Late-Onset Gastrointestinal Pain in Juvenile Dermatomyositis as a Manifestation of Ischemic Ulceration from Chronic Endarteropathy

Abstract

We present the clinical and pathologic features of two patients with juvenile dermatomyositis (DM) with severe gastrointestinal ulceration or perforation who required surgery. Abdominal pain which is persistent, progressive or severe, even in patients with improving or mildly active juvenile DM, should be carefully evaluated. The absence of occult blood in the stool and normal radiographs do not exclude these potentially serious complications. Chronic endarteropathy, not an acute vasculopathy previously reported, is the pathology associated with the ischemic ulceration in these patients. The current approach to treatment of juvenile DM with immunosuppressive agents may have contributed to delay in the onset of these gastrointestinal manifestations and to their pathologic features.

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 juvenile DM patients from the 1960s, prior to the optimal use of corticosteroids and other immunosuppressive agents, demonstrated frequent ulceration, perforation and vascular changes in the bowel of patients with juvenile DM (3).

We report two patients with severe gastrointestinal ulceration that resulted in surgery, and review the pathologic findings and risk factors for the development of these serious, often life-threatening manifestations of juvenile DM.

Case 1

A 14.6 year old Caucasian female was diagnosed with juvenile DM at age 11. She presented with muscle pain, fatigue and trouble walking, followed by difficulty raising her arms above her head and heliotrope rash. Serum creatine kinase (CK) was elevated at 11,734 U/L [normal range 0 − 252 U/L]. 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. Her juvenile DM improved, but two flares occurred with reduction of prednisone dose, so azathioprine was begun.

Four months after diagnosis, she developed two 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.

Her 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, she presented with an acute abdomen with severe diffuse periumbilical and right lower quadrant abdominal pain. There was marked percussion tenderness on exam. Flat and upright films of the abdomen revealed no signs of obstruction or evidence of free air. She 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 vessels in the lamina propria and submucosa, and a single occluded vessel (Figure 1).

Figure 1. Vascular changes present in the intestine of patient 1, with gastrointestinal ulceration and juvenile dermatomyositis (DM).

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 (H&E, 20×). B. A single occluded artery was seen in the adventia of this patient's bowel resection. The lumen shows concentric narrowing by a fibromyxoid neointima (H&E, 40×).

One month after surgery, von Willebrand factor VIII related antigen was elevated to 270% (normal 80 − 130%). She remained on daily oral prednisone and azathioprine, as well as monthly IVIG. Four months later, the ileostomy was taken down. Almost two years after surgery, her juvenile DM was inactive.

Case 2

A 13.3 year-old Hispanic/Asian girl with a history of type I diabetes mellitus was diagnosed with juvenile DM at age 11. She presented with 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. Weakness progressed, with an inability to dress or get out of bed. Initial serum CK was 1228 U/L, LDH 704 U/L and aldolase 10.4 U/L. Initial treatment consisted of weekly intramuscular methotrexate (MTX); daily oral prednisone was started one month later with a brisk response.

Twenty-two months after diagnosis, the patient discontinued her MTX when her illness was almost in remission. One month later, she relapsed with weakness, rash, dysphonia, and increased serum levels of CK to 4642 U/L and aldolase of 25.3 U/L. Prednisone was increased to 60 mg/day, weekly MTX was re-started, and she received three 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 two weeks later, she developed intermittent abdominal pain and constipation. Within five 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 four 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 sized 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, but not within, the vessel 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.

Figure 2. Vascular changes present in the intestine of patient 2, with bowel perforations and juvenile dermatomyositis (DM).

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. (H&E, 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 Geison, 60×) C. Staining for macrophages showed infiltration of macrophages through the muscle layer into the intima. (anti-CD68, 60×). Immunophenotyping of lymphocytes showed CD3+ T-cells around, 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-SMA, 60×).

Cyclophosphamide 10 mg/kg intravenously and IVIG 2 gm/kg twice monthly were started post-operatively. She gradually improved; she had no further abdominal pain, and her strength improved, but remained mildly impaired. One year after surgery, her muscle enzyme levels are normal and von Willebrand factor VIII related antigen remains elevated at 188%.

Discussion

We present the clinical and pathologic features of two patients with juvenile DM with severe gastrointestinal ulceration or perforation who required surgery. As these cases demonstrate, abdominal pain may occur at any time during the illness in patients with juvenile DM and pain which 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, not necessarily severe. In previous reports, gastrointestinal symptoms of abdominal pain, with accompanying vomiting, constipation, and hematemesis, occurred on average of seven months after the onset of the juvenile DM, with the majority presenting at less than six months from the time of diagnosis (4-8). This contrasts to our patients, who developed this complication at 16 and 25 months after diagnosis. The late presentation of abdominal findings may be masked by chronic corticosteroid and possibly other therapy.

Severe gastrointestinal ulceration and perforation in 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 non-inflammatory 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 sized 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 non-inflammatory endarteropathy has occasionally been observed in muscle, skin and gastrointestinal tract lesions (10). Two recent reports of ulceration and perforation in patients with juvenile DM who received oral and intravenous corticosteroids, along with a number of immunosuppressive agents, contain 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 non-inflammatory endarteropathy, and are reparative or healed.

Chronic vasculopathy has also been described in patients after bone marrow (11) and solid organ (12) transplantation, as well as in animal models of immunosupresion-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 juvenile DM patients (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 the 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 one month immediately prior to the development of the gastrointestinal complaints. The synthesis of endothelins, vasoconstrictor peptides produced by macrophages, can be induced by cyclosporine (16), which may contribute in the development of chronic vasculopathy (13) in both animals and humans.

In summary, we described two juvenile DM patients 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 juvenile DM with immunosuppressive agents may have contributed to delay in the onset of these gastrointestinal manifestations and to their pathologic features.