Patient Years Research Articles

534 - Incidence of venous thromboembolic events and atherosclerotic cardiovascular disease risk factors in adolescents and adults with atopic dermatitis in Denmark: a population-based cohort study

Abstract Background Atopic dermatitis (AD) is associated with substantial impairment in quality of life, including sleep disturbances, anxiety, and depression, which may increase the risk of cardiovascular disease (CVD). However, the association between CVD and AD is not well established. Objectives To evaluate incidence rates (IRs) of venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE) in patients with and without AD in a population-based cohort study in Denmark, and to assess IRs of malignancies, major adverse cardiovascular events (MACE), VTE, and the distribution of Atherosclerotic Cardiovascular Disease (ASCVD) risk factors in patients with AD and rheumatoid arthritis (RA) in a nested cohort analysis. Methods Data from all individuals aged ≥12 years (≥18 years in the nested cohort analysis) between January 1, 2000, and December 31, 2018, were extracted from the Danish National Patient Registry. Patients with ≥1 AD diagnosis during the study period were matched on sex and age with 10 individuals from the general population. The nested cohort analysis included patients diagnosed with RA as an additional comparison population. In the overall cohort, IRs of VTE, DVT, and PE were assessed; the nested cohort analysis evaluated the distribution of ASCVD risk factors and incidence of malignancies, MACE, and VTE in patients with and without ASCVD risk factors (age ≥65 years, and history of smoking, coronary artery disease, stroke, DVT, PE, and malignancy). The follow-up period was from the first diagnosis during the study period until the occurrence of death or an endpoint, the first instance of migration, or December 31, 2018. IRs are shown per 100 patient-years (PY) of exposure with 95% confidence intervals. Results The population-based cohort comprised 190,751 patients, including 17,341 patients with AD and 173,410 age- and sex-matched controls. The IR/100 PY of VTE was similar between the AD cohort (0.14 [95% CI, 0.12-0.16]) and the general population (0.11 [0.11-0.12]). The IR/100 PY for VTE was higher in patients with AD aged ≥65 years (0.71 [0.56-0.90]) than the age-matched general population (0.50 [0.46-0.54]) and lower in the younger AD cohorts (12 to <18 years, 0.02 [0.00-0.08]; 18 to <65 years, 0.12 [0.09-0.13]). The IRs/100 PY of DVT and PE were comparable between the AD cohort (DVT, 0.08 [0.06-0.09]; PE, 0.06 [0.05-0.08]) and the general population (DVT, 0.06 [0.06-0.07]; PE, 0.05 [0.05-0.05]).. The nested cohort analysis comprised 195,807 patients, including 13,432 with AD, 48,055 with RA, and 134,320 age- and sex-matched controls. Distribution of risk factors for malignancies (excluding nonmelanoma skin cancer [NMSC]), MACE, and VTE was comparable in the AD cohort and general population, but higher in patients with RA. The IR/100 PY for malignancies (excluding NMSC) was higher in patients with AD with a history of malignancy (11.41 [9.83-13.25]) than those without (0.44 [0.40-0.48]), and in those aged ≥65 years (3.09 [2.75-3.48]) versus <65 years (0.36 [0.33-0.40]). Similarly, the IR/100 PY for MACE was higher in patients with AD aged ≥65 years (2.30 [2.01-2.63]) versus <65 years (0.15 [0.13-0.17]), and patients with a history of ASCVD (5.02 [4.37-5.76]) versus without (0.15 [0.13-0.18]). Patients with AD with a history of VTE (including DVT/PE) and inherited thrombophilia had a greater risk of VTE than patients without these risk factors. Conclusions In these 2 large cohort studies of adults and adolescents with AD, IRs of VTE, DVT, and PE were comparable with the general Danish population. The risk of VTE, malignancy, and MACE was higher in patients with AD with a history of risk factors for ASCVD. This underscores the need for appropriate monitoring and reporting of cardiovascular events in patients with AD, and active management of risk factors with early and effective therapeutic intervention.

533 - Long-term 5-year safety of upadacitinib in moderate-to-severe atopic dermatitis: an integrated analysis including over 7000 patient-years of exposure

Abstract Introduction/Background Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease characterized by intense itch and eczematous skin lesions, impacting individuals at any age. There is a need for AD treatments that provide rapid itch relief and skin clearance that are safe for long-term use. Upadacitinib is a selective, reversible oral Janus kinase 1 (JAK1) inhibitor approved in multiple countries for the treatment of moderate-to-severe AD in adults and adolescents. Objectives We evaluated the long-term safety for up to 5 years of upadacitinib 15 mg and 30 mg use in adolescents and adults with moderate-to-severe AD, based on the results of integrated data from three ongoing global pivotal Phase 3 studies. Materials & Methods The Measure Up 1, Measure Up 2, and AD Up studies are ongoing pivotal Phase 3, randomized, placebo-controlled, multicenter studies evaluating the safety and efficacy of upadacitinib 15 mg and upadacitinib 30 mg in adolescents and adults with moderate-to-severe AD. Patients were randomized 1:1:1 to receive oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily alone (Measure Up 1 and 2) or with concomitant topical corticosteroids (AD Up). At Week 16, patients receiving upadacitinib 15 mg or 30 mg during the double-blinded period continued their assigned treatment in the blinded extension (BE) period, whereas patients receiving placebo were re-randomized 1:1 to receive either upadacitinib 15 mg or 30 mg in the BE period (upadacitinib treatment for up to 260 weeks). Results A total of 2683 patients (2154 adults, 529 adolescents) who received at least 1 dose of upadacitinib (15 mg,1337; 30 mg,1346) were included in the integrated analysis. Treatment-emergent adverse events of special interest (AESI) were analyzed as exposure-adjusted rates per 100 patient-years (PY) for the entire treatment period to adjust for potentially different durations of follow-up. Rates of AESIs were similar at the 1-year analysis and up to 5-year analysis for upadacitinib for: serious infections, 15 mg, 2.3 (1 yr) and 2.2 (5 yrs)/30 mg, 2.8 (1 yr) and 2.6 (5 yrs); opportunistic infections, 15 mg, 1.6 (1 yr) and 1.7 (5 yrs)/30 mg, 1.9 (1 yr) and 2.2 (5 yrs); active tuberculosis, <0.1 at both timepoints for both doses; herpes zoster, 15 mg, 3.5 (1 yr) and 3.1 (5 yrs)/30 mg, 5.2 (1 yr) and 5.5 (5 yrs); non-melanoma skin cancer (NMSC), 15 mg, 0.3 (1 yr) and 0.4 (5 yrs)/30 mg, 0.4 (1 yr) and 0.3 (5 yrs); malignancy excluding NMSC, 15 mg, 0.1 (1 yr) and 0.3 (5 yrs)/30 mg, 0.5 (1 yr) and 0.4 (5 yrs); gastrointestinal perforations, 15 mg, 0 at both time points/30 mg, 0 (1 yr) and <0.1 (5 yrs); adjudicated major adverse cardiovascular events (MACE), 15 mg, 0.1 (1 yr) and 0.2 (5 yrs)/30 mg, <0.1 at both timepoints; adjudicated venous thromboembolic events (VTE), <0.1 for both doses at 1 year and 0.1 for both doses at 5 years. Rates of adverse events leading to death were: 15 mg, 0 (1 yr) and <0.1 (5 yrs)/30 mg, <0.1 at both timepoints. Rates of serious infection at both timepoints and doses remained low (<3.0 E/100PYs). Upadacitinib was well-tolerated by both adults and adolescents. Conclusions The integrated analysis of long-term safety data for up to 5 years indicates that rates of AESIs remained low throughout treatment with upadacitinib 15 mg or 30 mg among adults and adolescents with moderate-to-severe AD. There were no new safety risks. The current safety analysis continues to support a favorable benefit-risk profile of upadacitinib in the treatment of adults and adolescents with moderate-to-severe AD for up to 5 years of treatment, including over 7000 years of patient exposure.

502 - Efficacy and safety of upadacitinib through 140 weeks in adolescents and adults with moderate-to-severe atopic dermatitis: phase 3 randomized clinical trial results

Abstract Introduction & Objectives Upadacitinib (UPA) is an oral Janus kinase 1 (JAK1) inhibitor approved in multiple countries for the treatment of adolescents and adults with moderate-to-severe atopic dermatitis (AD). Here, we present the efficacy and safety of UPA administered over 140 weeks in an ongoing randomized, double-blinded, multicenter phase 3 study (Measure Up 1, NCT03569293). Materials & Methods Patients (12–75 years) with moderate-to-severe AD were randomized 1:1:1 to receive UPA 15 mg (UPA15), UPA 30 mg (UPA30), or placebo (PBO) once daily at baseline. At week 16, PBO-treated patients were re-randomized 1:1 to receive UPA15 (PBO/UPA15) or UPA30 (PBO/UPA30) once daily. Co-primary endpoints were the proportion of patients achieving ≥75% reduction in EASI (EASI 75) from baseline and vIGA-AD of clear (0) or almost clear (1) with ≥2 grades of reduction from baseline (vIGA-AD 0/1) at week 16. A meaningful improvement in itch, defined as a ≥4-point reduction in Worst Pruritus Numeric Rating Scale (ΔWP-NRS≥4), was assessed among patients with baseline WP-NRS≥4. All efficacy endpoints were summarized using the Observed Cases (OC) approach, and no missing data imputation was applied. Safety was assessed by monitoring of serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), and treatment-emergent adverse events of special interest (AESI), which were analysed as exposure-adjusted rates per 100 patient-years (PY). Results Efficacy results were sustained up to week 140 since week 16. Proportions of patients in the UPA15 (205), UPA30 (206), PBO/UPA15 (91), and PBO/UPA30 (94) groups achieving EASI 75 at week 140 were 88.8% (182), 90.3% (186), 83.5% (76), and 89.4% (84), respectively, and for vIGA-AD 0/1 was 63.4% (130), 65.5% (135), 60.4% (55), and 75.5% (71), respectively. Proportions of patients achieving an improvement (reduction) in WP-NRS≥4 from baseline at week 140 were 68.0% (136), 70.5% (146), 71.3% (62), and 81.3% (74) respectively. Overall, the rates of AESIs were similar across treatment groups, which aligned with prior reports at earlier time points. Both UPA15 and UPA30 were well-tolerated in all patients, and no new safety signals were observed compared to the known safety profile of UPA. Data from two additional pivotal studies will be available at the time of presentation. Conclusion In this interim analysis, sustained skin clearance and itch and a consistent safety profile were observed with UPA 15 mg and UPA 30 mg across 140 weeks in adolescent and adult patients with moderate-to-severe AD.

Abstract TMP2: Longitudinal Risk of Seizures in Patients With Brain Arteriovenous Malformations

Objective: To examine longitudinal risk of seizures following diagnosis of brain arteriovenous malformations (bAVM). Methodology: A total of 1178 patients diagnosed with bAVM and enrolled into a prospective cohort study at our institution from 2000-2023 were included. We calculated the incidence rate (IR) of seizures pre- and post-bAVM treatment, censoring at either treatment, death, or last follow-up. Cox regression models tested whether treatment was associated with seizures during follow-up using treatment as a time-varying covariate (no treatment, radiosurgery only, and surgical resection),adjusting for age at diagnosis, prior seizure, prior hemorrhage, bAVM size, and lobar location. Results: The bAVM cohort was 51% female, 29% children (median age 9.5y, range 0-19y), and 71% adults (median age 44.5y, range 20-89y). 290 (25%) presented with seizures that led to bAVM diagnosis; of these, 52 had both acute seizures and hemorrhage at presentation. A total of 72 patients had seizure after diagnosis but before treatment over 2296 patient-years (PY) of follow-up (IR 3.1 per 100 PY, 95% CI: 2.5-4.0). Post-treatment, there were 167 seizures during 4712 PY of follow-up (4.8 per 100 PY, 95% CI: 4.2-5.5). Compared to untreated patients, treated patients were at 2-fold higher risk of seizures during follow-up (Figure) with either radiosurgery (HR=2.3, 95% CI: 1.6-3.2, P<0.001) or surgical resection (HR=1.9, 95% CI: 1.4-2.7, P<0.001). Prior seizures (HR=2.2, 95% CI: 1.6-3.0), lobar location (HR=1.9, 95% CI: 1.2-3.0), and AVM size (HR=1.11, 95% CI: 1.0-1.2) were independent predictors of seizures while prior hemorrhage (P=0.451) and age at diagnosis (P=0.481) were not. Conclusion: Risk of seizure persisted for decades after bAVM diagnosis, but highest in the years following bAVM treatment, independent of prior seizures, age at diagnosis, lobar location, AVM size or prior hemorrhage. This suggests greater attention is needed for seizure management after bAVM treatment.

DOP16 Safety of long-term ozanimod treatment for up to 4 years in patients with moderately to severely active Ulcerative Colitis: an interim analysis of the True North open-label extension

Abstract Background The 52-week, phase 3 True North (TN) study (NCT02435992) demonstrated the efficacy and safety of ozanimod (OZA), a highly selective sphingosine 1-phosphate receptor 1 and 5 modulator, in patients (pts) with moderately to severely active ulcerative colitis (UC). A prior analysis reported the long-term safety of up to 3 y of OZA in the ongoing TN open-label extension (OLE; NCT02531126; from TN baseline to OLE Week [W] 94). This analysis presents the cumulative long-term safety of OZA in TN and the TN OLE for an additional year (up to OLE W142). Methods The TN study design has been previously described. This analysis included all TN pts who entered the OLE from TN (clinical nonresponders at W10, lost response during maintenance, or completed maintenance at W52). Safety assessments were reported from the first dose of OZA either in TN or OLE up to OLE W142. Lab abnormalities, including absolute lymphocyte count (ALC) reductions, were reported. Exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) were calculated for all treatment-emergent adverse events (TEAEs). Results A total of 823 pts entered the TN OLE (average age: 41.7 y; 59% male); 62% had left-sided UC disease. Total PY exposure to OZA at OLE W142 was 2536 y. Overall, the cumulative safety assessments did not significantly change with an additional year of OZA exposure from OLE W94 to W142 (Table). A decrease in EAIRs per 100 PY was observed in overall TEAEs (85.5 vs 87.6) and serious TEAEs (7.0 vs 7.4) at OLE W142 vs OLE W94, respectively. Notably, with an additional year of OZA exposure, TEAEs leading to treatment discontinuation remained at 2.5 EAIR/100 PY, and there were no new cases of bradycardia or atrioventricular block. One new TEAE each of herpes zoster, macular oedema, cystoid macular oedema, myocardial ischaemia, pulmonary embolism, and deep vein thrombosis were noted. COVID-19 TEAEs increased at OLE W142 (n=103; EAIR: 4.3/100 PY) from OLE W94 (n=66; EAIR: 3.0/100 PY). Reductions in ALC <500 cells/mm3 were common in the OLE (OLE W94, 54.0%; OLE W142, 56.1%); few pts had ALC <200 cells/mm3 (OLE W94, 5.3%; OLE W142, 6.5%), but these pts had no serious infections. No serious hepatic safety events were observed. One new death due to adenocarcinoma, which was unrelated to OZA, was reported. Conclusion The ongoing safety profile of OZA is consistent with previous analyses, with no new safety signals identified compared with previous UC analyses. Long-term use of OZA representing 2536 PYs of exposure continues to be well tolerated in pts with moderately to severely active UC.

P1008 Efficacy and safety of retreatment with upadacitinib after treatment interruption in ulcerative colitis: Data from the phase 3 open-label extension study U-ACTIVATE

Abstract Background Upadacitinib (UPA) is an oral reversible Janus kinase (JAK) inhibitor designed to preferentially inhibit JAK1 approved for the treatment of moderately to severely active ulcerative colitis (UC). UPA may be temporarily discontinued for many reasons including adverse events (AEs) and lack of efficacy.1 As clinical consequences of discontinuing and restarting UPA are yet to be characterised, here, we assess the efficacy and safety of UPA retreatment in patients (pts) who lost response following UPA treatment withdrawal. Methods Pts with a clinical response to 8 weeks’ (wks) UPA 45 mg once daily (QD; UPA45) induction therapy in the Phase 3 U-ACHIEVE or U-ACCOMPLISH studies were re-randomised to placebo (PBO), UPA 15 mg QD (UPA15) or UPA 30 mg QD (UPA30) for the 52-wk maintenance phase of U-ACHIEVE. Pts randomised to PBO who lost response could enter the long-term extension (LTE), U-ACTIVATE, and be retreated with UPA15. Efficacy was analysed (i) at wk 4 of the LTE and (ii) at wk 48 of the LTE among pts with an inadequate response to UPA15 who dose escalated to UPA30 between wks 2 and 36. Exposure-adjusted event rates (EAERs) of treatment-emergent AE (TEAE) were assessed throughout. Results Of 223 pts with a clinical response to UPA45 induction randomised to PBO during maintenance, 112 (50.2%) lost response (mean [standard deviation (SD)] days to loss of response: 135.4 [84.6]) and 110 subsequently entered the LTE. Pts with loss of response vs those without were more likely to have a history of inadequate response, loss of response, or intolerance to ≥1 biologic (57.1% vs 46.8%, respectively) or corticosteroid use at baseline (42.0% vs 33.3%). After 4 wks of retreatment with UPA15, 75/108 (69.4%) and 39/108 (36.1%) pts achieved clinical response and remission, respectively (Figure A). In total, 38 (34.5%) pts dose escalated to UPA30 (mean [SD] days to escalation: 80.3 [57.8]); 30/31 (96.8%) and 22/31 (71.0%) achieved clinical response and remission at wk 48 of retreatment, respectively (Figure B). For safety during maintenance, 225 pts with 128.7 patient-years (PYs) of exposure (loss of response [n=112], 42.6 PYs; no loss of response [n=113], 86.1 PYs) were analysed. Generally, the EAERs of serious TEAEs were numerically lower in patients with vs without loss of response. However, patient years of exposure were low, restricting interpretation. During the LTE, EAERs were generally similar in pts who underwent dose escalation vs all pts. Conclusion In pts who experience loss of response following UPA withdrawal, efficacy can be recaptured following retreatment with UPA15 and UPA30. No new safety signals were identified. Reference 1. Sandborn WJ, et al. Gastroenterology. 2020;158(8):2139−2149.e14.

P763 Rare and severe adverse events in pediatric inflammatory bowel disease: identification of safety signals through the international prospective PIBD-SETQuality Safety Registry

Abstract Background Rare but severe adverse events (AEs) can occur in pediatric inflammatory bowel disease (PIBD) due to ongoing inflammation, secondary to immunosuppressive drugs or as coincidental finding. These events can lead to significant disability or even death. Limited prospective research hampers the understanding of the incidences, risk factors, and outcomes associated with these events. Methods As part of the ongoing international PIBD-SETQuality Safety Registry, participating pediatric gastroenterologists prospectively reported the occurrence of any of 10 listed rare and severe AEs in their PIBD patient population (<19 years) via monthly electronic surveys since October 2016. Additionally, physicians could report ‘other rare and severe AEs’. Participants received an annual denominator survey, to report the number of PIBD patients under their care. Incidence rates (IRs) were calculated for each AE using Poisson regression models and were compared between countries. Upon reporting AEs, participants received specific follow-up forms to collect patient and IBD characteristics, as well as complication details (diagnosis, risk factors, management, outcome). Results Over a 77-month study period (October 2016 to April 2023), 222 pediatric gastroenterologists from 167 centers across 36 countries actively contributed to the registry, completing 7,975 monthly surveys with a median response rate of 86% [IQR 82%-88%]. On average, participants contributed for 53 months [IQR 25-72]. They covered 30,192 PIBD patients, with 114,528 patient-years (PY) of follow-up. In total, 285 listed complications were reported, alongside 117 uncategorized ‘other rare and severe AEs’. The highest IRs (95%CI) per 10,000 PY were found for VTE (IR 5.50 [2.74-4.99]), renal failure (IR 3.67 [2.67-4.89]), opportunistic infections (IR 2.88 [2.01-3.98]), and cancer (IR 2.71 [1.86-3.77]) (Figure 1). The lowest IRs (95%CI) per 10,000 PY were found for liver failure (IR 0.35 [0.11-0.81]) and HLH (IR 0.52 [0.21-1.06]). Combined IRs of the listed AEs did not differ among the five countries with the highest contribution of PY (p=0.18). Conclusion Through international collaboration among a large network of PIBD specialists, the Safety Registry has confirmed the increased incidence of several AEs in PIBD, including VTE, cancer and renal failure. Clinical characterization of these events may lead to a better understanding of their underlying etiologies and outcomes. This improves patient care by providing guidance for management development, facilitating well informed clinical decision making and may lead to prevention of these rare and severe events.

Non-serious adverse events in patients with ulcerative colitis receiving etrasimod: an analysis of the phase II OASIS and phase III ELEVATE UC 52 and ELEVATE UC 12 clinical trials.

Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). It is known that non-serious treatment-emergent adverse events (TEAEs) may not lead to UC drug discontinuation but can affect treatment tolerability. This post hoc analysis evaluated the incidence of specific, common, non-serious TEAEs reported in the etrasimod UC clinical programme and the characteristics of affected patients. Data included patients from the Placebo-controlled UC cohort (phase II OASIS, and phase III ELEVATE UC 52 and ELEVATE UC 12 trials) receiving QD etrasimod (2 or 1 mg) or placebo. Proportions and incidence rates (IRs; the number of patients with a TEAE divided by the total exposure in patient-years (PYs), per 100 PY) of Headache, Pyrexia, Nausea and Dizziness TEAEs were reported. Changes in heart rate among patients with Dizziness TEAEs were also evaluated. Among 943 patients (etrasimod 2 mg, N = 577 (276.7 PY); etrasimod 1 mg, N = 52 (11.4 PY); placebo, N = 314 (115.1 PY)), 48, 34, 27 and 21 patients experienced events of Headache, Pyrexia, Nausea and Dizziness, respectively. All events were non-serious; one patient treated with etrasimod was discontinued due to a Pyrexia TEAE. Numerically, IRs of Headache and Dizziness TEAEs were higher, and Nausea slightly higher, with etrasimod versus placebo (13.45 vs 8.63 per 100 PY, 6.52 vs 1.69 and 7.18 vs 5.13 per 100 PY, respectively); IRs were similar for Pyrexia. The duration of most TEAEs was 1-10 days. In the etrasimod UC clinical programme, all Headache, Pyrexia, Nausea and Dizziness events were non-serious. Headache and Dizziness were more frequent, and Nausea slightly more frequent, among patients receiving etrasimod versus placebo. The post hoc nature of this analysis is a limitation. These results reiterate the favourable safety profile and tolerability of etrasimod. ClinicalTrials.gov: NCT02447302; NCT03945188; NCT03996369.

Long-Term Safety of Dupilumab in Patients With Moderate-to-Severe Asthma: TRAVERSE Continuation Study

Previous clinical trials have demonstrated dupilumab efficacy and safety in adults and adolescents with moderate to severe asthma for up to 3 years. The TRAVERSE continuation study (NCT03620747), a single-arm, open-label study, assessed safety and tolerability of dupilumab 300 mg every 2 weeks up to an additional 144 weeks (∼3 years) in patients with moderate to severe asthma who previously completed TRAVERSE (NCT02134028). Primary end points were incidence and event rates per 100 patient-years of treatment-emergent adverse events (TEAEs). Secondary end points included adverse events (AEs) of special interest, serious AEs, and AEs leading to study discontinuation. A total of 393 patients participated in the TRAVERSE continuation study (cumulative dupilumab exposure, 431.7 patient-years; median treatment duration, 309 days). A total of 29 patients (7.4%) received more than 958 days of treatment. A total of 214 (54.5%) patients reported at least 1 TEAE (event rate: 171.4); 37 (9.4%) experienced at least 1 treatment-related TEAE, none of which were considered severe; 2 patients reported 6 TEAEs of moderate intensity. A total of 22 (5.6%) patients reported serious AEs (event rate: 6.9). AEs of special interest were reported in 24 patients (6.1%; event rate: 6.0). Five (1.3%) deaths occurred (event rate: 1.2) following serious AEs of coronavirus disease 2019 (COVID-19)-related pneumonia (3 patients), pancreatitis (1 patient), and pulmonary embolism (1 patient). None of the TEAEs leading to death were considered treatment-related. Dupilumab treatment was well tolerated for up to an additional 3 years. Safety findings were consistent with the known safety profile of dupilumab. These findings further support the long-term use of dupilumab in patients with moderate to severe asthma.

Sex differences in adverse events from systemic treatments for psoriasis: A decade of insights from the Swiss Psoriasis Registry (SDNTT).

Psoriasis is a disease that often requires prolonged systemic treatment. It is important to determine the safety of available therapies. There is currently little insight into sex-specific differences in the safety of systemic psoriasis therapies. To examine the real-world, long-term safety of systemic psoriasis therapies with sex stratification in drug-related adverse events (ADRs). Ten-year data from adults with moderate-to-severe psoriasis requiring systemic treatment (conventional systemic therapies [CST], biologics) were obtained from the Swiss psoriasis registry (SDNTT). ADRs were categorized according to the international terminology Medical Dictionary for Regulatory Activities (MedDRA). Safety was assessed by calculating event rates per 100 patient-years (PY). We used descriptive statistics for patient and disease characteristics, and binomial and t-tests to compare treatment groups and sex. In total, 791 patients (290 females) were included with a mean age of 46 years. 358 (45%) received CSTs and 433 (55%) biologics; both groups had similar baseline characteristics except for more joint involvement in patients using biologics (26.86% vs. 14.8%, p < 0.0001). CSTs were associated with a 2.2-fold higher ADR rate (40.43/100 PY vs. 18.22/100 PY, p < 0.0001) and an 8.0-fold higher drug-related discontinuation rate than biologics (0.16/PY vs. 0.02/PY, p < 0.0001). Trends showed non-significant higher serious adverse event rates per 100 PY for biologics (8.19, CI 6.87-9.68) compared to CSTs (7.08, CI 5.39-9.13) (p = 0.3922). Sex stratification revealed a significantly higher overall ADR rate for all treatments in females (1.8-fold for CSTs [57.30/100 PY vs. 31.69/100 PY] and 2.0-fold for biologics [27.36/100 PY vs. 13.9/100 PY], p < 0.0001), and drug-related discontinuation rates for most CSTs in females. Females were associated with a significantly higher rate of ADRs and drug-related discontinuation rates. Sex stratification should be taken into consideration when designing studies in the patient-tailored management of psoriasis.

Recurrent heart failure hospitalizations in heart failure with preserved ejection fraction: an analysis of TOPCAT trial.

Recurrent heart failure hospitalization (HFH) is an important feature of the progression of heart failure (HF). In the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, we analysed risk factors for recurrent HFH events in HF patients with preserved ejection fraction (HFpEF) and developed a risk prediction model for recurrent HFH. This analysis focused on the subset of TOPCAT participants enrolled in the Americas (n=1767). Recurrent HFH was defined as two or more hospitalizations for HF during the follow-up period. Lasso regression and multivariate logistic regression were used to screen the risk factors, and the risk prediction model of recurrent HFH was established. During a median follow-up period of 3.4 (95% confidence interval: 3.3-3.6) years, 72.2% (542 of 751 total hospitalizations) of HFH events occurred in 9.4% (n=163) of patients with recurrent HFHs. Patients in the recurrent HFH group had higher cardiovascular mortality rate [6.2 per 100 patient-years (PY) vs. 3.8 per 100 PY, P=0.016] and all-cause mortality rate (10.0 per 100 PY vs. 6.8 per 100 PY, P=0.015) than those in the non-recurrent HFH group. The model consisting of nine predictors has moderate predictive power for recurrent HFH events in patients with HFpEF (AUC=0.75, Brier score=0.08). Decision curve analysis showed a net clinical benefit from the application of the prediction model. In patients with HFpEF, the majority of HFHs occur in a small proportion of patients with repeated hospitalizations, who typically have more comorbidities and are at higher risk of death. The predictive model developed in this study helps to identify patients at high risk of recurrent HFH.

Predictive models for hepatocellular carcinoma development after sustained virological response in advanced hepatitis C

Background & aimsLife-long hepatocellular carcinoma (HCC) surveillance is recommended after sustained virological response (SVR) in patients with advanced hepatitis C. Since the identification of patients who could be safely discontinued for surveillance is essential, we aimed to identify subsets of patients with low-risk HCC. Methods491 patients with advanced and compensated fibrosis (≥F3) were prospectively followed after achieving SVR with interferon-free therapies. Clinical–biological parameters and liver stiffness measurement (LSM) were performed before starting treatment (ST) and at SVR, and HCC surveillance was carried out. ResultsDuring a median follow-up of 49.8 months, 29 (5.9%) patients developed HCC [incidence rate: 1.6/100 patient-years (PYs)]. Two predictive models based on LSM (Model-A) or FIB-4 score (Model-B) were proposed. Only SVR parameters were included in the models, because they showed a higher accuracy for predicting HCC than ST measurements. Variables independently associated with HCC were LSM (HR, 1.03; 95% CI, 1.01–1.05), age (HR, 1.04; 95% CI, 1.01–1.08) and albumin levels (HR, 0.90; 95% CI, 0.84–0.97) in Model-A, and FIB-4 (HR, 1.22; 95% CI, 1.08–1.37) and albumin (HR, 0.90; 95% CI, 0.84–0.97) in model-B. Both models allow HCC risk stratification, identifying low-risk groups with an HCC incidence rate of 0.16/100 and 0.25/100 PYs, respectively. An overall increased hazard of HCC was observed over time. ConclusionSimple models based on non-invasive markers of liver fibrosis, LSM or FIB-4, together with age and albumin levels at SVR permit to identify subsets of patients with HCC risk clearly <1%/year, for whom HCC surveillance might not be cost-effective.

Short-term risk and long-term incidence rate of infection and malignancy with IL-17 and IL-23 inhibitors in adult patients with psoriasis and psoriatic arthritis: a systematic review and meta-analysis.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022363127.

Prevalence of Second Cancers in Patients with Polycythemia Vera (PV): A Retrospective Analysis of US Real-World Claims Data

Background:Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) associated with risk of leukemic or fibrotic progression (Tefferi and Barbui. Am J Hematol. 2017;92;94-108). In addition to the known risk of disease transformation, patients with MPNs have a 60% higher risk of developing second non-hematologic cancers compared to matched controls. Skin cancers are among the most prevalent second cancers, with a reported 2.8-fold increase in risk of non-melanoma skin cancer (NMSC) (Landtblom et al., Leukemia. 2018;32:2203-10). The inherent risk associated with MPNs is exacerbated by cytoreductive treatments, as patients treated with hydroxyurea (HU) were found to have a two-fold higher risk of NMSC compared to patients who were not treated with HU (Barbui et al., Leukemia. 2019;33:1996-2005). Previous studies examined fewer than 2000 patients; the study populations may have included patients with other MPNs and PV. Our objective was to evaluate the frequency of second cancers in patients with a primary PV diagnosis who were treated with HU compared to phlebotomy only using a large US real-world claims database. Methods:This real-world, retrospective cohort study used Optum's deidentified Market Clarity Data consisting of electronic health records (EHR) on 105 million US patients and linked medical and prescription claims between 1/1/2007 to 12/31/2019. More than 82,000 patients with ≥1 PV diagnosis at any time were identified within the extracted dataset. For this analysis, eligible patients were ≥18 years old and required ≥2 PV diagnosis codes with ≥60 days between the first and last diagnosis code in the data period. Patients were indexed at the first diagnosis code of PV preceded by ≥1 year of EHR data (“index”) and required ≥1 year of post-index data or death prior to data period end. Patients with a pre-index diagnosis of secondary polycythemia, leukemia, myelodysplastic syndrome, myelofibrosis, or stem cell transplant were excluded. Second cancers were identified at first occurrence of a diagnosis code for a defined cancer in EHR during specified time periods. Analysis of post-treatment cancer rates used a subset of patients with pre-index medication data and excluded cancer types identified prior to treatment. Results:The total study cohort included 20,089 patients with PV (mean age, 63.0 years; 57.8% male; 88.6% Caucasian). Some patients (15.5%; n=3112) had evidence of a pre-index cancer. Median duration of follow-up was 4.3 years (IQR, 2.4-5.9). Among the total cohort, 35.7% (7181 patients) reported at least one second cancer in the post-index period (“post-index period prevalence”). The rate of second cancers in the post-index period was 109.7 events per 1000 patient years (PY). The most common non-hematologic malignancies were skin cancers (22.1/1000 PY) followed by prostate cancer (8.1/1000 PY) and breast cancer (6.7/1000 PY) (Figure 1). Within the total cohort, 9.1% (1830 patients) reported at least one skin cancer in the post-index period, with 8.3% (1659 patients) experiencing NMSC and 1.4% (286 patients) experiencing melanoma (Figure 1). The post-index period prevalence rate of NMSC was 6 times higher vs. the rate of melanoma (19.8 vs. 3.3/1000 PY). Among NMSCs, the rate of basal cell carcinoma was higher than the rate of squamous cell carcinoma (8.7 vs. 6.9/1000 PY). However, the highest rate was observed for non-specific or unspecified malignant neoplasms (8.9/1000 PY). Within a subset of 17,402 patients with pre-index medication data, 20.2% (n=3512) were exposed to at least 4 weeks of HU (without ruxolitinib) at any time; 19.0% (n=3314) were treated with phlebotomy (PHL) only. The rate of any second malignancy subsequent to treatment was &amp;gt;2.5-times higher in the HU vs. PHL group (140.4 vs. 55.3/1000 PY) (Table 1). Rates of skin cancers were nearly two times higher in the HU vs. PHL group for any skin cancer (31.6 vs. 17.7/1000 PY), NMSC (28.9 vs. 15.7/1000 PY), and melanoma (4.5 vs. 2.9/1000 PY). Conclusion:To our knowledge, this is the largest retrospective study evaluating the frequency of second cancers in a cohort of US patients with PV to-date. We found that patients with PV had high rates of malignancies associated with their primary PV diagnosis. The highest rates were observed for skin cancers, driven by the frequency of NMSC. Patients treated with HU had nearly twice the rate of skin cancers (including NMSC and melanoma) compared to PHL-only treated patients.

Outcomes of Children with Sickle Cell Disease Born Outside Belgium Remain Different Compared to Those Born in Belgium Despite Similar Management

Sickle cell disease (SCD) is characterised by a multitude of phenotypic expressions that are influenced by the environment and genetics. The only well-established treatments are infection prevention, hydroxyurea (HU), chronic transfusions, and hematopoietic stem-cell transplantation (HSCT). Early strategies facilitated by neonatal screening programmes improve morbidity and mortality. In the context of an increasingly multiethnic society, not all our patients benefit from early intervention. This study aims to evaluate the overall outcomes of children with SCD born in Belgium (BiB) compared to those born outside Belgium (BoB) and receiving the same treatment upon arrival in Belgium. This cohort study is based on anonymized data extracted from the Belgian National Sickle Cell Registry (BNSCR). Prospective data were collected from the date of diagnosis (start of follow-up (FU) for BoB) until the last FU visit or death. Were included in this study: all SCD children born between 01.01.2000 and 31.12.2018, followed at the Hôpital Universitaire des Enfants Reine Fabiola till 31.12.2020 and registered in the BNSCR. Clinical and hematological data are compared between both groups. A total of 245 patients were identified, of which 186 BiB and 59 BoB (all born in Africa). No statistically significant differences were found in terms of sex, parents' origin and genotype between the two groups. The median age at diagnosis/start FU was significantly higher in BoB-patients while the median duration of FU was not statistically different in both groups. Expressed by 100 patient-years (PY), the rate of vaso-occlusive crises (VOC) was significantly higher in BoB-patients while the rate of acute chest syndrome was not (Table 1). BoB had significantly less acute anemic episodes and a trend toward less splenic sequestration. The rate of severe infections, stroke and death was similar in both groups (Table 1). At start of FU, BoB patients had a significantly higher neutrophil count (PMN) and lower fetal hemoglobin (HbF) while other hematological parameters didn't differ from BiB The prescribed rate of HU and the rate of HSCT was similar in both groups. However, BoB-patients were significantly older at the start of HU treatment or at the time of the HSCT (Table 1). Hematological values between BoB and BiB-patients after HU did not differ. Nevertheless, PMN and Hb levels seem to be higher in BoB-patients without reaching statistical significance (Table 2). BoB-patients have a median delay of 2 years to access to a comprehensive care program dedicated to SCD. At the same time, this group is 1.5-fold as likely to develop a VOC during FU. No clear explanation exists, but the start of HU at an older age might have an impact with reduced HbF response at distance of the physiological switch of Hb as observed in the BoB-group. In addition, children born in Africa are submitted to a different environment with a higher inflammatory burden as suggested by their higher PMN count at diagnosis. So far, the impact of early inflammation on the long-term outcome is not known and need to be investigated. These points could not be evaluated in this study. The BoB-group's lower rate of acute anemia and splenic sequestration is explained by the older age at start of FU as these potentially lethal complications occur in very young children and could not be recorded from birth of the BoB-group. This also raises the question of the bias presented by our BoB-patients as they don't represent the SCD population from the country they originate: 1) they survived infancy and early childhood, 2) they come from families economically privileged enough to finance the travel to Belgium. In conclusion, the outcomes between BiB and BoB-patients remain different even though the latter benefits from the same comprehensive care. It would be interesting to explore whether a deeper understanding of the underlying physiopathology in terms of genetics, inflammation/immunity, and nutritional status, could clarify the differences observed between our groups. A longer FU of the Registry will help enhance our findings.

Bimekizumab safety in patients with moderate-to-severe plaque psoriasis: pooled data from up to 3 years of treatment in randomized phase III trials.

Patients with psoriasis require long-term management; therefore, understanding the long-term safety of new treatments, such as bimekizumab (BKZ), is crucial. To evaluate BKZ's 3-year safety profile in patients with moderate-to-severe plaque psoriasis. Three years of safety data were pooled from three phase III trials (BE VIVID, BE READY and BE SURE) and their ongoing open-label extension (BE BRIGHT). Treatment-emergent adverse events (TEAEs) are reported using exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY). In total, 1495 patients received at least one BKZ dose; total BKZ exposure was 3876.4 PY. The overall EAIR of TEAEs was 175.5/100 PY and decreased with longer exposure to BKZ. The most commonly reported TEAEs were nasopharyngitis, oral candidiasis and upper respiratory tract infection (EAIRs of 15.0/100 PY, 10.1/100 PY and 6.5/100 PY, respectively); 99.3% of oral candidiasis events were mild or moderate in severity, none were serious and few led to discontinuation. EAIRs of other TEAEs of interest were low, including serious infections (1.2/100 PY), adjudicated inflammatory bowel disease (0.2/100 PY) and laboratory elevations in aspartate aminotransferase or alanine aminotransferase (> 5 × upper limit of normal: 0.6/100 PY). In these analyses pooled across 3 years, no new safety signals were observed with longer exposure to BKZ. The vast majority of oral candidiasis events were mild or moderate in severity, as reported previously.

Long-term trends in hepatitis C prevalence, treatment uptake and liver-related events in the Swiss HIV Cohort Study.

Treatment for chronic hepatitis C virus (HCV) infections changed dramatically in the last decade. We assessed changes in the prevalence of replicating HCV infection, treatment uptake and liver-related morbidity and mortality in persons with HIV (PWH) and hepatitis C in the Swiss HIV cohort study. We included all cohort participants between 2002 and 2021. We assessed yearly prevalence of replicating HCV infection, overall and liver-related mortality, as well as the yearly incidence of liver-related events in persons with at least one documented positive HCV-RNA. Of 14 652 participants under follow-up, 2294 had at least one positive HCV-RNA measurement. Of those, 1316 (57%) ever received an HCV treatment. Treatment uptake increased from 8.1% in 2002 to a maximum of 32.6% in 2016. Overall, prevalence of replicating HCV infection declined from 16.5% in 2004 to 1.3% in 2021. HCV prevalence declined from 63.2% to 7.1% in persons who inject drugs, and from 4.1% to 0.6% in men who have sex with men. Among the 2294 persons with replicating HCV infection, overall mortality declined from a maximum of 3.3 per 100 patient-years (PY) to 1.1 per 100 PY, and incidence of liver-related events decreased from 1.4/100 PY to 0.2/100 PY. The introduction of DAA therapy was associated with a more than 10-fold reduction in prevalence of replicating HCV infection in PWH, approaching the estimates in the general population. Overall mortality and liver-related events declined substantially in persons living with HIV and hepatitis C.

Safety of JAK and IL-6 inhibitors in patients with rheumatoid arthritis: a multicenter cohort study.

The ORAL Surveillance trial showed a potentially higher incidence of malignancy and major adverse cardiovascular events (MACEs) associated with tofacitinib than those associated with tumor necrosis factor (TNF) inhibitors (TNFis). However, few studies have compared the safety of non-TNFis or other Janus kinase (JAK) inhibitors (JAKis). This study was aimed at comparing the incidence rates (IRs) of malignancies and MACEs in patients with rheumatoid arthritis (RA) treated using interleukin-6 (IL-6) inhibitors (IL-6is) or JAKis. We retrospectively analyzed 427 patients with RA who were treated using an IL-6i (n = 273) or a JAKi (n = 154). We determined the IRs of malignancy and MACEs, and the standardized incidence ratio (SIR) of malignancies and investigated factors related to malignancy and MACEs. After adjusting the clinical characteristic imbalance by propensity score matching (PSM), we compared the IRs of adverse events between the JAKi and IL-6i groups. After PSM, the observational period was determined to be 605.27 patient-years (PY), and the median observational period was determined to be 2.28 years. We identified seven cases of malignancy (IR: 2.94 per 100 PY) in the JAKi-treated group and five cases (IR: 1.36 per 100 PY) in the IL-6i-treated group after PSM. The IR of MACEs was 2.56 and 0.83 (per 100 PY) in the JAKi- and IL-6i-treated groups. The IRRs of JAKi-treated patients versus IL-6i-treated patients were 2.13 (95% confidence interval (CI): 0.67-7.42) for malignancy and 3.03 (95% CI: 0.77-15.21) for MACE. There were no significant differences in IRR for malignancy and MACE between both groups after PSM. Univariate and multivariable Cox regression analyses revealed that older age and JAKi use were independent risk factors for malignancy, while older age, hypertension, and JAKi use were independent risk factors for MACEs. The overall malignancy SIR was significantly higher in the JAKi-treated group compared to the general population (2.10/100 PY, 95% CI: 1.23-2.97). The IRs of malignancy and MACE in patients with RA after PSM were comparable between IL-6i-treated and JAKi-treated patients. However, the SIR of malignancy in JAKi treatment was significantly higher than in the general population; therefore, further safety studies comparing JAKi to non-TNFi biologic disease-modifying antirheumatic drugs (bDMARDs) are needed.

Safety and Effectiveness of Baricitinib in Chinese Patients with Moderate-to-Severe Rheumatoid Arthritis: 24-Week Results from a Post-Marketing Safety Study.

Baricitinib, a JAK1/JAK2 inhibitor, is approved for treatment of moderate-to-severe rheumatoid arthritis (RA) in China. This single-arm, prospective, multi-center, post-marketing safety study (PMSS) evaluated the safety and effectiveness of baricitinib in Chinese patients. This study included adult patients with moderate-to-severe active RA who received baricitinib over periods of approximately 12 and 24 weeks. The primary endpoint was safety, defined as week 12 adverse event (AE)/serious AE incidence. Secondary endpoints were week 24 safety and effectiveness (disease activity score with 28 joints/C-reactive protein [DAS28-CRP] and simplified/Clinical Disease Activity Index [SDAI/CDAI]). Safety analyses included 667 patients (female, 82.3%; mean age, 53.3years; mean RA duration, 86.9months); 106/667 (15.9%) were 65-74years old and 19/667 (2.8%) were ≥ 75years old; 87.0% received baricitinib 2mg QD. Total exposure was 262.1 patient-years (PY). At week 12, AEs had occurred in 214 (32.1%; exposure-adjusted incidence rate [EAIR], 172.5 per 100PY) patients (serious AEs: 22 [3.3%; EAIR, 15.0]). At week 24, AEs had occurred in 250 (37.5%; EAIR, 125.9) patients (serious AEs: 28 [4.2%; EAIR, 10.9]). Two patients (0.3%) died (of pneumonia and unknown cause); EAIR for death, 0.77. Serious infection occurred in 1.2% of patients (EAIR, 3.1). Hepatotoxicity occurred in 3.4% of patients (EAIR, 9.0). No patients met potential Hy's law laboratory criteria (alanine/aspartate aminotransferases ≥ 3 × upper limit of normal (ULN) and total bilirubin ≥ 2 × ULN). Malignancy occurred in one patient. No patients experienced venous thromboembolism (VTE) or major adverse cardiovascular events (MACE). At week 24, 52.4%, 27.5%, and 27.6% of patients achieved remission per DAS28-CRP, SDAI, and CDAI, respectively. This PMSS investigated the safety and effectiveness of baricitinib in clinical practice in China. No VTE/MACE or new safety signals were reported and there was promising effectiveness, supporting the use of baricitinib in Chinese patients with moderate-to-severe active RA. EU PAS Register: EUPAS34213.

Five-year Maintenance of Clinical Response and Consistent Safety Profile for Guselkumab in Asian patients with Psoriasis from VOYAGE 1 and VOYAGE 2.

Guselkumab is a human monoclonal antibody against IL-23 used in the treatment of moderate-to-severe psoriasis. This post-hoc analysis evaluated the efficacy and safety of guselkumab in the Asian subpopulation of VOYAGE 1 and VOYAGE 2 through 5years. The proportions of guselkumab-treated Asian patients (VOYAGE 1 and 2) achieving Psoriasis Area and Severity Index (PASI) 90 and PASI 100, Investigator's Global Assessment (IGA) scores of 0/1 and 0, and Dermatology Life Quality Index (DLQI) scores of 0/1 (week 100 through week 252) were assessed. Non-responders were patients who met the treatment failure rules. Efficacy endpoints were analyzed using the as-observed methodology (no missing data imputation) for both studies and using non-responder imputation (for patients with any missing data) in VOYAGE 1. Safety outcomes were based on pooled data through week 252. Response rates through week 252 for 199 Asian patients in the guselkumab group in VOYAGE 1 and VOYAGE 2, respectively, were 76.8% and 80.6% (PASI 90), 26.8% and 38.7% (PASI 100), 64.3% and 87.1% (IGA 0/1), and 26.8% and 45.2% (IGA 0). DLQI (0/1) at week 252 was achieved by 52.7% of patients in VOYAGE 1 and 61.3% in VOYAGE 2, while DLQI (0) at week 252 was achieved by 32.7% of patients in VOYAGE 1 and 40.3% in VOYAGE 2. The safety profile was similar to the global population and remained consistent through 5years. Asian patients were followed for a total of 814 patient-years (PY). Over 85% of the guselkumab-treated patients continued treatment through week 264. The rate of serious adverse events (AEs) at week 252 was 3.07/100 PY. Rates of AEs of interest were low: serious infections, 0.74/100 PY; nonmelanoma skin cancer (NMSC), no patients; malignancies other than NMSC, 0.12/100 PY; and no major adverse cardiovascular events (MACE). These analyses confirm a continuous response over 5years, indicating that guselkumab shows therapeutic longevity in Asian patients requiring long-term treatment for moderate-to-severe psoriasis. ClinicalTrials.gov identifiers: VOYAGE 1 [NCT02207231] and VOYAGE 2 [NCT02207244].