Arthritis & Rheumatism

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1 ARTHRITIS & RHEUMATISM Volume 37 Number 9, September 1994, pp , American College of Rheumatology Arthritis & Rheumatism Official Journal of the American College of Rheumatology REVIEW GASTROINTESTINAL MOTILITY DISORDERS IN SCLERODERMA ROBERT W. SJOGREN Scleroderma is a systemic disease characterized by excessive deposition of collagen and other matrix elements by fibroblasts in skin and, sometimes, in multiple internal organs. It is associated with prominent and often severe alterations of the microvasculature (l), the autonomic nervous system (2), and the immune system (3). Scleroderma may exist as either a localized or a systemic disease process. In its localized form, linear scleroderma, or morphea, is confined to the skin and adjacent tissues, and gastrointestinal (GI) tract involvement is minimal or absent (4). This review will only deal with the systemic form of scleroderma. Shown in Table 1 is the classification of systemic sclerosis (SSc). The breakdown of SSc into limited cutaneous and diffuse cutaneous forms is helpful in predicting onset of GI manifestations (5). Limited cutaneous SSc is characterized by skin involvement limited to the hands, face, feet, and forearms and includes the CREST variant (calcinosis, Raynaud s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias). When GI involvement occurs, it tends to be late in the course of disease. Diffuse cutaneous SSc is characterized by diffuse skin involvement and early, significant visceral involvement. This second variant is the one that principally affects the GI sys- Presented in part at the 56th Annual Scientific Meeting of the American College of Rheumatology, Atlanta, GA, October 1992, and at the International Conference on Scleroderma, Sydney, Australia, February Robert W. Sjogren, MD: Kaiser Permanente Medical Center, Falls Church, VA. Address reprint requests to Robert W. Sjogren, MD, Gastroenterology Section, Kaiser Permanente Medical Center, 201 North Washington Street, Falls Church, VA Submitted for publication April 7, 1993; accepted in revised form May 3, tem, and gut involvement may actually precede skin manifestations. Unfortunately, many of the publications on gut involvement in SSc do not distinguish between these two types, and esophageal involvement is common in both variants. Clinically symptomatic and significant GI involvement occurs in approximately 50% of all patients with SSc (6). In addition, many patients with SSc who do not have GI symptoms will have subclinical GI involvement. Careful studies have revealed that as many as 75-90% of patients with SSc have abnormalities noted on esophageal motility testing, although in many, the involvement was not clinically significant (7,8). Involvement of the anorectum was the next most frequent, occurring in 5&70% (4), small bowel hypomotility in 40% (9), and colonic involvement (on barium enema radiographic series) in l&so% (10). Until recently, delayed gastric emptying was only occasionally reported. However, recent studies have suggested that gastric involvement may be much more common than previously thought (1 1,12). It has been suggested that many of these patients are asymptomatic because of a concurrent visceral sensory neuropathy, although visceral nerve involvement in SSc is less well-studied than in other conditions such as diabetes mellitus. Pathology The pathology of SSc is similar throughout the GI tract. Figure 1 shows a Masson trichrome stain of a transmural section of duodenum. The villus structure and epithelial cell morphology are normal ( 13,14). There is a mild infiltration of the lamina propria with 1265

2 1266 SJOGREN Table 1. Subsets of systemic sclerosis* Diffuse cutaneous systemic sclerosist Onset of Raynaud s phenomenon within 1 year of the onset of skin changes (puffy or hidebound) Truncal and acral skin involvement Presence of tendon friction rubs Early and significant incidence of interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement Absence of anticentromere antibodies Nailfold capillary dilatation and capillary destruction$ Anti-topoisomerase antibodies (30% of patients) Limited cutaneous systemic sclerosis Raynaud s phenomenon for years (occasionally, decades) Skin involvement absent or limited to the hands, face, feet, and forearms Significant late incidence of pulmonary hypertension, with or without interstitial lung disease, trigeminal neuralgia, skin calcifications, or telangiectasias High incidence of anticentromere antibodies (70430%) Dilated nailfold capillary loops, usually without capillary drodout * Reproduced, with permission, from Journal of Rheurnatology (5). t Experienced observers have noted that some patients with diffuse cutaneous systemic sclerosis do not develop organ insufficiency, and they suggest using the term chronic diffuse systemic sclerosis for such patients. t Nailfold capillary dilatation and destruction may also be seen in patients with dermatomyositis, overlap syndromes, and undifferentiated connective tissue disease. These syndromes may be considered part of the spectrum of scleroderma-associated disorders. ies. Capillary basement membranes are thickened and laminated. The veins are relatively spared (1,18). The vascular changes appear to precede the muscle changes (I). Hypothesis: progressive GI involvement by SSc Although there are no longitudinal studies, there is circumstantial evidence that when SSc affects an area of the GI tract, it does so by an orderly series of steps that result in progressive dysfunction (6,19). This concept has implications with regard to therapy. The earliest GI lesion induced by SSc is neural dysfunction. The basis for this lesion is uncertain, although there is some evidence in the esophagus, both physi- chronic inflammatory cells (15). In the submucosa there is collagenous encapsulation of Brunner s glands and periglandular sclerosis (16). Also note the fibrous replacement in the muscularis. Figure 2, a hematoxylin and eosin-stained section from the colon of another SSc patient, shows the muscle changes better. There is atrophy and fragmentation of the smooth muscle of the muscularis propria. Initially, the distribution is patchy and later (as shown here), it is extensive and leads to collagen infiltration and fibrosis (16,17). These changes are more marked in the circular than in the longitudinal layer (18) and muscle atrophy exceeds fibrosis (9). In addition to fibrosis, there are decreased numbers of gap junctions between smooth muscle cells, a feature which impairs transmission of peristalsis (17). There is thickening and fibrosis of the serosa. Autonomic nerves appear normal by light and electron microscopy, but there are no sophisticated studies using immunofluorescent markers for transmitters or specific silver stains for neural morpho~ogy. Vascular abnormalities include myointimal Proliferation with narrowing and irregularity of the lumen and disruption of the internal elastic lamina of small arter- Figure 1. Masson trichrome-stained transmural section of duodenum from a patient with systemic sclerosis, showing normal villus structure and epithelial cell morphology. There is mild infiltration of the lamina propria with inflammatory cells. There is a collagenous encapsulation of Brunner s glands and periglandular sclerosis in the submucosa. Also note fibrous replacement of the muscularis (magnification x 200).

3 GUT DYSMOTILITY IN SSc 1267 invoked at this stage is partially reversible by prokinetic drugs. The final lesion in SSc is muscle fibrosis and is superimposed upon the two previous stages. At this stage, the muscle is no longer capable of responding, and restoration of function is not possible. Figure 2. Hematoxylin and eosin-stained transmural section of colon from a patient with systemic sclerosis, showing atrophy and fragmentation of smooth muscle of the tunica muscularis. The advanced muscle degeneration shown in this section is associated with collagen infiltration and fibrosis. These changes tend to be more marked in the circular than in the longitudinal layer, and muscle atrophy exceeds fibrosis (magnification x 100). ologic and anatomic, that it is due to arteriolar changes in the vasa nervorum (1,9,19). Compression of nerve fibers by collagen deposits has been offered as an alternate explanation (20). This produces abnormalities of function before smooth muscle contractility is impaired by the infiltrative process. These functional abnormalities may remain asymptomatic for prolonged periods. Treatment with prokinetic drugs at this stage is usually effective in reversing the functional abnormalities. The second lesion is smooth muscle atrophy. This is the stage during which symptoms most commonly first present. The muscle atrophy is superimposed on existing neural dysfunction. The muscle is capable of responding, but it is weak. The dysfunction The esophagus The esophagus is the most commonly affected area of the GI tract and is the most important clinically (2 1). Motility. Esophageal motility in early-stage SSc. Although esophageal motility is often abnormal in SSc, it is usually normal in other connective tissue disorders (except mixed connective tissue disease) and this difference can be useful diagnostically (7,8). The earliest esophageal abnormalities are located in the distal two-thirds, or the smooth muscle portion, of the esophagus (22), and are suggestive of neural dysfunction. Manometric studies show increased speed of the peristaltic wave, incoordination between the arrival of the peristaltic wave and relaxation of the lower esophageal sphincter (LES), and failure of the LES to relax to gastric baseline (4,23,24). Some of these changes may resemble achalasia (24), and they may be so subtle as to require provocation with a cholinesterase inhibitor such as edrophonium (25). Generally, the low LES pressure in systemic sclerosis distinguishes it from achalasia, which has a high LES pressure. Upper esophageal sphincter (UES) function in SSc is variable. Early in SSc, UES pressures may be increased, which may reflect stimulation by acid reflux (4). At this stage of involvement, electrophysiologic studies of esophageal smooth muscle show spontaneous disorganized spike bursts between swallows (26). Sometimes this is associated with nonpropagating contractions. This type of activity is reminiscent of diffuse esophageal spasm. With deglutition, there are repetitive, uncoordinated spike bursts of higher amplitude and duration than normal (26). Normal esophageal peristalsis and relaxation of the LES is shown in Figure 3A. Esophageal manometry early in SSc (Figure 3B) shows low-amplitude peristaltic contractions, a low LES pressure, and failure of the LES to relax. Esophageal motility in mid-stage SSc. In moderately severe cases, manometric studies show decreased amplitude of peristalsis progressing to absent peristalsis in the smooth muscle portion of the esophagus (6), delayed esophageal emptying of both liquids (27) and solids (4,11,23,24), and decreased pressure of

4 1268 SJOGREN A B ws ws ws ws 1 I ws 1 1 Ocm 80mmHg LES 20 mm Hg LES I20 mm Hg I ONE MINUTE LES I ONE MINUTE C ws ws wswsws ws wsws oan 1- loan 5an mm Hg I w t ONE MINUTE Figure 3. Esophageal manometry in A, a normal subject, B, a patient with early systemic sclerosis (SSc), and C, a patient with late SSC. The distance above the lower esophageal sphincter (LES) is shown on the left and contraction amplitude on the right. WS marks ivet swallows. A, In a normal subject, there are high-amplitude (>80 mm Hg), ordered peristaltic waves in all portions of the esophagus. Resting LES pressure is 27 mm Hg above gastric baseline, and on swallowing, the LES relaxes to gastric baseline. LES relaxation precedes the arrival of the peristaltic wave. B, In early SSc, peristaltic contractions are of low amplitude (20-30 mm Hg). Resting LES pressure is low (10 mm Hg), and the LES fails to relax to gastric baseline on deglutition. The bottom 3 tracings are from radially oriented manometric tips placed in the LES. C, In late SSc, there is preserved peristalsis in the proximal esophagus and absent peristalsis in the distal two-thirds. LES pressure is virtually absent.

5 GUT DYSMOTILITY IN SSc 1269 the lower esophageal sphincter. These manometric findings have been shown to correlate with development of erosive esophagitis (28). Electrophysiologic studies of smooth muscle show no myoelectric activity between swallows and a markedly lower than normal spike burst response after swallowing (26). Other electrophysiologic studies at this stage suggest that circular muscle function is more severely affected than longitudinal muscle function (29). Esophageal motility in late-stage SSc. Figure 3C is from a patient with advanced SSc. It shows preserved peristalsis in the proximal esophagus and absent peristalsis in the distal two-thirds. The LES pressure is virtually absent. Very late in SSc, the proximal skeletal muscle portion of the esophagus may also be involved, with abnormal or absent peristalsis (7,23). By the time there is abnormal function in the proximal one-third of the esophagus, muscle atrophy and fibrosis have occurred and the esophageal muscle responds to neither neural (edrophonium) nor direct (methacholine) stimulation. The UES may have diminished pressure (4). Decreased function of the upper esophageal sphincter in conjunction with gastroesophageal reflux is particularly devastating because it removes the last barrier to aspiration of refluxed gastric contents. Clinical presentations. Raynaud s phenomenon and autoimmune markers. A longstanding adage has bqen that Raynaud s phenomenon is associated with p or esophageal function (4). Some patients with SSc h ve prolonged cold-induced vasospasm in the vessels 4 o the esophagus ( esophageal Raynaud s ) as well as in the vessels of the hand (30). Reversal of this vasospasm by intraarterial injection of reserpine relieves both Raynaud s phenomenon and abnormal esophageal motility (31). However, isolated Raynaud s phenomenon may occur in 45% of the general population (32), and repeated studies have convincingly shown that the presence of Raynaud s phenomenon per se is not a predictor of abnormal esophageal function, but rather, an association with existing scleroderma (33). As many as 95% of SSc patients have Raynaud s phenomenon, and the duration of Raynaud s phenomenon in a patient with SSc may be diagnostically helpful. Patients with diffuse cutaneous SSc and a high risk of early visceral involvement usually have a brief duration of Raynaud s phenomenon before the development of skin changes, whereas patients with limited cutaneous SSc usually have many years of Raynaud s phenomenon before overt skin and visceral involvement occur. Use of markers such as abnormal nailfold capillaries (34) and the presence of antinuclear antibodies may help predict which patients with new-onset Raynaud s phenomenon are at risk of scleroderma and visceral involvement (35). Other autoantibodies are also helpful. The anticentromere antibody is associated with limited cutaneous disease (sensitivity 60%, specificity 98%) and the anti-scl-70 antibody is associated with diffuse cutaneous disease (sensitivity 38%, specificity 100%) (35). Gastroesophageal reflux disease (GERD). The big problem in SSc is the occurrence of GERD. It stems from two physiologic defects (28,36). First, decreased LES pressure results in an increased number of gastroesophageal reflux events. Second, once acid is refluxed into the esophagus, poor peristaltic function delays its clearance. Clearance of esophageal acid is a 2-step process (37). First, immediately following a reflux event, 1 or 2 peristaltic contractions occur which empty the esophagus of the majority of the refluxate. Second, some residual acid clings to the esophageal mucosa, and it takes 6-7 minutes more for swallowed saliva to neutralize it. Poor esophageal peristalsis inhibits both expulsion of refluxate and delivery of saliva to the acid residue. In addition, coexistence of the sicca syndrome with systemic sclerosis may reduce the acid-neutralizing capacity of swallowed saliva. To evaluate the relative importance of these two factors, a recent report employed simultaneous manometry, esophageal ph monitoring, and esophageal scintigraphy to study SSc and non-ssc patients with severe gastroesophageal reflux (36). The SSc group had significantly fewer reflux events than did the non-ssc reflux group (although more than normal controls), but once acid was refluxed, it took substantially longer to clear from the esophagus. In addition, during these prolonged clearance intervals, additional episodes of gastroesophageal reflux would occur, adding more acid to the esophagus. These piggy back reflux events were not detected by the ph monitor because the esophageal ph was already low. They could be most reliably detected by manometry, which showed an additional increase in resting intraesophageal pressure. It was concluded that decreased smooth muscle peristalsis was the primary contributor to acid exposure and esophageal injury in SSc, in contrast to diminished LES pressure as the primary cause of esophageal injury in non-ssc reflux. These

6 1270 SJOGREN results are supported by previous findings that disordered motility is the primary abnormality contnbuting to GERD in scleroderma (28). Therefore, prokinetic agents may have a therapeutic niche in SSc, particularly early in the disease. Gastroesophageal reflux is especially severe in SSc, and there is an increased incidence of complications including Candidu esophagitis, erosive esophagitis,, stricture, Barrett s esophagus, and aspiration (28,38). Strictures may be especially severe due to both GERD and abnormal collagen synthesis by the esophageal mucosa (39). As many as one-third of patients with SSc may develop Barrett s esophagus with its accompanying potential for adenocarcinoma (40). There are no clear predictors of risk for developing Barrett s metaplasia, although the CREST syndrome, prolonged dysphagia, and very low LES pressure have been suggested (40). The role of chronic aspiration in restrictive lung disease in SSc is controversial. A recent report demonstrated a positive correlation between esophageal ph scores and diffusing capacity for carbon monoxide values, suggesting that aspiration may be an important contributor to pulmonary disease in SSc (441).Others, however, have not been able to reproduce these findings. Diagnosis. It is important to aggressively evaluate SSc patients with GERD because their reflux is vicious, is associated with complications, and is often resistant to therapy. Disordered esophageal motility can be assessed using I of 3 modalities: esophageal manometry, cine-esophagraphy, and esophageal transit scintigraphy. Early changes in esophageal function are most accurately assessed with esophageal manometry (4,23). However, when evaluating an already symptomatic patient, all 3 modalities are equally sensitive and specific (33). Esophageal manometry may remain the choice because ph probes can be positioned for reflux testing at the same time. Although the duration of SSc and the presence of dysphagia predict abnormal findings on esophageal function tests (42) and abnormal esophageal function predicts the presence of esophagitis (28), the degree of dysfunction does not correlate with symptoms (33). Which patients with SSc should undergo esophageal manometry and endoscopy? There is a wide range of practice standards without a clear consensus. Some would evaluate all patients with scleroderma, while others would only evaluate those resistant to standard doses of omeprazole. Since abnormal esophageal manometry has been shown to predict patients at risk for erosive esophagitis and since symptoms do not correlate with esophagitis, it has been suggested that all patients with SSc receive baseline esophageal manometry and those with abnormal manometry undergo upper GI endoscopy (28). If esophageal manometry is unavailable, then periodic endoscopies might be warranted. It is unclear, however, whether minimally symptomatic patients with esophagitis should be treated. My approach is to evaluate all patients with symptomatic reflux requiring prolonged H, blocker therapy and all those with any symptom suggestive of a complication (especially dysphagia or pulmonary symptoms). This evaluation includes an endoscopy, esophageal manometry, and 24-hour esophageal ph monitoring. Because of the high incidence of Barrett s esophagus in SSc, endoscopy should always be conducted as part of the esophageal evaluation for reflux. In addition, all patients with dysphagia should undergo endoscopy. Those with Barrett s esophagus should enter a program of periodic endoscopic surveillance for development of dysplasia or adenocarcinoma and should have either ph monitor-proven suppression of acid reflux or suppression of inflammation demonstrated endoscopically and histologically. By this scheme, most patients with diffuse cutaneous SSc will be evaluated. Treatment. Medical therapy can manage GERD in most patients with SSc. As first-line therapy, there are the general measures such as weight loss, elevation of the head of the bed, multiple small meals, avoidance of recumbency within 3 hours of eating, and cessation of smoking. The major drugs used in the treatment of GERD are the antisecretory drugs: H, blockers and proton-pump inhibitors. H, blockers have been demonstrated to reduce GERD, improve symptoms, and improve endoscopic evidence of esophagitis, both acute (43) and chronic (44). Omeprazole, the protonpump inhibitor, has truly revolutionized the treatment of GERD. Although there have been few studies on the efficacy of omeprazole in SSc, it would appear that most cases of severe, complicated GERD can be managed with omeprazole (38,4547). Usually, twicea-day dosing is required (47). Median doses in most studies in scleroderma are 40 mg/day, and individual doses range as high as 80 mg/day (38,45,47,48). One study by Hendel (45) found that omeprazole not only healed esophagitis, but reduced elevated hydroxyproline levels to normal, suggesting reversal of esophageal fibrosis. A second report from investigators at Thomas

7 GUT DYSMOTILITY IN SSc 1271 Jefferson University (Philadelphia, PA) (49) has demonstrated that endoscopic ultrasonography reliably documents both esophageal wall thickness and specific degree of fibrosis in the muscularis propria. If probe localization on repeated studies is reproducible, this approach could permit assessment of the reversal of fibrosis as an index of the adequacy of antireflux therapy. Although the long-term safety of omeprazole has yet to be determined, its use in doses up to 80 mg/day for periods of up to 5 years without serious adverse effects in SSc has been reported (47). Once started, it is frequently difficult to discontinue omeprazole in SSc patients. One approach to such situations is to document therapeutic efficacy by endoscopy and esophageal ph testing. Once endoscopic healing is achieved, a prokinetic agent is added and attempts are made to switch from omeprazole back to an H, blocker. If this fails, an attempt is made to minimize the dosage of omeprazole by concurrent use of cisapride. Often, however, longterm, high-dose omeprazole is required indefinitely. The prokinetic drug cisapride was recently marketed in the United States as an effective single agent for the treatment of GERD. In scleroderma, this may not be the case. However, as adjuncts to the antisecretory drugs, metoclopramide and cisapride may have a unique niche in the treatment of selected patients because of the importance of disordered motility. These drugs work by increasing the LES pressure, by improving peristalsis (to aid esophageal emptying), and by increasing gastric emptying (50,51). In addition, they seem to improve symptoms independent of their effects on motility (52). In this respect, it is interesting to note that they inhibit type 3 5-hydroxytryptamine (5-HT3) receptors, which are present on vagal afferents (53). Bethanechol as a prokinetic drug in scleroderma is usually ineffective. Should other measures fail, antireflux surgery should be a consideration (54-57). One must be cautious because impaired esophageal motor function can result in esophageal obstruction if too tight an antireflux procedure is performed, and such surgery requires an experienced surgeon. A Collis gastroplasty with fundoplication has been shown to significantly reduce GERD in SSc patients (54). The recurrence of symptoms following antireflux surgery in SSc, however, is high and may be related to delayed gastric emptying (54). All of these approaches are aimed at treating the complications of systemic sclerosis, and not the underlying cause. It would be appealing to arrest or reverse the GI complications of SSc by treating its underlying cause. However, esophageal function is reported to continue to deteriorate in patients treated with D-penicillamine (58,59) and with total lymphoid irradiation (60). The stomach and small intestine Although the stomach has been said to be rarely involved in systemic sclerosis (6), the small intestine is commonly affected, and the two tend to function as a unit (7). In addition, recent data suggests that gastric emptying and antroduodenal motility are more frequently abnormal in SSc than previously known (1 1,12,61). Motility. Figure 4A shows a normal antral and duodenal manometry during fasting. During the fasting state, a cyclical pattern of contractile activity, the migrating myoelectric complex (MMC), occurs at intervals of 1.5 to 2 hours. The MMC consists of regularly recurring sequence of absent, irregular, and regular peristaltic activity that originates in the stomach and slowly progresses a variable distance down the small intestine before stopping and recurring again in the stomach. The MMC has been termed the intestinal housekeeper by Charles Code (62). Teleologically, its purpose is to clear remnants of digestion and excessive bacterial colonization from the stomach and small intestine. Patients with SSc often lack the MMC and are therefore predisposed to developing bezoars and bacterial overgrowth in the small intestine. Eating disrupts the MMC and induces a marked increase in contractile activity (Figure 4B). Gastric emptying and intestinal transit occur primarily during the fed response. Although the control of the MMC remains a subject of controversy, hormones appear to be the key in MMC generation. Endogenous cycling of motilin appears to be related to MMC initiation. Once initiated, MMCs are transmitted distally in a coordinated manner by the enteric nervous system. Should initiation or propagation of the MMC fail, the enteric nervous system and endogenous enkephalins and somatostatin are capable of generating an ectopic distal MMC as backup. This neurohormonal control of motility is directly reflected in the effects of drug therapy of gastric and small bowel stasis with the long-acting somatostatin analog, octreotide, with the cholinergic agonist, cisapride, and with the motilin agonist, erythromycin.

8 1272 SJOGREN FASTING A POSTPRANDIAL tracing is characterized by the absence of MMCs and the presence of high-amplitude uncoordinated contractions in the distal antrum and small intestine (19). Postprandially, uncoordinated activity may persist, and often, there is an antral hypomotility, characterized by reduction of both the number and the amplitude of contractions (corresponding to delayed gastric emptying) (19). This type of tracing with duodenal hyperactivity is similar to that observed in ganglionectomized dogs (67) and in humans with diabetic neuropathy (68), and is suggestive of a neuropathic disorder (19). Additional evidence of a primarily neuropathic disorder comes from studies of duodenal myoelectric activity, which show preserved slow-wave frequency and propagation (a property of smooth muscle), but diminished or absent response of the duodenum to distention (an intrinsic neural reflex) (69). Chronic intestinal pseudoobstruction in late SSc. Late in the course of SSc, the gastrointestinal muscle becomes refractory, the MMC is absent, and there is dramatic hypomotility (19,63). In addition, there is no contractile response of the stomach or small intestine to a meal. Figure 6 is a postprandial antroduodenal manometry tracing of a patient with advanced intestinal SSc, demonstrating that the antral and small intestinal contractions are few and of low amplitude. This pattern suggests a myopathic disorder B Figure 4. Normal antroduodenal manometry in A, fasting and B, postprandial states. The fasting tracing shows a typical migrating myoelectric complex (MMC) slowly progressing from the stomach through the proximal jejunum. The MMC has 3 phases: phase I, during which contractile activity is nearly absent (end of each tracing); phase 11, a period of irregular contractile activity (beginning of each tracing); and phase 111, a brief period of intense contractile activity (middle of each tracing). The postprandial tracing shows irregular contractile activity induced throughout the small intestine within minutes of eating. Note the high-amplitude contractions in the antrum. (Adapted, with permission, from Malagelada J-R, Camilleri M, Stanghellini V: Manometric Diagnosis of Gastrointestinal Motility Disorders. New York, Thieme Medical Publishers, Inc., 1986.) FASTING Chronic intestinal pseudoobstruction in early SSc. Both fasting and postprandial gastric and small bowel motility are abnormal in systemic sclerosis (12,19,63-65). Intestinal transit is delayed (66). Figure 5 shows fasting antroduodenal motility in a patient early in the course of intestinal SSc. The fasting Figure 5. Fasting antroduodenal manometry of a patient with early gastrointestinal systemic sclerosis, showing high-amplitude, uncoordinated contractions in the distal antrum and small intestine. There are no migrating myoelectric complexes. Similar patterns can be seen in early diabetes and amyloidosis and are suggestive of a neuropathic process. (Adapted, with permission, from Gastroenterology [191.)

9 GUT DYSMOTILITY IN SSc 1273 (19). At this stage, the intestinal myoelectric response to the regulatory hormones secretin and gastrin is impaired (69). In addition, while endogenous cycling of motilin and pancreatic polypeptide continues in patients with SSc, the levels of both are increased, which suggests end-organ refractoriness (65). Clinical presentations. Symptoms suggestive of gastric and small bowel involvement include anorexia, early satiety, halitosis, nausea, vomiting, intestinal distention, abdominal pain, weight loss, steatorrhea, diarrhea, and obstipation (6). Although there are no good epidemiologic data, several authors have reported a high frequency of gastroparesis in SSc (1 1,12,61). Many of these patients were asymptomatic, but even a mild delay in gastric emptying can worsen GERD (1 1,12). In one report, Maddern et a1 (1 1) found that 75% of symptomatic SSc patients have gastroparesis (11). Solid emptying is affected earlier and more severely than is liquid emptying. Chronic intestinal pseudoobstruction. Even when gastroparesis is present, small bowel symptoms usually dominate the clinical picture, with nausea, vomiting, distention, abdominal cramps, malabsorption, and diarrhea and constipation. Various degrees of intestinal pseudoobstruction may occur in as many as 40% of patients with SSc. Figure 7 is an upper GI radiographic film of a patient with intestinal pseudo- POSTPRANOIAL Figure 6. Postprandial antroduodenal manometry of a patient with advanced intestinal pseudoobstruction due to systemic sclerosis. Even after eating, there is dramatic hypomotility of the stomach and proximal small intestine. Similar patterns are seen in hereditary visceral myopathy and are suggestive of a myopathic disorder. (Adapted, with permission, from Gastroenterology [Is].) 4 I Figure 7. Upper gastrointestinal radiograph of a patient with intestinal pseudoobstruction due to systemic sclerosis. The duodenum and proximal jejunum are dilated and mildly edematous. obstruction due to SSc. Note the dilated duodenum and proximal jejunum. Malabsorption. Nutrition may be a major management problem in advanced SSc, and malabsorption can be the immediate cause of death (70-72). Malabsorption in SSc may result from 3 causes: bacterial overgrowth of the small intestine, abnormalities of the intestinal absorptive surface, and pancreatobiliary insufficiency (6). The first 2 stem from disordered motility. By far the most clinically important cause is bacterial overgrowth. In 1977 Vantrappen et al(63) demonstrated that small bowel bacterial overgrowth was associated with absent MMCs. Subsequent studies in rats suggested that restoration of MMCs reduces bacterial colony counts (73). The presence of small bowel bacterial overgrowth is strongly suggestive of disordered motility. In addition, use of omeprazole can induce achlorhydria, increase bacterial colony counts in the stomach, and may predispose patients to enteric infection with ingested pathogens such as Salmonella, cholera, and mycobacteria. Whether achlorhydria also worsens small bowel bacterial overgrowth, which represents colonization from below with colonic gram-negative

10 1274 SJOGREN and anaerobic flora, is unknown. Overgrowing bacteria compete for essential nutrients (such as vitamin B12) and deconjugate bile acids, inducing fat malabsorption. Even in the absence of small bowel bacterial overgrowth, some patients have persistent malabsorption. Tests of passive mucosal uptake, such as the D-xylose absorption test and the glucose tolerance test, may show abnormal results (15,74). In addition, folic acid levels are sometimes low. Bacteria synthesize folic acid, which is passively absorbed by the mucosa, giving rise to increased serum levels of folic acid in the presence of bacterial overgrowth. These findings suggest there is a mucosal defect inhibiting absorption in SSc. Morphologically, the intestinal mucosa is intact, and two possible explanations for this malabsorption have been offered (6). First, increased submucosal collagen deposition could interfere with permeation across the intestinal wall. Alternatively, lack of motility may result in an increased depth of the unstirred water layer. The unstirred water layer is a stagnant layer of luminal contents immediately adjacent to the mucosa. All absorbed materials must cross it to enter the enterocyte. By reducing luminal flow, disorders of motility increase the width of the unstirred water layer. The clinical significance of this layer is uncertain. For caloric intake, it is probably not important. However, it may account for deficiencies of certain water-soluble vitamins such as folic acid and pyridoxine. Finally, abnormalities of pancreatobiliary secretion have been described in SSc. An increased frequency of primary biliary cirrhosis has been suggested, although its incidence is still uncommon (75). Associated with primary biliary cirrhosis is a decrease in bile acid excretion, leading to fat malabsorption. Pancreatic secretion of digestive enzymes such as trypsin and lipase may also be impaired. With sophisticated pancreatic testing, such as the Lundh test meal and the secretin-cholecystokinin test, abnormal pancreatic exocrine function has been demonstrated in -30% of unselected patients with SSc (76). Although these abnormalities are usually mild, they may be clinically significant in 10-15% of patients. In addition to gastroparesis, pseudoobstruction, and malabsorption, the following other intestinal presentations of SSc have been reported: pneumatosis cystoides intestinalis, small intestine telangiectasia, and small bowel diverticula. In many circumstances, pneumatosis cystoides intestinalis is a benign condition, but in SSc, it may be associated with rapidly Figure 8. Spot film of the mid-jejunum from a small bowel followthrough radiographic series in a patient with gastrointestinal systemic sclerosis (SSc). Multiple diverticula are characteristic of SSc and may be a source of small bowel bacterial overgrowth. progressive SSc and death (77). It is important to distinguish benign intraperitoneal gas associated with pneumatosis from that associated with an intraabdominal catastrophe for which emergent surgery is indicated (78). Cutaneous telangiectasias are part of the CREST syndrome. Gastric, small bowel, and colonic telangiectasias also occur and are indistinguishable from those in Osler-Weber-Rendu disease. They may be a cause of GI bleeding and iron deficiency, and endoscopic sclerosis or cautery may be required (79-81). As shown in Figure 8, small bowel diverticula may be extensive and may contribute significantly to bacterial overgrowth in the small intestine. Diagnosis. Radiographic assessment. Radiographic evidence of involvement of the stomach and small bowel occurs late in intestinal scleroderma. The most commonly affected area is the duodenum and proximal jejunum, which may show edematous, dilated loops and pooling of barium. Multiple small bowel diverticula are suggestive of scleroderma, but may be seen in other conditions. Finally, gastroparesis, if severe, may result in retention of barium on upper GI films. Radioisotope gastric emptying studies are readily available and are more sensitive and quantitative than barium studies for demonstrating gastro-

11 GUT DYSMOTILITY IN SSc 1275 paresis. Solid emptying is affected earlier and more severely than liquid emptying, and solid-phase studies are the gastric emptying studies of choice. Antroduodenal and small bowel manometry. The diagnostic tests of choice for demonstrating abnormal motility of the stomach and small intestine and for differentiating neuropathic from myopathic involvement are antroduodenal and small bowel manometry. These tests are most useful in patients with significant upper GI symptoms, but without dilatation on upper GI series. In addition, they are important in the functional assessment of intestinal segments when resection is contemplated. There are multiple protocols for the conduct of these tests, and at present, they are only available in a limited number of referral centers. In general, these tests require intubation of the stomach and small intestine for periods ranging from 5 to 24 hours, and manometry is recorded in both the fasting and postprandial states. Sometimes, the motor response to prokinetic drugs is also monitored. Tube placement is often difficult in patients with poor motility, and radiographic confirmation of recording site location is necessary. The introduction of ambulatory manometry may make these tests both more acceptable to patients and more available to clinicians. There are many tests used to diagnose small bowel bacterial overgrowth including culture, breath H, levels, abnormal Schilling test result corrected with antibiotics, and increased serum levels of unconjugated bile acids. Culture of duodenal or jejunal aspirates can be done at the time of endoscopy. Cultures of >lo3 organisms/ml are suggestive, and those > lo5 organisms/ml diagnostic, of small bowel bacterial overgrowth. The breath H, is probably the most widely used test and is noninvasive. In this test, the patient ingests a nonabsorbable carbohydrate, such as lactulose, and breath H, levels are determined every 15 minutes for 3 hours. Normally, the carbohydrate takes 2-3 hours to reach the cecum, where bacteria degrade the carbohydrate, releasing H,, which is picked up as a rise in H, levels in the expired air. A premature H, spike suggests bacterial overgrowth. The Schilling test is excellent, but expensive and involves the use of an isotope. Increases in serum bile acids result from bacterial deconjugation of bile acids in the small intestine. However, in many clinical settings, this test tends to be unreliable. Treatment. For chronic intestinal pseudoobstruction, the prokinetic drugs are a central element to therapy: metoclopramide, cisapride, octreotide, and erythromycin. Metoclopramide was the first truly efficacious prokinetic drug (82). It is both a dopaminergic antagonist and a cholinergic agonist (82). It facilitates acetylcholine release in the myenteric plexus, probably by interaction with serotonergic receptors on nerves. Metoclopramide can decrease symptoms of GERD even in the absence of endoscopic healing. This may be due to inhibition of 5-HT3 receptors on sensory neurons. Metoclopramide crosses the blood-brain barrier and has a central antiemetic effect. Because metoclopramide is a dopamine antagonist, it has important extrapyramidal side effects and may cause irreversible tardive dyskinesia. Metoclopramide has been shown to increase LES pressure, to increase gastric emptying, to induce MMCs, and to increase antral and small bowel peristalsis and transit (65,83). Its effects on esophageal transit and on esophageal contraction amplitude are inconsistent (82,83). Unlike cisapride, metoclopramide has little effect on the colon. Metoclopramide is indicated in the treatment of gastroparesis and small bowel stasis, and it has minor effects in GERD. Cisapride was released in the United States in 1993 for use in gastroesophageal reflux. It is chemically related to metoclopramide, but is devoid of antidopaminergic effects and therefore does not cause extrapyramidal side effects or prolactin secretion (84,85). The primary mechanism of cisapride is to facilitate release of acetylcholine in the myenteric plexus by stimulation of 5-HT, receptors (85). Like metoclopramide, cisapride decreases symptoms of GERD even in the absence of endoscopic healing. Finally, recent data have demonstrated the persistence of prokinetic effects in the presence of atropine and tetrodotoxin, suggesting that cisapride may have direct smooth muscle effects. In the esophagus, cisapride increases the LES pressure (50,86), increases the amplitude of peristaltic contractions (87), but has little effect on esophageal emptying (50,51). In the stomach, cisapride increases both liquid and solid emptying via increasing both fundic and antral contractions and improving antroduodenal coordination (87-89). In an uncontrolled trial, 1 month of oral cisapride at a dosage of 10 mg 4 times a day reduced symptom scores in SSc patients (51). In the small intestine, cisapride speeds transit time, induces frequent propagating contractions, and restores the MMC. In the colon, it speeds transit time and increases contractions. The effects of cisapride appear to be more prolonged than those of metoclopramide, and side effects appear to be fewer.

12 1276 SJOGREN It is the only drug for which symptomatic improvement sometimes correlates with demonstrated prokinetic effects. A new addition to the prokinetic armamentarium is the long-acting somatostatin analog, octreotide (90). In conventional high doses, octreotide is an antidiarrheal and may be used for this purpose in SSc patients. However, at low doses (50 pg at bedtime), octreotide has been shown to induce MMCs, to increase intestinal peristalsis, to decrease bacterial overgrowth, and to relieve symptoms of nausea, bloating, vomiting, and abdominal pain in a study of 5 patients (90). Because octreotide does not increase gastric emptying and because the motor and pancreatic responses to eating may be impaired in scleroderma, it is important to limit doses to once at bedtime (90,91). Hence, octreotide has limited usefulness for mealrelated symptoms. It is also important to remember that prolonged use of octreotide is associated with impaired gall bladder emptying and increased incidence of cholelithiasis. The macrolide antibiotics, such as erythromycin, are motilin agonists and can increase gastric emptying, induce MMCs, increase the peristaltic response of the small bowel to eating, and speed colonic transit. Erythromycin has been reported as therapy in a variety of conditions including SSc (92). Most notably, a 1990 paper in the New England Journal of Medicine reported that both intravenous and oral erythromycin were effective in increasing gastric emptying and in increasing postprandial spike responses in diabetic patients with autonomic neuropathy (93). However, the current dosage recommendation (250 mg with meals) often causes abdominal cramps and is poorly tolerated, and its prolonged use as a prokinetic agent is often disappointing. For the motility disorders, the current suggested, but untested, therapeutic algorithm is as follows. For neuropathic early SSc, prokinetic drugs are the treatment of choice. In SSc, cisapride has been shown to increase solid and liquid gastric emptying and to decrease GI symptom score (51). In chronic idiopathic pseudoobstruction, cisapride increases small intestine peristalsis and transit, and is the drug of choice (64). Metoclopramide is inconsistently effective, has neurologic side effects, but might also be tried (65). Both cisapride and metoclopramide also have some antireflux effects. Parenteral use of prokinetic drugs may be required if there is concern about absorption from a paretic gut. A limitation to the use of cisapride is its lack of a parenteral formulation. For late myopathic pseudoobstruction, prokinetic drugs are usually ineffective (although often tried), and surgery is the only option beyond nutritional support. Venting enterostomy, whether surgical (94), laparoscopic (99, or endoscopic (96), is a relatively new approach that is short of resection (97-99). It is used to decompress distended bowel, relieve pain and bloating, and may enable prokinetic drugs to be effective in less severe cases. When other forms of therapy fail, surgical resection to remove localized disease because of obstruction or for pain control may be considered (17, ). Such an approach requires careful localization of the atonic segment to conserve intestine and to assure that newly apposed segments are functional (103). Examples of such surgical procedures include jejunostomy, with or without decompressing gastrostomy, and total or partial colectomy. Simple pyloroplasty or antrectomy and gastrojejunostomy usually fail. As a group, patients with advanced SSc tolerate surgery very poorly, and a conservative stance should be taken when surgery is contemplated. In the future, small bowel transplantation may become an option. Malabsorption. Although many patients with SSc will have abnormal intestinal function, treatment of malabsorption should be restricted to patients with significant signs and symptoms. This should be a minority of patients. Intestinal SSc is a long-term, chronic disease, and nutritional support and pain control are major problems. There is no predictably effective therapy other than treatment of bacterial overgrowth and nutritional support. For all stages of intestinal SSc, antibiotics for bacterial overgrowth and dietary supplements (such as vitamins, low-residue and elemental diets, and medium-chain triglycerides) are mainstays of therapy. The usual treatment of small bowel bacterial overgrowth is antibiotics such as ciprofloxacin, amoxicillin, metronidazole, tetracycline, and oral vancomycin. Rotating monthly courses of different antibiotics and providing antibiotic holidays are believed by some to help prevent emergence of resistant strains and to preserve antibiotic efficacy (15). In most cases, antibiotics alone are sufficient. It should be noted, however, that antibiotics can worsen constipation, and abrupt cessation may exacerbate obstructive symptoms. If bacterial overgrowth persists, addition of a prokinetic agent may help, but may also increase diarrhea. Nutritional supplementations with fat-soluble vitamins, vitamin C, low-residue and elemental diets, and medium-chain triglycerides are mainstays of nu-

13 GUT DYSMOTILITY IN SSc 1277 tritional support. A recent study from Sweden (72) compared 30 patients with GI manifestations of SSc with matched healthy control subjects. It demonstrated that 43% of scleroderma patients had fat malabsorption and 50% had malnutrition, according to anthropometric measurements (72). Deficiencies of vitamin C and of all fat-soluble vitamins were noted. Selective avoidance of dietary fruits and fiber and fat malabsorption appeared to be a greater problem than insufficient caloric intake. However, during a 1-year followup, supplementation of oral intake did not alter these parameters. If correction of dietary deficiencies remains a problem after apparent successful treatment of bacterial overgrowth and nutritional supplementation, a trial of replacement pancreatic enzymes is worth considering. Such replacement therapy in cases of suspected or proven pancreatic insufficiency is logical, but there are no studies demonstrating efficacy. Antiemetics may afford symptomatic relief, although addressing the underlying GERD or gastroparesis is usually more rewarding. Use of prokinetic agents may improve absorption by increasing mucosal contact and decreasing bacterial overgrowth, although there are no studies documenting this. For an acute exacerbation, nasogastric suction, intravenous fluids, and antibiotics may be used. In severe, refractory cases, long-term parenteral nutrition may be required (104). This has been associated with complicatioddeath rates as high as 40%. Grabowski and Grant (104) established the following guidelines for nutritional support in scleroderma patients: 1) absence of rapid disease progression, 2) adequate pulmonary function, 3) adequate renal function, 4) adequate cardiac and circulatory function, 5) adequate mobility and manual dexterity, and 6) an adequate home support system. The colon Involvement of the colon in SSc is surprisingly common. The anorectum is the most commonly affected area, and recent studies suggest that it is almost as commonly involved as the esophagus (4). Careful manometric studies have documented that patients with abnormal esophageal manometry almost always also have abnormal anorectal motility (4). Although fecal incontinence is very common, clinically significant colonic presentations are usually related to colonic pseudoobstruction (105). 1.1.I NORMAL SCLERODERYA :/r- 3,A- - RECTUM INTERNAL, SPHINCTER EXTERNAL SPHINCTER -1 r II Figure 9. Anorectal manometry using a Schuster balloon, in a healthy volunteer and a patient with scleroderma and fecal incontinence. Arrow marks inflation of the rectal balloon. The normal tracing demonstrates an intact rectoanal inhibitory reflex, with relaxation of the internal anal sphincter and contraction of the external anal sphincter. The patient with scleroderma has an absent rectoanal inhibitory reflex, with no response of the internal anal sphincter to balloon distention and a weak contraction of the external anal sphincter. (Adapted, with permission, from Wald A: Anorectum, Atlas of Gastrointestinal Motility in Health and Disease. Edited by MM Schuster. Baltimore, Williams and Wilkins, 1993.) Motility. Colonic transit in SSc is prolonged and often shows decreased right colonic or pancolonic transit in SSc patients with constipation as compared with healthy control subjects and with SSc patients without constipation (61,106). This would suggest that colonic inertia, rather than functional obstruction at the anorectum, is the primary cause of constipation in SSc. Rectosigmoid function is abnormal in patients with SSc. Fasting rectosigmoid motility in SSc is normal (including slow waves, spike bursts, and contractions) (107). In normal subjects, rectosigmoid motility increases after eating. This is mediated by a cholinergic pathway (108). Patients with SSc lack this postprandial increase in motility (109). Administration of the anticholinesterase, neostigmine, restores the postprandial motility response in patients with early SSc, but not in those with longstanding disease (109). Disordered anorectal function occurs early in the course of scleroderma and is a major factor in the development of fecal incontinence. The most common manometric abnormality is an absent or diminished rectoanal inhibitory reflex (see Figure 9) (4,110). If a balloon is distended in the rectum, normal subjects will show a relaxation of the internal anal sphincter (which is smooth muscle) and a contraction of the

14 1278 SJOGREN external anal sphincter (which is skeletal muscle). In the early stages of SSc, the response of the internal anal sphincter is diminished or absent and the response of the external anal sphincter is either normal or increased (4,111). These changes correlate with reduction in the amplitude of relaxation of the LES in the esophagus (4). These findings are reminiscent of those seen in Hirschsprung s disease and are consistent with a neural defect in the myenteric plexus. In the later phases of SSc, decreases in resting pressures of the internal and external anal sphincters, decreased length of the anal canal, decreased maximum squeeze pressure, and finally, decreased rectal compliance due to collagen deposition occur (4,106,107,110,111). The only changes that correlate with symptoms are decreased squeeze pressures (106) and decreased rectal compliance (107), which correlate with diarrhea. Presence of a rectal prolapse further decreases anal sphincter pressures and can contribute to incontinence (1 10,111). Clinical presentations. Symptoms of constipation are extremely common (6). Constipation, defined as 52 spontaneous stools/week, may be severe, and barium impaction (1 12) and stercoral ulceration and perforation (1 13) of the colon have been reported in SSc. Fecal incontinence is probably the most common colonic presentation of SSc (4,110). Other presentations of colonic involvement in SSc include diarrhea (109), rectal prolapse (1 lo), spontaneous perforation (1 14), and colonic infarction (1 15). Diarrhea is most often a symptom of small intestine bacterial overgrowth. Diagnosis. Radiographic assessment. The incidence of pancolonic involvement identified on barium enema radiographic series in patients with SSc varies from 10% to 50% (6). Dilatation of the large bowel is common, and wide-mouthed antimesenteric pseudodiverticula in the colon are highly suggestive of SSc (18). These diverticula contain all layers of the intestinal wall, but the muscularis propria is atrophic. Colonic transit assessment. Total and regional colonic transit can be measured simply and inexpensively using the Sitz marks method according to the Mayo Clinic protocol (1 16). Patients ingest capsules containing 20 radiopaque markers on each of 3 consecutive days and an abdominal radiograph is obtained on day 4 and on day 7. The marks in the left colon, right colon, and rectosigmoid are counted, and by a simple formula, transit times are calculated. Anorectal manometry, defecatography, and anal electromyography. These are specialized techniques designed to assess the function of the anal sphincters and pelvic sling muscles. These techniques are useful in evaluating incontinence and colonic outlet obstruction and in the consideration of surgical approaches (1 10). Treatment. As in other intestinal areas, treatment of colon and anorectal disorders in SSc is symptomatic. Fecal incontinence is due to anal sphincter involvement. The first line of treatment is to treat diarrhea. Diarrhea is principally due to small intestinal causes. In addition to treatment of small bowel bacterial overgrowth, nonspecific measures including a low-residue diet, antidiarrheals (such as loperamide), and bile acid-binding resins (such as cholestyramine) may be tried. If this fails to work, biofeedback measures can be tried, although there are no studies of biofeedback in the management of SSc. Finally, surgical measures may be helpful. If proximal colonic motility is shown to be normal and decreased pressures of the anal sphincters are shown with an absent rectoanal inhibitory reflex, then a posterior anal repair may be helpful (1 I 1). Treatment of constipation is somewhat more complicated. Nonspecific measures should be tried first, although they often fail: increased fluids, increased fiber/metamucil (psyllium hydrophilic mucilloid), and bowel training. If these fail, the next step is to quantitate total and regional colonic transit. The most common finding in SSc is generalized slow transit, consistent with colonic inertia or pseudoobstruction. If this is the case, the algorithm discussed for the small intestine should be used: first, prokinetic drugs, then venting or surgical resections. Of note, metoclopramide is usually not effective in the colon; cisapride and erythromycin are reported effective. There are no data on the effect of octreotide on colonic function. If the colonic transit is normal except for delay at the rectosigmoid, colonic outlet obstruction should be considered. An evaluation of pelvic floor function should be initiated with anorectal manometry, defecatography, and anal electromyography (1 10). The purpose of this evaluation is to determine the function of the anal sphincter and the skeletal muscles in the pelvic sling. If pelvic floor dysfunction can be diagnosed, specific surgical reconstructions can be performed. Summary After the skin, the gastrointestinal tract is the second most common target of systemic sclerosis. The

15 GUT DYSMOTILITY IN SSc 1279 major clinical manifestations include gastroesophageal reflux, small bowel bacterial overgrowth, malnutrition, and intestinal pseudoobstruction. Treatment is symptomatic and supportive. Gastroesophageal reflux can usually be adequately managed with prokinetic drugs, omeprazole, and judicious use of antireflux surgery. If Barrett s esophagus is present, periodic endoscopic monitoring for development of dysplastic changes or adenocarcinoma is indicated. Bacterial overgrowth usually responds to rotating antibiotics and prokinetic drugs. Malnutrition and intestinal pseudoobstruction remain the major problems and often home total parenteral nutrition is required. Intestinal pseudoobstruction occurs in two phases: an early, neuropathic phase and a late, myopathic phase. The early neuropathic phase may respond to prokinetic drugs (metoclopramide, cisapride, octreotide, and erythromycin) and dietary modification (lowresidue diets, vitamin supplementation). 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