• Covid-19
• glucocorticoids
• therapeutics
• abatacept
• tumor necrosis factor inhibitors

We read with great interest the Global Rheumatology Alliance report on COVID-19 on biologic or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA).1 The first important result of the registry database is that B-cell depletion, by compromising the primary antibody response, increases the severity of infected patients. Considering the critical role of B cells in the adaptive immune response, this sounds quite correct.2 Even the data on interleukin 6 and tumour necrosis factor (TNF) inhibitors appear quite understandable considering the systemic inflammation raised by SARS-CoV-2 infection, the results of the Randomised Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia (REMAP-CAP) trial in patients on National Institute of Allergy and Infectious Diseases ordinal scale (NIAID)-Ordinal Scale 6 and 73 and the demonstrated role of TNF–TNF receptor 1 in inducing lymphopenia and T-cell dysfunction in severe–critical disease.4 Importantly, the death rate in abatacept was found close to that in JAK inhibitors. This appears contradictory to recent epidemiological retrospective surveys that showed in a large tertiary hospital in Barcelona (Spain) that abatacept-treated patients (42 patients from a cohort of 959 patients treated with biological and synthetic DMARDs) exhibited the lowest frequency of COVID-19 compatible symptoms.5 Similar data were also obtained from a hospital in Madrid (Spain), where it was noted that none of the 27 abatacept-treated patients (among 802 DMARD-treated patients) were admitted to hospital with COVID-19 symptoms, thus suggesting that the predisposition to be infected is not enhanced. On the other hand, if the patient is infected, abatacept might affect the activation of innate cells, such as monocytes and dendritic cells, and alter Tregs.6 Before any conclusion, results of trials on abatacept treatment in patients infected with COVID-19 are eagerly needed.7

However, really crucial appear the steroids and JAK inhibitors-related data. It has been clearly demonstrated that the replication phase of the virus occurs in the first 5–8 days.8 In this timeframe using steroids seems deleterious, since in almost all RA trials, the use of steroids showed an increased rate of infections. Then, the issue is: are the death rate data while on JAK inhibitors normalised for concomitant steroids use or are they influenced by concomitant steroids? This appears important in clinical practice because in the real-world JAK inhibitors are often used in severe patients with RA, resistant to other DMARDs, and needing at least a persistent or bridging steroid therapy. The second issue concerns more specifically the immunobiological consequences of JAK inhibition. Trials with baricitinib clearly demonstrated that JAK1–2 inhibition was clinically useful in hospitalised patients, only in the NIAID-Ordinal Scale Score 5–6 (not 4 or 7) (NIAID Ordinal Scale: 1. not hospitalised and no limitations of activities; 2. not hospitalised, with limitation of activities, home oxygen requirement, or both; 3. hospitalised, not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalisation was extended for infection control or other non-medical reasons); 4. hospitalised, not requiring supplemental oxygen but requiring ongoing medical care (related to COVID-19 or to other medical conditions); 5. hospitalised, requiring any supplemental oxygen; 6. hospitalised, requiring non-invasive ventilation or use of high-flow oxygen devices; 7. hospitalised, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation; and 8. death).

This means that the logical consequence should be that once COVID-19 infection occurs, JAK inhibitors should be discontinued (and eventually restarted if the disease progresses to the Ordinal Scale 5–6 in hospitalised patients).9 10 The question then is: were patients who died taking JAK inhibitors (along with remdesivir) at the time they were progressing and were patients taking JAK inhibitors when registered for death? The key point that emerged during the pandemic is that the different stages of the COVID-19 disease most likely need different approaches.11