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.

Genetic architecture underlying IgG-RF production is distinct from that of IgM-RF.

OBJECTIVE: HLA-DRB1 alleles, particularly the shared epitope (SE) alleles, are strongly associated with RA. Different genetic structures underlie the production of the various autoantibodies in RA. While extensive genetic analyses have been conducted to generate a detailed profile of ACPA, a representative autoantibody in RA, the genetic architecture underlying subfractions of RF other than IgM-RF, namely IgG-RF, known to be associated with rheumatoid vasculitis, is not well understood. METHODS: We enrolled a total of 743 RA subjects whose detailed autoantibody (IgG-RF, IgM-RF, and ACPA) data were available. We evaluated co-presence and correlations of the levels of these autoantibodies. We analysed associations between the presence or levels of the autoantibodies and HLA-DRB1 alleles for the 743 RA patients and 2008 healthy controls. RESULTS: We found both IgG-RF(+) and IgG-RF(-) RA subjects showed comparable associations with SE alleles, which was not observed for the other autoantibodies. Furthermore, there was a clear difference in SE allele associations between IgG-RF(+) and (-) subsets: the association with the IgG-RF(+) subsets was solely driven by HLA-DRB1*04:05, the most frequent SE allele in the Japanese population, while not only HLA-DRB1*04:05 but also HLA-DRB1*04:01, less frequent in the Japanese population but the most frequent SE allele in Europeans, were main drivers of the association in the IgG-RF(-) subset. We confirmed that these associations were irrespective of ACPA presence. CONCLUSION: We found a unique genetic architecture for IgG-RF(-) RA, which showed a strong association with a SE allele not frequent in the Japanese population but the most frequent SE allele in Europeans. The findings could shed light on uncovered RA pathology.

Region specificity of rheumatoid foot symptoms associated with ultrasound-detected synovitis and joint destruction.

OBJECTIVES: We aimed to clarify the clinical implication of ultrasound (US)-detected foot joint inflammation in tightly controlled patients with rheumatoid arthritis (RA). METHODS: We evaluated bilateral foot joints (second to fifth metatarsophalangeal joints of forefoot; tarsometatarsal, cuneonavicular and midtarsal joints of midfoot) of 430 RA patients for synovitis using Power Doppler (PD) imaging by US. We made a cross-sectional and a 3-year longitudinal analysis about the associations of US-detected synovitis with clinical, laboratory and radiographic data as well as foot-specific outcomes using a self-administered foot evaluation questionnaire (SAFE-Q). RESULTS: The US-detected foot synovitis was seen in 28% of patients. The US-detected synovitis was closely related to 28 joint-disease activity score (DAS28) more in the forefoot than in the midfoot, while related to joint destruction in both. Multiple regression analyses showed significant associations between midfoot PD positivity and SAFE-Q in the remission group. SAFE-Q was worsened after the 3-year interval, but PD positivity at baseline did not contribute to the changes. On the other hand, destruction of the joints with US-detected synovitis significantly progressed in 3 years than with not. CONCLUSIONS: US-detected synovitis on foot joints were related to systemic inflammation, clinical symptoms, and future joint destruction with region specificity.

Severe joint deformity and patient global assessment of disease are associated with discrepancies between sonographic and clinical remission: A cross-sectional study of rheumatoid arthritis patients.

OBJECTIVE: Although recent clinical trials showed that ultrasound (US) remission is not required to achieve good outcomes at the group level, it currently remains unclear whether the prognosis of individual patients in clinical remission, but not US remission, i.e. those with subclinical sonographic synovitis (SSS), is favorable. However, it is no longer acceptable to perform US on all patients in order to identify those with SSS. Therefore, the present study was initiated to elucidate the conditions under which SSS is frequently detected. METHODS: In total, 563 consecutive RA patients were recruited. Bilateral 2-5 MCP, wrist, ankle, and 2-5 MTP joints were scanned by US, and Gray scale and Power Doppler (PD) images were scored semi-quantitatively. Clinical data were obtained by physicians who were blind to US results. Changes in the modified Total Sharp Score (mTSS) of tocilizumab (TCZ) users were calculated. RESULTS: A total of 402 patients were included. SSS was more frequently detected in patients with more severe joint deformity, even if they were in remission. In contrast, a high Patient Global Assessment of Disease (PtGA) did not reflect SSS. Furthermore, the relationship between PtGA and PD scores was weak. Although the frequency of SSS was high in TCZ user, the presence of SSS in TCZ users not always results in the progression of mTSS. CONCLUSIONS: While remission is overestimated in patients with severe joint deformity, underestimations may occur in those who do not fulfill remission criteria because of a high PtGA.

Tenderness of the knee is associated with thinning of the articular cartilage evaluated with ultrasonography in a community-based cohort: The Nagahama study.

OBJECTIVES: This study aimed to elucidate the association between joint line tenderness (JLT) of the knee and knee joint structural changes evaluated with ultrasonography (US) for the early diagnosis of knee osteoarthritis (KOA). METHODS: This cross-sectional study included 121 participants (age 71.7 ± 5.8 years, 75 women) from a community-based population. Bilateral structural changes in the knee joint were evaluated with US, and the presence or absence of JLT was evaluated using a pressure algometer. Logistic regression analysis was performed to evaluate the odds ratios (ORs) of US findings for the presence of JLT. Moreover, when the analysis was limited to knees with pre-/early radiographic KOA, the ORs were also calculated using logistic regression analysis. RESULTS: Among the 242 knees, 38 had medial JLT, which was significantly associated with female sex (OR 11.87) and loss of cartilage thickness of the distal medial femoral condyle (CTh-MFC) (OR 0.12). Among 96 knees with Kellgren-Lawrence grade ≤ 2, 18 knees had medial JLT, which was also significantly associated with loss of CTh-MFC (OR 0.07) and medial osteophytes (OR 2.01). CONCLUSIONS: JLT is significantly associated with thinning of the femoral cartilage and larger osteophytes in elderly patients, even in those with pre-/early radiographic KOA.

Soluble Lectin-like Oxidized Low-Density Lipoprotein Receptor 1 Predicts the Changes of Rheumatoid Factor Titers in Rheumatoid Arthritis.

OBJECTIVE: The aim of this longitudinal study was to examine the clinical significance of soluble lectin-like oxidized low-density lipoprotein receptor 1 (sLOX-1) in patients with rheumatoid arthritis. METHODS: We gathered demographic and clinical data for a large rheumatoid arthritis cohort at 3 time points. Blood samples were collected at each time point; the number of samples was 282 cases in 2012, 431 cases in 2013, and 500 cases in 2014. Plasma sLOX-1 was measured by enzyme-linked immunosorbent assay. Correlations between sLOX-1 and clinical data were analyzed. Predictive factors associated with changes in sLOX-1 and rheumatoid factor (RF) were analyzed by multivariate linear regression. RESULTS: Plasma sLOX-1 level was significantly correlated with RF titer and other clinical parameters. The longitudinal analyses showed that changes in sLOX-1 were significantly correlated with changes in RF titers and with those at baseline. Multivariate linear regression analysis revealed that changes in RF and baseline RF were predictive factors for changes in sLOX-1. Conversely, the changes in RF were significantly correlated with the changes in sLOX-1 in all years. A stepwise regression analysis showed that the change in sLOX-1 was a predictive factor for the change in RF. CONCLUSIONS: The change in sLOX-1 has predictive value for assessing the change in RF, indicating the usefulness of sLOX-1 in clinical practice.

The minimum clinically important difference for the Japanese version of the new Knee Society Score (2011KSS) after total knee arthroplasty.

BACKGROUND: The new Knee Society Score (2011KSS) has been used to evaluate post-operative outcomes after total knee arthroplasty (TKA). However, there is no minimum clinically important difference (MCID) for 2011KSS. The purpose of this study is to define MCID of 2011KSS after TKA. METHODS: Patients who underwent primary TKA for primary knee osteoarthritis between April 2012 and December 2016 were included in the study. The Japanese version of 2011KSS and original Knee Society Score (OKSS) were recorded preoperatively and at one-year postoperatively. With improvement in pain score of OKSS as an anchor, an anchor-based approach was used to identify the MCID of 2011KSS. The improvement in pain of OKSS was classified into 5 categories. The MCID was determined using a linear regression analysis of delta 2011KSS against improvement in the category of pain in OKSS. The MCID for 2011KSS expectation was not calculated because the items of pre- and post-operative questionnaires were different. RESULTS: Five hundred and twenty-two cases were enrolled (age: 74.8 ± 7.3 years, female: 80.0%). After 1-year follow-up, 344 TKAs were finally included (age: 74.6 ± 7.1 years, female: 77.9%). Linear regression analyses showed that MCID for 2011KSS was 1.9 (95% confidential interval (CI): 1.3-2.5) in symptom, 2.2 (95%CI: 1.4-2.9) in satisfaction, and 4.1 (95%CI: 2.5-5.7) in functional activities. CONCLUSIONS: MCID for 2011KSS was successfully calculated. These MCID values make the 2011KSS a more efficient tool for evaluating the physical activities of the populations of patients undergoing TKA. These MCID values can also be used to calculate sample size to evaluate the power of a study in designing clinical studies.

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 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.

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.

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.

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.

Carbamylated albumin is one of the target antigens of anti-carbamylated protein antibodies.

Objectives: Anti-carbamylated protein (anti-CarP) antibodies are detected in RA patients. Fetal calf serum is used as an antigen source in anti-CarP ELISA, and the precise target antigens have not been found. We aimed to identify the target antigens of anti-CarP antibodies. Methods: Western blotting of anti-CarP antibodies was conducted. Anti-carbamylated human albumin (CarALB) antibody was detected by in-house ELISA for 493 RA patients and 144 healthy controls (HCs). An inhibition ELISA of anti-CarP antibodies by CarALB and citrullinated albumin (citALB) was performed using eight RA patients' sera. Serum CarALB was detected by liquid chromatography-tandem mass spectroscopy (LC/MS/MS), and the serum MPO concentration was measured by ELISA. Results: We focused on carbamylated albumin because it corresponded to the size of the thickest band detected by western blotting of anti-CarP antibodies. Anti-CarALB antibody was detected in 31.4% of RA patients, and the correlation of the titres between anti-CarALB and anti-CarP was much closer than that between anti-citALB and anti-CCP antibodies (ρ = 0.59 and ρ = 0.16, respectively). The inhibition ELISA showed that anti-CarP antibodies were inhibited by CarALB, but not by citALB. CarALB was detected in sera from RA patients by LC/MS/MS. The serum MPO concentration was correlated with disease activity and was higher in RA patients with anti-CarALB antibody than in those without. Conclusion: We found that carbamylated albumin is a novel target antigen of anti-CarP antibodies, and it is the first reported target antigen that has not been reported as the target of ACPA.

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.

Noise Generation With Good Range of Motion but Without Femorotibial Instability Has Small Effect on Patient Satisfaction After Total Knee Arthroplasty.

BACKGROUND: There are several causes of patient dissatisfaction after total knee arthroplasty (TKA). This study hypothesized that noise occurring in the knee would worsen patient satisfaction after TKA. METHODS: We mailed a newly developed questionnaire to 103 consecutive participants who were followed for one year, resulting in data from 61 knees in 60 patients (47 women and 13 men, mean age 73 years) who underwent cruciate-substituting TKA. We evaluated postoperative range of motion, knee instability, and the 2011 Knee Society Score in terms of noise generation after TKA. RESULTS: Over half of the patients noticed postoperative noise that occurred during the mid range of knee motion, but noise was not associated with feelings of instability. Postoperative range of motion differed significantly between the group with noise (122.8 ± 12.0°) and that without noise (106.3 ± 23.3°). The patellar tilt angle was also significantly larger in the group with noise (7.4 ± 5.5°) than that without noise (3.3 ± 2.6°). However, collateral ligament laxity had no significant effect on noise, and the 2011 Knee Society Score did not differ significantly different between the noise and no-noise groups. CONCLUSION: Our hypothesis was refuted, and these findings suggest patient satisfaction after TKA is influenced more by good knee function than by noise generation.

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.

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.

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.