VASCULITIS AND VASCULOPATHY

Kod ulceracija donjih ekstremiteta, najvažniju ulogu, među mnogobrojnim poznatim sastavnicama patofiziološkog procesa, imaju oštećenja krvnih žila. Vaskulitisom se označava heterogena skupina kliničkih entiteta, kojima je zajedničko obilježje upalni proces stijenke arterija i vena bilo koje veličine i u bilo kojem organu, a u koži vrlo često. Kod vaskulopatija riječ je o oštećenju stijenki krvnih žila i kapilara, npr. nekim medikamentima. Klasifikacija vaskulitisa prema veličini krvne žile služi za razumijevanje među kliničarima i istraživačima, a ne kao dijagnostičko sredstvo. Prema histološkom nalazu, pregledom bioptata stijenke krvne žile, vaskulitisi se mogu podijeliti u tri skupine: limfocitni, leukocitoklastični i anulomatozni. livedoidni vaskulitis (“livedo retikularis”) najčešče pogađa žene i lokaliziran je uglavnom na donjim ekstremitetima. Etiologija liveidnog vaskulitisa može biti posljedica autoimunih bolesti, posljedica opstrukcije kapilara krioglobulinima ili antifosfolipoidnog sindroma. livedoidna vaskulopatija (lV) je hijalinizacijska bolest vaskulature, s trombozama i ulceracijama na donjim ekstremitetima, nepoznate etiologije. lV je izdvojena kao zasebna bolest koja obično nije posljedica drugih primarnih bolesti.obilježja lV su: 71% oboljelih su žene, prosječna životna dob je 45 godina, raspon je 10-85 godina, bolest u 80,8% slučajeva zahvaća donje ekstremitete bilateralno, u 68,9% slučajeva bolest se prezentira ulceracijama, iza ulceracija može se razviti atrophie blanche u 71,1% slučajeva, u 74,1% slučajeva nalazi se smanjenje u transkutanoj oksimetriji, u 22,2% bolesnika nalazi se mutacija u faktoru V (heterozigoti leiden), smanjena je aktivnost proteina C u 13,3% slučajeva, mutacija gena za protrombin (G20210A) u 8,3% slučajeva, lupus antikoagulant pozitivan u 17,9% bolesnika, antikardiolipinska antitijela pozitivna u 28,6% bolesnika, povišena je razina homocisteina u 14,3% bolesnika, histološki pregled krvne žile pokazuje intaluminalnu trombozu u 97,8% bolesnika, direktna imunofluorescencija uzorka krvne žile pokazuje imunoglobuline i komponente komplementa u krvnim žilama na površini, u sredini dermisa ali i duboko u dermisu. Imunoflouorescentna slika različita je od bolesti imunih kompleksa. neki od lijekova kojima se pokušava liječiti lV su: pentoksifilin niskomolekularni heparin, hiperbarična oksigenoterapija, metilprednizolon i.v. s pentoksifilinom, rekombinantni tkivni aktivator plazminogena, intravenski imunoglobulini, kombinacija fenformina (bigvanid) i etilestrenola (anabolički steroid), varfarin, heparin, sistemska fotokemoterapija (PuVA terapija s peroralnim uzimanjem psoralena), niskomolekularni dekstran. inficirane ulceracije liječe se antibioticima. Može se primijeniti kombinirana terapija folnom kiselinom, vitaminom B12 i vitaminom B6.Many pathophysiological process components are known to be implicated in lower limb ulcerations, among which vascular lesions have a major role. Vasculitis denotes a heterogeneous group of clinical entities which all are characterized by the inflammatory process of arterial and venous walls of any size and in any organ, quite frequently in the skin. Vasculopathy, on the other hand, refers to vascular and capillary lesions caused by, for example, some medications. The classification of vasculitides according to the size of the blood vessels involved serves for proper understanding the issue among clinicians and researchers, and not as a diagnostic tool. According to histologic finding obtained by examination of blood vessel biopsy specimen, vasculitides are divided into three groups: lymphocytic, leukocytoclastic and granulomatous. Livedoid vasculitis (livedo reticularis) most commonly affects women and is generally localized on lower extremities. The etiology of livedoid vasculitis may imply autoimmune diseases, capillary obstruction with cryoglobulins, or antiphospholipid syndrome. Livedoid vasculopathy is a hyalinization disease of the vasculature, with thromboses and ulcerations on lower extremities, and of unknown etiology. Livedoid vasculopathy has been singled out as a separate disease that usually does not occur consequentially to other primary diseases. Livedoid vasculopathy typically affects women (71%) at a mean age of 45 (range 10-85) years; bilateral involvement of both lower limbs is present in 80.8%, disease manifested with ulcerations in 68.9%, ulcerations followed by development of atrophie blanche in 71.1%, transcutaneous oximetry reduction is found in 74.1%, factor V mutation (Leiden heterozygotes) in 22.2%, reduced protein C activity in 13.3%, prothrombin gene mutation (G20210A) in 8.3%, positive lupus anticoagulant in 17.9%, positive anticardiolipin antibodies in 28.6%, and elevated homocysteine level in 14.3% cases; blood vessel histology shows intraluminal thrombosis in 97.8% of patients, while direct immunofluorescence of blood vessel specimen shows immunoglobulins and complement components in blood vessels on the surface, in the mid-dermis as well as deep in the dermis. The immunofluorescence pattern differs from that found in immune complex diseases. Some of the agents tried in the treatment of livedoid vasculopathy include pentoxifylline, low-molecular heparin, hyperbaric oxygen therapy, methylprednisolone i.v. with pentoxifylline, recombinant tissue plasminogen activator, intravenous immunoglobulins, phenformin (biguanide) and ethylestrenol (anabolic steroid) combination, warfarin, heparin, systemic photochemotherapy (PUVA with oral psoralen), and low-molecular dextran. Infected ulcerations are treated with antibiotics. Combined therapy with folic acid, vitamin B12 and vitamin B6 can also be used

The Future of Diagnosis and Treatment of Asthma

Na temelju profi la ekspresije različitih gena na epitelnim stanicama bronha u budućnosti će se moći dijagnosticirati molekularni supfenotipovi astme: a) astma s jakim obilježjima Th2-upale, b) astma sa slabim obilježjima Th2-upale, c) astma bez obilježja Th2-upale. Analizom sveukupne ekspresije gena izdvojena su tri patognomonična IL-13-inducibilna gena u obrisku bronhalnog epitela: periostin, regulator kloridnih kanala 1 (CLCA1) i inhibitor serpin peptidaze B, 2. član (SERPINB2) koji mogu poslužiti kao surogatni biljezi Th2-infl amacije. Gen čija se ekspresija najviše razlikuje u astmi s jakim obilježjima Th2-upale i astmi sa slabim obilježjima Th2-upale jest CCL26 (eotaksin 3). Patofi ziološki mehanizmi preko IL-25, IL-33 i TSLP (engl. thymic stromal lymphopoietin) nalaze se u podlozi astme bez obilježja Th2-upale koja ima slab odgovor na trenutačno dostupnu antiastmatsku terapiju. Najveća je potreba za određivanjem fenotipa bolesti u populaciji bolesnika s teškom astmom te onih s astmom refraktornom na terapiju. Teška astma mogla bi se dokazivati i određivanjem genskog profila alveolarnih makrofaga iz induciranog sputuma. Prediktor porasta FEV1 nakon primjene anti-IL-13-monoklonskog protutijela jest kombinacija serumskog periostina s frakcijom NO u izdahnutom zraku, FeNO. Kombinacija urinarnog leukotrijena E4 s FeNO, tj. njihov omjer, pokazala se kao dobar biomarker kojim se može predvidjeti učinak terapije u astmi. Urinarni bromotirozin može biti marker kontrole astme i prediktor egzacerbacije astme u djece. Liječenje astme u budućnosti temeljit će se na farmakogenetičkim nalazima. U kliničkoj medicini samo je jedan lijek iz skupine bioloških lijekova (monoklonskih protutijela), omalizumab, blokator serumskog IgE, odobren za primjenu u bolesnika s teškom alergijskom astmom.The expression profile of various genes in epithelial cells of the bronchi will enable the diagnosis of molecular subphenotypes of asthma: a) asthma with strong features of Th2 infl ammation, b) asthma with weak features of Th2 infl ammation, and c) asthma without features of Th2 infl ammation. The analysis of the overall gene expression gave three pathognomonic genes, i.e. IL-13 inducible genes in bronchial epithelial swab: periostin, chloride channel regulator 1 (CLCA1) and serpin peptidase inhibitor, clade B (SERPINB2), which may serve as surrogate markers of Th2 inflammation. The gene whose expression diff ers most in asthma with strong features of Th2 infl ammation and asthma with weak features of Th2 infl ammation is CCL26 (eotaxin-3). Pathophysiological mechanisms, which act via IL-25, IL-33 and TSLP (thymic stromal lymphopoietin), underlie asthma without features of Th2 infl ammation and a weak response to the currently available antiasthmatic therapy. The need to identify a phenotype of the disease is the greatest in patients with severe asthma and those with asthma refractory to therapy. Severe asthma could be also diagnosed by determining the genetic profi le of alveolar macrophages from induced sputum. The predictor of FEV1 growth after the administration of anti-IL-13 monoclonal antibody is a combination of serum periostin with NO fraction in exhaled air (FeNO). The combination of urinary leukotriene E4 with FeNO, i.e. their ratio, proved to be a good biomarker of therapy efficiency in asthma. Urinary bromotyrosine could be a marker of asthma control and a predictor of asthma exacerbations in children. In the future, the treatment of asthma will be based on pharmacogenetic findings. In clinical medicine, there is only one biosimilar drug, i.e. omalizumab (monoclonal antibody, serum IgE blocker), authorised for use in patients with severe allergic asthma

ASTHMA PHENOTYPES AND DISORDER OF THE IMMUNE SYSTEM HOMEOSTASIS

Danas razumijemo mnoge regulatorne putove u signalizaciji koja se odvija prije i poslije sinteze IgE i poznajemo učinke mnogobrojnih medijatora u alergijskog kaskadi, ali astma ipak i dalje ostaje klinički i znanstveni problem. Suvremena civilizacija zbunjuje imunološki sustav pa nastaje kompleksna interakcija između epigenetske regulacije, varijabilnih vanjskih čimbenika i različitih kombinacija parova utjecaja: gena, antigena i razdoblja života. Stoga će biti potrebno odgovoriti na pitanje kako omogućiti dostatnu razinu neophodnih imunoloških stimulusa u vrijeme intenzivnog razvoja imunološkog sustava do šeste godine života. Napredak imunologije pružio je mogućnost postizanja potpune kontrole nad astmom u velikog broja bolesnika ali ne osigurava izlječenje. Zbog toga se u istraživačkom radu traže pojedinosti o posebnim upalnim podtipovima astme: eozinofilnom, neutrofilnom, mješovitom i astmi bez upalnih stanica. Proučava se i terapijski odgovor na inhalacijske i sistemske kortikosteroide u pojedinom podtipu. U rutinskoj kliničkoj praksi na raspolaganju su Smjernice globalne inicijative za astmu, izrađene od skupine eksperata i redovito dopunjavane novim znanstvenim spoznajama. Smjernice daju koristan okvir za izbor doze i vrste lijekova ali ne mogu zamijeniti prosudbu kliničara u individualnom pristupu bolesniku. U suvremenim uvjetima još uvijek ne postoje mogućnosti personalizirane terapije astmeMany regulatory pathways involved in the pre- and post-IgE synthesis signaling have been elucidated and effects of numerous mediators included in allergic cascade understood; however, asthma remains a clinical and scientific problem. Immune system is being confused by modern civilization, producing complex interaction among epigenetic regulation, variable extrinsic factors and various combinations of paired effects, i.e. genes, antigens and life periods. It is therefore necessary to answer the question of how to ensure an adequate level of necessary immune stimuli at the time of intensive immune system development until age 6. Advances in immunology have enabled full asthma control but not cure in a great proportion of patients. Therefore, researchers have focused on particular features of specific inflammatory asthma subtypes, i.e. eosinophilic, neutrophilic, mixed and asthma without inflammatory cells. Therapeutic response to inhalant and systemic corticosteroids in a particular subtype is also investigated. The Global Initiative for Asthma Guidelines, developed by the group of experts and regularly updated with new scientific concepts, are available in clinical routine. The guidelines provide a useful framework for the choice of drugs and dosage, but they cannot replace clinician’s evaluation in individual approach to patient. However, current conditions still cannot ensure personalized asthma therapy

Urban-Rural Gradient of Allergic Rhinitis: A Cross-Sectional Study in Croatian Children

Background: Children living in rural areas have a lower risk for developing allergic diseases, which has particulary been observed for allergic asthma and atopic dermatitis, but less for allergic rhinitis. Methods: A cross-sectional study was conducted in 39 randomly selected elementary schools in the urban environment of the city of Zagreb and the rural, surrounding area of Lonjsko polje National Park, during school-year 2017/2018. All children aged 6-7, 10 and 13-14 years were eligible to participate. The study was based on the original ISAAC questionnaires answered by parents. To assess skin sensitivity, skin prick tests on common inhalant allergens were done on 400 randomly selected children from both regions. Lonjsko polje is the biggest complex of natural and preserved lowland riparian forests in Europe and the ornithological reserve with more than 1500 species living there. The two areas differ in GDP and economy, with more than two times higher GDP in the city of Zagreb. Results: A total sample of 1745 children participated in the study, 646 (37%) from Lonjsko polje and 1099 (63%) from the city of Zagreb. The children from Lonjsko polje showed a lower risk for developing symptoms of allergic rhinitis ever in their lives in the 13-14-year age group (OR 0.531, 95% CI=0.37-0.76, p 0.001) and lower risk for active rhinitis in all age groups (6-7 y; OR 0.373, 95% CI=0.21-0.63 , p 0.003; 10 y; OR 0.563, 95% CI=0.32-0.98, p 0.042; 13-14 y; OR 0.173, 95% CI=0.07-0.40, p<0.0001). Also, children from urban areas reported using more medicines for allergic rhinitis (χ2 Yates correct 0.46, p<0.0001), and visited pharmacies more often (p 0.046). In the city of Zagreb, we identified brestfeeding (OR=0.855; 95% CI=0.734-0.997), contact with cats (OR=0.64; CI 95% 0.37-0.98) and cooked vegetables (OR 0.759, CI 0.596-0.965) as protective factors. Positive family history and mother´s smoking in the first year of the child´s life (OR=2.885; CI 95%=1.462-5.625) were identified as risk factors in both populations, as well as contact with dogs (OR=1.49; CI 95% 1.01-2.06) in the city of Zagreb. Allergic sensitization to inhalant allergens was highly connected with symptoms of allergic rhinitis in the city of Zagreb. Conclusion: We showed clear urban-rural gradient in symptoms of allergic rhinitis in Croatian schoolchildren

Churg-Straussov sindrom: prikaz slučaja

Churg-Strauss syndrome (CSS) is a necrotizing small vessel vasculitis characterized by the presence of asthma, hypereosinophilia and sinusitis. Other common manifestations are pulmonary infiltrates, skin, gastrointestinal and cardiovascular involvement. Although not a criterion for the diagnosis of CSS, the presence of antineutrophil cytoplasmic autoantibodies (ANCA) is now established as being associated with CSS. In this report, a 31-year-old male with a history of difficult-to-control asthma is presented. It was associated with peripheral and bronchoalveolar eosinophilia, sinusitis, and high level of ANCA (perinuclear labeling pattern). Clinical manifestations observed at the time of relapses were palpable purpura, erythema nodosum, arthralgia, musculoskeletal complications, and episcleritis. In spite of vasculitis remission, low doses of steroids to control asthma were necessary for 10 years. The aim of this case report is to point to the possibility of CSS in patients with severe persistent asthma and atypical allergic diathesis.Churg-Straussov sindrom (CSS) je granulomatozni vaskulitis posredovan antineutrofilnim citoplazmatskim autoantitijelima perinuklearne fluorescencije (P-ANCA). Očituje se kliničkim simptomima ustrajne astme i sinusitisa uz izraženu eozinofiliju, što kod progredirajućih oblika bolesti prethodi migrirajućim plućnim infiltratima uz izvanplućne pojavnosti na perifernim živcima, koži, središnjem živčanom, probavnom i krvožilnom sustavu. Prikazujemo bolesnika s CSS koji se očitovao teškom ustrajnom astmom, perifernom i tkivnom eozinofilijom, sinusitisom i izrazito visokim titrom P-ANCA. Kontrola astme postignuta je tek nakon 10-godišnje steroidne terapije uz mnogobrojne nuspojave. Cilj prikaza je upozoriti na mogućnost CSS kod težih oblika astme i ukazati na mogućnost autoimunih pojavnosti u bolesnika s atopijskom konstitucijom

CORRELATION BETWEEN PHOLCODINE AND PERIOPERATIVE ANAPHYLAXIS

Velik broj osoba u kojih je došlo do anailaktčike reakcije na neuromuskularne blokatore nije bio s njima u prethodnom kontaktu. Ispitivanje mogu ih senzibiliziraju ih molekula dovelo je norveške i švedske znanstvenike do folkodina, antitusika koji se nalazi u širokoj upotrebi u Europi i svijetu. Folkodin sadrži amonijev ion, epitop koji je zajednički tom lijeku i neuromuskularnim blokatorima te koji je temelj njihove križne reaktivnosti. Nakon objavljenih rezultata istraživanja koja su dovela u vezu perioperativnu anailaktičku reakciju i upotrebu folkodina došlo je do povlačenja folkodina sa tržišta u Norveškoj i u kasnijem istraživanju dokazanog smanjenja broja anailaktičkih reakcija u toj zemlji. Europska agencija za lijekove u svom posljednjem izvještaju nije donijela odluku o povlačenju pripravaka folkodina s tržišta, ali je zatražila daljnja istraživanja koja bi trebala dodatno razjasniti ovu križnu reaktivnost između folkodina i neuromuskularnih blokatora.A large number of individuals experiencing anaphylactic reaction to neuromuscular blocking agents have not previously been in contact with them. The search for a substance inducing sensitization to muscle relaxants has led Norwegian and Swedish scientists to pholcodine, a cough suppressant, which is widely used in Europe and worldwide. Ammonium ion is an epitope common to pholcodine and neuromuscular blocking agents and it is the basis of their cross-reactivity. Based on the results of published studies that pointed to a connection of the use of pholcodine and perioperative anaphylactic reaction, pholcodine was withdrawn from the Norwegian market and subsequent research revealed a reduction of anaphylactic reactions in that country. In its latest report, the European Medicines Agency made a decision not to withdraw pholcodine mixtures from the market but it urged further research with the aim to clarify the cross-reactivity between pholcodine and neuromuscular blocking agents

INCREASING INCIDENCE OF ANGIOEDEMA WITHOUT URTICARIA – CLINICAL FEATURES

Angioedem (AE) bez urtikarije je bezbolni i ograničeni otok subkutanog ili submukoznog, rahlog intersticijskog tkiva koji nastaje brzo, u epizodama od nekoliko do više sati u obliku blijedih „jastučića“ u koži, mukoznom tkivu lica, usana, usne šupljine, ždrijela, larinksa i genitalija ali može zahvatiti i sluznicu gastrointestinalnog trakta. U kliničkoj praksi najčešće se angioedemu pripisuje alergijska etiologija što može biti pogrešno a standarna antialergijska terapija neučinkovita. AE se klasificiraju prema uzročnim medijatorima u bradikininske (hereditarni, stečeni, izazvan ACE inhibitorima), histaminske (alergijske) i AE posredovane mješavinom medijatora (pseudoalergijske reakcija na NSAID). Postoji i idiopatski AE čija je etiologija nepoznata. Incidencija AE je povećana pa je to najčešći razlog hospitalizacije od svih alergijskih bolesti. Incidencija angioedema posredovanog inhibitorima konvertaze angiotenzina I (ACEi) iznosi 0,1-0,7% i taj se oblik AE još nedovoljno često prepoznaje. Dijagnoza AE temelji se na anamnezi (hereditarni, pojava nakon 4. dekade života, ekspozicija alergenima, uzimanju ACEi) te na laboratorijskim nalazima serumskog C1Inh ili njegove funkcije. Kod tipa 1 HAE i razina C1Inh i njegova funkcionalna sposobnost je manja od 50%, a kod tipa 2 HAE razina C1Inh je uredna, a funkcionalna sposobnost slaba. Angioedem posredovan ACEi dokazuje se pojavom AE kod terapije, a regresijom nakon izostavljanja lijeka. Teške atake AE liječe se koncentratom C1Inh te ikatibantom, selektivnim blokatorom bradikininskih receptora B2. Profilaksa se provodi atenuiranim androgenima (danazol, stanazolol, oksandrolon) ili fibrinoliticima.The causes of angioedema (AE), a self-limited, localized swelling of subcutaneous tissue or mucosa unaccompanied by urticaria, are diverse. The commonly applied label of “allergic” is frequently wrong and standard anti-allergic therapy can be ineffective. Types of AE could be categorized according to mediators which mediate vascular leakage: bradykinin AE (hereditary, acquired, angiotensin-converting enzyme inhibitor (ACEi)-related), histamine AE (allergic etiology), and various mediators mediated AE (pseudoallergic reaction to non-steroidal anti-inflammatory drugs). Idiopathic AE is a poorly understood syndrome. The growing relevance of AE without urticaria has been highlighted; angioedema is the most common cause of hospital admission among all acute allergic diseases. The diagnosis of AE is based on the presence of family history (hereditary), absence of family history with the onset during or after the fourth decade of life (acquired C1Inh deficiency), and treatment with ACEi (ACEi-related angioedema). About 0.1%-0.7% of patients taking ACEi develop angioedema as a well-documented but still frequently unrecognized side effect of drugs. Laboratory diagnosis is enabled by measuring serum levels of C1Inh antigen or C1Inh function. Type 1 (hereditary angioedema (HAE) was diagnosed when both antigenic and functional levels of C1Inh were below 50% of normal, and type 2 when functional levels of C1Inh were low, along with antigenic levels normal or higher. ACEi-related AE is diagnosed when AE recurs during therapy and disappears upon withdrawal. Symptoms may appear several years after therapy introduction. Severe acute attacks should be treated with C1Inh concentrate and icatibant, a selective and specific antagonist of bradykinin B2 receptors. Prophylaxis with attenuated androgens (danazol, stanazolol, oxandrolone) is effective in preventing symptom development

CORRELATION BETWEEN PHOLCODINE AND PERIOPERATIVE ANAPHYLAXIS

Velik broj osoba u kojih je došlo do anailaktčike reakcije na neuromuskularne blokatore nije bio s njima u prethodnom kontaktu. Ispitivanje mogu ih senzibiliziraju ih molekula dovelo je norveške i švedske znanstvenike do folkodina, antitusika koji se nalazi u širokoj upotrebi u Europi i svijetu. Folkodin sadrži amonijev ion, epitop koji je zajednički tom lijeku i neuromuskularnim blokatorima te koji je temelj njihove križne reaktivnosti. Nakon objavljenih rezultata istraživanja koja su dovela u vezu perioperativnu anailaktičku reakciju i upotrebu folkodina došlo je do povlačenja folkodina sa tržišta u Norveškoj i u kasnijem istraživanju dokazanog smanjenja broja anailaktičkih reakcija u toj zemlji. Europska agencija za lijekove u svom posljednjem izvještaju nije donijela odluku o povlačenju pripravaka folkodina s tržišta, ali je zatražila daljnja istraživanja koja bi trebala dodatno razjasniti ovu križnu reaktivnost između folkodina i neuromuskularnih blokatora.A large number of individuals experiencing anaphylactic reaction to neuromuscular blocking agents have not previously been in contact with them. The search for a substance inducing sensitization to muscle relaxants has led Norwegian and Swedish scientists to pholcodine, a cough suppressant, which is widely used in Europe and worldwide. Ammonium ion is an epitope common to pholcodine and neuromuscular blocking agents and it is the basis of their cross-reactivity. Based on the results of published studies that pointed to a connection of the use of pholcodine and perioperative anaphylactic reaction, pholcodine was withdrawn from the Norwegian market and subsequent research revealed a reduction of anaphylactic reactions in that country. In its latest report, the European Medicines Agency made a decision not to withdraw pholcodine mixtures from the market but it urged further research with the aim to clarify the cross-reactivity between pholcodine and neuromuscular blocking agents