Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database.

Increasing number of Janus kinase (JAK) inhibitors have been approved for chronic haematopoietic neoplasms and inflammatory/autoimmune diseases. We aimed to assess safety of the first three approved JAK inhibitors: ruxolitinib, tofacitinib and baricitinib. In this retrospective observational study, pharmacovigilance data were extracted from the World Health Organization database. Adverse events are classified according to Medical Dictionary for Regulatory Activities hierarchy. Until February 28, 2021, all Individual Case Safety Reports [ICSRs] with the suspected drug ruxolitinib, tofacitinib or baricitinib were included. Disproportionality analysis was performed and the information component (IC) was estimated. Adverse events were considered a significant signal if the lower end of the 95% credibility interval of the IC (IC025) was positive. We identified 126,815 ICSRs involving JAK inhibitors. Ruxolitinib, tofacitinib and baricitinib were associated with infectious adverse events (IC025 1.7, especially with viral [herpes and influenza], fungal, and mycobacterial infectious disorders); musculoskeletal and connective tissue disorders (IC025 1.1); embolism and thrombosis (IC025 0.4); and neoplasms (IC025 0.8, especially malignant skin neoplasms). Tofacitinib was associated with gastrointestinal perforation events (IC025 1.5). We did not find a significant increase in the reporting of major cardiovascular events. We identified significant association between adverse events and ruxolitinib, tofacinitib and baricitinib in international pharmacovigilance database.

Long-term safety and efficacy of rituximab in 248 adults with immune thrombocytopenia: Results at 5 years from the French prospective registry ITP-ritux.

Rituximab is a second-line option in adults with immune thrombocytopenia (ITP), but the estimated 5-year response rate, only based on pooled retrospective data, is about 20%, and no studies have focused on long-term safety. We conducted a prospective multicenter registry of 248 adults with ITP treated with rituximab with 5 years of follow-up to assess its long-term safety and efficacy. The median follow-up was 68.4 [53.7-78.5] months. The incidence of severe infections was only 2/100 patient-years. Profound hypogammaglobulinemia (<5 g/L) developed in five patients at 15 to 31 months after the last rituximab infusion. In total, 25 patients died at a median age of 80 [69.5-83.9] years, corresponding to a mortality rate of 2.3/100 patient-years. Only three deaths related to infection that occurred 12 to 14 months after rituximab infusions could be due in part to rituximab. At 60 months of follow-up, 73 (29.4%) patients had a sustained response. On univariate and multivariate analysis, the only factor significantly associated with sustained response was a previous transient response to corticosteroids (P = .022). Overall, 24 patients with an initial response and then relapse received retreatment with rituximab, which gave a response in 92%, with a higher duration of response in 54%. As a result of its safety profile and its sustained response rate, rituximab remains an important option in the current therapeutic armamentarium for adult ITP. Retreatment could be an effective and safe option.

Belatacept in renal transplant recipient with mild immunologic risk factor: A pilot prospective study (BELACOR).

The benefit of belatacept on antibody-mediated rejection (ABMR) incidence after kidney transplant with preformed donor-specific antibodies (DSAs) has never been assessed. Between 2014 and 2016, we conducted a multicenter prospective clinical trial with 49 patients to determine kidney allograft outcome in recipients with preformed DSAs (maximal mean fluorescence intensity 500 to 3000) treated with belatacept (BELACOR trial). Immunosuppressive strategy included antithymocyte globulin, belatacept, mycophenolate mofetil, and steroids. An ancillary control group was designed retrospectively, including patients fulfilling the same inclusion criteria treated with calcineurin inhibitors. In BELACOR group, no patient exhibited acute ABMR, patient and allograft survival at 1 year was 100% and 95.4%, respectively, and the estimated glomerular filtration rate was 53.2 mL/min/1.73 m2 . However, the 12-month incidence of acute T cell-mediated rejection was 25.4% (14.5% to 42.4%). Comparison with the control group showed significantly higher T cell-mediated rejection incidence only in the BELACOR group (P = .003). Considering the DSAs, the outcome was similar in the 2 groups except a significantly higher number of patients displayed a complete disappearance of class II DSAs in the BELACOR group (P = .001). Belatacept was not associated with an acute ABMR increased risk and may be considered as immunosuppressive strategy in transplant recipients with preformed DSAs (maximal mean fluorescence intensity 500 to 3000). Prospective randomized trials are needed to confirm these results.

Novel microarray-based method for estimating exposure to ionizing radiation.

Accurate estimation of the dose of ionizing radiation to which individuals have been exposed is critical for therapeutic treatment. We investigated whether gene expression profiles could be used to evaluate the dose received, thereby serving as a biological dosimeter. We used cDNA microarrays to monitor changes in gene expression profiles induced by ionizing radiation in mouse total blood. The subsets of genes best characterizing each dose were identified by resampling the original data set and calculating the intersection of the dose signatures. This analytical strategy minimizes the impact of potential genetic/epigenetic variation between mice and overcomes the bias in gene selection inherent to microarray technology. The significance of the identified signatures was evaluated by monitoring the type I error rate by in silico negative control simulation. Based on the distribution of the mean ratios of the selected probes, we were able to identify transcription profiles giving 83% to 100% correct estimation of the dose received by test mice, demonstrating that the selected probes could be used to determine the dose of radiation to which the animals had been exposed. This method could potentially be generalized to determine the level of exposure to other toxins and could be used to develop new related clinical applications.