Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study

Background Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much
negative publicity for adverse events associated with its authorisation for emergency use to treat patients with
COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to
determine the risk associated with its use in routine care in patients with rheumatoid arthritis.

Methods In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged
18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up
over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in
wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication.
Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine
plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records
from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration
using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated
hazard ratios (HRs) according to drug use. Estimates were pooled where the I² value was less than 0·4.

Findings The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of
hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk
of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Selfcontrolled
case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be
associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12–2·44]). Addition of azithromycin
appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI
1·22–3·95]), chest pain or angina (1·15 [1·05–1·26]), and heart failure (1·22 [1·02–1·45]).

Interpretation Hydroxychloroquine treatment appears to have no increased risk in the short term among patients
with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality.
The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term.
We call for careful consideration of the benefit–risk trade-off when counselling those on hydroxychloroquine
treatment.