Tumor necrosis factor antagonists in the treatment of pyoderma gangrenosum, acne and suppurative hidradenitis (PASH) syndrome

The clinical triad of pyoderma gangrenosum (PG), acne and suppurative hidradenitis (HS) has been described under the acronym PASH syndrome and is considered to represent a distinct entity in the group of autoinflammatory diseases. It is a fairly new, only recently recognized disorder with a limited number of reported cases and without defined treatment recommendations. We aimed to summarize currently available data on the use of tumor necrosis factor (TNF) antagonists in the management of PASH syndrome and report on our own experience with the use of adalimumab in a patient presenting with this specific constellation of clinical signs and symptoms. Among the 11 cases identified in the literature, infliximab and adalimumab were the most commonly used agents, both exhibiting favorable effects in the majority of, but not all, patients. This was particularly evident in terms of relatively rapid remission of PG whereas HS lesions seemed to be more resistant to treatment. In our patient, adalimumab monotherapy resulted in a remarkable and sustained remission, although significant improvement of HS lesions was observed only from week 16 of therapy onwards. In summary, TNF antagonists are a promising treatment for PASH; however, conclusions regarding the choice of a specific agent, optimal dosing or use in combination with other treatment modalities cannot yet be drawn. </p

DRESS/DIHS: a severe multisystem adverse drug reaction

Reakcija na lijek s eozinofilijom i sistemskim simptomima (DRESS, od engl. Drug Reactionwith Eosinophilia and Systemic Symptoms) ili jednostavnije sindrom preosjetljivostiuzrokovan lijekom (DIHS, od engl. Drug-Induced Hypersensitivity Syndrome) jedna je od teških,po život opasnih reakcija preosjetljivosti. DRESS/DIHS obilježava nagli nastup osipa s vrućicom,limfadenopatijom, eozinofilijom i atipičnom limfocitozom, hepatitisom te mogućimzahvaćanjem bubrega, pluća, srca, gušterače ili drugih organa. Zbog odgođenog nastupa nakonpočetka primjene uzročnog lijeka, kao i zbog raznolikosti u kliničkoj simptomatologiji,ovaj je sindrom često neprepoznat ili je njegova dijagnoza odgođena. DRESS/DIHS je najčešćeuzrokovan antiepilepticima, ali se povezuje i s brojnim drugim lijekovima. U podlozi bolestinajvjerojatnije se nalazi složena interakcija između samog lijeka, reaktivacije herpes virusa ineadekvatnog imunološkog odgovora. Ishod ovog akutnog oboljenja varira od potpunog oporavkado trajnih sistemskih posljedica, uključujući i pojavu autoimunih bolesti.The syndrome termed Drug Reaction with Eosinophilia and Systemic Symptoms(DRESS), also known as Drug-Induced Hypersensitivity Syndrome (DIHS) is a severe, lifethreatening,multiorgan adverse drug reaction. It is characterized by an abrupt onset offever and rash, lymphadenopathy, eosinophilia, atypical lymphocytes, liver damage aswell as possible involvement of kidney, lungs, heart, pancreas or other organs. Due to thedelayed onset after the introduction of the culprit drug and a variety of clinicalmanifestations, DRESS/DIHS is frequently unrecognized or its diagnosis is delayed. It ismost commonly caused by anticonvulsants, but various other drugs have been implicatedin its onset. The pathogenesis includes a complex interplay between drugs, reactivation ofherpes viruses and altered immune response. Outcome of the disease varies fromcomplete recovery to permanent systemic complications including development ofautoimmune diseases

Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnsonov sindrom (SJS) i toksična epidermalna nekroliza (TEN) rijetke su ali teške reakcije na lijekove koje mogu ugroziti život pacijenta, stoga predstavljaju hitna stanja u medicini. Karakterizirani bolnim, eritematoznim i erozivnim lezijama kože i sluznica, SJS i TEN u biti predstavljaju spektar istog oboljenja pri čemu razliku predstavlja postotak zahvaćene kože. Osim oštećenja kože i sluznica, moguća je i afekcija drugih organa te pojava potencijalno smrtonosnih komplikacija. One uključuju dehidraciju, pneumoniju, akutni respiratorni distres sindrom, gastrointestinalne ulceracije, višestruko zatajenje organa i tromboembolijska zbivanja. Od lijekova koji mogu uzrokovati ovaj sindrom najčešće se spominju alopurinol, antibiotici, antikonvulzivi i nesteroidni protuupalni lijekovi oksikamske skupine. Sve je više dokaza koji upućuju na genetičku podlogu bolesti. Pritom se humani leukocitni antigen B smatra ključnim čimbenikom u prezentaciji lijekova limfocitima T i započinjanju imunološkog odgovora koji potom dovodi do masivne apoptoze epitelnih stanica. Visok rizik mortaliteta kao i trajnih posljedica koje nerijetko zaostaju nakon preboljenog SJS/TEN-a zahtijevaju promptno postavljanje dijagnoze, brzu identifikaciju uzročnog lijeka i njegovo isključivanje iz terapije, evaluaciju prognoze primjenom bodovnog sustava SCORTEN (engl. Severity-of-Illness Score for Toxic Epidermal Necrolysis) te primjenu odgovarajuće potporne njege uz eventualno uvođenje imunomodulacijske terapije.Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe adverse drug reactions that can endanger patient’s life and are therefore considered to be true medical emergencies. Characterized by an abrupt onset of painful, more or less extensive erythematous and erosive lesions of the skin and mucous membranes, SJS and TEN are in fact considered to represent a spectrum of the same disease, differing only in the extent of skin detachment. In addition to the involvement of skin and mucosal surfaces, affection of other organs and potentially fatal complications may develop. These include dehydration, pneumonia and acute respiratory distress syndrome, gastrointestinal ulceration, multiple organ failure and thromboembolic events. Most common causative drugs include allopurinol, antibiotics, anticonvulsants and nonsteroidal anti-inflammatory drugs of the oxicam type. Recently there has been ample evidence supporting the role of genetic background in the development of the disease. Human leukocyte antigen B seems to be the key factor in presenting drugs to T lymphocytes and beginning the immune response which then results in massive apoptosis of epithelial cells. High mortality as well as the risk of longterm sequelae require rapid diagnosis, prompt identification and withdrawal of the culprit drug, evaluation of the prognosis using the SCORTEN (Severity-of-Illness Score for Toxic Epidermal Necrolysis) scale, supportive care and consideration of systemic therapy with immunomodulatory agents

DRESS/DIHS: a severe multisystem adverse drug reaction

Reakcija na lijek s eozinofilijom i sistemskim simptomima (DRESS, od engl. Drug Reactionwith Eosinophilia and Systemic Symptoms) ili jednostavnije sindrom preosjetljivostiuzrokovan lijekom (DIHS, od engl. Drug-Induced Hypersensitivity Syndrome) jedna je od teških,po život opasnih reakcija preosjetljivosti. DRESS/DIHS obilježava nagli nastup osipa s vrućicom,limfadenopatijom, eozinofilijom i atipičnom limfocitozom, hepatitisom te mogućimzahvaćanjem bubrega, pluća, srca, gušterače ili drugih organa. Zbog odgođenog nastupa nakonpočetka primjene uzročnog lijeka, kao i zbog raznolikosti u kliničkoj simptomatologiji,ovaj je sindrom često neprepoznat ili je njegova dijagnoza odgođena. DRESS/DIHS je najčešćeuzrokovan antiepilepticima, ali se povezuje i s brojnim drugim lijekovima. U podlozi bolestinajvjerojatnije se nalazi složena interakcija između samog lijeka, reaktivacije herpes virusa ineadekvatnog imunološkog odgovora. Ishod ovog akutnog oboljenja varira od potpunog oporavkado trajnih sistemskih posljedica, uključujući i pojavu autoimunih bolesti.The syndrome termed Drug Reaction with Eosinophilia and Systemic Symptoms(DRESS), also known as Drug-Induced Hypersensitivity Syndrome (DIHS) is a severe, lifethreatening,multiorgan adverse drug reaction. It is characterized by an abrupt onset offever and rash, lymphadenopathy, eosinophilia, atypical lymphocytes, liver damage aswell as possible involvement of kidney, lungs, heart, pancreas or other organs. Due to thedelayed onset after the introduction of the culprit drug and a variety of clinicalmanifestations, DRESS/DIHS is frequently unrecognized or its diagnosis is delayed. It ismost commonly caused by anticonvulsants, but various other drugs have been implicatedin its onset. The pathogenesis includes a complex interplay between drugs, reactivation ofherpes viruses and altered immune response. Outcome of the disease varies fromcomplete recovery to permanent systemic complications including development ofautoimmune diseases

Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnsonov sindrom (SJS) i toksična epidermalna nekroliza (TEN) rijetke su ali teške reakcije na lijekove koje mogu ugroziti život pacijenta, stoga predstavljaju hitna stanja u medicini. Karakterizirani bolnim, eritematoznim i erozivnim lezijama kože i sluznica, SJS i TEN u biti predstavljaju spektar istog oboljenja pri čemu razliku predstavlja postotak zahvaćene kože. Osim oštećenja kože i sluznica, moguća je i afekcija drugih organa te pojava potencijalno smrtonosnih komplikacija. One uključuju dehidraciju, pneumoniju, akutni respiratorni distres sindrom, gastrointestinalne ulceracije, višestruko zatajenje organa i tromboembolijska zbivanja. Od lijekova koji mogu uzrokovati ovaj sindrom najčešće se spominju alopurinol, antibiotici, antikonvulzivi i nesteroidni protuupalni lijekovi oksikamske skupine. Sve je više dokaza koji upućuju na genetičku podlogu bolesti. Pritom se humani leukocitni antigen B smatra ključnim čimbenikom u prezentaciji lijekova limfocitima T i započinjanju imunološkog odgovora koji potom dovodi do masivne apoptoze epitelnih stanica. Visok rizik mortaliteta kao i trajnih posljedica koje nerijetko zaostaju nakon preboljenog SJS/TEN-a zahtijevaju promptno postavljanje dijagnoze, brzu identifikaciju uzročnog lijeka i njegovo isključivanje iz terapije, evaluaciju prognoze primjenom bodovnog sustava SCORTEN (engl. Severity-of-Illness Score for Toxic Epidermal Necrolysis) te primjenu odgovarajuće potporne njege uz eventualno uvođenje imunomodulacijske terapije.Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe adverse drug reactions that can endanger patient’s life and are therefore considered to be true medical emergencies. Characterized by an abrupt onset of painful, more or less extensive erythematous and erosive lesions of the skin and mucous membranes, SJS and TEN are in fact considered to represent a spectrum of the same disease, differing only in the extent of skin detachment. In addition to the involvement of skin and mucosal surfaces, affection of other organs and potentially fatal complications may develop. These include dehydration, pneumonia and acute respiratory distress syndrome, gastrointestinal ulceration, multiple organ failure and thromboembolic events. Most common causative drugs include allopurinol, antibiotics, anticonvulsants and nonsteroidal anti-inflammatory drugs of the oxicam type. Recently there has been ample evidence supporting the role of genetic background in the development of the disease. Human leukocyte antigen B seems to be the key factor in presenting drugs to T lymphocytes and beginning the immune response which then results in massive apoptosis of epithelial cells. High mortality as well as the risk of longterm sequelae require rapid diagnosis, prompt identification and withdrawal of the culprit drug, evaluation of the prognosis using the SCORTEN (Severity-of-Illness Score for Toxic Epidermal Necrolysis) scale, supportive care and consideration of systemic therapy with immunomodulatory agents

Biologic and Targeted Therapy in the Treatment of Psoriasis – A Retrospective Study from a National Referral Center

Psoriasis is one of the most common chronic inflammatory skin disorders worldwide with a significant number of patients suffering from moderate to severe disease and requiring systemic therapy. Over the past two decades, better knowledge of disease pathophysiology has translated into treatment advances for both primary disease and its associated comorbidities. However, it is important to review the use of biologic or targeted therapy in a clinical setting in order to understand how to optimize therapeutic results and recognize any unmet needs in this patient subpopulation. We conducted a retrospective study on a cohort of patients diagnosed with psoriasis that had received at least one dose of biologic or targeted therapy for the treatment of psoriasis at the Rijeka Clinical Hospital Center. By documenting treatment trends and specific patient characteristics, we will be able to address any unmet needs in this patient population and provide individualized care strategies

Biologic and Targeted Therapy in the Treatment of Psoriasis – A Retrospective Study from a National Referral Center

Psoriasis is one of the most common chronic inflammatory skin disorders worldwide with a significant number of patients suffering from moderate to severe disease and requiring systemic therapy. Over the past two decades, better knowledge of disease pathophysiology has translated into treatment advances for both primary disease and its associated comorbidities. However, it is important to review the use of biologic or targeted therapy in a clinical setting in order to understand how to optimize therapeutic results and recognize any unmet needs in this patient subpopulation. We conducted a retrospective study on a cohort of patients diagnosed with psoriasis that had received at least one dose of biologic or targeted therapy for the treatment of psoriasis at the Rijeka Clinical Hospital Center. By documenting treatment trends and specific patient characteristics, we will be able to address any unmet needs in this patient population and provide individualized care strategies

THE ROLE OF PERFORIN MEDIATED CELL CYTOTOXICITY IN PSORIASIS

Psorijaza je kronično-recidivirajuća upalna bolest kože obilježena poremećajem diferencijacije i proliferacije keratinocita te upalnim infiltratom, mahom T-limfocita u dermisu i epidermisu. Dosadašnje spoznaje upućuju da je psorijaza genski poremećaj proliferacije keratinocita posredovan T-limfocitima koji nastaje zbog poreme}ene aktivacije čimbenika stečene, ali i prirođene imunosti. Glavne populacije izvršnih stanica u psorijatičnom imunosnom odgovoru su pomagački CD4+ i citotoksični CD8+ T-limfociti. Obje vrste izvršnih T-limfocita djeluju na ciljne stanice, bilo putem lučenja citotoksinâ (perforina i granzima) ili pak putem molekula vezanih na membranu citotoksičnih stanica poput liganda za molekulu Fas (FasL). Za sada, uloga mehanizama stanične citotoksičnosti u patogenezi psorijaze, napose onih posredovanih perforinom, još nije dovoljno istražena. Perforin je citolitički protein pohranjen u citoplazmatskim granulama citotoksičnih T-limfocita i priro|eno ubilačkih stanica s osnovnom ulogom stvaranja perforinskih pora čime se otvara prolaz za ulaz granzima i drugih proapoptotskih molekula u ciljnu stanicu i izaziva njezina smrt apoptozom. Povečana ekspresija molekula perforina utvrđena je u oboljelih od nekih autoimunosnih bolesti kao što su multipla skleroza, autoimunosni tireoiditis te reumatoidni artritis. Novija istraživanja govore u prilog uključenosti ovih mehanizama i u imunopatogenezu psorijaze. Nakupljanje perforin-pozitivnih (P+) stanica u psorijatičnom epidermisu tik do apoptotski promijenjenih keratinocita upučuje da upravo T-limfociti oslobađanjem citolitičkih molekula uništavaju psorijatične keratinocite. S druge strane, apoptotski keratinociti mogli bi aktivirati regenerativni program cijeljenja uzrokujuči hiperplaziju keratinocita, što je ujedno i glavno obilježje psorijaze. Napredak u poznavanju izvršnog dijela stanične citotoksičnosti u psorijatičnom plaku možda će u budućnosti omogućiti da se odabirno zaustave određeni citolitički mehanizmi i molekule čime se uspostavlja potpuno nov i specifičniji pristup u liječenju psorijaze.Psoriasis is a common chronic inflammatory skin disease characterized by hyperproliferation and incomplete differentiation of epidermal keratinocytes as well as by inflammatory infiltrate of T-lymphocytes in dermis and epidermis. Psoriasis is nowadays also recognized as a T cell mediated disease resulting from aberrant activation of both innate and adaptive immunity. The main effector cells in mediating psoriatic phenotype are helper CD4+ T cells and cytotoxic CD8+ T cells. Both, CD4+ and CD8+ T cells, mediate apoptosis via the release of cell granules, perforin and granzymes or by binding of ligands to their death receptors on target cells. The role of cell cytotoxicity mechanisms, particularly those mediated by perforin, in psoriasis is as yet unclear. Perforin is a pore forming molecule, located within the cytoplasm of cytotoxic T cells and natural killer cells, which enables entry of granzymes and other apoptotic molecules into the target cell in order to mediate programmed cell death. The importance of perforin-mediated cytotoxicity has been demonstrated in several autoimmune diseases and in some inflammatory skin diseases. Recent studies claimed its role in the immunopathogenesis of psoriasis as well. Accumulation of perforin-positive cells in psoriatic epidermis close to damaged keratinocytes suggests that T lymphocytes induce damage to keratinocytes by releasing cytolytic molecules. On the other hand, apoptotic keratinocytes might trigger an injury response program causing regenerative hyperplasia of epidermal keratinocytes, a hallmark of psoriasis. Progress in understanding of effector part of cell cytotoxicity in psoriatic plaque might in future enable more specific treatment of psoriatic patients by blocking selectively each of proposed cytolytic mechanisms and molecules as potential new therapeutic targets