Patient Years Research Articles

POS0087 LONG-TERM SAFETY AND EFFICACY OF UPADACITINIB OR ADALIMUMAB IN PATIENTS WITH RHEUMATOID ARTHRITIS: RESULTS AT 3 YEARS FROM THE SELECT-COMPARE STUDY

Background:In the SELECT-COMPARE study, the Janus kinase inhibitor, upadacitinib (UPA), demonstrated significant improvements in the signs and symptoms of rheumatoid arthritis (RA) when administered at 15 mg once daily (QD) on background methotrexate (MTX) compared with adalimumab (ADA) plus MTX at Week 12 that were maintained through 72 weeks in patients with prior inadequate response to MTX.1Objectives:To assess the long-term safety and efficacy of UPA vs ADA over 3 years in the ongoing long-term extension (LTE).Methods:Patients receiving background MTX were randomized 2:2:1 to UPA 15 mg QD, placebo (PBO), or ADA 40 mg every other week. Between Weeks 14-26, rescue was mandated for either lack of response (<20% improvement in tender or swollen joint counts: Weeks 14, 18, 22) or failure to achieve a targeted disease outcome (CDAI low disease activity: Week 26). Patients who completed the 48-week double-blind period could enter an LTE for up to 10 years total. This analysis describes patients through 3 years of treatment. Treatment-emergent adverse events (TEAEs) per 100 patient years (PY), including events of special interest (AESI), were summarized up to 3 years based on exposure to UPA and to ADA. Efficacy was analyzed by original randomized groups. Patients who were rescued or prematurely discontinued study drug were categorized as non-responders for visits after rescue or discontinuation. Descriptive analyses were performed without formal statistical comparisons.Results:In total, 651, 651, and 327 patients were randomized at baseline to receive UPA, PBO, and ADA, respectively. Between Weeks 14-26, 252 (39%) patients were rescued from UPA to ADA, 159 (49%) were rescued from ADA to UPA, and all PBO patients were switched to UPA by Week 26.1 A higher proportion of patients randomized to UPA completed 3 years without rescue compared to those randomized to ADA (47% vs 36%, respectively). UPA was generally well-tolerated as assessed by the rates of TEAEs, including serious AEs, AEs leading to discontinuation of study drug, and AESIs, including serious and opportunistic infections, malignancies, adjudicated major adverse cardiac events or venous thromboembolism; Figure 1). Consistent with previous analyses, the event rates of AESIs were generally comparable between the UPA and ADA groups, while herpes zoster, lymphopenia, hepatic disorder, and CPK elevation were reported at higher rates with UPA. Consistent with earlier time points, greater proportions of patients randomized to UPA achieved low disease activity and remission at 3 years based on CDAI, as well as DAS28(CRP) ≤3.2 or <2.6, compared with patients randomized to ADA (Table 1).Conclusion:The safety profile of UPA was consistent with the results reported previously and with the integrated Phase 3 safety analysis.1,2 Higher levels of clinical response continued to be observed with UPA vs ADA through 3 years of treatment.

O09 Safety profile of baricitinib for the treatment of RA up to 8.4 years: an updated integrated safety analysis

Abstract Background/Aims Baricitinib (BARI) is an oral selective inhibitor of Janus kinase (JAK)1/2, approved for treatment of moderate-to-severe- rheumatoid arthritis (RA) in adults. Here, we update the drug’s safety profile with data up to 8.4 years of treatment. Methods Long-term safety of BARI was assessed from 9 completed randomized trials(5 Ph3, 3 Ph2, 1 Ph 1b) and 1 ongoing long-term extension(LTE) study. Incidence rates(IRs) per 100 patient-years (PY) were calculated for all RA patients treated with ≥1 dose of BARI through 1-Sep-2019(All-BARI-RA set). IRs for deep vein thrombosis(DVT), pulmonary embolism(PE), and DVT and/or PE(DVT/PE) were also calculated for groups of patients while receiving BARI 2mg/4mg within All-BARI-RA. Major adverse cardiovascular events(MACE) were adjudicated in 5 Ph3 studies and the LTE. Results 3770 pts received BARI for 13,148 PY, with median and maximum exposure: 4.2 and 8.4 years, respectively. Overall IRs per 100 PY were: for any treatment-emergent adverse event (AE)(25.8); serious AE (including death)(7.2); temporary interruption due to AE (9.5); permanent discontinuation due to AE (4.8); death (0.52); serious infection (2.7); opportunistic infection (0.46)(excluding tuberculosis [TB], including multidermatomal herpes zoster [HZ]); TB (0.15); HZ (3.0); MACE (0.50); DVT (0.31); PE (0.24); DVT/PE (0.46); malignancies excluding non-melanoma skin cancer (NMSC)(0.91); NMSC (0.33); lymphoma (0.07); and gastrointestinal perforation (0.04). (IRs)[95% confidence intervals] for patients while receiving BARI 2mg (N = 1077) and BARI 4mg (N = 3400) were DVT 2mg (0.38)[0.18, 0.73] and 4mg (0.30)[0.21, 0.43]; PE 2mg (0.26)[0.09, 0.56] and 4mg (0.25)[0.16, 0.36]; and DVT/PE 2mg (0.47)[0.23, 0.84] and 4mg (0.46)[0.34, 0.61]. IRs for death tended to increase in later time intervals (beyond 192 weeks). No particular cause of death contributed to this increase. For all other safety topics of interest, across 48-week treatment intervals, IRs remained stable over time. Across safety topics, IRs were consistent with previous analyses. Conclusion In this update, with 3021 additional PY of exposure, BARI maintained a safety profile similar to that previously reported, with no increase of IRs across safety topics through exposures up to 8.4 years. Disclosure K.L. Winthrop: Consultancies; AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly and Company, Pfizer, and UCB Pharma. Grants/research support; Bristol Myers Squibb and Pfizer. T. Takeuchi: Consultancies; AbbVie, Asahi Kasei Medical, Astellas, AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen, Mitsubishi Tanabe Pharma, Nippon Kayaku, Novartis, Pfizer Japan, Taiho Pharmaceutical, Taiho Toyama Pharmaceutical, Takeda, and UCB Japan. G. Burmester: Consultancies; Eli Lilly and Company, Janssen, Novartis, and Pfizer. Grants/research support; Eli Lilly and Company. W. Deberdt: Shareholder/stock ownership; Eli Lilly and Company. D. Schlichting: Shareholder/stock ownership; Eli Lilly and Company. D. Mo: Shareholder/stock ownership; Eli Lilly and Company. C. Walls: Shareholder/stock ownership; Eli Lilly and Company. J.S. Smolen: Consultancies; AbbVie, Amgen, AstraZeneca, Astro Pharma, Bristol Myers Squibb, Celgene, Celltrion, Chugai, Eli Lilly and Company, Gilead Sciences, ILTOO Pharma, Janssen, MedImmune, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi-Aventis, and UCB Pharma. Grants/research support; AbbVie, Eli Lilly and Company, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche.

Incidence of Infections and Malignancy Among Elderly Male Patients with IBD Exposed to Vedolizumab, Prednisone, and 5-ASA Medications: A Nationwide Retrospective Cohort Study.

Vedolizumab (VDZ) is postulated to have a potentially safer side effect profile than other biologic medications owing to its gut-selective mechanism. However, extrapolating these safety data to older patients is challenging because of their underrepresentation in or exclusion from most clinical trials, higher rates of withdrawal, and higher rates of comorbidities. Our aim was to evaluate the absolute risk of infections and malignancies in an elderly group of patients with inflammatory bowel disease (IBD) exposed to VDZ vs. the absolute risks associated with 5-aminosalicyclic acid (5-ASA) medications and chronic steroid use. We conducted a retrospective cohort study among the US national Veterans Affairs Healthcare System (VAHS). Our cohort comprised patients who were followed in the VAHS, had a diagnosis of IBD, and were aged 65years or older. The patients were divided into three cohorts: primary exposure group (elderly patients on VDZ), assumed low-risk group (elderly patients on 5-ASA only), and assumed high-risk group (elderly patients on chronic prednisone). The low-risk and high-risk groups were matched to the VDZ group on race, gender, IBD type, age, and Charlson Comorbidity Index (CCI). Primary outcomes gathered and confirmed via chart review included mild infections, severe infections, malignancies, and non-melanoma skin cancers (NMSC). The results were based on a descriptive analysis. A total of 497 patients were included in our study with 213, 186, and 98 patients in the VDZ, 5-ASA, and steroid groups, respectively. The total patient-years (PYs) of follow up were 405, 656, and 303 in VDZ, 5-ASA, and steroid groups respectively. The incidence of mild infection was the lowest in the VDZ group with 93.1 outcomes per 1000 PYs as compared to the 5-ASA group (114.4 outcomes per 1000 PYs) and 155.1 outcomes per 1000 PYs in the steroid group. In regard to severe infections, the VDZ group had an incidence of 38.5 outcomes per 1000 PYs as compared to 30.6 outcomes per 1000 PYs in the 5-ASA group and 67.4 outcomes per 1000 PYs in the steroids group. Mild infections with the highest incidence in the VDZ group were upper respiratory infection (including pharyngitis and sinusitis) at 20.3 per 1000 PYs, Clostridium difficile (15.1 per 1000 PYs), and cellulitis (10.0 per 1000 PYs).The severe infection with the highest incidence was pneumonia for each group, with incidence rates of 10.0, 14.0, and 48.6 per 1000 PYs for the VDZ, 5-ASA, and steroid groups, respectively. Incidence of malignancies (excluding NMSC) was numerically similar in the VDZ and 5-ASA group (17.6 and 15.6 per 1000 PYs, respectively), while the steroid group showed a higher incidence of 42.6 per 1000 PYs. NMSC incidence was numerically similar in the VDZ and steroid groups (36.3 and 39.0 per 1000 PYs, respectively), with the 5-ASA group showing a much lower NMSC incidence (4.6 per 1000 PYs). In a large nationwide cohort of elderly patients, we found the safety profile of VDZ among elderly patients with IBD with respect to the risk of infection and malignancy to be numerically similar to elderly patients with IBD taking 5-ASA, and favorable when compared to the elderly patients with IBD taking chronic steroids.

POS-520 EPIDEMIOLOGY OF KIDNEY TRANSPLANTS IN KAZAKHSTAN: DATA FROM UNIFIED NATIONAL ELECTRONIC HEALTH SYSTEM 2014-2018

The epidemiology of kidney transplant recipients (KTR) in Kazakhstan, nationally haven not previously been evaluated. We examined the prevalence, incidence, patient and renal graft survival rates of KTR using a large-scale administrative healthcare data from the Unified National Electronic Health System (UNEHS) for 2014-2018. Data of 1,142 KTR registered between 2014-2018 years were extracted from the UNEHS encompassing available retrospective records starting from 2009. Data included date of birth, sex, ethnicity, address by region, date of kidney transplantation (KT), donor source (deceased or living) and date of first dialysis after KT (considered as a graft lost). Descriptive statistics of demographic, epidemiology and transplant related outcome characteristics were provided. There was a predominance of male recipients (63.3%), of Kazakh ethnicity (79.5%), of urban residents (79.5%) and of living donors KT (92.5%). The crude all-cause mortality rate was 11.5 per 1000 patient-years (PY) (95%CI: 8.8-15.0) (Table 1). Tabled 1VariableN=1142 (%)Mortality rate per 1000 PY [95% CI]Gender: FemaleMale419 (36.7%)723 (63.3%)6.25 [3.46-11.27]14.55 [10.83-19.55]Age groups:<1818-3435-50>5185 (7.4%)508 (44.5%)381 (33.4%)168 (14.7%)8.3 [2.7 -25.6]6.3 [3.8 -10.7]15.6 [10.5 -23.3]20.7 [12.3 -35.0]Ethnicity:KazakhRussianOthers908 (79.5%) 91 (8.0%)143 (12.5%)11.2 [8.2 - 15.1]15.9 [7.1 - 35.4]10.9 [5.2 - 22.9]Residency:RuralUrban250 (21.8%)892 (78.2%)16.0 [9.5 - 27.0]10.8 [7.9 - 14.6]Donor source:DeceasedLiving86 (7.5%)1,056 (92.5%)28.4 [15.3-52.8]10.2 [7.6-13.6] Open table in a new tab The median follow-up time was 3.59 (Interquartile range (IQR) 2.27- 5.22) years. The prevalent and incident cases, and the rate of graft loss for the period 2014-2018 are present in Figure 1. Males had 2.3-fold higher risk of death (Hazard ratio (HR): 2.30 [95%CI: 1.19-4.4], p=0.008) compared with females (Figure 2a), while KTR of living donors had 65% lower risk of death (HR: 0.35 [95%CI: 0.18-0.71], p=0.009) compared with KTR from cadaveric donations (Figure 2b).View Large Image Figure ViewerDownload Hi-res image Download (PPT) The median graft survival time during the follow-up period was 2.12 (IQR 0.96-3.47) years. In life-table analysis (Figure 3) the 1-, 5-, and 10-year cumulative survival probability of KTR were 98.5% (95%CI: 97.5-99.0), 94.3% (95%CI: 92.4-95.7) and 92% (95%CI: 88.1-94.6) respectively. At the end of 1-, 5- and 10-years the cumulative death-censored graft survival were 80.8% (95%CI: 78.3-83.0), 27.9% (95%CI: 24.6-31.3) and 10% (95%CI: 7.4-13.1) respectively (Figure 3). For the first time in Kazakhstan, we analyzed and described data of kidney transplant patients utilizing a large-scale records from UNEHS. We observed decrease in the annual number of kidney transplantations starting from 2017 with overall extremely low rate of transplantations from deceased donors. The male recipients and cadaveric graft had statistically significant higher mortality rates. Although the patient survival rate was comparable with other countries, the rate of graft loss remained high. This information is of great consequence to the national public health authorities involved in planning of renal replacement therapies, considering the increasing number of patients who need dialysis or returned to dialysis after the graft failure. Further healthcare and organizational efforts are needed to improve the graft survival and to increase the number of deceases donor transplants.

Incidence of Hepatitis C Virus Infections Among Users of Human Immunodeficiency Virus Pre-exposure Prophylaxis

Sexual transmission of hepatitis C virus (HCV) is well documented among human immunodeficiency virus (HIV)-uninfected individuals. The use of HIV pre-exposure prophylaxis (PrEP) may be associated with engagement in activities that facilitate the transmission of sexually transmitted infections (STIs) and possibly HCV among PrEP users. Between 2012 and 2019, the incidence of HCV and bacterial STIs were calculated among HIV-negative indviduals receiving PrEP at the University Health Network HIV Prevention Clinic.Mucosal, anal, and blood samples were taken to test for HIV, syphilis, and anti-HCV antibodies. Among 344 HIV-uninfected patients receiving PrEP, 86% were men having sex with men (MSM). Five individuals were HCV-antibody positive at the time of PrEP initiation. Serologic and virologic follow-up data were available for 109 HCV-negative individuals over 282 patient-years (PY). Two new infections were recorded, yielding an incidence of primary HCV infection of 0.7 per 100 PY. In contrast with HCV, the incidence rates of chlamydia, gonorrhea, and syphilis were 49.2 per 100 PY, 36.3 per 100 PY, and 5.2 per 100 PY, respectively. Both individuals with new HCV diagnoses reported being MSM with a history of unprotected intercourse and 1 individual also reported recreational drug use. Both individuals were asymptomatic at the time of diagnosis and the infections were detected by routine laboratory monitoring. The low incidence of HCV infections despite significantly higher rates of other STIs suggests that sexual transmission of HCV is uncommon in HIV-negative MSM PrEP users in this community. Performing routine risk-based HCV surveillance among PrEP users should be evaluated. The high incidence of STIs in this population indicates a vital role for periodic STI monitoring in those receiving PrEP.

Long-term survival, risk factors and causes of mortality in surgically treated chronic pancreatitis

Background/ObjectivesChronic pancreatitis (CP) is a complex disease with a high complications rate, poor quality of life and considerable mortality. Prospective investigations on long-term outcomes in chronic pancreatitis are scarce. Thus, we aimed to assess long-term survival, causes of death and impact of risk factors on survival in a cohort of surgically managed patients with chronic pancreatitis. MethodsAfter IRB approval, a prospective longitudinal cohort study with long-term follow-up (up to 19.6 years) was conducted. All consecutive single center patients operated between 1997 and 2019 were included. Data on health and social status, risk behavior, history of CP, indications for surgery, comorbidities and causes of death were collected. Survival analysis was performed using Kaplan-Meier analysis. Cox proportional multivariate hazard regression was used to assess the impact of risk factors on mortality. The results are reported as the hazard ratio (HR) with the 95% confidence interval (CI). The log-rank test was used to test for differences in survival between groups. ResultsA total of 161 patients with CP were subjected to operative management due to chronic pain or local complications of CP. Forty-eight patients (29.8%) died during the follow-up period. Mortality rate was 32.8 per 1000 patient-years (PY) since the diagnosis of CP. Standardized mortality ratio (SMR) was 1.8 (2.7 for the subgroup of continuous alcohol users). Median survival after surgical treatment was 13.3 years. Univariate analysis revealed the following risk factors on survival: preoperative and postoperative continuous moderate or heavy alcohol consumption, heavy smoking, age ≥50 years, Charlson’s comorbidity index (CCI) ≥4 and 2–3, unemployment, disability, insulin-dependent diabetes, pancreatic exocrine insufficiency (PEI), and low body mass index (BMI). In multivariate regression analysis lower survival was associated with continuous moderate/heavy alcohol consumption (hazard ratio (HR) 2.27), history of heavy smoking (HR 4.40), unemployment (HR 2.49), CCI 2–3 and ≥4 (HR 2.53 and HR 3.16, respectively), and BMI <18.5 (HR 4.01).Behavioral risk factors accounted for the vast majority of deaths due to chronic alcoholic liver disease (21 cases, 43.7%), smoking-related diseases (15 cases, 31.3%). CP-related mortality was 4.2%. ConclusionsLong-term outcomes of surgically treated chronic pancreatitis was associated with low CP-related mortality. Alcohol-related and smoking-related diseases caused the vast majority of deaths. Thus, surgery provides the best results in patients, preventing postsurgical relapse of original behavioral risks. For achieving this, ongoing postoperative support would be highly beneficial.

A212 INCIDENCE OF HEPATITIS C VIRUS INFECTIONS AMONG USERS OF HUMAN IMMUNODEFICIENCY VIRUS PRE-EXPOSURE PROPHYLAXIS

Abstract Background Sexual transmission of hepatitis C virus (HCV) is well-documented among HIV-uninfected individuals. The use of HIV pre-exposure prophylaxis (PrEP) may lead to increased engagement in activities that facilitate the transmission of sexually transmitted infections (STI) and possibly HCV among PrEP users. Aims To assess the incidence of Hepatitis C Virus Infections among HIV negative pre-exposure prophylaxis (PrEP) users Methods Between 2012 and 2019, the incidence of HCV and bacterial STIs were calculated among HIV-negative patients receiving PrEP at the University Health Network HIV Prevention Clinic. Mucosal, anal and blood samples were taken to test for HIV, syphilis, and anti-HCV antibodies. Results Among 344 HIV-uninfected patients receiving PrEP, 86% were men having sex with men (MSM). Five individuals were HCV-antibody positive at the time of PrEP initiation. Serological and virological follow-up was available for 109 HCV-negative individuals over 282 patient-years (PY). Two new infections were recorded, yielding an incidence of primary HCV infection of 0.7/100 PY. In contrast with HCV, the incidence rates of chlamydia, gonorrhea, and syphilis were 49.2/100 PY, 36.3/100 PY, and 5.2/100 PY, respectively. Both individuals with new HCV diagnoses reported being MSM with a history of unprotected intercourse and one also reported recreational drug use. Both individuals were asymptomatic at the time of diagnosis and were detected by routine laboratory monitoring. Conclusions The low incidence of HCV infections despite significantly higher rates of other STIs suggests that sexual transmission of HCV is uncommon in HIV-negative MSM PrEP users. Performing routine risk-based HCV surveillance among PrEP users should be evaluated. The high incidence of STIs in this population indicates a vital role for periodic STI monitoring in those receiving PrEP. Funding Agencies vircan

Safety and Effectiveness of Peficitinib (ASP015K) in Patients with Rheumatoid Arthritis: Final Results (32 Months of Mean Peficitinib Treatment) From a Long-Term, Open-Label Extension Study in Japan, Korea, and Taiwan.

IntroductionThis final analysis of a long-term extension (LTE) study assessed the safety, tolerability, and effectiveness of peficitinib (ASP015K), a pan-Janus kinase inhibitor, in Asian patients with rheumatoid arthritis (RA).MethodsPatients had previously completed the 12-week phase 2b (RAJ1), or 52-week phase 3 (RAJ3 and RAJ4) peficitinib studies in Japan, Korea, and Taiwan, and received oral peficitinib 50 or 100 mg/day. Dose increase to 150 mg/day or reduction to 50 mg/day was permitted. Efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP), and ACR components. Safety endpoints included treatment-emergent adverse events (TEAEs), and incidence rates (IRs) of adverse events of special interest per 100 patient-years (PY).ResultsOverall, 843 patients received peficitinib for a mean 32.0 months (maximum 85.2 months), and most (64.4%) received peficitinib 100 mg/day as a maximum dose. Respective ACR20/50/70 response rates were maintained from baseline (week 0 of LTE; 71.6, 52.1, and 34.7%) to end of treatment (78.7, 63.3, and 44.1%); continuous improvements in ACR components and DAS28-CRP were observed from the baselines of preceding studies and throughout the LTE. Overall, 796/843 (94.4%) patients experienced TEAEs; most were severity grade 1/2. Most common TEAEs were nasopharyngitis (47.0%) and herpes zoster (17.3%). Drug-related TEAEs leading to permanent discontinuation occurred in 140 (16.6%) patients, and IRs (95% confidence interval) per 100 PY of serious infections, herpes zoster-related disease, and malignancies were 2.7 (2.1, 3.4), 7.3 (6.2, 8.6), and 1.2 (0.9, 1.8), respectively. Two deaths occurred during the study; one each from diffuse large B cell lymphoma and pneumonia, which were, respectively considered probably and possibly related to study drug.ConclusionsImprovements in effectiveness variables were maintained during this long-term study of peficitinib in Asian patients with RA; peficitinib was generally well tolerated over a mean 32 months’ duration.Trial RegistrationClinicalTrials.gov. NCT01638013, retrospectively registered on 11 July 2012 https://clinicaltrials.gov/ct2/show/NCT01638013.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00280-5.

Long-Term Safety and Efficacy of Eculizumab in Aquaporin-4 IgG-Positive NMOSD.

ObjectiveDuring PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin‐4 immunoglobulin G‐positive neuromyelitis optica spectrum disorder (AQP4‐IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open‐label extension (OLE; NCT02003144) evaluating eculizumab's long‐term safety and efficacy.MethodsPatients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis.ResultsAcross PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1–276.9 weeks), for a combined total of 362.3 patient‐years (PY). Treatment‐related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab‐treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6–97.3) of patients remained adjudicated relapse‐free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013–0.048) in all eculizumab‐treated patients versus 0.350 (95% CI = 0.199–0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use.InterpretationThis analysis demonstrates that eculizumab's long‐term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long‐term eculizumab treatment to reduce relapse risk in patients with AQP4‐IgG+ NMOSD. ANN NEUROL 2021;89:1088–1098

Independent association of marijuana use and poor oral hygiene with HPV-negative but not HPV-positive head and neck squamous cell carcinomas.

Sexual behavior is associated with human papillomavirus (HPV)-positive head and neck cancer, whereas tobacco and alcohol use are associated with HPV-negative cancer. A case-control study was designed to investigate additional demographic and behavioral factors independently associated with these distinct oral cancers. From 2011 to 2014, 249 newly diagnosed oral cavity and oropharyngeal squamous cell carcinoma (OSCC) cases were matched (1:2) on age, gender, and self-identified race to 498 controls without a cancer history attending the outpatient otolaryngology clinic at The Ohio State University in Columbus. Cases were stratified by detection of high-risk HPV DNA and RNA in tumors. Demographic and behavioral data were collected using an audio computer-assisted self-interview, and associations with HPV-positive versus HPV-negative OSCCs were investigated by use of univariable and multivariable conditional logistic regression models. After adjustment for oral sexual behavior, the odds of HPV-positive cancer decreased with the patient's years of education. Annual income, tobacco smoking, alcohol drinking, marijuana smoking, and poor oral hygiene were not associated with HPV-positive OSCC. In contrast, the odds of HPV-negative OSCC increased independently with decreased annual income, decreased with a high number of marijuana hit-years, and increased with fewer than annual dental visits after adjustment for lifetime tobacco and alcohol use. Sexual behavior and education were not associated with HPV-negative OSCC. The distinct risk-factor profiles for HPV-positive and HPV-negative OSCC are confirmed and extended in this case-control study, thus supporting 2 principal etiological pathways for OSCC development. Sexually acquired human papillomavirus (HPV) infection is an established cause of tonsil and base of tongue cancers. This study compared and contrasted risk factors for HPV-positive and HPV-negative oral cancers. Low number of years of education and sexual behavior are associated with HPV-positive cancer. In contrast, low annual income, infrequent dental visits, and tobacco and alcohol use are associated with HPV-negative cancers. Long-term marijuana use appears protective for HPV-negative cancer. Public health efforts to address these modifiable risk factors may prevent oral cancer.

Clinical outcomes in adult patients with plaque psoriasis treated with ustekinumab under real-world practice in Korea: A prospective, observational, multi-center, postmarketing surveillance study.

Postmarketing surveillance is conducted to establish drug safety and effectiveness under real-world practice. We aimed to validate the effectiveness and safety of ustekinumab in the treatment of adult Korean patients with plaque psoriasis under real-world practice. This was a prospective, observational, and multi-center study. Subjects aged 18years or older who were treated with ustekinumab for plaque psoriasis were enrolled. We enrolled 977 patients; 654 (66.9%) were men, with mean body surface area (BSA, ± standard deviation) of 27.0±18.3% and mean psoriasis area severity index (PASI) score of 18.1±9.7. The effectiveness analysis was performed in 581 patients who had at least one follow-up assessment and met treatment criteria per local label and reimbursement guidelines. Of these patients, 287 had effectiveness data for visit 6 at 53.7±2.1weeks. At visit 6, 91.6% (263/287), 51.2% (147/287), and 9.4% (27/287) patients achieved PASI 75, 90, and 100 responses, respectively. Adverse events (AEs) occurred in 112 of the 977 (11.5%) patients with an incidence rate of 21.5 per 100 patient-years (PYs). Serious AEs occurred in eight (0.8%) patients with an incidence rate of 1.2 per 100 PYs. The estimated 1-year drug survival rate was 87.7%. The multiple logistic regression analysis showed that higher baseline PASI score and no prior biologic exposure were significant predictors for PASI 90 response at visit 6. Ustekinumab was effective and safe, and displayed a high survival rate in the treatment of adult Korean patients with plaque psoriasis in real-world practice.

1480. Incidence of Non-Invasive Pneumococcal Pneumonia in Children in the United States before and after Introduction Pneumococcal Conjugate Vaccines (PCV7 and PCV13) during 1998-2018

BackgroundPneumonia causes significant pediatric morbidity, mortality, and healthcare resource utilization. S. pneumoniae is a leading cause of bacterial pneumonia in children. Merck is developing V114, an investigational 15-valent PCV that contains PCV13 serotypes as well as 22F and 33F. To demonstrate the potential value of V114, it is important to estimate the remaining burden associated with pneumococcal pneumonia (PP). This study was to estimate incidence rates (IRs) of non-invasive PP before and after PCV7 and PCV13 introduction in children in the US.MethodsPP-related claims in children < 18 years were identified in the IBM MarketScan® Commercial database (1998-2018) using pneumococcal specific ICD9/10 codes. Claims with any invasive pneumococcal disease ICD9/10 codes were excluded. An episode could comprise one or more claims. Episodes with any inpatient stays were categorized as inpatient, and as outpatient otherwise. Age-stratified (< 2, 2-4, and 5-17 years) IRs were episodes per 100,000 patient-years (PYs) during the pre-PCV7 (1998-1999), early and late PCV7 (2001-2005, 2006-2009), and early and late PCV13 (2011-2013, 2014-2018) periods.ResultsInpatient and outpatient PP IRs decreased steadily in children < 2 years (146.8, 117.9, 102.0, 67.8, and 32.2 per 100,000 PYs for pre-PCV7, early and late PCV7, and early and late PCV13 periods, respectively; Figure 1). In children 2-4 years, IRs increased slightly from 88.6 to 90.0 per 100,000 PYs from the pre-PCV7 to early PCV7 period, then declined to 83.9 and 30.8 per 100,000 PYs in the late PCV7 and late PCV13 periods, respectively (Figure 2). In children 5-17 years, IRs declined from 35.3 to 34.2 per 100,000 PYs from the pre-PCV7 to early PCV7 period, stabilized at 34.1 per 100,000 PYs in the late PCV7 period, followed by a steeper decline to 12.5 per 100,000 PYs in the late PCV13 period (Figure 3). The majority of episodes were outpatient in all three age groups.Figure 1. Non-invasive pneumococcal pneumonia incidence in children <2 years, episodes per 100,000 patient-years (1998 - 2018) Figure 2. Non-invasive pneumococcal pneumonia incidence in children 2 - 4 years, episodes per 100,000 patient-years (1998 - 2018) Figure 3. Non-invasive pneumococcal pneumonia incidence in children 5 - 17 years, episodes per 100,000 patient-years (1998 - 2018) ConclusionIn children < 2 years, IRs of non-invasive PP decreased after introduction of PCV7 and PCV13. Following introduction of PCV 7 and PCV13, there remains a residual burden of non-invasive PP in children in the US. The impact of future PCVs on PP will depend on the proportion of PP caused by S. pneumoniae and vaccine-type serotypes.DisclosuresTianyan Hu, PhD, Merck (Employee, Shareholder) Yan Song, PhD, Merck (Consultant) Nicolae Done, PhD, Merck & Co., Inc. (Consultant) Qing liu, PhD, Merck (Consultant) James Signorovitch, PhD, Merck & Co., Inc. (Consultant) Tanaz Petigara, PhD, Merck & Co., Inc. (Employee, Shareholder)

Small Vessel Disease and Ischemic Stroke Risk During Anticoagulation for Atrial Fibrillation After Cerebral Ischemia.

The causes of recurrent ischemic stroke despite anticoagulation for atrial fibrillation are uncertain but might include small vessel occlusion. We investigated whether magnetic resonance imaging markers of cerebral small vessel disease (SVD) are associated with ischemic stroke risk during follow-up in patients anticoagulated for atrial fibrillation after recent ischemic stroke or transient ischemic attack. We analyzed data from a prospective multicenter inception cohort study of ischemic stroke or transient ischemic attack anticoagulated for atrial fibrillation (CROMIS-2 [Clinical Relevance of Microbleeds in Stroke Study]). We rated markers of SVD on baseline brain magnetic resonance imaging: basal ganglia perivascular spaces (number ≥11); cerebral microbleeds (number ≥1); lacunes (number ≥1); and white matter hyperintensities (periventricular Fazekas grade 3 or deep white matter Fazekas grade ≥2). We investigated the associations of SVD presence (defined as presence of ≥1 SVD marker) and severity (composite SVD score) with the risk of ischemic stroke during follow-up using a Cox proportional hazards model adjusted for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65-74, female score. We included 1419 patients (mean age: 75.8 years [SD, 10.4]; 42.1% female). The ischemic stroke rate during follow-up in patients with any SVD was 2.20 per 100-patient years (95% CI, 1.60-3.02), compared with 0.98 per 100 patient-years (95% CI, 0.59-1.62) in those without SVD (P=0.008). After adjusting for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65-74, female score, SVD presence remained significantly associated with ischemic stroke during follow-up (hazard ratio, 1.89 [95% CI, 1.01-3.53]; P=0.046); the risk of recurrent ischemic stroke increased with SVD score (hazard ratio per point increase, 1.33 [95% CI, 1.04-1.70]; P=0.023). In patients anticoagulated for atrial fibrillation after ischemic stroke or transient ischemic attack, magnetic resonance imaging markers of SVD are associated with an increased risk of ischemic stroke during follow-up; improved stroke prevention treatments are required in this population. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02513316.

Efficacy and Safety of Ixekizumab in Patients with Psoriatic Arthritis and Inadequate Response to TNF Inhibitors: 3-Year Follow-Up (SPIRIT-P2).

PurposeIxekizumab is a high-affinity monoclonal antibody that selectively targets interleukin-17A. The objective of this study was to assess the long-term efficacy and safety (to week 156) of ixekizumab in patients with active psoriatic arthritis and inadequate response or intolerance to one or two tumor necrosis factor inhibitors.MethodsIn the SPIRIT-P2 study (ClinicalTrials.gov ID: NCT02349295), patients were randomized to placebo or ixekizumab 80 mg every 4 weeks (IXE Q4W) or every 2 weeks (IXE Q2W) following a 160-mg starting dose. During the extension period (weeks 24–156), patients maintained their original ixekizumab dose, and placebo patients received IXE Q4W or IXE Q2W (1:1). Exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) are presented.ResultsOf 363 patients enrolled in the study, 310 entered the extension period. In all patients treated with IXE Q4W and IXE Q2W at week 0, responses persisted to week 156. At week 156, clinical responses (observed) in patients treated with IXE Q4W and IXE Q2W were assessed [American College of Rheumatology (ACR) response criteria and minimal disease activity (MDA) criteria]: 84 and 85% showed 20% improvement (ACR20); 60 and 58% showed 50% improvement (ACR50); 35 and 47% showed 70% improvement (ACR70), respectively; and 48 and 54% showed MDA. Placebo patients re-randomized to ixekizumab also demonstrated sustained efficacy, as measured by ACR and MDA responses. In the All Ixekizumab Exposure Safety Population (n = 337), with 644 PY of ixekizumab exposure, treatment-emergent adverse events (TEAEs) were reported by 286 patients (44.4 IR). The most common TEAEs were upper respiratory tract infection (9.80 IR), nasopharyngitis (8.2 IR), sinusitis (6.2 IR), and bronchitis (4.5 IR). Serious adverse events were reported by 42 (6.5 IR) patients (included 3 deaths and 10 infections).ConclusionIn this 156-week study of ixekizumab, improvements in signs and symptoms of psoriatic arthritis and the safety profile remained consistent with those in previous reports.Trial registrationClinicalTrials.gov identifier: NCT02349295.Electronic supplementary materialThe online version of this article (10.1007/s40744-020-00261-0) contains supplementary material, which is available to authorized users.

A pooled safety analysis of peficitinib (ASP015K) in Asian patients with rheumatoid arthritis treated over a median of 2 years

Objective To evaluate the safety of peficitinib for the treatment of rheumatoid arthritis (RA) in Asian patients. Methods Safety data from one Phase 2b, two Phase 3, and one open-label long-term extension study [data cut-off 31 May 2018] were pooled into Phase 3 studies (peficitinib 100 and 150 mg/day, and placebo) and Phase 2/3 studies (all peficitinib-treated patients). Incidence rates per 100 patient-years (PY) of adverse events (AEs) of special interest were calculated. Results Overall, 1052 patients received peficitinib for 2336.3 PY of exposure (median 2.1 years); four deaths occurred, including one death after the studies. AE incidence was similar across peficitinib 100 and 150 mg/day groups (Phase 3 studies). Respective peficitinib and placebo incidence rates (95% confidence interval) per 100 PY were 2.9 (1.9, 4.6) and 0.0 for serious infections, 5.7 (4.2, 7.9) and 2.3 (0.6, 9.4) for herpes zoster-related disease, and 0.6 (0.2, 1.6) and 1.2 (0.2, 8.3) for malignancies (excluding non-melanoma skin cancer) (Phase 3 studies), and 0.1 (0.0, 0.3) for venous thromboembolism in all peficitinib-treated patients (Phase 2/3 studies). Conclusion Peficitinib was well tolerated in Asian patients with RA over a median of 2 years, with no observed dose or temporal dependency for AEs with prolonged administration.

Analysis of first plus recurrent cardiovascular (CV) and hospitalisation events in the CAROLINA trial

Abstract Background/Introduction CAROLINA (cardiovascular outcome study of linagliptin versus glimepiride in type 2 diabetes) was a randomised controlled clinical trial designed to compare the effects of linagliptin with glimepiride on CV events and other outcomes in patients with relatively early type 2 diabetes at elevated CV risk. Purpose To characterise the effects on net CV disease and the hospitalisation burden of this population, we assessed the effects of linagliptin vs glimepiride on all first plus recurrent CV events and all cause hospitalisations. Methods Participants with relatively early type 2 diabetes, high CV risk and HbA1c 6.5–8.5% were randomized to linagliptin 5 mg or glimepiride 1–4 mg once daily on top of standard of care. Cox regression was used to produce hazard ratios for time to first event. A negative binomial model was used to produce event rate ratios for all events. Results A total of 6033 participants were enrolled (mean age 64.0 years, HbA1c 7.2%, body mass index 30.1 kg/m2, eGFR 77 ml/min/1.73 m2, median type 2 diabetes duration 6.3 years, urine albumin:creatine ratio 10 mg/g, 42% with CV disease, 4.5% with heart failure). Adding recurrent events increased the number of events for analysis from first event by 10% more to 77% across CV/heart failure outcomes and by 119% for all cause hospitalisations, with corresponding increases in rates per 100-patient years in both treatment groups (e.g. for the composite of CV death/MI/stroke from 2.1 to 2.8 for linagliptin and 2.1 to 2.9 for glimepiride) over a median follow up of 6.3 years. Results of analyses of first-event and first plus recurrent events are presented below (Fig). Conclusion No significant differences were observed between linagliptin and glimepiride for either first or first + recurrent CV or hospitalisation events. These data underscore the significant CV disease burden experienced even in relatively early type 2 diabetes and reinforce the similar CV safety between linagliptin and glimepiride, differing only on hypoglycaemia risk. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Boehringer Ingelheim and Eli Lilly and Company

Is there an association between long-term exposure to particulate matter and events of severe hypoglycaemia in children and adolescents with type 1 diabetes?

Background/Aim: Studies on long-term exposure to air pollution and the impact on diabetes outcomes in children and adolescents with type 1 diabetes (T1D) are rare. We aimed at investigating the impact of particulate matter &lt;10 µm (PM10) and &lt;2.5 µm (PM25) on event rates of severe hypoglycaemia in young individuals with T1D. Methods: We studied 55,283 children and adolescents with T1D &lt;21yrs which were documented in German centres of the multicentre diabetes patient follow-up registry (DPV). Demographic and clinical data of the most recent treatment year between 2009 and 2018 was aggregated by patient. PM10- and PM2.5-yearly-averages prior to the respective treatment year were linked via the five-digit postcode areas of residency. Negative binomial regression models were used to study the association between PM-quartiles (Q1 lowest, Q4 highest concentration) and events of severe hypoglycaemia and hypoglycaemic coma per 100 patient years (PY). Models were adjusted for sex, age, diabetes duration, treatment year, migration background, type of treatment, degree of urbanisation and socioeconomic index of deprivation. Results: The included individuals with T1D had a median age of 15.8yrs (Q1:12.0-Q3:17.6; HbA1c 7.8% (7.1-9.0), 53% males, 45% insulin pump). Event rates of severe hypoglycaemia and hypoglycaemic coma were significantly higher at high PM10-concentration ≥18.0 µg/m3 (Q4: 12.5 events/100 PY (95%confidence interval:11.4-13.8) and 3.0 events/100 PY (2.6-3.4)) compared to lower PM10-concentration &lt;14.3 µg/m3 (Q1: 9.4 events/100 PY (8.5-10.4) and 1.5 events/100 PY (1.3-1.8)). Similar results were observed with PM2.5 (Q4 ≥12.9 µg/m3: severe hypoglycaemia 11.7 events/100 PY (10.6-13.0), hypoglycaemic coma 3.0 events/100 PY (2.6-3.4), Q1 &lt;10.1 µg/m3: 9.6 events/100 PY (8.6-10.7), 1.4 events/100 PY (1.2-1.7)). Additional adjustment for HbA1c did not change the results. Conclusions: Our results indicated a positive association between long-term exposure to particulate matter and events of severe hypoglycaemia at PM levels well below the EU yearly limit values.

Ustekinumab is effective and safe for ulcerative colitis through 2 years of maintenance therapy.

The ongoing UNIFI long-term extension evaluates subcutaneous ustekinumab for moderate-to-severe ulcerative colitis (UC) from weeks 44 through 220. To assess efficacy (through week 92) and safety (through week 96) during the long-term extension METHODS: Overall, 399 responders to intravenous ustekinumab induction and who were randomised to maintenance therapy were treated in the long-term extension (115 received subcutaneous placebo, 141 received ustekinumab 90mg every 12weeks [q12w], and 143 received ustekinumab 90mg q8w). Placebo treatment was discontinued at unblinding after week 44. Partial Mayo scores were collected every 12weeks and at each dosing visit after unblinding. Safety was evaluated throughout. Among all patients randomised in maintenance, symptomatic remission rates (stool frequency=0/1; rectal bleeding=0) at week 92 were, 64.5% and 67.6% in the ustekinumab q12w and q8w groups, respectively. Among randomised patients treated in the long-term extension, 78.7% and 83.2% of patients receiving q12w and q8w, respectively, attained symptomatic remission at week 92; >95% of patients in symptomatic remission at week 92 were corticosteroid-free. Both ustekinumab groups maintained efficacy through week 92. From weeks 44 to 96, adverse events (AEs) per hundred patient-years (PY) of follow-up for combined ustekinumab vs placebo were: 255.68 vs 267.93; serious AEs, 9.34 vs 12.69; malignancies (including non-melanoma skin cancers), 0.93 vs 1.49; and serious infections, 2.33 vs 2.99. One patient with multiple comorbidities who received one ustekinumab dose after dose adjusting from placebo experienced a fatal cardiac arrest. The efficacy of ustekinumab in patients with UC was sustained through 92weeks. No new safety signals were observed (ClinicalTrials.gov number, NCT02407236).

Impact of individual stroke risk on outcome after Amplatzer left atrial appendage closure in patients with atrial fibrillation.

To investigate periprocedural and long-term outcome of left atrial appendage closure (LAAC) using Amplatzer occluders with respect to individual pre-procedural stroke risk. LAAC is a proven strategy for prevention from stroke and bleeding in patients with nonvalvular atrial fibrillation not amenable to oral anticoagulation. Whether individual pre-procedural stroke risk may affect procedural and long-term clinical outcome after LAAC is unclear. Multicenter study of consecutive patients who underwent Amplatzer-LAAC. Using pre-procedural CHADS2 score, outcomes were compared between a low (0-2 points) and a high stroke risk group (3-6 points). Five hundred consecutive patients (73.9 ± 10.1 years) who underwent Amplatzer-LAAC. Two hundred and forty eight had preprocedural CHADS2 score ≤ 2 points (low-risk group) and the remaining 252 patients had 3-6 points (high-risk group). Periprocedural complication rates (6.0% vs. 5.6%, p=.85), procedural success (LAAC without major periprocedural or device-related complications or major para-device leaks: 89.4% vs. 87.9%, p=.74), and 30-day-mortality (2.4% vs. 2.6%, p=.77) were comparable. After 1,346 patient-years (PY), the long-term composite efficacy endpoint (stroke, systemic embolism, cardiovascular, and unexplained death) was reached in 23/653 (3.5/100 PY) versus 52/693 (7.5/100 PY); HR=2.13; 95%-CI, 1.28-3.65, p=.002) with stroke rates 67% and 68% lower than anticipated by preprocedural CHADS2 score. Combined safety endpoint (major periprocedural complications and major, life-threatening or fatal bleedings) occurred in 22/653 (3.4/100 PY) versus 28/693 (4.0/100 PY); HR=1.20; 95%-CI, 0.66-2.20, p=.52). Compared with patients at low risk of stroke, LAAC with Amplatzer devices is associated with similar safety and efficacy in high-risk patients in our study.

Everolimus-eluting bioresorbable scaffolds and metallic stents in diabetic patients: a patient-level pooled analysis of the prospective ABSORB DM Benelux Study, TWENTE and DUTCH PEERS

BackgroundSeveral studies compared everolimus-eluting bioresorbable scaffolds (EE-BRS) with everolimus-eluting stents (EES), but only few assessed these devices in patients with diabetes mellitus.AimTo evaluate the safety and efficacy outcomes of all-comer patients with diabetes mellitus up to 2 years after treatment with EE-BRS or EES.MethodsWe performed a post hoc pooled analysis of patient-level data in diabetic patients who were treated with EE-BRS or EES in 3 prospective clinical trials: The ABSORB DM Benelux Study (NTR5447), TWENTE (NTR1256/NCT01066650) and DUTCH PEERS (NTR2413/NCT01331707). Primary endpoint of the analysis was target lesion failure (TLF): a composite of cardiac death, target vessel myocardial infarction or clinically driven target lesion revascularization. Secondary endpoints included major adverse cardiac events (MACE): a composite of all-cause death, any myocardial infarction or clinically driven target vessel revascularization, as well as definite or probable device thrombosis (ST).ResultsA total of 499 diabetic patients were assessed, of whom 150 received EE-BRS and 249 received EES. Total available follow-up was 222.6 patient years (PY) in the EE-BRS and 464.9 PY in the EES group. The adverse events rates were similar in both treatment groups for TLF (7.2 vs. 5.2 events per 100 PY, p = 0.39; adjusted hazard ratio (HR) = 1.48 (95% confidence interval (CI): 0.77–2.87), p = 0.24), MACE (9.1 vs. 8.3 per 100 PY, p = 0.83; adjusted HR = 1.23 (95% CI: 0.70–2.17), p = 0.47), and ST (0.9 vs. 0.6 per 100 PY, p > 0.99).ConclusionIn this patient-level pooled analysis of patients with diabetes mellitus from 3 clinical trials, EE-BRS showed clinical outcomes that were quite similar to EES.