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

Trial registration: ClinicalTrials.gov NCT00079768.

Figure 1

Changes in muscle strength using QMT. During a 12-month natural history period there is a decline in muscle strength based on QMT measurements by a mean of −14.9%. After 6 months of CAMPATH treatment the mean total muscle strength scores changed by a −1.9% from baseline (P = 0.002). At month 12 from CAMPATH initiation (6 months of follow-up without therapy), the patients’ strength had declined by a mean of −9.7% (P < 0.01) reaching almost the baseline.

Figure 2

Total muscle strength scores obtained with MRC measurements before and after CAMPATH. A mean of 13.8% decline was noted during a 24-month natural history period and 9.1% decline during a 12-month period. Six months after CAMPATH, the total strength improved be a mean of 11.4% (P = 0.0001) reaching almost the level of strength the patients had 2.5 years earlier.

Figure 3

Changes in peripheral blood lymphocytes after CAMPATH. (A) A reduction of total peripheral blood lymphocytes immediately after CAMPATH was noted with a steady repopulation (occurring slowly up to 12 months) in all patients. (B) The kinetics of CD8 + T cells subsets after CAMPATH, including changes in the memory T cells, is shown for a representative patient. A depletion of naïve CD4+ and CD8+ T cells, compared to effector memory cells, was noted in nine patients (shown in Table 2).

Figure 4

Quantification of T cells in all biopsies showed a significant (P < 0.008) decline in the total number of CD8+ T cells (A). In contrast, during the natural history period prior to CAMPATH, the total lymphocyte count had remained unchanged or increased (B).

Figure 5

(A) Representative muscle biopsy samples performed before and 6 months after treatment (stained with H&E) demonstrate reduction of lymphocytic infiltrates. With immunocytochemistry (B), a reduction of CD3- and CD8-positive lymphocytes was noted.

Figure 6

Quantitative mRNA expression of desmin (A) and aB crystalline (B) in the patients’ repeated muscle biopsies before and 6 months after CAMPATH. There is a significant increase of desmin and reduction of αB-crystallin. A significant decline of mRNA expression of Mip-1α (CCL-3) was also noted (not shown); at the protein level, CXCL9 was reduced in some patients, as observed in double immunohistochemical staining for CXCL-9 and CD8 (C). *P < 0.05; ^**P < 0.01.