Background: Hereditary angioedema (HAE) caused by C1 inhibitor deficiency is a rare condition marked by recurrent swelling of the skin and mucous membranes. This study evaluated the effectiveness and safety of lanadelumab in routine clinical practice in Russia (IISR-2021-200085). Methods: A prospective cohort of 30 individuals with HAE was observed. Most patients were women (87%), with a mean age of 34 years; Seventeen percent of participants were adolescents. Prior to initiating lanadelumab, 16 patients (53%) had been receiving long-term prophylaxis, which was discontinued once lanadelumab was started. Treatment outcomes were assessed by comparing attack frequency, medication use for acute events, disease control scores, and quality of life before and after lanadelumab therapy. Results: Before treatment, patients reported an average of 8.6 attacks per month. After 6 months of lanadelumab treatment, the mean attack frequency was reduced to 0.5 per month (p < 0.001). Use of acute therapies decreased from 4.73 to 0.43 doses per month (p < 0.001). Disease control improved substantially, and quality-of-life scores improved from 58.2 to 25.3 points (p < 0.001). No significant lanadelumab-related adverse events were observed. Conclusion: In routine clinical practice, lanadelumab proved highly effective in reducing attack rates, enhancing disease control, and improving quality of life in patients with hereditary angioedema. The therapy was well tolerated, with no serious safety concerns identified. These findings reinforce lanadelumab as a reliable long-term prophylactic option for hereditary angioedema management.

Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by unpredictable attacks of angioedema. MENTALIST (UnMEt Needs in herediTAry angioedema—a gLobal physIcian perSpecTive) is the first international survey uncovering unmet needs and identifying barriers to optimal management in HAE following the latest update of the World Allergy Organization (WAO)/European Academy of Allergy and Clinical Immunology (EAACI) HAE guidelines. This web-based survey comprised 24 questions on HAE management and unmet needs. HAE-expert physicians from the Angioedema Centers of Reference and Excellence network ranked unmet needs according to their own perspectives and their patients’ perspectives, using a 10-point Likert scale ranging from 0 (not a challenge/unmet need at all) to 10 (huge challenge/unmet need). Of 64 respondents from 32 countries, most (91

Subcutaneous immunoglobulin (SCIG) preparations are widely used in patients with inborn errors of immunity (IEI), with proven efficacy and good tolerance. We assessed treatment efficacy, safety, and quality of life in a large cohort of IEI patients who switched from intravenous immunoglobulin (IVIG) to SCIG. Our observational study included 200 patients aged 1–65 years with IEI. SCIG Cutaquig (16.5%) was administered every 7–10 days for at least 12 months via the rapid push method. We assessed the rate of infection, immunoglobulin G (IgG) concentration, adverse events, and quality of life. A total of 8,787 SCIG doses were administered during the study. The rate of infections (per person/month) during SCIG treatment was 0.05, which was significantly lower compared to 0.19 during the IVIG period (p<0.001). The median trough IgG was 6.9 g/L on IVIG, compared to 9.0 g/L during the first six months, and 9.2 g/L during the next six months on SCIG. Systemic reactions occurred in 12.4% of the IVIG infusions and 1.9% of the SCIG infusions. The total scores on quality of life summary assessments of physical and mental health were higher on SCIG therapy compared with IVIG (p<0.001). At the end of the study, 85.6% of the patients chose to remain on SCIG. Our data suggest that SCIG infusion via the rapid push method is effective, well tolerated, and feasible in large groups of IEI patients, including those in large countries such as Russia.

BACKGROUND:Itch is the most bothersome symptom in chronic spontaneous urticaria (CSU) and severely affects quality of life. OBJECTIVE:To analyze factors associated with itch severity, and how itch is associated with quality of life and health care use in CSU. METHODS:We retrieved patient data from the Chronic Urticaria Registry. Patients were categorized by self-reported itch severity (recall period of 7 days). We used ordinal logistic regressions as well as negative binomial and gamma regressions with log link to investigate possible associations. RESULTS:A total of 3,045 patients, 74.3% female, mean age 44.4 years, with no, mild, moderate, or intense itch (16.4%, 25.2%, 32.5%, and 25.9%, respectively) were included. A higher itch rating was associated with symptomatic dermographism (odds ratio [OR] = 1.25; P = .027), malaise (OR = 1.43; P < .001), depression (OR = 1.46; P = .008), and laboratory signs of inflammation (ie, elevated erythrocyte sedimentation rate (OR = 1.57; P = .031) and leukocyte counts (OR = 2.37; P = .004)). Intense itch was associated with worse quality of life (Chronic Urticaria Quality of Life Questionnaire; P < .001) and more patients visiting a general practitioner, allergologist or dermatologist, and the emergency room (P < .001). CONCLUSIONS:Higher itch levels are associated with inflammation and depression and are linked to worse quality of life and increased health care demand. Addressing itch is crucial to reducing the humanistic and societal burden in CSU.

In many situations, the use of PROMs in clinical practice is restricted by barriers that the doctor considers, such as the patient's dislike of filling out PROMs, time constraints, etc. That is why our aim is to assess patients' level of knowledge and level of satisfaction with the use of PROMs in chronic urticaria (CU).

BACKGROUND:Patients with partial DiGeorge syndrome (pDGS) can present with immune dysregulation, the most common being autoimmune cytopenia (AIC). There is a lack of consensus on the approach to type, combination, and timing of therapies for AIC in pDGS. Recognition of immune dysregulation early in pDGS clinical course may help individualize treatment and prevent adverse outcomes from chronic immune dysregulation. OBJECTIVES:Objectives of this study were to characterize the natural history, immune phenotype, and biomarkers in pDGS with AIC. METHODS:Data on clinical presentation, disease severity, immunological phenotype, treatment selection, and response for patients with pDGS with AIC were collected via retrospective chart review. Flow cytometric analysis was done to assess T and B cell subsets, including biomarkers of immune dysregulation. RESULTS:Twenty-nine patients with the diagnosis of pDGS and AIC were identified from 5 international institutions. Nineteen (62%) patients developed Evan's syndrome (ES) during their clinical course and twenty (69%) had antibody deficiency syndrome. These patients demonstrated expansion in T follicular helper cells, CD19hiCD21lo B cells, and double negative cells and reduction in CD4 naïve T cells and regulatory T cells. First-line treatment for 17/29 (59%) included corticosteroids and/or high-dose immunoglobulin replacement therapy. Other overlapping therapies included eltrombopag, rituximab, and T cell immunomodulators. CONCLUSIONS:AIC in pDGS is often refractory to conventional AIC treatment paradigms. Biomarkers may have utility for correlation with disease state and potentially even response to therapy. Immunomodulating therapies could be initiated early based on early immune phenotyping and biomarkers before the disease develops or significantly worsens.

Background: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment. Objective: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE). Methods: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022). Results: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms. Conclusion: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care.

Background: The problem of identifying vaccine-specific T-cell responses is still a matter of debate. Currently, there are no universal, clearly defined, agreed upon criteria for assessing the effectiveness of vaccinations and their immunogenicity for the cellular component of immunity, even for healthy people. But for patients with inborn errors of immunity (IEI), especially those with antibody deficiencies, evaluating cellular immunity holds significant importance. Aim: To examine the effect of one and two doses of inactivated adjuvanted subunit influenza vaccines on the expression of endosomal Toll-like receptors (TLRs) on the immune cells and the primary lymphocyte subpopulations in patients with common variable immunodeficiency (CVID). Materials and methods: During 2018–2019, six CVID patients received one dose of a quadrivalent adjuvanted influenza vaccine; in 2019–2020, nine patients were vaccinated with two doses of a trivalent inactivated influenza vaccine. The proportion of key lymphocyte subpopulations and expression levels of TLRs were analyzed using flow cytometry with monoclonal antibodies. Results: No statistically significant alterations in the absolute values of the main lymphocyte subpopulations were observed in CVID patients before or after vaccination with the different immunization protocols. However, after vaccination, a higher expression of TLR3 and TLR9 in granulocytes, monocytes, and lymphocytes was found in those patients who received two vaccine doses rather than one single dose. Conclusion: This study marks the first instance of using a simultaneous two-dose vaccination, which is associated with an elevated level of TLR expression in the immune cells. Administration of the adjuvanted vaccines in CVID patients appears promising. Further research into their impact on innate immunity and the development of more effective vaccination regimens is warranted.

GATA2 deficiency is a rare disease belonging to the group of phagocyte birth defects, which is clinically manifested by four syndromes: MonoMac syndrome (myedysplasia and immunodeficiency associated with the development of infections caused by Mycobacterium avium complex); monocyte, dendritic cell, B- and NK-lymphocyte deficiency syndrome; Emberger syndrome, including primary lymphedema with myelodysplasia and sensorineural hearing loss, as well as familial myelodysplastic syndrome and acute myeloid leukemia. The disease is inherited by autosomal dominant type, but in most cases, mutations ofthe germ line of the GATA2 gene occur de novo. The first manifestations of the disease occur in early adulthood, the course of GATA2 deficiency is variable and may differ in individuals in the same family with similar genetic variants. The article presents a clinical case of manifestation of GATA2 deficiency at the age of seven years in the form of development of generalized verrucosis, lymphostasis of the lower limb, generalized tuberculosis with involvement of the abdominal cavity, small pelvis, and chest organs. The examination revealed deficiency of monocytes, B- and NK-lymphocytes, myelodysplastic syndrome with multilineage dysplasia. We present a detailed description of the clinical picture and peculiarities of the course of the primary immunodeficiency state, the results of the examination and treatment.

Background: Deficiency of adenosine deaminase 2 (DADA2) results in heterogeneous manifestations including systemic vasculitis and red cell aplasia. The basis of different disease phenotypes remains incompletely defined. Objective: We sought to further delineate disease phenotypes in DADA2 and define the mechanistic basis of ADA2 variants. Methods: We analyzed the clinical features and ADA2 variants in 33 patients with DADA2. We compared the transcriptomic profile of 14 patients by bulk RNA sequencing. ADA2 variants were expressed experimentally to determine impact on protein production, trafficking, release, and enzymatic function. Results: Transcriptomic analysis of PBMCs from DADA2 patients with the vasculitis phenotype or pure red cell aplasia phenotype exhibited similar upregulation of TNF, type I interferon, and type II interferon signaling pathways compared with healthy controls. These pathways were also activated in 3 asymptomatic individuals with DADA2. Analysis of ADA2 variants, including 7 novel variants, showed different mechanisms of functional disruption including (1) unstable transcript leading to RNA degradation; (2) impairment of ADA2 secretion because of retention in the endoplasmic reticulum; (3) normal expression and secretion of ADA2 that lacks enzymatic function; and (4) disruption of the N-terminal signal peptide leading to cytoplasmic localization of unglycosylated protein. Conclusions: Transcriptomic signatures of inflammation are observed in patients with different disease phenotypes, including some asymptomatic individuals. Disease-associated ADA2 variants affect protein function by multiple mechanisms, which may contribute to the clinical heterogeneity of DADA2. (J Allergy Clin Immunol 2023;152:771-82.)

Показатели врожденного иммунитета при общей вариабельной иммунной недостаточности и X-сцепленной агаммаглобулинемии 1 Федеральное государственное бюджетное учреждение «Государственный научный центр «Институт иммунологии» Федерального медико-биологического агентства

Продукция цитокинов наивными В-лимфоцитами и В-клетками памяти при стимуляции in vitro 1 Федеральное государственное бюдж етное учреждение «Государственный научный центр «Институт иммунологии» Федерального медико-биологического агентства, 115522, г.Москва, Российская Федерация 2 Федеральное государственное бюджетное образовательное учреждение высшего образования «Московский государственный университет им.М.В.Ломоносова», 119234, г.Москва, Российская Федерация 3 Федеральное государственное автономное образовательное учреждение высшего образования «Российский университет дружбы народов имени Патриса Лумумбы» Министерства науки и высшего образования Российской Федер ации, 117198, г.Москва, Российская Федерация РезюмеВведение.В литературе довольно подробно описана роль отдельных цитокинов в индукции дифференцировки различных субпопуляций В-клеток в плазмабласты и плазматические клетки.В то же время остается малоизученным вопрос о том, какие цитокины продуцируют сами В-лимфоциты и их субпопуляции.Цель исследования -определить цитокиновый профиль В-лимфоцитов человека при стимуляции in vitro.В задачи исследования также входило сравнительное изучение спектра цитокинов, секретируемых наивными В-лимфоцитами, а также В-клетками памяти с переключенным и непереключенным синтезом Ig.Материал и методы.Субпопуляции наивных В-лимфоцитов, а также В-клеток памяти с переключенным (IgG + CD27 + ) и непереключенным (IgM + CD27 + ) синтезом Ig выделяли с помощью проточного сортировщика клеток.Выделенные В-лимфоциты стимулировали in vitro в присутствии экзогенного ИЛ-21 и фидерных клеток, несущих молекулу CD40L.Супернатанты, собранные от стимулированных В-клеток, анализировали на наличие цитокинов.Исследование носило скрининговый характер.Чтобы охватить максимально широкую панель цитокинов, в работе использовался высокопроизводительный метод мультиплексного анализа.В тестируемую панель входили следующие цитокины: ЭФР, эотаксин, Г-КСФ, ГМ-КСФ, ИФН-α2, ИФН-γ, ИЛ-10, ИЛ-12P40, ИЛ-12P70, ИЛ-13, ИЛ-15, ИЛ-17A, ИЛ-1RA, ИЛ-1α, ИЛ-1β, ИЛ-2, ИЛ-3, ИЛ-4, ИЛ-5, ИЛ-6, ИЛ-7, ИЛ-8, IP-10, MCP-1, MIP-1α, MIP-1β, RANTES, ФНОα, ФНОβ, VEGF, ФРФ-2, ТФРα, Flt-3L, фракталкин, GRO, MCP-3, MDC, PDGF-AA, PDGF-AB/BB и ИЛ-

Background: for the first time, the effect of one and two doses of adjuvanted influenza vaccines on toll-like receptors (TLRs) in patients with common variable immunodeficiency (CVID) was studied and compared (primary vaccination with one vs. two doses, primary vs. repeated vaccination). Materials and methods: Six patients received one dose of quadrivalent adjuvanted influenza vaccine during the 2018–2019 and 2019–2020 influenza seasons, and nine patients with CVID received two doses of trivalent inactivated influenza vaccine during 2019–2020. Expression of TLRs was measured by flow cytometry. Results: The expression of toll-like receptors in patients with CVID was noted both with repeated (annual) administration of the influenza vaccine and in most cases was accompanied by an increase in the proportion of granulocytes (TLR3 and TLR9), lymphocytes (TLR3 and TLR8), and monocytes (TLR3 and TLR9). When carried out for the first time as a simultaneous vaccination with two doses it was accompanied by an increase in the proportion of granulocytes, lymphocytes expressing TLR9, and on monocytes—TLR3 and TLR9. Conclusion: in CVID patients, the use of adjuvanted vaccines is promising, and research on the influence of the innate immunity and more effective regimens should be continued.

Поствакцинальный и постинфекционный гуморальный иммунный ответ на инфекциюSARS-CoV-2 1 Федеральное государственное бюджетное учреждение «Государственный научный центр «Институт иммунологии» Федерального медико-биологического агентства, 115522, г.Москва, Российская Федерация 2 Федеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет имени И.М.Сеченова» Министерства здравоохранения

Allergen-specific immunotherapy (AIT) is a safe, effective treatment for respiratory allergies (such as moderate-to-severe allergic rhinoconjunctivitis) that are not controlled by symptomatic medications. The indications and contraindications for AIT have been defined in international guidelines and consensus statements. However, some of these contraindications are not evidenced- based but have been deduced from the theoretical risk of an interaction between AIT disease-modifying effect and immune or inflammatory comorbidities. In the absence of clinical trial evidence, the accumulation of experience as case reports can narrow the spectrum of absolute contraindications. The majority of international guidelines list HIV infection as a contraindication to AIT. Here, we describe two cases of safe, effective sublingual birch pollen AIT in HIV-positive patients undergoing concomitant antiretroviral therapy. A 32-year-old female and a 63-year-old male sensitized to tree pollen and with clinically confirmed birch pollen allergy underwent pre- and co-seasonal sublingual birch pollen AIT for three and two pollen seasons, respectively. The therapy was associated with a marked reduction in the frequency and intensity of allergic symptoms, and the reduced use of (symptomatic) rescue medication. Mild, local, treatment-emergent adverse events were noted throughout the course of treatment but resolved spontaneously. No serious adverse events were reported. In particular, there were no obvious harmful effects on the patients' immune status or viral load. Hence, sublingual birch pollen AIT proved to be effective and safe in two HIV-positive patients.

According to the data from Russian primary immunodeficiencies (PID) registry 71% of registered patients were treated with immunoglobulins (IG). Regular immunoglobulin substitutions were reported in 90% of patients with primary antibody deficiencies (PAD), 86% - with syndromic PID and 91% of patients with combined T and B cell defects. The study was supported by Academic Council of Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology and approved by Local Ethical Committee within the Russian PID registry. Regular IG substitution was analyzed in the representative cohort of 235 PID patients from 12 Russian regions. Of these 121 were children, 114 – adults. In 78% cases IG treatment has been started during the first 10 years of life. 80% patients were treated with highly safe products (Octagam 5% and 10%, Privigen, IG VENA, Gamunex) reaching therapeutic median pre-infusion level of serum IgG of 7 g/l. Significantly lower levels of pre-infusion serum IgG were observed in patients treated with Gabreglobin-IgG. Irregular treatment was observed in 61% of patients mainly due to the poor drug supply (lack of medication in the health care centers). Infections were reported in 90% percent of patients with irregular treatment. Unscheduled hospitalizations were two times more frequent in the group of patients with irregular IVIG treatment. Additionally, we assessed quality of life of patients with regular IVIG treatment, which significantly improved in comparison with the pretreatment period and became comparable to the group of healthy controls.