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Psoriasis is a common inflammatory skin disease characterized by thickened scaly red plaques. Previously we have performed a genome-wide association study (GWAS) on psoriasis with 1,359 cases and 1,400 controls, which were genotyped for 447,249 SNPs. The most significant finding was for SNP rs12191877, which is in tight linkage disequilibrium with HLA-Cw*0602, the consensus risk allele for psoriasis. However, it is not known whether there are other psoriasis loci within the MHC in addition to HLA-C. In the present study, we searched for additional susceptibility loci within the human leukocyte antigen (HLA) region through in-depth analyses of the GWAS data; then, we followed up our findings in an independent Han Chinese 1,139 psoriasis cases and 1,132 controls. Using the phased CEPH dataset as a reference, we imputed the HLA-Cw*0602 in all samples with high accuracy. The association of the imputed HLA-Cw*0602 dosage with disease was much stronger than that of the most significantly associated SNP, rs12191877. Adjusting for HLA-Cw*0602, there were two remaining association signals: one demonstrated by rs2073048 (p = 2 x 10(-6), OR = 0.66), located within c6orf10, a potential downstream effecter of TNF-alpha, and one indicated by rs13437088 (p = 9 x 10(-6), OR = 1.3), located 30 kb centromeric of HLA-B and 16 kb telomeric of MICA. When HLA-Cw*0602, rs2073048, and rs13437088 were all included in a logistic regression model, each of them was significantly associated with disease (p = 3 x 10(-47), 6 x 10(-8), and 3 x 10(-7), respectively). Both putative loci were also significantly associated in the Han Chinese samples after controlling for the imputed HLA-Cw*0602. A detailed analysis of HLA-B in both populations demonstrated that HLA-B*57 was associated with an increased risk of psoriasis and HLA-B*40 a decreased risk, independently of HLA-Cw*0602 and the C6orf10 locus, suggesting the potential pathogenic involvement of HLA-B. These results demonstrate that there are at least two additional loci within the MHC conferring risk of psoriasis.

Testing of ∼25,000 putative functional single-nucleotide polymorphisms (SNPs) across the human genome in a genetic association study has identified three psoriasis genes, IL12B, IL23R, and IL13. We now report evidence for the association of psoriasis risk with missense SNPs in the interferon induced with helicase C domain 1 gene (IFIH1). The rare alleles of two independent SNPs were associated with decreased risk of psoriasis—rs35667974 (Ile923Val): odds ratio (OR) for minor allele carriers is 0.43, P=2.36 × 10−5 (2,098 cases vs. 1,748 controls); and rs10930046 (His460Arg): OR for minor allele carriers is 0.51, P=6.47 × 10−4 (2,098 cases vs. 1,744 controls). Compared to noncarriers, carriers of the 923Val and/or 460Arg variants were protected from psoriasis (OR=0.46, P=5.56 × 10−8). To our knowledge, these results suggest that IFIH1 is a previously unreported psoriasis gene.

Background Several different Physician Global Assessment (PGA) versions have been used in clinical studies as a co-primary end point to evaluate psoriasis severity. Tofacitinib is an oral Janus kinase inhibitor. We performed an analysis of the PGA using data from studies of tofacitinib in moderate to severe chronic plaque psoriasis. Methods Data from 3641 patients with moderate to severe chronic plaque psoriasis, enrolled in one of four phase III tofacitinib studies (OPT Pivotal 1 and 2, OPT Compare and OPT Retreatment), were used to evaluate a three-item PGA scale. Results Confirmatory Factor Analyses showed that equal weighting of the three items (erythema, induration and scaling) was appropriate. The PGA demonstrated acceptable test–retest reliability (Intraclass Correlation Coefficient, 0.7) and internal consistency (Cronbach’s Coefficient Alpha ≥ 0.9 at primary time points). The Clinically Important Difference was estimated as 0.55 (95% confidence interval: 0.546–0.563). Known-group validity was shown by demonstrating that PGA scores could discriminate between different degrees of disease severity. The PGA was significantly correlated with other clinical end points in the studies (Psoriasis Area and Severity Index, r = 0.75–0.79; Dermatology Life Quality Index, r = 0.44–0.57; Patient Global Assessment, r = 0.66–0.72). Conclusions Consistent with previous findings from a phase II study, these results indicate that this PGA is a valid, reliable instrument for evaluating disease severity in clinical studies of psoriasis.

In two phase 3 studies, the anti–interleukin-17 receptor A monoclonal antibody brodalumab was more effective than placebo or ustekinumab in patients with moderate-to-severe psoriasis. Adverse events associated with brodalumab included neutropenia and candida infections. Psoriasis is an inflammatory skin disease that occurs in 2 to 3% of the worldwide population. 1 , 2 Despite the availability of several therapies, many patients remain untreated, do not have an adequate response, or have treatment-related toxic effects. 3 Interleukin-17 cytokines have been implicated in the pathogenesis of psoriasis. Genomewide association studies have linked interleukin-17 pathway–related genes with psoriasis, 4 , 5 and interleukin-17 mRNA levels are higher in psoriatic lesions than in normal skin. 6 , 7 Numbers of type 17 helper T cells are increased in psoriatic lesions and are stimulated by interleukin-23 to release interleukin-17 cytokines. 8 Interleukin-17 cytokines, which include interleukin-17A, interleukin-17C, . . .

The product of Physician Global Assessment and Body Surface Area (PGA × BSA) is a new outcome measure for psoriasis severity and response to therapy. The objective of this study was to evaluate PGA × BSA as an alternative to Psoriasis Area and Severity Index (PASI) for psoriasis assessments. The relationship between PASI and PGA × BSA was assessed in a post hoc analysis of pooled data from the PRISTINE (NCT00663052) and PRESTA (NCT00245960) trials in patients with moderate-to-severe psoriasis who received etanercept 50 mg/week. Data were analyzed using Spearman and intra-class correlation coefficients, effect sizes, scatterplots, Bland-Altman plots, and Kappa statistics. Spearman correlations at baseline, week 12, and week 24 were strong for PGA × BSA versus PASI ( =0.78, 0.87, and 0.90, respectively; all <0.0001) as were intra-class correlations (0.76 [95% confidence interval 0.73-0.80], 0.80 [0.76-0.83], and 0.85 [0.82-0.87], respectively). The effect size was -1.53 for PASI and -0.94 for PGA × BSA (baseline to week 24). Scatterplots and Bland-Altman plots detected a trend across the range of measurement. Kappa statistics (at 12 and 24 weeks) between PASI50/75/90 and 50/75/90% improvement in PGA × BSA showed good agreement (0.58-0.69 at week 12 and 0.63-0.67, respectively; all <0.0001). At baseline, the Spearman correlation coefficients were 0.96, 0.51, 0.19, and 0.17 for PGA × BSA versus BSA, PGA, Patient Global Assessment, and Dermatology Life Quality Index, respectively (all <0.001). PGA × BSA has advantages over PASI for measuring moderate-to-severe psoriasis; it is intuitive, sensitive, and easy to use.

The results of this phase 2 randomized trial suggest that guselkumab, an anti–interleukin-23 monoclonal antibody, may be an effective therapy for psoriasis and that control of psoriasis can be achieved through specific anti–interleukin-23 therapy. Psoriasis is a chronic skin disease that is characterized by the infiltration of inflammatory cells into the skin and excessive keratinocyte proliferation, which result in raised, well-demarcated erythematous lesions 1 ; the disease has a substantial effect on quality of life. 2 , 3 The pathogenesis of psoriasis involves environmental factors and immune dysregulation in persons with a genetic predisposition. 4 The proinflammatory interleukin-12–mediated type 1 helper T (Th1) cell and interleukin-23–mediated type 17 helper T (Th17) cell signaling pathways 5 , 6 are up-regulated in psoriatic lesions; antibodies that inhibit both interleukin-12 and interleukin-23 7 , 8 and those that inhibit interleukin-17 9 – 13 inhibit the expression of . . .

ObjectiveTo identify a core set of domains (outcomes) to be measured in psoriatic arthritis (PsA) clinical trials that represent both patients' and physicians' priorities.MethodsWe conducted (1) a systematic literature review (SLR) of domains assessed in PsA; (2) international focus groups to identify domains important to people with PsA; (3) two international surveys with patients and physicians to prioritise domains; (4) an international face-to-face meeting with patients and physicians using the nominal group technique method to agree on the most important domains; and (5) presentation and votes at the Outcome Measures in Rheumatology (OMERACT) conference in May 2016. All phases were performed in collaboration with patient research partners.ResultsWe identified 39 unique domains through the SLR (24 domains) and international focus groups (34 domains). 50 patients and 75 physicians rated domain importance. During the March 2016 consensus meeting, 12 patients and 12 physicians agreed on 10 candidate domains. Then, 49 patients and 71 physicians rated these domains' importance. Five were important to >70% of both groups: musculoskeletal disease activity, skin disease activity, structural damage, pain and physical function. Fatigue and participation were important to >70% of patients. Patient global and systemic inflammation were important to >70% of physicians. The updated PsA core domain set endorsed by 90% of OMERACT 2016 participants includes musculoskeletal disease activity, skin disease activity, pain, patient global, physical function, health-related quality of life, fatigue and systemic inflammation.ConclusionsThe updated PsA core domain set incorporates patients' and physicians' priorities and evolving PsA research. Next steps include identifying outcome measures that adequately assess these domains.

Psoriatic arthritis (PsA) is a complex chronic musculoskeletal condition that occurs in ~30% of psoriasis patients. Currently, no systematic strategy is available that utilizes the differences in genetic architecture between PsA and cutaneous-only psoriasis (PsC) to assess PsA risk before symptoms appear. Here, we introduce a computational pipeline for predicting PsA among psoriasis patients using data from six cohorts with >7000 genotyped PsA and PsC patients. We identify 9 new loci for psoriasis or its subtypes and achieve 0.82 area under the receiver operator curve in distinguishing PsA vs. PsC when using 200 genetic markers. Among the top 5% of our PsA prediction we achieve >90% precision with 100% specificity and 16% recall for predicting PsA among psoriatic patients, using conditional inference forest or shrinkage discriminant analysis. Combining statistical and machine-learning techniques, we show that the underlying genetic differences between psoriasis subtypes can be used for individualized subtype risk assessment. Approximately 30% of psoriasis patients develop psoriatic arthritis (PsA) and early diagnosis is crucial for the management of PsA. Here, Patrick et al. develop a computational pipeline involving statistical and machine-learning methods that can assess the risk of progression to PsA based on genetic markers.

Most biologic therapies for psoriasis are delivered via subcutaneous injection. Ixekizumab, an anti-interleukin 17A monoclonal antibody approved for patients with moderate-to-severe plaque psoriasis, is delivered subcutaneously via prefilled syringe or autoinjector. Here we report the results of an ixekizumab autoinjector usability study as well as the patient-reported experience with the autoinjector in a clinical trial. The usability study enrolled 49 subjects (patients with a range of autoimmune conditions or their caregivers). Subjects were randomized to a trained or untrained group and were evaluated for their ability to perform an injection successfully when provided the device and the instructions for use. In the clinical trial, 102 subjects (patients with psoriasis or their caregivers) used the autoinjector to deliver injections of ixekizumab (80 mg every 2 weeks after a starting dose of 160 mg). At weeks 0, 4, and 8, subjects completed the subcutaneous administration assessment questionnaire, which assesses the ease of use and confidence with using an injection device. In the usability study, all subjects in the untrained arm performed successful injections, while two subjects in the trained arm had an injection failure. These incidences were not consistent with any pattern of issues with the device or the instructions for use. In the clinical trial, there were two injection failures of 674 total self-injections performed over 12 weeks. At the first use of the device, 95% of subjects either agreed or strongly agreed that the device was \"overall easy to use\", and they felt \"confident the dose was complete\" according to the subcutaneous administration assessment questionnaire. The ixekizumab autoinjector was used successfully by patients and caregivers with or without training. Subjects using the autoinjector in a clinical trial felt it was easy to use and felt confident while using it.

The Collaborative Association Study of Psoriasis, in partnership with the Genetic Association Information Network (GAIN), reports a genome-wide association study for psoriasis. They identify new replicated associations that highlight a role for the IL-23 and NF-κB pathways in psoriasis susceptibility. Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 × 10 −8 ). Loci with confirmed association include HLA-C , three genes involved in IL-23 signaling ( IL23A , IL23R , IL12B ), two genes that act downstream of TNF-α and regulate NF-κB signaling ( TNIP1 , TNFAIP3 ) and two genes involved in the modulation of Th2 immune responses ( IL4 , IL13 ). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.