Requirement for safety monitoring for approved multiple sclerosis therapies: an overview

Authors


Summary

During the last two decades, treatment options for patients with multiple sclerosis (MS) have broadened tremendously. All agents that are currently approved for clinical use have potential side effects, and a careful risk–benefit evaluation is part of a decision algorithm to identify the optimal treatment choice for an individual patient. Whereas glatiramer acetate and interferon beta preparations have been used in MS for decades and have a proven safety record, more recently approved drugs appear to be more effective, but potential risks might be more severe. The potential complications of some novel therapies might not even have been identified to their full extent. This review is aimed at the clinical neurologist in that it offers insights into potential adverse events of each of the approved MS therapeutics: interferon beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod and teriflunomide, as well as recently approved therapeutics such as dimethyl fumarate and alemtuzumab. It also provides recommendations for monitoring the different drugs during therapy in order to avoid common side effects.

Other Articles published in this series Paraneoplastic neurological syndromes. Clinical and Experimental Immunology 2014, 175: 336–48. Diagnosis, pathogenesis and treatment of myositis: recent advances. Clinical and Experimental Immunology 2014, 175: 349–58. Monoclonal antibodies in treatment of multiple sclerosis. Clinical and Experimental Immunology 2014, 175: 373–84. CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. Review of an increasingly recognized entity within the spectrum of inflammatory central nervous system disorders. Clinical and Experimental Immunology 2014, 175: 385–96. Disease-modifying therapy in multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy: common and divergent current and future strategies. Clinical and Experimental Immunology 2014, 175: 359–72. Myasthenia gravis: an update for the clinician. Clinical and Experimental Immunology 2014, 175: 408–18. Cerebral vasculitis in adults: what are the steps in order to establish the diagnosis? Red flags and pitfalls. Clinical and Experimental Immunology 2014, 175: 419–24. Multiple sclerosis treatment and infectious issues: update 2013. Clinical and Experimental Immunology 2014, 175: 425–38.

Introduction

Multiple sclerosis (MS) is an inflammatory disease affecting young adults and is a major cause of disability [1]. MS phenotypes have been differentiated into relapsing–remitting MS (RRMS), primary progressive MS (PPMS) and secondary progressive MS (SPMS). In the majority of patients, RRMS will proceed eventually to SPMS [2]. While relapsing forms of MS appear to be driven primarily by central nervous system (CNS) inflammation, progressive forms of MS are also characterized by extensive neurodegeneration [3]. Two decades ago, the first therapeutic agents were approved for treatment of relapsing forms of this disorder [4]. Since then, the therapeutic options have broadened tremendously. While it is now possible to lower the rate of clinical attacks and the lesion burden on magnetic resonance images (MRI), questions remain regarding the long-term benefits derived from any of the approved agents. In addition, all the drugs that are currently available for use in patients with MS have potential side effects [5], and a careful risk–benefit evaluation often helps the neurologist to identify the best agent for an individual patient.

Currently, glatiramer acetate (GA) (Copaxone®), interferon beta (IFN-β) preparations (Betaseron®, Extavia®, Rebif®, Avonex®), mitoxantrone (Novantrone®), natalizumab (Tysabri®), fingolimod (Gilenya®) and teriflunomide (Aubagio®) are approved for therapy of relapsing forms of MS in the United States and other countries. Laboratory screening tests for specific complications of these agents are becoming increasingly complex and a daily routine for MS neurologists. The requirement for such tests will be discussed in this review.

GA (Copaxone®)

GA is indicated for therapy in RRMS and in first clinical relapses in patients with MRI compatible with MS. It was approved for RRMS in 1996 by the Food and Drug Administration (FDA) [4]. GA reduces the risk of relapses in RRMS [6] and may decrease disease progression compared to patients who terminated treatment with it [7]. Twenty mg GA are administered subcutaneously (s.c.) daily [8].

GA is a polymer of amino acids (glutamic acid, lysine, alanine and tyrosine). This co-polymer was originally generated to mimic myelin basic protein, and to allow the induction of the MS animal model experimental autoimmune encephalomyelitis (EAE). Unexpectedly, disease resistance was observed [9], which led to clinical trials in MS patients. The complex mode of action of GA is still not understood fully. However, cellular immune responses are shifted from inflammatory to anti-inflammatory cytokines. This T helper type 1 (Th1) to Th2 shift seems to be responsible for some of the effects. Other mechanisms are inhibition of activation and proliferation of encephalitogenic T cells and a modulation of antigen-presenting cells [10-12]. Brain-derived neurotrophic factor (BDNF) production is increased in response to GA treatment. BDNF may possess neuroprotective capacity [13], as it may play an important role in the protection of axons [14].

Potential side effects of GA include immediate post-injection reactions such as flushing, chest pain, palpitations, anxiety, dyspnoea, urticaria and constriction of the throat. These side effects are usually self-limited and occur unpredictably several months after initiation. Chest pain may be associated with post-injection status, but it also may occur without a temporal relation to injections. Lipoatrophy has been reported [15, 16]. To avoid skin necrosis the patients should follow injection techniques as stated in the prescribing information. Antibodies targeting GA have been reported, but it is not plausible that they antagonize its actions in vivo. Usually, many of these side effects are self-limited or can be avoided by proper injection [8]. Whereas flu-like symptoms are less frequent in patients on GA therapy compared to patients on IFN-β treatment, injection side reactions are more common in patients under GA treatment [17]. Recent reports have shown hepatic toxicity under treatment with GA [18, 19]. These reports need to be validated.

No laboratory monitoring is required during GA therapy (see Table 1).

Table 1. Therapy monitoring in approved therapeutics. Possible side effects.
 Potential side effectsRecommended monitoring
  1. PML: progressive multi-focal leucoencephalopathy; ECG: electrocardiography; VZV: varicella zoster virus.
GlatiramerFlushing, chest pain, dyspnoeaNone
acetatePalpitations, urticaria, skin necrosis 
Interferon betaFlu-like symptoms, injection-site necrosisLiver enzymes
Depression, allergic reactionsBlood count
Hepatic injury, neutropeniaThryroid testing
LipoatrophyNeutralizing antibodies
MitoxantroneCongestion heart failureLeft ventricular ejection fraction
Urine colour blue-greenECG, differential blood count,
Birth deficiency, sterilityLiver enzymes, pregnancy testing
Hair loss, nausea 
NatalizumabPML, fever, joint painJC-virus
Liver disease, melanomaNeutralizing antibodies
Allergic reactions 
FingolimodBradycardia, heart failureECG, cardiological evaluation
Fever, diarrhoea, liver diseaseOphtalmological evaluation
Macular oedema, skin cancersVZV-antibodies, liver enzymes
Enzephalities 
TeriflunomideHepatic injury, elevated liver enzymes, infections, polyneuropathyLiver enzymes, pregnancy testing, white blood count
AlemtuzumabAutoimmune disorders (thyroid disorders, immune thrombocytic purpura), infusion-related side effectsComplete monthly blood counts, testing for autoimmunity
Dimethyl fumarateLymphopenia, gastrointestinal side effectsWhite blood cell count

GA is a pregnancy category B (see Table 2), meaning that no adverse effects on embryonal development were observed in animal reproduction studies. Well-controlled clinical trials in pregnant women are lacking. Consequently, GA should be used during pregnancy only if clearly needed [8].

Table 2. Potential risk of MS therapeutics in pregnancy.
FDA pregnancy categoryInterpretationTherapeutic agent
AWell-controlled trials in pregnant women revealed no increased risk for fetus 
BNo well-controlled trials, but animal trials revealed no increased risk or well-controlled trials revealed no risk, whereas animal trials have shown adverse effectsGlatiramer acetate
CAnimal studies have shown increased risk for the fetus or have not been conducted; no well-controlled trials in pregnant womenInterferon beta, natalizumab, fingolimod, alemtuzumab, dimethyl fumarate
DStudies have shown harm to the fetus; however, the benefit may outweigh risk under certain circumstancesMitoxantrone
XStudies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefitsTeriflunomide

IFN-β

IFN-β was first approved for MS in the in 1993. There are three different products available – IFN-β-1b preparations (Betaseron®, Extavia®) that are administered s.c. every other day, and IFN-β-1a preparations that are either administered s.c. (Rebif®) three times weekly or intramuscularly (i.m.) (Avonex®) once a week [4].

IFN-β is a purified, lyophilized protein product generated by recombinant DNA techniques. In response to viruses, IFN-β is produced by the innate immune systems. A reduction of T cell activation, a cytokine shift in favour of anti-inflammatory effects, induction of regulatory T cells and prevention of leucocytes from crossing the blood–brain barrier have been shown. In addition, IFN-β leads to higher neutrotrophic factor expression, promotes anti-viral effects and apoptosis of autoreactive T cells. The exact mechanisms by which IFN-β benefits patients with MS are currently not known [20].

The most common side effects are flu-like symptoms. Symptoms may be minimized by the intake of analgesics or anti-pyretics prior to injection. As with GA, injection site necrosis and reactions have been reported. Again, proper injection technique and the change of injection site are of importance in reducing the occurrence of these side effects. Injection side effects are more common in patients receiving IFN-β-1a three times weekly s.c. when compared with patients under IFN-β-1a weekly i.m. [21]. Allergic reactions and anaphylaxis are rare complications that have to be considered severe. In the case of anaphylaxis, treatment with interferon has to be discontinued. Severe hepatic injury has been reported under treatment with IFN-β preparations, mainly when therapy occurs in combination with other hepatotoxic agents. Depression has been reported in patients treated with IFN-β. Therefore, symptoms of depression have to be monitored, and treatment discontinued as indicated. In addition, haematological abnormalities including lymphopenia, neutropenia, anaemia and leukopenia have been reported [22-27]. Two other relatively common side effects of IFN-β therapy in patients with MS are thyroid autoimmunity and hypothyroidism [28], although other reports could not show a significant increase in thyroid dysfunction or anti-thyroid autoantibody positivity [29, 30].

In conclusion, treatment with IFN-β is considered safe and well tolerated. However, after the approval of IFN-β cases with autoimmune diseases, including idiopathic thrombocytopenia, hypo- and hyperthyroidism and autoimmune hepatitis, have been reported. Thus, liver enzymes should be monitored in regular intervals in the absence of signs of liver injury (1 month, 3 months and 6 months after initiation and each 6 months afterwards). Known liver disease is a contraindication to therapy with IFN-β. Liver transaminase levels of greater than five times of normal should lead to a dose reduction. If enzyme levels do not convert to normal, treatment has to be discontinued. If enzyme levels normalize after a dose reduction, a return to the full dose can be initiated with ongoing hepatic monitoring. In addition, complete blood counts should be obtained after 1 month, 3 months, 6 months and each 6 months thereafter. Thyroid testing should be performed initially and afterwards only in the case of abnormalities every 6 months and when clinical signs of hypo- or hyperthyroidism are obvious (see Table 1).

Like all therapeutic proteins, IFN-β is immunogenic and can induce the production of binding and neutralizing antibodies [31]. Neutralizing antibodies are up to seven times more prevalent in patients receiving IFN-β-1b every other day or IFN-β-1a s.c. three times weekly, when compared with IFN-β-1a i.m. once a week [21, 32]. Routine testing for IFN-β neutralizing antibodies is currently not universally recommended. Testing for neutralizing antibodies might be recommended in the setting of clinical disease progression under IFN-β treatment. If testing is performed, the presence of high titres against IFN-β on recurrent testing or the failure to induce interferon inducible protein (MxA) should perhaps lead to the discontinuation of therapy and a switch to a different class of drug [33].

One lethal case of capillary leak syndrome was reported in a patient with monoclonal gammopathy of unknown significance (MGUS) after one administration of IFN-β-1b. Post-mortem measurements showed a deficiency of C1 inhibitor (C1-INH) that controls the complement system. The release of proinflammatory cytokines appears to have resulted in an uncontrolled activation of complement factor. There are reports of associations of MGUS and C1-INH. An autopsy did not confirm the diagnosis of clinical definite MS [34]. In patients with MGUS and MS who are candidates for IFN-β therapy, the level of C1-INH should be determined.

IFN-β-1b has been assigned pregnancy category C. In animals, significant increases in embryolethal and arbotifacient effects could be shown under doses approximately two to three times higher than the doses used in patients with MS. Well-controlled trials in humans are lacking and not feasible. However, spontaneous abortions have been reported in clinical trials. Women should be informed about this risk and treatment should be discontinued when women intend to become pregnant or during pregnancy [35-37].

A polyethylene glycol (PEGylated) formulation of IFN-β with longer injection intervals is currently under investigation, showing promising preliminary data according to a recent press release [Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study] [38].

Mitoxantrone

Mitoxantrone (Novantrone®) was approved in 2000 by the FDA for rapidly worsening RRMS or secondary progressive MS [39]. It has proved its efficacy in several trials [40, 41]. Mitoxantrone is administered at doses of 12 mg/m2 every 3 months intravenously (i.v.) as short infusions. It is an anti-neoplastic cytotoxic agent that inhibits type II topoisomerase and disrupts DNA synthesis. Furthermore, mitoxantrone showed effects on the proliferation of T and B cells and induces natural killer (NK) cell maturation [42, 43]. It was first used in cancer therapy. From cancer patients receiving mitoxantrone it is known that there is a dose-dependent risk of developing cardiomyopathy [44].

Because of reports of congestive heart failure and decreases in the left cardiac ejection fraction, cardiac monitoring has been recommended. Heart failure may occur during or after termination of therapy with mitoxantrone [45, 46]. The risk correlates with accumulating doses of mitoxantrone, and a cumulative dose of 140 mg/m2 should not be exceeded. The incidence of secondary lymphoid cancer is estimated to be between 0·25 and 6%. There seems to be no correlation between the applied dose and the likelihood for lymphoma. These complications have substantially limited the use of mitoxantrone despite its proven efficacy [47].

Prior to initiation of therapy, left ventricular ejection fraction (LVEF) should be obtained by echocardiogram, multi-gated radionucleotide angiography (MUGA) or MRI. Prior to each infusion with mitoxantrone an electrocardiogram (ECG) should be performed. In addition, a quantitative re-evaluation of LVEF should be performed before initiation of mitoxantrone, during therapy with mitoxantrone and yearly after termination of mitoxantrone using the same method utilized at baseline [48]. A significant reduction of LVEF (below 50%) is a contraindication for initiation of therapy with mitoxantrone and a reason for terminating therapy.

Because mitoxantrone leads to a reduction in the number of leucocytes, administration of mitoxantrone is not recommended when neutrophil numbers fall below 1500 mm3. Complete blood count and differential blood count, as well as thrombocytes and liver enzymes, should be tested prior to each administration. Patients with hepatic insufficiency with threefold elevated liver enzymes should not be administered mitoxantrone, as it is metabolized in the liver (see Table 1) [48, 49]. Liver toxicity has been reported in as many as 15% of treated patients [50].

During therapy with mitoxantrone, vaccinations with live virus vaccines should be avoided. The application of other anti-neoplastic agents should be avoided. The patient should be aware that the urine may be blue–green in colour for some days after infusion. Other side effects include transient hair loss or thinning and nausea, and menstrual disorders in females. If there are signs of extravasation, the infusion has to be stopped immediately to avoid tissue necrosis [49].

Patients who have not completed their family planning should be informed that mitoxantrone may cause sterility. As mitoxantrone may cause birth defects, contraception is required during therapy. A pregnancy test should be conducted prior to each administration [49]. Well-controlled trials are currently lacking in pregnant women [51]. Mitoxantrone has been assigned to pregnancy category D by the FDA. Animal data suggest fetotoxicity (low fetal birth weight and retarded development of the fetal kidney) and premature delivery [48] (see Table 2).

Natalizumab

Natalizumab is a humanized recombinant monoclonal antibody against the α4-chain of integrins that was designed to diminish leucocyte migration from the peripheral blood into the CNS. Specifically, very late activating antigen-4 (VLA-4; identical with α4-chain of α4β1-integrin) is decreased in its ability to bind its ligand, vascular cell adhesion molecule (VCAM)-1 [52, 53]. Natalizumab received accelerated approval by the FDA in 2004 based on the results after 1 year of treatment in two placebo-controlled trials. The trials were ongoing for another year [54, 55]. The agent was withdrawn voluntarily by its manufacturers in 2005, after three cases of progressive multi-focal leucoencephalopathy (PML) in patients with MS and Crohn's disease were reported [5, 56, 57]. PML is an infection of cells in the CNS with the human polyoma virus JC (JCV). In 2006, natalizumab was reintroduced. It is approved for relapsing forms of MS in the United States [58] and for highly active forms of RRMS (defined as failed response to other therapeutics such as IFN-β or GA, or if disease is evolving rapidly) [58, 59].

Potential side effects are common and can be observed in about 10% of all patients. Side effects include fever, joint pains, headache, dizziness, depression, vaginitis, gastroenteritis, feeling or being sick and sore throat [60]. Herpes infections have also been reported in MS patients under natalizumab therapy, but it is unclear that there is an increased incidence compared to the general population [61].

Severe side effects and complications include PML, allergic reactions and liver disorders. Recently, risk stratification for patients with MS on natalizumab became possible. Specifically, a positive anti-JCV antibody status reflecting infection with JCV [62], previous treatment with immunosuppressants such as mitoxantrone or cyclophosphamide and treatment duration with natalizumab (more than 24 monthly infusions) were determined to be correlated with a higher risk of PML. The risk differs from fewer than one in 10 000 in patients with no risk factors to up to 11 in 1000 in patients with positive JCV status, previous treatment with immunosuppressants and treatment duration longer than 24 months [63]. Recently, a trial investigating the accuracy of JCV seropositivity revealed that there is a false negative rate of JCV in the serum of 37% when compared with the virus load in the urine. Thus, a negative JCV test may underestimate the rate of JCV latency in a given individual [64]. Regular monitoring warrants for clinical signs for PML and JCV testing should be repeated in negative patients every 6 months. Upon suspicion of PML, treatment with natalizumab should be terminated immediately. The clinical and imaging diagnosis of PML should be confirmed by MRI scan, cerebrospinal fluid (CSF) and polymerase chain reaction (PCR) testing for JCV. In cases with suspected PML and absence of JCV copies by PCR in CSF, a brain biopsy could be considered. Plasma exchange is often performed to accelerate the elimination of natalizumab. However, there is no evidence that the use of plasma exchange favourably alters clinical outcomes. In addition, nearly all PML patients develop paradoxical deterioration after termination of natalizumab. Responsible for this deterioration is the immune reconstitution inflammatory syndrome (IRIS), which is known from cases of PML in AIDS patients. In this situation, the use of glucocorticosteroids is recommended [65, 66].

Further side effects include liver dysfunction with an increase of liver enzymes and an increase of bilirubin. These effects can be observed typically within days of treatment initiation [60], although delayed reactions have also been described [67]. Even in the absence of relevant clinical signs, liver enzymes should be tested prior to treatment, after 1 month and after 3 months of therapy initiation. Complete blood counts with cell differential, as well as platelet count, should be determined 1, 3 and 6 months after initiation, and every 6 months thereafter [60] (see Table 1). Skin cancers have been reported under treatment with natalizumab [68, 69].

Persistent anti-idiotypic antibodies against natalizumab (detected at two time-points) will prevent the drug from being efficient. Thus, therapy has to be terminated. In the case of anaphylaxis or allergic reaction, neutralizing antibodies are typically detectable [54]. The prevalence of neutralizing antibodies appears higher in patients in whom natalizumab therapy was stopped within 6 months of initiation and then restarted later. Because of the risk of allergic reaction, post-infusion observation for 1 h is recommended.

Well-controlled trials in pregnant women are currently lacking. Natalizumab has been assigned a pregnancy category C. In animal studies, a higher rate of abortion was observed at doses seven times the human dose (see Table 2). Natalizumab therapy should be reserved for those patients in whom potential benefits outweigh potential risks [60]. As there is currently no exit strategy for natalizumab that prevents disease reactivation, discontinuation during pregnancy presents its own challenges.

Fingolimod (Gilenya®)

Fingolimod is approved by the FDA for RRMS [70] and in Europe by the European Medicines Agency (EMA) for patients with RRMS and disease activity, despite first-line treatment, or in patients with evolving severe RRMS. It is administered orally as 0·5-mg capsules daily [71]. Fingolimod binds to sphingosine-1-phospate (S1P) receptors on immune cells. Consequently, these immune cells are unable to egress from lymphatic tissue, and subsequently into the CNS [72]. Only lymphocytes that reside within secondary lymphoid organs are affected, which account for approximately 2% of all circulating lymphocytes. In addition to the effects on immune cells, there is emerging evidence that fingolimod may modulate S1P receptors in the CNS and may reduce neurodegenerative processes [73, 74].

The most common side effects of fingolimod are headache, flu-like symptoms, diarrhoea, back pain, liver enzyme elevations and cough. More severe side effects such as cardiac complications are common, with an incidence between 1 and 10% of patients treated with fingolimod. A first-degree atrioventricular block was reported in about 4·7% in patients treated with 0·5 mg fingolimod. Other risks include a minor increase in blood pressure, decrease in lung function, macular oedema and an increased frequency of viral infections, in particular varizella zoster [75-79].

Macular oedema may lead to progressive visual loss. The pathogenic role of fingolimod in macular oedema is currently not understood fully. In two Phase III trials, 13 patients developed macular oedema, 10 of them within the first 4 months of treatment. Eleven of the 13 patients with macular oedema were administered a dose that is more than twice as high as the currently approved dose [77, 78].

Cutaneous neoplasias were reported more often in the fingolimod group than in the IFN or placebo control groups. Basaliomas and melanomas (in situ) were reported [75, 76]. A dermatology screening examination could be suggested before the initiation of fingolimod therapy.

In the context of one Phase II clinical trial, one MS patient died from varicella zoster infection and consecutive hepatic failure, and another patient died from herpes simplex virus 1 encephalitis. A third patient was diagnosed with a life-threatening HSV encephalitis. All these patients were treated with the higher, non-approved 1·25 mg dose [78].

FDA and EMA currently recommend 6-h heart monitoring with continuous ECG monitoring during the first administration of fingolimod. If bradycardia occurs within the first 6 h, cardiac monitoring should be extended for another 2 h. The occurrence of severe bradycardia, QTC interval prolongation, AV block II Wenckeback or AV block III requires overnight observation. In patients who become clinically symptomatic during fingolimod-related bradyarrhythmias or who take other bradycardia-promoting agents should be assessed by a cardiologists to determine the feasibility of fingolimod therapy. In patients with atrioventricular block II, significant QT-prolongation, symptomatic known bradycardia or history of syncope, ischaemic heart disease or history of myocardial infarctions or cerebrovascular infarction, uncontrollable arterial hypertension or congestive heart disease, fingolimod cannot be recommended. Because of the first-dose cardiac side effects of fingolimod, cardiac monitoring has to be repeated in all patients who experience a treatment hiatus of 14 days or longer [78, 79]. Additionally, the EMA requires for repeated monitoring when the treatment is interrupted for 1 day during the first 2 weeks of treatment, or 7 days during week 3 and 4 of treatment [80].

Moreover, the majority of cases with macular oedema occurred within the first 3–4 months after onset of therapy. Patients may report blurred vision or decreased vision or may be asymptomatic. The incidence is about 0·4% in the 0·5 mg group, with a higher incidence with patients with a history of uveitis. After termination of therapy, macular oedema usually resolves spontaneously; therefore, evaluation of the fundus has to be performed prior to initiation of therapy, within 4 months after onset of therapy and at any time of decreased visual acuity [77, 78].

Vaccination during therapy with fingolimod may be less effective. Vaccination with live attenuated virus vaccines should be avoided during, and 2 months after, fingolimod therapy as it may carry the risk of infections. In addition, patients without a history of chickenpox or vaccination against varicella zoster virus (VZV) should be tested for VZV antibodies. In those without antibodies vaccination should be considered before initiation [81]. Vaccination is recommended 1 month prior to initiation with fingolimod therapy in order to ensure immunization. Monitoring of therapy should also include complete cell counts at initiation of therapy, months 1, 3 and 6 and in periodic intervals thereafter [82] (see Table 1).

Fingolimod has been assigned to pregnancy category C by the FDA. Animal studies demonstrated evidence of fetal outcomes, including teratogenicity and embryolethality. Well-controlled trials in women are currently lacking. Prior to initiation a pregnancy test has to be conducted. If a patient becomes pregnant during treatment, application of fingolimod should be terminated [82, 83] (see Table 2).

Teriflunomide (Aubagio®)

Teriflunomide was approved in 2012 by the FDA for treatment of relapsing forms of MS [84] after it had documented efficacy in several trials [85-87]. Teriflunomide is a pyrimidine synthesis inhibitor and has anti-inflammatory properties by inhibiting dihydroorotate dehydrogenase which, in turn, is necessary for pyrimidine synthesis. Proliferation of autoreactive B and T cells is reduced. Additionally, immunomodulatory effects on the expression of cytokines by lymphocytes have been shown [88, 89]. The exact mechanisms by which teriflunomide mediates its benefits in MS are not understood fully. Teriflunomide is available in two doses: 7 or 14 mg once daily in the United States [90] and 14 mg in Europe [91].

Hepatotoxicity was reported with leflunomide, the parent drug of teriflunomide, in patients with rheumatoid arthritis. Adverse effects of teriflunomide include decreased white blood count (WBC), and infections. Specifically, cases of tuberculosis were reported. Polyneuropathy, renal failure, skin reactions, hair thinning and an increase in blood pressure have also been observed [86, 92].

Teriflunomide is contraindicated in patients with severe hepatic injury. In other patients, liver enzymes have to be monitored prior to initiation and for at least 6 months after initiation. A complete blood count has to be conducted. In addition, blood pressure and screening for latent tuberculosis has to be performed. In the case of immunodeficiency teriflunomide should not be administered (see Table 1). Vaccinations with live vaccines are not recommended.

Teriflunomide has been assigned category X by the FDA [84, 93]. Thus, the agent is contraindicated in pregnant women. A pregnancy test prior to initiation is required. In the case of pregnancy, treatment with teriflunomide should be terminated immediately and accelerated elimination with cholestyramine for 11 days or with oral activated charcoal powder for 11 days should be initiated. Men with women who plan to become pregnant should not take teriflunomide. As in female MS patients, effective birth control is essential for men. Teriflunomide will stay in the blood for up to 2 years [84] (see Table 2).

Alemtuzumab (Lemtrada®)

On 27 June 2013, the Committee for Medical Products for Human Use (CHMP) adopted a positive opinion for granting market authorization for Lemtrada® 12 mg in 1·2 ml (10 mg/ml) concentrate for solution for infusion for treatment for RRMS. The agent is approved for patients with RRMS and active disease defined by clinical or imaging features [94]. In the United States, application for approval is submitted [95]. Two Phase III trials have shown efficacy of alemtuzumab in the treatment of RRMS, where it has been tested against placebo and/or IFN-β-1a [96, 97]. Alemtuzumab is a recombinant humanized monoclonal antibody that targets CD-52 antigen. CD52 is expressed on the surface of most leucocytes, including lymphocyte subsets, monocytes and granulocytes. Its immunoregulatory effects are mediated via antibody-dependent cell-mediated cytolysis (ADCC), complement-dependent cytolysis (CDC) and apoptosis [98].

Secondary autoimmunity has been reported in up to 20% in treated patients. While the exact aetiology of the immune aberration is not understood fully, it may be the result of sequential immune reconstitution: B cells emerge prior to regulatory T cells [99-101]. Up to 18% of the treated patients developed thyroid disorders in the Phase III trials [96, 97]. In addition, haematological, renal and dermatological autoimmune diseases may occur. In one Phase II trial immune thrombocytopenic purpura (ITP) was reported in three patients, one of whom died [102]. Infusion-related side effects are also quite common [5, 96, 97]. Beside secondary autoimmunity, infusion-related side effects such as urticaria, pyrexia and rigor may occur [103]. Concomitant medication with corticosteroids and histamines appears essential in alleviating these side effects. Infections was more common in the alemtuzumab group than the placebo groups [96, 97]. Furthermore, there are reports of PML in patients treated with alemtuzumab for chronic lymphocytic leukaemia (CLL) and non-Hodkgin lymphoma [104].

Regular monitoring includes monthly complete blood counts. The risk of secondary autoimmunity should be explained to the patient. Testing for thyroid disorders, renal and dermatological disorders needs to be performed regularly even up to 5 years after termination of treatment [105].

Alemtuzumab, administered as MabCampath® for CLL or non-Hodgkin lymphoma, is assigned pregnancy category C by the FDA. Like all IgG molecules, alemtuzumab can cross the blood–placenta barrier. Alemtuzumab should be given only if the benefits outweigh the potential risk to the fetus [106].

Dimethyl fumarate (Tecifidera®)

Dimethyl fumarate was approved by the FDA [107] for treatment of RRMS, and on 21 March 2013, based on the results of two Phase III trials testing the agent against placebo and/or against GA [108, 109]. The CHMP at the European Medicines Agency (EMEA) adopted a positive opinion for marketing authorization for Tecifidera® 120-mg and 240-mg capsules for the treatment of RRMS [110]. The exact mechanism of how dimethyl fumarate is benefiting patients with MS is currently unknown. Dimethyl fumarate and its metabolites monomethyl fumarate are are clearly anti-proliferative, as shown in studies on patients with psoriasis [111, 112]. Specifically, dimethyl fumarate seems to modulate immune-cell responses, i.e. by shifting dendritic cell differentiation. The suppression of proinflammatory cytokine production and/or inhibition of proinflammatory pathways are the biological results [108, 109]. In the experimental autoimmune encephalomyelitis (EAE) model of MS it was demonstrated that dimethyl fumarate activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo. This pathway is involved in the response to oxidative stress, and its activation might be neuroprotective and myeloprotective [113].

Dimethyl fumarate may cause lymphopenia. Lymphocyte numbers in peripheral decrease by about 30% on average during the first year, and then stabilize. After termination of dimethyl fumarate, lymphocyte counts increase but do not reach the baseline for a substantial period. Flushing was reported in up to 40% of the treated patients. In fewer than 1% of treated patients, flushing led to hospitalization. Gastrointestinal side effects such as vomiting, abdominal pain, diarrhoea and dyspepsia were more common in the dimethyl fumarate group when compared to the placebo group. A transient moderate increase during the first 2 months of treatment was reported [113]. Recently, there were two reports of PML, one with psoriasis and another with a diagnosis of MS, who received fumaric acid preparations containing dimethyl fumarate [113, 114]. Prolonged lymphopenia may have contributed to a higher risk for PML. Another contributing risk factor may be a history of prior immunosuppressant use [115]. Dimethyl fumarate has been assigned pregnancy category C, as no adequate or well-controlled studies are available in pregnant women. In experimental animals, side effects on the fetus were observed. Dimethyl fumarate should be given in pregnancy only when the benefit justifies the potential risk to the fetus [116].

Conclusions

Treatment options in MS patients have expanded tremendously in recent years, and will probably continue to expand in the near future. Whereas GA and IFN-β preparations have been used in MS for decades and have proven safety, some of the more recently approved drugs appear to be more effective, but potential side effects might be more severe or have not even been identified. Thus, stringent monitoring is essential. Each of the drugs has a different side effects profile. Routine laboratory examinations allow identification of some of these side effects. Additionally, neutralizing antibodies against recombinant proteins may be detected.

Understanding the side effects of MS therapies is highly relevant, as it will guide the clinician and the patient in choosing the right agent for their disease.

Disclosure

PSR served as consultant to Bayer Pharma AG and received speaker honorary from Shire. PSR has recently entered an employmanship with Novartis. UKZ has received speaker fees from Bayer Healthcare, Biogen Idec, Genzyme, Merck-Serono, Novartis, Sanofi and Teva. BK has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Health Care, Biogen Idec, Genzyme/Sanofi Aventis, Grifols, Merck Serono, Mitsubishi Europe, Novartis, Roche, Talecris, and TEVA. HPH has received speaker and consult fees from Bayer Healthcare, Biogen Idec, Genzyme, GeNeuro, MeckSerono, Novartis, Sanofi, Roche, TEVA. TM has received travel grants and speaker honoraria from Bayer Healthcare, Biogen Idec, Genzyme, Merck Serono, and Teva. EF has received speaker and consult fees from Novartis, Genzyme, TEVA, and Acorda. BG has received consulting fees from DioGenix, Amplimmune, Chugai, Biogen, Acorda, and GlaxoSmithKline. He has received grant support from PCORI, Guthy Jackson Charitable Foundation and Accelerated Cure Project. He owns equity in DioGenix and Amplimmune. BH has served on scientific advisory boards for Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micormet and Genzyme Corporation; serves on the international advisory board of Archives of Neurology and Experimental Neurology; has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five prime, Metanomics, Chugai Pharmaceuticals, Roche and Novartis. OS is on the editorial boards of JAMA Neurology, Multiple Sclerosis Journal, and Therapeutic Advances in Neurological Disorders. He has received grant support from Teva Pharmaceuticals.