A 2017 meta-analysis of 36 studies that included 30,000 patients with MS receiving IFN therapy found that after 1 year of continuous treatment, the proportion (SD) of patients developing NAbs to IFN was lower in those treated with IM IFN?-1a (4.7% [1.5%]; em n /em ?=?188) than in those treated with SC IFN?-1a (21.4% [2.8%]; em n /em ?=?716; em p? /em ?0.001) or SC IFN?-1b (32.2% [3.3%]; em n /em ?=?195; em p? /em ?0.001) [127]. MRI studies show that treatment with IFN?-1a, relative to placebo, reduces T2 and gadolinium-enhancing lesions and gray matter atrophy. Since the approval of intramuscular IFN?-1a, a number of high-efficacy therapies have been approved for MS, though SGI 1027 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 formulations may provide a particular benefit. In addition, the antiviral properties of IFNs may indicate potential therapeutic opportunities for IFN? in reducing the risk of viral infections such as COVID-19. Key Points Since 1981, clinical and real-world observational studies have demonstrated the effectiveness of interferon therapies in reducing relapse rate, disability worsening/progression, and the number of new or newly enlarging lesions in patients with multiple sclerosis (MS).The pivotal intramuscular interferon -1a phase III trial in 1996 (Multiple Sclerosis Collaborative Research Group [MSCRG]) was the first to demonstrate that disease-modifying therapy could reduce the accumulation of sustained disability in MS.Other studies suggest that interferon treatment may improve cognition and benefit patients quality of life. Open in a separate window Introduction Multiple sclerosis (MS) is usually a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) of unknown etiology with a projected 2020 prevalence of 0.9?million cases in the United States [1] and an estimated 2020 global prevalence of 2.8?million cases [2]. Symptoms of MS usually appear in adults between 20 and 50 years of age [3C5] and may include fatigue, visual impairment, motor weakness, ataxia, reduced mobility, tremor, sensory loss, pain, impaired SGI 1027 genitourinary function, depressive disorder, and cognitive impairment [6]. These symptoms have a negative impact on patients quality of life (QoL) by interfering with gainful employment, interpersonal relationships, intimate and leisure activities, and other daily activities [7, 8]. Most people with MS ( 85%) present with relapsing-remitting MS (RRMS) [4], characterized by an initial phase of recurrent neurologic episodes (relapses) followed by remission and a second phase consisting of the progressive accrual of neurologic disability [9, 10]. The pathological mechanisms underlying the initiation and progression of MS are multifactorial and not completely known (reviewed in [11C15]). The autoimmune inflammatory state is generally believed to be initiated by myelin-reactive CD4+ T helper cells [15C17], although other immune cells, including CD8+ T cells and B cells, are also significantly involved Rabbit Polyclonal to NFAT5/TonEBP (phospho-Ser155) [18, 19]. Epidemiological studies have identified geographic [20], environmental [21C23], commensal [24C26], and genetic [27] risk factors for MS. Genome-wide association studies show over 200 loci that may contribute to the genetic risk for MS, including major histocompatibility complex alleles and genes regulating interferon (IFN) responses (reviewed in [28C31]). While some of the genetic loci and most of the identified environmental risk factors affect adaptive and/or innate immunity, no one risk factor is able to explain all cases of MS. This suggests that one or more risk factors may help to trigger MS in genetically susceptible persons [32, 33]. Twenty-five years ago, intramuscular (IM) IFN?-1a (Avonex?) was shown to be the first treatment for patients with MS that could impact the course of the disease by reducing the accrual of sustained disability in addition to reducing relapses. Since the approval of IM IFN?-1a, the MS therapeutic scenery has changed considerably with the addition of new therapeutic brokers. In the following, we present a narrative review of the history, mechanism of action, and clinical and real-world experience with IM IFN?-1a for the treatment of MS. The Interferons (IFNs): Discovery and Mechanism of Action in Multiple Sclerosis Therapy The IFNs were discovered in 1957 during investigations into mechanisms of viral interference [34]. In humans, IFNs form a family of secreted autocrine and paracrine cytokines [35] with diverse and essential functions in mediating antiviral activity, regulating cell growth and proliferation, and modulating immune responses [36, 37]. Based on sequence homology and signaling properties, IFNs can be grouped into three types. All type I IFNs bind to and signal through the same heterodimeric IFNAR1/IFNAR2 receptor [38, 39]. In addition to the type I IFNs, a single type II IFN, IFN?, signals through different receptors and elicits different cellular responses [40], though SGI 1027 both types regulate SGI 1027 inflammatory responses, primarily by signaling through the JAK-STAT family of signal transducers [41]. The type III IFNs, which include IFN?1-4, primarily target epithelial cells and have antiviral and immunomodulatory functions [42]. Epidemiological evidence for a viral trigger of MS, coupled with the known antiviral activity of type I IFNs.