Yoichi Toyoshima

High bone turnover elevates the risk of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis

Hypocalcemia is the most common major adverse event in patients with osteoporosis receiving the bone resorption inhibitor denosumab; however, limited information is available regarding risk factors of hypocalcemia. Therefore, this study aimed to identify the risk factors of hypocalcemia induced by denosumab treatment for osteoporosis. We retrospectively reviewed the records of patients who had received initial denosumab supplemented with activated vitamin D for osteoporosis. Serum levels of the following bone turnover markers (BTMs) were measured at baseline: bone-specific alkaline phosphatase (BAP), total N-terminal propeptide of type 1 procollagen (P1NP), tartrate-resistant acid phosphatase 5b (TRACP-5b), and urinary cross-linked N-telopeptide of type 1 collagen (NTX). Of the 85 denosumab-treated patients with osteoporosis studied, 22 (25.9%) developed hypocalcemia. Baseline serum total P1NP, TRACP-5b, and urinary NTX were significantly higher in patients with hypocalcemia than in those with normocalcemia following denosumab administration (all P<0.01). Multivariate logistic regression analysis revealed that patients with total P1NP >76.5 μg/L, TRACP-5b >474 mU/dL, or urinary NTX >49.5 nmol bone collagen equivalent/mmol creatinine had a higher risk of hypocalcemia (P<0.01). Our study suggests that denosumab may have a greater impact on serum calcium levels in patients with postmenopausal osteoporosis with higher baseline bone turnover than in patients with postmenopausal osteoporosis with normal baseline bone turnover, because maintenance of normal serum calcium in this subgroup is more dependent on bone resorption. Close monitoring of serum calcium levels is strongly recommended for denosumab-treated patients with high bone turnover, despite supplementation with activated vitamin D and oral calcium.

Teriparatide Administration Increases Periprosthetic Bone Mineral Density After Total Knee Arthroplasty: A Prospective Study

BACKGROUND Teriparatide is a currently available therapeutic agent for osteoporosis. Previous studies have reported that teriparatide affects periprosthetic bone mineral density (BMD) after total knee arthroplasty (TKA). However, little agreement has been reached concerning the treatment of periprosthetic BMD after TKA with teriparatide. Moreover, BMD in the femoral and tibial sides of the joints together has never been examined. We investigated the efficacy of teriparatide to inhibit BMD loss in the femoral and tibial side and considered complications such as migration and periprosthetic fractures after TKA. METHODS Twenty-two knees in 17 patients were included in this study, and a control group of patients who underwent TKA was identified according to their medical records. Dual-energy X-ray absorptiometry was performed for different locations (knee, hip, and lumbar spine), and regions of interest were measured to estimate BMD at initiation of the study as a baseline reference, followed by subsequent measurements at 6 and 12 months. RESULTS As a result of adjusting the difference between the BMDs of the 2 groups at initiation, there was a significant increase in R3 (posterior condyle) and R4 (lateral) at 6 months. Furthermore, there was a significant increase in R2 (anterior condyle), R3 (posterior condyle), and R6 (tibial diaphysis) at 12 months. The study group had a higher adjusted mean BMD in all regions than did the control group at 6 and 12 months. CONCLUSION Teriparatide may be a reasonable treatment option for osteoporotic patients to preserve or improve periprosthetic BMD after TKA.

A disintegrin and metalloproteinase (ADAM)-10 as a predictive factor for tocilizumab effectiveness in rheumatoid arthritis

Abstract Objectives: A disintegrin and metalloproteinase (ADAM)-10 is expressed in rheumatoid arthritis (RA). In this study, we focused on ADAM-10 as a predictive factor for the treatment with biologics in RA. Methods: The levels of ADAM-10 and fractalkine/CX3CL1 in RA and healthy controls serum were measured using enzyme-linked immunosorbent assays. Fifteen patients were treated with adalimumab (ADA), and 20 patients were treated with tocilizumab (TCZ). Results: ADAM-10 positively correlated with fractalkine/CX3CL1 in the sera of RA patients and was presented at a significantly higher level compared to that in normal serum (487 ± 80 pg/ml and 85 ± 33 pg/ml, respectively, p < 0.05). ADAM-10 highly correlates with fractalkine/CX3CL1 in the sera of RA patients. The level of ADAM-10 decreased after the treatment with TCZ but not with ADA. In addition, we found that the level of ADAM-10 in TCZ responders was significantly higher than that of the TCZ nonresponders at 24 weeks (619 ± 134 pg/ml and 109 ± 25 pg/ml, respectively). Multiple regression analysis showed that ADAM-10 was only identified as independent predictive variable for the improvement of DAS28 (ESR) at 24 weeks. Conclusions: ADAM-10 may be a predictor of the effectiveness of TCZ in treating RA.

Metacarpophalangeal Joint Arthroplasty Using Flexible Hinge Toe Implant with Grommets for Boutonnière Deformity of Rheumatoid Thumb

BACKGROUND MP joint arthroplasty is one of the treatment options for the rheumatoid thumb with boutonniere deformity. The use of flexible hinge toe implant for MP joint reconstruction was introduced; however, the outcome of flexible toe implantation for the reconstruction of the MP joint has not as yet been reported in detail. Therefore, in this study, we retrospectively investigated the clinical outcome and radiological findings. METHODS We assessed 56 Swanson implant arthroplasties that used flexible hinge toe implants with grommets to address boutonnière deformity of the thumb MP joint. The minimum follow-up period was 6 months. Pain, the range of motion, grip strength, pinch strength, General health Visual analogue scale and DASH (Disabilities of Hand, Shoulder and Hand) were assessed. RESULTS For most of the patients, the procedure provided painless motion and stability to the thumb. In the radiological assessments, the preoperative flexion angles at the MP joint were 45° improved to 17°. The origin of arc was shifted toward the extended position and the average arc of motion was 21°, with a flexion arc from 23° to 44°. The severity of boutonniere deformity was improved in most cases. The average grip strength changed from 110 to 121 mmHg and the average side pinch power changed from 1.5 to 2.2 kgf. General health VAS improved from 40 to 29 (p = 0.019), and the DAS28-CRP decreased from 3.3 to 2.4 (p < 0.001). Infection occurred in one case, and there were no implant fractures. CONCLUSIONS Swanson flexible hinge toe implant arthroplasty with grommets applied to the MP joint of the thumb was one of the recommended procedures for the reconstruction of boutonnière deformity of the thumb.

Therapeutic failure and eventual solution for skin necrosis and exposed tendon of the dorsum of the foot: A case report

For the treatment of skin necrosis with exposed tendons in rheumatoid arthritis (RA) foot, we should perform microvascular free flap surgery at an early stage without conservative treatment considering the increased risk of infection and the decreased physical activity.

Assessment of malalignment at the metacarpophalangeal joint of the rheumatoid hand using three-dimensional computed tomogram

Objective. For the assessment of rheumatoid hand, three-dimensional (3D) malalignment including flexed or rotational deformities and dislocation at the finger joint is one of the important findings. The objective of this study is to prove usefulness of 3D computed tomography (3DCT) for the accurate measurement of palmoulnar flexion deformity at the metacarpophalangeal (MP) joint of the rheumatoid hand. Methods. Swanson implant arthroplasty at the 2nd through the 5th MP joints was performed at 179 joints in 46 hands of 40 patients with rheumatoid arthritis. Pre-and postoperatively, evaluations included Larsen grade and ulnar flexion angle by an x-ray; and ulnar flexion angle, palmar flexion angle, and resected bone length by a 3DCT. Results. With progression of Larsen grade and the joint dislocation, ulnar flexion angle increased. Average ulnar flexion angle was 18.7 ± 16.0° (mean ± SD) in grade III, 38.4 ± 21.2° in grade IV, and 40.1 ± 21.1° in grade V, 29.6 ± 16.0°in “subluxation,” 24.8 ± 21.2° in “dislocation,” and 41.1 ± 22.2° in “severe dislocation.” There was no significant difference between grade of the MP joint dislocation and palmar flexion angle. With progression of the MP joint dislocation, resected bone length increased. Conclusion. A 3DCT gives accurate information about deformity of the rheumatoid hand. Also, an appropriate length of bone resection can be determined in the preoperative planning.

THU0476 Efficacy of Denosumab for The Treatment of Osteoporosis in Japanese Patients with Rheumatoid Arthritis

Background Recent studies have reported that RA patient with osteoporosis administered Denosumab (DMAB) was associated with significant increases of low bone mineral density (BMD) at lumbar spine and femoral neck. DMAB increases cortical bone more effective than any other drug for treatment of osteoporosis. Objectives Therefore, we investigated efficacy of DMAB in the patient with RA for 12 months at lumbar spine, femoral neck, and radius. Methods Sixty RA patients with osteoporosis were administered DMAB between April 2014 and October 2015, 45 patients were evaluated for 12 months in our institute. The following items were examined just before administered and at the time of 6 months and 12 months after administration: BMD of lumbar/femur/radius, Biomarker (total P1NP, TRACP-5b), radiograph of the hand. Also, comparisons were performed on the basis of efficacy of DMAB at the time of 12 months in radius between the patients with the poorly effected group (NR group), and the patients with the well-effected group (R group). Results After treatment of DMAB at 12 months, 5.2 percent increase of BMD at the lumbar spine was obtained, 4.2 percent increase at the femoral neck. However, there was not significant change at the distal third of the radius. Comparing the NR group to the R group, there was statistically significant difference in Larsen grade at the wrist. Conclusions DMAB significantly increases bone mineral density in the patient with RA. However, in the patient with severe joint destruction, DMAB could not increase BMD at the radius. Disclosure of Interest None declared

FRI0153 Relationship between Serum Oxytocin Levels and Disease Activity, Depressive State, ADL, and QOL in Patients with Rheumatoid Arthritis

Background Oxytocin, which is also called a happy hormone, has been reported to be related to various conditions including depressive state. However, the positioning of oxytocin in rheumatoid arthritis (RA) remains unclear. Objectives The objective of this study was to investigate the relationship between serum oxytocin levels and disease activity, depressive state, activity of daily life (ADL), and quality of life (QOL) in RA. Methods The study included 20 patients with RA who received treatment with a biological agent. We measured the following items before and at 6 months after the start of treatment. The baseline characteristics included the age, sex, prednisolone dose, methotrexate dose, duration of disease, anti-cyclic citrullinated peptide antibody (anti-CCP antibody), rheumatoid factor (RF), serum matrix metalloproteinase-3 (MMP-3), erythrocyte sedimentation rate, and C-reactive protein (CRP). The disease activity of rheumatoid arthritis was assessed using the Simplified Disease Activity Index (SDAI), depressive state using Hamilton Depression Rating Scale (HAM-D), ADL using the Health Assessment Questionnaire (HAQ), and QOL using the 36-Item Short Form Health Survey (SF-36). Serum oxytocin levels were determined by enzyme-linked immunosorbent assay (ELISA). The correlation between each item and the serum oxytocin levels were examined. Results The serum oxytocin levels before the start of treatment were correlated with RF (r=−0.529), HAQ (r=0.446), HAM-D (r=0.508), and among the 8 categories of the SF-36, physical function (r=−0.676), role function (physical) (r=−0.801), pain (r=−0.506), general health perception (r=−0.787), role function (emotional) (r=−0.844), and mental health (MH) (r=−0.516). On the other hand, the serum oxytocin levels did not correlate with the SDAI (r=−0.078). The serum oxytocin levels after the start of treatment were correlated with the age (r=−0.549), SDAI (r=−0.539), HAQ (r=0.813), HAM-D (r=0.584), and all of the SF-36 categories except for MH (r=0.038) (r>0.4). Other items did not correlate to the serum oxytocin levels. Conclusions The serum oxytocin levels before the start of treatment were correlated with depressive state, ADL, and QOL but not with disease activity. Those after the start of treatment were correlated with the SDAI, depressive state, ADL, and QOL. Disclosure of Interest Y. Miwa Grant/research support from: Tanabemitsubishi, Chugai, phizer, Ono, R. Takahashi: None declared, S. Isojima: None declared, M. Saito: None declared, Y. Miura: None declared, S. Ishii: None declared, Y. Ikari: None declared, T. Tokunaga: None declared, T. Kasama: None declared, Y. Toyoshima: None declared, K. Inagaki: None declared

Posterior Tibial Artery Perforator-Based Fascial Flap for Skin Necrosis and Exposed Extensor Tendon After Revision Total Ankle Replacement

CASE Delayed wound-healing of anterior ankle incisions can be problematic for patients who have undergone total ankle replacement. We describe the case of a patient in whom a posterior tibial artery perforator-based fascial flap was effectively used to cover skin necrosis and to repair the extensor retinaculum in a wound following revision total ankle replacement. CONCLUSION When a tendon is exposed in the ankle, a skin flap is generally required. The creation of a perforator-based fascial flap is a useful technique for covering a wound with an exposed tendon and is an alternative to a musculocutaneous flap.Case: Delayed wound-healing of anterior ankle incisions can be problematic for patients who have undergone total ankle replacement. We describe the case of a patient in whom a posterior tibial artery perforator-based fascial flap was effectively used to cover skin necrosis and to repair the extensor retinaculum in a wound following revision total ankle replacement. Conclusion: When a tendon is exposed in the ankle, a skin flap is generally required. The creation of a perforator-based fascial flap is a useful technique for covering a wound with an exposed tendon and is an alternative to a musculocutaneous flap.

AB0328 A Study on Characteristics of Rheumatoid Arthritis Patients Achieving Clinical Remission After 6 Months of Treatment with Biologic Agents

Background Biologic agents are highly effective for rheumatoid arthritis (RA); however, not all cases achieve clinical remission. It is difficult to predict the effectiveness before starting the treatment. Objectives To study predictive factors for clinical remission, which is one of the treatment goals in RA, after using biologic agents for 6 months. Methods The subjects were 333 RA patients treated with biologic agents. The following patients characteristics were investigated: age, gender, the type of biologic agents, the number of previous drugs, disease duration, baseline steroid dosage, MTX dosage, serum RF, MMP-3, ACPA, TNF-α, and IL-6. For evaluation we used SDAI for RA disease activity, HAQ for ADL, Short Form (SF)-36 for QOL, and Hamilton Depression Rating Scale (HAM-D) or Self-rating depression scale (SDS) for depression status, respectively. Clinical remission was defined by SDAI3.3 after 6 months of treatment. The subjects were divided into two groups: patients with SDAI3.3 and patients with SDAI >3.3 at 6 months, and a retrospective study was conducted. 101 patients were excluded from the study due to loss to 6-month follow-up, and a total of 232 patients were analyzed. Results Compared with a group of RA patients without clinical remission (n=167), a group of patients with clinical remission (n=65) had younger age (50.0±15.5 vs. 59.6±14.1, p<0.001), lower steroid dosage (1.9±2.4 mg/day vs. 4.3±3.8, p<0.001), lower serum MMP-3 (151±197 ng/ml vs. 239±244, p<0.05), lower serum TNF-α (28.4±57.7 pg/ml vs. 76.0±193.8, p=0.028), and lower serum IL-6 (12.5±22.8 pg/ml vs. 60.6±180.8, p=0.017) at baseline. In addition, those who achieved remission showed lower SDAI (17.9±11.7 vs. 28.0±13.7, p<0.001), lower HAQ (0.26±0.38 vs. 0.71±0.63, p<0.001), higher SF-36 (p<0.05 in all categories), lower SDS (38.0±9.5 vs. 42.5±9.7, p=0.0061), and lower HAM-D (4.7±3.6 vs. 6.4±5.2, p<0.05) at baseline. On the other hand, there was no significant difference on gender, the types of biologic agents, the order of drugs used in the treatment, MTX dosage, disease duration, serum RF, and ACPA. Conclusions It was suggested that RA patients with lower disease activity, lower dosage of steroid, younger age, higher ADL and QOL, lower depression scores, and lower serum TNF-α and IL-6 at baseline are more likely to achieve clinical remission with biologic treatment. Disclosure of Interest Y. Miwa Grant/research support from: Astellas Pharm Inc., Mitsubishi Tanabe Pharma Corporation, AbbVie CK, Pfizer Japan Inc., Chugai Pharmaceutical Co., Ltd., and Eizai Co., Ltd., R. Takahashi: None declared, S. Isojima: None declared, T. Isozaki: None declared, M. Saito: None declared, N. Oguro: None declared, S. Nishimi: None declared, T. Kasama: None declared, K. Oh: None declared, Y. Toyoshima: None declared, K. Inagaki: None declared