Current Research and Treatment in Myositis
Adapted from a presentation to the Myositis Support Group at HSS
Dr. David R. Fernandez presented on the most current research and treatments in myositis. The first part of this presentation described some tests that are now done in addition to the standard, traditional forms to help better diagnose and monitor myositis.
Diagnosing and Monitoring Myositis
An inflammatory process or muscle damage may be present when levels measured by the following tests are elevated:
- Creatine phosphokinase (CPK) or creatine kinase (CK)
- Erythrocyte sedimentation rate (ESR)
- C-reactive protein (CRP)
- Lactate dehydrogenase (LDH)
- Aspartate aminotransferase (AST)
- Alanine aminotransferase (ALT)
Antibodies are proteins made by the immune system’s B cells (a type of white blood cell) to attack bacteria and viruses that can harm the body. Autoantibodies, however, are similar types of proteins that attack the body’s healthy cells and, in some cases, can cause damage.
In the last 20 years, autoantibodies specific to myositis have been identified and made available for clinical testing. These have been used to define certain subgroups of myositis, including: statin-associated autoimmune necrotizing myopathy; antisynthetase syndrome; and patients who have a higher risk of rapidly progressive lung disease or cancer related to myositis.1-4 The fact that this can be done through a blood test, rather than more invasive procedures such as muscle biopsies, is a great benefit. Disease may be diagnosed earlier and with greater certainty, especially for those in whom the disease does not present in a typical manner.5 Therefore, there is the possibility that treatment may begin sooner. Additionally, this may help to identify more clearly which patients are more likely to benefit from specific clinical trials.
Further, trials that make use of whole-body MRIs to diagnose and monitor myositis are now in progress. This technique may help to demonstrate the extent of progression of myositis, as well as identify which muscles specifically are affected. A large study on juvenile dermatomyositis that used this technique was completed, and additional studies for adults are underway.6
Research in Myositis
Dr. Fernandez discussed two major studies to help investigate the causes of myositis. The first is the MYORISK study, which investigates genetic and environmental risk factors that may be involved in the development of myositis. There is a large focus on patients with antisynthetase syndrome, an important subgroup of patients with myositis.
The second examines Environmental Risk Factors for Myositis in Military Personnel. In this study, the medical and environmental exposure history of military personnel who develop myositis will be compared to other members of the military, in order to identify specific experiences or exposures associated with development of myositis later in life. Using a limited number of patients, another part of this study will attempt to identify genetic markers of myositis through blood and muscle tests.
Dermatomyositis and Polymyositis
Current treatment for dermatomyositis (DM) and polymyositis (PM) may include: prednisone, methotrexate, azathioprine (Imuran), a combination of methotrexate and azathioprine, mycophenolate mofetil (CellCept), cyclosporine, intravenous immunoglobulin (IVIG), ACTH gel, tacrolimus, and ritxuximab.7,8 Dr. Fernandez discussed more recent clinical trials for DM and PM that may provide additional treatment options:
- In the original study of rituximab in myositis (RIM), which also included patients with juvenile dermatomyositis, all patients in the trial received rituximab, but were split into two groups – those who were treated early on, or later on. The expectation was that the patients who were treated early would improve more quickly than the others. While most patients improved over the course of the study, the trial did not succeed in showing that the early treatment group improved more rapidly.9
- Further analysis showed that patients who tested positive for Mi-2 and Jo-1 autoantibodies did improve more rapidly than other patients and may be more likely to respond to rituximab that those with other autoantibodies. It was further concluded that people with any myositis-associated autoantibody, and those with juvenile dermatomyositis, may be more likely to respond than those with no myositis-associated autoantibodies.10
- The following two trials investigated the use of combining steroids with other medications. In the Prometheus trial, 31 patients with DM or PM received either a combination of methotrexate and steroids, or steroids alone. In early results, published in abstract form, there was no clear benefit seen when methotrexate was added; however, the final results have not been published. In the second-line agents in myositis (SELAM) trial, the addition of methotrexate, cyclosporine, or both, to steroids for treatment was investigated in 58 patients who did not respond to steroids alone. All patients improved, with no clear benefit seen with the combination therapy over steroids alone. Importantly, the average daily dose of steroids in the trial was high, at 27mg.11
Dr. Fernandez considered some possible implications of these two studies: Larger trials may be necessary in order to identify benefits of current therapies; certain subgroups of patients might respond better than others; and tighter control of steroids may be necessary in order to be able to see benefit from added medicines.
Lastly, Dr. Fernandez discussed a trial using Abatacept, known as the ARTEMIS trial. Full results have not yet been published, but preliminary results have been made available in abstract form. In a group of 20 DM and PM patients treated with abatacept, eight of the 20 patients showed improved muscle strength and physical function at six months.
Inclusion Body Myositis
Generally, there are fewer treatment options for inclusion body myositis (IBM). Effective, current treatment options are very limited, but they may include methotrexate and intravenous immunoglobulin (IVIG). Additional small studies show there may be a role for subcutaneous (under the skin) immunoglobulin (IG) as well.12-16
- BYM338 (Bimagrumab) was recently studied for use in IBM. Initial results showed some improvement in muscle mass and ability to walk. Though this led to initial optimism,17 the earliest reports of findings from the larger trial do not appear to confirm that benefit. Final publication of the results may provide greater detail and understanding regarding possible effectiveness.
- Myostatin is a protein that may block muscle growth, which is controlled and blocked by a separate protein, follistatin. Follistatin has been targeted by gene therapy; a special virus that has the follistatin gene has been injected into muscle, thereby increasing follistatin levels in muscle. Though some encouraging results have been shown in people with muscular dystrophy,18 no preliminary results are yet available for those with IBM.
- A 13-patient trial showed slower decline of muscle strength in those who received alemtuzumab,19 however, alemtuzumab can cause very significant immunosuppression. Given the relatively modest benefit seen in this study, its role in treatment of IBM is unclear.
- Arimoclomol, rapamycin, and natalizumab20 are also being tested as possible treatments for IBM.
- In a randomized, controlled trial of 139 patients newly diagnosed with juvenile dermatomyositis (JDM), some were given only steroids, while others were given steroids in combination with either cyclosporine or methotrexate; patients were on a fixed steroid taper. This trial showed that patients receiving combination therapy with either cyclosporine or methotrexate were more likely to have improvement in symptoms; combination therapy was more likely to lead to discontinuing steroids and less likely to lead to failure of treatment.
Those receiving combination steroid-methotrexate therapy were more likely to enter remission than those receiving steroid alone or steroid-cyclosporine therapy.21 This is different from the results in the SELAM and Prometheus studies of adult patients. A larger trial, and the ability of investigators to reduce doses of steroids, can allow the effects of the combination therapy to be seen more clearly. This may be why this trial was able to show a difference. In addition, there are likely important, intrinsic differences in newly diagnosed JDM patients and adult PM/DM patients with a longer history of disease.
Exercise in Myositis
- Many studies have shown substantial benefit from physical therapy and improvement in strength, physical function, and activities of daily living. Studies have also shown improvement in performance on endurance testing and some evidence suggesting improvement in disease activity as well.
- A prescription from your doctor is needed to begin physical therapy. Other forms of exercise should be discussed first with your doctor as well.
To find out more about current clinical trials, some reliable sources are:
In conclusion, Dr. Fernandez stated that there are new developments on the horizon that will address the possible causes of myositis and have the potential to both improve the diagnosis of myositis and identify subgroups of patients that differ in key ways. Numerous clinical trials have been recently published or are ongoing, which may increase the effectiveness of existing treatments, develop new treatments, and, hopefully, come closer to a cure for myositis.
- Betteridge, Z. and McHugh, N. Myositis-specific autoantibodies: an important tool to support diagnosis of myositis. J. Intern. Med. 280, 8-23 (2016).
- Hill, C. L. et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet (London, England) 357, 96-100 (2001).
- Fiorentino, D. F. et al. Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1γ. Arthritis Rheum. 65, 2954-62 (2013).
- Mammen, A. L. Statin-Associated Autoimmune Myopathy. N. Engl. J. Med. 374, 664-9 (2016).
- Watanabe, K. et al. Detection of antisynthetase syndrome in patients with idiopathic interstitial pneumonias. Respir. Med. 105, 1238-47 (2011).
- Malattia, C. et al. Whole-body MRI in the assessment of disease activity in juvenile dermatomyositis. Ann. Rheum. Dis. 73, 1083-90 (2014).
- Gordon, C., Sutcliffe, N., Skan, J., Stoll, T. & Isenberg, D. A. Definition and treatment of lupus flares measured by the BILAG index. Rheumatology (Oxford). 42, 1372-9 (2003).
- Oddis, C. V. Update on the pharmacological treatment of adult myositis. J. Intern. Med. 280, 63-74 (2016).
- Oddis, C. V et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum. 65, 314-24 (2013).
- Aggarwal, R. et al. Predictors of clinical improvement in rituximab-treated refractory adult and juvenile dermatomyositis and adult polymyositis. Arthritis Rheumatol. (Hoboken, N.J.) 66, 740-9 (2014).
- Ibrahim, F. et al. Second-line agents in myositis: 1-year factorial trial of additional immunosuppression in patients who have partially responded to steroids. Rheumatology (Oxford). 54, 1050-5 (2015).
- Badrising, U. A. et al. Comparison of weakness progression in inclusion body myositis during treatment with methotrexate or placebo. Ann. Neurol. 51, 369-72 (2002).
- Dalakas, M. C. et al. Treatment of inclusion-body myositis with IVIg: a double-blind, placebo-controlled study. Neurology 48, 712-6 (1997).
- Dalakas, M. C. et al. A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology 56, 323-7 (2001).
- Walter, M. C. et al. High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J. Neurol. 247, 22-8 (2000).
- Cherin, P., Delain, J.-C., de Jaeger, C. & Crave, J.-C. Subcutaneous Immunoglobulin Use in Inclusion Body Myositis: A Review of 6 Cases. Case Rep. Neurol. 7, 227-32
- Amato, A. A. et al. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology 83, 2239-46 (2014).
- Mendell, J. R. et al. A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Mol. Ther. 23, 192-201 (2015).
- Dalakas, M. C. et al. Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis. Brain 132, 1536-44 (2009).
- Ahmed, M. et al. Targeting protein homeostasis in sporadic inclusion body myositis. Sci. Transl. Med. 8, 331ra41 (2016).
- Ruperto, N. et al. Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial. Lancet (London, England) 387, 671-8 (2016).
- Alexanderson, H. Physical exercise as a treatment for adult and juvenile myositis. J. Intern. Med. 280, 75-96 (2016).