Mild COVID-19 infection in a group of teriflunomide-treated patients with multiple sclerosis.

Dear Editor,

We have read with interest the recent paper published in this journal by Maghzi et al. [1] reporting a case series of five teriflunomide-treated multiple sclerosis (MS) patients who developed active COVID-19 infection and continued their therapy with a self-limiting infection, without any relapse. The authors hypothesized that, in these cases, COVID-19 infection could have had a better outcome because of the immune-biologic mechanisms pertaining to teriflunomide. In line with this hypothesis, Möhn and colleagues [2] reported another case of a 42-year-old male MS patient that, despite treatment with teriflunomide and high-dose methylprednisolone pulse therapy, developed a mild course of COVID-19.

To date, no other cases of COVID-19 teriflunomide-treated patients were reported.

We present here a case series of six patients treated with teriflunomide that developed a self-limiting COVID-19 infection. Diagnosis was confirmed in three of them with PCR from nasopharyngeal swabs and/or serology, while in the other three patients the diagnosis was based on typical symptomatology after a contact with COVID-19 patients during the epidemic peak in Lombardy between March and May 2020. All patients continued their therapy, and none of them experienced an MS relapse during the COVID-19 symptoms. Clinical characteristics and hematological values are reported in table in Table 1. Patients were mostly female (67%), with an average age of 45 (± 8.6) years and a disease duration of 15.8 (± 9.6) years. Median EDSS was 1.75 (range 1–4.5), and the average time on treatment with teriflunomide was 2.1 (± 1.6) years. None of these patients presented relevant comorbidities.

Table 1

Summary of cases

Patient	Age	Sex	MS type	MS duration (years)	EDSS	Years on teriflunomide	ALC*	CBC/LFTs*	Comorbidities
1	37	F	RR	19	1.5	0.5	WNL	WNL	No
2	54	F	RR	32	3.5	1	WNL	WNL	No
3	57	F	RR	22	1	0.5	WNL	WNL	No
4	40	M	RR	3	1	3	WNL	WNL	No
5	48	M	RR	10	2	2.5	WNL	WNL	No
6	34	F	RR	9	4.5	5	WNL	WNL	No

ALC absolute lymphocyte count, CBC complete blood count, EDSS Expanded Disability Status Scale score, LFTs liver function tests, MS multiple sclerosis, RR relapsing–remitting, WNL within normal limits

*At nearest available time preceding COVID-19 infection

None had lymphopenia, neutropenia or leukopenia. No patient required hospitalization, ICU care, or intubation. They all improved without receiving any specific treatment. One of the patients reported subjective diplopia, interpreted as a pseudo-relapse by the treating neurologist. Compared with the patients presented by Maghzi et al., the patients in our cohort were 8.6 years younger, average time on treatment with teriflunomide was about 0.5 years shorter, disease duration was 3 years longer and median EDSS was 0.75 point lower (2.5 with range 0–6 in Maghzi et al.). A weakness of our series is that infection was confirmed only in three patients.

Generally, patients with MS have an increased risk of infections [3], with about twice the risk of hospitalization with respect to the general population [4]. Infections also have a role in triggering MS relapses or worsening pre-existing MS symptoms [5], and they are more likely to happen in patients treated with disease-modifying therapies (DMTs), with a different risk depending on the mechanism of action of the drug [3].

The risk and course of COVID-19 in patients with MS is still unclear. Sormani et al. reported on 232 patients with MS from 38 different Italian MS centers presenting COVID-19 infection, 223 of whom experienced mild symptoms, 4 experienced severe infection and 6 with critical conditions [6]. In a study by Safavi et al., patients who were on a B-cell depleting antibody were at a higher risk of developing COVID-19 infection and being hospitalized [7]. Few reports about other therapies have been reported in the literature [8-12].

Teriflunomide is the active metabolite of leflunomide. Cai et al. reported a case of a patient with rheumatoid arthritis treated with leflunomide presenting a COVID-19 infection complicated by severe symptoms [13].

Our small case series, although in a different population compared to the paper of Maghzi and coauthors [1], seem to confirm that continuing therapy might be safe in teriflunomide-treated MS patients who develop COVID-19 infection. Withdrawal of teriflunomide does not seem to be necessary, especially if the lymphocyte count is higher than 500–800/mm3 [14].