Myeloid-derived suppressor cell-derived osteoclasts with bone resorption capacity in the joints of arthritic SKG mice.

Background: Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells with immunosuppressive functions. It is known that MDSCs are expanded at inflammatory sites after migrating from bone marrow (BM) or spleen (Sp). In chronic inflammatory diseases such as rheumatoid arthritis (RA), previous reports indicate that MDSCs are increased in BM and Sp, but detailed analysis of MDSCs in inflamed joints is very limited. Objective: The purpose of this study is to characterize the MDSCs in the joints of mice with autoimmune arthritis. Methods: We sorted CD11b+Gr1+ cells from joints (Jo), bone marrow (BM) and spleen (Sp) of SKG mice with zymosan (Zym)-induced arthritis and investigated differentially expressed genes (DEGs) by microarray analysis. Based on the identified DEGs, we assessed the suppressive function of CD11b+Gr1+ cells from each organ and their ability to differentiate into osteoclasts. Results: We identified MDSCs as CD11b+Gr1+ cells by flow cytometry and morphological analysis. Microarray analysis revealed that Jo-CD11b+Gr1+ cells had different characteristics compared with BM-CD11b+Gr1+ cells or Sp-CD11b+Gr1+ cells. Microarray and qPCR analysis showed that Jo-CD11b+Gr1+ cells strongly expressed immunosuppressive DEGs (Pdl1, Arg1, Egr2 and Egr3). Jo-CD11b+Gr1+ cells significantly suppressed CD4+ T cell proliferation and differentiation in vitro, which confirmed Jo-CD11b+Gr1+ cells as MDSCs. Microarray analysis also revealed that Jo-MDSCs strongly expressed DEGs of the NF-κB non-canonical pathway (Nfkb2 and Relb), which is relevant for osteoclast differentiation. In fact, Jo-MDSCs differentiated into osteoclasts in vitro and they had bone resorptive function. In addition, intra-articular injection of Jo-MDSCs promoted bone destruction. Conclusions: Jo-MDSCs possess a potential to differentiate into osteoclasts which promote bone resorption in inflamed joints, while they are immunosuppressive in vitro.

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.

Arthroscopic superior capsule reconstruction augmentation using a semitendinosus autograft in massive reparable rotator cuff tears.

Background: Arthroscopic superior capsule reconstruction (SCR) augmentation is a viable treatment option for massive reparable cuff tears. This study aimed to retrospectively compare clinical and imaging outcomes of patients with reparable massive rotator cuff tears after arthroscopic rotator cuff repair (ARCR) with those after SCR augmentation using a semitendinosus autograft. Methods: We retrospectively compared 50 patients with massive reparable rotator cuff tears who underwent ARCR and SCR augmentation (n = 25 each). Patients were clinically followed up for at least 2 years, and the American Shoulder and Elbow index, other patient-reported outcomes, active range of motion, and radiography and magnetic resonance imaging findings were assessed. Results: At the final follow-up, both patient groups showed significant improvements in forward elevation in range of motion and visual analog scale scores. Improvements in the American Shoulder and Elbow scores in the SCR augmentation group were significantly superior to those in the ARCR group (48.3 and 28.9, P < .01). There was a significant difference in the retear rate between the SCR augmentation group and ARCR group (20% and 56%, respectively; P = .009). Conclusion: Our study demonstrated that patient-reported outcomes and retear rates in patients who underwent SCR augmentation with rotator cuff repair for massive rotator cuff tears significantly improved compared with those in patients who underwent ARCR without augmentation. Augmentation with semitendinosus autografting during rotator cuff repair represents a solution for patients with massive reparable rotator cuff tears.

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.

Drug-dependent analgesic efficacy in interscalene block for postoperative pain after arthroscopic rotator cuff repair: a comparison between ropivacaine and levobupivacaine.

Background: Interscalene brachial plexus block (ISB) for arthroscopic rotator cuff repair (ARCR) provides high analgesic efficacy for postoperative pain. However, different drug efficacies remain unclear. This retrospective study compared the efficacy of ropivacaine and levobupivacaine in a single-dose ISB for pain control after ARCR. Methods: This study included 173 patients who underwent ARCR; they were divided into the ISBR group (n = 61) that received ISB with 20 mL 0.375% ropivacaine and 3.3 mg dexamethasone, and the ISBL group (n = 112) that received ISB with 20 mL 0.25% levobupivacaine and 3.3 mg dexamethasone. Visual analog scale (VAS) pain scores were evaluated at 1, 4, 8, 12, 24, and 48 hours, postoperatively. Rebound pain was defined as a difference of ≥ 5 points between the highest and lowest VAS pain scores. Results: The mean VAS pain scores at 1 hour were not significantly different between the groups. ISBL administration resulted in significantly lower VAS pain scores at 4, 8, 12, and 24 hours than ISBR administration. Rebound pain rates in the ISBR and ISBL groups were 41.0% and 17.9%, respectively. Rebound pain was more frequent in the ISBR than in the ISBL group. Conclusion: ISB with levobupivacaine and dexamethasone can provide more effective postoperative pain control after ARCR than ropivacaine and dexamethasone.

Fulminant myocarditis in a young woman with mixed connective tissue disease: a case report.

Background: Although cardiac involvement is relatively common in mixed connective tissue disease (MCTD), few reports on MCTD-associated fulminant myocarditis are available. Case summary: A 22-year-old woman diagnosed with MCTD was admitted to our institution for cold-like symptoms and chest pain. Echocardiography revealed that the left ventricular ejection fraction (LVEF) had rapidly decreased from 50 to 20%. Because endomyocardial biopsy revealed no significant lymphocytic infiltration, immunosuppressant drugs were not started initially; however, steroid pulse therapy (methylprednisolone, one1000 mg/day) was initiated due to prolonged symptoms and unimproved haemodynamics. Despite strong immunosuppressant therapy, the LVEF did not improve, and severe mitral regurgitation appeared. Three days after steroid pulse therapy initiation, she experienced a sudden cardiac arrest; thus, venoarterial extracorporeal membrane oxygenation (VA-ECMO) and intra-aortic balloon pumping (IABP) were initiated. Subsequent immunosuppressant therapy was continued with prednisolone (100 mg/day) and intravenous cyclophosphamide (1000 mg). Six days after steroid therapy initiation, the LVEF improved to 40% and then recovered to near-normal levels. After successful weaning off of VA-ECMO and IABP, she was discharged. Thereafter, a detailed histopathological examination revealed multi-focal signs of ischaemic micro-circulatory injury and diffuse HLA-DR in the vascular endothelium, suggesting an autoimmune inflammatory response. Discussion: We report a rare case of fulminant myocarditis in a patient with MCTD who recovered with immunosuppressive treatment. Despite the absence of significant lymphocytic infiltration findings on histopathological examination, patients with MCTD may experience a dramatic clinical course. Although it is unclear whether myocarditis is triggered by viral infections, certain autoimmune mechanisms may lead to its development.

Evaluation of hypervascularity in synovitis of the shoulder using ultrasound: comparison of preoperative ultrasound findings and intraoperative arthroscopic findings.

Background: Synovitis of the shoulder causes pain; however, it is difficult to accurately determine the area and degree of synovitis from preoperative images. This study investigated the correlation between intraoperative arthroscopic findings and preoperative power Doppler ultrasonography (PDUS) findings for synovitis evaluation. Methods: Forty patients (mean age = 62.0 years; 24 men and 16 women) underwent arthroscopic surgery for partial rotator cuff tears. Three observation areas were evaluated: rotator interval (RI), subacromial bursa, and bicipital groove. The Doppler flow areas and PDUS grade were measured one day before surgery. Arthroscopic findings were visualized intraoperatively and classified into 3 groups: pale, pink, and red. The correlation between the arthroscopic classification and PDUS findings was analyzed. Results: The correlation between intraoperative arthroscopic classification and preoperative PDUS findings, Doppler flow area and PDUS grade, was high for the RI (r = 0.82, 0.70). There was no correlation for the subacromial bursa (r = 0.01, -0.02) and the bicipital groove (r = -0.03, 0.3). Conclusion: Hypervascularity findings in the PDUS were highly correlated with arthroscopic color classification in the RI. Therefore, visualization of hypervascularity in the RI area could be a reliable measure for the assessment of glenohumeral synovitis in patients with partial-thickness rotator cuff tear.

Soluble guanylate cyclase stimulator reduced the gastrointestinal fibrosis in bleomycin-induced mouse model of systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune-mediated connective tissue disorder. Although the etiology of the disease remains undetermined, SSc is characterized by fibrosis and proliferative vascular lesions of the skin and internal organs. SSc involves the gastrointestinal tract in more than 90 % of patients. Soluble guanylate cyclase (sGC) stimulator is used to treat pulmonary artery hypertension (PAH) and has been shown to inhibit experimental skin fibrosis. METHODS: Female C57BL/6J mice were treated with BLM or normal saline by subcutaneous implantation of osmotic minipump. These mice were sacrificed on day 28 or day 42. Gastrointestinal pathologies were examined by Masson Trichrome staining. The expression of fibrosis-related genes in gastrointestinal tract was analyzed by real-time PCR, and the levels of collagen in the tissue were measured by Sircol collagen assay. To evaluate peristaltic movement, the small intestinal transport (ITR%) was calculated as [dyeing distance × (duodenum - appendix)] - 1 × 100 (%). We treated BLM-treated mice with sGC stimulator or DMSO orally and analyzed them on day 42. RESULTS: Histological examination revealed that fibrosis from lamina propria to muscularis mucosa in the esophagus was significantly increased in BLM-treated mice, suggesting that BLM induces esophageal hyperproliferative and prefibrotic response in C57BL/6J mice. In addition, the gene expression levels of Col3a1, CCN2, MMP-2, MMP-9, TIMP-1, and TIMP-2 in the esophagus were significantly increased in BLM-treated mice. More severe hyperproliferative and prefibrotic response was observed in the mice sacrificed on day 42 than the mice sacrificed on day 28. The ITR% was found to be significantly lower in BLM-treated mice, suggesting that gastrointestinal peristaltic movement was reduced in BLM-treated mice. Furthermore, we demonstrated that sGC stimulator treatment significantly reduced hyperproliferative and prefibrotic response of esophagus and intestine in BLM-treated mice, by histological examination and Sircol collagen assay. CONCLUSIONS: These findings suggest that BLM induces gastrointestinal hyperproliferative and prefibrotic response in C57BL/6J mice, and treatment with sGC stimulator improves the BLM-induced gastrointestinal lesion.

Temperature limits to deep subseafloor life in the Nankai Trough subduction zone.

Microorganisms in marine subsurface sediments substantially contribute to global biomass. Sediments warmer than 40°C account for roughly half the marine sediment volume, but the processes mediated by microbial populations in these hard-to-access environments are poorly understood. We investigated microbial life in up to 1.2-kilometer-deep and up to 120°C hot sediments in the Nankai Trough subduction zone. Above 45°C, concentrations of vegetative cells drop two orders of magnitude and endospores become more than 6000 times more abundant than vegetative cells. Methane is biologically produced and oxidized until sediments reach 80° to 85°C. In 100° to 120°C sediments, isotopic evidence and increased cell concentrations demonstrate the activity of acetate-degrading hyperthermophiles. Above 45°C, populated zones alternate with zones up to 192 meters thick where microbes were undetectable.

Suprascapular nerve block versus interscalene block for analgesia after arthroscopic rotator cuff repair.

OBJECTIVE: To retrospectively compare the efficacy of suprascapular nerve block (SSNB) versus interscalene block (ISB) for analgesia after arthroscopic rotator cuff repair (ARCR). METHODS: Ninety-seven patients who underwent ARCR were retrospectively divided into three groups. Group S comprised 33 patients who received SSNB, group I comprised 52 patients who received ISB, and group C comprised 12 patients who received a glenohumeral injection as a control. SSNB and ISB were performed with 20 ml of 0.375% ropivacaine before surgery, while glenohumeral injection was performed after surgery. The Visual analog scale (VAS) pain scores were recorded at 1,3, and 6 h and 1, 3, and 6 days postoperatively. The total number of additional analgesic administrations was also counted for 6 days postoperatively. RESULTS: Compared with group C, the VAS pain score was significantly lower in group S at 1 h and 6 days postoperatively, and in group I at 1 and 3 h postoperatively. There were no significant differences between groups S and I in the VAS pain scores, or the administration of additional analgesia. There were no major complications associated with SSNB or ISB. CONCLUSION: There were no significant differences between SSNB and ISB in the duration of analgesia and the VAS pain scores after ARCR.

Very high frequency of fragility fractures associated with high-dose glucocorticoids in postmenopausal women: A retrospective study.

Purpose To evaluate the incidence of fragility fractures associated with high-dose glucocorticoid therapy in patients with systemic rheumatic disease. METHODS: A retrospective study of patients who were treated with high-dose prednisolone (> 0.8 mg/kg) for systemic rheumatic disease at Kobe University Hospital from April 1988 to March 2012. The primary outcome was a major osteoporotic fracture (defined as a clinical vertebral, hip, forearm, or proximal humerus fracture) after high-dose glucocorticoid therapy. For postmenopausal women and men over 40 of age, the patient's fracture risk at the beginning of high-dose glucocorticoid therapy was assessed by the World Health Organization's Fracture Risk Assessment Tool (FRAX®). Results Of 229 patients (median age: 49 years), 57 suffered a fragility fracture during the observation period (median observation period: 1558 days). Of 84 premenopausal patients, 5 suffered a fracture. In contrast, of 86 postmenopausal female, 36 suffered a fracture. Fragility fractures were far more frequent than predicted by the FRAX® score. Patients with FRAX® scores over 8.3% had a particularly high risk of fracture. Conclusions Fragility fractures associated with high-dose glucocorticoid therapy are common among postmenopausal women. Extreme care should be taken especially for postmenopausal women when high-dose glucocorticoid therapy is required.

Classification of Olecranon Stress Fractures in Baseball Players.

BACKGROUND: Although the onset mechanism of an olecranon stress fracture (OSF) due to a throwing disorder is believed to involve valgus extension overload, olecranon posteromedial impingement, or triceps traction force, this issue is still debated in the literature. PURPOSE: To establish a classification system for the different types of OSFs to improve diagnosis and clarify the onset mechanism. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 200 baseball players (198 male, 2 female; mean age, 16.1 years; age range, 13-27 years) who were diagnosed with an OSF from January 1987 to July 2012 were studied. Combined disorders as well as the direction and form of the fracture line were analyzed on plain radiographs, computed tomography, and magnetic resonance imaging. Furthermore, the presence or absence of ulnar collateral ligament (UCL) injuries and avulsion fractures of the lower pole of the medial epicondyle was determined by imaging findings to calculate the combined percentage of OSFs. In addition, the prevalence of OSFs was evaluated among patients who were evaluated between April 2008 and March 2011 for throwing elbow disorders. RESULTS: There were 5 types of OSFs identified in the new classification system: physeal, classic, transitional, sclerotic, and distal. The physeal type was further separated into stages 1 to 4 based on severity. The mean age for each type identified was as follows: physeal, 14.1 years; classic, 18.6 years; transitional, 16.9 years; sclerotic, 18.0 years; and distal, 19.6 years. A concomitant UCL injury and/or medial epicondyle avulsion fracture was diagnosed in 71% to 95% of cases, depending on the OSF type. Among baseball-related elbow disorders, the incidence of OSFs was 5.4%. CONCLUSION: This study presents a new classification system for the different types of OSFs based on the origin and direction of the fracture plane. This new system was strongly influenced by the age at symptom onset. Such information is essential for successful open reduction and internal fixation by ensuring that fixation pressure is perpendicular to the fracture plane, which will avoid the recurrence of stress fractures. In addition, the prevalence of UCL injuries suggests that it is a major risk factor for the development of OSFs.

Recovery of injured adrenal medulla by differentiation of pre-existing undifferentiated chromaffin cells.

We described previous that the adrenal medulla recovers rapidly from the injuries due to salinomycin. In the present study we found the recovery to be apparently due to differentiation of pre-existing, primitive undifferentiated, chromaffin cells, rather than mitosis, as evidenced by lack of incorporation of 5-bromo-2-deoxyuridine in the differentiating and/or differentiated chromaffin cells. Electron-dense, striated fibrils observed within the necrotic cells and in the extracellular space were presumed to be intermediate degradation products. Schwann cells actively functioned as phagocytes in this study, and seemed to indirectly stimulate the differentiation of undifferentiated chromaffin cells.