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 immuno­fluorescence 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 immuno­fluorescence 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 „„Rituximab 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 „„Rationale 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, the achievement of the dose, all other immunosuppressive agents had primary end point was also similar between the been discontinued. Clinical remission was two treatment groups (RTX: 63%, CYC: 50%; induced in all patients and adverse effects were p = 0.11). Among the 101 patients with severe minimal. relapses upon enrollment, RTX was more effica- Building on this favorable experience, Keogh cious than CYC, with 67% of the RTX group et al. conducted an open-label pilot trial of achieving the primary end point, as compared RTX in conjunction with a strictly proto- with 42% of the CYC group (p = 0.01). The colized oral glucocorticoid-tapering regimen number of total adverse events, serious adverse [35]. Ten patients with active, severe, refractory events or nondisease-related adverse events was AAV – all of whom had PR3-ANCA – were also similar between the RTX and CYC groups. treated with RTX. All patients achieved remis- On extended follow-up, the rates of sustained sion by 3 months and, again, adverse effects were remission remained similar between the two minimal. Subsequently, at least 20 additional groups at 12 and 18 months, and no unexpected case series and uncontrolled studies have been safety issues were detected [39]. published describing the use of RTX in patients Another major randomized controlled study with refractory AAV, including 171 patients with RITUXVAS was initiated [38]. RITUXVAS was GPA [36]. Most of these studies describe treat- an open-label, two-group, parallel-design, ran- ment success, with an excellent overall rate of domized trial involving 44 patients with newly complete remission. Two subsequent random- diagnosed AAV. All patients were positive for ized controlled trials have firmly established the ANCA and all had evidence of renal involvement, efficacy of RTX in GPA [37,38]. Table 2 provides a as evidenced by biopsy demonstrating necrotizing comparison of these two trials. glomerulonephritis or by urinalysis demonstrat- The RAVE trial was a multicenter random- ing hematuria or red cell casts. In total, 22 of the ized, double-blind, double placebo-controlled patients had GPA. The patients were randomized trial that compared the efficacy and safety of 3:1 to receive a RTX-based regimen or standard RTX with CYC for remission induction in severe therapy. Prior to enrolling in the study, 25% of A AV [37]. A total of 197 patients were enrolled, the patients underwent plasma exchange. After including 147 with GPA. All subjects were posi- enrollment, all patients received a standard gluco- tive for ANCA. The patients were randomized corticoid regimen, including intravenous methyl- to receive RTX (four weekly intravenous doses prednisolone. The 33 patients randomized to the of 375 mg/m2) or CYC (2 mg/kg/day orally). RTX group received RTX (four weekly intrave- In addition, all patients received GCS treat- nous doses of 375 mg/m2) with two intravenous ment, consisting of one to three daily doses of CYC pulses given concomitantly with the first and 1000 mg of intravenous methylprednisolone, third RTX infusion. The 11 patients randomized followed by a protocolized tapering regimen of to the control group received intravenous CYC prednisone. By the end of month 5, prednisone pulses for 3–6 months followed by AZA admin- was completely discontinued. Once remission istration. The primary outcomes were sustained was achieved between months 3 and 6, patients remission (defined as BVAS of 0 for 6 months) receiving CYC were switched to maintenance and rates of severe adverse events at 12 months. therapy with AZA, while patients on RTX were The frequency of sustained remission was similar switched to an AZA placebo. The study’s pri- in the two treatment groups (76% in the RTX mary end point was disease remission, defined group vs 82% in the control group; p = 0.68). The as a Birmingham Vasculitis Activity Score/WG incidence rates of severe adverse events were also (BVAS/WG) of 0, in the absence of GCS similar (1.00 per patient-year in the RTX group therapy at month six. Patients were stratified vs 1.10 per patient-year in the control group; by ANCA type across the two treatment arms, p = 0.77) and 18% of the patients died in both and randomization resulted in patients with groups. On extended follow-up, rates of relapse, GPA being equally distributed. In total, 63 death and end-stage renal disease were similar (64%) of the patients in the RTX arm versus between the treatment groups at 2 years [40]. 52 (53%) in the CYC arm achieved the primary Both RAVE and RITUXVAS included the end point, which met criteria for noninferiority frequency of disease relapses as important sec- (p < 0.0001), but not superiority (p = 0.09) for ondary outcomes. In RITUXVAS, 15% of the the RTX group. The ANCA type did not affect patients in the RTX group and 10% in the con- the primary comparison when examined in a trol group had a relapse during the 12-month

future science group www.futuremedicine.com 385 Review Clain, Cartin-Ceba & Specks Biologic response modifiers for granulomatosis with polyangiitis (Wegener’s) Review onths) m

70) 0.

=

8) 77) 0. 0.6

= =

lucocorticosteroid; with Granulomatosis GPA: G

[38]

S Sustained remission (absence disease of activity at for least 6 Severe adverse events Sustained remission achieved RTX of in 76% group of and 82% control group (RTX not superior; p Incidence rates severe of adverse events per patient-year: in RTX 1.00 in control group (p group and 1.10 ITUXVA R AZA plus low-dose GCS Low-dose GCS CYC plus GCS CYC GPA: 22 patients patientsMPA: 16 Renal-limited vasculitis: six patient RTX plus GCS plus CYC ANCA-positive, newly diagnosed severe AAV with renal involvement 44 • • • • Not reported Reported as frequency relapse of during the study period: in the 15% RTX group in the and control 10% group (p Not tested 81) 30) 0.

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[37]

E onths Severe flares: 0.011 in RTX group and 0.018 in CYC group in RTXCYC (p group Severeand 0.018 flares: 0.011 Limited flares: in RTX 0.023 group in CYC (p group and 0.027 m AV

R Remission (absence disease of activity) plus completion taper GCS of at 6 AZA Placebo CYC plus GCS CYC GPA: 148 patientsGPA: 148 MPA: 48 patients Undetermined: one patient (51%) Randomized, double-blind, double-dummy, noninferiority trial197 Randomized, open-label, two-group, parallel-designed trial Primary end point achieved in 64% in RTX group and 53% in CYC group (RTX noninferior; p Reported per patient-month, according severity: to • • treatment groups (RTX group 63%group and 50%; CYC p Primary end point achieved RTX in in 67% in CYC group and 42% group (RTX superior; p icroscopic polyangiitis;icroscopic RTX: Rituximab. M

2

Primary end points Maintenance therapy in CYC/control group Maintenance therapy in RTX group Induction therapy in RTX groupInduction therapy in CYC/control RTX plus GCS group AAV subtype Disease-associated inclusion criteria ANCA-positive, either severe newly AAV, diagnosed (49%) or relapsing polyangiitis; MPA: Table feature Trial cytoplasmic antibody-associated vasculitis. antineutrophil in rituximab investigating trials controlled design two randomized of Trial Comparison . Patients enrolled (n) Antineutrophil cytoplasmicAAV: antibody-associated ANCA: vasculitis; Antineutrophil cytoplasmic antibody; AZA: Azathioprine; GCS: Cyclophosphamide; CYC: Main outcomes Disease flares Outcomes in subgroup with GPA Achievement the of primary end point was similar between the two Outcomes in subgroup with severe relapsing AAV at enrollment

386 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

follow-up period (p = 0.70). In RAVE, flare relapse rate at 28 months. Initial results have rates at 6 months were also similar between the found RTX to be superior to AZA for remission groups. Furthermore, during extended follow-up maintenance, with a major relapse rate of 3.6% of the RAVE cohort, neither the frequency nor in the RTX arm and 27.1% in the AZA arm. the severity of disease flares differed between the This issue will be re-examined in the forthcom- treatment groups at 18 months [39]. ing RITAZAREM trial, which will investigate The results of RAVE and RITUXVAS have RTX versus AZA for remission maintenance in established RTX as the first proven effective and relapsing AAV [201] . safe alternative to CYC in the management of Despite these questions, RTX is now well severe GPA. Based on the data from the RAVE established as a key agent in the armamentar- trial, the FDA approved RTX in combination ium of treatment options for GPA. RTX is an with GCS for remission induction in newly diag- apparently safe and proven effective alternative nosed and relapsing severe GPA and MPA. In to CYC in the management of severe GPA and it addition, in demonstrating superiority of RTX is the preferred agent for the treatment of severe over CYC in patients presenting with severe relapses. relapses, the results of the RAVE trial have strongly suggested that RTX be considered the Therapy directed against cytokines preferred agent for such patients [41] . „„TNF-a inhibition Nonetheless, several questions remain regard- Rationale for targeting TNF-a in GPA ing the use of RTX in GPA. First, long-term out- TNF-a is a key mediator in the inflammatory comes, including potential delayed-onset adverse cytokine network. While a variety of proin- effects, have not been fully established. Second, flammatory cytokines are detected in inflamed both RAVE and RITUXVAS restricted their tissues, TNF-a serves an integral role in the study populations to ANCA-positive patients development of the inflammatory cascade. For with severe disease. To date, only anecdotal example, in cultured synovial cells drawn from reports and a single case series have suggested patients with rheumatoid arthritis, TNF-a that RTX may also be effective in ANCA-neg- has been shown to be the dominant inducer of ative patients or those with limited GPA [42,43]. multiple proinflammatory cytokines, including Third, it remains unclear which remission IL-1, IL-6, IL-8 and GM-CSF [49]. Conversely, maintenance treatment, if any, newly diagnosed in patients with rheumatoid arthritis, disruption patients should receive following a successful of TNF-a signaling by means of inhibitory anti- first remission induction with RTX. Fourth, bodies results in the rapid reduction in circulat- questions remain regarding the significance of ing levels of many of these same cytokines [50]. a reconstituted B-lymphocyte population or a Given its primary role in the inflammatory cas- rising ANCA titer in predicting disease relapse cade, TNF-a has served as an important thera- following treatment with RTX [43,44]. Finally, the peutic target in a number of chronic inflamma- role of RTX itself in maintenance therapy has yet tory conditions. In fact, TNF-a blockade has to be established. In recent years, four retrospec- become a well-established therapeutic strategy tive studies have examined the use of RTX for in rheumatoid arthritis, juvenile rheumatoid remission maintenance, with all four concluding arthritis, Crohn’s disease, ankylosing spondy- that RTX may safely and effectively prevent dis- litis, psoriasis and psoriatic arthritis [51] . Given ease relapses in GPA [44–47]. Initial results from the clear benefits of TNF-a inhibitors in other the MAINRITSAN study, the first prospective, chronic inflammatory disorders, it was logical to randomized controlled trial to investigate the use consider their utility in AAV. of RTX for maintenance therapy, have also been Early investigations into TNF-a in AAV sug- promising [48]. In MAINRITSAN, 114 patients gested the potential for a key pathogenic role. with newly diagnosed or relapsing AAV (includ- Excess TNF-a production was demonstrated ing 86 with GPA) who had achieved remission within glomeruli affected by ANCA-associated with a conventional regimen were randomized to glomerulonephritis and from CD4+ T lympho- receive RTX or AZA for maintenance. Patients cytes from patients with GPA [52,53]. In addition, randomized to the RTX arm were given 500-mg serum levels of TNF-a receptor in patients with RTX infusions on days 1 and 15, then 5.5 months GPA correlates with disease activity [54]. later, and again every 6 months, for a total of five doses over 18 months. Patients in the AZA arm Experience with TNF-a inhibitors in GPA received AZA for 22 months at an initial dose of Several TNF-a inhibitors have been approved 2 mg/kg/day. The primary end point was major for use in chronic inflammatory disorders. These

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Table 3. Inhibitors of TNF-a in antineutrophil cytoplasmic antibody-associated vasculitis: a review of key studies and case series. Study Investigational Study design Control Patients (n), Main findings Ref. (year) drug group diagnosis Stone Etanercept Prospective, None 25 GPA Etanercept was well tolerated; may [55] et al. open-label pilot reduce disease activity and provide (2001) study steroid-sparing effect WGET Etanercept Randomized, Placebo plus 180 GPA No clinical benefit derived from addition [56] Research placebo-controlled standard of etanercept to standard therapy; Group trial therapy increased risk of solid malignancy in (2005) etanercept group Lamprecht Infliximab Case series None Six GPA Remission induced in five out of [64] et al. six patients with refractory GPA (2002) Bartolucci Infliximab Prospective, None Seven GPA All patients realized persistent [68] et al. open-label pilot Two RA-associated improvement at 6 months (2002) study vasculitis One cryoglobulinemia Booth Infliximab Prospective, None 19 GPA 28 out of 32 patients achieved disease [70] et al. open-label study 13 MPA remission; severe infections occurred in (2004) seven out of 32 patients Morgan Infliximab Prospective, Standard 22 GPA No clinical benefit derived from addition [71] et al. open-label, therapy 11 MPA of infliximab to standard therapy (2011) nonrandomized trial de Infliximab Prospective, RTX 17 GPA Results favor RTX for induction and [72] Menthon randomized trial maintenance of remission et al. (2011) Laurino Adalimumab Prospective, None Nine GPA Adalimumab was well tolerated; may [76] et al. open-label study Five MPA provide steroid-sparing effect (2010) GPA: Granulomatosis with polyangiitis; MPA: Microscopic polyangiitis; RTX: Rituximab.

agents differ in their molecular configurations weekly, in addition to conventional immuno- and precise mechanisms of action, as will be suppressive therapies, which were utilized in described below. To date, clinical trials in GPA accordance with disease severity. The standard have been performed with etanercept, infliximab therapies included GCS, CYC, MTX and AZA. and adalimumab. Features of the key studies are The authors found that etanercept was well tol- summarized in Table 3. erated, as no instances of serious adverse effects were experienced by any of the patients during Etanercept the 6 months of follow-up. In addition, there Etanercept is a fusion protein that consists of two were indications that the addition of etanercept extracellular p75 TNF receptors linked to the Fc had resulted in reduced disease activity and had portion of human IgG1. Etanercept functions as provided a steroid-sparing effect. At the end of a potent TNF-a inhibitor by binding circulating the study, the mean BVAS/WG score among all TNF-a and rendering it biologically inactive. patients had declined by 3 points (p < 0.001), Stone et al. published the first study to inves- and among the 14 patients for whom the addi- tigate the use of etanercept in GPA [55]. This tion of etanercept was the only medication study consisted of a 6-month open-label trial in change upon study entry, the mean BVAS/WG which etanercept was added to standard thera- score had declined by 3.14 points (p < 0.001). As pies. In total, 20 patents with GPA who were for etanercept’s potential steroid-sparing effect, experiencing either disease flares or persistent the mean daily prednisone dose for all patients disease activity were enrolled in the study at in the trial decreased from 19 mg at study entry two US academic centers. The subjects were to 7.4 mg at the end of the 6-month trial period treated with etanercept at a dose of 25 mg twice (p = 0.023).

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In light of these promising findings, a ran- (p = 0.39). Comparison with gender- and age- domized, placebo-controlled trial of the use of matched normal populations from the SEER etanercept in GPA was conducted by the WGET database showed that the increased risk of solid Research Group [56]. In this study, 180 patients malignancy in the etanercept group persisted with active GPA (experiencing either newly diag- during the follow-up period (standardized nosed disease or a flare of existing, previously- incidence ratio: 3.92, 95% CI: 1.69–7.72), but quiescent disease) were randomized to receive that the risk of solid malignancy in the placebo etanercept or placebo, in addition to standard group was increased to a similar degree (stan- therapy consisting of GCS plus either CYC or dardized incidence ratio: 2.89; p = 0.6). Thus, MTX. The dose of etanercept was 25 mg twice the increased risk of solid malignancy during weekly for all patients. The choice of standard long-term follow-up could not be solely attrib- therapy was made on the basis of the severity uted to etanercept exposure. Nonetheless, these of GPA manifestations. Those with disease that data suggest that etanercept should be avoided posed an immediate threat to either the patient’s in patients with GPA, particularly among those life or vital organ function (severe disease) were whose risk of developing malignancy is already treated with CYC and GCS, whereas those with elevated [59]. limited (nonsevere) disease received MTX and The negative findings of WGET, together GCS. The standard therapies were adjusted with concerns regarding the risk of inducing by established protocols on the basis of disease solid malignancy, ended the enthusiasm for activity. the use of etanercept in GPA. Its use is cur- The trial’s primary outcome was sustained rently not recommended for either induction or disease remission, defined as a BVAS/WG of ­maintenance of disease remission in GPA. zero for at least 6 months. After a mean duration of 27 months follow-up, there was no signifi- Infliximab cant difference in the rate of sustained remis- Despite the WGET study’s negative findings sion between the etanercept and placebo groups with regard to the use of etanercept, there (69.7 vs 75.3%; p = 0.39). In addition, there remained a rationale for the use of other TNF-a were no significant differences between the two inhibitors in GPA. The biologic effects of inf- groups in the time to achieve sustained remis- liximab, a chimeric monoclonal antibody to sion, the frequency of disease flares, the average TNF-a comprised of mouse variable and human disease activity or the quality of life. The major- constant regions, differ in some respects from ity of patients in both groups experienced disease those of etanercept, despite the fact that the pri- flares and significant adverse events. However, of mary action of both agents is to block TNF-a the six solid malignancies observed during the signaling. Unlike etanercept, which only binds study period, all occurred among patients in the soluble TNF, infliximab also binds TNF that is ­etanercept group (p = 0.01). expressed on cell surface membranes, thereby The disparity in the frequency of solid malig- inducing apoptosis in target cells in vitro [60,61] . nancies prompted further analyses. Based on a It is unclear whether this difference has signifi- gender- and age-matched normal population in cance in vivo, but it has been established that the NIH Surveillance Epidemiology and End there are instances in which infliximab is effec- Results (SEER) database, 1.9 solid malignan- tive while etanercept is not. For example, in cies would have been expected in the etanercept Crohn’s disease and sarcoidosis – both of which group during the study period. Therefore, the share the feature of granulomatous inflammation six observed solid malignancies give a standard- with GPA – treatment with infliximab is ben- ized incidence ratio of 3.1 (95% CI: 1.2–6.8; eficial, even though treatment with­ etanercept p = 0.01) [57]. A post-trial follow-up study was is not [62,63]. conducted to further investigate the relationship Early reports and uncontrolled studies regard- between etanercept therapy and solid malig- ing the use of infliximab in GPA suggested the nancy [58]. Follow-up data were available for 153 possibility that infliximab may succeed where of the 180 patients who comprised the original etanercept had failed. Lamprecht et al. reported WGET cohort, with 77 of the patients (50.3%) the first use of infliximab in GPA in a case series having received etanercept during the study. of six patients [64]. All six of these patients had During a median follow-up time of 43 months GPA refractory to treatment with CYC and from the common closeout date, 13 new solid GCS. Following the addition of infliximab to malignancies were detected, with eight in the standard therapy, five of the patients achieved etanercept group and five in the placebo group sustained remission. Other authors later reported

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similarly positive results with infliximab as a Finally, in a prospective, randomized, multi- ­rescue therapy in refractory GPA [65–67]. center trial, de Menthon et al. compared inflix- Subsequent uncontrolled studies also suggested imab with RTX in GPA [72]. In total, 17 patients a possible beneficial effect of infliximab. Barto- with GPA refractory or intolerant to treatment lucci et al. reported the successful use of infliximab with glucocorticoids and standard immuno- in an open-label pilot study of ten patients with suppressants were randomized to receive either systemic vasculitis refractory to GCS and receiv- infliximab or RTX in addition to their ongoing ing at least one standard immuno­suppressant regimen. The primary end point was complete [68]. Seven of these patients had GPA; all seven or partial remission at 12 months. Although the experienced complete or partial remission 6 weeks results of this small study should be interpreted after initiating infliximab, and all had persistent with caution, there was a trend favoring RTX improvement at 6 months. In a related long-term and post hoc analysis of long-term follow-up follow-up, involving many of the same patients, showed that RTX performed better in terms infliximab continued to be useful beyond 2 years of induction and maintenance of remission. of treatment initiation [69]. Separately, in a pro- In addition, among five patients in the inflix- spective, open-label, multicenter trial, Booth et imab group who failed to respond to the anti- al. studied the use of infliximab in 32 patients TNF therapy, four were subsequently treated with AAV, including 19 patients with GPA and s­uccessfully with RTX. 13 patients with MPA [70]. None of the subjects On the basis of these comparison studies, had immediately life-threatening disease manifes- enthusiasm for the use of infliximab in GPA has tations at study entry. All patients received inflix- sharply diminished. Despite the initial prom- imab in addition to standard therapy, consisting of ise, infliximab currently is not recommended either CYC and prednisolone or the patient’s exist- as a standard component of either induction or ing regimen. Mean follow-up was 16.8 months. A maintenance therapy in GPA and is generally total of 28 out of the 32 patients (88%) achieved only considered for salvage therapy. disease remission, with an overall mean time to remission of 6.4 weeks. Although severe infections Adalimumab occurred in seven of the 32 patients (22%) and Similar to infliximab, adalimumab is a monoclo- were associated with one death, these results were nal blocking antibody to TNF-a. However, while considered promising. infliximab is a chimeric antibody that requires However, further investigations that have intravenous administration, adalimumab is a included separate treatment arms have not ful- fully humanized, recombinant IgG1 antibody filled the promise that infliximab showed in the that is delivered subcutaneously. Adalimumab’s early case reports and uncontrolled studies. In a ease of administration and reduced potential single-center, open-label, nonrandomized, pro- for immunogenicity have made it an attractive spective study, Morgan et al. investigated two alternative to infliximab [73]. In Crohn’s disease, contemporaneous cohorts of patients with active adalimumab is effective for the induction and AAV who differed on the basis of whether they maintenance of remission, and retains efficacy in received infliximab in addition to standard remis- some patients who have lost response or become sion-induction therapy [71] . A total of 33 patients intolerant to infliximab [73–75]. with AAV, 22 of whom had GPA, were followed To date, only one uncontrolled study has inves- for 1 year. All patients received standard immu- tigated the use of adalimumab in AAV. Laurino et nosuppression consisting of prednisolone plus al. conducted an open-label, prospective study of CYC, mycophenolate mofetil or AZA, and those 14 patients with acute flares of AAV, nine of whom with life- or organ-threatening disease underwent had GPA [76]. The patients were treated with a plasma exchange. In addition, 16 of the patients 3-month course of adalimumab, dosed at 40 mg received infliximab, dosed at 5 mg/kg at study every 2 weeks. In addition, they received induc- entry and at weeks 2, 6 and 10. The primary out- tion CYC and prednisolone, followed by mainte- come was time to clinical remission, which did nance AZA or mycophenolate mofetil along with not differ between the two cohorts. Other clinical a reducing dose of prednisolone. The study found outcomes included disease activity and episodes that adalimumab was well tolerated and that the of relapse, neither of which differed between the rate of remission at 3 months was similar to his- cohorts. The authors concluded that the study toric controls, but with a reduction in exposure did not identify any obvious clinical benefit from to prednisolone. These results have yet to be con- the addition of i­nfliximab to standard therapy firmed in randomized controlled trials. Similar for A AV. to the other TNF inhibitors, adalimumab does

390 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

not currently have a defined role in thetr ­ eatment Other studies suggest the possibility that of GPA. BAFF facilitates reconstitution of B-cell pop- ulations and autoimmune disease relapse fol- „„B-cell-activating factor inhibition lowing B-cell depletion therapy, such as RTX. Rationale for targeting B-cell-activating In patients with rheumatoid arthritis, serum factor in GPA BAFF levels increase soon after RTX infusion B-cell-activating factor (BAFF; also called and remain above baseline until B cells return B-lymphocyte stimulator) is a member of the to the peripheral blood [88]. In patients with TNF family and plays an essential role in B-cell GPA, serum BAFF levels also significantly development and survival, and in immuno­ increase above baseline following initiation of globulin production [77]. BAFF has emerged as a RTX treatment [87]. Increased serum BAFF potential therapeutic target in autoimmune dis- levels may themselves contribute to the recon- eases on the basis of mechanistic considerations, stitution of B-cell populations. For example, in findings in animal models and observations in Sjögren’s syndrome, higher serum BAFF levels patients. following RTX infusion correlate with shorter Based on its function, BAFF may play a crucial durations of B-cell depletion [89]. It is con- role in the maintenance of autoimmunity. BAFF ceivable that the high serum BAFF levels that acts primarily as a B-lymphocyte survival fac- follow RTX infusion promote the survival of tor. Autoantigen-binding B cells appear to have small numbers of B cells, including autoreactive increased dependence on BAFF for their survival B lymphocytes [90]. compared with nonautoreactive B cells [78,79]. Given the potential for BAFF to perpetuate Animal models have suggested that excess BAFF ANCA-associated inflammation and to facili- may itself induce autoimmunity. For example, tate the reconstitution of B-cell populations fol- transgenic mice with overexpression of BAFF lowing therapy, BAFF is a potential target for have been shown to develop a lupus-like disease future therapeutic investigations in GPA. Anti- followed by a Sjögren-like disease [80]. In human BAFF therapy could conceivably serve either as studies, patients with a variety of rheumatologic an adjunct treatment in active GPA disease (to conditions have been found to have elevated serum help break the cycle of inflammation) or as a BAFF levels [81] . The targeting of BAFF via belim- secondary agent used in conjunction with B-cell umab, a human IgG-1λ monoclonal antibody that depleting mediations, such as RTX, to amplify binds to and neutralizes soluble BAFF, has been and extend their effects [90]. shown to be effective and safe in systemic lupus erythematosus [82,83]. Experience with BAFF inhibitors BAFF may also emerge as a therapeutic tar- The only BAFF antagonist currently approved get in GPA. Serum BAFF levels are increased in by the FDA is belimumab, the human monoclo- patients with GPA compared with healthy con- nal antibody used in systemic lupus erythema- trols and, among GPA patients, treatment with tosus, which is specific to soluble BAFF only. A GCS is associated with lower serum BAFF levels Phase III trial to investigate belimumab in com- [84–86]. Serum BAFF levels have not been shown bination with AZA for remission maintenance to positively correlate with either ANCA titers in GPA and MPA is currently being planned or GPA disease activity, but indirect evidence (BREVAS) [202]. Three other BAFF antagonists suggests that elevated BAFF levels in patients undergoing clinical investigation are: atacicept, a with GPA may perpetuate an inflammatory receptor fusion protein; blisibimod, a ‘peptibody’ cycle and may contribute to disease relapse under or fusion protein consisting of the Fc portion of certain conditions. Holden et al. showed that IgG and a peptide sequence that binds BAFF treating neutrophils with PR3-ANCA results with high affinity; and tabalumab, a monoclonal in the release of bioactive BAFF [87]. Further antibody that binds both soluble and membrane- experiments demonstrated that the BAFF-rich bound BAFF. None of these agents currently has supernatants from neutrophils treated with PR3- a role in the treatment of GPA. ANCA promote B-cell survival in vitro. These findings suggest the possibility of an inflamma- Therapy directed against tory cycle linking ANCA and BAFF, whereby T lymphocytes ANCA-activated neutrophils that arrive at an „„Rationale for targeting inflammatory site release BAFF and directly pro- T-lymphocyte activation in GPA mote the survival of ANCA-producing B cells T-cell activation provides yet another potential already in situ. therapeutic target in GPA. T cells are frequently

future science group www.futuremedicine.com 391 Review Clain, Cartin-Ceba & Specks Biologic response modifiers for granulomatosis with polyangiitis (Wegener’s) Review

found in the granulomatous lesions that define Investigations into the use of abatacept the disease [91]. In addition, serum markers of in GPA remain preliminary. A recent report T-cell activation, such as soluble IL-2 receptor describes an open-label trial of abatacept in and soluble CD30, are increased in GPA and 20 patients with mild relapsing GPA [106] . These associated with disease activity [92,93]. Abnormal- patients were treated with abatacept at a dose ities in T-cell activation may facilitate the loss of of 10 mg/kg intravenously on days 1, 15 and self-tolerance that is central to the p­athogenesis 29, and monthly thereafter, in addition to their of GPA. standard therapies. Abatacept was well tolerated Full activation of T cells requires at least and was associated with disease remission and two signals from an antigen-presenting cell discontinuation of prednisone in a high percent- (APC) [94]. The first signal is elicited by bind- age of patients. These promising findings suggest ing of the antigen-specific T-cell receptor to an that abatacept (or perhaps the next generation APC’s MHC peptide complex. The second sig- agent belatacept) warrants further study in the nal is delivered by binding of a T-cell costimu- treatment of GPA, particularly for remission latory receptor to a ligand on the same APC. maintenance. One important T-cell costimulatory receptor is CD28, which binds to CD80 or CD86 on „„Alemtuzumab APCs [95]. Binding of both the T-cell receptor Alemtuzumab is a humanized monoclonal anti- and CD28 results in T-cell proliferation and body against CD52, which consists of human proinflammatory cytokine release. Conversely, IgG1 constant and variable framework regions binding of the T-cell receptor without engaging together with murine complementarity-deter- the costimulatory CD28 results in suboptimal mining regions. The target CD52 antigen is activation, renders the T cell poorly responsive to widely expressed by B lymphocytes, T lympho- subsequent stimulus and may initiate apoptosis. cytes, monocytes, macrophages and natural Following activation, T cells express cytotoxic killer cells; however, the predominant effect of T-lymphocyte-associated antigen 4 (CTLA-4), alemtuzumab is prolonged T-lymphocyte deple- which serves to dampen the immune response by tion [107] . Thus, while treatment with abatacept inhibiting costimulatory signaling via the CD28 aims to modulate T-lymphocyte activity, the pathway [96]. CTLA-4 is a high-avidity receptor use of alemtuzumab is directed toward deplet- for both CD80 and CD86, binding these ligands ing and altering T-lymphocyte populations [108] . 500–2500-times as avidly as CD28. Therefore, Alemtuzumab’s only FDA-approved indication is abnormalities in CTLA-4 expression result in in the treatment of B-cell chronic lymphocytic a disruption in the balance of T-cell activation. leukemia, but it has drawn interest in T-lympho- Genetic association studies have demonstrated cyte-driven diseases, including multiple sclerosis, that GPA is associated with particular poly- rheumatoid arthritis and Behçet disease [107–110]. morphisms in the CTLA-4 gene [97–103], which To date, only one report describes long-term may reduce the efficacy of expressed CTLA- follow-up of the use of alemtuzumab in AAV. 4. Reduced CTLA-4 activity could, in turn, Walsh et al. describe 71 patients with AAV partly account for the increased T-cell activation who were treated with alemtuzumab at a single observed in GPA. Therapeutically supplement- center between 1991 and 1999, with a mean ing the activity of CTLA-4 therefore provides a follow-up of 5 years [111]. A total of 63 of these potential treatment strategy in GPA. patients had GPA, and all of them had either chronically relapsing or life-threatening disease, „„Abatacept despite standard treatment. Prior to receiving Abatacept is a soluble fusion protein, comprised alemtuzumab, all immunosuppressive medica- of the extracellular domain of human CTLA-4 tions (except prednisolone) were discontinued. and a fragment of the Fc domain of human Alemtuzumab was administered intravenously IgG1, modified to prevent complement fixation on five consecutive days at doses of 4, 10, 40, [96]. Abatacept serves to supplement the activity 40 and 40 mg/day. Clinical remission was of CTLA-4 and thereby modulate T-cell acti- achieved in 46 of the patients (65%), while an vation. Similar to CTLA-4, abatacept competi- additional 14 patients (20%) had clinically sig- tively inhibits CD28, reducing the frequency of nificant improvement. However, high rates of T-cell costimulatory signaling [104] . It has been relapse, severe infections and malignancy were approved for use in patients with rheumatoid also observed. arthritis who have had an inadequate response In order to build on this experience, a pro- to anti-TNF-a therapy [105] . spective, open-label, randomized, multicenter

392 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

study is ongoing to characterize the clinical is the only BRM that has been proven to be an response and severe adverse event rate associated effective and safe addition to the armamentarium with alemtuzumab for the treatment of relapsing of GPA therapies. Based on data from the RAVE or refractory AAV (ALEVIATE [203]). Outside trial, RTX in combination with GCS has been of an investigational context, alemtuzumab approved by the FDA for remission induction in ­currently has no role in the treatment of GPA. severe GPA. In addition, given the RAVE trial’s finding of superiority of RTX to CYC in patients Conclusion & future perspective presenting with severe relapses, it has become the In recent years, several BRMs have been inves- preferred therapy for such patients. Investigations tigated as alternative or adjunctive therapies in into BRMs that target B-lymphocyte stimula- GPA. While multiple BRMs are useful in a vari- tion (such as belimumab) and T-lymphocyte ety of other autoimmune diseases, to date, RTX activation or depletion (such as abatacept and

Executive summary Rationale for targeting B lymphocytes in granulomatosis with polyangiitis ƒƒ B lymphocytes are essential for the production of antineutrophil cytoplasmic antibody, which is considered a key contributor to the pathogenesis of granulomatosis with polyangiitis (GPA). ƒƒ The frequency of activated B lymphocytes is associated with both disease activity and severity. Rituximab in GPA ƒƒ Rituximab is a chimeric monoclonal antibody directed against CD20, a protein expressed on the surface of cells of B-lymphocyte lineage. ƒƒ Two randomized controlled trials (RAVE and RITUXVAS) have firmly established the efficacy of rituximab for remission induction in severe GPA. ƒƒ Rituximab is the preferred treatment for severe relapses in GPA. Rationale for targeting TNF-a in GPA ƒƒ TNF-a is a key mediator of the inflammatory cascade, serving as the dominant inducer of multiple proinflammatory cytokines. ƒƒ TNF-a blockade is a well-established therapeutic strategy in multiple autoimmune diseases. Etanercept in GPA ƒƒ Etanercept is a fusion protein that incorporates TNF receptor domains and serves to bind and inactivate circulating TNF-a. ƒƒ The WGET study, a randomized placebo-controlled trial, found no clinical benefit from the addition of etanercept to standard therapy in the treatment of GPA. ƒƒ Patients in WGET who were treated with etanercept were found to have an increased risk of solid malignancy. Infliximab in GPA ƒƒ Infliximab is a chimeric monoclonal antibody against TNF-a. ƒƒ No clear benefit has been shown to derive from the addition of infliximab to standard therapy in the treatment of GPA. Adalimumab in GPA ƒƒ Adalimumab is a fully humanized, recombinant monoclonal antibody against TNF-a. ƒƒ Investigations remain preliminary, but adalimumab may provide a steroid-sparing effect in GPA. Rationale for targeting B-cell-activating factor in GPA ƒƒ B-cell-activating factor serves an essential role in B-cell development and survival, and in immunoglobulin production; it may also be crucial to the maintenance of autoimmunity. Experience with B-cell-activating factor inhibitors ƒƒ The use of B-cell-activating factor inhibitors in GPA remains investigational. Rationale for targeting T-lymphocyte activation in GPA ƒƒ Markers of T-lymphocyte activation are elevated in GPA and are associated with disease activity. Abatacept in GPA ƒƒ Abatacept is a soluble fusion protein that incorporates the extracellular domain of CTLA-4 and serves to inhibit T-lymphocyte activation. ƒƒ Investigations remain preliminary, but abatacept has been well tolerated and associated with disease remission in a high percentage of patients. Alemtuzumab in GPA ƒƒ Alemtuzumab is a humanized monoclonal antibody against CD52, which induces prolonged T-lymphocyte depletion. ƒƒ Investigations remain preliminary and a prospective, open-label, randomized, multicenter study is ongoing.

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alemtuzumab) have only been preliminary with Financial & competing interests disclosure regard to their use in AAV, and these agents do Genentech Inc. and Biogen Idec have provided financial not yet have a role in the standard treatment of support to the National Institute of Allergy and Infectious GPA. Anti-TNF-a agents, including etanercept, Diseases for the conduct of the RAVE trial, and Ulrich infliximab and a­dalimumab, have not shown Specks was coprincipal investigator of the RAVE trial. clear benefits in GPA. Roche Pharmaceuticals Inc. has provided speaker hono- As our understanding of autoimmunity rarium payments for U Specks (

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