When Teriflunomide and Interferon Join Forces
Progressive multifocal leukoencephalopathy is a nightmare for all doctors prescribing disease-modifying therapies for multiple sclerosis. How Swiss colleagues dealt with this situation is illuminated by the following case study.
Virus Activation as a Complication of MS Treatment
Progressive multifocal leukoencephalopathy (PML) caused by John Cunningham Virus (JCV) is one of the most severe complications associated with disease-modifying drugs (DMDs). It is most commonly described in relation to natalizumab, less often with dimethyl fumarate and fingolimod. Unfortunately, the only option in the case of PML occurrence is currently the cessation of the respective DMD therapy. While this allows the immune system better access to the central nervous system, it also raises the risks of the rebound phenomenon and immune reconstitution inflammatory syndrome (IRIS).
Case Description
A 53-year-old female patient with relapsing-remitting multiple sclerosis (RRMS), initially diagnosed in 2000 and treated with interferon-beta-1b, was switched to fingolimod in 2011. Since the therapy escalation, her clinical status had been stable – the score on the Kurtzke Expanded Disability Status Scale (EDSS) had consistently been 3 points. However, in November 2017, a new T2-enhancing periventricular lesion was detected on magnetic resonance imaging (MRI), along with an elevation in serum neurofilament light chains (NfL) levels.
In March 2018, the patient reported expressive aphasia, but other objective neurological findings were consistent with previous examinations. However, the MRI revealed a high suspicion of PML. There was also a significant elevation in serum NfL levels. Laboratory results were normal, except for lymphopenia (expected due to current therapy). Nonetheless, cerebrospinal fluid analysis detected 341 copies of JCV/ml.
Fingolimod therapy was immediately discontinued, and a 5-day course of intravenous immunoglobulins (IVIG) at 30 g/day was initiated. After another 8 weeks, aphasia progressed, and mild right-sided hemiparesis appeared. The MRI findings were compatible with IRIS, and serum NfL levels reached their peak. Another 5-day IVIG course combined with glucocorticoids and the chemokine receptor 5 antagonist (maraviroc) was administered. Maraviroc was continued for one month at a daily dose of 600 mg, this time with a good effect.
Control lumbar puncture in June of the same year revealed 23 copies of JCV/ml, and a repeat examination in September confirmed the elimination of JCV from the cerebrospinal fluid. However, new lesions appeared on the control MRI in May 2018. Given the activity of the primary disease, teriflunomide was initiated for the patient. NfL levels decreased, but they still remained elevated compared to pre-2011 values.
Given further MRI findings progression, pegylated interferon-beta-1a was added to teriflunomide in September 2019. MRI findings in December 2019 and January 2020 showed no progression, and NfL levels returned to baseline. Except for intermittent expressive aphasia, the previously mentioned symptoms resolved clinically.
Combined Therapy as a Possible Solution?
Teriflunomide, registered for the treatment of RRMS, is an active metabolite of leflunomide. Studies on BK virus elimination in kidney transplant patients indicate leflunomide's good effectiveness in achieving this outcome while maintaining an immunosuppressive effect. Since BK virus and JCV belong to the same group (Polyomaviridae), a hypothesis arises about teriflunomide's similar effects on JCV. Hence, teriflunomide seems to be an ideal DMD for patients whose condition was complicated by progressive multifocal leukoencephalopathy.
Although the administration of teriflunomide led to PML lesion regression, decreased serum NfL levels, and JCV elimination, the primary disease activity remained elevated. Therefore, the authors of the case study decided to combine this DMD with another non-PML associated drug with a different mode of action – interferon-beta-1a. The patient tolerated this combined therapy well. The combination of teriflunomide and interferon-beta resulted in MRI findings stabilization and further reduction of serum NfL. This combination might represent a safe therapy for patients post-PML.
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Source: Fischer-Barnicol B., Oechtering J., Kuhle J. et al. Combination of teriflunomide and interferon as follow-up therapy after fingolimod-associated PML. Neurol Neuroimmunol Neuroinflamm 2020 Dec 3; 8 (1): e927, doi: 10.1212/NXI.0000000000000927.
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