Drug-induced IgA vasculitis in children and adults: Revisiting drug causality using a dual pharmacovigilance-based approach.

OBJECTIVES: IgA vasculitis (IgAV) is an immune complex small-vessel vasculitis. Drug-induced IgAV cases were rarely reported in the literature. Drug causality assessment is challenging as many other etiological factors can be involved. We performed a pharmacovigilance study to identify the main drugs reported to induce IgAV. METHODS: We used the French pharmacovigilance database (FPVD) and the WHO global individual case safety reports database (VigiBase) to retrieve IgAV cases. Cases from the FPVD were reviewed by two investigators using predefined criteria. Disproportionality analyses (case - non-case approach) were conducted in VigiBase to identify drugs significantly associated with IgAV reporting. RESULTS: Of the 467 IgAV cases retrieved from the FPVD, 115 (47 children and 68 adults) have been assessed as definite or probable, reported with 178 suspected drugs. Overall IgAV cases were mainly male (58%), with a median age of 33.5 (8.0-63.3) years. No death was reported. Besides, we identified 1558 possible IgAV cases in VigiBase. Among them, 40 were associated with a disproportionality in IgAV reporting. Drugs were mainly vaccines, antibiotics and TNF-α blockers, these finding being consistent in both databases. IgAV reporting with TNF-α blockers was significantly associated with their use in inflammatory bowel diseases, psoriasis or ankylosing spondylitis compared to other indications. CONCLUSIONS: Our systematic study enables the identification of culprit drugs in drug-induced IgAV. These results strengthen the immune pathophysiology of IgAV and the role of underlying disease. The list of suspected drugs may be useful for physicians to manage patients with IgAV and consider appropriate drug discontinuation. KEY MESSAGES: What is already known about this subject? IgA vasculitis has multifactorial etiology. To date, possible culprit drugs have been reported only in case reports. What does this study add? Using a dual pharmacovigilance-based approach, we identified drugs associated with the occurrence of IgA vasculitis, such as all types of vaccines, major antibiotics and immunomodulatory agents, mainly TNF-α blockers. How might this impact on clinical practice or future developments? Physicians should be aware of drug-induced IgA vasculitis and we provide evidence on the most frequent implicated drugs.

Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.

Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.

Thyroiditis and immune check point inhibitors: the post-marketing experience using the French National Pharmacovigilance database.

Immunotherapy with immune checkpoint inhibitors (ICIs) for cancer has become increasingly prescribed in recent years. Indeed, it is used to treat both solid and hematological malignancies due to their considerable potential in treating melanoma, non-small cell lung and other cancers. Immune-mediated related adverse endocrine toxicity, and especially thyroiditis, is seen as a growing problem needing specific screening and management. This study aims at describing thyroid dysfunctions induced by the ICIs marketed in France, which are registered in the French Pharmacovigilance database. This database was queried for nivolumab, pembrolizumab, and ipilimumab-induced adverse drug reactions reported before April 30, 2017. Both a pharmacologist and an endocrinologist have reviewed each case to select only those of peripheral thyroiditis (thyrotoxicosis and hypothyroidism). During this period, 110 thyroiditis following ICI therapy were reported. Sex/ratio was around one. Most of the cases (47.2%) were asymptomatic. Although some thyrotoxicosis cases were severe, no orbitopathy was reported. Hypothyroidism and thyrotoxicosis were equally described. Antithyroid antibodies were positive in only 16% patients. The ultrasonography was informative in 19% patients. Levothyroxine supplementation was necessary in 57% patients, leading to 19% recovery. With a dedicated optimized management, most of the cases did not require immunotherapy discontinuation. Finally, immune-mediated related thyroiditis is increasing due to a wider prescription of ICI therapy in various cancer conditions and systematic screening. Often asymptomatic, they lead to a local activation accompanied by hormonal deficiency in the long run. It is necessary to carry out an early and sustained multidisciplinary screening to allow immunotherapy continuation.