Browse

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

ID PMID Title PublicationDate abstract
11426322 Allele-specific quantification of tumor necrosis factor alpha (TNF) transcription and the 2001 May Interindividual variation in the expression of tumor necrosis factor alpha (TNF) suggests the existence of functionally distinct TNF alleles that could play a role in susceptibility to TNF associated diseases such as rheumatoid arthritis (RA). To determine whether differential expression of TNF alleles exists, the relative contribution of TNF alleles in total TNF RNA production in peripheral blood mononuclear cells (PBMC) of healthy individuals and synovial tissue of RA patients was analyzed. By using a Tai I restriction fragment length polymorphism (RFLP) located at position +489 in the first intron of the gene, the relative contribution of each allele in precursor transcript production in heterozygous individuals could be measured. By means of this method we studied whether differences exist between TNF alleles in TNF pre-mRNA production. The relative contribution of TNF alleles to the non-spliced RNA pool was measured in PBMC of healthy individuals which were stimulated with LPS, PMA and anti-CD3 and anti-CD28 monoclonal antibodies for different time periods. Moreover, synovial biopsy material of RA patients was analyzed. The results of this study do not reveal a difference in the contribution of distinct TNF alleles in TNF pre-mRNA production upon in vitro and physiological stimulation conditions in healthy individuals and RA patients. Since some of the individuals whose PBMC were tested were also heterozygous for either -308, -1031, -863, -857 TNF promoter/enhancer single nucleotide polymorphisms (SNPs), the data argue against functional relevance of these TNF promoter/enhancer SNPs in the regulation of transcription. In conclusion, the data do not provide evidence for the existence of transcriptionally distinct TNF alleles to explain interindividual variation in TNF expression.
9778959 [Slowly progressive IDDM with rheumatoid arthritis and Hashimoto disease in high elderly]. 1998 Jul We report a 79-year-old woman case of slowly progressive IDDM (SPIDDM) with rheumatoid arthritis (RA) and Hashimoto disease. High titer of anti-glutamic acid decarboxylase antibody (GAD) with a value of 16,400 U/ml (normal value: less than 5 U/ml) and deteriorated secretion of insulin, and clinical course led to the diagnosis of SPIDDM. Both anti-islet cell and anti-insulin antibodies were negative. One year prior to the diagnosis, at 78 years of age, she was newly diagnosed with NIDDM and had been medicated with sulfonylurea and voglibose, resulting her glucose levels well-controlled. Four months before admission, a gradual increase of plasma glucose was noticed, while oral hypoglycemic agents were fully administrated. On admission, her glycemic control was revealed as follows; a fasting blood glucose level of 458 mg/dl and an HbA1 C level of 14.3%. Urinary CPR was 22.5 micrograms day. Her insulin secretion was proved not to be induced with intravenous glucagon injection. Hyperinsulinemic euglycemic glucose clamp test showed the normal glucose uptake ratio; 9.5 mg/kg/min. Moderate doses of subcutaneous insulin (20 units daily) were effective on her diabetes control. She was newly diagnosed with Hashimoto disease that required thyroid hormone replacement 50 micrograms per day after having developed NIDDM. High titer of anti-thyroglobulin antibody (46.9 U/ml) and anti-thyroid peroxidase antibody (81.5 U/ml) were observed. The patient had been medicated for RA with anti-inflammatory drugs since her early seventieth. Rheumatoid factor was elevated to 127.7 IU/L and, anti-nuclear antibody (x 80) and anti-DNA antibody (x 80) were present. It may be of interest that a specific phenotype of HLA; A24 (9) and DR9 recognized to be susceptible to IDDM was detected in the high-elderly onset SPIDDM. Taken together HLA typing with her history of both RA and Hashimoto disease, our case may provide the information to the mechanism of pathogenesis of SPIDDM. Furthermore, to out knowledge, this is the first case of SPIDDM in the aged; 75-year-old or more.
11688778 Tension-band arthrodesis of the small joints of the hand. 2001 Oct A review of 72 cases of tension-band arthrodesis in the small joints of the digits was conducted. Fusion was achieved in all joints with no complications apart from 2 cases of superficial infection. No failure of the hardware was noted, although hardware was removed in 5 patients after fusion was attained due to technical failure or pain. This technique provides immediate skeletal stability, thereby facilitating early digital motion and recovery.
11034663 Transoral decompression, anterior plate fixation, and posterior wire fusion for irreducibl 2000 Oct 15 STUDY DESIGN: Fifteen consecutive patients with irreducible atlantoaxial kyphosis caused by rheumatoid arthritis were treated by combined transoral odontoid resection, anterior plate fixation, and posterior wire fusion. OBJECTIVES: To investigate the clinical results of this new surgical procedure. SUMMARY AND BACKGROUND DATA: Irreducible atlantoaxial kyphosis in rheumatoid arthritis results from a destruction of the craniocervical joint ligaments and the anterior aspects of the lateral atlantoaxial joints. The development of a paradental synovial pannus and atlantoaxial joint impaction prevents reduction by conservative treatment, such as skull traction. Posterior surgical procedures for the treatment of the irreducible atlantoaxial kyphosis with spinal cord compression have been associated with high morbidity and mortality. METHODS: Fifteen consecutive patients were treated by transoral odontoid resection. The fixation was performed with anterior plating, according to the method of Harms in combination with posterior wire fusion according to Brooks. Before and after surgery, evaluation was performed using the parameters of pain (visual analog scale), range of motion, and subjective assessment of improvement and the Health Assessment Questionnaire. The neurologic deficit was defined according to the classifications proposed by Ranawat, Frankel, and Nurwick. Plain radiographs, including lateral flexion and extension views, and magnetic resonance scans were obtained. RESULTS: No perioperative fatality occurred. The average clinical and radiographic follow-up was 50.7 +/- 15.6 months (range, 26-77). Postoperative pain was relieved (mean pain score before surgery, 7.9 +/- 1.87; after surgery, 3.8 +/- 1.27), and the range of motion of all patients increased (mean 21.5 +/- 14.0 degrees for rotation; mean 17.2 +/- 5. 54 degrees for bending). The score on the Health Assessment Questionnaire increased in three patients, remained unchanged in three and decreased in six patients (three had died). All patients improved at least one Ranawat level after surgery, except a patient in Ranawat Class II, whose condition remained unchanged. All patients were satisfied with the procedure and reported subjective improvement. CONCLUSION: Transoral plate fixation combined with posterior wire fixation after transoral odontoid resectionis an effective, reliable, and safe procedure for the treatment of irreducible atlantoaxial kyphosis in rheumatoid arthritis.
10087400 Nucleotide sequences specific for nonnominal immunoglobulin allotypes in rheumatoid arthri 1999 The production of antibodies against nonnominal immunoglobulin allotypes in rheumatoid arthritis (RA) patients suggests that the immune system of these patients has been exposed to such foreign allotypes. The presence of nonnominal allotypes is, however, a genetic enigma. We searched for nucleotide sequences specific for nonnominal G3mg and G3mb copies in individuals homozygous for these alleles. Using a sensitive and specific nested polymerase chain reaction (PCR) method with genomic DNA from blood of 18 RA patients and 5 normal controls, we found G3mg sequences in 18 of 18 tested G3mb homozygous persons. The allele specificity of the PCR fragments was confirmed by sequencing and RFLP analysis. The PCR products contained genomic nonspliced parts of the nonnominal sequences. An analysis of cDNA from inflammatory tissue of 5 RA patients detected nonnominal G3mb sequences in 1 of 3 tested G3mg homozygotes and G3mg sequences in 2 of 2 tested G3mb homozygotes. The cDNA-derived PCR products contained sequences from normally spliced nonnominal Ig fragments. The results also showed that the nonnominal Ig sequences were present in very low copy numbers, lower than the Mendelian 1-2 copies per cell. The origin of such a low copy number of Ig gene fragments may be explained by a virus-mediated capture and transfer mechanism of Ig gene fragments generated by the normal Ig switch-associated gene excision process.
10090195 A practical exercise in reading RA radiographs by the larsen and sharp methods. 1999 Mar A plenary radiograph reading session was conducted prior to the rheumatoid arthritis imaging group sessions to familiarize participants with radiograph scoring methods and their problems, and to introduce the concept of measurement error. After brief reviews on how to score radiographs using the Larsen and Sharp method, photographic slides of metacarpophalangeal joints of 2 patients were shown. Participants were asked to register their absolute scores on paper, and their progression scores on an interactive voting keypad, allowing immediate visualization of the results. The objectives of the session were clearly met, as evidenced by lively discussions in the groups. Participant mean scores agreed well with the expert scores. Sharp scores showed wider scatter between participants than Larsen scores. This was only partially explained by the greater score range inherent in the method. In addition, participants needed more time to score according to Sharp than Larsen. Participants were sensitized to the challenges of radiographic measurement of damage.
9479782 [Complete knee prosthesis in severe genu valgum. Retrospective review of 90 knees surgical 1997 Dec The authors have made a retrospective study of 90 total knee arthroplasties performed through a lateral approach in knees with a valgus deformity superior or equal to 10 degrees. The mean function score increased from 35.9 to 73.2 postoperatively; the mean knee score increased from 60.2 to 93.6. Radiological evaluation of the mechanical angle (HKA) showed 16 degrees of valgus deviation preoperatively versus only 1.5 degrees of valgus post-operatively. A strict operative technique using a lateral approach in severe valgus knee deformity makes it possible to reproducibly achieve joint stability with good mobility and a neutral mechanical axis in total knee arthroplasty.
9603673 Beyond good and bad coping: a multidimensional examination of coping with pain in persons 1997 Winter This article examines the utility of using a multidimensional instrument to assess pain coping in two samples of persons with rheumatoid arthritis (total N = 378). The predictive validity of the newly developed Vanderbilt Multidimensional Pain Coping Inventory (VMPCI), which assesses eleven distinct coping strategies, was compared to that of the previously validated Vanderbilt Pain Management Inventory (VPMI), which assesses the two broad dimensions of active and passive coping. In both samples, the VMPCI demonstrated reliable incremental validity over the VPMI in predicting both positive and negative psychological adjustment, and the predictive ability of the VPMI was highly redundant with that of the VMPCI. Moreover, using the VMPCI, both positive and negative adjustment were related to multiple coping strategies in ways that could not be revealed by the VPMI. These results offer considerable validation to the VMPCI and illustrate the value of assessing coping multidimensionally.
10403260 Estimating the incidence of rheumatoid arthritis: trying to hit a moving target? 1999 Jul OBJECTIVE: To examine the effect of delay between symptom onset and notification to an arthritis register and the effect of application of the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) 1987 criteria in a cumulative manner on estimates of the incidence of rheumatoid arthritis (RA). METHODS: General practitioners and/or hospital consultants in the Norwich Health Authority, Norfolk, UK, notified the Norfolk Arthritis Register (NOAR) of all patients who had onset of inflammatory polyarthritis (swelling of > or =2 joints) during 1990. The patients were assessed within 2 weeks of notification and annually thereafter. The ACR 1987 criteria for RA were applied at each assessment. Age- and sex-specific incidence rates were calculated. RESULTS: If up to 12 months elapsed from symptom onset to notification to NOAR and the ACR criteria were applied at the baseline assessment, RA incidence estimates, age-adjusted to the population of England and Wales, were 30.8/100,000 for women and 12.7/100,000 for men. If up to 5 years elapsed from symptom onset to notification, these estimates rose by 45% for women and 36% for men. If up to 5 years elapsed between symptom onset and notification and the criteria were applied cumulatively, the estimates rose by 75% and 93% for women and men, respectively, compared with the 1-year data, reaching 54.0/100,000 for women and 24.5 per 100,000 for men. CONCLUSION: Accurate estimation of the incidence of RA requires long-term followup of patients who present with undifferentiated inflammatory polyarthritis. The highest age-adjusted estimates from this study are probably the best that are available.
9640129 Effects of patient education on compliance with basic treatment regimens and health in rec 1998 Mar OBJECTIVES: To determine the effects of patient education on compliance and on health in patients with active, recent onset rheumatoid arthritis (RA). METHODS: A randomised, controlled, assessor blinded, one year trial. The experimental group followed an education programme. All patients started on sulphasalazine therapy. Compliance with sulphasalazine was measured by pill counting. Compliance rates with regimens of physical exercise, endurance activities, and energy conservation were measured by questionnaires. Compliance with prescriptions of joint protection was scored using a test for joint protection performance. Health was measured by a Disease Activity Score (function of erythrocyte sedimentation rate, Ritchie score, and number of swollen joints), C reactive protein, Dutch-AIMS scores, and M-HAQ scores, range of motion of shoulder, elbow, and knee joints. Parameters were scored at baseline and after three, six, and 12 months. RESULTS: Sixty of 65 patients gave informed consent, five of them withdrew from follow up. Compliance with sulphasalazine exceeded 80% with no differences between groups. Compliance with physical exercise (at three months), energy conservation (at three and at 12 months), and joint protection (at three months) improved significantly more in the experimental group. The improvements of health were not different in the groups. CONCLUSION: Compliance with sulphasalazine among patients with active, recent onset RA is high, whether formal patient education is followed or not. Compliance with physical exercise, energy conservation, and joint protection was increased by patient education. Formal patient education did not improve health status.
11296977 Development of a matrix of cost domains in economic evaluation of rheumatoid arthritis. 2001 Mar The aim of our study was to comprehensively review and critically appraise the cost domains used in economic evaluations of the rheumatic diseases and to use this information to propose standardization of cost domains. The literature search identified 210 abstracts, 32 of which included original cost data. The listed cost categories were grouped into 3 major areas: (direct) health care costs, other (direct) disease related costs, and productivity costs (indirect costs). The number of individual cost categories was reduced by considering the following criteria: (1) inclusion of all relevant cost domains; (2) avoidance of double counting; (3) summarizing of related categories under one representative heading; (4) feasibility of level of aggregation. After adjustment for synonymous labeling, 38 cost categories remained. The subsequent development of a classification scheme of cost categories led to a set of 19 separate cost domains including 7 outpatient, 3 inpatient, 6 other disease related, and 3 productivity cost domains. This literature review indicates that cost assessment in economic evaluations in rheumatoid arthritis lacks standardization. A preliminary scheme to categorize cost assessment in rheumatic conditions is presented. The adoption of standards for economic evaluation would greatly facilitate national and international comparisons.
11036827 Efficacy of fish oil concentrate in the treatment of rheumatoid arthritis. 2000 Oct OBJECTIVE: To determine the efficacy of fish oil derived (n-3) fatty acid supplementation (3-6 capsules/day) in subjects with rheumatoid arthritis (RA) whose (n-6) fatty acid intake in the background diet was < 10 g/day, compared to olive/corn oil capsule supplement over a 15 week period. METHODS: A placebo controlled, double blind, randomized 15 week study to determine the effect of supplementation on clinical variables in 50 subjects with RA whose background diet was naturally low in (n-6) fatty acids. Fish oil containing 60% (n-3) fatty acids was supplemented at a rate of 40 mg/kg body weight. RESULTS: Analysis of 9 clinical variables indicated there was a significant difference (p < 0.02) between control and treatment groups. Five subjects in the treatment group and 3 in the control group met the American College of Rheumatology 20% improvement criteria. Dietary supplementation resulted in a significant increase in eicosapentaenoic acid in plasma and monocyte lipids in the supplemented group. CONCLUSION: The findings suggest that fish oil supplementation that delivers (n-3) fatty acids at a dose of 40 mg/kg body weight/day, with dietary (n-6) fatty acid intake < 10 g/day in the background diet, results in substantial cellular incorporation of (n-3) fatty acids and improvements in clinical status in patients with RA.
10319827 The effect of arthrocentesis of the temporomandibular joint in patients with rheumatoid ar 1999 May PURPOSE: This study evaluated the objective and subjective changes in a group of rheumatoid arthritic (RA) patients with temporomandibular joint (TMJ) complaints who were subjected to joint lysis and lavage. PATIENTS AND METHODS: Twelve females with previous documented RA underwent baseline assessment with erythrocyte sedimentation rate, physical examination of TMJ function, and a visual analog pain scale (VAPS). The VAPS and jaw function changes were recorded at 2-week intervals for 6 weeks after lysis and lavage under local anesthesia in an ambulatory setting. RESULTS: All patients showed statistically significant post-treatment improvement in their pain, and function was enhanced. CONCLUSION: TMJ arthrocentisis is a useful adjunct in the short-term management of the symptoms of rheumatoid arthritis.
10050739 Discrimination between fluid, synovium, and cartilage in patients with rheumatoid arthriti 1999 Feb PURPOSE: The aim of this study was to compare fat-suppressed T1-weighted 3D-Gradient Echo (GE)-images and conventional T1-weighted contrast-enhanced SE images in the assessment of patients with rheumatoid arthritis in an attempt to improve discrimination of inflamed synovium, joint fluid, and cartilage. PATIENTS AND METHODS: 28 knee joints in 20 patients with rheumatoid arthritis were examined with a 3 D-GE-T1 weighted sequence with frequency-selective fat suppression (Flash 3D fat sat) and T1-weighted SE-sequences after intravenous gadolinium-containing contrast agent administration using a 1.5T system. Differentiation of cartilage, synovium, and joint effusion was assessed on both sequences qualitatively by two observers and quantitatively by signal intensity measurements. RESULTS: Qualititative analysis revealed higher grading rates for cartilage/fluid differentiation with fat-suppressed T1-weighted GE images than contrast enhanced T1-SE images. Quantitative analysis by measurements of contrast-to-noise ratios revealed significantly higher rates for the Flash 3D fat sat with regard to cartilage/fluid discrimination, significantly higher rates for T1-SE post-contrast for cartilage/synovium discrimination, and significantly higher rates for T1-SE post-contrast for synovium/fluid discrimination. CONCLUSION: 3D-GE-imaging with fat-suppressed T1 weighted sequences allows sufficient differentiation of cartilage and joint fluid in patients with rheumatoid arthritis without application of contrast agents and may assist in monitoring disease progression and response to therapy. The higher contrast to noise ratios of cartilage/synovium and synovium/fluid on T1-SE images following administration of gadolinium-containing contrast agents may improve detection of disease activity.
11035136 Pharmacokinetic, pharmacodynamic and clinical effects of a humanized IgG1 anti-CD4 monoclo 2000 Oct BACKGROUND: CD4(+) T cells are important mediators in the pathogenesis of rheumatoid arthritis (RA). In this open-label, dose-escalating study, we examined the pharmacokinetic (PK), clinical, biological and immunological effects of a humanized IgG1 anti-CD4 monoclonal antibody (mAb), 4162W94, in the peripheral blood (PB) and synovial fluid (SF) of RA patients. METHOD: Twenty-four patients in four cohorts (six patients in each cohort) were allocated to be treated with five consecutive daily doses of 4162W94 (10, 30, 100 or 300 mg i.v.). Disease activity was measured by the American College of Rheumatology (ACR) criteria and disease activity score (DAS). We also measured 4162W94 concentration, the percentage of 4162W94-coated CD4(+) lymphocytes, percentage down-modulation of CD4, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFalpha) levels in the PB and SF. RESULTS: A direct relationship between 4162W94 dose, biological response and clinical outcome was seen. Treatment with 10 and 30 mg of 4162W94 for 5 consecutive days resulted in transient coating and down-modulation of CD4(+) lymphocytes, with little effect observed beyond the final dose. However, treatment with 100 and 300 mg resulted in sustained coating and/or down-modulation for 3 weeks and 4 weeks, respectively, in PB and >4 weeks in SF in one patient from the 300 mg cohort. There was a dose-related moderate but transient depression in the CD4(+) lymphocyte count in most patients, with all but three returning to >0.40 x 10(9)/l or >75% baseline by the end of the study period. Significant clinical improvement (ACR 20%) was seen in only 1/6 patients in each of the 10- and 30-mg cohorts; however, 3/6 and 5/5 patients in the 100 and 300-mg cohorts, respectively, were ACR 20% responders. In addition, there were significant reductions in PB acute phase reactants as well as SF IL-6 and TNFalpha concentrations in parallel to clinical improvement. CONCLUSION: Data from this pilot study suggest that 4162W94 is a clinically active novel immunotherapeutic agent that may suppress inflammation in RA.
10364913 Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals progression 1999 Mar OBJECTIVES: To investigate the progression of joint damage in early rheumatoid arthritis (RA) using magnetic resonance imaging (MRI) of the wrist and determine whether this technique can be used to predict prognosis. METHODS: An inception cohort of 42 early patients has been followed up prospectively for one year. Gadolinium enhanced MRI scans of the dominant wrist were obtained at baseline and one year and scored for synovitis, tendonitis, bone marrow oedema, and erosions. Plain radiographs were performed concurrently and scored for erosions. Patients were assessed clinically for disease activity and HLA-DRB1 genotyping was performed. RESULTS: At one year, MRI erosions were found in 74% of patients (31 of 42) compared with 45% at baseline. Twelve patients (28.6%) had radiographic erosions at one year. The total MRI score and MRI erosion score increased significantly from baseline to one year despite falls in clinical measures of inflammation including erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and swollen joint count (p < 0.01 for all). Baseline findings that predicted carpal MRI erosions at one year included a total MRI score of 6 or greater (sensitivity: 93.3%, specificity 81.8%, positive predictive value 93.3%, p = 0.000007), MRI bone oedema (OR = 6.47, p < 0.001), MRI synovitis (OR = 2.14, p = 0.003), and pain score (p = 0.01). Radiological erosions at one year were predicted by a total MRI score at baseline of greater than 13 (OR = 12.4, p = 0.002), the presence of MRI erosions (OR = 11.6, p = 0.005), and the ESR (p = 0.02). If MRI erosions were absent at baseline and the total MRI score was low, radiological erosions were highly unlikely to develop by one year (negative predictive value 0.91 and 0.92 respectively). No association was found between the shared epitope and erosions on MRI (p = 0.4) or radiography (p = 1.0) at one year. CONCLUSIONS: MRI scans of the dominant wrist are useful in predicting MRI and radiological erosions in early RA and may indicate the patients that should be managed aggressively. Discordance has been demonstrated between clinical improvement and progression of MRI erosion scores.
9462354 Knee arthroplasty in rheumatoid arthritis. A report from the Swedish Knee Arthroplasty Reg 1997 Dec The Swedish Knee Arthroplasty Register has data on 4,381 primary operations performed 1985-1995 for rheumatoid arthritis. Of these, 192 were performed with unicompartmental prostheses and 4143 with tricompartmental. 77% were women and the mean age was 66 years. There were 126 first, 20 second, and 1 third revision in tricompartmental arthroplasties, mainly for loosening, infection and patellar problems. There were 38 first, 3 second, and 1 third revision in unicompartmental arthroplasties, mainly for progression of RA and loosening. Cumulative revision rates (Kaplan-Meier) were calculated. Tricompartmental knees had a 10-year cumulative revision rate of 5% and uni-knees 25%. Patients treated before 1990, men and patients younger than 55 had higher revision rates than patients treated after 1990, women and older patients, respectively. Cemented tibial components resulted in lower revision rates than uncemented ones. There was no significant difference in revision rates between patellar replaced and unreplaced knees or between the 9 commonest implant types.
10637962 [Non-steroidal anti-inflammatory drugs and cyclooxygenase-2-specific inhibitors]. 1999 The discovery of two isoenzymes of cyclooxygenase--COX-1 and COX-2--in the late eighties was followed by an intensive looking for drugs, which inhibit specifically COX-2 and have no influence on COX-1. After some years of trial and error it is now possible to measure the inhibition-capacity--e.g. of Rofecoxib, Celecoxib and all the conventional NSAIDs--in a human blood assay. New insights into localisation, expression and physiological function of COX-2 followed. We now are able to differentiate between "conventional" NSAIDs and COX-2 specific inhibitors (CSI, COXIBS), as a new class of substances. CSI firstly inhibit COX-1/COX-2 to a different extent and in a different manner. Secondly they have a different profile concerning unwanted--especially gastrointestinal--side effects. Further experiences and investigations have to confirm and establish this positive risk/benefit ratio.
9818646 Reduction of Th1 cell activity in the peripheral circulation of patients with rheumatoid a 1998 Nov OBJECTIVE: To test the hypothesis that administration of a non-depleting monoclonal antibody (Mab) to CD4 may alter T cell function in patients with rheumatoid arthritis (RA), possibly associated with clinical benefit. METHODS: The patients with RA treated were a subset from a multicenter, placebo-controlled, randomized, double-blind trial and were randomized into one of 2 treatment groups receiving placebo or +/-450 mg of a humanized anti-CD4 Mab (ORTHOCLONE OKTcdr4a) per week for 2 treatment cycles. For the third cycle, patients who had received Mab during the first 2 courses were given placebo, whereas the patients who were originally given placebo received anti-CD4 Mab. To evaluate the impact of anti-CD4 Mab treatment on T cell functions, cytokine production by mitogen-stimulated peripheral blood T cells was monitored, cytokine mRNA levels were assessed in stimulated peripheral blood mononuclear cells (PBMC) by semiquantitative polymerase chain reaction, and clinical activity was also measured during the study. RESULTS: Administration of the anti-CD4 Mab, but not placebo, was followed by an immediate transient clinical benefit accompanied by a significant decrease in C-reactive protein levels. There was no significant change in the number of circulating CD4+ T cells. However, 7 weeks after the second Mab treatment, interleukin 2 (IL-2) and IFN-gamma mRNA levels were significantly reduced in all anti-CD4 Mab treated patients, but neither was reduced in placebo-treated patients. CONCLUSION: Clinical improvement in patients with RA treated with a non-depleting Mab to CD4 may be related to a decrease in the function of IL-2 and IFN-gamma producing Th1 cells.
11196715 Genetic polymorphism of IL-12 p40 gene in immune-mediated disease. 2000 Feb Understanding of the genetic basis of autoimmune diseases is currently incomplete. Cytokine gene polymorphisms warrant consideration as factors explaining variation in the human immune and inflammatory responses and as candidate susceptibility genes for related pathological states. Interleukin 12 (IL-12) is a key regulator of the polarisation of immune responses to T helper 1 or 2 categories and plays a role in autoimmune and infectious diseases. Using a bioinformatic strategy, we aligned cDNA and expressed sequence tag sequences to identify putative polymorphic regions of the IL-12 p40 gene. Position 1188 in the 3' untranslated region (UTR) was polymorphic with the frequency of the common allele around 80% in healthy UK Caucasoids. PCR genotyping of multiple Caucasoid groups and an African group showed significant population variation. In a case-control design, the polymorphism was not associated with rheumatoid arthritis, Felty's syndrome or large granular lymphocyte syndrome with arthritis or multiple sclerosis. A nonsignificant increase in the B allele frequency was observed in the rare large granular lymphocyte syndrome without arthritis (odds ratio 2.02 95% CI 0.95-4.3). This new genetic marker could be useful in anthropological studies and should be investigated in other autoimmune, allergic, inflammatory and infectious diseases.