Pleuropulmonary Manifestations of Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic (VEXAS) Syndrome
2022; Elsevier BV; Volume: 163; Issue: 3 Linguagem: Inglês
10.1016/j.chest.2022.10.011
ISSN1931-3543
AutoresRaphaël Borie, Marie‐Pierre Debray, Alexis F. Guédon, A. Mékinian, Louis Terriou, Valentin Lacombe, Estibaliz Lazaro, A. Meyer, Alexis Mathian, Samuel Ardois, Guillaume Vial, T. Moulinet, Benjamin Terrier, Yvan Jamilloux, Maël Heiblig, Jean‐David Bouaziz, Ève Zakine, R. Outh, Sylvie Groslerons, A. Bigot, Edouard Flamarion, Marie Kostine, Pierrick Henneton, S. Humbert, Arnaud Constantin, Maxime Samson, Nadine Magy Bertrand, P. Biscay, C. Diéval, Hervé Lobbes, Juliette Jeannel, Amélie Servettaz, Leo Adelaide, J. Graveleau, Benjamin de Sainte-Marie, J. Galland, Vivien Guillotin, Eugénie Duroyon, Marie Templé, R. Bourguiba, S. Georgin Lavialle, Olivier Kosmider, Alexandra Audemard‐Verger, Julien Haroche, Zahir Amoura, M. Pha, Anne‐Sophie Moreau, Kilifa Meghit, M. Rondeau-Lutz, Jean‐Christophe Weber,
Tópico(s)IgG4-Related and Inflammatory Diseases
ResumoBackgroundThe vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a newly identified autoinflammatory disorder related to somatic UBA1 mutations. Up to 72% of patients may show lung involvement.Research QuestionWhat are the pleuropulmonary manifestations in VEXAS syndrome?Study Design and MethodsOne hundred fourteen patients were included in the French cohort of VEXAS syndrome between November 2020 and May 2021. Each patient included in the study who had an available chest CT scan was discussed in an adjudication multidisciplinary team and classified as showing potentially pleuropulmonary-specific involvement of VEXAS syndrome or others.ResultsFifty-one patients had a CT scan available for review and 45 patients (39%) showed pleuropulmonary abnormalities on chest CT scan that were considered related to VEXAS syndrome after adjudication. Most patients were men (95%) with a median age 67.0 years at the onset of symptoms. Among these 45 patients, 44% reported dyspnea and 40% reported cough. All 45 patients showed lung opacities on chest CT scan (including ground-glass opacities [87%], consolidations [49%], reticulation [38%], and septal lines [51%]) and 53% of patients showed pleural effusion. Most patients showed improvement with prednisone, but usually required > 20 mg/d. The main clinical and biological features as well the median survival did not differ between the 45 patients with pleuropulmonary involvement and the rest of the cohort, suggesting that the prevalence of pleuropulmonary involvement might have been underdiagnosed in the rest of the cohort.InterpretationPulmonary manifestations are frequent in VEXAS syndrome, but rarely are at the forefront. The initial outcome is favorable with prednisone and does not seem to lead to pulmonary fibrosis. The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a newly identified autoinflammatory disorder related to somatic UBA1 mutations. Up to 72% of patients may show lung involvement. What are the pleuropulmonary manifestations in VEXAS syndrome? One hundred fourteen patients were included in the French cohort of VEXAS syndrome between November 2020 and May 2021. Each patient included in the study who had an available chest CT scan was discussed in an adjudication multidisciplinary team and classified as showing potentially pleuropulmonary-specific involvement of VEXAS syndrome or others. Fifty-one patients had a CT scan available for review and 45 patients (39%) showed pleuropulmonary abnormalities on chest CT scan that were considered related to VEXAS syndrome after adjudication. Most patients were men (95%) with a median age 67.0 years at the onset of symptoms. Among these 45 patients, 44% reported dyspnea and 40% reported cough. All 45 patients showed lung opacities on chest CT scan (including ground-glass opacities [87%], consolidations [49%], reticulation [38%], and septal lines [51%]) and 53% of patients showed pleural effusion. Most patients showed improvement with prednisone, but usually required > 20 mg/d. The main clinical and biological features as well the median survival did not differ between the 45 patients with pleuropulmonary involvement and the rest of the cohort, suggesting that the prevalence of pleuropulmonary involvement might have been underdiagnosed in the rest of the cohort. Pulmonary manifestations are frequent in VEXAS syndrome, but rarely are at the forefront. The initial outcome is favorable with prednisone and does not seem to lead to pulmonary fibrosis. Take-home PointsStudy Question: What are the pleuropulmonary manifestations in vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome?Results: Among 45 patients, 44% reported dyspnea and 40% reported cough. All 45 patients showed lung opacities on chest CT scan (including ground-glass opacities [87%], consolidations [49%], reticulation [38%], and septal lines [51%]) and 53% showed pleural effusion. Most patients showed improvement with prednisone, but usually required > 20 mg/d.Interpretation: Pulmonary manifestations of VEXAS syndrome mimic infection or heart failure, which resist diuretics or antibiotics treatment, but eventually improve with high-dose prednisone. Pulmonary manifestations do not seem to evolve to pulmonary fibrosis. Study Question: What are the pleuropulmonary manifestations in vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome? Results: Among 45 patients, 44% reported dyspnea and 40% reported cough. All 45 patients showed lung opacities on chest CT scan (including ground-glass opacities [87%], consolidations [49%], reticulation [38%], and septal lines [51%]) and 53% showed pleural effusion. Most patients showed improvement with prednisone, but usually required > 20 mg/d. Interpretation: Pulmonary manifestations of VEXAS syndrome mimic infection or heart failure, which resist diuretics or antibiotics treatment, but eventually improve with high-dose prednisone. Pulmonary manifestations do not seem to evolve to pulmonary fibrosis. The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently described acquired monogenic disease in adults associated with UBA1 somatic mutation in hematopoietic progenitor cells.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 (318) Google Scholar VEXAS syndrome is associated with late-onset, treatment-refractory inflammatory syndrome with hematologic abnormalities secondary to acquired UBA1 mutations. UBA1 encodes the ubiquitin-activating enzyme 1 (E1),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 (318) Google Scholar which is necessary for initiating ubiquitination, a posttranslational modification of proteins involved in regulating intracellular signaling and protein degradation via the proteasome or autophagy-lysosome system.2Chang T.-K. Shravage B.V. Hayes S.D. et al.Uba1 functions in Atg7- and Atg3-independent autophagy.Nat Cell Biol. 2013; 15: 1067-1078Crossref PubMed Scopus (138) Google Scholar However, the precise mechanism leading to inflammation remains unknown.2Chang T.-K. Shravage B.V. Hayes S.D. et al.Uba1 functions in Atg7- and Atg3-independent autophagy.Nat Cell Biol. 2013; 15: 1067-1078Crossref PubMed Scopus (138) Google Scholar Initial cohorts showed a high mortality rate linked to a limited therapeutic arsenal, despite the effectiveness in some patients of high-dose glucocorticosteroids.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: 432-439Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar,4Georgin-Lavialle S. Terrier B. Guedon A.F. et al.Further characterization of clinical and laboratory features occurring in VEXAS syndrome in a large-scale analysis of multicenter case-series of 116 French patients.Br J Dermatol. 2021; 186: 564-574Crossref PubMed Scopus (76) Google Scholar UBA1 somatic mutations initially were identified in three men from a cohort of 1,477 patients screened with an exomes approach from a large cohort of patients with idiopathic inflammatory syndrome.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 (318) Google Scholar These patients presented severe inflammatory features associated with hematologic manifestations such as macrocytosis, anemia, and vacuoles in myeloid precursor cells.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 (318) Google Scholar,5Lacombe V. Prevost M. Bouvier A. et al.Vacuoles in neutrophil precursors in VEXAS syndrome: diagnostic performances and threshold.Br J Haematol. 2021; 195: 286-289Crossref PubMed Scopus (24) Google Scholar Indeed, in almost half of patients, myelodysplasia is associated with VEXAS syndrome.6Comont T. Heiblig M. Rivière E. et al.Azacitidine for patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS) and myelodysplastic syndrome: data from the French VEXAS registry.Br J Haematol. 2021; 196: 969-974Crossref PubMed Scopus (42) Google Scholar,7Huang H. Zhang W. Cai W. et al.VEXAS syndrome in myelodysplastic syndrome with autoimmune disorder.Exp Hematol Oncol. 2021; 10: 23Crossref PubMed Scopus (29) Google Scholar The most frequent characteristics include fever, arthralgia, alveolitis, ear and nose chondritis, skin lesions, and VTE.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 (318) Google Scholar,4Georgin-Lavialle S. Terrier B. Guedon A.F. et al.Further characterization of clinical and laboratory features occurring in VEXAS syndrome in a large-scale analysis of multicenter case-series of 116 French patients.Br J Dermatol. 2021; 186: 564-574Crossref PubMed Scopus (76) Google Scholar Among the first 25 patients reported, 18 patients (72%) showed pulmonary infiltrates, but the radiologic pattern and the impact of pulmonary infiltrates were not detailed.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 (318) 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: 432-439Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar,4Georgin-Lavialle S. Terrier B. Guedon A.F. et al.Further characterization of clinical and laboratory features occurring in VEXAS syndrome in a large-scale analysis of multicenter case-series of 116 French patients.Br J Dermatol. 2021; 186: 564-574Crossref PubMed Scopus (76) Google Scholar,8Sakuma M. Tanimura A. Yasui S. et al.Case of polychondritis-onset refractory organising pneumonia with cytopaenia diagnosed as VEXAS syndrome: the disease course of seven years.Rheumatol Oxf Engl. 2021; 60: e356-e359Crossref PubMed Scopus (12) Google Scholar This study aimed to provide more detailed information about lung disease in patients with VEXAS syndrome. French patients with VEXAS syndrome were included retrospectively in a national database between November 2020 and May 2021, including data on standardized clinical and laboratory parameters, outcome, and treatments.4Georgin-Lavialle S. Terrier B. Guedon A.F. et al.Further characterization of clinical and laboratory features occurring in VEXAS syndrome in a large-scale analysis of multicenter case-series of 116 French patients.Br J Dermatol. 2021; 186: 564-574Crossref PubMed Scopus (76) Google Scholar Two additional patients were included in the reported cohort of 116 patients.4Georgin-Lavialle S. Terrier B. Guedon A.F. et al.Further characterization of clinical and laboratory features occurring in VEXAS syndrome in a large-scale analysis of multicenter case-series of 116 French patients.Br J Dermatol. 2021; 186: 564-574Crossref PubMed Scopus (76) Google Scholar The diagnosis of VEXAS syndrome required the association of autoinflammatory features and the presence of a UBA1 somatic mutation. Sanger sequencing and next-generation sequencing were used to detect UBA1 mutations from bone marrow, blood samples, or both.4Georgin-Lavialle S. Terrier B. Guedon A.F. et al.Further characterization of clinical and laboratory features occurring in VEXAS syndrome in a large-scale analysis of multicenter case-series of 116 French patients.Br J Dermatol. 2021; 186: 564-574Crossref PubMed Scopus (76) Google Scholar This study was conducted in compliance with the Good Clinical Practices protocol and Declaration of Helsinki principles and received approval from the Cochin Hospital Institutional Review Board (CLEP decision no.: AAA-2021-08040). All patients underwent a detailed clinical evaluation by the primary investigative study team at inclusion in the database. Chest CT scan, performed according to the local physician’s judgement, was based on clinical symptoms including fever, dyspnea, chest pain, expectoration, cough, or hemoptysis. All chest CT scans were reviewed centrally by two study investigators (R. Borie and M. P. D.) (Fig 1). A radiologist (M. P. D.) specializing in interstitial lung disease reviewed all available chest CT scans for lung abnormalities, tracheal thickening and deformation, pleural and pericardial effusion, and mediastinal lymphadenopathies. Because only some of the available CT scans for review used IV contrast media and most CT scan protocols were not appropriate for vascular analysis, signs of aortitis or pulmonary embolism were not analyzed. The pulmonary CT signs were described according to the Fleischner Society glossary9Hansell D.M. Bankier A.A. MacMahon H. McLoud T.C. Müller N.L. Remy J. Fleischner Society: glossary of terms for thoracic imaging.Radiology. 2008; 246: 697-722Crossref PubMed Scopus (2816) Google Scholar and included ground-glass opacities, consolidations, linear atelectasis, reticular opacities, interlobular septal thickening, signs of lung fibrosis (including traction bronchiectasis and honeycombing), nodules, and micronodules (small nodules < 3 mm in diameter). Each sign was graded from 0 to 3 according to its extent or severity, and the percentage of lungs with any pulmonary abnormality was estimated visually to the nearest 10%. Each CT scan was classified by two of the authors (M. P. D. and R. Borie) as suggestive of heart failure, pulmonary infection, or cancer or as not suggestive of any of these and then considered a potential specific involvement of VEXAS syndrome. Each patient then was discussed in an adjudication multidisciplinary team (referring physician or team comprising M. P. D., A. A.-V., R. Borie, A. Mekinian, and S. G. L.) according to the clinical, biological, and radiologic features, including a pulmonary function test or BAL data when available and evolution under specific therapy. Patients eventually were classified as having heart failure, pulmonary infection, cancer, potentially specific involvement of VEXAS syndrome, or others. Response to treatment and flares were assessed by the referring physician. Good response to treatment was defined as clinical remission with ≥ 50% glucocorticosteroid dose reduction and dosage of < 10 mg/d of prednisone during ≥ 1 months.6Comont T. Heiblig M. Rivière E. et al.Azacitidine for patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS) and myelodysplastic syndrome: data from the French VEXAS registry.Br J Haematol. 2021; 196: 969-974Crossref PubMed Scopus (42) Google Scholar Flare was defined by fever, inflammatory syndrome, or inflammatory symptoms after eliminating an undercurrent infection and a need to increase prednisone or add an immunosuppressive drug. For patients with several chest CT scans, the first CT scan showing abnormalities was described, and the subsequent CT scans were analyzed for evolution (increase or decrease in lesions, any signs of lung fibrosis, and change of CT scan pattern). Data are expressed as median (interquartile range [IQR]) or number (percentage). Categorical and quantitative variables were compared by the Fisher and Kruskal-Wallis tests, respectively. Overall survival was defined as the time from diagnosis. Kaplan-Meier cumulative incidence curves for death were generated for the total population and were compared by the log-rank test. We performed a clustering analysis using the description of every CT scan available at baseline for patients with VEXAS syndrome with pulmonary involvement (e-Tables 1, 2). We used factor analysis of mixed data, handling missing data by using multiple imputation, with the R missMDA package version 1.18 (R Foundation for Statistical Computing).10Josse J. Husson F. missMDA: a package for handling missing values in multivariate data analysis.J Stat Softw. 2016; 70: 1-31Crossref Scopus (506) Google Scholar Then we performed k-means clustering based on factor analysis of mixed data coordinates by using euclidean distance (e-Appendix 1). We identified an optimal cluster number of 3 by using multiple methods (e-Appendix 2, e-Figs 1-3). To ensure the reproducibility of our clusters, we performed sensitivity analysis by using another clustering method, ascending hierarchical clustering, on our data (e-Appendix 3, e-Figs 4-7). Cluster number and characteristics were consistent with k-means clustering. To investigate potential cluster changes, we qualitatively analyzed follow-up CT scans available according to the phenotypic clusters identified with the clustering method. The Sankey diagram was used to depict shifts in clusters across time. Two-sided testing was used, with P < .05 considered statistically significant. All analyses were performed with R version 3.6.0 for Mac software (R Foundation for Statistical Computing). One hundred fourteen patients were included in the French cohort of VEXAS syndrome and reported previously.4Georgin-Lavialle S. Terrier B. Guedon A.F. et al.Further characterization of clinical and laboratory features occurring in VEXAS syndrome in a large-scale analysis of multicenter case-series of 116 French patients.Br J Dermatol. 2021; 186: 564-574Crossref PubMed Scopus (76) Google Scholar A UBA1 somatic mutation was detected for all patients as reported previously: p.Met41Thr (c.122T→C) (n = 47 [41%]), p.Met41Val (c.121A→G) (n = 37 [32%]), p.Met41Leu (c.121A→C) (n = 21 [18%]), and c.118-1G→C (n = 9 [7.2%]). Eighteen patients presented auto-antibodies: antinuclear antibodies (n = 17, including five with > 1/160), antineutrophil cytoplasmic antibodies (n = 2), rheumatoid factor (n = 7), and anti-citrullinated protein antibodies (n=2). Overall, 51 patients had a least one chest CT scan in full inspiration available for central review a median of 368 days (IQR, 110-1033 days) after the first symptoms of VEXAS syndrome. Symptoms at the time of CT scan frequently were of a respiratory nature: dyspnea (n = 23 patients), cough (n = 21 patients), fever (n = 20 patients), or respiratory insufficiency (n = 6 patients). Forty-five patients were considered to have VEXAS-related pulmonary involvement after adjudication (Tables 1, 2), one patient had heart failure, two patients had pulmonary infection (COVID-19 and varicella), and three patients showed only gravity-related abnormalities (Fig 1). The six patients without VEXAS-related pulmonary involvement (male sex, 100%; median age, 66 years; and fever, 50%) did not differ significantly from the group with VEXAS-related pulmonary involvement (Table 1). The presence of specific pleuropulmonary involvement was unknown for the 63 other patients of the cohort.Table 1Clinical Characteristics at Diagnosis of Patients With VEXAS Syndrome With Pulmonary Involvement (n = 45)CharacteristicsDataMale sex44 (98)Age at first symptoms, y67 (61-73)Age at diagnosis, y71 (65-76)Myelodysplasia20 (44)Weight loss30 (67)Fever26 (67)Dyspnea20 (44)Oxygen therapy3 (7)Cough18 (40)Chest pain1 (2)Arthralgia15 (39)Chondritis17 (38)Skin lesion33 (73)GI tract5 (11)Peripheral nervous system involvement2 (5)Ocular involvement17 (38)Heart involvement4 (9)Arterial involvement4 (9)Lymph node enlargement18 (40)Kidney involvement2 (4)Unprovoked thrombosis16 (35)Data are presented as No. (%) or median (interquartile range). VEXAS = vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic. Open table in a new tab Table 2Biological Characteristics at Diagnosis of Patients With VEXAS Syndrome With Pulmonary Involvement (n = 45)CharacteristicDataHemoglobin, g/dL10.30 (9.0-11.6)MCV, fL101 (96-106)Platelets, g/L222 (162-285)Leucocytes, g/L4.4 (3.1-6.5)Neutrophils, g/L2.9 (1.8-4.8)C-reactive protein, mg/L105 (57-156)Positive antinuclear antibodies6 (15)UBA1 somatic mutation45 (100) p.Met41Thr (c.122T→C)17 (38) p.Met41Val (c.121A→G)18 (40) p.Met41Leu (c.121A→C)6 (13) c.118-1G→C4 (9)Data are presented as No. (%) or median (interquartile range). MCV = mean corpuscular volume; VEXAS = vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic. Open table in a new tab Data are presented as No. (%) or median (interquartile range). VEXAS = vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic. Data are presented as No. (%) or median (interquartile range). MCV = mean corpuscular volume; VEXAS = vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic. Among the 45 patients, the indication for chest CT scan was fever (n = 28 [62%]), dyspnea (n = 20 [44%]), cough (n = 18 [40%]), and chest pain (n = 1 [2%]). Three patients required oxygen therapy, but 16 patients did not report any pulmonary symptoms, and a CT scan was performed because of fever. Chest CT scan results are summarized in Table 3. All patients showed signs of parenchymal disease on CT scan, the most frequent being ground-glass opacities (n = 39 [86.6%]) (Figs 1, 2). A total of 24 patients showed pleural effusion, most frequently of small abundance (95.8%), unilateral (58.3%), and predominant on the right side (64.2%). Only one patient showed signs of pulmonary fibrosis (reticulation with traction bronchiectasis). Mediastinal adenomegalies were frequent (n = 26 [57.7%]), mostly of < 20 mm (n = 24 [92%]) and multiple (n = 19 [73.0%]). No patient showed signs of tracheal chondritis.Table 3Pulmonary CT Scan Characteristics of Patients With VEXAS Syndrome With Pulmonary InvolvementCT Scan AbnormalitiesInitial (n = 45)Follow-up (n = 81)Parenchymal disease45 (100)73 (90) Ground-glass opacities39 (87)60 (74) Consolidations22 (49)42 (52) Reticulations17 (38)23 (28) Septal lines23 (51)46 (57) Fibrosis1 (2)1 (1) Nodules21 (47)20 (25) Micronodules17 (38)20 (25)Pleural effusion24 (53)37 (46) Small23 (96)28 (34) Unilateral14 (58)21 (26)Right915Left56Pericardial effusion7 (15)11 (13)Mediastinal adenomegaly26 (58)53 (65) < 20 mm24 (92)47 (88) Multiple19 (73)35 (66)Cluster 1aSuggests organising pneumonia or infection.15 (33)21 (26) 2bA nonspecific pattern.18 (40)37 (46) 3cSuggests heart failure.13 (28)18 (22)Extent of abnormalities < 10%21 (47)36 (44) 10%-20%10 (22)16 (19) 20%-30%8 (18)14 (17) 30%-40%3 (7)5 (6) 40%-50%3 (7)2 (2) > 50%0 (0)2 (2)Normal05 (5)Data are presented as No. (%) or No. VEXAS = vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic.a Suggests organising pneumonia or infection.b A nonspecific pattern.c Suggests heart failure. Open table in a new tab Data are presented as No. (%) or No. VEXAS = vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic. Cluster analysis of radiologic signs suggested three different patterns (Figure 2, Figure 3, Figure 4, e-Fig 1). Cluster 1 (n = 15) (Fig 1A, 1B) typically associated ground-glass opacities and consolidations that may evoke organizing pneumonia or infection. Cluster 2 (n = 18) (Fig 2C, 2D) associated lesions of milder extent, frequently unilateral and not evoking infection, organizing pneumonia, or heart failure, including atelectasis, bronchiectasis, less frequent nodules, and most frequently pleural effusion. Cluster 3 (n = 13) (Fig 2E, 2F) associated bilateral involvement with mediastinal adenomegaly, ground-glass opacities, and ever-present pleural effusion that may evoke heart failure.Figure 4A, K-means clustering plot showing cluster analysis of CT scan pattern at diagnosis. B, Sankey diagram showing cluster (1, 2, 3, or N) evolution from CT scan at diagnosis (CT_1) and CT scans of follow-up (CT_2 to CT_10). N = normal.View Large Image Figure ViewerDownload Hi-res image Download (PPT) BAL results were available for 24 patients at the same time as the scanner; infection was excluded for all, and results showed a median of 247 cells/mm3 (IQR, 70-670 cells/mm3), with a median of 66% (IQR, 18%-91%) macrophages, 17% (IQR, 0%-36%) lymphocytes, 13% (IQR, 0.5%-80%) neutrophils, and 2% (IQR, 0%-13%) eosinophils. The median Golde score was 120 (IQR, 0-300). Pleural effusion analysis was available for four patients and showed a sterile exudative profile (median, 45 g/L protides [IQR, 41-48 g/L protides]) with variable cytologic analysis (median lymphocyte count, 10% [IQR, 5%-98%]; median neutrophil count, 10% [IQR, 2%-80%]). The UBA1 somatic mutation was analyzed and confirmed in the BAL, with 82% macrophages and 4% neutrophils for one patient: p.Met41Thr (c.122T→C). Pulmonary function test results were available for 10 patients and showed an FEV1 of 72% predicted (IQR, 63%-86% predicted), FVC of 76% (IQR, 69%-83%), a total lung capacity of 86% (IQR, 80%-101%), and a diffusing capacity of the lungs for carbon monoxide of 64% (IQR, 59%-74%). Among the 45 patients, nine received diuretics and 29 received antibiotics, with no significant clinical improvement. A total of 41 patients received glucocorticosteroids of > 20 mg/d or immunosuppressive drugs (Table 4), with clinical and biological improvement in 34 of 41 patients (85%); three of 41 patients remained stable and four of 41 patients showed clinical degradation. Four patients did not initially receive high-dose glucocorticosteroids or immunosuppressive drugs, two patients showed an initial spontaneous improvement, and two patients remained stable, but experienced clinical and biological relapse during follow-up.Table 4Immunosuppressive TreatmentsDrugNo.ResponseDuration (Mo)Side EffectsIL-1 antagonists (anakinra/canakinumab)268 (30.7)2 (0-37)Skin reaction (n = 8), neutropenia (n = 3)IL-6 antagonists (tocilizumab/siltuximab)203 (15.0)5 (0-44)Neutropenia (n = 5), infection (n = 1)Janus kinase inhibitors (ruxolitinib, tofacitinib, baricitinib)158 (80)aEffect of ruxolitinib was not available for five patients at the time of data collection.2 (0-24)Thrombocytopenia (n = 1), cytopenia (n = 1)Methotrexate131 (7.6)6 (0-34)Elevated liver enzyme (n = 1)TNF antagonists (infliximab, etanercept, adalimumab, golimumab)101 (10)7 (0-28)Skin reaction (n = 2)Cyclophosphamide803 (2-4)…Azathioprine705 (2-22)Infection (n = 2)Mycophenolate mofetil603 (5-24)Neutropenia (n = 1)Rituximab601 (1-6)Progressive multifocal encephalopathy (n = 1), skin reaction (n = 1)Dapsone601 (0-2)Methemoglobinemia (n = 1), hemolytic anemia (n = 1)Colchicine306 (2-8)…Cyclosporine20(8-13)…IVIg20(1-1)…Ustekinumab10NA…Belimumab1011…IL-2102…Thalidomide11 (100)3…Hydroxychloroquine10141…Salazopyrin101…Data are presented as No. (%), No., or median (interquartile range), unless otherwise indicated. IVIg = IV immunoglobulin; NA = not available; TNF = tumor necrosis factor.a Effect of ruxolitinib was not available for five patients at the time of data collection. Open table in a new tab Data are presented as No. (%), No., or median (interquartile range), unless otherwise indicated. IVIg = IV immunoglobulin; NA = not available; TNF = tumor necrosis factor. All 45 patients eventually demonstrated at least one flare that required high-dose glucocorticosteroids of > 20 mg/d prednisone, and 40 patients received at least one other immunosuppressive drug, at a median of 3 drugs (IQR, 1-13 drugs) (Table 4). Janus kinase inhibitors and IL-1 antagonists yielded a good response rate, but the clinical, radiologic, and biological evaluation was not standardized, and IL-1 antagonist treatment was associated with skin reaction and neutropenia, without reported pulmonary reaction. In all, 27 patients underwent at least one other and up to 10 further chest CT scans after the initial specific CT scan available for review. The following CT scans were performed at a median of 244 days (IQR, 8-1,863 days) after the initial CT scan (Table 3) and usually because of new flares. Five CT scans were realized during a period of remission with immunosuppressant therapy and showed normal findings. Among the 81 follow-up CT scans, the global prevalence of radiologic abnormalities and the extent of lung abnormalities did not differ significantly from the initial CT scan, but could vary individually (Table 3, Figs 3, 4). From the 12 patients with available follow-up data classified in cluster 1 in the first CT scan, five patients were classified as cluster 1, five patients were classified as cluster 2, and two patients were classified as cluster 3 in the subsequent flare, but two patients showed normal CT scan results realized during a period of remission. In the same way, CT scan findings classified in cluster 3 initially could evolve unpredictably, being normal in remission or classified in cluster 1, 2, or 3 during new flares (Fig 4). All CT scans with radiologic abnormalities were concomitant with a new flare. We did not find any correlation between the nature of the flare (extrapulmonary manifestation, intensity, or C-reactive protein level), the treatment received or not, and the pattern of the CT scan or volume of the lung affected during the flare. Migratory opacities were observed in six patients during follow-up. No additional patient showed radiologic signs of fibrosis during follow-up. The median survival was 116 months and did not differ from the patients with unknown pulmonary involvement (135.6 months). VEXAS syndrome was reported first in 2020, and pulmonary manifestations including interstitial lung disease on CT scan were shown1Beck 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 (318) Google Scholar; however, descriptions of the pulmonary involvement have been limited. We report a cohort of 45 patients with VEXAS-related pleuropulmonary involvement. Chest CT scan most often showed ground-glass opacities, with or without consolidations, lung nodules and septal lines. Half of the patients showed associated pleural effusion, and the presentation could mimic heart failure or pulmonary infection or could evoke organizing pneumonia. Despite a response to high-dose glucocorticosteroids, relapses were frequent, and lung involvement did not seem to impair the overall survival in this cohort. The clinical and biological description of VEXAS syndrome initially was reported in 25 men with a UBA1 somatic mutation and has been reported since in several cohorts.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 (318) 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: 432-439Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar,4Georgin-Lavialle S. Terrier B. Guedon A.F. et al.Further characterization of clinical and laboratory features occurring in VEXAS syndrome in a large-scale analysis of multicenter case-series of 116 French patients.Br J Dermatol. 2021; 186: 564-574Crossref PubMed Scopus (76) Google Scholar,11Ferrada M.A. Sikora K.A. Luo Y. et al.Somatic mutations in UBA1 define a distinct subset of relapsing polychondritis patients with VEXAS.Arthritis Rheumatol. 2021; 73: 1886-1895Crossref PubMed Scopus (66) Google Scholar,12Arlet J.-B. Terrier B. Kosmider O. Mutant UBA1 and severe adult-onset autoinflammatory disease.N Engl J Med. 2021; 384: 2163Crossref PubMed Scopus (6) Google Scholar The main results of this cohort do not differ from those of previous reported cohorts, with the most frequent clinical presentations being fever, skin involvement, ear and nose chondritis, previous venous thrombosis, macrocytic anemia and bone marrow vacuoles, and elevated C-reactive protein level. Of note, no patient with VEXAS syndrome showed chondritis of the airways or costochondritis, as confirmed by the present study.11Ferrada M.A. Sikora K.A. Luo Y. et al.Somatic mutations in UBA1 define a distinct subset of relapsing polychondritis patients with VEXAS.Arthritis Rheumatol. 2021; 73: 1886-1895Crossref PubMed Scopus (66) Google Scholar The initial cohort study reported pulmonary infiltrates in 18 of 25 patients (72%), and the provided chest CT scan showed ground-glass opacities with mild left pleural effusion.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 (318) Google Scholar However, pulmonary manifestations of VEXAS syndrome have been described scarcely.13Beaumesnil S. Boucher S. Lavigne C. Urbanski G. Lacombe V. Ear, nose, throat, and bronchial involvements in VEXAS syndrome: specifying the spectrum of clinical features.JAMA Otolaryngol Head Neck Surg. 2022; 148: 284-286Crossref PubMed Scopus (8) Google Scholar In a series of 98 patients with relapsing polychondritis, 13 patients were associated retrospectively with VEXAS syndrome, and pulmonary infiltrates were more frequent in those with VEXAS syndrome than without VEXAS syndrome (77% vs 7%).11Ferrada M.A. Sikora K.A. Luo Y. et al.Somatic mutations in UBA1 define a distinct subset of relapsing polychondritis patients with VEXAS.Arthritis Rheumatol. 2021; 73: 1886-1895Crossref PubMed Scopus (66) Google Scholar One patient with organizing pneumonia confirmed by surgical lung biopsy and multiple episodes of new pulmonary infiltrates in VEXAS syndrome has been reported.8Sakuma M. Tanimura A. Yasui S. et al.Case of polychondritis-onset refractory organising pneumonia with cytopaenia diagnosed as VEXAS syndrome: the disease course of seven years.Rheumatol Oxf Engl. 2021; 60: e356-e359Crossref PubMed Scopus (12) Google Scholar Likewise, we observed several patients showing opacities that may evoke organizing pneumonia, some showing migratory consolidations over time. However, we cannot confirm the precise nature of lung opacities in these patients in the absence of pathologic confirmation. We observed three patterns of pleuropulmonary involvement: one showing mainly consolidations, ground-glass opacities, nodules, or features that could evoke pulmonary infection or organizing pneumonia; another showing ever-present pleural effusion with frequent ground-glass opacities and mediastinal adenomegalies or features that could evoke heart failure; and a third with mild unilateral involvement with frequent distal atelectasis and not evoking any of the previous diagnoses. Of note, the CT scan features could change over time during successive flares in the same patient. Pulmonary involvement was mildly symptomatic and almost half of the patients experienced isolated fever without respiratory symptoms; only 44% of patients reported dyspnea and 6% of patients required oxygen. This also suggests that pulmonary manifestations are frequent in VEXAS syndrome, but rarely are overt and probably are underdiagnosed. The prevalence of lung involvement and pleural effusion may be higher, and systematic chest CT scan during inflammatory flares could reveal a higher proportion of pulmonary manifestations. All patients from this cohort had a confirmed UBA1 somatic mutation already reported, with UBA1 loss of function.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 (318) Google Scholar Moreover, we could confirm a UBA1 mutation in the BAL of one patient, as reported for skin manifestations of VEXAS syndrome, which suggests that pulmonary manifestations are related to the syndrome.14Zakine 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 (32) Google Scholar,15Lacombe V. Beucher A. Urbanski G. et al.Distinction between clonal and paraclonal cutaneous involvements in VEXAS syndrome.Exp Hematol Oncol. 2022; 11: 6Crossref PubMed Scopus (9) Google Scholar The association of consolidations, ground-glass opacities, lung nodules, and pleural effusion on chest CT scan that were variable in time and space should be considered possible specific manifestations of VEXAS syndrome. However, and as for cryptogenic organizing pneumonia, the diagnosis requires the exclusion of infection or heart failure whose diagnosis can be difficult, despite normal echocardiography findings, especially in this elderly population.16Cordier J.-F. Cryptogenic organising pneumonia.Eur Respir J. 2006; 28: 422-446Crossref PubMed Scopus (377) Google Scholar,17King T.E. Lee J.S. Cryptogenic organizing pneumonia.N Engl J Med. 2022; 386: 1058-1069Crossref PubMed Scopus (17) Google Scholar In the absence of systematic scans for the entire cohort, the comparison of patients with pulmonary involvement with patients with unknown pleuropulmonary involvement must be interpreted with caution. Considering this limitation, we observed that the only clinical or biological measurements that differed between the two groups were the C-reactive protein level and platelet count, higher for patients with VEXAS syndrome with pulmonary involvement (105 mg/L vs 50 mg/L [P = .01] and 222 g/L vs 173 g/L [P = .02], respectively). We may not exclude that the higher C-reactive protein level in patients with pulmonary involvement was a selection bias, being related to the increased number of CT scans realized looking for pulmonary infection in these patients. The number of flares (median, 3 flares [IQR, 3-4 flares] vs 3 flares [IQR, 2-6 flares]) and their treatment (immunosuppression) or survival did not differ between the two groups. Our work has several limitations. The main limitations are the retrospective nature and the absence of standardized assessment at diagnosis, during flares, or during remission. Moreover, the absence of a standardized diagnosis and therapeutic algorithms and the lack of systematic key data like lung function measurements, BAL, or histologic findings limits the conclusions that can be drawn. The significance of clusters is limited, their description mainly helping to recognize lung manifestations of VEXAS syndrome and showing pattern modification during the follow-up in the same patient. The differential diagnosis with pulmonary infection, heart failure, or both may be challenging, particularly in this older population, despite normal echocardiography results in case of diastolic heart failure. However, most patients received diuretics, antibiotics, or both without improvement. For most, the BAL showed no infection, and all showed improvement with high-dose glucocorticosteroids.18Revel M.-P. Boussouar S. de Margerie-Mellon C. et al.Study of thoracic CT in COVID-19: the STOIC Project.Radiology. 2021; 301: E361-E370Crossref PubMed Scopus (14) Google Scholar The reported outcome suggests that Janus kinase inhibitors may have good response, but these findings do not allow any conclusions about the therapeutic option in VEXAS syndrome, with pulmonary involvement or with unknown pulmonary involvement, and only suggest dedicated studies to treatment.6Comont T. Heiblig M. Rivière E. et al.Azacitidine for patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS) and myelodysplastic syndrome: data from the French VEXAS registry.Br J Haematol. 2021; 196: 969-974Crossref PubMed Scopus (42) Google Scholar,19Heiblig M. Ferrada M.A. Koster M.J. et al.Ruxolitinib is more effective than other JAK inhibitors to treat VEXAS syndrome: a retrospective multi center study.Blood. 2022; 140: 927-931Crossref PubMed Scopus (30) Google Scholar Although this is a relatively large cohort given the novelty and rarity of the syndrome, the number of patients included limits the power of statistical analysis. Pulmonary manifestations of VEXAS syndrome are frequent, but rarely are at the forefront. The most frequent signs are pleural effusion, ground-glass opacities, and consolidations, which may mimic infection or heart failure, which resist diuretics or antibiotics treatment but eventually improve with high-dose glucocorticosteroids. Pulmonary manifestations do not seem to evolve to pulmonary fibrosis.20Ba I. Dieudé P. Crestani B. et al.Looking for somatic mutations in fibrosing interstitial lung diseases.Respir Med Res. 2021; 79100823PubMed Google Scholar, 21Borie R. Kannengiesser C. Sicre de Fontbrune F. Gouya L. Nathan N. Crestani B. Management of suspected monogenic lung fibrosis in a specialised centre.Eur Respir Rev. 2017; 2628446600Crossref PubMed Scopus (50) Google Scholar, 22Parry E.M. Alder J.K. Qi X. Chen J.J.-L. Armanios M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase.Blood. 2011; 117: 5607-5611Crossref PubMed Scopus (130) Google Scholar, 23Borie R. Tabèze L. Thabut G. et al.Prevalence and characteristics of TERT and TERC mutations in suspected genetic pulmonary fibrosis.Eur Respir J. 2016; 48: 1721-1731Crossref PubMed Scopus (109) Google Scholar, 24Esposito D.B. Lanes S. Donneyong M. et al.Idiopathic pulmonary fibrosis in United States automated claims. Incidence, prevalence, and algorithm validation.Am J Respir Crit Care Med. 2015; 192: 1200-1207Crossref PubMed Scopus (82) Google Scholar Although the results of this cohort should be confirmed by further study, pulmonary CT scan could be part of the entire evaluation of VEXAS syndrome and normalization of pulmonary abnormalities could be a marker of treatment efficacy. The authors have reported to CHEST that no funding was received for this study.
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