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/Objectives: Prior U.S. surveillance studies described changes in pulmonary hypertension mortality through 2020, but contemporary national data focused specifically on deaths coded as primary pulmonary hypertension (PPH; ICD-10 I27.0) are limited. We examined temporal, sex, racial, and geographic patterns in I27.0-coded mortality in the United States from 2018 to 2024. Methods: CDC WONDER Underlying Cause of Death data were analyzed. Annual deaths and mortality rates were examined by year, sex, Single Race 6 category, and U.S. Census region. Results: A total of 1831 deaths were coded as I27.0. Annual deaths declined from 344 in 2018 to 199 in 2024, while the exact crude rate declined from 0.105 to 0.059 per 100,000. Women accounted for 69.5% of deaths. Black individuals had a higher age-adjusted mortality rate than White individuals (0.10 vs. 0.06 per 100,000). The South accounted for the largest share of deaths (43.1%), although the West had a marginally higher exact crude rate. Conclusions: Deaths assigned to I27.0 declined substantially during 2018–2024. This trend occurred during a period of major evolution in PAH care, but the ecological design cannot determine whether therapeutic advances caused the decline. Changes in coding, classification, and assignment of underlying cause may also have contributed. Persistent demographic disparities warrant further investigation.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. The sequential approval of CFTR modulators ivacaftor (2012), lumacaftor/ivacaftor (2015), tezacaftor/ivacaftor (2018), and elexacaftor/tezacaftor/ivacaftor (2019) has transformed CF care, but population-level mortality trends across therapeutic periods have not been comprehensively assessed. We conducted a retrospective analysis of CF mortality in the United States from 1999 to 2024 using CDC WONDER Underlying Cause of Death data (ICD-10 codes E84.0–E84.9). Age-adjusted mortality rates (AAMR) per 100,000 were calculated using the 2000 U.S. standard population. The study period was divided into three periods: pre-modulator (1999–2011), early modulator (2012–2018), and elexacaftor/tezacaftor/ivacaftor (2019–2024). Annual mortality trends were evaluated using segmented log-linear Poisson regression, with annual death counts as the outcome and the corresponding U.S. population as an offset. Candidate models with multiple change points were compared to identify distinct temporal segments. Annual percent changes (APCs) and 95% confidence intervals (CIs) were estimated for each segment. Prespecified therapeutic periods, including pre-modulator (1999–2011), early modulator (2012–2018), and ETI period (2019–2024), were retained for descriptive analyses. Trends were stratified by sex and U.S. Census Region. A total of 10,959 CF deaths were recorded over 26 years. In the pre-modulator period, mortality was stable at a mean of 478 deaths/year (AAMR 0.14–0.17). The early modulator period showed a modest 5.4% reduction in mean annual deaths (452/year). The period following ETI availability was associated with a decline to 263/year, a 47% reduction from the pre-modulator period (AAPC −8.6%/year). The AAMR declined from 0.17 (1999) to 0.07 (2024). The female-to-male death count ratio shifted from 1.05 to 0.97 across periods, though age-adjusted rates were identical between sexes within each period, and this finding should be interpreted cautiously. Regionally, the South’s share of CF deaths grew from 37.2% to 41.6% despite absolute declines in all regions, suggesting potential geographic disparities that warrant further investigation with individual-level data. Segmented regression identified change points in 2005 and 2015. Mortality declined significantly from 1999 through 2005 (APC, −2.70%; 95% CI, −4.01% to −1.37%), remained stable from 2006 through 2015 (APC, +0.21%; 95% CI, −0.47% to +0.90%), and declined sharply from 2016 through 2024 (APC, −9.76%; 95% CI, −10.66% to −8.84%). CF mortality in the United States has declined by more than half since the introduction of CFTR modulators. The shift in the sex-based death count ratio and the concentration of remaining deaths in the South are hypothesis-generating observations that require confirmation with individual-level data. These ecological findings cannot establish causation, as concurrent changes in supportive care, lung transplantation practices, and COVID-19 pandemic effects may have contributed to the observed trends.

IgG4-related disease (IgG4-RD) is a subacute, progressive, multisystemic autoinflammatory condition which presents with nonspecific symptoms like weight loss, fatigue, and myalgia, and is marked by lymphoplasmacytic infiltrates rich in IgG4-positive plasma cells. IgG4-RD can involve various organs including the pancreas, bile ducts, thyroid, salivary and lacrimal glands, retroperitoneum, kidneys, lungs, and CNS, often mimicking malignancy. A rigorous literature review was done. Articles on IgG4 disease, CD-19 and the MITIGATE trials was done and included in the review.Glucocorticoids remain first-line therapy, but adverse effects and relapses are common. Rituximab, an anti-CD20 agent, is effective but may leave CD20-negative plasmablasts intact, contributing to relapse. In contrast, CD19-targeting therapies like inebilizumab offer more comprehensive B-cell depletion, including plasmablasts, potentially reducing relapses, fibrosis progression, and long-term organ damage.MITIGATE trials showed promise in the use of anti-CD-19 agent in preventing IgG4 disease flares and prolonging the time to first flare.

Background: Sarcoidosis is a [chronic granulomatous disease of unknown etiology that predominantly affects the lungs but can involve virtually any organ, including the liver. Pulmonary involvement occurs in over 90% of patients, while hepatic involvement is reported in 5–25% of cases. Despite the expanding therapeutic armamentarium, evidence regarding both pulmonary efficacy and hepatic safety/efficacy of sarcoidosis therapies remains fragmented across heterogeneous studies. This systematic review synthesizes the available evidence on pharmacological therapies for sarcoidosis, with a dual focus on pulmonary outcomes (forced vital capacity, steroid-sparing, radiographic response) and hepatic outcomes (hepatotoxicity, efficacy in hepatic sarcoidosis).Methods: A comprehensive literature search was conducted across PubMed, MEDLINE, Cochrane Library, and ClinicalTrials.gov through May 2025. Studies evaluating pharmacological therapies for sarcoidosis reporting pulmonary and/or hepatic outcomes were included. Therapies were categorized as first-line (glucocorticoids, methotrexate), second-line (antimetabolites, hydroxychloroquine), third-line (anti-TNF biologics, rituximab, repository corticotropin injection), and investigational agents (JAK inhibitors, efzofitimod, antifibrotics). Data were extracted on study design, sample size, pulmonary function outcomes, hepatic efficacy, hepatotoxicity, and adverse events. Quality assessment was performed using the Cochrane Risk of Bias tool for RCTs and the Newcastle-Ottawa Scale for observational studies.Results: A total of 22 therapies across 4 treatment lines were identified with reportable pulmonary and/or hepatic outcome data. The evidence base comprised 8 randomized controlled trials, 8 single-arm trials, multiple retrospective cohort studies, and real-world database analyses. Key findings are summarized by treatment line below.Conclusions: Methotrexate has emerged as a noninferior first-line alternative to prednisone for pulmonary sarcoidosis. Anti-TNF agents, particularly infliximab, provide modest but consistent pulmonary benefit and demonstrate efficacy in hepatic sarcoidosis phenotypes. JAK inhibitors and efzofitimod represent promising investigational therapies. Hepatotoxicity remains a critical consideration across multiple drug classes, necessitating structured monitoring. Prospective studies specifically evaluating hepatic sarcoidosis outcomes are urgently needed.