Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of vasculitides characterized by small to medium-sized blood vessel vasculitis and the presence of ANCA. AAV includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, Wegener's granulomatosis) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg–Strauss syndrome). AAV is a life-threatening disease and the mortality is 80% at 1 year in untreated patients . The previous clinical trials for the induction and maintenance of remission of AAV have led to the current standard therapy with the combination of high-dose glucocorticoids and cyclophosphamide for remission induction followed by azathioprine or methotrexate maintenance therapy [2,3]. This approach has high remission rates of 80–90% and has reduced mortality to 25% at 5 years but many patients will relapse and long-term therapy is required. These therapies are associated with early and late toxicity that contribute to the increased mortality risk and vital organ damage suffered by vasculitis patients. In addition, despite maintenance therapy at least 10% of patients relapse each year [4▪▪]. Reducing glucocorticoid exposure is now a major unmet need in order to reduce infection rates, cardiovascular risk and other side-effects reducing patients’ quality of life. The role of glucocorticoids in relapse prevention is unclear, with variance in clinical practice and a meta-analysis suggesting glucocorticoid withdrawal increased relapse rates . Thus, newer therapies are needed (Table 1).
Although the cause of AAV is not fully understood, abnormalities of components of the immune system such as B cells, T cells, neutrophils and complement (specially, the alternative pathway) are observed in AAV. B-cell depletion with rituximab is now a licensed therapy for AAV and other potential drugs are emerging, with more targeted modes of action than conventional immunosuppressants.
EMERGING THERAPIES WITH ‘CONVENTIONAL’-TYPE DRUGS
Mycophenolate mofetil, an oral immunosuppressant, has been used as an alternative agent for relapsing disease and in remission maintenance . As an induction agent mycophenolate mofetil has been studied in myeloperoxidase (MPO)-ANCA vasculitis in which it appears to compare well to cyclophosphamide in small studies [7,8]. A larger induction study with mycophenolate mofetil in AAV, the MYCYC trial (ClinicalTrials.gov number; NCT00414128) has finished and is under analysis now. It will provide further information.
Gusperimus (15-deoxyspergualin) inhibits mainly T-cell maturation and cytotoxic T-cell proliferation but also B cells. Two open label studies reported high response rates in refractory GPA . Administered in 28-day cycles of daily subcutaneous injection with washout periods, it has required close monitoring to avoid cytopaenias. The SPARROW trial (ClinicalTrials.gov number; NCT01446211) is evaluating the efficacy of gusperimus in relapsing and refractory GPA.
Plasma exchange is a treatment option for severe AAV. Confirmation of the pathogenicity of ANCA has contributed to a therapeutic rationale for plasma exchange in AAV, although removal of other factors may also be important. Meta-analysis of plasma exchange trials suggests a beneficial effect on the risk of end-stage renal disease but no effect on mortality . Current practice recommends plasma exchange for those presenting with severe renal disease or alveolar haemorrhage with little evidence supporting the latter indication. The ongoing PEXIVAS trial (ClinicalTrials.gov number; NCT00987389) is examining the effect of plasma exchange on patient and renal survival in those with a GFR below 50 ml/min or severe alveolar haemorrhage .
B CELL-TARGETED THERAPIES
A rationale for B cell-targeted therapy in AAV has emerged from the presence of B cells at the sites of inflammation [12,13], correlation of B-cell activation with disease activity in GPA , the efficacy of cyclophosphamide which is a relatively B-cell-specific immunosuppressant , and the contribution of autoantibodies, MPO-ANCA/proteinase 3 (PR3)-ANCA, to the pathogenesis [16,17▪]. CD20 is an antigen expressed on the surface of B cells, and rituximab is an anti-CD20 monoclonal antibody depleting B cells. Following several case series studies with promising results, two randomized trials evaluated rituximab for remission induction in new and relapsing patients. Both the RAVE  and RITUXVAS  trials showed similar remission rates for newly diagnosed patients between rituximab and cyclophosphamide based regimens when combined with high dose glucocorticoids. The RAVE trial also demonstrated superiority of rituximab for relapsing disease. However, no differences in safety were observed between treatment groups suggesting that high-dose glucocorticoids are currently the main modifiable contributor to adverse events in AAV.
Rituximab as remission induction therapy is indicated for relapsing AAV and newly diagnosed AAV, when cyclophosphamide avoidance is desirable. Follow-up of the RAVE trial demonstrated noninferiority of a single course of rituximab to cyclophosphamide followed by azathioprine in remission maintenance at 18 months [20▪▪]; however, relapses were frequently observed 6–12 months after a single rituximab course, specially after B cell-return [20▪▪,21▪▪]. Optimal remission maintenance therapy after rituximab-based remission induction is unclear. In the retrospective studies of relapsing AAV, repeat dosing of rituximab appears to reduce relapse risk either using time-based rituximab re-treatment [21▪▪,22] or re-treatment based on ANCA-return and B cell-return [23▪▪], though it was also reported that a small group of patients showed persistent hypogammaglobulinemia and frequent infection after repeated rituximab infusions. The randomized trials MAINRITSAN and RITAZAREM (ClinicalTrials.gov number; NCT00748644 and NCT01697267, respectively) are evaluating efficacy and safety of repeat time-based rituximab as maintenance therapy in newly diagnosed and relapsing AAV after cyclophosphamide or rituximab-based induction, respectively.
B-cell activating factor (BAFF) is an important molecule for the survival and maturation of B cells, and serum BAFF levels are elevated in GPA patients . Belimumab, an anti-BAFF monoclonal antibody, is another B cell-targeted biologic agent. The BAFF receptor is expressed in many stages of the B cell lineage including plasma cells; notably, this differs from CD20 that is not expressed by plasma cells. It is currently approved for systemic lupus erythematosus, and is in development as a relapse prevention therapy for AAV in the BREVAS trial (ClinicalTrials.gov number; NCT01663623).
CD22 is a molecule expressed on the surface of mature B cells, and acts as a negative regulator of B cell receptor signal transduction. Epratuzumab is an anti-CD22 monoclonal antibody. It acts more as an immunomodulatory agent inducing B-cell energy, not only as a cytotoxic agent with no complement-dependent cytotoxicity (CDC) and less antibody-dependent cellular cytotoxicity (ADCC), whereas rituximab acts essentially as B cells depleting agent with CDC and ADCC. Preliminary efficacy of epratuzumab for other autoimmune diseases such as lupus has been reported [24,25]; it might have potential as another B cell targeting agent in AAV.
T CELL-TARGETED THERAPIES
Several lines of evidence have shown the importance of T cells in AAV pathogenesis. Expansion of effector memory CD4+ T-helper cells contributes to the local tissue injury and disease progression of AAV, while functional impairment of regulatory T cells in AAV has been reported . Indeed, in the subanalysis of the RITUXVAS trial, T cell tubulitis was an independent predictor for renal outcome assessed by estimated GFR after 12 months [27▪]. Although B cell-targeted therapy with rituximab is effective in AAV, T cell-targeted therapy as an alternative may be superior in such cases.
Abatacept is a fusion protein of CTLA-4-Ig and the immunoglobulin Fc region, which binds to B7 on antigen professing cells. It inhibits a costimulatory signal of B7-CD28, and consequently inhibits T-cell activation. It is currently approved for rheumatoid arthritis. An open-label pilot study involving relapsing patients with nonsevere GPA demonstrated sustained disease control with abatacept (Vasculitis & ANCA Workshop, April 2013) (ClinicalTrials.gov number; NCT00468208).
Alemtuzumab is an anti-CD52 monoclonal antibody licensed for chronic lymphocytic leukemia and T-cell lymphoma. CD52 is expressed in mature lymphocytes including both T and B cells and macrophages that are depleted by alemtuzumab. Walsh et al. reported alemtuzumab led to sustained treatment free remissions in AAV, but it is strongly immunosuppressive and was associated with severe adverse events in the elderly and those with renal failure. Furthermore, evidence of the efficacy and safety of alemtuzumab in AAV is required before it can be included in treatment options for refractory disease.
COMPLEMENT TARGETED THERAPIES
Xing et al. detected components of the alternative pathway, factor B, factor P, C3d and the membrane attack complex in glomeruli and small blood vessels in kidney biopsy specimens from AAV patients. This was supported by the absence of disease in an MPA model after factor B knockout or C5 knockout . Moreover, Yuan et al.[31▪] reported that C5a was elevated in active AAV in both patients’ plasma and urine. These studies suggested that complement activation via the alternative pathway was crucial for the disease development.
C5a is a cleavage product of complement C5 with strong chemotactic and anaphylatoxic features. CCX168 is a novel orally administered small molecule inhibitor of C5a receptor and a phase II trial (CLEAR) (ClinicalTrials.gov number; NCT01363388) is ongoing.
Inflammatory cytokines are important components in the disease development of AAV. Among these, TNF-α is associated with disease activity in GPA and TNF-α blockade has abrogated experimental renal vasculitis . Although small studies in patients with refractory disease showed promising results [33,34], a randomized, placebo-controlled trial evaluating the efficacy of etanercept, one of the TNF-α inhibitors, in the achievement of sustained remission in GPA patients failed to show efficacy . A glucocorticoid sparing role of TNF-α inhibitors in remission induction was suggested in pilot studies [36,37] of infliximab and adalimumab but their further development has not been pursued. Consequently, TNF-α inhibitors are not currently recommended in AAV therapy.
Interleukin (IL)-6 is another representative inflammatory cytokine. It was demonstrated that ANCA induced the production of IL-6 by endothelial cells in vitro, and a case report suggested that tocilizumab, anti-IL-6 receptor antibody, was effective for MPA .
Recently, Th17 cells have been considered to play an important role in the disease development of AAV and in early granuloma formation in GPA . IL-23 is a cytokine essential for the proliferation of Th17 cells. Ustekinumab is an anti-IL-12/23p40 monoclonal antibody, and might be effective for AAV as well as other autoimmune disease related to Th17 cells such as psoriasis.
OTHER POTENTIAL TARGETS
Bortezomib, the proteasome inhibitor targeting plasmablasts and mature plasma cells, is licensed for multiple myeloma. In an MPO-ANCA mouse model, bortezomib demonstrated similar efficacy for the prevention of necrotizing crescentic glomerulonephritis to glucocorticoid/cyclophosphamide and a stronger effect of reducing MPO-specific plasma cells and MPO-ANCA titers than glucocorticoid/cyclophosphamide . Some plasma cells survive for years, and it might explain the long-term elevation of ANCA occasionally seen after B-cell depletion.
Natalizumab is an antiα4-integrin monoclonal antibody approved for multiple sclerosis and Crohn's disease. It binds to the α4-integrin component of adhesion molecules expressed on lymphocytes, and prevents migration of autoreactive lymphocytes to local sites of inflamed organs. An analogous mechanism explains the immunological effects of a sphingosine 1-phosphate receptor modulator, such as FTY720 (Fingolimod) also approved for multiple sclerosis. Adhesion molecules can be targets for the treatment of AAV.
Spleen tyrosine kinase (Syk) is a nonreceptor cytoplasmic tyrosine kinase, important for transmitting signals from various immunoreceptors including the B-cell receptor. It has been also known that ANCA activates Syk in neutrophil via Fcγ receptor . An English group presented at the 16th international Vasculitis & ANCA workshop in Paris, 2013 that fostamatinib, a small molecule Syk inhibitor, prevented glomerulonephritis and reduced autoantibody production in an autoantibody dependent rat model of crescentic glomerulonephritis.
On the contrary, signaling via type I/II cytokine receptors is transmitted by Janus kinase (Jak). Blocking Jak might be effective for autoimmune diseases with elevated proinflammatory cytokines. Tofacitinib, a small molecule Jak inhibitor, has already been approved for rheumatoid arthritis.
TREATMENTS FOR EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS
EGPA is a form of AAV characterized by asthma and eosinophilia. EGPA has been excluded from most AAV trials because of difficulty in evaluating the disease activity including asthmatic symptoms and likely differences in pathogenesis. There are fewer data supporting current EGPA treatments than for GPA/MPA. The French Vasculitis Study Group examined the response to glucocorticoids in nonsevere EGPA and to glucocorticoids and cyclophosphamide in severe EGPA. Relapse rates in nonsevere EGPA are high if treated with glucocorticoids alone and studies of combinations with other immunosuppressants are needed . Similarly, only anecdotal data exist for the role of rituximab in EGPA. Case reports and case series have demonstrated good responses to rituximab in certain manifestations of EGPA, though it lacked a clear pathophysiological rationale except the presence of ANCA [43,44].
A Th2 response with elevated IL-4, IL-5 and IL-13 is predominant in the disease development of EGPA. Two small open label studies [45,46] of an anti-interleukin-5 antibody, mepolizumab, have reported good effects with safety in EGPA, and a larger trial is being prepared. Pitakinra is a human recombinant protein and inhibits IL-4 and IL-13 pathway by acting as an IL-4 receptor α antagonist. Pitakinra might be effective for EGPA. Both drugs have shown efficacy for bronchial asthma.
IFN-α is known to counteract Th2 response, and small studies suggested its efficacy in both remission induction and maintenance in EGPA . However, its unfavorable safety profile has restricted its use.
FUTURE DIRECTION OF THE THERAPIES FOR ANTIBODY-ASSOCIATED VASCULITIS
The availability of targeted therapies, especially therapeutic antibodies and improved understanding of pathogenesis are providing new opportunities in vasculitis therapy. Consensus over disease definitions and subgrouping and the development of disease assessment tools and trial end-points have permitted the design and conduct of successful randomized controlled trials, difficult in rare, multisystem diseases. Reducing the toxicity of therapy is a major goal likely to be achieved with safer, more specific therapies. Although the RAVE and RITUXVAS trials did not demonstrate a safety benefit, the high level of efficacy of rituximab is inspiring regimens with reduced glucocorticoid exposure.
With evidence from a genome wide association survey [48▪], indicating quite different genetic predisposition between PR3 and MPO-ANCA vasculitis and the evidence from trials that PR3-ANCA is an independent factor for relapse [4▪▪], future studies may focus on separate serological subgroups. Also, subanalysis of the RAVE trial showed PR3-ANCA positivity was associated with early recurrence and persistence of severe disease [49▪]. As to remission maintenance therapy, optimal use of glucocorticoid, immunosuppressants and biologics may be different between PR3-/MPO-ANCA positive patients. From the clinical trial point of view, much of the recent progress in this field has developed from the creation of international collaborative networks permitting consensus approaches and large-scale clinical studies. Further development of these networks in both scale and quality is expected.
In addition to the main therapies, development of supportive therapies is also important in the treatment for AAV (e.g. bone and infection prophylaxis, renal replacement therapy). Although dialysis and renal transplantation have already been established for renal failure, severe respiratory failure is more difficult to manage and still can cause death. Recently there is more use of extracorporeal membrane oxygenation (ECMO) for acute respiratory failure including alveolar hemorrhage by AAV, and ECMO is useful . However treatment options for chronic progressive pulmonary fibrosis in some AAV, especially MPA, remain poor. Pirfenidone is an antifibrotic drug licensed for idiopathic pulmonary fibrosis, but currently is not widely used because of its mild efficacy compared with severe side-effects such as photosensitivity. Development of regenerative medicine using embryonic stem (ES) cells and induced pluripotent stem (iPS) cells appears promising, though its clinical application is just commencing.
In the field of AAV, various new drugs and potential candidates are approved or under evaluation in both clinical and experimental stages. To find optimal use of these drugs and to resolve the unmet needs, such as relapse prevention and reducing glucocorticoid dose, will be needed.
The authors acknowledge support from the Cambridge Biomedical Research Centre.
Conflicts of interest
S.F., there are no conflicts of interest; D.J., has received research grant from Roche/Genentech and consulting fees from GlaxoSmithKline, Roche/Genentech and UCB.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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