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ID PMID Title PublicationDate abstract
10202010 Binding motifs of copolymer 1 to multiple sclerosis- and rheumatoid arthritis-associated H 1999 Apr 15 Copolymer 1 (Cop 1, poly (Y, E, A, K)) is a random synthetic amino acid copolymer effective in the treatment of relapsing forms of multiple sclerosis (MS). Cop 1 binds promiscuously, with high affinity and in a peptide-specific manner to purified MS-associated HLA-DR2 (DRB1*1501) and rheumatoid arthritis-associated HLA-DR1 (DRB1*0101) or HLA-DR4 (DRB1*0401) molecules. In the present work at least 95% of added Cop 1 could be bound to recombinant "empty" HLA-DR1 and -DR4, and 80% could be bound to HLA-DR2 proteins. Amino acid composition, HPLC profiles, and sequencing patterns of Cop 1 eluted by acid extraction from HLA-DR molecules were similar to those of the unseparated Cop 1. Protruding N-terminal ends of Cop 1 bound to HLA-DR1, -DR2, or -DR4 molecules were then treated with aminopeptidase I, followed by elution, HPLC, and pool sequencing. In contrast to untreated or unbound Cop 1, this material exhibited distinct motifs at some positions with increases in levels of E at the first and second cycles, of K at the second and third cycles, and of Y (presumably at P1 of the bound peptide) at the third to fifth cycles, regardless of the HLA-DR molecule employed. No preference was seen at the following cycles that were mainly A. These first pooled HLA-DR binding epitopes provide clues to the components of Cop 1 that are biologically active in suppressing MS and possibly rheumatoid arthritis.
10809380 Abnormal distribution of CD45 isoforms expressed by CD4+ and CD8+ T cells in rheumatoid ar 2000 Apr CD45RO+ T cells are referred to as memory or helper-inducer while CD45RA+ T cells are regarded as naive or suppressor-inducer T cells. The former population predominates in the peripheral blood and even more in the synovial fluid of patients with rheumatoid arthritis, to the expense of the latter population. Within the CD45RB+ compartment, there appears to be more of the fully-differentiated than of the early-differentiated CD4+ T cells. In spite of the fact that these lymphocytes are close to undergoing apoptosis, this programmed cell death is inhibited in the rheumatoid synovium.
11511756 Serum interleukin-15 is elevated in systemic lupus erythematosus. 2001 Aug OBJECTIVE: To investigate if interleukin-15 (IL-15) (rather than IL-2) is increased in systemic lupus erythematosus (SLE) and might be responsible for immunological abnormalities of SLE such as the increased lymphocytic expression of Bcl-2 and CD25. METHODS: Serum IL-15, IL-2 and tumour necrosis factor (TNF) levels of 65 SLE patients, 20 healthy persons and 10 rheumatoid arthritis (RA) patients were measured by enzyme-linked immunosorbent assay (ELISA). For 25 SLE patients, the percentage of CD25 + lymphocytes and the lymphocytic Bcl-2 levels were simultaneously determined by fluorocytometry. Peripheral blood mononuclear cells (PBMC) of 15 SLE patients were incubated with or without recombinant IL-15 and the influence on Bcl-2 and CD25 was determined. RESULTS: IL-15 was found to be elevated in 25 SLE sera (38%), but in none of the 20 healthy sera (P = 0.0005) and none of the 10 RA sera. Both lymphocyte CD25 and Bcl-2 expression significantly correlated with serum IL-15 and were increased by recombinant IL-15. CONCLUSION: Serum IL-15 may in part be responsible for the immunological abnormalities seen in active SLE.
11469458 Characterization of changes in IgG associated oligosaccharide profiles in rheumatoid arthr 2001 Jul OBJECTIVE: To investigate fluorophore linked carbohydrate electrophoresis (FCE) as a method of analyzing serum immunoglobulin G (IgG) oligosaccharides in healthy individuals and those with rheumatic disease and compare with lectin binding assays of carbohydrate composition. METHODS: IgG was isolated from patients with rheumatoid arthritis (RA) (n = 21), ankylosing spondylitis (AS) (n = 20), psoriatic arthritis (PsA) (n = 20), and healthy adults (n = 36). IgG oligosaccharides were released enzymatically, fluorescently labelled using 8 aminonaphthalene-136 trisulfonic acid; and identification of the oligosaccharide bands was by stepwise enzymatic degradation. Comparison of FCE was made with lectin binding analysis in which the lectins Ricinus communis (RCA1) and Bandeiraea simplicifolia (BSII) were used to detect galactose (Gal) and N-acetylglucosamine (GlcNAc), respectively. RESULTS: Each disease could be differentiated from healthy adults on the basis of Band 1 asialodigalacto core fucosylated oligosaccharide (gf2) intensity (p = 0.001), but not from each other. Reduced levels of different sugars were associated with specific diseases: reduced gf2 with RA (p < 0.001), PsA (p < 0.001) and AS (p < 0.02), reduced Band 5 disialo-digalacto core fucosylated (a2f) oligosaccharide with AS (p < 0.001), reduced Band 6 disialo-digalacto (a2) oligosaccharide with AS (p < 0.001) and PsA (p = 0.021). All diseases were associated with a significant increase in Band 4 asialo-agalacto core fucosylated oligosaccharide (g0f) (p < 0.001). In RA, FCE band intensities correlated with sugar quantity when identified using lectin binding analysis (p < 0.003). In contrast, there was no correlation between the same bands in healthy individuals. CONCLUSION: FCE is an accurate method of analyzing IgG associated oligosaccharides and reveals unique band patterns or sugar prints associated with healthy adults and patients with RA, PsA, and AS, and comparison with lectin binding analysis suggests undetected RA glycoprotein structural differences. FCE has potential in the early diagnosis and differentiation of rheumatic diseases.
9093771 Elevation of serum ferritin levels as a marker for active systemic lupus erythematosus. 1997 Jan OBJECTIVE: To determine the clinical relevance of serum levels of ferritin in patients with systemic lupus erythematosus (SLE) vs. controls, we assessed the correlations between such levels and clinical disease activity, anti-DNA antibody titer, and serum levels of complement. METHODS: We evaluated 36 patients (3 males and 33 females) with SLE, including 21 patients with active disease. A total of 52 patients (3 males and 49 females) with rheumatoid arthritis (RA) served as controls. In a further study for reproducibility, 15 SLE and 21 RA patients were examined. Serum ferritin levels were measured by a 2-site radioimmunometric assay. Serum levels of C-reactive protein (CRP) were measured semiquantitatively by immunoprecipitation or quantitatively by laser immunonephelometry. Anti-DNA antibody was measured by the Farr assay. CH50 was measured by the hemolytic activity method. RESULTS: The SLE patients exhibited higher serum levels of ferritin and lower serum levels of CRP than the RA patients. Serum levels of ferritin at the active stage of SLE exceeded those at the inactive stage. The levels of serum ferritin in SLE were positively correlated with the anti-DNA antibody titer and negatively correlated with CH50 values. CONCLUSION: Serum levels of ferritin appear to provide a useful marker of disease activity in SLE patients.
10440996 Interference of rheumatoid factor activity by aspartame, a dipeptide methyl ester. 1999 Jul Circulating autoimmune complexes of IgM rheumatoid factors (RF) bound to the Fc portions of normal, polyclonal IgG antibodies are frequently present in humans with rheumatoid arthritis (RA). The sweet tasting methyl ester of L-Asp-L-Phe (aspartame or APM) was found to relieve pain and improve joint mobility in subjects with osteo- and mixed osteo/rheumatoid arthritis [Edmundson, A. B. and Manion, C. V. (1998). Clin. Pharmac. Ther. 63, 580-593]. These clinical observations prompted the testing of the inhibition by APM of the binding interactions of human IgM RFs with IgG Fc regions. The propensity of APM to inhibit IgM RF binding was assessed by competitive enzyme immunoassays with solid-phase human IgG. Ten RA serum samples and three purified monoclonal cryoglobulins, all of which had RF activity, were tested in this system. We found that the presence of APM significantly reduced the binding of IgM RFs. The inhibitory propensity of APM with monoclonal RF cryoglobulins was increased by the addition of CaCl(2) to the binding buffer. Similar inhibition of the binding of RA derived RFs to IgG was observed for Asp-Phe and its amidated derivative, indicating that the methyl ester is not required for APM's interaction with IgM antibodies. A human (Mez) IgM known to bind octameric peptides derived from the Fc portion of a human IgG(1) antibody was tested for binding of dipeptides by the Pepscan method of combinatorial chemistry. The relative binding constants of Asp-Phe and Phe-Asp were ranked among the highest values for 400 possible combinations of the 20 most common amino acids. Possible blocking interactions of APM were explored by computer-assisted docking studies with the model of a complex of an RF Fab with the Fc of a human IgG(4) antibody. Modeling of ternary immune complexes revealed a few key residues, which could act as molecular recognition sites for APM. A structural hypothesis is presented to explain the observed interference with RF reactivity by APM. Extrapolations of the current results suggest that APM may inhibit the binding of IgG in a substantial proportion of IgM RFs. Interference of RF reactivity, especially in RA patients, may alleviate the pain and immobility resulting from chronic inflammation of the joints.
11803732 Increased soluble CD4 molecules and the role of soluble CD4 production in patients with rh 2001 Nov We investigated the concentration of soluble CD4 molecules (sCD4) in serum, and the mechanism of sCD4 production from T lymphocytes, in patients with rheumatoid arthritis (RA). The concentration of sCD4 molecules was determined using a solid-phase enzyme-linked immunosorbent assay method. Using reverse transcription polymerase chain reaction (RT-PCR) techniques, we studied the presence of alternatively spliced mRNA encoding the transmembrane site of CD4, and the mRNA encoding a conservative region of the CD4 binding site of the human immunodeficiency virus (HIV), in the serum of RA patients. Levels of sCD4 found in RA patients were higher than in normal controls (199 U/ml compared with 8.4 U/ml, respectively), and correlated with additional medical parameters. The results of RT-PCR suggested that the higher sCD4 levels may be due to shedding from the cell membrane after protease digestion, not to alternative splicing or a reaction to viral binding to sCD4.
10990216 HFE gene mutations in patients with rheumatoid arthritis. 2000 Sep OBJECTIVE: To investigate the role of C282Y and H63D mutations in HFE gene in susceptibility to rheumatoid arthritis (RA). METHODS: The distribution of C282Y and H63D mutations in patients with RA and in healthy subjects was examined by restriction endonuclease digestion of polymerase chain reaction amplified genomic DNA. RESULTS: The prevalence of C282Y mutation in patients with RA was the same as in healthy controls. In contrast, the distribution of H63D mutation was significantly higher in the total RA patient population and in DRB1 QKRAA/QRRAA epitope positive patients compared to respective groups of controls. Analysis of data showed that (1) both H63D mutation and QKRAA/QRRAA DRB1 epitope are individually associated with RA susceptibility; (2) there is interaction between these 2 factors in development of RA; and (3) both these factors combined have stronger association with RA susceptibility than with these factors individually. CONCLUSION: H63D mutation appears to play a role in pathogenesis of RA. This study is small and must be regarded as preliminary. These data therefore need confirmation from independent studies.
11032962 Cyclooxygenase-2 inhibition and side-effects of non-steroidal anti-inflammatory drugs in t 2000 Nov Inhibition of prostaglandin biosynthesis via inhibition of the fatty acid cyclooxygenase (COX) is the mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs). This results in an inhibition of the inflammatory and pain-producing activities of prostaglandins at a site of tissue injury but also in inhibition of prostaglandin production in the gastrointestinal tract (GI) and platelets, i.e. sites where endogenous prostaglandins are possibly involved in control of physiological functions. The discovery of two COX isoenzymes, COX-1 and COX-2, and the detection of their separate function and regulation, has initiated the search for new and putatively more selective inhibitors of prostaglandin biosynthesis. Specifically, selective inhibitors of COX-2 were developed in order to improve the anti-inflammatory and analgetic specificity and potency of the compounds and to reduce side-effects in the GI tract. Available experimental and clinical data of selective COX-2 inhibitors, including flosulide, celecoxib or rofecoxib, suggest improved gastric tolerance as compared to conventional, non-selective NSAIDs. However, experimental evidence suggests that both, the analgetic and anti-inflammatory action of COX-inhibitors, might also require inhibition of COX-1. COX-2-selective compounds at anti-inflammatory doses might have other side-effects, and for example reduce vascular prostacyclin production. Evidence is accumulating that COX-2 might not only be considered as a putatively detrimental enzyme but rather a highly regulated enzyme that also contributes to tissue protection and is even constitutively expressed in healthy human stomach mucosa. This paper reviews some of these newer aspects of COX-2-selective inhibitors in clinical use and discusses their possible benefits and risks.
10743987 Mortality after total hip replacement: 0-10-year follow-up of 39,543 patients in the Norwe 2000 Feb We have studied the mortality after total hip replacement (THR) of 39,543 patients, having a mean age of 69 years, who were reported to the Norwegian Arthroplasty Register. The median follow-up time was 5.2 (0-10.4) years. 323 of 6201 deaths occurred during the first 60 postoperative days. The patient mortality was compared with the mortality in the Norwegian population, using standardized mortality ratios (SMR). The SMRs were compared and adjusted for age, gender, and other possible confounders in a Cox regression model incorporating the population mortality. We observed a lower mortality in patients with THR than in the Norwegian population (8-year patient mortality was 25%, versus 30% in the corresponding Norwegian population. SMR = 0.81). There was an increased standardized mortality ratio in patients less than 50 years (SMR = 2.50), patients 50-59 years (SMR = 1.16), patients with THR due to rheumatoid arthritis (SMR = 1.48), and patients with femoral neck fracture (SMR = 1.11). The SMR decreased with increasing age at the time of THR surgery. After revision surgery, the SMR was similar to that after the first primary operation, whereas a second primary operation in the opposite hip was associated with a further reduction in the SMR (SMR = 0.65). During the first 60 postoperative days, all patient categories had a higher mortality than the general population (0.8% mortality, SMR = 1.39).
11826734 Nociception, pain, and antinociception: current concepts. 2001 Dec The physiology of nociception involves a complex interaction of peripheral and central nervous system (CNS) structures, extending from the skin, the viscera and the musculoskeletal tissues to the cerebral cortex. The pathophysiology of chronic pain shows alterations of normal physiological pathways, giving rise to hyperalgesia or allodynia. After integration in the spinal cord, nociceptive information is transferred to thalamic structures before it reaches the somatosensory cortex. Each of these levels of the CNS contain modulatory mechanisms. The two most important systems in modulating nociception and antinociception, the N-methyl-D-aspartate (NMDA) and opioid receptor system, show a close distribution pattern in nearly all CNS regions, and activation of NMDA receptors has been found to contribute to the hyperalgesia associated with nerve injury or inflammation. Apart from substance P (SP), the major facilitatory effect in nociception is exerted by glutamate as the natural activator of NMDA receptors. Stimulation of ionotropic NMDA receptors causes intraneuronal elevation of Ca2+ which stimulates nitric oxide synthase (NOS) and the production of nitric oxide (NO). NO as a gaseous molecule diffuses out from the neuron and by action on guanylyl cyclase, NO stimulates in neighboring neurons the formation of cGMP. Depending on the expression of cGMP-controlled ion channels in target neurons, NO may act excitatory or inhibitory. NO has been implicated in the development of hyperexcitability, resulting in hyperalgesia or allodynia, by increasing nociceptive transmitters at their central terminals. Among the three subtypes of opioid receptors, mu- and delta-receptors either inhibit or potentiate NMDA receptor-mediated events, while kappa opioids antagonize NMDA receptor-mediated activity. Recently, CRH has been found to act at all levels of the neuraxis to produce analgesia. Modulation of nociception occurs at all levels of the neuraxis, thus, eliciting the multidimensional experience of pain involving sensory-discriminative, affective-motivational, cognitive and locomotor components.
11128663 Thrombin stimulates cell proliferation in human fibroblast-like synoviocytes in nuclear fa 2000 Dec OBJECTIVE: To examine the effect of thrombin on nuclear factor (NF)-kappaB activation and cell proliferation in synovial cells from patients with rheumatoid arthritis (RA). METHODS: Using cultured human synovial cells from patients with RA, electrophoretic mobility shift assay, [3H]thymidine incorporation assay, and MTT assay were performed. We tested the upregulatory effects of thrombin on NF-kappaB activation and cell proliferation. The effect of thrombin on degradation of IkappaB was analyzed by Western blot. RESULTS: Thrombin transiently induced DNA-binding activity of NF-kappaB, followed by degradation of IkappaBalpha, but not IkappaBbeta1. Moreover, synovial cell proliferation was stimulated by thrombin in a dose dependent manner. The kinetics of synovial cell proliferation induced by thrombin were almost parallel to those of NF-kappaB activation. Supershift analysis revealed that thrombin induced DNA-binding complexes were made up principally of the p65 and p50 Rel family members. Further, protein kinase C inhibitor calphostin C repressed thrombin induced NF-kappaB activation and cell proliferation in synovial cells. CONCLUSION: Thrombin stimulates synovial cell proliferation involved in NF-kappaB activation, at least in part, through a protein kinase C mediated pathway, possibly indicating that thrombin plays an important role in synovial hyperplasia in RA.
10834865 Aggressive treatment in early rheumatoid arthritis: a randomised controlled trial. On beha 2000 Jun OBJECTIVES: To compare three therapeutic strategies using slow acting antirheumatic drugs (SAARDs) in early rheumatoid arthritis (RA), for their disease modifying properties, toxicity, and lag time until treatment effect. METHODS: Patients with recent onset RA from six hospitals were randomly assigned to immediate initiation of one of three treatment strategies: (I) a "mild SAARD with a long lag time" (hydroxychloroquine, if necessary replaced by auranofin); (II) a "potent SAARD with a long lag time" (intramuscular gold, if necessary replaced by D-penicillamine); (III) a "potent SAARD with a short lag time" (methotrexate, if necessary replaced by sulfasalazine). Comparisons included two years of follow up. RESULTS: All SAARD strategies reduced mean disease activity. A greater percentage of patients improved clinically with strategies II and III than with strategy I: percentages of patients improved on joint score with strategies II and III (79% and 82%, respectively), which was statistically different from strategy I (66%). The same was true for remission percentages: 31% and 24% v 16%, respectively). Longitudinal analysis showed significantly less disability with strategy III, and a lower erythrocyte sedimentation rate with strategy II than with strategy I. In addition, radiological damage after one and two years, was significantly lower in strategies II and III (at two years median scores were 11 and 10 v 14 in strategy I, p<0.05). Toxicity was increased in strategy II compared with the other strategies. CONCLUSION: Strategy III, comprising methotrexate or sulfasalazine, produced the best results weighing effectiveness and toxicity. Strategy I (hydroxychloroquine or auranofin) was slightly less effective, and strategy II (intramuscular gold or D-penicillamine) was associated with increased toxicity.
10531772 Study of efficacy and tolerance of ketoprofen and diclofenac sodium in the treatment of ac 1998 Dec A comparative, multi-centre study, was conducted during June to December, 1996 to evaluate the efficacy and tolerance of Ketoprofen 100 mg Enteric Coated (EC) tablet and 100 mg intra-muscular injection; with that of Diclofenac Sodium 50 mg tablet and 75 mg intra-muscular injection in acute rheumatic and traumatic disorders. Total of 180 patients (90 per drug), were studied, 82 men and 98 women, between the ages of 18 and 75 years. The symptoms and the number of patients were backache 50, arthritis 64, frozen shoulder 32 and sprains 34. Pain was qualitatively assessed by visual analogue scale (VAS), XY pain index, pain at mobilization and the level of pain handicap. For pain (VAS 75-100) the treatment was initiated with an injectable bid, followed by tablets bid or tid. If the pain score on VAS was less than 75, tablets were given in a bid dosage. The duration of treatment was 15 days in each case. The overall complete relief of symptoms occurred in 25% (23/90) patients with Ketoprofen and in 10% (9/90) diclofenac sodium. Moderate to mild relief was found in 75% (67/90) cases with Ketoprofen and 87% (78/90) with diclofenac sodium. No pain relief was seen in 3% (3/90) with diclofenac sodium, as against no failure in pain relief in the ketoprofen group. Tolerance was found as excellent-good for ketoprofen in 72% (65/90) with diclofenac sodium in 50%, moderate to poor for ketoprofen in 28% (35/90) and with diclofenac sodium in 50% (45/90). Our results indicate that ketoprofen compared to diclofenac sodium is efficacious in acute rheumatic and traumatic injuries. Ketoprofen injection, compared to diclofenac sodium was found to be more effective in providing analgesia.
11308136 Sjogern's syndrome. 2001 Mar Sjogren's syndrome (SS) is a systemic autoimmune exocrinopathy that affects the salivary and lacrimal glands. It typically presents as the "sicca complex" of dry eyes (xerophthalmia) and dry mouth (xerostomia) along with other symptoms such as arthritis. SS is classified as either primary or secondary. In the primary form, dry eyes and dry mouth occur alone. In the secondary form, the dry eyes and dry mouth occur in the context of another rheumatic disease, most commonly rheumatoid arthritis. There is an increasing list of systemic manifestations affecting the lung, kidney, and nervous system in patients with SS. The skin is affected in half of SS patients. Despite this high frequency of cutaneous involvement, patients with SS are not commonly seen in dermatology practices. SS is underrecognized and underdiagnosed because the cutaneous manifestations are nonspecific (eg, xerosis, pruritus) and less severe than the oral, ocular, or musculoskeletal symptoms. Nonetheless, because of its high prevalence, risk of cutaneous vasculitis, and the increased risk of a lymphoproliferative disorder, it is important for dermatologists to be familiar with SS.
11545624 Analysis of urinary prostacyclin and thromboxane/prostacyclin ratio in patients with rheum 2001 Aug We investigated production of prostacyclin and the urinary ratio of thromboxane and prostacyclin in patients with rheumatoid arthritis. The prostacyclin production level was assessed according to the level of urinary 2,3-dinor-6-keto-prostaglandin F(1 alpha)measuring by gas chromatography/selected ion monitoring. In patients receiving medication, the prostacyclin level was lower and the thromboxane/prostacyclin ratio was greater compare with that of healthy volunteers. The prostacyclin level in patients without medication was approximately 4-fold higher than that of healthy volunteers and 8-fold higher than those of medicated groups. Although the ratio of the group without medication was similar to that of healthy volunteers, the urinary levels of each prostanoid were higher than those of other groups. Then, the ratios of groups receiving steroids were higher than that of other groups owing to high TX level. The present findings demonstrated that endogenous prostacyclin and thromboxane production increased in patients without medication, and prostacyclin production decreased with medication.
11475244 [Leflunomide--the first specific disease-modifying drug against rheumatoid arthritis]. 2001 Feb 7 Rheumatoid arthritis (RA) is a disabling disorder with chronic inflammation leading to significant disability and pain if not treated early and effectively. Leflunomide is the first drug developed and registered specifically for modifying disease course in RA, and is a good complement to other forms of drug therapy currently in use. In clinical trials, leflunomide has been proven to exert an effect on clinical parameters of RA-inflammation superior to placebo and equal to methotrexate and sulphasalazine, while clinical response evidently begins somewhat earlier than on these other drugs. There appears to be a retarding effect on radiographic progression over 13 months comparable to that of methotrexate and sulphasalazine. The very long elimination half-life as well as side effects including nausea, diarrhea, and elevated liver enzymes (almost as frequent as with methotrexate) hamper its usefulness, and its definitive place in modern RA-therapy remains to be established.
11519731 TCR peptide therapy in human autoimmune diseases. 2001 Jun Inflammatory Th1 cells reacting to tissue/myelin derived antigens likely contribute to the pathogenesis of diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), and psoriasis. One regulatory mechanism that may be useful for treating autoimmune diseases involves an innate second set of Th2 cells specific for portions of the T cell receptor of clonally expanded pathogenic Th1 cells. These Th2 cells are programmed to respond to internally modified V region peptides from the T cell receptor (TCR) that are expressed on the Th1 cell surface in association with major histocompatibility molecules. Once the regulatory Th2 cells are specifically activated, they may inhibit inflammatory Th1 cells through a non-specific bystander mechanism. A variety of strategies have been used by us to identify candidate disease-associated TCR V genes present on pathogenic Th1 cells, including BV5S2, BV6S5, and BV13SI in MS, BV3, BV14, and BV17 in RA, and BV3 and BV13S1 in psoriasis. TCR peptides corresponding to the mid region of these BV genes were found to be consistently immunogenic in vivo when administered either i.d. in saline or i.m. in incomplete Freund's adjuvant (IFA). In MS patients, repeated injection of low doses of peptides (100-300 microg) significantly boosted the number of TCR-reactive Th2 cells. These activated cells secreted cytokines, including IL-10, that are known to inhibit inflammatory Th1 cells. Cytokine release could also be induced in TCR-reactive Th2 cells by direct cell-cell contact with Th1 cells expressing the target V gene. These findings indicate the potential of regulatory Th2 cells to inhibit not only the target Th1 cells, but also bystander Th1 cells expressing different V genes specific for other autoantigens. TCR peptide vaccines have been used in our studies to treat a total of 171 MS patients (6 trials), 484 RA patients (7 trials), and 177 psoriasis patients (2 trials). Based on this experience in 824 patients with autoimmune diseases, TCR peptide vaccination is safe and well tolerated, and can produce significant clinical improvement in a subset of patients that respond to immunization. TCR peptide vaccination represents a promising approach that is well-suited for treating complex autoimmune diseases.
11752507 HLA-DQB1 CAR1/CAR2, TNFa IR2/IR4 and CTLA-4 polymorphisms in Tunisian patients with rheuma 2001 Dec OBJECTIVES: To evaluate the contribution of HLA class II region and the CTLA-4 gene in genetic susceptibility to rheumatoid arthritis (RA) and Sjögren's syndrome (SS) in the Tunisian population. METHODS: The polymorphisms of a (CA)n microsatellite of HLA-DQB1 CAR1/CAR2, TNFa IR2/IR4 and an (AT)n microsatellite in the 3'-untranslated region of exon 3 of the CTLA-4 gene were analysed after specific polymerase chain reaction (PCR) amplification. Typing of CTLA-4 A/G exon 1 polymorphism was achieved by the PCR-restriction fragment length polymorphism method. RESULTS: Genomic DNA from 60 patients with RA, 58 patients with SS and 150 healthy individuals was genotyped. The distribution of HLA-DQ CAR1/CAR2 allele frequencies differed between patients and controls in both diseases (RA, P<10(-15); SS, P=7.6x10(-15); RA+SS, P<10(-15)). The analysis of TNFa IR2/IR4 and CTLA-4 A/G polymorphisms did not show any differences in allele or genotype frequencies between patients and control subjects in either disease. The distribution of CTLA-4 (AT)n allele frequencies differed between patients with RA and controls (P=10(-3)), whereas no significant difference was detected between patients with SS and controls. CONCLUSION: These data suggest the involvement of HLA-DQ CAR1/CAR2 polymorphisms in genetic susceptibility to RA and SS and the participation of the CTLA-4 gene, or a gene closely associated with it, in the development of RA.
11358419 How is it best to treat early rheumatoid arthritis patients? 2001 Mar During the past decade, many important changes have occurred in the treatment of rheumatoid arthritis, perhaps the most important of which has been the realization that early diagnosis and early treatment are critical. This has challenged our health-care systems to make sure that patients with early arthritis have access to the appropriate physicians. Additionally, the last decade has also seen many new treatment options become available for patients with rheumatoid arthritis. These new options have included the use of old drugs more effectively; the use of combinations of two or more disease-modifying anti-rheumatic drugs; new evidence to support the use of steroids; the resurrection of tetracyclines; the introduction of leflunomide; and, finally, the tumour necrosis factor inhibitors etanercept and infliximab. The availability of all these new options is clearly excellent news for patients with RA and their physicians. It is hoped that we will, in the next few years, better understand how most effectively to utilize these treatment options for the optimal care of our patients.