Systemic Lupus Erythematosus

Chapter 11

Systemic Lupus Erythematosus M. Vilardell-Tarre´s, A. Selva-O’Callaghan and J. Ordi-Ros Vall D’Hebron General Hospital, Barcelona, Spain

1. INTRODUCTION Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a broad range of clinical manifestations. It is characterized by an immune system dysregulation resulting in the production of various autoantibodies and is considered a multifactorial disease with evidence of genetic susceptibility [1]. SLE affects several organ systems and leads to significant morbidity and mortality. Gastrointestinal (GI) manifestations caused by the disease per se or aggressive treatment regimens are not rare in SLE patients [2], but are seldom reported, likely being masked by other, more salient clinical features such as renal or central nervous system abnormalities. The incidence of GI symptoms attributable to the disease itself varies widely, ranging from 1.3% to 27.5% in the literature. Chronic intestinal pseudoobstruction (CIPO), protein-losing gastroenteropathy, and intestinal vasculitis are the most common identifiable SLE-related GI manifestations [3], which seem to occur more commonly in Asian populations. No specific autoantibodies associated with SLE-related gastroenteropathy have been identified to date. In this chapter, we describe the GI manifestations occurring in SLE patients. The liver manifestations of the disease are beyond the scope of this chapter and will be reviewed elsewhere.

2. OVERVIEW OF GASTROINTESTINAL MANIFESTATIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS Almost half of all lupus patients experience anorexia, nausea, and vomiting. These symptoms may result not only by GI involvement but also from the uremia associated with renal failure, or from the effects of cytostatic therapies, such as azathioprine and intravenous cyclophosphamide pulses, or the more recently used immunosuppressive drug, mycophenolate mofetil. The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00011-8 215 Copyright © 2017 Elsevier B.V. All rights reserved.

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Serositis (pleuritis, pericarditis, and less frequently, ascites) is a wellrecognized diagnostic criterion of SLE. It is present in 8e11% of patients and can be divided into inflammatory (true serositis) or noninflammatory serositis, mainly caused by the hypoalbuminemia resulting from nephrotic syndrome, liver cirrhosis, or protein-losing enteropathy. Chronic ascites due to lupus per se has a painless onset, progresses even in the absence of other signs of disease activity, and usually responds to corticosteroids or in refractory cases, cyclophosphamide [4,5]. GI symptoms are the first complaints in nearly one-third of lupus patients, although they can occur at any stage of the disease. It is important to be aware of these manifestations in SLE because misdiagnoses and delayed treatment can lead to unfavorable outcomes [3]. Abdominal pain is usually a nonspecific symptom, but it can be particularly important in lupus patients, occurring in adults with this condition [4] and in childhood-onset SLE [6]. Acute abdomen is always a challenging diagnostic and therapeutic problemdeven more so in SLE [7]dand the abdominal pain may also be caused by the complications of therapy or the disease, itself (Table 11.1). Immunosuppressive agents and corticosteroids, the usual treatments for SLE, may mask the classic symptoms of bowel perforation and ischemia, two of the main causes of acute abdomen. Nonsteroidal antiinflammatory drugs, azathioprine, calcineurin antagonists such as cyclosporine and tacrolimus, and mycophenolate mofetil can all cause abdominal pain to a greater or lesser extent. Evaluation of the patient’s disease activity using the

TABLE 11.1 Abdominal Pain in Systemic Lupus Erythematosus (SLE) SLE-Related

Treatment-Related

Non-SLE Causes

Renal vein thrombosis

Gastritis, duodenitis

Appendicitis

Mesenteric thrombosis

Pancreatitis (azathioprine)

Viral hepatitis

Acalculous cholecystitis

Sepsis

Biliary pancreatitis

Bowel perforation

Peptic ulcer

Diverticulitis

Vasculitis

Perforation

Surgical adhesions

Ectopic pregnancy

Enterocolitis

Pancreatitis

Salmonella infection

Serositis Splenic infarction Ischemic bowel disease Angioedema

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SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) may help physicians to choose the most effective approach. Intraabdominal vasculitis and mesenteric thrombosis, both severe abdominal complications of SLE, seem to be associated with higher scores on the SLEDAI [5] and other activity indices [8]. However, one study has reported that the SLEDAI is not reliable as a general marker of SLE-related GI manifestations [9]. Radiological examinations such as ultrasound and computed tomography (CT) scanning are essential to achieve the correct diagnosis; gastroscopy and colonoscopy, which can show ischemia and ulcers, are also of value. Prompt laparotomy is preferred in some cases, particularly acute abdomen with active SLE or a severe clinical presentation, because mortality is high in these patients [10,11]. Mesenteric insufficiency [4], sometimes referred to as intestinal angina, is a related complication that deserves special attention. It is well recognized that SLE patients are prone to premature atherosclerosis, affecting several vascular territories. In addition to the cerebral and coronary vessels, the splanchnic arteries may be affected, causing chronic intermittent abdominal pain, which should not be overlooked. The symptoms usually start after lunch and persist for 1e3 h. Weight loss and a fear of eating are common in patients with mesenteric insufficiency. Conventional angiography is the criterion standard diagnostic technique, but magnetic resonance imaging (MRI) and abdominal CT angiography are also useful in this regard and are less invasive. Longstanding disease, renal failure, long-term corticosteroid therapy, and the presence of classic cardiovascular risk factors such as hypertension, smoking, hyperlipidemia, and diabetes favor the development and progression of atherosclerosis in SLE. Healthy lifestyle habits and drug therapy (e.g., statins) are strongly recommended to control or minimize these factors. Therapeutic options include surgical revascularization and, in selected cases, percutaneous transluminal mesenteric angioplasty with or without stent placement. Anticoagulation therapy and antiplatelet therapy with aspirin or clopidogrel should be prescribed on an individual basis.

3. ORAL CAVITY, ESOPHAGUS, AND GASTROINTESTINAL ABNORMALITIES Oral ulcers are common in SLE, occurring in 6e52% of patients [2]. The lesions are usually painless and affect the hard palate, nasal cavity, and pharyngeal wall. As most lupus patients receive immunosuppressive therapy, infection should not be overlooked as a cause of oral ulcers. Candidiasis, herpes virus, and oral leukoplakia can produce oral ulcers or plaquelike lesions. Secondary sicca syndrome with dry mouth and dry eyes develops in almost 20% of lupus patients [12]. Dry mouth favors periodontal disease and aphthous ulcers, erythema, hemorrhage, and gingival overgrowth. Cyclosporine A treatment usually exacerbates gingival hypertrophy. Tissue biopsy may show

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lupus-specific histopathology similar to that seen in the skin. Histology and immunopathology of the oral lesions in these patients include an inflammatory perivascular lymphohistiocytic infiltrate, spongiosis, hyperkeratosis, and deposition of IgG/IgM, complement, or fibrinogen at the dermal/epidermal junction. The lesions may be difficult to distinguish from oral lichen planus or leukoplakia. Antimalarial agents (chloroquine and hydroxychloroquine) and topical corticosteroids are the treatments of choice for SLE-related oral lesions. Systemic steroids and/or azathioprine are generally used in severe cases. Thalidomide and cyclosporine A in Europe and methotrexate in the United States are used as second-line agents in the most refractory cases. To date, there are no evidence-based guidelines for systemic therapy of oral lesions in lupus patients. Sugar-free gum, artificial saliva, and systemic therapy with pilocarpine hydrochloride to increase salivation can be useful in cases of secondary Sjo¨gren syndrome. Esophageal symptoms in SLE include dysphagia and heartburn, but it cannot be assumed that these are due to the disease and not the therapy. The introduction of proton pump inhibitors has lowered the incidence of esophageal symptoms. Manometric abnormalities, particularly hypoperistalsis in the upper third of the esophagus, have been reported in almost two-thirds of lupus patientsdeven asymptomatic onesdand may be associated with CIPO, an uncommon GI complication discussed in the following text. Involvement of the lower esophageal sphincter is rare, and esophageal symptoms do not seem to correlate well with the manometry findings [7]. Conventional, symptomatic therapy (proton pump inhibitors and small, frequent meals) may be a better approach than immunosuppressive or antiinflammatory therapy. Nonetheless, if vasculitis or inflammation is seen on biopsy study, treatment of lupus itself is warranted, particularly when the disease is serologically and clinically active. Gastric disease is more often related to treatment complications [nonsteroidal antiinflammatory drugs (NSAIDs) and corticosteroids] than to the disease itself. Therefore patients on long-term NSAIDs may require a gastroprotective agent such as proton pump inhibitors. Clinicians should be aware of cytomegalovirus infection of the gastric mucosa, particularly in lupus patients receiving long-term treatment with mycophenolate mofetil, as this is a well-known complication in renal transplantation [13]. Gastric antral vascular ectasia, also referred to as watermelon stomach, is a rare vascular malformation that has been described in SLE. It can cause acute or chronic bleeding that, in turn, leads to persistent iron deficiency anemia. Moderate doses of prednisone are recommended, although transendoscopic treatment or antrectomy may occasionally be needed [14]. Colon and small bowel involvement includes pneumatosis cystoides intestinalis, an uncommon but important condition in which gas is found in a linear or cystic form in the submucosa or subserosa of the bowel wall [15]. The left colon and ileum are the bowel segments most often affected. There are a

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few reports of pneumatosis cystoides intestinalis in adults with systemic autoimmune diseases, especially systemic sclerosis and dermatomyositis, but it has been mainly described in SLE patients [7,16]. Several mechanisms have been proposed for the development of this condition, including breaks in the intestinal mucosa, infection, and ischemia due to vasculitis. Pneumatosis cystoides intestinalis is often asymptomatic and sometimes occurs with pneumoperitoneum, which is sterile and must be differentiated from a perforated viscus. Pneumoperitoneum should be considered a sign, not a disease, and its relevance should be interpreted within the overall clinical context. Differentiation between the benign variety, in which no intervention is indicated, and the life-threatening form, in which immediate surgery is necessary, is extremely important and sometimes challenging for the clinician. Radiologic study, mainly contrast-enhanced abdominal CT, usually assists the diagnosis. As a rule, bowel biopsies are not indicated in this benign pneumoperitoneum, although ischemic necrosis of the bowel wall due to vasculitis or thrombosis due to antiphospholipid antibodies (aPL) has been reported in SLE patients [17]. After excluding life-threatening illnesses such as bowel necrosis, perforation, and infections, patients whose symptoms are caused by the cysts themselves can be treated with oxygen or antibiotics. Because reports of pneumatosis cystoides intestinalis treatment are at best anecdotal, the decision to treat and the treatment chosen should be carefully balanced against the risks. In the absence of sepsis and peritonitis, treatment remains highly conservative [18]. Physicians should bear in mind the possibility that enteritis due to cytomegalovirus or Salmonella spp. infection may be the cause of the abdominal pain and diarrhea in immunocompromised lupus patients. Nearly 20% of patients with Salmonella bacteremia have underlying lupus disease.

4. MAIN IDENTIFIABLE LUPUS-RELATED GASTROINTESTINAL SYNDROMES 4.1 Lupus Mesenteric Vasculitis Lupus mesenteric vasculitis (LMV) is the main cause of acute abdominal pain and one of the most serious complications in SLE patients [9,19]. Acute, severe, and diffuse abdominal pain with a sudden onset is the clinical hallmark of the syndrome. In addition to abdominal pain, there is usually evidence of active disease in other organs, fever, acute-phase proteins elevation, and a high SLEDAI score. Occult blood in stool or even frank GI hemorrhage is also reported. Although the pathophysiology of LMV in these patients is not well defined, it seems that lupus cystitis, whether symptomatic or not, occurs simultaneously with LMV, perhaps due to immune complexemediated abdominal vasculitis. Data from a large study performed in China have suggested that leukopenia, hypoalbuminemia, and elevated serum amylase are

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negative prognostic factors in LMV, whereas cyclophosphamide therapy is associated with a better prognosis [20]. The small mesenteric vessels are usually affected, and pathology findings include both vasculitis and thrombosis, which would probably be related to the presence of aPL. The diagnosis is usually made on clinical criteria due to the difficulty in obtaining bowel specimens for pathology analysis. LMV is generally accompanied by bowel ischemia, which can lead to perforation and hemorrhage, with an associated mortality rate of almost 50%. Abdominal CT is extremely useful for establishing a prompt diagnosis, as it enables reliable visualization of the vasculature and can depict the bowel dilation, focal or diffuse bowel thickening with bowel wall enhancement (target sign), mesenteric edema (comb sign), and ascites commonly seen in this condition [19]. A clue to the diagnosis of LMV is involvement of several different vessels simultaneously. The most frequently affected anatomical structures are the jejunum and ileum, followed by the duodenum. Rectal involvement is fairly uncommon, even though this area is well supplied with blood. Improvement after intravenous glucocorticoid therapy (prednisolone pulses of 1 g/day for 3 days) may favor the diagnosis of reversible ischemic bowel disease caused by intestinal vasculitis. A differential diagnosis with inflammatory bowel disease is sometimes required. Glucocorticoids remain the therapy of choice and can be combined with immunosuppressive agents such as cyclophosphamide. Surgery is recommended when the patient’s general condition deteriorates [19,21].

4.2 Intestinal Pseudoobstruction CIPO is a rare, severe, and poorly understood GI complication of SLE. It has been defined as the presence of clinical features of intestinal obstruction without an identifiable organic obstructive lesion [22]. CIPO reflects a dysfunction of the visceral smooth muscle or the visceral autonomic nervous system. Ureterohydronephrosis and biliary tract abnormalities have been reported in association with CIPO, which indicate the existence of a smooth muscle motility problem [23,24] (Figs. 11.1 and 11.2). Interstitial cystitis resulting from immune complex deposition in the vessels of the bladder walls is present in one-third of cases. Nearly half the patients described are of Asian origin [24,25], which implies a genetic component, although studies to identify a specific related human leukocyte antigen have not been carried out. The clinical presentation is subacute, with mild abdominal pain and abdominal distension accompanied by very sluggish or absent peristalsis. Rebound tenderness is uncommon. CIPO can be the first manifestation of SLE, but it usually develops as a GI complication appearing during the course of the disease. Mortality is not related to CIPO itself, but instead to sepsis related to immunosuppressive treatment or to involvement of other major organs attributable to SLE. Most patients have a fluctuating course, with recurrent

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FIGURE 11.1 Abdominal magnetic resonance imaging with dilated urinary pelvicalyceal system and bilateral ureterohydronephrosis.

FIGURE 11.2 Magnetic resonance cholangiopancreatography showing dilatation of the extrahepatic common biliary tract and the pancreatic duct without extrinsic or intrinsic obstruction.

clinical relapses. The small bowel is affected more often than the large bowel [24,26]. Radiological examination, mainly ultrasonography and contrast-enhanced abdominal CT, often shows bilateral ureteral dilatation and decreased capacity of the urinary bladder. Chronic interstitial cystitis, a condition associated

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with immune complex deposition and a well-recognized complication of SLE, has been documented in some patients with CIPO [25e27]. The clinically suspected diagnosis is typically confirmed by antroduodenal manometry, which usually shows esophageal aperistalsis and intestinal hypomotility, which may be neurogenic or myogenic. Immune complexemediated vasculitis or a common autoantibody against the enteric nervous system or smooth muscle may be responsible for the symptoms of CIPO. Serositis, vasculitis, and bowel wall fibrosis are occasionally found on histopathological study. No specific autoantibodies have been consistently associated with CIPO, but most patients test positive to antinuclear antibodies and anti-Ro antibodies and have serology findings suggestive of active disease [22,25]. Antibodies against proliferating cell nuclear antigen have been reported in two lupus patients with chronic CIPO [28], although the clinical value of this finding is uncertain. The therapy of choice for CIPO in SLE is high doses of intravenous prednisone. Other immunosuppressive agents (e.g., azathioprine, cyclosporine A, and cyclophosphamide) have been successfully used as the initial treatment and as maintenance therapy in prednisone nonresponders. Broad-spectrum antibiotics, prescribed to decrease bacterial overgrowth, and promotility agents such as erythromycin are usually effective when combined with the immunosuppressive regimen. Octreotide, a long-acting somatostatin analog, and rituximab, an anti-CD20 monoclonal antibody, have been used successfully in isolated cases and may prove useful for refractory or severely ill patients. Early recognition of CIPO is important because it is potentially reversible when treated with immunosuppressive agents. Surgery should be avoided whenever possible.

4.3 Protein-Losing Enteropathy Lupus proteinelosing enteropathy (LUPLE) is a clinical syndrome characterized by hypoalbuminemia due to protein loss from the GI tract in the absence of significant loss from the kidneys, reduced protein intake, malnutrition, or severe liver disease [4]. Thus the diagnosis of LUPLE relies mainly on exclusion of other conditions. Nonetheless, the diagnosis should not be considered definite, because several GI abnormalities, such as intestinal lymphoma, lymphatic obstruction, lymphangiectasia, and malabsorption, can be responsible for a loss of proteins. The main symptoms of LUPLE are generalized edema, abdominal pain, and severe diarrhea. This disorder is a well-recognized, but uncommon, manifestation of SLE and can be the initial symptom of the disease. Moreover, as CIPO is also more frequent in Asian patients, specific genetic or environmental factors may play a role [29]. The pathogenesis of LUPLE is uncertain. Mesenteric vasculitis, which has occasionally been found in mucosal biopsies, may be a likely mechanism. Although no specific autoantibodies have been

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associated with this GI manifestation, it seems that an increase in mucosal capillary permeability as a result of complement deposition or cytokinemediated damage may be implicated in the pathogenesis [30]. The diagnosis of LUPLE should be confirmed by complementary examinations. Technetium 99melabeled human serum albumin scintigraphy is the criterion standard quantitative evaluation, and the alpha-1-antitrypsin stool test can be of value in the diagnosis. Other examinations such as endoscopy, barium studies, abdominal CT scanning, or the D-xylose absorption test may also be needed. Most LUPLE patients respond well to corticosteroid therapy, although intravenous pulse cyclophosphamide may be necessary in refractory cases. In one study, the combination of prednisolone and azathioprine proved effective and well tolerated for treating LUPLE in SLE patients [31]. A systematic review including 112 LUPLE patients has provided data that concur with most of the aforementioned concepts [32].

5. LUPUS-ASSOCIATED PANCREATITIS Pancreatitis is a rare complication of SLE. In the general population, choledocholithiasis, alcohol intake, and certain drugs are common causes of pancreatitis. However, some lupus patients develop pancreatitis of uncertain origin, which has been attributed to the disease itself. In the clinical approach to a patient with SLE-associated pancreatitis, the first step is to rule out the common causes, which can explain half the cases. The relationship between azathioprine and corticosteroids, which can cause drug-induced pancreatitis, is difficult to prove and remains elusive [33]. Although pancreatitis can be the presenting symptom of SLE [34], it is usually a complication of the disease and mainly related to SLE activity. The etiology is unknown, but several causes have been suggested, such as an autoimmune origin, vasculitis, aPL-related thrombosis, or exocrinopathy when sicca syndrome accompanies SLE. Autoimmune pancreatitis related to hyper-IgG4 syndrome has also been reported in lupus patients [35]. The usual clinical manifestations are seendsevere abdominal pain, nausea, and vomitingdbut mortality seems higher than in non-SLEeassociated pancreatitis [33]. Pancreatitis seems to be more common and severe in pediatric-onset SLE, and mortality is higher, likely in relation to a greater disease activity [36,37]. Steroid therapy combined with supportive measures seems to improve the prognosis of these patients.

6. OTHER SYSTEMIC LUPUS ERYTHEMATOSUSeRELATED GASTROINTESTINAL PROBLEMS Adult celiac disease, a chronic GI disorder characterized by mucosal atrophy due to gluten intolerance, has been associated with some autoimmune disorders, including SLE [38]. Antietissue transglutaminase antibodies are a

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serological hallmark of the disease. Although cases of SLE associated with Crohn disease are rare, the coexistence of these two diseases represents a conundrum for the treating clinician who may miss the Crohn disease diagnosis and fail to implement adequate therapy when needed [39]. Eosinophilic GI diseases, characterized by an inappropriate accumulation of eosinophils within the GI tract, have been related to allergic conditions and parasitic infections. However, as eosinophils act as modulators of the GI immune response, eosinophilic infiltration of the GI tract is also seen in connective tissue diseases, especially SLE [40]. It is important for clinicians to be aware of these associations in lupus patients with GI manifestations.

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