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Introduction: Autoimmunity in Rosai-Dorfman disease (RDD) has been reported in several case reports and small case series. The recent consensus RDD guidelines even classify “immune-related RDD” as a distinct entity, but little is known about the prevalence and patterns of autoimmune conditions in this rare disease. We conducted this study to evaluate a large cohort of patients with RDD for concomitant autoimmunity. Methods: We conducted a retrospective review of cases diagnosed with RDD from five referral centers globally. Data pertaining to autoimmunity were captured in terms of serology and a clinical diagnosis of autoimmune disease (AID) and compared to previously reported prevalence of AID and autoimmunity in the general population and in patients with other lymphomas. Results: We included 157 patients diagnosed with RDD from 2003-2023. Median age at the time of RDD diagnosis was 48 years, IQR 35.5-60. This included 103 females (65.6%) and 54 male (34.4%). Racial distribution included 54 Black (34.4%), 52 White (33.1%), 40 Asian (25.5%), 7 Middle Eastern (4.5%) and 4 other (2.5%). 83 patients had multi-systemic disease (52.8%) and 74 had single organ involvement (47.2%). Most common organs involved were skin/subcutaneous tissue (78, 49.7%), lymph nodes (63, 40.1%), bone (54, 34.2%). Tissue next generation sequencing data was available for 100 patients (63.7 %) and showed KRAS mutation (19, 19 %), MAP2K/MEK (13, 13%), other mutations (27, 27 %), and no mutations (41, 41%). Mean ESR at diagnosis of RDD was 28.42 mm/Hr and mean CRP was 19.5 mg/L. In our cohort, 28 patients (17.8%) were diagnosed with an AID. 19 (67.8%) were diagnosed with the AID prior to the diagnosis of RDD. Most common AID was systemic lupus erythematosus (6, 21.4%), rheumatoid arthritis (5, 17.8%), autoimmune hemolytic anemia (3, 10.7%), polymyalgia rheumatica (2, 7.1%). AID was more common in female vs male (64.3% vs 35.7%, p 0.8) and were more commonly seen in patients with multisystem compared to single organ RDD (60.7% vs 39.3%, p 0.3). Mean ESR and CRP at the time of RDD diagnosis in patients with AID were 40.63 mm/Hr and 37.04 mg/L respectively. Autoimmune antibodies were tested in 90 patients (57.3%), of which 43 (47.8%) were positive for atleast one autoantibody which included 15 patients (16.7%) with AID and a positive autoantibody and 6 (6.6%) with AID and negative antibodies (p 0.01). Most common antibodies were ANA (29/83, 34.9%), 42.3% with a titer higher than 1:160. Other antibodies include RF (10/60, 16.67%), anti-neutrophilic cytoplasmic antibody (3/19, 15.8%), double stranded DNA (6/56, 10.7%). Positive Antibodies were more common in female compared to male patients (72% vs 23%, p 0.04) and in patients from China compared to North America (45.7% vs 22.6%, p 0.007). Autoantibody positivity was common in multi-system vs single organ RDD (53.5% vs 46.5%, p 0.9). Mean ESR and CRP in this group of patients were 34.54 mm/Hr and 23.93 mg/L respectively. Median duration of follow up for our cohort was 32 months (IQR 14-65). Five-year survival was 93.4%. There were a total 8 deaths reported in the cohort, none of which were in patients with underlying AID. In a multivariable analysis, AID was associated with race (odds ratio [OR] for Middle Eastern compared with Chinese, OR 7, p=0.02) but other factors like organ involvement, mutational status, sex and age at diagnosis were not significant. Conclusions: Our study reveals a high prevalence of autoimmunity in RDD, both in terms of AID (17.8 %) and positive autoantibodies (47.8 %), which is much higher than the general population rates of approximately 3% and 16% respectively, and higher than patients with non-Hodgkin lymphoma, 7.6% and 39%, respectively. There was a trend toward association of AID with multisystem RDD and among individuals from North America and Middle East compared to China, although auto-antibody positivity was more common in Chinese patients. Mean ESR and CRP at the time of diagnosis of RDD was higher in the patients who had AID. We did not find any statistically significant association between AID and autoantibody positivity with the underlying driver mutation. Nearly half of the patients with RDD who also had AID did not have a positive autoantibody, thereby implying the need of clinical evaluation for rheumatological symptoms rather than empiric serological testing. Overall, this study also highlights the need to explore the biological link between RDD and autoimmunity.

Abstract Objectives To define the prevalence, distribution and characteristics of patients with VEXAS (vacuoles, E1-enzyme, X-linked, autoinflammation, somatic) syndrome who have confirmed vasculitis. Methods Patients with VEXAS syndrome, verified by positive UBA1 mutation, were included. Chart review was performed to identify patient characteristics and outcomes. Vasculitis diagnosis was based on either histopathology showing vascular inflammation or non-invasive angiography findings. Summary statistics were calculated. Results Eighty-nine patients met inclusion criteria. All were male with a median age of onset of 66.9 years (interquartile range 60.1, 72.7). Median (interquartile range) follow-up was 3.8 (2.2–5.5) years, during which 21 patients (23.6%) had evidence of vasculitis. Vasculitis subtypes included small vessel vasculitis (19.1%), cutaneous medium vessel vasculitis (2.2%) and large vessel vasculitis (2.2%). No patient had more than one vessel size involved. Histopathology in small vessel vasculitis patients was consistent with cutaneous leukocytoclastic vasculitis in the majority, though one patient had leukocytoclastic peritubular capillaritis on renal biopsy. Cranial symptoms (headache, vision changes or jaw pain) were noted in 18.0%. Two additional patients not experiencing cranial symptoms exhibited large vessel involvement with confirmed carotid thickening on non-invasive angiography; one of these had a positive temporal artery biopsy. Conclusion VEXAS syndrome manifests as a variable vessel vasculitis in a quarter of patients, with cutaneous small and medium vessel involvement being particularly common. Some patients may have positive ANCA serologies or even renal vasculitis leading to misdiagnosis. Cranial symptoms are common and may mimic GCA, though documented large vessel inflammation is rare.

Abstract Objectives Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is an autoinflammatory disease caused by somatic mutation of UBA1 and affects multiple organ systems. Involvement of the kidneys is not well characterized. We aimed to investigate the incidence, risk factors and histopathologic features of acute kidney injury (AKI) in VEXAS syndrome. Methods Patients with genetically confirmed UBA1 mutation consistent with VEXAS were included. Charts were manually reviewed. Cox regression analysis was used to identify variables associated with time-to-first AKI event. For patients with a kidney biopsy, histopathologic findings were reviewed. Results Eighty-one patients were included, all white men, with a mean age of 66.3 ± 8.6 years. Median (IQR) follow up was 3.5 (2.1–5.2) years during which 20 (25%) developed AKI and 22% died. AKI relapsed in 90% of cases for a median of 6 times during the follow up period. Cumulative incidence estimates (95% CI) for AKI at 1, 3 and 5 years were 6.2% (0.80–11.3%), 16.7% (7.5–25.0%) and 27.9% (14.9–38.9%), respectively. Age and baseline C-reactive protein (CRP) were significantly associated with time-to-first AKI event. Six patients underwent a kidney biopsy. Findings included, plasma cell-rich interstitial nephritis (n = 3), neutrophilic-rich interstitial inflammation (n = 1), leukocytoclastic peritubular capillaritis (n = 1) and acute tubular injury (n = 1). AKI responded well to treatment with glucocorticoids but had relapse upon tapering. Conclusion AKI is an underrecognized feature of VEXAS occurring in 25% of patients in this cohort. Age at diagnosis and CRP were associated with time to first AKI event during follow up. Plasma cell-rich interstitial nephritis was the most common histopathologic finding.

ObjectiveTo evaluate the impact of age on disease recurrence in idiopathic subglottic stenosis (iSGS) patients.MethodsThis was a retrospective chart review of iSGS patients treated with laser wedge excision. Patients did not have prior surgery. Survival rates free of recurrence were estimated using the Kaplan–Meier methods, and associations were evaluated using Cox Proportional Hazards models.ResultsEighty‐five female patients were included in the study. Most patients (68%) were postmenopausal, had first period at or before 13 years of age, had at least one full‐term pregnancy (82%), were not undergoing hormone replacement therapy (93%), were not using hormonal birth control (88%), and were either partially or completely compliant with triple therapy regime (80%). There was a statistically significant average reduction in risk of recurrence of 5% for every additional year of age (p < 0.0001). When compared to patients older than 65 years of age, patients less than 35 were nearly 10 times more likely to recur (p = 0.002), and patients 55–65 and 45–55 years of age were 8 and 5 times more likely to recur, respectively (p = 0.003 and 0.009). Additionally, females on birth control showed decreased risk of recurrence of 74% compared with their counterparts (p = 0.04).ConclusionThis is the first study to demonstrate an inverse relationship between age and disease recurrence in patients with iSGS following surgery. Using age as a surrogate for menopausal status, these results suggest that increased age and/or birth control provide a protective effect through decreased recurrence rates, possibly mediated by decreased estrogen levels.Level of Evidence4 Laryngoscope, 2024

ObjectiveTo evaluate the impact of methotrexate and rituximab therapy on highly recurrent idiopathic subglottic stenosis (iSGS) patients with a negative antineutrophil cytoplasmic antibody titer cANCA(−).MethodsThis 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.ResultsA 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%).ConclusionMTX 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 Evidence3 Laryngoscope, 2024

ObjectiveAvacopan, 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.MethodsWe 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.ResultsFifteen 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.ConclusionWe 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.

Abstract 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.