COVID-19 Vaccination and the Incidence of De Novo or Recurrent Rheumatoid Arthritis: A French and International (VigiBase) Signal Detection Study.

COVID-19 vaccination is critical in frequently immunocompromised patients with rheumatoid arthritis (RA). However, there is a question about the risk of RA flares following vaccination. Our study intended to find out about cases of new RA or flare-ups in people who already had RA that were reported in French and international pharmacovigilance databases after COVID-19 vaccination. We performed a "case-noncase" method in the international pharmacovigilance database VigiBase to identify the risk of RA following COVID-19 vaccination compared with other nonlive vaccines. Using the French Pharmacovigilance Database (FPVD), a descriptive analysis was carried out for RA cases after COVID-19 immunization and a multivariate logistic regression analysis was conducted to compare variables in the new-onset vs. flare-up groups. In 2021, 2,387 cases of RA were reported from 2,817,902 adverse drug reactions associated with COVID-19 vaccines recorded in VigiBase. The reporting odds ratio of RA onset with COVID-19 vaccines compared with the other nonlive vaccines was 0.66 (P < 0.0001). The FPVD reported 161 cases of RA with COVID-19 vaccines, including 77 new-onset RA and 84 cases of RA flare-up. In 88 cases (84.7%), RA occurred after the first dose. The mean time between vaccination and disease onset was 14 ± 21 days, and the delay was significantly shorter in the flare-up group. We do not show a higher risk of RA after COVID-19 vaccination compared with other nonlive vaccines in adults. De novo RA was more likely to happen quickly, be more severe, and have a worse outcome than flares in patients with RA.

Peripheral facial palsy post SARS-CoV-2 vaccine: A regional pharmacovigilance cases series.

Peripheral facial palsy (PFP) is a rare adverse reaction identified from clinical trials of coronavirus disease 2019 (COVID-19) vaccines (messenger ribonucleic acid [mRNA] and viral vector). Few data are available on their onset patterns and risk of recurrence after re-injection of a COVID-19 vaccine; the objective of this study was to describe PFP cases attributed to COVID-19 vaccines. All cases of facial paralysis reported to the Regional Pharmacovigilance Center of Centre-Val de Loire area between January and October 2021, in which the role of a COVID-19 vaccine was suspected, were selected. Based on initial data and following additional information requested, each case was reviewed and analyzed to include only confirmed cases of PFP for which the role of the vaccine could be retained. From the 38 cases reported, 23 were included (15 excluded because of diagnosis not retained). They occurred in 12 men and 11 women (median age of 51 years). The first clinical manifestations occurred with a median time of 9 days after COVID-19 vaccine injection, and the paralysis was homolateral to the vaccinated arm in 70%. The etiological workup, always negative, included brain imaging (48%), infectious serologies (74%) and Covid-19 PCR (52%). Corticosteroid therapy was prescribed for 20 (87%) patients, combined with aciclovir in 12 (52%). At 4-month follow-up, clinical manifestations had regressed completely or partially in 20 (87%) of the 23 patients (median time of 30 days). From them 12 (60%) received another dose of COVID-19 vaccine and none had a recurrence and the PFP regressed despite the second dose in 2 of the 3 patients not fully recovered at 4 months. The potential mechanism of PFP after COVID-19 vaccine, which don't have a specific profile, is probably the interferon-γ. Moreover, the risk of recurrence after a new injection appears to be very low, which makes it possible to continue the vaccination.

Unexpected severe hepatic and skin toxicities during high dose methotrexate course for osteosarcoma.

INTRODUCTION: high dose methotrexate (HD-MTX) regimen is used in osteosarcoma, leukemia and lymphoma treatment. Osteosarcoma is mostly diagnosed in children and adolescents. Most frequent methotrexate toxicities are mucositis, myelosuppression, renal failure, hepatitis and necrotizing encephalopathy. Toxicities increase with renal impairment, denutrition, in older patients, with some pharmacogenetics factors or with drug interactions. CASE REPORT: We report a 16th years old woman diagnosed with osteosarcoma and experienced an unexpected severe hepatic and skin toxicities as toxic epidermal necrolys, Steven Johnson syndrome. MANAGEMENT AND OUTCOME: This toxicity occurred despite acid folinic rescue performed as good practice recommendation. Fourteen hours after methotrexate administration, renal failure was observed and after 72 h an erythematous rash and epidermal detachment with toxic epidermal necrolys. Seven days after methotrexate administration, hepatic failure began until grade IV cytolysis. High dose of folinic acid were administered during all severe toxicities. Methotrexate were not longer administered to this young patient and chemotherapy with ifosfamide (IFO), doxorubicine and cisplatin were performed in this patient and complete histologic response were observed in the surgical bone resection. DISCUSSION: No classical toxicities risk factors were identified in this patient but a homozygote mutation of MTHFR gene and homozygote SLCO1B1 gene mutation were found. MTHFR and SLCO1B1 are both implicated in methotrexate metabolism.

Incidence and characteristics of intravascular pulmonary migration of etonogestrel implants: A French nationwide study.

OBJECTIVE(S): To describe the features of etonogestrel implant (Nexplanon and Implanon) migration into the pulmonary vasculature and to estimate its incidence in France. STUDY DESIGN: We retrospectively reviewed French cases of implant migration into the pulmonary vasculature reported up to 2018. Patient clinical data were collected. The annual incidence of migration was estimated from the number of cases reported and number of implants sold. RESULTS: Twenty-seven cases of migration into the pulmonary vasculature were identified. In 19 cases (70%) it was stated that this was into the pulmonary artery (nine into the left branch, four into the right branch and six unspecified) and in the other eight cases (30%) it was it not specified whether this was into the pulmonary artery or one of its branches. The migration was discovered following a request for implant removal in 59% of cases, following respiratory complaints in 24%, and because the implant was no longer palpable in 17%. In the 24 cases for which information on removal (or not) was available, the implant was removed in 15 (60% by an endovascular procedure and 40% by invasive surgery); in the remainder it was left in situ. The incidence of migration into the pulmonary vasculature was 1.23 per 100,000 implants sold [95% CI 0.25-3.58] in 2014, increasing to 3.17 per 100,000 implants sold [1.37-6.24] in 2017. In 2016, the French National Agency for Medicines and Health Products Safety (ANSM) had recommended performing a systematic search for non-palpable implants, including at thorax level. CONCLUSIONS: The incidence of migration into the pulmonary vasculature is low. Nonetheless, because the consequences are potentially serious, in December 2019 the ANSM made recommendations to reduce this risk.

Methylprednisolone-related liver injury: A descriptive study using the French pharmacovigilance database.

PURPOSE: Hepatotoxicity associated with methylprednisolone (MP) is rarely reported in the literature. The aim of the present study was to review the characteristics of acute liver injury associated with intravenous (IV) or oral MP registered in the French pharmacovigilance database (FPD). METHODS: All cases with MP coded as suspected, concomitant, or interacting drug associated with liver injury as the adverse effect reported up to May 2016 were extracted from the FPD. Cases were identified using the "Drug related hepatic disorders" Standard Medical Query. RESULTS: A total of 97 cases of liver injury associated with MP were analysed; 58.8% were women and the median age was 46 years (range: 1-91). MP was used for an autoimmune disease in 47.6% of cases including 26 cases of multiple sclerosis, and was IV in 79.4% of cases. Nearly three-quarters of patients (73,2%) had a hepatocellular type of injury, the severity of which was mainly mild (45%) or moderate (31%). Most patients (92%) spontaneously and fully recovered within a mean 38.4 days. A rechallenge using the IV route was performed in 13 patients and for 10 (76.9%) this was positive (the initial type of injury was hepatocellular for all these cases). Regarding IV route of administration (n=77), MP was coded as the only suspected drug in 22% of cases. DISCUSSION: The results suggest that IV MP causality should be considered in case of acute liver injury while data for oral MP is insufficient; systematic liver monitoring for high-dose IV MP may be recommended.

Liquid formulation of ifosfamide increased risk of encephalopathy: A case-control study in a pediatric population.

BACKGROUND: Several clusters of encephalopathy occurred after the market change from Holoxan® (ifosfamide lyophilized powder) to Ifosfamide EG® (liquid formulation) and justified a formal survey in 2015. In June 2016, the regulatory authority decided to apply a precautionary measure in reducing the shelf life of Ifosfamide EG® at 7 months. One-year study from spontaneous reports lead to suspect a potential residual risk. Due to the many limitations associated with spontaneous notifications, we performed a multicentric observational study, aiming to better explore this pharmacovigilance signal. METHODS: We performed a case-control study in pediatric oncology Departments of 25 university hospitals between July 1st, 2016 and July 1st, 2018. All children (<18 y.o.) receiving liquid formulation or lyophilized powder formulation during the study period were included. Patients with at least one occurrence of encephalopathy were considered as cases. Logistic regression model was used to estimate the odds ratio of encephalopathy between exposure groups. RESULTS: During the study period, 52 cases and 495 controls were included. A residual over-risk of encephalopathy was associated with ifosfamide 7-month shelf-life liquid formulation compared to lyophilized powder (adjusted OR 1.91, 95% CI: 1.03-3.53). CONCLUSIONS: Observed difference does not seem to be related to the pathology treated, the doses used, the co-medications, a meningeal localization and/or an irradiation of the central nervous system. This study confirms data from spontaneous reports that led to the precautionary measure for the liquid formulation. Even if the risk of encephalopathy seems reduced, our study suggests the persistence of a residual risk of encephalopathy associated with liquid formulation compared to the lyophilized powder.

Cytopenia induced by low-dose methotrexate: An analysis of 433 cases from the French pharmacovigilance database.

INTRODUCTION: Up to 5% of individuals exposed to low-dose methotrexate (MTX) (i.e., ≤30 mg/week) may develop cytopenia. However, MTX-induced cytopenia have been poorly described. MATERIAL AND METHODS: All cases of cytopenia (i.e., anaemia, leukopenia, thrombocytopenia, bi- or pancytopenia) in patients receiving low-dose MTX reported to the French pharmacovigilance database during 2006-2016 were analysed. Three groups were defined: cytopenia due to MTX medication errors (e.g., daily rather than weekly administration), cytopenia in people receiving several medications including MTX, cytopenia in people receiving only MTX. RESULTS: 433 cases were analysed. Eighty-four cases (19.4%) were due to medication errors, 180 (41.6%) occurred in individuals exposed both to MTX and other drugs, and 169 (39.0%) occurred in individuals only exposed to MTX. By comparison to other patients, those with cytopenia due to medication errors were older (74 ±â€¯13 vs 69 ±â€¯15 years, p = 0.002), received more frequently MTX orally (92.9% vs 65.3%, p<0.001) and had more frequently pancytopenia (71.4% vs 54.4%, p = 0.005). By comparison to individuals exposed to multiple drugs (n = 180), those exposed only to MTX (n = 169) were older (71 ±â€¯15 vs 67 ±â€¯14, p = 0.02), and had more often pancytopenia (62.7% vs 46.7%, p = 0.001). Among those only exposed to MTX, most cases (n = 140, 82.8%) were considered as toxic rather than idiosyncratic reactions and a trigger (e.g. diarrhoea) was found in 59.3% of those cases. Overall 30 (6.9%) deaths occurred, including 8 in the "medication error" group and 8 in the "MTX only" group. CONCLUSION: These data may be useful for defining optimal biological monitoring of patients prescribed low-dose MTX.

[Alitretinoin (Toctino®): A French follow-up study of harmacovigilance]. / Alitrétinoïne (Toctino®) : données françaises de pharmacovigilance.

INTRODUCTION: The adverse reaction profile of alitretinoin, a retinoid indicated in severe topical corticosteroid-refractory chronic hand eczema, is similar to that of other oral retinoids, especially isotretinoin. The objective of this study was to detect new adverse effects (not listed) of alitretinoin and to estimate the number of pregnancies exposed. MATERIAL AND METHODS: All cases of ADR reported in France with alitretinoin between October 1st, 2012 and February 29th, 2016 were analysed. RESULTS: During the 41 months of follow-up, 52 cases of serious adverse drug reaction (ADR) and 88 cases of non-serious and unexpected ADR were notified. The most frequent serious ADRs were psychiatric, neurological and dermatological. Psychiatric disorders, mainly depression and suicidal ideation represented 23% of serious ADRs. New adverse drug reactions were detected: myocardial infarction, pancreatitis and digestive haemorrhage. Three pregnancies exposed during the teratogenic risk period, were registered. DISCUSSION AND CONCLUSION: The safety profile of alitretinoin matches that of other retinoids. However, the rate of psychiatric disorders appears to be high. Otherwise, the risk of myocardial infarction in patients with cardiovascular risk factor should be considered as a safety concern. It could be explained by the hyperlipemic effects of alitretinoin and studies suggest a cardiovascular risk with retinoids through their effects on lipids (class effect), especially for patients with others cardiovascular risk factors. Pancreatitis and digestive hemorrhage are described with isotretinoin. The rate of reporting of pregnancy induced by a non-compliance with the Pregnancy Prevention Program is near the rate observed with isotretinoin. The high incidence of serious ADR and the non-application of pregnancy prevention program lead the French National Agency for Medicines to limit the first prescription of alitretinoin to dermatologists.