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We thank Dr Guilpain et al 1 for their comment regarding the case of a patient with granulomatosis with polyangiitis who developed signs of systemic acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection shortly after having received treatment with rituximab. The comment raises a series of important points of discussion. The differential diagnosis between infectious complications or manifestations of the underlying rheumatological condition has always been a challenge when managing patients with systemic diseases such as antineutrophil cytoplasmic antibody-associated vasculitis (AAV) or connective tissue diseases (CTD). The clinical picture and laboratory and imaging findings in patients with AAV or CTD are often non-specific and need to be differentiated from changes caused by treatment or by infectious complication.2–4 SARS-CoV-2 has been associated with clinical manifestations and complications that can resemble some changes found in AAV or CTD. The cardiovascular risk, including the risk of deep venous thrombosis and pulmonary embolism, is increased also in AAV and several types of CTD, especially during phases of active disease, and continuous surveillance is mandatory.5 6 This holistic, multidisciplinary clinical thinking process should always be applied when managing patients with AAV, even in a confirmed case of COVID-19, as correctly described by Guilpain et al.1 Furthermore, the authors hypothesised that treatment with glucocorticoids and rituximab might have delayed the occurrence of severe respiratory failure requiring mechanical ventilation in this patient compared with previous reports. Although this is a possibility, it is also likely that the intensive immunosuppressive regimen, particularly with a drug impairing B lymphocytes, and antibody production response might have played a significant role in the progressive worsening of the clinical conditions of the patient. There are several immunomodulatory treatment options, some with promising results, being tested for COVID-19 mainly targeting key proinflammatory cytokines or pathways, such as the interleukin (IL)-6, IL-1 or Janus Kinase-signal transducer and activator of transcription (JAK-STAT) signalling. However, it is conceivable that while some immunosuppressive agents routinely used for rheumatological conditions might offer an advantage on the exaggerated immune response and cytokine storm being triggered by SARS-CoV-2 in some individuals, other agents, including those acting on cells responsible for antibody production, would actually turn out to be particularly detrimental in the course of COVID-19. Rituximab is a drug with pleyotropic effects on the immune system, with the most prominent being the long-lasting reduction or abrogation of the humoral response by depleting antibody-producing B cells. The ultimate effect of the treatment with rituximab is the reduction of autoantibody production, but on the other hand this can expose the patient to an impaired response to infections and vaccines. Although further studies are needed, it is plausible from the biological effects of rituximab that this drug could interfere with the ability of the subject to properly and rapidly respond to SARS-CoV-2 infection. The hypothesis that a prompt and efficient antibody production against the infection would lead to better outcomes and faster resolution of COVID-19 was used as the rationale for an ongoing experimental treatment study at our hospital (ClinicalTrials.gov identifier NCT04321421) using hyperimmune plasma, rich in IgG against SARS-CoV-2 obtained from recovered patients. Nevertheless, there have also been reports on experimental models in coronaviruses infections suggesting that, again, an excessive reaction to the virus with high levels of antispike IgG production would actually contribute to the severity of the disease rather than accelerating its resolution.7 The comment from our French colleagues1 offers the grounds to underline once more the complexity of applying immunosuppressant treatments, usually used to treat rheumatological diseases, to a different condition, showing a striking interplay between infectious, inflammatory and immunological pathogenetic mechanisms that are still largely unknown.
Handling editor Josef S Smolen
Correction notice This article has been corrected since it published Online First. The formatting of the title has been corrected.
Contributors SM and CM contributed equally to the realisation 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, 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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