determine the lipid profile and to define the significance of Lp(a) levels in men with psoriasis. The other purpose was to learn whether a correlation exists between psoriasis area and severity index score and serum Lp(a) or other lipids. METHODS: Serum Lp(a) levels were measured with a commercially available noncompetitive enzyme-linked immunosorbent assay in 32 men with psoriasis and in 13 healthy men. Total serum cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, apolipoprotein A-I and apolipoprotein B levels, and atherosclerotic risk factors other than hyperlipidemia were determined. Secondary hyperlipidemia from various diseases and drugs was ruled out in both groups. RESULTS: Serum Lp(a) levels were higher in men with psoriasis than in healthy male subjects, but the difference was not significant (p = 0.063). Serum fasting glucose levels were also found to be higher in the psoriasis group (p < 0.05). Higher serum Lp(a) and fasting glucose levels tended to occur in patients with extensive and severe skin involvement. No statistical differences were observed in the total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, apolipoprotein A-I, and apolipoprotein B levels between the two groups (p > 0.05). CONCLUSION: Our results suggest that the increased Lp(a) level might be a factor involved in occlusive vascular disorders in patients with psoriasis and that patients with extensive and severe skin involvement are more predisposed to relatively high Lp(a) levels.

Adolescent↗

Psoriasis causes as much disability as other major medical diseases.

BACKGROUND: Little is known about how the health-related quality of life (HRQL) associated with psoriasis compares with that of other patient populations. OBJECTIVE: We describe HRQL associated with psoriasis and compare it with HRQL of patients with other major chronic health conditions. A second aim is to identify which specific aspects of psoriasis contribute most to HRQL. METHODS: A total of 317 patients completed a non-disease-specific measure of HRQL. Responses were compared with those of patients with 10 other chronic health conditions. HRQL was regressed on ratings of 18 aspects of psoriasis. RESULTS: Patients with psoriasis reported reduction in physical functioning and mental functioning comparable to that seen in cancer, arthritis, hypertension, heart disease, diabetes, and depression. Six aspects of psoriasis predicted physical functioning, and 5 different disease aspects predicted mental functioning. CONCLUSION: The impact of psoriasis on HRQL is similar to that of other major medical diseases. Different aspects of psoriasis are related to the different dimensions of HRQL supporting the need for multidimensional treatment models.

Adult↗

Overlapping cases with psoriasis and Sjögren syndrome: a study of lymphocyte response to staphylococcal enterotoxin B.

Sjgren syndrome (SjS) is an auto-immune disease and immunological mechanisms have recently been suggested in the pathogenesis of psoriasis; however, co-existence of these diseases is relatively rare. To determine whether or not there exist the nature of common underlying abnormalities, five patients with psoriasis and SjS were studied. Two patients had psoriasis vulgaris (PV), two had psoriasis arthropathica (PA), and the other had generalized pustular psoriasis (GPP). Lymphocyte response against staphylococcal enterotoxin B was examined by 3H-thymidine incorporation. In one patient with GPP, T-cell receptor (TCR) V beta repertoire of infiltrating T-cells into the lesional skin was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Stimulation index (S.I.) level of patients with psoriasis and SjS did not show any significant increases compared with patients with psoriasis or SjS alone; however, one patient with PV and SjS, who showed several serological immune imbalances, demonstrated a significant increase of S.I. level. Analysis of TCR V beta repertoire of the lesion of GPP showed strong expression of V beta 14 and 16 with mild expression of V 13-2 and 19, which may suggest that TCR V beta repertoire became oligoclonal in case of complication of these two disorders. In conclusion, our data did not suggest any common immunological responses to staphylococcal enterotoxin in induction of both psoriasis and SjS.

Adult↗

Diagnosis: psoriasis or not? What are the clues?

Psoriasis is a common inflammatory, hyperproliferative skin disorder that affects 1% to 2% of the population of Western Europe and the United States. Because the clinical presentation of psoriasis is varied, many times the definitive diagnosis depends on the histological examination. However, the histological changes of psoriasis are as varied as the clinical presentations. Therefore, a combination of histopathologic features must be present for the diagnosis of psoriasis to be made. In this article, we review the clues for the histopathologic diagnosis of each type and stage of psoriasis, such as psoriasis vulgaris, pustular psoriasis, and erythrodermic psoriasis, as well as the histopathologic differential diagnosis of these entities.

Diagnosis, Differential↗

Corneodesmosin expression in psoriasis vulgaris differs from normal skin and other inflammatory skin disorders.

SUMMARY: Corneodesmosin (Cdsn) is a late differentiation epidermal glycoprotein putatively involved in keratinocyte adhesion. The Cdsn gene lies within the susceptibility region on chromosome 6p21.3 (PSORS1) for psoriasis, a common chronic disfiguring skin disease. A particular allelic variant of Cdsn has a strong association with psoriasis. Therefore, genetically and biologically, Cdsn is a possible candidate gene for psoriasis susceptibility. To investigate a potential role for Cdsn in psoriasis pathogenesis, protein expression studies were performed by quantitative immunohistochemistry on normal skin, psoriatic skin (lesional and nonlesional), and other skin disorders using monoclonal antibodies (G36-19 and F28-27). In normal and nonlesional skin, Cdsn was expressed in stratum corneum and one or two layers of superficial stratum granulosum. In lesional psoriasis, there was a significant increase in Cdsn expression, which was observed in multiple layers of stratum spinosum and in stratum corneum. The expression pattern varied from granular, cytoplasmic immunoreactivity to cell surface labeling with weakly immunoreactive cytoplasm. In chronic atopic dermatitis, lichen planus, mycosis fungoides, and pityriasis rubra pilaris, Cdsn immunoreactivity was confined to stratum corneum and upper stratum granulosum with no stratum spinosum immunoreactivity. Immunoelectron microscopy of normal and lesional psoriatic skin demonstrated Cdsn release concomitant with involucrin incorporation into cell envelopes and completed before mature envelope formation. Extracellular release of Cdsn occurred at a lower level of the epidermis in psoriasis than normal skin. These protein expression studies provide evidence of altered Cdsn expression in psoriasis consistent with a role of Cdsn in disease pathogenesis. Further functional and genetic studies of Cdsn are justified to determine its role as a potential psoriasis-susceptibility factor.

Chromosomes, Human, Pair 6↗

HLA-C expression pattern is spatially different between psoriasis and eczema skin lesions.

Interactions between genetic and environmental factors underlie the immune dysregulation and keratinocyte abnormalities that characterize psoriasis. Among known psoriasis susceptibility loci (PSORS), PSORS1 on chromosome 6 has the strongest association to disease. Altered expression of some PSORS1 candidate genes has been reported but little is known about HLA-C expression in psoriasis. This study compared expression of major histocompatibility complex class Ia and HLA-C in psoriasis, allergic contact eczema, and normal skin. Although HLA-C was abundant in protein extracts from both eczema and psoriasis, a consistent and intriguing difference in the expression pattern was observed; strong immunoreactivity in the basal cell layer, polarized towards the basement membrane in psoriasis, whereas in eczema lesions HLA-C immunostaining was present mostly in suprabasal cells. Inflammatory cells in the dermis were strongly stained in both diseases. Normal skin epithelium showed less intense but similar HLA-C staining as eczema lesions. HLA class Ia expression overall resembled that of HLA-C in all samples. The distinct HLA-C expression patterns in psoriasis and eczema suggest a functional role in the specific psoriasis immune response and not only a general feature of inflammation.

Blotting, Western↗

The HCR gene on 6p21 is unlikely to be a psoriasis susceptibility gene.

The PSORS1 locus in the human major histocompatibility complex on 6p21 has been consistently associated with psoriasis in populations of diverse ethnicity. The HLA-C allele Cw*0602, located therein, has been found in up to 67% of psoriasis patients but is no longer considered a candidate gene in itself. The alpha-helix coiled-coil rod homolog gene (HCR, previously Pg8) is located 110 kb from the HLA-C gene, positioned between the CDSN and SC1 genes, within a region thought to harbor a psoriasis gene (PSORS1). We investigated the HCR gene for disease association by direct sequencing of nine polymerase chain reaction products amplified from a series of Swedish psoriasis patients and controls. We found that HCR is a very polymorphic gene with 25 polymorphisms in the open reading frame alone, of which 10 demonstrated disease association; however, the relationship between HCR polymorphisms and HLA-Cw*0602 indicates that HCR cannot truly be considered a likely candidate gene. We investigated Cw*0602 association while stratifying for HCR single nucleotide polymorphisms. We also investigated HCR single nucleotide polymorphism association with the disease while stratifying for the presence of Cw*0602. We found that whichever single nucleotide polymorphism that was stratified for, there was still a strongly significant Cw*0602 association with psoriasis; however, when we stratified for Cw*0602 presence, only one silent polymorphism showed significant association. In a recent similar study this polymorphism was actually found to be decreased in psoriasis individuals. Thus we conclude that HCR polymorphisms display association with psoriasis due to linkage disequilibrium with Cw*0602 and is, therefore, unlikely to be directly involved in the development of psoriasis.

Adolescent↗

HLA-C and guttate psoriasis.

BACKGROUND: Psoriasis is a heterogeneous disease in its clinical expression. Both genetic and environmental factors are thought to contribute to the pathogenesis of the inflammatory and hyperproliferative components of the typical skin lesions. Predisposing genetic influences include associations with human leucocyte antigens (HLA) of which that with HLA-Cw6 is the strongest. Guttate psoriasis is a specific clinical manifestation of psoriasis frequently associated with group A beta-haemolytic streptococcal throat infection. OBJECTIVES: We set out to determine whether further clinical subdivision of psoriasis is associated with tighter correlation with HLA-C alleles. PATIENTS/METHODS: We determined the HLA-C locus genotype of 29 caucasian patients with guttate psoriasis presenting consecutively with guttate psoriasis associated with a history of a sore throat and/or an antistreptolysin O titre > 200 IU mL-1. Polymerase chain reaction typing using sequence-specific primers was used to detect all known HLA-C alleles. These data were compared with a control population of 604 random caucasian cadaver donors. RESULTS: All patients (100%) with guttate psoriasis carried the Cw*0602 allele compared with 20% of the control population (odds ratio = infinity; 95% confidence limits 25.00-infinity; Pcorrected < 0.0000002). CONCLUSIONS: This result is consistent with HLA-Cw*0602 playing a part directly in the pathogenesis of guttate psoriasis.

Adolescent↗

Psoriasis: the future.

The aetiology of psoriasis is still unclear but our knowledge of the psoriatic process has grown substantially over the last two decades. The future will undoubtedly bring advances in our understanding of the pathogenesis of psoriasis and, as a consequence, new therapies. Defining the molecular genetics of psoriasis will enhance our understanding of the disease process and hopefully facilitate the development of a representative animal model. This in itself will be a key step in the development and testing of new therapies. Precise identification of the immunological events involved in psoriasis will allow specific T-cell- and cytokine-targeted, and perhaps less toxic. immunotherapies. Anti-angiogenic agents that are in development for use in oncology may also be effective in psoriasis. The adaptation of current topical therapies such as retinoids and vitamin D analogues to produce more effective and better-tolerated formulations will also play a significant role in our future first-line management of patients. The increased recognition and better management of environmental trigger factors such as psychological distress will become an important factor in future psoriasis care. The development of physical therapies including photodynamic therapy and excimer lasers has the potential to expand the remit of psoriasis therapy. There is little doubt that the future for our patients with psoriasis is bright. However, this will only be achievable by a concerted research effort to understand all facets of this enigmatic disease ranging from the molecular to the environmental.

Angiogenesis Inhibitors↗

Topiramate in the treatment of psoriasis: a pilot study.

BACKGROUND: This study was initiated following a serendipitous finding in which a patient who presented with both a mood disorder and psoriasis experienced significant improvement of her psoriasis following treatment with topiramate. OBJECTIVES: To determine the efficacy of topiramate for the treatment of psoriasis. METHODS: Seven other patients, six of whom presented with both mood disorders and psoriasis and one with psoriasis only, were treated in an open-label fashion with topiramate. Topiramate therapy was usually initiated at 15 mg day-1 and gradually titrated by 15 mg week-1 to an average final dose of 56 mg day-1. Patients were treated for a minimum of 4 months. Psoriasis severity was measured using the psoriasis area and severity index (PASI). RESULTS: For all patients, the mean PASI score decreased from 16.1 before treatment to 7.1. For patients exhibiting improvement, the mean PASI score decreased from 14.3 to 3.9. CONCLUSIONS: These results represent the first known report of the efficacy of topiramate in the treatment of psoriasis.

Adult↗

Development of the PSORIQoL, a psoriasis-specific measure of quality of life designed for use in clinical practice and trials.

BACKGROUND: Patients with psoriasis have significant impairment in their quality of life (QoL). Several patient-completed instruments are available to measure outcome in dermatological conditions but these primarily focus on severity of disease rather than on QoL. OBJECTIVES: To develop a new instrument specifically designed to measure QoL in psoriasis-the Psoriasis Index of Quality of Life (PSORIQoL). METHODS: The content of the instrument was derived from qualitative interviews with 62 psoriasis patients in the U.K., Italy and the Netherlands. Content analysis of the interview transcripts from the three countries identified potential items for the questionnaire. All further stages of the project were conducted in the U.K. only. Face and content validity were determined by means of a focus group held with seven psoriasis patients and face-to-face interviews with a further 21 patients. A new draft version of the PSORIQoL, together with the Dermatology Life Quality Index (DLQI) and the General Well-Being Index (GWBI), were completed by a new sample of psoriasis patients contacted by mail, in order to determine construct validity. A subsample of the respondents completed a similar package 2 weeks later, to assess reproducibility (reliability). RESULTS: The first version of the PSORIQoL consisted of 61 items covering the needs identified in the interviews as having been affected by psoriasis or its treatment. These included fear of negative reactions from others, self-consciousness and poor self-confidence, problems with socialization, physical contact and intimacy, limitations on personal freedom and impaired relaxation, sleep and emotional stability. Following the focus group and field-test interviews, a new draft measure consisting of 45 items was completed by 148 patients, 88 of whom completed and returned a similar package 2 weeks later. Application of Rasch analysis identified a final 25-item version of the PSORIQoL. This version had a test-retest reliability coefficient of 0.89, indicating good reproducibility. The levels of association with the DLQI and PGWB indicated that the PSORIQoL measures a related but distinct construct. CONCLUSIONS: The PSORIQoL appears to be a practical, reliable and valid instrument for measuring the impact of psoriasis on QoL. It remains necessary to establish the instrument's responsiveness to changes in QoL associated with treatment.

Adult↗

Expression of the T-helper 2-specific chemokine receptor CCR4 on CCR10-positive lymphocytes in atopic dermatitis skin but not in psoriasis skin.

BACKGROUND: Atopic dermatitis (AD) and psoriasis are inflammatory skin diseases. AD is generally perceived as a T-helper (Th) 2-dominated disease whereas psoriasis is a Th1-dominated disease. The chemokine cutaneous T-cell attracting chemokine (CTACK) and its receptor CCR10 attract skin-homing lymphocytes to inflamed skin, suggesting that CCR10+ cells in AD and psoriasis should be of Th2 and Th1 type, respectively. The chemokine receptor CCR4 is expressed selectively on Th2 lymphocytes and its ligand thymus and activation-regulated chemokine (TARC) is upregulated in AD lesions, suggesting that the CCR10+ cells in AD lesions should also express CCR4. OBJECTIVES: To examine the coexpression of CCR10 and CCR4 on skin-invading lymphocytes in AD and psoriasis lesions as well as the Th1/Th2 cytokine expression of the CCR10+ lymphocytes. METHODS: Skin biopsies from AD and psoriasis patients were double stained with antibodies against CCR10-CCR4, CCR10-CCR5, CCR10-interleukin (IL)-2 and CCR10-IL-4. RESULTS: The CCR10+ cells in AD showed a mixed IL-2/IL-4 expression pattern, and a minor proportion expressed CCR4, whereas a large proportion of the CCR4+ cells did not express CCR10. In psoriasis the CCR10+ cells only expressed IL-2, and no CCR4 expression was detected. CONCLUSIONS: The CCR10+ lymphocytes invading the skin in AD and psoriasis have different Th1/Th2 profiles, as measured by both their cytokine and chemokine receptor expression. This suggests that the CCR10+ subpopulation of lymphocytes is made up of different Th1/Th2 subsets. However, the Th1/Th2 lymphocytes of AD and psoriasis were either CCR10+ or CCR10-, suggesting that both the Th1 and Th2 subpopulation can be subdivided further. CCR4 was found only in AD skin and on both CCR10+ and CCR10- cells, supporting the hypothesis of TARC and CTACK as being independent lymphocyte-attracting chemokines in AD.

Adult↗

The depression, anxiety, life satisfaction and affective expression levels in psoriasis patients.

OBJECTIVE: The aim of this study was to determine the effect of stressful life events on the onset and exacerbation of psoriasis, depression, anxiety, life satisfaction and affective expression levels in psoriasis patients and psychological risk factors related to psoriasis. METHOD: Fifty psoriasis patients were examined dermatologically and psychiatrically and then administered the Beck Depression Inventory (BDI), Spielberger State-Trait Anxiety Scale (STAI I-II), Life Satisfaction Scale (LSS), Courtauld Emotional Control Scale (CECS) and Body Image Satisfaction Scale (BIS). Symptom severity was measured by the Psoriasis Area Severity Index (PASI). RESULTS: Thirty-four patients declared that they had had a psychologically stressful life event in the last 3 months prior to the beginning of the illness. The mean PASI score was 1.75+/-1.65; BDI score 13.58+/-6.11; STAI-I score 39.54+/-9.18, STAI-II score 46.58+/-8.05; LSS score 9.18+/-4.39; CECS score 51.64+/-9.75; BIS score 93.74+/-16.67. CONCLUSION: Psoriasis patients reported significantly higher degrees of depression and more body cathexis problems than controls. In addition, the risk for developing psoriasis increased significantly in patients with moderate and severe depression. We also found a relationship between symptom severity and low affective expression and high BDI scores in this study. These findings suggest that the relationship between psoriasis and psychological problems can be reciprocal and requires further investigation.

Adult↗