SAN DIEGO—In Hot Topics in Myositis, a session held Nov. 7 at the 2017 ACR/ARHP Annual Meeting, rheumatologists discussed treating myositis patients in three different clinical scenarios: persistently elevated creatine kinase (CK), immune-mediated necrotizing myopathies and lung disease.
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Patients with persistently elevated levels of CK enzyme and normal muscle strength “may still have minimal, nonspecific muscle symptoms, like a cramp or spasm that doesn’t interfere with their day-to-day life,” said Rohit Aggarwal, MD, MS, associate professor of medicine at the University of Pittsburgh Medical Center.
How do you proceed with these asymptomatic hyperCKemia patients? First, confirm whether a patient’s CK levels are truly elevated, he said. Thresholds for the upper limit of normal CK differ by race or ethnicity, and sex.1 Normal CK for African-American men is below 1,000, while normal for Caucasian men is below 200. CK levels are lower in women overall, but higher for African-American women than in Hispanic, Asian or Caucasian women. CK also decreases gradually with age.
Physical activity, particularly if it is unusual, “can have a transient CK increase up to 10–30 times the upper limit of normal,” said Dr. Aggarwal. “If you never exercise and go to the gym for an hour, your CK level can be really high.” After seven days of rest, about 70% of patients will have normal CK levels again, he said.
Based on the asymptomatic hyperCKemia guidelines, use a 97.5% cutoff for normal CK based on a patient’s race and sex, retest after seven days of rest, and look for 1.5 times the upper limit of normal to cut down on false positives.2 If a patient’s high CK levels are confirmed, look for non-neuromuscular causes that are easier to detect and treat, such as hypo- or hyperthyroidism, cardiovascular disease, pregnancy, celiac disease and medications. Statins are widely used and may raise CK levels from two to 10 times the upper limit of normal, he said.
“A common question is, ‘Do I need to stop the statin in someone with asymptomatic hyperCKemia? The answer is no. Can I start a statin if someone has asymptomatic hyperCKemia? The answer is absolutely yes,” he said. Check baseline CK before starting the patient on a statin. If they have no muscle symptoms, nothing more needs to be done. “If the patient does develop muscle symptoms, recheck the CK levels. If still normal and the patient has normal muscle strength, ask the patient if these symptoms are intolerable or if they affect day to day life. If not, continue the statin and follow up normally.” Patients with CK levels higher than five times the upper limit normal should stop their statin. Patients whose symptoms interfere with their daily life should also stop their statin, he said. After stopping the statin, muscle symptoms resolve in most cases.
“Look for drug interactions as well. Perhaps the statin wasn’t the problem at all, but the patient was on another drug that blocked the C3 or C4 pathway and raised the level of statin in the blood, causing the hyperCKemia or muscle symptoms,” said Dr. Aggarwal.
Both muscle biopsy and electromyography may help show why CK is elevated, but patients may choose to avoid these tests if their symptoms are tolerable. Some neuromuscular disorders have a benign course.
Immune-Mediated Necrotizing Myopathy
Recent findings on immune-mediated necrotizing myopathy (IMNM), an idiopathic inflammatory myopathy, include specific biomarkers, said Eleni Tiniakou, MD, an instructor of medicine at Johns Hopkins School of Medicine in Baltimore. Distinct from dermatomyositis or polymyositis, IMNM is “a third pattern we see in muscle biopsies: necrotizing myopathy, where we see prominent myofiber necrosis, degeneration and regeneration, and sparse inflammation,” she said. Two myositis-specific autoantibodies, anti-SRP and anti-HMCGR, play a role in IMNM.3
IMNM patients may have subacute or insidious disease onset, symmetrical proximal muscle weakness, elevated CK, and at least one of the following clinical features: irritable myopathy, edema on MRI or a myositis-specific autoantibody. Muscle biopsy confirms diagnosis.4
Women with IMNM often have the anti-SRP form, which has severe, rapid progression. Patients have highly elevated CK, minimal extramuscular manifestations, such as Raynaud’s phenomenon or interstitial lung disease (ILD), and may have dysphagia or cardiac involvement. Childhood- or early adulthood-onset predicts worse outcomes for those with anti-SRP IMNM, and patients may be very resistant to treatment, she said.
Patients with anti-HMCGR IMNM are female in up to 73% of cases, have severe muscle weakness, highly elevated CK, minimal extramuscular manifestations and may have dysphagia, but statin exposure is the most common culprit. Percentages of anti-HMCGR IMNM patients who have used statins are far lower in Asian studies than those conducted in the West. Patients in Asian cohorts tend to be younger overall, but they may also be exposed to statins in foods rather than prescription medication, said Dr. Tiniakou.
Statins were first described in fungi, and “mushrooms are a very common ingredient in Chinese and Japanese cuisine. Red yeast rice, a traditional Chinese medicinal product, contains high levels of statins, as does pu-erh tea, which is manufactured in China and has become popular for its cholesterol-lowering properties.” Younger age at diagnosis also tends to worsen anti-HMCGR IMNM outcomes, and this myopathy is also treatment resistant.
Immunoprecipitation is used to detect both autoantibodies in IMNM patients. Commercial ELISA tests are also available, but these are costly and may result in false positives, she said. Use ELISA tests only in patients with CK levels over 1,000 for more than eight weeks, or those who have persistent muscle weakness, she said.5 Combination therapy is the best approach for IMNM, usually prednisone and either azathioprine, mycophenolate mofetil or methotrexate.
Lung Disease in Myositis
Lung disease is treatable in some myositis patients, but may be life threatening in others, said Paul F. Dellaripa, MD, associate professor of medicine at Harvard Medical School and a rheumatologist at Brigham and Women’s Hospital in Boston.
“When you see a patient with myositis, you ask yourself two questions: When I treat their myositis or muscle weakness, will they respond to therapy? The second thing you consider is which patients will develop interstitial lung disease and then have progressive disease,” he said.
Muscle weakness and pulmonary complications are associated with higher mortality and morbidity in these patients, but not all patients do progress, or they do so slowly, he said. Patients presenting with radiographic and histologic patterns of nonspecific interstitial pneumonia or organizing pneumonia should raise the suspicion of connective tissue disease or ILD.
Look at phenotypic and serological data to spot myositis patients who may be at higher risk for ILD, said Dr. Dellaripa.6 Dermatomyositis patients have higher risk than those with polymyositis. Antisynthetase syndrome antibody-related disease has a moderate to high risk, as do patients with overlapping clinical features or other antibodies, like PM-Scl, U1 RNP, Ku or Ro-kD52, he said. Data are mixed on the ILD risk for patients with clinically amyopathic dermatomyositis (CADM), but it’s much clearer that patients with MDA5 antibody are at very high ILD risk, and this can be associated with CADM.
“If you look at such features as arthritis, fever, antisynthetase-antibody positivity, inflammation and the MDA5 antibody, what you find is that those are the factors that stand out as risk factors for ILD in your myositis patients. That means the focus is on the antisynthetase and MDA5 antibody patients,” he said.
Some myositis patients with ILD have chronic, smoldering disease, but others have an acute or subacute presentation.7 Most damage tends to occur in the first few years. “It’s rare to see a myositis patient with no ILD early on who develops it eight or 10 years later,” said Dr. Dellaripa. Patients with MDA5 antibody, older patients, patients with acute or subacute disease, and patients with early decline in forced vital capacity may have worse disease.8
Typical treatment of ILK in myositis patients is a corticosteroid in combination with a second immunosuppressive agent. Most patients have inflammatory lung disease effectively treated with anti-inflammatory medications, but if the predominant lesion is fibrotic, then an anti-fibrotic agent may be indicated, he concluded.
Susan Bernstein is a freelance journalist.
- Brewster LM, Mairuhu G, Sturk A, et al. Distribution of creatine kinase in the general population: Implications for statin therapy. Am Heart J. 2007 Oct;154(4):655–661.
- Kyriakides T, Angelini C, Schaefer J, et al. EFNS guidelines on the diagnostic approach to pauci- or asymptomatic hyperCKemia. Eur J Neurol. 2010 Jun 1;17(6):767–773.
- Betteridge Z, McHugh N. Myositis-specific autoantibodies: An important tool to support diagnosis of myositis. J Intern Med. 2016 Jul; 280(1):8-23.
- Mammen AL. Necrotizing myopathies: Beyond statins. Curr Opin Rheumatol. 2014 Nov;26(6):679–683.
- Mammen AL. Statin-associated autoimmune myopathy. New Engl J Med. 2016 Feb;374(7):664–669.
- Zhang L, Wu G, Gao D, et al. Factors associated with interstitial lung disease in patients with polymyositis and dermatomyositis: A systematic review and meta-analysis. PLoS One. 2016 May:11(5):e0155381.
- Fujisawa T, Hozumi H, Kono M, et al. Prognostic factors for myositis-associated interstitial lung disease. PLoS One. 2014 Jun;9(6):e98824.
- Labrador-Horrillo M, Martinez MA, Selva-O’Callaghan A, et al. Anti-MDA5 antibodies in a large Mediterranean population of adults with dermatomyositis. J Immunol Res. 2014;2014:290797.