The effects of age and frailty on the risks of end-stage renal disease, death, and severe infection in older adults with antineutrophil cytoplasmic antibody-associated vasculitis: a retrospective cohort study.

BACKGROUND: Frailty, a measure of biological age, might predict poor outcomes in older adults better than chronological age. We aimed to compare the effect of age and frailty on end-stage renal disease, death, and severe infection within 2 years of diagnosis in older adults with incident antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: This retrospective cohort study included individuals aged 65 years or older from the Mass General Brigham ANCA-associated vasculitis cohort in the USA who were treated between Jan 1, 2002, and Dec 31, 2019. Individuals with a diagnosis of eosinophilic granulomatosis with polyangiitis were excluded from the analysis. Baseline frailty was measured with a claims-based frailty index using data collected in the year before the date of treatment initiation in individuals with at least one health-care encounter before baseline; individuals who did not have an encounter within the 12 months before baseline were classified as pre-frail. Incidence rates of end-stage renal disease or death and severe infections (ie, infections leading to hospital admission or death) at 2 years were estimated, and multivariable analyses were performed to compare the association of age and frailty with these outcomes. Cumulative incidence rates and an additive interaction analysis were used to assess the interaction of age and frailty groupings. FINDINGS: Of the 234 individuals included, 136 (58%) were women, 98 (42%) were men, 198 (85%) were White, and 198 (85%) were positive for myeloperoxidase-specific ANCA. Frailty was present in 25 (22%) of 116 individuals aged 65-74 years and 44 (37%) of 118 aged 75 years or older. In the multivariable analysis, an age of 75 years or older was associated with an increased risk of end-stage renal disease or death (hazard ratio [HR] 4·50 [95% CI 1·83-11·09]), however, frailty was not (1·08 [0·50-2·36]). Both an age of 75 years or older (HR 2·52 [95% CI 1·26-5·04]) and frailty (8·46 [3·95-18·14]) were independent risk factors for severe infections. The effect of frailty on the incidence of end-stage renal disease or death was greater in individuals aged 65-74 years (frail vs non-frail or pre-frail incidence rate 7·5 cases vs 2·0 cases per 100 person-years) than in those aged 75 years or older (13·5 cases vs 16·0 cases per 100 person-years). The effect of frailty on the incidence of serious infections varied by age, with large differences observed among both individuals aged 65-74 years (frail vs non-frail or pre-frail incidence rate 38·9 cases vs 0·8 cases per 100 person-years) and individuals aged 75 years or older (61·9 cases vs 12·3 cases per 100 person-years). Despite the observed differences between the age groups, the additive interaction terms were not statistically significant for either frailty and end-stage renal disease or death (p for interaction=0·276) or frailty and serious infections (p for interaction=0·650). INTERPRETATION: Adults with ANCA-associated vasculitis aged 75 years or older had a higher incidence of end-stage renal disease, death, and severe infections within 2 years of diagnosis than adults aged 65-74 years. Frailty, an approximation of biological age, was a risk factor for severe infection. Assessment beyond chronological age could better inform management decisions in older adults with ANCA-associated vasculitis. FUNDING: National Institutes of Health and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Elevated preoperative lower esophageal sphincter pressure predicts improved clinical outcomes after per oral endoscopic myotomy (POEM).

BACKGROUND: Although per oral endoscopic myotomy (POEM) has shown to be beneficial for the treatment of achalasia, it can be difficult to predict who will have a robust and long-lasting response. Historically, it has been shown that higher lower esophageal sphincter pressures have been associated with poorer responses to alternative endoscopic therapies such as Botox therapy and pneumatic dilation. This study was designed to evaluate if modern preoperative manometric data could similarly predict response to therapy after POEM. METHODS: This was a retrospective study of 237 patients who underwent POEM at a single institution over a period of 13 years (2011-2023) and who had a high-resolution manometry performed preoperatively and an Eckardt symptom score performed both preoperative and postoperatively. The achalasia type and integrated relaxation pressures (IRP) were tested for potential correlation with the need for any further achalasia interventions postoperatively as well as the degree of Eckardt score reduction using a linear regression model. RESULTS: The Achalasia type on preoperative manometry was not predictive for further interventions or degree of Eckardt score reduction (p = 0.76 and 0.43, respectively). A higher IRP was not predictive of the need for further interventions, however, it was predictive of a greater reduction in postoperative Eckardt scores (p = 0.03) as shown by the non-zero regression slope. CONCLUSION: In this study, achalasia type was not a predictive factor in the need for further interventions or the degree of symptom relief. Although IRP was not predictive of the need for further interventions, a higher IRP did predict better symptomatic relief postoperatively. This result is opposite that of other endoscopic treatment modalities (Botox and pneumatic dilation). Therefore, patients with higher IRP on preoperative high-resolution manometry would likely benefit from POEM which provides significant symptomatic relief postoperatively.

Does practice make perfect? Studying the relationship between surgeon experience and patient outcomes for paraesophageal hernia repairs.

BACKGROUND: It has been reported that higher surgeon experience leads to better patient outcomes. In this study, we look at surgeon experience and its association with postoperative outcomes and variation among the practice of surgeons performing paraesophageal hernia repairs (PEH). METHOD: This was a retrospective study of 1155 patients who underwent PEH repair at a single institution (2010-2023). Surgeon experience was defined as the number of surgeries performed per surgeon and was split using the median surgeries (n = 100), with surgeons performing at or above the median categorized as high-experience and below the median as low-experience surgeons. A multivariable logistic regression model was used to test correlation between surgeon experience and variables, including demographics and intra- and post-operative outcomes. RESULTS: High-experience surgeons performed more elective cases (93.4% vs 85.5%), but low-experience surgeons operated more on emergent (2.7% vs 0.9%), semi-elective (2.3% vs 1.4%), and urgent cases (9.5% vs 4.3%). Low-experience surgeons operated more on patients who were older (67.5 vs 63.2 years, p < 0.001) and had an increased risk of CVD (72.9% vs 61.5%, p < 0.001). Intraoperative OR time was considerably less for high-experience surgeons (115.8 vs 172.9 min, p < 0.001). Low-experience surgeons had increased risk of intra-operative complications (4.5% vs 1.8%, p = 0.021) and post-op pneumonia within 30 days (1.8% vs 0.3%). However, long-term outcomes such as hernia recurrence (OR: 1.10, CI: 0.78-1.54) and redo-operations for hiatal hernia (OR: 1.10, CI: 0.65-1.75) were similar for both groups. CONCLUSION: High-experience surgeons perform more complex revisional surgeries in less time with fewer complications. Low-experience surgeons operated more on patients with higher comorbidities but had significantly higher OR times. Long-term results of recurrence and redo-operations were comparable. These variations suggest that high-experience surgeons are more efficient while operating on more complex cases. These findings have pivotal implications to facilitate mentorship and education among less-experienced surgeons.

Initial experience and outcomes of per oral pyloromyotomy for the treatment of refractory gastroparesis.

BACKGROUND: Gastroparesis can be a debilitating disease process for which durable treatment options are lacking. While dietary changes and pharmacotherapy have some efficacy, symptoms frequently recur and some patients progress to needing supplemental enteral feeding access. Per oral pyloromyotomy (POP) has been shown to be a durable minimally invasive treatment option for refractory gastroparesis with a low side effect profile, and therefore has been performed at this institution for the past 6 years. METHODS: This was a retrospective case series of all patients who underwent a POP at a single institution over a 6-year period (2018-2023). Patient demographics, preoperative symptomatology and subsequent workup, postoperative complications, and symptom recurrence were collected and analyzed. RESULTS: There were 56 patients included in the study. There was a 1.8:1 female:male ratio. The average patient age was 56 years old (range 23-85). The average duration of symptoms was 1-3 years. Thirty-eight percent of patients had undergone previous endoscopic therapy for gastroparesis (pyloric botox injection or pyloric dilation) and 16% of patients underwent multiple endoscopic therapies. Twenty-nine percent of patients were on a medication for gastroparesis. Past surgery was the most common gastroparesis etiology for POP (50% of patients). Diabetes (23%) and idiopathic (19%) were the other most common gastroparesis etiologies for POP. Nausea was the most common symptom at first follow-up (30%) but these patients continued to improve with 14% of patients continuing to endorse nausea at 6 months. Twenty-seven percent of patients developed symptom recurrence. Forty percent of patients with symptom recurrence underwent a repeat endoscopic or surgical therapy. CONCLUSIONS: In this present study, POP leads to durable results in approximately 75% of patients with minimal complications. Furthermore, the majority of patients who do develop symptom recurrence do not require additional gastroparesis interventions.

Does preoperative symptom duration affect outcomes following per oral endoscopic myotomy (POEM)?

BACKGROUND: Per oral endoscopic myotomy (POEM) is a safe therapy for the treatment of achalasia. Long-term effects of untreated achalasia include worsening dysmotility and disruptions in esophageal anatomy, i.e., tortuosity and dilation. We hypothesize that long-standing achalasia prior to intervention will have worse outcomes following POEM than in patients with symptoms for shorter duration. METHODS: We retrospectively analyzed achalasia patients who underwent POEM at our institution from 2011 to 2023, categorizing them into symptom duration cohorts (< 1 year, 1-3 years, 4-10 years, > 10 years). Inclusion criteria comprised patients with documented achalasia diagnosis who received POEM treatment at our facility. Exclusion criteria encompassed individuals lacking data pertaining to achalasia diagnosis, the time frame before intervention, or those missing pre and postoperative Eckardt scores. POEM failure was defined as symptom recurrence, necessity for repeat intervention, or high postoperative Eckardt score. We compared demographic, preoperative, and postoperative outcomes across these cohorts, and employed multivariable logistic regression to explore the link between symptom duration and POEM response. RESULTS: During the study period, in our increased cohort 234 patients met inclusion criteria. 75 patients had symptoms for < 1 year, 78 patients had symptoms from 1 to 3 years, 47 patients had symptoms from 4 to 10 years, and 34 patients had symptoms > 10 years. Patient demographics such as age, sex, BMI, Charleson-Deyo-Comorbidity-Index, and diabetes did not differ amongst cohorts. High-resolution manometry data, including achalasia type, Median IRP, LES residual pressure, and Basal LES pressure did not differ between groups. Preoperative Eckardt scores ranged from 4 to 5 across groups (p 0.24). Patients endorsed an average of three total preoperative symptoms across groups (p 0.13). Patients with symptoms greater than 4 years had significantly more endoscopic interventions prior to POEM (37% vs, 68% p .001). There was no significant difference in post-procedure mean Eckardt scores between cohorts. All cohorts experienced the same number of post-POEM symptoms. Post-POEM manometric measurements remained consistent across cohorts. Similarly, there were no significant differences in terms of symptom recurrence, requirement for repeat interventions, or repeat POEM among the cohorts. Multivariable logistic regression analysis determined achalasia symptoms greater than a decade did not result in increased odds of having a higher postoperative Eckardt score, worse dysphagia, regurgitation, or weight loss. CONCLUSIONS: In this increased cohort, this data once again suggests that longer symptom duration is not associated with increased rates of POEM failure.

Multiorgan involvement and circulating IgG1 predict hypocomplementaemia in IgG4-related disease.

OBJECTIVES: Hypocomplementaemia is common in patients with IgG4-related disease (IgG4-RD). We aimed to determine the IgG4-RD features associated with hypocomplementaemia and investigate mechanisms of complement activation in this disease. METHODS: We performed a single-centre cross-sectional study of 279 patients who fulfilled the IgG4-RD classification criteria, using unadjusted and multivariable-adjusted logistic regression to identify factors associated with hypocomplementaemia. RESULTS: Hypocomplementaemia was observed in 90 (32%) patients. In the unadjusted model, the number of organs involved (OR 1.42, 95% CI 1.23 to 1.63) and involvement of the lymph nodes (OR 3.87, 95% CI 2.19 to 6.86), lungs (OR 3.81, 95% CI 2.10 to 6.89), pancreas (OR 1.66, 95% CI 1.001 to 2.76), liver (OR 2.73, 95% CI 1.17 to 6.36) and kidneys (OR 2.48, 95% CI 1.47 to 4.18) were each associated with hypocomplementaemia. After adjusting for age, sex and number of organs involved, only lymph node (OR 2.59, 95% CI 1.36 to 4.91) and lung (OR 2.56, 95% CI 1.35 to 4.89) involvement remained associated with hypocomplementaemia while the association with renal involvement was attenuated (OR 1.6, 95% CI 0.92 to 2.98). Fibrotic disease manifestations (OR 0.43, 95% CI 0.21 to 0.87) and lacrimal gland involvement (OR 0.53, 95% CI 0.28 to 0.999) were inversely associated with hypocomplementaemia in the adjusted analysis. Hypocomplementaemia was associated with higher concentrations of all IgG subclasses and IgE (all p<0.05). After adjusting for serum IgG1 and IgG3, only IgG1 but not IgG4 remained strongly associated with hypocomplementaemia. CONCLUSIONS: Hypocomplementaemia in IgG4-RD is not unique to patients with renal involvement and may reflect the extent of disease. IgG1 independently correlates with hypocomplementaemia in IgG4-RD, but IgG4 does not. Complement activation is likely involved in IgG4-RD pathophysiology.

Sex as a predictor of clinical phenotype and determinant of immune response in IgG4-related disease: a retrospective study of patients fulfilling the American College of Rheumatology-European League Against Rheumatism classification criteria.

BACKGROUND: IgG4-related disease is a multiorgan fibroinflammatory disease considered to have an autoimmune origin. Case series describing individual organ involvement have suggested differences in phenotypic expression between males and females. We aimed to characterise differences in IgG4-related disease manifestations between male and female patients in a large single-centre cohort. METHODS: In this retrospective, single-centre cohort study, patients were recruited from the Massachusetts General Hospital Rheumatology Clinic (Boston, MA, USA) and classified according to the American College of Rheumatology-European Alliance of Associations for Rheumatology (ACR-EULAR) classification criteria. Only patients satisfying the ACR-EULAR classification criteria were included in the study. Data on age at diagnosis, organ involvement at baseline, treatment status, and pre-treatment laboratory values were collected. Circulating plasmablasts and B-cell subsets were quantitated by flow cytometry. Active disease was defined by an IgG4-related disease Responder Index score of more than 0. Laboratory values were analysed for patients who were untreated at baseline and had active IgG4-related disease. The main outcomes were assessed in all participants with available data. FINDINGS: Of the 564 participants enrolled in the Massachusetts General Hospital Rheumatology Clinic IgG4-related disease Registry, 328 fulfilled ACR-EULAR classification criteria and were included between January, 2008, and May, 2023. There was a strong male predominance (male:female ratio 2·2:1) with 226 (69%) males and 102 (31%) females, which contrasted markedly with our general rheumatology clinic population (0·4:1; p<0·001). The male predominance increased with each decade of life starting at age 40 years. On average, male patients were 5·5 years older at diagnosis than female patients (63·7 years vs 58·2 years; p=0·0031). We observed male patients to have higher ACR-EULAR classification criteria scores at baseline with a median score of 35·0 (IQR 28·0-46·0), compared with 29·5 (25·0-39·0) for females (p=0·0010). The proportion of male patients with pancreatic and renal involvement was almost double the proportion observed in female patients (50% of the male patients had pancreatic involvement, compared with about 26% of the female patients; p<0·0001). Male patients were more likely to have serological abnormalities at baseline. The distribution of IgG4 values differed significantly between male an female sexes, favouring higher values in males. We found that male patients with IgG4-related disease were more likely to have active B-cell responses in the blood as defined by plasmablast expansions. INTERPRETATION: IgG4-related disease is unusual among autoimmune diseases in that it is more likely to affect males than females and to present with a striking sex-dependent organ distribution and degree of B-cell response. These findings highlight important variation between IgG4-related disease and other conditions generally believed to have an autoimmune basis. Most autoimmune diseases, by contrast to IgG4-related disease, demonstrate pronounced predilections for affecting females more frequently than males. Hypotheses surrounding the cause and pathophysiology of this condition need to consider this unusual sex distribution among patients with IgG4-related disease. FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Rheumatology Research Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Current and future advances in practice: IgG4-related disease.

IgG4-related disease (IgG4-RD) is an increasingly recognized cause of fibroinflammatory lesions in patients of diverse racial and ethnic backgrounds and is associated with an increased risk of death. The aetiology of IgG4-RD is incompletely understood, but evidence to date suggests that B and T cells are important players in pathogenesis, both of which are key targets of ongoing drug development programmes. The diagnosis of IgG4-RD requires clinicopathological correlation because there is no highly specific or sensitive test. Glucocorticoids are highly effective, but their use is limited by toxicity, highlighting the need for studies investigating the efficacy of glucocorticoid-sparing agents. B cell-targeted therapies, particularly rituximab, have demonstrated benefit, but no randomized clinical trials have evaluated their efficacy. If untreated or under-treated, IgG4-RD can cause irreversible organ damage, hence close monitoring and consideration for long-term immunosuppression is warranted in certain cases.

Proliferative features of IgG4-related disease.

IgG4-related disease is an immune-mediated disease that can lead to substantial morbidity and organ damage. Capable of affecting nearly any organ system or anatomic site, and showing considerable overlap in clinical presentation with various other diseases, IgG4-related disease often poses a diagnostic challenge for clinicians. Furthermore, there are no diagnostic biomarkers with high specificity for IgG4-related disease, and histopathological examination is nuanced and requires clinical correlation for accurate diagnosis. Therefore, it is crucial for clinicians to recognise the clinical phenotypes of IgG4-related disease. The disease is generally considered to have predominantly fibrotic and proliferative (or inflammatory) manifestations, with distinct clinical, serological and histopathological findings associated with each manifestation. However, the fibrotic and proliferative manifestations of this disease frequently occur together, thereby blurring this dichotomous distinction. In this Series paper, we provide a detailed overview of the clinical manifestations typical of the proliferative features of IgG4-related disease, with an emphasis on the diagnostic evaluation and differential diagnosis of each proliferative disease manifestation. In addition, we summarise the immune mechanisms underlying IgG4-related disease, suggest a framework for how to approach management and monitoring after the diagnosis is established, and highlight current unmet needs for patient care surrounding this disease.

RheumMadness Over Two Years: Engaging Participants in Active Learning and Connecting Early Trainees to the Rheumatology Community.

OBJECTIVE: RheumMadness is an online learning collaborative that seeks to actively engage the rheumatology community. The objective of this manuscript is to analyze the educational experience of RheumMadness over two years. METHODS: Direct measures of participant engagement were obtained using web-based analytics. An electronic survey was created after the tournament to capture self-reported engagement and educational experience using the Community of Inquiry framework. Data were analyzed according to the following objectives: (1) compare demographics, engagement, and educational experience of participants between 2021 and 2022; (2) describe the educational experience of those who created scouting reports; (3) explore the impact of RheumMadness on early learners (medical students and residents). RESULTS: Compared with 2021, the 2022 tournament had more participants who submitted a bracket, more early learners, and more scouting report creators. Self-reported engagement and educational experience was high in both years of the tournament among all participants. Over 85% of scouting report creators reported that making a report was a fun and valuable learning experience. Early learners reported significantly higher levels of knowledge integration, sense of belonging in the rheumatology community, social connection, and overall learning experience compared with more advanced participants. Eighty-five percent of early learners reported that RheumMadness increased their interest in rheumatology. CONCLUSION: RheumMadness expanded from 2021 to 2022, engaging more participants in collaborative learning. Our results demonstrate that RheumMadness is particularly impactful among medical students and residents by helping them explore rheumatology topics and connect with the rheumatology community.

Enhancing Faculty Development Through Compiled Verbal Feedback on Clinical Teaching From Trainees.

OBJECTIVE: Feedback from fellows-in-training (FITs) is important for faculty development and to enrich clinical teaching. We sought to evaluate the effectiveness of traditional online evaluations and a novel compiled verbal feedback mechanism. METHODS: An annual feedback system was implemented in our rheumatology division in which FITs provided verbal feedback on all faculty to a facilitator who compiled, deidentified, and shared the feedback with individual faculty members. FITs also completed standard online annual evaluations of faculty. FITs and faculty completed surveys assessing the perceived effectiveness and confidentiality of each feedback mechanism. RESULTS: Thirteen of 15 eligible faculty and all 4 eligible FITs completed both surveys. Responses by FITs and faculty regarding the quality of online evaluations were generally unfavorable or neutral. Faculty responses regarding compiled verbal feedback were more favorable in all questions and significantly more favorable with respect to the feedback's ability to explain strengths (54% favorable for online evaluations vs 100% for compiled verbal feedback), the feedback's specificity (0% vs 54%), and the feedback's actionable nature (15% vs 62%). All FITs' responses regarding quality of compiled verbal feedback were favorable. FITs had concerns regarding confidentiality with both online evaluations (0% favorable) and compiled verbal feedback (25% favorable), though FITs had less concern for future faculty interactions with compiled verbal feedback (100% favorable) than with online evaluations (0% favorable). CONCLUSION: Compiled verbal feedback by FITs produced more actionable and effective feedback for faculty, with less concerns regarding future faculty interactions compared with traditional online evaluations. Further study of this method across different programs and institutions is warranted.

Assessment of patient-reported symptoms and distress in IgG4-related disease (IgG4-RD): Development, clinical validation, and content validation of the IgG4-RD Symptom Severity Index.

OBJECTIVE: IgG4-related disease (IgG4-RD), a multi-organ autoimmune disease, causes diverse manifestations that can lead to symptoms and distress. We developed and validated the Symptom Severity Index (SSI) to assess symptom burden. METHODS: A pilot SSI was tested in n = 5; several gaps were identified. Twenty semi-structured qualitative interviews were performed to expand the item set and identify missing symptoms. Subsequent changes resulted in the current SSI; it was administered with quality of life (QOL) measures to n = 136. We assessed symptom burden and the construct validity of the SSI. A distress score for each symptom is calculated by multiplying symptom frequency ("Never" [0 points] to "Every Day" [3 points]) by associated distress ("None" [0 points] to "Very Much" [4 points]). Each distress score is summed to calculate a total SSI score. RESULTS: The SSI assesses the frequency and distress of 24 symptoms. Among n = 136 with ≥ 1 SSI, 90% experienced ≥ 1 symptom and 88% had distress. The median SSI score was 6.5 (IQR 3.0, 18.0). Fear of more severe disease was observed in 49%. The SSI inversely correlated with the SF-36 (r= - 0.51, p<0.001), the feeling thermometer (r= - 0.28, p<0.001), and the EQ-5D (r= - 0.28, p<0.001). The median SSI score was higher during active vs non-active disease among n = 52 who completed >1 SSI (15 [6, 26] vs. 3 [2, 14], p = 0.008). CONCLUSIONS: Symptoms and distress are common in IgG4-RD and associated with worse health-related QOL. The SSI has face, content, and construct validity; it corresponds with QOL measures.

RheumMadness: Creating an Online Community of Inquiry in Rheumatology.

OBJECTIVE: To evaluate the educational impact of RheumMadness, an online tournament of rheumatology concepts grounded in social constructivist theory, as viewed through the community of inquiry (CoI) framework. METHODS: The curricular scaffold of RheumMadness was a bracket of 16 rheumatology concepts competing as "teams" in a tournament. Participants could create and review "scouting reports" about each team, listen to a RheumMadness podcast, discuss on social media, and submit a bracket predicting tournament outcomes according to the perceived importance of each team. Engagement was measured with direct analytics and through self-report on a survey. The survey also assessed participants' educational experience using an adapted 34-item CoI survey, which describes the cognitive, social, and teaching presences in a learning activity. RESULTS: One hundred brackets were submitted. On average, each scouting report was viewed 92 times, each podcast episode was downloaded 163 times, and 486 tweets were sent about #RheumMadness from 105 users. The survey received 58 of 107 responses (54%). Respondent agreement with prompts related to each CoI presence was: 70.3% cognitive, 61.7% social, 84.9% teaching. Reported engagement in RheumMadness correlated strongly with overall CoI survey scores (r = 0.72, P < 0.001). CONCLUSION: RheumMadness created an online CoI that fostered social constructivist learning about rheumatology.

IgG4-related disease as a variable-vessel vasculitis: A case series of 13 patients with medium-sized coronary artery involvement.

INTRODUCTION: IgG4-related disease (IgG4-RD) is a systemic autoimmune fibroinflammatory disease that can affect multiple organ systems. Although large-vessel vasculitis is a well-recognized manifestation of IgG4-RD, this condition is generally not regarded as a vasculitis. We aimed to describe coronary artery involvement (CAI), a vascular distribution about which little is known in IgG4-RD. MATERIAL AND METHODS: Patients with IgG4-related CAI were identified from a large, prospective IgG4-RD cohort. CAI was confirmed by imaging evidence of arterial or periarterial inflammation in any coronary artery. We extracted details regarding demographics, features of IgG4-RD, and manifestations of CAI. RESULTS: Of 361 cases in the cohort, 13 (4%) patients had IgG4-related CAI. All were male and all had highly-elevated serum IgG4 concentrations, with a median value of 955 mg/dL (interquartile range [IQR]: 510-1568 mg/dL; reference: 4-86 mg/dL). Median disease duration at the time of CAI diagnosis was 11 years (IQR: 8.23-15.5 years). Extensive disease in the coronary arteries was the rule: all three major coronary arteries were involved in 11 patients (85%). The coronary artery manifestations included wall thickening or periarterial soft tissue encasement (85%), stenosis (69%), calcification (69%), and aneurysms or ectasia (62%). Five patients (38%) had myocardial infarctions, 2 (15%) required coronary artery bypass grafting, and 2 (15%) developed ischemic cardiomyopathy. DISCUSSION: Coronary arteritis and periarteritis are important manifestations of IgG4-RD, which should be regarded as a variable-vessel vasculitis that is among the most diverse forms of vasculitis known. Potential complications of CAI include coronary artery aneurysms, myocardial infarction, and ischemic cardiomyopathy.

Proteomic signature for detection of high-grade ovarian cancer in germline BRCA mutation carriers.

No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average-risk population is warranted.

Environmental Triggers for Vasculitis.

Systemic vasculitides are autoimmune diseases characterized by vascular inflammation. Most types of vasculitis are thought to result from antigen exposure in genetically susceptible individuals, suggesting a likely role for environmental triggers in these conditions. Seasonal and geographic variations in incidence provide insight into the potential role of environmental exposures in these diseases. Many data support infectious triggers in some vasculitides, whereas other studies have identified noninfectious triggers, such as airborne pollutants, silica, smoking, and heavy metals. We review the known and suspected environmental triggers in giant cell arteritis, Takayasu arteritis, polyarteritis nodosa, Kawasaki disease, and antineutrophil cytoplasmic antibody-associated vasculitis.

The value of SOX2 in the differential diagnosis of SMARCA4 (BRG1)-deficient uterine neoplasms.

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4/BRG1)-deficient undifferentiated uterine sarcoma (SDUS) is a recently described uterine sarcoma. It is characterized by predominantly rhabdoid or large epithelioid cells with abundant cytoplasm and varying components of small and spindle cells, resembling the 'large cell variant' of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). In addition, SMARCA4-inactivating mutations have been described as the driver mutations in SDUS. However, undifferentiated endometrial carcinoma (UDEC) and dedifferentiated endometrial carcinoma (DDEC) may show some clinical and morphological overlaps with SDUS, and about 20% of reported UDEC/DDEC cases also have loss expression of SMARCA4. SDUS is a very aggressive disease and universally lethal in all reported cases. Differentiating SDUS from UDEC/DDEC is relevant for the prognosis, pathogenesis, and possible targeted therapies for the disease. In this study, we compared the clinical, morphological, immunohistochemical, and molecular characteristics of 10 tumors including 2 SDUS, 2 SCCOHT, 1 uterine carcinoma with neuroendocrine differentiation (UDEC?), and 5 UDEC/DDEC. All 5 UDEC/DDEC cases showed strong and diffuse nuclear positivity for SOX2, while all SCCOHT and SDUS cases were completely negative. We concluded that SOX2 could be a useful marker for the differential diagnosis between SDUS and UDEC/DDEC.

Association between depression, anxiety, chronic pain, or opioid use and tumor necrosis factor inhibitor persistence in inflammatory arthritis.

INTRODUCTION: Depression, anxiety, and chronic pain are common comorbidities in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) and may substantially impact patient outcomes. We aimed to determine whether these comorbidities were associated with earlier TNF-inhibitor (TNFi) discontinuation. METHODS: This retrospective cohort study using Optum's de-identified Clinformatics® Data Mart Database 2000-2014 identified patients with RA, PsA, and AS initiating a first TNFi. Depression/anxiety, chronic pain, and opioid use were identified using diagnosis codes and prescription fill data. Cox proportional hazards models were used to compare time to medication discontinuation in patients with or without each of these risk factors and to assess the additive effect of having multiple risk factors. RESULTS: Among 33,744 patients initiating a TNFi (23,888 RA, 6443 PsA, 3413 AS), depression/anxiety, chronic pain, and opioid use were common, with ≥ 1 risk factor in 48.1%, 42.5%, and 55.4% of patients with RA, PsA, and AS respectively. Each risk factor individually was associated with a 5-7-month lower median treatment persistence in each disease (all p < 0.001). Presence of multiple risk factors had an additive effect on time to discontinuation with HR (95% CI) 1.19 (1.14-1.24), 1.41 (1.33-1.49), and 1.47 (1.43-1.73) for 1, 2, or 3 risk factors respectively in RA. Findings were similar in PsA and AS. CONCLUSIONS: Depression, anxiety, chronic pain, and opioid use are common in inflammatory arthritis and associated with earlier TNFi discontinuation. Recognizing and managing these risk factors may improve treatment persistence, patient outcomes, and cost of care. Key Points • Depression, anxiety, chronic pain, and opioid use are common in patients with inflammatory arthritis. • In patients initiating treatment with a TNF-inhibitor, depression, anxiety, chronic pain, or recent opioid use are associated with sooner discontinuation of TNFi therapy. • Patients with multiple of these risk factors are even more likely to discontinue therapy sooner.

Clinical Perspectives on IgG4-Related Disease and Its Classification.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease. Since its discovery nearly two decades ago, our understanding of its pathophysiology and clinical manifestations has grown substantially. Early diagnosis and treatment of this elusive disease can prevent substantial organ damage from end-stage fibrosis, emphasizing the need for prompt recognition and accurate characterization of IgG4-RD. The classification criteria endorsed by the American College of Rheumatology and the European Alliance of Associations for Rheumatology in 2019 provide a framework for establishing the diagnosis in the clinical setting. This process involves recognizing the typical manifestations of the disease and incorporating clinical, radiological, serological, and histopathological information as well as excluding disease mimickers. Glucocorticoids and rituximab are effective at inducing remission in IgG4-RD in most patients, but the optimal approach to long-term management of IgG4-RD remains an area of active clinical research.