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We thank Drs Perricone et al for their thoughtful response1 to our manuscript, and agree that timing, dose and duration of colchicine will be important open questions should the agent be found to be helpful in COVID-19. Regarding the question of when in the COVID-19 course colchicine might be most efficacious, we postulated that earlier (ie, as an outpatient) might be better. In making this suggestion, we followed Perricone et al’s recommendation to apply clinical rheumatologic experience. In gout, colchicine seems to be most effective early in acute disease, compelling both the the American College of Rheumatology and the European League Against Rheumatism to recommend treating gout flares with colchicine only in the earliest stages of the attack (ie, within 1–2 days of onset)2 3; these recommendations suggest that administration of colchicine in the earliest stages of COVID-19 might be more effective than later administration. Moreover, we agree with a recent editorial by Kim et al, who underlined the urgency to find an effective, safe and inexpensive outpatient COVID-19 therapy,4 and we believe that colchicine could fit that bill. That said, several published studies included in our review support a potential benefit of colchicine in the early inpatient setting as well. We look forward to the results of Perricone et al’s ongoing inpatient investigations, and note that at least one additional recent study, by Brunetti et al, suggests a significant benefit of colchicine in improving outcomes among patients hospitalised with COVID-19.5
Regarding the dose of colchicine, we agree that this is an open question but would argue that neither known pharmacokinetics nor previous clinical experience provides much guidance. Clearly the tolerable dose of colchicine ranges from somewhere between 0.3 mg/day and less, and 1.8 mg/day in divided doses, and the authors correctly point to studies from our own group indicating that in vitro, higher doses invoke additional, potentially anti-inflammatory effects.6 In clinical practice, however, the lowest effective dose has not been established and may vary by disease. Patients with familial Mediterranean fever receive daily prophylactic doses up to 1.8 mg in divided doses, patients with gout 0.5–1.2 mg/day, and patients with cardiovascular disease benefit from 0.5 mg/day.7 Moreover, our own clinical experiences and those of our colleagues belie Perricone et al’s statement that ‘a dosage of 0.5 mg 3 times a day…appears to…ensure…minimal gastrointestinal toxicity’, since in clinical practice, a small but significant minority of patients treated initially even with lesser dosages require downward dose adjustment to alleviate gastrointestinal intolerance. In a disease like COVID-19, which itself causes gastroenteritis, this consideration is particularly relevant. On the other hand, higher doses might be required for efficacy and therefore worth accepting some gastrointestinal distress. The fact that patients with COVID-19 can rarely develop acute kidney injury that would mandate colchicine dose adjustment further supports the desirability of identifying the lowest effective dose. The approach that Perricone et al have taken in their CHOICE-19 study of using a higher dose initially and then dropping to a lower dose seems like a reasonable approach, and is one also adopted by the COLCORONA study8; however, only actual study data can answer this question.
BS and AZR are joint first authors.
J-CT and MHP are joint senior authors.
Handling editor Josef S Smolen
Contributors All authors contributed to conception or design of this correspondence response; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Commissioned; internally peer reviewed.
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