The assessment of canal flare index and proximal femoral bone density can improve stem selection for peri-prosthetic bone maintenance after total hip arthroplasty.

INTRODUCTION: Bone maintenance after total hip arthroplasty (THA) is important for implant success. This study aimed to investigate the relationship between patient characteristics and periprosthetic bone maintenance after THA for better implant selection. MATERIALS AND METHODS: This retrospective cohort study enrolled 112 consecutive patients who underwent THA using full hydroxyapatite (HA) compaction with short (n = 55) or short-tapered wedge (n = 61) stems. Periprosthetic bone mineral density (BMD) was compared between the two groups after propensity score matching, and the relationship between periprosthetic BMD changes and patient background was analyzed. RESULTS: Both groups showed similar periprosthetic BMD changes after adjusting for patient background using propensity score matching. Canal flare index > 3.7 in patients that underwent THA using tapered-wedge stem (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.3-7.9, p = 0.013) and baseline zone 1 BMD > 0.65 in patients that received with short HA compaction stems (OR, 430.0; 95% CI 1.3-1420, p = 0.040) were associated with proximal periprosthetic bone maintenance after THA. CONCLUSION: Considering their predictive value, canal flare index and zone 1 BMD assessment might be useful strategies for implant selection during THA.

Predictive factors and treatment outcomes associated with difficult-to-treat rheumatoid arthritis conditions: the ANSWER cohort study.

OBJECTIVES: To investigate the predictive factors for difficult-to-treat rheumatoid arthritis (D2T RA) and assess the efficacy of biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi). METHODS: Retrospective analysis was conducted on data from the ANSWER cohort comprising 3,623 RA patients treated with bDMARDs or JAKi in Japan. Multivariate Cox proportional hazards modelling was used to analyse the hazard ratios (HRs) for treatment retention. RESULTS: Of these, 450 (12.4%) met the first two criteria of EULAR D2T RA definition (defined as D2T RA in this study). Factors contributing to D2T RA included age over 75 (compared to those under 65, HR = 0.46, 95% CI: 0.31 to 0.69), higher rheumatoid factor (RF) titres (HR = 1.005, 95% CI: 1.00 to 1.01), higher clinical disease activity index (HR = 1.02, 95% CI: 1.01 to 1.03), lower methotrexate dosage (HR = 0.97, 95% CI: 0.95 to 0.99), and comorbidities like hypertension (HR = 1.53, 95% CI: 1.2 to 1.95) and diabetes (HR = 1.37, 95% CI: 1.09 to 1.73). Anti-interleukin 6 receptor antibodies (aIL-6R, HR = 0.53, 95% CI: 0.37 to 0.75) and JAKi (HR = 0.64, 95% CI: 0.46 to 0.90) were associated with fewer discontinuations due to ineffectiveness compared to tumour necrosis factor inhibitors. Oral glucocorticoids usage (HR = 1.65, 95% CI: 1.11 to 2.47) was linked to increased discontinuation due to toxic adverse events. CONCLUSION: Younger onset, higher RF titres, and comorbidities predicted D2T RA development. For managing D2T RA, aIL-6R and JAKi exhibited superior drug retention.

Krüppel-like factor 15 deficiency exacerbates osteoarthritis through reduced expression of peroxisome proliferator-activated receptor gamma signaling in mice.

OBJECTIVE: Krüppel-like zinc finger transcription factors (KLFs) play diverse roles in mammalian cell differentiation and development. In this study, we investigated the function of KLF15 in the progression of osteoarthritis (OA). METHODS: 0Destabilization of the medial meniscus (DMM) surgery was performed in 10-week-old male wild-type control (WT) mice and cartilage-specific KLF15 knockout (KO) mice. Histological analysis, immunohistochemistry, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining were performed. Morphological changes were measured using microcomputed tomography. Six mice from each group were analyzed (total number of mice analyzed: 60). In vitro, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blot analyses were performed. RESULTS: KLF15 KO DMM mice exhibited significant cartilage degradation compared to WT mice. According to the Osteoarthritis Research Society International cartilage OA-histopathology scoring system, the mean sum score in KLF15 KO mice was significantly higher than that in WT mice at 8 weeks after surgery. Immunohistochemistry results revealed KLF15 KO mice exhibited reduced peroxisome proliferator-activated receptor gamma (PPARγ) expression, increased pIKKα/ß, a disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTS) 5, and Matrix metalloproteinases (MMP13) expression, and reduced Forkhead box O (FOXO1) and Light chain 3B (LC3B) expression. Inhibition of PPARγ phosphorylation accelerated the effects of interleukin (IL) 1ß-treatment in both KLF15 KO and WT chondrocytes, and activation of PPARγ expression canceled the IL1ß-induced catabolic effects. CONCLUSION: Our results indicated that the OA phenotype of KLF15 KO DMM mice was influenced by reduced PPARγ expression, including enhanced pIKKα/ß, ADAMTS5, and MMP13 expression, reduced autophagy, and increased apoptosis. KLF15 regulation may constitute a possible therapeutic strategy for the treating OA.

Real-world comparative study of the efficacy of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study.

OBJECTIVE: This multicentre, retrospective study compared the efficacy and safety of tofacitinib, baricitinib, peficitinib and upadacitinib in real-world clinical settings after minimizing selection bias and adjusting the confounding patient characteristics. METHOD: The 622 patients were selected from the ANSWER cohort database and treated with tofacitinib (TOF), baricitinib (BAR), peficitinib (PEF) or upadacitinib (UPA). The patient's background was matched using propensity score-based inverse probability of treatment weighting (IPTW) among four treatment groups. The values of Clinical Disease Activity Index (CDAI), C-reactive protein (CRP), and modified Health Assessment Questionnaire (mHAQ) after drug initiation and the remission or low disease activity (LDA) rates of CDAI at 6 months after drug initiation were compared among the four groups. Further, the predictive factor for TOF and BAR efficacy was analysed. RESULTS: The retention and discontinuation rates until 6 months after drug initiations were not significantly different among the four JAK inhibitors treatment groups. Mean CDAI value, CDAI remission rate, and CDAI-LDA rate at 6 months after drug initiation were not significantly different among treatment groups. Baseline CDAI (TOFA: OR 1.09, P < 0.001; BARI: OR 1.07, P < 0.001), baseline CRP (TOFA: OR 1.32, P = 0.049), baseline glucocorticoid dose (BARI: OR 1.18, 95% CI 1.01-1.38, P = 0.035), a number of previous biological or targeted synthetic disease-modifying antirheumatic drugs (biological/targeted synthetic DMARDs) (BARI: OR 1.36, P = 0.004) were predictive factors for resistance to CDAI-LDA achievement to JAK inhibitor treatment. CONCLUSION: The efficacy and safety of TOF, BAR, PEF and UPA were not significantly different for the treatment of patients with rheumatoid arthritis.

Drug retention of biologics and Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study.

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.

Comparison study of periprosthetic bone remodeling between simultaneous bilateral total hip arthroplasty and unilateral total hip arthroplasty: a matched cohort study.

PURPOSE: The load-bearing pattern of periprosthetic bone may differ between patients who underwent simultaneous bilateral and unilateral total hip arthroplasty (THA). We investigated the differences in periprosthetic bone remodeling after simultaneous bilateral total hip arthroplasty and unilateral total hip arthroplasty. METHODS: This retrospective cohort study enrolled 154 consecutive patients undergoing THA using full hydroxyapatite (HA) compaction short stems. Patient characteristics including age, body mass index, University of California Los Angeles (UCLA) activity score, and bone shape of the proximal femur were adjusted by propensity score matching. Subsequently, periprosthetic bone mineral density changes were compared between simultaneous bilateral and unilateral THA. RESULTS: We found that bone mineral density loss in the simultaneous bilateral THA group was significantly higher in zones 6 and 7 at 24 months after THA (zone 6, p = 0.019; zone 7, p = 0.041). Periprosthetic bone mineral density loss was not associated with clinical factors, including age, body mass index, and daily activity. Additionally, we demonstrated that periprosthetic bone mineral density loss was higher in zones 1, 4, 6, and 7 of patients with a normal hip on the contralateral side after unilateral THA (zone 1, p = 0.041; zone 4, p = 0.041; zone 6, p = 0.037; zone7, p = 0.019). CONCLUSIONS: The postoperative periprosthetic bone remodeling was lower in patients who underwent simultaneous bilateral THA than in those who underwent unilateral THA, even though patient characteristics were adjusted by propensity matching. Further observation of periprosthetic bone mineral density loss is needed to clarify the differences between the groups.

Heterogeneous Cells as well as Adipose-Derived Stromal Cells in Stromal Vascular Fraction Contribute to Enhance Anabolic and Inhibit Catabolic Factors in Osteoarthritis.

The stromal-vascular fraction (SVF), comprising heterogeneous cell populations and adipose-derived stromal cells (ADSCs), has therapeutic potential against osteoarthritis (OA); however, the underlying mechanism remains elusive. This study aimed to investigate the therapeutic effects of heterogeneous cells in rabbit SVF on rabbit chondrocytes. Rabbit SVF and ADSCs were autografted into knees at OA onset. The SVF (1 × 105) and low-dose ADSCs (lADSC; 1 × 104) groups adjusted for their stromal cell content were compared. Animals were euthanized 8 and 12 weeks after OA onset for macroscopic and histological analyses of OA progression and synovitis. Immunohistochemical and real-time polymerase chain reaction assessments were conducted. In vitro, immune-fluorescent double staining was performed for SVF to stain macrophages with F4/80, CD86(M1), and CD163(M2). OA progression was markedly suppressed, and synovitis was reduced in the SVF groups (OARSI histological score 8 W: 6.8 ± 0.75 vs. 3.8 ± 0.75, p = 0.001; 12 W: 8.8 ± 0.4 vs. 5.4 ± 0.49, p = 0.0002). The SVF groups had higher expression of collagen II and SOX9 in cartilage and TGF-ß and IL-10 in the synovium, lower expression of MMP-13, and lower macrophage M1/M2 ratio than the lADSC groups. Immunofluorescent double staining revealed a markedly higher number of M2 than that of M1 macrophages in the SVF. The therapeutic effects of SVF on chondrocytes were superior than those of lADSCs, with enhanced anabolic and inhibited catabolic factors. Heterogeneous cells, mainly M2 macrophages in the SVF, enhanced growth factor secretion and chondrocyte-protective cytokines, thus benefiting chondrocytes and knee joint homeostasis. Overall, the SVF is a safe, relatively simple, and a useful treatment option for OA.

Targeting the neutral hip-to-calcaneus axis in kinematically aligned total knee arthroplasty is feasible with fewer alignment outliers for varus osteoarthritic patients.

PURPOSE: Assessment of the conventional mechanical axis (MA) (hip-to-talus axis) is reported to result in constitutional varus in the native knee. However, the ground MA (hip-to-calcaneus axis), which is the line from the hip center to the bottom of the calcaneus, passes through the center of the knee joint in the native knee and is a possible alternative target for total knee arthroplasty (TKA) assessments. Therefore, this study aimed to present a "ground kinematically aligned (KA)-TKA." In this technique, the femoral component is placed on the cylindrical axis using the calipered technique and the tibial component is placed to give a neutral ground MA. Radiographical investigation was used to determine whether physiological alignment can be individually achieved with ground KA-TKA; this was compared with that of a tibia-restricted modified KA-TKA, referring to conventional MA (hip-to-talus axis) results. METHODS: As the primary endpoint, this prospective cohort study compared the ground MA ratios of the knee joints in 40 ground KA-TKAs (G group: Coronal Plain Alignment of the Knee (CPAK) 28 type I, 7 II, 1 IV, and 4 V) with those of the preceding 60 modified KA-TKAs (M group: CPAK 46 type I, 12 II, and 2 V) performed for patients with varus osteoarthritis (OA). The number of outliers differing over ± 5% from the neutral were compared between groups using the χ2-test. The Hip-knee-ankle (HKA) angle, coronal femoral/tibial component alignment (FCA/TCA), and joint line orientation angle (JLOA) were compared between the groups using non-paired t-tests. Statistical significance was set at p < 0.05. RESULTS: The G group had a higher ratio of the ground MA passing through the knee center than the M group did; outliers differing over ± 5% from the neutral of the ground MA were 2/40 cases in the G group and 20/60 cases in the M group, which was a significant difference (p = 0.001). The HKA angle, FCA/TCA, and JLOA were not significantly different between the groups. CONCLUSIONS: Targeting the ground MA in KA-TKA for patients with varus OA was feasible and has the potential to provide a physiological alignment more similar to the native knee in TKA than other kinematic alignment techniques. LEVEL OF EVIDENCE: Level III.

Polyarthritis presented in a patient with untreated chronic hepatitis B infection.

Hepatitis B virus (HBV) infection can cause arthritis, but it is rarely reported. In the current report, we present a case of chronic polyarthritis in a patient with untreated HBV infection. A 63-year-old woman suffering from polyarthritis in her fingers visited our institution. She had experienced exacerbations and remissions of polyarthritis for more than 20 years. She had been diagnosed with rheumatoid arthritis and had been treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and nonsteroidal anti-inflammatory drugs by her primary care doctor, but the csDMARDs were discontinued at the request of the patient 10 years before the first visit to our hospital. The blood test showed negative for rheumatoid factor and anticyclic citrullinated peptides antibody but positive for hepatitis B surface antigen. Hepatitis B surface antigen and HBV-Deoxyribo Nucleic Acid (DNA) were increased to 312.6 (IU/ml) and 4.6 (log copies/ml), respectively. Based on the results of abdominal computed tomography and echography, she was diagnosed with liver cirrhosis. Treatment for HBV infection was begun with oral tenofovir at 25 mg/day. The polyarthritis in her fingers gradually disappeared and has not relapsed for 6 months after the initiation of treatment for HBV infection. When polyarthritis is diagnosed, the possibility that chronic HBV infection can be one of the causes of polyarthritis should be considered.

Comparison of the inhibitory effect of tocilizumab and etanercept on the progression of joint erosion in rheumatoid arthritis treatment.

We compared the efficacy of tocilizumab and etanercept in inhibiting radiographic progression of joint destruction in rheumatoid arthritis. Overall, 187 patients treated with etanercept or tocilizumab were selected. To adjust for baseline patient characteristics between the tocilizumab and etanercept treatment groups, a propensity score matching was performed. Radiographic progression of joint destruction was compared between patients treated with tocilizumab or etanercept. Clinical disease activity index (CDAI) and modified health assessment questionnaire (mHAQ) scores at the administration of biologic treatment and after 12 months of tocilizumab and etanercept therapy were measured and compared to radiographical parameters between the groups. Levels of C-reactive protein (CRP), matrix metalloproteinase-3 (MMP-3), CDAI, and mHAQ scores improved after 12 months of treatment in the two groups. Proportion of patients with no Sharp erosion score progression was significantly higher with tocilizumab treatment than with etanercept treatment (p = 0.032). Multivariate analysis demonstrated that Sharp erosion score was significantly associated with baseline CDAI (odds ratio, 1.05; 95% confidence interval, 1.003-1.099, p = 0.037). Tocilizumab treatment suppressed joint erosion progression compared to etanercept, and the progression correlated with baseline CDAI.

P21 deficiency exhibits delayed endochondral ossification during fracture healing.

INTRODUCTION: Endochondral ossification is a complex biological phenomenon involving a variety of factors and cells. Cyclin-dependent kinase inhibitor 1 (p21) inhibits cell cycle progression and is affected by external stress. We recently reported that embryonic endochondral ossification is unaffected by endogenous p21 deficiency. In this study, we evaluated whether p21 expression affects endochondral ossification during fracture healing. METHODS: Tibial fractures were introduced into p21 knockout (p21-/-) (n = 24) and wild-type C57BL/6 (p21+/+) (n = 24) mice at age 10 weeks. Fracture healing was evaluated using radiological, histological, and immunohistochemical (IHC) analyses. The effect of p21 small interfering RNA (siRNA) on ATDC5 cells was assessed in vitro. RESULTS: The Allen score for fracture healing was lower in p21-/- mice than in p21+/+ mice. In addition, p21-/- mice exhibited larger calluses and lower bone mineral density. IHC analyses showed that p21-/- mice exhibited delayed endochondral ossification via the Ihh-Runx2-Osterix pathway in vivo. Down-regulation of p21 expression in ATDC5 cells delayed endochondral ossification in vitro. CONCLUSIONS: p21 deficiency leads to delayed endochondral ossification by attenuating the Ihh-Runx2-Osterix pathway in vivo, and p21 deficiency in hypertrophic chondrocytes causes delayed differentiation of hypertrophic chondrocytes in vitro. p21 plays a role in endochondral ossification during fracture healing.

Paracrine effect of the stromal vascular fraction containing M2 macrophages on human chondrocytes through the Smad2/3 signaling pathway.

The adipose-derived stromal vascular fraction (SVF) is composed of a heterogeneous mix of adipose-derived stem cells (ADSCs), macrophages, pericytes, fibroblasts, blood, and other cells. Previous studies have found that the paracrine effects of SVF cells may be therapeutic, but their role in osteoarthritis treatment remains unclear. This study aimed to investigate the therapeutic effect of SVF cells on chondrocytes. Chondrocytes were seeded on culture plates alone (control) or cocultured with SVF or ADSCs on cell culture inserts. After 48 h of coculture, chondrocyte collagen II, tissue inhibitors of metalloproteinases-3 (TIMP-3), and matrix metalloproteinases-13 (MMP-13) messenger RNA (mRNA) expression levels were evaluated using reverse-transcription polymerase chain reaction, and the transforming growth factor-ß (TGF-ß) levels in the supernatant were measured using ELISA. Immunohistochemical staining and flow cytometry were used to evaluate the macrophages in the SVF. These macrophages were characterized according to phenotype using the F4/80, CD86, and CD163 markers. To determine whether the Smad2/3 signaling pathways were involved, the chondrocytes were pre-treated with a Smad2/3 phosphorylation inhibitor and stimulated with the SVF, and then Smad2/3 phosphorylation levels were analyzed using western blot. The mRNA expression levels of various paracrine factors and chondrocyte pellet size were also assessed. Collagen II and TIMP-3 expression were higher in the SVF group than in the ADSC group and controls, while MMP-13 expression was the highest in the ADSC group and the lowest in the controls. TGF-ß levels in the SVF group were also elevated. Immunohistochemical staining and flow cytometry revealed that the macrophages in the SVF were of the anti-inflammatory phenotype. Western blot analysis showed that the SVF increased Smad2/3 phosphorylation, while Smad2/3 inhibitors decreased phosphorylation. Smad2/3 inhibitors also reduced the expression of various other paracrine factors and decreased chondrocyte pellet size. These findings suggested that the paracrine effect of heterogeneous cells, such as anti-inflammatory macrophages, in the SVF partly supports chondrocyte regeneration through TGF-ß-induced Smad2/3 phosphorylation.

Evaluation of consistency of patient-satisfaction score in the 2011 Knee Society Score to other patient-reported outcome measures.

BACKGROUND: Patient-reported outcome measures (PROMs) are important aspects of evaluating clinical outcomes after total knee arthroplasty (TKA). The patient-satisfaction score in the 2011 Knee Society Score (KSS) is one of the most frequently used questionnaires; however, patient satisfaction is a subjective assessment and is affected by multiple factors. Therefore, we evaluated correlations between the patient-satisfaction score in the 2011 KSS and that of other categories of the 2011 KSS as well as other PROMs. Furthermore, the ceiling effects of each PROMS were also investigated. METHODS: We enrolled 85 patients aged ≥65 years who underwent cruciate retaining TKA. Patients completed various questionnaires, including the 2011 KSS, Forgotten Joint Score-12 (FJS-12), EuroQol 5 Dimension (EQ-5D), and Geriatric Locomotive Function Scale (GLFS-25), one year after TKA. Simple linear regression analysis was used to evaluate correlations between each PROM and the patient-satisfaction score in the 2011 KSS. Ceiling effects of the patient-satisfaction score in the 2011 KSS, FJS-12, EQ-5D and GLFS-25 were evaluated by comparing the number of patients categorized into the top 10% with each PROM. RESULTS: All scores were significantly correlated (p < 0.001) with the patient-satisfaction score in the 2011 KSS (symptoms: r = 0.69, functional activities: r = 0.69, patient expectations: r = 0.73, FJS-12: r = 0.72, EQ-5D: r = 0.67, GLFS-25: r = -0.74). The patient-satisfaction score in the 2011 KSS and GLFS-25 showed a ceiling effect. On the other hand, this effect was not observed in the results of the FJS-12 and EQ-5D. CONCLUSIONS: The patient-satisfaction score in the 2011 KSS correlated with other PROMs, and the indicated level of satisfaction was consistent. The results of the FJS-12 and EQ-5D had good positive correlation to patient satisfaction without ceiling effect.

Approximately 30% of Functioning Anterior Cruciate Ligaments Are Sacrificed for Knee Arthroplasty.

The anterior cruciate ligament (ACL) plays an important role in knee kinematics. Unicompartmental knee arthroplasty (UKA) preserves the ACL, an advantage over total knee arthroplasty (TKA), where it is sacrificed. This study aims to evaluate how often functional ACLs are sacrificed in arthroplasty. The type of arthroplasty (TKA or UKA) and condition of the ACL were studied in a total of 1,586 knees in 1,052 patients who underwent knee arthroplasties. Of 1,586 knees, TKA was performed on 653 knees (41%) and UKA on 933 knees (59%). The ACL was functioning in 77% of all knees. Of the TKA knees, the ACL was functioning in 357 knees (55%). Of these, around 30% of the functioning ACLs were sacrificed to perform TKA. To improve postoperative patient satisfaction after knee arthroplasty, further study regarding relationship between ACL preservation and clinical outcome will be required.