Download Gastrointestinal complications: the most frequent

Rheumatology 2008;48:iii36–iii39
doi:10.1093/rheumatology/ken485
Gastrointestinal complications: the most frequent internal
complications of systemic sclerosis
A. Forbes1 and I. Marie2
Manifestations of SSc in the gastrointestinal (GI) tract are common, occurring in 50–90% of patients. They typically result from the fibrosis that
characterizes this disease. Manifestations of SSc can affect many sites within the GI tract, and patients may experience substantial
dysfunction in the processes of motility, digestion, absorption and excretion. Oesophageal dysfunction is the most common GI manifestation,
but patients may also experience dysfunction of the stomach, small intestine, colon and rectum, each of which can be responsible for severe
and distressing symptoms. At present, few specific therapeutic options are available for the treatment of these patients, but relief of symptoms
is often possible with appropriate knowledge and support. It is therefore particularly important to identify, monitor and manage these patients
carefully, with a view to minimizing further degeneration and maximizing quality of life.
KEY
WORDS:
Gastrointestinal tract, Oesophagus, Stomach, Small intestine, Large intestine, Rectum, Anus, Systemic sclerosis.
well understood, oesophageal manifestations of SSc may not
always be symptomatic, but early diagnosis remains important as
delay increases the risk of complications. Moreover, the incidence
of severe oesophageal motor impairment may correlate with that
of interstitial lung disease (ILD), one of the leading causes of
death in SSc patients [10, 15, 16].
Introduction
The gastrointestinal (GI) tract is primarily responsible for the
processes of digestion and excretion, and is frequently affected by
manifestations of SSc [1]. The excessive fibrosis, inflammation and
vascular dysfunction characteristic of SSc is seen also in the GI
tract, and it is thought that GI impairment in affected patients
results from progressive histological lesions similar to those found
in other organs. Sjögren proposed a progression of sclerodermatous GI involvement: vascular damage (grade 0), neurogenic
impairment (grade 1) and myogenic dysfunction (grade 2) with the
replacement of normal smooth muscle by collagenous fibrosis and
atrophy [2]. It is the fibrotic aspect of this disease that is mainly
reported to underlie GI manifestations in SSc patients [3].
The GI tract is possibly the second most common site of SSc
organ damage, and can affect patients with lcSSc and dcSSc [1].
Manifestations of SSc can impair the function of many parts of
the GI tract, affecting motility, digestion, absorption and
excretion. GI manifestations of SSc can be severe, causing patients
to experience symptoms including pain, dysphagia, vomiting,
diarrhoea, constipation, faecal incontinence and substantial
weight loss. GI manifestations of SSc impact severely on prognosis and quality of life (QoL), and are associated with reduced
survival. The mortality rate attributable to GI involvement is
reported to be 6–12% [4–9].
Any site within the GI tract can be affected by SSc. Although
the oesophagus is most frequently implicated, it is disease at other
sites that is responsible for the more serious morbidity and death
[10–12]. In this article, we discuss the individual implications of
oesophageal, gastric, intestinal and rectal manifestations of SSc
and current diagnostic and treatment strategies.
Gastro-oesophageal reflux
Oesophageal dysfunction in SSc typically manifests within the
lower two-thirds of the oesophagus as a weakened lower
oesophageal sphincter and with profound loss of peristaltic
action [11, 17]. Patients may also experience uncoordinated
oesophageal motility or complete oesophageal paralysis, leading
to high morbidity [18]. Such dysfunction permits pathological
reflux of acidic gastric contents into the oesophagus, which is
more damaging still because of the poor antegrade motility
leading to it being improperly cleared [2, 17]. Oesophageal damage
resulting from gastric reflux may initially manifest as simple peptic
oesophagitis progressing to erosive oesophagitis, bleeding and
frank ulceration. If untreated, peptic stricture formation, fistulae
and an achalasia-like syndrome may occur. It is probable that
these features lead the affected SSc patient to a high risk of
Barrett’s oesophagus [2].
The routine screening of SSc patients for oesophageal
abnormalities during initial evaluation is therefore recommended.
The presence and severity of oesophageal involvement can be
determined from the combination of upper GI endoscopy,
ambulatory pH studies and oesophageal manometry, which
together facilitate decision-making in treatment and management.
In order to manage gastro-oesophageal reflux in SSc patients,
behavioural modifications (such as smoking cessation, elevation
of the head of the bed, avoiding eating in the hours before retiring)
are generally recommended, in addition to long-term, high-dose
proton pump inhibition (PPI) to reduce gastric acid secretion from
the parietal cells [10].
Oesophageal manifestations
Normal oesophageal function is estimated to be affected in
70–90% of patients with GI manifestations of SSc [1, 2, 13, 14].
Symptoms of oesophageal dysfunction typically include dysphagia, poor eating, heartburn and nausea or vomiting, which
can lead to severe weight loss. For reasons that are not
Barrett’s oesophagus and oesophageal adenocarcinoma
Chronic gastro-oesophageal reflux in SSc patients can be
complicated by Barrett’s oesophagus. Barrett’s oesophagus is a
disorder in which the normal stratified squamous epithelial lining
of the distal oesophagus undergoes metaplasia, with normal
epithelial cells being replaced by an abnormal columnar epithelium including goblet cells (Fig. 1) [10, 11, 17–21]. Barrett’s
oesophagus is thought to be relatively common in patients with
oesophageal manifestations of SSc, with an estimated incidence of
6.8–12.7% compared with the population risk of <1% [10, 11, 17].
1
Department of Gastroenterology and Nutrition, University College Hospital,
London, UK and 2Department of Internal Medicine, Rouen University Hospital,
Rouen, France.
Submitted 20 May 2008; revised version accepted 1 December 2008.
Correspondence to: A. Forbes, Department of Gastroenterology and
Nutrition, Maple House, University College Hospital, 235 Euston Road, London
NW1 2BU, UK. E-mail: [email protected]
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ß The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
Gastrointestinal manifestations in SSc
iii37
Gastric manifestations
The gastric manifestations of SSc include severe bleeding from
vascular ectasia, and, more commonly, an electrophysiological
dysfunction that leads mainly to delayed gastric emptying,
contributing in turn to gastro-oesophageal reflux [12, 28, 29].
Gastric pathology is associated with increased morbidity and
mortality [10–12].
Delayed gastric emptying
FIG. 1. Endoscopic appearance of long-segment Barrett’s oesophagus. The
metaplastic columnar epithelium contrasts with the normal, pale appearance of
the squamous lining. Image reproduced with permission from the BMJ Publishing
group [21].
The abnormal epithelium in Barrett’s oesophagus typically
exhibits DNA damage, and when the histological characteristics
have intestinal (rather than gastric) features there is evidence that
there is an increased risk of subsequent oesophageal adenocarcinoma [22, 23]. Although this increased incidence is now
established in the general population, there are few data specific
to SSc and conclusions must be more guarded. The prevalence of
oesophageal adenocarcinoma in SSc patients with GI manifestation has been estimated by three groups to be low. There are many
differences, however, between SSc patients with Barrett’s oesophagus and those in the general population, not least the high
risk of premature death from other manifestations of SSc, given
that Barrett’s cancers are rare in those under the age of 50 yrs
[10, 17, 24]. Conversely, one retrospective analysis suggested that
SSc patients with severe symptoms of Barrett’s oesophagus may
be at greater risk of oesophageal adenocarcinoma [25]. Another
study compared the incidence of cancer in SSc patients with the
Surveillance Epidemiology and End Results cancer registries,
concluding that SSc patients were at significantly greater risk of
oesophageal cancer (not specifically Barrett’s oesophagus) and
oropharyngeal cancers than the general population [26].
Cautious management of SSc patients with Barrett’s oesophagus is therefore recommended, and will be based mainly on
treatments for the underlying gastro-oesophageal reflux [21]. The
American College of Gastroenterology recommends that patients
with Barrett’s oesophagus undergo regular surveillance endoscopies, and in SSc patients who develop Barrett’s oesophagus,
screening by endoscopy every 2–3 yrs is recommended if no
dysplasia is present [21, 27]. If low-grade dysplasia is present,
endoscopic screening should be performed at least annually.
In those with high-grade dysplasia serious attention should be
given to non-operative therapies in patients who (because of
other elements of their SSc) are unsuited to oesophageal resection
[10, 27]. Photodynamic therapies and other endoscopically
delivered options are increasingly validated in the non-SSc patient
with high grade dysplasia, and may be effective even when frank
malignancy has supervened and the tumour is inoperable.
Gastric involvement in SSc can lead to significant delay in
emptying, particularly of solids, and this is most likely in patients
with abnormal oesophageal motility and in those with dcSSc
[29–31]. Delayed gastric emptying can result in complete food
intolerance and increased severity of gastro-oesophageal reflux
[29–31]. Delayed gastric emptying can usually be diagnosed by
electrogastrographic recordings or else from scintigraphic evaluation following a radiolabelled meal [29–31]. Current therapeutic
strategies are usually based on pro-motility agents such as
metoclopramide and domperidone, which can increase the tone
and amplitude of gastric contractions, and relax the pyloric
sphincter [30]. Beneficial effects of low-dose erythromycin have
also been demonstrated in SSc patients with prokinetic-resistant,
severely delayed gastric emptying, an effect that comes from its
motilin-like properties and are independent of any anti-microbial
action [11]. In severely affected patients it can be useful to place a
wide-calibre percutaneous gastrostomy tube to permit intermittent
drainage, and thereby avoid or diminish the tendency to vomiting.
It is not inevitably the case that such a patient will require artificial
nutritional support at this stage, but there is clearly a major
overlap with those entering a phase of established intestinal failure
(see below), and in the relatively early stages during which
gastrostomy may be used either for feeding or for drainage
according to the clinical priorities of a given day.
Gastric antral vascular ectasia
Some SSc patients with gastric manifestations may experience
frank haemorrhage or iron-deficiency anaemia from gastric antral
vascular ectasia (GAVE). GAVE, also known as ‘watermelon
stomach’, has a unique endoscopic appearance that is characterized by multiple, parallel longitudinal columns of red vessels
within the gastric antrum radiating to the pylorus, resembling the
stripes on a watermelon (Fig. 2) [32, 33]. GAVE is a key cause of
chronic, GI bleeding in SSc patients, and in some cases may be an
early manifestation; its aetiology remains unclear [11, 29, 34, 35].
For SSc patients with GAVE, therapeutic strategies have
usually included blood transfusion, iron supplementation and,
occasionally, antrectomy [36, 37]. More recent reports have
suggested that endoscopic laser ablation can be effective in as
many as 75% of cases [38–40]. The simpler and safer laser
technique of argon plasma coagulation (APC) offers an additional
option, although experience of this technique is still limited [33].
Intestinal manifestations
SSc can also affect the small and large intestine, including
the rectum and the anus. Involvement of the small intestine
causes malabsorption, sometimes in conjunction with pseudoobstructions, and can lead to severe malnutrition [12, 28].
Reduced blood flow within the small intestine may also contribute
to impaired nutrient absorption [41]. Colonic manifestations can
include diarrhoea, faecal incontinence and haemorrhage.
Small intestinal manifestations
Malabsorption syndrome typically occurs in SSc as a result of
bacterial overgrowth, which is in turn usually the consequence of
impaired motility. Following diagnosis (from endoscopic sampling or from hydrogen breath test) it will often initially respond
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A. Forbes and I. Marie
Sadly, the progressive nature of SSc may ultimately lead to
advanced intestinal failure. For these patients, intravenous
nutrition (IVN) is often required, administered using fairly
standard regimens but with relatively low volume and low
sodium, usually for 4 or 5 days/week. The short-term outcome
in patients treated with IVN can be good, but the advent of
intestinal failure appears to be a marker of poor long-term
outcome, most such patients succumbing within 2 yrs from the
more directly fatal consequences of SSc affecting other body
systems.
Colonic scleroderma
FIG. 2. Endoscopic image of GAVE, revealing multiple longitudinal stripes of red
vessels, limited to the gastric antrum and radiating in a spoke-like fashion from the
pylorus to the antrum. Image reproduced with permission from the Japanese
Society of Internal Medicine [33].
well to antibiotics. Unfortunately the response is rarely prolonged
and subsequent courses are rarely as effective as the first. The
small intestinal hypomotility may provoke luminal dilatation and
overt pseudo-obstructions. It is probable that this is the result
of abnormal collagen deposition as in the oesophagus but there
are fewer histological data. The net result is pain and food
intolerance, together with abdominal distension, and leads to
diarrhoea, and the risk of profound malnutrition [2, 28, 42].
The therapeutic options are essentially supportive, but simple
agents acting on motility can make huge differences initially
[12]. For patients who experience repeated intestinal pseudoobstruction, octreotide therapy (50 mg/day, subcutaneously) may
offer a relevant option, although experience of this treatment is
still limited. Indeed, such octreotide regimens have been reported
to induce Phase III-like migrating motor complexes, the normal
electrophysiological phenomena by which the peristaltic wave
is conducted in a co-ordinated fashion along the small intestine
[11, 28, 42].
Previous authors have suggested that small bowel manometry
should be performed to assist in the selection of symptomatic
SSc patients with intestinal pseudo-obstruction who may benefit
from octreotide therapy. These data may result in improvement of patients’ management and reduction of medical costs
(as octreotide is an expensive therapy) [28, 42]. The use of small
bowel manometry has also been proposed as a means to avoid
unnecessary initiation of octreotide therapy. Although octreotide
therapy is considered as a safe medication, it may be responsible
for severe adverse effects, such as intestinal perforation due to
octreotide-associated increased small bowel intraluminal pressure [28, 42]. Octreotide should accordingly be used with caution
in SSc.
Patients with severe small intestinal manifestations losing their
response to antibiotics are often helped by overnight tube feeding.
In most cases it will be more convenient and acceptable for the
patient if a percutaneous gastrostomy device is placed, but some
patients prefer to self-intubate with a fine-bore nasogastric tube
each evening. The latter is a very safe technique if (once in the
posterior pharynx) the tube is actively swallowed without the use
of a guidewire, which could permit its steered passage towards the
respiratory tract.
The early phases of colonic SSc are associated with constipation
from delayed intestinal transit. However, it is unusual for this to
persist, as parallel small intestinal hypomotility and luminal
dilatation leads to bacterial overgrowth and diarrhoea.
Colonic telangiectasiae are common in SSc and may bleed
overtly or be responsible for anaemia. Pseudodiverticula are
common but probably incidental, and patients may experience
troublesome rectal prolapse in a context in which surgical repair is
relatively contraindicated. Apart from the concerns in respect of
major co-morbidity in SSc, reconstructive GI surgery has a strong
tendency for slow and generally poor healing, which may be
linked to abnormalities of the supportive connective tissues.
Standard, bulk-forming, laxatives are helpful in the early constipated phases [40], and may also help in control of incontinence.
Collagen deposition in the rectum can lead to reduced rectal
compliance for some patients, and thus to anismus which can
appear to the patient as diarrhoea [40]. Urgency can be so
profound as to lead to incontinence that is only partially
responsive to opioids such as loperamide. ‘Watermelon rectum’
is also described in SSc (with GAVE in one published case [43]).
Rectal haemorrhage can then be managed with endoscopic
therapy using laser ablation or APC [43].
Anal scleroderma
Faecal incontinence reportedly affects 38% of SSc patients and in
many of these the principal pathology lies in the anal canal [40].
Connective tissue deposition and loss of the internal anal
sphincter are usually implicated; this can be detected at anal
endosonography [44]. For these patients, sphincter muscle training
can be beneficial, but when this is insufficient sacral nerve
stimulation may prove a much more acceptable solution than
creation of a defunctioning stoma [45]. Pilot studies suggest that
this technique may induce beneficial clinical effects, and can
abolish incontinence in some patients [45].
Conclusion
GI manifestations of SSc are common and widespread. Their
effects on prognosis, morbidity, mortality and QoL can be
substantial. While a number of therapeutic strategies exist, their
limitations and the progressive nature of the disease can mean that
their impact is both incomplete and short term.
The management of patients with SSc should therefore follow a
multidisciplinary approach, and include regular monitoring for
the development or progression of GI manifestations. It is
probable that earlier detection and treatment of GI disease will
reduce the risk of further complications, such as Barrett’s
oesophagus and malnutrition. There are clear needs for further
research into both pathogenesis and future therapeutic options.
Rheumatology key messages
SSc commonly affects many parts of the GI tract.
GI manifestations result from the characteristic fibrosis of SSc and
can impair motility, digestion, nutrient absorption and excretion.
Gastrointestinal manifestations in SSc
Acknowledgements
The authors received editorial assistance from Elements
Communications, supported by an educational grant from
Actelion Pharmaceuticals Limited (Allschwil, Switzerland).
A.F. is supported by the Comprehensive Biomedical Research
Centre of University College Hospital and University College
London.
Supplement: This paper forms part of the supplement entitled
‘Ten years of partnership: translating ideas into progress in
systemic sclerosis’. This supplement was supported by an unrestricted grant from Actelion Pharmaceuticals Ltd.
Disclosure statement: The authors have declared no conflicts of
interest.
References
1 Clements PJ, Becvar R, Drosos AA, Ghattas L, Gabrielli A. Assessment of
gastrointestinal involvement. Clin Exp Rheumatol 2003;21:S15–8.
2 Sjögren RW. Gastrointestinal motility disorders in scleroderma. Arthritis Rheum
1994;37:1265–82.
3 Denton CP, Black CM, Abraham DJ. Mechanisms and consequences of fibrosis in
systemic sclerosis. Nat Clin Pract Rheumatol 2006;2:134–44.
4 Altman RD, Medsger TA Jr, Bloch DA, Michel BA. Predictors of survival in systemic
sclerosis (scleroderma). Arthritis Rheum 1991;34:403–13.
5 Lee P, Langevitz P, Alderdice CA et al. Mortality in systemic sclerosis (scleroderma).
Q J Med 1992;82:139–48.
6 Medsger TA Jr, Masi AT, Rodnan GP, Benedek TG, Robinson H. Survival with
systemic sclerosis (scleroderma). A life-table analysis of clinical and demographic
factors in 309 patients. Ann Intern Med 1971;75:369–76.
7 Hesselstrand R, Scheja A, Akesson A. Mortality and causes of death in a Swedish
series of systemic sclerosis patients. Ann Rheum Dis 1998;57:682–6.
8 Jacobsen S, Ullman S, Shen GQ, Wiik A, Halberg P. Influence of clinical features,
serum antinuclear antibodies, and lung function on survival of patients with systemic
sclerosis. J Rheumatol 2001;28:2454–9.
9 Scussel-Lonzetti L, Joyal F, Raynauld JP et al. Predicting mortality in
systemic sclerosis: analysis of a cohort of 309 French Canadian patients with
emphasis on features at diagnosis as predictive factors for survival. Medicine
2002;81:154–67.
10 Marie I, Ducrotte P, Denis P, Hellot MF, Levesque H. Oesophageal mucosal
involvement in patients with systemic sclerosis receiving proton pump inhibitor
therapy. Aliment Pharmacol Ther 2006;24:1593–601.
11 Marie I. Atteinte digestive au cours de la sclérodermie systémique. Presse Med
2006;35:1952–65.
12 Sallam H, McNearney TA, Chen JD. Systematic review: pathophysiology and
management of gastrointestinal dysmotility in systemic sclerosis (scleroderma).
Aliment Pharmacol Ther 2006;23:691–712.
13 Poirier T, Rankin M. Gastrointestinal manifestations of progressive
systemic scleroderma based on a review of 364 cases. Am J Gastroenterol
1972;58:30–44.
14 Turner R, Lipshutz W, Miller W, Rittenberg G, Schumacher HR, Cohen S.
Oesophageal dysfunction in collagen disease. Am J Med Sci 1973;265:191–9.
15 Steen V. Pulmonary arterial hypertension in systemic sclerosis: risk factors and
diagnosis. Scleroderma Care Res 2006;3:14–22.
16 Marie I, Dominique S, Levesque H et al. Esophageal involvement and pulmonary
manifestations in systemic sclerosis. Arthritis Rheum 2001;45:346–54.
17 Wipff J, Allanore Y, Soussi F et al. Prevalence of Barrett’s esophagus in systemic
sclerosis. Arthritis Rheum 2005;52:2882–8.
18 Ntoumazios SK, Voulgari PV, Potsis K, Koutis E, Tsifetaki N, Assimakopoulos DA.
Esophageal involvement in scleroderma: gastroesophageal reflux, the common
problem. Semin Arthritis Rheum 2006;36:173–81.
iii39
19 Recht MP, Levine MS, Katzka DA, Reynolds JC, Saul SH. Barrett’s esophagus in
scleroderma: increased prevalence and radiographic findings. Gastrointest Radiol
1988;13:1–5.
20 Spechler SJ. Barrett’s esophagus. N Engl J Med 2002;346:836–42.
21 Spechler SJ. Managing Barrett’s oesophagus. Br Med J 2003;326:892–4.
22 Heath EI, Limburg PJ, Hawk ET, Forastiere AA. Adenocarcinoma of the esophagus:
risk factors and prevention. Oncology 2000;14:507–14.
23 Wong DJ, Paulson TG, Prevo LJ et al. p16(INK4a) lesions are common, early
abnormalities that undergo clonal expansion in Barrett’s metaplastic epithelium.
Cancer Res 2001;61:8284–9.
24 Segel MC, Campbell WL, Medsger TA, Roumm AD. Systemic sclerosis (scleroderma) and esophageal adenocarcinoma: is increased patient screening necessary? Gastroenterology 1985;89:485–8.
25 Katzka DA, Reynolds JC, Saul SH et al. Barrett’s metaplasia and adenocarcinoma of
the esophagus in scleroderma. Am J Med 1987;82:46–52.
26 Derk CT, Rasheed M, Artlett CM, Jimenez SA. A cohort study of cancer incidence in
systemic sclerosis. J Rheumatol 2006;33:1113–6.
27 Sampliner RE. The Practice Parameters Committee of the American College of
Gastroenterology. Updated guidelines for the diagnosis, surveillance, and therapy of
Barrett’s esophagus. Am J Gastroenterol 2002;97:1888–95.
28 Marie I, Ducrotte P, Denis P, Hellot MF, Levesque H. Outcome of small-bowel motor
impairment in systemic sclerosis: a prospective manometric 5-yr follow-up.
Rheumatology 2007;46:150–3.
29 Marie I, Levesque H, Ducrotté P et al. Gastric involvement in systemic sclerosis: a
prospective study. Am J Gastroenterol 2001;96:77–83.
30 Sridhar KR, Lange RC, Magyar L, Soykan I, McCallum RW. Prevalence of impaired
gastric emptying of solids in systemic sclerosis: diagnostic and therapeutic
implications. J Lab Clin Med 1998;132:541–6.
31 Franck-Larsson K, Hedenström H, Dahl R, Rönnblom A. Delayed gastric emptying
in patients with diffuse versus limited systemic sclerosis, unrelated to gastrointestinal symptoms and myoelectric gastric activity. Scand J Rheumatol
2003;32:348–55.
32 Jabbari M, Cherry R, Lough JO, Daly DS, Kinnear DG, Goresky CA. Gastric
antral vascular ectasia: the watermelon stomach. Gastroenterology 1984;87:
1165–70.
33 Shibukawa G, Irisawa A, Sakamoto N et al. Gastric antral vascular ectasia (GAVE)
associated with systemic sclerosis: relapse after endoscopic treatment by argon
plasma coagulation. Intern Med 2007;46:279–83.
34 Carbone LD, McKown KM, Hilaire RJ, Dean PJ, Kaplan SB. Scleroderma and the
watermelon stomach. Ann Rheum Dis 1996;55:560–1.
35 Marie I, Cailleux N, Levesque H. Watermelon stomach and systemic sclerosis:
localization of digestive system involvement? Arthritis Rheum 1996;39:1439.
36 Sebastian S, O’Morain CA, Buckley MJ. Review article: current therapeutic
options for gastric antral vascular ectasia. Aliment Pharmacol Ther 2003;18:157–65.
37 Lorenzi AR, Johnson AH, Davvies G, Gough A. Gastric antral vascular ectasia in
systemic sclerosis: complete resolution with methylprednisolone and cyclophosphamide. Ann Rheum Dis 2001;60:796–8.
38 Calamia KT, Scolapio JS, Viggiano TR. Endoscopic YAG laser treatment of
watermelon stomach (gastric antral vascular ectasia) in patients with systemic
sclerosis. Clin Exp Rheum 2000;18:605–8.
39 Sargeant IR, Loizou LA, Rampton D, Tulloch M, Bown SG. Laser ablation of upper
gastrointestinal vascular ectasias: long term results. Gut 1993;34:470–5.
40 Trezza M, Krogh K, Egekvist H, Bjerring P, Laurberg S. Bowel problems in patients
with systemic sclerosis. Scand J Gastroenterol 1999;34:409–13.
41 Kaye SA, Seifalian AM, Lim SG, Hamilton G, Black CM. Ischaemia of the small
intestine in patients with systemic sclerosis: Raynaud’s phenomenon or chronic
vasculopathy? Q J Med 1994;87:495–500.
42 Marie I, Levesque H, Ducrotté P et al. Manometry of the upper intestinal tract
in patients with systemic sclerosis: a prospective study. Arthritis Rheum 1998;
41:1874–83.
43 Singh D, Shill M, Kaur H. The watermelon rectum. J Clin Gastroenterol
2001;33:164–6.
44 Daniel F, De Parades V, Cellier C. Abnormal appearance of the internal anal
sphincter at ultrasound: a specific feature of progressive systemic? Gastroenterol
Clin Biol 2005;29:597–9.
45 Kenefick NJ, Vaizey CJ, Nicholls RJ, Cohen R, Kamm MA. Sacral nerve stimulation
for faecal incontinence due to systemic sclerosis. Gut 2002;51:881–3.