EULAR 2014 | Daily Highlights

RECONSTITUTION OF THE PERIPHERAL B LYMPHOCYTE COMPARTMENT IN PATIENTS WITH ANCA-ASSOCIATED VASCULITIDES TREATED WITH RITUXIMAB FOR RELAPSING OR REFRACTORY DISEASE

Abstract: FRI0476
Presenter: N. Venhoff
Co-Authors: L. Niessen, M. Kreuzaler, A.G. Rlink, M. Rizzi, R.E. Voll, J. Thiel

Background:
The dynamics of B cell reconstitution in relapsing or refractory ANCA-associated vasculitides (AAV) treated with rituximab (RTX) followed by standard immunosuppressants are not clear. While in patients with rheumatoid arthritis B cell repopulation generally starts 6 to 9 months after RTX therapy, an impaired early B-lymphocyte development resulting in a protracted peripheral B cell repopulation was reported recently in some AAV patients after B cell depletion with RTX.

Objectives:
This is of clinical importance as the relapse rates in AAV after discontinuation of RTX therapy are high, and there are no data on safety and efficacy of RTX retreatment in persistently B cell depleted patients. Furthermore, there are no defined parameters that could guide RTX retreatment. To date the frequency of AAV patients with impaired peripheral B cell regeneration and the mechanism leading to the constricted regenerative capacity of the B cell compartment are unknown.

Methods:
We analysed in a single center cohort comprising 125 patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) the B cell repopulation kinetics in 37 patients treated for relapsing or refractory disease with RTX followed by maintenance immunosuppressants in most patients. Furthermore, we report on serum concentrations of the B cell-activating factor of the TNF family (BAFF, BLyS) and immunoglobulin concentrations as well as on peripheral B cell subpopulations in a subgroup of patients that relapsed after RTX treatment.

Results:
B cells were re-detectable in only one patient within the 9 months period after RTX treatment. After a mean observation time of 21 months 14 patients (41%) had started repopulating the peripheral B cell compartment, with 7 of the 14 patients having re-detectable B cells within the first year after RTX treatment. In 20 patients (59%) no repopulation occurred within the observation period. Eight of these patients were observed for more than 24 months without a starting B cell repopulation. BAFF concentrations in serum of AAV patients after RTX treatment were increased compared to healthy controls and correlated inversely with peripheral B cell numbers, IgG- and IgA concentrations. Serum immunoglobulin concentrations declined significantly after RTX treatment, and serum IgG concentrations correlated with peripheral B cell numbers after RTX therapy. 13 patients relapsed after RTX treatment. All of the 13 relapses either occurred after beginning B cell reconstitution or were accompanied by rising ANCA titres. In patients that relapsed after RTX the B lymphocyte compartment consisted mainly of switched memory B cells.

Conclusions:
In summary, in our cohort of GPA and MPA patients treated with RTX followed by a standard maintenance immunosuppressive therapy a high proportion of patients had a long-lasting B cell depletion. Retreatment with RTX in long-term B cell depleted patients warrants close monitoring for adverse events and especially infectious complications and monitoring of serum immunoglobulin. Relapses after RTX treatment either occurred after beginning B cell reconstitution or were accompanied by rising ANCA titres.

Disclosure of Interest:
None declared

Comment:
The majority of AAV patients after RTX treatment followed by standard maintenance therapy show long-lasting B cell depletion. This is in clear contrast to patients with rheumatoid arthritis (RA), most of them start to repopulate between 6 and 9 months. Retreatment with RTX for active disease or maintenance therapy has become a valuable therapeutic option in AAV patients according to the data of the MAINRITSAN trial of the French Vasculitis Group (500mg RTX every 6 months for 2 years without concomitant classical immunosuppressive medication) that still have not been published. However, long-term and repetitively B cell depleted patients may develop secondary immunodeficiency with infectious complications. Therefore, the findings of this study are important for the guidance of appropriate time points and frequencies of repetitive RTX applications. The study clearly shows that periodical measurements of peripheral B cell counts, ANCAs and serum immunoglobulins are helpful to early detect patients both at risk of either disease relapse or infections, a strategy that has meanwhile become a routine in many vasculitis centers.

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