Abstract
Background/Introduction:
Systemic Sclerosis (SSc) is frequently associated with gastrointestinal tract (GIT). The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative study collecting longitudinal follow up data on SSc patients with less than 5-years disease duration enrolled at Scleroderma centers of excellence. This manuscript presents the GIT natural history and outcomes in relation to other scleroderma manifestations and medication exposures.
Methods:
CONQUER participants that had completed a minimum of two serial Scleroderma Clinical Trials Consortium GIT Questionnaires (GIT 2.0) were included in this analysis. Patients were categorized by total GIT 2.0 severity at baseline, and by category change: none-to-mild (0.49); moderate (0.50–1.00), and severe-to-very severe (1.01–3.00) at the subsequent visit. Based on this data, four groups were identified: none-to-mild with no change, moderate-to-severe with no change, improvement, or worsening. Clinical features, including demographics, disease duration, cutaneous subset, and autoantibodies, along with medication exposures were examined in each of these categories. Medications were categorized as gastrointestinal tract targeted therapy, anti-fibrotic, immunosuppression, or immunomodulatory drugs. Analysis included a proportional odds model accounting for linear and mixed effects of described variables.
Results:
415 enrolled CONQUER participants met project inclusion criteria. Most participants had stable mild GIT symptoms at baseline clinical assessments. In most patients, anti-reflux medication and immunosuppression initiation preceded the baseline visit, whereas anti-fibrotic initiation occurred at or after the baseline visit. In the proportional odds model, worsening GIT score at the follow-up visit was associated with current tobacco use.
Conclusion:
This report from the CONQUER cohort, suggests that most patients with early SSc have stable and mild GIT disease. Closer follow-up was associated with milder, stable GIT symptoms. There was no clear association between immunosuppression or anti-fibrotic use and severity of GIT symptoms. However, active tobacco use was associated with worse GIT symptoms, highlighting the importance of smoking cessation counselling in this population.
Keywords: Systemic sclerosis, gastrointestinal tract, immunosuppression, tobacco use
Introduction:
Gastrointestinal tract symptoms are common in systemic sclerosis (SSc).1 While there are established longitudinal markers for pulmonary and skin involvement in scleroderma including the modified Rodnan skin score (mRSS) and pulmonary function tests (PFT), serial assessment of the gastrointestinal tract is more challenging.2,3
The Scleroderma Clinical Trials Consortium University of California Los Angeles Gastrointestinal Tract Questionnaire (GIT 2.0) is a validated, patient-reported outcome measure to assess Health Related Quality Of Life (HRQOL) and gastrointestinal symptom severity in SSc.4,5 The 34-item GIT 2.0 allows a clinician to assess to the preceding seven days of reflux, bloating/distention, diarrhea, constipation, soilage as well as the emotional and social impact of gastrointestinal symptoms into an absent-to- mild, moderate, or severe categorization, which can then be trended over subsequent care visits. Similar to trending mRSS and PFT, the clinician may alter therapy in response to changes in GIT 2.0. Possible interventions may include initiation of anti-reflux therapy, pro-motility therapy, or laxative initiation; modifying medications known to have side effects on the GI tract, such as mycophenolate mofetil or nintedanib; or referring the patient for procedural diagnostics such as motility studies or endoscopy. Many gastrointestinal symptoms such as dyspepsia, diarrhea, and constipation may either be due to SSc pathogenesis or may be a potential adverse side effect of immunosuppressive and antifibrotic treatments for SSc. The GIT 2.0 can be a powerful instrument to guide initiation and response to therapy as well as to assess whether there is need for procedural referrals. Serial monitoring of the GIT 2.0 can thus be harnessed to identify patients in whom further intervention is warranted.
The Collaborative National Quality and Efficacy Registry (CONQUER) is a collaborative longitudinal study collecting data on a large cohort of early scleroderma patients followed at SSc centers of excellence in the United States.6 This registry enrolls patients that meet classification for SSc7 within 5 years of their first non-Raynaud’s symptom. CONQUER collects clinical data, biorepository specimens, and patient reported outcomes at six-month intervals with a manual of procedures that minimizes missing data.6,8,9 In this manuscript, we describe the natural history of SSc gastrointestinal tract symptoms in the CONQUER cohort.
Materials and Methods:
The inclusion criteria for this analysis included CONQUER participants who had completed a minimum of two serial GIT 2.0.10 Each SCTC GIT 2.0 total score collected on or after the patient’s baseline visit was categorized in a GIT status of none/mild (0–0.49) or moderate/severe (0.5–3.0). Chronological order of the GIT statuses was then used to categorize patients into the following GIT status change groups: none/mild with no change (no change mild), moderate/severe with no change (no change severe), went from none/mild to moderate/severe (worsened), or went from moderate/severe to none/mild (improved) with the last observation determining the analysis of the trajectory. Sankey diagrams were created to illustrate the changes in GIT scores across the visits (Figure 1).
Figure 1:
Change between GIT total severity score by category over an 18-month period
Medications were categorized as gastrointestinal tract targeted therapy or immunomodulatory drugs. Gastrointestinal tract medications included reflux medications (proton pump inhibitors, antacids, esophageal guardian, and histamine-2 blockers); anti-diarrheal (loperamide); anti-constipation (polyethylene glycol); pro-motility (metoclopramide and domperidone), and small intestinal bacterial overgrowth (SIBO)-specific antibiotics (rifaximin). Immunomodulatory drugs included hydroxychloroquine, methotrexate, mycophenolate, rituximab, azathioprine, tocilizumab, and cyclophosphamide, and anti-fibrotic drugs included pirfenidone and nintedanib. There were no participants on intravenous immunoglobulin (IVIG), pirfenidone, or other antibiotics for SIBO. Analysis included a proportional odds model accounting for linear and mixed effects of described variables.
Medications taken within 90 days of any survey were summarized using frequencies and percentages for each GIT status change group. For the no change groups, medication use was summarized before and after the baseline visit. For the improved group, medication use was summarized before and after the date of the last survey prior to improvement. For the worsened group, medication use was summarized before and after the date of the last survey prior to worsening. Medications started after the last recorded survey date were excluded from analysis.
Medications and survey timing were summarized for each of the GIT status change groups using a bar plot overlaid by a bubble plot in Figure 2. For patients with no change in GIT status, the length of the bar indicates the median time from baseline to last GIT recorded. For patients with improved GIT status, the length of the bar indicates the median time from baseline to the date of last moderate/severe GIT status. For patients with worsened GIT status, the length of the bar represents the median time from baseline to the date of last mild GIT status. Medication usage is summarized by medication category, prevalence, and start date. The size of each bubble represents the percentage of patients in the GIT change group who have taken the medication. The location of each bubble is the median start time of the medication relative to baseline.
Figure 2:
Medications and survey timing for each of the GIT status change groups
Results:
At the time of data analysis, there 415 CONQUER participants met the inclusion criteria with follow-up to 42 months. The sociodemographic and disease characteristics of those 415 participants are shown in Table 1. Most participants were female (n=344, 83%), white (n=366, 81%), and employed full-time (n=202, 49%) with a mean age of 52 years (SD 13.78), non-Raynaud’s symptom duration of 2.6 years (SD 1.40), and Raynaud’s symptoms duration of 4.8 years (SD 7.18). There was not a predominant SSc auto-antibody pattern in participants and GIT severity categories did not show differing antibody profiles. There was no significant difference in body mass index (BMI) across GIT severity categories.
Table 1:
Patient Characteristics by type of first change in GIT score
| Type of first change in GIT score | ||||||
|---|---|---|---|---|---|---|
| Overall (N = 415) |
No change (none/mild) (N = 214) |
No change (moderate/severe) (N = 64) |
Improved (N = 64) |
Worsened (N = 73) |
P-value | |
| Age (years) at baseline visit: N, Mean (SD) | 415, 51.8 (13.78) | 214, 52.1 (13.65) | 64, 51.4 (13.58) | 64, 50.6 (13.54) | 73, 52.2 (14.71) | 0.8561 |
| Sex: Female | 344 (82.9%) | 168 (78.5%) | 55 (85.9%) | 56 (87.5%) | 65 (89.0%) | 0.1012 |
| BMI at baseline (kg/m2): N, Mean (SD) | 401, 26.0 (5.20) | 206, 25.7 (4.63) | 64, 27.1 (5.58) | 62, 26.2 (5.44) | 69, 25.9 (6.13) | 0.2681 |
| Race | 0.2212 | |||||
| White | 336 (81.0%) | 171 (79.9%) | 53 (82.8%) | 49 (76.6%) | 63 (86.3%) | |
| Black or African American | 42 (10.1%) | 18 (8.4%) | 8 (12.5%) | 9 (14.1%) | 7 (9.6%) | |
| Other | 35 (8.4%) | 24 (11.2%) | 2 (3.1%) | 6 (9.4%) | 3 (4.1%) | |
| Ethnicity: Hispanic or Latino | 39 (9.4%) | 18 (8.4%) | 8 (12.5%) | 8 (12.5%) | 5 (6.8%) | 0.5232 |
| Employment status 3 | 0.0022 | |||||
| Full-time | 202 (48.7%) | 117 (54.7%) | 27 (42.2%) | 30 (46.9%) | 28 (38.4%) | |
| Retired | 75 (18.1%) | 41 (19.2%) | 10 (15.6%) | 7 (10.9%) | 17 (23.3%) | |
| Disabled | 48 (11.6%) | 11 (5.1%) | 14 (21.9%) | 13 (20.3%) | 10 (13.7%) | |
| Other | 85 (20.5%) | 43 (20.1%) | 11 (17.2%) | 13 (20.3%) | 18 (24.7%) | |
| Smoking status | 0.5692 | |||||
| Never | 281 (67.7%) | 143 (66.8%) | 42 (65.6%) | 44 (68.8%) | 52 (71.2%) | |
| Former | 118 (28.4%) | 65 (30.4%) | 19 (29.7%) | 15 (23.4%) | 19 (26.0%) | |
| Current | 16 (3.9%) | 6 (2.8%) | 3 (4.7%) | 5 (7.8%) | 2 (2.7%) | |
| Disease duration (years) from date of first non-Raynauds symptom to baseline visit: N, Mean (SD) | 415, 2.6 (1.40) | 214, 2.6 (1.42) | 64, 2.7 (1.34) | 64, 2.7 (1.30) | 73, 2.3 (1.45) | 0.2961 |
| Disease duration (years) from date of first Raynauds symptom to baseline visit: N, Mean (SD) | 403, 4.8 (7.18) | 207, 4.6 (5.99) | 64, 6.1 (10.54) | 61, 5.2 (8.55) | 71, 3.9 (5.01) | 0.3891 |
| SSc subtype at baseline | 0.7212 | |||||
| Limited cutaneous | 161 (38.8%) | 85 (39.7%) | 26 (40.6%) | 26 (40.6%) | 24 (32.9%) | |
| Diffuse cutaneous | 254 (61.2%) | 129 (60.3%) | 38 (59.4%) | 38 (59.4%) | 49 (67.1%) | |
| ANA status - any visit | 380 (91.6%) | 199 (93.0%) | 60 (93.8%) | 56 (87.5%) | 65 (89.0%) | 0.1802 |
| ANA pattern - any visit (accounting for changing patterns and anticentromere, collapsed) | 0.0572 | |||||
| Centromere | 70 (16.9%) | 36 (16.8%) | 14 (21.9%) | 15 (23.4%) | 5 (6.8%) | |
| Nucleolar | 61 (14.7%) | 34 (15.9%) | 12 (18.8%) | 5 (7.8%) | 10 (13.7%) | |
| Other | 215 (51.8%) | 108 (50.5%) | 28 (43.8%) | 34 (53.1%) | 45 (61.6%) | |
| Anti-centromere positive | 64 (15.4%) | 33 (15.4%) | 11 (17.2%) | 15 (23.4%) | 5 (6.8%) | 0.1462 |
| Anti-Scl-70 positive | 121 (29.2%) | 66 (30.8%) | 13 (20.3%) | 18 (28.1%) | 24 (32.9%) | 0.3282 |
| Anti-RNA Polymerase III positive | 112 (27.0%) | 57 (26.6%) | 14 (21.9%) | 16 (25.0%) | 25 (34.2%) | 0.4292 |
| Anti-U1-RNP positive | 27 (6.5%) | 11 (5.1%) | 4 (6.3%) | 5 (7.8%) | 7 (9.6%) | 0.7852 |
| Modified Rodnan Skin Score (mRSS) at baseline: N, Mean (SD) | 415, 13.0 (10.67) | 214, 12.6 (10.39) | 64, 14.0 (11.77) | 64, 11.5 (10.12) | 73, 14.4 (10.92) | 0.2961 |
| Digital pitting scars | 93 (22.4%) | 43 (20.1%) | 16 (25.0%) | 18 (28.1%) | 16 (21.9%) | 0.5462 |
| Ischemic digital ulcers at baseline | 28 (6.7%) | 14 (6.5%) | 6 (9.4%) | 3 (4.7%) | 5 (6.8%) | 0.7652 |
| Gastric antral vascular ectasia 5 | 38 (9.2%) | 16 (7.5%) | 7 (10.9%) | 2 (3.1%) | 13 (17.8%) | 0.0162 |
| GI Tract: Not normal 6 | <.0012 | |||||
| Normal esophagram; normal small bowel series; not GI symptoms | 115 (27.7%) | 74 (34.6%) | 5 (7.8%) | 16 (25.0%) | 20 (27.4%) | |
| Distal esophageal hypoperistalsis; small bowel abnormal (e.g. reflux, bloating, distension) | 285 (68.7%) | 136 (63.6%) | 53 (82.8%) | 44 (68.8%) | 52 (71.2%) | |
| Antibiotics required for bacterial overgrowth | 8 (1.9%) | 1 (0.5%) | 3 (4.7%) | 3 (4.7%) | 1 (1.4%) | |
| Malabsorbtion syndrome; episodes of pseudo-obstruction | 2 (0.5%) | 0 (0.0%) | 2 (3.1%) | 0 (0.0%) | 0 (0.0%) | |
| Hyperalimentation required | 1 (0.2%) | 0 (0.0%) | 0 (0.0%) | 1 (1.6%) | 0 (0.0%) | |
| GI Tract: Not normal 6 | 296 (71.3%) | 137 (64.0%) | 58 (90.6%) | 48 (75.0%) | 53 (72.6%) | <.0012 |
| Baseline supplemental oxygen use | 13 (3.1%) | 6 (2.8%) | 2 (3.1%) | 4 (6.3%) | 1 (1.4%) | 0.4142 |
| Creatine Kinase (CK) | 289, 164.7 (457.15) | 152, 191.1 (586.34) | 45, 109.1 (94.53) | 42, 109.9 (83.17) | 50, 180.9 (383.73) | 0.4941 |
| HRCT performed at baseline | 286 (68.9%) | 140 (65.4%) | 47 (73.4%) | 45 (70.3%) | 54 (74.0%) | 0.4302 |
| Medications at baseline | ||||||
| Azathioprine | 5 (1.2%) | 3 (1.4%) | 1 (1.6%) | 1 (1.6%) | 0 (0.0%) | 0.7782 |
| Cyclophosphamide | 2 (0.5%) | 0 (0.0%) | 1 (1.6%) | 0 (0.0%) | 1 (1.4%) | 0.2502 |
| Hydroxychloroquine | 98 (23.6%) | 56 (26.2%) | 20 (31.3%) | 14 (21.9%) | 8 (11.0%) | 0.0242 |
| Methotrexate | 32 (7.7%) | 19 (8.9%) | 4 (6.3%) | 5 (7.8%) | 4 (5.5%) | 0.7742 |
| Mofetil | 219 (52.8%) | 102 (47.7%) | 33 (51.6%) | 38 (59.4%) | 46 (63.0%) | 0.0912 |
| Nintedanib | 7 (1.7%) | 2 (0.9%) | 0 (0.0%) | 3 (4.7%) | 2 (2.7%) | 0.1222 |
| Prednisone | 76 (18.3%) | 32 (15.0%) | 14 (21.9%) | 17 (26.6%) | 13 (17.8%) | 0.1662 |
| Rituximab | 7 (1.7%) | 3 (1.4%) | 1 (1.6%) | 3 (4.7%) | 0 (0.0%) | 0.1842 |
| Tocilizumab | 8 (1.9%) | 4 (1.9%) | 2 (3.1%) | 1 (1.6%) | 1 (1.4%) | 0.8842 |
| PPI | 252 (60.7%) | 113 (52.8%) | 50 (78.1%) | 41 (64.1%) | 48 (65.8%) | 0.0022 |
Cohort contains subjects with at least two GIT surveys.
Kruskal-Wallis test.
Chi-squared test.
Employment status of 'Other' includes part-time, homemaker, student or unemployed.
ANA pattern of 'Other' includes speckled, homogenous and mixed pattern.
GAVE displays counts and percent of Yes out of No/Missing with missings assuming no GAVE.
GI Tract not normal: distal esophageal hypoperistalsis; small bowel abnormal (e.g. reflux, bloating, distension) or antibiotics required for bacterial overgrowth or malabsorption syndrome; episodes of pseudo-obstruction or hyperalimentation required.
Most patients had mild GIT symptoms that did not change between assessments. The change between GIT total severity score by category over an 18-month period is shown in Figure 1. Patients with shorter interval follow-up was associated with stable, mild GIT 2.0 scores. Medication use is shown in Table 2. The most common prescribed immunosuppressive drug was mycophenolate, and the most used gastrointestinal tract targeted therapy was omeprazole. In most patients these medications were initiated prior to the baseline CONQUER visit (Figure 2). Initiation of anti-fibrotic therapy, rifaximin for small-intestinal bowel overgrowth (SIBO), promotility agents, and constipation treatment typically occurred after the initial baseline visit. There were no patients on other antibiotics for SIBO, IVIG or pirfenidone.
Table 2:
Medications for GIT groups
| Improved (N = 64) |
Worsened (N = 73) |
|||||
|---|---|---|---|---|---|---|
| No change (none/mild) (N = 214) |
No change (moderate/severe) (N = 64) |
Moderate/severe | None/mild | None/mild | Moderate/severe | |
| Immunosupression | 152 (71.0%) | 50 (78.1%) | 49 (76.6%) | 47 (73.4%) | 54 (74.0%) | 60 (82.2%) |
| Cyclophosphamide | 0 (0.0%) | 2 (3.1%) | 0 (0.0%) | 0 (0.0%) | 1 (1.4%) | 1 (1.4%) |
| Mycophenolate Mofetil | 123 (57.5%) | 38 (59.4%) | 41 (64.1%) | 40 (62.5%) | 49 (67.1%) | 56 (76.7%) |
| Rituximab | 3 (1.4%) | 2 (3.1%) | 5 (7.8%) | 3 (4.7%) | 0 (0.0%) | 1 (1.4%) |
| Prednisone | 45 (21.0%) | 15 (23.4%) | 18 (28.1%) | 15 (23.4%) | 12 (16.4%) | 15 (20.5%) |
| Methotrexate | 22 (10.3%) | 7 (10.9%) | 8 (12.5%) | 6 (9.4%) | 7 (9.6%) | 8 (11.0%) |
| Azathioprine | 2 (0.9%) | 1 (1.6%) | 2 (3.1%) | 2 (3.1%) | 1 (1.4%) | 1 (1.4%) |
| Tocilizumab | 11 (5.1%) | 4 (6.3%) | 2 (3.1%) | 3 (4.7%) | 1 (1.4%) | 3 (4.1%) |
| Hydroxychloroquine | 74 (34.6%) | 17 (26.6%) | 20 (31.3%) | 22 (34.4%) | 13 (17.8%) | 15 (20.5%) |
| Antifibrotic | 6 (2.8%) | 2 (3.1%) | 4 (6.3%) | 5 (7.8%) | 5 (6.8%) | 5 (6.8%) |
| Nintedanib | 6 (2.8%) | 2 (3.1%) | 4 (6.3%) | 5 (7.8%) | 5 (6.8%) | 5 (6.8%) |
| Constipation | 3 (1.4%) | 2 (3.1%) | 0 (0.0%) | 1 (1.6%) | 1 (1.4%) | 5 (6.8%) |
| Polyethylene Glycol | 3 (1.4%) | 2 (3.1%) | 0 (0.0%) | 1 (1.6%) | 1 (1.4%) | 5 (6.8%) |
| Antidiarrheal | 2 (0.9%) | 1 (1.6%) | 2 (3.1%) | 3 (4.7%) | 2 (2.7%) | 2 (2.7%) |
| Loperamide | 2 (0.9%) | 1 (1.6%) | 2 (3.1%) | 3 (4.7%) | 2 (2.7%) | 2 (2.7%) |
| Small bacterial overgrowth treatment | 0 (0.0%) | 0 (0.0%) | 1 (1.6%) | 2 (3.1%) | 0 (0.0%) | 1 (1.4%) |
| Xifaxan | 0 (0.0%) | 0 (0.0%) | 1 (1.6%) | 2 (3.1%) | 0 (0.0%) | 1 (1.4%) |
| Promotility | 3 (1.4%) | 3 (4.7%) | 2 (3.1%) | 1 (1.6%) | 2 (2.7%) | 4 (5.5%) |
| Metoclopramide | 2 (0.9%) | 3 (4.7%) | 2 (3.1%) | 1 (1.6%) | 2 (2.7%) | 4 (5.5%) |
| Domperidone | 1 (0.5%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Reflux | 147 (68.7%) | 59 (92.2%) | 52 (81.3%) | 50 (78.1%) | 52 (71.2%) | 59 (80.8%) |
| Antiacid | 17 (7.9%) | 3 (4.7%) | 4 (6.3%) | 4 (6.3%) | 7 (9.6%) | 7 (9.6%) |
| Famotidine | 28 (13.1%) | 17 (26.6%) | 13 (20.3%) | 15 (23.4%) | 8 (11.0%) | 15 (20.5%) |
| Esomeprazole | 18 (8.4%) | 6 (9.4%) | 7 (10.9%) | 5 (7.8%) | 8 (11.0%) | 10 (13.7%) |
| Omeprazole | 93 (43.5%) | 28 (43.8%) | 28 (43.8%) | 27 (42.2%) | 31 (42.5%) | 35 (47.9%) |
| Dexlansoprazole | 6 (2.8%) | 2 (3.1%) | 4 (6.3%) | 2 (3.1%) | 0 (0.0%) | 0 (0.0%) |
| Lansoprazole | 4 (1.9%) | 6 (9.4%) | 0 (0.0%) | 0 (0.0%) | 2 (2.7%) | 2 (2.7%) |
| Rabeprazole | 1 (0.5%) | 5 (7.8%) | 1 (1.6%) | 1 (1.6%) | 0 (0.0%) | 0 (0.0%) |
| Pantoprazole | 22 (10.3%) | 20 (31.3%) | 16 (25.0%) | 14 (21.9%) | 9 (12.3%) | 11 (15.1%) |
Change is referring to the first change for a patient (ie. if patient improved and then later worsened just the first change is used here).
For the no change groups the medication was marked as taken if they ever took it from before baseline to last GIT date.
For improved patients, the medication counts in the the Moderate/Severe section if they ever started the medication before the change to mild. For the Mild section, the subject was on the medication anytime after the change to mild to last GIT.
For worsened patients, the medication counts in the Mild section if they ever started the medication before or on the last mild GIT date. For the Moderate/severe section, the subject was on the medication anytime after the last mild GIT to the last GIT.
No patients were on Alginate.
As shown in Table 3, female sex, black race, current tobacco use, promotility drugs, and anti-reflux medications were significantly associated with a longitudinally worse GIT 2.0 total score. However, SSc subtype by skin involvement or auto-antibody, immunosuppressive drugs, and nintedanib were not significantly associated with longitudinal GIT 2.0 score worsening.
Table 3:
Proportional odds model - modeling the odds of having a worse GIT score
| GIT score | ||
|---|---|---|
| Odds ratio (95% CI) | P-value | |
| Sex | 0.026 | |
| Male | Reference | |
| Female | 1.96 (1.08, 3.54) | |
| Number of days the first PRO that was completed from this visit is from baseline (days) | 1.00 (1.00, 1.00) | 0.807 |
| Race | 0.032 | |
| White | Reference | |
| Black or African American | 2.28 (1.18, 4.44) | |
| Other | 0.76 (0.34, 1.71) | |
| SSc subtype at baseline | 0.961 | |
| Limited cutaneous | Reference | |
| Diffuse cutaneous | 0.99 (0.60, 1.63) | |
| Anti-Centromere - any visit | 0.712 | |
| Negative or Not done | Reference | |
| Positive | 1.14 (0.57, 2.25) | |
| Anti-Scl-70 - any visit | 0.121 | |
| Negative or Not done | Reference | |
| Positive | 0.66 (0.39, 1.11) | |
| Anti-RNA Polymerase III - any visit | 0.507 | |
| Negative or Not done | Reference | |
| Positive | 0.83 (0.49, 1.43) | |
| Currently smoking cigarettes | 0.011 | |
| No | Reference | |
| Yes | 3.94 (1.37, 11.33) | |
| Antidiarrheal | 0.854 | |
| No | Reference | |
| Yes | 0.87 (0.20, 3.81) | |
| Antifibrotic | 0.063 | |
| No | Reference | |
| Yes | 2.51 (0.95, 6.61) | |
| Constipation | 0.430 | |
| No | Reference | |
| Yes | 1.68 (0.46, 6.06) | |
| Immunosupression | 0.380 | |
| No | Reference | |
| Yes | 1.28 (0.74, 2.24) | |
| Promotility | 0.031 | |
| No | Reference | |
| Yes | 3.53 (1.12, 11.14) | |
| Reflux | <.001 | |
| No | Reference | |
| Yes | 3.64 (2.14, 6.18) | |
| Small bacterial overgrowth treat | 0.105 | |
| No | Reference | |
| Yes | 4.71 (0.72, 30.76) | |
| Hydroxychloroquine | 0.139 | |
| No | Reference | |
| Yes | 0.71 (0.46, 1.11) | |
Discussion:
Gastrointestinal tract symptoms influence quality of life and medication utilization in SSc patients. Apart from diffuse cutaneous patients with low body mass index, the natural history of gastrointestinal tract symptoms has previously been reported to demonstrate longitudinal stability over five years in an established cohort of SSc patients.11 The purpose of the present analysis was to investigate GIT symptoms in the CONQUER cohort, which represents patients with disease less than 5 years duration. We found that more than half of the CONQUER patients showed stability of gastrointestinal disease irrespective of SSc-targeted therapy. However, current tobacco use was associated with worse GIT survey scores. This finding is important since it emphasizes the need for smoking cessation in patients with SSc.
While immunosuppressive and anti-fibrotic therapies have been shown to have disease modifying effect on skin and lung disease, the effects of these drugs on the gastrointestinal tract are less clear. It is known that alterations in cell-mediated immunity are important for development of SSc-related gastrointestinal disease, but reports have not examined the timing of these cellular changes, and whether symptoms correlate with disease duration.12,13 The current data suggest that immunosuppressive and anti-fibrotic drugs do not correlate with GIT 2.0 scores.
The CONQUER cohort is a valuable resource to investigate multiple different phenotypes of early SSc.6 Longitudinal cohorts such as CONQUER can inform clinical trial design since they allow better understanding of the natural history of SSc.8,14 Ongoing follow-up of the CONQUER cohort is planned and this will provide important data to discern damage and disease progression indicies. The CONQUER cohort allows integration of pharmacologic and other therapeutic interventions with longitudinal outcome data to identify interventions that are associated with stabilization of the more difficult to evaluate manifestations of SSc. The data presented shows that immunosuppression and antifibrotic therapies do not worsen GIT manifestations and may well contribute to GIT 2.0 stabilization in most SSc patients.
The natural history of gastrointestinal tract disease activity and damage in response to standard of care therapeutics is best characterized in longitudinal cohorts, such as CONQUER. The CONQUER registry is a valuable source for assessing the burden of symptoms and investigating diagnostic resource utilization in scleroderma. Ongoing follow-up of this longitudinal US-based early scleroderma cohort is planned
Funding:
TF is supported by VA Merit Award I01 CX002111. EJB’s work is supported by K23-AR-075112.
Footnotes
Statements and Declarations: SL, TF, LH, LC, FH, VKS, JVB, JA, MH, and NS have no relevant financial or non-financial interests to disclose.
References:
- 1.Zhu J & Frech T Gut disease in systemic sclerosis - new approaches to common problems. Current treatment options in rheumatology 5, 11–19 (2019). 10.1007/s40674-019-00117-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Khanna D et al. Measuring response in the gastrointestinal tract in systemic sclerosis. Current opinion in rheumatology 25, 700–706 (2013). 10.1097/01.bor.0000434668.32150.e5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hasegawa M et al. Investigation of prognostic factors for skin sclerosis and lung function in Japanese patients with early systemic sclerosis: a multicentre prospective observational study. Rheumatology 51, 129–133 (2012). 10.1093/rheumatology/ker333 [DOI] [PubMed] [Google Scholar]
- 4.Khanna D et al. Minimally important differences of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument. The Journal of rheumatology 38, 1920–1924 (2011). 10.3899/jrheum.110225 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Khanna D et al. Reliability and validity of the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument. Arthritis and rheumatism 61, 1257–1263 (2009). 10.1002/art.24730 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Shanmugam VK et al. Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma: outcomes from a multicenter US-based systemic sclerosis registry. Clinical rheumatology 39, 93–102 (2020). 10.1007/s10067-019-04792-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.van den Hoogen F et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis and rheumatism 65, 2737–2747 (2013). 10.1002/art.38098 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Frech TM et al. Does hand involvement in systemic sclerosis limit completion of patient-reported outcome measures? Clinical rheumatology 40, 965–971 (2021). 10.1007/s10067-020-05467-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Castelino FV et al. Baseline characteristics of systemic sclerosis patients with restrictive lung disease in a multi-center US-based longitudinal registry. Int J Rheum Dis (2021). 10.1111/1756-185X.14253 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Bernatsky S et al. Demographic and clinical factors associated with physician service use in systemic sclerosis. The Journal of rheumatology 36, 96–98 (2009). 10.3899/jrheum.080623 [DOI] [PubMed] [Google Scholar]
- 11.Bering J, Griffing WL, Crowell M & Umar SB Progression of gastrointestinal symptoms over time in patients with systemic sclerosis. Rheumatology international 41, 1281–1287 (2021). 10.1007/s00296-021-04806-6 [DOI] [PubMed] [Google Scholar]
- 12.Kumar S et al. Review article: pathogenesis and clinical manifestations of gastrointestinal involvement in systemic sclerosis. Alimentary pharmacology & therapeutics 45, 883–898 (2017). 10.1111/apt.13963 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Kumar S et al. Role of muscarinic-3 receptor antibody in systemic sclerosis: correlation with disease duration and effects of IVIG. Am J Physiol Gastrointest Liver Physiol 310, G1052–1060 (2016). 10.1152/ajpgi.00034.2016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Gordon JK & Domsic RT Clinical Trial Design Issues in Systemic Sclerosis: an Update. Current rheumatology reports 18, 38 (2016). 10.1007/s11926-016-0582-z [DOI] [PubMed] [Google Scholar]