Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy but are associated with immune-related adverse events, including musculoskeletal symptoms. We report a case of rapid exacerbation of bilateral hip osteoarthritis (OA) induced by nivolumab. A 56-year-old woman with a history of developmental hip dysplasia and malignant melanoma was treated with nivolumab. Following nivolumab administration, she developed severe bilateral hip pain and polyarthralgia, necessitating drug discontinuation. Despite cessation of the ICI, her symptoms persisted, accompanied by elevated C-reactive protein levels. Imaging showed end-stage OA with joint space narrowing and increased 18F-fluorodeoxyglucose uptake in both hip joints. She underwent staged bilateral total hip arthroplasty. Intraoperative pathology showed marked synovial hyperplasia. Immunohistochemical analysis showed diffuse positivity for CD68, tumour necrosis factor-α, interleukin-6, programmed cell death protein 1, and programmed death-ligand 1, findings consistent with an immune-mediated inflammatory process superimposed on degenerative changes. Postoperatively, her hip pain and associated symptoms gradually improved, accompanied by normalisation of inflammatory markers during follow-up. Histological evidence suggests that programmed cell death protein 1/programmed death-ligand 1 blockade may locally amplify inflammation within the osteoarthritic joint. Clinicians must be vigilant regarding the potential for ICIs to rapidly worsen underlying joint disease, warranting timely surgical intervention when conservative management fails.

Purpose:Therapies for treatment of rheumatoid arthritis (RA) have shown significant improvement since the introduction of biological agents (BIO) in 2003 and Janus kinase inhibitors (JAKi) in 2013 in Japan. The rate of orthopedic surgery, including total hip arthroplasties (THA), may reflect trends in disease severity, management, and health outcomes. Materials and Methods:An analysis of data on THAs performed at our institutes for treatment of RA with BIO or non-BIO therapy from 2004 to 2021 was conducted. Results:A total of 40,328 orthopedic surgeries, including 5,938 primary THAs and 204 RA-THAs, were performed between 2004 and 2021. An increase in the annual rate of THA performed for patients undergoing orthopedic surgery was observed. The rates of THA decreased annually for patients with RA when compared to the total number of orthopedic surgeries and primary THAs performed. Conclusion:The number of THAs performed for patients with RA may show an annual decrease resulting from early and aggressive drug therapy for management of RA in the era of BIO and JAKi. However, patients with RA undergoing THA have several unmet needs, including secondary osteoarthritis, dislocation, periprosthetic joint infection, and periprosthetic fracture with osteoporosis.

Background The paradigm shift has caused in the treatment for rheumatoid arthritis (RA) before the last decade [1]. The advent of high-dose MTX and biologics has maked it possible to treat RA with early and aggressive therapy, and prevent the joint destruction [2]. Objectives To aim of this study, we investigated the joint destruction and clinical outcomes in patients with early RA every 5 years in the last decade. Methods 81 patients with early RA (within 1 year from their onset of RA) enrolled retrospectively in this study. The number of patients with early RA were 21 in 2009, 23 in 2014, and 37 in 2019, respectively. They had 17 males and 64 females. Mean age was 59 years (19-92) at the first visit to our department. The following items were investigated: age, disease duration from onset to consultation, anti-cyclic citrullinated peptide antibody (ACPA) positivity (positivity was defined as >4.5 U/ml), CRP, DAS28CRP4, medications, and modified total sharp score (mTSS) at the time of initial consultation and 1 year later. Kruskal-Wallis test was used for statistics (PASW 25 software, SPSS Institute Inc., Chicago, IL, USA, p<0.05). Results The ACPA positivity rates were 71.4% (15/21) in 2009, 78.3% (18/21) in 2014, and 78.4% (29/37) in 2019, respectively. The mean value of DAS28CRP4 was 4.7 (2.4-6.8) in 2009, 4.2 (1.2-6.2) in 2014, and 4.2 (2.1-6.7) in 2019 at the time of the first visit to our department respectively. DAS28CRP4 under 2.6 was 29% (6/21) in 2009, 61% (14/23) in 2014, and 54% (20/37) in 2019 1 year after the first visit. The mean improvement of DAS28CRP4 (ΔDAS28CRP4) was -1.2 (-3.9 - 2.1) in 2009, -1.5 (-4.0 - 1.7) in 2014, and -1.7 (-4.1 - 0.4) in 2019, respectively. It had tended to improve gradually, however, it was not significantly different ( p = 0.20, Figure 1). Figure 1. Mean value of improvement of mTSS and DAS28CRP4 (ΔmTSS and ΔDAS28CRP4) from initial visit to 1 year later at 2009, 2014 and 2019. The changing of mTSS for a year (ΔmTSS) was 4.2 (0-17) in 2009, 0.9 (0-10) in 2014, and 0.6 (0-4) in 2019, respectivly. ΔmTSS in 2014 and 2019 was significantly lower compared to that in 2009 ( p <0.05, Figure 1). One year after the first visit to our department, the mean dose of MTX increased to 9.2 mg/week (2-14) in 2014 and 8.7 mg/week (4-16) in 2019 compared to 6.6 mg/week (2-8) in 2009 ( p =0.19). The mean dose of PSL decreased 4.2 mg/day (1-8) in 2014, and 3.8 mg/day (1-10) in 2019 compared to 4.9 mg/day (2-10) in 2009, respectively ( p =0.11). On the other hand, biological DMARDs were introduced in 24% (5/21) in 2009, 13% (3/23) in 2014, and 13% (1/37) in 2019, respectively. Conclusion Jonit destruction has been already reported to begin in patients with early-stage of RA [1, 2]. Based on the results of this study, joint desctruction in early RA was decreased in the last decade, because of more early and aggressive therapy for early RA with increasing mean dose of MTX gradually, not biologic DMARDs in real world. In addition, the mean dose of PSL in 2014 and 2019 decreased compared to that in 2009. The intensive therapy for early RA at our hospital has shown the improvement of joint destruction in the last decade. References [1]Emery P, Breedveld FC, Dougados M, et al. Early referral recommendation for newly diagnosed rheumatoid arthritis: evidence based development of a clinical guide. Ann Rheum Dis 2002;61:290–297. [2]Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020;79:685-699. Disclosure of Interests None declared

Background: Rheumatoid arthritis (RA) is a disease that can cause joint destruction and multiple arthritis. We retrospectively investigated bone and joint destruction during the perinatal period in adult patients with RA and juvenile idiopathic arthritis (JIA) in our hospitals in the last decade. Methods: The study included 15 women, with 20 pregnancies, 19 childbirths, and one fetal death recorded between 2009 and 2018. We analyzed patient characteristics, disease activity, the modified total Sharp score (mTSS), and Delta mTSS from prepregnancy to delivery and from delivery to one year after delivery in the biologics (BIO) group (biologics used before pregnancy) and non-BIO group (not using biologics). Results: There were five preterm births and seven low-birth-weight infants. The Clinical Disease Activity Index (CDAI) before pregnancy and postdelivery worsened from 12 +/- 1.8 to 19.9 +/- 2.7 (p<0.05). The mTSS at prepregnancy and postdelivery was 47.7 +/- 12.2 and 57.3 +/- 11.1 in the BIO group, respectively, and 58.9 +/- 11.9 and 75.0 +/- 13.1 in the non-BIO group, respectively. In addition, the Delta mTSS value from prepregnancy to delivery and from delivery to one year after delivery was 14.5 +/- 4.8 and 9.2 +/- 1.7 in the BIO group, respectively (p<0.05), and 16.1 +/- 5.2 and 8.3 +/- 4.0 in the non-BIO group, respectively. Conclusion: The disease activity worsened, and bone and joint destruction progressed in both the BIO and non-BIO groups during the perinatal period in adult patients with RA and JIA in the last decade.

Atypical femoral fractures (AFFs) have been correlated with long-term use of bisphosphonates (BPs), glucocorticoids (GCs), and femoral geometry. We investigated the incidence and characteristics of subtrochanteric (ST) and diaphyseal (DP) AFFs in all institutes in a super-aging prefectural area. We performed a blinded analysis of radiographic data in 87 patients with 98 AFFs in all institutes in Yamagata prefectural area from 2009 to 2014. Among the 98 AFFs, 57 AFFs comprising 11 ST fractures in 9 patients and 46 DP fractures in 41 patients with adequate medical records and X-rays were surveyed for time to bone healing and geometry. Of the 87 patients, 67 received BPs/denosumab (77%) and 10 received GCs (11%). Surgery was performed in 94 AFFs. Among 4 AFFs with conservative therapy, 3 required additional surgery. In univariate regression analyses for ST group versus DP group, male-to-female ratio was 2/7 versus 1/40, mean age at fracture was 58.2 (37–75) versus 78 (60–89) years, rheumatic diseases affected 55.5% (5/9) versus 4.9% (2/41), femoral lateral bowing angle was 1.7 (0–6) versus 11.8 (0.8–24)°, GC usage was 67% (6/9) versus 4.9% (2/41), and bone healing time was 12.1 (6–20) versus 8.1 (3–38) months (p < 0.05). In multivariate analyses, higher male-to-female ratio, younger age, greater proportion affected by rheumatic diseases, and higher GC usage remained significant (p < 0.05). The incidence of AFFs in our prefectural area was 1.43 cases/100,000 persons/year. This study suggests that the onset of ST AFFs have greater correlation with the worse bone quality, vice versa, the onset of DP AFFs correlated with the bone geometry. The developmental mechanisms of AFFs may differ significantly between ST and DP fractures.

Background: Joint-preserving surgery for the forefoot has been increasingly performed for rheumatoid arthritis (RA). We compared joint-preserving surgeries with resection arthroplasty for RA in the forefoot. Methods: Forefoot surgeries were performed on 62 toes in 42 patients with RA (men: 2; women: 40) between 2002 and 2018. Three groups were compared: PP—31 toes treated with joint-preserving surgery involving the modified Mann method for the big toe and offset osteotomy for lesser toes, PR—15 toes treated with joint-preserving surgery for the big toe and resection arthroplasty for lesser toes, and RR—16 toes treated with resection arthroplasty for all the toes. Results: The PP group had significantly higher mean scores on a scale for RA in the foot and ankle at the latest follow-up than the RR group (86 vs. 75 points; p < 0.05). Hallux valgus (angle > 20°) of the big toe at the latest follow-up recurred in 10 (32%), 9 (60%), and 16 (100%) patients in the PP, PR, and RR groups, respectively. A revision surgery was performed in one patient each in the PP and PR groups. Conclusions: Joint-preserving surgery is superior to resection arthroplasty in preventing function loss and the recurrence of hallux valgus.

Gouty tophi occur less frequently and disappear only with modern medication therapy for symptomatic or asymptomatic hyperuricaemia. However, the medication may require a long time to take effect due to the systemic urate pool associated with massive gouty tophi. We present the case of a 37-year-old woman who suffered from massive gouty tophi of both feet due to hyperuricaemia. After resection of the massive gouty tophi from her right foot and treatment with uricemia medication, the gouty tophi of her opposite foot disappeared rapidly due to reducing the patient's systemic urate pool with intensification of drug medication.

Prosthetic joint surgeries, total hip arthroplasty (THA) or bipolar hemiarthroplasty (BHA) and joint preservation surgeries can be performed for avascular osteonecrosis of femoral head (ONFH) with collapse. Although excellent surgical results have been reported, long-term survivorship and postoperative complications are a great concern. The purpose of this study was to report a case of bilateral disassembly of bipolar heads within 10 years after BHA for ONFH. A 61-year-old man, whose occupation was carpenter, underwent bilateral BHA for ONFH at another hospital when he was 57 years old. He had acute right hip pain during working and visited our institute. Radiographs revealed intra-articular (outer and inner head) disassembly of the right bipolar head, and conversion to THA was performed. Five years later, he had contralateral (left) hip pain. Radiographs revealed disassembly of bipolar head, as had occurred with the right hip, and similar conversion surgery was performed for the left hip. Marked wear and detachment of the polyethylene bearings of the outer head and failure of the locking mechanism between a skirted 22-mm-diameter inner head and polyethylene insert were observed in both hips at each revision surgery. Degeneration of the acetabulum were also observed in both hips. The failure of the self-centering mechanism because of degenerative change of the acetabulum, impingement of the outer head and neck, and high activity seemed to be the causes of disassembly of the bilateral bipolar heads. Therefore, it is important to select the type of prostheses depending on the age, activity and occupation of each patient.

Podoplanin (PDPN) is a transmembrane sialoglycoprotein, which is expressed in several normal tissues and malignant tumors. Although PDPN expression in rheumatoid arthritis (RA) has been reported, the role of PDPN in RA and other arthritic conditions has not been fully elucidated. In this study, we examined PDPN expression in inflammatory synovial tissues using an anti-human PDPN (hPDPN) monoclonal antibody (mAb) panel to select the most useful one for evaluation of synovitis. Synovial tissue samples were obtained from 11 RA patients and 9 osteoarthritis (OA) patients undergoing joint surgery. PDPN-positive cells were immunostained by a panel of PDPN mAbs (NZ-1, LpMab-3, LpMab-7, LpMab-10, LpMab-12, LpMab-13, and LpMab-17), followed by cell grading of inflammation and cell counting of PDPN-positivity by a quantitative analyzer. Immunohistochemistry showed that PDPN was markedly expressed in both macrophage-like type A and fibroblast-like type B lining cells of the hyperplastic synovial lining cell layer, and macrophages and fibroblasts in the stroma of RA. Among anti-PDPN mAbs, LpMab-12 showed the highest score. In inflammatory OA synovium, PDPN expression was also detectable. Although LpMab-12 also showed the highest score in OA, the difference was not statistically significant. The inflammatory synovitis score of RA was significantly higher than that of OA. PDPN was expressed in inflammatory lining cells and sublining stroma of RA and OA synovium. In the seven anti-hPDPN antibodies examined, LpMab-12 was the most stainable antibody for PDPN in RA synovitis. Thus, LpMab-12 for PDPN has a possible and promising specific biomarker for evaluating synovitis in RA and inflammatory OA.

Telomerase reverse transcriptase (TERT) is important for the biology of diffuse gliomas. TERT promoter mutations are selectively observed among 1p/19q-codeleted oligodendrogliomas and isocitrate dehydrogenase gene- (IDH-) wildtype glioblastoma (GBM). However, TERT transcripts range widely in various cancers including gliomas, and TERT protein expression has been rarely investigated thus far. It would be thus critical to examine the expression level of TERT in tumors in addition to its mutational status, and sensitive and specific methods are urgently needed to examine TERT protein expression for the assessment of TERT biology in gliomas. Using our newly developed TERT-specific monoclonal antibody (TMab-6) applicable to human tissue, we found an unexpected increase in TERT expression in TERT-wildtype as well as TERT-mutated gliomas and in tumor vasculature. This is the first extensive analysis on the expression of TERT immunoreactivity in human glioma tissue, suggesting that TERT protein expression may be regulated by several mechanisms in addition to its promoter mutation.

Background Increasing of remission reached by biologics agents in early and established RA patients1, 2. Data on withdrawn, spacing or reducing of biologics (BIO) medication after sustained remission are limited3,4. After withdrawn, spacing or reducing, it is less known to be influenced the radiographic destruction of the joints. Objectives To retrospectively analyse the joint destruction using modified Total Sharp Score (mTSS) in RA patients in sustained remission, either withdrawing, spacing and continuing BIO. Methods Local prefectural (ZAO) registry which is open-labelled BIO cohort study has registered 356 RA patients. RA Patients were enrolled into this study if they maintained in DAS remission (DAS28-ESR<2.6) more than one year after starting BIO. ΔmTSS1 was estimated between starting BIO and withdrawn or spacing or reaching remission in each group, ΔmTSS2 between the beginning of withdrawn or spacing, or reaching remission in continuing group and latest follow-up or flare-up. Results 40 RA patients (32 female) using BIO was fulfilled in the criteria of this study in ZAO registry. Of 40 RA Patients, 10 has withdrawn BIO, 15 has spaced and 15 has continued it after maintain DAS remission more than one year. Mean age was 43, 55, 54 year-old, mean RA affiliation 4.6, 15.3, 9.1 years before BIO and mean duration of remission 6.2, 7.6, 7 years, mean dosage of MTX and PSL was 7.7, 6, 5 mg/week and 1.1, 3, 4 mg/day, respectively. ΔmTSS1 and ΔmTSS2 was +2.4 and+4.5 in withdrawn group,+3.6 and+0.9 in spacing group,+0.2 and −1.4 in continuing group, respectively (figure 1, p<0.05). Five cases in withdrawing group had resumed BIO because of flare-up of their disease activity. Conclusions Several studies reported the potential of BIO withdrawing, spacing or reducing in the patients with RA who reached remission3), 5). All cases in spacing and withdrawing group have shown DAS28–4ESR<2.6 in this study, however, 50% (5/10 cases) in withdrawing group have re-flare and shown the radiological joint destruction. Spacing or reducing of BIO may have potential to maintain the remission of RA and prevent the joint destruction. Withdrawing of BIO after even sustained deeper remission may be difficult to keep real remission. References [1] O’Dell JR. Arthritis Rheum2002;46:283–85. [2] Smolen JS, et al. Ann Rheum Dis2017;76:960–77. [3] Tanaka Y, et al: Ann Rheum Dis2015;74:389–95. [4] Takeuchi T, et al: Ann Rheum Dis2014;73:536–43. [5] Fautrel B, et al. Ann Rheum Dis2016;75:59–67. Acknowledgements Disclosure of Interest None declared

ObjectivesBiologic agents (BIO) drastically changed the rheumatoid arthritis (RA) therapy from starting to use biologics at 2003 in Japan. The rate of orthopaedic surgery, especially total joint arthroplasty (TJA) may reflect trends in disease severity, management and health outcomes.MethodsWe surveyed the number and rate of orthopaedic surgeries and TJA in RA treatment with BIO in the last decade, so called BIO-era.ResultsWe had 18,701 cases of orthopaedic surgeries, including 491 rheumatoid surgeries from 2004 to 2013. They contained 382 cases of total joint arthroplasties (78%), including 258 total knee arthroplasty (TKA), 80 total hip arthroplasty (THA), 18 total elbow arthroplasty (TEA), 14 total ankle arthroplasty (TAA), 4 swanson arthroplasty for fingers. The numbers of orthopaedic surgery increased year by year. The rate of rheumatoid surgeries not changed in the last decade (r=0.8, p<0.05, Fig. 1). The numbers of TSA and TEA in 2009–2013 increased twice compared to them in 2004–2008, but TKA and ...

IntroductionMacrophages phagocytes implant wear debris and produce various cytokines to evoke inflammation and periprosthetic osteolysis of aseptic loosening. It had been reported that expression of Toll-like receptor (TLR) 2 and other TLRs increased in periprosthetic tissues of aseptic loosening. Pathogen-associated molecular patterns (PAMPs) and damaged-associated molecular patterns (DAMPs) have been known as ligands of TLRs and considered to be involved in the osteolytic reactions via TLRs. Another type of immune sensors, nucleotide-binding and oligomerization domain (NOD)-like receptors (NLR) with a pyrin domain 3 (NLRP3) can also recognize PAMPs and DAMPs as their lignds, which has been presumed to participate in the local host response of macrophage cascade via phagocytosis of implant wear particles. However, the contribution of NLRP3 in periprosthetic tissues of aseptic loosening and the correlation between TLR2 and NLRP3 are still unclear.Materials and methodsTLR1, TLR2, TLR6, NLRP3, TNF-α and IL-...

BackgroundA navigation system is useful tool to evaluate the intraoperative knee kinematics. Rheumatoid arthritis (RA) patients often need to have TKA operation, however, there are few TKA kinematics studies comparing RA and Osteoarthritis (OA) patients.ObjectiveThe purpose of this study was to evaluate intraoperative TKA kinematics, and to describe the difference of kinematics between RA and OA patients.Materials and methodsSeventy-four patients, 86 knees were included in this study. Unilateral posterior stabilized TKAs were performed (male 14, female 72, age 70 ± 1.1 years) using navigation system. Sixty-one knees had OA and 25 had RA. Evaluation items are coronal gaps, AP translation and rotation. Coronal gaps were defined as the distance between the femoral and tibial cut surface. Medial and lateral gaps are also measured. AP translation was defined as the sagittal movement between the center of femoral and tibial condyle. Rotation was defined as axial difference of axis between femur and tibia. All i...

IntroductionPatients undergoing total hip arthroplasty (THA) stand in the danger, a particularly high risk for venous thromboembolism (VTE). Fondaparinux and edoxaban, which inhibit FXa, indirectly and directly, respectively, have been used for prevention of VTE after THA in Japan. The aim of this study was to compare the efficacy of fondaparinux and edoxaban for VTE after elective THA in Japanese patients.Materials and methodsWe randomly assigned 320 patients underdoing elective cemented THA to receive postoperative 2.5 mg fondaparinux once daily for first postoperative 3 days and 1.5 mg once daily for the subsequent 7 days (FPX group) [1], postoperative 15 mg edoxaban once daily for postoperative 10 days (EDO15mg group), 30 mg edoxaban once daily for postoperative 10 days (EDO30mg group), and 30 mg edoxaban once daily for first postoperative 3 days and 15 mg once daily for the subsequent 7 days (EDOmix group). Deep venous thrombosis (DVT) was diagnosed by ultrasonography at postoperative day 3 and 14. C...