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ID PMID Title PublicationDate abstract
9881748 Reproducible and sensitive determination of charged oligosaccharides from haptoglobin by P 1998 May Many studies have reported changes in the carbohydrate structure of serum glycoproteins in disease, but this information is often of limited value for understanding disease mechanisms because it is obtained with simple and/or indirect methodologies that determine only one structural feature. On the other hand, more detailed carbohydrate methodologies are time-consuming and require a lot of purified material. Using haptoglobin (Hp) as a model protein, a new procedure was devised that determined the oligosaccharide composition of very small amounts of Hp in a relatively short time. The Hp was purified by batch affinity-chromatography, oligosaccharides were removed with PNGase F, and the oligosaccharide composition of charged species was determined using HPAEC/PAD (Dionex carbohydrate analyser). The method was applied to the analysis of Hp from eight healthy individuals and 37 patients with different inflammatory diseases or cancers. Twenty-seven oligosaccharides were consistently detected, but the majority could not be identified. However, by calculating retention times relative to the sialylated biantennary peak (Neu5Ac(alpha)2-3/6Gal(beta)1-4GlcNAc(beta)1-2Man(alpha)1-6(Neu 5Ac(alpha)2-3/6Gal(beta)1-4GlcNAc(beta)1-2Man(alpha)1-3)Man(beta)1-4G lcNAc(beta)1-4GlcNAc) it was possible to compare profiles quantitatively. Although no peak was identified as disease-specific, characteristic and reproducible profiles were obtained. Particularly striking were reductions in the major peaks in Crohn's disease, rheumatoid arthritis, stomach cancer, accompanied by increases in unidentified peaks. Previous studies suggested that many of the unknown peaks were due to increased sialylation and fucosylation. Only small changes in patterns were observed for breast and ovarian cancer. The new procedure will be very useful in the characterization of oligosaccharide composition of glycoproteins in clinical specimens.
11263779 Long-term outcome of mothers of children with isolated heart block in Finland. 2001 Mar OBJECTIVE: To study the long-term outcome of mothers of children with isolated heart block in a defined population. METHODS: We reviewed the Finnish hospital registries for patients born between 1950 and 1999 who had been diagnosed as having isolated heart block before the age of 15 years. We identified 101 children with isolated congenital heart block (CHB) and 55 with isolated heart block detected after the newborn period. Eighty-three (91%) of the 91 mothers of children with CHB and 48 (87%) of the 55 mothers of children with heart block detected after the newborn period were studied according to a protocol defining clinical characteristics (mean 9.9 years, range 0-49 years, and mean 22.9 years, range 4-47 years after the index delivery, respectively). Maternal survival was compared with survival in an age-matched population of normal Finnish women. RESULTS: Before the index delivery, 29 (37%) of the 78 surviving mothers of children with CHB had a self-reported clinical diagnosis of a chronic autoimmune disease, and 55 (71%) had had symptoms, signs, or abnormal laboratory findings suggesting an underlying subclinical disease. Of the 23 mothers who were completely asymptomatic before the index delivery, 10 (13% of the surviving mothers) remained so after a mean followup of 9.6 years (range 0-21 years). In mothers of children with CHB, clinical characteristics different from those of healthy mothers were photosensitivity, fatigue, dry eyes, and dry mouth. Forty-eight (58%) of these 83 mothers developed an autoimmune disease during followup. The most common diagnosis was primary Sjögren's syndrome (22 definite, 11 probable), followed by systemic lupus erythematosus (SLE). The standardized mortality ratio of mothers of children with CHB was 5.1, and 3 of the 5 deaths were associated with SLE. Mothers of children with heart block detected after the newborn period had similar symptoms and signs of autoimmune diseases as the healthy controls, and their standardized mortality ratio was 1.9. CONCLUSION: Primary Sjögren's syndrome, either definite or subclinical, is the predominant autoimmune disorder in mothers of children with CHB. Mothers of children with isolated heart block detected after the newborn period do not, as a group, have clinical features suggestive of autoimmune diseases.
11128699 Approaches to the treatment of Sjögren's syndrome. 2000 Dec Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by complaints of sicca symptoms (dry eye and mouth) and can be associated with other autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis, etc). As a result, SS can be difficult to diagnose. Currently, there are several criteria standards for SS, including the San Diego criteria and the European Study Group criteria. According to the San Diego criteria, the incidence of SS is about 0.5%, whereas for the European Study Group it ranges from 3% to 5%. This almost 10-fold difference in SS incidence has led to confusion for both the clinician and researcher. The tearing reflex involves a neural loop in which afferent nerve signals from the ocular surface are relayed centrally to the medulla. The input from the afferent nerves is then processed and sent back via efferent nerves stimulating blood vessels and secretory glands to provide and pump water for tears. Immune factors, such as cytokines, have a profound effect on the tearing mechanism by damaging secretory glands and releasing antibodies to influence the response of muscarinic M3 receptors. Thus, the interaction of neural and immune factors affects the secretory response of glands and contributes to the pathogenesis of SS sicca symptoms. The recent development of muscarinic agonists, such as pilocarpine and cevimeline, serves an important step in recognizing the interaction between the immune and neuroendocrine systems.
10485649 Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an I 1999 Aug PD-1, a 55 kDa transmembrane protein containing an immunoreceptor tyrosine-based inhibitory motif, is induced in lymphocytes and monocytic cells following activation. Aged C57BL/6(B6)-PD-1(-/-) congenic mice spontaneously developed characteristic lupus-like proliferative arthritis and glomerulonephritis with predominant IgG3 deposition, which were markedly accelerated by introduction of a Fas mutation (lpr). Introduction of a PD-1 null mutation into the 2C-TCR (anti-H-2Ld) transgenic mice of the H-2(b/d) background resulted in the chronic and systemic graft-versus-host-like disease. Furthermore, CD8+ 2C-TCR+ PD-1(-/-) T cells exhibited markedly augmented proliferation in vitro in response to H-2d allogenic cells. Collectively, it is suggested that PD-1 is involved in the maintenance of peripheral self-tolerance by serving as a negative regulator of immune responses.
10589572 Thin-section CT findings in rheumatoid arthritis-associated lung disease: CT patterns and 1999 Nov PURPOSE: The purpose of this study was to describe the long-term follow-up CT evaluation in rheumatoid arthritis (RA)-associated lung disease. METHOD: Thin-section CT scans from 29 patients with RA and suspected associated lung disease were reviewed. Twenty-two patients underwent sequential CT evaluation during 3 to 108 months of follow-up (mean 28 months). Histologic comfirmation of pulmonary involvement was available in 19 patients. RESULTS: Three major patterns were identified: reticulation with or without honey-combing (n = 19), centrilobular branching lines with or without bronchial dilatation (n = 5), and consolidation (n = 5). Reticulation and centrilobular branching lines corresponded to usual interstitial pneumonia (n = 14) and bronchiolitis obliterans (n = 1), respectively. Consolidation corresponded to bronchiolitis obliterans organizing pneumonia (BOOP; n = 3) and coexistent chronic eosinophilic pneumonia (CEP) and BOOP (n = 1). Patients with reticulation had rapid deterioration when there was new appearance of multifocal areas of ground-glass attenuation. Centrilobular branching lines progressed to bronchiectasis in one case. There was mild progression of existing bronchiectasis associated with centrilobular branching lines in one case. Area of consolidation in two patients with BOOP and one with coexistent CEP and BOOP evolved into honeycombing at serial CT. CONCLUSION: Thin-section CT is a noninvasive technique for monitoring disease morphology in RA-associated lung disease. Initial CT findings and their evolution on sequential examinations may be useful in evaluating prognosis.
9224247 Wear particulate species and bone loss in failed total joint arthroplasties. 1997 Jul The aim of this study was to evaluate the relative contribution of polyethylene, metal, and polymethylmethacrylate (cement) particles to the overall bone loss in aseptic loosening. Twenty-four interface tissues with adjacent bone were obtained during 17 revision total joint arthroplasties (11 hips and six knees). Osteoclasts and macrophages were identified immunohistochemically on the bone surface. The length of the bone surface in contact with these cell types was measured and analyzed with reference to the particulate species present within the fibrous interface. The presence of abundant polyethylene particles significantly increased the proportion of the bone surface in contact with macrophages but did not have a significant influence on that of osteoclasts. Osteoclastic bone resorption was significantly more extensive in the presence of metal particles. In contrast, the presence of cement particles did not have a significant influence on macrophage or osteoclast coverage of the bone surface. These results highlight the significance of polyethylene particles in macrophage recruitment and subsequent osteolysis and suggest a different mechanism of bone loss related to metal, namely mediation through osteoclastic activities. The relative contribution of cement particles was negligible and needs reevaluation in light of evidence provided by others.
9438085 Improved range of flexion after total knee arthroplasty. The total condylar knee versus th 1997 One objective of the modification of the total condylar knee is to increase the range of flexion without compromising the durability of the prosthesis. The KU knee prosthesis was designed to improve postoperative range of motion. This prosthesis has a unique ball-and-socket joint in the center of the posterior portion of the femorotibial articulation. A retrospective comparative study was undertaken to determine whether the KU knee prosthesis had achieved its design objectives. The study was based on the clinical observation of two populations: one (the TC group: 31 joints) with total condylar prostheses and the other (the KU group; 31 joints) with KU knee prostheses. At two years postoperatively, the mean postoperative range of flexion was 94 degrees (range: 60 degrees to 120 degrees) in the TC group and 120 degrees (range: 95 degrees to 150 degrees) in the KU group. The mean postoperative range of flexion was 24 degrees better in the KU group than in the TC group (p < 0.01). The mean functional score was 76 points (range: 61 to 86) in the TC group and 81 points (range: 56 to 92) in the KU group. There were no statistically significant difference in pain, walking ability, deformity, extension lag, and activities of daily living (ADL) score between the two groups. However, a statistically significant difference was detected in the range of motion (ROM) score (p < 0.01). No major complications occurred in either of the two groups. Although the follow-up period was not long enough, the KU knee was thought to be a promising modification of the total condylar knee prosthesis.
11053058 Leflunomide: mode of action in the treatment of rheumatoid arthritis. 2000 Nov Leflunomide is a selective inhibitor of de novo pyrimidine synthesis. In phase II and III clinical trials of active rheumatoid arthritis, leflunomide was shown to improve primary and secondary outcome measures with a satisfactory safety profile. The active metabolite of leflunomide, A77 1726, at low, therapeutically applicable doses, reversibly inhibits dihydroorotate dehydrogenase (DHODH), the rate limiting step in the de novo synthesis of pyrimidines. Unlike other cells, activated lymphocytes expand their pyrimidine pool by approximately eightfold during proliferation; purine pools are increased only twofold. To meet this demand, lymphocytes must use both salvage and de novo synthesis pathways. Thus the inhibition of DHODH by A77 1726 prevents lymphocytes from accumulating sufficient pyrimidines to support DNA synthesis. At higher doses, A77 1726 inhibits tyrosine kinases responsible for early T cell and B cell signalling in the G(0)/G(1) phase of the cell cycle. Because the immunoregulatory effects of A77 1726 occur at doses that inhibit DHODH but not tyrosine kinases, the interruption of de novo pyrimidine synthesis may be the primary mode of action. Recent evidence suggests that the observed anti-inflammatory effects of A77 1726 may relate to its ability to suppress interleukin 1 and tumour necrosis factor alpha selectively over their inhibitors in T lymphocyte/monocyte contact activation. A77 1726 has also been shown to suppress the activation of nuclear factor kappaB, a potent mediator of inflammation when stimulated by inflammatory agents. Continuing research indicates that A77 1726 may downregulate the glycosylation of adhesion molecules, effectively reducing cell-cell contact activation during inflammation.
11176545 The Work Limitations Questionnaire. 2001 Jan OBJECTIVE: The objective of this work was to develop a psychometrically sound questionnaire for measuring the on-the-job impact of chronic health problems and/or treatment ("work limitations"). RESEARCH DESIGN: Three pilot studies (focus groups, cognitive interviews, and an alternate forms test) generated candidate items, dimensions, and response scales. Two field trials tested the psychometric performance of the questionnaire (studies 1 and 2). To test recall error, study 1 subjects were randomly assigned to 2 different questionnaire groups, a questionnaire with a 4-week reporting period completed once or a 2-week version completed twice. Responses were compared with data from concurrent work limitation diaries (the gold standard). To test construct validity, we compared questionnaire scores of patients with those of healthy job-matched control subjects. Study 2 was a cross-sectional mail survey testing scale reliability and construct validity. SUBJECTS: The study subjects were employed individuals (18-64 years of age) from several chronic condition groups (study 1, n = 48; study 2, n = 121) and, in study 1, 17 healthy matched control subjects. MEASURES: Study 1 included the assigned questionnaires and weekly diaries. Study 2 included the new questionnaire, SF-36, and work productivity loss items. RESULTS: In study 1, questionnaire responses were consistent with diary data but were most highly correlated with the most recent week. Patients had significantly higher (worse) limitation scores than control subjects. In study 2, 4 scales from a 25-item questionnaire achieved Cronbach alphas of > or = 0.90 and correlated with health status and self-reported work productivity in the hypothesized manner (P < or = 0.05). CONCLUSIONS: With 25 items, 4 dimensions (limitations handling time, physical, mental-interpersonal, and output demands), and a 2-week reporting period, the Work Limitations Questionnaire demonstrated high reliability and validity.
10562307 Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from 1999 Nov During immune responses, antigen-presenting cells (APCs) process antigens and present peptide epitopes complexed with human leukocyte antigen (HLA) molecules. CD4 cells recognize these naturally processed and presented epitopes (NPPEs) bound to HLA class II molecules. Epitope identification is important for developing diagnostic and therapeutic tools for immune-mediated diseases and providing insight into their etiology, but current approaches overlook effects of natural processing on epitope selection. We have developed a technique to identify NPPEs using mass spectrometry (MS) after antigen is targeted onto APCs using a lectin-based antigen delivery system (ADS). We applied the technique to identify NPPEs of the intracellular domain of the type 1 diabetes mellitus-associated (type 1 DM-associated) autoantigen insulinoma-associated-2 (IA-2ic), presented by HLA-DR4 (0401). IA-2ic-derived NPPEs eluted from HLA-DR4 constitute 6 sets of peptides nested around distinct core regions. Synthetic peptides based on these regions bind HLA-DR4 and elicit primary T-cell proliferation frequently in HLA-DR4-positive type 1 DM patients, but rarely in non-HLA-DR4 patients, and in none of the HLA-DR4 nondiabetic controls we tested. This flexible, direct approach identifies an HLA allele-specific map of NPPEs for any antigen, presented by any HLA class II molecule. This method should enable a greater understanding of epitope selection and lead to the generation of sensitive and specific reagents for detecting autoreactive T cells.
9433874 Recognition of rheumatoid arthritis synovial antigen by CD4+,CD8- T cell clones establishe 1998 Jan OBJECTIVE: To investigate the rheumatoid arthritis (RA)-specific autoantigen(s) recognized by CD4+ T cells in patients with RA. METHODS: CD4+,CD45RO+ T cell clones were established from the joints of RA patients, and were examined for their proliferative response to synovial cells. RESULTS: Eight of 146 T cell clones responded to RA synovial cells in a DR-restricted manner. These T cell clones recognized solubilized antigens extracted from RA synovial cells in the presence of DR-matched antigen-presenting cells, but did not respond to those extracted from non-RA synovial cells. The antigens had a molecular weight of 50/25 kd. Five of the 8 T cell clones used T cell receptor BV6, and the remaining clones used BV12.2. CONCLUSION: The antigens recognized by joint-infiltrating CD4+ T cells are present exclusively in RA synovial cells. The expression of these antigens by synovial cells may trigger the autoreactivity of T cells in RA joints.
9235810 [Detection of dsDNA antibodies in diagnosis of systemic lupus erythematosus--comparative s 1997 Mar Antibodies to double-stranded DNA (anti-dsDNA, dsDNA-Ab) are frequently found in systemic lupus erythematosus (SLE), especially during active disease and differ with respect to immunoglobulin class and avidity. The detection of anti-dsDNA is one of the diagnostic criteria for SLE according to the American College of Rheumatology (ACR). Most of the commercial ELISA test systems have great advantages in routine laboratory testing but often detect dsDNA-Ab which are not specific for SLE and therefore give false positive results for non-SLE patients. The newly developed ELISA presented here, using human recombinant dsDNA (h-Rek) is compared to two commercial ELISA tests with genomic dsDNA from salmon testes (L-dsDNA) or plasmid dsDNA (P-dsDNA) and to the Chrithidia luciliae immunofluorescence test (CLIF) as well. In this study 143 sera were tested, 48 derived from patients with SLE, 40 from rheumatoid arthritis patients, 26 from non-rheumatoid patients whose sera were ANA-negative but L-dsDNA-Ab-positive and 30 from healthy volunteers. All patients were followed and clinically defined by the rheumatology outpatient clinic of our hospital. The prevalence for SLE of all sera was 32%. The sensitivity was 0.73 (h-Rek), 0.83 (L-dsDNA), 0.81 (P-dsDNA) and 0.57 (CLIF); specificity was determined 0.84 (h-Rek), 0.62 (L-dsDNA), 0.63 (P-dsDNA) and 0.98 (CLIF). The diagnostic efficiency of the L-dsDNA- and P-dsDNA-assay was identical, 0.69, and amounted to 0.81 for the h-Rek and 0.84 for the CLIF. Comparing all the ELISA tests and CLIF, the human recombinant dsDNA ELISA is much more sensitive than the CLIF, but considerably more specific than the ELISA assays using genomic or plasmid DNA, whereas the diagnostic efficiency is very close to that of the CLIF. This new generation of anti-dsDNA ELISA using human recombinant dsDNA seems to be a much better diagnostic tool for the detection of highly specific anti-dsDNA antibodies in the diagnosis of SLE than other commercial ELISAs. These results can only be explained by the use of a human recombinant antigen instead of undefined genomic or recombinant plasmid DNA for immobilization.
11507123 Thirty-day mortality after total knee arthroplasty. 2001 Aug BACKGROUND: There have been sporadic reports on perioperative mortality associated with total knee arthroplasty. The purpose of this study was to determine risk factors for such mortality. METHODS: A computer-assisted review of the records of 22,540 consecutive patients who had undergone total knee arthroplasty between 1969 and 1997 was performed to identify all patients who had died within thirty days after the procedure. A detailed analysis of the medical, surgical, anesthetic, and pathological records of the patients was performed, and the mortality was determined according to age, gender, diagnosis, and fixation method. RESULTS: The rate of mortality within thirty days after the operation was 0.21% (forty-seven of 22,540). All deaths occurred in the group of 18,810 patients who had received a cemented implant, and no deaths occurred among the 3730 patients who had received an uncemented implant (p < 0.0001). The mortality rate was 0.24% (forty-three of 18,165) after primary arthroplasty and 0.09% (four of 4375) after revision arthroplasty (p < 0.0003). Three patients (0.01%) died during the operation. Forty-three of the forty-seven patients who died had a history of preexisting cardiovascular and/or pulmonary disease. Simultaneous bilateral total knee arthroplasty was associated with a significantly higher rate of perioperative mortality (p < 0.002). CONCLUSIONS: Factors that were associated with a significantly increased mortality after total knee arthroplasty included an age of more than seventy years, primary (as compared with revision) knee surgery, use of a cemented prosthesis, preexisting cardiopulmonary disease, and simultaneous bilateral arthroplasty.
9256165 Inhibition of extracellular release of proinflammatory secretory phospholipase A2 (sPLA2) 1997 Jun 15 Sulfasalazine is widely used in rheumatoid arthritis and inflammatory bowel diseases. The mechanisms of its activity have not been elucidated. In leukocytes, sulfasalazine and its analogue, CL 42A, inhibited the formation of leukotrienes and possibly of the second messenger compounds at the level of phospholipase C. Partial inhibition of interleukin-lbeta (IL-1beta), IL-6 and tumor necrosis factor-alpha (TNF-alpha) was also found. Since the synthesis of eicosanoids is induced by phospholipase A2 and since secretory phospholipase A2 (sPLA2) is proinflammatory, we investigated the impact of sulfasalazine and related compounds on mRNA, protein synthesis, and release of sPLA2 from osteoblasts. Sulfasalazine and CL 42A markedly inhibited extracellular release of sPLA2. The impact of sulfasalazine was evident at 50 microM (P < 0.001) and maximal at 400 microM, and that of CL 42A at 10 microM (P < 0.001) and 200 microM, respectively. Split products of sulfasalazine, 5-aminosalicylic acid (400 microM) and sulfapyridine (400 microM), had no impact. The effect of sulfasalazine and CL 42A was evident regardless of whether the cells were stimulated with IL-1beta/TNF-alpha, lipopolysaccharide/forskolin, or dibutyryl-cAMP. Sulfasalazine and CL 42A did not alter the level of sPLA2 mRNA. Exposure of stimulated fetal rat calvaria osteoblasts (FRCO) to sulfasalazine did not show accumulation of the intracellular sPLA2 protein as tested by western blot; however, enzymatic activity of PLA2 in disrupted cells was definitely increased. Thus, the impact is on the post-transcriptional release of sPLA2 rather than on the synthesis. There was also an increase in the extracellular release of prostaglandin E2 from FRCO exposed to sulfasalazine or to CL 42A. In contrast, sulfasalazine had no effect on the extracellular release of gelatinase from the cells or on mRNA of cytosolic PLA2 or cyclooxygenase 2. We conclude that the anti-inflammatory activity of sulfasalazine may be related, in part, to the selective inhibition of the extracellular release of proinflammatory sPLA2.
10609815 Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised do 1999 Dec 18 BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclo-oxygenase (COX), which leads to suppression of COX-1-mediated production of gastrointestinal-protective prostaglandins. Gastrointestinal injury is a common outcome. We compared the efficacy, safety, and tolerability of long-term therapy with celecoxib, a COX-1 sparing inhibitor of COX-2, with diclofenac, a non-specific COX inhibitor. METHODS: 655 patients with adult-onset rheumatoid arthritis of at least 6 months' duration were randomly assigned oral celecoxib 200 mg twice daily or diclofenac SR 75 mg twice daily for 24 weeks. Anti-inflammatory and analgesic activity and tolerability were assessed at baseline, every 4 weeks, and at week 24. We assessed gastrointestinal safety by upper-gastrointestinal endoscopy within 7 days of the last treatment dose at centres where the procedure was available. Analysis was by intention-to-treat. FINDINGS: 430 patients underwent endoscopy (celecoxib n=212, diclofenac n=218). The two drugs were similar in management of rheumatoid arthritis pain and inflammation. Gastroduodenal ulcers were detected endoscopically in 33 (15%) patients treated with diclofenac and in eight (4%) in the celecoxib group (p<0.001). The rate of withdrawal for any gastrointestinal-related adverse event, most commonly abdominal pain, diarrhoea, and dyspepsia, was nearly three times higher in the diclofenac-treated group than in the celecoxib group (16 vs 6%; p<0.001). INTERPRETATION: Celecoxib showed sustained anti-inflammatory and analgesic activity similar to diclofenac, with a lower frequency of upper gastrointestinal ulceration or gastrointestinal adverse events, and tolerability was better.
10450509 HLA class II transgenic mice as models of human diseases. 1999 Jun Predisposition to develop various autoimmune disorders has been associated with certain HLA class II molecules but there is a lack of information on the pathophysiological role of HLA genes in conferring susceptibility. Various experimental animal models of autoimmune disease have been studied to address the role of immune response genes. To study the interactions involved between class II molecules (DQ and DR) and define the immunologic mechanisms in various diseases, we generated HLA-DR and DQ transgenic mice that lacked endogenous class II molecules. The HLA molecules in these mice are expressed on the cell surface and can positively select CD4+ T cells expressing various V beta T-cell receptors (TCR). A peripheral tolerance is maintained to transgenic HLA molecules thus indicating that these molecules act as self. Mouse co-stimulatory and accessory molecules can interact with the HLA-peptide-TCR complex leading to efficient T-cell activation. In this review, we describe immunogenetic models for human diseases using these transgenic mice. Our studies show that HLA class II transgene-restricted T cells recognize the immunodominant antigens and peptide epitopes, similar to HLA class II-restricted human T cells. Thus these mice provide powerful tools to understand the role of HLA class II molecules in predisposition and onset of human diseases and to develop immunotherapy and vaccines.
9195520 Interaction between cyclosporin A and nonsteroidal antiinflammatory drugs. 1997 Jun OBJECTIVE: Although cyclosporin A (CyA) has been shown in a series of controlled trials to be of benefit to patients with rheumatoid arthritis (RA), the majority of patients continue to require nonsteroidal antiinflammatory drugs (NSAID) for relief of joint pain and stiffness. Our aim was to determine whether there is a clinically important difference in calculated creatinine clearance when CyA is given concurrently with NSAID with high cyclooxygenase activity (indomethacin and ketoprofen) compared with sulindac, which has been claimed to have fewer renal effects than other NSAID, and compared with a simple analgesic, paracetamol. METHODS: Patients with RA started 2.5 mg/kg CyA/day and dosage was increased cautiously to 5 mg/kg/day or less if the serum creatinine rose by > or = 30% above baseline. The mean stabilized dose was 171.43 +/- 48.94 mg/day. Once CyA dose was stabilized, patients were allocated in random order to possible sequences of 4 week periods of acetaminophen, indomethacin, ketoprofen, and sulindac. Monitoring of cyclosporine levels, nephrotoxicity, and hepatoxicity, and adjustment of doses were by an "unblinded" clinician not in direct contact with study patients. All other assessments were made by a "blinded" clinician. Patients were instructed to take the identical appearing gelatin capsules qid. The multiple crossover design was analyzed using analysis of variance procedures for repeated measures. RESULTS: 35 patients were enrolled, of whom 32 patients completed the acetaminophen and at least one course of NSAID. The calculated creatinine clearance was increased by 2.79 ml/min (3.5%) on average for acetaminophen versus all 3 NSAID (6% for indomethacin, 2.3% for ketoprofen, 2.6% for sulindac). The study had adequate power to detect a true difference of more than 10% in mean creatinine clearance for each major comparison. CONCLUSION: NSAID studied did not produce a clinically important difference in the calculated creatinine clearance in these patients-the difference with acetaminophen was modest and not of clinical significance. There is no evidence that any of the 3 NSAID studied have an advantage or disadvantage. It seems reasonable to allow patients to continue an NSAID of their or their clinician's choice.
11309159 Analysis of Ig kappa light chain gene variable regions expressed in the rheumatoid synovia 2001 May Sequence analysis of antibody variable (V) regions can provide an insight regarding whether B cells have gone through an antigen-driven process of affinity maturation. In this study, we analyzed 16 V-regions of immunoglobulin (Ig) kappa light chain genes obtained from a cDNA library of a rheumatoid arthritis (RA) synovial tissue. A salient feature of our results is the high frequency utilization of germline V kappa I family genes, especially the O2/O12 gene (38%). All kappa V-regions showed extensive somatic hypermutation with 5.4% of an average mutation rate. Replacement to silent mutation (R/S) ratio in the complementarity determining region (CDR) was > 2.9 in 12 out of 16 clones, indicating that the majority of the RA synovial B cells had undergone affinity maturation. However, the four other clones showed R/S ratios of < 2.9 in the CDR despite a high mutation rate. In contrast to the previous reports, long CDR3 was not a characteristic feature of these clones. In summary, these data show the high frequency utilization of the germline O2/O12 gene and a high rate of mutation with an evidence of antigen selection in most of the Ig kappa genes expressed in the RA synovium.
10816508 Bacterial cell wall-induced arthritis: chemical composition and tissue distribution of fou 2000 Jun To study what determines the arthritogenicity of bacterial cell walls, cell wall-induced arthritis in the rat was applied, using four strains of Lactobacillus. Three of the strains used proved to induce chronic arthritis in the rat; all were Lactobacillus casei. The cell wall of Lactobacillus fermentum did not induce chronic arthritis. All arthritogenic bacterial cell walls had the same peptidoglycan structure, whereas that of L. fermentum was different. Likewise, all arthritogenic cell walls were resistant to lysozyme degradation, whereas the L. fermentum cell wall was lysozyme sensitive. Muramic acid was observed in the liver, spleen, and lymph nodes in considerably larger amounts after injection of an arthritogenic L. casei cell wall than following injection of a nonarthritogenic L. fermentum cell wall. The L. casei cell wall also persisted in the tissues longer than the L. fermentum cell wall. The present results, taken together with those published previously, underline the possibility that the chemical structure of peptidoglycan is important in determining the arthritogenicity of the bacterial cell wall.
10955326 Low dose weekly methotrexate in early pregnancy. A case series and review of the literatur 2000 Aug OBJECTIVE: To assess the teratogenic risk of low dose weekly pulses of methotrexate (MTX) inadvertently taken during the first trimester of pregnancy. METHODS: We assessed pregnancy and neonatal outcome of 4 patients with rheumatic disease treated with weekly pulses of 5 to 15 mg of MTX for a mean duration of 4 years. RESULTS: The 4 patients had continued MTX treatment from one to 6 weeks of gestation. One patient miscarried at Week 6, the other pregnancies ended with the delivery of healthy children. Chromosome analysis of one child was normal. CONCLUSION: In spite of the absence of congenital anomalies in our cases, safe contraception in fertile patients who start low dose weekly MTX is mandatory.