Description of the condition

Multiple sclerosis (MS) is an inflammatory disorder of the brain and spinal cord resulting from interaction between unidentified environmental factors and susceptibility genes. Several pathological processes occur in MS involving the immune system, T‐cell‐mediated and B‐cell‐mediated mechanisms, demyelination, remyelination, microglial activation, and chronic neurodegeneration (Bennett 2009; Compston 2008). The sequential involvement of these processes influences the clinical course, which is characterized by attacks of neurological dysfunction with recovery, attacks leaving persistent deficits, and progression that causes permanent physical and cognitive disability. MS is among the most common causes of neurological disability in young people, with an annual incidence ranging from 2 to 10 cases per 100,000 persons per year and a north‐south gradient, lower incidence being closer to the equator. Its clinical manifestations typically occur between 20 and 40 years of age, with symptoms and signs involving different regions of the central nervous system: optic nerve, brainstem, cerebellum, cerebral hemispheres, spinal cord.

MS has a chronic course that evolves over 30 to 40 years. The clinical phenotypes include relapsing‐remitting MS (RRMS), secondary‐progressive MS (SPMS), primary‐progressive MS (PPMS), and progressive‐relapsing MS (PRMS) (Lublin 1996). The development of progression after a relapsing‐remitting course is responsible for permanent long‐term disability; it supervenes in about 80% of RRMS patients by 20 to 25 years from disease onset (Kremenchutzky 2006). Times to need assistance to walk, be confined to bed, or have died were 14, 24, and 45 median years from disease onset and 3, 12, and 30 median years from onset of secondary progression, respectively (Scalfari 2014).

Male sex, older age at onset, and high early relapse frequency (more than three attacks during the first three years) predicted significantly higher risk of conversion to SPMS and shorter latency to progression (Scalfari 2014). In RRMS patients, the onset of secondary progression is the determinant of long‐term prognosis, and its prevention is the key therapeutic goal.

According to the older Poser criteria (Poser 1983), MS can be clinically diagnosed by demonstrating two separate clinical attacks (dissemination in time) involving at least two different areas of the central nervous system (dissemination in space). The 2001 McDonald criteria and their 2005 and 2010 revisions incorporate magnetic resonance imaging (MRI) criteria for dissemination in space and time, allowing a MS diagnosis at the time of first symptoms (McDonald 2001; Polman 2005; Polman 2011). Dissemination in space is demonstrated by greater than or equal to oneT2 lesion in at least two MS typical central nervous system regions (periventricular, juxtacortical, infratentorial, spinal cord). Dissemination in time is demonstrated by: (i) simultaneous asymptomatic contrast‐enhancing and non‐enhancing lesions at any time; or (ii) a new T2 and/or contrast‐enhancing lesions(s) on follow‐up MRI, irrespective of its timing. The diagnostic criteria include exclusion of other possible diagnoses.

A declining trend in on‐study relapse rate (one of the most commonly used primary outcomes in MS trials) of placebo participants in trials has been observed (Inusah 2010; Nicholas 2012; Steinvorth 2013; Stellmann 2012). This decline is thought to result from decreasing pretrial relapse rates and a shorter time period over which pretrial relapse rates were calculated in newer trials (Steinvorth 2013; Stellmann 2012). Pre‐study relapse rate was found to be the best predictor for on‐study relapse rate. Other participant characteristics have changed in newer trials. Participants were older and with longer disease duration, whereas Expanded Disability Status Scale (EDSS) scores remained relatively stable. The introduction of the new McDonald criteria led to inclusion in newer trials of participants who had had earlier diagnosis and were later in their disease course, which was less severe compared to patients in older studies (Steinvorth 2013). These changes may explain the decrease in pretrial relapse rate and the associated decrease in on‐trial relapse rate. Unwelcome consequences of the expected decreased event rate were that the sample size of newer trials has been inflated and follow‐up periods shortened.

Another difference between older and newer studies is that the latter can have included participants who had made prior use of immunomodulators or immunosuppressants.

Description of the intervention

Several treatments are available for patients with RRMS. For this review we will consider all immunomodulators and immunosuppressants that, up to 30 April 2014, have been studied in patients with RRMS in randomised clinical trials (RCTs) with more than six months' follow‐up.

Interferon beta‐1b (EMEA 2002; FDA 1993), interferon beta‐1a (Rebif) (EMEA 1998; FDA 2002), interferon beta‐1a (Avonex) (FDA 2003), and glatiramer acetate (FDA 1996) were the first agents approved by national regulatory agencies. Interferon beta‐1b, interferon beta‐1a (Rebif), and glatiramer acetate are administered by subcutaneous injection, interferon beta‐1a (Avonex) by intramuscular injection. The main adverse effects of interferon beta are local injection‐site reactions and flu‐like symptoms with hyperthermia. Five to 30 percent of treated patients develop persistent neutralising antibodies, usually in the first year of treatment and more commonly in those receiving interferon beta‐1b. The presence of persistent neutralising antibodies is associated with reduction in the treatment effect on relapse activity (Sorensen 2003).

Natalizumab was initially approved by the U.S. Food and Drug Administration (FDA) in November 2004 (FDA 2004), but was withdrawn by the manufacturer in February 2005, after three participants in the drug's clinical trials developed progressive multifocal leukoencephalopathy (PML), a rare and serious viral infection of the brain. Two of the patients died. Following a re‐examination of the participants in the previous clinical trials, the FDA allowed a clinical trial of natalizumab to proceed in February 2006. No additional cases of PML ()were reported and marketing of the drug for severe RRMS resumed (EMA 2006; FDA 2006; Yousry 2006). Natalizumab is administered by intravenous infusion, as a dose of 300 mg every four weeks.

Mitoxantrone was approved in 2000 under the indication "for reducing neurological disability and/or the frequency of clinical relapses in patients with SPMS, PRMS or worsening RRMS" (FDA 2000). Safety issues of concern for patients treated with mitoxantrone are cardiotoxicity and acute leukaemia.

Fingolimod was the first oral treatment approved for RRMS patients to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability (EMA 2011; FDA 2010). Even at the recommended low dose of 0.5 mg once daily, the FDA and European Medicines Agency (EMA) warned about decrease in heart rate following initiation of fingolimod treatment, recommending that all patients be monitored for at least six hours for signs and symptoms of bradycardia, and considering that in some patients the nadir of heart frequency can be observed up to 24 hours after the first dose.

Teriflunomide was the second oral agent approved for RRMS patients (EMA 2013a; FDA 2012). It is taken orally as a 7 or 14 mg tablet once daily. Warnings issued with this drug were hepatotoxicity and risk of teratogenicity.

Dimethyl fumarate has been approved as a first‐line oral treatment for RRMS patients (EMA 2014a; FDA 2013a). The recommended dose is 240 mg twice a day. The most commonly reported adverse events leading to discontinuation in clinical trials were flushing and gastrointestinal events.

Alemtuzumab has been approved by the EMA for treatment of RRMS patients with active disease defined by clinical or imaging features (EMA 2013b). The FDA rejected this drug due to concerns of serious risks that may outweigh its benefits, including the risk of autoimmune diseases, malignancies, serious infections, and infusion reactions (FDA 2013b). The drug is administered by intravenous infusion, as a dose of 12 mg/day for five consecutive days (60 mg total dose) followed by 12 mg/day for three consecutive days (36 mg total dose) administered 12 months after the initial treatment course.

Pegylated interferon beta‐1a is at a relatively advanced stage of drug development, with results from clinical trials available. It is administered by subcutaneous or intramuscular injection.

Daclizumab is currently being investigated in clinical trials for RRMS, but it has not yet been approved for MS by regulatory agencies. It is administered by subcutaneous or intravenous injections. Risks of serious infections and autoimmune diseases are increased with daclizumab.

Ocrelizumab is in development for treatment of RRMS, with two active phase clinical trials ongoing. It is administered by intravenous injections.

Laquinimod is an immunomodulator that is currently under evaluation for the treatment of RRMS. It is taken orally as a 0.6 mg tablet once daily. The EMA recommended refusal of the marketing authorisation for laquinimod as a treatment for RRMS due to concerns about potentially increased risks of cancer and teratogenicity in humans, especially given that the drug's mechanism of action is unclear (EMA 2014b). Further studies of laquinimod as a monotherapy and an add‐on therapy in RRMS patients are ongoing.

Azathioprine has been used for the treatment of MS in many countries on the basis of placebo‐controlled RCTs published more than two decades ago. However, since the approval of interferons beta, azathioprine has been dismissed as toxic and insufficiently effective (Casetta 2007). It is taken orally as a 2 or 3 mg/kg tablet daily.

Intravenous immunoglobulins may have a role for patients with severe and frequent relapses for whom other treatments are contraindicated (Association of British Neurologists 2005). Severe adverse events, including thrombosis of the jugular vein and allergic reaction leading to treatment discontinuation, were noted in 4% of 84 treatment courses with a total 341 infusions under routine clinical conditions (Elovaara 2008).

How the intervention might work

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

The mechanism of action of interferons beta in MS is incompletely understood. Interferons beta are naturally occurring cytokines possessing antiviral activity and a wide range of anti‐inflammatory properties. Recombinant forms of interferons beta are believed to directly increase expression and concentration of anti‐inflammatory agents, while down‐regulating the expression of pro‐inflammatory cytokines (Kieseier 2011).

Glatiramer acetate has an immunomodulatory action by inducing tolerance or anergy of myelin‐reactive lymphocytes (Schmied 2003). It is furthermore believed to promote neuroprotective repair processes (Aharoni 2014).

Natalizumab is a monoclonal antibody against the alfa4 integrin on the surface of lymphocytes. This integrin is essential in the process by which lymphocytes gain access to the brain by allowing the cells to penetrate the blood brain barrier. Natalizumab blocks the action of the alfa4 integrin so that lymphocytes are unable to enter the brain and attack myelin protein (Yednock 1992).

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

Fingolimod acts as a functional antagonist of sphingosine‐1‐phosphate(S1P) receptor on lymphocytes, resulting in a reduced egress of lymphocytes from the lymph nodes. In particular, auto‐aggressive T‐cells are prevented from recirculating to the central nervous system (Mandala 2002).

Teriflunomide is an inhibitor of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme involved in new pyrimidine synthesis for DNA replication. Consequently, the drug reduces T‐ and B‐lymphocytes activation, proliferation, and function in response to autoantigens. The exact mechanism of action in MS is not fully understood. The drug is thought to reduce the number of activated lymphocytes, which would cause inflammation and damage myelin in the central nervous system (Claussen 2012).

Dimethyl fumarate is a derivative of fumaric acid. It acts primarily by triggering the activation of a nuclear factor (Nrf2) transcriptional pathway, the primary cellular defense against the cytotoxic effects of oxidative stress. It is an anti‐inflammatory that promotes anti‐inflammatory activity and can inhibit expression of pro‐inflammatory cytokines and adhesion molecules (Wilms 2010).

Alemtuzumab is a monoclonal antibody against the CD52 antigen expressed on lymphocytes and monocytes. Its effects in MS are thought to be mediated by an extended lymphocyte depletion and change in the composition of lymphocytes that accompanies lymphocyte reconstitution (Hill‐Cawthorne 2012).

Pegylated interferon beta‐1a has a polyethylene glycol group attached to the α‐amino group of the N terminus of interferon beta‐1a (Avonex). Pegylation of interferon beta‐1a may improve its pharmacokinetic and pharmacodynamic properties, allowing for reduced dosing frequency while maintaining the clinical effectiveness and safety of the intramuscular interferon beta‐1a (Hu 2012).

Daclizumab is a monoclonal antibody against the CD25 antigen (interleukin 2 receptor) expressed on immune cells. The mechanisms by which the drug exerts effects in MS are not clear. Daclizumab leads to expansion of regulatory CD56 natural killer T lymphocytes, which may be an important mechanism of action in MS. Furthermore, daclizumab modulates the function of dendritic cells, resulting in decreased T‐cell activation (Wuest 2011).

Ocrelizumab is a monoclonal antibody against the CD20 antigen expressed on B‐lymphocytes. The antibody depletes circulating B‐lymphocytes predominately through antibody‐mediated cytotoxicity (Oh 2013).

Exactly how laquinimod works is unknown, but it is believed to have an immunomodulatory effect on the peripheral and central nervous systems. Data from animal studies indicate that laquinimod has a primary effect on innate immunity. The drug modulates the function of various myeloid antigen‐presenting cell populations, which then down regulate pro‐inflammatory T‐cell responses. Furthermore, data indicate that laquinimod acts directly on resident cells within the central nervous system to reduce demyelination and axonal damage (Varrin‐Doyer 2014).

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

The mechanism of action of intravenous immunoglobulins in MS remains unclear, although remyelination of demyelinated axons may occur through the mediation of the effects of cytokines (Stangel 1999).

Why it is important to do this review

Although there is consensus that immunotherapies reduce the frequency of relapses in MS, their relative effectiveness in delaying new attacks or disability progression remains unclear. This uncertainty is due to the limited number of direct comparison trials, which provide the most rigorous and valid research evidence on the relative efficacy and safety of different, competing treatments. A summary of the results, including both direct and indirect comparisons, may help to clarify the stated uncertainty (Caldwell 2005; Glenny 2005).