Warrington, Kenneth J

Abstract Objective To retrospectively identify patients with VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome) among male patients with bone marrow vacuolization using a clinically applicable, targeted-screening approach. Methods Bone marrow reports from 1 May 2014 through 18 February 2022 were reviewed for documentation of cytoplasmic vacuolization. Patients with acute leukaemia, lymphoma, metastatic solid tumour, amyloidosis or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome were excluded, as were those without clinical records available for direct chart review. Cases were rated for suspicion of VEXAS syndrome using a 5-point scale based on the presence of laboratory findings, clinical features and treatment response. Patients with available DNA material and moderate (three patients) or high (four to five patients) suspicion were tested for somatic UBA1 variants associated with VEXAS syndrome. Results A total of 315 reports from 292 unique patients included documentation of vacuolization. Following exclusion criteria, 64 patients underwent direct medical chart review to assess likelihood of VEXAS syndrome, for which 21 patients met moderate to high suspicion. Available DNA was present in eight patients, seven (87.5%) of whom had a pathogenic somatic UBA1 variant consistent with VEXAS syndrome. The distribution of cytoplasmic vacuolization in the bone marrow biopsy reports among patients with VEXAS syndrome were erythroid and myeloid precursors (6/7), erythroid precursors only (1/7) and myeloid precursors only (0/7). Conclusion In this study, the utilization of a clinically applicable targeted-screening approach to test bone marrow specimens (with vacuolization) for the presence of previously undiagnosed VEXAS syndrome resulted in a positive detection rate of 87.5%.

AbstractObjectiveVitamin D might participate in the pathogenesis of several immune-mediated diseases, but few related data are available for ANCA-associated vasculitis (AAV). In this study, we analysed the association between vitamin D status and disease in patients with AAV.MethodsSerum levels of 25(OH)D2/3 were measured in 125 randomly selected patients with AAV [granulomatosis with polyangiitis (n = 50), eosinophilic granulomatosis with polyangiitis (n = 50) or microscopic polyangiitis (n = 25)] enrolled in the Vasculitis Clinical Research Consortium Longitudinal Studies at the time of enrolment and a subsequent relapse visit. Sufficient, insufficient and deficient vitamin D status were defined as 25(OH)D3 levels >30, 20–30 and ˂20 ng/ml, respectively.ResultsSeventy of 125 patients (56%) were female, with a mean age of 51.5 (16) years at diagnosis; 84 (67%) were ANCA positive. Mean 25(OH)D was 37.6 (16) ng/ml, with vitamin D deficiency in 13 (10.4%) and insufficiency in 26 (20.8%). In univariate analysis, lower vitamin D status was associated with male sex (P = 0.027) and disease activity (P = 0.047). In univariate and multivariate analyses, deficient vitamin D status was associated with disease activity (P = 0.015). Mean 25(OH)D status in the 21 patients with a subsequent relapse did not differ between baseline and relapse visit [37.8 (16) vs 38.0 (10) ng/ml, respectively; P = 0.92].ConclusionMost patients with AAV have sufficient 25(OH)D levels, although those with lower vitamin D status were more likely to be male and to have active disease. Whether optimization of vitamin D status alters disease manifestations or activity in AAV remains to be determined.Trial RegistrationVasculitis Clinical Research Consortium (VCRC) Longitudinal Study (LS), NCT00315380, https://clinicaltrials.gov/ct2/show/NCT00315380

Abstract Objectives ANCA-associated vasculitis (AAV) is a group of multisystem diseases that can have several ocular manifestations. There are published data on ocular manifestations of granulomatosis with polyangiitis (GPA), but few for eosinophilic granulomatosis with polyangiitis (EGPA) or microscopic polyangiitis (MPA). There is little information concerning chronicity, complications, and association with other cranial manifestations of AAV. Methods This study retrospectively analysed longitudinal multicentre cohorts of individuals with AAV followed between 2006 and 2022. Data included diagnosis, demographics, cranial manifestations of disease, presence of manifestations at onset of disease and/or follow-up, and ocular complications of disease. Univariate and multivariable logistic regression analysis assessed associations across disease manifestations. Results Data from 1441 patients were analysed, including 395 with EGPA, 876 with GPA, and 170 with MPA. Ocular manifestations were seen within 23.1% of patients: 39 (9.9%) with EGPA, 287 (32.7%) with GPA, and 12 (7.1%) with MPA at any time in the disease course. There were more ocular manifestations at onset (n = 224) than during follow-up (n = 120). The most common disease-related manifestations were conjunctivitis/episcleritis and scleritis. In multivariable analysis, dacryocystitis, lacrimal duct obstruction, and retro-orbital disease were associated with sinonasal manifestations of GPA; ocular manifestations were associated with hearing loss in MPA. The most common ocular complications and/or damage seen were cataracts (n = 168) and visual impairment (n = 195). Conclusion Ocular manifestations occur in all forms of AAV, especially in GPA. Clinicians should be mindful of the wide spectrum of ocular disease in AAV, caused by active vasculitis, disease-associated damage, and toxicities of therapy.

Abstract ANCA-associated vasculitides (AAV) are a group of rare, primary, systemic necrotizing small-vessel vasculitides. Granulomatosis with polyangiitis and microscopic polyangiitis account for ∼80–90% of all AAV. Exposure to silica dust, farming and chronic nasal Staphylococcus aureus carriage are associated with increased risk of developing AAV. When a diagnosis of AAV is suspected, as in patients with multisystem organ dysfunction or those with features such as chronic recurrent rhinosinusitis, cavitated lung nodules, palpable purpura or acute kidney injury, then appropriate further investigations are needed, including ANCA testing. In this scenario, a structured clinical assessment should be conducted, evaluating all the organs possibly involved, and tissue biopsy may be necessary for confirmation of the diagnosis. Therapeutic algorithms vary based on the severity of AAV, the clinical diagnosis/ANCA specificity, and the patient’s age, weight, comorbidities and prognosis. Recent data favour rituximab as a preferable option for both induction and maintenance of remission. In addition, regimens with less glucocorticoids are equally effective and safer in inducing remission compared with conventional regimens, and avacopan is an effective glucocorticoid-sparing option. In contrast, there is not compelling evidence to support the routine use of plasma exchange in addition to standard remission-induction therapy in AAV. ANCA and other biomarkers can be helpful in association with clinical assessment to guide diagnosis and treatment decisions. Patients should be frequently evaluated during follow-up for possible disease relapses or treatment-related morbidity, and for monitoring damage accrual, especially metabolic and cardiovascular damage.

Abstract Objective To investigate the relation between biomarkers of inflammation and subsequent development of GCA. Method Participants in the population-based Malmö Diet Cancer Study (MDCS; N = 30 447), established 1991–96, who were subsequently diagnosed with GCA, were identified in a structured process. GCA-free controls, matched for sex, year of birth and year of screening were selected from the study cohort. Baseline plasma samples were analysed using the antibody-based OLINK proteomics inflammation panel (92 inflammatory proteins). Analyses were pre-designated as hypothesis-driven or hypothesis-generating. In the latter, principal component analysis was used to identify groups of proteins that explain the variance in the proteome. Within components selected based on eigenvalues, proteins with a factor loading of >0.50 were investigated. Results Ninety-four cases with a confirmed incident diagnosis of GCA (median 11.9 years after inclusion) were identified. Among biomarkers with a priori hypotheses, IFN-γ was positively associated with GCA [odds ratio (OR) per s.d. 1.52; 95% CI 1.00, 2.30]. Eight biomarkers in the hypothesis-generating analyses were significantly associated with development of GCA. Among these, higher levels of IFN-γ (OR 2.37; 95% CI 1.14, 4.92) and monocyte chemotactic protein 3 (MCP3) (OR 4.27; 95% CI 1.26, 14.53) were particularly associated with increased risk of GCA in the subset sampled <8.5 years before diagnosis. Several other proteins known to be important for T cell function were also associated with GCA in these analyses, e.g. CXCL9, IL-2, CD40 and CCL25. Conclusion Elevated IFN-γ levels were found years prior to diagnosis of GCA. T cell activation may precede the clinical onset of GCA.

ABSTRACTThe risk of progression to end-stage kidney disease (ESKD) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and glomerulonephritis (AAV-GN) remains high. At 5 years of follow-up, 14–25% of patients will evolve to ESKD, suggesting that kidney survival is not optimized in patients with AAV. The addition of plasma exchange (PLEX) to standard remission induction has been the standard of care, particularly in patients with severe renal disease. However, there is still some debate regarding which patients benefit from PLEX.A recently published meta-analysis concluded that the addition of PLEX to standard remission induction in AAV probably reduced the risk of ESKD at 12 months and that PLEX was associated with an estimated absolute risk reduction for ESKD at 12 months of 16.0% for those at high risk or with a serum creatinine >5.7 mg/dl (high certainty of important effects). These findings were interpreted as supportive of offering PLEX to patients with AAV and a high risk of progression to ESKD or requiring dialysis and are making their way into societies recommendations.However, the results of the analysis can be debated. We provide an overview on the meta-analysis as an attempt to guide the audience through how the data were generated, to comment on our interpretation of the results and to explain why we feel uncertainty remains. In addition, we would like to provide insights in two questions that we believe are very relevant to consider when addressing the role of PLEX: the role of kidney biopsy findings in the decision making of whom might benefit from PLEX and the impact of novel treatments (i.e. complement factor 5a inhibitors) in avoiding progression to ESKD at 12 months. The treatment of patients with severe AAV-GN is complex and further studies that include only patients at high risk of progression to ESKD are needed.

Abstract 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.

Abstract Objective To study the prevalence, risk and clinical associations of hypothyroidism among several forms of vasculitis. Methods Patients with GCA, Takayasu’s arteritis (TAK), PAN and the three forms of ANCA-associated vasculitis [AAV; granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA)] enrolled in a prospective, multicentre, longitudinal study were included. Results The study included data on 2085 patients [63% female, 90% White] with a mean age of 54.6 years (s.d. 17.2). Diagnoses were GCA (20%), TAK (11%), PAN (5%), GPA (42%), microscopic polyangiitis (8%) and EGPA (14%). Hypothyroidism was present in 217 patients (10%) (83% female), with a mean age 59.8 years (s.d. 14.5). Age- and sex-adjusted risk of hypothyroidism was GCA, odds ratio (OR) 0.61 (95% CI 0.41, 0.90); TAK, OR 0.57 (95% CI 0.31, 1.03); PAN, OR 0.59 (95% CI 0.25, 1.38); GPA, OR 1.51 (95% CI 1.12, 2.05); microscopic polyangiitis, OR 1.81 (95% CI 1.18, 2.80) and EGPA, OR 0.82 (95% CI 0.52, 1.30). Among patients with AAV, age- and sex-adjusted risk of hypothyroidism was higher with positive MPO-ANCA [OR 1.89 (95% CI 1.39, 2.76)]. The clinical manifestations of vasculitis were similar in patients with and without hypothyroidism, except transient ischaemic attacks, which were more frequently observed in patients with GCA and hypothyroidism (12% vs 2%; P = 0.001). Conclusions Differences in the risk of hypothyroidism among vasculitides may be due to genetic susceptibilities or immune responses. This study confirms an association of hypothyroidism with MPO-ANCA.