Risankizumab is a humanized IgG1 monoclonal antibody that binds to the p19 subunit of interleukin-23. It therefore inhibits this cytokine, which plays a key role in psoriatic inflammation. The aim of this study was to compare the efficacy and safety of risankizumab with placebo and with ustekinumab in moderate to severe chronic plaque psoriasis. Two replicate, multi-center, phase 3 studies across 14 countries involved 506 and 491 patients who were randomly assigned (3:1:1) to risakizumab 150 mg, ustekinumab 45 or 90 mg, or placebo for the initial double-blind 16 weeks. At week 16, the placebo group switched to risankizumab and the other patients continued on their original drug up to week 52. A Psoriasis Area and Severity Index (PASI) score of 90 was achieved at 16 weeks by 75.3% in the first study and 74.8% in the second study of patients on risakizumab, by 42% and 47.5% respectively, of patients on ustekinumab, and by 4.9% and 2.0% of patients on placebo. Confidence intervals were reported and demonstrated clear differences between the treatment groups. Secondary outcome measures included the Dermatology Life Quality Index (DLQI)* and the Psoriasis Symptom Scale (PSS), which scores the severity of pain, redness, itching, and burning. A DLQI score of 0 or 1 was achieved at week 16 by 66% and 67% of patients on risakizumab, by 43% and 46% on ustekinumab, and by 8% and 4% patients on placebo. A PSS score of 0 was achieved at 16 weeks by 29% and 31% of patients on risakizumab, 15% and 15% patients on ustekinumab, and 2% and 0% patents on placebo. Treatment-emergent adverse events were similar across patients treated with risakizumab, ustekinumab, and placebo.

This study from the Journal of Allergy and Clinical Immunology investigated the expression of IL-1 and IL-36 in generalized pustular psoriasis (GPP). The various cytokines involved in psoriasis were examined by gene expression studies in paraffin-embedded sections from lesional skin. GPP was compared with psoriasis vulgaris (PV). Significant contributions of IL-17A, TNF, IL-1, IL-36, and interferons in both diseases were detected in both variants, but GPP had higher IL-36 and IL-1 expression and lower IL-17A and IFN-g mRNA expression than PV lesions. The investigators detected prominent IL-36 expression by keratinocytes proximal to neutrophilic pustules and it was also shown that proteases from neutrophils activated IL-36. The protease inhibitors serpin A1 and A3, which are inhibitors of elastase and cathepsin G, were also detected in both diseases and inhibited IL-36. These findings explain why many standard treatments for PV, such as acitretin, cyclosporine and even TNF-α blockers, do not seem to work well in GPP. The data from this paper provides a basis for targeted effective drug therapy in GPP, which is characterized by periodic neutrophil infiltration into the skin and development of pustules. There was a strongly enhanced expression of the neutrophil chemokines CXCL1, CXCL2, and CXCL8 (IL-8) in GPP, which enhanced the induction of neutrophils into the epidermis. Compared to PV, there were between 5 to 15 more transcripts of these chemokines, thus establishing a clear difference in the pathomechanism of the two conditions. IL-1 has three isoforms, IL-35 alpha, beta, and gamma. They drive the keratinocyte inflammatory process and synergize with the rest of the inflammation in the skin. TNF-α is a central mediator in chronic plaque psoriasis as evidenced by the effectiveness of therapies that block TNF-α activity. Infliximab has most commonly been used for GPP and PV among the TNF-α blockers. This is because of the inhibition of the synergy between TNF-α and IL-36 and other cytokines. This study also detected increased IL-17A activity in GPP lesions, opening up an area of targeted therapy for GPP.

In this article by Gordon et al, 60-week data from the UNCOVER-1, 2, and 3 trials of the ixekizumab phase 3 program, and 12-week data from UNCOVER-1, are reported (12-week data from UNCOVER-2 and 3 have previously been presented1 ). Results from the placebo-controlled phase of UNCOVER-3 were consistent with those of UNCOVER-1 and 2. In the 2-weekly dosing group, 81.8% and 89.1% of patients achieved the co-primary endpoints of sPGA (static Physicians Global Assessment) score of 0/1 and PASI (Psoriasis Area Severity Index) 75 response, respectively, while 76.4% and 82.6% achieved these endpoints in the 4-weekly dosing group, and 3.2% and 3.9% in the in the placebo group (P<0.001).

At week 12 in UNCOVER-1 and 2, only patients who had an sPGA 0/1 response to ixekizumab continued into the long-term extension (LTE) period where they entered a randomized withdrawal period and were assigned to two dosing regimens of ixekizumab or placebo. If a patient achieved an sPGA 3 response at any stage between weeks 12 and 60, they were classified as a non-responder, regardless of their response at week 60. Despite these stringent criteria, 74% of patients receiving the currently approved maintenance dose of ixekizumab maintained an sPGA score of 0/1 compared with 7.0% of placebo-treated patients. In the UNCOVER-3 trial, all patients could enter the LTE period, where they received 80 mg of ixekizumab every 4 weeks until week 60, serving as a continuously treated cohort; 73% and 80% of patients who received continuous treatment of ixekizumab from week 0 to 60, achieved an sPGA 0/1 or PASI 75 response, respectively. Eleven patients reported inflammatory bowel disease (IBD) while receiving ixekizumab, with an additional 3 cases reported in patients receiving placebo during the randomized withdrawal period. The rate of cardiovascular events did not differ between ixekizumab and placebo-treated patients, but there were 22 (0.6%) cardiovascular events and two cardiovascular deaths throughout the 60 weeks. The rates of candida infection were significantly higher in ixekizumabtreated patients, the majority of which were mild.

This study describes the association of clinically effective biologic treatments with reduced coronary artery disease (CAD) progression in patients with severe psoriasis, measured with coronary computed tomography (CT). The authors investigated whether biologic therapy is associated with changes in coronary artery progression. The design of the clinical study was single-center, prospective, controlled, observer-blinded. It compared patients with severe psoriasis initiating biological therapy with matched controls not receiving systemic therapy. CT was performed at baseline and after 13 months of treatment in 28 patients treated initially with adalimumab (n=21), etanercept (3), infliximab (1) or ustekinumab (3) and 28 matched controls. Both groups were comparable regarding patient characteristics and cardiovascular risk factors except for Psoriasis Area Severity Index (PASI) 15.4 (SD 4.3) versus 12.4 (SD 3.9) (p = 0.01). Coronary artery calcium scores (CAC) remained stable in the intervention group, whereas the control groups showed progression. The number of segments with luminal abnormalities remained unchanged in both groups, but severity of luminal narrowing increased in the control group whereas the intervention group remained stable. Disease control in the intervention group was good during the study period, with a mean PASI reduction of almost 88%. The authors conclude that clinically effective treatment with biologics was associated with reduced CAC progression in patients with severe psoriasis, which supports a beneficial effect of biologic treatment in preventing cardiovascular disease progression in patients without symptomatic coronary artery disease.

The delineation between mild and severe psoriasis is commonly performed by clinical measures such as Psoriasis Area Severity Index (PASI) and body surface area (BSA). This study performed analysis of skin biopsies from 34 adult patients with mild psoriasis (mean PASI score 5.5) and 23 patients with severe disease (mean PASI score 23.2). Biopsies were taken from a representative plaque in untreated patients. There were no differences in sex, age, or disease duration between the patient groups. Biopsies were analyzed for histologic features, cytokine expression, messenger RNA expression, and gene expression for disease response pathway activation. Histological features showed that CD3+ T cells and CTLA4+ T cells were more abundant in both epidermis and dermis of mild psoriasis compared to severe psoriasis. A panel of disease-associated cytokines showed higher expression in mild psoriasis compared with severe psoriasis (Th17-regulated cytokines and Th1-regulated cytokines, as well as the expression of immune-mediated regulatory molecules). The expression of driver inflammatory cytokines decreased as the disease severity increased. Similarly, the expression of negative immune regulatory molecules decreased as the disease severity increased. Messenger RNA expression showed separate clustering of mild and severe psoriasis: mild psoriasis showed higher expression patterns of T-cell activation, Th17-regulated cytokines, Th1-regulated cytokines, and negative immune regulation compared with severe disease. In addition, disease response pathway activation was investigated using gene set variation analysis (GSVA). Both mild and severe psoriasis skin highly expressed psoriasis transcriptome, with higher GSVA scores for mild compared with severe psoriasis. In conclusion, mild psoriasis was characterized by higher numbers of T cells in skin lesions, higher IL-17A expression, and stronger expression of the core psoriasis transcriptome. In contrast, severe psoriasis was characterized by stronger expression of some epidermal response genes. However, the key molecular distinction was higher expression of negative immune regulatory genes in mild lesions compared with severe psoriasis lesions.

Patients and physicians certainly strive to achieve clear skin, but there is insufficient evidence illustrating the impact of total skin clearance from the patient perspective. This study by Strober et al looked at pooled data from nonplacebo arms of 3 phase-3 clinical trials studying brodalumab, a human anti-interleukin-17 receptor antibody that was approved in July by the federal Food and Drug administration for treating moderate to severe plaque psoriasis. The study compared outcomes for patients who achieved a Psoriasis Area and Severity Index (PASI) 100 response or a static Physician Global Assessment (sPGA)=0 (clear skin) response with patients who achieved a PASI 75-99 (but no full clearance) or sPGA=1 (almost clear). The results were based on Dermatology Life Quality Index (DLQI) and Psoriasis Symptom Inventory (PSI) scores. One study arm compared brodalumab with ustekinumab, a monoclonal antibody that blocks interleukins 12 and 23. A PSI score of 0 meant that the patient had symptom-free days. The DLQI score of 0/1 was achieved in patients with a PASI 100 in 80% of subjects, compared with a DLQI score of 0/1 in only 55% of those subjects achieving a PASI 75-99. The PSI score of 0 was achieved in 45% of subjects who achieved a PASI 100 response and only 8% for those subjects who achieved a PASI 75-99 response. Similar results were seen for sPGA of 0 versus 1. These differences were statistically significant with a value of <0.001. Based on these results, the authors concluded that complete skin clearance as measured by PASI 100 or sPGA=0 provides a clinically meaningful and statistically significant improvement in health-related quality of life as measured by DLQI and absence of psoriasis symptoms as measured by PSI. The PSI score of 0 meant that the patient had 100% symptom-free days. Therefore a PASI 100 or sPGA of 0 is clinically relevant to the patient.

Studies indicate that adherence to biologics is low among patients with psoriasis. Most adherence-to-biologics data are based on patients who have private insurance. There is lack of data for elderly and disabled patients who are covered by Medicare, a nationwide health insurance program provided by the federal government in the United States. This study by Doshi et al looked at a national sample of Medicare beneficiaries with psoriasis who started on the biologics infliximab, etanercept, adalimumab, or ustekinumab. Using Medicare data files, the investigators conducted a retrospective 3-year claims analysis, with 12-month follow-up after index prescription. Rates of and factors associated with biologic adherence, discontinuation, switching, and restarting were reported. However, reasons for nonadherence were not reported. More than 2,700 patients initiated adalimumab, etanercept, infliximab, and ustekinumab. During a 1-year follow-up, 38% were adherent and 46% discontinued treatment, with 8% switching to another biologic, and 9% later restarting biologic treatment. Patient-reported reasons for nonadherence or gaps in treatment are unavailable in claims data. Being female and being ineligible for low-income subsidies were associated with increased odds of decreased adherence. Compared with index users of ustekinumab, index users of all 3 remaining biologics had greater chances of switching. Comorbidities were also documented, with cardiovascular disease, dyslipidemia, and diabetes being the most common. Obesity was only reported in approximately 12% of patients studied. Psoriatic arthritis was reported in almost 30% of patients, consistent with accepted incidence. Overall, Medicare patients starting on a regimen of biologics to treat their psoriasis had low adherence and high discontinuation rates.

This manuscript investigated the genetics of ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, and ulcerative colitis to determine pleiotropy and the association between these clinically related diseases. Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously. An individual with a pleiotropic risk variant is more likely to acquire both diseases. The aims of this crossphenotype study were to (1) identify subsets of the five phenotypes with shared genetic risk loci using a crossphenotype meta-analysis approach; (2) identify additional susceptibility loci; (3) investigate comorbidity and pleiotropy among these phenotypes; and (4) improve the understanding of shared pathways and biological mechanisms common to subsets of the phenotypes studied. Using high-density genotype data from more than 86,000 individuals of European ancestry, they identified 244 independent multi-disease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared-risk loci. From 13 countries across Europe and North America, they collected 6,577 psoriasis cases. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes, or excessive comorbidity). In other words, their modeling supported (1) the presence of shared pathophysiological pathways as the basis for clinical co-occurrence and (2) the hypothesis that patients with concomitant syndromes are genetically distinct from patients without concomitant syndromes. The inflammatory bowel disease (IBD) and psoriasis phenotype type subsets showed enrichment for acetylation of histone H3 at lysine 27 (H3K27ac) in CD3 primary cells and for H3K27ac in adipose tissue, respectively.

Interleukin (IL)-36 (α, β and γ) are a family of IL-1 cytokines (usually produced in response to viral infection or skin trauma) sharing a common receptor with immunomodulatory effects. Loss-of-function mutations of an antagonist of the IL-36 receptor gene have been found in generalized pustular psoriasis, suggesting a role for IL-36 activation in the disease. There are also multiple lines of genetic and laboratory evidence connecting IL-36 to plaque psoriasis. This study aimed to further the analysis of IL-36 as a potential target for new therapies in psoriasis.

The first portion of the study treated keratinocytes with IL-36 and found that the genes upregulated after exposure were those genetically mapped to psoriasis but not to other diseases used as negative controls, implying that increasing levels of IL-36 have the potential to trigger psoriasis. Further analysis showed that 56% of keratinocyte genes upregulated by IL-17 (a fundamental cytokine in psoriasis pathogenesis) were also in the set upregulated by IL-36 exposure. Keratinocytes exposed to IL-36 also demonstrated further increases in IL-36 production (a positive feedback loop) and attracted TH17 cells and potentiated IL-17 production, which may help explain the continuous inflammation seen in psoriatic plaques.

The authors then analyzed mice that were pretreated with an IL-36 inhibitor and exposed to imiquimod to induce psoriasiform dermatitis. Mice so treated demonstrated significantly (30%) less acanthosis as well as less neutrophil infiltration compared to those treated with imiquimod alone. Although blunted, treatment with IL-36 blockade did not prevent psoriasiform dermatitis in this model.

Lastly, using a genetic registry, the authors identified 12 individuals who had homozygous mutations in the IL-36 receptor gene to ascertain if loss of IL-36 function might be dangerous. Reviews of their medical histories found no pattern of infections or cancers. Six of these patients underwent further testing, including normal blood tests and appropriate increase in levels of IL-17 when their peripheral blood mononuclear cells were exposed to vaccines.

Much has been learned in recent years about the local pathogenesis in psoriatic plaques, including the development of targeted treatments to influence the underlying biology. This study looked at plaques that were clinically resolved after treatment to assess the local T-cell population and presence of Interleukin (IL)-17, a key cytokine in the pathogenesis of psoriasis. Oligoclonal populations of T cells were analyzed to try to discern and quantify putative pathogenic T-cell clones. Skin samples were obtained from psoriatic plaques, resolved plaques (successfully treated with either etanercept or phototherapy), unaffected skin in psoriatic patients, and normal controls undergoing cosmetic procedures. High-throughput screening of the CDR3 region of the T-cell receptor and immunostaining for clonality and cytokine production were applied to these specimens. These techniques compared the same plaque before and after clearance with treatment and found oligoclonal populations of T cells in both. Clonal T cells were most common in the active plaques but were more common in the resolved plaques (93% reduction from active disease) than in normal skin of the same patient. This finding may imply that these residual T-cell clones set the stage for recurrence of disease at the same site if treatment is stopped. Further study of these clonal T cells in both active and resolved plaques demonstrated that they produce IL-17 and IL-22, key mediators of psoriasis, and that they have a psoriasis-specific TCR repertoire which was not seen in normal skin or other skin diseases.