Summary
Pyoderma gangrenosum (PG) represents a rare skin disorder, with several clinical variants and still not fully understood ethiopathogenesis. Often associated with inflammatory or neoplastic disease, PG is nowadays considered an inflammatory neutrophilic disease with common underlying morbidity. Modern treatment options are oriented towards key mechanisms underlying the pathogenesis of the disease, namely inflammatory mediators, and seem to be the most effective treatment currently available. Although promising, the results are not invariable and these treatments are sometimes surrounded by controversy, as recent studies have reported cases that are refractory to therapy with biological agents. It is possible that refractoriness to the use of biological agents as monotherapy stems from the fact that a single agent is not able to affect the entire inflammatory cascade, or to simultaneously influence all of its levels. Based on the pathogenesis of inflammation, we can suggest that an ideal targeted therapy should be able to induce the following changes: 1) reduction of the secretion of interleukin (IL)-1a/b from the inflammasome with subsequent blocking of its biological effect (by therapy with IL-1 receptor antagonists); 2) blocking of the activation of the secreted procytokines in their active form (by therapy with caspase-1 inhibitors; 3) blocking of the effect of the already released active cytokines (by therapy with tumour necrosis factor alpha, TNF-α, inhibitors); 4) blocking of the effector action of the cytokines on the target intracellular molecules (by therapy with kinase inhibitors). The specific therapy should aim to attack more than one link in the inflammatory cascade, in order to achieve maximum therapeutic effectiveness. Most surely, this could be achieved with combined therapy with different groups of biological agents (for example a combined therapy with IL-1 receptor antagonist and a TNF-α inhibitor). Currently, no data in the literature exist to support this statement, and there are no safety data relating to such approaches. We focus this review on the novel etiopathogenetic concepts of PG and the future therapeutic approaches based on blocking different levels of the inflammatory cascade, which seems to be the most promising weapon in the target-oriented treatment options.
Zusammenfassung
Das Pyoderma gangraenosum (PG) ist eine seltene Hauterkrankung mit verschiedenen klinischen Subtypen und einer noch immer nicht komplett verstandenen Ätiopathogenese. Das PG wird als entzündliche neutrophile Dermatose verstanden, die oftmals eine Assoziation zu anderen entzündlichen oder neoplastischen Erkrankungen zeigt. Moderne Behandlungsansätze orientieren sich an den Schlüsselpositionen der zugrunde liegenden Pathogenese, insbesondere den inflammatorischen Mediatorsubstanzen. Sie verkörpern die derzeit effektivsten Therapieoptionen. Obwohl der Ansatz durchaus erfolgversprechend ist, sind die klinischen Resultate nicht konstant. Der Umstand sog. therapierefraktärer Fälle gegenüber einer zielgerichteten Therapie wird kontrovers diskutiert. Dieses Therapieversagen könnte jedoch auch daher rühren, dass eine Monotherapie mit Biologika nicht in der Lage ist, die gesamte Entzündungskaskade zu beeinflussen bzw. gleichermaßen simultan zu kontrollieren. Auf der Entzündungspathogenese basierend schlagen die Autoren für eine ideale Therapie folgende Eckpunkte vor: 1) Verminderung der IL-1a/b-Sekretion des Inflammasoms mit nachfolgender Blockade ihrer biologischen Wirkung (durch Einsatz von IL-1-Rezeptorantagonisten); 2) Blockade der Aktivierung sezernierter Prozytokine in ihrer aktiven Form (durch Einsatz von Caspase-1-Inhibitoren; 3) Hemmung der bereits sezernierten Zytokine (durch TNF-α-Inhibitoren); 4) Blockade der Effektoraktion der Zytokine auf entsprechende intrazelluläre Moleküle (mittels Kinaseinhibitoren). Die spezifische Therapie sollte an mehreren Schnittstellen der Entzündungskaskade angreifen, um eine maximale Wirkung zu entfalten. Aller Wahrscheinlichkeit nach lässt sich dieses Ziel nur durch Kombination verschiedener Biologika errreichen (z. B. eine Kombination von IL-1-Rezeptorantagonist und TNF-α-Inhibitor). Allerdings existieren derzeit noch keine harten wissenschaftlichen Daten, die dieses Konzept unterstützen. Ein weiterer ungeklärter Aspekt ist die Patientensicherheit. Die vorliegende Übersicht fokussiert auf neue ätiopathogenetische Konzepte zum PG und daraus abzuleitende zukünftige Behandlungsansätze, die auf dem Prinzip basieren, die Entzündungskaskade auf verschiedenen Ebenen zu unterbrechen. Dies scheint der erfolgversprechendste Ansatz einer zielgerichteten Therapie zu sein.
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A.A. Chokoeva, J.C. Cardoso, U. Wollina and G. Tchernev declare that they have no competing interests.
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Chokoeva, A.A., Cardoso, J.C., Wollina, U. et al. Pyoderma gangrenosum—a novel approach?. Wien Med Wochenschr 167, 58–65 (2017). https://doi.org/10.1007/s10354-016-0472-z
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DOI: https://doi.org/10.1007/s10354-016-0472-z