Systematic review: pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma)

Authors


Dr J. Chen, 1108 the Strand, Room 221, University of Texas Medical Branch, Galveston, TX 77555-0632, USA.
E-mail: jianchen@utmb.edu

Summary

Gastrointestinal dysmotility in systemic sclerosis (scleroderma) is prevalent in 90% of patients, increasing morbidity and in some cases mortality. The resultant gastrointestinal complications are usually extensive, involving many regions of the gut from the oesophagus to the anus. Collagen replacement of vascular and enteric smooth muscle results in hypomotility, lumen dilatation, tensile rigidity and eventual loss of organ functions.

The aim of this paper is to provide an overview of systemic sclerosis-related gastrointestinal dysmotility and available/potential therapeutic options.

We evaluated published data on the pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis patients using the MEDLINE database for English and non-English articles from 1966 to July 2005.

Based on this systematic review, lifestyle and medical therapy approaches are preferred as they often improve and/or ameliorate symptoms. Surgery is only recommended with serious, rare complications such as bowel perforation or ischaemia.

Alternative therapies such as acupuncture-based therapies are well tolerated, with clinical improvement and may be of potential therapeutic benefit for systemic sclerosis gastrointestinal dysmotility.

Further elucidation of initiating and persistent mechanisms of systemic sclerosis-related gastrointestinal dysmotility will optimize the development of a multidisciplinary and more directed treatment regimen.

Introduction

Systemic sclerosis (scleroderma, SSc) is a chronic autoimmune disease characterized by proliferative vascular lesions with resultant fibrosis of skin and multiple organs, including the gastrointestinal (GI) tract. Its aetiology is unknown, occurring most frequently in females, aged 35–65 years. In the United States, the prevalence of SSc is about 240 per million in adults.1 Systemic sclerosis is classified as diffuse or limited cutaneous disease based on the extent of cutaneous involvement. Scleroderma (skin thickening) above the elbows or knees (except for facial involvement, which can be present in both) is classified as diffuse cutaneous SSc. Skin tightness limited to areas distal to the elbows or knees is classified as limited cutaneous SSc. The ongoing pathology of SSc is hypothesized to initiate with vascular endothelial activation (vacsulopathy), reflected in recurrent episodes of vasoconstriction and reperfusion which progress to episodic and sustained tissue ischaemia with inappropriate immunological and reparative changes. Excessive deposition of collagen and collagen matrix from activated profibrogenic fibroblasts ensue, resulting ultimately in fibrosis and replacement of tissue in the skin and multiple internal organs, including the GI tract.2–4

Upper or lower GI involvement as major visceral manifestations is reported in up to 90% of SSc patients5–7 in both diffuse and limited cutaneous forms of SSc. GI involvement in scleroderma primarily occurs as a spectrum of disorders of motility and transit time, clinically ranging from asymptomatic to severe paresis, and can affect any area from the oesophagus to the anus.2, 5, 8–16 Systemic visceral involvement in SSc may be slowly or rapidly progressive and can occur at any age, including children and adolescents.17 Oesophageal and anorectal disorders are the most frequently reported, in up to 80% of SSc patients.8, 9, 18 Severe GI involvement (malabsorption syndrome, recurrent intestinal pseudo-obstruction and other severe GI problems associated with a 10% weight loss or hospitalization) has been correlated with an increased mortality of 85% within 9 years of diagnosis, compared to patients with minor GI complaints.18 Generally, treatment regimens are designed to be symptom-based and thought to be more efficacious in early disease before extensive collagen deposition and GI tissue loss.

The pathogenesis of GI dysmotility in SSc has been hypothesized as a consequence of initial vascular damage, with initiating, concomitant or subsequent neurogenic or immunological events.12, 19–21 Currently, a vascular initiating event is the most popular (refer to Table 1 for grades of GI pathology in SSc). Theories supporting autonomic dysfunction as the initiating event argue the prominent autonomic nervous system (ANS) dysfunction in SSc-related hypomotility.12, 22–30 Theories were based on a sequential study of SSc intestinal smooth muscle showing initial axonal degeneration, followed by subsequent focal degeneration of the smooth muscle cells.31 With disease progression, generalized GI hypomotility is attributed to collagen deposition and fibrosis in the GI vascular and luminal smooth muscles. Studies supporting an autoimmune initiating event have demonstrated in histochemical staining of the rat intestine that the purified immunoglobulin (Ig)G fraction derived from plasma of the SSc patients co-localized with antimyenteric neuronal antibodies.32 Furthermore, incubation of the rat intestine with this SSc-derived IgG fraction demonstrated disruption and prolongation of rat intestinal myoelectrical activity by electrophysiological parameters.32

Table 1.  Grading of gastrointestinal (GI) pathology in systemic sclerosis (SSc)
GradeMucosaSubmucosaEnteric nervous systemMuscularis externaSerosa or adventitia
0 (vascular)NormalSubmucosal oedema
Endothelial oedema and dilatation
NormalNormalNormal
1 (neural)Normal epithelium morphology
Infiltration of lamina propria with inflammatory cells
Submucosal oedema
Collagen cuffing of vessels. Perivascular infiltration with inflammatory cells
Collagen cuffing of nerves and axonal degenerationNormalNormal
2 (muscular)Degeneration of epithelial cells (possible). Subepithelial collagen deposition. Patchy fibrosis
 and atrophy of muscularis mucosa
Increased thickness of vascular wall
Fibrous encapsulation of secretory glands
Collagen cuffing of nerves and more axonal degenerationPatchy fibrosis of muscle layers (mainly circular)
Decreased gap junctions between muscle cells
Collagen deposition in serosa (serosal thickening)
3 (fibrotic)Degeneration of epithelial cells and flattening of epithelium (possible)
Subepithelial fibrosis, fibrosis and atrophy of muscularis mucosa
Extensive fibrosis of submucosaExtensive axonal degenerationFibrosis of muscular wall and atrophy
Thinning of GI wall
Extensive serosal thickening

Generally, GI symptoms have not been predictably correlative of the histological or physiological severity of GI dysmotility or morbidity in SSc.12, 28, 30 To date, there are no validated questionnaires regarding GI symptoms focused to SSc patients that can elucidate correlative links between GI-related symptoms and GI dysmotility by conventional tests. Accordingly, it is important to assess the extent and severity of GI involvement early and on an ongoing basis to avoid potentially life-threatening complications. As part of this assessment, standardized, validated diagnostic methods include: manometry (oesophagus, small intestine and anorectum), 24 h esophageal pH study (oesophagus), scintigraphy (oesophagus to colon), electrogastrogram (EGG; stomach), ultrasonography (stomach to colon), hydrogen breath testing (small intestine) and barium studies (whole GI tract8).

This review evaluated published data regarding the pathophysiology and management of GI dysmotility in SSc patients using the MEDLINE database for English and non-English articles from 1966 to July 2005 (clinical trials are detailed in Table 2). Our strategy was to combine and distil all currently available studies and reviews in order to provide an overview on SSc-related GI dysmotility and available/potential therapeutic options from the oesophagus to the anus. The search was performed by combining the terms ‘systemic sclerosis’ and/or ‘scleroderma’ with ‘gastrointestinal motility’ or ‘neuropathy’, ‘esophagus’, ‘manometry’, ‘GERD’, ‘reflux’, ‘stomach’, ‘gastric tone’, ‘accommodation’, ‘gastric emptying’, ‘pacing’, ‘small intestine’, ‘small bowel’, ‘transit’, ‘colon’, ‘anorectal’, ‘prevalence’, ‘symptoms’, ‘treatment’, ‘surgery’, ‘diet’, ‘TENS’, ‘acupuncture’, ‘acupressure’, ‘electrical stimulation’, ‘proton-pump inhibitor’, ‘octreotide’, ‘erythromycin’, ‘metoclopramide’, ‘domperidone’, ‘tegaserod’ and ‘cisapride’. Clinical trials and review articles were specifically identified, and their reference citation lists were searched for additional publications not identified in the database searches. Our strategy was to combine all available information from previous literature, in order to provide a complete physiological and therapeutic review on GI dysmotility of SSc patients, including potential alternative therapies.

Table 2.  Current therapeutic recommendations for SSc-related GI dysmotility. (A) Diet and modification of lifestyle and (B) medications for treatment of GERD and GI dysmotility in SSc patients; (C) alternative therapy (potentially beneficial, more studies needed)
(A) OesophagusEat multiple small meals
Avoid fatty meals, chocolate, peppermint and alcohol
Raise the head of bed 6 inches
Cessation of smoking
Avoid heavy meals, exercise within 3 h of bedtime
StomachLow residue diet
Jejunal feeding tube for nutritional support
Small and large intestinesDietary plan based on symptoms:
 in diarrhoea: avoid lactose; add soluble bran to diet
 in constipation: drink six eight-ounce glasses of water. Avoid high fibre laxatives and/or food
TPN in severe hypomotility or malabsorption
Number of patients and study designDaily dose and duration of omeprazole ttt (po)Primary end pointReference
(B: 1) Antisecretory agents (PPI)
Omeprazole – mechanism of action: bonds with the hydrogen ion of the proton-pump transport enzyme (H+,K+-ATPase) in the stomach parietal cells, inhibits gastric acid secretion
3 SSc patients
No controls
Open pilot study
40 mg × 4 weeks ± 4 additional weeksSymptoms: all patients became asymptomatic after 4 weeks
Endoscopy: healing of oesophagitis in 2 patients in 4 weeks
One patient required additional 4 weeks of ttt till healing was achieved
Olive et al.196
8 SSc patients with GER vs. 8 idiopathic GER patients and 7 normal controls
No ttt for latter groups
20–60 mg × <12 and >18 weeks, till healing of oesophagitis (verified by endoscopy)Chemical analysis of oesophageal biopsies: drug normalized hydroxyproline* concentration in oesophageal mucosa in SSc patients vs. BsL (P = 0.014)Hendel197
3 SSc patients
Case reports
20–40 mg × 1–8 monthsSymptoms: all patients became asymptomatic on 20 mg maintenance doseHostein et al.198
7 SSc patients
Prospective, randomized, double-blind crossover study
Omeprazole 20 mg/day vs. ranitidine 160 mg b.d. × 8 weeksSymptoms, endoscopic and histological scores: all patients on omeprazole and those who were crossed over to omeprazole showed marked improvementKundrotas and Ward199
25 SSc patients enrolled, 23 patients completed the study
Prospective study
20–80 mg × 5 yearsEndoscopy: 10 patients showed improvement of stricture after 1–33 months of ttt
Symptoms: 10 patients improved after 1 month of ttt, 13 patients had residual GER in spite of 6 months of ttt. Healing required more time, or a higher dose
Hendel79
13 SSc patients
Prospective study
Stepwise increase of 20 mg above 40–60 mg till GER is controlled verified by pH-metry; dose maintained for 6 monthsEndoscopy and Histopathology: 60–140 mg (median 100 mg) is required in SSc patients to abolish GERHendel et al.200
11 SSc patients vs. 11 age- and sex-matched controls, 8 patients completed the study
Matched control study
20 mg × 2 yearsAmbulatory 24 h pH study: all 8 SSc patients showed reduction in overall oesophageal acid exposure (P < 0.01) vs. BsLShoenut et al.78
10 SSc patients pre- and post-ttt40 mg × 1 monthHydrogen breath test: omeprazole predisposed to small bowel bacterial overgrowth (in 2 of 10 patients)Gough et al.149
25 SSc patients and 16 patients with Zollinger–Ellison syndrome
Prospective study
20–140 mg × 7.5 yearsUpper endoscopy and gastric histopathology: all SSc patients showed no signs of neoplasia. Long-term high-dose ttt is safe and does not induce changes in gastric oxyntic mucosaHage et al.201
(2) Prokinetic agents – general mechanism of action: increase acetyl-choline release from enteric nerves to enhance gut motility
Metoclopramide – mechanism of action: dopamine receptor antagonist (central and peripheral) – cholinesterase inhibitor, blocks the inhibitory effect of dopamine with Ach release.
 Dose and duration of metoclopramide ttt  
14 SSc patients (14: no LESP, 11: aperistalsis, 3: hypomotility)
7 patients received isotonic saline IV vs. drug
Acute test (10 min): 20 mg in 2 mL solvent IV (single bolus)Oesophageal manometry: 7 of all 14 patients showed LESP, 5 of 11 aperistaltic patients showed pressure waves and all 3 patients having hypomotility showed a threefold increase in the amplitude of the pressure wavesRamirez-Mata et al.82
10 SSc patients vs. controls
No background data on controls
Acute test (blinded): 10 mg IV or neostigmine methyl sulphate (1 mg) IM, on 2 separate daysColonic manometry and myoelectric studies: both drugs increased PP intraluminal pressure and spike activity in all controls and in only 4 patients similar to levels seen in controls. Of note, the non-responders had more severe GI and systemic manifestationsBattle et al.156
15 SSc patients (9 without and 6 with GI involvement) vs. 8 healthy volunteers
Case control
10 mg IV over 5 min followed by 2.5 mg bethanecol Sc. during early and after MMC phase I respectivelyGastric, duodenal and jejunal manometry: metoclopramide increased motor activity in all groups. Bethanecol had a similar but blunted effectRees et al.116
12 SSc patients pre- and post-tttAcute test: 10 mg IV over 5 min
24 h pH monitoring: 10 mg 30 min AC, 2 doses evening before and 4 doses during pH-metry
Oesophageal manometry: all patients had improved LESP vs. BsL
Oesophageal scintigraphy: 4 of 4 patients initially with prolonged T1/2 GE showed decreased T1/2 GE on solid GE test
24 h pH study: 11 of 12 patients showed significant reduction of total number of reflux events vs. BsL
Johnson et al.81
14 SSc patients pre- and post-tttAcute test: 10 mg IV over 2 minRadionuclide oesophageal scintigraphy: all patients showed increased average % emptying vs. BsL (P < 0.01)
Oesophageal manometry: 12 of 12 patients showed increased LESP vs. BsL (P < 0.001)
Drane et al.83
20 SSc patients and 13 non-matched normal controlsAcute test: 10 mg IMRadionuclide gastric scintigraphy: drug accelerated GE in 4 of 4 patients with delayed GE vs. BsL (P < 0.05)Sridhar et al.6
Cisapride (restricted use due to its cardiac toxicity) – mechanism of action: 5-HT4 receptor agonist. Stimulates Ach release.
 Dose and duration of cisapride ttt  
20 SSc patients
Double-blind, randomized, placebo-controlled crossover study
10 mg drug or placebo IV over 2 min
2 acute sessions with 3-day interval
Oesophageal manometry: increased LESP (P < 0.001) and gastric fundic contractions (P < 0.01) vs. placeboKahan et al.120
16 SSc patients vs. 20 normal controls10 mg po t.d.s. × 1 weekRadionuclide colonic scintigraphy: drug increased colonic transit in patients vs. BsL at 4 and 24 h (P = 0.026 and 0.038 respectively). 8 of 12 patients with constipation reported symptomatic improvement after tttWang et al.169
12 SSc patients
Double-blind, randomized, placebo-controlled study
10 mg po t.d.s. or placebo × 1 weekRadionuclide oesophageal scintigraphy: no effect on oesophageal transit vs. placeboWang et al.85
9 SSc patients pre- and post-ttt20 mg po t.d.s. × 4 weeksMetal detector test: drug had no effect on GE, small bowel transit or colonic transit in ttt vs. BsLFolwaczny et al.123
19 SSc patients and 8 reflux oesophagitis vs. 9 normal controlsAcute test: 4 mg IV bolus injection, continuous infusion or oralUpper GI manometry: IV bolus and oral drug increased LESP and gastroduodenal motility in ttt vs. BsL. IV bolus increased the motility index of stomach and duodenum in patients vs. controlsNishioka et al.202
8 SSc patients vs. 22 normal controls
Double-blind, placebo controlled study
Acute test: 10 mg or placebo IV
Chronic: 10 mg po q.d.s. × 4 weeks
Acute (radionuclide gastric scintigraphy): drug increased solid (P < 0.001) and liquid GE vs. placebo (P = 0.01).
Chronic (upper GI symptoms): improved symptom scores vs. BsL (P < 0.001)
Horowitz et al.203
9 SSc patients and 9 IDDM** patients pre- and post-ttt vs. 15 historical normal controls10 mg po t.d.s. for 4 weeksRadionuclide gastric scintigraphy: drug decreased T1/2 GE in all SSc patients vs. BsL (P < 0.05). Drug increased gastric peristaltic amplitude in all SSc patients vs. BsL (P ≤ 0.05)Linke et al.204
Erythromycin – mechanism of action: macrolide antibiotic. Motilin receptor agonist, the regulator of MMCs
 Dose and duration of erythromycin ttt  
14 CIPO patients (5 SSc and 9 idiopathic)
Pre- and post-ttt
Acute (4 h apart – random): Erythromycin: 200 mg IV over 30 min
 Octreotide: 50 μg Sc.
Chronic: A combination of erythromycin 200 mg po t.d.s. and octreotide 50 μg Sc. × 4–48 weeks
 Follow-up for responders 33 ± 13 weeks
Acute effect of erythromycin (antroduodenal manometry): 12 of 14 showed increased antral motility amplitude and index vs. BsL
Decreased small intestinal contractions
Acute effect of octreotide (antroduodenal manometry): increased the frequency (P = 0.001), the duration (P = 0.0009) and the motility index (P = 0.007) of the small intestinal AF vs. BsL
Decreased antral activity vs. BsL (P = 0.04)
Chronic effect of both drugs (symptoms): 5 patients were responders (SSc n = 4) showing improvement of symptoms and decreased overall symptom score (P ≤ 0.04)
Verne et al.124
12 SSc patients vs. 14 normal controlsAcute: 2 mg/kg/h IV over 30 min AC
Chronic: 250 mg po t.d.s. 30 min AC × 4 weeks
Acute (gastric and GB ultrasonography): Drug reduced T1/2 GE in SSc (P < 0.01) and accelerated GB emptying (P < 0.001) vs. BsL
Chronic (gastric and GB ultrasonography and symptoms): Drug reduced T1/2 GE and accelerated GB emptying in patients vs. BsL (P < 0.01 each)
Decreased symptoms of early satiety, nausea, vomiting and abdominal pain vs. BsL (P < 0.01 each). Increased number of bowel movements in 4 patients with intestinal pseudo-obstruction vs. BsL (P < 0.05)
Fiorucci et al.122
7 SSc patients pre- and post-ttt250 mg po t.d.s. × 4 weeksMetal detector test: drug accelerated GE (P = 0.04), but had no effect on small bowel or colonic transits in patients vs. BsLFolwaczny et al.123
Octreotide – mechanism of action: long-acting somatostatin analogue, stimulates small bowel motility
 Dose and duration of octreotide ttt (Sc)  
5 SSc patients pre- and post-ttt50 μg × 4 weeksMetal detector test: drug had no effect on GE, small bowel or colonic transit in patients vs. BsLFolwaczny et al.123
Effect of octreotide and erythromycin – Refer to: Verne et al.124
5 SSc patients vs. 6 normal controlsAcute: 100 μg in patients vs. 10 μg in controls
Chronic: 50 μg at bedtime × 3 weeks
Acute (gastroduodenal manometry): increased initially absent phase III motility index in SSc patients to 50% of the motility index in controls (P = 0.005)
MMCs in SSc patients increased to 2/3 the amplitude of the spontaneous complexes seen in normal controls (P = 0.026)
Chronic (hydrogen breath test and symptoms scores): decreased bacterial overgrowth and abdominal symptoms vs. BsL (P < 0.05 each)
Soudah et al.154
1 SSc patient
Case report
50 μg at bedtime combined with erythromycin (125 mg t.d.s. AC) × 2 yearsSymptoms: complete relief of symptoms of recurrent small bowel obstruction vs. BsL. No hospitalizations since start of ttt, except once, when non-compliantLecomte et al.174
2 SSc patients
Case reports
Pt 1: 50 μg q.d.s. ×1 year
Pt 2: 50 mg b.d. ×3 years
Pt 1: Improved abdominal pain and vomiting. After several weeks of ttt, oral feeding resumed, TPN d/c'd, and prednisone was tapered. Small bowel manometric pattern was normalized at 1 year. No recurrence of CIPO for 4 years
Pt 2: Improved abdominal pain and distension. Digestive transit was normalized. Higher dose needed to prevent relapse. No relapse of digestive symptoms in 3 years of follow-up
Perlemuter et al.171
Prucalopride – mechanism of action: bensfuran carboxamides. Selective 5-HT4 receptor agonist. Stimulates Ach release
 Dose and duration of prucalopride ttt  
2 SSc patients
Case reports
2 mg po once daily or every other day × >1 yearSymptoms: Increased appetite, decreased abdominal distension and improved defecation. Maintenance of subjective improvement after 1 year
Manometry: Increased postprandial antroduodenal motility and accelerated total colonic transit time
Boeckxstaens et al.170
Number of patients and study designType of therapyDoseDurationEndpoints: GI and systemicReference
  1. * Hydroxyproline: an amino acid required for the triple helix structural formation of the collagen molecule. Hydroxyproline is an index of collagen and can be used to evaluate the potential for stricture formation in the oesophagus.

  2. AC, before meals; Ach, acetylcholine; acute, patient is tested in <24 h of drug administration; AF, activity front (phase III of MMC); b.d., 2 times/day; BsL, baseline; chronic, patient is tested in >24 h of drug administration; CIPO, chronic intestinal pseudo-obstruction; d/c'd, discontinued; EA, electroacupuncture; EGG, electrogastrogram; GB, gall-bladder; GE, gastric emptying; GER, gastro-oesophageal reflux; GERD, gastro-oesophageal reflux disease; GMA, gastric myoelectrical activity; Hatija, acupoints between the digits (super acupoint); HRV, heart rate variability; IBS, irritable bowel syndrome; IDDM, insulin-dependent diabetes mellitus; IM, intramuscular; LESP, lower oesophageal sphincter pressure; MMC, migrating motor complex; PC6, Neiguan acupoint, antiemetic point; po, per oral; PPI, proton-pump inhibitors; q.d., once a day; RP, Raynaud's phenomenon; Sc., subcutaneous; Shokai, acupoints at the elbow (joint pain acupoint); ST36, stomach acupoint; t.d.s., three times/day; T1/2, half time; TENS, transcutaneous electrical nerve stimulation; TPN, total parentral nutrition; ttt, treatment; VIP, vasoactive intestinal polypeptide; SSc, systemic sclerosis; GI, gastrointestine.

(C)
6 SSc patients and 2 achalasia patients
Case reports
Single channel low frequency (2 Hz) TENS on the non-dominant hand
Negative electrode on dorsal web between first and second metacarpal bones
Positive electrode at the ulnar border of the same hand
Bursts of 5 pulses
Pulse frequency: 100 Hz
Pulse width: 0.1–0.2 ms
Amplitude: 15–30 mA
Acute: 30–45 min
Chronic: 30 min once up to thrice daily, then every 2nd or 3rd day × 7 months to 4 years
Acute (in SSc patients, ttt vs. BsL):
Oesophageal barium study: increased lower oesophageal peristalsis and LESR (n = 1)
Oesophageal symptoms and RP: decreased (n = 6)
Hand skin temperature: increased (n = 6)
Skin softening: increased (n = 5).
Plasma VIP: increased 31%
Chronic (oesophageal symptoms and RP)
Withdrawal of TENS with no recurrence of GI symptoms or RP (follow-up of 5 months to 4 years)
Kaada95
9 SSc patients
9 postdilatation achalasia patients
7 untreated achalasia patients
High frequency TENS on non-dominant hand for all patient groups The last group was also treated with low frequency TENSParameters for high frequency TENS
 Frequency: 110 pulses/s
 Pulse width: 0.11 ms
Amplitude: ≥2 mA
30 minOesophageal manometry: no significant change in LESP, LESR or oesophageal body contraction amplitude in all patients groups vs. BsLMearin et al.96
34 SSc patients pre- and post-tttLow frequency EA between acupoints ‘Hatija’ and ‘Shokai’ on the clinically worst side of the elbows 1–2/week for out-patients and 5/week for in-patients for a duration of 3 months to 9 years and 2 monthsFrequency: 1–10 Hz
Amplitude: <15 mA
30 minSymptom scores: ttt improved symptom scores based on local (peripheral) and general (systemic, including GI) symptomsMaeda et al.94
16 SSc patients vs. 17 normal controlsAcupressure on PC6 and PC103-lb dumbbell with a pointed tip
Duration: alterating 1 min pressure, 1 min rest for 30 min
30-min intervals: BsL, acupressure and recoveryEGG and symptom scores:
Acupressure on PC6 induced changes in GMA during recovery interval vs. BsL (P < 0.05)
δGMA (BsL vs. recovery) significantly correlated with the frequency of heart burn symptoms (P < 0.05)
Wollaston et al.97
17 SSc patients pre- and post-tttTENS on PC6 and ST36Pulse trains
12 trains/min
Pulse frequency: 25 Hz
Train duration: 2 s
Amplitude: 2–10 mA
Acute: 30 min
Chronic: 30 min twice daily × 14 days
EGG, HRV and Symptom Scores:
Acute improves GMA vs. BsL (P < 0.05)
Chronic
Normalized sympathovagal balance (P < 0.05)
Improved GI symptoms vs. BsL (P = 0.02)
Sallam et al.146

Oesophagus

Alterations in oesophageal motility

Oesophageal dysmotility is the most common GI manifestation in SSc. Oesophageal motor dysfunction and gastro-oesophageal reflux disease (GERD) occur in the majority of SSc patients.8, 21, 33–40 However, the absence of oesophageal symptoms does not necessarily exclude oesophageal involvement.8, 15, 38, 41–44 SSc-related oesophageal dysmotility as measured by manometry, scintigraphy and/or barium include: (i) decreased lower oesophageal sphincter (LES) pressure,7, 15, 22, 45–54 or total incompetence of the LES;22, 48, 49, 55 (ii) ineffective (reduced amplitude) or absent distal oesophageal peristalsis7, 12, 22, 45–51, 53–57 and (iii) impaired coordination between the distal oesophagus and LES.12 These abnormalities result in prolonged oesophageal transit time or delayed oesophageal emptying, affecting primarily the distal two-thirds, or smooth muscle portion of the oesophagus.22, 33, 34, 40, 55, 58–63 The motility in the pharynx, upper oesophageal sphincter and proximal oesophagus, are generally normal in patients with SSc.48, 50, 64 Studies argue for9, 24, 65, 66 and against40, 45, 67 a higher prevalence and severity of oesophageal dysmotility with the diffuse SSc and severity of cutaneous involvement measured as patient skin scores.

GERD

The pathogenesis of GERD is multifactorial. Distal oesophageal dysmotility, aperistalsis and incompetent LES usually progress to severe GERD and occur in 50–80% of SSc patients.9, 45, 68 The ‘reduction or absence of LES pressure’ is the primary facilitator of gastric acid reflux into the oesophageal lumen. ‘Oesophageal dysmotility’ leads to impaired acid clearance and results in prolongation of oesophageal exposure time to gastric acid.69‘Delayed gastric emptying’ is also a promoter of GERD in SSc patients.6, 22, 33, 58, 70, 71‘Transient LES relaxation’ (TLESR) has been proposed as the major mechanism for the development of GERD in the normal population; however, TLESR has not been clearly established as the cause of GERD in SSc patients.72

GERD induces oesophagitis which is well correlated with motility disorders.67, 73, 74 Additional SSc-related oesophageal complications of chronic GERD include stenosis, strictures34 and ultimately Barrett's metaplasia which was reported in 40% of patients.75 Some studies recommended simultaneous monitoring of oesophageal pH and oesophageal manometry regardless of reflux symptoms.67, 73, 74

Therapeutic modalities for GERD in SSc

The treatment of GERD in SSc is important to: (i) relieve heartburn symptoms, (ii) reduce distal oesophageal scarring that may eventually produce strictures, (iii) deter the possible development of cellular metaplasia at the gastric-oesophageal junction (Barrett's oesophagus) which increases the risk of oesophageal cancer and (iv) reduce the potential contribution to lung inflammation by inappropriate aspiration of gastric contents which might promote scarring and fibrosis of lung tissue.76 Current therapeutic modalities for upper and lower GI dysmotility in SSc patients are listed in Table 2 and are similar to those in other patients with GI dysmotility, including: (i) diet and antireflux measures – ingestion of multiple small meals during the day and avoidance of large meals or strenuous exercise within 3 h of bedtime;9, 72 avoidance of fatty meals, chocolate, peppermint, alcohol and cessation of smoking and use of tobacco products;72 raising the head of bed by 6 inches using blocks or wedge pillows. (ii) Medical treatment – there are two main therapeutic categories. (a) Antisecretory agents, such as proton-pump inhibitors (PPI) which are safe and effective for treating GERD4, 77, 78 as well as oesophagitis.79, 80 SSc patients may require two- to fourfold of the normally recommended dose.79 This information is based on the use of omeprazole (Prilosec), as other PPIs, including esomeprazole (Nexium), pantoprazole (Protonix) and rabeprazole (Aciphex), have not been studied in SSc patients. (b) Prokinetic agents are reported to improve the SSc-associated GI dysmotility and GERD symptoms but only during the early stage when cholinergic nerve transmission is primarily affected and the GI musculature is still intact.5, 8, 12 The prokinetic agents are thought to improve gastric dysmotility which contributes about 25% of the GERD pathology. Domperidone is only useful when symptoms are mild.13 Erythromycin and metoclopramide have been shown to increase LES pressure in SSc patients.81–83 The selective serotonin (5-HT4) receptor agonist, cisapride has been shown to increase the LES pressure and amplitude of distal oesophageal body peristalsis,84 with no effect on oesophageal transit.85 Cisapride is now under strict use due to its potential cardiac toxicity.86, 87 Tegaserod, a 5-HT4 receptor partial agonist, is a relatively new agent with few reports of its efficacy in relieving GERD symptoms.88 (iii) Surgical procedure – the fundoplication, is considered a distant alternative to medical therapy for the treatment of GERD. However, this surgery is of limited success5, 72, 74, 89, 90 and is generally contraindicated in SSc patients.13, 22 (iv) Endoscopic procedures – endoscopic disruption of oesophageal strictures is performed in symptomatic SSc patients.91 Emerging techniques such as radiofrequency application, suture-plication, full-plication, biopolymer implant, microsphere injection and hydrogen prothesis, are promising innovative techniques for the treatment of GERD92 although there is scant information regarding their applications in SSc patients. (v) Novel pharmacological approaches for GERD –γ-aminobutyric acid B-receptor, cannabinoid receptor 1 agonists and selective cholecystokinin 1 receptor antagonists have been promoted as potential treatments for treating GERD via reduction of the TLESR.93 The success of these agents in SSc patients may be unpredictable, as the role of TLESR in SSc-associated GERD is not well established. (vi) Alternative and investigational therapies – improvement of dysphagia (and non-GI symptoms) has been reported in SSc patients using low frequency electrical acupunctural stimulation.94 Application of single channel transcutaneous electrical nerve stimulation (TENS) on the non-dominant hand for the treatment of SSc-associated oesophageal dysmotility has demonstrated contradictory results.95, 96

Stomach

Gastric dysfunction has been reported in at least 50% of patients with SSc and can result in significant morbidity and mortality in 15% of patients.8 Symptoms related to gastric dysmotility include heartburn, nausea, vomiting, abdominal bloating, pain, regurgitation, retrosternal pain, epigastric fullness and early satiety and contributes to significant weight loss and functional morbidity.9, 33, 71 Gastric dysfunction also contributes in the development of heartburn and GERD symptoms.5 Neither the presence and/or severity of the dyspeptic symptoms nor the subset and/or disease duration of SSc are predictive of gastric impairment as measured by the EGG and scintigraphy.58, 71, 97

Alterations in gastric accommodation

Gastric accommodation is vagally mediated and may reflect a systemic autonomic dysfunction in SSc patients. Barostat recordings, reflecting gastric wall tensile pressures and gastric wall compliance are similar between SSc patients and controls.25 However, SSc patients with higher scores of autonomic dysfunction showed greater impaired gastric compliance, compared to patients with normal autonomic function scores.25

Alterations in gastric motility

Gastric motility, assessed by antroduodenal manometry, is usually impaired in SSc patients.66 In the fasting state, the migrating motor complex (MMC), phase I and II, occurs less frequently, is of low amplitude; or may be completely absent.70 In the fed state, MMC phase III activity is associated with diminished antral contractility, reflected as decreased frequency and amplitude of contractions.7, 21 Postprandial antral dilatation measured by ultrasound has also been reported in SSc patients.98

Alterations in gastric myoelectrical activity

Single channel or multichannel EGG is an established, validated method to characterize gastric motility disorders by non-invasive measurement of gastric myoelectrical activity (GMA).99–101 The rhythmicity of gastric slow waves is accurately measured in the EGG and represented in the spectral analysis of the EGG. Surface (cutaneous) EGG has very good correlation with serosal EGG values100 and correlation between the EGG and gastric emptying was reported in a number of studies.102, 103 Disturbances in the EGG are associated with gastric hypomotility. Fasting and/or postprandial EGG parameters per se have not been reported as correlative or predictive of dyspeptic symptoms104, 105 although abnormal EGGs were reported in non-SSc patients with GERD.103

The prevalence of gastric slow wave disturbances assessed from the EGG is up to 80–90% in SSc patients.4, 71 Abnormalities in gastric slow waves in SSc patients include a reduced percentage of normal slow waves, increased frequencies of bradygastria or tachygastria and a reduced postprandial increase in slow wave amplitude.71, 106–108 Many of these patterns of EGG abnormalities have been described in other conditions with gastric motility disorders (i.e. with diabetes mellitus and functional dyspepsia) and are not specific to SSc. Studies using multichannel EGG have revealed impaired coupling or propagation of gastric slow waves in SSc patients.97, 106

Alterations in gastric emptying

Delayed gastric emptying is common in SSc patients6, 33, 58, 71, 107–111 and has been reported as more prominent in diffuse cutaneous SSc.30, 91 Autonomic dysfunction results in tonic contractile dysfunction of the proximal stomach and antroduodenal incoordination and ultimately delayed gastric emptying of both liquids and solids.33, 112, 113 Studies have reported that GI symptoms are reliable predictors of delayed gastric emptying diagnosed by scintigraphy6 although others have reported a poor correlation between gastric emptying and symptoms.30, 113 Studies have also reported contradictory results regarding the correlation of delayed gastric emptying to the disease duration of SSc when assessed by isotopic imaging.108, 113

Therapeutics

No uniform treatment strategy of gastric motility disorders in SSc patients has been successful. Clinical management of gastric motility disorders is difficult due to the lack of consistently effective prokinetic medications and poor correlation between gastric motility measurements and GI symptoms. The lack of a validated SSc-related GI symptoms questionnaire may contribute to this lack of correlation. Common treatment modalities include: (i) Medical therapy – medical treatment using prokinetic agents is the first choice for treating gastric motility disorders associated with SSc or other conditions. Domperidone, a peripheral dopamine receptor antagonist has been reported to improve gastric emptying in Parkinsonism,114 gastric dysrhythmia and dyspeptic symptoms in diabetics,115 but it is not approved in the US and no data are available for its use in SSc patients. The response to metoclopramide, a central and peripheral dopamine receptor antagonist, is unpredictable and may have significant side-effects.12, 116–118 In SSc patients, intramuscular administration of metoclopramide improved SSc-associated delayed gastric emptying.6, 81 When used with bethanechol, metoclopramide improves fasting antral motility.116 However, in one SSc patient, post-operative administration of metoclopramide induced bradycardia and cardiac arrest.119 Cisapride was shown to significantly improve gastric emptying but with limited improvement in symptoms of gastroparesis and has restricted availability and utility because of its reported cardiac toxicity. In SSc patients, cisapride proved to increase fundic contractions, associated with increased LES pressure.120 Erythromycin has been reported to be a potent agent in accelerating gastric emptying in patients with gastroparesis121 and in SSc patients.122, 123 However, the same dose (200 mg) that accelerates gastric emptying inhibits small bowel motility.124 Tegaserod was reported to increase gastric tone125 but have contradictory effects in gastric emptying;126–128 no literature was available regarding its use in SSc patients. Octreotide, used for intestinal hypomotility, inhibits antral contractions124, 129 and seems to have no effect on gastric emptying in SSc patients.123 (ii) Nutritional support – low residue diets and vitamins supplementation are recommended.9, 12 In patients with severely impaired gastric motility but acceptable intestinal motility and transit, a jejunal feeding tube is often placed to provide nutritional support.130 (iii) Surgical treatment – antrectomy was initially reported to improve SSc patients with severe gastric dysmotility;131–133 but failed in long-term follow-up.13 (iv) Alternative and investigational therapies includes: (a) gastric pacing – the therapeutic potentials of gastric electrical stimulation for diabetic gastroparesis have recently been reported.134 Short pulse gastric electrical pacing was reported to dramatically reduce nausea and vomiting in patients with gastroparesis.135 Long pulse gastric electrical pacing has been shown to improve gastric dysrhythmia,136 gastric emptying and dyspeptic symptoms in patients with gastroparesis.130 (b) Acupuncture–based therapies – a wrist band is sometimes used to relieve nausea in pregnancy.137, 138 Acupressure to GI associated acupuncture site (GI acupoint) PC6 was found to alter GMA in SSc patients by increasing the frequencies of bradygastria and tachygastria.97 Of interest, the alterations in GMA persisted for at least 30 min after the termination of acupressure. This effect was not seen when acupressure was applied to a non-GI acupoint (PC10, ‘sham acupressure’). Moreover, the fluctuations in GMA in response to acupressure in two EGG channels strongly correlated with the frequency of heart burn symptoms.97

Electroacupuncture (EA; application of electrical stimuli on the acupuncture needle at the acupuncture point) has been shown to normalize gastric dysrhythmias139–142 and accelerate gastric emptying in gastroparetic patients.143 Electroacupuncture has been reported to improve vasopressin-induced delays in gastric emptying144 as well as to increase gastric accommodation in animal models.145 In a recent study, we applied TENS to acupoints PC6 and ST36 in SSc patients with resultant improvement in both gastric dysrhythmia and GI symptoms.146 Mechanisms of TENS are based on brain studies in an animal model, supporting the differential release of neuropeptides and subsequent effects, based on the amplitude or frequency of the delivered electrical stimulation.147 Further studies are needed to determine if applications based on TENS or GI acupoint-based therapies offer potential efficacy as a monotherapy or as therapeutic adjuncts, targeted for the relief of specific gastric symptoms or to normalize gastric dysmotility.

Small bowel and colon

Small bowel

Intestinal motility dysfunction is commonly reported in SSc, with a 40–88% prevalence rate.8, 20, 36, 148 However, 65% of the SSc patients are asymptomatic, leading to an under-diagnosis or delayed diagnosis of small bowel involvement.22 Impairment of the small intestine is associated with a high morbidity and can lead to life-threatening complications, such as malabsorption syndrome, pseudo-obstruction and pneumatosis cystoides intestinalis (PCI).148 Intestinal hypomotility induces stasis of the small intestinal contents which enhances upstream bacterial colonization, resulting in bacterial overgrowth, a common complication in SSc patients which may contribute to intestinal malabsorption and diarrhoea.2 Bacterial overgrowth in SSc may also be predisposed by PPI treatment with subsequent achlorohydria.149 Pneumatosis cystoides intestinalis is a rare complication of SSc, where multiple air-filled cysts develop in the submucosa and subserosa of small intestinal wall, if ruptured, cause pneumoperitoneum. The eventual serosal fibrosis with a resultant loss of wall compliance of the muscularis layer also increases the risk of perforation.148, 150 Detailed pathophysiology of the condition has been previously reported.151

Alterations in small bowel motility

Small bowel manometry in SSc patients reveals alterations of phase III of the MMC including interrupted propagation, decreased frequency with low amplitude and complete absence of phase III activity.20, 22, 152, 153 In fasting SSc patients, the proximal small bowel shows uncoordinated or minimal motor activity.20–22, 116, 154 Postprandially, the overall motility is reduced7, 20–22 as evidenced by a decreased postprandial motility index which does not seem to be correlated with the severity of the SSc disease.20

Alterations in intestinal transit

Delayed transit time of the small intestine4, 21, 23, 70, 152, 155 and the whole gut has been reported.33 The duodenum is the most frequently involved part in the small intestine. Involvement of the intestine has not been shown to correlate or predict the extent of involvement of other areas of the GI tract.148

Colon

Colonic involvement has been reported to occur in almost 20–50% of SSc patients8, 9 and is usually asymptomatic.36 The progressive development of smooth muscle atrophy in the colonic wall results in colonic motor disturbances in SSc patients156 as the colonic wall becomes dilated with loss of its haustrations.157 The development of life-threatening colonic pseudo-obstruction or perforation secondary to colonic disease involvement has also been reported.158, 159

Alterations in colonic motility

Colonic contractions are usually reduced or even completely absent in SSc patients, reflected as decreased or absent spike activities in mucosal myoelectrical recordings.156, 160 Prolonged colonic transit has been reported in both right and left colon in SSc patients.112, 161

Constipation and diarrhoea in SSc

Systemic sclerosis patients often suffer from diarrhoea and/or constipation. Diarrhoea in SSc patients is a sequel of multiple factors including: bacterial overgrowth, diminution of the intestinal surface area for absorption, fibrosis of the lymphatic drainage, decreased intestinal permeability and chronic intestinal ischaemia, all predisposing to malabsorption and eventually diarrhoea.148

Alternatively, SSc patients frequently develop constipation from decreased colonic compliance162 and prolonged colonic transit time.163, 164

Therapeutics for intestinal involvement

The treatment for intestinal dysmotility in SSc patients is usually difficult and currently focused only on the relief of symptoms. Conventional therapies for intestinal dysmotility in SSc patients include: (i) diet – a dietary plan is usually considered essential to maintain adequate GI motility. For constipation, liberal ingestion of fluids is encouraged.14 High fibre laxatives and excessive ingestion of high fibre foods are avoided as their efficacy is reduced in the setting of hypomotility and may aggravate the condition. In long-term severely resistant cases, total parenteral nutrition (TPN) may be indicated to relieve obstructive symptoms and improve the quality of life.8, 9, 58, 165, 166 In cases of diarrhoea, foods containing lactose are avoided.8, 72 (ii) Antibiotics – monthly rotating and intermittent antibiotic treatment is recommended for the control of bacterial overgrowth and intestinal symptoms, including diarrhoea. Antibiotics include, but not limited to, amoxicillin, ampicillin, metronidazole, norfoloxacin, tetracyclines, ciproxycyclines and doxycyclines.4, 13 (iii) Prokinetic agents – domperidone has been reported to be effective in relieving pseudo-obstruction in SSc.4, 13, 167 Metoclopramide has been reported to improve both small bowel and colonic motility in SSc.12, 156, 160 Cisapride was shown to increase duodenal contractions168 and colonic transit in SSc patients.169 Erythromycin has no effect on intestinal dysmotility in SSc patients.123 A report describes the successful use of prucalopride, a new 5-HT4 receptor agonist, to treat gastrointestinal dysmotility in two SSc patients;170 however, further studies are needed to establish its effectiveness. The somatostatin analogue, octreotide has been shown to be effective in relieving chronic pseudo-obstructions secondary to SSc.124, 171, 172 According to Sjögren,13 octreotide is predominantly effective in small intestine dysfunction; however, it might have beneficial extra-digestive effects173 including improving skin scores.168 In SSc patients, subcutaneous treatment with octreotide resulted in an increased mean frequency of intestinal MMCs. The MMCs in SSc patients after octreotide treatment propagated at the same velocity but lower amplitude, compared with spontaneous complexes recorded in normal subjects.154 Although the use of erythromycin and octreotide each separately had no effect on the symptoms of intestinal dysmotility in SSc,123 a combination of both were shown to be effective.124, 174 However, the same dose of octreotide used to improve intestinal dysmotility may cause delayed gastric emptying.124 (iv) Surgical options – resection of involved tissue for SSc-associated small intestine dysfunction is usually discouraged as patients are at-risk to develop a prolonged ileus after operative manipulations.175 Still, surgery might be considered in patients with severe involvement such as colonic or intestinal pseudo-obstruction who fail conservative or medical therapies. Surgical excision should be as conservative as possible with preservation of the ileocecal valve.175 Colostomy followed by subtotal colectomy is sometimes beneficial in SSc patients with colonic involvement.158 Surgical resection is also recommended for severe cases and/or ruptured PCI.12, 151 (v) Investigational therapies: (a) electrical pacing – pacing was noted to accelerate the transit time of the small intestine and normalize intestinal dysrhythmia in dogs.176–179 Colonic pacing was also reported to improve colonic transit times in patients with constipation.180 (b) Acupuncture or acupressure – the literature regarding the effect of acupuncture or acupressure on bowel motility is based on limited animal studies. Electroacupuncture on GI acupoints has also been reported to enhance intestinal motility in rats and dogs.181, 182 No reports were found involving SSc patients.

Anorectum

The anorectum is the second most studied area of the GI tract in SSc patients, following the oesophagus. Anorectal dysfunction is reported in 50–70% of SSc patients exerting a direct impact on patients’ quality of life.8 Due to fibrosis of the internal anal sphincter, the SSc patient may develop outlet obstruction-constipation because of impaired relaxation and restricted dilation of the internal sphincter during straining.182 Chronic constipation usually progresses to fecal impaction, causing constant distention of the rectal wall. With increasing accumulation of collagen in the rectal wall, impaired rectal compliance develops. Fecal incontinence and rectal prolapse follow as the SSc associated anorectal involvement progresses.8, 183, 184 SSc patients with impaired anorectal function may complain of a variety of symptoms, including constipation, diarrhoea, increased rectal fullness or urgency.

Alterations of anorectal motility

The resting pressure of the anal sphincter was reported to be normal174, 185 or decreased.164, 184, 186 A decrease was noted in the maximum squeeze pressure of the anal sphincter,186 the rectal capacity and rectal wall compliance.164, 169, 183, 184, 187, 188 The rectoanal inhibitory reflex (RAIR) was reported to be normal in a few studies164, 174 but diminished or absent in the majority of studies.162, 183, 185, 186, 188–192 Abnormal RAIR leads to clinical findings of outlet obstruction-constipation. In addition to dysmotility, impairment in anorectal sensation, increased urgency and rectal fullness have also been reported in SSc.185, 188

Therapeutics

Conventional therapies of diet, medications and surgery for anorectal dysfunction are used to alleviate SSc patients’ symptoms, including: (i) diet – stool bulking agents (soluble fibres/bran) are usually recommended to maintain gut motility, especially in patients with diarrhoea and weak internal anal sphincter; a combination which can predispose to fecal incontinence.188 (ii) Antidiarrhoeal agents – can be effective.86 (iii) Surgical procedures – options for surgical treatment include sacral nerve stimulation by use of an implantable device as it is a safe and effective treatment for SSc patients with fecal incontinence. However, it does not provide a long-term benefit.193 Posterior anal repair can be successful in treating fecal incontinence.188 Anterior resection of the rectal and sigmoid walls can relieve rectal prolapse.183 (iv) Alternative therapy – acupuncture was reported to increase the frequency of bowel movement to the levels of controls over a 10-week treatment period in constipated children.194 However, this finding was not confirmed in adult patients.195 No studies using acupuncture in anorectal dysfunction in SSc patients have been reported.

Discussion and conclusions

Dietary and lifestyle changes and medications should be the mainstay of treatment for SSc-related GI dysmotility. In summary, the use of high-dose PPIs for GERD treatment is essential. The choice of prokinetic agent is dependent on the patients’ condition and the extent of GI dysmotility. Metoclopramide (for the whole gut), domperidone (for stomach and small bowel), tegaserod or erythromycin (for stomach) can be selected. Octreotide is effective only for small bowel dysmotility and can be used in combination with upper gut prokinetics. Although cisapride has been shown to be effective throughout the entire gut in SSc patients, it should only be used with caution and not concomitantly with erythromycin because of its potential cardiac toxicity. Surgery is not recommended unless serious complications of obstruction or perforation develop. Alternative therapeutic methods such as acupuncture-based modalities yield potential benefit in improving GI motility in SSc and available preliminary studies report good patient tolerability. Further studies are needed to understand the mechanism of action of acupuncture-based therapy as well as its role in modulating GMA or normalizing the physiological changes of SSc-related GI dysmotility. Importantly, development of a validated questionnaire regarding GI symptoms in SSc patients may elucidate correlative links between GI-related symptoms and GI dysmotility by conventional tests. Currently, there are no treatments to halt the progression of collagen deposition and resultant fibrosis in the skin or organs of SSc patients. Accordingly, the early and ongoing identification of specific organ involvement including the GI tract is important to treat debilitating symptoms and/or avoid potential life-threatening complications.

Ancillary