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Annals ofthe Rheumatic Diseases 1990; 49: 947-948 947

REVIEW ARTICLE Ann Rheum Dis: first published as 10.1136/ard.49.11.947 on 1 November 1990. Downloaded from

'Overlap' syndromes

Ricard Cervera, Munther A Khamashta, Graham R V Hughes

Many of us at the end of a weekly clinic disease often changes to one of progressive are tempted to reflect that almost all shades of systemic sclerosis. Interestingly, in such connective tissue 'overlap' occur, and that it is patients, it is common to see a gradual reduction perhaps pointless to attempt too precise a of the hyperglobulinaemia and disappearance of definition in individual cases. The introduction the to U-snRNP.' Finally, there have of the concept of overlap syndromes was a been no major advances in identifying the pragmatic way to resolve an imprecise com- aetiopathogenesis of this condition or in promise. It represented an attempt to categorise explaining the apparent association with anti- various groups of disorders having in common bodies to U-snRNP.29 This has led to a pro- some clinical and serological features, but fail- tracted debate about the specificity or otherwise ing to fulfil the established or proposed criteria of mixed connective tissue disease.24 for the classification of a distinct and separate The title subacute cutaneous lupus erythe- entity, such as , progressive matosus has been given to an overlap syndrome systemic sclerosis, systemic lupus erythe- whose main clinical feature is the appearance of matosus, or . Some claim that florid cutaneous lesions, often extremely photo- as many as 25% of patients with connective sensitive, sometimes with a characteristic tissue disease fall into one or other overlap serpiginous border. This disorder may include group. 1-5 other systemic features such as Sjogren's syn- In the past few years there has been limited drome, pericarditis, arthritis, and the occasional success with attempts to describe distinct clinical case of congenital heart block in the offspring entities, generally using serological markers. (neonatal lupus). The serological association These include polemic entities such as mixed is with antibodies to SSA/Ro." 12 Recent connective tissue disease,6'0 subacute cutaneous knowledge of the structures that bear the lupus erythematosus," 12 or the recently SSA/Ro antigens has enabled definition of described 'primary' antiphospholipid syn- biochemical differences among patients with drome, 1--6 among others. these antibodies. The first major antigen com-

Following the observation by Sharp et al6 that ponent of SSA/Ro to be described and cloned http://ard.bmj.com/ an overlap syndrome consisting of Raynaud's was a polypeptide of 6OkD. Immunoblot tech- phenomenon, swollen hands, arthritis, and niques have been used recently to identify two was strongly associated with the other polypeptides as 52 and 48 kD species. presence of antibodies to nuclear ribonucleo- Antibodies against the newly recognised 52 kD protein (RNP), the concept of mixed connective SSA/Ro peptide component have been found to tissue disease has been useful. The serological be predominant in the sera from mothers of

specificity of these antibodies has been defined infants with neonatal lupus, whereas antibodies on September 29, 2021 by guest. Protected copyright. to epitopes on a 68 kD phosphoprotein uniquely against the 60 kD antigens were not related.30 associated with the RNP containing uridylic The term antiphospholipid syndrome has acid-rich small nuclear RNA (U-snRNP). At been recently proposed for a group of patients least 12 U-snRNPs have been identified, which who have antiphospholipid antibodies-for account for about 1% of the total cellular RNA. example, anticardiolipin antibodies or the lupus The Ul to U6-snRNPs, with the exception of anticoagulant, and in whom multiple venous U3-snRNP, are known to play an important and arterial thrombosis, recurrent fetal loss, and part in messenger RNA processing. In addition, thrombocytopenia are common. These patients a number of core DNAs coding for these may also develop other features, including heart antigens have been cloned and some specific valve lesions, livedo reticularis, chorea, and characteristics of the deduced amino acid haemolytic anaemia.31-33 Whereas early studies sequences are known.'7 concentrated on systemic lupus erythematosus As the years go by clinical perception of or 'lupus-like' diseases,32 it is now recognised mixed connective tissue disease has evolved that these manifestations may occur without any considerably. For instance, patients with this other feature of lupus being present, leading to disorder may have many other overlap and the definition of the primary antiphospholipid non-specific features, including pulmonary Lupus Research Unit, syndrome.13-16 Nevertheless, long term follow The Rayne Institute, disease,'2' Sjogren's syndrome,22 and even, up of these patients has shown that some of St Thomas's Hospital, renal23 and cerebral disease.24 Therefore, them develop other connective tissue disease, London SEI 7EH, UK diagnosis of this entity must be based both on such as systemic lupus R Cervera erythematosus.34 On the M A Khamashta clinical and serological criteria. Although some other hand, it is surprising that patients with G R V Hughes attempts at classification have been made,2527 high titres of antiphospholipid antibodies do Correspondence to: no definite agreement has been achieved.28 29 In not necessarily develop any of these clinical Dr Hughes. addition, it has been seen that the pattern of this manifestations. 948 Cervera, Khamashta, Hughes

Among other proposed overlap syndromes, a clinicopathological study of 20 cases. Semin Arthritis Rheum

1980; 10: 25-52. Ann Rheum Dis: first published as 10.1136/ard.49.11.947 on 1 November 1990. Downloaded from subset which seems to have clinical and sero- 8 Bennet R. Mixed connective tissue disease and other overlap logical specificity is the group of patients with syndromes. Ip: Kelley W, Harris E D Jr, Ruddy S H, Sledge G. Textbook ofrheumatology. Philadelphia: Saunders, , pulmonary fibrosis, and antibodies 1985: 1115. 9 Ramos Niembro F, Alarc6n-Segovia D, Hernandez Ordtiz J. against Jo-l (histidyl-tRNA synthetase).35 In Articular manifestations of mixed connective tissue disease. addition, other overlap features are commonly Arthritis Rheun 1979; 22: 43-51. associated, including Raynaud's phenomenon 10 Sharp G, Singsen B. Mixed connective tissue disease. In: McCarthy D, ed. Arthritis andallied conditions. Philadelphia: and Sjogren's syndrome. Lea and Febiger, 1985: 962-70. It was obvious from the beginning that the 11 Sontheimer R D, Thomas J R, Gilliam J N. Subacute cutaneous lupus erythematosus: a cutaneous marker for a occurrence of these overlap entities varied distinct lupus erythematosus subset. Arch Dermatol 1979; considerably from one centre to another. The 115: 1409-15. 12 Herrero C, Bielsa I, Font J, et al. Subacute cutaneous lupus reasons for these discrepancies may be multiple. erythematosus. Clinicopathological findings in 13 cases. J Firstly, the clinical definitions of the major Am Acad Dermatol 1988; 19: 1057-62. 13 Asherson R A. A 'primary' antiphospholipid syndrome? components of these syndromes-Raynaud's J Rheumatol 1988; 15: 1742-6. phenomenon, Sjogren's syndrome, myositis, 14 Mackworth-Young C G, Loizou S, Walport M J. Primary antiphospholipid syndrome: features of patients with raised lung disease, cutaneous rash, or thrombosis-are anticardiolipin antibodies and no other disorder. Ann open to widely differing interpretation as well as Rheum Dis 1989; 48: 362-7. 15 Alarc6n-Segovia D, Sanchez-Guerrero J. Primary anti- to variation within individual patients over phospholipid syndrome. 7 Rheumatol 1989; 16: 482-8. time. Secondly, the proposed serological 16 Asherson R A, Khamashta M A, Ordi-Ros J, et al. The "primary" antiphospholipid syndrome: major clinical and 'markers'-anti-U-snRNP, anti-SSA/Ro, or serological features. Medicine (Baltimore) 1989; 68: 366-74. antiphospholipid antibodies-are not specific 17 Van Venrooij W J, Sillekens P T G. Small nuclear RNA associated proteins: autoantigens in connective tissue for these syndromes and may be present in a diseases. Clin Exp Rheumatol 1989; 7: 635-45. variety of other autoimmune diseases.36 18 Harman C, Wolfe J, Lillard S, Heed C, Cordon R, Sharp G. Pulmonary involvement in mixed connective tissue disease Clearly, the two reasons for attempts at [Abstract]. Arthritis Rheum 1976; 19: 801. subdivision concern treatment and prognosis. 19 Weiner-Kronish J, Solinger A, Warnock M, Churg A, Ordonez N, Golden J. Severe pulmonary involvement in Some therapeutic generalisations are already mixed connective tissue disease. Am Rev Respir Dis 1981; Mixed connective tissue disease in its 124: 499-503. possible. 20 Sullivan W, Hurst D, Harmon C, et al. A prospective florid form is often resistant to treatment evaluation emphasizing pulmonary involvement in patients more so than is 'classical' with connective tissue disease. Medicine (Baltimore) 1984; (frequently systemic 63: 92-107. lupus erythematosus), and the severity of joint 21 Derderian S, Tellis C, Abbrecht P, Welton R C, Rajagopal inflammation may require treatment similar to K R. Pulmonary involvement in mixed connective tissue disease. Chest 1985; 88: 45-8. that used in rheumatoid arthritis. The subset of 22 Alarc6n-Segovia D. Symptomatic Sjogren syndrome in mixed patients with subacute cutaneous lupus erythe- connective tissue disease. J7 Rheumatol 1976; 3: 191-5. 23 Kitridou R, Akmal M, Ehresmann G, Quismorio F, Massry matosus seems to be particularly amenable to S. Nephropathy in mixed connective tissue disease antimalarial treatment.37 Patients with the anti- [Abstract]. Arthritis Rheum 1980; 23: 704. 24 Lazaro M A, Maldonado Cocco J A, Catoggio L J, Babini phospholipid syndrome are more prone to S M, Messina 0 D, Garcia Morteo 0. Clinical and serologic thrombosis than to disease such characteristics of patients with overlap syndrome: Is mixed inflammatory connective tissue disease a distinct clinical entity? Medicine as and treatment is thus geared (Baltimore) 1989; 68: 58-65. 25 G C. criteria for MCTD. towards anticoagulation.38 As to prognosis, only Sharp Diagnostic classification of http://ard.bmj.com/ In: Kasukawa R, Sharp G C, eds. Mixed connective tissue time will tell. Perhaps, some of the overlap diseases and anti-nuclear antibodies. Amsterdam: Elsevier, may be better termed 'transitional' 1987: 23-32. syndromes 26 Alarc6n-Segovia D, Villarreal M. Classification and diagnostic syndromes because they will progress to another criteria for mixed connective tissue diseases. In: Kasukawa connective tissue disease. R, Sharp G C, eds. Mixed connective tissue diseases and anti- nuclear antibodies. Amsterdam: Elsevier, 1987: 33-40. Identification of the antigens at molecular 27 Kasukawa R, Tojo T, Miyawaki S, et al. Preliminary level into the diagnostic criteria for classification of mixed connective provides important insights patho- tissue disease. In: Kasukawa R, Sharp G C, eds. Mtxed

genesis of connective tissue diseases. Although connective tissue diseases and anti-nuclear antibodies. Amster- on September 29, 2021 by guest. Protected copyright. has contributed dam: Elsevier, 1987: 41-7. autoantibody 'fingerprinting' 28 Alarc6n-Segovia D, Cardiel M H. Comparison between 3 much to the definition of disease subsets, the diagnostic criteria for mixed connective tissue disease. run out of steam. Study of 593 patients. J Rheumatol 1989; 16: 328-34. whole movement has slightly 29 Maddison P J. Overlap syndromes, mixed connective tissue Ignorance of prognosis of these overlap syn- disease, and . Current Opinion in dromes dictates that precise clinical descriptions 1989; 1: 523-8. 30 Buyon J P, Ben-Chetrit E, Karp S, et al. Acquired congenital are still central to definition. heart block. Pattern of maternal response to biochemically defined antigens of the SSA/Ro-SSB/La system in neonatal lupus. J Clin Invest 1989; 84: 627-34. 31 Asherson R A, Harris E N. Anticardiolipin antibodies. Clinical associations. Postgrad MedJ7 1986; 62: 1081-7. I Hughes G R V. Overlap syndromes. In: Jayson M I V, Black 32 Boey M L, Colaio C B, Gharavi A E, Elkon K B, Loizou S, C M, eds. Systemic sclerosis: scieroderma. London: Wiley, Hughes G R V. Thrombosis in systemic lupus erythe- 1988: 331-40. matosus: striking association with the presence of circulat- 2 Tuffanelli D L, Winkelmann R K. Systemic . A ing lupus anticoagulant. Br MedJ 1983; 287: 1021-3. clinical study of 727 cases. Arch Dermatol 1%1; 84: 359-71. 33 Cervera R, Font J, L6pez-Soto A, et al. Isotype distribution 3 Dubois E L, Chandor S, Friou G J, Buschel M. Progressive of anticardiolipin antibodies in systemic lupus erythe- systemic sclerosis (PSS) and localized scleroderma matosus: prospective analysis of a series of 100 patients. (morphea) with positive LE cell test and unusual systemic Ann Rheum Dis 1990; 49: 109-13. manifestations compatible with systemic lupus erythe- 34 Baguley E, Asherson R A, Pal C, Harris E N, Khamashta M, matosus (SLE). Medicine (Baltimore) 1971; 50: 199-222. Hughes G R V. The antiphospholipid syndrome: treatment 4 Keil H. Dermatomyositis and systemic lupus erythematosus. and five year follow-up [Abstract]. BrJ Rheumatol 1989; 28 Arch Intern Med 1969; 60: 109-39. (suppl 2): 106. 5 Dubois E L. The relationship between systemic lupus 35 Bernstein R M, Morgan S J, Chapman J, et al. Anti-Jo-I erythematosus, progressive systemic sclerosis and mixed antibody: a marker for myositis with interstitial lung connective tissue disease. In: Dubois E L, ed. Systemic disease. Br Med J 1984; 289: 151-2. lupus erythematosus. Los Angeles: USC Press 1974: 477. 36 Bernstein R M. Humoral in systemic rheumatic 6 Sharp G E, Irving W, Tan E, Gould G, Holman H. Mixed disease. J R Coll Physicians Lond 1990; 24: 18-25. connective tissue disease: An apparently distinct rheumatic 37 Lanham J, Hughes G R V. Antimalarial therapy in SLE. Clin disease syndrome associated with a specific antibody to an Rhewn Dis 1982; 8: 279-98. extractable nuclear antigen (ENA). Am J Med 1972; 52: 38 Hughes G R V, Khamashta M A. Anticardiolipin antibody. A 148-59. cause of a tendency to thrombosis. Br Med J 1989; 299: 7 Bennet R, O'Connell D. Mixed connective tissue disease. A 1414-5.