Search

Objective Dupilumab, a monoclonal antibody specific for the human interleukin (IL)-4 receptor α, is used to treat severe asthma, especially in patients with elevated blood eosinophil counts and fractional exhaled nitric oxide (FeNO). The therapeutic response to dupilumab is highly variable. In this study, we explored new serum biomarkers to accurately predict the effect of dupilumab and examine the effect of dupilumab based on changes in the clinical parameters and cytokine levels. Methods Seventeen patients with severe asthma treated with dupilumab were enrolled. Responders, defined as those with a >0.5-point decrease in the Asthma Control Questionnaire (ACQ) score after 6 months of treatment, were included. Results There were 10 responders and 7 non-responders. Serum type 2 cytokines were equivalent between responders and non-responders; the baseline serum IL-18 level was significantly lower in responders than in non-responders (responders, 194.9±51.0 pg/mL; non-responders, 323.4±122.7 pg/mL, p=0.013). The cut-off value of IL-18 at 230.5 pg/mL could be used to distinguish non-responders from responders (sensitivity 71.4, specificity 80.0, p=0.032). Conclusion A low baseline serum IL-18 level may be a useful predictor of an unfavorable response to dupilumab in terms of the ACQ-6.

The use of biologic agents has enabled control of severe asthma, but there is a risk that eosinophilic granulomatosis with polyangiitis (EGPA) may be masked in some cases. We herein report a 71-year-old man who was administered dupilumab for 2 years to stabilize his asthma symptoms. A few months after discontinuation of dupilumab administration, an increase in the eosinophil count in peripheral blood, leg pain, and a rash appeared. Based on pathology, he was diagnosed with EGPA. EGPA in this case was considered to have become apparent due to the discontinuation of dupilumab administration.

Objective Mepolizumab, a humanized anti-interleukin-5 monoclonal antibody, is effective for treating eosinophilic severe asthma. However, there is a need for more biomarkers that can predict the patient response to mepolizumab before starting therapy. This study aimed to identify a new biomarker in the serum that is able to accurately predict the responsiveness to mepolizumab. Methods This study enrolled 11 patients who had all been diagnosed with severe eosinophilic asthma and were then administered mepolizumab every 4 weeks for at least 4 months. Blood samples were collected, and pulmonary function tests and questionnaires were administered at baseline and after 4, 8 and 16 weeks of treatment. The response to mepolizumab was then assessed based on the difference in the Asthma Quality of Life Questionnaire (AQLQ) score after 16 weeks of mepolizumab therapy compared with that at baseline. Patients with an increase in the AQLQ score of more than 0.5 were defined as responders. The cytokine levels in the blood were measured by LUMINEX 200 and ELISA. Results There were 6 responders and 5 non-responders. The responders showed a significantly lower serum level of chemokine (C-C motif) ligand 4/macrophage inflammatory protein-1β (CCL4/MIP-1β) at baseline compared to the non-responders. Receiver operating characteristic curves to distinguish responders from non-responders using the baseline serum CCL4/MIP-1β level showed a good area under the curve of 0.9. The non-responders showed a significant increase in the level of CCL4/MIP-1β after 4 weeks compared to the baseline. Conclusion A low baseline serum CCL4/MIP-1β level may be useful for predicting a good mepolizumab response in severe eosinophilic asthma.

A 77-year-old man who developed pancytopenia was administered granulocyte colony-stimulating factor (G-CSF) by another doctor, and referred to us for the evaluation of pancytopenia. He had hepatocellular carcinoma and was treated with transcatheter arterial chemoembolization (TACE) containg epirubicin (total dose: 300 mg over the last two years). Bone marrow aspiration smear demonstrated hypercellular marrow with promyelocytes. Cytogenetic analysis demonstrated del(7), t(15;17)(q22;q12), and a fluorescence in-situ hybridization (FISH) study demonstrated chimeric fusion genes of PML-RAR-alpha. He was diagnosed with therapy-related acute promyelocytic leukemia (APL), and treated with all trans-retinoic acid (ATRA). He showed the progressive accumulation of ascites with liver damage, without pulmonary symptoms of ATRA differentiation syndrome. After 60 days of ATRA treatment, complete hematological and cytogenetic responses were achieved. However, the patient died of septic circulatory failure.

A 66-year-old woman complained of fever, sore throat, and neck pain due to pharyngitis and painful lymph node swelling. CBC revealed severe pancytopenia and markedly hypocellular marrow. The administration of antibiotics and granulocyte-colony stimulating factor (G-CSF) successfully ameliorated the inflammatory lesions, and hematopoiesis recovered. Causes for pancytopnenia was unlikely to be virus infection or drugs, and aplastic anemia was also unlikely since only the plasma levels of tumor necrosis factor-alpha (TNF-alpha) was markedly elevated, erythropoietin (EPO) was slightly elevated, interferon-gamma (IFN-gamma) was normal, and flow cytometric analysis for paroxysmal nocturnal hemoglobinuria (PNH)-type cells was negative. These results suggested that the cause of impaired hematopoiesis in the present patient might have been due to elevated TNF-alpha in overwhelming infection, although the pathogen was not identified.