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Myositis-specific and myositis-associated autoantibody profiles and their clinical associations in a large series of patients with polymyositis and dermatomyositis

Abstract

OBJECTIVE:

To analyze the prevalence of myositis-specific and myositis-associated autoantibodies and their clinical correlations in a large series of patients with dermatomyositis/polymyositis.

METHOD:

This cross-sectional study enrolled 127 dermatomyositis cases and 95 polymyositis cases. The disease-related autoantibody profiles were determined using a commercially available blood testing kit.

RESULTS:

The prevalence of myositis-specific autoantibodies in all 222 patients was 34.4%, whereas myositis-associated autoantibodies were found in 41.4% of the patients. The most frequently found autoantibody was anti-Ro-52 (36.9%), followed by anti-Jo-1 (18.9%), anti-Mi-2 (8.1%), anti-Ku (4.1%), anti-SRP (3.2%), anti-PL-7 (3.2%), anti-PL-12 (2.7%), anti-PM/Scl75 (2.7%), and anti-PM/Scl100 (2.7%). The distributions of these autoantibodies were comparable between polymyositis and dermatomyositis, except for a higher prevalence of anti-Jo-1 in polymyositis. Anti-Mi-2 was more prevalent in dermatomyositis. Notably, in the multivariate analysis, anti-Mi-2 and anti-Ro-52 were associated with photosensitivity and pulmonary disorders, respectively, in dermatomyositis. Anti-Jo-1 was significantly correlated with pulmonary disorders in polymyositis. Moreover, anti-Ro-52 was associated with anti-Jo-1 in both diseases. No significant correlation was observed between the remaining autoantibodies and the clinical and/or laboratory findings.

CONCLUSIONS:

Our data are consistent with those from other published studies involving other populations, although certain findings warrant consideration. Anti-Ro-52 and anti-Jo-1 were strongly associated with one another. Anti-Ro-52 was correlated with pulmonary disorders in dermatomyositis, whereas anti-Jo-1 was correlated with pulmonary alterations in polymyositis.

Dermatomyositis; Idiopathic Inflammatory Myopathies; Myositis-Associated Autoantibodies; Myositis-Specific Autoantibodies; Polymyositis


INTRODUCTION

Idiopathic inflammatory myopathies (IIMs) constitute a heterogeneous group of chronic systemic autoimmune diseases with high morbidity and disability rates (11. Feldman BM, Rider LG, Reed AM, Pachman LM. Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood. Lancet. 2008;371(9631):2201-12, http://dx.doi.org/10.1016/S0140-6736(08)60955-1.
http://dx.doi.org/10.1016/S0140-6736(08)...
). Based on their clinical and histopathological features, IIMs can be classified as polymyositis (PM), dermatomyositis (DM), juvenile dermatomyositis, inclusion body myositis, malignancy-associated myositis, and other collagen disease-associated types of myositis.

The etiologies of PM and DM remain unknown, but they are believed to be multifactorial and might include genetic, immunological, and environmental causes. Moreover, there is strong evidence that cellular and humoral autoimmune mechanisms play important roles in these myopathies (22. Nagaraju K, Plotz PH, Miller FW. Inflammatory muscle disease: etiology and pathogenesis. In Rheumatology Edited by: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH. Elsevier, Toronto, Canada; 2003:1523-35.,33. Targoff IN. Laboratory testing in the diagnosis and management of idiopathic inflammatory myopathies. Rheum Dis Clin North Am. 2002;28(4):859-90, viii, http://dx.doi.org/10.1016/S0889-857X(02)00032-7.
http://dx.doi.org/10.1016/S0889-857X(02)...
).

Previous studies have reported that more than 50% of IIM patients have high autoantibody titers, but recent studies using high-sensitivity techniques have shown that the frequency of autoantibody positivity could reach 80% (44. Greenberg SA. Inflammatory myopathies: evaluation and management. Semin Neurol. 2008;28(2):241-9, http://dx.doi.org/10.1055/s-2008-1062267.
http://dx.doi.org/10.1055/s-2008-1062267...
,55. Gunawardena H, Betteridge ZE, McHugh NJ. Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression. Rheumatology (Oxford). 2009;48(6):607-12, http://dx.doi.org/10.1093/rheumatology/kep078.
http://dx.doi.org/10.1093/rheumatology/k...
). The description of a broad spectrum of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) (55. Gunawardena H, Betteridge ZE, McHugh NJ. Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression. Rheumatology (Oxford). 2009;48(6):607-12, http://dx.doi.org/10.1093/rheumatology/kep078.
http://dx.doi.org/10.1093/rheumatology/k...

6. Koenig M, Fritzler MJ, Targoff IN, Troyanov Y, Senécal JL. Heterogeneity of autoantibodies in 100 patients with autoimmune myositis: insights into clinical features and outcomes. Arthritis Res Ther. 2007;9(4):R78, http://dx.doi.org/10.1186/ar2276.
http://dx.doi.org/10.1186/ar2276...

7. O'Hanlon TP, Carrick DM, Targoff IN, Arnett FC, Reveille JD, Carrington M, et al. Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1, and -DQA1 allelic profiles distinguish European American patients with different myositis autoantibodies. 2006;85(2):111-27.

8. Chinoy H, Salway F, Fertig N, Shephard N, Tait BD, Thomson W, et al. UK Adult Onset Myositis Immunogenetic Collaboration (AOMIC). In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype. Arthritis Res Ther. 2006;8(1):R13, http://dx.doi.org/10.1186/ar1862.
http://dx.doi.org/10.1186/ar1862...

9. Love LA, Leff RL, Fraser DD, Targoff IN, Dalakas M, Plotz PH, et al. A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups. Medicine (Baltimore). 1991;70(6):360-74.

10. Hengstman GJ, Brouwer R, Egberts WT, Seelig HP, Jongen PJ, van Venrooij WJ, et al. Clinical and serological characteristics of 125 Dutch myositis patients. Myositis specific autoantibodies aid in the differential diagnosis of the idiopathic inflammatory myopathies. J Neurol. 2002;249(1):69-75.

11. Selva-O'Callaghan A, Labrador-horrillo M, Solans-Laque R, Simeon-Aznar CP, Mez XM, Vilardell-Tarres's M. Myositis-specific and myositis-associated antibodies in a series of eighty-eight Mediterranean patients with idiopathic inflammatory myopathy. Arthritis Rheum. 2006;55(5):791-8, http://dx.doi.org/10.1002/art.22237.
http://dx.doi.org/10.1002/art.22237...
-1212. Guirardello A, Rampudda M, Ekholm L, Bassi N, Tarricone E, Zampieri S, et al. Diagnostic performance and validation of autoantibody testing in myositis by a commercial line blot assay. Rheumatology (Oxford). 2010;49(12):2370-4, http://dx.doi.org/10.1093/rheumatology/keq281.
http://dx.doi.org/10.1093/rheumatology/k...
) has allowed for better clinical categorization of IIMs at diagnosis. Moreover, the characterization of different MSAs and MAAs has provided evidence of their putative clinical prognostic value and associations (55. Gunawardena H, Betteridge ZE, McHugh NJ. Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression. Rheumatology (Oxford). 2009;48(6):607-12, http://dx.doi.org/10.1093/rheumatology/kep078.
http://dx.doi.org/10.1093/rheumatology/k...
).

However, the majority of past studies have generally analyzed MSA and/or MAA profiles in patient groups with autoimmune IIM, without discriminating between DM and PM in subgroups (1313. Váncsaa A, Gergelyb L, Ponyic A, Lakosb G Némethd J, Szodorayb P, et al. Myositis-specific and myositis-associated antibodies in overlap myositis in comparison to primary dermatopolymyositis: Relevance for clinical classification: Retrospective study of 169 patients. Joint Bone Spine. 2010;77(2):125-30, http://dx.doi.org/10.1016/j.jbspin.2009.08.008.
http://dx.doi.org/10.1016/j.jbspin.2009....
), in small groups of DM or PM patients (66. Koenig M, Fritzler MJ, Targoff IN, Troyanov Y, Senécal JL. Heterogeneity of autoantibodies in 100 patients with autoimmune myositis: insights into clinical features and outcomes. Arthritis Res Ther. 2007;9(4):R78, http://dx.doi.org/10.1186/ar2276.
http://dx.doi.org/10.1186/ar2276...
,1111. Selva-O'Callaghan A, Labrador-horrillo M, Solans-Laque R, Simeon-Aznar CP, Mez XM, Vilardell-Tarres's M. Myositis-specific and myositis-associated antibodies in a series of eighty-eight Mediterranean patients with idiopathic inflammatory myopathy. Arthritis Rheum. 2006;55(5):791-8, http://dx.doi.org/10.1002/art.22237.
http://dx.doi.org/10.1002/art.22237...
,1414. Guirardello A, Zampieri S, Tarricone E, Iaccarino L, Bendo R, Briani C, et al. Clinical implications of autoantibody screening in patients with autoimmune myositis A. Autoimmunity. 2006;39(3):217-21, http://dx.doi.org/10.1080/08916930600622645.
http://dx.doi.org/10.1080/08916930600622...
), and in DM/PM overlap syndrome, malignancy-associated myositis, inclusion body myositis and/or other collagen disease-associated types of myositis (66. Koenig M, Fritzler MJ, Targoff IN, Troyanov Y, Senécal JL. Heterogeneity of autoantibodies in 100 patients with autoimmune myositis: insights into clinical features and outcomes. Arthritis Res Ther. 2007;9(4):R78, http://dx.doi.org/10.1186/ar2276.
http://dx.doi.org/10.1186/ar2276...
,1111. Selva-O'Callaghan A, Labrador-horrillo M, Solans-Laque R, Simeon-Aznar CP, Mez XM, Vilardell-Tarres's M. Myositis-specific and myositis-associated antibodies in a series of eighty-eight Mediterranean patients with idiopathic inflammatory myopathy. Arthritis Rheum. 2006;55(5):791-8, http://dx.doi.org/10.1002/art.22237.
http://dx.doi.org/10.1002/art.22237...

12. Guirardello A, Rampudda M, Ekholm L, Bassi N, Tarricone E, Zampieri S, et al. Diagnostic performance and validation of autoantibody testing in myositis by a commercial line blot assay. Rheumatology (Oxford). 2010;49(12):2370-4, http://dx.doi.org/10.1093/rheumatology/keq281.
http://dx.doi.org/10.1093/rheumatology/k...
-1313. Váncsaa A, Gergelyb L, Ponyic A, Lakosb G Némethd J, Szodorayb P, et al. Myositis-specific and myositis-associated antibodies in overlap myositis in comparison to primary dermatopolymyositis: Relevance for clinical classification: Retrospective study of 169 patients. Joint Bone Spine. 2010;77(2):125-30, http://dx.doi.org/10.1016/j.jbspin.2009.08.008.
http://dx.doi.org/10.1016/j.jbspin.2009....
). Moreover, no similar studies analyzing MSAs and MAAs have been performed in a Brazilian population with DM and PM.

Herein, we compared MSA and MAA autoantibody reactivity patterns and their possible clinical associations in a large series of Brazilian patients with autoimmune IIM, including PM and DM.

MATERIALS AND METHODS

The present cross-sectional study involved 222 patients with DM/PM who met at least three (for PM) or four (for DM) of the criteria defined by Bohan and Peter (1515. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344-7.). All patients were treated for inflammatory myopathies in the outpatient clinic of a tertiary hospital center. The patients (aged ≥18 years) were selected based on the availability of serum samples that had been obtained at the time of diagnosis (from 2000-2012) and stored at -20°C. The patients with systemic autoimmune comorbidities or malignancies were excluded.

Patient demographic features and clinical manifestations at disease onset were obtained through a systematic review of medical records. These features included bodily symptoms, cutaneous involvement (i.e., heliotrope, Gottron's sign, “V” of the neck, Shawl's sign, photosensitivity, Raynaud's phenomenon, ulcers, or calcinosis), heart involvement (i.e., myocarditis or heart failure, as revealed by myocardial scintigraphy and echocardiogram exam), gastrointestinal tract involvement (upper dysphagia), articular involvement (arthralgia or arthritis), pulmonary disorders (incipient pneumopathy, ground-glass lesions and/or basal pulmonary fibrosis, as revealed by computed tomography [CT]), and limb muscle strength graded according to the Medical Research Council classification: grade 0, absence of muscle contraction; grade I, slight signs of contractility; grade II, movements of normal amplitude but not against the force of gravity; grade III, normal range of motion against gravity; grade IV, full mobility against gravity and against a degree of resistance; and grade V, complete mobility against strong resistance and against the force of gravity (1616. Hanissian AS, Masi AT, Pitner SE, Cape CC, Medsger TA Jr. Polymyositis and dermatomyositis in children: an epidemiologic and clinical comparative analysis. J Rheumatol. 1982;9(3):390-4.).

Laboratory evaluations were performed at disease onset using automated kinetic methods. The evaluations included determining the serum levels of creatine kinase (normal range, 24-173 IU/L), lactate dehydrogenase (20-350 IU/L), alanine aminotransferase (10-36 IU/L), aspartate aminotransferase (10-36 IU/L), and aldolase (1.0-7.5 IU/L). The erythrocyte sedimentation rate ([ESR] < 20 mm/1st hour) and C-reactive protein ([CRP] <5 mg/L) levels were obtained using the Westergren and immunoturbidimetric methods, respectively, at the time of diagnosis.

The following autoantibodies were investigated in this study: anti-Jo-1 (histidyl-), anti-PL-7 (threonyl-), anti-PL-12 (alanyl-), anti-EJ (glycol-), anti-OJ (isoleucyl-tRNA synthetase), anti-SRP (signal recognition particle), anti-Mi-2 — all included in the group of MSA autoantibody profiles; and anti-PM-Scl 75, anti-PM-Scl 100, anti-Ku, anti-Mi-2, and anti-SS-A/Ro-52 kDa — all belonging to the MAA autoantibody profile. For assessment, a commercially available line blot test kit (Myositis Profile Euroline Blot test kit, Euroimmun, Lübeck, Germany) was used according to the manufacturer's protocol. The results were arbitrarily defined as negative (0/+++), weakly (+/+++), moderately (++/+++), or strongly (+++/+++) reactive by two independent researchers (MGPC and SKS) who had no knowledge of the diagnostic data from each analyzed case. In the present study, only the moderate or strong reactivity results were considered.

Statistical analysis. The Kolmogorov-Smirnov test was used to evaluate the distribution of each parameter. The demographic and clinical features are expressed as the means and standard deviations (SD) for the continuous variables or as frequencies and percentages for the categorical variables. The medians (25th-75th percentiles) were calculated for the continuous variables that were not normally distributed. Comparisons between the patients with and without specific autoantibodies were performed using Student's t-test or the Mann-Whitney u-test for continuous variables, and p<0.05 was considered significant. Moreover, for each disease (DM or PM), all statistically significant univariate parameters that were considered for adjustment were selected and analyzed by stepwise multiple logistic regression (multivariate analysis). Pearson's chi-squared test or Fisher's exact test was used to evaluate the categorical variables. Age at disease onset and gender were adjusted, and the measurements are expressed as odds ratios (ORs) with 95% confidence intervals (CIs). The STATA computer program, version 7 (STATA, College Station, TX USA), was used for the statistical analysis.

RESULTS

Demographic and clinical features of patients

The median ages at disease onset (interquartile ranges) were 43 years (33-57) and 41 years (31-53) for the PM and DM patients, respectively, with a predominance of female gender and Caucasian race in both groups (Table 1).

Table 1
Demographic, clinical and laboratory features of the patients with DM and PM at the time of diagnosis.

Bodily symptoms occurred in half of the patients in both groups. Regarding extra-muscular manifestations, articular involvement affected approximately 40% of the PM and DM patients, followed by dysphagia and Raynaud's phenomenon. Approximately one-fourth of the PM and DM patients were bedridden, and 10% of had dysphonia. No heart involvement was found in either group. As expected, cutaneous involvement was exclusively or more frequently observed in the DM patients and included heliotrope, Gottron's sign, photosensitivity, and other symptoms (e.g., ulcers, calcinosis, “V” of the neck, and Shawl's sign). At the time of diagnosis, muscle weakness was categorized as grade IV (upper and lower limbs) in the majority of PM and DM patients.

Pulmonary disorders, demonstrated by CT, were observed in one-third of the patients in both groups.

The median serum levels of muscle-related enzymes were increased in all PM patients and in approximately 90% of the DM patients (Table 1). Similarly, the median values for ESR and CRP were increased in both groups.

Autoantibody profile

The prevalence of reactivity to any autoantibody (MSA and/or MAA) was 54.1% in all patients included in this study. Patients from the PM and DM subgroups had similar prevalences of reactivity, 58.9% vs. 50.4%, respectively (p = 0.223). A higher prevalence of MSA was observed in the PM patients (45.3% vs. 13.5%, p = 0.036) because of higher positivity for anti-Jo-1 in this subgroup (31.6% vs. 9.5%, p<0.001). Conversely, anti-Mi-2 was more frequently found in the DM patients (11.8% vs. 3.2%, p = 0.019). Reactivity to the remaining MSA-related autoantibodies was low (<5%) and was comparable between the DM and PM patients. Anti-OJ binding was not found in any of the patients studied. Concomitant positivity for any of the autoantibodies included in the MSA and MAA sets was more frequently observed in the PM patients than in the DM patients (31.6% vs. 19.7%, p = 0.042). MAA positivity was similar in both groups (p = 0.317). The percentages of patients with reactivity to these autoantibodies among the PM and DM patients are shown in Table 2.

Table 2
Frequency of myositis-specific and myositis-associated autoantibodies in patients with DM and PM.

No differences in age at disease onset, gender, or clinical or laboratory findings were observed among the DM and PM patients with distinct MSA and/or MAA profiles. However, the univariate analysis showed that anti-Mi-2-positive DM patients were significantly more likely to exhibit photosensitivity and Shawl's sign (Table 3). Moreover, in the multivariate analysis, only the DM patients who were anti-Mi-2-positive were significantly more likely to be photosensitive. Furthermore, anti-Ro-52-positive DM patients were significantly more likely to exhibit pulmonary disorders and anti-Jo-1 positivity, as revealed by the univariate and multivariate analyses. Anti-Jo-1 reactivity was associated only with anti-Ro-52 positivity and not to a particular clinical manifestation in these patients (Table 3). Similarly, there was no significant association between the other MSAs and MAAs and any clinical or laboratory profiles for DM.

Table 3
Independent associations of autoantibodies with specific sets of clinical, imaging, and laboratory features by stepwise multiple logistic regression in patients with DM and PM.

Similar to the MAA findings in DM patients, anti-Ro-52-positive PM patients were significantly more likely to exhibit pulmonary disorders and positivity to anti-Jo-1 than those patients who were anti-Ro-52-negative, as demonstrated by the univariate analysis. In the multivariate analysis, only pulmonary disorders were independently associated with anti-Ro-52 positivity in the PM patients. Contrasted with the findings in DM patients, anti-Jo-1-positive PM patients were significantly more likely to exhibit pulmonary disorders and articular manifestations than the anti-Jo-1-negative patients. However, the multivariate analysis revealed that anti-Jo-1 reactivity was associated only with pulmonary disorders and anti-Ro-52 positivity with articular manifestations. Other MSAs and/or MAAs were not associated with any clinical or laboratory profiles for PM (Table 3).

DISCUSSION

Previous studies have shown that more than 50% of IIM patients have high titers of autoantibodies. However, new and improved detection methodologies established in conjunction with the descriptions of new target antigens in IIMs have contributed to the finding that the frequency of circulating autoantibodies against nuclear or cytoplasmic constituents with ubiquitous tissue distribution could be up to 80% in patients with DM/PM (22. Nagaraju K, Plotz PH, Miller FW. Inflammatory muscle disease: etiology and pathogenesis. In Rheumatology Edited by: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH. Elsevier, Toronto, Canada; 2003:1523-35.). In the present study, we observed positivity for MSA and/or MAA in half of the patients with DM/PM.

The target antigens in the IIMs are intracellular proteins that are involved in key processes in cells, such as gene transcription, protein synthesis and translocation. These antigens include the aminoacyl-tRNA synthetase family of enzymes, nuclear helicase Mi-2/histone deacetylase complex, and SRP (33. Targoff IN. Laboratory testing in the diagnosis and management of idiopathic inflammatory myopathies. Rheum Dis Clin North Am. 2002;28(4):859-90, viii, http://dx.doi.org/10.1016/S0889-857X(02)00032-7.
http://dx.doi.org/10.1016/S0889-857X(02)...
,1717. Nishikai M, Reichlin M. Heterogeneity of precipitating antibodies in polymyositis and dermatomyositis. Characterization of the Jo-1 antibody system. Arthritis Rheum. 1980;23(8):881-8, http://dx.doi.org/10.1002/art.1780230802.
http://dx.doi.org/10.1002/art.1780230802...

18. Mimori T, Imura Y, Nakashima R, Yoshifuji H. Autoantibodies in idiopathic inflammatory myopathy: an update on clinical and pathophysiological significance. Curr Opin Rheumatol. 2007;19(6):523-9, http://dx.doi.org/10.1097/BOR.0b013e3282f01a8c.
http://dx.doi.org/10.1097/BOR.0b013e3282...

19. Betteridge Z, Gunawardena H, North J, Slinn J, McHugh N. Antisynthetase syndrome: a new autoantibody to phenylalanyl transfer RNA synthetase (anti-Zo) associated with polymyositis and interstitial pneumonia. Rheumatology (Oxford). 2007;46(6):1005-8, http://dx.doi.org/10.1093/rheumatology/kem045.
http://dx.doi.org/10.1093/rheumatology/k...

20. Hirakata M, Suwa A, Nagai S, Kron MA, Trieu EP, Mimori T et al. Anti-KS: identification of autoantibodies to asparaginyl transfer RNA synthetase associated with interstitial lung disease. J Clin Invest. 1993;91(6):2556-64.

21. Targoff IN, Trieu EP, Miller FW. Reaction of anti-OJ autoantibodies with components of the multienzyme complex of aminoacyl-tRNA synthetases in addition to isoleucyl-tRNA synthetase. J Clin Invest. 1993;91(6):2556-64, http://dx.doi.org/10.1172/JCI116493.
http://dx.doi.org/10.1172/JCI116493...

22. Targoff IN, Trieu EP, Plotz PH, Miller FW. Antibodies to glycyl-transfer RNA synthetase in patients with myositis and interstitial lung disease. Arthritis Rheum. 1992;35(7):821-30, http://dx.doi.org/10.1002/art.1780350718.
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23. Bunn CC, Bernstein RM, Mathews MB. Autoantibodies against alanyl tRNA synthetase and tRNA Ala coexist and are associated with myositis. J Exp Med. 1986;163(5):1281-91, http://dx.doi.org/10.1084/jem.163.5.1281.
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24. Mathews MB, Reichlin M, Hughes GR, Bernstein RM. Antithreonyl-tRNA synthetase, a second myositis-related autoantibody. J Exp Med. 1984;160(2):420-34, http://dx.doi.org/10.1084/jem.160.2.420.
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25. Plotz PH, Targoff I. Myositis associated antigens. Aminoacyl-tRNA synthetases. In: Manual of Biological Markers of Disease. Eds, WJ Van Venrooij, R Maini. The Netherlands: Kluwer Academic Publications; 1994.

26. Hashish L, Tribu EP, Sadanandan P, Targoff IN. Identification of autoantibodies to tyrosyl-tRNA synthetase in dermatomyositis with features consistent with antisynthetase syndrome (abstract). Arthritis Rheum. 2004;50(1):209-15.

27. Kao AH, Lacomis D, Lucas M, Fertig N, Oddis CV. Anti-signal recognition particle autoantibody in patients with and patients without idiopathic inflammatory myopathy. Arthritis Rheum 2004;50:209-15, http://dx.doi.org/10.1002/art.11484.
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28. Reeves WH, Nigam SK, Blobel G. Human autoantibodies reactive with the signal-recognition particle. Proc Natl Acad Sci U S A. 1986;83(24):9507-11, http://dx.doi.org/10.1073/pnas.83.24.9507.
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29. Targoff IN, Johnson AE, Miller FW. Antibody to signal recognition particle in polymyositis. Arthritis Rheum. 1990;33(9):1361-70, http://dx.doi.org/10.1002/art.1780330908.
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30. Wang HB, Zhang Y. Mi-2, an auto-antigen for dermatomyositis, is an ATP dependent nucleosome remodeling factor. Nucleic Acids Res. 2001;29(12):2517-21, http://dx.doi.org/10.1093/nar/29.12.2517.
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-3131. Targoff IN, Reichlin M. The association between Mi-2 antibodies and dermatomyositis. Arthritis Rheum. 1985;28(7):796-803, http://dx.doi.org/10.1002/art.1780280711.
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).

In the present study, MSA and MSA + MAA were observed more frequently in the PM patients than in the DM patients, whereas MAAs had similar distributions in both groups. Among the MSA group of antibodies, anti-Jo-1 (anti-histidyl-tRNA synthetase) is the most prevalent (33. Targoff IN. Laboratory testing in the diagnosis and management of idiopathic inflammatory myopathies. Rheum Dis Clin North Am. 2002;28(4):859-90, viii, http://dx.doi.org/10.1016/S0889-857X(02)00032-7.
http://dx.doi.org/10.1016/S0889-857X(02)...
,1717. Nishikai M, Reichlin M. Heterogeneity of precipitating antibodies in polymyositis and dermatomyositis. Characterization of the Jo-1 antibody system. Arthritis Rheum. 1980;23(8):881-8, http://dx.doi.org/10.1002/art.1780230802.
http://dx.doi.org/10.1002/art.1780230802...
,1818. Mimori T, Imura Y, Nakashima R, Yoshifuji H. Autoantibodies in idiopathic inflammatory myopathy: an update on clinical and pathophysiological significance. Curr Opin Rheumatol. 2007;19(6):523-9, http://dx.doi.org/10.1097/BOR.0b013e3282f01a8c.
http://dx.doi.org/10.1097/BOR.0b013e3282...
) and the most common anti-aminoacyl-tRNA synthetase autoantibody described to date, characterizing anti-synthetase syndrome. However, this positivity is not an exclusive serological finding, as other autoantibodies can be present in this syndrome, including anti-EJ (glycyl-), anti-PL-7 (threonyl-), anti-PL-12 (alanyl-), anti-OJ (isoleucyl-), anti-KS (asparaginyl-), anti-Ha (tyrosinyl-), anti-Zo (phenylalanyl-), and anti-YRS (tyrosyl-) (1818. Mimori T, Imura Y, Nakashima R, Yoshifuji H. Autoantibodies in idiopathic inflammatory myopathy: an update on clinical and pathophysiological significance. Curr Opin Rheumatol. 2007;19(6):523-9, http://dx.doi.org/10.1097/BOR.0b013e3282f01a8c.
http://dx.doi.org/10.1097/BOR.0b013e3282...

19. Betteridge Z, Gunawardena H, North J, Slinn J, McHugh N. Antisynthetase syndrome: a new autoantibody to phenylalanyl transfer RNA synthetase (anti-Zo) associated with polymyositis and interstitial pneumonia. Rheumatology (Oxford). 2007;46(6):1005-8, http://dx.doi.org/10.1093/rheumatology/kem045.
http://dx.doi.org/10.1093/rheumatology/k...

20. Hirakata M, Suwa A, Nagai S, Kron MA, Trieu EP, Mimori T et al. Anti-KS: identification of autoantibodies to asparaginyl transfer RNA synthetase associated with interstitial lung disease. J Clin Invest. 1993;91(6):2556-64.

21. Targoff IN, Trieu EP, Miller FW. Reaction of anti-OJ autoantibodies with components of the multienzyme complex of aminoacyl-tRNA synthetases in addition to isoleucyl-tRNA synthetase. J Clin Invest. 1993;91(6):2556-64, http://dx.doi.org/10.1172/JCI116493.
http://dx.doi.org/10.1172/JCI116493...

22. Targoff IN, Trieu EP, Plotz PH, Miller FW. Antibodies to glycyl-transfer RNA synthetase in patients with myositis and interstitial lung disease. Arthritis Rheum. 1992;35(7):821-30, http://dx.doi.org/10.1002/art.1780350718.
http://dx.doi.org/10.1002/art.1780350718...

23. Bunn CC, Bernstein RM, Mathews MB. Autoantibodies against alanyl tRNA synthetase and tRNA Ala coexist and are associated with myositis. J Exp Med. 1986;163(5):1281-91, http://dx.doi.org/10.1084/jem.163.5.1281.
http://dx.doi.org/10.1084/jem.163.5.1281...

24. Mathews MB, Reichlin M, Hughes GR, Bernstein RM. Antithreonyl-tRNA synthetase, a second myositis-related autoantibody. J Exp Med. 1984;160(2):420-34, http://dx.doi.org/10.1084/jem.160.2.420.
http://dx.doi.org/10.1084/jem.160.2.420...

25. Plotz PH, Targoff I. Myositis associated antigens. Aminoacyl-tRNA synthetases. In: Manual of Biological Markers of Disease. Eds, WJ Van Venrooij, R Maini. The Netherlands: Kluwer Academic Publications; 1994.
-2626. Hashish L, Tribu EP, Sadanandan P, Targoff IN. Identification of autoantibodies to tyrosyl-tRNA synthetase in dermatomyositis with features consistent with antisynthetase syndrome (abstract). Arthritis Rheum. 2004;50(1):209-15.). The clinical presentation of patients with these autoantibodies is relatively homogeneous, with one or more of the following signs: myositis, interstitial lung disease, and joint involvement. The presence of fever, Raynaud's phenomenon and "mechanical hands" has also been observed (1717. Nishikai M, Reichlin M. Heterogeneity of precipitating antibodies in polymyositis and dermatomyositis. Characterization of the Jo-1 antibody system. Arthritis Rheum. 1980;23(8):881-8, http://dx.doi.org/10.1002/art.1780230802.
http://dx.doi.org/10.1002/art.1780230802...

18. Mimori T, Imura Y, Nakashima R, Yoshifuji H. Autoantibodies in idiopathic inflammatory myopathy: an update on clinical and pathophysiological significance. Curr Opin Rheumatol. 2007;19(6):523-9, http://dx.doi.org/10.1097/BOR.0b013e3282f01a8c.
http://dx.doi.org/10.1097/BOR.0b013e3282...

19. Betteridge Z, Gunawardena H, North J, Slinn J, McHugh N. Antisynthetase syndrome: a new autoantibody to phenylalanyl transfer RNA synthetase (anti-Zo) associated with polymyositis and interstitial pneumonia. Rheumatology (Oxford). 2007;46(6):1005-8, http://dx.doi.org/10.1093/rheumatology/kem045.
http://dx.doi.org/10.1093/rheumatology/k...

20. Hirakata M, Suwa A, Nagai S, Kron MA, Trieu EP, Mimori T et al. Anti-KS: identification of autoantibodies to asparaginyl transfer RNA synthetase associated with interstitial lung disease. J Clin Invest. 1993;91(6):2556-64.

21. Targoff IN, Trieu EP, Miller FW. Reaction of anti-OJ autoantibodies with components of the multienzyme complex of aminoacyl-tRNA synthetases in addition to isoleucyl-tRNA synthetase. J Clin Invest. 1993;91(6):2556-64, http://dx.doi.org/10.1172/JCI116493.
http://dx.doi.org/10.1172/JCI116493...

22. Targoff IN, Trieu EP, Plotz PH, Miller FW. Antibodies to glycyl-transfer RNA synthetase in patients with myositis and interstitial lung disease. Arthritis Rheum. 1992;35(7):821-30, http://dx.doi.org/10.1002/art.1780350718.
http://dx.doi.org/10.1002/art.1780350718...

23. Bunn CC, Bernstein RM, Mathews MB. Autoantibodies against alanyl tRNA synthetase and tRNA Ala coexist and are associated with myositis. J Exp Med. 1986;163(5):1281-91, http://dx.doi.org/10.1084/jem.163.5.1281.
http://dx.doi.org/10.1084/jem.163.5.1281...

24. Mathews MB, Reichlin M, Hughes GR, Bernstein RM. Antithreonyl-tRNA synthetase, a second myositis-related autoantibody. J Exp Med. 1984;160(2):420-34, http://dx.doi.org/10.1084/jem.160.2.420.
http://dx.doi.org/10.1084/jem.160.2.420...

25. Plotz PH, Targoff I. Myositis associated antigens. Aminoacyl-tRNA synthetases. In: Manual of Biological Markers of Disease. Eds, WJ Van Venrooij, R Maini. The Netherlands: Kluwer Academic Publications; 1994.
-2626. Hashish L, Tribu EP, Sadanandan P, Targoff IN. Identification of autoantibodies to tyrosyl-tRNA synthetase in dermatomyositis with features consistent with antisynthetase syndrome (abstract). Arthritis Rheum. 2004;50(1):209-15.). In agreement with the data from the literature, we found a predominance of anti-Jo-1 in our series of IIM patients, compared to other anti-aminoacyl-tRNA synthetase antibodies. In our series, anti-Jo-1 was more significantly present in the PM patients than in the DM patients. When analyzed by disease, anti-Jo-1 was significantly associated with anti-Ro-52 reactivity, but it was not correlated with pulmonary disorders or articular manifestations in DM patients. In contrast, in the group of PM patients, this autoantibody was correlated with pulmonary disorders and anti-Ro-52 reactivity.

Concerning the other anti-aminoacyl-tRNA synthetase antibodies, we found low prevalences in the present study. Moreover, we did not observe patients with positivity to anti-OJ.

Another subgroup of patients with IIMs is characterized by the presence of antibodies directed against SRP. This antibody has been detected in the serum of 4-6% of patients with IIMs (2727. Kao AH, Lacomis D, Lucas M, Fertig N, Oddis CV. Anti-signal recognition particle autoantibody in patients with and patients without idiopathic inflammatory myopathy. Arthritis Rheum 2004;50:209-15, http://dx.doi.org/10.1002/art.11484.
http://dx.doi.org/10.1002/art.11484...

28. Reeves WH, Nigam SK, Blobel G. Human autoantibodies reactive with the signal-recognition particle. Proc Natl Acad Sci U S A. 1986;83(24):9507-11, http://dx.doi.org/10.1073/pnas.83.24.9507.
http://dx.doi.org/10.1073/pnas.83.24.950...
-2929. Targoff IN, Johnson AE, Miller FW. Antibody to signal recognition particle in polymyositis. Arthritis Rheum. 1990;33(9):1361-70, http://dx.doi.org/10.1002/art.1780330908.
http://dx.doi.org/10.1002/art.1780330908...
), whereas in the present study, we found this positivity in 3.2% of the patients. Myopathies associated with anti-SRP antibodies are characterized by aggressive necrotizing myositis, which is evidenced by rapidly progressive proximal muscle weakness and marked increases in the creatine kinase level. Moreover, anti-SRP-positive patients are less responsive to conventional drug treatments (2727. Kao AH, Lacomis D, Lucas M, Fertig N, Oddis CV. Anti-signal recognition particle autoantibody in patients with and patients without idiopathic inflammatory myopathy. Arthritis Rheum 2004;50:209-15, http://dx.doi.org/10.1002/art.11484.
http://dx.doi.org/10.1002/art.11484...

28. Reeves WH, Nigam SK, Blobel G. Human autoantibodies reactive with the signal-recognition particle. Proc Natl Acad Sci U S A. 1986;83(24):9507-11, http://dx.doi.org/10.1073/pnas.83.24.9507.
http://dx.doi.org/10.1073/pnas.83.24.950...
-2929. Targoff IN, Johnson AE, Miller FW. Antibody to signal recognition particle in polymyositis. Arthritis Rheum. 1990;33(9):1361-70, http://dx.doi.org/10.1002/art.1780330908.
http://dx.doi.org/10.1002/art.1780330908...
). In our series, we found anti-SRP antibodies in seven patients (four PM and three DM patients), and in contrast to the literature, there were no correlations with signs of myositis severity or heart disease.

The anti-Mi-2 autoantibody is strongly associated with skin manifestations in juvenile and adult DM, with a low risk of interstitial pulmonary involvement and a good disease prognosis (3131. Targoff IN, Reichlin M. The association between Mi-2 antibodies and dermatomyositis. Arthritis Rheum. 1985;28(7):796-803, http://dx.doi.org/10.1002/art.1780280711.
http://dx.doi.org/10.1002/art.1780280711...
). Our findings demonstrated a correlation of anti-Mi-2 with different types of DM skin lesions, but in the multivariate analysis, this autoantibody was associated only with photosensitivity.

The main components of the Ro/SS-A system are two distinct major proteins with molecular weights of 52 kDa (Ro-52) and 60 kDa (Ro-60) (3232. Rutjes SA, Vree Egberts WTM, van Den Hoogen F, Pruijn GJM, van Vernrooij WJ. Anti-Ro52 antibodies frequently co-occur with anti-Jo-1 antibodies in sera from patients with idiopathic inflammatory myopathy. Clin Exp Immunol. 1997;109(1):32-40, http://dx.doi.org/10.1046/j.1365-2249.1997.4081308.x.
http://dx.doi.org/10.1046/j.1365-2249.19...
). Reactivity to the Ro-SS-A protein has been correlated with the clinical features of Sjögren's syndrome and systemic lupus erythematosus (3333. Ben-Chetrit E, Fox RI, Tan EM. Dissociation of immune responses to the SS-A/Ro 52-kd and 60-kd polypeptides in systemic lupus erythematosus and Sjögren's syndrome. Arthritis Rheum 1990;33(3):349-55, http://dx.doi.org/10.1002/art.1780330307.
http://dx.doi.org/10.1002/art.1780330307...
). However, the presence of anti-Ro in IIMs has also been described (3434. Isenberg D, Cambridge J, Maddison PJ. Prevalence of Ro (SS-A) antibodies in patients with polymyositis [abstract]. Arthritis Rheum 1987;30(11):1320, http://dx.doi.org/10.1002/art.1780301124.
http://dx.doi.org/10.1002/art.1780301124...

35. Yamagata H, Akizuki M, Tojo T, Homma M. Anti-Ro/SSA and-La/SSB antibodies in patients with connective tissue diseases. Scand J Rheumatol Suppl. 1986;61:98-101.
-3636. Kubo M, Ihn H, Asano Y, Yamane K, Yazawa N, Tamaki K. Prevalence of 52-kd and 60-kd Ro/SS-A autoantibodies in Japanese patients with polymyositis/dermatomyositis. J Am Acad Dermatol. 2002;47(1):148-51, http://dx.doi.org/10.1067/mjd.2002.121037.
http://dx.doi.org/10.1067/mjd.2002.12103...
), and the association of anti-Ro-52 with anti-Jo-1 has been described in IIM patients in 10% of cases (3434. Isenberg D, Cambridge J, Maddison PJ. Prevalence of Ro (SS-A) antibodies in patients with polymyositis [abstract]. Arthritis Rheum 1987;30(11):1320, http://dx.doi.org/10.1002/art.1780301124.
http://dx.doi.org/10.1002/art.1780301124...

35. Yamagata H, Akizuki M, Tojo T, Homma M. Anti-Ro/SSA and-La/SSB antibodies in patients with connective tissue diseases. Scand J Rheumatol Suppl. 1986;61:98-101.
-3636. Kubo M, Ihn H, Asano Y, Yamane K, Yazawa N, Tamaki K. Prevalence of 52-kd and 60-kd Ro/SS-A autoantibodies in Japanese patients with polymyositis/dermatomyositis. J Am Acad Dermatol. 2002;47(1):148-51, http://dx.doi.org/10.1067/mjd.2002.121037.
http://dx.doi.org/10.1067/mjd.2002.12103...
). Particularly in patients with anti-synthetase syndrome, the presence of anti-SSA/Ro-52 antibodies causes more severe interstitial lung disease (3737. La Corte R, Lo Mo Naco A, Locaputo A, Dolzani F, Trotta F. In patients with antisynthetase syndrome the occurrence of anti-Ro/SSA antibodies causes a more severe interstitial lung disease. Autoimmunity. 2006;39(3):249-53, http://dx.doi.org/10.1080/08916930600623791.
http://dx.doi.org/10.1080/08916930600623...
). Other authors have found that the presence of anti-Ro-52 is associated with a particular phenotype of anti-synthetase syndrome, resulting in more severe myositis and joint impairment. Moreover, the coexistence of anti-Ro-52 appears to be associated with an increased risk of cancer (3838. Marie I, Hatron PY, Dominique S, Cherin P, Mouthon L, Menard JF, et al. Short-term and long-term outcome of anti-jo1-positive patients with anti-Ro52 antibody. Semin Arthritis Rheum. 2012;41(6):890-9, http://dx.doi.org/10.1016/j.semarthrit.2011.09.008.
http://dx.doi.org/10.1016/j.semarthrit.2...
). In the present study, anti-Ro-52 was significantly associated with anti-Jo-1, independent of the type of disease. However, in DM patients, anti-Ro-52 was associated with pulmonary disorders, independent of anti-Jo-1 reactivity.

Regarding MAAs, anti-PM-Scl has been found in 8-10% of patients with myositis-scleroderma overlap, whereas anti-Ku has been observed in 20-30% of these patients (33. Targoff IN. Laboratory testing in the diagnosis and management of idiopathic inflammatory myopathies. Rheum Dis Clin North Am. 2002;28(4):859-90, viii, http://dx.doi.org/10.1016/S0889-857X(02)00032-7.
http://dx.doi.org/10.1016/S0889-857X(02)...
,99. Love LA, Leff RL, Fraser DD, Targoff IN, Dalakas M, Plotz PH, et al. A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups. Medicine (Baltimore). 1991;70(6):360-74.,3939. Targoff IN, Mamyrova G, Trieu EP, Perurena O, Koneru B, O'Hanlon TP, et al. Childhood Myositis Heterogeneity Study Group; International Myositis Collaborative Study Group. A novel autoantibody to a 155-kd protein is associated with dermatomyositis. Arthritis Rheum. 2006;54(11):3682-9, http://dx.doi.org/10.1002/art.22164.
http://dx.doi.org/10.1002/art.22164...
,4040. Matsushita T, Hasegawa M, Fujimoto M, Hamaguchi Y, Komura K, Hirano T, et al. Clinical evaluation of anti-aminoacyl tRNA synthetase antibodies in Japanese patients with dermatomyositis. J Rheumatol. 2007;34(5):1012-8.). The prevalence described herein was lower and could be explained by the exclusion of systemic autoimmune disease comorbidities, such as systemic sclerosis. Furthermore, these autoantibodies were not correlated with any clinical or laboratory parameters of DM or PM.

Our study was limited by being a retrospective study, with the typical problems specific to this type of cohort. Second, in the present study we also included patients with probable diagnoses of PM (i.e., meeting three of the four Bohan and Peter's criteria) (1515. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344-7.). In these cases, it was not possible to distinguish inclusion body myositis from other types of myositis or from certain dystrophies. Third, the blood samples had been stored for approximately 10 years and, therefore, might not have functioned properly in the antibody assays. Additionally, we did not include a healthy control group with which to compare antibody reactivity among the groups.

In conclusion, our data are consistent with those from other published studies involving other populations, although certain particularities do warrant consideration: a) we observed high frequencies of anti-Jo-1 and anti-Ro-52, followed by anti-Mi-2, in the subjects of the present study; b) anti-Ro-52 and anti-Jo-1 were strongly associated with one another; c) anti-Ro-52 was correlated with pulmonary disorders in dermatomyositis, whereas anti-Jo-1 was correlated with pulmonary alterations in polymyositis; and d) these autoantibodies should be analyzed routinely in practice, in contrast to the other MSAs and MAAs that were present in low frequencies and that were not associated with the clinical or laboratory parameters of PM and DM.

Marcela Helena Gambim Fonseca provided technical support. This study was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #s: 2011/12700-1 to SKS and 2011/03399-9 to MGPC) and by a grant from the Federico Foundation to SKS.

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    » http://dx.doi.org/10.1002/art.1780350718
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    » http://dx.doi.org/10.1073/pnas.83.24.9507
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    Ben-Chetrit E, Fox RI, Tan EM. Dissociation of immune responses to the SS-A/Ro 52-kd and 60-kd polypeptides in systemic lupus erythematosus and Sjögren's syndrome. Arthritis Rheum 1990;33(3):349-55, http://dx.doi.org/10.1002/art.1780330307.
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  • No potential conflict of interest was reported.

Publication Dates

  • Publication in this collection
    July 2013

History

  • Received
    31 Dec 2012
  • Reviewed
    1 Feb 2013
  • Accepted
    7 Mar 2013
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