A paper recently published in Blood Advances identified 30 drugs most often associated with immune hemolytic anemia for which practitioners should systematically screen as potential drug-induced triggers (see TABLE).1
In autoimmune hemolytic anemia (AIHA), the creation of autoantibodies results in destruction of red blood cells. Although AIHA can occur in the absence of any underlying disorder, it’s important to consider secondary causes, including malignancy, systemic autoimmune disease, infection, inherited immunodeficiency, or drug-induced etiologies in which patients may develop antibodies to drugs, their metabolites, or self-protein-drug epitopes.2
“Faced with a patient with a new hemolytic anemia, drugs should always be suspected,” said Guillaume Moulis, MD, PhD, an associate professor of medicine at Toulouse University Hospital in France and one of the authors and supervisors of the study.
Scientists can detect some drug-dependent antibodies using serologic methods, but Dr. Moulis pointed out that this is only available at a few expert centers, and drug-induced hemolytic anemia may not be distinguishable based on clinical and immunologic signs. Thus, clinicians must rely on lists of known potential triggers of drug-induced hemolytic anemia to remove an offending drug as soon as possible.
More than 130 drugs have been identified as potential triggers for drug-induced hemolytic anemia.2,3 However, most of these drugs have been identified based on case reports or retrospective series and not comparative studies.
Dr. Moulis and colleagues first used a database from the World Health Organization, Vigibase, which reports suspected adverse drug reactions from more than 148 countries. Using more than 20 million adverse drug reports from 1967 to 2020, they performed a disproportionality analysis to compare the frequency of drug exposure in reports of immune hemolytic anemia to the frequency in other reports. The researchers identified signals for 59 drugs that had not previously been identified as potential triggers, including some antibiotics, antineoplastics, and immunomodulating agents.1
One limitation of the study was potential under-reporting and selective reporting in Vigibase. “This database is used to detect signals of potential associations between drugs and adverse drug reactions, but these need to be confirmed by classical epidemiologic methods,” Dr. Moulis said.
Thus, the team followed up using data from the French national database, which has prospectively collected data for almost the entire population of France. They analyzed a specific cohort that included patients 15 or older with a recorded incident of autoimmune hemolytic anemia between 2012 and 2018, accounting for more than 6,500 patients. The team checked for drugs previously associated with drug-induced hemolytic anemia, as well as the 59 newly identified drugs.
To strengthen confidence in their results, Dr. Moulis and colleagues used both case-control and case-crossover designs. In the case-control design, they compared drug exposure in autoimmune hemolytic anemia cases to age and sex-matched controls. In the case-crossover design, the researchers analyzed frequency of exposure to the drug at different times in patients who had experienced immune hemolytic anemia.
Using both designs, the researchers identified 14 drugs associated with immune hemolytic anemia, with the highest risk associated with azathioprine. This included three newly identified drugs in Vigibase: sulfamethoxazole- trimethoprim, cefpodoxime, and azathioprine.1
One study limitation was a lack of statistical power in the case-crossover analysis. This may have contributed to the fact that the researchers found an additional 14 drugs in the case-control analysis that were not confirmed in the case-crossover analysis. The case-crossover analysis also identified an additional two drugs not found via the case-control analysis.
“Even though every drug should be suspected at the individual level, this study provides a list of drugs with the highest association with hemolytic anemia at the population level, i.e., the drugs hematologists should think of in priority, because they have a high association with the occurrence of hemolytic anemia,” Dr. Moulis said.
Any conflicts of interest declared by the authors can be found in the original article.
References
- Maquet J, Lafaurie M, Michel M, et al. Drug-induced immune hemolytic anemia: detection of new signals and risk assessment in a nationwide cohort study [published online ahead of print, 2023 Oct 2]. Blood Adv. doi: 10.1182/bloodadvances.2023009801.
- Garratty G. Immune hemolytic anemia associated with drug therapy. Blood Rev. 2010;24(4-5):143-150.
- Garratty G, Arndt PA. Drugs that have been shown to cause drug-induced immune hemolytic anemia or positive direct antiglobulin tests: some interesting findings since 2007. Immunohematology. 2014;30(2):66-79.
