Background: Treatment of patients with inadequate response to DMARDs and/or TNF-α blockers represents a challenge. B cell depletion represents one possible option. Objectives: To assess clinical and biological characteristics that could predict the efficacy of Rituximab (RTX) at 12 months follow-up and to assess the regeneration profile of B-cells after treatment. Methods: Forty-six patients with RA not responding to DMARDs and/or TNF-α blockers were treated with RTX. Patients received at least 2 infusions of RTX (500 mg on day 1 and day 15) and/or the haematological regimen once not efficacious at 6 mo. (375 mg/m2 on day 1,7,14,28). Repeated treatment was considered after at least 24 weeks in those who presented a residual disease activity or showed a clinical relapse. Clinical, immunological (anti-CCP and Rheumatoid Factor) and laboratory data were recorded at baseline and every 3 months. The EULAR response criteria based on DAS was used to assess the disease activity (DAS ≤ 2.4: low disease activity). To date, 26 patients reached 6 mo. follow-up (T6) and 17 patients reached 12 mo. (T12). A four-colour staining was performed at baseline and after 12 months treatment, using CD38, IgD, CD27 and CD19 cell surface markers. Results: The mean patient age was 60±12 years and the mean disease duration was 12±10 years. Besides RTX infusions, 32 patients (70.0%) were in methotrexate treatment and daily oral steroid therapy was given to 28 (58.7%) patients. At entry, 66.7% of patients were anti-CCP positive and 72,7% were RF positive. The mean levels of RF decreased significantly from 396.2±6.2 IU/ml at baseline to 101.4±108.1IU/ml after 12 months (p=0.02). The anti-CCP mean levels were similar at baseline and at 12 months of follow-up. Total IgM levels decreased (175.7±130.7 mg/dl at baseline vs.76.1±20.1 mg/dl at 12 months, p=0.03) and paralleled the changes in RF; also total IgG levels decreased significantly (1166.8±393.4 mg/dl and 1004.03±191.8 mg/dl respectively, p=0.03), differing from IgG-anti-CCP levels. The mean DAS44 score decreased significantly from 4.3±1.5 at baseline to 2.6±1.0 at 12 months (p<0.001). The DAS score ≤ 2.4 was reached at T6 by 8/26 (30.8%) patients and at T12 by 8/17 (47.1%). The main differences between patients with low disease activity (DAS44≤ 2.4) and patients with a DAS≥2.4 at T12 were represented by the different baseline values of CRP (8.1±8.6vs. 23.05±16 mg/l, p=0.02) and the IgA RF(53±50.7 vs.16.86IU/ml, p=0.05) and IgM RF (121±134.5 vs.40.5±77.7IU/ml, p=0.06). A plasma value of RF IgM ≥40 IU/ml at baseline allowed to discriminate patients poor responders at T12 (sensitivity:71.4% and specificity: 88.9%; with curve ROC analysis). The percentage of B cells (CD19+) in the peripheral blood was 0.80±0.38% at T12 compared to 12.9±12.6% at entry (p=0.03). Reduction in the mean percentage of eBM5 (IgD-/CD38+) (4.9±3.7%) cells and CD27+CD38+ (3.6±3.0%) cells was found at T12 compared to baseline (14.2±7.4% eBm5, p=0.01 and 9.5±6.2% for CD27+CD38+, p=0.02, respectively). Conclusion: According to our data, positive IgA and/or IgM RF appear to be predictive of a better response to RTX. Memory B cells and plasmablasts seem to be the main targets.
B-cell directed therapy in rheumatoid arthritis: predictive factors of efficacy and assessment of regeneration profile
Gremese E;
2009-01-01
Abstract
Background: Treatment of patients with inadequate response to DMARDs and/or TNF-α blockers represents a challenge. B cell depletion represents one possible option. Objectives: To assess clinical and biological characteristics that could predict the efficacy of Rituximab (RTX) at 12 months follow-up and to assess the regeneration profile of B-cells after treatment. Methods: Forty-six patients with RA not responding to DMARDs and/or TNF-α blockers were treated with RTX. Patients received at least 2 infusions of RTX (500 mg on day 1 and day 15) and/or the haematological regimen once not efficacious at 6 mo. (375 mg/m2 on day 1,7,14,28). Repeated treatment was considered after at least 24 weeks in those who presented a residual disease activity or showed a clinical relapse. Clinical, immunological (anti-CCP and Rheumatoid Factor) and laboratory data were recorded at baseline and every 3 months. The EULAR response criteria based on DAS was used to assess the disease activity (DAS ≤ 2.4: low disease activity). To date, 26 patients reached 6 mo. follow-up (T6) and 17 patients reached 12 mo. (T12). A four-colour staining was performed at baseline and after 12 months treatment, using CD38, IgD, CD27 and CD19 cell surface markers. Results: The mean patient age was 60±12 years and the mean disease duration was 12±10 years. Besides RTX infusions, 32 patients (70.0%) were in methotrexate treatment and daily oral steroid therapy was given to 28 (58.7%) patients. At entry, 66.7% of patients were anti-CCP positive and 72,7% were RF positive. The mean levels of RF decreased significantly from 396.2±6.2 IU/ml at baseline to 101.4±108.1IU/ml after 12 months (p=0.02). The anti-CCP mean levels were similar at baseline and at 12 months of follow-up. Total IgM levels decreased (175.7±130.7 mg/dl at baseline vs.76.1±20.1 mg/dl at 12 months, p=0.03) and paralleled the changes in RF; also total IgG levels decreased significantly (1166.8±393.4 mg/dl and 1004.03±191.8 mg/dl respectively, p=0.03), differing from IgG-anti-CCP levels. The mean DAS44 score decreased significantly from 4.3±1.5 at baseline to 2.6±1.0 at 12 months (p<0.001). The DAS score ≤ 2.4 was reached at T6 by 8/26 (30.8%) patients and at T12 by 8/17 (47.1%). The main differences between patients with low disease activity (DAS44≤ 2.4) and patients with a DAS≥2.4 at T12 were represented by the different baseline values of CRP (8.1±8.6vs. 23.05±16 mg/l, p=0.02) and the IgA RF(53±50.7 vs.16.86IU/ml, p=0.05) and IgM RF (121±134.5 vs.40.5±77.7IU/ml, p=0.06). A plasma value of RF IgM ≥40 IU/ml at baseline allowed to discriminate patients poor responders at T12 (sensitivity:71.4% and specificity: 88.9%; with curve ROC analysis). The percentage of B cells (CD19+) in the peripheral blood was 0.80±0.38% at T12 compared to 12.9±12.6% at entry (p=0.03). Reduction in the mean percentage of eBM5 (IgD-/CD38+) (4.9±3.7%) cells and CD27+CD38+ (3.6±3.0%) cells was found at T12 compared to baseline (14.2±7.4% eBm5, p=0.01 and 9.5±6.2% for CD27+CD38+, p=0.02, respectively). Conclusion: According to our data, positive IgA and/or IgM RF appear to be predictive of a better response to RTX. Memory B cells and plasmablasts seem to be the main targets.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
