Ultrasonographic Changes of the Knee Joint Reflect Symptoms of Early Knee Osteoarthritis in General Population; The Nagahama Study.

OBJECTIVE: Radiographic changes in knee osteoarthritis (OA) are not always associated with symptoms, especially in its early stages. Ultrasonography (US) can detect early changes in the knee joint, but the changes that reflect symptoms have not been fully elucidated. This study aimed to identify US-detectable changes in the knee that are often associated with knee symptoms and demonstrate the feasibility of early diagnosis in symptomatic knee OA using US. DESIGN: In this cross-sectional community-based study, 1,667 participants aged ≥60 years (1,103 women [66%]) were included. All participants concurrently underwent US and radiography of the knee and completed the Knee Society Knee Scoring System (KSS) questionnaire. Simple and multiple regression analyses were used to examine the associations between US findings and KSS symptom subscales. RESULTS: Among all participants, medial meniscus protrusion and medial osteophytes, age, and body mass index showed significant associations with KSS symptom scores. Among 894 participants with Kellgren-Lawrence (KL) grade ≤1, medial osteophytes and age were significantly associated with KSS symptom score. US measures were more related to KSS symptoms than KL grades. CONCLUSIONS: Among the knee US-detectable changes, medial osteophytes were strongly associated with knee symptoms. Osteophytes are reliable predictors of symptomatic early knee OA, even in participants with few radiographic OA changes.

Insufficient Recovery From C5 Palsy Following Anterior Cervical Decompression and Fusion.

STUDY DESIGN: Retrospective study. OBJECTIVE: To determine the risk factors for insufficient recovery from C5 palsy (C5P) following anterior cervical decompression and fusion (ADF). SUMMARY OF BACKGROUND DATA: Postoperative C5P is a frequent but unsolved complication following cervical decompression surgery. Although most patients gradually recover, some recover only partially. When we encounter new-onset C5P following ADF, the question that often arises is whether the palsy will sufficiently resolve. METHODS: We retrospectively reviewed consecutive patients who underwent ADF at our institution. We defined C5P as postoperative deterioration of deltoid muscle strength by two or more grades determined by manual muscle testing (MMT). We evaluated the following demographic data: patient factors, surgical factors, and radiological findings. C5P patients were divided into two groups: sufficient recovery (MMT grade≧4) and insufficient recovery (MMT grade < 4). Each parameter was compared between the two groups. RESULTS: Of 839 patients initially included in the study, 57 experienced new-onset C5P (6.8%). At the final follow-up (mean, 55 ±â€Š17 months), 41 patients experienced sufficient recovery, whereas 16 (28%) still exhibited insufficient recovery. Compared with the sufficient recovery group, patients with insufficient recovery exhibited a higher decompression combination score, a larger anterior shift in preoperative cervical sagittal balance, less lordosis of the pre- and postoperative C4/C5 segment, more frequent stenosis at the C3/C4 segment, lower deltoid strength at C5P onset, more frequent co-occurrence of biceps weakness, greater postoperative expansion of the dura mater, and more frequent presence of postoperative T2 high-intensity areas. Multivariate analysis revealed that co-occurrence of biceps muscle weakness, less lordosis at the preoperative C4/C5 segment, and postoperative expansion of the dura mater were independent predictors of insufficient recovery. CONCLUSION: The combination of unfavorable conditions, such as potential spinal cord disorder, cervical malalignment, and excessive expansion of the dura mater after corpectomy, predicts insufficient recovery from C5P.Level of Evidence: 4.

Tenderness of the knee is associated with thinning of the articular cartilage evaluated with ultrasonography in a community-based cohort: The Nagahama study.

OBJECTIVES: This study aimed to elucidate the association between joint line tenderness (JLT) of the knee and knee joint structural changes evaluated with ultrasonography (US) for the early diagnosis of knee osteoarthritis (KOA). METHODS: This cross-sectional study included 121 participants (age 71.7 ± 5.8 years, 75 women) from a community-based population. Bilateral structural changes in the knee joint were evaluated with US, and the presence or absence of JLT was evaluated using a pressure algometer. Logistic regression analysis was performed to evaluate the odds ratios (ORs) of US findings for the presence of JLT. Moreover, when the analysis was limited to knees with pre-/early radiographic KOA, the ORs were also calculated using logistic regression analysis. RESULTS: Among the 242 knees, 38 had medial JLT, which was significantly associated with female sex (OR 11.87) and loss of cartilage thickness of the distal medial femoral condyle (CTh-MFC) (OR 0.12). Among 96 knees with Kellgren-Lawrence grade ≤ 2, 18 knees had medial JLT, which was also significantly associated with loss of CTh-MFC (OR 0.07) and medial osteophytes (OR 2.01). CONCLUSIONS: JLT is significantly associated with thinning of the femoral cartilage and larger osteophytes in elderly patients, even in those with pre-/early radiographic KOA.

Association Between C5 Palsy and the Anterior Decompression Procedures, Corpectomy and Discectomy.

STUDY DESIGN: This is a retrospective study. OBJECTIVE: The aim was to evaluate the influence of various decompression procedures on the incidence of C5 palsy (C5P). SUMMARY OF BACKGROUND DATA: C5P is a well-known but unsolved complication of cervical spine surgery. Among anterior cervical decompressive procedures, both corpectomy and discectomy are important surgical methods, whose effects on the incidence of C5P are unknown. METHODS: We retrospectively analyzed 818 patients (529 men; mean age: 59.2±11.6 y) who underwent anterior cervical decompression and fusion. The surgical choice to use corpectomy, discectomy, or hybrid decompression was based on standard treatment strategies depending on local compressive pathology and presenting clinical symptoms. We introduced an original "decompression combination score" as a means of quantifying the effects of the procedures on the development of C5P. The scores were based on the relative severity of various risk factors associated with the eventual development of C5P and were assigned as follows: C4 corpectomy, 1 point; C5 corpectomy, 1 point; C3 corpectomy successive to C4 corpectomy, 0.5 point; C6 or C7 corpectomy successive to C5 corpectomy, 0.5 point; C4/5 discectomy, 0.5 point; discectomy at another segment, 0 point. Each patient's decompression combination score was then comprised of the sum of these points. RESULTS: C5P occurred in 55 (47 men, mean age: 65.7±8.7 y) of the 818 (6.7%) patients. A larger number of operated disc segments was significantly associated with C5P. Higher decompression combination score was significantly associated with C5P. Multivariate analysis revealed that male sex, higher decompression combination score, and older age were significant risk factors. CONCLUSIONS: Corpectomy increased the incidence of C5P, while discectomy decreased the risk. The lower incidence of postoperative C5P after discectomy may be because of minimizing tethering effect to the C5 nerve root. As a preventive measure against C5P, corpectomy should be avoided, while discectomy is recommended as much as possible. LEVEL OF EVIDENCE: Levels of Evidence: Step IV-Oxford Center for Evidence-Based Medicine 2011.

Soluble Lectin-like Oxidized Low-Density Lipoprotein Receptor 1 Predicts the Changes of Rheumatoid Factor Titers in Rheumatoid Arthritis.

OBJECTIVE: The aim of this longitudinal study was to examine the clinical significance of soluble lectin-like oxidized low-density lipoprotein receptor 1 (sLOX-1) in patients with rheumatoid arthritis. METHODS: We gathered demographic and clinical data for a large rheumatoid arthritis cohort at 3 time points. Blood samples were collected at each time point; the number of samples was 282 cases in 2012, 431 cases in 2013, and 500 cases in 2014. Plasma sLOX-1 was measured by enzyme-linked immunosorbent assay. Correlations between sLOX-1 and clinical data were analyzed. Predictive factors associated with changes in sLOX-1 and rheumatoid factor (RF) were analyzed by multivariate linear regression. RESULTS: Plasma sLOX-1 level was significantly correlated with RF titer and other clinical parameters. The longitudinal analyses showed that changes in sLOX-1 were significantly correlated with changes in RF titers and with those at baseline. Multivariate linear regression analysis revealed that changes in RF and baseline RF were predictive factors for changes in sLOX-1. Conversely, the changes in RF were significantly correlated with the changes in sLOX-1 in all years. A stepwise regression analysis showed that the change in sLOX-1 was a predictive factor for the change in RF. CONCLUSIONS: The change in sLOX-1 has predictive value for assessing the change in RF, indicating the usefulness of sLOX-1 in clinical practice.

The Effects of Well-Rounded Exercise Program on Systemic Biomarkers Related to Cartilage Metabolism.

Nonsurgical treatment such as exercise is the preferred method for management of knee osteoarthritis (OA). A combination of aerobic, muscle strengthening, and flexibility exercises is recommended for older adults. However, effects of the exercise intervention on cartilage metabolism remain unclear. This study used biomarkers to investigate the effects of well-rounded exercise program on cartilage metabolism in 42 women (mean age: 59 years). Participants started a weekly supervised exercise program and continued for 12 weeks. Before and after the program, we measured physical performance on the Timed Up-and-Go Test, 3-Minute Walk Test, and 30-Second Chair Stand Test. We collected serum and urine samples at the start of the program until 24 weeks and measured the concentrations of 4 biomarkers related to type II collagen metabolism: serum cartilage type II procollagen carboxy propeptide (sPIICP), urine C-terminal telopeptide of collagen type II (uCTX-II), urine cleavage of type II collagen by collagenases (uC2C), and serum cartilage oligomeric matrix protein (sCOMP). Participants were divided into pre-OA and OA groups based on X-ray findings. The pre-OA group showed significant increases and decreases in sPIICP and uCTX-II concentrations with improved physical performance, respectively. sCOMP concentrations significantly increased in both groups. The exercise also improved physical performance with no detrimental effect on type II collagen metabolism in the OA group. Thus, well-rounded exercise may not only improve physical capacity but also have beneficial effects on type II collagen metabolism, especially in people without radiological OA.

Human Sox4 facilitates the development of CXCL13-producing helper T cells in inflammatory environments.

In human inflammatory sites, PD-1hiCXCR5-CD4+ T cells are involved in the formation of ectopic lymphoid-like structures (ELSs) by the secretion of chemokine CXCL13, but how the transcription of CXCL13 is regulated in CD4+ T cells is still unclear. Here we show that Sox4 is a key transcription factor for CXCL13 production in human CD4+ T cells under inflammatory conditions. In vitro TGF-ß+, IL-2-neutralizing culture conditions give rise to PD-1hiCXCR5-CD4+ T cells that preferentially express CXCL13, and transcriptome analysis and lentiviral overexpression indicate Sox4 association with the CXCL13 transcription. In vivo, Sox4 is significantly upregulated in synovial CD4+ T cells, when compared with blood CD4+ T cells, from patients with rheumatoid arthritis (RA), and further correlates with ELS formation in RA synovium. Overall, our studies suggest that Sox4 contributes to CXCL13 production and ELS formation at inflammatory sites in humans.

How precisely does ultrasonographic evaluation reflect the histological status of the articular cartilage of the knee joint?

The thickness and the grade of the articular cartilages of the knee of 34 patients who underwent total knee arthroplasty were evaluated by ultrasound (US) and by histology. The US grade correlated with the histological grade and the thickness of the articular cartilage measured by US. The thickness measured by US was significantly correlated with that measured by histology for the medial condyle. The US thickness was significantly less than the histological thickness for thicker articular cartilages. US grading and the thickness of the articular cartilages evaluated by US is sufficiently reliable to indicate their histological status.

Subchondral bone fragility with meniscal tear accelerates and parathyroid hormone decelerates articular cartilage degeneration in rat osteoarthritis model.

The aims of this study were to investigate the influence of subchondral bone fragility (SBF) on the progression of the knee osteoarthritis by using a novel rat model, and to examine the preventive effect of parathyroid hormone (PTH) on cartilage degeneration. First, 40 rats were assigned to the following four groups: Sham, SBF, Medial meniscal tear (MMT), and MMT + SBF groups. In SBF and MMT + SBF groups, we induced SBF by microdrilling the subchondral bone. Second, 10 additional rats were randomly assigned to the following two groups: MMT + SBF + saline and MMT + SBF + PTH groups. Osteoarthritic changes in the articular cartilage and subchondral bone were evaluated using safranin-O/fast green staining, matrix metalloproteinase-13 (MMP-13), and type X collagen immunohistochemistry, toluidine blue staining, and micro-CT scanning. The combination of SBF and meniscal tear increased the number of mast cells in the subchondral bone, and led to the abnormal subchondral bone microarchitecture, such as abnormally decreased trabecular number and increased trabecular thickness, compared with meniscal tear alone. Moreover, SBF with meniscal tear enhanced articular cartilage degeneration and increased the expression of MMP-13 and type X collagen, compared with meniscal tear alone. The administration of PTH decreased the number of mast cells in the subchondral bone and improved the microstructural parameters of the subchondral bone, and delayed the progression of articular cartilage degeneration. These results suggest that SBF is one of the factors underlying the osteoarthritis development, especially in knees with traumatic osteoarthritis, and that the administration of PTH is a potential therapeutic treatment for preventing OA progression. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1959-1968, 2018.

Nardilysin is involved in autoimmune arthritis via the regulation of tumour necrosis factor alpha secretion.

OBJECTIVE: Tumour necrosis factor alpha (TNF-α) plays an important role in rheumatoid arthritis (RA). TNF-α is synthesised as a membrane-anchored precursor and is fully activated by a disintegrin and metalloproteinase 17 (ADAM17)-mediated ectodomain shedding. Nardilysin (NRDC) facilitates ectodomain shedding via activation of ADAM17. This study was undertaken to elucidate the role of NRDC in RA. METHODS: NRDC-deficient (Nrdc-/- ) mice and macrophage-specific NRDC-deficient (NrdcdelM ) mice were examined in murine RA models, collagen antibody-induced arthritis (CAIA) and K/BxN serum transfer arthritis (K/BxN STA). We evaluated the effect of gene deletion or silencing of Nrdc on ectodomain shedding of TNF-α in macrophages or monocytes. NRDC concentration in synovial fluid from patients with RA and osteoarthritis (OA) were measured. We also examined whether local gene silencing of Nrdc ameliorated CAIA. RESULTS: CAIA and K/BxN STA were significantly attenuated in Nrdc-/- mice and NrdcdelM mice. Gene deletion or silencing of Nrdc in macrophages or THP-1 cells resulted in the reduction of TNF-α shedding. The level of NRDC is higher in synovial fluid from RA patients compared with that from OA patients. Intra-articular injection of anti-Nrdcsmall interfering RNA ameliorated CAIA. CONCLUSION: These data indicate that NRDC plays crucial roles in the pathogenesis of autoimmune arthritis and could be a new therapeutic target for RA treatment.

Plasma sLOX-1 is a potent biomarker of clinical remission and disease activity in patients with seropositive RA.

OBJECTIVES: Soluble lectin-like oxidized low-density lipoprotein receptor 1 (sLOX-1) is present in the circulation and synovial fluid in patients with rheumatoid arthritis (RA). The aim of this study was to assess whether sLOX-1 level is associated with clinical remission and disease activity in patients with RA. METHODS: Clinical and laboratory data were analyzed for 282 patients with RA. Plasma sLOX-1 level was measured by enzyme-linked immunosorbent assay (ELISA). The remission status and sLOX-1 levels were compared between four groups of patients based on the positivity of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs). Relationships between sLOX-1 level and the 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) were analyzed by multivariate logistic regression. RESULTS: The patients in the RF + ACPA + group tended to exhibit higher sLOX-1 levels when compared to the other three groups. In the RF + ACPA + group, the sLOX-1 level was significantly higher in the non-remission group than in the remission group, irrespective of treatment. Multivariate logistic regression showed significant correlations between sLOX-1 level and DAS28-ESR. CONCLUSIONS: sLOX-1 level might be a useful biomarker for assessing clinical remission and disease activity in double-positive RA patients.