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Gastrointestinal systemic sclerosis in serologic mixed connective tissue disease.

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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,
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