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A histologic evaluation of mixed connective tissue disease in childhood
A Histologic Evaluation of Mixed Connective Tissue Disease in Childhood
BERNHARD H. SINGSEN. M.D.* VIRGINIA L. SWANSON, M.D. BRAM H. BERNSTEIN, M.D. EVA T. HEUSER, M.D. VIRGIL HANSON, M.D. BENJAMIN H. LANDING, M.D. Los Angeles, California
From the Division of Rheumatology and Rehabil ation, and the Department of Pathology, Chlldrens Hospital of Los Angeles; and the Departments of Pediatrics and Pathology, University of Southern California School of Medicine, Los Angeles, California. This study was supported in part by a grant from the Southern California Chapter of the Arthritis Foundation: Los Angeles, California. Requests for reprints should be addressed to Dr. Bernhard H. Singsen. Manuscript accepted September 19.1980. *Present address: Department of Child Health, University of Missouri Medical Center, 807 Stadium Boulevard, Columbia, Missouri 65212.
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Mixed connective tissue disease (MCTD) includes features of scleroderma, dermatomyositis and systemic lupus erythematosus (SLE), and has speckled antinuclear antibodies (ANA) and high titers of anti-RNP antibodies. There are no comprehensive investigations of its histopathology. We have followed $5 children with MCTD, of whom four have died (mean disease duration prior to death 5.4 years) The immediate causes of death were pneumococcal sepsis (two patients), meningococcal .sepsis (one patient) and uncontrollable thrombocytopenia.@e patient). Material from the three available autopsies and five ienal biopsies was reviewed. The most prominent histopathologic feature was widespread proliferative vascular lesions including intimal vascular change in 31 of 58 organs (53 per cent) and medial vessel wall thickening in nine organs (18 per cent). Systemic hypertension was absent; the normal vascular responses to aging could be excluded. Inflammatory infiltrates, often with prominent plasmacytosis, were present in 28 of 58 organs (45 per cent), but fibrinoid vascular change (9 per cent) and fibrosis (14 per cent) were rare. Eight renal specimens all showed some degree of glomerulonephritis; membranous change was present in three, and six showed significant vascular sclerosis. The histopathology of MCTD is superficially similar to systemic sclerosis, but it may be distinguished by less frequent fibrosis, the frequency of organs with intimal vascular change, and a predilection for intimal thickening of large arteries including coronary, pulmonary, renal and aortic. A distinctive replacement of muscle layers by hyaline in the gastrointestinal tract, and an unusual nodular hyperplasia of the thymic medulla were also observed and may be unique features of MCTD. The findings from this study suggest an immunologic basis for MCTD different from those postulated for other rheumatic diseases, and strongly suggest that adjustment of morbidity and mortality expectations for MCTD are necessary, Mixed connective tissue disease (MCTD], a syndrome characterized by overlapping clinical features of systemic lupus erythematosus (SLE), dermatomyositis and scleroderma, was first described by Sharp and co-workers in 1972 [l]. MCTD is also notable for its high titers of speckled antinuclear antibodies (ANA] and antibodies directed against the ribonucleoprotein (RNP) fraction of extractable nuclear antigen. Subsequent studies have compared the serologic characteristics of MCTD to those of other rheumatic diseases 12-91,further delineated its clinical features [lo-181 and described MCTD in children [19221. Two case reports of fatal MCTD in adults, with partial histologic descriptions, were published in 1976-1977 [23,24]. Prior to these reports,
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only isolated descriptions of skin (1,251. muscle [ZS] and renal [15-171 biopsy specimens were available. The present study describes the pathologic findings in MCTD in children on the basis of material from three autopsies, and five kidney and two skeletal muscle hiopsy specimens. MATERIAL During the past 16 years we have followed 15 children now confirmed to have MCTD. Their median age at onset of disease was 10.7 years [range four to 16 years). Four of these children have died. The range of observation prior to death was three to 10 years (mean: 5.4 years]. The immediate causes of death included pribumococcal sepsis in two, meningococcal sepsis in one (perhaps related to prior splenectomy for medically uncontrollable thrombocytopcnia) and cerebral hemorrhage associated with severe thrombocytopenia in one. Two of these children had not received corticosteroids for several years prior to death; the remaining two were receiving prednisolone. 5 mg/day and 7.5 mg every other day, respectively. Postmortem examination was refused in the latter patient with meningococcemia. It is belicvcd that the low corticosteroid dose in the former did not significantly alter the histologic features of the disease. Routine microscopic sections were stained with hcmatoxylin and eosin. Selected tissues were also stained with Masson’s trichromc. Jones’ silver mcthenamine. periodic acid-Schiff and Verhoeff-Van Gicson’s elastic stains.
ILLUSTRATIVE
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This girl, aged 15 vears in February 1974. had, from age 12 years, progres&c arthritis involving all large joints and the fingers. Spiking fevers were present for two months at the onset; Raynaud’s phenomenon had been present for one year. She had received aspirin and indomcthacin intermittently, and had been told she had either rheumatic fever or rheumatoid arthritis. There was rio familv history of rheumatic disease. Initial physical examination revealed taut, indurated skin over the fact and extreme thinning of skin on the arms. Finger joint flexion contractures, micrognathia with decreased jaw opening, and arthritis of the metatarso-phalangeal and ankle joints were also present. The remainder of the examination was within normal limits except for moderate muscle wasting. Neither an electrocardiogram nor a chest roentgenogram revealed any abnormalities, but roentgenograms of ihe hands revealed bony overgrowth at the proximal interphalangeal joints and advanced erosion of the distal phalanges of the index fingers bilaterally. Barium esophagram and pulmonary function studies were within normal limits. Speckled ANA was present at 1: 256. rheumatoid factor was absent. Titer of antibodies directed against RNP was 1:655.000; no anti-Sm or anti-DNA antibodies were present. The white blood cell count was 3,60O/mm”. the hemoglobin level was 10.3 g/d1 and the erythrocyte sedimentation rate was 57 mm/hour. The urinalysis showed trace protein. Serum
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creatine phosphokinase (CPK) was 360 IU (normal: 25 to 200 IU), lactic dehydrogenase (LDH] was 680 IIJ (normal: 200 to 500 IU). The serum total protein was 9.8 g/dl (normal: 6.5 to 8.5 g/dl), with 5.5 g/d1 of globulins; serum C3 was normal. Probable MCTD was diagnosed on the basis of arthritis, sclcroderma, Raynaud’s phenomenon, leukopenia. speckled ANA, RNP antibodies and evidence of myopathy. Prcdnisone therapy was refused. Aspirin and a physical therapy program were begun, but compliance with the aspirin was variable and complicated by tinnitus and gastritis. In March 1974. she experienced increased weakness and a violaceous rash over the knuckles and upper eyelids consistent with dermatomyositis (CPK 510 IU, LDH 760 IU). In July, the administration of prednisone. 15 mg twice daily, was begun. Joint swelling and pain decreased, and ranges of motion improved. Eight weeks later a reduction of the prednisone dose to 25 mg ori alternate days Icd to complaints of Raynaud’s phenomenon on the “off” days. She then discontinued taking prednisone because of cushingism. By June 1975 the patient had significant swallowing difficulty, and all other symptoms were exacerbated. A barium esophagram disclosed no abnormalities. In October, she experienced more pronounced proximal weakness, with further elevation of the serum muscle enzyme levels (CPK 2,400 IU, LDH 1,080 IU, SGOT 110 IU). The administration of prednisone. 10 mg twice daily, was restarted and hydroxychloroquine, 200 mg/day, was added. Rheumatoid factor was now present at 1:640. Over the next year calcinosis and recurrent cellulitis developed at several sites. During this final year the patient refused corticosteroid therapy. In June 1976, Diplococcus pneumoniae sepsis developed which responded to the intravenous administration of ampicillin. Pulmonary function test results were normal, but in October 1976 a barium esophagram revealed decreased peristalsis and moderate dilation. In December 1976, while visiting relatives in Mexico, the patient had a rapidly developing fever. headache and decreased vision. She was brought to a local hospital where the onset of seizures and coma preceded her death bv 6 hours. Blood and cerebrospinal fluid cultures grew Diplococcus pneumoniae. PATHOLOGIC MATERIAL At postmortem examination included the following:
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Autopsy A-l: Multiple petechiae, muscle wasting, subcutaneous fat loss, extensive sclerodermatous skin, slight cardiomegaly. diffuse lymphadenopathy, spleen twice normal size, prominent splenic lymphoid follicles and colonic Peycr’s patches, and diffuse left subdural, subarachnoid and intracerebral hemorrhage.
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Autopsy A-2: Moderate biventiicular cardiac hypertrophy, diffuse pulmonary edema, and hepatosplenomegaly.
patients (Table I), and medial wall thickening was observed in nine (16 per cent). A total of 33 of 58 organs (57 per cent] showed vascular lesions (Figures 1 through 4). None of the children ever had systemic hypertension. Fibrinoid vascular changes were seen in only five of 58 organs (9 per cent) and fibrosis in eight of 58 (14 per cent). Inflammatory infiltration, often containing plasmacytes, was present in 26 of the 58 organs (45 per cent), with skeletal muscle, myocardium, liver, salivary gland and esophagus the most common sites. Eight renal specimens were examined [three obtained at autopsy and five obtained at biopsy), including three biopsy specimens (1966-1978) from one patient. The findings are displayed in Table II. Immunofluorescent and electron microscopic studies were not available. Figures 1 through 4 illustrate the type and severity of vascular lesions observed; Figures 4 through 7 emphasize tissues in which the type or degree of histologic change found was unexpected. Other unique histopathologic features which are not illustrated included: (1) massive infiltration of lymphocytes and plasma cells in two of two parotid glands, with accompanying loss of acinar tissue, and epithelioid metaplasia of ducts (myoepithelial islands]: (2) marked plasmacytosis of all
Autopsy A-3 (illustrative case]: Arthritic deformities of the hands, fingers and toes, pulmonary congestion and edema, splenic congestion, and cloudy meninges. This autopsy was performed at another hospital; only selected tissues were available for histologic evaluation. Microscopic Findings. A summary of major histologic features found at autopsy is presented in Table I. The most prominent finding was that of widespread proliferative vascular lesions. In the material reviewed, only skin, bone and thymus revealed no such vascular changes. Of particular interest was the frequency of vascular change in organs which had not shown clinical abnormality, including myocardium, coronary vessels, aorta, pancreas, salivary gland and kidney for patient A-l; myocardium, coronary vessels, small and large bowel and pancreas for patient A-Z; and myocardium, large bowel, and salivary gland for patient A-3. Intimal vascular change was present in 31 of 58 (53 per cent) organs examined microscopically from the three
TABLE I
Histologic Findings in Childhood MCTD Proiifsrative Vascular L&HIS
Myocardium Coronary vessels Aorta Lung Spleen Esophagus Small intestine Colon Pancreas Liver Kidney Adrenal Bladder Gonad Uterus Breast Muscle Skin Lymph nodes Thymus Thyroid Salivary gland Synovium Bone
Medial Thickening
lnliial Thickening
Site Al
A2
+ + + + + +
+ +
-If + 0 + 0 + + NA NA + 0 0 NA 0 + NA 0 +
NA + + + + + 0 + 0 + 0 0 0 0 0 0 0 + 0 NA 0 0 0
A3
inflammalory infiitrales
Al
A2
A3
Al
A2
+
+
+
+
+
NA NA + 0 0 + + NA 0 0 NA NA NA NA NA 0 0 + NA NA + NA 0 0
0 0 0 + 0 0 0 + 0 + 0 0 0 NA NA + 0 + NA 0 0 NA 0 0
0 NA 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 NA 0 0 0
NA NA 0 + 0 0 0 NA 0 0 NA NA NA NA NA 0 0 0 NA NA 0 NA 0 0
0 0 0 + + + 0 0 + 0 0 + 0
NA NA + 0 0 NA 0 + NA 0 0
Fibrisoid Change
Fibrosis
A3
Al
A2
A3
Al
A2
A3
+
+
+
NA NA 0 + + 0 0 NA + + NA NA NA NA NA +
0 0 0
: NA NA + NA 0 0
0 NA NA 0 0 + 0 0 NA 0 0 NA NA NA NA NA 0 0 0 NA NA 0 NA 0 0
0 0 0 0 0 + 0 + + 0
0+ 0 + NA + 0 0
0 0 NA 0 0 + 0 0 0 0 + 0 0 0 0 0 0 0 0 0 0 NA 0 0 0
+
0 NA 0 + + + 0 0 + + 0 0 0 0 0 +
0 NA NA 0 0 0 0 0 NA 0 0 NA NA NA NA NA 0 + 0 NA NA 0 NA 0 0
0 +
0 0 0 0 0 0 0 0 NA NA 0 0 0 NA 0 0 NA 0 0
NOTE: •t = present; 0 = absent; NA = no tissue available. At autopsy: Al = 14.4 year old male; duration of disease year old female; duration of disease 3.5 years. A3 = 14.9 year old female; duration of disease 2.9 years.
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0 0 0 NA NA 0 + 0 NA 0 0 NA 0 0 9.9 years.
0 NA 0 0 + 0 0 0 0 0 0 0 0 0 0 0 + 0 0 0 NA 0 0 0
A2 = 15.1
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Figure 1. Photomicrograph of a coronary artery from patient A-l showing marked intimal thickening. Hematoxylin and eosin stain; magnification X 226, reduced by 50 per cent.
Figure 3. Photomicrograph of a small serosal artery from the ileo-cecal region showing striking intimal thickening (A-2). Hematoxylin and eosin stain; magnification X 226, reduced by 48 per cent.
Figure 5. Two glomeruli illustrating m lularity and extracapiltary proliferation (crescent;), with heavy interstitial round cell infiltrates. Hematoxylin and eosin stain; magnification X 566, reduced by 49 per cent.
demonstrated Fiiure 2. Significant intimaiproiiferation*is in this photomicrograph of the aorta from patient A-l. Hematoxylin and eosin stain; magnification X 226, reduced by 23 per cent.
Figure 4. This photomicrograph of myocardial th a patient with no prior clinical evidence of cardiac disease (A-l), shows focal muscle fiber necrosis, increased interstitial connective tissue and numbers of inflammatory cells, and arteriolar thickening. Hematoxylin and eosin stain: magnification X 226, reduced by 46 per cent.
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Ftgure 6. Photomicrograph of liver (A-3) demonstrating chronic portal infiltration. The infiltrate, which contains large numbers of plasma cells, has a nodular appearance. Hematoxylin and eosin stain; magnification X 566, reduced by 46 per cent.
Figure 7. Photomicrograph of the esophagus (A-2) demonstrating degenerating inner muscle layer, with hyaline material resembling “ground substance.” Similar muscle degeneration was found in the pylorus of patient A-2, and in the esophagus and colon of patient A-3. Trichrome stain; magnification X 226, reduced by 46 per cent.
three spleens, with typical “onion-skin” lesions of smaller arterioles and intimal thickening of arteries; (3) the one available thymus showed medullary nodular hyperplasia (lymphocytes and plasma cells] and a cortex which was not as involuted as might be expected for a chronic disease of three and a half years duration.
features of rheumatoid arthritis, dermatomyositis, SLE and scleroderma [27]. One feature which has been suggested as unique to MCTD, in addition to the high titers of anti-RNP antibodies, is its frequently dramatic responsiveness to corticosteroids [lO,28]. This observation, however, should be viewed in the light of recent clinical impressions, from many investigators [20,29-331, suggesting that corticosteroid nonresponsive, scleroderma-like disease may be a frequent late feature of MCTD. The present report was given impetus by the autopsy
COMMENTS The first specific delineation of MCTD was in 1972 [l], although many clinicians and investigators had long appreciated that some patients manifested various
TABLE II
MCTD Renal Tfssue Characterlstlcs
from Three Autopsy Specimens
Gbmenlli
Parahrma
8owce A-l
Mild mesangial hypercellularity
Normal
A-2
Membranous glornerulonephritis,
Focal atrophy
Biopsy- 1
with focal mesangial hypercellularity and focal glomerular scarring MIM focal mesangial hypercellularity; rare focal scarred glomerulus Mild mesangial proliferation
Biopsy-2
Mild focal glomerulitis
Biopsy-3a (1966) Biopsy-3b (1971)
Miid mesangial proliferation
A-3
Biopsy-3c (1976)
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Membranous glomerulonephritis, with membrane-proliferative and focal extracapillary proliferative Almost total glomerular scarring, membranous change in few functional glomeruli
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and Five Biopsy Specimens Ve6selr Mild to severe intimal sclerosis of arcuate, inter- and intra-lobular arteries Severe intimal sclerosis of intralobular arteries
Focal atrophy; some mononuclear cells about arcuate septum Heavy mononuclear interstitial infiltrate; tubules normal Mild mononuclear infiltrate
Focal intimal sclerosis, all levels of vessels Normal
Well developed atrophy and severe interstitial plasma cell infiltrate
Arterioles with medial thickening; larger arteries normal
End-stags atrophy and scarring: scanty lymphocytic infiltrates.
Severe intimal and medial sclerosis of arteries and arterioles.
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Marked intimal thickening in large arteries and medial hypertrophy of middle-sized vessels Normal
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findings in A-2. Our hypotheses, supported by the two subsequently available autopsies, were that in MCTD significant vascular abnormalities might be present years in advance of clinical symptoms and that, although histologically suggestive of scleroderma, important pathologic differences also existed. Rheumatic diseases with associated sclerodermatous skin have long been recognized [27]; however, scleroderma skin and, perhaps, the associated internal organ derangements, probably represent only one particular type of reaction to vascular or immunologic injury, rather than a pathognomonic finding for a specific disease [34]. This concept is important because of the prior tendency of some investigators to classify MCTD as a variant of SLE [35,36] and because others might define MCTD as merely a variant of scleroderma. Recently, emphasis has been placed on generalized involvement of the microvasculature as the primary site of injury in scleroderma [31,37,38]. The findings from the present study support the concept of a basic vascular process in MCTD. However, several important histopathologic features appear to distinguish MCTD from scleroderma. (1) Significant fibrosis, except in the skin, was strikingly absent in our patients with MCTD, in comparison to the frequency in lungs, myocardium and gastrointestinal tract found in the controlled study of scleroderma by D’Angelo and co-workers [38]. Whether the mild degree of fibrosis found in pediatric MCTD reflects younger age, shorter duration of disease or a basic difference in the disease process cannot yet be decided. (2) Comparison of the vascular lesions from this series of patients with MCTD with those of scleroderma is difficult because of the widely varying degrees of attention which have been directed towards vascular lesions in scleroderma. As noted by Campbell and LeRoy [31], the presence of vascular lesions in adult scleroderma may be underestimated if they are not present in all organs or if they are obscured by atrophy and fibrosis. The high frequency of proliferative intimal lesions observed in our patients may hence be due to younger age, with perhaps less advanced fibrosis and scarring, or to their having a disease process different from scleroderma. (3) Capillary involvement was conspicuous by its absence in our children with MCTD, in contrast to its frequency in scleroderma [31,37]. (4) Fibrinoid vascular change occurs in a number of vasculitides, including scleroderma and malignant hypertension; its rarity in MCTD, therefore, appears noteworthy. (5) Various investigators have noted the absence of large vessel involvement in scleroderma [31,37]. In our children with MCTD, intimal proliferation in the aorta and larger coronary, pulmonary and renal arteries was striking. This aspect of MCTD has not previously been described and deserves emphasis because, in a pediatric
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population, the various proliferative vascular process of aging are not present. In the few instances in which large vessel disease has been reported in scleroderma [39,40],one investigator has speculated that the changes were due to disease of the vasa vasorum [37]. An alternative is that the condition in some of those patients represented unrecognized MCTD. The widespread proliferative intimal lesions, in small and large arteries in MCTD, is worrisome. Vascular compromise, leading to hypertension and organ failure [l3], or to hemorrhage [24], has been documented in a few cases. The vascular changes that we observed may indicate that such complications of MCTD will become more common as durations of follow-up lengthen. Inflammatory infiltrates, often plasmacytic in character, were prominent in several organs including liver, salivary gland, and intestine. It is possible that these plasmacytic infiltrates are the histologic counterpart of the commonly observed hypergammaglobulinemia of MCTD [9,10,20]. All five muscle specimens showed some degree of inflammatory infiltration. Sarcolemmal nuclear proliferation and perivascular inflammation were observed in three patients, two of whom had no clinical weakness. These observations support the finding by Oxenhandler and co-workers [26], of a high incidence of focal inflammatory lesions in the skeletal muscles of adults with MCTD. Similar inflammatory infiltration was present in all three hearts, two of which had never been clinically abnormal. The observed myocardial inflammation and coronary vascular changes explain the frequency of cardiac involvement in childhood MCTD [zO], and may suggest that adults with MCTD will experience more cardiac complications as durations of follow-up lengthen. The relative importance of Sjogren’s syndrome in MCTD is not clear. Features of Sjogren’s syndrome were noted in early reports of pediatric and adult MCTD [10,19] and have recently been emphasized [22,41]. The frequent association of Sjogren’s syndrome with other rheumatic diseases, and its remarkable degree of immunologic hyper-reactivity when observed as an isolated entity [42], both make separation of its features from MCTD difficult. The degree of inflammation and myoepithelial change noted in the two salivary glands available, both from children without clinical findings of Sjogren’s syndrome, was initially surprising. The signs and symptoms of Sjogren’s syndrome may, however, remain subclinical unlesqcarefully searched for [zz]. These observations suggest that Sjogren’s syndrome may be a common feature of MCTD. Initial studies of MCTD suggested a low (5 to 10 per cent) incidence of renal disease [10,31], but evidence of membranous glomerulonephritis is increasingly common [11,15-17,20,21]. After case reports [15,16] are excluded because of prior selection, remaining recent
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studies give a combined incidence of 28 per cent. Most of these patients had evidence of glomerular immune complex deposition, an observation which is strengthened by a recent report wherein the frequency and titer of circulating immune complexes were found to be comparable in SLE and MCTD [43]. In our experience, seven of 15 children (47 per cent] have had clinical or histologic evidence of renal disease; five biopsy and three autopsy specimens, from a total of six children, have all shown proliferative or membranous glomerulonephritis. Five of these six also had renal vascular sclerosis. Of the living children, the disease in two has progressed to renal failure, and they are receiving hemodialysis. Another child, subjected to biopsy because of progressive hypertension, showed little glomerular inflammation but had severe intimal proliferation and luminal narrowing of renal arterioles. In SLE, membranous glomerulonephritis is frequently indolent, resistant to medical therapy, and slowly progressive, with renal failure occurring in some cases [44]. Our patients who eventually required hemodialysis document that significant renal morbidity may also result from MCTD. We concur with Bennett and Spargo [17] that the incidence of membranous glomerulonephritis in MCTD is underestimated and suggest that a
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better understanding of the frequency, severity and progression of renal disease in MCTD is needed. Two other unique findings from our data deserve comment. The first is the distinctive replacement of the inner, and occasionally outer, muscle layers of the esophagus, pylorus and colon by hyaline material. These changes, found in two of three autopsies, appear different from the gastrointestinal muscle atrophy or fibrosis commonly reported in scleroderma [38]. The second is the unusual degree of nodular hyperplasia of medullary lymphocytes and plasma cells, and striking lack of cortical involution in the one available thymus, relative to that expected for a chronic disease of three and a half years duration. Both of these thymic features are different from those usually seen in childhood SLE or juvenile rheumatoid arthritis [45]. The findings from this study indicate that significant histopathologic variations differentiate MCTD from scleroderma, and the other rheumatic components of MCTD, even though MCTD does occasionally progress to a systemic sclerosis-like pattern [3l]. The vascular and renal findings suggest that a significant adjustment of our present opinions of the prognosis of MCTD, as regards both morbidity and mortality, may become necessary.
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(abstract]. Arthritis Rheum 1975; 18: 404. 12. Silver TM, Farber SJ, Bole GG, Martel W: Radiological features of mixed connective tissue disease and scleroderma-systemic lupus etythematosus overlap. Radiology 1976: 120: 269-275. 13. Harmon C. Wolfe F. Lillard S. Held C. Cordon R. Sharo GC: Pulmonary involvement in mixed connective tissue d&ase (MCTD) (abstract). Arthritis Rheum 1976; 19: 801. 14. Alarcon-Segovia D: Symptomatic Sjiigren’s syndrome in mixed connective tissue disease. 1 Rheumatol 1978: 3: 191-195. 15. Rao KV. Berkseth RO. Crosson IT. Raii L, Shaoiro FL: Immune.complex nephritis in mixed connecti;e tissue disease. Ann Intern Med 1978; 84: 174-176. 16. Fuller TJ, Richman AV, Auerbach D, Alexander RW, Lottenberg R, Longley S: Immune-complex glomerulonephritis in a patient with mixed connective tissue disease. Am J Med 1977; 62: 781-764. 17. Bennett RM, Spargo BH: Immune complex nephropathy in mixed connective tissue disease. Am J Med 1977; 83: 534-541. 18. Gilliam JN, Prystowsky SD: Conversion of discoid lupus ervthematosus to mixed connective tissue disease. I Rheumatoll977; 4: 165-169. 19. Sanders DY. Huntlev CC. Sharo GC: Mixed connective tissue disease in a child. J Pediatri973; 83: 642-845. 20. Singsen BH, Bernstein BH, Kornreich HK. King KK, Hanson V, Tan EM: Mixed connective tissue disease in childhood: A clinical and serologic survey. J Pediatr 1977; 90: 893900. 21. Baldassare A, Weiss T, Auclair R, Zuckner J: Mixed connective tissue disease IMCTDl in children labstractl. Arthritis Rheum 1976; 191788. . 22. Fraga A, Gudino J. Ramos-Niembro F, Alarcon-Segovia D: Mixed connective tissue disease in childhood. Relationship with SjBgren’s syndrome. Am J Dis Child 1978: 132: 263265. 23. Kennedy JM: Mixed connective tissue disease: a case report.
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Arizona Med 1976; 33: 192-193 Cooke CL, Lurie HI: Case report: Fatal gastrointestinal hemorrhage in mixed connective tissue disease. Arthritis Rheum 1977; 20: 1421-1427. 25. Levitin PM, Weary PE, Giuliano VJ: The immunofluorescent “band” test in mixed connective tissue disease. Ann Intern Med 1975; 83: 53-55. 26. Oxenhandler R, Hart M, Corman L, Sharp G, Adelstein E: Pathology of skeletal muscle in mixed connective tissue disease. Arthritis Rheum 1977; 20: 985-988. 27 Tuffanelli DL, Winkelmann RK: Scleroderma and its relationship to the “collagenoses” dermatomyositis, lupus erythematosus, rheumatoid arthritis and Sjogren’s syndrome. Am J Med Sci 1962; 243: 133-146. 28. Sharp GC, Irvin WS. May CM, et al.: Association of antibodies to ribonucleoprotein and Sm antigens with mixed connective tissue disease, systemic lupus erythematosus and other rheumatic diseases. N Engl - ,I Med 1976: 295: 24.
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42. 43. 44. 45.
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Reichlin M: Mixed Connective Tissue Disease. Modern topics in rheumatology. London: W. H. Heineman, 1976; 157-162. Norton WL, Nardo JM: Vascular disease in progressive systemic sclerosis (scleroderma). Ann Intern Med 1970; 73: 317-324. D’Angelo WA, Fries JF, Masi AT, Shulman LE: Pathologic observations in systemic sclerosis (scleroderma): a study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med 1969; 46: 428-440. Rota LM, Kissane JM: Panaortitis and aortic valvulitis in progressive systemic sclerosis (scleroderma). Am J Clin Pathol 1964; 41: 287-296. Lee JE, Haynes JM; Carotid arteritis and cerebral infarction due to scleroderma. Neurology 1967; 17: 18-22. Alarcon-Segovia D: Symptomatic SjBgren’s syndrome in mixed connective tissue disease. J Rheumatol 1976; 3: 191-195. Shearn MA: Sjogren’s syndrome. Med Clin North Am 1977; 61: 271-282. Parker MD, Marion T: Circulating complement-fixing immune complexes in mixed connective tissue disease. Arthritis Rheum 1977; 20: 130. Baldwin DS, Lowenstein J, Rothfield NF, et al.: The clinical course of proliferative and membranous forms of lupus nephritis. Ann Intern Med 1970; 73: 929-942. Landing BH. Yutuc IL, Swanson VL: Clinicopathologic correlations in immunologic deficiency diseases of children, with emphasis on thymic histologic patterns. In: Kobayashi N. ed. Immunodeficiency: its nature and etiologic significance in human diseases. Tokyo: University of Tokyo Press, 1978.
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BERNHARD H. SINGSEN. M.D.* VIRGINIA L. SWANSON, M.D. BRAM H. BERNSTEIN, M.D. EVA T. HEUSER, M.D. VIRGIL HANSON, M.D. BENJAMIN H. LANDING, M.D. Los Angeles, California
From the Division of Rheumatology and Rehabil ation, and the Department of Pathology, Chlldrens Hospital of Los Angeles; and the Departments of Pediatrics and Pathology, University of Southern California School of Medicine, Los Angeles, California. This study was supported in part by a grant from the Southern California Chapter of the Arthritis Foundation: Los Angeles, California. Requests for reprints should be addressed to Dr. Bernhard H. Singsen. Manuscript accepted September 19.1980. *Present address: Department of Child Health, University of Missouri Medical Center, 807 Stadium Boulevard, Columbia, Missouri 65212.
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Mixed connective tissue disease (MCTD) includes features of scleroderma, dermatomyositis and systemic lupus erythematosus (SLE), and has speckled antinuclear antibodies (ANA) and high titers of anti-RNP antibodies. There are no comprehensive investigations of its histopathology. We have followed $5 children with MCTD, of whom four have died (mean disease duration prior to death 5.4 years) The immediate causes of death were pneumococcal sepsis (two patients), meningococcal .sepsis (one patient) and uncontrollable thrombocytopenia.@e patient). Material from the three available autopsies and five ienal biopsies was reviewed. The most prominent histopathologic feature was widespread proliferative vascular lesions including intimal vascular change in 31 of 58 organs (53 per cent) and medial vessel wall thickening in nine organs (18 per cent). Systemic hypertension was absent; the normal vascular responses to aging could be excluded. Inflammatory infiltrates, often with prominent plasmacytosis, were present in 28 of 58 organs (45 per cent), but fibrinoid vascular change (9 per cent) and fibrosis (14 per cent) were rare. Eight renal specimens all showed some degree of glomerulonephritis; membranous change was present in three, and six showed significant vascular sclerosis. The histopathology of MCTD is superficially similar to systemic sclerosis, but it may be distinguished by less frequent fibrosis, the frequency of organs with intimal vascular change, and a predilection for intimal thickening of large arteries including coronary, pulmonary, renal and aortic. A distinctive replacement of muscle layers by hyaline in the gastrointestinal tract, and an unusual nodular hyperplasia of the thymic medulla were also observed and may be unique features of MCTD. The findings from this study suggest an immunologic basis for MCTD different from those postulated for other rheumatic diseases, and strongly suggest that adjustment of morbidity and mortality expectations for MCTD are necessary, Mixed connective tissue disease (MCTD], a syndrome characterized by overlapping clinical features of systemic lupus erythematosus (SLE), dermatomyositis and scleroderma, was first described by Sharp and co-workers in 1972 [l]. MCTD is also notable for its high titers of speckled antinuclear antibodies (ANA] and antibodies directed against the ribonucleoprotein (RNP) fraction of extractable nuclear antigen. Subsequent studies have compared the serologic characteristics of MCTD to those of other rheumatic diseases 12-91,further delineated its clinical features [lo-181 and described MCTD in children [19221. Two case reports of fatal MCTD in adults, with partial histologic descriptions, were published in 1976-1977 [23,24]. Prior to these reports,
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only isolated descriptions of skin (1,251. muscle [ZS] and renal [15-171 biopsy specimens were available. The present study describes the pathologic findings in MCTD in children on the basis of material from three autopsies, and five kidney and two skeletal muscle hiopsy specimens. MATERIAL During the past 16 years we have followed 15 children now confirmed to have MCTD. Their median age at onset of disease was 10.7 years [range four to 16 years). Four of these children have died. The range of observation prior to death was three to 10 years (mean: 5.4 years]. The immediate causes of death included pribumococcal sepsis in two, meningococcal sepsis in one (perhaps related to prior splenectomy for medically uncontrollable thrombocytopcnia) and cerebral hemorrhage associated with severe thrombocytopenia in one. Two of these children had not received corticosteroids for several years prior to death; the remaining two were receiving prednisolone. 5 mg/day and 7.5 mg every other day, respectively. Postmortem examination was refused in the latter patient with meningococcemia. It is belicvcd that the low corticosteroid dose in the former did not significantly alter the histologic features of the disease. Routine microscopic sections were stained with hcmatoxylin and eosin. Selected tissues were also stained with Masson’s trichromc. Jones’ silver mcthenamine. periodic acid-Schiff and Verhoeff-Van Gicson’s elastic stains.
ILLUSTRATIVE
CASE
This girl, aged 15 vears in February 1974. had, from age 12 years, progres&c arthritis involving all large joints and the fingers. Spiking fevers were present for two months at the onset; Raynaud’s phenomenon had been present for one year. She had received aspirin and indomcthacin intermittently, and had been told she had either rheumatic fever or rheumatoid arthritis. There was rio familv history of rheumatic disease. Initial physical examination revealed taut, indurated skin over the fact and extreme thinning of skin on the arms. Finger joint flexion contractures, micrognathia with decreased jaw opening, and arthritis of the metatarso-phalangeal and ankle joints were also present. The remainder of the examination was within normal limits except for moderate muscle wasting. Neither an electrocardiogram nor a chest roentgenogram revealed any abnormalities, but roentgenograms of ihe hands revealed bony overgrowth at the proximal interphalangeal joints and advanced erosion of the distal phalanges of the index fingers bilaterally. Barium esophagram and pulmonary function studies were within normal limits. Speckled ANA was present at 1: 256. rheumatoid factor was absent. Titer of antibodies directed against RNP was 1:655.000; no anti-Sm or anti-DNA antibodies were present. The white blood cell count was 3,60O/mm”. the hemoglobin level was 10.3 g/d1 and the erythrocyte sedimentation rate was 57 mm/hour. The urinalysis showed trace protein. Serum
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creatine phosphokinase (CPK) was 360 IU (normal: 25 to 200 IU), lactic dehydrogenase (LDH] was 680 IIJ (normal: 200 to 500 IU). The serum total protein was 9.8 g/dl (normal: 6.5 to 8.5 g/dl), with 5.5 g/d1 of globulins; serum C3 was normal. Probable MCTD was diagnosed on the basis of arthritis, sclcroderma, Raynaud’s phenomenon, leukopenia. speckled ANA, RNP antibodies and evidence of myopathy. Prcdnisone therapy was refused. Aspirin and a physical therapy program were begun, but compliance with the aspirin was variable and complicated by tinnitus and gastritis. In March 1974. she experienced increased weakness and a violaceous rash over the knuckles and upper eyelids consistent with dermatomyositis (CPK 510 IU, LDH 760 IU). In July, the administration of prednisone. 15 mg twice daily, was begun. Joint swelling and pain decreased, and ranges of motion improved. Eight weeks later a reduction of the prednisone dose to 25 mg ori alternate days Icd to complaints of Raynaud’s phenomenon on the “off” days. She then discontinued taking prednisone because of cushingism. By June 1975 the patient had significant swallowing difficulty, and all other symptoms were exacerbated. A barium esophagram disclosed no abnormalities. In October, she experienced more pronounced proximal weakness, with further elevation of the serum muscle enzyme levels (CPK 2,400 IU, LDH 1,080 IU, SGOT 110 IU). The administration of prednisone. 10 mg twice daily, was restarted and hydroxychloroquine, 200 mg/day, was added. Rheumatoid factor was now present at 1:640. Over the next year calcinosis and recurrent cellulitis developed at several sites. During this final year the patient refused corticosteroid therapy. In June 1976, Diplococcus pneumoniae sepsis developed which responded to the intravenous administration of ampicillin. Pulmonary function test results were normal, but in October 1976 a barium esophagram revealed decreased peristalsis and moderate dilation. In December 1976, while visiting relatives in Mexico, the patient had a rapidly developing fever. headache and decreased vision. She was brought to a local hospital where the onset of seizures and coma preceded her death bv 6 hours. Blood and cerebrospinal fluid cultures grew Diplococcus pneumoniae. PATHOLOGIC MATERIAL At postmortem examination included the following:
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features
Autopsy A-l: Multiple petechiae, muscle wasting, subcutaneous fat loss, extensive sclerodermatous skin, slight cardiomegaly. diffuse lymphadenopathy, spleen twice normal size, prominent splenic lymphoid follicles and colonic Peycr’s patches, and diffuse left subdural, subarachnoid and intracerebral hemorrhage.
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Autopsy A-2: Moderate biventiicular cardiac hypertrophy, diffuse pulmonary edema, and hepatosplenomegaly.
patients (Table I), and medial wall thickening was observed in nine (16 per cent). A total of 33 of 58 organs (57 per cent] showed vascular lesions (Figures 1 through 4). None of the children ever had systemic hypertension. Fibrinoid vascular changes were seen in only five of 58 organs (9 per cent) and fibrosis in eight of 58 (14 per cent). Inflammatory infiltration, often containing plasmacytes, was present in 26 of the 58 organs (45 per cent), with skeletal muscle, myocardium, liver, salivary gland and esophagus the most common sites. Eight renal specimens were examined [three obtained at autopsy and five obtained at biopsy), including three biopsy specimens (1966-1978) from one patient. The findings are displayed in Table II. Immunofluorescent and electron microscopic studies were not available. Figures 1 through 4 illustrate the type and severity of vascular lesions observed; Figures 4 through 7 emphasize tissues in which the type or degree of histologic change found was unexpected. Other unique histopathologic features which are not illustrated included: (1) massive infiltration of lymphocytes and plasma cells in two of two parotid glands, with accompanying loss of acinar tissue, and epithelioid metaplasia of ducts (myoepithelial islands]: (2) marked plasmacytosis of all
Autopsy A-3 (illustrative case]: Arthritic deformities of the hands, fingers and toes, pulmonary congestion and edema, splenic congestion, and cloudy meninges. This autopsy was performed at another hospital; only selected tissues were available for histologic evaluation. Microscopic Findings. A summary of major histologic features found at autopsy is presented in Table I. The most prominent finding was that of widespread proliferative vascular lesions. In the material reviewed, only skin, bone and thymus revealed no such vascular changes. Of particular interest was the frequency of vascular change in organs which had not shown clinical abnormality, including myocardium, coronary vessels, aorta, pancreas, salivary gland and kidney for patient A-l; myocardium, coronary vessels, small and large bowel and pancreas for patient A-Z; and myocardium, large bowel, and salivary gland for patient A-3. Intimal vascular change was present in 31 of 58 (53 per cent) organs examined microscopically from the three
TABLE I
Histologic Findings in Childhood MCTD Proiifsrative Vascular L&HIS
Myocardium Coronary vessels Aorta Lung Spleen Esophagus Small intestine Colon Pancreas Liver Kidney Adrenal Bladder Gonad Uterus Breast Muscle Skin Lymph nodes Thymus Thyroid Salivary gland Synovium Bone
Medial Thickening
lnliial Thickening
Site Al
A2
+ + + + + +
+ +
-If + 0 + 0 + + NA NA + 0 0 NA 0 + NA 0 +
NA + + + + + 0 + 0 + 0 0 0 0 0 0 0 + 0 NA 0 0 0
A3
inflammalory infiitrales
Al
A2
A3
Al
A2
+
+
+
+
+
NA NA + 0 0 + + NA 0 0 NA NA NA NA NA 0 0 + NA NA + NA 0 0
0 0 0 + 0 0 0 + 0 + 0 0 0 NA NA + 0 + NA 0 0 NA 0 0
0 NA 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 NA 0 0 0
NA NA 0 + 0 0 0 NA 0 0 NA NA NA NA NA 0 0 0 NA NA 0 NA 0 0
0 0 0 + + + 0 0 + 0 0 + 0
NA NA + 0 0 NA 0 + NA 0 0
Fibrisoid Change
Fibrosis
A3
Al
A2
A3
Al
A2
A3
+
+
+
NA NA 0 + + 0 0 NA + + NA NA NA NA NA +
0 0 0
: NA NA + NA 0 0
0 NA NA 0 0 + 0 0 NA 0 0 NA NA NA NA NA 0 0 0 NA NA 0 NA 0 0
0 0 0 0 0 + 0 + + 0
0+ 0 + NA + 0 0
0 0 NA 0 0 + 0 0 0 0 + 0 0 0 0 0 0 0 0 0 0 NA 0 0 0
+
0 NA 0 + + + 0 0 + + 0 0 0 0 0 +
0 NA NA 0 0 0 0 0 NA 0 0 NA NA NA NA NA 0 + 0 NA NA 0 NA 0 0
0 +
0 0 0 0 0 0 0 0 NA NA 0 0 0 NA 0 0 NA 0 0
NOTE: •t = present; 0 = absent; NA = no tissue available. At autopsy: Al = 14.4 year old male; duration of disease year old female; duration of disease 3.5 years. A3 = 14.9 year old female; duration of disease 2.9 years.
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0 0 0 NA NA 0 + 0 NA 0 0 NA 0 0 9.9 years.
0 NA 0 0 + 0 0 0 0 0 0 0 0 0 0 0 + 0 0 0 NA 0 0 0
A2 = 15.1
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Figure 1. Photomicrograph of a coronary artery from patient A-l showing marked intimal thickening. Hematoxylin and eosin stain; magnification X 226, reduced by 50 per cent.
Figure 3. Photomicrograph of a small serosal artery from the ileo-cecal region showing striking intimal thickening (A-2). Hematoxylin and eosin stain; magnification X 226, reduced by 48 per cent.
Figure 5. Two glomeruli illustrating m lularity and extracapiltary proliferation (crescent;), with heavy interstitial round cell infiltrates. Hematoxylin and eosin stain; magnification X 566, reduced by 49 per cent.
demonstrated Fiiure 2. Significant intimaiproiiferation*is in this photomicrograph of the aorta from patient A-l. Hematoxylin and eosin stain; magnification X 226, reduced by 23 per cent.
Figure 4. This photomicrograph of myocardial th a patient with no prior clinical evidence of cardiac disease (A-l), shows focal muscle fiber necrosis, increased interstitial connective tissue and numbers of inflammatory cells, and arteriolar thickening. Hematoxylin and eosin stain: magnification X 226, reduced by 46 per cent.
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-l_l.-^..-
Ftgure 6. Photomicrograph of liver (A-3) demonstrating chronic portal infiltration. The infiltrate, which contains large numbers of plasma cells, has a nodular appearance. Hematoxylin and eosin stain; magnification X 566, reduced by 46 per cent.
Figure 7. Photomicrograph of the esophagus (A-2) demonstrating degenerating inner muscle layer, with hyaline material resembling “ground substance.” Similar muscle degeneration was found in the pylorus of patient A-2, and in the esophagus and colon of patient A-3. Trichrome stain; magnification X 226, reduced by 46 per cent.
three spleens, with typical “onion-skin” lesions of smaller arterioles and intimal thickening of arteries; (3) the one available thymus showed medullary nodular hyperplasia (lymphocytes and plasma cells] and a cortex which was not as involuted as might be expected for a chronic disease of three and a half years duration.
features of rheumatoid arthritis, dermatomyositis, SLE and scleroderma [27]. One feature which has been suggested as unique to MCTD, in addition to the high titers of anti-RNP antibodies, is its frequently dramatic responsiveness to corticosteroids [lO,28]. This observation, however, should be viewed in the light of recent clinical impressions, from many investigators [20,29-331, suggesting that corticosteroid nonresponsive, scleroderma-like disease may be a frequent late feature of MCTD. The present report was given impetus by the autopsy
COMMENTS The first specific delineation of MCTD was in 1972 [l], although many clinicians and investigators had long appreciated that some patients manifested various
TABLE II
MCTD Renal Tfssue Characterlstlcs
from Three Autopsy Specimens
Gbmenlli
Parahrma
8owce A-l
Mild mesangial hypercellularity
Normal
A-2
Membranous glornerulonephritis,
Focal atrophy
Biopsy- 1
with focal mesangial hypercellularity and focal glomerular scarring MIM focal mesangial hypercellularity; rare focal scarred glomerulus Mild mesangial proliferation
Biopsy-2
Mild focal glomerulitis
Biopsy-3a (1966) Biopsy-3b (1971)
Miid mesangial proliferation
A-3
Biopsy-3c (1976)
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Membranous glomerulonephritis, with membrane-proliferative and focal extracapillary proliferative Almost total glomerular scarring, membranous change in few functional glomeruli
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and Five Biopsy Specimens Ve6selr Mild to severe intimal sclerosis of arcuate, inter- and intra-lobular arteries Severe intimal sclerosis of intralobular arteries
Focal atrophy; some mononuclear cells about arcuate septum Heavy mononuclear interstitial infiltrate; tubules normal Mild mononuclear infiltrate
Focal intimal sclerosis, all levels of vessels Normal
Well developed atrophy and severe interstitial plasma cell infiltrate
Arterioles with medial thickening; larger arteries normal
End-stags atrophy and scarring: scanty lymphocytic infiltrates.
Severe intimal and medial sclerosis of arteries and arterioles.
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Marked intimal thickening in large arteries and medial hypertrophy of middle-sized vessels Normal
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findings in A-2. Our hypotheses, supported by the two subsequently available autopsies, were that in MCTD significant vascular abnormalities might be present years in advance of clinical symptoms and that, although histologically suggestive of scleroderma, important pathologic differences also existed. Rheumatic diseases with associated sclerodermatous skin have long been recognized [27]; however, scleroderma skin and, perhaps, the associated internal organ derangements, probably represent only one particular type of reaction to vascular or immunologic injury, rather than a pathognomonic finding for a specific disease [34]. This concept is important because of the prior tendency of some investigators to classify MCTD as a variant of SLE [35,36] and because others might define MCTD as merely a variant of scleroderma. Recently, emphasis has been placed on generalized involvement of the microvasculature as the primary site of injury in scleroderma [31,37,38]. The findings from the present study support the concept of a basic vascular process in MCTD. However, several important histopathologic features appear to distinguish MCTD from scleroderma. (1) Significant fibrosis, except in the skin, was strikingly absent in our patients with MCTD, in comparison to the frequency in lungs, myocardium and gastrointestinal tract found in the controlled study of scleroderma by D’Angelo and co-workers [38]. Whether the mild degree of fibrosis found in pediatric MCTD reflects younger age, shorter duration of disease or a basic difference in the disease process cannot yet be decided. (2) Comparison of the vascular lesions from this series of patients with MCTD with those of scleroderma is difficult because of the widely varying degrees of attention which have been directed towards vascular lesions in scleroderma. As noted by Campbell and LeRoy [31], the presence of vascular lesions in adult scleroderma may be underestimated if they are not present in all organs or if they are obscured by atrophy and fibrosis. The high frequency of proliferative intimal lesions observed in our patients may hence be due to younger age, with perhaps less advanced fibrosis and scarring, or to their having a disease process different from scleroderma. (3) Capillary involvement was conspicuous by its absence in our children with MCTD, in contrast to its frequency in scleroderma [31,37]. (4) Fibrinoid vascular change occurs in a number of vasculitides, including scleroderma and malignant hypertension; its rarity in MCTD, therefore, appears noteworthy. (5) Various investigators have noted the absence of large vessel involvement in scleroderma [31,37]. In our children with MCTD, intimal proliferation in the aorta and larger coronary, pulmonary and renal arteries was striking. This aspect of MCTD has not previously been described and deserves emphasis because, in a pediatric
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population, the various proliferative vascular process of aging are not present. In the few instances in which large vessel disease has been reported in scleroderma [39,40],one investigator has speculated that the changes were due to disease of the vasa vasorum [37]. An alternative is that the condition in some of those patients represented unrecognized MCTD. The widespread proliferative intimal lesions, in small and large arteries in MCTD, is worrisome. Vascular compromise, leading to hypertension and organ failure [l3], or to hemorrhage [24], has been documented in a few cases. The vascular changes that we observed may indicate that such complications of MCTD will become more common as durations of follow-up lengthen. Inflammatory infiltrates, often plasmacytic in character, were prominent in several organs including liver, salivary gland, and intestine. It is possible that these plasmacytic infiltrates are the histologic counterpart of the commonly observed hypergammaglobulinemia of MCTD [9,10,20]. All five muscle specimens showed some degree of inflammatory infiltration. Sarcolemmal nuclear proliferation and perivascular inflammation were observed in three patients, two of whom had no clinical weakness. These observations support the finding by Oxenhandler and co-workers [26], of a high incidence of focal inflammatory lesions in the skeletal muscles of adults with MCTD. Similar inflammatory infiltration was present in all three hearts, two of which had never been clinically abnormal. The observed myocardial inflammation and coronary vascular changes explain the frequency of cardiac involvement in childhood MCTD [zO], and may suggest that adults with MCTD will experience more cardiac complications as durations of follow-up lengthen. The relative importance of Sjogren’s syndrome in MCTD is not clear. Features of Sjogren’s syndrome were noted in early reports of pediatric and adult MCTD [10,19] and have recently been emphasized [22,41]. The frequent association of Sjogren’s syndrome with other rheumatic diseases, and its remarkable degree of immunologic hyper-reactivity when observed as an isolated entity [42], both make separation of its features from MCTD difficult. The degree of inflammation and myoepithelial change noted in the two salivary glands available, both from children without clinical findings of Sjogren’s syndrome, was initially surprising. The signs and symptoms of Sjogren’s syndrome may, however, remain subclinical unlesqcarefully searched for [zz]. These observations suggest that Sjogren’s syndrome may be a common feature of MCTD. Initial studies of MCTD suggested a low (5 to 10 per cent) incidence of renal disease [10,31], but evidence of membranous glomerulonephritis is increasingly common [11,15-17,20,21]. After case reports [15,16] are excluded because of prior selection, remaining recent
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studies give a combined incidence of 28 per cent. Most of these patients had evidence of glomerular immune complex deposition, an observation which is strengthened by a recent report wherein the frequency and titer of circulating immune complexes were found to be comparable in SLE and MCTD [43]. In our experience, seven of 15 children (47 per cent] have had clinical or histologic evidence of renal disease; five biopsy and three autopsy specimens, from a total of six children, have all shown proliferative or membranous glomerulonephritis. Five of these six also had renal vascular sclerosis. Of the living children, the disease in two has progressed to renal failure, and they are receiving hemodialysis. Another child, subjected to biopsy because of progressive hypertension, showed little glomerular inflammation but had severe intimal proliferation and luminal narrowing of renal arterioles. In SLE, membranous glomerulonephritis is frequently indolent, resistant to medical therapy, and slowly progressive, with renal failure occurring in some cases [44]. Our patients who eventually required hemodialysis document that significant renal morbidity may also result from MCTD. We concur with Bennett and Spargo [17] that the incidence of membranous glomerulonephritis in MCTD is underestimated and suggest that a
ET AL.
better understanding of the frequency, severity and progression of renal disease in MCTD is needed. Two other unique findings from our data deserve comment. The first is the distinctive replacement of the inner, and occasionally outer, muscle layers of the esophagus, pylorus and colon by hyaline material. These changes, found in two of three autopsies, appear different from the gastrointestinal muscle atrophy or fibrosis commonly reported in scleroderma [38]. The second is the unusual degree of nodular hyperplasia of medullary lymphocytes and plasma cells, and striking lack of cortical involution in the one available thymus, relative to that expected for a chronic disease of three and a half years duration. Both of these thymic features are different from those usually seen in childhood SLE or juvenile rheumatoid arthritis [45]. The findings from this study indicate that significant histopathologic variations differentiate MCTD from scleroderma, and the other rheumatic components of MCTD, even though MCTD does occasionally progress to a systemic sclerosis-like pattern [3l]. The vascular and renal findings suggest that a significant adjustment of our present opinions of the prognosis of MCTD, as regards both morbidity and mortality, may become necessary.
REFERENCES 1. Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR: Mixed connective tissue disease. An anparentlv distinct rheumatic disease syndro,ce associated with a specific antibody to an extractable myclear antigen IENAI. Am 1Med 1972: 52: v.
I
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148-159. 2.
3. 4.
5. 6. 7.
8. 9.
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Sharp GC, Irvin WS, La Roque RL, Velez C, Daly V, Kaiser AD, Holman HR: Association of autoantibodies to different nuclear antigen: -vith clinical patterns of rheumatic disease and responsiveness to therapy. 1 Clin Invest 1971; 50: 350-359. Notman DD, Kurata N, Tan EM: Profiles of antinuclear antibodies in systemic rheumatic diseases. Ann Intern Med 1975; 83: 464-469. Parker MD: Ribonucleoprotein antibodies. Fre uency and clinical significance in systemic lupus erytR ematosus, scleroderma, and mixed connective tissue disease. ] Lab Clin Med 1973: 82: 769-775. Farber SJ, Bole GG: Antibodies to components of extractable nuclear antigen: Clinical characteristics of patients. Arch Intern Med 1976; 136: 425-431. Leibfarth JH, Persellin RH: Characteristics of patients with serum antibodies to extractable nuclear antigens. Arthritis Rheum 1976; 19: 851-856. Parker MD, Turner RA: Comparison of the complementfixing activity of antinuclear antibodies in lupus nephritis, mixed connective tissue disease, and scleroderma. Arthritis Rheum 1976; 19: 857-861. Parker MD, Marion T: Circulating complement-fixing immune complexes in mixed connective tissue disease (abstract). Arthritis Rheum 1977; 20: 130. Halla JT. Schrohenloher RE, Hardin JG, Volanakis JE: Circulating immune complexes in mixed connective tissue disease (MCTD) (abstract). Arthritis Rheum 1978; 21: 562. Sharp GC: Mixed connective tissue disease. Bull Rheum Dis 1975; 25: 828-831. Hench PK. Edgington TS, Tan EM: The evolving clinical spectrum of mixed connective tissue dis-ase (MCTD)
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(abstract]. Arthritis Rheum 1975; 18: 404. 12. Silver TM, Farber SJ, Bole GG, Martel W: Radiological features of mixed connective tissue disease and scleroderma-systemic lupus etythematosus overlap. Radiology 1976: 120: 269-275. 13. Harmon C. Wolfe F. Lillard S. Held C. Cordon R. Sharo GC: Pulmonary involvement in mixed connective tissue d&ase (MCTD) (abstract). Arthritis Rheum 1976; 19: 801. 14. Alarcon-Segovia D: Symptomatic Sjiigren’s syndrome in mixed connective tissue disease. 1 Rheumatol 1978: 3: 191-195. 15. Rao KV. Berkseth RO. Crosson IT. Raii L, Shaoiro FL: Immune.complex nephritis in mixed connecti;e tissue disease. Ann Intern Med 1978; 84: 174-176. 16. Fuller TJ, Richman AV, Auerbach D, Alexander RW, Lottenberg R, Longley S: Immune-complex glomerulonephritis in a patient with mixed connective tissue disease. Am J Med 1977; 62: 781-764. 17. Bennett RM, Spargo BH: Immune complex nephropathy in mixed connective tissue disease. Am J Med 1977; 83: 534-541. 18. Gilliam JN, Prystowsky SD: Conversion of discoid lupus ervthematosus to mixed connective tissue disease. I Rheumatoll977; 4: 165-169. 19. Sanders DY. Huntlev CC. Sharo GC: Mixed connective tissue disease in a child. J Pediatri973; 83: 642-845. 20. Singsen BH, Bernstein BH, Kornreich HK. King KK, Hanson V, Tan EM: Mixed connective tissue disease in childhood: A clinical and serologic survey. J Pediatr 1977; 90: 893900. 21. Baldassare A, Weiss T, Auclair R, Zuckner J: Mixed connective tissue disease IMCTDl in children labstractl. Arthritis Rheum 1976; 191788. . 22. Fraga A, Gudino J. Ramos-Niembro F, Alarcon-Segovia D: Mixed connective tissue disease in childhood. Relationship with SjBgren’s syndrome. Am J Dis Child 1978: 132: 263265. 23. Kennedy JM: Mixed connective tissue disease: a case report.
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Arizona Med 1976; 33: 192-193 Cooke CL, Lurie HI: Case report: Fatal gastrointestinal hemorrhage in mixed connective tissue disease. Arthritis Rheum 1977; 20: 1421-1427. 25. Levitin PM, Weary PE, Giuliano VJ: The immunofluorescent “band” test in mixed connective tissue disease. Ann Intern Med 1975; 83: 53-55. 26. Oxenhandler R, Hart M, Corman L, Sharp G, Adelstein E: Pathology of skeletal muscle in mixed connective tissue disease. Arthritis Rheum 1977; 20: 985-988. 27 Tuffanelli DL, Winkelmann RK: Scleroderma and its relationship to the “collagenoses” dermatomyositis, lupus erythematosus, rheumatoid arthritis and Sjogren’s syndrome. Am J Med Sci 1962; 243: 133-146. 28. Sharp GC, Irvin WS. May CM, et al.: Association of antibodies to ribonucleoprotein and Sm antigens with mixed connective tissue disease, systemic lupus erythematosus and other rheumatic diseases. N Engl - ,I Med 1976: 295: 24.
1195.
36. 37. 38.
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