Venous and arterial thrombosis in patients with VEXAS syndrome.

ABSTRACT: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, caused by somatic mutations in UBA1, is an autoinflammatory disorder with diverse systemic manifestations. Thrombosis is a prominent clinical feature of VEXAS syndrome. The risk factors and frequency of thrombosis in VEXAS syndrome are not well described, due to the disease's recent discovery and the paucity of large databases. We evaluated 119 patients with VEXAS syndrome for venous and arterial thrombosis and correlated their presence with clinical outcomes and survival. Thrombosis occurred in 49% of patients, mostly venous thromboembolism (VTE; 41%). Almost two-thirds of VTEs were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. M41L was positively associated specifically with pulmonary embolism by univariate (odds ratio [OR]: 4.58, confidence interval [CI] 1.28-16.21, P = .02) and multivariate (OR: 16.94, CI 1.99-144.3, P = .01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival of the entire patient cohort at median follow-up time of 4.8 years was 88%, and there was no difference in survival between patients with or without thrombosis (P = .8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.

Spectrum of clonal hematopoiesis in VEXAS syndrome.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic autoinflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 patients with VEXAS for CH in their peripheral blood (PB) and correlated the findings with clinical outcomes in 77 of them. UBA1mut were most common at hot spot p.M41 (median variant allele frequency [VAF] = 75%). Typical CH mutations cooccurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mut was the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed 2 major patterns: with either typical CH preceding UBA1mut selection in a clone (pattern 1) or occurring as an UBA1mut subclone or in independent clones (pattern 2). VAF in the PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.

Ultra-rare genetic variation in relapsing polychondritis: a whole-exome sequencing study.

OBJECTIVE: Relapsing polychondritis (RP) is a systemic inflammatory disease of unknown aetiology. The objective of this study was to examine the contribution of rare genetic variations to RP. METHODS: We performed a case-control exome-wide rare variant association analysis that included 66 unrelated European American cases with RP and 2923 healthy controls (HC). Gene-level collapsing analysis was performed using Firth's logistics regression. Exploratory pathway analysis was performed using three different methods: Gene Set Enrichment Analysis, sequence kernel association test and higher criticism test. Plasma DCBLD2 levels were measured in patients with RP and HC using ELISA. RESULTS: In the collapsing analysis, RP was associated with a significantly higher burden of ultra-rare damaging variants in the DCBLD2 gene (7.6% vs 0.1%, unadjusted OR=79.8, p=2.93×10-7). Plasma DCBLD2 protein levels were significantly higher in RP than in HC (median 4.06 ng/µL vs 0.05 ng/µL, p<0.001). The pathway analysis revealed a statistically significant enrichment of genes in the tumour necrosis factor signalling pathway driven by rare damaging variants in RELB, RELA and REL using higher criticism test weighted by eigenvector centrality. CONCLUSIONS: This study identified specific rare variants in the DCBLD2 gene as a putative genetic risk factor for RP. These findings should be validated in additional patients with RP and supported by future functional experiments.

Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.

Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, whereas transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these 3 canonical VEXAS variants produce more UBA1b than any of the 6 other possible single-nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with 2 novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but coexpression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis.

Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease.

BACKGROUND: Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. METHODS: We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function. RESULTS: We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation. CONCLUSIONS: Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).

Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population.

Importance: VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes. Objective: To determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach. Design, Setting, and Participants: This retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022. Exposures: Exome sequencing was performed. Main Outcomes and Measures: Outcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays. Results: In 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669). Conclusions and Relevance: This study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.

Discordance in patient and physician global assessment in relapsing polychondritis.

OBJECTIVES: Relapsing polychondritis (RP) is a rare, heterogeneous, systemic inflammatory disease that targets cartilage. Patient-reported outcome measures may differ from physician assessment. This study compared patient global assessment (PtGA) and physician global assessment (PhGA) scores in a prospective cohort of patients with RP. METHODS: Adult patients with RP underwent a standardized comprehensive evaluation at ∼6 month intervals. At each visit, three physicians scored PhGA by consensus. The patient independently completed four patient-reported outcomes: PtGA, 36-item Short Form Health Survey (SF-36), Brief Illness Perception Questionnaire (BIPQ) and Multidimensional Fatigue Inventory (MFI). Patient-physician discordance was defined as a difference between PtGA and PhGA of ≥3 on a 0-10 scale. RESULTS: A total of 76 patients were evaluated over 154 visits. The median PhGA was 3 [interquartile range (IQR) 2-3] and the median PtGA was 5 (IQR 4-7). PtGA and PhGA were concordant in 66 visits (42.9%) and patients scored disease severity ≥3 points higher than physicians scored disease activity (positive discordance) in 84 visits (54.5%). Compared with visits with concordance, visits with positive discordance were associated with significantly worse scores on the MFI, BIPQ, SF-36 physical component score and SF-36 mental component score. CONCLUSION: Patients with RP typically self-report high PtGA that does not align with PhGA. Discordance is likely driven by the high physical and psychological burden of illness experienced by patients. Multifaceted treatment approaches that address the burden of disease in RP from the patient perspective are needed.

Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial.

BACKGROUND: Convalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression. METHODS AND FINDINGS: The study was an open-label, single-center randomized clinical trial performed in an academic medical center in Santiago, Chile, from May 10, 2020, to July 18, 2020, with final follow-up until August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptom onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted of immediate CP (early plasma group) versus no CP unless developing prespecified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days, or death. The key secondary outcomes included time to respiratory failure, days of mechanical ventilation, hospital length of stay, mortality at 30 days, and SARS-CoV-2 real-time PCR clearance rate. Of 58 randomized patients (mean age, 65.8 years; 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We failed to find benefit in the primary outcome (32.1% versus 33.3%, odds ratio [OR] 0.95, 95% CI 0.32-2.84, p > 0.999) in the early versus deferred CP group. The in-hospital mortality rate was 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17 p = 0.246), mechanical ventilation 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17, p = 0.246), and prolonged hospitalization 21.4% versus 30.0% (OR 0.64, 95% CI, 0.19-2.10, p = 0.554) in the early versus deferred CP group, respectively. The viral clearance rate on day 3 (26% versus 8%, p = 0.204) and day 7 (38% versus 19%, p = 0.374) did not differ between groups. Two patients experienced serious adverse events within 6 hours after plasma transfusion. The main limitation of this study is the lack of statistical power to detect a smaller but clinically relevant therapeutic effect of CP, as well as not having confirmed neutralizing antibodies in donor before plasma infusion. CONCLUSIONS: In the present study, we failed to find evidence of benefit in mortality, length of hospitalization, or mechanical ventilation requirement by immediate addition of CP therapy in the early stages of COVID-19 compared to its use only in case of patient deterioration. TRIAL REGISTRATION: NCT04375098.

Subglottic stenosis and endobronchial disease in granulomatosis with polyangiitis.

OBJECTIVES: To describe tracheobronchial disease in patients with granulomatosis with polyangiitis (GPA) and evaluate the utility of dynamic expiratory CT to detect large-airway disease. METHODS: Demographic and clinical features associated with the presence of subglottic stenosis (SGS) or endobronchial involvement were assessed in a multicentre, observational cohort of patients with GPA. A subset of patients with GPA from a single-centre cohort underwent dynamic chest CT to evaluate the airways. RESULTS: Among 962 patients with GPA, SGS and endobronchial disease were identified in 95 (10%) and 59 (6%) patients, respectively. Patients with SGS were more likely to be female (72% vs 53%, P < 0.01), younger at time of diagnosis (36 vs 49 years, P < 0.01), and have saddle-nose deformities (28% vs 10%, P < 0.01), but were less likely to have renal involvement (39% vs 62%, P < 0.01). Patients with endobronchial disease were more likely to be PR3-ANCA positive (85% vs 66%, P < 0.01), with more ENT involvement (97% vs 77%, P < 0.01) and less renal involvement (42% vs 62%, P < 0.01). Disease activity in patients with large-airway disease was commonly isolated to the subglottis/upper airway (57%) or bronchi (32%). Seven of 23 patients screened by dynamic chest CT had large-airway pathology, including four patients with chronic, unexplained cough, discovered to have tracheobronchomalacia. CONCLUSION: SGS and endobronchial disease occur in 10% and 6% of patients with GPA, respectively, and may occur without disease activity in other organs. Dynamic expiratory chest CT is a potential non-invasive screening test for large-airway involvement in GPA.

VEXAS Syndrome-Diagnostic Clues for the Dermatologist and Gaps in Our Current Understanding: A Narrative Review.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome is a newly recognized, acquired autoinflammatory disorder with broad systemic implications and a poor global prognosis. Because cutaneous lesions are present in the majority of those affected, it is necessary that dermatologists are equipped to recognize this important disease. Through identification, there is a greater opportunity for disease stratification, surveillance for systemic involvement, and selection of the best available therapies. As our understanding of this disease develops, dermatologists should also play a role in addressing the knowledge gaps that exist.

Relapsing polychondritis: clinical updates and new differential diagnoses.

Relapsing polychondritis is a rare inflammatory disease characterized by recurrent inflammation of cartilaginous structures, mainly of the ears, nose and respiratory tract, with a broad spectrum of accompanying systemic features. Despite its rarity, prompt recognition and accurate diagnosis of relapsing polychondritis is crucial for appropriate management and optimal outcomes. Our understanding of relapsing polychondritis has changed markedly in the past couple of years with the identification of three distinct patient clusters that have different clinical manifestations and prognostic outcomes. With the progress of pangenomic sequencing and the discovery of new somatic and monogenic autoinflammatory diseases, new differential diagnoses have emerged, notably the vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome, autoinflammatory diseases and immune checkpoint inhibitor-related adverse events. In this Review, we present a detailed update of the newly identified clusters and highlight red flags that should raise suspicion of these alternative diagnoses. The identification of these different clusters and mimickers has a direct impact on the management, follow-up and prognosis of patients with relapsing polychondritis and autoinflammatory syndromes.

VEXAS syndrome: Clinical manifestations, diagnosis, and treatment.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an adult-onset autoinflammatory syndrome characterized by somatic mutations in the UBA1 gene and is considered the prototype of hematoinflammatory diseases. Patients with VEXAS syndrome exhibit inflammatory and hematological manifestations that can lead to clinical diagnoses such as relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, and myelodysplastic syndrome. Diagnosis requires bone marrow evaluation to identify cytoplasmic vacuoles in myeloid and erythroid precursors. However, genetic confirmation of mutations in UBA1 is necessary. Treatment is challenging and often involves glucocorticoids and immunosuppressants with variable responses. Hypomethylating agents and allogenic haemopoietic stem cell transplant are considered promising therapies. Prognosis is influenced by genetic and clinical factors. The aim of this review is to provide an overview of the pathogenesis, clinical presentation, treatment, and prognosis of VEXAS syndrome for the Latin American medical community.

Skin Manifestations of VEXAS Syndrome and Associated Genotypes.

Importance: 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. Objective: To define the spectrum of cutaneous manifestations in VEXAS syndrome and the association of these findings with clinical, genetic, and histological features. Design, Setting, and Participants: 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. Main Outcomes and Measures: 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. Results: 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%]). Conclusions and Relevance: 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.

Candidemia in the critically ill: initial therapy and outcome in mechanically ventilated patients.

BACKGROUND: Mortality among critically ill patients with candidemia is very high. We sought to determine whether the choice of initial antifungal therapy is associated with survival among these patients, using need for mechanical ventilatory support as a marker of critical illness. METHODS: Cohort analysis of outcomes among mechanically ventilated patients with candidemia from the 24 North American academic medical centers contributing to the Prospective Antifungal Therapy (PATH) Alliance registry. Patients were included if they received either fluconazole or an echinocandin as initial monotherapy. RESULTS: Of 5272 patients in the PATH registry at the time of data abstraction, 1014 were ventilated and concomitantly had candidemia, with 689 eligible for analysis. 28-day survival was higher among the 374 patients treated initially with fluconazole than among the 315 treated with an echinocandin (66% versus 51%, P < .001). Initial fluconazole therapy remained associated with improved survival after adjusting for non-treatment factors in the overall population (hazard ratio .75, 95% CI .59-.96), and also among patients with albicans infection (hazard ratio .62, 95% CI .44-.88). While not statistically significant, fluconazole appeared to be associated with higher mortality among patients infected with glabrata (HR 1.13, 95% CI .70-1.84). CONCLUSIONS: Among ventilated patients with candidemia, those receiving fluconazole as initial monotherapy were significantly more likely to survive than those treated with an echinocandin. This difference persisted after adjustment for non-treatment factors.

Relapsing polychondritis: Best Practice & Clinical Rheumatology.

Relapsing polychondritis (RP) is an uncommon inflammatory disorder that predominantly targets cartilaginous structures. The disease frequently affects the nose, ears, airways, and joints, but it can also impact organs that aren't primarily cartilage-based, such as blood vessels, skin, inner ear, and eyes. Given its infrequent occurrence and recurrent symptoms, patients often experience delays in proper diagnosis. Lately, based on the organs involved, the disease's diverse manifestations have been categorized into specific clinical groups, based on the most likely organ involvement including auricular, nasal, pulmonary, and musculoskeletal. More recently the discovery of a new disease, called (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) VEXAS syndrome, due to mutations in UBA1 gene, identified the cause of 8 % of the patients with a clinical diagnosis of RP. VEXAS is likely the cause of a previously described "hematologic subgroup" in RP. This discovery is proof of concept that RP is likely more than one disease (Beck et al., Dec 31 2020; Ferrada et al., 2021). People diagnosed with RP face numerous hurdles, with the quality of their lives and overall prognosis being affected. Diagnosing the condition is particularly challenging due to its fluctuating symptoms, the absence of specific markers, and the lack of universally recognized classification criteria. For a correct diagnosis, it's imperative for healthcare professionals to identify its unique clinical patterns. Moreover, there are no approved metrics to gauge the disease's severity, complicating patient management. This review seeks to equip clinicians with pertinent insights to better diagnose and attend to these complex patients.

Ultra-Rare Genetic Variation in Relapsing Polychondritis: A Whole-Exome Sequencing Study.

Objective: Relapsing polychondritis (RP) is a systemic inflammatory disease of unknown etiology. The study objective was to examine the contribution of rare genetic variations in RP. Methods: We performed a case-control exome-wide rare variant association analysis including 66 unrelated European American RP cases and 2923 healthy controls. Gene-level collapsing analysis was performed using Firth's logistics regression. Pathway analysis was performed on an exploratory basis with three different methods: Gene Set Enrichment Analysis (GSEA), sequence kernel association test (SKAT) and higher criticism test. Plasma DCBLD2 levels were measured in patients with RP and healthy controls using enzyme-linked immunosorbent assay (ELISA). Results: In the collapsing analysis, RP was associated with higher burden of ultra-rare damaging variants in the DCBLD2 gene (7.6% vs 0.1%, unadjusted odds ratio = 79.8, p = 2.93 × 10-7). Patients with RP and ultra-rare damaging variants in DCBLD2 had a higher prevalence of cardiovascular manifestations. Plasma DCBLD2 protein levels were significantly higher in RP than healthy controls (5.9 vs 2.3, p < 0.001). Pathway analysis showed statistically significant enrichment of genes in the tumor necrosis factor (TNF) signaling pathway driven by rare damaging variants in RELB, RELA and REL using higher criticism test weighted by degree and eigenvector centrality. Conclusions: This study identified specific rare variants in DCBLD2 as putative genetic risk factors for RP. Genetic variation within the TNF pathway is also potentially associated with development of RP. These findings should be validated in additional patients with RP and supported by future functional experiments.

Early activation of inflammatory pathways in UBA1-mutated hematopoietic stem and progenitor cells in VEXAS.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a pleiotropic, severe autoinflammatory disease caused by somatic mutations in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene. To elucidate VEXAS pathophysiology, we performed transcriptome sequencing of single bone marrow mononuclear cells and hematopoietic stem and progenitor cells (HSPCs) from VEXAS patients. HSPCs are biased toward myeloid (granulocytic) differentiation, and against lymphoid differentiation in VEXAS. Activation of multiple inflammatory pathways (interferons and tumor necrosis factor alpha) occurs ontogenically early in primitive hematopoietic cells and particularly in the myeloid lineage in VEXAS, and inflammation is prominent in UBA1-mutated cells. Dysregulation in protein degradation likely leads to higher stress response in VEXAS HSPCs, which positively correlates with inflammation. TCR usage is restricted and there are increased cytotoxicity and IFN-γ signaling in T cells. In VEXAS syndrome, both aberrant inflammation and myeloid predominance appear intrinsic to hematopoietic stem cells mutated in UBA1.

A prospective observational cohort study and systematic review of 40 patients with mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome.

OBJECTIVE: Mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome is characterized by overlapping features of relapsing polychondritis (RP) and Behcet's disease (BD). To date, no studies have defined the clinical spectrum of disease in a cohort of patients with MAGIC syndrome. METHODS: Adult patients within an ongoing prospective, observational cohort study in RP were clinically assessed for MAGIC syndrome. A systematic review was conducted to identify additional cases of MAGIC syndrome by searching four databases: PubMed (US National Library of Medicine), Embase (Elsevier), Scopus (Elsevier) and Web of Science: Core Collection (Clarivate Analytics). The inclusion criteria used were: [1] patients of any age or gender who were diagnosed with MAGIC syndrome, or both RP and BD; [2] case report or case series study; [3] published from 1985 - July 2020; and [4] in English language. Risk of bias was assessed using a checklist developed by the authors and based on the Consensus-based Clinical Case Reporting (CARE) Guidelines. Search results screening, article inclusion, data extraction and risk of bais assessment was performed independently by two investigators. Clinical characteristics, particularly BD-related features, were compared between patients with MAGIC syndrome and cases of non-MAGIC RP. The performance characteristics of different criteria to classify MAGIC syndrome were also evaluated. RESULTS: Out of 96 patients with RP, 13 (14%) patients were diagnosed with MAGIC syndrome. For the systematic review, 380 articles were retrieved of which 90 were screened at title and abstract levels. Of these screened, 60 were excluded and 30 proceeded to full text review where an additional 8 were excluded. Twenty-two articles were included in our review and from which 27 additional cases of MAGIC syndrome were identified. Pooling all 40 cases together and comparing them with non-MAGIC RP, there was a significantly higher prevalence of ocular involvement (28% vs 4%, p<0.01), cutaneous involvement (35% vs 1%, p<0.01), GI involvement (23% vs 4%, p<0.01), and CNS involvement (8% vs 0, p = 0.04) in MAGIC syndrome. A higher prevalence of aortitis (23% vs 1%, p<0.01), Raynaud's phenomenon (54% vs 11%, p<0.01), and elevated anti-collagen II antibodies (50% vs 9%, p = 0.04) were observed in MAGIC syndrome. Fulfillment of either McAdam's or Damiani's Criteria for RP plus the International Criteria for Behçet's Disease had excellent sensitivity (98%) to classify cases of MAGIC syndrome. CONCLUSION: A substantial proportion of patients with RP can be clinically diagnosed with MAGIC syndrome. These patients have features of RP, BD, and other unique features including aortitis, Raynaud's phenomenon and elevated anti-collagen II antibodies.