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