Pediatric rheumatic diseases - per aspera ad astra

Dječja reumatologija je relativno mlada i dinamična subspecijalistička struka koja se bavi dijagnostikom i intradisciplinarnim liječenjem sistemskih i mišićnokoštanih bolesti koje nastaju kao posljedica poremećaja u regulaciji imunološkog sustava, a najčešće razultiraju razvojem autoimunosti ili autoinflamatorne reakcije te upalom. Postoje brojne razlike između djece i odraslih osoba koje boluju od reumatskih bolesti. Novija istraživanja pokazala su da se bolesti poput juvenilnog idiopatskog artritisa mogu ranije i preciznije dijagnosticirati korištenjem suvremenih metoda molekularne biologije i efikasnije liječiti ranijom primjenom biološke terapije. S druge strane rano prepoznavanje različitih autoinflamatornih bolesti je ključno za adekvatnu terapiju tih vrlo složenih stanja. Dakle, samo je pitanje vremena kada će moderne dijagnostičke metode molekularne biologije poput genetskog čipa radi određivanja “profila” i biomarkera bolesnika postati dio rutinske prakse, a rana biološka terapija po modernim principima farmakogenomike, prilagođena za svakog bolesnika ponaosob, biti temelj svakodnevne kliničke prakse.Progress in the field of pediatric rheumatolgy has been extraordinary; subspecialty is accepted as essential, vital, indispensible and distinct from adult rheumatology. It is clear that arthritis in children is more heterogeneous than RA. Although there are similarities between the inflammatory arthritides occuring in adults and children, RA and JIA appear to be distinct phenotypically with exception for the older child with RF-positive polyarticular arthritis. Progress in molecu­lar biology has enabled us to diagnose those children earlier, and treat them more efficaciously with variety of drugs and biologic agents. In recent years a new group of hereditary autoinflammatory disorders has emerged. These rare syndromes are charaterized by recurrent episodes of seemingly unprovoked, intermittent inflammation. In the near future we will be able to distinguish various subtypes of autoimune/autoinflammatory diseases earlier in the course, have a better understanding of the biomarkers and other prognostic factors, and most importantly treat them earlier with extended set of various new exciting drugs and biological therapy

The most frequent childhood vasculitides

Vaskulitisi u dječjoj dobi predstavljaju izazov za pedijatrijske reumatologe zbog raznolikosti kliničke prezentacije i sistemske prirode bolesti. Vaskulitisi nerijetko zahtjevaju multidisciplinski pristup više specijalista; reumatologa, dermatologa, kardiologa, nefrologa, neurologa i gastroenterologa. Vaskulitis definiramo prisustvom upale u zidu krvnih žila. Lokalizacija krvnih žila, veličina krvnih žila, obim ozljede žilja, te patohistološki nalaz određuju fenotip i težinu bolesti. U radu će se raspravljati o klasifikaciji i glavnim obilježjima vaskultisa dječje dobi, a detaljnije će biti razrađene dva najčešća oblika: Henoch-Schönleinova purpura i Kawasakijeva bolest.Childhood vasculitis is a challenge for pediatric rheumatologists. It is multisystem in nature and often requires integrated care from multiple subspecialties, including rheumatology, dermatology, cardiology, nephrology, neurology, and gastroenterology. Vasculitis is defined as the presence of inflammation in the blood vessel wall. The site of vessel involvement, size of the affected vessels, extent of vascular injury, and underlying pathology determine the disease phenotype and severity. This article explores the classification and general features of pediatric vasculitides, with detailed analisys of the two most common vasculitides: Henoch-Schönlein purpura and Kawasaki disease

The classification of juvenile spondyloarthritides

U radu je prikazana klasifikacija juvenilnih spondiloartropatija.The classification of juvenile spondyloarthritides is presented

Non-invasive imaging of chronic inflammatory myopathies

Cilj svakog uspješnog dijagnostičkog postupka je postići što pouzdaniji rezultat u što kraćem vremenu, koristeći se pritom što manje invazivnom dijagnostikom. Neinvazivnim slikovnim pretragama možemo u mišiću utvrditi edem, kolekcije tekućina, infiltracije masnog tkiva, atrofiju, fibrozu i kalcifikate. Najosjetljivija neinvazivna slikovna dijagnostička metoda u današnjoj suvremenoj dijagnostici upalnih bolesti mišića je MR u T2 slikovnim prikazima sa supresijom masnog tkiva i/ili STIR prikazu. MR je vrlo korisna metoda i pri određivanju preciznog mjesta biopsije mišića. Nespecifičnost nalaza promjena na mišiću, dostupnost, cijena, kao i kontraindikacije za primjenu kod bolesnika s metalnim protezama ili pacemakerima, kao i način izvođenja pretrage predstavljaju ozbiljna ograničenja te metode. Glavna prednost ultrazvuka mišića, u usporedbi s ostalim slikovnim metodama, je dostupnost i cijena pretrage. Pojačana vaskularnost mišića utvrđena pomoću PD-a korelira s dužinom trajanja miozitisa, a PD može biti i koristan za utvrđivanje pojačanog signala prokrvljenosti te isključivanje rupture mišića, bolesti poput cisticerkoze kao i apscesa mišića. Čini se da bi zbog dostupnosti i visoke osjetljivosti kvantitativni ultrazvuk s kontrastom (CEUS), metoda koja omogućuje procjenu pojačane vaskularnosti mišića u realnom vremenu, uz dodatak elastografije, uskoro mogao zauzeti važniju ulogu u potvrdi kliničke sumnje kronične upalne bolesti mišića.In patients with chronic inflammatory myositis noninvasive diagnostic modalities, such as magnetic resonance (MR) imaging, and ultrasonography (US), are able to demonstrate muscular edema, fluid collections, fatty infiltration, atrophy, fibrosis, and calcifications. Because MR imaging is sensitive to the presence of edema and offers better tissue differentiation, current MR imaging with fat suppressed T2-weighted techniques or STIR images appears to be more efficient than US in the diagnosis and management of inflammatory myopathies. MR imaging has also been proposed as a means to guide biopsy in an area of active disease, thereby reducing the problem of sampling error. These changes in signal intensity, however, are not specific for myositis. Although MR imaging is now the imaging modality of choice in this issue, reduced availability, patient discomfort, and exclusion of certain patients with indwelling metal objects, such as pacemakers, are disadvantages. The availability and ease of use of US makes it preferable to MR imaging. Real-time sonoelastography can be used for various musculoskeletal applications, but the clinical utility in diagnosis of myositis is yet to be established. On the other hand, the contrast-enhanced US is a feasible method for noninvasively demonstrating increased perfusion in the involved muscle groups, and most likely, will soon become preferable, noninvasive imaging method in patients with myositis

JUVENILE SPONDYLOARTHRITIS

Juvenilni spondiloartritis (jSpA) skupina je multifaktorskih bolesti u kojima dolazi do poremećenog međudjelovanja imunosnog sustava i čimbenika okoliša u ljudi s predisponirajućim genotipom, što dovodi do upale i strukturnih oštećenja ciljnog tkiva. Prvi simptomi jSpA rijetko su povezani s kralježnicom, a češće se javljaju nesimetrični oligoartritis zglobova donjih ekstremiteta, daktilitis i periferni entezitis. Postoje brojni kriteriji za klasifi kaciju jSpA, no većina pedijatrijskih reumatologa danas se koristi kriterijima Međunarodne lige reumatoloških udruženja (ILAR) prema kojima je najveći broj bolesnika s artritisom i entezitisom ili artritisom ili entezitisom uz još dvije ili više od karakteristika poput bolnosti sakroilijakalnih zglobova na dodir i/ili bolnosti kralježnice zbog upalnog procesa, HLA-B27-genotipa, bolesti povezane s HLA-B27-genotipom u jednog ili više rođaka u prvom ili drugom koljenu, uveitisa te muškog spola uz više od osam godina života, svrstan u podskupinu juvenilnog idiopatskog artritisa (JIA) koju nazivamo artritis pridružen entezitisu (ErA). Sukladno tomu, dijagnoza bolesti postavlja se uglavnom na temelju kliničke slike i anamnestičkih podataka; od laboratorijskih pretraga potrebno je odrediti antinuklearna antitijela (ANA), reumatoidni faktor (RF) te HLA-tipizaciju kako bi se utvrdila prisutnost HLA-B27, B7 i/ili DR4-genotipa. S obzirom na to da velik broj bolesnika ima i supkliničku upalu crijeva, preporučljivo je provjeriti i fekalni kalprotektin. Ako postoje simptomi perifernog entezitisa, potreban je pregled muskuloskeletnim ultrazvukom s osnaženim doplerom (PDUS), a pri znakovima zahvaćenosti kralježnice radiografsko snimanje te magnetska rezonancija (MR) s kontrastnim sredstvom. Najveći broj djece s jSpA-om liječi se fi zikalnom terapijom i nesteroidnim protuupalnim lijekovima (NSAIL), dok se refraktorni oblici periferne bolesti mogu liječiti sintetskim lijekovima koji utječu na tijek bolesti (DMARD), poput sulfasalazina. Kada bolest zahvati i kralježnicu, potrebno je liječenje biološkim DMARD-ovima poput adalimumaba, infl iksimaba i etanercepta. Usprkos mnogimJuvenile spondyloartrhritis is a group of multifactorial diseases in which a disturbed interplay occurs between the immune system and environmental factors on a predisposing genetic background, which leads to infl ammation and structural damage of the target tissue. First symptoms of jSpA rarely involve the spine, while asymmetrical oligoarthritis of lower extremities, dactylitis, and peripheral enthesitis are much more common. Th ere are many classifi cation criteria for jSpA, but the majority of pediatric rheumatologists currently use the International League Against Rheumatism (ILAR) criteria according to which most patients with jSpA are classifi ed into the enthesitis-related arthritis group of juvenile idiopathic arthritis. To meet these criteria, a patient should have arthritis and/or enthesitis, with two or more symptoms such as sacroiliac joint tenderness and/or infl ammatory back pain, HLAB27 genotype, HLA B27 genotype-associated disease in a fi rst- or second-degree relative, uveitis, and male sex with eight or more years of age. Th erefore, diagnosis is most oft en made only based on clinical examination and medical history. Antinuclear antibodies (ANA), rheumatoid factor (RF), and HLA testing with B27, B7, and DR4 alleles are preferred. Since subclinical gut infl ammation is present in many patients, it is recommended to check fecal calprotectin levels. In patients with signs of peripheral enthesitis it is warranted to perform power Doppler musculoskeletal ultrasound (PDUS), and in patients with signs of axial involvement radiographic and contrast-enhanced magnetic resonance imaging. Most patients are treated with nonsteroidal anti-infl ammatory drugs (NSAIDs) and physical therapy, while in refractory cases with peripheral disease synthetic disease- modifying antirheumatic drugs (DMARDs), such as sulfasalazine, are used. In patients with axial involvement, biological DMARDs such as adalimumab, infl iximab, and etanercept are obligatory. Although a number of studies gave us a good insight into the disease pathogenesis, the response to treatment and prognosis are still diffi cult to predict

Aberrant expression of shared master-key genes contributes to the immunopathogenesis in patients with juvenile spondyloarthritis

Association of juvenile spondyloarthritis (jSpA) with the HLA-B27 genotype is well established, but there is little knowledge of other genetic factors with a role in the development of the disease. To date, only a few studies have tried to find those associated genes by obtaining expression profiles, but with inconsistent results due to various patient selection criteria and methodology. The aim of the present study was to identify and confirm gene signatures and novel biomarkers in highly homogeneous cohorts of untreated and treated patients diagnosed with jSpA and other forms of juvenile idiopathic arthritis (JIA) according to ILAR criteria. For the purposes of the research, total RNA was isolated from whole blood of 45 children with jSpA and known HLA genotype, 11 children with oligo- and polyarticular forms of JIA, as well as 12 age and sex matched control participants without diagnosis of inflammatory disease. DNA microarray gene expression was performed in 11 patients with jSpA and in four healthy controls, along with bioinformatical analysis of retrieved data. Carefully selected differentially expressed genes where analyzed by qRT-PCR in all participants of the study. Microarray results and bioinformatical analysis revealed 745 differentially expressed genes involved in various inflammatory processes, while qRT-PCR analysis of selected genes confirmed data universality and specificity of expression profiles in jSpA patients. The present study indicates that jSpA could be a polygenic disease with a possible malfunction in antigen recognition and activation of immunological response, migration of inflammatory cells and regulation of the immune system. Among genes involved in these processes TLR4, NLRP3, CXCR4 and PTPN12 showed almost consistent expression in study patients diagnosed with jSpA. Those genes and their products could therefore potentially be used as novel biomarkers, possibly predictive of disease prognosis and response to therapy, or even as a target for new therapeutic approaches