Annals ofthe Rheumatic Diseases 1991; 50: 887-893 887 Ann Rheum Dis: first published as 10.1136/ard.50.Suppl_4.887 on 1 November 1991. Downloaded from Mixed connective tissue disease, overlap syndromes, and eosinophilic fasciitis P J Maddison While the cause of connective tissue diseases prominent, resembling primary Sjogren's syn- (CTDs) remains unknown the classification of drome, in which these features are common. individual patients will continue to depend on This contrasts with secondary Sjogren's syn- identifying certain patterns of clinical and drome accompanying rheumatoid arthritis, in laboratory features. This is the basis of the which they are uncommon. various classification criteria for systemic sclero- Antibodies to PM-Scl (PM-1), a nucleolar sis,'l systemic lupus erythematosus (SLE),2 and antigen,9 and Ku, a DNA binding nuclear other connective tissue diseases. As many as 25% protein complex composed of two polypeptides of patients with CTD, however, present with of 86 and 70 kD,'0 identify patients with overlapping clinical features. The term 'overlap overlap features of polymyositis and systemic syndrome' is applied to what appears to be a sclerosis. Antibodies to histidyl t-RNA synthe- very heterogeneous group of disorders, though tase identify patients with polymyositis who features associated with systemic sclerosis are develop interstitial pulmonary disease. " often a major component. Frequently, patients Possibly, CTDs represent a genetically deter- have a mild CTD characterised by Raynaud's mined host response to a number of environ- phenomenon, oedema of the hands, and, mental triggers. A number of studies, for possibly, acrosclerosis and arthritis, which has example, have shown that the presence of been termed 'undifferentiated CTD'.3 Other certain HLA class II genes is associated with patients present manifestations of more than specific immune responses to autoantigens such one defmiite CTD and commonest among these as Ro and La,l2 13 UIRNP,'3 Ku,'4 and Jo-l .'5 are disorders with features of systemic sclerosis combined with those of SLE4 or polymyositis,5 or both, with features of systemic sclerosis or Mixed connective tissue disease SLE and rheumatoid arthritis,6 7 and features Mixed connective tissue disease (MCTD) was of Sjogren's syndrome in association with any of initially described in 1972 by Sharp and the other CTDs. Overlapping features may coworkers'6 as a unique syndrome with features occur concurrently, but more commonly over of SLE, systemic sclerosis, and myositis asso- time one syndrome takes on the features of ciated with antibodies to a nuclear ribonucleo- http://ard.bmj.com/ another. It is still contentious whether or not protein, UIRNP. Subsequently, the serological overlap syndromes represent the coexistence of specificity was defined to epitopes on the 70 kD separate diseases, the broad clinical expression phosphoprotein uniquely associated with the of one of the rheumatic diseases, or distinct ribonucleoprotein particle containing UIRNA.1'7 clinical entities with distinctive aetiology and The original claims for MCTD have subse- pathogenesis. quently become points of contention. These In some casesoverlap syndromes areassociated include the clinical distinctiveness, based on the on September 27, 2021 by guest. Protected copyright. with a particular serological marker (table 1). presence of a particular group of features- Antibodies to the RNA binding proteins Ro notably, Raynaud's phenomenon, arthralgias (SSA) and La (SSB) are associated with Sjogren's and arthritis, puffy hands, abnormal oesopha- syndrome developing in association with other geal motility, myositis, and lymphadenopathy CTDs, such as systemic sclerosis or SLE. and by the absence of cerebral and renal disease Recent reviews suggest that Sjogren's syndrome and vasculitis, a benign prognosis, responsive- in this context resembles primary Sjogren's ness to corticosteroids, and the presence of high syndrome and differs significantly from secon- titres of anti-U1RNP. dary Sjogren's syndrome accompanying rheu- Since 1972 our concepts of this condition matoid arthritis.8 Severexerophthalmia, xerosto- have evolved and the original claims require mia, and parotid gland enlargement are often considerable modification. Organ involvement is often extensive and there is a tendency to evolve away from a 'mixed' clinical picture so Table I Serological markers of overlap syndromes that many patients eventually develop the Overlap Antibody HLA class II unequivocal picture of a classical CTD, most syndrome specifit antigen association often systemic sclerosis. The problem remains Sjogren's syndrome/systemic Ro DQw5, DQw6 as to whether or not MCTD, being essentially lupus erythematosus or Ro+La DR3 Royal National Hospital systemic sclerosis DQwl/DQw2 serologically defined, warrants the status of an for Rheumatic Diseases Systemic sclerosis/ PM-Scd (PM-I) independent disease. and School of polymyositis Ku DQwl The lack of consensus as to whether MCTD Postgraduate Medicine, Mixed connective tissue U1RNP DQw7, 8, 9 University of Bath, disease is a specific entity is due to a lack of criteria for Bath BAI 1RL Polymyositis/interstitial Jo-i DRw52 its diagnosis. Recently, at a meeting in Japan, P J Maddison pulmonary disease three different sets of criteria were described18 888 Maddison (shown in the appendix) and subsequently by Raynaud's phenomenon, striking acro- Ann Rheum Dis: first published as 10.1136/ard.50.Suppl_4.887 on 1 November 1991. Downloaded from Alarcon-Segovia and Cardiel'9 compared these osteolysis and, sometimes, scieroderma-like criteria in a large group of subjects with skin changes.25 In this disorder specific auto- connective tissue disease. The group included antibodies have not been detected.26 The patients considered to have genuine MCTD, all association with toxic exposure in these cases of ofwhom were positive for anti-U lRNP, together MCTD might be merely coincidental. As three with groups of patients fulfilling classification cases of MCTD have previously been reported criteria for systemic sclerosis, dermatomyositis after breast augmentation surgery,27 however, or polymyositis, primary Sjogren's syndrome, the question is raised whether or not a variety of SLE, and rheumatoid arthritis. Table 2 environmental insults can induce clinical and summarises the results, showing that all three serological features ofMCTD in a patient with a sets of criteria fared similarly in capturing particular genetic background. nearly all the patients with MCTD and distin- There are familial cases of MCTD but, until guishing them from those with other defined recently, no haplotype association has been CTDs. Alarcon-Segovia's criteria are simple described. Black and coworkers showed an compared with the others, comprising five increased instance of HLA-DR4 in patients clinical manifestations in addition to the sero- with MCTD compared with controls28 (table 3). logical status. Thus it is suggested by the The association, however, was only significant authors that MCTD has a group of core in patients with polyarthritis, some of whom manifestations and the occurrence of these early had erosive disease, though there was no asso- in the course of the disease permits diagnosis of ciation with rheumatoid factor. The association, MCTD in the absence of anti-UlRNP, which therefore, is related to a particular pattern of may appear later. disease expression rather than to MCTD per se. The basic premise is that the presence of high On the other hand, there was a significant titres of antibodies to U1RNP modifies the alteration in the Gm allotype frequencies in expression of a CTD in ways that are relevant to patients with MCTD. This Gm association may prognosis and treatment. To avoid a circular be particularly important because Gm associa- argument there is a need to include patients in tions are not well defined for rheumatoid studies with overlap features irrespective of arthritis, SLE, or systemic sclerosis. More serological findings. There are only a few recently, the presence of autoantibodies to reports analysing overlap syndromes defined by UIRNP both in association with MCTD and clinical criteria alone,20 21 and in these, anti- SLE has been strongly linked to the DQ, gene bodies to U1RNP fail to identify a distinctive associated with DQw7, 8, and 9.13 clinical group. Lazaro and Morteo,2' for The prevalence of MCTD is not known example, evaluated the influence ofanti-UlRNP precisely but it is generally considered to be in a group of 27 patients with overlap features more common than systemic sclerosis and and concluded that the range of clinical mani- polymyositis but less common than SLE. There festations was unrelated to the presence or is a marked female preponderance (about absence of these antibodies. Antibodies to 8F: 1M) and apparently no ethnic group is U1RNP have been known to disappear during particularly susceptible. Cases are recognised in http://ard.bmj.com/ the course of the disease,22 however, and children. It has been suggested that MCTD prospective clinical studies are now required. produces more morbidity in children with a The cause of MCTD is unknown. The higher prevalence of features such as significant transient appearance of antibodies to UIRNP myocarditis, glomerulonephritis, thrombocyto- has been reported during treatment with pro- penia, seizures, and aseptic meningitis. These cainamide,23 but drugs have not been associated observations, however, may be the result of a with the clinical syndrome.