Incidence of new carotid plaques in rheumatoid arthritis patients: 6-Year prospective results of the TOMORROW study.

OBJECTIVES: The purpose of this study was to evaluate the new incidence of carotid plaques in rheumatoid arthritis (RA) patients over a 6-year prospective follow-up and to assess the risk factors. METHODS: This is a 10-year prospective cohort study that included 208 RA patients and 205 age- and gender-matched controls. Ultrasound assessment of the bilateral carotid arteries was performed in 2011 and 2017. RESULTS: There were no differences in the incidence of new carotid atherosclerotic plaques over 6 years between the two groups (35.5% vs. 37.0%, respectively; p = .936). The mean Disease Activity Score 28-C-reactive protein over 6 years in RA patients was 2.73 ± 0.95. Multiple logistic regression analysis showed that RA was not a risk factor for new carotid atherosclerotic plaques (odds ratios, 0.708; 95% confidence interval, 0.348-1.440; p = .340). An average glucocorticoid dose of >1.8 mg/day over 6 years was a risk factor for new carotid atherosclerotic plaques (odds ratios, 8.54; 95% confidence interval, 1.641-44.455; p = .011). CONCLUSIONS: Incidence of new carotid atherosclerotic plaques was similar between well-controlled disease activity RA patients and control subjects. A mean glucocorticoid dose of >1.8 mg/day over 6 years was a risk factor for new carotid atherosclerotic plaques.

Impact of disease burden or inflammation on nutritional assessment by the GLIM criteria in female patients with rheumatoid arthritis.

BACKGROUND & AIMS: In 2018, the Global Leadership Initiative on Malnutrition (GLIM) released a global standard for evaluating malnutrition. The etiologies of malnutrition in the GLIM criteria includes disease burden/inflammation, but how this view affects nutritional assessment remains unclear. This study aimed to investigate the impact of disease burden/inflammation on the proportion of malnourished patients defined by GLIM criteria, and how differences in methods for determining disease burden/inflammation in GLIM criteria affect existing nutritional indices among patients with rheumatoid arthritis (RA). We also investigated factors associated with malnutrition in RA patients. METHODS: Data from 135 female RA patients (66.8 ± 12.6 years) were cross-sectionally analyzed. Among the etiologies of malnutrition, disease burden/inflammation was defined as: (1) moderate or higher disease activity score (disease activity score composite of the 28-joint score and erythrocyte sedimentation rate [DAS28-ESR] ≥ 3.2) [DAS-malnutrition (MN)]; (2) elevated C-reactive protein (CRP) ≥0.5 mg/dL (CRP-MN); and (3) presence of RA (RA-MN). In each of the three conditions, nutritional indicators between well-nourished and malnourished groups were compared by analysis of covariance. Factors associated with malnutrition were analyzed with logistic regression analysis. RESULTS: The frequencies of malnutrition as defined by DAS-MN, CRP-MN, and RA-MN were 39%, 30%, and 71%, respectively. When malnutrition was defined by the DAS-MN and/or the CRP-MN, grip strength and serum ceruloplasmin, iron, and zinc levels showed significant differences between the well-nourished and malnourished groups (p < 0.05). The use of targeted synthetic or biological disease-modifying antirheumatic drugs (ts-/b-DMARD) (OR = 0.29; 95% CI 0.11-0.82), grip strength (OR = 0.83; 95% CI 0.75-0.91), subjective reduction in walking speed (OR = 5.24; 1.85-14.86) were significantly associated with malnutrition as determined by DAS-MN. CONCLUSION: Differences in disease burden/inflammation affect nutritional assessments. The number of malnourished patients with RA was negatively associated with the use of ts-/b-DMARDs and high physical function in women.

Double-blinded randomized controlled trial to reveal the effects of Brazilian propolis intake on rheumatoid arthritis disease activity index; BeeDAI.

BACKGROUND AND AIMS: Brazilian propolis reportedly contributed to suppressing disease activity in a mouse model of rheumatoid arthritis (RA), suggesting new treatment options using Brazilian propolis. However, only results from animal experiments have been available, and the suppressive effects of Brazilian propolis on disease activity in humans with RA remain unknown. The purpose of this study was to clinically validate how Brazilian propolis intake changes disease activity in RA patients. METHODS: This study was conducted as a multicenter, double-blinded, randomized, placebo-controlled, parallel-group study of 80 women with RA (median age, 61.5 years; interquartile range, 56.0 to 67.3 years) showing moderate disease activity on Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR). Test tablets containing Brazilian propolis were used in Group P (40 patients), and Brazilian propolis-free placebo tablets were used as control in Group C (40 patients). Group P received 5 tablets of propolis (508.5 mg of propolis) daily, and Group C received 5 tablets of placebo daily. The intervention lasted 24 weeks, with change in DAS28-ESR set as the primary endpoint. As secondary endpoints, other disease activity assessment (DAS28 using C-reactive protein, simplified disease activity index, clinical disease activity index), ultrasonographic evaluation of synovitis, activities of daily living, quality of life, changes in cytokine levels, and adverse events over the course of the study were also assessed. Data were statistically analyzed by analysis of covariance. RESULTS: No significant differences in the primary endpoint were identified between groups (Group P vs Group C, effect: 0.14, 95% confidence interval: -0.21 to 0.49, p = 0.427). Likewise, no significant differences were seen between groups for any secondary endpoints. The adverse event rate during the study period was 28% in Group P and 33% in Group C. CONCLUSIONS: Brazilian propolis exerted no effects on disease activity in patients with RA.

Change in dietary inflammatory index score is associated with control of long-term rheumatoid arthritis disease activity in a Japanese cohort: the TOMORROW study.

BACKGROUND: The dietary inflammatory index (DII®), a quantitative measure of the inflammatory potential of daily food and nutrient intake, and associations between a variety of health outcomes have been reported. However, the association between DII score and disease activity of rheumatoid arthritis (RA) is unclear. Therefore, this study was designed to test whether higher DII score contributes to disease activity and as a corollary, whether reducing DII score helps to achieve or maintain low disease activity or remission in patients with RA. METHODS: We performed a cross-sectional and longitudinal analysis using 6 years of data (from 2011 to 2017) in TOMORROW, a cohort study consisting of 208 RA patients and 205 gender- and age-matched controls started in 2010. Disease activity of RA patients was assessed annually using DAS28-ESR (disease activity score 28 joints and the erythrocyte sedimentation rate) as a composite measure based on arthritic symptoms in 28 joints plus global health assessment and ESR. Dietary data were collected in 2011 and 2017 using the brief-type self-administered diet history questionnaire (BDHQ). Energy-adjusted DII (E-DII™) score was calculated using 26 nutrients derived from the BDHQ. Data were analyzed with two-group comparisons, correlation analysis, and multivariable logistic regression analysis. RESULTS: One hundred and seventy-seven RA patients and 183 controls, for whom clinical and dietary survey data were available, were analyzed. RA patients had significantly higher E-DII (pro-inflammatory) score compared to controls both in 2011 and 2017 (p < 0.05). In RA patients, E-DII score was not a factor associated with significant change in disease activity. However, anti-inflammatory change in E-DII score was associated maintaining low disease activity (DAS28-ESR ≤ 3.2) or less for 6 years (OR 3.46, 95% CI 0.33-8.98, p = 0.011). CONCLUSIONS: The diets of RA patients had a higher inflammatory potential than controls. Although E-DII score was not a factor associated with significant disease activity change, anti-inflammatory change in E-DII score appeared to be associated with maintaining low disease activity in patients with RA. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000003876 . Registered 7 Aug 2010-retrospectively registered.

Change in skeletal muscle mass is associated with lipid profiles in female rheumatoid arthritis patients -TOMORROW study.

BACKGROUND & AIMS: To examine the relationship between changes in skeletal muscle mass and lipid metabolism and glycometabolism in patients with rheumatoid arthritis (RA). METHODS: Data were analyzed from 148 female RA patients and 145 age-matched non-RA (control) female subjects from a prospective cohort study (TOMORROW; TOtal Management Of Risk factors in Rheumatoid arthritis patients to lOWer morbidity and mortality study). Appendicular skeletal muscle mass (ASM) was assessed using dual-energy x-ray absorptiometry and skeletal muscle mass index (SMI) was calculated as ASM divided by the square of height. The reference value for SMI in Asian women, 5.4 kg/m2, was used to define low SMI. Data were assessed using cross-sectional (2010 baseline data) and longitudinal (change in value from 2010 to 2013) methods from the retrospective cohort. RESULTS: At baseline in RA patients, the low SMI group showed significantly higher low-density lipoprotein cholesterol (LDL-chol) (p = 0.015), apolipoprotein (Apo)B (p = 0.046), and ApoB-to-A1 (ApoB/A1) (p = 0.025) than the normal SMI group. In multiple regression analysis of RA patients, sequential changes from 2010 to 2013 (Δ) in SMI and ApoB and ApoC2 showed significant negative relationships (ß = -0.19, -0.18, respectively) even after adjusting for age, RA duration, exercise habits, medication for RA, disease severity, activities of daily living (ADL) and body fat mass. No significant relation was evident between ΔSMI and various glycometabolism parameters in RA patients. CONCLUSIONS: Skeletal muscle mass might be related to lipid metabolism in RA patients. This relationship is independent of factors such as disease severity and body fat mass.

Soybean isoflavone can protect against osteoarthritis in ovariectomized rats.

Osteoarthritis (OA) is a chronic and incurable disease and a leading cause of significant pain and disability that is closely associated with aging and obesity. An appropriate long-term therapy regimen is presently unknown. An estrogen deficiency after menopause increases the incidence and severity of OA in women. Soybean isoflavone have weak estrogenic effects in several organs and have been considered as a potentially safe natural selective estrogen receptor modulator. The present study aimed to determine the effects of isoflavone on cartilage degradation in ovariectomized rats. Six-month-old female Sprague-Dawley (SD) rats (n = 40) were randomly assigned to sham operation (n = 10), ovariectomy (OVX) (n = 15) or OVX + isoflavone (OVXI) (n = 15) groups. The OVXI group was fed with soybean isoflavone (51.0 mg/kg/day) for nine weeks, then knee joints were excised. Cartilage degradation was evaluated by toluidine blue staining joint specimens, and by comparing values for serum C-telopeptides of Type II collagen (CTX-II) and cartilage oligomeric matrix protein (COMP) between baseline and the end of the study. Cartilage damage scored by Toluidine blue staining was significantly lower in the OXVI, than the OVX group (P < 0.016). The CTX-II values before the surgical procedure and the end of experiment, did not significantly differ among the groups. Values for COMP in all samples were below detection limits in all samples. Soy bean isoflavone limited the degeneration of cartilage induced by OVX in rats.

Do rheumatoid arthritis patients have low back pain or radiological lumbar lesions more frequently than the healthy population? - Cross-sectional analysis in a cohort study with age and sex-matched healthy volunteers.

BACKGROUND CONTEXT: Rheumatoid arthritis (RA) can affect the spine; however, the epidemiology of lumbar lesions and/or low back pain (LBP) in RA patients has not been well-studied. PURPOSE: The purpose of this study was to compare the prevalence of lumbar lesions and LBP in RA patients with that in healthy volunteers, and to elucidate the influence of RA on lumbar disease. STUDY DESIGN: Cross-sectional analysis in a cohort study with age- and sex-matched healthy volunteers. PATIENT SAMPLE: This study included 185 patients with RA and 188 gender/age-matched healthy volunteers without RA. OUTCOME MEASURES: Lumbar spondylolisthesis and prevalent vertebral fractures were evaluated using plain lateral X-ray images. Thoraco-lumbar scoliosis was evaluated using dual-energy X-ray absorptiometric images. LBP was assessed using the visual analogue scale (VAS) and Rolland-Morris disability questionnaire (RDQ). METHODS: The prevalence of radiological lumbar lesion and LBP was compared between the RA and control groups. In the RA group, factors associated with lumbar lesion and LBP were analyzed using a multiple logistic regression model. RESULTS: The prevalence rates of spondylolisthesis and prevalent vertebral fracture were significantly higher in the RA group than in the control group; the prevalence of thoraco-lumbar scoliosis tended to be higher in the RA group. There was no significant difference in the average LBP-VAS between the groups. However, the percentage of analgesic drug use was significantly higher, and RDQ scores tended to be worse in the RA group than the control group. Multivariate analysis revealed that age and disease activity score were both related to LBP in the RA group. CONCLUSIONS: RA patients are more likely to have radiological lumbar lesions. LBP in RA patients is well controlled, similar to the level in the healthy population; however, disease activity was related to LBP in RA patients. These results suggest that disease control is important for lumbar care in RA patients.

Comparison of median nerve stiffness with and without rheumatoid arthritis by ultrasound real-time tissue elastography: A propensity score matching study.

Objectives: This study aimed to compare median nerve stiffness measured by ultrasound real-time tissue elastography in patients with and without rheumatoid arthritis (RA and non-RA groups, respectively).Methods: Altogether, 402 hands of 201 RA group and 222 hands of 111 non-RA group were included in the study. Ultrasonography was performed to evaluate the circumference, cross-sectional area (CSA) and strain ratio as an elasticity of the median nerve at the inlet level of the carpal tunnel and the proximal portion of the carpal tunnel inlet. Using propensity score matching, the difference between RA and non-RA group were analyzed.Results: After propensity score matching, 135 hands in 104 RA group and 70 non-RA group were finally analyzed. There were no significant differences in the circumference and CSA of the median nerve between the two groups. The strain ratio of the median nerve was significantly higher in RA group than in non-RA group only at the inlet of the carpal tunnel level.Conclusions: The nerve stiffness in patients with RA measured by ultrasound real-time tissue elastography was higher than without RA. Inflammatory condition of the flexor tendon and wrist joint in patients with RA may generate fibrotic changes in the median nerve.Trial registration: University Hospital Medical Information Network Clinical Trials Registry: UMIN000015314.

Clinical and radiologic analysis of on-demand use of etanercept for disease flares in patients with rheumatoid arthritis for 2 years: The RESUME study: A case-control study.

To reduce costs of biological disease-modifying antirheumatic drugs (bDMARDs), we evaluated the efficacy of repeated etanercept (ETN) discontinuation and restarting in rheumatoid arthritis (RA) patients in a case-control study.Thirty-one bDMARD-naive RA patients with moderate to high disease activity received ETN until low disease activity (LDA) was achieved, after which ETN was discontinued. Upon flaring, ETN was readministered with observation every 2 months for 2 years, and radiographically evaluated in comparison with a historical control group treated continuously with ETN. Statistical methods including Fisher exact test, analysis of variance (ANOVA), Kruskal-Wallis test, multiple regression analysis, and Student t test were conducted as appropriate.Thirteen patients with inadequate response to ETN were withdrawn from the study, and 5 had no flare-up after ETN discontinuation. In the remaining 13 patients, ETN was used on-demand to maintain LDA. Multivariate analysis revealed that MTX was significantly correlated with ETN. All 13 patients achieved LDA at final follow-up. Although joint damage progressed in patients using ETN on-demand, structural damage progression in the on-demand group was not significantly different from that in controls.On-demand use of ETN for flaring reduced disease activity but not structural damage in 50% of patients (though not significantly). However, inhibition of joint damage was achieved in 50% of patients after 2 years, supporting on-demand use of ETN as a treatment option for patients with RA who cannot afford bDMARD or targeted synthetic DMARD therapy.

Evaluation of work disability in Japanese patients with rheumatoid arthritis: from the TOMORROW study.

To evaluate work disability and associated factors in patients with rheumatoid arthritis (RA) who participated in the TOMORROW study, a 10-year cohort study in Japan. Subjects in this cross-sectional analysis comprised 191 RA patients and 191 age- and sex-matched non-RA individuals. Work-related outcomes were measured using the Work Productivity and Activity Impairment questionnaire by employment status (full-time worker (FTW), employed ≥ 35 h/week; part-time worker (PTW), < 35 h/week; home worker (HW), non-employed). In addition, we assessed the EuroQol-5 Dimensions (EQ-5D) and Health Assessment Questionnaire (HAQ) to evaluate quality of life and activities of daily living. No significant differences were evident between groups in percentages of participants in each employment status (p = 0.11), percentages of absenteeism (FTW, p = 1.00; PTW, p = 0.29), presenteeism (FTW, p = 0.23; PTW, p = 0.54), overall work impairment (FTW, p = 0.23; PTW, p = 0.73), or percentage of activity impairment (AI) (FTW, p = 0.62; PTW, p = 0.60). In the HW group, percentage of AI was higher in RA patients than that in non-RA patients (p < 0.01). Among RA patients, HW showed lower EQ-5D and higher HAQ than FTW or PTW (p < 0.001 each). Higher disease activity was observed in HW than FTW (p < 0.01). In terms of the effect of biological disease-modifying anti-rheumatic drugs, no significant differences in work-related outcomes, health status, or daily activity were evident between users and non-users. No significant differences in employment status or work impairment were seen between RA and non-RA groups among paid workers. HW with RA showed more impaired daily activity and higher disease activity compared to working RA patients. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry: UMIN000003876 . Registered 1 Jun 2010.

Abatacept might increase bone mineral density at femoral neck for patients with rheumatoid arthritis in clinical practice: AIRTIGHT study.

We investigated the influence of abatacept (ABT) on bone mineral density (BMD) and bone metabolic markers (BMMs) in patients with rheumatoid arthritis (RA) compared to other biologic disease-modifying anti-rheumatic drugs (bDMARDs). This prospective, comparative, non-randomized study (the AIRTIGHT study; UMIN000005570) investigated the effects of ABT and other bDMARDs on bone metabolism. A total of 165 RA patients were divided into ABT (n = 50) and non-ABT (n = 115). We evaluated percentage changes in BMD (%ΔBMD) at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry. Urinary levels of cross-linked N-telopeptide of type I collagen (uNTx) and bone-specific alkaline phosphatase (BAP) were used as markers of bone resorption and formation, respectively. No significant differences in 1-year completion rates were seen between ABT (64%) and non-ABT (72%; p = 0.387). The %ΔBMD at the femoral neck was significantly higher in the ABT group (0.97%) than in the non-ABT group (- 2.19%; p = 0.026). Whereas, no significant difference in %ΔBMD at the lumbar spine was observed between groups (ABT, - 0.40%; Non-ABT, - 1.67%; p = 0.524). No significant differences were observed in changes to uNTx or BAP. ABT treatment was significantly associated with increased BMD at the femoral neck (odds ratio (OR) 8.84; 95% CI 1.08-72.4; p = 0.04), and baseline lumbar osteoarthritis was significantly associated with BMD at the lumbar spine (OR 2.97; 95% CI 1.23-7.13; p = 0.02). The efficacy of ABT for increasing BMD at the femoral neck was superior to that of other bDMARDs. ABT may offer good efficacy for improving BMD at the femoral neck in patients with RA.

Monounsaturated fatty acids might be key factors in the Mediterranean diet that suppress rheumatoid arthritis disease activity: The TOMORROW study.

BACKGROUND & AIMS: The Mediterranean diet is reportedly effective in suppressing disease activity in rheumatoid arthritis (RA), but the key elements responsible for this effect remain unknown. The presented study therefore aimed to identify such elements. METHODS: This study included 208 consecutive patients with RA (RA group) and 205 age- and sex-matched healthy volunteers (controls) from the prospective "TOMORROW" cohort study that has been ongoing since 2010 were included in this study. Food and nutrient intake was assessed using the brief self-administered diet history questionnaire (BDHQ), Mediterranean diet scores were calculated based on intake by controls and disease activity was determined from disease activity scores in 28 joints and erythrocyte sedimentation rates (DAS28-ESR). RESULTS: Intake of monounsaturated fatty acids (MUFA) was significantly lower in the RA, than in the control group (P = 0.003) and the ratio of consumed monounsaturated to saturated fatty acid (MUFA/SFA) significantly differed within the RA group after being sub-classified according to DAS28-ESR. Moreover, DAS28-ESR significantly correlated with MUFA/SFA intake after age adjustment (R = -0.228, P < 0.01). Logistic regression analysis selected high MUFA intake as an independent predictor of remission in the RA group with borderline boundary significance (odds ratio, 1.97; 95% CI, 0.98-3.98; P = 0.057). Changes in DAS28-ESR between 2010 and 2011 significantly correlated with MUFA/SFA intake after age adjustment (R = 0.180, P = 0.01). CONCLUSIONS: Daily MUFA intake, a component of the Mediterranean diet score, might suppress disease activity in RA patients.

High titer of anti-citrullinated peptide antibody is a risk factor for severe carotid atherosclerotic plaque in patients with rheumatoid arthritis: the TOMORROW study.

AIM: Cardiovascular disease is one of the complications of rheumatoid arthritis (RA). We researched the morbidity and severity of existing carotid atherosclerosis plaque and associated risk factors in patients with RA. METHOD: This study included 413 participants, including 208 patients with RA and 205 age- and sex-matched healthy volunteers. Carotid ultrasound, clinical data collection and assessment of cardiovascular risk factors were performed. Atherosclerotic plaque was defined as an intima-media thickness ≥ 1.1 mm. Severity of plaque was assessed by plaque score, defined as the sum of the maximal thickness of all plaques in bilateral carotid arteries. RESULTS: Data were analyzed from 200 patients with RA and 202 controls. Carotid plaque was observed more frequently in patients with RA than controls (47.0 vs. 36.1%, P = 0.027). Moreover, plaque score was significantly higher in RA patients (P = 0.032). In logistic regression analysis, RA represented an independent risk factor for the presence of plaque (adjusted odds ratio, 1.68; 95% confidence interval, 1.03-2.74). Comparing RA patients with and without plaque, anti-cyclic citrullinated peptide (anti-CCP) antibodies titer was significantly higher in patients with plaque (315.8 ± 454.1 U/mL) than in patients without (165.7 ± 281.1 U/mL; P = 0.005). Moreover, multiple linear regression analysis clarified that anti-CCP antibody titer was associated with plaque score in patients with RA. CONCLUSION: High prevalence of any carotid plaques and severe carotid plaques were more frequent in patients with RA. High titer of anti-CCP antibodies represented a risk factor for severe carotid atherosclerotic plaque in patients with RA.

Use of bisphosphonate might be important to improve bone mineral density in patients with rheumatoid arthritis even under tight control: the TOMORROW study.

Although patients with rheumatoid arthritis (RA) are prone to osteoporosis, tight control of disease activity might have a positive effect on bone metabolism. We aimed to determine whether bisphosphonate use is still important to improve bone mineral density (BMD) in RA patients whose disease activity was tightly controlled and the dose of glucocorticoid was reduced. This study was a sub-analysis of the 10-year prospective cohort TOtal Management Of Risk factors in Rheumatoid arthritis patients to lOWer morbidity and mortality: the TOMORROW which started from 2010. We compared BMD between 192 patients with RA and age- and sex-matched volunteers between 2010 and 2013 using dual-energy X-ray absorptiometry (DXA) in whole body mode. We then determined ratios of changes in BMD (%ΔBMD) to assess factors influencing increases in BMD among the patients using multivariate logistic regression analysis. The BMD was significantly lower in the patients than in the controls at all sites surveyed during 2010 and 2013. The %ΔBMD of the total spine was significantly higher among the patients treated with, than without bisphosphonate (6.2 vs. 1.8%, P = 0.0001). Multivariate logistic regression analysis revealed that use of bisphosphonate was a significant factor contributing to BMD increase (odds ratio 2.13; 95% confidence interval, 1.03-4.38, P = 0.041). Meanwhile, use of biologic agents, reducing glucocorticoid dose, and control of disease activity were not significant factors for gain of BMD. The BMD was lower among patients with RA than non-RA controls. Use of bisphosphonate significantly increased the BMD of the spine in patients over a period of 3 years and was important for maintaining the BMD among patients with RA under the control of inflammation and disease activity.

Loss of lean body mass affects low bone mineral density in patients with rheumatoid arthritis - results from the TOMORROW study.

OBJECTIVES: Osteoporosis is one of the complications for patients with rheumatoid arthritis (RA). Rheumatoid cachexia, the loss of lean body mass, is another. However, the relationship between decreased lean body mass and reduced bone mineral density (BMD) in patients with RA has not been well studied. METHODS: This study included 413 participants, comprising 208 patients with RA and 205 age- and sex-matched healthy volunteers. Clinical data, BMD, bone metabolic markers (BMM) and body composition, such as lean body mass and percent fat, were collected. Risk factors for osteoporosis in patients with RA including the relationship BMD and body composition were analyzed. RESULTS: Patients with RA showed low BMD and high BMM compared with controls. Moreover, lean body mass was lower and percent fat was higher in patients with RA. Lean body mass correlated positively and percent fat negatively with BMD. Lean body mass was a positive and disease duration was a negative independent factor for BMD in multivariate statistical analysis. CONCLUSION: BMD and lean body mass were significantly lower in patients with RA compared to healthy controls. Lean body mass correlated positively with BMD and decreased lean body mass and disease duration affected low BMD in patients with RA. TRIAL REGISTRATION: [UMIN Clinical Trials Registry, http://www.umin.ac.jp/ctr/ , UMIN000003876].

Incidence rate of falls and its risk factors in patients with rheumatoid arthritis compared to controls: Four years of the TOMORROW study.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have been recognized to experience falls frequently due to functional disabilities. The aim of this study was to prospectively investigate factors influencing falls in patients with RA compared to controls. METHODS: We compared the frequency of falls in 208 RA patients and 205 age- and sex-matched volunteers for four years and analyzed risk factors for falls in RA patients using multivariate regression analysis. RESULTS: No significant difference in the incidence rate of falls (/person-year) between patients with RA (median [interquartile range]: 0 [0, 0.5]) and controls (0 [0, 0.5]) was evident during four years. Logistic regression analysis identified age, sex, body mass index, history of falls, and lower limb implant at baseline as significant risk factors for falls. The highest quartile of anti-CCP antibody level (>300.6 U/ml) was the strongest predictor for multiple falls (odds ratio, 2.97; 95% confidence interval, 1.12-7.91, p = 0.029) among RA patients. CONCLUSION: During four years we could not observe the higher incidence rate of falls in RA patients compared to controls in our cohort. Subjects with a higher titer of anti-CCP antibody might be at higher risk of frequent falls among RA patients.

High frequency of vertebral fracture and low bone quality in patients with rheumatoid arthritis-Results from TOMORROW study.

OBJECTIVES: Osteoporosis is one of the complications in patients with rheumatoid arthritis (RA). In this study, we researched the morbidity of existing vertebral fractures and the risk factors for vertebral fractures in patients with RA. METHODS: This study included 413 participants, 208 patients with RA, and 205 age- and sex-matched controls without RA. Clinical data, radiographic assessment of vertebral fracture from T4 to L4 in thoracic and lumber spine, bone mineral density (BMD), and bone metabolic markers (BMM) were analyzed. RESULTS: Vertebral fractures were observed more frequently, severe and multiple in patients with RA. In the logistic regression analysis, age (adjusted odds ratios (OR): 1.07, 95% confidence interval (CI): 1.04-1.09) and RA (adjusted OR: 1.72, 95% CI: 1.04-2.83) were risk factors for existing vertebral fracture. Moreover, two bone matrix-related markers, undercarboxylated osteocalcin (ucOC) (adjusted OR: 1.68, 95% CI: 1.02-2.78), and urinary pentocidine (adjusted OR: 2.51, 95% CI: 1.48-4.24) were associated with existing vertebral fracture. CONCLUSIONS: High frequent, multiple, and severe vertebral fractures were found in patients with RA compared to the controls. Low bone quality might be the cause of the frequent prevalence of vertebral fracture in patients with RA.

Delayed wound healing and postoperative surgical site infections in patients with rheumatoid arthritis treated with or without biological disease-modifying antirheumatic drugs.

Biological disease-modifying antirheumatic drugs (bDMARDs) have become more popular for treating rheumatoid arthritis (RA). Whether or not bDMARDs increase the postoperative risk of surgical site infection (SSI) has remained controversial. We aimed to clarify the effects of bDMARDs on the outcomes of elective orthopedic surgery. We used multivariate logistic regression analysis to analyze risk factors for SSI and delayed wound healing among 227 patients with RA (mean age, 65.0 years; disease duration, 16.9 years) after 332 elective orthopedic surgeries. We also attempted to evaluate the effects of individual medications on infection. Rates of bDMARD and conventional synthetic DMARD (csDMARD) administration were 30.4 and 91.0 %, respectively. Risk factors for SSI were advanced age (odds ratio [OR], 1.11; P = 0.045), prolonged surgery (OR, 1.02; P = 0.03), and preoperative white blood cell count >10,000/µL (OR, 3.66; P = 0.003). Those for delayed wound healing were advanced age (OR, 1.16; P = 0.001), prolonged surgery (OR, 1.02; P = 0.007), preoperative white blood cell count >10,000/µL (OR, 4.56; P = 0.02), and foot surgery (OR, 6.60; P = 0.001). Risk factors for SSI and medications did not significantly differ. No DMARDs were risk factors for any outcome examined. Biological DMARDs were not risk factors for postoperative SSI. Foot surgery was a risk factor for delayed wound healing.

Levels of interleukin-1 beta can predict response to tocilizumab therapy in rheumatoid arthritis: the PETITE (predictors of effectiveness of tocilizumab therapy) study.

Predicting the responses of patients with rheumatoid arthritis (RA) to tocilizumab is difficult, because inflammatory markers such as C-reactive protein rapidly normalize regardless of clinical efficacy. We aimed to identify factors that could predict response to tocilizumab. Sixty-five patients completed 52 weeks of tocilizumab therapy. Serum fibrinogen, D-dimer and interleukin (IL)-1ß levels were measured at baseline and after 4 weeks of therapy. Clinical responses to tocilizumab were assessed using disease activity score 28-erythrocyte sedimentation rate and the clinical disease activity index at baseline and after 52 weeks of therapy (UMIN Clinical Trials Registry No. UMIN000002246). Mean age was 60.5 years (range 22-85 years). Mean disease duration was 11.2 years (range 0-45 years). All patients had moderate-to-severe disease activity and were resistant to disease-modifying anti-rheumatic drugs and/or other biologics. Baseline IL-1ß levels were significantly lower in responders than in non-responders (p = 0.045), but multiple logistic regression analysis found no significant difference (adjusted odds ratio 2.74; 95 % confidence interval 0.84-8.95; p = 0.096). Low D-dimer and IL-1ß levels at 4 weeks predicted greater decrease in disease activity after 52 weeks of treatment (p = 0.005 and p < 0.001, respectively). Effects of tocilizumab at 52 weeks could be predicted from D-dimer and IL-1ß levels after 4 weeks of tocilizumab treatment. These markers might be more useful than current inflammatory markers for early-stage prediction of response to tocilizumab in RA.

Hyperleptinemia suppresses aggravation of arthritis of collagen-antibody-induced arthritis in mice.

BACKGROUND: Leptin is an adipocytokine produced by adipocytes and controlling body weight. It is unclear whether leptin works as a proinflammatory or an anti-inflammatory cytokine. We investigated the effects of hyperleptinemia on leptin transgenic (LepTg) mice in terms of cartilage destruction, bone destruction, joint synovitis, and serum cytokine levels by using a mouse model of collagen-antibody-induced arthritis (CAIA). METHODS: CAIA was induced for female age-matched 6- to 8-week-old C57BL/6 J control mice and LepTg mice. Mice were injected intraperitoneally with 5 mg of a combination of monoclonal antibody specific for type II collagen on day 0 and 12.5 mg of lipopolysaccharide (LPS) on day 3. Clinical evaluation of arthritis was monitored for 14 days, and hind paws were examined clinically and histologically. Serum cytokine levels of interleukin (IL)-1ß, IL-6, IL-10, and IL-17 and tumor necrosis factor alpha (TNF-α) were also analyzed on days 0 and 5. Moreover, THP-1 cells, which are human monocytic cell line derived from an acute monocytic leukemia patient, were cultured and differentiated into macrophages. The effects of leptin on messenger RNA (mRNA) expression of IL-6 were examined by real-time quantitative polymerase chain reaction (RT-PCR). RESULTS: Serum leptin concentrations were approximately ninefold higher in LepTg mice (62.0 ± 20.7 ng/ml) than in control mice (7.2 ± 0.5 ng/ml). Severity of clinical paw swelling, arthritis score, synovial hyperplasia, and cartilage damage were suppressed in LepTg mice with CAIA. Although serum cytokine levels of IL-1ß, IL-17, and IL-10 and TNF-α showed no significant changes in two mice, serum levels of IL-6 in LepTg mice were suppressed at day 5. Moreover, in vitro study showed that IL-6 elevation following LPS exposure in THP-1 cells was suppressed with high leptin concentrations. CONCLUSION: Our finding suggests that hyperleptinemia suppress IL-6 responses and progression of joint inflammation. Leptin may play an anti-inflammatory role under hyperleptinemia.