Rates Of Serious Infections Research Articles

The reused-disposable scope in flexible ureteroscopy for stones as a cost-conscious approach: Reporting the outcomes of a real-world practice multicenter study of 2183 patients by the team of worldwide endourological researchers group

ABSTRACT Introduction: We aimed to assess complications and stone-free rate of flexible ureteroscopy (FU) reusing disposable scopes (RDS) after repeated sterilization. Methods: Data from adults from 11 centers were retrospectively reviewed (January 2020–December 2022). Inclusion criteria were proximal ureteral/renal stone(s). All cases were performed using an RDS to save costs for patients who come from economically challenged environments. Residual fragments (RFs) were defined as single fragment ≥4 mm or multiple fragments of any size within 3 months. Continuous variables are presented as median and interquartile range. Results: Two thousand one hundred and eighty-three patients were included, of whom 67.0% were male. Median age was 48.0 (36–59) years. The median stone diameter was 10.2 (9–14) mm. Flash sterilization was used in 90.2% (plasma in 60.5%). Approximately, 88% had FU with an RDS used ≤2 times (12%: 3–5 times). RDS needed to be changed intraoperatively in 3.9% of cases due to its malfunction. Commonly, defects in RDS function were reported in upward (1.6%) and downward deflection (6.5%) and image quality on white balancing (4.7%). Fever >38C was seen in 13.7% of cases, and sepsis in 0.5%. RFs were found in 31.4% of cases. Lower pole (odds ratio [OR] 5.63) or pelvis stone (OR 4.67), faulty scopes (OR 12.8), and total operation time (OR 1.05) were factors associated with higher odds of RFs. Stone size (OR 1.09), positive urine culture (OR 1.67), interpolar stone (OR 1.68), and prestenting (OR 1.37) were factors associated with higher odds of fever/sepsis. Conclusions: RDS was used as a cost-conscious approach with a low rate of serious infections but with a high rate of RFs.

Incidence of serious infection among etanercept and infliximab initiators: safety comparison between biosimilars and bio-originators with Canadian population-based data

BackgroundSafety remains a significant concern for biologic drugs, and studies are needed to ensure a comparable safety profile for biosimilars and their legacy treatments. Using Canadian administrative health data from 2015–2019, we compared the incidence of serious infection between biosimilars and bio-originators initiators for etanercept and infliximab, two of the most commonly used biologics during this time.MethodsWe performed a retrospective cohort study using pan-Canadian data (except Quebec) from the National Prescription Drug Utilization Information System linked to hospitalization data. We studied new users of infliximab or etanercept (January/2015-December/2019) and compared incidence rates of serious infection, defined as those which required hospitalization, by using Cox regression models adjusted by biological sex, age at treatment initiation, prior corticosteroid or biologic, province, and calendar year.ResultsWe studied 6,583 etanercept users (mean age 62) and 7,202 infliximab users (mean age 45). Hospitalization with infections occurred in 7% of infliximab and 2% of etanercept users. Comparing the risk of infection between biosimilar to bio-originator, the adjusted hazard ratio (95% confidence interval) was 1.33 (0.77, 2.30) for etanercept and 0.93 (0.72, 1.18) for infliximab.ConclusionsOur study found no clear difference between etanercept and infliximab biosimilars and their bio-originators for infection incidence, suggesting a similar safety profile.

Long-Term Safety of Risankizumab in Patients with Psoriatic Disease: A Comprehensive Analysis from Clinical Trials.

Risankizumab has demonstrated a favourable safety profile in patients with psoriatic disease (moderate-to-severe psoriasis [PsO] and psoriatic arthritis [PsA]). We evaluated the long-term safety of risankizumab in psoriatic disease. Long-term safety was evaluated by analysing data from 20 (phase 1-4) clinical trials for plaque PsO and four (phase 2-3) trials for PsA. Treatment-emergent adverse events (TEAEs) and AEs in areas of special interest were reported among patients receiving ≥ 1 dose of risankizumab. Exposure-adjusted event rates were presented as events (E) per 100 patient-years (PY). The long-term safety data analyses included 3658 patients with PsO (13,329.3 PY) and 1542 patients with PsA (3803.0 PY). The median (range) treatment duration for patients with PsO and PsA was 4.1 (0.2-8.8)years and 2.8 (0.2-4.0)years, respectively. In the PsO population, rates of TEAEs, serious AEs and AEs leading to discontinuation were 145.5 E/100 PY, 7.4 E/100 PY and 1.9 E/100 PY, respectively; in the PsA population, these rates were 142.6 E/100 PY, 8.6 E/100 PY, and 1.8 E/100 PY, respectively. The rates of serious infections (excluding COVID-19-related infections) in the PsO and PsA populations were 1.2 and 1.4 E/100 PY, respectively. The rates of opportunistic infections (excluding tuberculosis and herpes zoster) were low (< 0.1 E/100 PY) in both populations. The rates of both nonmelanoma skin cancer (NMSC) and malignant tumours excluding NMSC were 0.6 and 0.5 E/100 PY in PsO and PsA, respectively, which are within the benchmarks of prior epidemiological studies. Adjudicated major cardiovascular event rates were 0.5 E/100 PY in PsO and 0.3 E/100 PY in PsA, which are within the epidemiologic reference benchmarks for both indications. No additional safety concerns were identified with this long-term exposure. The results support the favourable safety profile of risankizumab for long-term treatment of psoriatic disease with no new safety concerns and similar safety profiles among both PsO and PsA populations.

Relapses and serious adverse events during rituximab maintenance therapy in ANCA-associated vasculitis: a multicentre retrospective study.

There are limited real-life data regarding the efficacy and safety of rituximab (RTX) as a remission-maintenance agent in microscopic-polyangiitis (ΜPA) and granulomatosis-with-polyangiitis (GPA). We aimed to estimate the incidence and risk factors for relapses, as well serious-adverse-events (SAEs) in MPA/GPA patients during RTX-maintenance. Retrospective cohort of newly-diagnosed/relapsing GPA/MPA patients who received RTX-maintenance (≥1 RTX-cycle, ≥6 months follow-up) following complete-remission (Birmingham-Vasculitis-Activity-Score-version-3 = 0 plus prednisolone ≤7.5 mg/day) with induction regimens. SAEs included serious-infections, COVID-19-associated hospitalizations, deaths, cardiovascular-events, malignancies and hypogammaglobulinemia. Incidence-rates (IR) and relapse-free survival through Kaplan-Meier plots were estimated. Cox-regression was conducted to investigate factors associated with the time-to-relapse. 101 patients were included; 48% females, 69% GPA, 53% newly diagnosed, median age: 63 years. During follow-up (294.5 patient-years, median: 3 RTX-cycles), 30 relapses (57% major) occurred among 24 patients (24%, IR 10.2/100 patient-years). Kidney involvement (adjusted-Hazard-Ratio/aHR: 0.20; 95% CI: 0.06-0.74, p= 0.016), prior induction with RTX plus cyclophosphamide (vs RTX monotherapy: aHR = 0.02; 95% CI: 0.001-0.43, p= 0.012) and shorter time-interval until complete-remission (aHR = 1.07; 95% CI: 1.01-1.14, p= 0.023) were associated with decreased relapse-risk. We recorded 17 serious-infections (IR 5.8/100 patient-years), 11 COVID-19-associated hospitalizations (IR 3.7/100 patient-years), 4 malignancies (IR 1.4/100 patient-years), 6 cardiovascular-events (IR 2/100 patient-years) and 10 deaths (IR 3.4/100 patient-years). In this real-world study, relapses during RTX-maintenance occurred in approximately in 1 out of 4 patients. Kidney involvement, induction with RTX plus cyclophosphamide and earlier achievement of complete-remission were associated with lower relapse-risk. Serious-infections rate was consistent with previous reports, whereas an increased rate of COVID19-associated hospitalizations was observed.

Upadacitinib monotherapy versus methotrexate monotherapy in patients with rheumatoid arthritis: efficacy and safety through 5 years in the SELECT-EARLY randomized controlled trial

BackgroundTo evaluate the efficacy and safety of upadacitinib monotherapy versus methotrexate (MTX) monotherapy over 5 years among MTX-naïve patients with moderately to severely active rheumatoid arthritis (RA) in the long-term extension (LTE) of the phase 3 SELECT-EARLY trial.MethodsPatients were randomized to receive upadacitinib 15 mg or 30 mg or MTX. Patients who did not achieve CDAI remission and had < 20% improvement in tender and swollen joint counts at week 26 received rescue therapy (addition of MTX in the upadacitinib group and addition of upadacitinib in the MTX group). Efficacy assessments were evaluated over 5 years and are reported as observed (AO) for patients who received continuous monotherapy with upadacitinib 15/30 mg or MTX and by randomized group applying non-responder imputation (NRI). Treatment-emergent adverse events (TEAEs) per 100 patient-years were summarized over 5 years.ResultsOf 945 patients randomized and treated, 775 (82%) completed week 48 and entered the LTE on study drug. Higher proportions of patients consistently achieved disease activity targets over 5 years with upadacitinib than MTX. In AO analyses, 53%/59% of patients attained CDAI remission with upadacitinib 15/30 mg versus 43% with MTX at week 260. NRI analyses showed better CDAI, DAS28(CRP), and ACR responses with upadacitinib relative to MTX at week 260 (all comparisons, nominal P < .001). Upadacitinib treatment also resulted in numerically greater inhibition of structural joint progression through week 260 compared to MTX. Most TEAEs, serious AEs, and AEs leading to discontinuation were numerically higher in patients receiving upadacitinib 30 mg. Rates of serious infections, herpes zoster, creatine phosphokinase elevation, nonmelanoma skin cancer, and neutropenia were numerically higher with upadacitinib than MTX. The observed safety profile of upadacitinib over 5 years was consistent with earlier trial results and integrated phase 3 safety analyses.ConclusionsUpadacitinib showed better clinical responses versus MTX in patients with RA throughout the 5-year trial. Higher rates of several AEs were observed with upadacitinib, especially in the 30 mg group, compared to MTX. When used as monotherapy in MTX-naïve patients, the approved upadacitinib 15 mg dose showed better long-term efficacy versus MTX and an overall favorable benefit-risk profile.Trial registrationNCT02706873.

Safety and Efficacy of Upadacitinib in Patients with Rheumatoid Arthritis Refractory to Biologic DMARDs: Results Through Week 216 from the SELECT-CHOICE Study.

Thesafety and efficacy of upadacitinib 15mg (UPA15) through week 216 was evaluated in patients with rheumatoid arthritis (RA) from the long-term extension (LTE) of the phase 3 SELECT-CHOICE study. Patients with RA refractory to biologic disease-modifying antirheumatic drugs (bDMARDs) were randomized to UPA15 or abatacept (ABA) for 24weeks. During the open-label LTE, patients on ABA switched to UPA15 at week 24, and those on UPA15 continued treatment. Thesafety and efficacy of continuous UPA15, and ABA to UPA15, are summarized through week 216. The LTE was comprised of 91.4% (n = 277/303) of patients that initially received UPA15, and 89.6% (n =277/309) that initially received ABA. Of patients on UPA15 in the LTE (n =547), 28.3% (n =155/547) discontinued the study drug by week 216. Relative to other adverse events of special interest, and largely consistent with previous findings at week 24, higher rates of serious infection, COVID-19, herpes zoster, and elevated creatine phosphokinase were reported, while rates of malignancy excluding nonmelanoma skin cancer (NMSC), NMSC, major adverse cardiovascular event (MACE), and venous thromboembolism (VTE) were low. Long-term safety data with UPA through week 216 aligned with previous observations and no new safety risks were identified, including in patients who switched from ABA to UPA15. Proportions of patients achieving 28-joint disease activity score based on C-reactive protein (DAS28[CRP]) < 2.6/ ≤ 3.2, clinical disease activity index (CDAI) and simple disease activity index (SDAI) low disease activity/remission, ≥ 20%/50%/70% improvement in theAmerican College of Rheumatology (ACR20/50/70) response criteria, and Boolean remission were maintained or improved with UPA15 through week 216. Improvements in theHealth Assessment Questionnaire-Disability Index (HAQ-DI), patient's assessment of pain, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were also maintained or improved with UPA15 through week 216. Across all efficacy endpoints, similar results were observed in patients who switched from ABA to UPA15 versus continuous UPA15. Patients with an inadequate response to ≥ 1 prior tumor necrosis factor (TNF) inhibitor (UPA15: n =263/303, 86.8%; ABA to UPA15: n =273/309, 88.3%) showed similar responses to the total population. The long-term safety profile of UPA was consistent with previous findings and the broader RA clinical program. Compared to the primary analyses at week 24, efficacy responses were maintained or further improved with UPA15 through week 216 in patients with RA. Trial registration, ClinicalTrials.gov identifier: NCT03086343.

Comparative Risk of Serious Infection With Vedolizumab vs Anti-Tumor Necrosis Factor in Inflammatory Bowel Disease: Results From Nationwide Swedish Registers.

We aimed to assess the risk of serious infection in patients with inflammatory bowel disease (IBD) treated with vedolizumab compared with those treated with anti-tumor necrosis factors (TNF) and the general population. In this Swedish cohort study, treatment episodes were identified from nationwide health registers. We used Cox regression with propensity score-matched cohorts to estimate hazard ratios (HRs) for incident serious infections, defined as infections requiring hospital admission. During 1,376 treatment episodes in Crohn's disease, the rate of serious infections per 100 person-years (PY) was 5.18 (95% CI = 3.98-6.63) with vedolizumab vs 3.54 (95% CI = 2.50-4.85) with anti-TNF; HR = 1.72 (95% CI = 1.12-2.65), partly explained by more gastrointestinal infections. Compared with the rate of 0.75/100 PY (95% CI = 0.59-0.92) in a matched general population cohort, vedolizumab demonstrated higher risk (HR = 7.00; 95% CI = 5.04-9.72). During 1,294 treatment episodes in ulcerative colitis, the corresponding rates were 3.74/100 PY (95% CI = 2.66-5.11) with vedolizumab vs 3.42/100 PY (95% CI = 2.31-4.89) with anti-TNF; HR = 0.80 (95% CI = 0.47-1.36) during the initial 1.1 years and HR = 2.03 (95% CI = 0.65-6.32) after 1.1 years (truncated due to nonproportional hazards). Pneumonia accounted for 40% of all infections among anti-TNF, whereas no case was observed among vedolizumab episodes. Compared with the rate of 0.69/100 PYs (95% CI = 0.53-0.87) in a matched general population cohort, vedolizumab showed an HR of 5.45 (95% CI = 3.67-8.11). Vedolizumab was associated with increased risks of serious infections compared with anti-TNF in Crohn's disease but not in ulcerative colitis. Nonetheless, the panorama of serious infections seemed to differ between the drugs. Our findings underscore the importance of clinical awareness of infections and the safety profile of the 2 therapies.

COMBAT-MS: A Population-Based Observational Cohort Study Addressing the Benefit-Risk Balance of Multiple Sclerosis Therapies Compared with Rituximab.

To assess comparative effectiveness, safety, and tolerability of off-label rituximab, compared with frequently used therapies approved for multiple sclerosis (MS). A Swedish cohort study of persons with relapsing-remitting MS, age 18 to 75 years at inclusion and with a first therapy start or a first therapy switch between 2011 and 2018. Low-dose rituximab was compared with MS-approved therapies. Primary outcomes were proportions with 12 months confirmed disability worsening and change in MS Impact Scale-29 (MSIS-29) scores, respectively. Secondary endpoints included relapses, therapy discontinuation, and serious adverse events. Analyses used an intention-to-treat approach and were adjusted for demographics, MS features, and health characteristics. We included 2,449 participants as first therapy start and 2,463 as first therapy switch. Proportions with disability worsening at 3 years were 9.1% for rituximab as first therapy and 5.1% after therapy switch, with no differences to MS-approved comparators. Worsening on rituximab was mostly independent of relapses. MSIS-29 with rituximab at 3 years improved by 1.3/8.4 points (physical/psychological) for first disease-modifying therapy (DMT) and 0.4/3.6 for DMT switch, and was mostly similar across therapies. Rituximab had lower relapse rates and higher therapy persistence in both groups. The rate of hospital-treated infections was higher with rituximab after a therapy switch, but not as a first therapy. This population-based real-world cohort study found low rates of disability progression, mostly independent of relapses, and without significant differences between rituximab and MS-approved comparators. Rituximab led to lower rates of inflammatory activity and higher treatment persistence, but was associated with an increased rate of serious infections. ANN NEUROL 2024.

Safety Profile of Upadacitinib up to 5 Years in Psoriatic Arthritis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis: An Integrated Analysis of Clinical Trials.

This integrated analysis of the phase 2/3 and phase 3 SELECT trials describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, for up to 5years of exposure across psoriatic arthritis (PsA), ankylosing spondylitis (AS), and non-radiographic axial spondyloarthritis (nr-axSpA) (including pooled axial spondyloarthritis [axSpA]). Safety data from five trials of upadacitinib in PsA (2 trials), AS (2 trials), and nr-axSpA (1 trial) were analyzed up to a data cut-off of August 15, 2022. One PsA study included adalimumab as an active comparator. Treatment-emergent adverse events (TEAEs) were summarized for PsA (pooled upadacitinib 15mg once daily and adalimumab 40mg biweekly), AS (pooled upadacitinib 15mg), nr-axSpA (upadacitinib 15mg), and pooled axSpA (pooled upadacitinib 15mg from axSpA trials). TEAEs were reported as exposure-adjusted event rates per 100 patient-years (E/100 PY). A total of 1789 patients (PsA, n = 907; AS, n = 596; nr-axSpA, n = 286) received ≥ 1 dose of upadacitinib 15mg for 3689 PY of exposure or adalimumab (n = 429) for 1147 PY of exposure. Overall TEAEs and serious TEAEs were highest in PsA and numerically higher with upadacitinib versus adalimumab; rates were similar between AS and nr-axSpA. In PsA, higher rates of serious infection, herpes zoster (HZ), lymphopenia, and nonmelanoma skin cancer (NMSC) were observed with upadacitinib versus adalimumab. Rates of malignancy excluding NMSC, adjudicated major adverse cardiovascular events, and adjudicated venous thromboembolic events were comparable between upadacitinib and adalimumab in PsA and were similar across diseases. Higher rates of serious infection, HZ, lymphopenia, and NMSC were observed with upadacitinib versus adalimumab in PsA; slightly elevated rates for most of these TEAEs were seen with upadacitinib in PsA versus axSpA. Upadacitinib 15mg demonstrated a generally consistent safety profile across disease states with no new safety signals identified. SELECT-AXIS 1: NCT03178487; SELECT-AXIS 2: NCT04169373; SELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.

Rates of severe neutropenia and infection risk in patients treated with deferiprone: 28 years of data

AbstractPatients treated with deferiprone for transfusional iron overload may experience idiosyncratic drug–induced neutropenia (IDIN) that may increase risk of infection. This analysis examined the rates of severe IDIN and risk of serious infections at different absolute neutrophil count (ANC) levels during deferiprone treatment. Events of severe IDIN (ANC <0.5 × 109/L) and associated serious infections from clinical trials and postmarketing setting were analyzed by discrete ANC levels: group 1, 0.2 × 109/L to 0.5 × 109/L; group 2, 0.1 × 109/L to 0.199 × 109/L; group 3, <0.1 × 109/L. In clinical trials, 22 events of severe IDIN occurred (group 1, n = 9; group 2, n = 3; group 3, n = 10), and rates of severe IDIN per 100 patient-years were 0.45 in group 1; 0.15 in group 2; and 0.50 in group 3 (1990.26 patient-years deferiprone exposure). All serious infections were in group 3 (3/10 [30.0%]). In the postmarketing setting, 176 events of severe IDIN were reported (group 1, n = 65; group 2, n = 20; group 3, n = 91) and rates of severe IDIN per 100 patient-years were 0.06 in group 1; 0.02 in group 2; and 0.08 in group 3 (111 570.24 patient-years deferiprone exposure). Rates of serious infection were 7.7% (5/65) in group 1; 10% (2/20) in group 2; and 13.2% (12/91) in group 3. Our findings suggest a high risk of serious infections with ANC <0.2 × 109/L during deferiprone treatment, a level consistent with the recent neutropenia guidelines.

The Vax effect: Role of global vaccination initiatives in pandemic control and impact in Dehradun during COVID-19

COVID-19 was one of the most contagious diseases spread throughout the world and caused by the Corona virus. Its cellular and molecular profiling was performed on individuals suffering from Covid-19-like sickness in Dehradun. During this investigation, 100 random samples were taken from patients. Real Time PCR amplification of suspected cases of Covid-19 was done where 68% of the cases were positive. The proportions and patterns of positive cases and hospital admissions for covid-19 in the third wave in Dehradun were significantly different when compared to the first and second waves. This disparity was caused by a number of factors, including changes in lifestyle, natural immunological ability to cope with recent waves of natural infections, and the most important factor, which was that more than 83% of people over the age of 18 years had received the first or both doses of the vaccine. The Covid-19 vaccines were so effective due to which there was a very low rate of serious infection, hospitalization, and mortality.

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 &amp; 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, &amp;lt;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 &amp;lt;0.1 (5 yrs); adjudicated major adverse cardiovascular events (MACE), 15 mg, 0.1 (1 yr) and 0.2 (5 yrs)/30 mg, &amp;lt;0.1 at both timepoints; adjudicated venous thromboembolic events (VTE), &amp;lt;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 &amp;lt;0.1 (5 yrs)/30 mg, &amp;lt;0.1 at both timepoints. Rates of serious infection at both timepoints and doses remained low (&amp;lt;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.

Outcomes after kidney transplant alone in patients with cirrhosis-A case-control study.

Guidelines recommend kidney transplant alone (KTA) in compensated cirrhosis based on a few small studies, but this is not widely performed despite its potential benefit to patients and the organ supply. Our aim was to determine the outcomes of KTA in patients with compensated cirrhosis. From 1/2012 to 12/2021, outcomes in KTA recipients with compensated cirrhosis were retrospectively compared to patients with chronic liver disease (CLD) but no cirrhosis. Patients with compensated cirrhosis were also compared to a matched cohort (based on age, time on hemodialysis, sex, and ethnicity) of KTA recipients without CLD. The outcomes included patient survival, allograft failure, allograft rejection, serious infection, liver decompensation, and length of stay (LOS). Over 9 years, 1562 KTAs were performed, with 150 (9.6%) patients having CLD mostly due to chronic hepatitis C, and a median follow-up of 3.5 years. 32/150 (21%) had compensated cirrhosis at the time of KTA with a mean MELD-Na of 22 (1.5). Matched controls (n=189) were identified. We found no differences in patient survival (p=.07), allograft failure (p=.6), allograft rejection (p=.43), rates of serious infection (p=.31), as well as LOS (p=.61) among patients with compensated cirrhosis compared to patients with CLD but no cirrhosis, but with higher rates of liver decompensation (p=.004). Similarly, compared to patients without CLD, patients with cirrhosis had similar rates of patient survival (p=.20), allograft failure (p=.27), allograft rejection (p=.62) and LOS (p=.19) but with higher rates of serious infections (p=.001). Our study supports the safety and efficacy of KTA in patients with compensated cirrhosis.

P115 Ustekinumab in DEVELOP: A safety analysis from an Inflammatory Bowel Disease multicenter, prospective, long-term registry of paediatric patients

Abstract Background DEVELOP is a multi-center, global, prospective, observational, longitudinal registry of long-term safety of infliximab (and other treatments) in paediatric patients (pts) with inflammatory bowel disease (IBD) &amp;lt;18 years (yrs) at diagnosis. Over the course of follow-up, many pts required changes in therapy. Ustekinumab (UST) is approved for treatment of Crohn’s disease (CD) in adults and is currently being evaluated for safety/efficacy in paediatric pts. This report focuses on assessment of safety of UST in paediatric pts with CD from DEVELOP. Methods Data included paediatric pts treated with UST from 31 May 2007 through 30 June 2022; data are collected every 6 months. The analyzed population included: all paediatric pts (all pts), pts weighing &amp;lt;40kg (&amp;lt;40kg group), and pts weighing ≥40kg (≥40kg group). Assessments included medical and treatment history, UST exposure, adverse events (AEs), serious AEs (SAEs), CD-related SAEs leading to hospitalization, IBD surgeries, serious and opportunistic infections, malignancies, and deaths. Results A total of 150 pts received UST (49.3% females); 31 in the &amp;lt;40kg group and 119 in the ≥40kg group (Table 1). Most treated pts (92.0%) were 12-17yrs. The majority (91%) of pts were initially dosed with UST every 8 weeks (q8w); at the last known dose, 64% received UST q8w and 22% q4w. Mean (SD) age of initial UST exposure was 15yrs (2.19). Prior IBD surgery was reported in 65.3% pts. The majority of pts (98%) had prior biologic therapy and 72% received ≥2 biologics prior to UST. Overall, 37/150 (24.7%) of pts discontinued UST during follow-up, with a mean (SD) time to discontinuation of 16.7 (17.00) months; 84/150 (56.0%) were exposed to UST for ≥24 months. Rates (events/100 pt-yrs) of AEs were higher in the ≥40kg group (177.62) than in the &amp;lt;40kg group (101.27). Rates of SAEs were slightly lower among the ≥40kg group (25.42) vs &amp;lt;40kg (32.67). There were no SAEs related to infusion or injection site reactions. Rates of serious infections and CD-related hospitalizations were low and similar between groups, and rates of IBD-related surgeries were similar between groups (Figure 1). One malignancy (malignant carcinoid tumor) was reported in a female (18yrs) in the ≥40kg group with a history of prior therapy with vedolizumab, methotrexate, and 6-MP. No deaths or opportunistic infections were reported. Conclusion The safety profile observed for this off-label use of UST in paediatric CD pts in DEVELOP was similar to that of the treated adult population, despite most paediatric pts having prior biologic exposure. No new safety signals are identified in this paediatric population.

Comparative risk of serious infections and tuberculosis in Korean patients with inflammatory bowel disease treated with non-anti-TNF biologics or anti-TNF-α agents: a nationwide population-based cohort study.

The risk of serious infection and active tuberculosis in patients with inflammatory bowel disease (IBD) has not been concurrently evaluated based on the use of anti-tumor necrosis factor (TNF)-α agents versus non-anti-TNF biologics (vedolizumab/ustekinumab) in the Korean population. We compared the risk of serious infection and active tuberculosis in Korean patients with IBD treated with non-anti-TNF biologics (vedolizumab/ustekinumab) or anti-TNF-α agents. This study was a population-based cohort analysis of nationwide administrative claims data. Health Insurance Review and Assessment Service claims data (representing 97% of the South Korean population) from between January 2007 and February 2021 were reviewed, and adults with IBD who initiated vedolizumab/ustekinumab or anti-TNF-α treatment (n = 6123) between 2017 and 2020 were enrolled. Intergroup differences in the risk of serious infection requiring hospitalization/emergency department visits or active tuberculosis during the follow-up period were analyzed. In the patients treated with anti-TNF-α agents or vedolizumab/ustekinumab during a mean follow-up of 1.55 ± 1.05 and 0.84 ± 0.69 years, the incidence rates of serious infection were 9.43/100 and 6.87/100 person-years, respectively. Multivariable analysis showed no significant intergroup difference in the risk of serious infection with vedolizumab/ustekinumab or anti-TNF-α treatment; the adjusted relative risk of vedolizumab/ustekinumab compared with anti-TNF-α agents was 0.81 (95% confidence interval 0.46-1.44, p = 0.478). Among patients treated with anti-TNF-α agents and vedolizumab/ustekinumab, the incidence rates of active tuberculosis were 0.87 and 0.37 per 100 person-years, respectively. The relative risk of vedolizumab/ustekinumab compared with anti-TNF-α agents was 0.31 (95% confidence interval 0.07-1.26, p = 0.101). In a subset analysis comparing vedolizumab and ustekinumab with anti-TNF-α agents, similar results were observed. In Korean patients with IBD, non-anti-TNF biologics (vedolizumab/ustekinumab) tended to be associated with a lower risk of serious infection or active tuberculosis than anti-TNF-α agents.

Infections in Lymphoma Patients Treated with Bispecific Therapies: A Systematic Review and Meta-Analysis

CONCLUSION BACKGROUND Bispecific antibodies (BsAb) demonstrate efficacy in newly diagnosed and relapsed/refractory lymphomas. BsAb act by forming immune synapses between an effector cell (T cell or NK cell) surface markers and target cell surface markers, typically CD19 and CD20 in B-cell lymphoma; and CD30 in T-cell lymphomas. Improved understanding of the infection risks associated with BsAbs is required to improve patient outcome. METHODS MEDLINE, EMBASE, Cochrane and Google Scholar were searched to identify relevant studies up to June 15, 2023. Phase I-III clinical trials and observational studies of BsAb monotherapy and combination therapy in adult patients were included. Study identification, data-extraction and bias-assessment were performed by two authors (Figure 1). The primary outcome was the number of bispecific-treated lymphoma patients who experienced ≥ 1 infection of any grade. Secondary outcomes included severe infections (grade ≥ 3), fatal infections and the incidence of microbiologically confirmed bacterial, viral and fungal infections. Sub-analysis by malignant target (CD19 vs CD20), and monotherapy versus combination therapy was performed. Meta-analysis of proportions estimated the pooled infection incidence using random effects model (Mantel-Haenszel). Cochran's Q test examined heterogeneity. PROSPERO registration (CRD42023433207). RESULTS Of 1796 studies, 23 studies (1423 pts) were included, with a median age of 64 years (IQR 60 - 66). Nineteen studies (1124 pts) reported the primary outcome of all-grade infections, which occurred in 37% of patients (95%CI: 30 - 45%) (Figure 2). 13% of patients experienced a grade ≥ 3 infection (12 studies, 843 pts, 95%CI: 9 - 17) and 2% (N = 35) experienced a fatal infection (18 studies, 1318 pts, 95%CI: 1 - 2%). 35 fatal infections were reported (1124 pts), with aetiology reported in 97% (N = 34). 68% of fatal infections (23/34) were microbiologically identified. Fatal infections were predominately viral (70%, 16 infections, 15 deaths from COVID-19, 1 death from EBV), followed by fungal (17%, 4 infections, 3 deaths from pneumocystis jirovecii, 1 death from candida species), bacterial (9%, 2 infections, E. coli and Klebsiella sepsis) and 1 parasitic infection (toxoplasmosis). 11 clinically defined fatal infections occurred; 3 fatal pneumonias, and 8 cases of fatal ‘septic shock’ without a causative pathogen listed. 302 patients (8 studies) with aggressive B-cell lymphoma were compared to 129 indolent lymphoma patients (2 studies). All-grade infections were significantly higher in the aggressive B-cell lymphoma subgroup (41%, 95%CI: 33 - 49%) compared to the indolent subgroup (27%, 95%CI: 10 - 44%, z = 2.77, p = 0.005). The weighted median of prior therapies in the aggressive lymphoma group was comparable to the indolent group (3 vs. 2.5 prior therapies). Grade ≥ 3 infections (14% vs 11%) and fatal infections (3% vs 0%) did not differ significantly between aggressive and indolent subtypes (p &amp;gt; 0.05). Patients receiving CD20/CD3 BsAb monotherapy experienced a significantly higher rate of all-grade infections (42% vs 29%, z = -3.14, p &amp;lt; 0.01) and grade ≥ 3 infections (17% vs 7%, z = -3.23, p &amp;lt; 0.01) than patients receiving CD19/CD3 monotherapy. Fatal infections were comparable between CD20/3 and CD19/3 products. Microbiological aetiology and clinical sites of infections were not commonly reported. In subanalysis of CD20/CD3 products, pooled all-grade infections did not differ significantly between monotherapy epcoritimab (34% 95%CI: 21 - 47%) and glofitamab (39% 95%CI: 21 - 56%). Analysis of all-grade and grade ≥ 3 infections related to monotherapy mosunetuzumab and odronextumab was not possible due to inconsistent reporting of these outcomes across studies. When used in combination, all-grade infections for epcoritimab were comparable to epcoritimab monotherapy (34% 95%CI: 21 - 47% vs 42% 95%CI: 31 - 52%, z = 1.13, p = 0.258). Mosunetuzumab was given with R-CHOP in a single study, but all-grade and severe infection rates were not reported. This systematic review reports a modest rate of serious infections in lymphoma patients receiving BsAb. The higher rate of fatal viral and fungal infections highlights a potential need for increased clinical vigilance for infections classically associated with T-cell depletion. Although further data is needed, CD20-targeted BsAb may confer higher infection risk than CD19-directed products.

Extended Follow-up of ALPINE Randomized Phase 3 Study Confirms Sustained Superior Progression-Free Survival of Zanubrutinib Versus Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL)

Introduction: ALPINE, a randomized, multinational phase 3 study (NCT03734016) in patients with R/R CLL/SLL, established the statistical and clinically meaningful superiority of zanubrutinib over ibrutinib on progression-free survival (PFS) and overall response rate (ORR) and confirmed the favorable safety/tolerability profile of zanubrutinib (Brown et al. NEJM; 2022). Now, with 3 years of overall study follow-up, we report the results of an extended follow-up analysis. Methods: As previously published, patients with R/R CLL/SLL who had received ≥1 prior therapy and had measurable disease were randomized 1:1 to receive zanubrutinib or ibrutinib. Efficacy assessments, including PFS and ORR, were evaluated by the investigator based on 2008 iwCLL criteria; sensitivity analyses to confirm PFS results were also conducted. Updated safety analyses were performed. All reported P-values are descriptive. Results: Overall, 652 patients were randomized to receive zanubrutinib (n=327) or ibrutinib (n=325). As of 15 May 2023, 63.3% (n=207/327) of patients remain on zanubrutinib and 52.3% (n=170/325) remain on ibrutinib. At a median study follow-up of 36.3 months, benefit of zanubrutinib over ibrutinib was sustained (HR: 0.67 [95% CI, 0.52-0.86]; 2-sided P=.002; Fig 1). At 36 months, the PFS rates were 65.8% with zanubrutinib and 54.3% with ibrutinib. Benefits in PFS with zanubrutinib were also observed across major subgroups, including in patients with del(17p)/ TP53 mutations (HR: 0.52 [95% CI, 0.32-0.83] 2-sided P=.005) where 36-month PFS rates were 60.1% and 43.6%, respectively. Additionally, the zanubrutinib PFS benefit was confirmed in a sensitivity analysis that included only progression and death events that occurred on active treatment (HR: 0.69 [95% CI, 0.49-0.97]; 2-sided P=.031). ORR remained higher with zanubrutinib compared with ibrutinib (85.0% vs 74.8%; 2-sided P=.001). Responses deepened in both arms with CR/CRi rates of 10.1% (zanubrutinib) and 7.4% (ibrutinib); therate of PR-L or better was 90.2% vs 82.8%, respectively. Fifty-nine (18.0%) patients treated with zanubrutinib and 71 (21.8%) treated with ibrutinib had died (OS HR: 0.76 [95% CI, 0.54-1.08]); 36-month OS rates were 82.6% (zanubrutinib) and 79.7% (ibrutinib). In this extended follow-up, median treatment duration was 34.7 months (zanubrutinib) and 31.5 months (ibrutinib). Across both arms, the most common reasons for treatment discontinuation were AEs (20.2%, zanubrutinib; 24.9%, ibrutinib) and progressive disease (12.2%, zanubrutinib; 16.3%, ibrutinib). Dose interruption and dose reduction due to AEs were 59.6% vs 61.1% and 14.2% vs 17.6% with zanubrutinib vs ibrutinib, respectively. The most common AEs of any grade with zanubrutinib and ibrutinib were COVID-19 (37.3% vs 25.6%), diarrhea (17.9% vs 25.6%), and upper respiratory tract infection (25.9% vs 17.3%). Rates of any grade ≥3 AEs and serious AEs were 72.2% vs 75.6% and 49.7% vs 57.4% with zanubrutinib vs ibrutinib, respectively. Most commonly reported grade ≥3 AEs were neutropenia (17.3% vs 16.4%) and hypertension (15.1% vs 12.0%). Rates of serious infections were 30.6% in each treatment arm. Discontinuation rates due to cardiac disorders were lower with zanubrutinib (0.6% [n=2]) vs ibrutinib (4.6% [n=15]). Overall cardiac events remain lower with zanubrutinib, including atrial fibrillation/flutter (6.2% vs 16.0%; 2-sided P&amp;lt;.0001). Across this study, no grade 5 AEs due to cardiac disorders were observed with zanubrutinib but were reported in 6 patients (1.9%) with ibrutinib ( Table 1). Conclusions: ALPINE was the first study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors. At a median follow-up of 3 years, the study showed sustained PFS benefits of zanubrutinib over ibrutinib. The durable PFS benefits with zanubrutinib were observed across major subgroups, including multiple sensitivity analyses. The overall safety/tolerability profiles were consistent with previous reports for both treatments. The cardiac safety profile remained favorable for zanubrutinib compared with ibrutinib, with no new safety signals emerging with longer follow-up. With over 3 years of treatment, zanubrutinib continues to be a more efficacious and better tolerated treatment than ibrutinib for patients with R/R CLL/SLL. At time of presentation, data with further follow-up will be presented.

Maternal and Neonatal Outcomes in Vedolizumab- and Ustekinumab-Exposed Pregnancies: Results From the PIANO Registry.

Pregnancy outcomes in patients with inflammatory bowel disease with quiescent disease are similar to those in the general population. Data from the Pregnancy Inflammatory bowel disease And Neonatal Outcomes registry have demonstrated the safety of antitumor necrosis factor (TNF) α agents and thiopurines in pregnancy. The objective of this study was to provide information from the Pregnancy Inflammatory bowel disease And Neonatal Outcomes registry on maternal and fetal outcomes in patients exposed to the newer biologics ustekinumab (UST) and vedolizumab (VDZ). In this multicenter prospective observational study, we included pregnant women with singleton pregnancies and a diagnosis of inflammatory bowel disease. Questionnaires were administered to women at study intake, each subsequent trimester, delivery, and 4, 9, and 12 months after birth. Bivariate analyses were used to determine the independent effects of specific drug classes on outcomes. The exposure cohorts were VDZ, UST, anti-TNF, immunomodulators, and combination with anti-TNF and immunomodulators. All were compared with no exposure and with biologics/immunomodulators. There were 1,669 completed pregnancies with 1,610 live births. The maternal mean age was 32.1 (SD 4.6) years at delivery with 66 VDZ exposed and 47 UST exposed. Women on UST were more likely to have Crohn's disease. There was no increased risk of spontaneous abortion, small for gestational age, low birth weight, neonatal intensive care unit stay, congenital malformations, or intrauterine growth restriction with in utero VDZ or UST exposure. The rate of preterm birth was lower (0.0%) for the UST-exposed cohort when compared with other cohorts including VDZ (13.8%), anti-TNF (8.2%), combination therapy (14.2%), immunomodulators (12.3%), and unexposed (9.7%) ( P = 0.03). Rates of serious infections at birth, 4 months, and within the first 12 months of life were comparable among all cohorts. Nonserious infections were lower at 12 months in UST-exposed pregnancies. There was no increased risk signal for placental complications in the VDZ cohort. UST infant concentrations at birth were increased whereas VDZ concentrations were overall decreased compared with maternal serum drug concentration. This analysis of UST and VDZ exposure during pregnancy suggests no increase in complications compared with TNF, immunomodulators, and combination TNF/immunomodulators. No signal was found for increased placental events with either therapy. Continuation of UST and VDZ throughout pregnancy is recommended.

Risk of serious infection and infection mortality in patients with psoriasis: A nationwide cohort study using the Taiwan National Health Insurance claims database.

The risks of serious infections that lead to hospitalization and mortality in patients with psoriasis in Asia have not been comprehensively studied. We examined the incidence of serious infection and infection mortality in patients with psoriasis. This population-based retrospective cohort study used the Taiwan National Health Insurance claims database from 2000 to 2017. Adult patients with psoriasis were identified by a relevant International Classification of Diseases (ICD) code and matched to six comparators without psoriasis on age and sex. Psoriasis patients were categorized as having moderate-to-severe disease once exposed to systemic therapies, phototherapy or biologic therapies. The incidence of serious infection and infection mortality were identified by ICD codes from inpatient hospitalization and death registration. Cox proportional hazard models were used to compare the risk, and the results were adjusted for covariates and presented as adjusted hazard ratios (aHR) and 95% confidence interval (95% CI). Overall, 185,434 psoriasis patients and 1,112,581 comparators were included. A higher rate of serious infection (aHR: 1.21, 95% CI: 1.19-1.22) was found in patients with psoriasis compared to matched comparators without psoriasis, and the risk was enhanced when patients had moderate-to-severe psoriasis (aHR: 1.30, 95% CI: 1.27-1.34). Specifically, there was an increased risk of serious infection due to respiratory infections (aHR: 1.11, 95% CI: 1.09-1.13), skin/soft-tissue infections (aHR: 1.57, 95% CI: 1.52-1.62), sepsis (aHR: 1.23, 95% CI: 1.19-1.27), urinary tract infections (aHR: 1.11, 95% CI: 1.08-1.14), hepatitis B (aHR: 1.18, 95% CI: 1.06-1.30) and hepatitis C (aHR: 1.49, 95% CI: 1.32-1.69). Furthermore, psoriasis patients were associated with a higher risk of infection-related mortality (aHR: 1.15, 95% CI: 1.11-1.18) compared to matched comparators. Patients with psoriasis had a higher risk of serious infection and infection mortality, which was enhanced by moderate-to-severe psoriasis. Practitioners should be aware of the increased risk in patients with psoriasis, but it should not be a barrier to offering effective treatment.

Systematic literature review informing the 2022 update of the EULAR recommendations for the management of ANCA-associated vasculitis (AAV): part 1—treatment of granulomatosis with polyangiitis and microscopic polyangiitis

ObjectiveTo summarise and update evidence to inform the 2022 update of the EULAR recommendations for the management of antineutrophil cytoplasm antibody-associated vasculitis (AAV).MethodsA systematic literature review (SLR) was performed to...