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 Gastrointestinal Manifestations of Rheumatologic Disorders, Review of Articles 

E. Aflaki, M.D.

Department of Internal Medicine, SUMS

Abstract:

Rheumatologic diseases are multisystem disorders which can involve any part of the gastrointestinal tract, hepatobiliary system and pancreas. Gastrointestinal manifestation may be the initial presentation of these disorders but it may also be the complication of treatment. Gastrointestinal complications are one of the major causes of morbidity and occasionally mortality especially if they are not diagnosed and treated at proper time. The gastrointestinal manifestations of  thirteen rheumatologic disorders are presented here in alphabetic order.

Contents:

Antiphospholipid Antibody Syndrome

The antiphospholipid antibody syndrome (APS) is a disorder characterized by recurrent vascular thromobsis, pregnancy loss and thrombocytopenia associated with persistently elevated levels of anliphospholipid antibodies. The features of APS may be alone ("Primary" APS) or more commonly associated with features of other autoimmune diseases, particularly systemic lupus erythematosus ("secondry" APS).
  The gastrointestinal manifestations of APS results from vasculopathy and tissue ischemia. There are case reports of intestinal and omental ischemia and infarction⁽¹⁾, giant gastric ulcerations⁽²⁾, and esophageal necrosis and perforation⁽³⁾, colonic ulceration and pancreatitis⁽⁴⁾. Budd-Chiari syndrome may occur as a result of portal venous occlusion and lead to hepatomegaly and abnormal liver function tests and development of esophageal varices^(5,6). Although liver has dual blood supply hepatic infarction has been documented in this disorder presumably as a result of wide spread vascular occlusion⁽⁶⁾.

Behcet's Disease

Behcet's disease is a systemic vasculitis characterized by recurrent oral and/or genital ulceration and eye inflammation. Other manifestations include arthritis, thrombosis and central nervous system involvement.
  Oral apthae are painful, shallow, round to oval ulcers with discrete borders which often occur in crops. Mucosal apthae are more frequent in the esophagus than in the stomach and duodenum⁽⁷⁾. Esophageal involvement may manifest as ulcers, varices and less often perforation⁽⁸⁾. Segmental mucosal ulceration in the ileocecal and colonic area may appear after several years of recurrent aphthosis and present in the form of acute complications (perforation, massive hemorrhage) or by prologed bloody diarrhea. The radiological and endoscopic signs are similar to Crohn's disease. The histopathology shows nonspecific inflammatory infiltrate affecting all of the colonic wall, lesions of vasculitis and perivasculitis with signs of leukocytoclasis and fibrinoid necrosis⁽⁷⁾.
  A small number of cases have been reported with involvement of the superior mesenteric artery in Behcet's disease, including aneurysm formation and intimal thickening leading to infarction and perforation of the small bowel⁽⁹⁾.

Churg-Strauss Syndrome

Allergic granulomatosis and angitis is a rare small vessel vasculitis, clinically characterized by asthma, eosinophilia, fever and accompanying vasculitis of various organ system. The classic histologic findings are tissue infiltration by eosinophils, extravascular necrotizing granuloma and vasculitis. Clinical features include cutaneous disease (purpura, nodules, erythema), nervous system disease (mononeuritis multiplex), cardiac disease (focal segmental glomerulonephritis).  Gastrointestinal involvement occurs in about 50% of patients⁽¹⁰⁾. Eosinophilic gastroenteritis may be the prodrome of churg-stauss syndrome. Common gastrointestinal symptoms included abdominal pain, bloody stools, diarrhea and occasional nausea and vomiting multiple ulcers may be seen and may lead to perforation. The small intestine is the most common site of involvement and is most commonly perforated^(11,12) but case report of multiple colonic ulcer and perforation exists⁽¹³⁾. Necrotizing granulomatous vasculitis of the mesenteric artery may occur and lead to mucosal ischemia. Cholecystitis is also reported in churg-strauss syndrome⁽¹⁴⁾.

Cogan's Syndrome

Cogan's syndrome is a rare systemic disease characterized by interstitial keratitis and audiovestibular system involvement. Clinical features include weight loss, fever, lymphadenopathy, hepatosplenomegaly. Rash occurs in about 50% of patients. The most serious manifestation is aortitis causing aortic aneurysm and insufficiency. Abdominal aortitis and mesenteric vasculitis may cause abdominal pain, nausea and vomiting after meal. On examination abdominal bruit is heard. Endoscopy is normal and the diagnosis can be achieved by angiography. Vasculitis can be refractory to immunosuppressive agents⁽¹⁵⁾.

Giant Cell Arteritis

Giant cell arteritis is a large vessel arteritis with strong predilection for the cranial and in particular, the temporal arteries. Headache, fever, high erythrocyte sedimentation rate and sudden blindness are major manifestations. Involvement of the facial arteries and resultant muscular ischemia leads to jaw claudication. Aortitis occurs in approximately 10% of patients. There are case reports of intestinal gangrene⁽¹⁶⁾ and acute pancreatitis⁽¹⁶⁾. Liver involvement characterized by elevation of transaminases and alkaline phosphatase occurs in approximately 20% of patients⁽¹⁷⁾. Liver biopsy is either normal or shows nonspecific changes, but granulomas, lymphocytic infiltration, dilated bile canaluli, and even hepatocellular necrosis with dropout have been reported^(17,18).

Henoch-Schonlein purpura

Honoch-Schonlein purpura (HSP) is the most common systemic vasculitis in children with IgA-mediated immune complex deposits affecting small vessels. HSP is a self-limited disorder lasting at most four weeks. Most children have the classic triad of palpable nonthrombocytopenic purpura in the dependent areas of the body, colicky abdominal pain and arthritis. Other features include renal involvement, scrotal swelling, testicular torsion, seizure, subdural hematoma, cortical hemorrhage and peripheral neuropathy.
  Gastrointestinal signs and symptoms have been reported in up to 75% of cases⁽¹⁹⁾. The most common presenting symptom is dull periumbilical pain⁽¹⁹⁾. Nausea and vomiting are common as well. The main cause of abdominal pain is ulceration of the bowel mucosa which is more marked in the second  part of the duodenum but less frequently seen in the stomach, jejunum, colon and rectum. Endoscopy may reveal redness, swelling, petechia, hemorrhage, erosion or ulceration of the mucosa⁽²⁰⁾.
  Computerized tumography scan may show multifocal bowel wall thickening with skipped areas, mesenteric edema and vascular engorgement to support the diagnosis⁽²¹⁾. Other gastrointestinal manifestations include intususseption (ileoileal)⁽¹⁹⁾, esophageal⁽²²⁾ and ileal strictures⁽²³⁾, protein losing enteropathy⁽²⁴⁾, gastric and small bowel perforation^(25,26), bowel infarction⁽²⁵⁾, pancreatitis⁽²⁷⁾, appendicitis⁽²⁸⁾, cholecystitis⁽²⁹⁾ and hydrops of the gall bladder. 

Inflammatory Muscle Disorders

Idiopathic inflammatory myopathies comprise a rare group in the autoimmune disease. Polymyositis and dermatomyositis are the two most common entities. Early in the disease the patients complain of proximal muscle weakness and sometimes pain and ultimately muscular atrophy and fibrosis.
  The most common gastrointestinal manifestations of idiopathic inflammatory myopathies are related to motor abnormalities, but the most serious and life threatening problems are secondary to ischemic vasculopathy. Patients may have difficulty in swallowing and nasal regurgitation, abnormal esophageal and gastrointestinal peristalsis, reduced gastrointestinal motility, hiatal hernia with reflux esophagitis with resultant  stricture formation^(30,31,32), dilated atonic esophagus associated with delayed gastric emptying and intestinal mucosal thickening resulting in a radiographic "stacked coin" appearance⁽³³⁾. Inflammatory process leads to changes in the endothelium of small arteries and capillaries which may cause ischemia and necrosis in any part of gastrointestinal tract resulting in ulceration, perforation or hemorrhage⁽³⁴⁾.
  Inflammatory myopathies have an association with inflammatory bowel diseases. Higher incidence of malignancies is seen in polymyositis and dermatomyositis. Those with dermatomyositis have a 10% incidence of malignancy within the first year after diagnosis⁽³⁵⁾. Investigation of the gastrointestinal tract as a site of malignancy should be done in these patients.

Kawasaki Disease

Mucocutaneous lymph node syndrome (Kawasaki disease) is an acute febrile disease occurring most commonly in infants and children under 5 years of age. The main clinical features include bilateral conjunctival congestion, dry and red lips, inflammation of oral mucosa, acute nonpurulent swelling of cervical lymph nodes and polymorphous exanthem of the trunk. The most serious complication is vasculitis especially of the coronary arteries. Gastrointestinal manifestations include abdominal pain, vomiting and diarrhea. Small bowel obstruction may occur as a result of  ischemia with stricture with adhesion formation⁽³⁶⁾. Mild jaundice may be seen secondary to hydrops of the gallbladder⁽³⁷⁾. Paralytic ileus and a slight increase of serum transaminase levels due to hepatitis are other manifestations.

Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is a systemic necrolizing, focal segmental vasculitis of medium sized and small arteries. PAN affects predominately males between the ages of 40 and 60 year. Common manifestations include fever, anorexia, weight loss, palpable purpura, livido reticularis, peripheral neuropathy, renal involvement with segmental necrotizing glomerulonephritis and hypertension.   The most common gastrointestinal symptom is abdominal pain which occurs in 23-70% of patients⁽³⁸⁾. The pain is vague, nonspecific and is thought to be secondry to bowel ischemia, most commonly in the small bowel. Hematemesis, melena and hematochezia may also occur. The diagnosis is based on the clinical picture and mesenteric angiography. The typical picture in arteriogram is narrowed tapered arteries and small aneurysms distal to branching points of the vessels⁽³⁹⁾.
  Tissue biopsy is the gold standard for diagnosis. Gastrointestinal ulceration may be found in 6% of patients and the most common site is the jejunum⁽⁴⁰⁾.  Perforation occurs in 5% and bowel infarction in  1.4% of PAN patients. Severe gut involvement is a worse prognostic sign and survival after bowel infarction is rare⁽⁴¹⁾.
  Liver involvement is a common finding in autopsy studies but is not usually clinically significant. Liver involvement may be associated with hepatitis B antigen. The only abnormality may be an elevated alkaline phosphatase, without elevated bilirubin or transaminase level.
 Other gastrointestinal manifestations of PAN include acalculous cholecystitis⁽⁴²⁾,  appendicitis, pancreatitis, biliary strictures and a chronic wasting syndrome^{(42,43,44,45)}.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic multisystem disease characterized chiefly by persistent inflammatory synovitis, usually involving peripheral joints in a symmetrical fashion. The hallmark of persistent synovitis are cartilaginous destruction, bony erosions and joint deformity. Extraarticular manifestations include rheumatoid nodules, rheumatoid vasculitis, pleuropulmonary inflammation, scleritis, sicca syndrome and felty's syndrome (splenomegly and neutropenia).
  Temporomandibular joint involvement may cause pain and crepitus during chewing⁽⁴⁶⁾. Rheumatoid vasculitis may occur in a small percentage of patients, more often in those with positive rheumatoid factor and subcutaneous nodules⁽⁴⁷⁾.
  Secondary ischemic changes may occur at the ileum and colon. Endoscopy shows multiple linear and apthoid ulcer lesions throughout the lumen. Histopathologic features include necrotizing vasculitis with fibrinoid necrosis and mural thrombus in small arteries of the submucosal layer.
  Esophgus may show diminished distal peristalsis, decreased lower esophageal sphincter tone and hiatal hernia. In patients with Felty's syndrome esophageal ulcer may occur. Peptic ulcer disease in RA is probably the result of pharmacologic therapy. Incidence of chronic atrophic gastritis is higher compared with normal control⁽⁴⁸⁾. Colonic inflammation may be accompanied by a subepithelial collagen band and the histologic picture of collagenous colitis. The thick collagen containing colonic wall cannot allow adequate water resorption, resulting in a typical presentation of profuse diarrhea possibly associated with pain, flatulance and weight loss⁽⁴⁹⁾. Endoscopy in this setting is most often  normal but may show mild hyperemia and congestion⁽⁴⁹⁾. Diagnosis is only with biopsy.
  Secondary amyloidosis occurs with RA and can be diagnosed by gastrointestinal biopsy. The complications of secondary amyloidosis include pseudo-obstruction, malabsorption, protein losing enteropathy and gastrointestinal hemorrhage^(50,51).  Liver function abnormalities may parallel the activity of the disease and with control of active inflammation the liver function abnormalities return to normal⁽⁵²⁾. Nonsteroidal anti-inflammatory drugs may also induce liver enzyme abnormalities and sometimes it is difficult to differentiate between drug effects and disease activity. Liver involvement may be present in up to 65% of patients with Felty's syndrome while abnormal liver function test may be present in only one third⁽⁵³⁾. The liver pathology ranges from abnormal lobular architecture, nodular regenerative hyperplasia, sinusoidal lymphocytosis to portal fibrosis^(53,54). Portal hypertension with bleeding esophageal varices is the most serious outcome of nodular hyperplasia in this condition^(53,54).

Sjogren's Syndrome

Sjogren's syndrome is a chronic inflammatory and lymphoproliferative disorder characterized by a progressive mononuclear cell infiltration of exocrine gland especially the lacrimal and salivary gland. Sjogren's syndrome may occur alone (primary) or in association with any of the autoimmune disease (secondary). The disease is characterized by gradual dryness of eyes and mouth as the most common clinical presentation. Other manifestations include nonerosive polyarthritis. Raynaud's phenomenon, pleuropulmonary and renal involvement.   Xerostomia is seen in all patients with sjogren's syndrome and may lead to dental caries. Difficulty in swallowing is a frequent problem and may be due to decrease in saliva production or abnormal esophageal motility. The presence of esophageal atrophy suggests that inflammatory infiltrate of esophageal exocrine glands may at times affects the musculature with resultant impairment of motor coordination⁽⁵⁵⁾.
  Epigastric pain^(56,57,58), dyspepsia^(56,58,59) and nausea are also common clinical symptoms and may result from chronic atrophic gastritis and lymphocytic infiltrates which are common in Sjogren's syndrome. The location of inflammatory involvement seems to be age related, with young patients having both antral and corpus lesions, middle-aged patients having antral lesions, and elderly patients having corpus lesions⁽⁵⁷⁾. In addition, Sjogren's syndrome patients may have  hypochlorohydria or achlorohydria, hypergastrinemia, hypopepsinogenemia, low levels of vitamin B12 and sometimes antibodies to parietal cells^(56,57,60).
  Subclinical pancreatic involvement is common but acute or chronic pancreatitis has been reported rarely^(58,61). Sjogren's syndrome can also involve the liver and biliary tree. Antimitochondrial antibodies are present in 5% of cases. Elevation of liver enzymes and alkaline phosphatase occurs in 70% of patients with antimitochondrial antibodies. Patients may have hepatomegaly, pruritus, palmar erythema and jaundice. Liver biopsy shows a picture of mild intrahepatic bile duct inflammation⁽⁶²⁾ or primary biliary cirrhosis⁽⁶³⁾.
  Other gastrointestinal manifestations include jejunitis⁽⁶⁴⁾ sigmoiditis^(56,57), inflammatory bowel disease malabsorptions sclerosing chloangitis⁽⁶⁵⁾ and cryptogenic cirrhosis.

Systemic Lupus Erythematosus

Systemic lupus erthematosus (SLE) is a disease of unknown etiology in which tissues and cells are damaged by deposition of pathogenic antibodies and immune complexes. The  disease primarily affects women of child-bearing age. SLE involves any organ system. Common features include fever, weight loss, skin rash (discoid rash, malar rash), photosenstitivity, arthritis, hematologic abnormalities, renal involvement and central nervous system involvement.  Any part of the gastrointestinal tract may become involved in SLE. Lupus enteritis refers to the alimentary tract lesions in SLE⁽⁶⁶⁾. 
  The most common area of involvement is the oral cavity, which can present with mucosal ulcers and decreased salivation. Oral ulcers may occur in up to 50% patients. Erythematous lesions are painless, but discoid ulcers tend to be painful. They usually occur in the hard palate, buccal mucosa, or the vermilion border⁽⁶⁷⁾.
  Esophageal symptoms are usually dysphagia or odynophagia. Manometry of the esophagus may reveal decreased esophageal peristalsis and decreased lower esophageal sphincter pressure^(68,69).
  Systemic vasculitis involving the esophagus can result in esophageal ulceration and perforation. Gastric ulceration with perforation may occur in SLE⁽⁷⁰⁾. Gastric antral vascular estasia may cause a "watermelon stomach" appearance⁽⁷¹⁾.
  Small and large intestinal abnormalities in SLE include dysmotility, vasculitis and malabsorption. Chronic intestinal pseudo-obstruction is reported in a small series⁽⁷²⁾. Isolated case reports have described necrotizing vasculitis affecting the appendix and cecum and perforating ulcers of retum^(73,74). Venous occlusion due to thrombosis can lead to ischemic bowel disease and damage to arteries can result in aneurysmal dilatation of intra-abdominal vessels⁽⁴²⁾. Protein-losing enteropathy is an unusual presentation of SLE⁽⁷⁵⁾. The association of SLE with inflammatory bowel disease is rare⁽⁷⁶⁾.
  The most common causes of elevated liver enzymes in SLE are the medications such as nonsteroidal anti-inflammatory medication or azathioprine⁽⁷⁷⁾. Antiphospholipid antibodies in SLE are associated with Budd-Chiari syndrome, which presents with abdominal pain, ascites and hepatic failure due to thrombosis of the portal vein and hepatic veins. Steatosis chronic active hepatitis, granulomatous hepatitis, cholestasis, centrilobular necrosis, microabscesses, primary biliary cirrhosis and hemochromatosis have been associated with SLE⁽⁷⁸⁾. Necrotizing vasculitis can affect the gall bladder and the bile ducts. There are case reports of acalculus cholecystitis⁽⁷⁹⁾ and benign stricture of the bile duct with intrahepatic dilatation of the intrahepatic biliary tree⁽⁸⁰⁾. 
  Pancreatitis is an uncommon initial presentation of SLE. The pancreatitis of SLE almost always presents acutely, although two cases of chronic pancreatitis have been reported⁽⁸¹⁾. Lupus  pancreatitis may result from SLE and most commonly occurs in patients whose flare up involves multiple organs⁽⁸¹⁾. In contrast to lupus enteritis, lupus pancreatitis even in patients with steroid therapy is usually symptomatic, with abdominal pain radiating to back associated with nausea, vomiting, and hyperamylasemia⁽⁸²⁾.
  Ascites occurs in approximately 10% of patients⁽⁸³⁾, perhaps as a result of peritoneal inflammation of SLE vasculitis. Other causes of ascites in SLE patients are nephrotic syndrome and constrictive pericarditis⁽⁸⁴⁾.

Systemic Sclerosis

Systemic slcerosis is a multisystem disorder characterized by inflammatory, vascular and fibrotic changes of skin and various internal organ systems. Clinical manifestations include Raynaud's phenomenon, fibrosis of the skin, telangectasia, clacinosis, pulmonary fibrosis, pulmonray hypertension and renal failure.
  Any part of the gastrointestinal tract can be involved in sclerodema. Many scleroderma patients are without significant symptoms despite demonstrable abnormalities of gastrointestinal function. Thinning of the lips and reduced oral apparatus are frequent. Temporomandibular joint involvement may also limit mouth opening in some patients⁽⁸⁵⁾. Atrophy of the mucous membrance and tongue papilla with impaired taste perception has been reported⁽⁸⁶⁾.
  Esophagus is the most common involved  site. It is involved in 80-90% of scleroderma patients. The most common symptoms are dysphagia and dyspepsia. Patients complain of solid food sticking in the mid or lower esophagus as a result of incoordination of the normal propulsive peristalsis of  middle and distal esophageal smooth muscle. Incomplete closure of the lower esophageal sphincter leads to gastroesophageal reflux with peptic esophagitis. Chronic reflux predisposes to Barrett's metaplasia⁽⁸⁷⁾. Gastric atony and dilation may occur, but involvement of the stomach is uncommon compared with other portions of the alimentary tract. In rare instances, telangectasia were the source of serious bleeding from the distal esophagus, stomach, or other gastrointestinal tract sites especially in persons with limited cutaneous disease⁽⁸⁸⁾.
  Dysmotility of small intestine may cause chronic pseudo-obstruction. Malabsorption occurs as a consequence of bacterial over growth in stagnant intestinal fluid⁽⁸⁹⁾.
  Occasionally pneumatosis intestinalis occur in patients with advanced bowel disease. In this situation intestinal gas dissects into the bowel wall, or on occasion, into the peritoneal cavity mimicking a ruptured bowel.
  Scleroderma patients have decreased distensibility of the colon that dose not necessarily correlate with symptoms⁽⁹⁰⁾. Rarely diarrhea but more frequently constipation, lower abdominal distension or fecal impaction are manifestations of colonic involvement.
  Because of muscular atrophy of the bowel wall, asymptomatic wide mouth diverticula unique to scleroderma are commonly found in the transverse and descending colon. Reduced anorectal motility, compliance and sphincter pressure have been reported^(91,92). Rectal incontinence and prolapse are uncommon but disabling  problems⁽⁹³⁾.

Takayasu Arteritis

Takaysu arteritis, a large vessel arteritis with strong predilection for aortic arch and its branches, most commonly affects young women. 
  The involvement of the descending abdominal aorta and its branches leads to gastrointestinal symptoms including abdominal pain, nausea, diarrhea and hemorrhage. Stenotic⁽⁹⁴⁾ and saccular ⁽⁹⁵⁾ aneurysmal lesions of intra-abdominal arteries are reported. There are some reports of inflammatory bowel disease, both Crohn's disease and ulcerative colitis, occurring in association with Takayasu arteritis ⁽⁹⁵⁾.

Wegener's Granulomatosis

Wegner's granulomatosis (WG) is a disease characterized by necrotizing vasculitis and granulomatous inflammation of the upper and lower respiratory tract. Small vessels and occasionally medium sized vessels are involved. Inflammatory destructive lesions affects eyes, ears, nose, trachea, bronchi and lungs. Renal disease occurs primarily in the form of glomerulonephritis, and vasculitis.
  Gastrointestinal manifestation of WG are less common with only scattered case reports of orpharyngeal mucosal lesions and gingivitis⁽⁹⁶⁾, gastric ulcer⁽⁹⁷⁾, small intestinal perforation ⁽⁹⁸⁾, colonic ulceration⁽⁹⁹⁾, nonhealing perianal ulcers⁽¹⁰⁰⁾, cholecystitis, recurrent acute pancreatitis⁽¹⁰¹⁾, pancreatic mass with extrahepatic biliary obstruction⁽¹⁰²⁾ and splenic necrosis⁽¹⁰³⁾.

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