|Ahead of print publication
Bye-bye muscle biopsy, we have autoantibodies with us now
Victoria Riddell1, Sarah L Tansley2
1 Department of Biology and Biochemistry, University of Bath, Bath, England, UK
2 Department of Pharmacy and Pharmacology, University of Bath, Bath, England, UK
|Date of Submission||01-May-2020|
|Date of Acceptance||07-Jun-2020|
Sarah L Tansley,
University of Bath, Bath
Source of Support: None, Conflict of Interest: None
Muscle biopsy is generally considered the gold standard diagnostic tool for patients with presenting with features suggestive of idiopathic inflammatory myopathy. Muscle biopsy is however an invasive test, the histopathological findings can be influenced by previous treatment and not all patients with myositis spectrum disease have muscle involvement. Myositis specific and associated autoantibodies can now be identified in the majority of patients with myositis. When present they identify homogeneous patient subgroups and have the potential to be key tools in developing a personalised approach to disease management. Here we review the utility of myositis specific and associated autoantibodies as diagnostic and prognostic tools.
Keywords: Autoantibody, biopsy, diagnosis, myopathy, myositis
| Introduction|| |
The idiopathic inflammatory myopathies (IIM) are multisystem diseases. The presenting disease features are variable but include skin disease and muscle weakness in addition to systemic features, such as fever, fatigue, and weight loss. Patients are traditionally divided into two subgroups: polymyositis and dermatomyositis depending on the presence or absence of skin disease and a third subgroup, inclusion body myositis (IBM), describes a very different group of patients with slowly progressive symptoms involving distal musculature which fail to respond to immunosuppressive medication. This classification system fails to adequately describe all the variation seen in these diseases, both in terms of clinical features and disease outcomes.,, While muscle inflammation is a defining feature of these diseases and muscle weakness is typically a prominent feature at disease presentation, amyopathic dermatomyositis, defined as the presence of pathognomonic cutaneous lesions in the absence of muscle involvement, is well described. Similarly, patients may have mild or progressive muscle disease that is not detected on initial assessment. Patients may also present with severe disease affecting other organ systems such as skin or lung disease, which may reduce the chance of IIM being considered early as a diagnosis. The heterogeneous nature of IIM creates a diagnostic challenge, not least because patients can present to a number of different medical specialties.
| Diagnosis of Idiopathic Inflammatory Myopathies|| |
Useful diagnostic tests depend on the organ systems affected, for those with muscle involvement elevated serum muscle enzymes and/or an increased T2/STIR signal on MRI suggesting muscle edema can be helpful findings but are both nonspecific and are also found in other conditions. Muscle biopsy is a well-established tool for the diagnosis of IIM and is generally considered to be the gold standard. It does, however, have a number of limitations. Not least that muscle biopsy is unlikely to be helpful in patients without muscle involvement. Furthermore, the histopathological findings can be directly influenced by any on-going or previous treatments, such as steroids. Findings can be nonspecific, or inconclusive, and muscular damage often appears similar across clinical myositis subsets, making it difficult to correctly provide a more specific diagnosis. IBM and polymyositis can be challenging to distinguish clinically and histologically, particularly early in the disease course. Indeed classical histopathological features of IBM, such as rimmed vacuoles, are absent in 20% of patients with typical clinical features. Nonetheless, muscle biopsy is helpful in excluding muscular dystrophies and other muscle disorders with overlapping clinical features. A biopsy result consistent with IIM provides a significant degree of diagnostic certainty and reports can be enhanced by systems developed to allow a standardized approach to interpretation which should facilitate the identification of homogeneous patient subgroups. Recently, published classification criteria for myositis endorsed by ACR and EULAR utilize muscle biopsy findings, laboratory features, and clinical features to determine the probability of myositis. A web-calculator for the criteria has been set up: http://www.imm.ki.se/biostatistics/calculators/iim/. The performance of these criteria is greatly enhanced where muscle biopsy data are available and can be included.
| Autoantibodies for the Diagnosis of Idiopathic Inflammatory Myopathies|| |
Autoantibodies are a hallmark feature of the autoimmune connective tissue diseases and IIM is no exception. An autoantibody can be identified in approximately 60% of patients, and have been proposed as means of diagnosing and sub-classifying affected patients. “Myositis-specific autoantibodies” (MSA) are exclusively found in patients with IIM, whereas “Myositis-associated autoantibodies” (MAA) can also be identified in both patients with IIM and other connective tissue diseases. MSA occur together only extremely rarely and are considered to be mutually exclusive while MAA may be found in conjunction with a MSA or another MAA., As a diagnostic tool, MSA/MAA have limitations: They are not present in all patients meaning that the absence of a MSA or MAA does not exclude myositis as a diagnosis. The identification of a MSA can increase diagnostic confidence, particularly where the biopsy findings are atypical or unusual. This was reported after examination of biopsy's taken alongside tests for anti-HGMCR antibody.
| Autoantibodies to Predict the Prognosis in Idiopathic Inflammatory Myopathies|| |
Perhaps the real advantage of MSA is that, where present, they divide patients into homogeneous subsets and provide a degree of phenotypic refinement not possible with other classification systems. The detailed phenotypic information provided by MSA subsets allows doctors to provide more detailed prognostic information to patients and their families and to plan further investigation and monitoring for anticipated complications. Identified MSA subsets are described in 1, which presents the known associated clinical features with each MSA.
Myositis autoantibodies are strongly associated with distinct clinical phenotypes and provide the treating physician with useful information which can then inform the approach to disease management. The clinical features associated with MSA in juvenile IIM can vary from adult IIM. For example, anti-TIf1-γ and anti-NXP2 strongly associated with malignancy in adult IIM patients. More than 50% of adult patients with the MSA anti-TIf1-γ have an associated cancer and anti-TIf1-γ associated malignancy has been demonstrated to occur exclusively in the 3-year period on either side of myositis onset,, The identification of this MSA can prompt careful cancer screening. In contrast, these autoantibodies are the most common MSA in predominantly Caucasian juvenile IIM cohorts,, yet no association with malignancy has been identified. It is not clear to what extent the differences observed between adult and juvenile MSA relate to different phenotypes associated with the MSA and the influence of age at disease onset. The association between anti-TIF1-γ is the highest risk in those over 39 years of age, yet the distinction between juvenile and adult IIM is typically either 16 or 18 years. A more detailed discussion of the clinical and serological features of adult versus juvenile IIM can be found in Tansley et al.
The major causes of mortality in patients with IIM are infection, mostly pneumonia, and malignancy, along with cardiac and lung complications. MSA can help identify those patients at high risk so appropriate interventions can be taken early, hopefully reducing both subsequent mortality and morbidity.,,, The recommendation that those patients with cancer associated MSA be subjected to cancer-specific screening appears justified and sensible. Recent evidence suggests that ovarian cancer is a particular concern in those with anti-TIF1-γ and the detection of this MSA could therefore also inform the nature of screening that is undertaken. A comprehensive investigation of lung disease in myositis patients identified that over 75% of all patients carried an MSA, predominantly an anti-synthetase MSA, or anti-MDA5. Comparing the clinical characteristics of the lung disease in these two MSA subgroups revealed that the anti-MDA5 patients had an increased risk of respiratory failure with a more acute onset of interstitial lung disease (ILD), while the identification of an anti-synthetase MSA could indicate a more positive prognosis.
MSA can also be helpful in identifying those patients with IIM presenting with predominantly extra-muscular disease. ILD, in the absence of any extra-pulmonary features can occur as a formefruste of IIM. These patients can be misdiagnosed as idiopathic ILD. Anti-Jo-1, targeting histidyl tRNA synthetase, is the most common MSA and can be identified in 15%–30% of adults with IIM., It is associated with the anti-synthetase syndrome; a well-described clinical syndrome consisting of myositis, ILD, nonerosive arthritis, Raynaud's phenomenon, fever, and characteristic skin changes termed “mechanics” hands. Seven further tRNA synthetase MSA have been reported; anti-PL7 (threonyl), anti-PL12 (alanyl), anti-OJ (isoleucyl), anti-KS (asparginyl), anti-EJ (glycyl), anti-Zo (phenylalanyl), and anti-Ha (tyrosyl) these are rarer, collectively occurring in 10%–20% of cases., The anti-synthetase syndrome can be incomplete and disease presentation varies depending on the autoantibody: While muscle disease is common in patients with myositis autoantibodies anti-Jo1, anti-PL-7, or anti-EJ, patients with anti-PL-12, anti-KS or anti-OJ in contrast often have lung dominant disease. The distinction between idiopathic ILD and IIM associated ILD is of the upmost clinical importance as, while immunosuppressive drugs are the mainstay of treatment in IIM, these are not only ineffective in idiopathic ILD but cause harm. Anti-synthetase MSA were retrospectively identified in 6.6% of a Japanese cohort with idiopathic ILD, none of whom displayed any extra-pulmonary features. A Canadian study retrospectively analyzed 165 patients referred for investigation of ILD and identified an MSA in 26.7%. Furthermore, as a consequence of MSA screening 8.5% of patients tested received a change in the diagnosis. Of those patients whose the diagnosis was altered as the result of MSA testing, 1.8% had undergone a surgical lung biopsy and 1.2% had received treatment with anti-fibrotic therapy, demonstrating the significant benefits earlier screening could have had for these patients. Interestingly, in addition to the different MSA associated with ILD described in [Table 1], the MAA anti-Ro52 has also been shown to increase patients underlying risk of ILD, even in those autoantibody subgroups not considered to be associated with ILD. The presence of anti-Ro52 alongside anti-Jo1 may suggest a higher risk of more severe pulmonary involvement as the disease progresses and analysis of a Japanese cohort suggested that the presence of both anti-Ro52 and anti-Jo1 could be linked to a distinct clinical subset. Further research is need to improve our understanding of this and other factors, which modify MSA associated phenotype including age at disease onset, ethnicity, and the environment.
|Table 1: Myositis specific autoantibodies and their clinical associations|
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Antibody detection can clearly be used to provide crucial prognostic information; however, MSA status should always be interpreted in the appropriate clinical context and in conjunction with other investigations and clinical findings. The combination of muscle biopsy findings and MSA status can be valuable: When juvenile DM patient biopsy samples were analysed and scored for severity, and the results analyzed in conjunction with MSA status findings not only did muscle biopsy scores vary according to MSA subgroup, but when the effects of the MSA were accounted for, increased severity of muscle biopsy features was predictive of a higher risk of remaining on the treatment. Similarly, an autoantibody result is only as reliable as the testing method used and a positive result not in keeping with the clinical picture should be interpreted with caution.
| Autoantibodies to Guide Treatment in Idiopathic Inflammatory Myopathies|| |
The evidence base for pharmacological therapies in IIM is extremely limited, but in practice, the majority of patients receive treatment with a prednisolone plus a steroid sparing agent such as methotrexate or azathioprine. Agents such as IVIg, rituximab, and cyclophosphamide are typically reserved for those with severe or refractory disease. This approach is arguably simplistic for such a diverse and heterogeneous disease and the ability to stratify patients with myositis in such a way as to allow a more personalized approach to treatment is highly desirable. Certain MSA are more likely to be resistant to standard treatment approaches and this has been extrapolated to suggest these patients may benefit from a more “aggressive” treatment approach.,, More intensive immunosuppression generally carries an increased risk of adverse events, and MSA can help ensure this is targeted appropriately. Hence, called triple therapy, a combination of corticosteroids, cyclophosphamide, and tacrolimus has been shown to be beneficial in patients with rapidly progressive–ILD associated with anti-MDA5. Indeed, not receiving this combination as initial treatment was linked to poor outcomes in a Japanese cohort.,, Undoubtedly, the diagnostic certainty provided by a positive myositis autoantibody can empower the physicians to escalate treatment in a patient not responding adequately to standard therapy and can prevent unnecessary further investigation to confirm the diagnosis. It is as yet, however, unclear if and how autoantibody status should influence recommended pharmacological treatment. The rituximab in myositis study was a randomized controlled trial, investigating the benefit of rituximab in patients with refractory myositis. Sub-group analysis of this study demonstrated a differential treatment response to rituximab dependant on MSA status., The presence of an anti-synthetase, anti-Mi-2, or another MSA predicted a shorter time to improvement compared to MSA-negative patients. Based on these findings, in the UK, NHS England guidance on the use of rituximab in patients with myositis stipulates the presence of a myositis relevant autoantibody to access the drug. Consensus-based recommendations for the management patients with juvenile-onset myositis published in 2017 do not recommend MSA for risk stratification but do acknowledge that these can be helpful where available. It will be important that future clinical trials investigating treatments in patients with myositis adjust for MSA status in order to prevent confounding, due to potentially different treatment responses between MSA subgroups.
| Challenges in Autoantibody Testing|| |
A key limitation of the use of MSA in the clinical practice is the availability of testing. Immunoprecipitation is considered the reference standard method for MSA identification. It has been used to identify novel MSA, and MSA specificity can subsequently be confirmed using immunoprecipitation blotting or mass spectrometry., Immunoprecipitation is, however, an impractical method for widespread diagnostic use; it is expensive, low throughput, and specialist facilities along with staff expertise are required. Consequently, the use of immunoprecipitation for diagnostic purposes is limited to a handful of specialist centers worldwide. With the growing interest in the use of MSA for the diagnosis and planning treatment, a number of commercial assays have been developed utilizing different immunological techniques. These assays facilitate the rapid detection of MSA inexpensively and without the need for specialist expertise. A major challenge with these assays has been validation. Myositis is a rare disease and some MSA are very rare within myositis cohorts: For example, some of the anti-synthetase MSAs included in commercial immunoassays are found in just 0.3% of myositis patients, making assay validation a significant challenge. We and others have raised the concerns regarding the sensitivity of commercial immunoassays to detect the some key MSA., The features of the MSA themselves may restrict the types of immunoassay that can be used. In the original description of anti-TIF1-γ (p155) in dermatomyositis by Targoff et al. reported the presence of a conformational epitope in a significant proportion of patients. This limits the utility of popular immunoblotting based assays which use denatured antigen. Interestingly, a similar phenomenon was also observed with MSA directed against anti-OJ for which we have also shown immunoblotting assays perform particularly poorly.,
False-positive rates may be unacceptably high with commercial immunoassays, with one study reporting antibody positivity in 17% of healthy controls.,,,, This is a concern as such false-positive results are likely to cause unnecessary patient anxiety in addition to the need for further testing, using valuable resources, to refute the result. In the worst-case scenario, a false-positive result could lead to the inappropriate use of immunosuppressive medication. At present, there is no guidance on which patients are likely to benefit from MSA testing, this guidance will be important if these tests are to be used for diagnostic purposes as the negative and positive predictive values of test results are dependent on the prevalence in the background population. Using optimal methods of MSA detection approximately 60% of adult and juvenile-onset patients with myositis will have an identifiable MSA., This means that at present, unless further MSA are discovered, MSA testing has a relatively low overall sensitivity for myositis, with 40% of patients having no detectable autoantibody. For MSA negative patients, the diagnosis can be more challenging and must be made on clinical grounds supported by other diagnostic tools including muscle enzyme testing, MRI, and muscle biopsy. MSA negative patients are a heterogeneous group and available prognostic information is limited meaning disease complications are difficult to anticipate before they occur.
In contrast to the low sensitivity, MSA are believed to be highly disease specific and therefore a positive result, even in the absence of obvious clinical symptoms, should warrant further investigation, assuming the testing method is considered reliable. The high specificity of MSA can be exploited in key patient populations where an underlying diagnosis of myositis would make a significant difference to the prognosis and treatment. One important such patient group is those presenting with ILD. In future, further refinement of MSA screening may provide additional information; a recent study demonstrated the IgG2 sub-class of anti-TIF1-γ to be particularly associated with malignancy. Indeed, 90% of IIM patients that were anti-TIF1-γ-IgG2 positive had a cancer diagnosis, and this increased to 100% on follow-up. Further work is needed to investigate whether the detection of IgG subclasses enhance the predictive value of MSA. MSA titre is another area for future research which may provide the treating clinician with additional prognostic information. Various small studies have demonstrated a relationship between MSA titer and disease activity measures,,,,, and MSA titer has been suggested as a means of assessing response to treatment in patients with anti-MDA5, however, data have been conflicting.
| Recommendations|| |
The diagnosis of IIM can be made in a patient with compatible clinical features supported by a variety of different investigations. MSA are highly specific and a diagnosis of IIM should be strongly considered in patients with a positive MSA test. A negative MSA test result, however, does not exclude IIM. Clinicians should be aware of the limitations of their chosen testing method.
Muscle biopsy remains a useful diagnostic tool in those patients who are MSA negative and selected MSA-positive patients where the findings could influence clinical management.
MSA may be helpful in identifying those IIM patients presenting with disease apparently confined to the pulmonary system.
The identification of a MSA provides useful prognostic information, particularly regarding the risk of malignancy and development of associated ILD. An appropriate plan for further investigation and monitoring should be created for those patients found to have a MSA strongly associated with malignancy or ILD.
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Conflicts of interest
There are no conflicts of interest.
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