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Summary: Background: Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal gammopathy, which manifest mostly in the second half of life. It involves overactivation of the interleukin (IL)‐1 system, but the exact pathophysiological pathways remain largely unknown. Objectives: To identify and characterize the pathogenetic players in SchS. Methods: Blood parameters were quantified in patients with SchS compared with healthy controls and patients with psoriasis and hidradenitis suppurativa using enzyme‐linked immunosorbent assay (ELISA). CCL2 expression in cultured primary cells was analysed by quantitative reverse‐transcriptase polymerase chain reaction and ELISA. Results: CCL2, a chemoattractant for monocytic and further mononuclear immune cells, was found to be significantly elevated in patients with SchS. CCL2 levels showed a positive association with global disease activity, especially with bone pain, but not disease duration, gammopathy, neutrophilia or skin disease. In vitro stimulation assays demonstrated a strong CCL2 production capacity of mononuclear immune cells and fibroblasts, but not epithelial or endothelial cells. Among a range of inflammatory mediators, only IL‐1β (immune cells, fibroblasts) and tumour necrosis factor (TNF)‐α (fibroblasts) were important CCL2 inducers. TNF‐α, but not IL‐17, strengthened the CCL2‐inducing effect of IL‐1β in fibroblasts. Accordingly, CCL2 levels positively correlated with both TNF‐α and IL‐1β serum levels in patients with SchS. Therapeutic IL‐1β blockade decreased CCL2 blood levels in these patients as early as 1 week after the initiation of treatment. Conclusions: CCL2 may be an important component of the pathogenetic cascade leading to bone alterations, and a suitable marker of disease activity in patients with SchS. What's already known about this topic?Schnitzler syndrome (SchS) is a very rare acquired autoinflammatory disease, clinically characterized by urticarial exanthema, arthralgia and osteosclerosis, and episodes of fever.The pathogenesis involves overactivation of the interleukin‐1 system.The exact pathogenetic pathways are mostly unknown, and biomarkers are not available to assess the inflammatory activity in SchS. What does this study add? The chemokine CCL2 is a marker of SchS; its blood levels are significantly upregulated and linked to global disease activity and early therapy response in patients with SchS.While no clear relationship with patients' urticarial exanthema was detected, CCL2 may be involved in bone alterations in these patients.The cellular sources of CCL2 include mononuclear immune cells and fibroblasts.Interleukin‐1β and tumour necrosis factor‐α, blood levels of which correlate with CCL2 levels in patients with SchS, are important CCL2 inducers. What is the translational message? Quantifying CCL2 blood levels may allow the objective estimation of inflammatory disease activity and may help with the therapy decision in patients with SchS.CCL2 may be a key element of the pathogenetic cascades in SchS, especially those important for osteosclerosis. Linked Comment:Kambe and Nguyen. Br J Dermatol 2019; 180:706–707. Respond to this article Plain language summary available online [ABSTRACT FROM AUTHOR]

Background: Mycosis fungoides (MF) is an indolent T-cell lymphoma that mainly affects the skin and presents with itch in more than half of the patients. Recently, the expression of Mas-related G protein-coupled receptor X2 (MRGPRX2), a receptor of mast cell (MC) responsible for the IgE-independent non-histaminergic itch, has been shown in lesional skin of patients with pruritic skin diseases, including chronic urticaria, prurigo, and mastocytosis. As of yet, limited knowledge exists regarding the MRGPRX2 expression in the skin of patients with MF., Objectives: To investigate the number of MRGPRX2-expressing (MRGPRX2+) cells in the skin of patients with MF and its correlation with clinical and laboratory characteristics of the disease., Methods: MRGPRX2 was analyzed in lesional and non-lesional skin of MF patients and healthy skin tissues by immunohistochemistry. Co-localization of MRGPRX2 with the MC marker tryptase was assessed by immunofluorescence. Public single-cell RNAseq data was reanalyzed to identify the MRGPRX2 expression on the distinct cell types., Results: In lesional skin of MF patients, MRGPRX2+ cell number was higher than in non-lesional skin and healthy control skin (mean:15.12 vs. 6.84 vs. 5.51 cells/mm 2 , p=0.04), and correlated with MC numbers (r=0.73, p=0.02). MC was the primary cell type expressing MRGPRX2 in MF patients. The ratio of MRGPRX2+ MCs to MRGPRX2+ cells in lesional and non-lesional skin correlated with the severity of disease (r=0.71, p=0.02 and r=0.67, p=0.03, respectively)., Conclusions: Our findings point to the role of MRGPRX2 and MC in the pathogenesis of MF that should be investigated in further studies., Competing Interests: SA has conducted studies for/was advisor for/was speaker for AstraZeneca, Allakos, ALK, Biocryst, CSLBehring, LeoPharma, Moxie, Novartis, Pharvaris, Sanofi, Takeda, Thermofisher. MaMe received honoraria advisory board, speaker from AbbVie, Amgen, AstraZeneca, argenx, Bayer, Beiersdorf, Celldex, Escient, Galderma, gsk, Jasper, Novartis, Pharvaris, Pfizer, Sanofi-Aventis, Tevapharm, ThirdHarmonicBio, Viforpharma, outside of submitted work. PK received honoraria advisory board, speaker from Novartis, Roche and ValenzaBio, outside of submitted work. Outside of this work, MMa is or recently was a speaker and/or advisor for and/or has received 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. DT-M has received research funds and/or was advisor for Celldex, Moxie, Novartis and Sanofi. Outside of this work, CS is an employee of the GV20 Therapeutics, which develops drugs and research models for profit. 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 © 2023 Hu, Pyatilova, Altrichter, Sheng, Liu, Terhorst-Molawi, Lohse, Ginter, Puhl, Maurer, Metz and Kolkhir.)

Introduction: In mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, itch is a frequent clinical symptom. Whether mast cells (MCs), eosinophils (Eos) or their mediators play a role in MF-associated itch or disease severity is controversially discussed. Here, we explored the role of MC and Eo numbers in the skin as well as blood levels of their mediators in disease severity and itch., Methods: In 10 patients with MF and 10 matched control subjects we assessed disease severity, itch, and quality of life impairment using dedicated tools such as the mSWAT, ItchyQoL and DLQI. We analyzed skin biopsies and measured serum levels of tryptase, a mast cell mediator, as well as of the eosinophil products eosinophil cationic protein (ECP) and major basic protein (MBP)., Results: The presence of chronic itch, in four of 10 patients, was associated with significantly higher disease severity (mSwat), larger body surface area affected, and stronger QoL impairment (Itchy-Qol, DLQI). Serum levels of tryptase, but not ECP and MBP, were linked with patient-reported disease severity, body surface area affected, and the presence of itch. Three of the four patients with chronic itch, but none of the six patients without, had tryptase levels above >6µg/l. Numbers of MCs in the papillary dermis were higher in MF skin lesions then in non-lesional skin of MF patients and skin of healthy controls., Discussion: The MC-mediator tryptase, in MF, is linked to disease activity and impact, most prominently to itch. Our findings call for larger studies that explore the role of MCs, tryptase and other MC mediators as drivers of itch and their role in MF pathogenesis., Competing Interests: DT-M has received research funds and was advisor for Celldex, Novartis, Sanofi and Moxie. MMe is or recently was a speaker and/or advisor for AbbVie, Amgen, ArgenX, AstraZeneca, Bayer, Celldex, Celgene, Escient, Galderma, Grünenthal, GSK, Menlo, Novartis, Pfizer, Pharvaris, Roche, Sanofi-Aventis, Third Harmonic Bio. MMa is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Aralez, Genentech, GSK, Menarini, Merckle Recordati, Moxie, Novartis, Sanofi, MSD, and Uriach. SA has conducted studies for received research funds/was advisor for Allakos, ALK, AstraZeneca, CSL Behring, LeoPharma, Moxie, Novartis, Sanofi, Takeda, Thermofisher. Published results are part of the study ROBERTIS, funded by AstraZeneca. 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 Terhorst-Molawi, Lohse, Ginter, Puhl, Metz, Hu, Maurer and Altrichter.)

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.)