Safety of Janus kinase inhibitors compared to biological DMARDs in patients with rheumatoid arthritis and renal impairment: the ANSWER cohort study.

Data on the safety of Janus kinase inhibitors (JAKis) in patients with renal impairment are lacking. This study aimed to investigate the safety of JAKis compared to biological (b) DMARDs in patients with rheumatoid arthritis (RA) and renal impairment. We used a multi-centre observational registry of patients with RA in Japan (the ANSWER cohort). We assessed the drug retention rates of b/targeted synthetic DMARDs with different modes of action (tumour necrosis factor inhibitors (TNFis), immunoglobulins fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), interleukin-6 receptor inhibitors (IL-6Ris), and JAKis) in patients with RA stratified by pre-treatment estimated glomerular filtration rate (eGFR) levels. The time to discontinuation of bDMARDs or JAKis was analysed using a multivariate Cox proportional hazards model This study included 3775 patients, who were classified into three groups (the normal group (eGFR ≥ 60 mL/min/1.73 m2): 2893 patients; CKDa group (eGFR 45-60 mL/min/1.73 m2): 551; and CKDb group (eGFR < 45 mL/min/1.73 m2): 331). In the CKDb group, the 12-month drug retention rate due to adverse events (AE) was the lowest in patients treated with JAKi (TNFi: 93.1%; IL-6Ri: 94.1%; CTLA-4-Ig: 92.3%; JAKi: 75.1%). In the normal and CKDa groups, drug retention rates due to AE were similar among patients treated with bDMARDs and JAKi. In contrast, drug retention rates due to inefficacy were similar between bDMARDs and JAKis in all groups. In the Cox-proportional model, in the CKDb group, TNFi, IL-6Ri, and CTLA-4-Ig showed lower incidence of drug discontinuation due to AE than JAKis (TNFi: hazard ratio = 0.23 (95% confidence interval 0.09-0.61), IL-6Ri: 0.34 (0.14-0.81), CTLA-4-Ig: 0.36 (0.15-0.89)). JAKis showed the lowest drug retention due to AE in patients with moderate-to-severe and severe renal impairment (eGFR < 45 mL/min/1.73 m2). Physicians should pay more attention to renal function when using JAKis than when using bDMARDs.

Association of large joint involvement at the start of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors with disease activity and drug retention in patients with rheumatoid arthritis: The ANSWER cohort study.

AIM: To investigate the association of large joint involvement (LJI) with disease activity and drug retention in patients with rheumatoid arthritis (RA) who started receiving a biological disease-modifying antirheumatic drug or Janus kinase inhibitor. METHODS: Patients with RA from a Japanese multicenter observational registry were enrolled. Our definition of large joints included the shoulder, elbow, hip, knee, and ankle joints. Linear mixed-effects models were used to examine changes in the clinical disease activity index (CDAI) score at Week 24 as the primary outcome, and drug retention rates were compared between patients with and without LJI using Cox proportional hazards models. We examined the potential effect modifications of changes in the CDAI by baseline characteristics. RESULTS: Overall, 2507 treatment courses from 1721 patients were included (LJI, 1744; no LJI, 763). Although LJI was associated with significantly higher changes in CDAI from baseline at Week 24 (difference in change in CDAI: -5.84 [-6.65 to -5.03], p < .001), CDAI was significantly higher in patients with LJI over time. Retention rates were similar in both groups. The association of LJI with changes in disease activity was more prominent in patients with a short disease duration, negative anti-citrullinated peptide antibodies, and interleukin-6 receptor inhibitor (IL-6Ri) use. CONCLUSION: Although LJI was associated with a greater reduction in disease activity from baseline, higher disease activity at baseline was not offset over time in patients with LJI, demonstrating that LJI is an unfavorable predictor. An early treat-to-target strategy using an IL-6Ri may be beneficial for patients with LJI.

LIGHT regulated gene expression in rheumatoid synovial fibroblasts.

BACKGROUND: Synovial hyperplasia caused by rheumatoid arthritis (RA), an autoimmune inflammatory disease, leads to the destruction of the articular cartilage and bone. A member of the tumor necrosis factor superfamily, Lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpes virus entry mediator on T cells (LIGHT) has been shown to correlate with the pathogenesis of RA. METHODS: We used cDNA microarray analysis to compare the expression of genes in rheumatoid fibroblast-like synoviocytes with and without LIGHT stimulation. RESULTS: Significant changes in gene expression (P-values < 0.05 and fold change ≥ 2.0) were associated mainly with biological function categories of glycoprotein, glycosylation site as N-linked, plasma membrane part, integral to plasma membrane, intrinsic to plasma membrane, signal, plasma membrane, signal peptide, alternative splicing, and topological domain as extracellular. CONCLUSIONS: Our results indicate that LIGHT may regulate the expression in RA-FLS of genes which are important in the differentiation of several cell types and in cellular functions.

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.

Trends of disease activity in Japanese patients over 75 years with rheumatoid arthritis from 2014 to 2021- the ANSWER cohort study.

OBJECTIVES: To investigate if disease activity among elderly RA patients over 75 years has changed over time in the real-world clinical setting. METHODS: Data from an observational multicentre registry of RA patients in Japan were analyzed. The primary outcome was to evaluate the changes in the proportion of very elderly RA patients (over 75 years) who achieved remission and low disease activity, from 2014 to 2021. The secondary outcome was to identify factors associated with remission and low disease activity by comparing demographic and clinical characteristics among the patients who had a study visit within the study period, using multivariate logistic regression. RESULTS: A total of 32 161 patient visits were identified from 2014 to 2021. The proportion of patients over 75 years increased from 16.5% to 26.9%, with biologics and targeted-synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) usage increasing and glucocorticoids usage decreasing, while conventional-synthetic DMARDs usage remained relatively stable. The proportion of RA patients over 75 years achieving remission and low disease activity significantly increased from 62.2% to 78.2% (p for trend < 0.001). A negative factor associated with achieving remission and low disease activity was glucocorticoid usage, seropositivity, and history of previous b/tsDMARDs use while MTX usage was associated positively, independent of other predictors. CONCLUSIONS: In our cohort, disease activity among very elderly RA patients has improved over time. The study suggests the importance of using a treat-to-target approach in very elderly RA patients to improve clinical outcomes.

Accuracy comparison of cup positioning during total hip arthroplasty using Hip Align and AR-Hip in the supine position.

INTRODUCTION: The aim of this study is to compare the accuracy of acetabular cup positioning between the accelerometer-based navigation system and the augmented reality-based navigation system during THA in the supine position. MATERIALS AND METHODS: This retrospective study included 66 patients (70 hips) who underwent THA using two types of portable navigation system, Hip Align or AR-Hip, in the spine position. The absolute difference between the intraoperative navigation record and postoperative measurement using computed tomography data was evaluated. Preoperative clinical factors that decreased the accuracy of cup positioning by ≥ 3° were analyzed via multiple logistic regression analyses. RESULTS: The average absolute error of inclination was 2.8 ± 2.6° in Hip Align and 2.7 ± 1.8° in AR-Hip, and absolute anteversion error was 2.5 ± 2.0° in Hip Align and 2.6 ± 2.2° in AR-Hip, and there was no significantly different between the two navigation systems. There was a significant association between the absolute measurement error (≥ 3°) of cup inclination and patients' BMI in the Hip Align group [odds ratio (OR) 1.350; 95% confidence interval (CI) 1.035-1.760; p = 0.027], but not in the AR-Hip group. CONCLUSIONS: The accuracy of the acetabular cup positioning between the Hip Align and AR-Hip showed no difference during THA in the spine position. The high BMI could have negative influence on the accuracy of cup positioning in THA using Hip Align, thus AR-Hip could be designable for obesity patients.

Acute Deterioration of Patient with Sudden Onset of Shock Caused by Group G Streptococcus Infection after Revision Total Knee Arthroplasty: A Case Report.

BACKGROUND Periprosthetic joint infection is a difficult complication, especially in patients with rheumatoid arthritis. Life-threatening septic shock due to periprosthetic joint infection caused by group G streptococcus is rare, and there have been few reports about its treatment. We describe a successful case of sudden onset septic shock due to group G Streptococcus infection after revision total knee arthroplasty. CASE REPORT A 61-year-old woman with rheumatoid arthritis treated with biological disease-modifying antirheumatic drugs for about 12 years presented with acute right knee pain and shock 6 months after revision total knee arthroplasty. Periprosthetic joint infection caused by group G Streptococcus was diagnosed. She was admitted to the Intensive Care Unit, treated with respiratory support and dialysis, and underwent irrigation, debridement, and polyethylene liner exchange as the first surgery. At 9 days after the first surgery, she underwent the second surgery, consisting of implant removal and antibiotic spacer placement due to failure. It took approximately 7 weeks to normalize the levels of systemic markers of inflammation with intravenous antibiotics and then oral antibiotics for further 12 weeks, but re-revision total knee arthroplasty was successfully performed 1.5 years later. At a 1-year follow-up from the final surgery, she was able to walk with a cane and had no symptoms of infection. CONCLUSIONS In such cases with sudden onset of septic shock due to periprosthetic joint infection, appropriate and prompt surgical treatment should be performed to save the infected limb as well as the patient's life.

Prosthetic orientation, limb alignment, and soft tissue balance with bi-cruciate stabilized total knee arthroplasty: a comparison between the handheld robot and conventional techniques.

PURPOSE: This study aimed to examine the prosthetic orientations, limb alignment, intraoperative soft tissue balance, and early clinical outcomes associated with the use of the relatively new handheld robot technique compared to those associated with the use of the conventional alignment guide for bi-cruciate stabilized total knee arthroplasty (TKA). METHODS: This retrospective cohort study compared the prosthetic orientation and limb alignment of 35 patients who underwent TKA using robotic assistance (robot group) with those of patients who underwent TKA using a conventional alignment guide (control group). The coronal femoral component alignment (FCA), coronal tibial component alignment (TCA), and the hip-knee-ankle (HKA) angle were compared between groups. Intraoperative soft tissue balance, including the joint component gap and varus/valgus balance assessed by an offset-type tensor, were also compared between groups. One year postoperatively, the clinical outcomes, including the range of motion and 2011 Knee Society Score (KSS), were compared between groups. RESULTS: The HKA angle and FCA were 0.1° varus and 0.1° varus, respectively, in the robot group and 1.3° varus and 1.3° varus, respectively, in the control group. The difference in the HKA angle and the FCA, but not the TCA, between groups was statistically significant (p < 0.05). The intraoperative soft tissue balance showed more stable joint component gaps and varus/valgus balances throughout the range of motion in the robot group than in the control group. Clinical outcomes of the robot group showed superior 2011 KSS subscales compared to those of the control group. CONCLUSION: The accuracy of the implantations and stable soft tissue balance in the robot group were superior to those of the control group. The robot group also had superior patient-reported scores for early clinical outcomes.

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.

Iguratimod versus salazosulfapyridine in rheumatoid arthritis patients with an inadequate response to methotrexate: Adjusted with propensity score matching.

OBJECTIVES: Methotrexate (MTX) is recommended as a first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD) for treating rheumatoid arthritis (RA). This retrospective study sought to identify an add-on csDMARD treatment strategy for RA patients with MTX-inadequate response (IR). METHODS: We collected the cases of RA patients treated with salazosulfapyridine (SASP) or iguratimod (IGU) as the additional csDMARD for MTX-IR during a 24-month follow-up. We performed propensity score matching to evaluate the retention rate, clinical efficacy, and safety profile (n = 54, each group). RESULTS: The retention rates at 24 months were 38.5% (MTX+SASP group) and 67.8% (MTX+IGU group). At 3 and 6 months, the MTX+IGU group's 28 joint-disease activity score (DAS28) was significantly decreased versus the MTX+SASP group, and at 3 months the MTX+IGU group's good-responder percentage (22.9%) was significantly higher versus the MTX+SASP group's good-responder percentage (10.7%). Conversely, compared to the MTX+SASP group, the MTX+IGU group showed a greater reduction in the estimated glomerular filtration rate from baseline during follow-up. CONCLUSIONS: IGU is a useful add-on csDMARD for RA patients with MTX-IR; its high retention rate and good clinical response make it a useful combination therapy for controlling RA disease activity. However, the renal function should be monitored during follow-up.

The Effect of Prosthesis Type on Intraoperative Soft-Tissue Balance and Clinical Outcomes in Modified Kinematically Aligned Cruciate-Retaining Total Knee Arthroplasty.

INTRODUCTION: Kinematically aligned total knee arthroplasty (KA-TKA) has gained interest for achieving more favorable clinical outcomes than mechanically aligned TKA. One of the advantages of KA-TKA is reported to be an easy acquisition of intraoperative soft-tissue balance without excessive medial release for varus osteoarthritis. However, we hypothesized that the prosthesis type affects intraoperative soft-tissue balance even in the KA-TKA. The present study aimed to compare intraoperative soft-tissue balance and clinical outcomes of KA-TKAs using single-radius (SR) or multiradius (MR) prostheses. MATERIALS: AND METHODS: Consecutive 70 cruciate-retaining modified KA-TKAs (31 SR and 39 MR) were performed in patients with varus-type osteoarthritis using a navigation system. Intraoperative soft-tissue balance including joint component gap and varus/valgus balance was measured with femoral component placement and patellofemoral joint reduction throughout the range of motion using offset-type tensor and compared between the two groups. Two years postoperatively, the range of motion and 2011 Knee Society Scores were compared between the two groups. RESULTS AND CONCLUSION: Joint component gaps showed no significant differences between the two groups from 0 to 30 degrees of flexion. However, during 60 to 120 degrees of flexion, joint component gaps of SR group showed significantly larger values than those of MR group (p < 0.05). There were no significant differences in varus/valgus balance throughout the range of motion between the two groups. The postoperative clinical outcomes showed no significant differences between the two groups. INTERPRETATION: Despite no difference in clinical outcomes, joint component gap showed different patterns due to the prosthesis type in modified KA-TKAs.

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.

Comparing the accuracy of three-dimensional mini-optical portable navigation and accelerometer-based portable navigation system for acetabular cup placement during total hip arthroplasty.

INTRODUCTION: This study compared the accuracy of three dimensional (3D) mini-optical navigation and accelerometer-based portable navigation systems for cup positioning during a total hip arthroplasty (THA) in the supine position. MATERIALS AND METHODS: This retrospective cohort study assessed data for 77 hips using 3D mini-optical navigation (n = 37) and accelerometer-based portable navigation (n = 40). The patients underwent THA through the mini-anterolateral approach in the supine position using a portable navigation system. We assessed the preoperative target angles, recorded intraoperative cup angles, postoperative CT imaging angles, cup angle measurement errors, and other clinical parameters. RESULTS: The mean absolute differences in radiographic inclination were similar between 3D mini-optical navigation and accelerometer-based portable navigation systems during THA in the supine position (2.8° ± 1.7° vs 2.8° ± 1.9°, p = 0.637). The mean absolute differences in radiographic anteversion were also similar (2.6° ± 2.3° vs 2.5° ± 1.9°, p = 0.737). Cup malalignment (absolute difference of inclination or anteversion between postoperative CT and preoperative target angle of > 5°) was significantly associated with body mass index (BMI) in accelerometer-based portable navigation but not in 3D mini-optical navigation. CONCLUSIONS: This is the first study to compare the accuracy of cup positioning between 3D mini-optical and accelerometer-based navigations in THA in the supine position. Both portable navigation systems accurately identified the orientation of cup placement. The accuracy of 3D mini-optical navigation is not affected by high BMI and may be preferred over other options in such patients.

A genome-wide association study identifying single nucleotide polymorphisms in the PPFIBP2 gene was predictive for interstitial lung disease in rheumatoid arthritis patients.

Objective: Genetic polymorphisms might serve as useful prognostic markers for the timely diagnosis of RA. The purpose of this study was to identify genomic factors predictive of the occurrence of interstitial lung disease (ILD) in RA by performing a genome-wide association study of genetic variants, including single nucleotide polymorphisms (SNPs). Methods: The study population included 306 RA patients. All patients were treated with conventional DMARDs, including 6-16 mg MTX per week. Clinical data and venous blood samples were collected from all patients before administration of DMARDs. A total of 278 347 SNPs were analysed to determine their association with ILD occurrence. Results: Several SNPs were strongly associated with ILD occurrence (P < 10-5). rs6578890, which is located on chromosome 11 in the intronic region of the gene encoding tyrosine phosphatase receptor type F polypeptide-interacting protein-binding protein 2 (PPFIBP2), showed the strongest association with ILD occurrence (odds ratio 4.32, P = 10-7.93). Conclusion: PPFIBP2 could be a useful genetic marker for occurrence of interstitial pneumonia in RA patients and might help to identify the risk of ILD occurrence before RA treatment, thereby improving patient outcomes.

The severity of preoperative varus deformity affects the feasibility of correcting lower limb alignment with medial unicompartmental knee arthroplasty.

BACKGROUND: The relationship between the severity of preoperative varus deformity and the amount of its correction in unicompartmental knee arthroplasty (UKA) as well as the thickness of the insert has not been well known. METHODS: One hundred and three patients who underwent medial fixed-bearing UKA with the use of the spacer block method were assessed. After the component gap in extension was measured using a UKA tensor, the pre-osteotomy gap was calculated from the thickness of the bone cuts. The relationship between the preoperative hip-knee-ankle (HKA) angle as well as the pre-osteotomy gap and the amount of change in HKA angle were analysed. Also, preoperative HKA angle and the thickness of the bone cuts were compared among groups by the insert thickness. RESULTS: The mean preoperative HKA angle was 7.7 ± 3.1° varus. Patients with more varus deformity and those with a wider pre-osteotomy gap showed a more valgus change in HKA angle. As for the thickness of the insert, the preoperative HKA angle of the patients with the thinnest insert was significantly smaller (less varus) than that of those with the thicker insert while no statistically significant difference was found among the insert groups regarding the amount of the bone cuts. CONCLUSIONS: The severity of the preoperative varus deformity as well as the intraoperative pre-osteotomy gap related to the amount of change in HKA angle. As thick inserts tended to be used in severe varus knees, the tibial bone cut can be reduced in such cases.

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.

Rotational mismatch between femoral and tibial components should be avoided in JOURNEY II bi-cruciate stabilized total knee arthroplasty.

BACKGROUND: JOURNEY II bi-cruciate stabilized (BCS) knee system, a guided motion total knee arthroplasty (TKA), has been reported to reproduce physiological knee kinematic motion with good clinical outcomes. However, this guided system may be sensitive to the femorotibial rotational alignment. METHOD: Forty-four patients (50 knees) who underwent JOURNEY II BCS TKA were included in this retrospective study. The 2011 Knee Society Score (KSS) and range of motion were assessed pre-operatively and one year postoperatively. The femoral component rotational angle relative to the surgical epicondylar axis and the tibial component rotational angle relative to Akagi's line were measured postoperatively. The absolute difference between the femoral and tibial component rotational angles was defined as femorotibial component rotational mismatch. The correlation between the parameters of these rotational alignments and postoperative clinical outcomes was evaluated. Additionally, receiver operating characteristic curve analysis was performed to determine the optimal cut-off point of the femorotibial component rotational mismatch. RESULTS: Mean femoral and tibial component rotational angles were 0.4° (internal rotation) and 0.7° (external rotation), respectively. The rotational mismatch of the femorotibial component was 3.2°. There were negative correlations between femorotibial rotational mismatch and clinical outcomes, including objective knee indicators, patient satisfaction, functional activities, and total 2011 KSS. The area under the curve of the femorotibial component rotational mismatch was 0.768 and the cut-off value identified by the Youden index was 2.8°. CONCLUSIONS: Excessive rotational mismatch between the femoral and tibial components can negatively influence the clinical outcomes of JOURNEY II BCS TKA.

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.