Tag Archives: eligibility

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.