Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
ID | PMID | Title | PublicationDate | abstract |
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10976085 | Ten year follow up of pulmonary function in patients with primary Sjögren's syndrome. | 2000 Sep | OBJECTIVES: To follow up a previous report on the lung function of patients with primary Sjögren's syndrome (SS), and describe the findings having followed up this cohort for a median duration of 10 years (range 8-12 years). METHODS: 30 patients fulfilling Fox's criteria for definite or probable primary SS were assessed within six months of diagnosis and after a median duration of four and then 10 years by a clinical examination, chest radiograph, and lung function studies (FEV(1), FVC, TLCO, and KCO). RESULTS: At baseline, symptomatic dyspnoea was a common finding, reported by 13/30 patients, of whom two had evidence of fibrosing alveolitis on plain chest radiograph. Five patients had a carbon monoxide transfer factor (TLCO) more than two standardised residuals below the predicted value. After four years' follow up two further patients developed radiological fibrotic changes and there were significant reductions in TLCO (p<0.02) and transfer coefficient (KCO) (p<0.02) compared with the baseline measurements. At 10 years' follow up four patients had died and four were lost to follow up. One patient with fibrosing alveolitis had died from chest disease. There were no further cases of pulmonary fibrosis identified on plain chest radiograph. The lung function studies showed no further deterioration from the results found at year four with significant improvements in both TLCO (p<0.001) and KCO (p<0.001). Those patients who were anti-Ro antibody positive had significantly lower transfer factors than patients with primary SS without this serological marker (p<0.02). CONCLUSION: This long term follow up of lung disease in primary SS is reassuring, and suggests that most patients do not develop progressive lung disease. Pulmonary disease occurs predominantly in anti-Ro antibody positive patients and presents early in the course of the disease. | |
9893680 | [Primary Sjögren's syndrome and glomerulonephritis]. | 1998 Dec 18 | HISTORY AND CLINICAL FINDINGS: An 82-year-old woman with hypertension for 20 years developed a nephrotic syndrome with severe oedema followed by acute oliguric renal failure after a bout of bronchitis and a gastrointestinal infection. She also complained of xerostomia and dry eyes of recent onset. INVESTIGATIONS: Biochemical tests showed a serum creatinine level of 6.1 mg/dl, a 1:5120 antinuclear antibody (ANA) titre, and positive values for Ro(SS-A) and La(SS-B) antibodies. HLA-DR typing demonstrated HLA-DR3 (HLA-DRB1*0301) and DR13 (HLA-DRB1*13) antigens. Renal biopsy revealed minimal glomerular lesions with focal and segmental glomerulo-sclerosis as well as (hypertension-induced) benign nephrosclerosis and focal tubular atrophy with interstitial fibrosis. TREATMENT AND COURSE: After two hemofiltrations and concomitant administration of 100 mg prednisone renal function quickly improved and the proteinuria fell to 1 g/dl. At the same time the xerostomia improved. The nephrotic syndrome recurred 7 months later after the prednisone dose had been reduced to 10 mg/d, but after the dose had been raised to 50 mg/d and cyclosporin A (150 mg/d) had been added a lasting remission occurred and renal function became stable though impaired. CONCLUSION: The relatively rare association of glomerular disease (here focal segmental glomerulosclerosis) with Sjögren's syndrome can, as in this case, be triggered by a viral infection. A genetic predisposition for Sjögren's syndrome is suggested by the demonstration of HLA-DR3 alleles. Administration of steroids is indicated for the treatment of the nephrotic syndrome and, in case of recurrence, can be combined with cyclosporin A. Both drugs also influence the symptoms of Sjögren's syndrome. | |
9021552 | Salivary gland scintigraphy with 99mTc-pertechnetate in Sjögren's syndrome: relationship | 1997 Jan | Salivary gland scintigraphy was performed on 52 patients who were suspected of having Sjögren's syndrome (SS), and the results were compared with clinicopathologic features of the salivary and lacrimal glands. The time-activity curves which were obtained from computer-assisted analysis of 99mTc-pertechnetate (99mTc) scintigraphy were classified into four types (normal, median, flat and sloped types). The stimulated parotid flow rate decreased and the incidence of SS-related sialographic and histopathologic findings increased significantly as the scintigraphic abnormality advanced. In addition, the lacrimal gland function decreased and the proportion of patients diagnosed as having keratoconjunctivitis sicca (KCS) increased significantly as the scintigraphic abnormality advanced. These results indicate that the results of scintigraphy are related not only to the clinicopathologic features of the salivary glands but also to the lacrimal gland function in SS. | |
10930881 | [Imaging of synovial lesions, neoplastic or non-neoplastic]. | 2000 Mar | The purpose of this paper is to present the contribution of imaging in the assessment of synovial diseases, especially in the differentiation between infectious synovitis and rheumatoid arthritis, and in the diagnosis of tumoral and pseudotumoral synovial lesions (idiopathic (osteo)chondromatosis, pigmented villonodular synovitis, synovial hemangioma, lipoma arborescens...). | |
11409666 | Differential efficacy of tumor necrosis factor inhibition in the management of inflammator | 2001 Jun | OBJECTIVE: To evaluate the clinical usefulness of tumor necrosis factor (TNF) inhibitors in patients with inflammatory eye disease that is resistant to conventional immunosuppressive therapies. METHODS: Sixteen patients (4 males and 12 females aged 7 to 78 years) who received etanercept (n = 14) or infliximab (n = 2) for either inflammatory eye disease or associated joint disease were studied retrospectively to determine the effect of these medications on their ocular inflammation. RESULTS: Nine cases of uveitis and 7 cases of scleritis were treated. Systemic diagnoses included rheumatoid arthritis (n = 8), juvenile rheumatoid arthritis (n = 3), ankylosing spondylitis (n = 1), and psoriatic spondylarthropathy (n = 1). Three patients had uveitis without associated systemic disease. Although 12 of 12 patients with active articular inflammation (100%) experienced improvement in joint disease, only 6 of 16 with ocular inflammation (38%) experienced improvement in eye disease. Five patients developed inflammatory eye disease for the first time while taking a TNF inhibitor. No patient discontinued treatment because of adverse drug effects. CONCLUSION: TNF inhibitors are well tolerated immunosuppressive medications that may benefit certain subgroups of patients with inflammatory eye disease, but they appear to be more effective in controlling associated inflammatory arthritis. | |
11277243 | Early postoperative assessment technique: a time-to-remission technique after condylar rep | 2000 Summer | Inconsistencies in reports of clinical outcome occur on many levels. Using life-table techniques for remission can increase reproducibility, facilitate comparisons with other studies, and answer patient questions about rehabilitation time. The complementary rate of Kaplan-Meier's cumulative survival rate was calculated for pain and knee mobility after unicondylar and bicondylar knee replacement in osteoarthritis and rheumatoid arthritis. Pain relief was quick, often within 2 months. Eventually, >50% had attained both pain alleviation and normal mobility. The probability of regaining at least 90 degrees flexion was greater than regaining 0 degrees extension. The probability of increasing the preoperative extension capacity was higher than that of increasing the flexion capacity. | |
11196366 | The CINCA syndrome: a rare cause of chronic arthritis and multisystem inflammatory disorde | 2000 Dec | Chronic infantile neurological cutaneous articular (CINCA) syndrome is a rare disorder with neonatal onset characterised by a chronic progressive inflammatory process with skin rash, articular and central nervous system involvement. This primary systemic inflammatory disorder should be distinguished from juvenile rheumatoid arthritis (JRA). Although the articular findings are characteristic features of CINCA syndrome, there is a certain degree of variability in the articular involvements which are not always symmetrical nor is the degree of severity uniform. The etiology of CINCA syndrome remains unknown. No single treatment has been found to be effective. This syndrome is known in the American medical literature as infantile onset multisystem inflammatory disease (IOMID). | |
12468865 | Multiple joint replacement in chronically neglected polyarthritic patients: Two case repor | 2000 Dec | Multiple joint replacement is a viable option for rehabilitation of young polyarthritic patients with unsalvageable joints. Young polyarthritic patients in this part of the world suffer from chronic neglect because of ignorance, apathy and low socio-economic status. During the period of chronic neglect, these patients acquire extreme deformities of various joints either due to active disease (ankylosing spondylitis, rheumatoid arthritis) or irreversible changes in the joint configuration like ankylosis and soft-tissue contracture. Associated spine and thoracic cage affection create problems for anaesthesia and peri-operative positioning. We report 2 cases of multiple joint replacements for young polyarthritic patients who were bedridden for 6 to 11 years. Surgeries were performed in a phased manner and after extensive rehabilitation both patients were able to walk unaided. Various problems and difficulties encountered have been addressed so as to serve as a guide to surgeons who may have to deal with such unusual situations of chronic neglect. We also report a modified exposure technique without trochanteric osteotomy for total hip replacement, which is valuable in extreme external rotation ankylosis. | |
19078468 | Factors Affecting Patient Satisfaction with Follow-up by a Nurse Practitioner in an Outpat | 2000 Aug | Although nurse practitioners have been shown to be accepted by patients in a rheumatology clinic, variables that could explain differences in acceptability have not been examined in the United States. We surveyed 150 consecutive patients followed up by nurse practitioners concerning satisfaction in 6 areas (empathy with the patient, provision of information, attitude toward the patient, technical competence, accessibility to the caregiver, and overall satisfaction). Patients expressed a high level of satisfaction with follow-up by a nurse practitioner. There was no correlation between satisfaction questionnaire score and age, sex, last grade of school completed, duration of disease, visual analog pain scale score, number of arthritis-related medications, or total number of medications. Satisfaction questionnaire scores were not statistically different between male and female patients, or between patients with rheumatoid arthritis and other patients. Follow-up by a nurse practitioner was widely accepted by our patients, independent of age, sex, duration of disease, or type of disease. | |
9558194 | Refractory hyperglycemia complicating an evolving connective tissue disease: response to c | 1998 Apr | A 33-year-old woman with longstanding rheumatoid arthritis and Sjögren's syndrome developed type B insulin resistance (diabetes mellitus due to anti-insulin receptor antibodies) simultaneous with the evolution of her rheumatic disease to mixed connective tissue disease. Cyclosporine therapy induced a remission of receptor antibody mediated insulin resistance and controlled clinical manifestations of her systemic lupus erythematosus and dermatomyositis, but had no effect on the sclerodermatous features of her illness. | |
9200924 | [Detection of antigen specific T cell clonality in autoimmune diseases and epitope analysi | 1997 Jun | In order to develop an ultimate therapy to overcome autoimmune diseases, it is very important to identify whether or not autoantigen-reactive T cells accumulate in such diseases. A novel method was established to analyze T cell clonality using a combination of reverse transcriptase-polymerase chain reaction of T cell receptor beta chain transcripts and single-strand conformation polymorphism (RT-PCR/SSCP). Using RT-PCR/SSCP, clonal expansion of T cells were identified in NOD mouse, collagen induced arthritis model, rheumatoid arthritis, Crohn's disease, Sjögren's syndrome, bone marrow transplantation, pregnancy, malignant tumors, HTLV-I associated myopathy, and interstitial pneumonia. By using a tandem mass spectrometry or a lymphocytic proliferation assay, T cell epitopes were mapped in NOD mice, EAE, MCTD, and melanoma. | |
9920018 | Salmonella-triggered reactive arthritis: use of polymerase chain reaction, immunocytochemi | 1999 Jan | OBJECTIVE: To investigate whether microbial components are present in the cells of synovial fluid or peripheral blood from patients with Salmonella-triggered reactive arthritis (ReA). METHODS: Synovial fluid cells and/or peripheral blood cells from 23 patients with Salmonella-triggered ReA and from 19 control patients with newly diagnosed rheumatoid arthritis were studied using 3 different polymerase chain reaction (PCR) techniques and immunocytochemical staining. Muramic acid from the synovial fluid was studied by gas chromatography-mass spectrometry. RESULTS: Salmonella chromosomal DNA was not detectable in the synovial fluid cells and peripheral blood leukocytes of patients with Salmonella ReA. Initially, positive reactions were observed in the synovial fluid cells and peripheral blood leukocytes of 3 of 17 and 3 of 18 patients with ReA, respectively, but in the subsequent PCR studies, these findings were not reproducible. Salmonella-specific antigen was detectable by immunofluorescence in the synovial fluid cells and peripheral blood leukocytes of 4 of 11 and 2 of 7 patients with ReA, respectively. Muramic acid was present in 2 of 15 synovial fluid samples from patients with ReA, but the bacterial cultures from synovial fluid were negative. CONCLUSION: These findings indicate the presence of bacterial degradation products, but not bacterial DNA, in the inflamed joints of patients with Salmonella-triggered ReA. | |
10742285 | The role of lipopolysaccharide injected systemically in the reactivation of collagen-induc | 2000 Apr | 1. We investigated the role of bacterial lipopolysaccharide (LPS) in the reactivation of autoimmune disease by using collagen-induced arthritis (CIA) in mice in which autoimmunity to the joint cartilage component type II collagen (CII) was involved. 2. CIA was induced by immunization with CII emulsified with complete Freund's adjuvant at the base of the tail (day 0) followed by a booster injection on day 21. Varying doses of LPS from E. coli were i.p. injected on day 50. 3. Arthritis began to develop on day 25 after immunization with CII and reached a peak on day 35. Thereafter, arthritis subsided gradually but moderate joint inflammation was still observed on day 50. An i.p. injection of LPS on day 50 markedly reactivated arthritis on a dose-related fashion. Histologically, on day 55, there were marked oedema of synovium which had proliferated by the day of LPS injection, new formation of fibrin, and intense infiltration of neutrophils accompanied with a large number of mononuclear cells. The reactivation of CIA by LPS was associated with increases in anti-CII IgG and IgG2a antibodies as well as various cytokines including IL-12, IFN-gamma, IL-1beta, and TNF-alpha. LPS from S. enteritidis, S. typhimurium, and K. neumoniae and its component, lipid A from E. coli also reactivated the disease. Polymyxin B sulphate suppressed LPS- or lipid A-induced reactivation of CIA. 4. These results suggest that LPS may play an important role in the reactivation of autoimmune joint inflammatory diseases such as rheumatoid arthritis in humans. | |
9272307 | Nerve growth factor and autoimmune rheumatic diseases. | 1997 Jul | Nerve growth factor (NGF) is the first discovered and best known neurotrophic factor and is required for the survival and differentiation of a variety of neuronal cell types in both the peripheral and central nervous system. Recent studies indicate that NGF is synthesized by cells of immune system lineage and that its level increases during inflammatory responses, while cytokines such as interleukin-1 beta and tumor necrosis factor-alpha are potent inducers of NGF secretion. The role played by NGF on cells of the immune system was strengthened by recent evidence demonstrating that cells normally present in inflammatory tissues, such as mast cells and lymphocytes, express NGF receptors and are receptive to the action of NGF. Studies carried out in our and other laboratories showed that NGF is expressed in the synovial fluid of patients with rheumatoid arthritis and other forms of chronic arthritis, as well as in the synovium of pharmacologically-induced arthritis in animal models. Moreover, arthritic transgenic mice which carry and express the human tumor necrosis factor-gene also showed elevated levels of NGF. Significant increases in NGF levels have been found in the sera of patients with systemic lupus erythematosus and in the dermis of patients affected by systemic sclerosis. In this paper the hypothesis that NGF is involved in the pathophysiology of autoimmune rheumatic arthritis is discussed. | |
11170291 | Trisomy 7 accumulates with age in solid tumors and non-neoplastic synovia. | 2001 Mar | Trisomy 7 is a common finding in benign and malignant solid tumors, in several non-neoplastic lesions (for example, osteoarthritis and rheumatoid arthritis), and in apparently normal tissues as well, suggesting that the occurrence of +7 might be associated with factors other than the disease process itself. To find out whether the frequency of +7 varies with a patient's age, we cytogenetically analyzed short-term-cultured synovial samples from elderly persons without signs of arthritis and from young patients affected by juvenile chronic arthritis (JCA). In normal synovia, gain of a chromosome 7 was present as a clonal change in five of 10 cases and in single cells in four of the five remaining cases. In synovia from patients with JCA, cells with +7 were detected in only one of nine cases, representing the oldest patient in the series. Furthermore, we reviewed the cytogenetic literature on tumors of the brain, breast, colon, kidney, lung, skin, thyroid, and upper aerodigestive tract. In the majority (six of eight) of these tumor types, the frequency of cases displaying a clone with +7 as the sole aberration increased with age. Taken together, the results presented here suggest that the acquisition of trisomy 7 in some neoplastic and non-neoplastic tissues might be associated with age rather than with disease. The finding of a completely different frequency distribution in two of the tumor types (tumors of the brain and the thyroid gland), however, emphasizes the heterogeneity of +7 and indicates that other, possibly tissue-specific, factors might influence the occurrence of this mutation. | |
11791648 | Absence of pulmonary fibrosis in patients with psoriatic arthritis treated with weekly low | 2001 Nov | OBJECTIVES: To analyse pulmonary toxicity in psoriatic arthritis patients treated with weekly low-dose methotrexate. METHODS: A transversal study was carried out to analyse the findings on chest x-rays and high resolution computed tomography, and the results of pulmonary function tests in 27 Caucasian psoriatic arthritis patients treated with weekly low-dose methotrexate. None of them had previous recognized interstitial lung disease. RESULTS: The median age of the patient cohort was 50 years (range 24-70 years) and the sex ratio was 20M/7F. 17 patients had previously used other disease-modifying antirheumatic drugs. The mean weekly dose of methotrexate was 8.46 mg (range 5-15 mg), the average treatment period was 52 months (range 3-240 months), and the median cumulative dose was 2241 mg (range 300-6520 mg). High resolution computed tomography failed to show alveolar or interstitial involvement in any patient. Diffusing lung capacity for carbon monoxide was mildly altered only in 2 cases. Pulmonary function tests did not show differences between patients with and without recognized risk factors for developing methotrexate-associated lung toxicity identified in rheumatoid arthritis patients (old age, diabetes, hypoalbuminemia, previous use of disease modifying antirheumatic drugs). CONCLUSION: In this cohort of 27 psoriatic arthritis patients methotrexate was not associated with pulmonary fibrosis evaluated by means of sensitive imaging findings and pulmonary function tests. | |
9809357 | Prevalence and clinical presentations of arthritis in HIV-positive patients seen at a rheu | 1998 Oct | OBJECTIVE: To determine the prevalence and clinical presentations of rheumatic manifestations in HIV-infected patients seen at a rheumatology department in Congo-Brazzaville. METHODS: Over a one-year period, all patients admitted to the Brazzaville Teaching Hospital's rheumatology unit underwent serologic testing for the HIV by ELISA confirmed by Western blot. Standard criteria were used to classify the inflammatory joint diseases seen during the study period. RESULTS: A total of 171 patients, 85 men and 86 women, were tested. The age range was 16 to 81 years, with a mean of 42.1 years. HIV tests were positive in 39 patients, 24 men and 15 women, with a mean age of 31.2 years, accounting for 22.8% of the overall patient population and for 35.1% of all patients with inflammatory rheumatic syndromes. HIV infection stage as determined based on Centers for Disease Control criteria was i.v. in 35 patients and II in the remaining four patients. Of the 39 HIV-positive patients, 32 had HIV-related arthritis, two had reactive arthritis, two had staphylococcal septic arthritis and three had infectious discitis. Of the 72 HIV-negative patients with inflammatory rheumatic syndromes, 22 had septic arthritis, 18 had infectious discitis, five had reactive arthritis, four had rheumatoid arthritis, four had gout, two had poststreptococcal rheumatic disease, one had juvenile chronic arthritis and 16 had unclassifiable arthritis. None of the remaining 60 HIV-negative patients had inflammatory joint manifestations. CONCLUSION: HIV infection was both the leading reason for admission and the leading cause of arthritis. Acute, febrile, asymmetric, nondeforming, nonerosive polyarthritis of the small and large joints responsive to nonsteroidal antiinflammatory drug therapy was the most common clinical pattern of arthritis in HIV-positive patients. Reactive arthritis, septic arthritis and infectious discitis were rarely seen and had no specific features as compared to HIV-negative patients. Patients with arthritis should be tested for HIV infection. It follows that rheumatologists need to know how to provide counselling about HIV testing and how to disclose the results to their patients. They also need to be familiar with the management of HIV infection and to direct careful attention to the prevention of HIV transmission in health care facilities. | |
9973156 | Long-term outcomes of an arthritis self-management programme. | 1998 Dec | OBJECTIVE: A previous UK evaluation of the Arthritis Self-Management Programme (ASMP) demonstrated 4 month improvements in physical and psychological well-being including increased arthritis self-efficacy and increased use of self-management behaviours such as cognitive symptom management, and reductions in pain, fatigue and anxiety. The purpose of this study was to determine whether these effects were maintained at 12 month follow-up. METHODS: Twelve month data were collected via self-administered questionnaires mailed to participants who had previously responded prior to attending the ASMP and at 4 months follow-up. RESULTS: The sample (n = 112) comprised 82% women with a mean age of 59.6 (S.D. 12.4) yr and a mean disease duration of 14.9 (S.D. 11.1) yr. The majority of participants had a general practitioner-recorded diagnosis of either rheumatoid arthritis (46%) or osteoarthritis (44%). Many of the changes noted at 4 months were sustained at the 12 month follow-up. CONCLUSION: This first long-term evaluation of a community-based patient education intervention delivered in the UK suggests that after participation in the ASMP, persons with arthritis derive substantial and prolonged benefits in terms of perceived ability to manage arthritis, reduction in pain and improved psychological well-being. | |
10553981 | Skeletal survey of Cayo Santiago rhesus macaques: osteoarthritis and articular plate excre | 1999 Oct | OBJECTIVES: This study was performed to complement studies on spondyloarthropathy in rhesus macaques by quantifying and characterizing another major form of arthritis and contrasting it with osteoarthritis. METHODS: Skeletons of 269 macaques of known age and troop affiliation from the free-ranging Cayo Santiago colony (Caribbean Primate Research Center) were macroscopically surveyed for the presence of articular changes of osteoarthritis, articular plate excrescences, and calcifications that project back over the joint surface in all diarthrodial joints. Statistical tests were used to establish the independence of pathological conditions, age, gender, troop membership, and specific joint involvement. RESULTS: Subchondral articular surface excrescences or calcific plate-like articular surface overgrowth were noted in 17% and osteoarthritis in 18% of Cayo Santiago macaques. Distribution of joint involvement and sex ratio (1:1) of the former condition were independent of either troop membership or the distribution of osteoarthritis. CONCLUSION: Three major forms of arthritis are common in rhesus macaques: osteoarthritis, spondyloarthropathy, and a category that might be referred to as apical plate excrescences (APE). The latter is very different from spondyloarthropathy, rheumatoid arthritis, osteoarthritis, gout, and infectious arthritis. It is quite similar to what in the past has been referred to as the radiographic form of calcium pyrophosphate deposition disease (CPPD) in humans. A new name has not been offered for the identification/categorization of this phenomenon in dry bone. Its occurrence in rhesus macaques appears to present a natural model for characterization of genetic, immunologic, and environmental aspects of this phenomenon. The acronym APE is offered for consideration in naming this category of arthritis in skeletal material. | |
11489951 | Genetic influences on the end-stage effector phase of arthritis. | 2001 Aug 6 | K/BxN T cell receptor transgenic mice are a model of inflammatory arthritis, most similar to rheumatoid arthritis, that is critically dependent on both T and B lymphocytes. Transfer of serum, or just immunoglobulins, from arthritic K/BxN animals into healthy recipients provokes arthritis efficiently, rapidly, and with high penetrance. We have explored the genetic heterogeneity in the response to serum transfer, thereby focussing on the end-stage effector phase of arthritis, leap-frogging the initiating events. Inbred mouse strains showed clear variability in their responses. A few were entirely refractory to disease induction, and those which did develop disease exhibited a range of severities. F1 analyses suggested that in most cases susceptibility was controlled in a polygenic additive fashion. One responder/nonresponder pair (C57Bl/6 x NOD) was studied in detail via a genome scan of F2 mice; supplementary information was provided by the examination of knock-out and congenic strains. Two genomic regions that are major, additive determinants of the rapidity and severity of K/BxN serum-transferred arthritis were highlighted. Concerning the first region, on proximal chromosome (chr)2, candidate assignment to the complement gene C5 was confirmed by both strain segregation analysis and functional data. Concerning the second, on distal chr1, coinciding with the Sle1 locus implicated in susceptibility to lupus-like autoimmune disease, a contribution by the fcgr2 candidate gene was excluded. Two other regions, on chr12 and chr18 may also contribute to susceptibility to serum-transferred arthritis, albeit to a more limited degree. The contributions of these loci are additive, but gene dosage effects at the C5 locus are such that it largely dominates. The clarity of these results argues that our focus on the terminal effector phase of arthritis in the K/BxN model will bear fruit. |