Scott W. Canna
· MDVerifiedUniversity of Pennsylvania · Rehabilitation Medicine
Active 1937–2025
About
Scott W. Canna, MD, is an Associate Professor of Pediatrics (Rheumatology) at the Children's Hospital of Philadelphia and a Board Certified Pediatric Rheumatologist. His clinical expertise focuses on autoinflammatory and immunodysregulatory syndromes, including Macrophage Activation Syndrome (MAS) and Hemophagocytic Lymphohistiocytosis (HLH). He combines insights from rheumatology and innate immunity to study systemic and organ-specific inflammation not attributable to infection, malignancy, or autoimmunity, with particular interest in hyperinflammation and autoinflammation. His research investigates the mechanisms underlying these conditions, especially the roles of the inflammasome and cytokines such as IL-1 and IL-18, aiming to identify new disease subtypes, biomarkers, and therapeutic strategies. Dr. Canna's work emphasizes the intersection of hyper- and auto-inflammation, utilizing basic models and clinical insights to advance understanding and treatment of inflammatory diseases.
Research topics
- Immunology
- Internal medicine
- Medicine
- Biology
- Cell biology
- Genetics
- Cancer research
- Bioinformatics
- Pediatrics
Selected publications
EULAR Rheumatology Open · 2025-05-01 · 3 citations
articleOpen access<h2>ABSTRACT</h2><h3>Objectives</h3> A systematic literature review was undertaken to summarise and analyse the available evidence on the initial hemophagocytic lymphohistiocytosis and macrophage activation syndrome (HLH/MAS) treatment according to the distinctive pathologic background and/or triggering factors. <h3>Methods</h3> An electronic search in the main medical databases (PubMed, EMBASE, and Cochrane Library) was conducted, in order to select the studies providing information related to the HLH/MAS therapy. To further maximise the evidence derived from this systematic review, we focused our attention on clinical studies that included and described >10 HLH/MAS cases. <h3>Results</h3> This literature search led to identify 18,020 articles. After the screening by title, removal of duplicated records, and full-text assessment of the relevant articles, the final search output consisted of 167 articles that provided enough information on the medical management of patients with HLH/MAS In total, 77 clinical studies (including >10 patients) describing the early treatment of HLH/MAS have been included in the present analysis. <h3>Conclusions</h3> Primary HLH is typically managed according to the HLH-94 or HLH-2004 protocols, with the main aim of bringing the patient to a hematopoietic stem cell transplant (HSCT). Secondary forms of HLH/MAS can arise in 3 main clinical contexts, namely rheumatic disorders, oncological diseases, and previously healthy patients developing specific and/or severe infections. Accordingly, different and variable therapeutic approaches have been applied to these 3 categories of secondary HLH/MAS. Despite the survival improvements achieved in the last decades in patients with HLH/MAS, there is a strong need for prospective and controlled studies focused on each specific group of HLH/MAS.
Multimodal induction of fulminant HLH by IL-18 includes virus-specific NK immunodeficiency
bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-08 · 1 citations
preprintOpen accessSenior authorCorrespondingAbstract Macrophage Activation Syndrome (MAS) is a cytokine storm syndrome associated with Still’s Disease, XIAP deficiency, and elevation of both total and free IL-18. Modeling excess IL-18 using Il18tg mice, we found mild NK-cytopenia and cytotoxic T lymphocyte (CTL) activation in resting mice reminiscent of Still’s patients. Infection with Lymphocytic Choriomeningitis Virus (LCMV) triggered MAS via and IFNγ, despite normal viral clearance. Il18tg NK cell transcriptomes showed replicative activity, but few changes in canonical NK function or maturation pathways. LCMV clearance is NK-independent, so we challenged Il18tg mice with mousepox in which NK cells are critical early orchestrators of clearance. Il18tg mice’s NK cells failed to activate or expand, but mousepox further activated their CTL and early viral control was normal. Il18tg mice soon developed “MAS” including hepatosplenic necrosis, but (contrasting with LCMV) they showed poor virus-specific CTL expansion and viral clearance. Though more normal at rest, Il18bp KO mice’s NK cells were similarly inert upon mousepox infection, and the mice succumbed to viremic MAS like Il18tg . Rescue of Il18tg mice, and mousepox-specific CTL responses, by NK cell transfer required in vitro NK pre-activation. Thus, IL-18 can induce both hyperinflammation (CTL hyper activation) and immunodeficiency (NK cell hypo activation) depending on the nature of the infectious trigger.
Excess IL-18 profoundly protects from CNS autoimmunity via continuous effects on CD8 T-cells 4546
The Journal of Immunology · 2025-11-01
articleOpen accessSenior authorAbstract Description IL-18 is an inflammasome-activated cytokine known for driving IFNγ production and “Type 1” immunity. Dramatically elevated IL-18 is observed in an autoinflammatory form of cytokine storm, but paradoxically patients may be protected from autoimmunity. We speculated that excess IL-18 may antagonize autoimmunity development. To understand this, we tested the effects of excess IL-18 (in Il18bp-/- or Il18tg mice, or IL-18 agonist administration) in MOG35-55 induced Experimental Autoimmune Encephalomyelitis (EAE). Regardless of delivery mechanism, mice were strongly protected from EAE onset and progression. Protection was associated with decreased MOG-specific CD4 T-cell activation and spinal cord abundance. Protection required signaling through the IL-18R, and was lost when signaling was disrupted even 12 days after EAE induction. By genetically restricting Il18r1 expression, we found that protection in Il18tg mice required signaling by T-cells, but not FoxP3+ CD4 Tregs. Partial, temporal deletion of Il18r1 in CD8T-cells, however, was sufficient to eliminate protection. IL-18 pretreatment enhanced EAE suppression by adoptively transferred CD8 T-cells. Protection by IL-18 required IFNg, but not perforin. These data demonstrate that IL-18 signaling on CD8 T-cells suppresses autoreactive CD4 T-cells, and EAE, in a manner dependent on IFNγ but not granule-mediated cytotoxicity. This novel protective mechanism may inform cytokine strategies or cellular therapeutics in autoimmunity. Funding Sources NIH/NICHD R01HD098428 Rheumatology Research Foundation Children’s Hospital of Philadelphia Research Institute Topic Categories Therapeutic Approaches to Autoimmunity (THER)
Cellular and Molecular Immunology · 2025-10-20 · 3 citations
articleOpen accessInflammasomes, particularly NLRC4, play crucial roles in immune responses to intracellular bacterial infections. However, gain-of-function mutations in NLRC4 are linked to severe autoinflammatory diseases, including autoinflammation with infantile enterocolitis (AIFEC). AIFEC patients who survive infancy typically have no further intestinal symptoms but retain susceptibility to macrophage activation syndrome (MAS). However, existing mouse models do not adequately replicate the inflammation observed in AIFEC patients. To better understand this, we developed a mouse model capable of conditional expression of the activating V341A mutation in NLRC4 (NLRC4-V341A KI). Global conversion to NLRC4-V341A at the germline resulted in symptoms closely mirroring those of human AIFEC, including severe infantile enterocolitis characterized by heightened intestinal inflammation, disrupted gut epithelium, compromised intestinal barrier integrity, severe diarrhea, and mortality within 10 days post-natally. Additionally, they displayed systemic autoinflammation marked by elevated levels of IL-1β, IL-18, and IL-6, alongside cytopenia and hemophagocytosis. In contrast, conditional conversion to NLRC4-V341A in adulthood caused systemic autoinflammation with only mild enterocolitis, mirroring AIFEC patients. Using this model, we demonstrated that IL-18 and TNF blockade effectively ameliorated AIFEC disease symptoms. Unexpectedly, glucose supplementation has emerged as a promising therapeutic strategy. These findings advance our understanding of AIFEC and illuminate the ways in which inflammasome activation contributes to very early onset inflammatory bowel disease (VEO-IBD) in the developing gut.
Pediatric Rheumatology · 2025-10-21 · 1 citations
articleOpen accessCorrespondingBACKGROUND: Systemic juvenile idiopathic arthritis (SJIA) is a severe form of juvenile idiopathic arthritis characterized by fever, rash, chronic arthritis, and systemic inflammation. The introduction of biologics has improved the treatment options for SJIA. Canakinumab selectively inhibits interleukin-1β and is approved for SJIA treatment. In this study that utilized the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, long-term safety data available from patients with SJIA who started either canakinumab treatment or an alternative therapy were assessed. METHODS: This long-term, prospective, non-interventional study was conducted from August 2015 to June 2022 using data from the CARRA Registry. Data for serious adverse events (SAEs) and pre-specified events of special interest (ESIs) were collected from patients with SJIA aged between ≥ 2 and < 18 years at the time of treatment initiation and followed for a minimum of 5 years. Data were summarized descriptively, and no hypothesis testing was performed. RESULTS: The final analysis included 177 patients: 90 in the overall canakinumab group (incident users [N = 39] and prevalent users [N = 51]) and 87 in the alternative treatment group. Median patient age at treatment initiation was 8.0 years in the overall canakinumab group. The incidence rates of SAEs per 100 patient-years were 3.62 (overall canakinumab group) and 3.39 (canakinumab incident users group). Of the predefined ESIs, macrophage activation syndrome (n = 5) and infections treated with intravenous anti-infectives (n = 1) were observed in the overall canakinumab group. The majority of patients (72.2%) treated with canakinumab received on-label dosing at some point during the first 5 years of the study. CONCLUSIONS: Overall, no changes were observed in the safety profile with long-term use of canakinumab in pediatric patients with SJIA. Particularly, no change in the frequency or severity of known ESIs occurred, and no new risks were identified. The findings suggest that canakinumab is effective in SJIA management and has a favorable safety profile with long-term use over a period of 5 years in real-world settings.
Critical Care Medicine · 2025-01-01
articleClinical Reasoning: A 9-Year-Old Girl With CNS Immune Dysregulation
Neurology · 2025-08-07
articleA 9-year-old girl presented with encephalopathy, left upper extremity rhythmic shaking, and fever, after 1 month of intermittent headaches and 1 week of upper respiratory symptoms. EEG confirmed focal seizures, and brain MRI revealed polyfocal T2/fluid-attenuated inversion recovery hyperintensities involving both the white and gray matter. CSF analysis showed lymphocytic pleocytosis, elevated protein, and elevated opening pressure. She was diagnosed with acute disseminated encephalomyelitis and treated with IV corticosteroids, plasmapheresis, IV immunoglobulins, and antiseizure medications with improvement in encephalopathy and seizures, but persistence of focal deficits. Six weeks after symptom onset, she again became critically ill with encephalopathy and a brain MRI demonstrated worsening of the previous lesions. Paraneoplastic and autoimmune encephalopathy antibody testing was negative, cultures and PCR testing did not identify infection, there was no evidence of rheumatologic conditions, and no malignant cells were found in the spinal fluid. Brain biopsy demonstrated an inflammatory infiltrate, primarily composed of macrophages, T cells, and a few B cells and neutrophils. A CD107a degranulation assay demonstrated a defect in natural and cytotoxic T-cell function, and ultimately, genetic testing revealed the diagnosis. This case highlights the diagnostic challenges faced in cases of CNS immune dysregulation, including differential diagnoses, interpretation of functional assays, and genetic considerations.
Journal of Human Immunity · 2025-04-25
articleOpen accessSenior authorPrimary immune disorders offer important pathoetiologic insights into human immune dysfunction. Often, studying pathogenic human mutations in murine systems provides an excellent system for probing those mechanisms. Recently, multiple groups found that de novo arginine-to-cysteine missense mutations at position 186 of the human cell division cycle (CDC42) gene, near its C terminus, were associated with a life-threatening hyperinflammatory disorder called NOCARH (neonatal onset of pancytopenia, autoinflammation, rash, and episodes of hemophagocytic lymphohistiocytosis (HLH). NOCARH patients demonstrate excessive activation and expansion of macrophages and CD8+ T lymphocytes. In vitro, human CDC42˄cterm mutants drove cell-intrinsic hyperactivation of the pyrin inflammasome. To better understand the immunobiology of NOCARH, we used CRISPR-Cas9 editing of C57Bl/6 mouse embryos to introduce the R186C transition in murine Cdc42, which is amino acid identical to human. We were successful in generating founders harboring mosaic R186C and R186F alleles, and these alleles transmitted to the germline of offspring upon breeding to wild-type mice. Both R186C and R186F heterozygous and homozygous mice appeared viable, fertile, and were similar to wild-type littermates in growth and development. Mice harboring the mutated alleles (even in homozygosity) also responded to transient LCMV infection similarly to WT. In vitro, activation of the pyrin inflammasome in bone marrow–derived macrophages (BMDM) was unaffected by the presence of Cdc42˄R186C. However, murine pyrin lacks a B30.2 domain present in humans, and this domain is the site of many classical Familial Mediterranean Fever mutations. However, BMDM pyrin activation was unaffected by Cdc42 genotype even in cells from mice also expressing a humanized mouse pyrin allele (Mefv˄B30.2). Murine express an alternative Cdc42 transcript in CNS tissues that utilizes an alternative exon 6 and therefore would not contain the engineered mutation. However, we found no change in the low expression of this alternative transcript in blood cells even in Cdc42˄R186C homozygous mice. These data suggest critical differences in the regulation mouse and human CDC42 that, if understood, could identify novel ways of regulating CDC42˄cterm-driven inflammation in NOCARH patients.
Insights from the 2024 pediatric rheumatology basic/translational years in review
Pediatric Rheumatology · 2025-05-23 · 1 citations
reviewOpen accessSenior authorCorrespondingBACKGROUND: Advances in Pediatric Rheumatology are driven by mechanistic insights from basic and translational science. We have selected and reviewed the most impactful basic/translational science from our "Year in Review (YIR)" presentations from the 2024 Pediatric Rheumatology European Society and American College of Rheumatology Convergence meetings (September and November 2024, respectively). MAIN BODY: We drew from fundamental immunology, human genetics, animal models, and computational & "omic" manuscripts published in the year preceding these meetings. Avoiding overlap with other topics presented in this "Perspectives" series, summarized herein are the major themes we gleaned from that process. These include (1) innovative concepts and tools to study immune health, (2) new mechanistic insights into pediatric rheumatic diseases and (3) novel therapeutic targets and treatment approaches in rheumatic disease. CONCLUSIONS: As part of a living relationship with the basic/translational literature that shapes our field and practice, we hope readers will be inspired to delve more deeply into the topics and manuscripts highlighted in this YIR summary.
Arthritis Care & Research · 2025-12-15 · 1 citations
articleOBJECTIVES: Chronic lung disease is a potentially life-threatening complication of systemic juvenile idiopathic arthritis (SJIA-LD). However, its natural history, etiology, and effective management are unclear. We aimed to describe the baseline characteristics and biomarker profiles of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry SJIA-LD cohort. METHODS: Baseline data from all CARRA Registry patients with SJIA and those with SJIA-LD were included and analyzed. Lung disease-specific data were obtained using a standardized case report form through REDCap Cloud. Plasma biomarker profiles were determined using a custom Luminex panel. RESULTS: A total of 37 patients with SJIA-LD from 16 CARRA sites were identified and compared to all 928 patients with SJIA without known LD in the CARRA Registry. Patients with SJIA-LD were significantly younger at disease onset and were more likely to be of Asian descent. A higher medication burden was also found. Patients with SJIA-LD had higher levels of multiple lung injury biomarkers, cytokines, and chemokines compared to patients with both active and inactive SJIA without LD and healthy controls. Cluster analysis proposed three groups of SJIA-LD patients with distinct biomarker patterns reflecting differences in proinflammatory cytokines, type II chemokines, and markers of macrophage activation syndrome (MAS). CONCLUSIONS: The CARRA SJIA-LD Cohort exhibits distinct clinical features, higher medication burden, frequent MAS, and plasma biomarker patterns specific to SJIA-LD compared to patients with SJIA without LD. A study is ongoing to assess more detailed clinical features, disease progression, patient-reported outcomes, and associated immune biomarkers.
Recent grants
Understanding Interleukin-18 Mediated Susceptibility to Systemic Hyperinflammation
NIH · $331k · 2021–2024
Understanding Interleukin-18 Mediated Susceptibility to Systemic Hyperinflammation
NIH · $1.4M · 2021–2025
Inflammatory consequences of NLRC4 dysregulation
NIH · $1.3M
NIH · $59k · 2013
Mechanisms of NLRC4 inflammasome-associated hyperinflammation
NIH · $270k · 2017–2019
Frequent coauthors
- 124 shared
Edward M. Behrens
Children's Hospital of Philadelphia
- 83 shared
Grant S. Schulert
University of Cincinnati
- 83 shared
Hamid Bassiri
Children's Hospital of Philadelphia
- 78 shared
Caroline Diorio
Children's Hospital of Philadelphia
- 72 shared
David T. Teachey
Children's Hospital of Philadelphia
- 65 shared
Elaine Cassidy
- 63 shared
Alexei A. Grom
Cincinnati Children's Hospital Medical Center
- 62 shared
Michele P. Lambert
Children's Hospital of Philadelphia
Labs
Canna LabPI
Awards & honors
- Highways to hell: mechanism based management of Cytokine Sto…
- American College of Rheumatology Clinical Guidance for Pedia…
- On the alert for cytokine storm: Immunopathology in COVID-19…
- Distict interferon signatures and cytokine patterns define a…
- Emergent high fatality lung disease in systemic juvenile art…
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