Search

Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies that are of paramount importance for the diagnosis and prognosis of the disease and have been implicated in its pathogenesis. Proteins resulting from post-translational modifications (PTMs) are capable of triggering autoimmune responses important for the development of RA. In this work, we investigate serum antibody reactivity in patients with an established RA against a panel of chimeric peptides derived from fibrin and filaggrin proteins and bearing from one to three PTMs (citrullination, carbamylation and acetylation) by home-designed ELISA tests (anti-AMPA autoantibodies). The role of anti-AMPAs as biomarkers linked to the presence of a more severe RA phenotype (erosive disease with radiological structural damage) and to the presence of interstitial lung disease (ILD), a severe extra-articular manifestation in RA patients entailing a high mortality, was also analyzed. In general, the association with the clinical phenotype of RA was confirmed with the different autoantibodies, and especially for IgA and IgM isotypes. The prevalence of severe joint damage was only statistically significant for the IgG isotype when working with the peptide bearing three PTMs. Furthermore, the median titers were significantly higher in patients with RA-ILD, a finding not observed for the IgG isotype when working with the single- and double-modified peptides., This research was funded by the Spanish Ministry of Economy, Industry and Competitiveness, and the European Regional Development Fund (Grant No. RTI2018-094120-B-I00)

SummaryBackground Information on the safety of tumour necrosis factor (TNF) antagonists frequently arises from their use in rheumatic diseases, their first approved indications, and is later applied to psoriasis. Whether the risk of biological therapy is similar in psoriasis and rheumatoid arthritis has been considered a priority research question. Objectives To compare the safety profile of anti-TNF drugs in patients with rheumatoid arthritis and psoriasis. Methods We compared two prospective safety cohorts of patients with rheumatoid arthritis and psoriasis that share methods (BIOBADASER and BIOBADADERM). Results There were 1248 serious or mortal adverse events in 16 230 person-years of follow-up in the rheumatoid arthritis cohort (3171 patients), and 124 in the 2760 person-years of follow-up of the psoriasis cohort (946 patients). Serious and mortal adverse events were less common in patients with psoriasis than in rheumatoid arthritis (incidence rate ratio of serious adverse events in psoriasis/rheumatoid arthritis: 0·6, 95% confidence interval 0·5–0·7). This risk remained after adjustment for sex, age, treatment, disease, hypertension, diabetes, hypercholesterolaemia and simultaneous therapy with methotrexate (hazard ratio 0·54, 95% confidence interval 0·47–0·61), and after excluding patients receiving corticosteroids. Patients with rheumatoid arthritis showed a higher rate of infections, cardiac disorders, respiratory disorders and infusion-related reactions, whereas patients with psoriasis had more skin and subcutaneous tissue disorders and hepatobiliary disorders. Conclusions Patients with rheumatoid arthritis clinical practice have almost double the risk of serious adverse events compared with patients with psoriasis, with a different pattern of adverse events. Safety data from rheumatoid arthritis should not be fully extrapolated to psoriasis. These differences are likely to apply to other immune-mediated inflammatory diseases.

OBJECTIVE To evaluate the efficacy and safety of increasing the dose interval of subcutaneous tocilizumab (TCZ-SC) in patients with rheumatoid arthritis (RA) who are in clinical remission. METHODS RA patients with active disease and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or to a biologic agent were entered into a single-arm treatment phase with 162 mg of TCZ-SC administered once weekly (TCZ-SC 162 mg qw) as monotherapy or in combination with a csDMARD for 24 weeks. Patients who achieved clinical remission at weeks 20 and 24 were randomized to continue with the same regimen or to switch to 162 mg TCZ-SC administered every 2 weeks (TCZ-SC 162 mg q2w) for 24 weeks (open-label). Patients with a Disease Activity Score in 28 joints (DAS28) of

Summary Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate. Methods ORAL Strategy was a 1 year, double-blind, phase 3b/4, head-to-head, non-inferiority, randomised controlled trial in patients aged 18 years or older with active rheumatoid arthritis despite methotrexate therapy. Patients were randomly assigned (1:1:1) to receive oral tofacitinib (5 mg twice daily) monotherapy, oral tofacitinib (5 mg twice daily) plus methotrexate, or subcutaneous adalimumab (40 mg every other week) plus methotrexate at 194 centres in 25 countries. Eligible patients received live zoster vaccine at investigators' discretion. The primary endpoint was the proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at month 6 in the full analysis set (patients who were randomly assigned to a group and received at least one dose of the study treatment). Non-inferiority between groups was shown if the lower bound of the 98·34% CI of the difference between comparators was larger than −13·0%. This trial is registered with ClinicalTrials.gov, number NCT02187055. Findings 1146 patients received treatment (384 had tofacitinib monotherapy; 376 had tofacitinib and methotrexate; and 386 had adalimumab and methotrexate). At 6 months, ACR50 response was attained in 147 (38%) of 384 patients with tofacitinib monotherapy, 173 (46%) of 376 patients with tofacitinib and methotrexate, and 169 (44%) of 386 patients with adalimumab and methotrexate. Non-inferiority was declared for tofacitinib and methotrexate versus adalimumab and methotrexate (difference 2% [98·34% CI −6 to 11]) but not for tofacitinib monotherapy versus either adalimumab and methotrexate (−6 [−14 to 3]) or tofacitinib and methotrexate (−8 [−16 to 1]). In total, 23 (6%) of 384 patients receiving tofacitinib monotherapy, 26 (7%) of 376 patients receiving tofacitinib plus methotrexate, and 36 (9%) of 386 patients receiving adalimumab plus methotrexate discontinued due to adverse events. Two (1%) of the 384 patients receiving tofacitinib monotherapy died. No new or unexpected safety issues were reported for either treatment in this study for up to 1 year. Interpretation Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination. Funding Pfizer Inc.

ObjectiveTo compare the effectiveness of switching to rituximab (RTX) with switching to alternative tumour necrosis factor (TNF) antagonists in patients with rheumatoid arthritis (RA) failing on TNF antagonists.MethodsA multicentre prospective 3-year observational study was performed in patients with RA treated with RTX or an alternative TNF antagonist. The baseline 28-joint disease activity score (DAS28) and Health Assessment Questionnaire (HAQ) score were compared with 6, 9 and 12 month values, adjusting for propensity score quintiles. Propensity scores were estimated for each patient using logistic regression with treatment as the dependent variable and baseline prior number of TNFs >1, years from diagnosis >5, extra-articular manifestations, previous toxicity, use of ≥2 disease-modifying antirheumatic drugs, age and sex as independent variables.Results1124 patients were treated with either RTX (n=591, 52.6%) or alternative TNF antagonists (n=533, 47.4%). RTX-treated patients had longer disease duration (p=0.0001), larger numbers of previous TNF antagonists (p0.22 (p=0.06).ConclusionsOptimal treatment for patients with RA failing on treatment with TNF antagonists may include RTX. This study suggests that the improvement in DAS28 is larger in patients treated with RTX than in those treated with monoclonal anti-TNF agents.

Background: Immune-mediated inflammatory diseases (IMIDs) are a group of complex and prevalent diseases where disease diagnostic and activity monitoring is highly challenging. The determination of the metabolite profiles of biological samples is becoming a powerful approach to identify new biomarkers of clinical utility. In order to identify new metabolite biomarkers of diagnosis and disease activity, we have performed the first large-scale profiling of the urine metabolome of the six most prevalent IMIDs: rheumatoid arthritis, psoriatic arthritis, psoriasis, systemic lupus erythematosus, Crohn's disease, and ulcerative colitis. Methods: Using nuclear magnetic resonance, we analyzed the urine metabolome in a discovery cohort of 1210 patients and 100 controls. Within each IMID, two patient subgroups were recruited representing extreme disease activity (very high vs. very low). Metabolite association analysis with disease diagnosis and disease activity was performed using multivariate linear regression in order to control for the effects of clinical, epidemiological, or technical variability. After multiple test correction, the most significant metabolite biomarkers were validated in an independent cohort of 1200 patients and 200 controls. Results: In the discovery cohort, we identified 28 significant associations between urine metabolite levels and disease diagnosis and three significant metabolite associations with disease activity (P-FDR < 0.05). Using the validation cohort, we validated 26 of the diagnostic associations and all three metabolite associations with disease activity (PFDR < 0.05). Combining all diagnostic biomarkers using multivariate classifiers we obtained a good disease prediction accuracy in all IMIDs and particularly high in inflammatory bowel diseases. Several of the associated metabolites were found to be commonly altered in multiple IMIDs, some of which can be considered as hub biomarkers. The analysis of the metabolic reactions connecting the IMID-associated metabolites showed an overrepresentation of citric acid cycle, phenylalanine, and glycine-serine metabolism pathways. Conclusions: This study shows that urine is a source of biomarkers of clinical utility in IMIDs. We have found that IMIDs show similar metabolic changes, particularly between clinically similar diseases and we have found, for the first time, the presence of hub metabolites. These findings represent an important step in the development of more efficient and less invasive diagnostic and disease monitoring methods in IMIDs.

Introduction: The aim was to study the association between 25-hydroxyvitamin D (25(OH) D) levels and the clinical characteristics of patients with chronic inflammatory rheumatic diseases (CIRD). Methods: We studied a cross-section from the baseline visit of the CARMA project (CARdiovascular in rheuMAtology), a 10-year prospective study evaluating the risk of cardiovascular events in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) patients, and non-CIRD patients who attended rheumatology outpatient clinics from 67 hospitals in Spain. Non-CIRD group was frequency matched by age with the joint distribution of the three CIRD groups included in the study. 25(OH) D deficiency was defined if 25(OH) D vitamin levels were < 20 ng/ml. Results: 2.234 patients (775 RA, 738 AS and 721 PsA) and 677 non-CIRD subjects were assessed. The median (p25-p75) 25(OH) D levels were: 20.4 (14.4-29.2) ng/ml in RA, 20.9 (13.1-29.0) in AS, 20.0 (14.0-28.8) in PsA, and 24.8 (18.4-32.6) ng/ml in non-CIRD patients. We detected 25(OH) D deficiency in 40.5 % RA, 39.7 % AS, 40.9 % PsA and 26.7 % non-CIRD controls (p < 0.001). A statistically significant positive association between RA and 25(OH) D deficiency was found (adjusted (adj.) OR = 1.46; 95 % CI = 1.09-1.96); p = 0.012. This positive association did not reach statistical significance for AS (adj. OR 1.23; 95 % CI = 0.85-1.80) and PsA (adj. OR 1.32; 95 % CI = 0.94-1.84). When the parameters of disease activity, severity or functional impairment were assessed, a marginally significant association between 25(OH) D deficiency and ACPA positivity in RA patients (adj. OR = 1.45; 95 % CI = 0.99-2.12; p = 0.056), and between 25(OH) D deficiency and BASFI in AS patients (adj. OR = 1.08; 95 % CI = 0.99-1.17); p = 0.07) was also found. Conclusions: Patients with RA show an increased risk of having 25(OH) D deficiency compared to non-CIRD controls., This publication was aided by members of the Research Unit of the SER. Dedicated to Dr Jose L Fernandez Sueiro who took part in the initial design of this project and passed away in 2012. The authors thank all of the health professionals and patients who generously participated in this study. Furthermore, the authors thank the approval of the study from all participating centers: Complejo Hospitalario A Coruna, A Coruna; Instituto Dexeus, Barcelona; Hospital Universitari Vall d'Hebron, Barcelona; Hospital Infanta Sofia, Madrid; Hospital S. Pedro de Alcantara, Caceres; Hospital Son Llatzer, Palma de Mallorca; Hospital Univ. de Guadalajara; Hospital Clinic i Provincial, Barcelona; Hospital Clinico Univ. San Carlos, Madrid; Hospital de Barbastro, Huesca; Hospital Univ. de Bellvitge, Barcelona; Hospital Univ. de La Princesa, Madrid; Hospital de Merida, Badajoz; Hospital General Carlos Haya, Malaga; Hospital General Virgen de la Concha, Zamora; Hospital Virgen de la Salud, Toledo; Hospital del Sureste, Madrid; Hospital Ramon y Cajal, Madrid; Hospital Univ. Miguel Servet, Zaragoza; Hospital Dr. Negrin, Las Palmas de Gran Canaria; Hospital de Cabuenes, Gijon; Hospital Gregorio Maranon, Madrid; Hospital Univ. de Salamanca; Hospital Univ. Marques de Valdecilla, Santander; Hospital de la Marina Baixa, Alicante; Hospital de San Rafael, Barcelona; Hospital General. Universitario, Valencia; Instituto Poal, Barcelona; Hospital Universitario Puerta de Hierro, Madrid; Hospital Clinico Univ. San Cecilio, Granada; Hospital Santiago Apostol, Vitoria-Gasteiz; Consorci Sanitari de Terrassa, Terrassa; Hospital de Viladecans, Barcelona; Hospital General de Albacete; Hospital Mutua Terrassa, Terrassa; Hospital Ntra. Sra. de Candelaria, Santa Cruz de Tenerife; Hospital Univ. de Canarias, La Laguna, Tenerife; Hospital Univ. de Valme, Sevilla; Instituto Provincial de Rehabilitacion, Madrid; Hospital de Cantoblanco, Madrid; Hospital de Jerez de la Frontera, Cadiz; Hospital Obispo Polanco, Teruel; Hospital Infanta Leonor, Madrid; Hospital General de Elda, Alicante; Hospital Los Arcos, Murcia; Hospital Severo Ochoa, Madrid; Hospital Principe de Asturias, Madrid; Hospital Univ. 12 de Octubre, Madrid; Hospital Univ. Reina Sofia, Cordoba; Hospital Univ. La Paz, Madrid; Hospital Gutierrez Ortega, Valdepenas, Ciudad Real; Hospital Virgen de la Arrixaca, Murcia; Hospital de El Escorial, Madrid; Hospital de Basurto, Bilbao; Hospital Dos de Maig, Barcelona; Hospital del Mar, Barcelona; Hospital Universitario Son Espases, Palma de Mallorca; Hospital de Donostia, Donostia; Hospital de la Santa Creu i Sant Pau, Barcelona; Hospital de Palamos, Gerona; Hospital Comarcal de L'Alt Penedes, Vilafranca del Penedes, Barcelona; Hospital Sierrallana, Torrelavega; Complejo Asistencial de Leon; Hospital General de Ciudad Real; Hospital General de Mostoles, Madrid; Hospital General Universitario de Elche, Alicante; Hospital Xeral Calde, Lugo. This project has been supported by an unrestricted grant from Abbvie, Spain. The design, analysis, interpretation of results and preparation of the manuscript has been done independently of Abbvie. Dr Gonzalez-Gay's studies have been supported by grants from Fondo de Investigaciones Sanitarias, PI06/0024, PS09/00748 and PI12/00060, and RD12/0009/0013 (RIER) from Instituto de Salud Carlos III (ISCIII) (Spain).

Objective To establish the cardiovascular (CV) morbidity and associated risk factors for CV disease (CVD) in Spanish patients with chronic inflammatory rheumatic diseases (CIRD) and unexposed individuals attending rheumatology clinics. Methods Analysis of data from the baseline visit of a 10-year prospective study [CARdiovascular in rheuMAtology (CARMA) project] that includes a cohort of patients with CIRD [rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA)] and another cohort of matched individuals without CIRD attending outpatient rheumatology clinics from 67 hospitals in Spain. Prevalence of CV morbidity, CV risk factors, and systematic coronary risk evaluation (SCORE) assessment were analyzed. Results A total of 2234 patients (775 RA, 738 AS, and 721 PsA) and 677 unexposed subjects were included. Patients had low disease activity at the time of recruitment. PsA patients had more commonly classic CV risk factors and metabolic syndrome features than did the remaining individuals. The prevalence of CVD was higher in RA (10.5%) than in AS (7.6%), PsA (7.2%), and unexposed individuals (6.4%). A multivariate analysis adjusted for the presence of classic CV risk factors and disease duration revealed a positive trend for CVD in RA (OR = 1.58; 95% CI: 0.90–2.76; p = 0.10) and AS (OR = 1.77; 95% CI: 0.96–3.27; p = 0.07). Disease duration in all CIRD groups and functional capacity (HAQ) in RA were associated with an increased risk of CVD (OR = 2.15; 95% CI: 1.29–3.56; p = 0.003). Most patients had a moderate CV risk according to the SCORE charts. Conclusions Despite recent advances in the management of CIRD, incidence of CVD remains increased in Spanish subjects with CIRD attending outpatient rheumatology clinics.

Objective To estimate cut-off points and to establish response criteria for the Hospital Universitario La Princesa Index (HUPI) in patients with chronic polyarthritis. Methods Two cohorts, one of early arthritis (Princesa Early Arthritis Register Longitudinal [PEARL] study) and other of long-term rheumatoid arthritis (Estudio de la Morbilidad y Expresion Clinica de la Artritis Reumatoide [EMECAR]) including altogether 1200 patients were used to determine cut-off values for remission, and for low, moderate and high activity through receiver operating curve (ROC) analysis. The areas under ROC (AUC) were compared to those of validated indexes (SDAI, CDAI, DAS28). ROC analysis was also applied to establish minimal and relevant clinical improvement for HUPI. Results The best cut-off points for HUPI are 2, 5 and 9, classifying RA activity as remission if ≤2, low disease activity if >2 and ≤5), moderate if >5 and

ObjectiveTo investigate in rheumatoid arthritis (RA) the rate and reason of discontinuation of tumour necrosis factor (TNF) antagonists over the past decade.MethodsRA patients in BIOBADASER 2.0 were stratified according to the start date of their first TNF antagonist into 2000–3, 2004–6 and 2007–9 interval years. Cumulative incidence function of discontinuation for inefficacy or toxicity was estimated with the alternative reason as competing risk. Competing risks regression models were used to measure the association of study groups with covariates and reasons for discontinuation. Association is expressed as subhazard ratios (SHR).Results2907 RA patients were included in the study. Competing risk regression for inefficacy shows larger SHR for patients starting treatment in 2004–6 (SHR 2.57; 95% CI 1.55 to 4.25) and 2007–9 (SHR 3.4; 95% CI 2.08 to 5.55) than for those starting in 2000–3, after adjusting for TNF antagonists, clinical activity and concomitant treatment. Competing risk regression analysis for adverse events revealed no differences across the three time intervals.ConclusionsIn RA, the discontinuation rate of TNF antagonists in the first year of treatment is higher more recently than a decade ago, inefficacy being the main reason for the increased rate. The rate of discontinuation for adverse events has remained stable.

Objective To describe the risk of cancer in patients exposed to tumor necrosis factor (TNF) antagonists. Methods The following 2 clinical cohorts were studied: (1) BIOBADASER 2.0: a registry of patients suffering from rheumatic diseases exposed to TNF antagonists (2531 rheumatoid arthritis (RA), 1488 spondyloarthropathies, and 675 other rheumatic conditions); and (2) EMECAR: a cohort of 789 RA patients not exposed to TNF antagonists. Cancer incidence rates (IR) per 1000 patient-years and incidence rate ratios (IRR) were calculated for BIOBADASER 2.0 and EMECAR patients. The IR over time in BIOBADASER 2.0 patients was analyzed by joinpoint regression. The IRR was estimated to compare cancer rates in exposed versus nonexposed RA patients. Standardized incidence and mortality ratios (SIR, SMR) were also estimated. Risk factors for cancer in patients exposed to TNF antagonists were investigated by generalized linear models. Results The SMR for cancer in BIODASER 2.0 was 0.67 (95% CI: 0.51-0.86), and the SIR was 0.1 (95% CI 0.03-0.23). The IR in RA patients exposed to TNF antagonists was 5.8 (95% CI: 4.4-7.6), and the adjusted IRR was 0.48 (95% CI: 0.09-2.45). The IR in patients with previous cancer was 26.4 (95% CI: 4.1-171.5). Age, chronic obstructive pulmonary disease, and steroids were associated with a higher risk of developing cancer. The IR decreased after the first 4 months of exposure, without statistical significance. Conclusion Overall cancer and mortality rates in patients with rheumatic diseases exposed to TNF antagonists are no higher than in the background Spanish population. However special attention should be paid to elderly patients, those with previous cancers, and patients treated with steroids.

Objective. To estimate the incidence of early arthritis (EA) and of RA in adults (>16 yrs) in Spain. Methods. Primary care physicians were instructed in the detection of new cases using a checklist. All cases were evaluated at EA units (EAUs) within 15 days of detection. ACR criteria for the classification of RA were assessed every 6 months thereafter. Results. In an area covering 4 342 378 inhabitants over the age of 16 yrs, 2467 patients were referred to the EAU, of whom 1063 fulfilled EA criteria (43.1%). After 6 months, 362 patients fulfilled RA criteria. The estimated annual incidence of EA was 25/100 000 population (95% CI: 23, 26). The annual incidence of RA was 8.3 cases/100 000 (95% CI: 7.5, 9.2): 11.3/100 000 in women (95% CI: 10.0, 12.8), and 5.2/100 000 in men (95% CI: 4.3, 6.3). The incidence of RA increased with age in both sexes. At the 6 months’ assessment, 187 (51.7%) of the patients with RA were RF positive. The presentation of RA was mainly polyarticular (n ¼ 268; 74.0%). There were 701/1063 patients with EA who did not fulfil RA criteria by 6 months after the first rheumatologist visit. If all cases of undifferentiated arthritis (n ¼ 118; 17%) became RA, the incidence would be in the range of 10 cases/100 000 population. Conclusions. RA incidence in Spain is in the lower range of published data. The incidence of EA is about three times that of RA.