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Improving responses in multiple sclerosis therapy

Multiple sclerosis (MS) is a chronic autoimmune disease of younger people affecting the central nervous system. Both genetic and environmental factors predispose to its development. The pathological hallmark of disease is focal demyelination that affects both the cortical grey matter and the white matter tracts in the brain and spinal cord, characterised by perivascular infiltration of activated macrophages and T-lymphocytes, and is clinically heterogeneous.

Diagnostic criteria that incorporate both clinical and MRI parameters have facilitated earlier diagnosis. In recent years several disease modifying therapies (DMTs) that target specific immune pathways have demonstrated increased efficacy in suppressing neuro-inflammation. Drugs with novel mechanisms of action, including B-lymphocyte targeting, are proving promising. Reliable biomarkers of treatment response, disease progression and MS subtypes are being developed.

As the disease progresses the majority of MS patients develop irreversible disability due to axonal loss. To date no DMT has been proven to alter the course of the progressive phase of the disease. However, recent advances in glial biology have provided valuable insights into mechanisms of neuroprotection and neuroregeneration and clinical trials of agents that promote remyelination are underway.

Development

MS is a chronic autoimmune disease characterised by demyelination of the central nervous system (CNS). It is the commonest cause of non-traumatic neurological disability in young adults. The exact aetiology is unknown, however, a combination of environmental triggers in genetically susceptible individuals are key events. Early epidemiological studies demonstrated the incidence of MS increases with distance from the equator, proposing a role for both the genetic composition of the population, but also for environmental factors such as sunlight exposure and vitamin D.

MS can develop in many forms, the most common of which is relapsing remitting MS (RRMS), characterised by discrete attacks, (relapses), followed by remissions. A relapse is characterised by development of new neurological symptoms that persist for greater than 24 hours and which are not associated with underlying infection. Relapses are usually followed by a period of complete or incomplete remission of variable duration. MS is characterised by this relapsing-remitting pattern in approximately 85 per cent of cases. About 80 per cent of relapsing remitting cases will progress to secondary progressive MS (SPMS) within two decades. SPMS is characterised by a slow disease progression as relapse associated disability accumulates; the onset of this stage is gradual and usually determined retrospectively.

Primary progressive MS (PPMS) accounts for 15-20 per cent of MS cases and is characterised by relapse-free progression at onset. There are no remissions, as the patient suffers a progressive decline in function, typically motor function. Between 15 and 20 per cent of MS patients will prove to have a benign form of the disease, remaining fully functional in all neurological systems more than 10 years after disease onset.

In terms of clinical features, MS is a heterogeneous disease, reflecting demyelination in the optic nerves, brain and spinal cord. Motor, sensory and visual disturbance are common, but non-specific. Acute bilateral internuclear ophthalmoplegia (INO), Lhermitte’s symptom, Uhthoff’s phenomenon, optic neuritis and trigeminal neuralgia should always raise the suspicion of MS, particularly when occurring in young adults.

Pathology

The pathological hallmark of MS is demyelination. The process is believed to start with activation and proliferation of autoreactive T-helper lymphocytes in the periphery. These cells then migrate across the blood brain barrier (BBB), where they recognise auto-antigens, and initiate inflammation directed against myelin. This leads to the formation of focal lesions within the CNS known as plaques; these are the visible lesions seen on MRI. The acute plaque is characterised by perivascular infiltration of activated macrophages and T-lymphocytes. Severe demyelination results in axonal loss and damage to surrounding oligodendrocytes.

Diagnosis

MS is primarily a clinical diagnosis, however, the availability of MRI has enhanced both diagnosis and surveillance of the disease. Typical MRI findings in MS patients include lesions perpendicular to the corpus callosum, known as Dawson’s fingers, in the juxtacortical white matter, cerebellum, brain stem, and spinal cord. Active plaques enhance with administration of contrast agents such as gadolinium. The McDonald criteria are a set of diagnostic criteria for MS incorporating the clinical characteristics of the disease along with MRI features. They were updated in 2010 and focus on providing evidence for dissemination of CNS lesions in both time and space. Cerebrospinal fluid (CSF) is routinely examined for intrathecal synthesis of oligoclonal bands, which are found in approximately 90 per cent of patients.

DMTs

Early treatment of RRMS with DMTs has long-term benefits in terms of disability. It is now recognised that there is a therapeutic “window of opportunity” during the first five years of the disease during which aggressive control of the inflammatory phase of the illness is necessary. DMTs aim to reduce the relapse rate and hence reduce the amount of relapse-associated disability accumulated. The last 10 years has seen a number of targeted DMTs developed, which, while more efficacious, have serious side-effect profiles.

The type 1 beta-interferons were the first immunomodulatory agents to be licensed for use in MS in 1993; there are currently four commercially available beta-interferon preparations in clinical use.

Glatiramer acetate is a synthetic peptide designed specifically to mimic the structure of myelin basic protein (MBP).

These drugs are self-administered injections given either subcutaneously or intramuscularly at a variable frequency depending on the specific agent.

All of these DMTs have comparable efficacy, reducing the relapse rate by about a third and slowing, but not preventing, the onset of disease progression. Injection-related skin reactions and flu-like side-effects seen with the interferon-beta preparations are reported, but long-term safety has been established.

The introduction of oral agents, starting in 2010, with fingolimod, has been a huge step forward in therapeutic options, primarily due to the easier administration route. Four oral agents have been approved for use in relapsing MS: Fingolimod, teriflunomide, dimethyl-fumarate and cladribine.

Fingolimod is a sphingosine-1-phosphate (S1P) receptor agonist, which binds to sphingosine receptors and acts as a functional antagonist. As such, it sequesters lymphocytes in lymph nodes resulting in a relative lymphopaenia. It also enters the CNS, where it affects neurons and supporting glia that express S1P receptors. A reduction in annualised relapse rate of 48 per cent was seen in trials comparing fingolimod to placebo. Adverse effects of the drug reflect the effects of lymphopaenia as well as the fact that S1P receptors are expressed in other tissues including the heart and the retina. The risk of opportunistic viral infections, in particular varicella zoster infection, is well described. Due to its effects on cardiac smooth muscle, fingolimod is contraindicated in those with a history of cardiac problems. Bradycardia is nearly always observed, but is rarely symptomatic. Cardiac monitoring is required for six hours after the administration of the first dose. There is a 0.5 per cent risk of macular oedema and ophthalmological assessment is required three months after initiation of therapy. There has been much recent interest in the possible neuroprotective role of fingolimod in addition to its anti-inflammatory effects. A previously unaddressed issue in MS has been the rate of brain atrophy. In three randomised, controlled, phase 3 trials, fingolimod reduced the annual rate of brain volume loss (BVL) in patients with relapsing MS (RMS) by approximately one-third relative to that in individuals receiving placebo or intramuscular interferon beta-1a.

Teriflunomide is a derivative of leflunomide, a drug used in rheumatoid arthritis. Teriflunomide selectively and reversibly inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway. This reduces the proliferation of stimulated T- and B-lymphocytes peripherally and diminishes the number of activated cells available to migrate into the CNS. An annualised reduction in relapse rate of 31 per cent versus placebo was demonstrated in clinical trials, in addition to fewer lesions on MRI. Teriflunomide can cause potentially serious hepatotoxicity and as such requires fortnightly liver function testing after its initiation. It is contraindicated in pregnancy due to teratogenicity and it is excreted in both breast milk and semen.

Dimethyl fumarate and its main active metabolite, monomethyl fumarate, have been shown to increase the levels of Nrf2, involved in the antioxidant responses. Dimethyl fumarate and monomethyl fumarate increase cellular redox potential, glutathione and adenosine triphosphate (ATP) levels and mitochondrial membrane potential. The upregulation of an Nrf2-dependent antioxidant response may explain the cytoprotective function of neurons, although the exact mechanism of action remains to be fully elucidated. Dimethyl fumarate reduces the annualised relapse rate compared to placebo, reduces disability progression and new lesions on MRI. More than 30 per cent of patients will experience flushing, as well as gastrointestinal side-effects, including abdominal pain and bloating, nausea and diarrhoea. The risk of opportunistic infection with this agent was thought to be low, however, a recent case of progressive multifocal leukoencephalopathy (PML) has been described.

Cladribine has recently been approved for treatment of active RRMS. Cladribine is an oral, synthetic deoxyadenosine analog prodrug, which preferentially depletes lymphocytes. The dosing regimen of cladribine tablets involves very short treatment periods relative to the length of clinical effect (eight to 10 days annually). Clinical trials demonstrated a reduction in annualised relapse rate of 56 per cent compared to placebo, reduced disability progression and significant reductions in enhancing MRI lesions. The most commonly reported adverse event is mild-to-moderate lymphopaenia, reflecting the mode of action of cladribine.

Natalizumab is a humanised monoclonal antibody that selectively targets the α4-subunit of VLA4 that is expressed on the surface of lymphocytes and monocytes. Binding of natalizumab prevents systemic lymphocytes crossing the blood brain barrier. When two natalizumab-treated patients developed PML in 2004, the drug was temporarily withdrawn from the market. It was re-introduced in 2006 and continues to be used with risk management guidelines for the development of PML. It is now known that PML is more likely to occur in patients who have positive anti-JC antibodies in the serum and in those who have had prior exposure to immunosuppressing drugs.

Alemtuzumab is a humanised monoclonal antibody directed against CD52, which is present on the surface of lymphocytes and monocytes. It causes a profound lymphopaenia with B-lymphocytes recovering to the lower limit of normal within six months but T-lymphocytes recovery to the lower limit of normal (LLN) can be up to one year after a single dose. Alemtuzumab was the first MS DMT to be trialled compared to an active comparator (Rebif 44) rather than a placebo. Somewhat surprisingly, serious infections are uncommon and PML has not been described to date. Mild viral infections including herpes virus infections are relatively common and antivirals such as acyclovir are recommended for one month after therapy. Secondary autoimmune conditions commonly occur, often several years after the standard dose of the drug has been administered. The commonest of these is autoimmune thyroid disease and idiopathic thrombocytopaenic purpura.

Recent developments

Genome-wide association studies have aimed to identify susceptibility loci for MS, both to assist with diagnostics and therapeutics. Studies from the International MS Genetics Consortium (IMSGC) have identified 110 candidate susceptibility loci, predominantly immune-associated genes based on an input of over 30,000 individuals. Interestingly, HLA retains the strongest relationship to disease susceptibility. CYP27B1 was also identified through this study and is known to be involved in vitamin D metabolism, which is implicated in epidemiological studies in MS.

Traditionally, MS was commonly referred to as a ‘white matter disease’, but it is now widely accepted that lesions frequently occur in grey matter, and indeed, grey matter lesions perhaps make a significant contribution to disease burden and progression. These advances have arisen from careful neuropathological and imaging studies. Grey matter lesions are more prominent in progressive MS than RMS; and tend to be less inflammatory with reduced immune cell infiltration. Post-mortem analysis identified meningeal lymphoid follicles containing B-cells associated with more extensive grey matter demyelination and atrophy. Such follicles were reported to occur in >40 per cent of SPMS cases studied. Much remains to be understood about grey matter lesions and subpial lymphoid follicles, however, given such prominence in progressive MS and the complete lack of DMTs for progressive disease, this will likely continue to be a topical area of active research.

Neuroprotection and neuroregeneration are two areas that hold great potentiation for inhibiting disease progression. Contrary to previous dogma, the CNS has profound regenerative capacity, particularly in the case of regenerating myelin (remyelination). A pool of oligodendrocyte progenitor cells (OPC) persists in the CNS throughout life even into old age. The most advanced therapeutic candidate in terms of clinical trial is anti-LINGO-1, a monoclonal antibody that binds the protein LINGO-1 – an inhibitor of oligodendrocyte differentiation. Anti-LINGO-1 is currently in phase 2 trials for relapsing and progressive MS.

Developments over the last 10 years have led to measureable improvements in quality-of-life for patients with MS. With ongoing research and product development, the future is brighter for MS patients than ever before. Treatment options are expanding, trials are underway for regenerative therapies and we have a greater understanding of the interplay between genetics and environment than ever before.

Suggested reading

Brownlee W J, Hardy T A, Fazekas F, Miller D H. ‘Diagnosis of multiple sclerosis: Progress and challenges’. Lancet. 2017 April 1;389(10076):1336-1346.

Yong H, Chartier G, Quandt J. ‘Modulating inflammation and neuroprotection in multiple sclerosis’. J Neurosci Res. 2017, June 5.

Bove R M, Green A J. ‘Remyelinating Pharmacotherapies in Multiple Sclerosis’. Neurotherapeutics. 2017, September 25.

McCarthy C, Thorpe J. ‘Some recent advances in multiple sclerosis’. J Neurol. 2016 September; 263(9):1880-6.

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