Objective
The appearance of anti–citrullinated protein antibodies (ACPAs) in the circulation represents a major risk factor for developing rheumatoid arthritis (RA). Patient‐derived ACPAs have been ...shown to induce pain and bone erosion in mice, suggesting an active role in the pathogenicity of RA. We undertook this study to investigate whether ACPAs can induce tenosynovitis, an early sign of RA, in addition to pain and bone loss and whether these symptoms are dependent on peptidyl arginine deiminase 4 (PAD4).
Methods
Monoclonal ACPAs generated from plasma cells of RA patients were transferred to wild‐type and PAD4‐deficient mice. Pain‐like behavior and macroscopic inflammation were monitored for a period of 4 weeks, followed by the analyses of tenosynovitis in the ankle joints using magnetic resonance imaging (MRI) and bone microarchitecture in the tibia using an X‐ray microscope. Microscopic changes in the tendon sheath were analyzed in decalcified ankle joint sections.
Results
The combination of 2 monoclonal ACPAs (1325:04C03 and 1325:01B09) induced long‐lasting pain‐like behavior and trabecular bone loss in mice. Although no synovitis was observed macroscopically, we detected tenosynovitis in the ACPA‐injected mice by MRI. Microscopic analyses of the joints revealed a cellular hyperplasia and a consequent enlargement of the tendon sheath in the ACPA‐treated group. In PAD4−/− mice, the effects of ACPAs on pain‐like behavior, tenosynovitis, and bone loss were significantly reduced.
Conclusion
Monoclonal ACPAs can induce tenosynovitis in addition to pain and bone loss via mechanisms dependent on PAD4‐mediated citrullination.
Proteins subjected to post-translational modifications, such as citrullination, carbamylation, acetylation or malondialdehyde (MDA)-modification are targeted by autoantibodies in seropositive ...rheumatoid arthritis (RA). Epidemiological and experimental studies have both suggested the pathogenicity of such humoral autoimmunity, however, molecular mechanisms triggered by anti-modified protein antibodies have remained to be identified.
Here we describe in detail the pathways induced by anti-MDA modified protein antibodies that were obtained from synovial B cells of RA patients and that possessed robust osteoclast stimulatory potential and induced bone erosion in vivo. Anti-MDA antibodies boosted glycolysis in developing osteoclasts via an FcγRI, HIF-1α and MYC-dependent mechanism and subsequently increased oxidative phosphorylation. Osteoclast development required robust phosphoglyceride and triacylglyceride biosynthesis, which was also enhanced by anti-MDA by modulating citrate production and expression of the glycerol-3-phosphate dehydrogenase 1 (GPD1) and glycerol-3-phosphate acyltransferase 2 (GPAT2) genes. In summary, we described novel metabolic pathways instrumental for osteoclast differentiation, which were targeted by anti-MDA antibodies, accelerating bone erosion, a central component of RA pathogenesis.
•Anti-MDA antibodies are inducers of osteoclast maturation and bone erosion in RA.•Anti-MDA antibodies boost glycolysis via FcγRI, HIF-1α and MYC in pre-osteoclast.•Osteoclast glycolysis fuels mitochondrial oxidation and overproduction of citrate.•Anti-MDA boosts lipid biosynthesis via regulating citrate and the GPD1/GPAT2 genes.•Glycerolipid biosynthesis is crucial for osteoclast development.
Rheumatoid arthritis (RA) often causes cervical spine lesions as the disease condition progresses, which induce occipital neuralgia or cervical myelopathy requiring surgical interventions. Meanwhile, ...patients with RA are susceptible to infection or other complications in the perioperative period because they frequently have comorbidities and use immunosuppressive medications. However, the risk factors or characteristics of patients with RA who experience perioperative complications after cervical spine surgery remain unknown. A risk factor analysis of perioperative complications in patients with RA who underwent primary cervical spine surgery was conducted in the present study.
A total of 139 patients with RA who underwent primary cervical spine surgery from January 2001 to March 2020 were retrospectively investigated. Age and height, weight, serum albumin, serum C-reactive protein, American Society of Anesthesiologists Physical Status (ASA-PS), Charlson comorbidity index, medications used, cervical spine lesion, surgery time, bleeding volume, and procedures were collected from medical records to compare the patients with complications to those without complications after surgery. The risk factors for perioperative complications were assessed by univariate and multivariate logistic regression analysis.
Twenty-eight patients (20.1%) had perioperative complications. Perioperative complications were significantly associated with the following factors data presented as odds ratio: lower height 0.928, p=0.007, higher ASA-PS 2.296, p=0.048, longer operation time 1.013, p=0.003, more bleeding volume 1.004, p=0.04, higher rates of vertical subluxation 2.914, p=0.015 and subaxial subluxation (SAS) 2.507, p=0.036, occipito-cervical (OC) fusion 3.438, p=0.023, and occipito-cervical/thoracic (long) fusion 8.021, p=0.002 in univariate analyses. In multivariate analyses, lower height 0.915, p=0.005, higher ASA-PS 2.622, p=0.045 and long fusion 7.289, p=0.008 remained risk factors. High-dose prednisolone use 1.247, p=0.028, SAS 6.413, p=0.018, OC fusion 17.93, p=0.034, and long fusion 108.1, p<0.001 were associated with severe complications.
ASA-PS and long fusion could be indicators predicting perioperative complications in patients with RA after cervical spine surgery. In addition, cervical spine lesions requiring OC fusion or long fusion and high-dose prednisolone use were suggested to be risk factors for increasing severe complications.
To further improve rheumatoid arthritis (RA) treatment, it is necessary to understand each RA patient's satisfaction and to identify the factors affecting their satisfaction. Despite the rise in ...medical costs for RA, little is known about the factors that influence patient satisfaction with the cost of treatment in RA patients.
This is a multicenter observational study of Japanese RA patients from the FRANK Registry with data analyzed from March 2017 to August 2020. We collected data on demographic characteristics, clinical data, quality of life which was evaluated using the EuroQol 5-dimensional questionnaire (EQ5D), and patient satisfaction. The four categories of patient satisfaction were evaluated individually (i.e., cost, treatment efficacy, activities of daily living ADL, and global treatment satisfaction). We analyzed the factors that affected each patient's satisfaction, such as age, sex, EQ5D, disease duration, disease activity, and treatment.
This study included 2235 RA outpatients (406 males, 1829 females). In RA patients, "very satisfied" and "satisfied" were given for nearly half of each satisfaction aspect (cost 49%; efficacy 72%; ADL 58%; global treatment 66%) at the time of the initial registration. To investigate the factors influencing each satisfaction, multivariate analysis has revealed that the use of b/tsDMARDs increased satisfaction of treatment effect (odds ratio OR 0.66) and ADL (OR 0.78) but decreased cost satisfaction (OR 2.21). Age (50-64 years; OR 0.91; 65-74 years, 0.55: ≥ 75 years, 0.35), female (OR 0.81), and history of musculoskeletal surgery (OR 0.60) all increased cost satisfaction. Patients with lower disease activity and higher EQ5D scores had higher levels of satisfaction in all areas.
In this study, patient satisfaction in terms of cost, treatment effect, ADL, and overall treatment was generally higher, but some patients were dissatisfied. The cost of satisfaction increased with age and a history of musculoskeletal surgery, while it decreased with a lower EQ5D score and the use of b/tsDMARDs.
Synovial tissue-resident macrophages (STRMs) maintain normal joint homeostasis in a steady state. However, it is unclear whether STRMs still play homeostatic roles or change the functions in the ...joint of rheumatoid arthritis (RA), where infiltrating peripheral blood monocyte-derived macrophages (PBMoMs) play proinflammatory roles. In the present study, we examined changes in the phenotypes and functions of STRMs in response to RA-related stimuli
. STRMs were prepared from non-inflammatory osteoarthritis (OA) joint synovium, which is histologically indistinguishable from normal joint synovium. PBMoMs were prepared and used for comparison. After stimulation with plate-bound IgG, which mimics anti-citrullinated protein antibody immunocomplex formed in RA joints, or with combinations of RA-related inflammatory mediators, namely tumor necrosis factor-α (TNF-α) and prostaglandin E2 or interferon-γ, PBMoMs downregulated surface markers and genes associated with anti-inflammatory macrophages, and upregulated cytokine and marker genes of proinflammatory macrophages in RA. On the other hand, STRMs hardly changed the expression of surface molecules and marker genes but altered the pattern of cytokine gene expression after stimulation like PBMoMs. Furthermore,
stimulated STRMs promote proinflammatory functions of cocultured synovial fibroblasts. Thus, STRMs might play proinflammatory roles in RA joints, while maintaining their phenotypes in the steady state.
IL-12, which is produced in response to intracellular bacteria, such as Listeria monocytogenes, promotes the development of pathogen-specific Th1 cells that play an important role in host defense. ...However, it has also been known that CD44(high) memory-phenotype CD4 T cells with Th1 functions naturally occur in naive mice, and that lymphopenia-induced proliferation of naive CD4 T cells generates memory-phenotype CD4 T cells with Th1 functions, although their differentiation mechanism and contribution to host defense are unclear. In this study, we analyzed the development and the functions of the different subsets of Th1 cells by using mice lacking tyrosine kinase 2 (Tyk2), a member of the Janus kinase family critically involved in IL-12 signaling. In contrast with the case of conventional Ag-specific Th1 cells, the development of naturally occurring Th1 cells was not impaired in Tyk2-deficient mice. In addition, Th1 cells were normally generated from Tyk2-deficient naive CD4 T cells via lymphopenia-induced proliferation. Nevertheless, all these Th1 subsets, including conventional Ag-induced Th1 cells, produced IFN-γ in response to IL-12 in a Tyk2-dependent manner. Importantly, such Tyk2-dependent bystander IFN-γ production of any Th1 subsets conferred early protection against L. monocytogenes infection. Thus, Tyk2-mediated IL-12 signaling is differentially required for the development of different Th1 cell subsets but similarly induces their bystander IFN-γ production, which contributes to innate host defense against infection with intracellular bacteria.
Objective
To establish a method to culture synovial tissue explants from patients with rheumatoid arthritis (RA).
Methods
Synovial tissue explants obtained from 10 patients with RA were cultured at ...the air–liquid interface or were submerged in culture medium. As a control, synovial explants were engrafted subcutaneously into SCID mice. The synovial explants were harvested at different time points, and histologic or flow cytometric analysis was performed. Cytokine levels in the culture supernatants were measured by enzyme‐linked immunosorbent assay. Infliximab was added to the air–liquid interface culture to evaluate the effect of tumor necrosis factor α blockade on inflammatory cytokine production.
Results
The histologic features of RA synovitis, including a hyperplastic lining layer and the presence of cellular infiltrate in the sublining layer, were maintained in synovial tissue explants in air–liquid interface culture. In synovial grafts harvested from SCID‐HuRAg mice, the cellular infiltrate was well maintained in the sublining, but the lining layer was lost. Viable CD4+ T cells and macrophages were abundant after air–liquid interface culture but were virtually absent after submerged culture. Furthermore, synovial tissue explants in air–liquid interface culture produced interleukin‐6 (IL‐6) and IL‐8 for a prolonged period of time. The addition of infliximab effectively reduced cytokine production.
Conclusion
RA synovial explants can be maintained for weeks using an air–liquid interface culture. This simple culture system might be useful for analyzing the pathogenesis of RA synovitis and for developing antirheumatic drugs.
To retrospectively evaluate the long-term results of cementless total hip arthroplasty (THA) in patients with rheumatoid arthritis (RA) and postoperative patient mortality after THA.
This study ...included 191 hips in 149 RA patients who underwent cementless THA between 1998 and 2005. Mean age at surgery was 54.2 years, and mean follow-up was 12.6 years. Implant and patient survivorships were determined using the Kaplan-Meier method, and the associated influencing factors were determined.
Implant survivals at 17 years were 99.5% for stems, 93.9% for cups, and 90.8% for liners. Among the liners used, THAs with highly cross-linked polyethylene showed better survivals compared with those with conventional polyethylene and alumina-bearing surface (93.4%, 90.9%, and 52.2%, respectively). A total of 64 deaths occurred; 45 patients died within 10 years and 19 patients died between 10 and 17 years. Malignancy (25.0%) was the leading cause of death, followed by pneumonia (20.8%) and sepsis (20.8%). The patient survival rate was 36.9% at 17 years after THA. Multivariate analysis exhibited that older age at operation and greater dose of concomitant corticosteroid resulted in shorter patient survivals.
Cementless THA worked well in patients with RA. Mortality remained high among RA patients who needed THA.
Acute rupture of the knee extensor mechanism after patellectomy is extremely rare. We present the case of a patient with acute patellar tendon rupture who had undergone patellectomy 53 years before. ...Twelve days after the injury, the ruptured patellar tendon was repaired with end-to-end suture. Postoperatively, we splinted the knee for 6 weeks but permitted the patient to walk without limiting weight bearing at 1 week postoperatively. At one-year follow-up, the patient is able to move his knee almost full range of motion and the Lysholm knee score is 81. The patient is satisfied with the outcome. This is the first report to treat acute rupture of the patellar tendon in a patient who had undergone patellectomy. Although careful rehabilitation is required, end-to-end suture might be an adequate surgical procedure for acute rupture of the knee extensor mechanism after patellectomy.
Although increased bone fragility is a well-recognized consequence in patients with rheumatoid arthritis (RA), the essential cause of degenerate bone strength remains unknown. This study aimed to ...determine factors contributing to bone dysfunction in RA by focusing on the bone matrix micro-arrangement, based on the preferential orientation of collagen and the related apatite c-axis as a bone quality index. The classical understanding of RA is limited to its severe pathological conditions associated with inflammation-induced bone loss. This study examined periarticular proximal tibiae from RA patients as compared with osteoarthritis (OA) patients as controls. Bone tissue material strength was disrupted in the RA group compared with the control. Collagen/apatite micro-arrangement and vBMD were significantly lower in the RA group, and the rate of decrease in apatite c-axis orientation (−45%) was larger than that in vBMD (−22%). Multiple regression analysis showed that the degree of apatite c-axis orientation (β = 0.52, p = 1.9 × 10−2) significantly contributed to RA-induced bone material impairment as well as vBMD (β = 0.46, p = 3.8 × 10−2). To the best of our knowledge, this is the first report to demonstrate that RA reduces bone material strength by deteriorating the micro-arrangement of collagen/apatite bone matrix, leading to decreased fracture resistance. Our findings represent the significance of bone quality-based analysis for precise evaluation and subsequent therapy of the integrity and soundness of the bone in patients with RA.
•Collagen/apatite micro-arrangement as a bone quality index contributes to bone mechanical function.•Rheumatoid arthritis (RA) patients' tibiae were compared with osteoarthritis (OA).•RA bone shows deteriorated alignment of collagen/apatite bone matrix.•Impaired collagen/apatite alignment significantly contributes to RA bone fragility.•Bone-immune interaction possibly regulates the micro-arrangement of bone matrix.
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