KADA POSUMNJATI NA AUTOINFLAMATORNU BOLEST?

Mario Šestan, Marija Jelušić

Autoinflammatory diseases are clinical disorders caused by a deficiency or dysregulation of innate immunity, characterized by recurrent or persistent inflammation (increased levels of acute phase reactants) and the absence of a primary pathogenic role of adaptive immunity (autoreactive T lymphocytes or antibody production). They are clinically manifested by recurrent episodes of systemic inflammation due to the activation of an intense nonspecific inflammatory reaction with no apparent or sufficient cause.
In terms of pathogenesis, autoinflammatory diseases can be divided into monogenic, or those that are caused by a mutation in a well-defined gene, and non-monogenic, also referred to as unclassified. According to the three main pathogenic patterns of emergence in monogenic autoinflammatory diseases described to date, they are divided into inflammasomopathies, interferonopathies, and ubiquitinopathies. Clinically, inflammasomopathies are most commonly manifested by fever (often periodic type), rash, serositis, hepatosplenomegaly, and lymphadenopathy. The therapeutic approach in many of these diseases is based on the use of an interleukin-1 inhibitor. Interferonopathies are most commonly manifested as acral and lung vasculopathy and fibrosis, with an onset of skin changes like chilblains, intracranial calcifications, and myositis. Janus kinase inhibitors are used in the treatment. Ubiquitinopathies are most commonly manifested by granuloma, ulceration, uveitis, and immunodeficiency. The therapeutic approach in these diseases is based on the use of tumor necrosis factor-alpha inhibitors. Unclassified autoinflammatory diseases include diseases that meet the clinical and biological criteria for autoinflammatory diseases but to date have no detected genetic background (for example, syndrome of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis, Schnitzler syndrome, or systemic-onset juvenile idiopathic
arthritis), and some multifactorial diseases that are polygenic or caused by complex interactions of multiple genes and environmental factors and not associated with Mendelian inheritance patterns (eg., gout, Behcet disease).
In the diagnosis of patients with suspected autoinflammatory disease, it is necessary to exclude infections, malignancies,
immunodeficiencies, and rheumatic diseases. The main indication for genetic testing is the presence of clinical
symptoms that meet the criteria for one or more autoinflammatory diseases. There are a number of unanswered questions
in genetic diagnostics, the main problem being the interpretation of the results.

Autoinflamatorne bolesti klinički su poremećaji uzrokovani nedostatkom ili poremećajem regulacije prirođene imunosti, a obilježavaju ih ponavljana ili stalna upala (povišeni reaktanti akutne faze) i odsutnost primarne patogenetske uloge stečene imunosti (autoreaktivni T-limfociti ili proizvodnja protutijela). Klinički se manifestiraju ponavljanim epizodama sustavne upale zbog aktivacije intenzivne nespecifične upalne reakcije bez očitog ili dovoljnog uzroka. U patogenetskom smislu mogu se podijeliti na monogenske, odnosno na one koje su uzrokovane mutacijom u jednom, dobro definiranom genu i na one koje nisu monogenske, a označavaju se i kao neklasificirane. Prema tri glavna patogenetska obrasca nastanka, do danas opisane monogenske autoinflamatorne bolesti dijele se na inflamasomopatije, interferonopatije i ubikvitinopatije. Klinički se inflamasomopatije najčešće manifestiraju vrućicom (nerijetko periodična tipa), osipima, serozitisom, hepatosplenomegalijom i limfadenopatijom. Terapijski pristup u velikom broju ovih bolesti temelji se na primjeni inhibitora interleukina 1. Interferonopatije se najčešće manifestiraju vaskulopatijama ekstremiteta i pluća, nastankom fibroznih promjena, kožnih promjena nalik na ozebline, intrakranijalnim kalcifikacijama i miozitisom. U liječenju se rabe inhibitori Janusove kinaze. Ubikvitinopatije se najčešće očituju nastankom granuloma, ulceracija, uveitisa te imunodeficijencijom. Terapijski pristup u ovim bolestima temelji se na primjeni inhibitora čimbenika tumorske nekroze alfa. U skupinu neklasificiranih autoinflamatornih bolesti ubrajaju se bolesti koje zadovoljavaju kliničko-biološke kriterije za autoinflamatorne bolesti, ali do danas nemaju otkrivenu gensku podlogu (primjerice, sindrom periodične vrućice, aftoznog stomatitisa, faringitisa i adenitisa, Schnitzlerin sindrom, sustavni oblik juvenilnog idiopatskog artritisa), kao i neke multifaktorske bolesti koje su poligenske, odnosno uvjetovane složenim interakcijama većeg broja gena i okolišnih čimbenika te nisu povezane s mendelovskim obrascem nasljeđivanja (primjerice, giht, Behçetova bolest). Pri obradi bolesnika sa sumnjom na autoinflamatornu bolest potrebno je isključiti infekcije, zloćudne bolesti, imunodeficijencije i reumatske bolesti. Glavna je indikacija za gensko testiranje prisutnost kliničkih simptoma koji ispunjavaju kriterije za jednu ili više autoinflamatornih bolesti. U genskoj dijagnostici postoji niz neodgovorenih pitanja, među kojima je glavni problem interpretacija nalaza.