Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Neurology: Neuroimmunology & Neuroinflammation COVID-19 Article Hub
    • Diversity, Equity, & Inclusion (DEI)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit New Manuscript
    • Submit Revised Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Neurology: Neuroimmunology & Neuroinflammation COVID-19 Article Hub
    • Diversity, Equity, & Inclusion (DEI)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit New Manuscript
    • Submit Revised Manuscript
    • Author Center
  • Home
  • Articles
  • Issues
  • COVID-19 Article Hub
  • Infographics & Video Summaries

User menu

  • My Alerts
  • Log in

Search

  • Advanced search
Neurology Neuroimmunology & Neuroinflammation
Home
A peer-reviewed clinical and translational neurology open access journal
  • My Alerts
  • Log in
Site Logo
  • Home
  • Articles
  • Issues
  • COVID-19 Article Hub
  • Infographics & Video Summaries

Share

March 2017; 4 (2) ArticleOpen Access

An observational study of alemtuzumab following fingolimod for multiple sclerosis

Mark Willis, Owen Pearson, Zsolt Illes, Tobias Sejbaek, Christian Nielsen, Martin Duddy, Kate Petheram, Caspar van Munster, Joep Killestein, Clas Malmeström, Emma Tallantyre, Neil Robertson
First published January 10, 2017, DOI: https://doi.org/10.1212/NXI.0000000000000320
Mark Willis
From the Department of Neurology (M.W., E.T., N.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; Department of Neurology (O.P.), Morriston Hospital, Heol Maes Eglwys, Morriston, Swansea, UK; Departments of Neurology (Z.I., T.S.) and Clinical Immunology (C.N.), Odense University Hospital, University of Southern Denmark; Department of Neurology (M.D.), The Royal Victoria Infirmary, Newcastle upon Tyne; Department of Neurology (K.P.), Sunderland Royal Hospital, UK; VU University Medical Center (C.v.M., J.K.), Amsterdam, the Netherlands; and Department of Neurology (C.M.), Sahlgrenska Academy at the University of Gothenburg, Institute of Clinical Neuroscience and Physiology, Gothenburg, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Owen Pearson
From the Department of Neurology (M.W., E.T., N.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; Department of Neurology (O.P.), Morriston Hospital, Heol Maes Eglwys, Morriston, Swansea, UK; Departments of Neurology (Z.I., T.S.) and Clinical Immunology (C.N.), Odense University Hospital, University of Southern Denmark; Department of Neurology (M.D.), The Royal Victoria Infirmary, Newcastle upon Tyne; Department of Neurology (K.P.), Sunderland Royal Hospital, UK; VU University Medical Center (C.v.M., J.K.), Amsterdam, the Netherlands; and Department of Neurology (C.M.), Sahlgrenska Academy at the University of Gothenburg, Institute of Clinical Neuroscience and Physiology, Gothenburg, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zsolt Illes
From the Department of Neurology (M.W., E.T., N.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; Department of Neurology (O.P.), Morriston Hospital, Heol Maes Eglwys, Morriston, Swansea, UK; Departments of Neurology (Z.I., T.S.) and Clinical Immunology (C.N.), Odense University Hospital, University of Southern Denmark; Department of Neurology (M.D.), The Royal Victoria Infirmary, Newcastle upon Tyne; Department of Neurology (K.P.), Sunderland Royal Hospital, UK; VU University Medical Center (C.v.M., J.K.), Amsterdam, the Netherlands; and Department of Neurology (C.M.), Sahlgrenska Academy at the University of Gothenburg, Institute of Clinical Neuroscience and Physiology, Gothenburg, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tobias Sejbaek
From the Department of Neurology (M.W., E.T., N.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; Department of Neurology (O.P.), Morriston Hospital, Heol Maes Eglwys, Morriston, Swansea, UK; Departments of Neurology (Z.I., T.S.) and Clinical Immunology (C.N.), Odense University Hospital, University of Southern Denmark; Department of Neurology (M.D.), The Royal Victoria Infirmary, Newcastle upon Tyne; Department of Neurology (K.P.), Sunderland Royal Hospital, UK; VU University Medical Center (C.v.M., J.K.), Amsterdam, the Netherlands; and Department of Neurology (C.M.), Sahlgrenska Academy at the University of Gothenburg, Institute of Clinical Neuroscience and Physiology, Gothenburg, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christian Nielsen
From the Department of Neurology (M.W., E.T., N.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; Department of Neurology (O.P.), Morriston Hospital, Heol Maes Eglwys, Morriston, Swansea, UK; Departments of Neurology (Z.I., T.S.) and Clinical Immunology (C.N.), Odense University Hospital, University of Southern Denmark; Department of Neurology (M.D.), The Royal Victoria Infirmary, Newcastle upon Tyne; Department of Neurology (K.P.), Sunderland Royal Hospital, UK; VU University Medical Center (C.v.M., J.K.), Amsterdam, the Netherlands; and Department of Neurology (C.M.), Sahlgrenska Academy at the University of Gothenburg, Institute of Clinical Neuroscience and Physiology, Gothenburg, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Duddy
From the Department of Neurology (M.W., E.T., N.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; Department of Neurology (O.P.), Morriston Hospital, Heol Maes Eglwys, Morriston, Swansea, UK; Departments of Neurology (Z.I., T.S.) and Clinical Immunology (C.N.), Odense University Hospital, University of Southern Denmark; Department of Neurology (M.D.), The Royal Victoria Infirmary, Newcastle upon Tyne; Department of Neurology (K.P.), Sunderland Royal Hospital, UK; VU University Medical Center (C.v.M., J.K.), Amsterdam, the Netherlands; and Department of Neurology (C.M.), Sahlgrenska Academy at the University of Gothenburg, Institute of Clinical Neuroscience and Physiology, Gothenburg, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kate Petheram
From the Department of Neurology (M.W., E.T., N.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; Department of Neurology (O.P.), Morriston Hospital, Heol Maes Eglwys, Morriston, Swansea, UK; Departments of Neurology (Z.I., T.S.) and Clinical Immunology (C.N.), Odense University Hospital, University of Southern Denmark; Department of Neurology (M.D.), The Royal Victoria Infirmary, Newcastle upon Tyne; Department of Neurology (K.P.), Sunderland Royal Hospital, UK; VU University Medical Center (C.v.M., J.K.), Amsterdam, the Netherlands; and Department of Neurology (C.M.), Sahlgrenska Academy at the University of Gothenburg, Institute of Clinical Neuroscience and Physiology, Gothenburg, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Caspar van Munster
From the Department of Neurology (M.W., E.T., N.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; Department of Neurology (O.P.), Morriston Hospital, Heol Maes Eglwys, Morriston, Swansea, UK; Departments of Neurology (Z.I., T.S.) and Clinical Immunology (C.N.), Odense University Hospital, University of Southern Denmark; Department of Neurology (M.D.), The Royal Victoria Infirmary, Newcastle upon Tyne; Department of Neurology (K.P.), Sunderland Royal Hospital, UK; VU University Medical Center (C.v.M., J.K.), Amsterdam, the Netherlands; and Department of Neurology (C.M.), Sahlgrenska Academy at the University of Gothenburg, Institute of Clinical Neuroscience and Physiology, Gothenburg, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joep Killestein
From the Department of Neurology (M.W., E.T., N.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; Department of Neurology (O.P.), Morriston Hospital, Heol Maes Eglwys, Morriston, Swansea, UK; Departments of Neurology (Z.I., T.S.) and Clinical Immunology (C.N.), Odense University Hospital, University of Southern Denmark; Department of Neurology (M.D.), The Royal Victoria Infirmary, Newcastle upon Tyne; Department of Neurology (K.P.), Sunderland Royal Hospital, UK; VU University Medical Center (C.v.M., J.K.), Amsterdam, the Netherlands; and Department of Neurology (C.M.), Sahlgrenska Academy at the University of Gothenburg, Institute of Clinical Neuroscience and Physiology, Gothenburg, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Clas Malmeström
From the Department of Neurology (M.W., E.T., N.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; Department of Neurology (O.P.), Morriston Hospital, Heol Maes Eglwys, Morriston, Swansea, UK; Departments of Neurology (Z.I., T.S.) and Clinical Immunology (C.N.), Odense University Hospital, University of Southern Denmark; Department of Neurology (M.D.), The Royal Victoria Infirmary, Newcastle upon Tyne; Department of Neurology (K.P.), Sunderland Royal Hospital, UK; VU University Medical Center (C.v.M., J.K.), Amsterdam, the Netherlands; and Department of Neurology (C.M.), Sahlgrenska Academy at the University of Gothenburg, Institute of Clinical Neuroscience and Physiology, Gothenburg, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Emma Tallantyre
From the Department of Neurology (M.W., E.T., N.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; Department of Neurology (O.P.), Morriston Hospital, Heol Maes Eglwys, Morriston, Swansea, UK; Departments of Neurology (Z.I., T.S.) and Clinical Immunology (C.N.), Odense University Hospital, University of Southern Denmark; Department of Neurology (M.D.), The Royal Victoria Infirmary, Newcastle upon Tyne; Department of Neurology (K.P.), Sunderland Royal Hospital, UK; VU University Medical Center (C.v.M., J.K.), Amsterdam, the Netherlands; and Department of Neurology (C.M.), Sahlgrenska Academy at the University of Gothenburg, Institute of Clinical Neuroscience and Physiology, Gothenburg, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Neil Robertson
From the Department of Neurology (M.W., E.T., N.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; Department of Neurology (O.P.), Morriston Hospital, Heol Maes Eglwys, Morriston, Swansea, UK; Departments of Neurology (Z.I., T.S.) and Clinical Immunology (C.N.), Odense University Hospital, University of Southern Denmark; Department of Neurology (M.D.), The Royal Victoria Infirmary, Newcastle upon Tyne; Department of Neurology (K.P.), Sunderland Royal Hospital, UK; VU University Medical Center (C.v.M., J.K.), Amsterdam, the Netherlands; and Department of Neurology (C.M.), Sahlgrenska Academy at the University of Gothenburg, Institute of Clinical Neuroscience and Physiology, Gothenburg, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Full PDF
Citation
An observational study of alemtuzumab following fingolimod for multiple sclerosis
Mark Willis, Owen Pearson, Zsolt Illes, Tobias Sejbaek, Christian Nielsen, Martin Duddy, Kate Petheram, Caspar van Munster, Joep Killestein, Clas Malmeström, Emma Tallantyre, Neil Robertson
Neurol Neuroimmunol Neuroinflamm Mar 2017, 4 (2) e320; DOI: 10.1212/NXI.0000000000000320

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
2370

Share

  • Article
  • Figures & Data
  • Info & Disclosures
Loading

Abstract

Objective: To describe a series of patients with relapsing multiple sclerosis (MS) who experienced significant and unexpected disease activity within the first 12 months after switching from fingolimod to alemtuzumab.

Methods: Patients with relapsing MS treated sequentially with fingolimod then alemtuzumab who experienced significant subsequent disease activity were identified by personal communication with 6 different European neuroscience centers.

Results: Nine patients were identified. Median disease duration to alemtuzumab treatment was 94 (39–215) months and follow-up from time of first alemtuzumab cycle 20 (14–21) months. Following first alemtuzumab infusion cycle, 8 patients were identified by at least 1 clinical relapse and radiologic disease activity and 1 by significant radiologic disease activity alone.

Conclusions: We acknowledge the potential for ascertainment bias; however, these cases may illustrate an important cause of reduced efficacy of alemtuzumab in a vulnerable group of patients with MS most in need of disease control. We suggest that significant and unexpected subsequent disease activity after alemtuzumab induction results from prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal, allowing these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provokes disease reactivation. Further animal studies and clinical trials are required to confirm these phenomena and in the meantime careful consideration should be given to mode of action of individual therapies and sequential treatment effects in MS when designing personalized treatment regimens.

GLOSSARY

ARR=
annualized relapse rate;
DMT=
disease-modifying treatment;
IFN=
interferon;
MS=
multiple sclerosis;
Treg=
regulatory CD4+ T cell

The pathophysiology of multiple sclerosis (MS) involves a complex interplay of immunologic factors, including a pivotal role for T and B lymphocytes. As a result, current disease-modifying treatments (DMTs) are targeted at immune cell trafficking, lymphocyte function, and lymphodepletion.1 With a growing range of interventions now available for relapsing disease, it has become of increasing importance to understand their place and timing in individualized therapy. In addition, the immediate and long-term consequences of sequential drug use and the optimum order in which they should be used is unclear but may significantly affect efficacy, adverse events, and longer-term immunocompetence. While awaiting clinical studies to address these issues, observations from clinical practice will be of value in guiding current protocols, generating hypotheses, and informing trial design.

We report a case series of 9 patients from 6 European neuroscience centers who switched to alemtuzumab following incomplete suppression of inflammatory disease activity by fingolimod. Despite the established efficacy of alemtuzumab, which reduces relapse frequency by up to 74% against an active comparator (interferon [IFN]–β-1a), and annualized relapse rates (ARR) from 2.1 to 0.2 in open-label studies,1 all patients experienced a lack of response to alemtuzumab with significant new disease activity. We hypothesize that this occurs as a result of prolonged lymph node sequestration of circulating lymphocytes following fingolimod withdrawal, which in turn limits the efficacy of alemtuzumab. In humanized mice, CD52-positive lymphocyte lysis is more profound in the peripheral circulation compared to the degree of depletion in lymphoid organs2 and suggests that in some patients lymphocytes may remain concealed from the usual therapeutic effects of alemtuzumab. This may have important implications for sequential drug selection and washout periods in a subset of patients who switch from fingolimod or drugs with similar biological mechanisms.

METHODS

Patients with relapsing MS treated sequentially with fingolimod followed by alemtuzumab were identified as having significant and unexpected subsequent disease activity by personal communication with 6 European neuroscience centers. History was obtained by clinical note review and radiologic outcomes analyzed.

RESULTS

Table 1 summarizes clinical information for each patient. All values are median times with ranges in parentheses. Age at disease onset was 22 (8–32) years and disease duration to alemtuzumab treatment 94 (39–215) months. Follow-up from first alemtuzumab cycle was 20 (14–21) months. Time on fingolimod was 13 months (5–33). All patients had received additional DMTs prior to fingolimod: 7 received IFN-β and 2 natalizumab as first-line therapy. Of patients commenced on IFN, 6 escalated to natalizumab, with 1 patient proceeding directly to fingolimod (table 2). Clinical disease or radiologic disease activity were principal reasons for switching from IFN-β and glatiramer acetate but in 8 patients who transitioned from natalizumab to fingolimod only 1 switched as a result of clinical disease activity.

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table 1

Summary of clinical cases

View this table:
  • View inline
  • View popup
Table 2

Disease-modifying treatment summary

Median fingolimod washout period was 6 (4–10) weeks prior to first alemtuzumab cycle. At first treatment, 5 patients had lymphocyte counts below normal range (median 0.64 × 109/L, range 0.24–1.76 × 109) and in 4 patients lymphocytes reconstituted more rapidly than expected (median 3 months). Following initial infusion, 8/9 patients experienced at least 1 clinical relapse in the first 12 months (ARR 1.6) with all patients having radiologic evidence for new disease activity on MRI in the form of new T2 lesions or gadolinium (Gd)–enhancing lesions (table 1 and figure). Median time to relapse following alemtuzumab induction was 4.5 months.

Figure
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure Axial T1 plus contrast images (time post alemtuzumab)

(A) Case 1 (8 months). (B) Case 2 (10 months). (C) Case 4 (8 months). (D) Case 8 (7 months). (E) Case 9 (6 months). White arrows = new gadolinium-enhancing lesions.

Despite the presence of disease activity in the first 12 months, all patients went on to receive the second planned infusion of alemtuzumab and further follow-up is currently available for a mean of 6 months from second treatment cycle. During this period, 8 patients have been relapse-free (combined ARR 0.3). Seven patients have had further imaging: 4 patients were radiologically stable and 3 developed new T2 lesions, 1 of whom had a single new Gd-enhancing lesion. Two patients have not yet undergone further interval imaging.

DISCUSSION

Fingolimod is an oral DMT causing internalization of S1P type 1 receptors and inhibition of lymphocyte trafficking from secondary lymphoid organs into the peripheral circulation. This results in a reduction of the number of lymphocytes available to cross the blood–brain barrier into the CNS, which is thought to be responsible for reducing disease activity.3

Alemtuzumab is a humanized monoclonal antibody targeted against the cell surface protein CD52. Treatment results in a rapid and profound reduction in peripheral lymphocytes as a result of antibody-dependent cell-mediated cytotoxicity, complement-dependent cytolysis, and induction of apoptosis.1 Repopulation occurs through proliferation of mature lymphocytes that escape deletion or by thymic repopulation from CD52-negative hematopoietic precursors.4 A relative increase in regulatory CD4+ T cells (Tregs) is observed following treatment and repopulation5 together with an increased representation of memory T lymphocytes.6 This pattern of subsequent reconstitution of the immune system is thought to be beneficial for MS.

Fingolimod has a pharmacologic half-life of 6–9 days7 and lymphocytes would be expected to normalize 2–4 weeks after discontinuation.3 However, there are case reports of prolonged lymphopenia following prolonged drug exposure, up to 37 months after discontinuation.8 Following discontinuation, there is also a risk of rebound disease activity 2–4 months from the time of withdrawal.3 In animal models, rebound is preceded by a burst of S1P1 overexpression in trapped lymphocytes, which also correlates with subsequent massive lymphocyte egress and CNS infiltration. In addition, Treg functionality is impaired following cessation of fingolimod, which may also contribute to rebound activity.3 It has therefore been suggested that patients continue on an alternative DMT after fingolimod discontinuation, preferably until peripheral lymphocyte counts have normalized. There is currently no consensus as to which subsequent therapeutic agent is optimal.

Following alemtuzumab, there is a significant reduction in relapse frequency, with phase III trials demonstrating 60%–74% of patients at 24 months having freedom from clinical disease, defined as the absence both of relapses and sustained accumulation of disability. In addition, only 7%–9% of patients had gadolinium-enhancing lesions at 24 months on annually performed MRI.1

In our own published cohort9 of 100 patients treated with alemtuzumab, only 4 patients experienced >1 relapse in the 12 months after initial infusion. In contrast, all 9 patients reported here experienced significant and unexpected disease activity. We consider the radiologic findings of these cases particularly striking, especially given the relatively short follow-up time.

We hypothesize that the significant and unexpected disease activity in these cases is caused by sequestrated lymphocytes, which remain concealed from the usual therapeutic effects of alemtuzumab, which has a relatively short half-life of between 7 and 21 days.10 Following this period, surviving CD52-positive lymphocytes then egress from lymph nodes, initiating the observed inflammatory disease activity. Variability in lymphocyte reconstitution may also contribute to these effects: in case 2, it took only 2 months for the peripheral lymphocyte count to return to normal range following the first cycle of alemtuzumab and 1 month after the second cycle. This is considerably faster than the reported mean of 7.1 months for B cells and 20 and 35 months for CD8+ and CD4+ T cells, respectively.1

Other factors that may influence disease activity include S1P1 overexpression and subsequent lymphocyte egress contributing to accelerated repopulation3 and modification of the circulating immune repertoire by fingolimod altering the expected deletion pattern following alemtuzumab. In support of this, 5 patients remained lymphopenic at the start of treatment. In the 4 who had normal lymphocyte counts, it could be speculated that an altered repopulating immune repertoire and impaired Treg functionality may be contributing to the observed disease activity. Alternatively, it may be that for some patients, pathogenic lymphocytes may continue to be released from the lymphoid system over a more prolonged period. While on fingolimod, the mean ARR was 1, increasing to 1.6 in the 12 months following alemtuzumab then reducing to 0.3 following the second dose to date, lending some support to the hypothesis that, after a period, sequestrated lymphocytes eventually become available for depletion by alemtuzumab.

Across the 6 centers, a total of 174 patients have been treated with alemtuzumab. Of these, 36 received fingolimod prior to administration of alemtuzumab. Therefore, these 9 patients with unexpected and significant disease activity following alemtuzumab represent 25% of the fingolimod-alemtuzumab cohort. Detailed outcome data are not currently available on all 174 patients treated with alemtuzumab but would clearly represent a valuable resource for more detailed investigation. Therefore, although we recognize the potential for selection bias in this case series, the degree of disease activity observed in these cases spontaneously and independently caught the attention of clinicians in different centers and may represent an important cause of lack of therapeutic efficacy in a group of patients most at need of disease control. Further studies including detailed immunophenotyping are required to confirm these phenomena and may have relevance in understanding causes of disease reactivation in general. In addition, future trials addressing longer-term outcomes of induction and escalation paradigms need to be designed in order to guide clinicians on strategies for treatment switches. In particular, careful consideration needs to be given to mode of action of individual therapies and sequential treatment effects.

AUTHOR CONTRIBUTIONS

Mark Willis coordinated data collection and wrote and edited the manuscript. Owen Pearson supplied clinical data and edited the manuscript. Zsolt Illes supplied clinical data and edited the manuscript. Tobias Sejbaek supplied clinical data and edited the manuscript. Christian Nielsen supplied clinical data and edited the manuscript. Martin Duddy supplied clinical data and edited the manuscript. Kate Petheram supplied clinical data and edited the manuscript. Caspar van Munster supplied clinical data and edited the manuscript. Joep Killestein supplied clinical data and edited the manuscript. Clas Malmeström supplied clinical data and edited the manuscript. Emma Tallantyre edited the manuscript. Neil Robertson edited the manuscript.

STUDY FUNDING

No targeted funding.

DISCLOSURE

M.D. Willis received research support from Wellcome Trust. O. Pearson served on the scientific advisory board for Biogen, Novartis, Roche, and UK MS Register; and received travel funding and/or speaker honoraria from Biogen, Roche, Merck Serono, Novartis, Teva, and Genzyme Sanofi. Z. Illes served on the scientific advisory board for Biogen, Novartis, Sanofi-Aventis-Genzyme, and Teva; received travel funding and/or speaker honoraria from Biogen, Novartis, Sanofi-Aventis-Genzyme, Teva, Bayer, and Merck Serono; served on the editorial board for Clinical and Experimental Neuroimmunology; holds a patent for fumaric acid derivates for medical use; and received research support from Biogen, Region of Southern Denmark, Odense University Hospital, Scleroseforeningen, Lundbeckfounden, Direktor Enjar Jonasson, Kaldet Johnsen, og Hustru's Mindelegat. T. Sejbaek served on the scientific advisory board for Novartis, Biogen, Teva, Merck, and Roche; and received travel funding and/or speaker honoraria from Biogen, Teva, and Novartis. C. Nielsen reports no disclosures. M. Duddy received speaker honoraria and/or travel funding from Sanofi Genzyme, Novartis, Biogen, Merck, Teva, Roche, and Medscape; is an associate editor for Multiple Sclerosis Journal; and received research support from Novartis, Biogen, Roche, Sanofi Genzyme, and MS Trust, London, UK. K. Petheram served on the scientific advisory board for Roche Product Limited and received travel funding and/or speaker honoraria from Genzyme Sanofi and Biogen. C. van Munster served on the scientific advisory board for Merck Serono and received travel funding and/or speaker honoraria from Novartis, Biogen, Merck Serono, Teva, and Sanofi Genzyme. J. Killestein served on the scientific advisory board for Novartis, Merck Serono, Biogen, Genzyme, Teva, and Roche; received speaker honoraria from Biogen, Novartis, Teva, Merck Serono, and Roche; is editor of the Dutch Society of Neurosurgeons and the Society of Flemis Neurologists; is on the editorial board for MS Journal; consulted for Novartis, Merck-Serono, Biogen, Genzyme, and Teva; and received research support from Schering AG, Biogen, Merck Serono, Teva, Genzyme, Novartis, and Roche. C. Malmestrom served on the scientific advisory board for Biogen, Merck Serono, Novartis, and Roche and received travel funding and/or speaker honoraria from Biogen, Merck Serono, Novartis, and Roche. E. Tallentyre received research support from Biogen. N. Robertson served on the scientific advisory board for Genzyme, Roche, Novartis, and Biogen; received travel funding and/or speaker honoraria from Biogen and Genzyme; served as editor for the Journal of Neurology; and received research support from Genzyme, Novartis, National Institute of Health Wales, Multiple Sclerosis Society of Great Britain, and Northern Ireland Welcome Trust. Go to Neurology.org/nn for full disclosure forms.

Footnotes

  • Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was paid by Wellcome Trust Allocation.

  • Received October 5, 2016.
  • Accepted in final form December 5, 2016.
  • Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

REFERENCES

  1. 1.↵
    1. Willis MD,
    2. Robertson NP
    . Alemtuzumab for multiple sclerosis. Curr Neurol Neurosci Rep 2016;16:84.
    OpenUrl
  2. 2.↵
    1. Hu Y,
    2. Turner MJ,
    3. Shields J, et al
    . Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 2009;128:260–270.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Ayzenberg I,
    2. Hoepner R,
    3. Kleiter I
    . Fingolimod for multiple sclerosis and emerging indications: appropriate patient selection, safety precautions, and special considerations. Ther Clin Risk Manag 2016;12:261–272.
    OpenUrl
  4. 4.↵
    1. Jones JL,
    2. Thompson SA,
    3. Loh P, et al
    . Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation. Proc Natl Acad Sci USA 2013;110:20200–20205.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Havari E,
    2. Turner MJ,
    3. Campos-Rivera J, et al
    . Impact of alemtuzumab treatment on the survival and function of human regulatory T cells in vitro. Immunology 2014;141:123–131.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Freedman MS,
    2. Kaplan J,
    3. Markovic-Plese S
    . Insights into the mechanisms of the therapeutic efficacy of alemtuzumab in multiple sclerosis. J Clin Cell Immunol 2013;4:pii: 1000152.
  7. 7.↵
    1. David OJ
    2. Kovarik J,
    3. Schmouder RL
    . Clinical pharmacokinetics of fingolimod. Clin Pharmacokinet 2012;51:15–28.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Johnson TA,
    2. Shames I,
    3. Keezer M, et al
    . Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients. Clin Immunol 2010;137:15–20.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Willis MD,
    2. Harding KE,
    3. Pickersgill TP, et al
    . Alemtuzumab for multiple sclerosis: long term follow-up in a multi-centre cohort. Mult Scler J 2016;22:1215–1223.
    OpenUrl
  10. 10.↵
    1. Somerfield J,
    2. Hill-Cawthorne GA,
    3. Lin A, et al
    . A novel strategy to reduce the immunogenicity of biological therapies. J Immunol 2010;185:763–768.
    OpenUrlAbstract/FREE Full Text

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Abstract
    • GLOSSARY
    • METHODS
    • RESULTS
    • DISCUSSION
    • AUTHOR CONTRIBUTIONS
    • STUDY FUNDING
    • DISCLOSURE
    • Footnotes
    • REFERENCES
  • Figures & Data
  • Info & Disclosures
Advertisement

Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis

Dr. Robert Pitceathly and Dr. William Macken

► Watch

Related Articles

  • No related articles found.

Topics Discussed

  • All Immunology
  • Autoimmune diseases
  • Multiple sclerosis

Alert Me

  • Alert me when eletters are published

Recommended articles

  • Articles
    Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 Clinical Trial
    A.J. Coles, E. Fox, A. Vladic et al.
    Neurology, March 21, 2012
  • Views & Reviews
    Alemtuzumab
    The advantages and challenges of a novel therapy in MS
    Til Menge, Olaf Stüve, Bernd C. Kieseier et al.
    Neurology, June 11, 2014
  • Article
    Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab
    Heinz Wiendl, Matthew Carraro, Giancarlo Comi et al.
    Neurology: Neuroimmunology & Neuroinflammation, October 29, 2019
  • Article
    Alemtuzumab CARE-MS II 5-year follow-up
    Efficacy and safety findings
    Alasdair J. Coles, Jeffrey A. Cohen, Edward J. Fox et al.
    Neurology, August 23, 2017
Neurology - Neuroimmunology Neuroinflammation: 10 (3)

Articles

  • Articles
  • Issues
  • Popular Articles

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Education
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology: Neuroimmunology & Neuroinflammation
Online ISSN: 2332-7812

© 2023 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise