SEARCH

SEARCH BY CITATION

Keywords:

  • monoclonal antibodies;
  • multiple sclerosis;
  • neuromyelitis optica;
  • progressive multi-focal leukoencephalopathy

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Monoclonal antibodies
  5. Discussion and conclusions
  6. Acknowledgements
  7. Disclosures
  8. References

The therapeutic armamentarium for autoimmune diseases of the central nervous system, specifically multiple sclerosis and neuromyelitis optica, is steadily increasing, with a large spectrum of immunomodulatory and immunosuppressive agents targeting different mechanisms of the immune system. However, increasingly efficacious treatment options also entail higher potential for severe adverse drug reactions. Especially in cases failing first-line treatment, thorough evaluation of the risk–benefit profile of treatment alternatives is necessary. This argues for the need of algorithms to identify patients more likely to benefit from a specific treatment. Moreover, paradigms to stratify the risk for severe adverse drug reactions need to be established. In addition to clinical/paraclinical measures, biomarkers may aid in individualized risk–benefit assessment. A recent example is the routine testing for anti-John Cunningham virus antibodies in natalizumab-treated multiple sclerosis patients to assess the risk for the development of progressive multi-focal leucoencephalopathy. Refined algorithms for individualized risk assessment may also facilitate early initiation of induction treatment schemes in patient groups with high disease activity rather than classical escalation concepts. In this review, we will discuss approaches for individiualized risk–benefit assessment both for newly introduced agents as well as medications with established side-effect profiles. In addition to clinical parameters, we will also focus on biomarkers that may assist in patient selection.

Other Articles published in this series

Paraneoplastic neurological syndromes. Clinical and Experimental Immunology 2014, 175: 336–48.

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.

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.

Requirement for safety monitoring for approved multiple sclerosis therapies: an overview. Clinical and Experimental Immunology 2014, 175: 397–407.

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.

Diagnosis, pathogenesis and treatment of myositis: recent advances 2014, 175: 349–58.

Neuromyelitis optica: clinical features, immunopathogenesis and treatment 2014, 176: 149–64.

Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Monoclonal antibodies
  5. Discussion and conclusions
  6. Acknowledgements
  7. Disclosures
  8. References

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are two distinct chronic progressive inflammatory diseases of the central nervous system (CNS) with different pathophysiology and epidemiology. Both are commonly associated with disability, impairment in quality of life, decreased work capacity and high socioeconomic burden [1-4].

The pathophysiology of MS is complex and highly heterogeneous with both inflammatory and neurodegenerative features [5], resulting in various phenotypes and disease courses.

In contrast, the discovery of aquaporin-4 immunoglobulin (Ig)G as an autoantibody with pathogenetic relevance for NMO [6, 7] had a direct impact on therapeutic approaches.

As most immunotherapies in neuroimmunology have been studied in MS [8-22] and – to a lesser extent – in NMO [23-27], this review focuses on disease-modifying drugs (DMDs) for these autoimmune CNS entities. Treatment options for other neuroimmunological diseases of the central or peripheral nervous system and neuromuscular disorders such as neuro-sarcoidosis [28, 29], myasthenia gravis [30] or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [31] have been reviewed in [32, 33].

Whereas first-line agents used in MS such as interferons and glatirameracetate exhibit moderate efficacy, we have witnessed several decades of use with highly favourable safety profiles [34]. In contrast, newer agents have surprised us with unexpected and sometimes even severe adverse drug reactions (SADR) or unanticipated high frequency of SADRs (Table 1) [35-37].

Table 1. Drugs and reported (severe) adverse reactions.
DrugReported adverse reactions
  1. PML = progressive multifocal leucoencephalopathy; TRAL = therapy-related acute leukaemia.

AlemtuzumabLeucopenia [71], infusion reactions, infections (herpes viruses, tuberculosis), immune-thrombopenia, thyreoiditis, nephritis (Goodpasture syndrome), cancer (thyroid, colon, vulvar) [10-12]
DaclizumabElevated liver enzymes, cutaneous symptoms including severe dermatitis, infections [14, 22]
DimethylfumarateGastrointestinal symptoms, flushing, lymphopenia, proteinuria, pruritus [123, 124]
EculizumabMeningococcal infection and sepsis [27], other infections, infusion reactions, pain (headache, arthralgia, myalgia, back, neck), leucopenia, thrombopenia, anaphylactic and cutaneous reactions, dizziness and vertigo, hypertension, oedema, gastrointestinal symptoms, paraesthesia [161]
FingolimodElevated liver enzymes, gastrointestinal symptoms, viral infections (herpes viruses, influenza), other infections (upper respiratory tract), cardiac arrhythmia, macula oedema, dermal malignancy, lymphopenia, pain (head, back) [9, 18], respiratory effects [105], haemophagocytic syndrome
MitoxantroneElevated liver enzymes [162], gastrointestinal symptoms, transient alopecia [130, 163], infections [145], neutro-/eosinophilia [164, 165], systemic/cutaneous symptoms [164, 165], teratogenicity, transient/permanent infertility [162], amenorrhoea [130, 166], anaemia/leucopenia/thrombopenia [37, 162], cardiotoxicity [36, 143, 150, 153, 155, 167], TRAL [36, 37, 137, 138, 142, 147-149, 159, 168]
NatalizumabElevated liver enzymes, gastrointestinal and cutaneous symptoms, pain (muscular, headache, arthralgia), dysmenorrhoea, infections, infusion reactions, hypersensitivity [169], neutralizing antibodies [170], PML [35, 45, 169], melanoma [171]
Rituximab/CD20-antibodiesInfusion reactions, hypotension, anaphylactic and cutaneous reactions, cytokine release, acute respiratory distress syndrome, cardiac events, infections (bacterial, viral) [102], PML [100]
TeriflunomideElevated liver enzymes, gastrointestinal symptoms, alopecia, neutro-/lymphopenia, infections (urinary tract, pyelonephritis, nasopharynx), pain (back, arthralgia), paraesthesia [116, 117]
TocilizumabElevated liver enzymes, increased cholesterol levels, gastrointestinal and cutaneous symptoms, headache, hypertension, infusion/injection site reactions, hypersensitivity, infections (respiratory tract, pneumonia), neutropenia, thrombopenia, neutralizing antibodies [172-174]

Due to the hypothesized selective mechanisms of action, fewer side effects were anticipated for different therapeutic monoclonal antibodies (mAB) coined initially as ‘magic bullets’ [38]. Rare but occasionally fatal adverse drug reactions have evolved; however, their pathophysiology is still not well explained. Based on potential SADRs, approval for substances such as natalizumab (NAT), mitoxantrone (MX) and – at least in some countries – fingolimod (FTY) was restricted to patients refractory to first-line MS treatment options or with highly aggressive disease course; but labelling is different from the formal inclusion criteria of respective clinical trials. In addition, restriction to escalation therapy may carry the risk of omission bias, i.e. the decision not to treat patients with potential high benefit in order not to put them actively at risk for SADRs. In the face of newly introduced highly efficacious treatment options, strategies are thus needed that allow patient selection and counselling based on individualized safety and efficacy considerations. Selected patient groups at risk of rapidly developing high disability may particularly benefit from a ‘hit hard and (relatively) early’ treatment strategy.

Optimization of the benefit-to-risk ratio for individual substances can be achieved on multiple levels, including (a) patient selection according to clinical/paraclinical criteria, (b) optimization of treatment and monitoring protocols, (c) identification of patients at higher risk for SADRs and (d) the development of biomarkers for treatment response and/or risk profile (Fig. 1).

figure

Figure 1. Factors of risk–benefit assessment.

Download figure to PowerPoint

In the following we will discuss these aspects, focusing on treatment of MS and NMO with mAbs (NAT, alemtuzumab, daclizumab and others), FTY, teriflunomide, dimethylfumarate (DMF) and MX.

Monoclonal antibodies

  1. Top of page
  2. Summary
  3. Introduction
  4. Monoclonal antibodies
  5. Discussion and conclusions
  6. Acknowledgements
  7. Disclosures
  8. References

Natalizumab

Patient selection

The alpha-4-integrin-inhibitor natalizumab (Tysabri®) [39] was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2005/06 for the treatment of highly active forms of the relapsing–remitting disease course (RRMS), but not chronic progressive forms [primary or secondary progressive MS (PPMS, SPMS)]. Efficacy in SPMS is under investigation in a Phase IIIb study, ASCEND in SPMS (A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With SPMS; ClinicalTrials.gov NCT01416181). Therapeutic efficacy has also been reported in paediatric cohorts with high disease activity [40, 41].

In NMO, the use of NAT should be avoided, as current data suggest negative effects on relapse rate and disease progression as well as severe astrocyte damage in spite of natalizumab treatment [42, 43].

Treatment and monitoring

Monthly NAT administration is standard treatment. So far, there are only few data on the prolongation of infusion intervals [44]. The REFINE trial (Exploratory Study of the Safety, Tolerability and Efficacy of Multiple Regimens of Natalizumab in Adult Subjects With Relapsing Multiple Sclerosis (MS); ClinicalTrials.gov NCT01405820) is investigating both different dosing schemes and application routes [intravenous (i.v.), subcutaneous (s.c.)]; thus far, this approach cannot be recommended outside clinical trials.

Safety considerations and monitoring were profoundly influenced by the occurrence of progressive multi-focal leucoencephalopathy (PML). This is a relatively rare but potentially fatal (22%) opportunistic viral infection of the CNS which can result in severe disability in 40% of the patients [45]. Epidemiological data on the frequency of NAT-associated PML has shown an increase of PML incidence after a treatment duration of 2 years (i.e. 24 infusions) [45]. Thus, therapy continuation for more than 24 infusions requires updated documented informed consent [46] and re-evaluation of the individual risk–benefit ratio. In addition, adequate counselling of patients and relatives is crucial for the early recognition of symptoms and signs of possible PML, as neuropsychological symptoms may prevail initially.

Regular clinical monitoring and magnetic resonance imaging (MRI) are required to detect symptoms suggestive of PML or suspicious lesions [47]. More frequent MRI scanning should be performed in high-risk patient groups (e.g. 3-monthly after a treatment duration of > 24 months).

SADR risk

Pathogenesis of PML – the most feared potential SADR of NAT – is multi-factorial, comprising cellular immunity of the host [48], reactivation of latent John Cunningham virus (JCV) infection or new infection combined with genetic variation of the virus. Both viral and host factors predisposing for PML development are under investigation. The differentiation between virulent and non-virulent JCV variants may be helpful, but relies on viraemia [49] and so far is not sufficiently validated.

Epidemiological risk factors for PML development are previous use of immunosuppressants, a positive anti-JCV antibody status and treatment duration [45, 50-52]. Hence, the estimated PML incidence ranges from ≤ 0·09/1000 to 11·1/1000 [45]. A total of 418 NAT-PML cases have been reported (as of November 2013 [53]).

PML must be suspected when new neurological symptoms occur in individuals on NAT therapy. In particular, neuropsychological symptoms and seizures are highly suspicious, whereas spinal or optic nerve symptoms are uncommon. Its diagnosis is based on clinical findings, MRI [47] and the detection of JCV DNA in cerebrospinal fluid (CSF) [35, 54], although there are JCV DNA-negative NAT–PML reports [55, 56]. In uncertain cases, biopsy of suspicious lesions has to be discussed.

In the course of PML, immune reconstitution inflammatory syndrome (IRIS) can occur with a mean of about 1 month after NAT removal via plasma exchange [57]. This inflammatory reaction directed against JCV can cause additional tissue damage with neurological deterioration after initial improvement after PML diagnosis. NAT and JCV elimination as well as control of IRIS evolution must be covered by PML treatment strategies which comprise plasma exchange, mefloquine, mirtazapine and corticosteroid pulses [35, 58]. However, due to relatively low patient numbers, none of these treatment options are evidence-based.

Although the outcome of NAT–PML seems to be better than HIV-associated PML [57], it is associated with disability [45, 57]. Seizures occur in more than 50% of patients [59] and are often linked to the appearance of IRIS, explaining the higher rate than in other PML cases; preventive anti-convulsive therapy may thus be beneficial [59].

Biomarkers

Routine anti-JCV antibody testing is established in clinical practice. However, false negative rates have to be considered for both first- and second-generation anti-JCV antibody testing. There is also a considerable proportion of seroconverters and – possibly linked to fluctuating antibody titres at the detection threshold – patients reverting from seropositive to seronegative [45, 52, 60, 61].

The prevalence of anti-JCV antibodies differs in patient groups according to age and gender [52]. Two studies reported antibody titres rather than mere serostatus. In one study, sera from patients who were diagnosed later with PML exhibited higher anti-JCV antibody reactivity than other seropositive patients [52]. In five patients from whom sera prior to PML diagnosis were available, antibody titres increased 5–10 months before PML diagnosis [61]. Methodological issues such as fluctuating serostatus around assay cut-points [52, 61] and false negative rates [60] argue for a refinement of assay procedures with better reproducibility in low-antibody reactivity ranges. Thus, a second-generation enzyme-linked immunosorbent assay (ELISA) with a reported sensitivity of 98% [62] was introduced; however, so far an independent validation is lacking. Using this refined assay, the possible value of antibody reactivity for PML risk stratification was reported recently as abstract. Whereas increased immunoreactivity to JCV prior to PML would be biologically plausible, more data are needed to corroborate these initial findings.

Higher NAT plasma levels have been associated with lower body mass index and a supposedly higher risk for the development of PML, which needs to be further confirmed as a possible biomarker feasible for clinical routine [44].

Host factors promoting PML development include the determination of immunocompetence. It has been shown conclusively that both CD4+ and CD8+ T cells are important in the immune response to JCV and containment of PML [48, 63]. Investigation of the role of CD4+ T cells has demonstrated a lacking or even anti-inflammatory interleukin (IL)-10 response to JCV in a small number of PML patients [64]. Intracellular adenosine triphosphate (ATP) levels as a functional parameter of T cell function were decreased in CD4+ T cells both after long-term NAT treatment and PML of different aetiology [65]. However, this assay was confronted with pre-analytical difficulties, so far impeding application in larger validating studies or clinical routine, as shown by analysis of STRATA samples (Natalizumab Re-Initiation of Dosing; ClinicalTrials.gov NCT00297232) that could not confirm ATP decrease in five pre-PML samples [66]. However, heterogeneous intervals of testing before PML onset may have influenced these results. It may be hypothesized that individual courses of ATP levels are more critical than absolute ATP level, and that a critical time-point of ATP decrease before PML onset has to be determined.

Recently, a lower proportion of L-selectin-expressing CD4+ T cells was associated with higher PML risk in NAT-treated MS patients (n = 8). Further validation as a potential biomarker for PML risk stratification is warranted [67]. The determination of its biological plausibility remains unclear thus far, as it might express the general activation status of the peripheral immune system or a defective T cell response to JCV infection on different levels [67].

Lesions suggestive of PML may be detected on MRI before clinical PML manifestation [68], which argues for frequent MRI scanning in patients at high risk for PML evolution such as patients on long-term NAT treatment (> 24 infusions) or with previous immunosuppressive treatment. Characteristic PML lesions have been described as large, subcortical, grey-matter-sparing lesions appearing hyperintense on T2 and fluid-attenuated inversion recovery and hypointense on T1 scans; contrast enhancement may occur [47].

Alemtuzumab

Patient selection

The anti-CD52 mAb alemtuzumab (Lemtrada®) has been shown to be highly effective and is approved for active relapsing MS in Europe [10-12, 69]. Disease activity is defined as clinical or radiological deterioration [70]. Mechanisms of action include depletion of CD52-expressing T/B lymphocytes, natural killer (NK) cells, dendritic cells and monocytes/macrophages with skewed repopulation leading to a reprogramming of the immune repertoire [71, 72]. Already in earlier studies, patients especially with an early relapsing disease course appeared to benefit most from alemtuzumab treatment, leading to the concept of a therapeutic window relatively early during the disease, when highly active immunotherapy may exert most profound effects [72]. This was reflected in the inclusion criteria for the pivotal Phase III trials CARE-MS I and II (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Studies One and Two). CARE-MS I included active relapsing, therapy-naive MS patients, whereas CARE-MS II focused on relapsing MS refractory to first-line therapy [10, 12]. Especially in terms of disease progression, the latter patient group appeared to benefit most. Whereas current EMA approval is relatively broad [70], careful patient selection is mandatory, as SADRs have been reported and thorough adherence to safety assessments is necessary. This is stressed by long-term data from the Phase II trial CAMMS223, with one additional SADR (Goodpasture syndrome), but also sustained reduction of disability accumulation and relapse rates compared to active comparator [73], revealing the dilemma of long-lasting efficacy versus potential SADRs.

Treatment and monitoring

Alemtuzumab is applied intravenously with a first treatment cycle of 12 mg over 5 days, followed by a second therapy cycle over 3 days after 12 months [10, 12, 69]. Further cycles are not intended, but the question of when and how to continue DMD treatment after two cycles is unanswered. There is no class I evidence for different treatment protocols in this indication.

During and for 1 month after treatment, acyclovir (200 mg twice daily) has to be administered prophylactically.

Therapy surveillance with large treatment intervals, but necessarily close safety monitoring, will be a challenge in clinical practice [74] and emphasizes even more the importance of patient education, counselling and informed consent to assure adherence to safety measures. These include differential blood count, serum creatinine and urine analysis before first administration and monthly afterwards; regular testing of thyroid stimulating hormone (TSH) levels has to be performed before treatment initiation and every 3 months up to 4 years after the last administration [70].

SADR risk

Secondary antibody-mediated autoimmunity, even with fatal outcome, has been observed. This includes cases of autoimmune thrombocytopenia (1–3%), thyroiditis (16–30%) and nephritis due to glomerular basal membrane disease (single cases) (Table 1) [10-12, 69]. These SADRs may occur with late onset up to 4 years after treatment cessation [73], which highlights the need for adequate monitoring long after the actual infusion cycles (see above).

SADRs from oncological indications, e.g. myelodysplastic changes and tuberculous hepatitis [75, 76], have thus far not been experienced in MS based on available long-term data from applications of CAMPATH-IH in the 1990s [77] or the Phase II trial CAMMS223 [73].

Biomarkers

Pathogenesis of secondary autoimmune phenomena remains incompletely understood, but the skewed repopulation with an imbalance of B cells and regulatory T cells may partly account for these SADRs [78]. The prognostic value of serum IL-21 as a risk marker for the development of secondary autoimmunity [79] was not confirmed. Hence, routine blood parameters and urinalysis remain critical regarding patient safety and early detection of SADRs.

Daclizumab

Patient selection

Daclizumab, used initially in transplant medicine, targets CD25, the alpha chain of the IL-2 receptor (IL-2Rα) [80, 81]. It is currently investigated on a Phase III level in RRMS after promising Phase II data. Daclizumab was investigated initially in combination with interferon (IFN)-beta [22]. Meanwhile a modified formulation for s.c. monotherapy [daclizumab high-yield process (dac-HYP)] demonstrated clinical and paraclinical efficacy in a Phase II study in RRMS [14]. Inclusion criteria required confirmed clinical or MRI disease activity [14]. A paediatric study on seven patients showed some efficacy of daclizumab as second-line treatment; however, four children experienced further disease activity [82].

Treatment and monitoring

The ongoing dac-HYP Phase III trial DECIDE (Efficacy and Safety of Daclizumab High Yield Process Versus Interferon β 1a in Patients With Relapsing-Remitting Multiple Sclerosis; ClinicalTrials.gov NCT01064401) has left the 300-mg dosage in favour of a 150-mg subcutaneous dosage every 4 weeks.

SADR risk

The mode of action of daclizumab appears to be pleiotropic despite selective blockade of IL-2Rα: thus, expansion of regulatory CD56bright NK cells [80, 83], reduction of proinflammatory signals [84] and interaction between T cells and antigen-presenting cells (APC) have been described [81].

To date, data on daclizumab show good tolerability and safety (Table 1) [14, 22]. However, the Safety and Efficacy Study of Daclizumab High Yield Process to Treat Relapsing-Remitting Multiple Sclerosis (SELECT) reports a fatal case after a series of events with initial possibly drug-related dermatitis [14]. A single case report on secondary CNS vasculitis has recently been published and was evaluated as linked to daclizumab treatment [85]. Long-term data and data from the Phase III trial are pending.

Biomarkers

Putative surrogate markers, especially CD56bright NK status, have been described for daclizumab-treatment responders [84]. In addition, they have been suggested for risk evaluation [85].

Other mAbs

Several other mAbs are being investigated in clinical programmes or used on an off-label basis for otherwise treatment-refractory neuroimmunological disease.

The chimeric anti-CD20 mAb rituximab (MabThera®) is approved for haematological indications. In several countries, rituximab is recommended as first-line treatment for NMO, although not approved for this indication. For the malignant NMO disease course refractory to other treatment options, use of the IL-6-receptor mAb tocilizumab (RoActemra®, approved for rheumatoid arthritis) or the terminal complement inhibitor eculizumab (Soliris®, approved for paroxysmal nocturnal haemoglobinuria) has been reported.

Patient selection

Especially for substances used on an off-label basis, patient selection is based on single-case decisions, sometimes supported by preclinical experimental data.

Beneficial outcomes in smaller studies were reported for the anti-CD20 mAb rituximab in different neurological autoimmune conditions such as RRMS [8, 15], NMO [86-88], myasthenia gravis [30, 89] and multi-focal motor neuropathy [90, 91]. In PPMS, only a subgroup of younger patients with focal inflammatory activity on cranial MRI appeared to have some benefit from rituximab treatment. There are some data on rituximab use in paediatric populations with different neuroimmunological conditions [92-94].

Treatment with the IL-6 receptor mAb tocilizumab was efficacious in single cases of NMO refractory to rituximab [23, 95] and other neuroimmunological conditions [96-98].

Inhibition of the complement system via eculizumab has been tested in a small number of NMO patients with positive results. As mostly feared from treatment of paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome, it was associated with one case of meningococcal sepsis from a total of 14 patients [27].

These concepts will have to be confirmed in larger prospective trials to evaluate efficacy and safety in neurological patient cohorts.

Treatment

Although formally off-label in each of the neuroimmunological disorders, rituximab is recommended as the first-line DMD for treatment of NMO in respective guidelines with two suggested regimens (haematological protocol 375 mg/m2 body surface area weekly over 4 weeks versus 2 × 1 g) [46, 99].

SADR risk

Adverse effects reported mainly from other indications are given in Table 1.

Rituximab-associated PML cases are described in rheumatoid arthritis, systemic lupus erythematosus and haematological populations, with combined rituximab and immunosuppressants [100, 101]. However, the risk appears to be considerably lower than with NAT–PML in MS [101]. Due to the high frequency of infusion-related adverse events [102], newer anti-CD20 mAb have been studied on a Phase II level, the humanized ocrelizumab [17] and human ofatumumab [21]. Results of further studies are pending. The clinical development of ocrelizumab in rheumatoid arthritis has been abandoned due to adverse effects. Eculizumab treatment has raised the special concern of meningococcal infections [27].

Biomarkers

Data on specific biomarkers for most of the agents described are widely lacking.

Repopulation of B cells via detection of CD19+ and CD20+ cells is sometimes used to determine reinfusion intervals for rituximab treatment, as it may be correlated with disease activity [103].

Fingolimod

Patient selection

FTY entails peripheral immunomodulatory effects and direct interactions within the CNS resulting from modulation of sphingosin-phosphate receptors (S1PR) [104]. Approval of Gilenya® for treatment of RRMS differs substantially between FDA and EMA [105, 106], reflecting divergent evaluations of its risk–benefit profile. Whereas, in the United States, FTY is approved as first-line therapy, in the European Union it is considered second-line therapy predominantly after a failure of IFN-beta or glatirameracetate. This approach is supported, at least in part, by subgroup analyses of the TRANSFORMS (TRial Assessing injectable interferoN vS FTY720 Oral in RrMS) study, especially for patients with high disease activity on IFN-beta therapy [107]. Ongoing studies investigate the use of FTY in PPMS (ClinicalTrials.gov NCT00731692), in paediatric MS (ClinicalTrials.gov NCT01892722) and in CIDP (ClinicalTrials.gov NCT01625182). Siponimod, a specific modulator of S1PR subtypes 1 and 5, [108] is being evaluated in a trial in SPMS patients (ClinicalTrials.gov NCT01665144).

Specific risk populations comprise patients with predisposing conditions for the development of macula oedema such as diabetes mellitus and (recurrent) uveitis. Patients with pre-existing cardiac arrhythmia, negative dromo- and chronotropic co-medication and pre-existing pulmonary disease should be evaluated closely. In addition, assessment of varizella zoster (VZV) immune status is mandatory [106].

Treatment and monitoring

FTY is administered orally as a 0·5-mg capsule once daily. Before treatment initiation, laboratory investigations including differential blood count, liver enzymes, pregnancy test and VZV status have to be performed. VZV-IgG-negative patients should be vaccinated. Electrocardiography (ECG) and continuous ECG monitoring are recommended during first-dose administration and selectively afterwards. Ophthalmological and dermatological screening are recommended as routine pretreatment investigation, most importantly in risk populations (see Patient selection). Routine laboratory testing, especially for lymphopenia, is required at close intervals; dermatological, opthalmological and pneumological check-up should be implied in bigger, but regular, intervals or by clinical indication [106]. Because FTY can moderately raise blood pressure, especially in hypertensive patients, blood pressure measurements should be performed regularly.

SADR risk

The described safety measures account for the potential adverse effects of FTY such as pronounced lymphopenia (0·2–1·0%) and cardiac arrhythmia, including symptomatic bradycardia (0·5–2·4%) and atrio-ventricular block (0·2–0·7%), macular oedema (0·5–1%), herpes infections (2·1–5·5%) and skin malignancies (0–0·7%) [9]. Optical coherence tomography (OCT) may help to detect increased macular volume that seems to occur frequently under FTY treatment; however, macular oedema is a rare condition [109, 110].

Two deaths were reported due to herpes virus infections: a primary VZV infection and a herpes-simplex encephalitis [9]. A PML case is being discussed [111], but thus far has not been fully elucidated.

In the post-marketing setting, mainly cardiac events have been reported thus far and have led to extended cardiovascular safety monitoring [112]. Recently, the marketing authorization holder published two fatal cases of haemophagocytic syndrome (HPS) associated with a 9- and 15-month treatment period with FTY. HPS is triggered typically by (viral) infections such as Epstein–Barr virus, as in the cases described. It results in a severe disturbance of the immune system and multi-organ involvement including fever, lymphadenopathy, organomegaly, cytopenia, liver failure and various neurological symptoms. Early diagnosis and treatment of both the triggering condition and the overwhelming immune response via immunosuppressive means are crucial to reduce mortality of HPS.

Biomarkers

The described safety set-up implies several putative biomarkers, although not evaluated formally thus far in terms of prediction of response or determination of SADR development. However, evaluation of lymphocyte counts may serve not only as a necessary safety measurement, but also as a therapy adherence marker.

Subclinical impairment of VZV and Epstein–Barr-virus reactivity have been found recently [113].

Teriflunomide

Patient selection

Teriflunomide (Aubagio®) is the active metabolite of leflunomide, a disease-modifying anti-rheumatic drug (DMARD). It is an inhibitor of the dihydroorotate dehydrogenase and interacts with de-novo pyrimidine synthesis [114].

Although the pivotal trial included 8·6% of SPMS patients [115, 116], it has been approved by the FDA and EMA for RRMS. Specific contraindications for teriflunomide include severe hepatic or renal disorders and hypoproteinaemia (due to high plasma protein-binding) [117]. As experimental data hint at teratogenic potential, FDA prescription guidelines emphasize the restriction of teriflunomide during pregnancy [118]. It may be hypothesized that teriflunomide treatment may be especially beneficial with co-existing neuroimmunological and rheumatic disorders. Due to the long half-life of the drug and pronounced enterohepatic recirculation, teriflunomide might be an option in patients having difficulties with adherence to treatment schedules, but may be used more cautiously in patients with an impending wish for children.

Treatment and monitoring

Oral teriflunomide is administered once daily, 7 or 14 mg (FDA approval), or 14 mg (EMA approval) [116]. Due to moderate elevation of blood pressure, regular blood pressure controls before and on treatment as well as the exclusion of severe infections before initiation are recommended. Interactions with warfarin [decrease of international normalized ratio (INR)] need to be controlled with frequent INR monitoring. There are no data with regard to marcumar, which is used more commonly in European countries. Adjunctive teriflunomide treatment with IFN-beta or glatirameracetate has been evaluated in several trials – Phase II trials showed a favourable safety profile and positive MRI outcomes [119] (and ClinicalTrials.gov NCT00475865), the results of extensions and other studies are pending. Regarding long drug half-life, drug washout after discontinuation can be accelerated via cholestyramine or activated charcoal powder [117], which is relevant in cases of unplanned pregnancy, newly acquired co-morbidities or rapid switch to other immune medications.

SADR risk

Long-term safety data on teriflunomide are being followed-up in extensions of Phases II and III trials (ClinicalTrials.gov NCT00228163, NCT00803049) [120]. Experience on SADRs has been widely favourable, but includes the rare occurrence of potentially fatal infections and tuberculosis (Table 1). Whereas severe liver injury was not reported in the clinical development programme of teriflunomide, few cases were reported with leflunomide. Thus, risk assessment for teriflunomide is conservative, with extrapolation from post-marketing experience with leflunomide of more than 2·1 million patient years.

Biomarkers

Plasma levels of teriflunomide can be measured that might be useful in special situations such as pregnancy in order to monitor the rapid elimination procedure [117].

Ongoing or projected studies are investigating the influence of teriflunomide on brain pathology by use of MRI (ClinicalTrials.gov NCT01881191) and the role of lymphocyte subsets as biomarkers for teriflunomide therapy (ClinicalTrials.gov NCT01863888).

Dimethylfumarate

Patient selection

Dimethylfumarate (DMF) is described to have differential modes of action, including anti-inflammatory [e.g. enhanced T helper type 2 (Th2) response, T cell apoptosis] and potentially neuroprotective aspects [modulation of the nuclear (erythroid-derived 2)-related factor (Nrf2) pathway, anti-oxidative effects] [121, 122]. Two Phase III trials have shown efficacy of DMF in RRMS [123, 124].

Due to possible gastrointestinal side effects, application of DMF in patients with severe gastrointestinal disorders such as peptic ulcers should be assessed cautiously. Whereas DMF (Tecfidera®) is approved in the United States, as of October 2013 marketing in the European Union has not yet begun.

Treatment and monitoring

DMF is an oral compound administered twice daily at a dose of 240 mg. The administration of 720 mg per day has not shown higher efficacy than the 480 mg daily dose [123, 124]. In order to improve the tolerability of DMF, dose titration is recommended. Lymphopenia will presumably be addressed in safety monitoring schedules in European treatment guidelines. This has not been accounted for in US prescription guidelines.

SADR risk

Similar to other agents discussed in this review, for fumaric acid esters there is also experience on the safety profile from other indications than MS. Fumaderm®, a mixture containing DMF as well as other different monoethyl fumarate salts, has been approved for the treatment of psoriasis since the early 1990s, and dermatological experience suggests a favourable safety profile with more than 185 000 patient years. However, PML cases have been reported recently during psoriasis treatment with fumaric esters [125-128], although confounding factors were identified in these cases. Two cases had experienced long-lasting lymphopenia without treatment adaption, as recommended [126, 127]; the other cases had a history of sarcoidosis, cancer, previous mAb (efalizumab) and immunosuppressive (methotrexate) treatment [128]. Tecfidera®, also with differences regarding galenics, is approved for MS. Thus far, no signal for opportunistic infections such as PML have been reported from the clinical programme or the short post-marketing interval (US) with Tecfidera®.

Biomarkers

The regular assessment of leuco- and lymphocyte counts is sensible and may serve treatment surveillance. At 1 year of treatment, leuco- and lymphocyte counts decreased by 10–12% and 28–32% (mean), respectively; 4–5% of patients experienced total lymphocyte counts below 0·5 × 109 per litre [123, 124].

As in other DMD treatments, regular MRI under DMF therapy will be reasonable for both therapy monitoring and determining effectiveness.

Mitoxantrone

Patient selection

Mitoxantrone (MX, Ralenova®/Novantrone®) has been approved for the treatment of secondary progressive and progressive relapsing MS following two placebo-controlled trials [19, 129] and two studies comparing MX or MX in combination with methylprednisolone (MP) to MP alone [130, 131]. Data on MX in primary progressive MS (PPMS) is discouraging [132-134], but has gained relevance in NMO treatment [24, 25]. Although not formally approved, MX has been used in children with aggressive forms of MS [135].

Treatment and monitoring

Different treatment protocols may be an influencing factor for SADR development, especially in terms of therapy-related acute leukaemia (TRAL) [136]. Whereas an intravenous infusion every 3 months according to the placebo-controlled, double-blind, randomised, multicentre, phase III trial of mitoxantrone in secondary progressive multiple sclerosis (MIMS) protocol [129], including dose adaption according to leucocyte nadir, is used widely in Germany, dose regimens differ substantially and may not include regular dose adaption [137, 138].

Additional differences may comprise pre- or co-treatments [37]. Thus, MP co-treatment has been shown to increase intracellular MX dosage in vitro [139], and may thus increase cellular toxicity.

Treatment de-escalation should be considered after 1 year of clinical and paraclinical stability of disease to minimize the risk of at least partially dose-dependent SADRs (e.g. cardiotoxicity). Haematological monitoring should include regular examination of blood counts up to 5 years after cessation of MX [140-142]. Cardiac ultrasound and electrocardiography (ECG) should be performed accordingly, as late-onset cardiotoxicity is described [143].

Thorough monitoring and vigilance is especially relevant for TRAL, as secondary leukaemia is potentially curable if diagnosed early and treated adequately [144], but is associated with potentially fatal complications [145-147] if overlooked.

SADR risk

Discussions about SADR incidence, especially TRAL and cardiotoxicity [36, 37, 137, 138, 142, 148-152], have led to reassessment of the proper risk–benefit profile of MX.

TRAL incidences vary from 0·07% [149] to 2·82% [138] and are subject to methodological difficulties (e.g. reporting bias especially for meta-analyses [36, 149] and largely lacking prospective data). Interestingly, there seem to be regional differences of TRAL incidence with similar German and French estimates [37, 142], but higher Italian and Spanish rates [137, 138].

Estimates of the incidence of cardiotoxicity are complicated by different definitions of an adverse cardiac event [reporting of clinical events versus paraclinical abnormalities in ECG, transthoracal echocardiography (TTE) [153] and radionuclide ventriculography [143, 150, 154]]. Subclinical decrease of left ventricular ejection fraction (LVEF) in TTE may be a dose-dependent effect [153]; however, this has not been confirmed by a study with 14% incidence of LVEF decrease in radionuclide ventriculography without dose-dependency [150]. Data on recovery and prognosis of cardiac events are inconsistent [143, 150, 151, 153, 155, 156].

Biomarkers

Clinical and paraclinical parameters for the prediction of MX response have been established [157].

SADR development might be associated with pronounced or lasting leucopenia before TRAL onset [37] and increased brain natriuretic peptide (BNP) in subclinical myocardial injury [158].

In addition to treatment-related factors, genetic factors (genes involved in detoxification: CYP3A4; cellular drug efflux: ABCB1, ABCG2; DNA repair: BRCA2, XRCC5) may influence susceptibility for SADRs [139, 155, 159]. Pharmacogenetic approaches may help early identification of patients at higher risk for side effects or even individualized treatment schemes.

Discussion and conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Monoclonal antibodies
  5. Discussion and conclusions
  6. Acknowledgements
  7. Disclosures
  8. References

The growing spectrum of treatment options for neuroimmunological diseases confronts us with complex risk–benefit considerations and treatment decisions. Whereas established first-line DMDs such as interferon-beta formulations and glatirameracetate are generally safe, newly emerging DMDs with higher efficacy often carry a higher potential of adverse effects with thorough therapy monitoring requirements. Long monitoring intervals, even after cessation of therapy, also pose new challenges for adherence to respective protocols.

If not in the clinical trial setting (FTY, alemtuzumab), post-marketing experience (NAT) has revealed relevant or even completely new safety issues not anticipated previously. We have to keep in mind that, for example, in order to identify an event occurring at a frequency of 0·1% as an adverse drug reaction, a sample size of 50 000 would be necessary to observe a twofold increased adverse event rate in comparison to a control group [160]. This emphasizes the need for thorough post-marketing surveillance, Phase IV trials and drug registries to enhance patient safety. Such studies would also be valuable as validation studies for putative biomarkers.

Principles for optimization of the benefit-to-risk ratio comprise thorough patient selection according to distinct clinical criteria, proper treatment intervals, dosage and duration, the evaluation of (individual) risk profiles for SADRs and the investigation and validation of biomarkers for risk stratification and treatment benefit. The transfer of these principles into clinical practice is difficult, and has thus far been only partially achieved for the substances described.

Treatment decisions may be based not only on ‘classic’ first- and second-line dichotomy and parallel concepts [‘hit hard and (relatively) early'] may be beneficial in distinct patient groups. Current guidelines tend to emphasize individual factors and contraindications to alleviate treatment decisions.

Safety monitoring of patients begins before treatment initiation and outlasts the actual active treatment period as, for many SADRs, late-onset cases have been reported.

For all treatment options discussed, routine laboratory investigations of liver and renal function, thorough assessment of existing severe infections or immunosuppression for any cause is relevant to allow safe treatment initiation, just as important as the assessment of pregnancy and information of (especially female) patients in terms of reproductive issues.

Regular safety assessments help in the early detection of severe side effects or their prodromal signs and symptoms. Clinical vigilance and education of patients for signs and symptoms of SADRs is key for improving the safety of modern DMD therapy, as early accurate treatment of SADRs is crucial and of prognostic relevance. Early interdisciplinary co-operation is necessary, as SADRs for many agents are described not only in the neurological field (PML, neuropathy, CNS infection), but also in dermatological, ophthalmological and internal medicine. Counselling of patients may also include gynaecological and/or andrological advice.

Biomarkers for SADR prediction and pharmacogenetic approaches for different agents will have to be validated in larger patient cohorts and may alleviate therapeutic decisions in the future.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Monoclonal antibodies
  5. Discussion and conclusions
  6. Acknowledgements
  7. Disclosures
  8. References

This work was supported by the German Bundesministerium für Bildung und Forschung (BMBF), German competence Network Multiple Sclerosis (KKNMS), 01GI0914.

Disclosures

  1. Top of page
  2. Summary
  3. Introduction
  4. Monoclonal antibodies
  5. Discussion and conclusions
  6. Acknowledgements
  7. Disclosures
  8. References

A. S. has received personal compensation for activities with Novartis, Sanofi and Almirall Hermal GmbH. R. G. has received personal compensation for activities with Bayer Healthcare, Biogen Idec and Teva Neuroscience and in an editorial capacity from Therapeutic Advances in Neurological Disorders, and also received patent payments from Biogen Idec and research support from Bayer Healthcare, Biogen Idec, Merck Serono, Teva Neuroscience, Novartis and from the German Ministry for Education and Research [BMBF, ‘German Competence Network Multiple Sclerosis’ (KKNMS), CONTROL MS, 01GI0914]. A. C. has received personal compensation for activities with Almirall Hermal GmbH, Bayer Schering, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience, research support from Bayer Schering, Biogen Idec, Merck Serono and Novartis and research grants from the German Ministry for Education and Research [BMBF, ‘German Competence Network Multiple Sclerosis’ (KKNMS), CONTROL MS, 01GI0914].

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Monoclonal antibodies
  5. Discussion and conclusions
  6. Acknowledgements
  7. Disclosures
  8. References
  • 1
    Thompson AJ, Toosy AT, Ciccarelli O. Pharmacological management of symptoms in multiple sclerosis: current approaches and future directions. Lancet Neurol 2010; 9:11821199.
  • 2
    Jacob A, McKeon A, Nakashima I et al. Current concept of neuromyelitis optica (NMO) and NMO spectrum disorders. J Neurol Neurosurg Psychiatry 2013; 84:922930.
  • 3
    Flensner G, Landtblom AM, Soderhamn O, Ek AC. Work capacity and health-related quality of life among individuals with multiple sclerosis reduced by fatigue: a cross-sectional study. BMC Public Health 2013; 13:224.
  • 4
    Chanson JB, Zephir H, Collongues N et al. Evaluation of health-related quality of life, fatigue and depression in neuromyelitis optica. Eur J Neurol 2011; 18:836841.
  • 5
    Hafler DA, Slavik JM, Anderson DE, O'Connor KC, De Jager P, Baecher-Allan C. Multiple sclerosis. Immunol Rev 2005; 204:208231.
  • 6
    Hinson SR, Pittock SJ, Lucchinetti CF et al. Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica. Neurology 2007; 69:22212231.
  • 7
    Lennon VA, Wingerchuk DM, Kryzer TJ et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004; 364:21062112.
  • 8
    Bar-Or A, Calabresi PA, Arnold D et al. Rituximab in relapsing–remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol 2008; 63:395400.
  • 9
    Cohen JA, Barkhof F, Comi G et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362:402415.
  • 10
    Cohen JA, Coles AJ, Arnold DL et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing–remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012; 380:18191828.
  • 11
    Coles AJ, Fox E, Vladic A et al. Alemtuzumab versus interferon beta-1a in early relapsing–remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol 2011; 10:338348.
  • 12
    Coles AJ, Twyman CL, Arnold DL et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012; 380:18291839.
  • 13
    Edan G, Comi G, Le Page E, Leray E, Rocca MA, Filippi M. Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: a 3-year randomised trial. J Neurol Neurosurg Psychiatry 2011; 82:13441350.
  • 14
    Gold R, Giovannoni G, Selmaj K et al. Daclizumab high-yield process in relapsing–remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 2013; 381:21672175.
  • 15
    Hauser SL, Waubant E, Arnold DL et al. B-cell depletion with rituximab in relapsing–remitting multiple sclerosis. N Engl J Med 2008; 358:676688.
  • 16
    Kappos L, Bates D, Edan G et al. Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring. Lancet Neurol 2011; 10:745758.
  • 17
    Kappos L, Li D, Calabresi PA et al. Ocrelizumab in relapsing–remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011; 378:17791787.
  • 18
    Kappos L, Radue EW, O'Connor P et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362:387401.
  • 19
    Millefiorini E, Gasperini C, Pozzilli C et al. Randomized placebo-controlled trial of mitoxantrone in relapsing–remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol 1997; 244:153159.
  • 20
    Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG. Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results. Neurology 2007; 69:785789.
  • 21
    Soelberg Sorensen P, Drulovic J, Havrdova E, Lisby S, Graff O, Shackelford S. Magnetic resonance imaging (MRI) efficacy of ofatumumab in relapsing–remitting multiple sclerosis (RRMS) = 24-week results of a phase II study. ECTRIMS; October 13–16, 2010; Gothenburg, Sweden P136 2010.
  • 22
    Wynn D, Kaufman M, Montalban X et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol 2010; 9:381390.
  • 23
    Ayzenberg I, Kleiter I, Schroder A et al. Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy. JAMA Neurol 2013; 70:394397.
  • 24
    Cabre P, Olindo S, Marignier R, Jeannin S, Merle H, Smadja D. Efficacy of mitoxantrone in neuromyelitis optica spectrum: clinical and neuroradiological study. J Neurol Neurosurg Psychiatry 2013; 84:511516.
  • 25
    Kim SH, Kim W, Park MS, Sohn EH, Li XF, Kim HJ. Efficacy and safety of mitoxantrone in patients with highly relapsing neuromyelitis optica. Arch Neurol 2011; 68:473479.
  • 26
    Lehmann-Horn K, Schleich E, Hertzenberg D et al. Anti-CD20 B-cell depletion enhances monocyte reactivity in neuroimmunological disorders. J Neuroinflammation 2011; 8:146.
  • 27
    Pittock SJ, Lennon VA, McKeon A et al. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol 2013; 12:554562.
  • 28
    O'Reilly MW, Sexton DJ, Dennedy MC et al. Radiological remission and recovery of thirst appreciation after infliximab therapy in adipsic diabetes insipidus secondary to neurosarcoidosis. QJM 2013; [Epub ahead of print].
  • 29
    Segal BM. Neurosarcoidosis: diagnostic approaches and therapeutic strategies. Curr Opin Neurol 2013; 26:307313.
  • 30
    Keung B, Robeson KR, Dicapua DB et al. Long-term benefit of rituximab in MuSK autoantibody myasthenia gravis patients. J Neurol Neurosurg Psychiatry 2013; 84:14071409.
  • 31
    Markvardsen LH, Debost JC, Harbo T et al. Subcutaneous immunoglobulin in responders to intravenous therapy with chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol 2013; 20:836842.
  • 32
    Yoon MS, Chan A, Gold R. Standard and escalating treatment of chronic inflammatory demyelinating polyradiculoneuropathy. Ther Adv Neurol Disord 2011; 4:193200.
  • 33
    von Ahsen N, Chan A. Therapeutic monitoring of immunotherapies in autoimmune diseases. Curr Pharm Des 2012; 18:45504555.
  • 34
    Goodin DS, Ebers GC, Cutter G et al. Cause of death in MS: long-term follow-up of a randomised cohort, 21 years after the start of the pivotal IFNbeta-1b study. BMJ Open 2012; 2:e001972.
  • 35
    Hellwig K, Gold R. Progressive multifocal leukoencephalopathy and natalizumab. J Neurol 2011; 258:19201928.
  • 36
    Marriott JJ, Miyasaki JM, Gronseth G, O'Connor PW. Evidence report: the efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2010; 74:14631470.
  • 37
    Stroet A, Hemmelmann C, Starck M et al. Incidence of therapy-related acute leukaemia in mitoxantrone-treated multiple sclerosis patients in Germany. Ther Adv Neurol Disord 2012; 5:7579.
  • 38
    Correale P, Cusi MG, Tagliaferri P. Immunomodulatory properties of anticancer monoclonal antibodies: is the ‘magic bullet’ still a reliable paradigm? Immunotherapy 2011; 3:14.
  • 39
    O'Connor P. Natalizumab and the role of alpha 4-integrin antagonism in the treatment of multiple sclerosis. Expert Opin Biol Ther 2007; 7:123136.
  • 40
    Kornek B, Aboul-Enein F, Rostasy K et al. Natalizumab therapy for highly active pediatric multiple sclerosis. JAMA Neurol 2013; 70:469475.
  • 41
    Arnal-Garcia C, Garcia-Montero MR, Malaga I et al. Natalizumab use in pediatric patients with relapsing–remitting multiple sclerosis. Eur J Paediatr Neurol 2013; 17:5054.
  • 42
    Kleiter I, Hellwig K, Berthele A et al. Failure of natalizumab to prevent relapses in neuromyelitis optica. Arch Neurol 2012; 69:239245.
  • 43
    Barnett MH, Prineas JW, Buckland ME, Parratt JD, Pollard JD. Massive astrocyte destruction in neuromyelitis optica despite natalizumab therapy. Mult Scler 2012; 18:108112.
  • 44
    Foley J. Natalizumab related PML: an evolving risk stratification paradigm. Neurology 2013; 80(Meeting Abstracts 1):S30.002.
  • 45
    Bloomgren G, Richman S, Hotermans C et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 366:18701880.
  • 46
    Gold R, Hanschke S, Hemmer B, Wiendl H. DGN/KKNMS Leitlinie zur Diagnose und Therapie der MS – online version, Stand: 09.08.2012. 2012. Available at: http://www.kompetenznetz-multiplesklerose.de/images/stories/PDF_Dateien/Leitlinie/dgn-kknms_ms-ll_20120809_frei.pdf (accessed 11 August 2013).
  • 47
    Yousry TA, Pelletier D, Cadavid D et al. Magnetic resonance imaging pattern in natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 2012; 72:779787.
  • 48
    Aly L, Yousef S, Schippling S et al. Central role of JC virus-specific CD4+ lymphocytes in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome. Brain 2011; 134:26872702.
  • 49
    Ryschkewitsch CF, Jensen PN, Major EO. Multiplex qPCR assay for ultra sensitive detection of JCV DNA with simultaneous identification of genotypes that discriminates non-virulent from virulent variants. J Clin Virol 2013; 57:243248.
  • 50
    Bozic C, Richman S, Plavina T et al. Anti-John Cunnigham virus antibody prevalence in multiple sclerosis patients: baseline results of STRATIFY-1. Ann Neurol 2011; 70:713721.
  • 51
    Gorelik L, Lerner M, Bixler S et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 2010; 68:295303.
  • 52
    Trampe AK, Hemmelmann C, Stroet A et al. Anti-JC virus antibodies in a large German natalizumab-treated multiple sclerosis cohort. Neurology 2012; 78:17361742.
  • 53
    BiogenIdec. Tysabri. 2013. Available at: http://tysabri.de/index.php?inhalt=tysabri.sicherheitsmanagement (accessed 17 December 2013).
  • 54
    Havla J, Berthele A, Kumpfel T et al. Co-occurrence of two cases of progressive multifocal leukoencephalopathy in a natalizumab ‘infusion group’. Mult Scler 2013; 19:12131215.
  • 55
    Kuhle J, Gosert R, Buhler R et al. Management and outcome of CSF-JC virus PCR-negative PML in a natalizumab-treated patient with MS. Neurology 2011; 77:20102016.
  • 56
    Mazda ME, Brosch JR, Wiens AL et al. A case of natalizumab-associated progressive multifocal leukoencephalopathy with repeated negative CSF JCV testing. Int J Neurosci 2013; 123:353357.
  • 57
    Dahlhaus S, Hoepner R, Chan A et al. Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients. J Neurol Neurosurg Psychiatry 2013; 84:10681074.
  • 58
    Hellwig K, Kleiter I, Gold R. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology 2012; 78:371; author reply.
  • 59
    Hoepner R, Dahlhaus S, Kollar S et al. Prophylactic antiepileptic treatment reduces seizure frequency in natalizumab-associated progressive multifocal leukoencephalopathy. Ther Adv Neurol Disord 2014; 7:36.
  • 60
    Berger JR, Houff SA, Gurwell J, Vega N, Miller CS, Danaher RJ. JC virus antibody status underestimates infection rates. Ann Neurol 2013; 74:8490.
  • 61
    Warnke C, Ramanujam R, Plavina T et al. Changes to anti-JCV antibody levels in a Swedish national MS cohort. J Neurol Neurosurg Psychiatry 2013; 84:11991205.
  • 62
    Lee P, Plavina T, Castro A et al. A second-generation ELISA (STRATIFY JCV DxSelect) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol 2013; 57:141146.
  • 63
    Koralnik IJ, Du Pasquier RA, Kuroda MJ et al. Association of prolonged survival in HLA-A2+ progressive multifocal leukoencephalopathy patients with a CTL response specific for a commonly recognized JC virus epitope. J Immunol 2002; 168:499504.
  • 64
    Perkins MR, Ryschkewitsch C, Liebner JC et al. Changes in JC virus-specific T cell responses during natalizumab treatment and in natalizumab-associated progressive multifocal leukoencephalopathy. PLOS Pathog 2012; 8:e1003014.
  • 65
    Haghikia A, Perrech M, Pula B et al. Functional energetics of CD4+-cellular immunity in monoclonal antibody-associated progressive multifocal leukoencephalopathy in autoimmune disorders. PLOS ONE 2011; 6:e18506.
  • 66
    Goelz S, Polman C, Rudick R et al. ImmuKnow® (Cylex) does not appear to be useful for PML risk stratification with natalizumab treatment. Mult Scler 2011; 17:S507S524, P1118.
  • 67
    Schwab N, Schneider-Hohendorf T, Posevitz V et al. L-Selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients. Neurology 2013; 81:865871.
  • 68
    Linda H, von Heijne A. Presymptomatic diagnosis with MRI and adequate treatment ameliorate the outcome after natalizumab-associated progressive multifocal leukoencephalopathy. Front Neurol 2013; 4:11. doi: 10.3389/fneur.2013.00011.
  • 69
    Coles AJ, Compston DA, Selmaj KW et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008; 359:17861801.
  • 70
    European Medicines Agency (EMA). Summary of Product Characteristics – Lemtrada. 2013. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003718/WC500150521.pdf (accessed 28 September 2013).
  • 71
    Klotz L, Meuth SG, Wiendl H. Immune mechanisms of new therapeutic strategies in multiple sclerosis-A focus on alemtuzumab. Clin Immunol 2012; 142:2530.
  • 72
    Coles AJ, Cox A, Le Page E et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 2006; 253:98108.
  • 73
    Coles AJ, Fox E, Vladic A et al. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology 2012; 78:10691078.
  • 74
    Ontaneda D, Cohen JA. The benefits and risks of alemtuzumab in multiple sclerosis. Expert Rev Clin Immunol 2013; 9:189191.
  • 75
    Braester A, Akria L, Suriu C, Sonkin V. Alemtuzumab and myelodysplasia: a story of love and hate (possible alemtuzumab-induced myelodysplastic changes). Acta Haematol 2012; 129:185186.
  • 76
    Bosch W, Poowanawittayakom N, Chaikriangkrai K et al. Tuberculous hepatitis in renal transplant recipients following alemtuzumab induction therapy. Transpl Infect Dis 2013; 15:E3339.
  • 77
    Moreau T, Coles A, Wing M et al. CAMPATH-IH in multiple sclerosis. Mult Scler 1996; 1:357365.
  • 78
    Costelloe L, Jones J, Coles A. Secondary autoimmune diseases following alemtuzumab therapy for multiple sclerosis. Expert Rev Neurother 2012; 12:335341.
  • 79
    Jones JL, Phuah CL, Cox AL et al. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest 2009; 119:20522061.
  • 80
    Bielekova B, Catalfamo M, Reichert-Scrivner S et al. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A 2006; 103:59415946.
  • 81
    Wuest SC, Edwan JH, Martin JF et al. A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nat Med 2011; 17:604609.
  • 82
    Gorman MP, Tillema JM, Ciliax AM, Guttmann CR, Chitnis T. Daclizumab use in patients with pediatric multiple sclerosis. Arch Neurol 2012; 69:7881.
  • 83
    Sheridan JP, Zhang Y, Riester K et al. Intermediate-affinity interleukin-2 receptor expression predicts CD56(bright) natural killer cell expansion after daclizumab treatment in the CHOICE study of patients with multiple sclerosis. Mult Scler 2011; 17:14411448.
  • 84
    Perry JS, Han S, Xu Q et al. Inhibition of LTi cell development by CD25 blockade is associated with decreased intrathecal inflammation in multiple sclerosis. Sci Transl Med 2012; 4:145ra106. doi: 10.1126/scitranslmed.3004140.
  • 85
    Ohayon J, Oh U, Richert N et al. CNS vasculitis in a patient with MS on daclizumab monotherapy. Neurology 2013; 80:453457.
  • 86
    Kim SH, Huh SY, Lee SJ, Joung A, Kim HJ. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol 2013; 70:11101117.
  • 87
    Cree BA, Lamb S, Morgan K, Chen A, Waubant E, Genain C. An open label study of the effects of rituximab in neuromyelitis optica. Neurology 2005; 64:12701272.
  • 88
    Jacob A, Weinshenker BG, Violich I et al. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol 2008; 65:14431448.
  • 89
    Collongues N, Casez O, Lacour A et al. Rituximab in refractory and non-refractory myasthenia: a retrospective multicenter study. Muscle Nerve 2012; 46:687691.
  • 90
    Chaudhry V, Cornblath DR. An open-label trial of rituximab (Rituxan(R)) in multifocal motor neuropathy. J Peripher Nerv Syst 2010; 15:196201.
  • 91
    Stieglbauer K, Topakian R, Hinterberger G, Aichner FT. Beneficial effect of rituximab monotherapy in multifocal motor neuropathy. Neuromuscul Disord 2009; 19:473475.
  • 92
    Leen WG, Weemaes CM, Verbeek MM, Willemsen MA, Rotteveel JJ. Rituximab and intravenous immunoglobulins for relapsing postinfectious opsoclonus–myoclonus syndrome. Pediatr Neurol 2008; 39:213217.
  • 93
    Koul R, Al Futaisi A, Abdwani R. Rituximab in severe seronegative juvenile myasthenia gravis: review of the literature. Pediatr Neurol 2012; 47:209212.
  • 94
    Pranzatelli MR, Tate ED, Travelstead AL et al. Rituximab (anti-CD20) adjunctive therapy for opsoclonus–myoclonus syndrome. J Pediatr Hematol Oncol 2006; 28:585593.
  • 95
    Kieseier BC, Stuve O, Dehmel T et al. Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses. JAMA Neurol 2013; 70:390393.
  • 96
    Urbaniak P, Hasler P, Kretzschmar S. Refractory neuro-Behçet treated by tocilizumab: a case report. Clin Exp Rheumatol 2012; 30:S7375.
  • 97
    Abisror N, Mekinian A, Lavigne C, Vandenhende MA, Soussan M, Fain O. Tocilizumab in refractory Takayasu arteritis: a case series and updated literature review. Autoimmun Rev 2013; 12:11431149.
  • 98
    Krogias C, Hoepner R, Muller A, Schneider-Gold C, Schroder A, Gold R. Successful treatment of anti-Caspr2 syndrome by interleukin 6 receptor blockade through tocilizumab. JAMA Neurol 2013; 70:10561059.
  • 99
    Sellner J, Boggild M, Clanet M et al. EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J Neurol 2010; 17:10191032.
  • 100
    Food and Drug Administration (FDA). Safety Information – Rituximab. 2009. Availale at: http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM187792.pdf (accessed 11 August 2013).
  • 101
    Carson KR, Focosi D, Major EO et al. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol 2009; 10:816824.
  • 102
    Kosmidis ML, Dalakas MC. Practical considerations on the use of rituximab in autoimmune neurological disorders. Ther Adv Neurol Disord 2010; 3:93105.
  • 103
    Pellkofer HL, Krumbholz M, Berthele A et al. Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab. Neurology 2011; 76:13101315.
  • 104
    Horga A, Montalban X. FTY720 (fingolimod) for relapsing multiple sclerosis. Expert Rev Neurother 2008; 8:699714.
  • 105
    Food and Drug Administration (FDA). Approved labelling text – Gilenya. 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022527s000lbl.pdf (accessed 11 August 2013).
  • 106
    European Medicines Agency (EMA). Summary of Product Characteristics – Gilenya. 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/04/WC500125687.pdf (accessed 11 August 2013).
  • 107
    Cohen JA, Barkhof F, Comi G et al. Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS. J Neurol 2013; 260:20232032.
  • 108
    Gergely P, Nuesslein-Hildesheim B, Guerini D et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol 2012; 167:10351047.
  • 109
    Zarbin MA, Jampol LM, Jager RD et al. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Ophthalmology 2013; 120:14321439.
  • 110
    Nolan R, Gelfand JM, Green AJ. Fingolimod treatment in multiple sclerosis leads to increased macular volume. Neurology 2013; 80:139144.
  • 111
    Reuters. Suspected PML on Gilenya. 2013. Available at: http://www.reuters.com/article/2013/07/30/novartis-gilenya-idUSL6N0G02A520130730 (accessed 18 August 2013).
  • 112
    European Medicines Agency (EMA). European Medicines Agency Gives New Advice to Better Manage Risk of Adverse Effects on the Heart with Gilenya. 2012. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/04/news_detail_001498.jsp&mid=WC0b01ac058004d5c1 (accessed 11 August 2013).
  • 113
    Ricklin ME, Lorscheider J, Waschbisch A et al. T-cell response against varicella-zoster virus in fingolimod-treated MS patients. Neurology 2013; 81:174181.
  • 114
    Balague C, Pont M, Prats N, Godessart N. Profiling of dihydroorotate dehydrogenase, p38 and JAK inhibitors in the rat adjuvant-induced arthritis model: a translational study. Br J Pharmacol 2012; 166:13201332.
  • 115
    Miller AE, O'Connor P, Wolinsky JS et al. Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. Mult Scler 2012; 18:16251632.
  • 116
    O'Connor P, Wolinsky JS, Confavreux C et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365:12931303.
  • 117
    Sanofi/Genzyme. Aubagio. 2012. Available at: http://products.sanofi.us/aubagio/aubagio.pdf (accessed 19 August 2013).
  • 118
    Food and Drug Administration (FDA). Approved labelling text – Aubagio. 2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202992s000lbl.pdf (accessed 27 October 2013).
  • 119
    Freedman MS, Wolinsky JS, Wamil B et al. Teriflunomide added to interferon-beta in relapsing multiple sclerosis: a randomized phase II trial. Neurology 2012; 78:18771885.
  • 120
    Confavreux C, Li DK, Freedman MS et al. Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8·5 years. Mult Scler 2012; 18:12781289.
  • 121
    Linker RA, Lee DH, Ryan S et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011; 134:678692.
  • 122
    Papadopoulou A, D'Souza M, Kappos L, Yaldizli O. Dimethyl fumarate for multiple sclerosis. Expert Opin Investig Drugs 2010; 19:16031612.
  • 123
    Gold R, Kappos L, Arnold DL et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367:10981107.
  • 124
    Fox RJ, Miller DH, Phillips JT et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012; 367:10871097.
  • 125
    Schwab N, Ulzheimer JC, Fox RJ et al. Fatal PML associated with efalizumab therapy: insights into integrin alphaLbeta2 in JC virus control. Neurology 2012; 78:458467; discussion 65.
  • 126
    Ermis U, Weis J, Schulz JB. PML in a patient treated with fumaric acid. N Engl J Med 2013; 368:16571658.
  • 127
    van Oosten BW, Killestein J, Barkhof F, Polman CH, Wattjes MP. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med 2013; 368:16581659.
  • 128
    Sweetser MT, Dawson KT, Bozic C. Manufacturer's response to case reports of PML. N Engl J Med 2013; 368:16591661.
  • 129
    Hartung HP, Gonsette R, Konig N et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002; 360:20182025.
  • 130
    Edan G, Miller D, Clanet M et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry 1997; 62:112118.
  • 131
    van de Wyngaert FA, Beguin C, D'Hooghe MB et al. A double-blind clinical trial of mitoxantrone versus methylprednisolone in relapsing, secondary progressive multiple sclerosis. Acta Neurol Belg 2001; 101:210216.
  • 132
    Cotte S, Stroet A, von Ahsen N et al. Lack of therapeutic effect of mitoxantrone in primary progressive multiple sclerosis independent of pharmacogenetic factors: multicentre, retrospective analysis. Neurology 2011; 76:A613; P07.198.
  • 133
    Leary SM, Thompson AJ. Primary progressive multiple sclerosis: current and future treatment options. CNS Drugs 2005; 19:369376.
  • 134
    Pelfrey CM, Cotleur AC, Zamor N, Lee JC, Fox RJ. Immunological studies of mitoxantrone in primary progressive MS. J Neuroimmunol 2006; 175:192199.
  • 135
    Kornek B, Bernert G, Rostasy K et al. Long-term follow-up of pediatric patients treated with mitoxantrone for multiple sclerosis. Neuropediatrics 2011; 42:712.
  • 136
    Stroet A, Gold R, Chan A. Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone. Neurology 2012; 78:933; author reply 4.
  • 137
    Martinelli V, Cocco E, Capra R et al. Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone. Neurology 2011; 77:18871895.
  • 138
    Pascual AM, Tellez N, Bosca I et al. Revision of the risk of secondary leukaemia after mitoxantrone in multiple sclerosis populations is required. Mult Scler 2009; 15:13031310.
  • 139
    Cotte S, von Ahsen N, Kruse N et al. ABC-transporter gene-polymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis. Brain 2009; 132:25172530.
  • 140
    Food and Drug Administration (FDA). Mitoxantrone Hydrochloride (marketed as Novantrone and generics) – Healthcare Professional Sheet. 2008. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126445.htm (accessed 11 August 2013).
  • 141
    Lee GR, Foerster J, Lukons J, Paraskevar F, Greer JP, Rodgers GM. 1999. Lippincott Williams & Wilkins, Philadelphia, PA, USA.
  • 142
    Le Page E, Leray E, Edan G. Long-term safety profile of mitoxantrone in a French cohort of 802 multiple sclerosis patients: a 5-year prospective study. Mult Scler 2011; 17:867875.
  • 143
    Goffette S, van Pesch V, Vanoverschelde JL, Morandini E, Sindic CJ. Severe delayed heart failure in three multiple sclerosis patients previously treated with mitoxantrone. J Neurol 2005; 252:12171222.
  • 144
    Lo-Coco F, Avvisati G, Vignetti M et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013; 369:111121.
  • 145
    Ammatuna E, Montesinos P, Hasan SK et al. Presenting features and treatment outcome of acute promyelocytic leukemia arising after multiple sclerosis. Haematologica 2011; 96:621625.
  • 146
    Taube F, Stolzel F, Thiede C, Ehninger G, Laniado M, Schaich M. Increased incidence of central nervous system hemorrhages in patients with secondary acute promyelocytic leukemia after treatment of multiple sclerosis with mitoxantrone? Haematologica 2011; 96:e31.
  • 147
    Meyer C, Ansorge N, Siglienti I et al. [Mitoxantrone-related acute leukemia by multiple sclerosis. Case report and practical approach by unclear cytopenia]. Nervenarzt 2010; 81:14831489.
  • 148
    Ellis R, Boggild M. Therapy-related acute leukaemia with mitoxantrone: what is the risk and can we minimise it? Mult Scler 2009; 15:505508.
  • 149
    Ghalie RG, Mauch E, Edan G et al. A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis. Mult Scler 2002; 8:441445.
  • 150
    Kingwell E, Koch M, Leung B et al. Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS. Neurology 2010; 74:18221826.
  • 151
    Mulroy E, Joyce E, Scott J et al. Long-term risk of leukaemia or cardiomyopathy after mitoxantrone therapy for multiple sclerosis. Eur Neurol 2012; 67:4547.
  • 152
    Paul F, Dorr J, Wurfel J, Vogel HP, Zipp F. Early mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis. BMJ Case Rep 2009. pii: bcr06.2009.2004. doi: 10.1136/bcr.06.2009.2004.
  • 153
    Franzen D, Haus A, Hellmich M. Serial assessment of cardiac function during and following mitoxantrone infusion in 30 consecutive patients with multiple sclerosis. Mult Scler Int 2010; 2010:351045.
  • 154
    Bernitsas E, Wei W, Mikol DD. Suppression of mitoxantrone cardiotoxicity in multiple sclerosis patients by dexrazoxane. Ann Neurol 2006; 59:206209.
  • 155
    Dorr J, Bitsch A, Schmailzl KJ et al. Severe cardiac failure in a patient with multiple sclerosis following low-dose mitoxantrone treatment. Neurology 2009; 73:991993.
  • 156
    Killestein J, van der Meer ML, Regelink JC, Huijgens PC, Polman CH. Severe cardiac failure in a patient with multiple sclerosis following low-dose mitoxantrone treatment. Neurology 2010; 74:934; author reply.
  • 157
    Debouverie M, Vandenberghe N, Morrissey SP et al. Predictive parameters of mitoxantrone effectiveness in the treatment of multiple sclerosis. Mult Scler 2004; 10:407412.
  • 158
    Luchowski P, Mitosek-Szewczyk K, Bartosik-Psujek H et al. B-type natriuretic peptide as a marker of subclinical heart injury during mitoxantrone therapy in MS patients = preliminary study. Clin Neurol Neurosurg 2009; 111:676678.
  • 159
    Hasan SK, Buttari F, Ottone T et al. Risk of acute promyelocytic leukemia in multiple sclerosis: coding variants of DNA repair genes. Neurology 2011; 76:10591065.
  • 160
    Berlin JA, Glasser SC, Ellenberg SS. Adverse event detection in drug development: recommendations and obligations beyond phase 3. Am J Public Health 2008; 98:13661371.
  • 161
    European Medicines Agency (EMA). Summary of Product Characteristics – Soliris. 2013. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000791/WC500054208.pdf (accessed 18 August 2013).
  • 162
    Anonymous. Summary of Product Characteristics Mitoxantrone/Ralenova. 2009. Available at: http://www.medapharma.de/extras/download/gebrauchsinfo.pdf?pdfIdx=214 (accessed 11 August 2013).
  • 163
    Martinelli V, Radaelli M, Straffi L, Rodegher M, Comi G. Mitoxantrone: benefits and risks in multiple sclerosis patients. Neurol Sci 2009; 30 (Suppl. 2):S167170.
  • 164
    Caruso A, Vecchio R, Patti F, Neri S. Drug rash with eosinophilia and systemic signs syndrome in a patient with multiple sclerosis. Clin Ther 2009; 31:580584.
  • 165
    Kumpfel T, Gerdes LA, Flaig M, Hohlfeld R, Wollenberg A. Drug-induced Sweet's syndrome after mitoxantrone therapy in a patient with multiple sclerosis. Mult Scler 2011; 17:495497.
  • 166
    Cocco E, Sardu C, Gallo P et al. Frequency and risk factors of mitoxantrone-induced amenorrhea in multiple sclerosis: the FEMIMS study. Mult Scler 2008; 14:12251233.
  • 167
    Strotmann JM, Spindler M, Weilbach FX, Gold R, Ertl G, Voelker W. Myocardial function in patients with multiple sclerosis treated with low-dose mitoxantrone. Am J Cardiol 2002; 89:12221225.
  • 168
    Brassat D, Recher C, Waubant E et al. Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS. Neurology 2002; 59:954955.
  • 169
    Food and Drug Administration (FDA). Prescribing Information – Tysabri. 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125104s813lbl.pdf (accessed 11 August 2013).
  • 170
    Oliver B, Fernandez O, Orpez T et al. Kinetics and incidence of anti-natalizumab antibodies in multiple sclerosis patients on treatment for 18 months. Mult Scler 2011; 17:368371.
  • 171
    Mullen JT, Vartanian TK, Atkins MB. Melanoma complicating treatment with natalizumab for multiple sclerosis. N Engl J Med 2008; 358:647648.
  • 172
    Burmester GR, Rubbert-Roth A, Cantagrel A et al. A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study). Ann Rheum Dis 2014; 73:6974.
  • 173
    Smolen JS, Beaulieu A, Rubbert-Roth A et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008; 371:987997.
  • 174
    Genovese MC, McKay JD, Nasonov EL et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 2008; 58:29682980.