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Gastrointestinal involvement in systemic lupus erythematosus: A systematic review

Introduction Gastrointestinal involvement is a common complain observed in 40–60% of systemic lupus erythematosus (SLE) patients. We performed a systematic review of clinically severe and potential life-threatening gastrointestinal manifestations and discuss clinical presentation, pathogenesis and treatment. Methods We performed a literature search in English literature using PubMed and Embase from 2000 to December 2020. The following MeSH terms: systemic lupus erythematosus, protein-losing enteropathy, ascites, pancreatitis, vasculitis, intestinal vasculitis, enteritis and diarrhea published in the English literature. Results We identified 141 studies (case reports, case series and cohort studies). The most frequent presenting symptoms are acute abdominal pain, nausea, and vomiting. Many of the manifestations were associated with disease activity. Histological features are rarely available, but both vasculitis and thrombosis have been described. There is no treatment guideline. The majority of patients were treated with corticosteroids and the most common immunososupressant were azathioprine, cyclophosphamide and mycophenolate. Conclusion Vasculitis and thrombosis may be responsible for severe life-threatening manifestations such as pancreatitis, protein loosing gastroenteritis, acalculous cholecistyitis and enteritis.


Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease with systemic inflammatory manifestations. Skin, kidney, central nervous system involvement, in addition to hematological abnormalities are most frequently observed [1].
Gastrointestinal involvement is a common complain observed in 40-60% of SLE patients [2]. A clinically recognized gastrointestinal manifestations have been described in 8-10% of patients [2,3]. Autopsy studies, on the other hand, report findings of gastrointestinal involvement in 60-70% of patients, suggesting that subclinical or unrecognized involvement is common [3].
Most gastrointestinal manifestations are usually mild [4]. Vasculitis and thrombosis may be responsible for life-threatening manifestations, leading to ischemia, perforation and infarction if not early diagnosed and adequately treated [5].
In this article we performed a systematic review of clinically severe and potential life-threatening gastrointestinal manifestations and discuss clinical presentation, pathogenesis and treatment.

Methods
We performed a systematic review of the literature and limited our search to articles published in the English literature from January 2000 to December 2020. The search of relevant references for the exploration of the electronic database in PubMed and Embase using the following MeSH terms: systemic lupus erythematosus, protein-losing enteropathy, ascites, pancreatitis, vasculitis, intestinal vasculitis, enteritis and diarrhea. The articles have been selected when presented this terms in Title/ Summary. Bibliographies of articles were reviewed for additional literature not identified through the PubMed and Embase search.
An evaluation of the studies was made using as inclusion criteria: 1. Patients with manifestations not due to disease activity or other connective tissue disease knowingly responsible for gastrointestinal involvement were excluded from the analyses; 3. Articles using animal models; 4. Studies containing overlapping or insufficient data.
At the end of the analysis, 141 relevant articles were included in this study and the PRISM flowchart is shown in Fig. 1.
In this review we did include only pancreatitis associated with SLE and excluded reports due to infections or mechanical causes. Most reported considered pancreatitis secondary to disease activity and treatment was based on prednisone [oral or intravenous] [15,17-20,23-32, 36-39,41-50,52,55-59].
Concomitant antiphospholipid antibodies (aPL) was identified in the minority of the cases [33], however most studies did not report on aPL positivity.
In a retrospective case-control study the odds of an SLE patient with anti-SSA positivity developing protein losing enteropathy was 3 times higher than an SLE patient who were anti-SSA-negative [96].
In addition, the best combination of findings predictive of protein losing enteropathy were the simultaneous detection of serum albumin (<22 g/l) and 24-h urine protein levels (<0.8 g/24 h), with a sensitivity of 0.818 and specificity of 0.989 [96]. With adequate treatment, serum albumin is the first parameter to improve, followed by serum complement C3 levels [96].
Additional treatment with octreotide [71,75] or ingestion of medium chain triglyceride (MCT) diet [75,85] may also be beneficial in this setting. Prognosis is generally good with full recovery; mortality is infrequently reported [21,.

Vasculitis
Vasculitis was described affecting the colon and/or the small bowel [19,40,46,.
Marked ascites has also been attributed to chronic lupus peritonitis, characterized by the insidious onset of massive, painless ascites, and found to be unrelated to disease activity [3]. In SLE patients, ascites and/or effusions are more frequently a complication of nephrotic syndrome rather than SLE peritonitis [5].

Discussion
The association of SLE with gastrointestinal autoimmune diseases is common, however mostly mild. Although severe gastrointestinal manifestations are uncommon, they are potentially life-threatening and have to be diagnosed timely to allow adequate treatment [5].
This hypothesis is further corroborated with the improvement or resolution with corticosteroid or other immunosuppressant use. In a few cases associations with aPL have been made and thrombosis as etiology cannot be excluded, however it is important to remember that we included only studies with pancreatitis due to SLE and other causes such as mechanical, infections (e.g CMV) and drug related (corticosteroid, azathioprine) have to be always excluded [7,16].
Outcome of pancreatitis is difficult to determine due to many case reports that may have publication bias. Most studies confirm that it is a life-threatening manifestation. In a literature review, corticosteroids were shown to decrease mortality [14].
Cohort studies show a higher frequency of chronic pancreatitis and complications. The overall mortality of pancreatitis in SLE is around 30% associated with other features of active SLE (macrophage activation syndrome, central nervous system manifestations), hypocalcemia, and pancreatic complications [18].
Comparing pancreatitis in childhood onset to adult onset SLE, the first group presents a higher prevalence, a higher disease activity score, more complications and greater mortality rate [17]. We previously reported a case series of acute pancreatitis (AP) and macrophage activation syndrome (MAS) in childhood (cSLE) patients [52].
Protein-losing gastroenteropathy is a clinical syndrome suspected in the presence of hypoalbuminaemia without significant proteinuria, severe liver disease, malabsorption, or poor oral intake [5,60-64,66-71, 74-86,88-99,103]. Protein-loss through the intestinal tract is usually diagnosed in an advanced stage with varying degree of edema and less commonly with initially symptoms of diarrhea or abdominal pain [88]. Hypoalbuminemia is the characteristic laboratorial finding, however serum cholesterol may be elevated, and lymphatic leakage may result in hypoglobulinemia, lymphopenia and steatorrhea [88].
Diagnosis can be made by dosage of fecal alpha-1 antitrypsin, a serum protein that is not digested in the gastrointestinal tract and is excreted mostly intact in stool but radioisotopic tests are usually more specific and sensitive [100]. Although α1-antitrypsin clearance is a reliable and easy test, it cannot detect the location of the leakage and results can be influenced by diarrhea or gastrointestinal hemorrhage [101]. False positives of 99 mTc HSA may result from active gastrointestinal bleeding and in vivo breakdown of 99 mTc HSA yielding free pertechnetate from radiolabeling [99,103].
Several mechanisms may underlie the pathogenesis of protein loosing enteropathy in SLE, including intravascular activation and conversion of complement, non-necrotizing vasculitis, acquired lymphangiectasia and increased microvascular/endothelial permeability [64,84].
Literature review has shown response to corticosteroid and other immunosupressants. Beneficial role of octreotide and microcomplement consumption test (MCT) has also been described [71,75,85]. Octreotide is potentially able to reduce microvascular intestinal blood flow, therefore decreasing local lymph formation and lymphatic flow. In addition, octreotide binds to somatostatin receptor SST2RA and exerts an immunomodulatory action [75]. MCT may be beneficially in protein-losing enteropathy because they are better absorbed than long chain fatty acids and they are transported by portal blood to the liver bypassing the lymphatic system [75].
There are only few reports of acalculous cholecystitis in SLE, making estimate prevalence difficult. It is a rare manifestation and usually associated with active SLE features. Histopathology varies from medium-size vasculitis to thrombotic microangiopathy associated with aPL in some articles, as written in the results. Corticosteroid and immunosuppressants have been used, but may not avoid cholecystectomy in all.
A number of terms have been used to describe vasculitis in the gastrointestinal tract including lupus mesenteric vasculitis, mesenteric arteritis, lupus enteritis, lupus arteritis, lupus vasculitis, gastrointestinal vasculitis, intra-abdominal vasculitis and acute gastrointestinal syndrome [5]. Although the underlying lesion in most cases of gastrointestinal (GI) vasculitis in SLE is a small vessel arteritis or venulitis, vasculitis in biopsy studies is not found in all cases [135].
Lupus vasculitis generally presents with abdominal pain, and other signs of abdominal obstruction (distention, nausea and vomiting and reduced bowel sounds) in the setting of SLE activity [19,117,120-124, 127,131-134,138].
Marked ascites has been attributed to chronic lupus peritonitis, characterized by the insidious onset of massive, painless ascites and unrelated to disease activity [72].
Most studies are case reports and case series, making adequate prevalence of this manifestation difficult. Large studies report an overall prevalence of enteritis in SLE patients ranging from 0.2 to 9.7% and from 29% to 65% in patients who had acute abdominal pain [121,133,135,136]. Imaging findings and biopsy help adequate diagnosis in most patients [115,[118][119][120][122][123][124]126,128,130,134].
Although the above reviewed gastrointestinal manifestations are rare they have a potential for severe complications and even death. A high index of suspicions is necessary to differentiate disease activity from infection or other secondary causes. Corticosteroids (oral or intravenous) is still the first line treatment. Responses to cyclophosphamide, cyclosporine A, azathioprine, mycophenolate, methotrexate, IVIg, rituximab and anti-TNFα have been described, however no randomized control trial exist up to date to determine the most adequate immunosuppressant medication.