Alimentary Pharmacology and Therapeutics

Review article: pathogenesis and clinical manifestations of

gastrointestinal involvement in systemic sclerosis
S. Kumar* , J. Singh*, S. Rattan*, A. J. DiMarino*, S. Cohen* & S. A. Jimenez†

*Department of Medicine, Division of SUMMARY

Gastroenterology and Hepatology,
Thomas Jefferson University, Sidney
Kimmel Medical College, Philadelphia,
Background
PA, USA. Gastrointestinal tract (GIT) involvement is a common cause of debilitating
†
Jefferson Institute of Molecular symptoms in patients with systemic sclerosis (SSc). There are no disease mod-
Medicine and Scleroderma Center, ifying therapies for this condition and the treatment remains symptomatic,
Thomas Jefferson University, Sidney
largely owing to the lack of a clear understanding of its pathogenesis.
Kimmel Medical College, Philadelphia,
PA, USA.
Aims
To investigate novel aspects of the pathogenesis of gastrointestinal involve-
Correspondence to:
ment in SSc. To summarise existing knowledge regarding the cardinal clini-
Prof. S. A. Jimenez, Jefferson Institute
of Molecular Medicine, Scleroderma
cal gastrointestinal manifestations of SSc and its pathogenesis, emphasising
Center, Thomas Jefferson University, recent investigations that may be valuable in identifying potentially novel
Sidney Kimmel Medical College, therapeutic targets.
Philadelphia, PA 19107, USA.
E-mail: sergio.jimenez@jefferson.edu Methods
Prof. S. Cohen, and Prof. S. Rattan,
Department of Medicine, Division of
Electronic (PubMed/Medline) and manual Google search.
Gastroenterology & Hepatology,
Thomas Jefferson University, Sidney Results
Kimmel Medical College, Philadelphia, The GIT is the most common internal organ involved in SSc. Any part of
PA 19107, USA. the GIT from the mouth to the anus can be affected. There is substantial
E-mail: sidney.cohen@jefferson.edu
variability in clinical manifestations and disease course and symptoms are
nonspecific and overlapping for a particular anatomical site. Gastrointesti-
Publication data nal involvement can occur in the absence of cutaneous disease. Up to 8%
Submitted 15 October 2016 of SSc patients develop severe GIT symptoms. This subset of patients dis-
First decision 18 November 2016
play increased mortality with only 15% survival at 9 years. Dysmotiity of
Resubmitted 29 December 2016
Accepted 11 January 2017
the GIT causes the majority of symptoms. Recent investigations have iden-
EV Pub Online 9 February 2017 tified a novel mechanism in the pathogenesis of GIT dysmotility mediated
by functional anti-muscarinic receptor autoantibodies.
The Handling Editor for this article was
Professor Jonathan Rhodes, and this
Conclusions
uncommissioned review was accepted
for publication after full peer-review. Despite extensive investigation, the pathogenesis of gastrointestinal involvement
in systemic sclerosis remains elusive. Although treatment currently remains
symptomatic, an improved understanding of novel pathogenic mechanisms
may allow the development of potentially highly effective approaches including
intravenous immunoglobulin and microRNA based therapeutic interventions.

Aliment Pharmacol Ther 2017; 45: 883–898

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doi:10.1111/apt.13963
S. Kumar et al.
INTRODUCTION
Systemic sclerosis (SSc) is a chronic systemic autoim-
mune disorder characterised by a severe and often pro-
gressive fibrotic process affecting the skin and numerous
internal organs. Tissue fibrosis in SSc is accompanied by
fibro-proliferative alterations in the microvasculature and
various humoral and cellular immunological alterations
leading to production of autoantibodies, tissue infiltra-
tion with chronic inflammatory cells and abnormalities
in innate immunity.1 Gastrointestinal tract (GIT)
involvement occurs in greater than 90% of SSc patients.2
Any part of the GIT from the mouth to the anus can be
involved with dysmotility being the cardinal pathological
abnormality contributing to the majority of symptoms.3
GIT involvement occurs in both the diffuse and limited
cutaneous subsets of SSc. Patients may present with
symptoms of SSc GIT involvement in the absence of
cutaneous disease. There is substantial variability in
extent of involvement, severity and disease course in SSc
GIT involvement with symptoms that are frequently
nonspecific and overlapping for a particular anatomical
site. Although GIT involvement is present in the major-
ity of SSc patients it has been described that up to 8% of
SSc patients develop severe GIT symptoms. This subset
of SSc patients display increased mortality with only 15%
survival at 9 years.4 Gastrointestinal (GI) symptoms have
also been associated with a reduction in health-related
quality of life and contribute to depression, sleep distur-
bances and pain in SSc patients.5–7 These factors create a
vicious circle and cause inability to carry out daily activi-
ties, work disability, and limited overall physical func-
tioning.
Despite their frequency and severity and largely
owing to the heterogeneity of clinical manifestations of
SSc and to the lack of appropriate animal models,
knowledge of the pathophysiology of GIT dysfunction
in SSc is limited. The purpose of this review is to criti-
cally examine the current literature and to shed novel
insights into the pathogenesis of GIT involvement in
SSc. In addition, we will discuss the cardinal clinical
manifestations of this complex disease and will identify
potential areas for the development of novel therapeutic
interventions.
METHODS
We searched PubMed, MEDLINE, and Google Scholar
for articles about Systemic Sclerosis published in English
between 1 January 1990, and 1 December 2016. We used
the search terms “systemic sclerosis”, “gastrointestinal”,
“oesophagus”, “stomach”, “intestine”, “rectum”, “anus”,
884
“antibody”, “vasculopathy”, “immune” and “pathogene-
sis”.
RESULTS
Pathogenesis of SSc
The exact mechanisms involved in SSc pathogenesis are
not well understood. However, it is apparent that the
clinical and pathologic manifestations of the disease are
the result of three distinct processes: (i) Fibroproliferative
vascular lesions of small arteries and arterioles, (ii) fibro-
sis of skin and various internal organs induced by the
increased production of various pro-fibrotic growth fac-
tors such as transforming growth factor-b (TGF-b), con-
nective tissue growth factor, and insulin-like growth
factor and (iii) multiple alterations of innate, humoral
and cellular immunity resulting in the accumulation of
lymphocytes and macrophages in affected tissues and the
production of numerous autoantibodies.8–12 Although
the putative aetiologic agent and the exact mechanisms
involved have not been determined, recent studies have
provided novel information about the early events in SSc
pathogenesis. As a result of those studies, it has been
postulated that there is a sequence of alterations initiated
by unknown aetiologic factors in a genetically receptive
host. The earliest events induce structural and functional
endothelial cell abnormalities affecting selectively the
microvasculature.13, 14 These alterations cause increased
production and release of numerous cytokines, chemoki-
nes and polypeptide growth factors that result in the
recruitment of bone marrow-derived and circulating
fibrocytes and in the phenotypic conversion of quiescent
tissue fibroblasts, and of epithelial and endothelial cells
into activated myofibroblasts, the cells ultimately respon-
sible for the fibroproliferative vasculopathy and progres-
sive tissue fibrosis.13, 15, 16 These alterations also result
in chemokine and cytokine-mediated attraction of speci-
fic inflammatory cellular elements from the bloodstream
and bone marrow to the affected tissues and in the acti-
vation of resident tissue macrophages resulting in the
establishment of a chronic inflammatory process.17, 18
This sequence of events is diagrammatically illustrated in
Figure 1.
Pathogenesis of GIT involvement in SSc
The pathogenesis of GIT SSc is complex and poorly
understood. There is a paucity of studies examining the
aetiology and pathogenesis of GI manifestations in SSc.
Smoking is the only environmental toxin that has been
linked to increased severity of GIT symptoms in patients
Aliment Pharmacol Ther 2017; 45: 883–898
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 Review: gastrointestinal involvement in systemic sclerosis

Environmental and Endothelial cell injury

genetic factors
-Reactive oxygen species
-Inflammatory cells
-Cytokines
-Growth factors

T cell B cell

CD4
IL-12 M3-R Autoantibodies
IL-4

TH1 TH2

Macrophage IL-4, IL-6, IL-13

TGF-β Fibroblast
Ach
Epithelial cells EMT
Endothelial cells Myofibroblast Neuromuscular M3-R
EndoMT junction
Other cells
miR-29

ECM deposition

Fibrosis

GIT dysmotility

Figure 1 | Pathogenesis of systemic sclerosis: unknown environmental factors in a genetically susceptible host trigger
initial endothelial cell injury. This results in release of reactive oxygen species, chemokines, cytokines, and growth
factors. The local cytokine milieu leads to recruitment and activation of chronic inflammatory cells, including T- and B-
lymphocytes and macrophages. B-cells evolve into plasma cells that produce M3-R antibodies, which occupy the
extracellular loop-2 of the M3-R on the intestinal smooth muscle and prevent acetylcholine released from the synaptic
terminal to act on the receptor. The CD4+ T cells under influence of IL-4 differentiate into Th2 subtype. Th2 cells
secrete pro-fibrogenic cytokines IL-4 and IL-13, which along with IL-6 stimulate TGF-b production. Fibroblasts are
activated into myofibroblasts by action of TGF-b. Myofibroblasts produce excess collagen, which causes structural
damage and fibrosis, distorting the normal architecture of the tissue, leading to dysmotility.

with SSc.19 Evidence that a strong genetic component is
linked to GIT SSc is highlighted by a study demonstrat-
ing that Canadian North American Native patients had
more severe GIT involvement compared to Caucasian
Americans.20 Studies have also demonstrated a high
prevalence of Helicobacter pylori infection in SSc
patients, supporting a role for an infectious aetiology.21
Fibroproliferative vasculopathy, immune dysfunction and
fibrosis have been postulated as pathogenic mechanisms
of GIT dysfunction and structural alterations in SSc (Fig-
ure 1). In the following sections, we highlight the impor-
tant role of each of these pathogenic processes in
relation to the GIT involvement in SSc. Furthermore, we
discuss the results of recent studies that have identified
and explored unique and novel mechanistic pathways
and have allowed to postulate a novel pathogenic model
for GIT involvement in SSc.
results in increased production of reactive oxygen species
and release of chemokines and growth factors, which
lead to recruitment of inflammatory T and B cells and
pro-fibrotic macrophages in the interstitium of affected
tissues. Activated inflammatory cells and tissue hypoxia
resulting from structural vascular damage cause further
release of reactive oxygen species, cytokines and pro-
fibrogenic mediators that propel the disease process.1
Studies in GIT SSc have shown evidence of dimin-
ished mucosal blood flow in the duodenum and gastric
antrum.22 Histological studies of the oesophagus and
stomach have demonstrated endothelial cell apoptosis,
perivascular infiltrates and basement membrane thicken-
ing.23, 24 Vascular lesions such as gastric antral vascular
ectasia (GAVE) and telangiectasia of the digestive tract
are representative of the diffuse vasculopathy affecting
the GIT as illustrated in Figure 2.25, 26

Vasculopathy. Endothelial cell injury has been recently Humoral immunity. Although the presence of numerous
suggested to play a crucial role in SSc pathogenesis and autoantibodies is one of the critical manifestations of

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S. Kumar et al.
(a)
SSc, the occurrence of functional autoantibodies capable
of causing significant dysfunction of mouse colonic
smooth muscle contraction by M3-R inhibition was not
described until quite recently when Goldblatt et al.
demonstrated the presence of such autoantibodies in the
serum of SSc patients.27 Subsequent studies revealed that
immunoglobulins isolated from the serum of SSc patients
(SScIgGs) interfere with neurally (cholinergic)-mediated
contraction of the GIT. This was evidenced by the
demonstration that SScIgGs caused specific attenuation
of the simultaneous rat colonic contractile response and
release of acetylcholine induced by electric field stimula-
tion. SScIgGs were also found to abrogate the M3-R ago-
nist-induced contractile response of rat colonic smooth
muscle in a dose-dependent manner.28, 29 Most recently,
it was shown that SScIgGs lead to GI cholinergic dys-
function by binding at the M3-R on the GI smooth
Smooth muscle
Myenteric plexus
Figure 3 | SScIgG binding to colon: Transverse section
of rat colon demonstrating specific binding of SScIgG to
the smooth muscle and myenteric plexus as evidenced
by increased immunofluorescence (green) intensity.
886
Figure 2 | Vascular
involvement in GIT SSc. (a)
Haematoxylin and eosin stain
(40 9 ) of gastric biopsy
specimen demonstrating
GAVE, (b) haematoxylin and
eosin stain (200 9 ), arrows
(b) point to microthrombi.
muscle and the myenteric cholinergic neurons of the rat
colon (Figure 3). Further analysis revealed that IgG’s iso-
lated from SSc patients early in their disease course bind
with greater intensity to the myenteric neurons. As the
disease duration increases, there is progressive increase
in binding at both the smooth muscle and myenteric
neurons. Of substantial therapeutic significance were the
observations that the neural and myogenic effects of the
SScIgGs were abrogated by the administration of pooled
human intravenous immunoglobulin (IVIG) and its anti-
gen binding fragment F(ab0 )2.30
Cell-mediated immunity. Numerous studies have
demonstrated strong evidence for the role of cell-
mediated immunity (CMI) in SSc.31–33 Recent studies
have shown that alterations in CMI are important partic-
ipants in GIT involvement in SSc. Gastric biopsy speci-
mens have demonstrated accumulation of immune cell
infiltrates mainly consisting of CD4+ T lymphocytes
with a pronounced increase in the CD4+/CD8+ T cell
ratio.34 SSc in general has a predominant Type 2 helper
(Th2) polarisation of CD4+ T cells.1 IL-4 causes na€ıve
CD4+ cells to differentiate into Th2 cells by downstream
activation of STAT6 and GATA3, which lead to further
production of IL-4 and IL-13, the classic Th2 cyto-
kines.35 IL-4 in a positive feedback amplifies its own
response and also up-regulates humoral immunity by
inducing immunoglobulin production and isotype
switching (Figure 1). IL-13 along with IL-6 released from
various cells are pro-fibrotic cytokines that cause fibrosis
by direct pro-fibrotic effects as well as by activating
TGF-b.33 The presence of increased CD4+ cells in gastric
biopsy specimens could be responsible for excessive pro-
duction of pathogenic autoantibodies and the extensive
GIT fibrosis, as described above.
Fibrosis. Fibrosis disrupts the normal tissue architecture
and leads to a nonfunctioning GIT. TGF-b produced by
activated fibroblasts and immune cells leads to extensive
fibrosis by Smad-dependent and Smad-independent
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 Review: gastrointestinal involvement in systemic sclerosis
Figure 4 | Fibrosis of GIT in
SSc: (a) 109, (b) 409 fibrosis
within the muscularis propria
causing atrophy of the smooth
muscle cells, (c) 109, (d)
409. Trichrome stain
highlighting the fibrosis.
pathways,36 and in conjunction with endothelin-1
(derived from endothelial cells) participates in the con-
version of fibroblasts into myofibroblasts.11, 16 Myofi-
broblasts produce excessive fibrillar type l and type lll
collagen along with other extracellular matrix compo-
nents, initiate expression of a-smooth muscle actin and
are the cells ultimately responsible for the fibrotic pro-
cess.9, 37–39 Gastric wall biopsies of SSc patients show
generalised patchy fibrosis, increase deposition of type l
and type lll collagen in the muscularis mucosae, submu-
cosa and muscularis propria, and strong expression of
fibrogenic cytokines including TGF-b, connective tissue
growth factor and the myofibroblast marker a-smooth
muscle actin (Figure 4).40 As collagen has a higher elas-
tic modulus than smooth muscle, its deposition in the
intestinal wall leads to increased stiffness, subsequently
causing impaired muscle contractility. Furthermore,
increased tissue stiffness has been recently shown to rep-
resent a potent stimulus for further fibrotic deposi-
tion.41, 42 Besides fibroblasts, telocytes (peculiar type of
stromal cells with long cytoplasmic processes) essential
for extracellular matrix scaffolding are damaged and
severely reduced in fibrotic areas of gastric muscle in
SSc.43 Recent studies have also highlighted the role
microRNA (miRNA) in SSc pathogenesis. Differentially
expressed miRNAs that target both inflammation and
fibrosis have been identified in SSc.44, 45 These miRNAs
may be either anti- or pro-fibrotic. Of these miRNAs,
the ones that modulate TGF-b signalling and the expres-
sion of related genes encoding collagens, metallopepti-
dases, and integrins are the most significant. The miR-29
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(a) (b)
(c) (d)
family has been extensively studied in relation to SSc.46
Indeed, miR-29, which targets collagen gene expression
and regulates fibrosis, has been shown to be severely
reduced in SSc skin biopsies47 and reduced levels of
miR-29 have been suggested to lead to increased tissue
deposition of collagen.
Proposed pathogenesis of SSc GIT involvement
We recently proposed that GIT dysfunction in SSc is a
staged process beginning with neuropathy and progress-
ing to myopathy, with eventual fibrosis.30 The initial
neuropathic damage leads to disrupted contraction in
response to neural stimulation, which is followed by a
substantial reduction in amplitude of contractions signi-
fying the development of myopathy.30 The earliest evi-
dence for neuropathy was obtained in a study that
showed contractile response of the oesophageal smooth
muscle of SSc patients to the direct acting muscarinic
agonist methacholine but not to edrophonium, which
acts indirectly.26 These and numerous subsequent studies
suggested that in the early stages of SSc GIT involvement
circulating M3-R autoantibodies block cholinergic neuro-
transmission by inhibition of acetylcholine release at the
myenteric cholinergic nerves (neuropathic damage), and
that progression of the disease leads to myopathy via
inhibition of acetylcholine action at the GI smooth mus-
cle cell.30 Some of these studies further suggested a tem-
poral increase in binding of SScIgGs to the neural and
myogenic M3-R with disease duration, observations that
may account for the progressive nature of GIT involve-
ment in SSc. The demonstration of autoantibody-
887
S. Kumar et al.
mediated inhibition of neurotransmission provides a
cogent rationale to the well-demonstrated observations
that SSc patients may develop GIT manometric abnor-
malities long before the occurrence of histological
changes in the GIT. As acetylcholine is the principal
excitatory neurotransmitter in the GIT, inhibition of its
release results in the absence of response of the smooth
muscle in the GIT and its inability to contract in
response to physiological stimuli. However, intestinal
dysfunction at this stage is still reversible if the M3-R
autoantibodies can be removed from the plasma or neu-
tralised. Subsequently, loss of GIT contractile function
may be the result of disuse muscle atrophy and progres-
sive SSc-related tissue fibrosis (Figure 4). Once fibrosis
ensues the smooth muscle is unable to respond to any
type of external stimuli and treatment of dysmotility at
this stage is ineffective. The fibrosed and dysfunctional
GIT leads to reflux of gastric acid contents into the
oesophagus, a dilated and noncompliant stomach, over-
growth of bacteria in the small intestine, colonic dilata-
tion and a nonfunctional internal anal sphincter,
alterations that manifest clinically as Barrett’s oesopha-
gus, gastroparesis, severe malabsorption and faecal
incontinence respectively. Increased accumulation of fib-
rillary collagens and reduced expression of matrix metal-
loproteinase-1 along with GIT dysmotility lead to
development to wide mouth diverticula, which have been
reported in the oesophagus, small intestine and the
colon.48 The pathogenesis of GAVE and vascular ectasia
in the small intestine has been suggested to be analogous
to the vasculopathy responsible for the cutaneous and
other vascular manifestations of SSc (Figure 2).
Clinical manifestations
Oral cavity. There are numerous oral cavity alterations
related to SSc involvement.49 Fibrosis and tethering of
the perioral skin leads to decreased oral aperture.
Approximately 20% of patients develop secondary
Sj€
ogren’s syndrome leading to difficulty in mastication
and poor dental hygiene. Typical oral cavity manifesta-
tions of SSc are the thickening of the sublingual frenu-
lum and the widening of the periodontal ligament that
may result in tooth loosening or tooth loss.50, 51 A total
of 10–20% of patients develop mandibular resorption,
which can pre-dispose to pathological fractures,
osteomyelitis and trigeminal neuralgia.52 An increased
incidence of tongue cancer has also been reported in
patients with the diffuse subset of SSc.53 Oropharyngeal
dysphagia has been reported in up to 25% of patients
and may occur as a reflex mechanism in patients with
888
gastroesophageal reflux (GERD) or be secondary to
thickening of the muscles of the lower pharynx and
upper oesophagus.54 All these factors together pre-dis-
pose to decreased oral intake, malnutrition and subse-
quent weight loss.
Oesophagus. The oesophagus is the most common GI
organ affected and oesophageal involvement occurs in
75–90% of SSc patients.55 Symptoms include dysphagia,
odynophagia, heartburn and regurgitation but patients
can also present with other symptoms related to oeso-
phageal reflux such as chronic cough, hoarseness,
pharyngitis, laryngospasm or asthma. Although oesopha-
geal involvement is present in both limited and diffuse
SSc, a recent study concluded that oesophageal dysmotil-
ity is more common in patients with diffuse SSc and is
more likely to deteriorate over time compared to patients
with limited SSc.56 Another study that assessed oesopha-
geal motor function by high-resolution manometry
found that severe oesophageal dysmotility is associated
with longer duration of SSc and with the presence of
interstitial lung disease.57 Characteristically, there is
decreased or absent primary peristalsis in the lower two-
thirds of the oesophagus with reduction in lower esopha-
geal sphincter (LES) tone leading to a dilated and patu-
lous oesophagus (Figure 5a). These two factors pre-
dispose to GERD, which can be further exacerbated by
gastroparesis. GERD is also associated with higher preva-
lence and rapid progression of interstitial lung disease,
most likely caused by repeated micro-aspiration of gas-
tric contents into the lungs.58, 59
Frequently, patients with long-standing GERD pro-
gress to develop severe reflux oesophagitis even associ-
ated with peptic strictures (Figure 6a) and Barrett’s
oesophagus (Figure 6b) with its potential for develop-
ment of oesophageal adenocarcinoma. The prevalence of
Barrett’s oesophagus in SSc is estimated to be 12%,
which is essentially similar to that in patients with
GERD without SSc. However, a recent study has
reported an increased risk of oesophageal adenocarci-
noma in a European cohort of SSc patients with Barrett’s
oesophagus.60 Pill-induced dysphagia secondary to
reduced clearance of oesophageal contents or candida
oesophagitis due to effect of immunosuppressive medica-
tion are other common causes of dysphagia in SSc
patients that require prompt diagnosis. Although SSc
oesophageal involvement is one of the most common
manifestations of SSc GIT, it should be emphasised that
up to 30% of SSc patients may have asymptomatic oeso-
phageal involvement.61
Aliment Pharmacol Ther 2017; 45: 883–898
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 Review: gastrointestinal involvement in systemic sclerosis

Figure 5 | Radiological
features of SSc: (a) Upper GI
series demonstrating a dilated
and patulous oesophagus, (b)
Longitudinal approximation of
the folds of the valvulae
(b) (c)
conniventes leading to hide-
bound appearance of small
bowel, (c) barium enema
demonstrating a wide mouth
diverticulum in the colon
(encircled). (a)

Stomach. Gastric involvement in SSc leads to gastro-
paresis and GAVE.62 Symptoms range from early satiety,
vomiting, epigastric discomfort and bloating to complete
intolerance of food contributing to severe weight loss
and malnutrition. Symptoms of vomiting, epigastric dis-
comfort and post-prandial bloating may indicate delayed
gastric emptying. Gastroparesis aggravates GERD as evi-
denced by studies demonstrating severe oesophageal
mucosal abnormalities in patients who have gastropare-
sis.63 Decreased frequency and low amplitude of migrat-
ing motor complex (MMC) is seen in phase I/II in the
fasting state and phase III in the post-prandial state.
Patients with SSc are pre-disposed to develop GAVE62
(Figure 6c). The pathophysiology of GAVE in SSc has
been suggested to be secondary to immune-mediated
vasculopathy similar to that responsible for the develop-
ment of telangiectasias and Raynaud’s phenomenon.64
The prevalence of GAVE in SSc is estimated to be
5.7–22.3%.25, 64, 65 Usually, GAVE occurs within the first
few years of SSc onset.66 However, in a subset of patients
GAVE could be the first manifestation of SSc occurring
even in the absence of any other cutaneous features. It
can present as asymptomatic iron deficiency anaemia,
occult GI bleeding, melena or haematemesis. Previous
studies have associated GAVE with the presence of anti-
RNA pol III autoantibodies and the absence of anti-
topoisomerase I antibodies.66 Recent studies confirmed
the negative association with anti-topoisomerase I anti-
bodies, but did not find any association with anti-RNA
pol III autoantibodies.25, 64 Further studies will be
needed to confirm these findings and to render them
clinically useful.
Small bowel. The small intestine is the second most
common GIT organ involved in SSc. The main clinical
entities associated with small bowel involvement are
chronic intestinal pseudo-obstruction (CIPO), pneumato-
sis cystoides intestinalis (PCI), small intestinal bacterial
overgrowth (SIBO) and jejunal diverticula. The small
intestine in SSc patients is dilated, and displays increased
stiffness and decreased muscle contractility.67 Small intes-
tine manometry shows abnormalities or absence of phase
III MMC and post-cibal small-bowel hypomotility.68
Patients have a wide variety of symptoms including nau-
sea, vomiting, bloating, abdominal distension/pain, diar-
rhoea or systemic symptoms secondary to malabsorption.

Figure 6 | Upper GI
endoscopy in SSc. (a)
Oesophageal stricture, (b)
Barret’s oesophagus, (c)
GAVE. Adapted from Watson
et al.62 (a) (b) (c)

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S. Kumar et al.
Pseudo-obstruction in SSc may be acute or chronic.69
Dilatation, atony and delayed transit of the small intestine
pre-dispose to pseudo-obstruction. Concomitant use of
opiates in SSc has an additive effect on delaying intestinal
transit. Intestinal stasis due to dysmotility predisposes to
SIBO that is present in up to 50% of SSc patients.70
Patients present with steatorrhea, weight loss and vitamin
and nutritional deficiencies. Studies have demonstrated
that SIBO contributes substantially to intestinal symptoms
and correlates with a high global digestive symptom
score.70, 71 PCI is a rare radiographic diagnosis charac-
terised by radiolucent cysts within the wall of the small
intestine caused by the presence of air in the submucosa
or subserosa.72 Impaired intestinal motility leading to bac-
terial overgrowth, ischaemic damage and mucosal atrophy
are thought to contribute to its pathogenesis. Usually
asymptomatic, these cysts can rupture occasionally and
cause benign spontaneous pneumo-peritoneum. As its
name implies, this condition is benign and should be trea-
ted conservatively with oxygen, antibiotics and bowel rest.
Jejunal diverticula are true diverticula that develop due to
protrusion of the intestinal wall at points of muscle atro-
phy. Although asymptomatic, they can sometimes perfo-
rate or lead to bacterial overgrowth.
Malnutrition. The prevalence of malnutrition in SSc is
reported to be 18–56% in different studies.73, 74
Although GIT pathology undoubtedly contributes to
malnutrition, cachexia from chronic inflammation is the
key mechanism for malnutrition in SSc patients as evi-
dent by studies demonstrating an association between
poor nutritional status and overall disease activity and
severity.74 Presence of malnutrition is a predictor of
shortened life survival with up to 4% deaths in SSc
attributed to it.73 As per the American Society of Par-
enteral and Enteral Nutrition, patients should be
screened for malnutrition when the SSc diagnosis has
been established and then annually, and those recognised
at risk should be closely monitored and treated
promptly.75 Parenteral nutrition is often the last resort in
patients with severe malnutrition. A trial of naso-enteral
feeding should be undertaken to determine tolerability
and benefit before a percutaneous endoscopic gastros-
tomy is performed. Percutaneous endoscopic jejunos-
tomy, which has the added benefit of reducing
pulmonary aspiration risk, should be considered in
patients with severe gastroparesis. In patients who can-
not tolerate this procedure or in those who have severe
intestinal involvement, long-term home parenteral nutri-
tion should be instituted.
890
Colon. Dysmotility, telangiectasia and diverticula are the
hallmarks of colonic involvement in SSc. Although colo-
nic involvement is often asymptomatic, it can clinically
manifest with abdominal distension, diarrhoea or chronic
constipation. Initially, dysmotility leads to constipation
that can be severe enough to cause faecal impaction or
even perforation of the large bowel requiring surgical
treatment. In advanced cases, the colon is dilated with
loss of haustrations. Diverticula are characteristically
described as ‘wide mouth’ as illustrated in Figure 5c and
generally are asymptomatic and not prone to diverticuli-
tis.
Anus. Anorectal involvement is present in 50–70% of
SSc patients.76 Patient’s symptoms include faecal impac-
tion, constipation, faecal incontinence, tenesmus or pain-
ful defecation. Faecal incontinence affects up to 40% of
patients in SSc and may be due to constipation with
overflow, rectal prolapse, internal anal sphincter dysfunc-
tion or reduced rectal compliance and capacity. In addi-
tion, diarrhoea resulting from small or large bowel
dysmotility and malabsorption can contribute to faecal
incontinence.77 The internal anal sphincter smooth mus-
cle is the main determinant of basal tone and contributes
to 80% of the resting anal pressure. Internal anal sphinc-
ter dysfunction secondary to neuropathy or myopathy is
thought to be the primary cause of faecal inconti-
nence.78, 79 The majority of patients have a thinned and
hyperechoic internal anal sphincter from SSc-related vas-
culopathy causing tissue atrophy but a sub-group of
patients may have a thick and hypoechoic pattern sec-
ondary to tissue fibrosis and excessive collagen deposi-
tion.80 Anal involvement in SSc is associated with
reduced anal sphincter resting pressure and compliance
with impaired rectoanal inhibitory reflex81 and normal
squeeze pressures. Similar to the manometric alterations
in the oesophagus, manometric anorectal abnormalities
in SSc may appear much before clinical symptoms
develop.78, 79
Liver. Primary biliary cholangitis (PBC) is the liver dis-
order most consistently reported in patients with SSc. Its
onset may precede or follow the diagnosis of SSc. The
association of PBC with Raynaud phenomenon is known
as Reynolds syndrome.82, 83 Compared to a prevalence
of 0.04% in the general population, the prevalence of
PBC has been reported to be 2–22% in patients with
SSc.84, 85 PBC is commonly associated with the limited
subset of SSc and anti-centromere antibody positivity.
However, up to 20% of SSc patients may harbor PBC
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 Review: gastrointestinal involvement in systemic sclerosis
screen antibodies (anti-mitochondrial, gp21 and sp100
antibodies) in the absence of liver disease.86 For
unknown reasons, PBC associated with SSc has a slower
progression to end stage liver disease and lower rate of
liver transplantation compared to patients with PBC
alone.87
Nodular regenerative hyperplasia (NRH), a rare cause
of noncirrhotic intrahepatic portal hypertension, has
been increasingly recognised in association with both
limited and diffuse SSc.88, 89 Several facts support this
observation. The pathogenesis of NRH, characterised by
obliterative changes in portal veins is similar to the
microvascular damage present in SSc.90 NRH has also
been associated with toxic oil syndrome an entity similar
to SSc.91 Moreover, a study of 35 liver biopsies of 30
patients with early PBC showed nodular hyperplastic
changes in 47% of specimens.92 Whether the association
of NRH to SSc is an effect modification due to PBC or
an epiphenomenon will have to be studied further. The
majority of patients with NRH are asymptomatic and
therefore a high index of suspicion in the SSc population
is essential to identify patients who may develop portal
hypertension.90
Autoimmune hepatitis,93 idiopathic portal hyperten-
sion, and primary sclerosing cholangitis are the other
liver diseases that have been reported in patients with
SSc. Owing to the autoimmune nature of SSc, some
patients may harbor anti-liver kidney microsomal anti-
bodies (anti-LKM) or anti-smooth muscle antibodies
(anti-SMA) in the absence of liver disease.94
Pancreas. Clinical evidence of pancreatic involvement in
SSc is rare. However, although usually attributed to
SIBO, malabsorption in SSc can also be caused by exo-
crine pancreatic insufficiency.95 Case reports of fatal pan-
creatic infarction and acute haemorrhagic pancreatitis
secondary to occlusion of medium-sized pancreatic arter-
ies in SSc, have been described as well.96
SSc GIT involvement: outcome measurements
The construction of validated questionnaires that corre-
late patient symptoms to objective assessment of disease
has been a major development in the last decade. The
initial GIT-targeted health-related quality of life instru-
ment known as Scleroderma Gastrointestinal Tract 1.0
(SSC-GIT 1.0) instrument97 was revised in 2009 to a
much shorter 34-item instrument that was termed
‘University of California, Los Angeles Scleroderma Clini-
cal Trial Consortium GIT 2.0 (UCLA SCTC GIT 2.0)’.98
The UCLA SCTC GIT 2.0 instrument retained 33 items
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from the SSC-GIT 1.0 and added 1 item for faecal soi-
lage (to assess rectal incontinence), and split the reflux/
indigestion scale into reflux and distention/bloating. Each
item in this scale is scored on a 0–3 range, with lower
values indicating better health related quality of life. This
scale has the added advantage of calculating the total
GIT score, which correlates with the overall burden of
GI disease in SSc patients.
Recently an initiative by the National Institutes of
Health has lead to the development of the Patient-
Reported Outcomes Measurement Information System
(PROMIS) GI symptom item bank containing 60 items
that capture 8 GI-specific symptom scales.99 Compared to
GIT 2.0, the PROMIS GI bank has additional scales for
disrupted swallowing and nausea/vomiting. A recent study
comparing PROMIS to the legacy instrument GIT 2.0 in
SSc revealed large correlation and demonstrated satisfac-
tory reliability amongst the two scales.100 PROMIS instru-
ments have an added advantage of reduction in
respondent burden, easy comprehensibility and usability
across diverse populations.
SSc GIT involvement: diagnosis and treatment
Diagnosis and management of GIT disease requires a col-
laborative and multidisciplinary approach.101 Once a
rheumatologist confirms the diagnosis of SSc, the patient
should be referred to a gastroenterologist even in the
absence of GI symptoms.102 Consultation with an oral sur-
geon should be obtained as well. Patients with GI symp-
toms should undergo annual screening to detect
malnutrition. Typical radiological, serological, endoscopic
and manometric findings assist in establishing a diagnosis
and detecting complications (Tables 1 and 2). Adverse
effects related to long-term use of proton pump inhibitors
should be closely monitored. The role of social and psy-
chological factors should not be ignored, as they might be
the cause rather than effect of some of the symptoms.
Treatment of GIT manifestations in SSc is symp-
tomatic and consists of acid reducing therapy, intermit-
tent or cyclic administration of antibiotics of different
classes and use of pro-kinetic agents (Table 3). Currently,
there are no disease modifying drugs for this devastating
complication of SSc as limited knowledge about patho-
genesis and lack of appropriate animal models of GIT
SSc has hampered development of new therapies. Early
diagnosis and identification of patients at high risk is cru-
cial, as once fibrosis ensues, dysmotility might become
irreversible. Immunosuppressive drugs that target pro-
fibrotic cytokines and IVIG offer hope for treatment of
GIT involvement in SSc. IVIG could potentially have
891
S. Kumar et al.

Table 1 | Diagnosis of GIT involvement in systemic sclerosis

Disease manifestation Clinical symptoms Diagnostic modality Comments

Secondary Sjogren’s Dry mouth Anti-ro and anti-la antibodies Rule out primary Sjogren’s
Mandibular resorption Difficult mastication Whole sialometry syndrome and other autoimmune
Salivary gland scintigraphy diseases
Salivary gland imaging  biopsy Early dental consult
Mandibular radiography Oral surgeon consult
Dysmotility Dysphagia Modified barium swallow Rule out pill oesophagitis/candida
Oesophageal stricture OGD oesophagitis
Oesophageal manometry
Impedance monitoring
Endoscopic ultrasound
GAVE Anaemia EGD GAVE can precede diagnosis of SSc
GI bleed
GERD Heartburn, reflux EGD Monitor for ILD
Barrett’s oesophagus Nocturnal cough pH monitoring Gastroparesis exacerbates GERD
Adenocarcinoma Asthma Oesophageal manometry
Capsule endoscopy
Gastric emptying study
Gastroparesis Early satiety Gastric emptying study Rule out SIBO if symptoms
Abdominal bloating Antroduodenal manometry overlap with gastoparesis
Abdominal distension Electrogastrography
Post-prandial fullness, Gastric emptying breath test
Weight loss Single photon emission CT
Flatulence
SIBO Diarrhoea Stool culture Rule out Clostridium
Pancreatic exocrine Steatorrhea Lactulose breath test difficile
insufficiency Jejunal aspirate/culture Measure fat soluble vitamin levels
Qualitative faecal fat
Quantitative 72 h faecal fat
pancreatic function tests
Colonic dysmotility Constipation Plain abdominal radiograph
CIPO Abdominal distension CT scan abdomen
Small intestinal manometry
Smart pill/radio opaque markers
Scintigraphy
IAS dysfunction Faecal incontinence Rectoanal manometry
Rectal prolapse Ballon expulsion test
Defecography
Telangiectasia Anaemia Colonoscopy
Capsule endoscopy
Balloon assisted and spiral
enteroscopy
PBC Abnormal liver function Autoimmune screen (AMA) Test for sp100 antibody in patient
tests Liver biopsy with negative AMA

AMA, anti-mitochondrial antibody; CIPO, chronic intestinal pseudo-obstruction; EGD, esophagogastroduodenoscopy; GAVE, gas-
tric antral vascular ectasia; GERD, gastro oesophageal reflux disease; IAS, internal anal sphincter; ILD, interstitial lung disease;
PBC, primary biliary cholangitis; SIBO, small intestinal bacterial overgrowth.

multiple beneficial effects in SSc not only by anti-idioty-
pic mediated neutralisation of muscarinic autoantibodies
but also by causing reduction in pro-fibrotic cytokines or
by counteracting the deleterious effects of anti-fibroblast
or anti-endothelial cell circulating antibodies. IVIG is rel-
atively safe compared to immunosuppression and has
been shown to be beneficial in halting progression of GI
symptoms in observational studies and to reverse cholin-
ergic dysfunction induced by M3-R autoantibodies
in vivo.29, 30, 103–105 Targeting miR-29 by anti-miRs,
which are chemically modified oligonucleotides, is
another promising therapeutic option in the future.46, 106
However, rigorous studies are needed before patients can
be benefited from these novel interventions.

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 Review: gastrointestinal involvement in systemic sclerosis

Table 2 | Clinical, manometric and radiological features of GIT involvement in systemic sclerosis

Organ Early Advanced Manometric Features Radiology

Oral cavity Secondary Sjogren’s Mandibular resorption
Perioral tethering
Oesophagus Dysmotility Stricture Oesophageal manometry: Modified Barium swallow:
GERD Barret’s oesophagus Decreased LES pressure Dilatation and shortening
Reflux oesophagitis Adenocarcinoma Reduced amplitude and/or of oesophagus
absent oesophageal peristalsis Patulous LES
in distal 2/3 Absence of primary
Prolonged oesophageal peristaltic waves
transit time Strictures
Saccular diverticulae
Impedance planimetry:
Increased cross-sectional area
Abnormal bolus transit
Normal distensibility
Stomach GAVE Severe gastroparesis Antroduodenal manometry: Scintigraphy:
Gastritis Malnutrition Decreased frequency and Tonic contractile
Gastric ulcers GAVE amplitude of phase I and dysfunction of proximal
II MMC stomach
Antroduodenal in
Electrogastrography: coordination
Normal slow waves replaced Delayed gastric emptying
with bradygastria or tachygastria of liquids and solids
Reduced post-prandial increase
in slow wave amplitude
Pancreas Pancreatic exocrine
insufficiency
Small intestine Telangiectasia Telangiectasia Abnormal propagation, decreased Mega-duodenum
Dysmotility Jejunal diverticula frequency with low amplitude Hide-bound appearance
PCI SIBO phase III MMC
Malnutrition
Colon Dysmotility Wide mouth diverticula Absent colonic contractions Dilatation
Constipation CIPO Decreased or absent spike Wide mouth diverticula
Megacolon activities in mucosal Loss of haustrations
myoelectrical recordings Prolonged colonic transit
Pneumatosis cystoides
intestinalis
Ano-rectum Tenesmus Faecal incontinence Rectoanal manometry: Endoanal MR imaging:
Reduced anal resting pressure Atrophy and forward
Normal squeeze pressure bucking of anterior
Absent RAIR part of IAS
Impaired ano-rectal sensation Slow gladolinium
enhancement
CIPO, chronic intestinal pseudo-obstruction; GAVE, gastric antral vascular ectasia; GERD, gastro esophageal reflux disease; LES,
lower esophageal sphincter; MMC, migrating motor complex; PCI, pneumatosis cystoides intestinalis; RAIR, rectoanal inhibitory
reflex; SIBO, small intestinal bacterial overgrowth.

CONCLUSION pathological, cellular and molecular changes in the GIT.

Gastrointestinal tract involvement is the most common
noncutaneous organ system involved in SSc and is asso-
ciated with substantial morbidity and mortality. Our cur-
rent understanding of the pathogenesis and treatment of
this entity is still far from complete, owing to the limited
number of studies that have focused on histo-
Autoantibody-mediated dysmotility offers a new avenue
for further research into the pathogenesis and treatment
of GI SSc. Moreover, there is lack of non-invasive tests
or biomarkers, which can identify patients who are at
high risk for development of GIT manifestations. Early
identification and symptomatic treatment of patients is

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S. Kumar et al.

Table 3 | Treatment of GIT Involvement in systemic sclerosis

Disease manifestation Treatment Comments

Oral cavity
Reduced oral aperture Maintain oral hygiene Mechanical soft food
Early consultation with dentist Small bolus size

Dry mouth Artificial saliva Generous liquids

Cholinergic agonist (pilocarpine)
Oesophagus
GERD Step wise increase in PPI dose until patient Small meals
asymptomatic and/or resolution of acid reflux Weight reduction
on pH studies Avoid alcohol, smoking
Add nocturnal H2-receptor antagonists in patients Elevate head of bed while sleeping
who are not responsive to high dose PPI Avoid large meals/exercise before bedtime
Combine with pro-kinetics
Dysmotility Prokinetics Avoid calcium channel blockers and
Cisapride: Increases LES pressure and distal anti-cholinergics
oesophageal contraction –
Metoclopramide: Increases LES pressure,
neurological side effects
Domperidone: No neurological side effects,
not approved in USA
Strictures Endoscopic dilatation
Treat GERD
Barrett’s oesophagus Treatment of underlying GERD
Regular surveillance endoscopy
Stomach
Gastroparesis Prokinetics: Low residue diet with frequent small meals
Metoclopramide: Improves antral contraction Treat GERD
Domperidone: Increases amplitude of gastric Erythromycin can decrease small intestinal
contractions, relaxes the pyloric sphincter motility
Cisapride: Increases fundic contractions, Gastric pacing
increases LES pressure
Erythromycin: Motilin-like action
PEG for drainage
Feeding jeunostomy
Parenteral nutrition
GAVE Iron infusion/blood transfusion
Endoscopic laser ablation
Argon plasma coagulation
IV cyclophosphamide in severe cases
Small intestine
CIPO Acute: Bowel rest, intravenous fluids
Octreotide  neostigmine
Chronic: Prokinetics Octreotide can delay gastric emptying
Metoclopramide: Improves both small bowel Surgery associated with poor healing and
and colonic motility severe ileus
Octreotide: Increases frequency of MMC
Cisapride: Increases duodenal contractions
and colonic transit
Prucalopride/domperidone
Parenteral nutrition
Colonic decompression/surgery
SIBO Cyclic antibiotics Treat secondary lactose intolerance
Probiotics Treat Clostridium difficile
Treat intestinal dysmotility
Vitamin supplementation for malabsorption

894 Aliment Pharmacol Ther 2017; 45: 883–898

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 Review: gastrointestinal involvement in systemic sclerosis

Table 3 | (Continued)
Disease manifestation Treatment Comments
PCI Watchful observation, oxygen, antibiotics
Jejunal diverticula No treatment Can pre-dispose to SIBO
Colon
Constipation Fluid ingestion Avoid high fiber diet and bulk forming
Osmotic laxatives: senna, lactulose, laxatives: can worsen constipation
bisacodyl, polyethylene glycol
Ano-rectum
FI Solidify stools with bulking agents Assess and treat psycho-social
Anti-diarrhoeals factors
Biofeedback: sphincter muscle training
Sacral nerve stimulation
Consultation with colorectal surgeon
Rectal Prolapse Surgery
Liver
PBC Ursodeoxycholic acid
Obetcholic acid
Consultation with hepatologist
Liver transplant
Pancreas
Exocrine pancreatic Pancreatic enzymes
insufficiency
CIPO, chronic intestinal pseudo-obstruction; FI, faecal incontinence; GAVE, gastric antral vascular ectasia; GERD, gastro esopha-
geal reflux disease; LES, lower esophageal sphincter; PBC, primary biliary cholangitis PCI, pneumatosis cystoides intestinalis; SIBO,
small intestinal bacterial overgrowth.

crucial until more targeted and effective disease-modify- of the data, designing of research study and in the writing of the
paper. All authors approved the final version of the manuscript.
ing therapeutic approaches become available. Improved
understanding of the pathogenesis of GIT manifestations
ACKNOWLEDGEMENT
of SSc employing focused and intensive cellular and
Declaration of personal interests: None.
molecular studies, research endeavours aimed at identifi-
Declaration of funding interests: The work was supported
cation of novel disease biomarkers, and extensive efforts
by grant number RO1-DK-035385 from the National
to develop personalised medical therapies should allow
Institutes of Diabetes and Digestive and Kidney Diseases,
achieving these goals in the near future.
an industrial support from CSL Behring, King of Prussia,
PA, and an institutional grant from Thomas Jefferson
AUTHORSHIP
University to SR.
Guarantor of the article: Sumit Kumar.
The authors declare no conflict of interest.
Author contributions: All authors contributed equally towards all
elements of the work in performing research, collecting and analysis

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