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Correspondence: Address to Margherita Milone, MD, PhD, Neuromuscular Medicine Division, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
Immune-mediated myopathies (IMMs) are a heterogeneous group of acquired muscle disorders characterized by muscle weakness, elevated creatine kinase levels, and myopathic electromyographic findings. Most IMMs feature the presence of inflammatory infiltrates in muscle. However, the inflammatory exudate may be absent. Indeed, necrotizing autoimmune myopathy (NAM), also called immune-mediated necrotizing myopathy, is characterized by a necrotizing pathologic process with no or minimal inflammation in muscle. The recent discovery of antibodies associated with specific subtypes of autoimmune myopathies has played a major role in characterizing these diseases. Although diagnostic criteria and classification of IMMs currently are under revision, on the basis of the clinical and muscle histopathologic findings, IMMs can be differentiated as NAM, inclusion body myositis (IBM), dermatomyositis, polymyositis, and nonspecific myositis. Because of recent developments in the field of NAM and IBM and the controversies around polymyositis, this review will focus on NAM, IBM, and dermatomyositis.
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Dr Milone received funding from the Center for Individualized Medicine and Department of Neurology, Mayo Clinic.
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Immune-mediated myopathies (IMMs) are a heterogeneous group of acquired muscle disorders characterized by muscle weakness, elevated creatine kinase (CK) levels, and myopathic electromyographic findings. Because of the frequent presence of inflammatory infiltrates on muscle biopsy, IMMs are often referred to as idiopathic inflammatory myopathies (IIMs). However, the inflammatory exudate may be absent in the muscle in some IMMs. Indeed, muscle biopsy of necrotizing autoimmune myopathy (NAM), also called immune-mediated necrotizing myopathy, often reveals prominent muscle fiber necrosis and regeneration with minimal or no inflammation.
ENMC Myositis Muscle Biopsy Study Group 205th ENMC International Workshop: pathology diagnosis of idiopathic inflammatory myopathies part II 28-30 March 2014, Naarden, The Netherlands.
there has been a constant effort to define diagnostic criteria and reclassify the IMMs, but to date, no diagnostic criteria or classification has found unanimous consensus.
On the basis of the clinical and muscle histopathologic findings, IMMs can be distinguished as DM, PM, inclusion body myositis (IBM), NAM, and nonspecific myositis.
ENMC Myositis Muscle Biopsy Study Group 205th ENMC International Workshop: pathology diagnosis of idiopathic inflammatory myopathies part II 28-30 March 2014, Naarden, The Netherlands.
Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients.
The distinction of DM, PM, IBM, NAM, and nonspecific myositis does not entirely reflect the true spectrum of IMMs. Indeed, a subset of IIM can have extramuscular involvement consisting of lung, skin, or joint involvement (overlap myositis). In addition, the recently discovered myositis-associated antibodies link to specific clinical and pathologic phenotypes and may even guide treatment.
These antibodies complement the clinical and myopathologic findings and contribute to the characterization of the IMMs. Therefore, these antibodies could be of tremendous value in the reclassification of IMMs.
This article will discuss NAM, IBM, and DM as defined by clinical and myopathologic features.
Needs in the Field
In light of the knowledge on noninflammatory IMMs, the rarity of PM, and the discovery of myositis-associated antibodies, it has become evident that the old Bohan and Peter classification,
ENMC Myositis Muscle Biopsy Study Group 205th ENMC International Workshop: pathology diagnosis of idiopathic inflammatory myopathies part II 28-30 March 2014, Naarden, The Netherlands.
119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands.
Diagnostic criteria for each subtype require definition and consensus.
Necrotizing Autoimmune Myopathy
Clinical Features
Necrotizing autoimmune myopathy manifests with subacute proximal limb muscle weakness and persistently elevated CK levels. In contrast to immune-mediated inflammatory myopathies, NAM muscle biopsies often reveal no or minimal inflammation but prominent muscle fiber necrosis and regeneration (Figure 1, Table 1).
The weakness is predominantly proximal and more prominent in the lower limbs. In a recent Mayo Clinic study, coexisting distal weakness involving foot dorsiflexors and finger extensors was documented in more than 40% of patients.
Myalgia may or may not be present. Respiratory muscle weakness is common as suggested by dyspnea, a restrictive pattern on pulmonary function tests, and abnormal findings on overnight oximetry. The respiratory muscle weakness can result in hypercapnic respiratory failure and the need for mechanical ventilation,
Although NAM is commonly a subacute myopathy, it can also manifest with slowly progressive weakness mimicking muscular dystrophies, clinically and pathologically.
Figure 1Muscle biopsy specimens from a patient with necrotizing autoimmune myopathy and anti–3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies. A, There are numerous scattered necrotic muscle fibers (asterisks), fewer regenerating fibers (arrow), and no inflammatory exudate; few fibers have internalized nuclei (arrowhead) (hematoxylin-eosin). B, Macrophages invading necrotic fibers appear red (acid phosphatase stain).
The diagnosis of NAM relies on the combination of clinical and pathologic features and the exclusion of other etiologies that can result in a similar muscle histopathologic pattern. The histologic features of NAM (necrotizing myopathy with minimal or no inflammation) are nonspecific and also compatible with early muscular dystrophy or toxic myopathies.
The subacute onset of the weakness makes hereditary myopathy unlikely. The presence of serologic markers (see “Necrotizing Autoimmune Myopathy,” “Serologic Markers” section) and clinical response to immunotherapy support the autoimmune nature of the disease. Often, biopsy specimens from patients with NAM exhibit C5b9 deposits on the sarcolemma of nonnecrotic muscle fibers and diffuse major histocompatibility complex (MHC) class 1 up-regulation.
ENMC Myositis Muscle Biopsy Study Group 205th ENMC International Workshop: pathology diagnosis of idiopathic inflammatory myopathies part II 28-30 March 2014, Naarden, The Netherlands.
However, the latter finding is nonspecific because it can be observed in muscular dystrophies, especially in those frequently associated with an inflammatory exudate in muscle.
Although muscle fiber necrosis and regeneration are the main histologic features of NAM, approximatly 20% of patients with anti–3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) antibody have minor inflammatory infiltrates.
When present, the inflammatory cells are located in the endomysium and perivascular sites (CD8+ T cells invading nonnecrotic muscle fibers, as observed in PM, are not a feature of NAM) and consist predominantly of macrophages. These macrophages are likely involved in tissue repair and not destruction, as suggested by their M2 polarization.
Levels of CK are always elevated in NAM, to the order of several thousands.
The 2 main antibodies associated with NAM are the anti-HMGCR and anti-SRP antibodies (Table 2). Approximately a third of patients with NAM have no detectable HMGCR or SRP antibodies.
Dermatomyositis and NAM are associated with an increased risk of cancer compared with age- and sex-matched controls. Risk of cancer is higher in the presence of certain antibodies.
Antibody
Phenotype
Additional clinical features
Anti–Mi-2
DM
NA
Anti–TIF-1γ
DM
↑ Risk of cancer ILD Severe skin disease
Anti-MDA5
DM Amyopathic DM
ILD
Anti-SAE
DM
Anti-NXP2
DM
↑ Risk of cancer (in adults) Calcinosis (in juvenile DM)
Anti-Jo1
Antisynthetase syndrome, myositis-predominant
ILD
Anti-HMGCR
NAM
↑ Risk of cancer
Anti-SRP
NAM
↑ vs unchanged risk of cancer
Anti-cN1A
IBM
NA
a cN1A = cytosolic 5′-nucleotidase 1A; DM = dermatomyositis; Jo1 = histidyl–transfer RNA synthetase; IBM = inclusion body myositis; ILD = interstitial lung disease; MDA5 = melanoma differentiation–associated gene 5; NAM = necrotizing autoimmune myopathy; NA = not available; NXP2 = nuclear matrix protein 2; SAE = small ubiquitinlike modifier activating enzyme; SRP = signal recognition particle; TIF-1γ = transcriptional intermediary factor 1-γ.
b Dermatomyositis and NAM are associated with an increased risk of cancer compared with age- and sex-matched controls. Risk of cancer is higher in the presence of certain antibodies.
3-Hydroxy-3-methylglutaryl coenzyme A reductase is the enzyme that catalyzes the rate-limiting step of cholesterol synthesis. Antibodies directed against HMGCR are present in patients with NAM who have been exposed to statins but also in statin-naive patients.
However, statins are also contained in dietary constituents, and therefore, individuals may not actually be statin naive. This factor has created confusion about the possible role of statins as a trigger for NAM. The duration of exposure to statins does not seem to affect the development of NAM, and in some patients, the myopathy has developed after discontinuation of the statins. In addition, statin discontinuation does not arrest the progression of the anti-HMGCR–associated myopathy.
Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy.
However, in a large cohort of Chinese patients with low prevalence of statin exposure, serum levels of anti-HMGCR antibody did not match disease activity.
Clinical characteristics of anti-3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies in Chinese patients with idiopathic inflammatory myopathies.
The anti-HMGCR antibodies are quite specific for NAM. A large international study of approximately 1900 sera detected anti-HMGCR antibodies in NAM and in only a few cases of inflammatory myopathies associated with muscle fiber necrosis (PM and DM) but not in the serum of patients with muscular dystrophy.
Anti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: a history of statins and experience from a large international multi-center study.
Patients with self-limiting statin intolerance and self-limiting cerivastatin-related rhabdomyolysis had no anti-HMGGCR antibodies, suggesting that the early detection of the anti-HMGCR antibodies could distinguish statin-associated NAM from the statin self-limiting myopathy.
Essentially, the detection of anti-HMGCR antibodies would allow the early diagnosis and treatment of NAM. However, the measurement of anti-HMGCR antibodies in the cohort of patients with self-limiting cerivastatin-related rhabdomyolysis was performed years after the diagnosis of rhabdomyolysis. Therefore, the possibility that these patients had circulating antibodies at the time of the myopathy or “seronegative” NAM cannot be excluded. In addition, cerivastatin was removed from the market in early 2000 because of renal failure secondary to rhabdomyolysis.
Therefore, the observation that cerivastatin-related rhabdomyolysis is not associated with anti-HMGCR antibodies cannot be generalized to all the statins.
Signal recognition particle is a complex consisting of 6 polypetides and a 7S RNA molecule that is important for the translocation of newly formed proteins to the endoplasmic reticulum. Similar to anti-HMGCR, anti-SRP antibody titers also correlate with CK levels and degree of muscle weakness, raising the possibility of a pathogenic role for such antibodies in NAM.
Moreover, the use of the terms NAM, PM, and myositis interchangeably in some studies limits the assessment of the diagnostic specificity of anti-SRP antibodies.
Comparing anti-HMGCR antibody–positive and anti-SRP antibody–positive patients with NAM, the latter seem to have more severe weakness and susceptibility to development of interstitial lung disease.
In comparison with the general population, patients who have NAM with anti-HMGCR antibodies, as well as those without anti-HMGCR or anti-SRP antibodies, have a higher incidence of malignant disease, which was not observed in a cohort of anti-SRP antibody–positive patients with NAM.
Therefore, independent from the coexisting serologic markers, broad screening for cancer is appropriate.
Pathogenesis
The role of anti-HMGCR and anti-SRP antibodies and their pathogenicity in NAM remain unknown. It has been suggested that the HMGCR up-regulation induced by statins may contribute to the development of the disease in immunogenetically predisposed individuals (only 2-3 per 100,000 statin-treated patients per year have development of NAM
In regard to anti-SRP antibodies, their potential pathogenicity in NAM is indirectly suggested by the correlation of the antibody titer with the CK values
No randomized clinical trials have been performed in patients with NAM, and treatment is based on expert opinion and data from case series. Although therapy should be individualized, it appears that corticosteroids alone are often not sufficient to treat the disease, and most patients require at least 2 immunosuppressant drugs. In the Mayo Clinic cohort, patients who received 2 or more immunotherapeutic agents (corticosteroids, intravenous immunoglobulin [IVIG], and a steroid-sparing immunosuppressant agent) in the first 3 months of treatment were more likely to experience significant improvement.
Inclusion body myositis is often indicated as sporadic IBM to distinguish it from hereditary IBM, which has a genetic etiology. The term IBM will be used here to indicate the acquired form. Inclusion body myositis is the most common acquired muscle disease in patients older than 50 years.
It has a mild male predominance and is characterized by early development of quadriceps and finger flexor weakness and atrophy (Figure 2, A and B). The weakness is frequently asymmetric. When present, quadriceps weakness greater than that in the hip flexors favors the diagnosis of IBM over other inflammatory myopathies. Dysphagia and weakness of the foot dorsiflexors are also common. Facial weakness occurs in up to 55% of cases (Figure 2, C), and axial weakness may occur in the advanced stage of the disease.
Asymptomatic impairment of respiratory function is common in IBM, as well as sleep-disordered breathing, independent from daytime respiratory function.
Although muscle weakness slowly progresses and may result in severe disability, life expectancy is not affected, although death can be related to aspiration pneumonia secondary to dysphagia.
There is no evidence that IBM affects cardiac tissue, and the prevalence of cardiac abnormalities in IBM seems similar to that observed in the general population with similar age distribution.
Figure 2Features of inclusion body myositis. Note weakness of the finger flexors (A) but spared strength of finger extensors (B) in the same patient and weakness of the orbicularis oculi (C), as suggested by inability to close the eyes, in another patient.
Muscle biopsy remains the criterion standard for the diagnosis of IBM. Patients with the classic pathologic features of IBM (Figure 3, Table 1)—autoaggressive CD8+ T cells invading nonnecrotic muscle fibers, rimmed vacuoles, congophilic inclusions, protein aggregates, and histologic signs of mitochondrial dysfunction—are diagnosed with definite IBM.
However, all the pathologic features of IBM may not be present in the muscle biopsy specimen, especially in the early stage of the disease. Therefore, researchers and clinicians have emphasized the relevance of clinical findings (eg, quadriceps weakness and flexor digitorum profundus weakness) in the diagnosis of IBM.
ENMC Myositis Muscle Biopsy Study Group 205th ENMC International Workshop: pathology diagnosis of idiopathic inflammatory myopathies part II 28-30 March 2014, Naarden, The Netherlands.
Figure 3Muscle biopsy specimens from a patient with inclusion body myositis. A, Autoaggressive inflammatory infiltrates invading a nonnecrotic muscle fiber (arrow) (hematoxylin-eosin, original magnification ×40). B, Rimmed vacuoles (arrow) (trichrome stain, original magnification ×40). C, Congophilic inclusions within a muscle fiber appear bright red (arrow) (Congo red–stained section viewed under rhodamine optics, original magnification ×40).
A recent study identified T-cell large granular lymphocytic leukemia in more than half of a cohort of 38 patients with IBM and muscle invasion by large granular lymphocytes.
These findings led to the hypothesis that transformation of T-cell expansion into a neoplastic disorder might contribute to IBM refractoriness to immunotherapy. This study was criticized because of the unknown chronology of the IBM and T-cell large granular lymphocytic leukemia (which of the 2 diseases manifested first?) and lack of coexisting hematologic abnormalities (anemia or neutropenia) in IBM.
Cytosolic 5′-nucleotidase 1A catalyzes the conversion of adenosine monophosphate into adenosine and phosphate. Moderate and high reactivity of anti-cN1A antibodies has been reported to be 92% and 98% specific for the diagnosis of IBM, respectively.
In a small group of patients with IBM, the anti-cN1A antibody seropositivity was associated with more severe motor disability and respiratory involvement.
However, anti-cN1A antibodies have also been detected in other autoimmune diseases, mainly systemic lupus erythematosus and Sjögren syndrome, and occasionally in nonautoimmune neuromuscular diseases.
ENMC Myositis Muscle Biopsy Study Group 205th ENMC International Workshop: pathology diagnosis of idiopathic inflammatory myopathies part II 28-30 March 2014, Naarden, The Netherlands.
Therefore, anti-cN1A positivity should be interpreted in relationship to the patient's clinical and myopathologic findings. Anti-cN1A antibodies can be supportive of the diagnosis of IBM when the canonical myopathologic features of IBM are missing.
Because amyloidogenic proteins accumulate in IBM muscle, investigators have studied amyloidogenic molecules as possible biomarkers of IBM. An increase of amyloid precursor protein β, β-secretase-1 (β-site amyloid precursor protein–cleaving enzyme 1) and γ-secretase (both enzymes process amyloid precursor protein), was demonstrated in the plasma from patients with IBM when compared with controls and other inflammatory myopathies.
BACE-1, PS-1 and sAPPβ levels are increased in plasma from sporadic inclusion body myositis patients: surrogate biomarkers among inflammatory myopathies [published online ahead of print November 3, 2015].
The pathogenesis of IBM remains unclear. The disease is thought to be the result of a combined inflammatory and degenerative process. The autoaggressive inflammatory infiltrates mainly consisting of CD8+ T cells, sarcolemmal overexpression of MHC-1 and II,
The rimmed vacuoles, abnormal protein aggregates, and lack of response to immunosuppressant therapy have pointed to a defect in protein degradation and a degenerative process as mechanisms contributing to the disease. Recently, a genetic contribution to the pathogenesis of IBM has emerged. Rare cases of sporadic IBM fulfilling diagnostic criteria for IBM were found to have sequence variants in genes causing hereditary IBM (eg, valosin containing protein, VCP; sequestosome 1, SQSTM1; slow/β cardiac myosin heavy chain 7, MYH7).
Moreover, association studies have suggested a genetic susceptibility to IBM (eg, strong association with HLA-DRB*03:01 or disease-modifying effect of a specific polymorphism in translocase of outer mitochondrial membrane 40, TOMM40).
To date, there is no evidence that immunosuppressant drugs are beneficial in IBM. A long-term observational study found that immunosuppressive treatment did not improve the disease course and may have exacerbated the progression of the disability.
A recent clinical trial with placebo vs bimagrumab, an activin receptor II inhibitor antibody, provided class I evidence that bimagrumab increases thigh muscle volume measured by magnetic resonance imaging (MRI).
However, a phase 2b/3 study found no evidence for beneficial effect of bimagrumab, leading to discontinuation of the study. Nevertheless, some physicians would consider a trial of treatment with corticosteroids and a steroid-sparing agent in patients with IBM who have rapidly progressive disease or associated autoimmune disease.
At the present time, treatment of IBM is largely supportive.
Dermatomyositis
Clinical Features
Dermatomyositis is an inflammatory disease with prominent muscle and skin involvement. It causes subacute or insidiously progressive proximal muscle weakness, sometimes accompanied by myalgia. Dysphagia occurs and is more frequent in patients with severe weakness of sternomastoid muscles.
Skin manifestations in DM include heliotrope rash, malar rash, Gottron papules, erythematous dermatitis, and photosensitivity. Nail beds can have dilated capillary loops. Oral features of DM are well characterized, such as lichen planus, gingival telangiectasia, desquamative gingivitis, and ovoid palatal patch.
The rash precedes or occurs at the same time as the weakness. Interstitial lung disease can be a facet of the multisystem inflammatory disease that causes DM. Older age at diagnosis, fever, heliotrope rash, and arthritis increase the risk of interstitial lung disease,
Juvenile DM frequently follows a febrile episode and rash. It often has multisystem involvement and much more frequent subcutaneous calcinosis compared with adult DM.
Dermatomyositis is associated with an increased risk of malignant disease compared with age- and sex-matched controls, especially in males and in patients older than 45 years.
The risk of cancer is higher in the 5 years surrounding the diagnosis of DM (2 years before and 3 years after) and also over the lifetime following the diagnosis of DM. The most frequent malignant disorders affect the breast, lung, pancreas, and colon. Patients with cancer seem less likely to have interstitial lung disease.
A form of amyopathic DM manifests with the hallmark skin findings and no clinical or laboratory evidence of myositis but preserved susceptibility to the development of interstitial lung disease.
In regard to the risk of malignancy in amyopathic DM, there is conflicting information. Therefore, cancer screening is advised in patients with amyopathic DM.
The diagnosis of DM relies on clinical manifestations and muscle pathologic findings. The hallmark pathologic feature of DM is the perifascicular muscle fiber atrophy, often accompanied by one or more of the following perifascicular structural abnormalities: internalized nuclei, muscle fiber necrosis, regeneration, focal basophilia, vacuolar changes, increased oxidative enzyme reactivity, and endomysial fibrosis (Figure 4, Table 1). The perifascicular atrophy is invariably associated with capillary depletion, often accompanied by membrane attack complex deposition on the muscle microvasculature.
The inflammation is predominantly perimysial and perivascular and consists of CD4+ T cells and plasmacytoid dendritic cells. Autoaggressive inflammatory CD8+ T cells invading nonnecrotic muscle fibers are not a feature of DM.
Figure 4Muscle biopsy specimens from a patient with dermatomyositis. A and B, Note perifascicular muscle atrophy (arrows), a hallmark of dermatomyositis (A, hematoxylin-eosin; B, ATPase stain, pH 4.3). C, The inflammatory exudate concentrates in the perimysium at perivascular sites (arrow) (hematoxylin-eosin). D, Additional structural abnormalities are present in perifascicular regions: internalized nuclei (blue arrow), necrotic (asterisk) and regenerating (arrowheads) muscle fibers, vacuolar changes (black arrow) (hematoxylin-eosin).
In DM, CK values are often but not always elevated. Therefore, CK measurement may not be helpful in measuring disease activity. Various antibodies can be associated with DM (Table 2).
The presence of anti–transcriptional intermediary factor 1-γ antibodies in adult patients with DM has a particularly high risk of cancer (48%-75%),
Childhood Myositis Heterogeneity Study GroupInternational Myositis Collaborative Study Group A novel autoantibody to a 155-kd protein is associated with dermatomyositis.
Antibodies directed against Mi2, a component of the nucleosome remodeling–deacetylase chromatin remodeling complex, have been associated with DM without lung involvement. Anti-Mi2 antibody–positive patients respond well to corticosteroids and rituximab.
They are associated with minimal or no perifascicular atrophy, despite the MHC-1 up-regulation in perifascicular regions, and their titer correlates with disease activity.
Anti-CADM-140/MDA5 autoantibody titer correlates with disease activity and predicts disease outcome in patients with dermatomyositis and rapidly progressive interstitial lung disease.
Anti-Jo1 (or anti–histidyl-tRNA synthetase) antibodies have long been known to predict interstitial lung disease with an incidence as high as 90%. The combination of inflammatory myopathy, interstitial lung disease, arthritis, Reynaud phenomenon, and mechanic's hand and antisynthetase antibodies characterize the antisynthetase syndrome.
In addition to anti-Jo1 antibodies, there are other less common antisynthetase antibodies, such as anti-PL-7, PL-12, OJ, KS, EJ, Zo, and Ha antibodies. Severe skin involvement and systemic features have also been linked to the anti–small ubiquitinlike modifier activating enzyme.
The pathogenesis of DM is still poorly understood. Several studies have focused on dissecting the mechanism leading to the myopathologic hallmark of perifascicular muscle atrophy. Results have been controversial, spanning from ischemia secondary to microvascular insult to increased expression of type 1 interferon–induced gene transcripts and proteins in the perifascicular muscle fibers and capillaries.
The mechanism driving the overproduction of type 1 interferon and how this process results in capillary damage remains to be elucidated. A recent study confirmed that the perifascicular muscle atrophy is associated with focal microvascular depletion and that ischemia contributes to the perifascicular atrophy.
The same study found that the observed microvascular membrane attack complex deposits in DM result from activation of the classic complement pathway, triggered by direct binding of C1q to injured endothelial cells. However, these observations did not explain the primary cause of the microangiopathy. An inflammatory vasculopathy has also been recognized as cause of the gastrointestinal ulceration and perforation in severe juvenile DM.
Higher dosages of prednisone may provide more immunosuppression but carry a risk of corticosteroid-induced myopathy. The greatest improvement in strength seems to occur in the first 6 to 12 months after treatment initiation.
Various immunotherapeutic agents (methotrexate, azathioprine, IVIG, cyclosporine, mycophenolate mofetil) can be used as second-line agents or first-line agents combined with corticosteroids, but none is superior to others.
Drug therapy of the idiopathic inflammatory myopathies: predictors of response to prednisone, azathioprine, and methotrexate and a comparison of their efficacy.
However, methotrexate carries the risk of pulmonary fibrosis. Therefore, methotrexate should be avoided in patients with interstitial lung disease or antibodies predicting interstitial lung disease. Rituximab has been used successfully in adult and pediatric patients with refractory myositis.
Recommended therapy includes combined use of corticosteroids and methotrexate. Intravenous immunoglobulin, mycophenolate mofetil, cyclophosphamide, rituximab, infliximab, and cyclosporine should be used only to treat more severe DM or a disease partially responsive to corticosteroids and methotrexate. Skin disease requires aggressive therapy because of the associated high morbidity. Calcinosis may respond to bisphosphonates. It has been suggested that discontinuation of the methotrexate or other disease-modifying drug be considered once the patient is in remission and has not taken corticosteroids for at least 1 year.
Additional Investigations
Needle electromyography is useful in confirming the myopathic nature of the weakness in IMMs but does not differentiate the various subtypes. Motor unit potentials have myopathic features (reduced amplitude and duration) in most autoimmune myopathies but in sporadic IBM exhibit mixed myopathic and neurogenic changes. Abnormal spontaneous muscle activity includes fibrillation potentials, sharp waves, and complex repetitive discharges. Myotonic discharges are often recorded in statin-associated NAM.
The lack of abnormal spontaneous muscle activity in a patient with IMM who has worsening weakness while taking corticosteroids often suggests a corticosteroid-induced myopathy.
T2-weighted muscle MRI may reveal signal abnormality in muscle and fascia due to inflammation, edema, or muscle replacement by connective tissue. In addition, MRI can be a useful tool to monitor disease activity.
Diagnostic criteria and classification of IMMs remain challenging. Some diagnostic criteria are based on clinical and muscle pathologic criteria, while others are more clinically and serologically oriented. Additional correlation between pathologic findings, specific antibodies, and extramuscular features would be valuable in better characterizing these diseases. The lack of universally accepted diagnostic criteria continues to be an obstacle to clinical trials, which are already hampered by the rarity of these myopathies. The variability of diagnostic criteria may lead to the enrollment of patients with different IMMs into a clinical trial and the exclusion of others. The crucial role of physical therapy and occupational therapy is not emphasized enough in clinical practice and should be part of the treatment plan.
Unsolved Clinical Questions
The role of myositis-associated antibodies remains poorly understood and requires further investigations. Their pathogenicity has not been proved. The correlation between the presence of a specific antibody and muscle pathologic findings should be better defined and validated. The value of anti-cN1A autoantibodies as a diagnostic and prognostic tool in IBM requires further investigation. Similarly, the role played by statins as a trigger for the anti-HMGCR antibody formation and development of NAM warrants further elucidation, especially in light of the presence of anti-HMGCR antibodies in statin-naive (or presumably naive) patients. Understanding what leads to microangiopathy in DM or whether IBM is a primary inflammatory or degenerative muscle disease would be fundamental to opening avenues to treatment. There is a need for randomized clinical trials to standardize and optimize evidence-based patient care. Longitudinal studies to learn more about the disease progression and markers of disease activity would enhance our understanding of these myopathies and would provide more solid guidance for timing of immunotherapy withdrawal.
Conclusion
Immune-mediated myopathies are clinically, serologically, and pathologically heterogeneous. The lack of inflammation on muscle biopsy does not exclude an IMM. The presence of certain antibodies may predict specific complications and a higher risk of cancer.
Acknowledgments
Special thanks to my patients who agreed to have photographs taken and reproduced to enhance our understanding of immune-mediated myopathy.
Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients.
119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands.
Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy.
Clinical characteristics of anti-3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies in Chinese patients with idiopathic inflammatory myopathies.
Anti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: a history of statins and experience from a large international multi-center study.
BACE-1, PS-1 and sAPPβ levels are increased in plasma from sporadic inclusion body myositis patients: surrogate biomarkers among inflammatory myopathies [published online ahead of print November 3, 2015].
Anti-CADM-140/MDA5 autoantibody titer correlates with disease activity and predicts disease outcome in patients with dermatomyositis and rapidly progressive interstitial lung disease.
Drug therapy of the idiopathic inflammatory myopathies: predictors of response to prednisone, azathioprine, and methotrexate and a comparison of their efficacy.
Potential Competing Interests: Dr Milone received funding from the Center for Individualized Medicine and Department of Neurology, Mayo Clinic.
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