Abstract
Inclusion-body myositis (IBM) is an inflammatory muscle disease that has proven resistant to treatment. Tumor necrosis factor molecules have been detected in muscle biopsies from patients with IBM. Etanercept is a TNFα receptor fusion protein that binds and inactivates tumor necrosis factor. Nine patients were treated with etanercept at a dose of 25 mg, two times a week for an average of 17 ± 6.1 months. Each patient was evaluated using quantitative strength testing. Their data were compared to two different control groups. The first control group consisted of patients who participated in trials of beta-interferon-1A and had received placebo. There was no significant difference. The second control group was a natural history cohort of IBM patients. There was no statistically significant difference between the treated group and the natural history group at 6 and 12 months when looking at elbow flexors, or 6 months when looking at hand grip. In the treated patients there was a small but significant improvement (p = 0.002) in handgrip at 12 months.
Although inclusion-body myositis (IBM) was originally considered a variant of polymyositis, multiple clinical and pathologic studies over the past 25 years have clearly defined IBM as a unique entity, distinct from the two other common idiopathic inflammatory myopathies: polymyositis and dermatomyositis. IBM is now recognized as the most common acquired muscle disease occurring over the age of 50 years, with an annual incidence estimated at 2–5:100,000.1 It is a painless, slowly progressive condition that causes both proximal and distal weakness. IBM seldom affects patients under 30 years, and is much more common over the age of 50 years. Despite a considerable body of evidence suggesting that IBM may be an immune-mediated disease, studies of a number of immunosuppressive agents have been negative.2–8
In IBM, cytotoxic T-cells and macrophages surround and invade nonnecrotic muscle fibers. Expression of major histocompatibility complex I (MHC-I) and intercellular adhesion molecule 1 (ICAM-1) is induced on muscle cells in patients with IBM.9,10 MHC-I and ICAM-1 appear to play important roles in the initiation and perpetuation of cell-mediated cytotoxicity.11 The expression of these proteins is controlled by cytokines. The production of proinflammatory cytokines, to include tumor necrosis factor alpha (TNFα), is increased in muscle tissue from patients with IBM.12 TNFα can be identified in macrophages and connective tissue of muscle from IBM patients but not normal controls.13 TNFα may play an important role in the genesis of IBM by activating T cells, B cells, and macrophages as well as by including MHC-1 and ICAM-1 gene products, mediating transendothelial transport of lymphocytes, and producing muscle atropyhy.13 Therefore, inhibition of TNFα could be a useful treatment option for IBM.
Etanercept is a TNFα receptor fusion protein that binds and inactivates tumor necrosis factor. Etanercept has been demonstrated to be safe and effective in the treatment of rheumatoid arthritis.14–17 We hypothesize that etanercept may be able to slow progression in patients with IBM.
Methods.
Patients.
Nine patients with IBM were treated with standard doses of etanercept: 25 mg subcutaneously twice weekly. Patients were treated for an average duration 17 ± 6.1 months. The diagnosis of IBM was based on established criteria.1 Each patient underwent quantitative strength testing by measuring maximal voluntary isometric contraction (MVIC; QMA system, Gainesville, GA). These patients were compared to two different set of controls. The first control group consisted of 29 IBM patients who had received placebo in two previous studies of beta-interferon 1A.7,8 These trials were of 6 months duration. The second control group consisted of five untreated IBM patients followed in the authors' clinics for whom there was MVIC data at 6 and 12 months. Quantitative strength testing was obtained as part of the routine care of these patients.
Measures of efficacy.
MVIC testing was performed in the following muscles: elbow flexors and extensors, knee flexors and extensors, and hand grip. A MVIC composite score was calculated, representing the average number of SD units from predicted normal strength, given the age, sex, and height of the subject.18 Changes in the strength measurements between treated patients and controls were assessed using an independent sample t-test.
Results.
Among the patients treated with etanercept, the mean change in the MVIC composite score was –0.36 (SD 0.26); the mean change in MVIC composite score in the first control group (placebo subjects from beta-interferon 1a trials) was –0.19 (SD 0.74, p > 0.05).
For the five untreated IBM patients (natural history controls) who had quantitative strength testing data at 6 and 12 months, only the elbow flexion and hand grip MVIC were analyzed. The mean changes in grip strength in the patients treated with etanercept were –0.36 + 2.6 kg at 6 months and 0.19 + 1.8 kg at 12 months; the mean changes in the natural history controls were –2.56 + 3.0 kg at 6 months and –7.78 + 6.0 kg at 12 months (p = 0.145 and 0.002, respectively). The mean changes in elbow flexion strength of the patients treated with etanercept was –0.18 + 1.0 kg at 6 months and –0.78 + 1.7 kg at 12 months; the mean changes in the natural history controls were –0.35 + 0.50 kg at 6 months and –1.01 + 0.98 kg at 12 months (p = 0.75 and 0.80, respectively). No patient had side effects from entanercept.
Discussion.
Etanercept did not improve composite MVIC strength scores at 6 months. There may have been a slight improvement in grip strength at 12 months in etanercept-treated IBM patients when compared to a small natural history control group. This was not seen until after 12 months of treatment. Interestingly, a recent study of high-dose beta-interferon-1A in IBM found a small but significant improvement in hand-grip strength (an increase of 1.68 kg, p = 0.01).8 As in the current study, no significant change in composite MVIC scores was found.8 In the beta-interferon-1A IBM study, subjects were followed for only 6 months.
There are several potential explanations for the observed improvement in grip strength. This may be an artifact of small patient numbers or due to the unblinded, retrospective study design. In the current study, improved hand-grip strength was not seen until 12 months. It may be that more than 6 months of treatment are required to bring about improvement in IBM patients. Future IBM treatment trials may need to be longer than 6 months. A larger, prospective, placebo-controlled trial of etanercept in IBM is indicated.
Footnotes
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This article was previously published in electronic format as an Expedited E-Pub at www.neurology.org.
Disclosure: The authors report no conflicts of interest.
Received June 22, 2005. Accepted in final form October 14, 2005.
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