Lotus Mallbris

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10−8 and two loci with a combined P < 5 × 10−7). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10−6). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.

Increased risk for cardiovascular mortality in psoriasis inpatients but not in outpatients

We have conducted a historical cohort study to assess cardiovascular mortality among psoriasis patients. Using the Swedish Inpatient Registry, we selected 8991 patients hospitalized for psoriasis at dermatological wards. To represent an outpatient cohort, 19,757 members of the Swedish Psoriasis Association were selected. Mortality from cardiovascular diseases was compared with the general population. We found no increased cardiovascular mortality among outpatients with psoriasis (standardized mortality ratio, SMR 0.94; 95% confidence interval, CI: 0.89–0.99). The overall risk among inpatients admitted at least once was increased by 50%(SMR 1.52; 95% CI: 1.44–1.60). The excess risk increased with increasing number of hospital admissions (p for trend <0.001). Cardiovascular mortality was higher among those admitted at younger ages (p for trend <0.001; SMR 2.62, 95% CI: 1.91–3.49, for patients aged 20 to 39 years at first admission). Young age at first admission appeared to further increase the risk among those who were repeatedly admitted. We conclude that a diagnosis of psoriasis per se does not appear to increase the risk for cardiovascular mortality. Severe psoriasis, however, here measured as repeated admissions, and early age at first admission, is associated with increased risk for cardiovascular death.

Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis

BACKGROUND Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. CONCLUSIONS In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known. (Funded by Eli Lilly; UNCOVER-1, UNCOVER-2, and UNCOVER-3 ClinicalTrials.gov numbers NCT01474512, NCT01597245, and NCT01646177, respectively.).

Excessive body weight and smoking associates with a high risk of onset of plaque psoriasis.

Accumulating evidence indicates that body weight, alcohol and smoking are associated with psoriasis. However, these factors have scarcely been investigated in relation to onset and disease activity at onset of psoriasis. A population-based case-control study was performed including 373 cases with onset of first-time plaque psoriasis within 12 months and matched healthy controls. Psoriasis activity was measured using the Psoriasis Area and Severity Index (PASI). Analyses were performed using conditional logistic regression. In multivariable analyses for each unit increment in body mass index, there was statistically significant 9% increased risk for psoriasis onset and 7% higher risk for increased PASI. Obesity (body mass index > or =30) compared with normal body weight was associated with a two-fold increased risk for psoriasis onset. Smoking was associated with a 70% increased risk for onset, but was not related to PASI. A positive association with alcohol drinking was observed among men, but not among women. No associations were observed for weight gain and use of smokeless tobacco. Our results indicate that excessive body weight and smoking are risk factors for onset of psoriasis and that higher body mass index increases the PASI of plaque psoriasis at onset.

Neutrophil gelatinase-associated lipocalin is a marker for dysregulated keratinocyte differentiation in human skin

Abstract: Neutrophil gelatinase‐associated lipocalin (NGAL) is a 25‐kDa protein initially isolated from the specific granules of human neutrophils. It is a member of the highly heterogeneous lipocalin protein family, which shares a common tertiary structure. Its synthesis is induced in gastrointestinal epithelium in association with inflammation and malignancy. To gain insight into its potential role in other epithelia we have investigated the expression of NGAL in human skin embryonic development, in normal adult skin, and in skin associated with inflammation and neoplastic transformation. In the present study we report that the embryonic expression of NGAL appears to be regulated in a spatio‐temporal pattern. It was induced in the interfollicular epidermis at 20–24 weeks of gestational age but thereafter progressively receded towards the hair follicles. In normal adult skin, NGAL was detected solely in association with hair follicles. However, strong induction of NGAL in the epidermis was seen in a variety of skin disorders characterized by dysregulated epithelial differentiation such as psoriasis, pityriasis rubra and squamous cell carcinoma. In these tissues production of NGAL was confined to spatially distinct subpopulations of keratinocytes underlying areas of parakeratosis, whereas skin samples lacking parakeratotic epithelium such as lichen ruber planus, acute contact eczema and basal cell carcinoma were negative for NGAL. Consistent with being a marker for disturbed terminal differentiation, NGAL immunoreactivity showed an inverse pattern when compared with that of the differentiation marker filaggrin. The biologic functions of NGAL in epithelia are not fully known, although an immunomodulatory role in host defense has been proposed. In addition, the transient interfollicular NGAL expression during skin embryogenesis along with the induction of NGAL in adult parakeratotic epidermis suggests it play a role in epithelial differentiation pathways.

Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial

Despite unmet need, 15 years have passed since a topical therapy with a new mechanism of action for atopic dermatitis (AD) has been approved. Janus kinase (JAK) inhibitor treatment effect via topical application in patients with AD is unknown.

Tofacitinib withdrawal and retreatment in moderate-to-severe chronic plaque psoriasis: a randomized controlled trial

Tofacitinib is an oral Janus kinase inhibitor being investigated for the treatment of moderate‐to‐severe plaque psoriasis.

Risk of Multiple Sclerosis in Patients with Psoriasis: A Danish Nationwide Cohort Study

Psoriasis and multiple sclerosis (MS) are inflammatory disorders with similarities in genetic risk variants and inflammatory pathways. Limited evidence is available on the relationship between the two diseases. We therefore investigated the risk of incident (new-onset) MS in patients with mild and severe psoriasis, respectively. All Danish citizens aged ≥ 18 years from 1 January 1997 to 31 December 2011 were identified by linkage of nationwide registries at the individual level. We estimated incidence rate ratios (IRRs) adjusted for age, gender, socioeconomic status, smoking, medication, comorbidity, and UV phototherapy by Poisson regression. There were 58,628 and 9,952 cases of mild and severe psoriasis, respectively, and 9,713 cases of MS. Incidence rates of MS per 10,000 person-years for the reference population, mild psoriasis, and severe psoriasis were 1.78, 3.22, and 4.55, respectively. Adjusted IRRs of MS were 1.84 (95% confidence interval [CI], 1.46-2.30) and 2.61 (95% CI, 1.44-4.74) in mild and severe psoriasis, respectively. Similar results were observed when adjustment for family history of MS was included in the analyses. Psoriasis may confer a disease severity-dependent risk of MS. Further studies are warranted to establish the mechanisms underlying this relationship and its potential clinical consequences.

Polymorphisms in the SEEK1 and SPR1 genes on 6p21.3 associate with psoriasis in the Swedish population.

Abstract:  Psoriasis is a chronic skin disease that results in red and scaly lesions. Several psoriasis susceptibility loci have been identified across the genome, of which PSORS1 on 6p21.3 is predominant. There is an ongoing debate regarding whether the HLA‐C allele, Cw*0602, can be considered the major predisposing factor in this region. Investigation of other genes in the PSORS1 region with regard to psoriasis may provide alternate candidates to HLA‐C. We have characterized two overlapping genes, SEEK1 and SPR1. SEEK1 encodes two putative protein isoforms: the first being one of 152 amino acids from the full‐length splice‐isoform (exon 1–6), and the second being one of 100 amino acids from an alternate splice‐isoform (exon 1 and 6). SPR1 encodes a highly conserved protein of 134 amino acids, and in addition to characterization of human SPR1 we report the cloning of its orthologs in mouse and pig. Both SEEK1 and SPR1 are expressed in normal and psoriasis skin. In a case–control study, five of the nine single nucleotide polymorphisms (SNPs) found in SEEK1 were associated with psoriasis, while one of the four SNPs found in SPR1 showed association. Testing the Cw*0602 confounding status revealed that two of the SEEK1 SNPs showed Cw*0602‐independent association, while the SPR1 SNP showed Cw*0602‐dependent association. The second exon of SEEK1, containing the two Cw*0602‐independent SNPs, showed the highest concentration of the psoriasis‐associating SNPs, but did not appear to be translated.

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study

BACKGROUND Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. OBJECTIVES We sought to report longer-term tofacitinib efficacy and safety in patients with moderate to severe psoriasis. METHODS Data from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID. RESULTS At week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure. LIMITATIONS There was no dose comparison beyond week 52. CONCLUSIONS Oral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed.