The impact of concomitant Sjögren's disease on rheumatoid arthritis disease activity: a systematic review and meta-analysis.

OBJECTIVES: Rheumatoid arthritis (RA) and Sjögren's syndrome (SS) frequently co-exist but the consequence for RA disease activity of having concomitant SS (RA/SS) is not well established. We conducted a systematic review and meta-analysis to investigate the impact of SS on disease outcomes in individuals with RA. METHODS: We searched Web of Science (Core Collection, FSTA, Medline), PubMed and Cochrane databases, without language restriction. Studies reporting RA disease activity scores, joint counts, visual analogue scales (VAS), disability and joint damage, and comparing RA and RA/SS were selected. Outcomes reported in at least 3 studies in which the diagnosis of SS fulfilled classification criteria underwent meta-analysis, using a random effects model where heterogeneity was detected. RESULTS: The literature search identified 2991 articles and abstracts; 23 underwent full-text review and 16 were included. The studies included a total of 29722 patients (8614 with RA/SS and 21108 with RA). Using studies eligible for meta-analysis (744 patients with RA/SS and 4450 with RA), we found higher DAS-28 ESR scores (mean difference 0.50, 95% CI -0.008-1.006; p=0.05), higher swollen joint count scores (mean difference 1.05, 95% CI 0.42-1.67; p=0.001), and greater functional disability as measured by HAQ (mean difference 0.19, 95% CI 0.05-0.34; p=0.009) in RA/SS compared to RA alone. Other outcome measures (tender joint count, fatigue VAS) showed a numerical trend towards higher scores in RA/SS but were not statistically significant. CONCLUSIONS: RA/SS patients appear to have higher disease activity and more functional disability than patients with RA alone. The aetiology and clinical implications of this are unclear and warrant further investigation.

Recurrence rate after posterior percutaneous screw fixation without anterior debridement for pyogenic spondylitis compared with conservative treatment: a propensity score-matched analysis.

PURPOSE: Previous studies have shown that percutaneous pedicle screw (PPS) posterior fixation without anterior debridement for pyogenic spondylitis can improve patient quality of life compared with conservative treatment. However, data on the risk of recurrence after PPS posterior fixation compared with conservative treatment is lacking. The aim of this study was to compare the recurrence rate of pyogenic spondylitis after PPS posterior fixation without anterior debridement and conservative treatment. METHODS: The study was conducted under a retrospective cohort design in patients hospitalized for pyogenic spondylitis between January 2016 and December 2020 at 10 affiliated institutions. We used propensity score matching to adjust for confounding factors, including patient demographics, radiographic findings, and isolated microorganisms. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence of pyogenic spondylitis during the follow-up period in the matched cohort. RESULTS: 148 patients (41 in the PPS group and 107 in the conservative group) were included. After propensity score matching, 37 patients were retained in each group. PPS posterior fixation without anterior debridement was not associated with an increased risk of recurrence compared with conservative treatment with orthosis (HR, 0.80; 95% CI, 0.18-3.59; P = 0.77). CONCLUSIONS: In this multi-center retrospective cohort study of adults hospitalized for pyogenic spondylitis, we found no association in the incidence of recurrence between PPS posterior fixation without anterior debridement and conservative treatment.

Acute non-traumatic spinal subarachnoid hematomas: A report of five cases and a systematic review of literature.

BACKGROUND: There is a lack of evidence on spinal subarachnoid hematomas because of the rarity of their spontaneous development and difficulty in diagnosis. The aim of this study was to identify the characteristics and outcomes of surgically confirmed acute non-traumatic spinal subarachnoid hematomas from a multicenter surgical database and conduct a systematic review of existing literature. METHODS: Five surgically confirmed cases of acute non-traumatic spinal subarachnoid hematomas were identified from our multicenter database with 22 cases from a systematic review of existing literature. RESULTS: The mean age of the 27 patients was 59 years. The length of the hematoma was longer than five vertebrae in 70% of the patients, most commonly distributed in the thoracic spine; 63% of all cases were idiopathic, 30% were under anticoagulant therapy, and the remaining 7% presented with coagulation abnormalities. As many as 70% of the patients showed some improvement in neurological symptoms after surgery during a mean follow-up period of 14 months. CONCLUSIONS: This study elucidated the characteristics of acute non-traumatic spinal subarachnoid hematomas in patients who were surgically confirmed. Most patients were middle-aged, complained of back pain, and had the hematoma located in the thoracic spine. Seventy percent of the patients in this study had some improvement in their neurological status, most likely due to surgical decompression and hematoma evacuation.

Estimation of Minimum Biofilm Eradication Concentration (MBEC) on In Vivo Biofilm on Orthopedic Implants in a Rodent Femoral Infection Model.

The formation of a biofilm on the implant surface is a major cause of intractable implant-associated infection. To investigate the antibiotic concentration needed to eradicate the bacteria inside a biofilm, the minimum biofilm eradication concentration (MBEC) has been used, mostly against in vitro biofilms on plastic surfaces. To produce a more clinically relevant environment, an MBEC assay against biofilms on stainless-steel implants formed in a rat femoral infection model was developed. The rats were implanted with stainless steel screws contaminated by two Staphylococcus aureus strains (UAMS-1, methicillin-sensitive Staphylococcus aureus; USA300LAC, methicillin-resistant Staphylococcus aureus) and euthanized on days 3 and 14. Implants were harvested, washed, and incubated with various concentrations (64-4096 µg/mL) of gentamicin (GM), vancomycin (VA), or cefazolin (CZ) with or without an accompanying systemic treatment dose of VA (20 µg/mL) or rifampicin (RF) (1.5 µg/mL) for 24 h. The implant was vortexed and sonicated, the biofilm was removed, and the implant was re-incubated to determine bacterial recovery. MBEC on the removed biofilm and implant was defined as in vivo MBEC and in vivo implant MBEC, respectively, and the concentrations of 100% and 60% eradication were defined as MBEC100 and MBEC60, respectively. As for in vivo MBEC, MBEC100 of GM was 256-1024 µg/mL, but that of VA and CZ ranged from 2048-4096 µg/mL. Surprisingly, the in vivo implant MBEC was much higher, ranging from 2048 µg/mL to more than 4096 µg/mL. The addition of RF, not VA, as a secondary antibiotic was effective, and MBEC60 on day 3 USA300LAC biofilm was reduced from 1024 µg/mL with GM alone to 128 µg/mL in combination with RF and the MBEC60 on day 14 USA300LAC biofilm was reduced from 2048 µg/mL in GM alone to 256 µg/mL in combination with RF. In conclusion, a novel MBEC assay for in vivo biofilms on orthopedic implants was developed. GM was the most effective against both methicillin-sensitive and methicillin-resistant Staphylococcus aureus, in in vivo biofilms, and the addition of a systemic concentration of RF reduced MBEC of GM. Early initiation of treatment is desired because the required concentration of antibiotics increases with biofilm maturation.

Neurological severity evaluation using magnetic resonance imaging in acute spontaneous spinal epidural haematomas.

PURPOSE: This study aimed to elucidate the severity of neurological deficits in a large series of patients with acute spontaneous spinal epidural haematoma (SSEH) using magnetic resonance imaging (MRI). METHODS: We included 57 patients treated for acute SSEH at 11 institutions and retrospectively analysed their demographic and MRI data upon admission. We investigated MRI findings, such as the haematoma length and canal occupation ratio (COR). The neurological severity of SSEH was assessed based on the American Spinal Injury Association score on admission. RESULTS: Of the 57 patients, 35 (61%) presented with severe paralysis. The MRI analysis showed that SSEH was often located in the cervical spine, dorsal to the spinal cord, and spread over more than three vertebrae. No differences in age, sex, and aetiology were found between patients with and without severe paralysis. The hypo-intensity layer encircling the haematoma, intra-haematoma heterogeneity, and increased CORs were observed more frequently in the severe paralysis group. Furthermore, pathological examination of a dissected haematoma from one patient with a hypo-intensity layer revealed a collagen layer around the haematoma, and patients with intra-haematoma heterogeneity were more likely to have a bleeding predisposition. CONCLUSIONS: In this large series of patients with SSEH, we identified some MRI features associated with severe paralysis, such as the hypo-intensity layer, intra-haematoma heterogeneity, and increased COR. Accordingly, patients with these MRI characteristics should be considered for early surgical intervention.

A unique salvage operation strategy: implantation of the ulnar total elbow component to the radius to overcome large ulnar bone defect caused by infection after total elbow arthroplasty.

The elbow joints of patients with rheumatoid arthritis (RA) are often destroyed, and total elbow arthroplasty (TEA) is one treatment for these patients. However, patients with RA tend to develop surgical site infections due to immunosuppression. Once an implant is infected, reoperation may be difficult because of the risk of reinfection. In such patients, the infected site must be debrided thoroughly, although this might reduce the bone scaffold needed for re-TEA. We used a unique method to manage a large ulnar bone defect and an infected implant. The patient with RA had undergone TEA 15 years earlier. Etanercept was initiated to control disease activity; however, this treatment led to infection of the elbow prosthesis. Several surgical debridements were performed to eradicate the bacteria, which improved the symptoms of infection. However, most of the proximal ulna was lost, and it seemed impossible to fix the prosthesis using the remaining small ulna after debridement. Therefore, we planned to implant the ulnar component into the radius as a salvage technique. With this procedure, we provided the patient with elbow mobility and eradicated the infection. This is an alternative method for restoring function in an elbow with a massive bone defect in the ulna.

The limitations of mono- and combination antibiotic therapies on immature biofilms in a murine model of implant-associated osteomyelitis.

Treatment of implant-associated orthopedic infections remains challenging, partly because antimicrobial treatment is ineffective after a mature biofilm covers the implant surface. Currently, the relative efficacy of systemic mono- and combination standard-of-care (SOC) antibiotic therapies over the course of mature biofilm formation is unknown. Thus, we assessed the effects of cefazoline (CEZ), gentamicin (GM), and vancomycin, with or without rifampin (RFP), on Staphylococcus aureus biofilm formation during the establishment of implant-associated osteomyelitis in a murine tibia model. Quantitative scanning electron microscopy of the implants harvested on Days 0, 3, and 7 revealed that all treatments except CEZ monotherapy significantly reduced biofilm formation when antibiotics started at Day 0 (0.46- to 0.25-fold; p < 0.05). When antibiotics commenced 3 days after the infection, only GM monotherapy significantly inhibited biofilm growth (0.63-fold; p < 0.05), while all antibiotics inhibited biofilm formation in combination with RFP (0.56- to 0.44-fold; p < 0.05). However, no treatment was effective when antibiotics commenced on Day 7. To confirm these findings, we assessed bacterial load via colony-forming unit and histology. The results showed that GM monotherapy and all combination therapies reduced the colony-forming unit in the implant (0.41- to 0.23-fold; p < 0.05); all treatments except CEZ monotherapy reduced the colony-forming unit and staphylococcus abscess communities in the tibiae (0.40- to 0.10-fold; p < 0.05). Collectively, these findings demonstrate that systemic SOC antibiotics can inhibit biofilm formation within 3 days but not after 7 days of infection. The efficacy of SOC monotherapies, CEZ particularly, is very limited. Thus, combination treatment with RFP may be necessary to inhibit implant-associated osteomyelitis.

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.

Biofilm Producing Staphylococcus epidermidis (RP62A Strain) Inhibits Osseous Integration Without Osteolysis and Histopathology in a Murine Septic Implant Model.

Despite its presence in orthopaedic infections, Staphylococcus epidermidis's ability to directly induce inflammation and bone destruction is unknown. Thus, we compared a clinical strain of methicillin-resistant biofilm-producing S. epidermidis (RP62A) to a highly virulent and osteolytic strain of methicillin-resistant Staphylococcus aureus (USA300) in an established murine implant-associated osteomyelitis model. Bacterial burden was assessed by colony forming units (CFUs), tissue damage was assessed by histology and micro-computed tomography, biofilm was assessed by scanning electron microscopy (SEM), host gene expression was assessed by quantitative polymerase chain reaction, and osseous integration was assessed via biomechanical push-out test. While CFUs were recovered from RP62A-contaminated implants and surrounding tissues after 14 days, the bacterial burden was significantly less than USA300-infected tibiae (p < 0.001). In addition, RP62A failed to produce any of the gross pathologies induced by USA300 (osteolysis, reactive bone formation, Staphylococcus abscess communities, marrow necrosis, and biofilm). However, fibrous tissue was present at the implant-host interface, and rigorous SEM confirmed the rare presence of cocci on RP62A-contaminated implants. Gene expression studies revealed that IL-1ß, IL-6, RANKL, and TLR-2 mRNA levels in RP62A-infected bone were increased versus Sterile controls. Ex vivo push-out testing showed that RP62A-infected implants required significantly less force compared with the Sterile group (7.5 ± 3.4 vs. 17.3 ± 4.1 N; p < 0.001), but required 10-fold greater force than USA300-infected implants (0.7 ± 0.3 N; p < 0.001). Taken together, these findings demonstrate that S. epidermidis is a commensal pathogen whose mechanisms to inhibit osseous integration are limited to minimal biofilm formation on the implant, and low-grade inflammation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:852-860, 2020.

Feasibility of patient-oriented ultrasound joint selection: Cross-sectional observational study on rheumatoid arthritis.

Objective: Ultrasonography (US) is a useful tool for evaluating the activity of rheumatoid arthritis (RA) patients. As the systemic evaluation of many joints is time-consuming, a method to evaluate this activity with a smaller number of joints is needed. The aim of this study was to clarify whether the number of joints assessed may be reduced using patient-oriented joint selection.Methods: A total of 492 RA patients were recruited at Kyoto University Hospital. Bilateral metacarpophalangeal (MCP), (proximal) interphalangeal (PIP/IP), and wrist joints were evaluated by US. Gray scale and power Doppler imaging findings were scored by a 0-3 semi-quantitative method. Clinical assessments were performed by physicians who were blind to US results, and a questionnaire on subjective symptoms was collected from each patient.Results: The correlation between the US score of all 22 joints (US22) and patient-oriented painful joints (PtUS) or physician-oriented tender and/or swollen joints were moderate (Spearman's ρ = 0.435) and weak (ρ = 0.383), respectively. These correlations were weaker than that between the total US score of 5 preselected joints (unilateral 2MCP, 3MCP, 2PIP, 3PIP, and the wrist) and US22 (ρ = 0.813). However, when focusing on patients whose painful joints were 5 and more, the correlation between PtUS and US22 was markedly stronger (ρ = 0.757).Conclusion: Patient-oriented joint selection reflected actual joint inflammation to some extent. However, excessive reductions in the number of joints assessed need to be avoided even if patients do not have arthralgia because of the potential for underestimations.

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.

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.

Gaseous chemical compounds in indoor and outdoor air of 602 houses throughout Japan in winter and summer.

A nationwide survey of indoor air quality in Japan was conducted using four types of diffusive samplers. Gaseous chemical compounds such as carbonyls, volatile organic compounds (VOC), acid gases, basic gases, and ozone were measured in indoor and outdoor air of 602 houses throughout Japan in winter and summer. Four kinds of diffusive samplers were used in this study: DSD-BPE/DNPH packed with 2,4-dinitrophenyl hydrazine and trans-1,2-bis(2-pyridyl)ethylene coated silica for ozone and carbonyls; VOC-SD packed with Carboxen 564 particles for volatile organic compounds; DSD-TEA packed with triethanolamine impregnated silica for acid gases; and DSD-NH3 packed with phosphoric acid impregnated silica for basic gases. These samplers are small and lightweight and do not require a power source, hence, it was possible to obtain a large number of air samples via mail from throughout Japan. Almost all compounds in indoor air were present at higher levels in summer than in winter. In particular, formaldehyde, toluene, and ammonia were strongly dependent on temperature, and their levels increased with temperature. The nitrogen dioxide concentration in indoor air particularly increased only during winter and was well correlated with the formic acid concentration (correlation coefficient=0.959). Ozone concentrations in indoor air were extremely low compared with the outdoor concentrations. Ozone flowing from outdoor air may be decomposed quickly by chemical compounds in indoor air; therefore, it is suggested that the indoor/outdoor ratio of ozone represents the ventilation of the indoor environment.

Simultaneous determination of volatile organic compounds and carbonyls in mainstream cigarette smoke using a sorbent cartridge followed by two-step elution.

We developed a simple method for the simultaneous determination of volatile organic compounds (VOCs) and carbonyls in the mainstream cigarette smoke using a sorbent cartridge at ambient temperature without the traditional cryogenic impinger. A sorbent cartridge is installed between intake filter and the pump of the smoking machine. Collection of cigarette mainstream smoke is performed according to the Canadian Intense regime or the ISO regime. As adsorbent, Carboxen 572 (CX-572) is the most suitable for collection of VOCs and carbonyls in the mainstream cigarette smoke. Elution of VOCs and carbonyls from CX-572 is performed by the two-step elution with carbon disulfide and methanol. VOCs are eluted by first elution with carbon disulfide and carbonyls are eluted by second elution with methanol. For VOCs, a portion of eluate is analyzed by gas chromatography-mass spectrometry. For carbonyls, a portion of eluate is derivatized with enriched 2,4-dinitrophenylhydrazine solution and analyzed by high-performance liquid chromatography. Measurement values by CX-572 cartridge method are very close to those obtained by traditional impinger method except for 2-butanone. Impinger methods use 2,4-dinitrophenylhydrazine solution containing 50% water and 2-butanone-DNPhydrazone may be hydrolyzed with water. In the CX-572 method, the hydrolysis of 2-butanone is prevented because the eluate solution contains no water. CX-572 method can measure cigarette smoke resulting from not only one whole cigarette but also from one puff volume because of its high sensitivity and simple operation.