In recent years, scientists and clinicians have learned a great deal about autoantibodies occurring in idiopathic inflammatory myopathies (IIMs). These new discoveries have reshaped our understanding of distinct clinical phenotypes in IIMs. Scientists continue to learn more about how these autoantibodies shape pathophysiology, diagnosis, disease monitoring, prognosis and optimum treatment. Moving forward, these autoantibodies will likely come to play an even greater role in the assessment and treatment of these conditions.
The idiopathic inflammatory myopathies are a complex, heterogeneous group of autoimmune diseases. These conditions affect primarily the muscles, but they sometimes affect multiple body systems. Because of this, IIMs often require coordinated care from rheumatologists, neurologists, respiratory physicians, dermatologists and other specialists.1-5
Historically, clinicians divided these patients into one of two groups: polymyositis (PM) or dermatomyositis (DM). Later classification schemes included the subcategories of immune-mediated necrotizing myopathy, sporadic body inclusion myositis, cancer-associated myositis and juvenile disease. The classification is even more complicated, because some cases of IIM share overlapping features with certain types of mixed connective tissue disease (CTD), such as systemic sclerosis. These are sometimes termed CTD-myositis overlap syndromes. But these standard categories do not fully demark the clinical or histopathological differences found in distinct subgroups of IMM patients.1-5
Harsha Gunawardena, MBChB, MRCP, PhD, is a consultant in rheumatology, autoimmune connective tissue disease and vasculitis at North Bristol NHS Trust and the University of Bristol, U.K. He explains that when he sees a new patient, he assesses their clinico-serological phenotype. He notes, “The key is early recognition. Although we see shared clinical features, such as rashes, muscle inflammation and fatigue, patients differ:
- “Some have severe muscle disease at onset.
- “Some are amyopathic, i.e. not weak, with normal creatinine kinase.
- “Some have more severe inflammatory joint disease.
- “Some have lung inflammation/fibrosis, and some never do. In some, the predominant manifestation is lung, with little in the way of other features.
- “Small numbers are associated with cancer.
- “Some have more severe skin disease—rash extent, ulceration or calcinosis.”
He adds, “It’s clear that the autoantibodies are associated with the above manifestations. We are moving toward defining disease subsets.”
What Are Myositis Autoantibodies?
Autoantibodies associated with myositis have traditionally been divided into two groups: myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs). Technically speaking, MSAs refer to autoantibodies that are observed only in acquired myopathies. MSAs are highly selective and, in most cases, mutually exclusive.2 In contrast, MAAs are also sometimes present in myositis-overlap syndrome patients or in mixed connective tissue disease patients without evidence of myositis. These may be present alongside an MSA.1
However, some researchers argue that the distinction between MSAs and MAAs may not be a valuable one, because some patients positive for MSAs never actually develop myositis. Some have even suggested replacing these terms with more general terms, such as CTD-myositis overlap or interstitial lung disease (ILD) autoantibodies, to emphasize the fact that these autoantibodies can present in a number of different clinical settings.3
Myositis-correlated autoantibodies (including MSAs and MAAs) are detected in about 80% of myositis patients.7 This number, however, may not reflect the true percentage of these patients with positive autoantibodies, because new autoantibodies continue to be discovered. More than 20 such MSAs and MAAs have been described.3
The pathophysiology of these autoantibodies is still uncertain, because scientists do not understand the full etiology of these conditions.8 These autoantibodies target ubiquitous intracellular antigens, and it is unclear why these autoantibodies would be associated with predominantly muscular symptoms. It is not known whether these autoantibodies play a role in the etiology of these diseases or whether they may simply serve as helpful disease markers.5
Rohit Aggarwal, MD, MS, is the medical director of the Arthritis and Autoimmunity Center, associate professor of medicine and co-director of the UPMC Myositis Center at the University of Pittsburgh. He explains, “These autoantibodies may be a silent bystander in some cases, but in some cases, evidence suggests these autoantibodies may be playing an active role in the pathogenesis of myositis. For example anti-synthetase antibodies, especially anti-Jo-1 antibodies, have been linked with pathogenesis.”
MSAs’ Clinical Impact
The following is a non-comprehensive sampling of relevant information about MSAs in IIM.
Anti-Aminoacyl-tRNA Synthetase Autoantibodies (Anti-ARS Antibodies)
This group of antibodies is the most common group as a whole. It includes the most commonly found MSA, the anti-Jo autoantibody, which targets a specific aminoacyl-tRNA synthetase used during protein synthesis. To date, eight such autoantibodies have been described, and more may be found in the future targeting the other known versions of the aminoacyl-tRNA synthetase enzyme.2,3
Patients with anti-ARS antibodies may have anti-synthetase syndrome, characterized by muscle symptoms, interstitial lung disease, joint involvement, “mechanic’s hand,” fever and Raynaud symptoms.
Dr. Gunawardena explains, “Some patients can present or develop all manifestations. Some patients have just a few (e.g., in lung-dominant anti-synthetase syndrome) and never develop myositis. Regardless of the anti-synthetase autoantibody subtype, if we see a patient with CTD-myositis overlap and they test positive for anti-synthetase, this indicates a higher risk of interstitial lung disease.”
Dr. Aggarwal advises, “It’s very important physicians screen for interstitial lung disease in these patients, because 70–80% may have or develop interstitial lung disease, and they need to be managed early.”
First described in 1976, the anti-Mi-2 autoantibody became the first serological marker closely linked to DM, occurring in 10 to 30% of DM patients. Researchers later learned that this antibody is directed against the chromatin-remodeling complex, Mi-2/NuRD.1
These patients tend to have classic skin eruptions alongside mild to moderate myositis and less systemic disease. “Patients with anti-Mi-2 autoantibodies have a milder phenotype, which means these patients in most cases get better more easily and much faster,” explains Dr. Aggarwal. “Generally, you [don’t] need big guns, in the form of second- or third-line immunosuppression, for these patients. A little steroid taper with or without methotrexate or azathioprine may get them significantly better.”
For patients with significant skin disease and lung disease, but little weakness, Dr. Gunawardena suggests an anti-MDA5 test. This autoantibody targets MDA5, a cytoplasmic sensor that triggers antiviral responses. It may be particularly prevalent in patients of Asian descent.2,3
“These patients have generally poor prognosis, especially if they have interstitial lung disease—seen in half of the cases in the U.S.,” explains Dr. Aggarwal. “Their interstitial lung disease can be of a rapidly progressing nature, so a physician needs to act fast when they recognize a patient with interstitial lung disease and anti-MDA5 antibody. Otherwise, 50% of these patients with interstitial lung disease may die within three to six months,” he continues. “In patients with these antibodies, the skin rash tends to be more severe and the outcomes poorer if it’s not treated aggressively.”
In addition to providing information about initial prognosis, some autoantibodies may be able to play a role in monitoring disease activity. For example, high levels of anti-MDA5 despite treatment are a sign of refractory lung disease and increased mortality risk.9
The Boards of EULAR & the ACR recently approved this new set of classification criteria for idiopathic inflammatory myopathies. … The new myositis classification guidelines include various clinical characteristics, muscle biopsy findings & autoantibody results. … Having myositis autoantibodies gives half the points needed to achieve diagnosis of IIM under the new classification criteria.
Anti-TIF1-γ (p155/140) Autoantibodies
The autoantibody anti-TIF1-γ is a particularly important one to consider when assessing risk for cancer-related myositis, which is more common in patients with DM than PM. Patients with these autoantibodies often have significant disease-resistant skin disease. The autoantibody targets proteins in the human transcription intermediary factor 1 (TIF1) family.2,3
Dr. Aggarwal notes, “If you have anti-TIF1-γ antibody, your prognosis is going to be poorer because you have higher likelihood to develop cancer associated dermatomyositis. This risk is much worse in elderly patients.” The antibody is particularly helpful because of its high negative predictive value. Patients with DM who are negative for anti-TIF1-γ have a low probability of occult malignancy.10
Dr. Gunawardena explains that there are sometimes differences in the ways myositis autoantibodies manifest in juvenile and adult DM. “For example, anti-TIF1-γ in juvenile DM [is associated] with difficult skin disease and ulceration, but not with cancer.”
Anti-Signal Recognition Particle (SRP) Autoantibody
Clinicians should think about anti-SRP autoantibodies in patients with severe, acute myopathy that is difficult to treat. The autoantibody forms against a cytoplasmic ribonucleoprotein called signal recognition particle.2,3
“Patients with anti-SRP antibody develop very severe muscle weakness [and] very high muscle enzyme levels, and they tend to develop atrophy rather quickly. The prognosis of these patients in terms of disability or muscle strength recovery is poor,” explains Dr. Aggarwal. “However, anti-SRP antibody patients don’t have any extramuscular manifestations, so these patients tend to live longer.”
Because MSAs are specific to IIMs, these autoantibodies can play a role in distinguishing IIMs from inherited or sporadic degenerative myopathies, such as muscular dystrophies.11 Anti-SRP autoantibodies, in particular, are often helpful in this context.2
Anti-SAE Autoantibody & Anti-MJ/NXP2 Autoantibody
Another MSA targets the small ubiquitin-like modifier activating enzyme (SAE). This autoantibody is associated with characteristic skin disease that initially presents without muscle disease. The clinical phenotype often includes systemic features, such as gastrointestinal involvement and dysphagia.3
The anti-MJ/NXP2 autoantibody targets a protein involved in the regulation of cellular senescence. Dr. Gunawardena notes, “The anti-NXP2 subset is associated with calcinosis in both adult and juvenile cases.” The autoantibody is also associated with muscle contractures and severe disease. Some studies have also shown an increased risk of cancer with this autoantibody, although this needs to be further investigated.12
High levels of anti-MDA5 despite treatment are a sign of refractory lung disease & increased mortality risk.
The newest myositis autoantibody to be reported is anti-FHL-1 (four-and-a-half LIM domain), an autoantibody against a muscle-specific protein. In contrast, most other MSAs are derived from proteins expressed ubiquitously.
Notably, mutations in the FHL-1 gene are associated with several known X-linked hereditary myopathies. In terms of IIM, this autoantibody is predictive of severe myopathy, dysphagia and vasculitis. The researchers who uncovered this autoantibody used a muscle-specific cDNA library to uncover autoantigens expressed in muscle tissue. Other researchers may use this approach to uncover other potential autoantibody targets in in IIM.13
New Classification Scheme for IIMs
A variety of classification schemes for IIMs have been proposed over the years, incorporating a variety of clinical and laboratory findings.14 Most recently, the International Myositis Classification Criteria Project (IMCCP) has been working with support from both the ACR and the European League of Associations for Rheumatology (EULAR) to define new classification criteria for IIM and its major subgroups.15 The Boards of EULAR and ACR recently approved this new set of classification criteria for IIMs. These criteria are currently pending publication while they undergo a second round of reviews.
The new myositis classification guidelines include various clinical characteristics, muscle biopsy findings and autoantibody results. The criteria utilize a scoring system to aid myositis classification. Dr. Aggarwal notes that having myositis autoantibodies gives half the points needed to achieve diagnosis of IIM under the new classification criteria.
The new criteria include only the autoantibody Jo-1, not other MSAs. Dr. Aggarwal explains that much more information was available on Jo-1 than for other autoantibodies when these classification criteria were being developed. “That’s why you will see Jo-1 as a representative of myositis autoantibodies in the new classification criteria, but not other autoantibodies.” He notes, “In the future, we hope that Jo-1 will be replaced by any myositis-specific antibody in the classification criteria.”
Ordering MSA & MAA Tests
Although access may be limited in certain clinical settings, tests for MSAs and MAAs are becoming more readily available. Quest Diagnostics provides an MSA autoantibody panel with eight myositis autoantibodies. Dr. Aggarwal also recommends myositis autoantibody panels available through RDL Reference Laboratory, which provide a more extensive selection of autoantibodies. RDL also provides additional myositis tests, which are not included as part of its standard myositis panels. Additionally, some of the most recently discovered autoantibodies may be available only through research centers.
Dr. Aggarwal advises his colleagues to order one of these comprehensive myositis panels if they suspect myositis, even though these panels do not test all MSAs and MAAs. If these tests come back negative, additional autoantibody testing may be warranted if a clinician suspects an autoantibody based on clinical symptoms.
For example, these panels don’t usually include the anti-HMGCR antibody, which is seen in patients who have been exposed to statins and have developed severe muscle weakness. “If you have that kind of phenotype, which is not getting better even after stopping a statin, there may be value in ordering the anti-HMGCR antibody
The extended myositis autoantibody panels are beginning to enter standard practice, but many centers do not yet use them routinely. One recent retrospective study looked at the outcomes of 22 patients who had been ordered such a panel. The panel had coverage for 23 autoantibodies. It was diagnostic in 27% of patients who had not received definitive diagnosis through other means. It also helped two patients avoid an invasive muscle biopsy procedure. Because of the results, clinicians initiated increased cancer surveillance in a patient with an anti-TIF1-γ autoantibody, and two patients with antisynthetase syndrome received further lung evaluation via high-resolution CT and pulmonary function tests.16
“If you look at the history of myositis-specific autoantibodies, every two to four years, we are able to discover an autoantibody that was not previously defined. Therefore, I am pretty sure we are missing several
myositis-specific autoantibodies,” says Dr. Aggarwal. Even at the Pittsburgh Myositis Center, which has an extremely comprehensive myositis lab, he notes that patients only have a positive myositis-specific autoantibody in about 60–70% of cases. He notes, “I think [that] in the future we will be able to discover these autoantibodies and, hopefully, come up to 90% or more.”
Research into myositis is challenging, partly because the group of conditions is both rare and heterogeneous in its manifestations. Autoantibodies may open up new research avenues as clinicians can bring more uniformity to myositis research. “We still enroll patients with clinical symptoms of polymyositis and dermatomyositis or juvenile myositis or cancer-associated myositis,” notes Dr. Aggarwal. “However, now we are able to do post hoc analyses in clinical studies to see which of the autoantibody subset groups show better outcomes or other unique features.”
For example, in a recent clinical trial, 200 myositis patients with refractory DM, PM and juvenile DM were treated with rituximab.17 A post hoc analysis allowed researchers to see that patients with antisynthetase syndrome showed the best improvement of all the antibody groups. “Within this heterogeneous group we are able to have some uniformity using autoantibodies,” Dr. Aggarwal explains.
Dr. Aggarwal provides another example from disease-subset-specific treatment in patients positive for the anti-HMGCR antibody.18 “These patients in a limited data set have been shown to respond very well to IVIG even as a monotherapy.”
When to Get Help
Many general rheumatologists can successfully care for these IIM patients, but Dr. Aggarwal recommends referral in certain situations. If clinicians are struggling with diagnosis or with treatment-resistant disease, expert help may be needed. Dr. Aggarwal adds, “When the patient has severe disease to begin with, for example a patient with severe interstitial lung disease with myositis, I recommend clinicians refer to a more experienced myositis center.”
Ruth Jessen Hickman, MD, is a graduate of the Indiana University School of Medicine. She is a freelance medical and science writer living in Bloomington, Ind.
- Allenbach Y, Benveniste O. Diagnostic utility of autoantibodies in inflammatory muscle diseases. J Neuromuscul Dis. 2015;2(1):13–25.
- Ghirardello A, Bassi N, Palma L, et al. Autoantibodies in polymyositis and dermatomyositis. Curr Rheumatol Rep. 2013 Jun;15(6):335.
- Gunawardena H. The clinical features of myositis-associated autoantibodies: A review. Clin Rev Allergy Immunol. 2017 Feb;52(1):45–57.
- Basharat P. Idiopathic inflammatory myopathies: Association with overlap myositis and syndromes: Classification, clinical characteristics, and associated autoantibodies. EMJ Rheumatol. 2016;3(1):128–135.
- Mandel DE, Malemud CJ, Askari AD. Idiopathic inﬂammatory myopathies: A review of the classiﬁcation and impact of pathogenesis. Int J Mol Sci. 2017 May 18;18(5): pii: E1084. doi:10.3390/ijms18051084.
- Lundberg IE. Myositis in 2016: New tools for diagnosis and therapy. Nat Rev Rheumatol. 2017 Jan 25;13(2):74–76. doi:10.1038/nrrheum.2017.1.
- Koenig M, Fritzler MJ, Targoff IN, et al. Heterogeneity of autoantibodies in 100 patients with autoimmune myositis: Insights into clinical features and outcomes. Arthritis Res Ther. 2007;9(4):R78.
- Haq SA, Tournadre A. Idiopathic inflammatory myopathies: From immunopathogenesis to new therapeutic targets. Int J Rheum Dis. 2015 Nov;18(8):818–825. doi:10.1111/1756-185X.12736.
- Sato S, Kuwana M, Fujita T, Suzuki Y. Anti-CADM-140/MDA5 autoantibody titer correlates with disease activity and predicts disease outcome in patients with dermatomyositis and rapidly progressive interstitial lung disease. Mod Rheumatol. 2013 May;23(3):496–502.
- Fujimoto M, Hamaguchi Y, Kaji K, et al. Myositis-specific anti-155/140 autoantibodies target transcription intermediary factor 1 family proteins. Arthritis Rheum. 2012 Feb;64(2):513–522.
- Mammen AL, Casciola-Rosen L, Christopher-Stine L, et al. Myositis-specific autoantibodies are specific for myositis compared to genetic muscle disease. Neurol Neuroimmunol Neuro Inflamma. 2015 Nov 19;2(6):e172.
- Ichimura Y, Matsushita T, Hamaguchi Y, et al. Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy. Ann Rheum Dis. 2012 May;71(5):710–713.
- Albrecht I, Wick C, Hallgren Å, et al. Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies. J Clin Invest. 2015 Dec;125(12):4612–4624.
- Selva-O’Callaghan A, Trallero-Araguás E, Martınez MA, et al. Inflammatory myopathy: Diagnosis and clinical course, specific clinical scenarios and new complementary tools. Expert Rev Clin Immunol. 2015 Jun;11(6):737–747.
- Tjärnlund A, Bottai M, Rider LG, et al. Progress report on development of classification criteria for adult and juvenile idiopathic inflammatory myopathies (abstract 753). Paper presented at 2012 ACR/ARHP Annual Meeting; 2012 Nov 9–14; Washington, D.C.
- O’Connor A, Mulhall J, Harney SMJ, et al. Investigating idiopathic inflammatory myopathy; initial cross specialty experience with use of the extended myositis antibody panel. Clin Pract. 2017 May 4;7(2):922.
- Aggarwal R, Bandos A, Reed AM, et al. Predictors of clinical improvement in rituximab-treated refractory adult and juvenile dermatomyositis and adult polymyositis. Arthritis Rheumatol. 2014 Mar;66(3):740–749.
- Mammen AL, Tiniakou E. Intravenous immune globulin for statin-triggered autoimmune myopathy. N Engl J Med. 2015 Oct 22;373(17):1680–1682.