Multiple Sclerosis Is A Chronic Inflammatory Disease

Published Date: 02 Nov 2017

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), where the body’s immune system attacks the white matter within the brain or spinal cord.1 The disease process induces inflammation in the CNS which may subsequently lead to demyelination, axonal damage and progressive neurological deterioration.1,2 The cause of MS remains elusive, but environment, viral and genetic factors are thought to carry a role.3

In the CNS, the nerve fibers are surrounded by a protective sheath of protein- and lipid-rich substance known as myelin.4 Myelin insulates the nerves and aids in the conduction of nerve impulses between the brain and the rest of the body.4 In MS, the removal or destruction of the insulating myelin disrupts the transmission of electrical messages along the nerves and impede various body functions controlled by the CNS such as muscle movement, sensation and thinking.3 Repeated events of inflammation and demyelination causes the buildup of scar tissues (sclerosis) along the nerve fibers, which can permanently destroy the axons.5 Axonal damage may consequently elicit the development of neurological impairment.5

The clinical course of MS is categorized into 4 different forms.1 About 80% of patients are diagnosed with relapsing remitting MS (RRMS) at their onset.1 RRMS is characterized by sudden or recurrent episodes of relapses, followed by periods of complete or partial remissions.6 Many patients with prior RRMS eventually enter a phase where gradual progression of disability with reduced frequency of relapses happens.5 This type of MS is regarded as secondary progressive (SPMS).5 In primary progressive MS (PPMS), the disability increases progressively over time from the beginning.1 Benign MS is a rare form of MS which is characterized by few mild relapses followed by periods of remissions with no symptoms.6

Numerous features are potentially prognostic of a favourable or unfavourable course in MS and are shown in Table 1 below.7

Indicator

Favorable Prognosis

Unfavorable Prognosis

Age at onset

< 40 years

> 40 years

Gender

Female

Male

Initial symptoms

Optic neuritis or sensory symptoms

Motor or cerebellar symptoms

Attack frequency in early disease

Low

High

Course of disease

Relapsing/remitting

Progressive

Table 1 : Prognosis Indicators in Multiple Sclerosis7

(Source: Bainbridge JL, Corboy JR. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill Medical; 2008. Chapter 57, Multiple Sclerosis. Table 57-1, Prognostic indicators in multiple sclerosis; p916.)

MS may aggravate a broad array of clinical consequences that impinges adverse impacts on the quality of life of MS patients.These MS clinical consequences may limit the roles of patients in society and restrict their usual family activities.8 For example, optic neutritis resulting from MS may cause visual disturbances like eye pain, temporary blurring or loss of vision in one eye and impairment of colour perception.3 MS-caused fatigue has become a key reason for unemployment because overwhelming feeling of tiredness can be severely disabling and simultaneously affect work performance.5 Chronic fatigue and bladder problems like urinary incontinence and frequent urination can indirectly weaken patients confidence and cause depression among MS patients.1,4

Depression is common in people with MS and may significantly elevate the risk of suicide.7 A current research in the UK has displayed that the suicide rate of MS patients was 7 times higher than the general population and there was a 3.5 fold increase in mortality rate for MS patients.7,9 Moreover, MS is a lifelong neurological disorder that can lead to secondary symptoms like respiratory and recurrent urinary tract infections.7 Besides, emotional and financial burdens are often imposed on both MS patients and their carers.1

Muscle spasticity is a potentially debilitating symptom in MS patients, resulting from destruction of descending motor pathways.7 It is clinically characterized by increased muscle tone, resistance to limb movement and association with painful involuntary muscular spasm.10 Muscle spasticity can cause pain, numbness in the lower extremities and sleeplessness.11 Elevated muscle stiffness level limits the ability of MS patients to walk and carry out daily activities.8,12 Spasticity has been estimated to have impacts on 40-60% of MS patients.11 A study in Oxfordshire, UK showed that 21% of the community MS patients reported painful leg spasm especially at night.12 Furthermore, current researches have found that muscle spasticity was the main contributor to disability in MS patients.1 Spasticity progressively induces the development of muscle contractures, resulting in complete immobility.8,12 Beard et al. presented that about 50% of MS patients were independent and had the capability to walk after 15 years.11 However, MS patients may experience substantial physical disability within 20-25 years after onset if they are left untreated.1

Treatment options

Treatment for MS can be classified into 3 categories: treatment for acute relapse, treatment for modifying the disease course and treatment for the specific MS symptom.6

Treat acute relapse in MS

High-dose of corticosteroids which given in short courses is used as the standard intervention for acute relapses in MS.1 The main therapeutic goal of corticosteroid therapy is to accelerate the recovery.13 Although the mode of action of corticosteroids in MS remains unclear, it is thought that corticosteroids speed up the recovery by destroying the body immune system or decreasing the accumulation of fluid around the site of demeyelination.6 However, there is no strong evidence indicated that corticosteroids affect the overall progression of MS.7 The course should be initiated promptly after the onset of relapse in patients who have episodes of acute attacks adequate to produce distressing symptoms.1 According to The National Institute for Health and Clinical Excellence (NICE) guideline, the recommended regimen for corticosteroid is intravenous methylprednisolone 500mg–1g daily for 3-5 days and high-dose oral methylprednisolone 500mg–2g daily for 3-5 days.1

A Cochrane review compared the efficacy and safety of oral versus intravenous corticosteroids for treatment of relapses in MS.14 The review reported no significant differences between the two routes of corticosteroids administration.14 Burton et al. demonstrated that both oral and intravenous routes seemed to be equally effective in promoting recovery in MS relapses and safe to be used.14 A meta-analysis of methylprednisolone in recovery from MS exacerbation indicated that high dose of methylprednisolone exhibited a statistically significant beneficial effect in the recovery rate as compared to the placebo group.15

The common side effects associated with short-term of corticosteroids include sleep disturbances, increased appetite and a metallic taste.13 A recent intervention review showed that gastrointestinal symptoms appeared more frequently in high oral doses of methylprednisolone group (38%) than in the placebo group (8%).16 However, these adverse effects were not stated in studies with intravenous methylprednisolone.16 Corticosteroids should not be used more than 3 times per year because it may cause cataracts, acne and osteoporosis.7

Modify the disease course of MS

Beta interferon

Beta interferon (IFNβ) is the first line disease modifying drug used in the MS treatment.17 There are two forms of IFNβ: IFNβ-1a (Avonex and Rebif) and IFNβ-1b (Betaferon).18 IFNβ-1a is licensed for RRMS treatment only whereas IFNβ-1b is licensed for both RRMS and SPMS treatment.17 IFNβ works by diminishing both inflammation and immune response which attacks the myelin sheath surrounding the nerve fibers.17 Avonex is given intramuscularly once a week whereas Rebif is given subcutaneously 3 times a week. Betaferon is administered under the skin on alternate days.18 In the UK, the annual cost of the beta interferon per patient is £7,259 for Betaferon, £9,061 Avonex, £9,088 for lower dose Rebif and £12,068 for higher dose Rebif.17

A single-center observational study compared the efficacy of Avonex, Rebif and Betaferon in preventing relapse among RRMS patients.19 The study revealed that the rate of relapse for these 3 formulations was significantly decreased (64% for Avonex, 74% for Rebif and 70% for Betaferon).19 According to Cochrane review, the included trials indicated that IFNβ displayed a modest effect in reducing exacerbations and disability progression in RRMS patients after one and two years of treatment.20 La Mantia and colleagues presented that IFNβ significantly diminishes short-term relapse-associated disability but it does not inhibit the permanent physical disability progression in patients with SPMS.21

The most common adverse effects of IFNβ are flu-like constitutional symptoms such as fever, muscle aches and headache.6 Injection-site reactions like redness and swelling are frequently reported in patients on Rebif (89%) and Betaferon (78%), but infrequent in patients on Avonex (3%).19 Furthermore, injection-site necrosis is often presented in patients taking IFNβ subcutaneously.19 Less common adverse events comprise alopecia, depression and liver abnormalities.13

Glatiramer acetate

Glatiramer acetate (GA) is a disease modifying drug licensed for the treatment of RRMS.22 It is a synthetic amino acid polymer, works by dampening down the inflammation and suppressing the immune response which are responsible for the myelin damage.17 Its mechanism of action is poorly understood, but it is speculated that GA appears to hinder antigen presentation to white blood cells and stimulate antigen-specific suppressor T cells.17 It is injected 20mg daily via the subcutaneous route.18 The annual cost of GA is about £6,650 per patient.17

According to the Association of British Neurologist (ABN) guideline, GA reduces the number of relapses by approximately one third over 2 years.22 The guideline showed that GA does not slow down the disability progression in MS which is not associated with relapses.22 A Cochrane review conducted by La Mantia et al. concluded that GA did exhibit beneficial effects in reducing relapse rate in RRMS but did not show significant improvement in MS disease progression.23 A randomized trial in 2001 revealed that GA significantly reduced the relapse rate by 33% in patients with RRMS.24

GA can cause immediate post-injection reaction (IPIR) such as flushing, palpitation, chest tightness and shortness of breath.18 These symptoms can happen instantaneously after the GA injection and rapidly recovered within 30 minutes.14 A recent study demonstrated that patients taking GA (24%) had a higher chance of experiencing IPIR than placebo-treated group (7%).23 Local injection-site reactions like swelling, redness and pain are the commonly reported side effects of GA.18 Furthermore, prolonged injection of GA may cause lipoatrophy in some MS patients.23 No major toxicity or adverse events leading to patient’s death was observed in patients on GA.23

Natalizumab

Natalizumab is another disease modifying medication approved for the treatment of RRMS.6 It is particularly reserved for patients with rapidly evolving RRMS who have experienced two or more disabling relapses within one year and patients with highly active RRMS who continued experience relapses after treatment with IFNβ.18 Natalizumab is a selective adhesion molecule inhibitor that binds to the alpha-4 integrin and hinders the interaction of α4β1 integrin with vascular cell adhesion molecules on the endothelial cell surface.25 This interaction may impede the entry of leucocytes into the CNS via blood brain barrier and thereby reducing inflammation.25 It is administered as an intravenous infusion 300mg once every 4 weeks under the supervision of health care professionals.26

In AFFIRM trial, the results showed that natalizumab decreased the relapse rate by 68% within 1 year and diminished the risk of disability progression by 42% over 2 years.25 SENTINEL trial data showed that the addition of natalizumab to IFNβ-1a reduced the sustained disability progression risk by 24%.27 Richard and colleagues reported that there was a 56% reduction in the number of relapses in patients who taking IFNβ-1a together with natalizumab as compared to those who taking IFNβ-1a plus placebo.27

Natalizumab is associated with an elevated risk of progressive multifocal leukoencephalopathy (PML).26 Bloomgren et al. suggested that the risk of developing PML was highest in patients who previously had received immunosuppressant, had taken natalizumab for 25-48 months and were positive for anti-C virus antibodies.28 The European Medicines Agency reported that although the PML risk rises after two years of treatment, the advantages of natalizumab still outweigh its disadvantages for patients with highly active RRMS.29 Besides, hypersensitivity reactions like anaphylaxis and urticaria presented in 4% of patients taking natalizumab.13 Infusion-related side effects of natalizumab includes headache, nausea, vomiting and fatigue.26

Fingolimod

Fingolimod is a disease modifying therapy licensed for patients with rapidly evolving severe RRMS and with high disease activity despite treatment with IFNβ.6 It is a sphingosine-1-phosphate-receptor modulator that works by trapping lymphocytes in the lymph nodes and reducing the penetration of lymphocytes into the CNS.30 The recommended regimen for fingolimod is 500 microgram once daily in oral capsule form.26 Treatment with fingolimod should be under the supervision of a healthcare specialist.26

Data from the FREEDOMS clinical trial portrayed that 0.5mg and 1.25mg fingolimod had significantly dampened down the risk of disability deterioration in RRMS patients over 1 year by 30% and 32% respectively.30 It is also reported that there were 54% and 60% reduction in the relapse rate for after treatment with fingolimod at doses of 0.5mg and 1.25mg correspondingly.30 In TRANSFORMS trial, results showed that the number of relapses was reduced more significantly in fingolimod-treated group as compared to IFNβ-treated group.31

Fingolimod is known to induce temporary bradycardia and atrioventricular heart block at the time after the initial administration of fingolimod.26 Hence, it is not strongly recommended for people at high risk of cardiovascular events unless its advantages outweigh the potential dangers.26 Cohen et al. reported that the heart rate that developed within 1 hour after the first dose of fingolimod reduced in a dose-dependent manner.30 Other usual side effects of fingolimod include cough, headache and back pain.26

Manage MS symptom - Chronic Severe Spasticity

Baclofen

Baclofen is the first line medication for the management of chronic severe muscle spasticity resulting from MS.1 It is a gamma aminobutyric acid (GABA) agonist which works by impeding neurological transmission in the spinal cord and thereby reducing the frequency of muscle spasm and muscle stiffness level.11 Its main therapeutic actions are to relax skeletal muscle, relieve flexor and associated pain in MS.6 Baclofen is given orally 5mg 3 times daily in the form of tablet or liquid.26 The dose is increased gradually up to a maximum 100mg daily.26 It can also be administered intrathecally using a programmable pump for patients with severe chronic spasticity unresponsive to oral baclofen.13

Three randomized crossover trials evaluated the effectiveness of oral baclofen in treating spasticity indicated that baclofen showed significant reduction on both the intensity and frequency of muscle spasm.1 A recent systematic review reported that intrathecal baclofen via pump delivery exhibited beneficial clinical outcomes with both the Penn spasm score and Ashworth scale score significantly declined.1 Rizzo et al. demonstrated that patients with intrathecal baclofen reported significantly fewer painful spasms, less stiffness in legs and less muscle spasticity than patients on oral baclofen.32

45% of patients receiving baclofen have experienced adverse effects like dizziness, fatigue, drowsiness and insomnia.6 Besides, recent researches found out that intrathecal baclofen had fewer systemic side effects than the oral baclofen because lower dose of intrathecal baclofen is required and it is administered directly into cerebrospinal fluid.33 Abrupt withdrawal may exacerbate spasticity, convulsion and hyperthermia.26 Therefore, the baclofen dose should be reduced gradually over at least 1-2 weeks if discontinue to reduce the risk of getting withdrawal symptoms.26

Gabapentin

Gabapentin is one of the first line treatment options for muscle spasticity in MS.1 It is an anti-convulsant as well as anti-epileptic drug which used widely in patients with neuropathic pain and spasticity due to MS.6 Although its mode of action remains unclear, it is speculated that gabapentin works predominantly on the CNS and increases GABA levels in the brain.34,35 It is given in an oral dose of 100-300mg daily up to a maximum of 2400mg for spasticity indication.34

A placebo-controlled trial investigated the effects of gabapentin in MS showed a statistically significant drop in spasticity impairment in patients receiving gabapentin therapy compared with the placebo group.36 Solaro et al. reported that gabapentin at a dosage of up to 600mg daily produced a significant improvement in painful muscle spasm within 8 weeks of therapy in patients with MS spasticity.34

Gabapentin was reported to cause drowsiness, dizziness, fatigue, diarrhea and abdominal pain.26 Moreover, sedation usually appeared in those patients who take gabapentin to relieve their muscle spasms compared with placebo.8 It is relatively expensive and the sedation effects is dose-limiting.8 No major adverse events related to gabapentin has been portrayed in the older controlled trials.11

Tinazidine

Tinazidine is a short-acting alpha2-adrenergic agonist used in the management of MS spasticity.6 It can only be offered to the patients if the treatment with baclofen or gabapentin is ineffective or side effects are uncontrollable.1 Tinazidine acts in the CNS to minimize spasticity associated with MS by promoting presynaptic inhibition of motor neurons.7 The effective tolerated dosages of tinazidine have ranged from 2mg to a maximum of 36mg daily in oral preparation.34

In a placebo-controlled clinical study, the mean muscle tone for patients with tizanidine treatment decreased by 37% whereas the mean muscle tone for patients in placebo group reduced by only 9%.37 According to the analysis from this study, there was 60-82% improvement in muscle tone with tizanidine treatment.37 Krach presented that tinazidine had equivalent efficacy to baclofen in terms of muscle tone reduction and had a more favourable tolerability profile.37

Dry mouth, drowsiness and fatigue are the common adverse effects of tinazidine.26 Recent researches displayed that tinazidine produced more sedation as compared to baclofen.37 Besides, it may induce nausea and vomiting especially when the dose is promptly increased.11 Reversible liver enzyme elevation was observed in patients taking tinazidine.11 It is contraindicated in patients with severe hepatic impairment.17 Abrupt discontinuation of tizanidine should be avoided, as it can cause rebound hypertension and tachycardia.26

3.0 Treatment recommendation

A short course of high-dose corticosteroid should be given rapidly after the onset of relapse if the 42 years old patient with MS is experiencing acute relapses to improve the recovery.1 Corticosteroid hinders the oedema formation in the area of nerve damage and suppress the body immune system.6 Substantial evidence demonstrated that patients receiving a high dose of corticosteroid showed a significantly higher rate of recovery than the patients on placebo.15 A Cochrane review included several studies comparing oral against intravenous corticosteroid for MS relapses did not show any statistically significant difference in both pharmacological and clinical outcomes.14 Moreover, it has been reported that high-dose of oral corticosteroids had better tolerability, greater convenience, lower cost and comparable bioavailablity compared to high dose of intravenous corticosteroids.6 Therefore, a high-dose of oral methylprednisolone 500mg-2g daily for 3-5days is recommended for the patient.1

If the patient is diagnosed with RRMS, either GA or IFNβ can be recommended to slow down the disease progression instead of Natalizumab and Fingolimod.22 Natalizumab and Fingolimod only limited their use for people with rapidly evolving severe RRMS or highly active RRMS despite treatment with IFNβ.22 Natalizumab is linked to a high risk of PML whereas Fingolimod is associated with an elevated risk of cardiovascular events.26 Hence, natalizumab and fingolimod are not recommended for the patient. A multicentre trial portrayed that GA and IFNβ had similar efficacy in reducing the clinical relapse rate in RRMS patients.38 O’connor et al. reported that flu-like symptoms occurred more often in patients on IFNβ (p<0.0001) whereas injection-site reaction occurred more frequently in patients on GA (p=0.0005).39 The overall tolerability to both GA and IFNβ were comparable even though they exhibited different side effect profiles.39 However, the annual cost of GA per patient (£6,650) was lower than that for IFNβ (£7,259 for Betaferon, £9,061 for Avonex, £9,088 for low dose Rebif and £12,068 for high dose Rebif).17 Therefore, GA 20mg daily via the subcutaneous route will be the best treatment option for the patient because GA is more cost-effective than IFNβ.18

On the other hand, if the patient is diagnosed with SPMS, Betaferon which is given subcutaneously on every other day is recommended to modify the disease course because it is the only licensed IFNβ product for the treatment of SPMS.17 Analysis of trials presented that IFNβ showed a significant reduction in the risk of progression for 3 months and a significant drop in the risk of developing new relapses at 3 years.21 Although IFNβ did not inhibit the permanent physical disability progression in SPMS patients, it significantly diminished the development of short-term relapse-associated disability.21

For the management of chronic severe muscle spasticity, baclofen is recommended for the patient instead of gabapentin or tinazidine. Recent trials concluded that baclofen was better tolerated that gabapentin because gabapentin produced significant sedation.8 Besides, sedative side effect was more common in patients treated with tinazidine than patients receiving baclofen.11 The mean daily cost of tinazidine per day at its recommended dosage (£4.49) was higher than the mean daily cost of oral baclofen per day at its maximum dosage (£2.58).11 Hence, tinazidine is less favourable than baclofen in the treatment of muscle spasticiy.

Baclofen is the first line therapy for MS spasticity that can be given either orally or intrathecally.1 Results derived from the trials indicated that baclofen exhibited a statistically significant beneficial effect on reducing the number and intensity of muscle spasm.1 It has demonstrated that intrathecal baclofen was more effective than oral baclofen in minimizing muscle stiffness and spasms.32 Although intrathecal baclofen has larger potency and less systemic side effects, it is more expensive as compared to oral baclofen.13 Furthermore, it is predominantly reserved for patient with severe disabling spasticity who are no longer ambulatory as it requires the installation of programmable pump.13 Therefore, oral baclofen 5mg 3 times daily is recommended for the patient initially.26 The dose is slowly titrated according to patient’s response up to a maximum of 100mg daily.26 However, if the patient is uncontrolled by oral baclofen, intrathecal baclofen is then recommended.