Histologic changes in rheumatoid synovitis induced by naproxen and methotrexate

OBJECTIVE: To study the changes in rheumatoid synovitis induced by the nonsteroidal antiinflammatory drug (NSAID), naproxen, and methotrexate (MTX). METHODS: Twelve patients were treated with naproxen, and 11 with MTX and a clinical activity index was measured before and after treatment. A synovial biopsy was taken, on entry into the study and after 73 +/- 43 days in the NSAID group and 145 +/- 35 in the MTX group. Synovial cells bearing CD3, CD4, CD8, CD19, LeuM5 (CD11c), HLA-DR, HLA-DP and CD25 antigens were measured by stereology. RESULTS: Patients treated with MTX showed a reduction in the number of CD3+ (p = 0.01), CD4+ (p = 0.007) and HLA-DR+ (p = 0.01) cells with an improvement in the activity index (p = 0.001). The patients treated with naproxen did not show changes in the activity index or in the synovial infiltrate. CONCLUSION: Our findings support the theory that clinical improvement in rheumatoid synovitis is associated with a significant decrease in the number of T cells infiltrating the synovial membrane.     

Arthroscopy for chronic hemophilic synovitis of the knee

Between 1988 and 1995, 32 knee joints (29 patients) with hemophilic arthropathy underwent arthroscopy. The spectrum of procedures ranged from resection of fibrous plicae to synovectomy. Technical difficulties appeared in cases of scarred fixed patella, pronounced posterior tibia subluxation, and severe fibrous ankylosis. All operations done between 1988 and 1991 (23 operations; 21 patients) were reviewed retrospectively. The mean age of the patients in this series was 30 years and the mean followup was 5 years. On subjective evaluation, 13 operations achieved a definite improvement, five showed slight improvement, and two had no improvement (three operations were excluded). Arthroscopic surgery, as a relatively low risk technique, combined with early functional rehabilitation, can be used to achieve satisfactory results in patients with hemophilic arthropathy.     

Measurement of synovial lining volume by magnetic resonance imaging of the knee in chronic synovitis

OBJECTIVES: Current methods of monitoring chronic synovitis in a single joint rely on clinical examination derived indices, such as the detection of synovial thickening. This study aimed to develop a reproducible method for quantifying the volume of synovial lining in chronic synovitis using contrast enhanced magnetic resonance (MR) imaging. METHODS: The knees of 18 patients with chronic synovitis were examined (34 studies). A 2D T1 weighted FLASH sequence was used to evaluate the temporal enhancement of synovial structures after intravenous contrast. Synovial lining volume was calculated from subtraction of pre and post-enhancement 3D T1 weighted MP RAGE images with thresholding and pixel counting. Eleven patients were examined before and after intra-articular glucocorticoid (mean interval 14 weeks) and MR data compared with changes in clinical examination derived indices of disease activity. RESULTS: Synovial lining volume varied from 52-267 ml. The coefficient of variation in volume calculation was 3.5% for a single observer and was 3.8% for two observers. Synovial lining volume was quantified in all patients where synovial lining thickening could not be detected clinically. A decrease in synovial lining volume of > 40% was associated with an improvement in synovial lining thickening, detected clinically. Decreases in synovial lining volume were quantified by MR in two of three patients where changes in clinical examination derived indices were inconsistent. CONCLUSIONS: A reproducible method of estimating the volume of synovial lining in patients with chronic synovitis has been developed. MR measurement of synovial lining volume may quantify changes in chronic synovitis that remain unidentified by clinical measures.     

Characteristic magnetic resonance imaging entheseal changes of knee synovitis in spondylarthropathy

Although studies generally support a positive association between alcohol consumption and lung-cancer risk, the relationship between specific alcoholic beverages and lung-cancer risk has been inconsistent. We examined recent and past alcoholic beverage intake among 261 incident cases and 615 population controls enrolled in a lung-cancer case-control study of African Americans and Caucasians in Los Angeles County between 1991 and 1994. An in-person interview elicited information about past alcohol intake from ages 30 to 40 y, smoking, other lung-cancer risk factors, as well as recent intake of alcohol, and recent dietary intake. An association was observed between recent hard-liquor consumption and lung-cancer risk. The odds ratio (OR) for 1 or more drinks (1.5 oz or 0.051 mL) per day of hard liquor compared with infrequent liquor drinking (0-3 drinks per month), adjusted for smoking, the matching factors, saturated fat and other alcoholic beverages was 1.87 [95% confidence interval (CI) = 1.02-3.42]. No appreciable association was observed for total alcohol, whereas small inverse associations were observed for beer and wine, although confidence intervals were wide. An elevated lung-cancer risk was also observed for past liquor consumption (between ages 30 and 40 y). The adjusted OR for 1 or more drinks per day of liquor compared with infrequent drinkers was 1.83 (95% CI = 1. 06-3.15). Confounding of the association between alcohol and lung cancer by smoking was apparent. Although we devoted considerable efforts to adjusting for smoking in our analyses, residual confounding is still possible because smoking and alcohol are closely associated. In addition, case-control studies including this study should be viewed with caution because of possible selection bias. An increased risk of lung cancer might occur with moderate drinking of hard liquor but confirmation is required in larger studies.     

Arthroscopic synovectomy of the knee joint in rheumatoid arthritis

The role of arthroscopic synovectomy in Rheumatoid arthritis is still in discussion. The evaluation of the available scientific data out of the literature should give a contribution to this discussion. The review of the studies done in only small numbers of patients demonstrates good clinical results for a short or middle lasting follow-up time. The evaluation showed a lot of differences and problems in the study design, amount of usable datas and results. For the scientific rating of the results of arthroscopic synovectomies it is necessary to have prospective studies with sufficient and reliable data on activity of the disease, the pre-, post- and intraoperative findings, standardized surgical procedures and longer lasting follow-up times.     

Production of cytokines and metalloproteinases in rheumatoid synovitis is T cell dependent

Agrin, a proteoglycan secreted by motoneurons, is a critical organizer of synaptic differentiation at skeletal neuromuscular junctions. Agrin is widely expressed in the nervous system so other functions seem likely, but none have been demonstrated. To test roles for agrin in interneuronal synapse formation, we studied hippocampi from mutant mice that completely lack the z+ splice form of agrin essential for neuromuscular differentiation and also exhibit severely ( approximately 90%) reduced levels of all agrin isoforms (M. Gautam et al., 1996, Cell 85, 525-535). The brains of neonatal homozygous agrin mutants were often smaller than those of heterozygous and wild-type littermates, but were morphologically and histologically indistinguishable. In particular, antibodies to pre- and postsynaptic components of glutamatergic synapses were similarly coaggregated at synaptic sites in both mutants and controls. Because mutants die at birth due to neuromuscular defects, we cultured neurons to assess later stages of synaptic maturation. In primary cultures, the agrin-deficient neurons formed MAP2-positive dendrites and tau-1-positive axons. Synaptic vesicle proteins, AMPA- and NMDA-type glutamate receptors, GABAA receptors, and the putative synapse-organizing proteins PSD-95, GKAP, and gephyrin formed numerous clusters at synaptic sites. Quantitatively, the number of SV2-labeled contacts per neuron at day 5 and the number of PSD-95 clusters per dendrite length at day 18 in culture showed no significant differences between genotypes. Furthermore, exogenous z+ agrin was unable to induce ectopic accumulation of components of central glutamatergic or GABAergic synapses as it does for neuromuscular cholinergic synapses. These results indicate that the z+ forms of agrin are dispensable for glutamatergic and GABAergic synaptic differentiation in the central nervous system.     

The correlation of indium-111 joint scans with clinical synovitis in rheumatoid arthritis

OBJECTIVE: An inflammatory compartment radionuclide such as Indium-111 chloride (111InCl3) may offer advantages over bone seeking radionuclides in the assessment of active rheumatoid synovitis. As an iron analog, 111InCl3 binds iron complexing proteins including transferrin. Active rheumatoid synovitis is a transferrin receptor rich compartment, reflecting profound cellular activation and proliferation. We investigated 111InCl3 scanning for the detection of active rheumatoid arthritis (RA). METHODS: Nine patients satisfying ACR criteria for definite or probable RA were scanned twice at a 28-day interval. Patients were undergoing multiple medication changes with resultant fluctuating disease activity. Blinded readings were performed by an experienced nuclear medicine physician and correlated with simultaneous clinical examinations by a single rheumatologist. Sixteen assessed joint areas/patient and a total of 144 joint areas were available for analysis. RESULTS: Scintigraphy correlated with swollen and tender joint scores at both timepoints. Specificity was highest with stringent scoring. Sensitivity was lowest for small joints with lower 111InCl3 uptake relative to background. A receiver operator curve (ROC), generated to analyze the diagnostic value of varying 111InCl3 scan stringency, demonstrated utilization of the most accurate portion of the ROC curve by the reader. CONCLUSION: 111InCl3 joint scintigraphy correlates with clinically detectable rheumatoid synovitis, supporting the hypothesis that transferrin receptor levels reflect rheumatoid disease activity.     

Anatomic bases of a vascularized allogenic knee joint transplantation: arterial blood supply of the human knee joint

The reliable identification of tumor cells in populations of atypical cells occurring in body cavity effusions is a well-known diagnostic problem. In order to improve tumor cell detection and to predict disease progression, we developed a cell scoring strategy based on a combination of DNA cytophotometry and immunocytochemistry. For this purpose, morphologically atypical cells obtained from 33 effusion samples were submitted to DNA content analysis and tested for Ber-EP4 immunoreactivity. It turned out that elevated DNA content alone has a low specificity (true negative ratio) and sensitivity (true positive ratio) in predicting disease outcome, whereas Ber-EP4 immunoreactivity alone has a high specificity (100%) but a low sensitivity (56%). In contrast, the use of a scoring system combining the two techniques and relating scores to the previous disease state and the cytomorphology of the atypical cells results in highly specific and sensitive prediction of the disease outcome. We therefore suggest that this approach is a valuable tool for reliably identifying tumor cells in effusions containing populations of cytologically suspect cells.     

Heparan sulfate proteoglycan on endothelium efficiently induces integrin-mediated T cell adhesion by immobilizing chemokines in patients with rheumatoid synovitis

OBJECTIVE: To clarify the role of heparan sulfate proteoglycan (HSPG) and chemokines in integrin-mediated T cell adhesion to endothelial cells in the synovium of patients with rheumatoid arthritis (RA). METHODS: Endothelial cells were purified from RA synovium. Expression of heparan sulfate, chemokines, and adhesion molecules on the endothelium was assessed by immunohistochemical analysis or flow cytometry. The effects of chemokines and heparan sulfate on T cell adhesion to RA endothelium were estimated with relevant antibodies and signaling inhibitors. Production of chemokines from synovial T cells was detected by Northern blotting and enzyme-linked immunosorbent assay. RESULTS: The endothelium in RA synovium highly expressed HSPG. The soluble form of chemokines, macrophage inflammatory protein 1beta (MIP-1beta), induced T cell adhesion to the endothelial cells. When MIP-lalpha and MIP-1beta were immobilized on RA endothelial cells, a more efficient integrin-mediated adhesion of T cells was induced compared with their soluble form. The induced T cell adhesion was reduced by pretreatment with either heparitinase, anti-MIP-lalpha antibody, or anti-MIP-lbeta antibody, indicating that these chemokines were bound to heparan sulfate on the cells. T cell adhesion was also inhibited by pertussis toxin, wortmannin, and cytochalasin B. MIP-lalpha and MIP-1beta were found on vessels in RA synovium in vivo, which were spontaneously produced from T cells purified from RA synovium. CONCLUSION: Endothelial cells in RA synovium characteristically express HSPG, which is involved in T cell integrin triggering by "posting" chemokines, which are produced by synovial T cells, and by "relaying" them to their receptors on T cells, which activate G protein-dependent phosphoinositide 3-kinase and actin-dependent integrin triggering.     

Long-term results of Yoshino total knee arthroplasties in rheumatoid arthritis

A review was made of 267 Yoshino total knee arthroplasties performed on 184 patients with rheumatoid arthritis between June 1978 and December 1983. The average duration of follow-up was 14.3 years. Of these patients 46.7% died during the follow-up period. The main causes of death were cardiac disease, respiratory disease and renal disease. According to the Japanese Orthopaedic Association (JOA) knee rating system, JOA scores decreased significantly with time after surgery, but remained significantly higher than the preoperative scores. The flexion angle after surgery had decreased compared with the preoperative flexion angle and decreased further 3 years after surgery and later. The cumulative survival rate was 88.6%. This rate was mainly affected by postoperative infection and aseptic loosening of the tibial components.     

Association of pyoderma gangrenosum with hepato-pancreatic involvement in rheumatoid polyarthritis

During a SCUBA course, a woman (26 yr) ascended from shallow water (< or = 8 m) in panic on 2 successive days. She suffered moderate symptoms of gas embolism (pain in the upper chest and in both knees), very likely owing to a pulmonary barotrauma. The woman remained untreated for 3 d until her return flight during which symptoms worsened. After another 24 d, she entered the hyperbaric center in Duisburg, Germany, where she was successfully treated by recompression with hyperbaric oxygenation (to 0.6 MPa on day 1, and to 0.28 MPa on days 2 and 3).     

Somatosensory evoked potentials in rheumatoid polyarthritis with radiologic involvement of the cervical spine

Somatosensory evoked potentials (SEP) have been recorded in 11 patients with cervical spine involvement, with or without signs of myelopathy due to rheumatoid arthritis (RA). In three patients, SEP have been recorded both before and after cervical spine surgery. In seven cases, the P14 (particularly the P9/P14 amplitude ratio) or P30 potentials were abnormal, whereas other potentials and conduction times were less often modified. Vertebral luxation sites that were predominantly observed at the upper cervical level account for these findings, thus supporting the diagnostic utility of P14 and P30 potentials which respectively take origin in the lower brain stem, close to or into the nuclei cuneatus and gracilis. Postoperative SEP were strongly correlated with the surgical outcome. SEP could be abnormal in the absence of overt clinical myelopathy or vertebral luxations, thus revealing infraclinical damage to the somatosensory pathways. This suggests that SEP recording is useful to discriminate RA patients with upper cervical cord dysfunction from those in whom vertebral lesion proves to have no direct impact on somatosensory conduction.     

Plain film and CT findings of pulmonary involvement in rheumatoid arthritis

Meiotic recombination of S. cerevisiae contains two temporally coupled processes, formation and processing of double-strand breaks (DSBs). Mre11 forms a complex with Rad50 and Xrs2, acting as the binding core, and participates in DSB processing. Although these proteins are also involved in DSB formation, Mre11 is not necessarily holding them. The C-terminal region of Mre11 is required only for DSB formation and binds to some meiotic proteins. The N-terminal half specifies nuclease activities that are collectively required for DSB processing. Mre11 has a DNA-binding site for DSB formation and another site for DSB processing. It has two regions to bind to Rad50. Mre11 repairs methyl methanesulfonate-induced DSBs by reactions that require the nuclease activities and those that do not.     

The role of CD8+ CD40L+ T cells in the formation of germinal centers in rheumatoid synovitis

In rheumatoid synovitis, lymphocytes can be arranged in follicular structures resembling secondary lymphoid follicles. To understand the organizing principles of this ectopic lymphoid tissue, the cellular components contributing to synovial follicles were examined. In 9 of 24 synovial tissue biopsies, lymphoid aggregates were found consisting of CD4+ T cells and CD20+ B cells. In four of the nine patients, the follicular centers were occupied by CD23+ CD21+ cellular networks representing follicular dendritic cells involved in germinal center reactions. In five patients, CD23+ cells were absent from the centers of the aggregates, suggesting that fully developed germinal centers are generated in only a subset of patients. To identify factors involved in the regulation of the synovial microarchitecture, cell populations contributing to the follicles were quantified by digital image analysis of immunostained tissue and by flow cytometry of tissue-derived lymphocytes. Proportions of CD4+, CD20+, and CD68+ cell subsets were surprisingly invariant, irrespective of the presence or absence of CD23+ follicular dendritic cells. Instead, tissue biopsies with CD23+ germinal center-like regions could be distinguished from those with CD23- T cell-B cell aggregates by a fourfold increase in the frequency of tissue-infiltrating CD8+ T cells, a fraction of which expressed CD40 ligand (CD40L). The data suggest a previously unsuspected role of CD8+ lymphocytes in modulating germinal center formation and raise the possibility that CD8+ CD40L+ T cells are involved in aggravating pathologic immune responses in rheumatoid synovitis.     

Stiffness of trabecular bone of the tibial plateau in patients with rheumatoid arthritis of the knee

Stiffness of subchondral proximal tibial trabecular bone is a factor in the stability of prostheses implanted into that bone. The stiffness of trabecular bone in osteoarthritis (OA) has been documented. Trabecular bone in rheumatoid arthritis (RA) is osteopenic in numerous sites and morphologically abnormal in the proximal tibia. Reliable data on proximal tibial bone in RA are lacking, although 1 study failed to identify abnormalities. The purposes of this study were (1) to document the stiffness of the proximal tibial cancellous bone in patients with RA, (2) to determine the effect of angular deformity on bone stiffness in rheumatoid patients, and (3) to compare RA stiffness values with those in published reports for OA. Fifteen tibial plateau were obtained from patients with RA during surgery. Each plateau was horizontally seated in a mold and covered with cement. The plateau was divided into 6 regions, which were used to facilitate comparison between specimens and the existing literature. Indentation tests were conducted with a 4-mm-diameter cylindrical indentor controlled by an MTS machine. The indentor descended at a rate of 2 mm/min to a maximum depth of 1.0 mm; load and displacement data were digitally recorded. Stiffness was calculated from the slope of the linear region of the curve using best-fit linear regression. Where varus deformity was present, stiffness in the medial plateau was higher overall than for the other compartment; whereas in the case of valgus deformity, stiffness of the lateral side was significantly higher (P < .05 for each observation). In comparison to older normal specimens, both the medial compartment of the varus RA specimens (P < .01) and the posterolateral compartment of the valgus RA specimens (P < .01) had significantly lower stiffness. Comparison with OA specimens showed that in varus RA, the posteromedial region had significantly lower stiffness than in varus OA at the same site (P < .01). In valgus RA, the lateral region had significantly lower stiffness than in valgus OA at the same site (P < .01). The mean stiffness ratio of the valgus RA was significantly (P < .01) altered from normal, and for the varus RA, it was significantly (P < .01) different from normal posteriorly. The stiffness ratios for the varus RA were significantly (P < .01) different from those for varus OA; there was no difference between valgus RA and valgus OA. It is concluded that RA affected bone has significantly lower stiffness than normal and osteoarthritic bone. The loaded plateau is stiffer than the unloaded plateau in angular deformity, but is still less stiff than normal bone and osteoarthritic plateaus with corresponding deformities.