Vasculitis expert and former editor of The Rheumatologist, Dr. Philip Seo gives us his picks for the 10 most important abstracts in ANCA-associated vasculitis to come out of ACR Convergence 2023.
SAN DIEGO—Anti-neutrophilic cytoplasmic antibody (ANCA) associated vasculitis, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), continues to be an area of active investigation. Multiple studies on ANCA-associated vasculitis were presented at ACR Convergence 2023. Here, we highlight important points from 10 of these studies.
1. Use of the PEXIVAS Regimen in GPA & MPA
Abstract 0725: Nagle et al.
The administration of high-dose glucocorticoids for the treatment of severe forms of ANCA-associated vasculitis has long been established as part of the standard of care. PEXIVAS challenged this dogma by demonstrating that a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death or risk of progression to end-stage kidney disease.2 However, it has been less clear whether a reduced-dose glucocorticoid regimen is adequate for all patients with ANCA-associated vasculitis.
This retrospective study addressed this question by examining the outcomes of 234 patients with ANCA-associated vasculitis, 54% of whom received a reduced-dose glucocorticoid regimen. The study included 93 patients with MPA and 148 patients with GPA. The primary end point was a composite that included death, end-stage kidney disease and disease progression before first achieving remission.
In multivariate analysis, patients who were treated with a reduced-dose glucocorticoid regimen were more likely to achieve the primary end point (hazard ratio 1.72; 95% confidence interval [CI] 1.08–2.74). However, the reduced-dose glucocorticoid regimen was not associated with an increased risk of death or progression to end-stage kidney disease (HR 1.62; 95% CI: 0.82–3.19). There was no significant difference in serious infections at one year (20.6% vs. 15.7%, P=0.427).
In subgroup analysis of patients treated with the reduced-dose glucocorticoid regimen, the primary end point was more likely to be achieved by patients treated with rituximab and patients with a baseline serum creatinine of 3.4 mg/dL (or greater). Patients who were treated with both rituximab and a reduced-dose glucocorticoid regimen had an increased risk of death or progression to end-stage kidney disease (HR 2.42; 95% CI: 1.04–5.66).
The use of a reduced-dose glucocorticoid regimen has been an important advance in the management of ANCA-associated vasculitis. However, this latest analysis implies that there may be a tradeoff, particularly among patients who receive remission-induction with rituximab. The association between the reduced-dose glucocorticoid regimen and the risk of death or end-stage kidney disease among patients treated with rituximab is particularly concerning, given that rituximab now dominates as the treatment of choice in both the U.S. and Europe.
2. Trimethoprim Sulfamethoxazole Prophylaxis
Abstract 1584: Mendel et al.3
Trimethoprim-sulfamethoxazole has been commonly prescribed to patients with granulomatosis with polyangiitis as chemoprophylaxis against Pneumocystis jirovecii infection. However, this practice has become less common among patients treated with rituximab, which specifically depletes B cells (rather than the T cells that prevent Pneumocystis infection).
In a commercial claims and encounters database, the researchers in this retrospective study identified 919 patients with GPA who had been treated with rituximab; 31% of these patients had also received prescriptions for trimethoprim-sulfamethoxazole. Patients in this study were followed for a median of 496 days. The rate of serious infection was 6.1/100 person-years. The most common serious infections were pulmonary (36%) or sepsis (45%).
In multivariate analysis, trimethoprim-sulfamethoxazole was negatively associated with serious infections (adjusted hazard ratio 0.5; 95% CI: 0.3–0.8) and outpatient infections (adjusted hazard ratio 0.7; 95% CI: 0.5–0.9). In this cohort, 13 infections with Pneumocystis jirovecii occurred, all in patients who had not received trimethoprim-sulfamethoxazole.
Adverse events attributable to trimethoprim-sulfamethoxazole occurred at a rate of 29.6/100-person years while exposed to trimethoprim-sulfamethoxazole, and 13.4/100-person years when not exposed to trimethoprim-sulfamethoxazole.
These data indicate that patients with GPA treated with rituximab may benefit broadly from chemoprophylaxis with trimethoprim-sulfamethoxazole, beyond the prevention of Pneumocystis jirovecii infection. However, the calculus is not straightforward; for every serious infection avoided, two or three patients will likely experience an adverse event from trimethoprim-sulfamethoxazole. A full presentation of these interesting data may help clinicians decide on the appropriate use of trimethoprim-sulfamethoxazole in this setting.
3. Avacopan & DAH
Abstract 0684: Specks et al.4
The alternative pathway of complement plays a critical role in the pathogenesis of both GPA and MPA. Avacopan inhibits the alternative pathway of complement by binding the C5a receptor. The ADVOCATE trial randomized 331 patients with ANCA-associated vasculitis to receive therapy with either avacopan (30 mg orally twice daily) or prednisone on a tapering schedule.5 At 26 weeks, the primary end point (defined as a Birmingham Vasculitis Activity Score of 0) was achieved by equal proportions of patients in both arms (72.3% vs. 70.1%).
The ADVOCATE trial demonstrated that patients with severe forms of ANCA-associated vasculitis could achieve remission with minimal exposure to glucocorticoids. However, clinicians may hesitate to use avacopan in place of glucocorticoids for patients who present with the most severe manifestations of ANCA-associated vasculitis.
This study was a post-hoc analysis of the 12 patients in the ADVOCATE study who presented with diffuse alveolar hemorrhage (DAH), most of whom had GPA (92%). Median glucocorticoid exposure during the first month following enrollment was considerably less among patients randomized to receive treatment with avacopan (625 mg vs. 1,627 mg). However, remission rates in both groups at 26 weeks were comparable (80% vs. 71.4%). No patients randomized to receive avacopan relapsed during the treatment period, and none of the patients in either group required mechanical ventilation.
Notably, ADVOCATE excluded patients who required invasive pulmonary ventilation support. However, this analysis mirrors the analysis of patients enrolled in ADVOCATE with glomerulonephritis, who also respond remarkably well to treatment with avacopan in place of glucocorticoids. This post-hoc analysis provides additional reassurance that avacopan is an appropriate substitute for oral glucocorticoids in patients who present with pulmonary-renal syndrome.
4. Relapse on Dialysis
Abstract 2382: Lee et al.6
Although outcomes among patients with ANCA-associated glomerulonephritis have improved dramatically with modern therapeutic strategies, many patients will eventually require renal replacement therapy. After hemodialysis is initiated, disease activity among patients with ANCA-associated glomerulonephritis often declines substantially.
This retrospective review examined this premise in 38 Korean patients, most of whom (92.1%) had MPA. Twelve of these patients relapsed a mean of 60 months following initiation of dialysis. These relapses included nine patients with DAH, and two patients with worsening interstitial lung disease. In multivariate analysis, prior episodes of DAH (hazard ratio 5.51, 95% CI: 1.57–19.3) and mean glucocorticoid dose (hazard ratio 1.38, 95% CI: 1.16–1.64) were significantly associated with relapse.
Case reports of recurrent vasculitis following renal replacement therapy are not new. However, this report implies that recurrence may occur in almost 25% of patients with MPA who are on dialysis. The authors posit that Asian patients may be at higher risk of relapse in this scenario; the specific protocol used for immunosuppression may also impact long-term risk of recurrence. For now, it seems prudent to monitor patients with MPA who are on dialysis carefully while tapering immunosuppression, particularly patients who have had prior episodes of pulmonary hemorrhage or have required high doses of glucocorticoids for remission induction.
5. Intensified B Cell Depletion Therapy
Abstract 0690: Roccatello et al.7
Rituximab tremendously improved the safety of remission induction regimens for patients with ANCA-associated vasculitis. However, remission induction with rituximab continues to require several months of glucocorticoid therapy, which drives many of the treatment-associated adverse events experienced by patients.
In this study, investigators compared the efficacy of an intensified B cell depletion therapy to conventional therapy. All of the patients enrolled in this study had renal failure due to ANCA-associated glomerulonephritis. Fifteen patients were treated with the intensified regimen, which included rituximab, cyclophosphamide and methylprednisolone pulses, but not oral glucocorticoids or other immunosuppressants. Ten patients were treated with oral cyclophosphamide and glucocorticoids followed by azathioprine. Patients in both groups who presented with alveolar hemorrhage, over 50% crescents on renal biopsy or dialysis dependence also received plasma exchange.
At six months, there was no difference between the two groups in terms of overall survival or renal survival. Among the patients who had received the intensified therapy, 93% entered complete remission, and 60% of the patients who were dialysis dependent at study onset were able to be weaned from dialysis.
This approach is similar to the Rituxilup regimen, which successfully used rituximab, mycophenolate mofetil and methylprednisolone pulses to treat lupus nephritis without oral glucocorticoids.8 The current proof-of-concept study paves the way for CD-19 CAR-T cell therapy, which also promises deep depletion of the B cell compartment. With both approaches, the durability of response remains unclear.
6. Risk of Major Adverse Cardiovascular Events
Abstract 2386: Idoate et al.9
Patients with ANCA-associated vasculitis have an increased risk of major adverse cardiac events, which include non-fatal stroke, non-fatal myocardial infarction and cardiac death. This retrospective study explores whether this increased risk differs according to ANCA status.
This study included 166 patients who had ANCA directed against proteinase-3 (PR3-ANCA) and 236 with ANCA directed against myeloperoxidase (MPO-ANCA). After a mean follow-up of 7.51 years, patients in this study had 15 myocardial infarctions and 12 strokes.
Ten years after diagnosis, the probability of MACE-free survival was lower among patients with MPO-ANCA (83.4% vs. 68.8%).
Patients with MPO-ANCA had a higher incidence of both myocardial infarction and stroke, both of which occurred earlier in the disease course when compared with patients with PR3-ANCA. The incidence rate of myocardial infarction was 6.16 per 1,000 patient-years in the MPO ANCA group and 4.09 per 1,000 patient-years in the PR3-ANCA group. The incidence rate of stroke was 6.13 per 1,000 patient-years in the MPO-ANCA group and 2.72 per 1,000 patient years in the PR3-ANCA group. The association between MPO-ANCA and stroke was statistically significant (hazard ratio 3.05; 95% CI: 0.88–10.6), but the association between MPO-ANCA and myocardial infarction was not.
The increased risk of major adverse cardiac events observed among patients with ANCA-associated vasculitis is often attributed to the high doses of glucocorticoids used for remission induction and maintenance. Given that patients with MPO-ANCA and PR3-ANCA are treated with similar regimens, it is difficult to see how differences in treatment strategies could account for the higher incidence of major adverse cardiac events seen in this study. The results of this study imply that patients with MPO-ANCA in particular may benefit from aggressive risk factor modification for cardiovascular disease.
7. ANCA Vasculitis & Serum Interleukin 7
Abstract 2375: Fukui et al.10
Interleukin (IL) 7 plays a critical role in the lymphocyte life cycle. IL-7 stimulates hematopoietic stem cells to differentiate into lymphoid progenitor cells, and stimulates the production of B cells, T cells and NK cells. IL-7 also promotes T cell and NK cell survival.
In this study, serum IL-7 was measured in 60 patients with either GPA or MPA and 101 healthy control patients.
Serum levels of IL-7 correlated with the Birmingham Disease Activity Score (Spearman’s rank correlation coefficient 0.28, P=0.028). However, there was no association between IL-7 level and ANCA status, clinical diagnosis (i.e., GPA vs. MPA), or clinical outcome (e.g., relapse or death).
The association between IL-7 and ANCA-associated vasculitis was first reported in 2010. McKinney et al. analyzed transcripts from CD8-T cells from patients with either systemic lupus erythematosus or ANCA-associated vasculitis. Their analysis demonstrated that patients with either diagnosis who had poor prognostic features were enriched for transcripts from the IL-7 pathway. The current report indicates that serum IL-7 levels also correlate with the total white blood cell count and C-reactive protein, implying that it may not distinguish active disease from infection, which is where the true clinical need lies. However, this report provides additional confirmation that IL-7 is important to the pathogenesis of ANCA-associated vasculitis.
8. Efficacy & Safety of Benralizumab in EGPA
Abstract L14: Wechsler et al.11
IL-5 is a T cell derived cytokine that controls the production, activation and localization of eosinophils. Mepolizumab is a humanized monoclonal antibody directed against IL-5 that prevents it from interacting with eosinophils. Currently, mepolizumab is the only agent approved by the U.S. Food & Drug Administration (FDA) for the treatment of EGPA. Benralizumab is a monoclonal antibody directed against the alpha chain of the IL-5 receptor. Benralizumab has been approved by the FDA for the treatment of severe eosinophilic asthma and eosinophilic esophagitis. However, whether this agent is also effective for the treatment of EGPA has been less clear.
In the MANDARA study, 140 patients with EGPA were randomized to receive monthly subcutaneous injections with either 30 mg of benralizumab or 300 mg of mepolizumab. All patients were at least 18 years old and had a history of relapsing or refractory disease requiring at least 7.5 mg of prednisone or prednisolone daily. The primary end point was defined as the proportion of patients achieving remission (defined as a Birmingham Vasculitis Activity Score of 0) while taking no more than 4 mg of prednisone or prednisolone daily.
At both weeks 36 and 48, equal proportions of patients in both groups achieved the primary end point (59.2% vs. 56.5%). At weeks 48 to 52, patients in the benralizumab group were more likely to have successfully tapered off of glucocorticoid therapy (41.4% vs. 25.8%) and had fewer serious adverse events (5.7% vs. 12.9%). However, 30% of patients in both groups experienced disease relapse.
The MANDARA study provides further evidence that the IL-5 blockade is an effective strategy for the treatment of EGPA. Mechanistically, benralizumab is more efficient at eliminating eosinophils, which may explain why patients treated with benralizumab were more likely to achieve a glucocorticoid-free remission. Notably, the benralizumab regimen used in this study differs from the regimen used for the treatment of severe eosinophilic asthma, which redoses patients every eight weeks. However, abstract 0678 (“Benralizuamb in eosinophilic granulomatosis with polyangiitis”) suggests the regimen used for patients with asthma may be equally effective for patients with EGPA.12
9. Remission-Induction Regimens for EGPA
Abstract 0854: Dutertre et al.13
The 2021 ACR/Vasculitis Foundation guideline for the management of ANCA-associated vasculitis recommends either rituximab or cyclophosphamide for remission induction of patients with active, severe eosinophilic granulomatosis with polyangiitis.14
Rituximab in Eosinophilic Granulomatosis with Polyangiitis (REOVAS) was a phase 3, double-blind trial that randomized 105 patients with newly diagnosed or relapsing EGPA to treatment with rituximab (1 gram pulses two weeks apart) or cyclophosphamide (nine intravenous pulses over five months).15 At the end of 180 days, remission was achieved in equal numbers of patients in both arms (63.5% vs. 60.4%), and had comparable rates of both relapse and major relapse. At the end of 360 days, remission rates in both arms remained comparable (59.6% vs. 64.2%).
In Abstract 0854, the authors present long-term follow-up from patients enrolled in REOVAS, who were followed for a median of 45 months. Only one patient was lost to follow-up.
After 45 months, the minor and major relapse-free survival rate was higher among patients treated with rituximab, but the difference between the two groups was not statistically significant (63.5% vs. 50.9%, P=0.24). However, the difference became statistically significant when the analysis included only patients who were MPO-ANCA positive (92% vs. 50%, P=0.02)
Several groups have previously demonstrated that the clinical manifestations of EGPA are influenced by ANCA status. Patients who are ANCA positive tend to have more manifestations traditionally linked to vasculitis, such as mononeuritis multiplex. In patients who are ANCA negative, the eosinophilic manifestations tend to dominate. Given that rituximab directly impacts B cell function, it seems rational that rituximab would be more effective among patients whose disease is characterized by ANCA production.
10. Dupilumab for Relapsing or Refractory EGPA
Abstract 0856: Molina et al.16
The cytokines IL-4 and IL-13 are responsible for mediating the allergic response in a wide range of diseases. IL-4 influences Th2 cell development and antigen-specific IgE responses. IL-13 induces IgE secretion from activated B cells. Dupilumab is a humanized monoclonal antibody that inhibits both IL-4 and IL-13 signaling by binding the IL-4 receptor alpha chain. Dupilumab has been approved by the FDA for the treatment of atopic dermatitis, asthma, eosinophilic esophagitis and prurigo nodularis.
This retrospective study included 50 patients with EGPA who were treated with dupilumab, most commonly for debilitating otolaryngologic manifestations, glucocorticoid dependency or poorly controlled asthma. Of the 50 patients in this study, 33 (66%) had a complete or partial response to dupilumab, which was associated with a reduction in the average daily dose of prednisone from 7 mg to 2.5 mg at 12 months.
Dupilumab-induced eosinophilia was reported in 33 patients (66%), but remained asymptomatic in 42% of cases. Disease flare was reported in 15 patients (30%) and occurred in association with blood eosinophilia in 87% of cases. Most adverse events were mild to moderate (including headache, injection site reactions, myalgias and arthralgias), but two patients experienced non-fatal anaphylactic shock.
Clinically, dupilumab is effective for eosinophilic chronic rhinosinusitis and nasal polyposis, which can be particularly problematic for patients with EGPA. However, clinicians have tended to avoid dupilumab in patients with EGPA due to a concern that dupilumab-induced hypereosinophilia could precipitate a disease flare. This study confirms both trains of thought: Dupiliumab may be an effective therapy for EGPA, but patients need to be monitored carefully for disease flare.
Dupilumab-induced hypereosinophilia tends to dissipate with time, and it will be interesting to see if future studies demonstrate that the associated risk of disease flare dissipates with prolonged therapy. Alternatively, simultaneous treatment with an IL-5 inhibitor may mitigate the risks associated with this drug for patients with underlying hypereosinophilic syndromes.
Philip Seo, MD, MHS, is an associate professor of medicine at Johns Hopkins University School of Medicine. He served as the third physician editor of The Rheumatologist.
References
- Nagle S, Nguyen Y, Puéchal X, et al. Real-life use of the PEXIVAS reduced-dose glucocorticoid regimen in granulomatosis with polyangiitis and microscopic polyangiitis [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Walsh M, Merkel PA, Chen-Au Peh C-A, et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med. 2020 Feb 13;382:622–631.
- Mendel A, Behlouli H, Vinet E, et al. Effect of trimethoprim sulfamethoxazole prophylaxis on infections during treatment of granulomatosis with polyangiitis with rituximab: A population-based study [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Specks U, Jayne D, Merkel P. Report on twelve patients with diffuse alveolar hemorrhage in the phase 3 trial of avacopan for the treatment of ANCA-associated vasculitis [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Jayne DRW, Merkel PA Schall TJ, et al.; the ADVOCATE Study Group. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med. 2021 Feb 18;384:599–609.
- Lee Y, Song H, Seo W, et al. Relapse of patients with ANCA-associated vasculitis who are on dialysis [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Roccatello D, Sciascia S, Foddai S, et al. Treating patients with ANCA-associated vasculitis and very severe renal injury with an intensified B cell depletion therapy: Comparison with a control cohort receiving a conventional therapy [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Condon MB, Ashby D, Pepper RJ, et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis. 2013;72:1280–1286.
- Idoate J, Mourguet M, David R, et al. Impact of ANCA specificity on risk of major adverse cardiovascular events in ANCA-associated vasculitis [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Fukui S, Matsuo H, Kojima K, et al. Clinical characteristics of ANCA-associated vasculitis with high levels of serum Interleukin 7 [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Wechsler M, Nair P, Terrier B, et al. Efficacy and safety of benralizumab compared with mepolizumab in the treatment of eosinophilic granulomatosis with polyangiitis in patients receiving standard of care therapy: Phase 3 MANDARA study [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Cottu A, Groh M, Desaintjean C, et al. Benralizumab in eosinophilic granulomatosis with polyangiitis [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Dutertre M, Pugnet G, De Moreuil C, et al. Long-term efficacy of remission-induction regimens for eosinophilic granulomatosis with polyangiitis [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2021 Aug;73(8):1366–1383.
- Terrier B, Pugnet G, de Moreuil C, et al. Rituximab versus conventional therapeutic strategy for remission induction in eosinophilic granulomatosis with polyangiitis: A double-blind, randomized, controlled trial [abstract]. Arthritis Rheumatol. 2021;73(suppl 9).
- Molina B, Padoan R, Urban M, et al. Dupilumab for relapsing or refractory eosinophilic granulomatosis with polyangiitis: A European retrospective study [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
