Experience in Multiple Sclerosis Patients with COVID-19 and Disease-Modifying Therapies: A Review of 873 Published Cases

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic is a challenge for all participants in the healthcare system. At the beginning of the pandemic, many physicians asked themselves what risk their patients, especially those with chronic diseases, were exposed to. We present an overview of all patients with multiple sclerosis (MS) and SARS-CoV-2 infection published in the literature so far. In total, there are publications on 873 SARS-CoV-2 positive MS patients and information on the outcome can be given for 700 patients. With regard to the different disease modifying therapies (DMTs), by far the most cases were described under anti-CD20 treatment (n = 317). The mortality rate of all MS patients was 4% and a further 3% required invasive or non-invasive ventilation. When looking at the severe and fatal cases, it is particularly noticeable that patients without DMTs, with previous cardiovascular diseases, or with a severe degree of disability are at risk. Immunosuppressive therapy itself does not appear to be a substantial risk factor. Rather, it is reasonable to assume that the therapies could be protective, either directly, by mitigating the cytokine storm, or indirectly, by reducing the disease activity of MS.


Introduction
The outbreak of the novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the resulting global pandemic has confronted the world and its health authorities with one of the biggest challenges in recent history. The rapid disease spread is especially impressive, as the virus has reached every country worldwide in less than six months [1]. SARS-CoV-2 is known to primarily affect the patients' lungs [2,3]. The primary cause of SARS-CoV-2 mortality is acute respiratory distress syndrome (ARDS) initiated by epithelial infection and alveolar macrophage activation in the lungs. Typical clinical presentations are fever, dry cough, fatigue, ageusia or anosmia and, less often, symptoms of sputum production, headache, sore throat, or myalgia [4]. However, clinicians and researchers worldwide have reported relevant effects of COVID-19 on other major organs, including blood vessels, brain, gastrointestinal tract, kidney, heart, and liver.

Outcome of SARS-CoV-2 Positive MS Patients
Out of a total of 873 patients, published, detailed clinical outcome data were available for 700 patients ( Figure 2). A total of 204 patients was hospitalized. Of these, 24 patients required non-invasive or invasive ventilation. Considering the 700 patients with known outcome, 4% (n = 28) of these patients died in total. The remaining 496 subjects were able to stay at home after SARS-CoV-2 infection had been diagnosed.

Outcome of SARS-CoV-2 Positive MS Patients
Out of a total of 873 patients, published, detailed clinical outcome data were available for 700 patients ( Figure 2). A total of 204 patients was hospitalized. Of these, 24 patients required non-invasive or invasive ventilation. Considering the 700 patients with known outcome, 4% (n = 28) of these patients died in total. The remaining 496 subjects were able to stay at home after SARS-CoV-2 infection had been diagnosed.  Figure 3 gives an overview of all the different DMTs. It shows the number of non-hospitalized, hospitalized, ventilated and deceased patients under each therapy. Of all deaths (n = 14), 50% occurred in untreated patients. We can conclude from the figure that individual patients treated with anti-CD20-therapies, natalizumab, injectables, DMF, fingolimod, or teriflunomide died of COVID-19. In each DMT group   In each DMT group there were hospitalized patients, although they rarely required ventilation. By far the majority of the published patients were treated with anti-CD20 therapy. Of these, 147 patients (64%) did not require hospital treatment, 64 (28%) were hospitalized but did not require ventilation, 13 patients (6%) were ventilated and a total of 7 patients (3%) out of 231 died. In the literature 83 SARS-CoV-2 positive MS patients without DMTs are found. Of these patients 14 (17%) died and a total of 31 patients (37%) were treated in hospital. None of the subjects treated with alemtuzumab or cladribine had a severe course of the disease. The hospitalization rates were 24% (cladribine) and 14% (alemtuzumab), respectively. With regard to the other DMTs, a very similar number of severe and fatal courses could be observed. Only two patients (natalizumab, teriflunomide) or one patient (fingolimod, dimethyl-fumarate, injectable) of all published cases died. Thus, the death rates were 4% (teriflunomide), 3% (natalizumab), 2% (dimethyl-fumarate), and 1% (fingolimod and injectable). Non-fatal severe courses requiring ventilation were only described for fingolimod (n = 3; 4%) and dimethyl-fumarate (n = 2; 3%). Table 1 contains detailed information on all deceased MS patients published to date. Twenty-eight of the described SARS-CoV2 positive MS patients died. Of these, 14 patients had no DMT and 7 received anti-CD20 treatment. Of the patients in whom the course of MS was known, 14 patients (64%) had a primary or secondary progressive form and only eight patients (36%) were diagnosed with relapsing MS. The median duration of the disease was 24 years (range 5-51 years) and the median EDSS value amounted to 6.5 (range 1.5-9.5). Information on the gender and age of the patients is unfortunately scarce. However, it is generally apparent that the deceased patients were on average of older age. Twelve (43%) of those who died from COVID-19 had at least one cardiovascular comorbidity, nine of whom were significantly overweight. Two patients were diagnosed with asthma or chronic obstructive pulmonary disease and nine further patients had other concomitant diseases, including four cases of malignant disease. Only five (18%) of the deceased patients had no pre-existing conditions other than MS.

Analysis of Detailed Case Reports
A total of 51 SARS-CoV-2 positive MS patients had been published in detailed case reports or small case series (Supplementary Table S1). The reported patients had a median age of 45 years (min. 18, max. 62 years). Their median Expanded Disability Status Scale (EDSS) was 3.5, ranging between 0 and 8.0. Most of them had a longer disease duration of up to 28 years; the mean disease duration was 11 years. Regarding the DMTs, 16 patients were receiving ocrelizumab, nine were treated with fingolimod and eight patients were under teriflunomide therapy. The remaining patients received the following therapies: alemtuzumab (n = 5), cladribine (n = 4), natalizumab (n = 4), rituximab (n = 4), and interferon beta 1-a (n = 1).
For a total of nine patients, cardiovascular comorbidities such as arterial hypertension, dyslipidemia, obesity, or diabetes mellitus had been reported. Two patients either suffered from asthma or COPD and another 7 patients had other comorbidities, for example breast cancer, epilepsy, or chronic migraine. The totality of the published case reports showed a quite favorable outcome: twenty-two patients were able to stay at home, and 25 patients had to be hospitalized, but did not require non-invasive or invasive ventilation. Only three patients had to be treated in the intensive care unit including intubation or non-invasive ventilation and one patient died from COVID-19. Two of the four patients with a severe or fatal disease course suffered from cardiovascular comorbidities. pitalization rates were 24% (cladribine) and 14% (alemtuzumab), respectively. With regard to the other DMTs, a very similar number of severe and fatal courses could be observed. Only two patients (natalizumab, teriflunomide) or one patient (fingolimod, dimethyl-fumarate, injectable) of all published cases died. Thus, the death rates were 4% (teriflunomide), 3% (natalizumab), 2% (dimethyl-fumarate), and 1% (fingolimod and injectable). Non-fatal severe courses requiring ventilation were only described for fingolimod (n = 3; 4%) and dimethyl-fumarate (n = 2; 3%).

Discussion
The SARS-CoV-2 pandemic is a threat to many billions of people, many of whom are chronically ill. As neurologists, we are particularly interested in assessing the risk for those patients whose immune system is impaired by drug therapy. When we summarize the data of the literature regarding MS therapeutics and their potential risk in the context of the pandemic, it must be remembered that there is a certain publication bias. In general, more results are published for the highly effective and more innovative therapies, such as anti-CD20 treatment, than for the platform therapies. However, the numbers of serious or fatal cases remain surprisingly low overall. Considering all published cases of MS patients with COVID-19, the rate of fatal outcome is 4%. Even in the group of patients with anti-CD20 therapies, the rate of reported deaths is 3%. The proportion of patients undergoing intensive care is 6%. Similar or even better outcome results have been reported for patients treated with other MS therapeutics. It is noticeable that the group of untreated MS patients falls off quite markedly. Of the 83 people for whom the outcome was published, 17% died from COVID-19 and another 7% needed non-invasive or mechanical ventilation. These results might indicate that the MS therapy itself could even be protective or that the patients without immunomodulating therapy rather belong to the group of progressive MS patients and thus are more likely to show an advanced stage of the disease [18]. This suggestion is in line with results of Parotta and colleagues who identified older age, presence of comorbidities, progressive disease, and a non-ambulatory status, but not DMTs as risk factors for COVID-19 critical illness or related death [19]. Similar results can be seen in Table 1, as the majority of deceased patients have (cardiovascular) comorbidities, a progressive course of MS and a high degree of disability. Considering that the hyperactivity of the immune system as a consequence of the SARS-CoV-2 infection may cause even greater damage [72][73][74], DMTs could possibly avert a severe disease course. Lung tissue is especially affected by the unleashed immune factors. Thus, COVID-19 associated hyperinflammation can ultimately lead to ARDS [75][76][77]. Kloc et al. show that the application of small GTPase RhoA pathway inhibitors prevents macrophage infiltration and inhibits lung inflammation [78]. The MS therapeutics fingolimod and Siponimod are able to inhibit RhoA and RhoA/actin-dependent macrophage receptors recycling, and expression, and might be evaluated as a potential ARDS protective treatment [78].
In addition to age, cardiovascular comorbidities have been identified as important risk factors for severe COVID-19 in recent studies [79][80][81]. Interestingly, obesity in particular appears to be a decisive risk factor. The fact that obesity can reduce immune cell functionality, induce gut microbiome imbalance, as well as an inflammatory cytokine phenotype, may be a possible explanation for the correlation between obesity and severe COVID-19 course [82]. In summary, there is strong evidence that the suggested risk factors and the disability of MS have a significantly greater impact on the risk of developing serious COVID-19 disease than treatment with different DMTs. In one particular case, a young MS patient showed a mild course of COVID-19 even a few days after an alemtuzumab infusion [23]. This example emphasizes the fact that, even during treatment with highly effective DMTs, severe disease progression is not necessarily to be expected. However, especially for anti-CD20 therapies, the risk profile needs to be further explored. Very similar observations were also made in patients treated with disease-modifying anti-rheumatic drugs (DMARDs) due to inflammatory bowel disease or rheumatoid diseases [83][84][85].
This work has some limitations: First, this is a retrospective work that does not allow for causal conclusions. Secondly, we only describe the results published so far, but further analyses including multivariate logistic regression models have not been made and would exceed the scope of this paper. Finally, the already mentioned publication bias must be taken into account.

Conclusions
In conclusion, it is important to address the risks of different patient groups in the context of the SARS-CoV-2 pandemic. It is reasonable to expect that patients with chronic autoimmune diseases such as MS, who often require immunosuppressive therapies, will be at a particularly high risk for severe COVID-19 course. However, the cases currently published in the literature show that even among these patients the death rate is comparatively low and that it is not the DMTs themselves that pose a risk; rather, age, co-morbidities and the severity of the underlying disease are much more important. The fact that patients without DMTs account for a significant proportion of all deaths suggests that DMTs may even be protective.