Rapid and sustained control of itch and reduction in Th2 bias by dupilumab in a patient with Sézary syndrome.

BACKGROUND: Sézary syndrome is a leukaemic variant of cutaneous T-cell lymphoma with poor prognosis. With the exception of stem cell transplantation, current treatments for SS are not curative. Rather, they aim at reducing disease burden and improving quality of life. Yet, pruritus - the major cause for impaired quality of life in these patients - is notoriously difficult to treat. Thus, supportive treatments addressing agonizing pruritus are urgently needed. OBJECTIVES: To explore the clinical and immunological effects of type 2 cytokine blockade with dupilumab as supportive treatment in Sézary syndrome. METHODS: A Sézary syndrome patient with stable disease but intractable pruritus was treated with dupilumab in combination with continued extracorporeal photopheresis. Close clinical and immunological monitoring on blood and skin samples from the patient was performed over 44 weeks. In vitro assays with patient's lymphoma cells were performed to address effects of dupilumab on Sézary cell's response to Th2 cytokines. RESULTS: Clinically, dupilumab treatment induced rapid and sustained reduction in itch and improvement of skin and lymph node involvement. In both blood and skin, a reduction in Th2 bias was observed. Intriguingly, lymphocyte counts and Sézary cells in blood increased and later stabilized under dupilumab treatment. In vitro, dupilumab abrogated the anti-apoptotic and activating effects of Th2 cytokines on Sézary cells. CONCLUSIONS: In this Sézary patient, inhibition of IL-4 and IL-13 signalling was associated with striking clinical benefit in terms of quality of life, pruritus and use of topical corticosteroids. While safety remains an important concern, our data support the future exploration of Th2 modulation for supportive care in Sézary Syndrome.

Increased expression of the interleukin-36 cytokines in lesions of hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a recalcitrant chronic skin disease with poorly understood immunopathogenic mechanisms. Previous studies reported that the interleukin-36 (IL-36) cytokines [IL-36α, IL-36ß, IL-36γ and IL-36 receptor antagonists (IL-36RA)] are important players in the pathogenesis of psoriasis (PS). OBJECTIVE: We aim to determine whether the IL-36 cytokines are upregulated in patients with HS. For this purpose, we analysed local expression and systemic levels of the IL-36 cytokines in patients with HS and compared the results to healthy donors and patients with PS. METHODS: Skin biopsies from healthy donors and HS and PS patients were analysed for expression of the IL-36 cytokines by immunohistochemistry and semiquantitative real-time PCR. The enzyme-linked immunosorbent assay (ELISA) was used to measure systemic levels of the IL-36 cytokines in the serum of the three donor groups. RESULTS: The agonists IL-36α, IL-36ß and IL-36γ were found to be upregulated in HS both systemically and lesionally, while the IL-36RA was not differently regulated in comparison to healthy donors. CONCLUSION: Our findings suggest that the agonistic IL-36 isoforms are upregulated in HS. The relevance of the enhanced production of IL-36 cytokines in HS pathogenesis remains to be determined.

Interleukin-32 is highly expressed in lesions of hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. Its immunopathogenic mechanisms are still poorly understood. Previous studies demonstrated that the proinflammatory cytokine interleukin (IL)-32 is implicated in the pathogenesis of other inflammatory diseases. OBJECTIVES: To investigate the tissue expression and systemic levels of IL-32, as well as its cellular sources, in patients with HS in comparison with healthy donors and patients with two other inflammatory skin diseases: psoriasis and atopic dermatitis (AD). METHODS: Tissue samples were obtained from healthy skin and lesional HS, psoriatic and AD skin to analyse the expression of IL-32 by immunohistochemistry and semiquantitative real-time polymerase chain reaction. The cellular source of the cytokine was determined by double immunofluorescence staining. Serum from the four donor groups was used to measure systemic levels of IL-32 by enzyme-linked immunosorbent assay. RESULTS: IL-32 was upregulated in patients with HS in both lesional skin and serum when compared with healthy donors and patients with AD or psoriasis. In HS, IL-32 was found to be expressed by natural killer cells, T cells, macrophages and dendritic cells in highly infiltrated areas of the dermis. High IL32 mRNA levels in lesional HS skin coincided with high amounts of T cells and macrophages. Additionally, IL32 mRNA levels in lesional HS skin correlate positively with interferon-γ and IL-17A and negatively with IL-13. CONCLUSIONS: Our findings suggest that IL-32 is overexpressed in HS. Targeting IL-32 may therefore represent a new therapeutic option for the treatment of this recalcitrant disease.

Distinct interferon-gamma and interleukin-9 expression in cutaneous and oral lichen planus.

BACKGROUND: Cutaneous (CLP) and oral lichen planus (OLP) as the main subtypes of lichen planus (LP) present with different clinical manifestation and disease course, although their histopathologic features such as the band-like lymphocyte infiltrate and keratinocyte apoptosis are similar. So far, the underlying cellular and molecular mechanisms remain poorly understood. OBJECTIVE: The aim of this study was to characterize and compare the in situ cellular infiltrates, cytokine expression profiles and apoptosis markers in CLP and OLP. METHODS: Using immunofluorescence staining and laser scanning microscopy, we evaluated the cellular infiltrate (CD1a, CD3, CD4, CD8, CD21, CD57, CD123), cytokine expression (interleukin (IL)-1, IL-6, IL-9, IL-10, IL-17, IL-22, IL-23, tumour necrosis factor-α, transforming growth factor-ß, interferon (IFN)-γ), and apoptosis markers (Fas, Fas ligand, cleaved caspase-3, TUNEL) of 21 anonymized biopsy specimens of LP (11 CLP, 10 OLP). RESULTS: Among infiltrating cells mainly T cells and natural killer (NK) cells as well as plasmacytoid dendritic cells (DC) were observed. A predominance of CD8+ T cells was noted in OLP. In both CLP and OLP, T helper (Th)1, Th9, Th17, and Th22-type cytokines were expressed. The expression of IL-9, IFN-γ and IL-22 was higher in CLP compared to that of OLP (P = 0.0165; P = 0.0016; P = 0.052 respectively). Expression of Fas and Fas ligand as well as cleaved caspase-3-positive cells was observed in the epithelium of all LP samples. CONCLUSIONS: The cell and cytokine patterns of CLP and OLP were partially distinct and generally resembled those reported for autoimmune diseases. The presence of CD8+ and NK cells as well as Fas/Fas ligand expression suggested that various pathways involved in keratinocyte apoptosis are relevant for LP. These results might help to establish targeted therapies for LP.

The continuing evolution of targeted therapy for inflammatory skin disease.

Treatment of inflammatory skin disease has evolved from non-specific suppression of immune cells to increasingly precise targeting and modulation of immune mechanisms at all levels. This has led to dramatic treatment successes and deepened understanding of the pathophysiology. The cycle of in vitro studies, animal models, clinical trials, and case series of non-primary indications is a feedback loop that informs and guides the design of ever better disease models and therapeutic targets. Not only are we constantly discovering new molecules driving skin inflammation, we have also found that psoriasis and other autoimmune conditions are driven by distinct mediators occurring in early and late phases, which could be an opportunity for phase-specific or multipronged interventions. The deeper our mechanistic understanding, the more likely we will be able to discover subtle strategies to reprogram each patients' immune cells without having to dampen or eliminate their protective effects against pathogens and tumors. Lastly, ongoing genomic studies might soon confirm interesting genetic markers for predictive personalized medicine, the earliest currently being evaluated in psoriasis such as HLA-Cw6 and TNFAIP3. Taken together, the continued evolution of immune therapies in skin will potentially allow an unprecedented form of medicine that is not bent on silencing the pathogenic mechanism, but rather aims at using subtle interventions to shepherd the immune cell swarm back on the correct path.

Update on skin allergy.

Skin diseases with an allergic background such as atopic dermatitis, allergic contact dermatitis, and urticaria are very common. Moreover, diseases arising from a dysfunction of immune cells and/or their products often manifest with skin symptoms. This review aims to summarize recently published articles in order to highlight novel research findings, clinical trial results, and current guidelines on disease management. In recent years, an immense progress has been made in understanding the link between skin barrier dysfunction and allergic sensitization initiating the atopic march. In consequence, new strategies for treatment and prevention have been developed. Novel pathogenic insights, for example, into urticaria, angioedema, mastocytosis, led to the development of new therapeutic approaches and their implementation in daily patient care. By understanding distinct pathomechanisms, for example, the role of IL-1, novel entities such as autoinflammatory diseases have been described. Considerable effort has been made to improve and harmonize patient management as documented in several guidelines and position papers.

High expression of FOXP3 in primary melanoma is associated with tumour progression.

BACKGROUND: The antitumour immune response plays an important role in the prognosis of melanoma. High numbers of circulating regulatory T cells have been associated with rapid disease progression. OBJECTIVES: To assess the influence of forkhead box protein (FOXP)3, CD1a and langerin expression on the prognosis of primary melanoma. METHODS: We analysed 185 primary melanomas by immunohistochemical staining for expression of the regulatory T-cell marker FOXP3 and the dendritic cell markers langerin and CD1a, and correlated marker expression with clinical outcome. RESULTS: Disease-free survival and overall survival were significantly longer in patients expressing low levels of FOXP3 in the primary melanoma, whereas they were associated with high expression of CD1a. The negative prognostic value of FOXP3 expression was independent of the Breslow tumour thickness. Langerin expression did not correlate with the clinical outcome. CONCLUSIONS: High expression of FOXP3 in the primary melanoma may be used as an additional independent prognostic marker for early tumour progression in patients with melanoma.

NKp46+ cells express granulysin in multiple cutaneous adverse drug reactions.

BACKGROUND: The spectrum of cutaneous adverse drug reactions (cADRs) ranges from benign presentations to severe life-threatening forms such as toxic epidermal necrolysis (TEN). In TEN, granulysin has been shown to be the key cytotoxic molecule. Still, little is known about the expression of granulysin in other cADRs. As an important source of granulysin, natural killer (NK) cells are of major interest in cADRs. Recently, NKp46 has been identified as the most selective NK-cell marker. However, the role of NKp46(+) cells in cADRs and their contribution to granulysin expression remain to be elucidated. METHODS: Immunohistochemical and immunofluorescence staining of tissue sections from multiple cADRs were quantitatively and qualitatively evaluated. Further, in vivo and in vitro drug-stimulation tests were performed. RESULTS: Granulysin is expressed at different levels in multiple cADRs both by NKp46(+) cells and by CD8(+) T cells. Even in mild forms of cADRs, granulysin can be induced in vivo and in vitro in a drug-specific manner. NKp46(+) cells were found to infiltrate the dermal/epidermal junction particularly in TEN. CONCLUSION: The impressive clinical differences of cADRs may not be uniquely explained by the expression of granulysin. Additional factors such as drug-specific activation and recruitment of NKp46(+) cells to the epidermis may play a role in determining the severity of cADRs. Therefore, unraveling the effects of drugs on NK-cell activation and trafficking may help to better understand the cytotoxic mechanisms behind cADRs.