Anike Lockmann

Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

Although reports documented aberrant cytokine expression in autoimmune bullous dermatoses (AIBDs), cytokine-targeting therapies have not been established in these disorders. We showed previously that IL-6 treatment protected against tissue destruction in experimental epidermolysis bullosa acquisita (EBA), an AIBD caused by autoantibodies to type VII collagen (COL7). The anti-inflammatory effects of IL-6 were mediated by induction of IL-1ra, and prophylactic IL-1ra administration prevented blistering. In this article, we demonstrate elevated serum concentrations of IL-1β in both mice with experimental EBA induced by injection of anti-COL7 IgG and in EBA patients. Increased IL-1α and IL-1β expression also was observed in the skin of anti-COL7 IgG-injected wild-type mice compared with the significantly less diseased IL-1R–deficient or wild-type mice treated with the IL-1R antagonist anakinra or anti–IL-1β. These findings suggested that IL-1 contributed to recruitment of inflammatory cells into the skin. Accordingly, the expression of ICAM-1 was decreased in IL-1R–deficient and anakinra-treated mice injected with anti-COL7. This effect appeared to be specifically attributable to IL-1 because anakinra blocked the upregulation of different endothelial adhesion molecules on IL-1–stimulated, but not on TNF-α–stimulated, cultured endothelial cells. Interestingly, injection of caspase-1/11–deficient mice with anti-COL7 IgG led to the same extent of skin lesions as in wild-type mice. Collectively, our data suggest that IL-1, independently of caspase-1, contributes to the pathogenesis of EBA. Because anti–IL-1β in a prophylactic setting and anakinra in a quasi-therapeutic setting (i.e., when skin lesions had already developed) improved experimental EBA, IL-1 appears to be a potential therapeutic target for EBA and related AIBDs.

Repetitive injections of botulinum toxin A continuously increase the duration of efficacy in primary axillary hyperhidrosis: A retrospective analysis in 101 patients

Botulinum toxin type A is an effective, well‐tolerated, albeit temporary treatment for primary axillary hyperhidrosis. However, little is known about the influence of repetitive injections on the duration of efficacy.

Mutually enhancing anti-inflammatory activities of dimethyl fumarate and NF-κB inhibitors – implications for dose-sparing combination therapies

Fumaric acid esters, dimethyl fumarate (DMF) in particular, have been established for the therapy of psoriasis and, more recently, multiple sclerosis. In the light of therapy‐limiting dose‐dependent side effects, such as gastrointestinal irritation, reducing the effective doses of FAE is a worthwhile goal. In search of strategies to maintain the anti‐inflammatory activity of DMF at reduced concentrations, we found that NF‐κB inhibition augmented key anti‐inflammatory effects of DMF in two complementary experimental settings in vitro. At non‐toxic concentrations, both proteasome inhibition with bortezomib as well as blocking NF‐κB activation through KINK‐1, a small molecule inhibitor of IKKβ‐profoundly enhanced DMF‐dependent inhibition of nuclear NF‐κB translocation in TNFα‐stimulated human endothelial cells. This resulted in significant and selective co‐operative down‐regulation of endothelial adhesion molecules crucial for leucocyte extravasation, namely E‐selectin (CD62E), VCAM‐1 (CD106) and ICAM‐1 (CD54), on both mRNA and protein levels. Functionally, these molecular changes led to synergistically decreased rolling and firm adhesion of human lymphocytes on TNF‐activated endothelial cells, as demonstrated in a dynamic flow chamber system. If our in vitro findings can be translated into clinical settings, it is conceivable that anti‐inflammatory effects of DMF can be achieved with lower doses than currently used, thus potentially reducing unwanted side effects.

TNF α-induced leukocyte–endothelial cell interactions show marked interindividual differences independent of the clinical response to adalimumab

The responses of patients with psoriasis to TNFα‐antagonists show interindividual differences. Here, TNFα‐incubation induced endothelial adhesion molecules, a prerequisite for leucocyte recruitment to inflamed tissues. Using a standardized flow chamber system equipped with near‐confluent endothelial cells and a mobile phase containing human leucocytes, proportions of leucocytes interacting with endothelial cells were remarkably different between individual donors (up to 3.5‐fold), regardless of whether the leucocytes originated from patients with psoriasis (n = 10) or healthy donors (n = 10). Adalimumab abrogated adhesion molecule induction and interactions with leucocytes when present prior to or simultaneously with, but not after exposure of the cultures to TNFα. This pattern was seen similarly with leucocytes from healthy donors (n = 4), and patients whose psoriasis responded well to adalimumab (n = 5) and non‐responders (n = 5). Thus, although considerable interindividual differences of leucocyte–endothelial cell interactions were demonstrated ex vivo in a TNFα‐governed microenvironment, such differences are not associated with individual responses to treatment with adalimumab in vivo.

Nd:YAG laser epilation to prevent recurrences after pilonidal sinus surgery.

Pilonidal sinus is a common and painful inflammatory disorder of the sacral tissues; it mainly affects men (M:F ratio is 2–4:1) in the 2nd to 3rd decade of life. The disease is found in fairskinned Europeans with an incidence of 26/100 000 people. It rarely occurs in black Africans and Asians [1, 2]. The sinus contains granulation tissue, hairs and cell detritus. The course of disease can be divided in asymptomatic, acute with abscess and chronic exudative. Pilonidal sinuses persist lifelong but can become acute at any moment. In this stage with bacterial superinfection surgical incision and drainage along with antibiotic treatment is recommended. Total excision of the sinus with all its fistula tracts down to the sacral fascia is indicated a noninflamed phase. The optimal treatment after surgical excision is still controversial. Open secondary wound healing, primary wound closure in the centerline or plastic reconstructive flaps are common treatment options. The relapse rate is high and is estimated at 5 % to 20 % [1, 3]. While some authors report the lowest relapse rate after open wound healing [2, 4], others describe best results after wound closure with flaps [5]. Surgical incision and drainage before definitive total excision reduces the longterm recurrence rate [4]. Hairs not only promote relapse but also hamper the process of secondary wound healing after pilonidal sinus surgery (Figure 1). In recent years epilation with different laser systems has successfully reduced the risk for relapse after pilonidal sinus surgery [3, 5–8].

Phenotypic and functional traits of peripheral blood mononuclear cells retained by controlled cryopreservation: implications for reliable sequential studies of dynamic interactions with endothelial cells

Many immunological experiments would be greatly facilitated if peripheral blood mononuclear cells (PBMC) preserved important functional properties over longer periods of time. Regarding adhesive interactions with endothelial cells, a crucial step of inflammatory processes, this had not been investigated yet. We demonstrate that PBMC subsets subjected to controlled cryopreservation retain their phenotypic traits inasmuch as the proportion of viable T cells, monocytes/macrophages and B cells was comparable with their freshly isolated counterparts. More importantly, we demonstrate for the first time that the procedure does not impede crucial adhesion‐mediated dynamic interactions with endothelial cells. Using a flow chamber system, freshly isolated and cryopreserved PBMC showed similar rolling and firm adhesion on TNF‐α‐activated endothelial cells under shear flow as compared to freshly isolated PBMC from the same donors. Thus, our observation is an important prerequisite for functional studies of leucocyte recruitment when sequential investigations with material from the same patients are required.

„Creeping eruption“ und eosinophile Follikulitis: Atypische kutane Larva migrans

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Creeping eruption and eosinophilic folliculitis: Atypical cutaneous larva migrans: Correspondence

Cutaneous larva migrans is caused by parasites, most commonly dog or cat hookworms (genus Ancylostoma). Infected animals excrete hookworm eggs; humans are incidental hosts [1]. Following contact with contaminated soil – frequently on beaches – hookworm larvae penetrate the host’s skin. In case of humans being incidental hosts, they burrow through the upper dermis where they cause extremely pruritic linear or serpiginous tracks, called “creeping dermatitis” [2, 3]. Occasionally, Gnathostoma spp., loiasis, or cutaneous pili migrans may also cause creeping eruptions [4]. Although cutaneous larva migrans is a self-limiting disease resolving within weeks to months, it impairs the quality of life due to the severe pruritus [5]. A 25-year-old woman from Germany presented with multiple pruritic red papules on both feet and legs. The lesions had developed five days earlier while she was on a two-week vacation in Thailand. Antihistamines had failed to provide sufficient pruritus relief. Likewise, topical antifungals (miconazole), corticosteroids, and permethrin 5 % had been ineffective. Within a few days, the lesions spread to the upper legs, some becoming hemorrhagic. This was followed by the appearance of serpiginous tracks and some vesicles (Figure 1a–c). In addition, our patient reported a cold and a sore throat for a few days but no fever. Although serum leukocyte and eosinophil counts were within normal limits, there was a mild “left shift” of neutrophils (79.7 %; normal range 40–76 %) accompanied by relative lymphocytopenia (10.2 %; normal range 20–45 %) and elevated C-reactive protein levels (39.4 mg/L; normal value ≤ 5.0 mg/L). Histology showed eosinophilic spongiosis (eosinophils within a sponge-like epidermis), eosinophils infiltrating hair follicles, and a dense lymphohistiocytic perifollicular infiltrate, again with abundant eosinophils (Figure 2a–b). The patient received a single oral dose of ivermectin (total dose: 9 mg; 0.14 mg/kg), which was well tolerated. The skin lesions resolved within a few weeks and never recurred. Cutaneous larva migrans is common in tropical and subtropical areas. In Northern Europe, the disease is usually seen in patients returning from tropical countries [1, 4, 6], although a few cases have been reported in Europeans without prior travel to the tropics [4, 6, 7]. The incubation period varies from a few days to several weeks [3]. The diagnosis is usually made on clinical grounds, based on the typical serpiginous burrows and the intense pruritus [3]. Blood eosinophilia may be present [3]. Most creeping eruptions are caused by hookworm larvae. Only few cases are caused by other parasites, including gnathostomiasis or loiasis. The lat-

Wiederholte Injektionen von Botulinumtoxin Typ A steigern kontinuierlich die Wirkdauer bei primärer axillärer Hyperhidrose: Eine retrospektive Analyse von 101 Patienten

Botulinumtoxin Typ A ist eine wirksame, gut verträgliche, wenn auch temporäre Therapieoption gegen primäre axilläre Hyperhidrose. Über den Einfluss von wiederholten Injektionen auf die Wirkdauer ist jedoch wenig bekannt.

Rapidly growing blue-red nodule on the cheek of a 4-year-old boy: Case for Diagnosis

Dermatoscopy (Handyscope for iPhone 4, FotoFinder Systems, Bad Birnbach, Germany) revealed a sharply demarcated, symmetric, round tumor with diffuse blue to bluish-red pigmentation (Figure 1c). Macroscopically visible telangiectases disappeared upon compression by the dermatoscopic contact plate. A few lightly colored streaks were visible. Rapidly growing blue-red nodule on the cheek of a 4-year-old boy Case for Diagnosis