Faculty Bibliography

PURPOSE OF REVIEW/UNASSIGNED:Dysphagia is a common medical condition among the geriatric population that can significantly impact a patient's quality of life. The manifestations, diagnosis, and treatment of esophageal dysphagia differ greatly based on the underlying etiology, especially in older individuals who may have accompanying complex medical comorbidities. This review explores the intricacies of esophageal dysphagia in the older population and how they are managed. RECENT FINDINGS/UNASSIGNED:Novel modalities, like the functional luminal imaging probe (FLIP) and timed barium esophagram (TBE), are now woven into our diagnostic schemas for esophageal dysphagia. Studies have also looked at the safety profile of available therapeutic interventions for older individuals. There are newer, less invasive treatment options, including radiofrequency application (RFA) and transoral incisionless fundoplication (TIF) for GERD management, that may benefit the geriatric population. SUMMARY/UNASSIGNED:In this review, we discuss the most likely etiologies of esophageal dysphagia in the elderly population. We then explore a diagnostic schema and highlight treatment choices based on diagnosis. Our review specifically explores the risks and benefits of management options in more medically complex geriatric patients.

BACKGROUND AND AIMS/OBJECTIVE:PredictSURE IBD is a prognostic blood test that classifies newly diagnosed, treatment-naïve Inflammatory Bowel Disease (IBD) patients into 'IBDhi' (high-risk) or 'IBDlo' (low-risk) groups (risk of future aggressive disease). We evaluated this assay in a multinational cohort and explored the effect of concomitant corticosteroids on its discrimination. METHODS:One hundred thirty-six (71 Ulcerative colitis [UC], 65 Crohn's Disease [CD]) and 41 (15 UC, 26 CD) patients with active IBD were 'unexposed' and 'exposed', respectively, to corticosteroids at baseline blood sampling. The number of treatment escalations, time to first escalation, and need for repeated escalations were compared between the biomarker subgroups. Another 20 patients (13 UC, 7 CD) were longitudinally sampled over 6 weeks after commencing corticosteroids. RESULTS:In corticosteroids-naïve UC and CD patients, all bowel surgeries (n = 6) and multiple therapy escalations (n = 10) occurred in IBDhi patients. IBDhi UC patients required significantly more treatment escalations, had a shorter time to first escalation, and a greater need for multiple escalations than IBDlo patients. No statistically significant differences were observed among CD patients. In corticosteroid-exposed patients, 66.6% of 'misclassifications' were IBDlo patients who required escalations. Among corticosteroid-treated patients with longitudinal sampling, 81.3% of those classified as IBDhi before steroids switched to IBDlo during therapy. CONCLUSIONS:No significant differences in treatment escalations were observed between biomarker-defined subgroups in CD. However, IBDhi UC patients required significantly earlier and more frequent therapy escalations, highlighting the need to further investigate PredictSURE IBD in UC. Notably, the discrimination ability of the biomarker was unreliable in patients receiving corticosteroid therapy.

BACKGROUND AND AIMS/OBJECTIVE:receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). In this post hoc analysis, induction and maintenance efficacy of etrasimod 2 mg vs placebo were assessed by baseline Mayo endoscopic subscore (ES) in ELEVATE UC 52 and ELEVATE UC 12. METHODS:Moderate and severe endoscopic disease were defined as a centrally-read ES of 2 and 3, respectively. Efficacy endpoints were evaluated at Weeks 12 (pooled population) and 52 (ELEVATE UC 52). Subgroup analyses were stratified by baseline modified Mayo score (4-6 vs 7-9) and prior biologic/Janus kinase inhibitor exposure. RESULTS:Overall, 235 patients with moderate and 292 with severe endoscopic disease received etrasimod; 112 and 148 patients, respectively, received placebo. At both time points, significantly greater proportions of patients receiving etrasimod compared with placebo achieved clinical remission in the moderate (Week 12: 38.3% vs 17.9%; Week 52: 36.5% vs 14.3%; both P < .001) and severe (Week 12: 18.2% vs 6.1%; Week 52: 29.4% vs 3.4%; both P < .001) endoscopic disease subgroups. Similar efficacy was observed at Weeks 12 and 52 for most endpoints. The proportion of etrasimod-treated patients with severe endoscopic disease achieving endpoints was generally numerically higher at Week 52 vs Week 12, relative to placebo. Subgroup analysis findings were generally similar. CONCLUSIONS:Etrasimod demonstrated significant induction and maintenance efficacy over placebo in both moderate and severe endoscopic disease. Response to etrasimod in patients with severe endoscopic disease may continue to improve beyond 12-week induction therapy (ClinicalTrials.gov: NCT03945188; NCT03996369).

Corticosteroids are one of the most frequently prescribed medications for the management of inflammatory bowel disease. While corticosteroids have a critical role for select cases for induction of remission, there is a notable risk of over-use and miss-use of corticosteroids. This narrative review updates the evolving use of corticosteroids in the management of inflammatory bowel disease. The review focuses on the appropriate use, route of administration and duration for the use of corticosteroids. Additionally, this review summarizes the side effects, use of steroids in special populations (e.g. geriatrics, pregnancy, underrepresented minorities), and their use in the peri-operative setting.

Therapeutically targeting pathogenic T cells in autoimmune diseases has been challenging. Although LAG-3, an inhibitory checkpoint receptor specifically expressed on activated T cells, is known to bind to major histocompatibility complex class II (MHC class II), we demonstrate that MHC class II interaction alone is insufficient for optimal LAG-3 function. Instead, LAG-3's spatial proximity to T cell receptor (TCR) but not CD4 co-receptor, facilitated by cognate peptide-MHC class II, is crucial in mediating CD4⁺ T cell suppression. Mechanistically, LAG-3 forms condensate with TCR signaling component CD3ε through its intracellular FSAL motif, disrupting CD3ε/lymphocyte-specific protein kinase (Lck) association. To exploit LAG-3's proximity to TCR and maximize LAG-3-dependent T cell suppression, we develop an Fc-attenuated LAG-3/TCR inhibitory bispecific antibody to bypass the requirement of cognate peptide-MHC class II. This approach allows for potent suppression of both CD4⁺ and CD8⁺ T cells and effectively alleviates autoimmune symptoms in mouse models. Our findings reveal an intricate and conditional checkpoint modulatory mechanism and highlight targeting of LAG-3/TCR cis-proximity for T cell-driven autoimmune diseases lacking effective and well-tolerated immunotherapies.

Pathogenic CD4 T cells drive autoimmunity in diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). Through a forward genetic screen, we identified chloride nucleotide-sensitive channel 1A (CLNS1A) as a key regulator of inflammation in the experimental autoimmune encephalomyelitis (EAE) model of MS. CLNS1A is expressed in several subsets of CD4 T cells, including pathogenic T helper 17 (pT_H17) cells. Deletion of Clns1a in T cells resulted in DNA damage, cell cycle arrest, impaired T cell proliferation, and effector function, thereby protecting mice from both EAE and IBD. We found that CLNS1A interacts with protein arginine methyl transferase 5 (PRMT5). Moreover, CLNS1A regulates symmetric histone dimethylation and the expression of genes involved in DNA repair, replication, and cell cycle progression. Thus, CLNS1A plays an important role in CD4 T cells by promoting genome stability and cell cycle progression.

IMPORTANCE/UNASSIGNED:Defining on-treatment remission in plaque psoriasis is important for benchmarking patient responses to therapies. This also helps to facilitate shared understanding, align treatment expectations, and enable more effective psoriasis management. OBJECTIVE/UNASSIGNED:To establish a consensus-based definition of on-treatment remission for plaque psoriasis through a multistage Delphi initiative. EVIDENCE REVIEW/UNASSIGNED:The Remission Workgroup from the medical board and scientific advisory board of the National Psoriasis Foundation engaged various stakeholders, both US based and international, to participate in the consensus process. Following a working group meeting to determine the overall consensus approach, a systematic review of remission definitions in the current literature was performed. This review helped to inform the content of consensus materials. The consensus effort involved 2 stages: pre-Delphi interviews and surveys to inform the Delphi questions, followed by a Delphi exercise with physicians to define on-treatment remission for plaque psoriasis. Outcome measures considered included body surface area (BSA), Investigator Global Assessment (IGA), the product of the Physician Global Assessment and body surface area (PGA × BSA), and Psoriasis Area and Severity Index (PASI) score at various cutoff levels and time points. FINDINGS/UNASSIGNED:The consensus process involved 92 stakeholders, including dermatologists, rheumatologists, researchers, patients, payers, and life sciences professionals. In the pre-Delphi interviews and surveys, patients emphasized that on-treatment remission meant the absence of psoriasis signs and symptoms while recieving therapy. Payers expressed that defining remission is important for long-term treatment coverage. Following the Delphi exercise and discussion with participating physicians specializing in psoriatic disease management, on-treatment remission in plaque psoriasis was defined as patients maintaining a BSA of 0% or IGA of 0 for at least 6 months while on treatment. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Through a Delphi consensus process, on-treatment remission for plaque psoriasis was defined as patients maintaining a BSA involvement of 0% or IGA of 0 for at least 6 months while on treatment. This clear and standardized benchmark is applicable to both research and practice settings.

Targeted therapies and immunotherapy have improved treatment outcomes for many melanoma patients. However, patients whose melanomas harbor driver mutations in the neurofibromin 1 (NF1) tumor suppressor gene often lack effective targeted treatment options when their tumors do not respond to immunotherapy. In this study, we utilized patient-derived short-term cultures (STCs) and multiomics approaches to identify molecular features that could inform the development of therapies for patients with NF1 mutant melanoma. Differential gene expression analysis revealed that the epidermal growth factor receptor (EGFR) is highly expressed and active in NF1 mutant melanoma cells, where it hyper-activates ERK and AKT, leading to increased tumor cell proliferation, survival, and growth. In contrast, genetic or pharmacological inhibition of EGFR hindered cell proliferation and survival and suppressed tumor growth in patient-derived NF1 mutant melanoma models but not in NF1 wild-type models. These results reveal a connection between NF1 loss and increased EGFR expression that is critical for the survival and growth of NF1 mutant melanoma cells in patient-derived culture and xenograft models, irrespective of their BRAF and NRAS mutation status.

PURPOSE OF REVIEW/OBJECTIVE:Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with 44% of deaths occurring in individuals aged 75 years and older. With 78 million adults over 65 years projected by 2035, optimizing CRC screening and surveillance is crucial. This review examines guidelines, risks, and personalized approaches. RECENT FINDINGS/RESULTS:CRC screening reduces incidence by 17-33% and mortality by 11-53%. Colonoscopy lowers mortality by 61% but has a 6.8% complication rate in those aged 75 years and older. The risk of gastrointestinal bleeding is 8.7 per 1,000 for polypectomy, and perforation occurs in 0.6 per 1,000. Frailty indices assess suitability, but surveillance guidelines lack clear discontinuation criteria. Screening should balance risk, complications, and health status. It may be cost-effective up to age 86 years in healthy individuals, but more research is needed to refine surveillance strategies and reduce overtreatment in older adults.