Abstract
Objective . To assess the 5-yr course of small-bowel motor disorders, using manometry in patients with systemic sclerosis (SSc), and to investigate for an association between small-bowel motor dysfunction outcome and other clinical manifestations of SSc.
Methods . Fasting and post-prandial motor activity of the small-bowel was systematically assessed in eight consecutive patients with SSc, using 24 h manometry: initially and at 5-yr follow-up.
Results . At 5-yr follow-up, the eight SSc patients (100%) exhibited deterioration of small-bowel motor activity on manometry as follows: (1) more severe abnormalities of migrating motor complex phase III during the fasting period; (2) decreased median duodenal and duodeno-jejunal index during the post-prandial period; and (3) more frequent alterations of small-bowel motor activity in response to octreotide infusion. Furthermore, an association could be found between the deterioration of small-bowel motor function and pitting scars’ onset.
Conclusion . Our study underscores the rapid deterioration of small-bowel motor impairment in SSc patients (100%). It also highlights the usefulness of small-bowel manometry in symptomatic SSc patients in objectively defining both the characteristics and degree of motor impairment, which may influence the choice of medical treatment in patients, particularly octreotide therapy.
Introduction
Systemic sclerosis (SSc) is a systemic disorder affecting the skin and other organs, especially the gastrointestinal tract where lesions have led to impaired motility [ 3 , 1–6 ]. Oesophageal and anorectal motility abnormalities are frequent in SSc patients (70–95%) and have extensively been described [ 1–8 ]. Gastric and intestinal involvement is less recognized in SSc, occurring in as many as 40 to 88% of patients [ 5–10 ]. Furthermore, gastrointestinal involvement is recognized to be associated with great morbidity and mortality in SSc patients, leading to malabsorption and intestinal pseudo-obstruction [ 1 , 3 , 5–8 , 11–13 ]. Gastrointestinal disorders directly related to SSc have therefore been reported to be one of the most common causes of death, as 5–12% of patients die from intestinal complications [ 12–17 ]. In 709 SSc patients, Mayes et al . [ 15 ] have further found that the 10 yrs survival rate was lower in patients with gastrointestinal involvement compared with patients without (55 vs 75%).
Nevertheless, to date, no authors have yet evaluated the course of small-bowel motor impairment in SSc. Since small-bowel manometry has proven to be an accurate test to define both characteristics and degree of motor disturbances, we conducted this prospective study in SSc patients to: (i) assess the manometric course of motor dysfunction at 5-yr follow-up and (ii) evaluate whether the outcome of small-bowel motor abnormalities is associated with other clinical manifestations of SSc.
Patients and methods
Patient population
Eight consecutive patients with a definite diagnosis of SSc were included in the study. The criteria for the diagnosis of SSc were based on the American College of Rheumatology criteria [ 18 ]. All patients had undergone a small-bowel manometry during initial evaluation, with plans for systematic 5-yr follow-up. The study was approved by the local Medical Research Ethics Committee. Informed consent was obtained from all patients.
At 5-yr follow-up, patients underwent assessment of organ involvement to detect systemic complications, i.e.: (i) digital pitting scars; (ii) degree of skin involvement, as determined by the modified Rodnan score [ 19 ]; (iii) arthralgia/arthritis; (iv) pulmonary arterial hypertension (PAH), characterized by pulmonary arterial systolic pressure >40 mmHg at rest on echocardiography; and (v) interstitial lung disease (ILD).
Digestive symptoms
SSc patients were assessed for digestive symptoms consistent with intestinal dysfunction. They were interviewed, using a standardized questionnaire regarding the occurrence of small-bowel symptoms, i.e.: nausea/vomiting, abdominal pain, bloating, diarrhoea and constipation.
Small-bowel manometry
Recording system
Non-ambulatory small-bowel manometry was performed with a tube assembly consisting of four polyvinyl catheters with side holes 10 cm apart. Sensors were located at 5, 15, 25 and 35cm from a rubber bag that was fixed to the tip and contained 2 ml of mercury to facilitate positioning. Recording lumens were perfused with distilled water via a low-compliance pneumohydraulic perfusion apparatus (0.5 ml/min) from a pressurized reservoir (which was refilled at regular interval). Pressure values from transducers (Gould Statham P23 ID, Oxnard, CA, USA) were digitized as eight-bit data with a frequency of 5 Hz/channel and stored on the hard disk of an IBM PC.
Study design
Medications that might affect intestinal motility were discontinued at least 72 h prior to manometry. After a 12 h overnight fast, the manometric probe was positioned so that the three proximal channels were placed in the proximal and distal duodenum.
Intestinal motility was continuously recorded for 24 h, i.e.: (i) during fasting state and (ii) after ingestion of two standard meals (20% protein, 50% carbohydrate and 30% fat) and a third standard meal (3% protein, 46% carbohydrate and 51% fat). At the end of the study, each patient received 50 μg of octreotide (a somatostatin analogue) intravenously, which has previously been shown to initiate a phase III-like activity within a few minutes in duodenum and jejunum of healthy subjects [ 3 , 12 ].
Analysis of the tracings
Both visual and computerized analyses were performed by two of us. For the manometric tracings during fasting, the recording chart was analysed to determine the phase III characteristics (number, amplitude and migration velocity) of the motor migrating complex (MMC) [ 20 ] and the onset of abnormal motor events. Motor activity following the meals was calculated by computerized analysis using the previously validated software 2ERL Lomatech [ 21 ]. This software analysed the digital recording [ 22 ]. The number of pressure waves and the area under the curve (AUC; in mmHg/minute) on the whole tracing and on every half-hour of recording were calculated to determine the motility index.
Comparison of small-bowel motor impairment outcome and other systemic manifestations of SSc
The course of small-bowel manometric parameters was compared with the outcome of systemic manifestations of SSc, i.e.: pitting scars, degree of skin involvement, joint signs, ILD and PAH.
Statistical analysis
For continuous outcome comparisons, we used the Wilcoxon test. Comparisons involving binary outcomes were performed using the McNemar's test. The results were regarded as significant when the P -value was <0.05.
Results
General background
The characteristics of SSc patients at 5-yr follow-up are shown in Table 1 . The SSc patients consisted of eight women with a median age of 63 yrs (37–73 yrs). The median duration of the disease, considered to have existed from the onset date of Raynaud's phenomenon was 11.5 yrs [6–34 yrs]. Patients were grouped according to the criteria of LeRoy et al . [ 23 ]; two patients (25%) had diffuse cutaneous SSc (dcSSc) while six (75%) had limited cutaneous SSc (lcSSc). Two patients (25%) exhibited articular manifestations and seven had pitting scars (87.5%). Four SSc patients had pulmonary involvement, as follows: ILD ( n = 2; 25%) and PAH ( n = 2; 25%); one of the patients had ILD-related PAH.
Clinical characteristics of patients with SSc during initial evaluation (T 0 ) and at 5-yr follow-up (T 5-yr )
| Modified Rodnan score | Pitting scar(s) | Arthralgia/arthritis | ILD * | PAH * | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient/Sex | Subset | T 0 | T 5-yr | T 0 | T 5-yr | T 0 | T 5-yr | T 0 | T 5-yr | T 0 | T 5-yr |
| 1/F | lcSSc * | 4 | 8 | − | + | − | − | − | − | − | + |
| 2/F | dcSSc * | 15 | 19 | + | + | − | + | + | + | − | − |
| 3/F | lcSSc | 4 | 4 | − | + | − | − | − | − | − | − |
| 4/F | lcSSc | 8 | 12 | − | − | − | − | − | − | − | − |
| 5/F | lcSSc | 4 | 8 | − | + | − | − | − | − | − | − |
| 6/F | lcSSc | 2 | 4 | + | + | − | − | − | − | − | − |
| 7/F | dcSSc | 26 | 33 | + | + | + | + | + | + | − | + |
| 8/F | lcSSc | 10 | 12 | + | + | − | − | − | − | − | − |
| Modified Rodnan score | Pitting scar(s) | Arthralgia/arthritis | ILD * | PAH * | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient/Sex | Subset | T 0 | T 5-yr | T 0 | T 5-yr | T 0 | T 5-yr | T 0 | T 5-yr | T 0 | T 5-yr |
| 1/F | lcSSc * | 4 | 8 | − | + | − | − | − | − | − | + |
| 2/F | dcSSc * | 15 | 19 | + | + | − | + | + | + | − | − |
| 3/F | lcSSc | 4 | 4 | − | + | − | − | − | − | − | − |
| 4/F | lcSSc | 8 | 12 | − | − | − | − | − | − | − | − |
| 5/F | lcSSc | 4 | 8 | − | + | − | − | − | − | − | − |
| 6/F | lcSSc | 2 | 4 | + | + | − | − | − | − | − | − |
| 7/F | dcSSc | 26 | 33 | + | + | + | + | + | + | − | + |
| 8/F | lcSSc | 10 | 12 | + | + | − | − | − | − | − | − |
*SSc, systemic sclerosis; lcSSc, limited cutaneous SSc; dcSSc, diffuse cutaneous SSc; ILD, interstitial lung disease; PAH, pulmonary arterial hypertension.
Digestive clinical symptoms
In this series, five SSc patients (62.5%) had clinical evidence of intestinal impairment, i.e.: nausea/vomiting ( n = 1), bloating ( n = 4), abdominal pain ( n = 5) and diarrhoea ( n = 1).
Outcome of small-bowel motor impairment on manometry
During initial evaluation, six patients (75%) had abnormal small-bowel manometry. At 5-yr follow-up, all SSc patients exhibited intestinal motor abnormalities on small-bowel manometry.
Fasting period
At 5-yr follow-up, all SSc patients had progression of intestinal motor dysfunction; patients had indeed more abnormalities of phase III MMC at 5-yr follow-up, compared with initial evaluation, as follows: (i) decreased median amplitude (17.75 vs 23.25 mmHg; P = 0.018) and (ii) lower duodenal velocity (5.6 vs 7.3 cm/min; P = 0.018) ( Table 2 ). Among two patients who had no spontaneous phase III MMC, one of them exhibited phase III MMC during initial evaluation ( Table 2 ).
Comparison of small-bowel manometric results, in the fasting and post-prandial periods, at initial evaluation and at 5-yr follow-up *
| Patients with SSc * | |||
|---|---|---|---|
| Initial evaluation | 5-yr follow-up | P -value * | |
| Interdigestive phase III MMC | |||
| Duration (minutes) | 5 (0–9) | 3.75 (0–8) | 0.027 |
| Amplitude (mmHg) | 23.25 (0–33) | 17.75 (0–21.5) | 0.018 |
| Duodenal velocity | 7.3 (0–34) | 5.6 (0–13.7) | 0.018 |
| Postprandial mean index | |||
| Duodenum (mmHg/minute) | 90 (5–192) | 19.8 (0–138.7) | 0.011 |
| Duodeno-jejunum (mmHg/minute) | 139 (18–266) | 45.9 (0–105.5) | 0.027 |
| PhaseIII like-MMC after octreotide infusion | |||
| Time of phase III MMC * occurrence after octreotide infusion (minute) | 0.75 (0–1.5) | 3 (1–8) | 0.027 |
| Number of phase III MMC * after octreotide infusion | 6.5 (3–12) | 2.5 (0–5) | 0.010 |
| Patients with SSc * | |||
|---|---|---|---|
| Initial evaluation | 5-yr follow-up | P -value * | |
| Interdigestive phase III MMC | |||
| Duration (minutes) | 5 (0–9) | 3.75 (0–8) | 0.027 |
| Amplitude (mmHg) | 23.25 (0–33) | 17.75 (0–21.5) | 0.018 |
| Duodenal velocity | 7.3 (0–34) | 5.6 (0–13.7) | 0.018 |
| Postprandial mean index | |||
| Duodenum (mmHg/minute) | 90 (5–192) | 19.8 (0–138.7) | 0.011 |
| Duodeno-jejunum (mmHg/minute) | 139 (18–266) | 45.9 (0–105.5) | 0.027 |
| PhaseIII like-MMC after octreotide infusion | |||
| Time of phase III MMC * occurrence after octreotide infusion (minute) | 0.75 (0–1.5) | 3 (1–8) | 0.027 |
| Number of phase III MMC * after octreotide infusion | 6.5 (3–12) | 2.5 (0–5) | 0.010 |
*Values are the median (range). P -values were obtained with Mann–Whitney tests; SSc, systemic sclerosis; phase III MMC, phase III migrating motor complex.
Furthermore, frequent bursts of uncoordinated hypercontractility were observed in one SSc patient who had normal baseline small-bowel manometry. Finally, two patients, who initially had uncoordinated hypercontractility, exhibited disappearance of such motor abnormalities.
Post-prandial period
Post-prandial index was lower in SSc patients at 5-yr follow-up, i.e.: duodenal (19.8 vs 90 mmHg/min; P = 0.011) and duodeno-jejunal (45.9 vs 139 mmHg/min; P = 0.027) ( Table 2 ).
Moreover, uncoordinated intestinal motor activity was observed in two SSc patients at 5-yr follow-up, who initially exhibited normal small-bowel manometry. In three other patients, frequent bursts of uncoordinated hypercontractility found on baseline manometry were not observed at 5-yr follow-up.
Octreotide infusion
As shown in Table 2 , median time of phase III MMC occurrence after octreotide infusion was longer at 5-yr follow-up (3 vs 0.75 min; P = 0.027). Median number of phase III-like MMC was also lower after octreotide infusion in SSc patients at 5-yr follow-up (2.5 vs 6.5; P = 0.010). Moreover, one patient had no phase III after octreotide infusion at 5-yr follow-up.
Comparison of small-bowel motor impairment outcome and other clinical manifestations related to SSc
The prevalence of systemic manifestations related to SSc was similar in patients at 5-yr follow-up, compared with initial evaluation, i.e.: median values of modified Rodnan score, arthralgia, PAH and ILD ( Table 1 ). Only pitting scars were more frequently observed in patients at 5-yr follow-up (87.5 vs 50%; P = 0.025) ( Table 1 ).
Finally, therapy was not different in SSc patients during initial evaluation compared with 5-yr follow-up: diltiazem (87.5 vs 100%), d -penicillamine (25 vs 12.5%), bosentan (0 vs 12.5%), prednisolone (0 vs 12.5%), proton-pump inhibitor (100 vs 100%), cisapride (50 vs 100%), domperidone (37.5 vs 0%) and octreotide (0 vs 12.5%).
Discussion
In patients with advanced SSc and symptoms consistent with intestinal involvement, earliest small-bowel manometric studies have revealed the following: absence or abnormalities of phase III MMC and post-cibal small-bowel hypomotility [ 9–11 , 24 ]. In our eight SSc patients who were not selected according to their clinical digestive presentation, we demonstrated a high frequency (75% at initial evaluation) of intestinal motor disturbances using 24 h small-bowel manometry. We, therefore, postulate that small-bowel impairment is somewhat more prevalent than has previously been described. Our findings may be explained, because earliest series consisted of short duration of small-bowel manometric recording during fasting (≤3 h) and post-prandial (1–2 h) periods and did not include sleep data. We suggest that previous protocols may have not allowed accurate assessment of small-bowel motor impairment [ 25 ]. During the fasting state, our manometric data showed that SSc patients present numerous alterations of phase III MMC: absence (25%), low amplitude (100%) and slow propagation (83.3%). During the post-prandial period, we found a marked post-cibal small-bowel hypomotility, since 62.5% of patients had a reduction in the frequency and amplitude of intestinal contractions.
However, no authors had yet evaluated the course of small-bowel motor impairment, using 24 h manometry in SSc. In the present small series of eight SSc patients, the main practical finding was a rapid deterioration of small-bowel motor dysfunction in all patients at 5-yr follow-up. We have therefore found that patients developed significant decrease of: (i) median duration, amplitude and duodenal velocity of phase III MMC during the fasting state and (ii) post-prandial index during the post-prandial period.
Intestinal clinical symptoms were more often moderate (bloating and abdominal pain) in our SSc patients, while only one patient complained of nausea/vomiting and another had diarrhoea and weight loss. Our findings underscore that digestive symptoms are not sensitive markers of intestinal motor impairment in SSc patients. However, our eight SSc patients received cisapride therapy, which may have resulted in decreased severity of intestinal manifestations; cisapride therapy (a prokinetic agent-benzamide derivative) has indeed been shown to improve intestinal clinical manifestations and motor activity on manometry in SSc patients [ 5 , 6 , 26 ]. Moreover, we suggest that it may be useful to perform systematic non-invasive tests in SSc patients to detect subclinical intestinal involvement, such as serum total protein, blood ferritin, vitamin B 12 and folic acid and steatorrhoea; whether small-bowel manometry should be performed in all patients with SSc to depict the motor abnormalities remains to be determined.
Interestingly, our study also demonstrates significant alterations of small-bowel motility in response to octreotide infusion at 5-yr follow-up. During follow-up, SSc patients exhibited, after octreotide infusion: (i) absence of or decreased number of low-amplitude phase III-like MMC and (ii) longer time before occurrence of phase III-like MMC. Our series underscores that octreotide therapy may be less effective in patients with advanced SSc. It demonstrates that small-bowel manometry should be performed to: (i) assist in the selection of symptomatic SSc patients who may benefit from octreotide therapy [ 3 , 12 ]. These data may result in the improvement of patients’ management and reduction of medical costs (as octreotide is an expensive therapy) [ 3 , 12 ] and (ii) avoid unnecessary initiation of octreotide therapy. Although octreoctide 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 [ 27 ]. In SSc patients, octreotide therapy should be prescribed in all cases with a cautious re-weighted risk/benefit consideration.
The pathological mechanisms of small-intestinal dysmotility in SSc remain unknown. It has been postulated that impairment of the small-bowel in SSc may result from progressive histological lesions, similar to those found in the skin [ 1 , 5 , 6 , 8–10 ]. Sjögren [ 3 , 5 , 6 ] has proposed the following steps for the occurrence of sclerodermatous intestinal involvement: vascular damage (grade 0), neurogenic involvement (grade 1) and myogenic involvement (grade 2) [ 12 , 28 ]. It is possible to classify intestinal motor disorders, as either myogenic (hypomotility) or neurogenic (abnormally propagated phasic contractions, and failure of fed pattern response development) [ 3 , 9 , 10 , 12 , 29 ]. In our series, we have shown that all SSc patients exhibited myogenic abnormalities at 5-yr follow-up. Furthermore, while three SSc patients, who initially had bursts of abnormal hypercontractility, exhibited disappearance of these abnormalities at 5-yr follow-up two other patients, who initially had normal small-bowel manometry, developed bursts of abnormal hypercontractility at 5-yr follow-up. Our findings underline that neurogenic abnormalities precede myogenic disturbances in small-bowel of SSc patients. We also suggest that small-bowel neurogenic and myogenic disorders occur early during the course of SSc, as the two patients with initial normal small-bowel manometry concomitantly exhibited myogenic and neurogenic patterns at 5-yr follow-up.
Finally, the present study underscores that skin involvement and systemic manifestations of SSc (joint involvement, ILD, PAH) could not be considered to be predictive of the deterioration of intestinal motor disturbances at 5-yr follow-up. Only pitting scars were more frequent at 5-yr follow-up in SSc patients; however, because of the small number of SSc patients in our series, no definite conclusion can be drawn from this latter finding, and this study warrants further investigation.
The authors have declared no conflicts of interest.
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