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 ≥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).

Immunotherapies for Immune-Mediated Myopathies: A Current Perspective

“…These findings indicate that immunosuppression per se is not sufficient to reverse all of the changes in IBM muscle and that the degenerative component of the disease persists even if the inflammation is suppressed. A similar conclusion is suggested by the results of the 2 small trials of T-cell depletion, initially using anti-T-lymphocyte globulin and subsequently alemtuzumab [74,132], which showed a possible slowing in the rate of disease progression, although this needs to be confirmed in larger groups of patients. In the case of the anti-Tlymphocyte globulin trial there was a suggestion that combining T-cell depletion and immunosuppression with methotrexate may be more effective.…”

“…Alemtuzumab, an anti-CD52 antibody that depletes T cells and mature monocytes, has been trialed in IBM but not in PM, DM or NAM [74]. However, there has been a single case report describing the efficacy of alemtuzumab in treatmentresistant PM [75].…”

Inflammatory Muscle Diseases

“…73 Intravenous immune globulin has been found to be ineffective in controlled trials but may transiently help some patients, especially those with dysphagia. 74,75 Alemtuzumab may provide short-term stabilization, 76 but a controlled study is needed. Treatment with anakinra has also not been successful.…”

Sporadic inclusion body myositis: A review of recent clinical advances and current approaches to diagnosis and treatment

“…There have been continuing attempts to find more effective ways of controlling the immune mediated component of the disease, including T-cell depletion using alemtuzumab (Dalakas et al, 2009) or anti-T-lymphocyte globulin , and therapies specifically targeting inflammatory cytokines such as TNFα with etanercept (Barohn et al, 2006), or IL-1 with anakinra (Kosmidis et al, 2013). Although initial studies have shown that these therapies may have some mild short-term benefits, targeting the immune response alone does not appear to be sufficient to prevent progression of the disease and as yet there are no effective therapies to counter the abnormal protein homeostasis and degenerative aspects of the disease (Breithaupt and Schmidt 2013).…”