Chapter 34 Gastrointestinal Disease in Systemic Lupus Erythematosus
Gastrointestinal (GI) manifestations of systemic lupus erythematosus (SLE) are protean. Any part of the GI tract, liver, biliary tract, and pancreas can be involved (Tables 34.1 and 34.2). Recognition is important because some of these manifestations carry significant mortality and morbidity. Presentations of GI lupus are nonspecific and have to be distinguished from infective, thrombotic, therapy-related, and non-SLE causes. Endoscopic procedures, biopsies, and imaging investigations, which can be invasive, may be needed.
|Small bowel and peritoneum|
The prevalence of GI manifestations of SLE varies widely, depending on study design, clinical characteristics of patients studied, and whether screening examinations are routinely performed. Oral symptoms and mucosal lesions appear to be most frequent, whereas acute abdominal pain is the most serious. Because of the lack of controlled trials, treatment of GI lupus is largely based on anecdotal experience and uncontrolled observational studies. The mainstay of treatment is immunosuppression. Anticoagulation is indicated when thrombosis is the underlying mechanism.
Oral ulceration is a common feature of SLE, occurring in 6 to 52% of patients.1 Oral ulcers is one of the 11 American College of Rheumatology (ACR) revised criteria for the classification of SLE, and is a marker for disease activity. Typically, these ulcers are superficial, painless, and mostly found on the hard palate, buccal cavity, and vermiform border. Less commonly, ulcers may also develop in the nasal cavity and the pharyngeal wall. Histology is usually nonspecific.
Chronic discoid lupus erythematosus (DLE) may develop in the oral mucosa. Up to 24% of patients with chronic cutaneous LE had concomitant mucous membrane lesions.2 Mucosal DLE usually starts as a painless erythematosus patch that slowly matures into a chronic plaque-like lesion. It is frequently found in the buccal mucosa, but the palate and tongue may also be involved. DLE lesions can be severely painful, and their morphology may be confused with lichen planus or leukoplakia. Tissue biopsy may show lupus-specific histopathology similar to that of the skin.
Oral ulceration may also be caused by infection and therapy of SLE. Viral infection such as herpes simplex and fungal infections such as candidiasis may lead to painful oral ulcers and plaque-like lesions. Immunosuppressive agents such as cyclophosphamide and methotrexate may induce mucositis and mucosal ulceration.
Sicca symptoms such as dry mouth and dry eyes are fairly common in SLE patients. Manoussakis and colleagues3 reported a 9.2% prevalence of secondary Sjögren’s syndrome in 283 unselected SLE patients using the American-European classification criteria. The clinical presentation of Sjögren’s syndrome in SLE was no different from that of primary Sjögren’s syndrome, but older age, Raynaud’s phenomenon, anti-Ro, anti-La, and rheumatoid factor were more frequent in SLE patients, whereas renal disease, lymphadenopathy, and thrombocytopenia were less common.
SLE patients are prone to poor dental health. This is a result of multiple factors, including disease activity, reduced salivary flow, bleeding diathesis, and the use of medications such as corticosteroids (risk of gingival infection), aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs) (platelet dysfunction), cyclosporin A (gingivitis, gingival hypertrophy), methotrexate (stomatitis and mucositis), antiepileptic agents (gum hypertrophy), and tricyclic antidepressants (which worsen sicca).
Meyer and colleagues4 studied the frequency of oral, dental, and periodontal findings in 46 patients with SLE. Compared with healthy matched controls, oral mucosal lesions such as aphthous ulcers, erythema, gingival overgrowth, and hemorrhage were more frequently found in SLE patients (48% vs. 25%). The extent of periodontal disease was related to the severity and duration of SLE. In addition to disease and treatment-related factors, chronic periodontitis in SLE has also been linked to genetic factors such as the FcgammaRIIa polymorphisms5 and the antineutrophil cytoplasmic antibodies.6 Periodontal disease may pose a potentially serious health risk in SLE patients because a recent systematic review suggested a modest association between periodontitis and cardiovascular diseases.7
Dysphagia occurs in 1 to 13% and heartburn in 11 to 50% of patients with SLE.1 These may be attributed to dry mouth, esophageal hypomotility, esophagitis, or esophageal ulceration because of acid reflux and infection. Manometry studies reveal functional abnormalities of the esophagus in 10 to 32% of SLE patients.8,9 Aperistalsis or hypoperistalsis is most frequently found in the upper one-third of the esophagus,9 and is associated with Raynaud’s phenomenon in some studies.8 The reasons for esophageal hypomotility in SLE remain elusive. Skeletal muscle fiber atrophy, inflammatory reaction in the esophageal muscles, and ischemic or vasculitic damage of the Auerbach plexus have been postulated.
Esophagitis with ulceration was reported in 3 to 5% of patients with SLE.1 This may be caused by gastroesophageal reflux or infections such as Candida, herpes simplex, and cytomegalovirus (CMV). Endoscopic examination with biopsy is necessary to establish the diagnosis. A true vasculitis leading to esophageal ulceration is probably rare.10 In addition, medications such as NSAIDs and the bisphosphonates are occasionally associated with esophagitis and bleeding esophageal ulcers.
Gastritis, gastric erosion, and ulceration in SLE patients may result from treatment with high-dose corticosteroids and NSAIDs. In two studies of acute abdomen in SLE patients, perforated peptic ulcer was diagnosed in 6 to 8% of cases.11,12 While the exact incidence of peptic ulcer disease in SLE patients is unknown, adverse effects of medications are the most common causes. Vasculitis of the gastric mucosa related to active SLE causing ulceration and bleeding is exceedingly rare.
Although pernicious anemia has been reported in patients with SLE, its prevalence is low. A study of 30 SLE patients reported that only one patient (3%) suffered from pernicious anemia characterized by low serum cobalamin level, macrocytic anemia, and the presence of antibody against intrinsic factor.13 Another study indicated that 19% of female SLE patients had low serum cobalamin levels, but none developed overt anemia.14
Gastric antral vascular ectasia (GAVE) is a rare vascular malformation in the GI tract that may cause acute or chronic bleeding. The characteristic endoscopic appearance is a collection of red spots of ectatic vessels arranged in stripes along the antral rugal folds. GAVE is mostly found in patients with systemic sclerosis, but has been reported in SLE.15
Although the stomach is relatively resistant to infection, CMV gastritis has been reported in heavily immunocompromised patients. Renal transplant recipients who receive mycophenolate mofetil (MMF)-based immunosuppressive protocols are prone to disseminated CMV infections. As MMF is increasingly used in patients with SLE, CMV infection of the GI tract should not be overlooked.
The prevalence of intestinal vasculitis in patients with SLE ranged from 0.2 to 1.1%.15 In SLE patients presenting with acute abdominal pain, intestinal vasculitis was diagnosed in 5 to 60% of patients.11,16–18 Most patients with mesenteric vasculitis present with cramping or persistent abdominal pain, a variable degree of nausea and vomiting, fever, diarrhea, and bloody stools. Abdominal distension, tenderness, and rebound tenderness are usually present, and bowel sound may be diminished or absent. In severe cases, mucosal ulceration with bleeding, bowel edema with paralytic ileus, hemorrhagic ileitis, intussusception, and even bowel gangrene and perforation may develop.19,20 Active SLE in other organs is usually evident.
Abdominal radiographs in patients with lupus mesenteric vasculitis may reveal changes such as pseudo-obstruction of the gastric outlet, duodenal hypomotility, bowel loop distension, effacement of the mucosal folds, and thumb-printing appearance (submucosal edema as a result of bowel ischemia). Intra-abdominal free gas may appear after intestinal perforation, or because of pneumatosis cystoids intestinalis. Ultrasound and computed tomography (CT) scan of the abdomen are important in excluding intra-abdominal abscesses, pancreatitis, and other intra-abdominal pathologies. In addition, a contrast CT scan may reveal bowel wall changes, mesenteric vascular and fat changes, fluid collection, retroperitoneal lymphadenopathy, peritoneal enhancement, and hepatomegaly. Conspicuous prominence of mesenteric vessels with a palisade pattern or comb-like appearance supplying focal or diffuse dilated bowel loops, ascites with slightly increased peritoneal enhancement, and bowel wall thickening with double halo or target sign (enhancing outer and inner rim with hypoattenuation in the center) are characteristic early CT findings of lupus mesenteric vasculitis.21
The typical histopathologic findings of lupus mesenteric vasculitis usually occur in the arterioles and venules of the submucosa of the small bowel wall rather in the medium-sized mesenteric arteries.20,22,23 Vasculitic lesions tend to be segmental and focal.19 Immunohistochemical staining of the tunica adventitia and media may reveal immune complex, C3 complement, and fibrinogen deposition. Fibrinoid necrosis, intraluminal thrombosis of affected vessels, acute or chronic inflammatory infiltrates consisting of lymphocytes, plasma cells, histiocytes, and neutrophils may also be demonstrated.23
Patients with SLE are prone to premature atherosclerosis. Chronic mesenteric insufficiency, or “intestinal angina,” should be considered in patients who present with chronic intermittent abdominal pain. Symptoms usually start in the postprandial state and persist for several hours. Abdominal pain may be mild at onset and progress in severity over weeks or months. Fear of eating often leads to weight loss. Concomitant atherosclerotic disease in the coronary and carotid vessels is usually present. SLE patients at risk are those with long-standing disease, renal insufficiency, persistent proteinuria, antiphospholipid positivity, chronic corticosteroid therapy, and traditional risk factors for atherosclerosis.
The diagnosis of chronic mesenteric insufficiency relies on a high index of suspicion. Conventional angiography is the gold-standard imaging procedure. Digital subtraction angiography, Doppler ultrasonography, and magnetic resonance imaging with angiography are adjunctive diagnostic modalities.24
Acute mesenteric ischemia can result from impaired blood flow within the mesenteric arterial or venous systems. Classically, abdominal pain is persistent and disproportionately severe relative to physical signs. Patients may also present with acute abdomen with distention, rigidity, fever, bloody diarrhea, melena, and hypotension. SLE patients with underlying chronic mesenteric insufficiency due to atherosclerosis or secondary antiphospholipid syndrome are particularly prone to acute intestinal ischemia, which may be precipitated by hypoperfusion states. Acute mesenteric thrombosis may result in bowel infarction, perforation, and peritonitis.
Intestinal pseudo-obstruction (IPO) is a clinical syndrome characterized by impaired intestinal motility as a result of dysfunction of the visceral smooth muscle or the enteric nervous system. IPO may be the initial presentation of SLE and usually occurs in the setting of active lupus.25 The small bowel is more commonly involved than the large bowel.
Common presenting symptoms of IPO are a subacute onset of abdominal pain, nausea, vomiting, abdominal distention, and constipation. Physical examination often reveals a diffusely tender abdomen with sluggish or absent bowel sound. Rebound tenderness is usually absent. Radiologic examinations may demonstrate dilated, fluid-filled bowel loops, with thickened bowel wall and multiple fluid levels (Fig. 34.1). Organic causes for intestinal obstruction should be sought, preferably by nonsurgical assessment but laparotomy may be necessary in some patients.
Manometry motility studies in patients with IPO may demonstrate esophageal aperistalsis and intestinal hypomotility.26 Interestingly, 63% of the reported cases of SLE-related IPO had concomitant ureterohydronephrosis and contracted urinary bladder, and around one-third of these patients had documented histologic features of interstitial cystitis.25 Lupus interstitial cystitis may lead to bladder wall thickening and reduced bladder capacity. This may in turn induce ureterohydronephrosis because of detrusor muscle spasm and secondary vesiculo-ureteric reflux.
The pathogenesis of IPO in SLE is unclear. The association with autoimmune cystitis and the demonstration of antibodies against proliferating cell–nuclear antigen in some patients27 suggests that vasculitis of the visceral smooth muscles is a mechanism which may lead to muscular damage and hypomotility. The simultaneous presence of ureterohydronephrosis in many patients with SLE-related IPO and the association of hypomotility of other parts of the GI tract indicate that the basic pathology may be dysmotility of the intestinal musculature. Whether this is caused by a primary myopathy, neuropathy, vasculitis, or antibodies directed against the smooth muscle of the gut wall requires further study.
Intestinal malabsorption in SLE may result in protein losing enteropathy, hypoalbuminemia, and ascites. Mader and colleagues28 screened 21 SLE patients for malabsorption by the D-xylose absorption test (DXT), microscopic examination of the stool for fat droplets, and biopsy from the second part of the duodenum. Two patients (10%) were found to have an abnormal DXT and excessive fecal fat excretion. In one of these patients, histologic examination revealed flattened and deformed villi with an inflammatory infiltrate. Immunoperoxidase staining did not reveal excessive deposition of immunoglobulins and light chains within the intestinal mucosa in these patients.
Up to 23% of patients with SLE may be tested positive for either the IgA or IgM antigliadin antibodies,29 but biopsy-proven celiac disease (gluten-sensitive enteropathy) is exceedingly uncommon.
Protein-losing gastroenteropathy (PLGE) is characterized by hypoalbuminemia secondary to loss of protein from the GI tract. It is usually identified by an elevated clearance of stool α1-antitrypsin or the technetium99m-labeled human serum albumin scan (Fig. 34.2). Significant loss of protein from the kidneys should be ruled out. A variety of pathologies from the stomach down to the colon may be responsible for protein loss. Investigations into the causes of PLGE such as gastrointestinal lymphoma, malabsorption state, bacterial overgrowth, chronic infection, polyposis, and lymphatic obstruction are essential. Endoscopic examination with mucosal biopsies, barium studies, radiologic examinations, and absorption tests may be required.
Fig. 34.2 99mTc-labelled human serum albumin (HSA) scan in a patient with SLE showing leakage of protein from the small bowel. A, An area of diffuse activity in upper and central lower abdomen at 2 hours (left). B, Intense activity at the ileocecal valve region at 7 hours (middle). C, Intense activity in cecum, ascending colon, and transverse colon at 24 hours (right).
PLGE is a rare manifestation of SLE, and fewer than 50 cases have been described. We recently reported 16 cases of SLE-related PLGE and reviewed 32 other patients in the literature.30 PLGE was the presenting feature in three-quarters of our patients and most patients had active SLE in other organs. The most common presentation was generalized or dependent edema, and abdominal symptoms, such as pain, nonbloody diarrhea, nausea, vomiting, and anorexia. Protein leakage occurred more frequently from the small bowel (69%) than the large bowel (31%). Specific endoscopic, imaging, and histologic findings were often absent. The most common endoscopic appearance was mucosal edema.31 The biopsy was either normal or revealed nonspecific findings such as villous atrophy, submucosal edema, dilated lacteals, and inflammatory infiltrates. Definite lymphangiectasia, vasculitis, or C3 deposition in the capillary walls of the lamina propriae of villi was uncommon.
The exact pathogenesis of PLGE remains elusive. Mucosal disruption and increase in mucosal capillary permeability as a result of complement- or cytokine-mediated damage, mesenteric venulitis, and dilated/ruptured mucosal lacteals have been postulated.30