Development of clinical prediction models for good or bad response to classic systemic drugs, anti-TNFs, and ustekinumab in psoriasis, based on the BIOBADADERM cohort.

BACKGROUND: Identifying patients likely to have very good or bad results from systemic psoriasis therapy could improve efficiency of therapy. OBJECTIVE: To develop prognostic models for good or bad response to classic systemic drugs, anti-TNFs, and ustekinumab in psoriasis. METHODS: Multivariable logistic regression of a prospective multicenter cohort of psoriatic patients in clinical practice (6449 person-years of follow-up). We used as possible predictors demographic characteristics, comorbidities, characteristics of the psoriasis (type, PASI, arthritis), history of past therapy at entry in the cohort, and history of response to previous cycles while in the cohort. We defined good response to a treatment cycle as either cycle end due to disease remission or a cycle longer than 2 years that does not end later due to inefficacy in the follow-up period. Bad response to a treatment cycle was defined as a cycle that is finished due to inefficacy, based on the physician judgment, after more than 3 months of treatment. RESULTS: Patients with fewer previous therapies, lower body mass index, older at start of therapy, and with previous history of good responses to therapy are more likely to have positive results of therapy. However, the predictive characteristics of models are poor. CONCLUSION: Predictive models of clinical response to systemic drugs in psoriasis with the studied variables do not seem to outperform drug selection by a dermatologist.

Use of off-label doses is frequent in biologic therapy for moderate to severe psoriasis: A cross-sectional study in clinical practice.

INTRODUCTION: Biologic medications increase dramatically the burden of a chronic and high prevalent disease like psoriasis. The objective of the study was to quantify the use of dose reduction or dose escalation strategies, not reflected in the drug summary of product characteristics, in clinical practice. METHODS: An observational, cross-sectional study of a subset of patients from the Spanish Registry for Systemic Treatments in Psoriasis (BIOBADADERM) treated for over six consecutive months with the same biologic agent. RESULTS: The study included 637 patients. At the cut-off date, the initial dose had been reduced in 223 patients (35%; 95% CI: 31.3-38.9%) and escalated in 46 (7.2%; 95% CI: 5.3-9.5%). When compared with the patients treated with standard doses, the patients on reduced doses had a lower PASI score at the cut-off date (a mean 2.6 versus 1; -1.6 points) and exhibited greater improvement in PASI since the start of biologic therapy (mean reduction over baseline 75% versus 87%). By contrast, the patients receiving an escalated dose had higher PASI scores (2.6 versus 8.0) and showed less improvement in PASI (75% versus 46.8%). CONCLUSION: Off-label doses of biologic agents for psoriasis are frequent in clinical practice. This information is especially relevant for pharmacoeconomic models.

Infections in patients with rheumatic diseases treated with TNF antagonists.

TNF has a critical role in inflammation and immunity, and therapeutic inhibition of TNF with antagonist could potentially lead to immune suppression. Data gathered from clinical trials and clinical observation show a minor but significant increased risk of infections in patients suffering from rheumatic diseases treated with monoclonal TNF antibodies and soluble TNF receptors. This increase risk applies to patients but also to the underlying disease. Pathogens causing these infections include intracellular bacteria, and to some extend opportunistic microorganisms as mycobacteria and fungi. Preventive strategies and patient selection have an important impact on the risk of these infections.

Demyelinating disease in patients treated with TNF antagonists in rheumatology: data from BIOBADASER, a pharmacovigilance database, and a systematic review.

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.

Infecciones en pacientes tratados con antagonistas del factor de necrosis tumoral: incidencia, etiología y mortalidad en el registro BIOBADASER / Infections in patients treated with tumor necrosis factor antagonists: incidence, etiology and mortality in the BIOBADASER registry

Background and objectives: 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.Patients and methods: Analysis of the Spanish registry BIOBADASER (Feb-2000 to Jan-2006), a national drug safety registry of patients with rheumatic diseases. Results: 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 p<0.0001). Pneumonia, sepsis, tuberculosis, abdominal infection and endocarditis were associated with significant attributable mortality.Conclusions: 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 (AU)

Fundamento y objetivo: El aumento del riesgo de infección en la utilización de los antagonistas del factor de necrosis tumoral (TNF) sigue siendo un tema de debate abierto. El desarrollo de estrategias eficaces de prevención y tratamiento empírico implica establecer la etiología y el pronóstico de las infecciones. Pacientes y métodos: Análisis del registro español BIOBADASER (febrero 2000 a enero 2006), un registro de terapias biológicas en pacientes con enfermedades reumáticas.Resultados: En los 6.969 pacientes registrados a la fecha del análisis, se produjeron 907 episodios de infección. La incidencia de infección observada fue de 53,09 casos/1.000 pacientes-año (IC 95% 49,69-56,66). Las infecciones más frecuentes fueron las de piel (12,18 casos/1.000 pacientes-año), neumonía (5,97 casos/1.000 pacientes-año), cistitis (3,92 casos/1.000 pacientes-año), tuberculosis (3,51 casos/1.000 pacientes-año) y articulares (3,76 casos/1.000 pacientes-año). Emergen como patógenos importantes Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa y Salmonella spp. El virus de la varicela zóster y el virus del herpes simple causaron la mayoría de los casos de infecciones virales con germen identificable. La candidiasis mucocutánea fue la más frecuente entre las infecciones fúngicas. La mortalidad fue mayor en los pacientes infectados (p-log-rank<0,0001). La aparición de una neumonía, sepsis, tuberculosis, infección abdominal y endocarditis se asociaron significativamente con la mortalidad. Conclusiones: Un número significativo de infecciones bacterianas, víricas y fúngicas se produjeron en pacientes con enfermedades reumáticas tratadas con antagonistas del TNF. La información de este estudio puede suponer un avance para la medicina sobre cómo tratar la infección en este grupo vulnerable de pacientes (AU)

Infections in patients treated with tumor necrosis factor antagonists: incidence, etiology and mortality in the BIOBADASER registry.

BACKGROUND AND OBJECTIVES: 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. PATIENTS AND METHODS: Analysis of the Spanish registry BIOBADASER (Feb-2000 to Jan-2006), a national drug safety registry of patients with rheumatic diseases. RESULTS: 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 p<0.0001). Pneumonia, sepsis, tuberculosis, abdominal infection and endocarditis were associated with significant attributable mortality. CONCLUSIONS: 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.

Demyelinating disease in patients treated with TNF antagonists in rheumatology: data from BIOBADASER, a pharmacovigilance database, and a systematic review.

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.

Cancer in patients with rheumatic diseases exposed to TNF antagonists.

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.

Incidence and risk of hospitalisation due to shingles and chickenpox in patients with rheumatic diseases treated with TNF antagonists.

OBJECTIVE: To estimate the incidence of hospitalisation due to varicella zoster virus (VZV) infection in patients treated with tumour necrosis factor (TNF) antagonists for inflammatory 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 Mínimo Básico 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 significantly 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 justified at present.

Reacciones adversas relacionadas con la administración de inhibidores del TNF. Análisis de un registro de terapias biológicas / Adverse reactions related to the administration of TNF inhibitors. Analysis of a registry of biologic therapy

Objetivo: Estimar la frecuencia de aparición de las reacciones relacionadas con la administración (RRA), los síntomas asociados a las graves o tardías, la ventana de exposición desde inicio de la terapia biológica y si hay diferencias entre infliximab, etanercept y adalimumab. Pacientes y método: BIOBADASER es un registro de acontecimientos adversos establecido en 2001 para determinar la seguridad de las terapias biológicas en enfermedades reumáticas. Contiene datos de los pacientes, tratamiento y acontecimientos adversos relevantes. Resultados: Se registró 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 años-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 más de la mitad de las RRA, el acontecimiento adverso da lugar a la interrupción del fármaco relacionado y en el 5% de los casos el paciente requiere ser hospitalizado. Más del 20% de las RRA ocurren después de 15 meses de tratamiento, incluso aparecen después de 5 años. En las reacciones adversas tardías los síntomas comunicados con más frecuencia son erupciones, fiebre, malestar general y mialgias. Conclusiones: Las RRA pueden aparecer en cualquier momento de la enfermedad, son una de las causas más frecuentes de interrupción de tratamiento con infliximab. Aunque con menor frecuencia, también se relacionan con etanercept y adalimumab en síntomas que pueden no identificarse como tales (AU)

Objective: To estimate the frequency of administration related reactions (ARR), the risk window from the starting date, and finally if there are any differences between infliximab, etanercept and adalimumab. Patients and method: BIOBADASER is an adverse events registry established in 2001 for active long-term follow-up of safety of biological therapies in rheumatic patients. Data from patients, diagnosis, treatment, and adverse events are recorded. Results: Four-hundred ninety six relevant ARR were registered, 19.6% (496/2531) of all the adverse events communicated and 6.3% (496/2531) of all the patients registered. The incidence rate per 1000 patients-year with infliximab is 28 cases (95% CI, 25-31), with etanercept 0.2 (95% CI, 0.1-0.4) and with adalimumab 0.2 (95% CI, 0.07-0.7). Treatment was interrupted in more than 50% of all the ARR and 5% of all patients were hospitalized. More than 20% ARR happened after 15 months of treatment; in addition 2 appeared after 5 years of treatment. In delayed reactions the symptoms that most frequently were recorded were rash, fever, malaise, and myalgia. Conclusions: ARR can appear in any moment of the treatment; they are among the most frequent causes of treatment interruption. Although with less frequency, ARR are also associated with etanercept and adalimumab with symptoms that cannot be identified as such (AU)

[Adverse Reactions Related to the Administration of TNF Inhibitors. Analysis of a Registry of Biologic Therapy]. / Reacciones adversas relacionadas con la administración de inhibidores del TNF. Análisis de un registro de terapias biológicas.

OBJECTIVE: To estimate the frequency of administration related reactions (ARR), the risk window from the starting date, and finally if there are any differences between infliximab, etanercept and adalimumab. PATIENTS AND METHOD: BIOBADASER is an adverse events registry established in 2001 for active long-term follow-up of safety of biological therapies in rheumatic patients. Data from patients, diagnosis, treatment, and adverse events are recorded. RESULTS: Four-hundred ninety six relevant ARR were registered, 19.6% (496/2531) of all the adverse events communicated and 6.3% (496/2531) of all the patients registered. The incidence rate per 1000 patients-year with infliximab is 28 cases (95% CI, 25-31), with etanercept 0.2 (95% CI, 0.1-0.4) and with adalimumab 0.2 (95% CI, 0.07-0.7). Treatment was interrupted in more than 50% of all the ARR and 5% of all patients were hospitalized. More than 20% ARR happened after 15 months of treatment; in addition 2 appeared after 5 years of treatment. In delayed reactions the symptoms that most frequently were recorded were rash, fever, malaise, and myalgia. CONCLUSIONS: ARR can appear in any moment of the treatment; they are among the most frequent causes of treatment interruption. Although with less frequency, ARR are also associated with etanercept and adalimumab with symptoms that cannot be identified as such.

Calidad de los estudios postautorización de tipo observacional registrados en España antes de su regulación / Quality of observational post-authorization studies registered in Spain before their regulation

Fundamento y objetivo: En julio de 2002, los estudios postautorización de tipo observacional quedaron definitivamente regulados en España. La justificación de dicha regulación ha sido cuestionada. El objetivo de este trabajo es evaluar la calidad científica y ética de los estudios registrados el año previo a la entrada en vigor de la normativa, así como el valor social de sus resultados utilizando su publicación como indicador. Material y método: Se ha recogido los datos de carácter administrativo, metodológico, ético y de seguimiento de los estudios postautorización presentados en la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) durante el año 2001. Resultados: En 2001 se presentó en la AEMPS un total de 162 estudios postautorización que pretendían incluir un total de 306.539 pacientes. El diseño más habitual fue el de «seguimiento prospectivo no controlado» (122 estudios [75%]) y prácticamente en su totalidad (99%) el médico fue la única fuente de información. En un 43% no se especifica el tamaño muestral o no se justifica. La duración de los estudios fue inferior a 12 meses en el 83%. Sólo en el 13% de los estudios se solicitó la revisión por un comité ético de investigación clínica y sólo en el 44% se preveía algún procedimiento de información a los sujetos de investigación. Once estudios se publicaron como originales en revistas (el 10% de los finalizados), 1 de ellos en una revista internacional, y 13 (el 12% de los finalizados) en forma de comunicaciones a congresos, 2 de ellos internacionales. Conclusiones: Los estudios postautorización presentados en la AEMPS durante el año 2001 tuvieron escasa calidad metodológica y ética. La mayoría de ellos no se publicó, lo cual pone en cuestión el valor de esas investigaciones al tiempo que alimenta las dudas sobre su verdadera finalidad. La regulación de esos estudios parecía, pues, justificada

Background and objective: In July, 2002, observational post-authorization studies were subjected to regulation in Spain, giving rise to an uproar among sponsors and investigators. The aim of the present report was to assess the scientific and ethical quality of the studies presented during the year before the regulation came into force. In addition, we explored how many of them reached publication. Material and method: We extracted information relative to administrative procedures, methods, follow-up and ethical issues from the protocol of the studies presented to the Spanish Agency for Medicines and Healthcare Products (AEMPS) during 2001. Results: A total of 162 studies intended to recruit 306,539 patients were registered as post-authorization studies in 2001. The most widely used design was the «non-controlled prospective follow-up study» (122 studies; 75%). Physicians were the only source of information in 99% of the studies. In 43% of them, the sample size was neither specified nor justified. In 83% of the studies the observation period per patient was less than 12 months. An ethical review was requested for only 13% of the studies while a procedure to inform patients was planned in 44%. Eleven studies (10% of those finalized) had been published in scientific journals (1 of them international) and 13 (12% of those finalized) were reported as a communication to a national (11) or international (2) congress. Conclusions: Most post-authorization studies presented to the AEMPS in 2001 had poor methodological and ethical quality. Only a few became published, raising doubts about their scientific aims. These results give empirical support to the regulation adopted