Drug-induced antiphospholipid syndrome: Analysis of the WHO international database

Abstract

Objective: As with drug-induced lupus, some drugs may induce an antiphospholipid syndrome (APS). With the always growing numbers of new molecules, the list of the liable treatments evolves rapidly. We herein analyzed VigiBase, the international pharmacovigilance database, to identify drugs suspected of inducing APS.

Methods: All the reported cases associated with "anti-phospholipid syndrome" using the preferred term level of medDRA (dictionary of regulated drug activity) when associated with anti-phospholipid antibodies in VigiBase were analyzed. For each treatment, a Bayesian disproportionality indicator (i.e. information component, IC) was calculated. A drug was significantly associated with APS if the 95% lower-end of the IC credibility interval was positive (IC₀₂₅ > 0). Drugs with potential protopathic bias were excluded.

Results: From 01/11/2000 to 25/07/2021, 790 reports of suspected drug-induced APS were found in VigiBase. After excluding drugs reported by a single country and drugs with protopathic bias, fourteen drugs (n = 359 reports) were associated with APS with an IC_{0 25} > 0. These drugs were hormons: ethinylestradiol-etonogestrel and drospirenone-ethynilestradiol; platelet growth factors: eltrombopag, romiplostim; vaccines: Human Papillomavirus vaccine, hepatitis A and B vaccines and typhoid vaccine; antibiotics: minocycline; nonstreroidal anti-inflammatory: rofecoxib; biotherapy: interferon beta-1-a, etanercept; anti-hypertensive drug: hydralazine; bisphosphonates: alendronic acid and antipsychotic: olanzapine. The mean age at diagnosis of drug-induced APS was 39.2 years [29.3;47.9] and there were 63.5% of female patients. The mean delay from first exposition to drug-induced APS was 19.7 months [4.5; 38.8]. Drug-induced APS was reported as a severe side effect in 66.3% of cases: 8.4% with a life-threatening event and 2.5% of death (n = 9). A third (n = 118, 32.9%) pulmonary embolism events were reported and 4.2% (15) cerebral infarctions. 14.8% (53) cases were associated with a systemic lupus, a sub-analysis without lupus cases showed the same severity of cases.

Conclusion: This study identified 14 drugs potentially associated with drug-induced APS that may prove useful in the investigational work-up in any new diagnosis of APS.

Trial registration number: NCT03994302.