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The article presents a case study of a 71-year old woman with systemic mastocytosis with history of smoking. It is noted that she was further diagnosed with tripe palms that are characterized clinically by thickened velvety palms with pronounced dermatoglyphics. The article mentions that Anaplastic lymphoma kinase (ALK) fusion oncogenes represent a novel molecular target in a small subset of non-small cell lung cancers (NSCLC).

Importance: Chronic spontaneous urticaria affects approximately 1% of the general population worldwide, including approximately 3 million people in the US, impairs patients' quality of life, and is associated with multiple comorbidities., Observations: Chronic spontaneous urticaria affects patients of any age but is most common in females aged 30 to 50 years. Diagnosis is based on clinical presentation, ie, spontaneously recurring wheals, angioedema, or both. Chronic spontaneous urticaria persists for more than 1 year in most patients (1 or repeated episodes) and may present with comorbidities including chronic inducible urticaria (>10%), autoimmune thyroiditis (approximately 20%), metabolic syndrome (6%-20%), and anxiety (10%-31%) and depression (7%-29%). Known autoimmune endotypes (subtypes of urticaria defined by distinct pathogenesis) of chronic spontaneous urticaria are mediated by mast cell-activating IgE and/or IgG autoantibodies (>50%). Approximately 40% of patients with chronic spontaneous urticaria have a Dermatology Life Quality Index of more than 10, corresponding to a very large or extremely large negative effect on quality of life. Second-generation H1 antihistamines are first-line treatment; partial or complete response, defined as a reduction in urticaria symptoms of greater than 50%, is observed in approximately 40% of patients. The 2022 international urticaria guideline recommends the monoclonal anti-IgE antibody omalizumab as second-line treatment for antihistamine-refractory chronic spontaneous urticaria. However, at least 30% of patients have an insufficient response to omalizumab, especially those with IgG-mediated autoimmune urticaria. Cyclosporine, used off-label, can improve symptoms in approximately 54% to 73% of patients, especially those with autoimmune chronic spontaneous urticaria and nonresponse to omalizumab, but has adverse effects such as kidney dysfunction and hypertension., Conclusions and Relevance: Chronic spontaneous urticaria is an inflammatory skin disease associated with medical and psychiatric comorbidities and impaired quality of life. Second-generation H1 antihistamines are first-line treatment, omalizumab is second-line treatment, and cyclosporine is third-line treatment for chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is a debilitating, inflammatory skin condition characterized by infiltrating immune cells. Available treatments are limited to improving the signs and symptoms. There is an unmet need to develop therapies that target disease-driving pathways upstream of mast cell activation to inhibit or delay the progression of CSU and associated comorbidities. Here, we aim to define disease modification due to a treatment intervention and criteria that disease-modifying treatments (DMTs) must meet in CSU. We have defined disease modification in CSU as a favorable treatment-induced change in the underlying pathophysiology and, therefore, the disease course, which is clinically beneficial and enduring. A DMT must fulfil the following criteria: (1) prevents or delays the progression of CSU, (2) induces long-term, therapy-free clinical remission, which is the sustained absence of CSU signs and symptoms without the need for treatment, and (3) affects the underlying mechanism of CSU, as demonstrated by an effect on disease-driving signals and/or a biomarker. DMTs in CSU should slow disease progression, achieve long-lasting disease remission, target disease-driving mechanisms, reduce mast cell-activating IgE autoantibodies, target cytokine profile polarization, and normalize the gut microbiome and barrier. Treating CSU at the immune system level could provide valuable alternatives to pharmacotherapy in CSU management. Specific DMTs in CSU are yet to be developed, but some show potential benefits, such as inhibitors of Bruton's Tyrosine Kinase, IL-4 and IL-13. Future therapies could prevent CSU signs and symptoms, achieve long-term clinical benefits after discontinuing treatment, and prevent associated concomitant disorders., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment., Objective: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE)., Methods: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022)., Results: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms., Conclusion: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care., (Copyright © 2024. Published by Elsevier Inc.)

Background: Patient-reported outcome measures (PROMs) are validated and standardized tools that complement physician evaluations and guide treatment decisions. They are crucial for monitoring atopic dermatitis (AD) and chronic urticaria (CU) in clinical practice, but there are unmet needs and knowledge gaps regarding their use in clinical practice., Objecctive: We investigated the global real-world use of AD and CU PROMs in allergology and dermatology clinics as well as their associated local and regional networks., Methods: Across 72 specialized allergy and dermatology centers and their local and regional networks, 2,534 physicians in 73 countries completed a 53-item questionnaire on the use of PROMs for AD and CU., Results: Of 2,534 physicians, 1,308 were aware of PROMs. Of these, 14% and 15% used PROMs for AD and CU, respectively. Half of physicians who use PROMs do so only rarely or sometimes. Use of AD and CU PROM is associated with being female, younger, and a dermatologist. The Patient-Oriented Scoring Atopic Dermatitis Index and Urticaria Activity Score were the most common PROMs for AD and CU, respectively. Monitoring disease control and activity are the main drivers of the use of PROMs. Time constraints were the primary obstacle to using PROMs, followed by the impression that patients dislike PROMs. Users of AD and CU PROM would like training in selecting the proper PROM., Conclusions: Although PROMs offer several benefits, their use in routine practice is suboptimal, and physicians perceive barriers to their use. It is essential to attain higher levels of PROM implementation in accordance with national and international standards., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Chronic prurigo (CPG), including prurigo nodularis, is a difficult disease to treat and considerably affects patients' quality of life. Helping patients obtain control of CPG is a major treatment goal., Objective: To develop and validate the Prurigo Control Test (PCT), a tool for assessing disease control in CPG, and to identify a cutoff value for controlled disease to aid treatment decisions., Design, Setting, and Participants: This qualitative study followed the current recommendations for patient-reported outcome measure development in the generation and validation of the PCT. The final PCT was obtained after item generation, followed by reduction and selection, and was then tested for internal consistency and test-retest reliability, convergent validity, known-group validity, screening accuracy, and banding. The item-generation phase resulted in an unselected list of 69 potential PCT items. Impact analysis, interitem correlation, and review for content (face) validity resulted in final set of 5 PCT items. The validation study was performed among patients across 2 expert centers in Germany. Data were analyzed from February 2017 to November 2019., Main Outcomes and Measures: A 5-item PCT with a recall period of 2 weeks was developed. A cutoff value of 10 points or higher was determined as suitable for identifying patients with well-controlled vs poorly controlled CPG., Results: Of the 95 patients included in the validation study, the median (range) age was 63 (19-87) years, 50 patients (53%) were women, and the median (range) disease duration was 72 (9-774) months. The validation study yielded good internal consistency reliability (Cronbach α, 0.86) and a high degree of convergent validity. The PCT demonstrated good known-group validity and could discriminate between patients who differed in prurigo control. Test-retest reliability was high, and the intraclass correlation coefficient was 0.94, indicating excellent reproducibility., Conclusions and Relevance: This qualitative study showed that the PCT is able to assess disease control in patients with CPG. Its retrospective approach, brevity, and simple scoring likely make the PCT suitable for clinical practice and trials.

Background: Concern about disease exacerbations and fear of reactions after coronavirus disease 2019 (COVID-19) vaccinations are common in chronic urticaria (CU) patients and may lead to vaccine hesitancy., Objective: We assessed the frequency and risk factors of CU exacerbation and adverse reactions in CU patients after COVID-19 vaccination., Methods: COVAC-CU is an international multicenter study of Urticaria Centers of Reference and Excellence (UCAREs) that retrospectively evaluated the effects of COVID-19 vaccination in CU patients aged ≥18 years and vaccinated with ≥1 dose of any COVID-19 vaccine. We evaluated CU exacerbations and severe allergic reactions as well as other adverse events associated with COVID-19 vaccinations and their association with various CU parameters., Results: Across 2769 COVID-19-vaccinated CU patients, most (90%) received at least 2 COVID-19 vaccine doses, and most patients received CU treatment and had well-controlled disease. The rate of COVID-19 vaccination-induced CU exacerbation was 9%. Of 223 patients with CU exacerbation after the first dose, 53.4% experienced recurrence of CU exacerbation after the second dose. CU exacerbation most often started <48 hours after vaccination (59.2%), lasted for a few weeks or less (70%), and was treated mainly with antihistamines (70.3%). Factors that increased the risk for COVID-19 vaccination-induced CU exacerbation included female sex, disease duration shorter than 24 months, having chronic spontaneous versus inducible urticaria, receipt of adenovirus viral vector vaccine, having nonsteroidal anti-inflammatory drug/aspirin intolerance, and having concerns about getting vaccinated; receiving omalizumab treatment and Latino/Hispanic ethnicity lowered the risk. First-dose vaccine-related adverse effects, most commonly local reactions, fever, fatigue, and muscle pain, were reported by 43.5% of CU patients. Seven patients reported severe allergic reactions., Conclusions: COVID-19 vaccination leads to disease exacerbation in only a small number of CU patients and is generally well tolerated., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The concept of autoinflammation includes a heterogeneous group of monogenic and polygenic diseases. These are characterized by excessive activation of the innate immune system without antigen-specific T cells or autoantibodies. The diseases are characterized by periodic episodes of fever and increased inflammation parameters. Monogenic diseases include familial Mediterranean fever (FMF) and the newly described VEXAS (vacuoles, E1 enzyme, X‑linked, autoinflammatory, somatic) syndrome. Heterogeneous diseases include adult-onset Still's disease and Schnitzler syndrome. Treatment is aimed at preventing the excessive inflammatory reaction in order to avoid long-term damage, such as amyloid A (AA) amyloidosis., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Urticarial vasculitis (UV) should be differentiated from chronic spontaneous urticaria (CSU) in patients initially presenting with recurrent wheals, although criteria for differential diagnosis remain ill-defined., Objectives: To set the goals, define criteria and unmet needs in UV diagnosis and differential diagnosis with CSU, and explore the possibility of coexistence of both diseases., Methods: Thirteen experts experienced in UV research participated in a Delphi survey of European Academy of Allergy and Clinical Immunology taskforce. This Delphi survey involved three rounds of anonymous responses to n = 32 questions with the aim to aggregate the experts' opinions and to achieve consensus. Urticaria specialists (n = 130, most from Urticaria Centers of Reference and Excellence) evaluated the consensus statements and recommendations in the fourth and final round., Results: The panel agreed that essential criteria to guide a skin biopsy in patients with recurrent wheals should include at least one of the following features: wheal duration >24 h, bruising/postinflammatory hyperpigmentation, and systemic symptoms. Leukocytoclasia and fibrin deposits were identified as a minimum set of UV histological criteria. As agreed by the panel members, CSU and normocomplementemic UV (NUV) may coexist in some patients., Conclusions: The use of established criteria for the diagnosis and differential diagnosis of UV in patients with recurrent wheals can help guide the diagnostic approach and prompt earlier treatment. Further studies should investigate whether CSU and NUV are different entities or part of a disease spectrum., (© 2023 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: The Angioedema Control Test (AECT) is a patient-reported outcome measure developed and validated for the assessment of disease control in patients with recurrent angioedema. Its sensitivity to change and minimal clinically important difference (MCID) have hitherto not been established., Methods: Patients with recurrent angioedema due to chronic spontaneous urticaria, hereditary angioedema, or acquired C1-inhibitor deficiency were repeatedly asked to complete the AECT along with the Angioedema Quality of Life Questionnaire (AE-QoL), Dermatology Life Quality Index (DLQI), and anchors for disease control and whether treatment was sufficient during routine care visits. The sensitivity to the change of the AECT was determined by correlating changes in its scores over time with changes in the applied anchors. The MCID was determined using anchor-based and distributional criterion-based approaches., Results: Eighty-six cases were used for this analysis. Changes in AECT scores correlated well with AE-QoL changes (but less with changes in the DLQI) as well as other applied anchors, demonstrating its sensitivity to change. The MCID was found to be three points for improvement of angioedema control. The available number of cases with meaningful deterioration in our dataset was too low to reach a definite conclusion on the MCID for deterioration of angioedema control., Conclusion: The AECT is a valuable tool to assess changes in disease control in patients with recurrent angioedema over time. The lowest AECT score change that reflects a meaningful improvement of disease control to patients (MCID) is three points., (© 2023 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: Chronic spontaneous urticaria (CSU) and urticarial vasculitis (UV) share several clinical features including the occurrence of wheals. As of yet, the criteria for differentiating the 2 disorders are not clearly defined., Objective: Here, we aimed to identify differences, similarities, and the likelihood for specific clinical features in patients with UV versus those with CSU., Methods: Across 10 Urticaria Centers of Reference and Excellence, 106 patients with skin biopsy-confirmed UV and 126 patients with CSU were prospectively recruited to complete a questionnaire on the clinical features, course, and response to treatment of their disease., Results: As compared with CSU, patients with UV more often experienced postinflammatory skin hyperpigmentation, wheals of ≥24-hour duration, eye inflammation, and fever (6.9, 4.0, 3.6, and 2.4 times, respectively). Clinical features that increased the risk for UV diagnosis when present at the onset of disease included wheals of ≥24-hour duration (7.3-fold), pain of the skin (7.0-fold), postinflammatory hyperpigmentation (4.1-fold), and fatigue (3.1-fold). The diagnostic delay was markedly longer for normocomplementemic UV as compared with hypocomplementemic UV and CSU (21 vs 5 vs 6 months, respectively). Oral corticosteroids and omalizumab were the most effective treatments in patients with UV and CSU, respectively. Patients with UV showed a higher need for immunosuppressive and anti-inflammatory therapies than patients with CSU., Conclusions: Long wheal duration, skin pain and hyperpigmentation, and systemic symptoms point to UV rather than CSU as the underlying disease and should prompt further diagnostic workup including a skin biopsy., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Indolent systemic mastocytosis (ISM) is characterized by excessive mast cell accumulation and mast cell-driven signs and symptoms. Currently used therapies are not approved and have limited efficacy. Lirentelimab (AK002) is a monoclonal antibody against sialic acid-binding immunoglobulin-like lectin (Siglec)-8 that inhibits mast cell activation., Objective: To determine the safety, tolerability, and efficacy of lirentelimab in reducing ISM symptoms., Methods: At a specialty center for mastocytosis in Germany, we conducted a phase 1, first-in-human, single-ascending dose and multidose clinical trial of lirentelimab in patients with ISM. Eligible adults had WHO-confirmed ISM and unsatisfactory response to available treatment. In Part A, patients received a single dose of lirentelimab 0.0003, 0.001, 0.003, 0.01, or 0.03 mg/kg; in Part B, patients received 1 lirentelimab dose of 0.3 mg/kg or 1.0 mg/kg; and in Part C, patients received either 1.0 mg/kg lirentelimab every 4 weeks for 6 months or ascending doses of lirentelimab (one 1-mg/kg dose followed by five 3- to 10-mg/kg doses every 4 weeks). The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in Mastocytosis Symptom Questionnaire (MSQ), Mastocytosis Activity Score (MAS), and Mastocytosis Quality of Life Questionnaire (MC-QoL) scores at 2 weeks after the final dose., Results: Across 25 patients with ISM (n=13 Part A+B, n=12 Part C; median age 51 years, 76% female, median 4.6 years from diagnosis), the most common treatment-related adverse events were feeling hot (76%) and headache (48%). No serious adverse events occurred. Part C median MSQ and MAS symptom severity scores improved across all symptoms (MSQ: skin [38%-56% improvement vs baseline], gastrointestinal [49%-60%], neurologic [47%-59%], musculoskeletal [26%-27%]; MAS: skin [53%-59%], gastrointestinal [72%-85%], neurologic [20%-57%], musculoskeletal [25%]). Median MC-QoL scores improved across all domains: symptoms (39%), social life/functioning (42%), emotions (57%), and skin (44%)., Conclusions: Lirentelimab was generally well tolerated and improved symptoms and QoL in patients with ISM. The therapeutic potential of lirentelimab should be considered for ISM., Trial Registration: ClinicalTrials.gov number, NCT02808793., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neutrophilic dermatoses are a group of clinically heterogeneous diseases characterized by infiltration of neutrophils in the affected tissue. Skin symptoms comprise a spectrum of wheals, papules, plaques, pustules, nodules and ulcerations often in combination with systemic symptoms. Although the pathogenesis of these diseases has not yet been elucidated in depth, broad pathophysiological and clinical overlaps exist with autoinflammatory syndromes. Additionally, recent years have shown the relevance of the signaling pathways of TNF-α, IL-1, IL-12/23 and IL-17 in neutrophilic dermatoses. In this review, we present four selected neutrophilic dermatoses, namely pyoderma gangraenosum, Sweet syndrome, generalized pustular psoriasis and Schnitzler syndrome, discuss pathophysiological aspects and specifically address novel therapeutic options derived from the most recent pathophysiological findings., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Background: Cold urticaria (ColdU) is characterized by pruritic wheals following exposure of the skin to cold. Many patients show insufficient response to antihistamines, the first line treatment. Based on the high efficacy of interleukin-1(IL-1)-inhibition in cold-induced urticarial autoinflammatory diseases, we assessed the effects of rilonacept, an IL-1 inhibitor, in ColdU patients unresponsive to standard treatment., Methods: In this randomized, double-blind, placebo-controlled two-center study, we included 20 patients with ColdU. In the first part, patients received 320 mg rilonacept or placebo (1:1) followed by weekly doses of 160 mg rilonacept or placebo for 6 weeks. In the second part, all patients received weekly 160 mg or 320 mg rilonacept for 6 weeks, open-label. The primary endpoint was change in critical temperature threshold (CTT). Secondary endpoints included changes in quality of life impairment (Dermatology Life Quality Index, DLQI), differences of inflammatory mediators upon cold provocation and safety assessment over the study period., Results: Baseline mean CTTs were 20.2°C (placebo) and 17.3°C (rilonacept). Mean CTTs did not change significantly during the 6-week double-blind treatment (placebo - 0.45°C; rilonacept +0.89°C). IL-6, IL-18 and HSP-70 blood levels showed interindividual variability without significant changes during hand cold water bath provocation in placebo- or rilonacept-treated patients. In contrast, DLQI significantly improved in the rilonacept (mean DLQI reduction of 3.8; p = 0.002) but not in the placebo group (mean DLQI reduction of 0). Comparing baseline with the rilonacept open-label treatment, there were no changes in CTTs or DLQI scores., Conclusion: IL-1 inhibition with rilonacept did not improve ColdU, but demonstrated a good safety profile., Clinical Trial Registration: EudraCT number: 2012-005726-30., Clinicaltrials: gov identifier: NCT02171416., (© 2023 The Authors. Clinical and Translational Allergy published by John Wiley and Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Chronic urticarial rash, mostly due to chronic spontaneous urticaria (CSU), is seen in up to 1 - 4% of the general population. Urticarial vasculitis (UV) and autoinflammatory syndromes, i.e., cryopyrin-associated periodic syndromes (CAPS) and Schnitzler syndrome (SchS), can mimic CSU-like rash but represent rare disorders with systemic symptoms including fever, headache, conjunctivitis, and arthralgia. Clinical and laboratory features can point to the presence of any of these diseases in patients initially presenting with chronic urticarial rash. These include long-lasting wheals (> 24 hours), lesional burning, systemic symptoms, and/or increase in inflammatory markers (e.g., C-reactive protein, serum amyloid A, and/or S100A8/9). Lesional skin biopsy usually demonstrates leukocytoclastic vasculitis (UV) or neutrophil-rich infiltrate (CAPS and SchS). In contrast to CSU, where second-generation H1 antihistamines and omalizumab allow to control symptoms in most patients, systemic immunosuppression and anti-interleukin (IL)-1 therapies are needed in case of UV and autoinflammatory diseases, respectively. The rarity and low awareness of CSU differential diagnoses may be related to the longer delays in diagnosis and therapy in those affected with UV, CAPS, and SchS. Knowledge of the differential diagnoses of CSU is important because only correct diagnosis allows adequate therapy. Complications such as the development of lymphoproliferative disease in SchS and amyloidosis in CAPS, and the presence of comorbid diseases, such as systemic lupus erythematosus in UV, must be considered and monitored., (© Dustri-Verlag Dr. K. Feistle.)

Background: Urticarial vasculitis (UV) is a rare and difficult-to-treat chronic skin disease defined by long-lasting urticarial lesions and the histopathologic finding of leukocytoclastic vasculitis. As of yet, little is known about UV patients' perspective on the disease., Objective: To assess UV patients' perspective on the clinical course, treatment response, greatest challenges, and quality-of-life (QOL) impairment., Methods: A web-based questionnaire was disseminated in a Facebook group of patients with UV. Patients with UV confirmed by skin biopsy were included., Results: Patients with UV had a mean age of 47.3 ± 12.3 years and were mostly female (94.3%; n = 82 of 87). The median delay in diagnosis was 8.1 months (interquartile range, 2.0-46.3). Normocomplementemia and hypocomplementemia were present in 54.0% (n = 27) and 46.0% (n = 23) of 50 patients, respectively. Most patients with UV (51.8%; n = 43 of 83) reported severely decreased QOL due to their disease. Low QOL was also the most frequently reported greatest challenge for patients with UV (40.7%), followed by the long-standing course of UV with frequent relapses (14.8%). Low QOL correlated with long disease duration (r = 0.298; P = .02) and high numbers of clinical symptoms (r = 0.294; P = .007). Patients with UV with allergies, lung diseases, and chronic infections reported lower QOL. Patients with UV with low QOL were treated with analgesics, dapsone, montelukast, omalizumab, and colchicine more often than patients with UV with higher QOL (P < .05 for all)., Conclusions: Our results show a considerable impairment in QOL in patients with UV associated with long disease duration, high symptom burden, and a high need for therapy. Improvement of the management of UV by further research is necessary., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, whereas transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these 3 canonical VEXAS variants produce more UBA1b than any of the 6 other possible single-nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with 2 novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but coexpression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis., (© 2022 by The American Society of Hematology.)

The group of granulomatous dermatoses refers to a multitude of clinically different diseases, which are characterized by a histopathologically similar pattern of inflammation. The cause of granulomatous inflammatory reactions can be infections and also noninfectious stimuli, such as cell disintegration or foreign bodies. The aim of this immunological defence reaction is encapsulation in order to prevent further spread and delimitation from healthy tissue. This is histologically expressed as a granuloma in the sense of a circumscribed aggregation of histiocytes and multinucleated giant cells mostly in dermal connective tissue. The following can be histologically differentiated: sarcoid granuloma characterized by a sparse lymphocytic inflammatory infiltrate and tuberculous granuloma with central necrosis and denser lymphocytic inflammatory infiltrate. Neutrophilic granulocytes together with macrophages occur in suppurative granulomas and palisaded granulomas are characterized by peripherally arrayed macrophages., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Recently, the expression of the mast cell (MC) receptor Mas-related G protein-coupled receptor X2 (MRGPRX2) has been detected in lesional skin of adult patients with cutaneous mastocytosis. As of yet, little is known about the clinical relevance of MRGPRX2 and its agonists in patients with mastocytosis, including indolent systemic mastocytosis (ISM)., Methods: MRGPRX2 and MRGPRX2 agonists, cortistatin (CST), and major basic protein (MBP) were analyzed in lesional and non-lesional skin of patients with ISM and skin of healthy controls by immunohistochemistry. Co-localization of MRGPRX2 and MRGPRX2-mRNA with the MC marker tryptase was assessed by immunofluorescence microscopy and in situ hybridization, respectively. We assessed clinical, demographic, and laboratory data, including mastocytosis activity score (MAS), serum tryptase, and KIT D816V allele burden., Results: The number of MRGPRX2-expressing (MRGPRX2+) cells, MRGPRX2-mRNA+ MCs, and CST-expressing (CST+) and MBP-expressing (MBP+) cells was significantly higher in lesional skin as compared to non-lesional skin and/or skin of healthy controls (all p < 0.05). Increased numbers of MRGPRX2+ cells, MRGPRX2-mRNA+ MCs, and CST+ and MBP+ cells were not associated with clinical and laboratory features of ISM, including disease burden, symptom severity, evidence of anaphylaxis, and tryptase levels., Conclusions: Skin lesions of patients with ISM showed high numbers of MRGPRX2+ cells, although they were not linked to symptom severity. Clinical relevance of the MRGPRX2-mediated pathway of MC activation in ISM remains unclear and should be investigated in further studies., Competing Interests: HB received honoraria (advisory board, speaker) from AbbVie, Novartis, and Sanofi-Aventis, outside of submitted work. JS has no relevant conflict of interest in relation to this work. Outside of it, JS is or recently was advisor for Boehringer Ingelheim. BY is employed by Allakos Inc. MM has no relevant conflict of interest in relation to this work. Outside of it, MM is or recently was a speaker and/or advisor or received institutional research funding from Astria, Allakos, Alnylam, Amgen, Aralez, ArgenX, AstraZeneca, BioCryst, Blueprint, Celldex, Centogene, CSL Behring, Dyax, FAES, Genentech, GIInnovation, GSK, Innate Pharma, Kalvista, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Pfizer, Pharming, Pharvaris, Roche, Sanofi/Regeneron, Shire/Takeda, Third Harmonic Bio, UCB, and Uriach. FS is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Blueprint, Celldex, CogentBio, Genentech, Novartis, Moxie, Sanofi/Regeneron, and Uriach. PK has no relevant conflict of interest in relation to this work. Outside of it, PK is or recently was a speaker and/or advisor for Novartis and Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pyatilova, Ashry, Luo, He, Bonnekoh, Jiao, Moñino-Romero, Hu, Scheffel, Frischbutter, Hermans, Youngblood, Maurer, Siebenhaar and Kolkhir.)

Chronic pruritus is a common and debilitating symptom in patients with atopic dermatitis and contributes to impairment of quality of life. Effective treatment of pruritus should therefore be one of the main treatment goals in patients with atopic dermatitis. Pathophysiologically, the histamine-independent pruritogens interleukin-31, interleukin-13, and interleukin-4, have been shown to play a major role in atopic dermatitis. All three cytokines can mediate chronic pruritus via Janus kinase 1/2 signaling pathways. Novel drugs target these pathways and have shown rapid and sustained reduction of pruritus in patients with atopic dermatitis in clinical use and in phase II and III clinical trials. Here we summarize the published data on the effects of these drugs on itch parameters such as overall reduction in pruritus intensity and percent of patients with atopic dermatitis achieving a relevant reduction in itch. Each of the novel drugs shows very good effects on pruritus. These data offer hope for an even better and possibly more specific treatment of pruritus in patients with atopic dermatitis in the future. In addition, the different pharmacological approaches give us the chance to learn more about the pathophysiology of pruritus in atopic dermatitis., (© 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Background: The pathogenesis of contact dermatitis, a common inflammatory skin disease with limited treatment options, is held to be driven by inflammasome activation induced by allergens and irritants. We here aim to identify inflammasome-targeting treatment strategies for irritant contact dermatitis., Methods: A high content screen with 41,184 small molecules was performed using fluorescent Apoptosis associated speck-like protein containing a CARD (ASC) speck formation as a readout for inflammasome activation. Hit compounds were validated for inhibition of interleukin (IL)-1β secretion. Of these, the approved thiuramdisulfide derivative disulfiram was selected and tested in a patch test model of irritant contact dermatitis in 25 healthy volunteers. Topical application of disulfiram, mometasone or vehicle was followed by application of sodiumdodecylsulfate (SDS) for 24 h each. Eczema induction was quantified by mexameter and laser speckle imaging. Corneocyte sampling of lesional skin was performed to assess inflammasome-mediated cytokines IL-1β and IL-18., Results: Disulfiram induced a dose-dependent inhibition of ASC speck formation and IL-1β release in cellular assays in vitro. In vivo, treatment with disulfiram, but not with vehicle and less mometasone, inhibited SDS-induced eczema. This was demonstrated by significantly lower erythema and total perfusion values assessed by mexameter and laser speckle imaging for disulfiram compared to vehicle ( p  < 0.001) and/or mometasone ( p  < 0.001). Also, corneocyte IL-18 levels were significantly reduced after application of disulfiram compared to vehicle ( p  < 0.001)., Conclusion: We show that disulfiram is a dose-dependent inhibitor of inflammasome pathway activation in vitro and inhibitor of SDS-induced eczema in vivo. Topical application of disulfiram represents a potential treatment option for irritant contact dermatitis., Competing Interests: Carolina Vera, Angela Abad‐Perez, Silke Radetzki, Martin Neuenschwander, Edgar Specker, Marc Nazaré, Jens v. Kries, Niklas Amadeus Mahnke, Jörg Scheffel and Stefan Frischbutter have no conflict of interest. Eicke Latz is the co‐founder and consultant to IFM Therapeutics. Hanna Bonnekoh received honoria (advisory board, speaker) from Novartis. Marcus Maurer is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Alnylam, Amgen, Aralez, ArgenX, AstraZeneca, BioCryst, Blueprint, Celldex, Centogene, CSL Behring, Dyax, FAES, Genentech, GIInnovation, Innate Pharma, Kalvista, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Pharming, Pharvaris, Roche, Sanofi/Regeneron, Shire/Takeda, ThirdHarmonicBio, UCB, and Uriach. Karoline Krause has received grants from Novartis and Roche and payment for lectures and/or consultancies from Novartis, Roche, and SOBI., (© 2021 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: Urticarial vasculitis (UV) is defined by long-lasting urticarial lesions combined with the histopathologic findings of leukocytoclastic vasculitis. As one of the major unmet needs in UV, diagnostic criteria are rather vague and not standardized. Moreover, there seems to be considerable overlap with chronic spontaneous urticaria (CSU), particularly for the normocomplementemic variant of UV. Therefore, this study aimed to develop a diagnostic scoring system that improves the histopathologic discrimination between UV and CSU., Methods: Lesional skin sections of patients with clinical and histopathologic diagnosis of UV (n = 46) and CSU (n = 51) were analyzed (blinded to the diagnosis) for the following pre-defined criteria: presence of leukocytoclasia, erythrocyte extravasation, fibrin deposits, endothelial cell swelling, ectatic vessels, blurred vessel borders, dermal edema, intravascular neutrophil, and eosinophil numbers and numbers of dermal neutrophils, macrophages and mast cells., Results: The greatest differences between UV and CSU samples were observed for leukocytoclasia (present in 76% of UV vs. 3.9% of CSU samples; p < 0.0001), erythrocyte extravasation (present in 41.3% of UV vs. 2.0% of CSU samples; p < 0.0001), and fibrin deposits (present in 27.9% of UV vessels vs. 9.7% of CSU vessels; p < 0.0001). Based on these findings, we developed a diagnostic score, the urticarial vasculitis score (UVS), which correctly assigned 37 of 46 cases of UV and 49 of 51 cases of CSU to the previously established diagnosis., Conclusion: Our results suggest that the UVS, a combined quantitative assessment of the three criteria leukocytoclasia, fibrin deposits and extravasated erythrocytes, distinguishes UV from CSU in skin histopathology. The UVS, if validated in larger patient samples, may help to improve the diagnostic approach to UV., (© 2021 The Authors. Clinical and Translational Allergy published by John Wiley and Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Systemic autoinflammatory diseases are characterized by a spontaneous chronic inflammatory reaction mediated by the innate immunity. The inflammatory processes involve many organs including the skin. Diagnosis remains a challenge despite new molecular genetic methods, but early diagnosis is crucial for the prevention of long-term complications such as amyloidosis. Skin manifestations are often observed early in the course of the disease and can be decisive in the diagnosis.