Baseline Disease Research Articles

Real-world experience and long-term outcomes of a mandatory non-medical switch of adalimumab originator to biosimilars in inflammatory bowel disease

BACKGROUND Over the last decade, the treatment options for inflammatory bowel disease (IBD) have significantly progressed with the emergence of new medications designed to target various immune pathways and mitigate inflammation. Adalimumab (ADA) is a tumor necrosis factor alpha antagonist and stands as an effective treatment for IBD. In April 2021, the province of British Columbia implemented a mandatory non-medical switch policy of the ADA originator Humira® to ADA biosimilars. Biosimilars offer a potential cost-effective, safe, and efficacious alternative to the originator, yet there remains limited real-world evidence on long-term outcomes of ADA non-medical switching in IBD. AIM To assess the long-term outcomes of non-medical switching from the ADA originator Humira® to an ADA biosimilar among IBD patients. METHODS A retrospective observational chart review study was conducted on IBD patients eligible for the provincially mandated non-medical switch to an ADA biosimilar. The primary outcome was treatment persistence at 30 months post-switch. Secondary outcomes included the proportion of and reasons for therapy alteration or ADA discontinuation, loss of response (LOR) rates, adverse events (AE), and clinical and biochemical remission status. Patients who remained on the originator throughout the switch period, through compassionate support or private pay, constituted the comparison group. RESULTS Patients in the originator (n = 43) and biosimilar switch (n = 228) groups displayed similar demographics and baseline disease characteristics. By the study endpoint of 30 months, there was no difference in the rate of treatment persistence in either group (n = 36, 83.7% originator group vs n = 201, 88.2% biosimilar group, P = 0.451). Treatment persistence demonstrated similar rates of discontinuation between both study groups (log-rank P = 0.543). There was a numerical but not statistically significant difference in rates of adverse outcomes between either group (39.5% originator vs 28.9% biosimilars, P = 0.206). This included comparable rates of LOR (27.9% vs 17.5%) or AE (11.6% vs 11.4%) between the originator and biosimilar cohorts, respectively. C-reactive protein and fecal calprotectin levels were similar one year pre- and post-switch. CONCLUSION These data support the long-term efficacy and safety of non-medical ADA switching in IBD and will help inform patients and physicians in jurisdictions currently undergoing biosimilar switching.

Pure open versus robotic radical cystectomy with intracorporeal urinary diversion: a propensity matched analysis.

To compare surgical parameters and short-term outcomes between open radical cystectomy (ORC) and robotic radical cystectomy with total intracorporeal urinary diversion (icRARC). Among the study period, 133 patients who underwent ORC and pelvic node dissection for bladder cancer (group 1) were matched and compared to 61 patients who underwent icRARC during the same period (group 2). The groups were matched 1:1 according to their propensity scores adjusted on their baseline demographics and disease characteristics. The main surgical parameters compared were: operative time, estimated blood loss (EBL), and postoperative outcomes including time to oral intake, ninety-day complications, readmission rate, and secondary procedures. Overall, 122 patients (61 in each group) were matched and finally analyzed. Although operative times (307 ± 97min vs. 444 ± 113min; p < 0.001) were longer, EBL (948 ± 657ml vs. 357 ± 219ml; p < 0.001) and transfusion rates were lower in the icRARC group. Overall complications were comparable but late complications tended to be lower in the icRARC group (p = 0.06). Readmission rate (54.8% vs. 26.8%, p = 0.01) was higher in the ORC group while secondary procedures (28.6% vs. 12.5%, p = 0.07) also tended to be lower in the robotic approach. Finally, in multivariable logistic regression the icRARC group was not associated with any complications of any grade including grade 3 or higher compared to the open approach. This study comparing open radical cystectomy to robotic radical cystectomy with total intracorporeal urinary diversion demonstrated encouraging outcomes for the minimally invasive management of urothelial carcinoma.

Proton Pump Inhibitor Use and Worsening Kidney Function: A Retrospective Cohort Study Including 122,606 Acid-Suppressing Users.

The impact of proton pump inhibitors (PPIs) use on worsening renal function is controversial and lacks a solid pathophysiological explanation. To assess the risk of worsening renal function and acute kidney injury (AKI) in PPI initiators as compared with H2-blockers initiators. Retrospective cohort study using longitudinal records from BIGAN, a population-based health database of Aragón (Spain). PPIs (n = 119,520) and H2-blockers (n = 3,086) initiators between 2015 and 2020 with preserved renal function. They were followed until the occurrence of an adverse kidney event, death, lost to follow-up or June 2021. Primary endpoints were worsening kidney function (measured as sCr ≥ 2 times baseline, eGFR < 60ml/min/1.73m2, a decrease in eGFR 30-50% from baseline or end stage renal disease) and AKI (measured by Aberdeen algorithm or hospitalization due to AKI). Incidence rates (IRs) per 1,000 persons-years were reported and Cox regression was used to calculate Hazard ratios (HRs), adjusted for confounders. Crude IRs for worsening kidney function were consistently lower for ranitidine than for PPIs (eGFR < 60ml/min/1.73m2: IR 18.7 95%CI (12.0-27.8) for ranitidine, IR 31.2 95%CI (29.9-32.5) for omeprazole). However, the risk of incident worsening function did not significantly differ in the Cox regression analysis adjusting for confounders (HR 0.99 95%CI (0.66-1.48) for omeprazole, as compared to ranitidine). PPI initiators consistently showed lower IRs of AKI using Aberdeen algorithm (IR 33.8 95%CI (32.4-35.1) for omeprazole, IR 52.8 95%CI (40.9-67.1) for ranitidine) and lower risk of AKI (HR 0.54 95%CI (0.42-0.70) for omeprazole, as compared to ranitidine). No clinically relevant differences were observed for worsening kidney function between PPIs and H2-blockers initiators. PPIs users presented a reduced risk of AKI compared to ranitidine initiators.

Effectiveness and Predictors of Long-Term Treatment Response to Tofacitinib in Rheumatoid Arthritis Cohort: General Analysis and Focus on High-Cardiovascular-Risk Subgroup—A Multicenter Study

Background and Objectives: The treatment landscape for Rheumatoid Arthritis (RA) has evolved significantly with the introduction of Janus kinase inhibitors (JAKi), such as Tofacitinib (TOFA), which offer a new therapeutic option for patients who have failed or are intolerant to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Safety concerns, particularly related to cardiovascular and cancer risks, prompted a need for additional investigation in real-world clinical settings. This study aimed to evaluate the long-term effectiveness and predictors of response to TOFA in two subpopulations of RA patients, categorized by differing cardiovascular risk profiles. Materials and Methods: This was a retrospective, multicenter observational study conducted as part of the BIRRA project, involving 23 Italian rheumatological referral centers. A total of 213 patients diagnosed with RA and treated with TOFA were included, with data collected on baseline demographics, clinical history, disease activity, and comorbidities. Patients were divided into high-risk and low-risk cardiovascular groups based on age (≥65 years) and the presence of at least one cardiovascular risk factor. Disease activity was assessed at baseline, 6 months, and 12 months using DAS28-ESR and DAS28-CRP. Treatment response was evaluated using intention-to-treat (ITT) and per-protocol (PP) approaches. Predictors of low disease activity (LDA) and remission were assessed through logistic regression, and clustering analyses were used to identify subgroups of patients with different therapeutic responses. Results: The study included 213 patients, with 129 classified as high-risk. For the overall cohort, patients achieving LDA and remission at 6 months were 20% and 12%, respectively, for the ITT analysis, and 29% and 14% for the PP analysis. At 12 months, 26% of patients reached LDA, and 17% achieved remission according to ITT, while for the PP analysis, these rates were 30% and 19%, respectively. No significant differences in remission or LDA rates were observed between the high-risk and low-risk groups. In the high-risk subgroup, 17% of patients reached LDA and 9% achieved remission at 6 months (ITT analysis), while these rates increased to 22% and 13%, respectively, in the PP analysis. At 12 months, 22% achieved LDA and 13% achieved remission in the ITT analysis, while 28% and 17% did so in the PP analysis. The reduction in DAS28-ESR and DAS28-CRP scores was significant (p &lt; 0.001) across all time points for both high-risk and low-risk patients. Logistic regression analyses revealed that none of the baseline characteristics—including age, sex, comorbidities, rheumatoid factor, anti-citrullinated protein antibody (ACPA) positivity, initial disease severity, or treatment history—were significant predictors of remission or LDA at 6 or 12 months. The clustering analysis suggested that older patients, particularly those with worse baseline DAS28 scores, tended to show a less favorable response to treatment, potentially indicating impacts of age-related factors such as immunosenescence on therapeutic outcomes. Conclusions: Tofacitinib demonstrated similar effectiveness in both high- and low-risk cardiovascular subgroups of RA patients, with significant reductions in disease activity observed at both 6 and 12 months. Despite safety concerns related to cardiovascular risk, TOFA remained an effective treatment option across patient subgroups, with no significant differences in remission or LDA rates based on cardiovascular risk profiles. Age appeared to negatively impact treatment response, highlighting the role of immunosenescence in RA management. These findings support the use of TOFA as a personalized therapeutic option for RA, emphasizing the need for careful evaluation of cardiovascular and age-related risks in clinical decision-making.

Associations Between Paramagnetic Rim Lesion Evolution and Clinical and Radiologic Disease Progression in Persons With Multiple Sclerosis.

Recent technological advances have enabled visualizing in vivo a subset of chronic active brain lesions in persons with multiple sclerosis (pwMS), referred to as "paramagnetic rim lesions" (PRLs), with iron-sensitive MRI. PRLs predict future clinical disease progression, making them a promising clinical and translational imaging marker. However, it is unknown how disease progression is modified by PRL evolution (PRL disappearance, new PRL appearance). This is key to understanding MS pathophysiology and may help inform selection of sensitive endpoints for clinical trials targeting chronic active inflammation. To this end, we assessed the longitudinal associations between PRL disappearance and new PRL appearance and clinical disability progression and brain atrophy. PwMS and healthy controls (HCs) were included from a larger prospective, longitudinal cohort study at the University at Buffalo if they had available 3T MRI and clinical visits at baseline and follow-up timepoints. PwMS with sufficient clinical data for confirmed disability progression (CDP) analysis were included in a Disability Progression Cohort, and pwMS and HCs with brain volumetry data at baseline and follow-up were included in MS and HC Brain Atrophy cohorts. PRLs were assessed at baseline and follow-up and assigned as disappearing, newly appearing, or persisting at follow-up. Linear models were fit to compare annualized PRL disappearance rates or new PRL appearance (yes/no) with annualized rates of CDP and progression independent of relapse activity (PIRA) or with annualized rates of brain atrophy, adjusting for covariates including baseline PRL number and follow-up time. Statistical analyses were corrected for false discovery rate (FDR; i.e., q-value). In total, 160 pwMS (73.8% female; mean baseline age 46.6 ± 11.4 years; mean baseline disease duration 13.8 ± 10.6 years; median follow-up time 5.6 [interquartile range 5.2-7.8] years; 26.9% progressive MS) and 27 HCs (74.1% female; mean baseline age 43.9 ± 13.6 years; median follow-up time 5.4 [5.2-5.6] years) were enrolled. Greater PRL disappearance rates were associated with reduced rates of CDP (β mean = -0.262, 95% CI -0.475 to -0.049, q = 0.028) and PIRA (β mean = -0.283, 95% CI -0.492 to -0.073, q = 0.036), and new PRL appearance was associated with increased rates of PIRA (β mean = 0.223, 95% CI 0.049-0.398, q = 0.036). By contrast, no associations between new PRL appearance or PRL disappearance and brain volume changes survived FDR correction (q > 0.05). Our results show that resolution of existing PRLs and lack of new PRLs are associated with improved clinical outcomes. These findings further motivate the need for novel therapies targeting microglia-mediated brain inflammation and adoption of clinical strategies to prevent appearance of new PRL.

A polygenic risk score derived from common variants of monogenic diabetes genes is associated with young-onset type 2 diabetes and cardiovascular-kidney complications.

Monogenic diabetes is caused by rare mutations in genes usually implicated in beta cell biology. Common variants of monogenic diabetes genes (MDG) may jointly influence the risk of young-onset type 2 diabetes (YOD, diagnosed before the age of 40 years) and cardiovascular and kidney events. Using whole-exome sequencing data, we constructed a weighted polygenic risk score (wPRS) consisting of 135 common variants (minor allele frequency >0.01) of 34 MDG based on r2>0.2 for linkage disequilibrium in a discovery case-control cohort of 453 adults with YOD (median [IQR] age 39.7 [34.9-46.9] years) and 405 without YOD (median [IQR] age 56.7 [50.3-61.0] years), followed by validation in an independent cross-sectional cohort with array-based genotyping for YOD and a prospective cohort of individuals with type 2 diabetes for cardiovascular and kidney events. In the discovery cohort, the OR of the 135 common variants for YOD ranged from 1.00 to 2.61. In the validation cohort (920 YOD and 4910 non-YOD), top-10%-wPRS was associated with an OR of 1.42 (95% CI 1.03, 1.95, p=0.033) for YOD compared with bottom-10%-wPRS. In 2313 individuals with type 2 diabetes (median [IQR]: age 53.4 [45.4-61.7] years; disease duration 4.0 [1.0-9.0] years) observed for a median (IQR) of 17.5 (14.4-21.8) years, standardised wPRS was associated with increased HR for incident cardiovascular events (1.16 [95% CI 1.06, 1.27], p=0.001), kidney events (1.09 [95% CI 1.02, 1.16], p=0.013) and cardiovascular-kidney events (1.10 [95% CI 1.03, 1.16], p=0.003). Using the 'bottom-20%-wPRS plus baseline disease duration <5 years' group as referent, the 'top-20%-wPRS plus baseline disease duration 5 to <10 years' group had unadjusted and adjusted HR of 1.60 (95% CI 1.17, 2.19, p=0.003) and 1.62 (95% CI 1.16, 2.26, p=0.005), respectively, for cardiovascular-kidney events compared with 1.38 (95% CI 0.97, 1.98, p=0.075) and 1.06 (95% CI 0.72, 1.57, p=0.752) in the 'bottom-20%-wPRS plus baseline disease duration ≥10 years' group. Common variants of MDG increased risk for YOD and cardiovascular-kidney events.

Clinical Prediction Score of 1-Year Sustained Remission to Methotrexate Combination Therapy in Patients with Early Rheumatoid Arthritis

Objective: To develop a prediction stratification score for the prediction of sustained remission (SR) to methotrexate (MTX) therapy in patients with early rheumatoid arthritis (ERA). Materials and Methods: Prognostic research with clinical prediction score was conducted. All patients with ERA who experienced moderate to high disease activity at a tertiary hospital were included. Multivariable logistic regression models were used to assess each variable predictor. Logistic coefficients of each predictor were used for generating scores. Predictive performance was internally validated using bootstrapping techniques. Results: One hundred seventy-five patients, of which 93 had SR, were included. The prediction score had four final predictors, age less than 65 years (0, 2), initial health assessment questionnaires less than 1 (0, 3), baseline disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) (0, 1), and DAS28-ESR at three months less than 3.2 (0, 5) were included in the logistic model. The positive predictive value for the high-risk score, which was greater than 3.5, was 87 (95% CI 76.7 to 93.9) results used in the model as a clinical predictor of MTX response. The SR score had a good predictive performance (AUROC 0.85, 95% CI 0.80 to 0.90). Conclusion: The SR score demonstrated good performance and discrimination for predicting SR to MTX combination therapy in patients with ERA for a safe long term follow up using simplified parameters in a clinical setting.

Cohort study profile: a cohort of Korean atomic bomb survivors and their offspring.

The Korean Atomic Bomb Survivor Cohort (K-ABC) study was designed to investigate the health impacts of atomic bomb exposure on Korean survivors and to explore whether these effects are passed down genetically to their descendants. This paper outlines the study's design, data collection methods, baseline sociodemographic characteristics, exposure status, and disease prevalence among the participants, based on survey responses and health examinations. From 2020 to 2024, a total of 2,544 individuals, comprising 1,109 atomic bomb survivors (G1), 1,193 children of G1 (G2), and 242 grandchildren of G1 (G3), consented to participate in the study. Of these, 1,828 participants (659 in G1, 927 in G2, and 242 in G3) completed the survey and underwent health examinations, representing a participation rate of 71.9%. Exposure information was gathered using a questionnaire and verified through records from the Korean Red Cross and a handbook issued by the Japanese government. Disease prevalence was determined based on participants' self-reported physician diagnoses. This study presents details about the K-ABC study and provides baseline data on the participants recruited. These data will be valuable for interpreting the results of future K-ABC studies.

Dupilumab Demonstrates a Higher Likelihood of Achieving Improvements in Signs, Symptoms, and Quality of Life vs. Tralokinumab at Week 16: Results from a Bucher Indirect Treatment Comparison

Background: Dupilumab and tralokinumab are biologics approved by the US Food and Drug Administration (FDA) for the treatment of patients with moderate-to-severe atopic dermatitis (AD), aged ≥6 months and ≥12 years, respectively. Dupilumab and tralokinumab have demonstrated efficacy and safety in clinical trials. However, no direct head-to-head trials have been performed to compare the efficacy of dupilumab vs tralokinumab. The Bucher indirect treatment comparison (ITC) is a robust, placebo-adjusted, and accepted method to evaluate the relative efficacy of drugs in the absence of direct comparisons. The objective of this analysis was to report results from a Bucher ITC comparing the efficacy of dupilumab+topical corticosteroid (TCS) vs tralokinumab+TCS at Week 16. Methods: The placebo-adjusted Bucher ITC included published data from the two similarly designed phase 3 trials, LIBERTY AD CHRONOS (NCT02260986) and ECZTRA 3 (NCT03363854). For both studies, data from the 16-week period were used, employing non-responder imputation, with the following doses: 300mg dupilumab every 2 weeks (q2w)+TCS or placebo+TCS, and 300mg tralokinumab q2w+TCS or placebo+TCS. The evaluated endpoints included the proportions of patients achieving an Investigator’s Global Assessment score 0/1 (IGA 0/1; clear/almost clear), 75% and 90% improvements from baseline in Eczema Area and Severity Index (EASI-75 and EASI-90), ≥4-point improvement from baseline in the Peak Pruritus Numerical Rating Scale score (PP-NRS &gt;4), and ≥4-point improvement from baseline in the Dermatology Life Quality Index (DLQI &gt;4). The Bucher ITC with the frequentist approach was performed using R software (v 4.20; netmeta package) with a fixed-effect model. Results were reported as odds ratio (OR) with 95% confidence interval (CI). Results: A total of 801 patients (LIBERTY AD CHRONOS: placebo+TCS: 315; dupilumab+TCS: 106; ECZTRA 3: placebo+TCS: 127; tralokinumab+TCS: 253) were included in the Bucher ITC. Baseline disease characteristics indicated comparable severity between the two trial populations based on IGA and PP-NRS. However, CHRONOS showed slightly higher baseline EASI scores (median [Q1, Q3] score 30.9 [22.3, 41.6] vs. ECZTRA 3: 24.7 [18.4, 35.9]), while ECZTRA 3 showed slightly higher DLQI scores (median [Q1, Q3] score 18.0 [12.0, 23.0] vs. CHRONOS: 13.5 [8.0, 20.0]). Patients treated with dupilumab+TCS had a significantly higher likelihood of achieving IGA 0/1 (OR=2.49, 95%CI 1.24–5.00), EASI-75 (OR=3.21, 95%CI 1.66–6.19), EASI-90 (OR=2.92, 95%CI 1.41–6.02), PP-NRS ≥4 (OR=3.62, 95%CI 1.87–7.00), and DLQI ≥4 (OR=2.16, 95%CI 1.03–4.54) at Week 16 vs those treated with tralokinumab+TCS. Conclusions: A placebo-adjusted Bucher ITC showed that the likelihood of achieving improvements in signs, symptom, and quality of life is significantly higher for patients treated with dupilumab+TCS vs tralokinumab+TCS at Week 16.

Efficacy and Safety of Clindamycin Phosphate 1.2%/Adapalene 0.15%/Benzoyl Peroxide 3.1% Gel: Post Hoc Analysis by Baseline Disease Severity

Introduction: Clindamycin phosphate (CLIN) 1.2%/adapalene (ADAP) 0.15%/benzoyl peroxide (BPO) 3.1% gel (CAB) is the only triple-combination topical treatment approved for acne. These analyses assessed efficacy and safety of CAB gel by baseline acne severity vs component dyads and branded ADAP/BPO gel. Methods: These post hoc analyses used data pooled from two phase 2 and two phase 3, double-blind, 12-week studies (NCT03170388, NCT04892706, NCT04214639, NCT04214652). Eligible participants aged ≥9 years (≥12 years in NCT04892706) were randomized to once-daily CAB or vehicle gel. One phase 2 study included dyad combinations of CAB’s active ingredients: ADAP/BPO, CLIN/BPO, and CLIN/ADAP. The other phase 2 study included a head-to-head comparison of CAB gel and branded ADAP 0.3%/BPO 2.5% gel. Efficacy assessments included least-squares mean percent change from baseline in inflammatory/noninflammatory lesions and treatment success (≥2-grade reduction from baseline in Evaluator’s Global Severity Score [EGSS] and clear/almost clear skin). Safety assessments included treatment-emergent adverse events (TEAEs) and cutaneous safety/tolerability. Participants were categorized by baseline disease severity: moderate (EGSS = 3; n=1557) or severe (EGSS = 4; n=230). Results: After 12 weeks, inflammatory lesion reductions in participants with moderate acne were significantly greater with CAB (77.1%) than vehicle (54.1%; P&lt;0.001), the 3 dyads (range, 64.4-69.4%; P≤0.001, all), and branded ADAP/BPO (72.8%; P&lt;0.05). In the severe group, inflammatory lesion reductions with CAB (74.5%) were significantly greater than vehicle (44.4%; P&lt;0.001) and 2 dyads (ADAP/BPO 63.9%, CLIN/BPO 61.3%; P&lt;0.05), and similar to branded ADAP/BPO and CLIN/ADAP (75.4%/73.7%). Reductions in inflammatory lesions were greater than noninflammatory. Over half of CAB-treated participants with moderate disease achieved treatment success at week 12 (53.9% vs 19.5% vehicle; P&lt;0.001), significantly greater than approximately one-third treated with dyads (range, 31.5-35.3%) or branded ADAP/BPO (38.1%; P≤0.001, all). Only CAB and CLIN/ADAP demonstrated significantly greater treatment success rates than vehicle in participants with severe acne at week 12 (30.9% and 34.0% vs 9.0%, respectively, P&lt;0.05). Across all groups, most TEAEs were of mild to moderate severity. Mean cutaneous safety/tolerability scores were ≤1 (1 = mild) across severity groups. Conclusions: CAB gel demonstrated efficacy and safety in participants with both moderate and severe acne. Acne improvements with CAB were superior to the 3 dyads tested and branded ADAP/BPO in participants with moderate acne and generally numerically greater in participants with severe acne. To our knowledge, these analyses of combination topical acne treatments include data from the only double-blind, vehicle-controlled, head-to-head study to date. Funding: Ortho Dermatologics.

Influence of study characteristics on harm estimates from randomised controlled trials in patients with inflammatory arthritis receiving biological or synthetic antirheumatic drugs: a meta-epidemiological study

ObjectiveTo examine the association between study characteristics and the harms reported in randomised controlled trials (RCTs) on biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients with inflammatory arthritis...

Efficacy of Janus Kinase Inhibitors (JAKi) in the treatment of biologic-naive and biologic-experienced patients with ulcerative colitis

Abstract Introduction Janus kinase inhibitors (JAKi) are an orally available treatment for patients with moderately to severe ulcerative colitis (UC). There are currently 3 JAKi for UC: tofacitinib, filgotinib and upadacitinib with variable selectivity to JAK-11. There is limited data comparing the outcomes between biologic-naive and biologic-experienced patients. This study describes the effectiveness of JAKi according to biologic exposure. Aim To investigate the effectiveness of 3 the JAKi’s, tofacitinib, filgotinib and upadacitinib according to biologic exposure. Method We undertook a retrospective study of UC patients treated with JAKi within a tertiary hospital. Clinical endpoints were assessed at week 8-12. Baseline disease activity, previous advanced therapies and use of corticosteroids were documented. Clinical response was defined as reduction in SCCAI score by ≥3 points from baseline or a sustained score of &amp;lt;2.5. Clinical remission was defined as a SCCAI score of &amp;lt; 2.5, and/ or a calprotectin level of &amp;lt;250 mg/g with a CRP of &amp;lt; 5mg/L. Ethical approval has been granted by HRA and Health and Care Research Wales (HCRW) (REC ref: 24/HRA/1198) Results 52 patients were reviewed at week 8-12 following their first dose. 15, 15 and 22 patients were on tofacitinib, filgotinib, and upadacitinib respectively. 3 (20%) of patient in the tofacitinib group were exposed to at least 3 biologics prior to initiating the JAK Inhibitor, followed by upadacitinib which was 3 (14%) of patients. In the tofacitinib group, most patients were exposed to 2 previous biologics (n=7, 47%), whereas majority of patients on filgotinib and upadacitinib had exposure to 1 previous biologic, 7 (47%) and 8 (36%) patients respectively. For the patient group exposed to 3 or more biologics (n=7, 14%), 100% patients on tofacitinib (n=3) and upadacitinib (n=3) achieved clinical remission by week 8-12, whereas none of the patients on filgotinib achieve clinical remission. In biologic naïve patients, filgotinib demonstrated the greatest improvement in calprotectin score with a reduction in 30% from baseline (n=2, 100%). In patients exposed to ≥3 biologics, upadacitinib achieved higher rates of improvement in faecal calprotectin score (n=2, 100%). Conclusion Our observations suggest that patients exposed to at least 3 biologics, tofacitinib and upadacitinib were the most effective, whereas filgotinib seems to be more effective in biologic naïve patients. Our patient cohort is small. We will continue to collect data and undertake further statistical analysis to examine the significance of the observations and factors associated with effectiveness. Reference 1. Goetsch, A et al. Advances in pharmacotherapy for ulcerative colitis: a focus on JAK1 inhibitors. Expert Opinion on Pharmacotherapy, 2023, 24(7), 849–861.

Real-Life Data of Secukinumab in Patients with Moderate to Severe Plaque Psoriasis, Psoriatic Arthritis, and Ankylosing Spondylitis: Patient Baseline Characteristics Data from the PROMPT Study.

Secukinumab has proven to be effective and safe in psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) in the phase3 studies. However, data on real-world practice is limited. This study is an ongoing, multicenter, 2-year observational study that focuses on patients with moderate to severe plaque PsO, active PsA, or AS receiving secukinumab. The aim of this study is to present baseline data for the entire study population. A total of 127 patients were enrolled, with 101having PsO, 12 with PsA, and 14 with AS. Among the patients, approximately 54.0% were male. The mean body mass index ranged from 25.0 to 27.4kg/m2 across all groups. Patients with PsO had the longest disease duration with an average of 11.0years, followed by AS (3.0years) and PsA (1.0year). Previous biologic therapy was observed in 6.9-8.1% of patients. Baseline disease severity scores revealed moderate to severe disease. In the PsO group, the mean Psoriasis Area and Severity Index score was 16.1. For patients with PsA, the mean Tender Joint Count was 9.1, and the mean Swollen Joint Count was 6.7. In the AS group, the mean Bath Ankylosing Spondylitis Disease Activity Index score was 4.6, and the mean Ankylosing Spondylitis Disease Activity Score was 3.7. The study demonstrates disease durations, disease activity, and treatment history in Thai patients that were generally consistent with previous randomized controlled studies. Long-term data on the efficacy and safety of the treatment will be presented in future publications.

Approaches and processes for paediatric chest X-ray classification used in the SHINE TB treatment-shortening trial.

<sec><title>INTRODUCTION</title>SHINE (Shorter Treatment for Minimal Tuberculosis in Children) was the first Phase 3 paediatric TB treatment-shortening trial. Robust chest X-ray (CXR) classification methods were integral to excluding severe disease for trial eligibility and to retrospectively adjudicating TB status at baseline. We describe and critically evaluate the CXR classification approaches and processes used in the SHINE trial.</sec><sec><title>METHODS</title>Children with non-severe TB were randomised to 4- vs 6-months anti-TB treatment. Radiologically non-severe TB was defined on CXR. CXRs were systematically interpreted by on-site clinicians prospectively for eligibility determination and retrospectively by experts to inform adjudication of baseline TB status and disease severity.</sec><sec><title>RESULTS</title>A screening CXR was successfully obtained from all 1,204 enrolled children; 1,134 CXRs from children with intra-thoracic TB were reviewed by expert readers. Compared with the expert panel, enrolling clinicians classified more CXRs as abnormal and 'typical TB' and all as radiologically non-severe. The expert panel retrospectively classified 71/1,134 (6%) CXRs as severe. Of these, 4 (5.6%) had unfavourable outcomes compared with 34 (3.0%) in the trial overall.</sec><sec><title>DISCUSSION</title>Using CXRs to classify radiological disease severity and inform eligibility decisions in real-time by local enrolling clinicians was feasible and safe in this large paediatric TB trial. Retrospective central expert CXR review was successful. Refinement of the CXR methods for the classification of both disease severity and TB status could support standardised implementation in routine care and research.</sec>.

Real word outcomes of cabozantinib therapy in poorly differentiated thyroid carcinoma.

Poorly differentiated thyroid carcinomas (PDTCs) are rare and aggressive head and neck malignancies with a poor prognosis. Systemic treatment for incurable PDTC consists of multi-kinase inhibitors (MKIs) based on extrapolation from the experience with radioiodine refractory differentiated thyroid cancer (DTC). Cabozantinib is an approved second line MKI therapy for DTC, but there are limited data regarding safety and efficacy of cabozantinib for PDTC. We conducted a single institution, retrospective analysis of patients with PDTC who received cabozantinib in any line of therapy. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the electronic medical record. Median PFS and OS were primary endpoints and estimated using Kaplan-Meier methodology. Seven patients with PDTC who received cabozantinib, were included. 4/7 (57%) patients had a partial response to cabozantinib, while 2/7 (29%) had SD as their best response. Median time on treatment for cabozantinib was 10.53 months. Median PFS from start of cabozantinib was 12.9 months and median OS was 14.21 months. Most adverse events to treatment (5/6) were low grade. Two (29%) patients were alive at date of last follow up. Cabozantinib is an effective and reasonably well-tolerated treatment option for patients with PDTC. Prospective studies are needed to further investigate the role of cabozantinib in the treatment of PDTC, alone and in combination with other agents including checkpoint inhibitors.

Risk-stratified treatment for drug-susceptible pulmonary tuberculosis

The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54–0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07–1.91; extensive disease: HR 2.02, 95%CI 1.07–3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.

A flexible, calibrated transformer-based risk model for prediction of clinical outcomes in patients with heart failure; an open cohort study using linked UK EHR

Abstract Background Numerous risk scores, both uni- and multi-variable, have been developed to conduct prognostication for a range of clinical outcomes in heart failure (HF) patients [1,2]. However, these models provide only modest discrimination and often depend on complex test data (e.g., ejection fraction) collected outside of routine clinical care [2]. Furthermore, transparency in reporting of key individual-level metrics (e.g., precision, recall) is notably lacking. Purpose We developed and validated a novel deep learning model, the second version of the Transformer-based Risk assessment survival model (TRisk2), for 36-month prediction of all-cause mortality, cardiovascular-related mortality, fatal and non-fatal cardiovascular events, and renal outcomes in patients with HF using routine, linked UK electronic health records (EHR) data. Methods An open cohort of 405 thousand patients with HF between 40 and 90 years of age was identified using linked EHR from 1,063 and 355 English general practices, which were used for TRisk2 model development and external validation, respectively. Comparison was conducted against MAGGIC [2], modified for use on routine linked EHR. Additional analyses compared discriminatory performance in other age groups, by sex, and by baseline disease. All analyses were repeated for prediction of cardiovascular-related mortality, fatal and non-fatal cardiovascular events, and renal outcomes. Results TRisk2 demonstrated superior discrimination with Concordance index (C-index) of 0.828; 95% confidence interval (CI): 0.824 to 0.832 for all-cause mortality prediction outperforming MAGGIC. The proposed model’s performance was found to be stable across stratified analyses by sex, age, and baseline disease status. Both models were overall well-calibrated, and TRisk2 demonstrated greater net benefit than MAGGIC across reasonable decision boundaries in decision curve analyses. At exemplar risk threshold of 50% for 36-month prediction, TRisk2 outperformed MAGGIC by 0.08 for both, precision and recall and identified 10% more events. At the same threshold for 12-month prediction, TRisk2 outperformed MAGGIC by 0.14 and 0.26 precision and recall respectively and captured 70% more events. The well-calibrated TRisk2 similarly outperformed MAGGIC in prediction of cardiovascular-related mortality, fatal and non-fatal cardiovascular events, and renal outcomes. Conclusion Utilising solely routine EHR from primary and secondary care, TRisk2 enabled more accurate prediction than MAGGIC with 10-20% gain in C-index across the four outcome investigations. Integration of TRisk2 into routine clinical care could simultaneously eliminate the reliance of complex tests and improve prognostication of key clinical outcomes, thereby refining management of HF.Models' discrimination on four outcomes

Coronary artery disease polygenic risk score in patients undergoing coronary angiography and risk of future revascularization

Abstract Background Coronary artery disease (CAD) polygenic risk score (PRS) is a strong predictor of incident CAD. The role of CAD PRS in patients with known or suspected CAD already presenting for invasive coronary angiography remains poorly understood. Purpose We aimed to (i) study the association between CAD PRS and coronary angiography traits, and (ii) determine whether CAD PRS can predict risk of future revascularization after an initial coronary angiogram. Methods Patients who underwent coronary angiography at a single hospital and were part of its biobank were included in the study. Participants were classified into 3 risk groups based on CAD PRS distribution–low (0-20%), intermediate (21-80%), and high (81-100%)–computed from a recently reported PRS comprised of 1,296,172 variants (GPSMult, PGS003725). Revascularization was defined as a composite of coronary artery bypass graft and percutaneous coronary intervention with a 3-month blocking window after the initial angiogram. Associations between coronary stenosis severity and burden, and CAD PRS were assessed using multinomial logistic regression adjusted for age, sex, and genetic ancestry. The cumulative incidence of revascularization was tested using Fine-Gray regression accounting for competing risk of all-cause mortality and compared across CAD PRS strata by log-rank test. Results Among 3,518 participants (29.90% female, mean age 63.29±12.14 years), 2,568 (73%) had angiographic evidence of CAD – 340 (13.24%) mild, 346 (13.47%) moderate, and 1,882 (73.29%) severe. Out of those with CAD, 844 (32.87%) presented with acute coronary syndromes (ACS) and 1,724 (67.13%) with stable CAD. CAD PRS was strongly associated with angiographic presence of CAD (OR 2.62, 95%CI 2.08-3.29) and this did not differ among patients presenting with ACS vs. stable CAD (Fig1A). The association was weakest for mild CAD (OR 1.14, 95%CI 0.77-1.68) and strongest for severe CAD (OR 3.04, 95%CI 2.40-3.84). Besides severity, CAD PRS was also strongly associated with angiographic burden of CAD with the strongest association observed for presence of left main coronary stenosis (OR 2.63, 95%CI 1.86-3.73). Each standard deviation increase in CAD PRS was associated with a 10-point increase in the Gensini score, a continuous measure of angiographic burden of CAD (p&amp;lt;2e-16) (Fig1B). Over a mean follow-up period of 9.26±5.81 years, 659 (18.73%) patients required revascularization at a mean period of 5.31±4.69 years. Risk of revascularization varied dramatically by CAD PRS; HR was 1.64 (95%CI 1.28-2.10, p=8.7e-5) for high vs. low CAD PRS (Fig2). CAD PRS remained predictive of future revascularization even after adjusting for the angiographic burden of CAD at baseline (HR 1.41, 95%CI 1.09-1.82, p=7.9e-3). Conclusion CAD PRS is strongly associated with severity and burden of CAD assessed on coronary angiography and is predictive of future risk of revascularization even after accounting for baseline disease burden.Figure 1.CAD PRS and angiographic traitsFigure 2.CAD PRS and revascularization

Multi-year recurrent pericarditis disease duration in Italian patients: clinical outcomes after cessation of long-term IL-1 pathway inhibition provide insights for chronic management

Abstract Background Recurrent pericarditis (RP) is a chronic disease mediated by IL-1 often lasting for years, and specific tools to guide treatment duration with IL-1 pathway inhibition at the individual patient (pt) level are limited. The Phase 3 trial RHAPSODY and 2-year long-term extension (LTE) demonstrated that rilonacept reduced risk of recurrence over long-term treatment (1,2). At the conclusion of the LTE, after a median of 28 months of rilonacept treatment (non-US pts), Italian pts returned to standard management because rilonacept was not commercially available. Clinical outcomes after rilonacept cessation and washout were followed to inform disease persistence and time to recurrence. Purpose Multicentric analysis of RP event rates in Italian pts after stopping long-term rilonacept. Methods Clinical records from Italian RHAPSODY pts were examined for the 18-month period post-LTE (To). Primary outcome: pericarditis recurrence (defined by tertiary-center experts as pericarditis pain plus c-reactive protein [CRP] elevation). Secondary outcomes: time to recurrence and proportion of pts requiring re-initiation of IL-1 pathway inhibition. Safety outcomes: serious adverse events (SAEs). Results 17 Italian pts were observed (Table 1). At To, median [Q1-Q3] disease duration (time from index episode) was 48 [41-56] months, during which pts had received a median 28 [27-30] months of continuous rilonacept treatment (all were in Clinical Response, i.e., no pain, normalized CRP, and on rilonacept monotherapy). After rilonacept cessation at To, no pts received prophylactic treatment. 82.4% (14/17) of pts experienced confirmed pericarditis recurrences, with time to recurrence 8 [6-9] weeks. Half of these pts (n=7) were given oral medications (NSAIDS, colchicine [n=3] and/or steroids [n=4], of whom 1 steroid-treated pt failed and resumed IL-1 pathway inhibition). The other half (n=7) resumed IL-1 pathway inhibition directly upon recurrence. The remaining 17.6% (3/17) of pts had no pericarditis recurrences after To and remained off treatment during the observation period. No pts experienced SAEs. Neither recurrence frequency nor time to recurrence was significantly related to baseline disease characteristics or demographics. Conclusions This exploratory analysis shows that in pts with RP of even 4-years’ duration (including a median 28-months’ rilonacept treatment), the 80% recurrence rate after treatment cessation was indicative of severe persistent underlying disease. Time to pericarditis recurrence after rilonacept cessation (median 8 weeks) was consistent with the predicted gradual pharmacokinetic washout and previously-reported 8.6-week time to flare in RHAPSODY (1). Pericarditis recurrences in these pts with long disease duration and systemic inflammation were severe enough to necessitate re-initiation of advanced therapy. Further studies could quantify optimal treatment duration for pts achieving prolonged remission on IL-1 pathway inhibition.

Subgroup results from KARDIA-2: impact of demographic and baseline disease characteristics on zilebesiran response in patients with hypertension uncontrolled by a standard oral antihypertensive

Abstract Background Zilebesiran is an investigational RNA interference therapeutic targeting hepatic angiotensinogen synthesis. In KARDIA-1, a single subcutaneous (SC) dose of zilebesiran monotherapy significantly reduced 24-hr mean ambulatory and office systolic blood pressure (SBP) from baseline to Months 3 and 6 versus placebo. The Phase 2 KARDIA-2 study assessed efficacy and safety of zilebesiran with a standard oral antihypertensive in patients with uncontrolled hypertension. Purpose Uncontrolled hypertension is a leading cause of cardiovascular morbidity and mortality, and medication non-adherence affects blood pressure control. Developing effective, long-lasting treatments is crucial for patients with hypertension uncontrolled by standard therapy. Methods KARDIA-2 enrolled adults with mild-to-moderate hypertension who were untreated or receiving stable therapy with ≤2 antihypertensives. Patients discontinued prior antihypertensive medication and were randomized 10:7:4 to open-label, once-daily oral treatment with 40 mg olmesartan, 5 mg amlodipine, or 2.5 mg indapamide. After ≥4 weeks on protocol-specified medication, patients with a 24-hr mean ambulatory SBP of 130–160 mmHg were randomized 1:1 in a double-blind manner to a single SC dose of zilebesiran 600 mg or placebo as add-on therapy. The primary endpoint was change from baseline to Month 3 in 24-hr mean ambulatory SBP versus placebo for each group. Efficacy and safety were also assessed in pre-specified subgroups: age (&amp;lt;65; ≥65 years), sex, race (Black; other), baseline 24-hr mean ambulatory SBP (&amp;lt;145; ≥145 mmHg), and baseline estimated glomerular filtration rate (≥60; &amp;lt;60 mL/min/1.73m2). Results The primary analysis included 667 patients (median age [range] 59 [27–75] years; 57% male, 28% Black). At Month 3, least-squares mean differences (LSMD) (95% confidence interval [CI]) between zilebesiran and placebo for the olmesartan, amlodipine, and indapamide groups were −4.0 (−7.6, −0.3), −9.7 (−12.9, −6.6), and −12.1 (−16.5, −7.6) mmHg, respectively, for 24-hr mean ambulatory SBP (all p&amp;lt;0.05). LSMD (95% CI) in office SBP for the same groups were −7.0 (−10.4, −3.6), −10.2 (−13.5, −6.9), and −18.5 (−22.8, −14.2) mmHg, respectively, (all p&amp;lt;0.001). SBP reductions were consistent across subgroups, except for a trend towards an attenuated response observed in Black patients (Figs 1, 2). More patients receiving zilebesiran (49–58%) than placebo (39–48%) experienced ≥1 adverse event through Month 6, with low rates of hyperkalaemia, hypotension, or acute kidney injury reported across all groups. Conclusion In KARDIA-2, a single dose of zilebesiran significantly reduced SBP versus placebo at Month 3 on top of a standard oral antihypertensive, with encouraging safety data. SBP reduction was consistent across most subgroups. Treatment with zilebesiran combined with standard antihypertensives may be effective for a broad population of patients with hypertension uncontrolled on monotherapy.