Hierarchical cluster and survival analyses of antisynthetase syndrome: Phenotype and outcome are correlated with anti-tRNA synthetase antibody specificity

doi:10.1016/j.autrev.2012.06.006

Autoimmunity Reviews

Volume 12, Issue 2, December 2012, Pages 210-217

https://doi.org/10.1016/j.autrev.2012.06.006 Get rights and content

Abstract

The clinical phenotype and evolution of antisynthetase syndrome (ASS) are heterogeneous. This study was therefore undertaken to identify subgroups of ASS patients with similar clinico-biological features and outcomes. This retrospective multicentric study included 233 consecutive patients with three different anti-aminoacyl-tRNA-synthetase antibodies (anti-ARS): anti-Jo1 (n = 160), anti-PL7 (n = 25) and anti-PL12 (n = 48). To characterise ASS patients, bivariate, multiple correspondence (MCA), cluster and survival analyses were performed.

Interstitial lung disease (ILD) and myositis were the most common ASS manifestations. However, their respective frequencies were correlated to anti-ARS specificity: ILD was more frequent (80% and 88% vs 67%, p = 0.014) whereas myositis was less common (44% and 47% vs 74%, p < 0.001) in patients with anti-PL7 and anti-PL12 compared to anti-Jo1. The MCA suggested that anti-PL7 and anti-PL12 phenotypes were close to one another and distinct from anti-Jo1. The clustering analysis confirmed these data, identifying subgroups strongly defined by the anti-ARS specificity and other clinical features. Cluster 1 (n = 175, 86% of anti-Jo1) defined patients with the most diffuse phenotype, whereas patients from cluster 2 (n = 48, 96% of anti-PL12 and anti-PL7) exhibited a disease more restricted to the lung. Patient survival was also conditioned by the anti-ARS specificity, and was significantly lower in patients with anti-PL7/12 rather than anti-Jo1 (p = 0.012). Other factors associated with poor survival were mostly related to pulmonary involvement, including severe dyspnea (p = 0.003) and isolated ILD (p = 0.009) at diagnosis. In patients with ASS, the phenotype and the survival were correlated with the anti-ARS specificity.

Introduction

Antisynthetase syndrome (ASS) has been characterised as the association of an inflammatory myositis, interstitial lung disease (ILD), arthritis, Raynaud's phenomenon (RP) and Mechanic's hands with the presence of anti-aminoacyl-tRNA-synthetase antibodies (anti-ARS) [1], [2]. Other symptoms overlapping with Sjögren syndrome (SS) and systemic sclerosis (SSc) are also quite commonly reported [2], [3]. Thus, ASS may be considered clinically as a heterogeneous disease. Several anti-ARS have also been described, with anti-Jo1 (anti-histidyl-tRNA-synthetase-Ab) being the most common. However, other anti-ARS (including anti-alanyl (PL12), anti-threonyl (PL7), anti-isoleucyl (OJ) and anti-glycyl (EJ) tRNA-synthetase antibodies) are now also diagnosed routinely (by immuno-DOT [4], [5]). Although these anti-ARS are mutually exclusive, they can be associated with other auto-antibodies (Abs), primarily anti-Ro-SSA (52 and 60 kDa) and other extractable nuclear antigen Abs [1], [2], [3], [6], [7].

Previous reports on ASS patients have attempted to associate anti-ARS specificity with distinctive phenotypic features[8]. Some of these reports suggested more or less frequent occurrences of particular symptoms with particular anti-ARS [9], [10], [11], [12]. However, most of these retrospective series included a small number of patients, and usually compared non-anti-Jo1 ASS to historical series of anti-Jo1 ASS only [10], [11]. Moreover, the long-term prognosis and the survival of ASS according to the anti-ARS specificity was rarely evaluated [13], [14], [15]. Nor has there been a thorough evaluation of the prognosis value of overlapping manifestations of SSc and SS. However, it has been suggested that auto-Abs associated with SS [6], [7], including anti-Ro/SSA-52 kDa [4], could be associated with a poor ASS prognosis.

Despite all these studies, the identification of ASS subgroups of patients sharing similar clinical and biological features has remained a challenge. This led us to conduct this large multicenter study of 233 ASS patients, our aim being to describe patients according to their similarities and to evaluate the outcome of ASS associated with different anti-ARS: anti-Jo1, anti-PL7 and anti-PL12.

Section snippets

Patients

This retrospective study was conducted in eight French university hospitals between 2008 and 2011. Identification of the patients was performed in each centre through the Laboratory of Immunology 2001–2011 databases. To exclude false positive patients, we only included patients who met the following inclusion criteria: 1) at least two consecutive positive tests for anti-ARS using the same method, either LUMINEX-100 system (Luminex, Austin, TX, USA) or ENA-LISA-kit (Biomedical diagnostics,

Overall cohort description (Table 1)

Among the 233 patients, 79% (n = 183) were Caucasian and the women/men ratio was 2.4. The medium age at onset was 48.1 ± 15.5 years and the mean follow-up was 77 ± 68 months.

Although the clinical phenotype of ASS was broad, over the course of the disease, ILD (83%, n = 193) and myositis (73%, n = 169) were the most common ASS manifestations. Both were associated in 142 (61%) patients. When both manifestations were present, their occurrence was concomitant in only 40% of the cases (n = 93), whereas they

Different ASS phenotypes according to anti-ARS specificity

The different descriptive analyses used in this study confirmed the diversity of ASS specificities among the 233 patients [7], [10], [11]. However, the comparison of patients according to their anti-ARS subtype showed distinct features. Anti-Jo1 was associated with a broad phenotype (with higher frequencies of myositis and polyarthralgia). Moreover, myositis seems more severe in patients with anti-Jo1. These results strongly demonstrate the hypotheses suggested in previous small series [11],

Conclusion

In summary, our series demonstrates that ASS diversity is largely associated with anti-ARS specificity. However, grouping ASS patients according to both clinical and biological features defined more homogenous subgroups, with different survival rates. These results should be taken into account when performing prospective drug trials in the future.

Disclosure statement

All the co-authors declare that they have no conflict of interest.

Take-home messages

•
Different ASS phenotypes according to anti-ARS specificity are defined: anti-Jo1 being associated with a broad phenotype and anti-PL7 and anti-PL12 being more restricted to the lungs.
•
Features associated with survival are mainly related to pulmonary involvement and patients with anti-PL7 & anti-PL12 have a lower survival than anti-Jo1.

Aknowledgements

We thank all physicians in charge of the ASS patients, including Pr Tillie-Leblond I (Lille), Dr Morell-Dubois S (Lille), Pr Valeyre D (Bobigny), Dr Lambert M (Lille), Pr Launay D (Lille), Dr Maillard-Lefebvre H, Dr Couret B (Toulouse), Dr Durant C (Nantes), Dr Agard C (Nantes), Dr Connault J (Nantes), Pr Delaval P (Rennes),Pr Costedoat-Chalumeau N (Paris), Pr Cacoub C (Paris), Dr Rigolet A, (Paris), Pr Camus P (Dijon), Pr Quoix E (Strasbourg), Dr Berthelot JM (Nantes), Pr Fautrel B (Paris), Pr

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Citation Excerpt :
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^☆: Author contributions: BH, MH, EH and OB designed the study; BH, RS and AM compiled the data, BH, HD and MG performed the statistical analyses; BH, HD and OB wrote the manuscript; LM, NOO and SD performed the immunological tests. TM performed electromyography, analysed the muscular biopsies and the neurological data. BH, RS, YU, AM, PYH, HN, BW, DA, PA, JS, DL, ZA, EH, MH and OB followed the patients, managed the treatments and planned the evaluations.

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ReviewHierarchical cluster and survival analyses of antisynthetase syndrome: Phenotype and outcome are correlated with anti-tRNA synthetase antibody specificity☆

Abstract

Introduction

Section snippets

Patients

Overall cohort description (Table 1)

Different ASS phenotypes according to anti-ARS specificity

Conclusion

Disclosure statement

Take-home messages

Aknowledgements

A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups

Medicine (Baltimore)

Polymyositis, pulmonary fibrosis and autoantibodies to aminoacyl-tRNA synthetase enzymes

Q J Med

Clinical heterogeneity and prognostic features of South Australian patients with anti-synthetase autoantibodies

Intern Med J

Clinical significance of anti-Ro52 (TRIM21) antibodies non-associated with anti-SSA 60kDa antibodies: results of a multicentric study

Autoimmun Rev

Use of a commercial line blot assay as a screening test for autoantibodies in inflammatory myopathies

Autoimmun Rev

In patients with antisynthetase syndrome the occurrence of anti-Ro/SSA antibodies causes a more severe interstitial lung disease

Autoimmunity

Short-term and long-term outcome of anti-Jo1-positive patients with anti-Ro52 Antibody

Semin Arthritis Rheum

Comparison of long-term outcome between anti-Jo1- and anti-PL7/PL12 positive patients with antisynthetase syndrome

Autoimmun Rev

Clinical manifestations of anti-synthetase syndrome positive for anti-alanyl-tRNA synthetase (anti-PL12) antibodies: a retrospective study of 17 cases

Rheumatology (Oxford)

Antisynthetase syndrome positive for anti-threonyl-tRNA synthetase (anti-PL7) antibodies

Eur Respir J

Clinical profile of anti-PL-12 autoantibody. Cohort study and review of the literature

Chest

Unusually high frequency of autoantibodies to PL-7 associated with milder muscle disease in Japanese patients with polymyositis/dermatomyositis

Arthritis Rheum

Short-term and long-term outcomes of interstitial lung disease in polymyositis and dermatomyositis: a series of 107 patients

Arthritis Rheum

Autoantibodies in idiopathic inflammatory myopathy: an update on clinical and pathophysiological significance

Curr Opin Rheumatol

Review
Hierarchical cluster and survival analyses of antisynthetase syndrome: Phenotype and outcome are correlated with anti-tRNA synthetase antibody specificity☆