81 1
GASTROINTESTINAL SYSTEMIC SCLEROSIS IN SEROLOGIC MIXED CONNECTIVE TISSUE DISEASE DANIEL A. NORMAN and ROY M. FLEISCHMANN Mixed connective tissue disease is a clinical entity defined by overlapping features of progressive systemic sclerosis, systemic lupus erythematosus, polymyositis, rheumatoid arthritis, and distinct serologic findings. Esophageal dilatation and dysmotility have been the only gastrointestinal manifestations reported. Three patients with serologic findings of mixed connective tissue disease and extensive gastrointestinal involvement compatible with the changes found in progressive systemic sclerosis are presented. Gastrointestinal manifestations of progressive systemic sclerosis are reviewed and were found to be indistinguishable from the findings in these patients. Sharp and colleagues (1) first described the clinical and serologic findings of an apparently distinct rheumatic disease syndrome which they termed mixed connective tissue disease (MCTD); their work has subsequently been confirmed (2-7). The syndrome is characterized by clinical features suggesting progressive systemic sclerosis (PSS), systemic lupus erythematosus (SLE), polymyositis (PM), and, more recently, rheumatoid arthritis (RA) (2) in varying combinations of over~
~~~
Daniel A . Norman, M.D.: Fellow in Gastroenterology, Department of internal Medicine, University of Texas Health Science Center, Parkland Memorial and Dallas Veterans Administration Hospitals. Dallas, Texas; Roy M. Fleischmann, M.D.: Division of Rheumatology, Baylor University Medical Center, Attending in Internal Medicine, Medical City Dallas, Clinical Instructor in Medicine, University of Texas Health Science Center, Dallas, Texas. Address reprint requests to Roy M. Fleischmann, Chief, Division of Rheumatology, St. Paul Hospital, 5959 Harry Hines Boulevard, Dallas, Texas 75235. Submitted for publication August 26, 1977; accepted in revised form March 13, 1978. Arthritis and Rheumatism, Vol. 21, No. 7 (September-October 1978)
lap. Serologic findings include the presence of an antinuclear antibody in high titer which is directed toward nuclear ribonucleoprotein, originally termed extractable nuclear antigen (ENA). Studies of ENA antibody specificities by immunodiffusion have shown that ENA consists of at least two distinct antigens, one sensitive to RNase and trypsin which is nuclear ribonucleoprotein (RNP), and another resistant to RNase which is identical to Sm antigen (5,8,9). Some sera containing hemagglutinating antibodies to ENA produce immune precipitates that are distinct from either the RNP or Sm system (43). In the original and more recent series of patients with MCTD, esophageal dysmotility is common and the only gastrointestinal manifestation reported ( 1,2,47,lO). Three patients with high titers of antibody to extractable nuclear antigen sensitive to RNase were recently seen in whom more extensive gastrointestinal involvement was found and who form the basis of this report.
METHODS All patients were evaluated radiographically with upper gastrointestinal series, including barium swallow and small bowel follow-through, as well as a barium enema. Malabsorption was evaluated by quantitative stool fat in grams per 24 hours on a 100gram fat intake(norma1 1-7 gm/day); D-xylose absorption was measured following a 25 gram oral load after overnight fast and adequate hydration (normal excretion is 4.1-9.0 gm/5 hours); serum vitamin B12 (normal 200-800 pg/ ml) and standard Schillings Stage I (normal 7-40%) were performed.
812
NORMAN A N D FLEISCHMANN
The titers of antibodies to extractable nuclear antigens were determined with the hemagglutination assay described by Sharp er al. (1). These antibodies were further differentiated into anti-RNP and anti-Sm antibodies on the basis of their activity with extractable nuclear antigen coated red cells digested with ribonuclease. C3 (normal 46-129 mg/dl) and C4 (normal 14-51 mg/dl) were determined with the use of Behring plates (Behring Diagnostics, American Hoechst Corporation, Somerville, New Jersey 08876). Total complement (normal 22-84 units/ml) was determined with the use of Quantiplates (Kallestad Company, Chaska, Minnesota 553 18).
CASE REPORT Patient 1 R.S. is a 25-year-old black female who was hospitalized because of an erythematous, tender rash of the lower extremities and anemia. She had a 20-year history of classic triphasic Raynaud’s phenomenon. Four months prior to admission, she developed mild elevations of temperature, dry cough, pleuritic chest pain, and occasional hemoptysis. Two months before admission she developed pain in both calves and nodules on the left calf and both thighs anteriorly. She noted weight loss of approximately 6 pounds over 2 months, fatigue lasting all day, myalgias, and areas of hyper- and hypopigmentation of the skin. She denied alopecia, photosensitivity, symptoms of Sj8gren’s syndrome, dysphagia, nausea, vomiting, diarrhea, constipation, heartburn, shortness of breath, palpitations, oliguria, or dysuria. At this time, she saw her family physician who treated her with antibiotics for a presumed upper respiratory infection. Her symptoms did not clear, and she was admitted to the hospital. Physical examination revealed normal vital signs with the exception of a temperature of 38.5’ C. Positive findings included areas of hyper- and hypopigmentation noted over all extremities, the anterior chest, and the back. She had numerous slightly raised, tender, 1-3 cm diameter nodules scattered over both lower extremities posteriorly and anteriorly. Recent nodules were red; older nodules were blue-black and nontender. Examination determined that the heart was normal with the exception that P2 was louder than A2. Examination of the extremities showed, in addition to the above mentioned lesions, swelling of all fingers with tight shiny skin from the finger-tips to the elbows bilaterally. Motion of the finger joints was normal. The patient also had thick skin over the neck, anterior chest, and both lower extremities from just distal to the knees to just proximal to the ankles. The calves were tender. Results of the remainder of the examination were normal. Laboratory evaluation revealed a n initial white blood cell count of 9,500 per mms with repeated counts of 4,000 and 3,500per mms and a normal differential. Hemoglobin was 11.2 gm% and hematocrit, 34 ~01%.Red blood cells were microcytic and hypochromic. Reticulocyte count was 0.6%, haptoglobin 356 mg/dl, direct Coombs’ was 2 f positive, and platelet count 330,000 per mms. Erythrocyte sedimentation rate was 54 mm/ hour with a repeated rate of 52 mm/hour. Two urinalyses showed n o protein, cells, or casts. An adequate 24-hour urine
showed protein excretion of 103 mg and creatinine clearance of 53 ml/min. C P K was 202 mU/ml (normal 0-95) and aldolase, 1 1 mU/ml (normal 3-8). E M G and muscle biopsy were not performed. VDRL was nonreactive; serum protein electrophoresis showed a polyclonal gammopathy and gammaglobulin of 3.5 gm/dl. L E preparation was positive on two occasions and latex fixation reaction for rheumatoid factor was 1:80 (normal is less than 1:20). An ANA was positive greater than 1:1280 in a speckled pattern; antibody to E N A was positive at a titer of 1:256,OOO with a fall in titer to 1:2000 after RNase treatment of ENA. Immunodiffusion studies to determine if the residual 1:2000 titer represented Sm antigen were not performed. C3 was 32 mg/dl; total complement was less than 21 units/ml, and C4 was 24 mg/dl. Antibody to D N A by the Farr technique was negative. Stool fat was 2 grams in 24 hours and a D-xylose absorption was 4.6 gm/5 hours. A roentgenogram of the chest was normal, but forced vital capacity was 49%, FEV, was 91%, and DLCO was 44%. EKG was within normal limits. A biopsy of a nodule located on the anterior aspect of the right lower leg revealed a minimal perivascular chronic inflammatory cellular infiltrate of nonspecific nature within the dermis. N o large lymphoid aggregates nor liquefactive degeneration of the basal layer was present. Within the underlying adipose tissue a subacute inflammation was present. N o granulomas were found. Vasculitis of the larger vessels at the dermal-subcutaneous junction was not found. This was felt to represent erythema nodosum. Fluoroscopy revealed passage of barium through the esophagus to be greatly impeded and no primary peristaltic waves were seen. Spot films of the barium esophogram demonstrated mild dilatation (Figure I). No evidence of achalasia was present. Upper gastrointestinal series demonstrated a normal mucosal pattern of the stomach. There was dilatation of the second and third portions of the duodenum with minimal thickening of the folds (Figure 2). Transit time through the small intestine was 40 minutes. Results of a barium enema were normal.
Patient 2 J.G. is a 54-year-old Latin American male who was hospitalized for hematemesis and seizures in July 1975. His medical history dates from 1959 when he was hospitalized following a stab wound to the abdomen. A laparotomy during this first hospitalization revealed an hepatic and small posterior peritoneal laceration. He complained of intermittent difficulty swallowing solid food for 3 to 4 months prior to this admission. An upper gastrointestinal series after surgery was thought to represent achalasia, and the patient underwent a Heller myotomy and Allison hernioplasty. A t followup 1 and 2 months later, there were n o complaints of dysphagia. The patient was next seen in the emergency room in July 1975 because of a syncopal episode. Shortly after arrival to the hospital, he vomited a small quantity of bright red blood and experienced a grand ma1 seizure. H e complained of occasional heartburn and frequent nausea for which he took aspirin for 2 to 3 weeks prior to admission. History at this time revealed a 10 pound weight loss over 1 year despite good appetite, malar facial rash that was intermittent without rela-
GI SYSTEMIC SCLEROSIS IN MCTD
813
Initial laboratory findings included a hemoglobin of 9.4 gm%, hematocrit of 29.5 vol%, mean corpuscular volume of 65, WBC count of 1 1,300 per mms with 5 1 polys, 38 bands, 10 lymphocytes, I monocyte, and adequate platelets. Initial urinalysis showed 100 mg% protein and numerous red and
white blood cells, but a repeated urinalysis failed to show these abnormalities. Results of plasma glucose, electrolytes, and renal and liver function tests were in the normal range. The patient was transfused with 5 units of packed red blood cells. Endoscopy revealed a trabeculated distal one-third of the esophagus with diverticula, one of which demonstrated bleeding, and a stricture to a 5 mm diameter at the esophagogastric junction with inability to pass the endoscope into the stomach. An upper gastrointestinal series demonstrated the esophagus to be dilated without peristalsis in the distal twothirds. A stricture, or diverticular outpouching with an area of narrowing, at the esophagogastric junction was seen. The gastric mucosal pattern was normal. The small bowel was dilated, especially the duodenum, with markedly reduced peristaltic activity (Figure 3). Transit time through the small intestine was 2 hours. A barium enema showed wide-mouthed, large
Figure 1. Barium swallow of patient R.S. demonstrating mild dilatation of the esophagus without primary peristaltic waves and a small hiatal hernia.
tion to sun exposure, generalized fatigue, a history of digital cyanosis and pain on cold exposure, and toughness of the skin of the distal fingers. He denied a history of peptic ulcer disease, dysphagia for 16 years following his myotomy and hernioplasty, diarrhea, melena, rectal bleeding, arthritis, alopecia, muscle pain or weakness, shortness of breath, or dyspnea on exertion. Positive findings on physicial examination included a blood pressure of 190/110 without orthostatic change, which on repeated determinations was normal, malar and forehead erythema that blanched with pressure and slight rhinophyma compatible with acne rosacea, a telangiectasis on the tip of the tongue, bibasilar inspiratory rales, hardening of the skin of the fingers to the proximal interphalangeal joints, and atrophy of the finger pads with mild loss of digital dermatographs compatible with sclerodactyly and clubbing. Finger motion was normal. Results of the remainder of the examination were normal.
Figure 2. Upper gastrointestinal series of patient R.S.demonstrating a normal stomach and dilated second and third portions of the duodenum.
814
Figure 3. Upper gastrointestinal series of patient J.G. demonstrates a dilated distal esophagus with stricture or pseudo-diverticular OUIpouching with an area of narrowing at the esophagogastricjunction. The small bowel is dilated, especially the duodenal area.
diverticula of the antimesenteric border of the transverse colon (Figure 4). These roentegenograms were felt to be consistent with the diagnosis of scleroderma. N o definite cause was found for the syncopal episode, grand ma1 seizure, or hematemesis. Serological evaluation revealed VDRL to be nonreactive; RA latex and LE preparation were negative; serum protein electrophoresis showed a polyclonal gammopathy with a gammaglobulin of 2.68 gm/dl; A N A was 1:640 speckled and ENA antibody titer was 1:32,000with complete elimination of reactivity after treatment of ENA with RNase. Serum B12 was 510 pg/ml, serum folic acid 8.95 ng/ml, Schillings Stage I within normal limits, and stool fat 12 gm/24 hours. Pulmonary function testing showed spirometry and diffusion to be within normal limits. Schirmer's test gave 2 mm of tear migration bilaterally.
NORMAN A N D FLEISCHMANN
health until 1974 when she developed intermittent episodes of nausea and vomiting, usually nocturnally, that were unrelated to food or position and lasted for several days. She also noted abdominal distention, anorexia, and weight loss of approximately 30 pounds over 1 year. During the next 3 years, the patient had multiple gastrointestinal tests but no diagnosis was made. She underwent four abdominal surgical procedures, one of which was a cholecystectomy, and the other three for what was thought to be intestinal obstruction with no abnormalities found. The patient was admitted to the hospital for further evaluation in December 1976. On admission, further history revealed an additional 30 pound weight loss in the past 9 months, increased pigmentation of the abdomen and legs for an indeterminate amount of time, a history of digital blanching and cyanosis on cold exposure with reactive erythema and tingling on rewarming compatible with Raynaud's phenomenon for 2 years, alopecia for 2 years, joint pain involving primarily the knees and elbows for several years, fatigue lasting all day, dryness of the mouth but not the eyes, difficulty in swallowing solid food for approximately 1 year (not due to dryness of the mouth or difficulty in initiation of swallowing), and constipation for approximately 6 months. The patient denied thickening of the skin, shortness of breath, chest pain, photosensitivity, muscle weakness or tenderness, headaches, morning stiffness, or joint swelling. On physical examination, blood pressure was 90/50, pulse 110 per minute and regular, weight 78 pounds, and she was afebrile. The patient was a cachectic appearing black female in no acute distress. Positive findings included poor dentition, areas of hyperpigmentation of both lower extremities and the abdomen as well as the upper arms, contractures of both elbows of approximately 15". pain on motion of both shoulders especially the right, and boggy swelling of both knees. N o increased skin thickness was noted and appearance and motion of the fingers were normal. Results of the remainder of the examination were normal. Laboratory studies on admission showed a white blood cell count of 9,400 per mms with a normal differential, hematocrit 28 vol%, platelets 250,000 per mms, haptoglobin 285 mg/dl, reticulocyte count 3.8%, fibrin split products nega-
Patient 3 I.S. was a 61-year-old black female who was hospitalized in December 1976 for complaints of intractable nausea, vomiting, anorexia, and diarrhea. The patient was in excellent
Figure 4. Barium enema of patient J . G. demonstrating wide-mouthed diverriculae of the antimesenteric border of the transverse colon.
GI SYSTEMIC SCLEROSIS IN MCTD
tive, and Coombs’ direct and indirect negative. Urinalysis was normal. BUN was 66 mg/dl, creatinine 3 mg/dl, calcium 7.9 mg/dl, phosphorus 4.8 mg/dl, G F R by isothalamate lf6I excretion 29 ml/min, albumin 2.9 gm/dl, serum folate 13.3 ng/ ml, iron-iron binding capacity 180/194 mg/dl, B12 920 pg/ml, Schillings Stage I 7.4%,and D-xylose absorption 2 grams in 5 hours. Stool fat could not be determined because the patient was unable to ingest an adequate diet throughout her hospitalization. CPK was 23 mU/ml. E K G showed a sinus tachycardia, short PR interval, and increased Q T interval. A roentgenogram of the chest demonstrated a normal cardiac silhouette with no basilar infiltrate. Serum protein electrophoresis showed a polyclonal gammopathy with a gammaglobulin of 2.09 gm/dl. C3 and C4 were within normal limits. VDRL was nonreactive, RA latex 1:1280, SSCA 1:224, L E preparation negative, antibody t o DNA by Farr technique negative, ESR 65 mm/hour, ANA 1:8000 speckled, and E N A antibody titer was 1:120,000, repeated titer 1:s 12,000, with complete elimination of reactivity after treatment of E N A with RNase. Upper gastrointestinal series showed normal esophageal peristaltic activity without dilation. The gastric mucosal pattern was normal. A small bowel series demonstrated duodenal and jejunal dilatation with a normal caliber distal ileum. The valvulae conniventes were not thickened and their approximation to one another was normal. Results of a barium enema were normal. The patient was treated initially with nasogastric suction, intravenous fluid therapy, and total parenteral nutrition. Within 24 hours of placement of a central venous catheter, pneumatosis cystoides intestinalis was noted (Figure 5 ) . This cleared spontaneously within several weeks. Over a period of 4 weeks there was no significant response with respect to anorexia, nausea, vomiting, and diarrhea. A trial of prednisone, 40 mg daily, was instituted. Two weeks after the institution of prednisone, sedimentation rate was 12 mm/hr, R A latex 1:160, and ANA 1:2000 speckled. An attempt to wean the patient from parenteral feeding was unsuccessful. Because of an assumed intestinal pseudo-obstruction, a resection approximately 130 cm in length of the distal duodenum, jejunum, and proximal ileum was performed. Pathological specimens were reviewed and the mucosa was shown t o be intact and the muscularis mucosa to be of normal thickness. The submucosa contained dilated vascular channels with dense eosinophilic collagenous stroma. There were focally increased numbers of lymphocytes. On Masson staining, the fibrous connective tissue was very dense and individually encircled the circumferential bundles of smooth muscle and extended into and replaced much of the longitudinal smooth muscle bundles. Much of the serosa was thickened by fibrous connective tissue and chronic inflammatory cells (Figure 6). N o vasculitis was demonstrated. The patient’s course of recovery was complicated by massive anasarca and diffuse gastrointestinal hemorrhaging, and four weeks postoperatively she died of these complications. Permission for autopsy examination was refused.
RESULTS All three patients presented in this report had definite gastrointestinal roentgenographic evidence of PSS (Table 1 ) in addition to the presence of high titers of
815
Figure 5. Upper gastrointestinal series of patient I.S. demonstrating spiculated mucosa of pneumatosis cystoides intestinalis. Insert in right lower corner shows a magnified view of this abnormality.
antibody to ENA with either a complete or significant fall in titer after RNase treatment of ENA (Table 2). Patient R.S. has clinical evidence that could be classified as sclerodermatomyositis with laboratory evidence of SLE or MCTD, as defined by her clinical presentation and serology (Table 3). I n addition to this, she had biopsy evidence of erythema nodosum. Patient J.G. could be classified as having scleroderma sine scleroderma (progressive systemic sclerosis with minimal skin changes) ( 1 1 ) by the presence of Raynaud’s phenomenon and extensive gastrointestinal radiographic changes of progressive systemic sclerosis. Alternatively, such symptoms might represent a patient with MCTD who has only one manifestation of the overlap as reported by Sharp et a/. (4). Patient I.S. should be classified as having overlapping progressive systemic sclerosis by the combination of Raynaud’s phenomenon and compatible gastrointestinal changes, as well as rheumatoid arthritis on the
816
Figure 6 . A. Surgical specimen of duodenum of patient I.S. demonstrating normal mucosa. extensive deposition of collagen in the submucosa. and infiltration and replacement of the longitudinal muscle fibers with collagenous fibers. (Masson trichrome stain, original magnification X lo.) B. High power view of same specimen detailing submucosa and longitudinal muscle fibers. (Masson trichrome stain, original magnification X 80.)
GI SYSTEMIC SCLEROSIS IN MCTD
Table 1. Laboratory Characteristics of Patients with Serologic MCTD and Gastrointestinal Systemic Sclerosis
817
Table 3. Clinical Characteristics of Patients with Serologic MCTD and Gastrointestinal Systemic Sclerosis
Patients
Patients Laboratory Characteristics Radiology Dilated and atonic esophagus Dilatation of the small bowel Wide-mouth sacculations of antimesenteric border of the colon Malabsorption Studies Stool fat (grams/24 hours) Serum B12 D-xylose excretion/5 hours Schillings Stage I
* ND
=
R.S.
J.G.
IS.
+ +
+
-
+
+
-
+
-
2
12
ND*
ND
510 ND
920 2
4.6
ND
6%
1.4%
test not done.
basis of symmetrical polyarthritis of the shoulders, elbows, and knees in the presence of a high titer rheumatoid factor (by both latex fixation and sensitized sheep cell agglutination) and a markedly increased erythrocyte sedimentation rate.
The association of extensive gastrointestinal changes of progressive systemic sclerosis in addition to the presence of high titers of antibody to nRNP has not previously been reported. The patients presented share the presence of Raynaud’s phenomenon and gastrointestinal involvement indistinguishable from that obTable 2. Serologic Characteristics of Patients with Serologic MCTD and Gastrointestinal Systemic Sclerosis
Patients R.S.
J.G.
1: 1280
I :256,000
1:640 1 : 32,000
I : 2000 0
0 NDt
I.S.
~
ANA (speckled):titer ENA :titer ENA :titer after RNase Antibody to native DNA* RA latex LE preparation Complement C3 Total complement VDRL Sedimentation r a t 4
* Normal
1:80
+
32 < 21
N RS 54
is 040%. test not done. $ NR non-reactive. 4 Normal is less than 20 mm/hour.
t ND
= =
Age Sex Race* Arthralgia/Arthritis Raynaud’s phenomenon Weight loss Fatigue Serositis Dyspnea Myalgia Morning stiffness Dysphagia Diarrhea Fever Alopecia Skin rash Swollen hands Scleroderma skin changes Sjogren’s syndrome
*B=
DISCUSSION
Serology
Clinical Profile
ND ND NR ND
1:8OOo 1 : 120,000 1 : 512,000 0 0 I : I280
-
I30
ND NR 65
R.S.
J.G.
I.S.
25
54 M MA
61
F B
+ + + + + + + + + +
+ + +
F
B
+ +
-
+ + +
black; MA = Mexican-American.
served in PSS. Because of this combination, they could very well be classified as patients who fall within the spectrum of progressive systemic sclerosis. Reichlin (12) has pointed out that there are no reports to date of serious systemic complications of progressive systemic sclerosis in patients with high titers of antibody to nRNP. In one report (13) 21% of patients with PSS had antibody to nRNP but generally in a titer below 1: 1000; such a low titer is rarely seen in MCTD (l,3). MCTD is characterized clinically by varying combinations of overlapping features of progressive systemic sclerosis, systemic lupus erythematosus, polymyositis, and rheumatoid arthritis in addition to the serologic characteristic of the presence of high titers of antibody to nuclear ribonucleoprotein (1-10). Although patients with MCTD generally have overlapping features of PSS, SLE, PM, and RA, occasional cases present with dominant clinical findings of a single disease and if followed may then develop either overlapping manifestations or dominant features of one of the other diseases that comprise the overlap syndrome. Patient R.S., though with clinical features of sclerodermatomyositis, has a positive lupus erythematosus preparation and direct Coombs’ test, as well as increased serum gammaglobulin and erythrocyte sedimentation rate consistent with the diagnosis of SLE. Patient J.G. with
818
Raynaud’s phenomenon and gastrointestinal changes of PSS may represent an example of a patient with MCTD who presents with one disease of the overlap syndrome. Patient I.S. has overlapping features of progressive systemic sclerosis and rheumatoid arthritis. Each of the patients presented had a high titer of antibody to nRNP. Since 1972, a strong body of literature has developed the thesis that a high titer of antibody to nRNP, with or without overlapping features of the above diseases, dictates the diagnosis of MCTD. In this light, we would have to consider the possibility that these patients are consistent and represent extensive gastrointestinal changes of PSS in MCTD. Gastrointestinal tract involvement in PSS has been reported to be as high as 80% (14-17). Radiographic features of this disease are seen throughout the gastrointestinal tract. The most common radiologic finding is dilatation of the distal two-thirds of the esophagus with absent peristalsis (18,19). An identical involvement in MCTD has been reported by several authors (10,20). The most characteristic finding in the duodenum, seen in approximately one-third of patients with PSS (21,22), is dilatation of the second and third portions (18,19,21-25) as well as hypomotility of these segments (19,23). Distal small bowel involvement, consisting of dilatation, occurs in 10% of patients (21,22,26,27). Involvement of the colon in PSS occurs less frequently than in the esophagus or small bowel (21 ). The characteristic radiographic feature is the presence of wide-mouthed diverticula of the antimesenteric border of the transverse and descending colon (15,16,18,19,21,28,29). With more advanced involvement, there is loss of haustration and generalized dilatation of the colon (18,23). All 3 of the patients discussed in this report had radiologic ,involvement of the duodenum, 2 had esophageal involvement, and 1 had antimesenteric diverticula of the colon identical to that seen in PSS. One patient demonstrated radiographic findings of pneumatosis cystoides intestinalis, a recognized complication of bowel involvement in progressive systemic sclerosis (30,3 1) not previously reported to occur in the MCTD syndrome. The typical morphologic change in PSS of the gastrointestinal tract is a patchy deposition of acellular collagenous fibrous tissue in the submucosal, muscular, and serosal layers. The muscular layer either undergoes atrophy or is replaced to a varying extent by connective tissue. The mucosa is usually spared. Infiltration of the lamina propria by chronic inflammatory cells is occasionally seen ( 1 1,18,23,32-37). Examination of the duodenum obtained at bowel resection in one patient revealed all of these changes. She had a normal mucosa,
NORMAN AND FLEISCHMANN
replacement of the muscular layer by dense collagen, and focal infiltration of the lamina propria by lymphocytes. It has been reported that clinical symptoms referrable to the gastrointestinal tract are less frequent than radiographic abnormalities in PSS (1 5,2 1,32,33). Patient R.S. was completely asymptomatic and demonstrated no evidence of malabsorption. Patient J.G. 16 years prior to his last admission had had dysphagia which disappeared after Heller myotomy and Allison hernioplasty. Although symptom free at the time of this evaluation, he did have radiographic involvement of the esophagus, duodenum, and large bowel, a quantitative stool fat of 12 gm/24 hours, and a Schillings Stage I of 6%. Patient I.S. presented with the complaints of nausea, vomiting, abdominal distention, and diarrhea. Three exploratory laparotomies were undertaken in the 4 years prior to diagnosis for what was thought to be small bowel obstruction; however, no evidence of obstruction was found at the time of surgery. This is not an uncommon occurrence in PSS with gastrointestinal involvement (35). Upper gastrointestinal series revealed classic changes of PSS. Her clinical course was typical of this diagnosis as well. She did not respond to antibiotics for possible bacterial overgrowth, elemental diets, or treatment with prednisone in high dosage. Abrams and co-workers (24) reported a case of PSS which appeared to respond to cortisone. Many authors (1,4-6, 10-13) have concluded that MCTD is amenable to prednisone therapy. On this treatment, the patient had a fall in ESR to normal and a significant decrease in titer of rheumatoid factor and ANA. In spite of this, she had no improvement in the condition of her gastrointestinal tract and subsequently had a small bowel resection with a stormy postoperative course ending in death 4 weeks later. It is not known how common extensive gastrointestinal tract involvement is in patients with high titers of antibody to nRNP. Three patients in this report ranged from being asymptomatic to having severe symptoms resulting in demise. It is suggested that radiographic examination of the gastrointestinal tract and malabsorption studies be undertaken in any patient with the diagnosis of MCTD who has symptoms suggestive of gastrointestinal involvement.
REFERENCES I . Sharp GC, Irvin WS, Tan EM, Could RG, Holman HR: Mixed connective tissue disease-an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 52:148-158, 1972
GI SYSTEMIC SCLEROSIS IN MCTD
2. Hench PK, Edgington TS, Tan EM: The evolving clinical spectrum of mixed connective tissue disease (MCTD). Arthritis Rheum 18:404, 1975 3. Notman D D , Kuvata N , Tan EM: Profiles of antinuclear antibodies in systemic rheumatic disease. Ann Intern Med 83:464-469, 1975 4. Sharp G C , Irvin WS, May CM, Holman H R , McDuffie FC, Hess EV, Schmid FR: Association of antibodies to ribonucleoprotein and SM antigens with mixed connective tissue disease, systemic lupus erythematosus and other rheumatic diseases. N Engl J Med 295:1149-1154, 1976 5 . Parker MD: Ribonucleoprotein antibodies: frequency and clinical significance in systemic lupus erythematosus, scleroderma, and mixed connective tissue disease. J Lab Clin Med 82:769-775, 1973 6. Minkin W, Rabhan N: Mixed connective tissue disease. Arch Dermatol 112:1535-1538, 1976 7. Farber SJ, Bole GG: Antibodies t o components of extractable nuclear antigen. Arch Intern Med 136:425-431, 1976 8. Reichlin M, Mattioli M: Correlation of a precipitin reaction to a n R N A protein antigen and a low prevalence of nephritis in patients with systemic lupus erythematosus. N Engl J Med 286:908-911, 1972 9. Northway JD, Tan EM: Differentiation of antinuclear antibodies giving speckled staining patterns in immunofluorescence. Clin Immunol Irnmunopathol I: 140-154, 1972 10. Sharp GC: Mixed connective tissue disease. Bull Rheum Dis 25:828-83 I , 1975 1 1 . Rodnan GP, Fennel1 RH: Progressive systemic sclerosis sine scleroderma. JAMA 180665-670, 1962 12. Reichlin M: Mixed connective tissue disease, Modern Topics in Rheumatology. London, W H Heineman, 1976, pp 157-162 13. Tan EM, Rodnan G P Profile of antinuclear antibodies in progressive systemic sclerosis (PSS). Arthritis Rheum 18:430, 1975 14. Medsger TA, Masi AT, Rodnan G P , Benedek T , Robinson H: Survival with systemic sclerosis (scleroderma). Ann Intern Med 75369-376, 1971 I S . Ballard JL, Snyder C R , Jansen GT: The gastrointestinal manifestation of generalized scleroderma. South Med J 62: 1243- 1247, 1969 16. Sleisenger M D , Fordtran JS: Gastrointestinal Disease. Philadelphia, WB Saunders Co., 1973, pp 396-398 17. Rosenow EC: Esophageal motility. Med Clin North Am 54~863-873, 1970 18. Berk RN: Scleroderma of the gastrointestinal tract. Am J Gastroenterol 61:226-231, 1974 19. Cassada WA, Armstrong RH, Neal MP: Involvement of
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20.
21. 22. 23.
24. 25. 26.
27. 28. 29. 30.
31. 32. 33. 34.
35.
36.
37.
the gastrointestinal tract by progressive systemic sclerosis. South Med J 61:475-481, 1968 Silver T M , Farber SJ, Bole GG, Martel W: Radiology features of mixed connective tissue disease and scleroderma-systemic lupus erythematosus overlap. Radiology 120~269-275, 1976 Kinder R R , Fleischmajer R: Systemic scleroderma: a review of organ systems. Int J Dermatol 13:382-395, 1974 Anderson FH: Megaduodenum, a case report and literature review. Am J Gastroenterol 62509-515, 1974 Heinz ER, Steinberg AJ, Sackner MA: Roentgenographic and pathological aspects of intestinal scleroderma. Ann Intern Med 59:822-826, 1963 Abrams HL, Carnes WH, Eaton J: Alimentary tract in disseminated scleroderma with emphasis on small bowel. Arch Intern Med 94:61-81, 1954 Goldgrader MB, Kirsner JB: Scleroderma of the gastrointestinal tract. Arch Pathol Lab Med 64:255-265, 1957 Peachy R D G , Creamer B, Pierce JW: Sclerodermatous involvement of the stomach and the small and large bowel. G u t 10:285-292, 1969 Reinhardt JF, Barry WF: Scleroderma of the small bowel. Am J Roentgenol 88:687-692, 1962 Haslock I, Wright V: The gut and arthritis. Rheumatol Rehabil 1351-60, 1974 Barnett AJ, Coventry DA: Scleroderma: 11. Incidence of systemic disturbance and assessment of possible etiological factors. Med J Aust 1:1040-1047, 1969 Gompels BM: Pneumatosis cystoides intestinalis associated with progressive systemic sclerosis. Br J Radio1 42~701-703, 1969 Meihoff WE, Hirschfield JS, Kern F: Small intestinal scleroderma with malabsorption and pneumatosis cystoides intestinalis. JAMA 204: 854-858, 1968 Rodnan GP: The natural history of progressive systemic sclerosis (diffuse scleroderma). Bull Rheum Dis 13:301304, 1963 Bluestone R, MacManon M, Dawson J: Systemic sclerosis and small bowel involvement. G u t 10:185-193, 1969 Greenberger NJ, Dobbins WO, Ruppert RD, Jesseph JE: Intestinal atony in progressive systemic sclerosis (scleroderma). Am J Med 45:301-308, 1968 Arcilla R , Bandler M , Farber M, Olivar A, Jr: Gastrointestinal scleroderma simulating chronic and acute intestinal obstruction. Gastroenterol 3 1:764-772, I956 Hoskins LC, Norris HT, Gottlieb LS, Zamcheck N: Functional and morphologic alterations of the gastrointestinal tract in progressive systemic sclerosis (scleroderma). Am J Med 33:459-470, 1962 D’Angelo WA, Fries J F , Masi AT, Shulman L: Pathologic observations in systemic sclerosis (scleroderma). Am J Med 46:428-440, 1969
GASTROINTESTINAL SYSTEMIC SCLEROSIS IN SEROLOGIC MIXED CONNECTIVE TISSUE DISEASE DANIEL A. NORMAN and ROY M. FLEISCHMANN Mixed connective tissue disease is a clinical entity defined by overlapping features of progressive systemic sclerosis, systemic lupus erythematosus, polymyositis, rheumatoid arthritis, and distinct serologic findings. Esophageal dilatation and dysmotility have been the only gastrointestinal manifestations reported. Three patients with serologic findings of mixed connective tissue disease and extensive gastrointestinal involvement compatible with the changes found in progressive systemic sclerosis are presented. Gastrointestinal manifestations of progressive systemic sclerosis are reviewed and were found to be indistinguishable from the findings in these patients. Sharp and colleagues (1) first described the clinical and serologic findings of an apparently distinct rheumatic disease syndrome which they termed mixed connective tissue disease (MCTD); their work has subsequently been confirmed (2-7). The syndrome is characterized by clinical features suggesting progressive systemic sclerosis (PSS), systemic lupus erythematosus (SLE), polymyositis (PM), and, more recently, rheumatoid arthritis (RA) (2) in varying combinations of over~
~~~
Daniel A . Norman, M.D.: Fellow in Gastroenterology, Department of internal Medicine, University of Texas Health Science Center, Parkland Memorial and Dallas Veterans Administration Hospitals. Dallas, Texas; Roy M. Fleischmann, M.D.: Division of Rheumatology, Baylor University Medical Center, Attending in Internal Medicine, Medical City Dallas, Clinical Instructor in Medicine, University of Texas Health Science Center, Dallas, Texas. Address reprint requests to Roy M. Fleischmann, Chief, Division of Rheumatology, St. Paul Hospital, 5959 Harry Hines Boulevard, Dallas, Texas 75235. Submitted for publication August 26, 1977; accepted in revised form March 13, 1978. Arthritis and Rheumatism, Vol. 21, No. 7 (September-October 1978)
lap. Serologic findings include the presence of an antinuclear antibody in high titer which is directed toward nuclear ribonucleoprotein, originally termed extractable nuclear antigen (ENA). Studies of ENA antibody specificities by immunodiffusion have shown that ENA consists of at least two distinct antigens, one sensitive to RNase and trypsin which is nuclear ribonucleoprotein (RNP), and another resistant to RNase which is identical to Sm antigen (5,8,9). Some sera containing hemagglutinating antibodies to ENA produce immune precipitates that are distinct from either the RNP or Sm system (43). In the original and more recent series of patients with MCTD, esophageal dysmotility is common and the only gastrointestinal manifestation reported ( 1,2,47,lO). Three patients with high titers of antibody to extractable nuclear antigen sensitive to RNase were recently seen in whom more extensive gastrointestinal involvement was found and who form the basis of this report.
METHODS All patients were evaluated radiographically with upper gastrointestinal series, including barium swallow and small bowel follow-through, as well as a barium enema. Malabsorption was evaluated by quantitative stool fat in grams per 24 hours on a 100gram fat intake(norma1 1-7 gm/day); D-xylose absorption was measured following a 25 gram oral load after overnight fast and adequate hydration (normal excretion is 4.1-9.0 gm/5 hours); serum vitamin B12 (normal 200-800 pg/ ml) and standard Schillings Stage I (normal 7-40%) were performed.
812
NORMAN A N D FLEISCHMANN
The titers of antibodies to extractable nuclear antigens were determined with the hemagglutination assay described by Sharp er al. (1). These antibodies were further differentiated into anti-RNP and anti-Sm antibodies on the basis of their activity with extractable nuclear antigen coated red cells digested with ribonuclease. C3 (normal 46-129 mg/dl) and C4 (normal 14-51 mg/dl) were determined with the use of Behring plates (Behring Diagnostics, American Hoechst Corporation, Somerville, New Jersey 08876). Total complement (normal 22-84 units/ml) was determined with the use of Quantiplates (Kallestad Company, Chaska, Minnesota 553 18).
CASE REPORT Patient 1 R.S. is a 25-year-old black female who was hospitalized because of an erythematous, tender rash of the lower extremities and anemia. She had a 20-year history of classic triphasic Raynaud’s phenomenon. Four months prior to admission, she developed mild elevations of temperature, dry cough, pleuritic chest pain, and occasional hemoptysis. Two months before admission she developed pain in both calves and nodules on the left calf and both thighs anteriorly. She noted weight loss of approximately 6 pounds over 2 months, fatigue lasting all day, myalgias, and areas of hyper- and hypopigmentation of the skin. She denied alopecia, photosensitivity, symptoms of Sj8gren’s syndrome, dysphagia, nausea, vomiting, diarrhea, constipation, heartburn, shortness of breath, palpitations, oliguria, or dysuria. At this time, she saw her family physician who treated her with antibiotics for a presumed upper respiratory infection. Her symptoms did not clear, and she was admitted to the hospital. Physical examination revealed normal vital signs with the exception of a temperature of 38.5’ C. Positive findings included areas of hyper- and hypopigmentation noted over all extremities, the anterior chest, and the back. She had numerous slightly raised, tender, 1-3 cm diameter nodules scattered over both lower extremities posteriorly and anteriorly. Recent nodules were red; older nodules were blue-black and nontender. Examination determined that the heart was normal with the exception that P2 was louder than A2. Examination of the extremities showed, in addition to the above mentioned lesions, swelling of all fingers with tight shiny skin from the finger-tips to the elbows bilaterally. Motion of the finger joints was normal. The patient also had thick skin over the neck, anterior chest, and both lower extremities from just distal to the knees to just proximal to the ankles. The calves were tender. Results of the remainder of the examination were normal. Laboratory evaluation revealed a n initial white blood cell count of 9,500 per mms with repeated counts of 4,000 and 3,500per mms and a normal differential. Hemoglobin was 11.2 gm% and hematocrit, 34 ~01%.Red blood cells were microcytic and hypochromic. Reticulocyte count was 0.6%, haptoglobin 356 mg/dl, direct Coombs’ was 2 f positive, and platelet count 330,000 per mms. Erythrocyte sedimentation rate was 54 mm/ hour with a repeated rate of 52 mm/hour. Two urinalyses showed n o protein, cells, or casts. An adequate 24-hour urine
showed protein excretion of 103 mg and creatinine clearance of 53 ml/min. C P K was 202 mU/ml (normal 0-95) and aldolase, 1 1 mU/ml (normal 3-8). E M G and muscle biopsy were not performed. VDRL was nonreactive; serum protein electrophoresis showed a polyclonal gammopathy and gammaglobulin of 3.5 gm/dl. L E preparation was positive on two occasions and latex fixation reaction for rheumatoid factor was 1:80 (normal is less than 1:20). An ANA was positive greater than 1:1280 in a speckled pattern; antibody to E N A was positive at a titer of 1:256,OOO with a fall in titer to 1:2000 after RNase treatment of ENA. Immunodiffusion studies to determine if the residual 1:2000 titer represented Sm antigen were not performed. C3 was 32 mg/dl; total complement was less than 21 units/ml, and C4 was 24 mg/dl. Antibody to D N A by the Farr technique was negative. Stool fat was 2 grams in 24 hours and a D-xylose absorption was 4.6 gm/5 hours. A roentgenogram of the chest was normal, but forced vital capacity was 49%, FEV, was 91%, and DLCO was 44%. EKG was within normal limits. A biopsy of a nodule located on the anterior aspect of the right lower leg revealed a minimal perivascular chronic inflammatory cellular infiltrate of nonspecific nature within the dermis. N o large lymphoid aggregates nor liquefactive degeneration of the basal layer was present. Within the underlying adipose tissue a subacute inflammation was present. N o granulomas were found. Vasculitis of the larger vessels at the dermal-subcutaneous junction was not found. This was felt to represent erythema nodosum. Fluoroscopy revealed passage of barium through the esophagus to be greatly impeded and no primary peristaltic waves were seen. Spot films of the barium esophogram demonstrated mild dilatation (Figure I). No evidence of achalasia was present. Upper gastrointestinal series demonstrated a normal mucosal pattern of the stomach. There was dilatation of the second and third portions of the duodenum with minimal thickening of the folds (Figure 2). Transit time through the small intestine was 40 minutes. Results of a barium enema were normal.
Patient 2 J.G. is a 54-year-old Latin American male who was hospitalized for hematemesis and seizures in July 1975. His medical history dates from 1959 when he was hospitalized following a stab wound to the abdomen. A laparotomy during this first hospitalization revealed an hepatic and small posterior peritoneal laceration. He complained of intermittent difficulty swallowing solid food for 3 to 4 months prior to this admission. An upper gastrointestinal series after surgery was thought to represent achalasia, and the patient underwent a Heller myotomy and Allison hernioplasty. A t followup 1 and 2 months later, there were n o complaints of dysphagia. The patient was next seen in the emergency room in July 1975 because of a syncopal episode. Shortly after arrival to the hospital, he vomited a small quantity of bright red blood and experienced a grand ma1 seizure. H e complained of occasional heartburn and frequent nausea for which he took aspirin for 2 to 3 weeks prior to admission. History at this time revealed a 10 pound weight loss over 1 year despite good appetite, malar facial rash that was intermittent without rela-
GI SYSTEMIC SCLEROSIS IN MCTD
813
Initial laboratory findings included a hemoglobin of 9.4 gm%, hematocrit of 29.5 vol%, mean corpuscular volume of 65, WBC count of 1 1,300 per mms with 5 1 polys, 38 bands, 10 lymphocytes, I monocyte, and adequate platelets. Initial urinalysis showed 100 mg% protein and numerous red and
white blood cells, but a repeated urinalysis failed to show these abnormalities. Results of plasma glucose, electrolytes, and renal and liver function tests were in the normal range. The patient was transfused with 5 units of packed red blood cells. Endoscopy revealed a trabeculated distal one-third of the esophagus with diverticula, one of which demonstrated bleeding, and a stricture to a 5 mm diameter at the esophagogastric junction with inability to pass the endoscope into the stomach. An upper gastrointestinal series demonstrated the esophagus to be dilated without peristalsis in the distal twothirds. A stricture, or diverticular outpouching with an area of narrowing, at the esophagogastric junction was seen. The gastric mucosal pattern was normal. The small bowel was dilated, especially the duodenum, with markedly reduced peristaltic activity (Figure 3). Transit time through the small intestine was 2 hours. A barium enema showed wide-mouthed, large
Figure 1. Barium swallow of patient R.S. demonstrating mild dilatation of the esophagus without primary peristaltic waves and a small hiatal hernia.
tion to sun exposure, generalized fatigue, a history of digital cyanosis and pain on cold exposure, and toughness of the skin of the distal fingers. He denied a history of peptic ulcer disease, dysphagia for 16 years following his myotomy and hernioplasty, diarrhea, melena, rectal bleeding, arthritis, alopecia, muscle pain or weakness, shortness of breath, or dyspnea on exertion. Positive findings on physicial examination included a blood pressure of 190/110 without orthostatic change, which on repeated determinations was normal, malar and forehead erythema that blanched with pressure and slight rhinophyma compatible with acne rosacea, a telangiectasis on the tip of the tongue, bibasilar inspiratory rales, hardening of the skin of the fingers to the proximal interphalangeal joints, and atrophy of the finger pads with mild loss of digital dermatographs compatible with sclerodactyly and clubbing. Finger motion was normal. Results of the remainder of the examination were normal.
Figure 2. Upper gastrointestinal series of patient R.S.demonstrating a normal stomach and dilated second and third portions of the duodenum.
814
Figure 3. Upper gastrointestinal series of patient J.G. demonstrates a dilated distal esophagus with stricture or pseudo-diverticular OUIpouching with an area of narrowing at the esophagogastricjunction. The small bowel is dilated, especially the duodenal area.
diverticula of the antimesenteric border of the transverse colon (Figure 4). These roentegenograms were felt to be consistent with the diagnosis of scleroderma. N o definite cause was found for the syncopal episode, grand ma1 seizure, or hematemesis. Serological evaluation revealed VDRL to be nonreactive; RA latex and LE preparation were negative; serum protein electrophoresis showed a polyclonal gammopathy with a gammaglobulin of 2.68 gm/dl; A N A was 1:640 speckled and ENA antibody titer was 1:32,000with complete elimination of reactivity after treatment of ENA with RNase. Serum B12 was 510 pg/ml, serum folic acid 8.95 ng/ml, Schillings Stage I within normal limits, and stool fat 12 gm/24 hours. Pulmonary function testing showed spirometry and diffusion to be within normal limits. Schirmer's test gave 2 mm of tear migration bilaterally.
NORMAN A N D FLEISCHMANN
health until 1974 when she developed intermittent episodes of nausea and vomiting, usually nocturnally, that were unrelated to food or position and lasted for several days. She also noted abdominal distention, anorexia, and weight loss of approximately 30 pounds over 1 year. During the next 3 years, the patient had multiple gastrointestinal tests but no diagnosis was made. She underwent four abdominal surgical procedures, one of which was a cholecystectomy, and the other three for what was thought to be intestinal obstruction with no abnormalities found. The patient was admitted to the hospital for further evaluation in December 1976. On admission, further history revealed an additional 30 pound weight loss in the past 9 months, increased pigmentation of the abdomen and legs for an indeterminate amount of time, a history of digital blanching and cyanosis on cold exposure with reactive erythema and tingling on rewarming compatible with Raynaud's phenomenon for 2 years, alopecia for 2 years, joint pain involving primarily the knees and elbows for several years, fatigue lasting all day, dryness of the mouth but not the eyes, difficulty in swallowing solid food for approximately 1 year (not due to dryness of the mouth or difficulty in initiation of swallowing), and constipation for approximately 6 months. The patient denied thickening of the skin, shortness of breath, chest pain, photosensitivity, muscle weakness or tenderness, headaches, morning stiffness, or joint swelling. On physical examination, blood pressure was 90/50, pulse 110 per minute and regular, weight 78 pounds, and she was afebrile. The patient was a cachectic appearing black female in no acute distress. Positive findings included poor dentition, areas of hyperpigmentation of both lower extremities and the abdomen as well as the upper arms, contractures of both elbows of approximately 15". pain on motion of both shoulders especially the right, and boggy swelling of both knees. N o increased skin thickness was noted and appearance and motion of the fingers were normal. Results of the remainder of the examination were normal. Laboratory studies on admission showed a white blood cell count of 9,400 per mms with a normal differential, hematocrit 28 vol%, platelets 250,000 per mms, haptoglobin 285 mg/dl, reticulocyte count 3.8%, fibrin split products nega-
Patient 3 I.S. was a 61-year-old black female who was hospitalized in December 1976 for complaints of intractable nausea, vomiting, anorexia, and diarrhea. The patient was in excellent
Figure 4. Barium enema of patient J . G. demonstrating wide-mouthed diverriculae of the antimesenteric border of the transverse colon.
GI SYSTEMIC SCLEROSIS IN MCTD
tive, and Coombs’ direct and indirect negative. Urinalysis was normal. BUN was 66 mg/dl, creatinine 3 mg/dl, calcium 7.9 mg/dl, phosphorus 4.8 mg/dl, G F R by isothalamate lf6I excretion 29 ml/min, albumin 2.9 gm/dl, serum folate 13.3 ng/ ml, iron-iron binding capacity 180/194 mg/dl, B12 920 pg/ml, Schillings Stage I 7.4%,and D-xylose absorption 2 grams in 5 hours. Stool fat could not be determined because the patient was unable to ingest an adequate diet throughout her hospitalization. CPK was 23 mU/ml. E K G showed a sinus tachycardia, short PR interval, and increased Q T interval. A roentgenogram of the chest demonstrated a normal cardiac silhouette with no basilar infiltrate. Serum protein electrophoresis showed a polyclonal gammopathy with a gammaglobulin of 2.09 gm/dl. C3 and C4 were within normal limits. VDRL was nonreactive, RA latex 1:1280, SSCA 1:224, L E preparation negative, antibody t o DNA by Farr technique negative, ESR 65 mm/hour, ANA 1:8000 speckled, and E N A antibody titer was 1:120,000, repeated titer 1:s 12,000, with complete elimination of reactivity after treatment of E N A with RNase. Upper gastrointestinal series showed normal esophageal peristaltic activity without dilation. The gastric mucosal pattern was normal. A small bowel series demonstrated duodenal and jejunal dilatation with a normal caliber distal ileum. The valvulae conniventes were not thickened and their approximation to one another was normal. Results of a barium enema were normal. The patient was treated initially with nasogastric suction, intravenous fluid therapy, and total parenteral nutrition. Within 24 hours of placement of a central venous catheter, pneumatosis cystoides intestinalis was noted (Figure 5 ) . This cleared spontaneously within several weeks. Over a period of 4 weeks there was no significant response with respect to anorexia, nausea, vomiting, and diarrhea. A trial of prednisone, 40 mg daily, was instituted. Two weeks after the institution of prednisone, sedimentation rate was 12 mm/hr, R A latex 1:160, and ANA 1:2000 speckled. An attempt to wean the patient from parenteral feeding was unsuccessful. Because of an assumed intestinal pseudo-obstruction, a resection approximately 130 cm in length of the distal duodenum, jejunum, and proximal ileum was performed. Pathological specimens were reviewed and the mucosa was shown t o be intact and the muscularis mucosa to be of normal thickness. The submucosa contained dilated vascular channels with dense eosinophilic collagenous stroma. There were focally increased numbers of lymphocytes. On Masson staining, the fibrous connective tissue was very dense and individually encircled the circumferential bundles of smooth muscle and extended into and replaced much of the longitudinal smooth muscle bundles. Much of the serosa was thickened by fibrous connective tissue and chronic inflammatory cells (Figure 6). N o vasculitis was demonstrated. The patient’s course of recovery was complicated by massive anasarca and diffuse gastrointestinal hemorrhaging, and four weeks postoperatively she died of these complications. Permission for autopsy examination was refused.
RESULTS All three patients presented in this report had definite gastrointestinal roentgenographic evidence of PSS (Table 1 ) in addition to the presence of high titers of
815
Figure 5. Upper gastrointestinal series of patient I.S. demonstrating spiculated mucosa of pneumatosis cystoides intestinalis. Insert in right lower corner shows a magnified view of this abnormality.
antibody to ENA with either a complete or significant fall in titer after RNase treatment of ENA (Table 2). Patient R.S. has clinical evidence that could be classified as sclerodermatomyositis with laboratory evidence of SLE or MCTD, as defined by her clinical presentation and serology (Table 3). I n addition to this, she had biopsy evidence of erythema nodosum. Patient J.G. could be classified as having scleroderma sine scleroderma (progressive systemic sclerosis with minimal skin changes) ( 1 1 ) by the presence of Raynaud’s phenomenon and extensive gastrointestinal radiographic changes of progressive systemic sclerosis. Alternatively, such symptoms might represent a patient with MCTD who has only one manifestation of the overlap as reported by Sharp et a/. (4). Patient I.S. should be classified as having overlapping progressive systemic sclerosis by the combination of Raynaud’s phenomenon and compatible gastrointestinal changes, as well as rheumatoid arthritis on the
816
Figure 6 . A. Surgical specimen of duodenum of patient I.S. demonstrating normal mucosa. extensive deposition of collagen in the submucosa. and infiltration and replacement of the longitudinal muscle fibers with collagenous fibers. (Masson trichrome stain, original magnification X lo.) B. High power view of same specimen detailing submucosa and longitudinal muscle fibers. (Masson trichrome stain, original magnification X 80.)
GI SYSTEMIC SCLEROSIS IN MCTD
Table 1. Laboratory Characteristics of Patients with Serologic MCTD and Gastrointestinal Systemic Sclerosis
817
Table 3. Clinical Characteristics of Patients with Serologic MCTD and Gastrointestinal Systemic Sclerosis
Patients
Patients Laboratory Characteristics Radiology Dilated and atonic esophagus Dilatation of the small bowel Wide-mouth sacculations of antimesenteric border of the colon Malabsorption Studies Stool fat (grams/24 hours) Serum B12 D-xylose excretion/5 hours Schillings Stage I
* ND
=
R.S.
J.G.
IS.
+ +
+
-
+
+
-
+
-
2
12
ND*
ND
510 ND
920 2
4.6
ND
6%
1.4%
test not done.
basis of symmetrical polyarthritis of the shoulders, elbows, and knees in the presence of a high titer rheumatoid factor (by both latex fixation and sensitized sheep cell agglutination) and a markedly increased erythrocyte sedimentation rate.
The association of extensive gastrointestinal changes of progressive systemic sclerosis in addition to the presence of high titers of antibody to nRNP has not previously been reported. The patients presented share the presence of Raynaud’s phenomenon and gastrointestinal involvement indistinguishable from that obTable 2. Serologic Characteristics of Patients with Serologic MCTD and Gastrointestinal Systemic Sclerosis
Patients R.S.
J.G.
1: 1280
I :256,000
1:640 1 : 32,000
I : 2000 0
0 NDt
I.S.
~
ANA (speckled):titer ENA :titer ENA :titer after RNase Antibody to native DNA* RA latex LE preparation Complement C3 Total complement VDRL Sedimentation r a t 4
* Normal
1:80
+
32 < 21
N RS 54
is 040%. test not done. $ NR non-reactive. 4 Normal is less than 20 mm/hour.
t ND
= =
Age Sex Race* Arthralgia/Arthritis Raynaud’s phenomenon Weight loss Fatigue Serositis Dyspnea Myalgia Morning stiffness Dysphagia Diarrhea Fever Alopecia Skin rash Swollen hands Scleroderma skin changes Sjogren’s syndrome
*B=
DISCUSSION
Serology
Clinical Profile
ND ND NR ND
1:8OOo 1 : 120,000 1 : 512,000 0 0 I : I280
-
I30
ND NR 65
R.S.
J.G.
I.S.
25
54 M MA
61
F B
+ + + + + + + + + +
+ + +
F
B
+ +
-
+ + +
black; MA = Mexican-American.
served in PSS. Because of this combination, they could very well be classified as patients who fall within the spectrum of progressive systemic sclerosis. Reichlin (12) has pointed out that there are no reports to date of serious systemic complications of progressive systemic sclerosis in patients with high titers of antibody to nRNP. In one report (13) 21% of patients with PSS had antibody to nRNP but generally in a titer below 1: 1000; such a low titer is rarely seen in MCTD (l,3). MCTD is characterized clinically by varying combinations of overlapping features of progressive systemic sclerosis, systemic lupus erythematosus, polymyositis, and rheumatoid arthritis in addition to the serologic characteristic of the presence of high titers of antibody to nuclear ribonucleoprotein (1-10). Although patients with MCTD generally have overlapping features of PSS, SLE, PM, and RA, occasional cases present with dominant clinical findings of a single disease and if followed may then develop either overlapping manifestations or dominant features of one of the other diseases that comprise the overlap syndrome. Patient R.S., though with clinical features of sclerodermatomyositis, has a positive lupus erythematosus preparation and direct Coombs’ test, as well as increased serum gammaglobulin and erythrocyte sedimentation rate consistent with the diagnosis of SLE. Patient J.G. with
818
Raynaud’s phenomenon and gastrointestinal changes of PSS may represent an example of a patient with MCTD who presents with one disease of the overlap syndrome. Patient I.S. has overlapping features of progressive systemic sclerosis and rheumatoid arthritis. Each of the patients presented had a high titer of antibody to nRNP. Since 1972, a strong body of literature has developed the thesis that a high titer of antibody to nRNP, with or without overlapping features of the above diseases, dictates the diagnosis of MCTD. In this light, we would have to consider the possibility that these patients are consistent and represent extensive gastrointestinal changes of PSS in MCTD. Gastrointestinal tract involvement in PSS has been reported to be as high as 80% (14-17). Radiographic features of this disease are seen throughout the gastrointestinal tract. The most common radiologic finding is dilatation of the distal two-thirds of the esophagus with absent peristalsis (18,19). An identical involvement in MCTD has been reported by several authors (10,20). The most characteristic finding in the duodenum, seen in approximately one-third of patients with PSS (21,22), is dilatation of the second and third portions (18,19,21-25) as well as hypomotility of these segments (19,23). Distal small bowel involvement, consisting of dilatation, occurs in 10% of patients (21,22,26,27). Involvement of the colon in PSS occurs less frequently than in the esophagus or small bowel (21 ). The characteristic radiographic feature is the presence of wide-mouthed diverticula of the antimesenteric border of the transverse and descending colon (15,16,18,19,21,28,29). With more advanced involvement, there is loss of haustration and generalized dilatation of the colon (18,23). All 3 of the patients discussed in this report had radiologic ,involvement of the duodenum, 2 had esophageal involvement, and 1 had antimesenteric diverticula of the colon identical to that seen in PSS. One patient demonstrated radiographic findings of pneumatosis cystoides intestinalis, a recognized complication of bowel involvement in progressive systemic sclerosis (30,3 1) not previously reported to occur in the MCTD syndrome. The typical morphologic change in PSS of the gastrointestinal tract is a patchy deposition of acellular collagenous fibrous tissue in the submucosal, muscular, and serosal layers. The muscular layer either undergoes atrophy or is replaced to a varying extent by connective tissue. The mucosa is usually spared. Infiltration of the lamina propria by chronic inflammatory cells is occasionally seen ( 1 1,18,23,32-37). Examination of the duodenum obtained at bowel resection in one patient revealed all of these changes. She had a normal mucosa,
NORMAN AND FLEISCHMANN
replacement of the muscular layer by dense collagen, and focal infiltration of the lamina propria by lymphocytes. It has been reported that clinical symptoms referrable to the gastrointestinal tract are less frequent than radiographic abnormalities in PSS (1 5,2 1,32,33). Patient R.S. was completely asymptomatic and demonstrated no evidence of malabsorption. Patient J.G. 16 years prior to his last admission had had dysphagia which disappeared after Heller myotomy and Allison hernioplasty. Although symptom free at the time of this evaluation, he did have radiographic involvement of the esophagus, duodenum, and large bowel, a quantitative stool fat of 12 gm/24 hours, and a Schillings Stage I of 6%. Patient I.S. presented with the complaints of nausea, vomiting, abdominal distention, and diarrhea. Three exploratory laparotomies were undertaken in the 4 years prior to diagnosis for what was thought to be small bowel obstruction; however, no evidence of obstruction was found at the time of surgery. This is not an uncommon occurrence in PSS with gastrointestinal involvement (35). Upper gastrointestinal series revealed classic changes of PSS. Her clinical course was typical of this diagnosis as well. She did not respond to antibiotics for possible bacterial overgrowth, elemental diets, or treatment with prednisone in high dosage. Abrams and co-workers (24) reported a case of PSS which appeared to respond to cortisone. Many authors (1,4-6, 10-13) have concluded that MCTD is amenable to prednisone therapy. On this treatment, the patient had a fall in ESR to normal and a significant decrease in titer of rheumatoid factor and ANA. In spite of this, she had no improvement in the condition of her gastrointestinal tract and subsequently had a small bowel resection with a stormy postoperative course ending in death 4 weeks later. It is not known how common extensive gastrointestinal tract involvement is in patients with high titers of antibody to nRNP. Three patients in this report ranged from being asymptomatic to having severe symptoms resulting in demise. It is suggested that radiographic examination of the gastrointestinal tract and malabsorption studies be undertaken in any patient with the diagnosis of MCTD who has symptoms suggestive of gastrointestinal involvement.
REFERENCES I . Sharp GC, Irvin WS, Tan EM, Could RG, Holman HR: Mixed connective tissue disease-an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 52:148-158, 1972
GI SYSTEMIC SCLEROSIS IN MCTD
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