A report of three cases which required tibialis anterior tendon resection to recover delayed wound healing after total ankle arthroplasty in patients with rheumatoid arthritis

Delayed wound healing is one of the severe complications after total ankle arthroplasty (TAA). In particular, once tibialis anterior (TA) tendon is exposed from tendon sheath of extensor retinaculum, wound healing will be critically intractable. We report three cases (mean age: 75.3 years old) of delayed wound healing after TAA cured by resection of TA tendon in patients with rheumatoid arthritis (RA). All three cases underwent TAA through an anterior approach, with careful suture of extensor retinaculum in wound closure. Ankle joint was fixed with splint and avoid weight bearing for three weeks after surgery. Delayed wound healing with TA tendon exposure was observed, and initially treated by debridement, basic fibroblast growth factor spray, and negative pressure wound therapy, which all failed to obtain wound healing. Finally, complete resection of TA tendon led to rapid wound healing. In all cases, ankle dorsal flexion was compensated by other extensors, with maintained range of motion and muscle strength (manual muscle testing 3 to 4) compared to pre-operation at 1 year after TAA operation. Resection of TA tendon may be considered as one of the salvage treatment options of severe delayed wound healing in TAA with anterior approach, especially in elderly patients.Etani Y., Ebina K., Hirao M., et al. A report of three cases which required tibialis anterior tendon resection to recover delayed wound healing after total ankle arthroplasty in patients with rheumatoid arthritis. Modern Rheumatology Case Reports 4, 6 (2020); https://doi.org/10.1080/24725625.2019.1641297

Effects of iguratimod on glucocorticoid-induced disorder of bone metabolism in vitro

Introduction: Glucocorticoids are widely used to treat various diseases including rheumatoid arthritis (RA); however, one of the most frequent and severe adverse effects is glucocorticoid-induced osteoporosis (GIOP). Iguratimod (IGU) is a novel conventional synthetic disease-modifying anti-rheumatic drug developed in Japan. The aim of this study is to investigate the effects of IGU on glucocorticoid-induced disorder of bone metabolism in vitro. Materials and methods: In osteoclastogenesis of mouse bone marrow-derived cells, tartrate-resistant acid phosphatase staining, resorption pit assay, western blotting, real-time polymerase chain reaction (PCR), and mRNA sequencing were performed. In osteoblastogenesis of MC3T3-E1 cells, alkaline phosphatase (ALP) staining and activity, alizarin red staining, and mRNA sequencing were performed, and real-time PCR and western blotting were conducted in MC3T3-E1 cells and murine osteocyte-like cell line MLO-Y4 cells. Results: IGU significantly suppressed a dexamethasone-induced increase in osteoclasts, differentiation, and bone resorption activity by inhibition of the receptor activator of the nuclear factor kappa-B (RANK)/tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6)/nuclear factor kappa-B (NFκB)-p52 pathway. In MC3T3-E1 cells, IGU significantly upregulated dexamethasone-induced downregulation of ALP activity, bone mineralization, and osteoblast-related gene and protein expression. In MLO-Y4 cells, IGU significantly upregulated dexamethasone-induced downregulation of the gene expression of ALP and osteocalcin, and also downregulated receptor activator of NFκB ligand (RANKL)/osteoprotegerin gene expression ratio without dexamethasone. Conclusion: These results suggest that IGU may improve glucocorticoid-induced disorder of bone metabolism and may exhibit positive effects against GIOP associated with RA.This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s00774-021-01206-5Miyama A., Ebina K., Hirao M., et al. Effects of iguratimod on glucocorticoid-induced disorder of bone metabolism in vitro. Journal of Bone and Mineral Metabolism 39, 639 (2021

The add-on effectiveness and safety of iguratimod in patients with rheumatoid arthritis who showed an inadequate response to tocilizumab

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.Ebina K., Miyama A., Tsuboi H., et al. The add-on effectiveness and safety of iguratimod in patients with rheumatoid arthritis who showed an inadequate response to tocilizumab. Modern Rheumatology 29, 581 (2019); https://doi.org/10.1080/14397595.2018.1486939

A novel anti-TNF-α drug ozoralizumab rapidly distributes to inflamed joint tissues in a mouse model of collagen induced arthritis

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.Oyama S., Ebina K., Etani Y., et al. A novel anti-TNF-α drug ozoralizumab rapidly distributes to inflamed joint tissues in a mouse model of collagen induced arthritis. Scientific Reports 12, 18102 (2022); https://doi.org/10.1038/s41598-022-23152-6

Impact of combining medial capsule interposition with modified scarf osteotomy for hallux valgus

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.Ebina K., Hirao M., Tsuboi H., et al. Impact of combining medial capsule interposition with modified scarf osteotomy for hallux valgus. Modern Rheumatology 30, 204 (2020); https://doi.org/10.1080/14397595.2019.1572261

Effects of follow-on therapy after denosumab discontinuation in patients with postmenopausal osteoporosis

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 =.31 between groups), and in FN BMD were −3.8%, −0.8%, and 1.8%, respectively (p =.02 between the RAL and ZOL; p =.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 =.048 between the RAL and ZOL; p =.015 between the RAL and BP). No significant differences were observed in these parameters between the wmBP and ZOL. Conclusion: These results may contribute to the selection of adequate follow-on therapy after DMAb discontinuation, although further investigations are required.Ebina K., Hashimoto J., Kashii M., et al. Effects of follow-on therapy after denosumab discontinuation in patients with postmenopausal osteoporosis. Modern Rheumatology 31, 485 (2021); https://doi.org/10.1080/14397595.2020.1769895

An investigation of the differential therapeutic effects of romosozumab on postmenopausal osteoporosis patients with or without rheumatoid arthritis complications: a case–control study

The version of record of this article, first published in Osteoporosis International, is available online at Publisher’s website: https://doi.org/10.1007/s00198-024-07019-2Summary: 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

Anti-NF-κB peptide derived from nuclear acidic protein attenuates ovariectomyinduced osteoporosis in mice

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.Takami K., Okamoto K., Etani Y., et al. Anti-NF-κB peptide derived from nuclear acidic protein attenuates ovariectomyinduced osteoporosis in mice. JCI Insight 8, e171962 (2023); https://doi.org/10.1172/jci.insight.171962

Effects of prior osteoporosis treatment on early treatment response of romosozumab in patients with postmenopausal osteoporosis

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 <.001 between groups) and FN BMD changes were 4.2%, 0.4%, 1.6%, and 1.5% (P =.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 =.0027) and TRACP-5b percentage change (r = −2.8, P =.0071) and PINP value at one month (r = 3.2, P =.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.Ebina K., Hirao M., Tsuboi H., et al. Effects of prior osteoporosis treatment on early treatment response of romosozumab in patients with postmenopausal osteoporosis. Bone 140, 115574 (2020); https://doi.org/10.1016/j.bone.2020.115574

Promoting effect of basic fibroblast growth factor in synovial mesenchymal stem cell-based cartilage regeneration

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.Okamura G., Ebina K., Hirao M., et al. Promoting effect of basic fibroblast growth factor in synovial mesenchymal stem cell-based cartilage regeneration. International Journal of Molecular Sciences, 22, 1, 1. https://doi.org/10.3390/ijms22010300