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Late-onset gastrointestinal pain in juvenile dermatomyositis as a manifestation of ischemic ulceration from chronic endarteropathy.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 57, No. 5, June 15, 2007, pp 881– 884
DOI 10.1002/art.22782
© 2007, American College of Rheumatology
Late-Onset Gastrointestinal Pain in Juvenile
Dermatomyositis as a Manifestation of Ischemic
Ulceration From Chronic Endarteropathy
Case 1
Juvenile dermatomyositis (DM) is a chronic inflammatory
disease characterized by proximal muscle weakness and
rash. Other organ systems, including the gastrointestinal
tract, are frequently involved. Gastrointestinal manifestations of juvenile DM include dysphagia, bowel dysmotility, and vasculitis with associated malabsorption (1). Gastrointestinal ulceration is thought to be characteristic of
the vasculopathy associated with juvenile-onset DM,
rather than adult-onset DM, and might uncommonly lead
to intestinal perforation (2). An autopsy series of patients
with juvenile DM from the 1960s, prior to the optimal use
of corticosteroids and other immunosuppressive agents,
demonstrated frequent ulceration, perforation, and vascular changes in the bowels of patients with juvenile DM (3).
We report 2 patients with severe gastrointestinal ulceration that resulted in surgery, and we review the pathologic findings and risk factors for the development of these
serious, often life-threatening manifestations of juvenile
The patient, a girl age 14.6 years presented with muscle
pain, fatigue, and difficulty walking, followed by difficulty
raising her arms above her head and heliotrope rash. She
had been diagnosed with juvenile DM at age 11. Serum
creatine kinase (CK) was elevated at 11,734 units/liter
(normal range 0 –252 units/liter). Muscle biopsy demonstrated scattered perivascular lymphocytes with a normal
capillary bed and no evidence of infarction. Initial treatment of her juvenile DM consisted of daily oral prednisone, but monthly intravenous immunoglobulin (IVIG)
was added due to lack of response. The patient’s juvenile
DM improved, but 2 flares had occurred with reduction of
prednisone dose, therefore azathioprine was started.
Four months after diagnosis, the patient developed 2
episodes of intermittent sharp abdominal pain in the right
upper quadrant with nausea and bilious emesis. This episodic pain was associated with bloating. Stool was negative for occult blood. Metronidazole relieved her symptoms; however, they recurred upon discontinuation.
Differential diagnosis included corticosteroid-induced ulceration, gastritis, or abdominal pain associated with small
bowel overgrowth. Esophagogastroduodenoscopy revealed
a shallow ulceration at the gastroesophageal junction and
mild esophagitis. Multiple medications, including ranitidine, lansoprazole, dicyclomine, and hyoscyamine sulfate,
provided no relief of her symptoms.
The patient’s juvenile DM remained active, with mild
but improving weakness, as well as with persistent Gottron’s papules and periungual erythema. Sixteen months
after diagnosis, the abdominal pain worsened and became
continuous, and she developed low-grade fever and vomiting. One month later, the patient presented with an acute
abdomen with severe diffuse periumbilical and right lower
quadrant abdominal pain. There was marked percussion
tenderness on examination. Flat and upright films of the
abdomen revealed no signs of obstruction or evidence of
free air. The patient underwent an exploratory laparotomy
with hemicolectomy and ileostomy. The colon was remarkable for hyperemia and areas of ulceration, with minimal inflammation in the submucosa, abnormally dilated
Supported in part by the intramural research programs of
the NIH, the National Institute of Environmental Health
Sciences, and the National Cancer Institute. Dr. Mamyrova
is a research fellow of the Cure JM Foundation and previously received support from the Myositis Association.
Gulnara Mamyrova, MD, PhD, Laura James-Newton,
PhD, RN, Frederick W. Miller, MD, PhD, Lisa G. Rider, MD:
Environmental Autoimmunity Group, National Institute of
Environmental Health Sciences, Bethesda, Maryland;
David E. Kleiner, MD: National Cancer Institute, National
Institutes of Health, Bethesda, Maryland; 3Bracha Shaham,
MD: University of Southern California School of Medicine,
Children’s Hospital, Los Angeles, California.
Address correspondence to Lisa G. Rider, MD, Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, NIH, CRC Room 4-2332, MSC 1301,
10 Center Drive, Bethesda, MD 20892-1301. E-mail: riderl@
Submitted for publication August 4, 2006; accepted in
revised form October 25, 2006.
Figure 1. Vascular changes present in the intestine of patient 1,
with gastrointestinal ulceration and juvenile dermatomyositis. A,
Chronic ulceration with sclerosis of the submucosa. Although
there was a fibrinopurulent exudate in the ulcer bed, there is
minimal chronic inflammation in the exposed submucosa and
essentially no granulation tissue (hematoxylin and eosin stained;
original magnification ⫻ 20). B, A single occluded artery was seen
in the adventitia of this patient’s bowel resection. The lumen
shows concentric narrowing by a fibromyxoid neointima (hematoxylin and eosin stained; original magnification ⫻ 40).
vessels in the lamina propria and submucosa, and a single
occluded vessel (Figure 1).
One month after surgery, von Willebrand factor VIII–
related antigen was elevated to 270% (normal 80 –130%).
The patient continued taking daily oral prednisone and
azathioprine, as well as monthly IVIG. Four months later,
the ileostomy was closed. Almost 2 years after surgery, the
patient’s juvenile DM was inactive.
Case 2
The second patient, a girl age 13.3 years with a history of
type 1 diabetes mellitus and a diagnosis of juvenile DM at
age 11, presented with reported difficulty skiing, muscle
pain, and fatigue. Three months later, she developed malar
rash and linear extensor erythema, as well as heliotrope
and V-sign rashes. Her weakness progressed, with an inability to dress or get out of bed. Initial serum CK was
1,228 units/liter, lactate dehydrogenase was 704 units/
Mamyrova et al
liter, and aldolase was 10.4 units/liter. Initial treatment
consisted of weekly intramuscular methotrexate (MTX);
daily oral prednisone was started 1 month later with a
rapid response.
Twenty-two months after diagnosis, the patient discontinued her MTX when her illness was almost in remission.
One month later, her disease relapsed with weakness,
rash, dysphonia, and increased serum CK levels of 4,642
units/liter and aldolase of 25.3 units/liter. Prednisone was
increased to 60 mg/day, weekly MTX was restarted, and
the patient received 3 doses of intravenous methylprednisolone (30 mg/kg/day). Her weakness progressed, however, and she became bed bound; she also developed dysphagia and sinus tachycardia. Daily intravenous
methylprednisolone and cyclosporine were added. Her
symptoms improved, but 2 weeks later she developed
intermittent abdominal pain and constipation. Within 5
days, the pain became severe. Examination revealed tenderness in the left lower quadrant and absent bowel
sounds. Abdominal computed tomography (CT) was normal, but a second scan 4 days later showed pneumoperitoneum with fluid adjacent to the duodenum, suggestive of
a duodenal perforation. Laparotomy revealed extensive
fecal soilage of the abdominal cavity with a full-thickness
perforation of the third portion of the duodenum.
Postoperatively, the patient gradually improved with
increased methylprednisolone and initiation of IVIG. One
week following surgery, the abdominal pain recurred and
progressively worsened. Abdominal CT showed multiple
perforations of the small and large intestine. Repeat laparotomy demonstrated free air and extensive purulent exudates throughout the abdominal cavity. Multiple spontaneous perforations were present in the transverse and
sigmoid colon. Surgical treatment included repair of the
perforations, transverse colectomy, and creation of a colostomy.
Pathology of the resected bowel showed fibrinous peritonitis and mucosal edema without evidence of mucosal
ulceration. Perforation of the bowel was not apparent in
sections made available for our review. Vascular changes
included narrowing or complete occlusion of multiple
small and medium arteries, with subintimal foamy cells,
fibrinoid degeneration, and significant luminal compromise, along with localized clusters of dilated veins (Figure
2). Immunophenotyping showed T cells surrounding the
vessel, but not within the vessel wall, and infiltration of
macrophages through the muscularis into the intima. Most
of the foam cells stained with smooth muscle actin, suggestive of a myofibroblast phenotype.
Cyclophosphamide 10 mg/kg intravenously and IVIG 2
gm/kg twice monthly were started postoperatively. The
patient gradually improved; she had no further abdominal
pain and her strength improved, but remained mildly impaired. One year after surgery, her muscle enzyme levels
were normal and von Willebrand factor VIII–related antigen remains elevated at 188%.
We present the clinical and pathologic features of 2 patients with juvenile DM with severe gastrointestinal ulceration or perforation who required surgery. As these cases
demonstrate, abdominal pain may occur at any time dur-
Ischemic Ulceration in Juvenile DM
Figure 2. Vascular changes present in the intestine of patient 2, with bowel perforations and juvenile dermatomyositis. A, Multiple small
arteries showed narrowing or complete occlusion, with a representative artery shown here. These occlusive changes were located both
within the initial resection of the perforated segment or in the subsequent bowel resection in which no acute perforation or ulceration was
noted. In most of the affected vessels, there was an accumulation of foamy cells between the endothelium and the muscular media
(hematoxylin and eosin stained; original magnification ⫻ 60). B, Elastin staining of a partially occluded vessel showed an intact elastic
lamina with accumulation of pale, foamy cells in the intima (elastin von Gieson stained; original magnification ⫻ 60). C, Staining for
macrophages showed infiltration of macrophages through the muscle layer into the intima (anti-CD68; original magnification ⫻ 60).
Immunophenotyping of lymphocytes showed CD3⫹ T cells around the vessel, but not within the vessel (not shown). D, Most of the foam
cells stained with antibodies directed against smooth muscle actin, suggesting that they may have a myofibroblastic character (anti–smooth
muscle actin; original magnification ⫻ 60).
ing the illness in patients with juvenile DM, and pain that
is persistent, progressive, or severe should be carefully
evaluated. The absence of occult blood in the stool and
normal radiographs do not exclude these potentially serious complications. Close observation and repeated studies
are often necessary to reach a diagnosis. Ulceration and
perforation should be included in the differential diagnosis of any patient with juvenile DM and abdominal pain.
Aggressive management with surgery and multiple immunomodulatory medications appears to have improved the
outcome for these severe gastrointestinal manifestations,
as many older reports describe a high death rate (4,5).
These gastrointestinal findings may occur later in the
course of illness, even when the underlying juvenile DM is
improving or only mildly active, and not necessarily when
it is severe. In previous reports, gastrointestinal symptoms
of abdominal pain, with accompanying vomiting, consti-
pation, and hematemesis, occurred an average of 7 months
after the onset of juvenile DM, with the majority presenting at less than 6 months from the time of diagnosis (4 – 8).
This is in contrast to our patients, who developed this
complication at 16 and 25 months after diagnosis. The late
presentation of abdominal findings may be masked by
long-term corticosteroids and possibly other therapy.
Severe gastrointestinal ulceration and perforation in patients with juvenile DM have been thought to be related to
vasculitis (4 –7). Our patients had elevation of von Willebrand factor VIII–related antigen, a laboratory test sometimes used as a measure of juvenile DM disease activity,
which suggests endothelial activation (9). The histopathologic manifestations of gastrointestinal tract involvement
in juvenile DM have been previously described in patients
with untreated or minimally treated disease as a noninflammatory acute endarteropathy with arterial and venous
intimal hyperplasia and occlusion of vessels by fibrin
thrombi in the submucosa, muscularis, and serosal layers
(2,3). This is in contrast to our patients, who showed a
chronic vasculopathy rather than an acute vasculitis. This
chronic vasculopathy is characterized by narrowing or
complete occlusion of multiple small and medium arteries, subintimal foam cells, fibromyxoid neointimal expansion, and significant luminal compromise and infiltration
of macrophages through the muscle layers into the intima.
This chronic form of noninflammatory endarteropathy has
occasionally been observed in muscle, skin, and gastrointestinal tract lesions (10). Two recent articles of ulceration
and perforation in patients with juvenile DM who received
oral and intravenous corticosteroids, along with a number
of immunosuppressive agents, report similar histopathologic findings, with occlusion of arteries and veins, intimal
hyperplasia, fibrin thrombi, endothelial proliferation with
infiltrating lymphocytes and foamy macrophages (5), and
ischemic changes (7). It is possible that some of the lesions
are a late consequence of the acute noninflammatory endarteropathy and are reparative or healed.
Chronic vasculopathy has also been described in patients after bone marrow transplantation (11) and solid
organ transplantation (12), as well as in animal models of
immunosuppression-associated vasculopathy (13). It is
characterized by involvement of small muscular arteries
with intimal or medial hyperplasia, luminal narrowing,
prominent myxoid changes, extravasated red blood cells,
and the presence of foamy histiocytes in the intima. Of
interest, a number of clinical features of idiopathic inflammatory myopathies resemble those of graft versus host
disease. Microchimerism, a mechanism that may initiate
graft versus host reactions that manifest as autoimmune
diseases, is frequently present in the peripheral lymphocytes and affected muscle tissue of patients with juvenile
DM (14).
Chronic endarteropathy, not acute vasculitis, appears to
be underlying the pathogenesis of the ischemic ulceration
associated with our patients with late-onset gastrointestinal ulceration and perforation. The chronic endarteropathy, with its delayed onset, may partly be the result of
therapy to treat juvenile DM. Longstanding treatment with
high doses of corticosteroids could also be a predisposing
factor for the development of gastrointestinal complications. The effects of high doses of corticosteroids on the
gastrointestinal tract include peptic ulcer disease, upper
gastrointestinal bleeding, and perforation (15). One of our
patients was also treated with cyclosporine, which was
administered for 1 month immediately prior to the development of the gastrointestinal symptoms. The synthesis of
endothelins, vasoconstrictor peptides produced by macrophages, can be induced by cyclosporine (16), which may
contribute to the development of chronic vasculopathy
(13) in both animals and humans.
In summary, we described 2 patients with juvenile DM
with severe, acute abdominal pain complicated by gastrointestinal ulceration or perforation, along with accompanying histopathology. Chronic endarteropathy, not acute
vasculopathy, is associated with the pathology of the ischemic ulceration. The current approach to treatment of
Mamyrova et al
juvenile DM with immunosuppressive agents may have
contributed to delay in the onset of these gastrointestinal
manifestations and to their pathologic features.
We thank Drs. Martha Quezado and Nikolay Nikolov for
their critical reading of the manuscript.
Dr. Rider had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the
data analysis.
Study design. Miller, Rider.
Acquisition of data. Mamyrova, Kleiner, James-Newton, Shaham,
Analysis and interpretation of data. Mamyrova, Kleiner, Miller,
Manuscript preparation. Mamyrova, Kleiner, James-Newton,
Shaham, Miller, Rider.
Figure preparation. Mamyrova, Kleiner, Rider.
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pain, ulcerative, ischemia, gastrointestinal, dermatomyositis, manifestation, latex, juvenile, endarteropathy, chronic, onset
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