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Persistence of rT-PCR-SARS-CoV-2 infection and delayed serological response, as a possible effect of rituximab according to the hypothesis of Schulze-Koops et al
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  1. Maurizio Benucci1,
  2. Luca Quartuccio2,
  3. Francesca Li Gobbi3,
  4. Arianna Damiani4,
  5. Valentina Grossi5,
  6. Maria Infantino6,
  7. Mariangela Manfredi7
  1. 1Rheumatology Unit, Ospedale San Giovanni di Dio, Firenze, Toscana, Italy
  2. 2Internal Medicie and Rheumatology Unit University of Udine, Udine, Italy
  3. 3Rheumatology Unit, Ospedale San Giovanni di Dio Hospital, Florence, Italy
  4. 4Rheumatology Unit Department Experimental Medicine University of Florence, Florence, Italy
  5. 5Maria Infantino Mariangela Manfredi Laboratory of Immunology and Allergology SGiovanni di Dio Hospital, Florence, Italy
  6. 6Laboratory of Immunology and Allergology, Ospedale San Giovanni di Dio, Firenze, Italy
  7. 7Ospedale San Giovanni di Dio, Firenze, Italy
  1. Correspondence to Dr Maurizio Benucci, Rheumatology Unit, Ospedale San Giovanni di Dio, Firenze, Toscana, Italy; maubenucci{at}tiscali.it

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The large study of 600 cases from 40 countries of the Covid-Global Rheumatology Alliance has shown that the use of conventional disease-modifying antirheumatic drug, alone or in combination with biologics/Janus Kinase inhibitors, and tumour necrosis factor inhibitor was associated with a reduced odds of hospitalisation.1 Schulze-Koops et al described two fatal outcomes in patients with rheumatoid arthritis treated with rituximab and focuses on careful vigilance on immunosuppression in the treatment of immune-mediated rheumatic diseases.2 To reinforce this observation, we report the case of a female patient aged about 60 years old, with a history of polymyositis and Sjögren’s syndrome. Her history was significant for previous cancer: thyroid carcinoma in 1995, phylloid tumour of the right breast in 2010 and carcinoid of the annexes in 2011. In January 2020, the patient had problem of fatigue, myalgia, together with rise in creatinekinase (CK) and Aldolase with positive anti-Mi-2 antibody, while on stable maintenance treatment with methotrexate 12.5 mg/weekly and prednisone 10 mg/day, rituximab 1 g 2 weeks apart was employed since 2017 with further cycles on the basis of B lymphocyte count (about 39 weeks between each cycle, accounting for four cycles in total). The last rituximab cycle was administered on February 2020. On 4 April, the patient showed fever 38.5°C, cough, dyspnoea, with the Horovitz Index of 108 and an X-ray demonstrating bilateral basal pulmonary thickenings with Echo Score of 38/42. The nose-pharyngeal swab rT-PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was found positive. She was admitted to the Covid-Unit Emergency Department, and soon transferred in intensive care unit for assisted ventilation and for subsequent endotracheal invasive ventilation. Table 1 shows clinical, laboratory parameters and treatments from hospitalisation to home discharge and in the subsequent follow-up. Laboratory data of the patient show an absence of replication in rT-PCR after treatment with remdesivir consisting of a loading dose of 200 mg intravenously on day 1, plus 100 mg daily for the following 9 days and 3 U of convalescent plasma. The treatments used also included tocilizumab (two 800 mg cumulative dose infusions), three-cycle intravenous immunoglobulins (0.4 g/kg day for 5 consecutive days) and dexamethasone 6 mg one time a day (table 1). During the hospitalisation and also 1-month follow-up after discharge, we did not detect anti-SARS-CoV-2 IgM and IgG production above the cut-off (iFlash1800 CLIA analyzer for anti‐SARS CoV‐2 antibodies IgM and IgG with a cut-off value of 10.0 AU/mL for both IgM and IgG antibodies). Furthermore, we did not observe B lymphocyte recovery in such subpopulations (CD27+ naive, CD27+ memory, CD38+, CD20+, CD19+) evaluated by flow cytometry (FACS CANTO II, BD Biosciences). B-lymphocytes play a key role through the B cell receptor in the early stages of innate immunity, along with the natural killer (NK) cells. B cells are important in the viral antigen processing mechanism, and also CD19+IgG+ memory elements are crucial to build up an immunological memory as well as in the production of antibodies with IgM (5–15 day) and IgG (10–21 day) isotypes, also in the response to a reinfection.3 Thus, rituximab may be hazardous in the present pandemic scenario, since it alarmingly inhibits the humoral response to SARS-CoV-2 infection and might contribute to possible secondary worsening.4 Differently from Schulze-Kopp’s cases, who underwent a fixed retreatment rituximab schedule, our patient undergoing a retreatment regimen at B cell recovery showed a good outcome. Notably, IgG levels before the last rituximab infusion were low, but over the dangerous threshold of 400 mg/dL. Therefore, it might be argued that rituximab retreatment regimen at B cell recovery rather than fixed retreatment schedule might be safer. Moreover, dexamethasone may have contributed to the favourable outcome of our patient.5 According to European League Against Rheumatism recommendations,6 patients undergoing cyclophosphamide or rituximab-mediated immunosuppression should represent the population of patients with rheumatic disease at highest risk of COVID-19 infection and its most severe consequences at this time; therefore, administration of these treatments should be based on a careful risk–benefit ratio. If needed, retreatment with rituximab should be based on B cell recovery or clinical (or laboratory) relapse, according to the disease, rather than with a fixed time schedule. Finally, a deeper analysis of the effect of each biological agent on COVID-19 infection is warranted.

Table 1

Clinic and laboratory data before treatment with rituximab, during hospitalisation, and in the follow-up

References

Footnotes

  • Contributors MB collected the patient data and wrote the manuscript. LQ contributed the revision of the manuscript. FLG collected the patient data. AD contributed the revision of the manuscript. VG, MI and MM determined the laboratory values.

  • 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 Not commissioned; internally peer reviewed.

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