Evaluation of low-dose rituximab for the retreatment of patients with active rheumatoid arthritis: a non-inferiority randomised controlled trial.

BACKGROUND: The licensed dose of rituximab in rheumatoid arthritis (RA) is two doses of 1000 mg given 2 weeks apart. A lower dose has never been specifically studied in patients with an inadequate response to anti-tumour necrosis factor (TNF) agents. OBJECTIVE: To compare the efficacy and safety of rituximab repeat treatment with two doses (1000 mg×1 and 1000 mg×2) following initial treatment with 1000 mg×2. METHODS: We set up an open-label, prospective, multicentre, non-inferiority study comprising a non-controlled period (24 weeks) followed by a randomised controlled period (weeks 24-104) in patients with RA and an inadequate response to anti-TNF agents. All patients received one course of rituximab (1000 mg×2) with methotrexate. At week 24, patients achieving a EULAR response (moderate or good) were randomised to rituximab retreatment at 1000 mg×1 (Arm A) or 1000 mg×2 (Arm B). The primary objective measure was disease activity in 28 joints C-reactive protein (DAS28-CRP) area under the curve (AUC) over 104 weeks with a non-inferiority margin defined by 20% (444) of the mean DAS28-CRP AUC (mean±SD 2218±967) of the reference data. RESULTS: The intent-to-treat and per-protocol (PP) populations comprised 143 (A/B: 70/73) and 100 (A/B: 51/49) patients, respectively. The adjusted mean difference in DAS28-CRP AUC (PP) was 51.4 (95% CI -131.2 to 234), demonstrating non-inferiority between arms A and B. The overall rituximab safety profile was similar with both retreatment regimens. CONCLUSIONS: Following a clinical response to a first course of rituximab in RA at the licensed dose of 1000 mg×2, retreatment with rituximab at 1000 mg×1 results in efficacy outcomes that are non-inferior to those achieved with retreatment at 1000 mg×2. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT01126541.

CCL19, a B cell chemokine, is related to the decrease of blood memory B cells and predicts the clinical response to rituximab in patients with rheumatoid arthritis.

OBJECTIVE: Migration of B cells from peripheral blood to the synovium in patients with rheumatoid arthritis (RA) may predict clinical response to rituximab (RTX). We undertook this study to investigate whether serum levels of chemokines involved in B cell trafficking are correlated with blood levels of memory B cells or serum levels of B cell activation biomarkers before B cell depletion and whether chemokine levels predict RTX responsiveness. METHODS: Blood B cell subsets were analyzed by flow cytometry (CD27, IgD), and serum B cell activation biomarkers (rheumatoid factor, anti-cyclic citrullinated peptide, free light chains, IgG, IgA, IgM, and BAFF) were measured in 208 RA patients and 70 control subjects. Serum CCL19, CXCL12, and CXCL13 chemokine levels in patients and controls were determined by enzyme-linked immunosorbent assay. The first course of RTX was administered to RA patients, and the response was evaluated at week 24 according to European League Against Rheumatism (EULAR) criteria. Results were expressed as the odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: Levels of all chemokines were increased in RA patients compared with controls, and levels were inversely correlated with CD27+ memory B cell frequency. CCL19 and CXCL13 levels correlated with levels of 6 serum B cell biomarkers and 4 serum B cell biomarkers, respectively. By univariate analysis, the CCL19 level was positively associated with EULAR response (OR 1.43 [95% CI 1.08-1.90], P = 0.01). By multivariate analysis, the CCL19 level was predictive of a response to RTX (OR 1.48 [95% CI 1.06-2.06], P = 0.02), but this did not persist after adjustment for autoantibody status. CONCLUSION: CXCL13 and CCL19 reflect blood B cell disturbances and their levels correlate with those of other serum B cell biomarkers. CXCL13 and CCL19 are, therefore, surrogate measures for serum B cell biomarkers in RA. Serum CCL19 measurement is a new hallmark of the B cell-mediated RA subtype and may predict clinical response to RTX.

A French national survey on infiltrating breast cancer: analysis of clinico-pathological features and treatment modalities in 1159 patients.

BACKGROUND: Despite the approximate 42,000 yearly new cases of breast cancer in France, there have been very few exhaustive studies on the clinicopathological features and treatment options of this disease. METHODS: Thus, a prospective, non-selective, nationwide survey on infiltrating breast cancer (IBC) was conducted in France from September 2001 to April 2002, in order to assess the epidemiological features of newly diagnosed disease, the prognostic and predictive variables with a special emphasis on hormone receptors, and the current approaches to therapy in everyday clinical practice. RESULTS: In total, 1159 patients were evaluable (median age 57 years); two-thirds of women were postmenopausal and 38% had undergone hormonal replacement therapy (HRT). Ductal and lobular infiltrating cancers represented 82.3% and 11.6% of cases, respectively. Most tumours expressed oestrogen (79.7%) and progesterone (69.7%) receptors. Overexpression of the human epidermal growth factor receptor-2 oncogene was found in 20.6% of the assessed cases. IBC diagnosed in women under HRT presented significantly better clinico-pathological features than in non-users. All patients underwent surgery as first treatment: 77.5% breast-conserving surgery (BCS) and 22.5% mastectomy; 1024 patients also underwent axillary surgery. The overall axillary lymph-node involvement rate was 44.4%. Radiotherapy was proposed in 98% and 83% of the women who had undergone BCS and mastectomy, respectively. Adjuvant chemotherapy was delivered in 58.7% of patients and hormonal treatment was provided in 76.5% of patients; tamoxifen was the most widely used hormonal treatment. CONCLUSIONS: This study showed a trend for global downstaging of IBC (with favourable clinico-pathological features), leading to a high rate of BCS. Postoperative treatments were widely used, in accordance with national and international guidelines. Use of aromatase inhibitors and taxanes was limited, but is likely to rise in the future.