Biologic Response Modifiers for Granulomatosis with Polyangiitis (Wegener’S): from Promise to Reality

REVIEW Biologic response modifiers for granulomatosis with polyangiitis (Wegener’s): from promise to reality Advances in the treatment of granulomatosis with polyangiitis (GPA; formerly Wegener’s granulomatosis) have resulted in marked improvements in patient outcomes. While severe GPA was originally described as progressive and invariably fatal, the use of immunosuppressive therapy has transformed the disease into a manageable, chronically relapsing illness. However, standard immunosuppressive therapies are associated with numerous side effects and significant treatment failures. In an effort to provide safer and more effective treatments for patients with GPA, several alternative therapies have been investigated in recent years, most notably among biologic response modifiers. The use of biologic response modifiers in GPA has had mixed results. The efficacy of rituximab in GPA is now firmly established, while inhibitors of TNF-a have not shown clear benefits. Investigations into other biologic response modifiers in GPA remain preliminary, but hold promise for a future in which the treatment of GPA achieves further improvements in outcomes with fewer side effects. KEYWORDS: alemtuzumab n ANCA-associated vasculitis n B-cell activating factor Jeremy M Clain1, n biologic response modifiers n CTLA-4 antigen n granulomatosis with polyangiitis Rodrigo Cartin-Ceba1 n rituximab n TNF-a n Wegener’s granulomatosis & Ulrich Specks*1 1Division of Pulmonary & Critical Care The antineutrophil cytoplasmic antibody reacting with myeloperoxidase (MPO-ANCA) Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA (ANCA)-associated vasculitides (AAV) com- [8]. PR3-ANCA occurs in the vast majority of *Author for correspondence: prise a group of three heterogeneous syndromes: patients with GPA, while MPO-ANCA occurs [email protected] granulomatosis with polyangiitis (GPA; formerly far less frequently. By contrast, MPO-ANCA is Wegener’s granulomatosis [WG]), microscopic the predominant type of ANCA in patients with polyangiitis (MPA) and eosinophilic granu- both MPA and EGPA. lomatosis with polyangiitis (EGPA; formerly Untreated, severe GPA follows a progressive Churg–Strauss syndrome) [1] . These three course with an invariably fatal outcome [9]. The entities share the histopathologic feature of use of cyclophosphamide (CYC) in combina- small-vessel vasculitis; that is, inflammation tion with glucocorticosteroids (GCS) heralded a and necrosis of blood vessel walls. In addition, major therapeutic breakthrough in GPA, trans- the majority of patients with AAV have ANCA forming the disease to a manageable, chroni- detectable in the serum at the time of initial cally relapsing illness [9,10]. Treatment with CYC presentation [2–4]. and GCS has remained the standard therapy for GPA is the most common AAV in European remission induction in patients with GPA for and North American populations, with an inci- decades. However, not all patients respond satis- dence of 8–10 cases per million per year [5–7]. factorily to CYC and GCS. Approximately 10% GPA characteristically involves necrotizing gran- of patients do not achieve remission with these ulomatous inflammation, affecting the upper medications, and up to half of the patients who and lower respiratory tract, which distinguishes initially achieve remission relapse within the first it from MPA. The GPA syndrome does not 3–5 years. Moreover, long-term and repeated include asthma or eosinophilia, which are defin- use of CYC is associated with substantial toxic- ing characteristics of EGPA [1] . GPA also differs ity, which is dependent on the cumulative dose from MPA and EGPA on the basis of its associ- applied over the patient’s disease course [11–14] . ated ANCA. Two types of ANCA are of clinical The search for less toxic alternatives to CYC significance in patients with vasculitis: ANCA led to the introduction of methotrexate (MTX) causing a cytoplasmic immuno fluorescence pat- as the standard for remission induction in tern on ethanol-fixed neutrophils and reacting patients with GPA with limited or nonsevere with proteinase 3 (PR3-ANCA), and ANCA disease manifestations [15,16] . The use of CYC causing a perinuclear immuno fluorescence in GPA has been further curtailed by the real- pattern on ethanol-fixed neutrophils and ization that CYC does not need to be continued part of 10.2217/IJR.13.23 © 2013 Future Medicine Ltd Int. J. Clin. Rheumatol. (2013) 8(3), 383–397 ISSN 1758-4272 383 REVIEW Clain, Cartin-Ceba & Specks Biologic response modifiers for granulomatosis with polyangiitis (Wegener’s) REVIEW for years, but can be replaced after 3–6 months contributor to the pathogenesis of the disease. In of remission induction therapy by MTX or aza- addition, the frequency of activated B lympho- thioprine (AZA) for more long-term remission cytes has been found to be associated with both maintenance [17,18]. disease activity and severity [22]. B lymphocytes Biologic response modifiers (BRMs) provide have been proposed as the primary target of an alternative therapeutic modality in the treat- the therapeutic effects of CYC in AAV and, ment of GPA. BRMs exert targeted effects on thus, targeting B lymphocytes with BRMs held specific immune pathways with the goal of reduc- particular promise for GPA [20,21,23]. ing maladaptive inflammation [19] . By modulat- ing the actions of the immune system, BRMs nRituximab have proven useful in the management of a vari- Rituximab (RTX) is a chimeric monoclonal ety of autoimmune diseases, including autoim- antibody directed against the cell-surface protein mune vasculitides. Among the agents in clinical CD20, a 297-amino acid phosphoprotein with use, BRMs act via depletion of B lymphocytes, four transmembrane domains, which is selec- inhibition of cytokine signaling and interference tively expressed on cells of B-lymphocyte lin- with T-lymphocyte activity. As summarized in eage [24,25]. Binding of RTX to CD20 causes the TABLE 1, several BRMs have been investigated in death of the target cell. The exact mechanisms GPA with the goal of improving treatment out- of RTX-mediated cell death remain unclear, but comes or limiting treatment-associated toxici- in vitro studies have demonstrated that RTX ties. This review aims to provide a perspective induces antibody-dependent cellular cytotoxic- on the current knowledge about the treatment of ity via macrophages and natural killer cells, com- GPA with BRMs by summarizing their actions, plement-mediated B-lymphocyte lysis, apoptosis theoretical benefits and clinical outcomes. and sensitization to cytotoxic agents or steroids [26–31]. Following treatment with RTX, circulat- Therapy directed against ing B lymphocytes remain undetectable in the B lymphocytes peripheral blood for approximately 6–12 months nRationale for targeting [32,33]. However, despite depletion in the circulat- B lymphocytes in GPA ing peripheral blood, B lymphocytes may persist B lymphocytes have been implicated in the in the bone marrow, spleen, lymph nodes and pathogenesis of GPA for more than two decades pathologic inflammatory tissue [34]. [20,21]. B lymphocytes are essential for the pro- The first published use of RTX in GPA was duction of ANCA, which is probably a key reported in 2001 [23]. A 66-year-old male diag- nosed with GPA in 1994 had developed CYC Table 1. Summary of biologic response modifiers investigated in toxicity, precluding its further use, while pred- granulomatosis with polyangiitis. nisone in combination with AZA or mycophe- nolate mofetil failed to restore remission during Target Name Proposed mechanisms a disease flare. This history prompted the use B lymphocytes of RTX on a compassionate-use basis under CD20 Rituximab B-lymphocyte depletion via antibody- the hypothesis that remission could be induced dependent cellular cytotoxicity, complement- by B-lymphocyte depletion, with consequent mediated lysis, apoptosis and sensitization to removal of ANCA. The treatment regimen con- cytotoxic agents or steroids sisted of four weekly RTX doses at 375 mg/m2, Cytokines accompanied by a prednisone taper. This dosing TNF-a Etanercept, Inhibition of inflammatory cascade via regimen had been approved by the US FDA in infliximab and reduced induction of proinflammatory 1997 for the use in relapsed or refractory, low- adalimumab cytokines grade or follicular B-cell non-Hodgkin’s lym- BAFF Belimumab Reduced survival of autoreactive phoma. Remission was achieved quickly in this B lymphocytes patient and prednisone could be discontinued. Following the success of this index case, T lymphocytes RTX was used on a compassionate basis in an CD80/CD86/ Abatacept Inhibition of T-lymphocyte activation via additional ten patients with severe refractory CTLA-4 reduced costimulatory CD28 signaling AAV, nine of whom had GPA [33]. All of these CD52 Alemtuzumab T-lymphocyte depletion via complement- patients received RTX as four weekly doses of mediated cell lysis, cell-mediated cytotoxicity 375 mg/m2, in combination with oral predni- and apoptosis sone for remission induction. While the major- BAFF: B-cell activating factor; CTLA: Cytotoxic T-lymphocyte-associated antigen. ity received intravenous methylprednisolone 384 Int. J. Clin. Rheumatol. (2013) 8(3) future science group REVIEW Clain, Cartin-Ceba & Specks Biologic response modifiers for granulomatosis with polyangiitis (Wegener’s) REVIEW and three patients underwent plasma-exchange logistic regression model and, among the subset immediately prior to receiving the first RTX of patients with GPA,

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