Common and distinct clinical features in adult patients with anti-aminoacyl-tRNA synthetase antibodies: heterogeneity within the syndrome

Abstract

Objective: To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs).

Methods: This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009.

Results: Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron's sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset.

Conclusion: Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the "anti-synthetase syndrome."

Figure 1. Enrollment and selection of patients.

DM; dermatomyositis, PM; polymyositis, SSc; systemic sclerosis, ILD; interstitial lung disease, SLE; systemic lupus erythematosus, MCTD; mixed connective tissue disease, Sjogren; Sjogren’s syndrome, RA; rheumatoid arthritis.

Figure 2. Representative immunoprecipitation assay for RNA with anti-aminoacyl-tRNA synthetase (anti-ARS) sera.

A, Immunoprecipitation of histidyl-tRNA synthetase, glycyl-tRNA synthetase, threonyl-tRNA synthetase, alanyl-tRNA synthetase, asparaginyl-tRNA, and isoleucyl-tRNA synthetase by sera. K562 cell extracts were immunoprecipitated with sera, and RNA was extracted, electrophoresed on 8% urea-polyacrylamide gels, and visualized by silver staining. Total RNA, with the 5.8 and 5.0 S small ribosomal RNAs and the tRNA region indicated; Lane 1, normal health serum (NHS) indicated; Lanes 2–7: anti-ARS sera indicated, with antibodies to Jo-1 (histidyl-tRNA synthetase), EJ (glycyl-tRNA synthetase), PL-7 (threonyl-tRNA synthetase), PL-12 (alanyl-tRNA synthetase), KS (asparaginyl-tRNA synthetase), and OJ (isoleucyl-tRNA synthetase). B, Immunoprecipitation of ³⁵S-methionine-labeled K562 cell extracts was performed on anti-ARS sera and NHS, separated on 10% SDS-PAGE, and analyzed by autoradiography. Molecular weight markers include protein bands corresponding to 220, 97.4, 66, 46, and 30 kDa.

Figure 3. Prevalence of dermatomysitis (DM), clinically amyopathic DM (CADM), polymyositis (PM), PM/DM-overlap, systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and interstitial lung disease (ILD) alone, in each subgroup of anti-synthetase syndrome.

Figure 4. The clinical course of anti-synthetase syndrome patients who developed myositis or interstitial lung disease (ILD) with or without skin manifestations at disease onset.

According to the clinical course, patients were classified into four types: remained with ILD alone, developed myositis during follow-up, developed ILD during follow-up, and remained with myositis alone. The clinical course of those who had ILD with or without skin manifestations, but without muscle involvement at their first assessment (A), and the clinical course of those who had myositis with or without skin manifestations, but without ILD at their first assessment (B).