Learning with an evolving medicine label: how artificial intelligence-based medication recommendation systems must adapt to changing medication labels.

INTRODUCTION: Artificial intelligence or machine learning (AI/ML) based systems can help personalize prescribing decisions for individual patients. The recommendations of these clinical decision support systems must relate to the "label" of the medicines involved. The label of a medicine is an approved guide that indicates how to prescribe the drug in a safe and effective manner. AREAS COVERED: The label for a medicine may evolve as new information on drug safety and effectiveness emerges, leading to the addition or removal of warnings, drug-drug interactions, or to permit new indications. However, the speed at which these updates are made to these AI/ML recommendation systems may be delayed and could influence the safety of prescribing decisions. This article explores the need to keep AI/ML tools 'in sync' with any label changes. Additionally, challenges relating to medicine availability and geographical suitability are discussed. EXPERT OPINION: These considerations highlight the important role that pharmacoepidemiologists and drug safety professionals must play within the monitoring and use of these tools. Furthermore, these issues highlight the guiding role that regulators need to have in planning and oversight of these tools.

Artificial intelligence or machine learning (AI/ML) based systems that guide the prescription of medications have the potential to vastly improve patient care, but these tools should only provide recommendations that are in line with the label of a medicine. With a constantly evolving medication label, this is likely to be a challenge, and this also has implications for the off-label use of medicines.

Comparative effectiveness of biologics in patients with rheumatoid arthritis stratified by body mass index: a cohort study in a Swiss registry.

OBJECTIVES: Obesity is associated with lower treatment response in patients with rheumatoid arthritis (RA). In patients with obesity, abatacept was suggested as a preferable option to tumour necrosis factor-alpha inhibitors. We aimed to assess the comparative effectiveness of etanercept, infliximab and abatacept, compared with adalimumab, in patients with RA with obesity. Secondarily, we also investigated this in patients with overweight and normal weight for completeness. DESIGN: Observational cohort study. SETTING: Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry (1997-2019). PARTICIPANTS: Adult patients with RA from the SCQM registry who received etanercept, infliximab, abatacept or adalimumab as their first biological or targeted synthetic disease-modifying antirheumatic drug were classified based on their body mass index (BMI) at the start of that treatment in three cohorts: obese, overweight, normal weight. They were followed for a maximum of 1 year. EXPOSURE: The study exposure of interest was the patients' first biological, particularly: etanercept, infliximab and abatacept, compared with adalimumab. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary study outcome was remission within 12 months, defined as 28-joint Disease Activity Score (DAS28) <2.6. Missingness was addressed using confounder-adjusted response rate with attrition correction. Logistic regression was used to compare the effectiveness of etanercept, infliximab and abatacept versus adalimumab. Each BMI cohort was addressed and analysed separately. RESULTS: The study included 443 obese, 829 overweight and 1243 normal weight patients with RA. There were no statistically significant differences in the odds of DAS28-remission at ≤12 months for etanercept, infliximab and abatacept, compared with adalimumab, in any of the BMI cohorts. CONCLUSIONS: No differences in DAS28-remission were found between the study drugs and adalimumab as first biologic in patients with RA, independently of the BMI cohort. We did not find evidence that treatment with abatacept increased the likelihood of remission compared with adalimumab among obese patients with RA.

The Unseen Hand: AI-Based Prescribing Decision Support Tools and the Evaluation of Drug Safety and Effectiveness.

The use of artificial intelligence (AI)-based tools to guide prescribing decisions is full of promise and may enhance patient outcomes. These tools can perform actions such as choosing the 'safest' medication, choosing between competing medications, promoting de-prescribing or even predicting non-adherence. These tools can exist in a variety of formats; for example, they may be directly integrated into electronic medical records or they may exist in a stand-alone website accessible by a web browser. One potential impact of these tools is that they could manipulate our understanding of the benefit-risk of medicines in the real world. Currently, the benefit risk of approved medications is assessed according to carefully planned agreements covering spontaneous reporting systems and planned surveillance studies. But AI-based tools may limit or even block prescription to high-risk patients or prevent off-label use. The uptake and temporal availability of these tools may be uneven across healthcare systems and geographies, creating artefacts in data that are difficult to account for. It is also hard to estimate the 'true impact' that a tool had on a prescribing decision. International borders may also be highly porous to these tools, especially in cases where tools are available over the web. These tools already exist, and their use is likely to increase in the coming years. How they can be accounted for in benefit-risk decisions is yet to be seen.

Longitudinal associations between body mass index and changes in disease activity and radiographic progression in rheumatoid arthritis patients treated with infliximab.

OBJECTIVES: Treatment response is worse in obese patients with rheumatoid arthritis (RA), including patients on weight-adjusted therapies like infliximab. We aimed to assess the association between body mass index (BMI) and changes in RA disease activity and radiographic progression over time. METHODS: We included infliximab users with an RA diagnosis in the Swiss Clinical Quality Management in Rheumatic Diseases registry (1997-2020). Two cohorts were defined: (1) starting from their first BMI measurement or disease activity score (DAS28-esr), and (2) from their first BMI measurement or radiographic assessment (Rau score). We evaluated the coefficient and 95% CI of BMI with changes in mean DAS28-esr (cohort 1) and mean Rau scores (a structural joint damage score, cohort 2) using generalised estimation equations, overall and stratified by BMI categories. RESULTS: Cohort 1 comprised 412 patients (74% women, mean age 53 years, mean BMI 25). We observed no change in mean DAS28-esr with increasing BMI overall (adjusted coefficient: 0.00, 95% CI -0.02 to 0.02), or in BMI categories. Cohort 2 comprised 187 patients highly alike to those in cohort 1. We observed a significant decrease of 1.05 in mean Rau scores for every increase in BMI unit (adjusted coefficient: -1.05, 95% CI -1.92 to -0.19). Results remained statistically non-significant across BMI categories. CONCLUSIONS: Our longitudinal investigation suggests that BMI increase may not lead to changes in DAS28-esr in patients receiving infliximab, despite the weight-adapted dose. Yet, there may be a decrease in erosions with increasing weight non-limited to obese patients.

Obesity Represents a Persisting Health Issue in Axial Spondyloarthritis, Particularly Affecting Socially Disadvantaged Patients.

OBJECTIVE: Obesity is an important comorbidity in axial spondyloarthritis (axSpA); however, the prevalence of obesity in axSpA compared with the general population and associated socioeconomic factors remain unknown. METHODS: This repeated cross-sectional study compared BMI (kg/m2) groups of patients with axSpA to the Swiss population at 3 timepoints (2007, 2012, and 2017). BMI categories were compared by different age, sex, and education categories using the chi-square goodness of fit test. Unpaired, 1-sided t tests were used to compare the BMI in patients with axSpA between the different timepoints. RESULTS: Compared to the general population, patients with axSpA had a higher proportion of overweight and obesity: 18.9% of all patients with axSpA were obese, compared to 11.3% of the Swiss population in 2017. Comparison of BMI groups within sex, age, and education groups consistently showed a trend toward higher rates of overweight and obesity in axSpA. Further, patients with axSpA, especially females, showed a trend of increasing BMI over the studied 10 years. At every time point, overweight and obese patients were significantly more likely to be male, were older, and had higher disease activity than patients with normal weight. Obesity was associated with a deprived socioeconomic status as indicated by a higher proportion of patients with manual labor jobs and lower levels of education. CONCLUSION: The prevalence of obesity was significantly higher among patients with axSpA compared to the Swiss population, with socially disadvantaged individuals being the most affected. There is an urgent need to initiate prevention strategies for obesity in patients with axSpA.

JAK-inhibitors and risk on serious viral infection, venous thromboembolism and cardiac events in patients with rheumatoid arthritis: A protocol for a prevalent new-user cohort study using the Danish nationwide DANBIO register.

Janus Kinase inhibitors (JAKis) are targeted synthetic disease-modifying antirheumatic drugs and represent an important alternative to treat patients with moderate to high rheumatoid arthritis (RA) disease activity. Safety concerns associated with increased risk for venous thromboembolism (VTE), serious viral infection, and, more recently, major adverse cardiovascular events (MACE) in JAKi users have emerged worldwide. However, as the exact mechanisms to explain these safety concerns remain unclear, the increased risk of VTE, MACE, and serious viral infection in JAKi users is heavily debated. In light of the need to enrich the safety profile of JAKis in real-world data, we aim to quantify the incidence and risk of MACE, VTE, and serious viral infections in RA patients registered in the Danish DANBIO registry, a nationwide registry of biological therapies used in rheumatology. Therefore, we will conduct a population-based cohort study using a prevalent new-user design. We will identify all RA patients in the DANBIO, ≥ 18 years old, receiving a JAKi or a tumor necrosis factor α inhibitor (TNF-αi) from January 2017 to December 2022. Prevalent and new users of JAKis will be matched to TNF-αi comparators with similar exposure history using time-conditional propensity scores (TCPS). We will describe the cumulative incidence of the outcomes (VTE, MACE, serious viral infection) in each exposure group (JAKi users; TNF-αi users), stratified by outcome type. Additionally, the Aalen-Johansen method will be used to estimate the time-to-event survival function stratified by outcome type. We will also estimate the hazard ratio (HR) with 95% confidence interval (CI) of each outcome in both exposure groups using the time-dependent Cox proportional hazards model. Results will enrich the safety profile of JAKis in real-world data.

Sex and gender in infection and immunity: addressing the bottlenecks from basic science to public health and clinical applications.

Although sex and gender are recognized as major determinants of health and immunity, their role is rarely considered in clinical practice and public health. We identified six bottlenecks preventing the inclusion of sex and gender considerations from basic science to clinical practice, precision medicine and public health policies. (i) A terminology-related bottleneck, linked to the definitions of sex and gender themselves, and the lack of consensus on how to evaluate gender. (ii) A data-related bottleneck, due to gaps in sex-disaggregated data, data on trans/non-binary people and gender identity. (iii) A translational bottleneck, limited by animal models and the underrepresentation of gender minorities in biomedical studies. (iv) A statistical bottleneck, with inappropriate statistical analyses and results interpretation. (v) An ethical bottleneck posed by the underrepresentation of pregnant people and gender minorities in clinical studies. (vi) A structural bottleneck, as systemic bias and discriminations affect not only academic research but also decision makers. We specify guidelines for researchers, scientific journals, funding agencies and academic institutions to address these bottlenecks. Following such guidelines will support the development of more efficient and equitable care strategies for all.

Lower odds of remission among women with rheumatoid arthritis: A cohort study in the Swiss Clinical Quality Management cohort.

OBJECTIVE: To compare the likelihood of achieving remission between men and women with rheumatoid arthritis (RA) after starting their first biologic or targeted synthetic disease-modifying anti-rheumatic drug (b/tsDMARD). METHODS: This cohort study in the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry included RA patients starting their first b/tsDMARD (1997-31/04/2018). The odds of achieving remission at ≤12-months, defined by disease activity score 28-joints (DAS28) <2.6, were compared between men and women. Secondary analyses were adjusted for age and seropositivity, and we investigated potential mediators or factors that could explain the main findings. RESULTS: The study included 2839 (76.3%) women and 883 (23.7%) men with RA. Compared to women, men were older at diagnosis and b/tsDMARD start, but had shorter time from diagnosis to b/tsDMARD (3.4 versus 5.0 years, p<0.001), and they had lower DAS28 at b/tsDMARD start. Compared to women, men had 21% increased odds of achieving DAS28-remission, with odds ratio (OR) 1.21, 95% confidence interval (CI) 1.02-1.42. Adjusting for age and seropositivity yielded similar findings (adjusted OR 1.24, 95%CI 1.05-1.46). Analyses of potential mediators suggested that the observed effect may be explained by the shorter disease duration and lower DAS28 at treatment initiation in men versus women. CONCLUSION: Men started b/tsDMARD earlier than women, particularly regarding disease duration and disease activity (DAS28), and had higher odds of reaching remission. This highlights the importance of early initiation of second line treatments, and suggests to target an earlier stage of disease in women to match the benefits observed in men.

Minimal disease activity and remission in patients with psoriatic arthritis with elevated body mass index: an observational cohort study in the Swiss Clinical Quality Management cohort.

OBJECTIVE: To assess the impact of elevated body mass index (BMI) in the achievement of minimal disease activity (MDA) and several definitions of remission in patients with psoriatic arthritis (PsA) in Switzerland. Secondarily, to assess the overlapping across the study outcomes. METHODS: This observational cohort study in the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry included patients with PsA starting their first biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) from 1997 to 30 June 2018. Exposure was BMI category at b/tsDMARD start: overweight, obese, and normal weight (reference). Logistic regression was used to assess the achievement of MDA and remission at ≤12 months, as well as treatment persistence at 1 year, in overweight patients and patients with obesity compared with the normal weight group. Remission was defined by Disease Activity for Psoriatic Arthritis (DAPSA), clinical DAPSA (cDAPSA) and 28-joint Disease Activity Score (DAS28). Additionally, overlapping across study outcomes was investigated. RESULTS: The study included 306 (39.5%) normal weight patients, 285 (36.8%) overweight patients and 183 (23.6%) patients with obesity. Compared with the normal weight group, patients with obesity had lower odds of achieving MDA at ≤12 months (adjusted OR (ORadj) 0.45, 95% CI 0.24 to 0.82). This was consistent with the observed reduced odds of achieving DAPSA-remission (ORadj 0.42, 95% CI 0.21 to 0.85), cDAPSA-remission (ORadj 0.51, 95% CI 0.27 to 0.96) and DAS28-remission (ORadj 0.51, 95% CI 0.32 to 0.81) in patients with obesity versus normal weight patients. Among the 125 patients achieving MDA, the majority (81.8% normal weight, 80.0% overweight, 78.9% obese) achieved cDAPSA-remission. No differences were observed in the odds to achieving treatment persistence between the BMI strata. CONCLUSIONS: Obesity halved the likelihood of achieving MDA and remission in patients with PsA with b/tsDMARDs compared with those with normal weight, while it did not impact treatment persistence. High overlapping of patients achieving the outcomes MDA and cDAPSA-remission was observed across every BMI group.

Non-cardiovascular medication and readmission for heart failure: an observational cohort study.

Background Among heart failure (HF) patients, hospital readmissions are a major concern. The medication taken by a patient may provide information on comorbidities and conditions and may be used as an indicator to identify populations at an increased risk of HF readmission. Aim This study explored the use of non-cardiovascular medication at hospital discharge from the first HF admission in search of indicators of high risk of readmission for HF. Method The study included 22,476 HF patients from the Dutch PHARMO Database Network at their first HF hospitalization. The data was divided into training and validation sets. A Cox regression model with demographics, date of first HF hospital admission and non-cardiovascular medication present at discharge, adjusted for cardiovascular medication, was developed in the training set and subsequently implemented in the validation set. Results The study included 22,476 patients, mean age 76.7 years (range 18-104) and median follow-up time 2.5 years (range 0-15.7 years). During the study period 6,725 (29.9%) patients were readmitted for HF, with a median time-to-readmission of 7 months (range 0-14.3 years). Non-cardiovascular medication associated with a high risk of readmission for HF were identified as indicators of high risk, with no implied causal relationship. Patients prescribed antigout medications presented a 25% increased risk of readmission (HR 1.25, 95%CI 1.09-1.45, P = 0.002). Patients using insulin had an 18% higher risk of readmission versus patients not using insulin (HR 1.18, 95%CI 1.06-1.32, P = 0.002), but not versus patients treated with other blood-glucose-lowering drugs. No association between the risk of readmission and NSAIDs use was observed. Conclusion The results suggest that diabetes is responsible for the higher HF-readmission risk observed in patients prescribed insulin. The observed risk in users of antigout medication should be further investigated. The absence of an association with the use of NSAIDs should be interpreted with caution.

Interruptions of biological and targeted synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis: a descriptive cohort study assessing trends in patient characteristics in Switzerland.

OBJECTIVES: To identify differing patient characteristics at the time of stop and restart of biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in rheumatoid arthritis (RA), stratified by stop reason. DESIGN: Explorative descriptive cohort study. SETTING: Swiss Clinical Quality Management in Rheumatic Diseases (1999-2018). PARTICIPANTS: Patients with RA who stopped their first b/tsDMARD. OUTCOME MEASURES: We assessed patient characteristics at b/tsDMARD stop and restart, stratified by stop reason (non-response, adverse event, remission, other). RESULTS: Among 2526 eligible patients, most patients (38%) stopped their b/tsDMARD due to non-response. At treatment stop, most characteristics did not differ by stop reason, yet some differed significantly (p<0.0001, those stopping due to remission had lowest median Health Assessment Questionnaire measurements (0.1) and were least likely to use leflunomide combination therapy (3.9%) and to have fibromyalgia (6.7%)). The majority of patients restarted b/tsDMARDs without changes in patient characteristics at restart. However, among the 48% of patients who restarted a b/tsDMARD after having previously stopped due to remission or other reasons, disease activity measurements were significantly worse compared with treatment stop date (mean disease activity score-erythrocyte sedimentation rate score of 2.0 at b/tsDMARD restart vs 3.5 at treatment stop (p<0.0001)). Furthermore, we observed non-significant trends in several patient characteristics (eg, higher proportion of women (75% at b/tsDMARD restart vs 70% at treatment stop, p=0.38), patients with seropositivity (anti-citrullinated protein antibody positive 67% vs 58%, p=0.25), with family history of rheumatic diseases (24% vs 20%, p=0.15), osteoarthritis/arthroplasty (25% vs 20%, p=0.34) and the metabolic syndrome (11% vs 6%, p=0.15). CONCLUSION: Differences among patient characteristics across b/tsDMARD cessation strata were few. However, differences between stop and restart may have identified an RA phenotype that is challenging to treat. Further research on identifying the patient characteristics predictive of successful drug holidays and the optimal time to initiate and stop a drug holiday is warranted.

Drug Triggers and Clinic of Acute Generalized Exanthematous Pustulosis (AGEP): A Literature Case Series of 297 Patients.

Acute generalized exanthematous pustulosis (AGEP) is a rare skin reaction, commonly caused by drugs. Available evidence mostly relies on small studies or case reports. We collected published AGEP case reports and, subsequently, described the patient characteristics, suspect and concomitant drugs, time to onset, disease management, and clinical prognosis. This study included 297 AGEP patients (64.3% women) obtained from 250 published case reports or case series with individual patient data. AGEP affected patients of all ages, but the majority of patients (88.2%) were ≥25 years old. The most frequently reported suspect drugs were anti-infectives for systemic use (36.5%), particularly antibacterials for systemic use (31.0%), and especially beta-lactam antibacterials (18.3%) and macrolides (4.3%). Other frequent suspect drugs were antineoplastics (12.2%), and anti-inflammatory/anti-rheumatic products (5.2%) plus hydroxychloroquine (12.8%). Mean time to onset was 9.1 days (standard deviation SD 13.94). Some patients developed fever (64.3%) and systemic involvement (18.9%), and most patients (76.4%) received pharmacological treatment for AGEP. Seven patients died, although five of them were already critically ill prior to AGEP. In conclusion, antibiotics remain the most common suspected cause of AGEP. While case mortality rate may be up to 2.5%, disentangling the role of AGEP on the fatal outcome from the role of the preexisting health conditions remains challenging.

Prediction of sustained biologic and targeted synthetic DMARD-free remission in rheumatoid arthritis patients.

OBJECTIVES: The aim was to develop a prediction model of sustained remission after cessation of biologic or targeted synthetic DMARD (b/tsDMARD) in RA. METHODS: We conducted an explorative cohort study among b/tsDMARD RA treatment episode courses stopped owing to remission in the Swiss Clinical Quality Management registry (SCQM; 2008-2019). The outcome was sustained b/tsDMARD-free remission of ≥12 months. We applied logistic regression model selection algorithms using stepwise, forward selection, backward selection and penalized regression to identify patient characteristics predictive of sustained b/tsDMARD-free remission. We compared c-statistics corrected for optimism between models. The three models with the highest c-statistics were validated in new SCQM data until 2020 (validation dataset). RESULTS: We identified 302 eligible episodes, of which 177 episodes (59%) achieved sustained b/tsDMARD-free remission. Two backward and one forward selection model, with eight, four and seven variables, respectively, obtained the highest c-statistics corrected for optimism of c = 0.72, c = 0.70 and c = 0.69, respectively. In the validation dataset (47 eligible episodes), the models performed with c = 0.99, c = 0.80 and c = 0.74, respectively, and excellent calibration. The best model included the following eight variables (measured at b/tsDMARD stop): RA duration, b/tsDMARD duration, other pain/anti-inflammatory drug use, quality of life (EuroQol), DAS28-ESR score, HAQ score, education, and interactions of RA duration and other pain/anti-inflammatory drug use and of b/tsDMARD duration and HAQ score. CONCLUSION: Our results suggest that models with up to eight unique variables may predict sustained b/tsDMARD-free remission with good efficiency. External validation is warranted.

Inhibition of Sema-3A Promotes Cell Migration, Axonal Growth, and Retinal Ganglion Cell Survival.

Purpose: Semaphorin 3A (Sema-3A) is a secreted protein that deflects axons from inappropriate regions and induces neuronal cell death. Intravitreal application of polyclonal antibodies against Sema-3A prevents loss of retinal ganglion cells ensuing from axotomy of optic nerves. This suggested a therapeutic approach for neuroprotection via inhibition of the Sema-3A pathway. Methods: To develop potent and specific Sema-3A antagonists, we isolated monoclonal anti-Sema-3A antibodies from a human antibody phage display library and optimized low-molecular weight Sema-3A signaling inhibitors. The best inhibitors were identified using in vitro scratch assays and semiquantitative repulsion assays. Results: A therapeutic approach for neuroprotection must have a long duration of action. Therefore, antibodies and low-molecular weight inhibitors were formulated in extruded implants to allow controlled and prolonged release. Following release from the implants, Sema-3A inhibitors antagonized Sema-3A effects in scratch and repulsion assays and protected retinal ganglion cells in animal models of optic nerve injury, retinal ischemia, and glaucoma. Conclusions and Translational Relevance: Collectively, our findings indicate that the identified Sema-3A inhibitors should be further evaluated as therapeutic candidates for the treatment of Sema-3A-driven central nervous system degenerative processes.

Comparison of Psoriatic Arthritis and Rheumatoid Arthritis Patients across Body Mass Index Categories in Switzerland.

Abnormal body mass index (BMI) was associated with worse rheumatic markers in psoriatic arthritis (PsA) and rheumatoid arthritis (RA). Aiming to describe PsA and RA patients stratified by BMI, we performed a descriptive study in PsA and RA patients (two distinct cohorts) in the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry. New users of biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) were stratified by BMI at the start of their treatment (underweight, normal weight, overweight, obese). The PsA underweight and normal weight categories were merged. Age at disease onset and further characteristics at the start of the first b/tsDMARD treatment were compared across BMI categories vs. the corresponding normal weight group. The study included 819 PsA (36.5% overweight, 23.8% obese) and 3217 RA patients (4.4% underweight, 31.8% overweight, 17.0% obese). Compared to the corresponding normal weight group, PsA and RA obese patients had significantly (p < 0.05) higher C-reactive protein, worse disease activity, and lower quality of life (QoL). Obese PsA patients had significantly worse skin manifestation and pain, while obese RA patients had significantly higher erythrocyte sedimentation rate and tender joint counts, as well as lower seropositive prevalence. To conclude, obese PsA and RA patients presented worse disease activity and poorer QoL than those with normal weight.

Cardiovascular Safety Profile of Romosozumab: A Pharmacovigilance Analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS).

Background: Cardiovascular safety concerns for major cardiovascular events (MACE) were raised during the clinical trials of romosozumab. We aimed to evaluate the cardiovascular safety profile of romosozumab in a large pharmacovigilance database. Methods: All cases reported between January 2019 and December 2020 where romosozumab was reported were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS). The outcome of interest was MACE (myocardial infarction (MI), stroke, or cardiovascular death). A disproportionality analysis was conducted by estimating the reporting odds ratios (RORs) and 95% confidence intervals. Disproportionality analyses were stratified by sex and reporting region (US, Japan, other). Results: Of the 1995 eligible cases with romosozumab, the majority (N = 1188; 59.5%) originated from Japan. Overall, 206 suspected MACE reports were identified, of which the majority (n = 164; 13.8%) were from Japan, and 41 (5.2%) were from the United States (US). Among Japanese reports, patients were older and more frequently male than reports from the US. Similarly, cases with a reported MACE were older and had higher reports of cardioprotective drugs than those without cardiovascular events. Elevated reports for MACE (ROR 4.07, 95% CI: 2.39-6.93) was identified overall, which was primarily driven by the significant disproportionality measures in the Japanese reports. Conclusions: The current pharmacovigilance study identified a potential signal for elevated MACE, particularly in Japan. The results support the current safety warnings from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to avoid use in high-risk patients.

Thromboembolic Safety Reporting of Tofacitinib and Baricitinib: An Analysis of the WHO VigiBase.

INTRODUCTION: The Janus kinase (JAK) inhibitors tofacitinib and baricitinib are new treatments for rheumatic diseases. Recent concerns regarding the risk of thrombosis have led to warnings by competent authorities. We therefore aimed to examine the thromboembolic safety signal for tofacitinib and baricitinib. METHODS: Individual case safety reports (ICSRs) for tofacitinib and baricitinib were retrieved from the World Health Organization global database VigiBase in April 2019. Primary outcomes were deep vein thrombosis (DVT) and pulmonary thrombosis (PT) or pulmonary embolism (PE). Patient demographics were summarized and then stratified by outcome. Disproportionality analyses were conducted by estimating the reporting odds ratios (RORs) and 95% confidence intervals (CIs) worldwide, and stratified by either Europe or the US. RESULTS: In both the tofacitinib (n = 40,017) and baricitinib (n = 2138) ICSRs, patients with reported DVT or PT/PE were older and had higher reporting of prothrombotic medications or antithrombotic treatments, suggesting a pre-existing thromboembolic risk/event. In Europe, tofacitinib was associated with increased reporting for DVT (ROR 2.37, 95% CI 1.23-4.56) and PT/PE (ROR 2.38. 95% CI 1.45-3.89). For baricitinib, a threefold increased reporting odds was observed for DVT (ROR 3.47, 95% CI 2.18-5.52) and PT/PE (ROR 3.44, 95% CI 2.43-4.88) in Europe. In the US, tofacitinib was only associated with an elevated ROR of PT (ROR 2.05, 95% CI 1.45-2.90) and no baricitinib ICSRs were reported. CONCLUSION: This study supports the current recommendation for cautious use of tofacitinib in patients with high thromboembolic risk. Moreover, with a similar patient profile and elevated reporting for baricitinib, a potential class effect of JAK inhibitors cannot be ruled out.