Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) that is considered to be mainly T cell-mediated. The disease is thought to affect about 2.5 million patients worldwide. It is mainly diagnosed in young adults, with a higher prevalence in women than in men. Care of patients diagnosed with MS has improved but has also become increasingly complex with the introduction of more treatment options.

Diagnosis

There is no single specific diagnostic test and in practice the diagnosis can be made clinically. According to the NICE Guidelines on Management of multiple sclerosis in primary and secondary care 2003 (which are due to be revised in 2014),¹ when an individual presents with a first episode of neurological symptoms or signs suggestive of demyelination and there is no reasonable alternative diagnosis, MS should be considered. This also applies when a patient presents with a second or subsequent set of neurological symptoms. Specialist referral is indicated.

MS may start with an acute neurological disturbance often described as ‘clinically isolated’. This is most likely to present in primary care. The illness may then progress with relapses and remissions over a number of years and eventually, disability without remission. It is difficult to give a prognosis but it is thought that a high relapse rate in the first two to five years, major disability after five years and an abnormal initial MRI with large lesion load may indicate a poorer picture.²

The diagnosis will be made by a specialist on the basis of CNS lesions scattered in space and time, and primarily on the history and examination, according to this guideline. Tests such as MRI, CT scans and analysis of cerebrospinal fluid may be appropriate in specific situations where there is uncertainty or alternative diagnoses are being ruled out.¹ MRI is also used to monitor disease activity.

MS Ireland is a useful support group for patients to complement the role of their health professional. It stresses that although MS is a progressive neurological condition that can affect a person’s health, lifestyle and relationships, many people with MS find ways to manage and cope with many of the effects and difficulties. Living from day-to-day for a person with is a combination of many factors. Medically, it is about working with GPs, hospital specialists and other health professionals to find suitable treatments and interventions that can maintain good health as much as possible.

As GPs are often a regular point of contact for many people living with MS, they can play a crucial role in helping patients maintain quality of life. Socially, MS Ireland points out, living with MS is about finding ways to maintain participation in society through home life, work, leisure pursuits and community activity. MS Ireland stresses that living comfortably with the condition is an achievable goal for many people.

The presence, severity and duration of all MS symptoms vary considerably from person to person. The unpredictable nature of the condition can sometimes make management a challenge. However, over time, many people begin to notice patterns and triggers to their symptoms, and with appropriate treatment and intervention, many symptoms can be managed quite successfully. 

To the patient, reduced mobility is often the most visually apparent symptom. Other symptoms such as fatigue, changes in sensation, memory and concentration problems are often ‘hidden’ and can be difficult to articulate. Patients should be encouraged to alert their GP when a new symptom appears, or an existing symptom changes. A wide range of symptoms may need to be monitored and treated at different stages in the disease. These include dysphagia, bladder dysfunction, bowel dysfunction, sexual dysfunction, spasticity, intention tremor, depression and pain.

Managing symptoms is not just about finding the best medical treatment. It is important too to advise the patient on healthy lifestyle options. A balanced diet, appropriate exercise and minimising stress can all help the patient in living with MS symptoms, according to MS Ireland.

Drug treatment 

The past two decades have seen major development in drug therapies available to the treating physician. Immuno-suppressive drugs such as azathioprine were used in the 1980s, with the interferons introduced in the 1990s and later, glatiramer acetate. Then came second-line drugs, the monoclonal antibody natalizumab and more recently fingolimod. Third-line agents for aggressive disease include immunosuppression drugs. 

The beta interferons and glatiramer acetate (GA) are the longest approved MS disease modifying drugs and are relatively safe and commonly used first-line agents. They are indicated for reduction of relapses in ambulatory relapsing remitting MS. 

Interferons are proteins produced naturally in the human body. Alpha, beta and gamma are different types of interferons that fight viral infections and can reduce inflammation which damages the nerve fibres in MS. Current injectable medications available are beta interferon-1a and beta interferon-1b. The brands Avonex and Rebif are beta interferon-1a, Extavia and Betaferon are beta interferon-1b. 

Glatiramer acetate (Copaxone) is indicated for the treatment of patients who have experienced a well-defined first clinical episode and are at high risk of developing clinically definite MS. An injectable therapy, it is also indicated for reduction in frequency of relapses in ambulatory patients with relapsing remitting multiple sclerosis (RRMS) characterised by at least two attacks of neurological dysfunction over the preceding two-year period. It is not indicated in primary or secondary progressive MS.

Natalizumab 

Natalizumab (Tysabri) is a recombinant monoclonal antibody targeting alpha-4 integrins. Alpha-4 integrin is expressed on the surface of inflammatory lymphocytes and plays a role in their adhesion to vascular endothelium.³ It is thought that inflammatory lesions in MS may involve lymphocytes that gain access to the brain from the circulation by first adhering to vascular endothelium. It is administered on a once-monthly schedule via the intravenous route.

Natalizumab is highly effective in the treatment of RRMS and two large trials (AFFIRM⁴ and SENTINEL⁵) demonstrated robust effects on both clinical and MRI parameters. However, due to its association with the rare brain infection by JC virus called progressive multifocal leukoencephalopathy (PML), it is not first-line in the treatment of RRMS. PML is a severe demyelinating disease of the CNS that is caused by re-activation of the polyomavirus JC. In most individuals JC virus lies dormant in the kidneys and lymphoid organs, but in the context of profound immunosuppression it can re-activate, spread to the brain and induce a lytic infection of oligodendrocytes that produce myelin.

Historically, the drug was actually withdrawn from the market in 2005 after the first two patients developed PML, a condition previously only seen in AIDS patients or otherwise immunosuppressed individuals. It is now known that three important factors influence one’s risk of developing PML on natalizumab treatment⁶ – duration of exposure to the drug, prior immunosuppressant use (does not include interferon therapy) and previous JC virus exposure (defined by baseline seropositivity for anti-JC virus antibodies). Collation of the above variables allows the treating physician to estimate the annual risk of PML on treatment and advise the patient accordingly.

As an example, a patient who tests negative for JC virus antibodies at baseline would have a very low risk of developing the disease; in the order of <0.09 per 1,000. However, a patient who tests positive for JC virus antibodies (demonstrating prior virus exposure) and has had prior immunosuppressant use would have an estimated PML risk of approximately 1.6 per 1,000 in the first two years of treatment, rising to 11.1 per 1,000 at four years’ treatment. Infection with the JC virus is not associated with a clinical syndrome/symptoms so patients testing negative initially should have repeat annual checks. Aside from the risk of PML, the drug is usually well tolerated but potential side effects include allergic reactions, pharyngitis, sinus congestion and peripheral oedema.

Due to the above, published guidelines recommend that natalizumab be reserved for selected patients who have failed other therapies or have severe disease.

Fingolimod 

Fingolimod (Gilenya) is an oral sphingosine-1-phosphate receptor modulator. It alters lymphocyte migration resulting in sequestration of lymphocytes in lymph nodes preventing their migration to inflammatory lesions in the brain.⁷ Evidence of its efficacy in treating MS comes from two large studies, FREEDOMS⁸ and TRANSFORMS.⁹ It is the first orally active medication for MS licensed in Ireland.

In each of the above studies (total of 2,472 patients), the annualised relapse rate was significantly reduced by both doses of fingolimod (0.5mg or 1.25mg). The FREEDOMS studied compared both doses to placebo, while the TRANSFORMS trial compared the same doses to intramuscular interferon beta-1a (Avonex). Both trials favoured fingolimod with regard to relapse rate and MRI parameters.

In the FREEDOMS trial, seven patient in the higher fingolimod dose group developed macular oedema but other adverse events were similar compared to placebo. In the TRANSFORMS study, the fingolimod group had more serious adverse events. These included two deaths from disseminated infections (VZV and herpes simplex encephalitis). Furthermore, 19 patients developed dose-related bradycardia or atrioventricular block versus none in the interferon group. One patient in the interferon group developed cancer, while 12 fingolimod patients developed skin or breast cancer.

Thus, fingolimod has been shown to be an effective disease modifying therapy in RRMS, but its use is associated with the risk of infections, cardiovascular complications and possibly tumour development. Contraindications to its use include recent MI (six months), unstable angina, second or third degree heart block, prolonged QT interval or treatment with anti-arrhythmic drugs.

Prior to starting therapy, patients should have a 12-lead ECG and ophthalmologic examination. Varicella zoster serology should be checked in those without a history of chickenpox and vaccination undertaken where necessary. The treatment is currently available in Ireland and patients are required to attend hospital for observation for bradycardia post-first dose administration. This takes approximately six hours. Live vaccines are to be avoided in patients taking the drug and it should be stopped two months prior to conception in women.

Oral dimethyl fumarate  

Two large-scale phase III clinical trials have demonstrated the clinical efficacy and favourable side effect profile of oral dimethyl fumarate (Tecfidera) also known as BG-12. The beneficial anti-inflammatory effects of fumaric acid in autoimmune disease had been proposed as early as 50 years ago and originally found clinical use in the treatment of psoriasis in the mid 1990s. Following on from promising small case series of its use in MS, two large clinical trials called DEFINE¹⁰ and CONFIRM¹¹ were undertaken.

In the DEFINE study, BG-12 at two different doses (240mg two to three times daily) was compared to placebo. A total of 952 patients completed the study. BG-12 was associated with a significant reduction in relapse rate over two years at both doses, with the proportion of patients with a relapse being 27%, 26% and 46% for BG-12 twice daily, three times daily and placebo respectively (p<0.001). Furthermore, all MRI parameters showed significant improvement with BG-12 therapy at both doses. As an example, the number of gadolinium-enhancing lesions evident was reduced by 68-78%.

The CONFIRM study comprised 1,417 patients and again compared both BG-12 doses against placebo, with an additional arm to the study which included the older therapy, glatiramer acetate (Copaxone). Treatment with BG-12 was again shown to reduce the annualised relapse rate relative to placebo by up to 51%. There was no significant difference between BG-12 and glatiramer acetate. MRI parameters were much more favourable in patients on active treatment, with new T2 lesions reduced by 71% and 73% for both doses of BG-12. There was no difference in adverse events in any group and the safety profile was similar to prior studies. In general, the medication was well tolerated with the main adverse events being gastrointestinal upset/pain, flushing and elevated liver function tests.

When attempting to compare newer MS therapies to the older ‘injectables’, ie. interferons and glatiramer acetate, it is important to recognise that study populations can vary significantly between trials. Also, the end-points studied in trials may differ and indeed in MS research newer concepts like ‘freedom from disease activity’ have emerged in more recent trials. That said, the use of the annualised relapse rate as a study parameter has been relatively consistent and, not withstanding the above limitations, it would appear that BG-12 is at least equally, if not more effective than the injectable therapies. Its safety profile is excellent but tolerability may be an issue given the high prevalence of flushing (30%) and diarrhoea (15%). Patient education and support will be needed to avoid early discontinuation of therapy.

Teriflunomide 

Teriflunomide (Aubagio), an immunomodulatory drug, is the active metabolite of leflunomide and inhibits pyrimidine biosynthesis, disrupting the interaction of T cells with antigen-presenting cells.¹² In the preliminary phase II study of its safety and efficacy, two doses of the drug (7mg/daily and 14mg/daily) were compared to placebo.¹³ MRI scans were performed every six weeks and the primary endpoint of the trial was the number of active lesions per MRI. The drug at both doses was superior to placebo in reducing MRI lesions. 

A second trial designed to look at the drugs’ effect on relapse rates found that either dose of teriflunomide significantly reduced the annualised relapse rate, by approximately 31% compared to placebo.¹⁴ In addition, the higher 14mg dose reduced disability progression compared to placebo (27% vs 20%). This trial has been criticised for a relatively high drop out rate, however (27% of patients).

Adverse effects of the drug include diarrhoea, nausea, hair thinning and elevation of alanine aminotransferase. Patients with known liver disease should avoid the drug and likewise treatment should be stopped if drug-induced liver damage is suspected. Teriflunomide is contraindicated in pregnancy and in those trying to conceive. The drug is also found in semen, so males who wish to conceive a child should also stop the drug. Activated charcoal powder and cholestyramine can be used to facilitate drug clearance as the drug can remain active in the serum for up to two years.

The drug is not yet available in Ireland but has found use in patients with MS who decline treatment with the more established injectable therapies (interferons and glatiramer acetate). Due to the risk of teratogenicity it is mostly used in males or postmenopausal women.

Treatment adherence

As described above, drug therapies in MS can positively influence the disease course by reducing relapses, inhibiting the formation of new brain lesions and slowing overall progression. However, outside the setting of a regimented clinical trial, patient adherence to therapy can be poor. One study of 682 patients with MS performed in Canada, who were treated with the first-line agents intramuscular IFN-B1a, subcutaneous IFN-B1b and glatiramer acetate, showed that approximately half of MS patients discontinued their therapy within two years of commencing.¹⁵ This was found to only rarely be due to switching drug therapy and was independent of drug cost.

Patients with MS are at especially high risk of discontinuing drug therapy for a variety of reasons. The available therapies do not typically reduce chronic symptoms; in fact patients may feel worse initially (eg. flu-like symptoms with the injectable interferons), while future benefits like relapse rate reduction are not readily apparent to the patient. Furthermore, during periods of disease quiescence, patients may become complacent with the medication or feel like they no longer need it. Cognitive issues and depression, which are prevalent in MS populations, may also serve to further worsen treatment adherence. The addition of oral therapies, as outlined above, to the MS treatment armamentarium may see more DM therapy being initiated but is unlikely to eradicate adherence difficulties entirely.

Few studies have looked at methods to increase treatment adherence in MS patients. The adoption of a telephone-based counselling service and the availability of specialist nurses affiliated with specific drug therapies has had some success but is not widely available. Treatment adherence may be improved by concise explanation of the rationale behind the drug (ie. future unseen benefits with regard to relapse rate, MRI progression etc.) and open patient-physician communication. 

Treatment of comorbid symptoms, such as depression and fatigue, may also help as well as a practical and proactive approach to side effects, such as injection site reactions and flu like symptoms with the injectables.

In summary, despite the development of effective drug therapies, as many as half of MS patients may discontinue their treatment or be poorly compliant. Existing evidence indicates that improved medication adherence could have a major impact on disease progression and overall health in patients with MS. Targeted and practical interventions, in addition to open communication, may improve adherence. Oral therapies provide an alternative delivery method.

Vaccinations

Several studies have shown that the risk of relapse in patients with MS is increased by infection. Indeed, this must be excluded as a cause of a relapse prior to initiating glucocorticoid therapy when a patient presents to the emergency department. Another important issue related to the use of vaccines in patients with MS is the ever-expanding list of immunomodulatory and immunosuppressive drugs. Some drugs may limit the effectiveness of a prophylactic vaccine, while treatment with other agents may require immunity to certain viruses (eg. varicella with fingolimod therapy) prior to initiation.

Similar to vaccination recommendations for healthy adults, patients with MS should have immunisations against diphtheria, tetanus, influenza and pneumococcus. The indications and contraindications in patients with MS are largely similar to those for healthy individuals. 

Vaccination against the influenza virus does not seem to exacerbate MS. In a recently published series on 60 MS patients administered the new H1N1 vaccine, relapse rates at 30, 60 and 90 days were unchanged when compared to rates prior to administration.¹⁶

With regard to additional supplementary vaccines, yellow fever requires special mention. This vaccine is required for entry into some countries and, owing to the risk of severe adverse effects, the yellow fever vaccine is largely contraindicated in immunocompromised patients, including MS patients on active drug therapy. One small study in MS showed a significant increase in exacerbation rates within three months following administration compared with prevaccination exacerbation rates.¹⁷ In light of this evidence, this vaccine is not recommended in patients with MS.

The hepatitis B vaccine is considered safe in MS after a review of the evidence in a French cohort.¹⁸ Two vaccines against the human papillomavirus (HPV) exist and recommendations generally advise use in adolescent females aged 11 and older. Five cases of relapse post use of the quadrivalent HPV vaccine have been reported in the literature,¹⁹ but current data on the effects on established MS is insufficient to determine a link between vaccination and relapse. Immunisation against measles, mumps and rubella (MMR) is generally recommended in childhood, but its use in patients receiving immunosuppressive therapy is to be avoided. In rare cases of unprotected adults with MS who have been exposed to the disease, passive immunisation with hyperimmunoglobulin should be undertaken. Varicella zoster virus (VZV) vaccination needs to be undertaken in non-immune adults prior to the initiation of immunosuppressive therapies.

The effect of MS drug therapies on the efficacy of vaccines is also a consideration. MS therapies can modulate or suppress the generation of adaptive immune responses and the maintenance of immunological memory. Large-scale studies or reviews in this area are not available. Given the possibility of MS drug therapies affecting vaccine efficacy, patients should be checked prior to initiation for missing vaccines. Providing there is no pressing need to commence therapy emergently, then vaccination should occur in advance of commencing treatment. To evaluate the success of vaccination in patients already treated with immunosuppressants, antibody testing can be performed four weeks after administration.

Avoidance of infection is important for patients with MS and they should receive vaccination against influenza, pneumococci, pertussis and hepatitis B. Inactivated vaccines are generally considered safe for use in patients with MS, whereas live attenuated vaccines may provoke MS relapses or cause vaccine-associated infection in patients undergoing immunosuppressive therapy.

Multiple sclerosis is the most common disabling disease of the central nervous system in young adults. It may present initially in primary care with diagnosis at specialist level and treatment initiated. The GP will have an ongoing role in care. Prognosis varies from patient to patient.

References

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