Citations

Purpose of review This review provides an update on current management strategies for giant cell arteritis (GCA), emphasizing the need for alternative therapies to reduce disease relapses and mitigate glucocorticoid (GC)-related morbidity. Recent findings The standard of care for GCA has traditionally involved prolonged use of GC, and recent studies are exploring faster GC tapering regimens in an effort to reduce adverse effects while maintaining disease control. Randomized clinical trials have highlighted the efficacy of tocilizumab (TCZ), an interleukin-6 receptor inhibitor, in reducing disease flares and sparing GCs. However, the optimal treatment duration with TCZ is unknown and patients remain at risk of relapse after treatment discontinuation. An unmet therapeutic need persists for patients who are not candidates for TCZ, and for those who have inadequate response to this biologic. Therefore, investigations into alternative therapies such as targeting interleukin-17A, blocking T-cell activation or inhibiting the Janus kinase–signal transducer and activator of transcription pathway, showcase potential avenues for tailored treatments. Summary While GCs remain the cornerstone of therapy, TCZ emerges as a promising GC-sparing agent. Ongoing research targeting different pathways implicated in GCA pathogenesis have led to encouraging results. However, the preliminary nature of these findings necessitates larger randomized controlled trials to establish their efficacy conclusively.

Abstract Background The optimal diagnosis and management of patients with brain tumors currently uses the 2021 WHO integrated diagnosis of histomorphologic and molecular features. However, neuro-oncology practice in resource-limited settings usually relies solely on histomorphology. This study aimed to classify glioma cases diagnosed in the Department of Anatomic and Molecular Pathology, Lagos University Teaching Hospital, using the 2021 WHO CNS tumor classification. Methods Fifty-six brain tumors from 55 patients diagnosed with glioma between 2013 and 2021 were reevaluated for morphologic diagnosis. Molecular features were determined from formalin-fixed paraffin-embedded (FFPE) tissue using immunohistochemistry (IHC) for IDH1-R132H, ATRX, BRAF-V600E, p53, Ki67, and H3-K27M, OncoScan chromosomal microarray for copy number, targeted next generation sequencing for mutation and fusion and methylation array profiling. Results Of 55 central nervous system tumors, 3 were excluded from histomorphologic reevaluation for not being of glial or neuroepithelial origin. Of the remaining 52 patients, the median age was 20.5 years (range: 1 to 60 years), 38(73%) were males and 14(27%) were females. Seventy-one percent of the gliomas evaluated provided adequate DNA from archival FFPE tissue blocks. After applying the 2021 WHO diagnostic criteria the initial morphologic diagnosis changed for 35% (18/52) of cases. Diagnoses of 5 (9.6%) gliomas were upgraded, and 7 (14%) were downgraded. Conclusions This study shows that the incorporation of molecular testing can considerably improve brain tumor diagnoses in Nigeria. Furthermore, this study highlights the diagnostic challenges in resource-limited settings and what is at stake in the global disparities of brain tumor diagnosis.

IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease whose pathomechanisms remain poorly understood. Here, we identified gene variants in familial IgG4-RD and determined their functional consequences. All 3 affected members of the family shared variants of the transcription factor IKAROS, encoded by IKZF1 , and the E3 ubiquitin ligase UBR4. The IKAROS variant increased binding to the FYN promoter, resulting in higher transcription of FYN in T cells. The UBR4 variant 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 the affected family members were hyperresponsive to stimulation. When transduced with a low-avidity, autoreactive T cell receptor, their T cells responded to the autoantigenic peptide. In parallel, high expression of FYN in T cells biased their differentiation toward Th2 polarization by stabilizing the transcription factor JunB. This bias was consistent with the frequent atopic manifestations in patients with IgG4-RD, including the affected family members in the present study. Building on the functional consequences of these 2 variants, we propose a disease model that is not only instructive for IgG4-RD but also for atopic diseases and autoimmune diseases associated with an IKZF1 risk haplotype.

Abstract Background/Aim Limited data exists on 30-day readmission rates, readmission causes and predictors following Ischemic Colitis (IC). The aim is to identify etiologies for the above using a national database. Methods A retrospective cohort study using the 2019 National Readmission Database (NRD) of adult patients with an index admission (IA) for IC from January to November and were readmitted within 30 days of discharge was performed. The primary outcome was readmission of any cause. Secondary outcomes were mortality and resource utilization associated with readmission. Independent risk factors for all-cause readmission were identified using Cox regression analysis. Results A total of 6,853 IC patients were identified. Readmission within 30 days occurred in 762 (11%). The primary readmission cause was sepsis. A total of 325 patients died during the IA and additional 30 patients died within 30 days of discharge. Independent predictors of readmission were discharge to short term hospital, a Charlson comorbidity index score ≥ 2 and admission at large size hospital. Having private insurance and undergoing colonoscopy were associated with lower readmission odds. Economic burden of readmission was $12 million in total costs and $51.4 million in total charges. Conclusion Among admitted IC patients, 30-day readmission rate was 11% with half of those secondary to sepsis. Undergoing colonoscopy during the IA is associated with 34% less risk of readmission and disposition to other facilities appears associated with increased early readmission risk. Prospective evaluation to confirm these findings along with development of optimal care strategies to reduce readmission post IC episodes are needed.

Abstract Objectives To evaluate damage and clinical characteristics associated with damage in Takayasu’s arteritis (TAK). Methods Patients with TAK enrolled in a multicentre, prospective, observational study underwent standardized damage assessment every 6 months using the Vasculitis Damage Index (VDI) and the Large-Vessel Vasculitis Index of Damage (LVVID). Results The study included 236 patients with TAK: 92% female, 81% Caucasian; median (25th, 75th percentile) disease duration = 2.6 (0.12, 6.9) years. Eighty-four percent had follow-up: median (25th, 75th) duration 4.1 (1.9, 7.5) years. Items of damage were present in 89% on VDI, 87% on LVVID, in the peripheral vascular (76% VDI, 74% LVVID) and cardiac (40% VDI, 45% LVVID) systems. During follow-up, 42% patients had new damage, including major vessel stenosis/arterial occlusion (8%), limb claudication (6%), hypertension (7%), aortic aneurysm (4%) and bypass surgery (4%). Disease-specific damage accounted for >90% of new items. Older age, relapse and longer duration of follow-up were associated with new damage items; a higher proportion of patients without new damage were on MTX (P <0.05). Among 48 patients diagnosed with TAK within 180 days of enrolment, new damage occurred in 31% on VDI and 52% on LVVID. History of relapse was associated with new damage in the entire cohort while in patients with a recent diagnosis, older age at diagnosis was associated with new damage. Conclusion Damage is present in >80% of patients with TAK even with recent diagnosis and >40% of patients accrue new, mainly disease-specific damage. Therapies for TAK that better control disease activity and prevent damage should be prioritized.

Abstract Background Anaplastic sarcoma of the kidney (ASK) is a DICER1 ‐related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1 ‐related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear. Methods Individuals with known or suspected DICER1 ‐related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/ DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance. Results Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two‐year event‐free survival (EFS) for stage I–II ASK was 81.8% (95% confidence interval [CI]: 67.2%–99.6%), compared with 46.6% EFS (95% CI: 24.7%–87.8%) for stage III–IV ( p = .07). Two‐year overall survival (OS) for stage I–II ASK was 88.9% (95% CI: 75.5%–100.0%), compared with 70.0% (95% CI: 46.7%–100.0%) for stage III–IV ( p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02–0.31) and 0.08 (95% CI: 0.02–0.42), respectively. Conclusion ASK is a rare DICER1 ‐related renal neoplasm. In the current report, we identify clinical and treatment‐related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors.

Abstract Background The US Centers for Disease Control and Prevention recommends HIV testing every 3 months in oral PrEP users. We performed a national assessment of HIV testing compliance among oral PrEP users. Methods We analyzed 408 910 PrEP prescriptions issued to 39 809 PrEP users using a national insurance claims database that contained commercial and Medicaid claims. We identified PrEP use based on pharmacy claims and outpatient diagnostic coding. We evaluated the percentage of PrEP prescription refills without HIV testing (identified by CPT codes) within the prior 3, 6, and 12 months using time to event methods. We performed subgroup and multivariate analyses by age, gender, race, insurance type, and geography. Results Of 39 809 persons, 36 197 were commercially insured, 3612 were Medicaid-insured, and 96% identified as male; the median age (interquartile range) was 34 (29–44) years, and the Medicaid-insured PrEP users were 24% Black/African American, 44% White, and 9% Hispanic/Latinx. Within the prior 3, 6, and 12 months, respectively, the percentage of PrEP prescription fills in individuals without HIV Ag/Ab testing was 34.3% (95% CI, 34.2%–34.5%), 23.8% (95% CI, 23.7%–23.9%), and 16.6% (95% CI, 16.4%–16.7%), and the percentage without any type of HIV test was 25.8% (95% CI, 25.6%–25.9%), 14.6% (95% CI, 14.5%–14.7%), and 7.8% (95% CI, 7.7%–7.9%). Conclusions Approximately 1 in 3 oral PrEP prescriptions were filled in persons who had not received an HIV Ag/Ab test within the prior 3 months, with evidence of health disparities. These findings inform clinical PrEP monitoring efforts and compliance with national HIV testing guidance to monitor PrEP users.