Extension contracture stiff knee in haemophilia: Surgical timing and procedure for total knee arthroplasty.

INTRODUCTION: Total knee arthroplasty (TKA) for a stiff knee of patients with haemophilia (PWH) represents a challenge for orthopaedic surgeons for the difficulties of exposing the knee and high complication rate compared to a flexible knee. AIM: To optimize the surgical exposure in primary TKA for PWH and to propose a threshold angle of extension contracture in treating haemophilic knee joints, retrospectively. METHODS: Sixty-seven primary TKAs for PWH (mean age, 48 years) were performed, and incisional approaches to joint were standard (58 cases) and V-Y quadricepsplasty (V-Y) (9 cases). The decision of surgical approach was decided intraoperatively by two surgeons. Pre- and post-knee angles were evaluated in each group. Variables in the V-Y group were evaluated using univariate logistic regression analysis and receiver operating characteristic curve analysis. RESULTS: Univariate logistic regression analysis demonstrated that the preoperative range of motion (ROM) and flexion were significantly associated with V-Y. Threshold values of preoperative flexion and ROM resulting in V-Y using receiver operating characteristic analysis were 45° and 35°, respectively. CONCLUSIONS: Primary TKA for PWH using a standard approach may be performed before the stage preoperative flexion <45° and ROM <35°.

Clinical Outcomes After First Metatarsophalangeal Joint Arthrodesis by Flat Cut Joint Preparation With Individual Adjustment for Sagittal Alignment.

Sagittal misalignment is a major cause of patient dissatisfaction and re-operation after first metatarsophalangeal (MTP) joint arthrodesis. The stereotypical application of the fixed angle would be undesirable, especially in cases of flat or cavus foot. We retrospectively reviewed 31 cases (27 patients) in which first MTP joint arthrodesis was performed using the flat cut joint preparation technique with reference to the plantar clearance beneath the pulp of the toe while simulating weightbearing by pushing a board against the sole. The most common underlying cause of surgery was rheumatoid arthritis (22 cases [71%]). Clinical outcomes were evaluated by the Japanese of Surgery of the Foot (JSSF) hallux scale and the self-administered foot evaluation questionnaire (SAFE-Q). Twenty-three cases were also examined by pedobarography to evaluate postoperative walking plantar pressure. At the most recent follow-up of a mean 19.6 months, the toe-to-floor distance of the hallux in static standing posture was a mean of 2.5 mm (range, 0-10 mm). All but 1 foot (97%) achieved bone union. There were no complications or revisions due to misalignment of the fused MTP joint. JSSF hallux scales improved significantly from 47 preoperatively to 82 postoperatively. All subscale scores except general health and well-being in the SAFE-Q improved significantly at final follow-up versus preoperative period. Plantar pressure under the hallux was correlated with the toe-to-floor distance but not radiographic parameter. In conclusion, first MTP joint arthrodesis achieved good clinical outcomes when using toe-to-floor distance and Kirschner wire template for flat cut joint preparation.

Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis.

OBJECTIVES: Synovial fibroblasts (SFs) are one of the major components of the inflamed synovium in rheumatoid arthritis (RA). We aimed to gain insight into the pathogenic mechanisms of SFs through elucidating the genetic contribution to molecular regulatory networks under inflammatory condition. METHODS: SFs from RA and osteoarthritis (OA) patients (n=30 each) were stimulated with eight different cytokines (interferon (IFN)-α, IFN-γ, tumour necrosis factor-α, interleukin (IL)-1ß, IL-6/sIL-6R, IL-17, transforming growth factor-ß1, IL-18) or a combination of all 8 (8-mix). Peripheral blood mononuclear cells were fractioned into five immune cell subsets (CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells, monocytes). Integrative analyses including mRNA expression, histone modifications (H3K27ac, H3K4me1, H3K4me3), three-dimensional (3D) genome architecture and genetic variations of single nucleotide polymorphisms (SNPs) were performed. RESULTS: Unstimulated RASFs differed markedly from OASFs in the transcriptome and epigenome. Meanwhile, most of the responses to stimulations were shared between the diseases. Activated SFs expressed pathogenic genes, including CD40 whose induction by IFN-γ was significantly affected by an RA risk SNP (rs6074022). On chromatin remodelling in activated SFs, RA risk loci were enriched in clusters of enhancers (super-enhancers; SEs) induced by synergistic proinflammatory cytokines. An RA risk SNP (rs28411362), located in an SE under synergistically acting cytokines, formed 3D contact with the promoter of metal-regulatory transcription factor-1 (MTF1) gene, whose binding motif showed significant enrichment in stimulation specific-SEs. Consistently, inhibition of MTF1 suppressed cytokine and chemokine production from SFs and ameliorated mice model of arthritis. CONCLUSIONS: Our findings established the dynamic landscape of activated SFs and yielded potential therapeutic targets associated with genetic risk of RA.

Association between fall history and performance-based physical function and postural sway in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of falling; therefore, fall prevision and prevention are critical. The present study aimed to evaluate the ability of physical performance assessments to discriminate between RA patients with and without a history of falling. METHODS: Fifty patients with RA were divided into two groups according to the presence or absence of a history of falls within the previous 1 year. Physical performance was assessed using the short physical performance battery (SPPB), which consists of the timed standing balance, gait speed, and chair stand tests. Standing balance was also assessed as postural sway using a force platform in several positions including standing with both feet together, semitandem, and tandem. Backgrounds, SPPB, and postural sway were compared between the two groups. RESULTS: Fourteen patients (28%) reported one or more falls within the previous year. There were no significant intergroup differences in baseline characteristics or SPPB score. The group with a history of falls had significantly longer measured time for the 5-repetition chair stand test and significantly longer postural sway in the semitandem position. The discriminate analysis revealed that 5-repetition chair stand test or its combination with postural sway in the semitandem position significantly discriminated between fallers and non-fallers. CONCLUSION: Numerical evaluation of the chair stand test and postural sway in the semitandem position seems more appropriate than SPPB for assessing the fall risk of patients with RA.

Constitutive Activation of Integrin α9 Augments Self-Directed Hyperplastic and Proinflammatory Properties of Fibroblast-like Synoviocytes of Rheumatoid Arthritis.

Despite advances in the treatment of rheumatoid arthritis (RA), currently approved medications can have significant side effects due to their direct immunosuppressive activities. Additionally, current therapies do not address residual synovial inflammation. In this study, we evaluated the role of integrin α9 and its ligand, tenascin-C (Tn-C), on the proliferative and inflammatory response of fibroblast-like synoviocytes (FLSs) from RA patients grown in three-dimensional (3D)-micromass culture. FLSs from osteoarthritis patients, when grown in the 3D-culture system, formed self-directed lining-like structures, whereas FLSs from RA tissues (RA-FLSs) developed an abnormal structure of condensed cellular accumulation reflective of the pathogenic features of RA synovial tissues. Additionally, RA-FLSs grown in 3D culture showed autonomous production of proinflammatory mediators. Predominant expression of α9 and Tn-C was observed in the condensed lining, and knockdown of these molecules abrogated the abnormal lining-like structure formation and suppressed the spontaneous expression of matrix metalloproteinases, IL-6, TNFSF11/RANKL, and cadherin-11. Disruption of α9 also inhibited expression of Tn-C, suggesting existence of a positive feedback loop in which the engagement of α9 with Tn-C self-amplifies its own signaling and promotes progression of synovial hyperplasia. Depletion of α9 also suppressed the platelet-derived growth factor-induced hyperplastic response of RA-FLSs and blunted the TNF-α-induced expression of matrix metalloproteinases and IL-6. Finally, α9-blocking Ab also suppressed the formation of the condensed cellular lining by RA-FLSs in 3D cultures in a concentration-related manner. This study demonstrates the central role of α9 in pathogenic behaviors of RA-FLSs and highlights the potential of α9-blocking agents as a nonimmunosuppressive treatment for RA-associated synovitis.

The utility of 25-question Geriatric Locomotive Function Scale for evaluating functional ability and disease activity in Japanese rheumatoid arthritis patients: A cross-sectional study using NinJa database.

OBJECTIVES: To investigate the distribution of 25-question Geriatric Locomotive Function Scale (GLFS-25) scores in Japanese rheumatoid arthritis (RA) patients and evaluate relationships with clinical variables. METHODS: Among 15,115 patients registered in the NinJa database for fiscal year 2015, 1710 with complete GLFS-25 and disease activity score-28 (DAS28) data were analyzed. Correlations between GLFS-25 score and clinical variables were assessed by Spearman coefficients. Mean GLFS-25 scores were compared among DAS28 groups (<2.6, 2.6-3.1, 3.2-5.0, ≥5.1) using the Kruskal-Wallis test. To evaluate the performance of the GLFS-25 and Health Assessment Questionnaire Disability Index (HAQ-DI) for predicting DAS28 ≥ 3.2 (moderate/high disease activity), receiver operator characteristic (ROC) curves were constructed. RESULTS: GLFS-25 score was significantly correlated with age, disease duration, DAS28, and HAQ-DI. GLFS-25 score increased in parallel with DAS28. The proportion of patients with locomotive syndrome stage 2 also increased with DAS28. Area under the curve values for HAQ-DI and GLFS-25 score were 0.739 and 0.768, respectively. At a GLFS-25 positive cutoff score ≥16, sensitivity was 0.716 and specificity was 0.661 for predicting DAS28 ≥ 3.2. CONCLUSION: This study documents the GLFS-25 score distribution in Japanese RA patients and demonstrates that GLFS-25 is a useful measure for evaluating functional ability in RA.

Pseudomonas furukawaii sp. nov., a polychlorinated biphenyl-degrading bacterium isolated from biphenyl-contaminated soil in Japan.

Strain KF707T was isolated from a biphenyl-contaminated site in Kitakyushu, Japan. Analysis of 16S rRNA gene sequences, retrieved from the whole-genome sequence, revealed that the isolate was closely related to members of the genus Pseudomonas, sharing the highest sequence similarities with Pseudomonas balearica strain SP1402T (DSM 6083) (97.8 %). The DNA G+C chromosome and plasmid content of strain KF707T were 65.5 and 60.5 mol%. The major cellular fatty acids were iso-C15 :  0 and C16 : 1ω7c/C16 : 1ω6c. Polyphasic analysis indicated that strain KF707T represents a novel species of the genus Pseudomonas, for which the name Pseudomonas furukawaii sp. nov. is proposed. The type strain is KF707T (=DSM 10086T=NBRC 110670T).

Lateral collapse of the tarsal navicular in patients with rheumatoid arthritis: Implications for pes planovarus deformity.

OBJECTIVES: In patients with rheumatoid arthritis (RA), the talonavicular joint is commonly involved and midfoot collapse can lead to progressive flattening of the arch. Despite a general awareness of the important structural role of the talonavicular joint in rheumatoid foot disease, details of its destructive pattern have not been elucidated. METHODS: We cross-sectionally investigated 176 RA patients (342 feet) and classified their feet into the following five groups according to radiographic findings: arthritis (RA changes with normal navicular shape), Müller-Weiss Disease (MWD) (collapse of the lateral aspect of the tarsal navicular), flat (flattened navicular), ankylosis (ankylosis of the talonavicular joint), and normal. We compared medical histories and radiographic measurements among all five groups. RESULTS: The arthritis group comprised 91 feet, 36 in the MWD group, nine in the flat group, 12 in the ankylosis group, and 194 classified as normal. The MWD group demonstrated a trend towards pes planovarus deformity in contrast to pes planovalgus deformity in the arthritis group. Corticosteroid use and the mean daily dosage were the highest in the MWD group. CONCLUSIONS: This report revealed a high prevalence of MWD-like changes to the navicular in RA patients and its association with pes planovarus deformity and corticosteroid usage.

[Joint disease and energy metabolism.]

Recently, it has been found that systemic metabolic disorders are associated with the onset and progression of various joint diseases. Although osteoarthritis(OA)is mainly a degradative condition of the articular cartilage induced by mechanical stress, there is a growing body of data demonstrating the involvement of metabolic factors including fat metabolism. Recent studies have revealed that adipokines including adiponectin and leptin are associated with inflammation of rheumatoid arthritis. A better understanding of these relationships may lead to new strategies to treat or prevent joint disease such as OA.

Cell-contact-dependent activation of CD4+ T cells by adhesion molecules on synovial fibroblasts.

OBJECTIVE: To determine how cell-cell contact with synovial fibroblasts (SF) influence on the proliferation and cytokine production of CD4+ T cells. METHODS: Naïve CD4+ T cells were cultured with SF from rheumatoid arthritis patients, stimulated by anti-CD3/28 antibody, and CD4+ T cell proliferation and IFN-γ/IL-17 production were analyzed. To study the role of adhesion molecules, cell contact was blocked by transwell plate or anti-intracellular adhesion molecule-1 (ICAM-1)/vascular cell adhesion molecule-1(VCAM-1) antibody. To study the direct role of adhesion molecules for CD4+ T cells, CD161+ or CD161- naïve CD4+ T cells were stimulated on plastic plates coated by recombinant ICAM-1 or VCAM-1, and the source of IFN-γ/IL-17 were analyzed. RESULTS: SF enhanced naïve CD4+ T cell proliferation and IFN-γ/IL-17 production in cell-contact and in part ICAM-1-/VCAM-1-dependent manner. Plate-coated ICAM-1 and VCAM-1 enhanced naïve CD4+ T cell proliferation and IFN-γ production, while VCAM-1 efficiently promoting IL-17 production. CD161+ naïve T cells upregulating LFA-1 and VLA-4 were the major source of IFN-γ/IL-17 upon interaction with ICAM-1/VCAM-1. CONCLUSION: CD4+ T cells rapidly expand and secrete IFN-γ/IL-17 upon cell-contact with SF via adhesion molecules. Interfering with ICAM-1-/VCAM-1 may be beneficial for inhibiting RA synovitis.

Validity of E-PASS System for Postoperative Morbidity of Spinal Surgery.

STUDY DESIGN: A single-center retrospective cohort study. OBJECTIVE: To evaluate the ability of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) system to predict postoperative risk in patients scheduled for spinal surgery. SUMMARY OF BACKGROUND DATA: The E-PASS system is a surgical audit to predict postoperative morbidity and mortality in general surgery. It is currently not applied in patients with spinal disorders. METHODS: The E-PASS system is comprised of a preoperative risk score (PRS), a surgical stress score (SSS), and a comprehensive risk score (CRS). The latter reflects both the PRS and SSS. We calculated the E-PASS scores for 275 consecutive patients who underwent spinal surgery and evaluated the relationship between the incidence of postoperative complications and each score of the E-PASS system and their ability to predict postoperative morbidity. RESULTS: Postoperative complications developed in 31 patients (11.3%). All E-PASS scores were significantly higher in patients with postoperative complications and they were linearly correlated with the overall incidence of postoperative complications. In particular, PRS was correlated with complications at nonsurgical sites and SSS with surgical site complications. The area under the receiver operating characteristic curve (AUC) for PRS and SSS was higher in patients with complications at nonsurgical and surgical sites, respectively. The AUC for CRS exhibited good predictive power for both types of complication. CONCLUSIONS: The E-PASS system correctly predicted morbidity. The predictive ability of CRS was good for overall morbidity. The E-PASS system is useful for the accurate prediction of the risk for in-hospital morbidity in individual patients scheduled for spinal surgery.

Evaluation of the utility of the Estimation of Physiologic Ability and Surgical Stress score for predicting post-operative morbidity after orthopaedic surgery.

PURPOSE: The purpose of this study was to investigate the utility of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) scoring system for predicting post-operative morbidity. METHODS: We included 1,883 patients (mean age, 52.1 years) who underwent orthopaedic surgery. The post-operative complications were classified as surgical site and non-surgical site complications, and the relationship between the E-PASS scores and post-operative morbidity was investigated. RESULTS: The incidence of post-operative complications (n = 274) significantly increased with an increase in E-PASS scores (p < 0.001). The areas under the curve for the comprehensive risk score of the E-PASS scoring system for overall and non-surgical site complications were 0.777 and 0.794, respectively. CONCLUSIONS: The E-PASS scoring system showed some utility in predicting post-operative morbidity after general orthopaedic surgery. However, creating a new risk score that is more suitable for orthopaedic surgery will be challenging.

Vertebral fractures affect functional status in postmenopausal rheumatoid arthritis patients.

Functional disability is a major concern in patients with rheumatoid arthritis (RA). This retrospective study investigated the risk factors for vertebral fractures (VFs) in postmenopausal RA patients and determined the impact of VFs on functional status. Data from a cohort of 200 postmenopausal RA patients in a single hospital registry were analyzed. Demographic and clinical data, imaging data from spine radiographs, and bone mineral density (BMD) data were collected from the patients at baseline and at the final visit (a mean of 2.9 years after the first visit). Risk factors for incident VFs and their impact on the modified health assessment questionnaire (mHAQ) were analyzed. Twenty-eight patients (14%) developed new VFs (NVFs). Logistic regression analysis adjusted for age, BMI, and disease duration revealed that daily dose of prednisolone, femoral neck BMD, use of active vitamin D3, and use of a bisphosphonate at baseline were factors associated with NVF, with odds ratios (95% confidence interval) of 1.27 (1.05-1.54), 0.94 (0.91-0.97), 0.34 (0.13-0.89), and 0.31 (0.12-0.82), respectively. Patients with NVF exhibited worse mHAQ scores and a greater increase in mHAQ scores from baseline compared with those without NVF. In conclusion, incident VFs were associated with reduced functional status in postmenopausal patients with RA. It is important to prevent VFs to maintain the functional status of RA patients.

Impact of Bone Mineral Density and Bone Structural Properties on Postmenopausal Women With Rheumatoid Arthritis in Japan: A Cross-Sectional Study.

Introduction There has been no study on bone structural properties in postmenopausal women with rheumatoid arthritis (RA) in Japan. This study investigated bone mineral density (BMD) and bone structural properties in Japanese postmenopausal women with RA. Methods The study had a cross-sectional design and included 119 postmenopausal women aged 50-80 years with RA symptoms for more than five years. BMD, trabecular bone score (TBS), and results of hip structure analysis (HSA) were measured on dual-energy X-ray absorptiometry scans. The control group consisted of 288 women aged 50-80 years without RA. The RA group and control group using bisphosphonates were compared after propensity score matching for age, body mass index, and fracture history. Women in the RA group were also compared according to the use of glucocorticoids (GCs). Results After the propensity matching score, there were no other significant differences in BMD, TBS, and HSA parameters between the RA group and the control group. In the RA group, the TBS was lower in patients on GCs than those not on GCs (1.272 vs 1.313, p=0.008). There were no other significant differences in BMD and HSA parameters between patients in the RA group according to the use of GCs. Conclusion Although there were no differences in BMD, the TBS was lower in patients on GCs than those not on GCs in the RA group. It is thus important for physicians who administer GCs to treat patients with RA to be aware of not only BMD but also TBS.

Histopathological Confirmation of Axonal Sprouting in Regenerative Peripheral Nerve Interface.

Symptomatic neuroma represents a debilitating complication after major limb amputation. The regenerative peripheral nerve interface (RPNI) has emerged as a reproducible and practical surgery aimed at mitigating the formation of painful neuroma. Although previous animal studies revealed axonal sprouting, elongation, and synaptogenesis of proximal nerve stump within the muscle graft in RPNI, there is a lack of reports confirming these physiological reactions at the histopathological level in human samples. This report presents a case of below-knee amputation with RPNI due to foot gangrene resulting from polyarteritis nodosa. Subsequently, an above-knee amputation was necessitated due to the exacerbation of polyarteritis nodosa, providing the opportunity for histopathological examination of the RPNI site. The examination revealed sprouting, elongation, and existence of neuromuscular junction of the tibial nerve within the grafted muscle. To the best of our knowledge, this is the first report demonstrating axonal sprouting, elongation, and possibility of synaptogenesis of the nerve stump within the grafted muscle in a human sample.

Application of electrolysis to inactivation of antibacterials in clinical use.

Contamination of surface water by antibacterial pharmaceuticals (antibacterials) from clinical settings may affect aquatic organisms, plants growth, and environmental floral bacteria. One of the methods to decrease the contamination is inactivation of antibacterials before being discharged to the sewage system. Recently, we reported the novel method based on electrolysis for detoxifying wastewater containing antineoplastics. In the present study, to clarify whether the electrolysis method is applicable to the inactivation of antibacterials, we electrolyzed solutions of 10 groups of individual antibacterials including amikacin sulfate (AMK) and a mixture (MIX) of some commercial antibacterials commonly prescribed at hospitals, and measured their antibacterial activities. AMK was inactivated in its antibacterial activities and its concentration decreased by electrolysis in a time-dependent manner. Eighty to ninety-nine percent of almost all antibacterials and MIX were inactivated within 6h of electrolysis. Additionally, cytotoxicity was not detected in any of the electrolyzed solutions of antibacterials and MIX by the Molt-4-based cytotoxicity test.

Diversity and Evolution of Integrative and Conjugative Elements Involved in Bacterial Aromatic Compound Degradation and Their Utility in Environmental Remediation.

Integrative and conjugative elements (ICEs) are mobile DNA molecules that can be transferred through excision, conjugation, and integration into chromosomes. They contribute to the horizontal transfer of genomic islands across bacterial species. ICEs carrying genes encoding aromatic compound degradation pathways are of interest because of their contribution to environmental remediation. Recent advances in DNA sequencing technology have increased the number of newly discovered ICEs in bacterial genomes and have enabled comparative analysis of their evolution. The two different families of ICEs carry various aromatic compound degradation pathway genes. ICEclc and its related ICEs contain a number of members with diverse catabolic capabilities. In addition, the Tn4371 family, which includes ICEs that carry the chlorinated biphenyl catabolic pathway, has been identified. It is apparent that they underwent evolution through the acquisition, deletion, or exchange of modules to adapt to an environmental niche. ICEs have the property of both stability and mobility in the chromosome. Perspectives on the use of ICEs in environmental remediation are also discussed.

Evolution of genetic architecture and gene regulation in biphenyl/PCB-degrading bacteria.

A variety of bacteria in the environment can utilize xenobiotic compounds as a source of carbon and energy. The bacterial strains degrading xenobiotics are suitable models to investigate the adaptation and evolutionary processes of bacteria because they appear to have emerged relatively soon after the release of these compounds into the natural environment. Analyses of bacterial genome sequences indicate that horizontal gene transfer (HGT) is the most important contributor to the bacterial evolution of genetic architecture. Further, host bacteria that can use energy effectively by controlling the expression of organized gene clusters involved in xenobiotic degradation will have a survival advantage in harsh xenobiotic-rich environments. In this review, we summarize the current understanding of evolutionary mechanisms operative in bacteria, with a focus on biphenyl/PCB-degrading bacteria. We then discuss metagenomic approaches that are useful for such investigation.

A-910823, a squalene-based emulsion adjuvant, induces T follicular helper cells and humoral immune responses via α-tocopherol component.

Background: Adjuvants are chemical or biological materials that enhance the efficacy of vaccines. A-910823 is a squalene-based emulsion adjuvant used for S-268019-b, a novel vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is currently in clinical development. Published evidence has demonstrated that A-910823 can enhance the induction of neutralizing antibodies against SARS-CoV-2 in humans and animal models. However, the characteristics and mechanisms of the immune responses induced by A-910823 are not yet known. Methods and Results: To characterize A-910823, we compared the adaptive immune response profile enhanced by A-910823 with that of other adjuvants (AddaVax, QS21, aluminum salt-based adjuvants, and empty lipid nanoparticle [eLNP]) in a murine model. Compared with other adjuvants, A-910823 enhanced humoral immune responses to an equal or greater extent following potent T follicular helper (Tfh) and germinal center B (GCB) cell induction, without inducing a strong systemic inflammatory cytokine response. Furthermore, S-268019-b containing A-910823 adjuvant produced similar results even when given as a booster dose following primary administration of a lipid nanoparticle-encapsulated messenger RNA (mRNA-LNP) vaccine. Preparation of modified A-910823 adjuvants to identify which components of A-910823 play a role in driving the adjuvant effect and detailed evaluation of the immunological characteristics induced by each adjuvant showed that the induction of humoral immunity and Tfh and GCB cell induction in A-910823 were dependent on α-tocopherol. Finally, we revealed that the recruitment of inflammatory cells to the draining lymph nodes and induction of serum cytokines and chemokines by A-910823 were also dependent on the α-tocopherol component. Conclusions: This study demonstrates that the novel adjuvant A-910823 is capable of robust Tfh cell induction and humoral immune responses, even when given as a booster dose. The findings also emphasize that α-tocopherol drives the potent Tfh-inducing adjuvant function of A-910823. Overall, our data provide key information that may inform the future production of improved adjuvants.

Synovial Tissue Heterogeneity in Japanese Patients With Rheumatoid Arthritis Elucidated Using a Cell-Type Deconvolution Approach.

OBJECTIVE: Recent advances in single-cell RNA sequencing technology have improved our understanding of the immunological landscape of rheumatoid arthritis (RA). We aimed to stratify the synovium from East Asian patients with RA by immune cell compositions and gain insight into the inflammatory drivers of each synovial phenotype. METHODS: Synovial tissues were obtained from East Asian patients in Japan with RA (n = 41) undergoing articular surgery. The cellular composition was quantified by a deconvolution approach using a public single-cell-based reference. Inflammatory pathway activity was calculated by gene set variation analysis, and chromatin accessibility was evaluated using assay of transposase accessible chromatin-sequencing. RESULTS: We stratified RA synovium into three distinct subtypes based on the hierarchical clustering of cellular composition data. One subtype was characterized by abundant HLA-DRAhigh synovial fibroblasts, autoimmune-associated B cells, GZMK+ GZMB+ CD8+ T cells, interleukin (IL)1-ß+ monocytes, and plasmablasts. In addition, tumor necrosis factor (TNF)-α, interferons (IFNs), and IL-6 signaling were highly activated in this subtype, and the expression of various chemokines was significantly enhanced. Moreover, we found an open chromatin region overlapping with RA risk locus rs9405192 near the IRF4 gene, suggesting the genetic background influences the development of this inflammatory synovial state. The other two subtypes were characterized by increased IFNs and IL-6 signaling, and expression of molecules associated with degeneration, respectively. CONCLUSION: This study adds insights into the synovial heterogeneity in East Asian patients and shows a promising link with predominant inflammatory signals. Evaluating the site of inflammation has the potential to lead to appropriate drug selection that matches the individual pathology.