Prevalence and clinical characteristics of patients with rheumatoid arthritis with interstitial lung disease using unstructured healthcare data and machine learning.

OBJECTIVES: Real-world data regarding rheumatoid arthritis (RA) and its association with interstitial lung disease (ILD) is still scarce. This study aimed to estimate the prevalence of RA and ILD in patients with RA (RAILD) in Spain, and to compare clinical characteristics of patients with RA with and without ILD using natural language processing (NLP) on electronic health records (EHR). METHODS: Observational case-control, retrospective and multicentre study based on the secondary use of unstructured clinical data from patients with adult RA and RAILD from nine hospitals between 2014 and 2019. NLP was used to extract unstructured clinical information from EHR and standardise it into a SNOMED-CT terminology. Prevalence of RA and RAILD were calculated, and a descriptive analysis was performed. Characteristics between patients with RAILD and RA patients without ILD (RAnonILD) were compared. RESULTS: From a source population of 3 176 165 patients and 64 241 683 EHRs, 13 958 patients with RA were identified. Of those, 5.1% patients additionally had ILD (RAILD). The overall age-adjusted prevalence of RA and RAILD were 0.53% and 0.02%, respectively. The most common ILD subtype was usual interstitial pneumonia (29.3%). When comparing RAILD versus RAnonILD patients, RAILD patients were older and had more comorbidities, notably concerning infections (33.6% vs 16.5%, p<0.001), malignancies (15.9% vs 8.5%, p<0.001) and cardiovascular disease (25.8% vs 13.9%, p<0.001) than RAnonILD. RAILD patients also had higher inflammatory burden reflected in more pharmacological prescriptions and higher inflammatory parameters and presented a higher in-hospital mortality with a higher risk of death (HR 2.32; 95% CI 1.59 to 2.81, p<0.001). CONCLUSIONS: We found an estimated age-adjusted prevalence of RA and RAILD by analysing real-world data through NLP. RAILD patients were more vulnerable at the time of inclusion with higher comorbidity and inflammatory burden than RAnonILD, which correlated with higher mortality.

Utility of cytokines CXCL4, CXCL8 and GDF15 as biomarkers in systemic sclerosis

Background and objectives: Systemic sclerosis (SSc) is an autoinmune disease that can affect several organs and its mortality is fundamentally related to its pulmonary involvement. There are some cytokines with high serum levels of patients with SSc. Our goal is to determine the role of CXCL4, CXCL8 and GDF15 in the physiopathology of SSc and whether they can be considered organic damage biomarkers.Patients and methodsObservational case–control study of SSc patients (ACR/EULAR 2013 criteria). Demographic, clinical, analytical, activity, severity, health perception, and disability variables were collected. Moreover, Videocapillaroscopy, Echocardiography and Respiratory Function Test were made. Serum levels of CXCL4, CXCL8 and GDF15 were measured both in SSc patients and in healthy controls.ResultsA total of 42 patients were included (95.4% women), with an average age of 59.2 years and a median of 4 years from diagnosis. We also included 42 healthy controls. We found significantly higher levels of GDF15 in SSc patients than in controls (p<0.001), but no higher CXCL4 or CXCL8 levels. GDF15 was associated with Diffuse SSc, pulmonary arterial hypertension, interstitial lung disease, less forced vital capacity, high titles of antiScl70, disease activity, and dilated loops in capillaroscopy. CXCL4 levels were associated to a higher Rodnan punctuation, while CXCL8 was associated to C4 fraction consumption and tortuosities in capillaroscopy. (AU)

Antecedentes y objetivos: La esclerosis sistémica (ES) es una enfermedad autoinmunitaria que afecta a diferentes órganos y cuya mortalidad se relaciona fundamentalmente con su afectación pulmonar. Los pacientes con ES presentan niveles séricos elevados de algunas citocinas. Nuestro objetivo es determinar el papel de CXCL4, CXCL8 y GDF15 en la fisiopatología de la ES, y si pueden considerarse biomarcadores de daño orgánico.Pacientes y métodosEstudio observacional de casos-controles, con pacientes afectados de ES (criterios ACR/EULAR 2013) y controles sanos. Se determinaron los niveles séricos de CXCL4, CXCL8 y GDF15 en ambos grupos, y se registraron variables demográficas, clínicas, analíticas, de actividad, gravedad, percepción de salud y discapacidad de pacientes con ES, a quienes, además, se les realizó videocapilaroscopia, ecocardiograma y espirometría.ResultadosSe incluyeron 42 pacientes (95,4% mujeres), con una edad media de 59,2 años y una mediana de 4 años desde el diagnóstico, con 42 controles sanos. Se hallaron niveles significativamente mayores de GDF15 en pacientes con ES que en controles (p<0,001), pero no de CXCL4 ni CXCL8. GDF15 se asoció a ES difusa, hipertensión pulmonar, enfermedad pulmonar intersticial, menor capacidad vital forzada, títulos altos de anti-Scl70, actividad de ES y dilataciones capilares. Asimismo, los niveles de CXCL4 se asociaron a mayor afectación cutánea (Rodnan), mientras que CXCL8 se asoció a consumo de la fracción C4 del complemento y tortuosidades en la capilaroscopia. (AU)

Real-world evidence of tofacitinib in rheumatoid arthritis patients in Spain.

The purpose of this narrative review is to provide an overview of the real-world data on the use of tofacitinib in patients with active rheumatoid arthritis (RA) in Spain. Sixteen retrospective studies carried out in Spain between 2019 and 2021 have been analyzed, considering patients' characteristics, and treatment patterns, effectiveness, and safety. In those studies, approximately 511 patients received tofacitinib during the study period. They were predominantly women (mean age: 48-61 years). The percentage of patients receiving tofacitinib as monotherapy ranged between 20.0% and 67.9%. Only five studies reported the combined use of corticosteroids (42.0-84.5% of patients), with a mean dose varying from 1.8 to 7.2 mg. A wide range of patients (36.0-85.7%) had failed a previous biological disease-modifying anti-rheumatic drug. The most frequent reason for treatment discontinuation was the lack of efficacy, and the most common adverse event described was herpes zoster infection. Real-world studies complement clinical trials by adding efficacy and safety data in real-world settings to the benefit/risk profile of the drug. The profile of RA patients receiving tofacitinib in Spain has similarities with other real-world studies conducted in other countries.

Utility of cytokines CXCL4, CXCL8 and GDF15 as biomarkers in systemic sclerosis.

BACKGROUND AND OBJECTIVES: Systemic sclerosis (SSc) is an autoinmune disease that can affect several organs and its mortality is fundamentally related to its pulmonary involvement. There are some cytokines with high serum levels of patients with SSc. Our goal is to determine the role of CXCL4, CXCL8 and GDF15 in the physiopathology of SSc and whether they can be considered organic damage biomarkers. PATIENTS AND METHODS: Observational case-control study of SSc patients (ACR/EULAR 2013 criteria). Demographic, clinical, analytical, activity, severity, health perception, and disability variables were collected. Moreover, Videocapillaroscopy, Echocardiography and Respiratory Function Test were made. Serum levels of CXCL4, CXCL8 and GDF15 were measured both in SSc patients and in healthy controls. RESULTS: A total of 42 patients were included (95.4% women), with an average age of 59.2 years and a median of 4 years from diagnosis. We also included 42 healthy controls. We found significantly higher levels of GDF15 in SSc patients than in controls (p<0.001), but no higher CXCL4 or CXCL8 levels. GDF15 was associated with Diffuse SSc, pulmonary arterial hypertension, interstitial lung disease, less forced vital capacity, high titles of antiScl70, disease activity, and dilated loops in capillaroscopy. CXCL4 levels were associated to a higher Rodnan punctuation, while CXCL8 was associated to C4 fraction consumption and tortuosities in capillaroscopy. CONCLUSIONS: GDF15 high levels were associated with diffuse SSc, lung impairment, disease activity and changes in capillaroscopy. Moreover, CXCL4 was only associated with skin impairment, while CXCL8 was not related to organic damage.

Influence of the EULAR recommendations for the use of imaging in large vessel vasculitis in the diagnosis of giant cell arteritis: results of the ARTESER register.

OBJECTIVE: The main study objective was to determine how giant cell arteritis (GCA) is diagnosed in our clinical practice and whether the EULAR recommendations have influenced the diagnostic procedures used. METHODS: ARTEritis of the Rheumatology Spanish Society -Sociedad Española de Reumatología (ARTESER) is a multicentre observational retrospective study conducted in 26 hospitals with support from the Spanish Society of Rheumatology. All patients diagnosed with GCA between 1 June 2013 and 29 March 2019 were included. The gold standard for the diagnosis of GCA was the judgement of the physician in charge, according to clinical criteria, supported by data available from laboratory tests, imaging studies (ultrasound, positron emission tomography (PET) and MRI/CT angiography) and temporal artery biopsy (TAB) when available. RESULTS: We included 1675 patients with GCA (mean age±SD (76.9±8.1) years, 1178 women (70.3%)). Of these, 776 patients had a positive TAB (46.3%), 503 (30.0%) positive ultrasound, 245 positive PET (14.6%) and 64 positive MRI/CT angiography (3.8%). These percentages changed substantially over the study. From 2013 to 2019, the use of ultrasound in diagnosis grew from 25.8% to 52.9% and PET from 12.3% to 19.6%, while use of TAB decreased from 50.3% to 33.3%. CONCLUSIONS: Biopsy was the most widely used diagnostic test for confirming GCA, but use of imaging as a diagnostic tool has grown in recent years. Following publication of the 2018 EULAR recommendations, ultrasound has displaced biopsy as the first-line diagnostic test; TAB was performed in a third and PET in a fifth of cases.

Desarrollo de una aplicación para teléfonos móviles (app) basada en la colaboración Sociedad Española de Reumatología/Sociedad Española de Medicina de Familia y Comunitaria para derivación de enfermedades autoinmunes sistémicas / Development of an application for mobile phones (App) based on the collaboration between the Spanish Society of Rheumatology and Spanish Society of Family Medicine for the referral of systemic autoimmune diseases from primary care to rheumatology

El diagnóstico y tratamiento de las enfermedades autoinmunes sistémicas (EAS) constituye un reto. Aunque infrecuentes, afectan a cientos de miles de pacientes en España. El médico de familia (MF) se enfrenta a síntomas o signos inespecíficos que hacen sospechar EAS al inicio del proceso, y tiene que decidir a quiénes debería derivar. Para facilitar su reconocimiento y mejorar su derivación, expertos de la Sociedad Española de Medicina de Familia y Comunitaria y de la Sociedad Española de Reumatología seleccionaron 26 síntomas/signos-guía y alteraciones analíticas. Se escogieron parejas de MF y reumatólogo para elaborar algoritmos diagnósticos y de derivación. Posteriormente se revisaron y adaptaron al formato de aplicación para móviles (app) descargable. El resultado es el presente documento de derivación de EAS para MF en formato de papel y app. Contiene algoritmos de fácil manejo utilizando datos de la anamnesis, exploración física y pruebas analíticas accesibles en atención primaria para orientar el diagnóstico y facilitar la derivación a reumatología o a otras especialidades

Management of systemic autoimmune diseases is challenging for physicians in their clinical practice. Although not common, they affect thousands of patients in Spain. The family doctor faces patients with symptoms and non-specific cutaneous, mucous, joint, vascular signs or abnormal laboratory findings at the start of the disease process and has to determine when to refer patients to the specialist. To aid in disease detection and better referral, the Spanish Society of Rheumatology and the Spanish Society of Family Medicine has created a group of experts who selected 26 symptoms, key signs and abnormal laboratory findings which were organized by organ and apparatus. Family doctors and rheumatologists with an interest in autoimmune systemic diseases were selected and formed mixed groups of two that then elaborated algorithms for diagnostic guidelines and referral. The algorithms were then reviewed, homogenized and adapted to the algorithm format and application for cell phone (apps) download. The result is the current Referral document of systemic autoimmune diseases for the family doctor in paper format and app (download). It contains easy-to-use algorithms using data from anamnesis, physical examination and laboratory results usually available to primary care, that help diagnose and refer patients to rheumatology or other specialties if needed

18 F-FDG PET/TC en pacientes con polimialgia reumática: despistando vasculitis / 18 F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with polymyalgia rheumatica: Screening for vasculitis

OBJETIVO: La polimialgia reumática (PMR) puede asociarse a vasculitis de grandes vasos (VGV). Este trabajo pretende evaluar el papel de 18F-FDG PET/TC en el diagnóstico de VGV asociado a PMR. MATERIALES Y MÉTODO: Estudio retrospectivo de pacientes con PMR. Se recogieron datos clínicos, analíticos, reactantes de fase aguda (RFA) (PCR, VSG), y a quienes tenían clínica persistente, elevación de RFA, precisaban dosis elevadas de corticoterapia o cuadros atípicos de PMR (febrícula, pérdida de peso, etc.) se realizó 18F-FDG PET/TC. RESULTADOS: Veintitrés pacientes se incluyeron; el 48% (11) de los cuales tuvieron VGV asociada a PMR. La localización fue heterogénea pero en su mayoría involucró a la aorta. En cuanto al tratamiento, se añadieron fármacos modificadores de la enfermedad a más del 80% de los pacientes con VGV. Los pacientes con VGV tenían niveles de PCR elevados comparado con aquellos con PMR aislada. CONCLUSIONES: La VGV en PMR no es infrecuente, tanto la clínica como los valores de PCR elevados deben hacer sospechar la posibilidad de VGV asociada. El estudio de imagen 18F-FDG PET/TC es una herramienta útil identificando VGV asociada a PMR

OBJECTIVE: Polymyalgia rheumatica (PR) can be associated with large vessel vasculitis (LVV). We evaluate the diagnostic role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and its impact on the treatment of LVV associated with PR. MATERIALS AND METHODS: Retrospective study of patients diagnosed with PR. Data was collected from health records. Blood analysis included acute-phase reactants (APR), C-reactive protein (CRP) and erythrocyte sedimentation rate. An 18F-FDG PET/CT scan was performed in those patients whose symptoms persisted, in those with elevated APR, those who required higher doses of steroids or those who had atypical features of PR (low-grade fever, weight loss, among others). RESULTS: Twenty-three were eligible; 48% (n = 11) of the patients were diagnosed with LVV associated with PR. The site was heterogeneous, but mostly involved the aorta. In 80% of the patients with LVV, a disease-modifying antirheumatic drug was added to their treatment. Elevated CRP values were associated with the likelihood of presenting LVV. CONCLUSIONS: LVV is not uncommon, clinical features and elevated CRP levels should raise suspicion of LVV associated with PR. 18F-FDG PET/CT is useful in identifying LVV associated with PR

18 F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with polymyalgia rheumatica: Screening for vasculitis. / 18 F-FDG PET/TC en pacientes con polimialgia reumática: despistando vasculitis.

OBJECTIVE: Polymyalgia rheumatica (PR) can be associated with large vessel vasculitis (LVV). We evaluate the diagnostic role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and its impact on the treatment of LVV associated with PR. MATERIALS AND METHODS: Retrospective study of patients diagnosed with PR. Data was collected from health records. Blood analysis included acute-phase reactants (APR), C-reactive protein (CRP) and erythrocyte sedimentation rate. An 18F-FDG PET/CT scan was performed in those patients whose symptoms persisted, in those with elevated APR, those who required higher doses of steroids or those who had atypical features of PR (low-grade fever, weight loss, among others). RESULTS: Twenty-three were eligible; 48% (n = 11) of the patients were diagnosed with LVV associated with PR. The site was heterogeneous, but mostly involved the aorta. In 80% of the patients with LVV, a disease-modifying antirheumatic drug was added to their treatment. Elevated CRP values were associated with the likelihood of presenting LVV. CONCLUSIONS: LVV is not uncommon, clinical features and elevated CRP levels should raise suspicion of LVV associated with PR. 18F-FDG PET/CT is useful in identifying LVV associated with PR.

Development of an application for mobile phones (App) based on the collaboration between the Spanish Society of Rheumatology and Spanish Society of Family Medicine for the referral of systemic autoimmune diseases from primary care to rheumatology. / Desarrollo de una aplicación para teléfonos móviles (app) basada en la colaboración Sociedad Española de Reumatología/Sociedad Española de Medicina de Familia y Comunitaria para derivación de enfermedades autoinmunes sistémicas.

Management of systemic autoimmune diseases is challenging for physicians in their clinical practice. Although not common, they affect thousands of patients in Spain. The family doctor faces patients with symptoms and non-specific cutaneous, mucous, joint, vascular signs or abnormal laboratory findings at the start of the disease process and has to determine when to refer patients to the specialist. To aid in disease detection and better referral, the Spanish Society of Rheumatology and the Spanish Society of Family Medicine has created a group of experts who selected 26 symptoms, key signs and abnormal laboratory findings which were organized by organ and apparatus. Family doctors and rheumatologists with an interest in autoimmune systemic diseases were selected and formed mixed groups of two that then elaborated algorithms for diagnostic guidelines and referral. The algorithms were then reviewed, homogenized and adapted to the algorithm format and application for cell phone (apps) download. The result is the current Referral document of systemic autoimmune diseases for the family doctor in paper format and app (download). It contains easy-to-use algorithms using data from anamnesis, physical examination and laboratory results usually available to primary care, that help diagnose and refer patients to rheumatology or other specialties if needed.

New structural insights into the role of TROVE2 complexes in the on-set and pathogenesis of systemic lupus erythematosus determined by a combination of QCM-D and DPI.

The mechanism of self-recognition of the autoantigen TROVE2, a common biomarker in autoimmune diseases, has been studied with a quartz crystal microbalance with dissipation monitoring (QCM-D) and dual polarization interferometry (DPI). The complementarity and remarkable analytical features of both techniques has allowed new insights into the onset of systemic lupus erythematosus (SLE) to be achieved at the molecular level. The in vitro study for SLE patients and healthy subjects suggests that anti-TROVE2 autoantibodies may undergo an antibody bipolar bridging. An epitope-paratope-specific binding initially occurs to activate a hidden Fc receptor in the TROVE2 tertiary structure. This bipolar mechanism may contribute to the pathogenic accumulation of anti-TROVE2 autoantibody immune complex in autoimmune disease. Furthermore, the specific calcium-dependent protein-protein bridges point out at how the TRIM21/TROVE2 association might occur, suggesting that the TROVE2 protein could stimulate the intracellular immune signaling via the TRIM21 PRY-SPRY domain. These findings may help to better understand the origins of the specificity and affinity of TROVE2 interactions, which might play a key role in the SLE pathogenesis. This manuscript gives one of the first practical applications of two novel functions (-df/dD and Δh/molec) for the analysis of the data provided by QCM-D and DPI. In addition, it is the first time that QCM-D has been used for mapping hidden Fc receptors as well as linear epitopes in a protein tertiary structure. Graphical abstract ᅟ.

Non-adherence to subcutaneous biological medication in patients with rheumatoid arthritis: a multicentre, non-interventional study.

OBJECTIVES: To evaluate non-adherence to prescribed subcutaneous biologicals in rheumatoid arthritis (RA) patients in Spain. METHODS: ARCO (Study on Adherence of Rheumatoid Arthritis patients to SubCutaneous and Oral Drugs) was a multicentre, non-interventional retrospective study involving 42 rheumatology clinics from representative hospitals throughout Spain. The primary objective was to assess the percentage of patients (aged ≥18 years with an established RA diagnosis) with non-adherence to prescribed subcutaneous biologicals using clinical records and hospital pharmacy dispensing logs as the primary information sources. Adherence was assessed using the Medication Possession Ratio (MPR). Additionally, patients completed the Morisky-Green Medication Adherence Questionnaire. RESULTS: A total of 364 patients (77.5% females, mean age 54.9 years, median RA duration since diagnosis 7.8 years) were enrolled in ARCO. Non-adherence (MPR ≤80%) was reported in 52/363 evaluable patients (14.3%), and was lower in patients receiving initial monthly drug administration (6.4%) than with weekly (17.4%; p=0.034) or every two weeks (14.4%; p=0.102) administration. By multivariate analysis, non-adherence was positively associated with RA duration above the median and with using induction doses. Monthly administration, compared to weekly administration, was inversely associated with non-adherence. Age, gender, order of administration, and changes in the interval of administration, showed no association with non-adherence. Compared with the MPR, the Morisky-Green questionnaire performed poorly in detecting non-adherence. CONCLUSIONS: Non-adherence to the prescribed subcutaneous biological drug occurred in 14.3% of patients with RA. Patients using the most convenient administration period (i.e. monthly) had better adherence than those using more frequent dosing schedules.

Label-free piezoelectric biosensor for prognosis and diagnosis of Systemic Lupus Erythematosus.

An autoantigen piezoelectric sensor to quantify specific circulating autoantibodies in human serum is developed. The sensor consisted on a quartz crystal microbalance with dissipation monitoring (QCM-D) where TRIM21 and TROVE2 autoantigens were covalently immobilized, allowing the selective determination of autoantibodies for diagnosis and prognosis of Systemic Lupus Erythematosus (SLE). The sensitivity of the biosensor, measured as IC50 value, was 1.51U/mL and 0.32U/mL, for anti-TRIM21 and anti-TROVE2 circulating autoantibodies, respectively. The sensor is also able to establish a structural interaction fingerprint pattern or profile of circulating autoantibodies, what allows scoring accurately SLE patients. Furthermore, a statistical association of global disease activity with TRIM21-TROVE2 interaction was found (n=130 lupic patient samples, p-value=0.0413). The performances of the biosensor were compared with standard ELISA and multiplex DVD-array high-throughput screening assays, corroborating the viability of piezoelectric biosensor as a cost-effective in vitro assay for the early detection, monitoring or treatment of rare diseases.

Evaluation of the impact of nursing clinics in the rheumatology services.

Nursing clinics in rheumatology (NCRs) are organisational care models that provide care centred within the scope of a nurse's abilities. To analyse the impact of NCR in the rheumatology services, national multicenter observational prospective cohort studied 1-year follow-up, comparing patients attending rheumatology services with and without NCR. NCR was defined by the presence of: (1) office itself; (2) at least one dedicated nurse; and (3) its own appointment schedule. Variables included were (baseline, 6 and 12 months): (a) test to evaluate clinical activity of the disease, research and training, infrastructure of unit and resources of NCR and (b) tests to evaluate socio-demographics, work productivity (WPAI), use of services and treatments and quality of life. A total of 393 rheumatoid arthritis and ankylosing spondylitis patients were included: 181 NCR and 212 not NCR, corresponding to 39 units, 21 with NCR and 18 without NCR (age 53 + 11.8 vs 56 + 13.5 years). Statistically significant differences were found in patients attended in sites without NCR, at some of the visits (baseline, 6 or 12 months), for the following parameters: higher CRP level (5.9 mg/l ± 8.3 vs 4.8 mg/l ± 7.8; p < 0.005), global disease evaluation by the patient (3.6 ± 2.3 vs 3.1 ± 2.4), physician (2.9 ± 2.1 vs 2.3 ± 2.1; p < 0.05), use of primary care consultations (2.7 ± 5.4 vs 1.4 ± 2.3; p < 0.001) and worse work productivity. The presence of NCR in the rheumatology services contributes to improve some clinical outcomes, a lower frequency of primary care consultations and better work productivity of patients with rheumatic diseases.

Tocilizumab en pacientes con artritis reumatoide activa y respuesta inadecuada a fármacos antirreumáticos modificadores de la enfermedad o antagonistas del factor de necrosis tumoral: subanálisis de los datos españoles de un estudio abierto cercano a la práctica clínica habitual / Tocilizumab in patients with active rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs or tumor necrosis factor inhibitors: Subanalysis of Spanish results of an open-label study close to clinical practice

Objetivos: Analizar la experiencia española en un estudio internacional para evaluar tocilizumab en pacientes con artritis reumatoide (AR) con respuesta insuficiente al tratamiento con fármacos antirreumáticos modificadores de la enfermedad convencionales (FAME) o anti-TNF en condiciones cercanas a la práctica clínica habitual. Material y métodos: Subanálisis de 170 pacientes con AR que participaron en España en un ensayo clínico, internacional abierto de fase iiib, que presentaban una respuesta inadecuada al tratamiento con FAME o anti-TNF. Los pacientes recibieron 8 mg/kg de tocilizumab cada 4 semanas en combinación con FAME o en monoterapia durante un periodo de 20 semanas. Se evaluaron la seguridad y la eficacia de tocilizumab distinguiendo entre pacientes con fallo a FAME o anti-TNF y, dentro de estos, entre los que habían hecho o no periodo de lavado del anti-TNF. Resultados: Los acontecimientos adversos más frecuentes fueron infecciones (25%) y elevación de colesterol total (38%) y transaminasas (15%). Cinco pacientes abandonaron el estudio por un acontecimiento adverso. El 71/50/30% de los pacientes cumplía criterios de respuesta ACR 20/50/70 a los 6 meses del inicio del tratamiento con tocilizumab. Los pacientes naïve para anti-TNF presentaron una mayor respuesta ACR20: el 76% frente a un 64% en el grupo anti-TNF con lavado previo y el 66% en el grupo anti-TNF sin lavado previo. Conclusiones: Se confirma el perfil de seguridad de tocilizumab en pacientes con AR y fallo a FAME o anti-TNF. Tocilizumab es más eficaz en pacientes que no responden de forma satisfactoria al tratamiento con FAME convencionales que con anti-TNF (AU)

Objectives: To analyze the Spanish experience in an international study which evaluated tocilizumab in patients with rheumatoid arthritis (RA) and an inadequate response to conventional disease-modifying antirheumatic drugs (DMARDs) or tumor necrosis factor inhibitors (TNFis) in a clinical practice setting. Material and methods: Subanalysis of 170 patients with RA from Spain who participated in a phase IIIb, open-label, international clinical trial. Patients presented inadequate response to DMARDs or TNFis. They received 8 mg/kg of tocilizumab every 4 weeks in combination with a DMARD or as monotherapy during 20 weeks. Safety and efficacy of tocilizumab were analyzed. Special emphasis was placed on differences between failure to a DMARD or to a TNFi and the need to switch to tocilizumab with or without a washout period in patients who had previously received TNFi. Results: The most common adverse events were infections (25%), increased total cholesterol (38%) and transaminases (15%). Five patients discontinued the study due to an adverse event. After six months of tocilizumab treatment, 71/50/30% of patients had ACR 20/50/70 responses, respectively. A higher proportion of TNFi-naive patients presented an ACR20 response: 76% compared to 64% in the TNFi group with previous washout and 66% in the TNFi group without previous washout. Conclusions: Safety results were consistent with previous results in patients with RA and an inadequate response to DMARDs or TNFis. Tocilizumab is more effective in patients who did not respond to conventional DMARDs than in patients who did not respond to TNFis (AU)

Tocilizumab in patients with active rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs or tumor necrosis factor inhibitors: subanalysis of Spanish results of an open-label study close to clinical practice.

OBJECTIVES: To analyze the Spanish experience in an international study which evaluated tocilizumab in patients with rheumatoid arthritis (RA) and an inadequate response to conventional disease-modifying antirheumatic drugs (DMARDs) or tumor necrosis factor inhibitors (TNFis) in a clinical practice setting. MATERIAL AND METHODS: Subanalysis of 170 patients with RA from Spain who participated in a phase IIIb, open-label, international clinical trial. Patients presented inadequate response to DMARDs or TNFis. They received 8mg/kg of tocilizumab every 4 weeks in combination with a DMARD or as monotherapy during 20 weeks. Safety and efficacy of tocilizumab were analyzed. Special emphasis was placed on differences between failure to a DMARD or to a TNFi and the need to switch to tocilizumab with or without a washout period in patients who had previously received TNFi. RESULTS: The most common adverse events were infections (25%), increased total cholesterol (38%) and transaminases (15%). Five patients discontinued the study due to an adverse event. After six months of tocilizumab treatment, 71/50/30% of patients had ACR 20/50/70 responses, respectively. A higher proportion of TNFi-naive patients presented an ACR20 response: 76% compared to 64% in the TNFi group with previous washout and 66% in the TNFi group without previous washout. CONCLUSIONS: Safety results were consistent with previous results in patients with RA and an inadequate response to DMARDs or TNFis. Tocilizumab is more effective in patients who did not respond to conventional DMARDs than in patients who did not respond to TNFis.

Re-treatment of relapsed Paget's disease of bone with zoledronic acid: results from an open-label study.

Six patients from the phase 3 trials of zoledronic acid in Paget's disease, who had received zoledronic acid initially and had subsequently relapsed, were entered into an open re-treatment study. Following re-treatment, each patient reached similar absolute nadirs of serum alkaline phosphatase to those recorded after their first dose. No significant adverse events were reported. It is concluded that, while re-treatment of Paget's disease with zoledronic acid is rarely needed, it is safe and effective, with no evidence of treatment resistance based on this small cohort.

Influence of the IL6 gene in susceptibility to systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotype expression of SSc. METHODS: We performed a large metaanalysis including a total of 2749 cases and 3189 controls from 6 white populations (Germany, The Netherlands, Norway, Spain, Sweden, and United Kingdom). Three IL6 single-nucleotide polymorphisms (SNP; rs2069827, rs1800795, and rs2069840) were selected by SNP tagging and genotyped using TaqMan(®) allele discrimination technology. RESULTS: Individual SNP metaanalysis showed no evidence of association of the 3 IL6 genetic variants with the global disease. Phenotype analyses revealed a significant association between the minor allele of rs2069840 and the limited cutaneous SSc clinical form (Bonferroni p = 0.036, OR 1.14, 95% CI 1.04-1.25). A trend of association between the minor allele of the rs1800795 and the diffuse cutaneous SSc clinical form was also evident (Bonferroni p = 0.072, OR 0.86, 95% CI 0.77-0.96). In the IL6 allelic combination analyses, the GGC allelic combination rs2069827-rs1800795-rs2069840 showed an association with overall SSc (Bonferroni p = 0.016, OR 1.13, 95% CI 1.04-1.23). CONCLUSION: Our results suggest that the IL6 gene may influence the development of SSc and its progression.

Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension.

The 3-year FREEDOM trial assessed the efficacy and safety of 60 mg denosumab every 6 months for the treatment of postmenopausal women with osteoporosis. Participants who completed the FREEDOM trial were eligible to enter an extension to continue the evaluation of denosumab efficacy and safety for up to 10 years. For the extension results presented here, women from the FREEDOM denosumab group had 2 more years of denosumab treatment (long-term group) and those from the FREEDOM placebo group had 2 years of denosumab exposure (cross-over group). We report results for bone turnover markers (BTMs), bone mineral density (BMD), fracture rates, and safety. A total of 4550 women enrolled in the extension (2343 long-term; 2207 cross-over). Reductions in BTMs were maintained (long-term group) or occurred rapidly (cross-over group) following denosumab administration. In the long-term group, lumbar spine and total hip BMD increased further, resulting in 5-year gains of 13.7% and 7.0%, respectively. In the cross-over group, BMD increased at the lumbar spine (7.7%) and total hip (4.0%) during the 2-year denosumab treatment. Yearly fracture incidences for both groups were below rates observed in the FREEDOM placebo group and below rates projected for a "virtual untreated twin" cohort. Adverse events did not increase with long-term denosumab administration. Two adverse events in the cross-over group were adjudicated as consistent with osteonecrosis of the jaw. Five-year denosumab treatment of women with postmenopausal osteoporosis maintained BTM reduction and increased BMD, and was associated with low fracture rates and a favorable risk/benefit profile.