Human neutrophils drive skin autoinflammation by releasing interleukin (IL)-26.

Autoinflammation is a sterile inflammatory process resulting from increased neutrophil infiltration and overexpression of IL-1 cytokines. The factors that trigger these events are, however, poorly understood. By investigating pustular forms of psoriasis, we show that human neutrophils constitutively express IL-26 and abundantly release it from granular stores upon activation. In pustular psoriasis, neutrophil-derived IL-26 drives the pathogenic autoinflammation process by inducing the expression of IL-1 cytokines and chemokines that further recruit neutrophils. This occurs via activation of IL-26R in keratinocytes and via the formation of complexes between IL-26 and microbiota DNA, which trigger TLR9 activation of neutrophils. Thus our findings identify neutrophils as an important source of IL-26 and point to IL-26 as the key link between neutrophils and a self-sustaining autoinflammation loop in pustular psoriasis.

The Prevalence Of Osteoporosis Is Low In Adult Cutaneous Mastocytosis Patients.

BACKGROUND: Systemic mastocytosis (SM) is a clonal disorder of mast cells (MCs) frequently associated with vertebral osteoporosis (OP) and subsequent vertebral fractures (VFs). The natural history of this OP remains unclear. Importantly, we do not know whether OP represents an early event triggered alongside MC abnormalities, and whether MC clonality is sufficient to trigger osteoporosis. OBJECTIVE: To describe OP in patients with medullar clonality in cutaneous mastocytosis (CM) and monoclonal mast cell activation syndrome (MMAS) and to compare their osteoporosis characteristics with those of nonadvanced SM patients (bone marrow mastocytosis and indolent systemic mastocytosis). METHODS: We retrospectively analyzed clinical, biological, and densitometric data of 27 CM, 13 MMAS, and 135 SM patients from the Mastocytosis Expert Center (CEREMAST) in Toulouse, France. RESULTS: The OP (respectively 3.7, 30.8, and 34.1%) and VFs (0.0%, 15.4%, and 20%) were less frequent in CM than in MMAS and SM, despite the presence of clonal MCs in the bone marrow. Most patients with OP and VFs in the non-SM groups had the usual risk factors for OP. Interestingly, the only non-SM patient with a typical SM-like OP had high bone marrow tryptase, developed bone marrow KIT mutation during follow-up, and had a family history of SM. Our data show that OP is not a common clinical finding in CM but is frequent in MMAS. When OP and VFs occur in CM and MMAS patients, they differ from the usual phenotype of SM bone fragility. CONCLUSIONS: Our findings suggest that, in most CM patients, the meaning and management of OP differs from that of OP in MMAS and nonadvanced SM. Prospective longitudinal studies and the validation of predictors are needed to identify CM and MMAS patients developing SM-related OP.

Integrated Safety Analysis of Ritlecitinib, an Oral JAK3/TEC Family Kinase Inhibitor, for the Treatment of Alopecia Areata from the ALLEGRO Clinical Trial Program.

BACKGROUND: The ALLEGRO phase 2a and 2b/3 studies demonstrated that ritlecitinib, an oral JAK3/TEC family kinase inhibitor, is efficacious at doses of ≥ 30 mg in patients aged ≥ 12 years with alopecia areata (AA). OBJECTIVE: The objective of this study was to evaluate the safety of ritlecitinib in an integrated analysis of four studies in AA. METHODS: Two cohorts were analyzed: a placebo-controlled and an all-exposure cohort. Proportions and study size-adjusted incidence rates (IRs) of adverse events (AEs) of interest and laboratory abnormalities are reported. RESULTS: In the placebo-controlled cohort (n = 881; median exposure: 169 days), the proportion of ritlecitinib-treated patients with AEs was 70.2-75.4% across doses versus 69.5% in the placebo group; serious AEs occurred in 0-3.2% versus 1.9% for the placebo. A total of 19 patients permanently discontinued due to AEs (5 while receiving the placebo). In the all-exposure cohort (n = 1294), median ritlecitinib exposure was 624 days [2091.7 total patient-years (PY)]. AEs were reported in 1094 patients (84.5%) and serious AEs in 57 (4.4%); 78 (6.0%) permanently discontinued due to AEs. The most common AEs were headache (17.7%; 11.9/100 PY), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (15.5%; 9.8/100 PY), and nasopharyngitis (12.4%; 8.2/100 PY). There were two deaths (breast cancer and acute respiratory failure/cardiorespiratory arrest). Proportions (IRs) were < 0.1% (0.05/100 PY) for opportunistic infections, 1.5% (0.9/100 PY) for herpes zoster, 0.5% (0.3/100 PY) for malignancies (excluding nonmelanoma skin cancer), and 0.2% (0.1/100 PY) for major adverse cardiovascular events. CONCLUSIONS: Ritlecitinib is well tolerated with an acceptable safety profile up to 24 months in patients aged ≥ 12 years with AA (video abstract and graphical plain language summary available). TRIAL REGISTRIES: ClinicalTrials.gov: NCT02974868 (date of registration: 11/29/2016), NCT04517864 (08/18/2020), NCT03732807 (11/07/2018), and NCT04006457 (07/05/2019).

Deucravacitinib in plaque psoriasis: 2-year safety and efficacy results from the phase III POETYK trials.

BACKGROUND: In the phase III POETYK PSO-1 and PSO-2 trials, deucravacitinib, an oral selective allosteric tyrosine kinase 2 inhibitor, was well tolerated and efficacious over 1 year in patients with psoriasis. OBJECTIVE: To evaluate deucravacitinib safety and efficacy over 2 years in patients participating in the phase III trials. METHODS: In the POETYK long-term extension (LTE), an ongoing phase IIIb open-label trial, adults with moderate-to-severe plaque psoriasis who completed PSO-1 or PSO-2 receive deucravacitinib 6 mg once daily. Safety was assessed via adverse events (AEs) and laboratory parameter abnormalities. Efficacy endpoints, including ≥ 75% reduction from baseline Psoriasis Area and Severity Index score (PASI 75) and static Physician's Global Assessment (sPGA) score of 0/1 (clear/almost clear), were evaluated in patients originally randomized to deucravacitinib, patients who crossed over from placebo at week 16 and patients who achieved PASI 75 at week 24 (peak efficacy). RESULTS: At data cutoff (1 October 2021), 1519 patients had received at least one dose of deucravacitinib; 79.0% and 39.9% had ≥ 52 weeks and ≥ 104 weeks of total deucravacitinib exposure, respectively. Exposure-adjusted incidence rates (EAIRs) per 100 person-years were similar at 1 year and 2 years for any AEs (229.2 vs. 154.4, respectively), serious AEs (5.7 vs. 6.1), discontinuations (4.4 vs. 2.8), deaths (0.2 vs. 0.4), serious infections (1.7 vs. 2.6), herpes zoster (0.9 vs. 0.8), major adverse cardiovascular events (0.3 vs. 0.4), venous thromboembolic events (0.2 vs. 0.1) and malignancies (1.0 vs. 0.9). EAIRs for COVID-19 infections were higher at 2 years than at 1 year (5.1 vs. 0.5) owing to the peak of the global COVID-19 pandemic occurring during the LTE. No clinically meaningful changes from baseline or trends were observed over 2 years in haematological, chemistry or lipid parameters. Clinical responses were maintained in patients who received continuous deu-cravacitinib treatment from baseline [PASI 75: week 52, 72.4%; week 112, 79.7%; sPGA 0/1: week 52, 57.9%; week 112, 61.1% (as observed)]. Responses at week 52 were also maintained in placebo crossovers and in week-24 PASI-75 responders. CONCLUSIONS: Deucravacitinib maintained efficacy and demonstrated consistent safety with no new safety signals observed through 2 years.

Psoriasis is a chronic inflammatory skin condition. Many available treatments for psoriasis are injected, but can be inadequate in terms of effectiveness, and/or cause serious side-effects. Deucravacitinib is a recently approved oral medicine that interferes with an enzyme involved in inflammation called 'tyrosine kinase 2' (TYK2). Deucravacitinib has been shown to improve psoriatic patches and symptoms (such as itching) through 1 year in two global clinical trials in adults with moderate-to-severe plaque psoriasis (POETYK PSO-1 and PSO-2). This study was an analysis of the safety and efficacy of deu­cravacitinib for up to 2 years. To do this, the researchers used data from approximately 1500 people who completed both trials and continued into an ongoing, long-term extension trial (POETYK LTE). Overall, there were no new side-effects, and the number, type and severity of side-effects, as well as the number of patients who stopped treatment because of these side-effects, remained low. The most frequent side-effects included common cold symptoms and COVID-19. Rates of shingles and serious side-effects were comparable to rates reported in the real world. Improvements in psoriasis symptoms seen at 1 year were maintained for up to 2 years in patients receiving deucravacitinib treatment from the start of PSO-1 or PSO-2, or who crossed over from placebo to deucravacitinib at 4 months. Long-term treatment with deucravacitinib improved psoriasis symptoms and resulted in mostly mild side-effects. The study findings suggest that deucravacitinib could be a well-tolerated and effective treatment for people with psoriasis.

Phase 3 Trial of Nemolizumab in Patients with Prurigo Nodularis.

BACKGROUND: Prurigo nodularis is a chronic, debilitating, and severely pruritic neuroimmunologic skin disease. Nemolizumab, an interleukin-31 receptor alpha antagonist, down-regulates key pathways in the pathogenesis of prurigo nodularis. METHODS: In this phase 3, double-blind, multicenter, randomized trial, we assigned adults with moderate-to-severe prurigo nodularis to receive an initial 60-mg dose of nemolizumab followed by subcutaneous injections of 30 mg or 60 mg (depending on baseline weight) every 4 weeks for 16 weeks or matching placebo. The primary end points were an itch response (a reduction of ≥4 points on the Peak Pruritus Numerical Rating Scale [PP-NRS; scores range from 0 to 10, with higher scores indicating more severe itch]) and an Investigator's Global Assessment (IGA) response (a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4] and a reduction from baseline to week 16 of ≥2 points). There were five key secondary end points. RESULTS: A total of 274 patients underwent randomization; 183 were assigned to the nemolizumab group, and 91 to the placebo group. Treatment efficacy was shown with respect to both primary end points at week 16; a greater percentage of patients in the nemolizumab group than in the placebo group had an itch response (56.3% vs. 20.9%; strata-adjusted difference, 37.4 percentage points; 95% confidence interval [CI], 26.3 to 48.5), and a greater percentage in the nemolizumab group had an IGA response (37.7% vs. 11.0%; strata-adjusted difference, 28.5 percentage points; 95% CI, 18.8 to 38.2) (P<0.001 for both comparisons). Benefits were observed for the five key secondary end points: itch response at week 4 (41.0% vs. 7.7%), PP-NRS score of less than 2 at week 4 (19.7% vs. 2.2%) and week 16 (35.0% vs. 7.7%), and an improvement of 4 or more points on the sleep disturbance numerical rating scale (range, 0 [no sleep loss] to 10 [unable to sleep at all]) at week 4 (37.2% vs. 9.9%) and week 16 (51.9% vs. 20.9%) (P<0.001 for all comparisons). The most common individual adverse events were headache (6.6% vs. 4.4%) and atopic dermatitis (5.5% vs. 0%). CONCLUSIONS: Nemolizumab monotherapy significantly reduced the signs and symptoms of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT04501679; EudraCT number, 2019-004789-17.).

Quality of life and stigmatization in people with skin diseases in Europe: A large survey from the 'burden of skin diseases' EADV project.

BACKGROUND: Several large studies on the burden of skin diseases have been performed in patients recruited in hospitals or clinical centres, thus missing people with skin diseases who do not undergo a clinical consultation. OBJECTIVES: To evaluate the burden of the most common dermatological diseases in adult patients across Europe, in terms of quality of life, work life, and stigmatization. METHODS: Population-based survey on a representative sample of the European general population aged 18 years or older. Participants who declared to have had one or more skin problem or disease during the previous 12 months completed the Dermatology Life Quality Index questionnaire, and answered questions regarding the impact of their skin disease on daily and work life, anxiety/depression, and stigmatization. RESULTS: The study population included 19,915 individuals, 44.7% of whom were men. Quality of life was particularly impaired in people with hidradenitis suppurativa (HS), and sexually transmitted diseases. About a half of participants with acne, alopecia, or chronic urticaria, and about 40% of those with atopic dermatitis (AD), skin cancers, or psoriasis reported a modest to extremely large effect of the disease on their quality of life. Overall, 88.1% of participants considered their skin disease as embarrassing in personal life and 83% in work life. About half of the respondents reported sleeping difficulty, feeling tired, and impact of the disease on taking care of themselves. Concerning stigmatization, 14.5% felt to have been rejected by others because of the skin disease, and 19.2% to have been looked at with disgust. Anxiety and depression were frequently reported by patients with all the diseases. CONCLUSIONS: Skin diseases may heavily affect patients' daily and work life, and cause feelings of stigmatization. An early intervention is needed to avoid consequences on the patients' life course.

Public perception of dermatologists in Europe: Results from a population-based survey.

BACKGROUND: The public perception of dermatology has been poorly investigated in Europe. OBJECTIVE: To determine the general public's perception of dermatologists in Europe. METHODS: This multinational, cross-sectional study was conducted within the framework of the EADV population-based survey on the 'Burden of skin diseases in Europe'. Data were collected using a web-based online survey on a representative sample of the general populations aged 18 years or more of 27 European countries. Proportional quota sampling with replacement design was used for each country. RESULTS: A total of 44,689 adult participants responded to the questionnaire, of whom 18,004 visited a dermatologist in the preceding 3 years. The dermatologist was the second most often visited specialist among all medical specialties, with 69.7%, 72.1%, 42.1% and 78.1% of participants in Western Europe (WE), Eastern Europe (EE), Northern Europe (NE) and Southern Europe (SE), respectively, having consulted a dermatologist over the past 24 months. Most participants across all regions agreed that the dermatologist was the first healthcare provider for chronic skin diseases (61.9% in WE, 69.8% in EE, 45.7% in NE and 60.4% in SE) and for skin cancers (65.5% in WE, 67.6% in EE, 42.4% in NE and 63.0% in SE). The five most common reasons for visiting a dermatologist among all participants were: naevi check-up or skin cancer screening (20.2%), chronic skin diseases (16.5%), acute skin diseases (12.4%), cosmetic advice or procedure (10.2%), hyperpigmentation or congenital lesions (9.1%) and hair or nail disorder (7.7%). Most participants (84.6% in WE, 82.5% in EE, 78.3% in NE and 82.8% in SE) were very swatisfied/somewhat satisfied with the service provided. CONCLUSION: Our study findings underscore the central role of dermatologists in skin health and highlights them as valued and trusted care providers across Europe. Understanding the perceived position of the dermatologist is the first step in improving health policy development and implementation. Notably, access to a dermatologist was lowest in NE, probably reflecting differences in healthcare organizational structures or possibly cultural differences in healthcare seeking behaviour.

The journey of patients with skin diseases from the first consultation to the diagnosis in a representative sample of the European general population from the EADV burden of skin diseases study.

BACKGROUND: The journey of patients with skin diseases through healthcare has been scarcely investigated. OBJECTIVE: To analyse the journey of people with skin diseases in the different healthcare environment in Europe. METHODS: This multinational, cross-sectional, European study was conducted on a representative sample of the adult general population of 27 European countries. The prevalence of the most frequent skin diseases was determined. Information was collected on the patient journey from the first medical consultation to the diagnosis, and the reasons for not consulting a healthcare professional. RESULTS: On a total of 44,689 individuals, 30.3% reported to have consulted a dermatologist during the previous 2 years. Participants consulted mainly for mole control or skin cancer screening (22.3%), followed by chronic skin diseases (16.2%). The diagnoses of acne, atopic dermatitis, psoriasis and rosacea were made most frequently by a dermatologist, while fungal skin infections were diagnosed more often by a general practitioner (GP), and sexually transmitted diseases (STD) by other specialists. The diagnosis was not always definitive at the first consultation, in particular for STD. The percentage of people who did not consult a healthcare professional for their skin disease was particularly high for acne (36.4%), alopecia (44.7%) and fungal infection (30.0%). Moreover, 17.7% of respondents with psoriasis did not consult. A high percentage of participants with alopecia thought that the disease was not worrying, while patients with psoriasis often answered that they were able to manage the disease since they had already consulted a doctor. Many patients with acne (41.1%) and fungal infection (48.2%) thought that they were able to handle the disease by themselves. CONCLUSION: The analysis of the self-reported medical journey of patients with common skin diseases may allow to understand the unmet needs of patients, thus improving outcomes and reducing expenses.

Landscape of mast cell populations across organs in mice and humans.

Mast cells (MCs) are tissue-resident immune cells that exhibit homeostatic and neuron-associated functions. Here, we combined whole-tissue imaging and single-cell RNA sequencing datasets to generate a pan-organ analysis of MCs in mice and humans at steady state. In mice, we identify two mutually exclusive MC populations, MrgprB2+ connective tissue-type MCs and MrgprB2neg mucosal-type MCs, with specific transcriptomic core signatures. While MrgprB2+ MCs develop in utero independently of the bone marrow, MrgprB2neg MCs develop after birth and are renewed by bone marrow progenitors. In humans, we unbiasedly identify seven MC subsets (MC1-7) distributed across 12 organs with different transcriptomic core signatures. MC1 are preferentially enriched in the bladder, MC2 in the lungs, and MC4, MC6, and MC7 in the skin. Conversely, MC3 and MC5 are shared by most organs but not skin. This comprehensive analysis offers valuable insights into the natural diversity of MC subtypes in both mice and humans.

Clinical features, therapeutic choice and response by phototype in psoriasis: analysis of the French PsoBioTeq cohort.

BACKGROUND: Little is known about phototype and the response to systemic treatment in psoriasis. OBJECTIVES: To assess the characteristics of psoriasis, the therapeutic choice and its efficacy according to phototype. METHODS: We included patients from the PsoBioTeq cohort initiating a first biologic. Patients were classified according to their phototype. The evaluation included disease characteristics, choice of the initial biologic and therapeutic response at 12 months based on 90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) and Dermatology Life Quality Index (DLQI) 0/1. RESULTS: Of the 1400 patients included, 423 (30.2%), 904 (64.6%) and 73 (5.2%) were in the phototype I-II, III-IV and V-VI groups, respectively. The V-VI group had a higher initial DLQI, and more frequently initiated ustekinumab. Patients in the V-VI group maintained the initial biologic prescribed as did the other phototype groups, even though the proportion of patients reaching PASI 90 and DLQI 0/1 at 12 months was lower in this group than the other groups. CONCLUSIONS: Patient phototype seems associated with quality of life and choice of the initial biologic in psoriasis. The phototype V-VI group less frequently switched treatments than did the other groups when the response was not efficient.

Treatment of plaque psoriasis with deucravacitinib (POETYK PSO-2 study): a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a paper published in a medical journal that describes the results of a study called POETYK PSO-2, which investigated a new treatment for plaque psoriasis. Plaque psoriasis appears on the body as dry, discolored, patches of skin that can be flaky and covered in scales. This can make the skin itch, crack or bleed and make it difficult for people with psoriasis to perform basic everyday tasks. Treatments are available, but some do not always reduce symptoms or may need to be injected or taken multiple times a day, which can be difficult to do, or can have undesirable side effects. Researchers are looking for new treatments for psoriasis. WHAT HAPPENED IN THE STUDY?: Deucravacitinib is a once-daily pill taken by mouth (orally) that was studied as a treatment for moderate to severe plaque psoriasis in two large studies conducted globally, PSO-1 and PSO-2. POETYK PSO-2 was a Phase 3 research study, which is a study that tests a treatment in a large group of participants, that looked at how well deucravacitinib worked in participants with moderate to severe plaque psoriasis compared to a placebo (an inactive pill that has no effect) and an approved psoriasis treatment called apremilast, which is a pill taken twice a day. These medications were tested in adults with moderate to severe plaque psoriasis, which is psoriasis involving 10% or more of their body (equal to 10 or more handprints). The aims of the POETYK PSO-2 study were to find out if treatment with deucravacitinib could improve psoriasis for the participants in the study and to see if there were any side effects. Side effects are events that happened during treatment that may or may not be caused by that treatment. The study also wanted to find out what would happen after stopping treatment with deucravacitinib in participants who had shown major improvements in their psoriasis. WHAT DO THE RESULTS OF THE POETYK PSO-2 STUDY SHOW?: After 4 months of treatment, more participants taking deucravacitinib had significantly greater improvements in psoriasis than those taking placebo or apremilast. The study also showed that participants continued to see these improvements after taking deucravacitinib for up to 1 year. Some participants maintained the improvements in their psoriasis with deucravacitinib after stopping treatment and switching to a placebo. Side effects for participants taking deucravacitinib were generally mild and occurred in similar numbers to those in participants taking placebo. The most common side effects in participants taking deucravacitinib were inflammation of the nose and throat (a common cold) which occurred at a similar rate in participants who took placebo. Clinical Trial Registration: NCT03611751 (POETYK PSO-2 study) (ClinicalTrials.gov).

Bimekizumab efficacy and safety in patients with moderate to severe plaque psoriasis: Two-year interim results from the open-label extension of the randomized BE RADIANT phase 3b trial.

BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that inhibits interleukin-17A/F. Bimekizumab is more efficacious than secukinumab over 1 year in the treatment of psoriasis. OBJECTIVE: Evaluate the safety and efficacy of bimekizumab through 2 years in patients with moderate to severe plaque psoriasis. METHODS: The BE RADIANT phase 3b randomized controlled trial consisted of a 48-week double-blinded period, where patients received bimekizumab (320 mg every 4 or 8 weeks) or secukinumab (300 mg weekly to Week 4, then every 4 weeks), and an open-label extension (OLE). From Week 48, all patients received bimekizumab in the OLE. RESULTS: At Week 48, more patients achieved complete skin clearance (PASI 100; modified non-responder imputation) with bimekizumab than secukinumab (74.8% vs 52.8%). PASI 100 responses were maintained to Week 96 in continuous bimekizumab patients (70.8%); patients who switched from secukinumab to bimekizumab had increased rates at Week 96 (76.6%). The most common adverse events were: nasopharyngitis, oral candidiasis, and urinary tract infection. Safety data were consistent with the known safety profile of bimekizumab. LIMITATIONS: Limited racial diversity; overlap with the COVID-19 pandemic. CONCLUSIONS: High PASI 100 responses achieved with bimekizumab over 48 weeks were sustained through Week 96; secukinumab patients who switched to bimekizumab achieved similar responses by Week 96.