Concomitant Use Of NSAIDs Research Articles

Abstract WMP102: Risk Factors for MACE and Major Bleeding in Patients With Atrial Fibrillation Undergoing Elective Surgery: Insights From the BRIDGE Randomized Trial

Introduction: Atrial fibrillation (AF) patients undergoing elective procedures are at risk for Major Adverse Cardiovascular Events (MACE) and major bleeding. This study aimed to identify risk factors to guide risk stratification and perioperative management. Methods: We performed a post-hoc analysis of the BRIDGE randomized trial. Patients who were randomized into the study with outcome follow-ups were included in the analysis. The primary outcome was MACE (stroke, myocardial infarction, and cardiovascular death) and clinically symptomatic major bleeding. Statistical techniques included standard univariate analysis, logistic stepwise regression, and Cox regression models with Schoenfeld residual test to validate proportional hazard assumption. Additional interaction analyses were performed to assess interactions between low-molecular-weight heparin bridge therapy with identified risk factors. Results: A total of 1,813 participants met inclusion criteria: mean age 71.6±8.8, 73.3% male. MACE occurred in 25 (1.4%) individuals, with pre-procedure clopidogrel use (adjusted hazard ratio [aHR] 7.73, 95% CI 2.63-22.72, p<0.001) and high CHA 2 DS 2 -VASc score (≥ 5; aHR 2.89, 95% CI 1.26-6.63, p=0.012) identified as risk factors. Major bleeding occurred in 41 (2.3%) individuals, with bridge therapy (aHR 2.53, 95% CI 1.29-4.96, p=0.007), history of renal disease (aHR 3.12, 95% CI 1.56-6.24, p=0.001), post-procedure aspirin use (aHR 3.02, 95% CI 1.61-5.68, p=0.001), post-procedure NSAID use (aHR 3.90, 95% CI 1.20-12.70, p=0.024), and major surgery (aHR 2.17, 95% CI 1.05-4.46, p=0.036) identified as risk factors. The interactions between above risk factors and bridge therapy for MACE and major bleeding outcomes were not significant (p>0.05). Conclusion: The importance of perioperative assessment in AF patients is underscored by our findings, which identify distinct predictors for MACE and major bleeding. Guided by these insights, clinicians may generally avoid bridging and concomitant post-operative aspirin and NSAID use, thereby optimizing perioperative management to minimize the risk of adverse outcomes.

Outcomes of Oral Anticoagulation with Concomitant NSAID Use: A Registry Based Cohort Study

Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs), available without a prescription, are some of the most commonly used drugs in the United States. For patients on oral anticoagulation (OAC), concomitant NSAID use can increase the risk of bleeding. Patients are often advised to avoid this drug combination, or else consider adding a proton pump inhibitor (PPI) or H2 receptor antagonists (H2RA) for gastroprotection when both NSAIDs and OAC are used. However, there are limited data on how NSAID use impacts thrombotic and hemorrhagic outcomes. Available data may be biased due to selection bias, confounding, misclassification, and variable NSAID exposure. We sought to determine the frequency of NSAID use among patients on OAC, the impact on clinical outcomes, and if gastroprotection may mitigate bleeding risk. We hypothesized that NSAIDs would increase bleeding risk without impacting thrombotic risk. We did not anticipate gastroprotection would mitigate this risk. Methods We conducted a retrospective registry-based cohort study of adults starting a direct oral anticoagulant (DOAC) or warfarin therapy for the indications of venous thromboembolism and/or non-valvular atrial fibrillation between June 2011 and June 2023. As part of the Michigan Anticoagulation Quality Improvement Initiative (MAQI 2), warfarin-treated patients were followed by six anticoagulation clinics, and four of the six clinics contributed data for patients on DOACs. Patients were excluded if they had a history of valvular AF, less than 3 months of follow-up, or on more than one antiplatelet drug. Two propensity matched cohorts (OAC alone vs. OAC+NSAID) of patients were analyzed based on NSAID use at the time of study enrollment, using a 4:1 matching ratio. Both prescribed and over the counter NSAIDs were included, potentially with the former being more frequently captured in the study registry. The primary outcome was any new bleeding event. Secondary outcomes included new episodes of arterial or venous thrombosis, bleeding event type (major, fatal, life threatening, central nervous system, and non-major bleeding), emergency room visits, hospitalizations, transfusions, and death. Random chart audits were done to confirm the accuracy of the abstracted data. Event rates were compared using Poisson regression. Results Of 12,083 patients on OAC, 449 (3.7%) were on concomitant NSAIDs. After propensity matching, we compared 1,796 patients on OAC to 449 patients on OAC+NSAIDs. Patient demographics, co-morbidities, indication for anticoagulation, history of bleeding or clotting, medications, and duration of follow-up were well-balanced after matching. Patients were followed for an average of 30 months (standard deviation 34.2 months). For patients on OAC alone vs. OAC+NSAIDs, bleeding event rates were similar: 25.1 (95% confidence interval [CI] 23.7-26.6) versus 24.3 (95% CI 21.4-27.3) bleeds per 100 patient years ( P=0.56). Rates of non-major, major, life-threatening, central nervous system, and fatal bleeding were also similar. Furthermore, rates of thrombosis, emergency room visits, hospitalizations, transfusion, and death were similar. A pre-defined subgroup analysis comparing patients on OAC+NSAIDs with gastrointestinal prophylaxis (PPIs or H2RAs, N=179) to patients on OAC+NSAIDs without gastrointestinal prophylaxis (N=270) also showed similar rates of bleeding and healthcare utilization. Conclusions Nearly 4% of patients were taking NSAIDs with OAC and outcomes were similar to patients on OAC alone. Study limitations include NSAIDs and gastroprotection were only reliably known at time of enrollment. In addition, the potential for unmeasured or unadjusted confounding inherent to observational studies. Further research is needed to determine if there is a “safe” level of NSAID use for patients on OAC and to better define the role of gastrointestinal prophylaxis.

Virtual Screening and Pharmacokinetic Studies of Vaccinium oxycoccos L. Phytonutrients in Ulcer Induced Proinflammatory Mediated Targets

Molecular docking is a computational online software tool for analyzing ligand-protein interactions. Phytoconstituents have rich antioxidant properties that play a leading role in treating various diseases. Generally, the incidence of peptic ulcers increases day by day due to the concomitant use of NSAIDs. Medicament that induces ulcers can suppress the release of all pro-inflammatory targets such as prostaglandin-endoperoxide synthase-1(COX 1), prostaglandin- endoperoxide-2 (COX 2), Prostin E-2 (EP2), Prostaglandin E-3 (EP3), Prostin E-4 (EP4), and stimulate histamine-2 (the H2 receptor). Herbal medicaments are generally used for treatment because they have decreased adverse effects. Docking studies on Phytonutrients are helpful for the investigation of complementarity of the ligand with the receptor at the molecular level. The main aim of this docking study is to target all mediators and compare the affinity of Phytomedicines. Chem Draw Pro 8.0, RCSB protein data bank, is the software used for docking. Additionally, pharmacokinetic studies are conducted on the herbal constituents to analyze the therapeutic efficacy.

PARACETAMOL AND BLOOD PRESSURE CONTROL IN 45211 PATIENTS TREATED FOR HYPERTENSION: A CROSS-SECTIONAL STUDY FROM THE SWEDISH PRIMARY CARE CARDIOVASCULAR DATABASE

Objective: Paracetamol (acetaminophen) is widely recommended for analgetic and antipyretic indications due to its perceived high safety. However, studies have shown contradicting results regarding the effect of paracetamol on blood pressure (BP). We aimed to study how regular paracetamol use could affect BP control in patients on antihypertensive mediation. Design and method: Data for 42 511 patients attending primary care and a documented diagnosis of hypertension before 2007 (to rule out new onset of hypertension) and with 1 or more BP measurements recorded 2007–2008 were collected from the Swedish primary care cardiovascular database (SPCCD). There were 8 367 paracetamol users, defined as 1 or more dispensed prescriptions 6 months prior to the last BP recorded, and 34 144 non-users of paracetamol. Target BP was set to <140/90 mm Hg. Dose-response relationships were examined by the number of defined daily doses (DDD) dispensed. Multivariate linear regression analyses accounted for potential confounders. Results: Paracetamol users were older, had higher creatinine levels, more often diabetes, cardiovascular diseases and musculoskeletal diseases, and lower educational level than non-users (all P < 0.001), but attained target systolic and diastolic BP to similar degrees (58 and 93% vs 58 and 92%, respectively). There were no relations between number of DDD and systolic and diastolic BP in paracetamol users, also when DDD deciles were evaluated to account for the low proportion of patients with high DDD dispensed (all R2 <0.001). Sensitivity analyses including dispensed prescriptions of paracetamol 3 months before and 6 months after the first BP measurement provided similar results. Paracetamol had no impact on attaining target BP in subgroup analyses on patients with diabetes, musculoskeletal diseases, with concomitant use of NSAID, or in relation to number of antihypertensive medications (suggesting severity of hypertensive disease). Conclusions: Concomitant use of paracetamol does not impair the ability to reach target BP in hypertensive patients. No dose-response relationship was observed between dispensed prescriptions of paracetamol and BP.

The Association of Improved Overall Survival with NSAIDs in Non–Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors

BackgroundImmune checkpoint inhibitors (ICI) are commonly used in the management of patients with advanced non-small cell lung cancer (NSCLC), but response is suboptimal. Preclinical data suggest ICI efficacy may be enhanced with concomitant nonsteroidal anti-inflammatory (NSAID) medications. Patients and MethodsIn this retrospective study, the Veterans Health Administration Corporate Data Warehouse was queried for patients diagnosed with NSCLC and treated with ICI from 2010 to 2018. Concomitant NSAID use was defined as NSAID dispensation by a VA pharmacy within 90 days of the any ICI infusion. To mitigate immortal time bias, patients who started NSAIDs 60 or more days after ICI initiation were excluded from analysis. Survival was measured from start of ICI. ResultsWe identified 3634 patients with NSCLC receiving ICI; 2336 (64.3%) were exposed to concomitant NSAIDs. On multivariable analysis, NSAIDs were associated with better overall survival (HR = 0.90; 95% CI, 0.83-0.98; P = .010). When stratifying by NSAID type, diclofenac was the only NSAID with significant association with overall survival (HR = 0.75; 95% CI, 0.68-0.83; P < .001). Propensity score matching of the original cohort yielded 1251 patients per cohort balanced in characteristics. NSAIDs remained associated with improved overall survival (HR = 0.85; 95% CI, 0.78-0.92; P < .001). ConclusionThis study of Veterans with NSCLC treated with ICI demonstrated that concomitant NSAIDs are associated with longer OS. This may indicate that NSAIDs can enhance ICI-induced antitumor immunity and should prospectively validated.

Abstract IA016: Vaccine approach for the interception of colon cancer

Abstract This year, in the US, an estimated 150,000 people will be diagnosed with colon cancer and ~52,000 will die of the disease. A vaccine approach is well suited to colon cancer prevention. First, a limited number of immunizations can be given over a short period of time to achieve a desired immune response. If immunologic memory develops, antigen specific T-cells will persist in the body for years, ready to be deployed when aberrant cells are detected. Finally, there are several well-defined high-risk populations that would be suitable for testing a preventative colon cancer vaccine including individuals (1) with a hereditary genetic syndrome such as familial adenomatous polyposis, (2) with a history of inflammatory bowel disease such as Crohn’s disease or ulcerative colitis, and (3) those with a history of hyperplastic colonic polyps. Vaccines targeting virally mediated cancers are effective, in part, because T-cells are primed to proteins involved in oncogenesis. The most common type of colon adenoma and invasive cancer associated antigens are non-mutated growth-related proteins that become markedly overexpressed in the disease state. Genes which are aberrantly up-regulated and conserved from adenoma to invasive colon carcinoma may encode overexpressed proteins that are associated with colon cancer initiation. Evaluating gene expression data derived from over 600 colorectal cancers, matched normal tissues, and colon adenomas we identified 160 genes overexpressed in the majority of adenomas and early-stage colon cancers, but not in normal tissues. Using siRNA screening we demonstrated 35 of those genes, when silenced, resulted in apoptosis or inhibition of growth of colon cancer cells and an adenoma cell line but not a non-neoplastic colon cell line. Of those genes, 16 have been shown to encode proteins that are overexpressed in both adenomas and colon cancer and are associated with disease progression and over a third of these proteins are immunogenic. These proteins could serve as potential candidate antigens for inclusion in a multi-antigen vaccine. Recently, we have identified epitopes within the natural sequences of non-mutated tumor antigens that only generate Th1 (Th1 selective) antigen specific T-cells. This discovery and the development of high throughput methods to both identify and screen putative Class II binding peptides for Th selective function has allowed us to develop antigen specific Th1 selective vaccines. A vaccine targeting CDC25B, COX2, and EGFR can inhibit intestinal tumor formation in both APCmin mice and mice with tumor induced by AOM. Concomitant use of NSAIDs potentiates the immune response generated with vaccination. The anti-tumor response observed after vaccination is significantly correlated with elevated CD8 T-cells found in the lesions and induced by immunization as well as high magnitude antigen specific T-cells identified in the spleen. These data validate a genomic approach to antigen discovery and anti-tumor efficacy of Th1 selective vaccines for colon cancer prevention. Citation Format: Mary Disis, Ying Liu, Lauren Corulli, Erin Rodmaker, Denise Cecil. Vaccine approach for the interception of colon cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr IA016.

Protective effect of proton pump inhibitor against gastrointestinal bleeding in patients receiving oral anticoagulants: a systematic review and meta-analysis

Abstract Background The concurrent use of proton pump inhibitor (PPI) in oral anticoagulant (OAC) treated patients may be associated with a lower risk of gastrointestinal bleeding (GIB), but evidence is still conflicting according to individual OACs. Purpose We conducted a meta-analysis to estimate the risk of GIB in patients with OAC and PPI co-therapy. Methods A systematic search of PubMed, EMBASE, and Cochrane was performed for studies reporting GIB risk in OAC and PPI co-therapy. Primary outcomes were total GIB and major GIB events. We calculated pooled estimates of GIB risk by a random-effect meta-analysis and reported as odds ratios (OR) and 95% CI. Stratified analyses according to the origin of GIB, ethnic groups, individual OACs, and the presence of underlying GIB risk factors were performed. Results A total of 10 studies (1 randomized controlled study and 9 observational studies) and 1,970,931 patients who received OAC were included. OAC and PPI co-therapy were associated with a lower risk of total GIB, and major GIB; OR (95% CI) was 0.67 (0.62–0.74) for total GIB and 0.68 (0.63–0.75) for major GIB, respectively. Among total GIB, only the risk of upper GIB was lower with OAC and PPI co-therapy (OR 0.67, 95% CI 0.64–0.70). No difference in the lower risk of primary GIB outcomes of PPI co-therapy was observed between Asians and non-Asians (p-for-difference, total GIB=0.695, major GIB=0.748, respectively) and among individual OACs except for edoxaban. The protective effect of PPI on total GIB was more significant in high-risk patients, defined as those with concurrent medication of antiplatelets or non-steroidal anti-inflammatory drugs (OR 0.62, 95% CI 0.52–0.73) and presence of high bleeding risk factors such as previous GIB history, HAS-BLED score ≥3, or underlying gastrointestinal diseases. (OR 0.65, 95% CI 0.61–0.70). Conclusion In patients who receive OAC, the use of PPI co-therapy was associated with a lower risk of total GIB and major GIB irrespective of ethnic group and OAC type except for edoxaban. PPI co-therapy can be considered particularly in patients on concomitant NSAID and antiplatelet use or patients with high GIB risk factors. Funding Acknowledgement Type of funding sources: None.

Review of gastrointestinal bleeding during use of SSRIs combined with use of NSAID

IntroductionIn recent years, more and more attention has been paid to the risks of using SSRIs. This group of antidepressants may be associated with an increased risk of gastrointestinal bleeding. This risk would be even further increased with concomitant use of NSAIDs. A number of studies have described this interaction, however they reported conflicting results.ObjectivesOur objective was to investigate the risk of gastrointestinal bleeding with SSRIs, with or without NSAID use.MethodsWe performed a literature search, using Pubmed, EMBASE, and Cochrane library, in order to investigate controlled trials, cohort, case-control and cross-sectional studies that reported the incidence of gastrointestinal bleeding s on SSRIs with or without concurrent NSAID use, compared to placebo or no treatment.Results15 case-control studies and 4 cohort studies were included in the analysis. There was an increased risk of gastrointestinal bleeding with SSRIs in the cohort studies and case-control studies. The risk of gastrointestinal bleeding was even further increased with the combined use of both SSRIs and NSAIDs.ConclusionsSSRIs are associated with a modest increase of gastrointestinal bleeding. However, this risk is significantly increased when SSRIs are used in combination with NSAIDs. Psychiatrists should be aware of the hazards in prescribing these medications together.DisclosureNo significant relationships.

Incidence, predictorsand 6-month overall outcome of acute kidney injury in Chinese patients receiving PD-1 inhibitors.

Aim: To explore the incidence, risk factorsand overall outcome of the first episode of immune checkpoint inhibitor-related acute kidney injury (ICI-AKI) in Chinese patients receiving PD-1 inhibitors. Methods: Data for patients receiving PD-1 inhibitors at Jiangsu Province Hospital between December 2017 and January 2020 were retrospectively reviewed. Results: A total of5.6% of 551 patients receiving PD-1 inhibitors developed ICI-AKI. Concomitant use of NSAIDs, ICI cyclesand extrarenal immune-related adverse eventsmay be independently associated with ICI-AKI. ICI-AKI may not be a risk factor for increased mortality or worse progression-free survival. Conclusions: ICI-AKI is relatively rare and its occurrence may not affect the overall 6-month outcome of patients receiving PD-1 inhibitors. Further studies are needed to verify these findings.

Incidence And Risk Factors of Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A Large Case-Control Study

The incidence of ACEI-induced angioedema ranges from 0.1% to 0.7% affecting more women, African Americans, and adults over 65 years old. We sought to determine the incidence of ACEI-induced angioedema among different geographical regions of the U.S., comparing patients' characteristics and risk factors. A case-control study from 2008 to 2018 using electronic health records of an integrated health-care system across four states of the country. Cohort development software was used to obtain all ACEI prescriptions and angioedema was identified using ICD-CM codes 995.1 and T78.3 (Angioneurotic edema). Out of 145,101 patients who received an ACEI, 716 patients developed angioedema (0.49%; 95% CI, 0.46%-0.53%). Their median age was 66 years (Range: 21.0, 99.0), 50.4% were female, 88.5% Caucasian, and 84.8% of the cases were prescribed lisinopril. The risk of ACEI-induced angioedema was higher among women compared to men (OR 1.44; 95% CI; 1.24-1.67; P < .001), African American compared to Caucasian (OR 2.88; 95% CI; 2.14-3.89; P <.001), patients with concomitant use of NSAIDs compared to patients not on NSAIDs (OR 2.28; 95% CI; 1.85-2.8; P <.001), and in the upper Midwest compared to the Southeast (OR 1.57; 95% CI; 1.24-1.99; P < .001). Seventy-nine patients (11%) had ACEI-induced angioedema within one month of being prescribed an ACEI, and 244 (34%) during the first year. The incidence and risk factors for ACEI-induced angioedema in our cohort were similar to previous reports. Women, African Americans, patients on NSAIDs, and patients in the upper Midwest were at higher risk of ACEI-induced angioedema.

Biological Agents in OA - Hopes and Disappointments

Purpose: To review the trial in humans using biologics in osteoarthritis (OA) which can be can be categorized according to the main target: pain, structure or both. Methods: A literature review (Medline, Cochrane, Embase) of the most recent trials in OA using biologics Results: The analgesic effect of anti-nerve growth factor (NGF) was initially dramatic using high dose and intravenous route of administration, but emerging severe arthropathies (in the targeted knee but not only) have dampened down this enthusiasm. Most recent trials used anti NGF Mab, administered subcutaneously, with lower dose, shorter interval of administration and without concomitant use of NSAIDS. The effect on pain is still superior to placebo but with a much lesser magnitude. Unfortunately, long term follow-up in those trials still shows a concern in terms safety profile. Thus, Patients who will benefit of this anti NGF therapy should be strictly selected and followed up. Biologics agents targeting main cytokines (interleukines 1 and 6, tumor necrosis alpha) have been tested in knee OA and in hand OA. The first randomized controled trial in humans using a single local administration of the antagonist of IL-1, at 2 doses: 50 and 150 mg, failed to show an analgesic effect, except at day 3 with the highest dose. This negative result has been confirmed in trials using systemic administration of monoclonal antibodies directed against only IL1-β or against IL-1 α and Il-1 β in patients with knee OA and in patients with hand OA. However, in the CANTOR trial recruiting patients with cardiovascular disease treated with canakinumab, post hoc analysis indicated that the patients in the verum group, shows a dramatic decrease in the number of total joint replacement (hip and knee) (about 50%). This might open a door for a possible anti IL-1 strategy dedicated to patients with some part of systemic inflammation. Most of trial with anti TNF inhibitors have been performed in patients with erosive digital hand OA and all were negative on pain and on structure (measured by different parameters on magnetic resonance imaging). Finally the last cytokine that has been targeted is IL-6. Results of the RCP trial in hand OA are ongoing. Taking all together, biologics in OA are really disappointing, raising more questions than answers: choice of the targets, choice of selected phenotype of pain, selection of the route of administration, too short time of intra articular residence of the drug etc. News biologics targeting WNT, bradykinin or anti sense micro RNA are under development but so far, the preliminary results needs to be confirmed in large trials in humans. Finally, the last option is to try to stimulate the cartilage repair response which is naturally weak. Fibroblast growth factor 18 (sprifremin), an anabolic and mitogenic factor for the chondrocyte, has been tested against placebo in an ambitious trial over 5 years with 2 years of treatment and 3 years of follow-up. The drug was intra-articularly delivered every 6 months or every 12 months, with 2 different dosages. At the first end point, at year 2, with the highest dose of FGF-18, a statistically significant difference with the placebo was observed on the cartilage volume measured by MRI in the global, medial and lateral compartment on the involved knee. Unfortunately, there was no effect on pain in the ITT population, except in a sub group of patients with a minimum threshold of pain and an initial joint space width between 1.5mm and 3.5 mm (around one third of the population) show a significant effect on pain reduction compared to placebo. If results of this long term trial are confirmed in others trials, FGF-18 may constitute the first real disease modifying drug in OA. Conclusions Conclusion: The trials in humans using biologics are disappointing. We should keep in mind that blocking a single mediator will not stop the catabolic process in OA. Thus in the next future, we should probably adapt a drug owing to the evolution of the disease, to the profile of patient, to the radiological aspect of the disease and to the phenotype of pain. The story is just starting ⋯⋯

P262 Guselkumab, an anti-interleukin-23p19 monoclonal antibody, in patients with active PsA who were biologic-naïve or prior TNFα inhibitor-treated: week 24 results of a Phase 3, randomised, double-blind, placebo-controlled study

Abstract Background Guselkumab (GUS), an anti-interleukin-23p19 monoclonal antibody, is approved to treat psoriasis (PsO). We evaluated GUS efficacy and safety in a Phase 3, double-blind, placebo (PBO)-controlled trial in patients with active PsA who were biologic-naïve or prior TNFα inhibitor (TNFi)-treated (DISCOVER-1). Methods Adults with active PsA (≥3 swollen + ≥3 tender joints; CRP ≥0.3mg/dL) despite standard therapies (eg, non-biologic DMARDs, apremilast, or NSAIDs) were eligible. ∼30% of patients previously could have received or have had inadequate response to 1-2 TNFi. Patients were randomised 1:1:1, stratified by Week [W]0 DMARD use and prior TNFi use, to GUS 100mg Q4W; GUS 100mg at W0, W4, Q8W (Q8W); or PBO. Concomitant stable use of select non-biologic DMARDs, oral corticosteroids, and NSAIDs was allowed. At W16, patients with &amp;lt;5% improvement in tender+swollen joints could initiate or increase the dose of permitted medications while continuing study treatment. The primary endpoint was ACR20 at W24. Major secondary endpoints included: Investigator’s Global Assessment (IGA) PsO response (IGA=0/1 + ≥2-grade reduction) at W24 in patients with ≥3% BSA PsO and IGA ≥2 at W0; changes in DAS28-CRP, HAQ-DI and SF-36 PCS scores and ACR50/70 response at W24; and ACR20/50 response at W16. As preplanned, enthesitis or dactylitis data were pooled with those from the companion Phase 3 study DISCOVER-2. Due to different regional health authority regulatory requirements, Global and US multiplicity control procedures were prespecified with statistical results from US procedures presented. Unadjusted (nominal) p-values are provided for other endpoints. Adverse events (AEs) through W24 are reported. Results 381 patients were treated and analyzed; baseline characteristics were consistent with moderate-to-severe disease (mean BSA involved with PsO: 13.4%, patients with IGA=3-4: 42.5%; mean swollen/tender joint counts: 9.8/19.3). Significantly more patients receiving GUS Q4W (58.6%) and Q8W (52.8%) vs PBO (22.2%, both p &amp;lt; 0.001) achieved ACR20 response at W24. Consistent response rates were observed in the subgroups of patients with or without prior TNFi use. Significantly greater improvements in HAQ-DI and SF-36 PCS scores were seen in GUS- vs PBO-treated patients from W0 to W24. Among 249 patients with ≥3% BSA PsO and IGA ≥2 at W0, significantly more GUS- vs PBO-treated patients achieved IGA response. Higher proportions of patients achieved ACR20 response at W16, ACR50 response at W16/24, ACR70 response at W24, and PASI75/90/100 responses at W24. More GUS Q4W- or Q8W- vs PBO-treated patients achieved MDA response at W24. Serious AEs, serious infections, and death occurred in 9/381 (2.4%), 2/381 (0.5%), and 1/381 (0.3%) patients, respectively. Conclusion In patients with active PsA who were biologic-naïve or had been treated with TNFi, both GUS Q4W and Q8W demonstrated efficacy for joint and skin symptoms, physical function, and quality of life relative to PBO. Observed AEs were consistent with GUS safety established in PsO. Disclosures A. Deodhar: Other; A.D. has been a study investigator for Janssen clinical trials. P. Helliwell: Other; P.H. has been a research investigator for Janssen. W. Boehncke: Other; W.B. has been a study investigator for Janssen. E.C. Hsia: Other; E.H. is a Janssen employee. A.P. Kollmeier: Other; A.K. is a Janssen employee. R.A. Subramanian: Other; R.S. is a Janssen employee. X.L. Xu: Other; X.X. is a Janssen employee. S. Sheng: Other; S.S. is a Janssen employee. B. Zhou: Other; B.Z. is a Janssen employee. P.C. Gorecki: Other; P.G. is a Janssen employee. C. Ritchlin: Other; C.R. has been a study investigator for Janssen.

P11 Etanercept persistence in juvenile idiopathic arthritis up to adult care in patients in Germany: a real-world analysis

Abstract Background Although juvenile idiopathic arthritis (JIA) occurs early in life, patients can require long-term treatment into adulthood due to active disease or flares. However, most available studies show that there are gaps in care during and after the transition to adult care. Transition has been associated with higher dropout rates, and there is limited evidence on treatment persistence in JIA patients. The current analysis evaluates etanercept bio-original (ETNBo) persistence up to 5 years and reports diagnostic patterns in early adolescence and young adults in Germany. Methods Patients with JIA (ICD10: M08) between 2-30 years of age with a first recorded ETNBo prescription between 1-January-2008 and 31-December-2012 were retrospectively identified in German health insurance claims data. Patients were followed until 31-December-2015 or end-of-record, whichever came first. Index date was set at the first ETNBo prescription after a 12-month etanercept-free look-back period. Patient characteristics, concomitant treatments and prior use of other biologic Disease-modifying antirheumatic Drugs (bDMARD) were evaluated in the 12-month look-back period. The 5-year etanercept treatment persistence, defined as median (95% confidence interval [CI]) months between the index date and a discontinuation (≥90-day treatment gap after last etanercept prescription), was estimated using Kaplan-Meier analysis, overall and for bio-naïve patients. Etanercept WHO defined daily dose (DDD) was adjusted by age; for patients 2-6, 7-10, 11-14 and &gt;15 daily doses were defined as 1.4mg, 3.6mg, 5.4mg and 7.0mg, respectively. The proportion of patients receiving an adult rheumatic diagnosis after the age of 11 was described. Results We identified 125 patients diagnosed with JIA (median age: 15 years; 30% male). At index quarter 56% of patients were in the 11-20 age group. Most patients (94%) were bio-naïve and 46%, 34%, and 17% had concomitant use of NSAIDS, other DMARDS, and corticosteroids, respectively. Overall median persistence was 13 months (95%CI: 10-16; IQR: 5-27). Persistence for the bio-naïve patients was 50% (95%CI: 41-57), 27% (95%CI: 20-34), 16% (95%CI: 10-23), 10% (95%CI: 5-17) and 9% (95%CI: 4-15) at 12, 24, 36, 48, and 60 months respectively. The majority of patients (68%) received an additional diagnosis of rheumatoid arthritis after age 11, while 15% were given other adult rheumatic diagnoses. Only 9% of JIA patients had received no additional diagnosis to JIA. Conclusion This analysis provides important understanding of care in young JIA patients. We observed a decreasing persistence of etanercept therapy as patients progressed in time through the transition period into early adulthood. Importantly, we found that the majority of JIA patients received additional adult diagnoses, which suggests the transition could impact on the clinical management of this disease. Diagnostic patterns, clinical and patient circumstances during this critical period and their impact on persistence requires further analysis. Conflicts of Interest The authors declare no conflicts of interest.

The effect of tumour necrosis factor inhibitors on radiographic progression in axial spondyloarthritis: a systematic literature review.

The effect of TNF-α inhibitors (TNFi), with or without concomitant NSAIDs, on radiographic progression in axial SpA remains unclear. Therefore, we performed a systematic literature review up to January 2019 to determine whether longer use of standard dose TNFi is superior vs lower duration or lower dose TNFi therapy, conventional synthetic DMARDs alone, or no therapy in inhibiting radiographic progression in patients with axial SpA. Our search yielded 373 titles of which 14 full text articles and five abstracts were eligible for quantitative analysis. Studies had an overall moderate to critical risk of bias. Data could not be pooled due to clinical and methodological heterogeneity. Individual studies showed conflicting results with mainly no significant difference in radiographic progression when comparing effect of TNFi therapy to no TNFi therapy or when comparing to less TNFi therapy until 2 years of follow-up. Results that are more significant are shown after 2 years' follow-up, mainly in subgroups with baseline syndesmophytes. Data on the additional or synergistic effect of concomitant NSAID use were inconclusive.

Effects of Non-Steroid Anti-Inflammatory Drugs on the Lower Gastrointestinal Tract.

BACKGROUND &amp; AIMS: Adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDS) on the upper gastrointestinal (GI) tract and small intestine are well described. Evidence is also accumulating that NSAIDS can induce and/or exacerbate the underlying pathology in the distal GI tract. The aim of this study was to estimate the effect NSAIDs on distal GIT&#x0D; METHODS: In 79 consecutive patients with chronic user of NSAIDs and 50 matched controls were included in this study which is done in Aldewanyia city. A detailed clinical history and physical examination were taking. Sigmoidoscopy; with or without colonoscopy were done were done to all patients and volunteer candidates, with histopathological study of rectal and colonic biopsies&#x0D; RESULTS: Of the 79 cases of patients, 38 (48%) were had lower clinical manifestation and 31(39%) of patients had histopathological which is mainly non-specific colitis vs. 9 (22%), 4(8%) of controls; P &lt; 0.0001). NSAID use was aspirin (alone or combined) in 34.2% of cases, and 70.25% were using other NSAIDs alone or combined. Other independent risk factors were also assessed like smoking, diabetes, and body weight.&#x0D; CONCLUSIONS: NSAID use is strongly associated with an increased risk of upper GIT. This review study point up that NSAIDs can cause significant morbidity in some patients ranging from changing of bowel motion, profuse diarrhea, exacerbating of underlying inflammatory bowel disease, to chronic blood loss with iron deficiency anemia. The pathogenesis is likely multifactorial and is thought to be related to inhibition of prostaglandin synthesis with direct effect of drugs or its metabolites.&#x0D; The high prevalence of aspirin and other NSAIDs use suggests that adverse effects on GIT are increasing and should increasing the clinical awareness of these adverse effect throughout the GI tract may reduce morbidity. Concomitant NSAID use, smoking, and alcohol use is a widely association.

Risk factors for upper gastrointestinal bleeding among aspirin users: An old issue with new findings from a population-based cohort study

We aimed to identify the risk factors of first-time occurrence of non-variceal upper gastrointestinal bleeding (UGIB) among aspirin users after adjusting for confounding factors like age, gender, underlying co-morbidities, and medications. Using the National Health Insurance Research Database of Taiwan and matching age, gender, underlying co-morbidities and enrollment time by propensity score, 11105 aspirin users and 11105 controls were identified for comparison from a cohort dataset of 1,000,000 randomly sampled subjects. Cox proportional hazard regression models were used to identify independent risk factors for first-time occurrence of non-variceal UGIB in the study cohort and in the aspirin users after adjusting for age, gender, underlying co-morbidities, and medications (e.g., non-steroidal anti-inflammatory drugs [NSAIDs], cyclooxygenase-2 [COX-2] inhibitors, steroids, thienopyridines, selective serotonin reuptake inhibitors, warfarin, and dipyridamole). By Cox proportional hazard regression analysis, aspirin use increased the risk of first-time occurrence of UGIB (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.28-1.72). Age, male gender, Helicobacter pylori (H. pylori)infection, diabetes, chronic kidney disease (CKD), cirrhosis, history of uncomplicated peptic ulcer disease (PUD), and use of NSAIDs, COX-2 inhibitors, steroids, and thienopyridines were independent risk factors for UGIB among aspirin users. In addition to age, male gender, H. pylori infection, and concomitant use of NSAIDs, COX-2 inhibitors, steroids, and thienopyridines, underlying co-morbidities including diabetes, CKD, cirrhosis, history of PUD are also important risk factors for first-time occurrence of non-variceal UGIB in aspirin users.

High diagnostic accuracy of white blood cell scintigraphy for fracture related infections: Results of a large retrospective single-center study

IntroductionWhite blood cell (WBC) scintigraphy for diagnosing fracture-related infections (FRIs) has only been investigated in small patient series. Aims of this study were (1) to establish the accuracy of WBC scintigraphy for diagnosing FRIs, and (2) to investigate whether the duration of the time interval between surgery and WBC scintigraphy influences its accuracy. Patients and methods192 consecutive WBC scintigraphies with 99mTc-HMPAO-labelled autologous leucocytes performed for suspected peripheral FRI were included. The golden standard was based on the outcome of microbiological investigation in case of surgery, or − when these were not available – on clinical follow-up of at least six months. The discriminative ability of the imaging modalities was quantified by several measures of diagnostic accuracy. A multivariable logistic regression analysis was performed to identify predictive variables of a false-positive or false-negative WBC scintigraphy test result. ResultsWBC scintigraphy had a sensitivity of 0.79, a specificity of 0.97, a positive predicting value of 0.91, a negative predicting value of 0.93 and a diagnostic accuracy of 0.92 for detecting an FRI in the peripheral skeleton. The duration of the interval between surgery and the WBC scintigraphy did not influence its diagnostic accuracy; neither did concomitant use of antibiotics or NSAIDs. There were 11 patients with a false-negative (FN) WBC scintigraphy, the majority of these patients (n = 9, 82%) suffered from an infected nonunion. Four patients had a false-positive (FP) WBC scintigraphy. ConclusionsWBC scintigraphy showed a high diagnostic accuracy (0.92) for detecting FRIs in the peripheral skeleton. Duration of the time interval between surgery for the initial injury and the WBC did not influence the results which indicate that WBC scintigraphy is accurate shortly after surgery.

Impact of methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism on the outcome of methotrexate treatment in a sample of Egyptian rheumatoid arthritis patients

Background: Methotrexate is the most commonly used disease-modifying anti-rheumatic drug (DMARD) and it is considered the first-line treatment in the management of rheumatoid arthritis (RA). MTX treatment outcome regarding response to the drug and adverse effects in RA patients are not universal. Therefore, it would be beneficial if we could predict the response of patients to MTX before starting MTX treatment in order to determine the patient’s drug-treatment plan. Objectives: The present study aimed to evaluate the impact of MTHFR A1298C SNP (rs1801131) on the clinical outcome of MTX treatment as regards treatment efficacy and toxicity in a cohort of Egyptian rheumatoid arthritis patients. Patients and methods: Fifty rheumatoid arthritis patients were included in the present study. Data about patient related variables such as age and sex, disease related variables such as disease duration as well as treatment related variables such as treatment duration, dose of MTX, its route of administration and concomitant use of other drugs (NSAIDs) were obtained. DAS28 was calculated to all patients to assess drug response. MTHFR A1298C polymorphism was investigated using real time 5′ nuclease allelic discrimination assay. Results: Multivariate regression analysis for factors predicting MTX drug response showed that MTHFR A1298C SNP and MTX dose were the most significant independent predictors for MTX treatment response (p = .016, OR = 39.113, 95% C.I = 1.970–776.558, p = .003, OR = 1.667, C.I = 1.184–2.348, respectively). Considering clinicopathological variables; longer disease duration, positive anti-CCP, NSAIDs users, higher MTX doses and longer treatment durations were significantly associated with non-response to MTX. Regarding MTX drug toxicity, MTHFR 1298 CC genotype, MTX dose and concomitant use of NSAIDs were significantly associated with MTX drug toxicity (MCp = .003, p = .031, p = .029, respectively). Conclusion: Our study proved that MTHFR A1298C SNP can predict clinical outcome of MTX treatment as regards treatment efficacy and toxicity in Egyptian rheumatoid arthritis patients.

Non-steroidal anti-inflammatory drugs and blood pressure control in patients treated for hypertension: results from the Swedish primary care cardiovascular database

Purpose: The aim of this observational cohort study was to investigate blood pressure level and the possibility to reach target blood pressure during concomitant use of NSAID in hypertensive patients.Materials and methods: From the Swedish primary care cardiovascular database (SPCCD) a cohort of 5463 patients (2007 to 2008) with at least one prescription of NSAID dispensed 6 months prior to the last blood pressure measurement were included. Clinical data were extracted from computerized medical records and linked to the Prescribed Drug Register. Multivariable logistic regression models were used for analysis.Results: Patients with NSAID usage were younger, more often female, with lower creatinine concentrations, more musculoskeletal diagnosis and less cardiovascular comorbidity compared to patients without dispensed NSAID (p < .0001 for all). Regular dose of NSAID was not associated with a decreased possibility to reach target blood pressure. A correlation between the dose of naproxen and an increase in SBP of 7 mm Hg was found. Impairment in renal function did not influence the association between blood pressure control and NSAID (p = .27).Conclusion: In hypertensive patients with concomitant use of NSAID the chance to reach target blood pressure was not impaired. In intermediate and frequent users of NSAID there was a dose response relation with naproxen and SBP which was not found in diclofenac and ibuprofen.

P720 Use of proton pump inhibitors associated with a markedly increased risk of microscopic colitis

Background: Microscopic colitis (MC) is a chronic inflammatory bowel disease with unknown etiology. Proton pump inhibitor (PPI) use has been consistently linked to an increased risk of MC. The specific role of the different classes of PPI is unknown. Based on the nationwide Danish registries we explored the association between MC and use of PPI and in addition the effect of different classes of PPIs and dose-dependency. Secondly we explored the effect of concomitant use of PPI and NSAID. Methods: In a ten-year period (January 2004 to December 2013) we identified 10652 patients with a first-time recorded diagnosis of MC including 6254 (59%) with collagenous colitis (CC) and 4398 (41%) with lymphocytic colitis (LC). MC cases were identified via the Danish Pathology Registry. For each MC case, we sampled 10 population controls. Information on PPI use was obtained from the Danish Prescription Register. The analysis conformed to a case-control design, estimating the odds ratio (OR) for the association between PPI use and the risk MC using conditional logistic regression, while adjusting for potential confounders. Results: We found strong associations between current PPI use and both CC (adjusted OR [aOR] 8.75; 95% CI: 8.12–9.43) and LC (aOR 5.03; 95% CI: 4.61–5.49). This association was seen across all individual PPIs, however, the strongest association was seen with current use of lansoprazole, for both CC (aOR 20.10; 95% CI: 18.05–22.37) and LC (aOR 7.70; 95% CI: 6.79–8.73). When considering timing, ORs were highest for current use of PPI, while the association quickly diminished when considering recent or past exposure. When analyzing the prescribed strength of PPI, we found no apparent dose-response pattern. The use of NSAID was associated with a modest increased risk of CC (aOR 1.70; 95% CI: 1.55–1.87). However, the combination of NSAID and PPI and was associated with a higher risk for CC (aOR 9.72; 95% CI: 8.65–10.92) compared to the use of one of the drugs alone. Conclusions: In a large comprehensive case-control study based on nationwide Danish registries we found an increased risk of MC associated with the use of PPI and especially an increased risk with the use of lanzoprazole. The combination of NSAID and PPI and was associated with a high risk for CC.