Massive gastrointestinal hemorrhage in systemic lupus erythematosus: successful treatment with corticosteroid pulse therapy

THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 1999 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.

Vol. 94, No. 11, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00610-3

CASE REPORTS

Massive Gastrointestinal Hemorrhage in Systemic Lupus Erythematosus: Successful Treatment With Corticosteroid Pulse Therapy Hideyuki Hiraishi, M.D., Toshiro Konishi, M.D., Shin’ichi Ota, M.D., Tadahito Shimada, M.D., Akira Terano, M.D., and Tsuneaki Sugimoto, M.D. Department of Gastroenterology, Dokkyo University School of Medicine, Tochigi; and Second Department of Internal Medicine and Second Department of Surgery, Faculty of Medicine, University of Tokyo, Tokyo, Japan

ABSTRACT Although mesenteric vasculitis due to systemic lupus erythematosus (SLE) is relatively uncommon, it is the most dangerous manifestation associated with high mortality. We describe the case of a SLE patient with life-threatening gastrointestinal hemorrhage due to mesenteric vasculitis in whom methylprednisolone pulse therapy was quite effective in controlling the hemorrhage and resulted in a satisfactory long term outcome. A 47-yr-old woman presenting with high fever, rash, and melena was diagnosed with SLE from positive antinuclear antibodies, anti-dsDNA, and low complement titers. Although fever and rash subsided with administration of prednisolone, massive hematemesis appeared with melena. Endoscopy demonstrated bleeding ulceration of the antrum, which was intractable despite intensive antiulcer therapy and transfusion. Surgical exploration revealed ileal penetration, and multiple bleeding ulcerations were observed over the resected ileum as well as the antral ulceration. However, bleeding persisted after surgery and surgical findings prompted us to select methylprednisolone pulse. Hemorrhage responded promptly to the therapy, and the patient has remained well since then for ⬎10 yr. Our report indicates that corticosteroid pulse may serve as one of the therapeutic options for SLE with massive hemorrhage due to widespread mesenteric vasculitis. (Am J Gastroenterol 1999;94:3349 –3353. © 1999 by Am. Coll. of Gastroenterology)

INTRODUCTION Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disease of unknown etiology. Gastrointestinal disturbances may be the presenting feature of SLE in up to 10% of patients, and approximately 40% of patients with active SLE may have gastrointestinal symptoms such as nausea, diarrhea, and vague discomfort in some series. Although mesenteric vasculitis remains relatively uncommon, affecting about 2% of all SLE patients (1), it is the most

dangerous manifestation, presenting with acute crampy abdominal pain, vomiting, diarrhea, and hemorrhage. We herein report the case of a SLE patient with lifethreatening gastrointestinal hemorrhage due to widespread mesenteric vasculitis, in whom pulse therapy with methylprednisolone was quite effective in controlling the hemorrhage and resulted in a satisfactory long term outcome.

CASE REPORT A 47-yr-old housewife was admitted to Tokyo University Hospital on February 3, 1988, for investigation of melena and high fever. On January 27, a rash appeared on her face. On January 29, she was admitted to another hospital because of high fever and oral ulcerations. On February 2, melena appeared, blood culture was found to be positive for Bacteroides fragilis, renal function was impaired, and the patient was transferred to our hospital. Upon arrival, her temperature was 38.2°C, pulse 112, respiration 18, and blood pressure 166/82 mm Hg. She was anemic and not icteric. There were purpuras on her face, back, and limbs. The heart and lungs were normal. Her abdomen was mildly distended and bowel sounds were hyperactive, but there was no tenderness, rebound, or rigidity. The liver and spleen were not palpable. There was edema of the lower extremities. She denied abdominal pain during the course of her illness. Laboratory data showed the following values: red blood cell count 258 ⫻ 104/␮l, hemoglobin 7.1 g/dl, hematocrit 21.2%, MCV 82 fl, MCH 27.5 pg, MCHC 33.5%, white cell count 13.0 ⫻ 109/L, platelets 276 ⫻ 109/L, total protein 50 g/L, albumin 17 g/L, urea nitrogen 72 mg/dl, creatinine 3.5 mg/dl, iron 6 ␮g/dl (normal 29 –158 ␮g/dl), and total iron binding capacity 76 ␮g/dl (normal 261– 421 ␮g/dl). Serologically, C-reactive protein was 15 mg/dl, she was positive for LE test, antinuclear antibodies (ANAs) (1/640), antidsDNA antibodies and direct Coombs’ test, and complement titers (CH50 and C3) were low. Prothrombin time, partial thromboplastin time, fibrin level, and fibrin degradation product (FDP) were within the normal range. Urinalysis

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Figure 1. Angitis with fibrinoid necrosis and perivascular infiltration of inflammatory cells around the antral ulceration. Stained with hematoxylin and eosin (left) and with elastica Van Gieson (right).

was positive for protein (950 mg/day); the sediment contained 10 white cells and occasional granular casts per high-power field. X-ray films of the abdomen were normal and revealed no evidence of free air in the peritoneal cavity. A diagnosis of systemic lupus erythematosus (SLE) was made on the basis that more than four of the 1982 criteria for classification of SLE (2) were present (oral ulcers, proteinuria ⬎0.5 g/day, positive anti-dsDNA, an abnormal titer of ANAs, and probable hemolytic anemia). Although her fever and skin rash subsided after the administration of prednisolone (30 mg/day) and antibiotics, melena persisted intermittently. On hospital days 2 and 8, gastroduodenal endoscopy demonstrated antral ulceration, but without hemorrhage. On hospital day 12, hematemesis appeared with melena, and reendoscopy demonstrated oozing hemorrhage of the antral ulceration. Repeat x-ray films of the abdomen were unchanged. Despite administration of cimetidine, antacid, and powdered thrombin, 8 U of blood transfusion was required for the following 3 days. On hospital day 15, although it was believed that the gastrointestinal bleeding might involve a more extensive process than the antral ulcer because of the massive gastrointestinal hemorrhage in the absence of arterial bleeding, we decided to treat the uncontrollable bleeding from gastric ulceration and referred her to the surgical division; distal gastrectomy was then performed. During the operation, part of the ileum was found to have been penetrated and been covered with omentum, and resection of the segment was also performed. Multiple bleeding ulcerations were observed macroscopically over the resected ileum as well as the antral ulceration. However, persistent bleeding required 4 U of transfusion to maintain hemodynamic stability on the day of operation.

The surgical findings led us to consider that gastrointestinal bleeding might have developed due to widespread vasculitis over the gastrointestinal tract. Because vasoconstrictor medication was shown to control gastrointestinal bleeding in some patients with SLE (3), intravenous administration of vasopressin was attempted, but without effect. On hospital day 16, pulse therapy with 1500 –2000 mg/day (equivalent to 1000 mg/day considering loss via the hemorrhage) of methylprednisolone for 5 days was started (4). Within a few days, her melena gradually subsided. Thereafter, prednisolone (60 mg/day) was administered, then reduced gradually. On pathological examination, a 14-cm-long segment of ileum contained multiple ulcerations, and the deepest was Ul-IV. Histologically, the ulcers were noted to have a luminal surface covering fibrin exudate; beneath this was a layer of granulation tissue with areas of fibrosis. All layers of the ulcers were noted to have inflammatory cell (polymorph nuclear cell dominant) infiltration. The vessels in the submucosa of the involved area (adjacent to the ulcers) revealed intraluminal fibrin deposition, focal arterionecrosis, cellular subendothelial proliferation with fibrinoid necrosis in the wall, and perivascular inflammation and cellular proliferation. The resected distal stomach also had an irregularly shaped ulcer (Ul-II) measuring 4 ⫻ 2 cm on the lesser curvature of the antrum. Marked angitis with fibrinoid necrosis and perivascular infiltration of inflammatory cells was also demonstrated microscopically around the antral ulceration (Fig. 1). After treatment of diabetes mellitus secondary to corticosteroid administration, the patient was discharged in April 1988. After discharge, corticosteroid was tapered carefully

N.D. (3 cases) N.D. 29/F

26/F

18/F

47/F

12

14

15

present case

cecum & distal ileum exploratory Lapa, sigmoidscopy & AG failed to disclose site of bleeding stomach & intestine exploratory Lapa

Gross Pathology/ Histopathology

subtotal gastrectomy steroid

steroid

resection of distal colon & right part of colon

injection of Prop & Epi into SMA

subtotal colectomy & ileo-rectal anastomosis due to uncontrollable bleeding MP pulse following resection

N.D. Onion skin periarterial fibrosis in spleen, N.D. on GI tract extensive ischemic ulcerations, hemorrhage and necrosis involving entire colon ulcerations of cecum & ascending colon/colonic venulitis gastric & ileal ulcerations/angitis with fibrinoid necrosis

colonic & ileal ulcerations/submucosal arteriolitis N.D.

N.D.

pulse CP monthly following resection diffuse intramucosal MP pulse failed to prevent small vessel arteritis subsequent GI bleeding injection of Prop & Epi into SMA N.D.

Treatment

exploratory Lapa because of subtotal colectomy, MP pulse failed suspicion of a perforated viscus to prevent subsequent bleeding

N.D. N.D.

stomach undetermined

throughout colon

N.D.

AG & exploratory Lapa

ND

terminal ileum & cecum

exploratory Lapa & AG failed to disclose site of bleeding AG

AG & Lapa

Diagnosis

alive after 10 years

alive 2 years & 5 months after operation

alive without GI complaints 2 years after surgery, receiving low dose of prednisolone

recovered uneventfully died 4 days after admission

all died of GI bleeding

no evidence of GI bleeding 1 year after treatment bleeding seemed to stop, but died of convulsion & coma 6 days after AG died of intracerebral hemorrhage 3 days after surgery

alive after 1 year

Outcome

Note: AG ⫽ arteriography; CP ⫽ cyclophosphamide; Epi ⫽ epinephrine; GI ⫽ gastrointestinal; Lapa ⫽ laparotomy; MP ⫽ methylprednisolone; N.D. ⫽ not described; Prop ⫽ propranolol; SMA ⫽ superior mesenteric artery; M ⫽ male; F ⫽ female.

13

26/M

hepatic flexure of colon

37/F

11

undetermined

47/F

3

proximal jejunum

21/F

Bleeding Sites

1

Reference Age/Sex

Table 1. Massive Gastrointestinal Hemorrhage in Systemic Lupus Erythematosus (SLE)

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to prevent the recurrence of vasculitis. Corticosteroid was discontinued in November 1993, because the activity indexes such as ANAs, anti-dsDNA, and complement titers remained within the normal range for ⬎1 yr. Since then, the patient has remained well, without any symptom or sign to indicate the recurrence of vasculitis in SLE.

DISCUSSION The basic pathological feature in SLE is vasculitis. This involves small arteries and arterioles with acute and chronic perivascular infiltrates. Fibrinoid degeneration may be noted in acute phases, followed by varying degrees of fibroblastic proliferation. Perivascular immunoglobulin deposition may be demonstrated (5). Mesenteric vasculitis due to SLE is relatively uncommon, developing in only 2% of all SLE patients (1). Common sequelae include ulceration, hemorrhage, perforation, and infarction. Thus, mesenteric vasculitis is associated with high morbidity and mortality despite its rarity. Indeed, the largest published series reported that the mortality rate is approximately 50% (6). Although the incidence of gastrointestinal hemorrhage in SLE is approximately 5% (7), the etiology of bleeding is multifactorial, including the administration of nonsteroidal anti-inflammatory drugs (8) and corticosteroids (9), as well as vasculitis involving the terminal mesenteric and submucosal vessels (10). Nonetheless, massive hemorrhage in SLE is rare; only several case reports of SLE have documented life-threatening hemorrhage (1, 3, 11–15), regardless of whether mesenteric vasculitis has been proved pathologically (Table 1). The diagnosis of mesenteric vasculitis in SLE is frequently difficult to make. The most typical pathological changes are seen in small vessels in the bowel wall rather than in medium-sized muscular arteries of the mesentery (6, 10). Therefore, angiography, although useful for determining the sites of gastrointestinal bleeding, may be less diagnostic for mesenteric vasculitis. Indeed, laparotomy with resection of the involved organs has been performed to make a definite diagnosis of mesenteric vasculitis in all cases of SLE in the literature (Table 1). Thus, when massive gastrointestinal bleeding is encountered in a seriously ill patient with active SLE, the possibility that the bleeding is due to mesenteric vasculitis should be considered, and an aggressive approach is essential for the treatment of lifeendangering complications (11). In the present case, because hemorrhage from gastric ulceration was intractable despite intensive antiulcer therapy and repeated transfusion, we selected surgical exploration as the optimal treatment. Ileal penetration found at operation led us to consider that the focus of bleeding included the intestine as well, and prompted us to select pulse therapy with methylprednisolone for treatment. Hemorrhage responded promptly and quite well to the therapy; and since then, the patient has been without relapse for ⬎10 yr. Methylprednisolone pulse therapy was first introduced as a therapeutic option for severe and diffuse lupus glomeru-

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lonephritis (16), and more recently for severe pulmonary hemorrhage (17), although it is unclear whether the long term outcome is changed. As to the gastrointestinal complications, only two case reports have documented the use of methylprednisolone pulse for the treatment of gastrointestinal vasculitis due to SLE. In these patients, who had previously received modest doses of prednisolone daily for as long as 3 yr, little beneficial effect has been demonstrated (1, 14) (Table 1). A course of methylprednisolone pulse, administered under the presumptive diagnosis of vasculitisinduced small bowel ischemia (1) or for treatment of acutely impaired renal function (14), failed to prevent subsequent massive gastrointestinal bleeding from mesenteric vasculitis. Thus, our report may emphasize the value of corticosteroid pulse therapy in the acute onset of SLE with lifethreatening hemorrhage due to widespread mesenteric vasculitis after differential diagnosis using surgical or radiological intervention (12, 13). A controlled trial is desirable to determine the possible efficacy of corticosteroid pulse therapy, but such a trial may be difficult because of the small number of patients with SLE complicated by mesenteric vasculitis. Therefore, this case report suggests that it is practical to consider the use of methylprednisolone pulse in SLE with mesenteric vasculitis presenting with life threatening bleeding, which should be followed by treatment with pulse intravenous cyclophosphamide (1) if prompt improvement is not seen during the course of methylprednisolone pulse therapy. Reprint requests and correspondence: Hideyuki Hiraishi, M.D., Department of Gastroenterology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. Received Apr. 2, 1998; accepted Nov. 30, 1998.

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systemic lupus erythematosus: A review of the literature. Sem Arth Rheum 1980;9:237– 47. Graham DY. Prevention of gastroduodenal injury induced by chronic nonsteroidal anti-inflammatory drug therapy. Gastroenterology 1989;96:675– 81. Conn HO, Blitzer BL. Nonassociation of adrenocorticosteroid therapy and peptic ulcer. N Engl J Med 1976;294:473–9. Finkbiner RB, Decker JP. Ulceration and perforation of the intestine due to necrotizing arteriolitis. N Engl J Med 1963; 268:14 – 8. Phillips JC, Howland WJ. Mesenteric arteritis in systemic lupus erythematosus. JAMA 1968;206:1569 –70. Matolo NM, Albo D Jr. Gastrointestinal complications of collagen vascular diseases. Surgical implications. Am J Surg 1971;122:678 – 82.

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13. Chatterjee CR. Massive gastro-intestinal haemorrhage due to systemic lupus erythematosus. J Ir Med Assoc 1973;66: 517– 8. 14. Kistin MG, Kaplan MM, Harrington JT. Diffuse ischemic colitis associated with systemic lupus erythematosus. Gastroenterology 1978;751147–51. 15. Helliwell TR, Flook D, Whitworth J, et al. Arteritis and venulitis in systemic lupus erythematosus resulting in massive lower intestinal hemorrhage. Histopathology 1985;9: 1103–13. 16. Cathcart ES, Idelson BA, Scheinberg MA, et al. Beneficial effects of methylprednisolone “pulse” therapy in diffuse proliferative lupus nephritis. Lancet 1976;1:163– 6. 17. Meyers J, Katzenstein A. Microangitis in lupus-induced pulmonary hemorrhage. Am J Clin Pathol 1986;85:552– 6.