Sehr geehrte Herausgeber, Die Pityriasis rubra pilaris (PRP) ist eine unvollständig verstandene dermatologische Erkrankung mit Störungen von Keratinisierung und Immunfunktionen.1 Die Diagnosestellung kann herausfordernd sein. Akantholytische Foci wurden bei der PRP beschrieben,2, 3 werden allerdings in dermatopathologischen Lehrbüchern nicht regelmäßig erwähnt. Eine stark ausgeprägte akantholytische Dyskeratose ist ungewöhnlich und kann zu Fehldiagnosen führen. Wir berichten über einen 67-jährigen Mann, der sich mit schuppenden, erythematösen Läsionen an Kopf und Brust vorstellte. Anfangs waren die Läsionen hauptsächlich papulös und ähnelten klinisch einem Morbus Grover mit atypischen Merkmalen wie erythematösen Plaques (Abbildung 1a). Über 3 Monate hinweg entwickelten sie sich die Effloreszenzen zu scharf begrenzten, erythematösen, schuppenden Plaques auf Brust, Rücken, Kopfhaut, Ohren und Augenbrauen. Die Extremitäten blieben ausgespart (Abbildung 1b). Symptome waren mäßiger Juckreiz, Brennen und Überempfindlichkeit der Haut. Zu diesem Zeitpunkt umfasste die klinische Differenzialdiagnose eine seborrhoische Dermatitis und einen Pemphigus foliaceus. Der Patient erhielt 1 bis 2 Monate vor dem Symptombeginn eine Coronavirus- (Comirnaty®, BioNTech) und eine Grippeimpfung. Eine umfassende Durchuntersuchung ergaben keinen Hinweis auf eine zugrundeliegende Erkrankung. Mehrere Biopsate nach 2 und 3 Monaten zeigten das ungewöhnliche Bild einer ausgeprägten akantholytischen Dyskeratose, ähnlich dem Morbus Grover oder präziser dem Morbus Darier, begleitet von milder Akanthose der Epidermis, leicht abgeblassten Keratinozyten in der oberen Epidermis und breiter Parakeratose (Abbildung 1c–d). Direkte und indirekte Immunfluoreszenz waren unauffällig. Nach anfänglicher Besserung der Symptomatik unter topischen Steroiden und Ketoconazol veränderte sich die Morphologie der Läsionen im Laufe der Zeit. Im neunten Monat hatte sich ein suberythrodermatisches Bild mit konfluierenden Plaques und follikulären Papeln gebildet, wobei nur kleine Bereiche der Haut ausgespart blieben (nappes claires) (Abbildung 2a–c). Es zeigte sich eine ausgeprägte plantare Keratodermie (Abbildung 2d). Zu diesem Zeitpunkt entnommene Biopsate zeigten ähnliche epidermale Veränderungen wie zuvor, jedoch waren akantholytische Foci äußerst selten und nur subtil (Abbildung 2e, f). Einige Proben zeigten ein minimales Entzündungsinfiltrat, breite, kompakte Orthohyperkeratose und follikuläre Okklusion (Abbildung 2g). Bei der erneuten Durchsicht der Schnittpräparate konnten sowohl in früh als auch spät im Erkrankungsverlauf gewonnenen Präparaten subtile Bezirke mit Schachbrett-Parakeratose nachgewiesen werden. Das klinische Bild und die histologischen Befunde erlaubten schließlich die sichere Diagnose einer PRP Typ I. Der vorliegende Fall unterstreicht die Herausforderungen der Diagnose einer frühen PRP und liefert wertvolle Einblicke, da den Autoren während des Krankheitsverlaufs des Patienten mehrere Gewebeproben und klinische Fotografien zur Verfügung standen. Während die akantholytische Dyskeratose in frühen Biopsaten ausgeprägt war, war die Akantholyse später nur subtil. Akantholyse und akantholytische Dyskeratose bei der PRP wurden zuvor berichtet.2-7 Ko, Milstone, Choi und McNiff beobachteten, dass die Akantholyse ausgeprägter ist, wenn die PRP am Rumpf beginnt und in der Differenzialdiagnose von papulosquamösen Erkrankungen als Hinweis auf eine PRP dienen kann.3 In ihrer Fallserie ähnelte die frühe PRP mit Akantholyse klinisch dem Pemphigus foliaceus, der Psoriasis guttata, der sekundären Syphilis, dem subakuten Lupus erythematodes und der Pityriasis rosea.3 Umgekehrt kann eine ausgeprägte Akantholyse und akantholytische Dyskeratose die Diagnose einer PRP verschleiern. In zwei veröffentlichten Fällen wurden akantholytische Dyskeratose und ausgeprägte Akantholyse in einer fortgeschrittenen Phase der Erkrankung mit ausgedehnten, konfluierenden Plaques und Erythrodermie beobachtet.6, 8 In einem anderen Fall wurde die akantholytische Dyskeratose früh im Erkrankungsverlauf beobachtet, wobei die klinische Differenzialdiagnose eine Pityriasis rosea umfasste.7 In einem vierten Fall gingen eine ausgeprägte akantholytische Dyskeratose und dem M. Grover ähnliche klinische Merkmale den typischeren klinischen und histologischen Veränderungen einer PRP voraus.4 Magro und Crowson2 berichten von mindestens zwei weiteren Patienten mit PRP, bei denen klinisch oder histologisch früh in der Erkrankung der Verdacht auf einen M. Grover bestand. Darüber hinaus wurden einige Fälle von vermeintlichem M. Grover veröffentlicht, bei denen sich im Verlauf PRP-ähnliche Eruptionen entwickelten.9, 10 Die publizierten histologischen Bilder in einem dieser Fälle zeigen, dass die akantholytischen Herde während der dem M. Grover ähnelnden Stadien bereits von breiter Hyperkeratose und Akanthose mit Blässe in der oberen Epidermis umgeben waren, die auf eine PRP hinweisen.9 In dem anderen Fall scheinen die klinischen und histologischen Bilder früher Einzelläsionen gut mit einem M. Grover vereinbar zu sein, bevor sich im Verlauf klassische PRP-ähnliche Eruptionen entwickelten. Die Beteiligung fast des gesamten Körpers einschließlich der Hand- und Fußrücken und die Persistenz über 10 Jahre während der dem M. Grover ähnlichen Phase sind jedoch auch in diesem Fall ungewöhnlich für einen M. Grover.10 Obwohl in diesen letzteren Fällen die Kollision eines M. Grover mit einer PRP denkbar ist, würden wir dem M. Grover ähnliche Frühphasen einer PRP favorisieren, die dem Auftreten der klassischen (Sub-)erythrodermie vorausgingen. Zusammenfassend ergänzen unsere Beobachtungen frühere Berichte über ausgeprägte Akantholyse und akantholytische Dyskeratose bei der PRP. Basierend auf unserem Fall und unserer Literaturrecherche vermuten wir, dass akantholytische Dyskeratosen in Frühphasen der Erkrankung häufiger auftreten und sowohl klinisch als auch histologisch Teil eines Grover-artigen Musters sein können. Zusätzliche histologische Befunde, die mit einer PRP vereinbar sind, oder die klinisch-pathologische Korrelation können in diesen Situationen eine korrekte Diagnosestellung ermöglichen. Open access Veröffentlichung ermöglicht und organisiert durch Projekt DEAL. Keiner.

Journal of the European Academy of Dermatology and VenereologyAccepted Articles LETTER TO THE EDITOR High-dose intravenous immunoglobulin co-treatment prolongs time-to-treatment escalation in autoimmune bullous diseases: a monocentric retrospective cohort study M. Bertlich, M. Bertlich University Hospital Heidelberg, Department of Dermatology, Heidelberg, Germany University Hospital Bonn, Department of Dermatology, Bonn, Germany both authors contributed equallySearch for more papers by this authorI. Bertlich, I. Bertlich University Hospital Heidelberg, Department of Dermatology, Heidelberg, Germany both authors contributed equallySearch for more papers by this authorN. Plümacher, N. Plümacher University of Kassel, Department of Electrical Engineering and Computer Science, Kassel, GermanySearch for more papers by this authorE. Hadaschik, E. Hadaschik University Hospital Heidelberg, Department of Dermatology, Heidelberg, Germany University of Duisburg-Essen, Department of Dermatology, Essen, GermanySearch for more papers by this authorA. Enk, A. Enk University Hospital Heidelberg, Department of Dermatology, Heidelberg, GermanySearch for more papers by this authorJ. H. O. Hoffmann, Corresponding Author J. H. O. Hoffmann [email protected] orcid.org/0000-0003-1579-626X University Hospital Heidelberg, Department of Dermatology, Heidelberg, Germany Correspondence Prof. Dr. med. Jochen Hoffmann, Hautklinik Heidelberg, INF 440, 69120 Heidelberg, Germany. Email: [email protected], Phone: +49 6221 56 8511Search for more papers by this author M. Bertlich, M. Bertlich University Hospital Heidelberg, Department of Dermatology, Heidelberg, Germany University Hospital Bonn, Department of Dermatology, Bonn, Germany both authors contributed equallySearch for more papers by this authorI. Bertlich, I. Bertlich University Hospital Heidelberg, Department of Dermatology, Heidelberg, Germany both authors contributed equallySearch for more papers by this authorN. Plümacher, N. Plümacher University of Kassel, Department of Electrical Engineering and Computer Science, Kassel, GermanySearch for more papers by this authorE. Hadaschik, E. Hadaschik University Hospital Heidelberg, Department of Dermatology, Heidelberg, Germany University of Duisburg-Essen, Department of Dermatology, Essen, GermanySearch for more papers by this authorA. Enk, A. Enk University Hospital Heidelberg, Department of Dermatology, Heidelberg, GermanySearch for more papers by this authorJ. H. O. Hoffmann, Corresponding Author J. H. O. Hoffmann [email protected] orcid.org/0000-0003-1579-626X University Hospital Heidelberg, Department of Dermatology, Heidelberg, Germany Correspondence Prof. Dr. med. Jochen Hoffmann, Hautklinik Heidelberg, INF 440, 69120 Heidelberg, Germany. Email: [email protected], Phone: +49 6221 56 8511Search for more papers by this author First published: 18 August 2023 https://doi.org/10.1111/jdv.19437 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1111/jdv.19437. AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Accepted ArticlesAccepted, unedited articles published online and citable. The final edited and typeset version of record will appear in the future. RelatedInformation

Abstract Necrobiotic xanthogranuloma (NXG) is a rare non‐Langerhans cell histiocytosis associated with paraproteinemia. Skin lesions of NXG are difficult to treat and various therapies have been evaluated with inconsistent results. A therapeutic standard has not been established. We report on a patient severely affected by mutilating skin and ocular lesions as well as lung infiltrates of necrobiotic xanthogranuloma. After failure of several previous therapies including dapsone and adalimumab, lesions significantly improved during therapy with intravenous immunoglobulins (IVIg). IVIg are an effective treatment option to evaluate in NXG.

Zusammenfassung Das Skleromyxödem Arndt-Gottron ist die systemische Variante des Lichen myxoedematosus. Kennzeichnend sind Muzinablagerungen im Bereich der Dermis mit Ausbildung von Papeln und flächigen Indurationen. Der Verlauf ist häufig chronisch progredient und extrakutane Manifestationen bzw. Komplikationen sind möglich. Meist liegt eine monoklonale Gammopathie vor. Die Pathogenese ist unbekannt. Als effektive Therapieoption gelten hochdosierte intravenöse Immunglobuline (IVIg). Wir berichten über eine Patientin mit Skleromyxödem, bei der im Rahmen einer SARS-CoV-2-bedingten Therapieunterbrechung ein infektgetriggertes dermato-neurologisches Syndrom auftrat. Eine ähnliche Episode ereignete sich bereits 2 Jahre zuvor im Rahmen einer Influenza-A-Infektion gegen Ende des IVIg-Infusionsintervalls. Bei dem dermato-neurologischen Syndrom handelt es sich um eine besonders schwerwiegende, potenziell lebensbedrohliche, akute neurologische Komplikation mit Fieberschüben, deliranter Symptomatik, epileptischen Anfälle und Koma.

Scleromyxedema Arndt-Gottron is the systemic variant of lichen myxedematosus in which mucin accumulation occurs in the dermis. The disease is usually chronically progressive and extracutaneous manifestations or complications are possible. The pathogenesis is unknown and the disease is usually associated with monoclonal gammopathy. High-dose intravenous immunoglobulins (IVIg) are considered to be an effective therapy. We report the case of a patient who developed dermato-neuro syndrome following an interruption of IVIg treatment and a SARS-CoV‑2 infection. A similar episode occurred 2 years earlier in association with an influenza A infection. Dermato-neuro syndrome is a potentially lethal neurological complication which is characterized by fever, delirium, convulsions, and coma.

Pemphigus vulgaris (PV) is a potentially lethal autoimmune bullous skin disorder caused by IgG autoantibodies against desmoglein 3 (Dsg3) and Dsg1. During the last three decades, high-dose intravenous immunoglobulins (IVIgs) have been applied as an effective and relatively safe treatment regime in severe, therapy-refractory PV. This prompted us to study T- and B- cell polarization by IVIg in a human-Dsg3-dependent mouse model for PV. Using humanized mice transgenic for HLA-DRB1*04:02, which is a highly prevalent haplotype in PV, we employed IVIg in two different experimental approaches: in prevention and quasi-therapeutic settings. Our data show that intraperitoneally applied IVIg was systemically distributed for up to 42 days or longer. IVIg-treated Dsg3-immunized mice exhibited, in contrast to Dsg3-immunized mice without IVIg, significantly less Dsg3-specific IgG, and showed induction of T regulatory cells in lymphatic tissue. Ex vivo splenocyte analysis upon Dsg3-specific stimulation revealed an initial, temporarily reduced antigen-induced cell proliferation, as well as IFN-γ secretion that became less apparent over the course of time. Marginal-zone B cells were initially reduced in the preventive approach but re-expanded over time. In contrast, in the quasi-therapeutic approach, a robust down-regulation in both spleen and lymph nodes was observed. We found a significant down-regulation of the immature transitional 1 (T1) B cells in IVIg-treated mice in the quasi-therapeutic approach, while T2 and T3, representing a healthy stage of B-cell development, appeared to be up-regulated by IVIg. In summary, in two experimental settings employing an active PV mouse model, we demonstrate distinct alterations of T- and B-cell populations upon IVIg treatment, compatible with a tolerance-associated polarization in lymphatic tissue. Our data suggest that the clinical efficacy of IVIg is at least modulated by distinct alterations of T- and B-cell populations compatible with a tolerance-associated polarization in lymphatic tissue.

Cutaneous squamous cell carcinoma (cSCC) is a serious public health problem due to its high incidence and metastatic potential. It may progress from actinic keratosis (AK), a precancerous lesion, or the in situ carcinoma, Bowen's disease (BD). During this progression, malignant keratinocytes activate dermal fibroblasts into tumor promoting cancer-associated fibroblasts (CAFs), whose origin and emergence remain largely unknown. Here, we generate and analyze >115,000 single-cell transcriptomes from healthy skin, BD and cSCC of male donors. Our results reveal immunoregulatory and matrix-remodeling CAF subtypes that may derive from pro-inflammatory and mesenchymal fibroblasts, respectively. These CAF subtypes are largely absent in AK and interact with different cell types to establish a pro-tumorigenic microenvironment. These findings are cSCC-specific and could not be recapitulated in basal cell carcinomas. Our study provides important insights into the potential origin and functionalities of dermal CAFs that will be highly beneficial for the specific targeting of the cSCC microenvironment.

n the case of our patient, we successfully confirmed paractamol as the offending drug by performing an LTT. As aracetamol has been reported to elicit enhanced proliferaion even in non-sensitised individuals [14], we performed parallel analysis in a healthy control and found a negaive stimulation index, which led us to estimate that LTT as contributory in our patient. Moreover, in our case, TT was also useful to find safe alternative drugs before eintroduction. e suggest that LTT could be an optional diagnostic tool for DE/NPFDE, although this hypothesis should be confirmed n large samples.

A 57-year-old Caucasian woman was presented to us in a consult by the neurologic department because she had developed sudden skin changes on the arms and the legs that were accompanied by increasing tetraataxia as well as weakness and dysesthesia of the limbs. Although she denied previous disease and did not take any long-term medication, her underweight was striking on presentation (weight: 45 kg; height: 159 cm; BMI 17.8). Her ventral arms, her shins and the dorsa of her feet showed extensive, sharply demarcated brown plaques with coarse scaling (Figure 1). A skin biopsy showed alternating layers of orthokeratosis and parakeratosis (sandwich sign), which is a clue for a multiphase course of disease. Furthermore, there were sparse lymphocytes at the dermoepidermal junction and increased subepidermal melanophages (Figure 2). These findings suggest a subacute stage of interface dermatitis. In accordance with this, the sharp demarcation and the distribution of the lesions were strongly suggestive of a phototoxic dermatitis. Neurological examination showed a distally focused tetraparesis and the nerve conduction velocity was diminished. A biopsy of the sural nerve showed a distinct loss of myelin nerve fibers and signs of axonal damage. The combination of neurologic symptoms and phototoxic dermatitis leaves room for few possible differential diagnoses. Porphyria was excluded using stooland blood samples. Zinc deficiency can cause similar, sharply demarcated eczematous plaques and may be accompanied by neurological symptoms; However, in zinc deficiency the skin lesions usually affect the periorificial areas [1]. The distribution of the skin changes did not suggest cutaneous lupus erythematodes, as the typical sites of chronical light exposure (nose, face, back of hands) were not affected and the lesions were continuous and large-scaled rather than single plaques. Therefore, serologic ANA titers and direct immunofluorescence were not performed. Although similarly discrete histological Clinical Letter

Background: Psoriasis is a chronic and systemic inflammatory disease with a loss of up to 5 life years, which is thought to be reduced by biologic treatment. Disease severity and eligibility for systemic treatment are often based on the cutaneous psoriasis area and severity index (PASI) with a cut-off of 10 in several European countries. However, it is unclear how well this cut-off reflects systemic inflammation and, consequently, the risk for the development of comorbidity. Objectives: (1) To assess whether specific PASI thresholds, in particular PASI 10, predict elevated biomarkers of systemic inflammation and cardiovascular risk on an individual patient level. (2) To assess the association of PASI and psoriatic arthritis with biomarkers of systemic inflammation and cardiovascular risk. Methods: Retrospective cross-sectional study of 72 psoriasis patients without systemic treatment. Results: Overall, 68, 42, and 50% of patients had cardiovascular risk level neutrophil-to-lymphocyte ratio (NLR), C-reactive protein, and elevated platelet-to-lymphocyte ratio (PLR) values, respectively. The respective positive predictive values of PASI 10 were 70, 45, and 70. The performance of the optimal PASI cut-offs according to the Youden index was similarly weak. Subgrouping of patients with a PASI below 10 did not result in a considerably improved reflection of systemic inflammation. PLR was significantly higher in patients with moderate-to-severe compared to mild psoriasis and significantly correlated with PASI in patients with a PASI above 2 (r(s) = 0.266, n = 64). NLR was significantly higher in patients with psoriatic arthritis. Conclusion: Specific PASI thresholds were not well suited to predict elevated biomarkers of systemic inflammation and cardiovascular risk on an individual patient level. Therefore, PASI, and possibly other purely cutaneous measures, may not be ideal as stand-alone parameters to define disease severity and eligibility for systemic treatment. Our results are relevant for the ongoing discussion on the definition of psoriasis severity and eligibility for systemic treatment. Further research addressing the added value of a set of biomarkers of systemic inflammation in the assessment of psoriasis severity would be desirable.

The most frequent autoimmune blistering disease, bullous pemphigoid (BP), has a high clinical significance owing to the enhanced mortality of the most elderly patients (Joly et al., 2012). The characteristic blister formation in BP goes along with autoantibody formation against the hemidesmosomal structure proteins BP180 and BP230 (Schmidt and Zillikens, 2013). The transmembrane protein BP180, in particular its immunodominant NC16a domain, is currently considered as major autoantigen responsible for blister formation in BP (Schmidt et al., 2000).

1228 © 2022 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2022/00 7 Torres-Alvarez B, Castanedo-Cazares JP, Moncada B. Pentoxifylline in the treatment of actinic prurigo. A preliminary report of 10 patients. Dermatology 2004; 208: 198–201. 8 Wozniacka A, Carter A, McCauliffe DP. Antimalarials in cutaneous lupus erythematosus: mechanisms of therapeutic benefit. Lupus 2002; 11: 71–81. 9 Magaña-García M. Antimalarials for children. J Am Acad Dermatol 1994; 30: 510. 10 Danza Á, Graña D, Goñi M et al. Hidroxicloroquina en el tratamiento de las enfermedades autoinmunes sistémicas. Revista médica de Chile 2016; 144: 232–40.

Subcutaneous panniculitis-like T-cell lymphoma is a rare, indolent cutaneous cytotoxic alpha-beta T-cell lymphoma, where no specific therapy regimen is defined. We present a case with a diagnostically challenging association with anti-double stranded DNA and provides one of the first reports of a successful treatment with mycophenolate mofetil and glucocorticosteroids.

The efficacy of psoriasis treatments is usually evaluated using the Psoriasis Area and Severity Index (PASI). However, there is a lack of systematic statistical assessments of PASI as a proxy for systemic disease in individual patients. Therefore, a retrospective study of 186 treat-ments with adalimumab, etanercept, and ustekinumab for psoriasis (341 patient-years) was performed. While PASI significantly and independently correlated with biomarkers of systemic inflammation (especially neutrophil-to-lymphocyte ratio, C-reactive protein), the strengths were only weak-to-moderate and varied considerably inter-individually. A decrease in PASI indicated a neutrophil-to-lymphocyte ratio decrease and a C-reactive protein decrease or stable low margin C-reactive protein in ≥ 80%. Sensitivity, specificity, and positive predictive value of PASI 0 and PASI 2.75 (optimal Youden Index) for low cardiovascular risk C-reactive protein were 24%, 92%, 85%, and 62%, 61%, 76%, respectively. Performance was similar using absolute thresholds and PASI 100 or PASI 75, and overall worse for low cardiovascular risk neutrophil-to-lympho-cyte ratio and if psoriasis arthritis was present. In conclusion, PASI allows robust low-order estimates of systemic inflammation, but cannot substitute for laboratory biomarkers for more precise assessments.