A total of 42 new drugs have been associated with drug-induced lupus in a study that mined the World Health Organization’s international pharmacovigilance drug monitoring database, leaving the overall number now standing at 118.

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Among the 118 suspected drugs found in VigiBase, the WHO’s global deduplicated individual case safety reports (ICSR) database, 42 had not been previously reported in association with drug-induced lupus (DIL) and 76 had been previously reported in association with DIL in Medline. DIL was reported as a serious adverse event in 55.4% of cases, according to French researchers led by Laurent Arnaud, MD, PhD, of the department of rheumatology at Hôpitaux Universitaires de Strasbourg and Centre National de Références des Maladies Systémiques Rares, Strasbourg, France.

Dr. Arnaud and his colleagues conducted a case-noncase analysis for each drug associated with DIL in order to compare the proportion of specific adverse drug reactions (ADRs) reported for a single drug with the proportion of the same ADR for all other treatments in VigiBase, which receives reports from more than 130 country members of the WHO Programme for International Drug Monitoring and contains over 16 million deduplicated ICSRs recorded by pharmacovigilance centers since 1967. They searched for cases classified as systemic lupus erythematosus (SLE) and identified 12,166 ICSRs of DIL; from these they found 118 suspected drugs with significant pharmacovigilance signal from 8,163 ICSRs that mostly originated from the Americas (65%) and Europe (23%).

In line with what the study authors expected, the drugs associated with the highest number of DIL cases were the antitumor necrosis factor agents infliximab, adalimumab, and etanercept, and the drugs associated with the highest disproportional reporting of DIL were procainamide and hydralazine.

“This is an important finding because these are the two drugs associated with the highest risk of DIL in the literature, therefore confirming the reliability of our approach using a large pharmacovigilance database,” the researchers wrote in Annals of the Rheumatic Diseases.

Overall, DIL was considered definite for 9 drugs (procainamide, hydralazine, minocycline, quinidine, isoniazid, terbinafine, methyldopa, dihydralazine, and chlorpromazine), probable for 19 drugs, and possible for 45 drugs.

The median age of DIL onset was 49 years, which the authors noted was about 2 decades older than that of spontaneous SLE.

They also observed a marked predominance in females (female to male sex ratio, 4.3), a finding that contrasted with previous studies reporting a female to male sex ratio closer to 1:1.

Dr. Arnaud and his colleagues stated that their finding of a median delay between the reported start of suspected treatment and DIL occurrence of 172 days (interquartile range, 35-610 days) suggested that DIL mostly appears after a few months and usually within the first 2 years of treatment with the suspected drug.

“The analysis of the median reporting years for each suspected drug shows a clear evolution of suspected drugs during the past decades. This further underlines that the constantly changing spectrum of DIL should be monitored continuously, and further validates the interest of our approach using the WHO international pharmacovigilance database, the biggest database of this kind with over 16 million deduplicated ICSRs,” they wrote.

The researchers added that distinguishing DIL from SLE is important because its prognosis is usually good when the drug is withdrawn, but the spectrum of DIL is constantly evolving, with drugs once described as strongly linked to DIL now prescribed less frequently.

“The first case of DIL was reported in 1945 with sulfadiazine, while hydralazine DIL was first reported in 1953. Since then, pharmacopoeia has strongly evolved, and one could hypothesize that so has the spectrum of drugs that can induce DIL,” they wrote.

“The detailed list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. Altogether, these findings may help in improving the identification of this constantly evolving disease,” they concluded.

The current study was limited by the lack of a uniform set of criteria for the diagnosis of DIL and by the level of reported details available in VigiBase.

The authors had no outside funding for the study and reported having no conflicts of interest.

SOURCE: Arnaud L et al. Ann Rheum Dis. 2019 Feb 4. doi: 10.1136/annrheumdis-2018-214598.