Safety of biologic therapy in combination with methotrexate in moderate to severe psoriasis: a cohort study from the BIOBADADERM registry.

BACKGROUND: Safety is an important consideration in decisions on treatment for patients with moderate-to-severe psoriasis and the study of drug safety is the main purpose of the BIOBADADERM registry. The combination of a biologic agent and a conventional systemic drug [generally methotrexate (MTX)] is a common treatment in clinical practice. However, there is a paucity of evidence from real-world practice on the safety of such combination regimens in the treatment of psoriasis. OBJECTIVES: The primary objective of this study was to ascertain whether the use of regimens combining biologic drugs with MTX in the management of moderate-to-severe psoriasis increases the risk of adverse events (AEs) or serious AEs (SAEs). We compared monotherapy using tumour necrosis factor (TNF), interleukin (IL)-17 and IL-23 inhibitors with the use of the same drugs in combination with MTX. METHODS: Using data from the BIOBADADERM registry, we compared biologic monotherapies with therapies that were combined with MTX. We estimated adjusted incidence rate ratios (aIRR) using a random effects Poisson regression with 95% confidence intervals for all AEs, SAEs, infections and serious infections and other AEs by system organ class. RESULTS: We analysed data from 2829 patients and 5441 treatment cycles, a total of 12 853 patient-years. The combination of a biologic with MTX was not associated with statistically significant increases in overall risk of AEs or SAEs in any treatment group. No increase in the total number of infections or serious infections in patients receiving combined therapy was observed for any group. However, treatment with a TNF inhibitor combined with MTX was associated with an increase in the incidence of gastrointestinal AEs (aIRR 2.50, 95% CI 1.57-3.98; P < 0.002). CONCLUSIONS: The risk of AEs and SAEs was not significantly increased in patients with moderate-to-severe psoriasis receiving different classes of biologic drugs combined with MTX compared with those on biologic monotherapy.

Study of Cognitive Function in Children Treated with Propranolol for Infantile Hemangioma.

BACKGROUND: Oral propranolol is considered the first choice for the treatment of infantile hemangiomas (IHs). There is a concern that administering propranolol in newborns and infants could induce adverse effects in learning and memory processes in the long term. The purpose of this study was to assess cognitive and memory functions in children who had been treated with propranolol for IH during their infancy. METHODS: A total of 23 children between 5 and 7.5 years of age who had been treated with oral propranolol for IH during infancy were tested for cognitive functions with the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) test and for memory functions with the Test of Memory and Learning (TOMAL). RESULTS: Comparison of our sample with a normal distribution by a Shapiro-Wilk W test showed no significant difference for any of the composite scores in the WPPSI-IV and TOMAL tests except for positive asymmetry and concentration of scores around average (p = 0.01) in the WPPSI-IV composite score (mean intelligence), due to one atypically high score. CONCLUSIONS: The distribution of scores for intelligence and memory scales in our study population was similar to that in the reference general population. These results fail to support any significant disturbance in intelligence and memory development in children treated during infancy with propranolol for IH.

Serious infections in patients with rheumatoid arthritis and other immune-mediated connective tissue diseases exposed to anti-TNF or rituximab: data from the Spanish registry BIOBADASER 2.0.

Data on infections in patients exposed to biologic therapies are mainly focused on rheumatoid arthritis (RA). Little is known about the safety profile in other immune-mediated connective tissue diseases (ICTD). The purpose of this study was to describe and to compare the risk of serious infections (SI) in patients with RA and other ICTD on anti-TNF or rituximab and to identify predictors of SI. We analyzed RA or other ICTD patients on anti-TNF or rituximab included in the Spanish registry BIOBADASER 2.0 (2000-2011). For each disease group, incidence rate (IR), mortality rate (MR) and IR ratio (IRR) of SI with 95% CI were estimated. Risks were then standardized by age and sex to the general population. Risk factors for SI were assessed by Poisson regression models. A total of 3,301 patients on anti-TNF (n = 3,166) or rituximab (n = 135), of which 176 (5%) had ICTD other than RA, were analyzed. IR of SI was higher in non-RA ICTD than in RA, with an IRR of 3.15 (95% CI 1.86, 5.31) before adjustment and 1.96 (95% CI 1.06, 3.65) after adjustment for age, comorbidity and corticoid use. Mortality due to infections was higher in ICTD although it did not reach statistical significance. Age, disease duration, comorbidities, corticosteroids and ICTD different to RA were all independently associated with SI. Patients with ICTD other than RA are at a high risk of SI when prescribed anti-TNF or rituximab, partly due to the excess comorbidity and immunosuppressive co-treatment, but also to the inflammatory disease. When evaluating the risk/benefit ratio of off-label medications in ICTD patients, age, comorbidities and corticoid use should carefully be taken into account, applying adequate preventive measures.

Variability in resource consumption in patients with spondyloarthritis in Spain. Preliminary descriptive data from the emAR II study.

OBJECTIVE: Our objective was to describe the variability in the management of spondyloarthritis (SA) in Spain in terms of healthcare resources and their use. METHODS: A review of 1168 medical files of patients seen in randomly selected Spanish hospital rheumatology departments. We analyzed demographic variables and variables related to the consumption of health resources. RESULTS: The total number of visits to rheumatology were 5,908 with a rate of 254 visits/100 patient-years. The total number of visits to rheumatology specialty nurses was 775, with a rate of 39 visits/100 patient-years, and there were 446 hospitalizations, representing a rate of 22 per 100 patient-years. The number of admissions due to SA was 89, with a rate of 18 admissions/100 patient-years. Total visits to other specialists was 4,307 with a rate of 200/100 patient-years. The total number of orthopedic surgeries was 41, which leads to a rate of 1.8 surgeries/100 patient-years. CONCLUSIONS: The data regarding visits to the rheumatologist and prosthetic surgery of patients with in Spain is similar to most studies published in our environment, however, other aspects concerning the use of health resources are different compared to other countries. This data may help to understand and improve organizational aspects of management of SA in Spanish hospitals.

Change in the discontinuation pattern of tumour necrosis factor antagonists in rheumatoid arthritis over 10 years: data from the Spanish registry BIOBADASER 2.0.

OBJECTIVE: To investigate in rheumatoid arthritis (RA) the rate and reason of discontinuation of tumour necrosis factor (TNF) antagonists over the past decade. METHODS: RA 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). RESULTS: 2907 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. CONCLUSIONS: In 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.

Age at treatment predicts reason for discontinuation of TNF antagonists: data from the BIOBADASER 2.0 registry.

OBJECTIVES: To assess the retention rate of TNF antagonists in elderly patients suffering from chronic arthropathies and to identify predictive variables of discontinuation by inefficacy or by adverse events (AEs). METHODS: All patients treated with TNF antagonists in BIOBADASER 2.0, with a diagnosis of either RA or spondyloarthritis (SpA: AS and PsA) were included and classified as <65 (younger) or ≥65 years of age (older) at start of the treatment. Cumulative incidence function for discontinuation (inefficacy or AE) was estimated as being the alternative reason for a competing risk. Competing-risks regression models were used to measure the association between study groups, covariates and reason for discontinuation. RESULTS: A total of 4851 patients were studied; 2957 RA (2291 in the younger group and 666 in the older group) and 1894 SpA (1795 in the younger group and 99 in the older group). Retention curves were statistically differently stratified by age groups, with the SpA younger group having the largest retention rate. Competing-risks regression models showed that in the older group, AEs were the most common reason for discontinuation regardless of the diagnosis of the patient and TNF antagonist molecule, whereas in the younger group, the most common cause of discontinuation was inefficacy. CONCLUSION: In conclusion, factors predicting discontinuation of TNF antagonists due to AEs are older age and diagnosis of RA. On the other hand, younger age predicts discontinuation due to lack of efficacy.

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.

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.

[Biobadaser 2.0: analysis and trends in 2009]. / Biobadaser 2.0: análisis y tendencias en 2009.

OBJECTIVE: To update the information on long-term safety of biological therapies used for the treatment of rheumatic diseases. METHODS: BIOBADASER is a safety registry of biological therapies established by the Spanish Society of Rheumatology. A description of BIOBADASER 2.0, a cohort composed of 14 centres within BIOBADASER is reported from 2000 until 2009. RESULTS: The 14 centres have registered 5,493 patients, who have received 8,081 cycles of treatment with biological therapies. 30% (1,666) has received treatment with more than one biologic agent during follow-up. There have been 3,784 treatment discontinuations, with inefficacy or loss of efficacy being the most frequent cause (1,453; 38%), followed by adverse events (1,297; 34%). Up to 7,289 adverse events (AE) have been reported, of which 80% (5,764) were considered as non serious, nearly 19% (1,340) were notified as serious and about 2% (110) were fatal. The most frequent AE were infections (2,668; 37%), followed by general problems and administration related events (10%). Cardiovascular events and cancer amounted a 7% of the total AE. CONCLUSIONS: There does not seem to be a trend regarding different risks in BIOBADASER 2.0 with respect to the general registry, or to previous years.

Cancer in rheumatoid arthritis: occurrence, mortality, and associated factors in a South European population.

OBJECTIVES: To estimate the prevalence, incidence, mortality, and predictors of cancer in patients with rheumatoid arthritis (RA). METHODS: We compared the incidence of cancer and the mortality by cancer in a cohort of 789 randomly selected RA patients (1999-2005) with the expected ones in the general population. We estimated standardized incidence ratios (SIR) and standardized mortality ratios (SMR) by indirect age and sex standardization. Additionally, we analyzed by generalized linear models the association of various predictors with cancer incidence, obtaining incidence rate ratios (IRR) with 95% confidence intervals (CI). RESULTS: The SIR of cancer in RA is 1.23 (95% CI: 0.78-1.85). By cancer type, there is an increased risk of leukemia, non-Hodgkin's lymphoma, and lung cancer in RA compared with the general population of the same sex and age. The SMR of cancer is 1.0 (95% CI: 0.53-1.7). By cancer type, RA patients with lung or kidney cancer have higher mortality than expected. Being male, elderly, with longstanding disease, and having used any cytotoxic drugs apart from methotrexate are confirmed as predictive factors for cancer. Additional independent predictors are increases in blood leukocyte counts (IRR per 3000 u/mm3 increase: 1.88 (95% CI: 1.6 -2.1)) and decreases in serum hemoglobin (IRR per 2 g/l decrease: 1.88 (95% CI: 1.19 -2.94)). CONCLUSIONS: The overall incidence and mortality of cancer in RA is not greater than the expected, although there is an increased risk of hematopoietic and lung cancers in RA patients compared with the general population. Hemoglobin and leukocyte counts may help to identify RA patients at risk for cancer.

All-cause and cause-specific mortality in rheumatoid arthritis are not greater than expected when treated with tumour necrosis factor antagonists.

BACKGROUND: Mortality is increased in rheumatoid arthritis (RA), mainly because of cardiovascular (CV) events, cancer and infections. Recent data suggest that treatment with tumour necrosis factor (TNF) antagonists may affect this trend. OBJECTIVE: To assess whether treatment with TNF antagonists is associated with reduction in CV events, cancer and infection rates, and in mortality in patients with RA treated and not treated with TNF antagonists. METHODS: BIOBADASER is a registry for active long-term follow-up of safety of biological treatments in patients with RA. It includes 4459 patients with RA treated with TNF antagonists. EMECAR is an external RA cohort (n = 789) established to define the characteristics of the disease in Spain and to assess comorbidity. The incidence density (ischaemic heart disease) of CV events, cancer and infections was estimated and compared. The standardised mortality ratio was compared with the rate in the general population. A propensity score was used to match cohorts by the probability of being treated. RESULTS: Rates of CV and cancer events are significantly higher in EMECAR than in BIOBADASER (RR 5-7 for different CV events, and RR 2.9 for cancer), whereas the rate of serious infections is significantly higher in BIOBADASER (RR 1.6). Mortality ratio of BIOBADASER by EMECAR is 0.32 (0.20-0.53) for all causes of death, 0.58 (0.24-1.41) for CV events, 0.52 (0.21-1.29) for infection and 0.36 (0.10-1.30) for cancer-related deaths. CONCLUSION: Morbidity, other than infection, and mortality are not higher than expected in patients with RA treated with TNF antagonists.