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Several therapies for multiple sclerosis (MS) exist, although there is no known cure. Multiple sclerosis is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS).

The most common initial course of the disease is the relapsing-remitting subtype, which is characterized by unpredictable attacks (relapses) followed by periods of relative remission with no new signs of disease activity. After some years, many of the people who have this subtype begin to experience neurologic decline without acute relapses. When this happens it is called secondary progressive multiple sclerosis. Other, less common, courses of the disease are the primary progressive (decline from the beginning without attacks) and the progressive-relapsing (steady neurologic decline and superimposed attacks). Different therapies are used for patients experiencing acute attacks, for patients who have the relapsing-remitting subtype, for patients who have the progressive subtypes, for patients without a diagnosis of MS who have a demyelinating event, and for managing the various consequences of MS.

The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. As with any medical treatment, medications used in the management of MS may have several adverse effects, and many possible therapies are still under investigation. At the same time different alternative treatments are pursued by many patients, despite the paucity of supporting, comparable, replicated scientific study.

This article focuses on therapies for standard MS; borderline forms of MS have particular treatments that are excluded.

Management of acute attacks

Chemical structure of methylprednisolone. Corticosteroids are used during acute multiple sclerosis relapses.

During symptomatic attacks, patients may be hospitalized. As of 2007, administration of high doses of intravenous corticosteroids, such as methylprednisolone,^[1]^[2] is the routine therapy for acute relapses. This is administered over a period of three to five days, and has a well-established efficacy in promoting a better recovery from disability.^[3]^[4]

The aim of this kind of treatment is to end the attack sooner and leave fewer lasting deficits in the patient. Although generally effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery: steroids produce a rapid improvement from disability, but this improvement only lasts up to thirty days following a clinical attack and is not evident thirty-six months after the attack. This treatment does not reduce the number of patients who subsequently develop a clinical relapse.^[5]

Potential side effects include osteoporosis^[6] and impaired memory, the latter being reversible.^[7]

Recent studies suggest that steroids administered orally are just as effective at treating MS symptoms as intravenous treatment. However, short-term treatment with high-dose intravenous corticosteroids does not seem to be attended by adverse effects, whereas gastrointestinal symptoms and psychiatric disorders are more common with oral corticosteroids.^[8]

Disease-modifying treatments

As of January 2013, seven disease-modifying treatments have been approved by regulatory agencies of different countries, including the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMEA) and the Japanese PMDA.

The approved drugs with their trademarks are interferon beta-1a (Avonex, Rebif, CinnoVex, ReciGen), interferon beta-1b (Betaseron), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri), fingolimod (Gilenya), and teriflunomide (Aubagio).^[9]^[10]

Most of these drugs are approved only for Relapsing-Remitting multiple sclerosis (RRMS).

Clinically isolated syndrome

The earliest clinical presentation of RRMS is the clinically isolated syndrome (CIS), that is, a single attack of a single symptom. During a CIS, there is a subacute attack suggestive of demyelination but the patient does not fulfill the criteria for diagnosis of multiple sclerosis.^[11] Several studies have shown that treatment with interferons and glatiramer acetate during an initial attack can decrease the risk that a patient will develop clinical definite MS.^[12] These results support the use of interferon after a first clinical demyelinating event and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.^[13]^[14]^[15]

Relapsing-remitting MS

The two approved interferons are the interferon beta-1a (with commercial formulations injected either weekly or three times a week),^[16]^[17] and the interferon beta-1b,^[18] injected every second day. Glatiramer acetate is a mixture of polypeptides injected daily which may protect important myelin proteins by substituting itself as the target of immune system attack.^[19]^[20] Mitoxantrone is an immunosuppressant also used in cancer chemotherapy whereas natalizumab is a monoclonal antibody.^[21] In 2010 fingolimod, a sphingosine-1-phosphate receptor modulator,^[22]^[23] became the first oral drug approved by the FDA,^[24] being followed in 2012 by teriflunomide,^[25] a drug that inhibits the synthesis of pyrimidine. Fingolimod and teriflunomide are taken through a daily single dose.^[26]^[25]

Another oral drug, cladribine, was approved in Russia and Australia in 2010. Its application was rejected by the FDA and EMEA in 2011 due to safety concerns in spite of the promising efficacy of the drug. This led the pharmaceutical to discontinue commercialization and withdraw all marketing applications.^[27]

Medications are modestly effective at decreasing the number of attacks in RRMS.^[28] Comparisons between interferons, glatiramer acetate and natalizumab show that the most effective is the latter, both in terms of relapse rate reduction and halting disability progression.^[29] Mitoxantrone may be the most effective of them all; however, it is generally not considered as a long-term therapy, as its use is limited by severe secondary effects.^[30]^[31] While more studies of the long-term effects of the drugs are needed,^[30]^[31]^[32] specially for the newest treatments, existing data on the effects of interferons and glatiramer acetate indicate that early-initiated long-term therapy is safe and it is related to better outcomes.^[32]

Not all the patients are responsive to all these therapies. In particular, a subset of RRMS patients with specially active MS, sometimes called "Rapidly Worsening MS" are normally non-responders to all immunomodulators and are treated with immunosuppressants, in particular, Mitoxantrone.^[33]^[34] To speak about degree of response to treatment, the concept has to be defined first.^[35] Several measures have been proposed but none is widely accepted.^[36] Nevertheless, the concept is widely used. For example, it is known that 30% of MS patients are non-responsive to Beta interferon.^[37] They can be classified in genetic, pharmacological and pathogenetic non-responders.^[37]

Even with appropriate use of medication, to varying degrees most patients with relapsing-remitting MS still suffer from some attacks and many suffer subsequent disability.

Secondary progressive MS and progressive relapsing MS

Treatment of advanced forms of MS is more difficult than relapsing-remitting MS. A wide range of medications have been used to try to slow the progression of the disease, with results that have been at best fair.

Mitoxantrone has shown positive effects in patients with a secondary progressive and progressive relapsing courses. It is moderately effective in reducing the progression of the disease and the frequency of relapses in patients in short-term follow-up.^[38] In 2007 it was the only medication approved in the USA for both secondary progressive and progressive relapsing multiple sclerosis; however, it causes dose-dependent cardiac toxicity which limits its long-term use. It is also not approved in Europe.

Natalizumab or Tysabri has shown efficacy and has been approved for secondary progressive MS with relapses.

Interferon-beta-1b (Betaseron or Betaferon) slowed progression of the disease in one clinical trial for secondary progressive MS, but not in another. However, both studies demonstrated that interferon recipients had fewer relapses and less disease activity, as assessed by magnetic resonance imaging (MRI). Therefore, interferons show promise in treating secondary progressive MS, but more data is needed to support their widespread use.^[39]

Primary progressive MS

Treatment of primary progressive multiple sclerosis (PPMS) is problematic as many patients do not respond to any available therapy, and no treatment has been approved specifically for use in this form of the disease.

Several trials have been designed specifically for PPMS, including trials with interferons and mitoxantrone, a phase III trial of glatiramer acetate, and an open-label study of riluzole.^[40] Patients with PPMS have also been included in trials of azathioprine,^[41] methotrexate,^[42] cladribine,^[43] intravenous immunoglobulin, cyclophosphamide,^[44] and studies of hematopoietic stem cell transplantation. However, no treatment in these trials has been shown to modify the course of the disease.^[45]

Side effects of treatments

Injectable medications can produce irritation or bruises at injection site. The bruise depicted was produced by a subcutaneous injection.

Both the interferons and glatiramer acetate are available only in injectable forms, and both can cause irritation at the injection site. Also over time, a visible dent at the injection site due to the local destruction of fat tissue, known as lipoatrophy, may develop.

Interferons are produced in the body during illnesses such as influenza in order to help fight the infection.^[46] They are responsible for the fever, muscle aches, fatigue, and headache common during influenza infections. Many patients report influenza-like symptoms when using interferon to fight MS. This reaction often lessens over time and can be treated with over-the-counter fever reducers/pain relievers like paracetamol (known in the U.S. as acetaminophen),^[47] ibuprofen,^[48] and naproxen.^[49] Rare, but potentially serious, liver function abnormalities have also been reported with interferons, requiring that all patients treated regularly be monitored with liver function tests to ensure safe use.^[50]^[51]^[52]^[53]^[54]^[55] Interferon therapy has also been shown to induce the production of anti-IFN neutralizing antibodies (NAb), usually in the second 6 months of treatment, in 3 to 45% of treated patients. However, the clinical consequences of the presence of antibodies are presently unclear: it has not been proved that these antibodies reduce efficacy of treatment. Therefore, any treatment decision should be based only on the clinical response to therapy.^[56]

Glatiramer acetate is generally considered to be better tolerated than the interferons, although some patients taking glatiramer experience a post-injection reaction manifested by flushing, chest tightness, heart palpitations, breathlessness, and anxiety, which usually lasts less than thirty minutes.^[57]

Mitoxantrone therapy may be associated with immunosuppressive effects and liver damage; however its most dangerous side effect is its dose-related cardiac toxicity. Careful adherence to the administration and monitoring guidelines is therefore essential; this includes obtaining an echocardiogram and a complete blood count before treatment to decide whether the therapy is suitable for the patient or the risks are too great. It is recommended that mitoxantrone be discontinued at the first signs of heart damage, infection or liver dysfunction during therapy.^[58]

In the phase III studies for both MS and Crohn's Disease, natalizumab was highly effective and well tolerated; however, three cases of progressive multifocal leukoencephalopathy (PML), a rare progressive demyelinating disease of the brain that typically causes permanent disability or death, were identified in patients; two who had received it in combination with interferons,^[59]^[60] the other a Crohn's Disease patient who had received it in combination with multiple other immuno-suppressants. As a result of a safety evaluation showing that no such cases had occurred in patients treated with natalizumab alone, it was approved as a monotherapy for MS patients.^[61] In August 2008, two further cases of PML were reported, one of which had not taken any other immunomodulatory treatment before.^[62]

Managing the effects of MS

Disease-modifying treatments only reduce the progression rate of the disease but do not stop it. As multiple sclerosis progresses, the symptoms tend to increase. The disease is associated with a variety of symptoms and functional deficits that result in a range of progressive impairments and handicap. Management of these deficits is therefore very important.

Both drug therapy and neurorehabilitation have shown to ease the burden of some symptoms, even though neither influence disease progression. For other symptoms the efficacy of treatments is still very limited.^[63]

Neurorehabilitation

Supervised physical therapy may be helpful to overcome some symptoms.

Although there are relatively few studies of rehabilitation in MS,^[64]^[65] its general effectiveness, when conducted by a team of specialists, has been clearly demonstrated in other pathologies such as stroke^[66] or head trauma.^[67] As for any patient with neurologic deficits, a multidisciplinary approach is key to limiting and overcoming disability; however there are particular difficulties in specifying a 'core team' because people with MS may need help from almost any health profession or service at some point.^[68] Neurologists are mainly involved in the diagnosis and ongoing management of multiple sclerosis, and any exacerbations. The comprehensive rehabilitation process for patients with multiple sclerosis is generally managed by physiatrists. Allied treatments such as physiotherapy,^[69]^[70] speech and language therapy^[71] or occupational therapy^[72] can also help to manage some symptoms and maintain quality of life. Treatment of neuropsychiatric symptoms such as emotional distress and clinical depression should involve mental health professionals such as therapists, psychologists, and psychiatrists,^[73] while neuropsychologists can help to evaluate and manage cognitive deficits.^[74] Multidisciplinary approaches have been shown to be effective in increasing activity levels and participation in multiple sclerosis.^[75]^[76] Due to the paucity of randomized controlled studies, there is limited evidence of the overall efficacy of individual therapy disciplines,^[77]^[77]^[78] though there is good evidence that specific approaches, such as exercise,^[79]^[80] psychology therapies, particularly cognitive behavioral approaches^[81] and energy conservation instruction^[82] are effective. More specifically psychological interventions seem useful in the treatment of depression, while evidence on effectiveness for other uses such as the treatment of cognitive impairments or vocational counseling is less strong.^[83]^[84] It is difficult to be specific about what types of rehabilitation will be most beneficial because therapies are tailored to meet the individual's specific needs ^[85]

In regards to well-being, physical therapy focused on gait training can be vital to maximizing MS patient participation via reduction of fatigue during walking and activities of daily living (ADLs).^[86] Most gait training is performed over-ground (i.e., in a gym room or outside on uneven ground), on treadmills or, less commonly, using robotic-assisted devices. Robotic-assisted body weight-supported treadmill training may be an effective therapeutic option in MS patients with severe walking impairments.^[87] In contrast, over-ground gait training may be most effective in improving gait speed in MS patients with less severe impairments.^[87] Equine-assisted therapies such as therapeutic horseback riding and hippotherapy are additional treatments that can positively influence gait,^[88] balance and quality of life in people with MS.^[89]

Historically, individuals with MS were advised against participation in physical activity due to worsening symptoms.^[90] However, under the direction of an expert, participation in physical activity can be safe and has been proven beneficial for persons with MS.^[91] Research has supported the rehabilitative role of physical activity in improving muscle power,^[92] mobility,^[92] mood,^[93] bowel health,^[94] general conditioning and quality of life.^[92] Depending on the person, activities may include resistance training,^[95] walking, swimming, yoga, tai chi, and others.^[94] Determining an appropriate and safe exercise program is challenging and must be carefully individualized to each person being sure to account for all contraindications and precautions.^[91]

An elevated core temperature, leading to increased symptom presentation has been noted during exercise, due to variations in circadian body temperature throughout the day, and due to heat exposure including warm temperatures, warm showers, sun bathing, etc. Care should be taken not to overheat a person with MS during the course of exercise. There is some evidence that cooling measures are effective in allowing a greater degree of exercise: cold showers, cold water limb immersion, applying ice packs, and drinking cold beverages. These strategies are effective when attempting to decrease core temperature post-exercise, and as a method of pre-cooling prior to physical activity or heat exposure.^[96] The interaction between an elevated core temperature and the pathological demyelination can cause a transient nerve conduction block that leads to temporarily impaired physical and cognitive function. These effects translate to reduced patient safety and performance of ADLs, however there are viable prevention strategies. Behavioral strategies to minimize heat exposure include performing outdoor physical activity when temperatures are cooler, or installing an air conditioner.

Medical treatments for symptoms

Multiple sclerosis can cause a variety of symptoms including changes in sensation (hypoesthesia), muscle weakness, abnormal muscle spasms, impaired movement, difficulties with coordination and balance, problems in speech (known as dysarthria) or swallowing (dysphagia), visual problems (nystagmus, optic neuritis, or diplopia), fatigue and acute or chronic pain syndromes, bladder and bowel difficulties, cognitive impairment, or emotional symptoms (mainly depression). The most common clinical measure of disability progression and severity of the symptoms is the Expanded Disability Status Scale or EDSS.^[97] At the same time for each symptom there are different treatment options. Treatments should therefore be individualized depending both on the patient and the physician.

Bladder: pharmacological treatments for bladder problems vary greatly depending on the origin or type of dysfunction; however, some examples of medications used are:^[98] alfuzosin for retention,^[99] anticholinergics such as trospium and flavoxate for urgency and incontinence,^[100]^[101] or desmopressin for nocturia.^[102]^[103] Non-pharmacological treatments include pelvic floor muscle training, stimulation, biofeedback, pessaries, bladder retraining, and sometimes intermittent catheterization.^[104]

Bowel: people with MS may suffer bowel problems in two ways: reduced gut mobility may follow from immobility and from the drugs used to treat various impairments; and neurological control of defecation may be directly impaired.^[68] Pain or problems with defecation can be helped with a diet change, oral laxatives or suppositories and enemas.^[105]

Cognitive and emotional: neuropsychiatric symptomatology is common in the course of the disease. Depression and anxiety appear in up to 80% of patients,^[106] and can be treated with a variety of antidepressants;^[107] selective serotonin reuptake inhibitors (SSRIs) are the most frequently employed.^[108] Other neuropsychiatric symptoms are euphoria and disinhibition. This dyad was called "euphoria sclerotica" by the first authors that described the disease during the 19th century, and affects 10% of patients.^[109]^[110] Anticholinesterase drugs such as donepezil^[111]—commonly used in Alzheimer disease—although not approved yet for multiple sclerosis, have shown efficacy in improving cognitive functions.^[112]^[113] Memantine, which is also used in Alzheimer's disease, has been reported to induce reversible neurological impairment that led to stop an ongoing clinical trial.^[114] Psychological interventions are also useful in the treatment of cognitive and emotional deficits.^[115]^[116]^[117]^[118]

Dysphagia and dysarthria: dysphagia is a difficulty with eating and swallowing which may cause choking and aspiration of food or liquid into the lungs, while dysarthria is a neurological motor speech disorder characterized by poor control over the subsystems and muscles responsible for speech ("articulation"). A speech and language therapist may give advice on specific swallowing techniques, on adapting food consistencies and dietary intake, on techniques to improve and maintain speech production and clarity, and on alternative communication approaches.^[68]^[71] In the case of advanced dysphagia, food can be supplied by a nasogastric tube, which is a tube that goes through the nose directly to the stomach; or a percutaneous endoscopic gastrostomy (PEG), which is a procedure for placing a tube into the stomach and therefore administering food directly to it. This second system, although more invasive, has better results in the long term than nasogastric intake.^[119]

Erectile dysfunction: erectile dysfunction is common in male patients with MS. There is some evidence indicating that sildenafil citrate may be a useful treatment. ^[120]

Fatigue: fatigue is very common and disabling in MS, and at the same time it has a close relationship with depressive symptomatology.^[121] When depression is reduced fatigue also tends to improve, so patients should be evaluated for depression before other therapeutic approaches are used.^[122] In a similar way, other factors such as disturbed sleep, chronic pain, poor nutrition, or even some medications can contribute to fatigue; medical professionals are therefore encouraged to identify and modify them.^[68] A few medications have been studied to treat MS-related fatigue, such as amantadine^[123]^[124] or pemoline (which is a psychostimulant also used for attention-deficit hyperactivity disorder and narcolepsy),^[125]^[126] as well as psychological interventions of energy conservation,^[127]^[128] but the effects of all of them are small. Fatigue is therefore a very difficult symptom to manage for which no drugs are recommended.^[123]

Pain: acute pain is mainly due to optic neuritis (with corticosteroids being the best treatment available), as well as trigeminal neuralgia, Lhermitte's sign, or dysesthesias.^[129] Subacute pain is usually secondary to the disease and can be a consequence of spending too long in the same position, urinary retention, and infected skin ulcers, amongst others. Treatment will depend on cause. Chronic pain is very common and harder to treat as its most common cause is dysesthesias. Acute pain due to trigeminal neuralgia is usually successfully treated with anticonvulsants such as carbamazepine^[130] or phenytoin.^[131]^[132]^[133] Both Lhermitte's sign and painful dysesthesias usually respond to treatment with carbamazepine, clonazepam,^[134] or amitriptyline.^[135]^[136] Sativex is approved for treatment of pain in MS in different countries, but due to its derivation from cannabis, it is currently not available in others, such as the USA.^[137] This medication is also being investigated for the management of other MS symptoms, such as spasticity,^[138] and has shown long-term safety and efficacy.^[139]

Spasticity: spasticity is characterized by increased stiffness and slowness in limb movement, the development of certain postures, an association with weakness of voluntary muscle power, and with involuntary and sometimes painful spasms of limbs.^[68] A physiotherapist can help to reduce spasticity and avoid the development of contractures with techniques such as passive stretching.^[140] Trials with Sativex have shown encouraging improvements of spasticicy. ^[141] There is evidence, albeit limited, of the clinical effectiveness of baclofen,^[142] dantrolene,^[143] diazepam,^[144] and tizanidine.^[145]^[146]^[147] In the most complicated cases intrathecal injections of baclofen can be used.^[148] There are also palliative measures like castings, splints or customized seatings.^[68]

Vision: different drugs as well as optic compensatory systems and prisms can be used to improve the symptoms of nystagmus or diplopia (double vision).^[149]^[150]^[151] Surgery can also be used in some cases.^[152]

Walking : dalfampridine (ampyra) is a broad-spectrum potassium channel blocker. It is approved by the FDA to treat walking difficulties in MS. It has been shown to increase walking speed, although its high cost (over 1000 dollars a month) limits its usage. ^[153]

Unfortunately, other symptoms, such as ataxia, tremor or sensory losses, do not have proven treatments.^[68]

Therapies under investigation

Scientists continue their extensive efforts to create new and better therapies for MS. There are a number of treatments under investigation that may curtail attacks or improve function. Some of these treatments involve the combination of drugs that are already in use for multiple sclerosis, such as the joint administration of mitoxantrone and glatiramer acetate (Copaxone).^[154]

However most treatments already in clinical trials involve drugs that are used in other diseases. These are the cases of alemtuzumab (Campath),^[155] daclizumab (Zenapax),^[156] inosine,^[157] or BG00012.^[158] Alemtuzumab performed better than interferon beta-1a in relapsing-remitting MS reducing disability, imaging abnormalities and frequence of relapses, at the cost of increased autoimmunity problems. These included three cases of thrombocytopenic purpura which led to the suspension of the therapy.^[159] Other drugs in clinical trials have been designed specifically for MS, such as fingolimod,^[160] laquinimod,^[161] or Neurovax.^[162]

In humans, BCG vaccine, the common, live, attenuated vaccine against tuberculosis, has substantially reduced recurrence of symptoms in multiple sclerosis patients.^[163] The frequency of new enhancing lesions as detected by Gd-enhanced MRI was reduced by more than half in 12 patients, comparing the six-month run-in phase to the six-month post BCG phase of the experiment. Persistence at subsequent MR scan was reduced from 18 to 1 lesion, and evolution to black holes was reduced from 28 to 6 lesions.^[164] The conventional explanation of such protection is that parasites (including bacteria) modulate the sensitivity of the immune system. BCG appears safe as a treatment for multiple sclerosis.^[163]^[165]

Many anecdotes are found on the Internet about the effectiveness of low dose naltrexone for MS, but no published scientific studies or case reports address its effectiveness.^[166] Finally, there are also many early-stage investigations that in the future may emerge as new treatments. Examples of these are the studies trying to understand the influence of Chlamydophila pneumoniae or vitamin D in the origin of the disease,^[167]^[168] or preliminary investigations on the use of helminthic therapy,^[169] or angioplasty and venous stents based on the theory that an incorrect blood drainage system weakens the blood–brain barrier.^[170]

An MS treatment has been developed containing an extract of sea anemone venom. The treatment inhibits T-cells - the white blood cells responsible for nerve damage in MS patients. Ten years into its development, the drug is on the cusp of undergoing clinical trials.^[171]

Alternative treatments

A recent study found that over 60% of MS patients use complementary and alternative medicine, possibly because conventional treatments lack effectiveness. Except for vitamin D, evidence is lacking for these treatments and there are no clear guidelines for their use.^[172]

The effect of diet on MS is unclear, with studies unable to show whether diet contributes to MS or can alter its course. Ecologic studies have found a link between high consumptions of polyunsaturated fats and low MS prevalence. The most promising evidence comes from daily supplementation with vitamin D. Evidence is lacking for several other widely promoted non-herbal supplements, including vitamin B12, alpha-lipoic acid, luteolin, and evening primrose oil.^[172] Many diets have been proposed for treating the symptoms of the disease. Patients have reported a decrease in symptoms after long-term application of changes in diet; however, no controlled trials have been able to prove their efficacy.^[173] Even if these diets are genuinely beneficial for people with MS, it is not known whether this is due to any special traits for MS, as opposed to their known benefits for whole body health.^[172] Two examples of such diets are the low saturated fat Swank Multiple Sclerosis Diet.^[174]^[175]

Herbal medicine is another source of alternative treatments. Many patients use medical marijuana to help alleviate symptoms; however, the results of experimental studies are scarce and further clinical trials are required.^[176]^[177] Derivatives from the herb common rue (Ruta graveolens); which contain compounds that block K_v1.3 channels in T cells; have also been suggested to ameliorate MS symptoms.^[178]^[179] K_v1.3 channel-blockers are in development for the treatment of the disease.^[180]^[181]

Bee venom therapy has been promoted as a possible treatment for MS, as it is thought to be an anti-inflammatory and inflammation is a component of MS. Research results have been variable and its benefit has not been demonstrated. Its greatest safety issue is the risk of anaphylactic shock, as about 15% of the population is allergic to bee stings.^[172]

Hyperbaric oxygenation has been the subject of several small studies with heterogeneous results which, overall, do not support its use.^[182]

Relaxation disciplines such as yoga, and general exercise, seem to mitigate fatigue and improve quality of life.^[183] Some studies also show benefits on physical variables, such as balance and strength or cardiovascular and respiratory function, but more investigation is needed as the studies are usually of low quality.^[184]

Notes and references

^ Methylprednisolone Oral. US National Library of Medicine (Medline) (2003-04-01). Retrieved on 2007-09-01.
^ Methylprednisolone Sodium Succinate Injection. US National Library of Medicine (Medline) (2003-04-01). Retrieved on 2007-09-01.
^ Sellebjerg F, Barnes D, Filippini G; et al. (2005). "EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses". Eur. J. Neurol. 12 (12): 939–46. doi:10.1111/j.1468-1331.2005.01352.x. PMID 16324087. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Goodin DS, Frohman EM, Garmany GP; et al. (2002). "Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines". Neurology. 58 (2): 169–78. PMID 11805241. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Brusaferri F, Candelise L (2000). "Steroids for multiple sclerosis and optic neuritis: a meta-analysis of randomized controlled clinical trials". J. Neurol. 247 (6): 435–42. doi:10.1007/s004150070172. PMID 10929272.
^ Dovio A, Perazzolo L, Osella G; et al. (2004). "Immediate fall of bone formation and transient increase of bone resorption in the course of high-dose, short-term glucocorticoid therapy in young patients with multiple sclerosis". J. Clin. Endocrinol. Metab. 89 (10): 4923–8. doi:10.1210/jc.2004-0164. PMID 15472186. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Uttner I, Müller S, Zinser C; et al. (2005). "Reversible impaired memory induced by pulsed methylprednisolone in patients with MS". Neurology. 64 (11): 1971–3. doi:10.1212/01.WNL.0000163804.94163.91. PMID 15955958. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Filippini G, Brusaferri F, Sibley WA; et al. (2000). Filippini, Graziella (ed.). "Corticosteroids or ACTH for acute exacerbations in multiple sclerosis". Cochrane database of systematic reviews (Online) (4): CD001331. doi:10.1002/14651858.CD001331. PMID 11034713. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Aubagio (teriflunomide), a once-daily tablet for adults with relapsing forms of MS (multiple sclerosis), has been approved by the US Food and Drug Administration (FDA) [1]
^ "FDA approves new multiple sclerosis treatment Aubagio" (Press release). US FDA. Retrieved 2012-09-14.
^ Miller D, Barkhof F, Montalban X, Thompson A, Filippi M (2005). "Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis". Lancet neurology. 4 (5): 281–8. doi:10.1016/S1474-4422(05)70071-5. PMID 15847841.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1517/14656561003677390, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1517/14656561003677390 instead.
^ Jacobs LD, Beck RW, Simon JH; et al. (2000). "Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group". N Engl J Med. 343 (13): 898–904. doi:10.1056/NEJM200009283431301. PMID 11006365. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Comi G, Filippi M, Barkhof F; et al. (2001). "Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study". Lancet. 357 (9268): 1576–82. doi:10.1016/S0140-6736(00)04725-5. PMID 11377645. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Kappos L, Freedman MS, Polman CH; et al. (2007). "Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study". Lancet. 370 (9585): 389–97. doi:10.1016/S0140-6736(07)61194-5. PMID 17679016. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Interferon beta-1a Intramuscular Injection. US National Library of Medicine (Medline) (2006-04-01). Retrieved on 2007-09-02.
^ Interferon beta-1a Subcutaneous Injection. US National Library of Medicine (Medline) (2004-04-01). Retrieved on 2007-09-02.
^ Interferon Beta-1b Injection. US National Library of Medicine (Medline) (2005-07-01). Retrieved on 2007-09-02
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@@ Line 19: / Line 19: @@
 == Disease-modifying treatments ==
-As of September 2012, seven disease-modifying treatments have been approved by regulatory agencies of different countries, including the [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA), the [[European Medicines Agency]] (EMEA) and the Japanese [[Ministry of Health, Labour and Welfare (Japan)|PMDA]].
+As of January 2013, seven disease-modifying treatments have been approved by regulatory agencies of different countries, including the [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA), the [[European Medicines Agency]] (EMEA) and the Japanese [[Ministry of Health, Labour and Welfare (Japan)|PMDA]].
-The approved drugs with their trademarks are [[interferon beta-1a]] (Avonex, Rebif, CinnoVex, ReciGen), [[interferon beta-1b]] (Betaseron), [[glatiramer acetate]] (Copaxone), [[mitoxantrone]] (Novantrone), [[natalizumab]] (Tysabri),  [[fingolimod]] (Gilenya), and
+The approved drugs with their trademarks are [[interferon beta-1a]] (Avonex, Rebif, CinnoVex, ReciGen), [[interferon beta-1b]] (Betaseron), [[glatiramer acetate]] (Copaxone), [[mitoxantrone]] (Novantrone), [[natalizumab]] (Tysabri),  [[fingolimod]] (Gilenya), and [[teriflunomide]] (Aubagio).<ref>Aubagio (teriflunomide), a once-daily tablet for adults with relapsing forms of MS (multiple sclerosis), has been approved by the US Food and Drug Administration (FDA) [http://www.medicalnewstoday.com/articles/250293.php]</ref><ref>{{cite press release |url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm319277.htm |title=FDA approves new multiple sclerosis treatment Aubagio |publisher=US FDA |accessdate=2012-09-14}}</ref>
-[[Teriflunomide]] (Aubagio).<ref>Aubagio (teriflunomide), a once-daily tablet for adults with relapsing forms of MS (multiple sclerosis), has been approved by the US Food and Drug Administration (FDA) [http://www.medicalnewstoday.com/articles/250293.php]</ref><ref>{{cite press release |url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm319277.htm |title=FDA approves new multiple sclerosis treatment Aubagio |publisher=US FDA |accessdate=2012-09-14}}</ref>
-Most of these drugs are approved only for the Relapsing-Remitting course.
+Most of these drugs are approved only for Relapsing-Remitting multiple sclerosis (RRMS).
 === Clinically isolated syndrome ===
-The earliest clinical presentation of relapsing-remitting MS (RRMS) is the clinically isolated syndrome (CIS), that is, a single attack of a single symptom. During a CIS, there is a subacute attack suggestive of [[demyelination]] but the patient does not fulfill the [[McDonald criteria|criteria]] for diagnosis of multiple sclerosis.<ref name="pmid15847841">{{cite journal |author=Miller D, Barkhof F, Montalban X, Thompson A, Filippi M |title=Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis |journal=Lancet neurology |volume=4 |issue=5 |pages=281–8 |year=2005 |pmid=15847841 |doi=10.1016/S1474-4422(05)70071-5}}</ref> Several studies have shown that treatment with [[interferon]]s and glatiramer acetate during an initial attack can decrease the risk that a patient will develop clinical definite MS.<ref>{{cite doi|10.1517/14656561003677390}}</ref> These results support the use of interferon after a first clinical demyelinating event and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.<ref>{{cite journal |author=Jacobs LD, Beck RW, Simon JH, ''et al.'' |title=Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group |journal=[[New England Journal of Medicine|N Engl J Med]] |volume=343 |issue=13 |pages=898–904 |year=2000 |pmid=11006365 |doi=10.1056/NEJM200009283431301}}</ref><ref>{{cite journal |author=Comi G, Filippi M, Barkhof F, ''et al.'' |title=Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study |journal=[[Lancet (journal)|Lancet]] |volume=357 |issue=9268 |pages=1576–82 |year=2001 |pmid=11377645 |doi=10.1016/S0140-6736(00)04725-5}}</ref><ref name="pmid17679016">{{cite journal |author=Kappos L, Freedman MS, Polman CH, ''et al.'' |title=Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study |journal=Lancet |volume=370 |issue=9585 |pages=389–97 |year=2007 |pmid=17679016 |doi=10.1016/S0140-6736(07)61194-5}}</ref>
+The earliest clinical presentation of RRMS is the clinically isolated syndrome (CIS), that is, a single attack of a single symptom. During a CIS, there is a subacute attack suggestive of [[demyelination]] but the patient does not fulfill the [[McDonald criteria|criteria]] for diagnosis of multiple sclerosis.<ref name="pmid15847841">{{cite journal |author=Miller D, Barkhof F, Montalban X, Thompson A, Filippi M |title=Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis |journal=Lancet neurology |volume=4 |issue=5 |pages=281–8 |year=2005 |pmid=15847841 |doi=10.1016/S1474-4422(05)70071-5}}</ref> Several studies have shown that treatment with [[interferon]]s and glatiramer acetate during an initial attack can decrease the risk that a patient will develop clinical definite MS.<ref>{{cite doi|10.1517/14656561003677390}}</ref> These results support the use of interferon after a first clinical demyelinating event and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.<ref>{{cite journal |author=Jacobs LD, Beck RW, Simon JH, ''et al.'' |title=Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group |journal=[[New England Journal of Medicine|N Engl J Med]] |volume=343 |issue=13 |pages=898–904 |year=2000 |pmid=11006365 |doi=10.1056/NEJM200009283431301}}</ref><ref>{{cite journal |author=Comi G, Filippi M, Barkhof F, ''et al.'' |title=Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study |journal=[[Lancet (journal)|Lancet]] |volume=357 |issue=9268 |pages=1576–82 |year=2001 |pmid=11377645 |doi=10.1016/S0140-6736(00)04725-5}}</ref><ref name="pmid17679016">{{cite journal |author=Kappos L, Freedman MS, Polman CH, ''et al.'' |title=Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study |journal=Lancet |volume=370 |issue=9585 |pages=389–97 |year=2007 |pmid=17679016 |doi=10.1016/S0140-6736(07)61194-5}}</ref>
 === Relapsing-remitting MS ===
 [[File:Injection 23.JPG|thumb|Disease-modifying treatments are expensive and most require frequent (up-to-daily) injections, under the skin or into the muscle. Newer treatments feature intravenous (IV) infusions (shown above) at 1 to 3-month intervals.]]
-The two approved interferons are the interferon beta-1a (with commercial formulations injected either weekly or three times a week),<ref name="interferon beta-1a intramuscular">[http://www.nlm.nih.gov/medlineplus/druginfo/meds/a693040.html Interferon beta-1a Intramuscular Injection.] US National Library of Medicine (Medline) (2006-04-01). Retrieved on 2007-09-02.</ref><ref name="interferon beta-1a subcutaneous">[http://www.nlm.nih.gov/medlineplus/druginfo/meds/a604005.html Interferon beta-1a Subcutaneous Injection.] US National Library of Medicine (Medline) (2004-04-01). Retrieved on 2007-09-02.</ref> and the interferon beta-1b,<ref name="interferon beta-1b">[http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601151.html Interferon Beta-1b Injection.] US National Library of Medicine (Medline) (2005-07-01). Retrieved on 2007-09-02</ref> injected every second day.
+The two approved interferons are the interferon beta-1a (with commercial formulations injected either weekly or three times a week),<ref name="interferon beta-1a intramuscular">[http://www.nlm.nih.gov/medlineplus/druginfo/meds/a693040.html Interferon beta-1a Intramuscular Injection.] US National Library of Medicine (Medline) (2006-04-01). Retrieved on 2007-09-02.</ref><ref name="interferon beta-1a subcutaneous">[http://www.nlm.nih.gov/medlineplus/druginfo/meds/a604005.html Interferon beta-1a Subcutaneous Injection.] US National Library of Medicine (Medline) (2004-04-01). Retrieved on 2007-09-02.</ref> and the interferon beta-1b,<ref name="interferon beta-1b">[http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601151.html Interferon Beta-1b Injection.] US National Library of Medicine (Medline) (2005-07-01). Retrieved on 2007-09-02</ref> injected every second day. Glatiramer acetate  is a mixture of [[peptide|polypeptides]] injected daily which may protect important [[myelin]] [[protein]]s by substituting itself as the target of [[Autoimmunity|immune system attack]].<ref name="glatiramer">[http://www.nlm.nih.gov/medlineplus/druginfo/meds/a603016.html Glatiramer injection.] US National Library of Medicine (Medline) (2003-07-01). Retrieved on 2007-09-02.</ref><ref name="pmid17531858">{{cite journal |author=Ziemssen T, Schrempf W |title=Glatiramer acetate: mechanisms of action in multiple sclerosis |journal=Int. Rev. Neurobiol. |volume=79 |issue= |pages=537–70 |year=2007 |pmid=17531858 |doi=10.1016/S0074-7742(07)79024-4 |series=International Review of Neurobiology |isbn=978-0-12-373736-6}}</ref> Mitoxantrone is an [[immunosuppressant]] also used in [[chemotherapy|cancer chemotherapy]] whereas natalizumab is a monoclonal antibody.<ref name="natalizumab">[http://www.nlm.nih.gov/medlineplus/druginfo/meds/a605006.html Natalizumab Injection.] US National Library of Medicine (Medline) (2006-10-01). Retrieved on 2007-09-02.</ref> In 2010 fingolimod, a sphingosine-1-phosphate receptor modulator,<ref>[http://www.clinicaltrials.gov/ct/show/NCT00340834 Information on the phase III trial for fingolimod]</ref><ref>{{doi-inline|10.1056/NEJMoa0907839|Cohen J, et al., NEJM 2010}}</ref>  became the first oral drug approved by the FDA,<ref>{{cite press release |url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm226755.htm|title=FDA approves first oral drug to reduce MS relapses  |publisher=US FDA |date=2010-09-22|accessdate=2013-01-21}}</ref> being followed in 2012 by teriflunomide,<ref name=Aubagio>{{cite press release |url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm319277.htm |title=FDA approves new multiple sclerosis treatment Aubagio |publisher=US FDA|date=2012-09-12 | accessdate=2013-01-21}}</ref> a drug that inhibits the synthesis of [[pyrimidine]]. Fingolimod and teriflunomide are taken through a daily single dose.<ref>{{cite book|title=Gylenya medication guide|year=2012|publisher=Novartis Pharmaceuticals Corporation|pages=17|url=http://www.pharma.us.novartis.com/cs/www.pharma.us.novartis.com/product/pi/pdf/gilenya.pdf|accessdate=2013-21-01|page=2|format=pdf|month=May}}</ref><ref name=Aubagio/>
-The other approved drugs are glatiramer acetate,<ref name="glatiramer">[http://www.nlm.nih.gov/medlineplus/druginfo/meds/a603016.html Glatiramer injection.] US National Library of Medicine (Medline) (2003-07-01). Retrieved on 2007-09-02.</ref> injected daily,<ref name="pmid17531858">{{cite journal |author=Ziemssen T, Schrempf W |title=Glatiramer acetate: mechanisms of action in multiple sclerosis |journal=Int. Rev. Neurobiol. |volume=79 |issue= |pages=537–70 |year=2007 |pmid=17531858 |doi=10.1016/S0074-7742(07)79024-4 |series=International Review of Neurobiology |isbn=978-0-12-373736-6}}</ref> which is a mixture of [[peptide|polypeptides]] which may protect important [[myelin]] [[protein]]s by substituting itself as the target of [[Autoimmunity|immune system attack]]. mitoxantrone is an [[immunosuppressant]] also used in [[chemotherapy|cancer chemotherapy]]. Natalizumab is a monoclonal antibody,<ref name="natalizumab">[http://www.nlm.nih.gov/medlineplus/druginfo/meds/a605006.html Natalizumab Injection.] US National Library of Medicine (Medline) (2006-10-01). Retrieved on 2007-09-02.</ref> fingolimod which is a sphingosine-1-phosphate receptor modulator,<ref>{{doi-inline|10.1056/NEJMoa0907839|Cohen J, et al., NEJM 2010}}</ref><ref>[http://www.clinicaltrials.gov/ct/show/NCT00340834 Information on the phase III trial for fingolimod]</ref> and finally teriflunomide, an inhibitor of [[pyrimidine]] synthesis.
-All seven approved medications differ in their efficacy rate and studies of their long-term effects are still lacking.<ref name="pmid17627671">{{cite journal |author=Ruggieri M, Avolio C, Livrea P, Trojano M |title=Glatiramer acetate in multiple sclerosis: a review |journal=CNS Drug Rev |volume=13 |issue=2 |pages=178–91 |year=2007 |pmid=17627671 |doi=10.1111/j.1527-3458.2007.00010.x}}</ref><ref name="pmid14974077">{{cite journal |author=Munari L, Lovati R, Boiko A |title=Therapy with glatiramer acetate for multiple sclerosis |journal=Cochrane Database Syst Rev |volume= |issue=1 |pages=CD004678 |year=2004 |pmid=14974077 |doi=10.1002/14651858.CD004678 |editor1-last=Munari |editor1-first=Luca M.}}</ref><ref name="pmid11687131">{{cite journal |author=Rice GP, Incorvaia B, Munari L, ''et al.'' |title=Interferon in relapsing-remitting multiple sclerosis |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD002002 |year=2001 |pmid=11687131 |doi=10.1002/14651858.CD002002 |editor1-last=Filippini |editor1-first=Graziella}}</ref><ref name="pmid16235298">{{cite journal |author=Martinelli Boneschi F, Rovaris M, Capra R, Comi G |title=Mitoxantrone for multiple sclerosis |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD002127 |year=2005 |pmid=16235298 |doi=10.1002/14651858.CD002127.pub2 |editor1-last=Martinelli Boneschi |editor1-first=Filippo}}</ref>
 Another oral drug, [[cladribine]], was approved in Russia and Australia in 2010. Its application was rejected by the FDA and EMEA in 2011 due to safety concerns in spite of the promising efficacy of the drug. This led the pharmaceutical to discontinue commercialization and withdraw all marketing applications.<ref>{{cite journal|last=Comi|first=G|coauthors=Hartung, HP; Kurukulasuriya, NC; Greenberg, SJ; Scaramozza, M|title=Cladribine tablets for the treatment of relapsing-remitting multiple sclerosis.|journal=Expert opinion on pharmacotherapy|date=2013 Jan|volume=14|issue=1|pages=123-36|pmid=23256518}}</ref>
-The percentage of non-responsive patients to each medication also varies, being around 30% with interferons.<ref name="pmid16281922">{{cite journal |author=Fernández O, Fernández V, Mayorga C, ''et al.'' |title=HLA class II and response to interferon-beta in multiple sclerosis |journal=Acta Neurol. Scand. |volume=112 |issue=6 |pages=391–4 |year=2005 |pmid=16281922 |doi=10.1111/j.1600-0404.2005.00415.x}}</ref> Comparisons between immunomodulators (all but mitoxantrone) show that the most effective is natalizumab in terms of relapse rate reduction.<ref name="pmid17350652">{{cite journal |author=Johnson KP |title=Control of multiple sclerosis relapses with immunomodulating agents |journal=J. Neurol. Sci. |volume=256 Suppl 1 |issue= |pages=S23–8 |year=2007 |pmid=17350652 |doi=10.1016/j.jns.2007.01.060}}</ref> Mitoxantrone is probably the most effective of them all in the short term;<ref>{{cite journal |author=Gonsette RE |title=Compared benefit of approved and experimental immunosuppressive therapeutic approaches in multiple sclerosis |journal=Expert opinion on pharmacotherapy |volume=8 |issue=8 |pages=1103–16 |year=2007 |pmid=17516874 |doi=10.1517/14656566.8.8.1103}}</ref> however, its use is limited by severe [[cardiotoxicity]],<ref name="pmid16503747">{{cite journal |author=Murray TJ |title=The cardiac effects of mitoxantrone: do the benefits in multiple sclerosis outweigh the risks? |journal=Expert opinion on drug safety |volume=5 |issue=2 |pages=265–74 |year=2006 |pmid=16503747 |doi=10.1517/14740338.5.2.265}}</ref> and it is not considered as a long-term therapy. This is the reason why it is mainly used to treat patients who have advanced relapsing-remitting or secondary progressive multiple sclerosis.
+Medications are modestly effective at decreasing the number of attacks in RRMS.<ref>{{cite journal|last=He|first=D|coauthors=Xu, Z; Dong, S; Zhang, H; Zhou, H; Wang, L; Zhang, S|title=Teriflunomide for multiple sclerosis.|journal=Cochrane database of systematic reviews (Online)|date=2012 Dec 12|volume=12|pages=CD009882|pmid=23235682}}</ref> Comparisons between interferons, glatiramer acetate and natalizumab show that the most effective is the latter, both in terms of relapse rate reduction and halting disability progression.<ref name="pmid17350652">{{cite journal |author=Johnson KP |title=Control of multiple sclerosis relapses with immunomodulating agents |journal=J. Neurol. Sci. |volume=256 |issue=Suppl 1 |pages=S23–8 |year=2007 |pmid=17350652 |doi=10.1016/j.jns.2007.01.060}}</ref> Mitoxantrone may be the most effective of them all; however, it is generally not considered as a long-term therapy, as its use is limited by severe secondary effects.<ref name="pmid18970977"/><ref name="pmid19882365">{{cite journal |author=Comi G |title=Treatment of multiple sclerosis: role of natalizumab |journal=Neurol. Sci. |volume=Suppl 2 |issue= S2|pages=S155–8 |series=30 |year=2009 |month=October |pmid=19882365 |doi=10.1007/s10072-009-0147-2 }}</ref> While more studies of the long-term effects of the drugs are needed,<ref name="pmid18970977"/><ref name="pmid19882365"/><ref name="pmid21205679"/> specially for the newest treatments, existing data on the effects of interferons and glatiramer acetate indicate that early-initiated long-term therapy is safe and it is related to better outcomes.<ref name="pmid21205679">{{cite journal|last=Freedman|first=M. S.|title=Long-term follow-up of clinical trials of multiple sclerosis therapies|journal=Neurology|date=27 December 2010|volume=76|issue=1, Supplement 1|pages=S26–S34|doi=10.1212/WNL.0b013e318205051d|pmid=21205679}}</ref>
 Not all the patients are responsive to all these therapies. In particular, a subset of RRMS patients with specially active MS, sometimes called "Rapidly Worsening MS" are normally non-responders to all immunomodulators and are treated with immunosuppressants, in particular, Mitoxantrone.<ref>{{cite journal |author=Buttinelli C, Clemenzi A, Borriello G, Denaro F, Pozzilli C, Fieschi C. |title=Mitoxantrone treatment in multiple sclerosis: a 5-year clinical and MRI follow-up |journal= European Journal of Neurology|volume= 14|issue= 11|pages= 1281–7|year= 2007|pmid=17956449 |doi=10.1111/j.1468-1331.2007.01969.x}}</ref><ref>{{cite journal |author=Boster A, Edan G, Frohman E, Javed A, Stuve O, Tselis A, Weiner H, Weinstock-Guttman B, Khan O |title=Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician |journal= Lancet neurology|volume= 7|issue= 2|pages= 173–83|year=2008 |pmid=18207115 |doi=10.1016/S1474-4422(08)70020-6}}</ref> To speak about degree of response to treatment, the concept has to be defined first.<ref name="pmid18690493">{{cite journal