TNFR2 is critical for TNF-induced rheumatoid arthritis fibroblast-like synoviocyte inflammation.

OBJECTIVES: TNF-induced activation of fibroblast-like synoviocytes (FLS) is a critical determinant for synovial inflammation and joint destruction in RA. The detrimental role of TNF-receptor 1 (TNFR1) has thoroughly been characterized. The contributions of TNFR2, however, are largely unknown. This study was performed to delineate the role of TNFR2 in human FLS activation. METHODS: TNFR2 expression in synovial tissue samples was determined by immunohistochemistry. Expression of TNFR2 was silenced using RNAi or CRISPR/Cas9 technologies. Global transcriptional changes were determined by RNA-seq. QPCR, ELISA and immunoblotting were used to validate RNA-seq results and to uncover pathways operating downstream of TNFR2 in FLS. RESULTS: TNFR2 expression was increased in RA when compared with OA synovial tissues. In particular, RA-FLS demonstrated higher levels of TNFR2 when compared with OA-FLS. TNFR2 expression in RA-FLS correlated with RA disease activity, synovial T- and B-cell infiltration. TNF and IL1ß were identified as inflammatory mediators that upregulate TNFR2 in RA-FLS. Silencing of TNFR2 in RA-FLS markedly diminished the TNF-induced expression of inflammatory cytokines and chemokines, including CXCR3-binding chemokines and the B-cell activating factor TNFSF13B. Immunobiochemical analyses revealed that TNFR2-mediated expression of inflammatory mediators critically depends on STAT1. CONCLUSION: Our results define a critical role for TNFR2 in FLS-driven inflammation and unfold its participation in the unresolved course of synovial inflammation in RA.

64Cu-ATSM and 99mTc(CO)3-DCM20 potential in the early detection of rheumatoid arthritis.

OBJECTIVES: Molecular imaging constitutes a promising technique for the early detection of rheumatoid arthritis (RA). Macrophages and hypoxia play significant roles in inflamed synovium. In the present study, we evaluated the efficacy of radiopharmaceuticals that target macrophage mannose receptors (99mTc-labeled mannosylated dextran or 99mTc(CO)3-DCM20) and hypoxia (copper(II) diacetyl-di(N4-methylthiosemicarbazone) or Cu-ATSM) for the early detection of RA in collagen-induced arthritis (CIA) mice models. METHODS: CIA model was developed in DBA/1 mice, and the clinical score for arthritis was visually assessed on a regular basis. Two biodistribution studies were performed in a paired-labeled format using 2-deoxy-2-18F-fluoro-D-glucose (18F-FDG) as a reference: (1) 99mTc(CO)3-DCM20 with 18F-FDG and (2) 67Cu-ATSM with 18F-FDG. RESULTS: The accumulation levels of 99mTc(CO)3-DCM20 and 67Cu-ATSM in forepaws, hindpaws, and knee joints of CIA mice were significantly higher than that of control mice. In contrast, 18F-FDG uptake in hindpaws and knee joints showed no significant difference between CIA and control mice. The radioactivity levels of 99mTc(CO)3-DCM20 and 67Cu-ATSM were significantly correlated with the clinical scores for the paws. CONCLUSION: These results suggest the potential usefulness of 99mTc(CO)3-DCM20 and radiolabeled Cu-ATSM for the imaging and early detection of RA.

The three-year efficacy of iguratimod in clinical daily practice in patients with rheumatoid arthritis.

Objectives: To assess the middle-term outcome of iguratimod (IGU) in rheumatoid arthritis (RA) patients. Methods: Sixty-nine RA patients (14 males and 55 females, mean age of 64.0 years) receiving IGU-containing therapies were enrolled. We divided these patients into three groups based on the treatment at the baseline: an IGU group, a methotrexate (MTX) plus IGU group, and a biologics plus IGU group. The baseline characteristics and clinical course were evaluated over three years. Predictive factors associated with the achievement of low disease activity (LDA) were statistically analyzed. Results: The survival rate of IGU therapy at 3 years was 40.6%. The disease activity was significantly decreased in the IGU group and MTX plus IGU group compared with the baseline. Furthermore, 38 patients (55.1%) were in remission or had LDA at 3 years. The patient gender, use of prednisolone (PSL) and DAS28-CRP at baseline were the factors associated with the achievement of remission or LDA at three years. Conclusion: IGU was effective without MTX or bDMARDs as well as in combination with MTX. A female gender, no use of PSL and a low DAS28-CRP at the initiation of IGU were associated with clinical remission or LDA achievement at three years.

Short-term daily teriparatide in patients with rheumatoid arthritis.

OBJECTIVE: The aim of this study was to compare the efficacy of six-month teriparatide treatment followed by six-month bisphosphonate therapy with 12-month bisphosphonate monotherapy in Japanese rheumatoid arthritis (RA) patients who had not been previously treated for osteoporosis. METHODS: A total of 34 RA patients with osteoporosis were enrolled. Thirteen patients received six-month teriparatide prior to six-month minodronate therapy (PTH group), and 21 patients received 12-month minodronate therapy (BP group). Bone mineral density (BMD), and bone turnover markers were measured prior to and 6 and 12 months after the initiation of treatment. RESULTS: Bone mineral density of the spine was significantly increased after 12 months of treatment in both groups. In the PTH group, the mean percent change of BMD of the spine was significantly higher at 12 months after the initiation of treatment, as compared to the BP group (PTH group: 9.9 ± 1.5%, BP group: 5.5 ± 0.7%). Femoral neck BMD was significantly increased only in the PTH group after 12 months. CONCLUSION: Therapy involving six-month teriparatide followed by six-month minodronate therapy increased spine BMD to a greater degree than 12-month minodronate monotherapy. The strategy of short-term administration of teriparatide for RA patients with osteoporosis might be useful when additional bisphosphonate therapy is considered.

Bony ankylosis of the facet joint of the cervical spine in rheumatoid arthritis: Its characteristics and relationship to the clinical findings.

OBJECTIVES: The purpose of this study was to clarify the characteristics of bony ankylosis of the facet joint of the cervical spine in rheumatoid arthritis (RA) patients who required cervical spine surgery, and its relationship to the clinical findings. METHODS: Eighty consecutive RA patients with cervical spine disorder who received initial surgery were reviewed. The occurrence of bony ankylosis of the facet joint of the cervical spine was investigated using computed tomography (CT) before surgery. We also evaluated the severity of neurological symptoms and the plain wrist radiographs taken before surgery; furthermore, we evaluated each patient's medical history for total knee arthroplasty (TKA) or hip arthroplasty (THA). RESULTS: The preoperative CT imaging demonstrated bony ankylosis of the facet joint of the cervical spine in 45 facet levels of 19 cases (BA + group). In all patients, responsible instability or stenosis was demonstrated just caudal or on the cranial side of those bony ankylosis. Before surgery, the BA + group included significantly more patients showing severe cervical myelopathy (p < 0.05), and significantly more cases showing progressed ankylosis in the wrist joint bilaterally (p < 0.01). There were also significantly more patients who received two or more TKA or THA before the cervical spine surgery in the BA + group (p < 0.01). CONCLUSIONS: Bony ankylosis of the facet joint of the cervical spine may be a risk factor of instability or stenosis at the adjacent disc level and severe cervical myelopathy. Furthermore, its ankylosis was demonstrated in RA patients with severe destroyed joints.

Predictive factors associated with the progression of large-joint destruction in patients with rheumatoid arthritis after biologic therapy: A post-hoc analysis using FDG-PET/CT and the ARASHI (assessment of rheumatoid arthritis by scoring of large-joint destruction and healing in radiographic imaging) scoring method.

OBJECTIVE: To investigate the associations between large-joint damage and findings on fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) using the "assessment of rheumatoid arthritis by scoring of large-joint destruction and healing in radiographic imaging (ARASHI)" scoring system. METHODS: A total of 270 large joints (shoulders, elbows, hips, knees, and ankles) in 27 rheumatoid arthritis patients were assessed. FDG-PET/CT was performed at the initiation of biologics. Radiographs at baseline and at 3 years were evaluated using the ARASHI score. RESULTS: Radiographic progression of damage was detected in 35 by Larsen grade vs. 87 by the ARASHI score. The maximum standardized uptake value (SUVmax) at baseline, Steinbrocker stage at baseline, concomitant prednisolone use, and disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) at 6 months were significantly higher in the radiographic progression group. An SUVmax higher than 1.65 at baseline was a significant predictive factor for progressive damage at 3 years. CONCLUSIONS: The ARASHI score may allow more detailed evaluation of large joints than the Larsen method. Joint destruction is likely to have progressed at 3 years in large joints, which had a higher SUVmax at the initiation of biologics.

Predictive factors related to shoulder joint destruction in rheumatoid arthritis patients treated with biologics: A prospective study.

OBJECTIVE: The aim of this study was to assess the risk factors for shoulder joint destruction in rheumatoid arthritis (RA) patients treated with biologics. METHODS: Thirty shoulders of 29 patients with RA were assessed using 18F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) before starting biologics and 6 months later. The mean age (range) was 54 (18-72) years, and the mean disease duration was 7 (0.8-30) years. The radiographic findings were assessed at baseline and 3 years later. The inflammation markers and RA disease activity were also assessed. These parameters were compared between the progression of joint destruction group and the no progression group. RESULTS: The SUVmax on PET, the rate of synovitis, and the rate of rotator cuff tear on MRI before biologic treatment were significantly higher in the progression of joint destruction group. SUVmax and synovitis on MRI after 6 months were also significantly higher in the progression of joint destruction group. On logistic regression analysis, the SUV at baseline of the shoulder joint was the main risk factor for joint destruction. CONCLUSION: The detection of synovitis by imaging was more important than disease activity and inflammation markers for assessing the progression of shoulder joint destruction.

[18F]fluorodeoxyglucose uptake as a predictor of large joint destruction in patients with rheumatoid arthritis.

The present retrospective study investigated the relationship between [(18)F]fluorodeoxyglucose-positron emission tomography (FDG-PET) findings and subsequent progression of joint destruction on plain X-ray. Nineteen rheumatoid arthritis (RA) patients (59 joints) who underwent FDG-PET and whose joints could be evaluated on plain X-ray 5 years later were included in this retrospective investigation. The relationship between the standardized uptake value (SUV) on FDG-PET and Larsen grade progression on plain X-ray was investigated for each joint. Factors related to progression of joint destruction were also investigated. Joints with advanced joint destruction (Larsen grades IV and V) on X-ray imaging at the time of FDG-PET were excluded. On initial plain X-ray images taken at the time of FDG-PET, a significant correlation was observed between the initial SUV of each joint and the progression of joint destruction 5 years later (R = 0.47, P < 0.01). Significant correlations between the SUV and progression of joint destruction were observed in both load-bearing (R = 0.52, P < 0.01) and non-load-bearing joints (R = 0.52, P < 0.01). On logistic regression analysis, higher SUV and lower prednisolone dose were associated with greater risk of progressive joint destruction (P < 0.05). On receiver operating characteristics curve analysis, the optimum threshold for identifying preceding joint destruction was an SUVmean of 1.33. In RA joints, FDG uptake was seen mostly by inflammatory cells; therefore, FDG uptake reflected joint inflammation. Additionally, the activity seen on FDG-PET might be associated with future radiographic changes in RA patients.

Comparison of golimumab 100-mg monotherapy to golimumab 50 mg plus methotrexate in patients with rheumatoid arthritis: Results from a multicenter, cohort study.

OBJECTIVE: The aim of this study was to compare the efficacy and safety of golimumab (GLM) 50 mg + methotrexate (MTX) combination therapy and GLM 100 mg monotherapy in patients with rheumatoid arthritis (RA). METHODS: The subjects were 115 RA patients (92 females and 23 males; median (range) age, 64 (17-87) years; median (range) disease duration, 8 (0.6-48) years) started on GLM. Eighty-three patients received GLM 50 mg/4 weeks + MTX (C group; median (range) MTX dosage 8 (2-16) mg/week), and 32 patients received GLM 100 mg/4 weeks (M group). Serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), matrix metalloproteinase-3, disease activity score (DAS) 28-ESR, DAS28-CRP, simplified disease activity index, and clinical disease activity index were evaluated 4, 12, and 24 weeks after starting GLM. RESULTS: There were no significant differences in disease activity, adverse events, and drug continuation rates at 24 weeks between the groups. The DAS28-ESR remission rate was 34% in the C group and 26% in the M group. CONCLUSIONS: GLM 100 mg monotherapy improved disease activity as well as GLM 50 mg + MTX combination therapy. GLM 100 mg monotherapy appears to have a sufficient therapeutic effect in RA patients who cannot take MTX.

Efficacy of the clinical use of iguratimod therapy in patients with rheumatoid arthritis.

OBJECTIVE: Iguratimod (IGU) is a new synthetic disease-modifying antirheumatic drug intended to treat patients with rheumatoid arthritis (RA). We conducted a 24-week study on the efficacy of IGU in RA patients with daily clinical use. METHODS: Forty-one patients were enrolled in this study, and the improvement in RA was evaluated every 4 weeks during the 24 weeks. RESULTS: The patient's global assessment of the disease activity with a scale (Pt VAS) was significantly decreased beginning at week 4. The disease activity score (DAS) 28-erythrocyte sedimentation rate, DAS28-C-reactive protein (CRP), simplified disease activity index and clinical disease activity index all significantly decreased at week 24. The matrix metalloproteinase-3 level was significantly decreased by the combination treatment with methotrexate at week 24. According to a logistic regression analysis, the factor which was most associated with the achievement of low disease activity (DAS28-CRP < 2.7) at week 24 was the DAS28-CRP at week 0. CONCLUSIONS: IGU had significant clinical effects on the RA patients within 24 weeks. IGU might therefore represent a new practical choice to treat RA patients.

Efficacy at 52 weeks of daily clinical use of iguratimod in patients with rheumatoid arthritis.

OBJECTIVE: In recent years, the use of one or more conventional synthetic disease-modifying antirheumatic drugs has been recommended for the treatment of rheumatoid arthritis (RA). We performed a 52-week study on the efficacy and safety of iguratimod (IGU) against patients with RA in daily clinical use. METHODS: Forty-one patients were enrolled in this study, and the clinical course of RA was regularly evaluated during the 52 weeks of treatment. RESULTS: The survival rate at week 52 was 53.7%. The disease activity score (DAS) 28-erythrocyte sedimentation rate, DAS28-C-reactive protein, simplified disease activity index, and clinical disease activity index were all significantly decreased at week 52. The matrix metalloproteinase-3 level was significantly decreased at week 52 by combination therapy of IGU and methotrexate. There were one case of the onset of interstitial pneumonia (IP), one exacerbation of IP, and one case of the onset of Pneumocystis jiroveci pneumonia. CONCLUSIONS: IGU is effective for RA patients when used for daily clinical treatment for 52 weeks.

Evaluation of tocilizumab therapy in patients with rheumatoid arthritis based on FDG-PET/CT.

BACKGROUND: Positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) can detect the presence of synovitis in rheumatoid arthritis (RA) patients. The aim of this study was to investigate whether the findings of FDG-PET matched the conventional assessments of the disease activity score (DAS) 28, DAS28-CRP, simplified disease activity index (SDAI) and clinical disease activity index (CDAI) in RA patients receiving tocilizumab (TCZ) therapy. METHODS: Seventeen RA patients treated with TCZ were assessed. FDG-PET was performed at baseline and three and six months after the initiation of TCZ therapy. The maximum SUV (SUVmax) of the bilateral shoulder, elbow, wrist, hip, knee and ankle joints were added together (total SUV) and were used to assess the degree of FDG uptake as a representative parameter. The correlations between the ΔSUV and the difference in the clinical parameters at baseline and at each observation period, and the differences in each clinical parameters, were assessed. RESULTS: The ΔSUV, the differences in the total SUV at baseline and at three/six months after starting treatment positively correlated with the ΔDAS28 (r = 0.615 p = 0.009/ r = 0.775 p < 0.001), ΔDAS28-CRP (r = 0.696, p = 0.002/ r = 0.828, p < 0.001), ΔSDAI (r = 0.652, p = 0.005/ r = 0.686, p = 0.002) and ΔCDAI (r = 0.662, p = 0.004/ r = 0.711, p = 0.001) for each period. The total SUV was significantly decreased at three and six months after the initiation of TCZ (p < 0.05). CONCLUSIONS: A reduction in the FDG uptake was observed at three and six months after the initiation of TCZ therapy. The disease activity estimated on FDG-PET/CT matched the conventional parameters following the TCZ therapy in RA patients.

Efficacy of switching from originator etanercept to biosimilar YLB113 in real-world patients with rheumatoid arthritis: A retrospective 12 months follow-up study.

Purpose: To investigate the disease activity in real-world patients with rheumatoid arthritis (RA) who switched from originator etanercept (ETN) to biosimilar YLB113. Methods: Forty one RA patients who switched from ETN to YLB113 were divided into 2 groups based on the Disease Activity Score based on the 28-joint count (DAS28) 12 months after switching (R group: DAS28 < 2.6, N group: DAS28 ≥ 2.6), and the baseline characteristics were statistically examined. A receiver operating characteristics (ROC) analysis was performed to estimate the cut-off value of DAS28 at baseline to achieve remission 12 months after switching. Results: There was no significant difference in the DAS28 at baseline and 12 months after switching (p = .83). Sixteen out of the 20 patients in remission at baseline achieved remission after switching. A univariate analysis revealed the rheumatoid factor (p = .04) and DAS28 (p < .001) at baseline were significantly lower in the R group than in the N group. Furthermore, logistic regression analysis revealed DAS28 was an independent factor (p = .004) for achieving remission 12 months after switching. An ROC curve analysis showed the optimal cut-off value for DAS28 at baseline to achieve remission at 12 months after switching was 2.5. Conclusions: RA patients who achieved remission using originator ETN, were able to maintain remission even if they switched to YLB113.

The impact of bDMARDs on postoperative complications in patients with rheumatoid arthritis: A systematic review and meta-analysis.

BACKGROUND: The influence of biological disease-modifying antirheumatic drugs (bDMARDs) on postoperative surgical site infection (SSI) and venous thromboembolism (VTE) in patients with rheumatoid arthritis (RA) has not yet been clarified. METHODS: A systematic literature search was performed using PubMed, Web of ScienceTM, Scopus, and The Cochrane Library databases to identify eligible studies published up to August 2023. All studies comparing postoperative SSI or VTE rates in RA patients with or without bDMARD treatment were included. The protocol for this study was registered in PROSPERO (CRD42021246264) and is available on the University of York website. RESULTS: Overall, 20 studies with 71,885 RA patients and 6 studies with 7918 RA patients were included for postoperative SSI and VTE comparisons, respectively. Patients treated with bDMARDs had significantly higher rates of postoperative SSI than those without treatment (odds ratio 1.50, 95% confidence interval 1.23-1.83, P < .0001). However, these significant differences disappeared in the analysis restricted to 9 studies involving non-tumor necrosis factor α inhibitors. The use of bDMARDs seemed to increase the rate of postoperative VTE (odds ratio 2.20, 95% confidence interval 1.30-3.72, P = .003). A subgroup analysis showed that postoperative osseous complications were significantly less frequent in RA patients with bDMARD treatment than in those without treatment. CONCLUSION: RA patients treated with bDMARDs had an increased risk of not only postoperative SSI but also VTE. While bDMARD usage merits appropriate attention, there might be positive aspects as well. Further data will be needed to confirm the postoperative risks of bDMARD usage in RA patients.

The assessment of biologic treatment in patients with rheumatoid arthritis using FDG-PET/CT.

OBJECTIVES: To evaluate whether there is a correlation between the differences in joint uptake of 2-[18F]-fluoro-2-deoxy-d-glucose ((18)F-FDG) and the improvement of clinical findings in RA patients undergoing anti-TNF therapies. METHODS: Twenty-two patients who received anti-TNF therapies, including infliximab for 16 patients and etanercept for 6 patients, were assessed. PET with (18)F-FDG studies and clinical assessments were performed at baseline and 6 months after the initiation of therapy. The maximal standardized uptake value (SUV(max)) was used as a representative value for the assessment of the FDG uptake in the bilateral shoulder, elbow, wrist, hip, knee and ankle joints. Spearman's rank correlation test was applied to assess the correlation between the SUV and the clinical parameters. RESULTS: The ΔSUV (12 joints), the difference in the SUV(max) of the affected 12 joints before and after treatment, was positively correlated with the ΔDAS28 (r = 0.609, P = 0.003), ΔDAS28-CRP (r = 0.656, P = 0.001) and Δtender joint count (TJC) (r = 0.609, P = 0.003). There were also significantly positive correlations between ΔSUV (8 joints); the difference in the SUV(max) of the bilateral shoulder, elbow, wrist and knee joints before and after treatment and the ΔDAS28 (r = 0.642, P = 0.001), ΔDAS28-CRP (r = 0.712, P < 0.001) and ΔTJC (r = 0.608, P = 0.003), respectively. CONCLUSION: The FDG uptake observed in the inflamed RA joints may reflect disease activity. The FDG-PET response was correlated with the clinical response to the biologic treatment of RA.

Anti-drug antibodies and rheumatoid factor level in patients with rheumatoid arthritis using the infliximab biosimilar CT-P13.

BACKGROUND: This study evaluated the existence of anti-drug antibodies (ADAs) before and 52 weeks after switching from intravenous infliximab (IFX) to intravenous CT-P13 in patients with rheumatoid arthritis (RA). METHODS: We performed a prospective observational study. Twenty-eight patients (7 males and 21 females) received intravenous CT-P13 after intravenous IFX, and the clinical data were collected from medical records. Rheumatoid factor (RF) and anti-CCP antibody were examined at baseline. At baseline and 52 weeks after the start of CT-P13 treatment, the Disease Activity Score based on the 28-joint count and the levels of C-reactive protein, matrix metalloproteinase-3, and ADA, as well as the erythrocyte sedimentation rate were evaluated. ADAs were measured using an enzyme-linked immunosorbent assay kit. RESULTS: Seven (25%) and 6 (21.4%) cases were positive for ADAs at baseline and 52 weeks after, respectively. One case became newly positive for ADAs at week 52. Two of the ADA-positive cases became ADA-negative 52 weeks after. The ADA-positive group showed significantly higher RF values at baseline than the ADA-negative group (p = 0.03). No difference was observed between the ADA-positive group and the ADA-negative group regarding other clinical parameters. CONCLUSIONS: The positive rate of ADAs did not increase after switching from intravenous IFX to intravenous CT-P13. Among the patients with ADAs, a high level of RF was observed at baseline.

Do biologic therapies reduce aortic inflammation in rheumatoid arthritis patients?

OBJECTIVES: Rheumatoid arthritis (RA) patients have an increased risk of cardiovascular disease (CVD). In the present study, we evaluated the inflammatory activity of the ascending aorta in RA patients who received biological treatment. METHODS: We assessed the aortic wall inflammation of RA patients using 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography before and after 6 months of biologic therapies. We also compared the inflammatory activity at the aortic wall in RA patients with remission or low disease activity (RLDA) and those with moderate or high disease activity (MHDA). The aortic uptake was measured by the standardized uptake value (SUV) and the target-to-background ratio (TBR). RESULTS: A total of 64 patients were included in the analysis (mean age, 58.4 ± 13.8 years old; female, 77%). The Disease Activity Score for 28 joints (DAS28) erythrocyte sedimentation rate (ESR) had significantly decreased after 6 months: from 5.0 ± 1.2 to 3.3 ± 1.2 (p < 0.001). The FDG uptake in the ascending aorta changed from baseline to 6 months, showing a maximum SUV (SUVmax) of 1.83 ± 0.34 to 1.90 ± 0.34 (p = 0.059) and TBR of 1.71 ± 0.23 to 1.75 ± 0.24 (p = 0.222). The SUVmax and TBR after 6 months were significantly higher in the RLDA group than in the MHDA group (2.05 ± 0.32 vs. 1.79 ± 0.33 (p = 0.002) and 1.89 ± 0.33 vs. 1.65 ± 0.20 (p = 0.001), respectively). The percentage of monocytes also significantly increased from baseline to 6 months: from 5.9 ± 1.6 to 6.9 ± 2.6 (p = 0.032). CONCLUSION: The inflammation activity at the ascending aorta in RA patients did not change significantly after 6 months of biological treatment. RA patients with a low disease activity or in clinical remission after 6 months of biological treatment still had an increased inflammatory activity at the aortic wall.

Cross-sectional Study of the Hip Joint Condition in Young Baseball Players.

OBJECTIVE: The hip joint is a crucial part of the kinetic chain for throwing baseball pitches. Nevertheless, few reports have described assessments of the functional development of the hip joint in young baseball players. METHODS: We examined 315 young baseball players, 7-14 years old, all of whom had completed a self-administered questionnaire including items related to the dominant side and throwing-related hip joint pain sustained during the previous year. We measured the hip ranges of motion (ROMs: external and internal rotation and flexion) and hip muscle strengths (external and internal rotation) on the dominant and non-dominant sides. The differences of hip ROMs and muscle strengths between the dominant and non-dominant sides and between age groups were investigated. Correlations were calculated between the players ages and hip ROMs and muscle strengths. RESULTS: No baseball player reported hip pain. The hip external rotation on the dominant side was smaller than that on the non-dominant side, whereas the hip internal rotation on the dominant side was greater than that on the non-dominant side. However, no significant difference was found between the dominant and non-dominant sides in terms of the hip muscle strength. Significant positive associations were found between the player's age and hip muscle strengths, whereas significant negative associations were found between the age and hip ROMs. CONCLUSIONS: Our data concerning the relationship between age and hip joint development could be useful for supporting strategies for the prevention and rehabilitation of throwing injuries; however, hip injuries might be rare among young baseball players.

Risk Factors for Throwing-Related Shoulder and Elbow Pain in Adolescent Baseball Players: A Prospective Study of Physical and Developmental Factors.

BACKGROUND: Throwing-related shoulder and elbow pain continues to be reported among adolescent baseball players. Few prospective studies have specifically examined the association between throwing-related shoulder and elbow pain and physical and developmental changes. PURPOSE: To evaluate the changes in physical and developmental characteristics during 1 year with respect to throwing-related shoulder and elbow pain in adolescent baseball players. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: This 1-year prospective follow-up study investigated 164 baseball players aged 7 to 13 years. Player data (age, height, weight, field position, and pitch count), lower extremity muscle tightness, and range of motion (ROM) of the shoulder, elbow, and hip joints were assessed during the 2016 and 2017 preseason medical examinations. After the 2016 season, the participants completed questionnaires related to throwing-related shoulder and elbow pain, defined as an inability to play for ≥1 week because of elbow or shoulder difficulties. For study participants with and without throwing-related shoulder or elbow pain during the 2016 season, we conducted univariate and multivariate logistic regression analysis to identify risk factors for throwing-related shoulder or elbow pain. RESULTS: Overall, 21 players (12.8%) reported a shoulder pain episode, 56 players (34.1%) had an elbow pain episode, and 70 players (42.7%) reported having experienced shoulder and/or elbow pain during the 2016 season. In multivariate logistic regression analysis, (1) shoulder pain was associated with 2016 preseason height (odds ratio [OR], 1.06; 95% CI, 1.01-1.11; P = .01) and change in dominant-side elbow extension ROM from 2016 to 2017 (OR, 1.12; 95% CI, 1.02-1.24; P = .02); (2) elbow pain was associated with change in weight from 2016 to 2017 (OR, 1.21; 95% CI, 1.04-1.41; P = .014); and (3) throwing-related shoulder and/or elbow pain was associated with greater 2016 preseason height (OR, 1.04; 95% CI, 1.003-1.68; P = .03) and an increase in height from 2016 to 2017 (OR, 1.17; 95% CI, 1.01-1.35; P = .03). CONCLUSION: Our results indicated that adolescent baseball players who were taller in the preseason and those with an increase in height over the 1-year study period faced significant risks for developing throwing-related shoulder and/or elbow pain.

Identification of nuclear localization and nuclear export signals in Ets2, and the transcriptional regulation of Ets2 and CTP:phosphocholine cytidylyltransferase alpha in tetradecanoyl-13-acetate or macrophage-colony stimulating factor stimulated RAW264 cells.

PC is made via the CDP-choline pathway, in which CTP:phosphocholine cytidylyltransferase alpha (CTalpha), encoded by Pcyt1a, is the rate-limiting enzyme whose mRNA expression is strictly regulated. Previously, we reported that Ets1 enhanced and Net repressed CTalpha transcription by binding at the Ets binding site (-49/-47) in the Pcyt1a promoter. In this study, we asked if an Ets1 analogue, Ets2, also regulates CTalpha transcription and investigated the importance of its nuclear localization signal (NLS) and nuclear export signal (NES). Ets2 is primarily detected in the nucleus. Various mutated Ets2 proteins fused with enhanced green fluorescent protein were constructed to identify the NLS and NES in Ets2. Mutation of Ets2 at amino acids 404-410 results in a protein that is evenly distributed in the cell. Interestingly, an Ets2 protein deleted at the C-terminus (amino acids 1-392 present) was localized to the cytoplasm and site-specific mutation in the region 364-372 of this construct resulted in cytoplasmic and nuclear distribution. These results suggest that the NLS in Ets2 is between amino acids 404 and 410, and that the NES is between amino acids 364 and 372. Ets2 enhanced, but the mutant forms of Ets2 had little effects on the transcription of a CTalpha-reporter construct. When RAW264 cells, murine macrophage cell-line, were stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA) or macrophage-colony stimulating factor, the transcription of CTalpha was enhanced accompanied by increased mRNA of Ets2. These results suggest that the induction of Ets2 is important for CTalpha transcription by TPA and macrophage-colony stimulating factor.