Investigations and Management of Gastrointestinal and Hepatic Manifestations of Systemic Lupus...

Best Practice & Research Clinical RheumatologyVol. 19, No. 5, pp. 741–766, 2005

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Investigations and management

of gastrointestinal and hepatic manifestations

of systemic lupus erythematosus

C.C. Mok* MD, FRCP

Consultant in Rheumatology

Department of Medicine and Geriatrics, Tuen Mun Hospital, New Territories, Hong Kong, China

Gastrointestinal (GI) manifestations of systemic lupus erythematosus (SLE) are protean. Any partof the GI tract and the hepatobiliary system can be involved. Up to two-third of SLE patientsdevelop GI symptoms at some stage of their illnesses. Clinical presentations of GI lupus are non-specific and can be difficult to differentiate from infective, thrombotic, therapy-related and non-SLE etiologies. Clinical acumen and appropriate endoscopic, biopsy and imaging procedures areessential for establishing the correct diagnosis. Acute abdominal pain in SLE patients can herald anintra-abdominal catastrophe and should be evaluated promptly. Surgical intervention should beinstituted without delay if conservative management fails or when there is clinical or radiologicalsuspicion of visceral perforation or intra-abdominal collections.

Key words: abdomen; complications; gut; hepatitis; liver; morbidity; serositis.

Systemic lupus erythematosus (SLE) is a multi-systemic disease that can affect all theorgan systems of the body. Gastrointestinal (GI) manifestations are fairly common andcan be the initial presentation of SLE. GI lupus often attracts less attention whencompared to renal, hematological and neuropsychiatric complications of the disease.The presentations of GI and hepatic manifestations of SLE are diverse, heterogeneousand non-specific. In addition to clinical assessment, investigations such as endoscopy,biopsy, plain radiography, barium studies, ultrasonography, CT scan, magneticresonance imaging (MRI), angiography are often needed to exclude infective,thrombotic and non-SLE related causes.

The prevalence of the GI manifestations of SLE varies widely, depending on whatsymptoms were included in analyses, whether examinations and investigationswere performed routinely or only in symptomatic patients, the selection of patients

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and the research interest of the investigators. Oral symptoms and mucosal lesionsappear to be most frequent, whereas acute abdominal pain is most serious. Because ofthe lack of controlled trials, treatment advice on gastrointestinal and hepaticmanifestations of SLE is largely based on clinical experience and uncontrolledobservational studies. Acute abdominal symptoms in SLE should be evaluated promptly.When infection and other important causes have been ruled out, immunosuppressivetreatment should be considered, preferably under coverage of broad-spectrumantibiotics. Surgical intervention should be instituted without delay when conservativemanagement fails.

MANIFESTATIONS OF GASTROINTESTINAL DISEASE

Disorders of the upper gastrointestinal tract in SLE patients

Oral ulceration

Oral ulceration is a common feature of SLE, occurring in 6–52% of patients.1 Oralulcers is one of the 11 American College of Rheumatology (ACR) revised criteria forthe classification of SLE.2 Superficial and self-limiting mucosal ulceration with a relativelynon-specific histology is frequently found in patients having active lupus. Typically, theseulcers are painless and mostly found on the hard palate, buccal cavity and vermiformborder. Occasionally, ulcers also develop in the nasal cavity and the pharyngeal wall.Symptomatic treatment includes chlorhexidine or soluble prednisone mouthwashesand corticosteroid-impregnated gels.3 Colchicine and pentoxifylline, which have beenused in the treatment of Behcet’s disease, can be considered in patients with recurrentaphthous ulcers.4,5

SLE patients are often immunocompromised as a result of their intrinsicimmunological aberrations and drug treatment. Infective causes of oral ulcerationshould not be overlooked. Fungal infection such as candidiasis and viral infection such asherpes simplex can give rise to oral ulcers and plaque-like lesions. In thesecircumstances, appropriate anti-fungal or anti-viral therapy should be instituted.However, oral ulceration and mucositis can develop in patients with severeneutropenia, and might complicate treatment with cyclophosphamide or methotrex-ate. Folic acid supplementation can alleviate some of these symptoms, particularly whenmethotrexate is used.6

Chronic mucosal discoid lupus erythematosus (DLE) can occur in the oral cavity.The study by Burge and co-workers,7 reported that the prevalence of mucousmembrane involvement was up to 24% in patients with chronic cutaneous lupuserythematosus. Mucosal DLE usually starts as a painless, erythematosus patch thatslowly matures into a chronic plaque-like lesion. It is frequently found in the buccalmucosa but the palate and tongue might also be involved. DLE lesions can be severelypainful and their morphology can confused with that of lichen planus or leukoplakia.Tissue biopsy might show lupus-specific histopathology similar to that of the skin. Thetreatment of mucosal DLE is similar to that of cutaneous DLE. Topical corticosteroidsand anti-malarials are the main stay of therapy. Intra-lesional corticosteroid injection,dapsone, azathioprine, thalidomide, retinoids, gold and mycophenolate mofetil (MMF)are indicated in difficult cases.8

GI and hepatic manifestations of SLE 743

Secondary Sjogren’s syndrome and oral health

Sicca symptoms such as dry mouth and dry eyes are common in patients with SLE.9

Andonopoulos et al10 reported an 8.3% prevalence of secondary Sjogren’s syndrome in60 consecutive patients with SLE based on histopathological criteria and objectivemeasurement of salivary flow. The same group of investigators re-visited this issuerecently in 283 unselected SLE patients using the American–European classificationcriteria.11 They demonstrated that 9.2% of their SLE patients had documentedsecondary Sjogren’s syndrome. SLE patients with Sjogren’s syndrome were significantlyolder, had a higher frequency of Raynaud’s phenomenon, anti-Ro, anti-La andrheumatoid factor, but had a significantly lower incidence of renal involvement,lymphadenopathy and thrombocytopenia. The clinical presentation was similar to thatof primary Sjogren’s syndrome.

Meyer et al12 studied the frequency of oral, dental and periodontal findings in 46patients with SLE. Compared with healthy matched controls, oral mucosal lesions suchas aphthous ulcers, erythema, gingival overgrowth and hemorrhage were morefrequently found in SLE patients (25 versus 48%). The prevalence of oral mucosalfindings and the extent of periodontal disease were dependent on the severity andduration of the disease. SLE patients are prone to poorer oro-dental health. This is aresult of multiple factors, including disease activity, reduced salivary flow, bleedingdiathesis due to thrombocytopenia or platelet dysfunction, and the long-term use ofvarious medications like corticosteroids (which increase the risk of mucosal infection),non-steroidal anti-inflammatory drugs (NSAIDs), anti-platelet agents (platelet dysfunc-tion), cyclosporin A (leads to gingivitis, gingival hypertrophy), methotrexate (causesstomatitis and mucositis) and anti-epileptic agents (gum hypertrophy). The use oftricyclic anti-depressants might worsen sicca symptoms.

Pharyngeal and esophageal disease

Dysphagia occurs in 1–13% and heartburn in 11–50% of patients with SLE.1 These canbe caused by dry mouth, impaired pharyngeal and esophageal function, esophagealinflammation or ulceration due to acid reflux and infection. Although dysfunction of thestriated pharyngeal muscles is a well-recognized feature of idiopathic inflammatorymyopathies, this was not reported in a series of patients with SLE and myositis.13

Manometry studies reveal functional abnormalities of the esophagus in 10–32% ofpatients with SLE.14,15 Aperistalsis or hypoperistalsis is most frequently found in theupper one-third of the esophagus;16 the lower esophageal sphincter was less commonlyaffected. The association between aperistalsis of the esophagus and Raynaud’sphenomenon has been demonstrated in some studies14,17 but not in others.16 Themechanisms of esophageal hypomotility in SLE remain elusive. Skeletal muscle fibreatrophy, inflammatory reaction in the esophageal muscles, and ischemic or vasculiticdamage of the Auerbach plexus have been postulated.18,19

Esophagitis with ulceration was reported in 3–5% of patients with SLE.1 Although thiscan be caused by gastro-esophageal reflux, infective causes such as candidiasis, herpessimplex and cytomegalovirus (CMV) infection have to be excluded. Investigations such asendoscopy with biopsy and gastrograffin swallow study are necessary. Esophagealulceration caused by a true vasculitis or that leads to perforation is rare.

The management of esophageal hypomotility and reflux symptoms in SLE patientsis no different from that occurring in patients with systemic sclerosis. High-doseH2-blockers, proton pump inhibitors and prokinetic agents are the main-stay of

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strategies to minimize symptoms. Immunosuppressive treatment is warranted foresophageal lesions that are proven histologically to be vasculitic in origin.

Severe non-pleuritic chest pain caused by diffuse esophageal spasm and dysphagiacaused by extensive bullous mucous disease and affecting the whole length of esophagushas been reported in patients with SLE.20,21

Osteoporosis and its complications are increasingly recognized in patients withSLE.22 Esophagitis and esophageal ulceration can occur with bisphosphonate treatment,especially if special precautions of drug administration are not followed properly.23

However, bleeding esophageal ulcers have been reported more frequently inassociation with the use of NSAIDs.24

Gastric disease

Gastritis, gastric erosion and gastric ulceration in SLE patients can result from treatmentwith high-dose corticosteroids and NSAIDs.25 However, their exact incidence in SLE inthe era of the new gastroprotective agents and the cyclo-oxygenase (Cox)-II inhibitorsis unknown. In a study of 51 SLE patients who presented with acute abdomen, three (6%)had perforated duodenal ulcer.26 Another study on 13 patients with SLE who wereadmitted to hospital because of severe abdominal pain reported perforated peptic ulcerin one patient only (8%).27 Although the exact etiologies of peptic ulcer disease were notmentioned in these studies, side effects from medications were the most likely causes.True vasculitis of the gastric mucosa causing ulceration and bleeding is probably rare.

Although pernicious anemia has been well reported in patients with SLE,28,29 a studyof 30 patients demonstrated that only one patient (3%) suffered from pernicious anemiacharacterized by low serum cobalamin levels, macrocytic anemia and the presence ofantibody against intrinsic factor.30 Another study of 43 female SLE patients confirmedthat pernicious anemia was very uncommon.31 Although six patients (19%) had lowserum cobalamin levels, none manifested overt anemia.

The stomach is relatively resistant to infection. CMV infection of the gastric mucosa,however, is possible in severely immunocompromised hosts.32 Although a literaturesearch did not reveal any reported cases of CMV gastritis in lupus patients, thispossibility should be borne in mind, particularly in those receiving long-term MMFtreatment. In renal transplant recipients, MMF-based regimens are associated with anincreased incidence of disseminated CMV infection.33

Gastric antral vascular ectasia (GAVE), also known as watermelon stomach, is a raretype of vascular malformation in the GI tract.34 The characteristic endoscopicappearance of GAVE is a collection of red spots of ectatic vessels arranged in stripesalong the antral rugal folds. GAVE can cause acute or chronic bleeding leading to irondeficiency anemia. It is mostly described in patients with limited or diffuse systemicsclerosis35,36 but its occurrence in SLE has also been described.37

Other rare gastric conditions reported in patients with SLE include hyperplasticgastropathy, carcinoid tumor, gastric outlet obstruction and esosinophilic gastro-enteritis.38–41

Generalized abdominal symptoms

Abdominal pain

Abdominal pain is a fairly common symptom in patients with SLE, although theactual incidence is unclear. Depending on the setting in which patients are assessed

Table 1. Causes of abdominal pain in patients with SLE.

SLE-related Treatment-related Non-SLE causes

Serositis Gastritis, duodenitis Infective gastroenteritis

Intestinal vasculitis/colitis Peptic ulcerGperforation Inflammatory bowel disease

Malabsorption Pancreatitis Cholecystitis/cholangitis

Intestinal pseudo-obstruction Intra-abdominal sepsis Pancreatitis

Protein-losing enteropathy Infective enteritis Viral hepatitis

Ischemic bowel disease Infective colitis Surgical adhesions

Mesenteric thrombosis Bacterial peritonitis Appendicitis

Hepatic vein thrombosis Diverticulitis

Hepatitis Intussusception

Pancreatitis Gynecological conditions

Acalculous cholecystitis Rupture of vascular aneurysms


(e.g. the emergency room, surgical ward or outpatient clinic), abdominal pain isreported in 8–37% of patients.1,42 Abdominal pain can be due to SLE-related,treatment-related or non-SLE-related causes (Table 1). Differentiation among thesecauses can be challenging and diagnostic procedures, sometimes invasive, might benecessary.

Zizic et al43 reported that 15 of 140 SLE patients (11%) developed signs andsymptoms of acute surgical abdomen. Eleven of these 15 patients (73%) underwentexploratory laparotomy, with nine showing intra-abdominal arteritis and two showingpolyserositis. Mortality was high (53%), which was partially related to a delay in thediagnosis of the underlying condition.

Medina et al26 studied 51 SLE patients who presented with acute abdomen andunderwent surgical exploration. Nineteen patients (37%) had vasculitis and threepatients (6%) had intra-abdominal thrombosis. Patients with inactive SLE (SLEDAI scorebelow 5) were more likely to have non-SLE-related causes for their acute abdominalpain. High SLE activity and a delay in surgical exploration were associated with a highermortality.

Al-Hakeem and McMillen27 studied 13 SLE patients who presented with acuteabdominal pain in a community teaching hospital. Most patients who required surgicalintervention had conventional diagnoses rather than SLE-related etiologies.

More recently, Lee et al44 reported that 38 of 175 SLE patients (22%) were admittedto hospital because of acute abdominal pain. Lupus enteritis (intestinal vasculitis) wasthe most common cause (45%), but the mean SLEDAI scores in these patients were notdifferent from other SLE patients presenting with abdominal pain but without enteritis.

By contrast, in another study of 56 SLE patients presenting with subacute abdominalpain (without peritoneal signs), intestinal vasculitis was diagnosed in 5% of patientsonly.45 These patients had SLEDAI scores of greater than 8. Lian et al46 reported thatamong 45 patients with SLE who presented with acute abdominal pain, serositis andbowel involvement was diagnosed by CT examination of the abdomen in 63% ofpatients who underwent this investigation.

Abdominal pain and tenderness in SLE patients might precede an intra-abdominaldisaster. Classical physical signs, such as rebound tenderness, might be masked by theuse of corticosteroids and immunosuppressive agents. Acute, persistent or severeabdominal symptoms in patients with SLE should be promptly investigated. Blood

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counts, serum amylase level, renal and liver function tests, anti-dsDNA, complementlevels and abdominal radiography are basic investigations. Depending on the clinicalpresentation and severity of the clinical signs and symptoms, further and morespecialized investigations, including endoscopy, paracentesis, ultrasound scan, contrastCT scan, MRI, gallium scan and angiography, might be indicated. A surgical opinion isrequired and exploratory laparotomy should be considered in patients with clinical andradiological suspicion of visceral perforation or intra-abdominal collections. Diagnosticlaparoscopy is a less invasive alternative in selected patients.47

Ascites and peritonitis/serositis

Ascites can be present in 8–11% of patients with SLE.48 It can be classified into eitheracute or chronic; or either inflammatory or non-inflammatory.49 Acute peritonealeffusion can be due to mesenteric vasculitis and peritonitis as a result of SLE activity,infection, bowel infarction, perforated viscera and pancreatitis. Chronic peritonealeffusion can be caused by lupus peritonitis, hypoalbuminemia (nephrotic syndrome,protein-losing enteropathy, liver cirrhosis), right heart failure, constrictive pericarditis,hepatic venous thrombosis, malignancy and more indolent infection such astuberculosis. The exudative type of ascitic fluid on paracentesis indicates inflammationwhereas the transudative type of peritoneal fluid suggests hypoalbuminemia.

Inflammatory peritonitis in SLE is generally painful but clinical signs can be masked bycorticosteroid and immunosuppressive treatment. Conversely, lupus peritonitis canmimic acute surgical abdomen and laparotomy might be negative.26,50 Inflammatoryinfiltrates, immunoglobulin and complement deposits might be demonstrated inperitoneal tissues and the peritoneal vessels.51,52 Imaging studies such as contrast CTscan might demonstrate ascites and asymmetric thickening of the small bowel wall.53

Mild cases of lupus peritonitis may be treated with NSAIDs alone. However, mostpatients with lupus peritonitis respond more rapidly to moderate doses ofcorticosteroids. In patients presenting with massive ascites and in those with recurrentor refractory peritonitis, high-dose corticosteroid in the form of pulse methylpredni-solone and additional immunosuppressive agents such as azathioprine, cyclosporin Aand cyclophosphamide might be needed.54–56

Disorders of the small intestine in SLE patients

Mesenteric/intestinal vasculitis

The prevalence of intestinal vasculitis in patients with SLE ranged from 0.2 to 1.1% inrecent studies.43,57,58 In SLE patients presenting with acute abdominal pain, intestinalvasculitis was diagnosed in 5–60% of patients.26,43–45 Most patients with mesentericvasculitis present with cramping or persistent abdominal pain, a variable degree ofnausea and vomiting, fever, diarrhea, and bloody stools. Abdominal distension,tenderness and rebound tenderness is usually present and bowel sounds can bediminished or even absent. Intestinal vasculitis in SLE can also cause mucosal ulcerationwith bleeding, bowel edema with paralytic ileus, hemorrhagic ileitis, intussusception,and even bowel gangrene and perforation. Active SLE in other organs is usually evident.

Abdominal radiographs in patients with lupus mesenteric vasculitis can revealchanges, including pseudo-obstruction of the gastric outlet, hypomotility of theduodenum, distension of bowel loops, effacement of the mucosal folds and thumb-printing (submucosal edema as a result of bowel ischemia). Intra-abdominal free gas


might appear after intestinal perforation or because of pneumatosis cystoidsintestinalis.59 Ultrasound and CT scan of the abdomen are important in excludingintra-abdominal abscesses, pancreatitis, and other intra-abdominal pathologies. Inaddition, contrast CT scan might reveal bowel wall changes, mesenteric changes, fluidcollection, retroperitoneal lymphadenopathy, peritoneal enhancement, and hepatome-galy. Bowel wall thickening, target sign, dilatation of intestinal segments, engorgement ofmesenteric vessels, and increased attenuation of mesenteric fat are suggestive of bowelischemia.60 Ko et al61 described the early CT findings (performed within 1–4 days ofonset of abdominal pain) of lupus mesenteric vasculitis in 11 patients. Conspicuousprominence of mesenteric vessels with palisade pattern or comb-like appearancesupplying focal or diffuse dilated bowel loops, ascites with slightly increased peritonealenhancement, bowel wall thickening with double halo or target sign (enhancing outerand inner rim with hypoattenuation in the center) were characteristic findings. Theauthors concluded that CT scan was very helpful for the diagnosis of lupus mesentericvasculitis.

Gallium and white cell scans can assist in locating the sites of inflammation and sepsisin difficult cases. Visceral angiography in patients with persistent GI bleeding can help tolocate the site(s) of hemorrhage so that embolization procedures can be performed.

The typical histopathological findings of lupus mesenteric vasculitis usually occur inthe arterioles and venules of the submucosa of the small bowel rather in the medium-sized mesenteric arteries.59,62,63 Vasculitic lesions tend to be segmental and focal.64

Immunohistochemical staining of the tunica adventitia and media can reveal immunecomplex, C3 complement and fibrinogen deposition. Fibrinoid necrosis and intra-luminal thrombosis of the affected vessels may occur. Acute or chronic inflammatoryinfiltrates consisting of lymphocytes, plasma cells, histiocytes and neutrophils might alsobe demonstrated.63 More serious inflammation of the bowel wall can lead to mucosalulceration, submucosal edema, necrosis, hemorrhage, infarction and even perfor-ation.65,66

The mortality among patients lupus mesenteric vasculitis is high.43 Aggressivetreatment has to be instituted early; high-dose intravenous methylprednisolone is theinitial treatment of choice. Surgical intervention is indicated when the response is notrapid or when there are clinical and radiological signs of bowel perforation. Intravenouspulse cyclophosphamide has been used with success in a SLE patient with relapsingintestinal vasculitis that was refractory to corticosteroid treatment.62

Mesenteric insufficiency

Patients with SLE are prone to premature atherosclerosis. In addition to the cerebraland coronary vessels, the splanchnic arteries might also be involved. Chronicmesenteric insufficiency, or ‘intestinal angina’ should not be overlooked in patientswho present with chronic intermittent abdominal pain.67 Symptoms usually start in thepostprandial state and persist for 1–3 hours. Abdominal pain can be minimal at theonset but might progress in severity over weeks or months. Weight loss and fear ofeating are often reported. SLE patients particularly at risk are those with long-standingdisease, renal insufficiency, chronic proteinuria, hyperlipidemia, diabetes mellitus,hypertension, obesity, smoking history, positive anti-phospholipid antibodies and thosewho receive long-term corticosteroid therapy.

The diagnosis of chronic mesenteric insufficiency relies on a high index of suspicion.Barium studies might demonstrate classic thumbprinting. Conventional angiography isthe gold-standard imaging procedure. Digital subtraction angiography, Doppler

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ultrasonography and MRI with angiography are adjunctive diagnostic modalities. Surgicalrevascularization has been shown to give long-term symptom relief in most patientswith chronic mesenteric ischemia. Percutaneous transluminal mesenteric angioplastywith or without a stent has become a viable alternative for selected patients.

Acute mesenteric ischemia can result from impaired blood flow within themesenteric arterial or venous systems. Classically, abdominal pain is persistent anddisproportionately severe relative to physical signs. Patients might also present withacute abdomen with distension, rigidity, fever, bloody diarrhea, melena andhypotension. SLE patients with underlying chronic mesenteric insufficiency due toatherosclerosis or secondary anti-phospholipid syndrome are particularly prone toacute intestinal ischemia,68 which might be precipitated by hypoperfusion states such ascongestive heart failure and shock.67 Acute mesenteric thrombosis can result in bowelinfarction, perforation and peritonitis. Surgical exploration, resection of gangrenousbowel and embolectomy is indicated.

Intestinal pseudo-obstruction (IPO)

IPO is a clinical syndrome characterized by impaired intestinal motility as a result ofdysfunction of the visceral smooth muscle or the enteric nervous system.69 Recently,Narvaez et al70 reported a patient SLE who presented with IPO and reviewed 21 othersimilar cases reported in the English literature. IPO was the initial presentation of SLE in41% of patients and usually occurred in the setting of an active lupus. The small bowelwas more commonly involved than the large bowel.

Common presenting symptoms of IPO are a subacute onset of abdominal pain,nausea, vomiting, abdominal distension and constipation. Physical examination oftenreveals a diffusely tender abdomen with sluggish or absent bowel sound. Reboundtenderness is usually absent. Radiologic examinations can demonstrate dilated, fluid-filled bowel loops, with thickened bowel wall and multiple fluid levels. Organic causesfor intestinal obstruction should be sought, preferably by non-surgical assessment, butlaparotomy might be necessary to exclude adhesions. Patients might present with ahistory of laparotomy on one or more occasions at which no cause for intestinalobstruction was found.

Manometry motility studies in patients with IPO can demonstrate esophagealaperistalsis and intestinal hypomotility.69 Interestingly, 63% of the reported cases ofSLE-related IPO in the literature had concomitant ureterohydronephrosis andcontracted urinary bladder, with around one-third of these patients had documentedhistological features of interstitial cystitis.70 Interstitial cystitis has been associated withautoimmune disorders, including SLE.71 Immune complexes, immunoglobulin andcomplement deposition can be demonstrated in the blood vessel walls of the bladder inpatients with lupus cystitis,72,73 suggesting an underlying immune mechanism. Interstitialcystitis leads to a contracted bladder, with thickened bladder wall and reduced bladdercapacity. It can also cause ureterohydronephrosis because of detrusor muscle spasmand secondary vesiculo-ureteric reflux.

The pathogenesis of IPO in SLE is unclear. The association with autoimmune cystitisand the demonstration of antibodies against proliferating cell nuclear antigen in somepatients74 suggests that this might be the result of vasculitis of the visceral smoothmuscles, which in turn leads to muscular damage and hypomotility. The simultaneouspresence of ureterohydronephrosis in many patients with SLE-related IPO and theassociation of hypomotility of other parts of the gastrointestinal tract indicate that thebasic pathology may be the dysmotility of the intestinal musculature. Whether this is


caused by a primary myopathy, neuropathy, vasculitis or antibodies directed against thesmooth muscle of the gut wall necessitate further delineation.

SLE-related IPO usually responds to treatment with high dose corticosteroids.70,75,76

Additional immunosuppression in the form of azathioprine, cyclosporin A andcyclophosphamide were used by some reports.75,77–79 Despite maintenance therapy,some patients have a relapsing course in the absence of other major organ involvement.Other adjunctive therapies in patients with IPO include broad-spectrum antibiotics andprokinetic agents such as erythromycin and octreotide (a long-acting somatostatinanalog).80 Early recognition of IPO in SLE patients is important because the condition ispotentially reversible with non-surgical measures and early institution of immunosup-pressive therapy. This will avoid unnecessary laparotomies for sub-acute intestinalobstruction.

Malabsorption

Intestinal malabsorption in SLE can result in protein losing enteropathy, hypoalbumi-nemia and ascites.81,82 Mader et al83 used the D-xylose absorption test (DXT) andmicroscopic examination of the stool for fat droplets to screen 21 patients with SLE formalabsorption. All patients also underwent upper GI endoscopy with biopsy from thesecond portion of the duodenum. Two patients (10%) were found to have an abnormalDXT and excessive fecal fat excretion. In one of these patients, histologic examinationrevealed flattened and deformed villi with an inflammatory infiltrate. Two other patientsshowed isolated excessive fecal fat excretion with a normal duodenal mucosalhistology. In all patients, immunoperoxidase staining did not reveal excessive depositionof immunoglobulins and light chains within the intestinal mucosa.

Concurrence of coeliac disease (gluten-sensitive enteropathy) and SLE has beenreported,84,85 but whether this merely represents a coincidence remains to beelucidated. Up to 23% of patients with SLE can be tested positive for either the IgA orthe IgM antigliadin antibodies but their predictive values for biopsy proven gluten-sensitive enteropathy is extremely low.86 As in primary celiac disease, a gluten-free dietoften leads to improvement in symptoms but partial villous atrophy tends to persist andcorticosteroid and azathioprine might be necessary in refractory cases.87

Protein-losing enteropathy (PLE)

PLE is a clinical syndrome characterized by hypoalbuminemia secondary to loss ofprotein from the GI tract. It is usually identified by an elevated clearance of stool a1-anti-trypsin or the technetium 99m-labeled human serum albumin scan. Significant lossof protein from the kidneys should be absent. PLE should not be regarded as a finaldiagnosis because a variety of pathologies from the stomach down to the colon mightbe responsible for the protein loss. Investigations into the causes of PLE, e.g.gastrointestinal lymphoma, malabsorption state, bacterial overgrowth, chronicinfection, polyposis and lymphatic obstruction, are crucial.88 Endoscopic examinationwith mucosal biopsies, barium studies, radiologic examinations and absorption testsmight be required.

PLE has infrequently been reported in patients with SLE and might be the initialmanifestation of the disease.89–92 Common symptoms are generalized edema,abdominal pain and diarrhea. Radiologic examination may reveal thickened folds withmultiple submucosal nodules in the bowel wall.93 Endoscopically, the duodenal villimight appear to be lustrous and swollen, and of various size.94 Histological examination

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might reveal villous atrophy with inflammatory infiltrates and submucosal edema;vasculitis is usually absent. Lymphangiectasia has been described in a case of lupus-related PLE.93

The exact pathogenesis of PLE remains elusive. Mucosal disruption, increase inmucosal capillary permeability as a result of complement- or cytokine-mediateddamage, mesenteric venulitis, and dilated/ruptured mucosal lacteals has beenpostulated.1,48

Most SLE patients with PLE respond to corticosteroid treatment. Intravenous pulsecyclophosphamide might be needed in refractory cases.90,91

Crohn’s disease

Coexistence of SLE and Crohn’s disease (regional ileitis) is rarely reported in theliterature.95,96 Whether there is a true association between these two diseases awaitsdelineation by further data.

Infective enteritis

SLE patients are prone to intestinal infections. This is the result of multiple factors,which include corticosteroid and cytotoxic treatment, low complement levels(diminished capacity for opsonization), functional hyposplenism, associated selectiveIgA deficiency, uremia and hypogammaglobulinemia (due to renal disease). Bacterialenteritis is the most common, with non-typhoidal Salmonella infection being mostfrequently reported.97–99 Campylobacter jejuni infection and CMV enteritis leading toileal perforation have been described in SLE patients.100,101

Disorders of the large intestine in SLE patients

Lupus colitis

Although lupus enteritis mainly involves the small bowel, the large bowel can also beaffected. In the series by Zizic et al102 and Medina et al,26 colonic involvement by SLEwith perforation was described. Most patients had active SLE with documentedvasculitis in other organs. The mortality was high.

Yuasa et al103 reported a patient with SLE presenting with vasculitic rectal ulcers thatresponded to corticosteroid treatment; disease activity in other organs was notevident. Amit and colleagues104 also described a patient with vasculitic rectal ulcer asthe sole manifestation of SLE. Rectal ulcers in SLE might perforate and lead tosepticemia.104,105

Ulcerative colitis

Ulcerative colitis (UC) is rarely associated with SLE. Clinically and pathologically, lupuscolitis might be indistinguishable from UC.106 Symptoms include persistent diarrhea,which might be bloody, lower abdominal discomfort and per-rectal bleeding. Theprevalence of UC in SLE patients is around 0.4%.48 Conversely, the incidence of SLE inpatients with UC is higher. In a study performed four decades ago, Alarcon-Segoviaet al107 reported SLE in 3% of patients with UC. In these cases, colitis preceded theonset of lupus, especially after treatment with sulphasalazine. As sulphasalazine is wellknown to be a cause of drug-induced lupus, it remains to be seen whether a genuine


association between SLE and UC exists. More cases of UC in patients with SLE haverecently been reported.108,109

Collagenous colitis

Collagenous colitis is a disorder characterized by colonic intra-epithelial lymphocytosis,expansion of the lamina propria with acute and chronic inflammatory cells, and athickened subepithelial collagen band.110 Patients usually present with chronic waterydiarrhea despite normal radiologic and endoscopic findings. Collagenous colitis hasbeen reported in association with discoid and systemic lupus erythematosus.111,112 Acase of colonic carcinoma in an SLE patient with renal insufficiency and collagenouscolitis has also been described.113 Treatment of collagenous colitis includesdiscontinuation of offending drugs, anti-diarrheal agents, 5-aminosalicylate drugs,corticosteroids, especially budesonide, bile-acid-binding resins, and bismuthsubsalicylate.

Infective colitis

Colonic infections should be considered in SLE patients presenting with lower GIsymptoms. CMV and amoebic colitis has been reported in patients with SLE.114,115

Lymphopenia, cytotoxic treatment, presence of renal disease and a travel history toendemic areas are predisposing factors.

Diverticular disease

Diverticulitis is a relatively common colonic disorder of the elderly. Diverticular diseaseis expected to occur in older patients with SLE but its incidence does not appear to behigher when compared to the general population.1 Diverticulitis can result in abscessformation and septicemia and is an important differential diagnosis in SLE patientspresenting with fever, abdominal pain and tenderness.

Diseases of the liver, biliary tract and pancreas

Liver function abnormalities

Liver function abnormalities can occur in SLE patients on routine blood checking duringclinic visits. However, they are usually mild and non-specific, and can be attributed tomultiple factors such as the use of aspirin, NSAIDs, azathioprine and methotrexate;fatty infiltration of liver as a result of corticosteroid treatment, diabetes mellitus andobesity; as well as viral hepatitis and alcoholism. Persistent and severe liver functionabnormalities are uncommon, but require further investigations such as ultrasono-graphy and liver biopsy to delineate the underlying causes.

Runyon et al116 reported that of 206 SLE patients they studied, 124 (60%) hadabnormal liver function test results. However, significant liver disease was diagnosed in43 patients (21%) only. Liver biopsy in 33 patients revealed steatotic hepatitis (36%),cirrhosis (12%), chronic active hepatitis (9%), chronic granulomatous hepatitis (9%),centrilobular necrosis (9%), chronic persistent hepatitis (6%) and microabscesses (6%).Eight patients improved with corticosteroid treatment but three died of liver failure atthe time of review. Gibson and Myers117 studied 81 patients with SLE and reported that45 (55%) had abnormal liver function results at some point. The majority of thesepatients had mild liver function derangement. No causes other than SLE itself for

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the liver function abnormalities were present in 19 patients (23%). Of the patients whohad liver biopsy performed, seven showed normal histology, five had portalinflammatory infiltrates, one had fatty liver and one had chronic active hepatitis. In aprospective study, Miller et al118 reported liver function abnormalities in 60 (23%) oftheir 260 SLE patients. Twenty-one (35%) of these patients did not have identifiablecauses for their liver problem. In 12 of 15 patients with persistent ‘unexplained’transaminase elevations during follow-up visits, changes in SGPT levels wereconcordant with SLE activity.

Taken together, liver function abnormalities can be fairly common in SLE patients andin around one-fifth of cases, no obvious causes other than the disease itself can beidentified. However, clinically significant and serious liver disease is uncommon. Furtherinvestigations in patients who have persistent or serious liver dysfunction are necessaryto identify treatable conditions.

Lupus hepatitis

Autoimmune hepatitis (AIH) is now considered to be a distinct disease entitycharacterized histologically by interface hepatitis and portal plasma cell infiltration,hypergammaglobulinemia and the presence of a variety of autoantibodies thatdirect against hepatic antigens or liver–kidney microsomal proteins such as ANA,anti-smooth muscle antibodies (SMA) and anti-LKM antibodies.119 AIH can be classifiedinto three types based on their immunoserologic markers. Type I AIH (the classic‘lupoid hepatitis’ described in 1950s) is the most common form worldwide and isassociated with ANA and/or SMA. Type II AIH is associated with anti-LKM1 antibodywhereas type III AIH is associated with anti-SLA/LP antibodies.

Patients with AIH usually present with insidious onset of non-specific symptoms,such as fatigue, malaise and anorexia. Liver enlargement, jaundice and ascites might bepresent in severe cases. AIH is also associated with lupus-like features such as positiveANA, hypergammaglobulinemia and joint symptoms. However, patients with AIHseldom fulfill the ACR criteria for the classification of SLE.2 Of 89 patients with AIHfollowed by investigators at the Mayo Clinic,120 only nine (10%) fulfilled the ACRcriteria for SLE. The term ‘lupus hepatitis’ should be reserved for patients who haveinsidious onset of chronic active hepatitis, with documented lymphocytic infiltration ofperiportal areas on liver histology, and who fulfill the ACR criteria for SLE. Othercauses of liver function derangement such as viral infection, alcoholism, metabolic orgenetic liver diseases and effect of drugs have to be excluded.

The incidence of AIH in SLE patients is unclear as not all patients will have thediagnosis confirmed by liver biopsy. In one study, evidence for chronic active hepatitiswas present in 4.7% of patients who fulfilled the ACR criteria for SLE.42 Chronic activehepatitis was reported in 2.4% of Japanese patients with SLE according to their autopsyregistry data.121 Arnett et al122 reported that four (3%) of their 131 SLE patients had aclinical picture of chronic active hepatitis. Evidence for chronic viral infection wasabsent and only one patient had low-titer SMA. Compared with non-SLE patients, SLEpatients with AIH are more likely to have autoantibodies against dsDNA, Sm and anti-ribosomal P. Anti-ribosomal P antibody is specific for SLE and has been reported to bestrongly associated with lupus hepatitis.122,123

High-dose prednisone alone or a lower dose of prednisone in conjunction withazathioprine is the main-stay of treatment for AIH.119,124 Remission can beachieved in 80% of patients within 3 years, and the 10- and 20-year survival ratesexceed 80%. Histological cirrhosis does not affect treatment response or survival.


The use of azathioprine is corticosteroid sparing and is associated with less sideeffects and lower relapse rates. Long-term maintenance therapy with low-doseprednisone and azathioprine is preferred for patients with multiple relapses. Newertreatment modalities of AIH include cyclosporine A, tacrolimus, MMF, and livertransplantation.

Chronic viral hepatitis

Chronic hepatitis B virus (HBV) infection does not seem to be preferentially increasedin patients with SLE when compared to the general population, even in areas wherehepatitis B infection is endemic.125–128 In a study in Taiwan, the prevalence of HBVinfection was reported to be significantly lower than that in the general population (3.5versus 14.7%).129 Patients with coexistent SLE and chronic HBV infection had less lupusactivity, including less proteinuria and a lower serum titer of anti-dsDNA than HBsAg-negative lupus patients. Another study from the Middle East did not find HBV infectionin 96 SLE patients, compared to prevalence of 2% in the general population.130

Perlemuter and colleagues131 studied 19 patients (3%) with chronic hepatitis C(HCV) infection among 700 SLE patients. Compared with 42 age- and sex-matchedpatients without anti-HCV antibodies, SLE patients with HCV infection had a higherprevalence of asymptomatic cryoglobulinemia. SLE by itself or treated withcorticosteroids did not seem to worsen HCV infection.

Ramos-Casals et al132 reported an increased prevalence of HCV infection in theirSLE patients compared to healthy blood donors (13 versus 1%). SLE patients withHCV infection were less likely to have cutaneous disease and anti-dsDNA but morelikely to have hepatic involvement, low complement levels and cryoglobulinemia thanthose without HCV infection. In these studies, anti-HCV was tested by enzyme-linked immunosorbent assay (ELISA) with or without confirmation by immunoblot-ting. One study using the polymerase chain reaction (PCR) for HCV showed thatfalse positive results with either the ELISA or immunoblot assay might occur inpatients with SLE.133

Drug-induced hepatitis

Many drugs used in the treatment of SLE can induce hepatotoxicity. Aspirin, NSAIDs,methotrexate and leflunomide can cause elevation of parenchymal liver enzymes andhepatitis. Corticosteroids can induce fatty liver disease (steatotic hepatitis).Azathioprine and hydroxychloroquine occasionally cause hepatitis. Of interest isminocycline, a drug used in the treatment of rheumatoid arthritis and acne, which caninduce a syndrome of drug-induced lupus and autoimmune hepatitis.134 The hydroxyl-methyl-glutaryl-coenzyme A reductase inhibitors (i.e. the statins) are increasingly usedin patients with SLE. Isolated case reports of statin-induced lupus-like syndrome andhepatitis should be noted.135,136

Other liver diseases

Thromboembolic disorders of the liver may occur in patients with SLE, especially in thepresence of the anti-phospholipid antibodies. Budd-Chiari syndrome, a disease causedby occlusion of the hepatic veins leading to portal hypertension, secondary cirrhosisand ascites, and hepatic veno-occlusive disease has been reported in patients with SLEand secondary anti-phospholipid syndrome.137–139 A case of histologically documented

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hepatic infarction has also been described in a SLE patient with end-stage renal failureand a circulating lupus anti-coagulant.140

Nodular regenerative hyperplasia (NRH) is a disorder characterized by diffusenodularity of the liver with little or no fibrosis. It is a cause of non-cirrhotic portalhypertension and can lead to ascites and variceal bleeding. NRH was first described inassociation with scleroderma, primary biliary cirrhosis and Felty’s syndrome.141,142

Subsequently, NRH has also been found in patients with SLE and the primary anti-phospholipid syndrome.143,144 In a study of 13 patients with NRH documented byhistological examination, anti-phospholipid antibodies were present in 77% of thesecases, as compared to 14% in normal controls and in patients with autoimmunehepatitis.145 The association with the anti-phospholipid antibodies suggests that NRHmight result from liver regeneration to maintain its functional capacity after ischemia-induced injury.

In an autopsy study of 160 livers, Matsumoto et al146 described seven cases of NRH,five of which was found in patients with SLE. NRH should be suspected in SLE patientswith unexplained portal hypertension. Diagnosis has to be established by liver biopsyand hepatic nodules might be better visualized with MRI of the liver.143 Many patientsdiagnosed as having NRH of the liver are asymptomatic with normal liver function.

Figure 1. An SLE patient with mesenteric vasculitis (lupus enteritis) and paralytic ileus. Plain abdominal

radiograph shows multiple dilated small bowel loops, with relative sparing of the large bowel.


Treatment should target at control of portal hypertension and its relatedcomplications.147

Other rare liver diseases that have been reported in SLE patients are giant cavernoushemangioma, primary liver lymphoma, secondary hepatic amyloidosis and hepaticartery aneurysm.148–151

Biliary tract disease

Gallbladder disease is no more common in patients with SLE than in the generalpopulation.48 Cholecystitis in SLE can be confused with serositis.152 Cases of acuteacalculous cholecystitis have been described in the literature.153–155 Patients usuallypresent with acute abdomen and cholecystectomy specimens might reveal vasculitis ofthe gall bladder. Although successful conservative treatment with corticosteroid hasbeen reported,155 many patients are diagnosed after surgical treatment, especially ifthere was evidence of septicemia.156 Treatment with intravenous corticosteroids andcyclophosphamide in patients without obvious infection might be appropriate but thereis no published evidence for this approach at present.

Primary biliary cirrhosis and sclerosing cholangitis

Although primary biliary cirrhosis (PBC) is usually associated with an autoimmunedisease, co-existence of PBC and SLE is rare.157–159 Autoimmune cholangiopathy (anti-mitochondrial antibody negative PBC) has been shown in a patient with SLE.160 Primarysclerosing cholangitis, a rare disorder frequently associated with the inflammatorybowel diseases, has also been reported in SLE patients.161

Figure 2. A magnified view of Figure 1 showing bowel wall thickening within the dilated bowel loops and the

thumb-printing appearance.

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Pancreatic disorder

Pancreatitis is an uncommon manifestation of SLE. The prevalence of pancreatitis in SLEpatients ranges from 0 to 4%.48,58,162 The use of medications such as corticosteroids,azathioprine and thiazide diuretics have been attributed to be the cause of pancreatitisin some SLE patients.

Pascual-Ramos et al162 analyzed 49 episodes of acute pancreatitis in 35 SLE patientsseen within a period of 17 years. Seventeen episodes were considered idiopathicand disease activity scores were significantly higher than those with identified causesof pancreatitis. Compared with non-SLE controls, ‘idiopathic’ pancreatitis was more

Figure 3. Another SLE patient with intestinal pseudo-obstruction predominantly involving the large bowel.

Plain abdominal radiograph reveals gross dilatation of the transverse and descending colon. Investigations

failed to reveal mechanical obstruction of the large bowel or colitis.


frequent in SLE patients. Medication use did not seem to be associated with thedevelopment of pancreatitis.

Saab et al163 reported eight SLE patients with pancreatitis. All manifested clinical andbiochemical resolution of their pancreatitis after corticosteroid treatment. Derket al164 studied 25 SLE patients diagnosed to have acute pancreatitis in a 20-year period.Three-quarters of the patients had active SLE in other organs. Most patients had theirpancreatitis improved with corticosteroids. These studies suggest that lupuspancreatitis is likely to be a distinct but uncommon entity that occurs in patientswith active disease and might respond to immunosuppressive treatment. In fact, in thepre-steroid era, cases of pancreatic vasculitis have been documented histopathologi-cally.48 Autopsy studies have also demonstrated vascular damage consisting of severeintimal proliferation in the pancreatic vessels in patients with lupus pancreatitis.165

Hasselbacher et al166 measured serum amylase and macroamylase activity in 25patients with SLE and demonstrated that 20% of patients had elevated amylase and 25%had a macroamylase present. None of the patients had clinical features of pancreatitis.

Eberhard et al167 measured serum immunoreactive cationic trypsinogen (IRT) in 35asymptomatic patients with SLE. Fifteen patients (43%) had elevated IRT levels on atleast one occasion. There was no apparent association with the use of drugs such asprednisone and azathioprine. The authors postulated that subclinical pancreaticdysfunction might be present in some patients with SLE. On the other hand, chroniccalcifying pancreatitis has also been demonstrated in lupus patients.168,169

Management of pancreatitis in SLE patients includes intravenous fluid resuscitation,bowel resting, discontinuation of non-essential but potentially offending drugs andthe use of antibiotics if necessary. Secondary causes of pancreatitis such ascholelithiasis, alcoholism and hypertriglyceridemia have to be ruled out. Close

Figure 4. Liver biopsy in a SLE patient showing active interface hepatitis with prominent plasmacytic

infiltrates. This is consistent with lupus hepatitis (H&E 200!).

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observation is mandatory and serial contrast CT scan of the abdomen might be neededto monitor the progress of pancreatitis and the development of complications.Corticosteroids should be considered in idiopathic cases of pancreatitis, particularly ifSLE is active in other systems.

SUMMARY

GI manifestations of SLE are diverse and may involve any part of the GI tract and thehepatobiliary system. Recognition is important because of some of thesemanifestations carry significant mortality and morbidity. Differentiation fromcomplications of treatment, infections and intercurrent illnesses is essential in theevaluation of GI symptoms in SLE patients. Endoscopic examination, biopsy andvarious imaging techniques are helpful but surgical intervention should not bedelayed in patients presenting with acute abdominal pain if conservative managementfails or when there is clinical suspicion of visceral perforation or intra-abdominalcollections. The main-stay of therapy, as with other manifestations of SLE, isimmunosuppression. Anti-coagulation should be considered when thrombosis is theunderlying mechanism. For patients who do not respond to corticosteroids alone,cyclophosphamide might be required, especially if there is a vasculitic component(Figures 1–4).

Practice points

† GI manifestations of SLE:† gastrointestinal (GI) manifestations are fairly common and might be the initial

presentation of SLE. GI symptoms occur in up to two-thirds of SLE patients atsome stage of their illness

† lupus involvement of the GI tract can be difficult to distinguish fromcomplications related directly or indirectly to treatment and concomitantnon-SLE pathologies. Active disease in other organs is a clue to GI lupus

† GI infections and intra-abdominal sepsis should always be sought beforeaugmentation of immunosuppressive therapy is considered. Co-administrationof broad-spectrum antibiotics might be required if infection cannot be excludedor is present in addition to inflammatory disease

† anorexia, nausea and vomiting may be prominent in patients with active SLE.Intestinal pseudo-obstruction due to SLE should not be overlooked in patientspresenting with persistent vomiting and abdominal distension

† abdominal pain in patients with SLE can herald an intra-abdominal catastropheand should be evaluated promptly. Plain radiograph, barium studies,ultrasonography contrast CT scan and angiography might be required fordiagnosis. Early surgical exploration can improve prognosis when conservativemanagement fails

† chronic intermittent abdominal pain in SLE should arouse the suspicion ofchronic mesenteric insufficiency

† ascites in SLE might be inflammatory in nature or secondary to hypoalbumi-nemia. Lupus serositis is usually corticosteroid responsive

† mesenteric or intestinal vasculitis in SLE can be life threatening. Active SLE inother systems is usually present. Aggressive immunosuppressive treatment isrequired and early surgery is indicated for impending bowel infarction with orwithout perforation/hemorrhage

† malabsorption syndromes, pancreatitis and cholecystitis can occur in SLEpatients but these are uncommon

† hepatic manifestations of SLE:† liver function derangement in SLE patients is usually mild and related to

medication use† lupus hepatitis is uncommon but is important and needs to be recognized.

Corticosteroid and azathioprine treatment can improve the outcome† chronic hepatitis B and hepatitis C infection does not appear to be more

prevalent in patients with SLE than in the general population† nodular regenerative hyperplasia is uncommon but should be suspected in SLE

patients with unexplained portal hypertension† primary biliary cirrhosis and sclerosing cholangitis have been associated with

SLE

Research agenda

† to devise and validate a new scoring scale for assessing SLE activity in the GI andhepatic systems, and the response to therapy

† to conduct controlled trials comparing different immunosuppressive regimensfor the treatment of lupus enteritis

† to compare the GI manifestations of SLE patients with and without theantiphospholipid antibodies


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Investigations and Management of Gastrointestinal and Hepatic Manifestations of Systemic Lupus...

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