Eosinophilic granulomatosis with polyangiitis developed after dupilumab administration in patients with eosinophilic chronic rhinosinusitis and asthma: a case report.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a form of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis characterized by eosinophil-rich granulomatous inflammation and small-to-medium vessel vasculitis associated with asthma, rhinosinusitis, and eosinophilia. EGPA is often difficult to distinguish from severe asthma and eosinophilic chronic rhinosinusitis (ECRS) in cases when there are no findings that suggest vasculitis. Dupilumab, an anti-IL-4Rα monoclonal antibody, is expected to be effective in eosinophilic airway inflammatory diseases, such as refractory asthma and chronic rhinosinusitis (CRS). Although transient eosinophilia and eosinophilic pneumoniae have been reported in patients with refractory asthma and CRS associated with dupilumab, few studies have examined the development of EGPA. CASE PRESENTATION: We report a case of a 61-year-old woman treated with dupilumab for refractory ECRS and eosinophilic otitis media (EOM) complicated by severe asthma. Although she had a previous history of eosinophilic pneumoniae and myeloperoxidase (MPO) ANCA positivity, there were no apparent findings of vasculitis before the initiation of dupilumab. After the second administration of dupilumab, several adverse events developed, including worsening of ECRS, EOM and asthma, and neuropathy. A blood test showed an eosoinophilia and re-elevation of MPO-ANCA levels after the administration of dupilumab. Therefore, dupilumab was discontinued owing to the development of EGPA, and prednisolone and azathioprine administration was initiated for a remission induction therapy. CONCLUSION: To the best of our knowledge, this is the first case report that suggests that dupilumab may directly trigger the manifestation of vasculitis in patients who were previously MPO-ANCA-positive. Although the precise mechanism of how dupilumab could trigger the development of EGPA requires further elucidation, measuring MPO-ANCA in patients with multiple eosinophilic disorders before the initiation of dupilumab might be helpful when considering the possibility of a latent EGPA. When administering dupilumab to patients with a previous history of MPO-ANCA positivity, clinicians must carefully monitor and collaborate with other specialists in the pertinent fields of study for appropriate usage.

Mepolizumab-Induced Posterior Reversible Encephalopathy Syndrome (PRES), a new patient report.

BACKGROUND: Posterior Reversible Encephalopathy Syndrome (PRES) is a neurotoxic state characterized by seizures, headache, vision change, paresis, and altered mental status. PRES has an important place in medicine due to the wide variety of causative diseases, infections, and medications that precipitate its mysterious onset. Although exposure to medications, particularly immunosuppressants, cancer chemotherapy, and biologic drugs, is a common occurrence in patients who develop PRES, Mepolizumab has never before been associated. CASE PRESENTATION: This report of a 67-year-old male patient outlines the first reported case of Mepolizumab-induced PRES in the literature. CONCLUSIONS: Treatment of severe asthma, asthma-exacerbations, and diseases such as eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss) with Mepolizumab is rapidly gaining popularity ever since the drug's recent FDA-approval. This report aims to raise awareness of this potentially life-threatening and previously unreported side effect of Mepolizumab since early identification of the causative agent is the key to preventing the severe neurologic disability and possible death that may occur from the delayed treatment of PRES.

Use of Systemic Corticosteroids for Reasons Other than Asthma in Subjects with Asthma.

BACKGROUNDS: Recent studies have reported increased risks of adverse events from systemic corticosteroids even with only low-dose or short-term use. Some patients with asthma experience complications requiring systemic corticosteroids. However, few studies have examined issues associated with administration of systemic corticosteroids for reasons other than asthma among subjects with asthma. OBJECTIVES: We investigated patterns of systemic corticosteroid exposure for reasons other than asthma in subjects with asthma. METHOD: We retrospectively reviewed the records of adult subjects with asthma followed up for >1 year at Yokohama City University Hospital from January 1, 2010, to December 31, 2019. We investigated patterns and reasons for systemic corticosteroid use during follow-up. In addition, factors related to systemic corticosteroid use for reasons likely other than asthma were investigated. RESULTS: Among the 568 subjects with asthma analyzed, 326 (57.4%) had received systemic corticosteroids for some reason. Among those 326 patients, 120 (36.8%) had received systemic corticosteroids for reasons likely other than asthma. Multivariable analysis revealed rheumatoid arthritis, eosinophilic granulomatosis with polyangiitis, other collagen vascular diseases, chronic rhinosinusitis, and malignancy as positively associated with systemic corticosteroid exposure for reasons likely other than asthma in subjects with asthma. CONCLUSIONS: About 40% of systemic corticosteroid use in subjects with asthma was for reasons likely other than asthma. Clinicians should be aware of their asthma patients' exposures to systemic corticosteroids for nonasthma reasons, to avoid missing adverse events or underestimating the severity of asthma, and to reduce systemic corticosteroid use.

Programmed cell death-1 blockade in kidney carcinoma may induce eosinophilic granulomatosis with polyangiitis: a case report.

BACKGROUND: Immune checkpoint inhibitors have potential applications in treating various cancers but are associated with immune-related adverse events, such as inflammation, in a wide range of organs; however, allergic inflammation caused by these agents has not been extensively studied. CASE PRESENTATION: A 65-year-old man was diagnosed with a kidney neuroendocrine carcinoma. Three months after kidney resection surgery, the tumor cells had metastasized to his liver and lymph nodes. Subsequently, the patient started chemotherapy; however, regardless of treatment, the tumor grew, and the patient experienced a series of adverse effects, such as taste disorder, anorexia, and general fatigue. Finally, he was administered a programmed cell death (PD)-1 inhibitor, nivolumab (biweekly, toal 200 mg/body), which was effective against kidney carcinoma. However, the patient had a bronchial asthma attack at 22 cycles of nivolumab treatment and chest computed tomography (CT) revealed an abnormal bilateral shadow after 37 cycles of nivolumab treatment. Bronchoscopy findings revealed eosinophil infiltration in the lungs along with severe alveolar hemorrhage. Paranasal sinus CT scanning indicated sinusitis and nerve conduction analysis indicated a decrease in his right ulnar nerve conduction velocity. Based on these findings, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis; he was treated with prednisolone, which alleviated his bronchial asthma. To restart nivolumab treatment, the dose of prednisolone was gradually tapered, and the patient was administered a monthly dose of mepolizumab and biweekly dose of nivolumab. To date, there have been no bronchial attacks or CT scan abnormalities upon follow up. CONCLUSIONS: We present a rare case in which a patient with cancer was diagnosed with eosinophilic granulomatosis with polyangiitis following treatment with a PD-1 inhibitor. Blockade of PD-1 and the programmed cell death ligand (PD-L) 1/PD-1 and PD-L2/PD-1 signaling cascade may cause allergic inflammation. Further studies are needed to identify the specific mechanisms underlying allergic inflammation after PD-1 blockade.

Pulmonary sarcoid-like granulomatosis induced by nivolumab.

The use of antibodies against programmed death (PD)1, such as nivolumab and pembrolizumab, has dramatically improved the prognosis of patients with advanced melanoma. Nivolumab is also approved in advanced squamous cell nonsmall-cell lung cancer. These immunotherapies are associated with a unique set of toxicities termed immune-related adverse events, which are different from toxicities observed with conventional cytotoxic chemotherapy. We report the case of a 56-year-old man who was diagnosed with metastatic melanoma and who received nivolumab. One week after the second infusion, he developed pulmonary symptoms, dry eye syndrome and a bilateral swelling of the parotid glands. Investigations were negative for infection. The bronchoalveolar lavage differential cell count showed 32% lymphocytes with an increased CD4 : CD8 ratio, and bronchial biopsies revealed noncaseating epithelioid granulomas, without malignant cells. The clinical and radiological courses were rapidly favourable with oral corticosteroid. This case illustrates that sarcoidosis can be induced by nivolumab treatment. With the increasing use of anti-PD1 inhibitors in patients with advanced melanoma and squamous cell nonsmall-cell lung cancer, clinicians should be aware of this potential associated immune-related adverse event.

Development of eosinophilic granulomatosis with poliangiitis (Churg-Strauss syndrome) and brain tumor in a patient after more than 7 years of omalizumab use: A case report.

Omalizumab is a monoclonal anti-immunoglobulin E antibody used for the treatment of severe perennial allergic asthma. Previous reports have suggested that omalizumab treatment can be associated with the development of eosinophilic granulomatosis with poliangiitis (EGPA) (formerly known as Churg-Strauss syndrome) and an increased risk of malignancy. Long-term risks of omalizumab treatment are not very well defined. Here, we report the case of a 75-year-old woman with concurrent occurrence of EGPA and brain tumor after more than 7 years of omalizumab treatment. The possibility of EGPA should be borne in mind during long-term treatment with omalizumab. Despite the absence of definitive data, an association may also exist between the development of malignancy and omalizumab use.

Novel finding of carbamazepine induced gall bladder granulomatous vasculitis.

We report a 63-year-old male patient who presented with eosinophilic granulomatous vasculitis of the gall bladder secondary to carbamazepine drug therapy. Following commencement of carbamazepine for treatment of partial seizures, the patient developed an allergic cutaneous drug rash. He continued to take carbamazepine postdischarge despite cessation by the treating team. He represented 7 weeks later with acute pancreatitis and cholecystis. Gall bladder histopathology showed a granulomatous vasculitis.

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.

Cytomegalovirus and rheumatic diseases: cases-based review.

Cytomegalovirus (CMV) infection is a common and typically benign disease in immunocompetent individuals. However, immunocompromised patients are at a greater risk of reactivation, leading to more severe outcomes. Patients with rheumatic diseases have a particularly high risk of opportunistic infections due to both the inherent immunosuppressive state conveyed by the disease itself and the use of potent immunosuppressant drugs, such as glucocorticoids, cyclophosphamide, and rituximab. Limited data are available regarding prophylactic or preemptive treatment of CMV infection in patients with rheumatic diseases. In this article the authors present two cases of rheumatic conditions complicated by CMV infection. The first case describes a patient with eosinophilic granulomatosis with polyangiitis, previously treated with glucocorticoids and cyclophosphamide, who developed CMV colitis with bowel perforation. The second case involves a woman with systemic lupus erythematosus who was diagnosed with CMV meningitis. Both cases reinforce the importance of establishing guidelines for surveillance and prophylaxis of CMV infection in these patients.

Advances in the maintenance of ANCA vasculitis remission.

The maintenance treatment of ANCA-associated vasculitides (AAVs) has benefited from the results of several prospective clinical trials focusing on the evaluation of new drugs, therapeutic strategies, and adjuvant treatments. They also showed that rituximab was the most effective agent to maintain remission. However, because treatments can induce adverse events, including facilitating infections, therapeutic strategies should be adapted to find the optimal dose(s) and their administration duration(s) and to make them commensurate to the expected severity of relapse. That task is not easy to achieve because we have not yet been able to identify the clinical or biological parameters that can predict when a relapse will occur and its severity. Among AAVs, eosinophilic granulomatosis with polyangiitis (EGPA) has pathogenic and clinical specificities, and new drugs directly address those features. If rituximab could have a place such as in other AAVs, anti-IL5 biotherapies could also be prescribed successfully for maintenance. Another aim of vasculitis maintenance therapy is to control the disease with less prednisone than in the past. Herein, we emphasize the importance of individually devising a maintenance regimen adapted to the objectives of keeping the patient in remission without the adverse events related to the prescribed treatment(s).

A case of Churg-Strauss syndrome treated with montelukast.

OBJECTIVE: To report a case of Churg-Strauss syndrome who had asthma and allergic rhinitis treated with montelukast. CLINICAL PRESENTATION AND INTERVENTION: A nonsmoking 59-year-old woman presented with fever, hemoptysis and dyspnea. Past medical history included allergic rhinitis and asthma which were diagnosed 18 years ago. The asthma was treated successfully with inhaled salmeterol and beclamethasone. She also received montelukast (10 mg/day) for 3 years. Although her chest X-ray was normal a week earlier, she had widespread bilateral pulmonary infiltrates on admission. She had leukocytosis (12.5 × 10(9)/l) with eosinophilia (15.6%). Her total IgE count was 550 U/ml. Testing for protoplasmic-staining antineutrophil cytoplasmic antibodies was positive. Bronchoalveolar lavage could not be performed due to bronchospasm and severe hypoxemia; however, mucosal biopsies were obtained, which revealed eosinophil leukocytes in the lumen and walls of small vessels. She was diagnosed to have Churg-Strauss syndrome and had remarkable clinical improvement on day 5 with high-dose of oral prednisolone (50 mg/day). Radiological improvement was detected at the end of the second week. CONCLUSION: This case shows the importance of being aware that leukotriene receptor antagonists could cause Churg-Strauss syndrome, in spite of the uncertainty about its mechanism.

Churg-Strauss syndrome related to montelukast.

A young male with complaints of cough, dyspnea and hemoptysis was admitted. He was using fluticasone propionate and salmeterol for two years for his asthma. Leukotriene receptor antagonist was prescribed two weeks prior to his admission and no reduction of his inhaled steroid therapy was performed. Eosinophil count was detected as 1460/mm³ (15%) and immunoglobulin E level was 547 IU/mL. Thorax computerized tomography revealed patchy infiltration. Increased eosinophilic inflammation were detected in bronchoalveolar lavage fluid and transbronchial biopsy. He received prednisolone treatment for Churg-Strauss syndrome. Improvement was observed on three months follow up period. He has no complaint in his follow up.

Churg-Strauss and montelukast.

Churg-Strauss syndrome (CSS) is a systemic small vessel vasculitis involving lungs, skin, heart, gastrointestinal tract and peripheral nerves. We report the case of a 36-year-old woman with a necrotic lesion on the left foot of two months duration, associated with hypereosinophilia, patchy lung infiltrates, cardiac damage and a mononeuritis. The personal history was remarkable only for an asthma, treated with Montelukast, a leukotriene receptor antagonist (LRA). Clinical symptoms, laboratory exams and instrumental examinations led us to the diagnosis of CSS. In recent years several studies have reported the possible relationship between use of leukotriene receptor antagonist (LRA) and CSS expression. We report this case to underline the possible relationship between LRA and CSS and its etiopathogenetic mechanism.

Omalizumab-associated eosinophilic granulomatosis with polyangiitis: cause or coincidence?

Omalizumab is an anti-IgE monoclonal antibody used in severe allergic asthma. Herein, we describe a case of eosinophilic granulomatosis with polyangiitis, which manifested 3 months after initiation of omalizumab therapy, while maintenance corticosteroid therapy dose was unchanged.