The whole document can be read online but here are some extracts:
In June 1999, the ABN first published guidelines for the use of the licensed MS DMT. This 2015 revised guideline replaces former versions. It includes all newly approved or licensed treatments for MS and represents a consensus concerning their use. These guidelines will require future revision as other treatments receive approval (eg, daclizumab and ocrelizumab).
The guideline is not intended to provide a complete description of the possible complications and monitoring of disease-modifying treatments in MS.
- In the individual patient, MS remains a fundamentally unpredictable condition.
- We stress the importance of shared conversations about disease activity, risk and benefit, to make the choice that is right for the individual and their circumstances.
- The ABN believes that people with MS should be managed by neurologists with specialist experience.
- All of the licensed disease-modifying treatments for MS - β-interferons, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, natalizumab and alemtuzumab - reduce relapse rate and MRI lesion load.
- We suggest that these seven agents can be divided into two broad classes: drugs of moderate efficacy (average relapse reduction in 30–50% range), including the β-interferons, glatiramer, teriflunomide, dimethyl fumarate and fingolimod; and drugs of high efficacy (average relapse reduction substantially more than 50%), alemtuzumab and natalizumab. Side effect profiles vary considerably between
- the Mitoxantrone has significant adverse effects and is not obviously superior in efficacy to the newer drugs of high efficacy. It is not licensed for MS in the UK, but is still used
- There is a consensus that none of the currently available disease-modifying therapies significantly modifies progressively increasing disability that is unrelated to relapses (progressive non-relapsing MS).The implication, however, is that no disease-modifying treatment is effective, or indicated, in patients with established progressive MS in the absence of relapses.
- It is not yet clear whether treatment should aim for a target such as ‘no evidence of disease activity’—either clinical or radiological.
- New MRI lesions are a more sensitive index of inflammatory disease activity than clinical relapses, occurring up to 10 times more frequently than clinically eloquent relapses.
- Many now substitute MRI activity for clinical activity in the classification, diagnosis and management of MS.
- Recently, the European Medicines Agency has explicitly recognised that MS may be defined as ‘active’ on radiological or clinical evidence.
- Meanwhile, particularly in the first years after diagnosis, it is appropriate to consider including MRI scanning during the annual review recommended by the 2014 NICE Clinical Guideline for the management of MS, both on grounds of monitoring efficacy and safety.
- There are now many people with relatively long-standing relapsing–remitting MS who have used β-interferons or glatiramer for perhaps several years and whose disease is stable clinically. It is unclear whether such patients would benefit from MRI monitoring.
- Immunotherapies appear particularly helpful when given early to people with active relapsing–remitting disease, before there is fixed disability or secondary progression.
- MS specialist neurologists may adopt either an ‘escalation’ strategy or an ‘induction’ strategy in treating MS. The ‘escalation’ strategy involves starting with the drug that is considered the least toxic but which will control the patient's disease, and escalating to more potent therapies in the face of continued disease activity. An ‘induction’ strategy involves giving a powerful drug, with significant side effects, early in the disease.
- As newer treatments emerge and when there is clinical equipoise agreed between clinician and patient, and there are clinical trials available for recruitment, then patients should be offered participation in relevant studies.
General management advice
- UK health systems have diverged with the devolved administrations in respect of treatment guidelines and/or restrictions.
- These differences render it now impossible to make treatment recommendations that are simultaneously compliant with all of the relevant advisory or statutory medicines agencies.
- The ABN continues to support a fundamental principle of the NHS that, despite these changes, all patients have a right to access the appropriate expertise and therapy.
- It is important that patients and neurologists fully appreciate the risk and benefit of drugs, and of leaving the disease untreated.
- Patients should also discuss the risk as well as expected benefit of treatment; monitoring requirements; and work, family and other factors that are personally important, and clinicians should take account of their views in making the treatment selection.
- MS specialist nurses play a key role in supporting patients
- Patients can also obtain information from patient groups, particularly the Multiple Sclerosis Trust and the Multiple Sclerosis Society, which have produced information leaflets in plain language, as well as a range of leaflets on other symptomatic, psychological and social aspects of living with MS. There are also several excellent websites particularly targeted towards patients, providing valuable information and guidance.
Recommendations for starting disease-modifying treatment
Eligible patients will normally be ambulant (maximum EDSS 6.5). There are no treatments licensed for use during pregnancy (but see below).
- Once started on therapy, continued supervision by the specialist MS team is essential to identify side effects and assess therapeutic efficacy.
As mentioned above, the currently licensed disease-modifying treatments divide broadly into two classes:
Drugs of moderate efficacy (‘Category 1’)
Drugs of high efficacy (‘Category 2’)
- β-interferons (including ‘pegylated’ β-interferon)
- glatiramer acetate
- dimethyl fumarate
Patients with relapsing–remitting MS who have had two or more clinical relapses in the previous two years are considered to have ‘active’ disease that warrants consideration of disease-modifying treatments. The European Medicines Agency has explicitly recognised that disease activity may be established on radiological or clinical grounds.
All individuals with active relapsing–remitting MS should be considered expeditiously for treatment.
Most are likely to start treatment with a Category 1 drug.
- Dimethyl-fumarate and fingolimod are the more effective drugs in this category, with the advantage of being oral agents.
- Some people with active disease will prefer to start dimethyl- fumarate or, if ‘highly active’, fingolimod in this group.
- The β-interferons and glatiramer acetate have been used extensively and there is a wealth safety experience
- Individuals with relatively quiescent disease and/or who are more risk-averse might choose one of the β-interferons or glatiramer acetate.
- Individuals with needle phobia may choose teriflunomide, dimethyl fumarate or, if eligible, fingolimod.
More active relapsing–remitting MS
The formal criteria for high-disease activity are despite interferon-β or glatiramer requires one relapse in the previous year on interferon-β and either (a) ≥1 gadolinium-enhancing MRI lesions or (b) at least nine T2-hyperintensive lesions on cranial MRI.
- We recommend that patients with more active disease use one of the Category 2 drugs, natalizumab or alemtuzumab. Indirect comparison suggests that alemtuzumab and natalizumab have similar efficacy.
- Although alemtuzumab's licensed indication is much less restrictive,we recommend that, given its potential adverse effects, it should be mainly confined to patients with more active disease.
- Alemtuzumab and natalizumab are appropriate where one is concerned to achieve high efficacy, despite the more complex safety profile compared to Category 1 drugs.
- Some people who have experienced relapses despite using a Category 1 agent may be particularly risk-averse or had occasional minor relapses. In such instances, it may be appropriate to change from one to another Category 1 agent.
- Switching between Category 1 agents because of continued disease activity may be justified on the basis of MRI-proven disease activity alone.
- Switching from a Category 1 agent to a Category 2 monoclonal antibody is probably justifiable only when there is clinical evidence of high-disease activity despite treatment.
Clinically isolated syndrome
Various disease-modifying treatments can delay the diagnosis of MS in patients with a clinically isolated syndrome
- Currently, only the β-interferons and glatiramer are licensed for clinically isolated syndrome.
People with MS aged under 18 years of age
We believe that minors aged between 16 and 18 years should be treated according to the above guidelines.
Children with MS aged <16 should consult with paediatric neurologists with a particular interest in MS.
- Significant side effects specific to any individual agent should trigger withdrawal of that agent and consideration of an alternative treatment.
- Development of non-relapsing secondary progressive MS.
- During pregnancy, disease-modifying treatments should normally be stopped.
- We recommend that women stop disease-modifying treatments while trying to conceive unless, the woman's clinical condition requires treatment.
- Given the increased risk of relapse, treatment should be restarted early after delivery, depending on discussions concerning breast feeding.
This is a consensus guideline and so not every neurologist will agree with the contents of this !
CoI: Prof G and I are co-authors of these guidelines (and neither of us agrees with every paragraph).