Sporadic Inclusion Body Myositis

Introduction

Sporadic Inclusion Body Myositis (sIBM) is a type of inflammatory myopathy or muscle disease. IBM is the most common form of myopathy in patients over 50 (only 20% of cases occur in patients younger than 50). While some forms of IBM are hereditary, sIBM is not. Moreover, unlike other inflammatory myopathies, which affect more women than men, IBM affects males more frequently than females. In her presentation, Dr. Manning discussed the following aspects of the disease:

• Diagnosis and clinical signs of IBM
• Current research
• Potential treatments

Diagnosing IBM

A diagnosis of IBM should strongly be considered in any patient with a pattern of muscle weakness in the quadriceps (the muscles in the thigh) and the forearm, wrist, and finger flexor muscles.

Sometimes, IBM is misdiagnosed as polymyositis (PM), an uncommon inflammatory disease that causes muscle weakness on both sides of the body, or as amyotrophic lateral sclerosis (ALS), a neurologic disease that also causes muscle weakness. In both ALS and IBM muscle involvement may be asymmetric. However, there is a different muscle weakness pattern associated with each of these conditions that can aid in their diagnosis.

To reach a diagnosis of IBM, physicians consider the following:

Clinical Presentation

Among patients ultimately diagnosed with IBM, the following features are seen.

• Two out of three patients with IBM have weakness and atrophy (loss of muscle mass) of the thigh muscle, forearm flexor muscles (those that control wrist and finger flexion), and ankle dorsiflexion muscles (those that move the ankle upward).
• Swallowing difficulties occur in 10-40% of IBM patients, and can cause weight loss and aspiration if diet is not monitored accordingly. Severe swallowing difficulties may require more extensive intervention.
• Mild facial weakness may occur in one-third of IBM patients; though there are usually no sensory symptoms, such as numbness and tingling, up to 30% of patients have sensory findings on exam or electrophysiological testing, such as nerve conduction studies as part of an electromyogram (EMG).
• Up to 15% of people with IBM have other autoimmune disorders such as lupus, Sjogren’s syndrome, or scleroderma; IBM also differs from other inflammatory myopathies, as there is no associated myocarditis, lung disease, or increased risk of malignancy.

Laboratory Features

Blood tests and imaging are used in patients suspected to have IBM. Physicians look at:

• Creatine kinase (a muscle enzyme), also called CK levels; in the presence of IBM these may be normal or only mildly elevated (less than 10 x normal).
• Positive ANA (antinuclear antibodies that can be elevated in some autoimmune diseases) may be present in 20% of patients but without myositis specific antibodies (antibodies seen in polymyositis and dermatomyositis);
• MRI and ultrasound show atrophy and other abnormalities in affected muscles.
• Recently, autoantibodies associated with IBM have been discovered, and are the focus of some IBM research. However, tests for these autoantibodies are not available for clinical use.

Nerve conduction studies/electromyelogram (EMG) may show muscle damage. However, sometimes findings in an IBM patient with very long-term muscle damage can look like nerve damage, a phenomenon that - in the absence of a muscle biopsy - suggests a diagnosis of ALS. (In fact, this confusion results in up to one-third of patients with IBM receiving an initial diagnosis of ALS).

Muscle Biopsy Findings

Biopsied tissue from affected muscles may show inflammation around muscle fibers and small groups of atrophied fibers. Muscle biopsy will also show rimmed vacuoles (abnormal cellular structures that are also called inclusion bodies), amyloid deposits (presence of abnormal proteins), and endomysial inflammation around muscle fibers (the endomysium is a protective tissue that surrounds the fibers). Repeat biopsies may be needed to distinguish IBM from Polymyositis (PM), a condition with findings that resemble those seen with IBM.

Research

Dr. Manning also presented a summary of some of the studies of sIBM that were completed between 1997-2013.

IVIG (Dalakas trial 1997)[6]

This was a double-blind placebo controlled cross-over trial, in which each patient received a drug and a placebo in turn, with wash out period between. (Double blind means that neither the patient nor the person administering the drug knew whether the patient was taking the drug or the placebo.) Twenty-two patients with IBM were given intravenous immunoglobulin (IVIG) or placebo monthly for 3 months.

Results: The IVIG group gained muscle strength and the placebo group lost muscle strength, but the results were not statistically significant. There was a statistically significant increase in leg strength, but this was an analysis of a sub-group, so it was more difficult to draw conclusions. Those on IVIG showed a statistically significant improvement in swallowing function.

IVIG (Walter trial 2000)[7]

This was a double blind placebo controlled cross-over trial, in which twenty-two patients with IBM were given IVIG or a placebo for six months.

Results: Ninety percent of patients showed increased strength, but no difference between IVIG and placebo. Neuromuscular symptom score improved on IVIG. There were mild adverse effects with IVIG: headache and rash.

IVIG + prednisone (Dalakas 2001)8

This was a double blind placebo controlled trial, in which 37 patients with IBM were given prednisone + IVIG or placebo monthly for 3 months.

Results: There was no difference between the groups in measurements of muscle strength at 1, 2 or 3 months. Those in the IVIG + prednisone group showed less necrotic (dying) muscle fibers and inflammation on muscle biopsy. Nine patients out of 19 in the IVIG group reported increased endurance and increased ability to perform daily activities, while none in placebo group reported this.

Etanercept (Enbrel)

This trial tested a medication that is usually used to treat rheumatoid arthritis; it inactivates the tumor necrosis factor (which plays a crucial role in the development of inflammation). Nine patients were treated for an average of 17 months compared to 29 patients with IBM who received a placebo in the beta-interferon 1a trials and 5 untreated IBM patients.

• Investigators measured maximum strength at baseline, 6 months, and 12 months (no data was gathered on the 29 placebo patients at 12 months)

Results: When compared to the 5 untreated patients, those treated with etanercept showed a small, statistically significant increase in grip strength at 12 months only.[1]

Alemtuzumab (Campath)

To enter the study, patients had to have a diagnosis of sIBM, be ambulatory, could not have been on immunosuppressants for one year prior to study entry, and had to undergo a 12-month assessment to establish natural history data. Exclusion criteria were: malignancy, low platelet count, anemia, cardiac insufficiency, and thyroiditis. Thirteen sIBM patients (4 female, 9 male) were given alemtuzumab intravenously in a pilot study. Alemtuzumab is a drug that is usually used in the treatment of leukemia and lymphoma.

Results: Strength in all patients declined by 14.9% in the observational period of a few months and a 1.9% increase in strength was observed after drug was administered (wrist flexion/extension improved the most). On muscle strength testing, there was a 9.1% decline in the observation period and a gain of 11.4% after being given the drug. No significant adverse events were observed; three patients had transient low blood pressure.[2]

Simvastatin

This was an open-label (both patient and researcher know the treatment that the patient is receiving)[3] pilot study, in which 14 patients received 40mg. of simvastatin daily. The theory behind this is that inflammation may be reduced and that high cholesterol may adversely affect muscle.

Results: 10 patients completed the trial with no adverse events, but also with no significant improvement in muscle strength.

Anakinra (Kineret)

This was an open-label study of a drug that has been approved for rheumatoid arthritis. Investigators assessed the drug to see if would reduce inflammation within muscle fibers and stop deposits of amyloid in patients with sIBM. Anakinra was given daily: 100 mg. for 5-12 months.

Results: There was no improvement in grip strength at 7, 8, or 12 months (all had worsened in strength). One patient dropped out after 5 months, due to increased muscle weakness.[4]

Exercise and IBM

Seven IBM patients in Australia with progressive decline in strength and overall function for 5-9 years were selected. They underwent a 12-week program that consisted of resistance, aerobic, and stretching exercises that were individualized and done at home. Patient tolerance was evaluated every 2 weeks, and intensity was adjusted accordingly.

Results: There was significant improvement in aerobic capacity and strength in hip, knee, and shoulder muscles. There was no change on CK or lactate levels or reporting of perceived exertion [5].

Ongoing studies in IBM

Dr. Manning focused on randomized controlled trials but also referred the group to clinicaltrials.gov for ongoing studies in the treatment of sIBM that include:

• Arimoclomol, phase 2-3 completed in 2012
• BYM338, phase 2 completed in 2012 (described further below)
• Etanercept, completed in 2014
• Pilot trial of lithium, completed 2009
• Follistatin (non- randomized with no control group)

BYM338 (Bimagrumab)

A double-blind placebo-controlled study to evaluate efficacy, safety, and tolerability on muscle strength and mobility at 52 weeks; considered to be a “long” study. Criteria to be enrolled in study are: age between 36-85 years old, sIBM diagnosis, ambulatory (assistive devices and intermittent use of wheelchair is permitted). Exclusion criteria: no other walking limitations, 3 months steroid-free, normal cardiovascular function, no chronic active infection There are 4 groups, 3 with different doses of drug (given intravenously), and placebo group. This is an international study, but currently there is recruitment only in Ohio, Arizona, and Texas in the U.S. The primary outcome measure is the 6-minute walking test (how far the patient can walk in 6 minutes.) It is estimated that this study will be completed in December, 2015.

Dr. Manning summarized the conclusions of her presentation:

• Sporadic IBM (non-hereditary) is the most common myopathy in patients over 50.
• The typical clinical syndrome presents as involvement in finger and wrist flexors and quadriceps muscle.
• Muscle biopsy will show rimmed vacuoles (inclusion bodies), amyloid deposits, and endomysial inflammation around muscle fibers.
• There has been little success with many treatments, the most common being immunosuppressant therapy.

Dr. Manning also emphasized several key points:

• There may be mild to moderate improvement with IVIG in certain patients, but this is still being debated. This uncertainty can lead to difficulty in obtaining insurance coverage.
• Several small pilot studies seem promising, but await results of larger studies.
• Potential new treatments are being pursued in animal models and in vitro (studies of cells in the laboratory setting.)
• Moderate aerobic and resistance exercise is beneficial.

Learn more about the HSS Myositis Support Group, a free support and education group, held monthly for people with myositis and their family and friends.

Summary by Suzan Fischbein, LCSW, Social Work Coordinator, Myositis Support Group
Edited by Nancy Novick.

Authors

References

1 Barohn RJ, Herbelin L, Kissel JT, et al. Pilot trial of etanercept in the treatment of inclusion-body myositis. Neurology. 2006;66(2 Suppl 1):S123–4.

2 Dalakas MC, Rakocevic G, Schmidt J, et al. Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis. Brain. 2009;132(Pt 6):1536–44.

3 Sancricca C, Mora M, Ricci E, et al. Pilot trial of simvastatin in the treatment of sporadic inclusion-body myositis. Neurol Sci. 2011;32(5): 841-7.

4 Kosmidis ML, Alexopoulos H, Tzioufas AG, Dalakas MC. The effect of anakinra, an IL1 receptor antagonist, in patients with sporadic inclusion body myositis (sIBM): a small pilot study. J Neurol Sci. 2013 Nov 15;334(1-2):123-5.

5 Johnson LG, Collier KE, Edwards DJ, et al. Improvement in aerobic capacity after an exercise program in sporadic inclusion body myositis. J Clin Neuromuscul Dis. 2009;10(4):178–84.

6 Dalakas MC, Sonies B, Dambrosia J, et al. Treatment of inclusion body myositis with IVIg: a double-blind, placebo-controlled study. Neurology. 1997;48(3):712–6.

7 Walter MC, Lochmüller H, Toepfer M, et al. High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double blind, placebo-controlled study. J Neurol. 2000;247(1):22–8.

8 Dalakas MC, Koffman B, Fujii M, et al. A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology. 2001;56(3):323–7.