Clinical Approach to Gastrointestinal Involvement in Patients with Systemic Sclerosis Author Timothy Kaniecki, MD1, Tsion Abdi, MD2, Zsuzsanna H

Timothy Kaniecki et al. Medical Research Archives vol 8 issue 10. Medical Research Archives

RESEARCH ARTICLE Clinical Approach to Gastrointestinal Involvement in Patients with Systemic Sclerosis Author Timothy Kaniecki, MD1, Tsion Abdi, MD2, Zsuzsanna H. McMahan, MD, MHS3

Affiliations 1. The Johns Hopkins Hospital, Department of Internal Medicine 2. Johns Hopkins University, Division of Gastroenterology 3. Johns Hopkins University, Division of Rheumatology Corresponding author: Zsuzsanna McMahan, MD, MHS 5200 Eastern Avenue Suite 5200, Mason F. Lord Building, Center Tower Baltimore, MD 21224 Tel: 410-550-2003; Fax: 410-550-2072 E-mail: [email protected]

Funding Statement: NIH/NIAMS K23 AR071473 to ZM; Scleroderma Research Foundation to ZM; Jerome L Greene Foundation to ZM; Scleroderma Research Foundation Conflict of interest statement: None of the authors received any financial support or other benefits from commercial sources for the work reported in this manuscript, nor do any of the authors have any financial interests, which could create a potential conflict of interest or appearance thereof.

Abstract Systemic sclerosis (SSc) is an autoimmune connective tissue disease that negatively impacts the function of the skin and internal organs. The gastrointestinal (GI) tract is the most commonly affected internal organ in SSc, though GI complications may also arise indirectly when infections occur in the setting of immunosuppression or concurrent disease processes arise for which patients with SSc are found to be at higher risk. In this review, we provide a systematic approach for the clinical assessment of GI complications in SSc from the oropharynx to the anorectum to guide both general internists and rheumatologists caring for this complex patient population. It is organized so that each component of the luminal GI tract has its own specified section, beginning with a review of a clinical approach to diagnosis, followed by a more detailed discussion of the literature surrounding approaches for an objective GI evaluation. A focused discussion early in the manuscript addressing what is known about pathogenesis, and later about in the manuscript about the assessment for GI bleeding are also included.

Key indexing terms: systemic sclerosis, scleroderma, clinical, gastrointestinal

Timothy Kaniecki et al. Medical Research Archives vol 8 issue 10. October 2020 Page 2 of 18

1.0 INTRODUCTION recruitment of fibrocytes. These factors result The evaluation of gastrointestinal (GI) in fibroproliferative vasculopathy and complaints in patients with systemic sclerosis progressive tissue fibrosis.6 However, the (SSc) can be a daunting task for both the response of the GI tissue to the SSc disease general internist and the rheumatologist. A milieu appears to be somewhat distinct from targeted and thorough assessment is essential, that of other organ systems, as smooth muscle as the majority of complaints are often non- atrophy, rather than fibrosis, is often the most specific and can have a wide variety of prominent feature.7 Numerous mechanistic potential therapies, depending on their processes for the development of GI etiology. Upwards of 90% of patients with SSc dysfunction in SSc have been proposed, report some form of GI symptoms, with a including a progressive vasculopathy, diffuse significant subgroup of this population fibrosis, dysbiosis, and an autoantibody-driven endorsing a noticeable reduced quality of life neuropathic process.8,9 More recently many (65% of patients in this group meeting clinical investigators have invoked a neuropathy as the criteria for depression).1 Additionally, GI initial pathologic event in SSc. For example, manifestations of SSc are associated with comparative studies of the lower esophageal significant morbidity and mortality, cited as sphincter in patients with SSc against control the third leading cause of death following groups exhibited an abnormal muscular pulmonary arterial hypertension and interstitial response to cholinergic neural stimulation, lung disease.2 These factors reveal the whereas direct muscle stimulation through importance of a thorough clinical evaluation gastrin and methacholine demonstrated a and strategic approach to diagnostic testing to normal response.10-12 Preservation of muscle minimize the risk of poor outcomes in this function was also suggested by the reversal of patient population. The goal of this review is to esophageal motility in select patients with SSc provide a succinct, anatomically-focused, when challenged with intraarterial reserpine.13 systematic approach to the clinical assessment This hypothesis is further supported by the and evaluation of common GI symptoms in discovery of functional autoantibodies in these patients with SSc for clinicians. The scope will patients that interfere with cholinergic- remain mostly on the luminal issues of the GI mediated contraction via the M3R receptor, tract, with an additional focused discussion for causing inhibition myopathy at the level of the GI bleeds. Manifestations within the smooth muscle within the GI tract. The extent hepatobiliary system are not in the scope of and intensity of this binding appears to be this review. The management options for these associated with the duration of disease.6 In a manifestations are also not in the scope of this cohort of patients with SSc and GI symptoms, review: reference materials for this may ultrastructural studies of rectal biopsies include the 2017 EULAR updated revealed axonal and smooth muscle cell recommendation guidelines,3 as well as degeneration. Biopsies throughout the GI tract excellent reviews by Shreiner et al.4 and Gyger demonstrated patchy atrophy with progression and Baron.5 to diffuse muscularis propria atrophy.11,14,15 Histologic examinations of autopsy specimens 1.1 Brief overview of pathogenesis from esophageal tissue of patients with SSc The proposed general mechanism of SSc have demonstrated a non-vascular distribution involves structural and functional endothelial of muscular atrophy with an absence of cell abnormalities, ultimately leading to the inflammatory infiltrates, significant fibrosis, or release of reactive species (cytokines, ischemic necrosis.7 Therefore this “neurogenic chemokines, and growth factors) and the hypothesis” suggests that a reduced neural

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Timothy Kaniecki et al. Medical Research Archives vol 8 issue 10. October 2020 Page 3 of 18 stimulation of smooth muscle via disease.18,20 This has been attributed to a autoantibodies ultimately leads to neural and reduction in salivary volume and enzymes muscle atrophy with varying degrees of which are essential in controlling oral bacterial fibrosis.11 These processes are thought to populations.21,22 A case-control study23 of 109 frame the pathophysiology behind many GI patients (54 with SSc, 55 control) in Italy complaints. found that patients with SSc had a significant 2.95 increased risk (95% CI 1.26-6.84) for 2.0 THE ORAL CAVITY periodontal disease as defined by clinical attachment loss. Another case-control study24 2.1 Clinical approach to screening for oral of 394 patients (163 with SSc, 231 control) in complications in SSc Canada found a significant increase in the Symptoms involving the oral cavity are a result number of decayed teeth as well as periodontal of both primary GI-SSc disease as well as disease defined by clinical attachment loss. secondary complications of cutaneous However it should be noted there is conflicting manifestations. Common presenting data on the correlation between SSc and complaints include microstomia, xerostomia, decayed teeth, as other studies have not found periodontal disease, and fibrosis of the base of significant differences when comparing SSc the tongue manifesting as tongue stiffness.2,16 patients to controls.18,25 Microstomia is a common, often disfiguring, and functionally impactful complication of 2.2 Objective evaluation SSc. Patients may report peri-oral vertical The examiner should take care to assess for creasing, as well as difficulty with fully facial changes such as a decreased oral opening the mouth when attempting daily aperture, thinning and retraction of the lips dental hygiene or when biting a large (leading to a puckered or grimaced sandwich. Such limitations may ultimately appearance), vertical wrinkling around the lead to poor nutrition and perioral care.2,14 mouth, and a thickened sublingular Acquired microcheilia is reported is 50-80% of frenulum.2,14 Diagnosis of microstomia is patients, and is reported to occur in the context primarily a clinical diagnosis, with a review of of perioral cutaneous thickening.2,17 systems positive for decreased mouth opening or limited range of motion of the mandible. Xerostomia, or dry mouth, has been reported in Panoramic dental imaging can be utilized to 30-70% of patients with SSc.14,17,18 The confirm this diagnosis, however this is unlikely majority of patients with SSc, however, do not to impact management from the standpoint of meet criteria for Sjogren’s Syndrome (SS): one a generalist or rheumatologist.17 Physical study19 of 133 patients with SSc found that limitations related to microstomia and 68% could be diagnosed with Sicca syndrome microcheilia may preclude an effective routine based on clinical symptoms and/or a Schirmer examination, and therefore a referral for a I test, yet only 20% fit diagnostic criteria for focused dental exam may be warranted.26 The SS as defined by the American-European value of mouth stretching exercises for Consensus Group criteria. Interestingly this microstomia is still a subject of debate, as study did find an association between SS and studies to date are limited by a number of the limited cutaneous subtype of SSc, with 18 factors including poor adherence to oral of the 19 patients diagnosed with SS falling exercise regimens, parallel systemic therapy under this SSc subtype. Xerostomia may lead changes, and small study group sizes.27,28 The to lingual and buccal mucosal crenations, and general consensus is that any benefit that may an increased incidence of periodontal exist is quickly lost with non-adherence.28

Patients should be counseled with the which is discussed below, or an overlapping knowledge that the true benefit is still ill- inflammatory myositis leading to weakness of defined, yet it remains an intervention with the pharyngeal muscles. Notably 42.6% of minimal potential harm. overlap myositis syndromes are associated with SSc (the most commonly associated While a formal evaluation for SS (i.e. connective tissue disease), and thus myositis is serologies, salivary gland functional testing, an important and relevant diagnosis to remain and biopsies) could be completed if there is on any clinician’s differential.30 concern for SSc-SS overlap, the history is likely to be sufficient for a diagnosis of 3.2 Objective evaluation xerostomia and more invasive studies are A history evaluating for symptoms of unlikely to change symptomatic management. uncontrolled GERD, proximal muscle One study29 compared the salivary gland weakness, and other systemic manifestations biopsies of 202 patients with primary SS of myositis should be performed to screen for disease and 27 patients with SSc-SS overlap pharyngeal involvement. Unfortunately little and noted that these processes appeared data exists on the workup of pharyngeal histologically identical. In addition, the myositis specifically in the setting of SSc, and presence of anti-Ro/SSA and anti-La/SSB dual thus this topic warrants further investigation. antibody positivity (prevalence: 35% in However, for the general population any primary SS vs 18.5% in SSc-SS overlap) was patient that describes new symptoms not associated with Sicca severity as measured concerning for pharyngeal myopathy should by complications, adverse prognosis factors, also be screened for symptoms of respiratory and activity markers (levels of erythrocyte muscle involvement. Some causes of proximal sedimentation rate, C-reactive protein, beta-2 myopathy (particularly involving the glycoprotein, C4 serum complement, pharyngeal or respiratory musculature) such as gammaglobulin, and cryoglobulin). myasthenia gravis may overlap with SSc and Interestingly, the study did find that patients should be quickly eliminated from the with SSc-SS overlap were less likely to have differential.31 One case report literature severe pulmonary fibrosis and peripheral review32 identified 14 patients with observed neuropathy than patients with SSc alone.29 A myasthenia gravis-SSc overlap. Laboratory dentist who has experience in the management values that may be useful as screening for an of patients with SSc is an essential partner to inflammatory myositis include serum creatine optimize patient care.26 Additionally, kinase (CK), aldolase, and antibodies identifying and limiting the use of medications associated with myasthenia gravis such as anti- which may further aggravate these problems is acetylcholine receptor antibodies.32,33 Swallow another important consideration for clinicians. videofluoroscopy (modified barium swallow study) may also be useful in determining 3.0 THE PHARYNX whether pharyngeal muscle involvement is contributing to dysphagia given the significant 3.1 Clinical approach to screening for overlap of symptoms.34 Clinical suspicion for pharyngeal complications in SSc this diagnosis must remain high as it may guide Pharyngeal involvement in SSc often presents the addition of certain therapeutics and provide as hoarseness, cough, and/or micro- opportunities to minimize aspiration risks. aspirations. Pharyngeal complications in SSc are most frequently caused by uncontrolled 4.0 THE ESOPHAGUS AND STOMACH gastroesophageal reflux disease (GERD)

4.1 Clinical approach to screening for epigastric pain.39 This has been attributed to gastroesophageal complications in SSc delayed gastric emptying and/or abnormalities It is estimated that approximately 90% of in gastric accommodation.40-42 In addition, as patients with SSc have some form of with the esophagus, it is suspected that there is esophageal involvement, whether it be a substantial subgroup of patients who have symptomatic or subclinical, making the subclinical gastric disease. Studies have found esophagus the most commonly involved that 80-90% of patients with SSc studied region of the GI tract.2,11 Symptoms typically showed signs of gastric slow wave arise from GERD or esophageal dysmotility disturbances, although the clinical significance (which can be seen at any level: the pharynx, of this data is uncertain.40,43 Impaired gastric upper esophageal sphincter, lower two thirds motility can also present more insidiously with of the esophagus, or lower esophageal weight loss secondary to decreased nutritional sphincter).14,17 The most common presenting intake from early satiety, and thus should complaint is that of heartburn, though remain on a clinician’s differential when additional complaints may include dysphagia, evaluated for malnutrition (discussed in more odynophagia, regurgitation, chronic cough, detail below).41 and hoarseness.17 Early diagnosis and treatment of esophageal involvement is Gastric Helicobacter pylori infection is also an important as chronic regurgitation and micro- important consideration in patients with SSc. aspiration are associated with the presence of Presenting complaints include abdominal pain interstitial lung disease, which is a leading and dyspepsia, however some infections may cause of mortality in SSc.35,36 Chronic present more insidiously with iron or vitamin untreated/undertreated GERD or dysmotility B12 deficiency.44-46 A meta-analysis of articles may also contribute to other complications, studying the relationship between this including esophagitis, ulcers, strictures, bacterium and SSc47 found an increased intestinal metaplasia, or esophageal incidence of H. pylori exposure in patients adenocarcinoma.2,17 Many of these with SSc by ELISA testing (although notably complications can present with reflux or an insignificant increase in cases detected by dysphagia as well, therefore it is imperative for urea breath testing, which would indicate an the clinician to maintain a wide differential active infection). Preliminary data comparing when evaluating these patients. An additional SSc patients with active H. pylori infection diagnosis that presents similarly is (diagnosed by urea breath testing and eosinophilic esophagitis (EoE), with recent histology) to those SSc patients with negative data supporting a connection between EoE and testing demonstrated increased modified connective tissue diseases.37 A Utah Rodnan skin scoring in the infected group.48 population analysis in 2016 reported 11 This data has been extrapolated to suggest patients with SSc-EoE overlap, and when eradication therapy may be beneficial in matched with controls for age and gender, a 6- mitigating disease activity, however more fold increased risk for SSc in patients research in this area is needed to support this diagnosed with EoE was identified.38 hypothesis.49

Approximately half of patients with SSc will 4.2 Objective evaluation present with symptoms suggestive of co- Given the significant symptom overlap with existing gastric involvement and report many of these manifestations, it is important to symptoms such as postprandial fullness, early think broadly when planning the work-up. In satiety, bloating, nausea/vomiting, or patients with solitary reflux symptoms without

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Timothy Kaniecki et al. Medical Research Archives vol 8 issue 10. October 2020 Page 6 of 18 dysphagia, empiric acid suppression therapy is abnormal pH was predictive for lower 1-year a reasonable first step of management in clinics survival rates. not equipped with direct endoscopy, as outlined by the Evidence-based Clinical Numerous expert consensus guidelines have Practice Guidelines for GERD 2015.50 In identified high-resolution esophageal patients with dysphagia, or heartburn that is manometry (HREM) as the appropriate test to recurrent or unresponsive to high doses of screen for aperistalsis, decreased amplitude of proton pump inhibitors (PPIs) and/or H2 smooth muscle contractions within the receptor blockers, the guidelines recommend esophageal body, or dysfunction within the esophagogastroduodenoscopy (EGD) as an lower esophageal sphincter.2,51,57-61 This is important diagnostic and potentially typically conducted following the exclusion of therapeutic intervention (e.g. screening for mechanical obstruction or mucosal disease via erosive esophagitis and Barrett’s esophagus, EGD, and can be done in conjunction with pH ruling out EoE, management of esophageal monitoring.62,63 HREM can also be utilized in strictures).37,50,51 One retrospective analysis of combination with esophageal pressure 13 SSc patients naïve to acid suppressant topography (a space-time pressure plot) and a medications52 found that low grade esophagitis functional luminal imaging probe (measuring had a prevalence of 77%. Another study distensibility of the esophageal body) to isolate evaluated 133 SSc patients on long-term PPI a dysfunctional component of the esophagus therapy53 (median treatment of 6 years, total that is contributing to symptoms for diagnostic range 1-38 years) and demonstrated a lower purposes.35,51,64 The accurate diagnosis of prevalence of esophagitis at 32.3% compared esophageal dysmotility may also have to the previously mentioned acid suppressant- systemic implications, as one study of 79 SSc naïve study. In both studies a variety of patients noted that abnormal contractility complications aside from esophagitis were diagnosed by HREM was associated with identified, including dysmotility, gastritis, H. increased severity of skin and lung disease.65 pylori infection, esophageal candidiasis, and While multiple small studies have confirmed hyperplastic gastric polyps. The noted lower the utility of HREM for esophageal prevalence of visible esophagitis following dysmotility diagnosis in the SSc patient PPI/H2 blocker therapy and the presence of population, additional research is needed to these other abnormalities further reinforces the understand its implications.66-70 importance of acid suppression therapy.51-53 In the setting of a confirmed case of Barrett’s As discussed above, in patients who report esophagus, routine follow up screening with symptoms suggestive of gastric involvement, EGD is typically recommended: every 3-5 such as early satiety, postprandial fullness, years in Barrett’s without dysplasia, every 6- bloating, or nausea/vomiting that is 12 months for low-grade dysplasia, and every unresponsive to medical management, further 3 months for high-grade dysplasia (based on evaluation of gastric function should be 2008 American Journal of Gastroenterology pursued in conjunction with an esophageal guidelines).54 pH monitoring has been shown workup. The American Journal of to be a useful subsequent study to diagnose Gastroenterology in 2013 published non-erosive reflux disease in cases with guidelines71 on the diagnosis and management normal mucosal findings on EGD.36,55 A of gastroparesis provides examples of three retrospective study of 10 SSc patients with separate tests useful in the detection of gastric reflux referred for lung transplant56 found that dysmotility: four-hour gastric emptying scintigraphy, the wireless motility capsule, and

C-octanoate or -spirulina breath testing. small bowel in patients with SSc is small However, it should be noted that these same intestinal bacterial overgrowth (SIBO). While guidelines acknowledge that the latter two tests this is often attributed to small bowel still require additional validation studies, and dysmotility, it may also be a consequence of therefore scintigraphy still ultimately remains large bowel dysmotility with a weakened the most reliable test.71 For this reason, a four- ileocecal valve and/or chronic gastric acid hour technetium-99 sulfur colloid gastric suppression.77 It is reported that the prevalence emptying study should be pursued when of SIBO in symptomatic patients is 30-62.5%, considering the diagnosis of impaired gastric however these figures may be a high estimate transit in patients with SSc.2,72,73 Ideally, this due to inconsistencies in outcome measures should be a combined solid-liquid study, as the both in terms of diagnostic modalities and inclusion of liquids increases the overall symptom presentation.2,78 All of these sensitivity of the test by an estimated 25- complications may contribute to chronic 36%.71 malnutrition leading to long-term morbidity, such as dependence on total parenteral While there is no gold standard test, an nutrition for adequate caloric intake.79 assessment for H. pylori infection could Therefore, the early identification of small include urea breath testing, as it has been bowel dysfunction and correction of studied in the SSc patient population and is malnutrition, SIBO, and/or dysmotility is proven to have high sensitivity and specificity essential.80 in general (96 and 93%, respectively) while remaining noninvasive.74,75 While not 5.2 Objective evaluation specifically studied for SSc, stool antigen Prior to attributing these symptoms to SSc, it is testing has also been proven to have high important for clinicians to rule-out other sensitivity and specificity for active infection causes of GI symptoms which are prevalent in (94 and 97%, respectively) and may also be a the general population. Important useful diagnostic tool given its ease of considerations include infection, inflammatory collection.75 or infiltrative bowel diseases, overlapping autoimmune bowel complications, and GI 5.0 THE SMALL BOWEL malignancies.

5.1 Clinical approach to screening for small Diagnostic modalities for the assessment of bowel complications in SSc small bowel dysmotility are limited. An Many patients with SSc may also present with abdominal x-ray may identify extensive symptoms of small bowel involvement, disease, demonstrating the classic “hide- including diarrhea, unintentional weight loss, bound” appearance indicative of tightly packed distention, bloating, and malnutrition.2,17 The valvulae conniventes in the duodenum and prevalence of small bowel dysmotility is jejunum, with dilated bowel loops.2,79 Small estimated to be between 40-88% based on intestinal manometry has been used to manometry studies. There is also increasing demonstrate the presence of dysmotility in evidence that small bowel involvement SSc, as evidenced by low-amplitude precedes symptoms. For example, one contractions with either absent or prolonged landmark study76 of 17 SSc patients noted that migrating motor complexes.81 Unfortunately 65% of patients with small bowel involvement this procedure has several clinical limitations, by manometry were asymptomatic at the time as it takes multiple hours to perform and is only of the study. A common complication of the able to assess the upper portions of the small

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Timothy Kaniecki et al. Medical Research Archives vol 8 issue 10. October 2020 Page 8 of 18 bowel.2,79 Other types of studies that are treatment. These guidelines similarly increasingly utilized include scintigraphy, acknowledge the need for additional wireless motility capsules, and computed randomized control trials to further support tomography/magnetic resonance specific antibiotic strategies.85 enterography.82 Clinicians should note that wireless motility capsules are to be avoided in Concurrently with this workup, patients should patients with known, severe gastroparesis or be regularly screened for overall malnutrition, bowel strictures.79 as this is indicative of worsened disease.79 The Malnutrition Universal Screening Tool The gold standard for diagnosis of SIBO is (MUST) has been frequently utilized for jejunal culture, where >10^5 organisms/mL preliminary screening in the SSc patient constitutes a positive test; however this test is population for its ease of use, correlation with limited in the SSc patient population as it is other screening tools, and validation in both invasive and not infrequently the the inpatient and outpatient setting.86-88 cardiopulmonary complications of SSc Positive screening with this tool has been prohibit routine anesthesia.78 The only shown to correlate with worsened outcomes.89 diagnostic tests for SIBO that are specifically The prevalence of malnutrition in SSc has been validated in this patient population are the variably described due to inconsistencies in the hydrogen and methane breath tests after an oral diagnostic criteria utilized, ranging from 5.3- glucose or lactulose bolus. While these tests 55.6%.86,90,91 For this reason, the use of the have been shown to have reasonable ESPEN (European Society for Clinical specificity ranging from 78-100%, their Nutrition and Metabolism) criteria for sensitivities range from 62-93%, which make malnutrition diagnosis following a positive their use as screening tests sub-optimal.79 screening should be highly considered, as these Clinicians can attempt to improve the criteria were developed with a goal to define sensitivity by preferentially ordering lactulose malnutrition terminology on a global level in over glucose boluses (82 versus 62.5%, line with the World Health Organization’s ICD respectively).78 Ultimately diagnosis and system.86,92 A suggested initial evaluation for treatment of SIBO may come down to strong malabsorption or malnutrition in patients with clinical suspicion in the setting of a broad SSc, based on expert consensus, should negative workup. Although not infrequently include hemoglobin, vitamin A, vitamin B12, used, there is mixed data to support the practice folate, albumin, iron panel, carotene, and of prescribing empiric antibiotic therapy; one selenium.93-95 meta-analysis of 10 studies found that while antibiotics were more effective than placebo to 6.0 THE COLON induce clinical improvement (as demonstrated by a normalized breath test), analysis of these 6.1 Clinical approach to screening for studies was complicated by overall study colonic complications in SSc heterogeneity and varying antibiotic The prevalence of colonic manifestations in choices.83,84 The most recent American SSc is hypothesized to be up to 50% of all Gastroenterological Association practice patients, but data is limited as these findings guidelines for SIBO,85 based on expert are often under-reported in the literature.40,96 consensus, recommend the identification and The typical presentation of colonic correction of underlying causes and nutritional involvement in SSc includes pain, distention, deficiencies with adjunct antibiotic use, taking constipation, and tenesmus, with less common note of the potential risk-benefit of empiric manifestations including fecal impaction and

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Timothy Kaniecki et al. Medical Research Archives vol 8 issue 10. October 2020 Page 9 of 18 recurrent intestinal pseudoobstruction.2 severe delays.102 One caveat to all available Related long-term complications of assessments of colonic dysmotility is that constipation and colonic dysmotility may while multiple testing modalities exist, these include pseudodiverticula, ulcerations, are only able to identify the presence of volvulus, and very rarely perforation or dysmotility and their data does not consistently infarction.5 correlate with symptom severity.101,103 Both abdominal imaging and endoscopy also have One additional GI tract complication to the potential to visualize PCI and/or consider is pneumatosis cystoides intestinalis pneumoperitoneum, with direct visualization (PCI). This can present with abdominal pain, by endoscopy showing beaded, grape-like, or distention, nausea, or vomiting. PCI is a rare cobblestone abnormalities within the bowel diagnosis that is felt to be indicative of end- wall.2,104 stage disease when associated with SSc, and is therefore considered a poor prognostic sign.97 7.0 THE ANORECTUM Most literature surrounding this diagnosis exists in the form of case reports with limited 7.1 Clinical approach to screening anorectal population data.5,98 A generalized review99 of a complications in SSc population with this diagnosis, not specific to Following the esophagus, the anorectum is the SSc, found that the colon was the most second most commonly involved portion of the commonly affected at 46% of cases, followed GI tract in patients with SSc. Up to 50-70% of by small bowel (27%) and simultaneous small patients report symptoms of dysfunction, with and large bowel disease (7%). one survey reporting the most common Pneumoperitoneum is a frequent complication, symptom as fecal incontinence (38%), and a with one case report series review100 of 37 need for regular digital stimulation or patients finding an incidence rate of 87%. evacuation of the rectum in 18% of patients.40,105 A case-control study106 found 6.2 Objective evaluation that 71.4% of patients within the SSc group As with the upper portions of the GI tract, had an impaired recto-anal inhibitory response complications of the large bowel can be (RAIR), which correlated with fecal evaluated by direct visualization through incontinence symptoms. Notably there was no sigmoidoscopy/colonoscopy and manometry.5 correlation found between various SSc Abdominal radiographs or computed subtypes, the duration of disease, or other GI tomography are beneficial in quickly symptoms. Another study107 of 44 SSc patients identifying complications of dysmotility, found that patients reporting fecal incontinence pseudoobstruction, or fecal impaction such as symptoms exhibited a lower mean resting colonic dilation and perforation. 97,101 pressure of the internal anal sphincter Manometry of the large bowel comes with compared to patients who were asymptomatic, similar complications and limitations as small suggesting hypotonia is a major contributor to bowel manometry, including length of symptoms; however, other studies did not procedure time and cardiopulmonary confirm these findings.106 A differential for limitations with anesthesia.78 Sitz markers abnormal RAIR diagnosed in adulthood (radiopaque markers that are used to assess should also include Chagas’ disease, colonic transit times) enable the assessment of dermatomyositis, peripheral neuropathy (such colonic transit over several days, though as in diabetes), neurovascular insult, and post- concerns exist regarding pellet retention and surgical complication.107-110 risk of bowel perforation in patients with

7.2 Objective evaluation traditionally considered a rare diagnosis, its History and physical exam is important in the true prevalence is up for debate: a large diagnosis of anorectal SSc involvement. A retrospective study114 had previously defined digital rectal exam may be used to identify the incidence of clinically significant gastric fecal impaction and evaluate anal sphincter antral vascular ectasia as 5.7%, however a tone, which is essential in differentiating more recent study of asymptomatic patients anorectal from colonic involvement.14 Beyond (the SCOT trial)115 reported a much higher the physical exam, anorectal manometry has prevalence of 22.3%.116 An association also been utilized to assess the resting tone of between GAVE and anti-RNA polymerase-III the internal and external anal sphincters. An antibodies is reported in several studies, important distinction found on manometry in though not all studies confirmed this SSc is that the internal anal sphincter is association.115,117 preferentially affected, and the external sphincter is typically spared.2,111 This finding Patients with SSc are also found to have a has been further supported by endoanal greater incidence of telangiectasias and ultrasound, which typically shows a thin or angiodysplasia throughout the GI tract, from atrophic internal anal sphincter – however this the oropharynx and throughout the bowel. As additional imaging beyond manometry is not these vascular abnormalities, particularly those typically needed for patient care.2,107 in the small bowel, can be difficult to diagnose and treat, they are frequently the culprit of 8.0 GASTROINTESTINAL BLEEDING recurrent bleeds.2,118,119 One capsule GI bleeding is a symptom that is relatively endoscopy study of 50 patients with SSc119 common in the general population, but found that patients with GI vascular lesions warrants the consideration of a broader were more likely to have the limited cutaneous differential diagnosis when seen in the SSc subtype of SSc (73.3% limited cutaneous population. As discussed above, many patients subtype vs. 26.7% diffuse cutaneous subtype, with SSc experience chronic GERD which can n=15). A standard GI bleeding workup should lead to esophagitis, and ulcers of the esophagus be pursued in all symptomatic patients or those Barrett’s esophagus, and progression to with signs of iron deficiency anemia, starting esophageal adenocarcinoma, seen in 1.9% of with a bidirectional endoscopy, followed by patients.2,17 The presence of persistent reflux consideration for capsule study, computed should also warrant consideration of peptic tomography or magnetic resonance ulcer disease as a source of GI bleeding. In enterography, and then push or balloon patients with SSc who utilize antibiotics endoscopy.116,120,121 Given the complexities of frequently for SIBO or digital ulcers, H. pylori using general anesthesia in SSc, patients infection must be considered as well.112 should be referred to an experienced center for these latter studies. An additional cause of bleeding that is more common in SSc patients relative to the general 9.0 CONCLUSIONS population is gastric antral vascular ectasia Clinicians should maintain a wide differential (GAVE). GAVE, also known as “watermelon in the evaluation of GI symptoms in patients stomach” given its appearance on endoscopy, with SSc (see Figure 1), taking care to rule out is defined as vascular ectasia of the mucosal diagnoses most prevalent in the general capillaries of the stomach, with focal population prior to pursuing a workup more thrombosis, spindle cell proliferation, and specific to SSc-linked processes. The fibrohyalinosis seen histologically.2,113 While possibility of multi-level disease throughout

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Timothy Kaniecki et al. Medical Research Archives vol 8 issue 10. October 2020 Page 11 of 18 the GI tract must be entertained. As mentioned underlying process of symptoms is imperative previously, GI involvement in SSc not only has to allow for appropriate targeted therapies. a significant impact on quality of life, but, As a mechanistic understanding of SSc and its when severe, is associated with increased impact on the GI tract is further established and mortality. While the treatments for these risk stratification improves, this may specific complications are outside the scope of potentially allow for more targeted this review, successful identification of the assessments in the future.

Figure 1. Differential for GI manifestations of SSc

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