Description of the condition

Since the revision of the McDonald criteria in 2010 (Polman 2011), multiple sclerosis (MS) can be diagnosed at the time of a first clinical attack when magnetic resonance imaging (MRI) shows the presence of focal lesions in the white matter of the central nervous system, which are considered typical for MS in terms of distribution, morphology, evolution and signal abnormalities on conventional MRI sequences (Filippi 2016). Opinion leaders have recommended early action as "treating at first clinical attack may be the most effective strategy to manage disease progression" (Freedman 2014). Revised guidelines of the Association of British Neurologists (Scolding 2015) and NHS England (NHS England 2014) suggest that treatment should be advised for patients within 12 months of a first attack, if MRI establishes a diagnosis of MS according to the 2010 McDonald criteria or predicts a high likelihood of recurrent attacks. The benefit of starting early treatment with disease‐modifying drugs has been demonstrated by some short‐term trials that showed delay of a second attack in participants given interferons beta (ETOMS 2001) or glatiramer acetate (PRECISE 2009) compared with those on placebo. On the basis of these results, interferons beta and glatiramer acetate were approved by national regulatory agencies for treating MS at clinical onset (EMA 2015a). However, the available evidence does not indicate that the prevention of recurrent attacks has an effect on disability (CHAMPS 2012 (10 years FU); Frischer 2009), and large variability of long‐term disability‐worsening has been reported, even among people with frequent early relapses (Scalfari 2013).
Once the decision for early treatment is made, patients and their healthcare providers need to select one of several disease‐modifying drugs. Most of the evidence about the relative efficacy and safety of interventions is non‐specific to early treatment. In a previously published review, moderate‐ to high‐quality evidence suggested that alemtuzumab, natalizumab and fingolimod were associated with greater benefit for preventing recurrent attacks compared with placebo, and evidence of moderate quality indicated that natalizumab was associated with greater benefit for preventing disability‐worsening among all treatments evaluated (Tramacere 2015). Despite alemtuzumab and natalizumab having been proven to exert higher relapse suppression, because of safety concerns, the guidelines of the Association of British Neurologists recommended their use as second‐line treatment, or as treatment for people with rapidly evolving relapsing‐remitting MS. Beta interferons, glatiramer acetate, teriflunomide, dimethyl fumarate and fingolimod are recommended as first‐line agents (Scolding 2015). Australian and New Zealand guidelines allow neurologists the discretionary use of all disease‐modifying drugs as first‐line treatments (Broadley 2014).

Description of the intervention

We considered all disease‐modifying drugs that are used, approved or off‐label, or are currently under marketing authorisation or investigation for people with a first clinical attack. We considered that all agents used or under investigation for relapsing‐remitting MS could be given to people with a first attack complying with the 2010 McDonald criteria. More specifically, we are interested in drugs that have been approved for a first attack complying with 2010 McDonald criteria.

• Beta interferons (Betaferon/Betaseron^®; Extavia^®; Rebif^®; Avonex^®) and glatiramer acetate (Copaxone^®) (EMA 2015a; FDA 2012a; FDA 2012b; FDA 2013). These medications are administered subcutaneously, except for beta interferon 1a (Avonex^®), which is administered via intramuscular injections. Approved for relapsing‐remitting MS

• Natalizumab (Tysabri^®) (EMA 2006; FDA 2006) administered by intravenous infusion at a dose of 300 mg every four weeks

• Fingolimod (Gilenya^®) (EMA 2011; FDA 2010) given at an oral dose of 0.5 mg once daily

• Teriflunomide (Aubagio^®) (EMA 2013a; FDA 2012) given at an oral dose of 7 mg or 14 mg once daily

• Dimethyl fumarate (Tecfidera^®) (EMA 2014a; FDA 2013) given at an oral dose of 240 mg twice daily

• Alemtuzumab (Lemtrada^®) (EMA 2013b; FDA 2014a) administered intravenously in two annual treatment courses ‐ the first at a dose of 12 mg daily on five consecutive days (60 mg total dose), and the second, 12 months later, on three consecutive days (36 mg total dose)

• Daclizumab (Zinbryta^®) administered by subcutaneous or intravenous injections and approved by the European Medicines Agency (EMA) (EMA 2016) and the Food and Drug Administration (FDA) (FDA 2016)

• Ocrelizumab (Ocrevus®) (FDA 2017) administered intravenously at an initial single dose of 300 mg followed two weeks later by a second 300 mg intravenous infusion. Subsequent doses of 600 mg intravenously every six months. Approved for relapsing forms of MS and primary progressive MS

• Pegylated interferon beta‐1a (Plegridy^®) (EMA 2014b; FDA 2014b) given by subcutaneous injection at a dose of 125 µg every 14 days

• Cladribine (Movectro^®) approved in Russia and Australia in 2010 (Murphy 2010). EMA (EMA 2015b) and FDA in 2011 did not approve it because of a suspected increase in cancer risk. A meta‐analysis failed to confirm these concerns (Pakpoor 2015)

• Mitoxantrone (Novantrone^®) approved in 2000 in the USA (FDA 2000), Europe and other countries for relapsing‐remitting and progressive MS. It is administered as a short intravenous infusion every three months. Safety concerns include cardiotoxicity and acute leukaemia

• Azathioprine (Imuran^®) used in many countries on the basis of placebo‐controlled randomised controlled trials (RCTs) published more than two decades ago. However, since interferons beta were approved, azathioprine is no longer recommended as first‐line therapy (Goodin 2002). It is taken orally, 2 mg/kg or 3 mg/kg per day. Intravenous immunoglobulins are used for people with severe and frequent relapses, for whom other treatments were contraindicated (Scolding 2015)

• Rituximab (Rituxan^® or Mabthera^®) administered intravenously. Currently under marketing authorisation or investigation

• Laquinimod (Nerventra^®) given at an oral dose of 0.6 mg daily. The drug received a negative opinion from EMA (EMA 2014c). Studies of laquinimod in relapsing‐remitting MS are ongoing (Active Biotech 2014).

How the intervention might work

Immunosuppressive or immunomodulatory effects are common to all treatments included in the review.

• Approved interventions

• • Beta interferons are naturally occurring cytokines that possess antiviral activity and a wide range of anti‐inflammatory properties. Recombinant beta interferons are believed to directly increase expression and concentration of anti‐inflammatory agents, while downregulating expression of pro‐inflammatory cytokines (Kieseier 2011).

  • Glatiramer acetate exerts an immunomodulatory action by inducing tolerance or anergy of myelin‐reactive lymphocytes (Schmied 2003). Glatiramer acetate may promote neuroprotective repair processes (Aharoni 2014).

  • Natalizumab is a humanised monoclonal antibody directed against the alfa4 integrin. This integrin is essential in the process by which lymphocytes gain access to the brain by allowing cells to penetrate the blood‐brain barrier. Natalizumab binds alfa4β1 and alfa4β7 integrin on the surface of circulating T lymphocytes, preventing interaction with cellular adhesion molecules that facilitate extravasation and migration from the circulation to the central nervous system (CNS) (Millard 2011).

  • Fingolimod is a sphingosine‐1‐phosphate (S1P) receptor modulator that prevents lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the CNS. S1P receptors are also expressed by many CNS cell types and have been shown to influence cell proliferation, morphology and migration. Fingolimod crosses the blood–brain barrier and therefore may have direct CNS effects (Chun 2010).

  • Teriflunomide acts as an inhibitor of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme involved in pyrimidine synthesis for DNA replication in rapidly proliferating cells. The drug reduces T lymphocyte and B lymphocyte activation and proliferation, and may attenuate the inflammatory response to autoantigens in MS. However, the exact mechanism of action for teriflunomide is not fully understood. Some observations suggest that the drug may have immunological effects outside of its ability to inhibit pyrimidine synthesis in rapidly proliferating cells (Claussen 2012; Oh 2013).

  • Dimethyl fumarate derives from fumaric acid, promotes anti‐inflammatory activity and can inhibit expression of pro‐inflammatory cytokines and adhesion molecules. Actions of neuroprotective and myelin‐protective mechanisms have been proposed (Linker 2011; Wilms 2010).

  • Alemtuzumab is a monoclonal antibody to CD52 on the cell surface of lymphocytes and monocytes. Its effects are thought to be mediated by extended B and T lymphocyte depletion followed by a distinctive pattern of T and B cell repopulation that begins within weeks of treatment and leads to a rebalanced immune system, including an increased percentage of regulatory and memory T cells. Effects of alemtuzumab persisted after it was cleared from the circulation (Lycke 2015).

  • Daclizumab is a monoclonal antibody to the interleukin‐2 receptor CD25 that is expressed on immune cells. The exact mechanism is not well understood. Daclizumab interrupts interleukin‐2‐mediated cell activation, thereby preventing expansion of autoreactive T lymphocytes and inhibiting survival of activated T cells (Wuest 2011).

  • Ocrelizumab is a recombinant monoclonal antibody designed to selectively target CD20‐positive B lymphocytes, a specific type of immune cell thought to be a key contributor to myelin and axonal nerve cell damage. The drug depletes CD20 B cells, it increases antibody‐dependent cell‐mediated cytotoxicity effects and reduces complement‐dependent cytotoxicity effects (Kappos 2011).

  • Pegylated interferon beta‐1a (PEG‐IFN) is the drug obtained by PEGylation of IFN beta‐1a (Avonex^®) (i.e. joining of a polyethylene glycol group (PEG) molecule to the IFN beta‐1a molecule). PEGylation has been applied to increase IFN stability, solubility and half‐life, and to reduce dosing frequency (Hu 2012).

  • Cladribine is a chemotherapeutic drug approved for treatment of people with hairy‐cell leukaemia, a subtype of chronic lymphoid leukaemia. Short courses of cladribine induce prolonged lymphopenia by selectively interfering with DNA synthesis and repair in T and B lymphocytes lasting months to years (Leist 2011).

  • Mitoxantrone is a cytotoxic drug that intercalates with DNA and inhibits both DNA and RNA synthesis, thus reducing the number of lymphocytes (Fox 2004).

• Interventions used off‐label

• • Azathioprine is a cytotoxic immunosuppressive drug that acts as a prodrug for mercaptopurine, inhibiting an enzyme required for DNA synthesis. Thus it most strongly affects proliferating cells, such as T cells and B cells of the immune system (Tiede 2003).

  • Intravenous immunoglobulins may improve remyelination of demyelinated axons through mediation of cytokines. However, their mechanism of action in MS remains unclear (Stangel 1999).

  • Rituximab is a monoclonal antibody to CD20 expressed on pre‐B and mature B cells; it acts by depleting these cells in the circulation and the CNS. Although MS was traditionally considered a T cell‐mediated disease, accumulating evidence suggests that B cells may play a role (Lycke 2015; Naismith 2010).

• Interventions currently under marketing authorisation or investigation

• • Laquinimod may have an immunomodulatory effect on the peripheral and central nervous systems. This drug modulates the function of various myeloid antigen‐presenting cell populations, which then downregulate pro‐inflammatory T cell responses. Furthermore, data indicate that laquinimod acts directly on resident cells within the CNS to reduce demyelination and axonal damage. However, exactly how the drug works remains unknown (Varrin‐Doyer 2014).

Why it is important to do this review