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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive joint inflammation, resulting in cartilage destruction and bone erosion. It was reported that low-dose radiation modulates immune disease. Here, we investigated whether low-dose whole-body irradiation has preventive and therapeutic effects in collagen-induced RA (CIA) mouse models. Fractionated low-dose irradiation (0.05 Gy/fraction, total doses of 0.1, 0.5 or 0.8 Gy) was administered either concurrently with CIA induction by Type II collagen immunization (preventive) or after CIA development (therapeutic). The severity of CIA was monitored using two clinical parameters, paw swelling and redness. We also measured total Immunoglobulin G (IgG) and inflammatory cytokines (interleukine (IL)-6, IL-1β and tumor necrosis factor-alpha (TNF-α)) in the serum by enzyme-linked immunosorbent assay, and we evaluated histological changes in the ankle joints by immunohistochemistry and hematoxylin and eosin staining. Low-dose irradiation reduced CIA clinical scores by up to 41% in the preventive model and by 28% in the therapeutic model, while irradiation in the preventive model reduced the typical CIA incidence rate from 82 to 56%. In addition, low-dose irradiation in the preventive model decreased total IgG by up to 23% and decreased IL-1β and TNF-α by 69 and 67%, and in the therapeutic model, decreased total IgG by up to 35% and decreased IL-1β and IL-6 by 59 and 42% with statistical significance (P < 0.01, 0.05 and 0.001). Our findings demonstrate that low-dose radiation has preventive and therapeutic anti-inflammatory effects against CIA by controlling the immune response, suggesting that low-dose radiation may represent an alternative therapy for RA, a chronic degenerative immune disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Myelin oligodendrocyte glycoprotein-associated disorders (MOGAD) is an autoimmune central nervous system disease. Antigen-specific immune tolerance using nanoparticles such as Polylactic-co-glycolic acid (PLGA) have recently been used as a new therapeutic tolerization approach for CNS autoimmune diseases. We examined whether MOG 1-125 conjugated with PLGA could induce MOG-specific immune tolerance in an experimental autoimmune encephalitis (EAE) mouse model. EAE was induced in sixty C57BL/6 J wild-type mice using MOG 1-125 peptide with complete Freund's Adjuvant. The mice were divided into 12 groups (n = 5 each) to test the ability of MOG 1-125 conjugated PLGA intervention to mitigate the severity or improve the outcomes from EAE with and without rapamycin compared to antigen alone or PLGA alone. EAE score and serum MOG-IgG titers were compared among the interventions.Kindly check and confirm the processed Affiliation &#x201C;4&#x201D; is appropriate.I confirmed the Aff 4.Affiliation: Corresponding author information have been changed to present affiliation. Kindly check and confirm.I checked and confirmed the Corresponding author's information., Results: Mice with EAE that were injected intraperitoneally with MOG 1-125 conjugated PLGA + rapamycin complex showed dose-dependent mitigation of EAE score. Intraperitoneal and intravenous administration resulted in similar clinical outcomes, whereas 80% of mice treated with subcutaneous injection had a recurrence of clinical score worsening after approximately 1 week. Although there was no significant difference in EAE scores between unconjugated-PLGA and MOG-conjugated PLGA, serum MOG-IgG tended to decrease in the MOG-conjugated PLGA group compared to controls., Conclusion: Intraperitoneal administration of PLGA resulted in dose-dependent and longer-lasting immune tolerance than subcutaneous administration. The induction of immune tolerance using PLGA may represent a future therapeutic option for patients with MOGAD., (© 2024. The Author(s).)

An 80-year-old woman with rheumatoid arthritis during treatment with etanercept, a tumor necrosis factor (TNF) inhibitor, showed swelling of the salivary glands and retroperitoneal fibrosis, which was diagnosed as IgG4-related disease. Although some reports have shown the efficacy of TNF inhibitors for IgG4-related disease or retroperitoneal fibrosis, TNF inhibitors sometimes cause paradoxical reactions like psoriasis, and the mechanisms are considered to involve the upregulation of plasmacytoid dendritic cells and IFN-α, which is also common in patients with IgG4-related disease. This is a case report of IgG4-related retroperitoneal fibrosis with the possibility of a rare paradoxical reaction by a TNF inhibitor.

Urokinase plasminogen activator (uPA) is a crucial activator of the fibrinolytic system that modulates tissue remodeling, cancer progression, and inflammation. However, its role in membranous nephropathy (MN) remains unclear. To clarify this issue, an established BALB/c mouse model mimicking human MN induced by cationic bovine serum albumin (cBSA), with a T helper cell type 2-prone genetic background, was used. To induce MN, cBSA was injected into Plau knockout (Plau -/- ) and wild-type (WT) mice. The blood and urine samples were collected to measure biochemical parameters, such as serum concentrations of immunoglobulin (Ig)G1 and IgG2a, using enzyme-linked immunoassay. The kidneys were histologically examined for the presence of glomerular polyanions, reactive oxygen species (ROS), and apoptosis, and transmission electron microscopy was used to examine subepithelial deposits. Lymphocyte subsets were determined using flow cytometry. Four weeks post-cBSA administration, Plau -/- mice exhibited a significantly higher urine protein-to-creatine ratio, hypoalbuminemia, and hypercholesterolemia than WT mice. Histologically, compared to WT mice, Plau -/- mice showed more severe glomerular basement thickening, mesangial expansion, IgG granular deposition, intensified podocyte effacement, irregular thickening of glomerular basement membrane and subepithelial deposits, and abolishment of the glycocalyx. Moreover, increased renal ROS levels and apoptosis were observed in Plau -/- mice with MN. B-lymphocyte subsets and the IgG1-to-IgG2a ratio were significantly higher in Plau -/- mice after MN induction. Thus, uPA deficiency induces a T helper cell type 2-dominant immune response, leading to increased subepithelial deposits, ROS levels, and apoptosis in the kidneys, subsequently exacerbating MN progression in mice. This study provides a novel insight into the role of uPA in MN progression., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Abdominal aortic aneurysm (AAA) is a multifactorial, degenerative disease characterized by progressive aortic dilation and chronic activation of inflammation, proteolytic activity, and oxidative stress in the aortic wall. The immune response triggered by antibodies against antigens present in the vascular wall participates in the formation and progression of AAA through mechanisms not completely understood. This work analyses the function of specific IgG receptors (FcγR), especially those expressed by monocytes/macrophages, in the development of experimental AAA., Methods: In the elastase-induced AAA model, the abdominal aortas from wildtype and FcγR deficient mice with/without macrophage adoptive transfer were analysed by histology and quantitative PCR. In vitro, mouse macrophages were transfected with RNA interference of FcγRIV/CD16.2 or treated with Syk kinase inhibitor before stimulation with IgG immune complexes., Results: Macrophage adoptive transfer in FcγR deficient mice increased the susceptibility to AAA development. Mice receiving macrophages with functional FcγR exhibited higher aortic diameter increase, higher content of macrophages and B lymphocytes, and upregulated expression of chemokine CCL2, cytokines (TNF-α and IL-17), metalloproteinase MMP2, prooxidant enzyme NADPH oxidase-2, and the isoforms FcγRIII/CD16 and FcγRIV/CD16.2. In vitro, both FcγRIV/CD16.2 gene silencing and Syk inhibition reduced cytokines and reactive oxygen species production induced by immune complexes in macrophages., Conclusions: Activation of macrophage FcγR contributes to AAA development by inducing mediators of inflammation, proteolysis, and oxidative stress. Modulation of FcγR or effector molecules may represent a potential target for AAA treatment., (Copyright © 2023 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Heparin-induced thrombocytopenia (HIT) is a potentially fatal, immune-mediated adverse drug reaction to heparin (both unfractionated and low molecular weight heparin) which is caused by the formation of IgG antibodies against an epitope composed by platelet-derived PF4 and heparin. Binding of IgG to PF4/heparin neoantigen induces platelet activation which may cause venous or arterial thrombosis, associated with thrombocytopenia. HIT diagnosis is based on both pre-test clinical probability evaluation and the detection of platelet activating antibodies. Laboratory diagnosis is based on immunologic and functional assays. When HIT is diagnosed any type of heparin should be stopped immediately and non-heparin alternative anticoagulant must be started in order to halt the pro-thrombotic process. Argatroban and danaparoid are currently the only drugs approved for HIT treatment. Bivalirudin and fondaparinux are also used for the treatment of this rare but severe condition.

Background: Regdanvimab has decreased the time to clinical recovery from coronavirus disease 2019 (COVID-19) and lowered the rate of oxygen therapy according to the results from phase 2/3 randomized controlled trial. More information is needed about the effects and safety of regdanvimab., Methods: We analyzed data for patients with high-risk mild or moderate COVID-19 being admitted to Busan Medical Center between December 1, 2020 and April 16, 2021. A propensity score (PS) matched analysis was conducted to compare patients treated with and without regdanvimab. The primary outcome was in-hospital death or disease aggravation which means the need for oxygen therapy (low- or high-flow oxygen therapy and mechanical ventilation) and secondary outcomes comprised the length of hospital stay and adverse reactions., Results: Among 1,617 selected patients, 970 (60.0%) were indicated for regdanvimab. Of these, 377 (38.9%) were administered with regdanvimab. Among a 1:1 PS-matched cohort of 377 patients each treated with and without regdanvimab, 19 (5%) and 81 (21.5%) reached the composite outcome of death, or disease aggravation, respectively (absolute risk difference, -16.4%; 95% confidence interval [CI], -21.1, -11.7; relative risk difference, 76.5%; P < 0.001). Regdanvimab significantly reduced the composite outcome of death, or disease aggravation in univariate (odds ratio [OR], 0.194; 95% CI, 0.112-0.320; P < 0.001) and multivariable-adjusted analyses (OR, 0.169; 95% CI, 0.095-0.289; P < 0.001). The hospital stay was shorter for the group with than without regdanvimab. Some hematological adverse reactions were more frequent in the group without regdanvimab, but other adverse reactions did not significantly differ between the groups., Conclusion: Regdanvimab was associated with a significantly lower risk of disease aggravation without increasing adverse reactions., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2022 The Korean Academy of Medical Sciences.)

Platelet factor 4 (PF4) is a highly cationic tetrameric protein that can be targeted by platelet-activating anti-PF4 antibodies of immunoglobulin G (IgG) class. Certain features of PF4, including its multivalent nature (duplicate antigen sites per tetramer), the ability of many PF4 tetramers to undergo close approximation through charge neutralization, and the dimeric binding of IgG molecules, results in formation of IgG-containing immune complexes in situ on platelets, neutrophils, and monocytes, resulting in Fcγ receptor-mediated pancellular activation that also activates hemostasis (potential for disseminated intravascular coagulation). This review discusses 4 anti-PF4 disorders: classic heparin-induced thrombocytopenia ([HIT]; triggered by heparin and certain other polyanionic pharmaceuticals, featuring predominantly heparin-dependent antibodies), autoimmune HIT (aHIT; severe subtype of HIT that features both heparin-dependent and heparin-independent platelet-activating antibodies), and spontaneous HIT (non-heparin triggers such as knee replacement surgery and infection; predominantly heparin-independent platelet-activating antibodies). Most recently, a novel fourth anti-PF4 disorder, vaccine-induced immune thrombotic thrombocytopenia (VITT), was identified as an ultrarare complication of adenovirus vector vaccines. VITT is characterized by thrombocytopenia, disseminated intravascular coagulation, a high frequency of thrombosis-including in unusual sites (cerebral veins, splanchnic veins)-and highly pathogenic anti-PF4 antibodies with heparin-independent platelet-activating properties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author. Published by Elsevier Inc. All rights reserved.)

Regdanvimab (Regkirona™) is a recombinant human monoclonal antibody targeted against the severe acute respiratory syndrome coronavirus 2. It is being developed by Celltrion Inc. for the treatment of coronavirus disease 2019 (COVID-19). In September 2021, regdanvimab received full approval in South Korea for the treatment of COVID-19 in elderly patients aged > 50 years with at least one underlying medical condition (obesity, cardiovascular disease, chronic lung disease, diabetes, chronic kidney disease, chronic liver disease, and patients on immunosuppressive agents) and mild symptoms of COVID-19 and in adult patients with moderate symptoms of COVID-19. This article summarizes the milestones in the development of regdanvimab leading to this first approval for COVID-19., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This large cohort study from the US Premier Healthcare Database evaluated the risk and predictors of anaphylaxis in association with intravenous immunoglobulin (IvIg) therapy in the inpatient and outpatient setting. Data were collected retrospectively (January 2009-December 2018) from 24 919 patients administered IgPro10 IvIg, median age 54 years. Immunoglobulins of interest were IgPro10 and other IvIg given before or after IgPro10. Moderate and severe anaphylaxis was identified from same-day parenteral epinephrine and IvIg use and reviews of patient record summaries. Predictors for first anaphylactic reactions associated with IvIg administration were derived from adjusted incidence rate ratios (IRR) using Poisson regression. Moderate anaphylaxis in IvIg use was rare and severe anaphylaxis very rare based on a total of 124 moderate and four non-fatal severe first anaphylactic events, incidence rate of 7.11 and 0.23/10 000 IvIg administrations, respectively. Age under 18 years was an independent predictor of moderate or severe anaphylactic events [adjusted incidence rate ratio = 2.94, 0.95 confidence interval  = 1.91-4.52] compared with those aged 18 years and older. First IvIg administration was a strong predictor of anaphylaxis. The IRR in those with a subsequent IvIg administration in the preceding 42 days decreased to 0.27 (0.17-0.42) and in those effectively IvIg-naive (no IvIg for > 42 days) to 0.76 (0.44-1.32) compared with first IvIg use. The key conclusions from this study are that the risk of anaphylaxis has progressively reduced over the last decade, from 14.87 of 10 000 in 2009-10 to 4.39 of 10 000 IvIg administrations in 2017-18 and is rare overall, and that the risk of anaphylaxis is increased in those aged under 18 years., (© 2021 British Society for Immunology.)

Pemphigus is a debilitating IgG-mediated autoimmune disease requiring better tolerated, more targeted, and rapid onset therapies. ALXN1830 is a humanized IgG4 antibody that blocks neonatal Fc receptor interactions with IgG. A multicenter, open-label safety and tolerability phase 1b/2 trial (NCT03075904) was conducted in North America from July 2017 to January 2019 and included patients aged ≥18 years with a confirmed diagnosis of pemphigus (vulgaris or foliaceus) and active disease. Dosing included five weekly intravenous doses of ALXN1830 (10 mg/kg) and follow-up through day 112 (study termination). Pharmacokinetics, pharmacodynamics, safety, and efficacy, as evaluated by determining the change in the median pemphigus disease area index, were determined. In this pilot study of eight patients, five weekly infusions of ALXN1830 produced a rapid improvement in the pemphigus disease area index score within 14 days of the first dose. Pemphigus disease area index improvement increased further together with reductions in IgG, circulating immune complexes of IgG, and anti-desmoglein antibodies without affecting albumin, IgM, IgA, or C-reactive protein levels. ALXN1830 was well-tolerated, with headache as the most common adverse event. This study reveals the importance of neonatal Fc receptor in the biology of pemphigus and the potential for use of ALXN1830 in pemphigus treatment., (Published by Elsevier Inc.)

Background: Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sézary syndrome., Methods: This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1-5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6-9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 μg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov, NCT02890368, and was closed by the sponsor to focus on intravenous studies with TTI-621., Findings: Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sézary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sézary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17-66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient., Interpretation: Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions., Funding: Trillium Therapeutics., Competing Interests: Declaration of interests CQ reports research grants from Celgene; is a clinical investigator for Trillium Therapeutics, MiRagen, Bioniz, and Kyowa Kirin; and reports participation in advisory boards for Helsinn, miRagen, Bioniz, Trillium Therapeutics, and Kyowa Kirin. JAT reports research grants from Merck, Hoffmann-LaRoche, Pfizer, Five Prime, Novartis, Incyte, Trillium Therapeutics, and Xencor; and participation in advisory boards for Neoleukin, AVEO Oncology, and Regeneron. MHT reports research funding to their institution from Bristol Myers Squibb, Merck, Pharmacyclics, AstraZeneca, Eisai, Incyte, EMD Serono, Novartis, Seattle Genetics, AbbVie, Genentech, Eli Lilly, Roche, Acerta Pharma, Genzyme Corporation, and Pfizer; consulting or participation in advisory boards for Bristol Myers Squibb, Eisai, Novartis, Bayer, Sanofi/Genzyme, Array BioPharma, LOXO oncology, Blueprint Medicines, and Arqule; and participation in speakers' bureaus for Bristol Myers Squibb and Eisai. JAD reports speaker fees from Helsinn; and consultant fees from Regeneron. JMZ reports participation in advisory boards for Kyowa Kirin, Secura Bio, Mudi Pharma, Seattle Genetics, Legend Bio tech, and Ono Pharma; and research funding to their institution from Seattle Genetics, AbbVie, Karyopharm, and CRSPR. ARS has been a consultant for Acrotech, Bristol Myers Squibb-Celgene, Kyowa-Hakko-Kirin, and Portolla. SM has been a sub-investigator for Trillium Therapeutics, Bioniz, Kyowa Kirin, Affimed, Galderma, Soligenix, Helsinn, and Eisai; and been on the nurse advisory board for Kyowa Kirin. GHYL, PSP, RAU, NM, and YS report employment by and stock ownership in Trillium Therapeutics. OEA reports research grants from Trillium Therapeutics, Pfizer, and Kyowa Kirin; has been a clinical investigator for Trillium Therapeutics, Bioniz, Kyowa Kirin, Affimed, Galderma, Soligenix, Helsinn, and Eisai; and reports participation in advisory boards for Bioniz, Trillium Therapeutics, Kyowa Kirin, Medivir, and Almirall. CJ declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Studies investigating the safety of IgPro10 (Privigen ® , CSL Behring, King of Prussia, PA, USA) in Japanese patients with primary immunodeficiency (PID) are lacking. This study evaluated safety and tolerability of IgPro10 in Japanese patients with PID. In this prospective, open-label, single-arm, registrational study for Japan, IgPro10 was administered intravenously at pre-study doses of 138-556 mg/kg body weight per 3-/4-weekly dosing cycle for up to 4 months. Frequency and intensity of adverse events (AEs), their relationship to IgPro10 and AE rate per infusion (AERI) were evaluated. Of 11 enrolled patients, 10 completed the study. The median (range) total duration of exposure was 16.14 (4.1-16.3) weeks. Eight patients reported 19 AEs, none severe (based on maximum severity), giving an AERI of 0.442. One AE was deemed related to IgPro10 treatment. Three patients experienced temporally associated AEs. No serious AEs or deaths were reported. Nine patients (90%) who completed the study tolerated flow rates of ≥ 8 mg/kg/min; 5 tolerated 12 mg/kg/min (7.2 mL/kg/h), translating into a threefold decrease in mean infusion time. IgPro10 was well tolerated at a flow rate of up to 12 mg/kg/min. Safety and tolerability findings were consistent with previously reported studies in non-Japanese patients with PID.

Purpose: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies., Patients and Methods: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR)., Results: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing., Conclusions: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL., (©2021 American Association for Cancer Research.)

To examine whether treatment with interleukin (IL)-1-, IL-6-, tumour necrosis factor α (TNFα)-inhibitors or Abatacept is associated with an increased risk of common infections, infections requiring hospitalization (SAE) or opportunistic infections among real-world juvenile idiopathic arthritis (JIA) patients. Furthermore, the influence of other patient-related covariates on the occurrence of infections was investigated. Patients diagnosed with JIA and treated with biologics were selected from the German BIKER registry. Incidence rates (IR) of infections per 100 person years were calculated and compared between the different cohorts. Using multivariate logistic regression, odds ratios with 95% confidence intervals (CI) were determined for the influence of patient-related covariates (age, diagnosis, laboratory data, concomitant medication, JIA activity, comorbidities, and premedication) on the occurrence of infections. 3258 patients entered the analysis. A total of 3654 treatment episodes were distributed among TNFα- (Etanercept, Adalimumab, Golimumab, Infliximab, n = 3044), IL-1- (Anakinra, Canakinumab, n = 105), IL-6- (Tocilizumab, n = 400) and T-cell activation inhibitors (Abatacept, n = 105). 813 (22.2%) patients had at least one infection, 103 (2.8%) patients suffered from an SAE infection. Both common and SAE infections were significantly more frequent in IL-1 (IR 17.3, 95% CI 12.5/24 and IR 4.3, 95% CI 2.3/8.3) and IL-6 cohort (IR 16.7, 95% CI 13.9/20 and IR 2.8, 95% CI 1.8/4.4) compared to TNFα-inhibitor cohort (IR 8.7, 95% CI 8.1/9.4 and IR 1, 95% CI 0.8/1.3). When comparing the influencing factors for various infectious diseases, the use of corticosteroids, younger age, cardiac comorbidities and higher JIA-activity are the most striking risk factors. Relative to TNFα inhibitors and Abatacept, IL-1 and IL-6 inhibitors were associated with an increased risk of common and SAE infections. The influencing covariates identified may be helpful for the choice of a suitable biologic to treat JIA.

Pediatric opsoclonus-myoclonussyndrome (OMS) is a rare autoimmune disorder of which 50% are associated with neuroblastoma (NB). We investigated whether surface-binding autoantibodies in OMS can enhance natural killer (NK) cell-mediated cytotoxicity in these patients. OMS immunoglobulin G (IgG) bound to NB cell lines and NK cell-mediated cytotoxicity to NB cells was enhanced after preincubation with OMS-IgG, but not IgG from NB without OMS or healthy controls. Activation of NK cells by surface-binding autoantibodies may be an additional mechanism of antitumor immunity in children with NB and OMS., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To evaluate the safety and tolerability of subcutaneous IgPro20 (Hizentra ® , CSL Behring, King of Prussia, PA, USA) administered at high infusion parameters (> 25 mL and > 25 mL/h per injection site) in patients with primary immunodeficiency., Methods: The Hizentra ® Label Optimization (HILO) study was an open-label, parallel-arm, non-randomized study (NCT03033745) of IgPro20 using a forced upward titration design for infusion parameters. Patients experienced with pump-assisted IgPro20 infusions received weekly IgPro20 infusions at a stable dose in the Pump-Assisted Volume Cohort (N = 15; 25-50 mL per injection site) and in the Pump-Assisted Flow Rate Cohort (N = 18; 25-100 mL/h per injection site). Responder rates (percentage of patients who successfully completed ≥ 75% of planned infusions), safety outcomes, and serum immunoglobulin G (IgG) trough levels were evaluated., Results: Responder rates were 86.7% (13/15, 25 mL) and 73.3% (11/15, 40 and 50 mL) in the Volume Cohort, and 77.8% (14/18, 25 and 50 mL/h), 66.7% (12/18, 75 mL/h), and 61.1% (11/18, 100 mL/h) in the Flow Rate Cohort. Infusion compliance was ≥ 90% in all patients in the Volume Cohort and in 83.3% of patients in the Flow Rate Cohort. The number of injection sites (Volume Cohort) and the infusion duration (Flow Rate Cohort) decreased with increasing infusion parameters. The rate of treatment-emergent adverse events per infusion was low (0.138 [Volume Cohort] and 0.216 [Flow Rate Cohort]). Serum IgG levels remained stable during the study., Conclusion: Pump-assisted IgPro20 infusions are feasible at 50 mL and 100 mL/h per injection site in treatment-experienced patients, which may result in fewer injection sites and shorter infusion times., Trial Registration: NCT03033745 ; registered January 27, 2017.

Introduction: The COVID-19 pandemic has changed many aspects of everyday life. Patients with primary immunodeficiency (PID) are in a particularly difficult situation. The purpose of the present study was to contribute to the very limited research on the everyday aspects of functioning in PID patients during the COVID-19 pandemic., Methods: The survey included 85 adult PID patients treated with immunoglobulin replacement therapy in four reference centers for immunology. Everyday functioning of the patients as well as their opinion concerning new solutions in medical care were analyzed., Results: During the pandemic, the percentage of patients experiencing fear/anxiety has increased from 47% to 70%. The wide dissemination of information about the SARS-CoV-2 in the media has increased anxiety in 40% of the patients. Patients diagnosed with PID were most afraid of the exposure to contact with strangers, especially in public places. As many as 67 respondents (79%) considered the introduction of restrictions concerning social functioning as good. Only every fifth person learned about the pandemic from reliable sources. Eighty three percent of the patients receiving immunoglobulin substitution experienced less fear of SARS-CoV-2 infection. The patients positively evaluated the solutions related to the direct delivery of drugs to the place of residence in order to continue home IgRT therapy. Fifty three respondents (62.5%) believed that the possibility of a remote consultation was a very good solution., Conclusion: It is necessary to increase educational activities concerning the pandemic provided by health care professionals, as patients obtain information mainly from the media and the Internet, which adversely affects the feeling of anxiety. The pandemic, in addition to the very negative impact on patients and the deterioration of their daily functioning, has made patients appreciate their life more, devote more time to family and friends, and do things they like.

Purpose: To evaluate the safety and tolerability of IgPro20 manual push (also known as rapid push) infusions at flow rates of 0.5-2.0 mL/min., Methods: Patients with primary immunodeficiency (PID) with previous experience administering IgPro20 (Hizentra ® , CSL Behring, King of Prussia, PA, USA) were enrolled in the Hizentra ® Label Optimization (HILO) study (NCT03033745) and assigned to Pump-assisted Volume Cohort, Pump-assisted Flow Rate Cohort, or Manual Push Flow Rate Cohort; this report describes the latter. Patients administered IgPro20 via manual push at 0.5, 1.0, and 2.0 mL/min/site for 4 weeks each. Responder rates (percentage of patients who completed a predefined minimum number of infusions), safety outcomes, and serum immunoglobulin G (IgG) trough levels were evaluated., Results: Sixteen patients were treated; 2 patients (12.5%) discontinued at the 1.0-mL/min level (unrelated to treatment). Responder rates were 100%, 100%, and 87.5% at 0.5-, 1.0-, and 2.0-mL/min flow rates, respectively. Mean weekly infusion duration decreased from 103-108 to 23-28 min at the 0.5- and 2.0-mL/min flow rates, respectively. Rates of treatment-related treatment-emergent adverse events (TEAEs) per infusion were 0.023, 0.082, and 0.025 for the 0.5-, 1.0-, and 2.0-mL/min flow rates, respectively. Most TEAEs were mild local reactions and tolerability (infusions without severe local reactions/total infusions) was 100% across flow rate levels. Serum IgG levels (mean [SD]) were similar at study start (9.36 [2.53] g/L) and end (9.58 [2.12] g/L)., Conclusions: Subcutaneous IgPro20 manual push infusions at flow rates up to 2.0 mL/min were well tolerated and reduced infusion time in treatment-experienced patients with PID., Trial Registration: NCT03033745.

Background: SYN023, a mixture of two anti-rabies humanized monoclonal antibodies (mAbs), namely, CTB011 and CTB012, has been developed as a safe and cost-effective alternative to RIG in the use of postexposure prophylaxis (PEP) after rabies exposure., Methods: This phase I bridging study was designed to compare the pharmacokinetics (PK) of SYN023 (0.3 mg/kg) alone (cohort A, n = 8) or in combination with a rabies vaccine (cohort B, n = 24) in healthy Chinese subjects with those in American subjects to guide the design of further clinical trials. Their safety was assessed for the development of adverse events (AEs) by laboratory examinations. The levels of serum CTB011, CTB012 and anti-drug antibodies (ADAs) were measured longitudinally for 85 days. Serum rabies virus neutralizing antibody (RVNA) levels were measured as a pharmacodynamic (PD) surrogate., Results: Some subjects with injectable SYN023 at 0.3 mg/kg developed temporary AEs and adverse drug reactions (ADRs) of Grade 1 or 2, particularly in cohort B, probably due to vaccine coadministration. SYN023 injection displayed a typical and reliable PK, similar to that of human IgGs. Following injection with SYN023, Chinese subjects had slower absorption with higher exposures for CTB011 but lower exposures for CTB012 than American subjects. The SYN023 recipients achieved protective levels of RVNA (≥0.5 IU/mL) on day 3 post injection. A few subjects developed temporary ADA, which did not affect the safety and PK/PD of SYN023 in Chinese subjects., Conclusion: SYN023 at 0.3 mg/kg is relatively saf e and effective and can be selected for further clinical trials in Chinese subjects. The clinical trial registration number is CTR20190281. http://www.chinadrugtrials.org.cn/eap/clinicaltrials.searchlist?a=a&reg&#95;no=CTR20190281., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A 49-year-old woman, previously healthy, presented with recurrent fractures provoked by minimal trauma. She had sustained seven fractures over the previous 2 years. While she was an avid runner, her injuries were determined to be out of proportion to the degree of trauma. Initial evaluation, exploring the more common causes such as low bone density and abnormal vitamin D metabolism, was unremarkable. On repeat of the some of the tests, a low alkaline phosphatase (AP) was noted, which raised suspicion for hypophosphatasia (HPP), a rare cause of recurrent fractures. Subsequent workup revealed a low bone-specific AP and elevated vitamin B 6 Subsequently, genetic testing confirmed the diagnosis of adult-onset HPP caused by a heterozygous mutation c.407G>A in the ALPL gene. Asfotase alfa was started; however, the patient developed an allergic reaction leading to the discontinuation of the drug., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Raxibacumab is a monoclonal antibody against protective antigen, which is the cell-binding part of Bacillus anthracis toxin, and is approved for treatment and postexposure prophylaxis of inhalational anthrax. Anthrax Vaccine Adsorbed (AVA), for anthrax prophylaxis, consists primarily of adsorbed protective antigen. We did a postapproval study to assess the effect of raxibacumab on immunogenicity of AVA., Methods: We did an open-label, parallel-group, randomised non-inferiority study at three centres in the USA. We enrolled healthy volunteers (aged 18-65 years) with no evidence of exposure to protective antigen. Participants were randomly allocated (1:1) according to a pregenerated balanced independent randomisation schedule to either subcutaneous 0·5 mL AVA on days 1, 15, and 29 or raxibacumab intravenous infusion (40 mg/kg) immediately before AVA on day 1, followed by AVA only on days 15 and 29. It was an open-label study to investigators and participants; however, the sponsor remained blinded during the study. The primary outcome was the ratio of geometric mean concentrations (GMCs) of anti-protective antigen antibodies (attributable to the immune response to AVA) between AVA and AVA plus raxibacumab 4 weeks after the first AVA dose in the per-protocol population. The per-protocol population comprised all individuals who received the allocated treatment within the protocol-specified visit window and completed the primary study outcome assessment, without a protocol deviation requiring exclusion. The non-inferiority margin for the ratio of GMCs was predefined (upper limit of 90% CI <1·5). This trial is registered with ClinicalTrials.gov, NCT02339155., Findings: Between Feb 24, 2015, and June 6, 2017, 873 participants were screened for eligibility, of whom 300 were excluded. 573 were randomly allocated either AVA (n=287) or AVA plus raxibacumab (n=286). The per-protocol population comprised 276 individuals assigned AVA and 269 allocated AVA plus raxibacumab. At week 4, the GMC of anti-protective antigen antibodies in participants allocated AVA was 26·5 μg/mL (95% CI 23·6-29·8) compared with 22·5 μg/mL (20·1-25·1) among individuals allocated AVA plus raxibacumab. The ratio between groups was 1·18 (90% CI 1·03-1·35; p=0·0019), which met the predefined non-inferiority margin. Adverse events in the safety population were similar across groups (87 [30%] of 286 in the AVA group vs 80 [29%] of 280 in the AVA plus raxibacumab group) and no treatment-related serious adverse events were reported., Interpretation: Co-administration of raxibacumab with AVA does not negatively affect AVA immunogenicity. This finding suggests that combining raxibacumab with AVA might provide added benefit in postexposure prophylaxis against inhalational anthrax., Funding: US Biomedical Advanced Research and Development Authority, and GlaxoSmithKline., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Polyclonal anti-D is a first-line therapy for immune thrombocytopenia (ITP). Monoclonal antibodies are desirable alternatives, but none have yet proven successful despite their ability to opsonize erythrocytes (or red blood cells, RBCs) and cause anemia. Here, we examined 12 murine erythrocyte-specific antibodies of different specificity and subtypes and found that 8 of these antibodies could induce anemia in antigen-positive mice. Of these 8 antibodies, only 5 ameliorated ITP. All antibodies were examined for their in vitro ability to support macrophage-mediated phagocytosis of erythrocytes. Antibodies which supported erythrocyte phagocytosis in vitro successfully ameliorated ITP in vivo. To examine the ability of each antibody to inhibit phagocytosis of platelets, the antibodies were used to sensitize erythrocytes in vitro and these were added to a platelet phagocytosis assay. Antibodies that inhibited platelet phagocytosis in vitro also all ameliorated ITP in vivo. We conclude that inducing anemia is not a sufficient condition for amelioration of ITP but that the antibody's ability to prevent platelet phagocytosis in vitro predicted its ability to ameliorate ITP. We suggest that inhibition of in vitro platelet phagocytosis may prove to be a valuable tool for determining which erythrocyte antibodies would likely be candidates for clinical use in ITP., (© 2020 by The American Society of Hematology.)

Introduction: HyQvia (Immune Globulin Infusion 10% [Human] with Recombinant Human Hyaluronidase) was developed to combine the advantages of intravenous and subcutaneous immune globulin (SCIG), allowing administration of larger volumes at a single subcutaneous site with less frequent dosing when compared to other SCIG products. Current US prescribing guidelines for HyQvia are limited to adults and do not encompass the flexibility required to achieve success in all patients with primary immunodeficiency (PID)., Methods: This retrospective study was designed to evaluate the clinical experience of treating patients with PID with HyQvia regimens outside of package insert recommendations as well as in pediatric patients. Data were abstracted from 38 patient records (317 HyQvia infusions), including five patients less than 16 years of age, from seven US immunology clinics., Results: Among 37 patients receiving HyQvia regimens differing from prescribing guidelines, the most notable variations included shorter ramp-up periods, use of two rather than one infusion site, and slower than maximal infusion rates to mitigate local adverse events (AEs). The medication volume infused for single site doses ranged from 75 to 200 mL and doses split between two sites ranged from 100 to 750 mL. The most common type of regimen variation was a condensed ramp-up phase (shorter schedule, higher doses), and 96% (24/25) of patients managed in this way completed ramp-up. The most common ramp-up schedule was three infusions (one at 25-45%, another at 50-75%, and the final at 100% of target dose) spread over 2-4 weeks., Conclusions: A shorter ramp-up schedule did not appear to increase the number of AEs compared to standard ramp-up schedules. For patients with AEs, slower infusion rates and the use of two sites may improve medication tolerability. Four of five pediatric patients reported no AEs, and only one discontinued, stating a fear of needles. HyQvia may be tailored to adults requiring alternative rates, ramp-up, and/or dosing regimens and may be especially well-suited to children.

Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1-56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4-65.1), and the median PFS was 7.4 months (95% CI: 6.7-13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.

The identification of useful biomarkers is an urgent issue in cancer treatment, particularly for immunotherapy, as only some patients experience benefits from this treatment. The early induction of the IgG response has been reported as a useful biomarker of favorable prognosis for cancer patients treated with a personalized peptide vaccination, but a portion of these patients (IgG nonresponders) fail to achieve an early induction of IgG response yet experience long-term survival. It is thus necessary to identify other biomarkers of favorable prognosis among these patients. Here we report the usefulness of classical T-cell markers (ie, the CD8 content and the CD4/CD8 ratio in peripheral blood) in IgG nonresponders among advanced or recurrent ovarian cancer patients treated with a personalized peptide vaccination. Among IgG nonresponders (n = 25), the overall survival (OS) of the increased-CD8 group (n = 7) was significantly longer than that of the decreased-CD8 group (n = 18; P = .018), and the OS of the patients with a decreased CD4/CD8 ratio (n = 10) was significantly longer than that of the patients with an increased ratio (n = 15; P = .0055). Thus, an increased content of CD8 and a decreased CD4/CD8 ratio are each favorable prognosis markers in IgG nonresponders treated with a personalized peptide vaccination., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Asfotase alfa (STRENSIQ®, Alexion Pharmaceuticals, Inc.) is the only approved treatment for patients with pediatric-onset hypophosphatasia, a disease caused by a mutation in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. ALP is often used as signaling system in routine immunoassays. Because asfotase alfa contains the active site of the full ALP enzyme, it can catalyze the substrate as the antibody-conjugated ALP would within an assay. Therefore, its presence in a treated patient's sample may generate false positive or false negative results. We investigated whether the presence of asfotase alfa within a sample induced interference in immunoassays that utilize ALP or alternative detection systems., Methods: Asfotase alfa was added to samples at concentrations from 0.08-5 µg/mL and analysed on various immunoassays following manufacturer's instructions., Results: Asfotase alfa was detected in all ALP assays but ALKP1 (RayBiotech). We observed no changes in normetanephrine and noradrenaline (IBL) at any asfotase alfa concentration. However, asfotase alfa notably interfered in an oxytocin (ENZO) assay in nonextracted samples. Extraction using a C18 column eliminated the interference. No interference was observed on automated analyzers using alternative detection system (COBAS fT4 and TSH; Advia Centaur FSH, fT4; Architect LH; FSH). Immulite 2000 fT4, TSH, testosterone and hCG (ALP-based) showed no interference. However, the presence of asfotase alfa resulted in a dose-dependent increase of Troponin I signal., Conclusion: The presence of asfotase alfa must be taken into consideration when analyzing blood samples in treated patients to avoid any risk of misinterpretation of false positive/negative results. It is essential that assays be tested for this possible interference., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Expressed on activated T and natural killer cells, 4-1BB/CD137 is a costimulatory receptor that signals a series of events resulting in cytokine secretion and enhanced effector function. Targeting 4-1BB/CD137 with agonist antibodies has been associated with tumor reduction and antitumor immunity. C-C chemokine receptor 4 (CCR4) is highly expressed in various solid tumor indications and associated with poor prognosis. This phase Ib, open-label study in patients with advanced solid tumors assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of utomilumab (PF-05082566), a human monoclonal antibody (mAb) agonist of the T-cell costimulatory receptor 4-1BB/CD137, in combination with mogamulizumab, a humanized mAb targeting CCR4 reported to deplete subsets of regulatory T cells (Tregs)., Methods: Utomilumab 1.2-5 mg/kg or 100 mg flat dose every 4 weeks plus mogamulizumab 1 mg/kg (weekly in Cycle 1 followed by biweekly in Cycles ≥2) was administered intravenously to 24 adults with solid tumors. Blood was collected pre- and post-dose for assessment of drug pharmacokinetics, immunogenicity, and pharmacodynamic markers. Baseline tumor biopsies from a subset of patients were also analyzed for the presence of programmed cell death-ligand 1 (PD-L1), CD8, FoxP3, and 4-1BB/CD137. Radiologic tumor assessments were conducted at baseline and on treatment every 8 weeks., Results: No dose-limiting toxicities occurred and the maximum tolerated dose was determined to be at least 2.4 mg/kg per the time-to-event continual reassessment method. No serious adverse events related to either treatment were observed; anemia was the only grade 3 non-serious adverse event related to both treatments. Utomilumab systemic exposure appeared to increase with dose. One patient with PD-L1-refractory squamous lung cancer achieved a best overall response of partial response and 9 patients had a best overall response of stable disease. No patients achieved complete response. Objective response rate was 4.2% (95% confidence interval: 0.1-21.1%) per RECIST 1.1. Depletion of Tregs in peripheral blood was accompanied by evidence of T-cell expansion as assessed by T-cell receptor sequence analysis., Conclusions: The combination of utomilumab/mogamulizumab was safe and tolerable, and may be suitable for evaluation in settings where CCR4-expressing Tregs are suppressing anticancer immunity., Trial Registration: ClinicalTrials.gov identifier: NCT02444793.

Purpose: Immunoglobulin substitution therapy is an essential therapeutic approach for patients with primary antibody deficiencies. Different methods of administration, including intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) preparations, provide effective and tolerable treatment and enable the adjustment of therapy to patients' needs. A new 20% SCIG represents a new therapeutic option and a new route of administration using rapid-push application. The aim of the Czech Hizentra Noninterventional Study With Rapid Push (CHHINSTRAP) is to evaluate patient satisfaction with as well as the tolerability and efficacy of nonmedical switch to 20% SCIG from previous treatment with IVIG or SCIG and rapid push as a new way to administer SCIG. CHHINSTRAP is the first Phase IV, noninterventional, open-label, prospective, multicentric study of this type conducted in Central and Eastern Europe., Methods: Primary end points, including efficacy, adverse effects, convenience of use, and overall satisfaction, were evaluated by Treatment Satisfaction Questionnaire for Medication version II. Secondary end points, such as serum IgG trough levels, infusion duration, number of application sites, frequency of infections, related hospital admissions, and antibiotic consumption, were obtained from patients at each follow-up visit., Findings: Together, 50 eligible patients with primary antibody deficiency were switched from SCIG or IVIG to an equivalent dose of 20% SCIG and were followed up for 12 months during 5 consecutive visits. The results indicate that patients switched from previous IVIG or SCIG preparations had significantly higher serum trough IgG levels and a lower incidence of infections and related events, such as hospital admissions or consumption of antibiotics. These findings were also reflected in gradually increasing convenience of use and overall satisfaction reported by patients. Apart from duration of application, no differences were found between patients previously receiving SCIG or IVIG. Moreover, our study found a high level of safety of 20% SCIG rapid push, which was comparable to other preparations and application methods., Implications: On the basis of the results of CHHINSTRAP study, we conclude that 20% SCIG is a tolerable and effective immunoglobulin preparation, representing a new therapeutic approach in patients with primary antibody deficiencies. Its efficacy and tolerability have been found in patients on nonmedical switch from previous treatment with IVIG or SCIG., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: This prospective, Phase III study assessed the pharmacokinetics (PK), safety and tolerability of immune globulin subcutaneous, human - klhw 20% solution (IGSC-C 20%) in participants with primary humoral immunodeficiency (PI), compared with immune globulin injection (human), 10% caprylate/chromatography purified (IGIV-C 10%). Patients & methods: About 53 participants enrolled. Total 44 received IGIV-C 10% in the run-in phase and then entered the IV phase (with an additional nine who were already receiving IGIV-C 10% and entered the IV phase directly) for steady-state IV PK assessments. Total 49 entered the SC phase (weekly doses of IGSC-C 20% for ∼24 weeks). The PK profiles of IGIV-C 10% and IGSC-C 20% and their safety and tolerability parameters were compared. Results: At a dose adjustment factor of 1.37, IGSC-C 20% provided comparable (noninferior and bioequivalent) overall total immunoglobulin G exposure to IGIV-C 10% over an equal time interval. About 33 participants reported 79 adverse events during run-in + IV phases; 41 participants reported 141 adverse events during the SC phase, with most being local infusion site reactions. The majority of infusion site reactions were mild to moderate in severity. Conclusion: IGSC-C 20% was bioequivalent to IGIV-C 10% and was well tolerated, with a safety profile comparable with IGIV-C 10%, in this study. Trial registration: ClinicalTrials.gov identifier: NCT02604810.

Objective: To investigate the long-term safety and efficacy of weekly subcutaneous IgPro20 (Hizentra, CSL Behring) in chronic inflammatory demyelinating polyneuropathy (CIDP)., Methods: In a 48-week open-label prospective extension study to the PATH study, patients were initially started on 0.2 g/kg or on 0.4 g/kg weekly and-if clinically stable-switched to 0.2 g/kg weekly after 24 weeks. Upon CIDP relapse on the 0.2 g/kg dose, 0.4 g/kg was (re)initiated. CIDP relapse was defined as a deterioration by at least 1 point in the total adjusted Inflammatory Neuropathy Cause and Treatment score., Results: Eighty-two patients were enrolled. Sixty-two patients initially received 0.4 g/kg, 20 patients 0.2 g/kg weekly. Seventy-two received both doses during the study. Sixty-six patients (81%) completed the 48-week study duration. Overall relapse rates were 10% in 0.4 g/kg-treated patients and 48% in 0.2 g/kg-treated patients. After dose reduction from 0.4 to 0.2 g/kg, 51% (27/53) of patients relapsed, of whom 92% (24 of 26) improved after reinitiation of the 0.4 g/kg dose. Two-thirds of patients (19/28) who completed the PATH study without relapse remained relapse-free on the 0.2 g/kg dose after dose reduction in the extension study. Sixty-two patients had adverse events (AEs) (76%), of which most were mild or moderate with no related serious AEs., Conclusions: Subcutaneous treatment with IgPro20 provided long-term benefit at both 0.4 and 0.2 g/kg weekly doses with lower relapse rates on the higher dose. Long-term dosing should be individualized to find the most appropriate dose in a given patient., Classification of Evidence: This study provides Class IV evidence that for patients with CIDP, long-term treatment with SCIG beyond 24 weeks is safe and efficacious.

Purpose: To assess for ectopic ocular calcification in a series of patients with hypophosphatasia (HPP) treated with asfotase alfa, a recombinant tissue-nonspecific alkaline phosphatase., Methods: This is a retrospective analysis of subjects enrolled at Duke University Medical Center in ENB-009-10 (ClinicalTrials.gov: NCT01163149), a randomized controlled trial of asfotase alfa in adolescents and adults with HPP. Seven patients between the ages of 45 and 66 years diagnosed with HPP based on clinical features and low serum alkaline phosphatase levels were enrolled at our site. Subjects were randomized to receive either daily subcutaneous injections of asfotase alfa or no treatment. After 24 weeks, during the open-label extension phase, all subjects received treatment for at least 4 years. All subjects underwent comprehensive eye examinations at baseline and at 24-week intervals throughout the study to assess for development of ocular calcifications., Results: By week 120, all 7 subjects developed asymptomatic white refractile deposits in the interpalpebral perilimbal conjunctiva. Biopsy of the conjunctival lesions in 2 subjects revealed elastosis with subepithelial calcification. The lesions were nonprogressive and in 5 subjects exhibited some degree of regression., Conclusions: Asfotase alfa was invariably associated with development of mild focal conjunctival calcification, likely through disinhibition of hydroxyapatite crystal propagation. The calcifications were not symptomatic or vision-threatening and should not preclude enzyme replacement therapy for patients with this rare and often debilitating disease.

Background: The U- phenotype is extremely rare and is found predominantly in black African populations at a frequency of between 0.2 and 1.7%. In European populations, U- units are therefore rare, with limited availability in the United Kingdom. Anti-U is clinically significant and is known to cause hemolytic transfusion reactions (HTRs) and hemolytic disease of the fetus and newborn. It has been suggested that intravenous immunoglobulin (IVIG) may be considered as an option among supportive therapy for urgent transfusion when clinically significant antigen-matched units are not available. We report three cases with anti-U transfused with least-incompatible RBC units, their outcomes, and their clinical management., Study Design and Methods: Intravenous immunoglobulin was prescribed when least-incompatible units must be issued in patients with anti-U to ameliorate acute HTR and prevent the development of delayed HTR. We report the outcome of these cases., Results: Of the case reports described, one patient with weak anti-U developed a delayed HTR after transfusion with incompatible units due to an anamnestic response. Two additional patients are described, with the use of IVIG as a precautionary measure to prevent the development of HTRs when transfused with antigen-positive incompatible units. No acute HTRs or delayed HTRs were noted upon follow-up., Conclusion: U- units are not always readily available and transfusion support requires close collaborative working among a multidisciplinary team. Transfusion with antigen-positive incompatible units with IVIG cover both ameliorates acute HTRs and prevents the development of delayed HTRs., (© 2019 AABB.)

Background: Anticardiolipin antibodies of the immunoglobulin G isotype (IgG aCL) have been suggested as risk factor for arterial and venous thrombosis. No conclusive data in patients with coronary artery disease (CAD) do exist. We investigate the risk of recurrent CAD according to the presence of IgG aCL., Methods: We performed a systematic review and meta-analysis to evaluate the risk of recurrent major adverse cardiac events (MACE) associated with the presence of IgG aCL in patients with CAD. MEDLINE and Cochrane databases were searched. We conducted a meta-analysis of the relative risk (RR) both at 12 and 24 months., Results: We included 11 eligible studies with a total of 2425 patients, 283 IgG aCL+ and 2142 IgG aCL-. The prevalence of IgG aCL+ ranged from 6.1% to 43.3%. A total of 341 cardiac events were reported: 71 (25.1%) in IgG aCL+ and 270 (12.6%) in IgG aCL- patients. We found an increased risk of recurrent MACE in patients with high IgG aCL both at 12 (RR 2.17, 2.5-97.5%CI, 1.54-3.00) and 24 months (RR 2.11, 2.5-97.5%CI, 1.62-2.66). This association was even stronger in patients with juvenile CAD (i.e. <50 years) at both 12 (RR 3.21, 2.5-97.5%CI, 1.74-5.41) and 24 months (RR 3.24, 2.5-97.5%CI, 1.84-5.21)., Conclusion: Patients with CAD and elevated IgG aCL have a doubled risk of recurrent MACE at 12 and 24 months. The presence of aCL should be suspected in patients with recurrent CAD events or in patients with juvenile CAD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Pemphigus foliaceus (PF) is an autoimmune dermatologic disease that typically presents with painful, superficial blisters that evolve into scaling erosions in a seborrheic distribution. This case study intends to demonstrate that due to the relative scarcity of the disease and its distribution on the body, PF can easily be misdiagnosed. We present a 43-year-old African American male that presented to the dermatology clinic with an 18-month history of non-pruritic, violaceous, scaling patches and plaques most prominent on the malar cheeks, upper chest and upper back. He had been evaluated at an outside hospital with a high suspicion for cutaneous lupus erythematosus (CLE) and seborrheic dermatitis. However, repeated biopsies revealed non-specific spongiotic dermatitis, not consistent with CLE or seborrheic dermatitis. Over the subsequent months, he received treatment for both conditions without improvement in his symptoms. When he was referred to our dermatology clinic, repeat biopsies were obtained which demonstrated acantholysis and dyskeratosis in the granular layer, consistent with PF. Direct immunofluorescence revealed intercellular IgG staining most prominent in the epidermis, also consistent with PF. Finally, enzyme-linked immunosorbent assay for anti-desmoglein 1 returned positive, confirming the diagnosis. Upon review of the previous biopsies, focal areas of acantholysis and dyskeratosis were noted in the granular layer, which would have pointed away from a diagnosis of CLE or seborrheic dermatitis if PF was included in the clinical differential diagnosis. This case serves as a reminder that when there is a discrepancy in clinical-pathologic correlation, it is important to revisit the case and consider other pathologies., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2018.)

IgG4-related diseases (IgG4-RDs) have recently been reported in many organs other than the salivary, pancreatic and hepatobiliary systems. A 64-year-old woman was referred to our department for her abdominal fullness and cardiomegaly on chest X-ray. After draining the pericardial fluid, her symptom promptly diminished, and pericardial friction rubbing became clearly audible. Elevated serum levels of IgG and IgG4 and ureteral wall thickening on computed tomography suggested IgG4-RD. After the initiation of oral corticosteroid therapy, the pericardial effusion was resolved, and she has been in a steady-state condition for the past two years.

This report will detail a case of immune-mediated encephalitis in the context of daclizumab therapy. Daclizumab is a humanised monoclonal antibody which, prior to its recent worldwide withdrawal due to safety concerns, was utilised as a disease-modifying therapy in relapsing-remitting multiple sclerosis. The withdrawal of this therapy was prompted by concerns over 12 cases of serious immune-mediated adverse reactions in the central nervous system. We report an additional case, including clinical data and results of neuroimaging, cerebrospinal fluid (CSF) examination and brain biopsy.

Hypophysitis is a rare entity characterized by inflammation of the pituitary gland and its stalk that can cause hypopituitarism and/or mass effect. Etiology can be categorized as primary or secondary to systemic disease, but may also be classified according to anatomical and hispathological criteria. Newly recognized causes of hypophysits have been described, mainly secondary to immunomodulatory medications and IgG4-related disease. Diagnosis is based on clinical, laboratory and imaging data, whereas pituitary biopsy, though rarely indicated, may provide a definitive histological diagnosis. For the clinician, obtaining a broad clinical and drug history, and performing a thorough physical examination is essential. Management of hypophysitis includes hormone replacement therapy if hypopituitarism is present and control of the consequences of the inflammatory pituitary mass (e.g. compression of the optic chiasm) using high-dose glucocorticoids, whereas pituitary surgery is reserved for those unresponsive to medical therapy and/or have progressive disease. However, there remains an unmet need for controlled studies to inform clinical practice., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Peritonitis is responsible for thousands of deaths annually in Germany alone. Even source control (SC) and antibiotic treatment often fail to prevent severe sepsis or septic shock, and this situation has hardly improved in the past two decades. Most experimental immunomodulatory therapeutics for sepsis have been aimed at blocking or dampening a specific pro-inflammatory immunological mediator. However, the patient collective is large and heterogeneous. There are therefore grounds for investigating the possibility of developing personalized therapies by classifying patients into groups according to biomarkers. This study aims to combine an assessment of the efficacy of treatment with a preparation of human immunoglobulins G, A, and M (IgGAM) with individual status of various biomarkers (immunoglobulin level, procalcitonin, interleukin 6, antigen D-related human leucocyte antigen (HLA-DR), transcription factor NF-κB1, adrenomedullin, and pathogen spectrum)., Methods/design: A total of 200 patients with sepsis or septic shock will receive standard-of-care treatment (SoC). Of these, 133 patients (selected by 1:2 randomization) will in addition receive infusions of IgGAM for 5 days. All patients will be followed for approximately 90 days and assessed by the multiple-organ failure (MOF) score, by the EQ QLQ 5D quality-of-life scale, and by measurement of vital signs, biomarkers (as above), and survival., Discussion: This study is intended to provide further information on the efficacy and safety of treatment with IgGAM and to offer the possibility of correlating these with the biomarkers to be studied. Specifically, it will test (at a descriptive level) the hypothesis that patients receiving IgGAM who have higher inflammation status (IL-6) and poorer immune status (low HLA-DR, low immunoglobulin levels) have a better outcome than patients who do not receive IgGAM. It is expected to provide information that will help to close the knowledge gap concerning the association between the effect of IgGAM and the presence of various biomarkers, thus possibly opening the way to a personalized medicine., Trial Registration: EudraCT, 2016-001788-34; ClinicalTrials.gov, NCT03334006 . Registered on 17 Nov 2017. Trial sponsor: RWTH Aachen University, represented by the Center for Translational & Clinical Research Aachen (contact Dr. S. Isfort).

In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre-randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow-up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post-study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal., (© 2019 CSL Behring. Journal of the Peripheral Nervous System published by Wiley Periodicals, Inc. on behalf of Peripheral Nerve Society.)

Background: We evaluated the antitumor activity and safety of avelumab, a human anti-PD-L1 IgG1 antibody, as first-line switch-maintenance (1 L-mn) or second-line (2 L) treatment in patients with advanced gastric/gastroesophageal cancer (GC/GEJC) previously treated with chemotherapy., Methods: In a phase 1b expansion cohort, patients without (1 L-mn) or with (2 L) disease progression following first-line chemotherapy for advanced GC/GEJC received avelumab 10 mg/kg intravenously every 2 weeks. Endpoints included best overall response, progression-free survival (PFS), overall survival (OS), and safety., Results: Overall, 150 patients were enrolled (1 L-mn, n = 90; 2 L, n = 60) and median follow-up in the 1 L-mn and 2 L subgroups was 36.0 and 33.7 months, respectively. The confirmed objective response rate was 6.7% in both subgroups (95% CI, 2.5-13.9% and 1.8-16.2%, respectively), including complete responses in 2.2% of the 1 L-mn subgroup (n = 2). In the 1 L-mn and 2 L subgroups, median duration of response was 21.4 months (95% CI, 4.0-not estimable) and 3.5 months (95% CI, 2.8-8.3) and disease control rates were 56.7 and 28.3%, respectively. Median PFS in the 1 L-mn and 2 L subgroups was 2.8 months (95% CI, 2.3-4.1) and 1.4 months (95% CI, 1.3-1.5), with 6-month PFS rates of 23.0% (95% CI, 14.7-32.4%) and 7.9% (95% CI, 2.6-17.2%), and median OS was 11.1 months (95% CI, 8.9-13.7) and 6.6 months (95% CI, 5.4-9.4), respectively. In the 1 L-mn subgroup, median OS measured from start of 1 L chemotherapy was 18.7 months (95% CI, 15.4-20.6). Across both subgroups, 20.7% had an infusion-related reaction of any grade. Other common treatment-related adverse events (TRAEs) of any grade included fatigue (10.0%) and nausea (6.7%). Treatment-related serious adverse events occurred in 4.0% of patients. Overall, 8.7% had a grade ≥3 TRAE, including 1 treatment-related death., Conclusion: Avelumab showed clinical activity and an acceptable safety profile in patients with GC/GEJC., Trial Registration: ClinicalTrials.gov NCT01772004 ; registered 21 January 2013.

Immunoglobulin replacement therapy is the cornerstone of management for most primary immunodeficiency disease patients. The selection of a particular product, dose, and route of administration requires an understanding of the features of therapeutic immunoglobulin as well as patient-specific risk factors in order to maximize efficacy and tolerability and minimize risk. Individualizing therapy, taking into consideration the burdens of care, is necessary in order to optimize patient outcomes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To assess the efficacy and safety of intravenous immunoglobulin (IVIG) 10% (Panzyga ® ), a novel human normal IVIG 10%, in patients with chronic immune thrombocytopenia (ITP)., Background: First-line treatment options in ITP include IVIGs., Methods: In this prospective, open-label, non-controlled, multicentre, phase III study, patients received a daily dose of IVIG 10% (1 g kg -1 body weight) for two consecutive days. The primary end point was clinical response rate; secondary end points included alternate response definitions, time to response, response duration, platelet counts, regression of bleeding and safety., Results: Forty patients were enrolled (57·5% male, mean age 36·7 years); the full analysis set comprised 36 patients. A clinical response was seen for 29 of 36 patients (80·6%). Median time to response and response duration was 2 days and 14 days, respectively. IVIG 10% was well tolerated at a maximum infusion rate of 8 mg (kg min) -1 in all but one patient; adverse events were mainly mild to moderate in severity, and the most frequent was headache (42·5%)., Conclusion: IVIG 10% is well tolerated even at a high infusion speed and induces a rapid platelet count increase, thus decreasing the bleeding rate and the severity of bleeding events., Trial Registry: ClinicalTrials.gov record: NCT01349790., (© 2019 The Authors. Transfusion Medicine published by John Wiley & Sons Ltd on behalf of British Blood Transfusion Society.)

Background: JS001, a humanized IgG 4 monoclonal antibody against the programmed death-1 (PD-1) receptor, blocks the interaction of PD-1 with its ligands and promotes T cell activation in preclinical studies. This phase I study is designed to evaluate the safety, tolerability, and clinical activity of JS001 in advanced melanoma or urologic cancer patients who are refractory to standard systemic therapy., Patients and Methods: In the dose escalation cohorts, subjects initially received a single-dose, intravenous infusion of JS001, and were followed for 28 days followed by multi-dose infusions every 2 weeks. In the dose expansion cohorts, subjects received multi-dose infusions every 2 weeks. Clinical response was evaluated after each 8-week treatment cycle according to RECIST v1.1 criteria., Results: Thirty-six subjects diagnosed with advanced melanoma (n = 22), urothelial cancer (UC) (n = 8), or renal cell cancer (RCC) (n = 6) were enrolled. Melanoma subjects included 14 acral and 4 mucosal subtypes. JS001 was well tolerated, and no dose-limiting toxicity was observed. By the safety data cutoff date, 100% of subjects had treatment-related adverse events (TRAE) with most adverse events being grade 1 or 2, and ≥ grade 3 TRAEs occurred in 36%. Among all 36 subjects, 1 confirmed complete response (acral melanoma), 7 confirmed partial responses (2 acral melanoma, 1 mucosal melanoma, 2 UC, and 2 RCC), and 10 stable disease were observed, for an objective response rate of 22.2% (95% CI, 10.1 to 39.2), and a disease control rate of 50.0% (95% CI, 32.9 to 67.1). Clinical responses were correlated with PD-L1 expression on tumor cells, the presence of tumor infiltrating lymphocytes (TIL), baseline tumor volume, ECOG performance status, serum LDH levels, high percentage of activated CD8+ T cells and CD3- CD16+ CD54+ NK cells in the peripheral blood as well as tumor mutational burden (TMB)., Conclusion: JS001 was well tolerated and demonstrated promising anti-tumor activity in UC and RCC as well as in previously underexplored acral and mucosal melanoma subtypes. Subjects with an immune-active profile in the tumor microenvironment or in peripheral blood responded favorably to JS001 treatment. The completion of the current phase I study has led to the initiation of the first prospective anti-PD-1 registration trial in Asia focusing on acral and mucosal melanoma subtypes, representative of the regional disease epidemiology., Trial Registration: Clinical Trial ID: NCT02836795 , registered July 19, 2016, retrospectively registered.