Tag Archives: GA

What are the attributes of the specific DMTs?

05/09/2024 Gavin Giovannoni

Multiple sclerosis (MS) treatment has evolved rapidly, with 11 classes of disease-modifying therapy (DMT) now available in the UK. I will summarise them briefly and explain how they fit within a treatment paradigm for effective and safe use.

Maintenance therapies versus immune reconstitution: what’s the difference?

There is a divide between the two main treatment philosophies: maintenance ̶ escalation versus immune reconstitution therapies (IRTs).

An IRT is given as a short course – a one-off treatment in the case of autologous haematopoietic stem cell transplantation (AHSCT) or intermittently for alemtuzumab, cladribine or mitoxantrone. IRTs are not given continuously, and additional courses are given only if inflammatory activity recurs. IRTs can induce long-term remission and, in some cases, potentially a cure.

Maintenance therapies, by comparison, are given continuously without an interruption in dosing (‘continuous’ administration may be daily, one or more times weekly, monthly or even once every few months). Although maintenance therapies can induce long-term remission, they cannot, by definition, result in a cure. The recurrence or continuation of inflammatory activity indicates a suboptimal response to treatment and typically requires a treatment switch. Ideally, this switch should be an escalation to a more effective class of DMT.

An article in our list of key questions, entitled How do I want my MS to be treated?, provides a more detailed comparison of maintenance and IRT therapies, including frequency of administration, efficacy, risks, use in pregnancy, vaccine response and potential for a cure.

The DMTs currently licensed in the UK (in August 2024) are listed in the table under the relevant category.

Disease-modifying therapies for MS licensed in the UK. *Please note, Bonspri is available in other markets but not the UK.

How effective are the different DMTs?

The measures used to assess the effectiveness of a DMT include its ability to reduce or prevent relapses, focal inflammatory activity (that is, new or enlarging lesions) on magnetic resonance imaging (MRI), and disability progression. Additional factors that can help to assess the relative efficacy of DMTs include the proportion of clinical trial subjects who experience improvement in disability and the impact of the treatment on brain volume loss.

The MS-Selfie InfoCards are an easy-to-use resource to help people with MS compare the key features of each DMT. They contain bite-sized information designed to aid treatment choices and an overview of the key aspects of each DMT.

Efficacy of the licensed DMTs for MS can be visualised as pyramid, with the moderately effective treatments at the bottom and the more effective approaches at the top. What determines the most appropriate DMT efficacy level for an individual depends on several factors, such as baseline prognostic profile, family planning requirements, local or national treatment guidelines, socioeconomic factors, consideration of any co-existing illnesses, cognitive impairment, risk aversion and lifestyle issues.

UK licensed DMTs for MS, in ascending order of efficacy.
HSCT/AHSCT, haematopoietic stem cell transplantation/autologous haematopoietic stem cell transplantation.

What is the goal of treatment? Introducing NEIDA as a target

In the past, we used no evident disease activity (NEDA) as a treatment target. ‘Disease activity’ included progression or disease worsening independent of relapse activity (termed smouldering MS). Although some of the more effective DMTs may modify this stage of the disease, many neurologists feel uncomfortable switching or stopping a DMT based simply on smouldering MS disease activity.

Relapses and ongoing focal MRI activity are associated with a worse short-term to intermediate-term prognosis. These observations have led to the increasing adoption of ‘no evident inflammatory disease activity’ (NEIDA) as a new treatment target. For more information about treatment targets, please see the article in our key questions, Do I understand the concepts of treat-2-target and NEDA?

Many healthcare professionals (HCPs) remain sceptical of using NEIDA as a treatment target, fearing that this could lead to more people with MS being on ‘riskier’ high-efficacy therapies. However, achieving long-term remission, or NEIDA, is a well-established treatment target in other autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. People with MS treated-to-target of NEIDA from the outset do better than those whose treatment is escalated following breakthrough disease (at a clinical or subclinical/MRI level)¹. I would, therefore, strongly encourage people with MS and their HCPs to adopt NEIDA as an initial treatment target.

Flipping the pyramid

The effectiveness, or relative effectiveness, of individual DMTs becomes less critical in the context of a treatment target of NEIDA. Choosing a DMT with a lower efficacy rate simply means that a greater proportion of treated people with MS will need to be switched to higher efficacy therapies over time to achieve NEIDA. We refer to the latter of these three approaches – starting with high-efficacy treatment – as flipping the pyramid. In recent trials of alemtuzumab, ocrelizumab, ofatumumab and ublituximab, people with MS randomised to 2 years of lower efficacy DMTs (interferon-beta-1a or teriflunomide) had poorer outcomes than those receiving highly active therapy from the outset. Real-world data from registries also support this; groups of people with MS with delayed access to high-efficacy DMTs did worse than those who received high-efficacy treatments early.^1,2

Horizontal versus vertical switching

If we consider the conventional step care paradigm, people with MS who switch horizontally from interferon-beta to glatiramer acetate, or vice-versa (i.e. from one moderate efficacy DMT to another moderate efficacy DMT) do less well than those who switch vertically to fingolimod, a highly effective DMT. Similarly, people with MS escalating to natalizumab, a very high-efficacy DMT, do better than those being escalated to the less effective, but still high-efficacy, DMT fingolimod.

Continuous and intermittent immunosuppression

Another useful way of classifying DMTs is whether they are immunosuppressive, that is, they reduce the activation, or effectiveness, of the immune system. Drug regulators stipulate that a drug may be classified as immunosuppressive if it (1) causes significant lymphopaenia (low lymphocyte count) or leukopenia (low white blood cell count), (2) is associated with opportunistic infections, (3) reduces the antibody and immune response to vaccines and (4) increases the risk of secondary malignancies.

The duration and intensity of immunosuppression further determine the risks. For example, short-term or intermittent immunosuppression associated with IRTs front-loads the risks, which are substantially lower once the immune system has reconstituted itself. In comparison, long-term continuous or persistent immunosuppression, which occurs with some of the maintenance DMTs, accumulates problems over time, particularly opportunistic infections and secondary malignancies. You can read more detail on this topic in the key question How immunosuppressed am I? The following table summarises the main attributes of intermittent and persistent immunosuppression.

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.²AHSCT, autologous haematopoietic stem cell transplantation; PML, progressive multifocal leukoencephalopathy.

Adverse effects, monitoring and risk reduction

The complications associated with immunosuppression vary from DMT to DMT. Each individual drug summary in the DMTs section of MS-Selfie contains detailed information about the main adverse events, key monitoring requirements, use (or contraindication) during pregnancy and breastfeeding, and response to vaccines. The MS-Selfie InfoCards provide bite-sized summaries of several practical aspects, including side effects, to enable easy comparison of any treatments you are considering; some of this information is collated below for easy reference.

Short-term versus long-term adverse effects

Each drug has been given scores from 1 to 10 based on published analyses of its short-term and long-term side effects. Short-term refers to side effects that emerge when a treatment is started and decrease in severity or disappear within days or weeks. A well-known example of short-term side effects on starting interferon-beta is flu-like symptoms that typically abate within 4 ̶ 8 weeks.

A long-term side effect persists for months or doesn’t disappear on continuing the DMT. Examples include intermittent but persistent flushing after taking dimethyl fumarate, or low B lymphocyte counts with anti-CD20 therapies that may lead to low antibody or immunoglobulin levels (hypogammaglobulinaemia).

A low score denotes few or rare side effects; a high score denotes many or frequent side effects. The score does not correlate to a percentage. More information can be found in each drug summary and the manufacturer’s Summary of Product Characteristics.

Scores for short-term and long-term side effects assigned to the individual DMTs summarised in the MS-Selfie InfoCards, based on a published network meta-analysis.³
Alem, alemtuzumab; GA, glatiramer acetate; HSCT, haematopoietic stem cell transplantation; IFN-beta; interferon-beta; Nat, natalizumab.

Monitoring and risk reduction

Numerous tests are carried out at the start of treatment, and ongoing monitoring is required for many factors, to reduce the risk from adverse events. The key question, How can I reduce my chances of adverse events on specific DMTs?, explains what needs to be done at the start of DMT administration (baseline) and during subsequent monitoring. The specifics vary from DMT to DMT; please refer to the individual summaries for details such as baseline tests, follow-up, infection prevention, cancer risk, pregnancy, breastfeeding and vaccination. It is important to remember that all licensed MS DMTs have had a thorough risk ̶ benefit assessment, and their benefits are considered to outweigh the potential risks.

Administration and other practical considerations

Routes and frequency of administration

The MS-Selfie InfoCards contain a symbol for each DMT, showing how it is administered. Some DMTs are available in more than one formulation (e.g. tablets and injection). The frequency of administration varies greatly from DMT to DMT; please consult the relevant summary in the DMTs section and discuss your preferences and priorities with your MS HCP.

The route of administration for each drug in the MS-Selfie InfoCards is clearly identified by the relevant symbol. (If a DMT is available in more than one formulation, there is a separate card for each delivery route.)

Number of clinic visits

It may be important for you to consider the frequency of clinic visits. This will depend on factors such as the delivery route of your DMT, the monitoring requirements of the drug regulators and the risk of specific side effects. The table below summarises the assessments from the MS-Selfie InfoCards. This is another factor to consider in discussions with your MS HCPs about the most appropriate DMT for you.

Conclusions

People with MS must understand the objectives of MS treatments and the different treatment strategies currently available to achieve these objectives. Although the MS therapeutic landscape is complex and hence may seem overwhelming, framing the choices using a relatively simple construct should help each individual to make informed decisions about managing their MS. MS-Selfie aims to guide you in the process of deciding on the most appropriate therapeutic strategy and specific DMT for treating your disease.

References

Rotstein D, et al. Association of No Evidence of Disease Activity with no long-term disability progression in multiple sclerosis: a systematic review and meta-analysis. Neurology 2022;99:e209̶ ̶ 20.
Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.
Samjoo IA, et al. Efficacy classification of modern therapies in multiple sclerosis. J Comp Eff Res 2021;10:495–507.

DMTsDetail

Glatiramer acetate

11/04/2023 Gavin Giovannoni

Summary

Glatiramer acetate (GA) has been an injectable workhorse of MS treatment for decades, alongside the interferon-beta preparations. It is moderately effective; only a minority of people with MS receiving GA achieve long-term NEIDA (no evident inflammatory disease activity). Its impact on preventing end-organ damage (brain volume loss) is modest.

In general, GA formulations are relatively well tolerated in the short-term, the main issues being injection site reactions, occasional flushing reactions with tightness of the chest, swelling of lymph nodes and (rarely) urticaria or hives. However, long-term use of GA leads to lipoatrophy (loss of fatty tissue under the skin). Major advantages are that GA has no monitoring requirements, and it is safe during pregnancy. Adherence has been a problem in the long term, owing to injection fatigue. Given that more effective DMTs are now available, with more favourable attributes, most people with MS now tend to choose non-injectable treatments. Despite this, there is still a role for GA in treating MS, particularly in women who are planning to start or extend their family.

Trade names

Copaxone, Brabio.

Mode of action

Immunomodulatory. GA is often referred to as the DMT with nine or more modes of action, because so many different effects on the immune system have been linked to it. Importantly, none of these immunological changes is associated with immunosuppression.

Efficacy

Moderate.

Class

Maintenance, immunomodulatory.

Immunosuppression

No.

Dosing

GA-20 mg, prefilled syringe, 20 mg/mL subcutaneous (SC) daily.
GA-40 mg, prefilled syringe, 40 mg/mL SC three times per week.

Main adverse events

Injection site reactions are the most frequent adverse events, with redness, pain, itching, swelling and (rarely) breakdown of the skin. Following prolonged injecting, lipoatrophy and skin necrosis may occur. Occasionally patients may experience an immediate reaction post injection, with flushing, chest tightness, shortness of breath, palpitations and a rapid heart rate.

Adverse events of special interest

Swelling of lymph nodes (pseudolymphoma).
Urticaria or hives.

Neutralizing antibodies (NAbs)

No.

Pharmacovigilance monitoring requirements

Baseline: none.
Follow-up: none.

Rebaselining

A rebaseline MRI needs to be done after GA has had sufficient time to work, ideally ~7 ̶ 12 months after starting treatment. GA is the one maintenance DMT that takes quite a long time to reach maximum effectiveness evident on MRI. I recommend including Gd-enhancement as part of the MRI. The presence of Gd-enhancing lesions on the rebaseline scan is sufficient evidence at this stage to switch/escalate treatment to another DMT.

Pregnancy

No known reproductive toxicity. Generally considered to be safe in pregnancy. In case of unplanned pregnancy while receiving GA, termination of the pregnancy is unnecessary. Most neurologists recommend continuing GA treatment throughout pregnancy.

Breastfeeding

Safe, not contraindicated.

Male fertility

Safe.

Vaccination

Safe.

Summaries of Product Characteristics (SmPC)

Copaxone 20 mg, Copaxone 40 mg, Brabio 20 mg, Brabio 40 mg

Switching-2-GA

GA-20 to GA-40 switch

People with MS may decide to switch between GA preparations because of local skin reactions. GA-40 is administered only three times per week and has demonstrated better tolerability than the daily GA-20 formulation.

Lack of efficacy

I would not recommend switching between GA preparations because of lack of efficacy or perceived lack of efficacy. If you have had a suboptimal response to one GA preparation it would make sense to switch classes. In general, I tend to escalate treatment rather than switch to another moderate efficacy DMT; vertical escalation rather than horizontal switching

Other DMTs

Provided the baseline screening blood tests are fine and there are no specific contraindications, I see no reason why GA can’t be used after any of the other licensed DMTs. However, if you are switching due to a suboptimal response, I would recommend a more efficacious DMT. There is reasonable real-life data that shows switching upwards (escalation) gives a better overall response rate than switching to a similar efficacy DMT (horizontal switching). I suspect that most people with MS who switch to GA will do so for family planning reasons, because GA has one of the best safety records in pregnancy. Another reason to switch may be an adverse event on another DMT, for example persistent lymphopaenia.

Special circumstances

The presence of other specific comorbidities may make it difficult to switch from certain DMTs to GA. These could include generalised urticaria or a known allergic reaction to GA in the past.

Switching

Switching-2-glatiramer acetate

07/02/2023 Gavin Giovannoni

Possible reasons to switch

Glatiramer acetate (GA) has one of the best safety records in pregnancy.
GA is relatively well tolerated in the short term and is not immunosuppressive.
Following an adverse event on another DMT, for example persistent lymphopaenia.
GA has no monitoring requirements.

Reasons for caution

Adherence can be a problem in the long term, owing to injection fatigue.
Long-term use of GA leads to lipoatrophy (loss of fatty tissue under the skin).
Its impact on preventing end-organ damage (brain volume loss) is only modest.

GA-20 to GA-40 switch

Lack of efficacy

I would not recommend switching between GA preparations because of a lack of efficacy or perceived lack of efficacy. If you have had a suboptimal response to one GA preparation it would make sense to switch classes. In general, I tend to escalate treatment rather than switch to another moderate efficacy DMT; vertical escalation rather than horizontal switching.

Other DMTs

Provided the baseline screening bloods are fine and there are no specific contraindications, I see no reason why GA can’t be used after any of the other licensed DMTs. However, if you are switching due to a suboptimal response, I would recommend a more efficacious DMT. There is reasonable real-life data that shows switching upwards (escalation) gives a better overall response rate than switching to a similar efficacy DMT (horizontal switching). I suspect that most people with MS who switch to GA will do so for family planning reasons, because GA has one of the best safety records in pregnancy. Another reason to switch may be an adverse event on another DMT, for example a persistent lymphopaenia.

Special circumstances

The presence of other specific comorbidities may make it difficult to switch from certain DMTs to GA. These could include generalised urticaria or a known allergic reaction to GA in the past.

DMTsShort

Glatiramer acetate – short summary

07/02/2023 Gavin Giovannoni

Summary

Trade names

Copaxone, Brabio.

Mode of action

Efficacy

Moderate.

Class

Maintenance, immunomodulatory.

Immunosuppression

No.

Dosing

GA-20 mg, prefilled syringe, 20 mg/mL subcutaneous (SC) daily.
GA-40 mg, prefilled syringe, 40 mg/mL SC three times per week.

Main adverse events

Injection site reactions (redness, pain, itching, swelling and, rarely, breakdown of the skin). Following prolonged injecting, lipoatrophy and skin necrosis may occur.
Occasional post-injection reaction (flushing, chest tightness, shortness of breath, palpitations and a rapid heart rate).

Adverse events of special interest

Swelling of lymph nodes (pseudolymphoma).
Urticaria or hives.

Further details about glatiramer acetate

Switching-2-glatiramer acetate

DMTs, Treatment strategy

How immunosuppressed am I?

07/09/2022 Gavin Giovannoni

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.

The main characteristics of continuous persistent and short-term (intermittent) immunosuppression. Modified from Giovannoni, Curr Opin Neurol.¹AHSCT, 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:

ageing (immunosenescence)
carryover effects from previous DMTs
concomitant medications
comorbidities (such as diabetes and other vascular illnesses)
lifestyle factors (including smoking, obesity, diabetes and sedentary lifestyle)
disability
social determinants of health (for example, levels of deprivation and the lived environment).

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

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

DMTs, Treatment strategy

Am I eligible for an MS disease-modifying therapy?

28/06/2022 Gavin Giovannoni

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?

Inactive MS – you are not currently eligible for DMTs.
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.
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).
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

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.
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).
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).