Elsevier

Autoimmunity Reviews

Volume 12, Issue 3, January 2013, Pages 363-373
Autoimmunity Reviews

Review
Overlap connective tissue disease syndromes

https://doi.org/10.1016/j.autrev.2012.06.004Get rights and content

Abstract

Overlap Syndromes (OSs) have been defined as entities satisfying classification criteria of at least two connective tissue diseases (CTDs) occurring at the same or at different times in the same patient. CTDs include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis/dermatomyositis (PDM), and Sjögren syndrome (SS). Every combination between these disorders has been reported.

In some OS a specific autoantibody has been indentified, supporting the hypothesis that these syndromes are not a mere association of two or more CTD in the same patient, but a well defined clinical entity with specific clinical characteristics. As an example, anti-t-RNA synthetase syndrome is characterized by the presence of anti-t-RNA synthetase antibodies. Notably, clinical manifestations observed in OS may be different from those observed in the single CTD.

The treatment of OS is mainly based on the use of corticosteroids and immunosuppressants. Biologic drugs, i.e. anti-TNFα or anti-CD20 monoclonal antibodies, have been recently introduced as alternative treatments in refractory cases. Moreover, there are some concerns with the use of anti-TNF agents in patients with systemic autoimmune diseases due to the risk of triggering disease exacerbations.

In this paper the most frequent OS are described with a special focus on the specific immunologic and clinical aspects. Furthermore, some personal data on anti-t-RNA synthetase syndrome and rhupus syndrome are reported.

Introduction

Connective tissue diseases (CTDs) are systemic autoimmune disorders characterized by a large spectrum of clinical features and multisystemic involvement. CTDs include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren syndrome (SS), systemic sclerosis (SSc), dermatomyositis (DM) and polymyositis (PM). All CTDs are classified using widely accepted criteria which consider peculiar clinical features and, when available, specific serological markers [1], [2], [3], [4], [5], [6], [7]. However, in clinical practice it is common to observe some patients who cannot be assigned to a single disease category and these patients are classified as having an undifferentiated connective tissue disease [8]. Another possibility is when manifestations from two or more CTDs are identified in the same patient. This condition has led to the concept of “Overlap Syndromes” (OSs). Every CTD can be a partner in an OS; for example RA can be a partner of SLE (rhupus syndrome), SSc or SS.

The identification of OS is useful in order to clarify the disease prognosis and facilitate management. Two approaches have been suggested in categorizing such conditions. The first is by the detection of a specific antibody marker combined with peculiar clinical findings. The second is by the identification of a pattern of clinical features without a specific serologic marker (Table 1) [9], [10], [11]. As an example of the former condition, anti-t-RNA synthetase syndrome (ASS) is characterized by anti-t-RNA synthetase antibodies and clinical features of RA, SSc, and PDM. As an example of the latter condition, rhupus syndrome is characterized by the coexistence of RA and SLE features; notably, in patients with rhupus, SLE manifestations are less severe than in those affected with SLE alone.

Here we reviewed immunologic, clinical, and therapeutic aspects of OSs with the exception of mixed connective tissue disease which is the focus of many other excellent review papers [12], [13]. Moreover, some personal data on ASS and rhupus syndrome were reported.

Section snippets

Anti-t-RNA synthetase syndrome

ASS is an OS characterized by the clinical features of SSc, RA and myositis and the presence of antibodies against aminoacyl-t-RNA synthetase (ARS). ARS is a distinct group of enzymes that catalyzes the ATP-dependent binding of each amino acid to its cognate t-RNA during protein synthesis. For example, histidyl-t-RNA synthetase catalyzes the esterification of histidine to the correct t-RNA; this process leads to the formation of a histidyl-t-RNA complex. As the coding sequence of a messenger

Rhupus syndrome

The exact definition of “rhupus” syndrome is still debated. Most of the authors suggest a clinical condition in which in the same patient clinical signs and symptoms of both SLE and RA occur [77], [78]. This hypothesis is supported by the coexistence of specific autoantibodies for SLE (anti-dsDNA and anti-Sm) and RA (anti-citrullinated peptides — ACPA) [78]. By contrast, other authors claim that rhupus syndrome should be regarded as an erosive subset of lupus arthropathy [79].

About 140 patients

Conclusions

By the influence of genetic and environmental factors, it is well known that autoimmune diseases tend to associate with each other in a single patient or in different members of the same family [168], [169], [170], [171]. In some cases these associations can delineate a specific clinical entity, especially when a specific serologic marker can be identified. This is the case of mixed connective tissue disease, ASS, scleromyositis, and LES/SS. These patients share not only a specific

Take-home messages

  • OS satisfies the classification criteria of two or more CTDs in the same patient.

  • OS is a well defined entity with specific clinical-serological characteristics.

  • Treatment of OS is based on corticosteroids and, if necessary, immunosuppressants.

  • In refractory cases biologic agents, i.e. anti-TNFα or anti-CD20 mab, are considered.

  • The use of anti-TNFα agents in some OS could induce disease exacerbations.

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