For Myopathy Basic Diagnostic Rules Hold

It’s amazing how far we’ve come—but how far we have to go,” reflected moderator Mary E. Cronin, MD, professor of medicine at the Medical College of Wisconsin in Milwaukee. She was echoing the sentiments of another presenter at the symposium, “Idiopathic Inflammatory Myopathies: Current Concepts,” at the 2009 ACR/ARHP Annual Scientific Meeting in Philadelphia. Paul H. Plotz, MD, chief of the Arthritis and Rheumatism Branch of the National Institute of Arthritis, Musculoskeletal, and Skin Diseases in Bethesda, Md., had just summarized a history of idiopathic inflammatory myopathies (IIM) from 1863 to the present and concluded, “a coherent model of pathogenesis has not yet emerged, a top cytokine has not been identified, and I think we have a long way to go.”

In the meantime, according to top investigators, clinicians can rely on foundational diagnostic criteria, track empirical data from investigations of new agents, and look to cross-disciplinary and international collaborations to further our understanding of this complex and heterogeneous group of diseases.

Evaluation: Back to Basics

Robert L. Wortmann, MD, professor of medicine at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., reviewed diagnostic tools for evaluating patients with muscle weakness. Quite often, a thorough history and physical allows clinicians to differentiate between a nerve problem, a muscular problem, or a neuromuscular junction problem, he stated. The basic rules, he said, “hold very well in the clinic, and I ask you not to just blow them off.” Myopathic problems, he noted, are proximal and symmetric, with the remainder of the neurologic exam normal. In contrast, although neuropathic problems can cause proximal muscle weakness, they also cause distal and asymmetric weakness as well as other neurologic abnormalities.

The timed stand test (in which the patient is asked to stand from a chair without using hands for assistance) is an easy test for quantifying lower extremity proximal weakness and is reproducible over time. In patients with proximal muscle weakness, additional findings of high levels of creatine kinase (CK), fatigue, morning stiffness, and weight loss point to differential diagnosis of an inflammatory myopathy, validating the criteria first devised by Bohan and Peter in 1975.

Laboratory tests, especially the muscle enzymes such as CK, aldolase, and succinyl-CoA:3-ketoacid CoA transferase (SCOT), should be measured. “Be aware,” Dr. Wortmann cautioned, “that at any one time, about a third of the population may have a high CK.” High levels can be due to multiple causes, such as racial differences (normal CK levels for black men are at the upper limit of normal in other racial groups); trauma; exercise; and recreational (alcohol, cocaine) and prescribed (statins, HIV medication) drugs.

It’s also important to measure electrolytes (calcium, phosphorus, magnesium, sodium), too much or too little of which can disrupt the orderly contraction and relaxation of muscle. Although he has recommended the forearm ischemic test in the past, Dr. Wortmann is less enthusiastic about it now, except as a screen for some forms of glycogen storage disease. Electromyography (EMG) results can be problematic because the test is operator dependent. Open dialogue with the person conducting the test can yield valuable information and the results of an EMG are often used as a mechanism to identify sites for muscle biopsy. Dr. Wortmann prefers to use magnetic resonance imaging (MRI), especially T2 and short T1 inversion recovery (STIR) images, to identify potential biopsy sites.

Finally, Dr. Wortmann advised rheumatologists obtaining a muscle biopsy to ensure that they collect enough tissue to conduct histology, histochemistry, electron microscopy, and even constituent analyses, if needed. Some patients tolerate the biopsy well, but for others it is very painful, and therefore it is preferable to avoid a repeat biopsy, he said.

Following Dr. Wortmann, Dr. Plotz gave a succinct five-minute history of the major discoveries in myositis, beginning with Ernst L. Wagner’s first case description in 1863 and Heinrich Unverricht’s published papers on polymyositis and dermatomyositis in 1887 and 1890. He sketched the history of inclusion body myositis, of which the first clear description surfaced in 1989, and described the advances in autoantibodies, as well as disease models including anti-Jo-1. Despite advances, new perspectives and new investigators are desperately needed, he said. Several cooperative groups offer hope for progress, notably the European-based Paediatric Rheumatology International Trials Organization (PRINTO), which is now conducting a five-year trial in patients with juvenile dermatomyositis, comparing prednisone alone with prednisone/methotrexate and prednisone/cyclosporine combination therapies (more information is available at http://www.printo.it). Dr. Plotz lauded the growing cooperation between rheumatologists and neurologists on clinical investigations in adult and pediatric myositis.

Tracking the Anatomic Footprint

As if on cue, the next speaker was Steven A. Greenberg, MD, PhD, professor of neurology and codirector of the neurology trials unit at Brigham and Women’s Hospital and Harvard Medical School in Boston, a leading investigator in dermatomyositis and inclusion body myositis, two well-defined entities within the larger group of diseases grouped under the term polymyositis.

Dr. Greenberg described what he calls the “anatomic footprint” of dermatomyositis: perifascicular atrophy (also termed perimysial myofiber injury) and tubuloreticular inclusions. For the past 25 years, investigators have attributed these muscle fiber injuries to ischemia. When Dr. Greenberg began his investigations profiling messenger RNA transcripts in muscle biopsy specimens, he found no increased abundance of transcripts that are up-regulated by ischemia or epoxia in dermatomyositis. “In dermatomyositis,” he noted, “we see injured muscle fibers with neither of these elements. There are no T cells invading these muscle fibers; there’s no antibody that is bound to them. Instead, there appear to be type 1 interferon-inducible transcripts and proteins that are produced inside these muscle fibers. So, this looks like a disease in which cells are being injured from the inside by molecules of the innate immune system, whose normal function is viral defense. But when they’re produced chronically and inappropriately in tissues, it’s possible that they injure tissues. How they do that is uncertain.”

While understanding progresses regarding dermatomyositis, inclusion body myositis remains poorly understood. Dr. Greenberg suspects that inclusion body myositis may be an RNA sequestration disease. He noted that earlier theories that had dominated thinking in the field—such as beta-amyloid and tau accumulation—are now viewed as unfounded.

Tempered Enthusiasm for New Treatments

Because of their heterogeneity and chronicity, idiopathic inflammatory myopathies pose challenges for physicians, said Chester V. Oddis, MD, professor of medicine in the division of rheumatology and clinical immunology at the University of Pittsburgh, who presented an overview of current treatment and future options. “We have to take care of these patients for quite some time, so we’ve got to have some things up our sleeves.”

Pharmacologically speaking, there are more treatment options for myositis, including steroids, immunosuppressive agents, combination regimens, immunomodulatory agents, and biologics. However, most of the data on the use of these therapies is empiric and anecdotal, he cautioned. At his institution, patients with active and aggressive myositis receive divided dose steroids, in 20-mg tolerable daily intake fashion. When their serum CK levels normalize, patients’ doses are consolidated to a single morning dose. The steroid dose is then tapered by 25% every three to four weeks until the 5–10-mg threshold is reached. “In an ideal setting—that is, in a patient who responds well to steroids—we oftentimes continue this [maintenance] dose for a year or so,” Dr. Oddis said.

Methotrexate and azathioprine are generally used after steroids, sometimes concomitantly to manage extramuscular manifestations. There is limited evidence that combination therapy is effective in treatment-resistant myositis, he said. Small studies have shown good results for mycophenolate mofetil to treat the cutaneous features and associated interstitial lung disease in DM.

Dr. Oddis discussed myositis patients with the Jo-1 anti-synthetase autoantibody. Patients with this clinical phenotype often present in the acute stages of systemic disease, with pulmonary symptoms, fever, inflammatory arthritis, and Raynaud’s phenomenon. The clinical picture can look like rheumatoid arthritis, and these patients are particularly challenging to treat, he said. They may also require concomitant antiinflammatory and immunosuppressant therapy, and his group has had some success with tacrolimus in these patients. Other potential targets of therapy, such as tumor necrosis factor–α, offer some promise. Dr. Oddis is principal investigator on the RIM (rituximab in myositis) Study, the first international, collaborative, multicenter clinical trial in 200 patients with IIM.

“This is an exciting time for autoimmune disease therapeutics, including myositis,” Dr. Oddis concluded. “We’ve got a lot of potential biologic and nonbiologic targets—but we always, always, always have to temper our enthusiasm with a respect for these agents and their downstream effects that we may appreciate down the road.”

Gretchen Henkel is a medical journalist based in California.