Leaders Autoantibodies and Overlap Syndromes in Autoimmune
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340 J Clin Pathol 2001;54:340–347 Leaders J Clin Pathol: first published as 10.1136/jcp.54.5.340 on 1 May 2001. Downloaded from Autoantibodies and overlap syndromes in autoimmune rheumatic disease E C Jury, D D’Cruz, W J W Morrow Abstract proteins. This article will consider, primarily, Many patients diagnosed with autoimmune overlap syndromes associated with autoim- rheumatic disease cannot be categorised mune rheumatic disease; specific reference will easily into one of the established clinical be made to autoantibody profiles and ramifica- entities such as systemic lupus erythema- tions for diagnosis and pathogenesis will be dis- tosus, dermatomyositis, or systemic sclero- cussed. It should be noted that overlap between sis. The term “overlap syndrome” has been organ specific autoimmune syndromes, such increasingly used to identify such patients as myasthenia gravis, Hashimoto’s thyroiditis, and is useful in terms of clarifying progno- and insulin dependent diabetes mellitus, is sis and facilitating disease management. frequently seen; however, a detailed discussion This article reviews overlap syndrome in of these conditions is beyond the scope of this autoimmune rheumatic disease, with paper. particular emphasis on the associated sero- Autoimmune rheumatic diseases are classified logical markers. using internationally accepted criteria, which (J Clin Pathol 2001;54:340–347) frequently incorporate the detection of specific Keywords: autoantibodies; overlap syndromes; autoantibodies as unique diagnostic markers. autoimmune rheumatic disease Examples include: antidouble stranded DNA Centre for Rheumatology (anti-dsDNA) and anti-Smith antigen (anti- Research, University The complexity of autoimmune disease is Sm) for establishing a diagnosis of systemic 1 College, London formidable and although the precise role of lupus erythematosus (SLE) ; the detection of W1T 4JF, UK autoantibodies in immunopathological proc- rheumatoid factor in the diagnosis of rheuma- E C Jury 2 esses remains uncertain, there is little doubt toid arthritis (RA) ; anticentromere, anti-DNA http://jcp.bmj.com/ topoisomerase I, and anti-RNA polymerase I Louise Coot Lupus that they contribute to disease advancement. Unit, St Thomas’s The formation of autoantibodies is a normal and III antibodies as markers for the sclero- Hospital, London physiological process: however, excessive pro- derma spectrum of disease; and a group of anti- SE1 7EH, UK duction of such antibodies can be harmful, bodies including antiliver/kidney microsomes D D’Cruz resulting in disease or injury. Autoantibodies (anti-LKM), antismooth muscle antigen (anti- may cause damage by reacting directly against a SMA), and antinuclear (ANA), included in Department of diagnostic criteria for autoimmune hepatitis.3 Immunology, St specific tissue or by the formation and deposi- on September 25, 2021 by guest. Protected copyright. Bartholomew’s and tion of circulating immune complexes in the However, many patients cannot be assigned The Royal London kidney, skin, joint, and nervous system. The to a single disease category. This diYculty has School of Medicine production of autoantibodies might be second- led to the concept of “overlap syndrome”, and Dentistry ary to tissue damage or induced by independent where symptoms from two or more autoim- W J W Morrow pathogenic factors; organ specific and/or non- mune conditions are identified in the same Correspondence to: organ specific autoantigens may be involved. patient. Overlap syndromes are commonly Ms Jury Autoimmune rheumatic disorders are char- associated with autoimmune rheumatic dis- [email protected] acterised by autoantibodies to non-organ spe- ease, where up to 25% of patients with early Accepted for publication cific antigens, specifically, antigens occurring in stage or mild variant disease fall into this 20 September 2000 nucleated cells or among circulating plasma category.45 Overlap syndrome has also been described in patients with autoimmune liver Table 1 Overlap syndromes in autoimmune rheumatic disease and associated autoantibodies78 diseases, including autoimmune hepatitis, pri- mary biliary cirrhosis, and primary sclerosing 6 Overlap syndrome Autoantibody directed to cholangitis (table 1). Mixed connective tissue disease nRNP; hnRNP(A2/RA33 complex); U1 Clinically, it is useful to define overlap RNA syndromes to clarify prognosis and facilitate dis- tRNA synthetase syndrome Jo-1, PL-7, PL-12, OJ, EJ ease management.9 Two approaches can be Polymyositis/pulmonary fibrosis KJ Polymyositis/systemic lupus erythematosus 56 kDa nRNP made when categorising such conditions. The Polymyositis/scleroderma Ku; PM-Scl; U2 RNP; DNA-PK first is by the identification of a pattern of clini- Secondary Sjögren’s syndrome Ro/SSA; La/SSB; Ki/SL cal features, and a good example is the tRNA Rheumatoid arthritis/systemic lupus erythematosus None identified Scleroderma (CREST)/primary biliary cirrhosis Centromere; pyruvate dehydrogenase synthetase syndrome. The second is by the complex initial detection of a unique autoantibody profile Systemic lupus erythematosus/autoimmune hepatitis tRNA combined with specific clinical findings—for hnRNP, heterogeneous nuclear ribonuclear protein; PM-Scl, polymyositis-scleroderma overlap example, mixed connective tissue disease syndrome. (MCTD).10 www.jclinpath.com Autoantibodies and overlap syndromes in autoimmune rheumatic disease 341 The most abundant snRNPs are denoted U1, Autoimmune rheumatic disease U2, U4/U6, and U5 and, together with J Clin Pathol: first published as 10.1136/jcp.54.5.340 on 1 May 2001. Downloaded from Connective tissue diseases (CTDs) are hnRNP, they form a major component of the characterised by considerable clinical diversity spliceosome, where premessenger RNA is and heterogeneity. Characteristic clinical fea- processed into mature mRNA. The snRNP tures and the detection of autoantibodies help spliceosomal complex has several associated to define these disorders and facilitate diagno- common proteins that might also be autoanti- sis and appropriate treatment. The CTD over- genic. Common proteins binding to U1 snRNP lap syndromes are distinguished by the con- particles are represented as U1–70K, U1A, and comitant occurrence of clinical and serological U1C. Antibodies can be directed to several features of the component diseases. Any CTD components of the spliceosome, although with can be a partner in an overlap disorder—for diVerent specificities in diVerent diseases.21 29 example, RA is a common partner to SLE, sys- Antibody specificity is normally determined by 11 12 temic sclerosis, or Sjögren’s syndrome (SS). western blot analysis. Autoantibodies binding In some cases, overlap syndromes have not to spliceosomal snRNPs (U1, U2, U4/U6, and been clearly circumscribed or widely accepted U5 complexes) are termed anti-Sm antibodies and the term “undiVerentiated” or “transi- and are associated with SLE. Antibodies tional” CTD has been used, implying that they recognising the U1 snRNP complex alone are are incompletely developed “classic” CTD, termed anti-nRNP and are considered the rather than distinct entities with overlapping hallmark of MCTD (reviewed by Klein Gun- 4 features. Disease in patients with undiVerenti- neweik and colleagues30). Anti-nRNP antibod- ated CTD might evolve into a more recognis- ies recognise primarily the U1 snRNP specific able syndrome, most commonly SLE, myositis, proteins U1–70K, U1A, and U1C and U1 13–15 or scleroderma, although one report sug- snRNA. There are conflicting reports detailing 16 17 gested that most remain undiVerentiated. the role of anti-nRNP antibodies in predicting Overall, the picture of overlap syndromes with disease severity and progression. On balance, respect to CTD is complex and heterogeneous. evidence suggesting that U1 snRNP antibody Observer bias might play a role in disease classi- titres correlate with clinical events is uncon- fication, so the presence of specific autoantibody vincing.31 Alternatively, antibodies to U1 RNA profiles might be a useful tool in the diagnosis have been shown to be associated with and management of such patients. progressive disease and exacerbation.27 Epitope spreading, whereby an immune response to an Mixed connective tissue disease epitope expands to include associated epitopes The existence of MCTD has been the subject on the same molecule, is implicated in the of much debate10 15 18–20 (reviewed by Smolen immune response to snRNA and the produc- and Steiner21). A detailed discussion is beyond tion of possibly pathogenic antibodies associ- the scope of this review, but suYce to say this ated with disease. Recent reports suggest that syndrome was originally described in 1972 by secondary light chain rearrangements in U1- http://jcp.bmj.com/ Sharp and colleagues.22 The syndrome is a RNA reactive B cells, possibly as a result of combination of features typically found in crossreactivity with viral immunogens, can lead patients with SLE, scleroderma, polymyositis/ to changing specificity and aYnity of anti-RNA dermatomyositis (PM/DM), or RA. The pres- antibodies (epitope spreading).32 It is interest- ence of high titre ANA with speckled pattern ing to note that long term follow up of clinical and antibodies to uridine rich U1 small nuclear and serological findings in patients with ribonucleoprotein (snRNP) diVerentiates this MCTD has demonstrated intramolecular on September 25, 2021 by guest. Protected copyright. MCTD from other CTDs. Three points spreading of autoantibody reactivity against provide a focus for controversy: first, patients