Povezanost polimorfizma gena za protein visoke pokretljivosti iz skupine 1 (rs41369348) i imunoglobulin A vaskulitisa kod djece

Immunoglobulin A vasculitis (IgAV) or Henoch-Schönlein purpura is the most prevalent systemic small vessel vasculitis in childhood. High mobility group box 1 protein (HMBG1) is a pleiotropic cytokine that functions as a pro-inflammatory signal, important for the activation of antigen-presenting cells and propagation of inflammation. HMGB1 is implicated in the pathophysiology of a variety of inflammatory diseases. The aim of this study was to investigate the role of single nucleotide polymorphism rs41369348 for HMGB1 gene in the susceptibility and clinical features of patients meeting the classification criteria for IgAV. DNA was extracted from blood cells of 76 children with IgAV and 150 age-matched healthy controls. Clinical data and laboratory parameters were collected for all IgAV patients. Although there was a higher frequency of heterozygous A/delA genotype of this gene polymorphism in IgAV group as compared with control group, no genotype difference was observed between these two groups. No statistically significant genotype differences were disclosed when patients with different IgAV clinical features were compared. In conclusion, in this study, polymorphism rs41369348 for HMGB1 was not associated with increased susceptibility to childhood IgAV, its severity or different clinical manifestations.Imunoglobulin A vaskulitis (IgAV) ili Henoch-Schönleinova purpura najčešći je sistemski vaskulitis malih krvnih žila u dječjoj dobi. Protein visoke pokretljivosti iz skupine 1 (high mobility group box-1 protein, HMGB1) pleiotropni je citokin koji djeluje kao proupalni signal, važan za aktiviranje antigen prezentirajućih stanica i širenje upale. HMGB1 ima ulogu u patofiziologiji različitih upalnih bolesti. Cilj ovog rada bio je istražiti povezanost polimorfizma gena (SNP)-rs41369348 za HMGB1 s predispozicijom za IgAV i kliničkom slikom bolesnika koji ispunjavaju kriterije za IgAV. DNA je ektstrahirana iz krvnih stanica 76 djece s IgAV-om i 150 zdrave kontrolne djece koja se po dobi nisu razlikovala. Klinički podaci i laboratorijski parametri prikupljeni su za sve bolesnike s IgAV-om. Iako postoji veća učestalost heterozigotnog genotipa A/ delA ovog genskog polimorfizma u skupini s IgAV-om u odnosu na kontrolnu skupinu, nije uočena genotipska razlika između navedenih skupina. Nije nađena statistički značajna genotipska razlika između bolesnika s različitom kliničkom slikom IgAV-a. Zaključno, u ovom istraživanju nije nađena povezanost polimorfizma rs41369348 za HMGB1 s predispozicijom za nastanak IgAV-a u djece, kao niti s težinom bolesti ili njezinim različitim kliničkim manifestacijama

Henoch-Schönlein purpura nephritis in children: experience of the two tertiary care centers for pediatric and adolescent rheumatology of the Republic of Croatia from 2006 to 2017

Cilj istraživanja: Valjalo je utvrditi vrste bubrežnih komplikacija, indikacije za biopsiju, načine liječenja te moguće ishode u bolesnika s Henoch-Schönleinovim purpurnim nefritisom (HSPN). Ispitanici i metode: Retrospektivna analiza podataka bolesnika s Henoch Schönleinovom purpurom (HSP) liječenih u Klinikama za pedijatriju Kliničkoga bolničkog centra Zagreb i Kliničkoga bolničkog centra Split, u razdoblju od 2006. do 2017. godine, u kojih se razvila bubrežna bolest prema kriterijima EULAR/PRINTO/PRES-a. Rezultati: Od 378 bolesnika s HSP-om u 81 (21,4%) razvila se bubrežna bolest, u 43 dječaka (53,1%) i 38 djevojčica (46,9%), s medijanom dobi 8,4 godine (2,5 – 16,8). Uočen je statistički značajan porast broja bolesnika s HSP-om tijekom jeseni i zime. Dob bolesnika pri dijagnozi pokazala se kao mogući prognostički čimbenik bubrežne bolesti. S povišenjem dobi bolesnika veći su izgledi za razvoj bubrežne bolesti, pri čemu se u dobi od 1 do 17 godina sa svakom godinom vjerojatnost razvoja nefritisa povećava u prosjeku oko 2,25%. Jednak broj bolesnika imao je istodobno hematuriju i proteinuriju (44,45%) te izoliranu hematuriju (44,45%), a njih samo 11,1% izoliranu proteinuriju. Biopsija bubrega obavljena je u 37 bolesnika (45,7%), a najviše bioptiranih bolesnika bilo je iz skupine s istodobnom hematurijom i proteinurijom (70,3%). Djeca s izoliranom hematurijom odnosno s izoliranom proteinurijom najčešće su liječena glukokortikoidima, dok su djeca s istodobnom hematurijom i proteinurijom najčešće liječena glukokortikoidima i inhibitorima enzima koji konvertira angiotenzin. Imunosupresivnim lijekovima liječeno je ukupno 16% bolesnika, među kojima je najviše onih iz skupine s istodobnom hematurijom i proteinurijom (69,2%). Samo se u jednog bolesnika (1,2%) razvilo bubrežno zatajenje uz potrebu za primjenom dijalize, dok je ishod ostalih ocijenjen kao dobar. Zaključak: Najvažniji čimbenik konačnog ishoda bolesnika s HSP-om jesu bubrežne komplikacije. Da bi se ovi bolesnici mogli optimalno liječiti, potrebno je donijeti konsenzus o indikacijama za biopsiju bubrega u HSPN-u te validirati postojeće patohistološke klasifikacije radi utvrđivanja koja od njih najbolje korelira s nepovoljnim ishodom bolesti.Aim: To determine types of renal complications, indications for biopsy, treatment methods and possible outcomes in patients with Henoch-Schönlein purpura nephritis. Patients and methods: Retrospective analysis of medical data of HSP patients treated at the Department of Paediatrics, University Hospital Centre Zagreb, and the Department of Paediatrics, University Hospital Centre Split, during the period from 2006 to 2017, who developed kidney disease according to EULAR/PRINTO/PRES criteria. Results: Out of 378 patients diagnosed with HSP, 81 (21.4%) developed kidney disease, out of whom 43 boys (53.1%) and 38 girls (46.9%), with the median age 8.4 years (2.5 16.8).. A statistically significant increase of patients with HSP was during autumn and winter. There is a greater chance of nephritis with the increase of patients age at diagnosis. For every year (from 1 to 17 years) the chances increase by around 2.25%. Equal number of patients, 44.45%, had both hematuria and proteinuria or isolated hematuria, and only 11.1% isolated proteinuria. Renal biopsy was performed in 37 patients (45.7%), and most biopted patients were from concurrent hematuria and proteinuria group (70.3%). Children with isolated hematuria or with isolated proteinuria were most often treated with corticosteroids while children with hematuria and proteinuria were most often treated with corticosteroids and angiotensin- -converting enzyme inhibitors. Immunosuppressives were used in 16% of the patients, including most of those in the group with concurrent hematuria and proteinuria (69.2%). Only one patient (1.2%) developed renal insufficiency with the need for dialysis, while the outcome of the others was evaluated as good. Conclusion: Renal complications are the most important factor in the outcome of patients with HSP. For the optimal treatment of these patients it is necessary to bring consensus about the indications for kidney biopsy in HSP, and also to validate the existing pathohistological classification to affirm which one best correlates with the adverse outcome of the disease

"High-mobility group box-1 gene (HMGB1) polymorphisms in children with IgA vasculitis (Henoch-Schönlein purpura (HSP))"

IgA vaskultis (IgAV) ili Henoch-Schönleinova purpura najčešći je sistemski vaskulitis malih krvnih žila u dječjoj dobi. Protein visoke pokretljivosti iz skupine 1 (engl. high mobility group box-1 protein, HMGB1) pleiotropni je citokin koji djeluje kao proupalni signal, važan za aktivaciju antigen prezentirajućih stanica i širenje upale. HMGB1 ima ulogu u patofiziologiji različitih upalnih bolesti. Cilj ovog istraživanja bio je istražiti povezanost četiri polimorfizma jednog nukleotida gena za HMGB1 (rs1045411, rs1060348, rs2249825 i rs41369348), s predispozicijom za IgAV i kliničkom slikom bolesnika koji ispunjavaju kriterije za IgAV. DNA je ektstrahirana iz krvnih stanica 81 djeteta s IgAV-om i 151 zdravih kontrola, koji su bili bez poznatih autoimunih bolesti. Klinički podaci i laboratorijski parametri prikupljeni su za sve bolesnike s IgAV-om. Nije utvrđen povećan omjer izgleda za nastanak IgAV-a s obzirom na analizirane polimorfizme gena za HMGB1, niti za pojavu nefritisa ili zglobnih manifestacija bolesti. Nositelji heterozigotnog genotipa C/T polimorfizma rs1045411 gena za HMGB1 čini se da imaju manje izgleda za razvoj GI manifestacija u sklopu IgAV-a. Alel T polimorfizma rs1045411 i alel C polimorfizma rs2249825 gena za HMGB1 čini se da povećavaju izglede za razvoj generaliziranog osipa u sklopu IgAV-a. Nositelji recesivnog homozigotnog genotipa T/T i heterozigotnog genotipa C/T polimorfizma rs1045411 te recesivnog homozigotnog genotipa C/C i heterozigotnog genotipa G/C polimorfizma rs2249825 čini se da imaju manje izgleda za razvoj generaliziranog osipa u sklopu IgAV-a. Zaključno, u ovom istraživanju nije nađena povezanost polimorfizama gena za HMGB1 s predispozicijom za nastanak IgAV-a u djece, ali pojedini genotipovi i aleli polimorfizma rs1045411 i rs2249825 čini se da imaju utjecaj na kliničke manifestacije IgAV-a.IgA vasculitis (IgAV) or Henoch-Schönlein's purpura is the most prevalent systemic small vessel vasculitis in childhood. High mobility group box-1 protein (HMBG1) is a pleiotropic cytokine that functions as a pro-inflammatory signal, important for the activation of antigen-presenting cells (APCs) and propagation of inflammation. HMGB1 is implicated in the pathophysiology of a variety of inflammatory diseases. The aim of this study was to investigate the role of four single nucleotide polymorphism (SNP) for HMGB1 gene (rs1045411, rs1060348, rs2249825 i rs41369348) in the susceptibility and clinical features of patients fulfilling classification criteria for IgAV. DNA was extracted from blood cells of 81 children with IgAV and 151 healthy controls, who were without known autoimmune diseases. Clinical data and laboratory parameters were collected for all IgAV patients. In this study analyzed polymorphisms for HMGB1 gene were not associated with increased susceptibility to childhood IgAV, neither for the occurrence of nephritis or joint involment. Heterozygote C/T carriers of rs1045411 polymorphism might less likely develop gastrointestinal manifestation within IgAV. The T allele of the rs1045411 polymorphism and the C allele of the rs2249825 polymorphism might increase the prospects of developing generalized rash within IgAV. Recessive homozygote T/T and heterozygote C/T carriers of rs1045411 and recessive homozygote C/C and heterozygote G/C carriers of rs2249825 polymorphisms might less likely develop generalized rash within IgAV. In conclusion, in this study no association of HMGB1 gene polymorphisms with a predisposition to IgAV in children was found, but individual genotypes and alleles of the rs1045411 and rs2249825 polymorphisms might affect clinical manifestations of IgAV

Geospatial clustering of childhood IgA vasculitis and IgA vasculitis-associated nephritis

Objectives: Research on spatial variability of the incidence of IgA vasculitis (IgAV) in children and its potential implications for elucidation of the multifactorial aetiology and pathogenesis is limited. We intended to observe spatial variability of the incidence of IgAV and IgA vasculitis-associated nephritis (IgAVN) using modern geostatistical methods, and hypothesised that their spatial distribution may be spatially clustered. Methods: Patients' data were retrospectively collected from 2009 to 2019 in five Croatian University Hospital Centres for paediatric rheumatology, and census data were used to calculate the incidence of IgAV. Using spatial empirical Bayesian smoothing, local Morans’ I and local indicator of spatial autocorrelation (LISA), we performed spatial statistical analysis. Results: 596 children diagnosed with IgAV were included in this study, of which 313 (52.52%) were male. The average annual incidence proportion was estimated to be 6.79 per 100 000 children, and the prevalence of IgAVN was 19.6%. Existence of spatial autocorrelation was observed in both IgAV and IgAVN ; however, clustering distribution differed. While IgAV showed clustering in Mediterranean and west continental part around cities, IgAVN was clustered in the northern Mediterranean and eastern continental part, where a linear cluster following the Drava and Danube river was observed. Conclusion: IgAV incidence in Croatia is similar to other European countries. Spatial statistical analysis showed a non-random distribution of IgAV and IgAVN. Although aetiological associations cannot be inferred, spatial analytical techniques may help in investigating and generating new hypotheses in non-communicable diseases considering possible environmental risk factors and identification of potential genetic or epigenetic diversity

Geospatial clustering of childhood IgA vasculitis and IgA vasculitis-associated nephritis

Objectives: Research on spatial variability of the incidence of IgA vasculitis (IgAV) in children and its potential implications for elucidation of the multifactorial aetiology and pathogenesis is limited. We intended to observe spatial variability of the incidence of IgAV and IgA vasculitis-associated nephritis (IgAVN) using modern geostatistical methods, and hypothesised that their spatial distribution may be spatially clustered. Methods: Patients' data were retrospectively collected from 2009 to 2019 in five Croatian University Hospital Centres for paediatric rheumatology, and census data were used to calculate the incidence of IgAV. Using spatial empirical Bayesian smoothing, local Morans’ I and local indicator of spatial autocorrelation (LISA), we performed spatial statistical analysis. Results: 596 children diagnosed with IgAV were included in this study, of which 313 (52.52%) were male. The average annual incidence proportion was estimated to be 6.79 per 100 000 children, and the prevalence of IgAVN was 19.6%. Existence of spatial autocorrelation was observed in both IgAV and IgAVN ; however, clustering distribution differed. While IgAV showed clustering in Mediterranean and west continental part around cities, IgAVN was clustered in the northern Mediterranean and eastern continental part, where a linear cluster following the Drava and Danube river was observed. Conclusion: IgAV incidence in Croatia is similar to other European countries. Spatial statistical analysis showed a non-random distribution of IgAV and IgAVN. Although aetiological associations cannot be inferred, spatial analytical techniques may help in investigating and generating new hypotheses in non-communicable diseases considering possible environmental risk factors and identification of potential genetic or epigenetic diversity

Association between High Mobility Group Box 1 Protein Gene (Rs41369348) Polymorphism and Immunoglobulin A Vasculitis in Children

Immunoglobulin A vasculitis (IgAV) or Henoch-Schönlein purpura is the most prevalent systemic small vessel vasculitis in childhood. High mobility group box 1 protein (HMBG1) is a pleiotropic cytokine that functions as a pro-inflammatory signal, important for the activation of antigen-presenting cells and propagation of inflammation. HMGB1 is implicated in the pathophysiology of a variety of inflammatory diseases. The aim of this study was to investigate the role of single nucleotide polymorphism rs41369348 for HMGB1 gene in the susceptibility and clinical features of patients meeting the classification criteria for IgAV. DNA was extracted from blood cells of 76 children with IgAV and 150 age-matched healthy controls. Clinical data and laboratory parameters were collected for all IgAV patients. Although there was a higher frequency of heterozygous A/delA genotype of this gene polymorphism in IgAV group as compared with control group, no genotype difference was observed between these two groups. No statistically significant genotype differences were disclosed when patients with different IgAV clinical features were compared. In conclusion, in this study, polymorphism rs41369348 for HMGB1 was not associated with increased susceptibility to childhood IgAV, its severity or different clinical manifestations

Gastrointestinal involvement and its association with the risk for nephritis in IgA vasculitis

Background: We analysed clinical and biochemical parameters in predicting severe gastrointestinal (GI) manifestations in childhood IgA vasculitis (IgAV) and the risk of developing renal complications. ----- Methods: A national multicentric retrospective study included children with IgAV reviewed in five Croatian University Centres for paediatric rheumatology in the period 2009-2019. ----- Results: Out of 611 children, 281 (45.99%) had at least one GI manifestation, while 42 of 281 (14.95%) had the most severe GI manifestations. Using logistic regression several clinical risk factors for the severe GI manifestations were identified: generalized rash [odds ratio (OR) 2.09 (95% confidence interval (CI) 1.09-4.01)], rash extended on upper extremities (OR 2.77 (95% CI 1.43-5.34)] or face [OR 3.69 (95% CI 1.42-9.43)] and nephritis (IgAVN) [OR 4.35 (95% CI 2.23-8.50)], as well as lower values of prothrombin time (OR 0.05 (95% CI 0.01-0.62)], fibrinogen [OR 0.45 (95% CI 0.29-0.70)] and IgM [OR 0.10 (95% I 0.03-0.35)]] among the laboratory parameters. Patients with severe GI involvement more frequently had relapse of the disease [OR 2.14 (CI 1.04-4.39)] and recurrent rash [OR 2.61 (CI 1.27-5.38)]. Multivariate logistic regression found that the combination of age, GI symptoms at the beginning of IgAV and severity of GI symptoms were statistically significant predictors of IgAVN. Patients in whom IgAV has started with GI symptoms [OR 6.60 (95% CI 1.67-26.06)], older children [OR 1.22 (95% CI 1.02-1.46)] with severe GI form of IgAV (OR 5.90 (95% CI 1.12-31.15)] were particularly high-risk for developing IgAVN. ----- Conclusion: We detected a group of older children with the onset of GI symptoms before other IgAV symptoms and severe GI form of the IgAV, with significantly higher risk for acute and chronic complications of IgAV