The different faces of shared autoimmunity.

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.

Overlap syndromes in the context of shared autoimmunity.

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.

[The future of medical investigation in Mexico]. / El futuro de la investigación médica en México.

The current situation of clinical research in Mexico is analyzed. The main findings are as follows: 10% of total number of researchers in Mexico are engaged in medical research; there is a highly centralized distribution in the Mexico City metropolitan area; there exists unequal academic development among disciplines, and there is an overwhelming number of researchers in public educational and health institutions. A substantial increase in medical publications during the last 15 years with reasonable citation impact was also found. Several urgent matters to attend were identified, such as financing problems, effect of health services descentralization completed in 1997, and the need to selectively support certain research areas such as accidents, mental health, addictions, geriatrics and chronic diseases.

El futuro de la investigación médica en México / The Future of Medical Investigation in Mexico

Se hace un análisis del estado que guarda la investigación médica en México. Destacamos el desigual desarrollo científico de las disciplinas médicas, el centralismo que prevalece en el área metropolitana y la abrumadora mayoría de los investigadores en instituciones publicas del sector salud y del educativo. Se analiza el incremento en la producción científica, en los últimos 15 años y su impacto en la literatura internacional. Concluimos que contamos con una comunidad de investigación médica productiva, aunque todavía pequeña para el país. Se señalan cuestiones urgentes de atender como: el agudo problema del financiamiento, los efectos de la descentralización de los servicios de salud y la necesidad de apoyar, por su importancia epidemiológica, áreas como las de accidentes, salud mental, adicciones, geriatría y enfermedades crónico degenerativas.

The current situation of clinical research in México is analyzed. The main findings are as follows: 10% of total number of researchers in Mexico are engaged in medical research; there is a highly centralized distribution in the Mexico City metropolitan area; there exists unequal academic development among disciplines, and there is an over whelming number of researchers in public educational and health institutions. A substantial increase in medical publications during the last 15 years with reasonable citation impact was also found. Several urgent matters to attend were identified, such as financing problems, effect of health services descentralization completed in 1997, and the need to selectively support certain research areas such as accidents, mental health, addictions, geriatrics and chronic diseases.

Systemic lupus erythematosus as a cause and prognostic factor of acute pancreatitis.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus: results from a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To determine whether LJP 394 delays or prevents renal flare in patients with systemic lupus erythematosus (SLE) and a history of renal disease. METHODS: 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. RESULTS: 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%). CONCLUSION: 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.

Valine/valine genotype at position 247 of the beta2-glycoprotein I gene in Mexican patients with primary antiphospholipid syndrome: association with anti-beta2-glycoprotein I antibodies.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Anticardiolipin and anti-beta2-glycoprotein-I antibodies in hypertensive disorders of pregnancy.

BACKGROUND: This study was undertaken in order to determine the frequency of anticardiolipin (aCL) and anti-beta2-glycoprotein-I antibodies (anti-beta2 GP-I) in patients with hypertensive disorders of pregnancy. METHODS: We studied aCL (IgG and IgM) and IgG anti-beta 2 GP-I by ELISA in the serum and IgG aCL and anti-beta 2 GP-I in the urine of 125 women with hypertensive disorders of pregnancy (cases) (75 had preeclampsia, 25 had eclampsia, and 25 had chronic hypertension). One hundred and twenty seven normal women were used as controls. Antibody positivity was defined as above the 90(th) percentile of the controls. RESULTS: We found no differences in frequency of serum anti-beta 2 GP-I or serum and urinary aCL between cases and controls. In contrast, we found that frequency of IgG anti-beta 2 GP-I was higher in the urine of cases (26.1%) compared to controls (9.4%, p = 0.001). Strength of association was stronger for urinary anti-beta2-glycoprotein-I in women with preeclampsia (odds ratio [OR] = 4.3, 95% confidence limit [CI 95%] = 1.95-9.62, p <0.0001). Cases and the subgroup of preeclamptic patients also had higher titers of urinary IgG anti-beta 2 GP-I than control women (p <0.0001). CONCLUSIONS: Our work suggests that urine testing is necessary in order to ascertain whether antibodies to beta(2)GP-I are associated with preeclampsia.

Prevalence of battering among 1780 outpatients at an internal medicine institution in Mexico.

Violence against women has recently drawn attention in the medical community as a leading cause of preventable morbidity and mortality. Specific algorithms designed to identify women at risk can be applied to create an opportunity for screening, diagnosis and treatment during medical care initiated for common conditions. This study investigated the incidence and history of battering among women seeking general medical care, and looked for potential risk factors and associations with presenting symptoms. We used a self-administered, anonymous survey to question 1780 adult female outpatients visiting a tertiary care internal medicine teaching hospital in Mexico City. We calculated current abuse (physical and/or sexual abuse by a partner within the past year), abuse during pregnancy, childhood abuse, and lifetime abuse. We found levels of violence against women in Mexico comparable to those reported from other countries. 152 women (9%) reported current physical and/or sexual abuse. An identical number also reported abuse during pregnancy. Lifetime prevalence was 41%. Women currently or previously abused reported more physical symptoms in the last six months than did non-abused participants. Pelvic pain, depression, headache and substance abuse were frequent among abused women. Currently abused women also scored higher (p<0.01) on indicators of depression. Current abuse correlated strongly with a childhood history of physical and/or sexual abuse, with low educational level of the victim, with substance abuse by the partner or by the woman herself, and with higher parity.

Anti-cardiolipin, anti-cardiolipin plus bovine, or human beta(2)glycoprotein-I and anti-human beta(2)glycoprotein-I antibodies in a healthy infant population.

BACKGROUND: Pathogenic antiphospholipid antibodies studies are usually conducted on populations of adults. Studies involving normal children are scant. METHODS: Antibody reactivity against CL alone (true aCL), CL-complexed to bovine beta(2)GP-I (aCL-bovine beta(2)GP-I), or human (aCL-human beta(2)GP-I) beta(2)GP-I, or to phospholipid-free human beta(2)GP-I (anti-human beta(2)GP-I) was determined by ELISA in serum samples from 360 Mexican children ranging from 1 month through 8 years of age. RESULTS: Statistical analysis of variance and rankings of Kruskal-Wallis demonstrated no significant difference in all tested antibody activities between ages and genders of the study population. Values are presented as a percentile distribution included between 5 and 99, corresponding to the percentages of the studied population. Normal arbitrary units (AU) for IgG, IgA, and IgM true aCL that correspond to the 95 and 99 percentiles are as follows: 2.15 and 3.5; 2.35 and 5.0, and 3.15 and 4.5, respectively. IgG, IgA, and IgM aCL-bovine beta(2)GP-I activities are 2.6 and 5.0, 3.0 and 5.0, and 2.7 and 6.0 AU, respectively, while IgG activities of aCL-bovine and human beta(2)GP-I are 1.45 and 1.80, respectively. Normal values for IgG anti-human beta(2)GP-I are 1.85 AU. CONCLUSIONS: While elevated serum levels of antibodies to CL and/or beta(2)GP-I have been associated with thrombotic and hematologic manifestations, the majority of reports deal with adult populations. We report the cut-off values (in AU, international PL units, and international units for beta(2)GP-I) of the specific serologic response of true aCL, aCL-bovine beta(2)GP-I, aCL-human beta(2)GP-I, and anti-human beta(2)GP-I in healthy Mexican children.

Distribution of class I and class III MHC antigens in the Tarasco Amerindians.

Class I and class III major histocompatibility complex (MHC) antigen frequencies were analyzed in 130 haplotypes from 33 families belonging to a group of Amerindians culturally and linguistically isolated for more than 12 centuries in Mexico: the Tarascos. The most frequent antigens in this ethnic group of the HLA-A locus are: A2 (gf 0.353), A24 (gf = 0.223), A31 (gf = 0.184), and A28 (gf = 0.161); and the most frequent of the HLA-B locus are: B35 (gf = 0.230), B39 (gf = 0.192), B15 (gf = 0.146), and B5 (gf = 0.123). On the other hand, class III antigens demonstrated relatively high frequencies of the SC31 (frequency = 0.561), SC01 (frequency = 0.076), and SC42 (frequency = 0.069) complotypes. Also important was the relatively high frequency of the HLA-B27 antigen (gf 0.061) and the SC33 complotype (frequency = 0.046), which are either absent or found infrequently in other Amerindian groups. Analysis of MHC haplotypes revealed that four of them have relatively high frequencies, these were the following: [B39;SC31] (11.6%), [B35;SC31] (11.6%), [B15;SC31] (8.0%), and [B5;SC31] (5.8%). Other MHC haplotypes had frequencies lower than 5.0%. The decreased frequency of BF alleles other than BF*S and the presence of the SC33 and SC32 complotypes suggest long time preservation from genetic admixture. This information withstands the basis for population genetic analysis and disease association studies in Mexican mestizos.

Antiprothrombin antibodies in patients with systemic lupus erythematosus or with primary antiphospholipid syndrome.

Some authors have found a strong statistical association of antibodies to prothrombin (aPT) with thrombosis in patients with antiphospholipid syndrome (APS); others have not confirmed this finding. It is unknown if the detection of aPT, in addition to anticardiolipin (aCL) and anti-beta2-glycoprotein-I (abeta2GP-I) antibodies, provides additional information in the clinical study of these patients. We studied 38 patients with primary antiphospholipid syndrome and 466 patients with systemic lupus erythematosus (SLE; 24 had a history of thrombosis and 69 had secondary APS). All were tested by ELISA for serum aPT (IgG and IgM) using irradiated and plain plates. We also detected aCL and anti-beta2GP-I by ELISA. One hundred sera from clinically healthy individuals were used as controls. Twenty-six percent and 11% primary APS sera were positive for IgG and IgM aPT, respectively, compared with 3% and 5% of controls (p < 0.001, both comparisons). We found no difference in the frequency of aPT in SLE patients and controls, but aPT were positive in 46% of lupus patients with a history of thrombosis (20% IgG, 33% IgM) and in 9% of those without thrombosis (6% IgG, 5% IgM; p < 0.001, both comparisons). Likewise, there was a significant difference in the frequency of aPT in SLE patients with (22%) or without (9%) secondary APS (p < 0.001). aPT titers decreased two- to sixfold when tested in plain plates. Thirty-five of 38 primary APS sera (92%) had IgG anti-beta2GP-I and 12 (31%) had aCL. No patient had aPT as the only antibody. The higher binding of aPT on irradiated plates suggests that aPT recognize a hidden epitope exposed by negative surfaces. The higher frequency of aPT found in patients with primary APS, SLE with thrombosis, or with secondary APS may suggest concerted pathogenic actions with other autoantibodies, but the detection of aPT does not seem to be of clinical value.

Frequencies of HLA-A and HLA-B alleles in a Mexico City mestizo sample.

The aim of the present study was to evaluate the frequency of HLA-A and HLA-B antigens in a sample of the Mexico City Mestizo population. Previous similar studies were done by other authors in nonrelated individuals, while the present investigation was performed in families (parents and offspring), and therefore, a more accurate estimate of gene and haplotype frequencies was obtained. The predominant antigens in descending order are A2, A24, and A28 at the A locus, whereas B39 and B35 are at the B locus, all with gene frequencies above 0.1. As expected, the two more frequent haplotypes were A2-B16 and A2-B35 (considering main specificities), both with frequencies of 0.056. Seven of the 18 significant delta values of the haplotypes (observed vs. expected) remained significant after correcting for the number of comparisons, indicating the presence of linkage disequilibrium between the HLA-A and HLA-B regions. However, only A1-B8 and A19-B13 were found to be in disequilibrium in another Mexico City Mestizo sample which had very similar HLA-A and HLA-B allele frequencies to those in the present survey, suggesting that the biological significance of the other associations is rather doubtful. Am. J. Hum. Biol. 9:1-5 © 1997 Wiley-Liss, Inc.