Interferons and Multiple Sclerosis: Lessons from 25 Years of Clinical and Real-World Experience with Intramuscular Interferon Beta-1a (Avonex)

Abstract

Recombinant interferon (IFN) β-1b was approved by the US Food and Drug Administration as the first disease-modifying therapy (DMT) for multiple sclerosis (MS) in 1993. Since that time, clinical trials and real-world observational studies have demonstrated the effectiveness of IFN therapies. The pivotal intramuscular IFN β-1a phase III trial published in 1996 was the first to demonstrate that a DMT could reduce accumulation of sustained disability in MS. Patient adherence to treatment is higher with intramuscular IFN β-1a, given once weekly, than with subcutaneous formulations requiring multiple injections per week. Moreover, subcutaneous IFN β-1a is associated with an increased incidence of injection-site reactions and neutralizing antibodies compared with intramuscular administration. In recent years, revisions to MS diagnostic criteria have improved clinicians’ ability to identify patients with MS and have promoted the use of magnetic resonance imaging (MRI) for diagnosis and disease monitoring. MRI studies show that treatment with IFN β-1a, relative to placebo, reduces T2 and gadolinium-enhancing lesions and gray matter atrophy. Since the approval of intramuscular IFN β-1a, a number of high-efficacy therapies have been approved for MS, though the benefit of these high-efficacy therapies should be balanced against the increased risk of serious adverse events associated with their long-term use. For some subpopulations of patients, including pregnant women, the safety profile of IFN β formulations may provide a particular benefit. In addition, the antiviral properties of IFNs may indicate potential therapeutic opportunities for IFN β in reducing the risk of viral infections such as COVID-19.

Interferon-β Activity Is Affected by S100B Protein

“…It possesses immunomodulatory, anti/pro-inflammatory, antiviral, anti/promicrobial, and antitumor activities [1,[4][5][6][7]. IFN-β and its derivatives are commonly used in treatment of multiple sclerosis (MS) [8]. Clinical studies confirmed the efficacy of IFN-β use in therapy of cancer, SARS-CoV-2, and asthma [9][10][11].…”

Neuroinflammation Associated With Inborn Errors of Immunity

“…In a mouse model of MS, USP18 expression specifically in microglia has an important role in dampening excessive interferon input that otherwise would result in pathological microglia activation, which reflects the human interferonopathy caused by USP18 deficiency ( 135 ). In contrast, IFN-β is a well-established therapy for MS ( 166 ) and has been reported to reduce the severity of mouse models of the disease ( 167 ). Notably, not all MS patients respond to IFN-β, and exacerbations have been described ( 168 , 169 ).…”

Adipokines as Immune Cell Modulators in Multiple Sclerosis

“…In today’s clinic, multiple disease-modifying treatments (DMTs) are available for the treatment of RRMS, targeting various disease aspects and with a large range of efficacy [ 19 ]. The first DMT, IFN-β, was approved in 1993 and is still widely prescribed [ 20 ]. Since then, 10 classes of DMTs are FDA (Food and Drug Administration) approved for MS and comprise interferons, sphingosine 1-phosphate (S1P) receptor modulators, cladribine, teriflunomide, mitoxantrone, glatiramer acetate, fumarates, CD20 antibodies, natalizumab, and alemtuzumab.…”

“…These DMTs have a wide range of mechanism of actions, administration routes, and efficacy, but all are immunomodulatory. The treatment effect of IFN-β is related to several overlapping mechanisms including the downregulation of major histocompatibility complex (MHC) class II expression present on antigen-presenting cells, production of interleukin 10 (IL-10), and inhibition of T cell migration into the brain [ 20 ]. S1P receptor modulators bind various subtypes of S1P receptors, which results in their internalization and sequestration of lymphocytes in lymph nodes.…”