Georgios Kokolakis

Increased Prevalence of Metabolic Syndrome in Patients with Acne Inversa

Background Acne inversa (AI; also designated as Hidradenitis suppurativa) is a common chronic inflammatory skin disease, localized in the axillary, inguinal and perianal skin areas that causes painful, fistulating sinuses with malodorous purulence and scars. Several chronic inflammatory diseases are associated with the metabolic syndrome and its consequences including arteriosclerosis, coronary heart disease, myocardial infraction, and stroke. So far, the association of AI with systemic metabolic alterations is largely unexplored. Methods and Findings A hospital-based case-control study in 80 AI patients and 100 age- and sex-matched control participants was carried out. The prevalence of central obesity (odds ratio 5.88), hypertriglyceridemia (odds ratio 2.24), hypo-HDL-cholesterolemia (odds ratio 4.56), and hyperglycemia (odds ratio 4.09) in AI patients was significantly higher than in controls. Furthermore, the metabolic syndrome, previously defined as the presence of at least three of the five alterations listed above, was more common in those patients compared to controls (40.0% versus 13.0%; odds ratio 4.46, 95% confidence interval 2.02 to 9.96; P<0.001). AI patients with metabolic syndrome also had more pronounced metabolic alterations than controls with metabolic syndrome. Interestingly, there was no correlation between the severity or duration of the disease and the levels of respective parameters or the number of criteria defining the metabolic syndrome. Rather, the metabolic syndrome was observed in a disproportionately high percentage of young AI patients. Conclusions This study shows for the first time that AI patients have a high prevalence of the metabolic syndrome and all of its criteria. It further suggests that the inflammation present in AI patients does not have a major impact on the development of metabolic alterations. Instead, evidence is given for a role of metabolic alterations in the development of AI. We recommend monitoring of AI patients in order to correct their modifiable cardiovascular risk factors.

IL-29 Is Produced by TH17 Cells and Mediates the Cutaneous Antiviral Competence in Psoriasis

Psoriasis, but not atopic dermatitis patients, express elevated antiviral proteins in lesional skin because of the TH17 cytokine IL-29. IL-29 Jumps Out of the Skin The skin is the first line of defense against infection. It serves not only as a physical barrier but also, when that barrier is broken, as a battleground for the immune system. But what happens during chronic skin diseases, such as psoriasis and atopic dermatitis (AD)? Although patients with both diseases have continuous impaired skin barrier function, only AD patients frequently suffer from cutaneous viral infection. Wolk et al. now report that psoriatic patients are protected by elevated antiviral proteins (AVPs) that are up-regulated in response to interleukin-29 (IL-29) produced by the adaptive immune system. The authors first compared lesions from AD and psoriatic patients and healthy controls. They found higher amounts of AVPs in the psoriatic lesions. They then compared expression of 30 different cytokines with AVP expression and found that only IL-29 correlated with AVPs. Notably, IL-29 was absent in healthy and AD subjects. Neutralization of IL-29 in psoriatic lesions reduced their AVP expression. The relationship between IL-29 and AVP production was direct because this cytokine increased AVP (but not antibacterial protein) production in multiple models both in vitro and in vivo. What’s more, the IL-29 was secreted by TH17 cells—a proinflammatory immune cell type not previously known to produce IL-29. Together, these results suggest that TH17 cell secretion of IL-29 in psoriatic, but not AD, patients is critical for AVP-mediated viral defense. Psoriasis and atopic dermatitis (AD) are the most common chronic inflammatory skin diseases. Although both patient groups show strongly impaired skin barrier function, only AD patients frequently suffer from cutaneous viral infections. The mechanisms underlying the distinct susceptibilities to these pathogenetic and often life-threatening infections are unknown. We show that antiviral proteins (AVPs) such as MX1, BST2, ISG15, and OAS2 were strongly elevated in psoriatic compared to AD lesions and healthy skin. Of 30 individually quantified cytokines in psoriatic lesions, interleukin-29 (IL-29) was the only mediator whose expression correlated with the AVP levels. IL-29 was absent in AD lesions, and neutralization of IL-29 in psoriatic skin reduced AVP expression. Accordingly, IL-29 raised AVP levels in isolated keratinocytes, epidermis models, and human skin explants, but did not influence antibacterial protein production. AVP induction correlated with increased antiviral defense of IL-29–treated keratinocytes. Furthermore, IL-29 elevated the expression of signaling elements, resulting in increased sensitivity of keratinocytes toward its own action. We identified T helper 17 (TH17) cells as IL-29 producers and demonstrated their ability to increase the antiviral competence of keratinocytes in an IL-29–dependent manner. Transforming growth factor–β and the activity of RORγt/RORα were most critical for the development of IL-29–producing TH17 cells. IL-29 secretion by these cells was dependent on NFAT and c-Jun N-terminal kinase and was inhibited by IL-4. These data suggest that TH17 cell–derived IL-29, which is absent in AD, mediates the robust antiviral state on psoriatic skin, and demonstrate a new function of TH17 cells.

IL-19 Is a Component of the Pathogenetic IL-23/IL-17 Cascade in Psoriasis

Psoriasis is a common chronic inflammatory disease with characteristic skin alterations and functions as a model of immune-mediated disorders. Cytokines have a key role in psoriasis pathogenesis. Here, we demonstrated that out of 30 individually quantified cytokines, IL-19 showed the strongest differential expression between psoriatic lesions and healthy skin. Cutaneous IL-19 overproduction was reflected by elevated IL-19 blood levels that correlated with psoriasis severity. Accordingly, anti-psoriatic therapies substantially reduced both cutaneous and systemic IL-19 levels. IL-19 production was induced in keratinocytes by IL-17A and was further amplified by tumor necrosis factor-α and IL-22. Among skin cells, keratinocytes were found to be important targets of IL-19. IL-19 alone, however, regulated only a few keratinocyte functions. While increasing the production of S100A7/8/9 and, to a moderate extent, also IL-1β, IL-20, chemokine C-X-C motif ligand 8, and matrix metalloproteinase 1, IL-19 had no clear influence on the differentiation, proliferation, or migration of these cells. Importantly, IL-19 amplified many IL-17A effects on keratinocytes, including the induction of β-defensins, IL-19, IL-23p19, and T helper type 17-cell- and neutrophil-attracting chemokines. In summary, IL-19 as a component of the IL-23/IL-17 axis strengthens the IL-17A action and might be a biomarker for the activity of this axis in chronic inflammatory disorders.

Immunological changes in psoriasis patients under long-term treatment with fumaric acid esters: risk of Kaposi sarcoma occurrence?

BACKGROUND Psoriasis is a chronic skin disorder. The most frequently used systemic anti-psoriatic therapy in Germany is fumaric acid esters (FAE). OBJECTIVES We aimed to characterize immunological changes in psoriasis patients under FAE treatment. METHODS AND MATERIALS Over 200 flow-cytometry analyses of blood from 27 psoriasis patients and histological, molecular, and serological analyses of samples from a patient who developed Kaposi sarcoma (KS) during FAE therapy were performed. RESULTS The patients receiving FAE showed decreased CD8+ T cell counts, in particular during the first six months. The CD4+ T cell decline was less pronounced and delayed in time. In a patient with KS, we found a profound CD4 and CD8 lymphocytopenia, as well as a NK cell number reduction, although leukocyte and lymphocyte counts were within the recommended limits. The patient was HIV negative, but positive for HHV8. After cessation of FAE therapy, KS regressed. DISCUSSION HHV8 infection and iatrogenic T cell reduction, prominently of CD8+ T cells, could have contributed to KS development in this patient. Therefore, we suggest a control of CD4+ and CD8+ T cell counts in addition to the commonly-used differential blood counts in patients with a higher HHV8 prevalence or at high risk of other latent viral infections.

Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation

Psoriasis is a chronic inflammatory disease resulting from dysregulated immune activation associated with a large local secretion of cytokines. Among them, IL-22 largely contributes to epithelial remodeling and inflammation through inhibiting the terminal differentiation of keratinocytes and inducing antimicrobial peptides and selected chemokines. The activity of IL-22 is regulated by IL-22 binding protein (IL-22BP); however, the expression and role of IL-22BP in psoriatic skin has remained unknown so far. Here we showed that nonaffected skin of psoriasis patients displayed lower expression of IL-22BP than skin of healthy controls. Furthermore, the strong IL-22 increase in lesional psoriatic skin was accompanied by a moderate induction of IL-22BP. To investigate the role of IL-22BP in controlling IL-22 during skin inflammation, we used imiquimod-induced skin disease in rodents and showed that rats with genetic IL-22BP deficiency (Il22ra2−/−) displayed exacerbated disease that associated with enhanced expression of IL-22–inducible antimicrobial peptides. We further recapitulated these findings in mice injected with an anti–IL-22BP neutralizing Ab. Hypothesizing that the IL-22/IL-22BP expression ratio reflects the level of bioactive IL-22 in psoriasis skin, we found positive correlations with the expression of IL-22–inducible molecules (IL-20, IL-24, IL-36γ, CXCL1, and BD2) in keratinocytes. Finally, we observed that serum IL-22/IL-22BP protein ratio strongly correlated with psoriasis severity. In conclusion, we propose that although IL-22BP can control deleterious actions of IL-22 in the skin, its limited production prevents a sufficient neutralization of IL-22 and contributes to the development and maintenance of epidermal alterations in psoriasis.

Interleukin-29 induces epithelial production of CXCR3A ligands and T-cell infiltration

Psoriasis is considered as a model for chronic immune-mediated disorders. Th17-cells are pivotal players in those diseases. Recently, we demonstrated that Th17-cells produce interleukin (IL)-29 and that IL-29 is highly present in psoriatic lesions. Whether IL-29, with its action on epithelial cells and melanocytes, contributes to psoriasis pathogenesis, was unknown so far. Analysis of IL-29-treated human keratinocytes revealed induction of the chemokines CXCL10, CXCL11, and, to a much lesser extent, CXCL9. Unlike these CXCR3A ligands, known to attract Th1-, CD8+, NK-, and Th1/Th17 transient cells, no influence was found on chemokines attracting other immune cell populations or on molecules modulating the CXCR3A/CXCR3A ligand interaction. CXCR3A ligand expression was also induced by IL-29 in melanocytes and in epidermis models and explanted skin. Regarding other psoriasis-relevant cytokines, interferon-γ and, less potently, tumor necrosis factor-α and IL-1β shared and strengthened IL-29’s capacity. Murine IL-29 counterpart injected into mouse skin provoked local CXCL10 and CXCL11 expression, T-cell infiltration, and, in consequence, skin swelling. The elevated IL-29 expression in psoriatic lesions was associated with upregulation of CXCR3A ligands compared to non-lesional skin of these patients and to the skin of healthy donors and atopic dermatitis patients, which lack IL-29 production. Importantly, neutralization of IL-29 reduced CXCR3A ligand levels in explant cultures of psoriatic lesions. Finally, elevated blood CXCL11 levels were found in psoriasis that might be useful for monitoring lesional activity of the IL-29 axis. In summary, the Th17-cytokine IL-29 induces specific chemokines and, in consequence, provokes skin infiltration of potentially pathogenic T-cells.Key messagesIL-29 selectively induces CXCR3A-binding chemokines (CXCL9, CXCL10, CXCL11) in skin cells.Murine IL-29 counterpart induces skin T-cell infiltration and inflammation in mice.CXCR3A ligands are IL-29-dependently increased in lesional skin of psoriasis patients.CXCR3A ligand levels in psoriatic skin correlate with epidermal T-cell numbers.Increased blood CXCL11 levels in psoriasis may be a biomarker for local IL-29 action.

Systemische Therapien der Psoriasis und Psoriasisarthritis

ZusammenfassungDie Psoriasis vulgaris ist eine der häufigsten chronischen Hauterkrankungen. Über 25 % der betroffenen Personen benötigen aufgrund der massiven Ausprägung der Symptome und/oder einer deutlichen Einschränkung der Lebensqualität eine wirksame systemische Therapie. Dank intensiverer Forschung und erfolgreicher Zusammenarbeit zwischen akademischen und industriellen Einrichtungen haben sich unsere Behandlungsmöglichkeiten für die Psoriasis in den letzten Jahren enorm erweitert. Insbesondere ermöglichen uns zielgerichtete Therapien eine personalisierte Medizin. Diese Übersichtsarbeit beschreibt das Spektrum der systemischen Therapien bei Psoriasis und Psoriasisarthritis und thematisiert Wirksamkeit, Sicherheit und Besonderheiten der einzelnen Substanzen.AbstractPsoriasis is one of the most common chronic dermatoses. More than 25 % of the affected individuals require effective systemic treatment because of severe symptoms and/or the significantly restricted quality of life. Thanks to intensive research and successful cooperation between academia and the pharmaceutical industry, the options for treating psoriasis have dramatically increased in recent years. Especially targeted therapies give us the opportunity for personalized regimen. This review describes the spectrum of the systemic treatments for psoriasis and psoriatic arthritis and discusses the efficacy, safety, and particular features of the individual substances.

Systemic treatments for psoriasis and psoriatic arthritis

ZusammenfassungDie Psoriasis vulgaris ist eine der häufigsten chronischen Hauterkrankungen. Über 25 % der betroffenen Personen benötigen aufgrund der massiven Ausprägung der Symptome und/oder einer deutlichen Einschränkung der Lebensqualität eine wirksame systemische Therapie. Dank intensiverer Forschung und erfolgreicher Zusammenarbeit zwischen akademischen und industriellen Einrichtungen haben sich unsere Behandlungsmöglichkeiten für die Psoriasis in den letzten Jahren enorm erweitert. Insbesondere ermöglichen uns zielgerichtete Therapien eine personalisierte Medizin. Diese Übersichtsarbeit beschreibt das Spektrum der systemischen Therapien bei Psoriasis und Psoriasisarthritis und thematisiert Wirksamkeit, Sicherheit und Besonderheiten der einzelnen Substanzen.AbstractPsoriasis is one of the most common chronic dermatoses. More than 25 % of the affected individuals require effective systemic treatment because of severe symptoms and/or the significantly restricted quality of life. Thanks to intensive research and successful cooperation between academia and the pharmaceutical industry, the options for treating psoriasis have dramatically increased in recent years. Especially targeted therapies give us the opportunity for personalized regimen. This review describes the spectrum of the systemic treatments for psoriasis and psoriatic arthritis and discusses the efficacy, safety, and particular features of the individual substances.

Erratum: Medikamentöse Therapie der Acne inversa

Erratum zu:Hautarzt 2017https://doi.org/10.1007/s00105-017-4094-1 Sehr geehrte Leserin, sehr geehrter Leser,im oben genannten Beitrag ist im Abschnitt „Systemische Therapien“, „Biologika in der Therapie der Acne inversa“ bei der Dosierungsangabe von Adalimumab leider ein Fehler unterlaufen. Der …Erratum zu: Hautarzt 2017 https://doi.org/10.1007/s00105-017-4094-1 Sehr geehrte Leserin, sehr geehrter Leser, im oben genannten Beitrag ist im Abschnitt „Systemische Therapien“, „Biologika in der Therapie der Acne inversa“ bei der Dosierungsangabe von Adalimumab leider ein Fehler unterlaufen. Der …

Systemische Therapien der Psoriasis und Psoriasisarthritis@@@Systemic treatments for psoriasis and psoriatic arthritis

ZusammenfassungDie Psoriasis vulgaris ist eine der häufigsten chronischen Hauterkrankungen. Über 25 % der betroffenen Personen benötigen aufgrund der massiven Ausprägung der Symptome und/oder einer deutlichen Einschränkung der Lebensqualität eine wirksame systemische Therapie. Dank intensiverer Forschung und erfolgreicher Zusammenarbeit zwischen akademischen und industriellen Einrichtungen haben sich unsere Behandlungsmöglichkeiten für die Psoriasis in den letzten Jahren enorm erweitert. Insbesondere ermöglichen uns zielgerichtete Therapien eine personalisierte Medizin. Diese Übersichtsarbeit beschreibt das Spektrum der systemischen Therapien bei Psoriasis und Psoriasisarthritis und thematisiert Wirksamkeit, Sicherheit und Besonderheiten der einzelnen Substanzen.AbstractPsoriasis is one of the most common chronic dermatoses. More than 25 % of the affected individuals require effective systemic treatment because of severe symptoms and/or the significantly restricted quality of life. Thanks to intensive research and successful cooperation between academia and the pharmaceutical industry, the options for treating psoriasis have dramatically increased in recent years. Especially targeted therapies give us the opportunity for personalized regimen. This review describes the spectrum of the systemic treatments for psoriasis and psoriatic arthritis and discusses the efficacy, safety, and particular features of the individual substances.