Methotrexate and Rituximab Use in Highly Recurrent Idiopathic Subglottic Stenosis.

OBJECTIVE: To evaluate the impact of methotrexate and rituximab therapy on highly recurrent idiopathic subglottic stenosis (iSGS) patients with a negative antineutrophil cytoplasmic antibody titer cANCA(-). METHODS: This was a retrospective cohort study of highly recurrent iSGS patients who recurred within 1 year or less and were treated with methotrexate (MTX), and rituximab (RTX), or a combination of both at different time points (MTX/RTX). Average surgical durations before and after drug treatment were summarized, and the differences were calculated. RESULTS: A total of 21 female patients with median age of 62 years were included. Fifteen patients were treated with MTX, three were treated with RTX, and five treated with both. Patients treated with immunosuppressants showed a trend toward longer intervals between operations (mean pre-drug interval: 338; mean post-drug interval: 697 days) (p-value = 0.25). Three patients did not recur following drug initiation with median follow-up of 1265 days. All three treatment groups demonstrated a trend toward increased post-drug recurrence intervals (MTX: 444 days, RTX: 374 days, MTX/RTX: 55 days), that was not statistically significant. Patients with prior dilations demonstrated longer post-drug recurrence intervals (mean pre-drug interval: 341 days, mean post-drug interval 978 days) (p-value = 0.17). Four patients in the cohort with the highest recurring disease improved from mean 129 days between operations to 509 days with drug therapy. The most common drug side effect was nausea (16%). CONCLUSION: MTX and RTX may be treatment options for some highly recurrent iSGS patients. Initial results are variable and demonstrate a need for further research on drug candidacy. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Subclinical Aortic Inflammation in Patients with Polymyalgia Rheumatica.

OBJECTIVES: To examine the clinicopathologic features of patients with polymyalgia rheumatica (PMR) who had thoracic aorta repair surgery. Findings were compared with those of a cohort of patients with giant cell arteritis (GCA) requiring thoracic aorta repair. METHODS: All patients evaluated at Mayo Clinic in Rochester, MN, with Current Procedural Terminology (CPT) codes for thoracic aorta repair surgery between 2000- 2021 were identified. All patients were screened for prior PMR diagnosis. Patients with PMR and no signs of GCA were categorized as clinically isolated PMR. The medical records of all patients were manually reviewed, and pathologists re-examined all the aortic tissues. RESULTS: Of the 4621 patients with at least one CPT code for thoracic aorta repair surgery, 43 patients were diagnosed with clinically isolated PMR before the surgery. Detailed histopathological examination of the aortic tissues revealed active inflammation in 30/43 (70%) patients after a median (IQR) of 10.0 (4.7- 13.3) years from the PMR diagnosis. When compared with aortic tissue from patients with a prior diagnosis of GCA, the aorta of patients with PMR had more severe inflammation (Grade 3: 15/30 [50%] vs 5/34 [15%], p= 0.002). Patients with PMR and thoracic aorta repair may experience a 40% increased risk of mortality compared with the general population, but this did not reach statistical significance (standardized mortality ratio: 1.40; 95% CI: 0.91- 2.07). CONCLUSIONS: Some patients with PMR have subclinical aortic inflammation that is detectable many years after initial diagnosis and may contribute to the development of aortic aneurysm.

Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Diffuse Alveolar Hemorrhage With Avacopan.

OBJECTIVE: Avacopan, an activated complement factor 5 receptor antagonist, has been approved as adjunct therapy for severe active antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Current evidence supports the management of AAV presenting with diffuse alveolar hemorrhage (DAH) by administering glucocorticoids combined with either rituximab or cyclophosphamide in addition to supportive care. The role of avacopan in patients with DAH as a primary severe disease manifestation of AAV has not been well established. Furthermore, concerns remain regarding timely access to avacopan, the best glucocorticoid tapering regimen, and long-term efficacy and safety of the drug. We sought to identify clinical features and outcomes of patients presenting with DAH secondary to AAV who received avacopan in addition to glucocorticoids and rituximab or cyclophosphamide. METHODS: We performed a retrospective cohort study of all consecutive patients presenting with DAH as part of active severe granulomatosis with polyangiitis or microscopic polyangiitis. Demographic and clinical characteristics were collected at presentation and follow-up. RESULTS: Fifteen patients met inclusion criteria and were observed for a median time of 17 weeks (interquartile range [IQR] 6-37 weeks) after initiation of avacopan. Patients were predominantly female and White, had never smoked, and were a median age of 66 years (IQR 52-72 years) at diagnosis. The majority had newly diagnosed severe AAV with renal involvement. Three patients progressed to respiratory failure. The timing of avacopan introduction and patterns of glucocorticoid tapers varied widely in this cohort. Two serious adverse events related to infection were observed, including one opportunistic infection leading to the patient's death, although neither was directly attributed to avacopan administration. CONCLUSION: We describe the clinical course of patients who presented with the severe AAV disease manifestation of DAH and received avacopan as adjunct therapy. Most patients achieved remission during follow-up, and adverse events, including infection, were observed.

IKZF1 and UBR4 gene variants drive autoimmunity and TH2 polarization in IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic immune-mediated' fibroinflammatory disease. The pathomechanisms remain poorly understood. Here, we identified gene variants in familial IgG4-RD and determined their functional consequences. All three affected members shared mutations of the transcription factor IKAROS, encoded by IKZF1, and the E3 ubiquitin ligase UBR4. The IKAROS mutation increased binding to the FYN promoter resulting in higher transcription of FYN in T cells. The UBR4 mutation prevented the lysosomal degradation of the phosphatase CD45. In the presence of elevated FYN, CD45 functioned as a positive regulatory loop, lowering the threshold for T cell activation. Consequently, T cells from affected family members were hyperresponsive to stimulation. When transduced with a low avidity, autoreactive T cell receptor, they responded to the autoantigenic peptide. In parallel, the high expression of FYN in T cells biased their differentiation towards TH2 polarization by stabilizing the transcription factor JunB. This bias is consistent with the frequent atopic manifestations in IgG4-RD patients including our afflicted family members. Building on the functional consequences of these two mutations, we propose a disease model that is not only instructive for IgG4-RD but also for atopic diseases for autoimmune diseases associated with an IKZF1 risk haplotype.

Giant cell arteritis in patients with systemic sclerosis: a case series.

OBJECTIVES: Giant cell arteritis (GCA) in patients with systemic sclerosis (SSc) is rare, and optimal treatment strategies for this group of patients have not been defined. We aim to describe the first case series of GCA/SSc overlap. METHODS: A single-institution retrospective study was performed reviewing all patients that had diagnosis codes for both SSc and GCA between January 1, 1996, and December 31, 2020. Demographic characteristic, clinical presentation, diagnostic modality, treatment, and outcome data were abstracted. Diagnosis of both SSc and GCA by a rheumatologist was required for inclusion. RESULTS: Eight patients were retrospectively identified, all of which were female. Seven patients fully met both respective ACR/EULAR classification criteria sets. One patient fulfilled GCA criteria and had 8/9 points for SSc criteria plus an oesophagogram which was consistent with clinical diagnosis of SSc. Three patients had a previous history of scleroderma renal crisis (SRC) prior to glucocorticoid initiation for GCA. No episodes of SRC occurred following initiation of glucocorticoids. Three patients were treated with tocilizumab. One patient developed a diverticular perforation while on tocilizumab requiring colonic resection and colostomy, one patient discontinued tocilizumab after a medication-unrelated complication and one patient has remained on treatment and in remission. CONCLUSIONS: Herein we present the largest single-institution series of patients with a history of GCA and SSc, an uncommon combination. Glucocorticoid treatment for GCA did not precipitate SRC, even in those with prior history of SRC. Further investigation regarding the benefit of tocilizumab in patients with SSc and GCA is required.

Medical Maintenance Therapy Following Laser Excision in Patients With Granulomatosis With Polyangiitis (GPA)-Associated Subglottic Stenosis.

OBJECTIVE: To report on a series of patients with cANCA/PR3-positive, granulomatosis with polyangiitis (GPA)-associated subglottic stenosis (SGS) and evaluate response to medical maintenance therapy with rituximab versus other immunosuppressants following initial endoscopic laser excision. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary academic center. METHODS: A retrospective chart review of patients with SGS and cANCA/PR3-positive GPA who received immunosuppressive maintenance therapy following endoscopic laser excision at our institution from June 1989 to March 2020 was performed. Data pertaining to patient demographics, clinical features, medications, and endoscopic laser procedures were collected. RESULTS: A total of 27 patients (15 women) with mean age (range) of 40 (19-59) years and mean (range) follow-up of 12.6 years (1.5-28.6) were identified. Sixteen patients (60%) had limited GPA. Six patients (24%) had previously received local intervention with open surgery (n = 1, 4%) or endoscopic techniques (n = 5, 20%). All patients experienced symptom improvement following initial CO2 laser excision at our institution without any procedural complications or adverse events. Following initial laser excision, 15 patients (60%) were treated with rituximab and 10 patients (40%) were treated with nonrituximab immunosuppressive agents. Patients treated with rituximab were less likely to recur (P = 0.040). Limited GPA was associated with an increased incidence of recurrence (P = 0.031). Median time (years) to recurrence (range) was 3.2 (0.3-19.3) and was not significantly associated with treatment or GPA subtype. CONCLUSION: Endoscopic CO2 laser excision is a safe and effective local intervention for GPA-associated SGS. Medical maintenance therapy with rituximab reduces risk of recurrence following initial laser excision relative to treatment with non-rituximab agents.

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.

Comprehensive morphologic characterization of bone marrow biopsy findings in a large cohort of patients with VEXAS syndrome: A single-institution longitudinal study of 111 bone marrow samples from 52 patients.

OBJECTIVES: VEXAS syndrome is an adult-onset autoinflammatory disease caused by a somatic pathogenic mutation in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. Patients present with rheumatologic manifestations and cytopenias and may have an increased predisposition to myelodysplastic syndrome (MDS) and plasma cell neoplasms. Prior studies have reported on the peripheral blood and bone marrow findings in patients with VEXAS syndrome. Due to the protean clinical presentation and lack of specificity of morphologic features (eg, vacuoles in early erythroid and granulocytic precursors), an optimal screening methodology to identify these patients in a timely fashion is desirable. METHODS: To further evaluate and describe the salient diagnostic morphologic features in VEXAS syndrome, we carried out a comprehensive study of the largest single-institution cohort to date. Diagnostic and follow-up bone marrow biopsy specimens from 52 male patients with molecularly identified VEXAS syndrome underwent central review. RESULTS: Cytopenias were common in all cases, primarily macrocytic anemia, monocytopenia, and thrombocytopenia. Bone marrow aspirate and biopsy were often hypercellular, with an increased myeloid/erythroid ratio, granulocytic hyperplasia with left shift, erythroid left shift, and megakaryocyte hyperplasia, which exhibited a range of striking morphologic findings. Distinctly vacuolated myeloid and erythroid precursors were seen in more than 95% of cases. CONCLUSIONS: Our data reveal potential novel diagnostic features, such as a high incidence of monocytopenia and distinct patterns of atypical megakaryopoiesis, that appear different from dysmegakaryopoiesis typically associated with MDS. In our experience, those findings are suggestive of VEXAS, in the appropriate clinical context.

Reappraisal of large artery involvement in giant cell arteritis: a population-based cohort over 70 years.

OBJECTIVE: To evaluate the incidence and outcomes of large artery (LA) involvement among patients with giant cell arteritis (GCA) and to compare LA involvement to non-GCA patients. METHODS: The study included Olmsted County, Minnesota, USA residents with incident GCA between 1950 and 2016 with follow-up through 31 December 2020, death or migration. A population-based age-matched/sex-matched comparator cohort without GCA was assembled. LA involvement included aortic aneurysm, dissection, stenosis in the aorta or its main branches diagnosed within 1 year prior to GCA or anytime afterwards. Cumulative incidence of LA involvement was estimated; Cox models were used. RESULTS: The GCA cohort included 289 patients (77% females, 81% temporal artery biopsy positive), 106 with LA involvement.Reported cumulative incidences of LA involvement in GCA at 15 years were 14.8%, 30.2% and 49.2% for 1950-1974, 1975-1999 and 2000-2016, respectively (HR 3.48, 95% CI 1.67 to 7.27 for 2000-2016 vs 1950-1974).GCA patients had higher risk for LA involvement compared with non-GCA (HR 3.22, 95% CI 1.83 to 5.68 adjusted for age, sex, comorbidities). Thoracic aortic aneurysms were increased in GCA versus non GCA (HR 13.46, 95% CI 1.78 to 101.98) but not abdominal (HR 1.08, 95% CI 0.33 to 3.55).All-cause mortality in GCA patients improved over time (HR 0.62, 95% CI 0.41 to 0.93 in 2000-2016 vs 1950-1974) but remained significantly elevated in those with LA involvement (HR 1.89, 95% CI 1.39 to 2.56). CONCLUSIONS: LA involvement in GCA has increased over time. Patients with GCA have higher incidences of LA involvement compared with non-GCA including thoracic but not abdominal aneurysms. Mortality is increased in patients with GCA and LA involvement highlighting the need for continued surveillance.

Rheumatic masqueraders: mimics of primary vasculitis - a case-based review.

INTRODUCTION: Vasculitis conditions are often serious and sometimes fatal diseases, therefore it is paramount to diagnose correctly and treat appropriately. Mimics of primary vasculitis can include either non-inflammatory syndromes or secondary vasculitis where the underlying etiology of the vasculitis is being driven by infection, malignancy, drug-effect or other. AREAS COVERED: This review comprises six individual cases of vasculitis mimics. Each case is presented and the clinical, radiographic, and histological features that distinguish the case from primary vasculitis are highlighted. Key mimics in large, medium and small vessel vasculitis are outlined. EXPERT OPINION: The diagnosis of vasculitis requires a comprehensive assessment of clinical, radiographic, and histologic features. Clinicians should be familiar with mimics of primary vasculitis conditions. In the case of non-inflammatory mimics, it is important to differentiate from primary vasculitides in order to avoid unnecessary and potentially harmful immunosuppression. For cases of secondary vasculitis, identification of the correct etiologic cause is critical because treatment of the underlying stimulus is necessary for successful management and outcomes.

VEXAS syndrome: Clinical, hematologic features and a practical approach to diagnosis and management.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a newly identified disease caused by somatic alterations in UBA1 which produce a recalcitrant inflammatory state along with hematologic disturbances. Patients with VEXAS can have a wide spectrum of clinical symptoms and providers should be familiar with the heterogeneity of associated clinical features. While hematologic parameters may be generally non-specific, peripheral blood features of macrocytosis, monocytopenia, and/or thrombocytopenia coupled with bone marrow vacuolization of erythroid or myeloid precursors should raise suspicion for this condition. Due to an increased mortality, prompt recognition and accurate diagnosis is paramount. Access to testing for confirmation of UBA1 variants is not yet universally available but clinicians should understand the current available options for genetic confirmation of this disease. Treatment options are limited due to lack of prospective clinical trials but cytokine directed therapies such as interleukin-6 inhibitors and JAK-STAT inhibitors as well as hypomethylating agents such as azacitidine have shown evidence of partial effect. Though cases are limited, allogeneic stem cell transplantation holds promise for durable response and potential cure. The intent of this review is to outline the pathophysiology of VEXAS syndrome and to provide a practical approach to diagnosis and treatment.

Genome-Wide Association Study Identifies the First Germline Genetic Variant Associated With Erdheim-Chester Disease.

OBJECTIVE: Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study. METHODS: After quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed. RESULTS: A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10-11 ; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease. CONCLUSION: Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.