Identification of Novel Adenosine Deaminase 2 Gene Variants and Varied Clinical Phenotype in Pediatric Vasculitis.

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.

The Czech version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient-reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Czech language. The reading comprehension of the questionnaire was tested in ten JIA parents and patients. The participating centre was asked to collect demographic and clinical data along the JAMAR questionnaire in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 103 JIA patients (5.8% systemic, 35.9% oligoarticular, 37.9% RF-negative polyarthritis, 20.4% other categories) and 100 healthy children, were enrolled. The JAMAR components discriminated well healthy subjects from JIA patients. Notably, there was no significant difference between healthy subjects and their affected peers in the school-related problems variable and in the Psychosocial Health of the Paediatric Rheumatology Quality of Life scale. All JAMAR components revealed good psychometric performances. In conclusion, the Czech version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Clinical features of childhood granulomatosis with polyangiitis (wegener's granulomatosis).

BACKGROUND: Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis (WG), belongs to the group of ANCA-associated necrotizing vasculitides. This study describes the clinical picture of the disease in a large cohort of GPA paediatric patients. Children with age at diagnosis ≤ 18 years, fulfilling the EULAR/PRINTO/PRES GPA/WG classification criteria were extracted from the PRINTO vasculitis database. The clinical signs/symptoms and laboratory features were analysed before or at the time of diagnosis and at least 3 months thereafter and compared with other paediatric and adult case series (>50 patients) derived from the literature. FINDINGS: The 56 children with GPA/WG were predominantly females (68%) and Caucasians (82%) with a median age at disease onset of 11.7 years, and a median delay in diagnosis of 4.2 months. The most frequent organ systems involved before/at the time of diagnosis were ears, nose, throat (91%), constitutional (malaise, fever, weight loss) (89%), respiratory (79%), mucosa and skin (64%), musculoskeletal (59%), and eye (35%), 67% were ANCA-PR3 positive, while haematuria/proteinuria was present in > 50% of the children. In adult series, the frequency of female involvement ranged from 29% to 50% with lower frequencies of constitutional (fever, weight loss), ears, nose, throat (oral/nasal ulceration, otitis/aural discharge), respiratory (tracheal/endobronchial stenosis/obstruction), laboratory involvement and higher frequency of conductive hearing loss than in this paediatric series. CONCLUSIONS: Paediatric patients compared to adults with GPA/WG have similar pattern of clinical manifestations but different frequencies of organ involvement.

PFAPA syndrome: clinical characteristics and treatment outcomes in a large single-centre cohort.

OBJECTIVES: This paper aims to describe clinical and laboratory features and disease outcome in a single-centre cohort of patients with PFAPA syndrome (Periodic Fever, Aphtous stomatitis, Pharyngitis, and Adenitis) and to test performance of diagnostic and therapeutic algorithms. METHODS: Patients fulfilling criteria were selected from the fever clinic population. Prospective follow-up together with recruitment of newly diagnosed patients followed pre-defined guidelines. Diagnostic and therapeutic algorithms and definitions of outcome and therapy response were formulated. Paired blood samples during febrile and afebrile periods were compared. RESULTS: Out of 176 patients referred for suspected periodic fever 125 children fulfilled criteria. Their age at onset was 23 months, median episode duration 3.5 days at 4-week intervals. Fever was associated with pharyngitis (91%), cervical adenitis (78%) and aphtae (41%). Among therapeutic options, episodic prednisone proved to be the most common first-line treatment. Administered to 77 patients, it reduced symptoms in 94%. Tonsillectomy led to the full symptom resolution in all 18 patients. Forty-six patients reached disease remission. CONCLUSIONS: Distribution of typical symptoms, response to therapies and disease outcome in a large patient cohort were documented. We offer diagnostic and therapeutic algorithms that have proven effective during this prospective trial. Our findings support the general belief of benign nature of this aetiologically unclear condition, despite proportion of patients having persistent disease for years. Maintenance of normal findings in afebrile intervals, striking response to a single dose of prednisone and normal growth and development together with spontaneous tendency towards prolongation of afebrile intervals are important confirmatory features of PFAPA syndrome.

Methotrexate therapy may prevent the onset of uveitis in juvenile idiopathic arthritis.

OBJECTIVE: To evaluate whether early treatment with methotrexate (MTX) prevents the onset of uveitis in children with juvenile idiopathic arthritis. STUDY DESIGN: The clinical charts of all consecutive patients seen between January 2002 and February 2011 who had a disease duration <1 year at first visit and had received a stable management for at least 2 years with or without MTX were reviewed. Patients who were given systemic medications other than MTX (except nonsteroidal anti-inflammatory drugs) were excluded. Patients with systemic arthritis, rheumatoid factor-positive arthritis, or enthesitis-related arthritis were also excluded. In each patient, the 2-year follow-up period after first visit was examined to establish whether uveitis had occurred. RESULTS: A total of 254 patients with a median disease duration of 0.3 year were included. Eighty-six patients (33.9%) were treated with MTX, whereas 168 patients (66.1%) did not receive MTX. During the 2-year follow-up, 211 patients (83.1%) did not develop uveitis, whereas 43 patients (16.9%) had uveitis a median of 1.0 year after the first visit. The frequency of uveitis was lower in MTX-treated than in MTX-untreated patients (10.5% vs 20.2%, respectively, P = .049). Survival analysis confirmed that patients treated with MTX had a lower probability of developing uveitis. CONCLUSION: Early MTX therapy may prevent the onset of uveitis in children with juvenile idiopathic arthritis. Because our study may be affected by confounding by indication, the potential of MTX to reduce the incidence of ocular disease should be investigated in a randomized controlled trial.

Delineating the role of multiple intraarticular corticosteroid injections in the management of juvenile idiopathic arthritis in the biologic era.

OBJECTIVE: To investigate the outcome and predicting factors of multiple intraarticular corticosteroid (IAC) injections in children with juvenile idiopathic arthritis (JIA). METHODS: The clinical charts of patients who received their first IAC injection in ≥3 joints between January 2002 and December 2011 were reviewed. The corticosteroid used was triamcinolone hexacetonide for large joints and methylprednisolone acetate for small or difficult to access joints. In each patient, the followup period after IAC injection was censored in case of synovitis flare or at the last visit with continued remission. Predictors included sex, age at disease onset, JIA category, antinuclear antibody (ANA) status, age and disease duration, disease course, general anesthesia, number and type of injected joints, acute-phase reactants, and concomitant systemic medications. RESULTS: A total of 220 patients who had 1,096 joints injected were included. Following IAC therapy, 66.4% of patients had synovitis flare after a median of 0.5 years, whereas 33.6% of patients had sustained remission after a median of 0.9 years. The cumulative probability of survival without synovitis flare was 50.0%, 31.5%, and 19.5% at 1, 2, and 3 years, respectively. On Cox regression analysis, positive C-reactive protein value, negative ANA, lack of concomitant methotrexate administration, and a polyarticular (versus an oligoarticular) disease course were the strongest predictors for synovitis flare. CONCLUSION: Multiple IAC injection therapy induced sustained remission of joint synovitis in a substantial proportion of patients. A controlled trial comparing multiple IAC injection therapy and methotrexate versus methotrexate and a tumor necrosis factor antagonist is worthy of consideration.

Disease activity assessment in childhood vasculitis: development and preliminary validation of the Paediatric Vasculitis Activity Score (PVAS).

BACKGROUND: Rare chronic childhood vasculitides lack a reliable disease activity assessment tool. With emerging new treatment modalities such a tool has become increasingly essential for both clinical practice and therapeutic trials to reproducibly quantify change in disease state. OBJECTIVE: To develop and validate a paediatric vasculitis activity assessment tool based on modification of the Birmingham Vasculitis Activity Score (BVASv.3). METHODS: A paediatric vasculitis registry was reviewed to identify clinical features missing in the BVASv.3. A modified nominal group technique was used to develop a working version of the Paediatric Vasculitis Activity Score (PVAS). Prospective validation provided tool reliability, reproducibility and responsiveness to change. Training of assessors was done according to the BVAS principles. RESULTS: BVAS items were redefined (n=22) and eight paediatric items added in Cutaneous (n=4), Cardiovascular (n=3) and Abdominal (n=1) sections. The final PVAS has 64 active items in nine categories. The principles of new/worse and persistently active disease were retained as were the overall score and weighting of categories. The median PVAS in 63 children with systemic vasculitis was 4/63 (0-38/63). There was a high interobserver agreement for the overall as well as for subsystem scores (linear-weighted-κ ≥0.87). PVAS correlated with physician's global assessment (p<0.01); treatment decision (p=<0.01) and erythrocyte sedimentation rate (ESR) (p=0.01). In response to treatment, 15/19 patients assessed demonstrated a significant fall in PVAS (p=0.002), with good agreement among assessors for this change. CONCLUSIONS: The PVAS validity in children with systemic vasculitis was demonstrated. Like the BVAS, we anticipate that the PVAS will provide a robust tool to objectively define disease activity for clinical trials and future research.

Activities of respiratory chain complexes in isolated platelets in females with anorexia nervosa.

OBJECTIVE: A broad spectrum of endocrine and biochemical disturbances was observed in patients with anorexia nervosa. In addition, metabolic changes may concern the efficiency of mitochondrial energy generating system. In our study we analyzed the activities of respiratory chain complexes in females with anorexia nervosa. METHOD: The activities of respiratory chain complexes I, II, IV, I + III, and citrate synthase serving as the control enzyme were measured spectrophotometrically in isolated platelets in 36 females with anorexia nervosa (BMI 15 +/- 1.7) at the age 18-35 years and in 37 age related female controls (BMI 21 +/- 2.2). RESULTS: In females with anorexia nervosa, the activities of respiratory chain complexes I and II in isolated platelets were significantly higher in comparison with controls. No differences were found in the activities of complexes IV and I + III and citrate synthase. CONCLUSION: Our results suggest higher efficiency of some respiratory chain complexes in platelets in females with anorexia nervosa.

Retrospective, multicentric study of 180 children with cytochrome C oxidase deficiency.

A retrospective, multicenter study of 180 children with cytochrome c oxidase (COX) deficiency analyzed the clinical features, prognosis, and molecular bases of the COX deficiency. Clinical symptoms including failure to thrive, encephalopathy, hypotony, Leigh syndrome, cardiac involvement, and hepatopathy appeared in most patients early after birth or in early childhood. Two thirds of all children died. Biochemical examination revealed an isolated COX deficiency in 101 children and COX deficiency combined with disturbances of other respiratory chain complexes in 79 children. Blood and cerebrospinal fluid lactate increased in 85% and 81% of examined cases, respectively. Pathogenic mutations in mitochondrial or nuclear DNA were established in 75 patients. Mutations in surfeit locus protein 1 gene (SURF1) were found in 47 children with Leigh syndrome; 2bp deletion 845-846delCT was found in 89% of independent alleles. Mutations in a mitochondrial copper-binding protein (SCO2) gene were found in nine children with encephalomyopathy and/or cardiomyopathy; all of them were homozygotes or heterozygotes for 1541G>A mutation. Different mitochondrial DNA (mtDNA) deletion or depletion were found in nine children, mtDNA mutation 3243A>G in six, mtDNA mutation 8363G>A in two children with Leigh syndrome and mtDNA mutations 8344A>G, and 9205-9206delTA in one child each. COX deficiency represents a heterogeneous group of diseases with unfavorable prognosis. Marked prevalence of two nuclear DNA mutations (845-846delCT in the SURF1 gene and 1541G>A in the SCO2 gene) associated with COX deficiency in a Slavonic population suggests the existence of regional differences in the genetic basis of COX deficiency.