[Rheumatoid arthritis. Genetics and histocompatibility].
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Publications and source records attributed to A Balsa.
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OBJECTIVE: To determine which activity indices better correlate with assessor's (AGA) and patient's (PGA) global assessment of disease activity and to compare the improvement with American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria and their association with PGA and AGA of overall improvement. METHODS: Seventy-five patients with rheumatoid arthritis (RA) were studied. Swollen and tender joints, morning stiffness, grip strength, pain, AGA, PGA, Health Assessment Questionnaire (HAQ) score, erythrocyte sedimentation rate (ESR), C-reactive protein (CPR), and hemoglobin were determined before and 6 months after treatment. Several activity indices were calculated: Disease Activity Score (DAS), DAS 3, DAS 28, DAS '28,' ACR > or = 20%, Mallya, Riel, IDA, and a modification of the Stoke index. RESULTS: All indices correlated with PGA and AGA before and after treatment (r > 0.38, p < 0.01), but better results were obtained with AGA than PGA. DAS, DAS 3, DAS 28, and modified Stoke had the best correlation with AGA (r > or = 0.77, p < 0.01). The indices that better detected the differences after treatment for AGA were DAS, DAS 3, DAS 28, and modified Stoke (r > or = -0.42, p < 0.01). The level of agreement between EULAR and ACR improvement classifications with both reduced and extensive joint counts was comparable and its association with PGA and AGA overall improvement was significant (p < 0.01). CONCLUSION: All activity indices correlated with PGA and AGA, although the best results were obtained with AGA. Although indices' correlations were similar, the DAS group and the modified Stoke seemed to be the most useful indices to measure disease activity in RA. The discriminating potential between ACR and EULAR improvement classification was comparable, as was the association with PGA and AGA overall improvement.
OBJECTIVE: To investigate whether the pathogenesis of rheumatoid arthritis (RA) is associated with the functional chemokine receptor CCR5, which is the primary CC chemokine receptor expressed by T cells in rheumatoid synovium, and its nonfunctional receptor, delta32CCR5, which is generated by the homozygous 32-basepair deletion (delta32) in the CCR5 gene. METHODS: The frequency of the CCR5 genotype was compared among 673 patients with RA, 113 patients with systemic lupus erythematosus (SLE), and 815 control subjects. The CCR5 genotype was studied by polymerase chain reaction amplification of the region flanking the delta32 deletion (delta32CCR5). RESULTS: Frequencies of the wild-type CCR5 alleles (0.929, 0.907, and 0.942, respectively) and delta32CCR5 alleles (0.071, 0.093, and 0.058, respectively) in controls, SLE patients, and RA patients did not differ significantly. However, none of the RA patients had the homozygous delta32CCR5 genotype, compared with a frequency of 0.009 in controls (P = 0.014 by Fisher's exact test; chi2 = 4.12 with Yates' correction, P = 0.042) and 0.027 in SLE patients (P = 0.003 by Fisher's exact test; chi2 = 11.63 with Yates' correction, P = 0.0006). CONCLUSION: The results suggest that the CCR5 receptor plays an important role in RA and may be a suitable target for therapy.
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OBJECTIVE: Antiperinuclear factor (APF) is an autoantibody detected in >50% of patients with rheumatoid arthritis (RA); it shows a specificity of roughly 90%. We investigated the possible role of APF as a prognostic marker in RA. METHODS: A series of 103 patients with RA who fulfilled the 1987 American College of Rheumatology criteria (88 women and 15 men; mean age 55.5 yrs, mean disease duration 9 yrs) were prospectively followed. Sixteen variables were assessed in each patient at inclusion and over a 3 year period. APF was determined by indirect immunofluorescence assay using human buccal mucosal cells as substrate. APF assays were done at entry and at the end of followup without knowledge of the clinical status of the patients. Mann-Whitney U, chi-squared tests, variance analysis, and kappa index were used for statistical analysis. RESULTS: Eighty of 103 patients completed followup. APF was detected in 40 of 80. At inclusion, APF correlated with the visual analog scale (VAS) of pain (p = 0.02). However, patients who showed APF positivity at entry had a less favorable course than APF negative individuals, as shown by a worse VAS of well being (p = 0.01), Ritchie index (p = 0.01), number of painful joints (p = 0.03), grip strength (p = 0.01), C-reactive protein (p = 0.04), and Health Assessment Questionnaire score (p = 0.03) at the end of the study. In addition, APF positive patients showed a worse radiological course (p = 0.03). CONCLUSION: Our results suggest APF is a possible marker of poor prognosis in RA.
Rheumatoid arthritis (RA), the most common autoimmune disease, is associated in families with other autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM). Its genetic component has been suggested by familial aggregation (lambdas = 5), twin studies, and segregation analysis. HLA, which is the only susceptibility locus known, has been estimated to account for one-third of this component. The aim of this paper was to identify new RA loci. A genome scan was performed with 114 European Caucasian RA sib pairs from 97 nuclear families. Linkage was significant only for HLA (P < 2.5.10(-5)) and nominal for 19 markers in 14 other regions (P < 0.05). Four of the loci implicated in IDDM potentially overlap with these regions: the putative IDDM6, IDDM9, IDDM13, and DXS998 loci. The first two of these candidate regions, defined in the RA genome scan by the markers D18S68-D18S61-D18S469 (18q22-23) and D3S1267 (3q13), respectively, were studied in 194 additional RA sib pairs from 164 nuclear families. Support for linkage to chromosome 3 only was extended significantly (P = 0.002). The analysis of all 261 families provided a linkage evidence of P = 0. 001 and suggested an interaction between this putative RA locus and HLA. This locus could account for 16% of the genetic component of RA. Candidate genes include those coding for CD80 and CD86, molecules involved in antigen-specific T cell recognition. In conclusion, this first genome scan in RA Caucasian families revealed 14 candidate regions, one of which was supported further by the study of a second set of families.
Factor J (FJ) is a complement inhibitor that is able to regulate in vitro both the classical and alternative human complement pathways. In the search of its biological significance, we have analyzed FJ levels in synovial fluid from patients with different arthropathies, in which IL-6 levels had been previously measured. The pathologies included in this study were: rheumatoid arthritis (RA) (n = 21), crystal deposition diseases (CDD) (n = 6), osteoarthritis (OA) (n = 23), spondyloarthritis (SpA) (n = 3) and other inflammatory arthropathies (OIA) (n = 4). We found a good correlation between IL-6 and FJ levels (r = 0.33, p = 0.0132) in the 57 processed samples. Synovial fluids had high levels of IL-6 (median: 3000 pg/ml). Besides, we found that FJ levels were elevated (241 +/- 429 micrograms/ml) when compared with NHS (5.32 +/- 2.82 micrograms/ml). Considering OA patients as control group for non-inflammatory situation, we found that FJ levels were significantly elevated in inflammatory patients only if RA patients were excluded. Furthermore, there were also significant differences with CDD patients. In addition, we have examined the presence of this inhibitor in synovial fluid by Western blot after running gels at acid pH and electrophoretical transference at the same pH. In these experiments, we evidenced the presence of a cationic protein immunoreactive with polyclonal and monoclonal anti-FJ antibodies. In conclusion, FJ levels are elevated in pathological synovial fluids. FJ could be an acute phase reactant as other molecules present in the synovial fluid, or could be shed from extracellular matrix as a consequence of the high enzymatic activity present in the articular fluid or as a response to the inflammatory stimulus.
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OBJECTIVE: We studied interleukin 6 (IL-6) and soluble IL-6 receptor (sIL-6R) in serum and synovial fluid (SF) to investigate their role in different arthropathies. METHODS: IL-6 was measured by ELISA and bioassay and sIL-6R by ELISA, in 210 sera and 73 SF samples from 49 patients with rheumatoid arthritis (RA), 20 crystal deposition disease, 17 osteoarthritis (OA), 24 with other inflammatory arthropathies, and 100 controls. In all patients, disease activity was assessed by erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); in patients with RA and other arthropathies pain, tender and swollen joints, and Ritchie index were also evaluated. Total leukocyte count in SF was determined. RESULTS: There was good correlation between IL-6 ELISA and bioassay levels both in serum (r = 0.62, p = 0.0001) and in SF (r = 0.72, p = 0.0001). Serum IL-6 was detected only in patients with inflammatory arthritis and SF IL-6 was detected in all patient groups. Serum IL-6 correlated with swollen joints (r = 0.35, p = 0.05), ESR (r = 0.46, p = 0.001), and CRP (r = 0.46, p = 0.001) in RA; and with CRP (r = 0.89, p = 0.0001) in crystal deposition disease. SF IL-6 correlated with ESR (r = 0.54, p = 0.007) and CRP (r = 0.42, p = 0.04) in RA; with SF total leukocyte count (r = 0.61, p = 0.004) in crystal deposition disease; and with SF total leukocyte count (r = 0.61, p = 0.009) in OA. No correlations were found in the group with other inflammatory diseases. No correlations were found between sIL-6R and IL-6 or between sIL-6R and disease activity variables in any group of patients. CONCLUSION: Unlike IL-6, sIL-6R is not produced at the site of inflammation and is not related to clinical or biological disease activity variables. Only in RA are both IL-6 and sIL-6R levels increased, suggesting that sIL-6R may reinforce the systemic effects of IL-6.
CD4+ T-lymphocytes require two signals to become activated--antigen receptor (TcR) occupancy and an antigen-presenting cell (APC)-derived costimulus. The latter may be provided by B7.1 (CD80) or B7.2 (CD86) on APC interacting with CD28 on T-cells. We have studied the expression of these costimulatory molecules in rheumatoid and osteoarthritic synovial membrane. Very few B7.1-positive cells were seen in synovial tissue from either established or early rheumatoid disease, or in rheumatoid arthritis (RA) or osteoarthritis (OA) synovia at arthroplasty. In contrast, B7.2 was readily detected in rheumatoid synovia, predominantly in the lining layer, in a pattern of expression that corresponded to the presence of CD68-positive macrophages. Only occasional B7.2-positive cells were seen in OA synovia. The presence of B7.2 but the relative lack of expression of B7.1 may be partly responsible for the observations of 'frustrated' T-cell activation or T-cell hyporesponsiveness in the rheumatoid synovium.
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The objective of this study was to determine: (1) the diagnostic value of antiperinuclear factor (APF), (2) the types of immunoglobulins involved in the reaction and (3) the presence of the antibody in paired samples of serum and synovial fluid (SF). We studied 408 serum samples from the following: healthy controls (n = 68), patients with rheumatoid arthritis RA; n = 160, 106 RF-positive and 54 RF-negative and patients with other rheumatic diseases (n = 180). We examined paired serum and SF samples in 27 patients (8 with RA and 19 with other rheumatic conditions). APF was determined by an indirect immunofluorescence assay. A group of 30 APF-positive serum samples was incubated with fluorescent-labelled antisera against IgG, IgM and IgA independently. APF was positive in 55.7% of patients with RF-positive RA, in 35.2% of patients with RF-negative RA, in 11.1% of patients with other rheumatic diseases and in 5.9% of healthy controls. Statistical differences were found between RF-positive RA and the other three groups (P = 0.02, P = 0.0001, P = 0.0001, respectively) and between RF-negative RA and the groups of other rheumatic diseases (P = 0.0001) and healthy controls (P = 0.005). The specificity of the test for RA was 90.2%. APF was present in three SF samples from RA patients (37.5%). The reaction was mediated by immunoglobulins of the IgG class in 100% of those tested, and, in addition, 30% were of IgA and 6.7% of IgM classes. We concluded that APF is a good diagnostic test that could be included in the classification criteria of RA, it can be present in SF and it is predominantly an antibody of the IgG class.
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OBJECTIVES: To determine (a) the influence of HIV in developing osteoarticular infections in intravenous drug abusers (IVDAs) and (b) the differences between the clinical features of osteoarticular infections in IVDAs and a control group of non-IVDAs. METHODS: A comparative study of the clinical features of osteoarticular infections in all HIV positive and HIV negative IVDAs admitted to the departments of rheumatology and internal medicine during a 10 year period was carried out. The joint infections of all IVDAs, irrespective of HIV status, were compared with those of a control group of non-IVDAs lacking risk factors for HIV infection. RESULTS: A total of 482 HIV positive and 85 HIV negative IVDAs was studied, in whom 25 (5%) and six (7%) osteoarticular infections were found respectively. There were no differences in age, sex, joints affected, and causative agents between these two groups. A comparison of the 31 (5.5%) osteoarticular infections in all IVDAs with 21 infections in 616 (3.4%) non-IVDAs showed significant differences in the mean age (27.5 v 54), the frequency of affection of the axial joints (hip, sacroiliac, and sternocostal joints) (64.5% v 16.6%), and in the incidence of Candida albicans (19% v 0%). CONCLUSIONS: (1) HIV may not predispose to osteoarticular infections in IVDAs. (2) The hip, sacroiliac, and sternocostal joints (axial joints) were most commonly affected in IVDAs. (3) In Spain, unlike other countries, Gram positive bacteria and C albicans seem to be predominant agents in osteoarticular infections in IVDAs, with a low incidence of Gram negative bacteria.
OBJECTIVE: To study the changes in rheumatoid synovitis induced by the nonsteroidal antiinflammatory drug (NSAID), naproxen, and methotrexate (MTX). METHODS: Twelve patients were treated with naproxen, and 11 with MTX and a clinical activity index was measured before and after treatment. A synovial biopsy was taken, on entry into the study and after 73 +/- 43 days in the NSAID group and 145 +/- 35 in the MTX group. Synovial cells bearing CD3, CD4, CD8, CD19, LeuM5 (CD11c), HLA-DR, HLA-DP and CD25 antigens were measured by stereology. RESULTS: Patients treated with MTX showed a reduction in the number of CD3+ (p = 0.01), CD4+ (p = 0.007) and HLA-DR+ (p = 0.01) cells with an improvement in the activity index (p = 0.001). The patients treated with naproxen did not show changes in the activity index or in the synovial infiltrate. CONCLUSION: Our findings support the theory that clinical improvement in rheumatoid synovitis is associated with a significant decrease in the number of T cells infiltrating the synovial membrane.
We studied in retrospect the rheumatic manifestations of 556 patients with human immunodeficiency virus (HIV) infection. Eighty percent were men. Eighty-six percent were intravenous drug abusers (IVDAs), 9% homosexual, 3% partners of high-risk persons having the infection, 0.4% hemophiliacs, and 2% had no known risk factors. We found rheumatic disorders in 63 (11%) patients. The most frequent findings were myalgias and/or arthralgias (4.5%; one patient had an inflammatory myopathy), skeletal infections (3.6%), and arthralgias (1.6%). Reiter's syndrome and seronegative arthritis were present only in 0.5%, and HIV-associated arthritis and vasculitis in 0.4%, respectively. Skeletal infections were caused predominantly by Staphylococcus aureus (60%) and Candida albicans (20%). All these patients were IV drug abusers whose clinical features were similar to those previously described in skeletal infections of non-HIV-infected IVDAs. Comparing these data with other studies composed primarily of homosexual men where Reiter's syndrome is the predominant rheumatic disorder, we conclude that the type of rheumatic complaint is more related to the risk factors than to HIV itself.