Systemic Sclerosis and the Gastrointestinal Tract—Clinical Approach

Systemic sclerosis (SSc) is a multisystem disease characterized by functional and structural abnormalities of small blood vessels, fibrosis of the skin and internal organs, immune system activation, and autoimmunity. The gastrointestinal tract is involved in nearly all patients and is a source of significant morbidity and even mortality. The aim of this review is to summarize the pathogenesis and to provide a clinical approach to these patients.

term "scleroderma," which is deriv ed from Greek terminology "skleros" (hard) and "derma" (skin). 1 The term "sy stemic sclerosis" was conceiv ed by Robert H. Goetz, a heart surgeon, in 1 945, who described scleroderma as a disease that infiltrates sev eral internal organs. 2

PAT HOGENESIS
Sy stemic sclerosis (SSc) is a multisy stem disease characterized by functional and structural abnormalities of small blood v essels, fibrosis of the skin and internal organs, immune system activation, and autoimmunity . The cause of SSc is unknown. An integrated hy po thesis of the pathogenesis of SSc includes a combination of abnormalities in the vascular and in the immune sy stems on a background of genetic susceptibility and in the presence of env ironmental stimuli, which leads to further augmentation of the immune sy stem's activation and, ultimately , to fibroblast proliferation, collagen deposition, and destruction of normal tissue architecture. 3 The v ascular hypothesis suggests that the primary ev ent in SSc occurs at the level of capillaries and small v essels and manifests as endothelial cell injury and activation. Vascular pathology is characterized by abnormal vasoreactivity, dysregulation of v asoconstrictiv e molecules and their receptors, upregulation of intracellular signaling kinases, altered balance of hypoxia-induced vascular growth factors, and aberrant function of v ascular cells and autoimmune effector cells, which all lead to insufficient neoangiogenesis. [4][5][6][7][8][9][10] During the last decade, studies have emphasized the role of the innate and the adaptiv e immu ne sy stem in the pathogenesis of SSc. Genome-wide approaches have revealed that increased expression of genes associated with SSc susceptibility and/or disease phenotype plays a major role in the regulation of the immune sy stem. T cells, fibroblasts, growth factors, chemokines, and endothelin-1 are all key factors in disease pathophy siology . [11][12][13][14][15][16] Sy stemic sclerosis has been classified according to the ex tent of clinically detectable skin tightness into limited cutaneous SSc (hardening confined to skin from elbows distally and from knees distally ) and diffuse cutaneous SSc (hardening of skin including prox imal ex tremities and the trunk). 17 Both forms inv olv e the internal organs.
Inv olvement of the gastrointestinal tract (GIT) in SSc is ex tremely frequent; it is a leading cause of morbidity and the third most common cause of mortality in this disease. Esophageal abnormalities occur in up to 90% of patients, stomach involvement can be documented in 50% or more of patients, and small bowel, colonic , and anorectal inv olv ement occur in 50%-7 0% of SSc patients. [18][19][20] The pathogenesis of GIT inv olvement is thought to include early vascular damage to the vasa nervorum of the nerv es innervating the GIT. This leads to neurological dy sfunction, particularly inv olv ing autonomic pathway s. 21 ,22 The activ ation of the immune sy stem may contribute to neurological dysfunction by production of antibodies which specifically inhibit M3-muscarinic receptor-mediated enteric cholinergic neurotransmission. 23 Endothelial/ly mphocyte activation leads to prominent infiltration of CD4+ T ly mphocytes as well as CD20+ B ly mphocytes into the gastric mucosa of patients with SSc and perhaps represents an early ev ent in gastrointestinal (GI ) pathology. 24 With damage to innerv ation, smooth muscle atrophies and is ev entually replaced by fibrotic tissue. With increasing atrophy and tissue replacement, the GIT becomes progressively less effective and less responsiv e to therapeutic agents. 25

SY MPT OMS AND SIGNS
Motility disorders and v ascular mucosal lesions are the main manifestations of GIT inv olvement in SSc. The entire GIT may be inv olved from the mouth to anus in both limited and diffuse SSc.
Oral cav ity abnormalities are common in SSc. Tightening of the perioral skin secondary to fibrosis may cause severe feeding impairment. Xerostomia due to Sicca sy ndrome may occur in 1 4%-20.5% of SSc patients and may further decrease oral intake. 26 Esophageal inv olv ement is the most frequent gastrointestinal manifestation of SSc and occurs in up to 90% of patients. Multiple abnormalities of esophageal function cause the clinical manifestations of sev ere gastroesophageal reflux and dy sphagia to liquids and solids. The hallmark of SSc in the esophageal body is ineffectiv e esophageal motility with low or absent contractile activ ity . Subsequently, the lower esophageal sphincter (LES) is hy potensive, and hiatal hernia is common, resulting in almost free regurgitation of gastric acidic contents into the esophagus. In addition, saliva and esophageal mucosal secretions production is reduced. Heartburn and dy sphagia are the most common complaints. Hoarseness, aty pical chest pain, nocturnal cough, and regurgitation may also occur.
Ineffective motility, hypotensive LES, poor acid and bolus clearance, and lack of buffer secretions all contribute to esophageal mucosal damage secondary to refractory acid reflux. Late complications include esophageal stenosis, strictures, and, ultimately , Barrett's esophagus and intestinal metaplasia. 19 The prev alence of Barret's esophagus in SSc was found to be 1 2.7 %, similar to the prev alence in patients with gastroesophageal reflux disease (GERD). 27 An increased risk of esophageal adenocarcinoma was reported in SSc patients and was associated with the occurrence of dy splasia in Barrett's esophagus. 28 Gastroesophageal reflux disease was suggested to be a risk factor for the development of interstitial lung disease. 29 Gastroparesis is common in SSc patients, but its true prev alence is unknown. It is important to be aware of diagnosis and activ ely look for it, as its appropriate management can relieve the patient 's sy mptoms significantly .
Early satiety, postprandial fullness, nausea and v omiting, regurgitation of gastric contents, abdominal pain, and, in sev ere cases, malnutrition due to inability to maintain adequate oral intake are the clinical manifestation of gastroparesis.
Autonomic dy sfunction plays an important role in the pathogenesis of this dy smotility . 21 Small bowel inv olvement has been reported in 50%-7 0% of SSc patients [18][19][20] and may lead to high morbidity and life-threatening complications, such as sev ere malabsorption and pseudo-obstruction. Small bowel hy pomotility induces stasis of intestinal contents and small intestinal bacterial overgrowth (SIBO), which contribute to bloating, abdominal pain, nausea, v omiting, diarrhea, malabsorption, and weight loss. 30 The prevalence of SIBO in SSc has been reported to be 30%-62%. 31 -35 Small intestinal bacterial overgrowth is one of the main pathogenetic factors of malabsorption which is associated with 50% mortality over 8.5 years in SSc patients. 36 Rare or absent motor migratory complex es (MMCs), which serv e as a house-keeping mechanism of intestines, contribute to SIBO, while decreased postprandial contractility of the small intestine is one of the causes of postprandial pain and discomfort. Clinically , diarrhea, bloating, and nutritional deficiencies due to malabsorption should raise the suspicion of SIBO.
Intestinal pseudo-obstruction is a rare cause of hospitalization in patients with SSc, but is associated with high in-hospital mortality . 37 Pneumatosis cystoides intestinalis (PCI) is a rare complication of SSc and is considered a sign of poor prognosis. 38,39 It is characterized by development of multiple intramural air-filled cysts, due to anaerobic bacterial overgrowth in the intestine and increased intraluminal hy drogen production. The cy sts may rupture and cause pneumoperitoneum and secondary peritonitis. The risk of perforation is already increased in SSc patients due to fibrosis and loss of compliance of the intestinal wall. 40 The colon is frequently involved in SSc, although it is not alway s sy mptomatic. Abnormal motility pattern has been found in 7 5% of asy mptomatic SSc patients. 41 Constipation and fecal incontinence due to reduced colonic motility and hy potensiv e anal sphincter are the main issues involving the colon. 42 Fecal incontinence is an under -reported but frequent complication of SSc. Patients with diarrhea are especially prone to incontinence episodes.
Malnutrition and weight loss result from the multiple anatomic and functional abnormalities through the whole gastrointestinal tract in SSc, but studies assessing their prev alence ar e lacking.
V ascular lesions of the mucosa may cause severe anemia in SSc patients. The lesions may be scattered throughout the entire intestine or may involve only the stomach antrum (gastric antral v ascular ectasia). 43 Gastric antral v ascular ectasia (GA VE) is characterized by a pathognomonic endoscopic pattern, mainly represented by red spots either organized in stripes radially originating at the py lorus ("watermelon stomach") or arranged diffusely ("honeycomb stomach"). 44 "Watermelon stomach" is the "classic" and more familiar form of GAVE. There are conflicting data regarding the prev alence of GAV E in SSc. Prev ious studies estimated a 1%-5.7 % prev alence of GAV E in SSc patients. 45,46 On the other hand, a study performed in patients with early diffuse SSc reported a much higher prev alence of GAV E: 22.3%. 47 A recent study, using video capsule endoscopy (VCE), found ev idence of "watermelon stomach" in 1 8% of SSc patients. 48

CLINICAL APPROACH AND ASSESSMENT T OOLS
In daily practice, the patient presents with a mixed clinical picture of refractory GERD, diarrhea, bloating, dy sphagia, weight loss, and nutritional deficiencies. The diagnostic studies should be directed to identify the GI site inv olv ed, assess sev erity, and rule out other etiologies. Sy stematic ev aluation of motoric function of the GI tract in SSc patients enables the clinician to build an appropriate treatment plan for the indiv idual patient.
Anamnesis should be directed to identify the most bothersome sy mptoms of the patient. First, nutritional status should be ev aluated, as often weight loss is a sensitiv e sign of poor functional status of the GI tract. Questions regarding sy mptoms of gastroparesis and fecal incontinence should be activ ely asked, because patients may hav e difficulties in sharing this information.
There is no single objective measure to assess the ex tent and sev erity of GI inv olv ement in SSc patients.
Upper gastrointestinal (UGI) endoscopy is the gold standard for esophagus and stomach morphology assessment. The procedure is a means for v isualizing tissue, for sampling, and for therapeutic interv entions (e.g. in cases of bleeding from GAVE). Standard endoscopic imaging is useful for the detection of grossly v isible lesions but may be less sensitiv e for the detection of early or subtle mucosal changes.
Gastroscopy is the gold standard for diagnosis of GAV E and for assessment of its sev erity . Gastric biopsy can help to diagnose the condition in equiv ocal cases. The histological pattern, although not pathognomonic, is characterized by the co-presence of ectasia and/or fibrin thrombi, spindle cell proliferation, and fibrohyalinosis. Gastric antral vascular ectasia can also be treated during UGI endoscopy using argon plasma coagulation.
In addition, information about the functional motility status of the upper GI tract can be obtained during UGI endoscopy : esophageal and gastric contents despite fasting, dilated esophagus, widely opened gastroesophageal junction, hiatal hernia, and lack of peristalsis are highly suggestiv e of hy pomotility .
Ev aluation of motor GI function should be performed in patients with sy mptoms suggesting motility abnormalities. High-resolution esophageal manometry is a new technique to evaluate esophageal motility. Reflux extent and severity, as well as a response to acid suppression medications, is studied using esophageal reflux monitoring with pH or pH/impedance probes based on intranasal catheter, or, recently, the more comfortable wireless Brav o pH-metry capsule.
Gastric empty ing can be assessed by gastric scintigraphy or breath test.
Small intestinal bacterial ov ergrowth is diagnosed by breaths tests, which have multiple limitations, or, rarely performed clinically, by culture of jejunal aspirate. 49 A more practical approach would be empirically treating SIBO with antibiotics and a retrospective diagnosis based on clinical response. 50 Colonic transit time can be non-inv asiv ely measured using the SITZMARKS test (ingestion of a capsule containing 24 radiopaque markers that are v isible throughout the digestiv e tract v ia X-ray ).
Anorectal function is studied by anorectal manometry, preferably using high-resolution technology, which provides information of the functional status of the sphincter. Transrectal ultrasound (US) can be used to visualize the anatomy of internal and ex ternal anal sphincters. Magnetic resonance imaging has been used for ev aluation of anorectal anatomy in SSc patients, but it is much more ex pensiv e and without clear adv antages in this patient group compared to US. 51 V ideo capsule endoscopy (VCE) identifies a high prev alence of gastrointestinal mucosal abnormalities, especially potentially bleeding vascular mucosal lesions (watermelon stomach, gastric and/or small intestinal telangiectasia, gastric and/or small intestinal angiodysplasia). 48 Hy pomotility problems in SSc may raise concern regarding the use of V CE in these patients.

T REATMENT
To date, the management of GIT inv olvement in SSc remains empirical and sy mptom-driv en. The ultimate goal of a sy stematic complex approach to GI abnormalities in scleroderma patient is the improv ement of their nutritional status and quality of life.
High-dose, twice daily acid suppression treatment with a proton pump inhibitor is a mainstay therapy for GERD. Sometimes a combination with H2 blockers (ranitidine, famotidine) is needed to control the night-time breakthrough acid reflux. It is important to notice that poorly controlled GERD in SSc patients, despite optimal medical treatment, is often secondary to gastroparesis, and specific measures to improv e gastric empty ing should be incorporated into the treatment plan.
Treatment of gastroparesis starts with nutritional interv ention-multiple small meals and low-fiber diet. When needed, pro-kinetic medications (domperidone, metoclopramide, erythromycin) are added to improv e gastric empty ing.
Small intestinal bacterial overgrowth is usually treated with antibiotics. Recently , rifax imin has been used for treating SIBO, with the adv antages of being a non-absorbable antibiotic with few systemic side effects, as well as possible positive influences on intestinal flora. 52 Octreotide has been reported to be helpful in selected cases, especially in patients with recurrent pseudo-obstruction of the small bowel. 41,53 Fecal incontinence requires a complex approach, combining medical and nutritional interv entions with phy sical therapy, preferably anorectal biofeedback training. Unfortunately, the response rate to these therapies is not usually satisfactory in SSc patients. New therapies for fecal incontinence, such as sacral nerve stimulation, have been reported to be unsuccessful in scleroderma. 54 Nutritional deficiencies should be corrected (v itamins B1 2, D, etc.). Deficiency of v itamin B12 is common and should be treated. In case of low BMI an appropriate nutritional plan should be developed for each patient. Patients with chronic intestinal pseudo-obstruction who cannot tolerate enteral feeding may need prolonged total parenteral nutrition. 55,56 Some studies suggest probiotics may be useful for treatment of SSc -associated distention and bloating, but the small number of patients and the div ersity of probiotics used do not permit any consistent treatment recommendation. 57 Gastric antral v ascular ectasia should be treated by endotherapy-argon plasma coagulation (APC). Treatment with APC can reduce the need for blood transfusions. 46 Most patients with early diffuse SSc and GAV E will need recurrent endoscopic coagulations to overcome UGI bleeding. In these patients with early diffuse progressiv e disease, concomitant immune suppression with cyclophosphamide or mycophenolate mofetil might contribute to significant improvement and eventually to final resolution of the UGI bleeding. 58-60 and our unpublished data Data regarding the influence of immunomod ulatory therapy on GIT inv olv ement are scarce. A recently published study reported a beneficial effect of long-term therapy with intrav enous immunoglobulins on some of the GI manifestations in patients with ov erlap of SSc and my ositis. 61 There are no data about the influence on GIT in SSc patients without my ositis.

CONCLUSIONS
The gastrointestinal tract is one of the main systems inv olved in SSc patients causing significant morbidity and ev en mortality. There is no single objective measure to assess the ex tent and sev erity of GI inv olv ement in SSc patients. A multidisciplinary approach with a rheumatologist, gastroenterologist, and sometimes a nutritionist is mandatory in all patients with sev ere gastrointestinal involvement. The management of GIT inv olv ement in SSc remains empirical and sy mptom-driv en. Data regarding the influence of immunomodulatory therapy on GIT inv olv ement are scarce. Welldesigned and high-powered prospective studies are needed to determine the effect of immunosuppressiv e treatment on the onset of GI tract disease, especially in early SSc.