Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis
Marinos C. Dalakas,Goran Rakocevic,Jens Schmidt,Mohammad Salajegheh,Beverly McElroy,Michael O. Harris-Love,Joseph A. Shrader,Ellen W. Levy,James M. Dambrosia,Robert L. Kampen,David A. Bruno,Allan D. Kirk +11 more
TLDR
It is concluded that in sIBM one series of Alemtuzumab infusions can slow down disease progression up to 6 months, improve the strength of some patients, and reduce endomysial inflammation and stressor molecules.Abstract:
Sporadic inclusion-body myositis (sIBM) is the most common disabling, adult-onset, inflammatory myopathy histologically characterized by intense inflammation and vacuolar degeneration. In spite of T cell-mediated cytotoxicity and persistent, clonally expanded and antigen-driven endomysial T cells, the disease is resistant to immunotherapies. Alemtuzumab is a humanized monoclonal antibody that causes an immediate depletion or severe reduction of peripheral blood lymphocytes, lasting at least 6 months. We designed a proof-of-principle study to examine if one series of Alemtuzumab infusions in sIBM patients depletes not only peripheral blood lymphocytes but also endomysial T cells and alters the natural course of the disease. Thirteen sIBM patients with established 12-month natural history data received 0.3 mg/kg/day Alemtuzumab for 4 days. The study was powered to capture ≥10% increase strength 6 months after treatment. The primary end-point was disease stabilization compared to natural history, assessed by bi-monthly Quantitative Muscle Strength Testing and Medical Research Council strength measurements. Lymphocytes and T cell subsets were monitored concurrently in the blood and the repeated muscle biopsies. Alterations in the mRNA expression of inflammatory, stressor and degeneration-associated molecules were examined in the repeated biopsies. During a 12-month observation period, the patients’ total strength had declined by a mean of 14.9% based on Quantitative Muscle Strength Testing. Six months after therapy, the overall decline was only 1.9% (P < 0.002), corresponding to a 13% differential gain. Among those patients, four improved by a mean of 10% and six reported improved performance of daily activities. The benefit was more evident by the Medical Research Council scales, which demonstrated a decline in the total scores by 13.8% during the observation period but an improvement by 11.4% (P < 0.001) after 6 months, reaching the level of strength recorded 12 months earlier. Depletion of peripheral blood lymphocytes, including the naive and memory CD8+ cells, was noted 2 weeks after treatment and persisted up to 6 months. The effector CD45RA+CD62L cells, however, started to increase 2 months after therapy and peaked by the 4th month. Repeated muscle biopsies showed reduction of CD3 lymphocytes by a mean of 50% (P < 0.008), most prominent in the improved patients, and reduced mRNA expression of stressor molecules Fas, Mip-1a and αB-crystallin; the mRNA of desmin, a regeneration-associated molecule, increased. This proof-of-principle study provides insights into the pathogenesis of inclusion-body myositis and concludes that in sIBM one series of Alemtuzumab infusions can slow down disease progression up to 6 months, improve the strength of some patients, and reduce endomysial inflammation and stressor molecules. These encouraging results, the first in sIBM, warrant a future study with repeated infusions (Clinical Trials. Gov NCT00079768).read more
Citations
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Journal ArticleDOI
Inflammatory Muscle Diseases
TL;DR: The four main types of inflammatory muscle disease — dermatomyositis, polymyositis," necrotizing autoimmune myositis", and inclusion-bodyMyositis — are summarized.
Journal ArticleDOI
188th ENMC International Workshop: Inclusion Body Myositis, 2-4 December 2011, Naarden, The Netherlands.
TL;DR: The 188th ENMC workshop titled “Inclusion Body Myositis” was held in Naarden, The Netherlands, 2–4 December 2011 and aimed to build on the work of two previous IBM workshops held in the MRC Centre London 2008 and Paris 2009.
Journal ArticleDOI
Long-term observational study of sporadic inclusion body myositis
Olivier Benveniste,Marguerite Guiguet,Jane Freebody,Odile Dubourg,Waney Squier,Thierry Maisonobe,Tanya Stojkovic,Maria Isabel Leite,Yves Allenbach,Serge Herson,Stefen Brady,Bruno Eymard,David Hilton-Jones +12 more
TL;DR: It is confirmed that sporadic inclusion body myositis is slowly progressive but not lethal and that immunosuppressive treatments do not ameliorate its natural course, thus confirming findings from smaller studies.
Journal ArticleDOI
Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis.
Lisa G. Rider,Victoria P. Werth,Adam M. Huber,Helene Alexanderson,Anand Prahalad Rao,Nicolino Ruperto,Laura Herbelin,Richard J. Barohn,David A. Isenberg,Frederick W. Miller +9 more
TL;DR: In this article, the authors focus on the assessment of myositis patients using a set of core set measures, including disease activity, quality of life, and disease damage, which can be used as outcomes for therapeutic trials.
Journal ArticleDOI
Review: An update on inflammatory and autoimmune myopathies.
TL;DR: An update on inflammatory and autoimmune myopathies is given in Neuropathology and Applied Neurobiology 37, 226–242.
References
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TL;DR: The evolution over the past 10 years of rather well defined clinical, demographic, histologic, and immunopathological criteria and the identification of inclusion-body myositis as a distinct type of polymyositis now means the inflammatory myopathies now are considered to be pathogenetically similar.
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Remission induction in non-hodgkin lymphoma with reshaped human monoclonal antibody campath-1h
G. Hale,Mike Clark,Robert Marcus,Greg Winter,Martin J. S. Dyer,Jenny M. Phillips,Lutz Riechmann,Herman Waldmann +7 more
TL;DR: A genetically reshaped human IgG1 monoclonal antibody (CAMPATH-1H) was used to treat two patients with non-Hodgkin lymphoma and might have an important use in the treatment of lymphoproliferative disorders and additionally as an immunosuppressive agent.
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Inclusion body myositis. Observations in 40 patients.
TL;DR: The findings support the notion that IBM is a distinct entity in which a set of pathological features is associated with a constellation of clinical findings, and Prednisone treatment at dose levels frequently effective in polymyositis failed to prevent disease progression in those patients observed for 2 or more years.
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The window of therapeutic opportunity in multiple sclerosis : Evidence from monoclonal antibody therapy
Alasdair Coles,Amanda L. Cox,E. Le Page,Joanne L. Jones,S. A. Trip,J. Deans,S. R. Seaman,David Miller,Geoff Hale,Herman Waldmann,D. A. S. Compston +10 more
TL;DR: It is speculated that the beneficial effects of early rescue of neurons and axons from a toxic inflammatory environment, and that prevention of demyelination will prevent long–term axonal degeneration, are currently being tested in a controlled trial comparing Campath–1H and IFN–beta in the treatment of drug–naïve patients with early, active RR MS.