Browsing by Author "Mahler, Michael"
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Item Anti-Protein-Arginine Deiminase 4 IgG and IgA Delineate Severe Rheumatoid Arthritis.(Diagnostics, 2022) Martínez Prat, Laura; Martinez-Taboada, Victor; Santos Tejedor, Cruz; Lopez-Hoyos, Marcos; Mahler, MichaelThere is a strong need for biomarkers of rheumatoid arthritis (RA) in all phases of the patient’s journey and to enable the implementation of precision medicine strategies to improve patient care. The objective of this study was to evaluate the presence of anti-protein-arginine deiminase (PAD) 4 IgG and IgA in the sera of RA patients and disease controls, and to investigate their association with joint erosion and biological treatment use. Sera from 104 RA and 155 controls were tested for the presence of anti-PAD4 IgG and IgA using a new particle-based multi-analyte technology (PMAT). Information on the erosive disease and biological treatment use was available for 54 of the RA patients, who were also tested for anti-citrullinated protein antibodies (ACPA). An association between the autoantibodies and these clinical features was investigated. Anti-PAD4 showed sensitivity and specificity values of 25.0% and 94.2% for IgG and of 21.2% and 94.8% for IgA for RA, respectively. The levels of these antibodies were also significantly higher in RA patients vs. controls, in erosive RA vs. non-erosive disease, and in patients under biologics vs. patients that were not on this treatment regimen. The anti-PAD4 IgG and IgA levels were correlated (rho = 0.60, p < 0.0001), but individuals that were positive for only one of the two isotypes were also observed. Anti-PAD4 IgG and IgA are associated with severe RA, and they represent valuable biomarkers for prognosis prediction and patient stratification.Item Association of anti-pad4 antibodies with erosion and biological treatment use in rheumatoid arthritis.(https://ard.bmj.com/content/78/Suppl_2/315.1, 2019) Martínez Prat, Laura; Martinez-Taboada, Victor; Lopez-Hoyos, Marcos; Mahler, MichaelBackground: Novel biomarkers have been described in rheumatoid arthritis (RA) patients, including antibodies to carbamylated proteins (anti-CarP) and to protein-arginine deiminases (PAD). Anti-PAD4 antibodies are associated with anti-citrullinated protein antibodies (ACPA) and worse baseline radiographic joint damage [1]. A subset of anti-PAD4 antibodies that cross-react with PAD3 and are associated with erosive disease, ACPA and progress despite treatment have also been described [1]. Objectives: To evaluate several novel RA markers in a cohort of RA and controls and their association with erosive disease and biological treatment use in RA. Methods: Sera from 116 RA patients [63 young onset RA (YORA) and 53 elderly onset RA (EORA)] and 155 controls [134 polymyalgia rheumatica (PMR) patients and 21 healthy individuals (HI) older than 60 years old] were included. Information on erosion status and biological treatment was available for 56 of the RA patients. The samples were tested for anti-PAD3 and anti-PAD4 IgG using the novel particle-based multi-analyte technology (PMAT, research use only, RUO), as well as for ACPA [CCP3 IgG ELISA and chemiluminescent immunoassay (CIA)] and anti-CarP IgG (ELISA, RUO). Results: Significantly higher levels of anti-PAD3, anti-PAD4 and ACPA (ELISA and CIA) but not CarP were observed in YORA vs. EORA (p<0.0001 for anti-PAD3 and ACPA ELISA and CIA, p=0.0016 for anti-PAD4). In the RA patients with erosion and treatment information available, anti-PAD4 antibody levels, but not ACPA, anti-CarP or anti-PAD3, were significantly higher in patients on biologic treatment vs. patients that were not on biologics (p=0.0017). Anti-PAD4 positive patients, were 10.1 [95% CI 2.5-52.0, p=0.0002] times more likely to be on biologic treatment vs. the negative group. Similarly, anti-PAD4 antibodies, but neither ACPA nor anti-CarP or anti-PAD3, were also significantly higher in patients with joint erosions (p=0.0354). All patients that were positive for anti-PAD4 antibodies (n=21) had erosive disease. Anti-PAD4 positive patients, were 20.2 [95% CI 1.1-363.2, p=0.0041] times more likely to have erosive disease.Item Multi-parametric model for the improved diagnosis and stratification of rheumatoid arthritis patients.(2020) Martínez Prat, Laura; Mahler, Michael; Santos Tejedor, Cruz; Doctorado en Biotecnología, Medicina y Ciencias BiosanitariasRheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases. Despite several serological markers are known for this disease and two of them, rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA), are included in the RA classification criteria, there are still many patients that are negative for these two biomarkers. For this reason, there is a need to identify novel biomarkers that can help close this serological gap in RA, as well as to improve patient stratification, prediction of prognosis and response to treatment, and disease monitoring. Objectives The main objective of this thesis was to develop a multi-parametric model that helps to improve RA diagnosis, patient stratification and prediction of prognosis. The specific objectives included, firstly, the assessment of the current practice, the evaluation of several immunoassays for the detection of the RA classification criteria markers, and the analysis of combinatory approaches. Secondly, among the RA novel biomarkers, the anti-protein-arginine deiminase (PAD) antibodies were selected to study their clinical and immunological relevance in RA. We then aimed to characterize the PAD enzymes as antigenic targets, to develop immunoassays for the detection of these antibodies, and to determine their clinical significance and utility in RA in several characterized cohorts. Methods Several methodologies were utilized to achieve the thesis objectives. These included literature screening; feasibility studies, early development and optimization of a range of immunoassays for the detection of autoantibodies in human samples; biochemical characterization of the antigens and the autoantibodies; measurement of biomarkers in different clinical cohorts using the immunoassays; data analysis; and drafting of combinatory approaches for the integration of the different data points. Results Combinatory approaches based on RF and ACPA showed an improved diagnostic performance over the individual markers and can help correctly classify a higher number of patients. During the study of the PAD enzymes and anti-PAD antibodies, several linear epitopes were identified on the five PAD family members, with data suggesting the presence of epitopes unique to PAD3 or to PAD4, in addition of the cross-reactive epitope. The presence of anti-PAD4 antibodies of the IgA isotype in RA was confirmed and an association with erosive disease was identified, a link also confirmed for anti-PAD3 IgG. We identified anti-PAD4 IgM and antibodies to PAD1 and 6 for the first time, and confirmed that anti-PAD4 IgG can help close the serological gap in RA and are associated with a more severe disease phenotype. We confirmed that antibodies to PAD2 are also present in the sera of RA patients, however the reported association with milder disease could not be reproduced. Conclusions A combinatory approach based on ACPA and RF IgM represents a promising tool to improve the diagnosis of RA. Anti-PAD3 and 4 antibodies are useful biomarkers for patient stratification. A multiparametric model for the improvement of RA diagnosis and patient stratification based on these autoantibodies and other features has been proposed.