JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study.

BACKGROUND: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. OBJECTIVE: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. METHODS: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. RESULTS: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. CONCLUSIONS: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.

[Cervical lymphadenitis caused by non-tuberculous mycobacteria in children with different residence]. / Zervikale Lymphadenitis durch atypische Mykobakterien bei Kindern mit unterschiedlichem Wohnsitz.

OBJECTIVE: Atypical mycobacteria form a heterogeneous group. Although more than 140 species have been identified, only 25 of them are considered responsible for infection in humans. The most frequent manifestation of the disease in immunocompetent children is the cervical lymphadenitis. Aims of this study were to identify a correlation of the location of residence with patients' demographics and disease characteristics, to evaluate the ultrasonographic findings and the different operative treatments modalities and to develop an algorithm for the diagnosis and treatment. MATERIALS AND METHODS: Cases were identified by using the hospital's correspondence, microbiology and pathology databases. Demographic and clinical data were collected. A statistical analysis of the results was performed. RESULTS: 32 patients were included. Our data revealed no significant correlation between area of residence and disease characteristics. Hypoechoic lymph nodes with intraglandular necrosis and low vascularity were observed in the majority of patients. Surgical treatment included abscess incision with biopsy, lymphadenectomy, selective neck dissection and partial parotidectomy. A recurrent disease was significantly more frequent after abscess incision. CONCLUSIONS: Further studies with prospective design are required, in order to confidently identify the correlation between area of residence and disease characteristics. Similar ultrasonographic findings suggest a constant constellation of changes that facilitate diagnostic evaluation. Complete surgical excision offers an effective management option as it combines definitive treatment and histological confirmation with low risk of complications.

Chronic natural killer cell lymphocytosis is associated with elevated cytotoxic activity of natural killer cells.

The authors describe a 16-year-old girl who has suffered from chronic natural killer cell lymphocytosis (CNKL) for 12 years. From age 4 years, she has shown a persistent lymphadenopathy and lymphocytosis. Clinically, she developed allergic skin involvement, thrombocytopenia, and peripheral polyneuropathy. Annual flow cytometry analyses of lymphocyte subsets revealed persistently elevated NK cell levels (55-75% of the lymphocyte fraction and 0.7-10 x 10(3) NK cells per microliter of blood). Furthermore, IgE serum concentrations were markedly increased. Based on CD16, CD161, and CD94 surface antigen expression, the NK cell population was characterized as mature NK cells. Functional analysis of these cells showed a 2-fold increase of intrinsic cytotoxic activity toward K-562 cells compared with NK cells from healthy controls. The authors present a clinical case of rare CNKL. The patient's NK cells possess significantly increased cytotoxic activity. These findings are discussed in context with elevated IgE concentrations.