Objective Rituximab-mediated late-onset neutropenia (LON) has been described in various diseases. We investigated its occurrence, consequences and contributing factors in patients with systemic lupus erythematosus (SLE). Methods Rituximab-treated patients from the Karolinska University Hospital ( n = 107) were surveyed. LON was defined as an absolute neutrophil count <1500 cells/μl, occurring four weeks to two years following rituximab treatment, or later during sustained B-cell depletion. Serum levels of B-cell-related cytokines and growth factors of the myeloid lineage were determined using enzyme-linked immunosorbent assay. Results Thirty-two patients (29.9%) developed LON after a median time of 201.5 days. Thirteen patients were admitted to the hospital; 10 due to fever. Three patients developed critical conditions. BAFF levels increased from baseline (median: 0.62 ng/ml) to the post-treatment evaluation (median: 1.16 ng/ml; p < 0.001); post-treatment levels were higher in the LON group ( p = 0.021). APRIL levels were higher in the LON group both at baseline (median: 1.54 versus 1.15 ng/ml; p = 0.027) and post-treatment (median: 2.39 versus 1.11 ng/ml; p = 0.011). IL-6 and GM-CSF levels decreased in the non-LON group ( p < 0.001), but not in LON patients. High baseline disease activity predicted LON development (OR: 4.1; 95% CI: 1.1-15.2 for SLEDAI-2K > 8). No association with neutropenia prior to rituximab treatment was documented. Conclusion Post-rituximab LON was a common complication. Although the phenomenon was predominantly self-limiting, several patients developed severe conditions. Distinct roles of BAFF and APRIL are implicated: BAFF may contribute to LON development, whereas high APRIL levels may be predictive. Rituximab-treated SLE patients should be monitored for neutrophil counts, fever and infections.

BackgroundRituximab-mediated late-onset neutropenia (LON) has been described in various diseases. We investigated its prevalence and contributing factors, including B cell related cytokines and growth factors of the myeloid lineage, in patients with systemic lupus erythematosus (SLE).MethodsRituximab-treated patients from the Karolinska University Hospital (n=107) were enrolled. LON was defined as an absolute neutrophil count <1,500 cells/µL, occurring four weeks to two years following treatment, or later in cases of sustained B cell depletion, provided that other apparent causes were excluded. B cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF) were measured using ELISA prior to and post-treatment.ResultsThirty-two patients (29.9%) developed LON after a median time of 201.5 days (IQR: 66.8–322.0). Thirteen patients were admitted to the hospital; ten developed fever, and three developed critical conditions. BAFF levels increased from baseline (median: 0.62 ng/mL; IQR: 0.42–1.07) through the post-treatment measurement, both in patients who developed LON (median: 1.73 ng/mL; IQR: 1.03–2.56; p=0.005) and patients who did not (median: 1.03; IQR: 0.65–1.55; p=0.001), with significantly higher BAFF levels in the LON group (p=0.021). APRIL levels were higher in the LON group both at baseline (median: 1.54 versus 1.15 ng/mL; p=0.027) and post-treatment (median: 2.39 versus 1.11 ng/mL; p=0.011). IL-6 and GM-CSF levels decreased in the non-LON group (p<0.001). Cumulative rituximab and cyclophosphamide doses were found to be associated with the development of agranulocytosis (p=0.022 and p=0.021, respectively).ConclusionPost-rituximab LON is a common complication in SLE. Although the phenomenon was self-limiting in most cases, a few patients developed life-threatening conditions; this highlights the importance of regular surveillance for neutrophil counts, fever and infections. Distinct roles of BAFF and APRIL are implicated; BAFF might contribute to granulopoiesis disruptions, whereas APRIL might have a value in distinguishing predisposed patients.

Background Rituximab-mediated late-onset neutropenia (LON) has been studied in various diseases, but data from systemic lupus erythematosus (SLE) are limited. Objectives To study the prevalence and contributing factors for LON following treatment with rituximab in patients with SLE, including B cell related cytokines and growth factors of the myeloid lineage. Methods Patients from the Karolinska SLE cohort treated with rituximab (n=107) were enrolled in this observational study. Rituximab was given according to the lymphoma course (weekly for four weeks), the arthritis course (at week 0 and 2), or as a single infusion, with or without concomitant pulses of cyclophosphamide. LON was defined as an absolute neutrophil count <1,500 cells/μL, occurring four weeks to two years after initiation of rituximab treatment, provided that other apparent causes were excluded. Neutropenia occurring later than two years after treatment initiation but during sustained B cell depletion were also considered LON. B lymphocyte stimulator (BLyS/BAFF), a proliferation-inducing ligand (APRIL), interleukin 6 (IL-6), granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) were measured by ELISA prior to treatment (n=70) and either at the incidence of LON in patients who developed LON or after approximately the same median time following rituximab treatment in patients who did not develop LON (n=52). Results Thirty-four of 107 patients developed LON after a median time of 222 days (IQR: 105–355 days). BLyS levels increased from baseline (median: 0.62 ng/mL; IQR: 0.42–1.07 ng/mL) through the post-treatment measurement, both in patients who developed LON (median: 1.73 ng/mL; IQR: 1.03–2.13 ng/mL; P=0.005) and patients who did not (median: 1.03; IQR: 0.67–1.56 ng/mL; P<0.001), but the increase was greater in patients who developed LON, resulting in significantly higher post-treatment BLyS levels (P=0.029). BLyS levels did not differ between the two groups at baseline (P=0.745). We observed a numerical increase in APRIL levels from baseline (median: 1.29 ng/mL; IQR: 0.85–2.3 ng/mL) through the post-treatment measurement in patients who developed LON (median: 2.39; IQR: 1.08–5.16 ng/mL; P=0.074) and a numerical decrease in patients who did not (median: 1.11 ng/mL; IQR: 0.77–1.64 ng/mL; P=0.064), resulting in significantly higher post-treatment APRIL levels in the LON group (P=0.032), from being similar at baseline (P=0.125). We found no difference in levels of G-CSF, GM-CSF or IL-6 between patients who developed LON and patients who did not, either at baseline or at the post-treatment measurement. Higher prednisone dose administered concomitantly to rituximab (P=0.003) and younger age (P=0.001) were found to be associated with the development of LON, whereas neither the use nor the doses of cyclophosphamide were found to have any impact. Conclusions The prevalence of rituximab-mediated LON within the SLE patients of the current study (31.8%) was higher compared to previous reports on patients with lymphoma (3–27%), ANCA-associated vasculitis (11.9%) and rheumatoid arthritis (3%). Our results imply a role of the BAFF/APRIL pathway in the immunologic mechanisms underlying this phenomenon and demonstrate that LON following rituximab treatment is a common complication in SLE patients. Disclosure of Interest None declared