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Abstract
Objectives While important progress was made regarding the treatment of systemic sclerosis (SSc), there is still no evidence-based disease-modifying treatment available for SSc-related gastrointestinal (GI) manifestations. We aimed to identify an association between immunosuppressive therapy and the the severity of GI symptoms, measured by the University of California at Los Angeles/Scleroderma Clinical Trial Consortium Gastro-Intestinal Tract instrument 2.0 (GIT).
Methods We selected patients with SSc who had at least two visits (further referred to as ‘baseline’ and ‘follow-up’) with completed GITs, within an interval of 12±3 months. The study outcome was the GIT score at follow-up. We used multivariable linear regression with the following covariates: immunosuppressive therapy during observation, immunosuppressive therapy before baseline, baseline GIT and several baseline parameters selected by clinical judgement as potentially influencing GI symptoms.
Results We included 209 SSc patients (82.3% female, median age 59.0 years, median disease duration 6.0 years, 40 (19.1%) diffuse cutaneous SSc, median baseline GIT 0.19). Of these, 71 were exposed to immunosuppressive therapy during the observation period, and, compared with unexposed patients, had overall more severe SSc and a higher prevalence of treatment with proton pump inhibitors. In multivariable linear regression, immunosuppressive therapy during the period of observation and lower baseline GIT scores were significantly associated with lower (better) GIT scores at follow-up.
Conclusion Immunosuppressive treatment was associated with lower GIT scores in our cohort, which suggests the potential effects of immunosuppressants on GI manifestations in patients with SSc, requiring confirmation in prospective randomised clinical trials.
- Systemic Sclerosis
- Scleroderma, Systemic
- Antirheumatic Agents
Data availability statement
Data are available on reasonable request. The data underlying this article will be shared on reasonable request to the corresponding author.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Gastrointestinal (GI) manifestations of systemic sclerosis (SSc) are frequent and may lead to severe complications and even death. However, to date, there is still no disease-modifying treatment for SSc-related GI disease.
In this study, we aimed to evaluate in a real-life cohort of patients with SSc the association of exposure to immunosuppressive treatment, including biological agents, with the severity of GI symptoms, assessed with the University of California at Los Angeles/Scleroderma Clinical Trial Consortium Gastro-Intestinal Tract instrument 2.0 (GIT).
WHAT THIS STUDY ADDS
In a retrospective analysis of prospectively collected data, we found that exposure to immunosuppressive therapy during a period of observation of 12±3 months was significantly associated with lower (better) GIT scores at follow-up.
These results suggest potential effects of immunosuppressants on GI manifestations in patients with SSc.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Our findings offer the basis for prospective studies on the treatment of GI-SSc manifestation with immunosuppressants, including randomised controlled clinical trials.
Introduction
Systemic sclerosis (SSc) is an autoimmune disease characterised by vasculopathy and fibrosis affecting the skin and internal organs.1 2 Gastrointestinal (GI) dysmotility is the most common visceral manifestation of SSc, affecting over two-thirds of patients.3 In some cases, it leads to severe complications such as chronic intestinal pseudo-obstruction, malabsorption and even death. While progress has been made in treating other organ manifestations such as SSc-related interstitial lung disease,4–6 there is no recommended disease-modifying treatment for SSc-related GI disease. SSc-related GI manifestations are still managed symptomatically with medications such as proton pump inhibitors (PPIs) and prokinetics. While small case series suggested that immunomodulating medications may improve GI symptoms7 and even control severe GI manifestations such as chronic intestinal pseudo-obstruction,8 larger studies examining immunosuppressants in SSc-related GI disease have not been able to detect any effect.9 10 However, these studies did not include patients receiving treatment with biological agents.
The aim of the present study was to determine, in a large cohort of unselected, consecutive patients with SSc, if the exposure to immunosuppressants including biological agents has effects on GI symptoms, as captured by the University of California at Los Angeles/Scleroderma Clinical Trial Consortium Gastro-Intestinal Tract instrument 2.0 (GIT).11
Patients and methods
Patients
For this post hoc analysis of prospectively collected data, we selected consecutive patients from our local European Scleroderma Trials and Research Group (EUSTAR) database, with the following inclusion criteria: age ≥18 years at study inclusion, fulfilment of the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for SSc12 and at least two consecutive visits (12±3 months apart) with completed GIT questionnaires. The observation period was defined as the interval between the first visit with a completed GIT questionnaire (baseline visit) and the following assessment (follow-up visit) (see online supplemental figure S1). In patients with multiple eligible observation periods, we analysed only the first interval. Data on the standardised clinical approach and workup of the annual EUSTAR visits have been published elsewhere.13
Supplemental material
GIT questionnaire
The GIT is a patient-completed questionnaire validated to assess severity of GI symptoms and health-related quality of life in SSc.11 It comprises 34 items, divided into 7 subcategories: reflux, distention/bloating, diarrhoea, faecal soilage, constipation, emotional well-being and social functioning. Subscale scores are computed for each category, ranging from 0 to 3, except for diarrhoea (0 to 2) and constipation (0 to 2.5). More severe symptoms correspond to higher scores. The total GIT score is computed as the mean of all subscale scores, except the one for constipation and ranges from 0 to 2.83.11 14 This instrument has been shown to be sensitive to identifying changes in GI symptoms following therapeutic intervention15 16 and has been used as an outcome measure in clinical trials of GI treatments in patients with SSc.17–19 In our study, we used the total GIT score at the follow-up visit as the main outcome measure. Severity categories of GI symptoms (none to mild, moderate and severe to very severe) have been previously calculated.20
Definition of exposure to immunosuppressive therapy
Immunosuppressive treatment was defined as exposure to one or more of the following drugs for at least 6 months during the observation period: rituximab, tocilizumab, abatacept, tumour necrosis factor inhibitors, methotrexate (MTX), azathioprine, cyclophosphamide, mycophenolate mofetil (MMF), calcineurin inhibitors, and glucocorticoids in a daily dose of ≥10 mg prednisone equivalent. Previous exposure to immunosuppressants was defined as treatment for >3 months during the 6 months before baseline with any of the above medication, with the exception of rituximab, for which we considered an interval of 12 months before baseline.
Statistical methods
The statistical analysis was performed with R language V.3.6 (packages: tidyverse, naniar, missforest, reshape2, mosaic, MatchIt and stargazer). A p<0.05 was considered statistically significant. Numeric variables are presented with median and IQR (Q1, Q3). Categorical variables are shown as the sample size (n) and percent.
In the primary analysis, we evaluated the association between exposure to immunosuppressants and GI symptoms in a prediction model, using multivariable linear regression, with immunosuppressive treatment during the follow-up period as a dichotomous independent variable and the GIT total score at follow-up as the dependent variable. Based on clinical judgement and evidence from medical literature,10 we also included several baseline variables which might influence GI symptoms: age, sex, baseline GIT score, immunosuppressants before baseline (as defined above), disease duration since first non-Raynaud symptom, body mass index (BMI), modified Rodnan Skin Score (mRSS), Forced Vital Lung Capacity (FVC) and the Erythrocyte Sedimentation Rate (ESR). We also considered the intake of PPIs during the observation period as an independent variable. We further repeated the analysis for each of the GIT subscale scores, using the respective subscale’s follow-up value as a dependent variable, and its baseline value as an independent variable. As sensitivity analyses, we repeated the analysis excluding (1) patients who already had immunosuppressants at baseline and (2) patients who had a GIT score of 0 at baseline.
As a secondary analysis, we applied the design of an efficacy study, keeping the same outcome (GIT score at follow-up) and replacing the baseline time-varying variables (age, disease duration, BMI, MRSS, FVC and ESR) with their respective values at the follow-up visit. For this analysis, we performed patient matching, following the nearest neighbour matching method with ratio of 1:1. We paired patients in the immunosuppressants group with the control group based on sex, age, disease duration, BMI, mRSS, FVC and ESR.
Improvement, stability and worsening of GIT at follow-up versus baseline were defined according to the validated minimal clinical important differences (MCID).15
Both the primary and secondary analyses were performed with and without multiple imputation for missing data, using the R package ‘Missforest’.
Results
Patients and baseline characteristics
Of 494 patients registered in our local EUSTAR database at the time of data export, 209 fulfilled the inclusion criteria. Of these, 71 (34.0%) received immunosuppressants during the observation period while 54 patients (25.8%) already had been exposed to immunosuppressants before baseline.
Patients’ demographics and clinical data at the time of inclusion in this study (‘baseline’) are displayed in table 1. Of 209 patients, 172 (82.3%) were female and 194 (92.8%) were Caucasian. The median age was 59.0 years and the median disease duration was 6.0 years. 40 (19.1%) had the diffuse cutaneous subset of SSc, and 114 (54.6%) were taking PPI at baseline. None of the study patients was on parenteral nutrition before or during this study. Patients who received immunosuppressants during the observation period, compared with those who did not, were more frequently males (28.2% vs 12.3%) and had more severe SSc phenotype, with a higher prevalence of the diffuse cutaneous subset, joint contractures and interstitial lung disease. However, they had a lower prevalence of intestinal symptoms at baseline as reported by the physician-recorded history data (table 1).
Demographic and clinical data of the patients at baseline
GIT scores at baseline and at follow-up
At baseline, 118 patients (56.5%) reported GI symptoms, according to the GIT (total score >0). The median GIT score was 0.19, with a median subscale score for reflux of 0.25 and for distention/bloating of 0.5 while the median scores of the other subscales were 0 (table 2). The total GIT score was numerically lower in patients with immunosuppressants during the observation period. This group included 12 (17%) cases with moderate and 5 (7%) cases with severe to very severe GI symptoms at baseline, vs 18 (13%) with moderate and 7 (5%) with severe to very severe GI symptoms in the other group.
GIT subscale scores and distribution of patients among GI symptom severity categories by GIT, at baseline and at follow-up
At follow-up, the patient distribution in the categories ‘moderate’ and ‘severe to very severe’ GI symptoms was largely unchanged compared with baseline in the group with immunosuppressants, while the proportion of patients in these categories increased in the other group (table 2).
The exposure to immunosuppressive treatment before and during the observation period is detailed in table 3. Both before and after baseline, MTX was the most frequently prescribed immunosuppressant, followed by tocilizumab, MMF and rituximab. The median duration of follow-up was 383 (IQR 364–408) days.
Exposure of the study patients (N=209) to immunosuppressive treatment
The use of immunosuppressants is associated with reduced GI symptoms at follow-up
Based on the change in the total GIT score from baseline to follow-up, the GI-reported symptoms worsened in 37 patients (17.7%), improved in 54 (25.8%) and remained stable in 118 (56.5%).
The prediction analysis identified a statistically significant negative relationship between immunosuppressive therapy during the observation period and the primary outcome measure, the total GIT score, at follow-up: estimate −0.115, 95% CI −0.225 to −0.005 (table 4). The strongest predictor of the GIT score at follow-up was the GIT score at baseline (estimate 0.693, 95% CI 0.574 to 0.812). Disease duration, although reaching statistical significance, had a low estimate (0.005), suggesting a lower clinical relevance.
Prediction of GI symptoms burden at follow-up, N=209 patients
Several sensitivity analyses were done to support our findings: repeating the analysis without imputation led to similar results (online supplemental table S1), despite 59 patients not being taken into account because of missing data. Similarly, by repeating the analysis on the total GIT score only in patients with GI symptoms at baseline (total GIT score >0), with and without imputation for missing data, we arrived at similar results as in the models including all patients (table 5 and online supplemental table S2). The same was true when only patients without immunosuppressive treatment at baseline (with and without imputation for missing data) were considered (online supplemental tables S3 and S4).
Prediction of GI symptoms burden at follow-up in patients who had GI symptoms at baseline (GIT total score >0 at baseline), N=118 patients
There was no significant association between immunosuppressive treatment during the observation period and any of the GIT subscales at follow-up, with the exception of the subscale for constipation (results are not shown). However, in all models, treatment with immunosuppressants consistently had negative estimates, similarly to the model for the total score. In all models, except for ‘constipation’ and ‘distention and bloating’, the baseline symptom score had a significant association with the score at follow-up.
Estimation of the treatment effect of immunosuppressants on GI symptoms at follow-up
In order to assess the effects of immunosuppressive treatment on the GI symptoms at follow-up, we first matched patients by baseline characteristics and used their values at the follow-up visit for the time-varying parameters (online supplemental tables S5 and S6). The results of the treatment effect model were similar to those of the prediction model (table 6), showing the same statistically significant negative relationship between immunosuppressive therapy and the total GIT score at follow-up. The total GIT score at baseline was again the strongest predictor of the total GIT score at follow-up, while BMI had a low estimate (0.02) and thus a reduced relevance, despite reaching statistical significance.
Treatment effect model of GI symptoms burden at follow-up, N=209 patients
Discussion
In this study, we have shown for the first time in a large cohort of unselected patients with SSc, that treatment with immunosuppressants is associated with a lower burden of GI symptoms after exposure to this treatment. The results are robust, as they were consistent in all our models and sensitivity analyses. All analyses took into account other factors that could potentially influence GI symptoms at follow-up, such as demographic data, disease duration, treatment with PPI, and the GIT score at baseline. Considering that patients with extensive fibrosis might have more severe GI symptoms, we included among the covariates the mRSS, as a measure of skin fibrosis, and the predicted FVC, reflecting the severity of lung fibrosis. We also included BMI as a surrogate of nutrition status, and ESR as a measure of inflammation. We preferred ESR to CRP because of more missing data and of possible influence of tocilizumab on the latter. Due to the real-life character of our data, we adjusted the models for treatment with immunosuppressants received in the previous 6 months before baseline (12 months for rituximab) and performed sensitivity analyses excluding patients who already had immunosuppressants at baseline. In all analyses, we could see a significant association between immunosuppressive treatment and less severe GI symptoms at follow-up, except when analysing only patients who did not take such medication at baseline. In these patients, however, repeating the prediction analysis without data imputation identified again a statistically significant association.
To date, only two previous large longitudinal cohort studies evaluated a potential effect of immunosuppressive treatment on GI symptoms, and both reported negative results: Richard et al followed 762 patients with early SSc (<3 years of disease duration), without severe GI disease at baseline. The outcome was the occurrence of severe GI disease, defined as physician-reported malabsorption, need for hyperalimentation, one or more episodes of pseudo-obstruction and/or a ≥10% wt loss in association with the use of antibiotics for small intestinal bacterial overgrowth or with oesophageal stricture. During a mean follow-up of 4.0±2.6 years, severe GI disease developed in 11.6% of the 319 patients exposed and in 6.8% of the 443 not exposed to immunosuppression. Thus, no effect of immunosuppression on the risk of severe GI involvement could be demonstrated.9
van Leeuwen et al studied prospectively 236 patients with early SSc (disease duration since first non-Raynaud sign or symptom <24 months) and 598 patients with SSc of longer disease duration. The outcome measure was worsening of the GIT, defined as change larger than the MCID for the total score. In total, n=685 (82%) never had immunosuppressive treatment (81% of early SSc and 83% of the others patients); of these, 258 (38%) started with immunosuppressants after baseline assessment (52% early, 32% other, p=0.02). After 1 year of follow-up, worsening of GI symptoms occurred more frequently in patients who started immunosuppressive treatment, who also had more severe overall disease than patients without such treatment. In logistic regression adjusted for disease duration and severity, there were no significant associations between immunosuppressive treatment and worsening of GI symptoms.10
The most important difference between these two cohort studies and ours relies on the immunosuppressive treatment, which did not include biological agents, while in our cohort 34/209 (16.3%) of all patients, and 34/71 (47.9%) of those receiving immunosuppressants, had either rituximab or tocilizumab. This raises the question if the association between treatment and GI symptoms might be due to biological agents, which due to the small number of cases and the real-life setting of the study cannot be answered based on our data. Another difference relies on the higher statistical power of our study, which, instead of analysing categorical change in the GIT or categorical appearance of severe GI disease as the main outcome, had the more robust numeric total GIT score at follow-up as outcome, and the numeric baseline GIT as one of the covariates. Regression modelling, as well as matched cohort approaches with patients paired based on baseline characteristics, may be applied to observational studies to assess treatment.21
Although no causal association between treatment and severity of GI symptoms can be demonstrated based on our results, the robust association we found suggests that such an effect is possible and should be investigated in further prospective, randomised controlled studies.
Our study also has limitations, coming from its real-life nature. Many patients had already immunosuppressive treatment before baseline, and when excluding these patients from the prediction analysis, statistical significance of the treatment-GI symptom association was maintained only in the model without imputation for missing data. The cohort size did not allow more restrictive exclusion criteria, nor separate analysis for individual immunosuppressants. Other limitations are the lack of detail regarding comedication, especially with regard to drugs prescribed for GI symptoms, such as prokinetics and antibiotics, and the lack of information regarding lifestyle and diet. Another important aspect is the potential influence of disease duration on the frequency and severity of GI symptoms. In our study, the disease duration at baseline was similar to that of the cohort studied by van Leeuwen et al.10 Conversely, the cohort examined by Richard et al9 had a markedly shorter disease duration at baseline (1.4 years compared with 6 years in both the van Leeuwen cohort and ours). Consequently, it is important to note that our findings may not be generalisable to patients with longer disease durations, such as those exceeding 10 years. Finally, as the pathogenesis of GI disease in SSc is only partially understood, there could be unmeasured bias between the patient groups, for which we made no adjustment in the analysis.
In conclusion, we found an association between immunosuppressive treatment and a reduced GI symptom burden, which suggests the potential effects of immunosuppressants on GI manifestations in patients with SSc. These results offer the basis for further research with prospective studies and randomised controlled clinical trials.
Data availability statement
Data are available on reasonable request. The data underlying this article will be shared on reasonable request to the corresponding author.
Ethics statements
Patient consent for publication
Ethics approval
The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and GCP guidelines. Ethical approval for data collection and analysis was issued by the Cantonal Ethics Committee (BASEC Nr. PB2016-01515 and 2018-02165), and all patients signed informed consent forms.
Acknowledgments
The authors would like to thank Dr. Sc. Stefanie von Felten (Epidemiology, Biostatistics and Prevention Institute, University of Zurich) for her comments and suggestions on the statistical analysis. They also wish to express their gratitude to all patients who participated in this study.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
X @CosimoBruni, @MurielElhai
Contributors CM is the guarantor and accepts full responsibility for the work and the conduct of the study, has access to the data and controls the decision to publish. All authors as listed on the title page of the manuscript have made substantial contributions which qualifies them as authors. All authors contributed to critical revisions and approved the final version of the manuscript. LS, AG, CB, MB, RD, ME, SJ, OD and CM designed the study. LS and CM wrote the manuscript, LS performed the statistical analysis. MB, RD, ME, NZ, SI and CM contributed to data collection. All authors discussed the results and revised the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests MB has received consultancy fees from GSK, Amgen, Novartis and Vifor. CB has received consultancy fees from Boehringer Ingelheim, grants/research support from Gruppo Italiano Lotta alla Sclerodermia (GILS), European Scleroderma Trials and Research Group (EUSTAR), Foundation for research in Rheumatology (FOREUM), Scleroderma Clinical Trials Consortium (SCTC), Scleroderma Research Foundation (SRF), EMDO foundation. Educational grants from AbbVie and Wellcome Trust, and congress support from Boehringer Ingelheim. RD has received speaker and/or consultancy fees from Actelion, Boehringer-Ingelheim; grant/research support from: Pfizer, Actelion, Iten-Kohaut; and congress participation support from Amgen and Otsuka. She also received the Walter and Sigrid Siegenthaler Fellowship. ME has received congress support from Janssen and Astra-Zeneca and research support from Novartis outside of the submitted work. She also received the Walter and Sigrid Siegenthaler Fellowship. SI has received a EULAR scientific long-term training grant for young fellows. OD has/had consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Argenx, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Cantargia AB, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Nkarta Inc., Novartis, Orion, Prometheus, Redxpharma, Roivant, EMD Serono, Topadur and UCB. Patent issued 'mir-29 for the treatment of systemic sclerosis' (US8247389, EP2331143). Cofounder of CITUS AG. CM received speaker and/or consultancy fees from Janssen-Cilag AG, Boehringer Ingelheim, MED Talks Switzerland, Medbase, Mepha, Novartis and PlayToKnow AG and travel support for congress from Boehringer Ingelheim.
Provenance and peer review Not commissioned; externally peer reviewed.
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