Functional Gastrointestinal Disease In Patients with Rheumatoid Arthritis: Disease Activity, Functionality, and Quality of Life

Functional gastrointestinal disorders (FGDs) are a collection of conditions in which recurrent gastrointestinal symptoms occur without discernible organic pathology. In its latest iteration, the Rome Group classifies FGDs in children and adolescents into nine major disorders. These include functional dyspepsia, irritable bowel syndrome (IBS), functional abdominal pain, abdominal migraine, aerophagia, adolescent rumination syndrome, cyclic vomiting syndrome, functional constipation, and functional non-retentive fecal incontinence.1 In view of the remarkably high prevalence, recurrent nature of symptoms, and lack of well-established management strategies, FGDs pose a formidable challenge to practicing pediatricians. A paper from Sagawa and colleagues in this issue of the journal reports a study on epidemiology and quality of school life (QoSL) of children with FGDs in Japan. It provides insightful details of high prevalence (14%) of FGDs in Japanese school children and documents the deleterious effects of FGD on QoSL.2 Results of the study highlight a growing public health problem in Asia in the new millennium, demanding our undivided attention. The prevalence of FGDs in children has increased dramatically across Asia during the past decade. There is mounting evidence to indicate that these conditions are becoming a significant regional health issue. A study evaluating the whole spectrum of FGDs in school children of 10–16 years has shown a remarkably high prevalence of 29%.3 Common FGDs reported in Asian children are IBS and functional constipation. Series of studies across the continent have reported IBS ranging from 4.1% in Iranian school children to 26% in Korean girls.4, 5 In China, the country with the largest population in the world, 13–21% of school children are suffering from IBS.6, 7 The prevalence of functional constipation is also on the rise. Two studies have shown exceptionally high prevalence of functional constipation in the industrialized areas of Asia, such as Hong Kong (12.2%) and Singapore (29.8%).8, 9 Similarly, several studies from our group have also shown IBS (10%), functional constipation (15%), aerophagia (7%), functional dyspepsia (2.5%), functional abdominal pain (4.4%), and abdominal migraine (1%) in Sri Lankan school-aged children.10-13 This “bird's-eye view” of data clearly shows that FGDs are rapidly increasing in both developed and developing nations of Asia. It is also more disturbing to note that these rates reported from Asia are way above those reported from the West, where FGDs were previously thought to be more prevalent. The pathophysiology of most of the FGDs is still far from clear. Primarily, visceral hypersensitivity and abnormal motility are proposed as main contributory factors for abdominal pain-predominant FGDs, such as IBS and functional dyspepsia. In addition, IBS is well known to follow gastrointestinal infections (postinfectious IBS), which are a major health problem in many developing nations in Asia. Abnormal colorectal motor functions and sensitivity are also considered to be the pathophysiological mechanisms for constipation. Modifiable risk factors such as diets low in fiber, increased consumption of junk foods, and adoption of sedentary lifestyles are known to predispose children to develop constipation.8, 14 Childhood obesity is another significant risk factor, especially for defecation disorders such as constipation and fecal incontinence.15 With changing standards of living and urbanization, these factors are becoming increasingly common in the Asian region. Moreover, the biology and pathophysiology of FGDs have increasingly been shown to be associated with psychological stress and early adverse life events, both common occurrences in Asian communities. Stressful life events, both school and home related, are well known to predispose children to develop many FGDs such as aerophagia, IBS, functional dyspepsia, functional abdominal pain, and defecation disorders.11-13 Psychological disturbances such as depression have been shown to be associated with IBS in adolescents.6 In addition, we have previously shown that constipation is common among children living in war-torn areas.16 Schools across Asia have a highly competitive education system, competition being triggered by the lack of opportunities and parental/peer pressure, leading to high level of stress among students. In addition, civil unrest is sweeping across several areas in the region. These factors could also contribute to sustain the higher occurrence of FGDs in Asia, and require further study. Despite these glaring facts, current diagnosis and management of FGDs in children are not optimal. There is poor awareness of FGDs among primary care physicians and pediatricians in the region. Children are often labeled as having “gastritis” or “psychological problems” instead of trying to make a definitive diagnosis and arriving at possible etiologies. To compound matters further, there is no consensus across the globe on how to investigate children with FGDs. Pediatric endoscopy services are not widely available in many Asian countries and other specialized investigations, such as barostat and gastrointestinal motility studies, are only available in tertiary care research centers which are not accessible to most of the children suffering from FGDs. Furthermore, there are no large-scale randomized controlled trials to establish evidence-guided treatment for FGDs. Some of the trials conducted in the West have failed to show significant benefits of commonly used therapeutic options such as tricyclic antidepressants17 and high-fiber diets18 in FGDs. Treatment options like psychotherapy, guided imagery, and biofeedback are difficult to implement due to the lack of trained personnel and scarce resources. Finally, due to the ever present and insurmountable workload faced by the clinicians, there is a significant reduction in the consultation time that is needed to manage FGDs, a condition by its very nature requiring more time to explore its roots and possible therapeutic approaches. Therefore, it is inevitable that childhood FGDs are poorly managed across the region. The World Health Organization has stressed the fact that health is not a mere absence of disease; physical, social, and emotional well-being are also integral parts of the concept of health.19 Although FGDs do not contribute directly to child mortality, poor management strategies would invariably lead to a series of deleterious ramifications including poor physical, social, and emotional well-being and disruption of education. Although there is mounting evidence that FGDs affect health-related quality of life (HRQoL) in adults,20 the understanding of interactions between childhood FGDs and HRQoL still remains in its infancy. Varni et al. have studied HRQoL in children with IBS and compared them with children having organic gastrointestinal diseases. This study has clearly shown that children with IBS have lower quality of life in physical, emotional, social, and school functioning.21 Using similar methods, Youssef and colleagues have also reported poorer HRQoL in children with functional constipation compared with that of children with gastroesophageal reflux and inflammatory bowel disease.22 Another study on children with slow transit constipation has reported similar results.23 All three studies have clearly identified the impact of FGDs on school performance in children. Long-standing symptoms, the recurrent nature of the disorder, and associated psychological consequences are likely to influence poor HRQoL in children with FGDs, even though precise mechanisms have not been elucidated. In addition, symptoms such as fecal incontinence are socially unacceptable, lead to rejection by peers, and thereby promote social isolation.24 Reduction of physical, mental, and social functioning ultimately affects school performance, creating a vicious cycle of psychological stress, aggravation of symptoms, and spiralling down of HRQoL. Interference with QoSL is commonly associated with poor education outcomes which invariably lead to poor earning capacity as adults. This would ultimately turn out to be an added burden to the society at large. This brings us back to the key findings of the paper by Sagawa and coworkers. They have shown a significantly lower QoSL in children with FGDs. FGDs such as cyclic vomiting syndrome and aerophagia, which were previously thought to be uncommon, have also contributed to significant reduction in QoSL. These findings seem to ring an early warning bell regarding the impact of FGDs on school performance of affected children. The findings of this study should be taken seriously by all interested stakeholders, including school and health authorities, clinicians, parents, and policy-makers. Awareness programs, expansion of facilities, improvement of man power, including specialized training, are needed to be implemented sooner than later to deal with the abysmally dark and ominously rising tide of FGDs in Asian children.

ObjectivesTo describe the feature of expression of syndecan-4 in serum, synovial fluid (SF) and synovium in rheumatoid arthritis (RA) patients, and to analyze the correlation of syndecan-4 with disease activity and serological characteristic of RA.MethodsSyndecan-4 in sera of 60 RA patients, 20 osteoarthritis (OA) patients, 20 healthy controls, and in SF of 25 RA patients and 25 OA patients were tested by enzyme linked immunosorbant assay. The expressions of syndecan-4 in synovium of RA and OA patients were detected by immunohistochemistry. The expression of syndecan-4 on synovial fibroblasts from RA and OA patients were detected by immunofluorescence. The correlation between serum syndecan-4 concentration and disease activity were analyzed in RA patients.ResultsThe serum syndedcan-4 concentration was significantly higher in RA patients than in OA patients and healthy controls, and was higher in rheumatoid factor (RF)-positive RA patients than in RF-negative ones. Syndecan-4 concentration in SF of RA patients was comparable with OA patients. Syndecan-4 expression in synovial tissue was similar between RA and OA patients. The syndecan-4 concentration was significantly lower in SF than in serum of RA and OA patients. Syndecan-4 concentration in both serum and SF was positively correlated with disease activity of RA patients.ConclusionThe serum syndecan-4 concentration was higher in RA patients than in OA patients, and significantly higher in RF-positive RA patients than in RF-negative ones. Syndecan-4 concentration in both serum and SF was positively correlated with disease activity of RA patients.

BackgroundSleep disturbance is closely related to inflammation and pain. Good sleep quality is essential for patients’ psychological and physical states as well as their quality of life. The aim of this study was to detect how insomnia as a major sleep disturbance could add to the disease burden in rheumatoid arthritis (RA) and osteoarthritis patients (OA) and to determine the predictor parameters in each of them in order to orient the rheumatologist to this unnoticed symptom that could adversely affect the patients’ life. This study included: 20 RA patients, 20 primary knee OA patients together with 20 healthy controls. RA disease activity was assessed by the disease activity score (DAS-28). All participants were assessed for sleep disturbances by the Athens Insomnia Scale, quality of life (QoL) using the short form QoL (SF-36 QoL) scale, depression by the Beck depression inventory (BDI), and functional disability by the Health Assessment Questionnaire Disability Index (HAQ-DI). OA patients were assessed by the Knee OA Flare Up Score (KOFUS) and the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Radiological evaluation for RA patients was done by the Simple Erosion Narrowing Score, while the Kellgren and Lawrence (K-L) radiological grading system was used for OA patients.ResultsInsomnia was found in 75% of the studied RA patients, 25% of the studied OA patients and none of the healthy control with significant difference (P < 0.001). Significant correlations of the insomnia scale with the number of tender and swollen joints (r = 0.66, 0.76 respectively and p = 0.001 both), DAS-28 (r = 0.71, P < 0.001), anti-CCP antibodies titre (r = 0.53, p = 0.02) and the BDI (r = 0.65, p = 0.002) among RA patients were found. Correlations among OA patients occurred with morning stiffness duration (r = 0.69, P = 0.001), number of affected joints (r = 0.81, P = 0.001), the BDI scale (r = 0.51, P = 0.02), the WOMAC index (r = 0.57, P = 0.009), the KOFUS score (r = 0.76, p < 0.001) and the K-L score (r = 0.67, P = 0.001). Linear regression analysis indicated that the predictors for insomnia in RA were DAS-28 and the BDI, while in OA were the number of affected joints and the KOFUS score.ConclusionsInsomnia is a disease burden especially in RA patients being one of the leading causes of depression and is greatly affected by the disease activity. In general the burden of insomnia is much less in OA except in severe cases with markedly affected joints. Rheumatologists should be aware of this disorder that could affect patients’ health, mood, and functional activity.

In this study, we investigated the hypothesis that regulatory T cells (T(reg)) are involved in the immunomodulatory effects of statins on rheumatoid arthritis (RA) patients. The 12-week study cohort consisted of 55 RA patients and 42 control subjects allocated to either a group treated with atorvastatin (AT) (20 mg/day) or a non-AT group. T(reg) numbers, suppressive function, serum inflammatory markers, and disease activity were evaluated before and after the therapy. Furthermore, the effects of AT on the frequency and suppressive function of T(reg) were determined in vitro. Our data revealed that the suppressive function of T(reg) from RA patients significantly decreased compared with that of control subjects. AT significantly reduced erythrosedimentation, C-reactive protein, and disease activity. Concomitantly, T(reg) numbers and suppressive functions were significantly improved by AT. Consistent with the in vivo experiments, AT promoted the generation of T(reg) from primary T cells and enhanced preexisting T(reg) function in vitro. Moreover, we showed that PI3K-Akt-mTOR and ERK signal pathways were involved in the induction of T(reg) by AT. In conclusion, AT significantly increased T(reg) numbers and restored their suppressive function in the RA patients, and this may be relevant in the modulation of uncontrolled inflammation in this disorder.

BackgroundHigh levels of serum immunoglobulin G4 (IgG4) would comprise a useful diagnostic tool in IgG4-related disease, but little information is available about IgG4 in conditions other than IgG4-related disease, including...

AB0229 Does Serum Level of IL-17 Affect Disease Activity and Functional Disability in Rheumatoid Arthritis Patients? Relation between Serum IL-17 Level, DAS-28 and HAQ-DI

AB1045 Efficacy of Etanercept on Radiographic Progression in Adult Patients with Rheumatoid Arthritis or Psoriatic Arthritis: Results from The Second Interim Analysis of A German Non-Interventional, Prospective, Multi-Center Study

Matrix metalloprotein ase-3 (MMP-3) is one of the MMPs produced in rheumatoid arthritis (RA) joints. The aim of this study was to evaluate serum and synovial fluid (SF) MMP-3 as markers of disease activity in early RA. Thirty early RA patients together with age-matched and sex-matched 12 primary knee osteoarthritis patients and 12 apparently healthy individuals as control groups were enrolled in this study. MMP-3 was measured in serum and SF samples using enzyme-linked immunosorbent assay. Assessment of disease activity in RA patients was carried out using disease activity score-28 (DAS-28), and radiographs of the hands, wrists, and forefeet were obtained and evaluated according to Larsen score. As regards mean serum levels of MMP-3, there was a statistically significant elevation in RA patients compared with the control groups (P<0.001). Moreover, the mean SF levels of MMP-3 in RA patients were statistically significantly higher than that in osteoarthritis patients (P<0.001). In RA patients, there was a statistically significant difference (P<0.001) between mean serum and SF levels, being higher in the SF. There was a statistically significant positive correlation (P<0.05) between serum MMP-3 with disease duration, DAS-28, and Larsen score. As regards mean SF MMP-3 levels, there was a high statistically significant positive correlation (P<0.001) with DAS-28 and a statistically significant positive correlation (P<0.05) with Larsen score. Elevated serum and synovial MMP-3 levels reflect disease activity in RA patients; thus, it could be used as a useful marker for disease activity. The cross-sectional design of our study did not allow us to produce conclusions with respect to disease course and prognosis. Thus, we recommend further studies on large numbers of patients and serial measurements of MMP-3 to determine the rate of disease progression.

SAT0715 Clinical significance of fibromyalgia syndrome in different rheumatic diseases: relation to disease activity and quality of life

Background:Rheumatoid arthritis (RA) is a complex chronic inflammatory disease with high heterogeneity. Characterizing the molecular mechanisms linked to different phenotypes might open new opportunities for the development of personalized therapeutic...

Clinical significance of fibromyalgia syndrome in different rheumatic diseases: Relation to disease activity and quality of life.

Clinical significance of fibromyalgia syndrome in different rheumatic diseases: Relation to disease activity and quality of life

AB0111 THE COMPARISON OF SYNDECAN-4 LEVEL IN SERA, SYNOVIAL FLUID AND SYNOVIUM OF RHEUMATOID ARTHRITIS AND OSTEOARTHRITIS

Aim: To evaluate the frequency and the predictors of extra-articular manifestations (EAMs) in rheumatoid arthritis (RA) patients. Patients and Methods: This study included 100 adult rheumatoid arthritis patients. A full medical history and a thorough clinical and rheumatological examinations, along with laboratory and radiological investigations were done. RA disease activity using the modified disease activity score (DAS28), validated Arabic version of the health assessment questionnaire (HAQ-A) and the simplified erosion narrowing score (SENS) were calculated. Results: EAMs were detected in 73 patients (73%) of the RA patients; the most common EAMs were subcutaneous rheumatoid nodules (45%), followed by anemia (43%), ocular affection (23%), pulmonary affection (interstitial lung disease ILD) (15%), neuropathy (10%) while renal and cardiac involvements were (2%) and (1%) respectively. There were statistically significant higher levels of age, disease duration, disease activity (DAS28), severe functional disability (HAQ-A), joint damage (SENS), rheumatoid factor (RF) positivity and CRP levels among RA patients with EAMs than those without EAMs. The multivariate regression analysis of the possible predictors of RA EAMs showed that disease duration (OR 1.8, 95% CI. 1.2-2.9, p=0.006) and disease activity DAS28 (OR 1.6, 95% CI 1.0-2.4, p=0.045) independently affect the occurrence of EAMs in RA patients. Conclusion: Extra-articular manifestations are common among rheumatoid arthritis patients. Disease duration and disease activity were independent predictors of extra-articular manifestations occurrence in rheumatoid arthritis.

Objective: the albumin to fibrinogen ratio (AFR) and the C-reactive protein (CRP) to albumin ratio (CAR) have been proposed as markers of systemic inflammation. The goal of this study was to differentiate rheumatoid arthritis (RA) patients from healthy people and to study the association between AFR/CAR and DAS28 in RA.Patients and methods. A case control study including 30 RA patients and 30 healthy controls was performed. Fibrinogen, albumin, CRP and erythrocyte sedimentation rate (ESR) were measured. We calculated CAR and AFR in each group and compared them. Correlations of AFR, and CAR with disease activity were examined. Receiver operation characteristic (ROC) curves of AFR and CAR were also used to detect cutoffs for disease activity assessment.Results and discussion. CAR was higher while AFR was lower in RA patients than in control group. ROC curve analyses showed that CAR can be used to detect disease activity of RA at cut off 2.66 with sensitivity 81.3% and specificity 64.3% with an area under the curve (AUC) 0.78. So, CAR was a fair parameter to discriminate disease activity among RA patients. AFR has AUC 0.62, sensitivity 87.5% and specificity 42.9% at cutoff value 5.96. So, in our group AFR was a poor indicator to discriminate disease activity among RA patients.Conclusion. AFR and CAR have been recently proposed as inflammatory markers for assessment of disease activity in RA. AFR and CAR are simple, and inexpensive biomarkers, they also can be rapidly evaluated. CAR was found to be a fair parameter to depict disease activity in RA patients. AFR poorly depicted RA activity.