[Show abstract][Hide abstract] ABSTRACT: The association of thrombosis and gestational morbidity with antiphospholipid antibodies is termed antiphospholipid syndrome (APS). Annexin 2 (A2) is a profibrinolytic endothelial cell surface receptor that binds plasminogen, its tissue activator (tPA), and beta(2)-glycoprotein I (beta2GPI), the main antigen for antiphospholipid antibodies. Here, we evaluate A2 as a target antigen in APS. Serum samples from 434 individuals (206 patients with systemic lupus erythematosus without thrombosis, 62 with APS, 21 with nonautoimmune thrombosis, and 145 healthy individuals) were analyzed by enzyme-linked immunosorbent assay (ELISA) and immunoblot for antiphospholipid and A2 antibodies. Anti-A2 antibodies (titer > 3 SDs) were significantly more prevalent in patients with APS (22.6%; venous, 17.5%; arterial, 34.3%; and mixed thrombosis, 40.4%) than in healthy individuals (2.1%, P < .001), patients with nonautoimmune thrombosis (0%, P = .017), or patients with lupus without thrombosis (6.3%, P < .001). Anti-A2 IgG enhanced the expression of tissue factor on endothelial cells (6.4-fold +/- 0.13-fold SE), blocked A2-supported plasmin generation in a tPA-dependent generation assay (19%-71%) independently of beta2GPI, and inhibited cell surface plasmin generation on human umbilical vein endothelial cells (HUVECs) by 34% to 83%. We propose that anti-A2 antibodies contribute to the prothrombotic diathesis in antiphospholipid syndrome.
[Show abstract][Hide abstract] ABSTRACT: The concept of shared autoimmunity comprises various forms of disease: rheumatic diseases in several members of the same family, the coincidence of autoimmune rheumatic with non-rheumatic diseases in relatives of patients, the presence of autoantibodies in healthy relatives of autoimmune disease patients, and the development of two or more autoimmune rheumatic diseases in one patient, the so-called overlap syndromes. The genetic and environmental factors that lead to these phenomena interact in a complex fashion and influence the distinct phenotypic characteristics of each patient. In a previous case series, we described 23 Mexican Mestizo patients with overlap syndromes. Interestingly, rhupus tends to develop sequentially while sclerodermatomyositis tends to appear simultaneously. The clinical course of the other overlap syndromes is rather aggressive, although clinical manifestations respond to standard treatment. The second and/or third disease appears while the first one is still active, even with adequate treatment. The distinct course of overlap syndromes may be partially explained by the interplay of environmental factors with genes that predispose to autoimmunity in general and to manifestations of specific diseases. The analyses of genes that will help understand the pathophysiology of these diseases include several MHC complex genes, cytokines, AIRE, and PDCD1 amongst others.
[Show abstract][Hide abstract] ABSTRACT: The presence of autoimmune rheumatic diseases in several members of the same family, the concurrence of autoimmune rheumatic with non-rheumatic diseases in relatives of patients, the presence of autoantibodies in sera from healthy relatives of autoimmune-disease patients, the development of two or more autoimmune rheumatic diseases in one patient and the interplay of genetic and environmental factors leading to the presence of several autoimmune disease and/or their autoantibodies in families, is being termed "shared autoimmunity". Herein we analyzed autoimmune rheumatic overlap syndromes in this context. We performed a retrospective analysis of the clinical, serological and radiological characteristics of patients with overlap syndromes from the Clinic of Rheumatic Diseases at the Department of Immunology and Rheumatology of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. We found 23 patients with overlap syndromes; 13 patients with rhupus, 5 with sclerodermatomyositis, 3 with scleroderma and SLE, one with sclerodermatomyositis and SLE and one with scleroderma and MPA. Rhupus tends to develop sequentially while sclerodermatomyositis tends to appear simultaneously. The other overlap syndromes are less common and their clinical course is rather aggressive, although clinical manifestations respond to standard treatment. The second and/or third disease appears while the first one is still active, even with adequate treatment. The coexistence of autoimmune rheumatic diseases may be partially explained by the interplay of environmental factors with genes that predispose to autoimmunity in general and to manifestations of specific diseases. This is part of the concept of Shared Autoimmunity.
[Show abstract][Hide abstract] ABSTRACT: To determine whether there is familial aggregation of systemic lupus erythematosus (SLE) and/or other autoimmune diseases in SLE patients and to identify clinical differences between patients with and those without familial autoimmunity.
We interviewed members of the Grupo Latinoamericano de Estudio del Lupus Eritematoso (GLADEL) inception cohort of 1,214 SLE patients to ascertain whether they had relatives with SLE and/or other autoimmune diseases. Identified relatives were studied. Familial aggregation was tested using reported highest and intermediate population prevalence data for SLE, rheumatoid arthritis (RA), or all autoimmune diseases, and studies were performed to identify the genetic model applicable for SLE.
We identified 116 first-, second-, or third-degree relatives with SLE, 79 with RA, 23 with autoimmune thyroiditis, 3 with scleroderma, 1 with polymyositis, and 16 with other autoimmune diseases, related to 166 of the 1,177 SLE patients in the GLADEL cohort who agreed to participate. Forty-two SLE patients had 2 or more relatives with an autoimmune disease. We found a lambda(sibling) of 5.8 and 29.0 for SLE and of 3.2-5.3 for RA, when comparing with their reported high or intermediate population prevalence, respectively. We also found familial aggregation for autoimmune disease in general (lambda(sibling) = 1.5) and determined that for SLE, a polygenic additive genetic model, rather than a multiplicative one, is applicable.
In SLE there is familial aggregation of SLE, RA, and autoimmune disease in general. A polygenic additive model applies for SLE. American Indian-white Mestizo SLE patients and those with higher socioeconomic level were more likely to have familial autoimmunity.
[Show abstract][Hide abstract] ABSTRACT: The objective of the study was to evaluate the influence of the male gender in the clinical presentation and outcome of systemic lupus erythematosus in a prospective inception cohort of Latin-American patients. Of the 1214 SLE patients included in the GLADEL cohort, 123 were male. Demographic characteristics as well as clinical manifestations, laboratory profile, activity and damage scores were evaluated at onset and during the course of the disease and compared with female patients. The median age at onset of the male patients was 27 and that at diagnosis 29.2 years. Delay to diagnosis was shorter in males (134 versus 185 days, P = 0.01). At onset, men more frequently showed fever (42.3 versus 27.0%, P = 0.001) and weight loss (23.6 versus 11.8%, P = 0.001). During disease course the incident of symptoms was: fever, 67.8 versus 55.6%, P = 0.012; weight loss, 47.2 versus 24.3%, P = 0.001; arterial hypertension, 37.4 versus 25.8%, P = 0.007; renal disease (persistent proteinuria and/or cellular casts), 58.5 versus 44.6%, P = 0.004); and hemolytic anemia, 19.5 versus 10.9%, P = 0.008. The laboratory results showed that: men more frequently had IgG anticardiolipin antibodies (68.2 versus 49%, P = 0.02) and low C3 (61.3 versus 48.1%, P = 0.03); 5/123 men died (4%) compared with 29/1091 women (2.7%). In conclusion, 10% of GLADEL's cohort patients were male. They showed a distinctive profile with shorter delay to diagnosis, higher incidence of fever, weight loss, arterial hypertension, renal disease, hemolytic anemia, IgG anticardiolipin antibodies and low C3. Although not statistically significant, mortality was higher in men.
[Show abstract][Hide abstract] ABSTRACT: To perform a systematic analysis and case-control study of our patients with systemic lupus erythematosus (SLE) to determine the prevalence of acute pancreatitis (AP).
All episodes of AP in SLE patients were identified (July 1984-July 2001). Prevalence was calculated. Etiology for each AP event was classified into mechanical, toxic-metabolic, or idiopathic. AP severity was defined based on Atlanta criteria. SLE disease activity was scored using Mex-SLEDAI index. A control group of non-SLE patients with AP was designed to establish the risk of developing severe or fatal idiopathic AP in patients with SLE.
Forty-nine AP episodes were identified in 35 SLE patients (30 +/- 14 yrs old, 94% female). Prevalence was 3.5%. A single episode was present in 26 patients. Identified AP causes were mechanical in 14 and toxic-metabolic in 10. Seventeen episodes were considered idiopathic. At least one drug related to AP was administered in 13 episodes. Corticosteroids were in use in 32 episodes, and as the only drug in 16. Mex-SLEDAI scores were significantly higher in idiopathic events. In the case-control analysis, idiopathic AP was more frequent in SLE cases (46% vs 14%). The strength of association of AP severity and related mortality was higher in SLE patients (OR 8.6 and 7.5, respectively).
AP is not a highly prevalent manifestation of SLE. Idiopathic cases predominate and show increased SLE activity. Drug consumption does not seem to participate in AP development. SLE episodes are more severe and frequently fatal.
The Journal of Rheumatology 05/2004; 31(4):707-12. · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In total, 189 consecutive women diagnosed with SLE were evaluated using the ACR 1990 criteria for fibromyalgia. Patients were classified into three subgroups. The fibromyalgia group (FM) included patients experiencing pain on palpation in at least 11 of the 18 tender points examined, as well as having a history of widespread pain for at least three months. Patients who were noted to have pain in fewer than four quadrants with less than 11 of 18 tender points were considered to have regional pain (RP). All patients who did not meet criteria for either FM or RP were classified as having no pain (NP). Measurement of SLE disease activity, sleep complaints, depression, fatigue severity and health status were performed. Only 18 of the SLE patients (9.5%) (95% CI 5.3-14%) fulfilled the ACR criteria for the classification of FM. Of the patients, 106 (56.1%) fulfilled criteria for RP and had a number of tender points of 5.4 +/- 3.4, and the rest of the patients (34.4%) had no tenderness at specific tender point sites. Age, body mass index, educational level and disease duration were comparable between the groups. FM and RP groups had different patterns of symptoms prevalence, with dysmenorrhea being more distinctive for FM. Sleep disturbances were more severe in the FM than in the RP group. Daytime complaints such as sleepiness, fatigue and depression were similar for RP and FM groups, but patients with FM reported more disability. Fibromyalgia is not common in Mexican patients with SLE and has a different pattern of symptoms in RP and NP patients. These data add evidence that ethnicity can play an important role in FM manifestations.
[Show abstract][Hide abstract] ABSTRACT: Clinical and laboratory manifestations and outcome of systemic lupus erythematosus (SLE) may vary in different populations. A prospective multinational inception cohort should prove useful in identifying the influence of ethnicity on the clinical characteristics of SLE. We therefore analyzed clinical, laboratory, and prognostic variables in Latin American SLE patients with disease of recent onset who were entered into a prospective cohort, and compared these variables in the cohort's 3 major ethnic groups. Thirty-four centers from 9 Latin American countries participated by randomly incorporating SLE patients within 2 years of diagnosis into a standardized database. Participating centers were selected for their expertise in diagnosing and managing SLE. We were then able to evaluate prospectively socioeconomic variables, ethnicity, type of medical care, clinical and laboratory features, disease activity, damage, and mortality at each site. A coordinating center controlled the quality of the information submitted. Of the 1,214 SLE patients included in the cohort, 537 were mestizos, 507 were white, and 152 were African-Latin American (ALA). (There were also small numbers of pure Amerindian and oriental individuals.) Significant differences were found between them in socioeconomic characteristics, type of care, and level of education favoring whites. Mestizos and ALA were younger at onset. Delay to diagnosis and disease duration was shorter in ALA. Fever was more frequent in whites; discoid lesions in ALA; renal disease and lymphopenia in mestizos and ALA. Although we found differences in background variables between ethnic groups from different countries, mestizos from 2 distant countries (Argentina and Mexico) were clinically akin and showed similar differences to whites. Mortality was associated with lower education, poor medical coverage, and shorter follow-up. In an exploratory model nonwhite ethnicity was associated with renal disease and lymphopenia, damage, and cumulative American College of Rheumatology criteria. These differences in clinical, prognostic, socioeconomic, educational, and access to medical care features in Latin American lupus patients of 3 major ethnic groups from 9 different countries may have an impact on the patients' disease. "Hispanics," as they have come to be generically termed on the basis of language, actually constitute a markedly heterogeneous group of subjects.
Medicine 02/2004; 83(1):1-17. · 4.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prolactin (PRL) secretion by the pituitary is under the control of dopamine. Hyperprolactinemia has been found in patients with systemic lupus erythematosus (SLE) and seems to be associated with clinical activity. T-lymphocytes express PRL and those from SLE patients appear to secrete more PRL than controls. In this study, immuno-(RIA) and bio-(BIO) assayable PRL in both serum and culture media of peripheral blood mononuclear cells (PBMNC) from SLE and control subjects were evaluated in the basal state and in response to 10 mg oral administration of metoclopramide, a dopamine receptor antagonist. Prolactin size heterogeneity in serum and culture media and PRL gene transcription in PBMNC were also studied. Basal serum RIA-PRL, BIO-PRL and the BIO/RIA ratio were similar in both groups. The serum BIO-PRL response after metoclopramide was higher than RIA-PRL in SLE, and this increment was also greater than in control subjects. PBMNC from SLE subjects secreted and produced more BIO-PRL. After metoclopramide, secretion and production of PRL increased only in PBMNC from control women and not in those from SLE patients. Our results demonstrated an increased central dopaminergic tone in SLE and suggest that lymphocyte-derived PRL might contribute to alter the functional activity of the hypothalamic dopaminergic system in SLE attempting to maintain serum PRL within a physiological range.
[Show abstract][Hide abstract] ABSTRACT: We studied antibodies to beta2-glycoprotein 1 (anti-beta2GP1) from 72 patients with systemic lupus erythematosus (SLE) with or without antiphospholipid syndrome (APS) or with or without anticardiolipin antibodies (aCL). Fifteen patients had APS and positive antiphospholipid antibodies [clinical APS(+)/aPL(+)], 12 patients had APS, negative serum IgG and IgM aCL, antiphosphatidylethanolamine, anti-phosphatidylserine and no lupus anticoagulant [clinical APS(+)/ aPL(-)]. A third group included 16 patients without APS but high aCL levels [clinical APS(-)/ aPL(+)]. In a fourth group we studied 29 patients without clinical manifestations of APS or aCL [clinical APS(-)/aPL(-)]. One hundred anticardiolipin and VDRL-negative normal sera were studied as controls. IgG antibodies to cardiolipin proper in a bovine beta2GP-free system, to human beta2GP1 immobilized on cardiolipin or to human beta2GP1 alone were detected in all sera by ELISA using irradiated and nonirradiated plates from two manufacturers. Sera from APS(+)/aPL(+) patients showed IgG binding to CL, CL + beta2GP1 and beta2GP1 in irradiated and nonirradiated plates. APS(+)/ aPL(-) sera had more significant IgG binding to beta2GP1 than normal controls when studied in both irradiated or nonirradiated plates (P = 0.001). This binding was inhibited by solid-phase cardiolipin in a dose-dependent manner. Sera from the APS(-)/aPL(+) subgroup had comparable IgG activity in both the CL and CL + beta2GP1 assays, while no anti-beta2GP1 activity was detected in these sera. Sera from the clinical APS(-)/aPL(-) patients were negative in the three ELISA systems. Antibodies to human beta2GP1 from SLE patients recognize various epitopes. Those from APS(+)/ aPL(+) patients appear to react with an epitope boosted by cardiolipin in addition to another one present in the native protein. In contrast, anti-beta2GP1 from patients with APS(+)/aPL(-) are blocked by cardiolipin, suggesting that their epitope is the phospholipid-binding site.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to analyze in families with SLE for the presence of linkage and the structure and transmission of haplotypes containing alleles for the low-affinity Fcg receptors. The Fcg receptor polymorphisms FcgRIIA-131R/H, FcgRIIIA- 176F/V and FcgRIIIB-NA1/2 and a polymorphism in the FcgRIIB gene were genotyped with RFLP, allele-specific PCR or pyrosequencing. Individual SNPs and haplotypes were tested for linkage in multicase families and for association using contingency tables, transmission disequilibrium test and affected family-based control groups in Swedish and Mexican single- case families. No linkage or association could be detected using the FcgR polymorphisms in the multicase families. However, an association was found for both FcgRIIA-131R and IIIA-176F alleles in the single-case families, but not for IIIB or IIB. Allelic association to SLE was found for a haplotype that included both risk alleles, but not in haplotypes where only one or the other was present. We propose that FcgRIIA-131R and FcgRIIIA-176F are both risk alleles for SLE transmitted primarily, but not exclusively on a single major haplotype that behaves functionally in a situation similar to that of compound heterozygozity.
Genes and immunity 01/2004; 5:130-137. · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to analyze in families with SLE for the presence of linkage and the structure and transmission of haplotypes containing alleles for the low-affinity Fcγ receptors. The Fcγ receptor polymorphisms FcγRIIA-131R/H, FcγRIIIA-176F/V and FcγRIIIB-NA1/2 and a polymorphism in the FcγRIIB gene were genotyped with RFLP, allele-specific PCR or pyrosequencing. Individual SNPs and haplotypes were tested for linkage in multicase families and for association using contingency tables, transmission disequilibrium test and affected family-based control groups in Swedish and Mexican single-case families. No linkage or association could be detected using the FcγR polymorphisms in the multicase families. However, an association was found for both FcγRIIA-131R and IIIA-176F alleles in the single-case families, but not for IIIB or IIB. Allelic association to SLE was found for a haplotype that included both risk alleles, but not in haplotypes where only one or the other was present. We propose that FcγRIIA-131R and FcγRIIIA-176F are both risk alleles for SLE transmitted primarily, but not exclusively on a single major haplotype that behaves functionally in a situation similar to that of compound heterozygozity.
Genes and Immunity 01/2004; 5(2):130-137. · 3.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the polymorphism at position 247 of the beta(2)-glycoprotein I (beta(2)GPI) gene in Mexican patients with antiphospholipid syndrome (APS) and to compare these data in patients with or without antibodies to beta(2)GPI and with the clinical manifestations of APS.
We studied 39 patients with primary APS and compared them with 106 clinically healthy subjects. Polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism. The presence of "true" anticardiolipin (aCL) antibodies, beta(2)GPI-dependent aCL antibodies (IgG and IgM), and phospholipid-free anti-beta(2)GPI antibodies (IgG isotype) were detected by enzyme-linked immunosorbent assay (ELISA) utilizing nonirradiated ELISA plates. Clinical manifestations associated with antiphospholipid antibodies were also evaluated.
We found no significant differences in the genotype expression between the control group and the primary APS patients (13% with VV, 52% with VL, and 35% with LL versus 23% with VV, 51% with VL, and 26% with LL, respectively). In contrast, anti-beta(2)GPI-positive patients had significantly higher frequencies of the VV genotype and V allele expression than the control subjects and the anti-beta(2)GPI-negative patients. These genotype and allele frequencies were also significantly higher in patients with arterial thrombosis than in patients without it. Anti-beta(2)GPI-negative patients without arterial thrombosis did not express the VV genotype. We found no differences in the Val/Leu(247) polymorphism of the beta(2)GPI gene in primary APS patients with or without "true" aCL antibodies or in primary APS patients with or without beta(2)GPI-dependent aCL antibodies.
Our results suggest that the VV genotype at position 247 of the beta(2)GPI gene may play a role in the generation of anti-beta(2)GPI antibodies and perhaps in the expression of arterial thrombosis in primary APS.
[Show abstract][Hide abstract] ABSTRACT: In a 76-week, randomized controlled trial, patients received 100 mg LJP 394 or placebo weekly for 16 weeks followed by three 12-week treatment cycles of 50 mg LJP 394 or placebo weekly each separated by eight-week periods when no therapy was administered. Health-related quality of life (HRQOL) was assessed using SF-36 at baseline, 16 weeks and every 12 weeks thereafter. Analyses populations included intent to treat (ITT) (n = 179) and patients with high-affinity anti-dsDNA antibody binding (HA): 157/179; 85% active, 90% placebo. In the ITT population, there were improvements in role emotional (RE) (+7.3 versus -8.2), social functioning (SF) (+4.3 versus +0.7), and role physical (RP) (+11.3 versus +6.0) domains in the active treatment group when compared with placebo, with similar changes observed in the HA population. In 37 patients with data pre- and post-renal flares, those receiving LJP 394 reported stabilization or improvement in all but one domain compared with deterioration in all domains with placebo. Changes in RE domain scores following a flare differed by 22.7 points between the two treatment groups, favouring LJP 394 treatment. Patients receiving LJP 394 reported stable or improved HRQOL with active treatment following renal flares compared with deterioration in placebo. Differences between treatment groups in RE and SF domains are clinically important and were replicated irrespective of the protocol population analysed.
[Show abstract][Hide abstract] ABSTRACT: To determine whether LJP 394 delays or prevents renal flare in patients with systemic lupus erythematosus (SLE) and a history of renal disease.
In a 76-week, double-blind, placebo-controlled study, 230 SLE patients were randomized to receive 16 weekly doses of 100 mg of LJP 394 or placebo, followed by alternating 8-week drug holidays and 12 weekly doses of 50 mg of LJP 394 or placebo. An assay measuring the affinity of the serum IgG fraction for the DNA epitope of LJP 394 identified a high-affinity population of patients (189 of 213 patients; 89% taking LJP 394 and 90% taking placebo). Analyses were performed on both the intent-to-treat population and the high-affinity population.
Anti-double-stranded DNA antibodies decreased and C3 levels tended to increase during treatment with LJP 394. In the intent-to-treat population, the time to renal flare was not significantly different between treatment groups, but patients taking LJP 394 had a longer time to institution of high-dose corticosteroids and/or cyclophosphamide (HDCC) and required 41% fewer treatments with HDCC. In the high-affinity population, the LJP 394 group experienced a longer time to renal flare, 67% fewer renal flares, longer time to institution of HDCC, and 62% fewer HDCC treatments compared with the placebo group. In patients with serum creatinine levels >/=1.5 mg/dl at study entry, those taking LJP 394 had 50% fewer renal flares; no renal flares were observed in the high-affinity group taking LJP 394. Serious adverse events were observed in 25 of the 114 LJP 394-treated patients (21.9%) and 34 of the 116 placebo-treated patients (29.3%).
Treatment with LJP 394 in patients with high-affinity antibodies to its DNA epitope prolonged the time to renal flare, decreased the number of renal flares, and required fewer HDCC treatments compared with placebo. The study drug appeared to be well tolerated.