RARE DISEASE
Eosinophilic granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis
Synonyms: Churg-Strauss syndrome, EGPA, Granulomatous allergic angiitis
Synonyms: Churg-Strauss syndrome, EGPA, Granulomatous allergic angiitis
Synonyms: Churg-Strauss syndrome, EGPA, Granulomatous allergic angiitis
Drug discovery
5
drugs
With orphan designations
Overview
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare ANCA-associated vasculitis characterized by eosinophilic inflammation, necrotizing granulomas, and small-to-medium vessel vasculitis. It typically progresses through three phases: allergic (asthma, sinusitis), eosinophilic (organ infiltration), and vasculitic (neuropathy, purpura). ANCA positivity occurs in 30–40% of cases, often linked to glomerulonephritis. Multisystem involvement includes respiratory (95% asthma), cardiac (leading cause of death), and gastrointestinal systems [1][6][10][11].
Burden
Morbidity: 35% relapse within 5 years; 26% develop new vasculitic manifestations (e.g., mononeuritis multiplex, cardiomyopathy) [5][18].
Healthcare: 19% require EGPA-related hospitalization (median 11 days); 39% receive ≥5 OCS prescriptions/year [2][9][10].
Comorbidities: Asthma (80.6%), nasal polyps (32.1%), and cardiac involvement (up to 50% mortality if untreated) [1][2][15].
Therapies
First-line: High-dose corticosteroids (≥47% OCS dependence post-diagnosis) ± immunosuppressants (cyclophosphamide, azathioprine) [3][9][15].
Biologics: Mepolizumab (anti-IL-5) for refractory/relapsing disease; rituximab (anti-CD20) in ANCA-positive cases [8][13][17].
Relapse management: Chronic low-dose corticosteroids; monitoring for hypogammaglobulinemia with biologics [3][8][13].
Categories: rare cardiac diseases, rare circulatory system diseases, rare neurological diseases, rare renal diseases, rare respiratory diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood, rare transplant-related disorders
Research Papers
1,327 drug discovery papers about Eosinophilic granulomatosis with polyangiitis, with 2 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,327 drug discovery papers about Eosinophilic granulomatosis with polyangiitis, with 2 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-04 | The Past, the Present, and the Future of Periostin in Allergy.
Periostin is a matricellular protein that binds to its receptors, which include several integrin molecules but mainly αvβ3 integrin on cell surfaces, thereby transducing its signals into cells. Almost 20 years have passed since we found that periostin is involved in the pathogenesis of asthma, which marked the first evidence of its involvement in allergic diseases. Over the past 2 decades, cumulative evidence has demonstrated that periostin plays important roles in the onset or progress of many allergic diseases such as chronic rhinitis with nasal polyp, atopic dermatitis (AD), allergic conjunctivitis, eosinophilic esophagitis, eosinophilic otitis media, allergic rhinitis, and eosinophilic granulomatosis with polyangiitis. Starting from the observation of highly expressed periostin in the lesions of these diseases, periostin studies have expanded to include how periostin contributes to the generation of allergic phenotypes, how measurement of periostin is useful as a biomarker for allergic diseases, and recently how periostin inhibitors can improve allergic diseases. Periostin contributes to the generation of allergic phenotypes by acting as a matricellular protein on many cells, including both non-immune and immune cells. Based on the characteristics of periostin as a surrogate biomarker of interleukin-13, a signature cytokine of type 2 inflammation, serum periostin has been used as a biomarker for stratifying endotypes, estimating disease severity, predicting or monitoring the efficacy of therapeutic drugs, and predicting disease relapse or recurrence. Moreover, a lot of attention is now being paid to periostin in body fluids such as tears and sputum as a biomarker directly reflecting type 2 inflammation. Since it has been shown that periostin evokes itch in AD, we hope to see the development of a novel therapeutic agent for AD targeting periostin/αvβ3 integrin. Here we summarize the discovery and characteristics of periostin, as well as questions and/or problems regarding periostin that remain to be resolved.
2026-08-03 | Clinical spectrum and outcomes of mononeuritis multiplex in rheumatic diseases: evidence from a nationwide multicenter study.
Mononeuritis multiplex (MM) is a severe and clinically heterogeneous form of peripheral neuropathy, most commonly arising in the context of systemic vasculitis in rheumatology practice. Despite its potential to cause substantial functional impairment, data on its clinical spectrum, management, and outcomes remain limited. This study aimed to comprehensively evaluate the clinical characteristics, underlying etiologies, treatment approaches, and outcomes of MM in a nationwide multicenter rheumatology cohort. Retrospective, multicenter observational study. Adult patients diagnosed with MM by rheumatologists across 27 tertiary referral centers were included. Data were collected using a standardized case report form, encompassing demographic features, clinical presentation, electrophysiological findings, laboratory parameters, treatment modalities, and outcomes. Neurological status was assessed at the final follow-up visit. A total of 72 patients were analyzed (mean age 53.5 ± 14.9 years; 61.1% male). Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis was the most common underlying etiology (68%), with eosinophilic granulomatosis with polyangiitis being the predominant subtype. The typical clinical presentation consisted of acute-onset, asymmetric, distal involvement of the lower extremities, with foot drop as the most frequent manifestation (69.4%). Electrophysiological findings were consistent with a classical MM pattern in the majority of patients. Most patients received high-dose glucocorticoids combined with immunosuppressive therapy. Over a median follow-up of 29 months, 81.9% of patients achieved complete or partial neurological improvement. Outcomes were similar between ANCA-associated and non-ANCA-related diseases. MM represents a clinically diverse but potentially manageable neurological complication of rheumatic diseases. Early recognition supported by electrophysiological assessment, together with timely immunosuppressive treatment, may improve clinical outcomes. A multidisciplinary approach is essential to optimize long-term recovery and functional status.
2026-03-01 | RARE ASSOCIATION: CASE REPORT OF CUTANEOUS LEISHMANIASIS AND EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS
A 49-year-old woman, previously healthy, was admitted with a 3-month history of fever associated with a painful ulcerated lesion on the right leg. Initially, she had an erythematous papule treated with topical dexamethasone, followed by several antibiotics, without favorable clinical response. She also reported ventilatory-dependent chest pain. On admission, she had an approximately 10-cm ulcerated lesion on the right leg with friable, partially necrotic borders and abundant purulent discharge, as well as a satellite lesion (3 cm). Pulmonary examination revealed decreased breath sounds on the left, and anterior rhinoscopy showed a nasal polyp. Due to suspicion of cutaneous leishmaniasis with secondary bacterial infection, empirical vancomycin and piperacillin-tazobactam were started, without clinical improvement. Chest CT showed bilateral pleural effusion and pericardial effusion. Thoracentesis revealed a lymphocytic exudative pleural effusion with eosinophilia (21%), negative cytology and no infectious agents. With persistent fever, chest pain and eosinophilic pleural effusion, CT angiography was performed, ruling out pulmonary embolism. Urinalysis showed hematuria. ANA and p-ANCA were nonreactive; c-ANCA was 1:80. Blood count showed eosinophilia, peaking at 1,772/mm³. Skin lesion biopsy revealed fibrinoid necrosis and dense inflammatory infiltrate suggesting vasculitis, and PCR for leishmaniasis was positive. Specific treatment with miltefosine was started, without satisfactory response. Repeat thoracentesis showed an increased proportion of eosinophils (48%) in pleural fluid. Pleural biopsy revealed mixed inflammatory infiltrate, predominantly neutrophilic, with scattered eosinophils. Microbiologic tests and special stains were negative. In light of therapeutic refractoriness, peripheral eosinophilia (>1,000/mm³), nasal polyp and necrotic skin lesion with eosinophils, the diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) was made based on the 2022 ACR/EULAR classification criteria. Methylprednisolone pulse therapy was initiated for 3 days with favorable clinical response. Associations between infectious agents and immune-mediated diseases have been described, with leishmaniasis reported as associated with or a trigger for diseases such as Takayasu arteritis and adult-onset Still’s disease; however, there are no reports of EGPA associated with leishmaniasis, making this the first case described in the literature.
2026-02-03 | NS-229, a novel Janus kinase 1 inhibitor, ameliorates eosinophilic vasculitis in an ovalbumin-induced mouse model by modulating multiple cytokine signaling pathways.
Methyl (1-{[6-{[(1S)-1-cyclopropylethyl]amino}-2-(pyrazolo[5,1-b][1,3]thiazol-7-yl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)carbamate mono(4-methylbenzenesulfonate) monohydrate (NS-229) is a novel Janus kinase 1 inhibitor currently being evaluated in a phase 2 global study (NCT06046222) for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). We investigated the nonclinical efficacy of NS-229 to support its therapeutic use in treating EGPA. Its effects were investigated in human peripheral blood eosinophils, human peripheral blood mononuclear cells, and a mouse model of eosinophilic vasculitis induced by ovalbumin. In human peripheral blood eosinophils, NS-229 and an anti-interleukin (IL)-5 antibody, but not prednisolone, significantly decreased the expression of CD69 induced by IL-5. In human peripheral blood mononuclear cells, NS-229 and prednisolone, but not the anti-IL-5 antibody, significantly decreased the production of cytokines such as interferon gamma, IL-5, and IL-13, induced by anti-CD3/CD28 antibody. NS-229 inhibited the development of vascular lesions, decreased eosinophil counts in the blood and bronchoalveolar lavage fluid, and lowered bronchoalveolar lavage fluid lymphocyte counts in the ovalbumin-induced eosinophilic vasculitis mouse model. The effects of NS-229 in the mouse model were comparable to those of prednisolone and tofacitinib, a pan-Janus kinase inhibitor. Regarding safety, NS-229 did not influence the platelet or red blood cell counts, which were significantly elevated with tofacitinib and prednisolone, respectively. NS-229 did not affect body weight, which was significantly increased with tofacitinib and significantly decreased with prednisolone. Collectively, the nonclinical investigation of NS-229 showed a suppression of multiple cytokine signals and inhibition of vascular lesion formation without impacting the relevant side-effect parameters, suggesting its potential as an additional treatment option for EGPA. SIGNIFICANCE STATEMENT: NS-229 inhibited the formation of vascular lesions in a mouse model of ovalbumin-induced eosinophilic vasculitis without affecting certain side-effect parameters. The underlying mechanism of action is suggested to be the selective inhibition of multiple cytokine signals via JAK1.
2026-02-02 | Case Report: Triple autoimmune overlap: rheumatoid arthritis, systemic lupus erythematosus, and hypereosinophilic asthma with systemic manifestations.
Overlap between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) ("rhupus") is recognized, but coexistence with a severe eosinophilic asthma syndrome is exceptionally rare. We describe a triple autoimmune overlap of RA, SLE, and hypereosinophilic asthma with systemic manifestations (HASM), initially managed as ANCA-negative eosinophilic granulomatosis with polyangiitis (EGPA) and subsequently re-classified in light of evolving concepts. A 44-year-old woman with a 10-year history of seropositive RA developed alopecia, Coombs-positive hemolytic anemia, hypocomplementemia, and ANA and anti-Sm positivity, fulfilling SLE criteria. While receiving prednisone, hydroxychloroquine and conventional DMARDs, she subsequently developed adult-onset asthma, chronic rhinosinusitis with nasal polyps, and marked hypereosinophilia (>3.5×109/L). Secondary causes were excluded; bone marrow showed reactive eosinophilia and ANCA (indirect immunofluorescence and ELISA for MPO/PR3) remained negative. She was diagnosed and treated as ANCA-negative EGPA with high-dose glucocorticoids plus methotrexate and hydroxychloroquine, leading to rapid normalization of eosinophils and durable remission of asthma and sinus disease. In retrospect, and according to the ERS/GERM'O'P proposal, this eosinophilic disorder is best classified as HASM within the EGPA-hypereosinophilic spectrum because ANCA and biopsy-proven vasculitis were absent. The case illustrates the evolving boundary between EGPA and hypereosinophilic syndromes and extends the concept of rhupus to include an EGPA-spectrum eosinophilic asthma syndrome. New-onset eosinophilic asthma in patients with established rheumatic disease should prompt evaluation for EGPA-spectrum or hypereosinophilic disorders. Even when the final label is HASM rather than definite EGPA, timely institution of EGPA-type immunosuppression may avert organ damage.
antibodies
2026-08-08 | Eosinophilic granulomatosis with polyangiitis complicated by pulmonary aspergillosis and misdiagnosed as allergic bronchopulmonary aspergillosis: a case report.
To enhance the diagnostic and therapeutic awareness of eosinophilic granulomatosis with polyangiitis (EGPA) complicated by pulmonary aspergillosis. We report a case of EGPA initially misdiagnosed as allergic bronchopulmonary aspergillosis (ABPA) in a 52-year-old female patient. The patient presented with intermittent wheezing for more than six months and had a history of sinusitis. An outside hospital diagnosed ABPA based on pulmonary opacities, bronchiectasis, and evidence of Aspergillus infection, but standard therapy proved ineffective. Upon admission, laboratory findings revealed a markedly elevated absolute peripheral blood eosinophil count (5.29 × 109/L) and positivity for MPO-ANCA and p-ANCA. Serum total IgE was 8.85 IU/mL, and specific IgE to Aspergillus fumigatus was <0.10 IU/mL, both of which were inconsistent with ABPA. Chest CT showed multiple bilateral patchy and nodular opacities with bronchiectasis. Bronchoalveolar lavage fluid targeted next-generation sequencing (tNGS) detected Aspergillus at the genus level (23 sequence reads, relative abundance 33.39%). The diagnosis was revised to EGPA complicated by pulmonary aspergillosis. The patient was treated with glucocorticoids combined with mepolizumab, supplemented with voriconazole. Following treatment, the patient's symptoms resolved, with near normalization of imaging findings and pulmonary function. After 10 months of follow-up, methylprednisolone was completely discontinued in December 2025, and at the last follow-up in May 2026, the patient had been off glucocorticoids for 5 months, with sustained remission and successful extension of the mepolizumab dosing interval to 8 weeks. For patients presenting with refractory asthma accompanied by eosinophilia and pulmonary opacities, EGPA should be highly suspected. Glucocorticoids combined with mepolizumab is effective. In patients achieving sustained remission, extending the mepolizumab dosing interval to 8 weeks may be a safe and effective long-term maintenance strategy in carefully selected patients, though this observation requires further validation in prospective studies.
2026-08-05 | Advances in the treatment of eosinophilic granulomatosis with polyangiitis.
Eosinophilic granulomatosis with polyangiitis (EGPA) is a small-vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies and characterized by blood and tissue eosinophilia, severe respiratory manifestations, and multiorgan involvement. The management of newly diagnosed EGPA still relies on therapeutic strategies that were initially validated for other forms of anti-neutrophil cytoplasmic antibody-associated vasculitis, including microscopic polyangiitis and granulomatosis with polyangiitis. Whereas the long-term prognosis of microscopic polyangiitis and granulomatosis with polyangiitis depends primarily on controlling initial organ involvement and preventing relapses, EGPA is distinguished by chronic involvement of both upper and lower respiratory airways, which often necessitates prolonged glucocorticoid therapy. Data from clinical trials suggest that targeting the IL-5 pathway with mepolizumab or benralizumab can effectively control persistent respiratory symptoms and reduce the need for glucocorticoids, yet the role of these agents in the management of EGPA at the time of diagnosis and in the long term remains to be defined. Emerging retrospective data on therapies targeting other type 2 cytokines (such as IL-4, IL-13 and thymic stromal lymphopoietin) suggest potential benefits for relapsing respiratory symptoms; however, prospective evidence remains limited and safety has yet to be established. This Review discusses the role of these new targeted therapies in the management of EGPA, alongside historical treatments.
2026-08-04 | Clinical outcomes after switching from mepolizumab to benralizumab in eosinophilic granulomatosis with polyangiitis: A single-centre retrospective cohort study.
To investigate the impact of switching to benralizumab on flare risk in patients with eosinophilic granulomatosis with polyangiitis (EGPA) previously treated with mepolizumab. We conducted a single-centre retrospective cohort study including 26 patients with EGPA who received mepolizumab. A landmark analysis was performed at 910 days after mepolizumab initiation (median time to switching), and patients were grouped according to treatment. The primary outcome was disease flares requiring treatment intensification. We used a Cox model with treatment switching as a time-dependent covariate. In the landmark analysis, the benralizumab group (n=4) had a higher flare rate than the mepolizumab group (n=10) (log-rank test, P = 0.002). However, the Cox model did not converge and the time-dependent analysis yielded an imprecise estimate (hazard ratio 3.14, 95% confidence interval 0.31-32.02). The 1-year flare-free rate after switching to benralizumab (n=19) was 94.1%, and no severe flares occurred. Most patients had low disease activity at switching, and switching was primarily driven by patient preference. Short-term flare-free survival after switching to benralizumab was high despite a small number of minor flares. Further evidence is warranted to assess long-term outcomes.
2026-07-30 | Case Report: Benralizumab-induced remission in adolescent-onset ANCA-positive eosinophilic granulomatosis with polyangiitis.
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis characterized by asthma, eosinophilia, and multi-organ involvement. Adolescent-onset disease is uncommon, and evidence guiding biologic therapy in this population remains limited. We report the case of an 18-year-old female with a history of chronic rhinosinusitis and eosinophilic asthma who presented with worsening asthma control, arthralgia, and peripheral eosinophilia (4, 600 cells/μL), with palpable purpura developing during hospitalization. Chest radiography was initially unremarkable, but chest computed tomography revealed peripheral ground-glass opacities and consolidations. Further workup demonstrated eosinophil-rich perivascular infiltrates with karyorrhectic debris without necrotizing vasculitis on skin biopsy, and high-titer anti-myeloperoxidase (anti-MPO) antibodies >200 RU/mL on immunologic testing. The diagnosis of EGPA was established according to the 2022 ACR/EULAR classification criteria with a total score of 10. Initial treatment with high-dose corticosteroids resulted in partial improvement, but the disease relapsed during tapering, indicating corticosteroid dependence. Benralizumab was subsequently introduced, leading to rapid eosinophil depletion, improved pulmonary function, successful corticosteroid reduction, and prompt clinical remission. At 12-month follow-up, the patient remained in complete remission, with normalized pulmonary function, no evidence of new organ involvement, and a marked decline in anti-MPO antibody titers. This case highlights the importance of considering EGPA in adolescents presenting with difficult-to-control eosinophilic asthma and systemic manifestations, and demonstrates that benralizumab can achieve stable, long-term remission with successful corticosteroid reduction even in ANCA-positive disease.
2026-07-23 | Case Report: From misdiagnosis to successful treatment using mepolizumab in ANCA-negative severe EGPA-clinical lessons in eosinophil-targeted therapy.
This paper presents the complex diagnostic course and treatment of a 33-year-old female patient with anti-neutrophil cytoplasmic antibodies (ANCA)-negative eosinophilic granulomatosis with polyangiitis (EGPA). The patient initially presented with asthma and chronic rhinosinusitis. After treatment with omalizumab and glucocorticoids, she progressed to severe EGPA with multi-organ involvement. Following discontinuation of omalizumab and initiation of mepolizumab (300 mg every 4 weeks), her symptoms resolved, and glucocorticoids were tapered. This case suggests that mepolizumab could be effective for inducing and maintaining remission in ANCA-negative severe EGPA with multi-organ involvement. Exposure to omalizumab in undiagnosed EGPA may either mask or unmask disease progression. Clinicians should carefully evaluate for EGPA before initiating biologic therapy in patients with asthma. Furthermore, we successfully extended the mepolizumab dosing interval to 8 weeks with sustained remission, providing preliminary, hypothesis-generating evidence that interval extension of MEP may be considered as a potential de-escalation strategy for maintenance therapy in stable EGPA.
proteins
2023-10-20 | Interactions between Siglec-8 and endogenous sialylated cis ligands restrain cell death induction in human eosinophils and mast cells
Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is a sialoside-binding receptor expressed by eosinophils and mast cells that exhibits priming status- and cell type-dependent inhibitory activity. On eosinophils that have been primed with IL-5, GM-CSF, or IL-33, antibody ligation of Siglec-8 induces cell death through a pathway involving the β2 integrin-dependent generation of reactive oxygen species (ROS) via NADPH oxidase. In contrast, Siglec-8 engagement on mast cells inhibits cellular activation and mediator release but reportedly does not impact cell viability. The differences in responses between cytokine-primed and unprimed eosinophils, and between eosinophils and mast cells, to Siglec-8 ligation are not understood. We previously found that Siglec-8 binds to sialylated ligands present on the surface of the same cell (so-called cis ligands), preventing Siglec-8 ligand binding in trans. However, the functional relevance of these cis ligands has not been elucidated. We therefore explored the potential influence of cis ligands of Siglec-8 on both eosinophils and mast cells. De-sialylation using exogenous sialidase profoundly altered the consequences of Siglec-8 antibody engagement on both cell types, eliminating the need for cytokine priming of eosinophils to facilitate cell death and enabling Siglec-8–dependent mast cell death without impacting anti–Siglec-8 antibody binding. The cell death process licensed by de-sialylation resembled that characterized in IL-5–primed eosinophils, including CD11b upregulation, ROS production, and the activities of Syk, PI3K, and PLC. These results implicate cis ligands in restraining Siglec-8 function on eosinophils and mast cells and reveal a promising approach to the selective depletion of mast cells in patients with mast cell-mediated diseases.
2023-03-07 | Activation of a Latent Epitope Causing Differential Binding of Antineutrophil Cytoplasmic Antibodies to Proteinase 3
Objective Proteinase 3 (PR3) is the major antigen for antineutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3‐targeting ANCAs (PR3‐ANCAs) recognize different epitopes on PR3. This study was undertaken to study the effect of mutations on PR3 antigenicity. Methods The recombinant PR3 variants, iPR3 (clinically used to detect PR3‐ANCAs) and iHm5 (containing 3 point mutations in epitopes 1 and 5 generated for epitope mapping studies) immunoassays and serum samples from patients enrolled in ANCA‐associated vasculitis (AAV) trials were used to screen for differential PR3‐ANCA binding. A patient‐derived monoclonal ANCA 518 (moANCA518) that selectively binds to iHm5 within the mutation‐free epitope 3 and is distant from the point mutations of iHm5 was used as a gauge for remote epitope activation. Selective binding was determined using inhibition experiments. Results Rather than reduced binding of PR3‐ANCAs to iHm5, we found substantially increased binding of the majority of PR3‐ANCAs to iHm5 compared to iPR3. This differential binding of PR3‐ANCA to iHm5 is similar to the selective moANCA518 binding to iHm5. Binding of iPR3 to monoclonal antibody MCPR3‐2 also induced recognition by moANCA518. Conclusion The preferential binding of PR3‐ANCAs from patients, such as the selective binding of moANCA518 to iHm5, is conferred by increased antigenicity of epitope 3 on iHm5. This can also be induced on iPR3 when captured by monoclonal antibody MCPR2. This previously unrecognized characteristic of PR3‐ANCA interactions with its target antigen has implications for studying antibody‐mediated autoimmune diseases, understanding variable performance characteristics of immunoassays, and design of potential novel treatment approaches. image
2022-01-12 | Secretory Leukocyte Protease Inhibitor Is Present in Circulating and Tissue-Recruited Human Eosinophils and Regulates Their Migratory Function
Eosinophils and secretory leukocyte protease inhibitor (SLPI) are both associated with Th2 immune responses and allergic diseases, but whether the fact that they are both implicated in these conditions is pathophysiologically related remains unknown. Here we demonstrate that human eosinophils derived from normal individuals are one of the major sources of SLPI among circulating leukocytes. SLPI was found to be stored in the crystalline core of eosinophil granules, and its dislocation/rearrangement in the crystalline core likely resulted in changes in immunostaining for SLPI in these cells. High levels of SLPI were also detected in blood eosinophils from patients with allergy-associated diseases marked by eosinophilia. These include individuals with eosinophilic granulomatosis with polyangiitis (EGPA) and atopic dermatitis (AD), who were also found to have elevated SLPI levels in their plasma. In addition to the circulating eosinophils, diseased skin of AD patients also contained SLPI-positive eosinophils. Exogenous, recombinant SLPI increased numbers of migratory eosinophils and supported their chemotactic response to CCL11, one of the key chemokines that regulate eosinophil migratory cues. Together, these findings suggest a role for SLPI in controlling Th2 pathophysiologic processes via its impact on and/or from eosinophils.
2021-05-11 | Danger-associated molecular pattern molecules and the receptor for advanced glycation end products enhance ANCA-induced responses
The pro-inflammatory activities of the calgranulins and HMGB1 can be counteracted by sRAGE, the soluble form of their shared receptor. To understand the role of these molecules in AAV and their potential as therapeutic targets we have studied (i) the relationship between these DAMPS and disease activity; (ii) the expression of RAGE and sRAGE in biopsy tissue and peripheral blood; and (iii) the effect of these molecules on ANCA-mediated cytokine production.We examined circulating levels of calgranulins (S100A8/A9 and S100A12), HMGB1 and sRAGE by ELISA. RAGE was examined in AAV kidney and lung biopsies by immunohistochemistry and RAGE expression was monitored in peripheral blood by qPCR. In vitro, the effect of co-stimulating PBMC with ANCA and S100A8/A9 on cytokine production was studied by ELISA.We found significantly raised levels of calgranulins and HMGB1 in active AAV regardless of clinical phenotype (PR3+/MPO+ AAV). Levels of calgranulins showed significant correlations with each other. RAGE protein and message was raised in peripheral blood and in cells infiltrating kidney and lung biopsy tissue, while sRAGE was lowered. Furthermore, ANCA-mediated production of IL-8 from PBMC was significantly enhanced by the presence of S100A8/A9 in a RAGE/TLR4-dependent manner.Raised circulating calgranulins provide a good marker of disease activity in AAV and are unlikely to be counteracted by sRAGE. Increased RAGE expression in AAV indicates receptor stimulation in active disease that may exacerbate ANCA-induced cytokine production. Targeting the RAGE pathway may provide a useful therapeutic approach in AAV.
2017-04-15 | Interferon-α for Induction and Maintenance of Remission in Eosinophilic Granulomatosis with Polyangiitis: A Single-center Retrospective Observational Cohort Study
Objective. Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by frequent relapses following induction therapy. Interferon-α (IFN-α) can reverse the underlying Th2-driven immune response and has successfully induced remission in previous reports. We undertook this study to investigate its efficacy and safety in patients with EGPA. Methods. We conducted a retrospective monocentric cohort study including 30 patients (16 women) with active EGPA under IFN-α treatment. Primary endpoints were remission induction, occurrence of relapses, prednisolone (PSL) dosage at time of remission, and adverse events. Remission was defined by a Birmingham Vasculitis Activity Score (BVAS) of 0. Pulmonary function tests were recorded at baseline and at time of remission. Health-related quality of life was analyzed by questionnaire at baseline and following 12 months of treatment. Results. At baseline, the median BVAS was 6 (interquartile range 4–13.5) and remission or partial response was achieved in 25/30 patients. After initiation of IFN-α treatment, the median PSL dosages could be reduced from 17.5 mg/day at baseline to 5.5 mg/day at time of remission. Following remission, 17 relapses (5 major) in 16 patients were observed. Pulmonary function tests improved and the time of hospitalization decreased. Adverse events at initiation of treatment were common, but mostly transient. Severe adverse events occurred during treatment in 4 patients (autoimmune hepatitis, n = 1; drug-induced neuropathy, n = 3). Conclusion. IFN-α treatment results in high rate of remission and maintenance in EGPA with significant reduction in oral corticosteroids, although reversible adverse events may occur. IFN-α represents an alternative therapeutic option in cases of refractory to standard treatment.
cell therapies
2024-09-17 | Mesenchymal stem cell therapy in eosinophilic granulomatosis with polyangiitis-related lower limb gangrene: a case report.
Eosinophilic granulomatosis with polyangiitis (EGPA), a rare but life-threatening systemic vasculitis, is distinguished by marked eosinophilia and presents with diverse symptoms, including asthma, cutaneous purpura, ecchymosis, skin necrosis, cardiac lesions, peripheral neuropathy, and necrotizing vasculitis. The etiology of EGPA involves a complex interaction among humoral, adaptive, innate, and allergic immune responses. Standard treatment employs prolonged high-dose glucocorticoid therapy, which is critical for survival; however, some patients' symptoms cannot be relieved. This case report details the medical management of an 11-year-old patient with EGPA, who was at risk of bilateral lower limb amputation due to differential arterial occlusion and severe, necrotizing vasculitis-induced gangrene in both feet. Treatment modalities administered included systemic infusion of Umbilical Cord Mesenchymal Stem Cells (UC-MSCs), targeted gastrocnemius muscle injections, and application of a Placenta-Derived Mesenchymal Stem Cells (PD-MSCs) hydrogel. After receiving a four-month regimen of allogeneic mesenchymal stem cell therapy via intravenous and local administration, the patient showed normalized eosinophil counts, reestablished blood flow in the dorsal arteries, and marked improvement in foot ulcerations. Mesenchymal stem cell therapy is a promising option for severe EGPA cases refractory to glucocorticoids.
2023-05-30 | POS1169 RECOVERY AND LONG-TERM RENAL OUTCOME OF PATIENTS WITH ANCA-ASSOCIATED VASCULITIS WHO ARE ON DIALYSIS AT PRESENTATION
Renal involvement in ANCA-associated vasculitis (AAV) can lead to severe renal dysfunction requiring dialysis at the time of diagnosis. Studies have demonstrated that a significant proportion of patients could discontinue dialysis after treatment, with dialysis recovery-associated factors including kidney pathology such as proportion of normal glomeruli and extent of tubular atrophy or interstitial fibrosis. However, these works focused on short-term outcomes within 6–12 months after AAV diagnosis (1, 2). Research reporting if patients who discontinued dialysis resumed during long-term follow-up are lacking. We assessed the clinical and pathologic characteristics of patients with AAV dependent on dialysis at presentation and the long-term renal outcomes of those who recovered after dialysis. This retrospective study analyzed the data of patients diagnosed with AAV who were on dialysis at baseline from July 2005 to May 2021 at a single tertiary center in Korea. Medical records, including renal function and dependence on dialysis, were obtained. We included 34 patients on dialysis at the time of AAV diagnosis in this study. The median age was 64.5 years, and 61.8% were female. Among all patients, 13 discontinued dialysis and 21 remained dialysis dependent. The proportions of normal glomeruli (p<0.001) and interstitial fibrosis (p=0.024) were significantly different between the two groups. The multivariable analysis revealed that the proportion of normal glomeruli tended to be associated with dialysis discontinuation (OR=1.34, 95% CI 0.88–1.27, p=0.068). Treatment modalities, including plasmapheresis, were not significantly associated with dialysis discontinuation. In the follow-up analysis of 13 patients who had discontinued dialysis for a median of 81 months, 12 did not resume dialysis, and their glomerular filtration rate values had significantly increased at follow-up compared with at dialysis cessation (37.5 [28.5–45.5] vs. 24.0 [18.5–30.0] mL/min/1.73 m², p=0.008). Approximately 38% of AAV patients discontinued dialysis, and the recovered patients had improved renal function without dialysis. Thus, patients with AAV on dialysis should be considered for dialysis discontinuation and renal recovery, especially those with normal glomeruli in kidney pathology. [1]J Am Soc Nephrol. 2007 Jul;18(7):2189-97 [2]Semin Arthritis Rheum. 2013 Apr;42(5):515-21 NIL. None Declared.
2023-02-01 | Successful treatment with rituximab and plasmapheresis of renal involvement of eosinophilic granulomatosis with polyangiitis
Abstract Background Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare disorder characterized by asthma, eosinophilia, and systemic vasculitis. Renal involvement is not regarded as a prominent feature and the treatment is still under study. Case presentation A 68-year-old woman was admitted to our hospital because of fever, renal dysfunction, eosinophilia, and the presence of MPO-ANCA. Based on the renal pathological examination which showed extravascular eosinophilic-predominant inflammation and crescentic glomerulonephritis, EGPA was diagnosed. Considering the acute kidney injury, prominent eosinophilia, and strongly positive anti-MPO antibodies, pulse steroid therapy was administered, followed by intravenous rituximab. Plasmapheresis was also provided (9 sessions). The eosinophil count was normalized, and renal dysfunction was reversed. The patient no longer requires dialysis. Conclusions Renal involvement of EGPA is rare, and consensus on its treatment is still lacking, because of a lack of large-scale randomized controlled trials. We treated our patient as a case with high severity. For patients with severe disease, the addition of cyclophosphamide to glucocorticoid therapy is commonly used. However, rituximab and plasmapheresis combined with systemic glucocorticoid therapy were found to be beneficial because the renal function and other clinical conditions were almost fully recovered. Thus, our treatment is highly effective against renal involvement of eosinophilic granulomatosis with polyangiitis.
2022-08-31 | Oral and Lower Extremity Ulcers as the Initial Presentation of Granulomatosis with Polyangiitis
Granulomatosis with polyangiitis (GPA) is a small vessel vasculitis characterized by lung and kidney involvement. It is typically a disease of white females and has a poor prognosis with the average life expectancy of 5 months for a patient without treatment. Oral and skin ulcers are considered to be rare presentations.A 39-year-old black male presented to the hospital with oral and skin ulcers and was diagnosed with GPA based on the biopsies of both cutaneous lesions and kidney. He was started on rituximab with minimal improvement. Later he was admitted to the ICU and had plasmapheresis, and he gradually improved and was discharged home 8 days after admission.GPA is an aggressive vascular disorder resulting in possible organ system damage and failure. The role of the sickle cell trait in this patient is undefined, but this combination of gender, race, and presenting symptoms in GPA is extremely unusual.
2022-05-19 | ANCA-Associated Vasculitis: Value of Apheresis in Initial Treatment
Introduction: Vasculitis associated with anti-neutrophil cytoplasm antibodies (ANCA) can be grouped with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MAP), and eosinophilic granulomatosis with polyangiitis (EGPA). Diagnosis of these rare pathologies is based on clinical presentation, the positivity of ANCA, and, if possible, histological proof of vasculitis. Our study describes a series of six cases of ANCA-associated vasculitis where due to the severity of symptoms apheresis sessions were started from the beginning of the therapy. Patients and methods: We conducted a retrospective, single-center observational, monocentric study on all patients treated by apheresis for ANCA vasculitis in the period January 01, 2016 to December 01, 2019. Results: We identified six cases of ANCA vasculitis treated by apheresis over a 3-year period. The mean age was 61 ± 19 years; M/F gender ratio was 1:1. Initial renal damage in all patients was rapidly progressive glomerulonephritis. Inflammatory syndrome occurred in all patients with average CRP of 82 mg/L. All patients had positive ANCA at diagnosis. Four patients required renal replacement therapy at the time of diagnosis. The induction regimen consisted of rituximab associated with IV boluses of methylprednisolone. The apheresis techniques used were the same for all patients, i.e. plasmapheresis. Outcomes were favorable for five patients; only one patient became dependent on hemodialysis. No mortality occurred. Conclusion: This study analyzed practices for the management of patients with ANCA vasculitis. No patient was treated with cyclophosphamide as a first approach but rituximab instead. Plasmapheresis was given because of symptoms severity at initial diagnosis.
small molecules
2026-08-04 | The Past, the Present, and the Future of Periostin in Allergy.
Periostin is a matricellular protein that binds to its receptors, which include several integrin molecules but mainly αvβ3 integrin on cell surfaces, thereby transducing its signals into cells. Almost 20 years have passed since we found that periostin is involved in the pathogenesis of asthma, which marked the first evidence of its involvement in allergic diseases. Over the past 2 decades, cumulative evidence has demonstrated that periostin plays important roles in the onset or progress of many allergic diseases such as chronic rhinitis with nasal polyp, atopic dermatitis (AD), allergic conjunctivitis, eosinophilic esophagitis, eosinophilic otitis media, allergic rhinitis, and eosinophilic granulomatosis with polyangiitis. Starting from the observation of highly expressed periostin in the lesions of these diseases, periostin studies have expanded to include how periostin contributes to the generation of allergic phenotypes, how measurement of periostin is useful as a biomarker for allergic diseases, and recently how periostin inhibitors can improve allergic diseases. Periostin contributes to the generation of allergic phenotypes by acting as a matricellular protein on many cells, including both non-immune and immune cells. Based on the characteristics of periostin as a surrogate biomarker of interleukin-13, a signature cytokine of type 2 inflammation, serum periostin has been used as a biomarker for stratifying endotypes, estimating disease severity, predicting or monitoring the efficacy of therapeutic drugs, and predicting disease relapse or recurrence. Moreover, a lot of attention is now being paid to periostin in body fluids such as tears and sputum as a biomarker directly reflecting type 2 inflammation. Since it has been shown that periostin evokes itch in AD, we hope to see the development of a novel therapeutic agent for AD targeting periostin/αvβ3 integrin. Here we summarize the discovery and characteristics of periostin, as well as questions and/or problems regarding periostin that remain to be resolved.
2026-08-03 | Clinical spectrum and outcomes of mononeuritis multiplex in rheumatic diseases: evidence from a nationwide multicenter study.
Mononeuritis multiplex (MM) is a severe and clinically heterogeneous form of peripheral neuropathy, most commonly arising in the context of systemic vasculitis in rheumatology practice. Despite its potential to cause substantial functional impairment, data on its clinical spectrum, management, and outcomes remain limited. This study aimed to comprehensively evaluate the clinical characteristics, underlying etiologies, treatment approaches, and outcomes of MM in a nationwide multicenter rheumatology cohort. Retrospective, multicenter observational study. Adult patients diagnosed with MM by rheumatologists across 27 tertiary referral centers were included. Data were collected using a standardized case report form, encompassing demographic features, clinical presentation, electrophysiological findings, laboratory parameters, treatment modalities, and outcomes. Neurological status was assessed at the final follow-up visit. A total of 72 patients were analyzed (mean age 53.5 ± 14.9 years; 61.1% male). Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis was the most common underlying etiology (68%), with eosinophilic granulomatosis with polyangiitis being the predominant subtype. The typical clinical presentation consisted of acute-onset, asymmetric, distal involvement of the lower extremities, with foot drop as the most frequent manifestation (69.4%). Electrophysiological findings were consistent with a classical MM pattern in the majority of patients. Most patients received high-dose glucocorticoids combined with immunosuppressive therapy. Over a median follow-up of 29 months, 81.9% of patients achieved complete or partial neurological improvement. Outcomes were similar between ANCA-associated and non-ANCA-related diseases. MM represents a clinically diverse but potentially manageable neurological complication of rheumatic diseases. Early recognition supported by electrophysiological assessment, together with timely immunosuppressive treatment, may improve clinical outcomes. A multidisciplinary approach is essential to optimize long-term recovery and functional status.
2026-03-01 | RARE ASSOCIATION: CASE REPORT OF CUTANEOUS LEISHMANIASIS AND EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS
A 49-year-old woman, previously healthy, was admitted with a 3-month history of fever associated with a painful ulcerated lesion on the right leg. Initially, she had an erythematous papule treated with topical dexamethasone, followed by several antibiotics, without favorable clinical response. She also reported ventilatory-dependent chest pain. On admission, she had an approximately 10-cm ulcerated lesion on the right leg with friable, partially necrotic borders and abundant purulent discharge, as well as a satellite lesion (3 cm). Pulmonary examination revealed decreased breath sounds on the left, and anterior rhinoscopy showed a nasal polyp. Due to suspicion of cutaneous leishmaniasis with secondary bacterial infection, empirical vancomycin and piperacillin-tazobactam were started, without clinical improvement. Chest CT showed bilateral pleural effusion and pericardial effusion. Thoracentesis revealed a lymphocytic exudative pleural effusion with eosinophilia (21%), negative cytology and no infectious agents. With persistent fever, chest pain and eosinophilic pleural effusion, CT angiography was performed, ruling out pulmonary embolism. Urinalysis showed hematuria. ANA and p-ANCA were nonreactive; c-ANCA was 1:80. Blood count showed eosinophilia, peaking at 1,772/mm³. Skin lesion biopsy revealed fibrinoid necrosis and dense inflammatory infiltrate suggesting vasculitis, and PCR for leishmaniasis was positive. Specific treatment with miltefosine was started, without satisfactory response. Repeat thoracentesis showed an increased proportion of eosinophils (48%) in pleural fluid. Pleural biopsy revealed mixed inflammatory infiltrate, predominantly neutrophilic, with scattered eosinophils. Microbiologic tests and special stains were negative. In light of therapeutic refractoriness, peripheral eosinophilia (>1,000/mm³), nasal polyp and necrotic skin lesion with eosinophils, the diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) was made based on the 2022 ACR/EULAR classification criteria. Methylprednisolone pulse therapy was initiated for 3 days with favorable clinical response. Associations between infectious agents and immune-mediated diseases have been described, with leishmaniasis reported as associated with or a trigger for diseases such as Takayasu arteritis and adult-onset Still’s disease; however, there are no reports of EGPA associated with leishmaniasis, making this the first case described in the literature.
2026-02-03 | NS-229, a novel Janus kinase 1 inhibitor, ameliorates eosinophilic vasculitis in an ovalbumin-induced mouse model by modulating multiple cytokine signaling pathways.
Methyl (1-{[6-{[(1S)-1-cyclopropylethyl]amino}-2-(pyrazolo[5,1-b][1,3]thiazol-7-yl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)carbamate mono(4-methylbenzenesulfonate) monohydrate (NS-229) is a novel Janus kinase 1 inhibitor currently being evaluated in a phase 2 global study (NCT06046222) for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). We investigated the nonclinical efficacy of NS-229 to support its therapeutic use in treating EGPA. Its effects were investigated in human peripheral blood eosinophils, human peripheral blood mononuclear cells, and a mouse model of eosinophilic vasculitis induced by ovalbumin. In human peripheral blood eosinophils, NS-229 and an anti-interleukin (IL)-5 antibody, but not prednisolone, significantly decreased the expression of CD69 induced by IL-5. In human peripheral blood mononuclear cells, NS-229 and prednisolone, but not the anti-IL-5 antibody, significantly decreased the production of cytokines such as interferon gamma, IL-5, and IL-13, induced by anti-CD3/CD28 antibody. NS-229 inhibited the development of vascular lesions, decreased eosinophil counts in the blood and bronchoalveolar lavage fluid, and lowered bronchoalveolar lavage fluid lymphocyte counts in the ovalbumin-induced eosinophilic vasculitis mouse model. The effects of NS-229 in the mouse model were comparable to those of prednisolone and tofacitinib, a pan-Janus kinase inhibitor. Regarding safety, NS-229 did not influence the platelet or red blood cell counts, which were significantly elevated with tofacitinib and prednisolone, respectively. NS-229 did not affect body weight, which was significantly increased with tofacitinib and significantly decreased with prednisolone. Collectively, the nonclinical investigation of NS-229 showed a suppression of multiple cytokine signals and inhibition of vascular lesion formation without impacting the relevant side-effect parameters, suggesting its potential as an additional treatment option for EGPA. SIGNIFICANCE STATEMENT: NS-229 inhibited the formation of vascular lesions in a mouse model of ovalbumin-induced eosinophilic vasculitis without affecting certain side-effect parameters. The underlying mechanism of action is suggested to be the selective inhibition of multiple cytokine signals via JAK1.
2026-02-02 | Case Report: Triple autoimmune overlap: rheumatoid arthritis, systemic lupus erythematosus, and hypereosinophilic asthma with systemic manifestations.
Overlap between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) ("rhupus") is recognized, but coexistence with a severe eosinophilic asthma syndrome is exceptionally rare. We describe a triple autoimmune overlap of RA, SLE, and hypereosinophilic asthma with systemic manifestations (HASM), initially managed as ANCA-negative eosinophilic granulomatosis with polyangiitis (EGPA) and subsequently re-classified in light of evolving concepts. A 44-year-old woman with a 10-year history of seropositive RA developed alopecia, Coombs-positive hemolytic anemia, hypocomplementemia, and ANA and anti-Sm positivity, fulfilling SLE criteria. While receiving prednisone, hydroxychloroquine and conventional DMARDs, she subsequently developed adult-onset asthma, chronic rhinosinusitis with nasal polyps, and marked hypereosinophilia (>3.5×109/L). Secondary causes were excluded; bone marrow showed reactive eosinophilia and ANCA (indirect immunofluorescence and ELISA for MPO/PR3) remained negative. She was diagnosed and treated as ANCA-negative EGPA with high-dose glucocorticoids plus methotrexate and hydroxychloroquine, leading to rapid normalization of eosinophils and durable remission of asthma and sinus disease. In retrospect, and according to the ERS/GERM'O'P proposal, this eosinophilic disorder is best classified as HASM within the EGPA-hypereosinophilic spectrum because ANCA and biopsy-proven vasculitis were absent. The case illustrates the evolving boundary between EGPA and hypereosinophilic syndromes and extends the concept of rhupus to include an EGPA-spectrum eosinophilic asthma syndrome. New-onset eosinophilic asthma in patients with established rheumatic disease should prompt evaluation for EGPA-spectrum or hypereosinophilic disorders. Even when the final label is HASM rather than definite EGPA, timely institution of EGPA-type immunosuppression may avert organ damage.
antibodies
2026-08-08 | Eosinophilic granulomatosis with polyangiitis complicated by pulmonary aspergillosis and misdiagnosed as allergic bronchopulmonary aspergillosis: a case report.
To enhance the diagnostic and therapeutic awareness of eosinophilic granulomatosis with polyangiitis (EGPA) complicated by pulmonary aspergillosis. We report a case of EGPA initially misdiagnosed as allergic bronchopulmonary aspergillosis (ABPA) in a 52-year-old female patient. The patient presented with intermittent wheezing for more than six months and had a history of sinusitis. An outside hospital diagnosed ABPA based on pulmonary opacities, bronchiectasis, and evidence of Aspergillus infection, but standard therapy proved ineffective. Upon admission, laboratory findings revealed a markedly elevated absolute peripheral blood eosinophil count (5.29 × 109/L) and positivity for MPO-ANCA and p-ANCA. Serum total IgE was 8.85 IU/mL, and specific IgE to Aspergillus fumigatus was <0.10 IU/mL, both of which were inconsistent with ABPA. Chest CT showed multiple bilateral patchy and nodular opacities with bronchiectasis. Bronchoalveolar lavage fluid targeted next-generation sequencing (tNGS) detected Aspergillus at the genus level (23 sequence reads, relative abundance 33.39%). The diagnosis was revised to EGPA complicated by pulmonary aspergillosis. The patient was treated with glucocorticoids combined with mepolizumab, supplemented with voriconazole. Following treatment, the patient's symptoms resolved, with near normalization of imaging findings and pulmonary function. After 10 months of follow-up, methylprednisolone was completely discontinued in December 2025, and at the last follow-up in May 2026, the patient had been off glucocorticoids for 5 months, with sustained remission and successful extension of the mepolizumab dosing interval to 8 weeks. For patients presenting with refractory asthma accompanied by eosinophilia and pulmonary opacities, EGPA should be highly suspected. Glucocorticoids combined with mepolizumab is effective. In patients achieving sustained remission, extending the mepolizumab dosing interval to 8 weeks may be a safe and effective long-term maintenance strategy in carefully selected patients, though this observation requires further validation in prospective studies.
2026-08-05 | Advances in the treatment of eosinophilic granulomatosis with polyangiitis.
Eosinophilic granulomatosis with polyangiitis (EGPA) is a small-vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies and characterized by blood and tissue eosinophilia, severe respiratory manifestations, and multiorgan involvement. The management of newly diagnosed EGPA still relies on therapeutic strategies that were initially validated for other forms of anti-neutrophil cytoplasmic antibody-associated vasculitis, including microscopic polyangiitis and granulomatosis with polyangiitis. Whereas the long-term prognosis of microscopic polyangiitis and granulomatosis with polyangiitis depends primarily on controlling initial organ involvement and preventing relapses, EGPA is distinguished by chronic involvement of both upper and lower respiratory airways, which often necessitates prolonged glucocorticoid therapy. Data from clinical trials suggest that targeting the IL-5 pathway with mepolizumab or benralizumab can effectively control persistent respiratory symptoms and reduce the need for glucocorticoids, yet the role of these agents in the management of EGPA at the time of diagnosis and in the long term remains to be defined. Emerging retrospective data on therapies targeting other type 2 cytokines (such as IL-4, IL-13 and thymic stromal lymphopoietin) suggest potential benefits for relapsing respiratory symptoms; however, prospective evidence remains limited and safety has yet to be established. This Review discusses the role of these new targeted therapies in the management of EGPA, alongside historical treatments.
2026-08-04 | Clinical outcomes after switching from mepolizumab to benralizumab in eosinophilic granulomatosis with polyangiitis: A single-centre retrospective cohort study.
To investigate the impact of switching to benralizumab on flare risk in patients with eosinophilic granulomatosis with polyangiitis (EGPA) previously treated with mepolizumab. We conducted a single-centre retrospective cohort study including 26 patients with EGPA who received mepolizumab. A landmark analysis was performed at 910 days after mepolizumab initiation (median time to switching), and patients were grouped according to treatment. The primary outcome was disease flares requiring treatment intensification. We used a Cox model with treatment switching as a time-dependent covariate. In the landmark analysis, the benralizumab group (n=4) had a higher flare rate than the mepolizumab group (n=10) (log-rank test, P = 0.002). However, the Cox model did not converge and the time-dependent analysis yielded an imprecise estimate (hazard ratio 3.14, 95% confidence interval 0.31-32.02). The 1-year flare-free rate after switching to benralizumab (n=19) was 94.1%, and no severe flares occurred. Most patients had low disease activity at switching, and switching was primarily driven by patient preference. Short-term flare-free survival after switching to benralizumab was high despite a small number of minor flares. Further evidence is warranted to assess long-term outcomes.
2026-07-30 | Case Report: Benralizumab-induced remission in adolescent-onset ANCA-positive eosinophilic granulomatosis with polyangiitis.
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis characterized by asthma, eosinophilia, and multi-organ involvement. Adolescent-onset disease is uncommon, and evidence guiding biologic therapy in this population remains limited. We report the case of an 18-year-old female with a history of chronic rhinosinusitis and eosinophilic asthma who presented with worsening asthma control, arthralgia, and peripheral eosinophilia (4, 600 cells/μL), with palpable purpura developing during hospitalization. Chest radiography was initially unremarkable, but chest computed tomography revealed peripheral ground-glass opacities and consolidations. Further workup demonstrated eosinophil-rich perivascular infiltrates with karyorrhectic debris without necrotizing vasculitis on skin biopsy, and high-titer anti-myeloperoxidase (anti-MPO) antibodies >200 RU/mL on immunologic testing. The diagnosis of EGPA was established according to the 2022 ACR/EULAR classification criteria with a total score of 10. Initial treatment with high-dose corticosteroids resulted in partial improvement, but the disease relapsed during tapering, indicating corticosteroid dependence. Benralizumab was subsequently introduced, leading to rapid eosinophil depletion, improved pulmonary function, successful corticosteroid reduction, and prompt clinical remission. At 12-month follow-up, the patient remained in complete remission, with normalized pulmonary function, no evidence of new organ involvement, and a marked decline in anti-MPO antibody titers. This case highlights the importance of considering EGPA in adolescents presenting with difficult-to-control eosinophilic asthma and systemic manifestations, and demonstrates that benralizumab can achieve stable, long-term remission with successful corticosteroid reduction even in ANCA-positive disease.
2026-07-23 | Case Report: From misdiagnosis to successful treatment using mepolizumab in ANCA-negative severe EGPA-clinical lessons in eosinophil-targeted therapy.
This paper presents the complex diagnostic course and treatment of a 33-year-old female patient with anti-neutrophil cytoplasmic antibodies (ANCA)-negative eosinophilic granulomatosis with polyangiitis (EGPA). The patient initially presented with asthma and chronic rhinosinusitis. After treatment with omalizumab and glucocorticoids, she progressed to severe EGPA with multi-organ involvement. Following discontinuation of omalizumab and initiation of mepolizumab (300 mg every 4 weeks), her symptoms resolved, and glucocorticoids were tapered. This case suggests that mepolizumab could be effective for inducing and maintaining remission in ANCA-negative severe EGPA with multi-organ involvement. Exposure to omalizumab in undiagnosed EGPA may either mask or unmask disease progression. Clinicians should carefully evaluate for EGPA before initiating biologic therapy in patients with asthma. Furthermore, we successfully extended the mepolizumab dosing interval to 8 weeks with sustained remission, providing preliminary, hypothesis-generating evidence that interval extension of MEP may be considered as a potential de-escalation strategy for maintenance therapy in stable EGPA.
proteins
2023-10-20 | Interactions between Siglec-8 and endogenous sialylated cis ligands restrain cell death induction in human eosinophils and mast cells
Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is a sialoside-binding receptor expressed by eosinophils and mast cells that exhibits priming status- and cell type-dependent inhibitory activity. On eosinophils that have been primed with IL-5, GM-CSF, or IL-33, antibody ligation of Siglec-8 induces cell death through a pathway involving the β2 integrin-dependent generation of reactive oxygen species (ROS) via NADPH oxidase. In contrast, Siglec-8 engagement on mast cells inhibits cellular activation and mediator release but reportedly does not impact cell viability. The differences in responses between cytokine-primed and unprimed eosinophils, and between eosinophils and mast cells, to Siglec-8 ligation are not understood. We previously found that Siglec-8 binds to sialylated ligands present on the surface of the same cell (so-called cis ligands), preventing Siglec-8 ligand binding in trans. However, the functional relevance of these cis ligands has not been elucidated. We therefore explored the potential influence of cis ligands of Siglec-8 on both eosinophils and mast cells. De-sialylation using exogenous sialidase profoundly altered the consequences of Siglec-8 antibody engagement on both cell types, eliminating the need for cytokine priming of eosinophils to facilitate cell death and enabling Siglec-8–dependent mast cell death without impacting anti–Siglec-8 antibody binding. The cell death process licensed by de-sialylation resembled that characterized in IL-5–primed eosinophils, including CD11b upregulation, ROS production, and the activities of Syk, PI3K, and PLC. These results implicate cis ligands in restraining Siglec-8 function on eosinophils and mast cells and reveal a promising approach to the selective depletion of mast cells in patients with mast cell-mediated diseases.
2023-03-07 | Activation of a Latent Epitope Causing Differential Binding of Antineutrophil Cytoplasmic Antibodies to Proteinase 3
Objective Proteinase 3 (PR3) is the major antigen for antineutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3‐targeting ANCAs (PR3‐ANCAs) recognize different epitopes on PR3. This study was undertaken to study the effect of mutations on PR3 antigenicity. Methods The recombinant PR3 variants, iPR3 (clinically used to detect PR3‐ANCAs) and iHm5 (containing 3 point mutations in epitopes 1 and 5 generated for epitope mapping studies) immunoassays and serum samples from patients enrolled in ANCA‐associated vasculitis (AAV) trials were used to screen for differential PR3‐ANCA binding. A patient‐derived monoclonal ANCA 518 (moANCA518) that selectively binds to iHm5 within the mutation‐free epitope 3 and is distant from the point mutations of iHm5 was used as a gauge for remote epitope activation. Selective binding was determined using inhibition experiments. Results Rather than reduced binding of PR3‐ANCAs to iHm5, we found substantially increased binding of the majority of PR3‐ANCAs to iHm5 compared to iPR3. This differential binding of PR3‐ANCA to iHm5 is similar to the selective moANCA518 binding to iHm5. Binding of iPR3 to monoclonal antibody MCPR3‐2 also induced recognition by moANCA518. Conclusion The preferential binding of PR3‐ANCAs from patients, such as the selective binding of moANCA518 to iHm5, is conferred by increased antigenicity of epitope 3 on iHm5. This can also be induced on iPR3 when captured by monoclonal antibody MCPR2. This previously unrecognized characteristic of PR3‐ANCA interactions with its target antigen has implications for studying antibody‐mediated autoimmune diseases, understanding variable performance characteristics of immunoassays, and design of potential novel treatment approaches. image
2022-01-12 | Secretory Leukocyte Protease Inhibitor Is Present in Circulating and Tissue-Recruited Human Eosinophils and Regulates Their Migratory Function
Eosinophils and secretory leukocyte protease inhibitor (SLPI) are both associated with Th2 immune responses and allergic diseases, but whether the fact that they are both implicated in these conditions is pathophysiologically related remains unknown. Here we demonstrate that human eosinophils derived from normal individuals are one of the major sources of SLPI among circulating leukocytes. SLPI was found to be stored in the crystalline core of eosinophil granules, and its dislocation/rearrangement in the crystalline core likely resulted in changes in immunostaining for SLPI in these cells. High levels of SLPI were also detected in blood eosinophils from patients with allergy-associated diseases marked by eosinophilia. These include individuals with eosinophilic granulomatosis with polyangiitis (EGPA) and atopic dermatitis (AD), who were also found to have elevated SLPI levels in their plasma. In addition to the circulating eosinophils, diseased skin of AD patients also contained SLPI-positive eosinophils. Exogenous, recombinant SLPI increased numbers of migratory eosinophils and supported their chemotactic response to CCL11, one of the key chemokines that regulate eosinophil migratory cues. Together, these findings suggest a role for SLPI in controlling Th2 pathophysiologic processes via its impact on and/or from eosinophils.
2021-05-11 | Danger-associated molecular pattern molecules and the receptor for advanced glycation end products enhance ANCA-induced responses
The pro-inflammatory activities of the calgranulins and HMGB1 can be counteracted by sRAGE, the soluble form of their shared receptor. To understand the role of these molecules in AAV and their potential as therapeutic targets we have studied (i) the relationship between these DAMPS and disease activity; (ii) the expression of RAGE and sRAGE in biopsy tissue and peripheral blood; and (iii) the effect of these molecules on ANCA-mediated cytokine production.We examined circulating levels of calgranulins (S100A8/A9 and S100A12), HMGB1 and sRAGE by ELISA. RAGE was examined in AAV kidney and lung biopsies by immunohistochemistry and RAGE expression was monitored in peripheral blood by qPCR. In vitro, the effect of co-stimulating PBMC with ANCA and S100A8/A9 on cytokine production was studied by ELISA.We found significantly raised levels of calgranulins and HMGB1 in active AAV regardless of clinical phenotype (PR3+/MPO+ AAV). Levels of calgranulins showed significant correlations with each other. RAGE protein and message was raised in peripheral blood and in cells infiltrating kidney and lung biopsy tissue, while sRAGE was lowered. Furthermore, ANCA-mediated production of IL-8 from PBMC was significantly enhanced by the presence of S100A8/A9 in a RAGE/TLR4-dependent manner.Raised circulating calgranulins provide a good marker of disease activity in AAV and are unlikely to be counteracted by sRAGE. Increased RAGE expression in AAV indicates receptor stimulation in active disease that may exacerbate ANCA-induced cytokine production. Targeting the RAGE pathway may provide a useful therapeutic approach in AAV.
2017-04-15 | Interferon-α for Induction and Maintenance of Remission in Eosinophilic Granulomatosis with Polyangiitis: A Single-center Retrospective Observational Cohort Study
Objective. Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by frequent relapses following induction therapy. Interferon-α (IFN-α) can reverse the underlying Th2-driven immune response and has successfully induced remission in previous reports. We undertook this study to investigate its efficacy and safety in patients with EGPA. Methods. We conducted a retrospective monocentric cohort study including 30 patients (16 women) with active EGPA under IFN-α treatment. Primary endpoints were remission induction, occurrence of relapses, prednisolone (PSL) dosage at time of remission, and adverse events. Remission was defined by a Birmingham Vasculitis Activity Score (BVAS) of 0. Pulmonary function tests were recorded at baseline and at time of remission. Health-related quality of life was analyzed by questionnaire at baseline and following 12 months of treatment. Results. At baseline, the median BVAS was 6 (interquartile range 4–13.5) and remission or partial response was achieved in 25/30 patients. After initiation of IFN-α treatment, the median PSL dosages could be reduced from 17.5 mg/day at baseline to 5.5 mg/day at time of remission. Following remission, 17 relapses (5 major) in 16 patients were observed. Pulmonary function tests improved and the time of hospitalization decreased. Adverse events at initiation of treatment were common, but mostly transient. Severe adverse events occurred during treatment in 4 patients (autoimmune hepatitis, n = 1; drug-induced neuropathy, n = 3). Conclusion. IFN-α treatment results in high rate of remission and maintenance in EGPA with significant reduction in oral corticosteroids, although reversible adverse events may occur. IFN-α represents an alternative therapeutic option in cases of refractory to standard treatment.
cell therapies
2024-09-17 | Mesenchymal stem cell therapy in eosinophilic granulomatosis with polyangiitis-related lower limb gangrene: a case report.
Eosinophilic granulomatosis with polyangiitis (EGPA), a rare but life-threatening systemic vasculitis, is distinguished by marked eosinophilia and presents with diverse symptoms, including asthma, cutaneous purpura, ecchymosis, skin necrosis, cardiac lesions, peripheral neuropathy, and necrotizing vasculitis. The etiology of EGPA involves a complex interaction among humoral, adaptive, innate, and allergic immune responses. Standard treatment employs prolonged high-dose glucocorticoid therapy, which is critical for survival; however, some patients' symptoms cannot be relieved. This case report details the medical management of an 11-year-old patient with EGPA, who was at risk of bilateral lower limb amputation due to differential arterial occlusion and severe, necrotizing vasculitis-induced gangrene in both feet. Treatment modalities administered included systemic infusion of Umbilical Cord Mesenchymal Stem Cells (UC-MSCs), targeted gastrocnemius muscle injections, and application of a Placenta-Derived Mesenchymal Stem Cells (PD-MSCs) hydrogel. After receiving a four-month regimen of allogeneic mesenchymal stem cell therapy via intravenous and local administration, the patient showed normalized eosinophil counts, reestablished blood flow in the dorsal arteries, and marked improvement in foot ulcerations. Mesenchymal stem cell therapy is a promising option for severe EGPA cases refractory to glucocorticoids.
2023-05-30 | POS1169 RECOVERY AND LONG-TERM RENAL OUTCOME OF PATIENTS WITH ANCA-ASSOCIATED VASCULITIS WHO ARE ON DIALYSIS AT PRESENTATION
Renal involvement in ANCA-associated vasculitis (AAV) can lead to severe renal dysfunction requiring dialysis at the time of diagnosis. Studies have demonstrated that a significant proportion of patients could discontinue dialysis after treatment, with dialysis recovery-associated factors including kidney pathology such as proportion of normal glomeruli and extent of tubular atrophy or interstitial fibrosis. However, these works focused on short-term outcomes within 6–12 months after AAV diagnosis (1, 2). Research reporting if patients who discontinued dialysis resumed during long-term follow-up are lacking. We assessed the clinical and pathologic characteristics of patients with AAV dependent on dialysis at presentation and the long-term renal outcomes of those who recovered after dialysis. This retrospective study analyzed the data of patients diagnosed with AAV who were on dialysis at baseline from July 2005 to May 2021 at a single tertiary center in Korea. Medical records, including renal function and dependence on dialysis, were obtained. We included 34 patients on dialysis at the time of AAV diagnosis in this study. The median age was 64.5 years, and 61.8% were female. Among all patients, 13 discontinued dialysis and 21 remained dialysis dependent. The proportions of normal glomeruli (p<0.001) and interstitial fibrosis (p=0.024) were significantly different between the two groups. The multivariable analysis revealed that the proportion of normal glomeruli tended to be associated with dialysis discontinuation (OR=1.34, 95% CI 0.88–1.27, p=0.068). Treatment modalities, including plasmapheresis, were not significantly associated with dialysis discontinuation. In the follow-up analysis of 13 patients who had discontinued dialysis for a median of 81 months, 12 did not resume dialysis, and their glomerular filtration rate values had significantly increased at follow-up compared with at dialysis cessation (37.5 [28.5–45.5] vs. 24.0 [18.5–30.0] mL/min/1.73 m², p=0.008). Approximately 38% of AAV patients discontinued dialysis, and the recovered patients had improved renal function without dialysis. Thus, patients with AAV on dialysis should be considered for dialysis discontinuation and renal recovery, especially those with normal glomeruli in kidney pathology. [1]J Am Soc Nephrol. 2007 Jul;18(7):2189-97 [2]Semin Arthritis Rheum. 2013 Apr;42(5):515-21 NIL. None Declared.
2023-02-01 | Successful treatment with rituximab and plasmapheresis of renal involvement of eosinophilic granulomatosis with polyangiitis
Abstract Background Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare disorder characterized by asthma, eosinophilia, and systemic vasculitis. Renal involvement is not regarded as a prominent feature and the treatment is still under study. Case presentation A 68-year-old woman was admitted to our hospital because of fever, renal dysfunction, eosinophilia, and the presence of MPO-ANCA. Based on the renal pathological examination which showed extravascular eosinophilic-predominant inflammation and crescentic glomerulonephritis, EGPA was diagnosed. Considering the acute kidney injury, prominent eosinophilia, and strongly positive anti-MPO antibodies, pulse steroid therapy was administered, followed by intravenous rituximab. Plasmapheresis was also provided (9 sessions). The eosinophil count was normalized, and renal dysfunction was reversed. The patient no longer requires dialysis. Conclusions Renal involvement of EGPA is rare, and consensus on its treatment is still lacking, because of a lack of large-scale randomized controlled trials. We treated our patient as a case with high severity. For patients with severe disease, the addition of cyclophosphamide to glucocorticoid therapy is commonly used. However, rituximab and plasmapheresis combined with systemic glucocorticoid therapy were found to be beneficial because the renal function and other clinical conditions were almost fully recovered. Thus, our treatment is highly effective against renal involvement of eosinophilic granulomatosis with polyangiitis.
2022-08-31 | Oral and Lower Extremity Ulcers as the Initial Presentation of Granulomatosis with Polyangiitis
Granulomatosis with polyangiitis (GPA) is a small vessel vasculitis characterized by lung and kidney involvement. It is typically a disease of white females and has a poor prognosis with the average life expectancy of 5 months for a patient without treatment. Oral and skin ulcers are considered to be rare presentations.A 39-year-old black male presented to the hospital with oral and skin ulcers and was diagnosed with GPA based on the biopsies of both cutaneous lesions and kidney. He was started on rituximab with minimal improvement. Later he was admitted to the ICU and had plasmapheresis, and he gradually improved and was discharged home 8 days after admission.GPA is an aggressive vascular disorder resulting in possible organ system damage and failure. The role of the sickle cell trait in this patient is undefined, but this combination of gender, race, and presenting symptoms in GPA is extremely unusual.
2022-05-19 | ANCA-Associated Vasculitis: Value of Apheresis in Initial Treatment
Introduction: Vasculitis associated with anti-neutrophil cytoplasm antibodies (ANCA) can be grouped with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MAP), and eosinophilic granulomatosis with polyangiitis (EGPA). Diagnosis of these rare pathologies is based on clinical presentation, the positivity of ANCA, and, if possible, histological proof of vasculitis. Our study describes a series of six cases of ANCA-associated vasculitis where due to the severity of symptoms apheresis sessions were started from the beginning of the therapy. Patients and methods: We conducted a retrospective, single-center observational, monocentric study on all patients treated by apheresis for ANCA vasculitis in the period January 01, 2016 to December 01, 2019. Results: We identified six cases of ANCA vasculitis treated by apheresis over a 3-year period. The mean age was 61 ± 19 years; M/F gender ratio was 1:1. Initial renal damage in all patients was rapidly progressive glomerulonephritis. Inflammatory syndrome occurred in all patients with average CRP of 82 mg/L. All patients had positive ANCA at diagnosis. Four patients required renal replacement therapy at the time of diagnosis. The induction regimen consisted of rituximab associated with IV boluses of methylprednisolone. The apheresis techniques used were the same for all patients, i.e. plasmapheresis. Outcomes were favorable for five patients; only one patient became dependent on hemodialysis. No mortality occurred. Conclusion: This study analyzed practices for the management of patients with ANCA vasculitis. No patient was treated with cyclophosphamide as a first approach but rituximab instead. Plasmapheresis was given because of symptoms severity at initial diagnosis.
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Drug Discovery Landscape
5 orphan drug designations for Eosinophilic granulomatosis with polyangiitis, including 2 approved therapies.
5 orphan drug designations for Eosinophilic granulomatosis with polyangiitis, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
small molecule, selective Janus kinase (JAK) 1 inhibitor | small molecules | FDA | 2025-04-14 | — | NS Pharma, Inc. |
Methyl-(1-{[6-{[(1S)-1-cyclopropylethyl]amino}-2-(pyrazolo[5,1-b][1,3]thiazol-7-yl)-pyrimidin-4-yl]carbonyl}piperidin-4-yl)carbamate mono(4-methylbenzenesulfonate) | antibodies | EMA | 2024-01-12 | — | Syneos Health Netherlands B.V. |
benralizumab [Fasenra] | antibodies | FDA | 2018-11-21 | 2024-09-17 | AstraZeneca Pharmaceuticals LP |
Mepolizumab | antibodies | EMA | 2013-03-12 | — | Glaxosmithkline (Ireland) Limited |
mepolizumab [NUCALA] | antibodies | FDA | 2011-07-14 | 2017-12-12 | GlaxoSmithKline LLC |
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