Clinical and pathological features of cutaneous manifestations in VEXAS syndrome: A multicenter retrospective study of 59 cases.

To the Editor: VEXAS (vacuoles, enzyme E1, X-linked, auto-inflammatory, somatic) syndrome is a late-onset autoinflammatory condition due to myeloid-restricted somatic mutations in the ubiquitin-activating enzyme 1 gene.1Beck D.B. Ferrada M.A. Sikora K.A. et al.Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease.N Engl J Med. 2020; 383: 2628-2638Crossref PubMed Scopus (309) Google Scholar Skin involvement seems to be one of the most common symptoms,1Beck D.B. Ferrada M.A. Sikora K.A. et al.Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease.N Engl J Med. 2020; 383: 2628-2638Crossref PubMed Scopus (309) Google Scholar, 2Georgin-Lavialle S. Terrier B. Guedon A.F. et al.Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients.Br J Dermatol. 2021; 186: 564-574https://doi.org/10.1111/bjd.20805Crossref PubMed Scopus (74) Google Scholar, 3van der Made C.I. Potjewijd J. Hoogstins A. et al.Adult-onset autoinflammation caused by somatic mutations in UBA1: a Dutch case series of patients with VEXAS.J Allergy Clin Immunol. 2022; 149: 432-439.e4Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 4Sterling D. Duncan M.E. Philippidou M. Salisbury J.R. Kulasekararaj A.G. Basu T.N. VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) for the dermatologist.J Am Acad Dermatol. 2022; https://doi.org/10.1016/j.jaad.2022.01.042Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar and may be the first manifestation of VEXAS syndrome.5Zakine E. Schell B. Battistella M. et al.UBA1 variations in neutrophilic dermatosis skin lesions of patients with VEXAS syndrome.JAMA Dermatol. 2021; 157: 1349-1354Crossref PubMed Scopus (31) Google Scholar However, most studies have been performed in non-dermatology departments with no centralized review of cutaneous involvement and limited numbers of patients.4Sterling D. Duncan M.E. Philippidou M. Salisbury J.R. Kulasekararaj A.G. Basu T.N. VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) for the dermatologist.J Am Acad Dermatol. 2022; https://doi.org/10.1016/j.jaad.2022.01.042Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar,5Zakine E. Schell B. Battistella M. et al.UBA1 variations in neutrophilic dermatosis skin lesions of patients with VEXAS syndrome.JAMA Dermatol. 2021; 157: 1349-1354Crossref PubMed Scopus (31) Google Scholar In this multicenter nationwide retrospective study, all 59 patients from the French VEXAS study group (NFVS) database with photographs of skin lesions and/or skin biopsies available for centralized review on June 15, 2021, were included. This study received approval from our Institutional Review Board (CLEP Decision no.:AAA-2021-08040). The median age at first symptoms was 68 years (interquartile range: 61.5-73) and 97% patients were male (Supplementary Table I, available via Mendeley at https://doi.org/10.17632/zpz5h43c4w.1). Cutaneous involvement was the first symptom for most patients (63%). The most common initial hypothesis for the skin involvement was Sweet syndrome (47%). Among the 37 patients with available photographs (Table I), all showed round shaped maculopapules of various sizes (57% showed both < and ≥1-cm lesions), mostly pink/red (76%), often numerous (89% of patients had ≥10 lesions), on the trunk (81%), the limbs (85%), and the face (30%). Lesions were arcuate in approximately one-third (32%, Fig 1). Other cutaneous lesions included livedo (16%), pustules (13%), and injection-site reactions (pathergy, 13%) (Supplementary Fig 1, available via Mendeley at https://doi.org/10.17632/zpz5h43c4w.1). Skin lesions were typically characterized by periods of flare and remission (81%). Among the 43 patients with available biopsies, most (89%) patients had infiltrates of the superficial dermis. The infiltrates consisted of immature myeloid cells and variable proportions of mature neutrophils, lymphocytes, and histiocytes, which led to retaining the diagnosis of neutrophilic dermatosis rich in immature myeloid cells in 77% patients (Supplementary Table II, available via Mendeley at https://doi.org/10.17632/zpz5h43c4w.1). Leukocytoclasia was present in 63% patients; however, no vasculitis was found. Few patients showed vessel thrombosis (venous in 3 patients, capillary in 2 patients, and arteriolar in 1 patient). Immunostaining revealed the presence myeloid precursors with overlapping expression of CD68 and MPO (myeloperoxidase) in 88% (Supplementary Fig 2, available via Mendeley at https://doi.org/10.17632/zpz5h43c4w.1). Cytological analysis was performed in 30 cases to better characterize the myeloid precursors. They were classified as metamyelocytes in 52%, as myelocytes in 42%, and as band neutrophils in 26%.Table IClinical characteristics of skin involvement (n = 37)Lesion description Lesion typeMaculopapules and nodules37 (100%)Pustules5 (13%)Vesicles/bullae4 (11%)Livedo6 (16%)Reticularis3 (8%)Racemosa3 (8%)Thickness of pattern <1 cm3 (8%) Lesion shapeRound/nummular36 (97%)Arcuate/annular12 (32%) Lesion colorPink28 (76%)Red27 (73%)Violaceous/purpuric18 (49%) Lesion size<1 cm29 (78%)≥1 cm29 (78%)Both21 (57%) Number of lesions≥1033 (89%)<104 (11%) LocalizationTrunk30 (81%)Arms32 (86%)Legs31 (84%)Face11 (30%)Pathergy5 (13%)Cutaneous symptoms Pain13 (35%) Pruritus9 (24%)Evolution of skin lesions Flare/remission periods30 (81%)Frequency of flare-ups (times/y, median [IQR])6 (2-12)Duration of flare-ups (d, median [IQR])9.8 (7-10) Permanent4 (11%)IQR, Interquartile range. Open table in a new tab IQR, Interquartile range. Overall, the spectrum of cutaneous lesions of VEXAS is characterized by a wide heterogeneity. About one-third of patients showed lesions with an arcuate shape (Fig 1), which we believe is suggestive of the diagnosis. Pathological infiltrates typically consisted of superficial perivascular and periadnexal lymphohistiocytic infiltrates with immature myeloid cells and displayed signs of dysplasia in most cases. In previous studies, vasculitis was frequently reported (25%-70%),1Beck D.B. Ferrada M.A. Sikora K.A. et al.Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease.N Engl J Med. 2020; 383: 2628-2638Crossref PubMed Scopus (309) Google Scholar,3van der Made C.I. Potjewijd J. Hoogstins A. et al.Adult-onset autoinflammation caused by somatic mutations in UBA1: a Dutch case series of patients with VEXAS.J Allergy Clin Immunol. 2022; 149: 432-439.e4Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 4Sterling D. Duncan M.E. Philippidou M. Salisbury J.R. Kulasekararaj A.G. Basu T.N. VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) for the dermatologist.J Am Acad Dermatol. 2022; https://doi.org/10.1016/j.jaad.2022.01.042Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 5Zakine E. Schell B. Battistella M. et al.UBA1 variations in neutrophilic dermatosis skin lesions of patients with VEXAS syndrome.JAMA Dermatol. 2021; 157: 1349-1354Crossref PubMed Scopus (31) Google Scholar but this rate has probably been overestimated. Indeed, despite the high prevalence of leukocytoclasia, we found no vasculitis after centralized review. The main limitation of our study is its retrospective design. In conclusion, VEXAS syndrome should be considered in patients ≥60 years with general symptoms, systemic inflammation, and with skin infiltrates showing neutrophilic dermatosis with immature myeloid cells. None disclosed. We thank the French National FAI2R network for their help in realizing this study, and the physicians involved in the French Vasculitis Study Group, in CeReMAIA and MINHEMON. We thank all the contributors that made this study possible by providing clinical photographs and organizing pathology material dispatch: Z. Amoura (Pitié-Salpêtrière), A. Aouba (Caen), C. Arnaud (Toulouse), A. Audemard-Verger (Tours), C. Bachmeyer (Tenon), B. Bienvenu (Marseille), P. Biscay (Pessac), F. Borlot (Béziers), L. Bouillet (Grenoble), G. Boursier (Montpellier), F. Carrat (Saint Antoine), T. Cluzeau (Nice), T. Comont (Toulouse), A. Constantin (Toulouse), B. de Sainte Marie (Bordeaux), C. Deligny (Martinique), C. Dieval (Rochefort), E. Duroyon (Centre), M. Ebbo (La Timone), O. Fain (Saint Antoine), B. Faucher (La Timone), P. Fenaux (Saint Louis), S. Georgin-Lavialle (Tenon), M. Gerfaud-Valentin (Hospices Civils de Lyon), J. Graveleau (Nantes), A.F. Guedon (Saint Antoine), T. Hanslik, (Ambroise Paré), M. Heiblig (Hospices Civils de Lyon), V. Jachiet (Saint Antoine), Y. Jamilloux (Hospices Civils de Lyon), J. Jeannel (Paris), M. Larue (Mondor), F. Le Pelletier (Paris), E. Liozon (Limoges), A. Meyer (Strasbourg), T. Moulinet (Nancy), M. Pha (Pitié-Salpêtrière), J. Rossignol (Necker), M. Roux (Nord Dauphiné), M. Roux-Sauvat (GHND), L. Sailler (Toulouse), G. Sarrabay (Montepellier), M. Sebert (Saint Louis), A. Servettaz (Reims), P. Sujobert (Besançon), L. Terriou (Lille), J. Vinit (Chalons), S. Vinzio (Grenoble), T. Weitten (Gap), L.P. Zhao (Saint Louis). We thank Laura Smales English language editing.