Cost-minimization Analysis of IgPro20, a Subcutaneous Immunoglobulin, in Japanese Patients With Primary Immunodeficiency

AbstractPurposeIgPro20, Hizentra® an L-proline−stabilized 20% human subcutaneous immunoglobulin (SCIG), has been shown in a Phase III pivotal study to be well tolerated and efficacious in adult and pediatric Japanese patients with primary immunodeficiency. Economic aspects of SCIG treatment in comparison with previous intravenous immunoglobulin (IVIG) therapy were analyzed in this Phase III study in Japan.MethodsTwenty-four Japanese patients with primary immunodeficiency on IVIG treatment were switched to IgPro20 at an equivalent dose (full analysis set). The study consisted of a screening period, an IVIG treatment period with 3 planned infusions every 3 or 4 weeks, a 12-week SCIG wash-in and wash-out period, and a 12-week SCIG efficacy period. The difference in medical cost and productivity loss resulting from changes in hospital frequency between the SCIG and IVIG treatment was evaluated. Information about treatment cost was collected as part of the Life Quality Index questionnaire. In addition, productivity loss and hospital-related absenteeism were evaluated.FindingsLife Quality Index scores for all domains were higher with SCIG than with IVIG in this patient population. In the full analysis set, the mean (SD) Life Quality Index score of the Costs domain increased from 45.1 (26.34) at Week 1 (IVIG period) to 71.9 (18.52) at Week 24 (end of the SCIG efficacy period), representing a mean change of 26.74 and a large score improvement effect size (1.01). Median productivity loss was reduced by 60% from baseline to Weeks 12 and 24. This resulted in a reduction in costs of JPY 10,875 per patient per month at Weeks 12 and 24. Subcutaneous treatment with IgPro20 also reduced hospital-related absenteeism. The number of patients, parents, or guardians who were not absent from work or housework duties and had no reduction in working time increased from 4 (17.4%) at Week 1 to 9 (39.1%) at Week 24. Similar results were obtained in the per-protocol set (n = 21).ImplicationsSwitching from IVIG to SCIG reduced markedly productivity loss and hospital-related absenteeism. The reduction in hospital visit frequency due to the use of home-based IgG therapy enabled by the change in administration route is expected to produce an important pharmacoeconomic benefit in Japan. Study Code: ZLB06_002CR, ClinicalTrials.gov identifier: NCT01199705

新生児期のインターロイキン2レセプタ-α鎖陽性ナイーブCD4[+]T細胞の機能とCD45抗原ファミリーの発現に関する研究

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第993号, 学位授与年月日：平成3年3月25日,学位授与年：199

Treatment satisfaction with subcutaneous immunoglobulin replacement therapy in patients with primary immunodeficiency: a pooled analysis of six Hizentra® studies

Purpose Primary immunodeficiency diseases (PIDDs) are a heterogenous group of disorders characterized by intrinsic impairment in the immune system. Most patients with PIDD require life-long immunoglobulin G replacement therapy, which has been shown to reduce the rate of infections and, related hospitalizations and reduce health-related quality of life (HRQOL). Here, treatment satisfaction and HRQOL in patients with PIDD was evaluated upon switching from intravenous (IVIG) or subcutaneous immunoglobulins (SCIGs) to 20% SCIG (Hizentra®), and during long-term steady-state Hizentra® treatment. Methods Analyses were based on two pivotal (switch) and four extension/follow-up (maintenance) Phase III studies of Hizentra® conducted in Europe (EU), Japan (JP), and the United States (US). Two validated questionnaires were used: Life Quality Index (LQI) for assessment of IgG-specific perceptions of HRQOL and Short Form 36 version 2 (SF-36v2). Results In the EU and JP switch studies, there was significant and meaningful improvement from Screening in LQI domain scores at all time points, largely driven by patients switching from IVIG to SCIG. In the EU switch study, there were also significant increases in mean SF-36v2 domain scores for Physical Function and General Health from Screening to Week 12. These improvements were observed also at Week 24. Overall, LQI and SF-36v2 domain scores were generally sustained in the maintenance studies. Conclusions These results showed that switching patients from IVIG to SCIG improves patient self-reported health status and IgG-specific HRQOL perception. The maintenance studies generally showed no deterioration of this improved health status over a long follow-up period

Cytokine profiles in children with primary Epstein-Barr virus infection

Primary Epstein-Barr virus (EBV) infection causes infectious mononucleosis and hemophagocytic lymphohistiocytosis (HLH) in children, where EBV infects B and CD8+ T cells, respectively. We measured pro-inflammatory and anti-inflammatory cytokines in both diseases. Significantly higher concentrations of various mediators, including interferon-γ, neopterin, interleukin (IL)-6, IL-10, IL-18, and heme oxygenase-1, were observed in EBV-HLH. Because of their similarity to the profile of familial HLH, this profile was likely a consequence of HLH, but not ectopic infection. TNF-α levels were elevated in both diseases. Elevation of those mediators may contribute to the disease pathogenesis of EBV-HLH by activating and inhibiting host immune responses. © 2013 Wiley Periodicals, Inc

Long-term efficacy and safety of Hizentra® in patients with primary immunodeficiency in Japan, Europe, and the United States: a Review of 7 Phase 3 Trials

Many patients with primary immunodeficiency (PID) require immunoglobulin G (IgG) replacement therapy, delivered as intravenous IgG (IVIG) or subcutaneous IgG (SCIG). We aim to identify trends in efficacy and safety that would not be evident in individual studies of small patient numbers. Seven open-label, Phase 3, prospective, multicenter studies of the efficacy and safety of Hizentra® (a SCIG), conducted in Japan, Europe, and the US were summarized. Overall, 125 unique patients received 15,013 weekly infusions during a total observation period of 250.9 patient-years. Mean weekly doses of Hizentra® were 83.22–221.3 mg/kg body weight; infusion rates per patient (total body rate) were 25.2–49.3 mL/h across studies. The rates of infections and serious bacterial infections were 3.10 and 0.03 events per patient/year, respectively. Annualized rates of days hospitalized due to infection, out of work/school, and prophylactic antibiotic use were 0.95, 5.14, and 36.78 per patient, respectively. For the equivalent monthly dose, weekly Hizentra® SCIG administration resulted in expectedly-increased serum IgG trough levels in patients switching from IVIG, and maintained levels in patients switching from previous SCIG. Adverse events (AEs) totaled 5039 (events/infusion 0.094–0.773), almost all of which were mild/moderate. Three thousand one hundred ninety-seven were considered treatment-related, the most common of which were injection site reactions (2919 events; 0.001–0.592 AEs per infusion). Systemic AEs were very uncommon. The results from these seven studies indicate that Hizentra® therapy was both efficacious and well tolerated during long-term treatment. This is particularly important in patients with PID, who may require lifelong IgG replacement therapy

Role of interleukin 6 for differential responsiveness of naive and memory CD4+ T cells in CD2-mediated activation

金沢大学大学院医学系研究科血管病態制御学The present study was undertaken to elucidate different requirements for CD2-mediated activation of naive (CD45RO-) and memory (CD45RO+) CD4+ T cells. A mitogenic combination of anti-CD2 (anti-T112 and anti-T113) mAbs could effectively induce the proliferation of memory CD4+ T cells even in the absence of monocytes. In marked contrast, naive CD4+ T cells did not disclose any proliferative responses to antiCD2 mAbs, when monocytes were absent in culture. This differential responsiveness of naive and memory CD4+ T cells appeared to be related largely to a difference in IL-6 - producing ability between both populations. IL-6 among monocyte-derived cytokines could correct unresponsiveness of naive CD4+ T cells to anti-CD2 stimulation. Unlike naive CD4+ T cells, memory CD4+ T cells produced IL-6 by themselves, with its mRNA being expressed on anti-CD2 stimulation. Anti-IL-6R mAb significantly inhibited proliferation of memory CD4+ T cells seen in the anti-CD2-stimulated cultures without monocytes, indicating the involvement of their own production of IL-6 in CD2-mediated activation. The results suggest an essential role of IL-6 for triggering of CD4+ T cells via the CD2 molecule

A sporadic case of CTLA4 haploinsufficiency manifesting as Epstein–Barr virus-positive diffuse large B-cell lymphoma

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is a coinhibitory receptor that plays an essential role in maintaining immune system homeostasis by suppressing T-cell activation. We report a sporadic case of CTLA4 haploinsufficiency in a patient with Epstein-Barr virus-positive diffuse large B-cell lymphoma and subsequent benign lymphadenopathy. A missense mutation in exon 2 of the CTLA4 gene (c.251T>C, p.V84A) was found in the patient's peripheral blood and buccal cell DNA, but not in her parents' DNA. CTLA4 expression decreased in the peripheral regulatory T cells upon stimulation, whereas CTLA4 and PD-1-positive T cell subsets increased, possibly to compensate for the defective CTLA4 function. This case suggests that some adult lymphoma patients with no remarkable medical history have primary immune disorder. As immune-targeted therapies are now widely used for the treatment of malignancies, it is increasingly important to recognize the underlying primary immune disorders to properly manage the disease and avoid unexpected complications of immunotherapies

Role of interleukin 6 for differential responsiveness of naive and memory CD4+ T cells in CD2-mediated activation

The present study was undertaken to elucidate different requirements for CD2-mediated activation of naive (CD45RO-) and memory (CD45RO+) CD4+ T cells. A mitogenic combination of anti-CD2 (anti-T112 and anti-T113) mAbs could effectively induce the proliferation of memory CD4+ T cells even in the absence of monocytes. In marked contrast, naive CD4+ T cells did not disclose any proliferative responses to antiCD2 mAbs, when monocytes were absent in culture. This differential responsiveness of naive and memory CD4+ T cells appeared to be related largely to a difference in IL-6 - producing ability between both populations. IL-6 among monocyte-derived cytokines could correct unresponsiveness of naive CD4+ T cells to anti-CD2 stimulation. Unlike naive CD4+ T cells, memory CD4+ T cells produced IL-6 by themselves, with its mRNA being expressed on anti-CD2 stimulation. Anti-IL-6R mAb significantly inhibited proliferation of memory CD4+ T cells seen in the anti-CD2-stimulated cultures without monocytes, indicating the involvement of their own production of IL-6 in CD2-mediated activation. The results suggest an essential role of IL-6 for triggering of CD4+ T cells via the CD2 molecule

Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency

X-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency characterized by increased vulnerability to Epstein-Barr virus infection. XLP type 1 is caused by mutations in SH2D1A, whereas X-linked inhibitor of apoptosis (XIAP) encoded by XIAP/BIRC4 is mutated in XLP type 2. In XIAP deficiency, hemophagocytic lymphohistiocytosis (HLH) occurs more frequently and recurrence is common. However, the underlying mechanisms remain mostly unknown. We describe the characteristics of the cytokine profiles of serum samples from 10 XIAP-deficient patients. The concentration of interleukin (IL)-18 was strikingly elevated in the patients presented with HLH, and remained high after the recovery from HLH although levels of other pro-inflammatory cytokines approached the normal range. Longitudinal examination of two patients demonstrated marked exacerbation of IL-18 levels during every occasion of HLH. These findings may suggest the association between HLH susceptibility and high serum IL-18 levels in XIAP deficiency. © 2013 Elsevier Ltd. All rights reserved