|Year : 2018 | Volume
| Issue : 3 | Page : 186-194
Role of myositis-specific autoantibodies in personalized therapy
Anand N Malaviya, Sanjiv Kapoor
Department of Rheumatology, ISIC Superspeciality Hospital, New Delhi, India
|Date of Web Publication||21-Aug-2018|
Prof. Anand N Malaviya
ISIC Super Speciality Hospital, Vasant Kunj, New Delhi - 110 070
Source of Support: None, Conflict of Interest: None
In a landmark breakthrough in 1976, Reichlin and Mattioli discovered the first myositis-specific antibody (MSA) called anti-Mi2 antibody that identified a specific clinical phenotype characterized by pathognomonic skin rash of dermatomyositis, typical proximal muscle weakness, good response to treatment, and the absence of interstitial lung disease and cancer. The discovery firmly placed inflammatory muscle diseases among the group of systemic rheumatic autoimmune diseases. Over the next four decades, a large number of additional MSAs have been discovered in this group of patients called “idiopathic inflammatory myopathy” (IIM). It is becoming clear that the increasing numbers of autoantibodies being discovered may necessitate a name change to “autoimmune myositis” (AIM), as recently suggested by a French-Canadian group. In the light of these discoveries, it was evident that a new classification system based on the combination of clinical phenotypes and the associated autoantibodies would soon be propounded. Preliminary report on such a classification was published in 2016 by the Swedish Group from Karolinska Institute led by Prof. Ingrid Lundberg. In October 2017, the European League Against Rheumatism and the American College of Rheumatology published the provisional classification criteria for IIM with the aim to categorize patients in uniform subgroups of clinical phenotype for meaningful drug trials. These are exciting times for clinicians, for research scientists, and for the patients with inflammatory myositis with reasons to be optimistic about a bright future. This short review provides a summary of the present knowledge with emphasis on its clinical implications.
Keywords: Dermatomyositis, inflammatory myopathy, myositis-associated autoantibodies, myositis-specific autoantibodies, overlap myositis, polymyositis
|How to cite this article:|
Malaviya AN, Kapoor S. Role of myositis-specific autoantibodies in personalized therapy. Indian J Rheumatol 2018;13:186-94
| Introduction|| |
Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of chronic inflammatory striated muscle diseases characterized by painless proximal muscle weakness with or without rash. The name derives from the typical histopathological findings of chronic nonsuppurative inflammatory infiltrates in the affected muscles of unknown cause. IIMs are characterized by (1) weakness of proximal muscles (limbs, neck flexors, and truncal muscles); (2) pathognomonic dermatological lesions, (3) often with features overlapping with other connective tissue diseases (CTDs); (4) elevated muscle enzymes; (5) typical abnormalities in electromyogram (EMG; e.g., myopathic pattern with spontaneous activity) and more recently characteristic muscle inflammation on magnetic resonance imaging; and (6) characteristic histopathology. Heterogeneity of IIM results in a broad spectrum of clinical presentations, ranging from normal muscle power (clinically amyopathic dermatomyositis [CADM] or ADM) to rapidly progressive muscle weakness causing severe disability and even death due to respiratory and pharyngeal muscle involvement. Similarly, skin manifestations may vary from minor, transient rash to extensive, severe, typical dermatological manifestations (Gottron's papules, Gottron's sign, heliotrope rash, photosensitivity, shawl sign, Holster sign, and palmer papules). Muscle enzymes may range from normal in some, mildly elevated in others, to extremely high in yet others. Similarly, associated clinical features of other CTDs may vary from minor to classical, so much so that myositis may be barely recognizable. EMG abnormality could vary from insignificant to severe changes, characteristic of muscle inflammation. At last, histopathology also shows a broad spectrum of changes, from almost entirely “normal” looking muscle fibers, extensive inflammatory infiltrates, to severe muscle fiber necrosis with minimal inflammation. Such heterogeneity not only makes the clinical diagnosis difficult but also presents difficulties in discovering therapeutic modalities. In the 1960s, efficacy of glucocorticoid (GC) was reported., It was not uniformly effective and also caused unacceptable adverse effects especially in those requiring large doses over long-term. Efficacy of methotrexate was demonstrated empirically , followed by azathioprine and other immunomodulators. However, the problem of “who will and who will not respond” has remained unsolved till recently. Testing efficacy of drug therapy may only be possible if the patients studied are homogenous. Therefore, characterizing such subsets of IIM has become increasingly important.
Over the last more than four decades, there have been several attempts (from Medsger in 1970 to latest attempts by Lundberg et al. recently ,) to classify IIM into homogeneous subsets, to achieve uniformity enabling better understanding of the pathogenesis with potentially different therapeutic implications. In this chaotic scenario, Bohan and Peter's seminal document in 1975 helped recognize different subsets of IIM, utilized extensively over the past more than four decades. Emerging evidence necessitates “revisiting” the IIM landscape to better understand their clinical, histopathological, immunological, and therapeutic aspects.,,,,, This manuscript attempts to present the current schema of IIMs.
| Anti-Myositis Antibodies: Technical Aspects|| |
Historically, autoantibodies found in lupus and later in other CTDs were detected by indirect immunofluorescence test (IFT) using rat or mouse liver tissue as substrate, further refined by switching to commercial human epithelial type 2 (Hep-2) cell line (originated from human laryngeal carcinoma). Researchers, led by Eng Tan (Scripps Clinic, California, USA), had observed immunofluorescence localized to nuclei in most CTD patients and only occasionally seen exclusively in the cell cytoplasm. It was likely that certain autoantibodies reacted only with cytoplasmic antigens. Detailed characterization of these sera was facilitated by testing patient sera with whole cell lysates from commercially cultured Hep-2 and K562 cells, initially by agar–gel diffusion and counter-immunoelectrophoresis (antibodies hitherto detected described as anti-extractable nuclear antigens [anti-ENAs] antibodies). Gradually, more sensitive techniques (e.g., immunoblotting and radioimmunoprecipitation tests) became popular; most recently, commercial high throughput method of immunoblotting utilizing line immunoassay with recombinant antigens have become more popular., Therefore, in the context of autoantibodies in IIM detected by IFT, these were further subclassified as “antinuclear” and “anticytoplasmic.” Since most such antibodies were detected using Hep-2 or K562 cell extracts of commercially available cultured cell lines, it would be conceptually correct to identify all myositis-specific antibodies (MSAs) and myositis-associated antibodies (MAAs) as anti-ENA antibodies. Notably, all such autoantibodies target nonmuscle antigens.
As mentioned above, Reichlin and Mattioli in 1976 first reported an autoantibody called anti-Mi-2 in DM  further confirmed over time., Anti-Mi-2 clinically identified a homogeneous subset of IIM characterized by pathognomonic skin rashes of DM, proximal limb muscle, neck flexor and truncal weakness, high creatine kinase (CK) levels, characteristic EMG findings, and chronic inflammatory cells in striated muscles on histopathology, with good response to GCs. This pivotal discovery indicated the systemic autoimmune nature of IIM (akin to other CTDs) and also suggested, more importantly, that autoantibodies in IIM may predict and determine treatment responsiveness, a perception strengthened by rapid discoveries of additional autoantibodies among IIM patients over the past decades. Therefore, characterizing autoantibody profile among IIM patients has become obligatory to determine prognosis, likely future complications, and the best treatment options for a given subset.
In this context, it became necessary to change the name from “IIM” to AIM. The next step has been a broad understanding of the autoantibodies discovered in different subsets of AIM and their influence on clinical features, disease complications, response to treatment, and prognosis [Figure 1]. Broadly, these autoantibodies are (1) MSAs, (typically restricted to AIM patients) or (2) MAAs (also detected in other CTDs).
|Figure 1: Repertoire of myositis-specific and myositis-associated autoantibodies|
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| Myositis-Specific Antibodies, Myositis-Associated Antibodies, and Their Clinical Correlates|| |
Five major subgroups exist based on autoantibodies and clinical characteristics:
- “Overlap myositis” (OM)
- Pure “DM”,
- Necrotizing AIM (NAM),
- “Pure” polymyositis ,
- Inclusion-body myositis (IBM).
These patients are characterized by either (i) certain specific MSAs with clinical features of myositis overlapping with subtle or overt manifestations of other CTDs (e.g., systemic lupus erythematosus [SLE], systemic sclerosis [SSc], mixed connective tissue disease [MCTD], and Sjögren's syndrome) or (ii) additional presence of MAAs seen in other CTDs. In a small proportion (~15%), neither clinical nor autoantibody overlap is present at disease onset but develops over time. Clinical features indicating such overlap with CTDs include Raynaud's phenomenon (RP), inflammatory arthritis, lower esophageal dysmotility, lupus features (butterfly rash to be distinguished from the photosensitive facial rash of DM crossing nasolabial fold as opposed to the lupus rash that does not), or features of Sjögren's syndrome. Another characteristic of “OM” (as against “pure” DM) is that muscle weakness appears before the skin rash, the caveat being not to confuse SLE or SSc lesions with pathognomonic rashes of “pure” DM [Table 1].
OM is further subclassified into two major categories based on MSAs or MAAs detected.
These autoantibodies belong to the MSA group, specific for myositis (not seen in other CTDs), with two broad categories [Table 1]:
- The antisynthetase antibody (ASA) is a generic name for autoantibodies against aminoacyl tRNA synthetases, enzymes found in all nucleated cells, and further classified based on eight distinct antibodies:
- Anti-Jo-1 (histidyl tRNA synthetase) syndrome: autoantibodies against histidyl tRNA synthetase
- Anti-Non-Jo-1 syndrome: Associated with seven different autoantibodies to other amino acyl-tRNA synthetase group members, named anti-PL12, -PL7, -EJ, -OJ, -KS, -Zo, and -Ha
- Anti-melanoma differentiation-associated gene 5 (MDA5) antibodies:,,,, Clinical features of overlap with CTDs may be subtle and easily overlooked. The central manifestation of such patients is severe, progressive, difficult-to-treat interstitial lung disease (ILD). Muscle weakness may be trivial or absent (CADM) with mildly elevated or normal muscle enzymes. ASA patients have none or minor transient skin rash;, in contrast, anti-MDA syndrome has extensive rash pathognomonic of DM (Gottron's papules, Gottron's sign) with ulceration over scared Gottron's lesions and painful reddish palmar papules., ASA patients with absent or trivial skin rash and lacking overt myositis are likely to be treated as idiopathic ILD, largely treatment resistant. On the other hand, the recent RIM trial demonstrated that anti-Jo-1 syndrome patients respond better to rituximab. ILD associated with anti-non-Jo-1 and anti-MDA5 syndromes is treatment refractory with even poorer prognosis than cancer-associated myositis. Therefore, it is increasingly important to screen ILD patients for MSAs and MAAs. Furthermore, anti-Jo-1, anti-Non-Jo-1, as well as anti-MDA5 syndromes are not associated with specific increased cancer risk within 3 years of disease onset. [Table 2] lists AIMs highly associated with ILD, while [Table 3] lists AIMs that may present with CADM.
|Table 3: Autoantibodies associated with clinically amyopathic dermatomyositis|
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Most such antibodies (>15 in number) belong to the MAA group, reactive to nuclear antigens. In contrast to those patients with autoantibodies against cytoplasmic antigens, the myositis patients in this group have overt CTD features. MAAs also overlap and are also seen in other CTDs. Management, response, and prognosis in this group are guided by the primary underlying CTD rather than myositis [Table 1].
These strongly correlate with the type of MAA(s) detected and therefore are variable with each antibody with overlap features of different CTDs in varying proportions. As mentioned earlier, myositis, ranging from trivial to severe, precedes skin manifestations of DM (common to all OM patients). Cutaneous manifestations are variable and often difficult to differentiate those of the associated CTD. ILD may be seen in similar proportions as in overlapping CTDs. Thus, those with overlap SSc features have a higher chance of ILD followed by those with RA and SLE. Chances of cancer within 3 years of disease onset are not increased and determined by the chances of malignancy in the overlapping CTD.
- Anti-U small ribonucleoprotein (a part of the spliceosome) antibodies and syndrome: Such antibodies react with U1 RNP, U3 RNP (fibrillarin), U5 RNP, and U11–12 RNP, a family of antinuclear antibodies (ANA) commonly seen in SSc along with antibodies against centromere, topoisomerase I, RNA polymerase III, PM/Scl, Ro52/TRIM21, and U1RNP. Most such patients have clinical features of MCTD or undifferentiated connective tissue diseases (UCTD)
- Anti-PM-Scl antibodies: Associated with a characteristic clinical overlap syndrome of inflammatory myositis and SSc, often termed scleromyositis or sclero-DM
- Anti-Ku antibodies:,, These are ANA reactive against a heterodimer of p70 and p80 subunits of a molecular complex called “Ku-complex” (with roles in DNA repair, transcriptional regulation, replication, telomere maintenance, V[D] J recombination, and neural development). Clinically, such patients show overlapping features of SSc and polymyositis, including myositis, arthritis, and joint contractures, negatively correlating with fingertip ulcers and telangiectasias. Overlap with SLE, UCTD is also reported. Anti-Ku-positive patients generally lack anti-centromere antibodies or anti-PM-Scl antibodies
- Anti-nucleoporin antibodies: These ANAs against anti-nuclear pore complex proteins present with predominant myositis associated with erosive, anti-CCP, and rheumatoid factor-positive inflammatory arthritis akin to rheumatoid arthritis, trigeminal neuralgia, RP, esophageal dysmotility, and weight loss. ILD is seen in about a third, usually mild, and GC responsive. Myositis is typically chronic, relapsing, and refractory to GC alone, requiring additional immunosuppressant
- Anti-CENP-A and B antibodies target two of three main human centromere antigenic components, CENP-A and CENP-B. Such patients resemble scleroderma with anti-centromere antibodies with some minor differences, e.g., more often seen in older women with limited skin involvement, much less severe digital ulcers, digital tuft resorption, scleroderma renal crisis (SRC), arthritis, myositis, and ILD, however, more likely to develop pulmonary arterial hypertension
- Anti-Th/To antibodies are ANA seen in 95% of SSc. In most, SSc-associated antibodies (i.e., centromere, topoisomerase I, RNA polymerase III, PM/Scl, Ro52/TRIM21, and U1RNP) are detected. RibonucleasePprotein subunit p25, (Rpp25) is an autoantigenic component of the Th/To complex. Contribution of anti-Th/To and anti-Rpp25 antibodies to ANA positivity in SSc remains unknown
- Anti-RuvB-like ½ autoantibodies, a novel SSc-related antibody associated with diffuse cutaneous and skeletal muscle involvement 
- Anti-DNA topoisomerase I antibodies  correlate with presence and severity of SSc. Muscle involvement in such patients would be classified under OM. The treatment, response, and the prognosis are determined by underlying SSc rather than myositis
- Anti-RNA polymerase III antibodies correlate with a unique clinical presentation of SSc (minimal skin manifestations, making recognition of SSc difficult). Such patients may present with thrombotic thrombocytopenic purpura (TTP), i.e., microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, i.e., SRC. Therefore, myositis and its treatment remain a secondary consideration 
- Anti-native DNA antibodies correlate mainly lupus as the primary underlying CTD, which determines treatment and prognosis
- Anti-Ro 52/60, anti-La antibodies, detected first in Sjögren's syndrome and lupus, are nonspecific, seen in almost all CTDs, including Sjögren's syndrome, SLE, SSc, MCTD, primary biliary cholangitis, and mothers of neonates at high risk for congenital heart blocks.,, Therefore, by themselves, these antibodies do not determine any specific clinical subset other than OM. Anti-Ro antibodies along with anti-Jo-1 antibodies confer greater treatment resistance.
This group comprises classical DM with pathognomonic and characteristic skin lesions, proximal muscle weakness, and raised muscle enzymes with little chance of ILD. Skin rashes precede onset of myositis [Table 4]., Two further subsets based on their negative or positive association with cancer (either simultaneously [paraneoplastic disease] or within 3 years of disease onset).
DM with pathognomonic skin lesions and proximal muscle weakness with no increased risk for ILD or cancer: Associated autoantibodies are as follows:
- Anti-Mi-2 (NuRD) antibodies: Historically, the first MSA described by Reichlin and Mattioli in 1976 and later by Targoff and Reichlin in 1985, reactive to a nuclear antigen (a component of the nucleosome remodelling-deacetylase [NuRD] complex involved in transcription regulation). It is a major serologic marker of IIM (sensitivity 4%–18% and specificity 98%–100%),
- Anti-small ubiquitin-like modifier enzyme (SAE) antibodies: Described for the first time by Betteridge et al., targeting small ubiquitin-like modifier activating enzyme,, it is the second antibody commonly associated with classical DM, with good response to the standard therapy with GCs and immunomodulators.
These patients present with classical DM with pathognomonic photosensitive skin lesions (preceding muscle weakness), proximal muscle weakness, and raised muscle enzymes  Patients with anti-SAE antibodies associate with HLADQB1*03 haplotype  and do not portend ILD or cancer (within the 3 years of disease onset), with good therapeutic response to GC and immunomodulators (MTX, AZA) and favourable prognosis.
DM with pathognomonic skin lesions and proximal muscle weakness with no increased risk for ILD but with very high risk for cancer [Table 5]. Associated autoantibodies are as follows:
- Anti-transcription intermediary factor 1-γ antibodies against 155-kDa protein associated with a smaller 140-kDa protein identified in 2006–2007,
- Anti-nuclear matrix protein 2 (NXP-2) autoantibodies: Originally termed anti-MJ antibodies, the target autoantigen is a 140-kDa autoantigen, an NXP-2 (also called MORC3), involved in the transcription regulation.
Prominent pathognomonic skin manifestations of DM precede muscle weakness with moderate to very high muscle enzymes and no increased ILD risk.
Anti-transcriptional intermediary factor-gamma (anti-155/140 autoantibodies) antibody syndrome: Besides typical features of DM, these patients have a high chance of associated cancer , in adults but not juvenile DM (JDM)., Juvenile-onset disease has less severe myositis, often clinically amyopathic. Associated cancer may be easily detectable on routine physical examination (including careful breast, per-vaginal, and per-rectal prostate examination), or else, positron emission tomography-scan is strongly recommended. Author's experience suggests that prostate biopsy may be recommended to exclude malignancy even if PSA is normal with prostatomegaly. Poor response is seen to GC and immunomodulators with anecdotal reports of DM disappearing after curing cancer.
Anti-nuclear matrix protein-2 antibody syndrome:First described among JDM, these associate with severe calcinosis cutis; however, this is generally the case with JDM as opposed to when this antibody is also detectable in older individuals with DM, wherein it increases risk of internal malignancy, especially in males., Myositis is severe, often quickly leading to atrophy and contractures. Such individuals have typical features of DM, with variable response to standard line of immunosuppressive treatment (better in JDM).
Necrotizing autoimmune myositis
Rapidly progressive proximal limb muscle involvement with high CK levels with characteristic absence of DM rash or CTD features,, such patients present with subacute myositis and high serum CK levels, and characteristic histopathology with widespread muscle fibers necrosis with some regenerating fibers without cellular infiltrates, unresponsive to standard therapy, and associated with cancer is certain subsets. Based on MSAs, there are four subsets [Table 5] and [Table 6]:
- Anti-3-hydroxy-3-methyl glutaryl-coenzyme A reductase autoantibodies: The target antigen is HMGCR (rate-limiting enzyme of mevalonate pathway). A smaller proportion of patients may provide a history of statin intake, lack association with cancer, and if initiated early and aggressively, responds well to GC. The larger subgroup without history of statin intake is a serious rapidly progressive disease unresponsive to standard therapy, often associated with cancer 
- Anti-signal recognition particle (SRP) antibodies: These autoantibodies react with a cytoplasmic autoantigen called SRP,, associated with minimal or no skin involvement (akin to polymyositis), with dysphagia and subacute progressive severe necrotizing myopathy that responds poorly to treatment. Association with cardiac involvement is controversial 
- Anti-survival of motor neuron (anti-SMN) complex antibodies: It reacts with a naturally occurring molecule complex (SMN complex), an autoantigen physiologically essential for the development and maintenance of motor neurons. Such patients have severe, rapidly progressive muscle disease and very high CK levels. Histopathology reveals extensive muscle fiber necrosis and attempts for fiber regeneration with minimal inflammatory infiltrates. Several MAA may coexist  with anti-SMN autoantibodies. There is no known treatment
- Autoantibody-negative NAM: These patients have similar clinical features of poorly responsive, severe necrotizing myositis, and increased association with cancer.
NAM and cancer association [Table 5]: Frequency of cancer is higher with anti-HMGCR autoantibodies (subgroup not exposed to statins) and seronegative NAM compared to anti-SRP-positive patients.
All the autoantibodies detected till recently targeted nonmuscle antigens. In 2015, leading researchers in myositis (Lundberg's group) published the first report of the presence of a muscle antigen-specific autoantibody among a particular subgroup with clinical features of AIM, against a molecule called four-and-a-half LIM domain 1 (FHL1), a component of striated muscles (anti-FHL1 antibody). Mutations in FHL-1 cause some of the X-linked hereditary myopathies (FHL1-related myopathies), characterized by severe muscle dysfunction and damage. Clinical features seen in patients positive for anti-FHL1 antibodies also have muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. Reports on therapeutic response are lacking in published literature.
Among a large number of different forms of myositis discussed above, conceptually two entities are of great importance, those associated with anti-SMN antibodies and anti-FHL1 antibodies, which react with antigens present in neuromuscular tissues (in contrast to previously discussed entities wherein target antigens were derived from cell lysates of cell lines grown in vitro or recombinant antigens). These two new antigenic targets for autoantibodies are also subjects for genetic mutations causing hereditary myopathies with severe muscle disease occurring from early childhood, with similar phenotype in myositis with autoantibodies against these neuromuscular antigens, the only difference being the autoimmune pathogenesis of the latter group. This opens a whole new research field for the investigating the autoimmune aspect of hereditary myopathies.
With increasing array of MSAs and MAAs being discovered in AIM, lesser patients are being diagnosed as “pure” polymyositis [Table 7]. It is likely that many such patients may actually be “mimics of myositis” (e.g., metabolic and endocrine myopathies, familial myopathies due to genetic mutations ,) rather than true “pure” polymyositis. Another reason for confusion is that some of the noninflammatory myopathies may also be partially GC responsive. Thus, the rheumatologists must exercise caution in diagnosing “pure” polymyositis. A biopsy with advanced immunohistopathological markers is becoming essential to accurately diagnose such patients.
|Table 7: Autoantibodies associated with polymyositis and inclusion body myositis|
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It is the rarest form of myositis, suspected in the presence of significant distal limb muscle involvement, unresponsive to treatment [Table 7]. Confirmation of diagnosis requires electron microscopy. The presence of MSAs and MAAs in several such patients lent suspicion that IBM was an AIM, now confirmed with detection of antibody against cytosolic 5'nucleotidase 1A (anti-cN1A). Interestingly, anti-cN1A antibodies are detected in approximately a third of Sjögren's and lupus patients. Therefore, it is likely that IBM may be considered in the future as an “OM.”
| Conclusion|| |
The discovery of the first anti-Mi2 autoantibody in myositis established the autoimmune nature of AIM, with characteristic features of classical DM, good response to therapy, and lack of association with ILD or cancer generating even greater excitement due to potential to predict clinical course, subsequently confirmed with a large number of autoantibodies in patients with inflammatory myositis over the next four decades. In the light of such discoveries, it is evident that a new classification system combining clinical phenotypes and autoantibody association would soon be propounded. Such a preliminary classification was proposed in 2016, now formally adopted by the European League Against Rheumatism and the American College of Rheumatology, hopefully helping to recruit patients with uniform clinical phenotype for meaningful drug trials. Such developments bring reason for excitement and optimism for all stakeholders in IIM.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]