Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study

Abstract

Objective: To assess the safety of interleukin-6 receptor inhibition and to collect preliminary data on the clinical and immunologic efficacy of tocilizumab in patients with systemic lupus erythematosus (SLE).

Methods: In an open-label phase I dosage-escalation study, 16 patients with mild-to-moderate disease activity were assigned to receive 1 of 3 doses of tocilizumab given intravenously every other week for 12 weeks (total of 7 infusions): 2 mg/kg in 4 patients, 4 mg/kg in 6 patients, or 8 mg/kg in 6 patients. Patients were then monitored for an additional 8 weeks.

Results: The infusions were well tolerated. Tocilizumab treatment led to dosage-related decreases in the absolute neutrophil count, with a median decrease of 38% in the 4 mg/kg dosage group and 56% in the 8 mg/kg dosage group. Neutrophil counts returned to normal after cessation of treatment. One patient was withdrawn from the study because of neutropenia. Infections occurred in 11 patients; none was associated with neutropenia. Disease activity showed significant improvement, with a decrease of > or =4 points in the modified Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index score in 8 of the 15 evaluable patients. Arthritis improved in all 7 patients who had arthritis at baseline and resolved in 4 of them. Levels of anti-double-stranded DNA antibodies decreased by a median of 47% in patients in the 4 mg/kg and 8 mg/kg dosage groups, with a 7.8% decrease in their IgG levels. These changes, together with a significant decrease in the frequency of circulating plasma cells, suggest a specific effect of tocilizumab on autoantibody-producing cells.

Conclusion: Although neutropenia may limit the maximum dosage of tocilizumab in patients with SLE, the observed clinical and serologic responses are promising and warrant further studies to establish the optimal dosing regimen and efficacy.

Trial registration: ClinicalTrials.gov NCT00046774.

Figures

Figure 1. Changes in absolute neutrophil counts, and complement products

There was a dose dependent decrease in absolute neutrophil counts. a. Absolute and b. proportional change from baseline. Values returned to baseline after treatment. c. Tocilizumab led to a similar decrease in complement C3 levels and complement activation products iC3b and C5b-9 (terminal activation complex). All returned to baseline after treatment. Values show the mean ± 1 standard error of the mean (SEM). *p

Figure 2. Serologic changes

a. Anti-dsDNA levels decreased during treatment mainly in the medium/high dose group. b. The proportional change in anti-dsDNA levels was substantially higher than the small non-significant decrease in IgG levels, especially in the medium/high dose group. Only patients with anti-dsDNA at baseline are included in this analysis. 1n=13 for the entire cohort, 2n=9 medium/high dose group. Box plots show the 10th, 25th, 50th (median), 75th and 90th percentiles. Values above the 90th and below the 10th percentile are plotted as points. (End of treatment values were compared to baseline by the Wilcoxon signed rank test)

Figure 3. Changes in circulating plasma cells

a. Patients had a significantly higher proportion of plasma cells at baseline compared to healthy controls (lines show the means of the groups; Student’s t-test) b. Flow cytometry showing a change in circulating CD38+++IgD- plasma cells before and after therapy in a representative patient. c. The frequency of plasma cells significantly decreased with tocilizumab treatment (means ± standard error of means. p value was calculated from repeated measures of ANOVA with the Bonferroni/Dunn correction for multiple comparisons).

Figure 4. Clinical efficacy

a. Improvement in arthritis. Swollen joint counts improved in all patients with arthritis at baseline (n=7) and completely resolved in 4 patients Box plots show the 10th, 25th, 50th (median), 75th and 90th percentiles. Values above the 90th and below the 10th percentile are plotted as points. (End of treatment values were compared to baseline by the Wilcoxon signed rank test) b. Improvement in overall disease activity. mSLEDAI and SLAM scores significantly decreased at the end of treatment (means ± SD, repeated measures of ANOVA)