We read with great interest the review by Rostami Mansoor and Ghasemi‐Kasman entitled “Impact of disease‐modifying drugs on the severity of coronavirus disease 2019 (COVID‐19) infection in multiple sclerosis patients” in your journal.¹ After examining the papers published on this topic, they conclude that it seems that disease‐modifying drugs (DMTs) do not confer an increased risk or provoke COVID‐19 infection in multiple sclerosis (MS) patients.

In this commentary, we want to focus the attention on the modification of prescribing habits by neurologists in MS patients during the pandemic. Case reports or case series of MS patients with COVID‐19 in both first‐line (teriflunomide and dymethil fumarate) and second‐line treatment (fingolimod, natalizumab, ocrelizumab, alemtuzumab, and cladribine) have been reported in the literature.^2-13 Nevertheless, the risk and course of COVID‐19 in patients with MS is unclear, and neurologists have to face different decisions when considering to initiate or continue therapies in these patients. Indeed, MS clinicians know that their patients are at a generally increased risk of infections and are twice as likely to be hospitalized for infections than the general population.¹⁴

At the beginning of the pandemic, Brownlee and colleagues¹⁵ published a paper highlighting the implications of COVID‐19 for people with MS and related disorders. The authors considered MS patients with and without COVID‐19 infection. For MS patients with COVID‐19 infection, the authors suggested that clinicians consider stopping highly immunosuppressive treatments in patients who have risk factors for severe COVID‐19 disease, have severe symptoms, or have a complicated COVID‐19 infection. On the other hand, they suggested continuing treatment in those with documented mild COVID‐19 infection. For patients without COVID‐19 infection, they speculated that therapies with immunosuppressive effects and alterations in lymphocyte number, trafficking, proliferation, and function might predispose to a greater risk of COVID‐19 infection and potentially more severe infection. The authors suggest to continue the therapies with a low risk of systemic immunosuppression, monitor blood test, consider transitioning to extended‐interval dosing for anti‐CD20 agents, consider avoiding initiation of or delaying current use of cladribine and alemtuzumab (considered at high risk of systemic immunosuppression).

More recently, Giovannoni et al.¹⁶ affirmed that it is essential to consider the potential risk of morbidity and possible mortality for each MS patient, pondering the individual's multifactorial risk profile. Any decision to initiate a DMT during the COVID‐19 pandemic will need to be made carefully, considering the COVID‐19 pandemic status. However, they suggested suspending a dose of alemtuzumab and assessing anti‐CD20 and cladribine risk, considering suspending dosing.

Hamdy and colleagues suggested that, in patients with active COVID‐19 infection, it is mandatory to stop all DMTs, and the timing of resuming treatment is not well defined.¹⁷

In a recent work by the Italian MS group, a large majority of deaths occurred in patients with advanced disease and disability due to MS, and anti‐CD20 treatment was associated with a higher risk of developing COVID‐19 symptoms and severe COVID‐19 course, with an association with treatment duration. Moreover, methylprednisolone in the month preceding COVID‐19 infection was significantly associated with a worse disease outcome.¹⁸ Even Safavi et al.¹⁹ reported that B‐cell depleting antibodies might increase susceptibility to acute respiratory illness in MS patients. In a pharmacovigilance‐based case series of 100 COVID‐19 patients treated with ocrelizumab, 28 of them presented a severe or critical course of infection.²⁰

Our group has recently published data from our patients in the first phase of the pandemic in Italy (from March to May 2020).²¹ At that time, 15 of 275 patients reported symptoms suggestive of COVID‐19 infection; 14 patients were qualified by their reported symptoms and one patient reported a positive PCR test. They all improved without receiving any specific treatment; none of them required hospitalization, intensive care unit, or intubation. No patients had to change/delay the ongoing treatment in our cohort.

However, this pandemic has undoubtedly changed the way many neurologists treat MS patients. The risk of new waves of pandemics may make neuro‐immunologists more prudent in choosing drugs for their at‐risk patients, particularly if the therapies have a higher toxicity profile and are less manageable. The second‐line drug that indeed finds the most benefit at the moment is natalizumab, which appears to be the safest for its mechanism of action due to the low risk of systemic immunosuppression. Brownlee et al.¹⁵ recommend that wherever there is a need for a high‐efficacy treatment, starting or switching to natalizumab is preferable to alemtuzumab, cladribine, or ocrelizumab because the risk of systemic immunosuppression is low and prolonged lymphocyte depletion does not occur. Giovannoni et al.¹⁶ considered natalizumab low risk, but the authors raised theoretical concerns of creating an environment in mucosal surfaces and the gut with a danger of prolonged viral shedding.

Another problem we wish to focus on is the flu‐like syndrome (as fever, muscle aches, chills, and fatigue), which is known to be associated with some drugs for MS treatment, particularly interferons. Today in Italy, as in other countries, to go to work and in restaurants and bars, body temperature measurement is required. How can patients with flu‐like syndrome solve this problem? Will they lose more business days? Will they have less adherence to the drug? Neurologists should be careful in evaluating these implications and be ready to vary therapy if necessary and indicated.

To conclude, the therapeutic scenario for MS has certainly changed with the pandemic, and probably also in the future, the attitude of neurologists will be different. However, in the past, we were already used to changing our habits with other infectious diseases. For example, when the correlation between natalizumab and progressive multifocal leukoencephalopathy was discovered, the quantification of anti‐JCV antibodies was introduced; or, after cases of chickenpox virus infection identified after fingolomod administration in patients with absent varicella‐zoster virus antibodies, the VZV vaccination was required before use.

As suggested by Giovannoni et al.,¹⁶ the COVID‐19 pandemic may trigger a large number of neurologists and patients to reconsider the treatment strategy and opt for less effective DMTs, but we must not forget the goal of treatment. Therefore, it is necessary to always use the most suitable drug for the patient while paying attention to safety. Relying on safety alone can do long‐term harm to patients.

我们非常感兴趣地阅读了Rostami Mansoor和Ghasemi-Kasman在您的期刊上发表的题为“疾病改变药物对多发性硬化症患者中2019年冠状病毒病（COVID-19）严重程度的影响”的评论。¹在检查了有关该主题的论文后，他们得出结论认为，疾病改变药物（DMT）不会增加多发性硬化症（MS）患者的风险或引起COVID-19感染。

在这篇评论中，我们希望将注意力集中在大流行期间MS患者神经科医生对处方习惯的改变上。文献报道了在一线（特氟米特和富马酸倍他米特）和二线治疗（芬戈莫德，那他珠单抗，ocrelizumab，阿仑单抗和克拉屈滨）的COVID-19 MS患者的病例报告或病例系列。^2-13然而，尚不清楚MS患者中COVID-19的风险和病程，神经科医师在考虑开始或继续治疗这些患者时必须面对不同的决定。的确，MS临床医生知道他们的患者感染的风险普遍增加，住院感染的可能性是普通人群的两倍。¹⁴

在大流行初期，Brownlee及其同事¹⁵发表了一篇论文，强调了COVID-19对MS和相关疾病患者的影响。作者考虑了有和没有COVID-19感染的MS患者。对于患有COVID-19感染的MS患者，作者建议临床医生考虑对有严重COVID-19疾病危险因素，严重症状或复杂COVID-19感染的患者停止高免疫抑制治疗。另一方面，他们建议对已证明有轻度COVID-19感染的患者继续治疗。对于没有COVID-19感染的患者，他们推测具有免疫抑制作用以及淋巴细胞数量，运输，增殖和功能改变的疗法可能使COVID-19感染的风险增加，甚至可能导致更严重的感染。

最近，Giovannoni等。¹⁶ 确认必须考虑每位MS患者的潜在发病风险和可能的死亡率，并考虑个人的多因素风险状况。考虑到COVID-19大流行状态，在决策期间必须谨慎地决定启动DMT。但是，他们建议暂停剂量的alemtuzumab，并考虑暂停给药，评估抗CD20和克拉屈滨的风险。

Hamdy及其同事建议，对于患有活动性COVID-19感染的患者，必须停止所有DMT，并且恢复治疗的时机还不确定。¹⁷

在意大利MS小组的最新工作中，绝大多数死亡发生在患有MS的晚期疾病和残疾患者中，抗CD20治疗与产生COVID-19症状和严重COVID-19病程的较高风险相关，与治疗持续时间有关。此外，在感染COVID-19之前的一个月中，甲基泼尼松龙与疾病恶化的趋势显着相关。¹⁸甚至Safavi等。¹⁹报告说，消耗B细胞的抗体可能会增加MS患者对急性呼吸道疾病的敏感性。在以药物警戒为基础的病例系列中，使用ocrelizumab治疗的100例COVID-19患者中，有28例出现了严重或严重的感染过程。²⁰

我们小组最近发布了来自意大利大流行第一阶段（2020年3月至2020年5月）患者的数据。²¹当时，在275名患者中，有15名报告了提示COVID-19感染的症状；14名患者通过其报告的症状合格，而一名患者报告PCR检测呈阳性。他们都得到了改善，没有接受任何特殊的治疗。他们都不需要住院，重症监护病房或插管。在我们的队列中，没有患者必须更改/延迟正在进行的治疗。

但是，这种流行病无疑改变了许多神经科医生治疗MS患者的方式。新一轮大流行的风险可能使神经免疫学家更加谨慎地为有风险的患者选择药物，特别是如果该疗法具有较高的毒性特征且较难管理的话。目前确实获益最大的二线药物是那他珠单抗，由于其全身免疫抑制的风险较低，它似乎是最安全的作用机理。布朗利等。¹⁵建议在需要高效率治疗的地方，开始或改用那他珠单抗比阿来珠单抗，克拉屈滨或奥珠单抗更可取，因为其全身免疫抑制的风险低且不会出现淋巴细胞耗竭的情况。Giovannoni等。¹⁶ 认为那他珠单抗的风险较低，但作者提出了在粘膜表面和肠道中创造环境的理论关注点，即存在病毒长时间脱落的危险。

我们希望关注的另一个问题是类似流感的综合症（如发烧，肌肉酸痛，发冷和疲劳），已知它与某些MS治疗药物（尤其是干扰素）有关。今天，在意大利和其他国家一样，上班以及在饭店和酒吧中，都需要进行体温测量。流感样综合征患者如何解决该问题？他们会失去更多的工作日吗？他们对药物的依从性会降低吗？神经科医生应谨慎评估这些影响，并准备在必要和有指征的情况下改变治疗方法。

总之，随着大流行，MS的治疗方案肯定已经改变，并且也许将来，神经科医生的态度也将有所不同。但是，在过去，我们已经习惯于改变其他传染病的习惯。例如，当发现那他珠单抗与进行性多灶性白质脑病之间的相关性时，就引入了抗JCV抗体的定量方法。或在无水痘带状疱疹病毒抗体的患者中施用芬戈莫德后发现水痘病毒感染病例后，在使用前需要接种VZV疫苗。

正如Giovannoni等[ ^16]所建议的那样，COVID-19大流行可能会触发大量的神经科医生和患者重新考虑治疗策略并选择效果较差的DMT，但我们一定不能忘记治疗的目标。因此，有必要在注意安全性的同时始终为患者使用最合适的药物。仅仅依靠安全性可能会对患者造成长期伤害。