Correspondence to Dr Natalia Mena-Vázquez; [email protected]
STRENGTHS AND LIMITATIONS OF THIS STUDY
The study employed validated instruments such as University of California, Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 and Eating Assessment Tool-10 for assessing gastrointestinal involvement and dysphagia, ensuring reliability and comparability of results.
Various aspects of gastrointestinal symptoms including reflux, constipation and dysphagia were thoroughly assessed, providing a comprehensive understanding of the issue.
Inclusion criteria based on standardised guidelines: patients were diagnosed with SSc according to the 2013 American College of Rheumatology/European League Against Rheumatism criteria, ensuring consistency and reliability in patient selection.
Due to the single centre, non-controlled cross-sectional design, causal relationships cannot be established.
Introduction
Systemic sclerosis (SSc) is a chronic systemic autoimmune disease characterised by vascular dysfunction and fibrosis of the skin and internal organs.1 The global combined prevalence of both types of SSc (limited and diffuse) is relatively low, at 17.6 cases per 100 000 persons; however, this value varies between studies. Owing to its low prevalence, SSc is considered a rare disease in the European Union, although its frequency could be greater in North America and Asia if milder cases are taken into account.2 Nevertheless, while an uncommon disease, SSc is characterised by high morbidity and mortality and generates a considerable health and socioeconomic impact.3
Gastrointestinal involvement is a significant problem in patients with SSc, affecting almost 90%, irrespective of skin involvement.4 While the pathogenesis of SSc is not fully known, the disease is thought to be triggered by an early vascular lesion with alteration of intestinal permeability followed by neural dysfunction, fibrosis and loss of function. Circulating antibodies are also thought to play a role in pathogenesis.5 6 Consequently, numerous clinical manifestations are triggered, and these can affect any part of the gastrointestinal tract from the mouth to the anus and lead to severe complications such as oesophagitis, Barret oesophagus, bleeding resulting from vascular dysplasia and toxic megacolon.7 8 Gastrointestinal involvement significantly increases morbidity and mortality, since it can lead to malnutrition of various causes, diminished health-related quality of life (HRQoL) and severe complications.9
The symptoms of gastrointestinal dysfunction are difficult to evaluate in SSc, because they can result from organ damage or the adverse effects of treatment.7 Therefore, recent years have seen the advent of validated measures, namely, patient-reported outcome measures (PROMs), which include measures aimed at evaluating the degree of gastrointestinal involvement in SSc. The most notable of the various instruments used is the University of California, Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) instrument10 11 owing to its viability, reliability (test–retest and internal consistency) and validity, which has been demonstrated in several observational studies.7 8 10 12 Recent studies have attempted to describe digestive involvement in patients with SSc using the UCLA SCTC GIT 2.0 instrument.13 14 Also notable for evaluation of digestive disorders is the ‘Eating Assessment Tool-10’ (EAT-10) questionnaire, which assesses dysphagia and complements the abovementioned PROM.15 However, no in-depth evaluation has been performed of the correlation between gastrointestinal involvement according to UCLA SCTC GIT 2.0 and EAT-10 and other characteristics and factors associated with the disease, or of comorbid conditions and their impact on HRQoL. Therefore, the objectives of our study were as follows: (1) to describe digestive involvement using UCLA SCTC GIT 2.0 and EAT-10 in a cohort of patients with SSc; (2) to determine the impact of digestive involvement on the HRQoL of patients with SSc and (3) to identify socioeconomic, clinical, laboratory and therapeutic factors associated with gastrointestinal symptoms.
Patients and methods
Study design, data source and sample
Ours was a single-centre, observational cross-sectional study. Data were collected from the Regional University Hospital of Málaga, where specialised rheumatologists and nurses manage patients with systemic autoimmune diseases by means of dedicated consultations.
Patients
Participating patients were recruited consecutively between May and November 2022. Patients with SSc were selected according to the 2013 criteria of the American College of Rheumatology/European League Against Rheumatism (score of ≥9)16 and had to be aged ≥16 years at the onset of their disease. The patients were stratified as having limited cutaneous SSc or diffuse cutaneous SSc according to the 2001 LeRoy and Medsger classification criteria.17 18 Patients with inflammatory diseases other than SSc (except secondary Sjögren syndrome or mixed connective tissue disease), active infection, or inflammatory and neoplastic gastrointestinal diseases were excluded.
Patient and public involvement
Neither patients nor the public had any involvement in formulating or executing the study, and participants were not engaged in the dissemination of the findings. The study results will be accessible to patients on request, and the conclusions will be disseminated through publications and conferences.
Study protocol
Patients with SSc are followed up and treated jointly by a rheumatologist and a nurse in specialist clinics every 3–6 months or more frequently if their clinical situation so requires. The reference rheumatologist invited the patients to participate in the study, confirmed that they met the selection criteria and collected clinical data using a specific questionnaire. The nurse provided a detailed explanation of the PROMs to assist patients with completion, recorded anthropometric data and collected biological samples after a fast of at least 8 hours. Anthropometric data, including measurements such as height, weight, body mass index (BMI), as well as the classification of underweight (BMI<18.5), normal weight (BMI 18.5–24.9), overweight (BMI 25–29.9) and obesity (BMI≥30) according to the WHO.19
Variables associated with digestive involvement, malnutrition and quality of life
The main outcome measures were intensity of digestive involvement according to UCLA SCTC GIT 2.020 and EAT-10.15 21 UCLA SCTC GIT 2.0 comprises 34 questions with 7 subscales that provide information on the severity of gastrointestinal symptoms (reflux, distension/bloating, diarrhoea, faecal soilage, constipation, emotional well-being and social functioning). The questionnaire generates a global score for the patient’s gastrointestinal health status (HRQoL-GI) and symptom severity. The scales are scored from 0.00 (ie, better HRQoL-GI) to 3.00 (worse HRQoL-GI), with the exception of diarrhoea and faecal soilage, which are scored from 0.00 to 2.00 and 0.00 to 2.50, respectively. Finally, UCLA SCTC GIT 2.0 provides a global evaluation of the severity of gastrointestinal disorders ranging from 0.00 to 2.83 as the result of the sum of all the scales, except for that associated with constipation. Patients were reclassified according to this severity scale as having (1) no digestive involvement or mild symptoms; (2) moderate involvement and (3) severe or very severe involvement based on published data from the National Scleroderma Foundation online survey7 (online supplemental table 1).
EAT-10 is used to provide an additional evaluation, but only of dysphagia. It comprises 10 questions designed to identify problems with swallowing and to evaluate how these problems affect HRQoL. Patients rate each question on a scale of 0–4, where 0 indicates no problem and 4 indicates a severe problem. The total score is obtained by adding the replies to the 10 questions, thus providing a global score for severity of dysphagia.15 A score ≥3 indicates dysphagia (ie, the patient experiences difficulty swallowing effectively and safely).22
Other variables
We also recorded various clinical and epidemiological data, namely, age, sex, educational level, income, smoking/drinking, comorbid conditions and medication. We recorded comorbid conditions associated with traditional cardiovascular risk factors (smoking, obesity, arterial hypertension, diabetes mellitus, dyslipidaemia and a history of cardiovascular disease), those associated with the Charlson Comorbidity Index (CCI),23 and other factors, such as osteoporosis.
Malnutrition was assessed using the Mini Nutritional Assessment Short Form (MNA-SF). HRQoL was evaluated using the 3-Level EuroQol-5D (EQ-5D-3L) questionnaire, with its Visual Analogue Scale (VAS).24 The MNA-SF is a short questionnaire that is used to evaluate nutritional status based on six questions associated with food intake, weight loss, mobility, psychological stress and diseases. It yields a total score ranging from 0 (worst nutritional status) to 14 (best nutritional status). According to the score, nutrition is classified as normal (>11 points), risk of malnutrition (8–11 points) and malnutrition (0–7 points).25–27
We also included SSc-specific variables, such as duration of symptoms since the first non-Raynaud symptom was reported, degree of involvement (diffuse or limited), clinical manifestations, and involvement of other organs and systems. The degree of skin fibrosis was measured using the modified Rodnan skin score (mRSS).28 We also recorded clinical data on the presence of interstitial lung disease and the presence of antibodies as follows: antinuclear (ANA), anti-U1RNP-specific autoantibodies, anticentromere, anti-Scl70, anti-RNA polymerase III, anti-PM-Scl, anti-Ro 52 kDa, anti-Ro 60 kDa, anti-La and anti-aminoacyl-tRNA synthetase. Similarly, we recorded treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biologic DMARDs, immunosuppressants and antifibrotic agents, as well as corticosteroids. Polypharmacy was defined as the routine use of ≥5 medications, according to the 2019 WHO criteria.29
Statistical analysis
First, we performed a descriptive analysis of the main variables in the 75 patients with SSc. The frequency of qualitative variables was expressed as number of observations and percentage. Quantitative variables are expressed as mean±SD when normally distributed and as median and percentiles 25 and 75 (p25–p75) when non-normally distributed. The normality of the distribution of continuous variables was confirmed using the Kolmogorov-Smirnov test. An analysis of variance was performed for patients with SSc and mild or no digestive involvement, moderate involvement, and severe or very severe involvement according to the UCLA SCTC GIT 2.0; the Pearson χ2 or t-test was used to compare patients with and without dysphagia according to the EAT-10. We also performed a correlation analysis (Pearson r) between UCLA SCTC GIT 2.0 and EAT-10 and the different clinical characteristics of SSc. Finally, we ran two multivariate models (logistic and linear regression) to identify factors associated with UCLA SCTC GIT 2.0 and EAT-10 (≥3). The variables entered into the model were those that proved significant in the bivariate analysis and other variables of clinical interest. Statistical significance was set at p<0.05 (two-tailed). The statistical analyses were performed using IBM SPSS Statistics for Mac OS, V.28.0 (IBM Corp., Armonk, NY, USA).
Results
Baseline characteristics of the sample
The sample comprised 75 patients with SSc and a median (p25–p75) disease duration of 10.0 (6.0–17.0) years since the first non-Raynaud symptom. As shown in table 1, most patients were women (97.3%). The mean (SD) age was 59.6 (10.6) years, and most patients were of Caucasian race (85.3%). Almost all had been educated to primary or secondary level and had an income of <€1500.
Table 1Baseline characteristics of 75 patients with systemic sclerosis
| Variable | N=75 |
| Epidemiological characteristics | |
| Female sex, n (%) | 73 (97.3) |
| Age in years, mean (SD) | 59.6 (10.6) |
| Caucasian, n (%) | 64 (85.3) |
| North African, n (%) | 1 (1.3) |
| Latin American, n (%) | 10 (13.3) |
| Educational level | |
| No formal study, n (%) | 3 (4.0) |
| Primary school, n (%) | 41 (54.7) |
| Secondary school, n (%) | 21 (28.0) |
| University, n (%) | 10 (13.3) |
| Monthly income | |
| None, n (%) | 19 (25.3) |
| <€1500, n (%) | 42 (56.0) |
| ≥€1500, n (%) | 14 (18.7) |
| Smoking | |
| Non-smoker, n (%) | 49 (65.3) |
| Smoker, n (%) | 5 (6.7) |
| Ex-smoker, n (%) | 21 (28.0) |
| Alcohol consumption, n (%) | 5 (6.7) |
| Body mass index (kg/m2), mean (SD) | 25.6 (4.4) |
| Underweight, n (%) | 1 (1.3) |
| Normal weight, n (%) | 34 (45.3) |
| Overweight, n (%) | 29 (38.7) |
| Obesity, n (%) | 11 (14.7) |
| Comorbid conditions | |
| Family history of CVD | 4 (5.3) |
| Diabetes mellitus, n (%) | 6 (8.0) |
| Arterial hypertension, n (%) | 20 (26.7) |
| Cardiovascular disease, n (%) | 1 (1.3) |
| Dyslipidaemia, n (%) | 23 (30.7) |
| Osteoporosis, n (%) | 9 (12.0) |
| COPD, n (%) | 6 (8.0) |
| Asthma, n (%) | 2 (2.7) |
| Age-adjusted Charlson Comorbidity Index, median (p25–p75) | 3.0 (2.0–4.0) |
| Clinical characteristics | |
| Disease duration in years, median (p25–p75) | 10.0 (6.0–17.0) |
| Skin pattern | |
| Sine scleroderma, n (%) | 3 (4.0) |
| Limited, n (%) | 56 (74.7) |
| Diffuse, n (%) | 16 (21.3) |
| Raynaud phenomenon, n (%) | 75 (100) |
| Digital ulcers, n (%) | 18 (24.0) |
| Puffy fingers, n (%) | 30 (40.0) |
| Arthritis, n (%) | 12 (16.0) |
| Oesophageal dysmotility, n (%) | 9 (12.0) |
| GER | 28 (37.3) |
| ILD, n (%) | 26 (34.7) |
| PAH, n (%) | 7 (9.3) |
| Renal crisis, n (%) | 2 (2.7) |
| mRSS, median (p25–p75) | 8.0 (2.0–13.0) |
| Laboratory data | |
| ANA, n (%) | 73 (97.3) |
| Anticentromere, n (%) | 42 (56.0) |
| Anti-Scl70, n (%) | 17 (22.7) |
| Anti-RNA polymerase III, n (%) | 2 (2.7) |
| Other autoantibodies, n (%) | 16 (21.3) |
| Treatment | |
| Polypharmacy, n (%) | 18 (24.0) |
| csDMARDs | 26 (34.7) |
| Immunosuppressants | 15 (20.0) |
| bDMARDs | 5 (6.7) |
| Calcium antagonists, n (%) | 48 (64.0) |
| PDE5I, n (%) | 10 (13.3) |
| Prokinetic agents, n (%) | 10 (13.3) |
| Nintedanib, n (%) | 3 (4.0) |
| Corticosteroids, n (%) | 16 (21.3) |
ANA, antinuclear antibodies; bDMARDs, biologic disease-modifying antirheumatic drugs; COPD, chronic obstructive pulmonary disease; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CVD, cardiovascular disease; GER, gastro-oesophageal reflux; ILD, interstitial lung disease; mRSS, modified Rodnan skin score; PAH, pulmonary arterial hypertension; PDE5I, phosphodiesterase 5 inhibitor.
Patients with SSc had a high age-adjusted CCI (3.0 (2.0–4.0)), with the main comorbid conditions being cardiovascular disease and osteoporosis. While more than one-third of patients were smokers, only 6.7% were current smokers.
Three in every four patients had a limited cutaneous SSc (74.7%), and the median mRSS was not high (median (p25–p75) 8.0 (2.0–13.0)). The most prevalent non-digestive clinical manifestations were Raynaud phenomenon, telangiectasias, microstomia, swollen fingers, digital ulcers, calcinosis cutis and diffuse interstitial lung disease. Almost all the patients had positive ANA values, with a predominance of anticentromere antibody (56.0%) and anti-Scl70 antibody (22.7%), although other antibodies were also detected (table 1).
Most patients (89.3%) were taking medication, and 25% were polymedicated. Calcium antagonists were the most widely prescribed drugs, followed by csDMARDs (37%), especially methotrexate (29.3%). Among the immunosuppressants (20%), the most widely used was mycophenolate mofetil (20.0%). More than 20% of patients were taking corticosteroids at ≤5 mg/d.
Digestive involvement, malnutrition and quality of life
Table 2 provides detailed results for the PROMs used to evaluate digestive involvement, nutrition and HRQoL in the 75 patients with SSc. In line with the results adjusted for the 7 subscales of the UCLA SCTC GIT 2.0 questionnaire, the severity of digestive symptoms was moderate (median (p25–p75) 0.5 (0.2–1.1)), with the highest scores corresponding to abdominal distension (median (p25–p75) 1.0 (0.5–2.0)) and reflux (median (p25–p75) 0.6 (0.1–1.1)). In fact, more than half of the patients reported moderate, severe, or very severe reflux (58.7%) and constipation (57.4%), and slightly less than half reported abdominal distension (49.7%). However, most patients reported mild or no symptoms in the subscales of faecal soilage and diarrhoea. Figure 1 shows the results for the UCLA SCTC GIT 2.0 subscales. Furthermore, when dysphagia was evaluated using EAT-10, slightly more than half of the patients (52%) reported difficulty swallowing efficiently and safely (EAT-10≥3).
Enlarge this image.Figure 1. Bar chart for University of California, Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) subscales.
Digestive involvement in 75 patients with systemic sclerosis
| Variable | N=75 |
| UCLA, median (p25–p75) | 0.5 (0.2–1.1) |
| UCLA classification | |
| None or mild, n (%) | 31 (41.3) |
| Moderate, n (%) | 23 (30.7) |
| Severe or very severe, n (%) | 21 (28.0) |
| Reflux, median (p25–p75) | 0.6 (0.1–1.1) |
| Reflux classification | |
| None or mild, n (%) | 31 (41.3) |
| Moderate, n (%) | 21 (28.0) |
| Severe or very severe, n (%) | 23 (30.7) |
| Abdominal distension, median (p25–p75) | 1.0 (0.5–2.0) |
| Abdominal distension classification | |
| None or mild, n (%) | 38 (50.7) |
| Moderate, n (%) | 8 (10.7) |
| Severe or very severe, n (%) | 29 (38.7) |
| Faecal soilage, median (p25–p75) | 0 (0.0–1.0) |
| Faecal soilage classification | |
| None or mild, n (%) | 64 (85.3) |
| Moderate, n (%) | 7 (9.3) |
| Severe or very severe, n (%) | 4 (5.3) |
| Diarrhoea, median (p25–p75) | 0 (0.0–1.0) |
| Diarrhoea classification | |
| None or mild, n (%) | 42 (56.0) |
| Moderate, n (%) | 16 (21.3) |
| Severe or very severe, n (%) | 17 (22.7) |
| Constipation, median (p25–p75) | 0.7 (0.0–1.2) |
| Constipation classification | |
| None or mild, n (%) | 32 (42.7) |
| Moderate, n (%) | 23 (30.7) |
| Severe or very severe, n (%) | 20 (26.7) |
| Social functioning, median (p25–p75) | 0.1 (0.0–1.0) |
| Social functioning classification | |
| None or mild, n (%) | 43 (57.3) |
| Moderate, n (%) | 17 (22.7) |
| Severe or very severe, n (%) | 15 (20.0) |
| Emotional well-being, median (p25–p75) | 0.2 (0.0–1.0) |
| Emotional well-being classification | |
| None or mild, n (%) | 45 (60.0) |
| Moderate, n (%) | 13 (17.3) |
| Severe or very severe, n (%) | 17 (22.7) |
| EAT-10, median (p25–p75) | 3.0 (0.0–11.0) |
| Dysphagia (EAT≥3), n (%) | 39 (52.0) |
| No dysphagia (EAT<3), n (%) | 36 (48.0) |
| MNA-SF, mean (SD) | 11.7 (2.3) |
| Normal (>11 points) | 48 (64.0) |
| Risk of malnutrition (8–11 points) | 23 (30.7) |
| Malnutrition (0–7 points) | 4 (5.3) |
| EQ-5D-3L, median (p25–p75) | 0.6 (0.4–0.7) |
| VAS-EQ-5D-3L, median (p25–p75) | 52.5 (43.7–71.2) |
EAT-10, Eating Assessment Tool-10; EQ-5D-3L, 3-Level EuroQol-5D; MNA-SF, Mini Nutritional Assessment Short Form; UCLA, University of California, Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0; VAS, Visual Analogue Scale.
All these digestive manifestations significantly affected social functioning (42.7%) and emotional well-being (40.0%) according to UCLA SCTC GIT 2.0. Moreover, when HRQoL was evaluated using the generic instrument EQ-5D-3L, the results indicated moderate involvement of health status (median (p25–p37), 0.6 (0.4–0.7)) and a global perception of health (VAS-EQ-5D-3L) of 52.5 (43.7–71.2), thus pointing to a marked impairment in HRQoL.
Finally, in terms of nutrition, while the results in the MNA-SF were relatively good (>11 points) for most patients, nutrition was deficient (ie, MNA-SF between 8 and 11 points) in a significant percentage (30.7%) or the patients were clearly undernourished (ie, MNA-SF≤7) requiring a nutritional intervention in 5.3%.
Factors associated with digestive involvement
According to the UCLA SCTC GIT 2.0 instrument, 21/75 patients (28%) experienced severe or very severe gastrointestinal involvement, whereas 23/75 patients (30.7%) had moderate involvement and 31/75 (41.3%) had mild or no involvement. When the sample was stratified according to these three findings on the UCLA SCTC GIT 2.0 (online supplemental table 2), patients with severe or very severe involvement had higher mRSS values than the others (p=0.005), a higher risk of malnutrition according to the MNA-SF (p=0.019), lower levels of vitamin D (p=0.025), poorer HRQoL according to the VAS-EQ-5D-3L (p=0.002), and more frequent treatment with rituximab (p=0.017) and prokinetic agents (p=0.030).
Furthermore, the heatmap chart (figure 2) shows a significant direct correlation between the adjusted total value of the UCLA SCTC GIT 2.0 and the mRSS (r=0.305, p=0.008) and an inverse correlation with the MNA-SF (r=–0.338, p=0.003), EQ-5D-3L (r=–0.312, p=0.007) and VAS-EQ-5D-3L (r=–0.331, p=0.004).
Enlarge this image.Figure 2. Linear correlations between the UCLA and EAT-10 questionnaires in systemic sclerosis. BMI, body mass index; EAT-10, Eating Assessment Tool-10; EQ-5D-3L, 3-Level EuroQol-5D; MNA, Mini Nutritional Assessment; mRSS, modified Rodnan skin score; UCLA, University of California, Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0; VAS, Visual Analogue Scale.
Stratification of the main variables of interest with respect to presence of dysphagia (39/75) or absence of dysphagia (36/75) according to the EAT-10 questionnaire revealed notable differences between the groups, such as greater frequency of osteoporosis (p=0.018), microstomia (p=0.001), digital ulcers (p=0.002), telangiectasias (p=0.030) and extended skin involvement (mRSS, p=0.001) in patients with dysphagia (online supplemental table 3). Similarly, the same patients more frequently received mycophenolate (p=0.015) and had poorer scores in the MNA-SF and for EQ-5D-3L (HRQoL). Finally, significant correlations were found between EAT-10 and the mRSS (r=0.516, p<0.001), total MNA (r=–0.469, p<0.001), EQ-5D-3L (r=–0.405, p<0.001) and VAS-EQ-5D-3L (r=–0.265, p=0.022) (figure 2).
Multivariate analysis
Table 3 shows the results of the univariate and multivariate linear regression analyses for the main factors associated with the overall degree of digestive involvement (UCLA SCTC GIT 2.0); table 4 shows the results of the univariate and multivariate logistic regression analyses for the factors associated with dysphagia (EAT-10) in patients with SSc. The predictive factors evaluated for both models were age, sex, mRSS, MNA-SF and VAS-EQ-5D-3L.
Table 3Results of the univariate and multivariate analyses of characteristics associated with digestive involvement in 75 patients with systemic sclerosis
| Predictor | Univariate | Multivariate | |||
| B | 95% CI | B | 95% CI | P value | |
| UCLA total score | |||||
| Female sex | 0.685 | −0.762 to 2.132 | |||
| Age, years | −0.009 | −0.031 to 0.014 | |||
| Disease duration | 0.034 | −0.046 to 0.115 | |||
| mRSS | 0.468 | 0.198 to 0.738 | 0.419 | 0.157 to 0.671 | 0.002 |
| MNA-SF≤7 | 0.485 | −0.553 to 1.523 | |||
| VAS-EQ-5D-3L, mm | −0.019 | −0.030 to 0.009 | −0.019 | −0.030 to 0.008 | 0.001 |
Variables included in the equation: sex, age, disease duration, MNA-SF, VAS-EQ-5D-3L, mRSS.
Nagelkerke R2=0.265.
EQ-5D-3L, 3-Level EuroQol-5D; MNA-SF, Mini Nutritional Assessment Short Form; mRSS, modified Rodnan skin scale; UCLA, University of California, Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0; VAS, Visual Analogue Scale.
Table 4Univariate and multivariate analyses of characteristics associated with dysphagia in 75 patients with systemic sclerosis
| Predictor | Univariate | Multivariate | |||
| OR | 95% CI | OR | 95% CI | P value | |
| Dysphagia* | |||||
| Female sex | 1.083 | 0.999 to 1.100 | |||
| Age, years | 1.000 | 0.958 to 1.044 | |||
| Disease duration | 1.005 | 1.003 to 1.110 | |||
| mRSS | 3.192 | 1.618 to 6.296 | 1.155 | 1.044 to 1.277 | 0.015 |
| MNA-SF≤7 | 8.024 | 2.574 to 16.013 | 4.210 | 1.195 to 14.833 | 0.025 |
| VAS-EQ-5D-3L, mm | 0.961 | 0.936 to 0.986 | 0.958 | 0.928 to 0.988 | 0.007 |
Variables included in the equation: sex, age, disease duration, MNA-SF, VAS-EQ-5D-3L, rMSS.
Dysphagia=EAT-10≥3.
*Nagelkerke R2=0.491.
EAT-10, Eating Assessment Tool-10; EQ-5D-3L, 3-Level EuroQol-5D; MNA-SF, Mini Nutritional Assessment Short Form; mRSS, modified Rodnan skin scale; VAS, Visual Analogue Scale.
After adjustment for multiple variables, the degree of skin involvement according to the mRSS (β=0.249; p=0.002) was significantly and positively associated with the intensity of the gastrointestinal manifestations measured using the total UCLA SCTC GIT 2.0 score, whereas an inverse correlation was observed for overall perception of HRQoL measured using the VAS-EQ-5D-3L (β=–0.302; p=0.001).
Similarly, the presence of dysphagia measured using the EAT-10 questionnaire (score ≥3) revealed, in addition to the mRSS (OR=2.794; p=0.015) and VAS-EQ-5D-3L (OR=0.950; p=0.005), that patients with dysphagia were four times more likely to have malnutrition based on an MNA-SF score ≤7 (OR=3.920; p=0.041).
Discussion
This study measured the severity of gastrointestinal symptoms and evaluated quality of life associated with the gastrointestinal system in patients with SSc using the UCLA SCTC GIT 2.0 and EAT-10 instruments. The objectives also included the study of potential associated factors. Our results showed that digestive involvement was moderate or severe in 58% of patients with SSc, that is, slightly higher than those reported by Khanna et al,10 possibly because the patients in our study were older and disease duration was longer. However, our results for the subscales of the UCLA SCTC GIT 2.0 that were most affected (ie, gastro-oesophageal reflux and abdominal distension) were similar. These results are also consistent with those of Zekovic and Damjanov,30 who also reported higher scores in the same subscales.
Global quantitative data on the UCLA SCTC GIT 2.0 instrument indicated moderate intensity (median 0.5), although values were somewhat higher than those observed in the study by Lee et al 31 in Korea, that is, global values of 0.3 in the UCLA SCTC GIT 2.0. While this difference could be clinically relevant, as it exceeds the minimally important differences in this questionnaire (0.20–0.50),10 it is probably due to genetic and methodological differences. Of note, the UCLA SCTC GIT 2.0 instrument has been specifically validated in patients with SSc20 32 and can prove useful in that it enables rheumatologists to better understand the burden of gastrointestinal symptoms on an individual basis and helps them to better identify patients requiring additional digestive assessment.33
Given that UCLA SCTC GIT 2.0 does not specifically evaluate the presence and severity of dysphagia, we performed an additional evaluation using the EAT-10 questionnaire. The results showed that 52% experienced difficulty swallowing effectively and safely (EAT-10≥3). While EAT-10 is usually administered as a tool for initial evaluation, it is important to point out that, to date, it has only been validated in patients with neurological diseases.22 Therefore, we lack specific comparative data for patients with SSc. Nevertheless, studies performed in patients with inflammatory myopathy have shown that the degree of involvement can range from 32% to 84%.34 35
In the present study, the main factors associated with digestive involvement according to UCLA SCTC GIT 2.0 were the mRSS and HRQoL assessed using the EQ-5D-3L. Our results revealed that the mRSS was significantly higher in the group of patients with severe digestive involvement, including dysphagia. This observation was confirmed after adjustment in the multivariate models, suggesting a direct relationship between the degree of skin involvement and the intensity of oesophageal symptoms. For many years, skin involvement has been considered a key marker of activity, severity and prognosis in SSc, as well as an independent factor for mortality.36 37 Studies reveal significant immune cell infiltration in SSc skin, with B cells playing a crucial role alongside T cells. B cell infiltration correlates with worse skin progression, especially in early-stage disease. These immune disturbances may target multiple tissues, which can lead to simultaneous involvement of the skin and other organs, including the gastrointestinal tract.38 39 Therefore, the association between mRSS and digestive involvement goes some way to explaining why morbidity and mortality are more frequent in patients with SSc.40 41 While such a direct relationship between severity of gastrointestinal involvement and mRSS has not been previously reported, the association between mRSS and gastrointestinal involvement is not new, since it has previously been observed to be directly related to abnormalities of oesophageal motility in imaging tests such as manometry and gammagraphy.42–44 Furthermore, a study performed based on the EUSTAR cohort45 showed that patients with SSc and diffuse skin involvement had gastrointestinal symptoms earlier and more frequently (p<0.05). We found that dysphagia patients had higher rates of conditions like osteoporosis, microstomia, digital ulcers and telangiectasia. While not significant in multivariate analysis, other studies confirm the considerable impact of gastrointestinal involvement on quality of life and comorbidity development.9 46
With respect to HRQoL, we recorded a significant association between digestive involvement (UCLA SCTC GIT 2.0) and EQ-5D-3L scores, both of which were also confirmed in multivariate models. Specifically, the UCLA SCTC GIT 2.0 subscales that address social functioning and emotional well-being were the most affected. These findings are coherent with those of previous studies showing that results for patients with SSc and gastrointestinal dysfunction are worse in the subscales that compare HRQoL with that of SSc patients who do not experience gastrointestinal dysfunction.47 A recent study by DiRenzo et al 48 supports these results. The authors found that a greater gastrointestinal symptom burden was associated with emotional anxiety. These findings highlight the negative impact of digestive involvement in patients with SSc, in terms of both HRQoL and emotional well-being.
In addition to the association we observed between dysphagia (EAT-10≥3) and the mRSS, we found an association between dysphagia and malnutrition in the multivariate model. The characteristics of gastrointestinal involvement, together with other manifestations of the disease, can play a role in impaired nutritional status, leading to a substantial burden in terms of morbidity and potential complications with a negative impact on mortality.49 This finding is supported by similar results reported by Hvas et al,50 who observed a correlation between risk of malnutrition and gastrointestinal manifestations. Oesophageal involvement, small intestine involvement, abdominal distension and malabsorption are all associated with malnutrition in SSc. We were unable to find studies published to date specifically on the association between dysphagia and MNA-SF. However, such an index could prove useful in SSc, since it has been validated in the general population and used in other autoimmune diseases, for example, rheumatoid arthritis.51
Of note, despite a decrease in deaths associated with malnutrition, possibly owing to improvements in nutritional support, these continue to account for up to 4% of deaths in SSc.52 Therefore, evaluation of nutritional status is still highly important in SSc.
Our study is subject to a series of limitations. First, as it is a non-controlled cross-sectional study, we cannot establish causal relationships or contextualise results. Nevertheless, this approach enabled us to identify factors associated with gastrointestinal manifestations in SSc and their prevalence, which have received little attention in the literature. Second, the PROMs we used in the study, UCLA SCTC GIT 2.0 and EAT-10, were designed to evaluate specific aspects of health and quality of life associated with nutrition and swallowing. However, the fact that they provide a subjective view of these aspects limits their capacity to identify the underlying causes of gastrointestinal problems in SSc. Despite the above, both instruments provide valuable information on how symptoms are perceived and the difficulties patients experience when swallowing. Moreover, they are easy to administer and are useful both in clinical and in research settings. Finally, it is important to note that our study was based on a single-centre sample, which, while sufficiently numerous for such a rare disease in a single centre, cannot be considered large, thus potentially limiting detection of some associations between gastrointestinal manifestations and other characteristics of SSc. Notwithstanding, we managed to identify significant associations with clinical, nutritional and HQRoL-related parameters. Furthermore, notably, the sample was analysed in depth and showed high internal coherence.
In conclusion, we found that digestive involvement is frequently responsible for symptoms in patients with SSc. Our findings indicate that approximately 60% of patients experience moderate or severe digestive involvement and that more than 50% experience dysphagia. We also observed that the severity of skin involvement, perceived HRQoL and nutritional status are significantly associated with greater gastrointestinal involvement in patients with SSc. These potential associations may have a considerable impact on the management and control of SSc.
The authors thank the Spanish Foundation of Rheumatology (FERBT2023) for providing medical writing/editorial assistance during the preparation of the manuscript.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Consent obtained directly from patient(s).
Ethics approval
This study involves human participants and the study was performed at Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma BIONAND by the Department of Rheumatology of Hospital Regional Universitario de Málaga (HRUM), Málaga, Spain. The study was conducted in accordance with the ethical guidelines outlined in the Declaration of Helsinki and was approved by the Clinical Research Ethics Committee of HRUM (Code No. 0343-N-22). The patients signed a written informed consent to participate.
LC-G and RR-R contributed equally.
Contributors LC-G, RR-R and NM-V participated in the design of the study. NM-V is the guarantor. LC-G, RR-R, SM-A, AG-S, FO-M and PB-G were contributors in including patients and carried out patient recruitment and data collection. NM-V, RR-R and AF-N were a major contributor in analysing and interpreting the patient data. They contributed in writing the manuscript. LC-G, NM-V and AF-N participated in the design of the study and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding RR-R was supported by a 'Rio Hortega' contract (CM21/00252) from the ISCIII-Madrid (Spain), cofunded by the Fondo Europeo de Desarrollo Regional-FEDER.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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; Manrique-Arija, Sara 2 ; García-Studer, Aimara 2 ; Ortiz-Marquez, Fernando 2 ; Borregón-Garrido, Paula 1 ; Fernández-Nebro, Antonio 2 1 Reumatología, Hospital Regional Universitario de Málaga, Malaga, Spain; Instituto de Investigación Biomédica de Málaga (IBIMA)-Pataforma BIONAND, Málaga, Spain
2 Reumatología, Hospital Regional Universitario de Málaga, Malaga, Spain; Instituto de Investigación Biomédica de Málaga (IBIMA)-Pataforma BIONAND, Málaga, Spain; Departamento de Medicina, Universidad de Málaga, Málaga, Spain