K. Mamoto

Relationships between serum 25-hydroxycalciferol, vitamin D intake and disease activity in patients with rheumatoid arthritis –TOMORROW study

Abstract Objectives. The effect of serum 25-hydroxycalciferol [25(OH)D] on rheumatoid arthritis (RA) activity remains controversial. This study was undertaken with an aim to clarify the relationship between serum 25(OH)D and RA activity, and to determine the effects of dietary vitamin D intake and age on serum 25(OH)D level. Methods. A total of 208 outpatients with RA were matched according to age and sex with 205 individuals without RA (controls) from the TOMORROW study (UMIN000003876). We excluded 27 patients with RA and 19 control subjects who had been prescribed vitamin D medication or were taking vitamin D supplements. Vitamin D intake was assessed in the remaining 181 patients and 186 controls using the brief-type dietary history questionnaire. Serum 25(OH)D levels were measured using a radioimmunoassay. Results. Serum 25(OH)D levels were significantly lower in patients with RA than in the controls (p < 0.001). There was a significant and positive correlation between age and 25(OH)D in the patients (r = 0.283, p < 0.001), as with vitamin D intake and 25(OH)D, even after adjusting for age (r = 0.313, p < 0.001). Disease activity and 25(OH)D did not significantly correlate. Conclusions. Patients with RA were observed to have serum 25(OH)D levels which correlated with vitamin D intake and age but not disease activity.

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

Abstract 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

Abstract 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.

Local co-application of zoledronate promotes long-term maintenance of newly formed bone induced by recombinant human bone morphogenetic protein 2

Bone Morphogenetic Proteins (BMPs) strongly induce the recruitment and differentiation of mesenchymal progenitor cells into mature osteoblasts, but also directly and indirectly stimulate differentiation of osteoclast progenitor cells and acceleration of mature osteoclasts function leading excessive bone resorption. Bisphosphonates, such as zoledronate (ZOL), inhibit osteoclasts function and osteoclasts mediated bone resorption. The short or middle term effect of BMPs and bisphosphonates on bone formation were previously reported, but there was no study that argue about the long term effect of bisphosphonates on BMP-induced bone anabolism. The present study demonstrated that the local administration of ZOL with recombinant human BMP-2 (rh-BMP-2) using beta tricalcium phosphate (β-TCP) as a carrier had superior efficacy not only to augment the BMP-induced new ectopic bone formation but to maintain the trabecular bone structure inside the new bone for long period. Histological analysis showed that rh-BMP-2/β-TCP composite induced trabecular bone resorption especially inside the new bone nodules over time, whereas no trabecular bone resorption was seen in rh-BMP-2/ZOL/β-TCP composite reducing the number of TRAP-positive cells. Thus, inhibition of bone resorption by bisphosphonate, such as ZOL, would be one of the advantageous ways to augment the new bone formation induced by rh-BMP-2, and moreover local co-application of ZOL using β-TCP as a carrier can be a useful material for long term suppression of osteoclastic resorption and thereby maintain the structure of new bone formation induced by rh-BMP-2.

AB0481 Abatacept Might not Alter Anti-Cyclic Citrullinated Peptide Levels in Established Rheumatoid Arthritis Patients -Airtight Study-

Background The percentage of anti-cyclic citrullinated peptide (CCP)-positive patients reported declines among early rheumatoid arthritis (RA) patients treated with abatacept (ABT). Objectives The AIRTIGHT study (UMIN:000005570) was conducted to assess the clinical and immunological impact of ABT on established RA patients. Methods The AIRTIGHT study included 32 patients (mean age, 60.7±13.6 years; mean duration of disease, 11.7±13.6 years; range, 0-35 years; MTX use, 81.9%; mean MTX dose, 6.1±4.6 mg/week) treated with ABT and 72 patients (mean age, 59.7±14.3 years; mean duration of disease, 9.5±10.9 years; range, 0-40 years; MTX use, 86.1%; mean MTX dose, 8.6±4.3 mg/week) treated with non-ABT biologics (adalimumab, n=20; etanercept, n=14; tocilizumab, n=19; infliximab, n=10; golimumab, n=9). Serum levels of anti-CCP, rheumatoid factor (RF), and autoantibody to galactose-deficient immunoglobulin (Ig)G (CA-RF) were measured at baseline and 48 weeks after treatment. Paired t-tests were used to compare changes in anti-CCP, RF, and CA-RF between each time point. Results Mean DAS28 score decreased from 4.5±1.3 to 3.5±1.3 after 48 weeks on ABT. Titers of anti-CCP were 143.4±176.0 U/ml at baseline and 151.1±176.1 after 48 weeks of treatment, values for RF were 150.4±233.7 IU/ml at baseline and 137.0±191.0 IU/ml after 48 weeks of treatment, and values of CA-RF were 163.0±301.4 AU/ml at baseline and 152.8±249.3 after 48 weeks of treatment on ABT. Titers of anti-CCP (p=0.64), RF (p=0.63) and CA-RF (p=0.57) were unchanged during ABT treatment. Seven patients who achieved improvement (good DAS28 response) on ABT also did not show the decraese of those titers. Titers of anti-CCP (p=0.47), RF (p=0.12) and CA-RF (p=0.12) did not correlate significantly with changes in DAS28. Mean DAS28 decreased from 4.5±1.3 to 2.8±1.1 at 48 weeks on non-ABT. Titers of anti-CCP were 147.1±145.9 U/ml at baseline and 109.7±138.8 IU/ml after 48 weeks of treatment, levels of RF were 145.5±201.3 IU/ml at baseline and 75.4±106.0 IU/ml after 48 weeks of treatment, and levels of CA-RF were 170.1±280.7 AU/ml at baseline and 95.3±130.1 AU/ml after 48 weeks of treatment with non-ABT. Titers of anti-CCP (p<0.001), RF (p<0.001) and CA-RF (p=0.002) were reduced significantly during non-ABT treatment. Conclusions These findings suggest that the titer of autoimmunity did not decrease during ABT treatment in established RA, regardless of disease activity. Although the titer of autoimmunity decreases during non-ABT treatment in established RA, percentage of MTX use might be involved (ABT: 71.9%, non-ABT: 86.1%; p=0.05). Disclosure of Interest None declared

FRI0137 Medication Interval of Adalimumab for Rheumatoid Arthritis Patients Might be Extended After the Achievement of Low Disease Activity -Kabuki Study-

Background Adalimumab (ADA) treatment in combination with methotrexate (MTX) is one of the established effective treatments for patients with rheumatoid arthritis (RA). However, the treatment with biologic disease-modifying anti-rheumatic drugs (bDMARDs) has unresolved risks such as infection or malignancy. Furthermore, the treatment with bDMARDs is accompanied with a financial burden. To extend the interval of ADA administration with maintaining efficacy might be useful option from the point of view of safety and economic aspect. Objectives The aim of this study was to investigate the possibility for extension of the interval of ADA administration after the achievement of low disease activity (LDA) in patients with RA. Methods This study was based on the KABUKI (keeping cartilaginous quality by adlimumab in patient with RA in Kansai area) study, an open-label, randomized trial. Sixty-eight patients who started ADA every other week treatment from July 2010 to October 2013 were included in this prospective randomized study. Patients archived LDA (DAS28-ESR3.2) at week 24 were randomly assigned to two groups receiving ADA 40mg every 2 or 4 weeks during next 24 weeks. Patients above LDA (DAS28-ESR >3.2) at week 24 were randomly assigned to groups receiving ADA 40mg plus increased dose of methotrexate (MTX) or switching ADA to other bDMARDs. Clinical, laboratory, ultrasonographic (US) and radiographic assessments were performed until week 48. Results Of 68 patients, 61 patients continued ADA 40 mg every other week until week 24. In these 61 patients, 29 patients achieved LDA at week 24. After week 24, the disease activity increased in only one patient of ADA 40 mg every 4 weeks group (n=13). However, others had kept LDA as well as patients receiving ADA 40 mg every other week. The increase of power Doppler signal in US assessment was not detected in patients with ADA 40 mg every 4 weeks. There was no difference in radiographic joint damage between ADA 40 mg every 4 and 2 weeks groups. Patients who could not achieve LDA at week 24 did not show siginificant difference in disease activity even after changing to different protocol with increasing MTX dosage or stwitching bDMARDs. Conclusions Treatment with ADA 40 mg every 4 weeks might be effective as well as ADA 40 mg every other week in patients with RA after the achievement of LDA at 24 weeks. The extension of the interval of ADA administration after the achievement of LDA in patients with RA may be a feasible treatment option. References Smolen JS, Emery P, Fleischmann R, van Vollenhoven RF, Pavelka K, Durez P, et al. Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial. Lancet. 2014;383(9914):321-32. Tanaka Y, Hirata S, Kubo S, Fukuyo S, Hanami K, Sawamukai N, et al. Discontinuation of adalimumab after achieving remission in patients with established rheumatoid arthritis: 1-year outcome of the HONOR study. Ann Rheum Dis. 2015;74(2):389-95. Disclosure of Interest T. Okano: None declared, K. Inui: None declared, M. Tada: None declared, Y. Sugioka: None declared, K. Mamoto: None declared, T. Koike Grant/research support from: Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Abbvie GK, Teijin Pharma Ltd., MSD K.K. and Ono Pharmaceutical Co., Ltd., H. Nakamura: None declared

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

Abstract 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.

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

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.

AB0430 Effects of Abatacept and TNF Inhibitors Compared with Ultrasonography in Patients with Rheumatoid Arthritis

Objectives The present study aimed to compare the effects of abatacept (ABT) and tumor necrosis factor inhibitors (TNFi) against rheumatoid arthritis (RA). Methods Patients with RA were treated with ABT (n=51) or TNFi (n=89; adalimumab, n=35; etanercept n=23; infliximab n=15; golimumab n=16). Twenty-six synovial sites comprising 22 joints (bilateral first to fifth metacarpophalangeal (dorsal recess), first interphalangeal and second to fifth proximal interphalangeal (dorsal recess) joints and dorsal radial, dorsal median and dorsal ulnar parts of the wrists) were assessed by musculoskeletal ultrasonography. Gray scale and power Doppler signals in these joints were semi-quantified using a scale from 0 to 3. We then compared disease activity, 28-CRP (DAS) scores and the sum of GSUS and PDUS scores between the two groups. Results The DAS score was significantly lower after two months of TNFi treatment compared with baseline, but did not significantly improve compared with baseline in the ABT group at two months. The DAS scores were lower for the TNFi than for the ABT group at six and eight months, but did not significantly differ at 12 months (Fig. 1). The sums of the GSUS and PDUS scores at 12 months were lower than those at baseline in both groups; however, these differences were not significant. Conclusions The clinical effect of ABT was slower than that of TNFi, but matched those of TNFi at 12 months. The effects of ABT and TNFi were similar according to ultrasound assessment. Disclosure of Interest K. Mamoto: None declared, T. Koike Grant/research support: Takeda Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical, Eisai, Abbott Japan, Teijin Pharma, Banyu Pharmaceutical and Ono Pharmaceutical, T. Okano: None declared, Y. Sugioka: None declared, M. Tada: None declared, K. Inui Grant/research support: Chugai Pharmaceutical Co., Ltd.,Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Abbvie GK, Eisai Co.,Ltd., MSD K.K. Speakers bureau: Bristol-Myers K.K., Takeda Pharmaceutical Corporation, Ltd., Chugai Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K.,Abbvie GK,Astellas Pharma Inc., H. Nakamura Grant/research support: Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Nippon Zoki Pharmaceutical Co., Ltd., Daiichi Sankyo Speakers bureau: Eisai Co.,Ltd., Daiichi Sankyo DOI 10.1136/annrheumdis-2014-eular.3222

AB0395 Restart for Sustaining Remission of Rheumatoid Arthritis in Use of Etanercept: Resume Study

Background Biological agents have recently proven to be an effective treatment for rheumatoid arthritis (RA). Biological agents are particularly recommended for patients with active RA who may incur further joint damage. However, in daily clinical practice, some patients with RA reject treatment with biological agents because of the high cost. To save costs for patients the use biological agents may be limited to only when disease activity is high. However, after biological agents have significantly reduced disease activity, and the biological agents are discontinued, potential flare-ups of disease activity are of concern. Objectives To examine if we could reduce the use of biologic agents, we tested the efficacy of restarting the same biologic agents in RA patients only when disease activity flared up. We conducted a prospective non-randomized non-blinded study using etanercept to control disease activity and prevent further joint destruction in patients with RA. Methods BIO-naive RA patients (N=31) with moderate to severe disease activity (DAS28≥3.2) were enrolled with written consent during 1 January 2011–31 December 2012. The average age was 60 years, and average disease duration was 5 years. Etanercept (50 mg/week) was administered each week until disease activity was measured as low (DAS28-ESR<3.2). Patients were then observed every 2 months. If disease activity recurred, the same dose of etanercept was re-administered weekly and patients were observed every 2 months. This strategy was maintained for 2 years. We aimed to control the disease activity below the low level (DAS28-ESR<3.2). If patients could not reach low disease activity after the administration of etanercept within 3 months, we used combined medicines with other synthetic disease-modifying antirheumatic drugs except glucocorticoid and tacrolimus. If low disease activity could not be achieved within 6 months, patients were withdrawn from the trial. Results Of the 31 patients enrolled in this study, 13 were withdrawn because of an inadequate response to etanercept, and 5 had no flare-up of disease activity after discontinuation of etanercept. In the remaining 13 cases (8 women) the strategy of re-administering etanercept when disease activity was above the low level was maintained. The mean dose of methotrexate was 10 mg/w, rheumatoid factor was positive in 11 patients, and the mean follow-up period was 20.5 months. All 13 cases of etanercept re-administration during a flare-up after discontinuation achieved low disease activity in 3.7 months on average. Cost saving calculations included 5 patients who maintained low disease activity without restarting etanercept, and were calculated as if etanercept treatment was continued. The actual saving was found to be approximately 35%. Conclusions All patients for whom etanercept was re-administered when a flare-up occurred after discontinuation of etanercept had achieved low DA at final follow up. Joint damage has yet to be evaluated. However, low DA was achieved at a low cost to the state. Disclosure of Interest K. Inui Grant/research support: Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Abbvie GK, Eisai Co.,Ltd., MSD K.K., Speakers bureau: Bristol-Myers K.K., Takeda Pharmaceutical Corporation, Ltd., Chugai Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Abbvie GK, Astellas Pharma Inc., T. Koike Grant/research support: Takeda Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical, Eisai, Abbott Japan, Teijin Pharma, Banyu Pharmaceutical and Ono Pharmaceutical, Speakers bureau: Takeda Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical, Eisai, Abbott Japan, Teijin Pharma, Banyu Pharmaceutical and Ono Pharmaceutical, M. Tada: None declared, Y. Sugioka: None declared, K. Mamoto: None declared, T. Okano: None declared, A. Sakawa: None declared, K. Fukushima: None declared, H. Nakamura Grant/research support: Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Nippon Zoki Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co.,Ltd., Takeda Pharmaceutical Co., Ltd., Hisamitsu Pharmaceutical Co.,Inc., Ono Pharmaceutical Co., Ltd., Osteopharma Inc., Teijin Pharma Ltd., Asahi Kasei Pharma Co., Speakers bureau: Eisai Co.,Ltd., Daiichi Sankyo Co., Ltd., Eisai Co.,Ltd., Ono Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Asahi Kasei Pharma Co., Teijin Pharma Ltd., Astellas Pharma Inc., Pfizer Japan Inc., Nippon Zoki Pharmaceutical Co., Ltd., Hisamitsu Pharmaceutical Co.,Inc., Janssen Pharmaceutical K.K. DOI 10.1136/annrheumdis-2014-eular.1098