Axillary lymph-node metabolic activity assessment on 18F-FDG-PET/CT in rheumatoid arthritis patients treated with biologic therapies.

Objective: Recent studies have provided new insights into the role of lymph nodes (LNs) in rheumatoid arthritis (RA). The aim of this study was to evaluate the metabolic activity of the axillary LNs in relation to that of the upper limb joints and the clinical assessment of disease activity in RA patients treated with biologic therapies.Method: 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) scans were acquired for 64 patients with RA at baseline and after 6 months of biologic therapy, and the patients' clinical status was evaluated. The maximum standardized uptake value (SUVmax), metabolic active volume, and total lesion glycolysis (TLG) were used to assess glucose metabolism in the LNs and 12 joints. Clinical evaluations included serum markers and the Disease Activity Score based on 28-joint count-erythrocyte sedimentation rate (DAS28-ESR).Results: Changes in the SUVmax and TLG for the axillary LNs correlated significantly with those of the ipsilateral wrist joints. There was a positive correlation between the changes in the three metabolic parameters of the axillary LNs and the changes in disease activity after treatment. After 6 months of biologic therapy, all metabolic parameters for the axillary LNs in patients with a DAS28-ESR < 3.2 were significantly lower than those of patients with a DAS28-ESR ≥ 3.2.Conclusion: A relationship between the glucose metabolism of the axillary LNs and the ipsilateral wrist joints was demonstrated by the 18F-FDG-PET/CT parameters. The metabolic activity and active volume of axillary LNs may reflect the therapeutic response to the biologic treatment of RA.

Digital image analysis protocol for determining the radiocarpal joint space in the rheumatoid arthritic wrist.

This paper describes a simple protocol for measuring the joint space of the rheumatoid arthritic (RA) wrist from projection radiographs. The protocol is implemented using a computer algorithm based upon the Interactive Data Language platform. The computerized algorithm features a user-friendly graphical interface to aid the operator to measure joint space parameters, namely distance and area, of the wrist vertebral morphometry at the radiocarpal region. Dual-energy X-ray absorptiometry (DXA) radiograph of a standard hand and wrist phantom was evaluated using the measurement protocol to determine the accuracy and precision of the protocol. The accuracy, parameterised by the systematic error, returned a mean of 5.20% for distance and is equal to 3.49% for area measurement. The precision of the measurement protocol, parameterised by the coefficient of variation (CV), for distance returned a mean of 1.96%; the CV for area measurement equals 2.1%. Three observers participated to investigate the repeatability (intra-observer) and reproducibility (inter-observer) of the measurement protocol, parameterised by the CV, using DXA radiographs from a healthy volunteer and a RA patient. The inter-observer repeatability for distance measurement for the respective observers returned mean values of 10.9%, 7.7% and 11.4% for the healthy wrist. However, the results revealed improved repeatability for the RA wrist; the CV for the respective observers returned mean values of 7.7% 7.1% and 10.0%. The inter-observer repeatability for area measurement for the respective observers returned mean values of 10.2%, 7.1% and 10.1% for the healthy wrist. However, the results revealed improved repeatability (in two out of the three observers) for the RA wrist; the CV for the respective observers returned mean values of 6.8% 6.5% and 10.8%. Student's t-test analysis of the intra-observer repeatability revealed that the measurements of distance and area were generally not intra-observer sensitive. On the other hand, student's t-test analysis of the inter-observer reproducibility revealed that half of the distance measurements were inter-observer sensitive; whereas the remaining were not. Similar findings were obtained for area measurements. Overall the results reveal that the variabilities in accuracy and precision tests and the repeatability and reproducibility tests were typically 10% or less. These findings, in addition to the versatility and simplicity of the digital image analysis protocol, lend to the potential of using the protocol to complement the acquisition of bone mineral density data derived from DXA for diagnosing the progression of RA in patients.

An optimal ultrasonographic diagnostic test for early gout: A prospective controlled study.

Objective To identify the optimal sites for classification of early gout by ultrasonography. Methods Sixty patients with monosodium urate crystal-proven gout (25 with early gout [≤2-year symptom duration], 35 with late gout [>2-year symptom duration], and 36 normouricemic healthy controls) from one centre were prospectively evaluated. Standardized blinded ultrasound examination of 36 joints and the triceps and patellar tendons was performed to identify tophi and the double contour (DC) sign. Results Ultrasonographic sensitivity was lower in early than late gout. Binary logistic regression analysis showed that two ultrasonographic signs (tophi in the first metatarsophalangeal joint [odds ratio, 16.46] and the DC sign in the ankle [odds ratio, 25.18]) significantly contributed to the final model for early gout diagnosis (sensitivity and specificity of 84% and 81%, respectively). The inter-reader reliability kappa value for the DC sign and tophi was 0.712. Conclusions Four-joint investigation (both first metatarsophalangeal joints for tophi and both ankles for the DC sign) is feasible and reliable and could be proposed as a screening test for early ultrasonographic gout classification in daily practice.

Topographical Anatomy of the Distal Ulna Attachment of the Radioulnar Ligament.

PURPOSE: The deep component of the distal radioulnar ligament provides translational stability and rotational guidance to the forearm. However, controversy exists regarding the importance of this structure as well as the nature of its attachment to the distal ulna. We aimed to evaluate the topographic anatomy of the distal ulna attachment of both the superficial and the deep components of the radioulnar ligament and to assess the relationship between its internal and its external morphometry. METHODS: Thirteen human distal ulnae attached by ulnar part of the distal radioulnar ligament were scanned using micro-computed tomography and reconstructed in 3 dimensions. In addition, the distal radioulnar ligaments were examined under polarized light microscopy to determine the histological characteristics of collagen contained within the ligaments. RESULTS: The deep limbs have broad marginal insertions at the fovea, whereas the superficial limbs have a circular and condensed insertion to the ulnar styloid. The center of the deep limb was separated from the base of the ulnar styloid by a mean of 2.0 ± 0.76 mm, and this distance was positively correlated with the width of the ulnar styloid. The mean distance between the center of the ulnar head and the center of the fovea was 2.4 ± 0.58 mm. The proportion of collagen type I was lower in the deep limb than in the superficial limb. CONCLUSIONS: This new observation of the footprint of the radioulnar ligament in the distal ulna indicates that the deep limb may serve as an internal capsular ligament of the distal radioulnar joint, whereas the superficial limb as the external ligament. CLINICAL RELEVANCE: Knowledge of the topographic anatomy of the radioulnar ligament's attachment to the distal ulna may provide a better understanding of distal radioulnar ligament-related pathologies.

Enhanced expression of Wnt9a in the flexor tenosynovium in idiopathic carpal tunnel syndrome.

This study aimed to clarify the association between abnormal Wnt signaling and the cause of idiopathic carpal tunnel syndrome (ICTS) and whether an association exists between Wnt signaling and cell proliferation in the flexor tenosynovium. The subjects included nine patients with ICTS; the controls were nine patients with distal radius fractures without any symptoms of carpal tunnel syndrome. We extracted mRNA from the flexor tenosynovium and compared the expression levels of genes encoding 17 types of Wnt in both subjects and controls via quantitative real-time polymerase chain reaction (PCR). Expression levels of factors involved in cell proliferation, such as estrogen-responsive finger protein, epidermal growth factor receptor, heparin binding-epidermal growth factor-like growth factor, insulin-like growth factor-1, and vascular endothelial growth factor (VEGF) were also measured using quantitative real-time PCR. In addition, we compared the Wnt and MIB-1 protein expression levels to clarify the effect of Wnt on cell proliferation. Quantitative real-time PCR revealed significantly greater expression of the gene encoding Wnt9a in subjects with ICTS than in controls and also revealed a positive correlation between the expression of genes encoding Wnt9a and VEGF in subjects with ICTS. Quantitative evaluation using immunohistochemical staining also indicated more marked Wnt9a expression in subjects than in controls. However, there was no relationship between the expression of Wnt9a and the cell proliferation index MIB-1. These results indicate that Wnt9a expression is enhanced in ICTS and that Wnt9a may be involved in VEGF expression in ICTS.

Use of ultrasound-guided small joint biopsy to evaluate the histopathologic response to rheumatoid arthritis therapy: recommendations for application to clinical trials.

OBJECTIVE: To examine in a cohort of rheumatoid arthritis (RA) patients undergoing serial ultrasound (US)-guided biopsies of small joints in the context of clinical trials whether sufficient synovial tissue could be obtained at both baseline and second biopsy to: 1) accurately evaluate the synovial immune phenotype, 2) permit adequate RNA extraction to determine molecular signatures, and 3) sensitively detect change in the number of synovial sublining macrophages (CD68+) following effective therapy. METHODS: Synovial samples from RA patients undergoing US-guided biopsy of small joints as part of 2 clinical trials (Barts Early Arthritis Cohort [n = 18] and the Clinical and Pathological Response to Certolizumab Pegol (CLIP-Cert) study [n = 17]) were examined, and the quality and quantity of histologic samples and RNA extracted per joint were determined and compared to synovial thickness and power Doppler scores determined by US before biopsy. Modulation of the number of CD68+ sublining macrophages was correlated with clinical response to treatment. RESULTS: Good quality synovial tissue that accurately reflected the synovial immune phenotype of the total joint was obtained in 80% of US-guided procedures when synovial thickness (higher than grade 2) was documented before biopsy. In 100% of the procedures, sufficient RNA was extracted to permit molecular analysis. There was a significant correlation between change in CD68+ sublining macrophage number and clinical response to treatment. CONCLUSION: This study provides minimum standards for sample retrieval for small joint biopsy. Furthermore, our findings confirm the clinical utility of the procedure in the largest reported cohort of US-guided small joint biopsies. The demonstration that small joint synovial tissue can be readily accessed by a technically simple, minimally invasive procedure is likely to facilitate critical advancements in the knowledge of RA pathobiology and personalized health care.

Exploring cartilage damage in gout using 3-T MRI: distribution and associations with joint inflammation and tophus deposition.

OBJECTIVE: Few imaging studies have investigated cartilage in gout. Magnetic resonance imaging (MRI) can image cartilage damage and also reveals other features of gouty arthropathy. The objective was to develop and validate a system for quantifying cartilage damage in gout. METHODS: 3-T MRI scans of the wrist were obtained in 40 gout patients. MRI cartilage damage was quantified using an adaptation of the radiographic Sharp van der Heijde score. Two readers scored cartilage loss at 7 wrist joints: 0 (normal), 1 (partial narrowing), 2 (complete narrowing) and concomitant osteoarthritis was recorded. Bone erosion, bone oedema and synovitis were scored (RAMRIS) and tophi were assessed. Correlations between radiographic and MRI cartilage scores were investigated, as was the reliability of the MRI cartilage score and its associations. RESULTS: The GOut MRI Cartilage Score (GOMRICS) was highly correlated with the total Sharp van der Heijde (SvdH) score and the joint space narrowing component (R = 0.8 and 0.71 respectively, p < 0.001). Reliability was high (intraobserver, interobserver ICCs = 0.87 [0.57-0.97], 0.64 [0.41-0.79] respectively), and improved on unenhanced scans; interobserver ICC = 0.82 [0.49-0.95]. Cartilage damage was predominantly focal (82% of lesions) and identified in 40 out of 280 (14%) of joints. Cartilage scores correlated with bone erosion (R = 0.57), tophus size (R = 0.52), and synovitis (R = 0.55), but not bone oedema scores. CONCLUSIONS: Magnetic resonance imaging can be used to investigate cartilage in gout. Cartilage damage was relatively uncommon, focal, and associated with bone erosions, tophi and synovitis, but not bone oedema. This emphasises the unique pathophysiology of gout.

Dual energy computed tomography for quantification of tissue urate deposits in tophaceous gout: help from modern physics in the management of an ancient disease.

Gout has been recognized for centuries but is also a modern day scourge. It is the most common type of inflammatory arthritis in men and appears to be increasing in both incidence and prevalence (Arromdee et al. in J Rheumatol 29(11):2403-2406, 2002). Despite these facts, few advances have been made in the diagnosis and treatment of gout for over 50 years. Difficult cases of gout challenge available therapeutic options. It is only recently that the Food and Drug Administration has approved febuxostat as a treatment option for patients intolerant of allopurinol. We describe a difficult case of tophaceous gout notable for several reasons: utilization of rasburicase as uricolytic treatment to dramatically reduce tissue urate burden; treatment of gout flares with interleukin-1ß inhibition; and quantification of tissue urate with novel dual energy computed tomography technology before and after uricolytic therapy.

Expression of leptin, leptin receptor, and connective tissue growth factor in degenerative disk lesions in the wrist.

PURPOSE: The purpose of this study was to identify whether leptin and connective tissue growth factor (CTGF) occur in the degenerative fibrocartilage disk and whether cartilage cells express leptin receptors. METHODS: The study included 23 patients diagnosed with degenerative articular disk tears of the triangular fibrocartilage (TFC) (Palmer type 2C). Patients were divided into 2 groups based on ulna length: 1 group consisted of patients with an ulna-positive variance (group A), and the other group included patients with ulna-negative or -neutral variance (group B). After arthroscopic debridement of the TFC, histologic sections of biopsy specimens were prepared. The biopsy specimens were immunohistochemically analyzed, and the quantity of leptin-, CTGF-, and leptin receptor-positive cells was assessed. RESULTS: Cells positive for leptin, leptin receptor, and CTGF were found. The number of cells positive for leptin was significantly increased in specimens of patients with an ulna-negative variance (group B). In contrast, no significant difference was found for leptin receptor and CTGF in biopsy specimens of patients with ulna-positive or ulna-negative/neutral variance. The inner, middle, and outer zones of the disk do not express significantly different quantities of marker-positive cells. CONCLUSIONS: Degenerative fibrocartilage disk tissue cells exhibit leptin receptors and are exposed to the markers leptin and CTGF, providing evidence of a local paracrine system and regenerative processes. Cells of disks from patients with an ulna-neutral/negative length express significantly higher numbers of leptin-positive cells. LEVEL OF EVIDENCE: Level II, diagnostic study.

Intra-articular distribution pattern after ultrasound-guided injections in wrist joints of patients with rheumatoid arthritis.

OBJECTIVE: To investigate the distribution of an ultrasound-guided intra-articular (IA) injection in the wrist joint of patients with rheumatoid arthritis (RA). METHODS: An ultrasound-guided IA drug injection into the wrist joint was performed in 17 patients with 1 ml methylprednisolone (40 mg/ml), 0.5 ml Lidocaine (5mg/ml) and 0.15 ml gadolinium (Omniscan 0.5 mmol/ml). The drug solution was placed in the central proximal part of the wrist between the distal radius and the lunate bone. Coronal and axial MRI sequences were performed after the injection to visualize the distribution. Carpal distribution (radio-carpal, inter-carpal, and carpo-metacarpal) as well as radio-ulnar distribution was recorded. Full distribution in one compartment was given the value 1, partial distribution 0.5 and no distribution 0. A sum of the total distribution for all four compartments was calculated and correlated to the clinical parameters and the MRI OMERACT scores. RESULTS: No uniform pattern was seen in the distribution of the contrast. Only two patients had full contrast distribution to all four compartments, and the mean distribution count for all patients was 2.4 (range 0.5-4). The distribution count correlated with the MRI OMERACT synovitis score (r=0.60, p=0.014), but not with the erosions, bonemarrow oedema scores or any clinical parameters. CONCLUSION: The distribution of contrast on MRI showed patient specific and random patterns after IA injections in active RA wrist joints. The degree of distribution increased with the MRI synovitis score, while no association was found with the erosion- and bonemarrow oedema score. These results indicate that a single injection into a standard injection site in the proximal part of the wrist cannot be assumed to distribute--and treat--the whole joint.

Kinetic modeling of contrast-enhanced MRI: an automated technique for assessing inflammation in the rheumatoid arthritis wrist.

In recent years, development of rheumatoid arthritis (RA) drug therapy has been more directly targeted to counteract specific mechanisms of inflammation, and it is now believed that early aggressive treatment with disease modifying drugs is important to inhibit future structural joint damage. The development of these new treatments has increased the need for methodologies to assess disease activity in RA and monitor the effectiveness of drug therapy. Unlike X-ray, which shows only structural bone damage, magnetic resonance imaging (MRI) can depict soft tissue damage and synovitis, the primary pathology of RA. Recent studies have also indicated that MRI is sensitive to pathophysiologic changes that may predate radiographic erosions and may predict future joint damage. In this study, we have developed a computer automated analysis technique for MR wrist images that provides an objective measure of RA synovitis. This method applies a two-compartment pharmacokinetic model to every voxel of a dynamic contrast-enhanced MRI (DCE-MRI) dataset and outputs resulting parametric images. The aim of this technique is to not only objectively quantify the severity of rheumatoid synovitis, but to also locally determine where areas of serious disease activity are situated through kinetic modeling of blood-tissue exchange. Preliminary results show good correlation to early enhancement rate, which has previously been shown to be a useful clinical marker of RA activity. However, the use of tracer kinetic modeling methods potentially provides more specific information regarding underlying RA physiology. This approach could provide a useful new tool in RA patient management and could substantially improve RA therapeutic studies by calculating objective biomarkers of the disease state.

The role of proteoglycans in idiopathic carpal tunnel syndrome.

Decompression of the carpal canal is the most common hand surgery performed in the United States. Hand surgeons perform 460,000 carpal tunnel releases (CTR) each year, which cost the medical industry in excess of two billion dollars per year. The focus of this investigation was to identify the changes, which occur in the flexor tenosynovium of patients undergoing CTR at the connective tissue level. The connective tissues determine the amount and arrangement of macromolecules (fibers, proteoglycans, and glycoproteins) in the extracellular matrix. The proteoglycans are soluble macromolecules that have both structural and metabolic roles. Glycoproteins help to form the interstitial space, basement membrane and function as cell surface receptors. The mechanical function of the proteoglycans includes stabilization of the collagen fibers as well as function in the hydration of the tissues. It has been previous shown that changes in the oxygen concentration at the tissue level can alter the proteoglycans profile of the tissue. During periods of hypoxia, such as those obtained during repetitive motion CTS; the glycolytic pathway acts as the energy source for the tissue. Productions of chondroitin sulfates are a process consumes NAD and would be potentially toxic to the cells under anaerobic conditions. Production of keratan sulfate is NAD sparing product, and may act as a survival pathway for cells under adverse conditions. The disruption in the proteoglycan balance will allow for alterations in the ECM and changes in hydration status of the tissues may have serious implication in CTS because the carpal canal is anatomically very narrow and increases in volume within the canal can result in further compression of the nerve. Flexor tenosyioum was obtained from patients undergoing CTR and compared with control tissue for dermatan, keratan and chondroitin sulfate. The results show a greater density of keratan reactivity in CTS tissues identified by immunostaining. In addition to changes in proteoglycan content there was also an increase in new vessel formation in the CTS tissues. The data obtained suggests that the shifts in the proteoglycan ratios may render the tissues less able to withstand the compressive forces and therefore allow for more force to be placed on the median nerve within the carpal canal.

Normal ranges of ulnar and radial deviation with reference to ulnar variance.

We aimed to determine the normal ranges of radial and ulnar deviation of the wrist in relation to the ulnar variance. A total of 102 healthy subjects (204 wrists) were included in the study. The ranges of radial and ulnar deviation of the wrists were measured using a universal goniometer. Ulnar variance was assessed manually or radiographically, and recorded as ulna minus, ulna plus or ulna minus/plus. When the ranges of radial and ulnar deviation were compared with ulnar variance, ulnar deviation was greater in ulna minus subjects and radial deviation was greater in ulna minus/plus subjects. There was no significant difference in the total range of radio-ulnar deviation. The results of this study indicate that ulnar deviation is greater in ulna minus wrists, and we suggest that ulnar variance should be recorded alongside measurements of radial and ulnar deviation.

Comparison of synovial tissues from the knee joints and the small joints of rheumatoid arthritis patients: Implications for pathogenesis and evaluation of treatment.

OBJECTIVE: Serial synovial biopsy samples are increasingly being used for the evaluation of novel therapies for rheumatoid arthritis (RA). Most studies have used tissues from knee biopsies, but technical improvements have made serial small joint arthroscopy feasible as well. Theoretically, there could be differences in the features of synovial inflammation between various joints as a result of mechanical factors, differences in innervation, and other factors. We therefore undertook this study to compare the cell infiltrate in paired synovial biopsy samples from inflamed knee joints and paired inflamed small joints of patients with RA. METHODS: Nine RA patients with both an inflamed knee joint and an inflamed small joint (wrist or metacarpophalangeal joint) underwent an arthroscopic synovial biopsy of both joints on the same day. Multiple biopsy specimens were collected and stained for macrophages, T cells, plasma cells, fibroblast-like synoviocytes, and interleukin-6 (IL-6) by immunohistochemistry. Sections were evaluated by digital image analysis. RESULTS: There were no significant differences in mean cell numbers for all markers investigated in samples from the knee joint compared with samples from the small joints. We detected statistically significant correlations for the numbers of sublining macrophages, T cells, and plasma cells, as well as for IL-6 expression, between the knee joint and the small joints. However, there was no significant correlation between different joints for the numbers of intimal macrophages or fibroblast-like synoviocytes. CONCLUSION: The results of this study show that the inflammation in one inflamed joint is generally representative of that in other inflamed joints. Therefore, it is possible to use serial samples from the same joint, selecting either large or small joints, for the evaluation of antirheumatic therapies.

Osteopenia in exercise-associated amenorrhea using ballet dancers as a model: a longitudinal study.

Few longitudinal studies have investigated the effects of amenorrhea and amenorrhea plus exercise on bone mineral density (BMD) of young women. We carried out a 2-yr comparison of dancers and nondancers, both amenorrheic and normal, that investigated the role of hypothalamic amenorrhea on bone in this context. We studied 111 subjects (mean age, 22.4 +/- 4.6 yr; age of menarche, 14.1 +/- 2.2 yr), including 54 dancers, 22 with hypothalamic amenorrhea, and 57 nondancers, 22 with hypothalamic amenorrhea. Detailed hormonal and nutritional data were obtained in all groups to determine possible causal relationship to osteoporosis. The amenorrheic groups, dancers and nondancers, both showed reduced BMD in the spine, wrist, and foot, which remained below controls throughout the 2 yr. Only amenorrheic dancers showed significant changes in spine BMD (12.1%; P < 0.05) but still remained below controls, and within this subgroup, only those with delayed menarche showed a significant increase. The seven amenorrheic subjects (three dancers and four nondancers) who resumed menses during the study showed an increase in spine and wrist BMD (17%; P < 0.001) without achieving normalization. Delayed menarche was the only variable that predicted stress fractures (P < 0.005), which we used as a measure of bone functional strength. Analysis of dieting and nutritional patterns showed higher incidence of dieting behavior in this group, as manifested by higher Eating Attitudes Test scores (16.3 +/- 2.00 vs. 11.5 +/- 1.45; P < 0.05) and higher fiber intakes (30.7 +/- 3.00 vs. 17.5 +/- 2.01 g/24 h; P < 0.001). We concluded that low bone mass occurs in young women with amenorrhea and delayed menarche, both exercisers and nonexercisers. Crucial bone mass accretion may be compromised by their reproductive and nutritional health.

Production of cytokines, vascular endothelial growth factor, matrix metalloproteinases, and tissue inhibitor of metalloproteinases 1 by tenosynovium demonstrates its potential for tendon destruction in rheumatoid arthritis.

OBJECTIVE: To investigate the role of proinflammatory cytokines, vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinases 1 (TIMP-1) in the destruction of tendons by tenosynovium in rheumatoid arthritis (RA). METHODS: Synovial specimens were obtained from encapsulating tenosynovium (n = 17), invasive tenosynovium (n = 13), and wrist joints (n = 17) in 18 RA patients undergoing wrist extensor tenosynovectomy. Synovial membrane cells were dissociated from connective tissue by enzyme digestion and cultured in vitro for 48 hours, and harvested supernatants were assayed for the cytokines tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6), VEGF, MMPs 1, 2, 3, and 13, and TIMP-1 by enzyme-linked immunosorbent assay. Gelatin zymography was performed to demonstrate enzyme activity. Statistical analysis was performed using Student's paired 2-tailed t-tests for parametric data and the Wilcoxon signed rank test for nonparametric data. RESULTS: MMP-1 and MMP-13 levels were approximately 2.5-fold higher in invasive tenosynovium compared with encapsulating tenosynovium. Levels of MMP-2 were approximately 1.5-fold higher in invasive tenosynovium compared with both encapsulating tenosynovium and wrist joint synovium. MMP-13 (P = 0.009) and IL-6 (P = 0.03) levels were significantly lower in encapsulating tenosynovium compared with wrist joint synovium. Levels of VEGF, TIMP-1, TNFalpha, and MMP-3 were similar in all synovial sample groups. Zymography demonstrated enzyme activity in all synovium samples from all 9 patients assessed. CONCLUSION: Tenosynovium produces proinflammatory cytokines and proteolytic enzymes that are important in the tissue degradation seen in RA. Increased production of the enzymes MMP-1, MMP-2, and MMP-13 by invasive tenosynovium suggests a possible explanation for the worse prognosis and increased rupture rate associated with invasive tenosynovitis in RA. Production of VEGF by tenosynovium suggests that angiogenesis may have a role in tenosynovial proliferation and invasion of tendons.

HLA-DR expression of synovium and correlation with clinical features of patients with rheumatoid arthritis.

To investigate whether the expression of human leukocyte antigen-DR (HLA-DR) in synovial tissues obtained at synovectomy contributes to the clinical features of patients with rheumatoid arthritis (RA), immunohistochemical analysis was performed to determine the intensity and pattern of HLA-DR expression in synovial tissue from 96 patients with RA. The clinical features before and 1 year after the synovectomy were investigated. At the time of the surgery, duration of morning stiffness was associated with the degree of HLA-DR expression in synovial lining layer, and this synovial lining expression of HLA-DR was more frequently observed in elbow and wrist joints than in knee joint. In patients who underwent knee synovectomy, erythrocyte sedimentation rate and C-reactive protein level one year after the surgery were significantly higher in the patients with intense expression of HLA-DR in the synovial lining. Our findings showed that the expression of HLA-DR in the synovial lining contributes to several clinical features, and the expression in large joint such as knee may related with disease course of patients with RA.

The advanced glycation endproduct, pentosidine, in the carpal ligament in patients with carpal tunnel syndrome undergoing hemodialysis: comparison with idiopathic carpal tunnel syndrome.

BACKGROUND/AIMS: Carpal tunnel syndrome (CTS) is a major complication that occurs in the musculoskeletal system in patients on long-term hemodialysis (HD). Pentosidine is an advanced glycation endproduct (AGE) and there is evidence that shows AGEs contribute to the pathogenesis of the complications in patients undergoing HD. The aim of this study is to investigate whether pentosidine accumulates in the carpal ligament in patients undergoing HD with CTS in comparison with idiopathic CTS. METHODS: Carpal ligaments and skin were obtained during surgery from 28 patients with CTS undergoing HD and 13 patients with idiopathic CTS (ID CTS). Pentosidine was measured by HPLC after hydrolysis of the samples, and amyloid deposits in the samples of HD CTS were examined histologically. RESULTS: Pentosidine levels in ligament and skin were significantly higher in HD CTS than ID CTS. On the other hand, there was no difference in pyridinoline which is a physical cross-link between HD and ID CTS. Amyloid deposits were observed in 14 ligament samples, whereas there was none in 14 other samples. There was no significant difference in pentosidine and pyridinoline in ligament, pentosidine in skin, duration of HD and serum beta2-microglobulin between the amyloid+ group and the amyloid- group. CONCLUSION: A greater concentration of pentosidine in the carpal ligament in HD patients compared with idiopathic patients suggests that an accumulation of AGEs contributes to one of the pathologies of occurrence of CTS in patients undergoing HD.

The formation of human synovial joint cavities: a possible role for hyaluronan and CD44 in altered interzone cohesion.

During fetal development, cavitation occurs within the primitive skeleton along planes destined to become the articular surfaces of synovial joints. A histochemical study of human fetal limbs was undertaken to identify the cell types involved in this cavitation and the possible role of interactions between cells and extracellular matrix. Cryostat sections were stained with antibodies to CD68, factor VIII related antigen, prolyl hydroxylase, beta 1 integrin, VCAM-1, proliferating cell nuclear antigen, chondroitin-4 sulphate, chondroitin-6-sulphate, hyaluronan synthase and CD44. Similar sections were reacted for uridine diphosphoglucose dehydrogenase (UDPGD) and acid phosphatase activity. Hyaluronan was demonstrated using an aggrecan core protein hyaluronan binding region probe. Macrophages were present prior to cavitation in the periphery of joint interzones but not at the presumptive joint line in the central interzone. Fibroblastic cells were present throughout. Absence of local VCAM-1 expression indicated that cavitation was temporally distinct from full fibroblast-like synoviocyte differentiation. CD44 was expressed by interzone cells at all stages. Staining for hyaluronan and hyaluronan synthase, but not chondroitin sulphates was present in the interzone before and at the time of cavitation. UDPGD activity was increased in a narrow band of cells at the presumptive joint line prior to cavitation. These findings suggest that joint cavitation is dependent on the behaviour of fibroblastic cells and/or adjacent chondrocytes, rather than macrophages. Since UDPGD activity is involved in hyaluronan synthesis, it is proposed that joint cavitation is facilitated by a rise in local hyaluronan concentration in an area of tissue where cohesion is dependent on the interaction between cellular CD44 and extracellular hyaluronan. As proposed by Toole et al. (1984) such a local rise in hyaluronan concentration may lead to a switch from intercellular cohesion to dissociation, leading to tissue cavitation.

Tumourous deposition of calcium pyrophosphate dihydrate crystals in the wrist. A case report.

A 63-year-old man had a tumourous deposition of calcium pyrophosphate dihydrate crystals in the palmar aspect of the wrist. Traumatic micro-fracture or osteoarthritis was thought to have triggered the deposition of these crystals. It should be possible to differentiate the lesion clinically and radiologically from tumoural calcinosis, in which the deposits consist of calcium carbonate and/or calcium phosphate.