Safety outcomes in patients with rheumatoid arthritis treated with abatacept: results from a multinational surveillance study across seven European registries.

BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased risk of infection and malignancy compared with the general population. Infection risk is increased further with the use of disease-modifying antirheumatic drugs (DMARDs), whereas evidence on whether the use of biologic DMARDs increases cancer risk remains equivocal. This single-arm, post-marketing study estimated the incidence of prespecified infection and malignancy outcomes in patients with RA treated with intravenous or subcutaneous abatacept. METHODS: Data were included from seven European RA quality registries: ATTRA (Anti-TNF Therapy in Rheumatoid Arthritis [Czech Republic]), DANBIO (Danish Rheumatologic Database), ROB-FIN (National Registry of Antirheumatic and Biological Treatment in Finland), ORA (Orencia and Rheumatoid Arthritis [France]), GISEA (Italian Group for the Study of Early Arthritis), BIOBADASER (Spanish Register of Adverse Events of Biological Therapies in Rheumatic Diseases), and the SCQM (Swiss Clinical Quality Management) system. Each registry is unique with respect to design, data collection, definition of the study cohort, reporting, and validation of outcomes. In general, registries defined the index date as the first day of abatacept treatment and reported data for infections requiring hospitalization and overall malignancies; data for other infection and malignancy outcomes were not available for every cohort. Abatacept exposure was measured in patient-years (p-y). Incidence rates (IRs) were calculated as the number of events per 1000 p-y of follow-up with 95% confidence intervals. RESULTS: Over 5000 patients with RA treated with abatacept were included. Most patients (78-85%) were female, and the mean age range was 52-58 years. Baseline characteristics were largely consistent across registries. Among patients treated with abatacept, IRs for infections requiring hospitalization across the registries ranged from 4 to 100 events per 1000 p-y, while IRs for overall malignancy ranged from 3 to 19 per 1000 p-y. CONCLUSIONS: Despite heterogeneity between registries in terms of design, data collection, and ascertainment of safety outcomes, as well as the possibility of under-reporting of adverse events in observational studies, the safety profile of abatacept reported here was largely consistent with previous findings in patients with RA treated with abatacept, with no new or increased risks of infection or malignancy.

Altered CD39 and CD73 Expression in Rheumatoid Arthritis: Implications for Disease Activity and Treatment Response.

In rheumatoid arthritis (RA) synovium, ATP, and ADP are released, sparking inflammation. Ectoenzymes CD39 and CD73 metabolize these purine nucleotides, generating anti-inflammatory adenosine. Therefore, dysregulated CD39 and CD73 expression may impact RA development. We assessed CD39 and CD73 expression in peripheral blood from 15 healthy controls (Cs) and 35 RA patients at baseline and after 3 and 6 months of tocilizumab treatment using flow cytometry. Additionally, ectoenzyme expression was examined on cultured T cells to understand activation and IL-6 effects. At baseline, RA patients exhibited a lower CD8+CD39-CD73+ cell percentage, which inversely correlated with DAS28. Additionally, they had lower percentages of Treg CD39+CD73+ and CD39-CD73- cells. Good responders tended to have lower B CD39+CD73+ cell percentages at baseline and 3 months. Additionally, Treg, CD8+ T and B cells inversely correlated with DAS28. T-cell activation increased CD39 and decreased CD73 expression, regardless of IL-6. IL-6 reduced IFNγ-secreting CD4+ T-cell percentage in Cs, but increased the percentage of IFNγ-secreting CD4+ and CD8+ T cells in RA patients. These findings indicate differing CD39 and CD73 expression in RA and Cs, influenced by T-cell activation and IL-6. Correlations between these molecules and RA activity suggest their role in dysregulated inflammation in RA.

Aporte de la solidaridad médica cubana a la salud de la población de Timor-Leste / Contribution of Cuban medical solidarity to the health of Timor-Leste´s population

Introducción: La solidaridad médica cubana llega a Timor-Leste cuando no habían transcurrido dos años de su independencia, con una infraestructura de salud muy dañada y prácticamente sin médicos disponibles para garantizar los servicios básicos de salud. Objetivo: Analizar el aporte de la solidaridad médica cubana en la mejora del estado de salud de la población de Timor-Leste en el periodo 2004-2019. Métodos: Se realizó una investigación cualitativa, que se apoyó en el estudio descriptivo y retrospectivo y se aplicó el método etnográfico. El periodo de estudio abarcó 15 años, desde 2004 hasta 2019. Conclusiones: La solidaridad médica cubana en la salud de Timor-Leste, durante estos 15 años, ha contribuido a modificar el cuadro sanitario que tenía ese país cuando logró su independencia en el año 2002, convirtiéndose en uno de los países con mejores indicadores en la Región de Oceanía. La asistencia médica y la formación de estudiantes en Cuba y en el propio Timor-Leste son elementos decisivos de la cooperación de Cuba en la trasformación y fortalecimiento del sistema sanitario timorense, factores esenciales para alcanzar la cobertura universal de salud(AU)

Introduction: Cuban medical solidarity arrives in Timor-Leste two years after its independence, with a badly damaged health infrastructure and practically no doctors available to guarantee basic health services. Objective: Analyze the contribution of Cuban medical solidarity in improving the health status of Timor-Leste´s population in the period 2004-2019. Methods: A qualitative research was carried out, which was based on the descriptive and retrospective study and the ethnographic method was applied. The study period spanned 15 years, from 2004 to 2019. Conclusions: Cuban medical solidarity in Timor-Leste, during these 15 years, has contributed to modify the health picture that the country had when it achieved its independence in 2002, becoming one of the countries with the best indicators in the Oceania Region. Medical assistance and the training of students in Cuba and in Timor-Leste itself are decisive elements of Cuba's cooperation in the transformation and strengthening of the Timorese health system, which are essential factors in achieving universal health coverage(AU)

Anti-IL6-Receptor Tocilizumab in Refractory and Noninfectious Uveitic Cystoid Macular Edema: Multicenter Study of 25 Patients.

PURPOSE: Cystoid macular edema (CME) is a leading cause of blindness. This study assessed the efficacy and safety of tocilizumab (TCZ) in refractory CME. DESIGN: Retrospective case series. METHODS: Patients with CME secondary to noninfectious uveitis who had inadequate response to corticosteroids and at least 1 conventional immunosuppressive drug, and in most cases to other biological agents, were studied. CME was defined as central retinal thickness greater than 300 µm. The primary outcome measure was macular thickness. Intraocular inflammation, best-corrected visual acuity (BCVA), and corticosteroid-sparing effect were also analyzed. RESULTS: A total of 25 patients (mean ± standard deviation age 33.6 ± 18.9 years; 17 women) with CME were assessed. Underlying diseases associated with uveitis-related CME are juvenile idiopathic arthritis (n = 9), Behçet disease (n = 7), birdshot retinochoroidopathy (n = 4), idiopathic (n = 4), and sarcoidosis (n = 1). The ocular patterns were panuveitis (n = 9), anterior uveitis (n = 7), posterior uveitis (n = 5), and intermediate uveitis (n = 4). Most patients had CME in both eyes (n = 24). TCZ was used in monotherapy (n = 11) or combined with conventional immunosuppressive drugs. Regardless of the underlying disease, compared to baseline, a statistically significant improvement in macular thickness (415.7 ± 177.2 vs 259.1 ± 499.5 µm; P = .00009) and BCVA (0.39 ± 0.31 vs 0.54 ± 0.33; P = .0002) was obtained, allowing us to reduce the daily dose of prednisone (15.9 ± 13.6 mg/day vs 3.1 ± 2.3 mg/day; P = .002) after 12 months of therapy. Remission was achieved in 14 patients. Only minor side effects were observed after a mean follow-up of 12.7 ± 8.34 months. CONCLUSION: Macular thickness is reduced following administration of TCZ in refractory uveitis-related CME.

Calprotectin strongly and independently predicts relapse in rheumatoid arthritis and polyarticular psoriatic arthritis patients treated with tumor necrosis factor inhibitors: a 1-year prospective cohort study.

BACKGROUND: Calprotectin is a biomarker of disease activity in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) and predicts relapse in juvenile idiopathic arthritis. Higher drug trough serum levels are associated with a good response in patients treated with tumor necrosis factor inhibitors (TNFi). Power Doppler ultrasound synovitis is predictive of relapse and structural damage progression in patients in clinical remission. The purpose of this study was to analyze the accuracy of serum calprotectin levels, drug trough serum levels (TSL), and power Doppler (PD) activity as predictors of relapse in RA and PsA patients in remission or with low disease activity receiving TNFi. METHODS: This was a longitudinal, prospective, 1-year single-center study of 103 patients (47 RA, 56 PsA) receiving TNFi in remission or with low disease activity (28-joint Disease Activity Score (DAS28) ≤ 3.2). The predictive value of serum calprotectin, TNFi TSL, and PD were assessed using receiver operating characteristic (ROC) analyses. To illustrate the predictive performance of calprotectin, TNFi TSL, and PD score, Kaplan-Meier curves were constructed from baseline to relapse. Associations between baseline factors and relapse were determined using Cox regression models. Multivariate models were constructed to analyze the effect of covariates and to fully adjust the association between calprotectin, TNFi TSL, and PD score with relapse. A generalized estimating equation model with an identity link for longitudinal continuous outcomes was used to assess the effect of covariates on TNFi TSL. RESULTS: Ninety-five patients completed 1 year of follow-up, of whom 12 experienced a relapse. At baseline, relapsers had higher calprotectin levels, lower TNFi TSL, and higher PD activity than nonrelapsers. ROC analysis showed calprotectin fully predicted relapse (area under the curve (AUC) = 1.00). TNFi TSL and PD had an AUC of 0.790 (95% confidence interval (CI) 0.691-0.889) and 0.877 (95% CI 0.772-0.981), respectively. Survival analyses and log rank tests showed significant differences between groups according to calprotectin serum levels (p < 0.001), TNFi TSL (p = 0.004), and PD score (p < 0.001). Univariate Cox regression models showed that time-to-remission/low disease activity (hazard ratio (HR) = 1.17, p < 0.001), calprotectin levels (HR = 2.38, p < 0.001), TNFi TSL (HR = 0.47, p = 0.018), and PD score (HR = 1.31, p < 0.001) were significantly associated with disease relapse. In the multivariate analysis, only baseline calprotectin levels independently predicted disease relapse (HR = 2.41, p = 0.002). The generalized estimating equation analysis showed that only disease activity by DAS28-erythrocyte sedimentation rate (ESR) was significantly associated with longitudinal changes in TNFi TSL (regression coefficient 0.26 (0.0676 to 0.0036), p = 0.001). CONCLUSION: Time-to-remission/low disease activity, calprotectin serum levels, TNFi TSL, and PD score were significantly associated with disease relapse. However, only baseline calprotectin serum levels independently predicted disease relapse in RA and PsA patients under TNFi therapy.

Comparative effectiveness of tocilizumab versus TNF inhibitors as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis after the use of at least one biologic disease-modifying antirheumatic drug: analyses from the pan-European TOCERRA register collaboration.

OBJECTIVE: To compare the effectiveness of tocilizumab (TCZ) and tumour necrosis factor (TNF) inhibitors (TNFi) as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) after the use of at least one biologic DMARD (bDMARD). METHODS: We included patients with RA having used at least one bDMARD from 10 European registries. We compared drug retention using Kaplan-Meier and Cox models and Clinical Disease Activity Index (CDAI) change over time with mixed-effects models for longitudinal data. The proportions of CDAI remission and low disease activity (LDA) at 1 year were compared using LUNDEX correction. RESULTS: 771 patients on TCZ as monotherapy (TCZ mono), 1773 in combination therapy (TCZ combo), 1404 on TNFi as monotherapy (TNFi mono) and 4660 in combination therapy (TNFi combo) were retrieved. Crude median retention was higher for TCZ mono (2.31 years, 95% CI 2.07 to 2.61) and TCZ combo (1.98 years, 95% CI 1.83 to 2.11) than TNFi combo (1.37 years, 95% CI 1.30 to 1.45) and TNFi mono (1.31 years, 95% CI 1.18 to 1.47). In a country and year of treatment initiation-stratified, covariate-adjusted analysis, hazards of discontinuation were significantly lower among patients on TCZ mono or combo compared with patients on TNFi mono or combo, and TNFi combo compared with TNFi mono, but similar between TCZ mono and combo. Average adjusted CDAI change was similar between groups. CDAI remission and LDA rates were comparable between groups. CONCLUSION: With significantly longer drug retention and similar efficacy to TNFi combo, TCZ mono or combo are reasonable therapeutic options in patients with inadequate response to at least one bDMARD.

Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behçet's Disease.

PURPOSE: To assess efficacy, safety, and cost-effectiveness of adalimumab (ADA) therapy optimization in a large series of patients with uveitis due to Behçet disease (BD) who achieved remission after the use of this biologic agent. DESIGN: Open-label multicenter study of ADA-treated patients with BD uveitis refractory to conventional immunosuppressants. SUBJECTS: Sixty-five of 74 patients with uveitis due to BD, who achieved remission after a median ADA duration of 6 (range, 3-12) months. ADA was optimized in 23 (35.4%) of them. This biologic agent was maintained at a dose of 40 mg/subcutaneously/2 weeks in the remaining 42 patients. METHODS: After remission, based on a shared decision between the patient and the treating physician, ADA was optimized. When agreement between patient and physician was reached, optimization was performed by prolonging the ADA dosing interval progressively. Comparison between optimized and nonoptimized patients was performed. MAIN OUTCOME MEASURES: Efficacy, safety, and cost-effectiveness in optimized and nonoptimized groups. To determine efficacy, intraocular inflammation (anterior chamber cells, vitritis, and retinal vasculitis), macular thickness, visual acuity, and the sparing effect of glucocorticoids were assessed. RESULTS: No demographic or ocular differences were found at the time of ADA onset between the optimized and the nonoptimized groups. Most ocular outcomes were similar after a mean ± standard deviation follow-up of 34.7±13.3 and 26±21.3 months in the optimized and nonoptimized groups, respectively. However, relevant adverse effects were only seen in the nonoptimized group (lymphoma, pneumonia, severe local reaction at the injection site, and bacteremia by Escherichia coli, 1 each). Moreover, the mean ADA treatment costs were lower in the optimized group than in the nonoptimized group (6101.25 euros/patient/year vs. 12 339.48; P < 0.01). CONCLUSION: ADA optimization in BD uveitis refractory to conventional therapy is effective, safe, and cost-effective.

Golimumab in refractory uveitis associated to juvenile idiopathic arthritis: multicentre study of 7 cases and literature review.

OBJECTIVES: To assess the efficacy of golimumab (GLM), a fully humanised anti-TNF-α monoclonal antibody, in refractory juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS: This was a multicentre study of JIA-associated uveitis refractory to standard synthetic immunosuppressive drugs and in most cases to other anti-TNF-α agents. Results were expressed as mean±standard deviation or as median (range or interquartile range). The Wilcoxon signed-rank test was used to compare continuous variables. A literature review of the efficacy of GLM in uveitis related to JIA was also conducted. RESULTS: We studied 7 patients (5 females; mean age 21.7±7.5 years; 13 affected eyes). Uveitis was bilateral in 6. Cystoid macular oedema (CME) occurred in 3 patients (5 eyes). Besides corticosteroids and synthetic immunosuppressive drugs, patients had received before GLM a median of 2 biologic agents (range 0-3) including adalimumab (n=6), etanercept (n=2), infliximab (n=3) and abatacept (n=2). GLM dose was 50 mg/sc every 4 weeks. After 6 months of therapy the number of anterior chamber cells decreased from 1 [0.25-1.5] to 0 [0-0.5] (p=0.02) and optical coherence tomography (in patients with CME) from 313.6±77.05 to 261.4±75.1 µm (p=0.03). The best-corrected visual acuity increased from 0.5 to 0.62 (p=0.018). Complete remission of uveitis was achieved in 4 of 7 patients after 16.8±11.4 months of follow-up. However, 2 of the seven patients had to be switched to tocilizumab due to inefficacy. Local erythema at the injection site was observed in 2. CONCLUSIONS: GLM may be considered in the management of refractory JIA-related uveitis.

The combination of IL-6 and its soluble receptor is associated with the response of rheumatoid arthritis patients to tocilizumab.

BACKGROUND: IL-6 contributes significantly to the chronic inflammatory process of rheumatoid arthritis (RA). Tocilizumab, a humanized anti-human IL-6 receptor antibody that blocks the signaling originated by the IL-6/IL-6R complex, is an effective treatment. However, predictors of the response to tocilizumab are still required. We aimed to combine IL-6 and soluble IL-6R (sIL-6R) levels to identify groups of responses. METHODS: Heparinized blood and clinical data from 63 RA patients were collected before treatment and after 3 and 6 months. Two-step clustering (SPSS v.18) was used to establish the relationship between IL-6 and sIL-6R. Then, we compared European League Against Rheumatism (EULAR) response criteria with remission achievement in the groups of patients. RESULTS: Three statistical significant clusters of RA patients (i.e., g1, g2, and g3) were defined by serum concentrations of IL-6 and sIL-6R at baseline. All groups of RA patients had higher IL-6 and sIL-6R levels than healthy donors. The levels of IL-6 expressed as median (IQR) in g1 patients were 124(90-183)pg/ml, in g2 12.3(4.4-24)pg/ml, and in g3 60.1(30-146)pg/ml (p < 0.001). The levels of sIL-6R expressed as mean ± sd in g1 patients were 250.5 ± 72ng/ml, in g2 269.1 ± 125ng/ml, and in g3 732.7 ± 243ng/ml (p < 0.001). Disease activity score (DAS)28, C-reactive protein, and erythrocyte sedimentation rate were comparable in the three groups at baseline. Disease duration in g3 was the longest (median(IQR) years: g1 = 11(5-15), g2 = 12(8-20), and g3 23(16-26); p = 0.006), with years of disease evolution being correlated with sIL-6R levels (R = 0.417, p < 0.001). Simple and Clinical Disease Activity Index (SDAI and CDAI) decreased significantly in the three groups. However, EULAR response criteria and remission achievement at 6m was different in the three groups (p = 0.03 and 0.04, respectively). In all. 17 out of the 18 patients in g1 had a good or moderate response to tocilizumab. Conversely, the percentage of patients with no response to tocilizumab was higher in g3 than in g1 and g2. We also observed different changing patterns of IL-6 and sIL-6R levels among the three groups. CONCLUSIONS: RA patients could be easily stratified prior to therapeutic intervention with two molecules related to the pathway blocked by tocilizumab. G1 patients, who had the best response to tocilizumab, had the highest level of IL-6 and the lowest level of sIL-6R.

Anti-Interleukin-6 Receptor Tocilizumab for Severe Juvenile Idiopathic Arthritis-Associated Uveitis Refractory to Anti-Tumor Necrosis Factor Therapy: A Multicenter Study of Twenty-Five Patients.

OBJECTIVE: To assess the efficacy of tocilizumab (TCZ) for the treatment of juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS: We conducted a multicenter study of patients with JIA-associated uveitis that was refractory to conventional immunosuppressive drugs and anti-tumor necrosis factor (anti-TNF) agents. RESULTS: We assessed 25 patients (21 female; 47 affected eyes) with a mean ± SD age of 18.5 ± 8.3 years. Uveitis was bilateral in 22 patients. Cystoid macular edema was present in 9 patients. Ocular sequelae found at initiation of TCZ included cataracts (n = 13), glaucoma (n = 7), synechiae (n = 10), band keratopathy (n = 12), maculopathy (n = 9), and amblyopia (n = 5). Before TCZ, patients had received corticosteroids, conventional immunosuppressive drugs, and biologic agents (median 2 [range 1-5]), including adalimumab (n = 24), etanercept (n = 8), infliximab (n = 7), abatacept (n = 6), rituximab (n = 2), anakinra (n = 1), and golimumab (n = 1). Patients received 8 mg/kg TCZ intravenously every 4 weeks in most cases. TCZ yielded rapid and maintained improvement in all ocular parameters. After 6 months of therapy, 79.2% of patients showed improvement in anterior chamber cell numbers, and 88.2% showed improvement after 1 year. Central macular thickness measured by optical coherence tomography in patients with cystoid macular edema decreased from a mean ± SD of 401.7 ± 86.8 µm to 259.1 ± 39.5 µm after 6 months of TCZ (P = 0.012). The best-corrected visual acuity increased from 0.56 ± 0.35 to 0.64 ± 0.32 (P < 0.01). After a median follow-up of 12 months, visual improvement persisted, and complete remission of uveitis was observed in 19 of 25 patients. Significant reduction in the prednisone dosage was also achieved. The main adverse effects were severe autoimmune thrombocytopenia in 1 patient, pneumonia and then autoimmune anemia and thrombocytopenia in 1 patient, and viral conjunctivitis and bullous impetigo in 1 patient. CONCLUSION: TCZ appears to be a useful therapy for severe refractory JIA-associated uveitis.

Calprotectin and TNF trough serum levels identify power Doppler ultrasound synovitis in rheumatoid arthritis and psoriatic arthritis patients in remission or with low disease activity.

BACKGROUND: Serum levels of calprotectin, a major S100 leucocyte protein, are associated with disease activity in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients. Higher drug trough serum levels are associated with good response in patients treated with tumour necrosis factor inhibitors (TNFi). Power Doppler ultrasound (PDUS) synovitis is predictive of flare and progression of structural damage in patients in clinical remission. The purpose of this study was to analyse the accuracy of calprotectin and TNFi trough serum levels in detecting PDUS synovitis in RA and PsA patients in clinical remission or with low disease activity who were receiving TNFi. METHODS: We conducted a cross-sectional study of 92 patients (42 with RA, 50 with PsA) receiving adalimumab (ADA), etanercept (ETN) or infliximab who were in remission or had low disease activity (28-joint Disease Activity Score based on erythrocyte sedimentation rate <3.2). Associations of calprotectin, TNFi trough serum levels and acute phase reactants with PDUS synovitis were assessed using correlation and linear regression analyses. The accuracy and discriminatory capacity in detecting PDUS synovitis was assessed using ROC curves. RESULTS: PDUS synovitis was found in 62.4 % of RA patients and 32 % of PsA patients. Both RA and PsA patients with PDUS synovitis had higher calprotectin levels and lower TNFi trough serum levels. Calprotectin positively correlated with ultrasound scores (all r coefficients >0.50 in RA). Calprotectin correlated with the PDUS synovitis score in patients treated with ADA and ETN. Using PDUS synovitis (yes or no) as the reference variable, calprotectin had an AUC of 0.826. The best cut-off was ≥1.66 µg/ml, with a likelihood ratio of 2.77. C-reactive protein (AUC 0.673) and erythrocyte sedimentation rate (AUC 0.731) had a lower discriminatory capacity. TNFi trough serum levels were significantly associated with PDUS synovitis (OR 0.67, 95 % CI 0.52-0.85, p < 0.001) but their accuracy (AUC <0.5) was less than that of calprotectin. TNFi trough serum levels were inversely correlated with calprotectin and PDUS synovitis in RA and PsA patients receiving ADA and ETN. CONCLUSIONS: Calprotectin and TNFi trough serum levels may help identify PDUS synovitis in RA and PsA patients in clinical remission or with low disease activity.

The effect of biologic therapy different from infliximab or adalimumab in patients with refractory uveitis due to Behçet's disease: results of a multicentre open-label study.

OBJECTIVES: To assess the efficacy of other biologic therapies, different from infliximab (IFX) and adalimumab (ADA), in patients with Behçet's disease uveitis (BU). METHODS: Multicenter study of 124 patients with BU refractory to at least one standard immunosuppressive agent that required IFX or ADA therapy. Patients who had to be switched to another biologic agent due to inefficacy or intolerance to IFX or ADA or patient's decision were assessed. The main outcome measures were the degree of anterior and posterior chamber inflammation and macular thickness. RESULTS: Seven (5.6%) of 124 cases (4 women/3 men; mean age, 43 (range 28- 67) years; 12 affected eyes) were studied. Five of them had been initially treated with ADA and 2 with IFX. The other biologic agents used were golimumab (n=4), tocilizumab (n=2) and rituximab (n=1). The ocular pattern was panuveitis (n=4) or posterior uveitis (n=3). Uveitis was bilateral in 5 patients (71.4%). At baseline, anterior chamber and vitreous inflammation were present in 6 (50%) and 7 (58.3%) of the eyes. All the patients (12 eyes) had macular thickening (OCT>250µm) and 4 of them (7 eyes), cystoid macular edema (OCT>300 µm). Besides reduction anterior chamber and vitreous inflammation, we observed a reduction of OCT values, from 330.4±58.5 µm at the onset of the biological agent to 273±50 µm at month 12 (p=0.06). Six patients achieved a complete remission of uveitis. CONCLUSIONS: The vast majority of patients with BU refractory to standard immunosuppressive drugs are successfully controlled with ADA and/or IFX. Other biologic agents appear to be also useful.

The safety of tumor necrosis factor-alpha inhibitors in the treatment of rheumatoid arthritis.

INTRODUCTION: Tumor necrosis factor inhibitors (TNFi) were the first biologic therapy authorized for rheumatoid arthritis (RA) treatment and are currently the most used biological drugs in these patients. Although clinical efficacy is proven, adverse events associated with these agents have been described, and further knowledge is essential to facilitate detection at very early stages. AREAS COVERED: We reviewed the safety profile of TNFi, including both articles and congress communications published on this topic, such as clinical trials, meta-analyses, observational studies, data from registries, and spontaneous clinical reports. We classified studies according to the most common and relevant adverse events associated with TNFi. EXPERT OPINION: There is a broad spectrum of possible adverse events associated with TNFi treatment, ranging from mild to serious, and with diverse clinical manifestations. However, most adverse events may be minimized by appropriate screening before starting treatment and with ongoing surveillance to ensure an early diagnosis. In conclusion, TNFi have a reasonable safety profile, and, globally, the benefits far outweigh the possible risk of adverse events, especially compared with the risk of the untreated underlying inflammatory condition.

Proinflammatory cytokines and C-reactive protein in uveitis associated with Behçet's disease.

The aim of the present study was to determine the serum cytokine profile and levels of high sensitivity C-reactive protein (hsCRP) in patients with uveitis associated with Behçet's disease (BD) and to compare them with those obtained from healthy control subjects. We determined the serum concentration of interferon-γ (IFN-γ), interleukin-1ß (IL-1ß), IL-12p70, IL-17A, tumor necrosis factor-α (TNF-α), and hsCRP in 13 patients with active uveitis associated to BD, 24 inactive BD patients, and 20 controls. In a subgroup of 10 active patients, a second serum sample was obtained when the disease was inactive. Cytokine profiles and hsCRP levels were correlated with disease activity, severity, complications, and visual outcome. Levels of IFN-γ and TNF-α were significantly increased in patients with active uveitis associated to BD compared to controls (P < 0.05). IFN-γ, TNF-α, and hsCRP were significantly higher during active uveitis associated to BD compared to inactive disease (P < 0.05). Furthermore, IL-17A was significantly increased in patients with active BD without pharmacological treatment compared to controls (P < 0.05). No significant correlations were found with specific cytokine profiles and disease severity, visual outcome, or complications. In summary, increased serum levels of IFN-γ, TNF-α, IL-17A, and hsCRP were associated with active uveitis associated with BD and might serve as markers of disease activity.

Anti-TNF-α therapy in patients with refractory uveitis due to Behçet's disease: a 1-year follow-up study of 124 patients.

OBJECTIVE: The aim of this study was to assess the efficacy of anti-TNF-α therapy in refractory uveitis due to Behçet's disease (BD). METHODS: We performed a multicentre study of 124 patients with BD uveitis refractory to conventional treatment including high-dose corticosteroids and at least one standard immunosuppressive agent. Patients were treated for at least 12 months with infliximab (IFX) (3-5 mg/kg at 0, 2 and 6 weeks and then every 4-8 weeks) or adalimumab (ADA) (usually 40 mg every 2 weeks). The main outcome measures were degree of anterior and posterior chamber inflammation, visual acuity, macular thickness and immunosuppression load. RESULTS: Sixty-eight men and 56 women (221 affected eyes) were studied. The mean age was 38.6 years (s.d. 10.4). HLA-B51 was positive in 66.1% of patients and uveitis was bilateral in 78.2%. IFX was the first biologic agent in 77 cases (62%) and ADA was first in 47 (38%). In most cases anti-TNF-α drugs were used in combination with conventional immunosuppressive drugs. At the onset of anti-TNF-α therapy, anterior chamber and vitreous inflammation was observed in 57% and 64.4% of patients, respectively. In both conditions the damage decreased significantly after 1 year. At baseline, 50 patients (80 eyes) had macular thickening [optical coherence tomography (OCT) >250 µm] and 35 (49 eyes) had cystoid macular oedema (OCT>300 µm) that improved from 420 µm (s.d. 119.5) at baseline to 271 µm (s.d. 45.6) at month 12 (P < 0.01). The best-corrected visual acuity and the suppression load also showed significant improvement. After 1 year of follow-up, 67.7% of patients were inactive. Biologic therapy was well tolerated in most cases. CONCLUSION: Anti-TNF-α therapy is effective and relatively safe in refractory BD uveitis.

Dose reduction of efavirenz: an observational study describing cost-effectiveness, pharmacokinetics and pharmacogenetics.

AIM: Antiretroviral treatment implies a high cost to the healthcare system. The aim of this study was to evaluate the clinical and economic impact of efavirenz (EFV) dose adjustment by monitoring plasma concentrations and pharmacogenetic analysis of the 516G>T CYP2B6 polymorphism. MATERIALS & METHODS: One hundred and ninety HIV patients treated with EFV were studied. Plasma EFV concentrations were measured by HPLC with ultraviolet detection, and pharmacogenetic analysis was performed by Real Time (RT)-PCR. RESULTS: One hundred and ninety patients initially treated with a standard dose of EFV (600 mg/day) were studied. In 31 (16.3%) patients, EFV dose was reduced. A total of 87.1% of patients were heterozygous/homozygous carriers (GT/TT). CD4(+) count increased while the minimum steady-state plasma concentration and adverse effects decreased significantly after dose adjustment. Considering only the dose reduction, the adjustments accounted for a saving of 43,539 €/year. CONCLUSION: The individualization of EFV dosage guided by genotyping 516G>T CYP2B6 and therapeutic drug monitoring could increase the efficiency of EFV use in antiretroviral treatment.

Current and future treatments for Behçet's uveitis: road to remission.

Behçet's disease (BD) is a multisystem inflammatory disorder of uncertain origin, although it remains defined within the spectrum of systemic immune-mediated vasculitic disorders and also represents a spectrum of putative autoimmune disease. Major symptoms include oral aphthous ulcers, genital ulcerations, skin lesions, and ocular lesions. Despite afflicting many systems, ocular complications of BD are some of the more devastating for the patient and their quality of life. Eye involvement, which affects 60-80 % of BD patients, is characterized in its more severe form by posterior or panuveitis including occlusive retinal vasculitis. While pathogenesis of BD remains complex, association with Class I MHC (HLA-B*51) predisposing to inflammation with engagement of the innate-immune system (neutrophils, NK cells), and perpetuated by the adaptive T cell responses against infectious- and/or auto-antigens. Despite the choice of conventional immunosuppressive therapies available, only recently with the advent of biologic therapy has visual prognosis and outcomes been substantially and favorably altered. For example, both interferon-α (IFN-α) and tumour necrosis factor (TNF)-α antagonists deliver promising results and for the first time improve prognosis. With IFN-α therapy, durable remissions of uveitis can be achieved and lead to drug-free remission. Similarly, anti-TNF therapy with infliximab is reported to be rapidly effective in inducing and maintaining remission. Most recently, rising evidence reports on the use of adalimumab, etanercept, and golimumab, while use of anti-interleukin (IL)-1 agents (anakinra, canakinumab, gevokizumab), IL-6 blockers (tocilizumab), and rituximab (depleting anti-CD20 antibody) is also increasing. The aim of this review is to provide evidence for the role of conventional therapies combined with evidence for advantages and disadvantages of biologic therapies in the treatment of ocular BD. Although randomized controlled trials remain sparse, evidence remains strong and enticing that biologic agents are invaluable for the treatment of sight-threatening Behçet's uveitis and makes it an exciting time for Behçet's specialists worldwide.

APL-1, an altered peptide ligand derived from human heat-shock protein 60, selectively induces apoptosis in activated CD4+ CD25+ T cells from peripheral blood of rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic T-cell mediated autoimmune disease that affects primarily the joints. The induction of immune tolerance through antigen-specific therapies for the blockade of pathogenic CD4+ T cells constitutes a current focus of research. In this focus it is attempted to simultaneously activate multiple regulatory mechanisms, such as: apoptosis and regulatory T cells (Tregs). APL-1 is an altered peptide ligand derived from a novel CD4+ T-cell epitope of human heat-shock protein of 60kDa, an autoantigen involved in the pathogenesis of RA. Previously, we have reported that APL-1 induces CD4+ CD25(high)Foxp3+ Tregs in several systems. Here, we investigated the ability of APL-1 in inducing apoptosis in PBMCs from RA patients, who were classified as active or inactive according to their DAS28 score. APL-1 decreased the viability of PBMCs from active but not from inactive patients. DNA fragmentation assays and typical morphological features clearly demonstrated that APL-1 induced apoptosis in these cells. Activated CD4+ CD25+ T cells but not resting CD4+ CD25- T cells were identified as targets of APL-1. Furthermore, CD4+ T-cell responses to APL-1 were found to be dependent on antigen presentation via the HLA-DR molecule. Thus, APL-1 is a regulatory CD4+ T cell epitope which might modulate inflammatory immune responses in PBMCs from RA patients by inducing CD4+ CD25(high)Foxp3+ Tregs and apoptosis in activated CD4+ T cells. These results support further investigation of this candidate drug for the treatment of RA.

Skin lesions and treatment with tumor necrosis factor alpha antagonists.

The efficacy shown by biological therapy with tumor necrosis factor (TNF) antagonists has led in the recent years to its increased and extended use in different inflammatory arthopathies. Initially, safety studies of these drugs were mainly focused on the risk of infection and the development of malignancies. Recently, several cases of skin lesions induced by anti-TNF drugs have been reported with an increased incidence, highlighting the importance of the skin as a major target of the side effects of these drugs. In addition to skin lesions directly related to drug administration there is a wide spectrum of skin lesions of different morphology and etiology, especially the development of cutaneous immune-mediated conditions, an emergent phenomenon associated with this treatment. We describe the main skin lesions associated with treatment with anti-TNF drugs according to an extensive review of the literature.

Effects of polymorphisms in TRAILR1 and TNFR1A on the response to anti-TNF therapies in patients with rheumatoid and psoriatic arthritis.

OBJECTIVES: As the role of polymorphisms in death receptors (DRs) such as Tumor Necrosis Factor-related Apoptosis-inducing Ligand Receptor 1 (TRAIL-R1) and Tumor Necrosis Factor Receptor 1A (TNF-R1A) on the response to anti-TNF therapy remains unknown, we evaluated the association between TRAILR1 and TNFR1A gene polymorphisms (rs20575/C626G and rs767455/G36A) and the pharmacogenetics of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with TNFα blockers. METHODS: One hundred and forty-five patients (90 RA and 55 PsA) treated with anti-TNFα therapy (RA: 75 infliximab, 8 etanercept, 7 adalimumab. PsA: 27 infliximab, 19 etanercept, 9 adalimumab) were genotyped for TRAILR1 and TNFR1A polymorphisms by allelic discrimination. The response to anti-TNFα was assessed by EULAR criteria. RESULTS: In RA, the TRAILR1 CC genotype was associated with a better response after 3 and 6 months of anti-TNFα treatment (CC: 91.7% vs. CG/GG: 62.2%; P=0.019, and CC: 82.6% vs. CG/GG: 56.1%; P=0.019, respectively). Similar results were observed in only infliximab-treated RA patients. With respect to the TNFR1A polymorphism, there was an association between the AA genotype and a poorer response at 3 months in RA patients (AA: 39.3% vs. AG/GG: 19.0%; P=0.04). In PsA, TRAILR1 CC genotype was only associated with EULAR response to infliximab at 6 months (CC: 71.4% vs CG/GG: 50%P=0.048). In contrast to RA, the TNFR1 polymorphism in PsA was associated with a better response at 3 months (AA 88% vs AG/GG 58.9%; P=0.04). CONCLUSIONS: This study provides the first evidence that a polymorphism in TRAILR1 influences the response to anti-TNFα therapy in RA and also suggests that TNFR1A polymorphism may have opposing effects on the response to anti-TNFα in RA and PsA.