Pyoderma gangrenosum (PG) is an ulcerative inflammatory disorder affecting the lower legs in 80% of patients. The use of biologic medications to treat PG is increasing, although there is a limited evidence base to guide treatment choices. In some health systems, such as the UK National Health Service, limitations are placed on biologic prescribing for PG, leading to wide variations in prescribing. A survey of mainly UK clinicians showed that prednisolone remains the first-line treatment for PG (90%, 34/38). Biologics have been used by 66% (25/38) of clinicians as second-line therapy, but 19% (7/38) have had prescribing requests declined. Further research is needed to determine optimal treatment strategies for PG.

Malignant melanoma is an aggressive form of cancer, which can be treated with anti-CTLA-4 and anti-PD-1 checkpoint inhibitor antibodies but while anti-CTLA-4 antibodies have clear benefits for some patients with melanoma, productive responses are difficult to predict and often associated with serious immune related adverse events. Antibodies specific to CTLA-4 bind two major isoforms of CTLA-4 in humans, the receptor isoform and a second naturally secretable, soluble isoform - sCTLA-4. The primary aim here was to examine the effect of selectively blocking the function of sCTLA-4 on in vitro immune responses from volunteer healthy or melanoma patient PBMC samples. Addition of recombinant sCTLA-4 to healthy PBMC samples demonstrated sCTLA-4 to have immunosuppressive capacity comparable to recombinant CTLA4-Ig, partially reversible upon antibody blockade. Further, we identified a mechanistic relationship where melanoma patient TGFβ2 serum levels correlated with sCTLA-4 levels and provided the basis for a novel protocol to enhance sCTLA-4 production and secretion by T cells with TGFβ2. Finally, a comparison of selective antibody blockade of sCTLA-4 demonstrated that both healthy and melanoma patient effector cytokine responses can be significantly increased. Overall, the data support the notion that sCTLA-4 is a contributory factor in cancer immune evasion.

Abstract Linked Article: Corbett et al. Br J Dermatol 2022; 187:494–506.

Linked Article: Ben Abdallah et al. Br J Dermatol 2021; 185:1169–1175.

Data presented in this paper can be made available by application. Please follow the steps under ‘Data Requests’ on the BADBIR website: http://www.badbir.org/Publications/

Background Seasonal variations have been reported for immune markers. However, the relative contributions of sunlight and vitamin D variability on such seasonal changes are unknown. Objective This double-blind, randomized, placebo-controlled trial tested whether daily 400 IU vitamin D 3 supplementation affected short-term (12 weeks) and long-term (43 weeks) natural regulatory T cell (nTreg) populations in healthy participants. Design 62 subjects were randomized equally to vitamin D versus placebo in March and assessed at baseline, April (4w), June (12w), September (25w) and January (43w). Circulating nTregs, ex vivo proliferation, IL-10 and IFN-γ productions were measured. Vitamin D metabolites and sunlight exposure were also assessed. Results Mean serum 25-hydroxyvitamin D (25(OH)D) increased from 35.8(SD 3.0) to 65.3(2.6) nmol/L in April and remained above 75 nmol/L with vitamin D supplementation, whereas it increased from 36.4(3.2) to 49.8(3.5) nmol/L in June to fall back to 39.6(3.5) nmol/L in January with placebo. Immune markers varied similarly between groups according to the season, but independently of 25(OH)D. For nTregs, the mean (%CD3 + CD4 + CD127 lo cells (SEM)) nadir observed in March (2.9(0.1)%) peaked in September at 4.0(0.2)%. Mean T cell proliferation peaked in June (33156(1813) CPM) returning to the nadir in January (17965(978) CPM), while IL-10 peaked in June and reached its nadir in September (median (IQR) of 262(283) to (121(194) pg/ml, respectively). Vitamin D attenuated the seasonal increase in IFN-γ by ~28% with mean ng/ml (SEM) for placebo vs vitamin D, respectively, for April 12.5(1.4) vs 10.0(1.2) (p=0.02); June 13.9(1.3) vs 10.2(1.7) (p=0.02) and January 7.4(1.1) vs 6.0(1.1) (p=0.04). Conclusions Daily low dose Vitamin D intake did not affect the nTregs population. There were seasonal variation in nTregs, proliferative response and cytokines, suggesting that environmental changes influence immune response, but the mechanism seems independent of vitamin D status. Vitamin D attenuated the seasonal change in T cell-produced IFN-γ, suggesting a decrease in effector response which could be associated with inflammation. Clinical Trial Registration https://www.isrctn.com , identifier (ISRCTN 73114576).

KJM has received honoraria from Janssen, LEO Pharma, Lilly and Novartis. ADB consults and lectures for Abbvie, Amgen, Boehringer Ingelheim, Celgene, Janssen, Lilly, Novartis and Pfizer. JNWN has received honoraria for advisory boards and lectures at sponsored symposia together with grants for research in the past 5 years from AbbVie, Amgen, Celgene, Janssen, Lilly, Novartis, and Pfizer. CEK has received honoraria and/or research funding from AbbVie, Celgene, Galderma, GSK-Stiefel, Janssen, Johnson & Johnson, LEO Pharma, Lilly, Novartis, Pfizer and UCB Pharma. KM has received honoraria from Lilly and UCB Pharma. CEMG has received honoraria and/or research grants from Abbvie, Actelion, Almirall, Amgen, Celgene, Galderma, LEO Pharma, GSK-Stiefel, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz, Sun Pharmaceuticals and UCB Pharma. NJR reports grants from PSORT industrial partners as listed (http://www.psort.org.uk/); other research grants from GSK-Stiefel and Novartis; and other income to Newcastle University from Almirall, Amgen, Janssen, Novartis, Sanofi Genzyme Regeneron and UCB Pharma Ltd for lectures/attendance at advisory boards. All other authors (ML; HA; MMS; ACG; ADO) declare no conflicts. Data presented in this paper can be made available by application. Please follow the steps under ‘Data Requests’ on the BADBIR website: http://www.badbir.org/Publications/.

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real‐world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first‐line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti‐drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one‐compartment model. A maximum effect (Emax) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half‐maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring “dashboard” to individualize dosing and improve treatment outcomes.

In this issue of the BJD, Smith et al. update the highly cited guidelines for biological therapy in psoriasis for 2020. This guideline covers all biological therapies currently approved by the National Institute of Health and Care Excellence (NICE). The field is fast moving, with the advent of biosimilars, new-indication certolizumab and the new biologics ixekizumab, brodalumab, risankizumab, tildrakizumab and guselkumab. These quality guidelines are accredited by NICE, and use Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and a contemporaneous updated systematic review. The remit is wide ranging and comprehensive. The GRADE method of framing recommendations makes dry reading, often repeating the older version of the guidelines, so it is worth lifting the lid off the guidelines and reading the evidence tables, which link the evidence to the recommendations. Here, there is a fuller narrative of the evidence and it provides for a better understanding of the current state of the evidence. The decision aids in Tables S2–S5 are particularly helpful. The comparative properties of the biologics and all-important considerations are tabulated, including efficacy and likelihood of continuing them. In the assessment of value and affordability, technology with greater efficacy than its comparators commands a higher price, although the guideline developers indicate that cost should not override all other considerations, as all therapies have met the NICE assessment of cost benefit. Achieving adequate levels to optimize treatment with a lower-cost agent, for example measuring adalimumab levels, may add value and the guideline provides strategies for dose escalation or dose interval reduction. Underpinning the evidence-based guideline is an updated network meta-analysis (NMA), which also appears in this issue. With 37 randomized controlled trials (RCTs) covering 11 biologics, methotrexate and placebo, the literature lends itself to this approach. For the most part, RCTs are comparable and use similar patients and outcome measures. Aside from the usual forest plots of each trial, the network can position and rank outcomes across the different trials. This is done with key efficacy outcomes, which the trials were designed to measure, and gives rise to a clear rank ordering for effectiveness. Unlike many other NMAs in this field the authors examine a second dimension of tolerability, which is important for the way the GRADE methodology examines harm before arriving at a recommendation. However, there is no easy way to measure tolerability; a surrogate for harm has to be chosen and, here, patients withdrawing owing to adverse events (AEs) were compared. There are caveats in that placebo controlled trials are limited to a short window. Also, AEs need not be related to the study drug. Withdrawals are few in number and specific AEs are not published. Trials capture, but are not powered or designed to test, tolerability. The authors applied hierarchical cluster analysis to test whether the different interventions are comparable or if there are outliers or distinct groups, for example predicated on mechanism of action. No single agent came out as best and most biologics cluster together and can be considered on their merits. Undoubtedly, this guideline, its linked evidence and decision aid will help the confused clinician make the best choices.

Background The cardiovascular safety profile of biologic therapies used for psoriasis is unclear. Objectives To compare the risk of major cardiovascular events (CVEs; acute coronary syndrome, unstable angina, myocardial infarction and stroke) in patients with chronic plaque psoriasis treated with adalimumab, etanercept or ustekinumab in a large prospective cohort. Methods Prospective cohort study examining the comparative risk of major CVEs was conducted using the British Association of Dermatologists Biologics and Immunomodulators Register. The main analysis compared adults with chronic plaque psoriasis receiving ustekinumab with tumour necrosis-alpha inhibitors (TNFi: etanercept and adalimumab), whilst the secondary analyses compared ustekinumab, etanercept or methotrexate against adalimumab. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using overlap weights by propensity score to balance baseline covariates among comparison groups. Results We included 5468 biologic-naive patients subsequently exposed (951 ustekinumab; 1313 etanercept; and 3204 adalimumab) in the main analysis. The secondary analyses also included 2189 patients receiving methotrexate. The median (p25-p75) follow-up times for patients using ustekinumab, TNFi, adalimumab, etanercept and methotrexate were as follows: 2.01 (1.16-3.21), 1.93 (1.05-3.34), 1.94 (1.09-3.32), 1.92 (0.93-3.45) and 1.43 (0.84-2.53) years, respectively. Ustekinumab, TNFi, adalimumab, etanercept and methotrexate groups had 7, 29, 23, 6 and 9 patients experiencing major CVEs, respectively. No differences in the risk of major CVEs were observed between biologic therapies [adjusted HR for ustekinumab vs. TNFi: 0.96 (95% CI 0.41-2.22); ustekinumab vs. adalimumab: 0.81 (0.30-2.17); etanercept vs. adalimumab: 0.81 (0.28-2.30)] and methotrexate against adalimumab [1.05 (0.34-3.28)]. Conclusions In this large prospective cohort study, we found no significant differences in the risk of major CVEs between three different biologic therapies and methotrexate. Additional studies, with longer term follow-up, are needed to investigate the potential effects of biologic therapies on incidence of major CVEs.

Background: Biologic therapies can be highly effective for the treatment of severe psoriasis, but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection could improve patient outcomes and treatment cost-effectiveness. Objective: We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the 2 most commonly prescribed biologics for psoriasis: adalimumab (anti-TNF-alpha) and ustekinumab (anti-IL-12/23). Methods: This study uses a national psoriasis registry that includes longitudinal treatment and response observations and detailed clinical data. HLA alleles were imputed from genome-wide genotype data for 1326 patients for whom 90% reduction in Psoriasis Area and Severity Index score (PASI90) response status was observed after 3, 6, or 12 months of treatment. We developed regression models of PASI90 response, examining the interaction between HLA-C*06:02 and drug type (adalimumab or ustekinumab) while accounting for potentially confounding clinical variables. Results: HLA-C*06:02-negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time points (most strongly at 6 months: odds ratio [OR], 2.95; P = 5.85 x 10(-7)), and the difference was greater in HLA-C*06:02-negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 x 10(-5)). Biologic-naive patients who were HLA-C* 06:02 positive and psoriatic arthritis negative demonstrated significantly poorer response to adalimumab at 12 months (OR, 0.31; P = 3.42 x 10(-4)). Results from HLA-wide analyses were consistent with HLA-C*06:02 itself being the primary effect allele. We found no evidence for genetic interaction between HLA-C*06:02 and ERAP1. Conclusion: This large observational study suggests that reference to HLA-C* 06: 02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.

这项英国研究使用的信息来自一个名为“英国皮肤科医师协会生物干预注册数据库”(British Association of Dermatologists Biologic Interventions Register,或称 BADBIR)的数据来源,建立该数据库是为了收集有关对比新型生物疗法与全身性非生物疗法用于皮肤病的效果和转归的信息。在本研究中,生物疗法“英夫利昔单抗”用于包括银屑病在内的多种皮肤病的情况与其他全身性疗法(“全身性”是指作用于整个身体,与此相对的是有些药物仅涂抹在皮肤上)进行了比较。本项研究工作聚焦于患者在接受不同治疗时的严重感染发生率。这类严重感染是指导致患者长时间住院、接受抗生素静注治疗或者死亡的感染。调查感染原因时也考虑到其他病症可能带来的影响,两组也均有可能存在因为其他病症出现的严重感染。本研究得出的主要结论是,接受英夫利昔单抗的患者发生严重感染的可能性(风险)是接受其他全身性治疗患者的两倍。主要感染是肺部感染或者皮肤和软组织感染。这些感染多发生于患者开始使用英夫利昔单抗后的最初六个月。这是一项重要发现,因为向患者告知此类风险将成为该药物用药前所进行初步评估的一个关键组成部分。作者指出,尚未在其他用于皮肤病治疗的生物制剂中得出类似信息,那些药物也可能与感染风险增加有关,但对结核病等既存慢性感染进行筛查已成为使用生物制剂治疗候选患者前进行调查评估的一个重要组成部分。

This study from the UK used information from a data source known as the British Association of Dermatologists Biologic Interventions Register, or BADBIR, which was established to collect information on the use and outcomes of new biologic treatments, versus nonbiologic systemic treatments, for skin disease. In this study, information on the use of the biologic treatment, Infliximab, used in a number of skin diseases including psoriasis was compared with other systemic therapies (systemic means treatments that work on the whole body, as opposed to something applied just to the skin). The focus of this work was on the occurrence of serious infections in patients under different treatments. These serious infections were those where patients had prolonged admissions to hospital, were treated with intravenous antibiotics or where they died. The investigation also considered the possible effects of other conditions which might also have led to the development of serious infections in both groups. The main conclusion of this work was that the likelihood (risk) of serious infection in patients receiving Infliximab compared with those receiving other systemic therapies was doubled. The main infections were either those affecting the lungs or skin and soft tissue infections. These infections were mainly seen in the first six months after patients started on Infliximab. This is an important finding as counselling patients on this risk will form a key part of preparatory assessment prior to use of this medicine. The authors point out that similar information is not yet available for other biologics used for the treatment of skin disease and these may also be associated with an increased risk of infection, although screening for existing chronic infections, such as tuberculosis, forms an important part of the pre‐treatment investigation of potential candidates for these biologic medications.

IMPORTANCE High-cost biologic therapies have transformed the management of immune-mediated inflammatory diseases. To optimize outcomes and reduce costs, dose adjustment informed by measurement of circulating drug levels has been shown to be effective in various settings. However, limited evidence exists for this approach with the interleukin 12 and interleukin 23 inhibitor ustekinumab. OBJECTIVE To evaluate clinical utility of therapeutic drug monitoring for ustekinumab in patients with psoriasis. DESIGN, SETTING, AND PARTICIPANTS A prospective observational cohort of 491 adults with psoriasis was recruited to the multicenter Biomarkers of Systemic Treatment Outcomes in Psoriasis study within the British Association of Dermatologists Biologic and Immunomodulators Register from June 2009 to December 2017; samples from some patients were taken between 2009 and 2011 as part of a pilot study with the same inclusion criteria. EXPOSURE Serum ustekinumab level measured at any point during the dosing cycle using an enzyme-linked immunosorbent assay. MAIN OUTCOMES AND MEASURES Disease activity measured using the Psoriasis Area and Severity Index (PASI) score. Treatment response outcomes were PASI75 (75% reduction in PASI score from baseline [primary outcome]), PASI90 (90% reduction of PASI score from baseline), and absolute PASI score of 1.5 or less. RESULTS A total of 491 patients (171 women and 320 men; mean [SD] age, 45.7 [12.8] years) had 1 or more serum samples (total, 853 samples obtained 0-56 weeks from start of treatment) and 1 or more PASI scores within the first year of treatment. Antidrug antibodies were detected in only 17 of 490 patients (3.5%). Early measured drug levels (1-12 weeks after starting treatment) were associated with PASI75 response 6 months after starting treatment (odds ratio, 1.38; 95% CI, 1.11-1.71) when adjusted for baseline PASI score, age, and ustekinumab dose. However, this finding was not consistent across the other PASI outcomes (PASI90 and PASI score of <= 1.5). CONCLUSIONS AND RELEVANCE This real-world study provides evidence that measurement of early serum ustekinumab levels could be useful to direct the treatment strategy for psoriasis. Adequate drug exposure early in the treatment cycle may be particularly important in determining clinical outcome.

Linked Article: van der Kraaij et al. Br J Dermatol 2019; 180:31–42.

Importance Pyoderma gangrenosum is a rare inflammatory skin condition that is difficult to diagnose. Currently, it is a “diagnosis of exclusion,” a definition not compatible with clinical decision making or inclusion for clinical trials. Objective To propose and validate diagnostic criteria for ulcerative pyoderma gangrenosum. Evidence Review Diagnostic criteria were created following a Delphi consensus exercise using the RAND/UCLA Appropriateness Method. The criteria were validated against peer-reviewed established cases of pyoderma gangrenosum and mimickers using k-fold cross-validation with methods of multiple imputation. Findings Delphi exercise yielded 1 major criterion—biopsy of ulcer edge demonstrating neutrophilic infiltrate—and 8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history of inflammatory bowel disease or inflammatory arthritis; (4) history of papule, pustule, or vesicle ulcerating within 4 days of appearing; (5) peripheral erythema, undermining border, and tenderness at ulceration site; (6) multiple ulcerations, at least 1 on an anterior lower leg; (7) cribriform or “wrinkled paper” scar(s) at healed ulcer sites; and (8) decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Receiver operating characteristic analysis revealed that 4 of 8 minor criteria maximized discrimination, yielding sensitivity and specificity of 86% and 90%, respectively. Conclusions and Relevance This Delphi exercise produced 1 major criterion and 8 minor criteria for the diagnosis of ulcerative pyoderma gangrenosum. The criteria may serve as a guideline for clinicians, allowing for fewer misdiagnoses and improved patient selection for clinical trials.

Psoriasis is a common skin disease that affects up to 3% of people worldwide. Psoriasis is driven by faults in the immune system (which protects the body from infection), which leads to excess skin production. People with the most severe form of psoriasis are given therapies to dampen down the immune system. Systemic therapies (methotrexate and ciclosporin) work to reduce the whole immune system, while biologic therapies (adalimumab, etanercept, and ustekinumab) are targeted to specific immune pathways in the skin. However, there is concern that these therapies may increase the risk of cancer. This study of psoriasis patients in Ireland, Israel, Italy, Spain, and the U.K. aimed to find out if the amount of time spent on these therapies increases the risk of cancer. Each person who developed a cancer during the study was compared to four cancer‐free psoriasis patients (controls) of the same sex, age, dermatology centre, and year of entry into the study. The total time spent on systemic and biologic therapies was calculated for each patient. The authors did not find a difference in the time spent on systemic or biologic therapies between patients who developed a cancer and controls. This result remained unchanged after considering the possible effects of previous exposure to other systemic therapies, duration of psoriasis, smoking, previous exposure to phototherapy and other simultaneous diseases. This study showed that cancers were not more likely to develop after up to 8 years of treatment with biologic therapies.

银屑病是一种常见的皮肤病,影响全世界高达 3% 的人。银屑病由免疫系统(保护身体免受感染)中的缺陷引起, 导致皮肤过度产生。最严重的银屑病患者需要接受治疗以抑制免疫系统。全身疗法(甲氨蝶呤和环孢素)有助于抑制整个免疫系统,而生物疗法(阿达木单抗、依那西普和优特克单抗)则针对皮肤中的特定免疫通路。然而, 亦存在对这些疗法可能会增加癌症风险的担忧。这项针对爱尔兰、以色列、意大利、西班牙和英国银屑病患者的研究旨在了解花在这些疗法上的时间是否会增加患癌症的风险。将研究期间患癌症的每名患者与性别、年龄、皮肤病中心和进入研究年份均相同的四名无癌银屑病患者(对照)进行比较。计算每位患者在全身和生物治疗上花费的总时间。作者并未发现患癌症的患者和对照患者在全身或生物治疗上花费的时间有所不同。如果考虑先前接触其他全身治疗、银屑病持续时间、吸烟、之前接触光疗和其他同时发生的疾病可能产生的影响,该结果保持不变。该研究表明,在使用生物疗法治疗长达 8 年后,癌症发生的可能性并未增大。

Psoriasis is a common condition that affects the skin and joints. Skin psoriasis tends to wax and wane throughout life without obvious reasons, and thus causes considerable distress. Someone with psoriasis may have other family members with the same problem but this is not usually the case. In psoriasis, more skin cells are made leading to build‐up on the top layer and formation of flaky patches on the skin or severe dandruff of the scalp. The cause is unknown and believed to involve the genes and immune system, and the treatments we use now can control psoriasis but don't cure it. This study from Aberdeen, UK looked into two types of cells of the immune system; one of them can start or cause psoriasis to happen, while the other has the power to fight back and calm down the skin. We tested the effect of certain injections, cream and light which we frequently use to treat psoriasis, on those cells by taking blood and skin samples. We found that the skin became better after six weeks. The light made the numbers of the “good” cells go higher, while the injection caused the “bad” cells to become fewer and had no effect on the “good” cells. The cream increased the “good” cells and reduced the “bad” cells. We noticed these changes in both the blood and skin which means that the cream and light can have an effect on cells in the circulation and this can be used in the future to make new and safer treatments.