Esophageal manifestations of rheumatic disorders

Seminars in

Arthritis and Rheumatism VOL 26, NO 4

FEBRUARY 1997

Esophageal Manifestations of Rheumatic Disorders Rebecca C. Fitzgerald and George Triadafilopoulos This study was performed to review information on functional and anatomic esophageal manifestations in patients with rheumatic disorders and to outline their pathogenesis, diagnosis, and treatment in light of the current medical, endoscopic, and surgical advances. A MEDLINE search of English-language articles published between 1985 and 1995, reviews of the bibliographies of textbooks, and a manual search of the reference lists of relevant articles formed the data sources, all combined with our own clinical experience. Primary research and review articles addressing the pathogenesis, diagnosis, treatment, prognosis, and complications of esophageal disease occurring in a rheumatic context were selected, with emphasis on recently developed medical, endoscopic, and surgical methods for diagnosis and management. Study design and quality were assessed, with particular attention paid to methods and aims. Relevant data on frequency, clinical presentation, and relationship to underlying rheumatic disorder, prognosis, and clinical management were analyzed. Esophageal manifestations are common in patients with rheumatic diseases and range in nature and severity from functional myopathic or neuropathic esophageal dysmotility to extrinsic lumenal compression and esophageal mucosal damage from gastroesophageal acid reflux or opportunistic infection. The primary symptoms of heartburn, dysphagia, odynophagia, chest pain, and bleeding may be directly related to the underlying rheumatic disease or may be the unwanted effects of therapy with nonsteroidal antiinflammatory drugs, immunosuppressants, or disease-modifying agents. Easily overlooked in the context of a multisystemic disease, these esophageal symptoms may be amenable to simple treatments, but frequently require a thorough assessment by modern, sophisticated diagnostic tools. In many instances, functional and structural involvement of the esophagus in patients with rheumatic disorders requires a high index of suspicion for an early diagnosis, correct assessment, intensive surveillance, and aggressive therapy to avoid

From the Stanford University School of Medicine, Stanford, CA, and the Gastroenterology Section, Veterans Affairs Health Care System, Palo Alto, CA. Rebecca C. Fitzgerald, MD: Gastroenterology Research Fellow, Stanford University School of Medicine; George Triadafilopoulos, MD: Associate Professor of Medicine, Stanford University School of Medicine, and Chief Gastroenterology Section, Veterans Affairs Health Care System. Address reprint requests to George Triadafllopoulos, MD, Chief Gastroenterology Section (Ill-G1), Veterans Affairs Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304. Copyright © 1997 by W.B. Saunders Company 0049-0172/96/2604-0001 $5.00/0 Seminars in Arthritis and Rheumatism, Vo126, No 4 (February), 1997: pp 641-666

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FITZGERALD AND TRIADAFILOPOULOS

end-organ damage and decline in quality of life. Significant recent advances in the understanding of esophageal pathophysiology, the development of diagnostic techniques, progress in diagnostic and therapeutic endoscopy, and minimally invasive surgery allow early detection and effective long-term therapy for esophageal dysfunction associated with rheumatic diseases. Semin Arthritis Rheum 26:641-667. Copyright © 1997 by W.B. Saunders Company

INDEX WORDS: Esophagus; rheumatic diseases. LINICIANS caring for patients with rheumatic disorders are frequently confronted with esophageal symptoms such as heartburn or dysphagia. These symptoms may be a manifestation of the rheumatic disease or may arise as a complication of therapy. Because rheumatic complaints dominate the patients' clinical presentation, the task for the clinician is to specifically inquire about esophageal symptoms and to initiate appropriate investigations. Recent advances in the understanding of esophageal pathophysiology and modem clinical diagnostic tools have led not only to an earlier recognition and prevention of esophageal disease, but also to highly successful medical or surgical therapy in such patients. The purpose of this article is to provide a practical overview of esophageal problems that may be encountered in patients with rheumatic diseases. The review begins with a description of the principal esophageal symptoms and the current diagnostic modalities used in their assessment. This is followed by a summary of the range of esophageal abnormalities seen in specific rheumatic disorders, their evolution, prognosis, and current methods of therapy.

C

PRINCIPAL ESOPHAGEAL SYMPTOMS ENCOUNTERED IN RHEUMATIC DISORDERS

Occasional heartburn occurs in everyone I and is not usually indicative of serious disease. However, frequent and persistent complaints of heartburn, or other esophageal symptoms such as dysphagia and chest pain, warrant further investigation and treatment (Fig 1).2

Heartburn Heartburn, derived from the Greek word pyrosis meaning fire, is a term that describes a plethora of symptoms, such as "bitter belching" or "acid indigestion." Classic heartburn is a substernal burning sensation that tends to rise toward the

mouth. The burning may radiate into the upper back, jaws, teeth, or arms. It usually occurs postprandially, is exacerbated by maneuvers that increase intraabdominal pressure, and often is relieved by the ingestion of antacids. There may be associated symptoms of belching, food or fluid regurgitation, or the sudden filling of the mouth with clear salty fluid (waterbrash). Heartburn occurs primarily as a result of transient relaxations of the lower esophageal sphincter (LES) leading to direct exposure of the esophageal mucosa to refluxed gastric contents. 3 In many patients with esophageal motility disturbances, heartburn also may result from impaired acid clearance. The physiological mechanism leading to pain is poorly understood, but it may be related to activation of mucosal chemoreceptors by low pH. However, the correlation between discrete episodes of acid reflux and symptoms is poor, suggesting that other factors, such as the buffering capacity of swallowed saliva or the volume of refluxed material, also may be important. 4,s The clinical importance of heartburn in the patient with rheumatic disease relates to the possibility of underlying gastroesophageal reflux disease (GERD) with mucosal inflammation or complications, such as ulceration, stricture formation, or Barrett's esophagus. 6

Dysphagia Dysphagia, derived from a Greek word meaning difficulty in swallowing, is a symptom specific to esophageal disease. There are two distinct types of dysphagia that may be encountered in the rheumatic patient: OropharyngeaI or transfer dysphagia, and esophageal dysphagia, and a careful history is crucial to distinguish the two] Orophayngeal dysphagia results from failure to initiate swallowing and to propel a food bolus from the hypopharynx through the upper esophageal sphincter into the esophagus. Typically it is associated with coughing, choking, and nasal regurgita-

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Associated symptoms: Dysphagia that occurs in association with heartburn suggests GERD; if it occurs with chest pain, it suggests esophageal spastic dysmotility. Dysphagia is always a serious symptom, and its occurrence in a patient with rheumatic disease warrants full evaluation. An algorithm for the investigation of dysphagia is shown in Figure 1.

tion. Oropharyngeal dysphagia is frequently encountered in inflammatory myopathies affecting the skeletal musculature, and when associated with coughing, choking, and nasal regurgitation, the impact of respiration on swallowing, 8 and the cough reflex should be assessed. Esophageal dysphagia results from either failure of esophageal body peristalsis, LES dysfunction, luminal obstruction (stricture), or a combination of these problems. A typical example is the patient who has systemic sclerosis that affects the smooth muscle portion of the esophageal body, thereby compromising peristaltic function. This situation may be complicated by peptic stricture formation attributable to gastroesophageal acid reflux through a chronically incompetent LES. Most patients with dysphagia complain that food "sticks" or "won't go down right"; others may describe a "slow down" of their swallowing, a "gurgling," or a sensation of pressure in their chest that dissipates when their esophagus empties over time or with fluid intake. There are three important factors from the history that will determine the likely cause of esophageal dysphagia9: (1) Solid versus liquid dysphagia: Dysphagia that occurs only with solids suggests a mechanical obstruction (ie, peptic stricture, carcinoma). Dysphagia to both solids and liquids suggests a neuromuscular disorder leading to disordered peristalsis (ie, systemic sclerosis). (2) Progressive versus intermittent dysphagia: Progressive dysphagia suggests structural esophageal obstruction (ie, carcinoma). Intermittent dysphagia is not necessarily present with every swallow and is caused by esophageal dysmotility or GERD. (3)

Odynophagia Odynophagia implies painful swallowing and is usually associated with dysphagia or difficulty with swallowing. Typically, odynophagia is encountered in rheumatic patients receiving immunosuppressive therapy who present with retrosternal pain with each swallow and inability to eat or to swallow their saliva. The occurrence of odynophagia should alert the clinician to consider esophageal infection (candida, herpes, cytomegalovirus), drugor chemical-induced esophagitis, or malignancy. 1° Esophageal motor dysfunction or reflux esophagitis rarely cause odynophagia.

Chest Pain Esophageal chest pain is clinically significant because of its association with GERD, esophageal motor disorders, or esophageal carcinoma. It therefore requires full evaluation, l°,H Pain resulting from esophageal disease may clinically mimic angina. The pain is frequently described as burning, substernal, radiating to the back, lasting for minutes to hours. Although the history is often nondiscriminatory, the association of pain with meals or other esophageal symptoms such as dysphagia or heartburn should alert the clinician to consider the

Detailed history & physical examination f

J

Predominant symptom

J

J

Dysphagia I Barium swallow Normal or dysmotility Fig 1. An algorithm for the investigation of esophageal problems in the rheumatic patient.

\

Structural lesion

Manometry pH monitoring

\

Heartburn I Empirical therapy t Persistence of symptoms

Atypical symptoms (cough, chest pain) I Heart & lung evaluation Normal J

Endoscopy (biopsy, cytology, dilation)

Abnormal

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esophagus as a potential source. 12 Making the correct diagnosis can nevertheless be difficult, not only because chest pain may be the only manifestation of esophageal disease in up to 10% of patients, but also because esophageal and cardiac problems may coexist, particularly in the elderly. In the rheumatic patient, musculoskeletal causes for chest pain also should be considered by looking for trigger points on the anterior chest wall. Pleuritic chest pain, a frequent occurrence in rheumatology practice, may be a manifestation of esophageal perforation or of extensive esophageal malignancy involving the pleura or the pericardium. The specific mechanisms that produce esophageal chest pain are not well understood. Proposed mechanisms include the stimulation of esophageal chemoreceptors by acid, bile, and pepsin and stimulation of mechanoreceptors by esophageal luminal distention triggered by dysmotility.~3 Alterations in pain perception also may contribute,~4 and this may explain why anxiolytics and antidepressants improve esophageal chest pain in the absence of changes in esophageal motility. 15

Other Symptoms Other, less specific symptoms of esophageal dysmotility include belching, anorexia, nausea and vomiting, weight loss, regurgitation of undigested material, syncope on swallowing, palpitations, xerostomia, and chronic hiccups, l° Although these symptoms may occur with esophageal motility disorders, they are most frequently associated with GERD. Regurgitation is particularly significant because it may lead to pulmonary aspiration, especially at night. Such a patient may be asymptomatic or have symptoms of nocturnal coughing, wheezing, or recurrent pulmonary infections. A

FITZGERALD AND TRIADAFILOPOULOS

discerning patient may notice food or fluid on the pillow after waking. Hoarseness (as a result of vocal cord trauma), chronic nonproductive cough, and wheezing may be manifestations of GERD in the absence of classic reflux symptoms, such as heartburn and regurgitation. 16

DIAGNOSTIC TESTS FOR ESOPHAGEAL DISEASE In most cases, the diagnosis of esophageal disease in the rheumatic patient will be established by combining the clinical history and physical examination with one or two diagnostic tests. If several symptoms are present, their combination taken in conjunction with the physical findings may direct the physician to the next most sensitive and specific test to facilitate and simplify the diagnostic management. However, the management of esophageal disease in patients with rheumatic diseases is frequently challenging and requires an in-depth understanding of its complex pathophysiology and severity. Fortunately, today a wide range of diagnostic tools allow the physician not only to confirm the diagnosis but also to intervene early, assess the magnitude of esophageal dysfunction, and carefully select appropriate medical or surgical therapy. Thus, complications and long-term sequelae may be prevented (Figs 1 to 4).

Radiographic Tests Chest radiograph. Signs of esophageal dysfunction notable on routine chest radiograph include mediastinal widening attributable to esophageal body distention and air-fluid levels attributable to stasis or hiatal herniation. Atelectasis, patchy con-

Fig 2. Esophageal scintigraphy showing delayed esophageal clearance of the radionuclide bolus and episodes of intraesophageal reflux (red and yellow peaks) corresponding to abnormal esophageal body peristalsis and incoordination. Esophageal emptying in this patient was 60 seconds (normal, < 12 seconds). Fig 5. Endoscopic view of an acute variceal bleed. Venous blood is seen here spurting from the bleeding varix (arrow), because of elevated portal pressures. Fig 6. (A) Endoscopic view of grade IV esophagitis in a patient with systemic sclerosis. A stricture is noted in the distal esophagus (arrowhead), and a sliding hiatal hernia is seen distal to the stricture. Linear, deep ulcers extend upward in the distal esophagus in a nearly circumferential fashion (arrows), (B) Endoscopic appearance of Barrett's esophagus that has developed as a complication of chronic reflux in a patient with systemic sclerosis. Well-defined areas of red, metaplastic mucosa occupy the distal esophagus (pink). Note islands of normal squamous esophagus within Barrett's epithelium (arrow).

ESOPHAGUS IN RHEUMATIC DISORDERS

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solidation, and chronic pulmonary fibrosis also may be seen as a result of nocturnal pulmonary aspiration.

Computed tomography ( CT) scans and magnetic resonance imaging (MRI). Both of these imaging modalities are increasingly used in the evaluation and staging of esophageal tumors. In patients with rheumatic disorders, both modalities may provide

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useful information about cervical and thoracic spine structural integrity and potential encroachment of the esophagus. Neoplastic or inflammatory disorders of the mediastinum causing extrinsic esophageal compression also may be recognized. Barium swallow. For most clinicians, barium swallow remains the test of choice for the investigation of dysphagia. A double-contrast barium swal-

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.

.

11.

Fig 7. (A) Endoscopic view of severe erosive esophagitis in a patient with systemic sclerosis. (B) The esophageal problems were subsequently treated by colonic interposition with good result. Note telangiectasia of the colon (arrow). Fig 8. Facial telangiectasias (left panel, arrow) in a patient with CREST syndrome. An endoscopic view of a midesophageal telangiectasia is shown (right panel, arrow). Fig 11. Endoscopic view of candida esophagitis circumferentially covering the esophageal mucosa.

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ESOPHAGUS IN RHEUMATIC DISORDERS

swallow

swallow

swallow

swallow

+

+

upperesophagus

mid esophagus

....

dislai esophagus

1+0

LES

A. Normal Study

B. Scleroderma

C. MCTD

Fig 3. Esophageal manometric pressure tracings: (A) Normal pressure profile showing sequential esophageal contractions from proximal to distal esophagus after a swallow. The lower esophageal sphincter (LES) has a normal resting tone and relaxes completely with swallowing. (B) Failure of esophageal body contractions in the distal (smooth muscle portion) of the esophagus in a patient with systemic sclerosis. The LES is hypotonic but relaxes normally with a swallow. (C) Failure of proximal esophageal contractility after a swallow in a patient with mixed connective tissue disease (MCTD). The distal esophagus exhibits normal peristalsis, and the LES is hypotonic.

esophageal motility. Although some information can be gained about sequential transit function and the coordination of peristalsis with sphincter relaxation, the strength of muscular contraction cannot be adequately assessed. When a barium swallow shows an esophageal stricture, cancer and peptic stenosis need to be considered. However, in patients with rheumatic disorders, drug-induced strictures and strictures resulting from candidiasis or herpes esophagitis may be encountered and require specific therapy and preventive measures. In patients receiving immunosuppressive therapy, diffuse mucosal involvement also should raise the possibility ofinfectious esophagitis, such as candida or cytomegalovirus, and endoscopic biopsies and mucosal brushings are required.

low, in preference to the single-column study used for many years, can provide exquisitely detailed views of the esophageal mucosa. This procedure enables the clinician to rule out an obstructive lesion and provides useful information about the presence of esophageal motor dysfunction and dilatation. For example, decreased peristalsis is frequently noted in patients with connective tissue diseases, such as systemic sclerosis, lupus, and polymyositis, or rarely in amyloidosis. An increase in the caliber of esophageal lumen is common in systemic sclerosis. Although free reflux of contrast into the proximal esophagus may be seen, barium studies have limited sensitivity in GERD because reflux is usually quite advanced before it can be detected by barium. Furthermore, barium studies are not the investigation of choice for assessing

M--

S--M--

141-1 H Fig 4. Ambulatory 24hour esophageal pH monitoring study showing multiple episodes of reflux (pH drops below 4.0), correlating with heartburn (H). M, meal; S, supine position.

M-- S

S

M--

HHH

H

itl

r-

"i

pH 4321

I t

10:00

14':00

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18:00

22':00

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Time (hrs.)

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Video fluorography. This is the best technique for investigating oropharyngeal (transfer) dysphagia. In this specialized barium study, the patient is asked to swallow liquid barium, barium paste, or solid food (eg, marshmallow) coated with barium. The swallow is then videotaped, providing a motion recording of the oropharyngeal and esophageal coordination. This technique is extremely useful for the diagnosis and management of functional disorders of the oropharynx and proximal (skeletal) esophagus, such as in cases of inflammatory myopathies. 17 Esophageal radionuclide scintigraphy. Although scintigraphy does not define the precise nature of esophageal dysfunction as accurately as esophageal manometry, it is simple, safe, and noninvasive and provides the most physiological and quantitative assessment of esophageal transit and emptying. The test involves the administration of radioactive technetium (99rnZc) sulfur colloid by mouth and quantification of bolus transit through the different segments of the esophagus using a computerized gamma camera (Fig 2). A single swallow differentiates most normal patients from those with a significant motor dysfunction. For example, in patients with systemic sclerosis, esophageal scintigraphy shows normal proximal transit but significant delay in the emptying of the distal two thirds of the esophageal body and gastroesophageal reflux. In contrast, patients with inflammatory myopathies have delayed proximal transit, occasionally associated with pulmonary aspiration detected scintigraphically in delayed views of the lung bases. Because of its simplicity, esophageal scintigraphy is more readily accepted by patients than manometry, and the results are comparable in terms of the detection and staging of esophageal involvement by the disease.~ 8,19 Endoscopic Studies Esophagogastroduodenoscopy and biopsy. This is the most important investigation for the diagnosis and staging of all esophageal mucosal lesions, such as gastroesophageal reflux, Barrett's esophagus, and cancer. Transendoscopic esophageal mucosal biopsies and mucosal brushings for cytological examination are pivotal in the assessment of infectious esophagitis and for the detection of inflammatory mucosal changes resulting from stasis or reflux in many connective tissue diseases. Furthermore, endoscopy allows for a variety of therapeutic

FITZGERALD AND TRIADAFILOPOULOS

maneuvers, such as dilation of peptic strictures in systemic sclerosis, foreign body removal in patients with drug-induced strictures, esophageal variceal injection sclerotherapy in patients with Felty's syndrome, or the placement of feeding tubes in patients with severe dysphagia and malnutrition. Endoscopy remains an ancillary tool in the diagnosis of esophageal dysmotility. In patients with orophayngeal dysphagia, transnasal fiberoptic examination of swallowing function is increasingly used. 20 Endoscopic ultrasound. This new technique combines endoscopy with ultrasonography and allows detailed definition of submucosal lesions and extraesophageal structures. Although endoscopic ultrasonography is most useful in cancer staging (depth of tumor infiltration, lymph node involvement), it recently has been found useful in the assessment of esophageal fibrosis in patients with systemic sclerosis. 21

Functional Studies Esophageal manometry. This is the definitive test for the diagnosis and classification of esophageal motility disorders. A manometry catheter is passed through the nose or mouth into the esophagus, and pressure changes are recorded by microtransducers or microperfusion techniques. The technique allows for accurate assessment of LES resting tone and relaxation and the strength and coordination of esophageal body contractile activity. In patients with rheumatic diseases, esophageal manometry may identify abnormal manometric patterns specific to particular diseases. For example, in patients with systemic sclerosis, poor LES resting tone is associated with low-amplitude contractility in the distal two thirds of the esophageal body, in contrast to systemic lupus erythematosus (SLE), where the latter changes are noted in the absence of LES hypotension (Fig 3). Preferential involvement of the proximal (skeletal) muscle portion of the esophagus in inflammatory myopathies leads to poor proximal esophageal contractility with relative sparing of the distal esophagus22 (Fig 2). The simplicity and safety of esophageal manometry makes it a procedure of choice not only for the early diagnosis of esophageal dysfunction in patients with rheumatic diseases, but also as a useful tool for the assessment of disease progression and response to therapy.

ESOPHAGUS IN RHEUMATIC DISORDERS

Ambulatory 24-hour esophageal pH monitoring. This is the most reliable test for the detection of gastroesophageal acid reflux, with a sensitivity and specificity of 80% to 9 0 % . 23 The study is performed using a thin, flexible pH probe attached to a compact, portable digital recorder that is worn by the patient for 24 hours. During the period of continuous pH recording, the patient records activities, meals, body position, and symptoms of esophageal dysfunction, such as dysphagia, heartburn, or cough (Fig 4). Analysis of the data at the end of the procedure allows for quantification of gastroesophageal acid reflux (frequency and duration of reflux events, total percentage of time with pH <4.0) and correlation of reflux episodes with reported symptoms during the study. In selected cases, ambulatory manometry can be performed simultaneously to correlate pH changes in the distal esophagus with esophageal dysmotility. The value of 24-hour pH monitoring in patients with rheumatic diseases rests in the identification of pathological acid reflux with its potentially damaging effect on esophageal and pulmonary function, particularly in systemic sclerosis. Esophageal provocation tests. These tests are used in an attempt to identify the esophagus as the source of chest pain. They should only be used after cardiac evaluation and endoscopy have been performed to exclude structural lesions. The edrophonium provocation test may reproduce chest pain in up to 35% of cases, u,24,25 Given intravenously, in a single-blinded and placebo-controlled fashion, a positive test identifies the esophagus as the source of the pain. It does not, however, identify the precise cause of the pain, and it may be falsely positive in patients with GERD. The acid-perfusion (Bernstein) test, which determines whether acid causes chest pain, has a sensitivity of 30%. For this test, normal saline and 0.1N hydrochloric acid are infused alternately into the midesophagus. Consistent reproduction of the patient's usual symptoms on!y during acid perfusion and rapid abatement during saline perfusion indicate a positive test. Failure to include other components of gastric contents (pepsin, bile) in the perfusate may account for falsely negative results in some patients. The balloon distension test involves the incremental inflation of a 10-mL balloon in the midesophagus. It may provoke chest pain in 50% to 75% of cases

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of noncardiac chest pain compared with 20% of healthy volunteers, and hence the visceral pain threshold can be assessed. 14 Used in conjunction with electrocardiography monitoring, the information gained from this simple test can be very reassuring. SPECIFIC RHEUMATIC DISEASES INVOLVING THE ESOPHAGUS

Rheumatoid Arthritis Esophageal involvement in rheumatoid arthritis (RA) usually results fi'om its long-term drug therapy rather than from the disease itself. Rarely, disease complications such as atlantoaxial subluxation or vasculitis may lead to esophageal symptoms (Table 1). The atlantoaxial joint is prone to subluxation in several directions, leading to dysphagia associated with other signs of spinal cord compression that demand prompt intervention?6 Because neurological symptoms do not directly correlate with the degree of subluxation but rather with the diameter of the spinal canal, CT or MRI are valuable tests. 27,2s Surgery is the definitive treatment for atlantoaxial subluxation, but if it is considered unwarranted or unsafe, a tight-fitting cervical collar may alleviate the dysphagia. 26 If recurrent pulmonary aspiration occurs, long-term gastrostomy feeding should be considered. Endoscopy is a high-risk procedure in such patients. Vasculitis is a serious complication that affects 1% of patients with RA. 29 Gastrointestinal involvement is rare but may cause esophageal dysmotility either directly by affecting the vessels of the esophageal wall, or indirectly as a result of amyloidosis. An ischemic esophageal stricture or nmscular fibrosis in the proximal third of the esophagus may result 3°. Patients typically present with dysphagia, odynophagia, or chest pain. The diagnosis can be difficult to make, unless the patient displays signs of cutaneous vasculitis. An endoscopy with biopsy should be performed to exclude other causes of the patient's symptoms and to assess mucosal damage such as stricture or ulceration. 3~ Esophageal dilation may be required more frequently in patients with RA who present with pulmonary fibrosis and rheumatoid nodules as compared with healthy subjects. 3° Rarely, rheumatoid vasculitis may present with esophagobronchiaI fistula in the context of an arthritic flare and the development of subcutaneous nodules. 32 The response to high-dose

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FITZGERALDAND TRIADAFILOPOULOS

Table 1: Overview of Common Esophageal Symptoms Associated With the Rheumatic Disorders

and Their Pathophysiology Esophageal Symptom(s)

Rheumatic Diagnosis Rheumatoid arthritis

Dysphagia, odynophagia

Juvenile rheumatoid arthritis Felty's syndrome Systemic sclerosis/limited cutaneous systemic sclerosis

Dysphagia Hematemesis Dysphagia, heartburn, regurgitation, weight loss

Systemic lupus erythematosus (SLE) Polymyositis/dermatomyositis Mixed connective tissue disease (MCTD) SjCgren's syndrome

Hematemesis Dysphagia, odynophagia Dysphagia, nasal regurgitation, aspiration Dysphagia Dysphagia

Cervical spine disorders

Dysphagia

Hypertrophic osteoarthropathy

Dysphagia

Seronegative spondyloarthropathies Paget's disease

Dysphagia

Vasculitic syndromes

Syndromes of impaired immune function Infiltrative disorders (amyloid, sarcold)

Dysphagia, chronic aspiration, disordered phonation Dysphagia, odynophagia, chest pain, hematemesis

Pathophysiology Atlantoaxial subluxation Esophageal vasculitis Secondary amyloid Micrognathia Esophageal varices Esophageal body dysmotility LES incompetence Esophagitis Barrett's esophagus Esophageal adenocarcinoma Telangiectasia Esophageal body dysmotility, esophageal vasculitis Oropharyngeal and esophageal body dysmotility Oropharyn/esophageal body dysmotility Xerostomia Esophageal mucosal dryness Oropharyn/esophageal body dysfunction Osteophytes causing esophageal compression Esophageal tumor Long-standing achalasia Stricture Osteophytes Neurological involvement

Dysphagia, odynophagia

Esophageal vasculitis Esophageal ulcers Pharyngeal stenosis Opportunistic infections

Dysphagia

Esophageal dysmotility

corticosteroids is modest; cytotoxic agents may be more effective. 33 The most common esophageal manifestations of RA are related to nonsteroidal antiinftammatory drug (NSAID) therapy, a9'34 Patients may complain of odynophagia, dysphagia, or chest and epigastric pain that occur as a result of mucosal erosions and ulcerations. Although hypergastrinemia has been reported in patients with RA, RA itself does not seem to be an independent risk factor for the

development of peptic ulcer disease or esophagitis. 35 The management of drug-induced esophageal injury is discussed separately. Juvenile rheumatoid arthritis can be associated with dysphagia. Although dysphagia in such patients may be attributable to cervical spine disease, micrognathia could potentially play a role. 36 Oral changes have been found in two thirds of children with juvenile rheumatoid arthritis, resulting in micrognathia with total loss of the mandibular

ESOPHAGUS IN RHEUMATIC DISORDERS

condyles and a retrusion of the jaw in up to 20% of c a s e s . 37 Video fluorography may be useful in pointing out the origin of the dysphagia and should be considered in conjunction with full clinical, neurological, and radiological examination of the jaws by a maxillofacial surgeon. Bimaxillary osteotomies combined with preoperative and postoperative orthodontic measures is the preferred treatment for both aesthetic and functional improvement.

Felty's Syndrome Felty's syndrome occasionally may lead to lymphocytic infiltration of the hepatic sinusoids and nodular regenerative hyperplasia. 3s Although these changes usually occur in the context of RA, similar hepatic abnormalities have been observed in SLE and other connective tissue disorders. 39 Patients with Felty's syndrome and hepatic nodular regenerative hyperplasia do not generally develop ascites or hepatic encephalopathy, but they may suffer from the sequelae of portal hypertension, particularly esophageal variceal bleeding. The portal hypertension results from increased resistance to portal vein flow caused by fibrosis and inflammatory cell infiltration of portal venules in conjunction with increased splenic blood flow. 4°,4~ Patients present with painless hematemesis or melena as a result of variceal bleeding (Fig 5). Thrombocytopenia caused by hypersplenism is at times a complicating factor. Emergency esophageal variceal sclerotherapy or band ligation of varices is frequently used. Optimal surgical management involves a splenectomy and portocaval shunting. However, in elderly and severly arthritic patients, a splenectomy alone may suffice.

Systemic Sclerosis The esophagus may be the first internal organ to be affected by systemic sclerosis. 4e,43Furthermore, esophageal dysfunction ultimately develops in more than 90% of patients with systemic sclerosis, regardless of the diffuse or limited nature of the disease. 44 Therefore, early recognition and aggressive management of the esophageal disease in systemic sclerosis is a critically important aspect of patient care. The pathogenesis of esophageal dysfunction in systemic sclerosis is complex and multifactorial and may vary, depending on the stage of the disease. 45 Esophageal dysmotility results from smooth muscle atrophy and fibrosis in the lower

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two thirds of the esophagus and LES. 46 Pharmacological studies suggest that patients with early systemic sclerosis have an abnormality in cholinergic function, manifested by a reduced peristaltic amplitude and LES hypotension. The lower esophageal sphincter response to cholinesterase inhibitors is diminished, but there is a preserved response to direct cholinergic receptor stimulation with methacholine. 45 Later in the disease, pharmacological studies have shown that it is the smooth muscle cell, rather than cholinergic nerve dysfunction, that may be impaired. 47 Raynaud's phenomenon is considered a hallmark of systemic sclerosis. Earlier studies correlated symptoms of Raynaud's phenomenon with esophageal dysmotility, raising the possibility of an underlying autonomic or vasomotor defect. 48 However, the presence of Raynaud's phenomenon has not been found to be useful in determining the prognosis or predicting the evolution of esophageal involvement in systemic sclerosis. 49 Furthermore, induction of Raynaud's phenomenon in patients with systemic sclerosis does not alter esophageal motor function assessed by esophageal motility or scintigraphy9 despite the fact that induction of Raynaud's decreases esophageal blood flow. 5~,52 Therefore, it appears that Raynaud's phenomenon is merely an associated finding in systemic sclerosis and bears no pathogenic importance to the induction of esophageal dysmotility. Patients with systemic sclerosis esophagus may volunteer no symptoms referable to the esophagus, and a thorough medical history is therefore needed. Dysphagia and heartburn are the main symptoms encountered, and they may occur even in the absence of skin changes. At the time of their first examination, approximately 60% of patients may complain of dysphagia and 35% of heartburn. 33 Dysphagia, primarily the result of esophageal dysmotility, is usually mild and intermittent and involves both solids and liquids. Sometimes patients may complain only of postprandial fullness in the chest that requires ingestion of fluids for relief. Regurgitation of undigested food is frequent. Because of their dysphagia, patients often reduce their food intake and may lose significant amounts of weight. Reflux symptoms of retrosternal burning, heartburn, and nocturnal cough or wheezing are frequent and debilitating. As the disease worsens, heartburn occurs in 70% to 80% of cases and is associated with signs and symptoms of gastric

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emptying delay, such as postprandial fullness, nausea, bloating, epigastric pain, and halitosis. Like dysphagia, heartburn occurs primarily as a result of esophageal dysmotility that delays esophageal clearance, combined with LES incompetence. Episodes of odynophagia may be caused by severe reflux esophagitis, foreign body impaction, bolus distension caused by a stricture, or superimposed infection. The clinical importance of investigating esophageal symptoms in these patients is highlighted by the potentially life-threatening complications that may ensue. Complications occurring as a result of dysmotility and secondary gastroesophageal reflux include Barrett's metaplasia, chronic pharyngitis, laryngitis, and aspiration pneumonia. Impaired lung function attributable to interstitial lung disease has been shown in some studies to correlate with the frequency of esophageal reflux.53 However, this observation was not substantiated by a recent study in which the findings from esophageal manometry, 24-hour ambulatory pH monitoring, and pulmonary function studies were compared. 54 Therefore, it appears unlikely that treatment of GERD prevents the pulmonary process. Many studies have found an association between systemic sclerosis and Barrett's esophagus as a result of acid reflux (Fig 6). 55-5v A large retrospective study in which patients with esophageal symptoms underwent endoscopy suggested a 37% prevalence of Barrett's esophagus in these patients. 58 Barrett's esophagus (specialized intestinal metaplasia type) is associated with a 30-fold increased risk for the development of esophageal adenocarcinoma and adenocarcinoma of the gastric cardia and requires careful follow-up. The investigation of choice in systemic sclerosis is esophageal manometry, because it is more sensitive than radiography in detecting esophageal dysmotility.59 In addition, manometry must be performed preoperatively in all patients who are considered candidates for surgical fundoplication to assess the presence and severity of esophageal dysmotility. The characteristic manometric findings in systemic sclerosis esophagus are diminished LES resting pressure, impaired LES relaxation, diminished amplitude of esophageal peristaltic contractions after swallowing, and increased frequency of nonperistaltic contractions (Fig 3B). Although these motility alterations occur mainly in the distal (smooth muscle) portion of the esopha-

FITZGERALD AND TRIADAFILOPOULOS

gus, they may involve the proximal (skeletal muscle) portion in the late stages of the disease. Esophageal scintigraphy is an acceptable method for the evaluation of esophageal dysfunction in patients with systemic sclerosis and has the additional advantage of quantitating esophageal emptying and reflux.5°,6° Indeed, because of its noninvasive nature, safety, and simplicity, scintigraphy is readily accepted and preferred by patients as an alternative to manometry.51 Typically, scintigraphy in systemic sclerosis shows delayed clearance of radioactivity in the distal two thirds of the esophageal body, with intraesophageal incoordination of bolus progression. These findings are fi'equently associated with gastroesophageal reflux and delayed gastric emptying. Ambulatory esophageal pH monitoring in patients with systemic sclerosis shows patterns similar to those observed in reflux esophagitis (Fig 4). Frequently the number and duration of acid relfux episodes increase in the supine position or postprandially, suggesting that acid clearance through the dysfunctioning esophagus and stomach is impaired. 61 Endoscopy should be performed in every patient with persistent heartburn or dysphagia to assess disease severity and rule out the development of complications, such as Barrett's esophagus, peptic esophageal stricture, or carcinoma. If Barrett's esophagus is identified, surveillance endoscopy with multiple biopsies of the entire surface of Barrett's epithelium should be performed every 1 to 2 years to detect dysplasia and early adenocarcinoma. 62 Endoscopic ultrasound may show a diffuse hyperechoic abnormality that correlates histologically with the replacement of the muscularis mucosa by connective tissue. 2~ The esophageal symptoms in systemic sclerosis can be among the most incapacitating and difficult to treat. Esophageal involvement never regresses even if the cutaneous lesions improve or ameliorate. For the treatment of dysphagia, patients should learn to masticate carefully and grind, puree, or moisten foods, such as meat and bread, to make them easier to swallow. Oral metoclopramide (10 mg by mouth four times daily before meals) is useful in some patients because it improves esophageal peristalsis, increases LES tone, and enhances gastric emptying.63 Its mechanism of action is related to the blockade of nonadrenergic inhibitory nerves with an enhanced response to acetylcholine. 63 However, its use is limited by the common

ESOPHAGUS IN RHEUMATIC DISORDERS

occurrence of side effects, particularly dystonic reactions, and tremor. The prokinetic drug cisapride (10 mg by mouth four times daily before meals) stimulates both gastric and esophageal emptying and may be helpful, providing that the atrophied esophageal muscle is capable of responding to the enhanced acetylcholine release. 64 This approach may help patients with heartburn and regurgitation as well as dysphagia. The calcium channel blocker nifedipine, frequently used for Raynaud's phenomenon in patients with systemic sclerosis, has been shown to significantly reduce LES pressure. 65 Although the correlation between reduced LES pressure and symptoms has not been examined, it is possible that nifedipine may further aggravate esophageal symptoms in these patients. 65Therapeutic trials have focused on altering the fibrotic process by using D-penicillamine, colchicine, or griseofulvin. 66 Although D-penicillamine can improve pulmonary function in these patients, it has not been shown to arrest the progression of esophageal involvement as assessed by esophageal manometry. 67When sicca symptoms make mastication and swallowing difficult, artificial saliva administered as a spray can be helpful. Acid reflux can be minimized by appropriate measures, for example, adopting an upright position during and after eating, avoiding food before bedtime, elevating the head of the bed to prevent nocturnal reflux, and the use of antacids 30 to 60 minutes after meals and at bedtime (Table 2). H2 antagonists have been used extensively in systemic sclerosis. However, even with prolonged and intensive cimetidine therapy (300 mg by mouth four times daily for a year), most patients' erosions fail to heal, despite a significant symptomatic benefit. In a 20-week study, ranitidine provided symptomatic relief, but had no effect on esophageal motility. 6s The proton pump inhibitor omeprazole (20 to 40 mg once or twice daily, by mouth) has recently been shown to be superior to ranitidine in relieving symptoms, as well as improving the endoscopic and histological appearance of esophagitis in patients with systemic sclerosis. 69 Omeprazole is generally well tolerated and may be safely used for long-term management of GERD in such patients. The effect of nasal continuous positive airway pressure (nasal CPAP) has been investigated in systemic sclerosis patients with aperistaltic esophagus, but so far has not been shown to be helpful. 7°

653

Table 2: A Stepwise Approach to the Management of Gastroesophageal Reflux Disease (GERD) in Systemic Sclerosis, Limited Cutaneous Systemic Sclerosis, and Mixed Connective 'tissue Disease Step 1 Modify diet, restrict smoking and alcohol Elevate head of the bed Avoid early recumbence after meals Review all medications, avoid polypharmacy Antacids 15-30 mL orally as needed every 4-6 hr Step 2 H2receptor antagonists Cimetidine 400 mg orally twice daily Ranitidine 300 mg orally twice daily Famotidine 20-40 mg orally daily Nizatidine 150-300 mg orally daily Evaluate gastric emptying Prokinetic drugs Cisapride 10-20 mg orally three times daily before meals and every hour of sleep Metoclopramide 10-15 mg orally three times daily before meals and every hour of sleep Step 3 Evaluate esophageal mucosa, rule out 8arrett's esophagus and stricture Proton pump inhibitors Omeprazole 20-40 mg orally daily Lansoprazole 15-30 mg orally daily Step 4 Evaluate esophageal motility and transit time Antireflux surgery (modified Nissen fundoplication)

CPAP is thought to reduce reflux by elevating the resting LES pressure. Surgical treatment should be considered in patients who are symptomatic despite medical therapy. Antireflux surgery in patients with systemic sclerosis esophagus and GERD should be carefully designed to prevent reflux without aggravating dysphagia. Because of poor motor function in the esophageal body, standard antireflux operations, such as Nissen's fundoplication, are associated with worsening dysphagia because of poor esophageal emptying into the stomach through the tkmdoplication barrier. Modified antireflux operations, such as combined Collis gastroplasty-fundoplication, are therefore usually undertaken with good results. 7~ In severe cases, when esophagectomy is required, colonic interposition is an alternative

654

approach (Fig 7) and is preferred in some centers5 2 Unreasonable delay in operative management diminishes the opportunity to salvage a functional esophagus and allows for symptomatic progression. 73 There is no increase in wound healing complications in these chronically ill patients. 71 When all options have been exhausted, longterm home total parenteral nutrition (TPN) allows the patients with severe esophageal systemic sclerosis to return to acceptable standards of living with remarkably few complications. However, because of its high cost, home TPN needs to be considered in relation to its social and medical benefits on an individual basis. 74 Limited cutaneous systemic sclerosis (eg, CREST). Esophageal involvement in limited cutaneous systemic sclerosis typically presents with heartburn, regurgitation, and chronic intermittent dysphagia to both solids and liquids. When a peptic stricture develops, dysphagia for solids becomes persistent and contributes to poor oral intake and weight loss. Upper gastrointestinal bleeding from esophageal telangiectasias occurs rarely, and it may be overt and severe or clinically silent, leading to iron deficiency anemia (Fig 8). Radiologically, the distal two thirds of the esophageal body appear atonic and dilated, and free gastroesophageal reflux is frequently noted through a patulous lower esophageal sphincter. The esophageal motility abnormalities are indistinguishable from those of systemic sclerosis. The medical and surgical management of patients with CREST syndrome generally follow the principles used for the treatment of esophageal symptoms in systemic sclerosis patients (Table 2). Calcium channel blockers, such as nifedipine and diltiazem, are frequently used in the treatment of Raynaud's phenomenon in these patients, but they may again precipitate and aggravate gastroesophageal reflux by lowering the LES pressure and decreasing esophageal clearance. Ambulatory 24hour esophageal pH monitoring performed while the patient is receiving these agents is useful in the diagnosis of pathological reflux and the institution of early anti-reflux therapy. Bleeding esophageal telangiectasias are usually treated by endoscopic laser photocoagulation or electrocautery with very good results.

Systemic Lupus Erythematosus Esophageal symptoms are not common in patients with SLE, and when present, they are gener-

FITZGERALD AND TRIADAFILOPOULOS

ally mild and coincide with an exacerbation of the diseaseY The most commonly encountered symptom is intermittent dysphagia to both solids and liquids resulting from esophageal body dysmotility, and esophageal manometry is the most sensitive test. The manometric findings appear to be a combination of the abnormalities seen in progressive systemic sclerosis and polymyositis, with decreased proximal and distal esophageal body peristalsis and decreased LES pressure. However, a more recent study72has found that, although abnormalities of peristalsis are common, the LES function is rarely impaired in SLE patients. Findings consistent with esophageal spasm and atonic dilation of the esophagus also have been reported and may contribute to chest pain, dysphagia, and regurgitation.V6,77 Vasculitis is the most dreaded complication of SLE, and it occasionally can involve the esophagus. The patient may present with symptoms of chest pain, bleeding, or odynophagia resulting from esophageal ulceration, perforation, or infarction. Although abnormal radiographs have been reported in 45% patients with presumed SLE vasculitis] 8 the diagnosis is difficult to establish, and endoscopy, CT scanning, or barium swallow examination may be required. Oral barium sulfate is contraindicated in patients with suspected esophageal perforation, so water-soluble contrast media (ie, gastrograffin) should be employed. The treatment of vasculitis involves high-dose corticosteroids (1 to 2 mg/kg/ day) in divided doses every 8 to 12 hours. Some patients may require cytotoxic agents to reduce the rate of disease severity and steroid requirements.79,80

Inflammatory Diseases of Muscle Polymyositis, dermatomyositis, cancer-associated myositis, and several other rare entities may be associated with gastrointestinal motor dysfunction. Patients with esophageal involvement present primarily because of dysphagia and regurgitation. Although dysphagia is found in only 10% to 15% of patients with polymyositis or dermatomyositis, it is generally associated with severe disease and poor prognosis. 81 Several factors may contribute to dysphagia in such patients. Oropharyngeal dysphagia and nasal regurgitation may be caused by decreased strength of pharyngeal contractions, poor palate elevation, tongue weakness, or dysfunction of the cricopharyngeus muscle, which exhibits spasm or

ESOPHAGUS IN RHEUMATIC DISORDERS

improperly timed sphincter closure. 82 Such oropharygeal dysfunction can result in aspiration in up to 20% of patients, s3 Esophageal dysphagia may involve both solids and liquids and results from esophageal dysmotility of the proximal third of the esophageal body. s4 Delayed transit through the middle and distal esophagus as well as delayed gastric emptying mimicking systemic sclerosis also have been found in patients with polymyositis, even if some of them are asymptomatic,s5 Indeed, the worse the skeletal muscle weakness, the more delayed is gastric emptying to solids. Such a correlation not only implies the presence of a more generalized upper gastrointestinal motor dysfunction but also may be used to monitor disease progression. The relationship between interstitial lung disease in such patients and esophageal dysfunction, oropharyngeal weakness, and pulmonary aspiration is not well established. In a survey of patients with the anti-Jo-1 antibody, most of whom had interstitial lung disease, none had demonstrable aspiration despite the presence of oropharyngeal dysfunction. s3 Nevertheless, all patients with myositis and dysphagia should undergo appropriate investigation to determine the existence and magnitude of oropharyngeal, cricopharyngeal, and esophageal dysfunction to further guide medical or surgical therapy. 86Such evaluation should include videofluorography to evaluate the oropharynx and proximal esophagus, barium swallow, and esophageal motility studies to assess the esophageal body and LES, and gastric scintigraphy to assess gastric emptying. In patients with oropharyngeal dysphagia, consultation with a speech therapist and review of the videofluorographic data provides guidance for the appropriate therapeutic techniques (such as head postures that help control the food bolus in the oral cavity, postswallow coughing, appropriate food preparations, and biofeedback) that may be necessary. When significant cricopharyngeal dysfunction is identified, cricopharyngeal myotomy should be offered. This procedure is generally well tolerated and can lead to complete amelioration of symptoms, thus aborting the need for increased corticosteroid administration. If significant delay in esophageal or gastric transit is identified, prokinetic therapy with cisapride (10 mg by mouth three times daily before meals and every hour during sleep) should be considered. Pill-induced esophageal injury should be avoided (see guidelines, Table 3).

655

Table 3: Guidelines for Prevention of NSAID-Induced Esophageal Injury 1. Before initiation of long-term NSAID therapy, inquire about esophageal symptoms, such as heartburn, dysphagia, or regurgitation. 2. Investigate preexisting esophageal symptoms with endoscopy or 24-hour ambulatory pH monitoring. 3. If GERD is present, consider concomitant antisecreto ry therapy. 4. NSAIDs intake should always be followed by at least a I2-oz glass of water. 5. NSAIDs intake should be with patient upright for at least 2 minutes. 6. NSAIDs intake should be at least 1 hour before recumbence. 7. Suspension or suppository forms of NSAIDs should be used for bed-ridden patients or patients with known esophageal disease and dysphagia. 8. Avoid polypharmacy, multiple NSAiDs, alcohol, tobacco. Abbreviations: NSAID, nonsteroidal antiinflammatory drug;

GERD, gastroesophageal reflux disease.

Another important consideration is the frequency of malignancy among adult patients with polymyositis/dermatomyositis, which ranges from 5% to 20% in different series. 8v,ss The types of associated malignancy vary, but neoplasms of the gastrointestinal tract and nasopharynx have been observed. Therefore, in patients with recent onset or worsening of progressive solid-food dysphagia, endoscopy should be performed to rule out the possibility of esophageal or gastric malignancy. Mixed Connective Tissue Disease and Other Overlap Syndromes Esophageal abnormalities are frequent in mixed connective tissue disease (MCTD) 89,9° and are often more severe than in patients with SLE. 91 Although the entire gastrointestinal tract may be affected, esophageal dysfunction is most common and leads to heartburn, dysphagia for both solids and liquids, and regurgitation. Pulmonary aspiration may occur. Because these symptoms are the result of esophageal dysmotility, the most sensitive investigation is manometry. However, manometric abnormalities occur frequently in asymptomatic patients, 92 and although the severity of measured esophageal dysfunction correlates with disease du-

656

ration, it does not necessarily correlate with the presence or the magnitude of esophageal symptoms. 93,94Common manometric changes in MCTD include both a decreased peristaltic amplitude throughout the esophageal body and reduced upper and lower esophageal sphincter resting pressures. 9s Diminished esophageal peristalsis also may be noted radiographically. These abnormalities predispose to gastroesophageal reflux, which may result in esophageal ulceration and stricture formation frequently seen on endoscopy. Long-term acid suppressive therapy with proton pump inhibitors is generally recommended and may be combined with prokinetic drugs (Table 2). Corticosteroid therapy may lead to both clinical and radiological improvement in patients with MCTD and esophageal involvement.96 Although high-dose and longterm steroid therapy is required for most of these patients, it remains unclear whether such therapy is more effective in early (inflammatory) stages of the disease rather than in its advanced stages. 97

SjOgren's Syndrome Dysphagia occurs in approximately 30% of cases of Sj6gren's syndrome as a result of the progressive destruction of exocrine glands leading to mucosal dryness. In addition, dysphagia may be caused by upper esophageal webs (10% of cases) and motility abnormalities (30% of cases). 9s,99 Saliva is important for oral health, prevention of dental caries, breakdown of a bolus before swallowing and initiation of the pharyngeal stage of the swallow reflex. Furthermore, the importance of saliva in the neutralization of residual acid in the esophagus has been demonstrated under experimental conditions in humans, although the clinical significance of prolonged salivary deficiency is not known. 1°° Recently, the effects of chronic xerostomia on parameters of gastroesophageal reflux and esophagitis were assessed in a study of patients with chronic xerostomia secondary to radiation for head and neck cancer or medications.~°l Clearance of acid from the esophagus and 24-hour intraesophageal pH were markedly abnormal, and symptoms and signs of esophagitis were significantly more frequent in subjects with xerostomia as compared with age-matched control subjects. Patients with dysphagia and Sj6gren's syndrome should be investigated with an endoscopy. At endoscopy, the esophageal mucosa may appear

FITZGERALD AND TRIADAFILOPOULOS

atrophic and sometimes pseudomembranous semilunar folds are seen. Although data on the treatment of patients with xerostomia are scarce, it appears reasonable to prevent acid production with H zreceptor antagonists or to neutralize the acid with antacids. In addition, artificial saliva sprays may be helpful.

Cervical Spine Disorders: Osteoarthritis, Atlantoaxial Spurs, Forestier's disease The main esophageal complaint in patients with cervical osteoarthritis is dysphagia for solid foods. Occasionally patients complain of painful swallowing, a foreign body sensation with an urge to clear the throat, cough, and hoarseness. Mechanical changes along the cervical spine can interfere with the hyolaryngeal elevation, epiglottic inversion, and displacement of the bolus even before entry into the upper esophagus. Videofluorography and a speech therapy consultation may aid the diagnosis of oropharyngeal dysphagia. In addition, mechanical compression of the esophagus by hypertrophic osteophytes protruding from the anterior portion of the cervical vertebrae may occur occasionally 1°2 (Fig 9). Considering the frequency of cervical

Fig 9. Endoscopic view of extrinsic compression of hypopharynx and proximal esophagus secondary to cervical osteophytes (arrowhead). Esophageal intubation may be difficult and risky in such cases.

ESOPHAGUS IN RHEUMATIC DISORDERS

osteoarthritis, dysphagia secondary to hypertrophic osteophytes is rare, and it is possible that esophageal dysfunction may account for dysphagia in some of these patients rather than the osteophyte per se. 102The best means to establish the diagnosis is barium esophagography with lateral views (Fig 10). Such views may show extrinsic compression of the posterior esophageal wall and hypopharynx by cervical osteophytes. Although endoscopy is frequently performed for the evaluation of dysphagia in such patients, it carries the risk of esophageal perforation. It therefore should be performed with extreme caution, particularly during introduction of the endoscope into the esophagus, m3 The appearance at endoscopy is that of extrinsic luminal obliteration with overlying normal mucosa. Polytomography has been advocated as a simple, noninvasire alternative, but it has been replaced largely by MRI of the spine, m4 In Forestier's disease (diffuse idiopathic skeletal hyperostosis), extensive calcification and ossification of the anterolateral aspects of the cervical vertebral bodies and osteophyte formation may cause extrinsic compression of the pharynx and cervical esophagus leading to neck stiffness and solid food dysphagia. It is highly probable that most cases of cervical dysphagia reported in the older literature represented patients with Forestier's disease, because the largest anterior osteophytes are found in this disorder. ~05 For most patients with cervical spine disorders and dysphagia, simple measures, such as small, well-chewed boluses of food followed by adequate fluids and careful positioning of the neck during swallowing, are sufficient. Preventive measures against pill-induced esophageal injury also should be implemented. For severe cases, radiation therapy, steroids, and other anti-inflammatory agents have been recommended for osteophytes by some authors, but surgical resection is considered the definitive treatment. 106-u0

tt3,pertrophic Osteoarthropathy The occurrence of hypertrophic osteoarthropathy in conjunction with esophageal symptoms such as dysphagia, regurgitation, and weight loss should alert the clinician to search for associated esophageal neoplasms, such as leiomyosarcoma or carcinoma.m.Jl2 In most cases, the malignancy is usually still potentially curable, and surgical resection

657

Fig 10. Barium study demonstrating extrinsic esophageal compression secondary to severe cervical osteophyte formation (arrow).

of the tumor leads to resolution of the hypertrophic osteoarthropathy. Hypertrophic osteoarthropathy also may be associated with long-standing esophageal achalasia, and it may resolve after a Heller's cardiomyotomy. ~ 3

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Seronegative Spondyloarthropathies (Ankylosing Spondylitis, Reiter's Syndrome, Psoriatic Arthritis, and Arthritis of Inflammatory Bowel Disease) Although frank intestinal inflammation can complicate any of the seronegative spondyloarthropathies, the esophagus is usually spared. In one case report, a stricture of the esophagus associated with ankylosing spondylitis was presumably a result of disease-associated inflammation. 114 Dysphagia has been reported to occur secondary to a thoracic spur in a man who had a long history of ankylosing spondylitis, 115but this is a rare occurrence. Because of the need for continuous NSAID treatment, most esophageal problems seen in these patients are secondary to pill-induced esophageal injury. Crohn's disease occasionally may present as a seronegative arthritis, both axial and peripheral. Although the small intestine is usually the major site of gastrointestinal involvement in Crohn's disease, the esophagus may be involved in approximately 5% of patients. Although cases of isolated esophageal Crohn's disease have been reported, most patients with esophageal involvement also have active ileocolonic disease. H6 The symptoms of Crohn's esophagitis are intermittent dysphagia, chest pain, and weight loss. A cough or recurrent chest infections in a patient with esophageal Crohn's disease should alert the clinician to the possibility of an esophageal-pulmonary fistula.J17 The spectrum of radiographic features seen on barium swallow studies resemble the classical features of regional enteritis and include ulcerations and esophageal strictures, but they are not pathognomonic. Endoscopy shows aphthous or shallow ulcers, frequently irregular in shape; nodularity, and segmental stricture formation. Esophageal mucosal biopsies show chronic inflammation but rarely show the characteristic granulomas of Crohn's disease. Systemic corticosteroids are the mainstay of treatment. Surgery is reserved only for severe cases, for the management of esophageal-puhnonary fistulae or severe stenoses not responsive to endoscopic balloon dilation.

Paget's Disease Skeletal deformity in Paget's disease may result in a variety of neurological symptoms. Although very rare, dysphagia may occur as a result of basilar invagination with compression of the inferior surface of the brain stem, leading to bulbar palsy. Characteristically, such oropharyngeal dysphagia is

FITZGERALD AND TRIADAFILOPOULOS

progressive, is greater for liquids than for solids, and is associated with nasal regurgitation. Disordered phonation and chronic aspiration may be accompanying symptoms. These patients should be promptly investigated by CT or MRI to determine whether surgical decompression is warranted. Subcutaneous administration of calcitonin may lead to improvement of dysphagia symptoms in less than 1 week. 1!8

Vasculitic Syndromes Although any vasculitic condition involving small and medium vessels may theoretically involve the esophagus, such an occurrence is extremely rare. In Churg-Strauss angiitis and Henoch-Sch6nlein purpura, multiple oral aphthous erosions may lead to odynophagia, but the esophagus is not typically affected. In Behcet's syndrome, odynophagia is usually attributable to oral and esophageal ulceration, which is characteristic of this disease. Involvement of the esophagus may be complicated by varices and perforation. In a study of 15 Japanese patients with intestinal Behcet's disease, three had esophageal lesions. H9 Dissection of esophageal mucosa, and esophageal varices caused by thrombophlebitis, were seen in the two patients with fully developed Behcet's disease. An esophageal ulcer was found in the patient with newly diagnosed Behcet's. Dysphagia resulting from an obstructive lesion is rare in Behcet's; however, pharyngeal stenosis secondary to healing of an ulcerated lesion with fibrosis has been reported.12° Alternatively, dysphagia may occur as a result of degenerative central nervous system involvement leading to achalasia. Treatment depends on the particular esophageal problem; prednisolone is the mainstay of treatment, but relapses are common, and some patients require long-term TPN.121

Syndromes of Impaired Immune Function Oropharyngeal and esophageal infections in immunocompromised patients are a frequent problem with grave consequences. They may be caused by bacteria or exotic fungi but are usually attributable to Candida or herpes simplex virus. Diagnosis of esophageal infections in the past has often been based on the history of esophageal symptoms and a barium swallow. ~22 However, because a precise causative diagnosis is necessary to institute effective and specific therapy, endoscopy with biopsy

ESOPHAGUS IN RHEUMATIC DISORDERS

and cytological brushings is mandatory123 (Fig 11). The only complications of endoscopy and biopsy were isolated episodes of spiking fever in 3% of these immunocompromised patients.124 The possibility of human immunodeficiency virus (HIV) infection should be considered in patients presenting with arthralgias and myalgias in conjunction with dysphagia, odynophagia, or chest pain. L25Opportunistic infections of the esophagus, particularly esophageal candidiasis, are prevalent in HIV-infected patients. In a study of HIVseropositive patients, 126it has been found that 64% of HIV patients with esophageal symptoms had an infectious cause. In the patients who had a normal esophagoscopy (24%), no infectious agents were identified histopathologically. The particular infectious agent should be sought by endoscopic biopsy and brushings so that specific therapy can be instituted. As preventive measures, immunocompromised patients at risk of oroesophageal infections should be encouraged to perform regular and thorough mouthwashes as well as to have regular dental checks.

Infiltrative Disorders Amyloidosis. Gastrointestinal involvement in primary and secondary amyloidosis is common; it may be noted in up to 50% of nonfamilial cases. Esophageal involvement in amyloidosis may be patchy or diffuse and has been reported to occur in 60% to 70% of cases.127 Despite such a frequency of esophageal involvement, esophageal symptoms are infrequent, and motor dysfunction is of variable clinical severity. Because the primary pathogenetic abnormality in amyloidosis is either myopathic or neuropathic infiltration of the esophagus, the most common symptom experienced is dysphagia, generally involving both solids and liquids. Esophageal obstruction and hemorrhage may occur occasionally. In most patients, the endoscopic appearance of the esophagus is normal; less frequently, mucosal granularity, erosions, and ulcers may be noted. 128 Transendoscopic mucosal biopsies may show amyloid deposits in the mucosa and submucosa of the esophagus in more than 70% of cases. Radiologically, the esophagus appears atonic and dilated, with frequent tertiary contractions with or without distal narrowing, mimicking esophageal achalasia or systemic sclerosis. Esophageal manometry is a very sensitive technique for the diagnosis of esopha-

659

geal amyloidosis and frequently shows simultaneous, repetitive esophageal contractions, impaired LES relaxation with swallowing, and sometimes total aperistalsis, simulating esophageal achalasia. j2v,129 There is no specific therapy for esophageal amyloidosis, although measures against acid reflux are frequently tried. Prokinetic drugs, :such as cisapride, may be useful in early cases. Severe forms of amyloidosis resulting in achalasia-like esophagus can be treated successfully by pneumatic balloon dilation.~29 Sarcoidosis. Well-documented accounts of esophageal sarcoidosis are rare. Esophageal dysphagia associated with sarcoid has been attrib~ated to dysmotility from neuropathy, mechanical obstruction from esophageal wall infiltration, and mechanical obstruction from extrinsic compression by subcarinal lymphadenopathy.13° However, the relative importance of these causes has not been adequately evaluated. Sarcoid-related liver disease, with granulomatous infiltration and massive liver fibrosis, is a rare cause of portal hyprtension, and this may cause esophageal variceal bleeding. ~3~.132 In such cases, esophageal variceat sclerotherapy may successfully control the hemorrhage before portosystemic shunting is considered.131.~32 ESOPHAGEAL DISORDERS RESULTING FROM THERAPY OF RHEUMATIC DISEASES

Injury to the esophagus may occur with a number of drugs used in rheumatology practice, and the likelihood of esophageal problems increases significantly when nmltiple medications are used. I33,134 Furthermore, the potential for esophageal injury is enhanced in patients who supplement their prescription drugs with additional over-thecounter preparations, typically analgesics or antiinflammatory agents. The injury to the esophagus may occur either directly, as a result of pro]longed contact, or through a systemic pharmaco][ogical effect. The two most common reasons for the development of drug-induced esophagitis are inadequate fluid intake with tablet or capsule medication and the ingestion of medications while in the supine position at bedtime. ~33 In many rheumatic patients, decreased salivation is superimposed on underlying esophageal dysmotility or structural alterations, predisposing them to slow esop]hageal transit, reduced buffering capacity in the esophageal lumen, and enhanced potential for esophageal injury. A variety of medications have been impli-

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FITZGERALD AND TRIADAFILOPOULOS

cated in the cause of pill-esophagitis. Table 4 lists common drugs implicated in pill-induced esophageal injury in patients with rheumatic diseases. Although most cases of drug-induced esophagitis may go unrecognized, common clinical features include odynophagia and chest pain. Typically, patients present with a sudden onset of retrosternal chest pain, awakening them from sleep and mimicking angina. The pain is characteristically exacerbated by swallowing, sometimes to the point that swallowing is impossible. The pain progressively intensifies over a period of 3 to 4 days and subsides slowly and spontaneously, or as a result of therapy. Isolated dysphagia without odynophagia is present in only 20% of cases and generally occurs in patients with a preexisting esophageal stricture. Hematemesis, weight loss, dehydration, and fever are occasionally noted. Sometimes, patients report the acute perception of a pill stuck in their chest, leading to acute odynophagia. Rarely, the evolution of drug-induced esophageal injury is insidious, over a course of weeks or months. 135The usual sites of injury seen at endoscopy are at the level of the aortic arch or proximally to a peptic stricture or Schatzki's ring. In cases of associated cardiomegaly, an enlarged right atrium may cause external compression and predispose to drug-induced injury. Endoscopic findings typically include disTable 4: Drugs Used in Rheumatic Diseases That Are Commonly Implicated in Pill-Induced Esophageal Injury Drug

Presentation/ F r e q u e n c y Complications

Doxycycline/ tetracycline

Frequent

Aspirin

Common

NSAIDs*

Common

Corticosteroids Potassium chloride

Rare Common

Iron sulfate or succinate

Rare

Odynophagia, bleeding, strictu re Odynophagia, bleeding, stricture Odynophagia, bleeding Odynophagia Odynophagia, bleeding, stricture Odynopbagia, stricture

~Nonsteroidal antiinfiammatory drugs (NSAIDs) commonl reported (may reflect common usage): indomethacin, pirox=cam, ibuprofen, naproxen, meclofenamate sodium.

Fig 12. A barium-impregnated tablet stagnating proximal to an area of pill-induced esophagitis and stricture formation at the level corresponding to the aortic arch.

crete ulcers or erosions, with surrounding exudates and nodularity. In some patients, remnants of the pill or capsule may be found retained in the esophagus, providing a clue as to the cause of injury. 135Double-contrast radiography is less sensitive than endoscopy in identifying mucosal damage; however, barium tablet radiography can be used to identify the point at which pills may get stuck (Fig 12). In general, the best treatment for drug-induced

ESOPHAGUS IN RHEUMATIC DISORDERS

esophageal injury is prevention. Patients should be cautioned against swallowing pills or capsules without adequate fluid intake or while in the recumbent position. High-risk patients should crush potentially injurious tablets and swallow them as a suspension. Therapy of drug-induced esophagitis involves the temporary discontinuation of the responsible medication, frequent use of antacids, local anesthetics, and occasionally, H: antagonists or prokinetic drugs. 135Alternatively, the offending medication may be replaced by a liquid or suppository preparation, r36 A number of serious complications may result from drug-induced esophagitis, including bleeding from esophageal ulceration, esophageal stricture formation, and perforation, but fortunately such incidences are rare.

Aspirin and NSAIDs Antinflammatory drugs are renowned for causing gastric injury, and although esophageal lesions are rarely reported in the literature, they should be remembered as a potential cause of significant injury. ~37-139In view of the magnitude of NSAID prescriptions, these drugs account for most cases of pill-induced esophageal injury in the rheumatic population (Table 4). Although aspirin and NSAIDs generally share a common spectrum of clinical toxicities, the incidence of particular side effects may vary with each compound. Heartburn and epigastric distress are the most common symptoms associated with aspirin and NSAID use. However, these symptoms do not generally correlate with the underlying presence of esophagitis, gastritis, peptic ulceration, or the amount of occult bleeding. ~4° More significantly, serious complications of NSAID use, such as gastrointestinal bleeding or perforation, may be unheralded. ~4~ In addition, Barrett's esophagus has been associated with NSAID use. 142 The mechanisms by which NSAIDs cause esophageal injury are complex and multifactorial. NSAIDs interfere with each component of mucosal defenses, either directly or through cyclooxygenase inhibition and depletion of endogenous prostaglandins.14° Prostaglandins have a protective effect on gastric mucosa, but their role in protecting esophageal mucosa has not been established, j37 Furthermore, through inhibition of platelet aggregation, these drugs may cause esophageal hemorrhageJ 43 The effects of prostaglandins on lower esophageal sphincter pressure and function remain controversial.137,H4

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Strategies to avoid local toxicity have included the use of enteric coatings, suspension, or suppository forms of drugs. Alternatively, prodrugs (eg, nambumetone), acid-suppressing drugs, or mucosal protective agents such as sucralfate may be used. None of these approaches has been shown to significantly reduce the risk of ulceration and bleeding, 145,146The most effective strategy to avoid toxicity is to discontinue the use of the drug. If this is not feasible, then using an NSAID with less toxic potential, such as a nonacetylated salicylate, may be beneficial. Although the proton pump inhibitor omeprazole] 47 and the prostaglandin E~ analog misoprostol reduce the incidence of aspirin and NSA1D-induced endoscopic gastroduodenal damage in rheumatic patients,t4s their role in preventing esophageal injury has not been adequately examined. Guidelines for the prevention of NSAIDinduced esophageal injury are presented in Table 3.

Sulfasalazine The most common symptoms of intolerance to sulfasalazine are heartburn, nausea, vomiting, and epigastric distress. Despite the occurrence of heartburn, true esophageal damage has not been documented. These symptoms appear to be associated with the serum sulfapyridine level and are more likely to occur in patients with the slow-acetylator phenotype, ~33

Antimalarials The use of antimalarial drugs, such as chloroquine and hydroxychloroquine, may lead to gastrointestinal side effects similar to those seen with NSAIDs. These side effects include heartburn, nausea, vomiting, and epigastric distress. Despite these symptoms, no esophageal mucosai injury has been described.

Methotrexate The toxicity of ~ow-dose methotrexate used in rheumatoid or psoriatic arthritis is generally less severe than the toxicity seen with higher doses used in cancer chemotherapy. Many of the adverse reactions with this drug are related to its pharmacological effect on rapidly proliferating tissue such as the gastrointestinal mucosa. Mucositis, characterized by oral mucosal erosions, ulcers, and inflammation, is a commonly recognized side effect of methotrexate. Patients complain of dysphagia and odynophagia shortly after drug administration. A1-

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though this is usually mild, it can be severe and lead to dehydration and poor nutrition. The premalignant condition Barrett's esophagus also may occur in patients receiving long-term methotrexa t e . 148The risk of esophageal malignancy developing in patients with Barrett's esophagus induced by methotrexate is not known and warrants further investigation.

Drugs Leading to Esophageal Infection Infection of the esophagus must be suspected in any patient with rheumatic disease who is receiving antibiotics, corticosteroids, or immunosuppresive drugs and who complains of dysphagia or odynophagia. These agents predispose the patient through a variety of mechanisms such as alteration of oral bacterial flora, leukopenia, and reduction of host defenses. Endoscopy should be performed in every case for direct visualization of the lesions, cultures, brush cytology, and mucosal biopsy. Esophageal candidiasis is the most common infection of the esophagus. Candida esophagitis is particularly common in patients with systemic sclerosis, SLE, and other systemic diseases affecting the esophageal musculature leading to stasis and formation of esophageal diverticulae. The symptoms resulting from candida infection may be subtle. In some patients, dysphagia and odynophagia may be absent; instead, such patients may present with chest pain, fear of eating, and progressive weight loss. Difficulty with initiation of a swallow and extreme pain in the hypopharynx may be experienced by some patients. Although white pseudomembranes (thrush) are frequently noted, their absence does not rule out the diagnosis of esophageal candidiasis. Esophagoscopy shows focal yellow-white plaques scattered over hyperemic mucosa (Fig 11). Direct potassium hydroxide smears of exudates and cytological brushings from these plaques as well as mucosal biopsies show mycelial forms. Treatment with nystatin suspension, 100,000 U/mL, is highly effective at a dose of 5 mL gargled and swallowed five times per day for 2 weeks. Alternatively, nystatin pastilles containing 200,000 units of nystatin or 10 mg nystatin tablets may be used 5 times per day for 2 weeks. Side effects are rare. Patients with severe systemic disease who have not responded to nystatin can be treated with ketoconazole (200 to 400 mg by mouth daily for 2 weeks) or fluconazole (100 to 400 mg by

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mouth daily for 2 weeks). If the response is incomplete, many weeks of therapy may be necessary. 149 GENERAL PRINCIPLES OF MANAGEMENT

In general, the management of esophageal disease depends on the nature and severity of symptoms, the degree of patient disability, and the potential for the occurrence of serious complications. Specific aspects of management related to various rheumatic diagnoses has already been discussed. As a general guideline, prescribed and nonprescribed medications should be reviewed to identify and avoid drugs that may induce or aggravate esophageal injury. Empirical management is recommended as a preliminary measure for patients with typical reflux symptoms. If symptoms continue despite such therapy, further evaluation with endoscopy, esophageal motility studies, and 24-hour ambulatory pH monitoring are recommended. (A stepwise approach for the management of GERD in patients with systemic sclerosis, limited cutaneous systemic sclerosis, and MCTD is outlined in Table 2). Patients with dysphagia should always be evaluated with endoscopy to exclude an obstructive lesion, particularly esophageal carcinoma. When medical therapy fails, surgery may be beneficial and does not necessarily carry a higher risk than in the general population. 71 Nevertheless, detailed investigation and a thorough understanding of the underlying esophageal pathophysiology is necessary to maximize the surgical success rate. Preoperative nutritional evaluation and support through TPN or gastrostomy feedings may be needed in certain patients with chronic debilitating rheumatic conditions. CONCLUSIONS

Esophageal problems are common in rheumatic diseases and can be easily identified provided that a pertinent clinical history is taken. A diagnostic evaluation is probably only indicated in symptomatic patients. Precise diagnosis depends on a thorough understanding of the natural history of the specific rheumatological disease and a stepwise clinical and laboratory evaluation. Modern technological advances in the diagnosis and therapy of esophageal involvement in rheumatic diseases will undoubtedly help clinicians provide a rational and effective approach when caring for such patients.

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