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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

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 , in laboratory features. This is the basis of the which they are uncommon. various classification criteria for systemic sclero- to PM-Scl (PM-1), a nucleolar sis,'l systemic 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 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 ,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 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, (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 CTDs, such as systemic sclerosis or SLE. and by the absence of cerebral and renal disease Recent reviews suggest that Sjogren's syndrome and , a benign prognosis, responsive- in this context resembles primary Sjogren's ness to , 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 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, 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 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. Interestingly, Khan selection bias. on September 27, 2021 by guest. Protected copyright. et al reported four patients with MCTD and The initial presentation is rarely distinctive antibodies to UlRNP who were exposed during and often comprises Raynaud's phenomenon, the course oftheir occupation to vinyl chloride.24 swollen puffy hands, polyarthritis, and rash. As The clinical picture in these cases contrasts with the disease evolves, overlapping features tend to 'vinyl chloride disease', which is characterised

Table 3 Prevalence of DR4 and major Gm phenotypes in patients with mixed connective tissue disease (MCTD) and Table 2 Concordance of three sets of critria with clinical normal controls. Results are shown as the percentage of diagnosis of mixed connective tissue disease (MCTD) in 593 subjects patients with connective tissue disease. (After Alarcon Segovia and Cardiel, 1989) MCTD Controls x2 (n=31) (n=200) Behaviour (n) Criteria % Concordance with clinical diagnosis DR4 48 32 with arthritis 62 4.93 Alarcon-Segovia Sharp Kasukawa Gm phenotypes* and Cardiel et al Gm 1-3 645 31 11-7 Gm 2-3 13 15 Confirming MCTD (80) 100 lOOt % Gm 3 19-4 43 5-3 Ruling out MCTD in: Gm 1 3 6 SLE* (200) 99 87-5 100 Gm 2 0 5 (80) 100 55 100 RA* (100) 100 100 100 *Gm 1-3-Glm (1), Glm (17), Glm (21), Glm (3), G3m (5), DM/PM* (53) 100 84 100 G3m (11) Sjogren's (80) 99 96 99 Gm 2-3=Glm (1), Glm (2), Glm (17), Glm (21), Glm (3), G3m (5), G3m (11) *SLE=systemic lupus erythematosus: RA=rheumatoid arth- Gm 3 =Glm (3), G3m (5), G3m (11) ritis; DM/PM=dermatomyositis/polymyositis Gm 1 =Glm (1), Glm (17), Glm (21) t57-5% as definite, 42-5% as probable. Gm 2 =GIm (1), Glm (2), Glm (17), Glm (21) Mixed connective tissue disease, overlap syndromes, and eosinophilicfasciitis 889

occur sequentially. A broad spectrum of mani- logically and can be extensive, mainly affecting Ann Rheum Dis: first published as 10.1136/ard.50.Suppl_4.887 on 1 November 1991. Downloaded from festations is seen (table 4). Features reported to the interphalangeal and first carpometacarpal be particularly characteristic of MCTD, occurr- joints (fig 1). In MCTD an association has been ing more commonly there than in other CTDs, noted between arthritis and the presence of include an erosive arthritis, multiple subcut- HLA-DR4.26 Rheumatoid factor is detected in aneous nodules in the peritendinous regions of about 50% of cases, and 40% have small, often the forearms and hands, juxta-articular calcino- multiple, subcutaneous nodules over the flexor sis, and pulmonary hypertension. tendons of the forearms, extensor tendons of the Polyarthritis is a prominent feature and is hands close to the metacarpophalangeal and somewhat more severe than in typical SLE. proximal interphalangeal joints, extensor There is a tendency to develop deformities ofthe tendons on the dorsum of the foot, and over the hands and feet as a result of periarticular Achilles tendon. Histologically they show non- involvement leading to ligamentous and capsular specific and not the typical laxity.29 Sometimes erosions are seen radio- morphology ofrheumatoid nodules.2' The most common neurological complication Table 4 Cumulative clinical manifestations in mixed is trigeminal neuropathy. Interestingly, this is connective tissue disease also a neurological manifestation of systemic Clinical manifestation Prevalence (%) sclerosis but is uncommon in more typical cases of SLE.30 Vascular headaches, often with fea- Skin and mucous membranes Swollen hands 60 tures of migraine are common, but other Rash 50 neurological complications are rarely seen. Mucosal ulceration 45 Sclerodactyly 40 Similarly, clinically significant glomeruloneph- Gottron's papules 10 ritis is uncommon, though cases of mem- Heliotrope Rare branous nephropathy have been seen.3' Musculoskeletal Abnormal lung function tests, especially the Arthritis 80 70 single breath diffusing capacity, are abnormal in Nodules 40 most patients, but only a minority are sympto- Jaccoud's arthropathy 30 Myositis 25 matic.32 Pulmonary hypertension, however, is Erosions 20 an increasingly recognised complication. Some- Gastrointestinal times this is secondary to interstitial pulmonary Reduced oesophageal motility 75 fibrosis but more commonly is a primary event Malabsorption Rare Pseudodiverticula Rare associated with intimal proliferation of pul- monary arterioles. Those affected often have a Cardiovascular Raynaud's phenomenon 95 poor prognosis and right ventricular failure can Pericarditis 40 progress rapidly.33 Pulmonary hypertension 40 Myocarditis Rare Involvement of the pulmonary arterioles is part of a generalised vasculopathy which charac- Respiratory Reduced CO transfer 75 terises MCTD and dominates the clinical picture Pleurisy 50 in a minority of patients. There are a few

Neuropsychiatric descriptions, forexample, ofintimalproliferation http://ard.bmj.com/ Trigeminal neuropathy 15 ofrenal vessels, resembling that seen in systemic Aseptic meningitis 5 sclerosis, resulting in hypertensive crisis and Renal renal failure.34 At least 50% have nailfold Glomerulonephritis 10 Hypertensive crisis Uncommon capillary changes similar to those found in systemic sclerosis.35 Angiography has been used to show organic obstruction of digital vessels in

a large proportion of patients with MCTD, on September 27, 2021 by guest. Protected copyright. emphasising the propensity of these patients to develop vasculopathy of both small and medium sized vessels.36 Proteins complexed in small nuclear ribo- nucleoprotein particles (snRNPs) to uridylic acid (U) enriched snRNAs are important targets for in CTDs. As summarised in table 5 these snRNPs have at least seven core

Table S Association ofproteins with snRNAs in the major snRNPs Protein Mol wt snRNA (kD) Ul U2 U4,5, 6 70 kD 70 + A 32 + A' 31 + B' 27 + + + B" 26 + B 25 + + + C 22 + D 16 + + + D' 15 + + + E 12 + + + Figure I Hand radiographs ofa patient with mixed connective tissue disease showing erosive arthropathy, particularly affecting the proximal interphalangeal andfirst F 11 + + + carpometacarpalilints. G 9 + + + 890 Maddison

proteins in common and a varying number of of systemic sclerosis as after one or two years a Ann Rheum Dis: first published as 10.1136/ard.50.Suppl_4.887 on 1 November 1991. Downloaded from particle specific proteins. Antibodies to U1RNP large proportion of patients develop chronic recognise three polypeptides, termed 70 kD, A, fibrotic and atrophic cutaneous features and and C, found uniquely in association with some develop systemic manifestations of syste- U1RNA (reviewed in ref 37). The great mic sclerosis. There are significant differences majority of serum samples containing anti- that seem to set eosinophilic fasciitis apart from U1RNP react with 70 kD and A with fewer systemic sclerosis, however. These include the reacting with the C polypeptide. About 60% of relative absence of Raynaud's phenomenon, serum samples react with BB'. cDNA clones normal nailfold capillaries, sparing of the coding for these proteins have been cloned, and epidermis and dermis, infrequent visceral assays based on recombinant antigens have been involvement, absence of the serological features developed by some laboratories to identify anti- which characterise systemic sclerosis, and the bodies to UIRNP of particular specificity.38 development of haematological complications, Another method for doing this, which is such as aplastic anaemia and thrombocytopenia, currently more accessible, is the Western tech- which are extremely rare in typical systemic nique of immunoblotting. It has been suggested sclerosis.42 that the reaction of antibodies with the 70 kD The cause is unknown. Multiple cases within polypeptide of UIRNP is an important sero- a family with sharing of HLA genes has been logical marker for MCTD, whereas antibodies reported, suggesting that genetic factors may be to UIRNP in MCTD associated with SLE are involved.43 An interesting feature is the associa- directed to epitopes on other polypeptides, tion of many cases with strenuous exertion, particularly BB'.17 28 This, however has not especially in men. There has been speculation been our experience, and during the course of a that there is a reaction to 10 year prospective clinical study of anti- muscle tissuefollowingexerciseinduceddamage, UIRNP positive patients we found anti-70 kD but there may be multiple aetiological triggers. with equal prevalence in patients satisfying the A temporal association has been reported with criteria for MCTD and SLE.39 Long term cancer,44 and the administration of drugs such follow up of large numbers of patients is as those used in antituberculous treatment45 and required to resolve this. phenytoin.' Although exposure to toxic agents In most patients the antibody profile to has been suggested in the pathogenesis of UIRNP is detected at the initial presentation eosinophilic fasciitis, there is no evidence for with clinical disease and remains constant during this in most cases. Recently, there have been the course. Occasionally, the antibody profile increasing reports, particularly from the USA, evolves after the disease has presented or, of L-tryptophan induced 'eosinophilia- alternatively, the antibodies subsequently syndrome', some cases ofwhich closely resemble disappear.22 Antibody titres sometimes fluctuate eosinophilic fasciitis.47 48 Consumption of L- but do not accurately reflect clinical disease tryptophan has been implicated, which is sold activity. 40 over the counter for a variety ofneuropsychiatric Antibodies to single stranded DNA, histones, disorders, insomnia, and various musculo-

and cardiolipin occur with a prevalence seen in skeletal complaints. Features of the syndrome http://ard.bmj.com/ SLE. Antibodies to double stranded DNA are include marked peripheral eosinophilia, intense uncommon, however, as are antibodies to other myalgias, and sensory symptoms, which can ribonucleoprotein antigens, such as Sm, Ro, progress to a severe neuromuscular disorder and La. with axonal degeneration and , con- Mixed connective tissue disease in many stitutional symptoms with and pulmonary patients has a benign course, but a follow up by manifestations, resembling Loffler's syndrome.

Nimelstein et a134 of the original 25 patients About one third of patients develop oedema and on September 27, 2021 by guest. Protected copyright. described by Sharp in 1972 showed that the cutaneous induration, mainly affecting the prognosis is not invariably favourable. Although extremities, similar to eosinophilic fasciitis.49 clinically significant glomerulonephritis and Interestingly, abnormal tryptophan metabolism neuropsychiatric disease is uncommon, some has been postulated in both idiopathic sclero- patients develop life threatening complications, derma and eosinophilic fasciitis.5' Raised basal such as pulmonary hypertension. urine and plasma concentrations of kynurenine have been reported as well as higher concentra- tions after L-tryptophan loading. The possibility Eosinophilic fasciitis of a toxic contant of L-tryptophan in cases Eosinophilic fasciitis is generally recognised by of eosinophilia-myalgia syndrome has not been the often rapid appearance of tender swelling of excluded, however. the arms and legs that evolves over days to In contrast with systemic sclerosis, the female weeks into brawny induration, which may to male ratio in eosinophilic fasciitis is about closely resemble systemic sclerosis. This is equal. In a recent review of 52 patients seen at associated with blood eosinophilia and a charac- the Mayo Clinic5' the mean age of onset was 47 teristic histological picture of inflammation and years (range 11-72) and in 24 (46%) it was sclerosis primarily affecting the deep fascia and related to strenuous exertion. A case has been subcutis. reported to occur during pregnancy.52 Cuta- The first published report was by Shulman in neous manifestations are the presenting feature 1975.41 Since then more than 200 cases have in most cases and evolve through three stages: been reported and the full extent of the clinical pitting oedema, which is frequently present at spectrum is becoming known. Some consider onset, peau d'orange or dimpling, and indura- eosinophilic fasciitis to be part of the spectrum tion. These stages are often present Mixed connective tissue disease, overlap syndromes, and eosinophilicfasciitis 891

simultaneously in different areas of the body Associated haematological disease is Ann Rheum Dis: first published as 10.1136/ard.50.Suppl_4.887 on 1 November 1991. Downloaded from and virtually any part of the body can be commonly reported. This includes aplastic involved, but the face is not usually affected. anaemia, attributed in some cases to a serum The arms and legs are most commonly affected inhibitor of erythroid stem cells, and thrombo- (fig 2) and, in contrast with previously held cytopenia associated in some cases with anti- views, simultaneous involvement of hands and bodies to platelets.55 Malignant transformation feet is not uncommon. Not previously empha- is also seen.56 sised is the fact that localised morphoea may Blood eosinophilia, often impressive, is the occur. Joint contractures, particularly of the most striking laboratory abnormality. Eosino- elbows, ankles, and knees, are common, result- philia greater than 7% of the differential count ing from induration and sclerosis of subcuta- occurs in over 60% of cases. Peripheral eosino- neous tissue. Carpal tunnel syndrome is philia can be transient, however, even in the commonly described and occurs in about 25% absence of treatment, and the of patients, sometimes preceding the skin diagnosis of eosinophilic fasciitis should not be manifestations. dismissed because of a normal laboratory find- Systemic involvement is more common than ing. Similarly, tissue eosinophilia seen on histo- previously thought. There have been isolated logical examination of the fascia correlates with cases of oesophageal, pulmonary, or cardiac the presence or absence of a peripheral eosino- involvement, but in contrast with systemic philia. Antinuclear antibodies, which charac- sclerosis there is relative sparing of the viscera. terise systemic sclerosis, are not found in On the other hand, synovitis is common and may eosinophilic fasciitis. be the presenting feature. Sometimes there is a A deep biopsy, which must include tissue symmetrical polyarthritis which resembles from the epidermis to including rheumatoid arthritis, and joint erosions can the deep fascia, confirms the diagnosis (fig 3). occur.53 When has been examined Changes range from inflammation with minimal it has been found to be inflammatory with a connective tissue change or connective tissue mononuclear cell infiltrate consisting mainly of alteration to severe sclerosis. The deep fascia lymphocytes, most ofwhich carry the phenotype and septa of the subdermal fat are most exten- ofactivated suppressor/cytotoxic T cells.54 sively affected, whereas the epidermis is normal A low grade myositis is commonplace. or only slightly atrophic. Some studies emphasise Lakhampal et al reported abnormal electromyo- that there is overlap of histological features with grams in 11 of 15 patients tested.5' Although systemic sclerosis.57 Tissue eosinophilia, for only one had a raised serum example, is also a feature of about 20% of level, four had low grade myositis on biopsy. patients with systemic sclerosis. Initialreports suggest thateosinophilic fasciitis is a condition responsive to corticosteroids with a benign course. This, however, is not borne out in all cases described, and effects of therapeutic intervention must be judged against http://ard.bmj.com/

Jrt &. on September 27, 2021 by guest. Protected copyright.

Figure 3 Histologicalfeatures ofeosinophilicfasciitis, Figre 2 Clinical involvement ofthe legs in eosinophilic including eosinophilic infiltration andfibrosis ofthe deep fasciitis showing tense induration ofthe skin. fascia. 892 Maddison Ann Rheum Dis: first published as 10.1136/ard.50.Suppl_4.887 on 1 November 1991. Downloaded from the background of spontaneous resolution, 1 Subcommittee for scleroderma criteria of the American Association diagnostic and therapeutic which occurs within three to five years of onset criteria committee. Preliminary criteria for the classifi- in a large proportion ofcases. Relapses, although cation of systemic sclerosis (scleroderma). Arthritis Rheum 1980; 23: 581-90. unusual, do occur. A clinical response to high 2 Tan E M, Cohen A S, Fries J F, et al. The 1982 revised criteria dose prednisolone is expected in about 70% for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271-7. (remission in 15%, partial improvement in the 3 Le Roy E C, Maricq H, Kahaleh M. Undifferentiated con- rest) irrespective of when in the course the drug nective tissue syndrome. Arthritis Rheum 1980; 23: 341-3. 4 Dubois E L, Condon S, Friou G J, Buschel M. Progressive is given. The erythrocyte sedimentation rate systemic sclerosis (PSS) and localized scleroderma and eosinophilia nearly always respond, but in (morphea) with positive LE cell test and unusual systemic manifestations compatible with systemic lupus erythemato- some cases the disease progresses despite normal sus (SLE). Medicine (Baltimore) 1971; 50: 199-207. laboratory values. Various other agents have 5 Clark J A, Winkelmann R K, Ward E. Serologic alterations in scleroderma and sclerodermatomyositis. Mayo Clin Proc been used, and reports suggest that a response 1971;46: 104-7. to hydroxychloroquine is more consistently seen 6 Tuffanelli D L, Winkelmann R K. . A clinical study of 727 cases. Arch Dermatol 1961; 84: than to colchicine or penicillamine. One patient 359-71. with carcinoma of the breast showed marked 7 Kantor G L, Bickel J B, Barnett E V. Coexistence of systemic lupus erythematosus and rheumatoid arthritis. Report of a improvement after mastectomy.5' case and review of the literature with clinical, pathologic and serologic observations. AmJ Med 1969; 47: 443-54. 8 Droxos A A, Andonopoulos A P, Costopoulos J S, Stavro- for MCTD* poulos E D, Papademetriou C S, Moutsopoulos H M. Appendix: Proposed criteria Siogren's syndrome in progressive systemic sclerosis. J Rheumatol 1988; 15: 965-9. 9 Reichlin M, Maddison P J, Targoff I, et al. Antibodies to a Sharp et al'9 nuclear/nucleolar antigen in patients with polymyositis Major criteria overlap syndromes. J Clin Immunol 1984; 4: 40-4. 1 Myositis, severe 10 Mimori T, Akizuki M, Yamagata H, Inada S, Yoshida S, 2 Pulmonary disease Homma M. Characterization of a high molecular weight acidic nuclear protein recognized by autoantibodies in the (a) CO diffusing capacity <70% normal lung sera from patients with polymyositis-scleroderma overlap. or (b) Pulmonary hypertension J Clin Invest 1981; 68: 611-7. or (c) Proliferative vascular lesions on lung biopsy 11 Wasicek C A, Reichlin M, Montes M, Raglan G. Polymyositis 3 or and interstitial lung disease in a patient with anti Jo-I Raynaud's phenomenon oesophageal hypomotility prototype. AmJ Med 1984; 76: 538-44. 4 Swollen hands or sclerodactyly 12 Harley J B, Sestak A L, Willis L G, Fu S M, Hanten J A, 5 Highest noted anti-extractable nuclear antigen titre Reichlin M. A model for disease heterogeneity in systemic l1/10 000 and anti-UIRNP positive and anti-Sm lupus erythematosus. Arthritis Rheum 1989; 32: 826-35. 13 Stephens A F, McHugh N J, Maddison P J, Isenberg D A, negative Welsh K I, Panayi G S. HLA class II restriction of auto- Definite diagnosis=4 major criteria. antibody production in patients with systemic lupus ery- thematosus. Immunogenetics (in press). et 14 Yaneva M, Arnett F C. Antibodies against Ku protein in sera Alarcon-Segovia al'9 from patients with . Clin Exp Immunol 1 Serological 1989; 76:366-72. Positive anti-RNP at a haemagglutination titre of 15 Arnett F C, Goldstein R, Duvic M, Reveille J D. Major 1/1600 or higher histocompatibility complex genes in systemic lupus ery- 2 Clinical (at least threet) thematosus, Sjogren's syndrome and polymyositis. Am J Med 1988;85(suppl 6A): 38-41. Oedema of hands 16 Sharp G C, Irving W, Tan E, Gould G, Holman H. Mixed Synovitis connective tissue disease: an apparently distinct rheumatic disease syndrome associated with a specific antibody to an Myositis (proved by laboratory findings or biopsy) extractable nuclear antigen (ENA). Am J Med 1972; 52: Raynaud's phenomenon (two or three colour phase) 148-59. Acrosclerosis (with or without proximal scleroderma) 17 Habets W J, de Rooij D J, Salden M H, Van Venrooij W R. http://ard.bmj.com/ association of oedema of the hands, Raynaud's Antibodies against distinct nuclear matrix problems are tThe characteristic for mixed connective tissue disease. Clin Exp phenomenon, and acrosclerosis requires the addition of Immunol 1983; 54: 267-76. at least one of the other two criteria. 18 Sharp G C. Diagnostic criteria for classification of MCTD. In: Kasukawa R, Sharp G C, eds. Mixed connective tissue diseases and anti-nuclear antibodies. Amsterdam: Elsevier, Kasukawa et al'9 1987: 23-32. I Common symptoms 19 Alarcon-Segovia D, Cardiel M M. Comparison between 3 1 Raynaud's phenomenon diagnostic criteria for mixed connective tissue disease. Study 16: 328-34. 2 Swollen fingers or hands of 593 patients.J Rheumatol 1989; on September 27, 2021 by guest. Protected copyright. 20 Ginsburg W, Conn D, Bunch M W, McDuffie F. Comparison II Anti-nRNP antibody of clinical and serologic markers in systemic lupus erythe- III Mixed findings matosus and : a review of 247 patients. (A) SLE-like findings J Rheumatol 1983; 10: 235-41. 21 Lazaro M A, Morteo 0 G. Clinical and serologic characteris- 1 Polyarthritis tics of patients with overlap syndrome: is mixed connective 2 Lymphadenopathy tissue disease a distinct entity? Medicine (Baltimore) 1989; 3 Facial erythema 68:281-9. 4 Pericarditis or pleuritis 22 Petterson I, Wang G, Smith E, et al. Analysis of sera of patients with mixed connective tissue disease and systemic 5 Leucocytopenia (<4x 109 cells/l) or lupus erythematosus. A cross sectional longitudinal study. thrombocytopenia (<100x 109 platelets/I) Arthritis Rheum 1986; 29: 986-96. (B) Progressive systemic sclerosis-like findings 23 Winfield J B, Koffler D, Kunkel H G. Development of anti- bodies to ribonucleoproteins following short term therapy 1 Sclerodactyly with procainamide. 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