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Background Rheumatoid arthritis (RA) is known to cause secondary osteoporosis and fragility fractures. This study aimed to identify biomarkers predictive of bone mineral density (BMD) change at three anatomical sites in patients with RA. Methods We conducted a prospective longitudinal study in patients with RA. In 2012, we recruited 379 patients from an RA cohort, 329 of whom underwent evaluation of blood and urine biomarkers together with measurement of BMD in the lumbar spine, proximal femur, and distal forearm. The BMD in these three regions was reassessed in 2014. We performed multivariate linear regression analysis to identify those factors associated with BMD change. Results The averages of age, body mass index, and disease activity score in 28 joints (DAS28) at baseline were 63.2 (minimum to maximum, 32–85), 21.3 (12.3–30.0), and 3.2 (0.1–5.9), respectively. Univariate analysis showed that the annual BMD change was significantly associated with the use of steroid, bisphosphonate (BP) or vitamin D (VitD), and serum homocysteine in the lumber spine; DAS28, the use of BP or VitD, CRP, and anti-cyclic citrullinated peptide antibody (ACPA) in the proximal femur; and the dosage of MTX, the use of BP or VitD, and serum tartrate-resistant acid phosphatase 5b (TRACP-5b) in the distal forearm, respectively. Conclusions Predictive biomarkers for BMD change in RA patients differ at each anatomical site. Practitioners should treat each anatomical site with different markers and prescribe osteoporosis drugs to prevent fractures for RA patients.

We analysed the vascular morphology of the palm using a photoacoustic tomography (PAT) instrument with a hemispherical detector array. The three-dimensional (3D) morphology of blood vessels was determined noninvasively. Overall, 12 females and 11 males were recruited as healthy volunteers. Their ages were distributed almost evenly from 22 to 59 years. In all cases, many vascular networks were observed just beneath the skin and were determined to be veins anatomically. To analyse the major arteries, the layer containing the subcutaneous venous network was removed from the image. The analysis focused on the common and proper palmar digital arteries. We used the curvature of these arteries as a parameter to analyse their morphologies. There was no significant difference in the curvature between genders when comparing the subjects as a whole. The blood vessel curvature increased with age. Good agreement was found between the 3D numerical analysis results and the subjective evaluation of the two-dimensional (2D) projection image. The PAT system enabled visualization of the 3D features of blood vessels in the palm and noninvasive analysis of arterial tortuousness.

BackgroundOsteoporosis and its related fractures is one of the most dominant, troublesome complications in rheumatoid arthritis (RA). Newly-introduced drugs such as methotrexate and biological and targeted synthetic disease modifying anti-rheumatic drugs have decreased disease activity drastically, but the improvement of osteoporosis remains to be investigated.ObjectivesTo find useful factors for bone mineral density (BMD) management of RA patients under the current treatment.MethodsWe consecutively recruited 370 RA patients treated at Kyoto University Hospital in 2012. We prospectively collected the BMD values of the lumbar spine and the distal forearm measured by dual-energy X-ray absorptiometry (DXA), blood sampling test, urinalysis including bone metabolic biomarkers and clinical parameters of the RA patients in 2012 and 2014. Multivariate regression analysis was performed after adjustment by age, sex, body mass index (BMI), steroid use, anti-osteoporosis medication. We set the annualised BMD change as an outcome variable and allotted the other parameters as explanatory variables by a stepwise procedure.ResultsThe average values (minimum-maximum value) of age and BMI were 63.3 (32–85) years and 22.1 (12.3–30.0), respectively. Female patients and steroid users accounted for 91.1%, and 41.0%, respectively. Coincidentally, anti-osteoporosis drug-user also reached 41.0%. User of biological accounted for 30.8%. The averages of disease activity score (DAS) 28-erythrocyte sedimentation rate, Health Assessment Questionnaire was 2.6 (0.1–5.9) and 0.8 (0–2.9), respectively. The average of total Sharp score was 122.6 (0–443). Laboratory data showed serum tartrate-resistant acid phosphatase (TRACP)−5b, serum homocysteine, serum undercarboxylated osteocalcin, bone specific alkaline phosphatase, and urinary pentosidine were 320.0 (68–877) mU/dl, 9.7 (3.2–28) nmol/ml, 4.8 (0–23) ng/mL, 15.6 (5.8–43.6) µg/L, and 50.0 (11.5–561) pg/ml, respectively. Next, we describe by the result of multiple regression analysis. The levels of serum homocysteine (β=−0.19; 95%CI: 0.24 to 1.75; p=0.01) and anti-osteoporosis drug (β=−0.19; 95%CI; −0.26 to −0.04; p=0.009) were consistently significant predictive variables of annualised BMD change of the lumbar-spine. On the other hand, serum TRACP-5b (β=−0.28; 95%CI; −0.005 to −0.001; p=0.002) was significant predictive one for the distal forearm.ConclusionsAnti-osteoporosis medication may be particularly important for lumbar spine BMD for RA patients, regardless of steroid-use. Specific biomarkers would be useful such as homocysteine as lumbar spine BMD and TRACP-5b as the forearm BMD. These findings would be helpful for osteoporosis management in RA patients.Reference[1] Hippisley-Cox J, Coupland C. Derivation and validation of updated QFracture algorithm to predict risk of osteoporotic fracture in primary care in the United Kingdom: prospective open cohort study. BMJ2012;344:e3427AcknowledgementsK. Nishitani, K. Murata, M. Azukizawa, K. Murakami, S. Nakabo, T. NakajimaDisclosure of InterestNone declared

Summary The relationship between periarticular osteoporosis in the distal forearm and joint destruction or functional impairment in patients with rheumatoid arthritis (RA) is not sufficiently elucidated. From a single institutional cohort study, we found a strong correlation between periarticular forearm bone mineral density (BMD) and joint destruction or functional impairment. Introduction This study was conducted to investigate (1) the difference between various periarticular regions of interest (ROIs) of BMD of the forearm, (2) the correlation between periarticular forearm BMD and joint destruction and physical function, (3) the independent variables for predicting BMD of the forearm, and (4) the forearm BMD of different ROIs in the early stage of RA. Methods We conducted a cross-sectional study in an RA cohort. Measurements included BMD of the distal forearm, joint destruction of the hands assessed by modified total Sharp score (mTSS), functional impairment assessed by a health assessment questionnaire (HAQ), and other clinical data. Variables affecting the forearm BMD values were analyzed by correlation and stepwise regression analyses. Results Of the 405 patients enrolled in the present study, 370 (average age; 62.9 years) were identified as having definite RA with a complete set of data. BMD in the distal end of the forearm (BMDud) was significantly reduced compared with that in the distal third of the forearm (BMD1/3). In a stepwise regression analysis, the mTSS in BMD1/3 was an independent predicting variable, while age and partial HAQ scores associated with the upper extremity were common independent variables in BMDud and BMD1/3. BMDud was significantly less than BMD1/3, even in patients with a short duration of the disease. BMD1/3 was significantly less in non-remission group compared with that in remission group in patients with a short duration of the disease. Conclusion Periarticular BMD in the distal forearm is closely correlated with joint destruction and functional impairment in RA. Periarticular BMD in the distal forearm may be already reduced at the clinical manifestation of the disease.

BackgroundAcute phase biomarkers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are usually used for the evaluation of the disease activity of rheumatoid arthritis (RA). However, these biomarkers are sometimes not useful in evaluating the disease activity of RA patients in daily clinical practice, because they often become within normal range after the initiation of treatments. Thus, new biomarker which reflects the disease activity of RA under the treatment is required. Leucine-rich-α2-glycoprotein (LRG) is a newly identified biomarker that reflects inflammation and is correlated with the 28-joint Disease Activity Score even in patients treated with IL-6 receptor antagonist.ObjectivesTo assess whether serum LRG levels could be a biomarker to evaluate the disease activity of RA under treatments in daily clinical practice.MethodsSerum LRG levels were measured by enzyme-linked immunoabsorbant assay in 370 consecutive RA patients who were under treatments in our facility in 2012. Disease activity was evaluated by Clinical Disease Activity Index (CDAI) that does not include ESR or CRP as components. Radiological joint destruction was evaluated by modified Total Sharp Score (mTSS). Multivaiate analysis of covariance (MANOVA) was used to assess the association between CDAI and LRG, ESR, CRP levels and the association between mTSS and LRG, ESR, CRP, disease duration, and anti-CCP antibody level.ResultsAmong 370 patients, 71% were treated by methotrexate and 29% by biological DMARDs and average CDAI was 7.8±6.2 (low disease activity). After MANOVA analysis, LRG but not ESR or CRP showed the significant correlation with CDAI (LRG; effect size 0.034, p=0.0007, CRP; effect size 0.010, p=0.055, ESR; effect size 0.0053, p=0.18). LRG significantly correlated with the disease activities in RA patients, even when ESR or CRP levels were within normal range. In addition, LRG showed the significant correlation with mTSS as well as disease duration and anti-CCP antibody level (LRG; effect size 0.019, p=0.017, disease duration; effect size 0.769, p<0.001, and anti-CCP antibody; effect size 0.036, p=0.0011), while ESR and CRP did not (ESR; effect size 0.0038, p=0.28, CRP; effect size 0.00073, p=0.64).ConclusionsLRG is useful marker to evaluate the disease activity and to estimate the joint damage of RA patients under treatments in daily clinical practice independent of CRP and ESR levels.Disclosure of InterestNone declared

BackgroundMechanical stress would play an important role on inflammation of rheumatoid arthritis (RA). Some studies reported that the dominant hand joints were more affected than the non-dominant ones, but many of them led to the conclusion by evaluating only the right-handed subjects.1–3Therefore, it is still inconclusive whether right or dominant hand gets more damaged in RA.ObjectivesTo clarify the relationship of handedness with clinical and radiological joint involvement in RA.MethodsWe enrolled a total of 334 patients from the KURAMA (Kyoto University Rheumatoid Arthritis Management Alliance) cohort.4 Clinical and radiological joint involvement were compared between the right and left sides, using the tender joint count (TJC) and swollen joint count (SJC) of the 28 joints evaluated for the Disease Activity Score-28, and erosion and joint space narrowing (JSN) of X-rays scored by the modified Total Sharp Score (mTSS). The right-handed and the left-handed groups were separately evaluated.ResultsThe right-handed were 96% (n=322) and the left-handed were 4% (n=12). Clinical and radiological involvement of upper extremities tended to be worse in dominant hands than in non-dominant ones. (The mean of the score difference (the right-side score minus the left-side score); mTSS 2.33 (p=0.00030), erosion 1.67 (p=0.0081), JSN 0.66 (p=0.14), SJC 0.32 (p=0.00080) and TJC 0.26 (p=0.00010) in the right-handed. mTSS -2.25 (p=0.14), erosion -2.75 (p=0.23), JSN 0.5 (p=0.15), SJC -0.05 (p=0.95) and TJC -0.03 (p=0.72) in the left-handed). There was a statistical significance in the number of affected joints between the right and left upper extremities in the right-handed group. Although this tendency was also seen in the left-handed group, it was not statistically significant likely due to the smaller sample size.On the contrary, non-dominant foot showed more damage than dominant foot in the right-handed subjects (The mean of the score difference (the right-side score minus the left-side score); mTSS-1.11 (p=0.57), erosion -0.89 (p=0.37), JSN -0.22 (p=0.63)ConclusionsHandedness influences the laterality of clinical and radiological joint involvement in RA. Laterality of damage in foot may be different from that in hand. This might be because the right-handed usually pivot with the left foot.5ReferencesMody, G. M. et al. Handedness and deformities,radiographics changes, and function of the hand in rheumatoid arthritis. Ann Rheum Dis 1989;48, 104–107.Koh, H. J. et al. Radiographic structural damage is worse in the dominant than the non-dominant hand in individuals with early rheumatoid arthritis. PLoS One 2015;10:e0135409.Owsianik, D. J. W. et al. Radiological articular involvement in the dominant hand in rheumatoid arthritis. Ann Rheum Dis 1980, 39, 508–510.Terao, C. et al. Three groups in the 28 joints for rheumatoid arthritis synovitis–analysis using more than 17,000 assessments in the KURAMA database. PLoS One 2013;8:e59341.Hatta, T. et al. Lower-limb asymmetries in early and late middle age. Laterality 2005;10:267–77.Disclosure of InterestNone declared

BackgroundThe number of osteoarthritis (OA) patients is increasing year by year because of the aging society. Especially, knee OA is reported to reduce the health life expectancy. The majority of patients are at the early stage of knee OA and are adapted to conservative treatments such as exercise therapy. A lot of biomarkers for cartilage metabolism were previously reported. However, there are few reports that exercise therapy has an effect on the biomarkers related for cartilage metabolism.ObjectivesTo investigate the effect of an exercise therapy on cartilage metabolism using biomarkers.MethodsThirty-eight females (mean age: 59 years) participated in this study. All participants started a weekly exercise and continued it for twelve weeks. Before and after the exercise program, we measured their physical activities; Timed Up and Go test (TUG) and Three Minutes Walking test (3MW). Since the program started, we have collected serum and urine samples from the participants at the start of the program (0 week), at the end of it (12 weeks) and 12 weeks after it (24 weeks). For the collected samples, we measured the following two anabolic and one catabolic biomarkers; serum cartilage type II procollagen carboxy propeptide (sPIICP), serum cartilage oligomeric matrix protein (sCOMP), urine C-terminal telopeptide of collagen type II (uCTX-II). These biomarkers were measured with the enzyme-linked immunosorbent assay method.ResultsAfter the twelve weeks exercise program, both TUG and 3MW were significantly improved (P <0.01 each, respectively) (Fig. A, B). sCOMP concentrations at 12 weeks were relatively greater than those at 0 week. However, sCOMP concentrations at 24 weeks were significantly greater than those at 12 weeks (P <0.01) (Fig. C). In contrast, uCTX-II concentrations at 24 weeks were significantly less than those at 0 week (P <0.01) (Fig. D). There was no significant difference between pre- and post-excise sPIICP concentrations.ConclusionsThese results suggest that an exercise therapy will improve physical activities and that this therapy could influence both cartilage anabolic and catabolic biomarkers.Disclosure of InterestNone declared

BackgroundFunctional disability is one of most important factor which should be improved in treatment with rheumatoid arthritis (RA).ObjectivesThe aim of this study is to explain prognosis factors for functional disability in RA.MethodsWe chose the 301 of consecutive RA patients, with both 2012 and 2013 RA survey in our observational Japanese cohort, and assessed clinical variables including age, duration, stage, class, ACPA, RF, DAS28, ΔDAS28 (DAS282013 minus DAS282012), HAQ, ΔHAQ (HAQ2013 minus HAQ2012), modified Total Sharp score (mTSS), and DMARDs. We search prognosis factor for ΔHAQ by multivariate analyses.ResultsMean age was 62.1 years old. Mean disease duration was 14.5 years. MTX was used 71.1% of patients. Biologics was used 32.6% of patients. Mean follow-up time was 414.5 days. In linear regression analysis, predictors for increasing ΔHAQ were HAQ2012 (t=-2.90, p <0.01), no-usage of MTX (t=2.28, p=0.02), no-usage of biologics (t=2.08, p=0.03), and age (t=2.23, p=0.02)(Table1). In logistic regression analysis, prognosis factors for ΔHAQ >0 were no-usage of MTX (OR=1.98, p=0.02) and no-usage of biologics (OR=2.63, p<0.01)(Table2). There was no correlation between ΔHAQ and DAS282012. There was statistically correlation between ΔHAQ and ΔDAS28 (r=0.43, p<0.01).ConclusionsOur study demonstrated that prognosis factors for functional disability in RA were no-usage of both MTX and biologics.Disclosure of InterestM. Furu Grant/research support from: Astellas Pharma Inc., Pfizer Japan Inc., Employee of: Mitsubishi Tanabe Pharma Co., Bristol-Myers K.K., Chugai Pharmaceutical Co., Ltd., AbbVie GK., Eisai Co., Ltd., M. Hashimoto Grant/research support from: Astellas Pharma Inc., Pfizer Japan Inc., Employee of: Mitsubishi Tanabe Pharma Co., Bristol-Myers K.K., Chugai Pharmaceutical Co., Ltd., AbbVie GK., Eisai Co., Ltd., T. Fujii Grant/research support from: Takeda Pharmaceutical Co., Santen Pharmaceutical Co., Ltd.,Astellas Pharma Inc., Asahi Kasei Pharma Corporation, and Daiichi Sankyo Co., Ltd, Employee of: Mitsubishi Tanabe Pharma Co., Bristol-Myers K.K., Chugai Pharmaceutical Co., Ltd., AbbVie GK., Eisai Co., Ltd., H. Ito Grant/research support from: Takeda, Daiichi-Sankyo, Chugai, Tanabe-Mitsubishi, Bristol-Meyers, M. Ishikawa: None declared, C. Terao: None declared, N. Yamakawa: None declared, W. Yamamoto: None declared, H. Yoshitomi: None declared, S. Matsuda Grant/research support from: Zimmer,Biomet,Smith and Nephew,Kyocera, Consultant for: Biomet,Kyocera, Speakers bureau: Zimmer, T. Mimori Grant/research support from: Asahi Kasei Pharma Corporation, Astellas Pharma Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd., Speakers bureau: AbbVie GK., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd

BackgroundForefoot deformity is one of the most dominant deformities in patients with rheumatoid arthritis (RA). However, which deformity has the most clinical relevance on global functional impairment in the lower extremities remains to be investigated. We conducted a cross-sectional study on this subject using a comprehensive RA cohort (KURAMA cohort).ObjectivesTo investigate relationship among forefoot deformities and the influence of functional impairment in the lower extremities from a RA cohort.MethodsA cross-sectional clinical cohort survey was performed on 740 feet of 370 patients with RA in KURAMA cohort. The average age was 62.8 years old, and the female ratio was 87.6%. Radiographic measurements such as hallux valgus angle (HV angle), metatarsal deformities (M1M2 and M1M5 angles), Larsen grade of the metatarsophalangeal joints (MTP joints), and lateral angle and dislocation of MTP joints were obtained along with clinical data such as age, duration of the disease, seropositivity, disease activity and medication.ResultsHV, M1M2, M1M5 angles and lateral angle of MTP joint were significantly correlated each other (p<0.05). The numbers of dislocation of MTP joint were most significantly correlated with HV angle and lateral angle of MTP joint (ρ=0.839, 0.514, respectively), while much less with M1M2 and M1M5 angles (ρ=0.277, 0.135, respectively). On the other hand, HV angle and lateral angle of the MTP joint had significant correlation with duration of disease, Steinbrocker stage, DAS28-ESR, CRP, and HAQ, while M1M2 and M1M5 angles did only with duration of the disease. When functional impairment of the lower extremity (lower HAQ) was exclusively counted among the scores of HAQ, multivariate analyses showed the number of dislocation of MTP joint was a sole independent significant predictor for lower-HAQ.ConclusionsMTP joint dislocation has the most significant influence on functional impairment in the lower extremities among forefoot deformities in patients with RA. To avoid daily disability, MTP joints should be paid careful attention and be treated appropriately.Disclosure of InterestH. Ito Grant/research support from: Takeda, Mitsubishi Tanabe, Chugai, Pfizer, Astellas Pharma, Daiichi Sankyo, Y. Hamamoto: None declared, M. Furu Grant/research support from: Mitsubishi Tanabe, Chugai, Eisai, Bristol-Myers, M. Hashimoto Grant/research support from: Mitsubishi Tanabe, Chugai, Eisai, Bristol-Myers, Astellas Pharma, T. Fujii Grant/research support from: Mitsubishi Tanabe, Chugai, Eisai, Bristol-Myers, M. Ishikawa: None declared, M. Azukizawa: None declared, C. Terao: None declared, T. Mimori: None declared, S. Matsuda: None declared

BackgroundDisease Activity Score 28 (DAS28) is one of correlates of joint destruction in rheumatoid arthritis (RA) as well as genetic components, RA-related autoantibodies, and disease duration. Joint destruction is considered to reflect the cumulative history of the disease activities, but one-time DAS28 is used in many studies. Relationship among the correlates is still unclear, while we previously showed that HLA-DRB1*04:05 is associated with joint destruction independently of anti-citrullinated protein antibody (ACPA).ObjectivesWe hypothesized the superiority of time-averaged DAS28 to one-time DAS28 to fit the model to assess joint destruction. We also hypothesized that DRB1*04:05 might be associated with joint destruction independently of ACPA and DAS28.MethodsWe recruited RA patients in the KURAMA (n=204) and IORRA cohort (n=557) whose data of modified Sharp/van der Heijde score (SHS), consecutive DAS28, and other correlates of SHS were available. We calculated time-averaged DAS28 and modeled SHS using time-averaged DAS28 and the other covariates. We randomly picked up DAS28 in each patient and constructed 1000 sets of DAS28 to model SHS. We empirically evaluated fitting of the model using time-averaged DAS28 among the 1000 models using one-time DAS28. Next, we analyzed an association between DRB1*04:05 and SHS of ACPA (+) patients in KURAMA (n=100) and IORRA (n=472).ResultsIn conditioned for the autoantibodies and disease duration, the time-averaged DAS28 showed significant improvement of model fitting in comparison with one-time DAS28 (R2 in KURAMA: p=0.037, R2 in IORRA: p=0.001). Generalized linear regression model in ACPA (+) patients showed a significant association between DRB1*04:05 and SHS (overall p=0.0002) in conditioned for time-averaged DAS28 and the other covariates. We observed this significant association even in patients whose time-averaged DAS28 was in low disease activity or remission.ConclusionsTime-averaged DAS28 fits SHS better than one-time DAS28 and usage of time-averaged DAS28 as a covariate would increase the power of studies to identify novel correlates of SHS. DRB1*04:05 demonstrates an association with joint destruction which is independent of ACPA and even DAS28 by using time-averaged DAS28, suggesting necessity of strong treatment for RA patients carrying DRB1*04:05 even when they are in low disease activity or remission.ReferencesNavarro-Compán V, et al. Rheumatology. 2015 54(6):994–1007.Terao C, et al. Arthritis Rheumatol. 2015 67(7):1744–50.Disclosure of InterestNone declared