## **Supplemental Online Content**

Tan IJ, Ferrada MA, Ahmad S, et al. Skin manifestations of VEXAS syndrome and associated genotypes. *JAMA Dermatol*. Published online June 12, 2024. doi:10.1001/jamadermatol.2024.1657

**eTable.** Comparison of Patients with VEXAS Reviewed Retrospectively vs. Patients Evaluated at the NIH

**eFigure.** Skin Responses to Treatment

This supplemental material has been provided by the authors to give readers additional information about their work.

## **eTable. Comparison of Patients with VEXAS Reviewed Retrospectively vs. Patients Evaluated at the NIH**

| CLINICAL FEATURES           | Chart Reviewed<br>n=73 | Evaluated at NIH<br>n=39 | P value |
|-----------------------------|------------------------|--------------------------|---------|
| UBA1 Genotype*              |                        |                          |         |
| p.Met41Leu                  | 12/23 (52%)            | 11/23 (48%)              |         |
| p.Met41Val                  | 14/24 (58%)            | 10/24 (42%)              | 0.12    |
| p.Met41Thr                  | 43/58 (74%)            | 15/58 (26%)              |         |
| Skin Disease                | 61 (84%)               | 32 (82%)                 | 1.00    |
| Constitutional Symptoms     | 63 (86%)               | 36 (92%)                 | 0.54    |
| Fever                       | 53 (73%)               | 27 (69%)                 | 0.83    |
| Weight Loss                 | 28 (38%)               | 15 (38%)                 | 1.00    |
| Fatigue                     | 52 (71%)               | 32 (82%)                 | 0.26    |
| Night Sweats                | 19 (26%)               | 18 (46%)                 | 0.04    |
| Hematologic Disorder        | 15 (21%)               | 9 (23%)                  | 0.81    |
| Myelodysplastic Syndrome    | 14 (19%)               | 3 (8%)                   | 0.17    |
| Multiple Myeloma            | 0                      | 3 (8%)                   | 0.04    |
| Monoclonal Gammopathy       | 1 (1%)                 | 4 (10%)                  | 0.05    |
| Thromboembolic Disease      | 31 (42%)               | 12 (31%)                 | 0.31    |
| Pulmonary Embolism          | 12 (16%)               | 6 (15%)                  | 1.00    |
| Deep Vein Thrombosis        | 28 (38%)               | 12 (31%)                 | 0.54    |
| Eye Disease                 | 39 (53%)               | 22 (56%)                 | 0.84    |
| Inflammatory Eye Disease    | 34 (47%)               | 12 (31%)                 | 0.11    |
| Periorbital Inflammation    | 20 (27%)               | 14 (36%)                 | 0.39    |
| Audiovestibular Disease     | 13 (18%)               | 10 (26%)                 | 0.34    |
| Ear or Nose Chondritis      | 36 (49%)               | 18 (46%)                 | 0.84    |
| Oral Ulcers                 | 6 (8%)                 | 1 (3%)                   | 0.42    |
| Heart Disease               | 5 (7%)                 | 1 (3%)                   | 0.66    |
| Myocarditis                 | 3 (4%)                 | 0                        | 0.55    |
| Pericarditis                | 1 (1%)                 | 1 (3%)                   | 1.00    |
| Pulmonary Disease           | 58 (79%)               | 33 (85%)                 | 0.62    |
| Pulmonary Infiltrate        | 51 (70%)               | 24 (62%)                 | 0.40    |
| Pleural Effusion            | 13 (18%)               | 6 (15%)                  | 0.80    |
| Shortness of Breath         | 36 (49%)               | 26 (67%)                 | 0.11    |
| Gastrointestinal Disease    | 4 (5%)                 | 4 (10%)                  | 0.45    |
| Colitis                     | 2 (3%)                 | 1 (3%)                   | 1.00    |
| Hepato/splenomegaly         | 2 (3%)                 | 3 (8%)                   | 0.34    |
| Neurologic Disease          | 5 (7%)                 | 1 (3%)                   | 0.66    |
| Ischemic Stroke             | 3 (4%)                 | 1 (3%)                   | 1.00    |
| Meningitis                  | 2 (3%)                 | 0                        | 0.54    |
| Arthritis                   | 47 (64%)               | 17 (44%)                 | 0.05    |
| Genitourinary Disease       | 5 (7%)                 | 3 (8%)                   | 1.00    |
| Laboratory Abnormalities    |                        |                          |         |
| Elevated ESR                | 51/51 (100%)           | 35/35 (100%)             | 1.00    |
| Elevated C-Reactive Protein | 54/54 (100%)           | 35/35 (100%)             | 1.00    |
| Macrocytic Anemia           | 59 (81%)               | 36 (92%)                 | 0.17    |
| Thrombocytopenia            | 46 (63%)               | 23 (59%)                 | 0.69    |
| Leukopenia                  | 41 (56%)               | 28 (72%)                 | 0.15    |

\*Genetic data not available for 3 patients (109 total genotypes). 4 patients had splice site mutations.

![](https://assets.reachrx.ai/images/10.1001%E2%98%8Djamadermatol.2024.1657/_page_2_Figure_0.jpeg)

## **eFigure. Skin Responses to Treatment**

Percentage of patients who responded based on physician impression of clinical improvement in skin findings. A. Therapeutics used on > 10 patients. B. Therapeutics used on V 10 patients. IVIG: intravenous immunoglobulin; SSKI: super-saturated potassium iodide.

JAMA Dermatology

<jats:sec id="ab-doi240018-4"><jats:title>Importance</jats:title><jats:p>VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined genetic disease with an estimated prevalence of 1 in 4269 men older than 50 years and is marked by systemic inflammation, progressive bone marrow failure, and inflammatory cutaneous manifestations.</jats:p></jats:sec><jats:sec id="ab-doi240018-5"><jats:title>Objective</jats:title><jats:p>To define the spectrum of cutaneous manifestations in VEXAS syndrome and the association of these findings with clinical, genetic, and histological features.</jats:p></jats:sec><jats:sec id="ab-doi240018-6"><jats:title>Design, Setting, and Participants</jats:title><jats:p>This observational cohort study included data from 112 patients who were diagnosed with VEXAS-defining genetic variants in <jats:italic>UBA1</jats:italic> between 2019 and 2023. Data were collected from medical record review or from patients with VEXAS directly evaluated at the National Institutes of Health in Bethesda, Maryland.</jats:p></jats:sec><jats:sec id="ab-doi240018-7"><jats:title>Main Outcomes and Measures</jats:title><jats:p>To define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histological, and other clinical findings. A secondary outcome was cutaneous response to treatment in VEXAS.</jats:p></jats:sec><jats:sec id="ab-doi240018-8"><jats:title>Results</jats:title><jats:p>Among the 112 patients (median [range] age, 69 [39-79] years; 111 [99%] male), skin involvement was common (93 [83%]), and the most frequent presenting feature of disease (68 [61%]). Of 64 histopathologic reports available from 60 patients, predominant skin histopathologic findings were leukocytoclastic vasculitis (23 [36%]), neutrophilic dermatosis (22 [34%]), and perivascular dermatitis (19 [30%]). Distinct pathogenic genetic variants were associated with specific cutaneous manifestations. The p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates (14 of 17 patients [82%]), often resembling histiocytoid Sweet syndrome. In contrast, the p.Met41Val variant was associated with vasculitic lesions (11 of 20 patients [55%]) with a mixed leukocytic infiltrate (17 of 20 patients [85%]). Oral prednisone improved skin manifestations in 67 of 73 patients (92%). Patients with VEXAS treated with anakinra frequently developed severe injection-site reactions (12 of 16 [75%]), including ulceration (2 of 12 [17%]) and abscess formation (1 of 12 [8%]).</jats:p></jats:sec><jats:sec id="ab-doi240018-9"><jats:title>Conclusions and Relevance</jats:title><jats:p>Results of this cohort study show that skin manifestations are a common and early manifestation of VEXAS syndrome. Genetic evaluation for VEXAS should be considered in older male patients with cutaneous vasculitis, neutrophilic dermatoses, or chondritis. Awareness of VEXAS among dermatologists is critical to facilitate early diagnosis.</jats:p></jats:sec>

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Allogeneic stem cell transplantation as a curative therapeutic approach for VEXAS syndrome: a case report.

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Vasculitis associated with VEXAS syndrome: a literature review.

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VEXAS-defining UBA1 somatic variants in 245,368 diverse individuals in the NIH All Of Us cohort.

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Cutaneous involvement in VEXAS syndrome: clinical and histopathologic findings.

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Atypical extensive lupus tumidus-like eruption as an early presentation of VEXAS syndrome.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined genetic disease with an estimated prevalence of 1 in 4269 men older than 50 years and is marked by systemic inflammation, progressive bone marrow failure, and inflammatory cutaneous manifestations.
To define the spectrum of cutaneous manifestations in VEXAS syndrome and the association of these findings with clinical, genetic, and histological features.
This observational cohort study included data from 112 patients who were diagnosed with VEXAS-defining genetic variants in UBA1 between 2019 and 2023. Data were collected from medical record review or from patients with VEXAS directly evaluated at the National Institutes of Health in Bethesda, Maryland.
To define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histological, and other clinical findings. A secondary outcome was cutaneous response to treatment in VEXAS.
Among the 112 patients (median [range] age, 69 [39-79] years; 111 [99%] male), skin involvement was common (93 [83%]), and the most frequent presenting feature of disease (68 [61%]). Of 64 histopathologic reports available from 60 patients, predominant skin histopathologic findings were leukocytoclastic vasculitis (23 [36%]), neutrophilic dermatosis (22 [34%]), and perivascular dermatitis (19 [30%]). Distinct pathogenic genetic variants were associated with specific cutaneous manifestations. The p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates (14 of 17 patients [82%]), often resembling histiocytoid Sweet syndrome. In contrast, the p.Met41Val variant was associated with vasculitic lesions (11 of 20 patients [55%]) with a mixed leukocytic infiltrate (17 of 20 patients [85%]). Oral prednisone improved skin manifestations in 67 of 73 patients (92%). Patients with VEXAS treated with anakinra frequently developed severe injection-site reactions (12 of 16 [75%]), including ulceration (2 of 12 [17%]) and abscess formation (1 of 12 [8%]).
Results of this cohort study show that skin manifestations are a common and early manifestation of VEXAS syndrome. Genetic evaluation for VEXAS should be considered in older male patients with cutaneous vasculitis, neutrophilic dermatoses, or chondritis. Awareness of VEXAS among dermatologists is critical to facilitate early diagnosis.

Skin Manifestations of VEXAS Syndrome and Associated Genotypes.

Skin Manifestations of VEXAS Syndrome and Associated Genotypes

Skin Manifestations of VEXAS Syndrome and Associated Genotypes

Clinical Summary

What was studied

Key findings

Study limitations

Clinical implications

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