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Partial small intestinal resection for successful surgical management of refractory protein-losing gastroenteropathy in systemic lupus erythematosus

Abstract Rationale: Although systemic lupus erythematosus (SLE) can be complicated by various gastrointestinal tract diseases, it is rarely associated with lupus enteritis and protein-losing enteropathy (PLE). We report here the successful surgical treatment of lupus enteritis and therapy-resistant and refractory PLE in a patient with SLE. We also provide a review of relevant literature. Patient concerns: A 16-year-old girl presenting with polyarthritis, malar rash, and palmar erythema was indicated for steroid therapy on the basis of positive results for antinuclear, anti-Smith, and antiphospholipid antibodies, which confirmed the diagnosis of SLE. During the course of steroid therapy, the patient developed acute abdomen and hypoalbuminemia. Diagnoses: Computed tomography and 99mTc-labeled human serum albumin scintigraphy revealed abnormal findings, and a diagnosis of lupus enteritis and PLE was made. Steroid treatment was continued but no significant improvement was observed, and the patient was referred and admitted to our hospital. Double-balloon enteroscopy revealed multiple ischemic stenoses and mucosal necroses in the small intestine, suggesting that PLE was associated with ischemic enteritis due to antiphospholipid syndrome. The patient received steroids, immunosuppressive drugs, and antithrombotic therapy, with no improvement in symptoms. Thus, the disease was judged to be refractory and resistant to medical therapy, and the patient was indicated for surgical treatment. Interventions: Partial small intestinal resection was performed by removing the segment of the small intestine presenting PLE lesions, and a double-end ileostomy was created. Outcomes: Multiple stenotic lesions were confirmed in the resected segment. Histopathology evaluation revealed marked inflammatory cell infiltration in the intestinal tract wall and recanalization of the vessels, suggesting a circulatory disorder caused by vasculitis and antiphospholipid syndrome. Postoperatively, the clinical course was good. Serum albumin levels and body weight increased as nutritional status improved significantly. Secondary enteroenterostomy with ileostomy closure could be performed at 2 months after the initial surgery. Lessons: Timely surgical treatment can be successful in managing therapy-resistant and refractory PLE in patients with SLE.


Introduction
Patients with systemic lupus erythematosus (SLE) may develop various types of gastrointestinal tract lesions, [1,2] including lupus enteritis and protein-losing enteropathy (PLE). However, the response to steroid therapy is good in more than 60% of cases, and symptoms generally remit in response to treatment with steroids and immunosuppressive drugs. [3][4][5] We report here a case in which surgical treatment was effective for therapy-resistant and refractory PLE caused by multiple ischemic stenoses and mucosal necroses in the small intestine, in a patient with antiphospholipid syndrome (APS). While receiving treatment for SLE, the patient had developed lupus enteritis and advanced ischemic enteritis presenting as acute abdomen; APS involvement was also suspected. Although the symptoms did not respond to steroid treatment, partial small intestinal resection was successful in resolving the symptoms and improving the patient's condition. This is a rare case in which such findings could be confirmed pathologically.

Ethics approval and patient consent
For each procedure and investigation described here, assent from the patient and informed consent from her legal guardians were obtained. Because this article is a case report, no ethical approval or patient consent is required if patient information is anonymized and patient identification data are not presented. We also confirmed that the patient and her parents have provided informed consent for publication of the case and gave permission to be included in the manuscript.

Clinical history and physical examination
In January 2014, a 16-year-old Japanese girl with joint pain, high fever, malar rash, and palmar erythema presented at another hospital. Because tests for antinuclear, anti-Smith, and antiphospholipid antibodies were positive, the diagnosis of SLE was made. After admission, the patient was started on steroid treatment. However, during the course of the therapy, the patient suddenly developed abdominal pain and hypoalbuminemia. Computed tomography (CT) of the abdomen revealed small intestinal lesions suggestive of lupus enteritis, whereas 99m Tc-labeled human serum albumin scintigraphy (HAS) revealed abnormal findings. The patient was diagnosed as having lupus enteritis complicated by PLE. Although steroid therapy was continued, abdominal pain and hypoalbuminemia did not improve.
In June 2015, the patient was referred to Jichi Medical University Hospital, and admitted to the Department of Rheumatology and Clinical Immunology. Double-balloon enteroscopy (DBE) confirmed the presence of high-grade stenoses and ischemic changes in the terminal ileum. Thus, the diagnosis of PLE caused by APS-induced ischemic enteritis was made. Over the following 2 months, the dose of prednisolone was increased to 60 mg/day, plasma exchange therapy was administered 6 times, and methylprednisolone pulse therapy was performed, adding antithrombotic therapy due to suspicion of APS. The patient also received immunosuppressive drugs and octreotide, but no improvement in hypoalbuminemia was observed. Because the condition was refractory and resistant to medical therapy, the patient was transferred to the Department of Surgery for surgical treatment (Fig. 1).
The patient had received total thyroidectomy for papillary thyroid cancer at the age of 15 years. There was no history of laparotomy. Family history was unremarkable. Physical examination revealed the following: height, 168.5 cm; weight, 33.4 kg; and body mass index (BMI), 11.8 kg/m 2 . Localized abdominal tenderness and mild muscular defense were confirmed only in the right lower quadrant. There were no other remarkable findings.

Imaging studies
Plain abdominal x-ray revealed gaseous distention at multiple sites in the small intestine. Contrast-enhanced CT of the abdomen revealed edematous thickening, stenosis, and associated dilation at multiple sites in the small intestine. In addition, engorgement of the mesenteric vessels, multiple inflammatory lymphadenopathies, and ascites were noted, but no intravenous thrombus was confirmed (Fig. 2). On 99m Tc-labeled HAS, extravascular distribution of the radiotracer in the distal ileum and transfer to the colon were observed at 3 and 6 hours after radiotracer injection, respectively (Fig. 3). Oral DBE indicated stenosis of the upper jejunum at a site 220 cm distally from the pyloric ring ( Fig. 4A, B). Transanal DBE revealed a friable stenotic lesion with loss of the villi in the distal ileum at a site 10 cm proximally to the ileocecal valve (Fig. 4C, D). Selective fluoroscopic enteroclysis using amidotrizoic acid (Gastrografin) with transanal DBE revealed multiple lead pipe-like stenoses on the proximal side of the friable lesion (Fig. 4E, F).

Surgical procedures
In November 2015, the patient underwent partial small intestine resection and received an ileostomy. Upon examination of the  small intestine, stenosis was confirmed at a site 250 cm distally from the Treitz ligament, with significant enlargement in both the intestinal tract wall and the mesentery, as well as multiple stenoses, over a segment of approximately 120 cm (250-370 cm distally from the Treitz ligament). No abnormal findings were noted in the proximal 250 cm of the jejunum or the terminal 20 cm of the ileum. Using an autosuture device, the small intestine was cut 250 cm distally from the Treitz ligament and 20 cm proximally to the ileocecal valve, and a double-end ileostomy was created using the margins of the small intestine on both the proximal and distal sides.

Pathological findings
A total of 6 stenotic lesions were confirmed in the resected specimen (Fig. 5A). On histopathology examination, moderateto-severe, almost transmural infiltration of inflammatory cells was confirmed, mainly in the mucosa and submucosa. Sloughing off of cells of the mucosa and lamina propria was noted, with formation of granulation tissue, as well as lymphocyte accumulation and formation of lymph follicles. Significant mucosal erosions with decrease or loss of crypts were observed, as well as formation of ulcers with some neutrophil infiltration and fibrin deposits. Edematous changes were confirmed in the submucosa. Although no fibrinoid necrosis or active thrombus formation was observed in the blood vessels, the vessels were markedly tortuous and dilated, with plexiform lesions and recanalization at the sites of thrombus formation. No venous stasis was observed (Fig. 5B-D).

Postoperative course
Because her general condition was stable, the patient was discharged from the intensive care unit on postoperative day 2, and resumed oral intake and oral administration of both prednisolone and immunosuppressive drugs. Because the amount of watery ileostomy output could be reduced by controlling the dose of antidiarrheal drugs, the patient was transferred back to the Department of Rheumatology and Clinical Immunology on postoperative day 7. Contrast-enhanced CT and 99m Tc-labeled HAS confirmed the absence of stenotic and protein-losing lesions in the intestinal tract. The patient was discharged from our hospital on postoperative day 26. At 2 months after the initial surgery, ileostomy closure was performed in the form of a hand-sewn, double-layer, end-to-end anastomosis. The patient was discharged from our hospital on postoperative day 8. Blood tests revealed a significant increase in both total serum protein and serum albumin levels, in addition to a substantial improvement in the patient's general condition and BMI (Fig. 1).

Discussion
SLE is a systemic inflammatory autoimmune disease of the connective tissues, with various clinical symptoms. [1,2] When intestinal tract lesions associated with SLE occur, the condition is referred to as lupus enteritis, SLE enteritis, or lupus mesenteric vasculitis, etc. Lupus enteritis occurs in no more than 10% of cases, [6] but the incidence of lupus enteritis presenting with abdominal pain in patients with active-phase SLE is 53%. [7] The average age at diagnosis of lupus enteritis was reported to be 32.5 years, with a male-female ratio of 1:14. At the time of diagnosis of lupus enteritis, 13% of patients have already been diagnosed with  www.md-journal.com SLE, and, in such patients, the median time from SLE diagnosis until onset of enteritis is 60 months. [1] Lupus enteritis is caused mainly by vasculitis of the intestinal tract and membrane, and develops due to deposition of immunocomplexes on the microvascular wall, leading to microvascular embolism caused by interaction with the antiphospholipid antibody. [2,6,[8][9][10][11] Although findings indicative of vasculitis and thrombosis are often noted on pathology examination, no such pathological findings were confirmed in our patient. However, shedding of the mucosa and inflammatory cell infiltration, both suggesting vasculitis, were observed in the resected specimen in the areas with ischemic enteritis. These pathological findings were thought to be the cause of PLE. Although no thromboembolism or deposition of immunocom- plexes was found in the blood vessels, high tortuosity, dilation, and recanalization of the vessels were observed. These findings were considered to indicate a circulatory disorder caused by vasculitis and APS. In SLE patients, bowel rest by fasting is first recommended for the treatment of gastrointestinal lesions, followed by steroid therapy. When the response to high-dose steroid therapy is good, immediate improvement of vasculitis can be expected. [3,12] In our patient, high-dose steroid therapy was initiated after bowel rest by fasting, and plasma exchange was performed; however, the patient did not respond to this conservative therapeutic approach. Moreover, the patient's general condition and nutritional status were extremely poor because of recurrent intestinal obstruction caused by multiple stenotic lesions associated with ischemic enteritis.
PLE associated with SLE develops in 2% to 3% of patients, and such patients generally respond well to steroid therapy. If PLE is caused by vasculitis-induced deposition of immunocomplexes and increased capillary permeability associated with complement activation, there may be a good response to steroids and immunosuppressive drugs. Some patients do not respond to highdose steroid therapy owing to vasa vasorum arteriosclerosis or mucosal ulcer associated with long-term steroid therapy, which may result in weakening of the intestinal tract wall and irreversible damage. Because our patient did not respond to therapy with steroids and immunosuppressive drugs, it was suggested that such nonautoimmune mechanisms or microvascular coagulation associated with SLE or APS might have been involved. [13,14] Jovaisas and Kraag recommend immediate high-dose steroid therapy in SLE patients with acute abdomen judged to be caused by vasculitis and not by steroid ulcers. Furthermore, they recommend considering surgical laparotomy if no symptomatic improvement is noted within 24 hours, or when intestinal perforation or irreversible intestinal stenosis is confirmed. [15] Since our patient's preoperative nutrition was very poor and high-dose steroids had been administered for a long period of time, we hesitated to perform a 1-stage surgery consisting of resection and anastomosis, judging that the risk of perioperative complications and death was too high. Therefore, we chose to perform a 2-stage surgery consisting of partial small intestine resection and ileostomy in the initial phase, followed by ileostomy closure in the second phase.
A previous report indicated that, of 22 patients with SLErelated acute abdomen, 15 underwent surgery and 11 of these died. Of note, 3 of 4 patients with simple intestinal ischemia underwent surgery, and none died, whereas >50% of patients with intestinal necrosis, perforation, mesenteric embolus, or intestinal obstruction died, suggesting an extremely poor prognosis associated with such conditions. [16] Taken together, these previous observations support our choice of a 2-stage surgery, which likely contributed to saving the life of this patient with severe lupus enteritis. The 10-year survival rate in SLE patients is approximately 70%. Interestingly, Asian studies typically report favorable prognosis, whereas studies performed in the United States and in European countries report a rather poor prognosis. This discrepancy is considered to be due to racial differences in hereditary predisposition. [6] However, disease recrudescence might occur when the management of SLE disease activity is insufficient after surgical resection, and thus close follow-up observation is necessary. [17] In our patient, the clinical course after ileostomy closure was favorable, with improvement in BMI and nutrition. The surgical follow-up period has completed successfully, and the patient is currently being carefully followedup on an outpatient basis at the Department of Rheumatology and Clinical Immunology.

Conclusion
We reported here our experience in a patient who developed lupus enteritis as acute abdomen during steroid treatment for SLE. The patient had multiple ischemic enteritis lesions causing stenosis, and medical treatment-resistant and refractory PLE, for which partial small intestine resection was effective. To highlight the relevance of this case, we included an overview of current literature on the management of gastrointestinal lesions in SLE, which typically reports poor prognosis in patients with severe mucosal changes. Thus, if PLE develops concomitantly with SLE and is resistant to medical treatment, surgical treatment should be provided immediately.