Novel GUCY2C variant causing familial diarrhea in a Mennonite kindred and a potential therapeutic approach.

Guanylate cyclase 2C (GC-C), encoded by the GUCY2C gene, is implicated in hereditary early onset chronic diarrhea. Several families with chronic diarrhea symptoms have been identified with autosomal dominant, gain-of-function mutations in GUCY2C. We have identified a Mennonite patient with a novel GUCY2C variant (c.2381A > T; p.Asp794Val) with chronic diarrhea and an extensive maternal family history of chronic diarrhea and bowel dilatation. Functional studies including co-segregation analysis showed that all family members who were heterozygous for this variant had GI-related symptoms. HEK-293 T cells expressing the Asp794Val GC-C variant showed increased cGMP production when stimulated with Escherichia coli heat-stable enterotoxin STp (HST), which was reversed when 5-(3-Bromophenyl)-5,11-dihydro-1,3-dimethyl-1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione (BPIPP; a GC-C inhibitor) was used. In addition, cystic fibrosis transmembrane conductance regulator (CFTR) activity measured with SPQ fluorescence assay was increased in these cells after treatment with HST, indicating a crucial role for CFTR activity in the pathogenesis of this disorder. These results support pathogenicity of the GC-C Asp794Val variant as a cause of chronic diarrhea in this family. Furthermore, this work identifies potential candidate drug, GC-C inhibitor BPIPP, to treat diarrhea caused by this syndrome.

Pneumocystis Pneumonia and the Rheumatologist: Which Patients Are At Risk and How Can PCP Be Prevented?

PURPOSE OF REVIEW: Immunosuppressive therapy for connective tissue diseases (CTDs) is steadily becoming more intense. The resultant impairment in cell-mediated immunity has been accompanied by an increasing risk for opportunistic infection (OI). Pneumocystis pneumonia (PCP) has been recognized as an OI in patients with CTDs, but specific risk factors and precise indications for PCP prophylaxis remain poorly defined. This review was undertaken to update information on the risk of PCP in patients with CTDs and to examine current guidelines for PCP prophylaxis in this population. RECENT FINDINGS: Data on the occurrence of PCP and indications for prophylaxis in patients with CTDs is sparse. Large systematic reviews did not incorporate patients with CTD secondary to the lack of randomized control trials. Upon reviewing guidelines published since 2015, prophylaxis for PCP is recommended only for patients with ANCA-positive vasculitis, specifically granulomatosis with polyangiitis (GPA), who are undergoing intense induction therapy. Evidence-based recommendations for the prophylaxis of PCP in patients with CTDs cannot be provided. There is expert consensus that PCP prophylaxis is warranted in patients with GPA undergoing induction therapy. Prophylaxis should perhaps also be considered for other CTD patients who are receiving similar intense immunosuppressive therapy especially if they are lymphopenic or have a low CD4 count.

Assessment of Clinical Reasoning in Undergraduate Medical Education: A Pragmatic Approach to Programmatic Assessment.

PURPOSE: Clinical reasoning, a complex construct integral to the practice of medicine, has been challenging to define, teach, and assess. Programmatic assessment purports to overcome validity limitations of judgments made from individual assessments through proportionality and triangulation processes. This study explored a pragmatic approach to the programmatic assessment of clinical reasoning. METHOD: The study analyzed data from 2 student cohorts from the University of Utah School of Medicine (UUSOM) (n = 113 in cohort 1 and 119 in cohort 2) and 1 cohort from the University of Colorado School of Medicine (CUSOM) using assessment data that spanned from 2017 to 2021 (n = 199). The study methods included the following: (1) asking faculty judges to categorize student clinical reasoning skills, (2) selecting institution-specific assessment data conceptually aligned with clinical reasoning, (3) calculating correlations between assessment data and faculty judgments, and (4) developing regression models between assessment data and faculty judgments. RESULTS: Faculty judgments of student clinical reasoning skills were converted to a continuous variable of clinical reasoning struggles, with mean (SD) ratings of 2.93 (0.27) for the 232 UUSOM students and 2.96 (0.17) for the 199 CUSOM students. A total of 67 and 32 discrete assessment variables were included from the UUSOM and CUSOM, respectively. Pearson r correlations were moderate to strong between many individual and composite assessment variables and faculty judgments. Regression models demonstrated an overall adjusted R2 (standard error of the estimate) of 0.50 (0.19) for UUSOM cohort 1, 0.28 (0.15) for UUSOM cohort 2, and 0.30 (0.14) for CUSOM. CONCLUSIONS: This study represents an early pragmatic exploration of regression analysis as a potential tool for operationalizing the proportionality and triangulation principles of programmatic assessment. The study found that programmatic assessment may be a useful framework for longitudinal assessment of complicated constructs, such as clinical reasoning.

Temporal artery biopsy.

Giant cell arteritis is a common vasculitis in patients over the age of 50 years old. If not promptly recognized and aggressively treated with high-dose glucocorticoids, ischemia resulting in permanent vision loss or stroke can occur. Yet, the treatment with high-dose glucocorticoids over a long period of time can be problematic in this particular patient population given their age and associated comorbidities. Temporal artery biopsies (TAB) are an important diagnostic tool to evaluate patients with suspected giant cell arteritis. Herein, we explore indications for TAB and practical points in obtaining a TAB based on available evidence. We review the surgical procedure itself and associated complications. Lastly, we examine common pathological findings and considerations of alternative diagnoses.

A case of VEXAS syndrome presenting with unusual bone marrow granulomas: a diagnostic dilemma.

BACKGROUND: VEXAS is a recently described inflammatory disease caused by mutations in the UBA1 gene. Symptoms are diverse and include fevers, cartilaginous inflammation, lung inflammation, vasculitis, neutrophilic dermatoses, and macrocytic anemia. Cytoplasmic inclusions in myeloid and erythroid progenitors in the bone marrow are a hallmark feature. Here we report the first case of VEXAS with non-caseating granulomas in the bone marrow. CASE PRESENTATION: A 62-year-old Asian male presented with fevers, erythema nodosum, inflammatory arthritis, and periorbital inflammation. Labs were significant for persistently elevated inflammatory markers and macrocytic anemia. Over the years his symptoms and inflammatory markers only improved with glucocorticoids and recurred when prednisone dose was lowered below 15-20 mg daily. He underwent bone marrow biopsy showing non-caseating granulomas and PET scan showing hilar/mediastinal lymphadenopathy. He was initially diagnosed with IgG4-related disease (treated with rituximab) and later sarcoidosis (treated with infliximab). After failing these agents, the possibility of VEXAS was considered and later confirmed by molecular testing. CONCLUSIONS: To the best of our knowledge, this is the first observation of non-caseating granulomas in VEXAS, a cautionary reminder of its non-specificity since misinterpretation can lead to diagnostic delay. VEXAS should be in the differential in patients with symptoms of chronic inflammation responding positively to steroids (but not to B-cell depletion or TNF inhibition), which is in line with previous literature.

Virtual Learning and Assessment in Rheumatology Fellowship Training: Objective Structured Clinical Examination Revisited.

OBJECTIVE: With the onset of the COVID-19 pandemic, an annual multi-institutional face-to-face rheumatology objective structured clinical examination (ROSCE) was transformed into a virtual format. The educational goals of the virtual ROSCE (vROSCE) were to reproduce the educational value of the previous in-person ROSCE, providing a valuable formative assessment of rheumatology training activities encompassing the 6 Accreditation Council for Graduate Medical Education (ACGME) core competencies for fellows-in-training (FITs). This article describes the novel design, feasibility, and stakeholder value of a vROSCE. METHODS: Through an established collaboration of 5 rheumatology fellowship training programs, in February 2021, a vROSCE was created and conducted using a Zoom platform. Station development included learning objectives, FIT instructions, faculty proctor instructions, and a checklist by which to provide structured formative feedback. An anonymous, optional web-based survey was sent to FIT participants to evaluate the experience. RESULTS: Twenty-three rheumatology FITs from 5 institutions successfully rotated through 6 stations in the vROSCE. Immediate feedback was given to each FIT using standardized rubrics structured around ACGME core competencies. A total of 65% of FITs (15 of 23) responded to the survey, and 93% of survey respondents agreed or strongly agreed that the vROSCE was a helpful educational activity and identified individualized opportunities for improvement. CONCLUSION: A vROSCE is an innovative, feasible, valuable, and well-received educational technology tool. The vROSCE enriched rheumatology FITs' education and offered collaborative learning experiences across institutions.

Incorporating Telemedicine in Rheumatology Fellowship Training Programs: Needs Assessment, Curricular Intervention, and Evaluation.

OBJECTIVE: To increase the confidence of rheumatology fellows in training (FITs) in delivering virtual care (VC) and prepare them for independent practice, we developed educational materials addressing gaps in their skills. METHODS: We identified gaps in telemedicine skills based on FIT performance in a virtual rheumatology objective structured clinical examination (vROSCE) station on VC delivery using video teleconference technology and survey (survey 1) responses. We created educational materials including videos of "mediocre" and "excellent" VC examples, discussion/reflection questions, and a document summarizing key practices. We measured change in the confidence levels of FITs for delivering VC with a post-intervention survey (survey 2). RESULTS: Thirty-seven FITs (19 first-year, 18 second- plus third-year fellows) from 7 rheumatology fellowship training programs participated in a vROSCE and demonstrated gaps in skills mapping to several Rheumatology Telehealth Competency domains. Confidence levels of FITs improved significantly from survey 1 to survey 2 for 22 of 34 (65%) questions. All participating FITs found the educational materials helpful for learning and reflecting on their own VC practice; 18 FITs (64%) qualified usefulness as "moderately" or "a lot." Through surveying, 17 FITs (61%) reported implementing skills from the instructional videos into VC visits. CONCLUSION: Continually assessing our learners' needs and creating educational materials addressing gaps in training are requisite. Using a vROSCE station, needs assessments, and targeted learning with videos and discussion-guidance materials enhanced the confidence level of FITs in VC delivery. It is imperative to incorporate VC delivery into fellowship training program curricula to ensure breadth in skills, attitudes, and knowledge of new entrants into the rheumatology workforce.

Rates of Pneumocystis jirovecii pneumonia and prophylaxis prescribing patterns in a large electronic health record cohort of patients with systemic lupus erythematosus.

Objective No guidelines exist for Pneumocystis jirovecii pneumonia (PJP) prophylaxis in patients with systemic lupus erythematosus (SLE). Limited data are available on incidence of PJP infection and use of PJP prophylaxis. Using a real-world, electronic health record (EHR) cohort, we investigated the frequency of PJP infections as well as patient and provider factors that impacted use and type of PJP prophylaxis. Methods  In a large, de-identified EHR, we identified possible SLE patients using a previously validated algorithm. PJP ICD-9 or ICD-10-CM billing codes and PJP keywords were used to identify possible PJP cases within this SLE cohort. We assessed for PJP prophylaxis prescribing in all SLE patients using keywords and reviewing medication lists for prophylactic agents. Chart review was used to confirm cases of SLE, PJP, and PJP prophylaxis and to obtain data on demographics, comorbidities, and immunosuppressants. Results Of 977 SLE patients, there were only four with confirmed PJP infection. Two of these patients had concurrent Acquired Immunodeficiency Syndrome, and none were on prophylaxis. Of 977 SLE patients, 132 (14%) were prescribed PJP prophylaxis. Of 617 SLE patients ever prescribed immunosuppressants, 128 (21%) were prescribed PJP prophylaxis. Sulfonamides were the most common prophylaxis prescribed (69%), and possible adverse events were documented in 22 out of 117 instances of being placed on a sulfonamide. Patients of younger age, Black race, nephritis, and renal transplant, and on chronic glucocorticoids were all more likely to have PJP prophylaxis prescribed. Patients who were on transplant induction medications, calcineurin/mTOR inhibitors, cyclophosphamide, and mycophenolate mofetil all were more likely to be prescribed PJP prophylaxis compared to other immunosuppressants. Conclusion PJP is a rare diagnosis among SLE patients, and prior studies may even overestimate its prevalence. PJP prophylaxis was less common in our cohort than previously described. Adverse events related to sulfonamides used for PJP prophylaxis were relatively rare with lower rates than previously reported. Our study demonstrates real-world PJP prophylaxis prescribing patterns in a large cohort of SLE patients.

Infection of arachnoid cyst associated with vasospasm and stroke in a pediatric patient: case report.

Arachnoid cysts are relatively common and benign intraarachnoid membrane outpouchings containing CSF-like fluid. The majority of arachnoid cysts remain stable and asymptomatic and do not require intervention in the pediatric population. Here, the authors present the first reported case of an infected arachnoid cyst in a pediatric patient resulting in severe vasospasm of the left terminal internal carotid artery, left A1 segment, and left M1 branches with a left middle cerebral artery infarct. Their experience suggests that close monitoring is warranted for this condition and that the pediatric population may be at higher risk for vasospasm.

Practice Patterns of Pneumocystis Pneumonia Prophylaxis in Connective Tissue Diseases: A Survey of Infectious Disease Physicians.

BACKGROUND: Immunosuppressive therapy for connective tissue diseases (CTDs) increases risk for opportunistic infections including Pneumocystis pneumonia (PCP). High mortality rates are reported in CTD patients with PCP, which suggests a potential need for prophylaxis, but indications remain poorly defined. Wide variations in the use of PCP prophylaxis among rheumatologists have been documented. This study evaluated PCP prophylaxis patterns for CTD patients among infectious disease (ID) physicians. METHODS: An electronic survey was emailed to 1264 adult ID physicians who are members of the Infectious Diseases Society of America Emerging Infections Network. RESULTS: Six hundred thirty-one physicians responded to the survey. Respondents to the survey were more likely to work in academics (P = .02) and be early (<5 years) or late (≥25 years) in their careers (P = .0002). Forty-three percent (n = 269) made no recommendations for PCP prophylaxis in non-HIV patients. Of the 362 respondents who did make such recommendations, the greatest consensus for disease-based prophylaxis was for granulomatosis with polyangiitis (53%). For therapy-based prophylaxis, corticosteroids ≥20 mg/d was the most frequently cited indication (87%). Surrogate laboratory markers to aid in decisions about prophylaxis were not routinely used (21%). Although the majority recommended discontinuation of PCP prophylaxis with tapering of corticosteroids (65%), there was variability in the specific dose. Eighty-nine percent of respondents felt that guidelines about PCP prophylaxis would be helpful. CONCLUSIONS: There is little consensus about PCP prophylaxis in CTDs among ID physicians. Guidelines for PCP prophylaxis would be helpful when caring for these complex patients.

Biologic Therapies for Autoimmune and Connective Tissue Diseases.

Biologic therapy continues to revolutionize the treatment of autoimmune disease, especially in rheumatology as the pathophysiology of both inflammation and autoimmune disease becomes better understood. These therapies are designed to dampen the response of the inflammatory cascades. Although the first biologic therapies were approved many years ago, expanding indications and new agents continue to challenge the traditional treatment strategies for rheumatic diseases. This article reviews the data supporting the current use of biologic therapies, including off-label indications, in a subset of rheumatic diseases including rheumatoid arthritis, lupus, inflammatory myositis, ankylosing spondylitis, psoriatic arthritis, vasculitis, and gout.