Gabriel J. Tobón

The environment, geo-epidemiology, and autoimmune disease: Rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by a distinctive pattern of bone and joint destruction. RA patients have an increased risk of death. The incidence and prevalence of RA vary across populations, statistical methods, and disease definitions. In North America and Northern Europe, the incidence of RA is estimated at 20-50 cases per 100,000 population and the prevalence at 0.5-1.1%. Lower incidences and prevalences have been reported in Southern Europe, and few data are available for developing countries. Some studies showed declining incidences and prevalences after the 1960s. RA is a multifactorial disease that results from interactions between genetic and environmental factors. The main genetic factors are HLA-DRB1 and the tyrosine-phosphatase gene PTPN22. Among environmental factors implicated in the development of RA, smoking shows the strongest association with RA susceptibility and is also linked to worse outcomes. The aim of this review is to discuss the available data on the incidence and prevalence of RA, as well as the genetic and environmental risk factors associated with RA.

The environment, geo-epidemiology, and autoimmune disease: Rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by a distinctive pattern of bone and joint destruction. RA patients have an increased risk of death. The incidence and prevalence of RA vary across populations, statistical methods, and disease definitions. In North America and Northern Europe, the incidence of RA is estimated at 20 to 50 cases per 100,000 population and the prevalence at 0.5% to 1.1%. Lower incidences and prevalences have been reported in Southern Europe, and few data are available for developing countries. Some studies showed declining incidences and prevalences after the 1960s. RA is a multifactorial disease that results from interactions between genetic and environmental factors. The main genetic factors are HLA-DRB1 and the tyrosine-phosphatase gene PTPN22. Among environmental factors implicated in the development of RA, smoking shows the strongest association with RA susceptibility and is also linked to worse outcomes. The aim of this review is to discuss the available data on the incidence and prevalence of RA, as well as the genetic and environmental risk factors associated with RA.

B cells in Sjögren's syndrome: from pathophysiology to diagnosis and treatment.

Primary Sjögrens syndrome (pSS) is a chronic autoimmune systemic disease, characterized by a lymphoplasmocytic infiltration and a progressive destruction of salivary and lachrymal glands, leading to ocular and mouth dryness. T cells were originally considered to play the initiating role in the autoimmune process, while B cells were restricted to autoantibody production. However, recent years have seen growing evidence that the roles of B cells in pSS pathophysiology are multiple, and that these cells may actually play a central role in the development of the disease. B cells are over-stimulated and produce excessive amounts of immunoglobulins and various autoantibodies. Peripheral blood and salivary-gland B-cell subset distribution is altered, leading to the constitution of ectopic germinal centers where auto-reactive clones may escape tolerance checkpoints. B cells control T-cell activation by different means: B effector cells guide Th1 or Th2 differentiation, whereas regulatory B cells inhibit T-cell proliferation. Several B-cell specific cytokines, such as BAFF or Flt-3L, are instrumental in the occurrence of B-cell dysfunction. Chronic and excessive stimulation of B cells may lead to the development of lymphoma in pSS patients. Autoantibodies and blood B-cell subset analysis are major contributors of a clinical diagnosis of pSS. These considerations led to the development of B-cell depletion therapies for the management of pSS. Rituximab, a monoclonal antibody to CD20, is the best studied biologics in pSS, but other treatments hold promise, targeting for example CD22 or BAFF. Thus, during the last 20 years, the understanding of the multifaceted roles of B cells in pSS has revolutionized the management of this complex disease.

Confirmation of an association between rs6822844 at the IL2-IL21 region and multiple autoimmune diseases: Evidence of a general susceptibility locus

OBJECTIVE Autoimmune diseases often have susceptibility genes in common, indicating similar molecular mechanisms. Increasing evidence suggests that rs6822844 at the IL2-IL21 region is strongly associated with multiple autoimmune diseases in individuals of European descent. This study was undertaken to attempt to replicate the association between rs6822844 and 6 different immune-mediated diseases in non-European populations, and to perform disease-specific and overall meta-analyses using data from previously published studies. METHODS We evaluated case-control associations between rs6822844 and celiac disease (CD) in subjects from Argentina; rheumatoid arthritis (RA), type 1 diabetes mellitus (DM), primary Sjögrens syndrome (SS), and systemic lupus erythematosus (SLE) in subjects from Colombia; and Behçets disease (BD) in subjects from Turkey. Allele and gene distributions were compared between cases and controls. Meta-analyses were performed using data from the present study and previous studies. RESULTS We detected significant associations of rs6822844 with SLE (P = 0.008), type 1 DM (P = 0.014), RA (P = 0.019), and primary SS (P = 0.033) but not with BD (P = 0.34) or CD (P = 0.98). We identified little evidence of population differentiation (F(ST) = 0.01) within cases and controls from Argentina and Colombia, suggesting that association was not influenced by population substructure. Disease-specific meta-analysis indicated significant association for RA (P(meta) = 3.61 x 10(-6)), inflammatory bowel disease (IBD; Crohns disease and ulcerative colitis) (P(meta) = 3.48 x 10(-12)), type 1 DM (P(meta) = 5.33 x 10(-5)), and CD (P(meta) = 5.30 x 10(-3)). Overall meta-analysis across all autoimmune diseases reinforced association with rs6822844 (23 data sets; P(meta) = 2.61 x 10(-25), odds ratio 0.73 [95% confidence interval 0.69-0.78]). CONCLUSION Our results indicate that there is an association between rs6822844 and multiple autoimmune diseases in non-European populations. Meta-analysis results strongly reinforce this robust association across multiple autoimmune diseases in both European-derived and non-European populations.

Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases

OBJECTIVES Recently, a non-synonymous (Gly307Ser) variant, rs763361, in the CD226 gene was shown to be associated with multiple autoimmune diseases (ADs) in European Caucasian populations. However, shared autoimmunity with CD226 has not been evaluated in non-European populations. The aim of the present study is to assess the association of this single nucleotide polymorphism (SNP) with ADs in non-European populations. METHODS To replicate this association in non-European populations, we evaluated case-control association between rs763361 and coeliac disease (CED) samples from Argentina; SLE, RA, type-1 diabetes (T1D) and primary SS (pSS) from Colombia; and SLE samples from China and Japan. We genotyped rs763361 and evaluated its genetic association with multiple ADs, using chi(2)-test. For each association, odds ratio (OR) and 95% CI were calculated. RESULTS We show that rs763361 is significantly associated with Argentinean CED (P = 0.0009, OR = 1.60). We also observed a trend of possible association with Chinese SLE (P = 0.01, OR = 1.19), RA (P = 0.047, OR = 1.25), SLE (P = 0.0899, OR = 1.24) and pSS (P = 0.09, OR = 1.33) in Colombians. Meta-analyses for SLE (using our three populations) and T1D (our population and three published populations) yielded significant association with rs763361, P = 0.009 (OR = 1.16) and P = 1.1.46 x 10(-9) (OR = 1.14), respectively. CONCLUSIONS Our results demonstrate that the coding variant rs763361 in CD226 gene is associated with multiple ADs in non-European populations.

Neurological Disorders in Primary Sjogren's Syndrome.

Sjögrens syndrome is an autoimmune disease characterized by an autoimmune exocrinopathy involving mainly salivary and lacrimal glands. The histopathological hallmark is periductal lymphocytic infiltration of the exocrine glands, resulting in loss of their secretory function. Several systemic manifestations may be found in patients with Sjögrens syndrome including neurological disorders. Neurological involvement ranges from 0 to 70% among various series and may present with central nervous system and/or peripheral nervous system involvement. This paper endeavors to review the main clinical neurological manifestations in Sjögren syndrome, the physiopathology, and their therapeutic response.

Prediction of Radiographic Damage in Early Arthritis by Sonographic Erosions and Power Doppler Signal: A Longitudinal Observational Study

To assess the ability of ultrasonography (US) to predict radiographic damage in early arthritis.

Autoimmune rheumatic diseases in the intensive care unit: experience from a tertiary referral hospital and review of the literature

Autoimmune rheumatic diseases (AIRD) are not uncommon in the general population and up to one third of hospitalized patients with AIRD may need admission to intensive care unit (ICU). This paper describes the causes of admission, the clinical features and outcome of 24 AIRD patients admitted to a medical ICU from a third level hospital. Thirteen patients had systemic lupus erythematosus (54.2%), three rheumatoid arthritis (12.5%), three pulmonary renal syndrome (12.5%), two dermatopolymyositis (8.3%), two scleroderma (8.3%) and one antiphospholipid syndrome (4.2%). The main causes for ICU admission were rheumatic disease flare-up (37.5%), infection (37.5%) and complications derived from rheumatic disease (29.1%). Mortality during ICU stay was 16.7% (four patients). Excluding shock requiring vasopressor support, no statistical difference was found between survivors and nonsurvivors; although there was a trend to higher test severity scores (APACHE II, ODIN) in nonsurvivors. Our results reveal a lower mortality rate in AIRD patients admitted to the ICU than reported previously. Severity scores such as APACHE II are predictors of mortality in patients with AIRD in the ICU.

The Fms-like tyrosine kinase 3 ligand, a mediator of B cell survival, is also a marker of lymphoma in primary Sjögren's syndrome

OBJECTIVE To determine if the Fms-like tyrosine kinase 3 ligand (Flt-3L), a cytokine implicated in B cell ontogenesis and proliferation in hematologic malignancies, might be responsible for the increased numbers of circulating Bm2 and Bm2′ B cell subsets in patients with primary Sjögrens syndrome (SS). METHODS Serum levels of Flt-3L were measured in 64 patients with primary SS and in 20 healthy controls matched for age and sex. Flt-3L and its receptor Flt-3 were quantified in circulating B cells and in salivary gland (SG) biopsy tissues by immunofluorescence analysis. The effect of Flt-3L on circulating B lymphocytes was then determined by coculture with cells of a human SG (HSG) epithelial cell line. RESULTS Serum levels of Flt-3L were increased in patients with primary SS as compared with controls (mean ± SD 135.8 ± 5.5 versus 64.4 ± 4.5 pg/ml; P < 0.001). Serum levels of Flt-3L in primary SS patients correlated with the numbers of Bm2 and Bm2′ cells (r = 0.46, P < 0.0006), and Flt-3 was selectively expressed in Bm2 and Bm2′ cells. B cell culture experiments showed that Flt-3L potentiated the proliferative effect of anti-IgM stimulation. In SGs, we found that infiltrating B cells expressed Flt-3 and epithelial cells produced Flt-3L. Finally, Flt-3L levels were associated with high disease activity scores and increased risk of developing lymphoma. CONCLUSION Serum levels of Flt-3L are elevated in patients with primary SS and correlate with abnormal B cell distribution. Flt-3 is mainly expressed by Bm2 and Bm2′ cells. Serum levels of Flt-3L might explain the clinical evolution of primary SS to B cell lymphoma that is observed in some patients, thus opening the possibility of new avenues for therapy.

Are autoimmune diseases predictable

Autoimmune diseases are complex diseases resulting of the interaction between both genetics and environmental factors over time. Different phases in the development of autoimmune diseases are characterized by the detection of serum autoantibodies several months or years before the onset of clinical manifestations and subsequent diagnosis. In addition to serum antibodies, genetic susceptibility factors may predict the future development of the disease. Currently, prediction in type 1 diabetes is the most accurate, with the analysis of genetic susceptibility factors in first-degree relatives of patients and several autoantibody tests. In the future, multiple antibodies test, in combination with the analysis of genetics, epigenetics and immunological anomalies in fine models may allow the precise prediction in autoimmune diseases. Prevention measures might thus be introduced as an attempt to avoid or delay the disease.