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Objectives Whether the characteristics of patients with rheumatoid arthritis (RA) undergoing total knee arthroplasty (TKA) have changed in the era of biologic disease-modifying antirheumatic drugs (bDMARDs) is unclear. We compared the radiographic findings of the knees in TKA recipients with RA before and after the introduction of bDMARDs. Methods Consecutive patients who underwent primary TKA between 1999 and 2002 (115 knees; 79 patients, group A) and between 2013 and 2017 (117 knees; 95 patients, group B) were retrospectively evaluated. Clinical data, including disease duration, medication, C-reactive protein, erythrocyte sedimentation rate, and rheumatoid factor, were collected. The Larsen classification, joint space narrowing (JSN), bone erosion, and geode and osteophyte formation were evaluated on preoperative radiographs. Results Osteophyte formation was significantly increased, and bone erosion and geode formation were significantly decreased in group B. In addition, medial-dominant JSN was significantly increased, and bicompartmental JSN was significantly decreased in group B. Medial-dominant JSN was positively and bone erosion was negatively associated with osteophyte formation. Conclusions Following the introduction of bDMARDs, typical radiographic findings of rheumatoid knees have decreased, and secondary osteoarthritis-like changes, characterized by osteophyte formation and medial-dominant JSN, have increased in the knees of TKA recipients.

Autoreactive CD4 T cells are thought to play pivotal roles in the pathogenesis of rheumatoid arthritis (RA). Recently, a subset of CD4 T cells that express high levels of programmed death-1 (PD-1) but are distinct from follicular helper T cells have been identified in the joints of RA patients and named peripheral helper T (Tph) cells. Because PD-1 is expressed on T cells chronically stimulated with the Ags, we tested a hypothesis that Tph cells are the pathogenic autoreactive CD4 T cells in RA. We found that human Tph cells in RA joints produce proinflammatory effector cytokines, including IFN-γ, TNF-α, and GM-CSF, in addition to B cell–helping cytokines, such as IL-21 and CXCL13. Flow cytometric analysis showed different bias of TCR Vβ usage between PD-1high Tph cells and PD-1low/neg CD4 T cells, including Th1 cells, in the joint or memory CD4 T cells in the peripheral blood, whereas there was little difference between the latter two subsets. In line with this, deep sequencing of TCR demonstrated an overlap of expanded clones between peripheral blood memory CD4 T cells and PD-1low/neg CD4 T cells but not Tph cells in the joint. Interestingly, Tph cells preferentially exhibited autologous MLR in vitro, which required recognition of self–MHC class II and was pronounced by blocking PD-1 signaling. Taken together, these results suggest that Tph cells are the pathogenic autoreactive CD4 T cells in RA, which expand locally in the joints and are regulated by PD-1 signaling.

Background 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. Methods 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. Results 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. Conclusions 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.

Objectives: To investigate the efficacy of suppressing joint destruction with subcutaneous tocilizumab (TCZ-SC) for Japanese rheumatoid arthritis (RA) patients in the real-world clinical setting.Me...

BackgroundFine specificity of anti-citrullinated protein antibodies (ACPAs), in which cross-reactivity exists, varies among patients with rheumatoid arthritis (RA), but it is unclear whether the mechanism of ACPA production is same or different among individuals. Since avidity of serum antibody reflects the direction of immune response, we compared the levels of avidity and cross-reactivity between various ACPAs in a cohort of RA patient.MethodsSera from 180 RA patients positive for anti-cyclic citrullinated peptide (CCP) 2 antibody were screened for positivity of antibodies against CCP1, and citrullnated fibrinogen (cFib), enolase (cEno), and vimentin (cVim) peptides. Avidity of the four ACPAs, and some autoantibodies and antibodies against foreign antigens was determined by an elution assay using sodium thiocyanate solution. Cross-reactivity between different ACPAs was estimated by measuring the inhibition of binding by competitor peptides. ResultsThe prevalence of anti-CCP1, anti-cFib, anti-cEno, and anti-cVim antibodies in the anti-CCP2-positive RA cohort were 37.7%, 38.3%, 15.6%, and 23.9%, respectively. The avidity of ACPAs, except for anti-cVim antibody, was significantly lower than that of antibodies against foreign antigens, while there was a large variety in the avidity of other autoantibodies. At individual levels, the avidity of anti-cVim was significantly higher than that of other ACPAs, and there was a significant correlation in the avidity of anti-CCP and anti-cFib antibodies. Substantial extent of cross-reactivity was seen between different ACPAs, which also showed a fixed hierarchy.ConclusionThe fixed hierarchy in the avidity and cross-reactivity between different ACPAs suggests that the mechanism underlying ACPA production is common to all RA patients. Presence of a dominant antigen that induces whole ACPA response is speculated.

Objective.To investigate whether abatacept (ABA) causes more adverse events (AE) than conventional synthetic disease-modifying antirheumatic drugs (csDMARD) after orthopedic surgery in patients with rheumatoid arthritis (RA).Methods.A retrospective multicenter nested case–control study was performed in 18 institutions. Patients receiving ABA (ABA group) were matched individually with patients receiving csDMARD and/or steroids (control group). Postoperative AE included surgical site infection, delayed wound healing, deep vein thrombosis or pulmonary embolism, flare, and death. The incidence rates of the AE in both groups were compared with the Mantel-Haenszel test. Risk factors for AE were analyzed by logistic regression model.Results.A total of 3358 cases were collected. After inclusion and exclusion, 2651 patients were selected for matching, and 194 patients in 97 pairs were chosen for subsequent comparative analyses between the ABA and control groups. No between-group differences were detected in the incidence rates of each AE or in the incidence rates of total AE (control vs ABA: 15.5% vs 20.7% in total, 5.2% vs 3.1% in death).Conclusion.Compared with csDMARD and/or steroids without ABA, adding ABA to the treatment does not appear to increase the incidence rates of postoperative AE in patients with RA undergoing orthopedic surgery. Large cohort studies should be performed to add evidence for the perioperative safety profile of ABA.

Cam deformity could lead to suboptimal articulation by causing secondary femoroacetabular impingement after periacetabular osteotomy; however, the inherent femoral head-neck morphology in dysplastic hips and the effect of an additional osteoarthritic deformity have not been well described. We compared femoral head-neck morphology using three-dimensional imaging of normal and dysplastic hips in pre/early (Tonnis grade 0 and 1) and advanced stage osteoarthritis (Tonnis grade 2). Using computed tomography, we measured the circumferential α-angle and head-neck offset ratio in 68 dysplastic hips and 24 normal hips. Locations of the head-neck junction were represented by the clock position. In the pre/early group, the α-angle was significantly larger at the anterosuperior and inferior aspects (1, 2, and 5-7 o'clock) and head-neck offset ratio was smaller at the anterosuperior aspect (2 o'clock) than in the control group. The α-angle was significantly larger at the anterior aspects (1-4 o'clock) in the advanced group than in the pre/early group. The maximum α-angle was most commonly found at 2 o'clock (60%, 41/68 hips) in dysplastic hips. The prevalence of cam deformity (maximum α-angle >55°) was 4.2% (1/24 hips) in the control group, 22% (11/50 hips) in the pre/early group, and 50% (9/18 hips) in the advanced group. Cam deformity, inherent in the pre/early group, was found with relatively high frequency. The higher prevalence in the advanced group reflected degeneration-modified changes. When performing periacetabular osteotomy, preoperative radiographic assessments should include the femoral head-neck junction to prevent secondary femoroacetabular impingement, especially in patients with advanced stage osteoarthritis. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1613-1619, 2016.

Since the presence of IgM antibodies is a hallmark of ongoing immune response, we aimed to identify immunologically active rheumatoid arthritis (RA) patients by detecting IgM anti-citrullinated protein antibody (ACPA) levels.IgM ACPA levels were determined in the serum of 176 RA patients by enzyme-linked immunosorbent assay, in which parameters of reactivity against citrullinated and non-citrullinated peptides were compared to ensure the specificity. Influence of IgM rheumatoid factor (RF) on IgM ACPA detection was examined by removing IgG, using protein G-conjugated beads, or by purifying ACPA, using citrullinated peptide-conjugated beads.Although IgM specific for citrullinated proteins was detected in some patients (11%), IgM molecules reactive to both citrullinated and non-citrullinated peptides were detected in a substantial number of patient samples (12%). IgM ACPA-positive reactions were associated with the presence of IgG ACPA and IgM RF. Surprisingly, protein G-mediated removal of IgG from the serum eliminated positivity for IgM ACPA, suggesting that IgG ACPA-IgM RF complex was being detected. This assumption was confirmed by the detection of IgM RF in the eluate of protein G beads and citrullinated peptide-conjugated beads.In an attempt to detect IgM ACPA, we mostly revealed false positive reactions due to the presence of IgM molecules, which were not specific for citrullinated proteins, and IgG ACPA-IgM RF immune complex. The latter complex had been proposed to play a role in the pathogenesis of RA, and here, for the first time, we have demonstrated its presence in the sera of RA patients.

Intraosseous hemangioma (IH) is commonly seen in the vertebral column and skull: however, IH occurring in the appendicular skeleton, including the clavicle, is uncommon. We herein report the case of a 69-year-old female presenting with IH of the left clavicle. The findings of preoperative imaging studies, including radiographs, computed tomography (CT), magnetic resonance imaging, fluorine-18-fludeoxyglucose ((18)F-FDG) positron emission tomography (PET)/CT and ultrasonography, are described. In particular, (18)F-FDG PET/CT showed an ill-defined osteolytic lesion with abnormally high FDG uptake. Surgical en bloc resection with preoperative embolization was carried out and a histopathological examination confirmed the presence of an intraosseous cavernous hemangioma in the clavicle.

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.

We clarified the prevalence of spondyloarthritis (SpA) symptom in inflammatory bowel disease (IBD).We performed the questionnaire survey of SpA symptom in IBD patients on their office visit.One hundred and thirty seven patients were evaluated. The SpA features group included 46 (33.6%) patients (32 Men). Among them there were 22 Crohn's disease (CD) patients and 24 ulcerative colitis (UC) patients. The patients had a mean age of 48.3 years with a mean disease duration of 12.3 years. Non-SpA group (66.4%) included 91 patients (49 Men). Among them there were 27 CD patients and 64 UC patients. The patients had a mean age of 43.3 years with a mean disease duration of 9.2 years. In univariate analysis, the SpA group (33.6%) had longer disease duration than non-SpA group (p0.05). However, age at onset and sex were not significantly different among the groups. Multivariate analysis showed that disease duration was independently associated with SpA symptom (OR, 1.05; 95% CI, 1-1.09; p = 0.036).The prevalence of SpA symptom was relatively higher than what we had expected. Physicians should consider SpA when they observe IBD patients with arthralgia, and refer them to an appropriate department if needed.

Cam deformity could lead to suboptimal articulation by causing secondary femoroacetabular impingement after periacetabular osteotomy; however, the inherent femoral head-neck morphology in dysplastic hips and the effect of an additional osteoarthritic deformity have not been well described. We compared femoral head-neck morphology using three-dimensional imaging of normal and dysplastic hips in pre/early (Tönnis grade 0 and 1) and advanced stage osteoarthritis (Tönnis grade 2). Using computed tomography, we measured the circumferential α-angle and head-neck offset ratio in 68 dysplastic hips and 24 normal hips. Locations of the head-neck junction were represented by the clock position. In the pre/early group, the α-angle was significantly larger at the anterosuperior and inferior aspects (1, 2, and 5-7 o'clock) and head-neck offset ratio was smaller at the anterosuperior aspect (2 o'clock) than in the control group. The α-angle was significantly larger at the anterior aspects (1-4 o'clock) in the advanced group than in the pre/early group. The maximum α-angle was most commonly found at 2 o'clock (60%, 41/68 hips) in dysplastic hips. The prevalence of cam deformity (maximum α-angle55°) was 4.2% (1/24 hips) in the control group, 22% (11/50 hips) in the pre/early group, and 50% (9/18 hips) in the advanced group. Cam deformity, inherent in the pre/early group, was found with relatively high frequency. The higher prevalence in the advanced group reflected degeneration-modified changes. When performing periacetabular osteotomy, preoperative radiographic assessments should include the femoral head-neck junction to prevent secondary femoroacetabular impingement, especially in patients with advanced stage osteoarthritis. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1613-1619, 2016.

Granulocyte macrophage colony-stimulating factor (GM-CSF), an immunomodulatory cytokine, is an emerging therapeutic target of rheumatoid arthritis (RA).1 Although GM-CSF is produced by various types of cells, including synovial fibroblasts, the importance of GM-CSF-producing CD4 T cells in the pathogenesis of RA was reported.2 Moreover, GM-CSF has been shown to be the critical effector cytokine produced by interleukin (IL)-23-stimulated Th17 cells in mice, leading to the prevailing notion that GM-CSF is a Th17-related cytokine.3 However, in humans, a distinct subset of CD4 T cells that produce only GM-CSF has recently been identified.4 The ‘GM-CSF-only’ T cells are characterised by the lack of lineage defining cytokines (interferon (IFN)-γ, IL-17 and IL-4) and are regulated independently of the master transcriptional regulators, T-bet, RORγt or GATA3. Furthermore, in contrast to mice, GM-CSF production by human CD4 T cells was promoted in Th1 conditions and was also detected in Th1 cells. At present, it is unclear which helper CD4 T cell subsets produce GM-CSF in human RA joints. Therefore, in this study, we performed multicolour flow cytometric analysis of cytokine production in CD4 T cells from patients with RA. Lymphocytes in the peripheral blood (PB) and in joints from the same patients were analysed to compare the profiles of cytokine production. Synovial fluid (SF) samples were obtained from seven patients by arthrocentesis, while synovial membrane (SM) samples were obtained from seven other patients who underwent joint replacement surgery. The mean age and disease duration of the patients was 63.5±15.5 and 16.5±10.1 years, respectively. Twelve patients (86%) were positive for RF and/or anti-CCP2 antibody, and the mean C reactive protein level was 1.2±1.1 mg/dL. In total, 11 (79%), 10 (71%) and 4 (29%) patients received …