PMC10097979_01
Clinical picture and genetic analysis. (A, B), non-pruritic recurrent annular urticarial plaques on the extremities and on the trunk. (C), resolution of urticarial plaques within hours in response to anakinra. (D), Haematoxylin-eosin staining of a lesional skin biopsy shows a perivascular and interstitial neutrophilic infiltrate (arrows). (E), Magnification of panel (D) with neutrophils in the epithelium and excretory ducts of sweat glands (arrows). (F), interaction network of the 3 genes with putatively deleterious somatic mutations that may affect the function of IL-1beta (IL1B) as primary mediator of inflammation in our patient: MALT1/ENST00000648670.1: c.167-2A>G (AF 13.6%, 17 of 120 reads), TYRO3/NG_033013.1: g.19447del (AF 18.5%, 28 of 151 reads) and PDGFB/NM_002608.4: p.Tyr30Ter (AF 13.9%, 11 of 79 reads). Putatively deleterious variations (Dann score >0.99 if available, CADD phred score >25, mutations detectable in at least 10 reads) were analysed for interactions using StringDB (URL: , last accessed September 29th, 2022).
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A 75-year-old man presented to our department with recurrent non-pruritic, not painful, annular urticarial plaques on the extremities and the trunk for 12 months ( Figure 1A ). Histopathology of lesional skin showed a perivascular and interstitial neutrophilic infiltrate, initially described as consistent with the diagnosis of urticaria vasculitis ( Figure 1D ). Within five hours, the urticarial plaques resolved entirely ( Figures 1B, C ,  2 ). We found neutrophilic granulocytes located in the epithelium of sweat gland ducts (neutrophilic epitheliotropism), a distinctive feature of cutaneous manifestations found in autoinflammatory disorders ( Figure 1E ). This network revealed interactions of IL-1beta with putatively pathogenic variations in MALT1 (MALT1 paracaspase), TYRO3 (TYRO3 protein tyrosine kinase) and PDGFB (platelet-derived growth factor subunit B) ( Figure 1F ), all of which are involved in cellular activation pathways and inflammation.
Overview of the patient's disease course. Step plots of laboratory parameters over time aligned with bar chart of treatment modalities. With the exception of an immediate relapse during a single anakinra withdrawal attempt, the patient has remained free of inflammatory episodes for a follow period of about 250 weeks (~5 years) now. Different antihistamines including cetirizine 10 mg p.o were given up to 4x standard dose. Topical corticosteroids included methylprednisolone and clobetasol. WBC, white blood cell counts, in 1/nl. CRP, C-reactive protein concentration in mg/l. SAA, serum amyloid A concentration in mg/dl. The reference ranges are shaded in green. Red dots indicate values outside the reference range, dark green dots values within. The white vertical grid lines indicate months, the grey vertical grid lines years.
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Laboratory investigations revealed leucocytosis (up to 16.56/nl, ref 3.6 - 10.5/nl), neutrophilia (up to 13.05/nl, ref. 1.5 - 7.7/nl), elevated CRP (32-193 mg/l, ref. <5 mg/l) and serum amyloid A (SAA, 5-212 mg/dl, ref. <0.6 mg/dl) during the episodes of skin inflammation ( Figure 2 ). Within five hours, the urticarial plaques resolved entirely ( Figures 1B, C ,  2 ). Temporary discontinuation of anakinra for two days resulted in a relapse with re-emergence of cutaneous urticarial plaques accompanied by fever, joint pain, and elevated inflammatory markers ( Figure 2 ).