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Abdominal symptoms during Sjogren’s syndrome: a pilot study

Abdominal symptoms during Sjogren’s syndrome: a pilot study Background: Abdominal symptoms in patients with primary Sjögren syndrome (pSS) are poorly documented. The objective of the study was to describe the abdominal symptoms of patients with pSS and to assess their association with characteristics of the disease. Methods: One hundred and fifty patients with pSS were evaluated using a composite global symptom score for abdominal symptoms and their severity. Data concerning the clinical and biological characteristics of pSS and abdominal disorders were also collected. Results: Of the patients with pSS, 95% suffered from abdominal symptoms (median global symptom score 7.5 ± 5.5 points out of 30). More than half of the patients experienced abdominal tension (68%), upper abdominal pain (54%), abdominal discomfort (58%) and/or constipation (54%). Regarding the pSS activity, in relation to European League Against Rheumatism (EULAR) Sjögren syndrome disease activity index score items, general and central nervous system involvement wereassociated with a high global symptom score. The EULAR Sjogren Syndrome Patient Reported Index (ESSPRI) symptom score was positively correlated with the global symptom score (p < 0.01). Multivariate analysis showed a significant association between a high global symptom score and SSA seronegativity, gastroparesis, and ESSPRI score (p < 0.01 for each). Conclusions: The majority of patients with pSS suffered abdominal symptoms. There is currently no therapeutic recommendation because of the lack of information on the underlying pathophysiological mechanisms. Trial registration: NCT03157011. Date of registration: July 17, 2017. Keywords: Sjögren’s syndrome, Abdominal symptoms, Gastroparesis, ESSPRI, ESSDAI, Quality of life Background Like other autoimmune diseases, negative impact, pain, Primary Sjögren syndrome (pSS) is a chronic autoimmune and fatigue predominate, reducing the quality of life. disorder characterized by lymphocytic infiltration of the Furthermore, abdominal disorders affect approximately exocrine glands and loss of secretory function with oral 25% of patients with pSS but are poorly documented in and ocular dryness. It affects predominantly females (fe- the literature [2]. Indeed, epidemiological characteristics male:male ratio 9:1), and the peak frequency of the disease vary among studies because of the small number of is about age 50 years. The etiology of pSS is unclear [1]. patients and use of old classification criteria [2]. Also, data concerning the frequency of abdominal symptoms and * Correspondence: simon.parreau@hotmail.com their associations with clinical and biological manifesta- Internal Medicine Department, Limoges University Hospital, 16 rue du tions of pSS are contradictory [2]. This heterogeneity led Professeur Bernard Descottes, 87042 Limoges, France 2 us to conduct a non-interventional prospective study of EA 3842 - Cellular Homeostasis and Diseases, Faculty of Medicine, University of Limoges, 2 rue du Docteur Marcland, 87025 Limoges, France abdominal symptoms in patients with pSS as defined by Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Parreau et al. Advances in Rheumatology (2021) 61:5 Page 2 of 8 the 2016 American College of Rheumatology-European percentages. For qualitative variables, a chi-squared or League Against Rheumatism (ACR-EULAR) criteria [3]. Fisher’s exact test was used to compare the groups (SSA +/− SSB patients and seronegative patients). For Methods normally distributed quantitative variables, Student’s t- Population test was used to compare groups of two or more classes. From July 2017 to June 2018, we conducted a single- For non-normally distributed quantitative variables, the center study in a French Hospital and University Center. Wilcoxon signed-rank test or the Kruskal–Wallis test It was a prospective, non-interventional study, and was was used to compare groups of two or more classes. approved by the Committee for the Protection of Univariate analyses between the abdominal symptoms Individuals “Sud-Ouest et Outre Mer III” (France). All and the other variables were performed. Variables with a patients (age > 18 years) followed in our center for pSS value of p < 0.20 were included in a multivariate logistic were considered for enrollment. All of them fulfilled the model, simplified by a stepwise elimination method [19], 2016 ACR-EULAR classification criteria for pSS [3]. The so that the final model included only variables signifi- patients provided written consent after receiving infor- cantly associated with digestive symptoms. Quantitative mation on the study. The patients’ characteristics (age at variables fulfilling the logit linearity assumption were disease onset, sex, and duration of pSS), clinical manifes- incorporated without modification, or otherwise catego- tations of pSS, associated organ-specific autoimmune rized. The relevance of the model was assessed using disorders, and treatments were recorded. pSS Activity as Pearson’s residual and deviance tests, and its quality by measured by the EULAR Sjögren syndrome disease means of a receiver operating characteristic curve. To activity index (ESSDAI) and pSS symptoms measured by test the correlation between the GSS score and continu- EULAR Sjogren Syndrome Patient Reported Index ous variables, Spearman’s rho was calculated. A super- (ESSPRI) were systematically evaluated concurrently vised discretization will be performed with a decision with abdominal symptoms [4]. The data were completely tree to identify thresholds for the GSS variable. Statis- anonymized before being assessed. Blood tests were tical analysis was conducted using R software (version performed at the time of diagnosis and concurrently 3.2.2, rpart package). Values of p < 0.05 were considered with assessment of the abdominal symptoms score. indicative of significance. Evaluation of abdominal symptoms Results The patients with pSS were interviewed by a physician Patients’ characteristics and treatments using a questionnaire. The questionnaire comprised 10 A total of 150 patients (mean age 63 ± 13 years, male abdominal symptoms (nausea, vomiting, upper and lower n = 9) with pSS were enrolled. Eighty patients (53%) had abdominal pain, abdominal discomfort, bloating, diarrhea, anti-SSA antibodies and 31 (21%) had anti-SSB anti- constipation, tenesmus, dysuria). Each symptom was scored bodies (22%). One hundred and four patients (86%) had from 0 (no symptom) to 3 (severe) as evaluated by profes- a Chisholm score of ≥3 at the time of diagnosis. None of sional judgement. A global symptom score (GSS), calcu- the patients had auto-antibodies, symptoms, or capillaro- lated as the sum of all symptom scores, was assigned to scopy findings suggestive of an associated systemic scler- each patient (maximum score, 30) [5–13]. This score has osis. The most common systemic involvements, defined been used for another chronic autoimmune disease, sys- in the ESSDAI score, were articular (n = 107; 71%) and temic sclerosis, as well as for two chronic digestive patholo- muscular (n = 68; 45%). Twenty-two percent of the gies (i.e., diverticulitis and functional dyspepsia) [5–13]. patients (n = 33) had neurological involvement (central Previously diagnosed digestive, pancreatic, and hepatic dis- n = 20 [13%] and/or peripheral n = 24 [16%] with 14 [9%] eases, as well as treatments for digestive complaints, were biopsy-proven small-fiber neuropathies) [20]. Other systematically recorded in the medical file. Previous diagno- systemic involvements were hematologic (n = 30; 20%), sis of gastroparesis was based on international clinical pulmonary (n = 17; 11%), cutaneous vasculitis (n = 11; guidelines [14] and irritable bowel syndrome on the Rome 7%) and interstitial nephritis (n = 8; 5%) (Table 1). The IV classification [15]. After completing the questionnaire, average ESSDAI score was 3.4 ± 4.8 points out of 123. only those patients with alarm signs (endoscopy) or signs The average ESSPRI score was 5.9 ± 2.1 out of 10. The evocative of gastroparesis (gastric emptying scintigraphy) latter score is the average of the dryness (6.2 ± 2.4 out of underwent exploration of the digestive system, in accord- 10), fatigue (6.2 ± 2.4) and pain (5.5 ± 2.7) scores. Hydroxy- ance with the French recommendations [16–18]. chloroquine was taken by 46% (n = 70) of the patients, cor- ticosteroids by 23% (n = 35), immunosuppressive drugs by Statistical analysis 14% (n = 22; including three patients taking mycophenolate Quantitative variables are presented as means ± standard mofetil), targeted therapies by 3% (n = 5), and intravenous deviations, and qualitative variables as numbers and immunoglobulin by 5% (n = 8). Symptomatic treatments Parreau et al. Advances in Rheumatology (2021) 61:5 Page 3 of 8 Table 1 Characteristics of patients according to serological status SSA+ (n = 80) SSA- (n = 70) TOTAL (n = 150) p-value n (%) Male 3 (3.7) 6 (8.7) 9 (6.0) n.s. Age at diagnosis, years 51.2 (13.4) 55.0 (11.0) 53.0 (12.5) n.s. Mean follow-up, years 10.3 (7.9) 9.6 (6.9) 10.0 (7.4) n.s. Salivary gland enlargement 21 (26.3) 19 (27.1) 40 (26.5) n.s. Raynaud’s phenomenon 29 (36,3) 18 (25.7) 47 (31.1) n.s. Articular involvement 56 (70.0) 51 (72.9) 107 (70.9) n.s. Muscular involvement 32 (40.0) 35 (50.0) 67 (44.4) n.s. Neurologic involvement 15 (18.8) 19 (27.1) 34 (22.5) n.s. Cutaneous vasculitis 9 (11.3) 1 (1.4) 10 (6.6) 0.026 Pulmonary involvement 11 (13.8) 5 (7.1) 16 (10.6) n.s. Interstitial nephritis 6 (7.5) 2 (2.9) 8 (5.3) n.s. Fibromyalgia 2 (2.5) 10 (7.0) 12 (8.0) n.s. Depression 12 (15.0) 20 (28.6) 32 (21.3) 0.0481 Hematological involvement 23 (28.8) 8 (11.4) 31 (20.5) 0.0090 Non-Hodgkin lymphoma 2 (2.5) 0 2 (1.3) n.s. Hypergammaglobulinemia 35 (43.8) 2 (2.9) 37 (24.5) < 0.0001 Positive RF 12 (15.0) 2 (2.9) 14 (9.3) 0.0115 Cryoglobulinemia 4 (5.0) 1 (1.4) 5 (3.3) n.s. Symptomatic treatment of pSS 67 (83.7) 58 (84.0) 126 (84.0) n.s. Specific treatment of pSS 52 (65.0) 35 (50.7) 88 (58.7) n.s. Digestive treatment 33 (41.2) 39 (56.5) 73 (48.7) n.s. mean (sd) ESSDAI score 3.5 (4.9) 3.2 (4.8) 3.4 (4.8) n.s. ESSPRI score 5.5 (2.1) 6.4 (1.9) 5.9 (2.1) 0.0082 RF rheumatoid factor, pSS primary Sjögren’s syndrome, n.s not significant,sd standard deviation For qualitative variables, a Chi-2 or Fisher’s exact test was used to compare different groups of patients (SSA+ patients and seronegative patients). For quantitative variables in a normal distribution, the Student’s t-test was used to compare groups of two or more classes; for variables that do not follow a normal distribution, the Wilcoxon signed-rank test or the Kruskal-Wallis test was used to compare groups of two or more classes. The value p< 0.05 was considered significant included standard analgesics (n = 51; 34%), specific neuro- none of whom had gastroparesis. Another 7 patients had pathic pain treatments (n = 26; 17%), and nonsteroidal anti- autoimmune hepatitis with 4 cases of primary biliary inflammatory drugs (n = 13; 8%). Seventeen percent of the cholangitis and 3 of sclerosing cholangitis. Twenty-seven patients (n = 26) used antidepressants and 15% (n = 23) cases of gastritis (18%), mostly atrophic, were reported, used benzodiazepines. as well as three cases of pernicious anemia (2%) and one of coeliac disease. Thirty cases of irritable bowel syn- Previous digestive disease drome were documented (20%). Sixteen patients had Forty-four patients had symptomatic gastroesophageal enteric endoscopic diverticulosis (11%), which was reflux (29%). Thirteen patients had at least one gastric complicated by diverticulitis in five patients. Three cases emptying scintigraphy for clinical signs suggestive of of dolichocolons were noted. Forty-eight percent of the gastroparesis (9%); among them, nine had a confirmed patients had used at least one treatment for abdominal gastroparesis. Of these nine patients, three had mild, symptoms in the previous 2 weeks. The most highly three had moderate, and three had severe gastroparesis, represented drug classes were proton pump inhibitors according to the fixation rate at 4 h . All of the patients (n = 45; 30%), laxatives (n = 14; 9%), antispasmodics (n = received medical treatment, three patients received botu- 19; 13%), sodium alginates and/or coals (n = 11; 7%), linum toxin injections, and two underwent endoscopic ursodeoxycholic acid (n = 6; 4%), prokinetics (n = 5; 3%), pylorotomy. Only 7 patients (4.7%) had diabetes mellitus, and anti-diarrheals (n= 5; 3%). Parreau et al. Advances in Rheumatology (2021) 61:5 Page 4 of 8 Abdominal symptoms gastric emptying scintigraphy (GSS = 14.6 ± 6.1 vs. 9.3 ± Ninety-five percent of the patients (n = 143) suffered 6.0, p = 0.0037). No pSS-specific therapy was correlated from abdominal symptoms (median GSS score = 7.5 ± with a high abdominal symptoms score. Serologic status 5.5 points). The abdominal complaints are shown influenced the overall abdominal score as well as the according to severity in Fig. 1. More than half of the pa- prevalence of several abdominal symptoms (Table 3). tients had upper abdominal pain, abdominal discomfort, Indeed, the median GSS score was significantly higher bloating and/or constipation. Several features of pSS in seronegative patients (GSS = 11.8 ± 5.8 vs. 7.9 ± 5.9, were associated with a GSS using a score higher than 10 p = 0.02). obtained by supervised discretization (Table 2). There The multivariate analysis of the total GSS score (linear was no correlation between abdominal symptoms and regression) and upper gastrointestinal symptoms (logis- focus score on minor salivary gland biopsy or unstimu- tic regression) vs. patient characteristics is shown in lated salivary flow. Table 4. No item was significantly related to reduced Regarding the ESSDAI score items, articular involve- abdominal symptoms in the multivariate analysis. The ment was associated with a GSS > 10. Muscular, pulmon- multivariate analysis confirmed the significant associ- ary and neurological involvement were more present with ation between the GSS total score, ESSPRI score, and a GSS > 10 but not significantly (Table 2). seronegativity (p < 0.01; Table 4). The fatigue and fever The total ESSPRI score was correlated with the GSS items of the GSS score were associated with seronegativ- score (0.48; Rho = 0.5, p < 0.0001). The three items of the ity (OR = 8.45; p = 0.0152) and a high ESSPRI score ESSPRI score were also correlated with a high GSS score (OR = 1.31; p < 0.0001). (dryness Rho = 0.3, p = 0.0014, fatigue Rho = 0.5, p < 0.0001 and pain Rho = 0.4, p < 0.0001). Discussion Several digestive antecedents were correlated with a This study is the first to use the 2016 ACR-EULAR cri- high GSS score: hiatal hernia (GSS = 12.4 ± 5.6 vs. 9.0 ± teria to systematically evaluate the severity of abdominal 6.1, p = 0.007), gastroesophageal reflux (GSS = 12.3 ± 6.1 symptoms in patients with pSS. Abdominal disorders are vs. 8.7 ± 5.9, p = 0.001), gastroparesis (GSS = 15.9 ± 2.5 rarely reported during pSS and are probably underesti- vs. 9.4 ± 6.1, p = 0.0032), atrophic gastritis (GSS = 15.1 ± mated [2]. The reported prevalence varies markedly 4.9 vs. 9.4 ± 6.1, p = 0.0097), irritable bowel syndrome depending on the pSS diagnostic criteria and the (GSS = 13.4 ± 5.8 vs. 8.8 ± 5.9, p = 0.0002), at least one number of patients evaluated. Moreover, studies have previous abdominal surgery (GSS = 13.4 ± 5.8 vs. 8.8 ± typically focused on one type of abdominal involvement 5.9, p = 0.0440), and pernicious anemia (GSS = 19.0 ± 8.5 [2]. For example, Retamozo reported a 6.2% prevalence vs. 9.6 ± 6.0, p = 0.0306). Use of treatments for gastro- of abdominal disorders but evaluated only chronic gas- intestinal symptoms was correlated with a high GSS tritis, acute pancreatitis, and dysphagia [21]. We found a (trimebutine [GSS = 15.6 ± 6.5 vs. 9.4 ± 6.0, p = 0.0047] high frequency of major upper and lower abdominal and proton pump inhibitors [GSS = 12.4 ± 6.5 vs. 8.6 ± 5.6, complaints in patients with pSS. p = 0.0004]). In addition, a high GSS score was correlated These symptoms are likely to be responsible for deteri- with a higher frequency of endoscopic explorations and oration in the quality of life of pSS patients. Indeed, Krogh Fig. 1 Severity of abdominal symptoms according to the results of the abdominal symptoms score Parreau et al. Advances in Rheumatology (2021) 61:5 Page 5 of 8 Table 2 Association between a GSS and characteristics of pSS GSS ≤ 10 (n = 85) GSS > 10 (n = 63) p-value n (%) or mean (sd) GSS 5.2 (2.8) 15.8 (3.5) < 0.0001 ESSPRI score 16.4 (5.9) 20.1 (5.3) 0.0001 SSA negative status 28 (32.9%) 23 (63.5%) 0.0003 Articular involvement 54 (63.5%) 52 (82.5%) 0.0112 Muscular involvement 33 (38.8%) 34 (54.0%) 0.0672 Pulmonary involvement 6 (7.1%) 10 (15.9%) 0.0877 Neurological involvement 16 (18.8%) 18 (28.6%) 0.1633 Antecedent of gastroparesis 0 (0%) 9 (14.3%) 0.0003 Standard antalgics 21 (24.7%) 28 (44.4%) 0.0116 Neurotropic antalgics 11 (12.9%) 14 (22.2%) 0.1362 Digestive treatment 35 (41.2%) 37 (58.7%) 0.0346 GSS global symptom score,sd standard deviation, pSS primary Sjögren’s syndrome For quantitative variables in a normal distribution, the Student’s t-test was used to compare groups of two or more classes; for variables that do not follow a normal distribution, the Wilcoxon signed-rank test or the Kruskal-Wallis test was used to compare groups of two or more classes as defined by the ESSDAI score et al. demonstrated that abdominal complaints were a Despite their frequency, digestive symptoms are not source of impairment of quality of life for pSS patients part of the ESSDAI activity score for pSS. Likewise, the [22]. However, the correlation between abdominal com- ESSPRI score evaluating the frequent symptoms of pSS plaints and ESSPRI score has not been evaluated [22]. Our did not account for abdominal complaints. Almost half study showed a strong association between abdominal of the patients used treatments for digestive symptoms, symptoms and a high ESSPRI score. which was correlated with a high abdominal score. This A retrospective Indian study showed clustering of suggests that these treatments are ineffective and unsuit- gastrointestinal symptoms and depression/psychiatric able for pSS with digestive involvement. Otherwise, pSS symptoms in pSS, but only evaluated irritable bowel treatments did not influence abdominal symptoms, syndrome [23]. Although depressive symptoms were suggesting both their ineffectiveness and the absence of themostfrequentinseronegative patients with pSS, an exclusive adverse side effect that may explain such they were not significantly associated with gastro- symptoms. Therefore, large prospective studies of the intestinal symptoms. pathophysiology of these frequent symptoms are needed. Table 3 Comparison of GSS symptoms and serological status SSA+ (n = 80) SSA- (n = 70) Total (n = 150) p-value n (%) or mean (sd) Upper abdominal symptoms 63 (78.8) 67 (97.1) 131 (87.3) 0.0008 Upper abdominal pain 31 (38.7) 52 (75.4) 84 (56.0) < 0.0001 Abdominal discomfort 40 (50.0) 47 (68.1) 88 (58.7) 0.0253 Bloating 50 (62.5) 54 (78.3) 105 (70.0) 0.0367 Nausea 25 (31.2) 35 (50.7) 60 (40.0) 0.0157 Vomiting 10 (12.5) 11 (15.9) 21 (14.0) n.s. Lower abdominal symptoms 63 (78.8) 59 (85.5) 123 (82.0) n.s. Lower abdominal pain 35 (43.7) 39 (56.5) 75 (50.0) n.s. Diarrhea 21 (26.2) 35 (50.7) 56 (37.3) 0.0021 Tenesmus 14 (17.5) 13 (18.8) 28 (18.7) n.s. Constipation 42 (52.5) 40 (58.0) 82 (54.7) n.s. Dysuria 10 (12.5) 19 (27.5) 29 (19.3) 0.0208 sd standard deviation, GSS global symptoms score, n.s not significant For quantitative variables in a normal distribution, the Student’s t-test was used to compare groups of two or more classes; for variables that do not follow a normal distribution, the Wilcoxon signed-rank test or the Kruskal-Wallis test was used to compare groups of two or more classes. The value p< 0.05 was considered significant Parreau et al. Advances in Rheumatology (2021) 61:5 Page 6 of 8 Table 4 Multivariate analysis investigating effect of GSS on patient characteristics GSS total Coef 95% CI p-value SSA negative status 2.34 [0.62–4.06] 0.00812 Number of past lower abdominal events 0.74 [0.23–1.25] 0.00499 Antecedent of gastroparesis 4.77 [1.20–8.35] 0.00912 ESSPRI score 0.36 [0.21–0.51] < 0.0001 Upper abdominal symptoms OR Seronegative status 6.01 [1.52–40.12] 0.0239 Digestive treatment 4.64 [1.37–21.50] 0.0241 ESSPRI score 1.11 [1.02–1.21] 0.0201 Coef coefficient,CI confidence interval, GSS global symptoms score, OR odds ratio p-values for trend are obtained with multivariable linear regression for GSS and logistic regression for upper abdominal symptoms Dysfunction of the autonomic nervous system plays an on inhibition of gastric emptying by anti-muscarinic re- important role in the pathogenesis of gastrointestinal ceptor type 3 antibodies [25]. Unfortunately, no study manifestations of pSS. Autonomic neuropathy has been has evaluated the correlation of the level of these described in patients with pSS and is associated with antibodies with the gastric emptying time. Our findings orthostatic hypotension, urinary retention, segmental suggest the necessity of excluding gastroparesis in the anhidrosis, and dysfunction of the digestive and urinary presence of unexplained persistent upper digestive systems [24]. Muscarinic receptors M3 are expressed on symptoms in a patient with pSS. vascular smooth muscle cells, particularly in the gastro- This study had several limitations. The GSS is based intestinal and genitourinary systems, as well as on on a questionnaire that is easy to use in routine practice exocrine gland cells [25, 26]. In patients with pSS, auto- with patients, but it is a non-validated tool. We did not antibodies are directed against muscarinic receptors evaluate abdominal symptoms in a healthy patient [25], suggesting these antibodies to be the cause of cohort. It is a preliminary study mainly to highlight the autonomic neuropathy, which can lead to bladder insuf- presence of these symptoms in a cohort of Sjögren’s ficiency or gastrointestinal disorders [26]. Such autoanti- patients and to evaluate their relationship to disease bodies were implicated in altered colonic contraction in activity (ESSDAI) and to the most frequent symptoms an ex vivo model [27]. Intravenous immunoglobulin (ESSPRI). This exploratory study included only patients shows promise for the treatment of immunologically attending a single university hospital center, which could induced digestive or urinary disorders. Smith et al. have resulted in selection bias. However, the prevalence showed that intravenous immunoglobulin neutralized of systemic involvement was consistent with the findings anti-muscarinic M3 receptor antibodies and improved of other French pSS studies [31, 32]. The non-interventional the urinary and diarrhea scores in a patient with pSS [28]. study design precluded demonstration of a causal link be- The multivariate analysis showed an association be- tween digestive symptoms and pSS. Also, we did not system- tween a high abdominal symptom score and a prior atically investigate digestive symptoms by endoscopy, which diagnosis of gastroparesis. Gastroparesis is likely to be may have led to their mis- or under-diagnosis. Regarding the underdiagnosed in patients with pSS. We found a 69% hypothetical link between gastrointestinal involvement and rate of confirmed gastroparesis among patients who autonomic neuropathy, we did not perform physiological underwent emptying gastric scintigraphy to explore testing, quantitative measurement of autonomic nervous symptoms suggestive of this condition. Few studies have system function, or assays of anti-muscarinic receptor evaluated gastroparesis during pSS [25, 29, 30]. Kovacs antibodies. et al. reported a 70% rate of scintigraphy-proven gastro- The chief strength of this study was its evaluation of a paresis in 30 symptomatic patients with pSS [25]. An- simple and rapid tool to screen and assess digestive other study of 28 patients with pSS found a prevalence symptoms among a large cohort of pSS patients. The of 43% for subjective signs of gastroparesis and 29% for majority of patients with pSS had abdominal complaints gastroparesis confirmed by octanoate breath tests [29]. that affected their quality of life. Therefore, the question- In a retrospective study of 11 patients with pSS- naire could enable not only detection but also monitor- associated gastroparesis, 82% had bloating and abdom- ing of abdominal complaints over time. Furthermore, inal pain [30]. The relationship between gastroparesis the questionnaire was capable of diagnosing gastropar- and involvement of the autonomic nervous system in esis, a poorly described, potentially debilitating condition pSS is unclear. Such a relationship is hypothesized based associated with pSS. Parreau et al. Advances in Rheumatology (2021) 61:5 Page 7 of 8 Conclusion 7. Di Mario F, Aragona G, Leandro G, Comparato G, Fanigliulo L, Cavallaro LG, et al. Efficacy of mesalazine in the treatment of symptomatic diverticular We detected gastrointestinal symptoms in the majority disease. Dig Dis Sci. 2005;50:581–6. of patients with pSS. Prospective studies are needed to 8. Di Mario F, Stefani N, Dal Bò N, Rugge M, Pilotto A, Cavestro GM, et al. clarify the relationship between abdominal complaints Natural course of functional dyspepsia after helicobacter pylori eradication: a seven-year survey. Dig Dis Sci. 2005;50:2286–9. and depressive disorders and/or fibromyalgia, and inves- 9. Marie I, Leroi AM, Gourcerol G, Levesque H, Menard JF, Ducrotte P. Lactose tigate the underlying pathophysiological mechanisms. malabsorption in systemic sclerosis. Aliment Pharmacol Ther. 2016;44:1123–33. 10. Gemignani L, Savarino V, Ghio M, Parodi A, Zentilin P, de Bortoli N, et al. Acknowledgements Lactulose breath test to assess oro-cecal transit delay and estimate None. esophageal dysmotility in scleroderma patients. Semin Arthritis Rheum. 2013;42:522–9. Authors’ contributions 11. Marie I, Ducrotté P, Denis P, Menard JF, Levesque H. Small intestinal Each named author has substantially contributed to the research and/or bacterial overgrowth in systemic sclerosis. Rheumatology. 2009;48:1314–9. drafting of the manuscript. The author(s) read and approved the final 12. Parodi A, Sessarego M, Greco A, Bazzica M, Filaci G, Setti M, Savarino E, manuscript. Indiveri F, Savarino V, Ghio M, Parodi A, et al. Small intestinal bacterial overgrowth in patients suffering from scleroderma: clinical effectiveness of Funding its eradication. Am J Gastroenterol. 2008;103:1257–62. The work was not funded. 13. Marie I, Antonietti M, Houivet E, Hachulla E, Maunoury V, Bienvenu B, et al. Gastrointestinal mucosal abnormalities using videocapsule endoscopy in Availability of data and materials systemic sclerosis. Aliment Pharmacol Ther. 2014;40:189–99. The data were completely anonymized before being accessed by the 14. Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L. American College of authors. Gastroenterology. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013;108:18–37. 15. Palsson OS, Whitehead WE, van Tilburg MA, Chang L, Chey W, Crowell MD, Ethics approval and consent to participate et al. Development and validation of the Rome IV diagnostic questionnaire All procedures performed in this study were in accordance with the ethical for adults. Gastroenterology. 2016;150:1481–91. standards of the Institutional Research Committee and with the 1964 16. Carayon P. Guidelines of the French Society of Digestive Endoscopy: total Helsinki Declaration and its later amendments. The study was approved by colonoscopy indications. The Council of the French Society of digestive the Committee for the Protection of Individuals “Sud-Ouest et Outre Mer III” endoscopy (SFED). Endoscopy. 2000;32:434–5. (France). All patients provided written consent after receiving information about the study. 17. https://www.has-sante.fr/portail/upload/docs/application/pdf/gastro_ endoscopy.pdf. 18. Couturier O, Victor G, Faivre-Chauvet A, Baulieu F, Le Rest C, Bridji B, et al. Consent for publication Guide de bonnes pratiques en scintigraphie de la vidange gastrique. Méd All patients provided written consent after receiving information about Nucl. 2002;26:211–9. publication. 19. Harrell F. Regression modeling strategies: with applications to linear models, logistic regression, and survival analysis. New York: Springer; 2001. Competing interests 20. Chai J, Herrmann DN, Stanton M, Barbano RL, Logigian EL. Painful small- The authors declare no conflict of interest. fiber neuropathy in Sjogren syndrome. Neurology. 2005;65:925–7. Provided written consent after receiving information about the study. 21. Retamozo S, Acar-Denizli N, Rasmussen A, Horváth IF, Baldini C, Priori R, et al. Systemic manifestations of primary Sjögren's syndrome out of the ESSDAI Author details classification: prevalence and clinical relevance in a large international, multi- Internal Medicine Department, Limoges University Hospital, 16 rue du ethnic cohort of patients. Clin Exp Rheumatol. 2019;37:97–106. Professeur Bernard Descottes, 87042 Limoges, France. EA 3842 - Cellular 22. Krogh K, Asmussen K, Stengaard-Pedersen K, Laurberg S, Deleuran BW. Homeostasis and Diseases, Faculty of Medicine, University of Limoges, 2 rue Bowel symptoms in patients with primary Sjögren's syndrome. Scand J du Docteur Marcland, 87025 Limoges, France. Gastroenterology Rheumatol. 2007;36:407–9. Department, Limoges University Hospital, 2 Avenue Martin Luther King, 23. Sandhya P, Jeyaseelan L, Scofield RH, Danda D. Clinical characteristics and 87042 Limoges, France. BioEM, UMR 7252, CNRS, Limoges, France. outcome of primary Sjogren's syndrome: A large Asian Indian cohort. Open Rheumatol J. 2015;9:36–45. Received: 13 September 2020 Accepted: 2 January 2021 24. Pavlakis PP, Alexopoulos H, Kosmidis ML, Mamali I, Moutsopoulos HM, Tzioufas AG, et al. Peripheral neuropathies in Sjögren's syndrome: a critical update on clinical features and pathogenetic mechanisms. J Autoimmun. References 2012;39:27–33. 1. Qin B, Wang J, Yang Z, Yang M, Ma N, Huang F, et al. Epidemiology of 25. Kovács L, Papós M, Takács R, Róka R, Csenke Z, Kovács A, et al. Autonomic primary Sjögren’s syndrome: a systematic review and meta-analysis. Ann nervous system dysfunction involving the gastrointestinal and the urinary Rheum Dis. 2015;74:1983–9. tracts in primary Sjögren’s syndrome. Clin Exp Rheumatol. 2003;21:697–703. 2. Ebert EC. Gastrointestinal and hepatic manifestations of Sjogren syndrome. J 26. Goodman BP, Crepeau A, Dhawan PS, Khoury JA, Harris LA. Spectrum of Clin Gastroenterol. 2012;46:25–30. autonomic nervous system impairment in Sjögren syndrome. Neurologist. 3. Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, 2017;22:127–30. et al. 2016 American College of Rheumatology/European league against 27. Park K, Haberberger RV, Gordon TP, Jackson MW. 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Impaired gastric emptying in test in patients with systemic sclerosis. Arthritis Rheum. 2012;64:2346–55. primary Sjogren’s syndrome. J Rheumatol. 2010;37:2313–8. 6. Latella G, Pimpo M, Sottili S, Zippi M, Viscido A, Chiaramonte M, et al. 30. Geyl S, Jacques J, Parreau S, Cypierre A, Tabouret T, Gondran G, et al. Rifaximin improves symptoms of acquired uncomplicated diverticular Gastroparesis may be the cause of unexplained dyspepsia in patients with disease of the colon. Int J Color Dis. 2003;18:55–62. primary Sjögren syndrome. Rev Med Interne. 2018;39:427–30. Parreau et al. Advances in Rheumatology (2021) 61:5 Page 8 of 8 31. Martel C, Gondran G, Launay D, Lalloué F, Palat S, Lambert M, et al. Active immunological profile is associated with systemic Sjögren’s syndrome. J Clin Immunol. 2011;31:840–7. 32. Carvajal Alegria G, Guellec D, Mariette X, Gottenberg JE, Dernis E, Dubost JJ, et al. Epidemiology of neurological manifestations in Sjögren's syndrome: data from the French ASSESS cohort. RMD Open. 2016;20:e000179. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Advances in Rheumatology Springer Journals

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Abstract

Background: Abdominal symptoms in patients with primary Sjögren syndrome (pSS) are poorly documented. The objective of the study was to describe the abdominal symptoms of patients with pSS and to assess their association with characteristics of the disease. Methods: One hundred and fifty patients with pSS were evaluated using a composite global symptom score for abdominal symptoms and their severity. Data concerning the clinical and biological characteristics of pSS and abdominal disorders were also collected. Results: Of the patients with pSS, 95% suffered from abdominal symptoms (median global symptom score 7.5 ± 5.5 points out of 30). More than half of the patients experienced abdominal tension (68%), upper abdominal pain (54%), abdominal discomfort (58%) and/or constipation (54%). Regarding the pSS activity, in relation to European League Against Rheumatism (EULAR) Sjögren syndrome disease activity index score items, general and central nervous system involvement wereassociated with a high global symptom score. The EULAR Sjogren Syndrome Patient Reported Index (ESSPRI) symptom score was positively correlated with the global symptom score (p < 0.01). Multivariate analysis showed a significant association between a high global symptom score and SSA seronegativity, gastroparesis, and ESSPRI score (p < 0.01 for each). Conclusions: The majority of patients with pSS suffered abdominal symptoms. There is currently no therapeutic recommendation because of the lack of information on the underlying pathophysiological mechanisms. Trial registration: NCT03157011. Date of registration: July 17, 2017. Keywords: Sjögren’s syndrome, Abdominal symptoms, Gastroparesis, ESSPRI, ESSDAI, Quality of life Background Like other autoimmune diseases, negative impact, pain, Primary Sjögren syndrome (pSS) is a chronic autoimmune and fatigue predominate, reducing the quality of life. disorder characterized by lymphocytic infiltration of the Furthermore, abdominal disorders affect approximately exocrine glands and loss of secretory function with oral 25% of patients with pSS but are poorly documented in and ocular dryness. It affects predominantly females (fe- the literature [2]. Indeed, epidemiological characteristics male:male ratio 9:1), and the peak frequency of the disease vary among studies because of the small number of is about age 50 years. The etiology of pSS is unclear [1]. patients and use of old classification criteria [2]. Also, data concerning the frequency of abdominal symptoms and * Correspondence: simon.parreau@hotmail.com their associations with clinical and biological manifesta- Internal Medicine Department, Limoges University Hospital, 16 rue du tions of pSS are contradictory [2]. This heterogeneity led Professeur Bernard Descottes, 87042 Limoges, France 2 us to conduct a non-interventional prospective study of EA 3842 - Cellular Homeostasis and Diseases, Faculty of Medicine, University of Limoges, 2 rue du Docteur Marcland, 87025 Limoges, France abdominal symptoms in patients with pSS as defined by Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Parreau et al. Advances in Rheumatology (2021) 61:5 Page 2 of 8 the 2016 American College of Rheumatology-European percentages. For qualitative variables, a chi-squared or League Against Rheumatism (ACR-EULAR) criteria [3]. Fisher’s exact test was used to compare the groups (SSA +/− SSB patients and seronegative patients). For Methods normally distributed quantitative variables, Student’s t- Population test was used to compare groups of two or more classes. From July 2017 to June 2018, we conducted a single- For non-normally distributed quantitative variables, the center study in a French Hospital and University Center. Wilcoxon signed-rank test or the Kruskal–Wallis test It was a prospective, non-interventional study, and was was used to compare groups of two or more classes. approved by the Committee for the Protection of Univariate analyses between the abdominal symptoms Individuals “Sud-Ouest et Outre Mer III” (France). All and the other variables were performed. Variables with a patients (age > 18 years) followed in our center for pSS value of p < 0.20 were included in a multivariate logistic were considered for enrollment. All of them fulfilled the model, simplified by a stepwise elimination method [19], 2016 ACR-EULAR classification criteria for pSS [3]. The so that the final model included only variables signifi- patients provided written consent after receiving infor- cantly associated with digestive symptoms. Quantitative mation on the study. The patients’ characteristics (age at variables fulfilling the logit linearity assumption were disease onset, sex, and duration of pSS), clinical manifes- incorporated without modification, or otherwise catego- tations of pSS, associated organ-specific autoimmune rized. The relevance of the model was assessed using disorders, and treatments were recorded. pSS Activity as Pearson’s residual and deviance tests, and its quality by measured by the EULAR Sjögren syndrome disease means of a receiver operating characteristic curve. To activity index (ESSDAI) and pSS symptoms measured by test the correlation between the GSS score and continu- EULAR Sjogren Syndrome Patient Reported Index ous variables, Spearman’s rho was calculated. A super- (ESSPRI) were systematically evaluated concurrently vised discretization will be performed with a decision with abdominal symptoms [4]. The data were completely tree to identify thresholds for the GSS variable. Statis- anonymized before being assessed. Blood tests were tical analysis was conducted using R software (version performed at the time of diagnosis and concurrently 3.2.2, rpart package). Values of p < 0.05 were considered with assessment of the abdominal symptoms score. indicative of significance. Evaluation of abdominal symptoms Results The patients with pSS were interviewed by a physician Patients’ characteristics and treatments using a questionnaire. The questionnaire comprised 10 A total of 150 patients (mean age 63 ± 13 years, male abdominal symptoms (nausea, vomiting, upper and lower n = 9) with pSS were enrolled. Eighty patients (53%) had abdominal pain, abdominal discomfort, bloating, diarrhea, anti-SSA antibodies and 31 (21%) had anti-SSB anti- constipation, tenesmus, dysuria). Each symptom was scored bodies (22%). One hundred and four patients (86%) had from 0 (no symptom) to 3 (severe) as evaluated by profes- a Chisholm score of ≥3 at the time of diagnosis. None of sional judgement. A global symptom score (GSS), calcu- the patients had auto-antibodies, symptoms, or capillaro- lated as the sum of all symptom scores, was assigned to scopy findings suggestive of an associated systemic scler- each patient (maximum score, 30) [5–13]. This score has osis. The most common systemic involvements, defined been used for another chronic autoimmune disease, sys- in the ESSDAI score, were articular (n = 107; 71%) and temic sclerosis, as well as for two chronic digestive patholo- muscular (n = 68; 45%). Twenty-two percent of the gies (i.e., diverticulitis and functional dyspepsia) [5–13]. patients (n = 33) had neurological involvement (central Previously diagnosed digestive, pancreatic, and hepatic dis- n = 20 [13%] and/or peripheral n = 24 [16%] with 14 [9%] eases, as well as treatments for digestive complaints, were biopsy-proven small-fiber neuropathies) [20]. Other systematically recorded in the medical file. Previous diagno- systemic involvements were hematologic (n = 30; 20%), sis of gastroparesis was based on international clinical pulmonary (n = 17; 11%), cutaneous vasculitis (n = 11; guidelines [14] and irritable bowel syndrome on the Rome 7%) and interstitial nephritis (n = 8; 5%) (Table 1). The IV classification [15]. After completing the questionnaire, average ESSDAI score was 3.4 ± 4.8 points out of 123. only those patients with alarm signs (endoscopy) or signs The average ESSPRI score was 5.9 ± 2.1 out of 10. The evocative of gastroparesis (gastric emptying scintigraphy) latter score is the average of the dryness (6.2 ± 2.4 out of underwent exploration of the digestive system, in accord- 10), fatigue (6.2 ± 2.4) and pain (5.5 ± 2.7) scores. Hydroxy- ance with the French recommendations [16–18]. chloroquine was taken by 46% (n = 70) of the patients, cor- ticosteroids by 23% (n = 35), immunosuppressive drugs by Statistical analysis 14% (n = 22; including three patients taking mycophenolate Quantitative variables are presented as means ± standard mofetil), targeted therapies by 3% (n = 5), and intravenous deviations, and qualitative variables as numbers and immunoglobulin by 5% (n = 8). Symptomatic treatments Parreau et al. Advances in Rheumatology (2021) 61:5 Page 3 of 8 Table 1 Characteristics of patients according to serological status SSA+ (n = 80) SSA- (n = 70) TOTAL (n = 150) p-value n (%) Male 3 (3.7) 6 (8.7) 9 (6.0) n.s. Age at diagnosis, years 51.2 (13.4) 55.0 (11.0) 53.0 (12.5) n.s. Mean follow-up, years 10.3 (7.9) 9.6 (6.9) 10.0 (7.4) n.s. Salivary gland enlargement 21 (26.3) 19 (27.1) 40 (26.5) n.s. Raynaud’s phenomenon 29 (36,3) 18 (25.7) 47 (31.1) n.s. Articular involvement 56 (70.0) 51 (72.9) 107 (70.9) n.s. Muscular involvement 32 (40.0) 35 (50.0) 67 (44.4) n.s. Neurologic involvement 15 (18.8) 19 (27.1) 34 (22.5) n.s. Cutaneous vasculitis 9 (11.3) 1 (1.4) 10 (6.6) 0.026 Pulmonary involvement 11 (13.8) 5 (7.1) 16 (10.6) n.s. Interstitial nephritis 6 (7.5) 2 (2.9) 8 (5.3) n.s. Fibromyalgia 2 (2.5) 10 (7.0) 12 (8.0) n.s. Depression 12 (15.0) 20 (28.6) 32 (21.3) 0.0481 Hematological involvement 23 (28.8) 8 (11.4) 31 (20.5) 0.0090 Non-Hodgkin lymphoma 2 (2.5) 0 2 (1.3) n.s. Hypergammaglobulinemia 35 (43.8) 2 (2.9) 37 (24.5) < 0.0001 Positive RF 12 (15.0) 2 (2.9) 14 (9.3) 0.0115 Cryoglobulinemia 4 (5.0) 1 (1.4) 5 (3.3) n.s. Symptomatic treatment of pSS 67 (83.7) 58 (84.0) 126 (84.0) n.s. Specific treatment of pSS 52 (65.0) 35 (50.7) 88 (58.7) n.s. Digestive treatment 33 (41.2) 39 (56.5) 73 (48.7) n.s. mean (sd) ESSDAI score 3.5 (4.9) 3.2 (4.8) 3.4 (4.8) n.s. ESSPRI score 5.5 (2.1) 6.4 (1.9) 5.9 (2.1) 0.0082 RF rheumatoid factor, pSS primary Sjögren’s syndrome, n.s not significant,sd standard deviation For qualitative variables, a Chi-2 or Fisher’s exact test was used to compare different groups of patients (SSA+ patients and seronegative patients). For quantitative variables in a normal distribution, the Student’s t-test was used to compare groups of two or more classes; for variables that do not follow a normal distribution, the Wilcoxon signed-rank test or the Kruskal-Wallis test was used to compare groups of two or more classes. The value p< 0.05 was considered significant included standard analgesics (n = 51; 34%), specific neuro- none of whom had gastroparesis. Another 7 patients had pathic pain treatments (n = 26; 17%), and nonsteroidal anti- autoimmune hepatitis with 4 cases of primary biliary inflammatory drugs (n = 13; 8%). Seventeen percent of the cholangitis and 3 of sclerosing cholangitis. Twenty-seven patients (n = 26) used antidepressants and 15% (n = 23) cases of gastritis (18%), mostly atrophic, were reported, used benzodiazepines. as well as three cases of pernicious anemia (2%) and one of coeliac disease. Thirty cases of irritable bowel syn- Previous digestive disease drome were documented (20%). Sixteen patients had Forty-four patients had symptomatic gastroesophageal enteric endoscopic diverticulosis (11%), which was reflux (29%). Thirteen patients had at least one gastric complicated by diverticulitis in five patients. Three cases emptying scintigraphy for clinical signs suggestive of of dolichocolons were noted. Forty-eight percent of the gastroparesis (9%); among them, nine had a confirmed patients had used at least one treatment for abdominal gastroparesis. Of these nine patients, three had mild, symptoms in the previous 2 weeks. The most highly three had moderate, and three had severe gastroparesis, represented drug classes were proton pump inhibitors according to the fixation rate at 4 h . All of the patients (n = 45; 30%), laxatives (n = 14; 9%), antispasmodics (n = received medical treatment, three patients received botu- 19; 13%), sodium alginates and/or coals (n = 11; 7%), linum toxin injections, and two underwent endoscopic ursodeoxycholic acid (n = 6; 4%), prokinetics (n = 5; 3%), pylorotomy. Only 7 patients (4.7%) had diabetes mellitus, and anti-diarrheals (n= 5; 3%). Parreau et al. Advances in Rheumatology (2021) 61:5 Page 4 of 8 Abdominal symptoms gastric emptying scintigraphy (GSS = 14.6 ± 6.1 vs. 9.3 ± Ninety-five percent of the patients (n = 143) suffered 6.0, p = 0.0037). No pSS-specific therapy was correlated from abdominal symptoms (median GSS score = 7.5 ± with a high abdominal symptoms score. Serologic status 5.5 points). The abdominal complaints are shown influenced the overall abdominal score as well as the according to severity in Fig. 1. More than half of the pa- prevalence of several abdominal symptoms (Table 3). tients had upper abdominal pain, abdominal discomfort, Indeed, the median GSS score was significantly higher bloating and/or constipation. Several features of pSS in seronegative patients (GSS = 11.8 ± 5.8 vs. 7.9 ± 5.9, were associated with a GSS using a score higher than 10 p = 0.02). obtained by supervised discretization (Table 2). There The multivariate analysis of the total GSS score (linear was no correlation between abdominal symptoms and regression) and upper gastrointestinal symptoms (logis- focus score on minor salivary gland biopsy or unstimu- tic regression) vs. patient characteristics is shown in lated salivary flow. Table 4. No item was significantly related to reduced Regarding the ESSDAI score items, articular involve- abdominal symptoms in the multivariate analysis. The ment was associated with a GSS > 10. Muscular, pulmon- multivariate analysis confirmed the significant associ- ary and neurological involvement were more present with ation between the GSS total score, ESSPRI score, and a GSS > 10 but not significantly (Table 2). seronegativity (p < 0.01; Table 4). The fatigue and fever The total ESSPRI score was correlated with the GSS items of the GSS score were associated with seronegativ- score (0.48; Rho = 0.5, p < 0.0001). The three items of the ity (OR = 8.45; p = 0.0152) and a high ESSPRI score ESSPRI score were also correlated with a high GSS score (OR = 1.31; p < 0.0001). (dryness Rho = 0.3, p = 0.0014, fatigue Rho = 0.5, p < 0.0001 and pain Rho = 0.4, p < 0.0001). Discussion Several digestive antecedents were correlated with a This study is the first to use the 2016 ACR-EULAR cri- high GSS score: hiatal hernia (GSS = 12.4 ± 5.6 vs. 9.0 ± teria to systematically evaluate the severity of abdominal 6.1, p = 0.007), gastroesophageal reflux (GSS = 12.3 ± 6.1 symptoms in patients with pSS. Abdominal disorders are vs. 8.7 ± 5.9, p = 0.001), gastroparesis (GSS = 15.9 ± 2.5 rarely reported during pSS and are probably underesti- vs. 9.4 ± 6.1, p = 0.0032), atrophic gastritis (GSS = 15.1 ± mated [2]. The reported prevalence varies markedly 4.9 vs. 9.4 ± 6.1, p = 0.0097), irritable bowel syndrome depending on the pSS diagnostic criteria and the (GSS = 13.4 ± 5.8 vs. 8.8 ± 5.9, p = 0.0002), at least one number of patients evaluated. Moreover, studies have previous abdominal surgery (GSS = 13.4 ± 5.8 vs. 8.8 ± typically focused on one type of abdominal involvement 5.9, p = 0.0440), and pernicious anemia (GSS = 19.0 ± 8.5 [2]. For example, Retamozo reported a 6.2% prevalence vs. 9.6 ± 6.0, p = 0.0306). Use of treatments for gastro- of abdominal disorders but evaluated only chronic gas- intestinal symptoms was correlated with a high GSS tritis, acute pancreatitis, and dysphagia [21]. We found a (trimebutine [GSS = 15.6 ± 6.5 vs. 9.4 ± 6.0, p = 0.0047] high frequency of major upper and lower abdominal and proton pump inhibitors [GSS = 12.4 ± 6.5 vs. 8.6 ± 5.6, complaints in patients with pSS. p = 0.0004]). In addition, a high GSS score was correlated These symptoms are likely to be responsible for deteri- with a higher frequency of endoscopic explorations and oration in the quality of life of pSS patients. Indeed, Krogh Fig. 1 Severity of abdominal symptoms according to the results of the abdominal symptoms score Parreau et al. Advances in Rheumatology (2021) 61:5 Page 5 of 8 Table 2 Association between a GSS and characteristics of pSS GSS ≤ 10 (n = 85) GSS > 10 (n = 63) p-value n (%) or mean (sd) GSS 5.2 (2.8) 15.8 (3.5) < 0.0001 ESSPRI score 16.4 (5.9) 20.1 (5.3) 0.0001 SSA negative status 28 (32.9%) 23 (63.5%) 0.0003 Articular involvement 54 (63.5%) 52 (82.5%) 0.0112 Muscular involvement 33 (38.8%) 34 (54.0%) 0.0672 Pulmonary involvement 6 (7.1%) 10 (15.9%) 0.0877 Neurological involvement 16 (18.8%) 18 (28.6%) 0.1633 Antecedent of gastroparesis 0 (0%) 9 (14.3%) 0.0003 Standard antalgics 21 (24.7%) 28 (44.4%) 0.0116 Neurotropic antalgics 11 (12.9%) 14 (22.2%) 0.1362 Digestive treatment 35 (41.2%) 37 (58.7%) 0.0346 GSS global symptom score,sd standard deviation, pSS primary Sjögren’s syndrome For quantitative variables in a normal distribution, the Student’s t-test was used to compare groups of two or more classes; for variables that do not follow a normal distribution, the Wilcoxon signed-rank test or the Kruskal-Wallis test was used to compare groups of two or more classes as defined by the ESSDAI score et al. demonstrated that abdominal complaints were a Despite their frequency, digestive symptoms are not source of impairment of quality of life for pSS patients part of the ESSDAI activity score for pSS. Likewise, the [22]. However, the correlation between abdominal com- ESSPRI score evaluating the frequent symptoms of pSS plaints and ESSPRI score has not been evaluated [22]. Our did not account for abdominal complaints. Almost half study showed a strong association between abdominal of the patients used treatments for digestive symptoms, symptoms and a high ESSPRI score. which was correlated with a high abdominal score. This A retrospective Indian study showed clustering of suggests that these treatments are ineffective and unsuit- gastrointestinal symptoms and depression/psychiatric able for pSS with digestive involvement. Otherwise, pSS symptoms in pSS, but only evaluated irritable bowel treatments did not influence abdominal symptoms, syndrome [23]. Although depressive symptoms were suggesting both their ineffectiveness and the absence of themostfrequentinseronegative patients with pSS, an exclusive adverse side effect that may explain such they were not significantly associated with gastro- symptoms. Therefore, large prospective studies of the intestinal symptoms. pathophysiology of these frequent symptoms are needed. Table 3 Comparison of GSS symptoms and serological status SSA+ (n = 80) SSA- (n = 70) Total (n = 150) p-value n (%) or mean (sd) Upper abdominal symptoms 63 (78.8) 67 (97.1) 131 (87.3) 0.0008 Upper abdominal pain 31 (38.7) 52 (75.4) 84 (56.0) < 0.0001 Abdominal discomfort 40 (50.0) 47 (68.1) 88 (58.7) 0.0253 Bloating 50 (62.5) 54 (78.3) 105 (70.0) 0.0367 Nausea 25 (31.2) 35 (50.7) 60 (40.0) 0.0157 Vomiting 10 (12.5) 11 (15.9) 21 (14.0) n.s. Lower abdominal symptoms 63 (78.8) 59 (85.5) 123 (82.0) n.s. Lower abdominal pain 35 (43.7) 39 (56.5) 75 (50.0) n.s. Diarrhea 21 (26.2) 35 (50.7) 56 (37.3) 0.0021 Tenesmus 14 (17.5) 13 (18.8) 28 (18.7) n.s. Constipation 42 (52.5) 40 (58.0) 82 (54.7) n.s. Dysuria 10 (12.5) 19 (27.5) 29 (19.3) 0.0208 sd standard deviation, GSS global symptoms score, n.s not significant For quantitative variables in a normal distribution, the Student’s t-test was used to compare groups of two or more classes; for variables that do not follow a normal distribution, the Wilcoxon signed-rank test or the Kruskal-Wallis test was used to compare groups of two or more classes. The value p< 0.05 was considered significant Parreau et al. Advances in Rheumatology (2021) 61:5 Page 6 of 8 Table 4 Multivariate analysis investigating effect of GSS on patient characteristics GSS total Coef 95% CI p-value SSA negative status 2.34 [0.62–4.06] 0.00812 Number of past lower abdominal events 0.74 [0.23–1.25] 0.00499 Antecedent of gastroparesis 4.77 [1.20–8.35] 0.00912 ESSPRI score 0.36 [0.21–0.51] < 0.0001 Upper abdominal symptoms OR Seronegative status 6.01 [1.52–40.12] 0.0239 Digestive treatment 4.64 [1.37–21.50] 0.0241 ESSPRI score 1.11 [1.02–1.21] 0.0201 Coef coefficient,CI confidence interval, GSS global symptoms score, OR odds ratio p-values for trend are obtained with multivariable linear regression for GSS and logistic regression for upper abdominal symptoms Dysfunction of the autonomic nervous system plays an on inhibition of gastric emptying by anti-muscarinic re- important role in the pathogenesis of gastrointestinal ceptor type 3 antibodies [25]. Unfortunately, no study manifestations of pSS. Autonomic neuropathy has been has evaluated the correlation of the level of these described in patients with pSS and is associated with antibodies with the gastric emptying time. Our findings orthostatic hypotension, urinary retention, segmental suggest the necessity of excluding gastroparesis in the anhidrosis, and dysfunction of the digestive and urinary presence of unexplained persistent upper digestive systems [24]. Muscarinic receptors M3 are expressed on symptoms in a patient with pSS. vascular smooth muscle cells, particularly in the gastro- This study had several limitations. The GSS is based intestinal and genitourinary systems, as well as on on a questionnaire that is easy to use in routine practice exocrine gland cells [25, 26]. In patients with pSS, auto- with patients, but it is a non-validated tool. We did not antibodies are directed against muscarinic receptors evaluate abdominal symptoms in a healthy patient [25], suggesting these antibodies to be the cause of cohort. It is a preliminary study mainly to highlight the autonomic neuropathy, which can lead to bladder insuf- presence of these symptoms in a cohort of Sjögren’s ficiency or gastrointestinal disorders [26]. Such autoanti- patients and to evaluate their relationship to disease bodies were implicated in altered colonic contraction in activity (ESSDAI) and to the most frequent symptoms an ex vivo model [27]. Intravenous immunoglobulin (ESSPRI). This exploratory study included only patients shows promise for the treatment of immunologically attending a single university hospital center, which could induced digestive or urinary disorders. Smith et al. have resulted in selection bias. However, the prevalence showed that intravenous immunoglobulin neutralized of systemic involvement was consistent with the findings anti-muscarinic M3 receptor antibodies and improved of other French pSS studies [31, 32]. The non-interventional the urinary and diarrhea scores in a patient with pSS [28]. study design precluded demonstration of a causal link be- The multivariate analysis showed an association be- tween digestive symptoms and pSS. Also, we did not system- tween a high abdominal symptom score and a prior atically investigate digestive symptoms by endoscopy, which diagnosis of gastroparesis. Gastroparesis is likely to be may have led to their mis- or under-diagnosis. Regarding the underdiagnosed in patients with pSS. We found a 69% hypothetical link between gastrointestinal involvement and rate of confirmed gastroparesis among patients who autonomic neuropathy, we did not perform physiological underwent emptying gastric scintigraphy to explore testing, quantitative measurement of autonomic nervous symptoms suggestive of this condition. Few studies have system function, or assays of anti-muscarinic receptor evaluated gastroparesis during pSS [25, 29, 30]. Kovacs antibodies. et al. reported a 70% rate of scintigraphy-proven gastro- The chief strength of this study was its evaluation of a paresis in 30 symptomatic patients with pSS [25]. An- simple and rapid tool to screen and assess digestive other study of 28 patients with pSS found a prevalence symptoms among a large cohort of pSS patients. The of 43% for subjective signs of gastroparesis and 29% for majority of patients with pSS had abdominal complaints gastroparesis confirmed by octanoate breath tests [29]. that affected their quality of life. Therefore, the question- In a retrospective study of 11 patients with pSS- naire could enable not only detection but also monitor- associated gastroparesis, 82% had bloating and abdom- ing of abdominal complaints over time. Furthermore, inal pain [30]. The relationship between gastroparesis the questionnaire was capable of diagnosing gastropar- and involvement of the autonomic nervous system in esis, a poorly described, potentially debilitating condition pSS is unclear. Such a relationship is hypothesized based associated with pSS. Parreau et al. Advances in Rheumatology (2021) 61:5 Page 7 of 8 Conclusion 7. Di Mario F, Aragona G, Leandro G, Comparato G, Fanigliulo L, Cavallaro LG, et al. Efficacy of mesalazine in the treatment of symptomatic diverticular We detected gastrointestinal symptoms in the majority disease. Dig Dis Sci. 2005;50:581–6. of patients with pSS. Prospective studies are needed to 8. Di Mario F, Stefani N, Dal Bò N, Rugge M, Pilotto A, Cavestro GM, et al. clarify the relationship between abdominal complaints Natural course of functional dyspepsia after helicobacter pylori eradication: a seven-year survey. Dig Dis Sci. 2005;50:2286–9. and depressive disorders and/or fibromyalgia, and inves- 9. Marie I, Leroi AM, Gourcerol G, Levesque H, Menard JF, Ducrotte P. Lactose tigate the underlying pathophysiological mechanisms. malabsorption in systemic sclerosis. Aliment Pharmacol Ther. 2016;44:1123–33. 10. Gemignani L, Savarino V, Ghio M, Parodi A, Zentilin P, de Bortoli N, et al. Acknowledgements Lactulose breath test to assess oro-cecal transit delay and estimate None. esophageal dysmotility in scleroderma patients. Semin Arthritis Rheum. 2013;42:522–9. Authors’ contributions 11. Marie I, Ducrotté P, Denis P, Menard JF, Levesque H. Small intestinal Each named author has substantially contributed to the research and/or bacterial overgrowth in systemic sclerosis. Rheumatology. 2009;48:1314–9. drafting of the manuscript. The author(s) read and approved the final 12. Parodi A, Sessarego M, Greco A, Bazzica M, Filaci G, Setti M, Savarino E, manuscript. Indiveri F, Savarino V, Ghio M, Parodi A, et al. Small intestinal bacterial overgrowth in patients suffering from scleroderma: clinical effectiveness of Funding its eradication. Am J Gastroenterol. 2008;103:1257–62. The work was not funded. 13. Marie I, Antonietti M, Houivet E, Hachulla E, Maunoury V, Bienvenu B, et al. Gastrointestinal mucosal abnormalities using videocapsule endoscopy in Availability of data and materials systemic sclerosis. Aliment Pharmacol Ther. 2014;40:189–99. The data were completely anonymized before being accessed by the 14. Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L. American College of authors. Gastroenterology. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013;108:18–37. 15. Palsson OS, Whitehead WE, van Tilburg MA, Chang L, Chey W, Crowell MD, Ethics approval and consent to participate et al. Development and validation of the Rome IV diagnostic questionnaire All procedures performed in this study were in accordance with the ethical for adults. 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