Considerations on long-term immuno-intervention in the treatment of multiple sclerosis: an expert opinion

ABSTRACT

Introduction: As management of multiple sclerosis (MS) requires life-long treatment with disease-modifying agents, any risks associated with long-term use should be considered when evaluating therapeutic options.

Areas covered: Immune cells of the innate and adaptive immune systems play various roles in the pathogenesis of MS. MS therapies affect the immune system, each with a unique mode of action, and consequently possess different long-term safety profiles. Rare, but serious safety concerns, including an increased risk of infection and cancer, have been associated with immunosuppressant use. The risks associated with newer immunosuppressive agents, which target specific elements of MS disease pathophysiology, are not yet fully established as the duration of clinical trials is relatively short and post-marketing experience is limited. Non-immunosuppressants used to treat MS have well-defined safety profiles established over a large number of patient-years demonstrating them to be well-tolerated long-term treatment options. When considering the long-term use of disease-modifying agents for treating MS, classification as immunosuppressants or non-immunosuppressants can be useful when evaluating potential risks associated with chronic use.

Expert opinion: A successful therapeutic strategy for any serious, chronic disease such as MS should weigh effectiveness versus long-term safety of available treatments.

KEYWORDS:

• Cancer
• immunosuppressants
• long-term risks
• multiple sclerosis
• non-immunosuppressants
• opportunistic infections
• safety

Article highlights

• Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), in which immune cells of the innate and adaptive immune system play various roles in its pathogenesis, resulting in demyelination, glial scars and axonal loss. Patients require life-long treatment with disease-modifying agents, necessitating the consideration of long-term benefit-risk.

• Disease-modifying therapies used to treat MS are fundamentally either immunosuppressant, defined as an agent that completely or selectively suppresses one or more factors in the immune system, or a non-immunosuppressant, an agent targeting circumscribed elements or pathways in the immune system without compromising immune surveillance.

• Immunosuppressants used for the treatment of MS can be further classified as selective and non-selective immunosppressants. Non-selective agents (such as corticosteroids, azathioprine, mitoxantrone, ciclosporin and cyclophosphamide) reduce the activity of the immune system resulting in immunodeficiency. Selective immunosuppressants that act in the CNS and/or periphery (fingolimod, teriflunomide, alemtuzumab and natalizumab) have broad and varied immunosuppressant potential and the long-term risk of opportunistic infections and cancer is not yet fully established.

• The established non-immunosuppressive therapies interferon (IFN)-β and glatiramer acetate display favorable and well-defined short- and long-term safety profiles. IFN β-1a has been shown to interfere with multiple processes involved in the pathological immune reactions in MS, with no increased risk of infections nor increased incidence of malignancy compared with placebo; glatiramer acetate suppresses the inflammatory processes in the CNS by increasing production of anti-inflammatory cytokines and decreasing production of pro-inflammatory cytokines and is considered a safe treatment in terms of its adverse events profile overall.

• The long term benefits and risks of these agents should be considered and discussed with the patient. Treatment with agents with a well-known profile over a longer duration (life time) should be considered together with those that have attractive short-term efficacy outcomes but may have the risk of possible safety concerns in the future. Post-marketing surveillance systems and patient registries, should be kept constantly updated and made available to clinicians.

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Declaration of interest

N Alexandri is an external service provider to Merck SA, a subsidiary of Merck KGaA, Darmstadt, Germany. S Muehl is an employee of Merck (Schweiz) AG, a subsidiary of Merck KGaA, Darmstadt, Germany. G Hofbauer has received research support from Almirall, Biofrontera, Clinuvel, Galderma Spirig, LEO, L’Oréal, MEDA Pharmaceuticals, La Roche-Posay, Sunlight Research Forum, Wyeth/Pfizer, Vivosight; speaker’s fee from AbbVie, Galderma Spirig, LEO, L’Oréal, MEDA Pharmaceuticals, Merck, Novartis, Pfizer, Pierre Fabre; and a consultant for AbbVie, Biofrontera/Louis Widmer, Galderma Spirig, Hoffmann-La Roche, LEO, MEDA Pharmaceuticals. N Grigoriadis has received honoraria and travel support from Biogen Idec, Novartis, TEVA, Bayer, Merck Serono, Genesis Pharma, Sanofi-Aventis; consultancy fees from Biogen Idec, Novartis, TEVA, BAYER, Bayer, Merck Serono, Genesis Pharma, Sanofi-Aventis; lecture fees from Biogen Idec, Novartis, TEVA, Bayer, Merck Serono, Genesis Pharma, Sanofi-Aventis, Genzyme; research grants from Biogen Idec, Novartis, TEVA, Merck Serono and Genesis Pharma. M Linnebank has received grants, funding or honoraria from Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Teva. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was utilised in the preparation of this manuscript, it was funded by Merck KGaA and carried out by Loraine Ralph (InScience Communications, Chester, UK).

Additional information

Funding

This paper received funding from Merck KGaA.