Comparison and Influence of a Multicomponent Educational Program on the Patient-Reported Outcomes of a Group of Patients With Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic disease that affects different areas of the patient's body. Patient education and health literacy is essential for them to participate actively in follow-up. OBJECTIVES: The aim of this study was to assess differences between clinimetric measurements done by a medical team and patient-reported outcome measures (PROMs) in RA and understand the impact of patient education strategies in order to identify differences between RA assessment methods. METHODS: This is a longitudinal cohort study. It included adult patients with RA and access to digital tools. These were divided into 3 groups by type of education. Group 1 included patients who participated in a multicomponent RA educational program. Group 2 did not have this multicomponent RA education. Group 3 did not receive any education. The 3 groups performed PROMs. Disease activity scales, functional class, and quality of life were measured. Univariate and bivariate analysis (χ2 and Wilcoxon for paired data) were done. RESULTS: Twenty-eight patients were included in group 1, 26 in group 2, and 37 in group 3. All were women. In group 1, there were no significant differences in clinimetrics between the medical team and patient's PROMs except for fatigue. In group 2 and group 3, significant differences were found. The RAPID3 and PAS variables did not show significant differences when analyzed by intervention subgroups. CONCLUSIONS: This study shows no differences between clinimetrics/PROMs for patients with a high-level education on RA and physicians. On the other hand, when patient did not have any RA education, the clinimetric results differed from physician measurement.

Expectations and Experiences of a Group of Patients Enrolled in an Educational Program for Rheumatoid Arthritis at a Specialized Care Center in Colombia.

Introduction: Rheumatoid arthritis is a chronic inflammatory disease diagnosed in a productive stage of life. Patients with RA experience changes in their musculoskeletal system, overall health and quality of life. It has been identified that patients with RA do not have appropriate knowledge about their condition. Educational programs can provide new knowledge, accompaniment, and closer follow-up to improve empowerment and quality of life in patients with RA. Purpose: To describe rheumatoid arthritis patients' experiences, perceptions, and expectations when enrolling on a multicomponent educational program in a specialized RA setting. Patients and Methods: A qualitative study was done. Patients with RA who attended a specialized center and enrolled in an educational program participated in two focus groups. The focus group discussions and the interviews were recorded, transcribed verbatim, analyzed, and emerging themes were constructed. Results: Thirty-one participants were included in the focus groups. The median age was 60 years IQR (54-67), 92% were female. Two relevant categories emerged: first, the experience of being diagnosed with RA. Second, the program's ability to empower participants with knowledge and the possibility of transferring knowledge to other patients with the same condition. In addition, patients gave a high score to the expectations regarding the educational program. Conclusion: Understanding patients' expectations when enrolling in an educational program allows educators and clinicians to understand their motivations to create tailored programs that can contribute to acquiring empowerment in the educational process and managing their disease. Stakeholders should consider patients' expectations when implementing these interventions for patients with RA to adapt the intervention according to the patient's context and needs, which will directly affect the patient's adherence and lead to better use and allocation of resources for educational activities.

Is Tofacitinib Effectiveness in Patients with Rheumatoid Arthritis Better After Conventional Than After Biological Therapy? - A Cohort Study in a Colombian Population.

Purpose: Tofacitinib is recommended for treatment of rheumatoid arthritis (RA) in patients with moderate to severe disease activity, but there is not enough evidence on its effectiveness after conventional DMARDs vs its use after biologics. The aim was evaluating the effectiveness of tofacitinib in RA as first-line treatment (after conventional DMARDs) in a real-life setting in Colombian (Latin-American) patients. Patients and Methods: Retrospective cohort study conducted at a specialized center for RA management. A complete statistical analysis was performed to compare the values of the change in the DAS28 at months 3, 6, and 12 in both treatment groups. Results: A total of 152 RA patients who received tofacitinib: first-line 85 patients (55.9%) after failure on conventional DMARDs or second-line 67 patients (44.1%) after failure on biologic DMARDs. Comparative analysis of response to treatment showed a reduction in DAS28 at 3, 6, and 12 months in both study groups without statistical differences, but a higher proportion of first-line patients achieved remission (45% vs 23%). Nonresponse at three months were associated with no response at six months of follow-up. Baseline DAS28 was significantly associated with response at 12 months (OR: 1.87, 95%CI: 1.06-3.30, p-value 0.028). In second-line patients, response to tofacitinib was not related to number of biologic DMARDs previously used. Conclusion: Tofacitinib is an effective treatment option for patients with RA, maybe better after conventional DMARDs than after biologic therapy failure. Further studies are required to determine the role of tofacitinib in different lines of RA treatment and in other groups of patients.

[Peculiarities of allergy to plant foods in South-Eastern Spain]. / Peculiaridades de la alergia a los alimentos vegetales en el sureste de España.

Allergy to fruits and vegetables is the most common primary food allergy in Mediterranean countries, especially the lipid transfer proteins (LTPs) syndrome. This study is the first research that studies multiple clinical, allergological and therapeutics characteristics of allergies to plants in the South-East of Spain, and assessing whether these characteristics differ in emergency room or outpatient clinic. This is a prospective study of patients who consult for the first time for allergy to vegetables at Granada, Spain. We record demographic data, symptoms, allergological study and indicated therapy. The characteristics obtained agree with the current bibliographic except the higher prevalence than other areas of positive sensitization of Pru p 3, Cor a 9 and Ara h 9, which predisposes to severe allergic reactions. We conclude: Allergy to plant food in Granada is a more severe phenotype than other geographic areas from Spain, especially in young adults sensitized by different LTPs and pollinosis to olive pollen.

La alergia a frutas y verduras es la alergia alimentaria más común en los países mediterráneos, especialmente el síndrome LTP (lipid transfer proteins). Este es el primer estudio que analiza múltiples características clínicas, alergológicas y terapéuticas de la alergia a vegetales en el sureste de España y que evalúa si difieren en urgencias o consultas externas. Se trata de un estudio prospectivo de pacientes que consultan por primera vez debido a alergia a verduras en Granada, España. Registramos datos demográficos, clínicos, alergológicos y tratamiento prescrito. Las características obtenidas concuerdan con las infomadas en la bibliografía actual, excepto en la mayor prevalencia de Pru p 3, Cor a 9 y Ara h 9, que predisponen a reacciones alérgicas graves. La conclusión es que la alergia a vegetales en Granada es un fenotipo más grave que en otras áreas de España, especialmente en adultos jóvenes sensibilizados a diferentes proteínas de transferencia de lípidos y polinosis a polen del olivo.

Therapeutic potential of peptides from Ole e 1 in olive-pollen allergy.

Olive-pollen allergy is one of the leading causes of respiratory allergy in Mediterranean countries and some areas of North America. Currently, allergen-specific immunotherapy is the only etiophatogenic treatment. However, this approach is not fully optimal, safe, or effective. Thus, efforts continue in the search for novel immunotherapy strategies, being one of the most promising the use of peptides derived from major allergens. This work tries to determine the therapeutic potential and safety of 5 dodecapeptides derived from the main allergen of olive-pollen allergy, Ole e 1. The immunomodulatory capacity of these peptides was studied using peripheral blood mononuclear cells (PBMCs) obtained from 19 olive-pollen-allergic patients and 10 healthy controls. We determined the capacity of these peptides to inhibit the proliferative response toward olive-pollen allergenic extract and to induce the regulatory cytokines, IL-10 and IL-35. To test the safety and absence of allergenicity of the peptides, the basophil activation was analyzed by flow-cytometry, using peripheral blood. The results showed that two of five peptides inhibited near to 30% the proliferative response against the total olive-pollen allergenic extract in olive-pollen-allergic patients. Inhibition increased to nearly 35% when the 5 peptides were used in combination. In both cases, a statistically significant induction of IL-10 and IL-35 secretion was observed in the supernatants of allergic patients PBMCs cultures. None of the 5 peptides induced basophil activation and cross-link inflammatory cell-bound IgE. In conclusion, these results open up new possibilities in the treatment of olive-pollen allergy, which could solve some of the problems facing current therapy approaches.

Discriminatory Molecular Biomarkers of Allergic and Nonallergic Asthma and Its Severity.

Asthma is a complex disease comprising various phenotypes and endotypes, all of which still need solid biomarkers for accurate classification. In a previous study, we defined specific genes related to asthma and respiratory allergy by studying the expression of 94 genes in a population composed of 4 groups of subjects: healthy control, nonallergic asthmatic, asthmatic allergic, and nonasthmatic allergic patients. An analysis of differential gene expression between controls and patients revealed a set of statistically relevant genes mainly associated with disease severity, i.e., CHI3L1, IL-8, IL-10, MSR1, PHLDA1, PI3, and SERPINB2. Here, we analyzed whether these genes and their proteins could be potential asthma biomarkers to distinguish between nonallergic asthmatic and asthmatic allergic subjects. Protein quantification was determined by ELISA (in serum) or Western blot (in protein extracted from peripheral blood mononuclear cells or PBMCs). Statistical analyses were performed by unpaired t-test using the Graph-Pad program. The sensitivity and specificity of the gene and protein expression of several candidate biomarkers in differentiating the two groups (and the severity subgroups) was performed by receiver operating characteristic (ROC) curve analysis using the R program. The ROC curve analysis determined single genes with good sensitivity and specificity for discriminating some of the phenotypes. However, interesting combinations of two or three protein biomarkers were found to distinguish the asthma disease and disease severity between the different phenotypes of this pathology using reproducible techniques in easy-to-obtain samples. Gene and protein panels formed by single biomarkers and biomarker combinations have been defined in easily obtainable samples and by standardized techniques. These panels could be useful for characterizing phenotypes of asthma, specifically when differentiating asthma severity.

Nonallergic Asthma and Its Severity: Biomarkers for Its Discrimination in Peripheral Samples.

Asthma is a complex and heterogeneous respiratory disorder characterized by chronic airway inflammation. It has generally been associated with allergic mechanisms related to type 2 airway inflammation. Nevertheless, between 10 and 33% of asthmatic individuals have nonallergic asthma (NA). Several targeted treatments are in clinical development for patients with Th2 immune response, but few biomarkers are been defined for low or non-Th2-mediated inflammation asthma. We have recently defined by gene expression a set of genes as potential biomarkers of NA, mainly associated with disease severity: IL10, MSR1, PHLDA1, SERPINB2, CHI3L1, IL8, and PI3. Here, we analyzed their protein expression and specificity using sera and isolated peripheral blood mononuclear cells (PBMCs). First, protein quantification was carried out using ELISA (in sera) or Western blot (proteins extracted from PBMCs by Trizol procedure), depending on the biomarker in 30 healthy controls (C) subjects and 30 NA patients. A receiver operating characteristic curve analysis was performed by using the R program to study the specificity and sensitivity of the candidate biomarkers at a gene- and protein expression level. Four kinds of comparisons were performed: total NA group vs C group, severe NA patients vs C, moderate-mild NA patients vs C, and severe NA patients vs moderate-mild NA patients. We found that all the single genes showed good sensitivity vs specificity for some phenotypic discrimination, with CHI3L1 and PI3 exhibiting the best results for C vs NA: CHI3L1 area under the curve (AUC) (CI 95%): 0.95 (0.84-1.00) and PI3 AUC: 0.99 (0.98-1.00); C vs severe NA: PI3 AUC: 1 (0.99-1.00); and C vs moderate-mild NA: CHI3L1 AUC: 1 (0.99-1.00) and PI3 AUC: 0.99 (0.96-1.00). However, the results for discriminating asthma disease and severity with protein expression were better when two or three biomarkers were combined. In conclusion, individual genes and combinations of proteins have been evaluated as reliable biomarkers for classifying NA subjects and their severity. These new panels could be good diagnostic tests.

Data set on a study of gene expression in peripheral samples to identify biomarkers of severity of allergic and nonallergic asthma.

This article contains information related to the research article entitled "Biomarkers associated with disease severity in allergic and nonallergic asthma" (S. Baos, D. Calzada, L. Cremades, J. Sastre, J. Quiralte, F. Florido, C. Lahoz, B. Cárdaba, In press). Specifically, the clinical criteria stablished for selecting the study population (n=104 subjects) are described. Moreover, this article describes the criteria for selecting the 94 genes to be analyzed in PBMCs (peripheral blood mononuclear cells), it is provided a description of these genes and a Table with the genes most differentially expressed by clinical phenotypes and, finally it is detailed the experimental methodology followed for studying the protein expression of MSR1 (macrophage scavenger receptor 1), one of the genes evaluated in the research.

Biomarkers associated with disease severity in allergic and nonallergic asthma.

Asthma is a complex, chronic respiratory disease with a wide clinical spectrum. Use of high-throughput technologies has generated a great deal of data that require validation. In this work the objective was to validate molecular biomarkers related to asthmatic disease types in peripheral blood samples and define their relationship with disease severity. With this purpose, ninety-four previously described genes were analyzed by qRT-PCR in 30 healthy control (HC) subjects, 30 patients with nonallergic asthma (NA), 30 with allergic asthma (AA), and 14 patients with allergy (rhinitis) but without asthma (AR). RNA was extracted from peripheral blood mononuclear cells (PBMCs) using the TRIzol method. After data normalization, principal component analysis (PCA) was performed, and multiple approaches were used to test for differential gene expression. Relevance was defined by RQ (relative quantification) and corrected P value (<0.05). Protein levels of IL-8 and MSR1 were determined by ELISA and Western blot, respectively. PCA showed 4 gene expression clusters that correlated with the 4 clinical phenotypes. Analysis of differential gene expression between clinical groups and HCs revealed 26 statistically relevant genes in NA and 69 in AA. Protein interaction analysis revealed IL-8 to be a central protein. Average levels of IL-8 were higher in the asthma patients' sera (NA: 452.28±357.72, AA: 327.46±377pg/ml) than in HCs (286.09±179.10), but without reaching statistical significance. Nine genes, especially MSR1, were strongly associated with severe NA. In conclusion, several molecular biomarkers of asthma have been defined, some of which could be useful for the diagnosis or prognosis of disease severity.

Exploratory study of tolerability and immunological effect of a short up-dosing immunotherapy phase with a standardised allergen extract derived from pollen of Olea europaea.

BACKGROUND: A new subcutaneous specific immunotherapy (SCIT) product adsorbed on aluminium hydroxide has been developed with a short and simplified up-dosing phase, containing a biologically standardized allergen pollen extract from Olea europaea. OBJECTIVE: To assess the tolerability profile of the updosing phase and its immunological effect, in terms of specific IgG4 and IgE levels and immediate skin reactivity. MATERIAL AND METHODS: The study was an exploratory, multi-centre, open-label, single-arm, phase II/III clinical trial. Adults with a clinical history of allergic rhinoconjunctivitis with/without asthma due to sensitization to olive pollen were selected. Five up-dosing doses (300, 600, 3000, 6000 and 15000SQ+) were administered at weekly intervals, followed by a maintenance dose (15000SQ+) after 2 weeks. Adverse events were collected during the 30 min observation period after injections, after a telephone contact 2 days after each visit, and after reviewing the subjects' diary. IgG4 and IgE levels and immediate skin reactivity were evaluated at the beginning and at the end of the trial. RESULTS: Ninety-three subjects were included in the trial (mean age, 35.7 ± 10.3 years; women, 66.7 %). A total of 95 adverse drug reactions, all mild in intensity and non-serious, were reported during the trial: 85 local in 34.4 % subjects, 9 systemic in 4.3 % subjects and one non-specific (grade 0). Within 6 weeks, significant changes in IgG4 and IgE levels and in immediate skin reactivity to Olea europaea were accomplished. CONCLUSION: This new SCIT derived from pollen of Olea europaea presented a good tolerability profile and induced significant immunological responses already after a 6 week treatment. However, the non-controlled design may limit the interpretation of these results. TRIAL REGISTRATION: EudraCT no: 2011-004852-20; ClinicalTrials.gov Identifier: NCT01674595.

Therapeutic targets for olive pollen allergy defined by gene markers modulated by Ole e 1-derived peptides.

Two regions of Ole e 1, the major olive-pollen allergen, have been characterized as T-cell epitopes, one as immunodominant region (aa91-130) and the other, as mainly recognized by non-allergic subjects (aa10-31). This report tries to characterize the specific relevance of these epitopes in the allergic response to olive pollen by analyzing the secreted cytokines and the gene expression profiles induced after specific stimulation of peripheral blood mononuclear cells (PBMCs). PBMCs from olive pollen-allergic and non-allergic control subjects were stimulated with olive-pollen extract and Ole e 1 dodecapeptides containing relevant T-cell epitopes. Levels of cytokines were measured in cellular supernatants and gene expression was determined by microarrays, on the RNAs extracted from PBMCs. One hundred eighty-nine differential genes (fold change >2 or <-2, P<0.05) were validated by qRT-PCR in a large population. It was not possible to define a pattern of response according the overall cytokine results but interesting differences were observed, mainly in the regulatory cytokines. Principal component (PCA) gene-expression analysis defined clusters that correlated with the experimental conditions in the group of allergic subjects. Gene expression and functional analyses revealed differential genes and pathways among the experimental conditions. A set of 51 genes (many essential to T-cell tolerance and homeostasis) correlated with the response to aa10-31 of Ole e 1. In conclusion, two peptides derived from Ole e 1 could regulate the immune response in allergic patients, by gene-expression modification of several regulation-related genes. These results open new research ways to the regulation of allergy by Oleaceae family members.

Chip-based capillary electrophoresis profiling of olive pollen extracts used for allergy diagnosis and immunotherapy.

Standardization of protein extracts for clinical purposes represents an important task in order to maintain adequate reactivity, presence of the relevant allergens, and safety among other factors. The main objective of this work was to explore the potential use of a chip-based automated CE system commercially available to analyze several of the most common forms of allergenic extracts from olive pollen used in allergy clinics. These include experimental extracts prepared from olive pollens, in-house reference extracts, extracts designed for skin prick test assays, and a panel of vaccine variants aimed to specific immunotherapy. As a major conclusion of the study, chip-based CE allowed in all cases to determine accurate protein profiles with different degrees of sensitivity, where several allergens (particularly the major olive pollen allergen Ole e 1) were easily recognized. Moreover, several purified allergens were also analyzed by this method, and proposed as specific standards for different purposes. In the present condition, the method can only provide the protein profile of the extracts with respect to a preestablished standard extract, but not allergen identification. However, these and other future developments and applications are discussed.

A novel multiplex method for the simultaneous detection and relative quantitation of pollen allergens.

Standardization of pollen protein extracts is essential in order to ensure efficiency and safety in allergy diagnosis and immunotherapy. In this paper, we have optimized a multiplex Western blotting method for the simultaneous detection of four olive pollen allergens (Ole e 1, Ole e 2, Ole e 5, and Ole e 9) on a single blot using a monoclonal antibody from mouse and three polyclonal antibodies raised in rabbit. We utilized unconjugated Fab antibody fragments for blocking rabbit primary antibodies, and fluorescence-based detection. These changes allowed an accurate and reliable comparative quantitation of these allergens among pollen-protein samples from six olive cultivars. In addition, we also tested the IgE-binding capacity of these pollen extracts by reprobing the same blot with a pool of sera from eight patients allergic to olive and detection with enzyme conjugated antibodies. A noticeable variability regarding allergen content and IgE-reactivity was found among the olive cultivars analyzed. Moreover, we could easily confirm the identity of some of the IgE-binding proteins by simply overlapping both fluorescence and chemiluminescence images. This method is versatile since it can be applied to other allergogenic plant species and extended to other allergens.

Diagnosis of Alternaria alternata sensitization with natural and recombinant Alt a 1 allergens.

BACKGROUND: Diagnosis of Alternaria alternata sensitization is hampered by the variability and complexity of fungal extracts, and thus simplification of the diagnostic procedures with purified allergens should be pursued. OBJECTIVE: We sought to compare A alternata extract and purified natural Alt a 1 (nAlt a 1) and recombinant Alt a 1 (rAlt a 1) allergens for their diagnostic value. METHODS: Forty-two patients allergic to A alternata , 10 atopic patients with negative skin prick test responses to A alternata extract, and 10 healthy subjects were investigated. Skin prick tests and determination of specific IgE levels were performed with nAlt a 1 and 2 different types of rAlt a 1: rbAlt a 1, expressed in Escherichia coli , and ryAlt a 1, expressed in the yeast Yarrowia lipolytica . RESULTS: Prevalence for Alt a 1, Alt a 2, and Alt a 11 by IgE dot-blot testing was 98%, 0%, and 15%, respectively, and therefore Alt a 1 was used as a marker for A alternata sensitization. Immunoblotting and inhibition analysis showed no IgE-binding differences between nAlt a 1 and rAlt a 1. The whole group of patients with allergy to A alternata had positive skin test reactions to purified allergens at 100 microg/mL, whereas no false-positive reactions were detected. Natural or ryAlt a 1 elicited a similar response in skin tests compared with A alternata extract, although a reduced reactivity was observed with rbAlt a 1. Specific IgE levels to nAlt a 1 or rAlt a 1 showed significant correlation and similar sensitivity and specificity. CONCLUSIONS: Alt a 1, either in its natural or recombinant form, is sufficient for a reliable diagnosis of A alternata sensitization and induces skin prick reactivity comparable with that produced by A alternata extract.