Cutaneous involvement in VEXAS syndrome: clinical and histopathologic findings

Abstract

Background VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic) syndrome is an autoinflammatory disease with frequent cutaneous manifestations. Methods We conducted a retrospective study of all patients with genetically confirmed VEXAS syndrome seen at our institution. Available clinical photographs and skin biopsy slides were reviewed. Results Cutaneous manifestations developed in 22/25 (88%) patients with VEXAS syndrome. From this group, 10/22 (45%) developed skin involvement before or at the time of other clinical features of VEXAS. Twenty distinct dermatologic presentations of VEXAS from 14 patients were reviewed, and histopathologic patterns were classified as follows: neutrophilic urticarial dermatosis (n = 5, 25%), leukocytoclastic/urticarial vasculitis (n = 4, 20%), urticarial tissue reaction (n = 4, 20%), neutrophilic dermatosis (n = 3, 15%), neutrophilic panniculitis (n = 2, 10%), and nonspecific chronic septal panniculitis (n = 2, 10%). Common systemic findings included macrocytic anemia (96%), fever (88%), thrombocytopenia (76%), weight loss (76%), ocular inflammation (64%), pulmonary infiltrates (56%), deep venous thrombosis or pulmonary embolism (52%), and inflammatory arthritis (52%). Conclusions Cutaneous involvement is a common feature of VEXAS syndrome, and histopathologic findings exist on a spectrum of neutrophilic inflammatory dermatoses.

VEXAS‐Syndrome, a newly described autoinflammatory systemic disease with dermatologic manifestations

“…15 Leukocytoclasia has been found in up to two-thirds of skin biopsies, which led to classification as vasculitis in early case reports of VEXAS syndrome. 14,15 It has recently been demonstrated that the dermal infiltrates seen in VEXAS syndrome display the same "loss of function" mutations of the UBA1 gene as paired bone marrow samples; thus, the skin infiltrates are a direct consequence of mutated cell clones of inflammatory cells rather than the result of generalized pro-inflammatory activity. 16 Another characteristic of VEXAS syndrome is the presence of subcutaneous nodules histologically reminiscent of septal panniculitis, as well as erythematous periorbital edema.…”

“…In some cases, the skin infiltrations of VEXAS syndrome have been histopathologically characterized as neutrophil urticarial dermatosis (NUD), but unusually, these were sometimes accompanied by epidermal dyskeratosis 15 . Leukocytoclasia has been found in up to two‐thirds of skin biopsies, which led to classification as vasculitis in early case reports of VEXAS syndrome 14,15 . It has recently been demonstrated that the dermal infiltrates seen in VEXAS syndrome display the same “loss of function” mutations of the UBA1 gene as paired bone marrow samples; thus, the skin infiltrates are a direct consequence of mutated cell clones of inflammatory cells rather than the result of generalized pro‐inflammatory activity 16 …”

“…Histology shows mostly superficial but sometimes deep‐reaching infiltrates of immature myeloid cells (metamyelocytes, myelocytes, band neutrophils), accompanied by mature neutrophils but also lymphocytes and histiocytes as well as interstitial edema. In some cases, the skin infiltrations of VEXAS syndrome have been histopathologically characterized as neutrophil urticarial dermatosis (NUD), but unusually, these were sometimes accompanied by epidermal dyskeratosis 15 . Leukocytoclasia has been found in up to two‐thirds of skin biopsies, which led to classification as vasculitis in early case reports of VEXAS syndrome 14,15 .…”

VEXAS‐Syndrom, eine neu beschriebene autoinflammatorische Systemerkrankung mit dermatologischen Manifestationen

“…15 Bei bis zu zwei Drittel der Fälle ist in Hautbiopsien eine Leukozytoklasie zu beobachten, was in frühen Fallberichten zum VEXAS-Syndrom zur Einordnung als Vaskulitis führte. 14,15 Es konnte kürzlich demonstriert werden, dass die dermalen Infiltrate beim VEXAS-Syndrom dieselben Loss-of-Function-Mutationen des UBA1-Gens aufweisen wie gepaarte Knochenmarksproben; die Hautinfiltrationen sind demnach unmittelbar auf die mutierten Zellklone der Entzündungszellen zurückzuführen und entstehen nicht infolge eines generalisierten proinflammatorischen Aktivierungszustands. 16 Charakteristisch für das VEXAS-Syndrom sind weiterhin subkutane Knoten, die histologisch an eine septale Pannikulitis erinnern, sowie periorbitale, rötliche, ödematöse Schwellungen.…”

“…Histologisch zeigen sich in der Haut meist superfizielle, mitunter auch tiefreichende Infiltrate unreifer myeloider Zellen (Metamyelozyten, Myelozyten, stabkernige Neutrophile), die von reifen Neutrophilen, auch Lymphozyten und Histiozyten sowie einem interstitiellen Ödem begleitet sind. In einem Teil der Fälle wurden die Hautinfiltrate des VEXAS‐Syndroms histopathologisch als neutrophile urtikarielle Dermatose (NUD) eingeordnet, wobei diese ungewöhnlicherweise mitunter von epidermalen Dyskeratosen begleitet waren 15 . Bei bis zu zwei Drittel der Fälle ist in Hautbiopsien eine Leukozytoklasie zu beobachten, was in frühen Fallberichten zum VEXAS‐Syndrom zur Einordnung als Vaskulitis führte 14,15 .…”