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Rheumatol Int. 2025 Nov 4;45(11):264. doi: 10.1007/s00296-025-06020-0.

NO ABSTRACT

PMID:41186676 | DOI:10.1007/s00296-025-06020-0

BMC Pediatr. 2025 Nov 3;25(1):898. doi: 10.1186/s12887-025-06286-0.

ABSTRACT

INTRODUCTION: Activated PI3Kδ Syndrome (APDS) is a rare inborn error of immunity characterized by recurrent infections, lymphoproliferation, and autoimmunity. It results from mutations in the phosphoinositide 3-kinase delta (PI3Kδ) signalling pathway, leading to either gain-of-function (APDS1) or loss-of-function (APDS2) phenotypes. Clinical presentation ranges from asymptomatic to severe, depending on the underlying genetic defect. Malignancy, particularly lymphoma, represents the most frequent and life-threatening complication. Due to overlapping features with other primary immunodeficiencies, APDS is often misdiagnosed as combined immunodeficiency. Early molecular testing, particularly genetic analysis, is therefore crucial for accurate diagnosis. Although management remains complex and heterogeneous, there is growing interest in targeted approaches, particularly PI3Kδ-specific therapy.

CASE REPORT: We describe a 12-year-old boy with recurrent respiratory and ear infections since infancy, accompanied by persistent lymphadenopathy, hepatosplenomegaly, and thrombocytopenia. Initial immunological evaluation suggested combined immunodeficiency, and prophylactic antibiotics were initiated, but genetic testing was deferred due to mild clinical features and parental reluctance. Following multiple years of enduring symptoms, genetic investigation identified a PIK3CD mutation leading in a missense alteration p.Glu1021Lys, confirming APDS 1. The patient was subsequently commenced on immunoglobulin replacement therapy and consulted for consideration of immunosuppressive and targeted pathway blocker therapy.

CONCLUSION: This case highlights the diagnostic challenges of APDS, arising from both overlapping clinical features with other immunodeficiencies and external factors such as cost and parental decision-making. Early genetic testing facilitates accurate diagnosis, and timely recognition of APDS enables appropriate management, including immunosuppressive, targeted therapies and, in selected cases, potentially curative hematopoietic stem cell transplantation.

PMID:41184801 | DOI:10.1186/s12887-025-06286-0

J Med Invest. 2025;72(3.4):430-433. doi: 10.2152/jmi.72.430.

ABSTRACT

BACKGROUND: Adenosine deaminase 2 (ADA2) deficiency is a rare autosomal recessive autoinflammatory disorder characterized by systemic vasculitis, recurrent stroke, and immunodeficiency. This results from the biallelic loss-of-function variants of ADA2, leading to enzymatic dysfunction and endothelial impairment. Although it is commonly diagnosed during childhood, adult-onset cases with milder phenotypes have also been reported.

OBJECTIVE: We report a case of adult-onset ADA2 deficiency that presented with recurrent juvenile stroke and systemic vasculitis.

CASE: A 42-year-old female with recurrent juvenile stroke and systemic vasculitis symptoms was diagnosed with ADA2 deficiency by genetic testing. The patient had a known pathogenic variant, c.139G>C (p.Gly47Arg), in a homozygous state. Given the mild phenotype and stable condition, the patient continued long-term aspirin therapy without additional immunosuppressive treatment.

CONCLUSION: This case highlights the importance of considering ADA2 deficiency in patients with unexplained stroke and recurrent vasculitis, particularly those with a history of parental consanguinity. Measurement of serum ADA activity may serve as a potential screening tool for ADA2 deficiency, especially in settings in which genetic testing is not readily available. J. Med. Invest. 72 : 430-433, August, 2025.

PMID:41183948 | DOI:10.2152/jmi.72.430

Front Pediatr. 2025 Oct 17;13:1670623. doi: 10.3389/fped.2025.1670623. eCollection 2025.

ABSTRACT

Atopic dermatitis is a common inflammatory skin disease with rapidly expanding worldwide prevalence. Increasingly, cases of severe and early-onset dermatitis have been identified and found to be due to underlying monogenic mutations, leading to immune dysregulation. These conditions, called primary atopic disorders, have become an area of extensive study over the last 30 years. Simultaneously, our understanding of the human microbiome has steadily grown, and there is clear evidence that dysbiosis plays a major role in atopic dermatitis, not only in severity of disease and as a potential trigger but also offering clues for targeted treatment strategies. Unfortunately, despite our growing understanding of the cutaneous microbiome and the expanding availability of genetic testing allowing for diagnosis of primary atopic disorders, there remains very limited understanding regarding the microbiomics changes that underlie these disorders. Here we review the current research regarding atopic dermatitis in the setting of primary atopic disorders, understanding regarding primary atopic disorders and associated cutaneous dysbiosis, and identify specific gaps in knowledge.

PMID:41181176 | PMC:PMC12575195 | DOI:10.3389/fped.2025.1670623

Front Immunol. 2025 Oct 16;16:1613195. doi: 10.3389/fimmu.2025.1613195. eCollection 2025.

ABSTRACT

INTRODUCTION: Long COVID (LC) affects approximately 10% of individuals post-SARS-CoV-2 infection, with symptoms persisting beyond 12 weeks. The underlying mechanisms remain unclear, and current models often focus on pre-existing comorbidities.

METHODS: This cohort study aimed to identify robust biomarkers and clarify LC pathogenesis through a comprehensive analysis performed in 32 LC individuals 26 months post-infection compared with 35 fully recovered individuals recruited between March and July 2022. Blood and fecal samples were collected, and multiple parameters associated with immune dysfunction, endothelial damage, bacterial translocation, and coagulation alterations, alongside signs of viral persistence and sociodemographic and clinical features, were analyzed.

RESULTS: Although viral RNA was undetected on blood or stool, elevated plasma IgG against the nucleocapsid may indicate frequent reinfections, greater infection severity, or delayed immune normalization. Increased levels of prothrombin, thrombin, fibrinogen, sEPCR, and CRP pointed to persistent endothelial dysfunction and coagulation imbalance. Lower levels of the bactericidal protein REG3A suggest potential disruptions in mucosal immune response. We found no major differences in traditional comorbidities, highlighting that LC may stem from distinct pathogenic mechanisms beyond pre-existing conditions. Importantly, our study revealed impaired humoral immunity and identified an association between vaccine heterogeneity and increased LC risk, emphasizing the relevance of consistent vaccination strategies. A Random Forest model using the measured biomarkers achieved 100% accuracy in classifying LC individuals, reinforcing their diagnostic potential.

DISCUSSION: These findings support a multifactorial model of LC involving immune dysregulation and persistent endothelial damage that led to coagulation abnormalities and a pro-thrombotic profile, supporting that LC is more closely related to a sustained, uncontrolled inflammatory response rather than immunodeficiency, and underscoring the value of multidimensional biomarker profiling for guiding clinical management and prevention strategies.

PMID:41181095 | PMC:PMC12571756 | DOI:10.3389/fimmu.2025.1613195

Cureus. 2025 Sep 28;17(9):e93439. doi: 10.7759/cureus.93439. eCollection 2025 Sep.

ABSTRACT

Background Children with primary immunodeficiency disorders (PIDDs) are at an increased risk of developing malignancies due to impaired immune surveillance and genomic instability. In Saudi Arabia, limited data exist regarding the frequency, characteristics, and outcomes of secondary malignancies in this vulnerable population. Therefore, this study aimed to evaluate the clinical features, types of PIDD, associated secondary malignancies, treatment modalities, and outcomes among pediatric patients with PIDD treated at a tertiary care center in Saudi Arabia. Methods This retrospective observational cohort study included 28 pediatric patients diagnosed with both PIDD and malignancy at King Fahad Medical City, Riyadh, between January 2009 and January 2023. Clinical, demographic, and treatment-related data were collected and analyzed using descriptive statistics and Kaplan-Meier survival analysis. Results Among the 1,793 pediatric oncology patients reviewed, 28 (1.56%) were diagnosed with both PIDD and a secondary malignancy. Most patients were male (64.3%) and Saudi nationals (82.1%). Hematologic malignancies were predominant (85.7%), with secondary hemophagocytic lymphohistiocytosis (42.9%) and diffuse large B-cell lymphoma (21.4%) being the most common. Griscelli syndrome (32.1%) and ataxia-telangiectasia (17.9%) were the most frequently observed PIDD. Chemotherapy was administered to 96.4% of patients, with dose adjustments required in 25.9%. Febrile neutropenia was reported in 70.4%, and infections were documented in 75% of cases. Bone marrow transplantation was performed in 39.3% of patients. Progression-free survival was 92.2%, and overall survival was 64.3%, with sepsis accounting for 80% of deaths. Conclusion Children with PIDD are at high risk for developing early-onset, aggressive malignancies, especially hematologic cancers. Despite significant treatment-related complications and infection susceptibility, curative approaches such as chemotherapy and transplantation are feasible. Early identification, individualized treatment, and aggressive infection control are crucial to improving survival outcomes in this high-risk population.

PMID:41179098 | PMC:PMC12571695 | DOI:10.7759/cureus.93439

J Allergy Clin Immunol. 2025 Oct 30:S0091-6749(25)01079-6. doi: 10.1016/j.jaci.2025.10.020. Online ahead of print.

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) includes a heterogeneous group of patients with predominantly antibody deficiencies featuring infectious and non-infectious complications that might lead to severe organ-damage and shortened survival. Appropriate clinical management of CVID has been hampered by the lack of robust biomarkers to predict the development of clinical complications and patient outcome.

OBJECTIVE: Here, we investigated the association of individual serological, cellular and molecular biomarkers with disease behavior and outcome in CVID.

METHODS: A multicentric cohort of 209 CVID patients was studied using age-matched reference values (from 334 healthy donors) to better define TCD4⁺ naive-cell defects (late-onset combined immunodeficiency -LOCID-) and classify CVID-associated B-cell/plasma cell (PC) and NK-cell defects.

RESULTS: Globally, susceptibility to respiratory infections was strongly associated with low serum immunoglobulin (sIg), particularly sIgA, whereas non-infectious complications and disease severity mostly depended on TCD4⁺ naive-cell, NK-cell and B-cell/PC defects. LOCID was independently associated with splenomegaly, lymphadenopathy, interstitial lung disease, cytopenia and lymphoma. Milder B-cell/PC defects (MBC⁺/PC⁺/Ab^–) protected from non-infectious complications, whereas a marked defect of classical CD27⁺ memory B-cells (27MBC^–) (with decreased NK-cell and sIgM) was associated with enteropathy and (with LOCID and sIgA) liver disease. Together, lower sIgG, LOCID and particularly, 27MBC^–, were strongly associated with shortened survival and early-death in CVID. Conversely, CVID-associated pathogenic/risk alleles did not emerge as independent factors associated with disease behavior and outcome.

CONCLUSION: Our results provide a new set of biomarkers closely associated with infectious and non-infectious complications of CVID, which together, predict survival and might contribute to guide patient monitoring and clinical management.

PMID:41176068 | DOI:10.1016/j.jaci.2025.10.020

An Acad Bras Cienc. 2025 Oct 27;97(4):e20250206. doi: 10.1590/0001-3765202520250206. eCollection 2025.

ABSTRACT

Hereditary Angioedema (HAE) is a rare and severe genetic disorder caused by the deficiency of C1 Esterase Inhibitor (C1-INH), leading to unexpected and potentially fatal episodes of edema. This study assessed the quality of life (QoL) of adults with HAE in a Brazilian cohort, which comprised 29 adult patients with a confirmed HAE diagnosis, recruited from a public referral hospital. Participants completed the international HAE-specific quality of life questionnaire (IHAE-QoL v.1.1) at three time intervals: baseline, 6 months, and 1 year. This instrument assesses multiple QoL domains, including physical, emotional, social, and treatment-related aspects. Data were analyzed using SPSS v.29.0. and descriptive statistics. Group comparisons were conducted using chi-square, Student’s t-test, and Mann-Whitney U tests. The results showed statistically significant differences in the impact of HAE on QoL between sexes. While 42.9% of males reported work/study limitations, 90.9% of females expressed concern over treatment availability. Additionally, 57.1% of men reported a moderate impact on social life. The findings highlight the substantial impact of HAE on patients’ quality of life and highlight sex-specific challenges, reinforcing the need for targeted interventions to enhance disease management and QoL.

PMID:41172405 | DOI:10.1590/0001-3765202520250206

Pediatr Allergy Immunol. 2025 Nov;36(11):e70234. doi: 10.1111/pai.70234.

ABSTRACT

BACKGROUND: Patients with chronic granulomatous disease (CGD) can develop hemophagocytic lymphohistiocytosis (HLH), exacerbating mortality risk. Despite its clinical significance, data on HLH in CGD from international cohorts remain limited. This study aims to describe the occurrence of HLH in a cohort of patients with CGD, providing clinical insight into this association and emphasizing the need for early recognition and effective management.

METHODS: The records of 60 patients with CGD were reviewed. Those meeting the diagnostic criteria for HLH based on the HScore were included in the analysis. Both descriptive and inferential statistics were employed to evaluate the data.

RESULTS: Eleven patients (18.3%) fulfilled the HLH diagnostic criteria. The median interval between CGD genetic diagnosis and HLH onset was 36 months, with a median age at HLH diagnosis of 67 months. Infectious triggers were identified in eight cases, with Salmonella and Aspergillus species being the most common. One case involved an inflammatory trigger-multisystem inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection. Mortality was high: 72.7% of the patients with HLH died. No significant difference (p = .338) was observed between those who died after receiving only immunosuppressive therapy (n = 2) and those who received both intravenous immunoglobulin and immunosuppressive therapy (n = 6).

CONCLUSION: HLH in CGD is associated with a high mortality rate. Notably, MIS-C can present as an inflammatory trigger for HLH in this population. Careful evaluation of HLH parameters is recommended for all patients with CGD admitted with infection or inflammation to facilitate early diagnosis and guide management.

PMID:41174960 | DOI:10.1111/pai.70234

Mol Ther. 2025 Oct 30:S1525-0016(25)00929-3. doi: 10.1016/j.ymthe.2025.10.054. Online ahead of print.

ABSTRACT

Gene therapies offer new possibilities for the precise correction of monogenic disorders. Here, we present the first prime editing (PE)-based gene repair strategy for pathogenic COL17A1 variants that cause junctional epidermolysis bullosa (JEB). Type XVII collagen (C17), encoded by COL17A1, plays a critical role in skin aging, regeneration, and the maintenance of epidermal stem cell integrity. Treatment of primary human JEB keratinocytes with PE mRNAs resulted in COL17A1 editing efficiencies of up to 60% in bulk-treated cells, leading to the restoration of full-length, accurately shed C17. CAST-Seq analysis of gene-edited JEB keratinocytes confirmed the absence of unintended chromosomal rearrangements at potential off-target sites and only minimal on-target aberrations. Remarkably, in a xenograft model, in which C17-positive cells represented only 55.9% of the input population, COL17A1-corrected cells populated 92.2% of the basal keratinocyte layer in the resulting skin grafts after 6 weeks. These observations highlight a potential selective advantage imparted by C17 restoration, in line with its canonical role in anchoring hemidesmosomes to the basement membrane and preserving the structural integrity of the interfollicular epidermal stem cell niche. Based on our results, we envision prime editing as an efficient and safe option to restore gene function in EB and other genodermatoses.

PMID:41174881 | DOI:10.1016/j.ymthe.2025.10.054