Description of the condition
Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system. It is pathologically characterised by inflammation, demyelination, and axonal and neuronal loss. Clinically it is characterised by recurrent relapses or progression, or both, typically striking adults during the primary productive time of their lives and ultimately leading to severe neurological disability.
There are four clinical phenotypes of MS. Initially, more than 80% of individuals with MS experience a relapsing-remitting disease course (RRMS), characterised by clinical exacerbations of neurological symptoms followed by complete or incomplete remission (Lublin 1996). After 10 to 20 years, or a median age of 39.1 years, about half of these people gradually accumulate irreversible neurological deficits, with or without clinical relapses (Confavreux 2006), which is known as secondary progressive MS (SPMS). Another 10% to 20% of individuals with MS are diagnosed with primary progressive MS (PPMS), clinically defined as a disease course without any clinical attacks or remission from onset (Lublin 1996). A significantly rarer form is progressive relapsing MS (PRMS), which initially presents as PPMS; however, during the course of the disease these individuals develop true neurological exacerbations (Tullman 2004).
MS causes a major socioeconomic burden, both for the individual patient and for society. Increasing costs and decreasing quality of life are associated with advancing disease severity, disease progression and relapses (Karampampa 2012a; Karampampa 2013). From a patient's perspective, a MS relapse is associated with a significant increase in economic costs as well as a decline in health-related quality of life and functional ability (Oleen-Burkey 2012). Effective treatment that reduces relapse frequency and prevents progression could have an impact both on costs and quality of life, and may help to reduce the social burden of MS (Karampampa 2012b).
Natalizumab and interferon (IFN) β-1a (IFNβ-1a) (Rebif) have been shown to be superior to mitoxantrone, glatiramer acetate, IFNβ-1b (Betaseron) and IFNβ-1a (Avonex) for preventing clinical relapses in RRMS in the short term (24 months) compared to placebo, based on high-quality evidence. However, they are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable (Filippini 2013). Furthermore, administration of IFNβ is not associated with a reduction in the progression of disability among patients with RRMS (Shirani 2012). Therefore, there is a need for safer and more effective drugs with new modes of action that lead to anti-inflammation and neuroprotection in MS.
Inflammation and oxidative stress are thought to cause tissue damage in MS. Therefore, oxidative stress and antioxidative pathways are important in MS pathophysiology (Gilgun-Sherki 2004; Lee 2012), and novel therapeutics that enhance cellular resistance to free radicals could prove useful for MS treatment. Recent data support this important role of antioxidative pathways for tissue protection in progressive MS, particularly by activation of the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) antioxidant pathway (Johnson 2010), which is not yet targeted by other disease-modifying therapies for MS (Linker 2011).
Description of the intervention
Several lines of research have demonstrated immunomodulatory but also neuroprotective effects of fumaric acid esters, as shown in vitro as well as in experimental models of MS (Lukashev 2007). Fumaric acid esters include methyl hydrogen fumarate and dimethyl fumarate. Immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity (Albrecht 2012). In the acute phase of experimental autoimmune encephalomyelitis, treatment with dimethyl fumarate resulted in a significant reduction of macrophage/microglia infiltration in inflamed lesions (Schilling 2006). In an in vitro model of brain inflammation, dimethyl fumarate inhibited microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, interleukin (IL)-1β, tumour necrosis factor (TNF)-α and IL-6 (Wilms 2010). Dimethyl fumarate and its primary metabolite, monomethyl fumarate, are cytoprotective of neurons and astrocytes against oxidative stress-induced cellular injury and loss, potentially by induction of the transcription factor Nrf-2 and up-regulation of an Nrf2-dependent antioxidant response (Scannevin 2012). In addition, dimethyl fumarate treatment for type 1 helper T cells (Th1) and T helper type 17 (Th17)-mediated MS induces IL-4-producing Th2 cells in vivo and generates type II dendritic cells that produce IL-10 instead of IL-12 and IL-23 (Ghoreschi 2011). Dimethyl fumarate inhibits maturation of dendritic cells and subsequently Th1 and Th17 cell differentiation by suppression of both nuclear factor κB (NF-κB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) (ERK1/2-MSK1) signalling (Peng 2012).
Dimethyl fumarate, the active component of BG00012 (BG-12), is absorbed almost exclusively in the small intestine within two hours after oral administration and is rapidly hydrolysed by esterases to its metabolite, monomethyl fumarate, in the intestinal mucosa (Litjens 2004). Dimethyl fumarate possesses a pharmacological half-life of about 12 minutes and does not show any binding activity to serum proteins, which may further contribute to its rapid turnover in the circulation (Lee 2008). There is no evidence for a cytochrome P450-dependent metabolism of fumaric acid esters in the liver (Lee 2008).
How the intervention might work
An oral formulation of dimethyl fumarate (BG-12) has shown promising results for RRMS in clinical trials, combining anti-inflammatory and possibly clinically relevant neuroprotective effects with the convenience of oral administration. An exploratory, prospective, open-label pilot study showed that fumaric acid esters produced significant reductions from baseline in the number and volume of gadolinium-enhancing lesions in patients with RRMS (Schimrigk 2006). A phase II study with oral BG-12 revealed a dose-dependent, significant reduction in brain lesion activity. Oral BG-12 at a dose of 240 mg three times daily significantly reduced the number of new gadolinium-enhancing lesions, new or enlarging T2-hyperintense and new T1-hypointense lesions, and the annualised relapse rate (ARR) in patients with RRMS (Kappos 2008; Kappos 2012; MacManus 2011). A randomised, double-blind, placebo-controlled phase III study (DEFINE) showed that both oral BG-12 doses (at a dose of 240 mg twice daily and 240 mg three times daily) significantly reduced the proportion of patients who had a relapse, the ARR, the rate of disability progression and the number of lesions in patients with RRMS (Bar-Or 2013; Gold 2012) when compared with placebo. Another phase III study (CONFIRM) showed that both oral BG-12 doses and glatiramer acetate (subcutaneous daily injections of 20 mg) significantly reduced the ARR and the numbers of new or enlarging T2-weighted hyperintense lesions and new T1-weighted hypointense lesions in patients with RRMS, compared with placebo, but the reductions in disability progression with twice-daily BG-12, thrice-daily BG-12 and glatiramer acetate were not significant (Fox 2012). Post hoc comparisons of BG-12 with glatiramer acetate showed significant differences in the ARR (thrice-daily BG-12) (Hutchinson 2013), new or enlarging T2-weighted hyperintense lesions (both BG-12 doses) and new T1-weighted hypointense lesions (thrice-daily BG-12). Furthermore, BG-12 had positive effects on health-related quality of life in patients with RRMS (Kappos 2014; Kita 2014).
Why it is important to do this review
A recent non-Cochrane review based on indirect comparison has shown that dimethyl fumarate offers an effective oral treatment option for patients with RRMS, with an overall promising efficacy and safety profile, compared to IFNβ-1a, IFNβ-1b, glatiramer acetate, fingolimod, natalizumab and teriflunomide (Hutchinson 2014). However, the authors did not perform a comprehensive analysis of study quality. No systematic review based on direct comparison, which solely evaluates the absolute and comparative efficacy and safety of dimethyl fumarate for MS, currently exists in the peer-reviewed literature.