B Cell Therapy In Anca Associated Vasculitis Biology Essay

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Microscopic polyangiitis (MPA) and Wegener's granulomatosis (WG) are classified as antineutrophil nuclear cytoplasmic antibody (ANCA-) associated vasculitides. MPA and WG are autoimmune diseases and are characterized by antibodies against particular lysosomal constituents of neutrophils and monocytes, primarily myeloperoxidase (MPO) and proteinase-3 (PR3). Neutrophils that have been activated by ANCA release mediators of acute inflammation, and adhere to and kill endothelial cells (Jenette et al., 2006). Hence, characteristics of these autoimmune diseases are inflammation of (small) blood vessels, resulting in damage and destruction of these vessels. The induction of ANCA-associated vasculitis is a multifactorial process, including genetic susceptibility, such as differences in the expression of ANCA-antigens by neutrophils and environmental factors such as infections (e.g. S. aureus) (Jenette et al., 2006).

MPA and WG share clinical features but also have important differences, mainly in histology and serology. Histologically, WG is characterized by granuloma formation, which is not found in MPA. Serologically, WG is often accompanied by anti-PR3-antibody positivity, whereas patients with MPA are often anti-MPO-antibody positive (van Pesch et al., 1999; Villiger et al., 2010).

Key targets and current therapies

Important players in the pathogenesis of ANCA-associated vasculitides are B lymphocytes. B lymphocytes differentiate into plasmocytes to produce autoantibodies (such as ANCA) or long-lived memory B cells. B lymphocytes are also known to have features like antigen presentation and are able to co-stimulate T cells by the production of pro-inflammatory cytokines (Witko-Sarsat et al., 2009). This significant role of B cells in the pathogenesis of ANCA-associated vasculitis suggests an interesting therapeutic target for disease control.

One drug that targets B cells is cyclophosphamide. Cyclophosphamide suppresses various stages of the B cell cycle, including activation, proliferation, and differentiation (Zhu et al., 1987). Cyclophosphamide, in combination with glucocorticoids, has been the standard remission-induction therapy for ANCA-associated vasculitis for decades. Although this therapy has proven to be effective in controlling symptoms and inducing remission of the disease, the drug has many serious adverse effects, e.g. infertility, cytopenia, infections and cancer. In addition, long-term glucocorticoid therapy has many adverse side effects as well (Stone et al., 2010).

In the past years, much research has been done in developing new therapies for ANCA-associated vasculitis. A new player in this field is the anti-CD20 monoclonal antibody rituximab. Rituximab has shown promising results in uncontrolled trials, where it induced sustained remission in 80-90% of patients with refractory ANCA-associated vasculitis (Smith et al., 2006), and has proved to be successful in other autoimmune diseases (Gürcan et al., 2009). It would be very advantageous if rituximab proves to be more effective and safer than cyclophosphamide.

Rituximab as a possible candidate for treatment of ANCA-associated vasculitis

In the study of Stone et al., the authors performed a multicenter, randomized, double-blind, double-dummy, noninferiority trial, comparing rituximab therapy in combination with corticosteroids (investigational treatment) to the standard therapy of cyclophosphamide in combination with corticosteroids (control treatment). Stone et al. used proteinase 3-ANCA or myeloperoxidase-ANCA positive patients with WG and MPA, who had manifestations of severe disease and a Birmingham Vasculitis Activity for Wegener's granulomatosis of 3 or more (BVAS/WG, with higher scores indicating a more active disease, scores range from 0-63). Both newly diagnosed and patients with relapsing disease were eligible for enrollment. Patients were randomly assigned to a treatment in a 1:1 ratio and randomization was stratified according to clinical site and ANCA type. The remission-induction period was 6 months and the investigational group received 375 mg rituximab/m2 per week for 4 weeks, the control group received 2 mg cyclophosphamide/kg per day, both in combination with glucocorticoids. The primary end point of the study was remission of disease without the use of Prednisone at 6 months, which was assessed by a BVAS/WG of 0 (Stone et al., 2010).

Of the rituximab group, 64% of the patients had reached the primary end point, as compared with 53% of the cyclophosphamide group. This result indicates noninferiority for the investigational treatment (p<0.001). For inducing remission in the relapsing disease group, rituximab proved to be more efficient: 67% of the patients in the rituximab group reached the primary end point as compared with 42% in the cyclophosphamide group. Rituximab seemed to be really effective in B cell depletion, as in 94% of the rituximab group the number of peripheral B cells decreased extensively. Furthermore, 47% in the rituximab group became ANCA-negative by 6 months, compared to 24% in the cyclophosphamide group. There were no significant differences between the treatment groups in total adverse events, which was unexpected. The authors of the article conclude that treatment with rituximab and glucocorticoids in patients with severe ANCA-associated vasculitis is not inferior to the cyclophosphamide therapy in the early stage of the disease, and that it might even be superior for remission induction in severe relapsing ANCA-associated vasculitis.

Stone et al.'s study strengthens the assumption that rituximab may be as beneficial as cyclophosphamide in the induction of remission in early phase ANCA-associated vasculitis, as shown in uncontrolled trials before. Moreover, the effects of rituximab in patients with relapsing vasculitis may be even better. The adverse effects of rituximab however, seem to be as detrimental as those of cyclophosphamide, although it could be that part of the adverse effects were due to the use of glucocorticoids. Besides this, the duration of this study (6 months) may not have been sufficient to monitor all adverse effects of cyclophosphamide (like infertility) (Stone et al., 2010). Moreover, the study of Stone et al. was not designed to evaluate the side effects of the drugs, and more cyclophosphamide-associated side effects could have occurred if it was not for the rigorous monitoring of the patients.

In the case of rituximab, a study by Stasi et al. described no acute or delayed relevant side effects attributable to rituximab in a range from 26-45 months follow-up (Stasi et al., 2006) and the use of rituximab as a therapy in other diseases was shown to be very well tolerated (Gürcan et al., 2009). Therefore it is important to consider rituximab as a possible candidate for first-line treatment of ANCA-associated vasculitis instead of, or at least in combination with cyclophosphamide.

Future prospective

The replacement or the reduction of cyclophosphamide with the use of rituximab will refine the current standard therapy in a great number of patients who experience severe morbidity due to the treatment of their disease and therefore it is important to continue with the optimization of this alternative treatment. Stone et al. showed the effectiveness of rituximab in a very balanced study in numbers of type of ANCA-associated vasculitis (WG versus MPA), disease phase (newly diagnosed versus patients with relapsing disease) and pre-enrollment therapy. Also the criteria for remission-induction were very strict, had the authors mitigated these criteria, the effectiveness may have proven to be even higher.

In future studies however, it is important to work with a longer follow-up than Stone et al. did to address differences in long-term adverse effects and also to evaluate the duration of remission in rituximab-treated patients and the possible need for re-treatment with rituximab.

The effector mechanisms of rituximab are known to deplete B cells; this can be achieved through various pathways. The most likely B cell-depleting mechanisms seem to act either by the induction of B cell killing by natural killer cells through antibody-dependent cellular toxicity, or by inducing complement dependent cytotoxicity on target B cells (Gürcan et al., 2009). Which mechanism is the most likely to appear in the treatment of ANCA-associated vasculitides has not been clarified up to now.

Indeed, a great reduction in the number of peripheral B cells was seen in several studies. In addition, several studies report a fall in autoantibody titer after treatment with the anti-CD20 monoclonal antibody rituximab (Ferraro et al., 2008; Stasi et al., 2006). However, ANCA are thought to be produced by long-lived plasma cells, which are negative for CD20. Obviously, anti-CD20-antibodies would not target the autoantibody producing cells in this case, although this was the initial goal. This would mean that the mechanism of action in ANCA associated vasculitis is not via the suppression of autoantibodies, but remission is induced through another pathway. This is supported by the study of Stone et al. considering the fact that there was no difference in attainment of the primary end point in patients with loss of ANCA-reactivity.

Since B cells are not confined to the production of antibodies, but have antibody-independent functions like antigen presentation and T cell co-stimulation as well (Sanz and Lee, 2010) it seems only rational to hypothesize that there may be an important role for T cells in the pathogenesis of ANCA-associated vasculitis. Could it be that the mechanism of action of rituximab is not through suppression of autoantibodies by B cell depletion, but that rituximab targets an important step of the actual pathogenic pathway by depleting B cells? To further investigate the use of rituximab as a first-line therapeutic agent, it is important to elucidate the exact pathogenesis of ANCA-associated vasculitis and search for a way to intervene in this pathogenesis more specifically, without global depletion of B cells and thus the suppression of all B cell functions.