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ABSTRACT: To analyze the mechanisms involved in the characteristic hyperexpression of CD23 on peripheral blood B cells from patients with rheumatoid arthritis (RA).
Peripheral blood mononuclear cells (PBMC) were obtained from patients with active disease and activated during 18 h with an anti-CD3 monoclonal antibody in the presence or absence of blocking antibodies to CD154 or CD40. PBMC were further purified by rosetting and CD23 expression was assessed on B cells by flow cytometry after double staining (CD19/CD23). Lymphocytes were also isolated from synovial fluid (SF). CD154 expression was analyzed on PB or SF CD4+ T cells after double staining (CD4/CD154) by flow cytometry at basal conditions and after different stimuli [anti-CD3 or phorbol myristic acetate (PMA) plus ionomycin]. Co-culture experiments between SF and PB cells were performed to analyze the involvement of the CD40-CD154 interaction on CD23 expression. CD154 and CD23 expression was also analyzed on synovial membrane by immunohistochemical techniques.
A high proportion of activated CD23 B cells was detected in patients with RA. Blocking experiments with both anti-CD40 and anti-CD154 Mab showed a significant reduction in the proportion of PB B cells expressing CD23. Following activation with anti-CD3 Mab or PMA plus ionomycin, CD154 expression was mainly induced on PB CD4+ T cells. In co-culture experiments, SF T cells were more efficient than PB T cells in inducing CD40 dependent CD23 expression on PB B cells. In addition, CD4+ T cells from synovial membrane clearly expressed CD154.
Our results establish a link between CD154-CD40 pathway and CD23 expression on PB B cells from patients with RA. T cells from the synovial microenvironment were active participants in this CD23 expression, presumably in the context of cell recirculation.
The Journal of Rheumatology 07/2001; 28(6):1222-8. · 3.69 Impact Factor
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ABSTRACT: Corticosteroids remain the cornerstone of therapy for giant-cell arteritis, but relapse during dose tapering and corticosteroid-related adverse events often complicate management of this condition. Although several approaches, including combined therapy with cytotoxic agents, have been suggested to overcome these problems, no study has clearly shown benefits of alternate treatments.
To analyze the safety and efficacy of combined therapy with corticosteroids and methotrexate in giant-cell arteritis.
Randomized, double-blind, placebo-controlled trial.
University-based clinic.
42 patients with new-onset giant-cell arteritis according to biopsy.
High initial doses of corticosteroid were given; the dose was then tapered quickly until therapy was completely withdrawn. Methotrexate or placebo was given weekly from the start of corticosteroid therapy for 24 months.
Number of relapses, cumulative dose of corticosteroid, and number of adverse events were assessed on completion of follow-up.
Compared with combined prednisone and placebo therapy, treatment with prednisone and methotrexate reduced the proportion of patients who experienced at least one relapse (45% vs. 84.2%; P = 0.02) and the proportion of patients who experienced multiple relapses (P = 0.004). The mean cumulative dose of prednisone was 4187 +/- 1529 mg in the methotrexate group and 5489.5 +/- 1396 mg in the placebo group (mean difference, 1302 mg [95% CI, 350 to 2253 mg]; P = 0.009). Overall, the rate and severity of adverse events were similar between groups. Treatment was discontinued in 3 patients in the methotrexate group who experienced definite drug-related adverse events. In sensitivity analysis that included patients lost to follow-up, differences between groups in number of relapses and cumulative dose of prednisone were significant.
Treatment with methotrexate plus corticosteroid is a safe alternative to corticosteroid therapy alone in patients with giant-cell arteritis and is more effective in controlling disease.
Annals of internal medicine 02/2001; 134(2):106-14. · 16.73 Impact Factor
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C Hernández-García,
E Vargas,
L Abásolo,
C Lajas,
B Bellajdell,
I C Morado,
P Macarrón,
E Pato,
B Fernández-Gutiérrez, A Bañares,
J A Jover
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ABSTRACT: To study demographic and clinical variables associated with a longer delay in disease modifying antirheumatic drug (DMARD) therapy initiation in a cohort of patients with rheumatoid arthritis (RA).
We studied 527 new RA patients (74.3% female, median age at symptom onset 55 yrs) in a hospital setting who fulfilled the ACR criteria for the diagnosis of RA. Demographic, clinical, laboratory, and treatment variables were collected longitudinally into a computerized research database. Risk factors for delay in use of DMARD therapy and first evaluation by a rheumatologist were analyzed using a Cox regression model.
The median lag time between symptom onset and first rheumatologist encounter was 17 months and between onset of symptoms and first DMARD therapy 19 months. Variables associated with longer delay to DMARD therapy were the lag time between symptom onset and first rheumatologist visit (RR 0.73, 95% CI 0.71-0.76) and years of education. Variables associated with longer delay in first visit with rheumatologist were swollen/tender joint count, age at symptom onset, home support, labor force status, marital status, and years of education.
Awareness of factors associated with a longer delay in access to rheumatology care and DMARD therapy may help break down barriers that prevent their early access, irrespective of patient age, socioeconomic status, initial symptoms, or need for treatment.
The Journal of Rheumatology 11/2000; 27(10):2323-8. · 3.69 Impact Factor
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ABSTRACT: To investigate patients with formerly undiagnosed underlying spondyloarthropathy (SpA) in a series of anterior uveitis (AU) cases and to describe the rheumatologic and ophthalmologic characteristics of these patients.
Patients with anterior uveitis referred to the Uveitis Clinic between January 1992 and December 1998 who had a final diagnosis of SpA were included in the study group. The diagnosis of SpA was based on current diagnostic criteria. Patients were classified into 2 groups: formerly diagnosed, or undiagnosed SpA before attendance at the uveitis clinic. Demographic features, clinical symptoms, ophthalmologic characteristics, and laboratory tests were collected prospectively in each patient. A regression logistic model was applied.
We evaluated 514 patients with anterior uveitis; 117 (22.7%) had some type of SpA. Ankylosing spondylitis was the most frequent diagnosis (64.1%). More than half the patients (53%) were diagnosed with SpA after an episode of uveitis; the percentage was up to 90.9% in undifferentiated SpA. Clinically, the formerly diagnosed and undiagnosed groups were quite similar, inflammatory low back pain being the most frequent symptom in both groups. Radiological sacroiliitis was less common and with a lower grade in the formerly undiagnosed group. Acute recurrent unilateral anterior uveitis was the most frequent clinical pattern in the group as a whole (68.3%), observed in all subgroups, except for inflammatory bowel disease related SpA, which presented panuveitis as the most frequent pattern.
SpA was the most frequent systemic disease related to anterior uveitis, seen in more than 50% of our SpA cases diagnosed after an episode of uveitis. The undiagnosed SpA patient is generally an atypical case, with a shorter clinical evolution and less radiological damage.
The Journal of Rheumatology 10/2000; 27(9):2198-202. · 3.69 Impact Factor
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ABSTRACT: To assess the effects of sulfasalazine in preventing recurrences and reducing the severity of anterior uveitis associated with ankylosing spondylitis and chronic intestinal inflammation.
Twenty-two patients with anterior uveitis associated with ankylosing spondylitis were studied. Ten patients were randomised to receive oral sulfasalazine (group 1) and 12 patients randomised to no treatment (group 2); all were followed for 3 years. Blood-aqueous barrier permeability was determined by fluorophotometry and bowel biopsies were taken.
A statistically significant difference was observed between the two groups regarding the number of recurrences of uveitis (p = 0.016). The blood-aqueous barrier permeability was significantly higher during acute attacks in group 2 (group 1: 31.3 +/- 26.4 x 10(-4) min-1 vs group 2: 66.2 +/- 28.5 x 10(-4) min-1; p = 0.019) but not during the disease-free period. We observed a higher incidence of chronic intestinal inflammation at the end of the study in group 2 (group 1: 3/8 vs group 2: 7/9, p = 0.153). No relation was observed between blood-aqueous barrier permeability and the number of recurrences. The number of patients with severe persistent posterior synechiae at the end of the study was higher in group 2 (group 1: 4 patients before and 4 patients at the end; group 2: 4 patients before and 8 patients at the end; p = 0.65).
Sulfasalazine may be beneficial in preventing recurrences and reducing the severity of anterior uveitis associated with ankylosing spondylitis.
Eye 07/2000; 14 ( Pt 3A):340-3. · 1.85 Impact Factor
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ABSTRACT: Immunosenescence is characterized by an increase in autoantibody production. Because both T and B cell stimulation are key events for producing antibodies, we investigated early T and B cell activation by means of CD23 and CD40L (two very early activation antigens). PBMC from elderly humans (EH) were studied following culture with either medium, anti-CD3mAb, rIL-4, or PMA + ionomycin. CD23 expression on elderly B cells after anti-CD3 challenge of PBMC, a reflect of T-dependent B cell activation, was clearly defective. Conversely, CD23 expression on EH B cells following activation with soluble factors as rIL-4 was preserved. CD40L expression was also impaired in EH T cells following anti-CD3 challenge. However, activation by means of PMA and/or ionomycin was preserved both in T cells (CD40L expression) and in B cells (CD23 expression). These results indicate that a defective T-dependent B cell activation related to defective T cell activation located between surface membrane and PKC/ionomycin function is an intrinsic characteristic of immunosenescence. We have not found intrinsic B-cell defects, and we conclude that the characteristically impaired early B cell activation in EH is mostly due to T cell defects.
Experimental Gerontology 05/1999; 34(2):217-29. · 3.74 Impact Factor
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ABSTRACT: the antigen CD28, expressed in most T cells, has co-stimulatory properties and plays a pivotal role in clonal T cell anergy mechanisms.
we have compared proliferative T cell responses after anti-CD3 or in phorbol myristate acetate activation with concomitant CD28 signal in peripheral blood mononuclear cells from healthy donors aged over 65 [elderly donors; ED] and young healthy donors (YD); mean age 30+/-2.7 years).
no proliferative responses were observed in ED and YD with anti-CD28 monoclonal antibody alone. These responses both were defective in ED, particularly after anti-CD3 monoclonal antibody stimulus (7604 compared with 12,438 c.p.m. in YD, P=0.001) and were corrected when anti-CD28 monoclonal antibody was added to the culture (17,216 vs 18,536, not significant). Functional integrity of the CD28 co-stimulatory pathway was demonstrated by analysis of CD25 expression, interleukin-2 secretion and interleukin-2 gene expression on T cells from ED and YD. Age-associated phenotypic T cell changes were not crucial for an adequate CD28 response.
these experiments demonstrate the integrity of the CD28 pathway in elderly people, and suggest that ageing does not affect different T cell activation pathways equally.
Age and Ageing 04/1999; 28(2):221-7. · 3.09 Impact Factor
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ABSTRACT: Eye inflammation, especially uveitis, is a prominent feature of spondyloarthropathies. Uveitis associated with ankylosing spondylitis and Reiter's syndrome usually is a unilateral acute anterior uveitis with a high tendency to recur sometimes in the contralateral eye. Uveitis associated with undifferentiated spondyloarthropathy, inflammatory bowel disease, and psoriasis may be less characteristic in its presentation, with a higher tendency to posterior pole involvement, bilaterality, and chronicity. Although acute anterior uveitis is grouped into the spectrum of human leukocyte antigen B27-related disease, other genetic and environmental factors including infections by gram-negative bacteria and gut inflammation can play a role in its pathogenesis. The prognosis of uveitis usually is excellent with topical treatment, and only those with posterior pole involvement or a high tendency to recur or to chronicity might benefit from immunosuppressive therapy.
Rheumatic Disease Clinics of North America 12/1998; 24(4):771-84, ix. · 3.02 Impact Factor
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ABSTRACT: To perform a clinical, laboratory and pathologic evaluation in patients who had developed a postsurgical necrotizing sclerocorneal ulceration to detect a serious associated autoimmune disorder and to treat the ocular disease early.
Nine patients with postsurgical necrotizing sclerocorneal ulceration after uneventful cataract extraction were studied by means of immunohistochemical techniques on conjunctival resections, immunologic serologic studies, and rheumatologic evaluation. Nine healthy subjects who underwent uneventful cataract surgery were used as controls.
The pathologic studies showed a local immunoglobulin M (IgM) and IgG deposition, increased human leukocyte antigen (HLA-DR) expression, and a significant T-helper cell participation in conjunctival biopsies in the most severe ulcerations, which were detected in four patients with underlying autoimmune systemic disorder (rheumatoid arthritis, 45%) and only a macrophagic infiltration in the mildest ulcers in patients (55%) without immune disorders. Serologic features included high titers of rheumatoid factor in the four (45%) patients with rheumatoid arthritis, nonspecific serologic immune alteration in three (33%) patients, and were unremarkable in two (22%) patients. The medical and immunologic evaluations were negative in the control cases. Topically administered cyclosporin A healed the ocular disease.
A surgically induced local autoimmune reaction could occur in the incision area in patients with systemic vasculitic disease. There was no underlying systemic disorder in the mildest ulcers, and these ulcers could be due to a defect in the surgical technique. Our results suggest the need for a detailed systemic evaluation in patients with severe postsurgical necrotizing ulceration. Early diagnosis and aggressive medical treatment of the ocular disorder improves the visual outcome.
Cornea 08/1998; 17(4):371-5. · 1.73 Impact Factor
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ABSTRACT: Systemic lupus erythematosus (SLE) is characterized by autoantibody production of unknown origin. Since T-B cell interaction is a key event to produce antibodies, we investigated this interaction through study of CD69, CD40 ligand (CD40L) and CD23 expression (three very early activation antigens). Peripheral blood mononuclear cells (PBMC) from inactive lupus patients were studied following culture with either medium alone, anti-CD3 monoclonal antibody (mAb), recombinant interleukin-4 (rIL-4) or phorbol myristate acetate (PMA)+/-ionomycin. Analysis of CD23 expression on lupus B cells in basal conditions and after anti-CD3 challenge of PBMC, a reflection of cognate interaction between T and B cells, was clearly defective. Conversely, CD23 expression on lupus B cells following non-cognate T cell signals (rIL-4) was preserved. CD69 and CD40L expression was also impaired in lupus T cells following anti-CD3 challenge. Nonetheless, activation by means of PMA and/or ionomycin was preserved both in T cells (CD69 and CD40L expression) and in B cells (CD23 expression). These results indicate that B cells from inactive lupus patients display a normal early response to direct B-cell stimuli. Conversely, T-dependent B-cell stimuli are clearly defective in SLE patients in remission. These results indicate that T-B cognate interaction related to defective T cell activation located between surface membrane and protein kinase C (PKC)/ionomycin function is an intrinsic characteristic of these patients.
Lupus 02/1998; 7(5):314-22. · 2.34 Impact Factor
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ABSTRACT: To describe the patterns of clinical presentation in a series of 407 patients with uveitis and to establish the relationship between these patterns and the final diagnosis.
Patients were referred to the Uveitis Clinic of a tertiary hospital from January 1992 to January 1996. All patients received a complete ophthalmologic examination, and a general clinical history was obtained. The current International Uveitis Study Group classification system was used for anatomic classification. To establish the final diagnosis of the most common entities causing uveitis, current diagnostic criteria were used. A discriminant analysis, with diagnostic grouping as the outcome variable and the clinical presentation features as discriminating variables, was performed.
With our classification system, 66.5% of the cases could be correctly classified according to the clinical pattern and morphologic findings. By diagnostic groups, discriminant analysis showed that 75% of patients with Behçet's disease, 77.1% of those with spondylarthropathy (including inflammatory bowel disease), 33.3% of those with sarcoidosis, 97.9% of those with toxoplasmosis, 85.7% of those with Vogt-Koyanagi-Harada syndrome, 100% of those with herpes, and 50.4% of those with idiopathic uveitis were correctly classified. In the miscellaneous group, which included disease entities with fewer than 5 cases, 42.9% were correctly classified.
Rheumatologic evaluation of the patient with uveitis can be more cost-effective if the referring ophthalmologist follows the classification system described herein, allowing a tailored approach in which only specific and necessary diagnostic tests are used.
Arthritis & Rheumatism 03/1997; 40(2):358-70. · 7.87 Impact Factor
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ABSTRACT: This study characterizes the early steps of T lymphocyte activation in elderly subjects. The expression of CD69, the earliest inducible antigen which appears with T lymphocyte activation, was assessed in T cells cultured with medium, anti-CD3 or PMA. The proliferative responses of T cells stimulated through CD69 and CD3 pathways were also studied. Donors included 31 healthy elderly [age mean (SD) 80(8) years] and 33 healthy young [age 30(5) years] subjects. In elderly people, the expression of CD69 was lower in T cells cultured with medium [3.4% (1.65-5.9; 25-75 percentiles) vs. 10% (6-18), p < 0.0003] and anti-CD3 activated [28.1% (16.5-53.8) vs. 79.5% (73-89), p < 0.0002] T cells. With PMA at 10 ng/ml, CD69 expression was higher in both groups of T cells, though still lower in the aged [84.5% (70.9-94.9) vs. 99% (65.7-100), p = 0.051]. CD69 T cells expression was equal in both groups with 2 ng/ml of PMA, but the co-stimulatory responses to CD69 under these conditions and in the presence of anti-CD3 were lower in the aged (16914 vs. 28904 cpm, p < 0.02) and (6944 vs. 14370 cpm, p < 0.02) respectively. Aged T cells failed to express CD25 at the same levels of young T cells when stimulated with CD69. These results suggests an age-associated defect in the very early steps of T lymphocyte activation that might influence later stages of lymphocyte function. An alteration in the transmission of the activation signal from the cell surface to protein kinase C may play a primary role in this defect.
Age and Ageing 11/1996; 25(6):470-8. · 3.09 Impact Factor
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ABSTRACT: PURPOSE/METHODS: A 14-year-old girl with a history of contact with puppies and chronic bilateral panuveitis was examined. The fundus of the right eye showed an inferotemporal pars plana exudate. The fundus of the left eye showed an elevated posterior mass. RESULTS/CONCLUSION: Toxocara antibodies in the aqueous humor detected by enzyme-linked immunosorbent assay had a Goldmann-Witmer coefficient of 8.63 in the right eye and 8.94 in the left eye. Toxocariasis may be a cause of bilateral panuveitis.
American Journal of Ophthalmology 05/1995; 119(4):514-6. · 4.22 Impact Factor
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Annals of the Rheumatic Diseases 04/1994; 53(3):211. · 8.73 Impact Factor
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ABSTRACT: Eleven newly-diagnosed GCA patients were included in a prospective open study and treated with high initial prednisone doses, a quick-tapering CS schedule and weekly oral MTX for two years. It took a mean of 14 weeks to reach a 10 mg/day dose of prednisone and 29.8 weeks until steroid withdrawal. The mean cumulative dose of prednisone was 3.4 g. Two patients relapsed and five developed CS side effects. No serious MTX side effects were observed. Our results suggest that MTX is safe and could be useful in the therapy of GCA.
Scandinavian Journal of Rheumatology 02/1994; 23(6):295-8. · 2.47 Impact Factor
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ABSTRACT: Acetylator phenotype has been determined with sulphamethazine (sulphadimidine) in 69 Spanish patients with rheumatoid arthritis (48 females), all of whom were on second line therapy, and in 96 age-matched normal controls (54 females). Thirty-two patients (46.4%) and 56 controls (58.3%) were classified as slow acetylators. On analysing separately the females in both groups, 37.5% of patients and 63% of controls were found to be slow acetylators. No difference was found in the males (patients 66.3% and controls 52.4% slow acetylators). Rapid acetylator phenotype may be a risk factor for the development of severe rheumatoid arthritis in women.
European Journal of Clinical Pharmacology 02/1993; 45(3):279-81. · 2.85 Impact Factor
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ABSTRACT: The blood-aqueous barrier (BAB) permeability was studied by fluorophotometry in 17 healthy control subjects and in 27 eyes from 27 patients with HLA-B27-positive acute anterior uveitis (HLA-B27 AAU). Twenty of these patients had an associated spondyloarthropathy. BAB permeability was studied during the ocular inflammatory crisis and in the disease-free periods in the same patients. Anterior chamber fluorophotometric scans were performed before and 30 minutes after the intravenous injection of 14 mg/kg of sodium fluorescein. The diffusion coefficient (Kd) was obtained from the ratio between the fluorescein concentration in the anterior chamber and the NPBF. Data were analyzed using the Student's t test and analysis of variance. A statistically significant difference (P < 0.001) was found between the Kd of active HLA-B27 AAU (61.4 +/- 16.8 x 10(-4) min-1) and the Kd of inactive HLA-B27 AAU (4.8 +/- 1.6 x 10(-4) min-1). No statistically significant differences were found between the Kd of inactive HLA-B27 AAU and the Kd of the control subjects (4.3 +/- 1.0 x 10(-4) min-1). We also failed to detect significant differences between patients with and without spondyloarthropathy either during the acute attack or during the disease-free period. On the basis of these results we conclude that the permeability of the BAB remains intact in inactive HLA-B27-positive AAU. The parallel fluorophotometric behaviour of HLA-B27-positive AAU with spondyloarthropathy and without spondyloarthropathy suggests that both share a common pathogenetic mechanism.
International Ophthalmology 18(4):233-6.
