Language：English   Publishing type：Research paper (scientific journal)  

This report describes the case of an 85-year-old woman who was found to have seronegative rheumatoid arthritis during preoperative investigations for knee replacement surgery for osteoarthritis. Follow-up for knee osteoarthritis was continued for many years without any symptoms involving other joints. Before total knee arthroplasty for osteoarthritis, preoperative investigations revealed a highly inflammatory state. After differential diagnosis, seronegative rheumatoid arthritis was diagnosed. Even in preoperative investigations before total knee arthroplasty for very old patients with osteoarthritis, the possibility of rheumatoid arthritis developing should always be kept in mind.

DOI： 10.1093/mrcr/rxae076

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BACKGROUND: Generally, scarf osteotomy is recommended for moderate-severe hallux valgus (HV) deformity. Although severe HV deformity is defined to be more than 40 degree (°), this definition of angular setting includes broad range of HV angle (HVA). Actually, very severe HV deformity such as more than 60° of the HVA is often seen. At present, whether scarf osteotomy would truly contribute to maintaining the correction status against such very severe deformity is elusive. Then, in this study corrective effectiveness of modified scarf osteotomy including very severe deformity (HVA ≥ 60°) was evaluated. METHODS: A retrospective, observational study of 93 feet [mean follow-up: 56.0 months after the surgery] was performed. Hallux scores of the Japanese Society for Surgery of the Foot (JSSF), a self-administered foot evaluation questionnaire (SAFE-Q), and pre-postoperative radiographic parameters were evaluated. The patients were categorized into three groups [44 feet: (mildly severe) 40° ≤ HVA < 50°, 30 feet: (moderately severe) 50° ≤ HVA < 60°, 19 feet: (very severe) HVA ≥ 60°]. RESULTS: Both JSSF hallux and SAFE-Q score showed significant improvement in all groups, except social activity score in SAFE-Q, in very severe cases (P = 0.08). HVA also significantly improved in all groups without significant change of the HVA between post 1-month and final follow-up in each groups. No difference was seen among the three groups in complications after surgery and frequency of recurrence of HV deformity. CONCLUSION: Modified scarf osteotomy has sufficient potential to be indicated for very severe (HVA ≥ 60°) deformity, but it might be recommended before the HVA reaches > 60° from the perspective of clinical score improvement. LEVEL OF EVIDENCE: Level III.

DOI： 10.1186/s12891-024-08113-6

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Although distal tibial oblique osteotomy (DTOO) has usually been indicated for non-inflammatory diseases such as osteoarthritis, we encountered three patients with rheumatoid arthritis (RA) who underwent DTOO. We evaluated radiographic parameters and clinical scores, including self-reported scores for the foot and ankle (SAFE-Q) and the Japanese Society for Surgery of the Foot (JSSF) ankle/hindfoot scale. In all three cases, radiographic improvements were achieved along with improvements in SAFE-Q and JSSF scores after mid-term follow-up. Supramalleolar osteotomy including DTOO could be indicated even for inflammatory diseases such as RA, if erosive changes are not evident in the ankle joint.

DOI： 10.1093/mrcr/rxae068

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This report describes the arthroscopic treatment of septic arthritis of the ankle joint in two patients with inflammatory diseases, including rheumatoid arthritis (RA) and nail psoriasis. We treated both the ankle joints with antibiotic administration and urgent arthroscopic synovectomy and irrigation, although the procedure was performed several days (4 and 6 days) after the time at which the infection would have occurred. Fortunately, no recurrence has been seen for more than 18 and 20 months, respectively, after surgery, without antibiotic administration. Although septic arthritis of the ankle joint accounts for a small proportion of joint arthritis cases, diagnosis as early as possible is important. Our experience suggests that arthroscopic synovectomy and irrigation are effective for septic ankle arthritis even in chronic inflammatory disease cases.

DOI： 10.1093/mrcr/rxae041

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CASE: Three cases of inflammatory joint diseases (systemic lupus erythematosus and ongoing juvenile idiopathic arthritis) with painful flexible progressive collapsing foot deformity (PCFD) underwent flatfoot surgery. All cases maintained sufficient radiological correction and achieved good clinical condition at final follow-up. CONCLUSION: Although the prospect for recurrence of the deformity is not clear, even in inflammatory joint diseases, flat foot surgery such as flexor digitorum longs transfer, spring ligament reconstruction, and lateral column lengthening could have a possibility to be indicated against PCFD, as long as disease activity could be well suppressed by drug therapy, subsequently subtalar and talonavicular joints could be preserved.

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Introduction: Biomechanical stimulation is reportedly pivotal in meniscal regeneration, although its effect on mesenchymal stem cell (MSC) meniscal differentiation remains elusive. In this study, we investigated how cyclic compressive loading (CCL) could impact MSCs using three-dimensional cultures in atelocollagen-based meniscal substitute (ACMS).

Methods: We extracted MSCs from the meniscus, synovium, and articular cartilage, cultured them in three-dimensional cultures, and exposed them to CCL for 7 days. We then compared the transcriptomes of MSCs treated with and without CCL.

Results: Our RNA-seq analysis revealed that CCL induced significant transcriptome changes, significantly affecting chondrocyte-related genes, including SOX9, TGFB1, and PRG4 upregulation. CCL induced transcriptional differentiation of meniscus progenitors toward mature meniscal cells.

Conclusion: This study unveils the potential of mechanical stress in promoting MSC meniscal differentiation within ACMS. Our investigations provide new insights for mechanisms underlying meniscal regeneration with ACMS.

DOI： 10.3389/fbioe.2024.1394093

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BACKGROUND: In end-stage arthritis indicated for total ankle arthroplasty (TAA), full-thickness cartilage damage, subchondral bone defect/shaving, and fluttering of the talar dome occur, shortening the distance between the tibial and talar insertions of ligaments and leading to laxity of ligaments surrounding the ankle joint. Under such conditions, medial ligaments (including the deltoid ligament) would not be expected to function properly. To stabilize the ankle joint during the stance phase, medial ligament function under tension is important. This study therefore examined whether TAA contributes to lengthening of the medial tibio-talar joint as evaluated radiographically, as a preferable method for achieving tensile effects on medial ligaments. MATERIALS AND METHODS: Twenty-four feet with end-stage varus deformity of the ankle joint that underwent TAA were retrospectively investigated, excluding cases with any malleolar osteotomy or fracture. Distance between proximal and distal insertions of medial ligaments, lateralization of the talus, and talar tilt angle under valgus/varus stress condition were evaluated pre- and postoperatively. RESULTS: Distance between proximal and distal insertions of medial ligaments was significantly elongated after TAA. At the same time, the talus showed significant lateralization. Furthermore, talar tilt under valgus/varus stress conditions was also significantly reduced after TAA. CONCLUSION: TAA affects distal translation and lateralization of the talus in cases of varus ankle deformity. These effects might contribute to re-providing tensile force on lax medial ligaments, improving ligament function.

DOI： 10.1007/s12306-024-00820-6

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Of the three ankles after total ankle arthroplasty (TAA) with medial malleolar osteotomy for severe varus deformity (talar varus tilt >10°), two failed in varus migration of the tibial component. In these two cases, tibial osteotomy was performed with varus alignment of 5°and 2°, and with medially shifted placement of tibial component, while one ankle showed no migratoin of prostheses after 5 years, even with nonunion. In this case, tibial osteotomy was performed with a valgus alignment of 4°. Internal fixation after medial malleolar osteotomy should be done for severe varus cases. Medially shifted placement of tibial component should be avoided. Fortunately, the failure did not occur in a case of valgus of the distal tibia. Valgus tibial osteotomy might help to reduce the collision of the talus against the medial malleolus.

DOI： 10.1093/jscr/rjae358

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.7759/cureus.58197

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Disuse osteoporosis is a prevalent complication among patients afflicted with rheumatoid arthritis (RA). Although reports have shown that the antirheumatic drug iguratimod (IGU) ameliorates osteoporosis in RA patients, details regarding its effects on osteocytes remain unclear. The current study examined the effects of IGU on osteocytes using a mouse model of disuse-induced osteoporosis, the pathology of which crucially involves osteocytes. A reduction in distal femur bone mass was achieved after 3 weeks of hindlimb unloading in mice, which was subsequently reversed by intraperitoneal IGU treatment (30 mg/kg; five times per week). Histology revealed that hindlimb-unloaded (HLU) mice had significantly increased osteoclast number and sclerostin-positive osteocyte rates, which were suppressed by IGU treatment. Moreover, HLU mice exhibited a significant decrease in osteocalcin-positive cells, which was attenuated by IGU treatment. In vitro, IGU suppressed the gene expression of receptor activator of NF-κB ligand (RANKL) and sclerostin in MLO-Y4 and Saos-2 cells, which inhibited osteoclast differentiation of mouse bone marrow cells in cocultures. Although IGU did not affect the nuclear translocation or transcriptional activity of NF-κB, RNA sequencing revealed that IGU downregulated the expression of early growth response protein 1 (EGR1) in osteocytes. HLU mice showed significantly increased EGR1- and tumor necrosis factor alpha (TNFα)-positive osteocyte rates, which were decreased by IGU treatment. EGR1 overexpression enhanced the gene expression of TNFα, RANKL, and sclerostin in osteocytes, which was suppressed by IGU. Contrarily, small interfering RNA-mediated suppression of EGR1 downregulated RANKL and sclerostin gene expression. These findings indicate that IGU inhibits the expression of EGR1, which may downregulate TNFα and consequently RANKL and sclerostin in osteocytes. These mechanisms suggest that IGU could potentially be used as a treatment option for disuse osteoporosis by targeting osteocytes.

DOI： 10.1016/j.bone.2024.117026

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UNLABELLED: The impact of ROMO on the width of anabolic windows and the increase in BMD was reduced in the RA group compared to the non-RA group, and this reduction was associated with correlations to RA-related factors. PURPOSE: To investigate the effects of romosozumab (ROMO) in postmenopausal osteoporosis, with and without comorbid rheumatoid arthritis (RA). METHODS: In this retrospective, case-controlled, multicenter study, 171 postmenopausal patients who did not receive oral glucocorticoid, comprising 59 in the RA group and 121 in the non-RA group, received uninterrupted ROMO treatment for 12 months. Propensity score matching was employed to ensure comparability in clinical backgrounds, resulting in 41 patients in each group. Baseline characteristics were as follows: overall (mean age, 76.3 years; T-score of lumbar spine (LS), - 3.0; 45.1% were treatment-naive for osteoporosis); RA group (anti-cyclic citrullinated peptide antibody (ACPA) positivity, 80.5%; titer, 206.2 U/ml; clinical disease activity index (CDAI), 13.6; health assessment questionnaire disability index (HAQ-DI), 0.9). Bone mineral density (BMD) and serum bone turnover markers were monitored over a 12-month period. RESULTS: The rate of increase in the bone formation marker, PINP, and the rates of decrease in the bone resorption marker, TRACP-5b, exhibited a trend toward smaller changes in the RA group compared to the non-RA group, implying a smaller anabolic window. After 12 months, the RA group displayed lower BMD increases in the LS (9.1% vs. 12.6%; P = 0.013) and total hip (2.4% vs. 4.8%; P = 0.025) compared to the non-RA group. Multiple regression analysis in the all RA group (n = 59) for the association between RA-specific factors and 12-month BMD changes revealed negative correlations between ACPA titer and LS BMD and between HAQ-DI and femoral neck BMD. CONCLUSIONS: The efficacy of ROMO may be attenuated by RA-related factors.

DOI： 10.1007/s00198-024-07019-2

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BACKGROUND: According to the conventional postoperative procedure after total ankle arthroplasty (TAA) against end-stage osteoarthritis (OA) and rheumatoid arthritis (RA), mobilization and weight-bearing is currently started after completion of wound healing. Recently, early mobilization for dorsiflexion after TAA with modified antero-lateral approach was reported to be feasible and safe. To investigate the further possibility of expediting rehabilitation, this study evaluated the feasibility and safety of early full weight-bearing and gait exercise after cemented TAA utilizing a modified antero-lateral approach. MATERIALS AND METHODS: This retrospective, observational study investigated 23 consecutive ankles (OA: 14 ankles, RA: 9 ankles) that had received cemented TAA with a modified antero-lateral approach. These ankles were divided into three groups [1. conventional postoperative protocol: 8 ankles, 2. early dorsiflexion protocol: 7 ankles, 3. early dorsiflexion+full weight-bearing protocol: 8 ankles]. In group 3, after early dorsiflexion mobilization (day 3), full weight-bearing/gait exercise was started from 7 days after surgery (10 days after if malleolar osteotomy was added). Postoperative wound complications were observed and recorded. Number of days for hospitalization was also evaluated. Range of motion (ROM) of dorsiflexion/plantar flexion was measured. Patients also completed a self-administered foot evaluation questionnaire (SAFE-Q) and the scale of Japanese Society for Surgery of the Foot (JSSF) ankle/hindfoot score preoperatively and at final follow-up. RESULTS: No postoperative complications related to wound healing were observed even after early full weight-bearing and gait exercise. Days for hospitalization was significantly shortened in early full weight-bearing and gait exercise group (group 3) from 35-38 days to 24 days. ROM for both dorsiflexion and plantar flexion significantly increased in group 3, furthermore all indices of SAFE-Q score also showed stronger significant improvement in group 3. JSSF score improved significantly after TAA in all groups. CONCLUSION: Within this small number of cases, early full weight-bearing and gait exercise from 7 days after cemented TAA was feasible and safe with the modified antero-lateral approach. Combination of early dorsiflexion mobilization and weight-bearing/gait exercise contributed to shortening the hospitalization day, and improving ROM for both dorsiflexion and plantar flexion after surgery. Innovations in postoperative procedures for rehabilitation after TAA can be expected.

DOI： 10.1093/mr/roae005

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This study evaluated reverse V-shaped osteotomy for ankylosing rocker-bottom foot deformity in patients with rheumatoid arthritis. We experienced 3 feet: rheumatoid rocker-bottom deformities with painful and/or infectious bony prominence towards the bottom of the foot, treated with a reverse V-shaped osteotomy in the mid-hindfoot. In all three cases, significant correction was achieved with restoration of the medial longitudinal arch, and improvement in clinical scores was confirmed. Reverse V-shaped osteotomy has the potential to be a useful and definitive procedure for ankylosing rocker-bottom deformity in patients with rheumatoid arthritis.

DOI： 10.1093/mrcr/rxae005

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Language：Japanese   Publisher：日本リウマチの外科学会  

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NF-κB is a transcription factor that is activated with aging. It plays a key role in the development of osteoporosis by promoting osteoclast differentiation and inhibiting osteoblast differentiation. In this study, we developed a small anti-NF-κB peptide called 6A-8R from a nuclear acidic protein (also known as macromolecular translocation inhibitor II, Zn2+-binding protein, or parathymosin) that inhibits transcriptional activity of NF-κB without altering its nuclear translocation and binding to DNA. Intraperitoneal injection of 6A-8R attenuated ovariectomy-induced osteoporosis in mice by inhibiting osteoclast differentiation, promoting osteoblast differentiation, and inhibiting sclerostin production by osteocytes in vivo with no apparent side effects. Conversely, in vitro, 6A-8R inhibited osteoclast differentiation by inhibiting NF-κB transcriptional activity, promoted osteoblast differentiation by promoting Smad1 phosphorylation, and inhibited sclerostin expression in osteocytes by inhibiting myocyte enhancer factors 2C and 2D. These findings suggest that 6A-8R has the potential to be an antiosteoporotic therapeutic agent with uncoupling properties.

DOI： 10.1172/jci.insight.171962

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We present the case of a patient with rheumatoid arthritis who underwent talonavicular joint fusion using an autologous calcaneal bone graft. At the same time, the bony defect at the harvest site was supplemented with ReBOSSIS-J® [70% β-TCP and 30% poly(L-lactide-co-glycolide)](ORTHOREBIRTH Co. Ltd., Kanagawa, Japan), a synthetic bioresorbable bone void filler for the repair of bony defects with handling characteristics similar to a cotton ball. Material resorption and new bone formation had already started one week postoperatively. Transposition to host bone trabeculae was almost completed by 26 days postoperatively. Very rapid reactive graft resorption, repair with new bone formation, and subsequently, most of the transformation to host bone trabeculae were confirmed. ReBOSSIS-J® appears feasible to contribute to early heel weight-bearing exercise after foot or ankle surgery. In addition, preventing the fracture at the harvesting site of the calcaneal bone graft can also be expected.

DOI： 10.7759/cureus.45812

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OBJECTIVE: To investigate the efficacy of basic fibroblast growth factor (bFGF) in promoting meniscus regeneration by cultivating synovial mesenchymal stem cells (SMSCs) and to validate the underlying mechanisms. METHODS: Human SMSCs were collected from patients with osteoarthritis. Eight-week-old nude rats underwent hemi-meniscectomy, and SMSCs in pellet form, either with or without bFGF (1.0 × 106 cells per pellet), were implanted at the site of meniscus defects. Rats were divided into the control (no transplantation), FGF (-) (pellet without bFGF), and FGF (+) (pellet with bFGF) groups. Different examinations, including assessment of the regenerated meniscus area, histological scoring of the regenerated meniscus and cartilage, meniscus indentation test, and immunohistochemistry analysis, were performed at 4 and 8 weeks after surgery. RESULTS: Transplanted SMSCs adhered to the regenerative meniscus. Compared with the control group, the FGF (+) group had larger regenerated meniscus areas, superior histological scores of the meniscus and cartilage, and better meniscus mechanical properties. RNA sequencing of SMSCs revealed that the gene expression of chemokines that bind to CXCR2 was upregulated by bFGF. Furthermore, conditioned medium derived from SMSCs cultivated with bFGF exhibited enhanced cell migration, proliferation, and chondrogenic differentiation, which were specifically inhibited by CXCR2 or CXCL6 inhibitors. CONCLUSION: SMSCs cultured with bFGF promoted the expression of CXCL6. This mechanism may enhance cell migration, proliferation, and chondrogenic differentiation, thereby resulting in superior meniscus regeneration and cartilage preservation.

DOI： 10.1016/j.joca.2023.07.010

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We present a case of a patient who underwent a modified scarf osteotomy and tumor excision based on a preoperative diagnosis of hallux valgus deformity and accompanying bursitis. Subsequent histopathological examination revealed that the tumor was an angioleiomyoma. While tumors around the first metatarsophalangeal (MTP) joint are typically associated with gouty nodules, infections, or swollen bursa (bursitis) in patients with hallux valgus deformity, the occurrence of soft tissue tumors in this area is rare. Moreover, angioleiomyoma is an even rarer form of soft tissue tumor and is seldom suspected prior to resection. To our knowledge, there have been no reports of angioleiomyoma arising in the first MTP joint. However, it is important to consider the possibility of an atypical tumor in cases where soft tissue masses are present, even in patients with hallux valgus deformity, and to perform at least imaging tests such as ultrasound and magnetic resonance imaging (MRI) before surgery. This prospect should always be kept in mind.

DOI： 10.1093/mrcr/rxad047

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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OBJECTIVES: This multicentre retrospective study in Japan aimed to assess the retention of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors (JAKi), and to clarify the factors affecting their retention in a real-world cohort of patients with rheumatoid arthritis. METHODS: The study included 6666 treatment courses (bDMARD-naïve or JAKi-naïve cases, 55.4%; tumour necrosis factor inhibitors (TNFi) = 3577; anti-interleukin-6 receptor antibodies (aIL-6R) = 1497; cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig) = 1139; JAKi=453 cases). The reasons for discontinuation were divided into four categories (ineffectiveness, toxic adverse events, non-toxic reasons and remission); multivariate Cox proportional hazards modelling by potential confounders was used to analyse the HRs of treatment discontinuation. RESULTS: TNFi (HR=1.93, 95% CI: 1.69 to 2.19), CTLA4-Ig (HR=1.42, 95% CI: 1.20 to 1.67) and JAKi (HR=1.29, 95% CI: 1.03 to 1.63) showed a higher discontinuation rate due to ineffectiveness than aIL-6R. TNFi (HR=1.28, 95% CI: 1.05 to 1.56) and aIL-6R (HR=1.27, 95% CI: 1.03 to 1.57) showed a higher discontinuation rate due to toxic adverse events than CTLA4-Ig. Concomitant use of oral glucocorticoids (GCs) at baseline was associated with higher discontinuation rate due to ineffectiveness in TNFi (HR=1.24, 95% CI: 1.09 to 1.41), as well as toxic adverse events in JAKi (HR=2.30, 95% CI: 1.23 to 4.28) and TNFi (HR=1.29, 95%CI: 1.07 to 1.55). CONCLUSIONS: TNFi (HR=1.52, 95% CI: 1.37 to 1.68) and CTLA4-Ig (HR=1.14, 95% CI: 1.00 to 1.30) showed a higher overall drug discontinuation rate, excluding non-toxicity and remission, than aIL-6R.

DOI： 10.1136/rmdopen-2023-003160

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(一社)日本骨代謝学会  

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Language：Japanese   Publisher：(一社)日本関節病学会  

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Exposure of the tibialis anterior (TA) tendon with wound dehiscence after total ankle arthroplasty (TAA) with the anterior approach is a problematic complication, especially in rheumatoid arthritis (RA) patients. Once the TA tendon is exposed, the duration of wound healing is prolonged, and it could be a risk factor for deep infection. Thus, early resection of the TA tendon was evaluated for tendon exposure with wound dehiscence after TAA in RA patients. In this case report, three rheumatoid ankles that showed wound dehiscence with exposure of the TA tendon after TAA with the anterior approach are presented. Early resection of the TA tendon and debridement under local anesthesia were performed within two days after wound dehiscence. In all cases, wound healing was completed within two weeks after the treatment. Drop foot was not seen in any patients, and there was no difference between the pre and postoperative (1 year after TAA) range of dorsiflexion. Muscle strength for ankle dorsiflexion was also maintained. In conclusion, early resection of the TA tendon appears to be a useful option for undesirable tendon exposure with wound dehiscence to prevent deep infection and prolonged wound healing after total ankle arthroplasty in RA patients.

DOI： 10.7759/cureus.40441

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BACKGROUND: According to the conventional postoperative procedure after total ankle arthroplasty (TAA), mobilization is currently started after completion of wound healing. To investigate the possibility of expediting rehabilitation, this study evaluated the feasibility and safety of early mobilization of dorsiflexion after cemented TAA utilizing a modified antero-lateral approach. MATERIALS AND METHODS: This retrospective, observational study investigated 14 consecutive ankles that had received cemented TAA. Mobilization of dorsiflexion was started from 3 days after surgery. Postoperative wound complications including blister formation, eschar formation, wound dehiscence, peri-incisional decreased sensation were observed and recorded. Range of motion (ROM) of dorsiflexion/plantar flexion was measured. Patients also completed a self-administered foot evaluation questionnaire (SAFE-Q) and the scale of Japanese Society for Surgery of the Foot (JSSF) ankle/hindfoot score preoperatively and at final follow-up. RESULTS: No postoperative complications related to wound healing were observed. ROM for dorsiflexion, SAFE-Q score, and JSSF score improved significantly after TAA. CONCLUSION: Within this small number of cases, early mobilization of dorsiflexion from 3 days after cemented TAA was feasible and safe with the modified antero-lateral approach. Innovations in postoperative procedures for rehabilitation after TAA can be expected.

DOI： 10.1016/j.jos.2023.04.010

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DOI： 10.1016/j.jos.2023.02.023

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)中部日本整形外科災害外科学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(一社)中部日本整形外科災害外科学会  

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関節リウマチ(RA)患者では、外反母趾角(HVA)が60°、70°を超えるような超重度外反母趾変形がしばしばみられる。本研究では、RA患者の超重度外反母趾変形(HVA 60°以上)に対する中足骨水平骨切り術であるscarf変法の有効性について検討した。2016～2022年に当院でHVA 60°以上のRA患者に対してscarf変法にて外反母趾矯正手術を行った11人12足(全例女性、平均68.0歳)を対象とした。最終診察時、HVAは7.4°と有意な改善を認め、Hardy gradeも1～4までが術前0足であったものが術後10足に増加していた。JSSF score(母趾判定基準)およびSAFE-Q scoreに関しても、SAFE-Q scoreの社会生活機能と全体的健康感を除いて有意な改善を認めた。術中AKIN骨切り術を3足に施行し、術後内反母趾2足、外反母趾角の再発を2足認めたが、再手術を施行した症例はなかった。scarf変法は超重度外反母趾変形に対する術式として推奨できると考えられた。

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In clinical studies, the next-generation anti-tumor necrosis factor-alpha (TNF-α) single domain antibody ozoralizumab showed high clinical efficacy shortly after the subcutaneous injection. To elucidate the mechanism underlying the rapid onset of the effects of ozoralizumab, we compared the biodistribution kinetics of ozoralizumab and adalimumab after subcutaneous injection in an animal model of arthritis. Alexa Fluor 680-labeled ozoralizumab and adalimumab were administered by subcutaneous injection once (2 mg/kg) at five weeks after induction of collagen-induced arthritis (CIA) in an animal arthritis model. The time-course of changes in the fluorescence intensities of the two compounds in the paws and serum were evaluated. The paws of the CIA mice were harvested at four and eight hours after the injection for fluorescence microscopy. Biofluorescence imaging revealed better distribution of ozoralizumab to the joint tissues than of adalimumab, as early as at four hours after the injection. Fluorescence microscopy revealed a greater fluorescence intensity of ozoralizumab in the joint tissues than that of adalimumab at eight hours after the injection. Ozoralizumab showed a significantly higher absorption rate constant as compared with adalimumab. These results indicate that ozoralizumab enters the systemic circulation more rapidly and is distributed to the target tissues earlier and at higher levels than conventional IgG antibodies. Our investigation provides new insight into the mechanism underlying the rapid onset of the effects of ozoralizumab in clinical practice.

DOI： 10.1038/s41598-022-23152-6

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This study investigated modified scarf osteotomy as a salvage procedure after resection arthroplasty or silicone implant arthroplasty to preserve mobility of the 1st metatarsophalangeal (MTP) joint after hallux valgus surgery in patients with rheumatoid arthritis (RA). We investigated 3 feet with rheumatoid forefoot deformities that showed recurrence of forefoot deformity or breakage of the implant after resection or silicone implant arthroplasty in the 1st MTP joint. All feet were treated using modified scarf osteotomy with capsular interposition. All cases achieved obvious correction after modified scarf osteotomy despite resection of the 1st MTP joint, and consequently showed both radiographic and clinical improvements. Modified scarf osteotomy offers potential as a definitive salvage procedure after resection arthroplasty or silicone implant arthroplasty for forefoot deformity in patients with RA, because the procedure can realign the 1st MTP joint obviously with preservation of the ROM. Concomitant medial capsular interposition into the newly formed 1st MTP joint is also recommended where possible, to protect the edges of the proximal basal phalanx and distal 1st metatarsal, and also to smoothen the motion of newly formed 1st MTP joint.

DOI： 10.1093/mrcr/rxac079

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Language：Japanese   Publisher：(一社)日本足の外科学会  

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Language：Japanese   Publisher：(一社)日本足の外科学会  

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Language：Japanese   Publisher：(一社)日本足の外科学会  

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Language：Japanese   Publisher：(一社)日本足の外科学会  

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DOI： 10.1007/s00198-022-06545-1

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Language：Japanese   Publisher：(一社)日本関節病学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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OBJECTIVES: This multicenter, retrospective study evaluated the effectiveness of add-on methotrexate (MTX) or iguratimod (IGU) in patients with rheumatoid arthritis exhibiting an inadequate response to Janus kinase inhibitors (JAKi). METHODS: Forty-five patients were treated with new additional MTX (n = 22) or IGU (n = 23) and followed for 6 months. Patients' background: age, 59.2 years; Disease activity score of 28 joints with C-reactive protein (DAS28-CRP), 3.4; clinical disease activity index (CDAI), 15.7; biological disease-modifying antirheumatic drug (DMARD)-switched cases, 77.8%; first JAKi cases, 95.6%; JAKi treatment: tofacitinib (n = 25), baricitinib (n = 17), upadacitinib (n = 2), and peficitinib (n = 1) for 9.6 months. RESULTS: Thirty-five patients continued the combination therapy for 6 months without significant change of concomitant glucocorticoid or other conventional synthetic DMARDs. DAS28-CRP (MTX, 3.6 to 2.6, P < 0.05; IGU, 3.3 to 2.1, P < 0.001) and CDAI (MTX, 16.7 to 8.8, P < 0.05; IGU, 14.6 to 6.5, P < 0.01) improved significantly from baseline. Using the EULAR criteria, 45.4% (MTX) and 39.1% (IGU) achieved moderate or good response, and 40.9% (MTX) and 39.1% (IGU) achieved ACR20 criteria. CONCLUSIONS: Adding MTX or IGU to inadequate responders of JAKi can be considered as a complementary treatment.

DOI： 10.1093/mr/roac092

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Language：Japanese   Publisher：(一社)日本骨粗鬆症学会  

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Language：Japanese   Publisher：(一社)日本骨粗鬆症学会  

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Language：Japanese   Publisher：(一社)日本骨代謝学会  

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BACKGROUND: Patients who have noninflammatory arthritis of the feet may develop destructive changes on the first metatarsal head and painful dislocation of the metatarsophalangeal (MTP) joint of 1 or more lesser toes. This aim of this study was to compare feet with noninflammatory arthritis and those with rheumatoid arthritis (RA) with respect to the clinical and radiographic outcomes after treatment of these destructive deformities with a modified Scarf osteotomy with medial capsular interposition into the newly formed first MTP joint, combined with metatarsal shortening offset osteotomy. METHODS: A retrospective observational study of 93 feet (31 with noninflammatory arthritis and 62 with RA) was performed. Hallux and lesser-toe scores on the Japanese Society for Surgery of the Foot (JSSF) scoring system, a self-administered foot evaluation questionnaire (SAFE-Q), and preoperative and postoperative radiographic parameters were evaluated. RESULTS: There were significant improvements at the time of the final follow-up in the mean scores on the hallux and lesser-toe scales of the JSSF system and in the SAFE-Q score. The postoperative JSSF lesser-toes function score was better for the feet with noninflammatory arthritis feet than the feet with RA. There was no significant difference in the hallux valgus angle (HVA) between 1 month postoperatively and the final follow-up for both groups. Furthermore, the HVA showed a strong correlation between the 1-month and final follow-up values. CONCLUSIONS: The combination of the modified Scarf osteotomy with medial capsular interposition and shortening metatarsal offset osteotomy was useful and safe in feet with noninflammatory arthritis. The HVA at 1 month after surgery is useful to predict the HVA within 5 years after surgery. The postoperative clinical score for the lesser toes was better in the feet with noninflammatory arthritis. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

DOI： 10.2106/JBJS.21.01486

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BACKGROUND: Increasing of intermetatarsal angle between the first and second metatarsals (M1-M2A) has been reported as a risk factor for recurrence of hallux valgus (HV) deformity, on the other hand, increasing of intermetatarsal angle between the second and fifth metatarsals (M2-M5A) has been reported as a risk factor for resubluxation of the metatarsophalangeal (MTP) joint of the lesser toe after rheumatoid forefoot surgery. In this study, parameters related to increasing M2-M5A were investigated, as compared with M1-M2A and M1-M5A. METHODS: Radiographic parameters including M1-M2A, M1-M5A, and M2-M5A were retrospectively evaluated for 119 lower limbs from 68 patients with rheumatoid arthritis (RA). To clarify the clinical importance of these intermetatarsal angles, relationships with results from the timed up-and-go (TUG) test were also investigated. RESULTS: M1-M5A showed no correlation with mid-hind foot parameters, whereas M1-M2A and M2-M5A correlated with valgus/varus parameters. An increased M1-M2A was associated with lateral shift of the loading axis in the tibial plafond, whereas an increased M2-M5A was associated with medial shift, but M1-M5A showed no associations. M2-M5A/M1-M2A was significantly lower (1.7) in the normal TUG group than in the delayed TUG group (2.8) (p=0.045). CONCLUSIONS: Different patterns of spread are seen for the forefoot. One has a predominantly increased M1-M2A with lateral shift of the loading point in the tibial plafond, whereas the other has a predominantly increased M2-M5A with medial shift of the loading point in the tibial plafond. M2-M5A also should be calculated, and M2-M5A/M1-M2A might be meaningful in understanding physical mobility in RA patients.

DOI： 10.7759/cureus.24831

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In patients with postmenopausal osteoporosis, prior osteoporosis treatment affected the bone mineral density increase of following treatment with 12 months of romosozumab, although it did not affect that of following treatment with 12 months of denosumab after romosozumab. PURPOSE: To investigate the effects of prior osteoporosis treatment on the response to treatment with romosozumab (ROMO) followed by denosumab (DMAb) in patients with postmenopausal osteoporosis. METHODS: In this prospective, observational, multicenter study, treatment-naïve patients (Naïve; n = 55) or patients previously treated with bisphosphonates (BP; n = 37), DMAb (DMAb; n = 45) or teriparatide (TPTD; n = 17) (mean age, 74.6 years; T-scores of the lumbar spine [LS] - 3.2 and total hip [TH] - 2.6) were switched to ROMO for 12 months, followed by DMAb for 12 months. Bone mineral density (BMD) and serum bone turnover markers were evaluated for 24 months. RESULTS: A BMD increase was observed at 12 and 24 months in the following patients: Naïve (18.2% and 22.0%), BP (10.2% and 12.1%), DMAb (6.6% and 9.7%), and TPTD (10.8% and 15.0%) (P < 0.001 between the groups at both 12 and 24 months) in LS and Naïve (5.5% and 8.3%), BP (2.9% and 4.1%), DMAb (0.6% and 2.2%), and TPTD (4.3% and 5.4%) (P < 0.01 between the groups at 12 months and P < 0.001 at 24 months) in TH, respectively. The BMD increase in LS from 12 to 24 months was negatively associated with the levels of bone resorption marker at 24 months. Incidences of major fragility fractures for the respective groups were as follows: Naïve (5.5%), BP (16.2%), DMAb (11.1%), and TPTD (5.9%). CONCLUSIONS: Previous treatment affected the BMD increase of following treatment with ROMO, although it did not affect that of following treatment with DMAb after ROMO.

DOI： 10.1007/s00198-022-06386-y

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CASE: Marked varus or valgus hindfoot deformities in 3 patients with ankle osteoarthritis or rheumatoid arthritis were treated by corrective surgery using total ankle arthroplasty or distal tibia oblique osteotomy. All cases achieved not only sufficient correction and satisfactory clinical/radiographic hindfoot improvement but also improvements in both knee alignment and function. CONCLUSION: Corrective surgery for hindfoot deformity can potentially change or improve ipsilateral knee alignment and function, representing an unexpected benefit of hindfoot realignment.

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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Language：Japanese   Publisher：(一社)日本移植学会  

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CASE: Ankylosing midfoot inversion deformities in 3 patients with rheumatoid arthritis (RA) treated by midfoot derotational osteotomy to remove the pain due to excessive loading of the fifth metatarsal base and to obtain the plantigrade position are presented. All cases achieved sufficient correction and good clinical and radiographic improvement. CONCLUSION: Midfoot derotational osteotomy seems useful and has the possibility to be a definitive surgical procedure for ankylosing inversion deformity in patients with RA. Osteotomy should be performed from both medial and lateral sides, and careful retraction of soft tissues should always be kept in mind.

DOI： 10.2106/JBJS.CC.21.00613

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This multi-center, retrospective study aimed to clarify the factors affecting drug retention of the Janus kinase inhibitors (JAKi) including baricitinib (BAR) and tofacitinib (TOF) in patients with RA. Patients were as follows; females, 80.6%; age, 60.5 years; DAS28-ESR, 4.3; treated with either BAR (n = 166) or TOF (n = 185); bDMARDs- or JAKi-switched cases (76.6%). The reasons for drug discontinuation were classified into four major categories. The drug retention was evaluated at 24 months using the Kaplan-Meier method and multivariate Cox proportional hazards modelling adjusted by confounders. Discontinuation rates for the corresponding reasons were as follows; ineffectiveness (22.3%), toxic adverse events (13.3%), non-toxic reasons (7.2%) and remission (0.0%). Prior history of anti-interleukin-6 receptor antibody (aIL-6R) ineffectiveness significantly increased the risk of treatment discontinuation due to ineffectiveness (p = 0.020). Aging (≥ 75 years) (p = 0.028), usage of PSL ≥ 5 mg/day (p = 0.017) and female sex (p = 0.041) significantly increased the risk of treatment discontinuation due to toxic adverse events. Factors not associated with treatment discontinuation were: number of prior bDMARDs or JAKi, concomitant MTX usage, difference of JAKi, and prior use of TNF inhibitor, CTLA4-Ig or other JAKi.

DOI： 10.1038/s41598-021-04075-0

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Language：Japanese   Publisher：日本リウマチの外科学会  

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Language：Japanese   Publisher：日本リウマチの外科学会  

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Language：Japanese   Publisher：日本リウマチの外科学会  

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Language：Japanese   Publisher：(一社)日本関節病学会  

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Language：Japanese   Publisher：(一社)日本関節病学会  

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Language：Japanese   Publisher：(一社)日本関節病学会  

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Language：Japanese   Publisher：(一社)日本関節病学会  

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With the progress of medical treatment for rheumatoid arthritis (RA), several joint-preserving forefoot surgical procedures have been established and performed. In this situation, we have been choosing the combined surgery: modified scarf osteotomy for the great toe and metatarsal shortening offset osteotomy for the lesser toes in RA cases. A retrospective observational study of 53 RA patients (mean follow-up period: 4.6 years) who underwent the surgery was completed. RA foot ankle scores were assessed, using the Japanese Society for Surgery of the Foot (JSSF) standard rating system, and a self-administered foot evaluation questionnaire (SAFE-Q) was also checked to evaluate clinical outcomes. For radiological evaluations, deformity parameters were measured using radiographs of the feet with weight-bearing. JSSF hallux and lesser toes scores and the SAFE-Q score showed significant improvement in all indices. HVA, M1-M2A, M1-M5A, M2-M5A, and sesamoid position were significantly improved after surgery. At the final follow-up, the hallux valgus deformity had recurred in 4 feet (7.5%), and hallux varus deformity had developed in 8 feet (15.1%). No case of recurrent hallux valgus deformity required revision surgery. Recurrence of dorsal dislocation/subluxation of the lesser toe MTP joint was seen in 6 feet (11.3%) after surgery. A combination of modified scarf osteotomy for the great toe and modified metatarsal shortening offset osteotomy for the lesser toes is one of the novel surgical procedures for rheumatoid forefoot deformity. Preoperative disease activity of RA negatively affected the clinical score of the hallux. The spread of M2-M5A was a risk factor for resubluxation of the lesser toe MTP joint.

DOI： 10.3390/ijerph181910473

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Language：Japanese   Publisher：(一社)日本足の外科学会  

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jos.2021.08.018

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Language：Japanese   Publisher：(一社)日本足の外科学会  

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Foot/ankle problems remain important issues in rheumatoid arthritis (RA) patients. Although forefoot deformity generally takes a major place in surgical treatment, concomitant mid-hindfoot deformity is also commonly seen. In this situation, it can be easy to overlook that mid-hindfoot deformity can also induce or exacerbate clinical problems behind the forefoot events. Thus, the relationship between mid-hindfoot deformity/destruction and physical activity/ADL was investigated. Radiographic findings of 101 lower limbs (59 patients) were retrospectively evaluated. Alignment parameters in the lower extremity and joint destruction grade (Larsen grade) were measured. The timed-up-and-go (TUG) test, modified health assessment questionnaire (mHAQ), pain, self-reported scores for the foot and ankle (SAFE-Q), and RA disease activity were investigated to assess clinical status. The relationships among these parameters were evaluated. Subtalar joint destruction was correlated with TUG time (r = 0.329), mHAQ score (r = 0.338), and SAFE-Q: social functioning (r = 0.332). TUG time was correlated with the HKA (r = -0.527), talo-1st metatarsal angle (r = 0.64), calcaneal pitch angle (r = -0.433), M1-M5A (r = -0.345), and M2-M5A (r = -0.475). On multivariable linear regression analysis, TUG time had a relatively strong correlation with the talo-1st metatarsal angle (β = 0.452), and was negatively correlated with calcaneal pitch angle (β = -0.326). Ankle joint destruction was also correlated with TUG time (β = 0.214). Development of structural problems or conditions in mid-hindfoot, especially flatfoot deformity, were related with decreased physical activity in RA patients. Wearing an insole (arch support) as a preventative measure and short foot exercise should be considered from the early phase of deformity/destruction in the mid-hindfoot in the management of RA.

DOI： 10.3390/ijerph181910037

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Language：Japanese   Publisher：(一社)日本骨粗鬆症学会  

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Language：Japanese   Publisher：(一社)日本骨粗鬆症学会  

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s10067-021-05609-7

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Other Link： https://link.springer.com/article/10.1007/s10067-021-05609-7/fulltext.html

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OBJECTIVES: To investigate the effects of prior treatment and determine the predictors of a 12-month treatment response of romosozumab (ROMO) in 148 patients with postmenopausal osteoporosis. METHODS: In this prospective, observational, and multicenter study, treatment naïve patients (Naïve; n = 50) or patients previously treated with bisphosphonates (BP; n = 37) or denosumab (DMAb; n = 45) or teriparatide (TPTD; n = 16) (mean age, 75.0 years; T-scores of the lumbar spine [LS] -3.2 and total hip [TH] -2.6) were switched to ROMO due to insufficient effects of prior treatment. Bone mineral density (BMD) and serum bone turnover markers were evaluated for 12 months. RESULTS: At 12 months, changes in LS BMD were Naïve (18.2%), BP (10.2%), DMAb (6.4%), and TPTD (11.2%) (P < 0.001 between groups) and changes in TH BMD were Naïve (5.6%), BP (3.3%), DMAb (0.6%), and TPTD (4.4%) (P < 0.01 between groups), respectively. In all groups, the LS BMD significantly increased from baseline at 6 and 12 months, although only the DMAb group failed to obtain a significant increase in TH BMD during 12-month treatment. Mean values of N-terminal type I procollagen propeptide (PINP; μg/L) from baseline → 1 month → 12 months were Naïve (67.9 → 134.1 → 51.0), BP (32. 2 → 81.7 → 40.9), DMAb (30.4 → 56.2 → 75.3), and TPTD (97.4 → 105.1 → 37.1), and those of isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b; mU/dL) were Naïve (500.4 → 283.8 → 267.1), BP (273.4 → 203.1 → 242.0), DMAb (220.3 → 246.1 → 304.8), and TPTD (446.6 → 305.1 → 235.7), respectively. Multiple regression analysis revealed that the significant predictors of BMD change at 12 months were difference of prior treatment (r = -2.8, P < 0.001) and value of PINP at 1 month (r = 0.04, P < 0.01) for LS, and difference of prior treatment (r = -1.3, P < 0.05) and percentage change of TRACP-5b at 1 month (r = -0.06, P < 0.05) for TH. CONCLUSIONS: The early effects of ROMO on LS and TH BMD increase at 12 months were significantly affected by the difference of prior treatment and are predicted by the early change in bone turnover markers.

DOI： 10.1016/j.jbspin.2021.105219

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Level V.

DOI： 10.1177/24730114211013342

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00774-021-01206-5

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Other Link： http://link.springer.com/article/10.1007/s00774-021-01206-5/fulltext.html

Language：Japanese   Publisher：日本リウマチの外科学会  

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Language：Japanese   Publisher：日本リウマチの外科学会  

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Language：Japanese   Publisher：日本リウマチの外科学会  

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Language：Japanese   Publisher：日本リウマチの外科学会  

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Language：Japanese   Publisher：日本リウマチの外科学会  

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Language：Japanese   Publisher：日本リウマチの外科学会  

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Language：Japanese   Publisher：日本リウマチの外科学会  

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Synovial mesenchymal stem cell (SMSC) is the promising cell source of cartilage regeneration but has several issues to overcome such as limited cell proliferation and heterogeneity of cartilage regeneration ability. Previous reports demonstrated that basic fibroblast growth factor (bFGF) can promote proliferation and cartilage differentiation potential of MSCs in vitro, although no reports show its beneficial effect in vivo. The purpose of this study is to investigate the promoting effect of bFGF on cartilage regeneration using human SMSC in vivo. SMSCs were cultured with or without bFGF in a growth medium, and 2 × 105 cells were aggregated to form a synovial pellet. Synovial pellets were implanted into osteochondral defects induced in the femoral trochlea of severe combined immunodeficient mice, and histological evaluation was performed after eight weeks. The presence of implanted SMSCs was confirmed by the observation of human vimentin immunostaining-positive cells. Interestingly, broad lacunae structures and cartilage substrate stained by Safranin-O were observed only in the bFGF (+) group. The bFGF (+) group had significantly higher O'Driscoll scores in the cartilage repair than the bFGF (-) group. The addition of bFGF to SMSC growth culture may be a useful treatment option to promote cartilage regeneration in vivo.

DOI： 10.3390/ijms22010300

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We report 2 cases of ipsilateral ankle and knee osteoarthritis (OA), with the chief complaint being chronic ankle and knee pain. In the first patient, the ankle pain was more severe than the knee pain, whereas the second patient had more severe pain in the knee than in the ankle. In both cases, varus malalignment of the knee and varus tilt of the ankle joint were detected on standing radiographs. The severity of OA was found to be grade 4 in the knee, according to the Kellgren-Lawrence grading system, and stage IIIa in the ankle, according to the modified Takakura ankle OA classification system. Navigation-assisted total knee arthroplasty was performed in both cases, leading to a decreased degree of varus malalignment in the knee and ankle, as well as a significantly improved patient-based outcome in both joints. Correction of malalignment of the ankle by total knee arthroplasty relieved the severe pain and restored optimal function in the ankle without surgical intervention.

DOI： 10.1016/j.artd.2020.09.005

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© 2020 Elsevier Inc. Objective: The purpose of this study was to examine the effect of single or combination therapy of teriparatide (TPTD) and a monoclonal antibody against the murine receptor activator of nuclear factor κB ligand (anti-RANKL Ab) on cancellous and cortical bone regeneration in a mouse model of glucocorticoid-induced osteoporosis (GIOP). Methods: C57BL/6 J mice (24 weeks of age) were divided into five groups: (1) the SHAM group: sham operation + saline; (2) the prednisolone (PSL) group: PSL + saline; (3) the TPTD group: PSL + TPTD; (4) the Ab group: PSL + anti-RANKL Ab; and (5) the COMB group: PSL + TPTD + anti-RANKL Ab (n = 8 per group). With the exception of the SHAM group, 7.5 mg of PSL was inserted subcutaneously into mice, to generate a mouse model of GIOP. Four weeks after insertion, bone defects with a diameter of 0.9 mm were created to assess bone regeneration on both femoral metaphysis (cancellous bone) and diaphysis (cortical bone). After surgery, therapeutic intervention was continued for 4 weeks. Saline (200 μl) or TPTD (40 μg/kg) was injected subcutaneously five times per week, whereas the anti-RANKL Ab (5 mg/kg) was injected subcutaneously once on the day after surgery. Subsequently, the following analyses were performed: microstructural assessment of bone regeneration and bone mineral density (BMD) measurement via micro-computed tomography, and histological, histomorphometrical, and biomechanical analyses with nanoindentation. Results: The COMB group showed the highest lumbar spine BMD increase (vs. the PSL, TPTD, and Ab groups). The volume of regenerated cancellous bone at the bone defect site was higher in the COMB group compared with the PSL, TPTD, and Ab group. The volume of the regenerated cortical bone was significantly higher in the COMB group compared with the PSL group, and its hardness was significantly higher in the COMB group compared with the PSL and TPTD groups. Conclusion: In a mouse model of glucocorticoid-induced osteoporosis, the combination therapy of TPTD plus the anti-RANKL Ab increased bone mineral density in the lumbar spine and regenerated cancellous bone volume compared with single administration of each agent, and also increased regenerated cortical bone strength compared with single administration of TPTD.

DOI： 10.1016/j.bone.2020.115525

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Language：Japanese   Publisher：(株)全日本病院出版会  

関節リウマチ(RA)による足部の変形は罹病早期よりみられるが、RA診療の中で足部の診察はおろそかになりがちであり、変形が進行してから治療介入される患者が多い。足は荷重関節であるため、足部の変形に伴い全身のアライメントのアンバランスを招く一因となる。そのため罹病早期の変形が少ない時期から治療介入することが望まれる。薬物治療の進歩とともにRA外科手術の全体数は近年減少傾向にある一方で、足部機能の重要度が認知されてきていることからRA足部の手術は増加傾向にある。またRA患者にも人生100年時代が実現可能のものとなってきていることから、再発防止や機能改善の観点から術後のリハビリテーションも重要となる。RA足部に対する治療は今なお進歩しているが、これまでに当院を含めた大阪大学整形外科RAグループでは様々な治療法を報告し確立してきた。(著者抄録)

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PURPOSE: To investigate the effects of prior treatment and the predictors of early treatment response to romosozumab (ROMO) in patients with postmenopausal osteoporosis. METHODS: In this prospective, observational, multicenter study, 130 treatment-naïve patients (Naïve; n = 37) or patients previously treated with bisphosphonates (BP; n = 33), denosumab (DMAb; n = 45), or teriparatide (TPTD; n = 15) (age, 75.0 years; T-scores of the lumbar spine [LS] -3.2 and femoral neck [FN] -2.9) were switched to ROMO based on their physician's decision. Bone mineral density (BMD) and serum bone turnover markers were evaluated for six months. RESULTS: At six months, LS BMD changes were 13.6%, 7.5%, 3.6%, and 8.7% (P < 0.001 between groups) and FN BMD changes were 4.2%, 0.4%, 1.6%, and 1.5% (P = 0.16 between groups) for Naïve, BP, DMAb, and TPTD groups, respectively. Changes in N-terminal type I procollagen propeptide (PINP; μg/L) levels from baseline→one month were 72.7→139.0, 33.5→85.4, 30.4→54.3, and 98.4→107.4, and those of isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b) (mU/dL) were 474.7→270.2, 277.3→203.7, 220.3→242.0, and 454.1→313.0 for Naïve, BP, DMAb, and TPTD groups, respectively. Multivariate regression analysis revealed that significant predictors of LS BMD change at six months were prior treatment difference (r = -3.1, P = 0.0027) and TRACP-5b percentage change (r = -2.8, P = 0.0071) and PINP value at one month (r = 3.2, P = 0.0021). CONCLUSION: Early effects of ROMO on the increase in LS BMD are significantly affected by the difference of prior treatment and are predicted by the early change in bone turnover markers. Mini Abstract Early effects of ROMO on the increase in LS BMD at six months is significantly affected by the difference of prior treatment and also predicted by the early change of bone turnover markers in patients with postmenopausal osteoporosis.

DOI： 10.1016/j.bone.2020.115574

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：日本リウマチの外科学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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OBJECTIVE: The purpose of this study was to examine the effect of single or combination therapy of teriparatide (TPTD) and a monoclonal antibody against the murine receptor activator of nuclear factor κB ligand (anti-RANKL Ab) on cancellous and cortical bone regeneration in a mouse model of glucocorticoid-induced osteoporosis (GIOP). METHODS: C57BL/6 J mice (24 weeks of age) were divided into five groups: (1) the SHAM group: sham operation + saline; (2) the prednisolone (PSL) group: PSL + saline; (3) the TPTD group: PSL + TPTD; (4) the Ab group: PSL + anti-RANKL Ab; and (5) the COMB group: PSL + TPTD + anti-RANKL Ab (n = 8 per group). With the exception of the SHAM group, 7.5 mg of PSL was inserted subcutaneously into mice, to generate a mouse model of GIOP. Four weeks after insertion, bone defects with a diameter of 0.9 mm were created to assess bone regeneration on both femoral metaphysis (cancellous bone) and diaphysis (cortical bone). After surgery, therapeutic intervention was continued for 4 weeks. Saline (200 μl) or TPTD (40 μg/kg) was injected subcutaneously five times per week, whereas the anti-RANKL Ab (5 mg/kg) was injected subcutaneously once on the day after surgery. Subsequently, the following analyses were performed: microstructural assessment of bone regeneration and bone mineral density (BMD) measurement via micro-computed tomography, and histological, histomorphometrical, and biomechanical analyses with nanoindentation. RESULTS: The COMB group showed the highest lumbar spine BMD increase (vs. the PSL, TPTD, and Ab groups). The volume of regenerated cancellous bone at the bone defect site was higher in the COMB group compared with the PSL, TPTD, and Ab group. The volume of the regenerated cortical bone was significantly higher in the COMB group compared with the PSL group, and its hardness was significantly higher in the COMB group compared with the PSL and TPTD groups. CONCLUSION: In a mouse model of glucocorticoid-induced osteoporosis, the combination therapy of TPTD plus the anti-RANKL Ab increased bone mineral density in the lumbar spine and regenerated cancellous bone volume compared with single administration of each agent, and also increased regenerated cortical bone strength compared with single administration of TPTD.

DOI： 10.1016/j.bone.2020.115525

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BACKGROUND: This multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of 7 biological disease-modifying antirheumatic drugs (bDMARDs) and tofacitinib (TOF), one of the janus kinase inhibitors, in bDMARDs-naïve and bDMARDs-switched patients with rheumatoid arthritis (RA). METHODS: This study assessed 3897 patients and 4415 treatment courses with bDMARDs and TOF from 2001 to 2019 (2737 bDMARDs-naïve courses and 1678 bDMARDs-switched courses [59.5% of switched courses were their second agent], female 82.3%, baseline age 57.4 years, disease duration 8.5 years; rheumatoid factor positivity 78.4%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate 4.3; concomitant prednisolone [PSL] dose 6.1 mg/day [usage 42.4%], and methotrexate [MTX] dose 8.5 mg/week [usage 60.9%]). Treatment courses included abatacept (ABT; n = 663), adalimumab (ADA; n = 536), certolizumab pegol (CZP; n = 226), etanercept (ETN; n = 856), golimumab (GLM; n = 458), infliximab (IFX; n = 724), tocilizumab (TCZ; n = 851), and TOF (n = 101/only bDMARDs-switched cases). Drug discontinuation reasons (categorized into lack of effectiveness, toxic adverse events, non-toxic reasons, or remission) and rates were estimated at 36 months using Gray's test and statistically evaluated after adjusted by potential clinical confounders (age, sex, disease duration, concomitant PSL and MTX usage, starting date, and number of switched bDMARDs) using the Fine-Gray model. RESULTS: Cumulative incidence of drug discontinuation for each reason was as follows: lack of effectiveness in the bDMARDs-naïve group (from 13.7% [ABT] to 26.9% [CZP]; P < 0.001 between agents) and the bDMARDs-switched group (from 18.9% [TCZ] to 46.1% [CZP]; P < 0.001 between agents); toxic adverse events in the bDMARDs-naïve group (from 4.6% [ABT] to 11.2% [ETN]; P < 0.001 between agents) and the bDMARDs-switched group (from 5.0% [ETN] to 15.7% [TOF]; P = 0.004 between agents); and remission in the bDMARDs-naïve group (from 2.9% [ETN] to 10.0% [IFX]; P < 0.001 between agents) and the bDMARDs-switched group (from 1.1% [CZP] to 3.3% [GLM]; P = 0.9 between agents). CONCLUSIONS: Remarkable differences were observed in drug retention of 7 bDMARDs and TOF between bDMARDs-naïve and bDMARDs-switched cases.

DOI： 10.1186/s13075-020-02232-w

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OBJECTIVES: To clarify the effects of follow-on therapy after denosumab (DMAb) discontinuation. METHODS: In this retrospective, multicenter study, postmenopausal patients with osteoporosis who were previously treated by oral bisphosphonates (BP) (n = 26) or teriparatide (TPTD) (n = 27) were switched to DMAb (administered 2.6 times), and then discontinued. Patients (73.1 years, T-scores of the lumbar spine [LS] -2.7 and femoral neck [FN] -2.2) were switched to either (1) raloxifene (RAL) (n = 13) or BP [(2) weekly or monthly BP (wmBP) (n = 29) or (3) zoledronate (ZOL) (n = 11)], based on each physician's decision (mean interval after final DMAb administration was 7.2 months). Bone mineral density (BMD) at final DMAb administration were set as baseline. RESULTS: Changes in LS BMD at 1.5 years after final DMAb administration were -2.7% in the RAL, 0.7% in the wmBP, and 1.9% in the ZOL (P = 0.31 between groups), and in FN BMD were -3.8%, -0.8%, and 1.8%, respectively (P = 0.02 between the RAL and ZOL; P = 0.048 between the RAL and BP). Clinical vertebral fracture incidence during 1.5 years after final DMAb administration was 23.1% in the RAL, 3.4% in the wmBP, and 0.0% in the ZOL (P = 0.048 between the RAL and ZOL; P = 0.015 between the RAL and BP). No significant differences were observed in these parameters between the wmBP and ZOL. CONCLUSIONS: These results may contribute to the selection of adequate follow-on therapy after DMAb discontinuation, although further investigations are required.

DOI： 10.1080/14397595.2020.1769895

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Language：Japanese   Publisher：(一社)日本手外科学会  

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OBJECTIVES: The aim of this multicenter, retrospective study was to clarify the retention of secondary biological disease-modifying antirheumatic drugs (bDMARDs) or Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis (RA) who were primarily treated by tocilizumab (TCZ) or abatacept (ABT) as first bDMARDs. METHOD: Patients who were treated by either TCZ (n = 145) or ABT (n = 76) and then switched to either tumor necrosis factor inhibitors (TNFi), TCZ, ABT, or JAKi (including only cases switched from TCZ) from 2001 to 2019 (female 81.0%, age 59.5 years, disease duration 8.8 years; rheumatoid factor positivity 75.4%; Disease Activity Score in 28 joints using C-reactive protein 3.7; concomitant prednisolone (PSL) dose 6.0 mg/day (51.8%) and methotrexate (MTX) dose 8.0 mg/week (56.1%); 81.9% discontinued first bDMARDs due to lack of effectiveness) were included. Drug retention and discontinuation reasons were estimated at 24 months using the Kaplan-Meier method and adjusted for potential confounders by Cox proportional hazards modeling. RESULTS: Drug retentions for each of the reasons for discontinuation were as follows: lack of effectiveness in TCZ-switched group (TNFi (59.5%), ABT (82.2%), and JAKi (84.3%); TNFi vs. ABT; P = 0.009) and ABT-switched group (TNFi (79.6%) and TCZ (92.6%); P = 0.053). Overall retention excluding non-toxic reasons and remission for discontinuation were TNFi (49.9%), ABT (72.7%), and JAKi (72.6%) (TNFi vs. ABT; P = 0.017) in the TCZ-switched group and TNFi (69.6%) and TCZ (72.4%) (P = 0.44) in the ABT-switched group. CONCLUSIONS: Switching to ABT in TCZ-treated patients led to higher retention as compared with TNFi. Switching to TCZ in ABT-treated patients tended to lead to higher retention due to effectiveness, although total retention was similar as compared with TNFi.Key Point• This is the first retrospective, multi-center study aimed to clarify the retention rates of secondary bDMARDs or JAKi in patients with RA who were primarily being treated by TCZ or ABT as the first bDMARDs.

DOI： 10.1007/s10067-020-05015-5

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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BACKGROUND: When soft tissue balance is not acceptable at total ankle arthroplasty (TAA) for rheumatoid varus deformity, medial malleolar osteotomy has been performed. At the same time, the shape of the ankle joint changes after soft tissue balancing with such an osteotomy, however there is few information for the radiographic findings after the osteotomy. Thus, radiographic changes in the coronal view of such cases were investigated. METHODS: JSSF-RA foot and ankle scale and SAFE-Q scores were determined along with pre/postoperative radiographic parameters of the ankle joint in 70 ankles (65 patients) with rheumatoid arthritis followed for a mean of 7.9 years (range, 2-16 years) after TAA. Seven ankles were excluded because those underwent lateral or lateral/medial malleolar osteotomy. Twenty-seven ankles underwent medial malleolar osteotomy, and compared with 36 ankles without osteotomy. RESULTS: All ankles achieved bone union after medial malleolar osteotomy, and the tibial medial malleolus (TMM) angle was significantly decreased [30.3°-19.1°] following significant valgus correction [TC angle: -2.7° to 0.5°]. The gap due to medial soft tissue tightness was significantly improved by medial malleolar osteotomy [4.95° to 0.7°]. Lateral malleolar fractures sometimes occurred (19%: 5/27 ankles) at valgus correction, but they healed completely without any internal fixation. CONCLUSION: Medial malleolar osteotomy was useful in rheumatoid varus ankle for not only controlling the soft tissue balance, but also providing a stabilized shape of the ankle joint. Lateral malleolar fractures were caused by valgus correction following medial malleolar osteotomy in some cases, but all fractures were completely healed without any internal fixation.

DOI： 10.1016/j.jos.2020.01.005

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Background: Osteoporotic fragility fractures frequently occur at the distal part of the radius. This suggests that initial osteoporosis evaluation at this site may inform screening and treatment to prevent additional fractures. The purpose of this study was to investigate the utility of distal forearm dual x-ray absorptiometry (DXA) as a screening tool to assess the risk of fragility fractures at the distal part of the radius. Methods: This retrospective, case-control study included postmenopausal women who had sustained a distal radial fracture (fracture group, n = 110) and postmenopausal women with no history of fracture (control group, n = 95). DXA measurements at the spine, hip, and distal part of the forearm (ultra-distal, mid-distal, and one-third distal sections) were compared between the groups on the basis of bone mineral density (BMD), T-score, and the proportion of patients with a T-score of £–2.5 standard deviations (SD). We also investigated the regional differences on the basis of T-score among the skeletal sites. Furthermore, the reliability of distal forearm DXA measurements was validated by assessing the statistical correlation (r) with volumetric BMD by computed tomography (CT). Results: Compared with the control group, the fracture group showed significantly lower BMD and T-scores and higher proportions of patients with a T-score of £–2.5 SD at the ultra-distal, mid-distal, and one-third distal forearm; however, the spine and hip measurements did not differ significantly between the 2 groups. With respect to regional differences, in the fracture group, T-scores were significantly lower and the proportions of patients with a T-score of £–2.5 SD were significantly higher for the 3 distal forearm sites compared with the spine and hip. DXA measurements at all 3 of the distal forearm regions exhibited high correlation with volumetric BMD by CT (r = 0.83 to 0.92). Conclusions: Some postmenopausal women were found to exhibit bone loss preferentially at the distal part of the radius, which may render them vulnerable to fragility fractures. Forearm DXA for the assessment of local bone loss may demonstrate benefit in screening for those at risk for distal radial fractures and facilitate the early identification of patients who require intervention for osteoporosis. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

DOI： 10.2106/JBJS.OA.19.00036

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Osteoclasts have a unique bone-destroying capacity, playing key roles in steady-state bone remodeling and arthritic bone erosion. Whether the osteoclasts in these different tissue settings arise from the same precursor states of monocytoid cells is presently unknown. Here, we show that osteoclasts in pannus originate exclusively from circulating bone marrow-derived cells and not from locally resident macrophages. We identify murine CX(3)CR1(hi)Ly6C(int)F4/80(+)I-A(+)/I-E+ macrophages (termed here arthritis-associated osteoclastogenic macrophages (AtoMs)) as the osteoclast precursor-containing population in the inflamed synovium, comprising a subset distinct from conventional osteoclast precursors in homeostatic bone remodeling. Tamoxifen-inducible Foxml deletion suppressed the capacity of AtoMs to differentiate into osteoclasts in vitro and in vivo. Furthermore, synovial samples from human patients with rheumatoid arthritis contained CX(3)CR1(+)HLA-DR(hi)D11c(+)CD80(-)CD86(+) cells that corresponded to mouse AtoMs, and human osteoclastogenesis was inhibited by the FoxM1 inhibitor thiostrepton, constituting a potential target for rheumatoid arthritis treatment.

DOI： 10.1038/s41590-019-0526-7

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Language：Japanese   Publisher：(一社)日本関節病学会  

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Language：Japanese   Publisher：日本リウマチの外科学会  

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Language：Japanese   Publisher：(一社)日本足の外科学会  

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Objectives: To evaluate the effectiveness of add-on iguratimod (IGU) in patients with rheumatoid arthritis (RA) who showed an inadequate response to tocilizumab (TCZ), especially patients who were intolerant of an effective dose of methotrexate (MTX). Methods: Thirty-one patients with RA (22 women, age 62.4 years, disease duration 13.8 years, prior TCZ duration 35.7 months, 25 intravenous [8 mg/kg/4 weeks] and 6 subcutaneous [162 mg/2 weeks] TCZ treatments, concomitant MTX 8.5 mg/week [35.5%], and prednisolone (PSL) 4.3 mg/day [25.8%]) who showed an inadequate response to TCZ (disease activity score assessing 28 joints with C-reactive protein [DAS28-CRP] 2.9, clinical disease activity index [CDAI] 15.0, 28 secondary inadequate responders) were treated with additional IGU (final dose 41.7 mg/day) and enrolled in this 24-week, multicenter, retrospective study. Results: Twenty-nine patients (93.5%) continued the treatment for 24 weeks (one dropped out for pneumonia and one for digestive symptoms). The TCZ and the concomitant dose and rate of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (MTX, salazosulfapyridine [SASP], and tacrolimus [TAC]) were not significantly changed during this period. Outcome measures improved significantly, as follows: DAS28-CRP from 2.9 to 1.7 (p < .001); CDAI from 15.0 to 6.0 (p < .001); modified Health Assessment Questionnaire (mHAQ) from 0.8 to 0.6 (p < .05); and rheumatoid factor (RF) from 382.1 to 240.3 IU/mL (p < .001). Using the EULAR criteria, 64.5% achieved a moderate response, and 51.6% achieved ACR 20 at 24 weeks. Conclusion: Adding IGU to inadequate responders to TCZ may be a promising and safe complementary treatment option.

DOI： 10.1080/14397595.2018.1486939

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Following publication of the original article [1], the authors noticed that two corrections were not implemented during the production process.

DOI： 10.1186/s13075-019-1897-8

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BACKGROUND: The aim of this study is to evaluate the retention rates and reasons for discontinuation for seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of elderly patients (65 years of age or older) with rheumatoid arthritis (RA). METHODS: This multi-center, retrospective study assessed 1,098 treatment courses of 661 patients with bDMARDs from 2009 to 2018 (females, 80.7%; baseline age, 71.7 years; disease duration 10.5 years; rheumatoid factor positivity 81.3%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.6; concomitant prednisolone dose 2.8 mg/day (45.6%) and methotrexate dose 4.4 mg/week (56.4%); and 60.2% patients were bio-naïve). Treatment courses included abatacept (ABT; n = 272), tocilizumab (TCZ; n = 234), etanercept (ETN; n = 184), golimumab (GLM; n = 159), infliximab (IFX; n = 101), adalimumab (ADA; n = 97), and certolizumab pegol (CZP; n = 51). Drug retention rates and discontinuation reasons were estimated at 36 months using the Kaplan-Meier method and adjusted for potential clinical confounders (age, sex, disease duration, concomitant PSL and MTX, starting date and switched number of bDMARDs) by Cox proportional hazards modeling. RESULTS: A total of 51.2% of treatment courses were stopped, with 25.1% stopping due to lack of effectiveness, 11.8% due to toxic adverse events, 9.7% due to non-toxic reasons, and 4.6% due to remission. Drug retention rates for each discontinuation reason were as follows; lack of effectiveness [from 55.4% (ETN) to 81.6% (ABT); with significant differences between groups (Cox P<0.001)], toxic adverse events [from 79.3% (IFX) to 95.4% (ABT), Cox P = 0.043], and remission [from 94.2% (TCZ) to 100.0% (CZP), Cox P = 0.58]. Finally, overall retention rates excluding non-toxic reasons and remission for discontinuation ranged from 50.0% (ETN) to 78.1% (ABT) (Cox P<0.001). CONCLUSIONS: ABT showed lowest discontinuation rate by lack of effectiveness and by toxic adverse events, which lead to highest overall retention rates (excluding non-toxic reasons and remission) among seven bDMARDs in adjusted model of elderly RA patients.

DOI： 10.1371/journal.pone.0216624

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Language：Japanese   Publisher：(一社)日本手外科学会  

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BACKGROUND: The aim of this study is to evaluate the retention rates and reasons for discontinuation for seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with rheumatoid arthritis (RA). METHODS: This multi-center, retrospective study assessed 4466 treatment courses of 2494 patients with bDMARDs from 2009 to 2017 (females, 82.4%; baseline age, 57.4 years; disease duration 8.5 years; rheumatoid factor positivity 78.6%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.3; concomitant prednisolone (PSL) 2.7 mg/day (43.1%) and methotrexate (MTX) 5.0 mg/week (61.8%); and 63.6% patients were bio-naïve). Treatment courses included tocilizumab (TCZ; n = 895), etanercept (ETN; n = 891), infliximab (IFX; n = 748), abatacept (ABT; n = 681), adalimumab (ADA; n = 558), golimumab (GLM; n = 464), and certolizumab pegol (CZP; n = 229). Drug retention rates and discontinuation reasons were estimated at 36 months using the Kaplan-Meier method and adjusted for potential confounders (age, sex, disease duration, concomitant PSL and MTX, and switched number of bDMARDs) using Cox proportional hazards modeling. RESULTS: A total of 56.9% of treatment courses were stopped, with 25.8% stopping due to lack of effectiveness, 12.7% due to non-toxic reasons, 11.9% due to toxic adverse events, and 6.4% due to disease remission. Drug retention rates for each discontinuation reason were as follows: lack of effectiveness [from 65.5% (IFX) to 81.7% (TCZ); with significant differences between groups (Cox P < 0.001)], toxic adverse events [from 81.8% (IFX) to 94.0% (ABT), Cox P < 0.001], and remission [from 92.4% (ADA and IFX) to 97.7% (ETN), Cox P < 0.001]. Finally, overall retention rates excluding non-toxic reasons and remission for discontinuation ranged from 53.4% (IFX) to 75.5% (ABT) (Cox P < 0.001). CONCLUSIONS: TCZ showed the lowest discontinuation rate by lack of effectiveness, ABT showed the lowest discontinuation rate by toxic adverse events, ADA and IFX showed the highest discontinuation rate by remission, and ABT showed the highest overall retention rates (excluding non-toxic reasons and remission) among seven bDMARDs in the adjusted model.

DOI： 10.1186/s13075-019-1880-4

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Control of rheumatoid arthritis (RA) disease activity is an important factor related to the development of hallux valgus (HV) deformity. Furthermore, if valgus hindfoot remains and/or appears after HV surgery, the affected foot is at risk of recurrence of HV deformity. We experienced a case suggesting the possibility that hindfoot valgus deformity appeared after HV surgery because of poor control of RA disease activity, and the HV deformity recurred in the very early period after surgery.

DOI： 10.1080/14397595.2016.1209817

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Objectives: Joint-preserving rheumatoid forefoot surgery improves clinical outcomes, but postoperative range of motion (ROM) of the metatarsophalangeal (MTP) joint remains an issue. The objective of this study was to evaluate the effect of ROM exercise from the early period after lesser toe MTP joint-preserving surgery.Methods: A retrospective, observational study of 22 rheumatoid arthritis patients who underwent modified metatarsal shortening offset osteotomy was completed. Lesser toe scales were administered using the Japanese Society for Surgery of the Foot (JSSF) standard rating system, and the maximum distance of continuous walking was checked to evaluate clinical outcomes. Maximum passive ROM of the lesser toe MTP joints and the extension angle of the 2nd MTP joint at the terminal stance phase during gait were measured and evaluated.Results: Pain scores and ROM-related indices of the JSSF lesser toe scale improved significantly in the exercise group. The extension angle of the 2nd MTP joint at the terminal stance phase during gait was increased, and the maximum distance of continuous walking seemed longer.Conclusion: Passive/active ROM exercise from 2-weeks after surgery can improve a patient's activity and forefoot function through increasing ROM of the MTP joint at the terminal stance phase.

DOI： 10.1080/14397595.2019.1601853

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Objectives: To clarify the effect of combining medial capsule interposition with modified scarf osteotomy for hallux valgus.Methods: A multicenter, retrospective study included 64 cases [59 osteoarthritis patients (excluding rheumatoid arthritis); age 68.8 years, range 40-93 years] of modified scarf osteotomy which were performed from 2013 to 2017 and followed for 26.6 (range, 13-50) months. Patients were treated by either (1) without medial capsule interposition (33 cases) or (2) combined with interposition (31 cases) at each senior surgeon's discretion. The Japanese Society for Surgery of the Foot (JSSF) hallux metatarsophalangeal (MTP)-interphalangeal scale was evaluated along with radiographic parameters (hallux valgus angle [HVA], first and second metatarsals intermetatarsal angles, and Hardy grade).Results: All JSSF scale and radiographic parameters were similar at baseline and significantly improved at final follow-up in both groups (pre-operation vs. final follow-up: p < .001). However, compared to without interposition group, interposition group showed significantly higher improvement in the JSSF scale (pre-operation to final follow-up: p value between the two groups at final follow-up) for pain (without interposition: 19.4-34.2, interposition: 18.4-37.1; p = .02), function (without interposition: 20.8-33.6, interposition: 18.3-36.6; p = .005), total score (without interposition: 41.5-81.8, interposition: 38.5-88.5; p < .001), and the MTP joint space (without interposition: 1.4-1.5 mm, interposition: 1.6-2.6 mm; p < .001) with significant correlation between the total JSSF score (r = .40; p = .001).Conclusion: Combining medial capsule interposition with modified scarf osteotomy significantly improved mid-term clinical outcomes.

DOI： 10.1080/14397595.2019.1572261

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BACKGROUND: Arthrodesis of the first metatarsophalangeal (MTP) joint has been recommended for severe hallux valgus deformity in patients with rheumatoid arthritis. We developed an alternative procedure that preserves motion of the first MTP joint while restoring alignment and balance to the forefoot. This procedure was shown to be effective in a series of 60 patients with a 3-year follow-up. DESCRIPTION: We perform a modified Scarf osteotomy, with the longitudinal first metatarsal cut parallel to the sole of the foot and with shortening of the metatarsal to realign the first ray. This is combined with an interpositional capsular arthroplasty of the first MTP joint and shortening offset osteotomies of the lesser metatarsals. ALTERNATIVES: Alternatives include arthrodesis of the first MTP joint combined with resection arthroplasty of the lesser MTP joints, or of all 5 MTP joints, or perhaps interpositional (total) joint arthroplasty for severe rheumatoid forefoot deformity/destruction. RATIONALE: The purpose of the modified Scarf osteotomy is preservation of motion of the first MTP joint and protection against destruction of the rheumatoid joint. The metatarsal shortening offset osteotomy provides rigid stabilization at the site of osteotomy after dynamic correction to make the transverse arch.

DOI： 10.2106/JBJS.ST.18.00004

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DOI： 10.1007/s00223-018-0508-z

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Language：Japanese   Publisher：(一社)日本足の外科学会  

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Language：Japanese   Publisher：(一社)日本足の外科学会  

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Language：Japanese   Publisher：(一社)日本足の外科学会  

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Language：Japanese   Publisher：(一社)日本足の外科学会  

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Language：Japanese   Publisher：(一社)日本足の外科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Apolipoprotein E (ApoE) plays crucial roles not only in lipid metabolism but also in bone metabolism. Specifically ApoE4, one of major ApoE isoforms, has been demonstrated to be associated with increased risk of developing osteoporosis compared to another major isoform ApoE3. However, the detailed mechanism of how the different ApoE isoforms affect bone metabolism remains unclear. Micro-CT analyses of distal femora demonstrated severely decreased bone mass in 48-week-old female homozygous ApoE-knockout (ApoE-KO) mice compared to age- and gender-matched wild type C57BL/6 J (WT) mice. Physiological levels of either ApoE3 or ApoE4 protein (1-20 μg/ml) significantly increased the expression of osteoblast-related genes and alkaline phosphatase (ALP) activity of primary calvarial osteoblasts by inhibiting extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in a dose-dependent manner, and ApoE3 showed greater osteoblastic induction compared to ApoE4. Furthermore, both ApoE3 and ApoE4 protein inhibited osteoclastogenesis and the expression of osteoclast-related genes of mouse bone marrow derived macrophages (BMDM) via down regulation of c-Fos, nuclear factor of activated T-cells 1 (NFATc1) and nuclear factor-kappa B (NF-κB) pathway. Moreover, ApoE3 showed greater inhibition of c-Fos, dendritic cell-specific transmembrane protein (DC-STAMP), and Cathepsin K gene expression compared to ApoE4. Collectively, ApoE plays crucial roles in preserving bone mass, suggesting that targeting ApoE and its isoforms as a promising treatment candidate of both osteoporosis and hyperlipidemia.

DOI： 10.1016/j.bbrc.2018.06.055

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Hallux valgus (HV) deformity is associated with hindfoot valgus deformity. We experienced a case that suggests the possibility that valgus correction for varus hindfoot with bony ankylosis of the subtalar joint by total ankle arthroplasty may have caused a forefoot HV deformity, despite adequate valgus correction.

DOI： 10.3109/14397595.2016.1170947

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00198-018-4492-y

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Other Link： http://link.springer.com/content/pdf/10.1007/s00198-018-4492-y.pdf

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The aim of this observational, non-randomized study was to clarify the unknown effects of switching oral bisphosphonates (BPs) to denosumab (DMAb) or daily teriparatide (TPTD) in patients with rheumatoid arthritis (RA). The characteristics of the 194 female patients included in the study were 183 postmenopausal, age 65.9 years, lumbar spine (LS) T score -1.8, femoral neck (FN) T score -2.3, dose and rate of taking oral prednisolone (3.6 mg/day) 75.8%, and prior BP treatment duration 40.0 months. The patients were allocated to (1) the BP-continue group (n = 80), (2) the switch-to-DMAb group (n = 74), or (3) the switch-to-TPTD group (n = 40). After 18 months, the increase in bone mineral density (BMD) was significantly greater in the switch-to-DMAb group than in the BP-continue group (LS 5.2 vs 2.3%, P < 0.01; FN 3.8 vs 0.0%, P < 0.01) and in the switch-to-TPTD group than in the BP-continue group (LS 9.0 vs 2.3%, P < 0.001; FN 4.9 vs 0.0%, P < 0.01). Moreover, the switch-to-TPTD group showed a higher LS BMD (P < 0.05) and trabecular bone score (TBS) (2.1 vs -0.7%; P < 0.05) increase than the switch-to-DMAb group. Clinical fracture incidence during this period was 8.8% in the BP-continue group, 4.1% in the switch-to-DMAb group, and 2.5% in the switch-to-TPTD group. Both the switch-to-DMAb group and the switch-to-TPTD group showed significant increases in LS and FN BMD, and the switch-to-TPTD group showed a higher increase in TBS compared to the BP-continue group at 18 months. Switching BPs to DMAb or TPTD in female RA may provide some useful osteoporosis treatment options.

DOI： 10.1007/s00774-017-0861-4

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BACKGROUND: Arthrodesis of the first metatarsophalangeal (MTP) joint has been recommended for severe hallux valgus deformity in patients with rheumatoid arthritis (RA). However, with the progress of medical treatment of RA, joint preservation surgery has recently been performed. The aim of this study was to investigate the clinical and radiographic outcomes of modified Scarf osteotomy with medial capsule interposition for RA cases including severe destruction of the first MTP joint and to evaluate risk factors for recurrence. METHODS: A retrospective observational study of 76 cases (60 patients) followed for a mean of 35.3 months (range, 24 to 56 months) after a modified Scarf osteotomy was performed. Scores on the Japanese Society for Surgery of the Foot (JSSF) RA foot and ankle scale, the JSSF hallux scale, and a self-administered foot evaluation questionnaire (SAFE-Q) were determined along with preoperative and postoperative radiographic parameters. RESULTS: There was a significant improvement, from preoperatively to final follow-up, in the mean JSSF RA foot and ankle score (from 52.2 to 76.9 points) and the mean JSSF hallux score (from 38.2 to 74.5 points). There was a recurrence (hallux valgus angle [HVA] of >20°) in 12 feet (16%). The preoperative DAS28-CRP score (disease activity score [based on 28 joints in the body]-C-reactive protein score) and intermetatarsal angles between the first and second metatarsals (M1M2A) and between the first and fifth metatarsals (M1M5A) were significantly greater in the recurrence group, as were the HVA, M1M2A, M1M5A, and Hardy grade at 3 months after surgery. There was a significant negative correlation between the preoperative DAS28-CRP score and the JSSF RA foot and ankle score at final follow-up (β = -0.39, p = 0.02) and a significant positive correlation between the preoperative DAS28-CRP score and the HVA at final follow-up (β = 0.44, p = 0.001). CONCLUSIONS: The modified Scarf osteotomy with medial capsule interposition for hallux valgus deformity improved clinical and radiographic outcomes in RA cases with severe destruction of the first MTP joint. Increased preoperative M1M2A and M1M5A; incomplete reduction of the sesamoid bone; and the HVA, M1M2A, and M1M5A at 3 months after surgery should be evaluated as they are associated with recurrence of the deformity. The preoperative DAS28-CRP score was associated with the clinical and radiographic outcomes after surgery. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

DOI： 10.2106/JBJS.17.00436

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DOI： 10.3390/ijms19051395

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Human synovial mesenchymal stem cells (hSMSCs) are a promising cell source for cartilage regeneration because of their superior chondrogenic potential in vitro. This study aimed to further optimize the conditions for inducing chondrogenesis of hSMSCs, focusing on the dose of dexamethasone in combination with transforming growth factor-β3 (TGFβ3) and/or bone morphogenetic protein-2 (BMP2). When hSMSCs-derived aggregates were cultured with TGFβ3, dexamethasone up to 10 nM promoted chondrogenesis, but attenuated it with heterogeneous tissue formation when used at concentrations over than 100 nM. On the other hands, BMP2-induced chondrogenesis was remarkably disturbed in the presence of more than 10 nM dexamethasone along with unexpected adipogenic differentiation. In the presence of both TGFβ3 and BMP2, dexamethasone dose dependently promoted cartilaginous tissue formation as judged by tissue volume, proteoglycan content, and type 2 collagen expression, whereas few adipocytes were detected in the formed tissue when cultures were supplemented with over 100 nM dexamethasone. Even in chondrogenic conditions, dexamethasone thus affected hSMSCs differentiation not only toward chondrocytes, but also towards adipocytes dependent on the dose and combined growth factor. These findings have important implications regarding the use of glucocorticoids in in vitro tissue engineering for cartilage regeneration using hSMSCs.

DOI： 10.1007/s10616-018-0191-y

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Other Link： http://orcid.org/0000-0002-6289-3778

Language：Japanese   Publisher：(公社)日本整形外科学会  

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DOI： 10.1177/2050313X18784413

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The purpose of this study was to evaluate the retention and discontinuation reasons of seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with rheumatoid arthritis (RA). 1,037 treatment courses with bDMARDs from 2009 to 2016 [female, 81.8%; baseline age, 59.6 y; disease duration 7.8 y; rheumatoid factor positivity 81.5%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR), 4.4; concomitant prednisolone 43.5% and methotrexate 68.6%; Bio-naïve, 57.1%; abatacept (ABT), 21.3%; tocilizumab (TCZ), 20.7%; golimumab (GLM), 16.9%; etanercept (ETN), 13.6%; adalimumab (ADA), 11.1%; infliximab (IFX), 8.5%; certolizumab pegol (CZP), 7.9%] were included in this multi-center, retrospective study. Drug retention and discontinuation reasons at 36 months were estimated using the Kaplan-Meier method and adjusted by potent confounders using Cox proportional hazards modeling. As a result, 455 treatment courses (43.9%) were stopped, with 217 (20.9%) stopping due to inefficacy, 113 (10.9%) due to non-toxic reasons, 86 (8.3%) due to toxic adverse events, and 39 (3.8%) due to remission. Drug retention rates in the adjusted model were as follows: total retention (ABT, 60.7%; ADA, 32.7%; CZP, 43.3%; ETN, 51.9%; GLM, 45.4%; IFX, 31.1%; and TCZ, 59.2%; P < 0.001); inefficacy (ABT, 81.4%; ADA, 65.7%; CZP, 60.7%; ETN, 71.3%; GLM, 68.5%; IFX, 65.0%; and TCZ, 81.4%; P = 0.015), toxic adverse events (ABT, 89.8%; ADA, 80.5%; CZP, 83.9%; ETN, 89.2%; GLM, 85.5%; IFX, 75.6%; and TCZ, 77.2%; P = 0.50), and remission (ABT, 95.5%; ADA, 88.1%; CZP, 91.1%; ETN, 97.5%; GLM, 94.7%; IFX, 86.4%; and TCZ, 98.4%; P < 0.001). In the treatment of RA, ABT and TCZ showed higher overall retention, and TCZ showed lower inefficacy compared to IFX, while IFX showed higher discontinuation due to remission compared to ABT, ETN, GLM, and TCZ in adjusted modeling.

DOI： 10.1371/journal.pone.0194130

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Background: Outcomes after total ankle arthroplasty (TAA) combined with additive techniques (augmentation of bone strength, control of soft-tissue balance, adjustment of the loading axis) for the treatment of rheumatoid arthritis were evaluated after intermediate to long-term follow-up. The influences of biologic treatment on the outcomes after TAA were also evaluated. Methods: We performed a retrospective observational study involving 50 ankles (44 patients) that underwent TAA for the treatment of rheumatoid arthritis. The mean duration of follow-up was 7.1 years. Clinical outcomes were evaluated with use of the Japanese Society for Surgery of the Foot (JSSF) scale score and a postoperative self-administered foot-evaluation questionnaire (SAFE-Q). Radiographic findings were evaluated as well. These parameters also were compared between patients managed with and without biologic treatment. Results: This procedure significantly improved the clinical scores of the JSSF rheumatoid arthritis foot and ankle scale (p < 0.0001). Forty-eight of the 50 ankles had no revision TAA surgery. Subsidence of the talar component was seen in 8 ankles (6 in the biologic treatment group and 2 in the non-biologic treatment group); 2 of these ankles (both in the biologic treatment group) underwent revision TAA. The social functioning score of the SAFE-Q scale at the time of the latest follow-up was significantly higher in the biologic treatment group (p = 0.0079). The dosage of prednisolone (p = 0.0003), rate of usage of prednisolone (p = 0.0001), and disease-activity score (p < 0.01) at the time of the latest follow-up were all significantly lower in the biologic treatment group. Conclusions: TAA is recommended for the treatment of rheumatoid arthritis if disease control, augmentation of bone strength, control of soft-tissue balance, and adjustment of the loading axis are taken into account. The prevention of talar component subsidence remains a challenge in patients with the combination of subtalar fusion, rheumatoid arthritis, and higher social activity levels. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

DOI： 10.2106/JBJS.OA.17.00033

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

The aim of this 12-month, retrospective study was to compare the effects of denosumab (DMAb; 60 mg subcutaneously every 6 months) plus native vitamin D (VD) (cholecalciferol) combination therapy with DMAb plus active VD analog (alfacalcidol) combination therapy in patients with postmenopausal osteoporosis. Patients [N = 127; mean age 75.6 years (range 58-93 years); 28 treatment-na &lt; ve patients, 59 patients treated with oral bisphosphonate therapy, 40 patients treated with teriparatide daily] were allocated to either (1) the DMAb plus native VD group (n = 60; cholecalciferol, 10 mu g, plus calcium, 610 mg/day; 13 treatment-na &lt; ve patients, 28 patients treated with oral bisphosphonate therapy, and 19 patients treated with teriparatide daily) or (2) the DMAb plus active VD group [n = 67; alfacalcidol, 0.8 +/- 0.0 mu g, plus calcium, 99.2 +/- 8.5 mg/day; 15 treatment-na &lt; ve patients, 31 patients treated with oral bisphosphonate therapy, and 21 patients treated with teriparatide daily) on the basis of each physician's decision. Changes in bone mineral density (BMD), serum bone turnover marker levels, and fracture incidence were monitored every 6 months. There were no significant differences in baseline age, BMD, bone turnover marker levels, and prior treatments between the two groups. After 12 months, compared with the DMAb plus native VD group, the DMAb plus active VD group showed similar increases in the BMD of the lumbar spine (6.4% vs 6.5%) and total hip (3.3% vs 3.4%), but significantly greater increases in the BMD of the femoral neck (1.0% vs 4.9%, P &lt; 0.001) and the distal part of the forearm (third of radius) (-0.8% vs 3.9%, P &lt; 0.01). These tendencies were similar regardless of the differences in the prior treatments. The rates of decrease of bone turnover marker levels were similar for tartrate-resistant acid phosphatase isoform 5b (-49.0% vs -49.0%), procollagen type I N-terminal propeptide (-45.9% vs -49.3%), and undercarboxylated osteocalcin (-56.0 vs -66.5%), whereas serum intact parathyroid hormone levels were significantly lower in the DMAb plus active VD group (47.6 pg/mL vs 30.4 pg/mL, P &lt; 0.001). The rate of hypocalcemia was 1.7% in the DMAb plus native VD group and 1.5% in the DMAb plus active VD group, and the rate of clinical fracture incidence was 8.3% in the DMAb plus native VD group and 4.5% in the DMAb plus active VD group, with no significant difference between the groups. DMAb with active VD combination therapy may be a more effective treatment option than DMAb with native VD combination therapy in terms of increasing BMD of the femoral neck and distal part of the forearm and also maintaining serum intact parathyroid hormone at lower levels.

DOI： 10.1007/s00774-016-0792-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER LONDON LTD  

Oxygen ultra-fine bubbles (OUB) saline injection prevents bone loss of glucocorti\coid-induced osteoporosis in mice, and OUB inhibit osteoclastogenesis via RANK-TRAF6-c-Fos-NFATc1 signaling and RANK-p38 MAPK signaling in vitro.
Ultra-fine bubbles (&lt; 200 nm in diameter) have several unique properties, and they are tested in various medical fields. The purpose of this study was to investigate the effects of oxygen ultra-fine bubbles (OUB) on glucocorticoid-induced osteoporosis (GIO) model mice.
Prednisolone (PSL, 5 mg) was subcutaneously inserted in 6-month-old male C57BL/6J mice, and 200 mu l of saline, OUB-diluted saline, or nitrogen ultra-fine bubbles (NUB)-diluted saline was intraperitoneally injected three times per week for 8 weeks the day after operations. Mice were divided into four groups; (1) control, sham-operation + saline; (2) GIO, PSL + saline; (3) GIO + OUB, PSL + OUB saline; (4) GIO + NUB, PSL + NUB saline. The effects of OUB on osteoblasts and osteoclasts were examined by serially diluted OUB medium in vitro.
Bone mass was significantly decreased in GIO [bone volume/total volume (%): control vs. GIO 12.6 vs. 7.9; p &lt; 0.01] while significantly preserved in GIO + OUB (GIO vs. GIO + OUB 7.9 vs. 12.9; p &lt; 0.05). In addition, tartrate-resistant acid phosphatase (TRAP)-positive cells in the distal femur [mean osteoclasts number/bone surface (mm(-1))] was significantly increased in GIO (control vs. GIO 6.8 vs. 11.6; p &lt; 0.01) while suppressed in GIO + OUB (GIO vs. GIO + OUB 11.6 vs. 7.5; p &lt; 0.01). NUB did not affect these parameters. In vitro experiments revealed that OUB significantly inhibited osteoclastogenesis by inhibiting RANK-TRAF6-c-Fos-NFATc1 signaling, RANK-p38 MAPK signaling, and TRAP/Cathepsin K/DC-STAMP mRNA expression in a concentration-dependent manner. OUB did not affect osteoblastogenesis in vitro.
OUB prevent bone loss in GIO mice by inhibiting osteoclastogenesis.

DOI： 10.1007/s00198-016-3830-1

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Objectives: To determine whether preoperative pain intensity in callosities of the lesser toe metatarsopharangeal (MTP) joint was associated with the grade of fore-mid-hindfoot deformities, because rheumatoid arthritis (RA) foot deformity includes the whole part of foot, and curiously differences between cases in the pain intensity of MTP joint callosities are often observed.
Methods: We evaluated 24 feet that had undergone forefoot surgery [August, 2014 - December, 2015] for painful lesser toe MTP joint deformity (callosities) in RA cases. A preoperative self-administered foot evaluation questionnaire (SAFE-Q) and pressure distribution information for foot function were also investigated. X-rays of the whole lower extremities and foot at weight-bearing were used to check fore-mid-hindfoot deformities.
Results: Group M (mild) [n=9] included patients with the pain visual analog scale (VAS) less than 40mm, while group S (severe) [n=15] included patients whose VAS was over 40mm. Group M showed stronger hindfoot valgus and pronated (abducted) deformity, and group M showed higher pressure on the first MTP joint compared with group S.
Conclusions: These observations reconfirm that hindfoot valgus deformity and/or pronated (abducted) foot deformity affects the forefoot loading distribution, subsequently the pain of callosities in lesser toe MTP joints could be decreased.

DOI： 10.1080/14397595.2016.1192746

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OBJECTIVES: Tocilizumab (TCZ) shows good retention in patients with rheumatoid arthritis (RA), but no previous reports demonstrated hopeful treatment options against inadequate response to TCZ. Tacrolimus (TAC) has proved to show efficacy against inadequate response to tumor necrosis factor alpha inhibitors, yet its add-on effects on TCZ remain unknown. METHODS: Twenty patients with RA (17 women, age 58.6 years, disease duration 12.1 years, prior TCZ duration 2.6 years, 18 intravenous [8 mg/kg/month] and 2 subcutaneous [324 mg/month] TCZ treatments, methotrexate 6.1 mg/week [70.0%]) who showed an inadequate response to TCZ (clinical disease activity index [CDAI] ≥ 5.8, 18 secondary non-responders) were additionally treated with TAC (1.1 mg/day), and enrolled in this 24-week, prospective study. RESULTS: Seventeen patients (85.0%) continued the treatment for 24 weeks. Statistically significant decreases in outcome measures were as follows: disease activity score based on 28 joints with C-reactive protein (DAS28-CRP) from 3.3 at baseline to 2.1 at week 24 (p < 0.001), CDAI from 17.7 to 7.6 (p < 0.001), and serum matrix metalloproteinase-3 levels from 232.8 to 66.2 ng/ml (p < 0.001). About 15 patients (75%) achieved low disease activity or remission (DAS28-CRP ≤2.7 or CDAI ≤10) at week 24. CONCLUSIONS: Adding low-dose TAC to inadequate responders to TCZ may be a promising complementary treatment option.

DOI： 10.1080/14397595.2016.1181315

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

The aim of this 12-month, observational study was to compare the effects of switching daily teriparatide (TPTD) to oral bisphosphonates (BP) therapy or denosumab (DMAb) therapy in patients with primary osteoporosis. Patients [n = 78; 71 postmenopausal women and seven men; mean age 76.3 (64-94) years; mean duration of prior daily TPTD therapy 20.1 (6-24) months] were allocated to either the (1) "switch-to-BP" group [n = 36; weekly alendronate 35 mg (n = 19), weekly risedronate 17.5 mg (n = 12), monthly minodronate 50 mg (n = 5)]; or (2) "switch-to-DMAb" group (n = 42; 60 mg sc every 6 months) based on each physicians' decision. Changes in bone mineral density (BMD) and serum bone turnover markers were monitored every 6 months. No significant difference was observed in baseline clinical characteristics between the groups. After 12 months, the increase in BMD was significantly greater in the switch-to-DMAb group compared to the switch-to-BP group: lumbar spine (6.2 vs. 2.6 %; P &lt; 0.01), total hip (4.2 vs. 1.1 %; P &lt; 0.05), and femoral neck (3.5 vs. 1.4 %; P &lt; 0.05). In addition, the patients in the switch-to-DMAb group showed a significant decrease compared to those in the switch-to-BP group in TRACP-5b (-55.8 vs. -32.8 %; P &lt; 0.01) and ucOC (-85.5 vs. -65.0 %; P &lt; 0.001), while no significant difference was observed in PINP (-67.5 vs. -62.1 %). Switching daily TPTD to DMAb significantly increased BMD and decreased bone resorption marker compared to switching to oral BP at 12 months, and thus may provide an effective sequential treatment option after daily TPTD treatment.

DOI： 10.1007/s00774-015-0731-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Objectives: Advances in drug therapy for rheumatoid arthritis (RA) have been encouraging us to preserve the metatarsopharangeal (MTP) joint in correction of forefoot deformities, and original metatarsal shortening offset osteotomy was recommended as one of the conventional surgical options for forefoot deformities in RA cases. The objective of this study was to evaluate short- to mid-term outcomes of modified metatarsal shortening offset osteotomy.Methods: A retrospective observational study was completed for 80 RA cases (mean follow-up period: 3.2 years) who underwent modified metatarsal shortening offset osteotomy. Both lesser toe scales and RA foot ankle scales were administered using the Japanese Society for Surgery of the Foot (JSSF) standard rating system, and a postoperative self-administered foot evaluation questionnaire (SAFE-Q) at final follow-up was also checked to evaluate clinical outcomes.Results: This procedure significantly improved clinical scores of both the JSSF [lesser toes and RA foot and ankle] scales. Of 80 feet, 24 (30%) showed recurrence of MTP joint subluxation/dislocation. Furthermore, the feet in the recurrence group showed significant varus hindfoot. On the other hand, valgus foot in the recurrence group more frequently included midfoot bony ankyloses. All of the affected feet showed the limitation of MTP joints (&lt;70 degrees) after surgery.Conclusions: Modified metatarsal shortening offset osteotomy was recommended for RA forefoot disorders as one of the joint preservation surgeries in short- to mid-term follow-up. However, some modifications to avoid limitation of ROM in the MTP joint are required. It must be borne in mind that varus hindfoot and/or bony ankyloses in the mid-hindfoot can cause recurrence of dorsal dislocation/subluxation of the lesser toe MTP joint.

DOI： 10.1080/14397595.2016.1276512

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PURPOSE: The purpose of this retrospective study is to clarify the difference in plantar pressure distribution during walking and related patient-based outcomes between forefoot joint-preserving arthroplasty and resection-replacement arthroplasty in patients with rheumatoid arthritis (RA). METHODS: Four groups of patients were recruited. Group1 included 22 feet of 11 healthy controls (age 48.6 years), Group2 included 36 feet of 28 RA patients with deformed non-operated feet (age 64.8 years, Disease activity score assessing 28 joints with CRP [DAS28-CRP] 2.3), Group3 included 27 feet of 20 RA patients with metatarsal head resection-replacement arthroplasty (age 60.7 years, post-operative duration 5.6 years, DAS28-CRP 2.4), and Group4 included 34 feet of 29 RA patients with metatarsophalangeal (MTP) joint-preserving arthroplasty (age 64.6 years, post-operative duration 3.2 years, DAS28-CRP 2.3). Patients were cross-sectionally examined by F-SCAN II to evaluate walking plantar pressure, and the self-administered foot evaluation questionnaire (SAFE-Q). Twenty joint-preserving arthroplasty feet were longitudinally examined at both pre- and post-operation. RESULTS: In the 1st MTP joint, Group4 showed higher pressure distribution (13.7%) than Group2 (8.0%) and Group3 (6.7%) (P<0.001). In the 2nd-3rd MTP joint, Group4 showed lower pressure distribution (9.0%) than Group2 (14.5%) (P<0.001) and Group3 (11.5%) (P<0.05). On longitudinal analysis, Group4 showed increased 1st MTP joint pressure (8.5% vs. 14.7%; P<0.001) and decreased 2nd-3rd MTP joint pressure (15.2% vs. 10.7%; P<0.01) distribution. In the SAFE-Q subscale scores, Group4 showed higher scores than Group3 in pain and pain-related scores (84.1 vs. 71.7; P<0.01) and in shoe-related scores (62.5 vs. 43.1; P<0.01). CONCLUSIONS: Joint-preserving arthroplasty resulted in higher 1st MTP joint and lower 2nd-3rd MTP joint pressures than resection-replacement arthroplasty, which were associated with better patient-based outcomes.

DOI： 10.1371/journal.pone.0183805

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Objectives: To clarify the difference of patient-based outcome between joint-preserving arthroplasty and resection-replacement arthroplasty in forefoot surgery for patients with rheumatoid arthritis (RA).
Methods: A total of 63 feet of 49 RA patients who underwent forefoot surgery were asked to answer pre-operative and post-operative self-administered foot evaluation questionnaire (SAFE-Q). Patients were treated with either (1) metatarsal head resection-replacement arthroplasty (28 feet, post-operative mean age 63.8 years, follow-up 4.2 years, DAS28-CRP 2.2) or (2) metatarsophalangeal joint-preserving arthroplasty (35 feet, post-operative mean age 63.1 years, follow-up 3.6 years, DAS28-CRP 2.1) at each surgeon's discretion.
\Results: Mean pre-operative and post-operative subscale scores of SAFE-Q of group (1) and (2) were as follows. Pain and pain-related [(1) pre-op 36.8 to post-op 75.0 vs. (2) pre-op 42.2 to post-op 82.6], physical functioning and daily-living [(1) 43.2-68.8 vs. (2) 52.778.1], social functioning [(1) 44.3-72.0 vs. (2) 52.5-81.9], general health and well-being [(1) 48.4-68.4 vs. (2) 45.5-84.4], and shoe-related [(1) 30.1-50.3 vs. (2) 30.6-64.4]. Both general health and well-being subscale scores (p&lt; 0.05) and shoe-related subscale scores (p&lt; 0.05) were significantly more improved in group (2) compared with group (1).
Conclusions: Joint-preserving arthroplasty resulted in better patient-based outcomes than resection-replacement arthroplasty.

DOI： 10.1080/14397595.2016.1259968

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.joca.2016.03.006

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The aim of this observational, nonrandomized study was to compare the effects of 12 months of monthly minodronate (MIN; 50 mg/month) monotherapy and MIN combination therapy with vitamin K2 (VK; 45 mg/day) or eldecalcitol (ELD; 0.75 μg/day) in treatment-naïve patients with primary osteoporosis. Patients (n = 193; 178 postmenopausal women and 15 men; mean age 71.6 years) were treated with (1) MIN monotherapy (n = 63), (2) MIN plus VK combination therapy (n = 50), or (3) MIN plus ELD combination therapy (n = 80) for 12 months. Changes in bone mineral density (BMD) and the levels of serum bone turnover markers were monitored. No significant difference was observed in baseline BMD among the three groups. After 12 months, BMD increased by 2.93, 4.65, and 6.55 % in the lumbar spine, 0.66, 2.57, and 3.42 % in the total hip, and 0.05, 2.06, and 3.58 % in the femoral neck in groups 1, 2, and 3, respectively. The BMD increase induced by MIN plus ELD combination therapy was significantly greater than that induced by MIN monotherapy in the lumbar spine (P = 0.0002), total hip (P = 0.003), and femoral neck (P = 0.004), and also that induced by MIN plus VK combination therapy in the lumbar spine (P = 0.03). MIN plus ELD combination therapy compared with MIN monotherapy resulted in a greater decrease in serum procollagen type I N-terminal propeptide levels (-37.4 % vs -54.6 %; P = 0.001) and tartrate-resistant acid phosphatase isoform 5b levels (-41.1 % vs -52.9 %; P = 0.009) at 3 months, and a greater decrease in procollagen type I N-terminal propeptide levels (-64.3 % vs -50.3 %; P = 0.03) and a decrease in intact parathyroid hormone levels (-12.3 % vs 14.0 %; P = 0.01) at 12 months. Combination therapy with MIN and VK or ELD for 12 months showed additive effects in decreasing the levels of bone turnover markers compared with MIN monotherapy, whereas MIN plus ELD combination therapy resulted in the highest BMD increase compared with MIN monotherapy and MIN plus VK combination therapy.

DOI： 10.1007/s00774-015-0710-2

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UNLABELLED: Switching weekly ALN or RIS to monthly MIN in patients with RA, of whom two-thirds were treated with low-dose PSL, significantly decreased bone turnover markers and increased BMD at 12 months, suggesting that monthly MIN may be an effective alternative treatment option of oral bisphosphonate treatment. INTRODUCTION: The aim of this prospective, observational study was to evaluate the effects of switching weekly alendronate (ALN 35 mg) or risedronate (RIS 17.5 mg) to monthly minodronate (MIN 50 mg) in patients with rheumatoid arthritis (RA). METHODS: Patient characteristics were as follows: n = 172; 155 postmenopausal women, age 65.5 (44–87) years; T-score of lumbar spine (LS), −1.4; total hip (TH), −1.8; femoral neck (FN), −2.1; dose and rate of oral prednisolone (2.3 mg/day), 69.1 %; prior duration of ALN or RIS, 46.6 months; were allocated, based on their preference, to either the (1) continue group (n = 88), (2) switch-from-ALN group (n = 44), or (3) switch-from-RIS group (n = 40). RESULTS: After 12 months, increase in BMD was significantly greater in group 3 compared to group 1: LS (4.1 vs 1.2 %; P < 0.001), TH (1.9 vs −0.7 %; P < 0.01), and FN (2.7 vs −0.5 %; P < 0.05); and in group 2 compared to group 1: LS (3.2 vs 1.2 %; P < 0.05) and TH (1.5 vs −0.7 %; P < 0.01). The decrease in bone turnover markers was significantly greater in group 3 compared to group 1: TRACP-5b (−37.3 vs 2.5 %; P < 0.001), PINP (−24.7 vs −6.2 %; P < 0.05), and ucOC (−39.2 vs 13.0 %; P < 0.05); and in group 2 compared to group 1: TRACP-5b (−12.5 vs 2.5 %; P < 0.05) at 12 months. CONCLUSIONS: Switching weekly ALN or RIS to monthly MIN in patients with RA may be an effective alternative treatment option of oral bisphosphonate treatment.

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Objectives. To examine whether or not earlier therapeutic intervention with methotrexate (MTX) prevents the development of rheumatoid arthritis (RA) in patients with recent-onset undifferentiated arthritis (UA) showing high anti-citrullinated peptide antibody (ACPA) titers.Methods. The patients were divided into two groups, one was treated with MTX (MTX+ group, n = 29), and the other was treated without MTX (MTX- group, n = 19), and other disease-modifying anti-rheumatic drugs were not permitted in the two groups before the primary endpoint was met. The primary endpoint is the occurrence of definite RA, and it was compared in the two groups after 1 year.Results. The percentage of patients who developed definite RA in the MTX+ group (17.2%) was significantly lower than that in the MTX- group (78.9%) (log-rank test, P < 0.001, n = 48); adjusted hazards ratio: 0.028 [95% confidence interval (CI): 0.003-0.250, P = 0.001, n = 39]. Treatment effectiveness was not decreased by major risk factors of RA onset such as smoking habits and human leukocyte antigen-DRB1 shared epitope (SE) (smoking habit, odds ratio [OR]: 0.041 [95% CI: 0.007-0.246] P < 0.001; SE, OR: 0.022 [95% CI: 0.002-0.204] P < 0.001). The safety issues were comparable between the two groups.Conclusions. This suggests that early therapeutic intervention with MTX could safely prevent the development of RA in patients with recent-onset UA showing high ACPA titers.

DOI： 10.3109/14397595.2015.1031364

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A close correlation between atherosclerosis, inflammation, and osteoporosis has been recognized, although the precise mechanism remains unclear. The growth factor progranulin (PGRN) is expressed in various cells such as macrophages, leukocytes, and chondrocytes. PGRN plays critical roles in a variety of diseases, such as atherosclerosis and arthritis by inhibiting Tumor Necrosis Factor-α (TNF-α) signaling. The purpose of this study was to investigate the effect of PGRN on bone metabolism. Forty-eight-week old female homozygous PGRN knockout mice (PGRN-KO) (n = 8) demonstrated severe low bone mass in the distal femur compared to age- and sex-matched wild type C57BL/6J mice (WT) (n = 8) [BV/TV (%): 5.8 vs. 16.6; p < 0.001, trabecular number (1/mm): 1.6 vs. 3.8; p < 0.001]. In vitro, PGRN inhibited TNF-α-induced osteoclastogenesis from spleen cells of PGRN-KO mice. Moreover, PGRN significantly promoted ALP activity, osteoblast-related mRNA (ALP, osteocalcin) expression in a dose-dependent manner and up-regulated osteoblastic differentiation by down-regulating phosphorylation of ERK1/2 in mouse calvarial cells. In conclusion, PGRN may be a promising treatment target for both atherosclerosis and inflammation-related osteoporosis.

DOI： 10.1016/j.bbrc.2015.08.077

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DOI： 10.1007/s00198-014-2993-x

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Language：English   Publishing type：Part of collection (book)   Publisher：Springer International Publishing  

Ankle arthrodesis is still performed more frequently than total ankle replacement for treatment of painful degenerative changes about the ankle joint. However, total ankle replacement has advanced during the last few decades and the clinical results have been improved substantially. Prosthesis design, preoperative planning, operative techniques to balance the joint, and postoperative evaluation of outcomes have made progress and have allowed surgeons to achieve good clinical results reliably. Since 2003, we started to use the three-component total ankle prosthesis with a mobile-bearing polyethylene insert. As a result, the FINE Total Ankle System is the most frequently employed ankle prosthesis in Japan today. It was designed to allow not only dorsiflexion and plantar flexion but also ±10° of internal and external rotation and ±3-mm anterior-posterior sliding along the mobile-bearing mechanism. We have investigated the in vivo kinematics of this three-component total ankle replacement. The preliminary results are promising and the prosthesis mimics the normal ankle kinematics during gait. Since 2006, the sliding medial malleolar osteotomy technique to balance varus malalignment, the use of a preoperative three-dimensional preoperative bone model based upon DICOM data obtained from a preoperative computed tomography scan, and dedicated patient-specific surgical instruments have played important roles in total ankle replacement surgery precision. However, we previously have limited the indication for total ankle replacement to only inflammatory arthritis due to low-demand physical activities, but more recently, we started expanding our indications to include osteoarthritis patients with higher daily activities. Even with the limited clinical experiences, the midterm results may be promising.

DOI： 10.1007/978-3-319-24415-0_26

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Patients with rheumatoid arthritis showed greater response to 18-month administration of daily teriparatide especially in the increase of bone formation markers at 1 month and femoral neck bone mineral density at 18 months compared to postmenopausal osteoporosis patients.
The aim of this study was to evaluate the effects of 18-month administration of daily teriparatide (TPTD) in osteoporosis patients with rheumatoid arthritis (RA) by comparing that of postmenopausal osteoporosis patients (Porosis).
The effects of TPTD were examined between RA (n = 70; age 68.4 years; disease activity score assessing 28 joints with CRP [DAS28-CRP] 2.8; rheumatoid factor [RF] positivity 75.5 %) with 77.1 % of prior bisphosphonate (BP), 84.3 % of oral prednisolone (PSL) (4.4 mg/day at baseline), 25.7 % of biologics, and Porosis (n = 62; age 71.3 years) with 77.4 % of prior BP.
Femoral neck (FN) bone mineral density (BMD) increase at 18 months was significantly greater in RA compared to Porosis (4.7 vs. 0.7 %, P = 0.038), whereas it was 9.7 versus 7.9 % (P = 0.736) in the lumbar spine (LS). The increase of bone formation markers (bone alkaline phosphatase [bone ALP] and N-terminal type I procollagen propeptide [PINP]) at 1 month were all significantly greater in RA compared to Porosis. A multivariate logistic regression analysis revealed that the significant indicator of 18-month BMD increase in RA was a 3-month increase of under-carboxylated osteocalcin (ucOC) for LS (beta = 0.446, P = 0.005) and baseline ucOC for FN (beta = 0.554, P = 0.001), in which both showed significant negative correlation with baseline PSL dose.
RA showed greater response to daily TPTD administration, especially in the increase of bone formation markers at 1 month and FN BMD increase at 18 months compared to Porosis.

DOI： 10.1007/s00198-014-2819-x

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It has been suggested that interleukin-6 (IL-6) plays a key role in the pathogenesis of rheumatoid arthritis (RA), including osteoporosis not only in inflamed joints but also in the whole body. However, previous in vitro studies regarding the effects of IL-6 on osteoblast differentiation are inconsistent. The aim of this study was to examine the effects and signal transduction of IL-6 on osteoblast differentiation in MC3T3-E1 cells and primary murine calvarial osteoblasts. IL-6 and its soluble receptor significantly reduced alkaline phosphatase (ALP) activity, the expression of osteoblastic genes (Runx2, osterix, and osteocalcin), and mineralization in a dose-dependent manner, which indicates negative effects of IL-6 on osteoblast differentiation. Signal transduction studies demonstrated that IL-6 activated not only two major signaling pathways, SHP2/MEK/ERK and JAK/STAT3, but also the SHP2/PI3K/Akt2 signaling pathway. The negative effect of IL-6 on osteoblast differentiation was restored by inhibition of MEK as well as PI3K, while it was enhanced by inhibition of STAT3. Knockdown of MEK2 and Akt2 transfected with siRNA enhanced ALP activity and gene expression of Runx2. These results indicate that IL-6 negatively regulates osteoblast differentiation through SHP2/MEK2/ERK and SHP2/PI3K/Akt2 pathways, while affecting it positively through JAK/STAT3. Inhibition of MEK2 and Akt2 signaling in osteoblasts might be of potential use in the treatment of osteoporosis in RA.

DOI： 10.1007/s00774-013-0514-1

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DOI： 10.1097/BTO.0b013e318294cdbb

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa Healthcare  

The involvement of valgus hindfoot deformity in hallux valgus deformity was confirmed in a rheumatoid arthritis case with a destructive valgus hindfoot deformity. Correction of severe valgus, calcaneal lateral offset, and pronated foot deformity instantly normalized hallux valgus deformities postoperatively. Thus, careful hindfoot status evaluation is important when assessing forefoot deformity, including hallux valgus, in rheumatoid arthritis cases. © 2014 Japan College of Rheumatology.

DOI： 10.3109/14397595.2013.874738

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Arthrodesis of the first metatarsophalangeal (MTP-1) joint is a widely used procedure for the treatment of hallux valgus in patients with MTP-1 degeneration, severe or recurrent deformity, or inflammatory arthritis. In this case, ten years earlier, the patient's MTP-1 joint had been fused in a severe pronation deformity position. Subsequently, a laterally shifted tibial sesamoid and osseous rising of the phalanx base caused painful callosities. To correct the pronated deformity accurately, a custom-made surgical guide based on a three-dimensional computer tomography (3D-CT) simulation system was used. After correction of the deformity, the MTP-1 joint was again fused. Adequate correction was achieved, and the patient no longer complains of pain and can perform full weight-bearing on the forefoot. The difficulty and importance of placing the MTP-1 joint in an adequate rotational position in MTP-1 joint arthrodesis surgery were confirmed, as was the utility of 3D evaluation and a custom-made surgical guide for rotational adjustment between the metatarsal and the proximal phalanx. We believe that this system should be one of the indicators for adjusting the rotation, especially in revision MTP-1 joint fusion surgery.

DOI： 10.3109/10929088.2014.885992

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Arthrodesis of the first metatarsophalangeal (MTP-1) joint is a widely used procedure for the treatment of hallux valgus in patients with MTP-1 degeneration, severe or recurrent deformity, or inflammatory arthritis. In this case, ten years earlier, the patient's MTP-1 joint had been fused in a severe pronation deformity position. Subsequently, a laterally shifted tibial sesamoid and osseous rising of the phalanx base caused painful callosities. To correct the pronated deformity accurately, a custom-made surgical guide based on a three-dimensional computer tomography (3D-CT) simulation system was used. After correction of the deformity, the MTP-1 joint was again fused. Adequate correction was achieved, and the patient no longer complains of pain and can perform full weight-bearing on the forefoot. The difficulty and importance of placing the MTP-1 joint in an adequate rotational position in MTP-1 joint arthrodesis surgery were confirmed, as was the utility of 3D evaluation and a custom-made surgical guide for rotational adjustment between the metatarsal and the proximal phalanx. We believe that this system should be one of the indicators for adjusting the rotation, especially in revision MTP-1 joint fusion surgery.

DOI： 10.3109/10929088.2014.885992

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We often see painful ankle joint destruction with painful hindfoot valgus deformity in rheumatoid arthritis. Our policy in such cases has been to first correct the hindfoot deformity in the subtalar joint with fusion, but then ankle joint pain has been observed. Two women with rheumatoid arthritis underwent correction and fusion surgery for hindfoot valgus deformity. They had been using wheelchairs because of severe pain in the ankle joint and hindfoot despite extensive medical treatment. After surgery, both patients complained of no pain in the hindfoot. Furthermore, dramatic pain reduction in the ankle joint was also observed especially in a case without ankle joint instability. Consequently, the patients could walk without any support. Correction of valgus hindfoot deformity contributes to centralizing the weight-bearing line in the ankle joint, leading to ankle joint pain relief. It appears possible to preserve the ankle joint without additional ankle surgery even in rheumatoid arthritis cases, if ankle is stable.

DOI： 10.1177/2050313X14553694

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OBJECTIVES: Vitamin K2 (VitK2) is reported to induce not only bone mineralization of human osteoblasts and apoptosis of osteoclasts, but also apoptosis of rheumatoid arthritis (RA) synovial cells, while its clinical effect on disease activity of RA remains unknown. METHODS: 158 female RA patients (mean age 62.5 years) who had not been treated with warfarin, biologics, or teriparatide were enrolled in this study. VitK2 (45 mg/day) was administered in 70 patients with a serum undercarboxylated osteocalcin level of >4.5 ng/ml or with decreased bone mineral density in spite of the treatment with other anti-osteoporosis medications, regardless of RA disease activity. A longitudinal study was conducted in 52 patients who were additionally treated with VitK2 without changing their other medications for three months. RESULTS: In the cross-sectional study, as compared to the VitK2-naïve group (n = 88), the VitK2-treated group (n = 70) showed lower serum CRP (1.7 ± 0.2 vs. 0.5 ± 0.1 mg/dl; P < 0.001), MMP-3 (220.4 ± 21.9 vs. 118.0 ± 14.4 ng/ml; P < 0.001), and DAS28-CRP (2.9 ± 0.1 vs. 2.4 ± 0.1; P < 0.05). In the longitudinal study, patients who were additionally treated with VitK2 showed significant decreases in serum CRP (1.1 ± 0.2 to 0.6 ± 0.2 mg/dl; P < 0.001), MMP-3 (160.1 ± 25.6 to 125.0 ± 17.8 ng/ml; P < 0.05), and DAS28-CRP (3.1 ± 0.2 to 2.4 ± 0.1; P < 0.001). CONCLUSIONS: VitK2 may have the potential to improve disease activity besides osteoporosis in RA.

DOI： 10.1007/s10165-012-0789-4

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Gastroesophageal reflux disease (GERD) is common in patients with many chronic diseases, but has not been well recognized in rheumatoid arthritis (RA). We investigated the prevalence of GERD symptoms in 278 outpatients with RA and their association with such clinical factors as age, sex, height, weight, body mass index, medications drugs, and functional status evaluated by the Modified Health Assessment Questionnaire (MHAQ). GERD symptoms were evaluated by Frequency Scale for the Symptoms of GERD (FSSG). The mean FSSG score for all patients was 5.6, and 82 patients were considered to have GERD symptoms (FSSG score ≥8), thus the overall prevalence of GERD symptoms was 29.5%. MHAQ score and height were significantly higher and lower, respectively, and prednisolone usage was significantly more in the patients with GERD symptoms than those without. These three clinical factors were also significantly associated with GERD symptoms by univariate logistic regression. Multivariate logistic regression analysis demonstrated that MHAQ was the only clinical factor related to GERD symptoms. In conclusion, the prevalence of GERD symptoms in RA patients was high and strongly associated with decreased functional status, suggesting that physicians should pay attention to GERD symptoms in RA management, especially for patients with low functional status.

DOI： 10.3164/jcbn.12-83

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The involvement of valgus hindfoot deformity in hallux valgus deformity was confirmed in a rheumatoid arthritis case with a destructive valgus hindfoot deformity. Correction of severe valgus, calcaneal lateral offset, and pronated foot deformity instantly normalized hallux valgus deformities postoperatively. Thus, careful hindfoot status evaluation is important when assessing forefoot deformity, including hallux valgus, in rheumatoid arthritis cases.

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© Springer Science+Business Media, LLC 2013. All rights reserved. Oxidative stress induced by reactive oxygen species (ROS) is a key underlying mechanism of destructive and proliferative synovitis in rheumatoid arthritis (RA). Abundant ROS have been detected in the synovial fluid of inflamed joints. ROS are also important mediators of cardiovascular degeneration. Patients with RA have a higher risk for cardiovascular events. Recent studies reported the significant suppression of ROS and oxidative stress in the serum of patients with RA by biologics targeting the cytokines tumor necrosis factor (TNF)- a and interleukin (IL)-6. Indeed, serum ROS levels in patients with RA treated with an IL-6-blocking drug are significantly suppressed. Therapy blocking IL-1 also suppresses oxidative stressinduced changes in tissues of patients with RA. Taken together, these findings suggest that anti-cytokine therapies may not only reduce joint damage but vascular degeneration in patients with RA. Given that recent reports have pointed to the beneficial effects of anti-cytokine agents on cardiovascular degeneration, the observed beneficial effects in RA may rely in part on the reduction of oxidative stress.

DOI： 10.1007/978-1-4614-6166-1_16

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Nanobubbles (<200 nm in diameter) have several unique properties such as long lifetime in liquid owing to its negatively charged surface, and its high gas solubility into the liquid owing to its high internal pressure. They are used in variety of fields including diagnostic aids and drug delivery, while there are no reports assessing their effects on the growth of lives. Nanobubbles of air or oxygen gas were generated using a nanobubble aerator (BUVITAS; Ligaric Company Limited, Osaka, Japan). Brassica campestris were cultured hydroponically for 4 weeks within air-nanobubble water or within normal water. Sweetfish (for 3 weeks) and rainbow trout (for 6 weeks) were kept either within air-nanobubble water or within normal water. Finally, 5 week-old male DBA1/J mice were bred with normal free-chaw and free-drinking either of oxygen-nanobubble water or of normal water for 12 weeks. Oxygen-nanobubble significantly increased the dissolved oxygen concentration of water as well as concentration/size of nanobubbles which were relatively stable for 70 days. Air-nanobubble water significantly promoted the height (19.1 vs. 16.7 cm; P<0.05), length of leaves (24.4 vs. 22.4 cm; P<0.01), and aerial fresh weight (27.3 vs. 20.3 g; P<0.01) of Brassica campestris compared to normal water. Total weight of sweetfish increased from 3.0 to 6.4 kg in normal water, whereas it increased from 3.0 to 10.2 kg in air-nanobubble water. In addition, total weight of rainbow trout increased from 50.0 to 129.5 kg in normal water, whereas it increased from 50.0 to 148.0 kg in air-nanobubble water. Free oral intake of oxygen-nanobubble water significantly promoted the weight (23.5 vs. 21.8 g; P<0.01) and the length (17.0 vs. 16.1 cm; P<0.001) of mice compared to that of normal water. We have demonstrated for the first time that oxygen and air-nanobubble water may be potentially effective tools for the growth of lives.

DOI： 10.1371/journal.pone.0065339

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Regarding the pathobiology of rheumatoid arthritis, oxidative stress induced by reactive oxygen species is an important mechanism that underlies destructive and proliferative synovitis. Abundant amounts of reactive oxygen species have been detected in the synovial fluid of inflamed rheumatoid joints. It is reported that drugs that block tumor necrosis factor-α reduce the oxidative stress marker levels in patients with rheumatoid arthritis. In this study, we measured reactive oxygen species using a free radical analytical system in patients with rheumatoid arthritis treated with disease-modifying antirheumatic drugs, tumor necrosis factor-α-blocking drugs (infliximab, etanercept), and an interleukin-6-blocking drug (tocilizumab). The serum level of oxidative stress was drastically low in patients with rheumatoid arthritis treated with tocilizumab, suggesting that interleukin-6 blocking therapy reduces not only joint damage, but also vascular degeneration in patients with rheumatoid arthritis. We believe that such a drastic effect would reduce the incidence of cardiovascular events and mortality in patients with rheumatoid arthritis.

DOI： 10.1007/s00296-011-2135-0

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DOI： 10.1002/jbt.21428

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Previous studies have demonstrated that oxygen environment is an important determinate factor of cell phenotypes and differentiation, although factors which affect pericellular oxygen concentration (POC) in murine chondrogenic cell culture remain unidentified. Oxygen concentrations in vivo were measured in rabbit musculoskeletal tissues, which were by far hypoxic compared to 20% O(2) (ranging from 2.29 ± 1.16 to 4.36 ± 0.51%). Oxygen concentrations in murine chondrogenic cell (C3H10T1/2) culture medium were monitored in different oxygen concentrations (20% or 5%) in the incubator and in different medium volumes (3,700 or 7,400 μl) within 25-cm(2) flasks. Chondrogenic differentiation was assessed by glycosaminoglycan production with quantitative evaluation of Alcian blue staining in 12-well culture dishes. Expression of chondrogenic genes, aggrecan, and type II collagen α1, was examined by quantitative real-time polymerase chain reaction. Oxygen concentrations in medium decreased accordingly with the depth from medium surface, and POC at Day 6 was 18.99 ± 0.81% in 3,700-μl medium (1,480-μm depth) and 13.26 ± 0.23% in 7,400-μl medium (2,960-μm depth) at 20% O(2) in the incubator, which was 4.96 ± 0.08% (1,480-μm depth) and 2.83 ± 0.42% (2,960-μm depth) at 5% O(2), respectively. The differences of POC compared by medium volume were statistically significant (p = 0.0003 at 20% and p = 0.001 at 5%). Glycosaminoglycan production and aggrecan gene expression were most promoted when cultured in moderately low POC, 1,000 μl (2,960-μm depth) at 20% O(2) and 500 μl (1,480-μm depth) at 5% O(2) in 12-well culture dishes. We demonstrate that medium volume and oxygen concentration in the incubator affect not only POC but also chondrogenic differentiation.

DOI： 10.1007/s11626-011-9479-3

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BACKGROUND: The Nkx3.2 transcription factor promotes chondrogenesis by forming a positive regulatory loop with a crucial chondrogenic transcription factor, Sox9. Previous studies have indicated that factors other than Sox9 may promote chondrogenesis directly, but these factors have not been identified. Here, we test the hypothesis that Nkx3.2 promotes chondrogenesis directly by Sox9-independent mechanisms and indirectly by previously characterized Sox9-dependent mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: C3H10T1/2 pluripotent mesenchymal cells were cultured with bone morphogenetic protein 2 (BMP2) to induce endochondral ossification. Overexpression of wild-type Nkx3.2 (WT-Nkx3.2) upregulated glycosaminoglycan (GAG) production and expression of type II collagen α1 (Col2a1) mRNA, and these effects were evident before WT-Nkx3.2-mediated upregulation of Sox9. RNAi-mediated inhibition of Nkx3.2 abolished GAG production and expression of Col2a1 mRNA. Dual luciferase reporter assays revealed that WT-Nkx3.2 upregulated Col2a1 enhancer activity in a dose-dependent manner in C3H10T1/2 cells and also in N1511 chondrocytes. In addition, WT-Nkx3.2 partially restored downregulation of GAG production, Col2 protein expression, and Col2a1 mRNA expression induced by Sox9 RNAi. ChIP assays revealed that Nkx3.2 bound to the Col2a1 enhancer element. CONCLUSIONS/SIGNIFICANCE: Nkx3.2 promoted primary chondrogenesis by two mechanisms: Direct and Sox9-independent upregulation of Col2a1 transcription and upregulation of Sox9 mRNA expression under positive feedback system.

DOI： 10.1371/journal.pone.0034703

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Hypoxia is a key factor in the maintenance of chondrocyte identity. However, crucial chondrogenic transcription factors in the Sox families are not activated in this phenomenon, indicating that other pathways are involved. Nkx3.2 is a well-known chondrogenic transcription factor induced by Sonic hedgehog (Shh); it suppresses a key osteogenic transcriptional factor, Runt-related transcription factor 2 (Runx2), to maintain the chondrogenic phenotype in mesenchymal lineages. The purpose of this study was to examine the function of Nkx3.2 in hypoxia-dependent maintenance of chondrocyte identity. C3H10T1/2 pluripotent mesenchymal cells were cultured with rh-BMP2 (300 ng/ml) to induce chondrogenesis under normoxic (20% O(2)) or hypoxic (5% O(2)) conditions. Immunohistological detection of Nkx3.2 in a micromass cell culture system revealed that hypoxia promoted expression of the Nkx3.2 protein. Real-time RT-PCR analysis revealed that hypoxia promoted Nkx3.2 mRNA expression and suppressed Runx2 mRNA expression; however, Sox9 mRNA expression was not altered by oxygen conditions, as previously described. Over-expression of exogenous Nkx3.2 promoted glycosaminoglycan (GAG) production and inhibited Runx2 mRNA expression and, based on a dual luciferase assay, Runx2 promoter activity. Interestingly, downregulation of Nkx3.2 using RNAi abolished hypoxia-dependent GAG production and restored Runx2 mRNA expression and promoter activity. These results demonstrated that Nkx3.2-dependent suppression of Runx2 was a crucial factor in hypoxia-dependent maintenance of chondrocyte identity.

DOI： 10.1016/j.bbrc.2011.11.026

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DOI： 10.1007/s10165-011-0459-y

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DOI： 10.1002/jbm.b.31457

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Publishing type：Research paper (scientific journal)   Publisher：BMJ  

Objectives:

To understand the acute phase responses to surgical intervention in patients with rheumatoid arthritis (RA) treated with the anti-interleukin (IL)6 receptor antibody, tocilizumab.

Methods:

In a retrospective 1:1 pair-matched case-control study, 22 tocilizumab-treated RA cases and 22 cases treated with conventional disease-modifying antirheumatic drugs (DMARDs) and matched for type of surgery, age and sex were evaluated for body temperature every day, and blood C-reactive protein (CRP) levels and white blood cell (WBC), neutrophil and lymphocyte counts on days −1, 1, 3 and weeks 1 and 2 after joint surgery. Safety issues were also monitored.

Results:

No complications of infection or delay of wound healing occurred in either patient group. Tocilizumab partially, but significantly, suppressed the increase in body temperature on postoperative days 1 and 2, compared with DMARDs (average (SD) maximum increase in temperature was 0.45 (0.1)°C in the tocilizumab group and 0.78 (0.1)°C in the DMARD group; p&lt;0.01). Tocilizumab completely suppressed the increase in CRP after surgery, whereas all cases treated with DMARDs showed a significant increase of CRP at postoperative day 1 (5.5 (0.6) mg/dl; p&lt;0.001). WBC, neutrophil and lymphocyte counts showed no remarkable change after surgery, and there was no significant difference in any cell counts between the patient groups.

Conclusions:

Within this small number of cases, safe operations on patients were performed during tocilizumab treatment. Tocilizumab suppressed fever and increase of CRP after surgery, whereas there was no influence on the transition in number of leukocytes. This characteristic postoperative response should be considered during tocilizumab treatment.

DOI： 10.1136/ard.2008.090068

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Ebina K, Fukuhara A, Ando W, Hirao M, Koga T, Oshima K, Matsuda M, Maeda K, Nakamura T, Ochi T, Shimomura I, Yoshikawa H, Hashimoto J, Clinical rheumatology, 2009, vol. 28, no. 4, pp. 445-451, 2009

DOI： 10.1007/s10067-008-1074-y

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Other Link： http://orcid.org/0000-0002-6289-3778

DOI： 10.1016/j.bone.2008.09.015

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DOI： 10.1007/s10165-008-0147-8

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DOI： 10.1007/s00774-007-0823-3

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Publishing type：Research paper (scientific journal)  

We investigated the fundamental properties of quick-forming hydroxyapatite (HAp)/agarose gel composites, and evaluated their potential as an injectable bone substitute. From scanning electron microscope observations, the HAp/agarose gel composites produced by an innovative electrophoretic process showed an interconnecting structure with the HAp particles. The diameter of the HAp particles was roughly 1 μm, and the total amount of HAp particles was estimated by a quantification of the calcium ions. In the case of 1 mg of dry composite, 10 pg of HAp was formed in the agarose gel. Moreover, X-ray diffraction analysis revealed that the HAp particles had an amorphous structure, so the HAp particles were expected to dissolve under physiological conditions relative to the HAp with higher crystallinity. The advantages of the resultant HAp/agarose gel composites are ease of handling, close contact with the surrounding tissues, and ease of use as an injectable material. As a preliminary animal study, the composites were implanted into the medial femoral condyle of rabbits. After implantation, the process of bone regeneration was evaluated by microfocus-computed tomography (μCT) and histological analysis. At 2 weeks postoperatively, newly-formed bone was observed at the edge of the bone defect site, and at 4 weeks postoperatively, excellent bone regeneration was observed. The implanted composite gradually degraded, and disappeared at 8 weeks postoperatively. This result indicated that the composite dissolved rapidly, and was replaced by newly-formed bone. Quick-forming HAp/agarose gel composites may be a good candidate as an injectable biomaterial, particularly in the fields of orthopedic, oral, and maxillofacial surgery. © 2007 Wiley Periodicals, Inc.

DOI： 10.1002/jbm.a.31435

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Language：Japanese   Publisher：(一社)日本骨代謝学会  

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DOI： 10.1007/s00774-007-0765-9

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DOI： 10.1074/jbc.M602296200

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Language：Japanese   Publisher：ライフサイエンス出版(株)  

アレンドロネートとビタミンK2を併用した際に,どのようにundercarboxylated osteocalcin(ucOC)やcarboxylated osteocalcin(COC)が変化するか無作為化比較試験で検討した.閉経後女性44例を対象とし,1日5mgのアレンドロネートのみ服用するA群,1日5mgのアレンドロネートと45mgのビタミンK2を併用するAK群に分けた.ucOCは,A群が約20%の減少,AK群が約60%もの減少を認め,いずれの時期においてもAK群が有意に減少率が高かった.COCは,A群ではほとんど変化がなかったが,AK群では3ヵ月後から約50%の増加を認めた.COCに対するucOCの割合は,A群は10から15%と減少を認めた.AK群では約60%の減少を認め,AK群が有意に低下した.第2-4腰椎での骨密度は12ヵ月後にはA群が3.7%,AK群が約6%増加した.大腿骨全体の骨密度は,A群ではほとんど増加は認めなかったが,AK群では1.7%の増加を認めた.しかし,両者に有意差はなかった

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Language：Japanese   Publisher：(一社)日本骨代謝学会  

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Publishing type：Research paper (international conference proceedings)  

We developed a novel biomineralization for agarose gel using the electrophoresis approach. The hydroxyapatite (HAp) was formed homogeneously in the agarose gel within 30 min. Through this process, each ion could migrate into the agarose gel to an alternative electrode side, and HAp was then formed in the agarose gel. A total amount of HAp in 1mg of the agarose gel with equilibrium swelling state was 130 ng. Thus, the electrophoresis approach accelerated the hydroxyapatite formation, particularly, the diffusion coefficient (3.7×10-2 cm2/sec) by electrophoresis approach showed roughly 104 times larger than that of simple diffusion (10-6 cm2/sec). After 4 weeks implantation, satisfactory bone regeneration was observed in the HAp-agarose composite. The preliminary result suggested that this HAp-agarose composite is capable of implantable materials for bone regeneration.

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DOI： 10.1016/j.bone.2005.05.009

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DOI： 10.1002/jbm.a.30277

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DOI： 10.1016/j.joca.2004.12.014

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DOI： 10.1007/s00774-005-0608-5

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Language：English   Publishing type：Research paper (international conference proceedings)  

The development a new method using a YAG laser beam scanning to process a metal surface of a human joint prosthesis was discussed. For the study, various kinds of plaid ditches were engraved on the surfaces of cylindrical metal pieces using a YAG laser scanning to decide a proper width of a ditch for a new bone invasion into the cavities of ditches. It was observed that the proper width of the ditch for a new bone invasion was 500μm irrespective of the material of a metal piece form the view points of rapidity and quantity of new bone invasion. The results show extremely good bonding to bones by the metal processing method using a laser scanning compared to a porous-coated method.

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Language：Japanese   Publisher：THE CENTRAL JAPAN ASSOCIATION OF ORTHOPAEDIC SURGERY AND TRAUMATOLOGY  

DOI： 10.11359/chubu.2000.131

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DOI： 10.11477/mf.1408201448

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

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DOI： 10.15106/J00764.2017306977

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