Factors associated with anxiety and depression in rheumatoid arthritis patients: a cross-sectional study

Abstract Background: The management of anxiety and depression symptoms in rheumatoid arthritis (RA) patients is vital. Previous study findings on this topic are conflicting, and the topic remains to be thoroughly investigated. This study aimed to clarify the association of RA disease activity with anxiety and depression symptoms after controlling for physical disability, pain, and medication. Methods: We conducted a cross-sectional study of RA patients from the XXX Rheumatoid Arthritis Management Alliance cohort. We assessed patients using the Disease Activity Score (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI), and Hospital Anxiety and Depression Scale (HADS). Anxiety and depression symptoms were defined by a HADS score ≥ 8. We analyzed the data using multivariable logistic regression analyses. Results: Of 517 participants, 17.6% had anxiety symptoms and 27.7% had depression symptoms. The multivariable logistic regression analysis demonstrated that DAS28 was not independently associated with anxiety symptoms (odds ratio [OR] [95% confidence interval; CI] 0.93 [0.48-1.78]; p = 0.82) and depression symptoms (OR [95% CI] 1.45 [0.81-2.61]; p = 0.22). However, DAS28 patient global assessment (PtGA) severity was associated with anxiety symptoms (OR [95% CI] 1.15 [1.02-1.29]; p = 0.03) and depression symptoms (OR [95% CI] 1.21 [1.09-1.35]; p < 0.01). Additionally, HAQ-DI scores ≤ 0.5 were associated with anxiety symptoms (OR [95% CI] 3.51 [1.85-6.64]; p < 0.01) and depression symptoms (OR [95% CI] 2.65 [1.56-4.50]; p < 0.01). Patients using steroids were more likely to have depression than those not using steroids (OR [95% CI] 1.66 [1.03-2.67]; p = 0.04). Conclusions: No association was found between RA disease activity and anxiety and depression symptoms in the multivariable logistic regression analysis. Patients with high PtGA scores or HAQ-DI scores ≤ 0.5 were more likely to experience anxiety and depression symptoms, irrespective of disease activity remission status. Rather than focusing solely on controlling disease activity, treatment should focus on improving or preserving physical function and the patient's overall sense of well-being.

Destructive arthritis with cutaneous polyarteritis nodosa requiring surgical intervention: a case report and review of the literature.

Arthralgia is a well-known complication of cutaneous polyarteritis nodosa (CPN). However, few cases of destructive arthritis with CPN resulting in chronic pain and disability have been documented. Here we report a case of CPN associated with destructive arthritis of the right foot, accompanied by seronegative arthritis in the right ankle, for which orthopaedic surgery was necessary. X-ray and computed tomography revealed progressive joint destruction in the right talonavicular joint, and magnetic resonance imaging demonstrated severe synovitis of the right talocrural joint. When the talonavicular joint was opened, we observed marked synovitis and a defect in the cartilage that had expanded within the joint. Although mild cartilage degeneration was observed in the talocrural joint, arthroscopic observation revealed no massive defect on the articulated surface. Arthrodesis and arthroscopic synovectomy yielded a good midterm clinical outcome, indicating that surgical intervention was useful for the treatment for destructive arthritis with CPN. Rheumatologists and orthopaedic surgeons should be aware of potential complications such as destructive arthritis when treating patients with CPN.

Prevalence and factors associated with sarcopenia in patients with rheumatoid arthritis.

Objectives: Sarcopenia is characterized by loss of muscle strength and mass, leading to falls and adverse health outcomes. Our aim was to determine the prevalence of sarcopenia in patients with rheumatoid arthritis (RA) and to identify factors associated with sarcopenia in these patients. Methods: A cross-sectional study of 388 consecutive women with RA was conducted, assessing muscle mass and strength, and walking speed. Falls and bone fractures sustained over the prior year were evaluated. The association between sarcopenia and RA characteristics, falls, and bone fractures was evaluated using logistic regression analyses. Results: The prevalence of sarcopenia was 37.1% (14.7%, severe sarcopenia; 22.4%, sarcopenia), with 49.0% classified as having low muscle mass. The incidence of falls, fractures, and lower bone mineral density was higher in patients with than without sarcopenia. Age, RA duration, Steinbrocker's stage, the high Mini-Nutritional Assessment-Short Form score and the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) were independent factors associated with sarcopenia. Conclusion: We confirmed that sarcopenia develops in a significant proportion of patients with RA. Age, longer disease duration, joint destruction and malnutrition were positively associated with sarcopenia, with the use of bDMARDs being negatively associated.

Factors associated with the achievement of biological disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: the ANSWER cohort study.

BACKGROUND: Clinical remission can be maintained after the discontinuation of biological disease-modifying antirheumatic drugs (bDMARDs) in some patients with rheumatoid arthritis (RA) (bDMARD-free remission (BFR)). It is unknown which bDMARD is advantageous for achieving BFR or under which conditions BFR can be considered. This study aimed to determine the factors associated with BFR achievement in clinical practice. METHODS: Patients with RA were enrolled from a Japanese multicenter observational registry. Patients with RA who achieved clinical remission (Disease Activity Score 28-C-reactive protein < 2.3) at the time of bDMARD discontinuation were included. Serial disease activities and treatment changes were followed up. BFR was considered to have failed if the disease activity exceeded the remission cutoff value or if bDMARDs were restarted. RESULTS: Overall, 181 RA patients were included. BFR was maintained in 21.5% of patients at 1 year after bDMARD discontinuation. BFR was more successfully achieved after discontinuation of anti-tumor necrosis factor (TNF) monoclonal antibodies (TNFi(mAb)) (infliximab, adalimumab, and golimumab), followed by CTLA4-Ig (abatacept), soluble TNF receptor or Fab fragments against TNF fused with polyethylene glycol (etanercept and certolizumab), and anti-interleukin-6 receptor Ab (tocilizumab). After multivariate analysis, sustained remission (> 6 months), Boolean remission, no glucocorticoid use at the time of bDMARD discontinuation, and use of TNFi(mAb) or CTLA4-Ig remained as independent factors associated with BFR. CONCLUSIONS: BFR can be achieved in some patients with RA after bDMARD discontinuation in clinical practice. Use of TNFi(mAb) or CTLA4-Ig, sustained remission, Boolean remission, and no glucocorticoid use at the time of bDMARD discontinuation are advantageous for achieving BFR.

Intraoperative medial joint laxity in flexion decreases patient satisfaction after total knee arthroplasty.

INTRODUCTION: The relationship between postoperative tibiofemoral ligament balance and patient satisfaction in total knee arthroplasty (TKA) has been explored previously. However, the optimal intraoperative medial-lateral ligament balance during knee flexion in terms of postoperative patient satisfaction remains unknown. We evaluated the effect of intraoperative flexion instability on patient satisfaction after TKA. MATERIALS AND METHODS: This study consisted of 46 knees with varus osteoarthritis undergoing TKA. Medial-lateral component gaps at 0° knee extension and 90° flexion were measured intraoperatively using a knee balancer. Differences in postoperative patient outcomes at 3 weeks and 1 year were compared between medially tight knees in 90° flexion with a medial component gap of < 4 mm and medially loose knees in 90° flexion with a gap of ≥ 4 mm. Outcomes were measured using the 2011 Knee Society Scoring System (2011 KS). RESULTS: The median total 2011 KS score at 1 year postoperatively in the medially loose knees [median 97; interquartile range (IQR) 75-117] was significantly lower than that in the medially tight knees (median 128; IQR 104-139, P < 0.01), while preoperative and 3-week postoperative scores were similar. In addition, medial flexion gaps were not significantly associated with total 2011 KS scores before surgery or at 3 weeks postoperatively. However, at 1 year after surgery, medial component flexion gaps were negatively associated with the total 2011 KS score (R = - 0.42; P < 0.01) and the 2011 KS satisfaction subscale score (R = - 0.36; P = 0.01). CONCLUSIONS: Excessive intraoperative medial joint laxity of ≥ 4 mm at 90° flexion progressively decreased patient satisfaction for 1 year. Since intraoperative medial laxity in flexion is likely to interfere with functional recovery after TKA, medial stabilization during TKA is important throughout knee flexion. LEVEL OF EVIDENCE: Therapeutic study, Level III.

Preoperative factors related to the ambulatory status at 1 year after total knee arthroplasty.

PURPOSE: The purpose of this study is to investigate whether preoperative factors can predict the ambulatory status at 1 year after primary total knee arthroplasty (TKA). METHODS: The subjects were 115 patients who had undergone TKA. Isometric lower limb muscle strength was measured and the Timed Up and Go (TUG) test and the 2011 knee society scoring were conducted preoperatively. Then, the patients were divided into two groups after surgery: a cane-assisted walking group (n = 42) and independent walking group (n = 73). Unpaired t-test, chi-square test, Mann-Whitney U-test, logistic regression analysis and the receiver-operating characteristic curve analysis were used in this study. RESULTS: A multiple logistic regression analysis selected age, TUG test and functional activities as significant variables estimating the use of a cane after surgery. Receiver-operating characteristic curve analyses revealed that the cut-off score for TUG test was 10.8 s (sensitivity = 69%, specificity = 67%, area under curve = 0.81) and the cut-off score for functional activities was 39 points (sensitivity = 83%, specificity = 63%, area under curve = 0.83) in predicting the ambulatory status. CONCLUSIONS: Preoperative TUG test with a cut-off score of 10.8 s and functional activities with a cut-off score of 39 points are reliable assessment tools for predicting the use of walking aid following TKA. Implications for Rehabilitation An accurate prediction of the ambulatory status after total knee arthroplasty can aid patients in understanding their own goals of the activities of daily living. Preoperative timed up and go test of <10.8 s and a preoperative functional activities functional activities score in the 2011 knee society scoring >39 points are useful for predicting the ambulatory status after total knee arthroplasty.

Factors influencing spinal sagittal balance, bone mineral density, and Oswestry Disability Index outcome measures in patients with rheumatoid arthritis.

PURPOSE: To identify the factors influencing spinal sagittal alignment, bone mineral density (BMD), and Oswestry Disability Index (ODI) outcome measures in patients with rheumatoid arthritis (RA). METHODS: We enrolled 272 RA patients to identify the factors influencing sagittal vertical axis (SVA). Out of this, 220 had evaluation of bone mineral density (BMD) and vertebral deformity (VD) on the sagittal plane; 183 completed the ODI questionnaire. We collected data regarding RA-associated clinical parameters and standing lateral X-ray images via an ODI questionnaire from April to December 2012 at a single center. Patients with a history of spinal surgery or any missing clinical data were excluded. Clinical parameters included age, sex, body mass index, RA disease duration, disease activity score 28 erythrocyte sedimentation rate (DAS28-ESR), serum anti-cyclic citrullinated peptide antibody, serum rheumatoid factor, serum matrix metalloproteinase-3, BMD and treatment type at survey, such as methotrexate (MTX), biological disease-modifying anti-rheumatic drugs, and glucocorticoids. We measured radiological parameters including pelvic incidence (PI), lumbar lordosis (LL), and SVA. We statistically identified the factors influencing SVA, BMD, VD, and ODI using multivariate regression analysis. RESULTS: Multivariate regression analysis showed that larger SVA correlated with older age, higher DAS28-ESR, MTX nonuse, and glucocorticoid use. Lower BMD was associated with female, older age, higher DAS28-ESR, and MTX nonuse. VD was associated with older age, longer disease duration, lower BMD, and glucocorticoid use. Worse ODI correlated with older age, larger PI-LL mismatch or larger SVA, higher DAS28-ESR, and glucocorticoid use. CONCLUSIONS: In managing low back pain and spinal sagittal alignment in RA patients, RA-related clinical factors and the treatment type should be taken into consideration.

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.

Hypoxia-Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human Macrophages and Suppresses Osteoclastogenesis.

Hypoxia augments inflammatory responses and osteoclastogenesis by incompletely understood mechanisms. We identified COMMD1 as a cell-intrinsic negative regulator of osteoclastogenesis that is suppressed by hypoxia. In human macrophages, COMMD1 restrained induction of NF-κB signaling and a transcription factor E2F1-dependent metabolic pathway by the cytokine RANKL. Downregulation of COMMD1 protein expression by hypoxia augmented RANKL-induced expression of inflammatory and E2F1 target genes and downstream osteoclastogenesis. E2F1 targets included glycolysis and metabolic genes including CKB that enabled cells to meet metabolic demands in challenging environments, as well as inflammatory cytokine-driven target genes. Expression quantitative trait locus analysis linked increased COMMD1 expression with decreased bone erosion in rheumatoid arthritis. Myeloid deletion of Commd1 resulted in increased osteoclastogenesis in arthritis and inflammatory osteolysis models. These results identify COMMD1 and an E2F-metabolic pathway as key regulators of osteoclastogenic responses under pathological inflammatory conditions and provide a mechanism by which hypoxia augments inflammation and bone destruction.

Varus femoral and tibial coronal alignments result in different kinematics and kinetics after total knee arthroplasty.

PURPOSE: Abnormal knee motion under various conditions has been described after total knee arthroplasty (TKA). However, differences in kinematics and kinetics of knees with varus femoral versus varus tibial alignment have not been evaluated. It was hypothesized that varus femoral and tibial alignments have the same impact on knee motion. METHODS: A musculoskeletal computer simulation was used. Femoral and tibial alignment in the coronal plane was each varied from neutral to 5° of varus in 1° increments. Lift-off, defined as an intercomponent distance of >2 mm, and tibiofemoral contact forces were evaluated during gait up to 60° of knee flexion. Knee kinematics and contact stresses were also examined during squat, with up to 130° of knee flexion. RESULTS: During gait, lift-off occurred readily with more than 3° of varus tibial alignment and slight lateral joint laxity. In contrast, lift-off did not occur with varus femoral or tibial alignment of up to 5° during squat. Peak medial contact forces with varus femoral alignment were approximately twice those observed with varus tibial alignment. The lowest points of the femoral condyles moved internally with varus femoral alignment, contrary to the kinematics with neutral or varus tibial alignment. On the other hand, there was femoral medial sliding and edge loading against the tibia in mid-flexion with varus tibial alignment. CONCLUSION: Varus femoral alignment affects the non-physiological rotational movement of the tibiofemoral joint, whereas varus tibial alignment causes medial-lateral instability during mid-flexion. Varus femoral and tibial alignments might lead to post-TKA discomfort and unreliability.

Long-Term Durability of Ceramic Tri-Condylar Knee Implants: A Minimum 15-Year Follow-Up.

BACKGROUND: Ceramic bearings are not commonly used in total knee arthroplasty (TKA). So far, little information is available about whether long-term survivorship and good clinical outcomes can be ensured with ceramic knee implants. The purposes of the present study were to evaluate the clinical and radiological outcomes, and to assess the long-term durability of a ceramic tri-condylar implant. METHODS: A total of 507 consecutive TKAs were carried out using a ceramic tri-condylar femoral implant. The posterior cruciate ligament was sacrificed, and all components were fixed with bone cement. Clinical outcomes were assessed retrospectively with the Knee Society scoring system. Kaplan-Meier survivorship was calculated to determine the cumulative survival rate. RESULTS: One hundred sixty-seven knees (114 patients) were available for clinical outcomes. The average range of flexion improved from 118.1° preoperatively to 123.7° at a minimum 15-year follow-up (P < .001). The average Knee Society knee score improved from 39.1 to 92.8 (P < .001). The functional score also improved from 36.0 to 47.0 (P < .001). With revision for any surgery or radiographic failure as the end point, Kaplan-Meier survivorship at 15 years was 94.0%. With revision of any component as the end point, the corresponding survivorship was 96.2%. CONCLUSION: Clinically, the postoperative knee flexion range and Knee Society scores were good after long-term follow-up. The survivorship of the ceramic knee implant was excellent over the 15-year follow-up, and long-term durability was achieved, making ceramic a promising alternative material for the femoral component in TKA.

Subsidence of total ankle component associated with deterioration of an ankle scale in non-inflammatory arthritis but not in rheumatoid arthritis.

OBJECTIVES: Modern three-component total ankle arthroplasty (TAA) has favorable clinical results and survival rates. However, radiographic deterioration and worsening of clinical symptoms may occur in patients with rheumatoid arthritis (RA) or non-inflammatory arthritis (NA). The associations between outcomes and clinical and radiological factors are not clear. We compared midterm clinical and radiographic outcomes after TAA between patients with RA and those with NA. METHODS: Twenty-six TAAs were performed using a three-component prosthesis, the FINE Total Ankle System during the study period. Fourteen TAAs with 11 RA patients undergoing primary TAA were compared with twelve TAAs with 12 NA patients. Clinical and radiographic outcomes were evaluated before and after operation, and at the final follow-up. RESULTS: The Japanese Society for Surgery of the Foot (JSSF) scale improved significantly following TAA in both groups (p = 0.0039 and 0.0156, respectively). Tibial subsidence, talar subsidence and age were significantly associated with postoperative JSSF score only in the NA group (p = 0.0027, 0.0017 and p < 0.0001, respectively). Stepwise regression analysis showed that talar subsidence was an independent predictor of a worse JSSF score in the NA group (F = 10.3). CONCLUSIONS: The final clinical outcome was negatively influenced by talar subsidence in patients with NA, but not in those with RA.

Immunogenicity and Lupus-Like Autoantibody Production Can Be Linked to Each Other along With Type I Interferon Production in Patients with Rheumatoid Arthritis Treated With Infliximab: A Retrospective Study of a Single Center Cohort.

Besides anti-drug antibodies, anti-nuclear antibodies and anti-DNA antibodies are often induced in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors. We examined the association between immunogenicity, autoantibody production, and serum cytokine profiles in patients with rheumatoid arthritis treated with infliximab. Japanese patients with rheumatoid arthritis (n = 57) were retrospectively examined. Serum trough levels of infliximab, anti-drug antibody, anti-nuclear antibody, and anti-DNA (Farr), anti-single-stranded DNA and anti-double-stranded DNA antibodies were measured. Interleukin-6, interferon-γ, interferon-α, and B-cell activating factor levels were also measured in the same sera. Then, we validated the association between anti-drug antibody and these serum markers along with clinical response to infliximab. Anti-drug antibodies developed in twenty-one patients (36.8%), whose serum trough levels of infliximab were significantly lower than those in anti-drug antibody-negative patients (0.09 ± 0.03 vs. 2.48 ± 0.326 µg/mL, p < 0.0001). There were no significant differences in clinical backgrounds between the two groups. The anti-drug antibody-positive patients were more likely to develop anti-nuclear antibody titers of ≥ ×160 compared to the negative patients (14 to 57% vs. 17 to 33%). In addition, anti-DNA antibodies (Farr) (from 1.5 ± 0.4 to 35 ± 17 IU/mL, p = 0.0001), especially IgM-anti-double stranded DNA antibody (from 5.1 ± 0.7 to 41 ± 8.9 IU/mL, p < 0.0001), and IgG-anti-single stranded DNA antibody (from 13 ± 1.1 to 35 ± 13, p = 0.0145) were significantly increased in anti-drug antibody-positive but not in negative patients. Moreover, the anti-drug antibody-positive, but not the negative patients, showed significant increased levels of interferon-α (from 248.7 ± 102.3 to 466.8 ± 135.1 pg/mL, p = 0.0353) and B-cell activating factor (from 1073 ± 75.1 to 1387 ± 136.5 pg/mL, p = 0.0208) following infliximab treatment. The development of anti-drug antibody against infliximab and lupus-like autoantibody production in patients with rheumatoid arthritis treated with infliximab can be linked each other along with increased lupus-associated cytokine levels including type I interferons.

Bone-protective Functions of Netrin 1 Protein.

Netrin 1 was initially identified as an axon guidance factor, and recent studies indicate that it inhibits chemokine-directed monocyte migration. Despite its importance as a neuroimmune guidance cue, the role of netrin 1 in osteoclasts is largely unknown. Here we detected high netrin 1 levels in the synovial fluid of rheumatoid arthritis patients. Netrin 1 is potently expressed in osteoblasts and synovial fibroblasts, and IL-17 robustly enhances netrin 1 expression in these cells. The binding of netrin 1 to its receptor UNC5b on osteoclasts resulted in activation of SHP1, which inhibited VAV3 phosphorylation and RAC1 activation. This significantly impaired the actin polymerization and fusion, but not the differentiation of osteoclast. Strikingly, netrin 1 treatment prevented bone erosion in an autoimmune arthritis model and age-related bone destruction. Therefore, the netrin 1-UNC5b axis is a novel therapeutic target for bone-destructive diseases.

Influence of Posterior Cruciate Ligament Tension on Knee Kinematics and Kinetics.

The posterior cruciate ligament (PCL) has an important role in cruciate-retaining total knee arthroplasty to achieve good clinical results. The purpose of the study was to examine the influence of PCL tension on knee kinematics and kinetics and to propose an indicator for proper PCL tension during surgery. A squatting activity was simulated in a weight-bearing deep knee bend using a musculoskeletal computer simulation knee model. The length of the PCL was changed to represent different PCL tension models. The amount of PCL tension significantly influenced knee kinematics and kinetics. In the normal PCL model, the facet center positions at 90 degrees of knee flexion were positioned at almost the same position as in full extension. A loose PCL-induced paradoxical anterior movement and greater patellofemoral forces, whereas a tight PCL was related to excessive rollback and increased tibiofemoral forces. This study suggested ideal knee kinematics with proper PCL tension, in which the medial contact position at full flexion was almost similar to the position at 90 degrees of knee flexion.

No condylar lift-off occurs because of excessive lateral soft tissue laxity in neutrally aligned total knee arthroplasty: a computer simulation study.

PURPOSE: Condylar lift-off can induce excessive polyethylene wear after total knee arthroplasty (TKA). A computer simulation was used to evaluate the influence of femoral varus alignment and lateral collateral ligament (LCL) laxity on lift-off after single-design TKA. It was hypothesised that proper ligament balancing and coronal alignment would prevent lift-off. METHODS: The computer model in this study is a dynamic musculoskeletal program that simulates gait up to 60° of knee flexion. The lift-off phenomenon was defined as positive with an intercomponent distance of >2 mm. In neutrally aligned components in the coronal plane, the femoral and tibial components were set perpendicular to the femoral and tibial mechanical axis, respectively. The femoral coronal alignment was changed from neutral to 5° varus in 1° increments. Simultaneously, the LCL length was elongated from 0 to 5 mm in 1-mm increments to provide a model of pathological slack. RESULTS: Within 2° of femoral varus alignment, lift-off did not occur even if the LCL was elongated by up to 5 mm. However, lift-off occurred easily in the stance phase in femoral varus alignments of >3° with slight LCL slack. The contact forces of the tibiofemoral joint were influenced more by femoral varus alignment than by LCL laxity. CONCLUSIONS: Aiming for neutral alignment in severely varus knees makes it difficult to achieve appropriate ligament balance. Our study suggests that no lift-off occurs with excessive LCL laxity alone in a neutrally aligned TKA and therefore that varus alignment should be avoided to decrease lift-off after TKA. LEVEL OF EVIDENCE: Case series, Level IV.

TGF-ß induces the differentiation of human CXCL13-producing CD4(+) T cells.

In the ectopic lymphoid-like structures present in chronic inflammatory conditions such as rheumatoid arthritis, a subset of human effector memory CD4(+) T cells that lacks features of follicular helper T (Tfh) cells produces CXCL13. Here, we report that TGF-ß induces the differentiation of human CXCL13-producing CD4(+) T cells from naïve CD4(+) T cells. The TGF-ß-induced CXCL13-producing CD4(+) T cells do not express CXCR5, B-cell lymphoma 6 (BCL6), and other Tfh-cell markers. Furthermore, expression levels of CD25 (IL-2Rα) in CXCL13-producing CD4(+) T cells are significantly lower than those in FoxP3(+) in vitro induced Treg cells. Consistent with this, neutralization of IL-2 and knockdown of STAT5 clearly upregulate CXCL13 production by CD4(+) T cells, while downregulating the expression of FoxP3. Furthermore, overexpression of FoxP3 in naïve CD4(+) T cells downregulates CXCL13 production, and knockdown of FoxP3 fails to inhibit the differentiation of CXCL13-producing CD4(+) T cells. As reported in rheumatoid arthritis, proinflammatory cytokines enhance secondary CXCL13 production from reactivated CXCL13-producing CD4(+) T cells. Our findings demonstrate that CXCL13-producing CD4(+) T cells lacking Tfh-cell features differentiate via TGF-ß signaling but not via FoxP3, and exert their function in IL-2-limited but TGF-ß-rich and proinflammatory cytokine-rich inflammatory conditions.

Limited extension after linked total elbow arthroplasty in patients with rheumatoid arthritis.

OBJECTIVE: Total elbow arthroplasty (TEA) has become an established procedure to relieve pain and to increase the range of motion of the destructed elbow in patients with rheumatoid arthritis (RA). However, some patients still have limited extension after TEA, and the causes of limited extension after TEA have yet to be elucidated. METHODS: To examine whether widening of the joint space can cause such limited extension, we retrospectively analyzed 55 cases of linked TEA in patients with RA. There were seven male and 40 female with a mean age of 63.8 years (range, 30-80 years) and a mean follow-up of 7.5 ± 4.2 years (range, 2.5-15.6 years). The Mayo Elbow Performance Score (MEPS) and radiological measurements were recorded. Widening of the joint space was calculated by subtracting the length measured on postoperative radiograph from preoperative radiograph. RESULTS: MEPS and range of motion were significantly improved after surgery except for extension. The degree of extension was significantly correlated with radiological widening of the joint space in the limited extension group. Correlation analyses showed that postoperative limited extension was correlated with lower MEPS daily function. CONCLUSIONS: Limited extension after linked TEA is partly derived from perioperative widening of the joint space and potentially limits daily function in patients with RA.

Rheumatoid Factor Is Associated With the Distribution of Hand Joint Destruction in Rheumatoid Arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic disease leading to joint destruction. Although many studies have addressed factors potentially correlated with the speed of joint destruction, less attention has been paid to the distribution of joint destruction in patients with RA. In this study, destruction of the hand bones in patients with RA was classified into 2 anatomic subgroups, the fingers and the non-fingers, with the aim of analyzing which factors are associated with destruction of the finger joints. METHODS: A total of 1,215 Japanese patients with RA were recruited from 2 different populations. The degree of joint destruction was assessed using the total modified Sharp/van der Heijde score (SHS) of radiographic joint damage. The SHS score of joint damage in the finger joints was used as the dependent variable, and the SHS score in the non-finger joints was used as a covariate. Age, sex, disease duration, smoking, C-reactive protein level, treatment for RA, and positivity for and levels of anti-citrullinated protein antibodies and rheumatoid factor (RF) were evaluated as candidate correlates. Overall effect sizes were assessed in a meta-analysis. In addition, associations observed in the Japanese patients were compared to those in a cohort of 157 Dutch RA patients in the BeSt study (a randomized, controlled trial involving 4 different strictly specified treatment strategies for early RA). RESULTS: Not surprisingly, disease duration in Japanese patients with RA was associated with the finger SHS score (P ≤ 0.00037). Both positivity for and levels of RF showed significant associations with the finger SHS score after adjustment for covariates (P = 0.0022 and P = 8.1 × 10(-7) , respectively). These associations were also true in relation to the time-averaged finger SHS score. An association between RF positivity and the finger SHS score was also observed in Dutch patients with RA in the BeSt study (P = 0.049). CONCLUSION: Positivity for and levels of RF are associated with finger joint destruction independent of non-finger joint destruction and other covariates. Our findings suggest that there are different mechanisms of joint destruction operating in the finger joints of patients with RA.

Morphology of the Proximal Tibia at Different Levels of Bone Resection in Japanese Knees.

The purpose was to measure the morphology of the proximal tibia at different levels for consideration of tibial tray design and placement. The morphology was analysed in 51 knees at 10, 15, 20, and 25 mm below the centre of the lateral tibial plateau. Surface rotation was measured by fitting an ellipse on the resection surface. The anteroposterior (AP), mediolateral (ML), medial AP (MAP) and lateral AP (LAP) dimensions were also measured. The resection surface showed internal rotation of 22.9° from the 10 mm level to the 25 mm level. More distally, the ML/AP and MAP/LAP ratios showed significant changes. Surgeons should pay attention to morphological changes for patients with gross tibial bone defects in primary and revision total knee arthroplasty.