In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

Abstract

Objective. Interleukin-6 (IL-6) receptor inhibition by tocilizumab was recently licensed for the treatment of rheumatoid arthritis (RA). IL-6 induces in vitro differentiation of B cells into antibody-forming cells; however, the in vivo effects of IL-6 inhibition on the B cell compartment are currently not known. The purpose of this study was to examine this feature.Methods. Sixteen patients with active RA were treated in an open-label study with tocilizumab (8 mg/kg every 4 weeks). Immunophenotyping was performed at baseline, week 12, and week 24.Results. Memory B cell subsets declined significantly during tocilizumab therapy. Preswitch memory B cells decreased from a median of 19.6% to 12.3% at week 24 and postswitch memory B cells declined from a median of 18.6% to 15.0% at week 24 (P ‫؍‬ 0.04). In parallel, CD19؉IgA؉ and CD19؉IgG؉ B cells decreased significantly. The proportion of IgA-expressing B cells fell from a median of 9.2% at baseline to 4.3% at week 12 and to 3.6% at week 24 (P ‫؍‬ 0.01). IgG؉ B cells declined from a median of 6.7% at baseline to 4.9% at week 12 (P ‫؍‬ 0.007) and 2.8% at week 24 (P ‫؍‬ 0.01). In parallel, serum levels of IgA and IgG were significantly diminished at week 24 (P < 0.05). There was a good correlation between relative and absolute numbers of IgA؉ B cells with serum IgA at week 24.Conclusion. Tocilizumab induced a significant reduction in the frequency of peripheral preswitch and postswitch memory B cells. In addition, the number of IgG؉ and IgA؉ B cells declined and correlated well with reduced serum immunoglobulin levels. The data indicate that IL-6 blockade affects the B cell hyperreactivity in RA patients.

Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling

“…Indeed, the anti-IL-6R mAb tocilizumab may be viewed more broadly as a robust inhibitor of IL-6/STAT3 activity. Tocilizumab intervention in rheumatoid arthritis leads to a rapid and sustained improvement in disease activity, a reduction in radiographic joint damage, and inhibition of B cell hyperactivity (6,51). These changes are also associated with a dramatic normalization of the acute phase response (including C-reactive protein [CRP]) and improvements in both pain and fatigue (6).…”

The effect of targeted rheumatoid arthritis therapies on anti-citrullinated protein autoantibody levels and B cell responses

“…A recent study by Roll et al [50] indicated that IL-6 blockade ( Fig. 2) with tocilizumab in RA patients led to reductions in total IgG and IgA levels but not reductions in RF levels; results of anti-CCP levels were not reported.…”

“…1). Among these biological therapies, B cell depletion [33] and neutralization of TNF-a [38][39][40][41][42][43][44][45][46][47][48][49] and IL-6 [50,51] have been studied most successfully for their effects on ACPA levels and B cell populations. There are some limited data on the effects of oral disease-modifying anti-rheumatic drugs (DMARDs) on ACPA levels [38] and very few data on the effects of CTLA-4-Ig and IL-17 neutralization on ACPA levels, although there is good reason to believe that T cell co-stimulation and IL-17 also regulate ACPA levels.…”

Analysis of the Mechanism of Action of Biological Therapies in Monotherapy in Patients with Rheumatoid Arthritis: Beyond the ADACTA Study

“…Tocilizumab reduces the levels of circulating neutrophils, myeloid dendritic cells and monocytes [65,66] and the infiltration of neutrophils into inflamed joints of animal models of RA [67]. Tocilizumab also reduces the frequency of peripheral memory B cells and B cell hyper reactivity in RA patients [68], expands an intriguing B regulatory subset [69] and skews the balance between Th17 and Tregs towards a more protective status [70,71]. In this balance, tocilizumab plays a dual role.…”

“…Reduces neutrophil adhesion and chemotaxis [57] Decreases adhesion molecule expression Decreases levels of circulating neutrophils and the infiltration of neutrophils into inflamed joints [67] Dendritic cells Decreases the level of circulating dendritic cells and reduces the expression of activation markers [58] Reduces circulating myeloid dendritic cells [65] Monocyte-macrophage cells Inhibits macrophage activation [62] Decreases activating receptors for IgG on monocytes [63] Reduces the production of pro-inflammatory cytokines [59] and nitric oxide [61] Decreases levels of monocyte cells [65] Decreases serum macrophage migration inhibitory factor [66] T cells Reduces antigen-dependent T-cell proliferation [64] Decreases Th17 cells and increases Tregs cells [70][71] B cells Decreases antibody production by B cells [49] Reduces the development of anti-drug antibodies [56] Reduces the frequency of peripheral memory B cells and B cell hyperreactivity [68] Induces the expansion of B regulatory cells 69 …”