The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 266 AAV patients.

OBJECTIVES: Prospective long-term observational data on the disease course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were missing in Germany to date. Therefore, the Joint Vasculitis Registry in German-speaking countries (GeVas) has been established to follow the course of patients with AAV. The aim of this study is to present baseline data of patients with newly diagnosed and relapsing AAV enrolled in the GeVas registry. METHODS: GeVas is a prospective, web-based, multicentre, clinician-driven registry for the documentation of organ manifestations, damage, long-term outcomes, and therapy regimens in various types of vasculitis. Recruitment started in June 2019. RESULTS: Between June 2019 and October 2022, 266 patients with AAV were included in the GeVas registry: 173 (65%) with new-onset and 93 (35%) with relapsing AAV. One hundred and sixty-two (61%) patients were classified as granulomatosis with polyangiitis (GPA), 66 (25%) as microscopic polyangiitis (MPA), 36 (13%) as eosinophilic granulomatosis with polyangiitis (EGPA), and 2 (1%) as renal limited AAV. The median age was 59 years (51-70 years, IQR), 130 (51%) patients were female. Most patients were ANCA positive (177; 67%) and affected by general symptoms, pulmonary, ear nose throat (ENT), renal and neurological involvement. For induction of remission, the majority of patients received glucocorticoids (247, 93%) in combination with either rituximab (118, 45%) or cyclophosphamide (112, 42%). CONCLUSIONS: Demographic characteristics are comparable to those in other European countries. Differences were found regarding ANCA status, frequencies of organ manifestations, and therapeutic regimens. The GeVas registry will allow longitudinal observations and prospective outcome measures in AAV.

Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA. METHODS: We conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecified noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety. RESULTS: A total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P = 0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per microliter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per microliter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively. CONCLUSIONS: Benralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.).

Safety of dupilumab in T2 airways conditions: focus on eosinophilia across trials and real-life evidence.

INTRODUCTION: Dupilumab, a monoclonal antibody targeting the IL-4 receptor alpha subunit, effectively blocks both IL-4 and IL-13 mediated pathways. Its introduction has represented a significant advancement in the treatment of severe asthma and other Type 2 (T2) conditions, including nasal polyps, atopic dermatitis, and eosinophilic esophagitis. To date, Dupilumab has demonstrated optimal efficacy and safety profile. AREAS COVERED: The safety profile of dupilumab has been extensively studied, especially for its effects on blood eosinophil count. Transient eosinophil increase during treatment is typically insignificant from a clinical point of view and related to its mechanism of action. Rare cases of hyper-eosinophilia associated with clinical conditions like eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES) have been reported. Those cases are often related to the drug's steroid-sparing effect or the natural trajectory of the underlying disease rather than a direct cause-effect relationship with dupilumab. EXPERT OPINION: The management of hyper-eosinophilia during dupilumab treatment requires comprehensive diagnostic work-up and strict follow-up monitoring for early detection of systemic disease progression in order to avoid unnecessary discontinuation of an effective treatment. This approach highlights the importance of a personalized treatment.

Long-Term Effectiveness of Benralizumab in Eosinophilic Granulomatosis With Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disease characterized by eosinophilic tissue inflammation. Benralizumab, an anti-IL-5 receptor (anti-IL-5R) monoclonal antibody, induces rapid depletion of eosinophils; its longer-term effect in EGPA is unknown. OBJECTIVE: To assess the real-world effectiveness and clinical remission rates of anti-IL-5R therapy in EGPA. METHODS: We performed a retrospective cohort analysis of patients with EGPA, who commenced treatment with benralizumab. Clinical remission, assessed at 1 year and 2 years after the initiation of benralizumab, was defined as an absence of active vasculitis (Birmingham Vasculitis Activity Score of 0) and an oral corticosteroid (OCS) dose of ≤4 mg/d of prednisolone. "Super-responders" were defined as patients in remission and free of any significant relapses (asthma or extrapulmonary) over the preceding 12 months. The corticosteroid-sparing capacity of benralizumab, patient-reported outcome measures, and characteristics associated with clinical remission and super-responder status were also analyzed. RESULTS: A total of 70 patients completed at least 1 year of treatment with benralizumab, of whom 53 completed 2 years. Of 70 patients, 47 (67.1%) met the definition for clinical remission at 1 year, with a similar proportion in remission at 2 years. Excluding asthma-related relapses, 61 of 70 (87.1%) patients were relapse free at 1 year, and of the 53 who completed 2 years, 45 (84.9%) were relapse free. A total of 67.9% of patients no longer needed any OCS for disease control. No significant difference was seen between antineutrophilic cytoplasmic antibody (ANCA)-positive and ANCA-negative subgroups. CONCLUSIONS: In this real-world setting of patients with EGPA, treatment with benralizumab was well tolerated and resulted in corticosteroid-free clinical remission for the majority of patients.

Azathioprine vs methotrexate in eosinophilic granulomatosis with polyangiitis: a monocentric retrospective study.

OBJECTIVES: To analyse the effectiveness, safety and steroid-sparing effect of AZA and MTX as induction of remission and maintenance treatment in eosinophilic granulomatosis with polyangiitis. METHODS: We retrospectively collected data from 57 patients divided into four groups according to treatment: MTX/AZA as first-line agents (MTX1/AZA1) in non-severe disease or as second-line maintenance therapy (MTX2/AZA2) in severe disease previously treated with CYC/rituximab. During the first 5 years of treatment with AZA/MTX we compared the groups according to: remission rate [defined as R1: BVAS = 0; R2: BVAS = 0 with prednisone ≤5 mg/day; R3 (MIRRA definition): BVAS = 0 with prednisone ≤3.75 mg/day], persistence on therapy, cumulative glucocorticoid (GC) dose, relapse and adverse events (AEs). RESULTS: There were no significant differences in remission rates (R1) in each group (63% in MTX1 vs 75% in AZA1, P = 0.53; 91% in MTX2 vs 71% in AZA2, P = 0.23). MTX1 allowed R2 more frequently in the first 6 months compared with AZA1 (54% vs 12%, P = 0.04); no patients receiving AZA1 achieved R3 up to the first 18 months (vs 35% in MTX1, P = 0.07). The cumulative GC dose was lower for MTX2 vs AZA2 (6 g vs 10.7 g at 5 years, P = 0.03). MTX caused more AEs compared with AZA (66% vs 30%, P = 0.004), without affecting the suspension rate. No differences emerged in time-to-first relapse, although fewer patients treated with AZA2 had asthma/ENT relapses (23% vs 64%, P = 0.04). CONCLUSION: A significant proportion of patients achieved remission with both MTX and AZA. MTX1 had an earlier remission on a lower GC dose but MTX2 had a better steroid-sparing effect.

[Eosinophilic small vessel vasculites (EGPA) a hidden severe asthma comorbitity].

A 72-year-old woman presented to the emergency department due to worsening dyspnea. She had been diagnosed with asthma a year earlier. At arrival, her oxygen saturation was only 84%. During lung auscultation, wheezing was noted over all lung fields. A blood test showed a significant increase in eosinophils in peripheral blood, highest value of 1.4 x 10E9/L. Further investigations in the respiratory ward showed a positive MPO-ANCA, which, together with clinical features of asthma, chronic rhinosinusitis with polyps, mononeuritis multiplex and eosinophilia, led to the diagnosis of eosinophilic granulomatosis with polyangiitis, or what used to be called Churg-Strauss syndrome. Corticosteroid treatment was initiated and subsequently tapered down when treatment with mepolizumab was started, which is an IL-5 inhibitor. Her symptoms quickly became much better. Frequent exacerbations and pulmonary symptoms became things of the past.

ANCA-negative ANCA-associated vasculitis: pitfalls of the 'vasculitis screen'.

Despite its recognition as an 'ANCA-associated vasculitis' (AAV), eosinophilic granulomatosis with polyangiitis (EGPA) is ANCA negative in up to 60% of cases. Herein, we report the case of a young man with a clinical syndrome highly suggestive of EGPA but with repeated negative ANCA serology, ultimately presenting with cardiac arrest before recognition of the primary systemic vasculitis, whereupon he received successful induction therapy with high dose glucocorticoids and cyclophosphamide. The case illustrates the importance of awareness of ANCA negative AAV among general physicians in order to minimise morbidity and mortality.

Eosinophilic Granulomatosis With Polyangiitis Following COVID-19 Vaccination: A Case Report.

The current emergence of the coronavirus disease 2019 (COVID-19) pandemic and the possible side effects of COVID-19 mRNA vaccination remain worrisome. Few cases of vaccination-related side effects, such as vasculitis, have been reported. Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome, is a type of vasculitis characterized by the histological richness of eosinophils, asthma, polyneuropathy, sinusitis, and skin or lung involvement. Here, we report the first case of new onset EGPA following COVID-19 vaccination in Korea. A 71-year old woman developed a skin rash and presented with progressive weakness of the upper and lower extremities after the BNT162b2 vaccination (Pfizer-BioNTech). She was diagnosed with EGPA and her symptoms improved after systemic steroid and immunosuppressant therapy. Although it is very rare, clinicians should be aware that EGPA may occur after COVID-19 vaccination.

Dupilumab suppresses relapsing chronic eosinophilic pneumonia with severe asthma.

Dupilumab-induced hypereosinophilia is mediated by blockade of the IL-4/IL-13 pathway, which reduces eosinophil migration from peripheral blood. The increase in peripheral blood eosinophils may lead to chronic eosinophilic pneumonia (CEP) and/or eosinophilic granulomatosis with polyangiitis, but a direct causal connection between dupilumab and eosinophilic lung diseases has not been established. A 33-year-old Japanese woman with bronchial asthma since age three was treated with fluticasone propionate plus salmeterol twice daily after several asthma exacerbations at age 17. Her course was complicated by CEP at age 33 which resolved without the need for systemic steroids. However, in the four months following resolution of her CEP, the patient had three asthma exacerbations, and a recurrence of CEP, with blood leukocytes of 8500/µL, of which 25.0% were eosinophils. She was treated with prednisolone 50 mg/day, but she could not continue this dose due to the onset of myalgia. Then she had relapsing CEP twice within three months. She was treated with prednisolone 15 mg/day for CEP, but she had persistent asthma for more than one month; dupilumab was added at 600 mg, followed by 300 mg every two weeks. In the first month of treatment with dupilumab, the patient's asthma symptoms resolved completely, and she had only one relapse of CEP. In 12 months of follow-up, she had neither an asthma exacerbation nor another relapse of CEP. Dupilumab may be a promising treatment for patients with refractory asthma complicated by recurring CEP and undesirable steroid side effects.

Eosinophilic granulomatosis with polyangiitis: sequential use of mepolizumab following rituximab for inadequate asthma control despite vasculitis remission.

We report the case of a 54-year-old woman with antineutrophilic cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis presenting with mononeuritis multiplex, intestinal hemorrhage, cardiomyopathy, fever, and worsening asthma symptoms. She was initially treated with steroids and cyclophosphamide but eventually required rituximab to control a vasculitis flare. However, her asthmatic symptoms did not improve, despite attaining vasculitis remission. Symptoms abated only after the treatment transition to mepolizumab. After a 1-year interval, there were no further episodes of asthma exacerbation and no requirement for systemic steroid therapy. This report reinforces the use of rituximab for induction and maintenance of remission in patients with eosinophilic granulomatosis with polyangiitis and predominant vasculitic manifestations, whereas mepolizumab demonstrated better control of the persistent eosinophilic manifestations, ensuing sustained remission and improved quality of life.

[Anti-IL-5 in severe asthma associated with eosinophilic granulomatosis with polyangiitis. Real-life study]. / Anti-IL-5 dans l'asthme sévère associé à une granulomatose éosinophilique avec polyangéite. Étude en vie réelle.

INTRODUCTION: Eosinophilic granulomatosis with polyangiitis (EGPA) is a form of necrotizing vasculitis affecting small vessels and typically characterized by severe glucocorticoid (GC)-dependent eosinophilic asthma. While mepolizumab, which is indicated at a dose of 100mg/4weeks in severe eosinophilic asthma, has been shown to be an effective treatment for EGPA-related asthma at a dose of 300mg/4weeks, it was only recently approved at this dose. METHODS: This retrospective, single-center, observational study was conducted to investigate over a 5-year period (2014-2019) the effect of mepolizumab 100mg/4weeks at 12months in patients with EGPA and glucocorticoid-dependant severe asthma. Response to treatment was defined as reduction in daily dose of oral corticosteroids to at most 5mg/day or reduction in annual exacerbation by at least 50%. RESULTS: Thirty patients were included, of whom twenty-three were treated (two were not fully evaluable). Among the 21 evaluable treated patients, 13 (62%) had responded at 12months. At baseline, non-responders had lower FEV1 levels and lower blood eosinophil levels than responders. CONCLUSIONS: Mepolizumab at a "severe asthma" dose (100mg/4weeks) is effective in treatment of GC-dependent severe asthma in most patients with EGPA.

Characteristics and Disease Burden of Patients With Eosinophilic Granulomatosis With Polyangiitis Initiating Mepolizumab in the United States.

BACKGROUND/OBJECTIVE: Although the high disease burden associated with eosinophilic granulomatosis with polyangiitis (EGPA) has been established, the disease burden in patients initiating mepolizumab in real-world practice is poorly understood. This study aimed to assess characteristics and burden of real-world patients with EGPA initiating mepolizumab. METHODS: This was a database study (GSK study ID: 214156) of US patients (≥12 years old) with EGPA and ≥1 mepolizumab claim (index date) identified from the Merative MarketScan Commercial and Medicare Supplemental Databases (November 1, 2015, to March 31, 2020). Outcomes assessed in the 12-month baseline period before index (inclusive) included patient characteristics, treatment use, EGPA relapses, asthma exacerbations, health care resource utilization, and costs. RESULTS: In the 103 patients included (mean age, 51.1 years; 63.1% female), the most common manifestations were asthma (89.3%), chronic sinusitis (57.3%), and allergic rhinitis (43.7%). In total, 91.3% of patients had ≥1 oral corticosteroid (OCS) claim (median dose, 7.4 mg/d prednisone-equivalent), 45.6% were chronic OCS users (≥10 mg/d during the 90 days preindex), 99.0% had ≥1 EGPA-related relapse, and 62.1% ≥1 asthma exacerbation. During the baseline period, 26.2% and 97.1% of patients had EGPA-related inpatient admissions and office visits, respectively. Median all-cause total health care costs per patient were $33,298, with total outpatient costs ($16,452) representing the largest driver. CONCLUSIONS: Before initiating mepolizumab, a substantial real-world EGPA disease burden is evident for patients, with resulting impact on health care systems, and indicative of unmet medical needs. Mepolizumab treatment, with a demonstrated positive clinical benefit-risk profile may represent a useful treatment option for reducing EGPA disease burden.

Dupilumab for relapsing or refractory sinonasal and/or asthma manifestations in eosinophilic granulomatosis with polyangiitis: a European retrospective study.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is often associated with glucocorticoid-dependent asthma and/or ear, nose and throat (ENT) manifestations. When immunosuppressants and/or mepolizumab are ineffective, dupilumab could be an option. We describe the safety and efficacy of off-label use of dupilumab in relapsing and/or refractory EGPA. PATIENTS AND METHODS: We conducted an observational multicentre study of EGPA patients treated with dupilumab. Complete response was defined by Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone dose ≤4 mg/day, and partial response by BVAS=0 and prednisone dose >4 mg/day. Eosinophilia was defined as an eosinophil count >500/mm3. RESULTS: Fifty-one patients were included. The primary indication for dupilumab was disabling ENT symptoms in 92%. After a median follow-up of 13.1 months, 18 patients (35%) reported adverse events (AEs), including two serious AEs. Eosinophilia was reported in 34 patients (67%), with a peak of 2195/mm3 (IQR 1268-4501) occurring at 13 weeks (IQR 4-36) and was associated with relapse in 41%. Twenty-one patients (41%) achieved a complete response and 12 (24%) a partial response. Sixteen (31%) patients experienced an EGPA relapse while on dupilumab, which was associated with blood eosinophilia in 14/16 (88%) patients. The median eosinophil count at the start of dupilumab was significantly lower in relapsers than in non-relapsers, as was the median time between stopping anti-IL-5/IL-5R and switching to dupilumab. CONCLUSION: These results suggest that dupilumab may be effective in treating patients with EGPA-related ENT manifestations. However, EGPA flares occurred in one-third of patients and were preceded by eosinophilia in 88%, suggesting that caution is required.

Eosinophilic granulomatosis polyangiitis (EGPA) complicated with periaortitis, precipitating role of dupilumab? A case report a review of the literature.

Eosinophilic granulomatosis with polyangiitis (EGPA) is an ANCA-associated vasculitis that affects small size vessels. Only four cases of periaortitis associated with EGPA have been reported in the literature. We report the case of a 67-year-old woman with EGPA who developed periaortitis 11 months after the initiation of dupilumab for uncontrolled asthma with hypereosinophilia. Complete remission of the periaortitis, and of EGPA, was obtained after switching from dupilumab to mepolizumab combined with oral prednisone therapy. Dupilumab has been associated with hypereosinophilia, that is usually asymptomatic and transitory, but symptomatic cases including EGPA were exceptionally reported. Although causality has not yet been established, caution is advisable when prescribing dupilumab for uncontrolled asthma with features that might suggest EGPA.

New-onset severe eosinophilic granulomatosis with polyangiitis following the third dose of mRNA COVID-19 vaccine: A case report.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a complex multifactorial disease that results in multisystemic inflammation of the small- and medium-sized arteries. The exact pathogenesis of this syndrome is poorly understood, but it is postulated to result from a combination of eosinophilic dysfunction, genetic predisposition, and the development of autoantibodies after exposure to an unknown stimulus. We describe a case of new-onset EGPA following the third dose of the Pfizer-BioNTech mRNA vaccine in an infection-naive middle-aged man with a background history of allergic respiratory symptoms. The patient developed acute onset of mononeuritis multiplex, pauci-immune glomerulonephritis, and leucocytoclastic vasculitis 10 days after receiving the booster dose. His laboratory markers including eosinophil count, antineutrophil cytoplasmic antibodies, and renal function tests improved markedly after the initiation of pulse steroid therapy and rituximab infusion. However, his peripheral muscle weakness and neuropathic pain did not respond to the initial therapy but improved later with intravenous cyclophosphamide and intravenous immunoglobulin. To the best of our knowledge, this is the fourth case report of post-coronavirus disease 2019 vaccination precipitation of EGPA. All reported cases including our report were in patients with previous allergic manifestations who received mRNA-based coronavirus disease 2019 vaccines, and all the patients developed mononeuritis multiplex at presentation. Despite the few reported cases of post-vaccination autoimmune phenomena, the temporal association between vaccination administration and disease onset does not indicate causality, given the mass vaccination programmes employed. However, the novel use of the mRNA platform in vaccine delivery necessitates vigilant monitoring by the scientific committee.

Successful Treatment with Mepolizumab for Coronary Spastic Angina Associated with Eosinophilic Granulomatosis with Polyangiitis.

A 46-year-old man with a history of bronchial asthma and chronic sinusitis presented to our hospital with chest pain. We suspected angina evoked by epicardial coronary spasm and performed an ergonovine provocation test to diagnose coronary spastic angina (CSA). The patient also met the diagnostic criteria for eosinophilic granulomatosis with polyangiitis (EGPA) and was treated with 60 mg prednisolone (PSL) for EGPA-associated CSA. After PSL administration, eosinophils decreased, and angina attacks disappeared. However, when PSL was tapered to 12.5 mg, chest pain recurred. We administered mepolizumab subcutaneously and chest pain disappeared. Additional mepolizumab may be effective for EGPA with CSA.

ANCA-negative eosinophilic granulomatosis with polyangiitis complicated by peripheral nerve damage: A case report.

RATIONALE: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare autoimmune disease that can affect multiple systems of the body and is characterized by asthma, blood and tissue eosinophilia, and small vascular inflammation. Eosinophilic tissue infiltration and extravascular granuloma formation can lead to any organ damage, but peripheral neuropathy is relatively rare. PATIENT CONCERNS: A 29-year-old male patient was admitted to the hospital due to fever and rash on both lower extremities for 18 days. The patient complained of muscle pain in both lower extremities, with nausea, anorexia, abdominal pain, and diarrhea. He had a 2-year history of asthma and bronchiectasis. The physical examination results were as follows: temperature, 37.8 °C; multiple patchy red rashes on both lower extremities; and no obvious abnormalities in other systems. The patient was negative for anti-neutrophil cytoplasmic antibody (ANCA). Chest computed tomography showed bilateral ground-glass opacities, small nodules, and bronchiectasis. Histopathology of rectal tissues revealed numerous eosinophilic infiltrations. One week after admission, the patient developed symptoms of peripheral nerve damage, presenting with distal weakness in both lower extremities, foot drop, cross-threshold gait, and hypoalgesia on the lateral sides of both lower legs. Electromyography showed that the motor sensory fibers of the lower extremities were damaged. DIAGNOSES: Referring to the diagnostic criteria of the American College of Rheumatology in 1990, the patient was diagnosed with systemic EGPA (vasculitic phase) with rare peripheral nerve damage. INTERVENTIONS: After diagnosis, the patient was administered oral prednisone (60 mg/d; 1.0 mg/kg/d), and cyclophosphamide (900 mg) was infused on the 5th and 18th days of hormone therapy. Prednisone was reduced to 50 mg/d 1 month thereafter. OUTCOMES: After 1+ months of treatment, most of the symptoms disappeared. Limb weakness did not improve. Currently, the patient is undergoing outpatient follow-up and is adhering to treatment. LESSONS: EGPA is a rare disease that can affect multiple systems and has diverse clinical manifestations, with no specific manifestations in the early stage. Diagnosis is difficult, and there is a high misdiagnosis rate. The rate of ANCA positivity for this disease is not high, and clinicians should consider the possibility of ANCA-negative EGPA.