http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(2): 291–295 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.843749
ORIGINAL ARTICLE
Gastroesophageal reflux disease in patients with rheumatoid arthritis Yasushi Miura1,2, Koji Fukuda1, Toshihisa Maeda1, and Masahiro Kurosaka1
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1Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan and 2Division of Orthopedic Sciences, Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
Abstract
Keywords
Objective. Patients with rheumatoid arthritis (RA) are frequently complicated with gastric mucosal injury; however, there are few reports investigating gastroesophageal reflux disease (GERD) among patients with RA. We investigated the frequency of GERD and the correlation between GERD and the clinical characteristics of RA including patient’s global assessment (PGA). Methods. Patients with RA were investigated for GERD using self-administered frequency scale for the symptoms of GERD (FSSG). The correlation between GERD and the clinical characteristics of RA was analyzed statistically. Results. Two hundred and eleven patients in Japan were investigated. The prevalence of GERD among patients with RA (24.6%) was significantly higher than that in the Japanese population (11.5%) (p ⬍ 0.001). FSSG was positively correlated with modified health assessment questionnaire (mHAQ), PGA, evaluator’s global assessment (EGA) (p ⬍ 0.001), disease activity score (DAS)28erythrocyte sedimentation rate (ESR) (p ⬍ 0.05), DAS28-C-reactive protein (CRP), simplified disease activity index (SDAI) and clinical disease activity index (CDAI) (p ⬍ 0.001). The patients with GERD showed significantly higher scores in mHAQ, PGA, EGA, tenderness joint count, DAS28-ESR, DAS28-CRP, SDAI and CDAI (p ⬍ 0.001). Furthermore, the patients with GERD showed lower remission rates based on DAS28-ESR (p ⬍ 0.05), DAS28-CRP, SDAI and CDAI (p ⬍ 0.001). Conclusion. GERD complicated with RA increases PGA and the indices of disease activity. GERD symptoms analyzed using FSSG may be desirable to avoid the overestimation as part of the total management of patients with RA.
Gastroesophageal reflux disease, Frequency scale for the symptoms of GERD, Patient’s global assessment, Proton pump inhibitor, Rheumatoid arthritis
Introduction Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease principally developing in articular synovial tissues. RA is characterized by persistent symmetric polyarthritis, which causes severe articular swelling and pain and results in cartilage and bone destruction in the affected joints. Both chronic polyarthralgia and progressive physical disability markedly impair the activities of daily living (ADL) and quality of life (QOL) of patients with RA. RA was previously considered an incurable disease; however, combination therapy with methotrexate (MTX) and an anti-TNF biological agent introduced at the end of the 20th century caused a paradigm shift in the treatment of RA. These days, RA is considered a disease for which remission can be achieved; however, once destroyed by RA, joints never recover spontaneously. Thus, the current main target of RA treatment is to achieve clinical, structural and functional remissions in the early phase of RA and to maintain the QOL of patients. Meanwhile, gastroesophageal reflux disease (GERD) is defined as unpleasant symptoms or complications caused by reflux of the stomach contents into the esophagus, and the main symptoms are acid reflux symptoms, such as heartburn
Correspondence to: Yasushi Miura, Division of Orthopedic Sciences, Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma, Kobe 654-0142, Japan. Tel: ⫹ 81-78-796-4595. Fax: ⫹ 81-78-796-4595. E-mail: miura@ kobe-u.ac.jp
History Received 25 January 2013 Accepted 27 April 2013 Published online 31 October 2013
[1]. Unpleasant symptoms of GERD impair patients’ QOL [2]; therefore, adequate treatment of GERD is necessary to improve the QOL [3]. Furthermore, it has been suggested that patients with GERD have recently increased in Japan [4] owing to a reduced Helicobacter pylori infection rate and gastric acid secretion enhanced by the westernization of diets [5]. A high incidence of complications by gastric mucosal disorder in patients with RA has also been reported [6], and GERD is considered an important complication in RA [7]. Since GERD complication in patients with RA further reduces their QOL [7], the close investigation and treatment of GERD symptoms are important to improve the overall QOL of patients with RA. It was reported that the mean prevalence of GERD in Japan was 11.5% when the occurrence of heartburn twice a week or more was defined as GERD [4]. As GERD symptoms include not only symptoms of reflux, such as heartburn, but also those of dyspepsia, such as a heavy stomach feeling, it is not easy to evaluate GERD based on a single symptom. A GERD medical questionnaire developed by Kusano et al. [8], frequency scale for the symptoms of GERD (FSSG), is capable of comprehensively identifying diverse symptoms of GERD and separately evaluating symptoms of reflux score (RS) and dyspepsia score (DS). The validity of judging an FSSG score of 8 or higher as GERD has been demonstrated in a study on the sensitivity and specificity of endoscopic findings in patients with GERD and those without GERD. We use FSSG to identify and evaluate GERD for every patient’s visit. Against this background, in this study, we investigated the correlation
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Mod Rheumatol, 2014; 24(2): 291–295
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Table 1. Baseline characteristics of patients with RA in GERD group and non-GERD group. Variable Age (year) Female/male Duration of the disease (year) class stage Steroid dose of PSL (mg) Steroid use (%) NSAID use (%) Biologics use (%) MTX use (%) DMARD use (%) PPI use (%) H2RA use (%) mHAQ PGA EGA TJC (28) SJC (28) CRP ESR DAS-CRP4 DAS-ESR4 SDAI CDAI
GERD (n ⫽ 52)
non-GERD (n ⫽ 159)
61.3 ⫾ 14.5 44/8 18.4 ⫾ 14.8 2.0 ⫾ 0.71 2.8 ⫾ 1.17 2.4 ⫾ 2.71 59.6 63.5 32.7 55.8 69.2 59.6 12.8 6.29 ⫾ 5.83 4.50 ⫾ 2.65 2.17 ⫾ 1.57 1.70 ⫾ 1.90 1.00 ⫾ 1.84 0.44 ⫾ 0.92 17.87 ⫾ 15.13 2.86 ⫾ 0.96 3.17 ⫾ 1.08 9.57 ⫾ 5.70 9.14 ⫾ 5.37
59.6 ⫾ 13.5 134/25 15.0 ⫾ 13.7 1.8 ⫾ 0.82 2.6 ⫾ 1.24 1.6 ⫾ 2.22 45.3 52.8 39.0 67.3 78.0 38.8 23.0 2.63 ⫾ 5.07 2.05 ⫾ 2.17 1.23 ⫾ 1.20 1.10 ⫾ 2.52 1.00 ⫾ 2.09 0.32 ⫾ 0.47 19.25 ⫾ 17.18 2.22 ⫾ 1.00 2.56 ⫾ 1.17 5.41 ⫾ 6.38 5.11 ⫾ 6.20
P-value 0.41 0.95* 0.08 0.06 0.60 0.06 0.07* 0.22* 0.42* 0.13* 0.20* 0.01* 0.13* ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 0.67 0.79 0.88 ⬍ 0.001 ⬍ 0.01 ⬍ 0.001 ⬍ 0.001
P-value indicates the differences between GERD group and non-GERD group by Wilcoxon rank sum test, except for gender, steroid, NSAID, biologics, MTX, DMARD, PPI and H2RA use, which were analyzed by Chi-square test (marked with asterisks). *Chi-square test.
between the pathology and GERD symptoms in patients with RA using FSSG.
Subjects and methods The subjects were 211 patients with RA (178 females and 33 males) under outpatient treatment in July–October 2011 who met the diagnostic criteria established by the American College of Rheumatology in 1987 [9]. No specific exclusion criteria were set for this study. GERD symptoms were evaluated using FSSG, and patients with FSSG ⱖ 8 were regarded as having GERD symptoms (GERD group) and those with FSSG ⬍ 8 as having no GERD symptoms (non-GERD group). The correlations and the differences in the patient background between the GERD and non-GERD groups with the disease activity indices of RA (disease activity score (DAS)-C-reactive protein (CRP)4, DASerythrocyte sedimentation rate (ESR)4, simplified disease activity index (SDAI), clinical disease activity index (CDAI)), ADL score (modified health assessment questionnaire (mHAQ)), inflammatory markers (CRP and ESR), and FSSG total score (TS), RS, and DS, and the influence of GERD on the remission rates of RA were statistically analyzed using Chi-square, Wilcoxon rank sum or Spearman’s rank correlation test. This study was retrospectively performed from medical records in accordance with proper ethical standards laid down in the 1964 Declaration of Helsinki.
Results The mean age of the patients with RA was 60.0 ⫾ 13.9 years, the mean disease duration was 15.9 ⫾ 14.1 years, and the mean prednisolone (PSL)-converted oral steroid dose was 1.8 ⫾ 2.4 mg/day.
Figure 1. Correlation between FSSG scores and mHAQ, PGA and EGA. mHAQ, PGA and EGA were positively and significantly correlated with total scores (TS), reflux score (RS) and dyspepsia score (DS) of FSSG by Spearman’s rank correlation test.
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DOI 10.3109/14397595.2013.843749
Figure 2. Correlation between FSSG scores and DAS-CRP4, DAS-ESR4, SDAI and CDAI. DAS-CRP4, DAS-ESR4, SDAI and CDAI were positively and significantly correlated with total scores (TS), reflux score (RS) and dyspepsia score (DS) of FSSG by Spearman’s rank correlation test.
Non-steroidal anti-inflammatory drugs (NSAIDs) were administered to 117 patients (55.5%). When FSSG ⱖ 8 was regarded as GERD, the complication rate of GERD was 24.6%. mHAQ, the patient’s global assessment (PGA) and evaluator’s global assessment (EGA), tenderness joint count (TJC), DAS-CRP4, DAS-ESR4, SDAI, CDAI, and rates of treatment with proton pump inhibitors (PPI) were significantly higher in the GERD group than in the non-GERD group, but no significant differences were observed in the mean age, disease duration, gender ratio, Steinbrocker functional classification and staging, steroid dosages, rates of treatment with steroid, NSAIDs, biologics, MTX,
Table 2. Remission rates depending of DAS-CRP4, DAS-ESR4, SDAI and CDAI in GERD group and non-GERD group. mHAQ DRS-CRP4 DAS-ESR4 SDAI CDAI
GERD (%) 47.1 33.3 36.4 12.5 12.5
non-GERD (%) 78.8 56.1 56.7 45.7 42.4
P-value P ⬍ 0.0001 P ⬍ 0.01 P ⬍ 0.05 P ⬍ 0.001 P ⬍ 0.001
P-value indicates the differences between GERD group and non-GERD group analyzed by Chi-square test.
disease-modifying anti-rheumatic drugs (DMARDs), and H2 receptor antagonists (H2RA), swelling joint count (SJC), CRP, or ESR (Table 1). In addition, mHAQ, PGA, EGA (Figure 1), DAS-CRP4, DAS-ESR4, SDAI and CDAI (Figure 2) were positively and significantly correlated with TS, RS and DS of FSSG, while either CRP or ESR was not correlated (data not shown). Furthermore, the remission rates in mHAQ, DAS-CRP4, DASESR4, SDAI and CDAI were significantly lower in the GERD group than in the non-GERD group (Table 2).
Discussion Various complications develop in patients with RA. GERD has been reported [4] to complicate various diseases, such as diabetes mellitus, hypertension, angina pectoris, liver disease and asthma, and it may also complicate RA and reduce the QOL of patients with RA in combination with disuse, periarticular, and steroidinduced osteoporosis [10] and NSAID- and steroid-induced gastric mucosal disorder. In the current RA treatment involving early diagnosis and aggressive drug therapy targeting complete remission, the countermeasures against these complications are also essential to maintain a high QOL. Amano [11] reported that the GERD complication rate in Japanese patients with RA on FSSG was 23%, and the rate in
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this study, 24.6%, was similar to this, suggesting that the patients in this study may be representative of patients with RA from the perspective of the GERD complication rate. In this study, we newly investigated how the presence of GERD symptoms influenced the clinical condition of RA, and clarified that GERD symptoms and subscales of these, reflux and dyspepsia symptoms, strongly influence the disease activity indices and ADL in patients with RA. In addition, the presence of GERD symptoms increases the RA disease activity indices because FSSG was significantly correlated with each disease activity index and the remission rate significantly decreased in the presence of GERD symptoms. RA disease activity indices: DAS28-ESR4, DAS28-CRP4, SDAI and CDAI, include PGA, which represents the overall health condition evaluated by patients. We revealed that PGA and FSSG were positively correlated in patients with RA. Self-rating PGA represents the subjective evaluation by patients themselves; therefore, it is disputable whether the scale reflects only the RA-associated physical condition, although the filling-in procedure is explained to patients beforehand. Since the present study demonstrated that there are no significant differences in prescription rates of steroids, NSAIDs, biologics, MTX and DMARD; steroid dose; ESR and CRP between GERD and non-GERD groups, the activities of synovitis may be similar between the two groups, although neither rheumatoid factor nor matrix metalloproteinase-3 was examined. Thus, to avoid the overtreatment in patients with RA, overestimation by disease activity indices should be carefully considered especially when complicated with GERD. Actually, the explanation about the filling-in procedure of PGA has recently altered from ‘please describe your overall condition’ to ‘please answer how you feel about your arthritis condition today in consideration of various influences of arthritis on you’ [12]. This study was performed before this change in the explanation, and it is necessary to investigate whether this change influenced the PGA score. FSSG was also significantly correlated with TJC, mHAQ and EGA, which do not include PGA, suggesting that high levels of RA disease activity and the presence of GERD symptoms may interact with each other. It has also been reported that reduction in QOL caused dyspepsia symptoms [13], suggesting that reduction in QOL caused by the poor control of disease activity induces GERD symptoms in patients with RA, and that the presence of GERD symptoms impairs the overall health condition and further reduces QOL. Meanwhile, since FSSG and mHAQ were significantly correlated, limitation of physical activity may be likely to induce GERD symptoms. Actually, a significantly higher incidence of GERD symptoms has been reported in patients with RA with impaired ADL of HAQ ⱖ 1 than in non-RA subjects [14]. In addition, various types of osteoporosis [10] developed in the patients with RA could be one of the pathophysiological mechanisms of the induction of GERD symptoms. Miyakoshi et al. reported that increases in lumbar kyphosis represent a risk factor for GERD in patients with osteoporosis [15], and suggested that an increased intra-abdominal pressure by lumbar kyphosis might contribute to the development of GERD. Further, the presence of vertebral deformities in RA, independent of steroid use and osteoporosis [16] and the tendency of forward-bending posture [17] may also increase the intra-abdominal pressure, leading to GERD. Therefore, it is suggested that the prevention of physical disability by early treatment of RA may lead to the prevention of GERD symptoms in patients with RA. Furthermore, when there is a discrepancy between objective evaluation of RA disease activity and patient subjective evaluation of general health status, the complication of GERD symptoms should be considered. In other
Mod Rheumatol, 2014; 24(2): 291–295
words, the proper evaluation and treatment of GERD symptoms in patients with RA will be helpful to grasp the general health status that may influence PGA and the RA disease activity indices including PGA. Using FSSG, diverse symptoms of GERD can be simply and repeatedly evaluated in detail by adding the total score of the 12 questions, and it could be applied without a problem in this study, suggesting that FSSG is a useful medical questionnaire in clinical practice. Furthermore, a PPI exhibiting a strong acid secretioninhibitory effect is considered to be the first-line drug for GERD symptoms [18]. To ensure the inhibition of GERD symptoms in patients with RA, PPI administration at the standard dose should be considered. GERD can be classified into reflux esophagitis (RE) and nonerosive reflux disease (NERD) based on esophagoscopic findings. Since the present study was a cross-sectional retrospective study in medical practice where esophagoscopy was not performed routinely, there are limitations in the discussion of our findings in relation to RE or NERD. Further, since the present study did not examine the effects of PPI intervention, there are also limitations in the discussion of the effect of PPI in patients with RA. However, the higher rate of PPI use in the GERD group may reflect PPI prescription in patients with severe GERD symptoms.
Conclusion GERD symptoms in patients with RA increases PGA and the indices of disease activity and may serve as an inducer of the overestimation of disease activity and a disincentive for achieving remission of RA. Diagnosis and treatment of GERD symptoms utilizing FSSG may be desirable to avoid the overestimation and achieve remission as part of the total management of patients with RA.
Acknowledgements The authors thank to the patients who participated in this study.
Declaration of interest The authors have no conflict of interest and certify this to be true and original work.
References 1. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101(8):1900–20. 2. Wiklund L. Quality of life in patients with gastroesophageal reflux disease. Am J Gastroenterol. 2001;96(8 Suppl):46–53. 3. Japanese Society of Gastroenterology. Guidelines for Diagnosis and Treatment of Gastroesophageal Reflux Disease (in Japanese). Tokyo; 2009. p. 44–6. 4. Fujiwara Y, Arakawa T. Epidemiology and clinical characteristics of GERD in the Japanese population. J Gastroenterol. 2009;44(6): 518–34. 5. Kinoshita Y, Kawanami C, Kishi K, Nakata H, Seino Y, Chiba T. Helicobacter pylori independent chronological change in gastric acid secretion in the Japanese. Gut. 1997;41(4):452–8. 6. Shiokawa Y, Nobunaga M, Saito T, Asaki S, Ogawa N. Epidemiology study on upper gastrointestinal lesions induced by nonsteroidal anti-inflammatory drugs (in Japanese). Ryumachi. 1991; 31(1):96–111. 7. Wolfe F, Kong SX, Watson DJ. Gastrointestinal symptoms and health related quality of life in patients with arthritis. J Rheumatol. 2000;27(6):1373–8. 8. Kusano M, Shimoyama Y, Sugimoto S, Kawamura O, Maeda M, Minashi K, et al. Development and evaluation of FSSG: frequency scale for the symptoms of GERD. J Gastroenterol. 2004;39(9): 888–91.
DOI 10.3109/14397595.2013.843749
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9. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24. 10. Deal C. Bone loss in rheumatoid arthritis: systemic, periarticular, and focal. Curr Rheumatol Rep. 2012;14(3):231–7. 11. Amano K. Pathology and management of scleroderma: Reflux esophagitis/gastroesophageal reflux disease (in Japanese). Ryumachi-ka. 2008;39(4):306–11. 12. Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al; American College of Rheumatology; European League Against Rheumatism. American College of Rheumatology/ European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011;63(3):573–86. 13. Ford AC, Forman D, Bailey AG, Axon AT, Moayyedi P. Initial poor quality of life and new onset of dyspepsia: results from a longitudinal 10-year follow-up study. Gut. 2007;56(3):321–7.
Gastroesophageal reflux disease 295 14. Myasoedova E, Talley NJ, Manek NJ, Crowson CS. Prevalence and risk factors of gastrointestinal disorders in patients with rheumatoid arthritis: results from a population-based survey in olmsted county, Minnesota. Gastroenterol Res Pract. 2011;2011:745829. 15. Miyakoshi N, Kasukawa Y, Sasaki H, Kamo K, Shimada Y. Impact of spinal kyphosis on gastroesophageal reflux disease symptoms in patients with osteoporosis. Osteoporos Int. 2009; 20(27):1193–8. 16. Ørstavik RE, Haugeberg G, Mowinckel P, Høiseth A, Uhlig T, Falch JA, et al. Vertebral deformities in rheumatoid arthritis: a comparison with population-based controls. Arch Intern Med. 2004; 164(4):420–5. 17. Ekdahl C, Andersson SI. Standing balance in rheumatoid arthritis. A comparative study with healthy subjects. Scand J Rheumatol. 1989;18(1):33–42. 18. Japanese Society of Gastroenterology. Guidelines for Diagnosis and Treatment of Gastroesophageal Reflux Disease (in Japanese). Nankodo; 2009. p. 54–61.
ORIGINAL ARTICLE
Gastroesophageal reflux disease in patients with rheumatoid arthritis Yasushi Miura1,2, Koji Fukuda1, Toshihisa Maeda1, and Masahiro Kurosaka1
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1Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan and 2Division of Orthopedic Sciences, Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
Abstract
Keywords
Objective. Patients with rheumatoid arthritis (RA) are frequently complicated with gastric mucosal injury; however, there are few reports investigating gastroesophageal reflux disease (GERD) among patients with RA. We investigated the frequency of GERD and the correlation between GERD and the clinical characteristics of RA including patient’s global assessment (PGA). Methods. Patients with RA were investigated for GERD using self-administered frequency scale for the symptoms of GERD (FSSG). The correlation between GERD and the clinical characteristics of RA was analyzed statistically. Results. Two hundred and eleven patients in Japan were investigated. The prevalence of GERD among patients with RA (24.6%) was significantly higher than that in the Japanese population (11.5%) (p ⬍ 0.001). FSSG was positively correlated with modified health assessment questionnaire (mHAQ), PGA, evaluator’s global assessment (EGA) (p ⬍ 0.001), disease activity score (DAS)28erythrocyte sedimentation rate (ESR) (p ⬍ 0.05), DAS28-C-reactive protein (CRP), simplified disease activity index (SDAI) and clinical disease activity index (CDAI) (p ⬍ 0.001). The patients with GERD showed significantly higher scores in mHAQ, PGA, EGA, tenderness joint count, DAS28-ESR, DAS28-CRP, SDAI and CDAI (p ⬍ 0.001). Furthermore, the patients with GERD showed lower remission rates based on DAS28-ESR (p ⬍ 0.05), DAS28-CRP, SDAI and CDAI (p ⬍ 0.001). Conclusion. GERD complicated with RA increases PGA and the indices of disease activity. GERD symptoms analyzed using FSSG may be desirable to avoid the overestimation as part of the total management of patients with RA.
Gastroesophageal reflux disease, Frequency scale for the symptoms of GERD, Patient’s global assessment, Proton pump inhibitor, Rheumatoid arthritis
Introduction Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease principally developing in articular synovial tissues. RA is characterized by persistent symmetric polyarthritis, which causes severe articular swelling and pain and results in cartilage and bone destruction in the affected joints. Both chronic polyarthralgia and progressive physical disability markedly impair the activities of daily living (ADL) and quality of life (QOL) of patients with RA. RA was previously considered an incurable disease; however, combination therapy with methotrexate (MTX) and an anti-TNF biological agent introduced at the end of the 20th century caused a paradigm shift in the treatment of RA. These days, RA is considered a disease for which remission can be achieved; however, once destroyed by RA, joints never recover spontaneously. Thus, the current main target of RA treatment is to achieve clinical, structural and functional remissions in the early phase of RA and to maintain the QOL of patients. Meanwhile, gastroesophageal reflux disease (GERD) is defined as unpleasant symptoms or complications caused by reflux of the stomach contents into the esophagus, and the main symptoms are acid reflux symptoms, such as heartburn
Correspondence to: Yasushi Miura, Division of Orthopedic Sciences, Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma, Kobe 654-0142, Japan. Tel: ⫹ 81-78-796-4595. Fax: ⫹ 81-78-796-4595. E-mail: miura@ kobe-u.ac.jp
History Received 25 January 2013 Accepted 27 April 2013 Published online 31 October 2013
[1]. Unpleasant symptoms of GERD impair patients’ QOL [2]; therefore, adequate treatment of GERD is necessary to improve the QOL [3]. Furthermore, it has been suggested that patients with GERD have recently increased in Japan [4] owing to a reduced Helicobacter pylori infection rate and gastric acid secretion enhanced by the westernization of diets [5]. A high incidence of complications by gastric mucosal disorder in patients with RA has also been reported [6], and GERD is considered an important complication in RA [7]. Since GERD complication in patients with RA further reduces their QOL [7], the close investigation and treatment of GERD symptoms are important to improve the overall QOL of patients with RA. It was reported that the mean prevalence of GERD in Japan was 11.5% when the occurrence of heartburn twice a week or more was defined as GERD [4]. As GERD symptoms include not only symptoms of reflux, such as heartburn, but also those of dyspepsia, such as a heavy stomach feeling, it is not easy to evaluate GERD based on a single symptom. A GERD medical questionnaire developed by Kusano et al. [8], frequency scale for the symptoms of GERD (FSSG), is capable of comprehensively identifying diverse symptoms of GERD and separately evaluating symptoms of reflux score (RS) and dyspepsia score (DS). The validity of judging an FSSG score of 8 or higher as GERD has been demonstrated in a study on the sensitivity and specificity of endoscopic findings in patients with GERD and those without GERD. We use FSSG to identify and evaluate GERD for every patient’s visit. Against this background, in this study, we investigated the correlation
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Y. Miura et al.
Mod Rheumatol, 2014; 24(2): 291–295
Mod Rheumatol Downloaded from informahealthcare.com by Dalhousie University on 01/02/15 For personal use only.
Table 1. Baseline characteristics of patients with RA in GERD group and non-GERD group. Variable Age (year) Female/male Duration of the disease (year) class stage Steroid dose of PSL (mg) Steroid use (%) NSAID use (%) Biologics use (%) MTX use (%) DMARD use (%) PPI use (%) H2RA use (%) mHAQ PGA EGA TJC (28) SJC (28) CRP ESR DAS-CRP4 DAS-ESR4 SDAI CDAI
GERD (n ⫽ 52)
non-GERD (n ⫽ 159)
61.3 ⫾ 14.5 44/8 18.4 ⫾ 14.8 2.0 ⫾ 0.71 2.8 ⫾ 1.17 2.4 ⫾ 2.71 59.6 63.5 32.7 55.8 69.2 59.6 12.8 6.29 ⫾ 5.83 4.50 ⫾ 2.65 2.17 ⫾ 1.57 1.70 ⫾ 1.90 1.00 ⫾ 1.84 0.44 ⫾ 0.92 17.87 ⫾ 15.13 2.86 ⫾ 0.96 3.17 ⫾ 1.08 9.57 ⫾ 5.70 9.14 ⫾ 5.37
59.6 ⫾ 13.5 134/25 15.0 ⫾ 13.7 1.8 ⫾ 0.82 2.6 ⫾ 1.24 1.6 ⫾ 2.22 45.3 52.8 39.0 67.3 78.0 38.8 23.0 2.63 ⫾ 5.07 2.05 ⫾ 2.17 1.23 ⫾ 1.20 1.10 ⫾ 2.52 1.00 ⫾ 2.09 0.32 ⫾ 0.47 19.25 ⫾ 17.18 2.22 ⫾ 1.00 2.56 ⫾ 1.17 5.41 ⫾ 6.38 5.11 ⫾ 6.20
P-value 0.41 0.95* 0.08 0.06 0.60 0.06 0.07* 0.22* 0.42* 0.13* 0.20* 0.01* 0.13* ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 0.67 0.79 0.88 ⬍ 0.001 ⬍ 0.01 ⬍ 0.001 ⬍ 0.001
P-value indicates the differences between GERD group and non-GERD group by Wilcoxon rank sum test, except for gender, steroid, NSAID, biologics, MTX, DMARD, PPI and H2RA use, which were analyzed by Chi-square test (marked with asterisks). *Chi-square test.
between the pathology and GERD symptoms in patients with RA using FSSG.
Subjects and methods The subjects were 211 patients with RA (178 females and 33 males) under outpatient treatment in July–October 2011 who met the diagnostic criteria established by the American College of Rheumatology in 1987 [9]. No specific exclusion criteria were set for this study. GERD symptoms were evaluated using FSSG, and patients with FSSG ⱖ 8 were regarded as having GERD symptoms (GERD group) and those with FSSG ⬍ 8 as having no GERD symptoms (non-GERD group). The correlations and the differences in the patient background between the GERD and non-GERD groups with the disease activity indices of RA (disease activity score (DAS)-C-reactive protein (CRP)4, DASerythrocyte sedimentation rate (ESR)4, simplified disease activity index (SDAI), clinical disease activity index (CDAI)), ADL score (modified health assessment questionnaire (mHAQ)), inflammatory markers (CRP and ESR), and FSSG total score (TS), RS, and DS, and the influence of GERD on the remission rates of RA were statistically analyzed using Chi-square, Wilcoxon rank sum or Spearman’s rank correlation test. This study was retrospectively performed from medical records in accordance with proper ethical standards laid down in the 1964 Declaration of Helsinki.
Results The mean age of the patients with RA was 60.0 ⫾ 13.9 years, the mean disease duration was 15.9 ⫾ 14.1 years, and the mean prednisolone (PSL)-converted oral steroid dose was 1.8 ⫾ 2.4 mg/day.
Figure 1. Correlation between FSSG scores and mHAQ, PGA and EGA. mHAQ, PGA and EGA were positively and significantly correlated with total scores (TS), reflux score (RS) and dyspepsia score (DS) of FSSG by Spearman’s rank correlation test.
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DOI 10.3109/14397595.2013.843749
Figure 2. Correlation between FSSG scores and DAS-CRP4, DAS-ESR4, SDAI and CDAI. DAS-CRP4, DAS-ESR4, SDAI and CDAI were positively and significantly correlated with total scores (TS), reflux score (RS) and dyspepsia score (DS) of FSSG by Spearman’s rank correlation test.
Non-steroidal anti-inflammatory drugs (NSAIDs) were administered to 117 patients (55.5%). When FSSG ⱖ 8 was regarded as GERD, the complication rate of GERD was 24.6%. mHAQ, the patient’s global assessment (PGA) and evaluator’s global assessment (EGA), tenderness joint count (TJC), DAS-CRP4, DAS-ESR4, SDAI, CDAI, and rates of treatment with proton pump inhibitors (PPI) were significantly higher in the GERD group than in the non-GERD group, but no significant differences were observed in the mean age, disease duration, gender ratio, Steinbrocker functional classification and staging, steroid dosages, rates of treatment with steroid, NSAIDs, biologics, MTX,
Table 2. Remission rates depending of DAS-CRP4, DAS-ESR4, SDAI and CDAI in GERD group and non-GERD group. mHAQ DRS-CRP4 DAS-ESR4 SDAI CDAI
GERD (%) 47.1 33.3 36.4 12.5 12.5
non-GERD (%) 78.8 56.1 56.7 45.7 42.4
P-value P ⬍ 0.0001 P ⬍ 0.01 P ⬍ 0.05 P ⬍ 0.001 P ⬍ 0.001
P-value indicates the differences between GERD group and non-GERD group analyzed by Chi-square test.
disease-modifying anti-rheumatic drugs (DMARDs), and H2 receptor antagonists (H2RA), swelling joint count (SJC), CRP, or ESR (Table 1). In addition, mHAQ, PGA, EGA (Figure 1), DAS-CRP4, DAS-ESR4, SDAI and CDAI (Figure 2) were positively and significantly correlated with TS, RS and DS of FSSG, while either CRP or ESR was not correlated (data not shown). Furthermore, the remission rates in mHAQ, DAS-CRP4, DASESR4, SDAI and CDAI were significantly lower in the GERD group than in the non-GERD group (Table 2).
Discussion Various complications develop in patients with RA. GERD has been reported [4] to complicate various diseases, such as diabetes mellitus, hypertension, angina pectoris, liver disease and asthma, and it may also complicate RA and reduce the QOL of patients with RA in combination with disuse, periarticular, and steroidinduced osteoporosis [10] and NSAID- and steroid-induced gastric mucosal disorder. In the current RA treatment involving early diagnosis and aggressive drug therapy targeting complete remission, the countermeasures against these complications are also essential to maintain a high QOL. Amano [11] reported that the GERD complication rate in Japanese patients with RA on FSSG was 23%, and the rate in
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this study, 24.6%, was similar to this, suggesting that the patients in this study may be representative of patients with RA from the perspective of the GERD complication rate. In this study, we newly investigated how the presence of GERD symptoms influenced the clinical condition of RA, and clarified that GERD symptoms and subscales of these, reflux and dyspepsia symptoms, strongly influence the disease activity indices and ADL in patients with RA. In addition, the presence of GERD symptoms increases the RA disease activity indices because FSSG was significantly correlated with each disease activity index and the remission rate significantly decreased in the presence of GERD symptoms. RA disease activity indices: DAS28-ESR4, DAS28-CRP4, SDAI and CDAI, include PGA, which represents the overall health condition evaluated by patients. We revealed that PGA and FSSG were positively correlated in patients with RA. Self-rating PGA represents the subjective evaluation by patients themselves; therefore, it is disputable whether the scale reflects only the RA-associated physical condition, although the filling-in procedure is explained to patients beforehand. Since the present study demonstrated that there are no significant differences in prescription rates of steroids, NSAIDs, biologics, MTX and DMARD; steroid dose; ESR and CRP between GERD and non-GERD groups, the activities of synovitis may be similar between the two groups, although neither rheumatoid factor nor matrix metalloproteinase-3 was examined. Thus, to avoid the overtreatment in patients with RA, overestimation by disease activity indices should be carefully considered especially when complicated with GERD. Actually, the explanation about the filling-in procedure of PGA has recently altered from ‘please describe your overall condition’ to ‘please answer how you feel about your arthritis condition today in consideration of various influences of arthritis on you’ [12]. This study was performed before this change in the explanation, and it is necessary to investigate whether this change influenced the PGA score. FSSG was also significantly correlated with TJC, mHAQ and EGA, which do not include PGA, suggesting that high levels of RA disease activity and the presence of GERD symptoms may interact with each other. It has also been reported that reduction in QOL caused dyspepsia symptoms [13], suggesting that reduction in QOL caused by the poor control of disease activity induces GERD symptoms in patients with RA, and that the presence of GERD symptoms impairs the overall health condition and further reduces QOL. Meanwhile, since FSSG and mHAQ were significantly correlated, limitation of physical activity may be likely to induce GERD symptoms. Actually, a significantly higher incidence of GERD symptoms has been reported in patients with RA with impaired ADL of HAQ ⱖ 1 than in non-RA subjects [14]. In addition, various types of osteoporosis [10] developed in the patients with RA could be one of the pathophysiological mechanisms of the induction of GERD symptoms. Miyakoshi et al. reported that increases in lumbar kyphosis represent a risk factor for GERD in patients with osteoporosis [15], and suggested that an increased intra-abdominal pressure by lumbar kyphosis might contribute to the development of GERD. Further, the presence of vertebral deformities in RA, independent of steroid use and osteoporosis [16] and the tendency of forward-bending posture [17] may also increase the intra-abdominal pressure, leading to GERD. Therefore, it is suggested that the prevention of physical disability by early treatment of RA may lead to the prevention of GERD symptoms in patients with RA. Furthermore, when there is a discrepancy between objective evaluation of RA disease activity and patient subjective evaluation of general health status, the complication of GERD symptoms should be considered. In other
Mod Rheumatol, 2014; 24(2): 291–295
words, the proper evaluation and treatment of GERD symptoms in patients with RA will be helpful to grasp the general health status that may influence PGA and the RA disease activity indices including PGA. Using FSSG, diverse symptoms of GERD can be simply and repeatedly evaluated in detail by adding the total score of the 12 questions, and it could be applied without a problem in this study, suggesting that FSSG is a useful medical questionnaire in clinical practice. Furthermore, a PPI exhibiting a strong acid secretioninhibitory effect is considered to be the first-line drug for GERD symptoms [18]. To ensure the inhibition of GERD symptoms in patients with RA, PPI administration at the standard dose should be considered. GERD can be classified into reflux esophagitis (RE) and nonerosive reflux disease (NERD) based on esophagoscopic findings. Since the present study was a cross-sectional retrospective study in medical practice where esophagoscopy was not performed routinely, there are limitations in the discussion of our findings in relation to RE or NERD. Further, since the present study did not examine the effects of PPI intervention, there are also limitations in the discussion of the effect of PPI in patients with RA. However, the higher rate of PPI use in the GERD group may reflect PPI prescription in patients with severe GERD symptoms.
Conclusion GERD symptoms in patients with RA increases PGA and the indices of disease activity and may serve as an inducer of the overestimation of disease activity and a disincentive for achieving remission of RA. Diagnosis and treatment of GERD symptoms utilizing FSSG may be desirable to avoid the overestimation and achieve remission as part of the total management of patients with RA.
Acknowledgements The authors thank to the patients who participated in this study.
Declaration of interest The authors have no conflict of interest and certify this to be true and original work.
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