Juvenile Idiopathic Arthritis Subtype- and Sex-specific Associations with Genetic Variants in the PSMA6/PSMC6/PSMA3 Gene Cluster

BackgroundThe ubiquitin proteasome system plays an exceptional biological role in the antigen processing and immune response and it could potentially be involved in pathogenesis of many immunity-related diseases, including juvenile idiopathic arthritis (JIA).MethodsThe PSMB5 (rs11543947), PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827), and PSMA3 (rs2348071) proteasomal genes were genotyped on JIA subtype- and sex-specific association; plasma proteasome levels was measured in patients having risk and protective four-locus genotypes and eventual functional significance of allele substitutions was evaluated in silico.ResultsLoci rs11543947 and rs1048990 were identified as disease neutral and other loci as disease susceptible (p < 0.05). The rs2277460, rs2295826, and rs2295827 loci had the strongest association with oligoarthritis [odds ratio (OR) = 2.024, 95% confidence interval (CI) 1.101–3.722; OR = 2.371, 95% CI 1.390–4.044; OR = 2.183, 95% CI 1.272–2.737, respectively), but the rs2348071 locus was associated with polyarthritis in females (OR = 3.438, 95% CI 1.626–7.265). A strong (p < 0.001) association was detected between the rs2277460/rs2295826/rs2295827/rs2348071 four-locus genotypes and the healthy phenotype when all loci were homozygous on common alleles (OR 0.439, 95% CI 0.283–0.681) and with the disease phenotype when the rs2348071 and the rs2295826 and/or rs2295827 loci were represented by risk genotypes simultaneously (OR 4.674, 95% CI 2.096–10.425). Rarely observed in controls, the double rs2277460/rs2348071 heterozygotes were rather frequent in affected males and more strongly associated with polyarthritis (p < 0.05). Haplotypes carrying the rare rs2295826/rs2295827 and rs2277460 alleles showed a strong (p < 0.001) association with oligo- and polyarthritis, respectively. The plasma proteasome level was found to be significantly higher in females having four-locus risk genotypes compared with protective genotypes (p < 0.001). Sequence affinity to transcription factors and similarity to splicing signals, microRNAs and/or hairpin precursors potentially depend on allele substitutions in disease susceptible loci.ConclusionWe demonstrate for the first time evidence of a sex-specific association of PSMA6/PSMC6/PSMA3 genetic variants with subtypes of JIA and plasma proteasome concentrations. Theoretical models of the functional significance of allele substitutions are discussed

The Latvian 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 the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Latvian language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR 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\u2019s alpha, interscale correlations, test\u2013retest reliability, and construct validity (convergent and discriminant validity). A total of 100 JIA patients (2% systemic, 56% oligoarticular, 17% RF negative polyarthritis, 25% other categories) and 204 healthy children, were enrolled at the paediatric rheumatology centre. The JAMAR components discriminated healthy subjects from JIA patients, except for the paediatric rheumatology quality of life (HRQoL), psychosocial health (PsH) subscales, the HRQoL total score and for the school-related problems variable. All JAMAR components revealed good psychometric performances. In conclusion, the Latvian 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

Association of Obesity with Proteasomal Gene Polymorphisms in Children

The aim of this study was to ascertain possible associations between childhood obesity, its anthropometric and clinical parameters, and three loci of proteasomal genes rs2277460 (PSMA6 c.-110C>A), rs1048990 (PSMA6 c.-8C>G), and rs2348071 (PSMA3 c. 543+138G>A) implicated in obesity-related diseases. Obese subjects included 94 otherwise healthy children in Latvia. Loci were genotyped and then analyzed using polymerase chain reactions, with results compared to those of 191 nonobese controls. PSMA3 SNP frequency differences between obese children and controls, while not reaching significance, suggested a trend. These differences, however, proved highly significant (PG SNP differences, while being nonsignificant, likewise suggested a trend in comparison to the nonobese controls. No PSMA6 c.-110C>A SNP differences were detected in the obese group or its subsets. Finally, PSMA3 SNP differences were significantly associated (P<0.05) with circulating low-density lipoprotein cholesterol (LDL) levels. Our results clearly implicate the PSMA3 gene locus as an obesity risk factor in those Latvian children with a family history of obesity. While being speculative, the clinical results are suggestive of altered circulatory LDL levels playing a possible role in the etiology of obesity in the young

Juvenile Idiopathic Arthritis Subtype- and Sex-specific Associations with Genetic Variants in the PSMA6/PSMC6/PSMA3 Gene Cluster

BackgroundThe ubiquitin proteasome system plays an exceptional biological role in the antigen processing and immune response and it could potentially be involved in pathogenesis of many immunity-related diseases, including juvenile idiopathic arthritis (JIA).MethodsThe PSMB5 (rs11543947), PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827), and PSMA3 (rs2348071) proteasomal genes were genotyped on JIA subtype- and sex-specific association; plasma proteasome levels was measured in patients having risk and protective four-locus genotypes and eventual functional significance of allele substitutions was evaluated in silico.ResultsLoci rs11543947 and rs1048990 were identified as disease neutral and other loci as disease susceptible (p < 0.05). The rs2277460, rs2295826, and rs2295827 loci had the strongest association with oligoarthritis [odds ratio (OR) = 2.024, 95% confidence interval (CI) 1.101–3.722; OR = 2.371, 95% CI 1.390–4.044; OR = 2.183, 95% CI 1.272–2.737, respectively), but the rs2348071 locus was associated with polyarthritis in females (OR = 3.438, 95% CI 1.626–7.265). A strong (p < 0.001) association was detected between the rs2277460/rs2295826/rs2295827/rs2348071 four-locus genotypes and the healthy phenotype when all loci were homozygous on common alleles (OR 0.439, 95% CI 0.283–0.681) and with the disease phenotype when the rs2348071 and the rs2295826 and/or rs2295827 loci were represented by risk genotypes simultaneously (OR 4.674, 95% CI 2.096–10.425). Rarely observed in controls, the double rs2277460/rs2348071 heterozygotes were rather frequent in affected males and more strongly associated with polyarthritis (p < 0.05). Haplotypes carrying the rare rs2295826/rs2295827 and rs2277460 alleles showed a strong (p < 0.001) association with oligo- and polyarthritis, respectively. The plasma proteasome level was found to be significantly higher in females having four-locus risk genotypes compared with protective genotypes (p < 0.001). Sequence affinity to transcription factors and similarity to splicing signals, microRNAs and/or hairpin precursors potentially depend on allele substitutions in disease susceptible loci.ConclusionWe demonstrate for the first time evidence of a sex-specific association of PSMA6/PSMC6/PSMA3 genetic variants with subtypes of JIA and plasma proteasome concentrations. Theoretical models of the functional significance of allele substitutions are discussed

Etanercept treatment for extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or psoriatic arthritis

To describe the 6-year safety and efficacy of etanercept (ETN) in children with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA) METHODS: Patients who completed the 2-year, open-label, phase III CLinical Study In Pediatric Patients of Etanercept for Treatment of ERA, PsA, and Extended Oligoarthritis (CLIPPER) were allowed to enroll in its 8-year long-term extension (CLIPPER2). Children received ETN at a once-weekly dose of 0.8 mg/kg, up to a maximum dose of 50 mg/week. Efficacy assessments included the JIA core set of outcomes, the JIA American College of Rheumatology response criteria (JIA-ACR), and the Juvenile Arthritis Disease Activity Score (JADAS). Efficacy data are reported as responder analyses using a hybrid method for missing data imputation and as observed cases. Safety assessments included treatment-emergent adverse events (TEAEs).Out of 127 patients originally enrolled in CLIPPER, 109 (86%) entered CLIPPER2. After 6 years of trial participation (2 years in CLIPPER and 4 years in CLIPPER2), 41 (32%) patients were still taking ETN, 13 (11%) entered the treatment withdrawal phase after achieving low/inactive disease (of whom 7 had to restart ETN), 36 (28%) discontinued treatment for other reasons but are still being observed, and 37 (29%) discontinued treatment permanently. According to the hybrid imputation analysis, proportions of patients achieving JIA ACR90, JIA ACR100, and JADAS inactive disease after the initial 2 years of treatment were 58%, 48%, and 32%, respectively. After the additional 4 years, those proportions in patients who remained in the trial were 46%, 35%, and 24%. Most frequently reported TEAEs [n (%), events per 100 patient-years] were headache [28 (22%), 5.3], arthralgia [24 (19%), 4.6], and pyrexia [20 (16%), 3.8]. Number and frequency of TEAEs, excluding infections and injection site reactions, decreased over the 6-year period from 193 and 173.8, respectively, during year 1 to 37 and 61.3 during year 6. A single case of malignancy (Hodgkin's lymphoma) and no cases of active tuberculosis, demyelinating disorders, or deaths were reported.Open-label etanercept treatment for up to 6 years was safe, well tolerated, and effective in patients with eoJIA, ERA, and PsA.ClinicalTrials.gov: CLIPPER, NCT00962741 , registered 20 August, 2009, CLIPPER2, NCT01421069 , registered 22 August, 2011

Efficacy and safety of open-label etanercept on extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis and psoriatic arthritis: part 1 (week 12) of the CLIPPER study

OBJECTIVE: To investigate the efficacy and safety of etanercept (ETN) in paediatric subjects with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). METHODS: CLIPPER is an ongoing, Phase 3b, open-label, multicentre study; the 12-week (Part 1) data are reported here. Subjects with eoJIA (2-17 years), ERA (12-17 years), or PsA (12-17 years) received ETN 0.8 mg/kg once weekly (maximum 50 mg). Primary endpoint was the percentage of subjects achieving JIA American College of Rheumatology (ACR) 30 criteria at week 12; secondary outcomes included JIA ACR 50/70/90 and inactive disease. RESULTS: 122/127 (96.1%) subjects completed the study (mean age 11.7 years). JIA ACR 30 (95% CI) was achieved by 88.6% (81.6% to 93.6%) of subjects overall; 89.7% (78.8% to 96.1%) with eoJIA, 83.3% (67.2% to 93.6%) with ERA and 93.1% (77.2% to 99.2%) with PsA. For eoJIA, ERA, or PsA categories, the ORs of ETN vs the historical placebo data were 26.2, 15.1 and 40.7, respectively. Overall JIA ACR 50, 70, 90 and inactive disease were achieved by 81.1, 61.5, 29.8 and 12.1%, respectively. Treatment-emergent adverse events (AEs), infections, and serious AEs, were reported in 45 (35.4%), 58 (45.7%), and 4 (3.1%), subjects, respectively. Serious AEs were one case each of abdominal pain, bronchopneumonia, gastroenteritis and pyelocystitis. One subject reported herpes zoster and another varicella. No differences in safety were observed across the JIA categories. CONCLUSIONS: ETN treatment for 12 weeks was effective and well tolerated in paediatric subjects with eoJIA, ERA and PsA, with no unexpected safety findings

Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: Analysis by the Pharmachild Safety Adjudication Committee

Background: To derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC). Methods: The SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI. Results: A total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI. Conclusions: We found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies. Trial registration: Clinicaltrials.gov NCT 01399281; ENCePP seal: awarded on 25 November 2011

Juvenila hroniska artrita epidemiologija, imungenetika un prognoze

In the investigation the following objects have been clarified by using epidemiological (analytic-prospective, cohort method), immunogenetical (polymerize chain reaction), immunological (detection of antinative collagen antibodies and rheumatoid factor) and statistical methods: the epidemiological indices of juvenile chronic arthritis (JCA) in the prevalence group (including 318 patients) and the incidence group (including 222 patients); immunogenetical characteristics of JCA (HLA class 2 DQ, DR genes); the clinical importance of anticollagen antibodies and RF and their association with HLA genes in 127 patients; the prognostic factors for JCA and its different variants (rapidly progressing, slowly progressing arthritis; arthritis with and without course conversion). In the epidemiological investigation it has been established that the prevalence indices of JCA are higher using combined data acquisition method (data from hospital and outpatient contingent) than using the data from hospital contingent. The prevalence in Latvia is 62.1/100 000 children, the incidence is 12.3/100 000 children. In the immunogenetical investigation JCA risk and protective genes have been determined. JCA risk factor is the gene HLA-DQA1* 0301; the risk factors for JCA monoarticular onset variant are associated haplotypes HLA-DQA* 0102 - B* 0502 and DQA* 0301 - B* 0301. JCA risk is decreased by negatively associated gene HLA-DQB1* 0501, haplotypes HLA-DQA* 0101 - B* 0501 and HLA-DRB* 01-A* 0101 - B* 0501. The risk of polyarticular onset is decreased by HLA-DQB1* 0501, haplotypes HLA-DQA* 0101 - B* 0501 and DRB* 01 - A* 0101 - B* 0501. We have determined that class IgG, IgA,IgM antinative collagen antibodies are not associated with the clinical features. ACA associations with HLA genes have been detected. Analyzing correlation coefficient and variants, the prognostic factors for rapidly progressing JCA have been detected (early age at the onset of the disease, elevated CRP, ESR, positive IgM RF and Child HAQ index &gt; 0.5 units). The prognostic factors of monoarthritis course conversion (the age at the onset of disease) and oligoarthritis course conversion (early age at the onset of disease, IgM RF seropositivity, Child HAQ index &gt; 0.5 u.) have been determined. The marker of persisting oligoarthritis is HLA-DRB* 01 - A* 0101 - B* 0501Separate annotation in Latvian, English, German, 35 p.Available from Latvian Academic Library / LAL - Latvian Academic LibrarySIGLELVLatvi

Maternal and Neonatal Characteristics for Late Foetal Death in Latvia between 2001 and 2014: Population-Based Study

Introduction. Stillbirth is one of the most common adverse pregnancy outcomes worldwide. Late foetal death (LFD) rates are mostly used for international comparisons because of the large variations in stillbirth rates between countries. Objective. To examine trends in LFD (including antepartum and intrapartum) by multiple births, birth weight, and maternal age in two time periods. Methods. A retrospective cohort study was used to analyse data from the Medical Birth Register (2001–2014), divided into 2 periods of 7 years each. In total, data on 1,340 singletons were analysed. This study calculated LFD rates and rate ratios (RR). Results. The overall LFD rate showed a slight statistically significant reduction (p < 0.001) of 18% between 2001–2007 and 2008–2014. There was a slight increase in the mortality rate from multiple pregnancies (RR 1.1/1000; 95% CI 0.6-1.9). There were no major differences in the LFD rate by maternal age during the time periods. Conclusions. LFD decreased (RR 0.8/1000 births), as well as intrapartum LFD (RR 0.6/1000 births). Older maternal age influenced pregnancy outcomes, and higher LFD rates were observed in the age group ≥35 years. Substantial intrapartum stillbirths rates indicate problems with quality of intrapartum care and emergency obstetric care. Further research is needed to evaluate the strategies necessary to substantially reduce the number of stillbirths in the country

Infant mortality gap in the Baltic region - Latvia, Estonia, and Lithuania - in relation to macroeconomic factors in 1996-2010

Background and Objective. A constant gap has appeared in infant mortality among the 3 Baltic States - Latvia, Estonia, and Lithuania – since the restoration of independence in 1991. The aim of the study was to compare infant mortality rates in all the 3 Baltic countries and examine some of the macro- and socioeconomic factors associated with infant mortality. Material and Methods. The data were obtained from international databases, such as World Health Organization and EUROSTAT, and the national statistical databases of the Baltic States. The time series data sets (1996–2010) were used in the regression and correlation analysis. Results. In all the 3 Baltic States, a strong and significant correlation was found: Latvia (r=–0.81, P<0.01), Lithuania (r=–0.93, P<0.01), and Estonia (r=–0.91, P<0.01). There was also a correlation between infant mortality and healthcare expenditure in local currency per capita: Latvia (r=– 0.81, P<0.01); Lithuania (r=–0.90, P<0.01) and Estonia (r=–0.88, P<0.01). In Latvia (r=0.87, P<0.01) and Estonia (r=0.70; P<0.01), a significant correlation between infant mortality and unemployment levels was observed from 1996 to 2008, whereas the statistical significance disappeared in the period from 1996 to 2010. In Lithuania, the relationship was not significant. Conclusions. Higher infant mortality rates and a less stable decreasing tendency in Latvia are apparently explained by less successful adaptation to a new political and economic situation and limited skills in adjusting the healthcare system to the reality of life