Review
A REVIEW OF MIXED CONNECTIVE TISSUE DISEASE ANDREW CHUBICK, M.D. AND JAMES N. GILLIAM, M.D.
In 1972 Sharp and co-workers described a new and apparently distinct clinical syndrome sharing features of systemic lupus erythematosus (SLE), progressive systemic sclerosis and polymyositis.' A common finding in these patients was the presence of high concentrations of serum anti body which reacted with saline-extractable nuclear antigens? The overlap of clinical features of various connective tissue diseases suggested the name mixed connective tissue disease (MCTD) for this ~yndrome.~ It i s our purpose in this review to define and compare the major antigen-antibody systems found in patients with connective tissue diseases, to describe the clinical and serologic manifestations of MCTD and to show how serologic studies may identify subgroups of connective tissue disease patients with common clinical features. Antigen-Antibody Systems
The discovery of the LE cell phenomenon4 and the application of the indirect immunofluorescent technique for the study of antinuclear antibodies5 have led to an increased This study was supported in part by USPHS research grant # A M 1 91 01, USPHS program project grant #AM09989 and USPHS national research service award training grant #AM07055. Address for reprints: James N. Cilliam, M.D., Department of internal Medicine, The University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75235.
From the Department of lnternal Medicine, Divisions of Rheurnatology and Dermatology, The University of Texas Southwestern Medical School, Dallas. Texas
interest in the role of antinuclear antibodies in the pathogenesis of connective tissue diseases. Table 1 shows the antigenic specificity of the common antibodies present in SLE and mixed connective tissue disease. Although antibodies directed against nonnuclear antigens, such as cytoplasmic antigens,6-'o ribonucleic acids," and synthetic polynucle~tides,'~-'~ have been described the antibodies which have been most thoroughly studied are those directed against nuclear antigens. Fluorescent Antinuclear Antibody Test
The fluorescent antinuclear antibody test (FANA) has become the most widely used diagnostic procedure in the evaluation of suspected cases of connective tissue disease. The pattern of nuclear fluorescence, as well as the dilution of a serum at which fluorescence i s lost, may provide important diagnostic and prognostic information. Table 2 presents 6 common antinuclear antibody patterns seen in the connective tissue diseases. The terminology used is modified from Burnham and Bank.I5 The particulate pattern (Fig. 1A) is the most common pattern. It has been referred to as
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Fig. 1. Fluorescent ANA patterns. A, Top left, particulate; B, Top right, homogenous; C, Bottom left, peripheral; D, Bottom right, nucleolar.
speckled16or thread^.'^,'^ This pattern is nonspecific, having been associated with several connective tissue diseases, as well as malignancies.'s Antibodies producing the particulate pattern frequently have specificities for saline-extractable nuclear antigens.1,1s--20 When antibodies producing the particulate pattern are present in high titer, a significant incidence of mixed connective tissue disease is seen.'s3 Although the particulate pattern frequently is not observed in undiluted serum, it becomes evident on dilution. This is due to the presence of nuclear antibodies of other specificities which interfere with the expression of particulate nuclear staining at the lower dilutions.18*20 The homogenous pattern16 (Fig. 1B) has also been referred to as diffuse2' or solid. It i s associated with the presence of serum antibodies directed against deoxyribonucleo-
protein (DNP).'6-18,20-22 This pattern is also common and nonspecific.'s In patients with active SLE, the homogenous pattern is usually detected in high titers, and in remission, a marked fall in titer is often o b s e r ~ e d . ' ~ , ~ ~ , ~ The peripheral pattern (Fig. lC), also referred to as shaggy, rim or membranous, i s the most specific pattern for SLE. It rarely occurs. in other connective tissue diseases or druginduced lupus syndromes.'s,21,22Antibodies producing this pattern of immunofluorescence are directed against DNA or the D N A moiety of the DNA-Histone complex.18*21,22,2s The peripheral pattern i s more common in SLE patients who are severely i1122,26 and frequently disappears or changes
Table 1. Antigenic Specificity of Antibodies in Connective Tissue Diseases Cell surface antigens Lymphocyte Red cell Platelet Cytoplasmic antigens Ribosomes Soluble cytoplasmic antigen (Ro) Cytoplasmic RNA protein (La) Single stranded RNA Nuclear antigens DNA: Double stranded (native) and single stranded DNA histone Extractable nuclear antigens Ribonucleoprotein (RNP) Saline-soluble glycoprotein (Srn) Polymyositis associated antigen (Prn) Nucleolar Miscellaneous Clotting factors Lipoproteins Synthetic polynucleotides Viral antigens
Fig. 2. Particulate epidermal nuclear staining on direct immunofluorescence of clinically normal skin from a patient with MCTD.
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Pattern Particulate Homogenous Peripheral Speckled Nucleolar Leukocyte Specific
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Fluorescent Antinuclear Antibody Patterns
Nucleolar RNA
Associated cI inica I disease Connective tissue disease' malignancy Connective tissue d iseaset malignancy Systemic lupus erythematosus Scleroderma, Raynaud phenomenon Scleroderma, Raynaud phenomenon
?
Rheumatoid arthritis*
Previous nomenclature Speckled, thready fibrillar, reticular Diffuse, solid
Associated antigens Extractable nuclear antigens, others Deoxyribonucleoprotein
Shaggy, rim membranous True speckled, pepper dots Large discrete speckles
Native DNA, DNA-histone ?
* W h e n present in high titer, MCTD common. t When present in high titer, SLE common. Seen predominantly in RA patients with Felty's syndrome.
*
trations of antibodies to native DNA occur in to homogenous or particulate when patients' conditions go into r e r n i s s i ~ n . The ~ ~ diag~ ~ ~ , ~ rheumatic ~ diseases other than SLE,34,35 the nosis of lupus nephritis must be considered in presence of significant amounts of anti-native DNA antibodies remains the most important untreated patients with a peripheral pattern." serologic marker for SLE. The presence of the The speckled or true speckled27 pattern, DNA:anti-DNA system in SLE patients corredescribed by Burnham as "multiple, evenly lates with disease activity3sZ3and occasiond istr ibuted ,s mal I round 'pepper dots,' " is seen ally antedates the appearance of active cliniin scleroderma and the Raynaud phenomecal di~ease.37,~~ In addition, there is solid evinon, but not in SLE.15 The nucleolar pattern dence that DNA:anti-DNA complexes par(Fig. 1 D), indicative of antibodies to nucleolar RNA, i s seen predominately in scleroderma ticipate i n the immunologically mediated renal disease of SLE.37-40 and the Raynaud phenomenon and o n l y The last major nuclear antigen to be conrarely in other connective tissue diseases.15 sidered i s the extractable nuclear antigen. The leukocyte-specific pattern i s seen preOriginally described by Holman et a1.141*42 dominantly in rheumatoid arthritis and Felty's extractable nuclear antigen consists of several syndromez8 and occasionally in other conantigenic constituents, 2 of which ha+e been nective tissue d i ~ 0 r d e r s . l ~ partially characterized. The Sm antigen In addition to the FANA test, other serologic (named for the patient whose serum possesassays have allowed the quantitation of autoantibodies. directed against specific nuclear sed specific antibody to this antigen) is a antigens. Of these autoantibodies, those disaline-soluble non-nucleic acid, non-histone acidic glycoprotein, which i s not susceptible rected against DNA and saline-extractable to ribonuclease digestion. Anti-Sm antibodies nuclear antigens have proven useful in diaghave been found almost exclusively i n nosis of SLE and MCTD. Antibodies to purified DNA were described in 1957.29-3zAntibodies SLE.1e,35 The ribonucleoprotein antigen (RNP, against denatured or single-stranded DNA are M o ~is~composed ) of a ribonucleic acid and a found in most SLE patients (92%) but have nucleoprotein. Ribonuclease will destroy its antigenicity. RNP antibodies are found in viralso been described in drug-induced SLE tually all patients with mixed connective tis(57% 1, nonrheumatic diseases (8-58%) and normal controls (4%).33Although recent sue disease.' Two methods, hemagglutination studies have suggested that low concenof erythrocytes coated with extractable nu-
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clear antigens' and double diffusion in agarM have been used to identify sera withantibody to extractable nuclear antigen. Clinical Manifestations of Mixed Connective Tissue Disease The incidence of MCTD i s unknown. In the original description of this syndrome,' Sharp identified 25 such patients in a group of 375 SLE and 50 scleroderma patients. Farber and found 1 3 patients w i t h RNP antibodies in 155 patients studied, 8 of whom had clinical manifestations of 2 or more connective tissue disorders. There is a female predominance w i t h a mean age of 37 although a similar illness has been described in ~ h i l d r e n . 4The ~ , ~most ~ common symptom is joint pain, manifested as either polyarthralgias or a symmetrical polyarthritis. Occasional patients have been described w i t h rheumatoid-like arthritis, and subcutaneous nodules have been described."n This pattern of arthritis, associated with the high incidence of fatigue, morning stiffness and rheumatoid factor positivity?' may suggest an initial diagnosis of rheumatoid arthritis. In a retrospective study of 15 MCTD 10 patients began with a syndrome resembling classic, definite or probable rheumatoid arthritis and had rheumatoid factor. In the majority, a second and even a third c Ii n ical syndrome was suspected before MCTD was diagnosed. The next most common symptoms, the Raynaud phenomenon and swollen hands, are the most suggestiveclinical featuresofthis disease. A significant difference in the incidence of these 2 features has been noted in MCTD patients with RNP antibodies when compared to SLE patients with Sm and/or DNA a n t i b ~ d i e s . ~ Involvement ~,~~ of the fingers leads to a swollen or "sausage" appearance. Skin biopsy shows considerable intradermal edema, similar to early scleroderma The Raynaud phenomenon may be the only evidence of disease for months to years before other manifestations of MCTD
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appear. Muscle tenderness and proximal muscle weakness occur in two-thirds and may be the predominant manifestation in these patients. Lymphadenopathy is often present and may be so massive as to suggest a lymphoproliferative disease, sarcoidosis or a chronic infection. Cutaneous manifestations of MCTD include alopecia (67%), cutaneous forms of discoid (33%) or systemic LE (20%), and cutaneous sclerosis (7%).53The alopecia i s usually diffuse, nonscarring and unusually persistent. It frequently fails to respond to therapy for the underlying disease, in contrast to the alopecia in acute SLE. Pigmentary disturbances included hyperpigrnentation (diffuse and focat) and hypopigmentation. The hypopigmented areas often have follicular retention of pigment, as in scleroderma or repigmenting vitiligo. We have observed 3 patients in whom discoid LE was the initial diagnosis, preceding the systemic manifestations of mixed connective tissue disease by several years. Less common symptoms included fever, weight loss, serositis (including pleuritis and pericarditis), dyspnea and evidence of thyroid disease. Neurologic abnormalities are uncommon and major central nervous system involvement i s extremely rare. The most frequent neurologic abnormality i s a trigeminal neuropathy. Dysphagia and Sjogren's syndrome have been described. Hepatomegaly and splenomegaly are not common, although they have been described. laboratory Findings in Mixed Connective Tissue Disease All MCTD patients have had high titer antibody to RNP. Serial observations have indicated that, in the majority of patients, these high RNP antibody titers persist during periods of remission. Antibodies to native DNA are uncommon in MCTD, a finding which may explain the low incidence of nephritk6 The reason for this negative association between RNP and DNA antibodies shown by ReichIin6,54and others3 remains unexplained.
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The FANA titer i s usually very high, frequently positive at a serum dilution of 1 : 1280 or more.* The pattern i s particulate in essentially all patients. Rheumatoid factor has been observed in more than half and LE cells were present i n 12-33% of MCTD patients. Hypocomplementemia i s uncommon in MCTD, occurring much less frequently than in SLE.5O Although not mentioned as part of the original syndrome, a recent studP5 has found a high incidence of pulmonary disease i n MCTD patients. Exertional dyspnea and/or evidence of pulmonary hypertension may occur. Pulmonary function studies reveal a decreased diffusing capacity and restrictive changes, and chest x-rays show interstitial fibrosis, findings similar to those described in progressive systemic sclerosis. Additional evidence suggesting overlap with progressive systemic sclerosis is the high incidence of esophageal motiIity abnormalities, occurring in two-thirds of the patients studied.5O Although myositis is common, occurring in two-thirds of MCTD patients, it may be "silent'' without evidence of muscle tenderness or weakness. For this reason the presence of RNP antibodies in the patient with a clinical diagnosis of SLE or progressive systemic sclerosis should cause the physician to search for concomitant muscle disease by obtaining muscle enzymes and electromyography. The incidence of hyperglobulinemia is higher in individuals with MCTD as compared with SLE ~atients.4~ This hyperglobulinemia i s often striking, reaching concentrations of 3 to 5 g m / l 0 0 ml. Anemia, leukopenia and an elevated sedimentation rate are also common find ings. Immunofluorescence studies of skin biopsies obtained from MCTD patients frequently show epidermal nuclear staining by the direct antibody stainingtechnique (Fig. 2). Thestaining pattern of the epidermal and dermal nuclei is particulate and IgG is the only immunoglobulin present. In our experience, ENA titers
* Substrate used was human tumor cells (BK substrate) fixed to glass slides, purchased from Electronucleonics Laboratories, Inc., Bethesda, MD.
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of 1 : 32000 or more are usually present in the serum of patients with epidermal nuclear staining. Particulate epidermal nuclear staining on direct fluorescent antibody staining indicates the presence of extractable nuclear antigen antibodies which may be anti-RNP or anti-Sm. This nuclear staining appears to be produced in vitro. Presumably, high concentrations of easily diffusi ble extractable nuclear antigen antibodies in the dermis gain access to epidermal nuclear antigens at the time the tissue is sectioned, air dried or prewashed. Very likely the process of freezing and thawing destroys membrane integrity and allows free diffusion of antibody into the cell nuclei.56The most important feature of patients with RNP antibodies is the low incidence of nephritis. Both M C T D ' S ~ and ~ SLE54 patients who possess this antibody show a significantly lower incidence of renal disease (12%) than SLE patients w i t h Sm or D N A ant i b ~ d i e s Renal . ~ ~ changes, when present, are frequently minimal, showing only mesangial hypercellularity. Diffuse membranoproliferative changes consistent with SLE and intimal proliferation with arteriolar obliteration, consistent with scleroderma, have also been described.5O Treatment and Prognosis Mixed connective tissue disease may involve several different organ systems, either alone or in combination. Choice of treatment must be individualized and based om the specific organ system involved. Myositis frequently requires corticosteroid 'therapy; the patient will usually show a rapid response, with decreased muscle pain and weakness and a fall in serum muscle enzymes. Significant renal disease, when present, is treated with prednisone, 1 mg/kg, as in lupus nephritis. Immunosuppressive drugs, although rarely necessary, may be used in patients who develop significant corticosteroid side effects or require high levels to suppress disease activity. It has been our experience that pulmonary involvement may be stabilized but not neces-
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sarily reversed with corticosteroid therapy. If myositis i s associated with pulmonary symptoms, a significant subjective i mprovement may be seen when the myositis is controlled. In contrast, other have described significant i mprovement i n pulmonary function after steriod therapy. Minor manifestations of the disease (arthralgias, myalgias, fatigue, morning stiffness, fever, hand swelling and lymphadenopathy), are usually very sensitive to low-dose steroid therapy. These symptoms may be treated with nonsteroidal anti-inflammatory agents alone if no major organ involvement is present. Regression of skin tightening and repigmentation of previously hypopigmented skin have been d e s c r i b e d ' ~but ~ ~ the response of these skin manifestations to therapy is variable. Most MCTD patients have a relatively benign illness. Sharp has described several patients with a prolonged remission after one course of prednisone. More frequently, the course has been one of remission and relapse similar to, but less severe than, that seen in SLE patients. Frequently, long-term maintenance therapy is required to prevent recurrence of disease. In general, the prognosis in all series has 4% of patients been good. In one study;' died, with a mean duration of disease of 6 years (range 6 months to 22 years). These deaths were due to cerebral infarction,' myocardial infarction' and renal failure.2 MCTD: A Distinct Entity or Part of the SLE Spectrum?
The major controversy surrounding MCTD is whether it is a separate disease or simply a variant of SLE. Until the etiology of one or both of these conditions is clarified, one cannot with certainty answer this question. However, it is apparent, that several differences exist between MCTD patients with RNP antibodies and SLE patients with D N A and/or Sm antibodies. The unifying feature of patients with MCTD i s the presence of high-titer RNP antibody. Table 3 shows clinical diagnoses of patients found to have high titer RNP antibody. It can
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Table 3. Clinical Diagnoses of Patients With High Titer RNP Antibodies
Mixed connective tissue disease Systemic lupus erythematosus Progressive systemic sclerosis Mild undifferentiated connective tissue disease Polymyositis
Sharp50
Farber and Boles45
74%
61 %
12%
15%
8%
8%
6%
8%
-
8%
be seen that, although the majority of patients show overlapping features consistent with the clinical picture of MCTD, several patients have clinical features of only SLE, progressive systemic sclerosis or polymyositis. Some patients with RNP antibodies lack sufficient criteria to be classified into any single connective tissue disease subset (called mild undifferentiated connective tissue disease). has emphasized the relative specificity of anti-Sm antibody for SLE. SharpSo has found that Sm antibodies are present in 85% of patients with classic SLE, but may also occur i n M C T D ( 7 % ) , scleroderma (4%) and dermatomyositis (4%). These studies suggest that KNP antibodies correlate with MCTD and that Sm antibodies are seen primarily in SLE, but that neither antibody is found exclusively in either disease. Reichlin has argued that MCTD i s a variant of SLE, since the majority of MCTD patients fulfill the preliminary ARA criteria for SLE.54 He believes that patients with RNP antibodies form a subset of SLE patients with a low prevalence of nephritis. This concept does not explain other equally important characteristics of this group of patients. Although the incidence of serositis, arthritis, anemia and leukopenia is similar, the incidence of other connective tissue disease manifestations are significantly different i n RNP positive and RNP negative patients. The Raynaud phenomenon i s much more common in
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2. Discoid lupus 3. Alopecia 4. Photosensitivity
Progressive systemic sclerosis 1. Bilateral hand edema including puffy swelling of fingers 2. Scleroderma skin changes 3. Pigmentary abnormality of skin 4. Telangiectasis
5. Oral or nasopharyngeal ulceration
5. The Raynaud phenomenon
6. Arthritis without x-ray evidence of bone erosion
6. Digital ischemia
7. LE Cells
7. Dyspnea (without pleurisy) with either restrictive pulmonary function tests and reduced diffusion capacity for CO, or bi-basilar pulmonary fibrosis on chest x-ray.
8. Chronic false-
8. Distal esophageal
positive STS 9. Profuse proteinuria
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Criteria for the Diagnosis of Mixed Connective Tissue Disease
Systemic lupus erythematosus 1. Facial erythema (butterfly)
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dysphagia or esophageal motor dysfunction by x-ray or manometric studies
Polymyositis, dermatomyositis 1. Violaceous discoloration of upper eyelids
2. Muscle tenderness on palpation 3. Proximal muscle weakness (progressive) 4. Serum muscle enzyme elevations 5. Abnormal electromyogram compatible with inflammatory myopathy 6. Erythematous scaling atrophic papules over extensor surfaces of joints (Gottron’s papules) 7. Proximal dysphagia (Nasal voice, regurgitation of fluid through nose, weakness in initiation of swallowing)
8. Muscle biopsy showing myositis
10. Cellular casts 11. Pleuritis or pericarditis 12. Psychosis or convulsions 13. Hemolytic anemia Leukopenia or Thrombocytopen ia
RNP-positive patients. Pu lmonary disease, esophageal dysfunction, myositis, hypergammaglobulinemia, the Sjogren syndrome, swollen hands, scleroderma skin changes and high-titer speckled ANA pattern are also more common i n the R N P positive group. Hypocomplementemia, significant nephritis and major CNS disease are uncommon in RNP-positive patients. In addition, a lower incidence of DNA antibodies occurs in the RNP-positive group. It would appear that MCTD is a true overlap OC SLE, progressive
systemic sclerosis and polymyositis with a unique serologic finding, RNP antibodies.
Criteria for Classification of MCTD Table 4 lists the clinical manifestations of MCTD and its contributing diseases, SLE, progressive systemic sclerosis and polymyositis. The first column is a modification of the preliminary criteria for the classification of SLE as proposed by the Diagnostic and Therapeutic
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Criteria Committee of the American Rheumatism Association of the Arthritis Fo~ndation.5~ Column 2 is a list of criteria for the diagnosis of progressive systemic sclerosis. Column 3 lists criteria for the diagnosis of derrnatomyositis/polymyositis. These criteria are not proposedas definitivediagnostic criteria for the individual diseases which overlap to form MCTD. Rather, it is suggested that when an individual has 2 or more criteria of each of 2 of the individual diseases listed and, in addition, has RNP antibodies, the diagnosis of MCTD may be made. Furthermore, the diagnosis of possible MCTD may be made in patients who manifest 2 or more criteria for the diagnosis of only one of the major diagnostic possibilites and high titer RNP antibodies. A patient with high titer RNP antibodies initially may have symptoms suggesting only scleroderma, SLE or myositis and weeks or months of observation may be required before manifestations suggesting other components of MCTD become evident. It i s suggested that a1I the patients manifesting symptoms of SLE, progressive systemic sclerosis, polymyositis, dermatomyositis, or rheumatoid arthritis be screened with a FANA test. Those patients with a positive FANA test in a particulate pattern at high serum dilution should be further evaluated for the presence of MCTD. Conclusions
Table 5 lists the distinguishing features of patients with MCTD. Patients with this illness have overlapping features suggesting SLE, scleroderma, polymyositis and, at least superficially, rheumatoid arthritis. The most important clinical manifestations of this syndrome are Raynaud phenomenon, swollen hands, pulmonary fibrosis, myositis and esophageal motility disturbances. When any of these manifestations of connective tissue disease are present, or when a high titer, particulate FANA i s detected, the level of RNP antibodies should be measured. The presence of RNP antibodies suggests better prognosis,
Chubick and Cilliam Table 5.
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Characteristics of Mixed Connective Tissue Disease Patients
1. At least two features of two of the following illnesses: Systemic lupus erythematosus Progressive systemic sclerosis Polymyositis 2. High titer particulate FANA 3. High titer ribonucleoprotein antibody 4. Epidermal nuclear staining on direct immunofluorescence 5. High incidence of pulmonary interstitial fibrosis 6. Low incidence of renal disease 7. Good response to corticosteroid therapy 8. Good prognosis
with a low incidence of renal disease, a low incidence of major central nervous system disease, and steroid responsiveness. The lack of antibody to ribonucleoprotein, or the presence of antibodies to the Sm or DNA, defines a different group of patients who are at higher risk of developing renal disease and major central nervous system disease. These patients require close observation of possibly more aggressive therapeutic measures. The finding of antibody systems in connective tissue disease patients which serve as specific markers for disease subsets with distinct clinical deatures has significant theoretical as well as practical implications. As with DNA: anti-DNA, the ENA: anti-ENA system provides additional evidence for the role of autoantibodies in connective tissue disorders. The .presence of different antibodies in SLE and MCTD may indicate that each disease i s triggered by a different agent. Alternatively, it may suggest that a certain genetic predisposition exists, which, when specifically or nonspecifically triggered, produces a specific disease syndrome. Solving these problems may allow a more definitive approach to therapeutic intervention in the future. References 1. Sharp, C. C., Irvin, W. C., Tan, E. M., Gould, R. G., and Holman, H. R.: Mixed connective tissue disease-an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am. J. Med. 52:148, 1972.
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2. Holman, H. R.: Partial purification and characterization of an extractable nuclear antigen which reacts with SLE sera. Ann. NY Acad. Sci. 124:800, 1965. 3. Sharp, C. C., Irvin, W. S., LaRoque, R. L., Velez, C., Daly, V., Kaiser, A. D., and Holman, H. R.: Association of autoantibodies to different nuclear antigens with clinical patterns of rheumatic disease and responsiveness to therapy. J. Clin. Invest. 50:350, 1971. 4. Hargraves, M. M., Richmond, H., and Morton, R.: Presentation of two bone marrow elements: the "Tart" cell and "LE" cell. Proc. Staff Meet. Mayo Clinic 23:25, 1948. 5. Friou, G. 1.: Clinical application of lupus serumnucleoprotein reaction using fluorescent antibody technique. J. Clin. Invest. 36:890, 1957. 6. Reichlin, M., and Mattioli, M.: Antigens and antibodies characteristic o f systemic lupus erythematosus. Bull. Rheum. Dis. 24:756, 1974. 7. Sturgill, B. C., and Carpenter, R. R.: Antibody to ribosomes in systemic lupus erythematosus. Arthritis Rheum. 8:213, 1965. 8. Schur, P. H., Moroz, L. A,, and Kunkel, H. C.: Precipitating antibodies to ribosomes i n the serum of patients with systemic lupus erythematosus. Immunochemistry 4:447, 1967. 9. Clark, G., Reichlin, M., and Tomasi, T. B.: Characterization of a soluble cytoplasmic antigen reactive with sera from patients with systemic lupus erythematosus. J. Immunol. 102:117, 1969. 10. Mattioli, M., and Reichlin, M.: Heterogeneity of RNA-protein antigens reactive with sera of patients with systemic lupus erythematosus: Description of a cytoplasmic nonribosomal antigen. Arthritis Rheum. 17:421, 1974. 11. Schur, P. H., and Monroe, M.: Antibodies to ribonucleicacid insystemic lupuserythematosus. Proc. Nat. Acad. Sci. 63:1102, 1969. 12. Steinberg, A. D., Baron, S., and Talal, N.: The pathogenesis of autoimmunity in New Zealand mice. I. Induction of antinucleic acid antibodies by polyinosinic and polycytidylic acid. Proc. Nat. Acad. Sci. 63:1102, 1969. 13. Schur, P. H., Stollar, D., Steinberg, A. D., et al.: Incidence of antibodies to double-stranded RNA in systemic lupus erythematosus and related diseases. Arthritis Rheum. 14:342, 1971. 14. Talal, N., Steinberg, A. D., and Daley, G.: Inhibition o f antibodies binding polyinosinic-polycytidylic acid in human and mouse lupus sera by viral and 'synthetic ribonucleic acids. J. Clin. Invest. 50:1248, 1971. 15. Burnham, T. K., and Bank, P. W.: Antinuclear antibodies. I. Patterns of nuclear immunofluorescence. J. Invest. Dermatol. 62:526, 1974. 16. Beck, J. S.: Variations in morphological patterns of "autoimmune" nuclear fluorescence. Lancet 1 :1203, 1961. 17. Burnham, T. K.: Antinuclear antibodies: II. The prognostic significance of nuclear immunofluorescent patterns in lupus erythematosus. Arch. Dermatol. 11 1 :203, 1975. 18. Tan, E. M.: Relationship of nuclear staining patterns with precipitating antibodies in systemic lupus erythematosus. J. Lab. Clin. Med. 70:800, 1967.
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19. Tan, E. M., and Kunkel, H. G.: Characteristics of a soluble nuclear antigen precipitating with sera of patients with systemic lupus erythematosus. J. Irnmunol. 96:464, 1966. 20. Northway, 1. D., and Tan, E. M.: Differentiation of antinuclear antibodies giving speckled staining patterns in immunofluorescence. Clin. Immunol. Immunopathol. 1 :140, 1972. 21. Rothfield, N. F., and Stollar, B. D.: The relationship of immunoglobulin class, pattern of antinuclear antibody and complement-fixing antibodies to DNA i n sera from patients w i t h systemic lupus erythematosus. J. Clin. Invest. 46:1785, 1967. 22. Casals, S., Friou, G., and Teague, P.: Specific nuclear reaction pattern of antibody to DNA in lupus erythematosus sera. J. Lab. Clin. Med. 62:625, 1963. 23. Casals, S. P., Friou, G. J., and Myers, L. L.: Significance of antibody to D N A in systemic lupus erythematosus. Arthritis Rheum. 7:379, 1964. 24. Townes, A. S.: Immunologic studies of systemic lupus erythematosus. I. Quantitative estimations of nucleoprotein-reactive gamma globulin in systemic lupus erythematosus and other diseases. Bull. Johns Hopkins Hosp. 112:183, 1963. 25. Robitaille, P., and Tan, E. M.: Relationship between deoxyribonucleoprotein and deoxyribonucleic acid antibodies in systemic lupus erythematosus. J. Clin. Invest. 52:316, 1973. 26. Gonzales, E. N., and Rothfield, N. F.: Immunoglobulin class and pattern of nuclear fluorescence in systemic lupus erythematosus. N. Engl. J. Med. 274:1333, 1966. 27. Burnham, T. K.: Antinuclear antibodies in lupus erythematosus. Arch. Dermatol. 112:1329, 1976. 28. Hurd, E. R., Personal communication, 1976. 29. Cepellini, R., Polli, E., and Celeda, F.: DNA-reacting factor in serum of a patientwith lupus erythematosus diffusus. Proc. SOC. Exp. Biol. Med. 96:572, 1957. 30. Deicher, H. R., Holman, H. R., and Kunkel, H. G.: The precipitin reaction between DNA and a serum factor in systemic lupus erythematosus. J. Exp. Med. 109:97, 1959. 31. Robbins, W. C., Holman, H. R., Deicher, H., and Kunkel, H. G.: Complement fixation with cell nuclei and DNA in lupus erythematosus. Proc. SOC. Exp. Biol. 'Med.96:575, 1957. 32. Seligman, M.: Evidence in the serum of patients with systemic lupus erythematosusof a substaqce producingaprecipitation reaction with DNA.C. R. SOC. Biol. 245:243, 1957. 33. Koffler, D., Carr, R. I., Agnello, V., Feizl, T., and Kunkel, H. G.: Antibodies to polynucleotides: distribution in human serums. Science 166:1648,1969. 34. Tan, M., and Epstein, W. V.: A solid-phase immunoassay for antibody to DNA and RNA. J. Lab. Clin. Med. 81:122, 1973. 35. Notman, D. D., Kurata, N., andTan, E. M.: Profilesof antinuclear antibodies in systemic rheumatic diseases. Ann. Int. Med. 83:464, 1975. 36. Tan, E. M., Schur, P. H.,Carr, R. I.,and Kunkel, H. C.: Deoxyribonucleic acid (DNA) and antibodies to DNA in the serum of patients with systemic lupus erythematosus. 1. Clin. Invest. 45:1732, 1966. 37. Koffler, D., Schur, P. H., and Kunkel, H,. G.: Immunologic studies concerning the nephritis of sys-
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temic lupus erythematosus. J. Exp. Med. 126:607, 1967. Immunologic factors Schur, P. H., and Sandson, I.: and clinical activityin systemic lupuserythematosus. N. Engl. 1. Med. 278:533, 1968. Krishnan, C., and Kaplan, M. H.: lmmunopathologic studies of systemic lupus erythematosus. II. Antinuclear reaction ofy globulin eluted from homogenates and isolated glomeruli of kidneys from patients with lupus nephritis. J. Clin. Invest. 46:569, 1967. Cochrane, C. G., and Koffler, D.: Immune complex disease in experimental animals and man. Adv. Immunol. 16:185, 1973. Holman, H. R., Deicher, H. R. G., and Kunkel, H. G.: The LE cell and the LE serum factors. Bull. N.Y. Acad. Med. 35:409, 1959. Holman, H. R.: Partial purification and characterization of an extractable nuclear antigen which reacts with SLE sera. Ann. N.Y. Acad. Sci. 124:800, 1965. Mattioli, M., and Reichlin, M.: Characterization of a soluble nuclear ribonucleoprotein antigen reactive with SLE sera. J. Immunol. 107:1281, 1971. Parker, M. D.:Ribonucleoprotein antibodies: frequency and clinical significance in systemic lupus erythematosus, scleroderma and mixed connective tissue disease. J. Lab. Clin. Med. 82:767, 1973. Farber, S. J., and Bole, G. G.: Antibodies to componentsofextractable nuclear antigen: Clinical characteristics of patients. Arch. Int. Med. 136:425, 1976. Sharp, G. C.: Mixed connective tissue disease. Bull. Rheum. Dis. 25:828, 1975. Sharp, G. C., May, C., Irvin, W. S., Holman, H. R., McDuffie, F. C., Hess, E. V., and Schmid, F. R.: Clinical and laboratory characteristics of patients with antibodies to the ribonucleoprotein (RNP) component ofextractablenuclear antigen (ENA).Arthritis Rheum. 16:569, 1973. Singsen, B., Kornreich, H., King, K., Bernstein, B.,
49.
50.
51.
52.
53.
54.
55.
56.
57.
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Hanson, V., and Tan, E.: Mixed connective tissue disease in children. Arthritis Rheum. 19:822, 1976. Baldassare, A,, Weiss, T.,Auclair, R., andZuchner,J.: Mixed connective tissue disease in children. Arthritis Rheum. 19:788, 1976. Sharp, G. C.: Mixed connective tissue diseaseoverlap syndromes. Clin. Rheum. Dis. 1:561, 1975. Sharp, G. C., Irvin, W. S., May, C. M., Holman, H. R., McDuffie, F. C., Hess, E. V., and Schmid, F. R.: Association of autoant ibod ies to r ibonucleoprote in and Sm antigens with mixedconnective tissue disease (MCTD), systemic lupus erythematosus (SLE) and other rheumatic diseases. Clin. Res. 23:50A, 1976. Hench, P. K., Edgington, T. S., and Tan, E. M.: The evolvingcl inical spectrumofmixed connectivetissue disease. Arthritis Rheum. 17:404, 1975. Gilliam, J. N., and Prystowsky, S. D.: Mixed connective tissue disease syndrome: The cutaneous manifestations of patients with high titer serum antibody to RNase sensitive extractable nuclear antigen (ENA). Arch. Dermatol. In press. Reichlin, M., and Mattioli, M.: Correlation of a precipitin reaction to an RNA protein antigen and a low prevalence of nephritis in patients with systemic lupus erythematosus. Engl. 1. Med. 286:908, 1972. Harmon, C., Wolfe, J. F., Lillard, S., Held, C., Cordan, R., and Sharp, G. C.: Pulmonary involvement in mixed connective tissue disease. Arthritis Rheum. 19:801, 1976. Gilliam, J. N.: The significance of cutaneous immunoglobulin deposits in lupus erythematosus and NZBlN ZW FI hybrid mice. J. Invest. Dermatol. 65:154, 1975. Cohen, A.S., Reynolds, W. E., Franklin, E.C., Kuller,J. P., Ropes, M. W., Shulman, L. E., and Wallace, S. L.: Preliminary criteria for the classification of systemic lupus erythematosus. Bull. Rheum. Dis. 21 :643, 1971.
Pediculosis Corporis This disease constitutes about three-quarters o f one per cent of all skin disorders. It occurs with equal frequency in the whites and blacks. There i s practically generalized itching, but the lesions are more numerous where the clothes are in close contact with the skin, as upon the shoulders. At times there may b e seen small haemorrhagic points, due to the bites, but these are not always present. The secondary lesions are the scratch-marks, usually linear, and most pronounced between the shoulder blades, and upon the shoulders. These often produce some scarring or atrophy, showing the violence of the scratching. Marked pigmentation of the skin may result and b e mistaken for Addison's disease.- Hazen, H. H.: Diseases of the Skin, Sf. Louis, C. V . Mosby, 1915, p. 233.
A REVIEW OF MIXED CONNECTIVE TISSUE DISEASE ANDREW CHUBICK, M.D. AND JAMES N. GILLIAM, M.D.
In 1972 Sharp and co-workers described a new and apparently distinct clinical syndrome sharing features of systemic lupus erythematosus (SLE), progressive systemic sclerosis and polymyositis.' A common finding in these patients was the presence of high concentrations of serum anti body which reacted with saline-extractable nuclear antigens? The overlap of clinical features of various connective tissue diseases suggested the name mixed connective tissue disease (MCTD) for this ~yndrome.~ It i s our purpose in this review to define and compare the major antigen-antibody systems found in patients with connective tissue diseases, to describe the clinical and serologic manifestations of MCTD and to show how serologic studies may identify subgroups of connective tissue disease patients with common clinical features. Antigen-Antibody Systems
The discovery of the LE cell phenomenon4 and the application of the indirect immunofluorescent technique for the study of antinuclear antibodies5 have led to an increased This study was supported in part by USPHS research grant # A M 1 91 01, USPHS program project grant #AM09989 and USPHS national research service award training grant #AM07055. Address for reprints: James N. Cilliam, M.D., Department of internal Medicine, The University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75235.
From the Department of lnternal Medicine, Divisions of Rheurnatology and Dermatology, The University of Texas Southwestern Medical School, Dallas. Texas
interest in the role of antinuclear antibodies in the pathogenesis of connective tissue diseases. Table 1 shows the antigenic specificity of the common antibodies present in SLE and mixed connective tissue disease. Although antibodies directed against nonnuclear antigens, such as cytoplasmic antigens,6-'o ribonucleic acids," and synthetic polynucle~tides,'~-'~ have been described the antibodies which have been most thoroughly studied are those directed against nuclear antigens. Fluorescent Antinuclear Antibody Test
The fluorescent antinuclear antibody test (FANA) has become the most widely used diagnostic procedure in the evaluation of suspected cases of connective tissue disease. The pattern of nuclear fluorescence, as well as the dilution of a serum at which fluorescence i s lost, may provide important diagnostic and prognostic information. Table 2 presents 6 common antinuclear antibody patterns seen in the connective tissue diseases. The terminology used is modified from Burnham and Bank.I5 The particulate pattern (Fig. 1A) is the most common pattern. It has been referred to as
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Fig. 1. Fluorescent ANA patterns. A, Top left, particulate; B, Top right, homogenous; C, Bottom left, peripheral; D, Bottom right, nucleolar.
speckled16or thread^.'^,'^ This pattern is nonspecific, having been associated with several connective tissue diseases, as well as malignancies.'s Antibodies producing the particulate pattern frequently have specificities for saline-extractable nuclear antigens.1,1s--20 When antibodies producing the particulate pattern are present in high titer, a significant incidence of mixed connective tissue disease is seen.'s3 Although the particulate pattern frequently is not observed in undiluted serum, it becomes evident on dilution. This is due to the presence of nuclear antibodies of other specificities which interfere with the expression of particulate nuclear staining at the lower dilutions.18*20 The homogenous pattern16 (Fig. 1B) has also been referred to as diffuse2' or solid. It i s associated with the presence of serum antibodies directed against deoxyribonucleo-
protein (DNP).'6-18,20-22 This pattern is also common and nonspecific.'s In patients with active SLE, the homogenous pattern is usually detected in high titers, and in remission, a marked fall in titer is often o b s e r ~ e d . ' ~ , ~ ~ , ~ The peripheral pattern (Fig. lC), also referred to as shaggy, rim or membranous, i s the most specific pattern for SLE. It rarely occurs. in other connective tissue diseases or druginduced lupus syndromes.'s,21,22Antibodies producing this pattern of immunofluorescence are directed against DNA or the D N A moiety of the DNA-Histone complex.18*21,22,2s The peripheral pattern i s more common in SLE patients who are severely i1122,26 and frequently disappears or changes
Table 1. Antigenic Specificity of Antibodies in Connective Tissue Diseases Cell surface antigens Lymphocyte Red cell Platelet Cytoplasmic antigens Ribosomes Soluble cytoplasmic antigen (Ro) Cytoplasmic RNA protein (La) Single stranded RNA Nuclear antigens DNA: Double stranded (native) and single stranded DNA histone Extractable nuclear antigens Ribonucleoprotein (RNP) Saline-soluble glycoprotein (Srn) Polymyositis associated antigen (Prn) Nucleolar Miscellaneous Clotting factors Lipoproteins Synthetic polynucleotides Viral antigens
Fig. 2. Particulate epidermal nuclear staining on direct immunofluorescence of clinically normal skin from a patient with MCTD.
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Pattern Particulate Homogenous Peripheral Speckled Nucleolar Leukocyte Specific
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Fluorescent Antinuclear Antibody Patterns
Nucleolar RNA
Associated cI inica I disease Connective tissue disease' malignancy Connective tissue d iseaset malignancy Systemic lupus erythematosus Scleroderma, Raynaud phenomenon Scleroderma, Raynaud phenomenon
?
Rheumatoid arthritis*
Previous nomenclature Speckled, thready fibrillar, reticular Diffuse, solid
Associated antigens Extractable nuclear antigens, others Deoxyribonucleoprotein
Shaggy, rim membranous True speckled, pepper dots Large discrete speckles
Native DNA, DNA-histone ?
* W h e n present in high titer, MCTD common. t When present in high titer, SLE common. Seen predominantly in RA patients with Felty's syndrome.
*
trations of antibodies to native DNA occur in to homogenous or particulate when patients' conditions go into r e r n i s s i ~ n . The ~ ~ diag~ ~ ~ , ~ rheumatic ~ diseases other than SLE,34,35 the nosis of lupus nephritis must be considered in presence of significant amounts of anti-native DNA antibodies remains the most important untreated patients with a peripheral pattern." serologic marker for SLE. The presence of the The speckled or true speckled27 pattern, DNA:anti-DNA system in SLE patients corredescribed by Burnham as "multiple, evenly lates with disease activity3sZ3and occasiond istr ibuted ,s mal I round 'pepper dots,' " is seen ally antedates the appearance of active cliniin scleroderma and the Raynaud phenomecal di~ease.37,~~ In addition, there is solid evinon, but not in SLE.15 The nucleolar pattern dence that DNA:anti-DNA complexes par(Fig. 1 D), indicative of antibodies to nucleolar RNA, i s seen predominately in scleroderma ticipate i n the immunologically mediated renal disease of SLE.37-40 and the Raynaud phenomenon and o n l y The last major nuclear antigen to be conrarely in other connective tissue diseases.15 sidered i s the extractable nuclear antigen. The leukocyte-specific pattern i s seen preOriginally described by Holman et a1.141*42 dominantly in rheumatoid arthritis and Felty's extractable nuclear antigen consists of several syndromez8 and occasionally in other conantigenic constituents, 2 of which ha+e been nective tissue d i ~ 0 r d e r s . l ~ partially characterized. The Sm antigen In addition to the FANA test, other serologic (named for the patient whose serum possesassays have allowed the quantitation of autoantibodies. directed against specific nuclear sed specific antibody to this antigen) is a antigens. Of these autoantibodies, those disaline-soluble non-nucleic acid, non-histone acidic glycoprotein, which i s not susceptible rected against DNA and saline-extractable to ribonuclease digestion. Anti-Sm antibodies nuclear antigens have proven useful in diaghave been found almost exclusively i n nosis of SLE and MCTD. Antibodies to purified DNA were described in 1957.29-3zAntibodies SLE.1e,35 The ribonucleoprotein antigen (RNP, against denatured or single-stranded DNA are M o ~is~composed ) of a ribonucleic acid and a found in most SLE patients (92%) but have nucleoprotein. Ribonuclease will destroy its antigenicity. RNP antibodies are found in viralso been described in drug-induced SLE tually all patients with mixed connective tis(57% 1, nonrheumatic diseases (8-58%) and normal controls (4%).33Although recent sue disease.' Two methods, hemagglutination studies have suggested that low concenof erythrocytes coated with extractable nu-
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clear antigens' and double diffusion in agarM have been used to identify sera withantibody to extractable nuclear antigen. Clinical Manifestations of Mixed Connective Tissue Disease The incidence of MCTD i s unknown. In the original description of this syndrome,' Sharp identified 25 such patients in a group of 375 SLE and 50 scleroderma patients. Farber and found 1 3 patients w i t h RNP antibodies in 155 patients studied, 8 of whom had clinical manifestations of 2 or more connective tissue disorders. There is a female predominance w i t h a mean age of 37 although a similar illness has been described in ~ h i l d r e n . 4The ~ , ~most ~ common symptom is joint pain, manifested as either polyarthralgias or a symmetrical polyarthritis. Occasional patients have been described w i t h rheumatoid-like arthritis, and subcutaneous nodules have been described."n This pattern of arthritis, associated with the high incidence of fatigue, morning stiffness and rheumatoid factor positivity?' may suggest an initial diagnosis of rheumatoid arthritis. In a retrospective study of 15 MCTD 10 patients began with a syndrome resembling classic, definite or probable rheumatoid arthritis and had rheumatoid factor. In the majority, a second and even a third c Ii n ical syndrome was suspected before MCTD was diagnosed. The next most common symptoms, the Raynaud phenomenon and swollen hands, are the most suggestiveclinical featuresofthis disease. A significant difference in the incidence of these 2 features has been noted in MCTD patients with RNP antibodies when compared to SLE patients with Sm and/or DNA a n t i b ~ d i e s . ~ Involvement ~,~~ of the fingers leads to a swollen or "sausage" appearance. Skin biopsy shows considerable intradermal edema, similar to early scleroderma The Raynaud phenomenon may be the only evidence of disease for months to years before other manifestations of MCTD
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appear. Muscle tenderness and proximal muscle weakness occur in two-thirds and may be the predominant manifestation in these patients. Lymphadenopathy is often present and may be so massive as to suggest a lymphoproliferative disease, sarcoidosis or a chronic infection. Cutaneous manifestations of MCTD include alopecia (67%), cutaneous forms of discoid (33%) or systemic LE (20%), and cutaneous sclerosis (7%).53The alopecia i s usually diffuse, nonscarring and unusually persistent. It frequently fails to respond to therapy for the underlying disease, in contrast to the alopecia in acute SLE. Pigmentary disturbances included hyperpigrnentation (diffuse and focat) and hypopigmentation. The hypopigmented areas often have follicular retention of pigment, as in scleroderma or repigmenting vitiligo. We have observed 3 patients in whom discoid LE was the initial diagnosis, preceding the systemic manifestations of mixed connective tissue disease by several years. Less common symptoms included fever, weight loss, serositis (including pleuritis and pericarditis), dyspnea and evidence of thyroid disease. Neurologic abnormalities are uncommon and major central nervous system involvement i s extremely rare. The most frequent neurologic abnormality i s a trigeminal neuropathy. Dysphagia and Sjogren's syndrome have been described. Hepatomegaly and splenomegaly are not common, although they have been described. laboratory Findings in Mixed Connective Tissue Disease All MCTD patients have had high titer antibody to RNP. Serial observations have indicated that, in the majority of patients, these high RNP antibody titers persist during periods of remission. Antibodies to native DNA are uncommon in MCTD, a finding which may explain the low incidence of nephritk6 The reason for this negative association between RNP and DNA antibodies shown by ReichIin6,54and others3 remains unexplained.
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The FANA titer i s usually very high, frequently positive at a serum dilution of 1 : 1280 or more.* The pattern i s particulate in essentially all patients. Rheumatoid factor has been observed in more than half and LE cells were present i n 12-33% of MCTD patients. Hypocomplementemia i s uncommon in MCTD, occurring much less frequently than in SLE.5O Although not mentioned as part of the original syndrome, a recent studP5 has found a high incidence of pulmonary disease i n MCTD patients. Exertional dyspnea and/or evidence of pulmonary hypertension may occur. Pulmonary function studies reveal a decreased diffusing capacity and restrictive changes, and chest x-rays show interstitial fibrosis, findings similar to those described in progressive systemic sclerosis. Additional evidence suggesting overlap with progressive systemic sclerosis is the high incidence of esophageal motiIity abnormalities, occurring in two-thirds of the patients studied.5O Although myositis is common, occurring in two-thirds of MCTD patients, it may be "silent'' without evidence of muscle tenderness or weakness. For this reason the presence of RNP antibodies in the patient with a clinical diagnosis of SLE or progressive systemic sclerosis should cause the physician to search for concomitant muscle disease by obtaining muscle enzymes and electromyography. The incidence of hyperglobulinemia is higher in individuals with MCTD as compared with SLE ~atients.4~ This hyperglobulinemia i s often striking, reaching concentrations of 3 to 5 g m / l 0 0 ml. Anemia, leukopenia and an elevated sedimentation rate are also common find ings. Immunofluorescence studies of skin biopsies obtained from MCTD patients frequently show epidermal nuclear staining by the direct antibody stainingtechnique (Fig. 2). Thestaining pattern of the epidermal and dermal nuclei is particulate and IgG is the only immunoglobulin present. In our experience, ENA titers
* Substrate used was human tumor cells (BK substrate) fixed to glass slides, purchased from Electronucleonics Laboratories, Inc., Bethesda, MD.
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of 1 : 32000 or more are usually present in the serum of patients with epidermal nuclear staining. Particulate epidermal nuclear staining on direct fluorescent antibody staining indicates the presence of extractable nuclear antigen antibodies which may be anti-RNP or anti-Sm. This nuclear staining appears to be produced in vitro. Presumably, high concentrations of easily diffusi ble extractable nuclear antigen antibodies in the dermis gain access to epidermal nuclear antigens at the time the tissue is sectioned, air dried or prewashed. Very likely the process of freezing and thawing destroys membrane integrity and allows free diffusion of antibody into the cell nuclei.56The most important feature of patients with RNP antibodies is the low incidence of nephritis. Both M C T D ' S ~ and ~ SLE54 patients who possess this antibody show a significantly lower incidence of renal disease (12%) than SLE patients w i t h Sm or D N A ant i b ~ d i e s Renal . ~ ~ changes, when present, are frequently minimal, showing only mesangial hypercellularity. Diffuse membranoproliferative changes consistent with SLE and intimal proliferation with arteriolar obliteration, consistent with scleroderma, have also been described.5O Treatment and Prognosis Mixed connective tissue disease may involve several different organ systems, either alone or in combination. Choice of treatment must be individualized and based om the specific organ system involved. Myositis frequently requires corticosteroid 'therapy; the patient will usually show a rapid response, with decreased muscle pain and weakness and a fall in serum muscle enzymes. Significant renal disease, when present, is treated with prednisone, 1 mg/kg, as in lupus nephritis. Immunosuppressive drugs, although rarely necessary, may be used in patients who develop significant corticosteroid side effects or require high levels to suppress disease activity. It has been our experience that pulmonary involvement may be stabilized but not neces-
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sarily reversed with corticosteroid therapy. If myositis i s associated with pulmonary symptoms, a significant subjective i mprovement may be seen when the myositis is controlled. In contrast, other have described significant i mprovement i n pulmonary function after steriod therapy. Minor manifestations of the disease (arthralgias, myalgias, fatigue, morning stiffness, fever, hand swelling and lymphadenopathy), are usually very sensitive to low-dose steroid therapy. These symptoms may be treated with nonsteroidal anti-inflammatory agents alone if no major organ involvement is present. Regression of skin tightening and repigmentation of previously hypopigmented skin have been d e s c r i b e d ' ~but ~ ~ the response of these skin manifestations to therapy is variable. Most MCTD patients have a relatively benign illness. Sharp has described several patients with a prolonged remission after one course of prednisone. More frequently, the course has been one of remission and relapse similar to, but less severe than, that seen in SLE patients. Frequently, long-term maintenance therapy is required to prevent recurrence of disease. In general, the prognosis in all series has 4% of patients been good. In one study;' died, with a mean duration of disease of 6 years (range 6 months to 22 years). These deaths were due to cerebral infarction,' myocardial infarction' and renal failure.2 MCTD: A Distinct Entity or Part of the SLE Spectrum?
The major controversy surrounding MCTD is whether it is a separate disease or simply a variant of SLE. Until the etiology of one or both of these conditions is clarified, one cannot with certainty answer this question. However, it is apparent, that several differences exist between MCTD patients with RNP antibodies and SLE patients with D N A and/or Sm antibodies. The unifying feature of patients with MCTD i s the presence of high-titer RNP antibody. Table 3 shows clinical diagnoses of patients found to have high titer RNP antibody. It can
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Table 3. Clinical Diagnoses of Patients With High Titer RNP Antibodies
Mixed connective tissue disease Systemic lupus erythematosus Progressive systemic sclerosis Mild undifferentiated connective tissue disease Polymyositis
Sharp50
Farber and Boles45
74%
61 %
12%
15%
8%
8%
6%
8%
-
8%
be seen that, although the majority of patients show overlapping features consistent with the clinical picture of MCTD, several patients have clinical features of only SLE, progressive systemic sclerosis or polymyositis. Some patients with RNP antibodies lack sufficient criteria to be classified into any single connective tissue disease subset (called mild undifferentiated connective tissue disease). has emphasized the relative specificity of anti-Sm antibody for SLE. SharpSo has found that Sm antibodies are present in 85% of patients with classic SLE, but may also occur i n M C T D ( 7 % ) , scleroderma (4%) and dermatomyositis (4%). These studies suggest that KNP antibodies correlate with MCTD and that Sm antibodies are seen primarily in SLE, but that neither antibody is found exclusively in either disease. Reichlin has argued that MCTD i s a variant of SLE, since the majority of MCTD patients fulfill the preliminary ARA criteria for SLE.54 He believes that patients with RNP antibodies form a subset of SLE patients with a low prevalence of nephritis. This concept does not explain other equally important characteristics of this group of patients. Although the incidence of serositis, arthritis, anemia and leukopenia is similar, the incidence of other connective tissue disease manifestations are significantly different i n RNP positive and RNP negative patients. The Raynaud phenomenon i s much more common in
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INTERNATIONAL JOURNAL OF DERMATOLOGY Table 4.
2. Discoid lupus 3. Alopecia 4. Photosensitivity
Progressive systemic sclerosis 1. Bilateral hand edema including puffy swelling of fingers 2. Scleroderma skin changes 3. Pigmentary abnormality of skin 4. Telangiectasis
5. Oral or nasopharyngeal ulceration
5. The Raynaud phenomenon
6. Arthritis without x-ray evidence of bone erosion
6. Digital ischemia
7. LE Cells
7. Dyspnea (without pleurisy) with either restrictive pulmonary function tests and reduced diffusion capacity for CO, or bi-basilar pulmonary fibrosis on chest x-ray.
8. Chronic false-
8. Distal esophageal
positive STS 9. Profuse proteinuria
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Criteria for the Diagnosis of Mixed Connective Tissue Disease
Systemic lupus erythematosus 1. Facial erythema (butterfly)
March 1978
dysphagia or esophageal motor dysfunction by x-ray or manometric studies
Polymyositis, dermatomyositis 1. Violaceous discoloration of upper eyelids
2. Muscle tenderness on palpation 3. Proximal muscle weakness (progressive) 4. Serum muscle enzyme elevations 5. Abnormal electromyogram compatible with inflammatory myopathy 6. Erythematous scaling atrophic papules over extensor surfaces of joints (Gottron’s papules) 7. Proximal dysphagia (Nasal voice, regurgitation of fluid through nose, weakness in initiation of swallowing)
8. Muscle biopsy showing myositis
10. Cellular casts 11. Pleuritis or pericarditis 12. Psychosis or convulsions 13. Hemolytic anemia Leukopenia or Thrombocytopen ia
RNP-positive patients. Pu lmonary disease, esophageal dysfunction, myositis, hypergammaglobulinemia, the Sjogren syndrome, swollen hands, scleroderma skin changes and high-titer speckled ANA pattern are also more common i n the R N P positive group. Hypocomplementemia, significant nephritis and major CNS disease are uncommon in RNP-positive patients. In addition, a lower incidence of DNA antibodies occurs in the RNP-positive group. It would appear that MCTD is a true overlap OC SLE, progressive
systemic sclerosis and polymyositis with a unique serologic finding, RNP antibodies.
Criteria for Classification of MCTD Table 4 lists the clinical manifestations of MCTD and its contributing diseases, SLE, progressive systemic sclerosis and polymyositis. The first column is a modification of the preliminary criteria for the classification of SLE as proposed by the Diagnostic and Therapeutic
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CONNECTIVE TISSUE DISEASE
Criteria Committee of the American Rheumatism Association of the Arthritis Fo~ndation.5~ Column 2 is a list of criteria for the diagnosis of progressive systemic sclerosis. Column 3 lists criteria for the diagnosis of derrnatomyositis/polymyositis. These criteria are not proposedas definitivediagnostic criteria for the individual diseases which overlap to form MCTD. Rather, it is suggested that when an individual has 2 or more criteria of each of 2 of the individual diseases listed and, in addition, has RNP antibodies, the diagnosis of MCTD may be made. Furthermore, the diagnosis of possible MCTD may be made in patients who manifest 2 or more criteria for the diagnosis of only one of the major diagnostic possibilites and high titer RNP antibodies. A patient with high titer RNP antibodies initially may have symptoms suggesting only scleroderma, SLE or myositis and weeks or months of observation may be required before manifestations suggesting other components of MCTD become evident. It i s suggested that a1I the patients manifesting symptoms of SLE, progressive systemic sclerosis, polymyositis, dermatomyositis, or rheumatoid arthritis be screened with a FANA test. Those patients with a positive FANA test in a particulate pattern at high serum dilution should be further evaluated for the presence of MCTD. Conclusions
Table 5 lists the distinguishing features of patients with MCTD. Patients with this illness have overlapping features suggesting SLE, scleroderma, polymyositis and, at least superficially, rheumatoid arthritis. The most important clinical manifestations of this syndrome are Raynaud phenomenon, swollen hands, pulmonary fibrosis, myositis and esophageal motility disturbances. When any of these manifestations of connective tissue disease are present, or when a high titer, particulate FANA i s detected, the level of RNP antibodies should be measured. The presence of RNP antibodies suggests better prognosis,
Chubick and Cilliam Table 5.
131
Characteristics of Mixed Connective Tissue Disease Patients
1. At least two features of two of the following illnesses: Systemic lupus erythematosus Progressive systemic sclerosis Polymyositis 2. High titer particulate FANA 3. High titer ribonucleoprotein antibody 4. Epidermal nuclear staining on direct immunofluorescence 5. High incidence of pulmonary interstitial fibrosis 6. Low incidence of renal disease 7. Good response to corticosteroid therapy 8. Good prognosis
with a low incidence of renal disease, a low incidence of major central nervous system disease, and steroid responsiveness. The lack of antibody to ribonucleoprotein, or the presence of antibodies to the Sm or DNA, defines a different group of patients who are at higher risk of developing renal disease and major central nervous system disease. These patients require close observation of possibly more aggressive therapeutic measures. The finding of antibody systems in connective tissue disease patients which serve as specific markers for disease subsets with distinct clinical deatures has significant theoretical as well as practical implications. As with DNA: anti-DNA, the ENA: anti-ENA system provides additional evidence for the role of autoantibodies in connective tissue disorders. The .presence of different antibodies in SLE and MCTD may indicate that each disease i s triggered by a different agent. Alternatively, it may suggest that a certain genetic predisposition exists, which, when specifically or nonspecifically triggered, produces a specific disease syndrome. Solving these problems may allow a more definitive approach to therapeutic intervention in the future. References 1. Sharp, C. C., Irvin, W. C., Tan, E. M., Gould, R. G., and Holman, H. R.: Mixed connective tissue disease-an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am. J. Med. 52:148, 1972.
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2. Holman, H. R.: Partial purification and characterization of an extractable nuclear antigen which reacts with SLE sera. Ann. NY Acad. Sci. 124:800, 1965. 3. Sharp, C. C., Irvin, W. S., LaRoque, R. L., Velez, C., Daly, V., Kaiser, A. D., and Holman, H. R.: Association of autoantibodies to different nuclear antigens with clinical patterns of rheumatic disease and responsiveness to therapy. J. Clin. Invest. 50:350, 1971. 4. Hargraves, M. M., Richmond, H., and Morton, R.: Presentation of two bone marrow elements: the "Tart" cell and "LE" cell. Proc. Staff Meet. Mayo Clinic 23:25, 1948. 5. Friou, G. 1.: Clinical application of lupus serumnucleoprotein reaction using fluorescent antibody technique. J. Clin. Invest. 36:890, 1957. 6. Reichlin, M., and Mattioli, M.: Antigens and antibodies characteristic o f systemic lupus erythematosus. Bull. Rheum. Dis. 24:756, 1974. 7. Sturgill, B. C., and Carpenter, R. R.: Antibody to ribosomes in systemic lupus erythematosus. Arthritis Rheum. 8:213, 1965. 8. Schur, P. H., Moroz, L. A,, and Kunkel, H. C.: Precipitating antibodies to ribosomes i n the serum of patients with systemic lupus erythematosus. Immunochemistry 4:447, 1967. 9. Clark, G., Reichlin, M., and Tomasi, T. B.: Characterization of a soluble cytoplasmic antigen reactive with sera from patients with systemic lupus erythematosus. J. Immunol. 102:117, 1969. 10. Mattioli, M., and Reichlin, M.: Heterogeneity of RNA-protein antigens reactive with sera of patients with systemic lupus erythematosus: Description of a cytoplasmic nonribosomal antigen. Arthritis Rheum. 17:421, 1974. 11. Schur, P. H., and Monroe, M.: Antibodies to ribonucleicacid insystemic lupuserythematosus. Proc. Nat. Acad. Sci. 63:1102, 1969. 12. Steinberg, A. D., Baron, S., and Talal, N.: The pathogenesis of autoimmunity in New Zealand mice. I. Induction of antinucleic acid antibodies by polyinosinic and polycytidylic acid. Proc. Nat. Acad. Sci. 63:1102, 1969. 13. Schur, P. H., Stollar, D., Steinberg, A. D., et al.: Incidence of antibodies to double-stranded RNA in systemic lupus erythematosus and related diseases. Arthritis Rheum. 14:342, 1971. 14. Talal, N., Steinberg, A. D., and Daley, G.: Inhibition o f antibodies binding polyinosinic-polycytidylic acid in human and mouse lupus sera by viral and 'synthetic ribonucleic acids. J. Clin. Invest. 50:1248, 1971. 15. Burnham, T. K., and Bank, P. W.: Antinuclear antibodies. I. Patterns of nuclear immunofluorescence. J. Invest. Dermatol. 62:526, 1974. 16. Beck, J. S.: Variations in morphological patterns of "autoimmune" nuclear fluorescence. Lancet 1 :1203, 1961. 17. Burnham, T. K.: Antinuclear antibodies: II. The prognostic significance of nuclear immunofluorescent patterns in lupus erythematosus. Arch. Dermatol. 11 1 :203, 1975. 18. Tan, E. M.: Relationship of nuclear staining patterns with precipitating antibodies in systemic lupus erythematosus. J. Lab. Clin. Med. 70:800, 1967.
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19. Tan, E. M., and Kunkel, H. G.: Characteristics of a soluble nuclear antigen precipitating with sera of patients with systemic lupus erythematosus. J. Irnmunol. 96:464, 1966. 20. Northway, 1. D., and Tan, E. M.: Differentiation of antinuclear antibodies giving speckled staining patterns in immunofluorescence. Clin. Immunol. Immunopathol. 1 :140, 1972. 21. Rothfield, N. F., and Stollar, B. D.: The relationship of immunoglobulin class, pattern of antinuclear antibody and complement-fixing antibodies to DNA i n sera from patients w i t h systemic lupus erythematosus. J. Clin. Invest. 46:1785, 1967. 22. Casals, S., Friou, G., and Teague, P.: Specific nuclear reaction pattern of antibody to DNA in lupus erythematosus sera. J. Lab. Clin. Med. 62:625, 1963. 23. Casals, S. P., Friou, G. J., and Myers, L. L.: Significance of antibody to D N A in systemic lupus erythematosus. Arthritis Rheum. 7:379, 1964. 24. Townes, A. S.: Immunologic studies of systemic lupus erythematosus. I. Quantitative estimations of nucleoprotein-reactive gamma globulin in systemic lupus erythematosus and other diseases. Bull. Johns Hopkins Hosp. 112:183, 1963. 25. Robitaille, P., and Tan, E. M.: Relationship between deoxyribonucleoprotein and deoxyribonucleic acid antibodies in systemic lupus erythematosus. J. Clin. Invest. 52:316, 1973. 26. Gonzales, E. N., and Rothfield, N. F.: Immunoglobulin class and pattern of nuclear fluorescence in systemic lupus erythematosus. N. Engl. J. Med. 274:1333, 1966. 27. Burnham, T. K.: Antinuclear antibodies in lupus erythematosus. Arch. Dermatol. 112:1329, 1976. 28. Hurd, E. R., Personal communication, 1976. 29. Cepellini, R., Polli, E., and Celeda, F.: DNA-reacting factor in serum of a patientwith lupus erythematosus diffusus. Proc. SOC. Exp. Biol. Med. 96:572, 1957. 30. Deicher, H. R., Holman, H. R., and Kunkel, H. G.: The precipitin reaction between DNA and a serum factor in systemic lupus erythematosus. J. Exp. Med. 109:97, 1959. 31. Robbins, W. C., Holman, H. R., Deicher, H., and Kunkel, H. G.: Complement fixation with cell nuclei and DNA in lupus erythematosus. Proc. SOC. Exp. Biol. 'Med.96:575, 1957. 32. Seligman, M.: Evidence in the serum of patients with systemic lupus erythematosusof a substaqce producingaprecipitation reaction with DNA.C. R. SOC. Biol. 245:243, 1957. 33. Koffler, D., Carr, R. I., Agnello, V., Feizl, T., and Kunkel, H. G.: Antibodies to polynucleotides: distribution in human serums. Science 166:1648,1969. 34. Tan, M., and Epstein, W. V.: A solid-phase immunoassay for antibody to DNA and RNA. J. Lab. Clin. Med. 81:122, 1973. 35. Notman, D. D., Kurata, N., andTan, E. M.: Profilesof antinuclear antibodies in systemic rheumatic diseases. Ann. Int. Med. 83:464, 1975. 36. Tan, E. M., Schur, P. H.,Carr, R. I.,and Kunkel, H. C.: Deoxyribonucleic acid (DNA) and antibodies to DNA in the serum of patients with systemic lupus erythematosus. 1. Clin. Invest. 45:1732, 1966. 37. Koffler, D., Schur, P. H., and Kunkel, H,. G.: Immunologic studies concerning the nephritis of sys-
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Hanson, V., and Tan, E.: Mixed connective tissue disease in children. Arthritis Rheum. 19:822, 1976. Baldassare, A,, Weiss, T.,Auclair, R., andZuchner,J.: Mixed connective tissue disease in children. Arthritis Rheum. 19:788, 1976. Sharp, G. C.: Mixed connective tissue diseaseoverlap syndromes. Clin. Rheum. Dis. 1:561, 1975. Sharp, G. C., Irvin, W. S., May, C. M., Holman, H. R., McDuffie, F. C., Hess, E. V., and Schmid, F. R.: Association of autoant ibod ies to r ibonucleoprote in and Sm antigens with mixedconnective tissue disease (MCTD), systemic lupus erythematosus (SLE) and other rheumatic diseases. Clin. Res. 23:50A, 1976. Hench, P. K., Edgington, T. S., and Tan, E. M.: The evolvingcl inical spectrumofmixed connectivetissue disease. Arthritis Rheum. 17:404, 1975. Gilliam, J. N., and Prystowsky, S. D.: Mixed connective tissue disease syndrome: The cutaneous manifestations of patients with high titer serum antibody to RNase sensitive extractable nuclear antigen (ENA). Arch. Dermatol. In press. Reichlin, M., and Mattioli, M.: Correlation of a precipitin reaction to an RNA protein antigen and a low prevalence of nephritis in patients with systemic lupus erythematosus. Engl. 1. Med. 286:908, 1972. Harmon, C., Wolfe, J. F., Lillard, S., Held, C., Cordan, R., and Sharp, G. C.: Pulmonary involvement in mixed connective tissue disease. Arthritis Rheum. 19:801, 1976. Gilliam, J. N.: The significance of cutaneous immunoglobulin deposits in lupus erythematosus and NZBlN ZW FI hybrid mice. J. Invest. Dermatol. 65:154, 1975. Cohen, A.S., Reynolds, W. E., Franklin, E.C., Kuller,J. P., Ropes, M. W., Shulman, L. E., and Wallace, S. L.: Preliminary criteria for the classification of systemic lupus erythematosus. Bull. Rheum. Dis. 21 :643, 1971.
Pediculosis Corporis This disease constitutes about three-quarters o f one per cent of all skin disorders. It occurs with equal frequency in the whites and blacks. There i s practically generalized itching, but the lesions are more numerous where the clothes are in close contact with the skin, as upon the shoulders. At times there may b e seen small haemorrhagic points, due to the bites, but these are not always present. The secondary lesions are the scratch-marks, usually linear, and most pronounced between the shoulder blades, and upon the shoulders. These often produce some scarring or atrophy, showing the violence of the scratching. Marked pigmentation of the skin may result and b e mistaken for Addison's disease.- Hazen, H. H.: Diseases of the Skin, Sf. Louis, C. V . Mosby, 1915, p. 233.
