Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
11357500 A phase I/IIa study on intra-articular injection of holmium-166-chitosan complex for the t 2001 Apr Previous animal studies have established that the intra-articular injection of holmium-166-chitosan complex (DW-166HC) causes effective necrosis of the inflamed synovium with litle leakage of radioactivity from the injected joint. Based on these findings, we conducted a phase I/IIa study to examine the biodistribution of DW-166HC and to assess the safety of DW-166HC for the treatment of knee synovitis in patients with rheumatoid arthritis (RA). A total of 16 patients [1 man, 15 women; median age 49 (range 36-65) years] who had RA knee synovitis refractory to disease-modifying anti-rheumatic drug treatments of > 3 months' duration were randomly assigned to three treatment groups with different radiation doses of DW-166HC: 370 MBq (n = 6), 555 MBq (n = 5) and 740 MBq (n = 5). In each treatment group, blood and urine radioactivity were analysed by beta counter and biodistribution of the injected DW-166HC was evaluated using a gamma scan camera. Clinical assessment was done according to three variables (evaluation method): knee joint pain (visual analogue scale), range of motion (goniometry) and joint swelling (circumference of knee joint). The duration of follow-up observation was 3 months. Following the intra-articular injection of DW-166HC, the blood radioactivity was little changed from the baseline measurement and the accumulated radioactivity excreted in urine was minimal. Gamma scan study indicated that most of the injected radiochemical was localized within the injected joint cavity, and the extra-articular leakage was negligible at 24 h after the injection: brain, 0.3%; lung, 0.6%; abdomen, 0.7%; and pelvis, 0.8%. Major adverse events were transient post-injection knee joint pain and swelling. These results suggest that DW-166HC might be a safe agent for radiation synovectomy, particularly for the treatment of knee synovitis of RA, and further trials in a larger patient population are warranted to evaluate the therapeutic efficacy of DW-166HC.
9312762 [The effect of immunosuppressive drugs on expression of surface antigens of lymphocytes in 1997 Feb One hundred and fifty patients with rheumatoid arthritis (RA) were treated with immunosuppressive drugs for 12 months. Fifty nine patients were treated with methotrexate (MTX), 15 with cyclophosphamide (CTX), 30 with prednisone (PRE) and 46 with non steroidal antiinflammatory drugs (NSAID). The cell surface phenotype of lymphocyte was analyzed using immunofluorescence methods ans a variety of monoclonal antibodies. The studies were performed using fluorescence activated cell scanner (FACScan) and epifluorescence microscope. No changes in the percentage of CD3, CD4, CD8 were observed. However, in the MTX treated group the percentage of CD19+ (15.1% before treatment vs 10.2% after 12 months MTX treatment (p < 0.05) and CD5+CD19+ B-cells was decreased. In CTX treated group the percentage of both B cells (17.4% vs 11.0% (p < 0.5)) and activated T cells was decreased (CD25+: 2.8% vs 1.1%, p < 0.05 and HLA-DR+: 22.1% vs 12.7%, p < 0.01). Patients treated with prednisone expressed several changes in lymphocyte phenotype i.e. decreasing of activated T cells (CD3+CD25+: 6.9% vs 3.6%, p < 0.01), B cells (CD5+CD19+: 3.4% vs 0.8%, p < 0.001), and NK cells (CD16+: 14.8% vs 8.5, p < 0.01 and CD56+: 16.3% vs 10.7%, p < 0.01). Analyzing immunosuppressive drugs appeared to be very sufficient in the RA treatment. Moreover, the correlation between percentage of both B lymphocytes and activated T cells, and activity of disease were shown.
9861495 Modulation of sialyl Lewis X dependent binding to E-selectin by glycoforms of alpha-1-acid 1998 Nov Alpha-1-acid glycoprotein (AGP) is an extensively glycosylated acute phase protein of imprecisely defined physiological function. Nonetheless it is known that the oligosaccharide component comprising 42% of the 41 kDa molecular weight is critical to the previously described multifarious immunomodulatory functions of AGP in vitro. Complex oligosaccharides were enzymically released from AGP purified from the blood of rheumatoid arthritis sufferers by our oligosaccharide protective method. Oligosaccharide profiling was by means of high pH anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD). Monosaccharide composition analysis revealed increased fucosylation of inflammatory AGP oligosaccharide chains, suggesting the potential for expression of the tetrasaccharide antigen and E-Selectin ligand, sialyl Lewis X (sLeX). The hypothesis that AGP may function to inhibit blood cell binding to activated endothelium at E-Selectin was tested in a microtitre cell-protein binding assay. In this system we have shown that the oligosaccharide moiety of AGP, as expressed in inflammatory disease, can inhibit the sLeX/E-Selectin interaction. Thus we have identified a correlation between the abnormal glycosylation of AGP in rheumatoid arthritis and suppression of sLeX dependent cell adhesion through inhibition of E-selectin binding which could be the basis of a novel, site specific, anti-inflammatory agent.
9438087 Radiographic changes in the patella after total knee arthroplasty without resurfacing the 1997 The necessity of patellar resurfacing has aroused considerable controversy. Between 1986 and 1996, we have routinely performed 208 primary total knee arthroplasties (TKAs) without resurfacing the patella. However, we have occasionally observed gradual postoperative patellar deterioration which caused peripatellar pain. This study observed the radiographic changes in the patella after TKA without resurfacing the patella to assess the effect of the changes on the clinical results. Sixty out of 208 TKAs were assessed in this study. The original diagnoses were osteoarthrosis (OA) in 17 joints and rheumatoid arthritis (RA) in 43 joints. Fourteen patients (23.3%) complained of postoperative peripatellar pain: 2 of the 17 patients with OA (11.8%) and 12 of the 43 with RA (27.9%). Lateral tilt of the patella slightly decreased with time, but lateral shift increased slightly. Patellar length and width increased throughout the follow-up period. The thickness of the patella, especially in the RA cases, significantly (Mann-Whitney, p < 0.05) decreased with time. According to these radiographic findings, as time passed the thickness of the patella decreased, its length and width increased, and the patella as a whole became flattened. On examining the effect of this flattening on postoperative pain, it was found that about 70% of those patients whose patellar thickness had decreased to 80% or less complained of peripatellar pain. In the case of the OA patients, however, there was no statistically significant correlation between patellar flattening and pain. It is concluded that patellar resurfacing should be considered for the patient with rheumatoid arthritis. Because patellar flattening did not develop in many patients with OA and few of them complained of peripatellar pain, patellar resurfacing should not be performed routinely.
10931160 Different regulation of factor H and FHL-1/reconectin by inflammatory mediators and expres 2000 Aug Factor H and the FHL-1/reconectin protein are two human plasma proteins that act as important regulators of the alternative complement pathway. Each protein is encoded by a unique transcript, but both mRNAs are derived from the factor H gene by means of alternative processing. In order to address potential functional differences between the two proteins we analysed their expression in hepatic and non-hepatic cells and studied their regulation by inflammatory mediators. We demonstrate that factor H and FHL-1/reconectin transcripts which are regulated by the same gene promoter and are initiated at the same transcription start site are differently expressed. Expression of the molecules is induced and regulated by the inflammatory mediators interferon-gamma (IFN-gamma) and the anti-inflammatory glucocorticoid dexamethasone. Both factor H and FHL-1/reconectin are expressed and secreted by synovial fibroblasts and are present in synovial fluid derived from patients suffering from rheumatoid or reactive arthritis. The local synthesis in synovial fibroblasts and their induction by IFN-gamma and dexamethasone, but not by tumour necrosis factor-alpha, suggests for each of the two complement regulators a protective role in RA.
9517756 Trends in antirheumatic medication use among patients with rheumatoid arthritis, 1981-1996 1998 Mar OBJECTIVE: To describe changes in antirheumatic medication use by patients with rheumatoid arthritis (RA) over the 15 years 1981 to 1996. METHODS: Medication use was ascertained every 6 months by mailed Health Assessment Questionnaire in a cohort of patients recruited from the local community (n = 305; mean duration of RA at study entry 14.2 yrs). Patients were treated by 53 rheumatologists and over 200 other physicians during the study. The proportions of patients treated with nonsteroidal antiinflammatory drugs (NSAID), disease modifying antirheumatic drugs (DMARD), prednisone, intraarticular corticosteroids, and analgesics were determined in serial cross sectional analyses, and trends in medication use over time were analyzed using linear regression. RESULTS: From 1981 to 1996, the proportion of patients treated with DMARD increased from 32 to 47% (average increase 1.06% each year; p < 0.0001), while the proportion treated with NSAID decreased from 86 to 76% (average decrease 0.57% each year; p < 0.0001). The proportion of patients treated with prednisone remained between 30 and 40%, with a trend toward increasing use over time (average increase 0.2% each year; p = 0.05). In contrast, the proportion treated with intraarticular corticosteroids decreased from 14.4 to 6.7% (average decrease 0.46% each year; p < 0.0001). In 1996, the most prevalent patterns of medication use were the use of NSAID alone (24.4%), use of an NSAID and DMARD (16.3%), and use of an NSAID, DMARD, and prednisone (12.2%). Use of an NSAID as the only antirheumatic medication decreased over time, and the use of DMARD in combination with other medications increased. CONCLUSION: The proportion of patients with RA treated with DMARD increased substantially from 1981 to 1996. This change in practice occurred during the time in which the concept of inverting the traditional therapeutic pyramid became popular, and may reflect a translation among clinicians of the philosophy of "early DMARD use" to "consistent DMARD use," even among patients with RA of moderate or longstanding duration.
10600661 Hip and knee arthroplasty: a comparison and the endocrine, metabolic and inflammatory resp 2000 Jan Changes in circulating levels of catecholamines, cortisol, glucose, interleukin-6 and C-reactive protein and in the leucocyte count were investigated for 7 days after surgery in 158 patients undergoing hip or knee arthroplasty. We compared the responses to the two operations, and also examined the effects of pathology (osteoarthritis and rheumatoid arthritis) on the changes associated with knee arthroplasty. Exploratory factor analysis was applied to the data to identify the variables and sampling times that could be used in future to provide a concise description of the response. Patients undergoing knee arthroplasty showed significantly greater changes in noradrenaline, adrenaline and glucose levels, but not in cortisol levels, compared with those undergoing hip arthroplasty. Interleukin-6 and C-reactive protein concentrations were also significantly greater in knee patients than hip patients; however, when corrected for pathology, many of these differences were not significant. Minimal effects of pathology (chronic inflammation with rheumatoid arthritis) were found on the hormonal changes in knee patients. In particular, there was little evidence to support the inference from animal data that the hypothalamic-pituitary-adrenal axis is impaired. The expected increases in interleukin-6 and C-reactive protein concentrations were found in the rheumatoid arthritis patients. Exploratory factor analysis showed that the response could be separated into six components, accounting for 60% of the total variance, and identified the variables and sampling times indicative of each. In conclusion, there are differences in the hormonal, but not inflammatory, responses to hip and knee arthroplasty. Little evidence was found for an important effect of pathology on the changes associated with knee surgery. Factor analysis provided a useful summary of the data.
10070274 Nuclear factor-kappa B activity in T cells from patients with rheumatic diseases: a prelim 1998 Dec OBJECTIVE: The NF-kappa B/Rel family of transcription factors regulates the expression of many genes involved in the immune or inflammatory response at the transcriptional level. The aim of this study was to determine whether distinctive patterns of NF-kappa B activation are seen in different forms of joint disease. METHODS: The DNA binding activity of these nucleoproteins was examined in purified synovial and peripheral T cells from patients with various chronic rheumatic diseases (12: four with rheumatoid arthritis; five with spondyloarthropathies; and three with osteoarthritis). RESULTS: Electrophoretic mobility shift assays disclosed two specific complexes bound to a NF-kappa B specific 32P-labelled oligonucleotide in nucleoproteins extracted from purified T cells isolated from synovial fluid and peripheral blood of patients with rheumatoid arthritis. The complexes consisted of p50/p50 homodimers and p50/p65 heterodimers. Increased NF-kappa B binding to DNA in synovial T cells was observed relative to peripheral T cells. In non-rheumatoid arthritis, binding of NF-kappa B in synovial T cells was exclusively mediated by p50/p50 homodimers. CONCLUSION: Overall, the results suggest that NF-kappa B may play a central part in the activation of infiltrating T cells in chronic rheumatoid arthritis. The activation of this nuclear factor is qualitatively different in rheumatoid synovial T cells to that in other forms of non-rheumatoid arthritis (for example, osteoarthritis, spondyloarthropathies).
11272273 Differential effects of anti-Fc gamma RIIIb autoantibodies on polymorphonuclear neutrophil 2001 Feb Anti-Fc gamma receptor IIIb (Fc gammaRIIIb) human autoantibodies (Ab) have been classified previously into three groups, based on the results of an indirect immunofluorescence (IIF) test and an enzyme-linked immunosorbent assay (ELISA): IIF+/ELISA+ (group A), IIF+/ELISA- (group B), and IIF-/ELISA+ (group C) sera. In this study, differential effects between IIF+ autoAb, recognizing cell-bound Fc gammaR, and those ELISA+, recognizing only cell-free Fc gammaR, were studied on polymorphonuclear neutrophils (PMN). Neither group A nor B autoAb was cytotoxic, although both prolonged the survival of PMN by delaying spontaneous apoptosis. By the same extent, the PMN-binding antisera stimulated the appearance of a CD11b(dim) population, following a 12-h incubation. This event was associated with a lowered expression of beta2 integrin molecules, resulting in altered PMN function. Treatment with groups A and B autoAb reduced adhesiveness and respiratory burst. This impairment of the responses was more pronounced when the cells originated from donors NA1+ NA1+ rather than donors NA2+ NA2+. From our observations, the influences of anti-Fc gammaRIIIb autoAb on PMN survival, as well as function and subsequent dysregulation of the inflammatory response, have proven somewhat dependent on their target antigens, as determined by IIF coupled with ELISA and Fc gammaRIIIb polymorphism.
10420896 [Psoriasis. Rheumatologic manifestations]. 1999 Jun 26 THE CONTEXT: Psoriasic arthritis lies somewhere between rhumatoid polyarthritis and spondyloathropathy. Its prevalence is about 0.1% with a 1/1 sex ratio. Mean age at onset of symptoms is 40 years. In 10 to 15% of the cases, rhumatological manifestations are observed before skin lesions. Ungueal involvement is particularly frequent. FIVE CLINICAL FORMS: Classically, five clinical forms are described: arthritis limited to the distal interphalangeal joints, mutilating arthritis, symmetrical polyarthritis, asymmetrical mono- or oligoarthritis, and spondylitis. Asymmetrical oligoarticular forms and polyarithrtis predominate. DISEASE SEVERITY: In general psoriasic arthritis is a benign condition. Severe forms have however been described with erosion and osteolysis involving the distal interphalangeal joints. Typical radiological may be observed. THERAPEUTIC OPTIONS: Non-steroidal antiinflammatory drugs help control disease progression in about one-third of the cases. In other patients, gold salts, D-penicillamine, methotrexate, or sulfasalazine may be required.
9410434 [Production of tumor necrosis factor alpha and interleukin-6 by alveolar macrophages from 1997 Jul The aim of this study was to measure the production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) by alveolar macrophages in patients with rheumatoid arthritis and interstitial lung disease (ILD). Rheumatoid arthritis patients diagnosed by ACR criteria (n = 8) with associated ILD documented by pulmonary function tests and high resolution computerized tomography scanning, and 12 healthy volunteers (6 smokers and 6 nonsmokers). We determined the spontaneous and induced production of bacterial lipopolysaccharides (LSP), TNF-alpha and IL-6 by alveolar macrophages obtained by bronchoalveolar lavage. The macrophages were isolated by Ficoll-Hypaque gradient centrifugation and plastic adherence and cultured in serum-containing medium (low endotoxin) in the presence and absence of LPS (100 ng/ml). TNF-alpha and IL-6 levels contents were determined in supernatants by ELISA. In the patient group both spontaneous and induced production of TNF-alpha were significantly higher than in controls (p < 0.01). Macrophages stimulated with LPS in patients with rheumatoid arthritis and ILD also released greater amounts of IL-6 than did those of the healthy controls. IL-6 spontaneous and induced production was significantly lower in smokers than in nonsmokers. TNF-alpha and IL-6 production in patients with rheumatoid arthritis and ILD, studied in bronchoalveolar lavage specimens reveals that alveolar macrophages are hyperreactive in these patients, who are possibly sensitized as a consequence of the inflammatory lung process inherent to the disease. Further study is needed to define the pathogenic role of these mediators.
11161440 High concentration of soluble HLA-DR in the synovial fluid: generation and significance in 2000 Dec 15 In the search for its role in inflammatory joint diseases, soluble HLA-DR (sHLA-DR) was quantitated in 72 synovial fluids (SF) by a newly established immunoenzyme assay. Unlike other soluble receptors which accumulated only moderately (sCD25, sCD4) or negligibly (sHLA class I, sCD8) in the SF, SF sHLA-DR levels exceeded serum levels by up to 3 orders of magnitude and varied disease dependently from "control" values (traumatic synovitis and osteoarthritis: 9.9 +/- 6.1 ng/ml). Clear-cut different SF sHLA-DR values in HLA-DR-associated "rheumatoid-like" (136.5 +/- 130.0 ng/ml) vs HLA-B27-associated "spondylarthropathy-like" arthritic forms (28.4 +/- 29.1 ng/ml) were most significant comparing oligoarticular juvenile chronic arthritis type I (147.6 +/- 112.6 ng/ml) and type II (3.3 +/- 1.1 ng/ml), thus offering a new classification marker. Also ex vivo, large amounts of sHLA-DR were released spontaneously by SF mononuclear cells and found to be related to the T-cell activation state. SF sHLA-DR may be shed in large complexes or micelles, as it eluted mainly at >450 kDa on gel filtration. Western blotting revealed that the majority of SF sHLA-DR consisted of full-length alpha- and beta-chains. Minor fractions of smaller sized antigens seemed to be generated by proteolytic cleavage rather than by alternative splicing, since only minute amounts of HLA-DRB mRNA lacking the transmembrane exon could be amplified by RT-PCR. Distinct forms of high-dose sHLA-DR, able to provoke rather than to suppress T-cell responses, are discussed as contributing to some HLA-DR disease association.
9834130 The role of CD8+ CD40L+ T cells in the formation of germinal centers in rheumatoid synovit 1998 Dec 1 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.
11729824 Superantigens and their role in autoimmune disorders. 1999 The ability of superantigens to activate large numbers of T cells suggests that they may play a role in the course of autoimmune disorders. Data from several animal models of autoimmune disorders including experimental allergic encephalomyelitis and collagen induced arthritis supports this hypothesis. Administration of bacterial superantigens can induce an exacerbation of the autoimmune process in these models, or induce disease de novo in the appropriately immunized animal. Studies of several human disorders including rheumatoid arthritis, Kawasaki disease, insulin-dependent diabetes, and psoriasis lend credence to the concept that bacterial superantigens may play a role in the pathogenesis of these diseases. Nevertheless, in some cases, depending on the timing of administration and the model, superantigens may lead to an amelioration of the autoimmune process. Based on these results in seems logical to conclude that superantigens can have a significant impact on the course of the immune and autoimmune mediated disorders.
11480090 [Endoprosthetic surface replacement of the head of the humerus]. 2001 Jun The concept of an endoprosthetic surface replacement of the humeral head differs from that of stemmed endoprostheses. It is the replacement of the destroyed joint surface with reconstruction of the normal anatomy and minimal bone resection. The aim of this prospective study was to evaluate the short-term results of a newly developed cup arthroplasty (Durom-Cup) for the humeral head. In a prospective study, 39 patients with 46 Durom-Cups were evaluated preoperatively and every 3 months postoperatively. The average follow-up was 15 +/- 9 months. The group included 28 shoulders with rheumatoid arthritis, 15 joints with osteoarthritis, and 3 humeral head necroses. The Constant-score and SAS-function score were used. The Constant-score increased from 20.25 +/- 9.06 points preoperatively to 46.62 +/- 14.05 at 3 months, to 48.11 +/- 14.49 at 6 months, and to 55.25 +/- 11.6 at 9 months postoperatively. The Constant-score stayed at this level during further follow-up and was 55.81 +/- 16.31 at 12 months postoperatively. The best results were seen in the group of humeral head necroses with a Constant-score of 71.0 +/- 12.2 compared to 54.66 +/- 13.89 in the group of osteoarthritis and 56.78 +/- 13.33 in patients with rheumatoid arthritis at 12 months postoperatively. The results with the Durom-Cup are encouraging so that cup arthroplasty seems to be a good alternative to stemmed prostheses. The main advantages of the humeral head resurfacing are the bone-preserving fixation and the relatively simple surgical technique.
10524688 Comparison of two schedules for administering oral low-dose methotrexate (weekly versus ev 1999 Oct OBJECTIVE: To compare the efficacy of 2 low-dose oral methotrexate (MTX) schedules in maintaining remission in patients with rheumatoid arthritis (RA). METHODS: Patients with RA were included if they were receiving treatment with weekly MTX for at least 9 months and the RA was in remission (defined by American College of Rheumatology [ACR] criteria) for at least 6 months. Patients were stratified by treatment and randomly assigned to weekly or every-other-weekly (EOW; reducing their monthly dose by half) treatment with MTX. Patients were evaluated by a rheumatologist (blinded to the treatment schedule) at baseline and at 6, 12, and 24 weeks. The evaluations included joint counts, Ritchie Articular Index, Health Assessment Questionnaire Disability Index, physician's and patient's global health assessments, visual analog scale for pain, and incidence of adverse effects. Laboratory evaluations were done at baseline and at week 24. RESULTS: Fifty-one patients were included (26 taking weekly MTX, 25 taking EOW MTX). Baseline comparisons showed no differences between the groups. The mean duration of RA was <3 years in both groups, and they had been started on weekly MTX treatment early after diagnosis. After 24 weeks, >90% of the patients in both groups continued in remission. Evaluations of disease activity at 6 and 12 weeks showed no between-group differences. EOW MTX patients who experienced relapse were switched back to weekly MTX, and after a few weeks, their RA was again controlled. The incidence of adverse effects was slightly higher in the weekly MTX group, although the difference did not reach statistical significance. The observed laboratory values were very similar for both groups, except for the serum aspartate aminotransferase and alanine aminotransferase levels, which decreased in the EOW MTX group and were statistically significant at week 24 (P = 0.04 and P = 0.006, respectively). CONCLUSION: EOW MTX represents a valid therapeutic alternative for a specific subgroup of RA patients, as outlined by the ACR remission criteria. Patients with a short disease duration who were treated early after disease onset with weekly MTX and who achieve sustained remission have a higher probability of success with the EOW MTX schedule.
9666833 A novel culturing and grafting system for the treatment of leg ulcers. 1998 May The purpose of this study was to develop and test an efficient culturing and grafting system for the treatment of leg ulcers. The culturing system consisted of a Petriperm culture vessel (20 cm2) aseptically placed in a larger standard Petri dish (60 cm2). Skin cultures were established and cultivated in the Petriperm dish. The cells grew on the bottom of the Petriperm dish, which was made of a gas-permeable 25-micron thick transparent Teflon film. Grafts were produced simply by cutting the film from the bottom of the Petriperm dish with a scalpel. The system was used to produce subconfluent epidermal autografts which were used to heal a 32 cm2 chronic rheumatoid arthritis leg ulcer. The cultured autografts were transferred cell side down on to the cleaned wound bed without an enzymatic digestion. The grafts consisted of autologous keratinocytes, melanocytes and fibroblasts. Caution was taken not to disturb the wound bed for 7-9 days at which time the Teflon film was removed. The wound closed 2 weeks after the last grafting and has remained closed for more than a year post-treatment. The culturing and grafting system presented here will make it possible to develop cellular-based therapies that were previously not possible.
10211879 Modulation of hyaluronan receptor (CD44) function in vivo in a murine model of rheumatoid 1999 Apr OBJECTIVE: To determine how in vivo modulation of CD44 function by antibodies influences disease severity in a murine model of rheumatoid arthritis. METHODS: Mice with proteoglycan (PG)-induced arthritis were subjected to systemic treatment with 3 different monoclonal antibodies against CD44. Joint swelling and serum levels of hyaluronan (HA) and soluble CD44 (sCD44) were monitored. Inflammatory leukocyte infiltration in the joints, cell surface CD44 expression, and leukocyte adhesion to HA were compared. The effects of anti-CD44 treatment on the immune status of arthritic animals were also determined. RESULTS: Antibody IRAWB14, which enhances HA binding, aggravated the inflammatory symptoms, while KM201, which blocks ligand binding, reduced the severity of arthritis. The most effective suppression of inflammation was noted upon treatment with antibody IM7, whose epitope lies outside the HA binding domain of CD44. Serum levels of sCD44 increased, and HA levels decreased, in response to IM7. KM201 and IM7 treatment reduced, but IRAWB14 treatment enhanced, the adhesion of leukocytes to HA. However, these antibodies had little effect on PG-specific immune responses. CONCLUSION: Each antibody acted in vivo by virtue of its combined effects on CD44-HA binding and CD44 shedding. The dramatic reduction in arthritis severity effected by IM7 treatment was associated with extensive shedding of cell surface CD44 molecules. Loss of CD44 appears to be a major factor in preventing CD44- and HA-dependent cell-matrix interactions at the inflammatory site. Our study indicates a critical role for CD44 in the pathology of joint inflammation and reveals a unique mechanism of receptor down-regulation, which can be used therapeutically.
9704197 The long-term efficacy and tolerability of the new anti-inflammatory agent zaltoprofen in 1998 This paper reports on a non-comparative multicentre study designed to assess the usefulness of the non-steroidal anti-inflammatory agent zaltoprofen in the long-term treatment of rheumatoid arthritis. The efficacy and safety of zaltoprofen in the long-term treatment of rheumatoid arthritis were evaluated on the bases of changes of symptoms and presentation signs in the patients including the following: averaged bilateral grip strength, blood sedimentation rate, the duration of morning stiffness, joint pain for Lansbury scoring, restriction of activities of daily living (ADL) and pain score, and on patients' impressions at each hospital on the first day of attendance and then at 6 and 12 months after the start of administration of zaltoprofen, in a total of 46 patients. Overall improvements were recorded as 'marked' in 9%, 'moderate' or better in 60%, 'slight' or better in 80%, 'no change' in 17% and 'worse' in 3%, after 12 months' treatment. The overall safety was recorded as 'safe' in 86% and 'almost safe' or better in 97% after 12 months' treatment. On the basis of these results it can be concluded that, in the long-term treatment of rheumatoid arthritis, zaltoprofen is a well-tolerated and safe non-steroidal anti-inflammatory agent.
10648030 Circulating anticentromere CENP-A and CENP-B antibodies in patients with diffuse and limit 2000 Jan OBJECTIVE: To determine the disease sensitivity and specificity of testing for autoantibodies against 2 of the 3 main human centromere antigenic components, CENP-A and CENP-B (recombinant, expressed in baculovirus). METHODS: ELISA with CENP-A and CENP-B antigens were used to test 45 sera showing a centromere pattern by immunofluorescence (IFA) and sera from 96 patients with systemic sclerosis (SSc), subdivided into diffuse (dSSc) and limited (lSSc) forms. For controls, the same tests were performed on sera from 100 patients with rheumatoid arthritis (RA), 100 with systemic lupus erythematosus (SLE), and 50 random blood donors. Sera from all the patients with SSc were also tested for the presence of anti-Scl70 antibody by ELISA (bovine antigen), and for pattern and titer by IFA (HEp-2 cells). RESULTS: Of the 45 IFA positive sera, 93% were positive for anti-CENP-A and 91% for anti-CENP-B. There was a very good quantitative correlation between the antibody levels against these 2 centromere components (r = 0.597; p<0.001). Anti-CENP-A and B were found in 48% of patients with lSSc, and in 11% and 9%, respectively, of those with dSSc. The difference in the frequency of anti-CENP-A between the 2 patient groups was significant (chi-squared, p<0.001). Similar levels of anticentromere staining pattern by IFA were observed for these 2 groups. Anti-Scl70 was elevated in 8% of lSSc and 25% of dSSc patients; this difference was also significant (chi-squared, p = 0.02). Neither CENP-A nor CENP-B reacted with IgG from SSc patients containing anti-Scl70. The frequency of abnormal levels in patients with SLE and RA was, respectively, 11% and 3% for anti-CENP-A and 4% and 3% for anti-CENP-B. The reaction of IgG from SLE and RA patients with CENP-A was not inhibited by histone H3, i.e., it was not due to recognition of the histone-like domain in CENP-A. Thus, when 96 SSc patients were compared to 200 patients with RA and SLE, the disease specificity of anti-CENP-A and B was 93% and 96.5%, respectively. CONCLUSION: In addition to IFA, ELISA tests for CENP-A and CENP-B yield results with similar sensitivity and specificity for the diagnosis of SSc. CENP-A and CENP-B are primarily associated with lSSc. In SSc the autoantibody response is directed simultaneously and with similar amplitude against these 2 components of the centromere structure, whereas in other autoimmune diseases the response is directed mainly against one of the 2 components.