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Peter A Nigrovic

Publications and source records attributed to Peter A Nigrovic.

10 recordsLinked to original sources
PubMed2025

Diagnostic Implications and Correlates of Plasma Adenosine Deaminase 2 Activity and ADA2 Variants.

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disease manifested as polyarteritis nodosa, stroke, and bone marrow failure. Leveraging an international cohort of 200 DADA2 cases, we aimed to characterize the diagnostic utility of a plasma ADA2 enzyme activity assay and understand the implications of residual ADA2 activity. METHODS: Data were collected from individuals who underwent ADA2 testing from 2018 to 2025. Plasma ADA2 activity was determined using an established spectrophotometric assay. ADA2 variants were analyzed in transfected cells by enzyme assay and western blotting. RESULTS: We determined that plasma ADA2 activity is 99.0% and 96.0% sensitive and 99.7% and 98.8% specific in distinguishing genetically confirmed DADA2 cases from controls and carriers, respectively. Eighteen individuals with DADA2 (9%) possessed detectable ADA2 activity, including several cases with levels seen in carriers. Residual ADA2 activity was associated with the vasculitis/inflammatory phenotype but not with disease severity. Genotype analysis revealed that 14 of 18 cases with residual plasma activity possessed at least one hypomorphic missense variant with greater than 20% residual ADA2 function when overexpressed in 293T cells, often occurring in trans with a more deleterious variant. In vitro analysis revealed that missense ADA2 variants exert variable dominant-negative effects by forming large intracellular protein aggregates via disulfide bond formation at a cysteine residue (Cys408). CONCLUSION: We confirmed the utility of plasma ADA2 activity as a diagnostic assay and showed that the inflammatory phenotype of DADA2 occurred in cases with residual activity. In vitro findings illustrate potential interactions of ADA2 variants to synergistically disrupt protein function.

Humans↗
PubMed2006

Neutrophil-derived leukotriene B4 is required for inflammatory arthritis.

Neutrophils serve as a vanguard of the acute innate immune response to invading pathogens. Neutrophils are also abundant at sites of autoimmune inflammation, such as the rheumatoid joint, although their pathophysiologic role is incompletely defined and relevant effector functions remain obscure. Using genetic and pharmacologic approaches in the K/BxN serum transfer model of arthritis, we find that autoantibody-driven erosive synovitis is critically reliant on the generation of leukotrienes, and more specifically on leukotriene B4 (LTB4), for disease induction as well as perpetuation. Pursuing the cellular source for this mediator, we find via reconstitution experiments that mast cells are a dispensable source of leukotrienes, whereas arthritis susceptibility can be restored to leukotriene-deficient mice by intravenous administration of wild-type neutrophils. These experiments demonstrate a nonredundant role for LTB4 in inflammatory arthritis and define a neutrophil mediator involved in orchestrating the synovial eruption.

Animals↗
PubMed2006

Particularities of the vasculature can promote the organ specificity of autoimmune attack.

How certain autoimmune diseases target specific organs remains obscure. In the 'K/BxN' arthritis model, autoantibodies to a ubiquitous antigen elicit joint-restricted pathology. Here we have used intravital imaging to demonstrate that transfer of arthritogenic antibodies caused macromolecular vasopermeability localized to sites destined to develop arthritis, augmenting its severity. Vasopermeability depended on mast cells, neutrophils and FcgammaRIII but not complement, tumor necrosis factor or interleukin 1. Unexpectedly, radioresistant FcRgamma-expressing cells in an organ distant from the joint were required. Histamine and serotonin were critical, and systemic administration of these vasoactive amines recapitulated the joint localization of immune complex-triggered vasopermeability. We propose that regionally distinct vascular properties 'interface' with immune effector pathways to foster organ-specific autoimmune damage, perhaps explaining why arthritis accompanies many human infectious and autoimmune disorders.

Animals↗
PubMed2006

Patients with juvenile psoriatic arthritis comprise two distinct populations.

OBJECTIVE: Psoriatic arthritis (PsA) in children is clinically heterogeneous. We examined a large population of children with juvenile PsA for evidence of phenotypic clustering that could suggest the presence of distinct clinical entities. METHODS: We reviewed the medical records of 139 patients meeting the Vancouver criteria for juvenile PsA. To identify segregation into phenotypic groups, we compared younger patients with their older counterparts and subjected the whole population to 2-step cluster analysis. RESULTS: Among patients with juvenile PsA, the age at onset is biphasic, with peaks occurring at approximately 2 years of age and again in late childhood. Compared with children ages 5 years and older, younger patients are more likely to be female, exhibit dactylitis and small joint involvement, and express antinuclear antibodies. Progression to polyarticular disease (>or=5 joints) is more common in younger children, although joint involvement remains oligoarticular in the majority of children. In contrast, older patents tend to manifest enthesitis, axial joint disease, and persistent oligoarthritis. Uveitis is equally represented in both age groups. Despite a higher utilization of methotrexate therapy, younger patients required, on average, more than twice as long to achieve clinical remission (23 months versus 9.2 months; P = 0.044). Cluster analysis identified largely overlapping subgroups but suggested that the presence of dactylitis, rather than age, has the greatest capacity to predict essential features of the clinical phenotype. CONCLUSION: Juvenile PsA comprises 2 distinct populations of patients. Although the pathophysiologic correlate of this finding remains undefined, future studies should avoid the assumption that PsA in childhood constitutes a single etiologic entity.

Age of Onset↗
PubMed2006

Extreme thrombocytosis predicts Kawasaki disease in infants.

Infants with Kawasaki disease are at high risk of developing life-threatening coronary complications, yet may elude timely diagnosis because they often lack the full complement of classic clinical features. We retrospectively studied 26,540 children 1 year of age or less who were evaluated at a tertiary care pediatric emergency department in whom a platelet count was performed. Among those infants with fever without a source identified, 8.5% with platelet counts of 800,000 cells/mm(3) or greater had Kawasaki disease compared to 0.4% with platelet counts of less than 800,000 cells/mm(3) (likelihood ratio for Kawasaki disease was 17 [95% confidence interval, 8-34]). Because many infants present atypically, Kawasaki disease should be considered in all children of 1 year or less with prolonged fever, extreme elevation of the platelet count, and no compelling alternative diagnosis.

Age Factors↗
PubMed2005

Coronary artery dilation among patients presenting with systemic-onset juvenile idiopathic arthritis.

OBJECTIVE: To evaluate coronary artery diameters among patients presenting with systemic-onset juvenile idiopathic arthritis (SoJIA). METHODS: Fifty cases of SoJIA were reviewed. At the time of initial presentation with fever, 12 patients had echocardiograms that included a complete evaluation of the coronary arteries. A single reviewer measured the diameters of the left main, proximal left anterior descending, and proximal right coronary arteries. Body surface area-adjusted z scores were calculated with respect to a normative population. RESULTS: Coronary artery dilation (z score: >2) was observed for 5 of the 12 patients with SoJIA who had echocardiograms performed at the time of presentation with fever. No patient developed a coronary artery aneurysm, and all of the coronary artery z scores normalized within 4 months. Only 2 of the 5 patients with coronary artery z scores of >2 fulfilled the clinical criteria for Kawasaki disease, the most commonly recognized cause of coronary artery dilation among children. CONCLUSIONS: Children presenting with SoJIA may have coronary artery dilation similar to that observed for children with Kawasaki disease. These data suggest that the presence of coronary artery dilation on initial echocardiograms for patients with fever does not exclude the diagnosis of SoJIA.

Arthritis, Juvenile↗
PubMed2004

Mast cells in inflammatory arthritis.

Mast cells are present in limited numbers in normal human synovium, but in rheumatoid arthritis and other inflammatory joint diseases this population can expand to constitute 5% or more of all synovial cells. Recent investigations in a murine model have demonstrated that mast cells can have a critical role in the generation of inflammation within the joint. This finding highlights the results of more than 20 years of research indicating that mast cells are frequent participants in non-allergic immune responses as well as in allergy. Equipped with a diversity of surface receptors and effector capabilities, mast cells are sentinels of the immune system, detecting and delivering a first response to invading bacteria and other insults. Accumulating within inflamed tissues, mast cells produce cytokines and other mediators that may contribute vitally to ongoing inflammation. Here we review some of the non-allergic functions of mast cells and focus on the potential role of these cells in murine and human inflammatory arthritis.

Animals↗
PubMed2003

Raynaud's phenomenon in children: a retrospective review of 123 patients.

OBJECTIVE: To examine the clinical presentation and disease associations of Raynaud's phenomenon (RP) in children and adolescents. METHODS: A systematic retrospective chart review was conducted of 123 cases drawn from 2 computerized databases at the Children's Hospital of Boston. Participants aged <19 years with episodic reversible color changes in the extremities were examined. Case records were analyzed for clinical presentation, disease associations, and physical examination and laboratory findings. RESULTS: In contrast to the findings of smaller pediatric series reported to date, the large majority of our patients-approximately 70%-did not have a recognized underlying connective tissue disease. For both primary and secondary RP, approximately 80% of patients were female, and mean age of onset was similar in the 2 groups. Biphasic or triphasic color changes were less common than monophasic changes and were no more common in secondary than primary RP. Findings predictive of secondary RP were limited to the presence of antinuclear antibodies and abnormal nailfold capillaries. Antiphospholipid antibodies were found at some time in at least 21% of patients with both primary and secondary RP. CONCLUSIONS: RP in children, as in adults, principally affects girls and is frequently free of association with connective tissue disease. Antinuclear antibody positivity and abnormal nailfold capillaries correlate with secondary disease. Antiphospholipid antibodies are surprisingly common, a new finding of uncertain implications.

Adolescent↗
PubMedDate not supplied

Subpopulations within juvenile psoriatic arthritis: a review of the literature.

The presentation of juvenile psoriatic arthritis (JPsA) has long been recognized to be clinically heterogeneous. As the definition of JPsA expanded to accommodate atypical manifestations of psoriasis in young children, studies began to reflect an increasingly clear biphasic distribution of age of onset, with peaks in the first few years of life and again in early adolescence. These two subpopulations differ in gender ratio, pattern of joint involvement, laboratory findings and potentially response to therapy. Intriguingly, a similar distribution of age of onset has been observed in juvenile rheumatoid arthritis (JRA), and correlates with patterns of HLA association. While a secure classification of subpopulations within JPsA awaits improved pathophysiologic understanding, future research must consider the possibility that different disease mechanisms may be operative in distinct subsets of patients with this disorder.

Adolescent↗