Perspective on the Budgetary Impact of FP/FORM pMDI on Treatment and Management of Exacerbation in Moderate-to-Severe Asthma Patients in Singapore.

PURPOSE: Reducing the risk of exacerbation is a long-term goal of managing moderate-to-severe asthma. The use of fluticasone propionate/formoterol fumarate dihydrate (FP/FORM) pressurized metered-dose (pMDI, Flutiform®), a type of inhaled corticosteroid (ICS) and long-acting ß2 agonist (LABA) fixed-dose combination, has been associated with lower oral corticosteroid-requiring exacerbation rates than other ICS/LABA fixed-dose combinations, fluticasone propionate/salmeterol xinafoate (FP/SAL) and budesonide/formoterol fumarate (BUD/FORM). This study presents the first budget impact analysis of drug and exacerbation management cost savings associated with the increased access to FP/FORM compared to the currently available ICS/LABAs for treating moderate-to-severe asthma in Singapore. PATIENTS AND METHODS: A budget impact model showed changes to annual drug and exacerbation costs over 5 years for patients with moderate-to-severe asthma in Singapore, following the inclusion of FP/FORM on a government subsidy list. The eligible patient population was identified based on national statistics data. Different treatment costs pertaining to the population were applied according to the usage data (IQVIA Singapore National Sales Data) for different scenarios. Drug costs were obtained from public-sector hospitals. Exacerbation management costs were obtained from literature searches. RESULTS: The analysis showed that increased access to FP/FORM as a result of switching from FP/SAL could help achieve drug (S$1,042,289) and exacerbation management (S$223,550) cost savings over 5 years. In the scenario where patients switched from BUD/FORM, greater drug (S$2,572,797) and exacerbation management (S$256,781) cost savings were observed over 5 years. CONCLUSION: The analysis provides a perspective that the increased access to FP/FORM could help achieve drug and exacerbation cost savings for the treatment of moderate-to-severe asthma.

CD137 signaling in Hodgkin and Reed-Sternberg cell lines induces IL-13 secretion, immune deviation and enhanced growth.

CD137 and its ligand, CD137L, are expressed on activated T cells and antigen-presenting cells (APC), respectively, and are powerful inducers of cellular, type 1 immune responses. CD137 is ectopically expressed by Hodgkin and Reed-Sternberg (HRS) cells, the malignant cells in Hodgkin lymphoma (HL). Here we report that CD137 transmits signals into HRS cells, which induce the secretion of IL-13. IL-13 in conditioned supernatants of HRS cell lines inhibits the secretion of IFNγ by peripheral blood mononuclear cells (PBMC). Since IFNγ is essential for the development of a type 1 immune response, CD137-induced IL-13 secretion facilitates escape from immune surveillance. Further, CD137-induced IL-13 enhances the growth of HRS cell lines. CD137, IL-13 double-positive cells could be detected in the majority (58%) of HL patient samples, providing clinical evidence for a role of IL-13 induction by CD137 during HL pathogenesis. This study validates CD137 as a candidate target for immunotherapy of HL.

Ectopic CD137 expression facilitates the escape of Hodgkin and Reed-Sternberg cells from immunosurveillance.

CD137 is ectopically expressed on Hodgkin and Reed-Sternberg (HRS) cells, causing the removal of the immunostimulatory CD137 ligand from HRS cells as well as from surrounding antigen presenting cells. This inhibits T-cell co-stimulation and supports the immune evasion of Hodgkin's lymphoma.

Expression of CD137 on Hodgkin and Reed-Sternberg cells inhibits T-cell activation by eliminating CD137 ligand expression.

Hodgkin lymphoma is caused by a minority population of malignant Hodgkin and Reed-Sternberg (HRS) cells that recruit an abundance of inflammatory cells. The long-term survival of HRS cells among the vast majority of immune cells indicates that they have developed potent immune escape mechanisms. We report that the TNF receptor family member CD137 (TNFRSF9) is expressed on HRS cells, while normal B cells, from which HRS cells are most often derived, do not express CD137. In 48 of 53 cases of classical Hodgkin lymphoma, CD137 was detected on HRS cells. Ectopically expressed CD137 transferred by trogocytosis from HRS cells to neighboring HRS and antigen-presenting cells, which constitutively express the CD137 ligand (CD137L and TNFSF9), became associated with CD137L and the CD137-CD137L complex was internalized. Disappearance of CD137L from the surface of HRS and antigen-presenting cells led to reduced costimulation of T cells through CD137, reducing IFN-γ release and proliferation. Our results reveal a new regulatory mechanism for CD137L expression that mediates immune escape by HRS cells, and they identify CD137 as a candidate target for immunotherapy of Hodgkin lymphoma.