Search

The natural history of pulmonary rheumatoid nodules in rheumatoid arthritis remains uncertain. We present a case of a patient with rheumatoid arthritis with pulmonary rheumatoid nodules diagnosed while receiving etanercept in whom pulmonary nodules resolved completely after 5 years of rituximab treatment. Rituximab has been evaluated in case series of patients with pulmonary rheumatoid nodules, resulting in most cases in no progression or a reduction in the size of the nodules, although the complete resolution is uncommon probably due to the short follow-up period. Complete disappearance of pulmonary rheumatoid nodules may be expected after long-term treatment with rituximab.

Calprotectin is a calcium-binding protein that can be measured in serum, plasma, and feces. Increased serum and plasma calprotectin concentrations have been found in chronic inflammatory rheumatic disorders. An analytical and clinical evaluation of the DiaSorin Liaison® fecal Calprotectin assay using LIAISON® XL was performed.The protocol included an analytical and clinical evaluation in which imprecision, the linearity of dilution, differences between serum and plasma samples and method comparison with CalproLab™ ELISA kit were assessed. Serum calprotectin concentrations in active (n = 26) and remission (n = 23) rheumatoid arthritis (RA) patients were compared.The intra-day and inter-day analytical imprecision CVs ranged from 2.9% to 4.0% and 2.7% to 10.4%, respectively. Correlation between measured and expected values was high (R 0.99), indicating good linearity. The Wilcoxon signed-rank test showed that serum and plasma matched samples presented statistically significant differences (p 0.001) being the highest concentrations of calprotectin observed in serum samples. Deming regression equation was as follows: Diasorin calprotectin (μg/ml) = -0.32 (95% CI: -0.65 - -0.05) +1.58 (95% CI: 1.42-1.79).* Calprolab calprotectin (μg/ml). Significantly higher serum calprotectin levels were found in RA patients with active disease when compared to patients with low disease activity or in clinical remission (mean ± SD) [(3.35 μg/ml ± 1.55) vs. (1.63 μg/ml ± 0.52), p 0.001] and these levels correlated well with all disease activity indices.The DiaSorin Liaison® fecal Calprotectin assay adapted for serum samples showed adequate technical performances and the clinical performances were similar to other assays.

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.

Objective: To identify characteristics of early arthritis units, that may be associated with better referral eficiency. Methods: A national survey of the 36 early arthritis units (EAU) in Spanish Rheumatology Units in 2004 (SERAP project). Survey collected information about general practitioners (GP) educational program to improve knowledge and practical skills of early arthritis, networking and feed-back system and referral efficiency. EAU were classified in two groups according to 25 and 50% of inappropriate referral process, respectively.

Objetivo: Estimar la frecuencia de aparicion de las reacciones relacionadas con la administracion (RRA), los sintomas asociados a las graves o tardias, la ventana de exposicion desde inicio de la terapia biologica y si hay diferencias entre infliximab, etanercept y adalimumab. Pacientes y metodo: BIOBADASER es un registro de acontecimientos adversos establecido en 2001 para determinar la seguridad de las terapias biologicas en enfermedades reumaticas. Contiene datos de los pacientes, tratamiento y acontecimientos adversos relevantes. Resultados: Se registro un total de 496 RRA relevantes en 442 pacientes, lo que representa un 19,6% (496/2.531) de todos los acontecimientos adversos comunicados y un 6,3% de los pacientes registrados (442/6.969). La tasa de incidencia de RRA por 1.000 anos-paciente con infliximab es de 28 casos (intervalo de confianza [IC] del 95%, 25-31), con etanercept 0,2 (IC del 95%, 0,1-0,4) y con adalimumab 0,2 (IC del 95%, 0,07-0,7). En mas de la mitad de las RRA, el acontecimiento adverso da lugar a la interrupcion del farmaco relacionado y en el 5% de los casos el paciente requiere ser hospitalizado. Mas del 20% de las RRA ocurren despues de 15 meses de tratamiento, incluso aparecen despues de 5 anos. En las reacciones adversas tardias los sintomas comunicados con mas frecuencia son erupciones, fiebre, malestar general y mialgias. Conclusiones: Las RRA pueden aparecer en cualquier momento de la enfermedad, son una de las causas mas frecuentes de interrupcion de tratamiento con infliximab. Aunque con menor frecuencia, tambien se relacionan con etanercept y adalimumab en sintomas que pueden no identificarse como tales

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.

To compare the accuracy of serum calprotectin and acute-phase reactants (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) in stratifying disease activity in rheumatoid arthritis (RA) patients receiving tumor necrosis factor inhibitors (TNFi), and to correlate calprotectin levels with TNFi trough serum levels.We conducted a cross-sectional study of 87 RA patients receiving adalimumab, etanercept (ETN), or infliximab (IFX); 56 psoriatic arthritis (PsA) patients and 40 healthy blood donors were included as controls. Associations between calprotectin, CRP, and ESR and composite articular indices (Disease Activity Score in 28 joints [DAS28], Simplified Disease Activity Index [SDAI], and Clinical Disease Activity Index) were analyzed by correlation and linear regression and the accuracy and discriminatory capacity of calprotectin by receiver operator characteristic curves (area under the curve [AUC]).Calprotectin levels correlated better with all composite activity indices than CRP and ESR (all r coefficients0.70). Calprotectin levels were significantly lower in RA and PsA patients in clinical remission compared with those with low disease activity for all articular indices. In RA, ESR discriminated between remission and low disease activity only when using DAS28, and CRP only with SDAI. In RA patients in remission/low disease activity, calprotectin but not CRP or ESR distinguished between patients with no swollen joints and those with ≥1 swollen joint (1.74 μg/ml versus 3.04 μg/ml; P = 0.010). Using DAS28 ≥2.6 as the reference variable, calprotectin showed an AUC of 0.92; the best cutoff was ≥2.47 μg/ml with a likelihood ratio of 6.3 (95% confidence interval 2.5-15.8). Calprotectin serum levels inversely correlated with trough serum drug levels of ETN (ρ = -0.671, P 0.001) and IFX (ρ = -0.729, P = 0.017).Calprotectin may more accurately discriminate disease activity in RA patients receiving TNFi than acute-phase reactants, even in patients with low inflammatory activity.

Objetivo: Desarrollar y validar un instrumento especifico para valorar la satisfaccion con el tratamiento en pacientes afectados de artritis reumatoide (AR). Material y metodos: El cuestionario de satisfaccion se desarrollo utilizando un procedimiento de 3 fases: revision de la literatura medica por parte de expertos en desarrollo de medidas centradas en el paciente, evaluacion de los items seleccionados por parte de 4 expertos en AR en terminos de comprension, formato y aplicabilidad y administracion mediante entrevista personal a un grupo de 14 pacientes con AR en tratamiento con infliximab. La validacion del cuestionario se realizo en una muestra de 180 pacientes con AR que cumplian los criterios del American College of Rheumatology (ACR), mayores de 18 anos y que iniciaron tratamiento con infliximab por insuficiente control de su enfermedad. Los cuestionarios fueron administrados en la visita basal (inicio del tratamiento) y a las 2, 6 y 14 semanas, coincidiendo con las infusiones de infliximab. La validez del cuestionario se evaluo en terminos de validez de constructo (analisis factorial) y validez de contenido. La validez de contenido se evaluo analizando la relacion de la satisfaccion con las distintas variables de efectividad y con el cumplimiento de expectativas creadas antes de iniciar el tratamiento. Resultados: La validacion del cuestionario se realizo en una muestra de 180 pacientes con una edad media (DE) de 52 (13) anos, donde el 80,7% eran mujeres y el 72,4% llevaba mas de 3 anos de evolucion. La puntuacion obtenida del cuestionario de satisfaccion se mostro relacionada con los distintos aspectos que constituyen los criterios ACR, a excepcion de la velocidad de sedimentacion globular (VSG) y la proteina C reactiva (PCR), con el cumplimiento de criterios ACR20, ACR50 y ACR70 y con el cumplimiento de expectativas creadas con el tratamiento (p < 0,01). Discusion: Los resultados obtenidos confirman la validez del cuestionario para evaluar la satisfaccion de los pacientes con el tratamiento para la AR, tanto en condiciones de practica clinica habitual como en condiciones de investigacion.

OBJECTIVE The aim of the present study was to determine the extent to which a label of fibromyalgia (FM) could have a harmful effect on short- and long-term prognosis. METHODS We performed a systematic review using a sensitive search strategy. All studies published in PubMed (since 1961), Embase (since 1991) and Cochrane Library Plus (up to 2005) were selected. The titles and abstracts of articles retrieved from the search were reviewed and clinical trials and studies on prognosis were included. RESULTS Of a total of 650 references retrieved, only 5 were analyzed in detail. Two were longitudinal studies that completely fulfilled the inclusion criteria. These studies were performed in different countries (Canada and the United Kingdom) with sufficient and representative samples. Both studies reported lower resource utilization after a diagnosis of FM. The remaining studies were analyzed in detail, although they did not fulfill the inclusion criteria: there was one longitudinal study to determine the accuracy of the diagnosis of FM, one qualitative study, and a review article. No studies against the hypothesis that a diagnosis of FM worsens prognosis were found. CONCLUSIONS There is no evidence that a diagnosis of FM per se could worsen prognosis in patients with this condition. Indeed, the available evidence, which is of moderate-good quality, suggests that, on the contrary, diagnosis reduces healthcare utilization by patients.

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

Objectives To estimate the rate of demyelinating diseases in patients with rheumatic diseases treated with tumor necrosis factor (TNF) antagonists and to describe the cases reported to 3 different pharmacovigilance sources. Methods All confirmed cases of demyelinating disease, optic neuritis, and multiple sclerosis (MS) in patients with rheumatic diseases treated with TNF-antagonists were reviewed from 3 different sources: (1) the Spanish Registry of biological therapies in rheumatic diseases (BIOBADASER); (2) the Spanish Pharmacovigilance Database of Adverse Drug Reactions (FEDRA); and (3) a systematic review (PubMed, EMBASE, and the Cochrane Library). In BIOBADASER, the incidence rate per 1000 patients was estimated with a 95% confidence interval (95% CI). Results In 21,425 patient-years in BIOBADASER, there were 9 patients with confirmed demyelinating disease, 4 with optic neuritis, and 1 with MS. In addition, 22 patients presented polyneuropathies, paresthesias, dysesthesias, facial palsy, or vocal cord paralysis without confirmed demyelination. The incidence rate of demyelinating disease in patients with rheumatic diseases exposed to TNF-antagonists in BIOBADASER was 0.65 per 1000 patient-years (95% CI: 0.39-1.1). The incidence of MS in BIOBADASER was 0.05 (95% CI: 0.01-0.33), while the incidence in the general Spanish population was 0.02 to 0.04 cases per 1000. Compared with BIOBADASER, cases in FEDRA ( n = 19) and in the literature ( n = 48) tend to be younger, have shorter exposure to TNF-antagonists, and recover after discontinuation of the drug. Conclusions It is not clear whether TNF antagonists increase the incidence of demyelinating diseases in patients with rheumatic diseases. Differences between cases depending on the pharmacovigilance source could be explained by selective reporting bias outside registries.

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.

Whether the use of tumor necrosis factor antagonists increases the risk of infection remains a subject of open debate. Developing effective strategies of prevention and empirical treatment entails carefully establishing the etiology and prognosis of the infections.Analysis of the Spanish registry BIOBADASER (Feb-2000 to Jan-2006), a national drug safety registry of patients with rheumatic diseases.907 episodes of infection occurring in 6,969 patients were analyzed. The infection incidence observed was 53.09 cases/1,000 patients-years (CI 95% 49.69-56.66). The most frequent infections were skin infection (12.18 cases/1,000 patients-yrs), pneumonia (5.97 cases/1,000 patients-yrs), cystitis (3.92 cases/1,000 patients-yrs), tuberculosis (3.51 cases/1,000 patients-yrs) and arthritis (3.76 cases/1,000 patients-yrs). Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa and Salmonella spp. emerged as important pathogens. Varicella zoster virus and Herpes simplex virus caused most cases of viral infections. Mucocutaneous candidiasis accounted for most fungal infections. Mortality was increased in infected patients (log-rank test p0.0001). Pneumonia, sepsis, tuberculosis, abdominal infection and endocarditis were associated with significant attributable mortality.A significant number of bacterial, viral and fungal infections occurred in patients with rheumatic diseases treated with TNF antagonists. The information of this study can illuminate clinicians globally on how to address infection in this vulnerable group of patients.

Objective. To compare the safety and retention rate of TNF antagonists used in approved indications (AIs) and non-AIs. Methods. Analysis of the Spanish registry BIOBADASER 2.0 (February 2000 to October 2009). Patients were classified into AIs and off-label uses (OUs), according to the European Medicines Agency approval. Retention rates, incidence rates (IRs) and IR ratios (IRRs) of adverse events (AEs) with 95% CI were compared between uses, by log-rank test, cause-specific Cox regression models and generalized linear models with Poisson’s distribution. Results. First treatment with TNF antagonist was available in 5150 patients, of whom 4594 (89%) were AIs (2854 RA, 882 AS and 858 PsA) and 556 (11%) were OUs [437 chronic arthropathies in the spectrum of SpAs (CA) and 119 chronic immune-mediated diseases (CIDs)]. The IR of AE was largest in CID (649 events per 1000 patient-years) and lowest in PsA (250 events per 1000 patient-years). The occurrence of AEs was significantly associated with OU [IRR of CA vs RA 1.33 (95% CI 1.19, 1.49); IRR of CID vs RA 1.94 (95% CI 1.62, 2.31). The largest hazard ratio for discontinuation was for CID vs RA (1.33; 95% CI 1.02, 1.71) and especially vs AS (2.18; 95% CI 1.63, 2.90). Conclusions. OUs of TNF antagonists need a very close ascertainment of risk/benefit. The safety and retention pattern for CID is similar to that for RA and the pattern for CA resembles that of AS. This study shows an additional value of a national registry.

Objective To estimate the incidence of hospitalisation due to varicella zoster virus (VZV) infection in patients treated with tumour necrosis factor (TNF) antagonists for infl ammatory rheumatic conditions and to compare it with the expected rate in the general population. Methods Secondary data analysis was performed of two large databases: (1) the national registry of rheumatic diseases patients treated with biological agents (BIOBADASER); and (2) the national hospital discharge database Conjunto Minimo Basico de Datos al Alta Hospitalaria. Hospitalisations due to shingles or chickenpox were analysed. For each condition the incidence rate (IR) and the age and gender standardised IR per 100 000 person-years plus the standardised incidence ratio (SIR) and the standardised incidence difference (SID) were estimated. Results In patients exposed to TNF antagonists, the estimated IR of hospitalisation due to shingles was 32 cases per 100 000 patient-years (95% CI 14 to 78), the expected rate in the general population was 3.4 (95% CI 3.2 to 3.5), the SIR was 9 (95% CI 3 to 20) and the SID was 26 (95% CI 14 to 37). The estimated IR of hospitalisation due to chickenpox was 26 cases per 100 000 (95% CI 10 to 69), the expected rate was 1.9 (95% CI 1.8 to 2.0), the SIR was 19 (95% CI 5 to 47) and the SID 33 (95% CI 21 to 45). Conclusions Patients suffering rheumatic diseases exposed to TNF antagonists are hospitalised due to VZV infections signifi cantly more frequently than expected in the general population. Since the absolute IR of hospitalisations due to chickenpox and shingles is low in these patients, the implementation of risky preventive measures may not be justifi ed at present.

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.

To determine the adequacy of disease modifying antirheumatic drug (DMARD) prescription to disease activity in patients with rheumatoid arthritis (RA) and to assess whether the reasons for DMARD discontinuation agree with published evidence.Cross-sectional analysis of the baseline year of a RA cohort (n = 788) randomly selected from the clinical registries of 34 centers. Data about current and previous DMARD use was collected from medical records and confirmed by the patient. Disease activity score (DAS), Health Assessment Questionnaire (HAQ) and Larsen scores, and other clinical data were obtained during the study visit.At baseline visit, 607 patients (77%) were receiving one or more DMARD. Mean DAS, HAQ, and Larsen scores (+/- SD) were: 3.40 +/- 1.22, 1.6 +/- 0.4, and 54.68 +/- 26.37, respectively. Methotrexate (MTX) was the most frequently prescribed DMARD and parenteral gold salts (GS) showed the highest rate of discontinuation. MTX was used as single therapy in a significantly higher proportion (64.3%) than other DMARD (50%) and treatment discontinuation due to inefficacy was significantly less frequent (25.5%) than with other DMARD (40%). However, the DAS28 was significantly worse in the group treated with MTX in single therapy than in the group treated with GS alone (4.13 vs 3.43; p = 0.032).Despite the high use of DMARD among Spanish patients with RA, a significant number of them still have poor control of the disease. In addition, our data show a different perception of ineffectiveness depending on the DMARD used. A non-systematic use of objective quantitative tools for assessment of RA activity and some non-evidence based decisions on the management of DMARD may account for these findings.

There are different diseases which are associated with articular chondrocalcinosis (ACC) although in some it is debated whether this is a real association or an accidental coexistence. The aim of the present study was to analyze the prevalence and type of associated diseases in a series of patients with ACC and to compare with other series in the literature, as well as determine the performance of a protocol directed to the search for such diseases in patients with ACC.A total of 95 patients diagnosed of ACC and attended in the out patients department of Rheumatology in a general hospital over a 5 year period (1987-1991) were included in a protocol specially designed to search for diseases associated to ACC.Twelve (13%) of these patients had one of the diseases classically associated to ACC: gout in 8 cases, hypothyroidism in 2 cases and hyperparathyroidism, adult hemochromatosis and hypophosphatasia in one case each (in one patient two of these diseases coexisted). In most of the patients with secondary ACC the coexisting disease had already been diagnosed. Only two patients (one with hypothyroidism and the other with adult hypophosphatasia) were aided by the application of the protocol and were diagnosed having ACC as the only guiding sign.The number of diseases associated in patients with articular chondrocalcinosis is relatively low. In the absence of clinical suspicion the performance of different laboratory investigations for diagnosis of diseases related with articular chondrocalcinosis is of little benefit.