Incidence Rate Of Serious Adverse Events Research Articles

The long-term safety and tolerability of anifrolumab for patients with systemic lupus erythematosus in Japan: TULIP-LTE subgroup analysis.

Evaluate the long-term safety and tolerability of anifrolumab 300 mg, alongside standard therapy, in patients from Japan with systemic lupus erythematosus (SLE) in the TULIP-LTE trial (NCT02794285). TULIP-LTE was a 3-year, randomized, double-blind, placebo-controlled long-term extension (LTE) of the TULIP trials. The primary safety outcome included serious adverse events (SAEs) and AEs of special interest (AESIs) during the LTE period. Exploratory efficacy outcomes included SLE Disease Activity Index 2000 (SLEDAI-2K) scores and glucocorticoid use. We performed a post hoc subgroup analysis of patients who enrolled in Japan. Exposure-adjusted incidence rates of SAEs during the LTE and follow-up for patients receiving anifrolumab 300 mg (n=21) were 8.7 per 100 patient-years; AESIs included influenza (6.9) and herpes zoster (3.5). One of three patients receiving placebo had an SAE (13.9). One patient per group discontinued due to an AE. There were no deaths. During the TULIP+LTE period, patients receiving anifrolumab 300 mg (n=24) had sustained reduction from baseline in mean SLEDAI-2K scores and cumulative glucocorticoid dosage. Anifrolumab 300 mg showed a favourable benefit-risk profile for the long-term treatment of adult patients with moderate to severe SLE from Japan, with safety, tolerability, and efficacy profiles consistent with the overall population.

Real-life drug retention rate and safety of rituximab when treating rheumatic diseases: a single-centre Swiss retrospective cohort study

BackgroundIn Switzerland, rituximab (RTX) is licenced for the treatment of rheumatoid arthritis (RA) and ANCA-associated vasculitis (AAV) but is frequently used off-label to treat other auto-immune diseases (AID), especially connective tissue diseases (CTD). We aimed to characterise the use of RTX in AID in a real-life Swiss setting and compare RTX retention rates and safety outcomes between patients treated for RA, CTD and AAV.MethodsA retrospective cohort study of patients who started RTX in the Rheumatology Department for RA or AID. The RTX retention rate was analysed using Kaplan–Meier survival curves. Occurrences of serious adverse events (SAE), low IgG levels and anti-drug antibodies (ADA) were reported.ResultsTwo hundred three patients were treated with RTX: 51.7% had RA, 29.6% CTD, 9.9% vasculitis and 8.9% other AIDs. The total observation time was 665 patient-years. RTX retention probability at 2 years (95%CI) was similar for RA and CTD 0.65 (0.55 to 0.73), 0.60 (0.47 to 0.72) and lower for vasculitis 0.25 (0.09 to 0.45). Survival curves for RTX retention matched closely (p = 0.97) between RA and CTD patients but were lower for patients with vasculitis due to a higher percentage of induced remission. Patients with vasculitis (95%) and CTD (75%) had a higher rate of concomitant glucocorticoid use than RA (60%). Moderate to severe hypogammaglobulinaemia was observed more frequently in patients with vasculitis (35%) than with RA (13%) or CTD (9%) and was associated with an increased risk of presenting a first infectious SAE (HR 2.01, 95% CI 1.04 to 3.91). The incidence rate of SAE was 23.3 SAE/100 patient-years (36% were infectious). When searched, ADAs were observed in 18% of the patients and were detected in 63% of infusions-related SAE. 10 patients died during RTX treatment and up to 12 months after the last RTX infusion, 50% from infection.ConclusionRTX retention rates are similar for patients with RA and CTD but lower for those with vasculitis due to more frequent remission. Patients treated with RTX for vasculitis present more SAE and infectious SAE than patients with RA and CTD, potentially due to a higher use of concomitant glucocorticoids and the occurrence of hypogammaglobulinaemia.

AB0892 Targeted Safety Analyses of Guselkumab: Long-Term Results from Randomized Clinical Trials in Patients with Active Psoriatic Arthritis and Moderate to Severe Psoriasis

BackgroundGuselkumab (GUS) demonstrated efficacy and a favorable safety profile in active PsA in the Phase (Ph) 21 and Ph3 DISCOVER-1&2 trials2,3 and in moderate-to-severe plaque psoriasis (PsO) in the Ph3 VOYAGE-1&2 trials.4,5ObjectivesTo assess long-term safety of GUS across PsA/PsO trials.MethodsUsing pooled safety data through 2 years (yrs) from PsA trials (N=1229; GUS 100 mg every 4/8 weeks [Q4W/Q8W])1-3 and through 5 yrs from PsO trials (N=1721; GUS 100 mg Q8W),4,5 incidences of serious adverse events (SAEs); gastrointestinal (GI)-related SAEs and other targeted AEs; including candidiasis, uveitis, and opportunistic infections (OIs) were evaluated. Incidence rates (IRs) were calculated as the number of events per 100 pt-yrs (PY) of follow-up with 95% CI. Patients (pts) with an IBD history were not excluded in PsA/PsO trials. Max exposure duration was W100 for PsA trials and W252 for PsO trials.ResultsThe PsA and PsO populations had comparable mean age and BMI. IRs of SAEs and GI-related SAEs were generally similar between GUS- and PBO-treated pts during PBO-controlled periods, and between PsA pts receiving GUS Q4W/Q8W for up to 2 yrs and PsO pts receiving GUS Q8W for up to 5 yrs (Table 1). IRs of other targeted AEs of interest were low. OIs did not occur in PsO pts and were infrequent in PsA pts (Table 1). Candidal infections were infrequent and non-serious. Iridocyclitis was reported in 1 PBO- and 1 GUS Q8W-treated PsA pt. No exacerbations or new onset of IBD or active tuberculosis was reported in GUS-treated PsA/PsO pts.Table 1.Targeted AEs of InterestPooled PsA*Pooled PsOThrough 2 YrsThrough 5 YrsGUS 100 mg Q4W (N=373)GUS 100 mg Q8W (N=475)PBO→GUS 100 mg Q4W (N=352)aPBO→GUS 100 mg Q8W (N=29)aGUS Combined (N=1229)GUS 100 mg Q8W (N=1221)bADA→GUS 100 mg Q8W (N=500)cGUS Combined (N=1721)Total PY645748461171871525419127166Mean PY1.71.61.30.61.54.33.84.2Events/100 PY (95% CI)Overall SAEs4.65(3.14, 6.64)6.42(4.73, 8.51)5.86(3.86, 8.52)0.00(0.00, 17.24)5.61(4.59, 6.79)5.18(4.58, 5.83)4.55(3.64, 5.61)5.01(4.50, 5.56)GI-related SAEs0.46(0.10, 1.36)0.27(0.03, 0.97)0.00 (0.00, 0.65)0.00(0.00, 17.24)0.27(0.09, 0.62)0.44(0.28, 0.66)0.42(0.18, 0.82)0.43(0.29, 0.61)OIsd0.00(0.00, 0.46)0.27(0.03, 0.97)0.22(0.01, 1.21)0.00(0.00, 17.24)0.16(0.03, 0.47)0.00(0.00, 0.06)0.00(0.00, 0.16)0.00(0.00, 0.04)Candida infections0.31(0.04, 1.12)0.00(0.00, 0.40)0.00(0.00, 0.65)0.00(0.00, 17.24)0.11(0.01, 0.39)0.49(0.32, 0.73)0.52(0.25, 0.96)0.50(0.35, 0.70)Non-pathogen specific fungal infections, suspicious for candida0.00(0.00, 0.46)0.27(0.03, 0.97)0.00(0.00, 0.65)0.00(0.00, 17.24)0.11(0.01, 0.39)0.11(0.04, 0.25)0.16(0.03, 0.46)0.13(0.06, 0.24)Uveitis/ Iridocyclitis0.00(0.00, 0.46)0.13(0.00, 0.75)0.00(0.00, 0.65)0.00(0.00, 17.24)0.05(0.00, 0.30)0.00(0.00, 0.06)0.00(0.00, 0.16)0.00(0.00, 0.04)*In PsA Ph2, data after early escape at W16 were excluded. AEs are coded using MedDRA Version 23.1aFor PBO→GUS, data on/after 1st GUS administration were includedbPBO crossover pts were included in GUS column after crossover to GUScEvents prior to GUS (ADA events) were excluded. Only includes pts randomized to ADA at W0 and crossed over to GUS at/after W52 for VOYAGE-1 & W28 for VOYAGE-2dHerpes zoster disseminated, fungal oesophagitis, and meningitis listeria (1 each)ADA=AdalimumabConclusionIRs of SAEs; GI-related SAEs; and AEs of interest including candidiasis, uveitis, and OIs were low, or no cases were reported. No new safety concerns were identified with GUS treatment through 2 yrs and 5 yrs of follow-up in the pooled PsA and PsO trials, respectively, supporting a durable and favorable GUS safety profile consistent between pts with active PsA and moderate-to-severe PsO.

P436 SPOSAB ABP 501 - A Sicilian Prospective Observational Study of Patients with Inflammatory Bowel Disease Treated with Adalimumab Biosimilar ABP 501

Abstract Background Clinical data on the use of Adalimumab (ADA) biosimilar ABP 501 in inflammatory bowel disease (IBD) are lacking. Methods SPOSAB ABP 501 is a multicenter, observational, prospective study performed among the cohort of the Sicilian Network for Inflammatory Bowel Disease (SN-IBD). All consecutive patients with Crohn’s Disease (CD) or Ulcerative Colitis (UC) treated with ABP 501 from the introduction of the drug in Sicily (February 2019) to February 2020 (12 months) were enrolled. Patients were divided into 3 groups (group A: naive to ADA and naive to anti-TNFs; group B: naive to ADA and previously exposed to anti-TNFs; group C: switch from ADA originator to ABP 501). The primary end-point was the assessment of safety, in terms of rate of serious adverse events (SAEs). Secondary end-point was the evaluation of effectiveness, in terms of clinical response and steroid-free clinical remission at 12 weeks for group A and B, and as treatment persistency for all 3 groups. Results 559 patients (median age 39 years; CD 88.0%, UC 12.0%) were included [group A: 189 (33.8%); group B: 30 (5.4%); group C: 340 (60.8]. Overall, the mean follow-up was 8.7 months (median 10.0 months, interquartile range: 6.0–12.0 months), and the total follow-up time was 403.4 patient-years. 36 SAEs occurred in 36 patients (6.4%), with an incidence rate of 8.9 per 100 person-years (PY), and 22 of them caused the withdrawal of the drug (incidence rate: 5.5 per 100 PY). The incidence rate of SAEs was higher among patients in group A compared with group C (17.4 vs. 4.8 per 100 PY; incidence rate ratio=3.61; p<0.001) and among patients in group B compared with group C (16.4 vs. 4.8 per 100 PY; incidence rate ratio=3.42; p=0.041). The effectiveness of ABP 501 after 12 weeks of treatment was assessed in patients naïve to ADA (group A + B; n=219): 188 patients (85.8%) had a clinical response, including 165 (75.3%) who achieved a steroid-free remission. Among the patients who responded at 12 weeks, a subsequent loss of response was reported in 17 subjects (9.0%). At the end of follow-up, 56 patients (10.0%) interrupted the treatment, with higher treatment persistency estimations for patients in group C compared with group A and B (log-rank p<0.001). Conclusion This is the first prospective study on the use of ADA biosimilar ABP 501 in IBD. Safety and effectiveness of ABP 501 seem to be overall similar to those reported for ADA originator. Switching from originator to ABP 501 was safe and effective.

Safety of Tofacitinib in a Real-World Cohort of Patients With Ulcerative Colitis

Adverse events (AEs) including reactivation of herpes zoster (HZ) and venous thromboembolism (VTE) have been reported from clinical trials of tofacitinib in ulcerative colitis (UC). We investigated the incidence rates of AEs in a real-world study of UC patients given tofacitinib. We collected data from 260 patients with UC in the Tofacitinib Real-world Outcomes in Patients with ulceratIve colitis and Crohn's disease consortium study, performed at 6 medical centers in the United States. Patients were followed up for a median of 6 months (interquartile range, 2.7-11.5 mo). AEs were captured using a standardized data collection instrument before study initiation and at weeks 8, 16, 26, 39, and 52. Serious AEs were defined as life-threatening or resulting in a hospitalization, disability, or discontinuation of therapy. Logistic regression was performed to examine risk factors for AEs. AEs occurred in 41 patients (15.7%); most were infections (N= 13; 5.0%). The incidence rate of any AE was 27.2 (95% CI, 24.4-30.7 per 100 patient-years of follow-up evaluation). Fifteen were serious AEs (36.6% of AEs), and tofacitinib was discontinued for 12 patients (4.6% of cohort). The incidence rates of serious AEs was 10.0 (95% CI, 8.9-11.2 per 100 patient-years of follow-up evaluation). Five patients developed HZ infection and 2 developed VTE (all receiving 10 mg tofacitinib, twice per day). Real-world safety signals for tofacitinib are similar to those for clinical trials, with AEs reported from almost 16% of patients. HZ infection and VTE occurred in patients receiving 10 mg tofacitinib twice per day. These results support dose de-escalation after induction therapy, to reduce the risk of AEs.

Serious Adverse Events Associated with Anti-Tumor Necrosis Factor Alpha Agents in Pediatric-Onset Inflammatory Bowel Disease and Juvenile Idiopathic Arthritis in A Real-Life Setting.

Anti-tumor necrosis factor alpha (anti-TNF-α) agents are generally well tolerated, yet they can be associated with serious adverse events (SAEs) in a minority of patients. We examined the incidence of SAEs in a pediatric referral center for chronic rheumatologic and gastroenterological inflammatory disorders. Retrospective analysis of SAEs occurring during treatment with anti-TNF-α agents in patients with juvenile idiopathic arthritis (JIA) (n=78) or pediatric-onset inflammatory bowel disease (IBD) (n=105)seen at the Institutefor Maternal and Child Health IRCCS "Burlo Garofolo" in Trieste, Italy, between June 2001 and February 2016. Only SAEs grade 3-5 according to the Common Terminology Criteria for Adverse Events version 4.03 and/or requiring definitive therapy discontinuation were reported. Total anti-TNF-α exposure was 390.5 patient-years (PYs). The overall incidence rate of SAEs for etanercept was 4.14/100PYs. Four patients developed uveitis, two had anxiety disorders, one had a serious zoster infection, and one developed TNF-α antagonist-induced lupus-like syndrome (TAILS). The overall incidence rate of SAEs for infliximab was 22.49/100PYs. The most common SAEs were anaphylactoid reactions (n=18), followed by infectious events (n=9) and TAILS (n=3). The overall incidence rate of SAEs for adalimumab was 4.71/100PYs (two infectious SAEs). No malignancies or deaths were observed. A greater incidence rate of infectious SAEs was observed in IBD patients receiving infliximab compared to JIA patients receiving etanercept (8.11 vs 0.52 per 100PYs). Anti-TNF-α therapy was generally well tolerated. SAEs leading to anti-TNF-α discontinuation were rare and non-fatal. Infliximab was associated with the highest incidence of SAEs. Infectious SAEs were more frequently observed in IBD patients treated with infliximab than in JIA patients receiving etanercept.

The risk associated with spinal manipulation: an overview of reviews

BackgroundSpinal manipulative therapy (SMT) is a widely used manual treatment, but many reviews exist with conflicting conclusions about the safety of SMT. We performed an overview of reviews to elucidate and quantify the risk of serious adverse events (SAEs) associated with SMT.MethodsWe searched five electronic databases from inception to December 8, 2015. We included reviews on any type of studies, patients, and SMT technique. Our primary outcome was SAEs. Quality of the included reviews was assessed using a measurement tool to assess systematic reviews (AMSTAR). Since there were insufficient data for calculating incidence rates of SAEs, we used an alternative approach; the conclusions regarding safety of SMT were extracted for each review, and the communicated opinion were judged by two reviewers independently as safe, harmful, or neutral/unclear. Risk ratios (RRs) of a review communicating that SMT is safe and meeting the requirements for each AMSTAR item, were calculated.ResultsWe identified 283 eligible reviews, but only 118 provided data for synthesis. The most frequently described adverse events (AEs) were stroke, headache, and vertebral artery dissection. Fifty-four reviews (46%) expressed that SMT is safe, 15 (13%) expressed that SMT is harmful, and 49 reviews (42%) were neutral or unclear. Thirteen reviews reported incidence estimates for SAEs, roughly ranging from 1 in 20,000 to 1 in 250,000,000 manipulations. Low methodological quality was present, with a median of 4 of 11 AMSTAR items met (interquartile range, 3 to 6). Reviews meeting the requirements for each of the AMSTAR items (i.e. good internal validity) had a higher chance of expressing that SMT is safe.ConclusionsIt is currently not possible to provide an overall conclusion about the safety of SMT; however, the types of SAEs reported can indeed be significant, sustaining that some risk is present. High quality research and consistent reporting of AEs and SAEs are needed.Systematic review registrationPROSPERO CRD42015030068.

Drug retention and safety of TNF inhibitors in elderly patients with rheumatoid arthritis.

BackgroundThe concerns about the development of adverse events (AEs) in elderly RA patients as a result of age-related changes in drug metabolism and the presence of comorbid illnesses are emphasizing due to increasing prevalence of rheumatoid arthritis (RA) in old age. However, they tend to be inadequately represented in RA clinical trials because of the exclusion criteria that are commonly applied. The tolerability and safety of TNF inhibitors in elderly patients have not been also evaluated in clinical practice. This study aimed to evaluate the retention rate and safety of TNF inhibitors (TNFI) in elderly RA patients.MethodsTotal 429 RA patients (838 person-years [PYs]) treated with TNFI from a retrospective biologic DMARDs registry. Patients were divided into an elderly (age ≥60 years) and a younger group (<60 years). The drug retention rates of both groups were compared using Kaplan-Meier curves. Potential predictors of TNFI discontinuation in the elderly were examined using Cox regression analysis. The incidence rate (IR) of serious adverse events (SAEs) in the elderly group was compared to that of the young group.ResultsOf the patients, 24.9 % (n = 107, 212 PYs) were in the elderly group. Regarding the retention rates of TNFI in 3 years, there was no significant difference between the elderly and younger group (p = 0.33). The major cause of discontinuation in elderly patients was AE (34.3 %), whereas that was drug ineffectiveness (41.7 %) in younger patients. Age (HR 1.09, CI 1.02-1.16) was a predictor of discontinuation, while the presence of comorbidity (HR 0.37, CI 0.15-0.91) had a protective effect against drug discontinuation in the elderly. The IR of SAEs in the elderly (6.13/100 PYs) was higher than in the younger group (5.11/100 PYs).ConclusionsThe retention rate of TNFI in the elderly was comparable with that in younger patients. The major cause of discontinuation in the elderly patients was AEs, while it was drug ineffectiveness in younger patients. The IR of SAEs in the elderly was higher than in the younger patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12891-016-1185-6) contains supplementary material, which is available to authorized users.

SAT0096 Safety of TNF Inhibitors and Predictors of Its Discontinuation in Elderly Patients with Rheumatoid Arthritis

BackgroundThe concerns about development of adverse events (AEs) in elderly RA patients as a result of age-related changes in drug metabolism and the presence of comorbid illnesses are emphasizing due...

Safety and effectiveness of adalimumab in patients with rheumatoid arthritis over 5 years of therapy in a phase 3b and subsequent postmarketing observational study

IntroductionPatients with active rheumatoid arthritis who had failed at least one disease-modifying anti-rheumatic drug (DMARD) were treated with adalimumab (ADA) in the ReAct study with the option to continue treatment for 5 years in ReAlise. The purpose of this study was to evaluate the long-term safety and effectiveness of ADA as prescribed from the first injection in ReAct to the last observation in ReAlise.MethodsPatients received ADA alone or in combination with DMARDs according to usual clinical care practices. Adverse events (AEs) were tabulated by five time windows after the first ADA injection. Effectiveness measures included achievement of low disease activity (LDA), defined as Simplified Disease Activity Index (SDAI) ≤11, or remission, (REM), defined as SDAI ≤3.3.ResultsOf the 6,610 ReAct patients, 3,435 (52%) continued in ReAlise. At baseline in ReAct, mean age was 54 years, mean DAS28 was 6.0 and mean HAQ DI was 1.64. The mean treatment duration was 1,016 days, representing 18,272 patient-years (PYs) of ADA exposure. Overall incidence rates of serious AEs and serious infections were 13.8 and 2.8 events (E)/100 PYs, respectively. Serious AEs occurred most frequently in the first 6 months and deceased thereafter. Standardised mortality ratio was 0.71 (95% CI 0.57 to 0.87) and standardised incidence ratio for malignancies was 0.64 (95% CI 0.53 to 0.76). LDA was achieved by 50% and REM by 21% of patients at last observation.ConclusionsResults of this large observational study of ADA in routine clinical practice were consistent with controlled trials, with no new safety concerns during a follow-up of more than 5 years. Effectiveness of ADA was maintained during long-term observation.Trial registrationNCT00448383, NCT00234884

A comparison of incidence and risk factors for serious adverse events in rheumatoid arthritis patients with etanercept or adalimumab in Korea and Japan

Objective. To compare the incidence and risk factors of serious adverse events (SAEs) in rheumatoid arthritis (RA) patients treated with etanercept (ETN) or adalimumab (ADA) between Korean and Japanese registries.Methods. We recruited 416 RA patients [505.2 patient-years (PYs)] who started ETN or ADA from Korean registry and 537 RA patients (762.0 PY) from Japanese registry. The patient background, incidence rate (IR) of SAE in 2 years, and risk factors for SAEs were compared.Results. Korean patients were younger and used more nonbiologic DMARDs, higher doses of methotrexate, and lower doses of prednisolone (PSL). The IR of SAEs (/100 PY) was higher in the Japanese registry compared to the Korean [13.65 vs. 6.73]. In both registries, infection was the most frequently reported SAE. The only significant risk factor for SAEs in Korean registry was age by decade [1.45]. In Japanese registry, age by decade [1.54], previous use of nonbiologic DMARDs ≥ 4 [1.93], and concomitant use of oral PSL ≥ 5 mg/day [2.20] were identified as risk factors for SAEs.Conclusions. The IR of SAE in Japan, especially infection, was higher than that of Korea, which was attributed to the difference of demographic and clinical characteristics of RA patients and treatment profiles.

AB0467 Rapid achievement of remission with certolizumab pegol was maintained for one year: interim results from fast, a german non-interventional study in rheumatoid arthritis real life patients

BackgroundCertolizumab pegol (CZP) demonstrated a fast response and acceptable safety profile in clinical studies in rheumatoid arthritis (RA).1-3ObjectivesTo assess use of CZP in daily clinical practice in Germany.MethodsThe efficacy and...