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Gastrointestinal Manifestations of Rheumatological Diseases

Kröner, Paul T. MD, MSc1; Tolaymat, Omar A. MD2; Bowman, Andrew W. MD, PhD3; Abril, Andy MD2; Lacy, Brian E. MD, PhD, FACG1

American Journal of Gastroenterology: September 2019 - Volume 114 - Issue 9 - p 1441–1454
doi: 10.14309/ajg.0000000000000260
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Rheumatological diseases (RDs) represent a diverse group of diseases that are inherited or related to environmental factors. RDs frequently affect the gastrointestinal (GI) tract, and gastroenterologists are often asked to evaluate patients with symptoms thought to represent an underlying or coexisting RD. GI manifestations of RDs vary based on the organ involved as well as the extent and duration of involvement. Although most manifestations of RD are nonspecific and not life-threatening, the chronicity and severity of symptoms can be debilitating and may lead to serious injury. This narrative review discusses the most common RD encountered by gastroenterologists: systemic lupus erythematosus, systemic sclerosis (scleroderma), dermatomyositis/polymyositis, rheumatoid arthritis, Sjögren syndrome, overlap syndromes, mixed connective tissue disease, Ehlers-Danlos syndromes, and other vasculitides. Each section begins with a brief overview of the condition, followed by a discussion of the etiopathophysiology, physical examination findings, GI manifestations, diagnostic tools (i.e., serologic, imaging, endoscopic, and functional), and treatment options.

1Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA;

2Division of Rheumatology, Mayo Clinic, Jacksonville, Florida, USA;

3Division of Radiology, Mayo Clinic, Jacksonville, Florida, USA.

Correspondence: Paul T. Kröner, MD, MSc. E-mail: kroner.paul@mayo.edu.

Received August 14, 2018

Accepted May 12, 2019

Online date: June 12, 2019

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INTRODUCTION

Rheumatological diseases (RDs) may affect any body organ system. For a host of gastrointestinal (GI) disorders, a careful history and physical examination, rather than a novel imaging or endoscopic procedure, remains the cornerstone of making an accurate diagnosis. This is especially true for RDs and their effects on the GI tract. These disorders frequently manifest with nonspecific symptoms of abdominal pain, bloating, dyspepsia, nausea, and diarrhea. Diagnosing RD involvement of the GI tract can be difficult because symptoms are often insidious, can evolve slowly, and may wax and wane in intensity.

A basic understanding of RDs, especially the most common ones and their influence on the GI tract is important for clinicians because, for many patients with RDs, the first reported symptom of a RD emanates from the GI tract. Gastroenterologists can, in many cases, make the initial diagnosis of a RD, generate an appropriate referral to a rheumatologist, answer patients' questions, and initiate appropriate and timely treatment.

In this narrative review, we will describe the most common RDs, emphasizing their impact on the GI tract. More specifically, we will discuss the epidemiology; etiopathophysiology; diagnosis and treatment of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory myopathies, Sjögren syndrome (SS), rheumatoid arthritis (RA), Ehlers-Danlos syndromes (EDSs); and other vasculitides. In the interest of space, we will not address fibromyalgia because this is a topic unto itself. Unfortunately, the lack of randomized controlled trials in patients with RDs using GI symptoms as a primary outcome precludes performing a proper systematic analysis.

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SYSTEMIC LUPUS ERYTHEMATOSUS

SLE can potentially affect nearly every organ system, although it has a predilection for the skin, joints, kidneys, and serous membranes. Approximately 50% of patients have GI involvement (1). The prevalence of SLE is 20–150 cases per 100,000; it is higher in African Americans (406 per 100,000) and Hispanics compared with Caucasians (2,3). SLE is 3–15 times more common in female population. Genetic, immunologic, and hormonal factors play a role in sustained autoantibody production and loss of immune tolerance in susceptible individuals; environmental factors may trigger disease activity. Defective clearance of immune complexes, debris from apoptotic cells, and abnormalities in interferon production lead to tissue injury (4,5). No specific autoantibody is associated with GI involvement (6).

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GI manifestations

Symptoms are nonspecific (e.g., abdominal pain, nausea, vomiting, anorexia, and diarrhea) and range from mild to life-threatening. Symptoms may signify autoimmune-mediated inflammation, bowel vasculitis, decreased oncotic pressure from hypoalbuminemia, or other causes. Symptoms in the pediatric population are more likely related to vasculitis, peritonitis, ascites, or pancreatitis (7).

GI symptoms may be associated with multiorgan involvement (Table 1). The spectrum of involvement varies from mild inflammation with bowel edema and stricturing to life-threatening complications (e.g., ischemia, infarction, and perforation). The most common GI physical examination finding in up to 50% of patients are painless oral ulcerations, usually localized to the hard palate (8).

Table 1

Table 1

Esophageal dysmotility, dyspepsia, gastric ulcerations, intestinal pseudo-obstruction, serositis, ascites, and peritonitis are less common manifestations. Esophageal dysmotility presenting as dysphagia or pyrosis may suggest a coexisting RD such as SSc, Sjogren syndrome, or polymyositis (PM).

Intestinal pseudo-obstruction can be the presenting manifestation of SLE (9,10). Lupus enteritis, a small bowel vasculitis, either inflammatory or thrombotic, occurs in up to 9.7% of patients with SLE and accounts for up to 65% of cases of acute abdomen in patients with SLE (11).

Microvascular and endothelial permeability alterations from vasculitis may cause protein-losing enteropathy (PLE). Excessive GI tract protein loss leads to hypoalbuminemia, hyperlipidemia, edema, ascites, and hypocomplementemia (12,13). Measuring GI loss of intravenously administered labeled albumin can support the diagnosis of PLE.

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Diagnosis

Serologic testing for SLE is depicted in Table 2. Computed tomography (CT) imaging may demonstrate thickening and edema of the bowel wall. Two radiologic signs are consistent with lupus enteritis: the “double-halo” (“target sign”) is a marker of abnormal bowel wall submucosal thickening, whereas the “comb sign” correlates with mesenteric vessel prominence (Figure 1a,b, respectively). Involvement is usually segmental or multifocal, rather than in a vascular territory from thromboembolic events (14). Concomitant findings may include bowel dilatation, pneumatosis, mesenteric venous gas, and ascites. Because SLE affects mostly medium-low caliber vessels, a mesenteric angiogram is usually unrevealing (13). Barium-based studies may reveal thumb-printing, another sign of abnormal submucosal thickening.

Table 2

Table 2

Figure 1

Figure 1

Dysmotility can be found in any esophageal segment, with findings of lower esophageal aperistalsis and lower esophageal sphincter (LES) hypotonia considered classic. Esophagogastroduodenoscopy may reveal mucosal punched-out ulcers or findings suggestive of ischemia. Colonoscopy may rarely precipitate ischemic colitis or perforation (15). Superficial biopsies are usually nonspecific because affected submucosal vessels are beyond the reach of regular biopsy forceps (7,11,12,16).

Acute pancreatitis occurs in 0.7%–4% as a disease complication or secondary to corticosteroids and azathioprine, with mortality as high as 20% (17,18). The presence of anti-Ro antibodies is associated with an earlier onset of acute pancreatitis (19).

The ascitic fluid usually reveals a serum ascites albumin gradient of <1.1 g/dL, hypocomplementemia, and positive antinuclear antibody (ANA) and double-stranded DNA antibodies (20).

Elevated liver chemistries suggest hepatic involvement, which is thought to be a form of autoimmune hepatitis (21).

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Treatment

The mainstay of treatment is systemic corticosteroids. Cyclophosphamide is reserved for steroid-refractory cases (11,14). PLE may require the use of somatostatin analogues or immunomodulatory therapy (e.g., azathioprine, tacrolimus, and cyclophosphamide), leading to remission in most cases (16,22,23).

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SYSTEMIC SCLEROSIS (SCLERODERMA)

SSc is a chronic, progressive RD that can affect multiple organ systems. The incidence is 5.6 cases per 100,000 person-years, with a prevalence of approximately 20 cases per 100,000 persons (24). Women are more likely to be affected; African-Americans have a higher incidence and more severe disease (25,26). Genetic susceptibility, environmental factors, endothelial cell changes, fibroblast dysfunction, and heightened immune responses trigger neurodegenerative and myopathic processes leading to progressive muscular atrophy and fibrosis (27). Connective tissue inflammatory infiltrates, excessive collagen deposition, smooth muscle atrophy, and vasculopathy characterize SSc (28).

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GI manifestations

Up to 90% of patients have GI manifestations, which may occur at any site of the GI tract. In contrast, half of the patients with juvenile scleroderma manifest with GI complaints, which essentially mirrors adult symptomatology (29). Microstomia due to perioral skin thickening (Figure 2a), thickened sublingual frenulum, xerostomia, and periodontal disease with tooth loss may be evident (30). Hoarseness and cough may arise as manifestations of gastroesophageal reflux disease (GERD). Telangiectasias can be found on the hands, lips, and oral cavity.

Figure 2

Figure 2

The esophagus is involved in up to 90% of patients (31). Symptoms include heartburn, dysphagia, odynophagia, and regurgitation. Fibrosis of esophageal smooth muscle leads to reduced peristalsis and decreased LES resting pressure (32). Untreated reflux increases the risk of esophagitis, strictures, intestinal metaplasia, and esophageal adenocarcinoma. Candida esophagitis may develop because of impaired peristalsis, dilation, immunosuppressive therapy, or chronic proton pump inhibitor (PPI) use (33).

Delayed gastric emptying may cause symptoms of abdominal pain, nausea, vomiting, and early satiety, which is present in up to 50% of patients (34).

Small-intestinal dysmotility and diverticuli from smooth muscle fibrosis, as well as recurrent antibiotic and PPI use, can lead to small-intestinal bacterial overgrowth (SIBO), which occurs in up to 43% of patients with SSc (35). Abdominal pain, distension, nausea, vomiting, and constipation may arise secondary to chronic intestinal pseudo-obstruction (CIPO) or pneumatosis cystoides intestinalis (PCI). Intestinal permeability abnormalities may cause PLE, vitamin D/B12 deficiencies, and malabsorption leading to malnutrition (36). Intestinal involvement in SSc has been established to be a significant predictor of mortality, with a 2-year mortality odds ratio of 2.14 compared with patients with no GI involvement (defined as: dysphagia; pyrosis; esophageal, duodenal or small intestinal dysmotility; SIBO requiring oral antibiotics; gastric antral vascular ectasia (GAVE); colonic diverticulosis; or malabsorption) (37).

Colonic involvement may lead to abdominal pain, distension, diarrhea, constipation, incontinence, and/or tenesmus. Hematochezia may occur secondary to diverticuli or bleeding telangectasias (38). Complications include stricturing, volvulus, fecal impaction, rectal prolapse, CIPO, PCI, and perforation (39,40).

Deposition of connective tissue on the internal anal sphincter (IAS) may cause rectal prolapse, diarrhea, or fecal incontinence, present in up to 70% of patients (41).

Hepatobiliary involvement is uncommon. The association with primary biliary cholangitis (PBC) is well-documented, with an estimated 15% having SSc. Patients usually display nonspecific elevation of liver chemistry tests, with positive anti-centromere, anti-mitochondrial, anti-sp100, and anti-Beta 2 glycoprotein antibodies (38).

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Diagnosis

There are 3 disease hallmarks: fibrosis, the presence of ANA, and vasculopathy. Serologic testing and physical examination findings are described in Table 2. Anemia can develop because of chronic inflammation, GI bleeding, malabsorption, or hemolysis.

Esophageal pH monitoring is abnormal in more than 85% of patients. High-resolution esophageal manometry (HREM) findings include aperistalsis, low-amplitude contractions in the distal two-thirds of the esophageal body, and reduced LES pressure (Figure 3). Incomplete bolus clearance may be evident on impedance testing (42).

Figure 3

Figure 3

Upper endoscopy may reveal severe erosive esophagitis, stricturing disease, Candida esophagitis, or Barrett's esophagus. Given the association of Barrett's esophagus with development of adenocarcinoma, periodic screening with upper endoscopy and mucosal biopsies is warranted in all patients (43). Esophagograms can be used to identify a stricture, a patulous gastroesophageal junction, or esophageal dilation. CT may demonstrate distal esophageal dilation, intraluminal air, or mediastinal lymphadenopathy (44).

A 4-hour technetium-99m sulfur colloid gastric emptying study can reveal delayed gastric emptying (45). GAVE secondary to vasculopathy occurs in 5% of patients and may manifest as iron deficiency anemia or upper GI bleeding (46). Gastric endosonography may reveal submucosal and muscularis thickening.

Small intestinal manometry may demonstrate low-amplitude contractions, absent migrating motor complexes, a prolonged migrating motor complex cycle, or phase III hypoactivity (47). Abdominal x-rays may reveal dilated bowel loops; the small bowel can appear dilated and somewhat featureless on barium studies. Dilation of the duodenum and jejunum, with tightly packed valvulae conniventes creating the characteristic “hide-bound” appearance, are frequently seen in advanced disease (Figure 4) (48,49). Air within the bowel wall is evident in PCI, and pneumoperitoneum is found in 87% of these patients (50).

Figure 4

Figure 4

Large-mouthed jejunal and colonic diverticula, CIPO, and rarely, PCI may occur (Figures 5 and 6, respectively) (51). Plain films may reveal colonic dilation or stool burden. Barium enemas may display diverticuli in the antimesenteric border of the transverse and descending colon, colonic dilation, loss of haustrae, and significant postevacuation residuals that may become impacted and lead to perforation.

Figure 5

Figure 5

Figure 6

Figure 6

On anorectal manometry, the IAS (smooth muscle) displays decreased resting tone, although the external anal sphincter (skeletal muscle) is not affected. Rectal compliance is reduced. The rectoanal inhibitory reflex may also be absent, potentially reflecting neuropathy (52). Magnetic resonance imaging (MRI) of the anus assists in delineating the IAS and may display muscular atrophy (53). Endoanal ultrasonography may demonstrate a thin and atrophic IAS. Cases of rectal vascular ectasia have been reported (54).

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Treatment

Treatment requires a multidisciplinary approach depending on the organ system involved, with the aim of decreasing the frequency and intensity of symptoms, as well as delaying end-organ damage progression. The anti-CD20 agent rituximab has shown to limit the severity of skin sclerosis, pruritus, calcinosis, and arthritis (55). Another promising agent, tocilizumab, was linked to histologic thinning of collagen fiber bundles in 2 patients with SSc (56). Currently, a phase 3 trial evaluating its use is ongoing and is expected to conclude soon (ClinicalTrials.gov identifier: NCT02453256).

In addition to lifestyle modifications, current evidence supports long-term daily single or double dose PPI therapy in all patients with SSc because GERD is associated with fibrosis progression. Combination therapy (e.g., H2-receptor antagonists, sucralfate, baclofen, and prokinetics) is typically reserved for refractory cases, although no randomized clinical trials currently support their use (45,57). Antireflux surgery has also been described in patients with SSc and refractory GERD with symptomatic improvement, although this option is highly invasive and has significant associated morbidity, thus mandating a careful selection process (58).

Maintaining adequate hydration, avoiding fiber-rich foods, decreasing meal volume, and increasing meal frequency may improve symptoms of poor gastric motility. Antiemetics/prokinetics can be considered if conservative measures fail. Jejunostomy or parenteral nutrition is usually reserved for severely symptomatic or malnourished patients (38). Patients with GAVE may be treated conservatively with iron supplementation and regular monitoring. If conservative therapy is ineffective, endoscopic therapy with laser, argon plasma coagulation, or band ligation may be needed (59).

Patients with SIBO require antibiotics (e.g., rifaximin, amoxicillin, metronidazole, trimethoprim-sulfamethoxazole, and neomycin) that target both aerobes and anaerobes for 14 days (60). Recurrence occurs in up to 40% of patients and warrants re-treatment. Although prospective comparative trials are lacking, patients who receive antibiotics other than rifaximin as first-line therapy should be treated with a different regimen for the second course of therapy (61). Further recurrences are generally treated with cyclic antibiotic therapy, although randomized controlled trials supporting this regimen are lacking. Patients with persistent diarrhea may benefit from a low-fat diet, medium-chain triglyceride supplementation, lactose avoidance, bile acid sequestrants, or pancreatic enzymes (62).

Pseudo-obstruction is treated conservatively with bowel rest and supportive measures. Octreotide improves intestinal motility and can be administered subcutaneously on a monthly basis (63). Pyridostigmine has the potential to improve symptoms, although trial data are lacking. Probiotics may improve reflux, distension, and emotional symptomatology (64).

For the treatment of constipation, osmotic laxatives and adequate hydration promote colonic transit. Bulk-forming agents or diets high in fiber content should be avoided, as they may worsen bloating and possibly exacerbate diarrhea (65,66). Anecdotal experience with prokinetics has shown some degree of effectiveness in selected patients (67). Colonic pseudo-obstruction should be treated conservatively. If conservative measures fail, manual disimpaction, enemas, and even colonoscopic decompression may be warranted. Surgical treatment is reserved for severe complications such as megacolon, volvulus, strictures, and rectal prolapse.

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INFLAMMATORY MYOPATHIES

Dermatomyositis (DM) and PM are idiopathic inflammatory myopathies and have an incidence of 1.2–19 per million. The prevalence of PM is estimated at 35 per million, whereas the prevalence of DM ranges from 5 to 210 per million (68,69). DM/PM can affect both children and adults, with peak incidences in adolescence and late adulthood (mean age of 55 years). Women are more likely to be affected than men (70).

A maladaptive immune response is believed to play a key etiopathogenic role in both disorders. DM is characterized by type 1 interferon production, generation of autoantibodies, elevated levels of CD4(+) T-cells, a perivascular inflammatory infiltrate, and microvascular complement deposition (71–73). This leads to capillary injury that causes myofiber ischemia, necrosis, and perifascicular atrophy (74). PM is characterized by an antigen-driven inflammatory infiltrate of muscle fibers. CD8(+) T-cells invade muscle fibers and major histocompatibility 1 molecules are increased, leading to myocyte injury. The triggering event for complement deposition in DM and T-cell infiltration in PM is unknown (74,75).

Although PM affects muscles primarily, DM affects both muscle and skin, reflected by the characteristic skin findings discussed in Table 2 and depicted in Figure 7.

Figure 7

Figure 7

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GI manifestations

Over 50% of patients have GI involvement. Dysphagia, pyrosis, nasal regurgitation, and hoarseness due to weakness of the proximal esophageal skeletal muscles (oropharyngeal and cricopharyngeal) are common symptoms (76).

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Diagnosis

Proximal muscle weakness with muscle inflammation but without sensory involvement is the hallmark for both entities. Non-GI presenting features, physical examination findings, and serologic testing are presented in Table 2.

Tongue weakness or impaired soft palate motion may be evident on physical examination. Contrast swallow studies may display nasal reflux, airway aspiration, retained contrast in the hypopharynx, and prolonged transit time at the level of the pharynx (77). Esophageal and gastric emptying studies may demonstrate decreased transit time, reflecting smooth muscle involvement. Duodenal dilation (i.e., “megaduodenum”) and intestinal pseudo-obstruction are uncommon findings.

Upper endoscopy should be performed if symptoms of dysphagia are present. Acute or chronic esophagitis or strictures are common findings (78). The association between DM and colon cancer is well-established, although the yield of endoscopic screening in patients with these myopathies is low (79).

Manometric abnormalities may be more prevalent in patients with PM than DM. Findings include low-amplitude contractions in the body of the esophagus, failed peristalsis, and decreased upper esophageal sphincter pressure; these correlate poorly with symptoms (80).

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Treatment

Treatment depends on disease manifestation and severity (81,82). Dysphagia generally responds to systemic corticosteroids. Second-line therapy includes intravenous immunoglobulin and antitumor necrosis factor (TNF) agents, although randomized controlled trials are lacking (81,83).

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RHEUMATOID ARTHRITIS

RA develops because of autoantibody formation with subsequent synovial, perisynovial, and systemic inflammation. The prevalence is 0.5%–2% in adults, and the annual incidence is 5–50/100,000 persons, predominantly affecting the female population (84). In children, it is included in the systemic juvenile idiopathic arthritis (formerly juvenile RA) category, which encompasses all forms of arthritis lasting for at least 6 weeks before 16 years (85). Although mainly involving joints and interfering with patient functionality, the GI tract is also frequently involved.

The role of the microbiome in the pathogenesis of RA has received much scientific interest. There is an increasing body of evidence linking dysbiosis to autoimmunity because intestinal alterations may be found years before detectable joint inflammation (86). Interestingly, evidence that treated patients with RA display a partially restored microbiome further supports this hypothesis (87).

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GI manifestations

Symptoms may arise as a result of direct involvement by RA, or occur because of a secondary autoimmune process or even a treatment adverse reaction. Symptoms and severity also depend on the site of the GI tract involved and the degree of inflammation. Temporomandibular joint involvement may cause pain and impair mastication, whereas atlantoaxial subluxation may cause dysphagia and make upper endoscopy a high-risk procedure. Sicca symptoms and oral ulcers may occur from secondary SS and coexisting inflammatory bowel disease, respectively.

Dysphagia due to esophageal dysmotility (particularly in coexisting SS, amyloidosis, or cranial nerve compression in atlantoaxial subluxation), pyrosis, and esophagitis are present in up to one-third of patients (88). Chronic superficial and chronic atrophic gastritis has been described in up to 62.5% of gastric biopsy specimens of patients with RA (89). Atrophic gastritis causes hypochlorhydria or achlorhydria, which may lead to development of SIBO or pernicious anemia from impaired vitamin B12 absorption (90).

Rheumatoid vasculitis (RV), an immune complex-mediated small-sized and medium-sized vessel vasculitis, present in up to 5% of patients with RA, primarily affects skin and peripheral nervous system, and can affect the GI tract in up to 38% of patients (91).

Any segment of the GI tract can be involved, resulting in esophageal and gastric ulcers, intestinal bleeding, perforation, and appendicitis (92). Intrahepatic hemorrhage, pancreatic necrosis, and abdominal aneurysmal rupture have been reported in patients with RA and RV (93).

The occurrence of Crohn's disease and ulcerative colitis has also shown to be increased in patients with RA, suggesting overlapping pathogenic mechanisms (94). An association with celiac disease has also been suggested because of shared factors like dysbiosis and alterations in bowel permeability, resulting in activation of autoimmune pathways, although the subject remains highly debated (84). GI amyloidosis may also occur in up to 13% of patients with RA and can manifest as abdominal pain, nausea, GERD, GI bleeding, jaundice, or malabsorptive features like diarrhea, weight loss, and PLE (95).

Hepatosplenomegaly, fatty liver, hepatitis, cirrhosis, and resulting portal hypertension from juvenile RA or secondary amyloidosis involvement may also occur. Less than 1% of patients have the triad of splenomegaly, neutropenia, and RA (Felty syndrome). These patients tend to present with hepatosplenomegaly, portal hypertension, and more significant liver chemistry abnormalities.

Drug-induced liver injury from the multiple medications used may also occur (e.g., methotrexate, aspirin, and sulfapyridine), which may manifest as nonspecific symptoms of nausea, vomiting, or abdominal pain. For this reason, it is recommended that patients receiving methotrexate should undergo periodic monitoring of liver chemistry testing.

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Diagnosis

Serological testing for patients with suspected RA is depicted in Table 2. HREM may reveal lower amplitude pressure waves in the distal two-thirds of the esophagus, as well as decreased LES tone. Elevated gastrin or decreased vitamin B12 levels may reflect hypochlorhydria or achlorhydria in patients with atrophic gastritis (96).

Because the stomach and duodenum are frequently affected sites by amyloidosis, which may occur with RA, esophagogastroduodenoscopy may reveal tissue frailty, ulcerations, hematomas, or thickened, irregular mucosal protrusions (95). Upper endoscopy with biopsies, as well as rectal biopsies with Congo red staining, can assist in establishing the diagnosis.

Although bilirubin and transaminases are generally within normal range, alkaline phosphatase isoenzymes, 5'nucleotidase, gamma-glutamyl transferase, and lactate dehydrogenase may show elevations.

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Treatment

The mainstay treatment for RA GI manifestations is to control the disease activity. Medications include systemic corticosteroids, disease-modifying antirheumatic drugs (e.g., methotrexate, sulfasalazine), tofacitinib, biologic TNF inhibitors (TNFi; e.g., infliximab, adalimumab, etanercept), and non-TNF biologics (e.g., rituximab, tocilizumab). Health care providers should be aware that tocilizumab, tofacitinib, and systemic steroids have been linked to increased occurrence of intestinal perforation (97).

Given that RV is uncommon, no consensus exists on specific treatment. Although data supporting treatment with biologics is controversial, a regimen involving administration of cyclophosphamide and systemic steroids for severe manifestations is widely cited in the literature (98). Both TNF inhibitors and tocilizumab have evidence supporting their effectiveness in the treatment of amyloidosis (92).

Immunosuppressants are associated with increased risk of opportunistic infections that may affect the GI tract, such as mycobacteria, mycoses, herpes simplex, and cytomegalovirus. It must be noted that treatment with TNFi may exacerbate chronic hepatitis B virus (HBV); all patients with RA should be screened before considering treatment. Naturally, patients with RA considered for TNFi therapy who have active HBV infection should receive antiviral treatment.

Treatment targeting particular disease manifestations is otherwise supportive and includes nutritional therapy, vitamin supplementation, and addressing emerging infections related to the immune compromised state (93).

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SJOGREN SYNDROME

SS is a chronic autoimmune disorder characterized by a lymphocytic infiltrate of the exocrine glands. The prevalence is 20–100 per 100,000 people and the incidence is 5.8 per 100,000 (99,100). It affects more women than men, with a 9:1 ratio; the mean age at onset is 50–60 years (101). The etiopathogenesis involves genetic predisposition and environmental triggers that activate an autoantibody-mediated response in mucosal epithelial cells that lead to lymphocyte-mediated destruction of the salivary and lacrimal glands (101).

The classic symptoms of SS include dryness of the eyes and mouth, fatigue, and joint pain. Sjogren syndrome is classified as primary (if isolated or in association with thyroiditis or PBC) or secondary (in association with SLE, SSc, PM, or RA) (101).

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GI manifestations

The most common GI symptoms are xerostomia and dysphagia. Reduced saliva production is associated with dysgeusia, dental decay, and oropharyngeal candidiasis. Dysphagia is not associated with a specific motility disorder and occurs in 30%–80% of patients (102). Other forms of dysmotility may manifest as delayed gastric emptying. Dyspepsia may be secondary to gastritis with reduced acid production and the presence of antiparietal cell antibodies, and is not related to Helicobacter pylori status (101,103). The prevalence of celiac disease in this population is reported as 10-fold higher than the general population (104).

Chronic inflammation may lead to pancreatitis and pancreatic insufficiency, although steatorrhea is uncommon (105). Liver involvement ranges from mild elevation in liver chemistries to severe lymphocytic infiltration causing autoimmune hepatitis and PBC (106). Patients with hepatitis C virus co-infection may have accelerated liver injury (107).

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Diagnosis

The diagnosis is based on the symptoms described, which are highly nonspecific, in conjunction with the presence of anti-SS antibodies, lymphocytic sialadenitis on labial salivary gland biopsy, and/or an abnormal Schirmer test (a measure of tear production) (101,103). Serologic testing and physical examination findings are presented in Table 2.

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Treatment

Antimuscarinic agents (e.g., pilocarpine hydrochloride and cevimeline hydrochloride) improve symptoms of xerostomia and dry eyes. Initiating therapy at a low dose with gradual escalation minimizes side effects. Hydroxychloroquine, azathioprine, methotrexate, and mycophenolate have also been used to treat SS manifestations.

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OVERLAP SYNDROMES AND MIXED CONNECTIVE TISSUE DISEASE

Overlap syndromes are disorders that fulfill criteria for at least 2 major RD. Precise data for the epidemiology of these disorders is not available. The etiology is likely similar to the proposed causes for the individual disorders. The most common overlap syndromes include combinations of SSc with SS, DM or PM, RA, or SLE.

Mixed connective tissue disease (MCTD) is often thought of as an overlap syndrome. In this situation, patients have clinical features of 2 or more RDs, including SLE, PM, and SSc. Raynaud phenomenon commonly coexists in these patients.

The diagnosis of overlap syndrome rests on the criteria for the individual disorders (see sections above), whereas MCTD has defined criteria (Alarcón-Segovia criteria) consisting of a positive U1-ribonucleoprotein > 1:1,600 in combination with hand edema, synovitis, myositis, Raynaud phenomenon, and acrosclerosis. ANA may show a speckled pattern (108).

Dysphagia is the most common manifestation of MCTD. HREM may reveal upper esophageal sphincter hypotension, low-amplitude contractions or aperistalsis of the distal esophagus, and LES hypotonia. Secondary reflux disease and development of peptic strictures may ensue. In patients with associated SS, decreased saliva production contributes to dysphagia. Additional GI manifestations include motility-related complications such as pseudo-obstruction, PCI, malabsorption, diarrhea, and GI bleeding secondary to GAVE (109).

Diagnostic testing should be guided by the predominant symptoms or features of the conditions involved, as discussed previously.

Therapy for overlap syndrome and MCTD with GI features should be based on the patient's predominant disorder and symptomatology. Patients with overlap syndromes and MCTD generally respond well to systemic corticosteroids.

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EHLERS-DANLOS SYNDROME

EDS is a group of genetic connective tissue disorders that are characterized by joint and skin hypermobility and tissue fragility. Central to its pathogenesis are genetic mutations that cause defective collagen synthesis. The estimated prevalence is 1 in 5,000 persons (110).

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GI manifestations

GI symptoms may be present in up to 50% of patients and include abdominal pain (56%), IBS-like symptoms (up to 47%), nausea (42%), constipation (39%), vomiting (24%), diarrhea (21%), and dysphagia (11%) (111,112). Constipation is the most common GI symptom in the pediatric population. The high prevalence of these symptoms in the general population makes it difficult to confidently establish causation. Symptom expression depends on the type and severity of EDS. In 1 study, EDS has been linked with the presence of hiatal hernia, rectal evacuation disorders, and diverticulosis (113).

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Diagnosis

The diagnosis is established clinically by the Beighton criteria for joint hypermobility (110). Diagnostic testing may reveal important information in some EDS patients. Both delayed and early-accelerated gastric emptying has been reported (113). Colonic transit studies frequently reveal delayed transit times. On colonoscopy, diverticulosis is present in up to 10% of patients with EDS, which are believed to be due to a weakened bowel wall in the setting of impaired collagen synthesis. In patients with constipation, anorectal manometry may reveal a rectal evacuation disorder (113).

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Treatment

No disease-specific modifying intervention exists at present. A multidisciplinary care approach to address symptoms and potential complications is often necessary, involving cardiology, ophthalmology, spine care, and physical/occupational therapy. Consultations with a genetic counselor may be helpful; psychosocial support is frequently needed.

For GI manifestations of Ehlers-Danlos, supportive management is advised after conducting appropriate investigations to identify alternate causes of symptoms. Because patients with EDS may have tissue fragility, propensity for joint dislocations, temporomandibular joint dysfunction, and cervical spine instability, careful positioning at the time of endoscopic procedures should be exercised.

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OTHER VASCULITIDES

Immunoglobulin A vasculitis (formerly known as Henoch-Schönlein purpura)

Immunoglobulin A vasculitis (IgAV) is a systemic vasculitis that primarily affects children (over 90% of cases) and is characterized by the presence of palpable purpuric lesions (in the absence of thrombocytopenia or coagulopathy), arthropathy, renal involvement, and abdominal pain. In the Western world, the estimated peak incidence in the most affected age group (between 4 and 6 years of age) is 70 per 100,000 patients, and displays male predominance (114).

It is characterized by a leukocytoclastic vasculitis of small vessels resulting from increased immunoglobulin A production, inflammation, and immune activation. In the GI tract, it primarily affects the arterioles, venules, and capillaries. Several etiopathogenic factors have been proposed and include allergens, immunizations, medications, and infections (mainly group B streptococcus but also enteric pathogens like Campylobacter jejuni, H. pylori, Entamoeba histolytica, Yersinia, and Shigella).

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GI manifestations.

Cutaneous lesions typically precede the GI manifestations in patients with IgAV, although a subset of patients present with initial GI symptoms, which can make the diagnosis challenging. Up to 85% of these patients report abdominal symptoms, which range from diffuse colicky abdominal pain, nausea, and vomiting to intestinal obstruction and perforation (115). GI bleeding occurs in one-third of patients and may present as hematemesis, hematochezia, or melena. Essentially, any segment of the GI may be involved, although the small intestine is most frequently involved.

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Diagnosis.

The diagnosis of IgAV is clinical, requiring the presence of 2 of the 4 diagnostic criteria, which include age < 20 years, palpable purpura, acute abdominal pain, and granulocytes within the arteriolar or venule walls. Small bowel GI series may show submucosal edema, ulceration, and small-intestinal spasm. Transabdominal ultrasound may display evidence of intussusception, ascites, or bowel wall edema. Abdominal CT may display multifocal areas of bowel wall thickening, mesenteric edema, vascular engorgement, and nonspecific lymphadenopathy (116). Endoscopic findings consist of petechial lesions in the mucosa, which can progress to ecchymoses and hemorrhagic erosions and are mainly located in the duodenum (115).

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Treatment.

Symptomatic management and treatment of emerging complications remain the cornerstones of treatment because nearly all patients recover with no medical intervention. Patients with GI bleeding, severe abdominal pain, proteinuria as evidence of renal involvement, or who are unable to ambulate should be admitted to the hospital (117).

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Behçet disease

Behçet disease (BD) is a systemic vessel vasculitis that can affect blood vessels of all sizes. Oral and genital ulcers are the hallmark of the disease; however, the skin, joints, and the GI tract may also be affected. Although the prevalence is highest in the Middle East and East Asia (up to 370 cases per 100,000), it is lowest in North America and Europe (6 cases per 100,000) (118).

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GI manifestations.

All patients with BD develop painful oral ulcers (119). In the Western world, up to 53% of patients may display GI disease (other than oral ulcers), which can affect any region of the GI tract, primarily the ileocecal area (in up to 88% of patients) (120). Abdominal pain (82%), weight loss (25%), diarrhea (18%), and melena (14%) are the most common symptoms (120). Vasculitis can trigger portal hypertension from thrombotic occlusion of these vessels or contribute to aneurysmal formation.

GI involvement can range from inflammation and ulcers, if small vessels are affected, to ischemia and infarction in larger vessels. Ulcerations typically occur over remnants of Peyer patches and, less frequently, resemble punched-out lesions. These can penetrate the tissue sufficiently to cause GI bleeding or perforation and typically recur at anastomotic sites (119). With significantly lower frequency, the liver and pancreas may also be affected and may manifest as steatosis/hepatitis and pancreatitis, respectively. In rare instances, esophageal involvement may cause dysphagia and hematemesis.

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Diagnosis.

Diagnostic criteria include recurrent oral ulcers, genital or ocular lesions, and a positive pathergy test, which consists of the development of skin papules or pustules in response to a needle-prick in the forearm. Oral ulcers are punched-out, surrounded by erythema and may have a necrotic center. Enteroclysis studies may demonstrate ulcers and mucosal thickening in up to 71% of affected patients (121). Upper endoscopy may reveal pharyngeal, esophageal, or gastric aphthous lesions that are not responsive to antisecretory therapy. Capsule endoscopy can further evidence these lesions and pseudopolyps throughout the length of the small intestine (122). Characteristic ulcerations in the ileocecal area are a hallmark finding during colonoscopy. Imaging studies such as CT or MRI enterography may show polypoid lesions, thickened bowel wall with enhancement or dilated blood vessels. BD shares many features with Crohn's disease; distinguishing these 2 disorders is critical. The small-vessel vasculitis in BD may cause deep ulcerations, although there is typically less inflammation, and granulomas and cobblestoning are not seen.

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Treatment.

As several organ systems may be involved, a multidisciplinary approach is essential. Topical steroids or sucralfate can alleviate symptoms in patients with isolated oral ulcers. For luminal GI manifestations, a regimen consisting of corticosteroids plus azathioprine is generally recommended as first-line therapy, with the goal of tapering the steroid dose within 3 months. TNF-alpha inhibitors such as infliximab or adalimumab may be considered if first-line treatments fail. Treatment for up to 2 years may be required (123).

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Polyarteritis nodosa

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis affecting medium-sized vessels. Besides the GI tract, it commonly affects the skin, joints, kidneys, and peripheral nerves (124). The incidence increases with age, with children also being affected in the same etiopathogenic manner as adults, and is estimated at 0.7 cases per 100,000; there is no gender predilection. Immune-complex deposition in the vessel wall causes inflammation and fibrinoid necrosis of the middle and innermost arterial layers. This may result in thrombosis, stenosis, aneurysmal formation, and rupture, which compromises perfusion to distal tissues (125).

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GI manifestations.

Manifestations depend on the anatomical location of the affected vessels and the tissues they perfuse. Up to 65% of patients with PAN may have GI involvement. Abdominal pain is a common symptom (65% of cases), and typically occurs postprandially, reflecting intestinal ischemia secondary to mesenteric vasculitis. Intestinal ischemia may lead to bowel infarction and perforation. Other symptoms include nausea, vomiting, melena, hematochezia, or diarrhea (126). Gallbladder involvement can cause cholecystitis and gallbladder infarction. Involvement of the appendicular artery may also cause acute appendicitis. Portal vein and hepatic artery involvement may result in hepatic lobar atrophy, infarction, and acute liver failure. Pancreatic infarction with resulting necrotizing pancreatitis has also been described (127).

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Diagnosis.

The diagnosis is suspected on the basis of presenting symptoms, physical exam, serologic testing and angiography, with confirmation by biopsy being necessary in selected cases. Table 2 includes physical examination and laboratory findings. The presence of fecal occult blood suggests possible involvement of mesenteric vessels. Upper endoscopy may show bleeding and nonbleeding ulcerations in the stomach, duodenum, and jejunum. Colonoscopy may also reveal ulcerations and findings suggestive of ischemic colitis. In a patient undergoing colonoscopy in whom there is a high clinical suspicion of colonic PAN involvement, the clinician should minimize insufflation, and even consider terminating the procedure if evidence of ischemic colitis is appreciated (125).

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Treatment.

After confirming the diagnosis, determining the extent and severity of PAN should guide treatment considerations. Immune-suppressing therapy is the cornerstone of treatment, with several options available (e.g., systemic corticosteroids, cyclophosphamide, azathioprine, methotrexate, or mycophenolate). Use of these medications as monotherapy or combined regimens depend on disease severity, extent, resistance to corticosteroids, medication safety profile, and coexistence of other diseases. Naturally, management in concert with rheumatology experts should be sought.

It is important to note that in patients with PAN stemming from associated HBV or hepatitis C virus infections, the focus of treatment should be to administer antiviral therapy in an effort to control the viral illness. The use of immunosuppressants in this subset of patients is reserved for those with significantly severe vasculitis (128). The use of plasmapheresis has been suggested for more severe cases, although clinical trials are lacking (129). Finally, any suspected GI perforation requires prompt surgical intervention.

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NONSTEROIDAL ANTI-INFLAMMATORY DRUG AND CORTICOSTEROID SIDE EFFECTS

Patients with RA and other rheumatic conditions widely use nonsteroidal anti-inflammatory drugs (NSAIDs) for symptomatic relief. Although being effective anti-inflammatories, inhibition of the cyclo-oxygenase enzyme disrupts prostaglandin synthesis and alters mucosal permeability, resulting in inflammation and ulcer formation (130). In addition, evidence suggests that NSAIDs may be implicated in triggering changes in the gut microbiota and free-radical formation, further contributing to mucosal damage (131). As no therapy eliminates the risk of NSAID-associated GI complications, judicious use of these medications in patients requiring their use is warranted. Strategies that may be considered include co-administration of NSAIDs with PPIs or H-2 receptor antagonists, use of cyclo-oxygenase-2 selective inhibitors, topical NSAIDs that minimize systemic exposure, and H. pylori eradication (130).

The cornerstones of management of many rheumatological conditions are systemic corticosteroids. Although short-term treatment courses are generally well-tolerated and associated with mild side effects, long-term courses may result in a variety of potentially irreversible complications. Short-term use complications may include skin discoloration, hypokalemia, myopathy, glucose intolerance, edema, psychosis, hypertension, or leukocytosis. These are short-lived and usually resolve with discontinuation of treatment. Long-term use may lead to more serious complications such as osteoporosis, adrenal insufficiency, peptic ulcer disease, infection, glaucoma, hyperlipidemia, and even congenital malformations, among others (132). Given the milieu and significant morbidity caused by these complications, the clinician should, if possible, consider systemic corticosteroids as bridging therapy for other steroid-sparing medication regimens that control disease activity.

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CONFLICTS OF INTEREST

Guarantor of the article: Paul T. Kröner, MD, MSc.

Specific author contributions: P.T.K.: structuring of the subject, acquisition and revision of literature, and manuscript drafting and revision. O.A.T.: manuscript drafting assistance, table design and editing, and literature review assistance. A.W.B.: acquisition of radiological imaging for figures and manuscript revision. A.A.: manuscript structuring and revisions. B.E.L.: conception and structuring of the subject and critical draft revisions.

Financial support: No funding was required in the preparation of this manuscript.

Potential competing interests: None.

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