Stefano Volpi

Correction on: Manganelli M, Cantalice P, Papri J, Drago E, De Lucchi N, Accorsi G, Fresia C, Simonetti S, Guida G, Cazzato G, Della Mura M, Ingravallo G, Caorsi R, Volpi S, La Torre F and Gattorno M (2026) SAVI: molecular mechanisms, clinical spectrum and precision medicine approaches beyond type-I IFN. Front. Immunol. 17:1928419. doi: 10.3389/fimmu.2026.1928419 Funder name incorrect An incorrect Funding statement was provided.The correct funder is Finanziato dall'Unione europea -Next Generation EU -PNRR M6C2 -Investimento 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN, codice progetto PNRR-POC-2023-12377470.The author(s) declared that financial support was received for this work and/or its publication. This research was supported by funds from Finanziato dall'Unione europea -Next Generation EU -PNRR M6C2 -Investimento 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN, codice progetto PNRR-POC-2023-12377470.The original version of this article has been updated.

Type I interferonopathies (TI-IFN) represent a heterogeneous group of autoinflammatory disorders characterized by upregulated type I interferon (IFN) signaling. Among them, STING-associated vasculopathy with onset in infancy (SAVI) is a rare, severe autoinflammatory disease caused by gain-of-function mutations in the STING1 gene. Mechanistically, these mutations lead to a constitutive activation of the STING protein, resulting in excessive type I interferon production, which drives chronic inflammation and damage to various organs, primarily as cutaneous vasculopathy and progressive interstitial lung disease (ILD). Emerging clinical data indicate that current therapeutic options – including Janus kinase inhibitors (JAKi), biological agents as anifrolumab and solid organ transplantation – for SAVI face limited and often inconsistent long-term efficacy, highlighting a significant unmet need. Consistently, preclinical models highlight that SAVI pathogenesis is not only driven by the interferon storm, but relies also on non-canonical IFN-independent cellular pathways across distinct hematopoietic and non-hematopoietic compartments. This review provides a comprehensive overview of SAVI pathogenesis, from mutational mechanisms and comparative phenotypes to the clinical challenges of advanced interventions. Finally, we discuss future therapeutic prospects and clinical implications, exploring next-generation frontiers such as patient-derived induced pluripotent stem cell (iPSCs) models, hematopoietic stem cell transplantation (allo-HSCT) and gene editing (GE) technologies. The transition from immune - to a mutational-perspective, provides a foundational framework to optimize diagnostic and therapeutic strategies for precision medicine in SAVI patients.

Caring for children with complex immune disorders is part of the heritage of pediatric rheumatology that extends back to the original founders of the field. Over the past 50 years, pediatric rheumatologists have been central to advancing discovery and pioneering innovative treatment approaches for pediatric patients with multifaceted immune dysfunction. This includes dissecting disease mechanisms and identifying novel genes associated with inflammasome activation, IL‐18 opathies, type I interferonopathies, monogenic mosaic disorders, and other forms of immune dysregulation. Pediatric rheumatologists have made foundational contributions to the management of patients with these conditions by leveraging their expertise in existing immunomodulatory medications and recognizing new drug targets. In the next 50 years, scientists and clinicians in the field are poised to make substantial innovations in understanding the causes and biomarkers of immune dysregulation. By harnessing the power of precision medicine, cellular therapies, and immune multidisciplinary teams, pediatric rheumatologists will continue to drive discoveries that will improve outcomes for patients with immune dysregulation.

The combined newborn screening program for Spinal Muscular Atrophy (SMA) and Severe Combined Immunodeficiency (SCID) was evaluated in Liguria through a five-year pilot study involving 32,289 newborns. A single multiplex real-time PCR assay on dried blood spots enabled simultaneous detection of SMN1 exon 7 deletions and quantification of T-Cell Receptor Excision Circles (TREC) and Kappa-Deleting Recombination Excision Circles (KREC), achieving near-complete population coverage and a low recall rate. Ten newborns received a confirmed diagnosis of a targeted condition: five newborns were diagnosed with spinal muscular atrophy (SMA), of whom four were treated presymptomatically and achieved favorable clinical outcomes, whereas one with SMA type 0 died a few days after birth. Five newborns were diagnosed with immunodeficiencies, including two cases of adenosine deaminase (ADA)-related severe combined immunodeficiency (SCID), and three clinically significant secondary findings (idiopathic T-cell lymphopenia, DiGeorge syndrome, and transient B-cell lymphopenia). No false-negative cases were observed during follow-up. The TREC and KREC profiles were consistent with the underlying immunological diagnoses. Overall, the study demonstrates that combined SMA and SCID newborn screening is feasible, reliable, and clinically impactful, supporting its integration into public health screening programs.

Objective: To develop evidence‐based criteria to classify patients with syndrome of undifferentiated recurrent fevers (SURF). Methods: One hundred twelve patients with SURF observed in a single tertiary referral center were analyzed. Patients with genetically confirmed hereditary recurrent fever (HRF) or with periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome already analyzed for the Eurofever classification criteria were used as disease controls. A decision tree approach was tested by randomly splitting the available data in a training set and in an internal test set. An alternative model using a classical regression model was also analyzed. An external validation for both approaches was performed on 123 patients recruited from four other centers. Results: The decision tree model integrating clinical and genetic data identified 91% of patients with SURF. A decision tree model based solely on clinical variables identified up to 88% of patients with SURF. The logistic regression model including genetic tests exhibited an overall accuracy of 89.2% (95% confidence interval [CI] 81.1–94.7). In contrast, the logistic regression model exclusively based on clinical manifestations displayed an overall accuracy of 66.7% (95% CI 56.1–76.1). When the classification criteria including genetic tests were applied to the external validation cohort, the model demonstrated a strong discriminative power, with areas under the receiver operating characteristic curve of 96.3% using the decision tree model and 88.0% with the logistic regression model. Conclusion: The study shows the possibility of achieving evidence‐based criteria that can classify SURF at least with respect to the main HRF and PFAPA syndrome and may be considered as a preliminary tool for the enrollment of more homogeneous cohorts of patients in future studies.

Objectives: H syndrome is a rare autosomal recessive disorder caused by mutations in SLC29A3, encoding the nucleoside transporter hENT3. Its heterogeneous clinical presentation often includes skin hyperpigmentation, systemic inflammation, endocrinopathies and sensorineural hearing loss. However, typical cutaneous signs may be absent, leading to diagnostic challenges. The objective was to describe a patient with H syndrome misdiagnosed until adulthood as having cryopyrin-associated periodic syndrome (CAPS), due to overlapping clinical and functional features. Methods: We conducted clinical, immunological, genetic and functional assessments in a 24-year-old male with a complex history of early-onset urticarial rash, fever, hearing loss, oral ulcers, colitis and episodic inflammation. Genetic analyses included whole-exome sequencing (WES) and segregation study by quantitative PCR (qPCR). Functional assays evaluated IL-1β secretion, ASC speck formation, reactive oxygen species (ROS) production and type I interferon signature. Results: The patient showed enhanced and accelerated IL-1β secretion and increased ASC speck formation in CD14+ cells after lipopolysaccharide (LPS) stimulation, indicating NLRP3 inflammasome hyperactivation, hallmark features of CAPS. ROS production was significantly elevated in both granulocytes and monocytes, even at baseline. A type I interferon signature was intermittently positive. Genetic testing ultimately revealed a homozygous deletion of exon 2 in the SLC29A3 gene, confirming H syndrome. Conclusion: This case highlights the phenotypic overlap between H syndrome and CAPS, including shared inflammasome dysregulation. Absence of typical skin hyperpigmentation delayed diagnosis despite early-onset systemic inflammation and partial response to IL-1 blockade. Functional assays may support diagnostic refinement in autoinflammatory syndromes with atypical features or inconclusive genetics.

Objectives: To investigate the genetic basis of early-onset systemic lupus erythematosus (EOSLE) in a large Indian pediatric SLE (pSLE) cohort. Method: This prospective observational study investigated monogenic causes in 97 of 365 pSLE patients. Inclusion criteria for the study comprised patients with EOSLE (age ≤8 years) and/or those with a clinical suspicion of monogenic lupus. Monogenic cause was suspected in 97 patients. Genetic screening using targeted next-generation sequencing on the Ion S5 system in 55 of 97 patients [complement defect gene panel in 28 and type 1 interferonopathy gene Interferon (IFN)+ Adaptive Immunity panel in 27] was performed. The remaining 42 patients underwent whole-exome sequencing (WES). Results: Among 97 patients, 22 (22.68%; 11 boys and 11 girls) were found to carry pathogenic variants. Median symptom onset in monogenic cases was 2 years (range: 2 months to 9 years). Monogenic lupus was identified in both EOSLE and older children with strong clinical suspicion. EOSLE patients showed a higher diagnostic yield (28.4%) compared with older children (4.4%). Consanguinity was reported in 7/22 (31.8%) patients. Variants were found in C1QA (n = 7), C1QC (n = 2), C1QB (n = 1), C1R (n = 1), C3 (n = 2), ACP5 (n = 2), STING1, DNASE2, ADAR, TREX1, DNASE1L3, PEPD and SLC7A7 (each n = 1). Conclusions: Monogenic causes were found in at least 6.1% of the overall cohort of pSLE and in 22.7% of genetically screened cases, with the highest yield in EOSLE (28.4%). C1QA was the most common single-gene defect (7.2%). These findings underscore the value of genetic testing in pSLE, especially those with EOSLE or suggestive clinical features.

Suppressor of cytokine signaling 1 (SOCS1) haploinsufficiency is a recently described inborn error of immunity characterized by autoimmunity, inflammation, lymphoproliferation, and increased infection susceptibility. SOCS1, a negative regulator of cytokine signaling via the JAK/STAT pathway, explains the condition’s broad phenotypic variability. Single nucleotide polymorphisms in SOCS1 have been linked to multiple sclerosis (MS), and SOCS1 mimetics have shown efficacy in MS animal models. However, neurological involvement has not been previously reported in patients with SOCS1 insufficiency. We describe a family with a heterozygous SOCS1 variant, highlighting neurological manifestations such as MS, autoimmune encephalitis, and recurrent complex regional pain syndrome as novel features. Next-Generation Sequencing and segregation analysis were performed on PBMCs from patients and healthy donors. Functional studies included luciferase reporter assays in HeLa cells expressing the SOCS1 mutant, flow cytometry for phenotypic analysis, and gene expression profiling of the type-I interferon (IFN) signature. Intraepidermal nerve fiber density was evaluated via immunohistochemistry on skin biopsy. Genetic analysis confirmed the variant’s inheritance. Transfected cells carrying the SOCS1 variant showed increased STAT1 transcriptional activity after IFN-γ stimulation. Elevated STAT5 phosphorylation and T-cell proliferation were observed in response to IL-2. Peripheral blood revealed an elevated IFN signature during relapse. Skin biopsy showed reduced intraepidermal nerve fiber density. This report expands the clinical spectrum of SOCS1-related disorders to include neurological symptoms, emphasizing SOCS1’s critical role in regulating inflammation in the central and peripheral nervous systems.

Introduction: Syndrome of undifferentiated recurrent fever (SURF) refers to a group of recurrent fevers without a clear monogenic cause. Clinical spectrum, treatment response predictors and management strategies remain unclear. Objective: This study aims to longitudinally analyse a homogeneously selected cohort of 101 SURF patients, to identify factors associated with colchicine resistance and to evaluate the efficacy of interleukin-1 (IL-1) inhibitors. Methods: Patients were enrolled in the Eurofever Registry, carefully excluding those with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA); familial Mediterranean fever and other known monogenic recurrent fevers. Demographic, clinical and treatment data were analysed to identify predictors of colchicine resistance and define subgroups through cluster analysis. Results: Common symptoms included fever, arthralgia, abdominal pain and myalgia, with PFAPA-like features (lymphadenopathy, tonsillitis, oral aphthae) observed in one-third of cases, sporadically. Colchicine efficacy, assessed in 77 patients, revealed complete response in the majority of patients (61%). Univariable analysis identified PFAPA-like features, including aphthous stomatitis (p=0.001), cervical lymphadenopathy (p=0.012) and exudative tonsillitis (p=0.004), as associated with colchicine resistance. Multivariable analysis confirmed aphthous stomatitis as an independent predictor of resistance (p=0.014). Tonsillectomy was ineffective. IL-1 inhibitors (anakinra, canakinumab) were beneficial in refractory cases. Cluster analysis revealed three distinct subgroups with varying symptoms and colchicine responses. Conclusions: These findings provide new insights into SURF, identifying predictors of colchicine resistance and supporting the efficacy of IL-1 blockade. Cluster analysis suggests the heterogeneity within SURF, reinforcing the need for refined diagnostic criteria and personalised treatment strategies.

TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly) syndrome is a rare, life‐threatening inflammatory condition linked to infections, neoplasms, and idiopathic multicentric Castleman disease. Interleukin (IL)‐6 inhibitors are the primary treatment, but refractory cases require alternatives. This study reports the first two pediatric TAFRO cases successfully treated with anakinra, an IL‐1 receptor antagonist. Both patients had severe, rapidly progressing disease with multiorgan involvement. Anakinra, combined with corticosteroids, led to significant improvement and remission. We provide a literature review of pediatric TAFRO, confirming its rarity and the partial efficacy of IL‐6 inhibitors in many cases.