Disclosures: Christopher-Stine reports no relevant financial disclosures. Fernandez reports receiving research support from Bristol Myers Squibb, Corbus Pharmaceuticals and Northwell Health, and being an editor for Medpage Today.
August 28, 2020
6 min read

Diagnosis Detective: Untangling the web of myositis and its mimics

Disclosures: Christopher-Stine reports no relevant financial disclosures. Fernandez reports receiving research support from Bristol Myers Squibb, Corbus Pharmaceuticals and Northwell Health, and being an editor for Medpage Today.
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Patients with myositis typically present with telltale muscle inflammation. However, properly identifying the source of inflammation can be a challenging prospect for clinicians, especially when other diseases bear oddly similar features.

“Myositis mimics take many forms,” David R. Fernandez, MD, PhD, a rheumatologist at the Hospital for Special Surgery in New York City, told Healio Rheumatology. “The closest mimics of myositis are those illnesses characterized by proximal muscle weakness, myopathy and elevated creatine kinase (CK), including inclusion body myositis (IBM) and limb-girdle muscular dystrophy (LGMD) like facioscapulohumeral dystrophy or dysferlinopathy.”

“Delays in diagnoses are common with myositis itself as well as its mimics,” Lisa Christopher-Stine, MD, told Healio Rheumatology, noting one key reason for delays or misdiagnosis. “The patient usually requires evaluation by multiple specialists. This can take time, and it calls for a degree of expertise to try to tease out these fine nuances.” Source: Adobe Stock

While there are significant challenges presented by these conditions and the myopathies they mimic, Fernandez suggested that the mimics fall into two broad categories. “The most common referrals to me that are not myositis take one of two forms: either they are related to abnormal elevation of muscle lab tests, such as CK, or they are related to new onset weakness,” he said.

Lisa Christopher-Stine, MD, director of the Johns Hopkins Myositis Center, added that she suspects a myositis mimic when a patient has failed to respond to multiple immune suppressants. “An important thing to remember is that many of the inflammatory myopathies have associated myositis-specific antibodies, or at least a myositis-associated antibody,” she said. “In the absence of these antibodies, a mimic should at least be entertained.”

David R. Fernandez

Similarly, Christopher-Stine noted that typical clinical features of rheumatic complications — such as Raynaud’s phenomenon, inflammatory arthritis, sicca symptoms or interstitial lung disease — point toward myositis. “The absence of those features suggests against it,” she said.

Elevated CK

Both Fernandez and Christopher-Stine highlighted CK elevations as a primary consideration when it comes to myositis mimics.

“Let’s start with the lab abnormalities,” Fernandez said. “Some patients have circulating CK that is found incidentally, relatively stable over time, not associated with weakness and is of no real long-term consequence.”

This has been referred to as “asymptomatic hyper-CKemia” in the literature, according to Fernandez.

“Other mimics to think about are elevated CK in African-American patients, especially men,” Christopher-Stine said. “Rare instances of macro CK may occur, and some of the metabolic myopathies such as McArdle’s Disease can present with persistently elevated CK and confuse clinicians.”

Mild to moderate elevations in CK associated with exercise are a “variation on this theme,” Fernandez said. “CK levels rise with exercise but should fade with rest and come back to normal,” he said. “Exercise-induced rhabdomyolysis, the most extreme version of this phenomenon, with extreme elevation of CK and discoloration of the urine with potential for renal injury, is generally not related to myositis but can be related to inborn errors of metabolism.”

Statins or anabolic steroids may yield elevated CK levels, along with hypothyroidism, Fernandez added. “It is important to recognize this as the treatment of hypothyroidism is the supplementation of thyroid hormone,” he said.

Associations in the Musculature

Taking a harder look at the muscles, Christopher-Stine said one of the most “underappreciated” mimics is adult onset muscular dystrophy. “Several of the dystrophies can present in adulthood and have inflammatory infiltrates on the muscle biopsy which sometimes confuses clinicians and pathologists, as they can be labeled as an inflammatory myopathy,” she said. “These patients are sometimes put into the category of polymyositis, a long-standing term but one that really needs updating because of issues such as this.”

Lisa Christopher-Stine

Myotonic dystrophy (DM 2) is another adult onset condition of this type that clinicians may see, along with the dysferlin and FSHD.

Fernandez broadened the discussion to associations between the neurological and musculoskeletal systems. “With new onset weakness, any disruption in the communication between nerves and muscles can result in weakness,” he said. “If we focus on neurologic issues, that includes disorders of the central nervous system, like multiple sclerosis, or the spinal nerve roots like in spinal stenosis or radicular disease.”

Conditions that affect the motor neurons in a more general way include chronic inflammatory demyelinating polyneuropathy or amyotrophic lateral sclerosis, according to Fernandez. He also said that myasthenia gravis may be found in the neuromuscular junction.

In those instances, Fernandez recommended that clinicians observe neurological symptoms in the patient’s medical history and specific findings on exam, such as changes in reflexes or diplopia.

“IBM is particularly important to recognize, as it can behave almost indistinguishably from polymyositis — at least at the disease outset — with proximal weakness, elevation of CK, muscle edema on MRI testing, and highly similar findings on muscle biopsy,” Fernandez added. “One useful clue is early involvement of the deep finger flexors, which is very rare in other forms of myositis. However, it typically does not respond well to immunosuppressive medications.”

Making a Diagnosis

Christopher-Stine acknowledged that diagnosing a myositis mimic is difficult even for clinicians who are familiar with them. “Delays in diagnoses are common with myositis itself as well as its mimics,” she said, noting one key reason for delays or misdiagnosis. “The patient usually requires evaluation by multiple specialists. This can take time, and it calls for a degree of expertise to try to tease out these fine nuances.”

Clinicians should carefully examine the patient history for clues that show deviations from established myositis symptoms, according to Fernandez. He stressed that weakness from myositis often takes a symmetric, proximal form.

In terms of diagnostic criteria specific to mimics, Fernandez listed excessive pain, atypical features like cramping, early or localized atrophy, localized weakness, stiffness and isolated gait issues, prominent ocular symptoms like diplopia, paresthesia, numbness or fasciculations.

“Lastly, clinicians should always be concerned when patients are not responding to therapy,” Fernandez said. “Whenever that happens, reconsidering the diagnosis is a valuable place to start.”

Patient Workup

While myositis and their mimics can present a number of diagnostic pitfalls, Christopher-Stine holds that the workup should be similar to the approach for any rheumatology patient. “If it is an elevated CK that brings the patient to my attention, the first thing I do is repeat it and make sure it is sustained and continuously elevated,” she said. “If it is normal, I try to determine other features if there is weakness present.”

For Christopher-Stine, the next step is to look at family history. After that, she checks for medications, drugs or toxins, neurologic abnormalities and other clinical features. “If further evaluation warrants, an [electromyogram] with nerve conduction can be done,” she said. “Often the history itself is very telling and helps to determine whether or not a muscle biopsy is indicated.”

While Fernandez believes that biopsy is not perfectly sensitive, it can show evidence of many causes of muscle dysfunction. “These include mitochondrial disease, neurologic disease like fiber-type grouping, necrotic and regenerating fibers, and inflammatory cells as well as rare findings like amyloidosis,” he said.

Genetic testing may also come into play. “Sometimes genetic testing can be done on blood and sometimes a muscle biopsy is indicated,” Christopher-Stine said. “It really depends on the presentation of the patient.”

“Further genetic testing is becoming easier to perform to examine for known mutations implicated in LGMD, and that can be considered in select cases,” Fernandez added.

During workup, a second opinion from a “trusted neurology colleague” can be valuable, according to Fernandez. “Also, it is still valuable to do antibody testing to look for myositis in patients with symptoms resembling LGMD, since some of these patients can have polymyositis or IMNM that presents atypically,” he said. “These patients can respond to immunosuppressive therapy, and halt further progression of their symptoms.”

Treatment Decisions

Most rheumatologists are apt to refer patients to neuromuscular or genetic specialists to help with treatment of myositis mimics, according to Christopher-Stine. “In the event of an endocrinopathy or a rarer mimic — such as macroCK — referral to an endocrinologist or working with a specialist to uncover the reason for the abnormalities is important,” she said.

As for specific therapies, while Christopher-Stine noted that prednisone can reduce a patient’s muscle enzymes, it is often a biochemical response that is “decoupled with the clinical response.”

“The danger of clinicians merely basing response rate on a CK drop is problematic,” she said. “They need to look at the whole picture, including whether the patient is actually getting any stronger. Prednisone can often cause a burst of energy as well and this is sometimes misinterpreted as an increase in muscle strength.”

For Fernandez, treatment is all about risk-reward. “If a patient with a myositis mimic is treated with steroids or immunosuppressant agents, they are at risk of side effects without significant chance of benefit, in most cases,” he said. “If they have a neurologic condition that is better treated with other medications or surgery, this delay can allow damage to accumulate, and not all of that may be reversible in every case.”

To that point, if Christopher-Stine could offer an over-arching message for treating these patients, it is that there is no time to waste. “Essentially, once the mimic is identified, it is often an all-hands-on-deck approach to find the appropriate referral for the patient to help maximize their benefit,” she said.

For more information:

  • Lisa Christopher-Stine, MD, can be reached at 5200 Eastern Avenue, Mason F Lord Center Tower, Baltimore, MD 21224; email: lchrist4@jhmi.edu.
  • David R. Fernandez, MD, PhD, can be reached at 535 East 70th Street, New York, NY 10021; email: carnevalen@HSS.EDU.