title: Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis.
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 > or =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 alphaB-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
authors.affiliation: Clinical Neurosciences, Neuromuscular Diseases, Imperial College, London, Hammersmith Hospital Campus, Du Cane Rd, London, UK. m.dalakas@imperial.ac.uk
authors.forename: Marinos C
authors.initials: MC
authors.lastname: Dalakas
authors.forename: Goran
authors.initials: G
authors.lastname: Rakocevic
authors.forename: Jens
authors.initials: J
authors.lastname: Schmidt
authors.forename: Mohammad
authors.initials: M
authors.lastname: Salajegheh
authors.forename: Beverly
authors.initials: B
authors.lastname: McElroy
authors.forename: Michael O
authors.initials: MO
authors.lastname: Harris-Love
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Shrader
authors.forename: Ellen W
authors.initials: EW
authors.lastname: Levy
authors.forename: James
authors.initials: J
authors.lastname: Dambrosia
authors.forename: Robert L
authors.initials: RL
authors.lastname: Kampen
authors.forename: David A
authors.initials: DA
authors.lastname: Bruno
authors.forename: Allan D
authors.initials: AD
authors.lastname: Kirk
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000009:adverse effects / Q000627:therapeutic use*; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000378:metabolism; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion / Q000379:methods; D008297:Male; D008875:Middle Aged; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics; D020127:Recovery of Function; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D012333:RNA, Messenger; D000074323:Alemtuzumab