Review article

Interdisciplinary Risk Management in the Treatment of Multiple Sclerosis

Dtsch Arztebl Int 2016; 113(51-52): 879-86; DOI: 10.3238/arztebl.2016.0879

Havla, J; Warnke, C; Derfuss, T; Kappos, L; Hartung, H; Hohlfeld, R

Background: Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system. There are at least 150 000 persons with MS in Germany. Recent years have seen the approval of new drugs against MS with various mechanisms of action and differing adverse effect profiles.

Methods: This article is based on pertinent literature retrieved by a selective search in PubMed as well as on documentation of relevant risks and adverse effects in “red hand letters” (information bulletins from pharmaceutical companies to physicians about adverse drug effects) and elsewhere, along with data provided by the German Multiple Sclerosis Competence Network.

Results: In recent years, there have been major advances enabling better, more individualized treatment of patients with MS. Physicians must, however, give due consideration to potentially severe or even life-threatening adverse drug effects. These can include, for example, transaminase elevation (hepatotoxicity), cardio- and nephrotoxicity, or lympho- and leukopenia with a variable risk of infection. Among patients taking natalizumab, the cumulative risk of developing progressive multifocal leukencephalopathy (PML) may be 1:100 or higher, depending on the individual risk profile. Rare cases of PML have also been seen under treatment with fingolimod and dimethyl fumarate. Moreover, any type of immunosuppressive treatment can, at least theoretically, increase the risk of malignant disease. Secondary autoimmune diseases can arise as well: approximately 35% of patients treated with alemtuzumab develop autoimmune thyroid disease within two years, and 2% of patients who take daclizumab have severe autoimmune dermatological side effects. Teriflunomide, fingolimod, natalizumab, mitoxantrone, interferon β1-a/b, and daclizumab can all damage the liver. There are also psychiatric, reproductive, and vaccine-associated risks and side effects that must be considered.

Conclusion: Newer drugs for MS have enabled more effective treatment, but are also associated with a higher risk of side effects. Interdisciplinary risk management is needed.

Starting with the introduction of the first interferon (IFN) β preparations over 20 years ago, the treatment of multiple sclerosis (MS) has been developing at an ever-increasing pace (eFigure). Because the improved efficacy of some of the new preparations is associated with greater hazards, risk management plans have been implemented and preparation-specific strategies for treatment monitoring established. Effective monitoring requires close interdisciplinary cooperation.

Ever since the licensing of the first interferon β preparation in 1995, the number of preparations available for the treatment of relapsing-remitting multiple sclerosis has grown constantly.
eFigure
Ever since the licensing of the first interferon β preparation in 1995, the number of preparations available for the treatment of relapsing-remitting multiple sclerosis has grown constantly.

Immunotherapy

The arsenal of medications for the treatment of MS includes a variety of substances with differing mechanisms of action (Table 1, eBox 1). These include B- and T-cell-oriented and cytokine-based immunotherapy as well as treatments that influence the adhesion, chemotaxis, migration, and/or activation and proliferation of immune cells. Apart from advances in efficacy and selectivity, there are now a number of modes of administration. Patients can choose among oral, subcutaneous, intramuscular, and intravenous treatments with various dose intervals, and this has a positive effect on treatment adherence (1).

Overview of the drugs used to treat multiple sclerosis
Table 1
Overview of the drugs used to treat multiple sclerosis
Brief descriptions (risks, adverse drug reactions)*
eBox 1
Brief descriptions (risks, adverse drug reactions)*

The primary treatment goals are to reduce flare frequency, delay the onset of disability progression, and slow or halt disability progression. Exhaustive licensing studies (phases I to III) have shown that all MS therapeutics achieve meaningful reductions in flare rate, disability progression, and the computed tomography criteria of MS, e.g., lesion burden, lesion activity (contrast medium uptake), and cerebral atrophy (2). No evidence of disease activity (NEDA), i.e., a period of 1 or 2 years with no flares or progression and no activity on magnetic resonance imaging (MRI), i.e., no new gadolinium-enhancing T1 lesions and no new or enlarging T2 lesions, has been proposed as an overall criterion for treatment success. To lend more weight to tissue damage, or in other words the tissue-protective effect of the treatment, lack of acceleration of physiological cerebral volume reduction has been suggested as an additional criterion (NEDA-4). However, the NEDA criteria have not yet been evaluated in clinical studies and do not take account of all disease-relevant clinical factors (e1e3). Correspondingly, it remains unclear whether treatment decisions should be based on NEDA criteria. Moreover, no studies (head-to-head studies, NEDA comparisons) have been carried out to compare modern immunotherapeutics with one another or with older preparations. Therefore, despite similarities in study design, the effect sizes of various investigations cannot be compared. Furthermore, the improved efficacy of modern immunotherapeutics may go hand in hand with a higher number of severe risks. With the exception of neutralizing antibodies, there are no laboratory parameters to predict the efficacy of individual treatments. Neutralizing antibodies against natalizumab and, though somewhat controversial, antibodies against interferons are consistently associated with diminished response to treatment. For comprehensive accounts of efficacy and effect strengths, we refer the reader to recently published review articles (3). The focus of our review is on the known adverse drug reactions (ADR) of modern treatments for MS.

Interdisciplinary risk management

The danger of potentially serious and in some cases even fatal side effects necessitates effective risk management and proper monitoring of the MS treatment (4). However, even well-established risk management programs do not offer complete protection. Despite use of a risk management plan, the incidence of progressive multifocal leukencephalopathy (PML) in patients treated with natalizumab has not yet decreased (e4). We will now discuss the principal categories of important side effects, basing our remarks in part on the treatment recommendations of the Competence Network Multiple Sclerosis (5) and a selective literature review.

Infection risk in immunocompromised patients with multiple sclerosis during immunosuppressive therapy

The extent of global changes in (differential) blood count and changes in lymphocyte subpopulations varies greatly and is dependent on the active substance used. Inferences with regard to the patient’s immune competence often cannot be drawn, because the peripheral blood contains only a small proportion (ca. 2%) of the whole reservoir of immune cells. Not picked up, for example, are the immune cells located in the lymph nodes and other lymphatic organs (6). Therefore, the lymphocytes in the peripheral circulation also permit no direct conclusions regarding the risk of rare infectious complications such as PML. Further information on current risk management plans can be found in an article (in German, with an English abstract) by Klotz et al. (4). Treatment with teriflunomide involves only a slight increase in general infection risk, but the levels of leukocytes (−15%) and thrombocytes (−10%) may go down (e5). No instance of PML during teriflunomide treatment has yet been recorded (as of September 2016), but isolated cases of opportunistic infection have been reported:

  • Klebsiella sepsis
  • Intestinal tuberculosis
  • Gram-negative sepsis (7, e6).

Dimethylfumarate leads to a mean lymphocyte reduction of ca. 30% (e7) and in 6% of cases to lymphopenia with absolute lymphocyte counts of <500/µL. In individual patients this leukopenia may persist, sometimes leading to infectious complications (e8, e9). Four cases of PML during treatment of MS with dimethylfumarate have been reported so far (Table 2). Treatment with fingolimod can also be associated with susceptibility to infection (8). A direct connection between the extent of lymphopenia—and, in occasional cases, granulocytopenia—and an increased risk of infection under fingolimod treatment has not been demonstrated (8). To date, nine cases of PML have been reported in patients being given fingolimod alone who had not been treated with natalizumab immediately beforehand (Table 2) (9). Furthermore, cases of generalized fatal varicella zoster virus (VZV) infection/reactivation, cases of herpes encephalitis (herpes simplex virus 1, HSV-1), and one case of cerebral cryptococcosis have been reported (10, 11, e10, e11). Very rarely, hemophagocytic syndrome occurs (6, e12e14). During treatment with natalizumab, in contrast to other drugs used to treat MS, peripheral leukocyte and/or lymphocyte counts do not fall, but rather rise slightly. The composition of the cell populations also changes (12, e15, e16). A significant degree of lymphopenia is not usual, but if it is found the reason must be sought. Plainly the immune functions suppressed by natalizumab are connected with a measurable change in immune surveillance in the central nervous system (CNS), and they may also be important for defense against opportunistic pathogens in the periphery, such as the PML-triggering John Cunningham polyomavirus (JCV) (13, e17). While other infectious complications during treatment with natalizumab are rare, to date (as of June 2016, Biogen) more than 667 cases of PML have been documented in ca. 490 000 patient-years of natalizumab treatment (Table 2). Thus in a specific risk constellation the cumulative risk of the occurrence of PML over time may be ≥ 1/100, particularly given that the calculation of PML incidence and especially the estimation of individual PML risk can vary (e18). By definition, such a risk constellation represents a frequently occurring ADR (14). Owing to the regular performance of MRI in patients with MS and awareness of this ADR among MS neurologists, cases of PML in this indication are detected with relative reliability. Nevertheless, the diagnosis is not always easy; it may, for example, be difficult to rule out an MS flare associated with a change in treatment. The JCV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR), on which the diagnosis of PML is often crucially based, may yield both false-negative and (more rarely) false-positive results. This, coupled with the rarity of confirmation by biopsy, means there is uncertainty as to the true number of cases (e19). Clinically, the course of PML is characterized by high morbidity and mortality. Recent investigations suggest that early diagnosis of PML, ideally prior to its clinical manifestation by cranial MRI (cMRI) screening, may be associated with an improved prognosis (Dear Healthcare Provider Letter [Rote Hand Brief], Biogen, 11 March 2016). Apart from PML, cases of herpes encephalitis have been described during treatment with natalizumab (15).

Drugs licensed for multiple sclerosis with which progressive multifocal leukencephalopathy has been observed
Table 2
Drugs licensed for multiple sclerosis with which progressive multifocal leukencephalopathy has been observed

Current incidence figures and recommendations for minimizing the risk of PML can be found in the eTable and eBox 2. Administration of alemtuzumab is followed first of all by depletion of B and T cells in peripheral blood. Because of the lasting treatment-associated depletion of immune cells, which is not amenable to influence after drug administration, a hematologist must be consulted in the event of persisting abnormal findings such as a thrombocyte concentration of more than 100 000/µL or cytopenias that do not follow the usual kinetics of repopulation. In line with the mechanism of action, a higher rate of infections is to be expected predominantly in the first 6 months after infusion. Prophylactic administration of aciclovir for 4 weeks is recommended after an infusion cycle. Occasional cases of severe VZV infection or reactivation of a latent virus infection (16, 17, e20), tuberculosis, spirochete gingivitis, Pasteurella infection, esophageal candidiasis, Listeria meningitis, and nocardiosis have been described (6, 18, 19, e21, e22). One case of so-called carry-over PML after prior natalizumab treatment with a fatal outcome has been reported to date (as of June 2016, Genzyme). In the licensing studies for daclizumab, leukopenia <3000/µL was documented in 6% and lymphopenia <500/µL in 2% of patients. However, opportunistic infections have not yet been described. Severe infections such as sepsis, pneumonia, appendicitis, cellulitis, urinary tract infection, and viral infections occurred in <5% of those concerned. During treatment with mitoxantrone all blood cells are greatly reduced. Heightened clinical vigilance with regard to opportunistic infections is thus essential; for example, cMRI and CSF testing in the event of atypical infections or unexplained neurological deterioration.

Risk management of progressive multifocal leukencephalopathy during treatment with natalizumab
eBox 2
Risk management of progressive multifocal leukencephalopathy during treatment with natalizumab
Risk stratification of progressive multifocal leukencephalopathy*
eTable
Risk stratification of progressive multifocal leukencephalopathy*

Secondary autoimmune diseases

Around 35% of patients treated with alemtuzumab develop an autoimmune disease of the thyroid gland within the first 48 months. Both hyper- and hypothyroidism are possible. In most patients with mild or moderate disease the prognosis is favorable. This complication reaches its peak in the third year of treatment. For this reason, patients must be monitored clinically and by means of laboratory tests for at leat 48 months following the last infusion of alemtuzumab, independent of their anti-thyroid peroxidase (TPO) antibody status before the inception of treatment. A further autoimmunological risk is nephropathy, including anti-glomerular basal membrane disease (a-GBM). In studies, nephropathy occurred in ca. 0.3% of patients, a rate classed as “occasional” by the German Federal Institute for Drugs and Medical Devices (BfArM). Signs of nephropathy, such as an elevated blood creatinine level, hematuria, and/or proteinuria should prompt immediate consultation of a nephrologist. In addition, immunothrombocytic purpura (ITP, acute Werlhof disease) has been observed in around 1% of patients treated with alemtuzumab. Occasional cases of autoimmune hepatitis and colitis have been described during treatment with daclizumab, possibly indicating that this drug does not always boost immunoregulatory mechanisms but may sometimes weaken them. A BfArM communication in August 2014 reported an accumulation, in patients treated with IFN ß1-a/b, of cases of thrombotic microangiopathy (TMA), some with fatal outcome, and of nephrotic syndrome with various underlying nephropathies.

Dermatological risks

Of patients treated with daclizumab, 30 to 70% experience cutaneous side effects and 2% suffer severe autoimmune dermatological side effects (20). The most frequently observed adverse effects, such as exanthema and eczema, have no local relationship to the injection sites. They may be persistent, and there may a be a long latency period between treatment and adverse effect (20). At the beginning of treatment with IFN ß1-a/b or glatiramer acetate, the skin may exhibit irritation at the injection site. Lipoatrophy may occur on long-term administration of glatiramer acetate.

Hepatotoxicity

Acute or chronic liver damage with elevation of transaminases may be diagnosed in patients being treated with teriflunomide, fingolimod, natalizumab, mitoxantrone, IFN ß1-a/b, or daclizumab. Isolated cases of fulminant liver failure have also been described, e.g., in a patient treated with IFN ß1-a (e23). For this reason, close monitoring of the liver function parameters glutamate-pyruvate transaminase (GPT) and γ-glutamyl transferase (γ-GT) is necessary, particularly in the early phase of treatment. If the transaminase levels continue to rise and reach 3 to 5 times the upper limit of normal (ULN), treatment should be interrupted or discontinued (4).

Cardiac risks

Cardiac and circulatory risks play a role particularly in treatment with fingolimod, teriflunomide, and mitoxantrone. The heart rate may decrease following the first dose of fingolimod and should therefore be monitored for the first 6 h (21). Moreover, the blood pressure may be slightly elevated by fingolimod and teriflunomide. Mitoxantrone is known to be a cause of considerable cardiotoxicity, particularly in doses over 140 mg/m2 body surface area (BSA), but occasional cases of cardiotoxicity have been described in patients with lower total life doses (e24). Cardiac pump function must therefore be closely monitored by means of echocardiography before and during treatment with mitoxantrone. In the event of a 10% reduction, or the occurrence of any absolute value below 50% of the ejection fraction, the treatment should be interrupted or discontinued.

Pulmonary risks

Some drugs used against MS are suspected to be associated with lung pathology. Individual cases of severe interstitial lung disease were reported in patients treated with leflunomide, the precursor of teriflunomide. Vigilance is therefore advisable when using the latter drug. In addition, fingolimod may reduce the forced expiratory volume in 1 s and the diffusion capacity. However, no link has been shown between pulmonary disease and intake of fingolimod (22).

Vaccinations

Various aspects of vaccination in MS patients merit attention:

  • Therapeutic immunosuppression may be accompanied by a higher risk of infection with diseases preventable by vaccination.
  • The success of vaccination may be reduced by immunosuppression.
  • Vaccination may increase disease activity.
  • Vaccination may be more hazardous owing to the impairment or suppression of immune defenses, particularly if live vaccines are used.

Nevertheless, the recommendations for vaccination with dead vaccines and toxoids in healthy persons are valid also for MS patients. Attenuated live vaccines, on the other hand, should be avoided if possible, although the individual risk of infection should be taken into account. The success of every vaccination should be verified and the vaccination repeated if the response is found to be inadequate. Information on the response to influenza vaccine can be found in Table 3 (2326, e25). A review of vaccination recommendations was recently published by Williamson et al. (27).

Response to influenza vaccinations in patients on various treatments for multiple sclerosis
Table 3
Response to influenza vaccinations in patients on various treatments for multiple sclerosis

Polyneuropathy

In the TEMSO and TOWER studies (teriflunomide), neuropathy was diagnosed in 1.9% (versus 0% in the placebo group) and 2.5% (versus 1.1% in the placebo group) of the patients treated with teriflunomide (e6, 28).

Nephrotoxicity

Nephropathy, both acute and chronic, has been described in individual case reports of treatment with teriflunomide. In the licensing studies, acute renal failure was diagnosed in 1.2% of the patients treated with this drug. However, renal function returned to normal in all patients within 48 days at most and with no specific intervention, despite continuation of teriflunomide treatment. Dimethylfumarate was also shown to affect kidney function in clinical studies. Monitoring of renal function should therefore include urine analysis together with determination of creatinine, glomerular filtration rate, and, if indicated, cystatin C. Nephropathy has also been reported during treatment with IFN ß1-a/b.

Risk of malignancy

An increased risk of cancer is a theoretical possibility in all immunosuppressive treatments. The relatively small absolute case numbers make it difficult, however, to provide a statistical basis for this hypothesis. Accordingly, no elevated risk of malignancy has yet been confirmed for dimethylfumarate, teriflunomide, alemtuzumab, natalizumab, or fingolimod (29). Nevertheless, 13 cases of basal cell carcinoma and six cases of melanoma occurred in the licensing studies for fingolimod. After approval of this drug, further isolated cases of skin tumors (e26, 30) and lymphomatous disease (B- and T-cell lymphomas, lymphomatoid papulosis) were publicized (31, e27). Female patients treated with alemtuzumab should be tested annually for human papilloma virus (HPV) to minimize the risk of cervical dysplasia. Leukemia has been reported as an acute or late complication of treatment with mitoxantrone (32, e28, e29).

Ophthalmological risks

Ophthalmological risks have been reported only for fingolimod. During the licensing studies and thereafter, cases of macular edema occurred (incidence 0.5 to 0.7%) (e30, e31). As a rule the macular edema resolved after discontinuation of fingolimod; in individual cases the treatment could be continued under close ophthalmological observation (e32, e33).

Pregnancy

All drugs used for treatment of MS are contraindicated, or at least restricted, during pregnancy and breastfeeding. Nevertheless, the increasing number of pregnancy registries supply empirical data that aid decision making in individual situations. Table 4 provides an overview of the available information on teratogenicity, fertility, passage into breast milk and the placenta, and breastfeeding (3336).

Treatments for multiple sclerosis during pregnancy and breastfeeding (35, 36)
Table 4
Treatments for multiple sclerosis during pregnancy and breastfeeding (35, 36)

Pharmacological interactions

Pharmacological interactions are known particularly for teriflunomide. Potent cytochrome-P450 (CYP) inductors reduce the teriflunomide concentration. Teriflunomide inhibits CYP2C8 and organic anion transporter 3 (OAT3) and weakly induces CYP1A2. Correspondingly

Correspondingly metabolized drugs should be avoided if at all possible. IFN ß1-a/b seems to reduce the activity of CYP-dependent liver enzymes.

Psychiatric risks

Patients treated with IFN ß1-a/b or daclizumab must be monitored for the occurrence or worsening of symptoms of depression. However, depression is only a relative contraindication for these drugs.

Conclusion

The growing number of drugs used to treat MS demands even greater efforts to minimize the potential risks. To this end, interdisciplinary risk management plans are essential. Such plans take account of the type and extent of risks, describe the measures needed for prevention and early detection, and provide practical advice for the necessary monitoring. Individual risk management represents a first step towards individualized treatment. Supplementary information on the risk management plans currently in use can be found in the cited literature (4, 5, e34).

Conflict of interest statement

Dr. Havla has received consultancy fees from Novartis, Genzyme, and Biogen. He has received reimbursements of congress attendance and travel costs from Novartis, Biogen, Merck Serono, and Bayer.

Dr. Warnke has received consultancy fees from Novartis and Biogen. He has received reimbursements of congress attendance and travel costs, lecture fees, and study support (third-party funds) from Novartis, Biogen, Teva, and Bayer.

Prof. Derfuss has shares in Novartis. He has received consultancy fees fromBiogen, Merck Serono, Bayer, Novartis, Roche, Mitsubishi Pharma, Genzyme, and Geneuro. Congress attendance and travel costs have been reimbursed by Biogen, Genzyme, Novartis, Bayer, and Merck Serono. He has received lecture fees from Biogen, Genzyme, Novartis, Bayer, Merck Serono, and Roche. He has been the beneficiary of study support (third-party funds) from Biogen, Novartis, Geneuro, and Roche.

Prof. Kappos has received reimbursements of congress attendance and travel costs from Bayer, Biogen, Novartis, Merck Serono, Sanofi-Aventis, Genzyme, and Teva. He has been paid for giving lectures by Allergen, Bayer, Biogen, Excemed, Genzyme, Merck Serono, Novartis, Pfizer, Sanofi-Aventis, Teva, and UCB. He has been the beneficiary of study support (third-party funds) for projects of his own initiation from Bayer, Biogen, Novartis, and Roche. He has received support for conducting clinical studies (third-party funds) from Novartis, Biogen, Mitsubishi, Roche, Merck Serono, and Sanofi-Aventis.

Prof. Hartung has received consultancy fees fromBiogen, Novartis, Merck Serono, Genzyme, MedImmune, Teva, Geneuro, Bayer, CSL Behring, Octapharma, and Opexa. He has received reimbursements of congress attendance and travel costs from Biogen, Novartis, and Genzyme. He has been paid for giving lectures by Biogen, Kedrion, Novartis, and Genzyme. He has been the beneficiary of study support (third-party funds) from Teva, Biogen, and Novartis.

Prof. Hohlfeld has received consultancy fees from Actelion, Bayer, Biogen, Genzyme Sanofi, Medday, Merck Serono, Novartis, Roche, and Teva. He has received lecture fees and reimbursements of congress attendance and travel costs from Actelion, Bayer, Biogen, Genzyme Sanofi, Medday, Merck Serono, Novartis, Roche, and Teva. He has been the beneficiary of study support (third-party funds) from Bayer, Biogen, Genzyme Sanofi, Merck Serono, Novartis, and Teva.

Manuscript submitted on 20 June 2016, revised version accepted on
5 October 2016.

Translated from the original German by David Roseveare.

Corresponding author
Dr. med. Joachim Havla

Institut für Klinische Neuroimmunologie

Biomedizinisches Zentrum und Klinikum der Ludwig-Maximilians Universität

Marchioninistr. 15, 81377 München, Germany

Joachim.Havla@med.lmu.de

@Supplementary material
For eReferences please refer to:
www.aerzteblatt-international.de/ref5116

eBoxes, eTable, eFigure:
www.aerzteblatt-international.de/16m0879

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Kappos L, Wiendl H, Selmaj K, et al.: Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2015; 373: 1418–28 CrossRef MEDLINE
39.
Mendes D, Alves C, Batel-Marques F: Benefit-risk of therapies for relapsing-remitting multiple sclerosis: testing the number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and the likelihood to be helped or harmed (LHH): a systematic review and meta-analysis. CNS Drugs 2016; 30: 909–29 CrossRef MEDLINE
e1.
Imitola J, Racke MK: Is no evidence of disease activity a realistic goal for patients with multiple sclerosis? JAMA Neurol 2015; 72: 145–7 CrossRef MEDLINE
e2.
Dorr J, Paul F: The transition from first-line to second-line therapy in multiple sclerosis. Curr Treat Options Neurol 2015; 17: 354 MEDLINE
e3.
Stangel M, Penner IK, Kallmann BA, Lukas C, Kieseier BC: Towards the implementation of ’no evidence of disease activity’ in multiple sclerosis treatment: the multiple sclerosis decision model. Ther Adv Neurol Disord 2015; 8: 3–13 CrossRef MEDLINE PubMed Central
e4.
Cutter GR, Stuve O: Does risk stratification decrease the risk of natalizumab-associated PML? Where is the evidence? Mult Scler 2014; 20: 1304–5 CrossRef MEDLINE
e5.
Warnke C, Stuve O, Kieseier BC: Teriflunomide for the treatment of multiple sclerosis. Clin Neurol Neurosurg 2013; 115: S90–4 CrossRef MEDLINE
e6.
O’Connor P, Wolinsky JS, Confavreux C, et al.: Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365: 1293–303 CrossRef MEDLINE
e7.
Ma BB, Ostrow LW, Newsome SD: Disseminated zoster with paresis in a multiple sclerosis patient treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm 2016; 3: e203 CrossRef MEDLINE PubMed Central
e8.
Gross CC, Schulte-Mecklenbeck A, Klinsing S, Posevitz-Fejfar A, Wiendl H, Klotz L: Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2016; 3: e183 CrossRef MEDLINE PubMed Central
e9.
Longbrake EE, Ramsbottom MJ, Cantoni C, Ghezzi L, Cross AH, Piccio L: Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients. Mult Scler 2016; 22: 1061–70 CrossRef MEDLINE
e10.
Pfender N, Jelcic I, Linnebank M, Schwarz U, Martin R: Reactiva-
tion of herpesvirus under fingolimod: A case of severe herpes simplex encephalitis. Neurology 2015; 84: 2377–8 CrossRef MEDLINE PubMed Central
e11.
Issa NP, Hentati A: VZV encephalitis that developed in an immunized patient during fingolimod therapy. Neurology 2015; 84: 99–100 CrossRef MEDLINE
e12.
Janka GE: Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007; 166: 95–109 MEDLINE
e13.
Ishii E, Ohga S, Imashuku S, et al.: Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol 2007; 86: 58–65 CrossRef MEDLINE
e14.
Ikumi K, Ando T, Katano H, et al.: HSV-2-related hemophagocytic lymphohistiocytosis in a fingolimod-treated patient with MS. Neurol Neuroimmunol Neuroinflamm 2016; 3: e247.
e15.
Bonig H, Wundes A, Chang KH, Lucas S, Papayannopoulou T: Increased numbers of circulating hematopoietic stem/progenitor cells are chronically maintained in patients treated with the CD49d blocking antibody natalizumab. Blood 2008; 111: 3439–41 CrossRef MEDLINE PubMed Central
e16.
Warnke C, Smolianov V, Dehmel T, et al.: CD34+ progenitor cells mobilized by natalizumab are not a relevant reservoir for JC virus. Mult Scler 2011; 17: 151–6 CrossRef MEDLINE
e17.
Warnke C, Menge T, Hartung HP, et al.: Natalizumab and progressive multifocal leukoencephalopathy: what are the causal factors and can it be avoided? Arch Neurol 2010; 67: 923–30.
e18.
Borchardt J, Berger JR: Re-evaluating the incidence of natalizumab- associated progressive multifocal leukoencephalopathy. Mult Scler Relat Disord 2016; 8: 145–50 CrossRef MEDLINE
e19.
Warnke C, Olsson T, Hartung HP: PML: The dark side of immunotherapy in multiple sclerosis. Trends Pharmacol Sci 2015; 36: 799–801 CrossRef MEDLINE
e20.
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: 2052–61 CrossRef
e21.
Menge T, Stuve O, Kieseier BC, Hartung HP: Alemtuzumab: the advantages and challenges of a novel therapy in MS. Neurology 2014; 83: 87–97 CrossRef MEDLINE
e22.
Penkert H, Delbridge C, Wantia N, Wiestler B, Korn T: Fulminant central nervous system nocardiosis in a patient treated with alemtuzumab for relapsing-remitting multiple sclerosis. JAMA Neurol 2016; 73: 757–9 CrossRef MEDLINE
e23.
Pietrosi G, Mandala L, Vizzini GB, et al.: Fulminant hepatic failure and autoimmune disorders in patient with multiple sclerosis on interferon beta 1a: a fatal combination? Transpl Int 2008; 21: 502–4.
e24.
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: 991–3 CrossRef MEDLINE
e25.
Pellegrino P, Carnovale C, Perrone V, et al.: Efficacy of vaccination against influenza in patients with multiple sclerosis: The role of concomitant therapies. Vaccine 2014; 32: 4730–5 CrossRef MEDLINE
e26.
Kappos L, Cohen J, Collins W, et al.: Fingolimod in relapsing multiple sclerosis: an integrated analysis of safety findings. Mult Scler Relat Disord 2014; 3: 494–504 CrossRef MEDLINE
e27.
Turrion-Merino L, Perez-Gala S, Hermosa-Zarza E, Urech-Garcia-de-la-Vega M, Carrillo-Guijon R, Jaen-Olasolo P: Primary cutaneous CD30+ anaplastic large cell lymphoma treated with radio-
therapy and methotrexate with development of xanthomas at the sites of prior disease. J Cutan Pathol 2016; 43: 400–5 CrossRef MEDLINE
e28.
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: 75–9 CrossRef MEDLINE PubMed Central
e29.
Buttmann M, Seuffert L, Mader U, Toyka KV: Malignancies after mitoxantrone for multiple sclerosis: a retrospective cohort study. Neurology 2016; 86: 2203–7 CrossRef MEDLINE PubMed Central
e30.
Cohen JA, Barkhof F, Comi G, et al.: Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362: 402–15 CrossRef MEDLINE
e31.
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: 387–401 CrossRef MEDLINE
e32.
Li V, Kane J, Chan HH, Hall AJ, Butzkueven H: Continuing fingolimod after development of macular edema: a case report. Neurol Neuroimmunol Neuroinflamm 2014; 1: e13 CrossRef MEDLINE PubMed Central
e33.
Jain N, Bhatti MT: Fingolimod-associated macular edema: incidence, detection, and management. Neurology 2012; 78: 672–80 CrossRef MEDLINE
e34.
Dubey D, Cano CA, Stuve O: Update on monitoring and adverse effects of first generation disease modifying therapies and their recently approved versions in relapsing forms of multiple sclerosis. Curr Opin Neurol 2016; 29: 272–7 CrossRef MEDLINE
e35.
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: 1098–107 CrossRef MEDLINE
e36.
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: 1087–97 CrossRef MEDLINE
e37.
Dubey D, Kieseier BC, Hartung HP, et al.: Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety. Expert Rev Neurother 2015; 15: 339–46 CrossRef MEDLINE
e38.
Gerschenfeld G, Servy A, Valeyrie-Allanore L, de Prost N, Cecchini J: Fatal toxic epidermal necrolysis in a patient on teriflunomide treatment for relapsing multiple sclerosis. Mult Scler 2015; 21: 1476–7 CrossRef MEDLINE
e39.
Rudick RA, Stuart WH, Calabresi PA, et al.: Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354: 911–23 CrossRef MEDLINE
e40.
Polman CH, O’Connor PW, Havrdova E, et al.: A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354: 899–910 CrossRef MEDLINE
e41.
Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N: Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992; 356: 63–6 MEDLINE
e42.
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: 1829–39 CrossRef
e43.
Hartung HP, Aktas O, Boyko AN: Alemtuzumab: a new therapy for active relapsing-remitting multiple sclerosis. Mult Scler 2015; 21: 22–34 CrossRef MEDLINE PubMed Central
e44.
Volz-Zang C, Keller-Stanislawski B: Aktualisierte Empfehlungen zur Minimierung des Risikos einer PML unter Tysabri-Behandlung. Bulletin zur Arzneimittelsicherheit 2016; 7: 11–20.
Institute for Clinical Neuroimmunology, Biomedical Center and Hospital, Ludwig-Maximilians Universität München, Munich: Dr. Havla, Prof. Hohlfeld
Department of Neurology, Faculty of Medicine, Heinrich Heine University Düsseldorf: PD Dr. Warnke,
Prof. Hartung FRCP
Department of Neurology, University Hospital Basel: Prof. Derfuss, Prof. Kappos
Munich Cluster for Systems Neurology (SyNergy): Prof. Hohlfeld
Key messages
Overview of the drugs used to treat multiple sclerosis
Table 1
Overview of the drugs used to treat multiple sclerosis
Drugs licensed for multiple sclerosis with which progressive multifocal leukencephalopathy has been observed
Table 2
Drugs licensed for multiple sclerosis with which progressive multifocal leukencephalopathy has been observed
Response to influenza vaccinations in patients on various treatments for multiple sclerosis
Table 3
Response to influenza vaccinations in patients on various treatments for multiple sclerosis
Treatments for multiple sclerosis during pregnancy and breastfeeding (35, 36)
Table 4
Treatments for multiple sclerosis during pregnancy and breastfeeding (35, 36)
Brief descriptions (risks, adverse drug reactions)*
eBox 1
Brief descriptions (risks, adverse drug reactions)*
Risk management of progressive multifocal leukencephalopathy during treatment with natalizumab
eBox 2
Risk management of progressive multifocal leukencephalopathy during treatment with natalizumab
Ever since the licensing of the first interferon &#946; preparation in 1995, the number of preparations available for the treatment of relapsing-remitting multiple sclerosis has grown constantly.
eFigure
Ever since the licensing of the first interferon β preparation in 1995, the number of preparations available for the treatment of relapsing-remitting multiple sclerosis has grown constantly.
Risk stratification of progressive multifocal leukencephalopathy*
eTable
Risk stratification of progressive multifocal leukencephalopathy*
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2. Filippi M, Rocca MA, Ciccarelli O, et al.: MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol 2016; 15: 292–303 CrossRef
3. Wingerchuk DM, Weinshenker BG: Disease modifying therapies for relapsing multiple sclerosis. BMJ 2016; 354: i3518 CrossRef MEDLINE
4. Klotz L, Berthele A, Bruck W, et al.: [Monitoring of blood parameters under course-modified MS therapy: Substance-specific relevance and current recommendations for action]. Nervenarzt 2016; 87: 645–59 CrossRef MEDLINE
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6. Winkelmann A, Loebermann M, Reisinger EC, Hartung HP, Zettl UK: Disease-modifying therapies and infectious risks in multiple sclerosis. Nat Rev Neurol 2016; 12: 217–33 CrossRef MEDLINE
7. Papadopoulou A, Kappos L, Sprenger T: Safety of teriflunomide for the management of relapsing-remitting multiple sclerosis. Expert Opin Drug Saf 2015; 14: 749–59 CrossRef MEDLINE
8. Warnke C, Dehmel T, Ramanujam R, et al.: Initial lymphocyte count and low BMI may affect fingolimod-induced lymphopenia. Neurology 2014; 83: 2153–7 CrossRef MEDLINE
9. Gyang TV, Hamel J, Goodman AD, Gross RA, Samkoff L: Fingolimod-associated PML in a patient with prior immunosuppression. Neurology 2016; 86: 1843–5 CrossRef MEDLINE
10. Achtnichts L, Obreja O, Conen A, Fux CA, Nedeltchev K: Cryptococcal meningoencephalitis in a patient with multiple sclerosis treated with fingolimod. JAMA Neurol 2015; 72: 1203–5 CrossRef MEDLINE
11. Arvin AM, Wolinsky JS, Kappos L, et al.: Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol 2015; 72: 31–9 CrossRef MEDLINE
12. Saure C, Warnke C, Zohren F, et al.: Natalizumab and impedance of the homing of CD34+ hematopoietic progenitors. Arch Neurol 2011; 68: 1428–31 CrossRef MEDLINE
13. Warnke C, Stettner M, Lehmensiek V, et al.: Natalizumab exerts a suppressive effect on surrogates of B cell function in blood and CSF. Mult Scler 2015; 21: 1036–44 CrossRef MEDLINE
14. Major EO, Nath A: A link between long-term natalizumab dosing in MS and PML: Putting the puzzle together. Neurol Neuroimmunol Neuroinflamm 2016; 3: e235 CrossRef MEDLINE PubMed Central
15. Fine AJ, Sorbello A, Kortepeter C, Scarazzini L: Central nervous system herpes simplex and varicella zoster virus infections in natalizumab-treated patients. Clin Infect Dis 2013; 57: 849–52 CrossRef MEDLINE
16. 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: 1819–28 CrossRef
17. Klotz L, Meuth SG, Wiendl H: Immune mechanisms of new therapeutic strategies in multiple sclerosis-A focus on alemtuzumab. Clin Immunol 2012; 142: 25–30 CrossRef MEDLINE
18. Rau D, Lang M, Harth A, et al.: Listeria meningitis complicating alemtuzumab treatment in multiple sclerosis—report of two cases. Int J Mol Sci 2015; 16: 14669–76 CrossRef MEDLINE PubMed Central
19. Hohlfeld R, Kumpfel T: Alemtuzumab and multiple sclerosis: another note of caution. JAMA Neurol 2016; 73: 637–8 CrossRef MEDLINE
20. Cortese I, Ohayon J, Fenton K, et al.: Cutaneous adverse events in multiple sclerosis patients treated with daclizumab. Neurology 2016; 86: 847–55 CrossRef MEDLINE
21.Gold R, Comi G, Palace J, et al.: Assessment of cardiac safety during fingolimod treatment initiation in a real-world relapsing multiple sclerosis population: a phase 3b, open-label study. J Neurol 2014; 261: 267–76 CrossRef CrossRef MEDLINE PubMed Central
22. Schmouder R, Hariry S, David OJ: Placebo-controlled study of the effects of fingolimod on cardiac rate and rhythm and pulmonary function in healthy volunteers. Eur J Clin Pharmacol 2012; 68: 355–62 CrossRef MEDLINE
23. Olberg HK, Cox RJ, Nostbakken JK, Aarseth JH, Vedeler CA, Myhr KM: Immunotherapies influence the influenza vaccination response in multiple sclerosis patients: an explorative study. Mult Scler 2014; 20: 1074–80 CrossRef MEDLINE
24. Bar-Or A, Freedman MS, Kremenchutzky M, et al.: Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis. Neurology 2013; 81: 552–8 CrossRef MEDLINE PubMed Central
25. Kappos L, Mehling M, Arroyo R, et al.: Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis. Neurology 2015; 84: 872–79 CrossRef CrossRef PubMed Central
26. McCarthy CL, Tuohy O, Compston DA, Kumararatne DS, Coles AJ, Jones JL: Immune competence after alemtuzumab treatment of multiple sclerosis. Neurology 2013; 81: 872–6 CrossRef MEDLINE PubMed Central
27. Williamson EM, Chahin S, Berger JR: Vaccines in multiple sclerosis. Curr Neurol Neurosci Rep 2016; 16: 36 CrossRef MEDLINE
28. Confavreux C, O’Connor P, Comi G, et al.: Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014; 13: 247–56 CrossRef
29. Gold R, Giovannoni G, Phillips JT, et al.: Efficacy and safety of delayed-release dimethyl fumarate in patients newly diagnosed with relapsing-remitting multiple sclerosis (RRMS). Mult Scler 2015; 21: 57–66 CrossRef MEDLINE PubMed Central
30. Havla JB, Pellkofer HL, Meinl I, Gerdes LA, Hohlfeld R, Kumpfel T: Rebound of disease activity after withdrawal of fingolimod (FTY720) treatment. Arch Neurol 2012; 69: 262–4 CrossRef MEDLINE
31.Samaraweera AP, Cohen SN, Akay EM, Evangelou N: Lymphomatoid papulosis: a cutaneous lymphoproliferative disorder in a patient on fingolimod for multiple sclerosis. Mult Scler 2016; 22: 122–4 CrossRef MEDLINE
32. Martinelli V, Cocco E, Capra R, et al.: Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone. Neurology 2011; 77: 1887–95 CrossRef MEDLINE
33. Thiel S, Langer-Gould A, Rockhoff M, et al.: Interferon-beta exposure during first trimester is safe in women with multiple sclerosis—A prospective cohort study from the German Multiple Sclerosis and Pregnancy Registry. Mult Scler 2016; 22: 801–9 CrossRef MEDLINE
34. Herbstritt S, Langer-Gould A, Rockhoff M, et al.: Glatiramer acetate during early pregnancy: a prospective cohort study. Mult Scler 2016; 22: 810–6 CrossRef MEDLINE
35. Cree BA: Update on reproductive safety of current and emerging disease-modifying therapies for multiple sclerosis. Mult Scler 2013; 19: 835–43 CrossRef MEDLINE
36. Coyle PK: Management of women with multiple sclerosis through pregnancy and after childbirth. Ther Adv Neurol Disord 2016; 9: 198–210 CrossRef MEDLINE PubMed Central
37. Johnson KP, Brooks BR, Cohen JA, et al.: Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995; 45: 1268–76 CrossRef MEDLINE
38. Kappos L, Wiendl H, Selmaj K, et al.: Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2015; 373: 1418–28 CrossRef MEDLINE
39. Mendes D, Alves C, Batel-Marques F: Benefit-risk of therapies for relapsing-remitting multiple sclerosis: testing the number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and the likelihood to be helped or harmed (LHH): a systematic review and meta-analysis. CNS Drugs 2016; 30: 909–29 CrossRef MEDLINE
e1. Imitola J, Racke MK: Is no evidence of disease activity a realistic goal for patients with multiple sclerosis? JAMA Neurol 2015; 72: 145–7 CrossRef MEDLINE
e2. Dorr J, Paul F: The transition from first-line to second-line therapy in multiple sclerosis. Curr Treat Options Neurol 2015; 17: 354 MEDLINE
e3. Stangel M, Penner IK, Kallmann BA, Lukas C, Kieseier BC: Towards the implementation of ’no evidence of disease activity’ in multiple sclerosis treatment: the multiple sclerosis decision model. Ther Adv Neurol Disord 2015; 8: 3–13 CrossRef MEDLINE PubMed Central
e4. Cutter GR, Stuve O: Does risk stratification decrease the risk of natalizumab-associated PML? Where is the evidence? Mult Scler 2014; 20: 1304–5 CrossRef MEDLINE
e5. Warnke C, Stuve O, Kieseier BC: Teriflunomide for the treatment of multiple sclerosis. Clin Neurol Neurosurg 2013; 115: S90–4 CrossRef MEDLINE
e6. O’Connor P, Wolinsky JS, Confavreux C, et al.: Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365: 1293–303 CrossRef MEDLINE
e7. Ma BB, Ostrow LW, Newsome SD: Disseminated zoster with paresis in a multiple sclerosis patient treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm 2016; 3: e203 CrossRef MEDLINE PubMed Central
e8. Gross CC, Schulte-Mecklenbeck A, Klinsing S, Posevitz-Fejfar A, Wiendl H, Klotz L: Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2016; 3: e183 CrossRef MEDLINE PubMed Central
e9. Longbrake EE, Ramsbottom MJ, Cantoni C, Ghezzi L, Cross AH, Piccio L: Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients. Mult Scler 2016; 22: 1061–70 CrossRef MEDLINE
e10. Pfender N, Jelcic I, Linnebank M, Schwarz U, Martin R: Reactiva-
tion of herpesvirus under fingolimod: A case of severe herpes simplex encephalitis. Neurology 2015; 84: 2377–8 CrossRef MEDLINE PubMed Central
e11. Issa NP, Hentati A: VZV encephalitis that developed in an immunized patient during fingolimod therapy. Neurology 2015; 84: 99–100 CrossRef MEDLINE
e12. Janka GE: Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007; 166: 95–109 MEDLINE
e13. Ishii E, Ohga S, Imashuku S, et al.: Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol 2007; 86: 58–65 CrossRef MEDLINE
e14. Ikumi K, Ando T, Katano H, et al.: HSV-2-related hemophagocytic lymphohistiocytosis in a fingolimod-treated patient with MS. Neurol Neuroimmunol Neuroinflamm 2016; 3: e247.
e15. Bonig H, Wundes A, Chang KH, Lucas S, Papayannopoulou T: Increased numbers of circulating hematopoietic stem/progenitor cells are chronically maintained in patients treated with the CD49d blocking antibody natalizumab. Blood 2008; 111: 3439–41 CrossRef MEDLINE PubMed Central
e16. Warnke C, Smolianov V, Dehmel T, et al.: CD34+ progenitor cells mobilized by natalizumab are not a relevant reservoir for JC virus. Mult Scler 2011; 17: 151–6 CrossRef MEDLINE
e17. Warnke C, Menge T, Hartung HP, et al.: Natalizumab and progressive multifocal leukoencephalopathy: what are the causal factors and can it be avoided? Arch Neurol 2010; 67: 923–30.
e18. Borchardt J, Berger JR: Re-evaluating the incidence of natalizumab- associated progressive multifocal leukoencephalopathy. Mult Scler Relat Disord 2016; 8: 145–50 CrossRef MEDLINE
e19. Warnke C, Olsson T, Hartung HP: PML: The dark side of immunotherapy in multiple sclerosis. Trends Pharmacol Sci 2015; 36: 799–801 CrossRef MEDLINE
e20. 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: 2052–61 CrossRef
e21. Menge T, Stuve O, Kieseier BC, Hartung HP: Alemtuzumab: the advantages and challenges of a novel therapy in MS. Neurology 2014; 83: 87–97 CrossRef MEDLINE
e22. Penkert H, Delbridge C, Wantia N, Wiestler B, Korn T: Fulminant central nervous system nocardiosis in a patient treated with alemtuzumab for relapsing-remitting multiple sclerosis. JAMA Neurol 2016; 73: 757–9 CrossRef MEDLINE
e23. Pietrosi G, Mandala L, Vizzini GB, et al.: Fulminant hepatic failure and autoimmune disorders in patient with multiple sclerosis on interferon beta 1a: a fatal combination? Transpl Int 2008; 21: 502–4.
e24. 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: 991–3 CrossRef MEDLINE
e25. Pellegrino P, Carnovale C, Perrone V, et al.: Efficacy of vaccination against influenza in patients with multiple sclerosis: The role of concomitant therapies. Vaccine 2014; 32: 4730–5 CrossRef MEDLINE
e26. Kappos L, Cohen J, Collins W, et al.: Fingolimod in relapsing multiple sclerosis: an integrated analysis of safety findings. Mult Scler Relat Disord 2014; 3: 494–504 CrossRef MEDLINE
e27. Turrion-Merino L, Perez-Gala S, Hermosa-Zarza E, Urech-Garcia-de-la-Vega M, Carrillo-Guijon R, Jaen-Olasolo P: Primary cutaneous CD30+ anaplastic large cell lymphoma treated with radio-
therapy and methotrexate with development of xanthomas at the sites of prior disease. J Cutan Pathol 2016; 43: 400–5 CrossRef MEDLINE
e28. 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: 75–9 CrossRef MEDLINE PubMed Central
e29. Buttmann M, Seuffert L, Mader U, Toyka KV: Malignancies after mitoxantrone for multiple sclerosis: a retrospective cohort study. Neurology 2016; 86: 2203–7 CrossRef MEDLINE PubMed Central
e30. Cohen JA, Barkhof F, Comi G, et al.: Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362: 402–15 CrossRef MEDLINE
e31.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: 387–401 CrossRef MEDLINE
e32. Li V, Kane J, Chan HH, Hall AJ, Butzkueven H: Continuing fingolimod after development of macular edema: a case report. Neurol Neuroimmunol Neuroinflamm 2014; 1: e13 CrossRef MEDLINE PubMed Central
e33. Jain N, Bhatti MT: Fingolimod-associated macular edema: incidence, detection, and management. Neurology 2012; 78: 672–80 CrossRef MEDLINE
e34. Dubey D, Cano CA, Stuve O: Update on monitoring and adverse effects of first generation disease modifying therapies and their recently approved versions in relapsing forms of multiple sclerosis. Curr Opin Neurol 2016; 29: 272–7 CrossRef MEDLINE
e35. 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: 1098–107 CrossRef MEDLINE
e36. 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: 1087–97 CrossRef MEDLINE
e37. Dubey D, Kieseier BC, Hartung HP, et al.: Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety. Expert Rev Neurother 2015; 15: 339–46 CrossRef MEDLINE
e38. Gerschenfeld G, Servy A, Valeyrie-Allanore L, de Prost N, Cecchini J: Fatal toxic epidermal necrolysis in a patient on teriflunomide treatment for relapsing multiple sclerosis. Mult Scler 2015; 21: 1476–7 CrossRef MEDLINE
e39. Rudick RA, Stuart WH, Calabresi PA, et al.: Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354: 911–23 CrossRef MEDLINE
e40. Polman CH, O’Connor PW, Havrdova E, et al.: A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354: 899–910 CrossRef MEDLINE
e41.Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N: Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992; 356: 63–6 MEDLINE
e42. 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: 1829–39 CrossRef
e43. Hartung HP, Aktas O, Boyko AN: Alemtuzumab: a new therapy for active relapsing-remitting multiple sclerosis. Mult Scler 2015; 21: 22–34 CrossRef MEDLINE PubMed Central
e44. Volz-Zang C, Keller-Stanislawski B: Aktualisierte Empfehlungen zur Minimierung des Risikos einer PML unter Tysabri-Behandlung. Bulletin zur Arzneimittelsicherheit 2016; 7: 11–20.

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