Consuelo Romero-Sánchez

Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci

Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis–associated haplotypes at 11 loci. Two ankylosing spondylitis–associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.

Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1.

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

Serum monocyte chemotactic protein-1 concentrations distinguish patients with ankylosing spondylitis from patients with mechanical low back pain.

Objectives This study aimed to identify potential blood-derived biomarkers distinguishing patients with ankylosing spondylitis from those with mechanical low back pain. Methods Serum and synovial fluid samples from our cohorts were assayed by using enzyme-linked immunosorbent assay for the following inflammatory biomarkers: interleukin (IL)-1&agr;, IL-6, IL-8, IL-17, IL-23, monocyte chemotactic protein (MCP)-1, macrophage inflammatory proteins (MIP)-1&agr;, MIP-1&bgr;, tumor necrosis factor-&agr; (TNF-&agr;), interferon-&agr; (IFN-&agr;), IFN-&bgr;, metalloproteinase (MMP-3), and bone morphogenetic protein 7 (BMP-7). Results After screening, a panel of serum and synovial fluid samples with a series of potential biomarkers, cytokines including IL-6, IL-8, MMP-3, and MCP-1 were selected for additional testing because they exhibited higher concentrations than paired serum samples in the synovial fluid. Sera obtained from 50 patients with ankylosing spondylitis and 27 patients with mechanical low back pain were measured for these biomarkers. Conclusions The MCP-1 serum was identified as a biomarker candidate, distinguishing ankylosing spondylitis from mechanical low back pain with a sensitivity of 96% and a specificity of 83.3%.

Periodontal Disease in Individuals With a Genetic Risk of Developing Arthritis and Early Rheumatoid Arthritis: A Cross-Sectional Study

BACKGROUND Recent consensus emphasizes the importance of studying individuals at risk for rheumatoid arthritis (pre-RA) and those with early RA (eRA). Periodontal tissues have been recently evaluated, but these studies are limited. To evaluate the periodontal condition, immunoglobulin (Ig)G subclasses against Porphyromonas gingivalis in individuals with pre-RA and eRA were compared with controls to establish an association between periodontal infection markers and rheumatic activity. METHODS Rheumatologic and periodontal condition was evaluated in 119 individuals with pre-RA, 48 patients with eRA, and matched controls. P. gingivalis IgG1 and IgG2 were analyzed. C-reactive protein, erythrocyte sedimentation rate (ESR), rheumatoid factor, anticitrullinated protein antibodies (ACPAs), and RA activity were measured. The groups were compared with McNemar test and paired t-test. Conditional logistic regression was performed for pre-RA confounders, and χ(2) test was used to evaluate periodontal variables and RA activity indices. RESULTS Pre-RA individuals showed significantly higher levels of plaque index (P = 0.01) and bleeding on probing (P = 0.03) and higher severity of periodontal disease (P = 0.02). Periodontitis was associated with pre-RA (odds ratio, 3.39; 95% confidence interval, 1.64 to 7.01) but not with eRA. In pre-RA, P. gingivalis-specific IgG2 was associated with ACPAs (P = 0.049) and disease severity visual analog scale (P = 0.03). In eRA, IgG2 against P. gingivalis was associated with ESR (P = 0.046) and ACPAs (P = 0.04). P. gingivalis was associated with ACPAs (P = 0.04). CONCLUSIONS This study shows that individuals with pre-RA have significant inflammatory periodontal involvement. There was a significant association between IgG against P. gingivalis and ACPAs in pre-RA and markers of RA activity in individuals with eRA.

Epidemiology of Spondyloarthritis in Colombia

There are no formal statistics about the incidence, prevalence or demographics of patients with spondyloarthropathies (SpAs) in Colombia. However, information from a few studies provides a preliminary snapshot of SpAs in the country. In this article, the authors review what has been published; document what their group is doing and outline what they still need to do in the future. The analysis suggests that although information on SpA in Colombia is limited, it is known that the diagnostic entities of SpA are different than those reported at other latitudes. Thus, it is important to improve and expand the current database of SpA, particularly undifferentiated SpA, not only in Colombia but in all of Latin America.

Biomarcadores en espondiloartropatías

Among rheumatic diseases and specifically spondyloarthropathies (SpA), the study of biomarkers, defined as molecules that reflect either biologic or specific pathological process, is an important and necessary area in basic and clinical research, being a consequence or the response of an intervention. Other markers provide information about the pathogenesis of this disease. Recently, HLA-B27 has been used as diagnostic criteria to detect SpA. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) are clinical scores used to assess disease activity. A new activity index, Ankylosing Spondylitis Disease Activity Score (ASDAS) considers erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as biomarkers. This review describes the state of the art of research on SpA biomarkers. There are promising new candidates as biomarkers such as metallopro-teinase 3, Type II collagen neoepitopes (C2C and C1-2C), C-propeptide of Type II collagen (CPII), aggrecan 846 epitope, macrophage colony stimulating factor, serum amyloid A protein and interleukin-6, among others.

Is the Treatment with Biological or Non-biological DMARDS a Modifier of Periodontal Condition in Patients with Rheumatoid Arthritis?

BACKGROUND AND OBJECTIVE Experimental models suggest the use of different therapy protocols in rheumatoid arthritis (RA) as modulators on periodontal condition. This study evaluated the effects of conventional drug treatment and anti-TNF therapy in patients with RA on microbiological and periodontal condition, establishing the association of markers of periodontal infection with indexes of rheumatic activity. MATERIALS AND METHODS One hundred seventy nine individuals with RA were evaluated (62 with anti-TNF-. and 115 with only DMARDs). The periodontal evaluation included plaque and gingival indexes, bleeding on probing (BOP), clinical attachment loss (CAL), pocket depth (PD) and subgingival plaque samples for microbiological analysis. Rheumatologic evaluations included a clinical examination, rheumatoid factor (RF), antibodies against cyclic-citrullinated peptides (ACPAs), and activity markers (DAS28-ERS), high sensitive C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR). RESULTS Anti-TNF-alpha therapy influenced periodontal microbiota with a higher frequency of T. denticola (p=0.01). Methotrexate combined with leflunomide exhibited a higher extension of CAL (p=0.005), and anti-TNF-alpha therapy with methotrexate was associated with a lower extension of CAL (p=0.05). The use of corticosteroids exerted a protective effect on the number of teeth (p=0.027). The type of DMARD affected P. gingivalis, T. forsythia and E. nodatum presence. Elevated ACPAs titers were associated with the presence of red complex periodontal pathogens (p=0.025). Bleeding on probing was associated with elevated CPR levels (p=0.05), and ESR was associated with a greater PD (p=0.044) and presence of red complex (p=0.030). CONCLUSION Different pharmacological treatments for RA affect the clinical condition and subgingival microbiota.

Is there a relationship between spondyloarthritis and periodontitis? A case-control study

Objective To compare the frequency and severity of periodontitis in patients with spondyloarthritis (SpA) with healthy control individuals, through the evaluation of clinical, serological and microbiological periodontal condition. Methods Patients with a diagnosis of SpA (n=78) and biological disease-modifying antirheumatic drug (bDMARD) naive fulfilling the Assessment of SpondyloArthritis international Society (ASAS) classification criteria as well as 156 healthy controls matched for age/gender were included. Two trained and calibrated periodontologists performed the periodontal clinical assessment. The presence of periodontitis and its severity were determined according to the criteria established by the Centers for Disease Control and Prevention-American Academy of Periodontology. The clinical periodontal variables, IgG1/IgG2 antibodies against Porphyromonas gingivalis andperiodontopathic bacterial identification, were also established. Comparisons of periodontal characteristics between the patients with SpA and the control group were performed using univariable analyses. A logistic regression analyses was performed to calculate the OR (95% CI) for diagnosis of periodontitis in patients with SpA and matched controls. Results A diagnosis of periodontitis was established in 56% in patients with SpA versus 69% of healthy controls (P≤ 0.01). Severe periodontitis was found in 3% versus 12% in SpA versus healthy controls, respectively (P≤ 0.01). There was no significant increase of frequency of any periodontal variable, IgG1/IgG2 antibodies against P. gingivalis or the presence of periodontopathic bacteria between patients with SpA and control group. Periodontitis was not positively associated with a diagnosis of SpA (OR: 0.57, 95% CI 0.32 to 1.00, P=0.05) in the logistic regression analyses. Conclusions We found a lower rather than a higher frequency and severity of periodontitis in patients with SpA in comparison with healthy control individuals. Our findings suggest that there is no positive association between SpA and periodontitis in Colombian patients.

The Frequency of HLA-B27 in a Colombian Population with Signs of Spondyloarthritis

BACKGROUND The strong association between HLA-B27 and spondyloarthritis (SpA) has demonstrated that typing the HLA-B27 antigen is a crucial step in diagnosis and aids in defining the progression and severity of disease. OBJECTIVE To describe the frequency of HLA-B27 in Colombian individuals with clinical manifestations associated with SpA. MATERIALS AND METHODOLOGY We retrospectively analyzed 4109 HLA-B27 typing requests to the Hospital Militar Central and the Instituto de Referencia Andino from Colombian individuals with clinical signs suggestive of SpA between 2009 and 2012. We used basic digital cytometry followed by Polymerase Chain Reaction with sequence specific primers when confirmation was needed. We determined the frequency of HLA-B27 in the population and levels of association of HLA-B27 with SpA. RESULTS Our population included 1585 men (36.8%) and 2524 women (61.4%). The predominant age range was between 19 and 45 years (49.9%). The majority (95.4%) of the study population came from the Andean region and eastern plains. The most frequent clinical manifestations were peripheral. Only a small fraction (12.1%) of the 4109 subjects was HLA-B27 positive. Of those, 56.9% were male, and 54.7% were between 19 and 45 years old. In contrast, when rheumatologists referred the HLA B27, 64% were found to be positive. CONCLUSION The frequency of the HLA-B27 allele in individuals with clinical signs suggestive of SpA was low, in accordance with the lower prevalence found in Colombian patients diagnosed with SpA compared to American and European population.

Autoantibodies and gastrointestinal symptoms in colombian children with juvenile idiopathic arthritis.

BACKGROUND Juvenile Idiopathic Arthritis (JIA) is the most common inflammatory joint disease in children. JIA and autoimmune inflammatory Gastrointestinal (GI) diseases share common etiologic mechanisms, including genetic predisposition and environmental influences. OBJECTIVE To Investigate association between gastrointestinal, rheumatologic clinical variables and the presence of autoantibodies in patients with JIA in treatment. METHODOLOGY In a cross-sectional study of patients with JIA according to diagnostic criteria and the ILAR classification. GI symptoms and autoantibody expression were evaluated with respect to their association with JIA clinical variables. Anti-Saccharomyces Cerevisiae IgG/IgA (ASCA), 6 antigen associated with anti polymorphonuclear neutrophil (ANCA), anti Transglutaminase (tTG) IgG/IgA, anti deaminated gliadin peptide (DGP) IgG/IgA autoantibodies, ANAS and IgA were measured in all patients. The association between clinical variables and auto-antibodies were evaluated using the Fisher test with significant value of p <0.05. The study was approved by the ethics committee of the all institutions. RESULTS Samples were collected from ninety-seven patients, 63% of whom were female. The average age was 14 years. The JIA subtype associated with the most common GI symptoms was enthesitis- related arthritis. Of these patients, 44.3% and 14% reported abdominal pain and diarrhea, respectively. Anti-DPG and anti-tTG antibodies were found in 9.28% and 7.22%, respectively and 11.34% were positive for p-ANCA, and 2% were positive for ASCA. CONCLUSION GI symptoms and autoantibodies associated with inflammation of the GI mucosa were detected in JIA patients but were not associated with autoantibodies or clinical variables. However, it is the monitoring of these patients diagnosis is important.