WRITE A NOTE ON NEWER DISEASE MODIFYING THERAPIES IN MULTIPLE SCLEROSIS ?
A 2 INTRODUCTION
1 There are four eras in the history of disease-modifying therapies for multiple sclerosis. ( vv imp )
A ) In the first era of nihilism, before 1993, there was no effective treatment and many neurologists thought the disease to be untreatable.
B ) Then, in the second era of modest efficacy, interferon beta and glatiramer acetate were found to reduce the relapse rate and accumulation of disability in the short term, in people with relapsing-remitting multiple sclerosis.
C ) Over the next decade, we learnt that these drugs had a moderate impact on the disease and were very safe.
D ) For nearly all patients, they were preferable to the more efficacious drugs available then, such as cyclophosphamide or mitoxantrone, because of these drugs’ serious side effects.
E ) Then, in 2004, the era of complexity was introduced by the licensing of natalizumab. Clearly more effective than the drugs of the second era, the emergent adverse effect of progressive multifocal leukoencephalopathy soon tempered the early enthusiasm for the drug.
F ) Over the next 10 years, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab have become licensed in many countries for the treatment of multiple sclerosis, and it is likely that daclizumab (a nondepleting antibody against CD25) and ocrelizumab (a depleting antibody against CD20, similar in effect to rituximab) vv imp
G ) Autologous bone marrow transplantation has also been reevaluated for the treatment of multiple sclerosis.
CLASSIFICATION
1 Each drug should be considered in three domains: efficacy, safety, and treatment burden (i.e., mode of administration, intensity of monitoring, and so on)
2 There is no international consensus but the Association of British Neurologists has recently divided treatments into drugs of moderate efficacy (category 1) and drugs of high efficacy (category 2).
A ) In discussions with patients, these may be caricatured as “low risk, low gain” and “high risk, high gain”
B ) Not all have accepted this classification; some have argued that fingolimod and dimethyl fumarate ought to occupy a third category, lying somewhere between 1 and 2, given their claimed greater efficacy than interferon beta and a signal that both may increase the risk of progressive multifocal leucocencephalopathy (PML)
C ) There is a further category of treatments, which might be regarded as “very high risk” and which include more than 2 years of natalizumab for John Cunningham virus (JC) virus-positive patients and autologous bone marrow transplantation.
D ) It is likely that daclizumab will be in category 1 and ocrelizumab in category 2, if licensed.
LIST OF DRUGS ACCORDING TO INCREASED EFFICACY AND WORST SAFETY ( IN ASCENDING ORDER ) VV IMP
1 GLATIARMER AND IFN B
2 TERIFLUONOMIDE
3 DIMETHYLFUROATE AND DACARBAZINE
4 RITUXIMAB / OCRELIZUMAB AND FINGOLIMOD
5 NATALIZUMAB
6 ALEMTUZUMAB
7 MITOXANTRONE
8 AUTOLOGOUS STEM CELL TRANSFER
RISK ASSESSMENT ***
1 patients should be assessed for latent infection with human immunodeficiency virus (HIV), treponema, hepatitis B and hepatitis C, cytomegalovirus (CMV), and tuberculosis (in endemic areas) before starting treatment.
2 If patients are not immune to varicella, vaccination should be considered.
3 All female patients should have recent cervical smears and annually on the more potent immunotherapies, such as alemtuzumab, to monitor for dysplastic change.
4 vv imp A key early test should be anti-JC virus serology; where this is negative, patients may be reassured that their current risk of PML was low and natalizumab should be considered as a treatment option although this will change with treatment duration and serological status.
5 Where patients have positive anti-JC virus serology, they can be given the soundest advice on the risks of natalizumab treatment.
A ) The incidence of PML on natalizumab is now estimated at 3.72/1,000 patients (95% CI 3.4-4.06/1,000 patients) and this risk varies with serological index, prior use of immunotherapies and duration of natalizumab treatment
B ) Wherever alemtuzumab (and perhaps ocrelizumab in the future) is available, a reasonable starting position would be to offer this to JC virus-positive patients ahead of natalizumab.
6 More difficult is how to counsel patients with positive JC virus serology who are considering the other immunotherapies.
A ) There have now been case reports of PML in multiple sclerosis patients on fingolimod and dimethyl fumarate as well as people with other diseases treated using rituximab and alemtuzumab to date, teriflunomide has not been associated with PML but its parent compound, leflunomide.
WHEN TO START / WHAT DRUG TO START / APPROPRIATE TIME / PROTOCOL ***
1 Such as 1st line , 2nd line and 3rd line - The advantage of this strategy is that only patients with a very active disease are exposed to the most risky drugs. The disadvantage is that they have almost certainly accumulated disability on the way, which cannot be recovered.
2 This approach is called “induction” therapy
A ) The straightforward rationale for this is aggressive disease activity such as defined by the “rapidly evolving severe” indication for natalizumab is as follows: two disabling relapses over 1 year, with gadolinium enhancement on a magnetic resonance imaging (MRI) of the brain.
3 However, there is also a trend toward induction therapy of patients who do not have aggressive disease. The alemtuzumab trials were focused on people with early disease (within 3-10 years from onset) low disability (EDSS < 3.0) and moderate relapse rate (at least two relapses in 2 years) (Cohen et al.,[13] Coles et al.,[14] Coles et al.) The positive results of these trials, including seeing disability improvement, led to the liberal European license of “radiological or clinical evidence of active disease.”
4 Patient-related factors may suggest one treatment over another **
A ) Those with a greater tolerance of risk may opt for more potent therapies; those with a needle phobia may prefer tablets; and those contemplating pregnancy may be attracted to alemtuzumab, which allows safe conception 4 months after the last infusion, with continued suppression of multiple sclerosis disease activity throughout the pregnancy and beyond.
5 There are a few concerns when escalating from interferon beta or glatiramer to more potent agents.
A ) If there is any evidence of bone marrow suppression, such as leukopenia, most investigators will “wash out” these agents for 1 month or so.
B ) vv imp For people on fingolimod who wish to escalate to depleting therapies such as alemtuzumab, it is important to wait until the patient’s total lymphocyte count returns to normal before administering alemtuzumab.
B ) If one administers alemtuzumab earlier, when the lymphocytes remain trapped in the lymph nodes, lymphocyte depletion may be suboptimal and alemtuzumab’s efficacy may be compromised based on a single case.
C ) This usually takes 1 month but it may take longer.
D ) The most challenging switching relates to JC virus-positive patients on natalizumab who wish to move to other therapies such as alemtuzumab.
1 The tension is between starting an alternative treatment early in order to minimize the risk of disease rebound or breakthrough and starting it late in order to ensure that the patient does not have incipient PML, which will be exacerbated by the novel therapy.
6 It is important to early identify a breakthrough of disease on therapy in order to consider switching to a more potent drug (if adopting an escalation strategy) or consider a further cycle of the same drug, as in the case of alemtuzumab after the first two cycles.
7 All patients should be encouraged to report possible relapses in time for a competent assessment to distinguish these from pseudo-relapses.
8 The place of routine MRI monitoring is controversial although intuitively it would seem that the accumulation of new lesions on a scan, even if clinically silent, marks a poor prognosis.
9 Evidence suggests that one or more gadolinium-enhancing MRI lesions in the first year of interferon beta treatment predicts higher chance of more than two relapses over 5 years but does not predict a higher chance of accumulating disability at 2 years
10 MRI scans beyond the first year of treatment are less predictive.
11 The Barcelona’s group “Rio score” helpfully combines MRI and clinical markers for prognosticating although it is undermined by the fact that disability accumulation (which may mark the onset of the progressive phase) is taken as a marker of disease activity.
12 None of the newer agents is as safe as interferon beta or glatiramer acetate.
A ) An important component of this, aside from the specific requirements of individual agents, is effective communication between the physician and patient, perhaps facilitated by a multiple sclerosis nurse or other professional.
B ) For the more intensive drugs, monitoring may be more easily achieved in larger centers, with good administrative and nursing support but this inevitably leads to greater travel for patients.
C ) This has led to a debate about whether there should be a hierarchy of health care agencies providing multiple sclerosis care.
13 There are no licensed therapies to protect neurons or promote remyelination in multiple sclerosis.
14 But there is encouraging recent data to suggest that repurposed licensed therapies may be useful, for instance, amiloride and phenytoin to protect neurons and bexarotene to promote remyelination.These need to be tested more rigorously before they may be used routinely.
WHEN TO STOP OR DISCONTINUE
1 Patients with SPMS who have ongoing progression and no new brain or spinal cord MRI lesions in the prior 12 to 24 months.
2 Stable RRMS patients, aged 65 or older, with no brain or spinal cord MRI lesions in the prior 12 to 24 months.
3 Stable RRMS patients, aged 55 to 65, with no new brain or spinal cord lesions during the prior 5 years.
4 Patients who are pregnant, trying to conceive, or breastfeeding (because of safety concerns).