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We thank Favalli et al for their comment on our letter1 regarding the effect of antimalarials for the prevention of coronavirus disease 2019 (COVID-19).2 The authors provide updated information on a cohort of 914 patients with rheumatic and musculoskeletal diseases (RMDs), 112 of whom were treated with hydroxychloroquine (HCQ). The prevalence of confirmed or suspected COVID-19 cases was similar in both groups, and a patient with systemic sclerosis-associated lung disease treated with HCQ had a fatal outcome. Notably, 87% of patients reported rigorous compliance with contagion prevention measures.
These data are in accordance with accumulating evidence published over the last 2 months, indicating the occurrence of mild and severe cases of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with RMDs treated with antimalarials (table 1).1–16 Out of 869 reported patients with RMDs with confirmed COVID-19, 190 (22%) were taking long-term antimalarials prior to the infection.1–16 Of those, 99 out of 181 (55%) with available data developed severe disease that required hospitalisation. While these figures are limited by confounding by indication and selection bias, they attest to the fact that RMD patients treated with antimalarials can indeed be infected by SARS-CoV-2 and develop severe disease. Further, this seems to occur at a similar rate to patients not previously exposed to these drugs, considering the lack of association of previous antimalarial treatment with disease outcome in the studies that specifically assessed this aspect.11–14 Of note, this conclusion persisted even after adjustment for other clinically relevant variables, including sex, age, comorbidities and concomitant immunosuppressive and glucocorticoid therapy.11–13
At this point, although several questions regarding the risk and impact of COVID-19 for patients with RMDs remain unanswered, a few aspects begin to emerge. There is so far no convincing evidence to support the fact that patients with RMDs have an increased risk or worse prognosis of COVID-19.17 The reported incidence of SARS-CoV-2 infection and hospitalisation seems to be in line with that observed for the general population in various severely hit western countries.3–5 9 14 Moreover, hospitalisation rates are not increased, and most RMD patients on immunosuppressive therapies seem to have a favourable disease course,11 13 14 although three studies did report a high frequency of intensive care unit admission.6 11 15 Concomitant demographic (older age), clinical (comorbidities), and treatment (moderate-to-high-dose glucocorticoids) factors are likely more important detrimental prognostic factors.11–14
As noted by Konig et al, dosing and blood concentration issues may hamper an eventual beneficial antiviral effect of HCQ on patients with RMDs.12 Nevertheless, high-dose antimalarials have been shown to be ineffective and even potentially harmful in randomised controlled trials (RCTs).18 19 Large observational studies also failed to demonstrate a positive effect of HCQ for the treatment of COVID-19,20–22 but overall evidence is conflicting and insufficient.23 The results of ongoing large RCTs (eg, SOLIDARITY, ISRCTN83971151; DisCoVeRy, NCT04315948) are thus warranted for definite conclusions.
Regarding prophylaxis, a recently published RCT (n=821) failed to demonstrate a benefit of starting HCQ within 4 days after moderate-to-high-risk exposure to SARS-CoV-2, for preventing the development of COVID-19.24 As alluded to by Moiseev et al, additional RCTs are currently enrolling impressive numbers of patients to investigate the efficacy of pre-exposure and postexposure antimalarials in the prophylaxis of COVID-19.25 Though the findings of these trials may not be entirely generalisable to patients with RMDs on long-term treatment with antimalarials, they will definitely contribute to better define what role, if any, do these drugs play in the protection against SARS-CoV-2.
In conclusion, following the initial enthusiasm on the prospect of a putative preventive effect of antimalarial drugs in patients with RMDs, emerging data suggest otherwise. We are certainly still far from a final verdict, but RMD patients treated with antimalarials do develop mild-to-moderate and severe COVID-19. Thus, for now, focus should remain on advising patients to reinforce effective infection control measures, such as social distancing, hand/respiratory hygiene and face mask use.17 26
Handling editor Josef S Smolen
Contributors VCR, ARC-M, JEF: study conception and design, data acquisition, data analysis, manuscript preparation and critical revision. All authors approved the final version of the manuscript.
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, conduct, reporting or dissemination plans of this research.
Provenance and peer review Commissioned; internally peer reviewed.
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