Tag Archives: criteria

Pregnancy and childbirth, Women's health

Planning for pregnancy

This article discusses the effects of MS on fertility, decisions about starting or stopping a DMT, the use and safety of oral contraceptives and the possible impact of in vitro fertilisation on MS disease course.

Does MS affect my fertility?

No, MS does not affect fertility. Women and men with MS are as fertile as people without MS. However, MS does not protect women and men from other causes of infertility. Fertility treatment may impact MS (see below). Please be aware that mitoxantrone, AHSCT (autologous haemopoietic stem cell treatment) and other chemotherapy treatments, such as cyclophosphamide used off-label to treat MS, may be toxic to ovarian and testicular function and require egg and sperm banking before treatment.

Should I go onto a DMT and get my MS under control before starting a family or first start my family?

In general, I recommend that women with active MS delay pregnancy until their disease is under control, optimise their general health and prepare properly for becoming a parent. There is no point in having active MS, not starting a DMT and having a catastrophic relapse in the period during which you are trying to fall pregnant.

However, a desire to start or extend your family should not change the way you want your MS managed. Early effective treatment, treating to a target of NEIDA, potentially flipping the pyramid, preventing end-organ damage and the holistic management of MS are all compatible with pregnancy. There are no rules for implementing this strategy in pregnancy because all decisions should be personalised. For example, a woman with rapidly evolving severe MS may choose natalizumab and stay on it throughout pregnancy and while breastfeeding because her MS was so active and potentially devastating. Another woman who is young, risk adverse and with a very good prognosis may choose to delay starting a DMT until she has had a child. Yet another woman, diagnosed at 40, may not want to delay falling pregnant and may opt for a DMT that is safe during pregnancy.

It is up to the person with MS, their partner and sometimes their extended family to make the final decisions about how to manage their MS during pregnancy. The healthcare professional (HCP) is there to provide information and guidance in this process.

Are oral contraceptives safe in people with MS?

To my knowledge, contraceptives are safe and effective in women with MS. The same contraindications and relative contraindications to specific contraceptives apply to women with MS as to the general population. Hormonal contraceptives are associated with an increased risk of thrombosis; women with MS who are immobile thus have a higher risk of deep vein thrombosis than those who are mobile.

Which contraceptive would you recommend?

MS should not be the deciding factor around the choice of contraceptive unless the degree of MS-related disability makes managing menstrual hygiene difficult. In this case, contraceptives that suppress menstruation have advantages, for example, continuous hormonal contraceptives or the progestin-tipped intrauterine contraceptive device (Mirena).

Inclusion criteria for participation in specific drug trials sometimes mandate double contraception, for example, a hormonal contraceptive and a barrier method. This is to try and avoid accidental pregnancies while taking an investigational compound without a safety track record in humans.

How long before I fall pregnant must I stop my DMT?

It depends on which DMT you are taking. Only the DMTs that are teratogenic or potentially teratogenic (i.e., may cause foetal malformations) need to be stopped before you fall pregnant. It is essential to allow sufficient time for these agents to be eliminated from the body.

Teriflunomide

Teriflunomide has the potential to cause birth defects; therefore, patients must have effective contraception whilst on this treatment. It has a very long half-life because it is reabsorbed in the intestine and is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes up to 8 months to reach plasma concentrations of less than 0.02 mg/l, which are considered safe. Remarkably, due to individual variations in teriflunomide clearance, it may take up to 2 years to fall to acceptable levels. An accelerated elimination procedure with cholestyramine or activated charcoal can be used at any time after the discontinuation of teriflunomide.

Teriflunomide accelerated elimination procedure

After stopping treatment with teriflunomide:

• Cholestyramine 8 g is administered three times daily for 11 days, or cholestyramine 4 g three times a day can be used if cholestyramine 8 g three times a day is not well tolerated.

• Alternatively, 50 g of activated powdered charcoal is administered every 12 hours for 11 days.

Following either of the accelerated elimination procedures, it is recommended to verify elimination by checking teriflunomide blood levels and allow a waiting period of 1.5 months between the first occurrence of a plasma concentration below 0.02 mg/l and planned fertilisation.

S1P modulators

S1P modulators are contraindicated during pregnancy, owing to the risk to the foetus. Before starting treatment in women of childbearing potential, we do a urine pregnancy test. Women taking an S1P modulator must use effective contraception during treatment and then continue for:

  • 2 months after stopping treatment with fingolimod (Gilenya)
  • 10 days after stopping treatment with siponimod (Mayzent)
  • 3 months after stopping treatment with ozanimod (Zeposia)
  • 7 days after stopping treatment with ponesimod (Ponvory).

Stopping the S1P modulators brings the potential for rebound disease activity, so most neurologists now prefer to transition women on one of these therapies to another class of DMT that is considered safer in pregnancy.

Safer options

Safer options during pregnancy include an injectable (interferon-beta or glatiramer acetate), a fumarate, an anti-CD20 therapy, natalizumab or an immune reconstitution therapy (cladribine or alemtuzumab). I cover some of the issues related to anti-CD20 therapies in the MS-Selfie case study ‘Wait to fall pregnant or start a DMT now?’.

The good news is that several DMT options are now available to women with MS wanting to fall pregnant.

Can I have IVF, and what will IVF do to my MS?

There is no reason why a person with MS cannot have IVF (in vitro fertilisation). However, there appears to be a slightly increased risk of relapse after IVF and egg harvesting. Whether this is due to stopping DMTs before undergoing IVF or due to the drugs used to stimulate ovulation is unknown. Studies reporting an increase in disease activity after IVF are more likely to be published than studies not showing such an increase so that publication bias may affect the findings. I recommend viewing IVF as a planned pregnancy and giving women with MS the option of receiving a DMT that is relatively safe in pregnancy or treating their MS with immune reconstitution therapy before IVF.

References

Krysko KM et al. Treatment of women with multiple sclerosis planning pregnancy. Curr Treat Options Neurol 2021;23:11.

Other articles in this series on Pregnancy and childbirth:
Managing MS during pregnancy
Preparing to give birth
Breastfeeding if you are on a DMT
Concerns about parenting

Treatment strategy

Do I understand the concepts of treat-2-target and NEDA?

Has anyone discussed a treatment target with you, including the need to rebaseline your disease activity? Have the concepts of preventing end-organ damage to the central nervous system (the ‘end-organ’ in MS) and brain volume loss or atrophy been broached?

Key points

  • Achieving long-term remission is a well-established treatment target in MS and several other autoimmune diseases.
  • Key measures of MS disease activity are used to define composite treatment targets; they provide objective means for monitoring and decision-making.
  • To demonstrate a target of no evident disease activity (NEDA) requires a minimum of three criteria to be met: no relapses, no MRI activity and no disability progression.
  • More stringent definitions of NEDA targets have evolved and will continue to do so as new predictors of treatment response are developed.

If you are on a disease-modifying therapy (DMT), what is the objective or treatment target for your MS? This is another question to be answered before committing yourself to a specific treatment strategy.

Treat-2-target

Relapses and ongoing focal inflammatory activity on MRI (new or enlarging T2 lesions and T1 gadolinium-enhancing lesions [Gd-enhancing]) are associated with poor outcomes. This has led to the adoption of ‘no evident disease activity’ (NEDA) as a treatment target in MS. NEDA, or NEDA-3, is a composite of three related measures of MS disease activity: (i) no relapses, (ii) no MRI activity (new or enlarging T2 lesions or Gd-enhancing lesions) and (iii) no disability progression. NEDA is an important goal for treating individuals with MS.

When to rebaseline

To use NEDA as a treatment target in day-to-day clinical practice, it is advisable to be ‘rebaselined’ after the onset of action of the DMT you have been started on. The timing of the MRI to provide a new baseline depends on the DMT concerned. The recommendations for immune reconstitution therapies (IRTs) are very different from those for maintenance therapies. In the case of an IRT (for example alemtuzumab or cladribine, which are given as short courses), breakthrough disease activity can be used as an indicator to retreat rather than necessarily to switch therapy. Therefore, a rebaselining MRI should be delayed until after the final course of therapy, e.g. 2 years, or close enough to the time when a third, or subsequent course, can be administered.

Determining treatment failure: IRTs

Questions remain of how many treatment cycles need to be given before considering that a specific IRT has not been effective.

  • For alemtuzumab, the threshold is three cycles under NHS England’s treatment algorithm (based on their cost-effectiveness analysis). Alemtuzumab is a biological or protein-based treatment, so the risk of developing neutralising anti-drug antibodies increases with each infusion.
  • Cladribine on the other hand is a small molecule, so neutralising antibodies are not a problem and there is no real limit on the number of courses that can be given.
  • Although HSCT tends to be a one-off treatment, there are rare reports of people with MS receiving more than one cycle.

Please note there are potentially cumulative risks associated with multiple cycles of an IRT: secondary malignancies in the case of HSCT and persistent lymphopaenia with cladribine. 

Determining treatment failure: maintenance therapies

In comparison to IRTs, if you have disease activity on a particular maintenance DMT, and provided you have been adherent to your treatment, this is usually interpreted as a suboptimal response or non-response and it should trigger a switch to another class of DMT. 

A criticism of NEDA is the omission of so-called ‘non-relapse-associated disease worsening’ as a component of the treatment target (in addition to evidence of incomplete recovery from relapses). I refer to this disease worsening as smouldering MS. Worsening disability in the absence of relapses may have little to do with ongoing focal inflammatory activity. It may simply represent a delayed dying-off of axons and nerve fibres following earlier focal inflammatory lesions. As a result, many neurologists feel uncomfortable switching, or stopping a DMT, based simply on non-relapse-associated worsening disability. For more information, please see Getting worse – smouldering MS.

Beyond NEDA-3

The definition of NEDA is evolving with clinical practice. Some centres are now testing for brain volume loss (that is, brain atrophy) and/or increased neurofilament light chain (NFL) in cerebrospinal fluid (CSF) as part of the NEDA-3 treatment target. NEDA-4 builds on NEDA-3, by including the target of normalising brain atrophy rates to within the normal range. The problem we have found with this is that the measurement of brain atrophy in an individual with MS level is very unreliable. For example, dehydration, excessive alcohol consumption and some symptomatic medications can cause the brain to shrink temporarily. We, therefore, think that CSF NFL levels are a better treatment target, less prone to misinterpretation. Neurofilaments are proteins that are found in nerves and axons (nerve fibres) and are released in proportion to the amount of nerve fibre damage that occurs in MS. Normalising CSF NFL levels, which would indicate that nerve damage is stopped, is referred to as NEDA-5. From a scientific perspective, including a more objective end-organ biomarker makes sense and will almost certainly be incorporated into our treatment target in the future.  

Table format updated 180625 SS

The components of NEDA-recommended targets are expanding as our ability to measure predictors of treatment response grows.
CSF, cerebrospinal fluid; MRI, Magnetic resonance imaging; NEDA, no evident disease activity; NEIDA, no evident inflammatory disease activity; NFL, neurofilament light; PROMS, patient-related outcome measures.

End-organ damage

The combination of relapses, the development of new MRI lesions and brain volume loss over 2 years in clinical trials predicts quite accurately who will become disabled over the same time period. From a treatment perspective, it is important to stop relapses, new MRI lesions and brain volume loss if we are to prevent or slow down worsening disability. Therefore, we must go beyond NEIDA (no evident inflammatory activity), which refers to relapses and focal MRI activity, and normalise brain volume loss if we can. 

Alternatives to NEDA?

Many neurologists are critical of using NEDA as a treatment target in clinical practice, fearing that it encourages people with MS to take highly effective DMTs that they consider may be ‘more risky’ (see short summaries of the available DMTs for information about individual drugs). Such neurologists, therefore, promote a less proactive approach and allow for some residual MS disease activity, but at a lower level. This treatment target is referred to as minimal evidence of disease activity, or MEDA.

In my opinion, MEDA flies in the face of the science of focal inflammatory lesions being ‘bad’ and it is associated with poor short-term, intermediate and long-term outcomes. If most people with MS end up receiving so-called high-efficacy therapies because of breakthrough disease activity, then this is what they probably need, that is, to have their MS treated adequately. Compelling evidence has emerged from trials, large registries and real-world data that people with MS treated early with highly effective DMTs (flipping the pyramid) do better than those who have delayed access to more effective DMTs.1,2,3 You can find a short summary of some key findings on the MS Brain Health website.

Implementing NEDA in clinical practice

Please note that achieving long-term remission, or NEDA, is a well-established treatment target in other autoimmune diseases, such as rheumatoid arthritis, autoimmune kidney disease and inflammatory bowel disease. People with MS treated to a target of NEDA do better than those with breakthrough disease activity. I would therefore strongly encourage you to discuss this treatment target with your own MS neurologist. 

The flowchart below illustrates how we implement a treat-2-target of NEDA strategy. The important take-home message is that the treatment targets in MS have moved; goal-setting and the active monitoring of outcomes is now required to achieve these goals. 

Treat to target NEDA algorithm

Recommended approaches to implementing a treat-2-target of NEDA strategy, using maintenance ̶ escalation or immune reconstitution therapy (IRT). The dotted lines indicate that if treatment fails you can either switch within the class (maintenance or IRT) or reassess the strategy. From Giovannoni, Curr Opin Neurol.4
Alem, alemtuzumab; Clad, cladribine; DMF, dimethyl fumarate; Fingo, fingolimod; GA, glatiramer acetate; HSCT, haematopoietic stem cell transplantation; IFNβ, interferon-beta; Mitox, mitoxantrone; NEDA, no evident disease activity; Nz, natalizumab; Ocre, ocrelizumab; Ofat, ofatumumab; Teri, teriflunomide.

There is also a clear need to update the definition of NEDA regularly as new technologies become available and are validated as predictors of treatment response. I therefore envisage the definition of NEDA changing still further in future to include more objective measures, particularly ones measuring end-organ damage and the inclusion of patient-related outcome measures.

References

DMTs, Treatment strategy

How immunosuppressed am I?

Do you understand the difference between short-term intermittent and long-term continuous immunosuppression? Here we address another of the key questions to consider before deciding on a specific disease-modifying therapy (DMT).

Key points

  • Immunosuppressive disease-modifying therapies (DMTs) reduce the immune system’s effectiveness.
  • It is important to weigh up the benefits and risks of short-term versus continuous immunosuppression.
  • Non-selective DMTs suppress the adaptive and innate immune systems; selective DMTs do not affect the innate immune system and are thus associated with a low risk of bacterial infections.
  • The implications of immunosuppression need to be considered within the context of other health and lifestyle factors.

Which DMTs cause immunosuppression?

A useful way of thinking about DMTs is based on whether they are immunosuppressive. Broadly speaking, an immunosuppressive is any DMT that reduces the immune system’s activation or effectiveness. 

From a regulatory perspective, for a drug to be classified as immunosuppressive, it should: 

  • cause significant lymphopaenia or leukopenia (reduced white cell counts)
  • be associated with opportunistic infections (infections that don’t occur in people with a normal, healthy immune system)
  • reduce antibody and/or T-cell responses to vaccines 
  • increase the risk of secondary malignancies. 

Based on the above criteria, the interferon-beta preparations and glatiramer acetate are immunomodulatory rather than immunosuppressive. Teriflunomide is also an immunomodulatory therapy with the potential, albeit small, to cause immunosuppression. In real life, however, very few people with MS treated with teriflunomide develop significant lymphopaenia or leukopenia; if they do, we tend to stop the drug. The other licensed DMTs are immunosuppressive to a greater or lesser degree. 

Short-term versus continuous immunosuppression

The duration and intensity of immunosuppression further determine the risks. Short-term or intermittent immunosuppression associated with an immune reconstitution therapy (IRT) front-loads the risks, which decrease substantially once the immune system has reconstituted itself. In comparison, long-term continuous or persistent immunosuppression, which occurs with most maintenance DMTs, accumulates problems over time, particularly opportunistic infections and secondary malignancies.

Live vaccines are, in general, contraindicated in patients on continuous immunosuppressive therapies. However, someone with MS on an IRT who has reconstituted their immune system can tolerate and respond to live vaccines. The benefits of administering live vaccines always need to be balanced against the risks of the vaccine.

How immunosuppressed are you table updated format 180625 SS

The main characteristics of continuous persistent and short-term (intermittent) immunosuppression. Modified from Giovannoni, Curr Opin Neurol.1
AHSCT, autologous haematopoietic stem cell transplantation; PML, progressive multifocal leukoencephalopathy.

Selective versus non-selective immunosuppression

Immunosuppression that accompanies DMTs may be selective or non-selective. Non-selective therapies deplete and/or suppress both the adaptive immune system (T cells and B cells) and the innate immune system (monocytes, neutrophils and natural killer [NK] cells). Alemtuzumab, AHSCT (autologous haematopoietic stem cell transplantation) and mitoxantrone are non-selective and are therefore associated with acute bacterial infections such as listeriosis, nocardiosis and cytomegalovirus reactivation. In comparison, anti-CD20 agents (ocrelizumab and ofatumumab) and cladribine are selective, do not affect the innate immune system and are therefore associated with a low risk of acute bacterial infections. 

How immunosuppressed are you_MET vs IRT_2 Dec 2024

Classification of disease-modifying therapies for relapsing forms of MS. Modified from Giovannoni, Curr Opin Neurol.1
AHSCT, autologous haematopoietic stem cell transplantation.

Other considerations

Please note that the implications of immunosuppression are not black and white but interact with other factors such as:

These factors have been highlighted during the COVID-19 pandemic, particularly in relation to the risk of severe COVID-19 and the variations in vaccine responses among people with MS (including waning of the immune response).

It is important to realise that we can derisk (reduce the risk of) some complications associated with long-term immunosuppression and the use of DMTs. Please see the post entitled How can I reduce my chances of adverse events on specific DMTs?

References

  1. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.
Diagnosis

Am I sure that I have MS?

The multiple sclerosis misdiagnosis rate is around 5% and this has major implications for individuals and the treatment of MS.

Key points

  • A wrong diagnosis of MS may have financial, social and psychological consequences for the individuals concerned, affecting major life decisions.
  • Some MS treatments have life-threatening complications and should only be prescribed for people with a clear diagnosis of MS.
  • Some of the diseases that mimic MS can be made worse by disease-modifying treatments for MS.
  • Diagnostic criteria for MS have evolved and now take account of clinical, electrical, laboratory and magnetic resonance imaging findings.

A case study

She had been diagnosed with multiple sclerosis 8 years ago and had been taking interferon-beta since her diagnosis. I told her that I didn’t think she had MS and that her diagnosis was almost certainly complicated migraine with aura. The lesions on her magnetic resonance imaging (MRI) scan were non-specific white matter lesions and not inflammatory. Her neurological examination, spinal fluid analysis and evoked potentials (EPs) were normal. What clinched the non-MS diagnosis for me was the history of neurological events, which were too short-lived and migratory to be MS attacks. The final piece of the jigsaw was that a special MRI sequence showed none of her white matter lesions had a central vein, which told me that none of her white matter lesions was an MS lesion.  Her anger was palpable. She was angry because she had decided not to start a family and had changed her career because of the fear of becoming disabled in the future and not being able to work or look after a child.  This case illustrates why I always try to review the diagnosis of patients referred to me with MS and why it is important to answer this question before starting a disease-modifying therapy (DMT).   

Making a diagnosis of MS

Unfortunately, there is no single test to diagnose MS. Rather, MS is diagnosed by combining a set of clinical and MRI findings, electrical or neurophysiological investigations and laboratory tests. If these tests fulfil a set of so-called MS diagnostic criteria, the healthcare professional (HCP) or neurologist makes a diagnosis of MS. 

The underlying principles of diagnosing MS are to show the dissemination of lesions in space and time and exclude possible mimics of MS. The diagnostic criteria have evolved over time from 1) being based purely on clinical attacks,1 to 2) include electrical and spinal fluid tests as well as clinical attacks,2 and 3) to add on the use of MRI to help confirm dissemination in time and space.3–6  

Dissemination in time 

This means that two attacks or MS lesions must occur at least 30 days apart or that oligoclonal bands (OCBs) of immunoglobulins can be detected in the spinal fluid.

Dissemination in space 

This requires MS lesions to occur in different locations, for example, the optic nerve and the spinal cord. 

Electrical tests

The electrical or neurophysiological tests are called evoked potential (EPs) and test electrical conduction in a particular pathway. They can show lesions in nerve pathways that are not evident on the neurological examination or seen on MRI. The EPs can also show slow electrical conduction, which is one of the hallmarks of diseases that affect myelin, the insulation around nerves that is responsible for speeding up the electrical conduction of nerve impulses.

Laboratory tests

The laboratory tests are typically done to exclude other diseases that can mimic MS. Examining the spinal fluid for the presence of OCBs is useful in helping to make an MS diagnosis. OCBs are the fingerprint of a specific type of immune activation within the central nervous system (CNS). The OCB fingerprint is relatively specific for the diagnosis of MS in the correct clinical context. (OCBs are also found in CNS infections and other autoimmune diseases, but these are relatively easy to differentiate from MS.)

Please be aware that you may have MS according to the latest diagnostic criteria when you could not be diagnosed with MS using past criteria.

Why is a correct diagnosis important?

Neurologists get the diagnosis wrong in approximately 5% of people with MS. In other words, one in 20 people who have a diagnosis of MS in life does not have MS when their brain is studied post mortem. This data is based on a large study in a region of Denmark.7 More recently, a study from a specialist MS centre in the United States reported a misdiagnosis rate of approximately 15% in patients with presumed MS referred to their centre for treatment.8 

Why is getting the diagnosis of MS correct so important? Firstly, some MS treatments have life-threatening complications; you don’t want to expose people without MS to these complications. More concerning is that some of the diseases that mimic MS can be made worse by MS DMTs. Finally, a diagnosis of MS has many psychological, social, financial and economic implications. Even if you turn out to have ‘benign disease’, just having a diagnosis of MS, has implications for your life choices and may impact your ability to get insurance cover, to name obvious examples. I, therefore, advise you to make sure you have MS and not an MS mimic.

Common MS mimics

References

  1. Schumacher GA, et al. Problems of experimental trials of therapy in multiple sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552–68.
  2. Poser CM, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227–31.
  3. McDonald WI, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–7.
  4. Polman CH, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005;58:840–6.
  5. Polman CH, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69:292–302.
  6. Thompson AJ, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018;17:162–73.
  7. Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand 1988;78:39–44.
  8. Kaisey M, et al. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord 2019;30:51–6.
DMTs, Treatment strategy

Am I eligible for an MS disease-modifying therapy?

Key points

Do you know the eligibility criteria for MS disease-modifying therapies? And who decides what drugs can be prescribed for your MS?

  • Disease-modifying treatments (DMTs) change the long-term trajectory of MS and protect the central nervous system from further damage.
  • Regulators such as the European Medicines Agency (EMA) and the Federal Drug Administration (FDA) decide in which group(s) of patients a particular drug can be used, based on the results of clinical trials.
  • Once a drug has been licensed in your region, local payers decide whether to make it available within your country, based on cost-effective assessments.
  • If you have active MS, your level of disease activity, its severity and speed of development will determine which DMTs you can be offered.
  • In some countries, ocrelizumab has been approved for the treatment of active primary progressive MS (PPMS) and siponimod has been approved for the treatment of active secondary progressive MS.
  • Protecting upper limb function has been a neglected area; studies are now ongoing, however, with a view to finding DMTs that limit the progression of upper limb disability.

What do disease-modifying drugs do?

Disease-modifying therapies (DMTs) are treatments that change the natural history – that is, the long-term trajectory – of the disease. They reduce the rate of disability worsening and so protect the end-organ (in the case of MS, this is the central nervous system). To simplify, let’s say that a person with MS on no treatment may manage for an average of 18-20 years before needing to use a walking stick (corresponding to Expanded Disability Status Scale [EDSS] 6.0), while someone on treatment might manage without aid for 24 years, i.e. a 4-6-year delay, then the treatment can be called disease-modifying. (Please note, the treatment effect or 4-6-year delay in reaching EDSS 6.0 is an average and some people with MS will do better than others. Conversely, some will do worse than average.) 

Is interferon a DMT?

In the early days of interferon therapy, there was debate about whether simply reducing the relapse rate by 30% relative to placebo treatment, without slowing down the worsening of the disease over 2 years, was disease-modification. However, subsequent trials and follow-up of people with MS treated with interferon-beta showed a slowing down of disease worsening, delays in developing secondary progressive MS and a favourable impact on survival.1 

Do symptomatic treatments modify the disease?

Symptomatic treatments improve the symptoms associated with MS without affecting the natural history. Treatments are classified as symptomatic in relation to their mode of action; but some classes of treatment may yet prove to be disease-modifying. For example, we often use sodium channel blocking agents, such as phenytoin, carbamazepine, oxcarbazepine and lamotrigine, for MS-related neuralgia and other pain syndromes. However, there is evidence that this class of therapy may be neuroprotective and hence disease-modifying. 

Who decides on eligibility for a licensed DMT?

Regulators decide in which group of people with MS the DMT can be used, and they grant a licence for its use. Regulators include the EMA, the FDA and the Medicines and Healthcare products Regulatory Agency (MHRA in the UK).

Payers hold the purse strings and decide which licensed drugs to make available. They makecost-effectiveness assessments to try and optimise the use of the drug in clinical practice. Payers include medical insurance companies and the NHS in the UK. 

Guidelines are formulated to help healthcare professionals use DMTs in the most appropriate way within a particular healthcare system. Guidelines often go much further than the regulators and payers, in that they try to address potential ambiguities in the prescribing of DMTs. National, regional or local guidelines that provide expert clinical guidance include the UK NICE (National Institute for Health and Care Excellence) MS management guidelines and the Association of British Neurologists guidelines. 

In the NHS in England, we must abide by NHS England’s algorithm that is predominantly based on NICE technology appraisals, NICE standards of care and the Association of British Neurologists guidelines. To navigate the specifics of the eligibility criteria is quite complex. However, a simpler way of looking at this is to start by defining how active your MS is. 

How does disease activity affect my treatment options?

To be eligible for DMTs, you must have active MS. A summary of the four categories of disease activity is given below. Further details can be found in the section entitled Do I have active MS?

  1. Inactive MS – you are not currently eligible for DMTs.
  2. Active MS – you should be eligible for a so-called platform therapy (interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate or ponesimod) and ocrelizumab or ofatumumab.
  3. Highly active MS – you are eligible for all therapies except natalizumab. Please note in England fingolimod can only be used as a second-line therapy (after another DMT has failed).
  4. Rapidly evolving severe MS – you should be eligible for all DMTs.

Advanced or progressive MS

Ocrelizumab and siponimod are now approved in several countries for the treatment of active PPMS and active SPMS, respectively. A classification of active PPMS requires recent MRI evidence of disease activity, that is, the formation of new T2 lesions and/or the presence of gadolinium-enhancing lesions in the last 3 years. Active SPMS is confirmed by the occurrence of superimposed relapses and/or the presence of new T2 lesions and/or gadolinium-enhancing lesions in the last 2 years. Based on these very narrow definitions, most patients with PPMS and SPMS will not be eligible for ocrelizumab or siponimod, respectively. The differences between the MRI criteria for active PPMS and active SPMS reflect the reality that people with PPMS are less likely to be having regular monitoring MRI scans.

Stages of MS currently not eligible for treatment

In the UK, people with MS who are wheelchair users are not eligible for DMTs. The reason for this is that patients with more advanced MS have generally been excluded from phase 3 clinical trials; hence there are no data to show whether licensed DMTs are effective in this group.

There is a long-held view that inflammation is reduced or absent in advanced MS. However, clinical, imaging and pathological data show that inflammation still plays a large, and possibly a major, role in advanced MS. Therefore, not targeting more advanced MS with an anti-inflammatory is counterintuitive.

The importance of upper limb function

In 2016, the #ThinkHand campaign was launched to raise awareness of the importance of hand and arm function in people with MS and the need for clinical trials in this population. Studies currently ongoing that focus on limiting upper limb disability progression include ChariotMS (oral cladribine)2 in people with advanced MS (UK only) and the global, multicentre O’HAND trial  (ocrelizumab)3 in participants with PPMS. 

Once someone with MS becomes a wheelchair user, they still have neuronal systems that are potentially modifiable – for example, upper limb, bulbar (speech and swallowing), cognition and visual function. There is an extensive evidence base showing that several licensed DMTs can slow the worsening of upper limb function despite subjects having advanced MS. Now that ocrelizumab and siponimod have been licensed for active primary and secondary progressive MS, respectively, these DMTs may form the platform for future add-on trials. 

References

  1. Goodin DS, et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology 2012;78:1315 ̶ 22.
  2. National Institute for Health and Care Research (NIHR). MS clinical trial to focus on people who can’t walk. November 2020. Available at https://www.nihr.ac.uk/news/ms-clinical-trial-to-focus-on-people-who-cant-walk/26227 (accessed June 2022).
  3. US National Library of Medicine. A Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (O’HAND). First posted July 2019. Available at https://clinicaltrials.gov/ct2/show/NCT04035005 (accessed June 2022).
Diagnosis, Stages of MS

Do I have active MS?

Before deciding to start a disease-modifying therapy you need to know if you have active MS.

Key points

  • To qualify for a disease-modifying treatment for MS you must have active disease.
  • Active MS is characterised by relapses (new symptomatic or asymptomatic lesions); the clinical diagnosis of relapse may be supported by MRI or CSF evidence of activity.
  • Different levels of disease activity qualify for different types of DMT.
  • Diagnostic criteria for MS have evolved considerably over the past two decades; this has helped to make treatment decisions earlier and easier, both for MS neurologists and for people with MS.

To be eligible for disease-modifying therapy (DMT) you must have ‘active MS’. This term is increasingly used to refer to current or recent evidence of focal inflammatory activity, i.e. new lesions on magnetic resonance imaging (MRI) or a relapse. Inflammation damages axons, or nerve processes. When a lesion develops, the effects of inflammatory mediators can cut (transect) axons, demyelinate them or stop them from working.

By contrast, the gradual worsening of disability that occurs in people with more advanced MS (which may, or may not, occur in the presence of focal inflammatory activity) has many potential causes, only one of which is focal inflammation.

Signs of active MS

Relapses

When a new MS lesion occurs in an eloquent part of the central nervous system it causes new symptoms or exacerbates old ones – this is usually interpreted as a relapse. Relapses, by definition, last at least 24 hours in the absence of infection or fever.

Criteria for ‘active’ MS accepted by many MS health professionals. CSF, cerebrospinal fluid; NFL, neurofilament light.
*Some neurologists accept 24 months, 36 months or even more when assessing MRI activity. There is no international consensus on the gap between the baseline and new MRI scan to define active disease.

Asymptomatic lesions

Most focal MS disease activity does not cause any overt symptoms because the brain has a way of compensating for damage. For every clinical relapse, there are at least 10 or more lesions on MRI. Therefore, what we see clinically in terms of relapses is the tip of the iceberg. Even standard MRI is relatively insensitive in detecting and monitoring MS disease activity; it misses new lesions that are smaller than 3 ̶ 4 mm in size and does not detect most lesions that occur in the grey matter of the brain (cortex and deep grey matter nuclei, e.g. thalamus and basal ganglia). Therefore, MRI scans also reveal just the tip of the iceberg. This is one of the reasons we also use cerebrospinal fluid (CSF) neurofilament levels as a marker of this microscopic activity.

Disease activity levels

Inactive MS

Many people with MS experience frequent intermittent symptoms or ‘pseudorelapses’ that come on when they are tired, after exercise or have a raised body temperature from a fever, exercise, hot bath or a warm environment. These intermittent symptoms are usually quite stereotyped and last minutes to hours. They are indicative of a previously damaged pathway but do not represent a relapse or disease activity.

Active MS

Most neurologists require evidence of disease activity in the last 12 months, with some of us accepting a 24-month or 36-month window if there is no serial or regular MRI support. However, if you have had no relapses or MRI evidence of new lesions in the last 24 months, then your MS is defined as inactive. (This does not mean your MS is necessarily stable; you could have worsening disability as part of the progressive or smouldering phase of the disease.) Inactive MS needs to be monitored in case it reactivates, in which case you could become eligible for treatment.

Inactive MS - format updated 180625 SS

Schematic showing different levels of MS disease activity.
*Some neurologists accept MRI activity in the last 24 months, 36 months or even longer as a criterion for active MS.

Highly active MS and rapidly evolving severe MS

Active MS has been divided into an additional two categories that have implications for DMT prescribing (depending on where you live).

  • Highly active MS describes MS with unchanged or increased relapse rates, or ongoing severe relapses compared with the previous year, despite treatment with beta-interferon or another so-called first-line therapy. In England, patients in this subgroup are eligible for natalizumab, alemtuzumab, fingolimod and cladribine.
  • Rapidly evolving severe MS (RES) is defined as two disabling relapses and MRI evidence of activity within a 12-month period. In England, patients in this subgroup are eligible for natalizumab, alemtuzumab and cladribine.

Evolution of diagnostic criteria

In the early 2000s, disease activity was defined using clinical criteria only; you needed at least two documented relapses in the last 2 years to be eligible for DMT.1 This meant that a neurologist had to examine you to confirm abnormalities compatible with a relapse. However, many people with MS without rapid access to a neurologist would recover before being assessed, meaning that their relapses often could not be documented. This was very frustrating for someone wanting to start a DMT. If patients had MRI evidence to support recent disease activity, how could we deny them access to a DMT because they were not seen in a timely way to have their relapse documented in the clinical notes?

In 2009, the criteria for diagnosing MS incorporated MRI into the definition to allow us to treat so-called high-risk patients with CIS (clinically isolated syndromes compatible with demyelination). These criteria required patients with CIS to have nine or more T2 lesions on MRI or at least one gadolinium-enhancing lesion. These MRI criteria were based on the McDonald diagnostic criteria at the time.2 These eligibility criteria evolved further in 2014, once alemtuzumab was licensed, to include clinical or MRI activity.

References

  1. McDonald WI, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–7.
  2. Polman CH, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69:292–302.
Stages of MS

What type of MS do I have?

MS has historically been classified into different subtypes, and this subdivision dictates what treatments you are eligible for. These MS disease subtypes are not supported biologically, however, and many MS neurologists are of the opinion that MS is one disease.1

Key points

  • The difference between relapsing MS and non-relapsing progressive MS is explained.
  • The stages of MS have different labels, for historical development and reimbursement reasons, but biologically MS is one disease.
  • From a treatment perspective, the key thing is to know if your MS is active or inactive.
  • Active MS can be differentiated from inactive MS by relapses, MRI evidence of disease activity and raised neurofilament levels in the cerebrospinal fluid.

Type of MS

You should be able to classify yourself as having either relapsing MS or non-relapsing progressive MS. Knowing what type of MS has been diagnosed and whether your MS is active or inactive will allow you to ask your MS neurologist questions about the MS treatments available to you. 

Around 85–90% of people with MS start with so-called relapse-onset MS, i.e. they have a definite attack of symptoms that is usually followed by a period of complete or incomplete recovery. A single attack may be labelled as a clinically isolated syndrome (CIS): it does not fulfil the current diagnostic criteria for full-blown MS, but it means someone is at risk of further attacks and hence of developing MS in the future.

EDSS, Expanded Disability Status Scale score
EDSS, Expanded Disability Status Scale score

Once you have more attacks, either clinically in the form of relapse or subclinically with new lesions on magnetic resonance imaging (MRI), then you are usually diagnosed as having MS. The diagram below illustrates the typical course of repeated relapses and remissions, with worsening disability over time, that characterises so-called relapsing–remitting MS (RRMS).

After a variable period, people with relapse-onset MS may notice worsening neurological function without improvement. This is called secondary progressive MS (SPMS) and it can occur with superimposed relapses (so-called relapsing SPMS [RSPMS]) or without relapses.

EDSS, Expanded Disability Status Scale score
EDSS, Expanded Disability Status Scale score

A small number of people with MS (10–15%) will present with worsening neurological function without a prior history of relapses; this is called primary progressive MS (PPMS).

Interestingly, some people with PPMS go on to have relapses, and this is referred to as progressive relapsing MS (PRMS).

EDSS, Expanded Disability Status Scale score
EDSS, Expanded Disability Status Scale score

Rarely, someone may present with worsening neurological function, similar to PPMS, but have a prior history of just one relapse. This is referred to as single-attack progressive MS (SAP), but most MS specialists classify these patients as having SPMS. 

In summary …

  • Relapsing MS captures all people with MS who are still having relapses, i.e. within the last 2 years, and includes RRMS, RSPMS and PRMS.
  • Non-relapsing progressive MS refers to SPMS and PPMS: these latter two groups should have no history of recent relapses, i.e. in the last 2 years.

To further confuse things, non-relapsing progressive MS used to be referred to as chronic progressive MS (see below). 

Why is this important?

Different DMTs are licensed for different types of MS, and many treatment guidelines specifically state the type of MS for which a particular drug can be used.

Is MS one or more diseases?

In the past, MS was regarded as one disease: either you had MS, or you did not. The stages were referred to as early relapsing MS or chronic progressive MS, but MS was still one disease. 

When disease-modifying therapies (DMTs) were developed, MS was split into multiple sub-types. This categorisation was driven by commercial considerations, and it allowed interferon-beta to be licensed in the US under the Orphan Drug Act. The classification of orphan disease in the US requires there to be fewer than 200,000 people with that diagnosis. Dividing MS into RRMS, SPMS, PPMS and later CIS ensured that each category met this criterion. 

Since then, PRMS and radiologically isolated syndrome (RIS) have been added as potential subtypes. These classifications tend to be arbitrary and overlap, but there is no biological basis to support MS being more than one disease. 

Is your MS active or inactive?

From a treatment perspective, it is important to know if your disease is active or inactive. In active MS, there is evidence of ongoing inflammation in the brain and spinal cord. If you are having relapses, are developing new lesions on MRI or have raised neurofilament (NFL) levels in your cerebrospinal fluid (CSF) or blood, your MS is active. 

Active MS responds to anti-inflammatory treatments; inactive MS is less responsive to currently licensed DMTs. 

Criteria for ‘active’ MS accepted by many MS health professionals. CSF, cerebrospinal fluid; NFL, neurofilament light.
*Some neurologists accept 24 months, 36 months or even longer when assessing MRI activity. There is no international consensus on the gap between the baseline and new MRI scan to define active disease.

The term progressive MS refers to the stage of MS when your disability gets worse – independent of relapses, and possibly of focal inflammatory lesions. I say ‘possibly’, because our current MRI scans don’t show new or enlarging microscopic lesions but only those that are larger than ~3–4 mm. NFL measurements in either the CSF or blood have the advantage of being additive and integrating inflammatory activity. In my experience, about one in ten patients classified as ‘inactive’ based on clinical and MRI activity is found to have active MS when CSF NFL levels are analysed. Unfortunately, however, many MS neurologists, regulators and payers do not accept this latest definition of MS disease activity because tests for NFL levels are currently not widely available. 

In conclusion, knowing the type of MS you have and whether your disease is active or inactive will allow you to discuss with your MS specialist the kinds of treatment available to you. 

References

Giovannoni G, et al. Smouldering multiple sclerosis: the ‘real MS’. Ther Adv Neurol Disord 2022;15:17562864211066751.