Aktivnost eritrocitne glutation S-transferaze u djece oboljele od HenochSchönleinove purpure [Erythrocyte glutathione S-transferase activity in children with Henoch-Schönlein purpura]

Introduction: Henoch-Schönlein purpura (HSP) is the most common vasculitis of the childhood. Among all possible symptoms / complications, nephritis (HSPN) is the main and almost only cause of morbidity and mortality in HSP. The aim of this study was to investigate the value of erythrocyte glutathione S-transferase (eGST) activity as an early predictor of nephritis in HSP. ----- Subjects and methods: Ninety-seven children with HSP were enrolled into the study. The control group consisted of 52 children without clinical and laboratory signs of inflammation. In all patients e-GST activity was determined spectrometrically from the whole blood samples, after incubation with a commercial GST assay at the time of enrolment and twice more in regular intervals during follow up period of six months. In children from the control group e-GST activity was determined at the time of enrolment. ----- Results: At the beginning of the disease the e-GST activity values were significantly higher in the group of patients with HSPN compared to the group of HSP patients without nephritis: median (interquartile range) 5,70 U/gHb (4,38-7,50 U/gHb) compared to 3,10 U/gHb (2,20-4,20 U/gHb); P˂0,001. Similar results were obtained after the comparison of the patients with HSPN and control group: 5,70 U/gHb (4,38-7,50 U/gHb) vs. 3,13 U/gHb (1,91-4,20 U/gHb); P˂0,001. There were no statistically significant differences between the group of HSP patients without nephritis and a control group (P=0,837). During the follow up period of six months, a significant decrease of e-GST activity was observed in the HSPN patients, but it was still significantly higher compared to the group of HSP patients without nephritis (P˂0,001 / P˂0,001). In the ROC analysis of the e-GST activity determination value in the prediction of HSP nephritis, at the e-GST values >4,1 U/gHb a significant area under the curve (AUC) of 91.1% (P < 0.001) and sensitivity of 90.5% and specificity of 72.7% was found at the beginning of the study. The sensitivity of the nephritis detection tests decreased, and the specificity increased during the follow up period. No significant correlation between e-GST activity and severity of skin changes, or used therapy was found. Among the routine laboratory tests, a consistent, statistically significant, positive correlation was found only between e-GST activity and the number of erythrocytes per mm3 in urine samples. ----- Conclusion: e-GST activity is a reliable, independent marker of early nephritis risk assessment in children with HSP. As a sensitive and specific, feasible and inexpensive laboratory test, it has potential practical utility in the diagnostic algorithm and monitoring of the children with HSP

VASCULITIDES IN CHILDHOOD

Primarni sistemski vaskulitisi u djece relativno su rijetke bolesti, većinom nepoznate etiologije, kojima je zajedničko obilježje upala u stijenci krvne žile. Teško ih je dijagnosticirati jer su zahvaćeni mnogi organi, a simptomi su uglavnom nespecifi čni. U posljednjih 10 godina postignut je znatan napredak u području vaskulitisa u dječjoj dobi: defi nirani su i validirani klasifi kacijski kriteriji, razvijeni i validirani upitnici za procjenu aktivnosti bolesti i ishoda, pedijatrijski bolesnici uključeni su u međunarodna multicentrična istraživanja vezana uz terapiju vaskulitisa, započeta su klinička istraživanja izuzetno rijetkih vaskulitisa i izdvojena je zasebna skupina rijetkih monogenskih vaskulitisa. Ovim radom želimo upoznati čitaoce s velikim iskorakom u području vaskulitisa u dječjoj dobi, nastalim na osnovi mukotrpnog rada pedijatrijskih reumatologa u radnim skupinama za vaskulitise.Primary systemic vasculitides in children are relatively rare diseases. In most cases, they have an unknown etiology and are defi ned as the presence of infl ammation in the blood vessel wall. Establishing the diagnosis of vasculitis is oft en challenging, since the disorder is multisystem in nature with mostly nonspecifi c symptoms. Th e last 10 years have seen signifi cant advances in the fi eld of pediatric vasculitis: the development and validation of classifi cation criteria as well as tools to assess clinical disease activity and disease outcome, the inclusion of pediatric patients in international multicentre randomized controlled trial designs for therapies of vasculitis, clinical trials for very rare pediatric vasculitides, and identifi cation of a special group of monogenic vasculitides. In this paper we want to introduce readers to the giant leap in the fi eld of pediatric vasculitis as a result of the hard work of pediatric rheumatologists in vasculitis work groups

Rituximab in Treatment of Children with Refractory Vasculitis and Systemic Lupus Erythematosus – Single Center Experience in Croatia

The aim of this study was to present our experience in rituximab therapy in patients with childhood-onset systemic lupus erythematosus, lupus nephritis, and ANCA-associated vasculitis. We conducted a retrospective clinical chart review of all patients treated with rituximab in the time period from January 2009 to December 2015. Eight patients (3 boys and 5 girls) aged 8 to 15 at the onset of disease were treated with rituximab. Remission of disease was accomplished in 4 patients with childhood-onset systemic lupus erythematosus and lupus nephritis, a partial improvement was achieved in 1 patient with childhoodonset systemic lupus erythematosus and lupus nephritis as well as in 2 patients with vasculitis, while in one patient with vasculitis treatment with rituximab showed no effect and the patient died due to Candida sepsis. Reduction of corticosteroid doses was enabled by rituximab treatment. Rituximab appeared to be a safe and efficient therapeutic option in severe cases of childhood-onset systemic lupus erythematosus or ANCA-associated vasculitis that failed to respond to conventional therapy or as a rescue therapy in life-threatening conditions

Rituximab in Treatment of Children with Refractory Vasculitis and Systemic Lupus Erythematosus – Single Center Experience in Croatia

The aim of this study was to present our experience in rituximab therapy in patients with childhood-onset systemic lupus erythematosus, lupus nephritis, and ANCA-associated vasculitis. We conducted a retrospective clinical chart review of all patients treated with rituximab in the time period from January 2009 to December 2015. Eight patients (3 boys and 5 girls) aged 8 to 15 at the onset of disease were treated with rituximab. Remission of disease was accomplished in 4 patients with childhood- onset systemic lupus erythematosus and lupus nephritis, a partial improvement was achieved in 1 patient with childhoodonset systemic lupus erythematosus and lupus nephritis as well as in 2 patients with vasculitis, while in one patient with vasculitis treatment with rituximab showed no effect and the patient died due to Candida sepsis. Reduction of corticosteroid doses was enabled by rituximab treatment. Rituximab appeared to be a safe and efficient therapeutic option in severe cases of childhood- onset systemic lupus erythematosus or ANCA-associated vasculitis that failed to respond to conventional therapy or as a rescue therapy in life-threatening conditions

Kako liječiti bolesnike nakon teških neželjenih djelovanja uzrokovanih inhibitorima TNF

Biological agents are widely used in the treatment of autoimmune rheumatic disorders. We report on serious adverse events during treatment with anti-tumor necrosis factor antibody in two of our patients with juvenile idiopathic arthritis. One patient was treated with a biological agent due to juvenile idiopathic arthritis complicated by uveitis, developing miliary tuberculosis during treatment. After treatment with antituberculotics, she recovered completely. Her underlying disease is currently in remission. Another patient was treated for juvenile spondyloarthritis and developed an inflammatory process of the central nervous system with serious neurological deficits. He was treated with high-dose corticosteroids, followed by slowly tapering doses of corticosteroids. His neurological deficits improved, but are still present. Similar cases have been described previously, but there are no recommendations how to treat arthritis afterwards in such patients. We would like to emphasize the need of developing guidelines for further treatment of arthritis after the occurrence of serious adverse effects during treatment with biological agents.Biološki lijekovi se primjenjuju u liječenju brojnih autoimunih reumatskih bolesti. U ovom članku prikazujemo dva slučaja ozbiljnih nuspojava liječenja inhibitorima čimbenika nekroze tumora (tumor necrosis factor, TNF) kod bolesnika s juvenilnim idiopatskim artritisom (JIA): bolesnice liječene zbog JIA kompliciranog razvojem uveitisa, kod koje se javila milijarna tuberkuloza tijekom liječenja. Nakon liječenja antituberkuloticima došlo je do potpunog oporavka. Njena osnovna bolest je u remisiji. Drugi bolesnik je liječen zbog juvenilnog spondiloartritisa te je razvio upalni proces središnjega živčanog sustava s ozbiljnim neurološkim posljedicama. Liječen je visokim dozama kortikosteroida koje su potom postupno snižavane. Neurološki ispadi su se dijelom poboljšali, ali su ipak još uvijek prisutni. Slični slučajevi su opisivani i ranije, ali nema preporuka kako bi trebalo liječiti artritis nakon što nastupe takve nuspojave. Željeli bismo naglasiti potrebu stvaranja smjernica za daljnje liječenje artritisa nakon pojave teških nuspojava prilikom liječenja biološkim lijekom

Usporedba različitih dijagnostičkih smjernica za dijagnozu sindroma aktivacije makrofaga koji komplicira sistemski tip juvenilnog idiopatskog artritisa: iskustvo jednog centra

Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA), caused by exaggerated but ineff ective immune response. The aim of the study was to compare the capacity of the HLH-2004 guidelines with the capacity of the MAS guidelines from 2005, and with the new set of classifi cation criteria from 2016 in diagnosing MAS complicating sJIA. Th e study included 35 children aged 1-18 diagnosed with sJIA according to ILAR criteria and treated at the Department of Pediatrics, Division of Immunology and Rheumatology, Zagreb University Hospital Centre, in the period from 2009 to 2015. Out of 35 patients diagnosed with sJIA, there were 12 girls and 23 boys, with the mean age at disease onset (±SD) 5.51±3.65 years. Eight patients had fl are of disease. With the guidelines from 2005, MAS was diagnosed in six (17.1%) patients with sJIA. With the new set of classifi cation criteria from 2016, MAS was diagnosed in four (11.4%) patients with sJIA. MAS was not diagnosed with the HLH-2004 guidelines. In our study, four out of six patients had MAS at the onset of sJIA, and in the rest two it occurred during relapse. Two patients with MAS developed full-blown clinical picture while another four had incomplete clinical features with minor laboratory alteration. Due to the use of diff erent diagnostic guidelines, we found diff erence in the prevalence of MAS. It was slightly higher in comparison to available studies, while other researched features, such as clinical characteristics, were similar.Sindrom aktivacije makrofaga (MAS) potencijalno je smrtonosna komplikacija sistemskog tipa juvenilnog idiopatskog artritisa (sJIA) uzrokovana prekomjernim, ali neučinkovitim imunim odgovorom. Cilj ovoga istraživanja bio je usporediti dijagnostičku mogućnost smjernica HLH-2004 sa smjernicama za MAS iz 2005. godine, kao i s novim skupom klasifi kacijskih kriterija iz 2016. godine u dijagnostici MAS-a koji komplicira sJIA. U istraživanje je bilo uključeno 35 djece u dobi od 1 do 18 godina kojima je postavljena dijagnoza sJIA prema kriterijima ILAR-a i koja su liječena u Klinici za pedijatriju, Zavodu za imunologiju i reumatologiju Kliničkog bolničkog centra Zagreb u razdoblju od 2009. do 2015. godine. Od 35 bolesnika kojima je postavljena dijagnoza sJIA bilo je 12 djevojčica i 23 dječaka koji su u vrijeme početka bolesti bili prosječne dobi (±SD) 5,51±3,65 godina. Osmero bolesnika imalo je recidiv bolesti. Prema smjernicama iz 2005. godine dijagnoza MAS-a postavljena je u šestero (17,1%) bolesnika sa sJIA. Prema novom skupu klasifi kacijskih kriterija iz 2016. godine dijagnoza MAS-a postavljena je u četvero (11,4%) bolesnika sa sJIA. Dijagnoza MAS-a nije postavljena ni u jednog bolesnika prema smjernicama HLH-2004. U našem istraživanju četvero od šestero bolesnika imalo je MAS na početku sJIA, a u preostalih dvoje on se pojavio tijekom recidiva bolesti. Dvoje bolesnika s MAS-om razvilo je punu kliničku sliku bolesti, dok ih je preostalih četvoro imalo nepotpuna klinička obilježja s manjim odstupanjem u laboratorijskim nalazima. Primjenom različitih dijagnostičkih smjernica utvrdili smo razliku u učestalosti MAS-a. Učestalost je bila nešto viša u usporedbi s postojećim istraživanjima, dok su ostala istraživana obilježja poput kliničkih karakteristika bila slična

Diagnosis and surgical treatment of intestinal malrotation in a patient with Cornelia de Lange syndrome

Prikazujemo žensko dojenče s fenotipskim karakteristikama sindroma Cornelia de Lange kod kojeg je dokazana i uspješno kirurški liječena pridružena malrotacija crijeva. Svrha je rada upozoriti na činjenicu da malrotacija crijeva, iako ne pripada skupini učestalih simptoma sindroma Cornelia de Lange, ne smije biti izostavljena u diferencijalnoj dijagnostici gastrointestinalnih tegoba u navedenih bolesnika.We report on a female infant with phenotypic characteristics of Cornelia de Lange syndrome and associated, successfully surgically treated, intestinal malrotation. The purpose of this report is to point out that intestinal malrotation, as a rare element of Cornelia de Lange syndrome, should not be left out on the diff erential diagnosis of gastrointestinal symptoms in these patients

Povezanost kožnih manifestacija i kliničkih značajki IgA vaskulitisa

Introduction: IgA vasculitis (IgAV ) is the most common systemic vasculitis in childhood. Purpuric rash is a mandatory criterion for diagnosing IgAV , it is mostly localized on the lower extremities and gluteal region, although it can also appear atypically affecting the face, trunk and upper extremities. In the most severe cases, ulcerations, necrosis and bullae can be present. Objectives: To evaluate the characteristics of cutaneous manifestations in patients with IgAV and to examine its association with clinical features. Subjects and methods: Retrospective analysis of data from patients with IgAV diagnosed and treated at the Referral Centre for Paediatric and Adolescent Rheumatology of the Ministry of Health of the Republic of Croatia, in the period from January 2009 to December 2021. Results: IgAV was diagnosed in 234 patients, 124 boys and 110 girls with the median (range) age at the time of diagnosis of 6.5 (4.5–8.2) years. All patients had a purpuric rash, and in 127 of them (54.3%) IgAV began with a rash. Cutaneous manifestations were most often presented in the form of palpable purpura and/or petechiae (87.2%) and in all patients were localized on the lower extremities. In 103 patients (44%) purpuric rash spread further to the upper extremities, trunk and/or face. At least one skin relapse occurred in 47 patients (20.1%). The most severe cutaneous manifestations which included ulcerations and necrosis developed in 11 patients (4.7%). Patients with cutaneous manifestations spread above the waist had a more statistically significant gastrointestinal involvement compared to patients with cutaneous manifestations affecting the lower extremities and gluteal region (50.5% vs. 36.6%, p=0.033), higher incidence of IgA vasculitis nephritis (IgAVN ) (31.1% vs. 19.8%, p=0.048) and were more frequently treated with systemic glucocorticoids (68% vs. 52.7%, p=0.018) and angiotensin-converting enzyme inhibitors (14.5% vs. 5.3%, p=0.016). Almost all patients with ulcerations and necrosis required treatment with systemic glucocorticoids compared to the rest (90.9% vs. 57.8%,p=0.031). Conclusion: We observed that patients with purpuric rash spread above the waist have more frequently affected gastrointestinal system and a higher incidence of IgAVN . The prevalence of ulcerations and necrosis in IgAV is less common than the standard purpuric rash and this group of patients required systemic glucocorticoid therapy.Uvod: IgA vaskulitis (IgAV ) najčešći je sistemski vaskulitis dječje dobi. Purpurični osip ključan je kriterij za dijagnozu IgAV -a, a najčešće je rasprostranjen po donjim udovima i gluteusima, iako može biti proširen i na atipičnim mjestima poput lica, trupa i gornjih udova. U najtežim slučajevima mogu biti prisutne ulceracije, nekroze i bule. Cilj: Utvrditi osobitosti kožnih promjena u bolesnika s IgAV -om te ispitati njihovu povezanost s kliničkim značajkama. Ispitanici i metode: Retrospektivna analiza podataka bolesnika s IgAV -om dijagnosticiranih i liječenih u Referentnom centru za pedijatrijsku i adolescentnu reumatologiju Ministarstva zdravstva RH, u razdoblju od siječnja 2009. do prosinca 2021. godine. Rezultati: IgAV je dijagnosticiran u 234 bolesnika, 124 dječaka i 110 djevojčica s medijanom (rasponom) dobi u trenutku dijagnoze 6,5 (4,5 – 8,2) godina. Svi su bolesnici imali kožni osip, a u njih 127 (54,3%) IgAV je i započeo osipom. Kožne promjene najčešće su bile zastupljene u obliku palpabilne purpure i/ili petehija (87,2%) i u svih bolesnika bile su lokalizirane po donjim udovima. U 103 bolesnika (44%) kožni osip se dalje proširio na ruke, trup i/ili lice. U 47 bolesnika (20,1%) došlo je do barem jednog recidiva kožnih promjena. Najteže kožne promjene u vidu ulceracija i nekroza razvilo je 11 bolesnika (4,7%). Bolesnici s kožnim promjenama proširenim iznad donjih udova imali su statistički značajno češće zahvaćen gastrointestinalni sustav u odnosu na bolesnike s kožnim osipom ograničenim na donje udove i glutealno (50,5% u odnosu na 36,6%, p=0,033), veću pojavnost nefritisa (IgAVN) (31,1% u odnosu na 19,8%, p=0,048) te su češće liječeni sistemskim glukokortikoidima (68% u odnosu na 52,7%, p=0,018) i inhibitorima angiotenzin konvertaze (14,5% u odnosu na 5,3%, p=0,016). Gotovi svi bolesnici s ulceracijama i nekrozama zahtjevali su liječenje sistemskim glukokortikoidima u odnosu na sve preostale bolesnike (90,9% u odnosu na 57,8%, p=0,031). Zaključak: Uočili smo da bolesnici s kožnim osipom proširenim iznad donjih udova imaju češće zahvaćen gastrointestinalni sustav i češću pojavu IgAVN -a. Učestalost ulceracija i nekroza u IgAV -u rjeđa je od klasične slike kožnog osipa i takvi bolesnici zahtijevali su liječenje sistemskim glukokortikoidima

VASCULITIDES IN CHILDHOOD: A RETROSPECTIVE STUDY IN A PERIOD FROM 2002 TO 2012 AT THE DEPARTMENT OF PAEDIATRICS, UNIVERSITY HOSPITAL CENTRE ZAGREB

Cilj istraživanja bio je analizirati klinička obilježja, laboratorijske nalaze, liječenje, tijek bolesti i ishod pojedinih oblika vaskulitisa u djece. U istraživanje su bili uključeni svi bolesnici u dobi do 18 godine života kojima je u razdoblju od 2002. do 2012. godine u Klinici za pedijatriju KBC-a Zagreb utvrđena dijagnoza vaskulitisa prema kriterijima EULAR/ PRES/PRINTO. Vaskulitis je dijagnosticiran u 180 djece, 101 djevojčice i 79 dječaka, u dobi 7,19±3,7 godina. Prosječno vrijeme praćenja bolesnika bilo je 5,58±3,28 godina. Henoch- Schönleinova purpura (HSP) dijagnosticirana je u 155 bolesnika (86 %), nodozni poliarteritis (PAN) u 6 (3,3 %), izolirani kutani leukocitoklastični vaskulitis u 5 (2,8 %), Takayasuov arteritis (TA) u dva (1,1 %), Kawasakijeva bolest (KB) u dva (1,1 %), hipokomplementarni urtikarijski vaskulitis u jednog (0,5 %) te drugi vaskulitisi u 10 (5,5 %) bolesnika (vaskulitisi povezani sa sistemnim bolestima veziva u sedam i neklasifi cirani u tri bolesnika). U svih bolesnika upalni laboratorijski parameteri (C-reaktivni protein, sedimentacija eritrocita) bili su povišeni. Antineutrofi lna citoplazmatska protutijela (ANCA) bila su pozitivna u samo jednog bolesnika s mikroskopskim poliarteritisom. Potporne mjere liječenja u obliku nesteroidnih protuupalnih lijekova bili su način liječenja u većine bolesnika, dok su bolesnici sa zahvaćenim bubrežnim i gastrointestinalnim sustavom tretirani glukokortikoidima i/ili imunosupresivima. U bolesnika s najtežim simptomima primijenjena je i biološka terapija (anti-CD20, rituksimab). Tijekom praćenja umrlo je jedno dijete (0,56%) oboljelo od mikroskopskog poliarteritisa radi zatajenja bubrega. Četrdeset bolesnika (22,6%) je imalo jedan relaps, a šest (3,4%) dva relapsa bolesti. Zaključno, primijetili smo neke razlike u naših bolesnika u odnosu na literaturne podatke, poput niže učestalosti povišenih vrijednosti antistreptolizinskog O titra u bolesnika s HSP-om te veće učestalosti PAN-a u ženskog spola, dok se ostala klinička obilježja, laboratorijski nalazi, liječenje i ishod nisu razlikovali.Th e aim of our study was to analyze clinical features, laboratory fi ndings, treatment, course and outcome of diff erent types of vasculitis in children. All children aged up to 18 years that have been diagnosed with a vasculitis disorder from 2002. to 2012. at the Department of Paediatric, University Hospital Centre Zagreb according to EULAR/PRES/PRINTO criteria were included in the study. Vasculitis was diagnosed in 180 children, 101 girls and 79 boys, mean age 7.19±3.7 years, with an average follow-up of 5,58±3,28 years. Most of the children (155 or 86%) were diagnosed with Henoch-Shönlein purpura (HSP), polyarteritis nodosa (PAN) was diagnosed in 6 children (3.3%), isolated cutaneous leukocytoclastic vasculitis in 5 (2.8%), Takayasu arteritis (TA) and Kawasaki disease in 2 (1.1%) respectively, hypocomplementemic urticarial vasculitis in one patient (0.5%) and other types of vasculitis in 10 (5.5%) patients (vasculitides in systemic connective tissue disorders in 7 and unclassifi ed vasculitides in 3 patients). All patients had elevated infl ammatory markers (C-reactive protein and erythrocyte sedimentation rate). Anti-neutrophil cytoplasmatic antibodies (ANCA) were positive only in one patient, suff ering from microscopic polyangiitis. Treatment modality in most patients were NSAIDs, while children with kidney or gastrointestinal system aff ection were treated with glucocorticoids and/or immunosuppresive drugs. Biological therapy (anti-CD20, rituximab) was used in patients with most severe symptoms. One child (0.56%), suff ering from microscopic polyangiitis, died due to kidney failure during the follow-up. Forty patients (22.6%) had one disease relapse, while 6 (3.4%) had two relapses. In conclusion, we found some diff erences in laboratory parameters (e.g. lower incidence of elevated antistreptolysin O titer in HSP) and epidemiological data (e.g. higher prevalence of PAN in female children) in comparison to data from available studies, while other clinical features, laboratory fi ndings, disease outcome and treatment were similar