Uvod: Takajaši arteritis (TA) je idiopatska, zapaljenska bolest hroničnog toka,
koja se karakteriše granulomatoznim zapaljenjem aorte i njenih grana. Određeni
genetički faktori mogu imati značaja u nastanku TA. Sekundarni antifosfolipidni
sindrom (AFS) se može javiti u sklopu TA i karakteriše se vaskularnim i/ili
komplikacijama u vezi sa trudnoćom i/ili porođajem, u prisustvu antifosfolipidnih (AF)
antitela. U dijagnostici i praćenju ovih bolesnika se primenjuje ehosonografski (EHO)
Doppler pregled krvnih sudova, kompjuterizovana tomografija sa kontrastnom
angiografijom (CTA) i poslednjih godina, poziciona emisiona tomografija u kombinaciji
sa niskorezolutivnom komjuterizovanom tomografijom uz primenu radioobeleživača -
fluorodeoksiglukoze (18FDG PET-CT). Za procenu aktivnosti bolesti se najčešće koriste
klinički skor NIH (National Institute of Health) i Indijski skor aktivnosti TA (Indian
Takayasu’s Arteritis score, ITAS2010). Progresija bolesti se može indirektno proceniti i
primenom skorova: Indeksa ošećenja kod vaskulitisa (Vasculitis Damage Index, VDI),
Indeksa oštećenja za pacijente sa TA (Takayasu Arteritis Damage Score, TADS) i
Kombinovanog skora oštećenja kod pacijenata sa arteritisom (Combined Arteritis
Damage Score, CARDS). Pouzdani serumski biomarkeri vaskularnog i/ili sveukupno
oštećenja do sada nisu identifikovani.
Ciljevi istraživanja: Identifikacija biomarkera i dijagnostičkih procedura od
značaja za postavljanje dijagnoze i praćenje toka TA; analiza genetičkih faktora i
biomarkera koji bi mogli da se dovedu u vezu sa različitom fenotipskom ekspresijom,
statusom aktivnosti, odgovorom na primenjene različite modalitete lečenja i pojavom
komplikacija bolesti.
Pacijenti i metode: Ovom studijom preseka obuhvaćeno je 33 pacijenata sa TA;
dijagnoza je postavljena na osnovu klasifikacionih kriterijuma Američkog koledža za
reumatologiju (American College of Rheumathology, ACR) iz 1990. godine za adultne
pacijente, i kriterijuma EULAR/PRINTO/PRES za pedijatrijski uzrast. DNK je izolovana
iz periferne krvi korišćenjem automatizovanog sistema Maxwell 16 Purification Kit.
Tipizacija humanih leukocitnih antigena (Human Leucocyte Antigens, HLA) je učinjena
korišćenjem oligonukleotidnih proba koje su specifične za sekvencu (Sequence-specific
oligonucleotide, SSO). Dobijena p vrednost je korigovana primenom Benjamini-
Hochberg metoda. Polimorfizam TNF (Tumor necrosis factor) gena (rs1800692) je
ispitivan TaqMan metodom sa komercijalno dostupnom smešom (#C__514879_10).
Koncentracije aminoterminalnog propeptida prokolagena tipa III (Aminoterminal
propeptide of procollagen type III, PIIINPI), hijaluronske kiseline (Hyaluronic acid, HA),
i tkivnog inhibitora matriksne metaloproteinaze-1 (Tissue Inhibitor of Matrix
Metalloproteinase-1, TIMP-1) su analizirane pomoću imunoeseja ADVIACentaur®, a
skor ELF (Enchanced Liver Fibrosis) je automatski izračunavan prema proizvođačkoj
specifikaciji. Takođe, analizirani su rezultati imidžing dijagnostike, antikardiolipinskih
(AclA), antitela protiv β2 glikoproteina 1 (β2GPI), lupus antikoagulansa (LA) i rutinskih
biohumoralnih parametara.
Rezultati: Ispitanike je činilo 93,9% osoba ženskog pola. Prosečna starost
iznosila je 43,9±16,3 godina, uz medijanu kašnjenja u postavljanju dijagnoze od 2 (1-
4,5) godine, u odnosu na pojavu prvih simptoma...Introduction: Takayasu arteritis (TA) is a chronic, idiopathic, inflammatory
disease, characterized by granulomatous inflammation of the aorta and its branches.
Certain genetic factors may play an important role in the development of TA. Secondary
antiphospholipid syndrome (APS) may occur in patients with TA and it is characterized
by vascular and/or complications related to pregnancy and/or delivery, in the presence
of antiphospholipid (AP) antibodies. Echosonographic (ECHO) Doppler examination,
computed tomography with contrast angiography (CTA), and the positional emission
tomography combined with a low-resolution computed tomography using the
fluorodeoxyglucose (18FDG PET-CT), can be used for diagnosis and monitoring in
patients with TA. The NIH (National Institute of Health) clinical score and the Indian
Takayasu’s Arteritis score (ITAS2010) are used the most often for assessing disease
activity. Disease progression can be assessed using the Vasculitis Damage Index (VDI),
Takayasu Arteritis Damage Score (TADS) and Combined Arteritis Damage Score
(CARDS). Serum biomarkers reflecting vascular and/or overall progression of the
disease have not been identified so far.
Objectives: This study aimed to identify serum biomarkers and diagnostic
procedures relevant for diagnosis and disease monitoring; analysis of genetic factors
and biomarkers that might be related to different phenotypic expression, disease
activity status, response to different treatment and disease related complications.
Patients and methods: This cross-sectional study included 33 patients with TA;
the diagnosis was made according to the 1990 American College of Rheumatology
(ACR) classification criteria for adults, and the EULAR/PRINTO/PRES criteria for
pediatric patients. DNA was isolated from peripheral blood using the automated
Maxwell 16 Purification Kit. Human Leukocyte Antigens (HLA) typing was performed
using the sequence-specific oligonucleotide (SSO) probes; p values were corrected using
the Benjamini-Hochberg method. TNF (Tumor necrosis factor) gene polymorphism
(rs1800692) was examined using the TaqMan method with a commercially available
mixture (# C__514879_10). Concentrations of Aminoterminal Propeptide Procollagen
Type II (PIIINPI), Hyaluronic Acid (HA), and Tissue Inhibitor of Matrix
Metalloproteinase-1 (TIMP-1) were analyzed using the ADVIACentaur®, and the ELF
(Enhanced Liver Fibrosis) score is automatically calculated according to the
manufacturer's specification. The results of imaging procedures, routine serology
parameters and AP antibodies: anticardiolipin (AclA), antibodies against β2
glycoprotein 1 (β2GPI) and lupus anticoagulants (LA) were also analyzed.
Results: Of all patients, 93.9% were females with an average age of 43.9 ± 16.3
years, and a median delay in diagnosis of 2 (1-4.5) years from the appearance of the first
symptoms. The HLA-B*52, HLA-A*32, HLA-B*15, HLA-B*57, and HLA-C*03 alleles, and
DRB1*15:02-DQB1*05 haplotype were more frequent in TA than controls, although
only HLA-B*52 remained significance after the statistical correction. HLA-B*52 allele in
the TA group was 10% (5/50), while it was present in 1.2% controls (46/3984) (p =
0.0004, padj = 0.011). Carriage of HLA-B*52 was associated with a significantly earlier
disease onset and more severe clinical presentations. Carriers of HLA-C*03 experienced
a milder clinical form of the disease..
