ROP-ET: a prospective phase III trial investigating the efficacy and safety of ropeginterferon alfa-2b in essential thrombocythemia patients with limited treatment options.

Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.

A controlled trial of intravenous immunoglobulin in multifocal motor neuropathy.

Intravenous immunoglobulin (IVIG) has become the standard treatment for multifocal motor neuropathy (MMN) based on limited data. To critically assess the efficacy, safety, and tolerability of 10% liquid IVIG (IVIG), 44 adults with MMN were randomized 1 : 1 to either double-blind treatment of IVIG followed by placebo for 12 weeks each or the reverse. Open-label IVIG was administered for 12 weeks at the beginning and end of the study for clinical stabilization, and between double-blinded periods to prevent a carry-over effect. To avoid potential worsening, switching to open-label IVIG was permitted if deterioration occurred during blinded treatment. Mean maximal grip strength of the more affected hand declined 31.38% during placebo and increased 3.75% during IVIG (p = 0.005). In 35.7% of participants, Guy's Neurological Disability scores for upper limbs worsened during placebo and not during IVIG, whereas the converse was true in 11.9% (p = 0.021). Sixty-nine percent (69.0%) switched prematurely from placebo to open-label IVIG and 2.4% switched from blinded to open-label IVIG (p < 0.001). One serious adverse reaction (pulmonary embolism) and 100 non-serious reactions (69 mild, 20 moderate, and 11 severe) to IVIG occurred. IVIG was effective in improving disability and muscle strength, and was safe and well tolerated in adults with MMN.

Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency.

BACKGROUND: Subcutaneous immunoglobulin (IGSC) replacement therapy for primary immunodeficiency (PI) is equally efficacious to intravenous immunoglobulin (IGIV), induces fewer systemic reactions, and may be self-infused. Limited SC infusion volumes and reduced bioavailability, however, necessitate multiple infusion sites, more frequent treatment, and dose adjustment to achieve pharmacokinetic equivalence. Recombinant human hyaluronidase (rHuPH20) increases SC tissue permeability and facilitates dispersion and absorption, enabling administration of monthly doses in one site. OBJECTIVE: This study investigated the efficacy and tolerability of rHuPH20-facilitated IGSC (IGHy) in patients with PI. METHODS: In this open-label, multicenter phase III study, 87 patients with PI aged ≥2 years received 10% IGIV for 3 months, then IGHy (n = 83) for approximately 14 to 18 months at 108% of the IGIV dose. IGHy infusions began weekly, increasing to 3- or 4-week intervals. RESULTS: The majority (94.0%) of IGHy infusions were administered every 3 or 4 weeks, using one site (median, 1.09/month), with a mean volume of 292.2 mL. The bioavailability of IGHy measured by area under the concentration versus time curve was 93.3% of IGIV, which is pharmacokinetically equivalent. Systemic reactions were less frequent with IGHy than with IGIV (8.3% vs 25.0% of infusions). Local reactions to IGHy were generally mild to moderate, with a rate of 0.203 per infusion. The acute serious bacterial infection rate per subject-year for IGHy was low (0.025; upper 99% CI limit, 0.046). Overall infection rates per subject-year were 2.97 for IGHy and 4.51 for IGIV. CONCLUSION: IGHy was effective, safe, and pharmacokinetically equivalent to IGIV at the same administration intervals, but it caused fewer systemic reactions. Tolerability was good despite high infusion volumes and rates.

Evidence for a role for the p110-alpha isoform of PI3K in skeletal function.

Signaling through phosphatidylinositol-3 kinases (PI3K) regulates fundamental cellular processes such as survival and growth, and these lipid kinases are currently being investigated as therapeutic targets in several contexts. In skeletal tissue, experiments using pan-specific PI3K inhibitors have suggested that PI3K signaling influences both osteoclast and osteoblast function, but the contributions of specific PI3K isoforms to these effects have not been examined. In the current work, we assessed the effects of pharmacological inhibitors of the class Ia PI3Ks, alpha, beta, and delta, on bone cell growth, differentiation and function in vitro. Each of the class Ia PI3K isoforms is expressed and functionally active in bone cells. No consistent effects of inhibitors of p110-beta or p110-delta on bone cells were observed. Inhibitors of p110-alpha decreased osteoclastogenesis by 60-80% (p<0.001 vs control) by direct actions on osteoclast precursors, and decreased the resorptive activity of mature osteoclasts by 60% (p<0.01 vs control). The p110-alpha inhibitors also decreased the growth of osteoblastic and stromal cells (p<0.001 vs control), and decreased differentiated osteoblast function by 30% (p<0.05 vs control). These data suggest that signaling through the p110-alpha isoform of class Ia PI3Ks positively regulates the development and function of both osteoblasts and osteoclasts. Therapeutic agents that target this enzyme have the potential to significantly affect bone homeostasis, and evaluation of skeletal endpoints in clinical trials of such agents is warranted.

The natural killer cell: a further innate mediator of gouty inflammation?

Natural killer (NK) cells are vital effector cells of innate immunity because of their rapid cytotoxic and cytokine-producing responses to cell stress or infection. A distinguishing feature of NK cells is the ability to balance these signals with those of normal homeostasis through the expression of an array of inhibitory and activating receptors. Two functional subsets of NK cells exist: the more mature CD56(dim) population is potently cytotoxic, whereas CD56(bright) NK cells have low cytotoxicity but produce much greater amounts of cytokines, and express homing molecules for secondary lymphoid organs and sites of inflammation. NK cells have been identified as important modulatory cells in shaping adaptive immune responses by interacting with dendritic cells (DCs) and T cells. NK cells also interact with cells of the innate immune system such as monocytes and macrophages. This review outlines the biology of NK cells and the potential role of NK cells in modulating gouty inflammation.

Actions of fibroblast growth factor-8 in bone cells in vitro.

The fibroblast growth factors (FGFs) are a group of at least 25 structurally related peptides that are involved in many biological processes. Some FGFs are active in bone, including FGF-1, FGF-2, and FGF-18, and recent evidence indicates that FGF-8 is osteogenic, particularly in mesenchymal stem cells. In the current study, we found that FGF-8 was expressed in rat primary osteoblasts and in osteoblastic UMR-106 and MC3T3-E1 cells. Both FGF-8a and FGF-8b potently stimulated the proliferation of osteoblastic cells, whereas they inhibited the formation of mineralized bone nodules in long-term cultures of osteoblasts and reduced the levels of osteoblast differentiation markers, osteocalcin, and bone sialoprotein. FGF-8a induced the phosphorylation of p42/p44 mitogen-activated protein kinase (MAPK) in osteoblastic cells; however, its mitogenic actions were not blocked by either the MAPK kinase (MEK) inhibitor U-0126 or the PI 3-kinase (PI3K) inhibitor LY-294002. Interestingly, FGF-8a, unlike FGF-8b and other members of the family, inhibited osteoclastogenesis in mouse bone marrow cultures, and this was via a receptor activator of NF-kappaB ligand (RANKL)/osteoprotegerin (OPG)-independent manner. However, FGF-8a did not affect osteoclastogenesis in RAW 264.7 cells (a macrophage cell line devoid of stromal cells) exogenously stimulated by RANKL, nor did it affect mature osteoclast function as assessed in rat calvarial organ cultures and isolated mature osteoclasts. In summary, we have demonstrated that FGF-8 is active in bone cells, stimulating osteoblast proliferation in a MAPK-independent pathway and inhibiting osteoclastogenesis via a RANKL/OPG-independent mechanism. These data suggest that FGF-8 may have a physiological role in bone acting in an autocrine/paracrine manner.

Human immunoglobulin (KIOVIG®/GAMMAGARD LIQUID®) for immunodeficiency and autoimmune diseases: an observational cohort study.

AIM: To document the therapeutic efficacy and safety of Human Normal Immunoglobulin 10% Liquid (KIOVIG(®)/GAMMAGARD LIQUID(®) [IVIG 10%]) under clinical routine conditions. PATIENTS & METHODS: Subjects received IVIG 10% according to the prescribing information and were followed for 6 ± 1 weeks to 12 ± 2 months depending on indication. Efficacy, adverse events, infusion rates and duration and dose were recorded. RESULTS: Overall efficacy of IVIG 10% was rated as good or very good by the investigator in 81.8% of subjects; overall tolerability was good or very good in 87.5%. One serious adverse drug reaction (ADR) occurred (urticaria); no severe ADRs occurred. CONCLUSION: In this observational study, the efficacy and safety of IVIG 10% in routine clinical practice was similar to that previously reported in clinical studies.