Management of multiple sclerosis – Wikipedia, the free …

As of November 2014, nine 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, Plegridy), interferon beta-1b (Betaseron), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri), fingolimod (Gilenya), teriflunomide (Aubagio),[5][7][8]dimethyl fumarate (BG12, Tecfidera).[9][10] and alemtuzumab (Campath, Lemtrada)[11]

In 1993 interferon beta-1b was the first drug to ever be approved for MS, being soon followed by interferon beta-1a and glatiramer acetate.[12]

Interferon beta-1a is injected either weekly (intramuscular injection) or three times a week (subcutaneous injection) depending on commercial formulations,[13][14] while interferon beta-1b is injected subcutaneously every second day.[15] In 2014, a pegylated form of interferon beta-1a was introduced with the brand name Plegridy, which is available as a subcutaneous injection.[16] This peginterferon beta 1-a attaches polyethylene glycol to the interferon molecules allowing longer lasting biological effects in the body while decreasing the frequency of administration to once every two weeks.[17]Interferon beta balances the expression of pro- and anti-inflammatory agents in the brain, and reduces the number of inflammatory cells that cross the bloodbrain barrier.[18] Overall, therapy with interferon beta leads to a reduction of neuron inflammation.[18] Moreover, it is also thought to increase the production of nerve growth factor and consequently improve neuronal survival.[18]

Glatiramer acetate is a mixture of random polymers of four amino acids which is antigenically similar to the myelin basic protein, a component of the myelin sheath of nerves with which it competes for presentation to T cells . It is injected subcutaneously on a daily basis.[19][20][21]

Mitoxantrone is an immunosuppressant also used in cancer chemotherapy which was approved for MS in the year 2000;[22] whereas natalizumab is a monoclonal antibody that was initially approved in 2004.[23] Both are given by intravenous infusion at monthly intervals in the case of natalizumab and every three months in the case of mitoxantrone.[22][24][23]

In 2010 fingolimod, a sphingosine-1-phosphate receptor modulator, became the first oral drug approved by the FDA, being followed in 2012 by teriflunomide, a drug that inhibits the synthesis of pyrimidine and disrupts the interaction of T cells with antigen presenting cell.[7][8][25][26] Fingolimod and teriflunomide are taken through a daily single dose.[8][27] In 2013 one further oral drug, dimethyl fumarate -or BG12- (which is an improved version of fumaric acid, an already existing drug), was approved by the FDA. Dimethyl fumarate is taken twice daily.[10][28]

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.[29]

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

Both the interferons and glatiramer acetate are available only in injectable forms, and both can cause skin reactions at the injection site, specially with subcutaneous administration.[30][31] Skin reactions vary greatly in their clinical presentation and may include bruising, erythema, pain, pruritus, irritation, swelling and in the most extreme cases cutaneous necrosis.[30][31] They usually appear within the first month of treatment albeit their frequence and importance diminish after six months of use.[30] Mild skin reactions usually do not impede treatment whereas necroses appear in around 5% of patients and lead to the discontinuation of the therapy.[30][30] Also over time, a visible dent at the injection site due to the local destruction of fat tissue, known as lipoatrophy, may develop.[30][30]

Interferons, a subclass of cytokines, are produced in the body during illnesses such as influenza in order to help fight the infection. They are responsible of many of the symptoms of influenza infections, including fever, muscle aches, fatigue, and headaches.[32] Many patients report influenza-like symptoms hours after taking interferon-beta that usually improve within 24 hours, being such symptoms related to the temporary increase of cytokines.[5][30] This reaction tends to disappear after 3 months of treatment and its symptoms can be treated with over-the-counter nonsteroidal anti-inflammatory drugs, such as ibuprofen, that reduce fever and pain.[30] Another common transient secondary effect with interferon-beta is a functional deterioration of already existing symptoms of the disease.[30] Such deterioration is similar to the one produced in MS patients due to heat, fever or stress (Uhthoff's phenomenon), usually appears within 24 hours of treatment, is more common in the initial months of treatment, and may last several days.[30] A symptom specially sensitive to worsening is spasticity.[30] Interferon-beta can also reduce numbers of white blood cells (leukopenia), lymphocytes (lymphopenia) and neutrophils (neutropenia), as well as affect liver function.[30] In most cases these effects are non-dangerous and reversible after cessation or reduction of treatment.[30] Nevertheless, recommendation is that all patients should be monitored through laboratory blood analyses, including liver function tests, to ensure safe use of interferons.[30]

Glatiramer acetate is generally well tolerated.[31] The most common secondary effect with glatiramer acetate after skin problem is a post-injection reaction manifested by flushing, chest tightness, heart palpitations, breathlessness, and anxiety, which usually lasts less than thirty minutes and does not require additional treatment.[31][33]

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.[34] Heart problems (mainly systolic dysfunction) appear in over 10% of patients, while leukemia prevalence is 0.8%.[22]

Soon after its approval natalizumab was withdrawn from the market by its manufacturer after it was linked with three cases of the rare but hazardous neurological condition called progressive multifocal leukoencephalopathy (PML).[23] PML is an opportunistic infection with neurological progressive symptoms caused by the replication of the JC virus in the glial cells of the brain.[23] All 3 initial cases were taking natalizumab in combination with interferon beta-1a. After a safety review the drug was returned to the market in 2006 as a monotherapy for MS under a special prescription program.[23] As of May 2011, over 130 cases of PML had been reported, all in patients who had taken natalizumab for more than a year.[23] While none of them had taken the drug in combination with other disease-modifying treatments, previous use of MS treatments increases the risk of PML between 3 and 4-fold.[23] The estimated prevalence of PML is 1.5 cases per thousand natalizumab users.[23] Around 20% of MS patients with PML die, while most of the remaining are importantly disabled.[23]

During clinical trials fingolimod gave rise to side effects such as hypertension and bradycardia, macular edema, elevated liver enzymes or reduction in lymphocite levels.[26] Teriflunomide is considered a very safe drug. Nevertheless, there have been reports of liver failure, and PML.[26] Teriflunomide is also known to be dangerous for fetal development.[26] Most common secondary effects of dimethyl fumarate during clinical trials were flushing and gastrointestinal problems.[9][10][26] These problems were generally mild and occurred more frequently during the first month of treatment.[9][10][26] While dimethyl fumarate leads to a reduction in white blood cell count and levels should be monitored in patients, there were no reported cases of opportunistic infections during the clinical trials.[9][10] Moreover, fumaric acid is also used to treat psoriasis, another autoinmune disorder, and there is long term safety data from over 14 years of use without any indication of further dangerous secondary effects.[26]

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.[35] Treatment with interferons or glatiramer acetate after an initial attack decreases the risk of developing clinical definite MS.[5][36]

Medications are modestly effective at decreasing the number of attacks in RRMS and in reducing the accumulation of brain lesions, which is measured using gadolinium-enhanced magnetic resonance imaging (MRI).[5] Interferons and glatiramer acetate are roughly equivalent, reducing relapses by approximately 30% and their safe profile make them the first-line treatments.[5] Nevertheless, not all the patients are responsive to these therapies. It is known that 30% of MS patients are non-responsive to Beta interferon.[37] One of the factors related to non-respondance is the presence of high levels of interferon beta neutralizing antibodies. Interferon therapy, and specially interferon beta-1b, induces the production of neutralizing antibodies, usually in the second 6 months of treatment, in 5 to 30% of treated patients.[5][38] Moreover, a subset of RRMS patients with specially active MS, sometimes called "rapidly worsening MS" are normally non-responders to immunomodulators and are treated with either mitoxantrone or natalizumab.[39]

Natalizumab and mitoxantrone are considered highly effective both in terms of relapse rate reduction and halting disability progression, however, they are related to dangerous side-effects that have led them to be considered second-line treatments. Natalizumab halves the risk of suffering relapses when compared to interferons, having an overall efficacy of over 70%.[23] Moreover, mitoxantrone is also highly useful to reduce attacks and disability, but it is generally not considered as a long-term therapy due to its severe cardiac toxicity.[5][40]

There are no official guidelines yet on the use of disease-modifying oral treatments due to their recent development.[26] While some believe that they will probably reduce the usage of first-line treatments the long-term safety of interferons and glatiramer acetate will probably slow this trend.[26] It has been recommended that at the moment oral treatments should be mainly offered in those cases where patients do not use existing treatments due to needle phobia or other reasons such as perceived inefficacy of interferons and glatiramer acetate.[26] They could also be used in patients taking natalizumab who have developed JC virus antibodies and are therefore at an increased risk of PML.[26] Dimethyl fumarate is potentially one of the most interesting oral drugs due to the long term data from use in psoriasis which points towards a very good safety profile.[26]

While more studies of the long-term effects of the drugs are needed,[5][40][41] specially for the newest treatments,[42][23] 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.[41]

Oral contraceptive pills have contradictory results from different studies regarding any effect of decreasing relapse rate in women with multiple sclerosis.[43] Certain medications for MS symptoms, such as carbamazepine (used to treat spasms and pain) and modafinil (used to treat fatigue) can make oral contraceptive pills less effective.[43]

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.

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 people 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 people after two years.[44] 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 has shown efficacy and has been approved for secondary progressive MS with relapses. Studies on the use of Interferon-beta-1b in secondary progressive and progressive relapsing MS do not support that it slows progression of the disease, although it is effective in reducing the number of relapses.[45]

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. There have been several trials investigating the efficacy of different drugs for PPMS without positive results. Drugs tested include interferon beta, mitoxantrone, glatiramer acetate or riluzole.[46] People with PPMS have also been included in trials of azathioprine, methotrexate, intravenous immunoglobulin, cyclophosphamide and hematopoietic stem cell transplantation.[47]

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