BACKGROUND: Global healthcare disparities, stemming from organizational differences in healthcare systems, lead to variable availability and funding, resulting in a gap between recommended and implemented practices for interleukin (IL)-1-mediated autoinflammatory diseases. We aimed to assess diagnostic, treatment and follow-up options for these diseases in Central and Eastern European countries, comparing them with the 2021 recommendations of the European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR). METHODS: In 2023, a structured collaborative effort was organized with representatives from 10 Central and Eastern European countries to address autoinflammatory diseases. The discussion focused on potential strategies to achieve the goals mentioned above. RESULTS: Almost all the participating countries have specialized centers for the diagnosis and treatment of autoinflammatory diseases and the care is provided either by rheumatologists and/or clinical immunologists. Genetic testing is available in all countries, but there is variation in the types of tests offered. Massive parallel sequencing panels for autoinflammatory diseases are available in all countries, with waiting periods for results ranging from 3 to 6 months in most cases. The availability of disease-specific laboratory assessments, such as S100 proteins, is limited. IL-1 inhibitors are available in all countries, but there are differences in practices regarding the licensing and reimbursement of anakinra and canakinumab based on specific indications or diagnoses. The age at which the transition process begins varies, but in most countries, it typically starts around the age of 18 or beyond and in majority of the participating countries there is no structured transition program. CONCLUSIONS: Adherence to the 2021 EULAR/ACR recommendations for IL-1-mediated autoinflammatory diseases is achievable in Central and Eastern European countries. Determining the prevalence and incidence of these diseases in this region remains a persistent challenge for future research efforts, with the overarching goal of identifying new patients with autoinflammatory diseases.

• MeSH
• Hereditary Autoinflammatory Diseases * diagnosis   therapy   drug therapy   epidemiology   MeSH
• Antibodies, Monoclonal, Humanized MeSH
• Interleukin-1 * antagonists & inhibitors   MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Europe MeSH
• Europe, Eastern MeSH

Intravenous immunoglobulins (IVIG) are commonly used in peri-transplant desensitization, but evidence supporting their efficacy is limited. We conducted a prospective, randomized single-center, open-label, Phase IIIb non-inferiority clinical pilot trial to compare the efficacy of IVIG (administered at a dose of 3 × 0.5 g/kg) versus no IVIG, in conjunction with rabbit anti-thymocyte globulin (5-7 mg/kg) induction, in pre-sensitized patients with donor-specific antibodies who had negative pre-transplantation Flow- and CDC-crossmatches, between July 2020 and November 2022. The primary endpoint was the rate of efficacy failure, defined as biopsy-proven rejection within 12-month post-transplant. Secondary endpoints included the incidence of rejection at protocol biopsies, evaluated by histology and biopsy-based transcripts diagnostics. Of the screened patients, 53 (72.6%) were excluded due to crossmatch positivity. Ten patients were randomized to the IVIG+, and 7 to the IVIG-arm. The trial was prematurely terminated due to futility at interim analysis. In the IVIG-arm, 3 patients (43%) experienced the primary endpoint compared to none in the IVIG+ arm (p = 0.026). MMDx identified one molecular ABMR in the IVIG+ and 2 in the IVIG-arm in 12-month protocol biopsies. There was one graft loss in the IVIG-arm. The results of this pilot study, although not definitive, do not support the use of IVIG-sparing regimens in HLA-incompatible kidney transplantation (NCT04302805). This study is registered on ClinicalTrials.gov under the identifier NCT04302805.

• MeSH
• Antilymphocyte Serum * administration & dosage   MeSH
• Desensitization, Immunologic * methods   MeSH
• Adult MeSH
• Immunoglobulins, Intravenous * administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Pilot Projects MeSH
• Prospective Studies MeSH
• Graft Rejection * prevention & control   immunology   MeSH
• Kidney Transplantation * adverse effects   MeSH
• Treatment Outcome MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH

Východiská: Schnitzlerovej syndróm je získané autoinflamačné ochorenie so základom v poruche prirodzenej imunity. Podozrivým je proteín MyD88 – toll-like receptor zapojený do zápalovej kaskády vyúsťujúcej aj do zvýšenej sekrécie interleukínu-1 (IL-1), kľúčového cytokínu v patogenéze a klinickej manifestácii viacerých autoinflamačných stavov. Syndróm je pomenovaný po francúzskej kožnej lekárke Liliane Schnitzler, ktorá v roku 1972 opísala kazuistickú sériu pacientov s prejavmi urtikárie v spojení s monoklonálnou gamapatiou. V klinickom obraze dominujú prejavy chronickej urtikárie, pričom histologicky ide najčastejšie o neutrofilovú dermatózu. Nevyhnutným kritériom na zadefinovanie Schnitzlerovej syndrómu je monoklonálna gamapatia, pričom až v 90 % prípadov ide o monoklonálnu IgM gamapatiu. Zvyšná skupina pacientov má prítomnú gamapatiu v triede IgG. Z vedľajších kritérií potrebných na potvrdenie syndrómu podľa Strassburgskej klasifikácie je to zvýšená nešpecifická zápalová aktivita (elevácia sérového CRP, leukocytóza), morfologické zmeny na kostiach (verifikované hyperostotické či osteosklerotické zmeny skeletu na CT, scintigraficky, alebo PET/CT s použitím rádioaktívneho natrium fluoridu NaF18), bolesti kostí či artralgia. Pacienti sú vo zvýšenom riziku rozvoja lymfoproliferačného ochorenia ako Waldenströmovej makroglobulinémie alebo low-grade lymfómu (15–20 %). Rizikom je tiež rozvoj AA amyloidózy pri dlhodobej nekontrolovanej hyperinflamácii. Akútnou, život ohrozujúcou komplikáciou môže byť syndróm aktivovaných makrofágov. Vzhľadom na imunologickú podstatu ochorenia a eleváciu zápalových cytokínov je základom anticytokínová liečba. Najlepšie výsledky sú pozorované pri anakinre (antagonista receptora pre IL-1), inou možnosťou je eventuálne kanakinumab (monoklonálna protilátka proti IL-1b). Pozitívny efekt bol opisovaný aj pri inhibítoroch Brutonovej tyrozínkinázy. Kortikoidy a konvenčné imunosupresíva nie sú dostatočne efektívne. Prípad: V predkladanom texte prezentujeme formou kazuistickej série dve pacientky so Schnitzlerovej syndrómom s raritnejšími klinickými príznakmi a s diferencovanou odpoveďou na anticytokínovú liečbu. Cieľom autorov bolo informovať a zlepšiť povedomie o tomto vzácnom ochorení a jeho možnostiach liečby. Záver: Ochorenie je chronické, liečba je len symptomatická, ale vedie k ústupu klinických príznakov a dosiahnutiu kontroly nad zápalom. Riziko vzniku hematologickej malignity anticytokínová liečba pravdepodobne neovplyvňuje.

Background: Schnitzler‘s syndrome is an acquired autoinflammatory disease with a disorder in innate immune response. The suspect is the protein MyD88 – a toll-like receptor involved in the inflammatory cascade resulting in increased secretion of interleukin-1 (IL-1), a key cytokine in the pathogenesis and clinical manifestation of several autoinflammations. The syndrome is named after the French dermatologist Liliane Schnitzler, who described a case series of patients with manifestations of urticaria and monoclonal gammapathy in 1972. The clinical picture is characterized by chronic urticaria, histologically it is most often neutrophilic dermatosis. A necessary criterion for defining Schnitzler‘s syndrome is monoclonal gammapathy. In up to 90% of cases, it is monoclonal IgM gammapathy, the remaining group of patients has IgG gammapathy. Among the secondary criteria necessary to define the syndrome according to the Strasbourg classification, non-specific inflammatory activity is present in patients (elevation of CRP, leukocytosis), morphological changes on the bones (hyperostotic or osteosclerotic changes of the skeleton verified by CT, scintigraphy or PET/CT using radioactive sodium fluoride NaF18), bone pain or arthralgia. Patients are at an increased risk of developing a lymphoproliferative disease, especially Waldenström‘s macroglobulinemia or low grade lymphoma (15–20%). There is also a risk of the development of AA amyloidosis due to long-term uncontrolled hyperinflammation. Macrophage activating syndrome can be an acute life-threatening complication, as we describe in our patient. Considering the immunological nature of the disease and the elevation of inflammatory cytokines, the basis of treatment is anticytokine therapy. The best results are seen with anakinra (IL-1 receptor antagonist), possibly canakinumab (a monoclonal antibody against IL-1b). A positive effect was also described with Bruton‘s tyrosine kinase inhibitors. Corticoids and conventional immunosuppressants are not effective enough. Case: In this text, we present a case series of two patients with Schnitzler‘s syndrome with rare clinical symptoms. The authors‘ goal was to improve awareness of this rare hematoinflammatory disease and its treatment options. Conclusion: The disease is chronic, the treatment is only symptomatic, but can lead to the reduction of clinical symptoms. Anticytokine treatment probably does not affect the risk of hematological malignancy.

• MeSH
• Diagnosis, Differential MeSH
• Adult MeSH
• Immunoglobulin G immunology   MeSH
• Interleukin-1 immunology   MeSH
• Humans MeSH
• Paraproteinemias genetics   immunology   MeSH
• Aged MeSH
• Macrophage Activation Syndrome diagnosis   etiology   MeSH
• Schnitzler Syndrome * diagnosis   drug therapy   genetics   immunology   MeSH
• Urticaria diagnosis   etiology   immunology   MeSH
• Inflammation diagnosis   etiology   immunology   classification   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

Histone deacetylases (HDACs) are frequently deregulated in cancer, and several HDAC inhibitors (HDACi) have gained approval for treating peripheral T cell lymphomas. Here, we investigated the effects of pharmacological or genetic HDAC inhibition on NPM::ALK positive anaplastic large cell lymphoma (ALCL) development to assess the potential use of HDACi for the treatment of this disease. Short-term systemic pharmacological inhibition of HDACs using the HDACi Entinostat in a premalignant ALCL mouse model postponed or even abolished lymphoma development, despite high expression of the NPM::ALK fusion oncogene. To further disentangle the effects of systemic HDAC inhibition from thymocyte intrinsic effects, conditional genetic deletions of HDAC1 and HDAC2 enzymes were employed. In sharp contrast, T cell-specific deletion of Hdac1 or Hdac2 in the ALCL mouse model significantly accelerated NPM::ALK-driven lymphomagenesis, with Hdac1 loss having a more pronounced effect. Integration of gene expression and chromatin accessibility data revealed that Hdac1 deletion selectively perturbed cell type-specific transcriptional programs, crucial for T cell differentiation and signaling. Moreover, multiple oncogenic signaling pathways, including PDGFRB signaling, were highly upregulated. Our findings underscore the tumor-suppressive function of HDAC1 and HDAC2 in T cells during ALCL development. Nevertheless, systemic pharmacological inhibition of HDACs could still potentially improve current therapeutic outcomes.

• MeSH
• Anaplastic Lymphoma Kinase * metabolism   genetics   MeSH
• Lymphoma, Large-Cell, Anaplastic * drug therapy   pathology   genetics   metabolism   MeSH
• Benzamides pharmacology   MeSH
• Histone Deacetylase 1 * genetics   antagonists & inhibitors   physiology   metabolism   MeSH
• Histone Deacetylase 2 genetics   MeSH
• Histone Deacetylase Inhibitors * pharmacology   therapeutic use   MeSH
• Humans MeSH
• Mice MeSH
• Pyridines pharmacology   MeSH
• Genes, Tumor Suppressor * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

WW domain binding protein 1-like (WBP1L), also known as outcome predictor of acute leukemia 1 (OPAL1), is a transmembrane adaptor protein, expression of which was shown to correlate with ETV6-RUNX1 translocation and favorable prognosis in childhood leukemia. It has a broad expression pattern in hematopoietic and non-hematopoietic cells. Our previous work described WBP1L as a regulator of CXCR4 signaling and hematopoiesis. Here, we show that hematopoiesis in the mice with Wbp1l germline deletion is dysregulated, already at the level of hematopoietic stem cells and early progenitors. We further demonstrate that thymi of WBP1L-deficient mice are significantly enlarged and contain increased numbers of thymocytes of all subsets. This can potentially be explained by increased generation of multipotent progenitors 4 (MPP4) in the bone marrow, from which the thymus-seeding progenitors are derived. We also observed increases in multiple cell types in the blood. In addition, we show that WBP1L regulates hematopoietic stem cell functionality and leukocyte progenitor proliferation and gene expression during hematopoietic stem and progenitor cell transplantation, which contribute to more efficient engraftment of WBP1L-deficient cells. WBP1L thus emerges as a regulator of hematopoietic stem and progenitor cell function, which controls leukocyte numbers at the steady state and after bone marrow transplantation.

• MeSH
• Adaptor Proteins, Signal Transducing genetics   metabolism   MeSH
• Cell Differentiation MeSH
• Hematopoietic Stem Cells * metabolism   cytology   MeSH
• Hematopoiesis * genetics   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout * MeSH
• Mice MeSH
• T-Lymphocytes immunology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Progress in cytokine engineering is driving therapeutic translation by overcoming these proteins' limitations as drugs. The IL-2 cytokine is a promising immune stimulant for cancer treatment but is limited by its concurrent activation of both pro-inflammatory immune effector cells and antiinflammatory regulatory T cells, toxicity at high doses, and short serum half-life. One approach to improve the selectivity, safety, and longevity of IL-2 is complexing with anti-IL-2 antibodies that bias the cytokine toward immune effector cell activation. Although this strategy shows potential in preclinical models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multiprotein drug and concerns regarding complex stability. Here, we introduced a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine toward immune effector cells. We optimized IC construction and engineered the cytokine/antibody affinity to improve immune bias. We demonstrated that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared with natural IL-2, both alone and combined with immune checkpoint inhibitors. Moreover, therapeutic efficacy was observed without inducing toxicity. This work presents a roadmap for the design and translation of cytokine/antibody fusion proteins.

• MeSH
• Cytokines metabolism   MeSH
• Interleukin-2 * immunology   MeSH
• Humans MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Neoplasms immunology   therapy   drug therapy   MeSH
• Protein Engineering methods   MeSH
• T-Lymphocytes, Regulatory immunology   drug effects   MeSH
• Recombinant Fusion Proteins * pharmacology   immunology   administration & dosage   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

It has been reported in prospective randomized trials that antithymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis has benefits in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with unrelated donors (UDs). However, the optimal GVHD prophylaxis strategy has been challenged recently by the increasing use of posttransplant cyclophosphamide (PTCY). We report from the European Society for Blood and Marrow Transplantation registry the outcomes of 960 patients with myelodysplastic neoplasms who underwent allo-HSCT from UD with PTCY or ATG as GVHD prophylaxis. The primary outcomes were overall survival (OS) and progression-free survival (PFS). The disease characteristics were similar in both groups. Day 28 neutrophil engraftment was significantly better with ATG (93% vs 85%). Over a median follow-up of 4.4 years, the 5-year OS was 58% with PTCY, and 49% in the ATG group. The 5-year PFS was higher for PTCY at 53% vs 44% for ATG. Grade 2 to 4 acute GVHD incidence was lower when PTCY was used (23%), whereas there was no difference in the incidence of chronic GVHD at 5 years. Multivariable analyses confirmed better OS and PFS with PTCY with a hazard ratio (HR) for ATG of 1.32 (1-1.74) and a better PFS for PTCY with a HR for ATG of 1.33. This study suggests that GVHD prophylaxis using PTCY instead of ATG in this setting remains a valid option. Further prospective randomized studies would be essential to confirm these results.

• MeSH
• Antilymphocyte Serum * therapeutic use   MeSH
• Cyclophosphamide * therapeutic use   MeSH
• Adult MeSH
• Transplantation, Homologous MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Myelodysplastic Syndromes * therapy   mortality   MeSH
• Graft vs Host Disease * prevention & control   etiology   MeSH
• Unrelated Donors * MeSH
• Transplantation Conditioning methods   MeSH
• Aged MeSH
• Hematopoietic Stem Cell Transplantation * methods   adverse effects   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Cytokines * pharmacology   immunology   classification   therapeutic use   MeSH
• Erythropoietin analogs & derivatives   pharmacology   classification   therapeutic use   MeSH
• Granulocyte Colony-Stimulating Factor pharmacology   immunology   classification   therapeutic use   MeSH
• Interferons pharmacology   immunology   classification   therapeutic use   MeSH
• Interleukin-1 pharmacology   immunology   therapeutic use   MeSH
• Interleukin-2 pharmacology   immunology   therapeutic use   MeSH
• Receptors, Cytokine immunology   classification   MeSH
• Thrombopoietin agonists   pharmacology   classification   therapeutic use   MeSH
• Tumor Necrosis Factor-alpha pharmacology   therapeutic use   MeSH
• Publication type
• Review MeSH

Anti-T-lymphocyte globulin (ATLG) is used in hematopoietic stem cell transplantation (HSCT) to prevent graft-versus-host disease (GVHD) and graft failure. To date, insight in ATLG pharmacokinetics and -dynamics (PK/PD) is limited, and population PK (POPPK) models are lacking. In this prospective study, we describe ATLG POPPK using NONMEM® and the impact of ATLG exposure on clinical outcome and immune reconstitution in a homogeneous cohort of pediatric acute lymphoblastic leukemia (ALL) patients transplanted with a matched unrelated donor and receiving uniform ATLG dosing. Based on 121 patients and 812 samples for POPPK analysis, a two-compartmental model with parallel linear and non-linear clearance and bodyweight as covariate, best described the ATLG concentration-time data. The level of ATLG exposure (day active ATLG <1 AU/mL, median 16 days post-HSCT) was strongly associated with aGVHD grade II-IV, with a lower incidence in patients with prolonged active ATLG exposure (≤day 16 50% vs. >day 16 8.2%; P<0.001). When stratified for remission state, patients transplanted in complete remission (CR) 2 or 3 with prolonged ATLG exposure had a higher relapse risk, while this effect was not seen in CR1 patients (P=0.010). High level ATLG exposure was associated with delayed CD4 T-cell recovery at 4 and 8 weeks post-HSCT, but not at 12 weeks, and overall and relapse-free survival were not influenced by CD4 recovery at 12 weeks post-HSCT. This study underlines the importance of individualized ATLG exposure with the use of model-informed precision dosing in order to optimize the HSCT outcome in pediatric ALL.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * therapy   mortality   diagnosis   MeSH
• Antilymphocyte Serum * administration & dosage   MeSH
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Graft vs Host Disease * etiology   prevention & control   MeSH
• Child, Preschool MeSH
• Prospective Studies MeSH
• Recurrence MeSH
• Hematopoietic Stem Cell Transplantation * adverse effects   methods   MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

BACKGROUND: Infliximab selectively targets recently activated effector cells and, as an induction agent, might enable the safe elimination of mycophenolate from maintenance immunosuppression in kidney transplantation. METHODS: This is a phase II international multicenter open-label single-arm confidence interval (CI)-based clinical trial of the BIO-DrIM EU consortium aimed at assessing the efficacy and safety of rabbit antithymocyte globulin and infliximab induction in kidney transplantation. Sixty-seven primary kidney transplant recipients at low risk (panel-reactive antibodies <20%, no donor-specific antibodies [DSA]) received rabbit antithymocyte globulin (2 × 1.5 mg/kg, postoperative days 0 and 1) and infliximab (5 mg/kg, postoperative day 2), followed by mycophenolate-free tacrolimus-based immunosuppression for 12 mo. The primary endpoint was efficacy failure, defined as a composite of acute rejection, graft loss, or poor graft function (estimated glomerular filtration rate <40 mL/min) at 12 mo and was based on the endpoint of the comparator study. Additionally, a historical propensity-matched control cohort was established. RESULTS: Primary endpoint occurred in 22 of 67 patients (32.84%), with upper bound of an exact 1-sided 95% CI of 43.47%, which met the predefined criteria (efficacy failure of <40% and upper-bound 95% CI of <50%) and was similar in the historical matched cohort. By 12 mo, 79.1% of patients remained on the study protocol. Lower rates of BK replication (6% versus 22.4%; P = 0.013) but higher rates of de novo DSAs (11.9% versus 1.5%; P = 0.039) were observed in the study cohort. CONCLUSIONS: A similar efficacy of the study immunosuppression regimen to the comparator study and the historical matched cohort was found. However, a higher de novo DSA emergence points to an increased risk of antibody-mediated rejection (NCT04114188).

• MeSH
• Antilymphocyte Serum * MeSH
• Immunosuppressive Agents adverse effects   MeSH
• Immunosuppression Therapy MeSH
• Infliximab adverse effects   MeSH
• Enzyme Inhibitors MeSH
• Humans MeSH
• Graft Survival MeSH
• Antibodies MeSH
• Graft Rejection prevention & control   MeSH
• Tacrolimus * adverse effects   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial MeSH
• Multicenter Study MeSH