Background
Adenosine deaminase 2 (ADA2) is a homodimeric, extracellular enzyme and putative growth factor that is produced by cells of the myeloid lineage and, catalytically, deaminates extracellular ...adenosine to inosine. Loss-of-(catalytic)-function variants in the
ADA2
gene are associated with Deficiency of ADA2 (DADA2), an autosomal recessive disease associated with an unusually broad range of inflammatory manifestations including vasculitis, hematological defects and cytopenia. Previous work by our group led to the identification of
ADA2
variants of novel association with DADA2, among which was a unique c.1052T>A (p.Leu351Gln; herein referred to as L351Q) variant located in the catalytic domain of the protein.
Methods
Mammalian (Flp-IN CHO) cells were engineered to stably express wild-type ADA2 and ADA2 protein variants, including the pathogenic L351Q variant identified in DADA2 patients. An enzyme assay and immunoblotting were used to assess ADA2 catalytic activity and secretion, respectively, and the outcome of experimentally induced inhibition of protein processing (Golgi transport and N-linked glycosylation) was assessed. Reverse transcription quantitative real-time PCR (RT-qPCR) was applied to determine the relative expression of Type I Interferon stimulated genes (ISGs),
IFIT3
and
IRF7
.
Results
In addition to abrogating catalytic activity, the L351Q variant impaired secretion of L351Q ADA2 resulting in an intracellular accumulation of L351Q ADA2 protein that was not observed in cells expressing wild-type ADA2 or other ADA2 protein variants. Retention of L351Q ADA2 was not attributable to impaired glycosylation on neighboring asparagine residues and did not impact cell growth or integrity. Constitutive expression of Type I ISGs
IFIT3
and
IRF7
was observed in cells expressing L351Q ADA2.
Conclusions
The impaired secretion of L351Q ADA2 may be an important factor leading to the severe phenotype observed in patients with this variant further emphasizing the importance of assessing impacts beyond catalytic activity when evaluating genotype-phenotype relationships in DADA2.
ObjectivesThe objective of this study is to evaluate whether anti-neutrophil cytoplasmic antibody (ANCA) seropositivity and antigen specificity at diagnosis have predictive utility in ...paediatric-onset small vessel vasculitis.MethodsChildren and adolescents with small vessel vasculitis (n=406) stratified according to the absence (n=41) or presence of ANCA for myeloperoxidase (MPO) (n=129) and proteinase-3 (PR3) (n=236) were compared for overall and kidney-specific disease activity at diagnosis and outcomes between 1 and 2 years using retrospective clinical data from the ARChiVe/Paediatric Vasculitis Initiative registry to fit generalised linear models.ResultsOverall disease activity at diagnosis was higher in PR3-ANCA and MPO-ANCA-seropositive individuals compared with ANCA-negative vasculitis. By 1 year, there were no significant differences, based on ANCA positivity or specificity, in the likelihood of achieving inactive disease (~68%), experiencing improvement (≥87%) or acquiring damage (~58%). Similarly, and in contrast to adult-onset ANCA-associated vasculitis, there were no significant differences in the likelihood of having a relapse (~11%) between 1 and 2 years after diagnosis. Relative to PR3-ANCA, MPO-ANCA seropositivity was associated with a higher likelihood of kidney involvement (OR 2.4, 95% CI 1.3 to 4.7, p=0.008) and severe kidney dysfunction (Kidney Disease Improving Global Outcomes (KDIGO) stages 4–5; OR 6.04, 95% CI 2.77 to 13.57, p<0.001) at onset. Nonetheless, MPO-ANCA seropositive individuals were more likely to demonstrate improvement in kidney function (improved KDIGO category) within 1 year of diagnosis than PR3-ANCA seropositive individuals with similarly severe kidney disease at onset (p<0.001).ConclusionsThe results of this study suggest important paediatric-specific differences in the predictive value of ANCA compared with adult patients that should be considered when making treatment decisions in this population.
Kawasaki disease (KD) is an acute systemic vasculitis of childhood. The diagnosis can be made in a patient who presents with a prolonged high fever and meeting at least four of five criteria ...including polymorphous rash, mucosal changes, extremity changes (including swelling and/or palmar and plantar erythema), bilateral nonsuppurative conjunctivitis, and unilateral cervical lymphadenopathy. Atypical KD refers to patients who have not met the full criteria and in whom atypical features may be present. We discuss a case of a 6-year-old male who presented to the Emergency Department with torticollis. A series of investigations for elevated inflammatory markers revealed dilated coronary artery aneurysms on echocardiogram, and thus he was diagnosed with atypical KD. His only other criteria were bilateral nonsuppurative conjunctivitis and a prior brief febrile illness. He was treated with high-dose intravenous immune globulin (IVIG) and low-dose aspirin. Low-molecular-weight heparin and atenolol were added due to the presence of giant aneurysms.
Physical activity (PA) patterns in children with juvenile idiopathic arthritis (JIA) over time are not well described. The aim of this study was to describe associations of physical activity (PA) ...with disease activity, function, pain, and psychosocial stress in the 2 years following diagnosis in an inception cohort of children with juvenile idiopathic arthritis (JIA).
In 82 children with newly diagnosed JIA, PA levels, prospectively determined at enrollment, 12 and 24 months using the Physical Activity Questionnaire for Children (PAQ-C) and Adolescents (PAQ-A) raw scores, were evaluated in relation to disease activity as reflected by arthritis activity (Juvenile Arthritis Disease Activity Score (JADAS-71)), function, pain, and psychosocial stresses using a linear mixed model approach. Results in the JIA cohort were compared to normative Pediatric Bone Mineral Accrual Study data derived from healthy children using z-scores.
At enrollment, PA z-score levels of study participants were lower than those in the normative population (median z-score - 0.356; p = 0.005). At enrollment, PA raw scores were negatively associated with the psychosocial domain of the Juvenile Arthritis Quality of Life Questionnaire (r = - 0.251; p = 0.023). There was a significant decline in PAQ-C/A raw scores from baseline (median and IQR: 2.6, 1.4-3.1) to 24 months (median and IQR: 2.1, 1.4-2.7; p = 0.003). The linear mixed-effect model showed that PAQ-C/A raw scores in children with JIA decreased as age, disease duration, and ESR increased. The PAQ-C/A raw scores of the participants was also negatively influenced by an increase in disease activity as measured by the JADAS-71 (p < 0.001).
Canadian children with newly diagnosed JIA have lower PA levels than healthy children. The decline in PA levels over time was associated with disease activity and higher disease-specific psychosocial stress.
Pachydermodactyly is characterized by asymptomatic, progressive swelling of the lateral aspects of the 2nd to 4th finger along the proximal interphalangeal (PIP) joint without involving the joint ...itself. We present 2 interesting cases of patients with periarticular swelling who were initially diagnosed and treated as juvenile idiopathic arthritis (JIA) with subsequent clinical and pathology confirmation of pachydermodactyly. These cases emphasize the importance of considering pachydermodactyly in young patients with development of periarticular swelling and no joint involvement.
BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify ...diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator NEMO), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.
Objective
Individuals with deficiency of adenosine deaminase 2 (DADA2), a recently recognized autosomal recessive disease, present with various systemic vascular and inflammatory manifestations, ...often with young age at disease onset or with early onset of recurrent strokes. Their clinical features and histologic findings overlap with those of childhood‐onset polyarteritis nodosa (PAN), a primary “idiopathic” systemic vasculitis. Despite similar clinical presentation, individuals with DADA2 may respond better to biologic therapy than to traditional immunosuppression. The aim of this study was to screen an international registry of children with systemic primary vasculitis for variants in ADA2.
Methods
The coding exons of ADA2 were sequenced in 60 children and adolescents with a diagnosis of PAN, cutaneous PAN, or unclassifiable vasculitis (UCV), any chronic vasculitis with onset at age 5 years or younger, or history of stroke. The functional consequences of the identified variants were assessed by ADA2 enzyme assay and immunoblotting.
Results
Nine children with DADA2 (5 with PAN, 3 with UCV, and 1 with antineutrophil cytoplasmic antibody–associated vasculitis) were identified. Among them, 1 patient had no rare variants in the coding region of ADA2 and 8 had biallelic, rare variants (minor allele frequency <0.01) with a known association with DADA2 (p.Gly47Arg and p.Gly47Ala) or a novel association (p.Arg9Trp, p.Leu351Gln, and p.Ala357Thr). The clinical phenotype varied widely.
Conclusion
These findings support previous observations indicating that DADA2 has extensive genotypic and phenotypic variability. Thus, screening ADA2 among children with vasculitic rash, UCV, PAN, or unexplained, early‐onset central nervous system disease with systemic inflammation may enable an earlier diagnosis of DADA2.
To describe clinical outcomes of juvenile idiopathic arthritis (JIA) in a prospective inception cohort of children managed with contemporary treatments.
Children newly diagnosed with JIA at 16 ...Canadian paediatric rheumatology centres from 2005 to 2010 were included. Kaplan-Meier survival curves for each JIA category were used to estimate probability of ever attaining an active joint count of 0, inactive disease (no active joints, no extraarticular manifestations and a physician global assessment of disease activity <10 mm), disease remission (inactive disease >12 months after discontinuing treatment) and of receiving specific treatments.
In a cohort of 1104 children, the probabilities of attaining an active joint count of 0 exceeded 78% within 2 years in all JIA categories. The probability of attaining inactive disease exceeded 70% within 2 years in all categories, except for RF-positive polyarthritis (48%). The probability of discontinuing treatment at least once was 67% within 5 years. The probability of attaining remission within 5 years was 46-57% across JIA categories except for polyarthritis (0% RF-positive, 14% RF-negative). Initial treatment included joint injections and non-steroidal anti-inflammatory drugs for oligoarthritis, disease-modifying antirheumatic drugs (DMARDs) for polyarthritis and systemic corticosteroids for systemic JIA.
Most children with JIA managed with contemporary treatments attain inactive disease within 2 years of diagnosis and many are able to discontinue treatment. The probability of attaining remission within 5 years of diagnosis is about 50%, except for children with polyarthritis.
Abstract only
Background:
We sought to determine the utility of current echocardiography surveillance recommendations for coronary artery (CA) involvement for children with Kawasaki disease (KD) with ...normal baseline studies.
Methods:
The International KD Registry enrolled 1200 patients (36 sites, 7 countries) with a site diagnosis of KD from 01/2020 to 01/2023; 139 with positive/possible COVID-19 infection/exposure and 174 with no echo within 10 days of admission were excluded, leaving 887 patients for analysis of results of serial echos and associated factors.
Results:
An initial echo was performed within 5 days of admission for 96% and within 10 days of symptom onset for 83% of patients; the max Z score in any CA branch at initial echo was normal (Z <2) 78.9%, dilation (Z 2-<2.5) 6.6%, small aneurysm (CAA; Z 2.5-<5) 10.5%, medium CAA (Z 5-<10) 2.9% and large CAA (Z ≥10) for 1.2% of patients. Higher CA Z score/Z score category were both significantly related to greater time from symptom onset to echo (p<0.001). For those with initial normal CAs, a second echo (median of 16 days after admission) was normal for 94.2%, dilation 1.9%, small CAA 2.7%, medium CAA 0.6%, and large CAA for 0.6%. For those with 2 normal echos, a third echo (median of 44 days after admission) was normal for 97.6%, dilation 1.4%, small CAA 0.5%, and 1 patient each with medium and large CAA. Additionally, after up to 6 normal echos, 3 patients had developed small CAA, 1 medium and 1 large CAA. Overall, a total of 24 (2.8%) patients had large CAA (13 admitted >10 days after symptom onset). Of these, 10 had large CAA evident at initial echo performed at day 0-3 after admission, 9 had lesser involvement at initial echo that then progressed to large CAA, and 5 had normal initial and subsequent echos and then were noted to have large CAA at an echo performed 14, 17, 21, 23 and 53 days after admission (the patient with a large CAA first detected at 53 days had no interim echos performed since their first normal echo).
Conclusions:
Current recommendations for serial echo assessment are effective in detecting all patients with large CAA. For rare patients, despite a normal initial echo large CAA may nonetheless develop. Additionally, important CA involvement may be evident at presentation (often delayed presentation), precluding prevention.
In nine patients with neonatal onset of severe inflammatory lesions affecting mainly bone and skin and associated with mutations of
IL1RN,
which encodes the inhibitor of proinflammatory ...interleukin-1β and the interleukin-1–receptor antagonist, functional studies showed the unfettered release of proinflammatory cytokines from mononuclear cells in the absence of the interleukin-1–receptor antagonist. Treatment with the recombinant interleukin-1–receptor antagonist anakinra promptly resolved the signs and symptoms of the disorder.
An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist In nine patients with neonatal onset of severe inflammatory lesions affecting mainly bone and skin and associated with mutations of
IL1RN,
which encodes the inhibitor of proinflammatory interleukin-1β and the interleukin-1–receptor antagonist, functional studies showed the unfettered release of proinflammatory cytokines from mononuclear cells in the absence of the interleukin-1–receptor antagonist.
Autoinflammatory diseases constitute a group of genetic disorders whose main clinical features are recurrent episodes of inflammatory lesions that can affect the skin, joints, bones, eyes, gastrointestinal tract, and nervous system, in association with signs of systemic inflammation.
1
Examples of these disorders are familial Mediterranean fever
2
,
3
; the tumor necrosis factor receptor–associated periodic syndrome
1
; the hyper-IgD syndrome
1
; a syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne
4
; the cryopyrin-associated periodic syndromes
5
–
7
; and others. The cryopyrin-associated periodic syndromes are related disorders that arise from abnormalities in the control of the potent proinflammatory cytokine interleukin-1β and are . . .
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