Managing gastrointestinal manifestations in systemic sclerosis, a mechanistic approach

Abstract

Introduction:

Systemic sclerosis (SSc) is a connective tissue disease with heterogeneous presentation. Gastrointestinal (GI) complications of SSc are characterized by esophageal reflux, abnormal motility, and microbiome dysbiosis, which impact patient quality of life and mortality. Preventative therapeutics are lacking, with management primarily aimed at symptomatic control.

Areas covered:

A broad literature review was conducted through electronic databases and references from key articles. We summarize the physiology of gastric acid production and GI motility to provide context for existing therapies, detail the current understanding of SSc-GI disease, and review GI medications studied in SSc. Finally, we explore new therapeutic options. We propose a management strategy that integrates data on drug efficacy with knowledge of disease pathophysiology, aiming to optimize future therapeutic targets.

Expert opinion:

SSc-GI complications remain a challenge for patients, clinicians, and investigators alike. Management presently focuses on treating symptoms and minimizing mucosal damage. Little evidence exists to suggest immunosuppressive therapy halts progression of GI involvement or reverses damage, leaving many unanswered questions about the optimal clinical approach. Further research focused on identifying patients at risk for GI progression, and the underlying mechanism(s) that drive disease will provide opportunities to prevent long-term damage, and significantly improve patient quality of life.

1. Introduction

Systemic sclerosis or scleroderma (SSc) is a rare immune-mediated connective tissue disease that may involve multiple organ systems. Treatment is typically dictated by an individual’s specific organ-based complications, as significant heterogeneity exists in terms of the extent of organ involvement and the response to a given therapy [1]. Gastrointestinal (GI) complaints affect up to 90% of SSc patients [2]. Such symptoms may result in significant morbidity and mortality [3,4]. The goals of this review are to summarize the GI manifestations in SSc, examine the current literature pertaining to treatment, and discuss management when considering specific pharmacological targets. Studies selected for inclusion of this scoping review were found via literature searches of PubMed and Google Scholar, as well as a manual review of references from key articles. Articles not available through the Johns Hopkins University electronic literature databases were not included. To facilitate a broad search strategy, no filters were applied aside from English language, with articles published prior to December 10, 2023 reviewed

2. Gastroesophageal Reflux Disease (GERD)

2.1. Reflux in SSc

GERD, most commonly manifesting as heartburn or reflux, is the most reported GI manifestation in SSc patients, with an estimated 50-90% of patients having clinical or subclinical esophageal involvement. This is driven by esophageal or gastric dysmotility and reduced lower esophageal sphincter (LES) tone [3,5-7]. This high incidence of GERD is subsequently associated with an increased risk for mucosal injury complications such as esophageal strictures, Barrett’s esophagus, and esophageal adenocarcinoma, the presence of any informing the choice and duration of therapy [8,9]. Disorders that mimic or exacerbate reflux are important to consider and include Helicobacter pylori infection, hiatal hernias, inflammatory myositis, eosinophilic esophagitis, infectious or pill esophagitis, and esophageal adenocarcinoma [8,10-13]. The management of such disorders is outside the scope of this review. It is unknown if SSc patients have increased levels of gastric acid production, although small control studies [14,15] have not found increased levels of the hormone gastrin in this population, a primary driver of acid production. As the underlying pathophysiology of esophageal and gastric dysfunction in SSc is not well-understood, first-line treatment of GERD remains primarily symptomatic with a focus on acid suppression and the application of pro-motility agents in refractory cases or when dysmotility of the esophagus or stomach is identified (detailed in later sections). Surgical management of refractory reflux symptoms remains a last resort, as multiple studies [16-19] found a significant increase in postoperative dysphagia in this population.

2.2. Physiology of Gastric Acid Production

Gastric acid production is complex and modulated by the parasympathetic nervous system (PNS) and neuroendocrine molecules. Gastric lumen distension triggered by ingested food causes gastrin cells (G cells) in the pylorus to secrete the hormone gastrin, which then stimulates enterochromaffin-like (ECL) cells to produce histamine. Histamine acts on histamine-2 receptors (H2R) located on parietal cells, stimulating hydrochloric acid (HCl) secretion into the stomach via membrane proton pumps (Hydrogen-Potassium ATPase). Gastrin also is a growth factor, increasing the cell mass of both ECL and parietal cells [20,21]. Vagal nerve stimulation of murine G cells is mediated by muscarinic receptor subtypes 3 and 5 (M3R and M5R), with M3R knockouts demonstrating impaired gastric acid secretion despite exposure to elevated gastrin levels [20,22,23]. Food initially buffers gastric acid, but as digestion progresses the intraluminal gastric pH falls and stimulates somatostatin secretion, reducing acid production via paracrine inhibition of G cells and direct inhibition of parietal and ECL cells [20,24].

2.3. Proton Pump Inhibitors

Proton pump inhibitors (PPIs) function by directly inhibiting the gastric proton pumps that secrete HCl. Their long-term efficacy lies in the blockage of this final step of gastric acid production, which is not overcome by physiologic up-regulation of alternative pathways [20,25]. This effect is acid-dependent, requiring HCl for conversion of the drugs to their active binding form [26]. The European League against Rheumatism (EULAR), UK Scleroderma Study Group (UKSSG), and the British Society for Rheumatology (BSR) with the British Health Professionals in Rheumatology (BHPR) have all published guidelines recommending PPIs as the first-line treatment for GERD and dysphagia in SSc [27-29]. This is consistent with recommendations for the management of GERD in the general population from the American Gastroenterological Association (AGA), which support PPI use for treating GERD symptoms and mucosal injury [30].

Data for the use of PPIs in SSc is largely limited to small clinical trials. Two trials assessed the effect of omeprazole, the first [31] finding that low-dose (20mg daily) was effective in reducing reflux events measured by esophageal pH monitoring independent of symptoms (n=8), while the second [32] assessed variable daily dosing (20-80mg) for up to five years and noted statistically significant improvement in symptoms and visualized esophagitis with a favorable safety profile (n=25). However, nearly half of patients had incomplete mucosal healing. Daily lansoprazole (30mg) showed symptomatic benefit at six months in a randomized placebo-control trial, [33] but this effect waned at twelve months and did not improve esophageal dysmotility (n=11). In the largest clinical trial [34], the benefit of rabeprazole 10mg daily was examined in 151 patients over a four- and eight-week interval. Significant improvement in GERD symptom scoring was found by four weeks. While no clinical studies have directly assessed the efficacy of twice daily dosing in SSc, predictors of incomplete symptomatic response to this dosing were examined in a prospective study [35]. Patients with esophageal dysphagia were at higher risk for incomplete response to PPI in the multivariate analysis (n=243).

Of interest, a newer agent, vonoprazan, inhibits proton pumps through a novel mechanism that targets the potassium-binding component of the enzyme, independent of HCl. A systematic review [36] found that vonoprazan was non-inferior to most PPIs in the treatment of GERD-associated mucosal damage, with subgroup analysis suggesting higher efficacy than PPIs in patients with severe disease. This agent has been approved for use only in select countries presently, with the majority of data coming from the Japanese general population. In one prospective trial in SSc [37], vonoprazan (20mg baseline dose) significantly improved endoscopic reflux and mucosal healing in PPI-refractory GERD (n=10). Another study [38] noted significant improvement in patient-reported reflux symptoms (n=15), although not all patients were assessed for mucosal injury.

Given the limited data in SSc, the recommendation to treat with PPIs is largely supported by literature from the general population. However, many safety concerns have been raised, which are potentially relevant to the SSc patient population (such as increased risk of infection, kidney disease, and impaired bone health) [39]. A Cochrane review [40] confirmed the superiority of PPIs to H2R antagonists and placebo in the treatment of symptomatic GERD and esophageal mucosal injury, finding no difference in efficacy across individual PPIs. AGA guidelines support the use of twice-daily dosing for persistent symptoms, citing expert opinion, with the caveat that medications should be titrated to the lowest possible therapeutic dose [28,30]. Optimal dosing and duration of therapy have not been studied in SSc, therefore a need for the assessment of associated long-term outcomes remains. The management of structural complications from mucosal injury should be done in conjunction with a gastroenterologist, as therapy decision-making is driven by endoscopic reassessment [9,39]. Vonoprazan may be considered in PPI-refractory disease in countries with access to this therapy.

2.4. Histamine-2 Receptor Antagonists

While H2R antagonists are inferior to PPIs in the treatment of symptomatic GERD and esophageal mucosal injury, data suggest they have a role in the treatment of refractory symptoms when PPI use is maximized or full dosing is not tolerated [30,40]. H2R antagonists target the histamine-2 receptor pathway of gastric acid secretion by competitively inhibiting parietal cell stimulation of proton pumps. [41] Their short duration of action and ability to have their therapeutic effects overcome by reflexive increases in gastrin production and subsequent stimulation of alternative gastric acid secretion pathways are major contributors to their reduced efficacy relative to PPIs [20,25].

Two small clinical trials demonstrate the efficacy of H2R antagonists in SSc. One randomized cross-over trial [42] compared cimetidine 300mg four times daily with a combination antacid (aluminum hydroxide, magnesium hydroxide, simethicone) (n=15), with cimetidine providing more symptomatic relief and significant mucosal improvement endoscopically over an eight-week period. The esophageal stricture size was unaffected. In a separate prospective trial [43] symptomatic patients (n=18) were treated with a six-week course of ranitidine, before randomizing to ranitidine or placebo for an additional fourteen weeks. Efficacy of ranitidine was maintained with continued use, however immediately waned in the placebo group with corresponding increases in mucosal inflammation. In contrast, another randomized control, cross-over trial [44] found that combining omeprazole 20mg twice daily with ranitidine 300mg nightly did not significantly improve symptoms, nocturnal acid breakthrough, or quality of life compared to combining PPI with placebo (n=14) [30]. Only the BSR/BHPR guidelines [29] include a recommendation regarding the use of H2R antagonists, advocating for their use in SSc based on data from the general population and expert opinion.

Data suggest that H2R antagonists may also impact motility. In vitro and animal models demonstrate weak inhibition of the enzyme acetylcholinesterase (AChE) by H2R antagonism, which may indirectly increase overall cholinergic activity that mediates intestinal smooth muscle activity [45-48]. Human studies show mixed results. Within the SSc population, a controlled study [49] showed that intravenous famotidine (n=13) significantly increased LES pressures compared to a saline infusion, with a follow up study [50] replicating these findings with intravenous famotidine (n=13) but not cimetidine (n=6).

2.5. Antacids and Other Acid Barriers

Antacids are basic compounds that relieve symptoms of GERD through neutralization of HCl. Typically, these compounds contain magnesium, aluminum hydroxide, bicarbonate, or calcium carbonate [51]. They do not provide the same level of mucosal protection as PPIs and H2R antagonists as they do not prevent gastric acid formation, rather they exert their effects once gastric acid is present [30]. There are no formal studies directly assessing the efficacy of antacids in SSc, beyond the previously discussed comparator study of cimetidine versus combination antacid [42]. Alginic acid, which when complexed with antacids, reacts with saliva to form a viscous protective surface barrier to block reflux of gastric contents and reduced GERD symptoms in general population studies [52,53] more than antacids alone. When used as add-on therapy in SSc, the alginic acid-antacid compound algycon (dosed at 1 chewing tablet three times daily) improved symptom severity and quality of life in patients with PPI-refractory GERD (n=37). This benefit was comparable to that seen with the prokinetic, domperidone [54].

3. Dysphagia and Early Satiety

3.1. Esophageal and Gastric Dysmotility in SSc

Dysmotility is a common manifestation of SSc and may affect all parts of the gut. While pathogenesis of SSc-GI dysmotility remains poorly defined, various hypotheses suggest that a progressive pathologic fibrosis, progressive vasculopathy, or neuropathy with subsequent smooth muscle atrophy may play a role [55-57]. The latter hypothesis has become of increased interest in recent years, particularly following the discovery of muscarinic receptor antibodies [58,59].

Esophageal involvement is common (estimated upwards of 90% of cases), typically manifesting as abnormal smooth muscle peristalsis (affecting the distal two thirds of the esophagus) and reduced LES tone. In addition to symptomatic GERD, patients may report nocturnal/morning cough, chest pain, dysphagia, or hoarseness [3,60]. Symptom severity does not consistently correlate with disease, however severe esophageal disease and ongoing micro-aspiration do correlate with the severity of interstitial lung disease, therefore careful attention should be paid to such symptoms [6,61]. Delayed gastric emptying occurs in 30-55% of SSc patients and is associated with dysmotility of other areas of the GI tract [62]. Dysfunction of gastric pacemaker cells called intramuscular interstitial cells of Cajal (ICC) is also reported, resulting in dysrhythmia. Common symptoms of gastric involvement include functional dyspepsia, early satiety, bloating, and nausea/vomiting [3,63]. Prokinetic therapy should be considered in patients with refractory upper GI dysmotility symptoms despite lifestyle modifications and maximally tolerated PPI acid suppression. While numerous prokinetic therapies are available, their efficacy along regions of the GI tract differs and their application must be targeted to the specific area of dysfunction (i.e. upper, lower, or global GI dysmotility).

3.2. Regulation of Normal Upper GI Motility

The GI tract is under neurohormonal, myogenic, and microbacterial regulation that coordinates digestion, absorption, and motility. Anatomically, the GI tract consists of four layers: the internal mucosa (lumen), submucosa, muscularis externa, and external serosa layer. The submucosa possesses nerves that respond to luminal mechanical and chemical stimuli [64,65]. The muscularis externa contains an inner and an outer smooth muscle layer, which are innervated by the myenteric plexus. These neural layers together comprise the terminal components of the enteric nervous system (ENS). The ENS is part of the autonomic nervous system and is a key regulator of GI physiology and motility [3,64]. Beyond the ENS, specialized ICC pacemaker cells contribute intrinsic myogenic activity to produce rhythmic smooth muscle contractions. They also transduce and amplify neurogenic impulses to smooth muscle [65,66]. ENS muscarinic cholinergic receptors coordinate smooth muscle contraction against this background of ICC activity. The function of acetylcholine (ACh) as a neurotransmitter in this regard was well documented, with muscarinic antagonists significantly reducing transit times [67-69].

Coordination of esophageal peristalsis occurs in a biphasic pattern, with vagal short-latency inhibitory pathways first prompting smooth muscle relaxation (via nicotinic receptors), followed by vagal long-latency excitatory pathways initiating contraction (via muscarinic receptors). The ratio of inhibitory to excitatory neural stimulation exists in a gradient that decreases in a caudal direction, coordinating the proximal-to-distal orientation of peristalsis [69,70]. The LES remains contracted at baseline, with relaxation coordinated to peristalsis through similar inhibitory/excitatory pathways. The LES also possesses an additional isolated relaxation reflex that is triggered when gastric vagal nerves are stimulated. This reflex is physiologically utilized in belching and vomiting and entirely mediated by the inhibitory pathway. The neurotransmitter gamma-aminobutyric acid (GABA) can act on LES neural receptors to block this relaxation reflex [70,71].

ICCs in the stomach intermittently initiate smooth muscle contraction to modulate baseline peristalsis, an effect that increases in frequency with gastric distention. Esophageal and gastric distention also stimulate the gastric accommodation reflex through inhibitory relaxation vagal pathways, like those discussed with the esophagus [72]. Vagotomy in animal models leads to a reduction of this accommodation reflex [73,74]. Excitatory vagal pathways coordinate peristalsis in a caudal direction [72]. Further facilitation of gastric emptying is coordinated by the hormone motilin, which is released by duodenal M-cells when stimulated by gastric acid and bile. Motilin receptors in the stomach stimulate contractile bursts of the migrating motor complex (MMC), which propel gastric contents in a caudal direction through phasic muscle contractions and a reduced accommodation reflex. Motilin receptors also exist within the LES, inducing contraction when stimulated [75].

Distention and other changes in bowel contents stimulate the release of regulating hormones such as 5-hydroxytryptamine (5-HT) by intestinal cells. These help to regulate both upper and lower GI motility, enzyme secretion, and digestion [76]. 5-HT, also known as serotonin, is predominantly secreted by enterochromaffin (EC) cells located within the mucosa when mechanically stimulated. Although studies in knockout mice suggest that they are not essential in stimulating peristalsis, loss of 5-HT production generally delays enteral transit [77-80]. 5-HT receptors are sub-divided into different receptor families and subtypes based on composition and function. 5-HT1D, 5-HT2B, 5-HT3, and 5-HT4 receptors have been found on GI smooth muscle and myenteric neurons, facilitating gastric accommodation and peristalsis [80-84]. The 5-HT3 receptor has an additional role in modulating nausea, with antagonism demonstrating potent antiemetic benefits [83].

Another hormone that helps facilitate GI motility is dopamine. Approximately half of all circulating dopamine is produced by the mesentery, and synthesized by ENS dopaminergic neurons, immune cells, epithelia, and the microbiome [85,86]. Dopamine acts via two families of receptors in the GI tract, classified as either D1-like or D2-like, located on both nerves and smooth muscle. In animal models, D1-like receptors are stimulatory whereas D2-like receptors are inhibitory at the level of the smooth muscle, supporting the role of dopamine in modulating peristalsis [87-89]. In contrast to 5-HT, dopamine appears to be essential to GI tract functionality, with double knockout mutations in mice found to be lethal [90]. There is also evidence to support the role of dopamine in the modulation of acid production and maintenance of the GI mucosal barrier [87].

3.3. Dopamine-2-Like Receptor Antagonists

Antagonism or knockout of D2-like receptors accelerates whole gut transit [91,92]. Metoclopramide, which possesses D2-like receptor antagonist, 5-HT3 antagonist, and 5-HT4 agonist effects, is presently the only medication approved by the U.S. Food and Drug Administration (FDA) for the treatment of gastroparesis [93,94]. Whether its therapeutic effects are specifically mediated through D2-like receptor antagonism versus 5-HT4 agonism (or a combination of the two) is unclear. The AGA in their clinical practice guidelines for gastroparesis [94] acknowledge the multiple clinical trials in the general population demonstrating efficacy of metoclopramide in the short-term treatment of gastric dysmotility, with lack of long-term data outcomes. In SSc patients, three small clinical trials [95-97] for intravenous metoclopramide (10-20mg) all noted benefit in treating symptoms and increasing LES tone. One study also noted accelerated gastric emptying [96]. Interestingly, the effect on esophageal body dysmotility was less consistent across all three studies. Use of metoclopramide remains limited by an extensive side effect profile, including tardive dyskinesia, other extrapyramidal side effects, and QT interval prolongation. Another consideration is drug-drug interactions, given metoclopramide is partially metabolized through the cytochrome p450 pathway [94].

Domperidone is a selective D2-like receptor antagonist which has similar efficacy to metoclopramide in the treatment of upper GI tract dysmotility, but with less central side effects as it does not cross the blood-brain barrier [3,94]. Data for its use primarily comes from the study of gastroparesis in the general population, with the AGA citing multiple positive studies (both open and randomized control trials) in their clinical practice guidelines [94]. Two previously mentioned studies are the only presently available studies which assess the use of domperidone in SSc: (a) a comparator trial [54] which found domperidone 10mg three times daily to be equally efficacious to algycon as add-on therapy to PPIs in refractory GERD; and (b) another [98] which did not find domperidone to have an effect on LES pressures (although gastric and symptomatic outcomes were not assessed). Side effect considerations with domperidone include QT interval prolongation and hyperprolactinemia, as well as a drug-drug interaction risks (similar to metoclopramide) involving the cytochrome p450 pathway [94,99]. The hyperprolactinemia is of particular clinical interest, as prolactin is known to activate immune signaling pathways leading to proliferation and differentiation, and SSc patients have been found to have elevated baseline levels of prolactin relative to healthy controls. Correlation of prolactin levels to SSc disease outcomes, however, remains controversial [100].

Buspirone functions as a direct D2-like receptor antagonist and 5-HT1A/5-HT2 receptor agonist, increasing esophageal peristaltic tone and LES pressures in healthy individuals [101,102]. Trials by Karamanolis et al. [98,103] (n=20 and 30, respectively) in SSc determined that buspirone 10-20mg daily associated with increased LES pressures and reductions in heartburn/regurgitation. Whether the therapeutic benefits are driven by its pro-serotonergic or anti-dopaminergic effects is uncertain.

3.4. Motilin Receptor Agonists

In SSc patients, one study [104] found that plasma levels of motilin positively correlate with slow wave coupling (coordination of MMCs to incite motility), highlighting the motilin pathway as a possible therapeutic target. SSc patients have been shown to have higher plasma levels of motilin relative to healthy controls; whether this finding is representative of a pathologic or a compensatory process is unclear [15]. Macrolide antibiotics possess motilin receptor agonist activity, stimulating increased MMC activity to facilitate gastric emptying [105,106]. This effect is well-documented and utilized for the treatment of gastroparesis in the general population, particularly with erythromycin [107,108]. While motilin promotes motility in the small bowel as well, erythromycin does not affect small bowel contractions [109]. In SSc patients, 2mg/kg/hr intravenous erythromycin was found to stimulate both gastric and gallbladder emptying when administered immediately prior to meals (n=12) [110]. Continuous use of macrolides for gastric dysmotility has the limitation of eventual tachyphylaxis from physiologic downregulation of motilin receptors, occurring around four weeks following onset of therapy [108,111]. Additional considerations include antimicrobial effects of macrolides and their potential impacts on the microbiome and antimicrobial resistance [105,108].

3.5. GABA-B Receptor Agonists

GABA is a neurotransmitter synthesized by presynaptic neurons with inhibitory properties. Type B GABA receptors (GABA-B) function as G-protein coupled receptors which hyperpolarize neural cells to prevent action potential conduction, by decreasing presynaptic calcium and increasing postsynaptic potassium [112]. GABA-B stimulation inhibits the effects of gastric distention on parasympathetic activity, reducing the accommodation and isolated LES relaxation reflexes when agonized.

Baclofen is a GABA-B agonist typically used to treat muscle spasticity given its inhibitory effects in the periphery, but it was also demonstrated to reduce GERD symptoms via increasing LES tone [71]. A systematic review [113] found that baclofen improved symptoms, pH monitoring, and manometry findings in patients with GERD, although 20% of patients experienced neurologic side effects (such as sedation, dizziness, confusion, and nausea). These effects were dose-dependent, with increased risk with higher doses and among patients with renal insufficiency. Baclofen has not been studied in SSc patients.

4. Constipation and Recurrent Pseudo-Obstruction

Small bowel dysmotility may present as symptoms of bloating, diarrhea, recurrent pseudo-obstruction, malnutrition, or unintentional weight loss. The true prevalence of small bowel involvement is unknown, though estimates range between 40-88% of patients [63]. One study [114] found that 65% of SSc patients with small bowel involvement (by manometry) reported no symptoms, suggesting high prevalence of subclinical disease. Colonic dysmotility is similarly felt to be under-reported, involving ~50% of SSc patients. Constipation is the most common symptom, although abdominal distention, pain, tenesmus, and recurrent pseudo-obstruction are reported [63,115]. First-line therapy for slow lower GI motility involves the use of laxatives or secretagogues, with refractory cases requiring the use prokinetics. Again, the choice of prokinetic should be dependent on the extent of GI dysmotility. The management of chronic diarrhea symptoms not attributable to overflow from obstruction/constipation is detailed later in this manuscript.

4.1. Regulation of Normal Lower GI Motility

Similar to the stomach, the small and large intestines have pacemaker activity and propulsive contractility activity, the latter mediated via the ENS [65]. 5-HT and dopamine play a role in coordinating enteral peristalsis in both the upper and lower GI tracts. An additional hormone called somatostatin, also known as growth hormone release inhibiting factor, is a peptide that plays an inhibitory role in secretory activity while mediating digestive enzymes and absorption. It is secreted by delta cells located in the stomach and small intestine, which are under inhibitory control via muscarinic acetylcholine receptors (specifically subtype 4, or M4R) [116]. Three types of somatostatin receptors (SSTR) are found in the GI tract: SSTR1 and SSTR3 are expressed on smooth muscle and neuronal cells in the GI tract (both myenteric and mucosal), and SSTR2 are expressed on endocrine cells and nerve fibers [24,105]. When released, somatostatin inhibits the secretion of hormones such as gastrin and motilin [24,75,105]. The prevalence of SSTRs decreases caudally through the GI tract. The influence of somatostatin on GI motility is still not well-characterized, however this appears to be a dose-dependent response where analogs at low doses accelerate motility and moderate-to-high doses prolong GI transit [117,118].

4.1. Somatostatin Receptor Agonists

The use of moderate-to-high doses of somatostatin analogs in the treatment of excessive motility syndromes, such as postoperative dumping syndrome and idiopathic refractory diarrhea, is well characterized in general population studies [119-123]. In contrast, studies conducted in the SSc population have focused on the efficacy of low dose octreotide (a somatostatin analog) on facilitating small intestinal motility. It was a landmark study by Soudah et al. [124] that first described therapeutic efficacy of subcutaneous octreotide in SSc (n=5), noting that an optimal dose of 100mcg induced MMCs to an amplitude comparable to that of healthy controls, improved hydrogen breath testing (a surrogate for small intestinal bacterial overgrowth, or SIBO), and improved abdominal symptoms (nausea, bloating, and pain). Two small subsequent studies [125,126] (n=5 and 7) also noted similar results. Another study [127] assessed the benefit of combining 50mcg subcutaneous octreotide with 200mg intravenous erythromycin therapy for the treatment of chronic intestinal pseudoobstruction in SSc (n=14), noting that combination therapy was able to initiate small intestinal motor activity that would not be elicited by erythromycin alone. Side effects such as abdominal cramping, bloating, and diarrhea are common, but typically self-resolve. Octreotide is also associated with cholelithiasis and reduced gallbladder contractility, potentially altering luminal fat absorption [128]. It is hypothesized that octreotide may benefit the treatment of cutaneous fibrosis by inhibiting insulin-like growth factor-I, which is up-regulated in dermal fibrosis samples, however further research is needed within the SSc population [129-131].

4.3. Laxatives

In cases of isolated constipation, a trial of conservative therapies prior to escalation with prokinetic agents is appropriate. The AGA in their clinical practice guidelines for idiopathic constipation [132] outline a therapeutic protocol for chronic constipation without alarm features (such as no bleeding, anemia, or weight loss to warrant endoscopic evaluation), recommending a first-line trial of stool bulking with fiber. If symptoms are refractory, then escalation to osmotic laxatives followed by alternative therapies (stimulant laxatives versus secretagogues versus prokinetic agents) is recommended. The UKSSG in their guidelines [28] for SSc patients modify this recommendation, suggesting that the initial choice of conservative laxative therapy (fiber versus osmotic laxative versus stimulant laxative) should be instead based on symptoms of urge and subjective effort needed to defecate, recommending fiber for those with normal urge but difficulties in emptying, osmotic laxatives for those with both infrequent urgent and difficulty emptying, and stimulant laxatives with both normal urge and emptying effort but still persistent constipation. However, there does not appear to be clear data to support this modified approach.

Osmotic laxatives function by increasing the water content of stool through creation of an intestinal intraluminal environment with higher osmotic properties, increasing the ease of transit. The AGA and other GI expert groups prefer the use of polyethylene glycol or magnesium oxide-containing agents over lactulose. The former two are available over the counter and are associated with fewer side effects, particularly diarrhea and bloating [132,133]. None of these agents were directly studied in SSc-associated constipation.

Examples of simulant laxatives include bisacodyl and senna. Bisacodyl is metabolized by intestinal enzymes to an active component, bis-(phydroxyphenyl)-pyridyl-2-methane (BHPM). This is shown to increase both circular and longitudinal smooth muscle tone in the intestines, through direct stimulation of the mucosa [134]. Senna acts via a different mechanism, metabolized by gut microbiota to rheinanthrone and rhein, which work by simulating the release of prostaglandin E2 and chloride transit to facilitate peristalsis [132]. As with the osmotic laxatives, none of these agents were studied in SSc patients.

4.4. Secretagogues

The AGA recommends the use of secretagogue agents as a possible therapeutic pathway in idiopathic constipation refractory to osmotic laxatives [132]. Intestinal fluid content is in part regulated by sodium and chloride transport. Epithelial enterocytes and colonocytes possess chloride channels that secrete chloride into the intestinal lumen to induce fluid secretion. The primary chloride channels of the GI tract are the cystic fibrosis trans-membrane regulator (CFTR), calcium-activated chloride channel (CaCC), and chloride channel type 2 (ClC-2). In a normal physiologic state, intracellular signaling through increased cytosolic calcium ions and cyclic nucleotides (cAMP and cGMP) stimulates these channels [135]. These cells also possess sodium exchangers that work to absorb luminal sodium, facilitating fluid absorption. The sodium-hydrogen exchanger 3 (NHE3) is identified as the primary contributor of intestinal sodium absorption and subsequent fluid uptake. NHE3 activity is upregulated by increased peptide proton gradients and downregulated by cGMP, further illustrating the interplay between chloride and sodium in the regulation of stool fluid content [136]. Secretagogues take advantage of these pathways, increasing intraluminal fluid to improve ease of transit.

Lubiprostone is a fatty acid derivative of prostaglandin E1 that directly activates ClC-2, increasing intraluminal chloride [132,135]. Several double-blinded placebo-controlled trials [137-139] in the general population demonstrated efficacy in treating chronic constipation. Linaclotide and plecanatide are agonists of guanylate cyclase-C, which is an enterocyte surface enzyme responsible for increasing cGMP formation. Both agents are demonstrated in several randomized trials [140-144] to effectively treat chronic constipation. The use of lubiprostone, linaclotide, and plecanatide is given a strong recommendation in the AGA guidelines [132]. Tenapanor, a direct inhibitor of NHE3, is the newest secretagogue approved by the FDA. Inhibition of NHE3 leads to increased intraluminal sodium, and subsequent increase in intraluminal fluid. Two large placebo-controlled trials [145,146] demonstrated efficacy in treatment of constipation-predominant IBS. All four of these agents are minimally absorbed, with limited side effects, including diarrhea and bloating. These agents are contraindicated in cases of known mechanical bowel obstruction [132,135,145]. Only linaclotide was specifically studied in SSc by Dein et al. [147] who reported effectiveness of both low-dose and high-dose therapy (defined as less than or greater than 145mcg daily, respectively) for treating refractory lower GI symptoms in a retrospective analysis.

5. Global GI Dysmotility

A subset of SSc patients will experience global GI involvement, noting a combination of some or all the previously described symptoms. Lifestyle modification, PPI acid suppression, and laxative therapy should still remain first-line given the lower side effect profiles and relative ease in obtaining these therapies. However with refractory symptoms, certain prokinetic therapies such as serotonin receptor agonists or muscarinic receptor agonists may be better utilized in this subpopulation, as many pharmacotherapies within these medication classes simultaneously target both the upper and lower GI tracts (to varying degrees). This approach can reduce polypharmacy and the risk for medication interactions, which remains common in SSc.

5.1. Serotonin Receptor Agents

Cisapride was the first 5-HT4 receptor agonist to be studied in SSc, with one observational study [148] demonstrating improved colonic transit (n=16). However, multiple small studies [149-152] on the upper GI tract had conflicting results regarding effects on esophageal and gastric motility. Cisapride is no longer available given associated cardiotoxic events [28,152]. Prucalopride is a more specific 5-HT4 receptor agonist without the cardiotoxicity profile, with several large general population studies [153,154] showing efficacy in chronic constipation treatment. Additional benefits in promoting upper GI motility are noted in smaller studies [155-158]. Data for the SSc population is limited, with one placebo control cross-over study [159] (n=29) finding a significant increase in bowel movement frequency and improvement in symptoms of constipation, reflux, and bloating using a dose of 2mg daily. Tegaserod, another 5-HT4 receptor agonist, was originally withdrawn from the market due to concerns for increased cardiovascular events but has since been reintroduced as an alternative treatment for irritable bowel syndrome (IBS) with constipation in women with minimal cardiovascular risk factors [160]. No data currently exists for the use of tegaserod in SSc.

Mirtazapine works through multiple mechanisms, including antagonism of alpha-2 adrenergic receptors, 5-HT2 receptors, and 5-HT3 receptors. This leads to increased noradrenergic and, indirectly, serotonergic activity, the latter particularly through the 5-HT1A receptor [161]. This 5-HT1A agonism accelerates upper GI motility. Mirtazapine also has additional benefits including increased appetite, weight gain, and reduced early satiety in small studies, [162] which are attributed to 5-HT3 receptor antagonism [161,163]. These effects are yet to be studied in SSc.

5.2. Muscarinic Acetylcholine Receptor Agonists

Bethanechol is a direct muscarinic receptor subtype 2 and 3 (M2R and M3R) agonist that is shown to increase smooth muscle contractions throughout the GI tract, increase LES pressures, and improve GERD symptoms in SSc patients; however, clinical use is limited as these contractions can impair motility by causing excess muscular spasm, as well as a known association with significant cholinergic side effects [102,164-167]. Pyridostigmine, which increases synaptic concentrations of ACh through inhibition of the metabolizer AChE, has demonstrated similar efficacy in enhancing motility of the esophagus and colon in general population studies. [102,168-172] It also has been shown to improve SIBO symptoms, in a study [173] of HIV patients. Data for its use in SSc comes primarily from an observational study [174] (n=31) that noted primarily symptomatic improvement in refractory constipation after four weeks of pyridostigmine therapy (doses ranging 30-60mg one to three times daily), with diarrhea noted as a common side effect.

6. Functional Diarrhea, Malnutrition, and Small Intestinal Bacterial Overgrowth (SIBO)

Approximately 50% of SSc patients report frequent episodes of diarrhea, attributable to SIBO, overflow symptoms in the setting of constipation, infections, or dysmotility [8]. These symptoms may be coupled with bloating, nausea, malnutrition and weight loss. Multiple studies [175-180] demonstrate that the GI microbiome composition in SSc patients differs from that of non-disease controls. Whether this is a consequence of underlying GI disease, or an inciting pathologic process, is presently unknown [181]. SIBO is a common complication of SSc, which has an estimated prevalence of 30-62.5%, and is attributed to chronic gastric acid suppression from PPI use and/or chronic intestinal dysmotility [63,182,183]. SIBO is characterized by an increase of large intestinal aerobic and anaerobic microbes within the small intestine, causing symptoms such as abdominal bloating, diarrhea, and malabsorption [184]. Treatment of SIBO is often empiric (both in the general population and in SSc), because the gold standard diagnostic test (i.e., jejunal culture) is invasive. Hydrogen or methane breath testing for a SIBO diagnosis is validated in SSc patients, the sensitivity of these tests is very low and no SSc expert guidelines recommend this test for diagnosis over empiric treatment [27,28,185]. The EULAR and UKSSG guidelines [27,28] advocate for the use of empiric antibiotic therapies to treat suspected SIBO, and for repeat or rotating antibiotics for recurrent cases. This is consistent with the AGA’s recommendations [186] for the general population. Given the higher prevalence for SIBO in the SSc, population, it is reasonable to consider empiric antibiotics in cases of chronic diarrhea not attributable to diet, medications, or overflow.

6.1. Antibiotics

Several antibiotic regimens for SIBO are studied in the SSc population. One study [187] of SSc patients (n=30) found that a ten-day course of rifaximin 400mg three times daily effectively treated GI symptoms attributed to SIBO and improved lactulose breath testing in 73.3% of patients. In a meta-analysis [188] assessing prevalence rates for SIBO in the SSc population, rifaximin was more effective than rotating courses of antibiotics in the treatment of SIBO. With regards to other regimens, another study [189] found that SSc patients with diarrhea who received ciprofloxacin 250mg twice daily (n=6) had dramatic symptomatic improvement within 48 hours. A partial response to trimethoprim 200mg twice daily was noted for two additional patients included in this study. A rotating regimen of norfloxacin 200mg twice daily and metronidazole 250mg three times daily for three months (total seven days per month) was studied by Marie et al. [190] in SSc patients with SIBO confirmed by breath testing (n=22). Approximately half of these patients exhibited a therapeutic response.

Importantly, the AGA proposes the use of agents such as amoxicillin-clavulanic acid, doxycycline, metronidazole, neomycin, and tetracycline, [186] though none of these were studied specifically in SSc. Given that rifaximin is now also recommended by AGA for management of IBS with diarrhea, [191] and given the increased prevalence of SIBO in the SSc population, and the data above, rifaximin may be a reasonable first-line choice in SSc patients reporting chronic diarrhea. Combination therapy with rifaximin and neomycin may be another alternative. This regimen showed higher efficacy than either agent alone in a retrospective study [192] of non-SSc patients, but further studies are needed.

6.2. Probiotics and Fecal Microbiota Transplantation

In more recent years, interest in the management of dysbiosis has shifted from antimicrobial therapy to microbial replacement therapy given the side effect profiles of antibiotics (e.g., impact on healthy gut flora, antimicrobial resistance). An open trial [193] compared seven days of monotherapy with metronidazole 500mg twice daily vs. probiotic Saccharomyces boulardii 200mg twice daily vs. combination therapy for the treatment of SIBO in SSc patients (n=40). Combination therapy was more effective in reducing SIBO prevalence than metronidazole therapy alone. Another prospective trial [194] treated ten SSc patients with reported moderate-to-severe GI symptom scores (as assessed through the University of California at Los Angeles Scleroderma Clinical Trial Consortium GI tract 2.0 instrument, or UCLA GIT 2.0) with either daily Bifidobacterium infantis or Lactobacillus GG capsules. Both treatments resulted in significant improvement in subjective symptom scores. Finally, two randomized placebo-control trials [195,196] assessed the efficacy of probiotic therapy in improving reported GI symptom severity scores. One combination probiotic (Streptococus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, and Lactobacillus delbrueckii ssp. bulgaricus) was found to significantly improve reflux scores after three months (n=30); in contrast, a different combination probiotic (Lactobacillus paracasei, Lactobacillus rhamnosus, Lactobacillus acidophilus, and Bifidobacterium lactis) was not found to significantly improve symptoms (n=73). All studied agents have demonstrated minimal side effect profiles.

Fecal microbiota transplantation (FMT) may also introduce new flora to the GI microbiome, utilizing multi-organism stool samples from healthy donors. It is used to treat antibiotic-refractory Clostridium difficile colitis and inflammatory bowel disease, with reasonable safety, making it an interesting candidate for SSc treatment [181]. One randomized control clinical trial [197] enrolled SSc patients with severe upper and lower GI symptoms and showed improved lower GI symptoms in 4/5 participants with FMT. Major adverse events were related to endoscopic procedural complications. Another placebo-control trial [198] assessed the effect of FMT on duodenal histopathology (n=9). Improved GI symptoms correlated with a reduction of certain inflammatory cell populations in the FMT group, supporting the hypothesis that dysbiosis may play a pathologic role in disease.

6.3. Opioid Receptor Agonists and Other Antidiarrheals

In patients unresponsive to antibiotics or confirmatory testing inconsistent with SIBO, antidiarrheal agents may be considered. Enteric neurons synthesize opioid peptides that act on three different receptors within the GI tract, (i.e., mu-, kappa-, and delta)-opioid receptors (ORs). These endogenous opioids may be localized to the enteric neural plexuses or to endocrine cells, depending on their underlying structure, and play a role in regulation of motility, mucosal secretion, and membrane transport. OR stimulation decreases cAMP formation and calcium channel activity, and increases potassium-associated cellular signaling. These functions result in reduced neurotransmitter release, neural activity, and luminal water content [199,200].

In their clinical practice guidelines [191] for the management of IBS with diarrhea, the AGA recommends the use of loperamide (a synthetic OR agonist) as a first-line agent. Loperamide improves abdominal pain symptoms and stool consistency in general population studies, [201,202] but no studies are presently available for SSc patients. Other agents recommended by the AGA for functional diarrhea include eluxadoline (mixed mu- and kappa-OR agonist and delta-OR antagonist), alosetron (5-HT3 antagonist), rifaximin, tricyclic antidepressants (TCAs), and antispasmodics (e.g., hyoscine, dicyclomine, peppermint oil) [191]. Aside from rifaximin, [187] none of these agents were studied in the SSc population, with cautionary use given the high prevalence of concurrently reduced GI motility in these patients.

6.4. Diet

Recommendations regarding dietary modification or supplementation in SSc are becoming increasingly common in guidance statements, although a systematic review [203] of dietary interventions for GI symptoms in SSc found that the existing literature surrounding this topic is low-quality and at times contradictory. Manifestations such as dysphagia, delayed gastric emptying, small bowel dysmotility, and SIBO may all contribute to malnutrition in SSc, affecting both caloric intake and nutrient absorption. Prevalence of malnutrition in the SSc population is poorly defined due to varying diagnostic criteria in studies, however is estimated to range anywhere from 5.3-55.6% [63,185,204]. The Malnutrition Universal Screening Tool (MUST) is often utilized in the literature, with Codullo et al. [205] demonstrating that a positive screening correlated with worsened clinical outcomes. A recent Italian study [206] of the Mediterranean diet, which has shown benefit in the reduction of cardiovascular disease, in SSc patients (n=387) noted dietary adherence inversely correlated with patient-reported depression, anxiety, Raynaud’s phenomenon severity, and reflux severity scores. Further investigation is needed to assess the effects of the Mediterranean diet and others on SSc disease activity and symptom management, however it seems reasonable to counsel in favor of the Mediterranean diet given the benefits for cardiovascular health, despite the limited SSc-specific literature.

8. Miscellaneous Therapies

8.1. Intravenous Immunoglobulin (IVIG)

Circulating autoantibodies to M3R were identified in SSc and Sjogren’s syndrome in recent years, with passive serum transfer from these patients into animal models reducing colonic myoelectrical activity and internal anal sphincter contractility [59,207-209]. Binding affinity for these autoantibodies at the level of cholinergic neurons and smooth muscle was shown to increase with disease duration in the SSc population, correlating with the progressive nature of SSc-GI disease [210]. IVIG possesses neutralizing capabilities to anti-MR3 antibodies through binding with F(ab’)2 fractions contained in the pooled donor immunoglobulins, reversing the effects on motility in animal models, making this a therapy of interest for SSc-GI disease [207,208,211].

In a multicenter study [212] analyzing outcomes of IVIG in SSc patients it was noted that total UCLA GIT 2.0 scores significantly improved following administration (n=9), although when broken down by individual symptoms only the fecal soilage subdomain reached statistical significance for improvement. An observational study [213] found that IVIG (2gm per ideal body weight, divided over one to three days) significantly improved frequency of GERD events and total UCLA GIT 2.0 scores (n=15), although these results were specific to SSc patients with overlapping myositis, who may also experience pharyngeal muscle weakness which is IVIG responsive. Another case series [214] of SSc-myositis overlap patients (n=3) noted IVIG response in intestinal pseudo-obstruction (dosed at 2gm/kg divided over five days). Notably none of these studies looked for the presence of anti-M3R autoantibodies in participants.

Presently there is only one case series published describing the use of IVIG in SSc patients and confirmed anti-M3R autoantibodies: Mendoza et al. [215] treated two patients with 6 months of IVIG (at a dose of 2gm/kg/mo divided over two days), following which improvement in both UCLA GIT 2.0 scores and radiographic esophageal dysmotility were noted, with both patients able to resume oral feedings and have their feeding tubes removed. While promising, not all severe GI disease in SSc is associated with anti-M3R autoantibodies, suggesting that additional mechanistic pathways leading to GI tract disease likely exist [3,216].

8.2. Transcutaneous Electrical Nerve Stimulation

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive neuromodulation technique where electrical current is applied to the skin via electrodes at specific sites, shown to create a frequency-dependent analgesic effect through peripheral and central activation of mu-opioid, delta-opioid, alpha-2, GABA-A, 5-HT2, 5-HT3, and muscarinic receptors [217]. A meta-analysis [218] found that TENS was efficacious in reducing subjective pain symptoms in patients with chronic musculoskeletal pain and certain rheumatologic conditions (specifically, rheumatoid arthritis and ankylosing spondylitis). However, comparison between clinical trials remains challenging due to variability in electrode placement, TENS devices, and parameters used.

Despite these limitations, the non-invasive nature and the encompassing receptor effects have made TENS a new therapy of interest for the SSc population. In a randomized cross-over trial, Bellocchi et al. [219] demonstrated that TENS at the auricular branch of the vagal nerve significantly reduced generalized chronic pain scores in SSc patients (n=21), however it had no effect on UCLA GIT 2.0 scores. In contrast, others [220] noted significant improvement in GI symptoms in patients treated with TENS (n=17) compared to non-SSc controls, when administered at the GI acupuncture sites PC6 and ST36. A follow up study [221] noted that this TENS therapy also resulted in significantly improved gastric myoelectric activity, with increased slow wave coupling.

8.3. Vibrating Capsule

A novel non-pharmacologic vibrating capsule for chronic idiopathic constipation was recently approved by the FDA. This single-use capsule is ingested in the evening several times per week and designed to have delayed activation for several hours to allow for passage to the colon. Once activated, the product vibration is proposed to stimulate colonic peristalsis. This device was found to be efficacious in treating constipation in a phase 3 placebo-control trial [203] (n=312) with a minimal side effect profile. While not yet studied in the SSc population, this therapy represents a potential new mechanistic class, particularly for patients with isolated constipation symptoms.

9. The Role for Immunosuppression in SSc-GI Disease

9.1. Immunosuppression for Dysmotility

While immunosuppression has demonstrated a role in the treatment of other aspects of SSc such as cutaneous disease or interstitial lung disease, data for its use in SSc-GI disease has not been promising. Many immunosuppressive agents come with their own set of GI side effects, further complicating outcome analysis. One combined prospective longitudinal cohort study [222] looked at patients without severe GI disease (defined as malabsorption, hyperalimentation, pseudo-obstruction, or >10% weight loss) that received methotrexate, cyclophosphamide, mycophenolate mofetil, or azathioprine for another indication, and compared to those without immunosuppression exposure (n=762). Exposure to immunosuppression was not found to modify the risk of developing severe GI disease. Smaller studies [223,224] of abatacept and cyclosporine A have similarly found no effect on GI involvement.

9.2. Immunosuppression for Gastric Antral Vascular Ectasia (GAVE)

Of interest, two case series [225,226] noted clinical improvement of GAVE, a condition of dilated veins and capillaries of the stomach that are prone to erosive bleeding, with treatment of cyclophosphamide. The underlying pathophysiology of GAVE in SSc appears to be separate from other GI manifestations, with histologic changes of inflammation and thrombus formation more like findings also seen in pulmonary arterial hypertension or renal crisis, which may contribute to this isolated response [227]. Standard management of GAVE and other types of GI bleeding are typically managed endoscopically and are outside the scope of this review.

10. Conclusions

Treatment of SSc-GI disease at this time remains primarily focused on symptomatic management, with no identified preventative or restorative therapeutics. While there are an increasing number of available therapies, with a widening range of mechanistic targets (see Table 1), very few of these have been extensively studied in the SSc population. As SSc involvement of the GI tract is heterogeneous, identifying appropriate candidates for therapeutic trials is challenging, and the use of many agents is driven by efficacy seen from general population data and expert opinion. With these limitations in mind, we propose a symptom-based approach to choosing therapeutics in the management of SSc-GI disease (see Figure 1). After ruling out overlapping disease processes, treatment decisions should be aimed at reducing polypharmacy when possible and choosing therapies that most closely target the afflicted areas of the GI tract, which can be done with an appreciation of underlying therapeutic mechanism (see Figure 2). The lowest, most symptomatically efficacious dose should be prescribed, with dose escalation (to a maximum dose specified by manufacturers’ specifications) and add-on therapy utilized in refractory cases. Therapeutic choice and dose should aim for symptomatic control while considering the acceptability of potential side effect profiles. In the treatment of dysmotility, baseline motility testing can be utilized to confirm the site of dysmotility within the GI tract, so that appropriate agents are chosen [8]. Dose tapering should be considered once symptomatic control has been achieved, aside from situations of treating mucosal injury (such as esophageal strictures and Barrett’s esophagus) that require additional guidance from a gastroenterologist. Optimal duration of therapy is unknown at this time, but as current therapies aim at treating symptoms rather than reversing underlying pathology, expected use is likely chronic presuming no limitations from toxicity. Novel GI therapeutics such as TENS and IVIG need more data to identify the appropriate stimulation parameters and patient selection for such therapies. Currently, there is no clear role for immunosuppression in the treatment of SSc-GI dysmotility. Overall, more research is needed to understand the underlying pathologic mechanism(s) that drive SSc-GI disease to optimize therapeutic strategies.

Table 1.

Pharmacologic Target Receptors, Enzymes, Ion Channels, or Ion Pumps in the Gastrointestinal (GI) Tract

Target	Label	Location in the GI Tract	Effect of Agonism in the GI Tract
Primary Targets for Gastroesophageal Reflux Disease
Proton Pump	PP	Gastric Parietal Cells	Increased stomach acid, lower stomach pH
Histamine-2 Receptor	H2R	Gastric Parietal Cells	Stimulates proton pumps, increasing stomach acid and lowering stomach pH
Primary Targets for Upper Gastrointestinal Dysmotility
Dopamine-2-Like Receptor Family	D2-like	Neurons and Smooth Muscle	Inhibits smooth muscle contraction
Type B GABA Receptor	GABA-B	Neurons	Hyperpolarizes neural cells to prevent conduction, reducing neurotransmitter release
Motilin Receptor		Gastric Smooth Muscle	Stimulates stomach migrating motor complex contractions and appetite
Primary Targets for Lower Gastrointestinal Dysmotility
Somatostatin Receptor 1	SSTR1	Neurons and Smooth Muscle	Modulates peristalsis
Somatostatin Receptor 2	SSTR2	Neurons and Endocrine Cells	Inhibits hormone secretion (gastrin, motrilin, insulin, and glucagon) and modulates peristalsis
Somatostatin Receptor 3	SSTR3	Neurons and Smooth Muscle	Modulates peristalsis
Primary Targets for Global Gastrointestinal Dysmotility
Acetylcholinesterase	AChE	Neuromuscular Junction	Degrades acetylcholine, reducing cholinergic activity (reduced smooth muscle contraction)
Muscarinic Acetylcholine 3 Receptor	M3R	Smooth Muscle >> Neurons	Stimulated by acetylcholine, increases stomach acid production and contracts smooth muscle
Serotonin Receptor 1D	5-HT1D	Neurons	Increases gastric accomodation, modulates peristalsis
Serotonin Receptor 2B	5-HT2B	Neurons	Decreases gastric accomodation, contracts smooth muscle
Serotonin Receptor 3	5-HT3	Neurons	Modulates serotonin release, initiates emetic response, contracts smooth muscle
Serotonin Receptor 4	5-HT4	Neurons	Contracts smooth muscle
Primary Targets for Constipation
Chloride Channel Type 2	ClC-2	Intestinal Enterocytes	Increases intraluminal chloride, subsequently increasing stool water content
Sodium-Hydrogen Exchanger 3	NHE3	Intestinal Enterocytes	Reduces intraluminal sodium, subsequently reducing stool water content
Guanylate Cyclase-C Receptor	GCC	Intestinal Enterocytes	Forms cGMP, which stimulates chloride channels and downregulates sodium exchangers
Primary Targets for Functional Diarrhea
Opioid Receptors	OR	Neurons	Reduces cAMP formulation, which downregulates chloride channels and reduces neurotransmitter release

Figure 1.

A Proposed Treatment Algorithm for GI Symptoms in SSc, Based on Available Study Data and Expert Opinion

Figure 2.

Known Mechanistic Targets for GI Symptom Therapeutics and Applications for SSc

11. Expert Opinion

The management of GI complications of SSc remains a major challenge for patients, clinicians, and clinical investigators alike (see Figure 3). GI symptoms not only significantly disrupt function but are associated with depression and social isolation. While scleroderma is an autoimmune rheumatic disease, there is little evidence to suggest treatment with immunosuppressive therapy halts the progression of GI involvement or reverses damage, leaving many unanswered questions about the most appropriate approach for clinical care.

Figure 3.

Identified Challenges in the Management of Gastrointestinal Symptoms in Systemic Sclerosis

It may be that immunosuppressive therapy has little impact on GI outcomes in SSc, however it could also be that such effects are just challenging to measure. Mechanisms driving GI progression are poorly understood and precise measures of GI disease activity are not defined. Therefore, we cannot yet identify the appropriate patients for clinical trials, and we do not yet understand which disease stage (if any) would most likely respond to specific immunosuppressive therapies. The high cost and often invasive nature of objective measures of GI function (e.g., manometry, whole gut scintigraphy) also limit objective outcome measurement in clinical trials. Access to GI tissues for histopathologic assessment is another significant challenge in assessing disease activity, particularly when aiming to acquire the deeper layers of the gut, such as the longitudinal muscle and myenteric plexus layer, which is arguably most involved in the regulation of GI motility.

Because of these challenges pertaining to study design and the acquisition of objective outcome measures, studies often utilize patient-reported outcomes as surrogate measures to determine drug efficacy in the gut. This is a reasonable approach if targeting patient-reported symptoms alone. However, when assessing SSc-associated GI disease activity this is a more significant issue. GI symptoms are not specific to SSc, and therefore they may be impacted by a variety of other factors such as stress, diet, exercise, medication side effects, and the composition of the microbiome. Therefore, assessing GI disease activity using patient reported outcomes alone is suboptimal, and using immunosuppression in this setting is thus complicated by an absence of guidance on when to start immunosuppressive therapy, how to accurately measure response to the drug, and when to discontinue therapy. Considering the substantial side effect profiles of immunosuppression, balancing risks and benefits in this setting is a major challenge. This limits the adoption of immunosuppressive therapies for SSc-GI management in clinical practice. Addressing these limitations is a high priority on the current research agenda as these data would have major implications on the way SSc-GI disease is diagnosed, monitored and managed.

Limited data do suggest that IVIG may play a role in the management of SSc-related GI activity, with cases series demonstrating GI benefit in SSc patients with myositis using primarily patient-reported symptom scoring metrics (such as UCLA GIT 2.0). IVIG, while costly, is generally well-tolerated and there is some mechanistic data supporting its use in a subset of patients with SSc. Anti-M3R antibodies are present in this SSc patient subset, and are shown to negatively impact motility, the effects of which are reversed by the application of human immunoglobulin. However, a deficit of strong clinical data supporting the application of this immunomodulator for SSc-GI disease is still lacking. As anti-M3R antibody assays are not available clinically, and their prevalence and specificity among SSc GI disease subset remains unclear, future work will need to identify the patients who would benefit from this intervention and establish screening assays which are accessible in the clinical setting.

Due to the above limitations, the current management of SSc-GI disease is largely defensive, with the primary focus on treating patient symptoms and minimizing and/or addressing mucosal damage. While such medications do significantly improve patient symptoms and function, there is no known impact on GI disease progression, and chronic therapy is associated with a variety of adverse effects. While chronic therapy may maintain symptom control in patients with stable GI disease, this is rarely adequate for controlling symptoms in patients with disease progression.

Further research focused on identifying patients at risk for GI progression, and the underlying mechanism(s) that drive disease will provide opportunities to prevent long term damage, and significantly improve patient quality of life. As SSc is heterogeneous, and there are likely multiple mechanisms driving disease, classifying patients in biologically anchored subgroups will be important. For example, dysmotility in some patients may be a consequence of functional autoantibodies targeting the enteric nervous system (such as anti-M3R antibodies), while in other subsets it may be driven by autonomic dysfunction (autoimmune or not), and in others by dysbiosis and related neuronal toxicities. Targeted therapies that directly address disease mechanisms in patient subgroups may prevent progression and complications such as recurrent hospitalizations, severe intestinal pseudo-obstruction, and fecal incontinence.

From our perspective, we anticipate that current clinical procedures will continue to evolve in the coming decades as SSc patients at risk for progressive disease will be identified earlier, mechanisms of disease will be better understood, and patients will be classified into more biologically relevant subgroups. Studies that leverage advanced technologies, such as GI organoids, spatial proteomics, transcriptomics, and single cell sequencing to identify important phenotypes will advance our understanding of disease subsets. Symptomatic therapy for patients with GI involvement will continue but will no longer be primary therapies, but supplemental to therapies targeting GI disease mechanism(s). We anticipate that the need for motility studies will be reduced over time as such complications will be easier to prevent. Finally, targeted cellular and microbial therapies are likely to play a more significant role in the longer term.

Article Highlights:

• Gastroesophageal reflux is the most common SSc-GI symptom and is a consequence of dysmotility, with management primarily focused on acid suppression before advancing to prokinetic options, and surgery can be considered in select patients

• SSc dysmotility is heterogeneous and may involve any component of the GI tract, with therapeutic decision-making often dependent on the specific site efficacy of medications

• SSc-GI dysbiosis is common and may be a consequence of underlying dysmotility or treatments, versus an inciting pathologic mechanism; antibiotic regimens such as rifaximin show efficacy in treatment of bacterial overgrowth in SSc, with emerging therapeutics such as probiotics and fecal microbiota transplantation showing promise

• Novel SSc-GI therapies such as intravenous immunoglobulin, transcutaneous electric nerve stimulation, and the vibrating capsule show potential in treating specific GI complications, with a current need to identify appropriate therapeutic candidates