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Psoriasis News

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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.

Association between skin and aortic vascular inflammation in patients with psoriasis: a case-cohort study using positron emission tomography/computed tomography.

Dey AK, Joshi AA, Chaturvedi A, et al. JAMA Cardiol. 2017 Sep 1;2(9):1013-1018. doi: 10.1001/jamacardio.2017.1213. Clinical trials 2018
Summary

Vascular inflammation demonstrated by fluorodeoxyglucose positron emission tomography/ computed tomography (FDG PET/CT) is an important biomarker of cardiovascular risk, and psoriasis, especially in its severe forms, has been associated with vascular inflammation by FDG PET/CT, suggesting a relationship between skin inflammation and vascular disease.

This is an observational prospective cohort study intended to investigate the association between improvement in skin disease and consequent improvement in aortic vascular inflammation, as well as to characterize the impact of anti-TNF therapy on vascular inflammation.

Using vascular inflammation by FDG PET/CT as a primary outcome, the authors hypothesized that improvement of psoriasis severity would be associated with improvement of vascular inflammation at one year. A total of 115 patients were recruited and followed up to a year. The study group was middle-aged (mean 50.8 years), predominately male, had a formal diagnosis of moderate plaque psoriasis (mean PASI score 5.2), and were at low cardiovascular risk by the Framingham Risk Score. All of the patients underwent FDG PET/CT scans at baseline and at 1 year, and all the scans were read in a blinded fashion to patient characteristics.

Psoriasis was treated with different therapeutic modalities, including topical, phototherapy, systemic, and biologic treatments. Psoriasis severity was associated with vascular inflammation at baseline. At 1-year follow-up, the cohort had an improvement in different inflammatory biomarkers, including high-density lipoprotein cholesterol level and high-sensitive C-reactive protein. Reduction in skin disease severity was associated with reduction in vascular inflammation and the greater the improvement in psoriasis severity (PASI > 75) the greater the improvement in vascular inflammation. A subgroup analysis of anti-TNF-treated patients demonstrated significant reduction in psoriasis severity as well as significant improvement in vascular inflammation.

IPC Expert Commentary

This study offers further evidence of the systemic nature of psoriasis and how its control provides a beneficial effect on vascular inflammation, shown by the improvement demonstrated by highly sensitive vascular imaging modalities, in this case FDG PET/CT, as well as amelioration in inflammatory biomarkers. Though not designed to prove causality, the findings in this study suggest that reduction in severity or clearance of the disease can have potential impact in decreasing future cardiovascular events and, hence, cardiovascular morbidity-mortality. Some observational studies have already reported a reduction in the incidence of vascular disease in patients with well-controlled psoriasis. Randomized clinical trials with prolonged observation periods will be needed to confirm this hypothesis. – Nancy Powdosa, Mexico

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Coronary Plaque Characterization in Psoriasis Reveals High-Risk Features That Improve After Treatment in a Prospective Observational Study

Lerman JB, Joshi AA, Chaturvedi A, et al. Circulation. 2017 Jul 18;136(3):263-276. doi: 10.1161/ CIRCULATIONAHA.116.026859. Guidelines 2018
Summary

This important paper by Lerman et al looks to further establish the connection between inflammation in psoriasis and the risk of coronary artery disease. While it is known that psoriasis is associated with an increased risk of myocardial infarction and a variety of coronary risk markers, this study compares imaging of the coronary arteries in patients with psoriasis and controls to assess relative damage. Patients with psoriasis, patients with hyperlipidemia who were approximately 10 years older than the psoriasis patients, and healthy volunteers all underwent coronary computed-tomography angiography to assess for total coronary plaque burden, noncalcified burden, and the presence of high-risk plaques. Total burden and noncalcified burden have previously been established to prospectively predict cardiac events. Patients with psoriasis exhibited significantly more total burden, noncalcified burden, and high-risk plaques than healthy volunteers. Psoriasis was strongly associated with high-risk plaque formation (about 6 times higher than the healthy population and independent of traditional cardiac risk factors). Compared to older patients with hyperlipidemia, psoriasis patients had increased noncalcified plaque burden and a similar number of high-risk plaques despite being younger and having fewer traditional risk factors. The first 50 patients with psoriasis were followed for 1 year and then re-imaged. Interestingly, when the Psoriasis Area and Severity Index (PASI) had improved over that year, there was a significant improvement in both the total plaque burden and the noncalcified burden after adjustment for other coronary risk factors. When the PASI worsened during the year, there was an increase in noncalcified plaque burden. 

IPC Expert Commentary

This paper adds significantly to the increasing evidence that psoriasis is not only associated with coronary disease, but that inflammation is at the heart of both conditions. Psoriasis may be a “hidden risk factor” that, so far, is not commonly considered alongside lipids, blood pressure, and obesity. Even when a patient with psoriasis has few traditional cardiac risk factors, it is important for dermatologists and other physicians to consider that patient’s cardiac risk similar to that of a higher-risk, older patient. Prevention (diet, exercise), cardiac monitoring, and possibly even interventions (such as statins) may be necessary in patients with psoriasis when they would not be in a similar patient who does not have psoriasis. The other key message of this paper is that treating psoriasis successfully shows, even in just one year, improvement in signs of cardiac risk. As we consider how aggressively to treat moderate to severe psoriasis, we must consider the mounting evidence that reducing body-wide inflammation will not only help the patient’s skin and joints, but also may lower the risk of serious and even fatal comorbidities. Psoriasis is a systemic disease, and dermatologists must continue to look to educate colleagues and monitor patients using a team approach to treat not only the skin, but the serious potential complications of chronic inflammation. – Colby Evans, USA

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An analysis of IL-36 signature genes and individuals with IL1RL2 knockout mutations validates IL-36 as a psoriasis therapeutic target.

Mahil SK, Catapano M, Di Meglio P, et al. Sci Transl Med. 2017 Oct 11;9(411).pii:eaan2514.doi:10.1126/scitranslmed.aan2514. Clinical trials 2018
Summary

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.

IPC Expert Commentary

Future improvements in psoriasis treatment will likely rely on the discovery of new immunologic pathways involved in the pathogenesis of different disease subtypes. This study cleverly demonstrates the potential relevance of IL-36 in psoriasis pathophysiology and the immunologic health of patients who are genetically deprived of its function. Although it is far from demonstrating clinical relevance and safety, IL-36 blockade may be an avenue to consider for the next line of psoriasis treatment, especially in pustular psoriasis, where few convincingly effective treatments exist. – Colby Evans, USA

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Psoriasis and suicidality: a systematic review and meta-analysis.

Singh S, Taylor C, Kornmehl H, Armstrong AW. J Am Acad Dermatol. 2017 Sep;77(3):425-440.e2. doi: 10.1016/j.jaad.2017.05.019. Comorbidities 2018
SummaryAlthough psoriasis has been associated with a high prevalence of a wide range of psychiatric comorbidities, including all aspects of suicidality (ideation, suicidal attempts, and completed suicides), few studies have addressed the relationship between psoriasis and the latter.

In order to shed light on the epidemiological association between psoriasis and suicidality, the authors conducted a systematic review and meta-analysis of PubMed, EMBASE, PsyclNFO, and Cochrane databases. The search was limited to English-written studies and included studies published from database inception (1946) to 2017. Inclusion criteria applied were noninterventional studies, study participants 18 years or older, documented psoriasis diagnosis, and documented suicidality, which had to be a primary or secondary endpoint and assessed in conjunction with psoriasis and numerically reported.

Eighteen studies were identified with a total of 1,767,583 participants, of whom 18.6% had psoriasis. The study showed that patients with psoriasis have increased odds of all aspects of suicidality compared to the general population, with suicidal ideation the most pronounced. Patients with psoriasis are twice as likely to contemplate suicide and have a 32% higher likelihood of attempting suicide and 20% higher likelihood of completed suicide. A subanalysis demonstrated that the prevalence of suicidality presents a direct relation with the severity of the disease and that younger patients were more likely to experience suicidality than older patients, putting them especially at risk of suicidal behavior.

IPC Expert Commentary

Despite the fact that many reports have confirmed a higher prevalence of depression and anxiety among psoriatic patients, few have addressed suicidality, and many of these studies have claimed that the risk of suicidal ideation and/or suicidal behavior is not increased in this population. Nevertheless, the present study, despite some limitations, shows that psoriasis can have a substantial emotional impact on an individual, with high rates of suicidality among patients with the disease.

Besides direct effects of psoriasis (isolation, itch, sleeplessness, etc) contributing to psychiatric comorbidity in these patients, shared inflammatory pathways and/or an elevated inflammatory state provided by psoriasis may affect the development and progression of psychiatric diseases, including suicidality.

This finding has important implications in the integral management of psoriasis. Dermatologists and others involved in the care of patients with psoriasis should consider and recognize this association so that those suffering from suicidality can be identified. Then, effective interventions can be established aimed at controlling and reducing the severity of the skin disease as well as this potentially lethal comorbidity. – Nancy Podoswa, Mexico

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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 2018
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

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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

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Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis

Papp KA, Blauvelt A, Bukhalo M, et al. N Engl J Med. 2017 Apr 20;376(16):1551-1560. doi: 10.1056/NEJMoa1607017. Biologics, Clinical trials, Comorbidities, Quality of life 2017
Summary

The development of several highly effective biologic drugs in the past decade has revolutionized the treatment of moderate to severe plaque psoriasis. With increased understanding of the immunopathogenesis of psoriasis, the emphasis has turned toward more specific targets for psoriasis drugs. Although the complex immunological pathways of psoriasis are not yet completely understood, molecules such as IL-23 and IL-17 that are produced by skin or immune cells during the disease process are secreted and then bind to other immune cells. This leads to their differentiation or activation, thereby triggering inflammation. IL-23 itself is thought to induce and maintain T helper 17 cells, Th22 cells, innate lymphoid cells and the effector cytokines IL-17, IL-22 and tumor necrosis factor (TNF)-a. Biologics targeting IL-23 include BI-655066 (risankizumab), briakinumab, guselkumab, tildrakizumab, and ustekinumab. Drugs targeting IL-17 include brodalumab, ixekizumab, and secukinumab. While many of these drugs have shown safety and efficacy in clinical trials of moderate to severe plaque psoriasis, long-term safety is still to be established. IL-23 is composed of two protein subunits: p19 and p40. The p19 subunit is unique to IL-23, whereas the p40 subunit is found in both IL-12 and IL-23. More recently, risankizumab (BI 655066), a drug targeting the p19 subunit of IL-23, has been developed. In a phase 1 trial of patients with moderate to severe psoriasis, risankizumab produced rapid and durable clearing of skin lesions.

The article by Papp et al, cited above, reported the results of a phase 2, head-to-head trial conducted over 48 weeks at 32 sites across North America and Europe. It compared the effects of treating psoriasis patients with either one of 3 dosages of risankizumab (18-mg dose at week 0 or a 90-mg or 180-mg dose at weeks 0, 4 and 16) or ustekinumab (45 mg for patients with body weight <100k or 90 mg for patients with body weight >100k, at weeks 0, 4, and 16). A total of 166 patients received subcutaneous injections of risankizumab (126 patients received a single 18-mg dose at week 0, or 90-mg or 180-mg doses at weeks 0, 4 and 16) or ustekinumab (40 patients treated with 45 mg or 90 mg at weeks 0, 4 and 16). After 12 weeks, the percentage of patients with a 90% or greater reduction in their Psoriasis Area Severity Index (PASI) score was determined. At week 12, risankizumab (90 and 180 mg, pooled) was superior to ustekinumab with regard to the primary endpoint, PASI 90 (77% vs 40%, P<0.001). Adverse events reported for the risankizumab group and ustekinumab group at 48 weeks were similar; however, larger and longer studies are needed to determine the full safety profile of risankizumab.

The authors also looked at the Dermatology Life Quality Index (DLQI) status of these groups. These results showed that 72% of patients receiving risankizumab achieved a DLQI score of 0 or 1, in comparison to 53% of the group treated with ustekinumab at week 12. Treatment with risankizumab also led to a greater mean reduction in scalp, fingernail and palmoplantar disease. In addition, skin sample analysis demonstrated decreased expression of genes involved in the IL-23 pathway and genes associated with psoriasis pathogenesis in only the samples taken from risankizumab-treated patients. Overall blockade of IL-23 with risankizumab was associated with a clinical response that was superior to those associated with ustekinumab.

IPC Expert Commentary

As rightly mentioned by the authors themselves, future studies on the effect of blocking TNF-a on vascular inflammation should involve patients with more extensive skin psoriasis and patients with psoriatic arthritis. In addition, studies should compare the effects of long-term treatment using a TNF-α antagonist to another non-TNF-α-blocking active treatment on vascular inflammation in a double-blind randomized way. Serum biomarkers studies and possibly other imaging studies that are practical are warranted in order to further the understanding of vascular inflammation in patients with psoriasis. - Nawaf Al-Mutairi, Kuwait

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TNF-alpha antagonist and vascular inflammation in patients with psoriasis vulgaris: a randomized placebo-controlled study

Bissonnette R, Harel F, Krueger JG, et al. J Invest Dermatol. 2017 Aug;137(8):1638-1645. doi: 10.1016/j.jid.2017.02.977. Epub 2017 Mar 9. Biologics, Cardiovascular, Clinical trials, Comorbidities 2017
Summary

In this randomized, double-blind, multicenter study, the authors evaluated the effects of adalimumab on vascular inflammation in patients with moderate to severe psoriasis. The psoriasis severity was assessed using PASI (Psoriasis Area Severity Index) scoring and a 6-scale physician global assessment, and by evaluating the body surface area involved. A total of 107 patients were randomized (1:1) to receive adalimumab 80 mg, followed by 40 mg at week 1 and 40 mg every other week for 52 weeks, or to receive placebo for 16 weeks followed by adalimumab 80 mg at week 16, 40 mg at week 17, and 40 mg every other week thereafter, for a total of 52 weeks. Vascular inflammation was assessed with positron emission tomography (PET) and computed tomography (CT) after injection of radiolabeled fluoro-2- deoxy-D-glucose (FDG) at baseline, at week 16, and at week 52/week 68. The primary endpoint of the study was the change from baseline in the TBR (target-to-background ratio) from the ascending aorta at week 16. Secondary endpoints included similar changes from the mean of carotid arteries at week 16, change in TBR from the ascending aorta, and from the mean of carotid arteries at 52 weeks after the first dose of adalimumab. The study showed no difference between adalimumab and placebo in change from baseline vascular inflammation in the aorta and carotid arteries after 16 weeks.

Also, they did not find any change from start of treatment in the ascending aorta, but did find a modest increase in vascular inflammation in carotids after 52 weeks of treatment with adalimumab. Thus, the authors concluded that these results suggest that adalimumab does not decrease vascular inflammation in patients with psoriasis. Moreover, the increase in carotid vascular inflammation observed after 52 weeks of treatment suggests that adalimumab cannot completely prevent the natural progression of carotid wall atherosclerosis in patients with psoriasis.

IPC Expert Commentary

As rightly mentioned by the authors themselves, future studies on the effect of blocking TNF-a on vascular inflammation should involve patients with more extensive skin psoriasis and patients with psoriatic arthritis. In addition, studies should compare the effects of long-term treatment using a TNF-α antagonist to another non-TNF-α-blocking active treatment on vascular inflammation in a double-blind randomized way. Serum biomarkers studies and possibly other imaging studies that are practical are warranted in order to further the understanding of vascular inflammation in patients with psoriasis.  - Nawaf Al-Mutairi, Kuwait

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An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Warren RB, Mrowietz U, von Kiedrowski R, et al. Lancet. 2016 Dec 21. pii:S0140-6736(16)32127- 4. doi: 10.1016/S0140-6736(16)32127-4. Clinical trials, Systemic therapies 2017
Summary

The evidence for methotrexate, one of the most commonly used systemic drugs for psoriasis, is limited to oral dosing. This is the first study on subcutaneous methotrexate (MTX) compared with placebo in patients with psoriasis. Adult patients naïve to methotrexate were randomized 3:1 to MTX 17.5 mg/week or placebo for the first 16 weeks. After 16 weeks, all patients were treated with MTX in combination with folic acid 5 mg/ week. Patients remained on the same dose unless they had not reached PASI 50 at 24 weeks of MTX treatment. In that case, they could be escalated to MTX 22.5 mg/week. Primary efficacy endpoint was PASI 75 after 16 weeks, analyzed by modified intention to treat with non-responder imputation. The study contained 120 patients. At week 16, PASI 75 response was achieved in 41% of patients on MTX versus 10% in the placebo group. Subcutaneous MTX was generally well tolerated. Serious adverse events were seen in 3 patients (3%) who received MTX for the full period of 52 weeks. The study shows a favorable risk-benefit profile of subcutaneous MTX, as well as the beneficial effect of updosing in patients with insufficient response.

IPC Expert Commentary

This well-performed, randomized trial closes the gap in the evidence for methotrexate, which has been and still is an important drug for patients with psoriasis. The evidence regarding efficacy and safety is complemented by patient-reported outcome measures and histological analyses of skin biopsies. Dermatology Quality of Life Index (DLQI) ≤5 was seen in 59% of patients treated with MTX and a DLQI score of 0-1 in 43% of patients, versus 34% and 10% in the placebo group at 16 weeks. The percentage of serious adverse events was low (n=3) and was attributed to the categories gastrointestinal, decreased white blood cell count, and hepatic enzyme increase, necessitating permanent discontinuation of treatment. In addition, biopsies were taken at baseline and 16 weeks, which correlated well with PASI especially when PASI 75 or better was reached. Evidence available before this study virtually consisted of orally administered methotrexate only. In addition, evidence about dosing strategies was sparse in dermatology. This study provides the important first step in gathering evidence: a randomized, placebo-controlled study on the effects of subcutaneous MTX in psoriasis patients. Although a head-to head trial is needed to determine the difference between oral and subcutaneous MTX regarding effects and side-effects, this study by Warren et al provides unique and important evidence that helps to guide future recommendations for optimum dosing of MTX.  - Elke de Jong, Netherlands

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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

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Psoriasis News

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12/15/2018 7:18:00 AM
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11/15/2018 7:28:00 AM
IPC President Jonathan Barker, United Kingdom, and IPC Board Member Lluís Puig, Spain, were co-chairs for IPC’s second Psoriasis Master Class, a comprehensive educational program IPC launched in early 2018 for dermatologists wanting to expand their expertise in caring for people with psoriasis.
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