Distinct biomarkers for different bones in osteoporosis with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is known to cause secondary osteoporosis and fragility fractures. This study aimed to identify biomarkers predictive of bone mineral density (BMD) change at three anatomical sites in patients with RA. METHODS: We conducted a prospective longitudinal study in patients with RA. In 2012, we recruited 379 patients from an RA cohort, 329 of whom underwent evaluation of blood and urine biomarkers together with measurement of BMD in the lumbar spine, proximal femur, and distal forearm. The BMD in these three regions was reassessed in 2014. We performed multivariate linear regression analysis to identify those factors associated with BMD change. RESULTS: The averages of age, body mass index, and disease activity score in 28 joints (DAS28) at baseline were 63.2 (minimum to maximum, 32-85), 21.3 (12.3-30.0), and 3.2 (0.1-5.9), respectively. Univariate analysis showed that the annual BMD change was significantly associated with the use of steroid, bisphosphonate (BP) or vitamin D (VitD), and serum homocysteine in the lumber spine; DAS28, the use of BP or VitD, CRP, and anti-cyclic citrullinated peptide antibody (ACPA) in the proximal femur; and the dosage of MTX, the use of BP or VitD, and serum tartrate-resistant acid phosphatase 5b (TRACP-5b) in the distal forearm, respectively. CONCLUSIONS: Predictive biomarkers for BMD change in RA patients differ at each anatomical site. Practitioners should treat each anatomical site with different markers and prescribe osteoporosis drugs to prevent fractures for RA patients.

Interleukin-18 is associated with the presence of interstitial lung disease in rheumatoid arthritis: a cross-sectional study.

OBJECTIVE: Serum interleukin-18 (IL-18) levels are increased in patients with interstitial lung disease (ILD). In addition, IL-18 levels are increased in patients with rheumatoid arthritis (RA) and are associated with arthritis activity. We determined whether increased IL-18 levels are associated with ILD in RA. METHOD: RA patients were enrolled using an RA cohort database. Plasma IL-18 levels were measured by enzyme-linked immunosorbent assay. ILD was determined by a pulmonologist and a radiologist based on chest radiography and computed tomography findings. IL-18 levels for RA with ILD and RA without ILD were compared. Associations between ILD and various markers including IL-18 and confounding factors (e.g. smoking history) were investigated by logistic regression analysis. Diagnostic values of IL-18 for the presence of ILD were investigated using receiver operating characteristics curve analysis. RESULTS: ILD was complicated in 8.2% (n = 26) of the study population (N = 312). Plasma IL-18 levels were higher for RA patients with ILD than for RA patients without ILD (721.0 ± 481.4 vs 436.8 ± 438.9 pg/mL, p < 0.001). IL-18, Krebs von den Lungen-6, and anti-cyclic citrullinated peptide antibody titre and glucocorticoid doses were independently associated with the presence of ILD during multivariate logistic regression analysis. Sensitivity and specificity of IL-18 levels for the detection of ILD in RA patients were 65.3% and 76.3%, respectively (area under the curve = 0.73). CONCLUSION: Plasma IL-18 levels were higher for RA patients with ILD than for those without ILD. Increased IL-18 levels were associated with the presence of ILD.

Label-free photoacoustic imaging of human palmar vessels: a structural morphological analysis.

We analysed the vascular morphology of the palm using a photoacoustic tomography (PAT) instrument with a hemispherical detector array. The three-dimensional (3D) morphology of blood vessels was determined noninvasively. Overall, 12 females and 11 males were recruited as healthy volunteers. Their ages were distributed almost evenly from 22 to 59 years. In all cases, many vascular networks were observed just beneath the skin and were determined to be veins anatomically. To analyse the major arteries, the layer containing the subcutaneous venous network was removed from the image. The analysis focused on the common and proper palmar digital arteries. We used the curvature of these arteries as a parameter to analyse their morphologies. There was no significant difference in the curvature between genders when comparing the subjects as a whole. The blood vessel curvature increased with age. Good agreement was found between the 3D numerical analysis results and the subjective evaluation of the two-dimensional (2D) projection image. The PAT system enabled visualization of the 3D features of blood vessels in the palm and noninvasive analysis of arterial tortuousness.

The effects of kinematically aligned total knee arthroplasty on stress at the medial tibia: A case study for varus knee.

OBJECTIVES: Little biomechanical information is available about kinematically aligned (KA) total knee arthroplasty (TKA). The purpose of this study was to simulate the kinematics and kinetics after KA TKA and mechanically aligned (MA) TKA with four different limb alignments. MATERIALS AND METHODS: Bone models were constructed from one volunteer (normal) and three patients with three different knee deformities (slight, moderate and severe varus). A dynamic musculoskeletal modelling system was used to analyse the kinematics and the tibiofemoral contact force. The contact stress on the tibial insert, and the stress to the resection surface and medial tibial cortex were examined by using finite element analysis. RESULTS: In all bone models, posterior translation on the lateral side and external rotation in the KA TKA models were greater than in the MA TKA models. The tibiofemoral force at the medial side was increased in the moderate and severe varus models with KA TKA. In the severe varus model with KA TKA, the contact stress on the tibial insert and the stress to the resection surface and to the medial tibial cortex were increased by 41.5%, 32.2% and 53.7%, respectively, compared with MA TKA, and the bone strain at the medial side was highest among all models. CONCLUSION: Near normal kinematics was observed in KA TKA. However, KA TKA increased the contact force, stress and bone strain at the medial side for moderate and severe varus knee models. The application of KA TKA for severe varus knees may be inadequate.Cite this article: S. Nakamura, Y. Tian, Y. Tanaka, S. Kuriyama, H. Ito, M. Furu, S. Matsuda. The effects of kinematically aligned total knee arthroplasty on stress at the medial tibia: A case study for varus knee. Bone Joint Res 2017;6:43-51. DOI: 10.1302/2046-3758.61.BJR-2016-0090.R1.

Systemic effects of surgical intervention on disease activity, daily function, and medication in patients with rheumatoid arthritis.

OBJECTIVES: Although tight control of rheumatoid arthritis (RA) has been achieved through the development of effective medication, surgical intervention is still required for a certain subpopulation of patients. To examine the systemic effects of orthopaedic surgery, we evaluated improvements in disease activity, daily function, and medication after surgery. METHOD: A prospective cohort study was conducted in 196 cases of elective orthopaedic surgery in 150 patients with RA from January 2011 to March 2014 in our institution. The 28-joint count Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR) and modified Health Assessment Questionnaire (mHAQ) scores just before surgery and at 6 and 12 months after surgery were examined prospectively. Concomitant medications were also investigated. RESULTS: Significant improvement was seen in the DAS28-ESR and mHAQ scores for replacement surgery in both the upper and lower extremities, and for arthroplasty/arthrodesis in the upper extremities at the 12-month follow-up. Partial mHAQ scores for the lower extremities were significantly reduced in lower replacement surgery, and partial mHAQ scores for the upper extremities were significantly reduced in upper arthroplasty/arthrodesis surgery. Although the use of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) did not decrease after surgery, the dose of prednisolone (PSL) decreased significantly at 12 months after surgery, especially in the well-controlled group and in surgical procedures in the lower extremities. CONCLUSIONS: Elective orthopaedic surgery improves both systemic disease activity and general functional impairment. Orthopaedic surgery is effective in reducing the amount of medication required postoperatively.

Periarticular osteoporosis of the forearm correlated with joint destruction and functional impairment in patients with rheumatoid arthritis.

UNLABELLED: The relationship between periarticular osteoporosis in the distal forearm and joint destruction or functional impairment in patients with rheumatoid arthritis (RA) is not sufficiently elucidated. From a single institutional cohort study, we found a strong correlation between periarticular forearm bone mineral density (BMD) and joint destruction or functional impairment. INTRODUCTION: This study was conducted to investigate (1) the difference between various periarticular regions of interest (ROIs) of BMD of the forearm, (2) the correlation between periarticular forearm BMD and joint destruction and physical function, (3) the independent variables for predicting BMD of the forearm, and (4) the forearm BMD of different ROIs in the early stage of RA. METHODS: We conducted a cross-sectional study in an RA cohort. Measurements included BMD of the distal forearm, joint destruction of the hands assessed by modified total Sharp score (mTSS), functional impairment assessed by a health assessment questionnaire (HAQ), and other clinical data. Variables affecting the forearm BMD values were analyzed by correlation and stepwise regression analyses. RESULTS: Of the 405 patients enrolled in the present study, 370 (average age; 62.9 years) were identified as having definite RA with a complete set of data. BMD in the distal end of the forearm (BMDud) was significantly reduced compared with that in the distal third of the forearm (BMD1/3). In a stepwise regression analysis, the mTSS in BMD1/3 was an independent predicting variable, while age and partial HAQ scores associated with the upper extremity were common independent variables in BMDud and BMD1/3. BMDud was significantly less than BMD1/3, even in patients with a short duration of the disease. BMD1/3 was significantly less in non-remission group compared with that in remission group in patients with a short duration of the disease. CONCLUSION: Periarticular BMD in the distal forearm is closely correlated with joint destruction and functional impairment in RA. Periarticular BMD in the distal forearm may be already reduced at the clinical manifestation of the disease.

Self-assessment of Rheumatoid Arthritis Disease Activity Using a Smartphone Application. Development and 3-month Feasibility Study.

INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Methodologies, Models and Algorithms for Patients Rehabilitation". BACKGROUND: Rheumatoid arthritis (RA) is a progressive inflammatory disease that causes damage to multiple joints, decline in functional status, and premature mortality. Thus, effective and frequent objective assessments are necessary. Then, we developed a self-assessment system for RA patients based on a smartphone application. OBJECTIVE: The purpose of this study was to investigate the feasibility of a self-assessment system for RA patients using a smartphone application. METHODS: We measured daily disease activity in nine RA patients who used the smartphone application for a period of three months. A disease activity score (DAS28) predictive model was used and feedback comments relating to disease activity were shown to patients via the smartphone application each day. To assess participants' RA disease activity, the DAS28 based on the C-reactive protein level was measured by a rheumatologist during monthly clinical visits. RESULTS: The disease activity measured by the application correlated well with the patients' actual disease activity during the 3-month period, as assessed by clinical examination. Furthermore, most participants gave favourable responses to a questionnaire administered at the end of the 3-month period containing questions relating to the ease of use and usefulness of the system. CONCLUSIONS: The results of this feasibility study indicated that the DAS28 predictive model can longitudinally predict DAS28 and may be an acceptable and useful tool for assessment of RA disease activity for both patients and healthcare providers.

Discordance and accordance between patient's and physician's assessments in rheumatoid arthritis.

OBJECTIVES: The American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria for rheumatoid arthritis (RA) are more stringent than index-based criteria, making it more difficult to achieve a patient's global assessment (PGA) than an evaluator's global assessment (EGA). We investigated the reason for the discrepancy between the PGA and the EGA in a Japanese clinical cohort. METHOD: We assessed clinical and laboratory variables in our clinical cohort. The frequency of remission achievement according to the ACR/EULAR remission criteria and predictors of the discrepancy between the PGA and EGA were analysed. RESULTS: Of 370 patients with RA, 89 fulfilled PGA criteria and 167 patients fulfilled EGA criteria. The PGA was highly correlated with the visual analogue scale (VAS) pain score and non-inflammatory variables including Steinbrocker class and the Health Assessment Questionnaire Disability Index (HAQ-DI). Conversely, inflammatory variables, including swollen joint count (SJC), tender joint count (TJC), and C-reactive protein (CRP) levels, were significantly associated with the EGA. The main predictors of the discrepancy between the PGA and the EGA were patient's VAS pain score, SJC, and functional disability. CONCLUSIONS: Increased pain and functional disability led to a discrepancy towards a worse PGA than EGA, whereas increased SJC led to an accordance towards a worse EGA.

Identification of AFAP1L1 as a prognostic marker for spindle cell sarcomas.

Spindle cell sarcomas consist of tumors with different biological features, of which distant metastasis is the most ominous sign for a poor prognosis. However, metastasis is difficult to predict on the basis of current histopathological analyses. We have identified actin filament-associated protein 1-like 1 (AFAP1L1) as a candidate for a metastasis-predicting marker from the gene expression profiles of 65 spindle cell sarcomas. A multivariate analysis determined that AFAP1L1 was an independent factor for predicting the occurrence of distant metastasis (P=0.0001), which was further confirmed in another set of 41 tumors by a quantitative mRNA expression analysis. Immunohistochemical staining using paraffin-embedded tumor tissues revealed that the metastasis-free rate was significantly better in tumors negative for AFAP1L1 (P=0.0093 by log-rank test). Knocking down the AFAP1L1 gene in sarcoma cells resulted in inhibition of the cell invasion, and forced expression of AFAP1L1 in immortalized human mesenchymal stem cells induced anchorage-independent growth and increased cell invasiveness with high activity levels of matrix metallopeptidase. Furthermore, tumor growth in vivo was accelerated in AFAP1L1-transduced sarcoma cell lines. These results suggest that AFAP1L1 has a role in the progression of spindle cell sarcomas and is a prognostic biomarker.

PGE2 signal via EP2 receptors evoked by a selective agonist enhances regeneration of injured articular cartilage.

OBJECTIVE: The effect of the prostaglandin E2 (PGE2) signal through prostaglandin E receptor 2 (EP2) receptors on the repair of injured articular cartilage was investigated using a selective agonist for EP2. METHODS: Chondral and osteochondral defects were prepared on the rabbit femoral concave in both knee joints, and gelatin containing polylactic-co-glycolic acid microspheres conjugated with or without the EP2 agonist was placed nearby. Animals were sacrificed at 4 or 12 weeks post-operation, and regenerated cartilage tissues and subchondral structure remodeling were evaluated by histological scoring. The quality of regenerated tissues was also evaluated by the immunohistochemical staining of EP2, type II collagen, and proliferating cell nuclear antigen (PCNA). As an evaluation of side effects, the inflammatory reaction of the synovial membrane was analyzed based on histology and the mRNA expression of matrix metalloproteinase3 (MMP3), tissue inhibitor of metalloproteinase 3 (TIMP3), and interleukin-1 beta (IL-1 beta). Also, the activity of MMP3 and the amount of tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein in joint fluid were measured. RESULTS: In both models, the EP2 agonist enhanced the regeneration of the type II collagen-positive tissues containing EP2- and PCNA-positive chondrocytes, and the histological scale of regenerated tissue and subchondral bone was better than that of on the control side, particularly at 12 weeks post-operation. No inflammatory reaction in the synovial membrane was observed, and no induction of pro-inflammatory cytokines was found in joint fluid. CONCLUSION: Selective stimulation of the PGE2 signal through EP2 receptors by a specific agonist promoted regeneration of cartilage tissues with a physiological osteochondral boundary, suggesting the potential usefulness of this small molecule for the treatment of injured articular cartilages.

Individual perception of education and treatment versus actual outcome. A theoretical model exemplified by an interventional study on patients with insulin-dependent diabetes mellitus.

An educational model is presented that stresses the importance of the interaction between individual characteristics and intentional educational influences on outcome variation. This model is exemplified by an interventional study of patients with insulin-dependent diabetes mellitus who, despite long-term conventional medical treatment, had been unable to achieve satisfactory hemoglobin Alc levels. Treatment modes and their importance for understanding variations in outcomes are discussed from the interactional perspective suggested in the model.

A longitudinal study on the significance of environmental and individual factors associated with the development of essential hypertension.

Altogether 379 men of the same age have been followed for more than 40 years, mainly as regards socioeconomic conditions during the first 10 years as well as cognitive ability measured at the ages of 10 and 20, education, income development, and psychosocial conditions in adulthood. At the age of 48 a health investigation was performed. In order to identify possible risk factors associated with the development of raised blood pressure 38 subjects with essential hypertension were compared with 155 men without any obvious mental or somatic diseases. No differences regarding socioeconomic conditions during childhood could be observed between the two groups. However, there was a very strong difference between father's education and the son's cognitive ability in the group with hypertension. The low income development for the group with hypertension can probably be explained partly by the lower cognitive ability. In the total group there was a positive correlation between IQ at the age of 10 and income at the age of 43 (r = 0.42; p less than 0.001). The hypertensive men were psychosocially disadvantaged with respect to divorce rate and job dissatisfaction, and furthermore they reported low physical activity during leisure time. Hypertensive men were more obese and had inferior respiratory function. The observation that a lower cognitive ability seems to be related to the development of hypertension is compatible with the observation that early mortality in this investigated group has a correlation of a low IQ with poor socioeconomic conditions in childhood.

Menarcheal age in Stockholm girls, 1967.

Using the status quo method on 917 girls aged 10-17 years in 1967, mean age at menarche was computed to be 13-09 +/- 0-08 years (SD 1-10). There was no difference in mean age at menarche between girls from different social groups defined by father's or mother's occupation. The menstrual periods evoked severe discomfort in 9 per cent of the individuals. These were on an average significantly younger at menarche than the other girls. The percentage of the girls feeling discomfort during the menstrual periods as well as its intensity increased with time since menarche.