A practical approach to the evaluation and management of gastrointestinal symptoms in patients with systemic sclerosis

Abstract

The gastrointestinal (GI) tract is the most commonly affected internal organ system in systemic sclerosis (SSc). SSc may lead to impaired function in any region of the GI tract, from the esophagus to the anorectum, causing significant morbidity, as well as mortality in patient subsets. Given the low prevalence of SSc in the community, many rheumatologists may not have a systematic framework for diagnosing or treating the GI complaints in this disease. These practice recommendations aim to summarize and consolidate the current guidelines from the fields of gastroenterology and rheumatology, and establish a symptom-based framework for diagnosis and management based on available evidence in the literature. Subject areas in need of additional research are also identified.

1.0. INTRODUCTION

Systemic sclerosis (SSc) is a rare immune-mediated rheumatic disease that is associated with high morbidity and mortality.[1] Gastrointestinal (GI) disease is a frequent manifestation of SSc and affects up to 90% of cases, making it the most commonly affected internal organ system.[2] Mortality is high among patients with severe GI complications (i.e. pseudo-obstruction, malabsorption, requiring total parenteral nutrition), and falls just behind that of pulmonary arterial hypertension and pulmonary fibrosis. GI symptoms are common and attributed to a variety of factors such as delayed GI transit, dysbiosis, and dietary or medication intolerances.[3–6] The heterogeneous clinical presentation, limited understanding of disease pathogenesis, absent biomarkers of GI disease activity, and reduced familiarity with managing SSc-GI complications can lead to significant challenges in clinical practices and ultimately suboptimal patient care.[1]

Data to guide the diagnosis and management of SSc-GI complications is limited; however, several groups have developed expert consensus-based recommendations to help address this challenge. The European League Against Rheumatism (EULAR) Scleroderma Trials and Research group and United Kingdom scleroderma study group (UKSSG) each published clinical recommendations[7,8] while acknowledging limited data and a lack of controlled trials in SSc patients. However, the Canadian Scleroderma Research Group (CSRG) found that the aforementioned guidelines did not significantly change rheumatologists’ behavior when treating SSc-GI patients, citing symptom-guided care as a possible explanation.[9]

With these limitations in mind, the goals of this review are to provide a symptom-based practical systematic approach, integrating data from the rheumatologic and GI literature, to guide the diagnosis and treatment of GI complications in patients with SSc. Symptoms were classified into six groupings that are clinically relevant to the SSc population:

• Oropharyngeal dysphagia, globus sensation

• Heartburn, reflux, esophageal dysphagia

• Nausea, vomiting, bloating, abdominal distention

• Diarrhea

• Constipation

• Fecal incontinence

A focused differential of common considerations for each of these groups (in the context of SSc) can be found in Table 1. With guidance from an expert clinical gastroenterologist (TA), diagnostic schema for these symptom groups (see Figures 1 and 2) were developed using current gastroenterology and rheumatology guidelines, and incorporating relevant clinical studies of the SSc population when available. We also aimed to provide a quick resource representing all available clinical trial data related to the management of SSc-related GI manifestations (see Table 2).

Table 1.

Differential Diagnosis and Diagnostic Considerations for Gastrointestinal Symptoms in Systemic Sclerosis

Symptom	Differential Diagnosis and Potential Complications	Considerations for Diagnostic Evaluation
Oropharyngeal	Proximal Esophageal Dysmotility	Modified Barium Swallow
Dysphagia	Pharyngeal Myositis	High-Resolution Esophageal Manometry
Globus Sensation	Sicca Syndrome	Laboratory Studies for Myopathy: CK, aldolase
	Myasthenia Gravis	Antibodies for Myasthenia Gravis
Heartburn	Gastroesophageal Reflux Disease	Esophagogastroduodenoscopy (EGD)
Reflux	Esophageal Body Dysmotility	High-Resolution Esophageal Manometry
Esophageal Dysphagia	Esophageal Strictures	pH Monitoring
	Lower Esophageal Sphincter Dysfunction
	Hiatal Hernia
	Eosinophilic Esophagitis
	Esophageal Candidiasis and/or Other Infection
	Barrett’s Esophagus
	Esophageal Adenocarcinoma
Nausea	Gastroparesis	EGD
Vomiting	Abnormal Gastric Accommodation	4 Hour Scintigraphy-Based Gastric Emptying
Bloating	Peptic Ulcer Disease	Study
Distention	H. pylori Infection	Urea Breath Testing or H. pylori Stool Antigen
	Small and/or Large Bowel Dysmotility	Testing
	Pneumatosis Cystoides Intestinalis	Abdominal Film
		Assessment of Small or Large Bowel Transit
Diarrhea	Spontaneous Bacterial Overgrowth Syndrome	Hydrogen/Methane Breath Test
	Small Bowel Dysmotility	Celiac Disease Biomarker Testing +/− EGD
	Malabsorption	C. difficile Stool Antigen Testing
	Overflow Diarrhea	Infectious Diarrhea Testing
	Infectious Diarrhea	Labs to Rule Out Malabsorption
	Inflammatory Bowel Disease	Colonoscopy
Constipation	Colonic Dysmotility	Abdominal Film
	Fecal Impaction	Assessment of Large Bowel Transit
	Colon Cancer	Colonoscopy
	Anorectal Dysfunction
Fecal Incontinence	Internal Anal Sphincter Dysfunction	Digital Rectal Examination
	Diarrhea	Anorectal Manometry
		Control/Treat Diarrhea

Figure 1.

A Proposed Diagnostic Protocol for Upper Gastrointestinal Symptoms in Systemic Sclerosis

Figure 2.

A Proposed Diagnostic Protocol for Lower Gastrointestinal Symptoms in Systemic Sclerosis

Table 2.

Clinical tiuls of therapeutics lor gastrointestinal disease in systemic sclerosis.

	Investigators	Study	Type of Study	Number of SSc Patients	Key Findings
Prokinetic Drugs and Therapies (Upper GI Tract)	Ramirez-Mata, M., et al. [41]	Metoclopramide (1 dose of 20mg PO); effect on esophageal aperistalsis and LES pressure	Randomized cross-over trial	14	Metoclopramide was associated with increased frequency of esophageal contractions and increased LES pressure in some patients
	Johnson, D.A., et al. [58]	Metoclopramide (10mg PO before meals and at bedtime); effect on esophageal motility and gastric emptying	Clinical trial	12	Metoclopramide was associated with increased LES pressures and reduced gastric emptying delay in most patients
	Horowitz, M., et al. [95]	Cisapride (10mg PO QID); effect on gastric/esophageal emptying and upper GI symptoms	Clinical trial	8	Cisapride was associated with significant improvement in gastric emptying and improved upper GI symptoms; there was no significant improvement in esophageal emptying
	Kahan, A., et al. [40]	Cisapride (1 dose of 10mg IV); effect on LES pressure and gastric contractions	Randomized cross-over trial	20	Cisapride was associated with increased LES pressure and increased number of fundic gastric contractions
	Fiorucci, S., et al. [96]	Erythromycin (2mg/kg/hr IV) in SSc patients vs no disease control; effect on gastric and gallbladder emptying	Non-randomized control trial	12	Erythromycin was associated with accelerated gastric and gallbladder motility in all patients
	Wang, S.J., et al [89]	Cisapride (10mg PO TID); effect on oesophageal transit	Randomized cross-over trial	12	Cisapride did not have an impact on oesophageal transit times
	Sallam, H., et al. [62]	Transcutaneous electrical nerve stimulation (acupoints ST36 and PC6); effect on GI symptom scores	Clinical trial	17	Prolonged transcutaneous electrical nerve stimulation therapy was associated with improved GI symptom scores
	McNearney, T.A., et al. [63]	Transcutaneous electrical nerve stimulation (acupoints ST36 and PC6); effect of gastric myoelectrical activity and frequency of awakening due to abdominal pain/bloating	Clinical trial	17	Prolonged transcutaneous electrical nerve stimulation therapy was associated with significantly decreased nighttime awakenings due to abdominal pain
	Ariyasu, H., et al. [97]	Grehlin (5.0mcg/kg IV) vs placebo; effect on gastric emptying	Randomized cross-over trial	10	Grehlin was associated with accelerated gastric emptying times
Anti-Reflux Drugs	Horikoshi, T., etal. [98]	Cimetidine (200mg IV) vs Famotidine (20mg IV) vs positive control (sodium bicarbonate) and negative control; effect on gastric motility and LES pressure	Non-randomized control trial	41	Cimetidine and Famotidine were associated with significant increases in LES pressure, however when corrected for changes in gastric phasic motor activity this significance was limited to Cimetidine and now Sodium Bicarbonate
	Pakozdi, A., et al. [27]	Lansoprazole (30mg PO daily) vs placebo; evaluation for long-term benefit in symptom control and effect on the progression of oesophageal dysmotility	Randomized control trial	24	Lansoprazole was not associated with long-term benefit for symptoms, and had no effect on prevention of progression of esophageal dysmotility
	Karamanolis, G.P., et al. [45]	Buspirone (20mg PO daily); effect as add-on therapy to PPI for LES pressures and reflux/regurgitation scores	Clinical trial	30	Buspirone was associated with increased LES pressure and improved reflux and regurgitation scores
	Foocharoen, C., et al. [48]	Domperidone (10mg PO TID) vs Algycon (1 tablet TID); effect on GERD symptoms as add-on therapy with omeprazole (20mg PO BID)	Randomized control trial	148	Domperidone and algycon were equally effective as add-on therapies to omeprazole, showing significant improvement in GERD symptoms and quality of life scores
Prokinetic Drugs (Lower GI Tract)	Soudah, H.C., et al. [77]	Octreotide (10mcg SC) in SSc patients vs no disease control; effect on motility and bacterial overgrowth	Clinical trial	5	Octreotide was associated with inducing migrating complexes, as well as reducing hydrogen breath excretion with reduced symptoms
	Wang, S.J., et al. [88]	Cisapride (10mg PO TID); effect on colonic transit	Clinical trial	16	Cisapride was associated with increased colonic transit
	Nikou, G.C., et al. [78]	Octreotide (0.1mg BID SC or 20mg monthly IM); effect on small bowel disease unresponsive to other prokinetic agents	Clinical trial	7	Octreotide was associated with significant reduction in symptom severity
	Vigone, B., et al. [44]	Prucalopride (20mg PO daily) vs placebo; evaluation of intestinal dysmotility and symptom scoring	Randomized cross-over trial	40	Prucalopride was associated with increased intestinal evacuations, improved reflux and bloating symptoms, and improved constipation scores
Probiotic Drugs and Therapies	Frech, T.M., et al. [80]	Probiotics (Bifidobacterium infantis 1 billion units daily or lactobacillus rhamnosusGG 1 billion units daily); effect on GI symptom scoring	Clinical trial	10	Probiotics were associated with improvement in reflux scores at 2 months
	Low, A.H.L., et al [99]	Probiotics (Vivomixx® 1800 billion units daily) vs placebo; effect on GI symptom scoring	Randomized control trial	40	Probiotics were associated with improvement in reflux scores at 120 days
	Marighela, T.F., et al. [100]	Probiotics (Invictus Lacto Pró 1 capsule daily) vs placebo; effect on GI symptom scoring	Randomized control trial	73	No significant difference in GI symptom scoring
	Garcia-Collinot, G., et al. [81]	Probiotic (Saccharomyces boulardii 200mg BID for 7 days) vs Metronidazole (500mg BID for 7 days) vs Combination Therapy (Metronidazole 500mg BID for 7 days and Saccharomyces boulardii 200mg for 14 days); treatment of SIBO	Randomized clinical trial	40	Combination therapy was more effective than probiotic monotherapy, which was more effective than metronidazole monotherapy in treating SIBO
	Fretheim, H., et al. [82]	Fecal microbiota transplant (single-donor, commercially-available anaerobic cultivated human intestinal microbiota) vs placebo; effect on GI symptom scoring	Randomized control trial	10	Fecal microbiota transplant was associated with mild transient adverse events and improved symptom scoring

SSc: Systemic Sclerosis: mg: milligrams: PO: per os (by mouth): LES: lower esophageal sphincter: QID: quater in die (four times daily): Cl: gastrointestinal: IV: intravenous: kg: kilograms: hr: hour: TID: ter in die (three times daily): GERD: gastroesophageal reflux disease: BID: bis in die (twice daily): SC: subcutaneous: IM: intramuscularly: SIBO: spontaneous bacterial overgrowth syndrome.

2.0. OROPHARYNGEAL DYSPHAGIA OR GLOBUS SENSATION

Subjective dysphagia is a common complaint among patients with SSc. Dysphagia can involve the oral cavity, pharynx, and/or esophagus.[10] Esophageal sources of dysphagia have different diagnostic considerations and are thus discussed separately in this review (see Section 3.0). In the oropharynx, dry mouth (often related to sicca symptoms) may contribute to oropharyngeal dysfunction, as the reduction in salivary flow may impede the ease of normal swallowing.[11] This may be complicated by fibrosis of the base of the tongue, which may further impair normal swallowing.[12] Patients with SSc may also experience pharyngeal inflammation related to uncontrolled gastroesophageal reflux disease (GERD), often manifesting as hoarseness or dry cough. Additionally overlap autoimmune syndromes, such as cases of co-existing inflammatory myositis[13] or myasthenia gravis,[14] may contribute to dysphagia by impairing normal pharyngeal muscle function.

2.1. Use of a Modified Barium Swallow to Determine Anatomic Origin of Dysphagia

When evaluating for pure dysphagia in patients without reflux symptoms, the UKSSG and the American College of Radiology both recommend a modified Barium swallow study (also known as a video fluoroscopy swallow study) as a reasonable first diagnostic test based on expert consensus.[8,15] Clinical trials[16] support its use in SSc, highlighting its ability to identify the anatomic source of dysphagia as originating from the oral cavity, pharynx, and/or esophagus. Patients with concurrent reflux symptoms or evidence of esophageal dysmotility by the Barium swallow study should be further assessed by esophagogastroduodenoscopy (EGD), as outlined in Section 3.2.

2.2. Additional Workup for Oropharyngeal Dysphagia

If a Barium swallow study suggests dysphagia originating at the level of the oropharynx, overlap syndromes should be considered. The presence of sicca symptoms can be confirmed by a thorough history and physical exam, taking particular care to note any reported xerostomia (dry mouth), oral sores, or glossodynia that may contribute to dysphagia.[17] Salivary gland biopsies and Sjogren’s Syndrome antibodies do not correlate with sicca symptom severity in SSc patients, and thus are likely unnecessary as they would not affect management.[18] A comprehensive review of the diagnosis and treatment options of Sjogren’s Syndrome and/or sicca was recently published here.[17] Elevations in serum creatinine kinase (CK), aldolase, or antibodies associated with autoimmune myositis or myasthenia gravis (e.g. anti-acetylcholine receptor or muscle specific tyrosine kinase [MUSK] antibodies) would provide support for an underlying myopathy as a potential contributor to pharyngeal muscle weakness.[14,19] Although the identification of myositis or myasthenia gravis is important in determining optimal treatment strategies for oropharyngeal dysfunction, the nuances of their treatment are outside the scope of this review but may be found here.[20,21] Practice points for oropharyngeal dysphagia and/or globus sensation can be found in Table 3.

Table 3.

Practice Points and Research Agenda for Oropharyngeal Dysphagia or Globus Sensation in Systemic Sclerosis

Practice Points: In patients with SSc reporting symptoms of dysphagia, a modified Barium swallow study (video fluoroscopy swallow study) is a reasonable screening test to distinguish oropharyngeal versus esophageal dysfunction History and physical exam are sufficient to diagnose sicca symptoms, and symptomatic treatment should be pursued (in addition to good oral hygiene) if there is clinical concern for dry mouth as a contributor to oropharyngeal dysphagia Patients with oropharyngeal dysphagia may benefit from a laboratory assessment for myositis (CK, aldolase, autoantibodies) and/or myasthenia gravis (anti-acetylcholine receptor or anti-MUSK antibodies)

Research Agenda: The utility of screening for asymptomatic dysphagia and related aspiration risks in SSc is not yet defined

SSc: Systemic Sclerosis; CK: creatine kinase; MUSK: muscle-specific tyrosine kinase

3.0. HEARTBURN, REFLUX, OR ESOPHAGEAL DYSPHAGIA

Estimates suggest that approximately 90% of patients with SSc report symptoms suggestive of esophageal involvement, most commonly heartburn or reflux. Dysphagia, regurgitation, chronic cough, and hoarseness are other frequently reported symptoms. These are attributed to chronic, inadequately controlled baseline GERD, reduced lower esophageal sphincter (LES) pressures, and hypomotility of the distal two-thirds of the esophagus in SSc leading to reduced clearance.[22,23]

The Montreal definition for GERD, adopted by the American Gastroenterological Association (AGA), defines GERD as “a condition which develops when the reflux of stomach content causes troublesome symptoms and/or complications,”[24] further clarifying the signifier “troublesome” to mean a symptom or complication with an adverse effect on the well-being of the individual. The reported incidence of GERD symptoms is much higher in SSc than in the general population, and thus patients with SSc are at higher risk for complications such as strictures, esophageal erosions/ulcerations, Barrett’s esophagus, and adenocarcinoma. Clinicians should also have an awareness of overlap disorders such as eosinophilic esophagitis (EoE), hiatal hernia, or gastroparesis, which may mimic or exacerbate GERD symptoms.[23,25]

3.1. Empiric Acid Suppression Therapy

The AGA guidelines for the management of GERD[24] outline that daily standard-dose proton pump inhibitors (PPIs) (see Table 4) should be considered first-line therapy based on strong support from clinical trial data. PPIs are beneficial both for symptom management and for treating complications such as esophageal ulcers and strictures.[7] This recommendation is supported by a Cochrane review[26] that concluded that PPIs are superior to histamine-2 receptor antagonists (H2RAs), which in turn are superior to placebo in the treatment of symptomatic reflux and healing of esophagitis. No significant difference was found in the efficacy among different PPIs (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) by meta-analysis. In patients that initially responded to therapy, this symptomatic benefit extended to the 6- and 12-month follow up periods. While the only small randomized control trial[27] for PPIs in SSc did not see benefit at 12-month follow up, this study only investigated lansoprazole and did not assess for outcomes related to esophageal healing. Acknowledging the limitations of this small study, chronic PPI therapy in SSc is guided by abundant data from the GI literature, with both the EULAR and the UKSSG guidelines in agreement with the AGA’s recommendation.[7,8]

Table 4.

Standard Dosing for Proton Pump Inhibitors (PPIs) and Histamine-2 Receptor Antagonists (H2RAs)

	Standard Dosing
PPIs	Esomeprazole 40mg daily
	Lansoprazole 30mg daily
	Pantoprazole 40mg daily
	Omeprazole 20mg daily
	Rabeprazole 20mg daily
H2RAs	Cimetidine 400mg twice daily
	Famotidine 20mg twice daily
	Nizatidine 150mg twice daily
	Ranitidine 150mgtwice daily

While limited data exists for the efficacy of twice-daily dosing of PPIs, the AGA guidelines[24] state that gastroenterologist expert opinion supports this increased dosing for patients with breakthrough symptoms. The guidelines propose H2RAs as an alternative acid suppressant when patients experience significant adverse effects from PPIs.[24] Expert consensus across gastroenterologists and rheumatologists (when dealing with reflux in SSc) is that all medications should be titrated to optimize symptom control, while utilizing the lowest possible therapeutic medication dose.[8,24] Any patients that continue to experience symptoms despite maximal acid-suppression therapy should be considered “treatment failures” and should undergo additional diagnostic evaluation.

3.2. Workup for Treatment-Refractory Reflux

The AGA and UKSSG both recommend that EGD should be utilized in treatment-refractory GERD to rule out other complications and diagnoses, particularly if “red flag” or concerning symptoms, such as dysphagia, are present.[8,24] Appropriate treatment for esophageal strictures, EoE, esophageal candidiasis or other infections, esophageal adenocarcinoma, etc., should be pursued if present.[28–30] While there is evidence[31] that suggests esophageal mucosal abnormalities may predate symptoms in SSc, further research is needed to determine the utility of screening asymptomatic patients with EGD and/or the role of prophylactic acid suppression in this patient population. Currently, the EULAR recommendations state that prescribing empiric PPI therapy in asymptomatic patients should be done with caution, given that long-term use may be associated with nutritional deficiencies and increased infection risk.[7]

3.3. Esophageal Dysmotility Evaluation and Consideration of Prokinetic Therapies

If EGD does not reveal an alternative cause for reflux symptoms in SSc, then an esophageal dysmotility evaluation is warranted.[23] Symptoms suggestive of esophageal dysmotility include dysphagia with both solids and liquids and chronic reflux (note: dysphagia primarily with solids would be more suggestive of a structural issue).[32] Gastric dysmotility must also be considered, as the two may co-exist and the diagnostics and management may differ from the presence of esophageal dysmotility alone; please see Section 4.0 for further discussion of this subject.

Multiple gastroenterology expert societies[33–35] recommend high-resolution esophageal manometry (HREM) as an appropriate follow-up test to EGD for confirming a diagnosis of esophageal dysmotility or lower esophageal sphincter (LES) dysfunction in the general population. Multiple small studies[36,37] provide support for the use of HREM in SSc for this indication. The utility of screening and treatment for dysmotility in asymptomatic SSc patients is an area that needs additional research, as growing evidence supports an association between chronic regurgitation, micro-aspiration, and the presence of interstitial lung disease. Therefore, identifying and treating asymptomatic, uncontrolled dysphagia may positively impact long-term outcomes.[38,39]

Both the EULAR and UKSSG guidelines recommend the use of prokinetic agents for SSc patients with GI dysmotility.[7,8] Notably there are very few clinical trials examining the use of prokinetic agents in SSc, particularly in the treatment of esophageal dysmotility. Two drugs, cisapride and metoclopramide, were specifically studied in SSc as treatments for esophageal dysmotility, each demonstrating benefit in small randomized cross-over trials.[40,41] However, cisapride has since been restricted in the United States due to its known association with QT prolongation leading to an increased risk of developing torsades de pointes, and the AGA guidelines for GERD recommend against the use of metoclopramide citing lack of high-quality data and a negative toxicity profile.[8,24] Prucalopride, which has a similar mechanism to cisapride but also a significantly improved cardiac profile, has demonstrated an enhancing effect on esophageal motility in general population studies,[42,43] but has not been studied in SSc-esophageal disease.[44] Another drug, buspirone, has shown benefit as add-on therapy to PPIs in SSc in one clinical trial.[45] Bethanechol is an additional promising agent seen to provide benefit in a small study of esophageal dysmotility.[46] Rheumatologist expert consensus recommends the use of prokinetic agents in the treatment of dysphagia on a case-by-case basis, as there is a great need for research on the long-term efficacy of these agents in the SSc population.[7]

3.4. Combination Therapy in Refractory Reflux

Studies examining combinations of acid suppressant pharmacotherapies demonstrated no significant benefit in the general population, though studies in the SSc population are limited.[24] A new area of interest is combining acid suppression with promotility agents and other classes of medications to improve symptoms in patients with treatment-refractory disease.

For example, buspirone, domperidone, and algycon were each found to improve reflux symptoms when used in combination with PPIs in small placebo-control trials within the SSc population.[47,48] However, given the lack of long-term outcome data in combination therapy and the potential for adverse events with select agents, such decisions should generally be made in consultation with an experienced gastroenterologist.

3.5. Anti-Reflux Surgery in SSc

While the management of pharmacotherapy-refractive reflux symptoms in the general population typically involves surgery, this approach should be avoided when possible in patients with SSc.[8,24] Multiple studies[49–52] have found that while surgical interventions (such as Nissen fundoplication, Belsey fundoplication, Collis gastroplasty, and Roux-en-Y gastric bypass) are effective in immediately reducing reflux symptoms in SSc, a significant number of cases ultimately develop postoperative dysphagia as a complication. Interestingly, one retrospective review[51] compared Roux-en-Y gastric bypass to several other surgical interventions for GERD, and found that Roux-en-Y was associated with fewer symptoms of dysphagia at 21-month follow-up. However, this procedure is also associated with increased incidence of small intestinal bacterial overgrowth (SIBO). Given the already increased prevalence of small bowel dysmotility and SIBO in the SSc patient population, this is a procedure that should still be pursued with caution.[29] Practice points for heartburn, reflux, and/or esophageal dysphagia can be found in Table 5.

Table 5.

Practice Points and Research Agenda for Heartburn, Reflux, or Esophageal Dysphagia in Systemic Sclerosis

Practice Points: Empiric standard-dose daily PPI is first-line treatment for reflux without dysphagia in SSc PPI dosing should be titrated to maximize symptom benefit at lowest possible dose; the maximum dose is considered the standard dose administered twice daily H2RAs may be considered as an alternative acid suppressant medication when significant side effect or relative contraindication inhibits PPI usage Patients with suboptimal response to acid suppression therapy or with additional concurrent GI symptoms (dysphagia, abdominal distention, nausea, vomiting, or bloating) should be evaluated by EGD to rule out GERD complications or alternative diagnoses High-resolution esophageal manometry with pH testing may be pursued to assess for esophageal dysmotility if EGD does not reveal an alternative cause of dysphagia Prokinetic drugs may be used in the management of esophageal dysmotility to improve high symptom burden Patients with continued reflux symptoms despite maximal acid suppression therapy, following rule-out of alternative diagnoses by EGD and HREM, should be treated in consultation with an experienced gastroenterologist for consideration of combination therapies Surgical management of reflux symptoms in SSc is generally not recommended due to increased incidence of postoperative dysphagia

Research Agenda: More randomized control trials are needed to assess the short- and long-term benefit of acid suppression therapy in the SSc patient population, both in improving symptoms and quality of life as well as evaluating for the prevention of future complications There is a need for head-to-head comparisons of individual acid suppression pharmacotherapies to determine if any therapy is more efficacious in SSc More research is needed to define whether there is benefit in EGD screening and/or prophylactic acid suppression in asymptomatic SSc patients There is a need for head-to-head comparison of prokinetic drugs in SSc esophageal dysmotility to identify the most efficacious and tolerable therapies More research is needed in the development of pharmacotherapies, such as promotility agents, to determine whether early initiation prevents or slows the progression of esophageal dysmotility and related smooth muscle atrophy in SSc More research is needed in the development of novel acid suppression therapies for SSc patients with treatment-refractory symptoms

PPI: proton pump inhibitor; SSc: Systemic Sclerosis; H2RA: histamine-2 receptor antagonist; GI: gastrointestinal; EGD: esophagogastroduodenoscopy; GERD: gastroesophageal reflux disease; HREM: high resolution esophageal manometry

4.0. NAUSEA, VOMITING, BLOATING, OR ABDOMINAL DISTENTION

The differential diagnosis for nausea, vomiting, bloating, and/or abdominal distention symptoms is broad and should receive a thorough standard evaluation prior to pursuit of SSc-specific disease processes. The AGA has published an excellent technical review[53] encompassing the evaluation of both acute and chronic nausea/vomiting symptoms, but particularly important considerations for the SSc population should include GI dysmotility, dysbiosis (including SIBO), and malabsorption. Assessment of the adverse effects of medications, particularly immunosuppressives used in the management of SSc (e.g. mycophenolate mofetil, nintedanib, methotrexate) and dose-adjustments when necessary should be considered prior to pursuing further GI testing.

Though symptoms do not consistently associate with specific areas of GI dysmotility, if nausea, vomiting, bloating, and/or abdominal distention are coupled with diarrhea and/or constipation, small or large bowel involvement should receive additional consideration as discussed in Sections 5.0 and 6.0.[23] In contrast, overlying symptoms of refractory reflux, epigastric pain, early satiety, and/or postprandial fullness may suggest an underlying gastric dysmotility (such as gastroparesis or abnormal gastric accommodation), which affects up to 50% of SSc patients.[23,54]

4.1. Evaluation of Gastric Motility

Gastroparesis is defined as “a syndrome of objectively delayed gastric emptying in the absence of mechanical obstruction and cardinal symptoms including early satiety, postprandial fullness, nausea, vomiting, bloating, and upper abdominal pain.”[55] AGA guidelines[53] recommend EGD to assess for peptic ulcers, Helicobacter pylori infection, and gastric outlet obstruction. The UKSSG guidelines are in agreement and recommend follow-up testing with gastric emptying studies or ultrasonography if symptoms are suggestive of gastric dysmotility but there is no evidence of outlet obstruction.[8] The 4-hour gastric emptying scintigraphy study is the diagnostic standard for gastroparesis, and a combined solid-liquid phase study shows increased sensitivity.[55,56]

4.2. Management of Gastric Dysmotility

In patients with confirmed gastric dysmotility, the UKSSG guidelines recommend dietary modification with or without adjunct prokinetic therapies as the mainstay of treatment.[8] While the studies[57] available on dietary modification in SSc are small and limited in scope, dietary counseling may recommend such interventions as a low-fat and low-fiber diet, small meal sizes, and high-calorie liquids to optimize nutrition.[55] There is very limited data specific to SSc in the use of prokinetic agents for the treatment of gastric dysmotility, and thus existing guidelines recommend that these agents be used with caution.

Presently metoclopramide is the only medication that is formally approved in the United States for the long-term treatment of gastroparesis.[55] One small trial[58] has shown the benefit of improved gastric emptying times extends to SSc patients as well. Unfortunately, significant extrapyramidal side effects such as tardive dyskinesia warrant caution in its use. For this reason, the lowest possible therapeutic dose is recommended (starting with 5mg before meals and at bedtime, with a maximal total daily dose of 40mg). Drug holidays should be initiated whenever possible, and physicians should maintain a low threshold to discontinue therapy, particularly in the setting of any new neurologic symptoms.[55]

Domperidone, a dopamine-2 antagonist similar to metoclopramide with fewer side effects, can be obtained only through special government programs in the United States. Intravenous erythromycin is another consideration, although this medication is limited by its multiple times a day dosing and chronic propensity towards tachyphylaxis.[55] Prucalopride has also been identified in general population studies[59] as a new effective agent for the treatment of gastroparesis. Patients with persistent or progressive symptoms despite dietary modification and/or adjunct prokinetics may be treated together with an experienced gastroenterologist for consideration of alternative or combination therapies (e.g. mirtazapine, buspirone, pyridostigmine, etc.).[60,61] Recent studies[62,63] suggest that transcutaneous electrical nerve stimulation may also improve gastric transit in SSc patients, but larger studies are needed to prove clinical efficacy.

An evaluation by a gastroenterologist and nutritionist is particularly important when managing patients with progressive weight loss and/or malnutrition attributed to GI dysfunction. Patients may need an assessment for supplemental enteral or parenteral access for nutrition if they are unable to maintain a normal BMI and balanced diet on oral intake alone.[55,64] Practice points for nausea, vomiting, bloating, and/or distention can be found in Table 6.

Table 6.

Practice Points and Research Agenda for Nausea, Vomiting, Bloating, or Distention in Systemic Sclerosis

Practice Points: Patients with SSc that report abdominal distention, bloating, nausea, and/or vomiting should first be evaluated by careful history and physical exam to rule out common symptom etiologies Symptoms including post-prandial fullness, early satiety, and/or epigastric pain should be particularly concerning for gastric etiology, and should first be evaluated by EGD to rule out gastric ulcers, infection, and gastric outlet obstruction A 4-hour gastric emptying study (ideally a combined solid-liquid study) should be conducted to confirm a diagnosis of gastroparesis in SSc, following an EGD evaluation Dietary modification with low-fat low-fiber intake, small meal adjustments, and increased high-calorie liquids is the current management recommendation for patients with abnormal gastric motility Prokinetic agents such as metoclopramide, domperidone, erythromycin, and prucalopride may be considered on a case-by-case basis as adjunct therapy in patients with more severe symptoms Partnering with an experienced gastroenterologist for consideration of alternative therapies (e.g. pyridostigmine, mirtazapine, etcetera) may be beneficial if symptoms are persistent despite dietary modification Patients with malnutrition secondary to poor oral intake should be evaluated for supplemental enteral or parenteral nutrition if within goals of care

Research Agenda: More randomized control trials are needed in the SSc population to assess the effect of prokinetic agents in the treatment of gastric dysmotility (gastric transit and accommodation) More research is needed to identify alternative therapies to treat and/or slow the progression of gastric dysmotility in SSc More research is needed to determine the optimal dietary interventions for SSc patients with gastric dysmotility

SSc: Systemic Sclerosis; EGD: esophagogastroduodenoscopy

5.0. DIARRHEA

Diarrhea is another common presenting GI complaint in SSc, estimated to affect approximately 50% of patients.[8] Causes of diarrhea in this patient population are frequently attributed to SIBO, malabsorption, and GI tract dysmotility; however, an assessment for other common causes of diarrhea such as infection and inflammatory bowel disease should also be pursued.[64] Clostridium difficile infection is of particular concern given high exposure to the medical environment and frequent use of antibiotics (in the setting of immunosuppression, SIBO, digital ulcers, etc.). Excellent reviews for the workup of acute and chronic diarrhea in the general population have been published by the American Academy of Family Physicians and New England Journal of Medicine, respectively, and are provided here for reference.[65,66]

5.1. Clinical Presentation, Diagnosis, and Treatment of SIBO in SSc

Patients with SSc are at increased risk for SIBO due to the presence of small and/or large bowel dysmotility (leading to luminal stasis of food) and chronic exposure to high-dose acid suppression therapy, which reduces the physiologic gastric acid protection against excessive bacterial colonization of the GI tract.[67] SIBO is defined by the American Journal of Gastroenterology as “a condition in which the small bowel is colonized by excessive numbers of aerobic and anaerobic microbes that are normally found in the large intestine.”[68] This may present as a number of symptoms, such as episodic loose stools, halitosis, abdominal discomfort, distention, or bloating.[8,69] Symptoms may also present more insidiously as malnutrition, and thus rheumatologists should maintain a high index of suspicion for this diagnosis.[67] Identifying the true prevalence of SIBO in the SSc population remains challenging due to poor diagnostic testing options and therefore a high incidence of empiric antibiotic therapy trials. The gold standard test for diagnosis, jejunal culture, is often prohibited by the need for general anesthesia, which is frequently contraindicated in SSc due to the cardiopulmonary complications of the disease.[70] With these significant limitations, the incidence of SIBO in SSc is estimated to be somewhere between 30–62%.[69]

Currently, the utility of diagnostic testing versus empiric therapy in clinical cases with high suspicion for SIBO in SSc is unknown. The only validated diagnostic test for SIBO in SSc, given the relative contraindication for the gold standard jejunal culture, is the hydrogen or methane breath test following a glucose or lactulose bolus.[64] The EULAR guidelines recommend empiric courses of intermittent or rotating broad-spectrum antibiotics for the treatment of SIBO in SSc, based on expert consensus, acknowledging a lack of randomized control trial data available in SSc. No recommendation is made regarding the utility of diagnostic testing.[7] The UKSSG recommendations do not provide definitive guidance regarding diagnostic testing versus empiric treatment, stating that hydrogen breath testing may be used for diagnosis and empiric antibiotics may be used for treatment.[8] Finally, the AGA’s recent clinical practice update for SIBO, not specific to SSc, acknowledges that empiric antibiotics are the mainstay of treatment based on poor-quality data, and that hydrogen/methane breath testing may be useful in identifying the subset of patients that will respond to therapy.[71] Additional research is needed in the general population, as well as in SSc, to further define the risk-benefit ratio of empiric therapy versus initial breath testing. The AGA guidelines do state, however, that repeated diagnostic testing is not necessary if patients respond to antibiotic therapy.[71]

As a whole, antibiotic treatment for SIBO remains empiric with limited data to support one antibiotic regimen versus another. Rifaximin has the most robust data to support its use, with successful clinical trials in both the general population[72] and SSc population.[73] There is no consensus on the appropriate dosing of rifaximin for SIBO, and thus the current AGA guidelines[71] suggest a regimen of dividing a total daily dose of 800–1200mg throughout the day. There is also no consensus on length of antibiotic therapy, with studies ranging 1–4 weeks of therapy. Rate of recurrence is known to be high, cited as up to 44% of cases by 9 months, and thus the AGA, EULAR, and UKSSG guidelines suggest that some patients may need repeated or rotating antibiotic courses.[7,8,71] Other antibiotics that have been studied in SSc for the treatment of SIBO, with moderate success, include ciprofloxacin, norfloxacin, amoxicillin, and metronidazole.[69] A full list of proposed antibiotic regimens for SIBO from the AGA is listed in Table 7.[71]

Table 7.

Proposed Antibiotic Regimens for Spontaneous Bacterial Overgrowth Syndrome (SIBO)

Antibiotic	Recommended Dosing for SIBO Treatment
Amoxicillin-clavulanic acid	500–125mg three times daily
Ciprofloxacin	250mg twice daily
Doxycycline	100mg twice daily
Metronidazole	250mg three times daily
Neomycin	500mg twice daily
Norfloxacin	800mg daily
Rifaximin	800–1200mg daily total in divided doses
Tetracycline	250mg four times daily
Trimethoprim-sulfamethoxazole	1 double strength tablet twice daily

5.2. Evaluation and Treatment of Small Intestinal Dysmotility

Dysmotility of the small bowel is estimated to affect anywhere between 40–88% of patients with SSc, although more precise figures are challenging to define as studies have shown that motility abnormalities likely precede symptoms. Complications of small bowel dysmotility may include SIBO, chronic intestinal pseudo-obstruction (CIPO), or pneumatosis cystoides intestinalis (a rare complication of SSc where air-filled cysts develop within the submucosa of the intestines, which have a propensity to spontaneously rupture and cause pneumoperitoneum).[74] One screening test that may be particularly beneficial is a plain abdominal radiograph, which can distinguish overflow diarrhea secondary to constipation or chronic intestinal pseudo-obstruction from other causes.[75] Appropriate bowel regimen therapies and additional workup for constipation are discussed in Section 6.0. While manometry may be diagnostic for small bowel dysmotility, this method is time-intensive and the need for routine anesthesia limits its use to patients without significant cardiopulmonary complications.[64] Scintigraphy is recommended as an alternative diagnostic tool to assess small bowel transit times.[76] Given the relative safety and non-invasive approach of scintigraphy, it may be a reasonable to obtain prior to the initiation of anti-diarrheal agents or other motility agents.

Data supporting motility agents in the management of small intestinal SSc remains limited, although both octreotide and prucalopride have demonstrated symptomatic benefit in studies.[44,77,78] Pyridostigmine is an additional agent that shows promise in the treatment of CIPO, as demonstrated in pediatric case series.[79] For the management of diarrhea symptoms, the UKSSG guidelines recommend lifestyle modification through diet to increase stool consistency and/or a trial of loperamide.[8,57] Importantly, anti-diarrheal agents should not be utilized until a thorough evaluation of other treatable causes of diarrhea is complete.

5.3. Gut Microbiome Modification

A new area of study for GI symptom therapy involves modulation of the GI luminal microbiome. The UKSSG guidelines state that probiotics “may be useful in some patients” with SSc, but do not provide additional recommendations regarding strains, treatment strategies, or duration of use.[8] The probiotics Bifidobacterium infantis and Lactobacillus rhamnosusGG subjectively improve bloating, distention, and reflux in patients with SSc.[80] Data suggests that combination therapy of Saccharomyces boulardii with metronidazole may be more effective treatment for SIBO than either agent alone in SSc.[81] Fecal transplant has also demonstrated symptomatic benefit for SSc in a small randomized control trial.[82] Ultimately the data for all microbiome modulation agents is still limited and this is an area that requires further study in this population. Practice points for diarrhea can be found in Table 8.

Table 8.

Practice Points and Research Agenda for Diarrhea in Systemic Sclerosis

Practice Points: All patients with SSc reporting symptoms of diarrhea should first be ruled out for common causes of diarrhea that affect the general population (infectious, malabsorption, inflammatory bowel disease, etc.) Hydrogen/methane breath testing after a glucose/lactulose bolus may have utility in identifying a subset of patients that will respond to empiric antibiotic therapy for SIBO Rifaximin has the most robust data supporting its use as a first-line agent for the treatment of SIBO, but beyond that, clinical data is limited in supporting the use of one empiric antibiotic regimen over another; the medication risk profile should be used to guide decision-making on an individual patient basis Cyclic antibiotic regimens may be considered for patients with recurrent symptoms Scintigraphy is likely a non-invasive diagnostic study for small intestinal dysmotility Consider anti-diarrheal agents should only after all other causes of diarrhea are ruled out Promotility agents should be used with caution, as they may exacerbate diarrhea

Research Agenda: There is a need to determine whether empiric therapy or objective testing is the best initial approach in the management of patients with diarrhea There is a need for head-to-head, randomized clinical trials of empiric antibiotic regimens for the treatment of SIBO Further research is needed on the long-term outcomes of empiric, cyclic antibiotic therapy in the SSc patient population Additional research is needed on the subject of GI microbiome modulation, such as probiotics and fecal transplant, and its effect in SSc

SSc: Systemic Sclerosis; SIBO: spontaneous bacterial overgrowth syndrome

6.0. CONSTIPATION

Patients with SSc are prone to experience constipation due to colonic dysmotility leading to reduced transit times.[64] The AGA defines constipation as a subjective patient symptom, which may include the traditional “definition” of infrequent bowel movements (generally less than 3 weekly), but may also be broadened to include symptoms such as “hard stools, a feeling of incomplete evacuation, abdominal discomfort, bloating, and distention.”[83] Given the range of clinical presentations, a careful history and physical is essential to determine the nature of symptoms and to rule out contributory causes, such as endocrine or metabolic sources;[8] the AGA’s clinical position statement is provided here for reference.[83] Notably, colonoscopy is an appropriate first step for those patients who have not completed age-appropriate colon cancer screenings, or are exhibiting additional “alarm symptoms” such as sudden-onset constipation, blood in stools, anemia on lab work, or unintentional weight loss.[83]

6.1. Therapeutic Laxative Trial for Constipation

In patients who do not warrant initial colonoscopy screening or have no endoscopic findings to explain constipation symptoms, the AGA recommends an empiric trial of stool-bulking agents and/or laxatives to help improve symptoms.[83] The UKSSG guidelines suggest breaking down cases into three distinct symptom groups: normal urge with difficulty emptying, infrequent urge with difficulty emptying, and normal urge with normal emptying. Stool-bulking agents such as fiber may have symptomatic benefit in those patients with difficulty emptying but a normal urge to void. However, caution must be used in patients with SSc who have significantly delayed colonic transit, as stool bulking may not adequately stimulate bowel movements as would be expected in patients with a normal colon, and therefore may exacerbate bloating or distention.[84] Osmotic laxatives (such as polyethylene glycol or milk of magnesia) may benefit patients with an infrequent urge to void and difficulty evacuating the colon, however they can have the drawback of worsening bloating symptoms. Stimulant laxatives (such as bisacodyl or glycerol suppositories) may improve symptoms in those with a normal urge to void and normal sensation of emptying.[8,83] Newer agents that rheumatologists may utilize include colonic secretory agents such as lubiprostone, linaclotide, and plecanatide; studies[85–87] in the general population have demonstrated their symptomatic benefit in the treatment of chronic idiopathic constipation. Notably, these agents have not yet been specifically studied in the SSc population.

6.2. Assessment of Colonic Motility and Prokinetic Therapies

Patients who fail a therapeutic laxative trial for constipation are candidates for additional colonic transit studies, according to the AGA. These can include the use of radio-opaque markers or scintigraphy, following a rule out of defecatory disorders (please see Section 7.0 for additional discussion of fecal incontinence).[83] These diagnostic tests have been used in the SSc population with success.[88] Following a confirmation of slow colonic transit, patients may be considered for prokinetic therapy. Cisparide and prucalopride demonstrate symptomatic benefit in SSc patients experiencing constipation.[44,89] Prucalopride was also validated in general population studies, identifying this is an effective alternative medication in the treatment of constipation.[90] Practice points for constipation can be found in Table 9.

Table 9.

Practice Points and Research Agenda for Constipation in Systemic Sclerosis

Practice Points: All patients with new-onset constipation should undergo screening for colon cancer if age-appropriate or exhibiting “alarm symptoms” such as blood in stool, anemia, or weight loss An empiric therapeutic trial of stool-bulking agents (fiber), osmotic laxatives (polyethylene glycol, milk of magnesia), or stimulant laxatives (bisacodyl, glycerol suppository) is appropriate in patients with negative colonoscopy findings, and medications should be titrated for optimal symptom reduction Radio-opaque markers or colonic scintigraphy studies are appropriate diagnostic tests to assess for colonic dysmotility in patients with suboptimal response to empiric laxatives Prucalopride is a prokinetic agent that can be considered for treatment of slow-transit constipation unresponsive to stool-bulking agents or laxatives Patients with continued constipation symptoms despite medical therapy should be referred to a gastroenterologist for consideration of alternative management strategies

Research Agenda: There is a need for head-to-head, randomized clinical trials comparing the efficacy of different constipation therapies in SSc There is a need for evaluation of the long-term benefit of prokinetic agents in SSc-constipation Additional studies need to be developed to help discern different etiologies of SSc-related constipation (e.g. slow transit versus dysbiosis)

SSc: Systemic Sclerosis

7.0. FECAL INCONTINENCE

Symptoms of anorectal dysfunction are reported in up to 70% of patients with SSc, making this the second most involved portion of the GI tract following the esophagus.[74] The most commonly reported symptom is that of fecal incontinence (FI), defined by the American College of Gastroenterology (ACG) as the “involuntary loss of solid or liquid feces.”[91] Patients with SSc have been found in clinical studies[92] to have an impaired recto-anal inhibitory response (RAIR) that contributes to internal anal sphincter dysfunction, and consequently, FI. However, prior to RAIR assessment, the ACG guidelines recommend identifying whether patients have any other conditions that may predispose to FI symptoms, such as diarrhea, pelvic floor trauma (particularly obstetric injury), and neuropathy.[91] An evaluation of diarrhea in SSc is further discussed in Section 5.0.

7.1. Digital Rectal Examination and Conservative Management of FI

The ACG currently provides a strong recommendation[91] for performing a digital rectal examination (DRE) to assess for anal sphincter tone and presence of rectal masses if history and physical exam do not provide an alternative predisposing source; there are no rheumatology society guidelines presently on the subject of FI. Reduced internal anal sphincter tone would support an impaired RAIR that may be seen in SSc.[92] Patients with loose stools, diarrhea, or constipation that are contributing to FI should be managed with stool-modifying medications, discussed further in Sections 5.0 and 6.0, respectively. The ACG recommends that these medications are trialed, if clinically appropriate, prior to further diagnostic testing.[91]

7.2. Anorectal Manometry, Pelvic Physical Therapy, and Invasive Management of FI

In patients who do not respond to conservative management, the ACG provides a strong recommendation for anorectal manometry, balloon expulsion testing, and rectal sensation evaluation for follow-up diagnostic testing.[91] Presently only anorectal manometry has been studied[37] in the SSc population, and thus the clinical utility of the latter two diagnostics for SSc is currently unknown. Anorectal manometry may be used to confirm an impaired RAIR, and normal testing should prompt the reconsideration of alternative diagnoses.[37] For patients with confirmed anorectal dysfunction that have not responded to conservative management, the ACG provides a strong recommendation for pelvic floor rehabilitation therapy.[91] Studies[93] have demonstrated the benefits of this therapy extends to the SSc population as well.

The ACG guidelines outline a few alternative invasive options for the management of FI in patients that do not respond to symptom-modifying therapies or pelvis exercises. In the general population, minimally invasive sphincter bulking agents are given a weak recommendation and sacral nerve stimulation is given a strong recommendation. Additional surgical options include sphincteroplasty, artificial anal sphincters, and colostomy.[91] Sacral nerve stimulation has been studied in SSc with favorable outcomes,[94] but additional research is needed to clarify the benefit of other invasive management options. Pursual of these options in FI should not be conducted without the assistance of a specialized gastroenterologist or anorectal surgeon. Practice points for fecal incontinence can be found in Table 10.

Table 10.

Practice Points and Research Agenda for Fecal Incontinence in Systemic Sclerosis

Practice Points: In patients with SSc and symptoms of fecal incontinence, contributing causes of diarrhea, pelvic floor injury, or neuropathy must first be ruled out through careful history and potentially an additional laboratory evaluation A digital rectal exam is a useful screening exam to evaluate for dysfunctional anal sphincter tone prior to more invasive manometry studies SSc patients with concern for internal anal sphincter dysfunction by digital rectal exam can undergo anorectal manometry to confirm this diagnosis Fecal incontinence secondary to confirmed anal sphincter dysfunction can be first managed through a trial of pelvic physical therapy Patients who continue to experience fecal incontinence that affects quality of life, despite conservative management and physical therapy, should be referred to a gastroenterologist or anorectal surgeon for consideration of alternative management strategies

Research Agenda: There is a need for clinical trials examining the efficacy of invasive management strategies for FI

SSc: Systemic Sclerosis; FI: fecal incontinence

8.0. SUMMARY

In the evaluation of SSc-GI disease, a symptoms-based approach is practical and may help to guide the initial diagnostic assessment. While GI disease is common in SSc, there remains a great need for additional research understanding disease mechanism and assessing the efficacy of both known and novel therapies for these patients. Risk stratification of asymptomatic patients is also an area that needs further study, as the utility of empiric therapies to prevent or slow progression of symptoms is not known. Clinicians should aim to treat symptoms to optimize quality of life and potentially reduce the risk of known GI complications in SSc.