Novel Serology Testing for Sporadic Inclusion Body Myositis

Disease-Specificity and Diagnostic Utility

Megan K. Herbert; Ger J.M. Pruijn


Curr Opin Rheumatol. 2015;27(6):596-600. 

In This Article

Abstract and Introduction


Purpose of review The purpose of this article is to discuss recent advances in serological testing for sporadic inclusion body myositis (sIBM) and to provide a review of their diagnostic utility and disease-specificity of auto-antibodies in sIBM.

Recent findings The identification, prevalence and diagnostic utility of a new auto-antibody targeting cytosolic 5'-nucleotidase 1A (cN-1A) in the serum of sIBM patients have recently been published. These studies have shown that anti-cN-1A auto-antibodies have diagnostic utility for differentiating sIBM from other forms of myositis and from other neuromuscular diseases. Anti-cN-1A-positive patient sera are directed to multiple epitopes of cN-1A and contain, in addition to IgG, IgA and IgM, anti-cN-1A auto-antibodies. Recent studies have also shown a relatively high prevalence of these auto-antibodies in sera form Sjögren's syndrome and systemic lupus erythematosus patients.

Summary The recent discovery of auto-antibodies to cN-1A provides a serological tool to aid the differentiation between inflammatory myopathies and supports the idea that apart from degeneration, an adaptive immune response may also play a role in sIBM pathophysiology. Future research will need to focus on standardization of methods to detect these auto-antibodies in order to further explore their specificity and diagnostic utility for sIBM.


Idiopathic inflammatory myopathies (IIMs) are systemic autoimmune, inflammatory muscle diseases characterized by chronic peripheral muscle weakness and inflammatory infiltrates in skeletal muscle. The most common of these include polymyositis, dermatomyositis, sporadic inclusion body myositis (sIBM) and necrotizing autoimmune myositis (NAM).[1,2] Differentiation of polymyositis, dermatomyositis, sIBM and NAM is based on the presence of unique clinical, histological and immunological features. Dermatomyositis is a disease affecting both skin and muscle, and the presence of a typical rash makes its distinction from the other myopathies relatively straightforward.[1] CD8-positive cytotoxic T-cell invasion of endomysia in muscle biopsy is observed in both polymyositis and sIBM, but additional degenerative features such as rimmed vacuoles, centralizing nuclei and inclusion bodies are generally only observed in sIBM muscle biopsies.[3] The clinical features of polymyositis are less distinct than those of the other IIMs; it often mimics other myopathies and is, therefore, often a diagnosis of exclusion. Moreover, about 30% of clinically diagnosed cases of sIBM lack the characteristic degenerative muscle features associated with sIBM, thus adding to ambiguity in the differentiation of sIBM from polymyositis.[4] Hence, the differential diagnosis of IIM, particularly the distinction between polymyositis and sIBM, remains challenging. Therefore, additional diagnostic tools to improve classification and diagnostic accuracy of myositis would be invaluable.

Serological testing of myositis-specific auto-antibodies (MSAs) in up to 50% of polymyositis/dermatomyositis cases has proven useful both in contributing to differential diagnosis of IIM and their association with clinical phenotype, complications, response to therapy and prognosis.[5] Auto-antibodies directed against the aminoacyl-transfer ribonucleic acid (tRNA) synthetase are present in up to 30% of polymyositis and dermatomyositis patients, and have a particularly important role in diagnosis of anti-synthetase syndrome characterized by interstitial lung disease with myositis.[6–9] Since the identification of the first of these auto-antibodies, anti-Jo-1 directed against histidyl-tRNA synthetase [histidyl-tRNA synthetase (RS)], other similar auto-antibodies directed against a range of tRNA-synthetases have been identified: PL-7 (threonyl-RS), PL-12 (alanyl-RS), OJ (isoleucyl-RS), EJ (glycyl-RS), KS (asparaginyl-RS), Zo (phenylanlanyl-RS) and Ha (tyrosyl-RS).[8–10] Other less common MSAs include anti-Mi-2, present in about 10–15% of polymyositis and dermatomyositis cases, and anti-signal recognition particle, anti-melanoma differentiation-associated gene 5, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), anti-nuclear matrix protein 2, anti-small ubiquitin like modifier activating enzyme, anti-transcription intermediary factor 1 (TIF1) (TIF1-α, β, γ) and anti-eukaryotic initiation factor 3. While some of the MSAs are preferentially or uniquely associated with one of the subtypes of IIM mentioned above, such as anti-HMGCR with NAM, many MSAs are strongly associated with specific clinical features, such as anti-RS auto-antibodies with interstitial lung disease (ILD) and anti-TIF1-γ with malignancy.[11–14] Fig. 1 provides an overview of the auto-antibody landscape in IMM.

Figure 1.

Overview of myositis-specific auto-antibodies. While some auto-antibodies appear to be rather specific for DM, PM, sIBM or NAM, most show at least some overlap with other types of myositis. Some MSAs are more frequently present in sera from patients with clinically amyopathic dermatomyositis (CADM), juvenile dermatomyositis (JDM) or the anti-synthetase syndrome. Associations of MSAs with clinical features are indicated by their proximity to the respective features indicated in blue. DM, dermatomyositis; MSAs, myositis-specific auto-antibodies; NAM, necrotizing autoimmune myositis; PM, polymyositis; sIBM, sporadic inclusion body myositis.

Due to a lack of evidence for circulating auto-antibodies in sIBM sera, sIBM has largely been considered to be a degenerative disorder with secondary autoimmune features. However, the recent discovery of serum auto-antibodies targeting a 44-kDa skeletal muscle protein in the serum of many sIBM patients has aroused new interest in the role for autoimmunity in the pathogenesis of sIBM[15]). Two separate groups have since identified the target auto-antigen for these auto-antibodies as the cytosolic 5'-nucleotidase 1A (cN-1A, also indicated with cN1A, cN-IA and NT5C1A) and, using immunoblotting methods, the presence of anti-cN-1A auto-antibodies could be detected in up to 72% of sIBM sera, but in less than 5% of polymyositis and dermatomyositis sera.[16,17]

Cytosolic 5'-nucleotidase 1A is highly expressed in skeletal muscle tissue and is involved in several cellular processes including physiological control of energy balance, metabolic regulation and cell replication. It catalyses the hydrolysis of adenosine monophosphate to adenosine and organic phosphate, and, interestingly, early studies using lead salt-based staining methods for 5'-nucleotidases showed interstitial staining of skeletal muscle in patients with inflammatory myopathies.[18] The observation in immunohistochemical staining of muscle biopsies showing accumulation of cN-1A within rimmed vacuoles and cN-1A perinuclear localization[17] suggests that aberrant cN-1A localization could play a role in the degenerative process occurring in sIBM skeletal muscle. Thus, the anti-cN-1A auto-antibodies in sIBM serum could represent a highly promising sIBM-specific diagnostic biomarker.