MEDICINE
REVIEW ARTICLE
Interdisciplinary Risk Management in the Treatment of Multiple Sclerosis Joachim Havla, Clemens Warnke, Tobias Derfuss, Ludwig Kappos, Hans-Peter Hartung, Reinhard Hohlfeld
SUMMARY 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 vaccineassociated 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. ►Cite this as: Havla J, Warnke C, Derfuss T, Kappos L, Hartung HP, Hohlfeld R: Interdisciplinary risk management in the treatment of multiple sclerosis. Dtsch Arztebl Int 2016; 113: 879–86. DOI: 10.3238/arztebl.2016.0879
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
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2016; 113: 879–86
tarting 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.
S
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). 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 (e1–e3). Correspondingly, it remains unclear whether treatment decisions should be based on NEDA criteria. Moreover, no studies (head-to-head studies,
879
MEDICINE
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
880
with absolute lymphocyte counts of
REVIEW ARTICLE
Interdisciplinary Risk Management in the Treatment of Multiple Sclerosis Joachim Havla, Clemens Warnke, Tobias Derfuss, Ludwig Kappos, Hans-Peter Hartung, Reinhard Hohlfeld
SUMMARY 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 vaccineassociated 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. ►Cite this as: Havla J, Warnke C, Derfuss T, Kappos L, Hartung HP, Hohlfeld R: Interdisciplinary risk management in the treatment of multiple sclerosis. Dtsch Arztebl Int 2016; 113: 879–86. DOI: 10.3238/arztebl.2016.0879
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
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2016; 113: 879–86
tarting 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.
S
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). 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 (e1–e3). Correspondingly, it remains unclear whether treatment decisions should be based on NEDA criteria. Moreover, no studies (head-to-head studies,
879
MEDICINE
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
880
with absolute lymphocyte counts of
