bs_bs_banner
`
`doi:10.1111/cei.12206
`
`Clinical and Experimental Immunology
`
`TRANSLATIONAL NEUROIMMUNOLOGY REVIEW SERIES
`Series originators and editors: Olaf Stu¨ve and Uwe Zettl
`
`Requirement for safety monitoring for approved multiple sclerosis
`therapies: an overview
`
`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.
`
`P. S. Rommer,* U. K. Zettl,†
`B. Kieseier,‡ H.-P. Hartung,‡
`T. Menge,‡ E. Frohman,¶
`B. M. Greenberg,¶ B. Hemmer§ and
`O. Stüve‡¶§**
`*Department of Neurology, Medical University
`of Vienna, Vienna, Austria, †Department of
`Neurology, University of Rostock, Rostock,
`‡Department of Neurology, Medical Faculty,
`Heinrich Heine University, Düsseldorf,
`§Department of Neurology, Klinikum rechts der
`Isar, Technische Universität München, Munich,
`Germany, ¶Department of Neurology, University
`of Texas Southwestern Medical Center, and
`**Neurology Section, VA North Texas Health
`Care System, Dallas VA Medical Center, Dallas,
`TX, USA
`
`Accepted for publication 11 September 2013
`Correspondence: O. Stüve, Neurology Section,
`VA North Texas Health Care System, Medical
`Service, 4500 South Lancaster Road, Dallas, TX
`75216, USA.
`E-mail: olaf.stuve@utsouthwestern.edu
`
`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 poten-
`tial 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 terifluno-
`mide, as well as recently approved therapeutics such as dimethyl fumarate
`and alemtuzumab. It also provides recommendations for monitoring the dif-
`ferent drugs during therapy in order to avoid common side effects.
`
`Keywords: activation, acute respiratory distress syndrome, multiple sclerosis
`(MS)
`
`Introduction
`
`Multiple sclerosis (MS) is an inflammatory disease affecting
`young adults and is a major cause of disability [1]. MS phe-
`notypes have been differentiated into relapsing–remitting
`MS (RRMS), primary progressive MS (PPMS) and second-
`ary 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
`
`© 2013 British Society for Immunology, Clinical and Experimental Immunology, 175: 397–407
`
`397
`
`Merck 2034
`TWi v Merck
`IPR2023-00049
`
`

`

`TRANSLATIONAL NEUROIMMUNOLOGY REVIEW SERIES
`
`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®), inter-
`feron beta (IFN-β) preparations (Betaseron®, Extavia®,
`Rebif®, Avonex®), mitoxantrone (Novantrone®), natalizu-
`mab (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 dis-
`cussed 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 Admin-
`istration (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 gen-
`erated to mimic myelin basic protein, and to allow the
`induction of the MS animal model experimental autoim-
`mune
`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 respon-
`sible for some of the effects. Other mechanisms are inhibi-
`tion 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 unpre-
`dictably 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 prescrib-
`ing information. Antibodies
`targeting GA have been
`reported, but it is not plausible that they antagonize its
`
`P. S. Rommer et al.
`
`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).
`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].
`
`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 admin-
`istered 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 reduc-
`tion 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, treat-
`ment with interferon has
`to be discontinued. Severe
`hepatic injury has been reported under treatment with
`IFN-β preparations, mainly when therapy occurs in com-
`bination with other hepatotoxic agents. Depression has
`been reported in patients treated with IFN-β. Therefore,
`symptoms of depression have to be monitored, and treat-
`ment discontinued as indicated. In addition, haematolo-
`gical abnormalities including lymphopenia, neutropenia,
`
`398
`
`© 2013 British Society for Immunology, Clinical and Experimental Immunology, 175: 397–407
`
`

`

`Safety monitoring in MS therapies
`
`Table 1. Therapy monitoring in approved therapeutics. Possible side effects.
`
`TRANSLATIONAL NEUROIMMUNOLOGY REVIEW SERIES
`
`Potential side effects
`
`Recommended monitoring
`
`Glatiramer
`acetate
`Interferon beta
`
`Mitoxantrone
`
`Natalizumab
`
`Fingolimod
`
`Teriflunomide
`
`Alemtuzumab
`
`Dimethyl fumarate
`
`Flushing, chest pain, dyspnoea
`Palpitations, urticaria, skin necrosis
`Flu-like symptoms, injection-site necrosis
`Depression, allergic reactions
`Hepatic injury, neutropenia
`Lipoatrophy
`Congestion heart failure
`Urine colour blue-green
`Birth deficiency, sterility
`Hair loss, nausea
`PML, fever, joint pain
`Liver disease, melanoma
`Allergic reactions
`Bradycardia, heart failure
`Fever, diarrhoea, liver disease
`Macular oedema, skin cancers
`Enzephalities
`Hepatic injury, elevated liver enzymes,
`infections, polyneuropathy
`Autoimmune disorders (thyroid disorders, immune
`thrombocytic purpura), infusion-related side effects
`Lymphopenia, gastrointestinal side effects
`
`None
`
`Liver enzymes
`Blood count
`Thryroid testing
`Neutralizing antibodies
`Left ventricular ejection fraction
`ECG, differential blood count,
`Liver enzymes, pregnancy testing
`
`JC-virus
`Neutralizing antibodies
`
`ECG, cardiological evaluation
`Ophtalmological evaluation
`VZV-antibodies, liver enzymes
`
`Liver enzymes, pregnancy testing,
`white blood count
`Complete monthly blood counts,
`testing for autoimmunity
`White blood cell count
`
`PML: progressive multi-focal leucoencephalopathy; ECG: electrocardiography; VZV: varicella zoster virus.
`
`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 hypothy-
`roidism [28], although other reports could not show a sig-
`nificant 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 auto-
`immune 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 monitor-
`ing. 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).
`
`Table 2. Potential risk of MS therapeutics in pregnancy.
`
`FDA pregnancy
`category
`
`A
`B
`
`C
`
`D
`
`X
`
`Interpretation
`
`Therapeutic agent
`
`Well-controlled trials in pregnant women revealed no increased risk for fetus
`No well-controlled trials, but animal trials revealed no increased risk or
`well-controlled trials revealed no risk, whereas animal trials have shown
`adverse effects
`Animal studies have shown increased risk for the fetus or have not been
`conducted; no well-controlled trials in pregnant women
`Studies have shown harm to the fetus; however, the benefit may outweigh risk
`under certain circumstances
`Studies 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 benefits
`
`Glatiramer acetate
`
`Interferon beta, natalizumab, fingolimod,
`alemtuzumab, dimethyl fumarate
`Mitoxantrone
`
`Teriflunomide
`
`© 2013 British Society for Immunology, Clinical and Experimental Immunology, 175: 397–407
`
`399
`
`

`

`TRANSLATIONAL NEUROIMMUNOLOGY REVIEW SERIES
`
`Like all therapeutic proteins, IFN-β is immunogenic and
`can induce the production of binding and neutralizing anti-
`bodies [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 sig-
`nificance (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 clini-
`cal 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 approxi-
`mately 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 discon-
`tinued 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 investiga-
`tion, 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
`
`P. S. Rommer et al.
`
`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 moni-
`toring 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 likeli-
`hood for lymphoma. These complications have substan-
`tially 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 electro-
`cardiogram (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 signifi-
`cant 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 recom-
`mended 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 admin-
`istered 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 tran-
`sient hair loss or thinning and nausea, and menstrual disor-
`ders 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 con-
`ducted 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).
`
`400
`
`© 2013 British Society for Immunology, Clinical and Experimental Immunology, 175: 397–407
`
`

`

`TRANSLATIONAL NEUROIMMUNOLOGY REVIEW SERIES
`
`Safety monitoring in MS therapies
`
`Natalizumab
`
`Natalizumab is a humanized recombinant monoclonal anti-
`body 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
`identical with α4-chain of α4β1-integrin) is
`(VLA-4;
`decreased in its ability to bind its ligand, vascular cell adhe-
`sion 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 infec-
`tion 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, gastroen-
`teritis, 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, aller-
`gic 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 immuno-
`suppressants 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 sus-
`pected 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 dete-
`rioration is the immune reconstitution inflammatory syn-
`drome (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 anti-
`bodies are typically detectable [54]. The prevalence of neu-
`tralizing 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 cat-
`egory 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 pre-
`vents disease reactivation, discontinuation during preg-
`nancy 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) recep-
`tors 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 sec-
`ondary lymphoid organs are affected, which account for
`approximately 2% of all circulating lymphocytes.
`In
`
`© 2013 British Society for Immunology, Clinical and Experimental Immunology, 175: 397–407
`
`401
`
`

`

`TRANSLATIONAL NEUROIMMUNOLOGY REVIEW SERIES
`
`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 head-
`ache, 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 cur-
`rently 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 sim-
`plex 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 monitor-
`ing 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 hyper-
`tension 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].
`
`P. S. Rommer et al.
`
`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, evalua-
`tion 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 initia-
`tion 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 treat-
`ment of relapsing forms of MS [84] after it had docu-
`mented 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. Prolif-
`eration of autoreactive B and T cells is reduced. Addition-
`ally,
`immunomodulatory effects on the expression of
`cytokines by lymphocytes have been shown [88,89]. The
`exact mechanisms by which teriflunomide mediates its ben-
`efits in MS are not understood fully. Teriflunomide is avail-
`able 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 arthri-
`tis. 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 pres-
`sure have also been observed [86,92].
`Teriflunomide is contraindicated in patients with severe
`hepatic injury. In other patients, liver enzymes have to be
`
`402
`
`© 2013 British Society for Immunology, Clinical and Experimental Immunology, 175: 397–407
`
`

`

`TRANSLATIONAL NEUROIMMUNOLOGY REVIEW SERIES
`
`Safety monitoring in MS therapies
`
`monitored prior to initiation and for at least 6 months after
`initiation. A complete blood count has to be conducted. In
`addi