Bipneet Singh, Palak Grover, and Gurleen Kaur. J Neurogastroenterol Motil -0001;0:. https://doi.org/10.5056/jnm25033

Patients with inflammatory bowel disease (IBD) require long-term immunosuppressive therapy, raising concerns about treatment associated malignancy risk. The comparative ma-lignancy profiles of biologic and advanced small-molecule therapies remain incompletely characterized. A systematic review was conducted following PRISMA guidelines. PubMed, Embase, Cochrane Library, and Web of Science were searched from inception through June 2025, with supplementary screening via Google Scholar. Eligible studies included randomized controlled trials and observational cohort studies evaluating malignancy outcomes in adult IBD patients receiving anti-tumor necrosis factor (TNF) agents, anti-integrin therapies, anti-interleukin (IL)-12/23 and IL-23 inhibitors, Janus kinase (JAK) inhibitors, or sphingosine-1-phosphate (S1P) receptor modulators. Studies evaluating thiopurines alone or in combination with biologic therapy were included when malignancy risk was specifically assessed. The Newcastle-Ottawa Scale was used for quality assessment of observational studies and the Cochrane risk-of-bias tool for randomized trials. A formal quantitative meta-analysis was not performed due to heterogeneity in study designs, populations, comparators, outcome definitions, and follow-up durations. Twenty-eight studies met the inclusion criteria. Thiopurines showed the most consistent malignancy association, including lymphoma (pooled SIR 4.92; 95% CI, 3.10–7.78), NMSC, acute myeloid leukemia/myelodysplastic syndrome, and urinary tract cancers. Anti-TNF monotherapy showed no significant increase in overall cancer incidence but carried a modest lymphoma risk (aHR 2.41; 95% CI, 1.60–3.64). Combination anti-TNF plus thiopurine therapy was associated with the highest lymphoma risk (aHR 6.11; 95% CI, 3.46–10.8). Vedolizumab and ustekinumab showed no increased malignancy risk, including in patients with prior cancer. JAK inhibitor data from rheumatoid arthritis (ORAL Surveillance: HR 1.48; 95% CI, 1.04–2.09 for tofacitinib vs. TNF inhibitors) have not been replicated in IBD-specific studies through 9.2 years of follow-up. S1P receptor modulators showed low malignancy rates (0.4 per 100 patient years over 10 years for ozanimod). Malignancy risk with IBD therapies is heterogeneous and drug class dependent. Thiopurines and combination therapy carry the highest risk. Gut-selective agents (vedolizumab, ustekinumab) have the most favorable safety profiles and are preferred in patients with prior malignancy. JAK inhibitor and S1P modulator data in IBD are reassuring but require continued long-term surveillance.

Background/Objectives: Prior U.S. surveillance studies reported modest pulmonary hypertension mortality declines through 2020, but contemporary trends incorporating expanded combination therapy and novel therapeutics remain uncharacterized. This study analyzed primary pulmonary hypertension (PPH) mortality trends and demographic disparities from 2018 to 2024. Methods: A retrospective, population-based cross-sectional study was conducted using the CDC WONDER Underlying Cause of Death database (2018–2024, Single Race series). Deaths with ICD-10 code I27.0 as the underlying cause were identified. Age-adjusted mortality rates (AAMRs) per 100,000 population were standardized to the 2000 U.S. standard population. Deaths were stratified by sex, race, calendar year, and U.S. Census Region. Mortality rate ratios with 95% confidence intervals were calculated using exact Poisson methods. Results: From 2018 to 2024, 1,831 deaths were attributed to PPH. Annual deaths declined from 344 to 199, a 42.2% reduction, with the AAMR decreasing from 0.10 to 0.06 per 100,000 (estimated compound annual rate of change, 9.3%). Women accounted for 69.5% of deaths (female-to-male AAMR ratio, 2:1). Black individuals had the highest AAMR (0.10 vs. 0.06 per 100,000 for White individuals; Black-to-White ratio, 1.67:1). The South bore the highest burden (43.1% of deaths; crude rate, 0.09 per 100,000) while the Northeast had the lowest (12.3%; crude rate, 0.06 per 100,000). Conclusions: PPH mortality declined substantially from 2018 to 2024, coinciding with increased adoption of combination therapy and the introduction of sotatercept. Persistent disparities by sex, race, and geography suggest therapeutic advances may not be reaching all populations equitably, underscoring the need for targeted interventions to improve access to PAH-specific therapies.

Background: Alpha-1 antitrypsin deficiency (A1ATD) is a hereditary disorder affecting approximately 1 in 2,000 to 5,000 individuals of European ancestry. While severe deficiency (PiZZ genotype) is well-characterized, the clinical significance of relatively intermediate deficiency states (serum A1AT 40-80 mg/dL), predominantly comprising PiSZ, PiMZ, and PiSS genotypes, remains poorly defined. This study aimed to compare hepatic and pulmonary outcomes in patients with moderate versus mild intermediate A1ATD. Methods: Using the TriNetX US Collaborative Network (43 healthcare organizations), we identified 1,410 adult patients with A1ATD (ICD-10 code E88.01) and serum A1AT levels between 40-80 mg/dL. Patients were stratified into two cohorts- 40-60 mg/dL (n=324) and 60-80 mg/dL (n=324) after 1:1 propensity score matching for age, sex, race, BMI, diabetes, and baseline laboratory values. Exclusion criteria included A1AT level of less than 40 mg/dL, pre-existing cirrhosis, and other chronic liver diseases. Primary outcomes included emphysema, COPD exacerbation, cirrhosis, hepatic decompensation, and mortality. Results: Following propensity matching, baseline characteristics were well-balanced except for albumin (4.0±0.8 vs 4.2±0.6 g/dL, p=0.001) and INR (1.4±0.6 vs 1.2±0.4, p=0.001). Patients with A1AT 40-60 mg/dL demonstrated trends toward increased emphysema risk (10.8% vs 7.4%; OR 1.51, 95% CI 0.88-2.61, p=0.133; HR 1.63, 95% CI 0.97-2.74, log-rank p=0.063) and cirrhosis (10.5% vs 7.4%; OR 1.47, 95% CI 0.85-2.53, p=0.169; HR 1.58, 95% CI 0.94-2.66, log-rank p=0.085). No significant differences were observed for COPD exacerbation (14.2% vs 13.0%, p=0.646), hepatic decompensation (4.6% vs 3.7%, p=0.555), or mortality (OR 1.07, p=0.854). Conclusions: The observed trends toward worse outcomes with lower A1AT levels (40-60 mg/dL range, likely enriched for PiSZ genotype) warrant further investigation in larger cohorts with genotype confirmation. Limitations include a lack of genotyping data, reliance on ICD-10 coding, and potential type II error due to limited sample size. These preliminary findings highlight an important knowledge gap in understanding disease burden among the more prevalent intermediate A1ATD.