Eosinophilic granulomatous polyangiitis with central nervous system involvement in children: a case report and literature review.

Objective: To explore the clinical characteristics and treatment outcomes of children with central nervous system (CNS) involvement in eosinophilic granulomatosis with polyangiitis (EGPA). Methods: A child who presented with EGPA complicated by CNS involvement was admitted to our hospital in June 2023. The clinical features were analyzed retrospectively, and relevant literatures were reviewed to provide a comprehensive overview of this condition. Results: A ten-year-old girl, who had a history of recurrent cough and asthma accompanied by peripheral blood eosinophilia for eight months, was admitted to our hospital. On admission, spotted papules were visible on her hands and feet, bilateral pulmonary rales were audible. The laboratory examination revealed that the proportion of eosinophils (EOS) exceeded 10% of white blood cells, the anti-neutrophil cytoplasmic antibody (MPO-ANCA) was positive, the immunoglobulin G level was 15.80g/L, and the immunoglobulin E level was greater than 2500.00IU/mL. The imaging examination showed multiple patchy and nodular high-density shadows in both lungs as well as sinusitis. Pulmonary function tests indicated moderate ventilation and diffusion dysfunction. Bone marrow cytology demonstrated a significant increase in the proportion of eosinophils. Skin pathology confirmed leukocytoclastic vasculitis. During the hospitalization, the child had a convulsion. The magnetic resonance imaging (MRI) scan of the brain showed multiple abnormal signal shadows in the bilateral cerebral cortex and the electroencephalogram (EEG) showed epileptic waves. Following the administration of methylprednisolone pulse therapy in combination with cyclophosphamide treatment, her cough and asthma resolved, the skin rash disappeared without any further convulsions. We found that only a young EGPA patient with CNS involvement had been previously reported. The previously reported case began with long-term fever, weight loss, and purpuric rash. Both patients responded well to treatment with glucocorticoids and cyclophosphamide, experiencing significant improvement in their clinical symptoms and normalization of their peripheral blood eosinophils. Conclusion: The diagnosis of EGPA in children can be challenging. When a child is affected by EGPA, it is essential to remain vigilant for signs of CNS involvement. The treatment with glucocorticoids and cyclophosphamide is effective in managing EGPA in children.

Eosinophilic granulomatosis with polyangiitis and its association with montelukast: a case-based review.

The association between the use of certain medications (including sulfonamides, hydralazine, and procainamide) and the occurrence of drug-induced lupus or hepatitis is well established. More recently, cases of immune-related adverse events ranging from inflammatory polyarthritis to necrotizing myositis in patients taking checkpoint inhibitors have been reported. However, data linking drugs to systemic vasculitis are scarce and at times debatable. Propylthiouracil, hydralazine, and minocycline have been associated with rare cases of ANCA-associated syndromes, including life-threatening pulmonary-renal syndromes and systemic polyarteritis nodosa-like diseases. Eosinophilic granulomatosis with polyangiitis (EGPA) has been reported in patients taking leukotriene inhibitors. Since the link between the use of leukotriene inhibitors and occurrence of EGPA remains highly controversial, we performed a literature review for cases of EGPA in patients taking montelukast without prior history of oral corticosteroid use. We found 24 cases, along with our own two cases described, making 26 cases in total. The mean age was 43 and a majority (18/26) were female. In majority of cases EGPA-like disease never relapsed after they were taken off leukotriene inhibitors suggesting a clear causal relationship between the use of these drugs and occurrence of eosinophil-rich systemic EGPA.

Proteinase 3-specific antineutrophil cytoplasmic antibody-associated vasculitis.

Proteinase 3 (PR3)-specific antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is one of two major ANCA-associated vasculitis variants and is pathogenically linked to granulomatosis with polyangiitis (GPA). GPA is characterised by necrotising granulomatous inflammation that preferentially affects the respiratory tract. The small vessel vasculitis features of GPA are shared with microscopic polyangiitis. Necrotising granulomatous inflammation of GPA can lead to PR3-ANCA and small vessel vasculitis via activation of neutrophils and monocytes. B cells are central to the pathogenesis of PR3-ANCA-associated vasculitis. They are targeted successfully by remission induction and maintenance therapy with rituximab. Relapses of PR3-ANCA-associated vasculitis and toxicities associated with current standard therapy contribute substantially to remaining mortality and damage-associated morbidity. More effective and less toxic treatments are sought to address this unmet need. Advances with cellular and novel antigen-specific immunotherapies hold promise for application in autoimmune disease, including PR3-ANCA-associated vasculitis. This Series paper describes the inter-related histopathological and clinical features, pathophysiology, as well as current and future targeted treatments for PR3-ANCA-associated vasculitis.

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.

Unexpected discovery of renal mass in a patient with granulomatosis with polyangiitis: accidental or inevitable?

Granulomatosis with polyangiitis (GPA) is an uncommon disorder that mainly involves the upper and lower respiratory tract and kidney, presenting as sinusitis, saddle nose, otitis media, pulmonary nodule and cavity, rapidly progressive glomerulonephritis. It also affects skin, eye, heart, joint and nervous system. Renal involvement in GPA is commonly manifested as necrotising glomerulonephritis, while renal mass is very rare. We herein present two hospitalised cases with fever, pulmonary cavity and renal mass. Clinical course and examinations of the cases, from symptoms to diagnosis, will be discussed in detail, along with a relevant literature review of this unusual renal manifestation.

Significance of clinical-immunological patterns and diagnostic yield of biopsies in microscopic polyangiitis and granulomatosis with polyangiitis.

BACKGROUND: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are the two major antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). OBJECTIVES: To characterize a homogenous AAV cohort and to assess the impact of clinicopathological profiles and ANCA serotypes on clinical presentation and prognosis. Clinical differences in GPA patients according to ANCA serotype and the diagnostic yield for vasculitis of biopsies in different territories were also investigated. RESULTS: This retrospective study (2000-2021) included 152 patients with AAV (77 MPA/75 GPA). MPA patients (96.1% myeloperoxidase [MPO]-ANCA and 2.6% proteinase 3 [PR3]-ANCA) presented more often with weight loss, myalgia, renal involvement, interstitial lung disease (ILD), cutaneous purpura, and peripheral nerve involvement. Patients with GPA (44% PR3-ANCA, 33.3% MPO, and 22.7% negative/atypical ANCA) presented more commonly with ear, nose, and throat and eye/orbital manifestations, more relapses, and higher survival than patients with MPA. GPA was the only independent risk factor for relapse. Poor survival predictors were older age at diagnosis and peripheral nerve involvement. ANCA serotypes differentiated clinical features in a lesser degree than clinical phenotypes. A mean of 1.5 biopsies were performed in 93.4% of patients in different territories. Overall, vasculitis was identified in 80.3% (97.3% in MPA and 61.8% in GPA) of patients. CONCLUSIONS: The identification of GPA presentations associated with MPO-ANCA and awareness of risk factors for relapse and mortality are important to guide proper therapeutic strategies in AAV patients. Biopsies of different affected territories should be pursued in difficult-to-diagnose patients based on their significant diagnostic yield.

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.).

Diagnosis and management of ANCA-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis consists of two main diseases, granulomatosis with polyangiitis and microscopic polyangiitis, and remains among the most devastating and potentially lethal forms of autoimmune inflammatory disease. Granulomatosis with polyangiitis and microscopic polyangiitis are characterised by a necrotising vasculitis that can involve almost any organ, and have generally been studied together. The diseases commonly affect the kidneys, lungs, upper respiratory tract, skin, eyes, and peripheral nerves. Granulomatous inflammation and multinucleated giant cells are key pathological hallmarks of granulomatosis with polyangiitis, but are absent in microscopic polyangiitis. Many immune system events are essential to disease aetiopathogenesis, such as activation of the alternative complement pathway, neutrophil activation via complement receptors, and the influx of inflammatory cells, including monocytes and macrophages. These cells perpetuate inflammation and lead to organ damage. During the 21st century, the management of ANCA-associated vasculitis has moved away from reliance on cytotoxic medications and towards targeted biological medications for both the induction and maintenance of disease remission. Earlier diagnosis, partly the result of more reliable ANCA testing, has led to improved patient outcomes and better survival. Reductions in acute disease-related mortality have now shifted focus to long-term morbidities related to ANCA-associated vasculitis and their treatments, such as chronic kidney disease and cardiovascular disease. Therapeutic approaches in both clinical trials and clinical practice still remain too reliant on glucocorticoids, and continued efforts to reduce toxicity from glucocorticoids remain a priority in the development of new treatment strategies.

Ileal perforation involvement in Wegener granulomatosis comorbid with COVID-19 infection: A case report and review of the literature.

RATIONALE: Granulomatosis with polyangiitis (GPA) is a systematic autoimmune disease. The typical clinical involvement of GPA entails the upper and lower respiratory tracts, and the kidneys. Gastrointestinal (GI) involvement is uncommon and unless detected and treated promptly, may lead to life-threatening complications such as perforation. We aim to review all available publications since the first description in 1982 dealing with GI perforation in patients with Wegener granulomatosis and draw attention to this serious situation. PATIENT CONCERNS: We present a 54-year-old man diagnosed with GPA who presented initially with nasal symptoms and suffered ileal perforation following Corona Virus Disease 2019 infection. We also review previously reported patients with Wegener granulomatosis who had GI perforation to investigate the perforation site and period, pathology, diagnosis, and treatment methods. DIAGNOSES AND INTERVENTIONS: The case of a GPA-diagnosed patient who presented initially with nasal symptoms and suffered ileal perforation following Corona Virus Disease 2019 infection. We recommended a renal puncture biopsy, steroids, and immunosuppressants to improve the patient condition. The patient and his family refused these treatment recommendations. OUTCOMES: Our patient exhibited continued progressive vascular inflammatory changes and eventual irreversible systemic damage. These sequelae were attributed to the patient declining prednisolone and immunosuppressant therapy. LESSONS: GI perforation is rare in GPA but severe complication. Consequently, we recommend that early diagnosis and treatment with steroid hormones and immunosuppressants for GPA patients with GI perforation.

Clinical characteristics of hypertrophic cranial pachymeningitis in granulomatosis with polyangiitis: a retrospective single-center study in China.

BACKGROUND: Hypertrophic cranial pachymeningitis (HCP) is uncommon but a poorly understood complication of granulomatosis with polyangiitis (GPA). OBJECTIVES: We conducted this retrospective study to elucidate the clinical characteristics and factors independently associated with granulomatosis with polyangiitis (GPA) complicated by hypertrophic cranial pachymeningitis (HCP) in China. METHODS: We collected the medical records of 78 patients diagnosed with GPA who were admitted to the inpatient department of Peking Union Medical College Hospital between January 2003 and September 2021. Clinical features, laboratory and radiological findings, and Birmingham Vasculitis Activity Scores (excluding meningitis score) were recorded. A binary logistic regression analysis was performed to analyze factors independently associated with GPA-related HCP. RESULTS: Headache (100%) and cranial nerve palsy (61.5%) were common manifestations of HCP. Compared to 52 GPA patients without HCP, 26 patients with HCP required more time from initial symptoms to diagnosis, with a lower ratio of pulmonary and renal involvement, a higher ratio of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) positivity, conductive or sensorineural hearing loss, mastoiditis, and decreased vision or sudden visual loss. Binary logistic regression analysis indicated that proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) negativity (OR 10.698, p = 0.001), conductive or sensorineural hearing loss (OR 10.855, p = 0.005), and decreased vision or sudden visual loss (OR 8.647, p = 0.015) were significantly associated with GPA-related HCP. Of the 26 patients, 18 received methylprednisolone pulse treatment, and 18 received intrathecal injections of dexamethasone and methotrexate. CONCLUSIONS: HCP was a severe manifestation of GPA in our study. Independent factors associated with the occurrence of HCP in patients with GPA included PR3-ANCA negativity, conductive or sensorineural hearing loss, and decreased vision or sudden visual loss. Furthermore, GPA-related HCP was associated with higher disease activity, requiring more intensive treatments.

Pituitary hypophysitis in granulomatosis with polyangiitis (GPA): a case series.

Granulomatosis with polyangiitis (GPA) rarely involves the pituitary gland. Pituitary involvement has been reported in ~ 1% of all cases of GPA. Most commonly, pituitary swelling and inflammation results in symptoms due to pituitary mass effect and arginine vasopressin deficiency. To date, there are no pituitary-specific treatment guidelines for this rare condition. We present three patients with GPA-related hypophysitis highlighting the spectrum of pituitary involvement. All three patients were successfully treated with immunosuppressive regimens that included rituximab (RTX). Following remission induction with high-dose glucocorticoids, patients received 6 monthly RTX for remission maintenance. RTX was well tolerated without significant side effects.

Disease Activity and Tendency to Relapse in ANCA-Associated Vasculitis Are Reflected in Neutrophil and Intermediate Monocyte Frequencies.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases with inflammation affecting small blood vessels and includes granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). In this study, we investigated granulocyte and monocyte subsets in a large cohort of AAV patients with emphasis on disease activity and tendency to relapse. A cohort of 105 patients with GPA or MPA and 126 healthy controls (HCs) were included. Clinical and laboratory data were collected for all patients, including disease activity, tendency to relapse, and pharmacological treatment. Using flow cytometry, circulating eosinophils, basophils, neutrophils, and monocytes were assessed. The monocytes were subdivided into classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14-CD16+) monocytes. Mature (CD16high) or newly released (CD16dim) neutrophils were defined, as well as the frequency of CD177+ neutrophils. AAV patients displayed increased frequencies of intermediate monocytes, mature and newly released neutrophils, and an expanded population of CD177+ neutrophils compared to HC. MPA patients differed from GPA patients in terms of lower frequency of classical monocytes. No differences in cell frequencies regarding ANCA phenotype were observed. Paired data from 23 patients demonstrated that active disease was associated with an increased frequency of mature neutrophils and a decreased frequency of monocytes, in particular intermediate monocytes. Moreover, GPA patients with a tendency to relapse displayed an increased frequency of mature neutrophils with increased expression of CD177+. Relapsing MPA patients, on the other hand, showed decreased frequency of intermediate monocytes. Finally, rituximab treatment was associated with increased frequencies of classical and intermediate monocytes. In conclusion, AAV patients exhibit a skewing of different neutrophil and monocyte subpopulations that are associated with disease subtypes, disease activity, rituximab treatment, and propensity to relapse. These changes may contribute to the inflammatory process and could potentially be used as biomarkers for relapse prediction.

Granulomatosis with polyangiitis presenting headache: A case report and review of literature.

RATIONALE: Central nervous system involvement is a rare manifestation of active-phaselocalized Granulomatosis with polyangiitis (GPA). In hypertrophic dura meningitis, GPA with headache is typical. In this case, cerebral magnetic resonance (MR) enhancement revealed no meningeal thickening, to our knowledge, this manifestation had not been found previously. PATIENT CONCERNS: The patient presented to the Rheumatology and Immunology Clinic with severe headache and hearing loss, and central nervous system granulomatosis with polyangiitis was confirmed after a series of examinations. The patient had no significant effect after treatment with cyclophosphamide (CTX), but after the use of rituximab, the headache and hearing loss were significantly improved, and laboratory indicators returned to normal levels. DIAGNOSIS: We comprehensively screened for craniocerebral infection and malignant tumors, diagnosed central nervous system granulomatosis with polyangiitis. INTERVENTIONS: We gave sequential treatment of rituximab. OUTCOMES: All indicators are mostly back to normal when the patient was monitored at the outpatient clinic. LESSONS: GPA and severe headache are more prevalent in hypertrophic dura meningitis, but the patient early headache could not be explained by hypertrophic dura meningitis or localized granulomatous lesions that invaded the central nervous system. Patients with severe headaches likely have vascular inflammation and local bone destruction at the base of the skull.

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.

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.