Advancing Knowledge. Enhancing Care.
Advancing Knowledge. Enhancing Care.

Psoriasis News

the latest news from ipc, industry and others

Top Manuscripts

Manuscript summary and expert opinion

Every 6 months, IPC's board and councilors suggest and vote on articles that make the greatest impact on psoriasis research. Please find summaries and commentaries of those Top 5 articles searchable by topic in the list below.

Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials.

Gordon KB, Strober B, Lebwohl M, et al. Lancet. 2018 Aug 25;392(10148):650-661. Epub 2018 Aug 7. 2018
Summary

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.

IPC Expert Commentary

This is another well-organized and well-reported study adding major new evidence of the outstanding effectiveness of risankizumab and of superior effectiveness compared to ustekinumab. Interleukin- (IL-) 23 drives the development of psoriasis by stimulating T-helper-17 and innate immunity cells, which are major sources of pro-inflammatory cytokines. Whereas ustekinumab blocks the p40 subunit that both IL-12 and IL-23 share, risankizumab targets the p19 subunit, specific for only IL-23. The study is notable and especially valuable clinically, as it is one of the very few major studies to directly compare, head-to-head, two biologics with differing modes of action. Clinicians are now overwhelmed with choice of biologics for psoriasis, all providing greater benefit than our previous systemics. For each, the evidence of individual effectiveness may be clear, but the clinician needs to know how they directly compare: We need many more similar head-to-head studies. Pharmaceutical companies Boehringer Ingelheim and AbbVie closely cooperated over this study: Boehringer Ingelheim had sold the commercialization rights of risankizumab to AbbVie in 2016. It is not stated whether the maker of ustekinumab was involved in the study. The baseline demographics table reveals that 72% of the 996 patients weighed >100kg, regrettably reflecting accurately the reality of this comorbidity in patients with severe psoriasis. However, the ethnic origin of study participants in these international studies was 78% white, 17% Asian and only 1.6% black or African-American. This raises the general broader question of what steps clinical study organizers take to ensure recruitment of an appropriate racial mix. – Andrew Y. Finlay

*Dr. Finlay is joint copyright owner of the DLQI. He and Cardiff University receive royalties.

Link to PubMed
More
Close

IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis

Johnston A, Xing X, Wolterink L, et al. J Allergy Clin Immunol. 2016 Dec 31. pii: S0091-6749(16)32489-7. doi: 10.1016/j.jaci.2016.08.056. Biologics 2016
Summary

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.

IPC Expert Commentary

The targeted therapy of various phenotypes of psoriasis was ushered in with the onset of biologics in the early 2000s. Subsequently, much of the research has focused on making therapy with biologics safer and more effective. With this in mind, researchers began looking at patients with psoriasis who failed standard biologic therapy or developed adverse effects to the older generation of biologics, and a new generation of drugs emerged. Basic research into pathomechanisms, such as this study, proved that specific subsets will require specific treatments. Research has shown that GPP is often difficult to treat with TNF-α blockers alone. This unique study by Johnston et al will show the way toward the use of biologics that target IL-36 in GPP. In addition, some reports describe the use of anakinra, an IL-1 receptor antagonize, already available, to treat GPP. Laboratory evidence will stimulate large GPP trials with this drug and similar agents Eventually, patients who have GPP may be treated with shorter courses of a specific biologic than currently available. This is an important concept in which treatment of psoriasis is becoming less cumbersome and less expensive, while, at the same time, more precise and personalized. - Murlidhar Rajagopalan, India

Link to PubMed
More
Close

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

Gordon KB, Blauvelt A, Papp KA, et al, for the UNCOVER-1, UNCOVER-2, and UNCOVER-3 Study Groups. N Engl J Med. 2016 Jun 8. [Epub ahead of print] Biologics, Clinical trials 2016
Summary

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.

IPC Expert Commentary

Over the past two decades, de-convolution of the complex molecular basis of psoriasis has driven pharmacologic development, and the identification of the central role of interleukin (IL)-17 in disease pathogenesis has led to the advent of anti-IL-17 agents. In this large phase-3 program, ixekizumab has proven to be a highly efficacious treatment, with the vast majority of patients maintaining a high level of response up to 60 weeks. With the increasing efficacy of new treatments such as ixekizumab, achievement of PASI 90 and PASI 100 responses are soon becoming the measures of optimal response in biologic studies. The future for our patients is bright, with an ever-growing number of highly effective psoriasis treatments. However, despite revolutionary advances in the treatment of psoriasis, our long-term experience of these agents is still limited, and robust evidence of long-term safety over many years is still an absolute necessity with newly developed drugs. In the case of anti-IL-17 agents, further study is needed to explain the association between IL-17 blockade and the onset/exacerbation of IBD. Furthermore, the frequency of IBD flares on IL-17 inhibitors in real-world practice needs to be examined carefully. There is conflicting evidence regarding the effect of IL-17 on cardiovascular inflammation. The use of carefully constructed registries would be very helpful to monitor the long-term safety of anti-IL-17, particularly with regard to rarer side effects such as cardiovascular events, malignancy, and serious infections, and to examine pregnancy outcomes. –Catriona Ryan, USA

Link to PubMed
More
Close

Association between changes in coronary artery disease progression and treatment with biologic agents for severe psoriasis

Hjuler KF, Bøttcher M, Vestergaard C, Bøtker HE, Iversen L, Kragballe K. JAMA Dermatol. 2016 Oct 1;152(10):1114- 1121. doi: 10.1001/jamadermatol.2016.1984 Biologics, Comorbidities 2016
Summary

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.

IPC Expert Commentary

Although inflammatory pathways of psoriasis share similarities with the mechanisms identified in atherosclerosis, the effect of anti-inflammatory drugs on the development of coronary atherosclerosis is largely unknown. Studies about psoriasis and cardiovascular disease are increasingly published and much attention is drawn to this important field of research. Literature about the effect of biologic treatment on CAD in patients with psoriasis is sparse. This study adds important evidence to the influence of anti-inflammatory treatment with biologics on parameters for coronary artery diseases (CADs). The patients in the group treated with biologics showed a reduced progression of CAC together with a clear improvement of PASI score and a decrease of mean serum levels of C-reactive protein (CRP) during the study. In the control group, CRP did not decrease, but this group started already at a lower mean CRP level. As psoriatic arthritis (PsA) can influence CRP, it would have been interesting to see whether patients with concomitant PsA were present and whether the effects in these patients could be even larger. Confirmation of the beneficial effect of highly effective anti-inflammatory psoriasis treatments on CAD is important to further strengthen the observations of this important study. Their findings can lead to a tool to improve the prognosis of patients with severe psoriasis and asymptomatic CAD and prelude a significant change in patient care. -- Elke de Jong, Netherlands

Link to PubMed
More
Close

The spectrum of mild to severe psoriasis vulgaris is defined by a common activation of IL-17 pathway genes, but with key differences in immune regulatory genes

Kim J, Bissonnette R, Lee J, et al. J Invest Dermatol. 2016 Nov;136(11):2173-2182. doi: 10.1016/j.jid.2016.04.032. Biologics, Genetics, Immunology 2016
Summary

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.

IPC Expert Commentary

The current paradigm in psoriasis is that severity of psoriasis is associated with more inflammation of skin and even systemic inflammation. This study shows important evidence that changes this paradigm. The investigators found that mild psoriasis skin lesions have a higher density of immune infiltrates, higher expression of IL-17 and downstream induced products, and overall higher global genomic score for molecular disease alterations compared with more severe disease. Skin lesions from patients with mild disease also have increased expression of negative immune regulators compared with those with severe disease. Numbers of T cells in psoriasis skin and T-cell proliferation seem to be important factors in progression from mild to severe disease, and facilitated by less effective immune regulations in patients who develop more extensive psoriasis lesions. The strength of this study is that a variety of methods are used to strengthen these surprising but very robust findings. Measuring PASI and BSA may not be sufficient in future psoriasis research to determine the severity of skin involvement in psoriatic disease. – Elke de Jong, Netherlands

Link to PubMed
More
Close

Clinical meaningfulness of complete skin clearance in psoriasis.

Strober B, Papp KA, Lebwohl M, et al. J Am Acad Dermatol. 2016 Jul;75(1):77-82.e7. doi: 10.1016/j.jaad.2016.03.026. Biologics, Prevalence, Quality of life, Registries, Severity 2016
Summary

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.

IPC Expert Commentary

The overall comfort and improvement in quality of life is one of the most important driving forces in helping patients living with psoriasis feel satisfied with their treatment and can now be achieved safely and effectively with the advent of biologics. However, the significance to these patients of achieving a PASI 100 or sPGA of 0 has not been truly known. This pooled analysis shows that the impact is significant. There has been much controversy, however, on the treat-to-target goal that should be expected from any treatment offered to patients with psoriasis. Although PASI 100 or an sPGA of 0 may be desired by both the physician and patient alike, this goal might not be achieved nor maintained with the biologics currently available for a majority of patients. Therefore, over-promising and under-delivering is not a desirable position to be placed in during the course of treatment. This study also showed that a PASI 90 to <100 or sPGA of 1 was still important at reducing the DLQI and PSI, albeit not as significant as a PASI 100 or sPGA of 0. It is also a limitation that this pooled analysis focused on results from one main biologic medication (except for the one study arm that compared brodalumab to ustekinumab) and only measured outcomes at week 12 (end of placebo period) and week 52. Overall, however, it shows that PASI 100 or sPGA of 0 is important to patients in order to improve their symptom-free days and quality of life. – Ron Vender, Canada

Link to PubMed
More
Close

Biologic therapy adherence, discontinuation, switching, and restarting among patients with psoriasis in the US Medicare population

Doshi JA, Takeshita J, Pinto L, et al. J Am Acad Dermatol. 2016 Jun;74(6):1057-1065.e4. Biologics 2016
Summary

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.

IPC Expert Commentary

Several terms have been proposed to indicate biologic adherence, including biologic persistence and biologic survival. Because so many factors influence this status, it is difficult to pinpoint just one reason for low or high values. Several factors, including patient preference, safety, efficacy, coverage, comorbidities, medication supply, prescriber preference, convenience, or other external influences may have a direct or indirect influence on whether patients adhere to biologics. Optimization of treatment is generally preferred to switching in order to avoid a potential decrease in the number of options available if a change is warranted for medical, financial, or other reasons. Unfortunately, this study was also limited by the fact that it may only pertain to the Medicare system in the U.S. and not necessarily extrapolated to other government-provided health insurance plans. In addition, this study uses data from 2009 to 2012, four years out of date. However, it does provide interesting and important information regarding comorbidities in this specific population. The incidences for most well-known comorbidities associated with psoriasis for this large sample size of more than 2,700 patients are listed and could be used for comparative purposes for future studies. It was also shown that Medicare beneficiaries who have psoriasis are more likely to have more comorbidities overall, compared with the normal population of patients with psoriasis. However, with the exception of atherosclerotic disease, comorbidities were not significantly associated with adherence. - Ron Vender, Canada

Link to PubMed
More
Close

Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci

Ellinghaus D, Jostins L, Spain SL, et al. Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14. Genetics 2016
Summary

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.

IPC Expert Commentary

This study provides a breakthrough in genetics studies by looking at a large number of patients to understand the genetic associations and overlap with five common chronic inflammatory diseases. These genes were even linked to a core network of genes that are commonly chosen as targets for therapeutic drugs. The study identified 9 drug-target genes that overlapped with 36 genes from the core network. This discovery could potentially represent new and upcoming candidates for novel drug discovery in the treatment of ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis. Despite the recent explosion of new drug therapies for psoriasis, these genomic studies can further enhance the availability of safe and effective therapies for these patients and their associated comorbidities. – Ron Vender, Canada

Link to PubMed
More
Close

Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants

Tsoi LC, Stuart PE, Tian C, et al. Nat Commun. 2017 May 24;8:15382. doi: 10.1038/ncomms15382. 2017
Summary

Susceptibility to psoriasis is due to both genetic and environmental risk factors. For more than 20 years, scientists have been searching for the predisposing genetic risk factors leading to psoriasis. Initially, studies involved families in which several members had psoriasis. However, with the exception of a few significant findings in some large families, this approach has not explained psoriasis in the majority of individuals. For over a decade, an approach known as the genome-wide association study (GWAS) has been performed. These studies rely on the common and numerous natural genetic variants (SNPs or single nucleotide polymorphisms) found in everyone. An investigation of the frequency of natural variants in patients with psoriasis versus individuals lacking psoriasis has revealed more than 40 common variants that predispose to disease. In turn, these variants lie in genes that can provide important insights into the cellular pathways that are altered in psoriasis. These include signaling of the IL-23 cytokine and activation of genes involved in inflammation via a pathway known as the NF-kB (nuclear factor of kappa B). However, a number of these GWAS investigations involved a subset of variants associated with immune activation queried via an “Immunochip.” This has limited findings.

The current study incorporated old and new GWAS (a total of seven studies) and one Immunochip data set, all consisting of psoriasis cases and controls of European origin. The total number of individuals queried was more than 30,000, which is about 3 times larger than any previous analysis. This meta-analysis revealed 16 regions of association in addition to those 47 that had already been described. Many of the causative variants driving the GWAS signals are thought to lie in regions of the genome that regulate genes rather than genes themselves, and the authors were able to show that a number of the signals may reflect changes in genomic regions operating in CD4+ T helper and CD8+ cytotoxic T cells. They also found that 7 genes from 6 of the novel GWAS regions are targets for 18 different drugs, some of which have already been used to treat psoriasis in clinical practice. It is important to note that many of the additional individuals in this study came from the genetic testing company 23andMe and their diagnosis of psoriasis was self-reported. This required sophisticated statistical tests, as part of the study, to ensure that only individuals likely to have psoriasis were included in the final analysis. It became apparent via this study that such individuals who thought that they had psoriasis sometimes had other diseases that might include atopic dermatitis and seborrheic dermatitis. The 63 regions of association identified in this and earlier GWAS now account for more than 28% of the estimated heritability of psoriasis.

IPC Expert Commentary

This study is important because it expands the number of potential genes with common variants that increase risk of psoriasis; it is the largest study performed to date, incorporating both previous and novel studies, and it shows that data from individuals who are “self-reporting” can be incorporated as long as an appropriate algorithm is included to adjust for misdiagnosis. It also provides further insights into what these variants are in these regions of association and illustrates the potential for GWAS to identify novel drug targets for psoriasis. – Anne M. Bowcock, USA

Link to PubMed
More
Close

Clinically resolved psoriatic lesions contain psoriasis-specific IL-17-producing αβ T cell clones.

Matos TR, O’Malley JT, Lowry EL, et al. J Clin Invest. 2017 Nov 1;127(11):4031-4041. doi: 10.1172/JCI93396. Epub 2017 Sep 25. Clinical trials 2017
Summary

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.

IPC Expert Commentary

Our understanding of the cellular and cytokine activity in active psoriatic plaques has grown tremendously in the last 20 years. Furthering that understanding will require studies such as this that look at the immunologic tableau during or after treatment and in recurrence. This study establishes that populations of long-lived clonal T cells exist in active psoriatic plaques but also in resolved plaques and therefore may stand ready to reinitiate the inflammatory cascade if triggered or if treatment is withdrawn. Even in clinically resolved lesions, these clonal T cells continue to produce IL-17, indicating that they have not been destroyed or deactivated but simply suppressed by the successful treatment. As the authors point out, better understanding of these persistent clonal T cell populations could potentially lead to treatments that can kill or inactivate these populations, possibly leading to longer-term control of psoriasis. – Colby Evans, USA

Link to PubMed

More
Close

Search Reviews:

Filter by Topic:


congress coverage

EADV 2019

Read the psoriasis highlights from the EADV 2019 congress

In the latest

Psoriasis Review

IPC's bi-annual review of the latest news in the field of psoriasis.

 

read the latest issue

Latest news

May 28, 2020
Searching for signals of increased risk of infection in specific subgroups is vitally important, especially when confronted with a severe threat to health, like the worldwide spread of the SARS-CoV-2 virus.
May 27, 2020
US-based rheumatologist and IPC Councilor Arthur Kavanaugh, MD, discusses his plans to continue offering telemedicine appointments to patients after the pandemic. "Telemedicine is a new skill set that [we] providers need to learn," says Dr. Kavanaugh in this week's Stories from the Field video.
May 26, 2020
May 20, 2020
Due to COVID-19 restrictions, patients in Egypt with severe psoriasis are not getting timely access to biologic treatment. IPC Board Member Mahira Hamdy El Sayed, MSc, MD, discusses the potential fallout for Egyptians with psoriasis, post-COVID-19.
  More News

We use cookies on this site to enhance your online experience. By continuing to use this site, you agree to accept cookies.
OK