key: cord-331283-bfyoavon
authors: Meca-Lallana, Dra. Virginia; Aguirre, Dra. Clara; Beatrizdel Río; Cardeñoso, Dra. Laura; Alarcon, Dra. Teresa; Vivancos, Dr. José
title: COVID-19 IN 7 MULTIPLE SCLEROSIS PATIENTS IN TREATMENT WITH ANTI-CD20 THERAPIES
date: 2020-06-15
journal: Mult Scler Relat Disord
DOI: 10.1016/j.msard.2020.102306
sha: 
doc_id: 331283
cord_uid: bfyoavon

BACKGROUND AND AIM: In December 2019, the first cases of SARS-CoV-2 infection were detected in Wuhan. Within two months, it had begun to spread around the world in what became an unprecedented pandemic. Patients with Multiple Sclerosis (MS) in a state of immunosuppression may be considered at risk for complications in the COVID-19 pandemic, although there is increasing evidence postulating a possible protective role of selective immunosuppression. One group of such immunosuppressants used in MS comprises the anti-CD20 monoclonal antibodies (mAbs) ocrelizumab and rituximab. Anti-CD20 mAbs bind to the surface of B cells, causing their depletion. We describe our experience in seven cases of patients with multiple sclerosis who have been affected by SARS-COV-2 (with a clinical/serological diagnosis or PCR diagnosis) and who were being treated with anti-CD20+ monoclonal antibodies. MATERIAL AND METHODS: We review the development of patients during infection as well as the resolution of their clinical picture. We also analyze the serology status against SARS-CoV-2 after resolution of the infection. RESULTS: Although the severity of the clinical pictures was variable, patients' development was good. Not all patients, however, developed antibodies against SARS-CoV-2. CONCLUSIONS: Patients treated with anti-CD20+ have adequate resolution of COVID-19 despite the fact that the presence of antibodies against SARS-CoV-2 was not detected in all cases. It is possible that the presence of humoral immunity is not always necessary fora good clinical course of SARS-CoV-2 infection.

In December 2019, the first cases of SARS-CoV-2 (Severe Acute Respiratory Syndrome

Coronavirus 2) infection were detected in Wuhan. This is the third coronavirus zoonosis to affect humans in 20 years and this time it has led to a rapidly spreading pandemic 1 Here, we describe our experience with seven patients treated with these drugs who suffered from COVID-19. The main clinical characteristics and treatments of the cases detailed below are summarized in Table 1 . Control RT-PCR on April 22 was negative. Complete COVID-19 serology (IgG + IgM) was also negative. Seven days later, ELISA serology for IgG and IgM showed negative results. The patient has remained asymptomatic throughout this time and the second ocrelizumab infusion (300 mg) was performed in May 2020 without incident following two negative PCR tests. PCR for SARS-CoV-2 were performed before administering his treatment dose in May 2020.

Both were positive, but the patient was asymptomatic.

Anti-CD20+ monoclonal antibodies are used in MS treatment. The incidence of severe infections from ocrelizumab in clinical trials was very low (1.3% for relapsing MS and 6.2% for primary progressive MS) 3 . Ocrelizumab is associated with decreased levels of IgM (and to a lesser degree for IgA and IgG), and serious infections occurred, but their incidence was low in clinical trials and extended phases 4 In this work, we report our experience in MS patients with anti-CD20+ antibodies who have 2. B cells and immunoglobulin may not be absolutely necessary for viral elimination. Perhaps in some especially milder cases, innate immunity anti-viral T cells may be sufficient for recovery 8,9 . 3. Several publications have suggested that selective immunosuppression prior to SARS-CoV-2 infection could benefit and even protect patients from its hyperinflammation phase, which is accompanied by a release of proinflammatory cytokines that can ultimately be fatal. It is hypothesized that the decrease in IL-6 releasing peripheral B cells could confer this protection to patients in the hyperinflammation phase 10, 11 .

In our series, all patients presented a favorable evolution, but it is worth mentioning patients 1, 6 and 7, who were older and had a higher EDSS. Worse infection evolution might therefore have been expected, yet they present adequate resolution of the clinical picture. Patients 6 and 7 in particular present a very mild clinical picture and an asymptomatic picture respectively. It should also be noted that patients 4 and 7 were asymptomatic carriers. Serology testing could not detect immune response to the virus in patients 4 and 5, but it did in patients 2, 3 and 7. This does not seem to be associated either with severity of the picture presented or with being an asymptomatic carrier, as patient 7 for example did not present a clinical picture and developed antibodies. The absence of CD19+ B cells cannot fully explain this either, since this occurs in all the patients we have reported on. This could be explained by the fact that patients with negative serology (4 and 5) came off rituximab treatment before ocrelizumab and perhaps the use of both therapies was detrimental to antibody formation. In the VELOCE study, humoral responses were attenuated in patients who were B-cell depleted having received ocrelizumab.

Patients were nonetheless able to have humoral responses to the vaccines and cellular immune responses were not assessed 12 . Adding in the use of rituximab, it is possible that this humoral response is reduced. Another option to consider is the possibility of false negatives in the test results.

As mentioned previously, COVID-19 resolution may not always necessarily require B cells. It is theorized that innate immunity or T-cell-mediated immunity might be sufficient in some patients to resolve the picture 8 because of the favorable evolution of infection in patients without B lymphocytes, as in X-linked agammaglobulinemia 9 .

Our experience with the evolution of patients treated with anti-CD20 drugs has been positive.

We can hypothesize a 'protective' role of selective immunosuppression in the COVID-19 hyperinflammation phase, in addition to the preserved ability of patients treated with anti-CD20 to make an adequate primary immune response. This may help us make decisions in treatment doses in the current pandemic 11 . We have found antibodies against SARS-CoV-2 in patients treated with ocrelizumab, but in patients who previously used rituximab this immunity is not achieved or we are not able to detect it. Regardless of the presence or absence of antibodies, progression has been favorable in all cases and so resolution of the condition could be considered to be independent of humoral immunity. Greater experience through patient records is required in order to draw firm conclusions.

Another Decade, Another Coronavirus

Anti-CD20 monoclonal antibodies in multiple sclerosis

Ocrelizumab: eficacia y seguridad en la esclerosis múltiple

P36 Serum immunoglobulin levels and risk of serious infections in the pivotal phase III trials of ocrelizumab in multiple sclerosis and their open-label extensions

Rituximab: its efficacy, effectiveness and safety in the treatment of multiple sclerosis

Ocrelizumab does not impair B-and T-cell responses to primary VZV infection in a patient with MS

Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis

Long-term coexistence of SARS-CoV-2 with antibody response in COVID-19 patients

Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover

COVID-19 in a MS patient treated with ocrelizumab: does immunosuppression have a protective role? Mult Scler Relat Disord

Anti-CD20 immunosuppressive disease-modifying therapies and COVID-19

A Bar-Or. VELOCE (NCT02545868) Effect of Ocrelizumab on Vaccine Responses in Patients With Multiple Sclerosis