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.

arthritis domain both at month 6 (p<0.001) and 12 (p<0.001). From baseline to month 6, the mean tender joints count decreased from 5.7 to 2.7 (p=0.010), and the swollen joints count from 3.6 to 0.7 (p<0.001); the decreases were sustained through month 12 (p=0.001 for both counts). No impact of smoking habits on treatment outcomes in relation to articular SLE was observed. Conclusion In line with previous reports, belimumab treatment was effective in limiting mucocutaneous and articular symptoms in patients with SLE. A history of past or current smoking was found to reduce the efficacy of belimumab in mucocutaneous manifestations. Further survey on the impact of smoking on the efficacy of belimumab at a mechanistic level is merited.

BackgroundRituximab-mediated late-onset neutropenia (LON) has been studied in various diseases, but data from systemic lupus erythematosus (SLE) are limited.ObjectivesTo 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.MethodsPatients 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).ResultsThirty-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.ConclusionsThe prevalence of rituximab-mediated LON within the SLE patients of the current study (31.8%) was higher compared to previous reports on patients with lympho...