The biological basis of disease recurrence in psoriasis: a historical perspective and current models.

A key challenge in psoriasis therapy is the tendency for lesions to recur in previously affected anatomical locations after treatment discontinuation following lesion resolution. Available evidence supports the concept of a localized immunological 'memory' that persists in resolved skin after complete disappearance of visible inflammation, as well as the role of a specific subpopulation of T cells characterized by the dermotropic CCR4+ phenotype and forming a local memory. Increasing knowledge of the interleukin (IL)-23/T helper 17 (Th17) cell pathway in psoriasis immunopathology is pointing away from the historical classification of psoriasis as primarily a Th1-type disease. Research undertaken from the 1990s to the mid-2000s provided evidence for the existence of a large population of CD8+ and CD4+ tissue-resident memory T cells in resolved skin, which can initiate and perpetuate immune responses of psoriasis in the absence of T-cell recruitment from the blood. Dendritic cells (DCs) are antigen-presenting cells that contribute to psoriasis pathology via the secretion of IL-23, the upstream regulator of Th17 cells, while plasmacytoid DCs are involved via IL-36 signalling and type I interferon activation. Overall, the evidence discussed in this review indicates that IL-23-driven/IL-17-producing T cells play a critical role in psoriasis pathology and recurrence, making these cytokines logical therapeutic targets. The review also explains the clinical efficacy of IL-17 and IL-23 receptor blockers in the treatment of psoriasis.

Patient perspectives in the management of psoriasis: results from the population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis Survey.

BACKGROUND: Available psoriasis surveys offer valuable information about psoriasis and psoriatic arthritis (PsA), but are limited by methodology or enrollment requirements. OBJECTIVE: To further the understanding of the unmet needs of psoriasis and PsA patients. METHODS: This was a large, multinational, population-based survey of psoriasis and/or PsA patients in North America and Europe. Patients were selected by list-assisted random digit dialing and did not have to currently be under the care of a health care provider, a patient organization member, or receiving treatment; 139,948 households were screened and 3426 patients completed the survey. RESULTS: The prevalence of psoriasis/PsA ranged from 1.4% to 3.3%; 79% had psoriasis alone and 21% had PsA. When rating disease severity at its worst, 27% (psoriasis) and 53% (PsA ± psoriasis) of patients rated it as severe. Psoriasis patients indicated that their most bothersome signs or symptoms were itching (43%), scales (23%), and flaking (20%). Of psoriasis patients, 45% had not seen a physician in a year; >80% of psoriasis patients with ≥ 4 palms body surface area and 59% of PsA patients were receiving no treatment or topical treatment only. Of patients who had received oral or biologic therapy, 57% and 45%, respectively, discontinued therapy, most often for safety/tolerability reasons and a lack/loss of efficacy. LIMITATIONS: The survey lacked a control group, did not account for ethnic and health care system differences across countries, and was limited by factors associated with any patient survey, including accurate recall and interpretation of questions. CONCLUSIONS: Several identified unmet needs warrant additional attention and action, including improved severity assessment, PsA screening, patient awareness, and treatment options.

Pharmacokinetics of topical calcineurin inhibitors in adult atopic dermatitis: a randomized, investigator-blind comparison.

OBJECTIVE: We sought to compare pharmacokinetics of pimecrolimus cream 1% and tacrolimus ointment 0.1% in adults with extensive, moderate to severe atopic dermatitis. Secondary end points included efficacy and safety. METHODS: Patients received twice-daily treatment for 13 days. Blood concentrations of pimecrolimus and tacrolimus were measured at days 1, 5, and 13. Treatment success was defined as an Investigators' Global Assessment score of 0 (clear) or 1 (almost clear). RESULTS: Tacrolimus was detectable in 36% of blood samples and pimecrolimus was detectable in 12%. In patients with measurable blood drug concentrations, systemic exposure to tacrolimus (mean area under the curve(0-10h) < 9.7 ng.h/mL; n = 7) was higher than to pimecrolimus (mean area under the curve(0-10h) < 2.5 ng.h/mL; n = 2). Whole-body treatment success (day 13) was achieved in 1 of 18 (5.6%) and 2 of 19 (10.5%) patients treated with pimecrolimus and tacrolimus, respectively, and face/neck treatment success in 5 of 18 (27.8%) and 5 of 19 (26.3%) patients, respectively. Patients included in the study were adult patients with severe atopic dermatitis. The results and conclusions drawn from this study population may not be applicable for the majority of patients with atopic dermatitis who have mild to moderate disease. CONCLUSION: Pimecrolimus appears to be associated with lower systemic drug exposure than tacrolimus.

Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study.

This prospective long-term cohort study investigated the incidence of malignancies in severe psoriasis patients treated with cyclosporine. A total of 1252 patients were followed prospectively for up to 5 y. Malignancies were recorded prospectively. Incidence rates for malignancies were compared with the general population using standardized incidence ratios. The effect of duration of exposure to cyclosporine and to previously administered anti-psoriatic treatments on the incidence of malignancies was investigated using Poisson regression models. The mean age of patients was 43 y and on average, patients received cyclosporine for 1.9 y. Malignancies were diagnosed in 47 patients (3.8%), 49% of them had skin malignancies. The standardized incidence ratio in the study cohort was 2.1 as compared with the general population. The higher incidence of malignancies was attributed to a 6-fold higher incidence of skin malignancies, most of which were squamous cell carcinoma. The incidence of nonskin malignancy overall was not significantly higher in this study than in the general population. Duration of exposure to cyclosporine, exposure to psoralen and ultraviolet A, exposure to methotrexate, and exposure to immunosuppressants showed a significant effect on the incidence of nonmelanoma skin malignancies. In conclusion, treatment of psoriasis with cyclosporine is associated with an increased risk of nonmelanoma skin cancer. Patients treated for more than 2 y with cyclosporine were shown to have a higher risk. In addition, exposure to psoralen and ultraviolet A and to other immunosuppressants was shown to contribute to the overall risk.

Why statistics matter: limited inter-rater agreement prevents using the psoriasis area and severity index as a unique determinant of therapeutic decision in psoriasis.

Although the demand for evidence-based decisions is increasing in clinical practice, recent systematic reviews on the accuracy of existing psoriasis severity scales, including the Psoriasis Area and Severity Index (PASI), suggest that their validity is not fully characterized. We simulated the evaluation of PASI by two practitioners in 1,000 sets of 100 patients. PASI data from several practitioners who examined the same patients were used to generate PASI scores by two practitioners, in order to compare how well commonly used statistics assess the inter-rater agreement for the PASI. Because the PASI score has an asymmetric distribution, statistics such as Pearson's linear correlation coefficient "r" and Spearman's rank correlation coefficient overestimated the inter-rater agreement of PASI as compared with the intra-class correlation coefficient (ICC; r=0.8, ρ=0.7, ICC=0.5). When restricting the analysis to patients with a PASI <20, inter-rater agreement severely decreased (r=0.38, ρ=0.41, ICC=0.17), resulting in unacceptable therapeutic decision agreement (κ=0.38). Our study indicates that owing to the skewed distribution of the PASI its validity to influence therapeutic decisions is questionable. The ICC is preferable to the commonly used statistics (r and ρ) for assessing the inter-rater agreement reliability of asymmetrically distributed scores such as the PASI.

Cancer risk evaluation in psoriasis: in search of the Holy Grail?

Benefit-risk assessment of systemic treatment in psoriasis is a dynamic process. Long-term safety of psoriasis therapies has been questioned, with the spectrum of systemic immunosuppression potentially leading to increased cancer risk. In this issue, Brauchli et al. report on a population-based analysis of cancer risk in a large cohort of psoriasis patients, most of whom had not been treated with systemic agents. The study prepares the ground for future prospective long-term cohort studies in psoriasis patients treated with systemic therapies, including biological agents.

Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis.

Systemic use of immunosuppressant agents increases the risk of lymphoma in transplantation. We performed a nested case-control study in the PharMetrics database to evaluate the association between topical immunosuppressants and lymphoma in a cohort of patients with atopic dermatitis. We identified cases of lymphoma and randomly selected four controls for each case, matched by length of follow-up. We used conditional logistic regression to calculate odds ratio (OR) and 95% confidence intervals (CIs) of the association between topical immunosuppressants and lymphoma. Two hundred and ninety-four cases of lymphoma occurred in 293,253 patients, 81 in patients younger than 20 years. The adjusted analysis yielded the following OR (95%CI) for: severity (OR 2.4; 95% CI 1.5-3.8), oral steroids 1.5 (1.0-2.4), "super potent" topical steroids 1.2 (0.8-1.8) , "low potency" topical steroids OR 1.1 (0.7-1.6); pimecrolimus 0.8(0.4-1.6), tacrolimus OR 0.8 (0.4-1.7), and concomitant topical steroids, pimecrolimus, and tacrolimus 1.0 (0.3-4.1). We did not find an increased risk of lymphoma in patients treated with topical calcineurin inhibitors. It is difficult to disentangle the effects of severity of disease on outcome versus the true effects of drugs. However, in the adjusted analysis, severity of AD was the main factor associated with an increased risk of lymphoma.