Immune checkpoint inhibitors-induced nephropathy: a French national survey.

Immune checkpoint inhibitors (ICIs), aiming to foster cancer-targeted immune response, proved to be effective in several advanced malignancies at the price of immune-related adverse events affecting various organs, notably the kidneys. Herein, a retrospective descriptive analysis was performed on all biopsy-confirmed cases of ICI-induced nephropathy notified to the French Pharmacovigilance database to date. Data were gathered about patients' characteristics, acute kidney injuries and histopathological features. A total of 63 biopsy-proven cases were included for analysis. Immune-related nephropathy occurred after a mean of 105.5 ± 98.6 (standard deviation) days after the introduction of the ICI. Kidney Disease: Improving Global Outcomes acute kidney injury stage 3 occurred in 36.5% of patients, and the mean peak serum creatinine was 288 µmol/L. Histopathology suggested acute tubule-interstitial nephritis in 52 patients (83%), while signs of acute tubular necrosis were found in 18 (29%) and glomerular involvement in 5 of them (8%). Another immune-related adverse event was documented in 25 patients (39.7%). Patients were treated with corticosteroids in 88.9% of cases. All in all, 27.0% fully recovered, 54.0% partially recovered, 12.7% did not recover. Rechallenge was attempted in 19 patients and one patient relapsed. Three-quarters of patients received a medication known to cause acute tubule-interstitial nephritis. The major limits of this study are those inherent to pharmacovigilance studies, such as its retrospective nature and incomplete data. Although it cannot pretend drawing any pathophysiological conclusion, this study depicts the clinical and histopathological pictures of ICI-induced nephropathies in a large cohort of biopsied patients with all grades of severity.

Occurrence of type 1 and type 2 diabetes in patients treated with immunotherapy (anti-PD-1 and/or anti-CTLA-4) for metastatic melanoma: a retrospective study.

Anti-PD-1 and anti-CTLA-4 antibodies cause immune-related side effects such as autoimmune type 1 diabetes (T1D). It has also been suggested that by increasing TNF-α, IL-2 and IFN-γ production, anti-PD-1 and/or anti-CTLA-4 treatment could affect pancreatic beta cell function and insulin sensitivity. This study was based on a retrospective observational analysis from 2 July 2014 to 27 June 2016, which evaluated the occurrence of T1D and changes in glycemia and C-reactive protein (CRP) plasma concentrations in patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma at the Saint Louis Hospital. All cases of T1D that developed during immunotherapy registered in the French Pharmacovigilance Database (FPVD) were also considered. Among the 132 patients included, 3 cases of T1D occurred. For the remaining subjects, blood glucose was not significantly affected by anti-PD-1 treatment, but CRP levels (mg/l) significantly increased during anti-PD-1 treatment (p = 0.017). However, 1 case of type 2 diabetes (T2D) occurred (associated with a longer therapy duration). Moreover, glycemia of patients pretreated (n = 44) or concomitantly treated (n = 8) with anti-CTLA-4 tended to increase during anti-PD-1 therapy (p = 0.068). From the FPVD, we obtained 14 cases of T1D that occurred during immunotherapy and were primarily characterized by the rapidity and severity of onset. In conclusion, in addition to inducing this rare immune-related diabetes condition, anti-PD-1 treatment appears to increase CRP levels, a potential inflammatory trigger of insulin resistance, but without any short-term impact on blood glucose level.

Adverse drug reaction profile of third-generation smallpox vaccines used in France during the 2022 monkeypox epidemic.

Due to the start of the monkeypox epidemic in 2022, we retrospectively analyzed the adverse drug reactions (ADRs) reported in France after monkeypox vaccinations with the third-generation smallpox vaccine. Ninety-eight cases, representing 172 ADRs, were reported. ADRs were mostly expected reactogenicity reactions occurring within days after the first dose of vaccine and having a quick favorable outcome. Unexpected facial palsy and vaccination failure are discussed.

Trends in adverse drug reactions related to oral weak opioid analgesics in therapeutic use in adults: A 10-year French vigilances retrospective study.

AIM: To describe the symptoms, patient demographics, and trends over time of adverse drug reactions (ADRs) related to weak opioid analgesics reported to the French vigilance networks. METHODS: Retrospective study of data from French Poison Control Centers and Pharmacovigilance Centers databases of weak opioid analgesics-related ADRs cases, with high causality score, in adults, in therapeutic analgesic use, without co-exposure, between 2011 and 2020. RESULTS: The number of cases was 388 in the Poisonings database and 155 in the Pharmacovigilance database; ratio of the number of these cases to all reported cases during the study period was 0.02% and 0.03%, respectively. Tramadol was most often involved (74% and 56.1%, respectively), followed by codeine (26% and 38.7%, respectively). There was no significant variation in the number of cases reported. Cases most often involved young adults (median age: 40 years) and mostly women (76%). Gastrointestinal symptoms were mostly reported (80% and 65%, respectively) as described in the Summary of Products Characteristics. Patterns of ADRs were comparable in both databases, except for codeine-associated acute pancreatitis and anaphylaxis that were reported in the Pharmacovigilance database. No fatality was observed. Severity was more often observed in the Pharmacovigilance database (30%) than in the Poisonings database (moderate toxicity: 7%). CONCLUSION: ADRs mostly occurred among young women using tramadol, without significant variation in the number of reported cases over time. Serious ADRs were more frequently reported to the Pharmacovigilance database, particularly for codeine. Women seemed to be at greater risk of ADRs.

Risk factors associated with immune checkpoint inhibitor-induced acute kidney injury compared with other immune-related adverse events: a case-control study.

Background: Immune checkpoint inhibitors (ICIs) foster anti-cancer immune responses. Their efficacy comes at the cost of immune-related adverse events (IRAEs). The latter affects various organs, including kidneys, mostly as acute tubulointerstitial nephritis, the pathophysiology of which remains unclear. We conducted a multicentre case-control study to compare the characteristics of patients with renal IRAEs (ICI-AKI) with those of patients diagnosed with other IRAEs. Methods: We queried the French pharmacovigilance database for all adverse events involving ICIs. Reports were classified as ICI-AKI or extrarenal IRAE. For each ICI-AKI report, four reports of extrarenal IRAEs were randomly included (control group, 4:1 ratio). Variables showing an association with a P < 0.05 were included as covariates in a multivariate analysis. Results: Therefore, 167 ICI-AKI reports were compared with 668 extrarenal IRAEs. At least one concomitant extrarenal IRAE was mentioned in 44.3% of ICI-AKI reports. Patients with ICI-AKI were significantly older than patients with extrarenal IRAEs (69.1 versus 64.6 years; P = 0.0135), and chronic kidney disease was significantly more prevalent (12.0% versus 3.3%; P = 0.0125). Patients with ICI-AKI were significantly more likely to be treated with fluindione [adjusted odds ratio (OR) 6.53, 95% confidence interval (95% CI) 2.21-19.31; P = 0.0007], a non-steroidal anti-inflammatory drug (NSAID, OR 3.18, 95% CI 1.07-9.4; P = 0.0368) or a proton-pump inhibitor (PPI, OR 2.18, 95% CI 1.42-3.34; P = 0.0004). Conclusion: This study is limited by a lack of data, preventing confirmation of numerous reports therefore not included in the analysis. We are unable to draw definite pathophysiological conclusions from our data. Nonetheless, we suggest that ICIs may be a 'second-hit' that precipitates acute kidney injury caused by another concomitant drug (fluindione, NSAID or PPI).