Role of MDA5 in regulating CXCL10 expression induced by TLR3 signaling in human rheumatoid fibroblast-like synoviocytes.

C-X-C motif chemokine 10 (CXCL10) is an inflammatory chemokine and a key molecule in the pathogenesis of rheumatoid arthritis (RA). Melanoma differentiation-associated gene 5 (MDA5) is an RNA helicase that plays a role in innate immune and inflammatory reactions. The details of the regulatory mechanisms of CXCL10 production and the precise role of MDA5 in RA synovitis have not been fully elucidated. The aim of this study was to examine the role of MDA5 in regulating CXCL10 expression in cultured human rheumatoid fibroblast-like synoviocytes (RFLS). RFLS was stimulated with Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA mimetic. Expression of interferon beta (IFN-ß), MDA5, and CXCL10 was measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay. A neutralizing antibody of IFN-ß and siRNA-mediated MDA5 knockdown were used to determine the role of these molecules in regulating CXCL10 expression downstream of TLR3 signaling in RFLS. Poly I:C induced IFN-ß, MDA5, and CXCL10 expression in a concentration- and time-dependent manner. IFN-ß neutralizing antibody suppressed the expression of MDA5 and CXCL10, and knockdown of MDA5 decreased a part of CXCL10 expression (p < 0.001). The TLR3/IFN-ß/CXCL10 axis may play a crucial role in the inflammatory responses in RA synovium, and MDA5 may be partially involved in this axis.

Non-vascularized bone grafting in scaphoid nonunion: principles and type of fixation.

In scaphoid fractures, delayed diagnosis and nonunion are fairly common as a result of several factors, including the difficulty of radiographic diagnosis of non-displaced fractures and underestimation of the injury by the patient. Main factors to consider when deciding treatment are the type of fracture and fracture stability. In the stable nonunion (Type D1 according to the Filan and Herbert classification, or linear type of Ikeda's classification), percutaneous screw fixation without bone graft is recommended. The indications of non-vascularized bone grafting are as follows: (1) arthroscopic cancellous bone graft in type D1 and cystic type of Ikeda's classification. (2) tricortical bone graft from the iliac crest in type D2 or D3 if the possibility of avascular necrosis of the proximal fragment is excluded. In this paper, our non-vascularized bone grafting for scaphoid nonunion would like to be described mainly about principles and type of fixation.

Diseases and comorbidities associated with early-onset scoliosis: a retrospective multicenter analysis.

PURPOSE: To determine the frequencies of various diseases associated with all types of early-onset scoliosis, both idiopathic and nonidiopathic. METHODS: Retrospective collection of patients within a 21-year interval. Children under 10 years old presenting with scoliosis were included. Medical records were used to collect: identifier, date of birth, sex, diagnosis, follow-up, curve pattern, comorbidities, initial and final cobb angle. Different patient variables were tabulated with associated comorbidities for comparison. RESULTS: The cohort contained 469 patients, with 227(48.4%) males and 242(51.6%) females. Total comorbidities equaled 1051, where 190 were unique. Only 124(26.4%) patients had an isolated diagnosis of early-onset scoliosis, 79(16.8%) had a single comorbidity, and 266(56.7%) had multiple comorbidities. "Global developmental delay" was most commonly observed, 198(42.2%) times. The central nervous system was involved more often than other organ systems, seen in 394(54.4%) instances. Males had more comorbidities than females. Idiopathic patients had the least number of comorbidities, while neuromuscular patients had the most. Idiopathic types had more musculoskeletal conditions, while congenital types had more cardiovascular diseases. Curve sides did not affect distributions. Cases which progressed had more comorbidities, especially in the respiratory, digestive, and cardiovascular systems. Diseases that could affect either extremity or side, were more likely to be bilateral. CONCLUSIONS: Early-onset scoliosis patients may present with complex comorbidities in multiple organ systems. The most commonly observed disease entities were: global developmental delay, developmental dysplasia of the hip, and epilepsy. Clinicians should be aware of the common associations, in order to screen for and begin appropriate investigations, referrals, and treatments in affected cases. LEVEL OF EVIDENCE: Level III.

Deriving a Novel Score for the Stratification of Risk Progression in Early-onset Scoliosis: A Multicenter Initiative.

STUDY DESIGN: This was a retrospective multicenter study. OBJECTIVE: To develop a novel progression risk stratification scoring system for early-onset scoliosis. SUMMARY OF BACKGROUND DATA: There is a lack of investigations into variables affecting the risk of curve progression in early-onset scoliosis, which prevents stratification. A novel risk score system is needed to help in progression risk estimation. METHODS: A retrospective analysis was done at three centers, from 1995 to 2020. Scoliosis cases before the age of 10 years, were included. Medical identifier, date of birth, sex, primary diagnosis, curve type, date/modality of treatment, date of follow-up appointments, and Cobb angles, were collected. Five ranks were selected for stratification. Categories with the same ranks were discarded. Point scores started at 0, for the lowest risk, and ended at 4, for highest risk. Iterations of variable combinations were conducted and clinical relevance was determined by evaluating sensitivity, specificity, positive predictive value, and negative predictive value based on score ranges for low and high risk of progression. RESULTS: A total of 476 (230 males, 246 females) early-onset scoliosis patients were collected. The average age at diagnosis was 4.8 years (SD±2.8 yr). The average follow-up duration was 9.3 years (SD±6.9 yr, range: 5 mo-38 yr). Appointments totaled 2911, giving 2182 observations for the analysis. Patient observations numbered: 800 (36.7%) ending in progression, 1265 (58.0%) for nonprogression, 117 (5.4%) for inadequate follow-up, and 368 (16.9%) for rapid progression. The risk scoring system contained four categories: etiology, age, curve magnitude, and curve type. Categorized point combinations totaled 755, giving 1975 iterations. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated to be 85.8%, 96.5%, 89.7%, and 95.1%, respectively. CONCLUSION: A novel progression risk score for early-onset scoliosis was derived. The system can reliably differentiate between low and high-risk cases in clinical settings. Further validation in other regions may be important for verifying clinical relevance. LEVEL OF EVIDENCE: Level 3.

Treating to target matrix metalloproteinase 3 normalisation together with disease activity score below 2.6 yields better effects than each alone in rheumatoid arthritis patients: T-4 Study.

OBJECTIVES: To assess whether therapy to achieve both a disease activity score in 28 joints (DAS28) less than 2.6 and matrix metalloproteinase (MMP) 3 normalisation offers better outcomes than either target alone in early rheumatoid arthritis (RA) at 56 weeks: Treating to Twin Targets (T-4) Study. METHODS: 243 early RA patients were randomly allocated to one of four strategy groups: routine care (R group; n=62); DAS28-driven therapy (D group; n=60); MMP-3-driven therapy (M group; n=60); or both DAS28 and MMP-3-driven therapy group (twin; T group; n=61). Medication was started with sulfasalazine (1 g/day) in all intervention groups. Targets were DAS28 less than 2.6 for the D group, MMP-3 normalisation for the M group and both DAS28 less than 2.6 and MMP-3 normalisation for the T group. If the value in question did not fall below the previously measured level, medication was intensified, including methotrexate, other disease-modifying antirheumatic drugs and biological agents. Primary, secondary and outcome measures consisted of the proportions of patients showing clinical remission (DAS28 <2.6), radiographic non-progression (Δmodified total Sharp score ≤0.5), normal physical function (modified health assessment questionnaire score 0), or comprehensive disease remission defined as the combination of clinical remission, radiographic non-progression and normal physical function. RESULTS: Clinical remission at 56 weeks was achieved by more patients in the T group (56%) than in the R group (p<0.0005) or M group (p<0.0005). CONCLUSIONS: Results of the T-4 Study reveal that a twin target strategy can achieve a high clinical remission rate in early RA.

The incidence and prevalence of early-onset scoliosis: a regional multicenter epidemiological study.

BACKGROUND CONTEXT: Despite the many advances in understanding and treating early-onset scoliosis, the incidence and prevalence of this disease in the population remains unknown. Such knowledge is important for guiding clinical practice, directing research and raising awareness. PURPOSE: To identify the incidence and prevalence of early-onset scoliosis, including all categories, within the population. STUDY DESIGN: A regional multicenter retrospective cohort study PATIENT SAMPLE: All patients diagnosed with early-onset scoliosis in the region, who were followed-up between January 2000 and December 2020. OUTCOME MEASURES: Frequency distributions for early-onset scoliosis subtypes, demographics, curve patterns and progression statuses. METHODS: Relevant population data, for children under 10 years old, was extracted from the official government census for the years 2000 to 2020. Identification of cases was carried out by pediatricians at mandatory government funded regular child wellness check-up visits. Outpatient records were reviewed for all included patients, with extraction of the following: Medical identifier, date of birth, date of initial visit, sex, primary diagnosis, length of follow-up, curve pattern, initial cobb angle, and final cobb angle. Incidence and prevalence values were calculated using population figures and case numbers. Kaplan-Meier survival analysis and Log-rank testing was performed on curve progression data. RESULTS: The regional population of children, under the age of 10 years, included a total of 2,295,929 children, 1,170,149 (51.0%) males and 1,125,780 (49.0%) females, between the years 2000 and 2020. Early-onset scoliosis cases followed within the same timeframe, totaled 469 patients, 227 (48.4%) males and 242 (51.6%) females. The annual incidence of early-onset scoliosis was found to be 0.019% (95% CI: 0.015%-0.023%), and the prevalence was 0.077% (95% CI: 0.059%-0.096%). The most common age at first presentation was 6 years old. More females (51.6%) than males (48.4%) were observed, and more left-sided curves (54.2%) than right-sided curves (45.8%) were encountered, with the majority being single thoracic curves (38.2%). Scoliosis curves did not progress in 44.3% of cases, while they progressed in 38% of them. Follow-up was inadequate to determine progression status in 17.7% of cases. Neuromuscular etiologies were the most common, at 40.1%, of which 83.5% had cerebral palsy. CONCLUSIONS: Based on the regional population included in this study, the annual incidence of early-onset scoliosis in children under 10 years old was calculated to be 0.019%, while the prevalence of early-onset scoliosis in children under 10 years old was found to be 0.077%.

Prevalence of reactivation of hepatitis B virus replication in rheumatoid arthritis patients.

Reactivation of hepatitis B involves the reappearance of active necroinflammatory liver disease after an inactive hepatitis B surface antigen (HBsAg) carrier state or resolved hepatitis B, occurring during or after immunosuppression therapy or chemotherapy. We prospectively investigated the reactivation rate for hepatitis B virus (HBV) DNA replication in cases of rheumatoid arthritis (RA) with resolved hepatitis B. HBV markers were evaluated in 428 RA patients. Patients with positive findings of HBsAg or HBV DNA at enrolment were excluded. The study population comprised 422 RA patients, with resolved hepatitis B diagnosed in 135 patients based on HBsAg-negative and antihepatitis B core antibody/antihepatitis B surface antibody-positive results. HBV DNA was measured every 3 months in this group, and if HBV DNA became positive after enrolment, measurement was repeated every month. HBV DNA became positive (≥3.64 log copies/mL) in 7 of 135 patients for 12 months. Use of biologic agents was significantly more frequent in patients who developed reactivation of HBV DNA replication (85.7%) than in patients who did not (36.0%, p = 0.008). Hazard ratios for use of biologic agents and etanercept were 10.9 (p = 0.008) and 6.9 (p = 0.001), respectively. RA patients with resolved hepatitis B need careful monitoring when receiving biologic agents, regardless of HBV DNA levels.

Epidemiology of Dupuytren's Disease in Japanese General Population.

Background: Dupuytren's disease (DD) is well known as a fibromatous disorder of the palmar aponeurosis. Although there is a large body of literature on the etiology of DD in Europe, there have been few studies in Japan. The purpose of our study was to investigate the etiology and risk factors of DD in a large population in Japan. Methods: The subjects were voluntary participants from the 2014 Health Promotion Project, and 1,112 individuals were included (421 men and 691 women; mean age = 54.2 ± 15.3 years) in this study. The severity of DD was assessed using the Meyerding classification. All participants completed a questionnaire on age, sex, lifestyle, and occupations. All participants also completed the Short Form Health Survey (SF-36) to investigate the QOL. Fasting venous blood specimens were taken for biochemical analysis. Results: DD was found in 44 participants (3.9%). The prevalence was 8.3% among the men and 1.3% among the women. The prevalence in these older than 60 years was 7.7% (men; 18.5%, women; 2.4%). There were 17 participants that had DD of both hands. Multiple digits were affected in 9 participants. The ring finger was the most affected finger (71.2%), followed by the little finger (16.4%), and middle finger (12.3%). In Meyerding classification, 39 cases were stage 0, one case was stage 1, and four cases were stage 2. The multivariate logistic regression analysis revealed that age, sex, smoking, and occupation were significantly associated with DD. There was no significant association between DD and other parameters. When associations between DD and the SF-36 subscales were analyzed, there were significant associations with physical functioning, physical role functioning, and mental health. Conclusions: Our study is the largest in Japan to date. These results will provide very useful data to aid understanding of DD.

Usefulness of serum hyaluronic acid levels as a predictor of incidence of hand osteoarthritis analyzed by longitudinal analysis from the Iwaki cohort.

The factors predicting hand osteoarthritis (HOA) in patients remain unknown. We aimed to investigate the usefulness of serum hyaluronic acid (sHA) levels in predicting HOA progression from a 6-year longitudinal epidemiological study. A total of 417 participants in the Iwaki cohort were followed-up over 6 years. Hand and knee radiographs taken at baseline and follow-up were scored according to Kellgren-Lawrence grades and Kallman score. Participants were classified into the HOA group and the non-HOA group. sHA levels at baseline were determined by ELISA. Correlations between sHA levels, the number of involved joints, and Kallman score were estimated. Factors related to the incidence or progression of HOA over 6 years were analyzed. The prevalence of HOA was 19.9% at baseline, and 3.6 ± 2.1 joints were involved. sHA levels in the HOA group at baseline were significantly higher than in the non-HOA group (p < 0.001) and correlated with the number of involved joints (r = 0.399, p < 0.001) and Kallman score (r = 0.540, p < 0.001). The incidence rate was 14.5%, and the progression rate was 46.1% over 6 years. Higher sHA levels at baseline were the risk factor of HOA incidence. Thus, sHA levels predicted the incidence of HOA over 6 years.

Tumor-necrosis factor-alpha induces retinoic acid-inducible gene-I in rheumatoid fibroblast-like synoviocytes.

Tumor-necrosis factor-alpha (TNF-alpha) is a potent proinflammtory cytokine and a key molecule in the pathogenesis of rheumatoid arthritis (RA). Retinoic acid-inducible gene-I (RIG-I) is a DExH box protein, which is known to play a role in the inflammatory and immune reactions. We previously reported about potential involvement of RIG-I in synovial inflammation in RA. In the present study, we demonstrated the expression of RIG-I in fibroblast-like synoviocytes stimulated with TNF-alpha. RNA interference against interferon (IFN)-beta abolished the TNF-alpha-induced RIG-I expression. In addition, knockdown of RIG-I partially inhibited the TNF-alpha-induced expression of CC chemokine ligand (CCL) 5, a chemokine with chemotactic activity toward lymphocytes and monocytes. These findings suggest that the TNF-alpha/IFN-beta/RIG-I/CCL5 pathway may be involved in the pathogenesis of synovial inflammation in RA.