Severe autoimmune hemolytic anemia following immunotherapy with checkpoint inhibitors in two patients with metastatic melanoma: a case report.

Introduction: Over the past decade, immune checkpoint inhibitors such as antibodies against cytotoxicity T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have become an important armamentarium against a broad spectrum of malignancies. However, these specific inhibitors can cause adverse autoimmune reactions by impairing self-tolerance. Hematologic side effects of immune checkpoint inhibitors, including autoimmune hemolytic anemia (AIHA), are rare but can be life-threatening. Case report: Herein, we report two patients on immune checkpoint inhibitors for metastatic melanoma who developed AIHA with symptoms of dyspnea and fatigue. In the first patient, symptoms alleviated after discontinuation of combined anti CTLA-4 and anti-PD-1 therapy, initiation of corticosteroids and application of a single red blood cell transfusion. Due to subsequent progress of melanoma, combinational anti-PD-1 and tyrosine kinase inhibitor therapy was initiated based on multidisciplinary tumor board decision. After two months, she again developed the described hematological and clinical signs of AIHA leading to cessation of anti-PD-1 therapy and initiation of corticosteroids, which again resulted in an alleviation of her symptoms. Due to further progression, the patient received dacarbazine for several months before she decided to stop any therapy other than palliative supportive care. In the second patient, discontinuation of anti-PD-1 therapy and initiation of corticosteroids entailed a complete alleviation of his symptoms. After refusing chemotherapy due to subsequent melanoma progression, he received radiotherapy of bone metastases and is currently enrolled in a clinical trial. The patient did not develop AIHA ever since. Conclusion: Hematologic immune-related adverse events due to treatment with immune checkpoint inhibitors are rare but can have life-threatening consequences. If dyspnea and other clinical symptoms are present, AIHA should be considered as a potential cause and treated promptly in a multidisciplinary setting. An expanded comprehension of risk factors and pathogenesis of AIHA is needed to identify high-risk patients beforehand, leading to more effective predictive and reactive treatment approaches.

Bullous Pemphigoid in Patients Receiving Immune-Checkpoint Inhibitors and Psoriatic Patients-Focus on Clinical and Histopathological Variation.

BACKGROUND: The most common autoimmune blistering disease, bullous pemphigoid (BP), shows an increased prevalence in psoriatic patients and oncologic patients undergoing immune-checkpoint blockade (ICB). Even though the same autoantigens (BP180/BP230) are detectable, it remains obscure whether clinical or histopathological differences exist between these different groups of BP patients. In this study, we strived to analyze this matter based on own data and previously published reports. METHODS: We performed an institutional chart review from 2010-2020 to identify BP patients with psoriasis (n = 6) or underlying ICB (n = 4) and matched them with idiopathic cases of BP (n = 33). We compared clinical characteristics, subtypes, and dermatopathological determinants (e.g., tissue eosinophilia/neutrophilia, papillary edema, lymphocytic infiltration) among the groups. RESULTS: ICB-associated BP affects men more often and might show mucosal involvement more frequently. We found no statistically significant dermatopathological differences among the groups. CONCLUSIONS: Clinicians should be aware of an increased risk of BP in patients with psoriasis and oncologic patients receiving ICB; atypical pruritic skin lesions should prompt a workup including a skin biopsy for histopathology and direct immunofluorescence in these patients. Larger studies might be necessary to detect slight dermatopathological variation.

Blastic plasmacytoid dendritic-cell neoplasia: a challenging case report.

Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an extremely rare disease that originates from dendritic cells and is associated with a poor overall survival (OS). Diagnostic and therapeutic standards are less well-established in comparison to other leukemic conditions and standards of care are lacking. Morphologic and molecular similarities to acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are hard to distinguish. We here report a BPDCN patient with a long, challenging diagnostic period. While bone marrow biopsies initially failed to prove the correct diagnosis, a cutaneous biopsy finally identified a CD45+/CD56+/CD4+/CD123+/CD33+/MPO- population suggestive of BPDCN which was confirmed by flow cytometry. Molecular analysis revealed an ASXL-1, TET2 and SRSF2-mutation, cytogenetic analysis showed a normal karyotype. Treatment with the recently approved CD123-cytotoxin Tagraxofusp showed initially a very good response. This case reflects diagnostic and therapeutic difficulties in BPDCN as very rare, easily misdiagnosed neoplasia and the need for precise diagnostic care.

NKG2D and its ligands as cytotoxic factors in cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is an autoimmune skin disorder that is characterized by an anti-epidermal lymphocytic infiltrate invading the dermo-epidermal junction, causing an interface dermatitis (ID). Pathogenesis of CLE has been linked to activation of innate immunity. NKG2D is an innate immune receptor on NK cells and distinct T-cell populations. The NKG2D ligands MHC class I polypeptide-related sequence A and B (MICA, MICB) have been associated to CLE susceptibility. Our gene microarray analyses of chronic discoid lupus erythematosus (CDLE) skin lesions, separated in epidermal, junctional and dermal skin areas via laser microdissection, revealed a high expression of NKG2D in the lymphocytic infiltrate and led us to further investigate the role of NKG2D in CLE. Pathway analyses showed a strong "interferon (IFN) signature" and vast activation of innate immune response pathways (TLR, RIG-I, cytosolic DNA sensing, JAK/STAT) in CDLE, that expressed the high NKG2D signal. Immunohistochemistry (IHC) confirmed the presence of NKG2D and its ligand MICB in CDLE and subacute cutaneous lupus erythematosus (SCLE) lesions. Finally, HaCaT cells were stimulated with nucleic acids and extracted RNA was sequenced with Illumina HiSeq and showed that stressed keratinocytes express typical NKG2D ligands MICA/B and ULBP2. This study provides first evidence that NKG2D is present in CDLE and SCLE skin lesions and could be relevant for cytotoxicity in IFN-driven skin lesions with upregulated innate immune response pathways present in CLE. It could furthermore play a role in CLE inflammation promoted by keratinocytes under cell stress.

Grzybowski's Generalized Eruptive Keratoacanthomas in a Patient with Terminal Kidney Disease-An Unmet Medical Need Equally Ameliorated by Topical Imiquimod Cream and Lapacho Tea Wraps: A Case Report.

INTRODUCTION: Development of singular keratoacanthoma (KA) is generally considered a benign condition as it has a tendency to regress spontaneously in spite of histological similarity to squamous cell carcinoma. Most KAs undergo excision to rule out differential diagnoses. Several alternative treatment modalities (keratinolytic, ablative, immunomodulating, antiproliferative, or targeted therapy) have been described in the past with varying success, underlining the therapeutic challenges associated with large or multiple lesions. Isomorphic response (Koebner phenomenon) may limit the efficacy of ablative options, and comorbidity may limit the use of systemic treatments. Less aggressive topical immunomodulatory treatment options represent an alternative with varying therapeutic success. CASE REPORT: Here, we describe the clinical course of a 51-year-old male patient with terminal kidney disease who suffered from the rare benign pruritic condition of Grzybowski's generalized eruptive keratoacanthomas (GEKA) and experienced a significant reduction of lesions and symptoms upon topical therapy with imiquimod 5% cream and lapacho tea dressings alike. CONCLUSIONS: Very little is known about the potential antiinflammatory or antiproliferative effects on the epidermis of the popular phytotherapeutic agent lapacho tea. More studies are warranted considering both the etiology and treatment of GEKA and topical use of phytotherapeutics in dermatology in general. Management of large or multiple KAs remains challenging.

APRIL expression is upregulated in atopic dermatitis skin lesions and at sites of antigen driven allergic skin inflammation in mice.

Atopic dermatitis (AD) is the most common inflammatory skin disease. It is characterized by a defective skin barrier and a Th2 dominated skin inflammation. The TNF family member a proliferation-inducing ligand (APRIL) and its receptors transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) are expressed by immune cells and epithelial cells including keratinocytes. We demonstrate that APRIL expression is upregulated in the epidermis of skin lesions from patients with AD as well as in mouse skin undergoing allergic inflammation elicited by epicutaneous (EC) sensitization with the antigen ovalbumin. We show that APRIL from OVA sensitized mouse skin causes keratinocytes to upregulate the expression of IL-6, an inflammatory cytokine implicated in AD pathogenesis. These results suggest a role for APRIL in allergic skin inflammation and a potential role for APRIL blockade in treating AD.

Successful treatment of psoriatic arthritis and comorbid annular atrophic lichen planus with etanercept.

Psoriasis vulgaris and lichen planus are distinct T-cell-driven inflammatory skin diseases. Both present in a variety of clinical subtypes. Mucosal or nail involvement may be present. Here, we report the rare concomitant clinical presentation of psoriatic arthritis and annular atrophic lichen planus on the trunk of a 52-year-old male patient. Treatment with sulfasalazine failed to control inflammatory activity; methotrexate and leflunomide were ceased due to side-effects. After confirmation of both diagnoses, we initiated a tumor necrosis factor (TNF)-α-directed therapy with the fusion protein etanercept resulting in significant improvement of both conditions. This case report aims to highlight the rare colocalization of psoriasis and lichen planus, the rare entity of annular atrophic lichen planus, and to discuss a possible beneficial impact of certain TNF-α inhibitors on subtypes of lichen planus.

High expression of B lymphocyte stimulator in lesional keratinocytes of patients with cutaneous lupus erythematosus.

Belimumab, an anti-B lymphocyte stimulator (BLyS) monoclonal antibody, is approved for systemic lupus erythematosus; however, it is unclear if it can be used to treat specific skin lesions in this disease. In this analysis, we investigated the expression of BLyS and its receptors in skin lesions of different subtypes of cutaneous lupus erythematosus (CLE) using immunohistochemistry and gene expression analyses. Compared to healthy controls, the expression of BLyS was significantly higher in skin lesions of all included CLE subtypes. Similar results were seen for the BLyS receptors BAFF-R and BCMA. Moreover, CLE-typical pro-inflammatory mediators (immunostimulatory DNAs) significantly enhanced the BLyS expression of keratinocytes in vitro. This study suggests a potential role for BLyS as therapeutic target in the treatment of CLE skin lesions.

The role of histological presentation in erythroderma.

BACKGROUND: Erythroderma is a serious medical condition characterized by inflamed red skin involving over 90% of the body. It can be the common presentation of different diseases, therefore clinical diagnosis can be problematic. Controversial data are reported regarding the diagnostic value of histological examination in erythroderma subjects. METHODS: A retrospective study was performed, investigating histological skin specimens of patients with a clinical diagnosis of erythroderma admitted to the Department of Dermatology of State Pediatric Medical University, Saint Petersburg, from 2001 to 2014. Histopathology examination was performed in each case by a pathologist with a special interest in the skin disease who was blind to any clinical information as well as to final diagnosis. RESULTS: Blinded histopathology examination alone was able to give the correct diagnosis in 61% (n = 50/82) of cases when compared to final diagnosis. A diagnosis of psoriasis was made in 23.2% (n = 19/82) of subjects, spongiotic dermatitis/eczema in 20.7% (n = 17/82), mycosis fungoides in 8.5% (n = 7/82), and drug eruption in 8.5%; histological diagnosis was inconclusive or not matching the final diagnosis when available in the remaining 39.1% of cases (n = 32/82). CONCLUSION: Erythroderma remains a condition difficult to study and treat. We showed that a correct judgment about its cause can be based on objective histopathological criteria in up to 60% of cases. More studies are needed to try to find out further histological and/or immunohistochemical markers that could help the clinician with the erythroderma etiology diagnostic process.

IL-36γ (IL-1F9) is a biomarker for psoriasis skin lesions.

In recent years, different genes and proteins have been highlighted as potential biomarkers for psoriasis, one of the most common inflammatory skin diseases worldwide. However, most of these markers are not only psoriasis-specific but also found in other inflammatory disorders. We performed an unsupervised cluster analysis of gene expression profiles in 150 psoriasis patients and other inflammatory skin diseases (atopic dermatitis, lichen planus, contact eczema, and healthy controls). We identified a cluster of IL-17/tumor necrosis factor-α (TNFα)-associated genes specifically expressed in psoriasis, among which IL-36γ was the most outstanding marker. In subsequent immunohistological analyses, IL-36γ was confirmed to be expressed in psoriasis lesions only. IL-36γ peripheral blood serum levels were found to be closely associated with disease activity, and they decreased after anti-TNFα-treatment. Furthermore, IL-36γ immunohistochemistry was found to be a helpful marker in the histological differential diagnosis between psoriasis and eczema in diagnostically challenging cases. These features highlight IL-36γ as a valuable biomarker in psoriasis patients, both for diagnostic purposes and measurement of disease activity during the clinical course. Furthermore, IL-36γ might also provide a future drug target, because of its potential amplifier role in TNFα- and IL-17 pathways in psoriatic skin inflammation.

Ultraviolet light protection by a sunscreen prevents interferon-driven skin inflammation in cutaneous lupus erythematosus.

Irradiation with ultraviolet (UV) light is an important exacerbating factor in cutaneous lupus erythematosus (CLE) and induces various effects in the skin of patients with the disease, such as cell death and inflammation. Recently, we demonstrated the ability of a broad-spectrum sunscreen to prevent UV-induced damage both in patients with CLE and healthy controls (HCs). The aim of this study was to evaluate whether the UV-dependent activation of interferon (IFN)-driven inflammation in CLE can also be prevented by application of the sunscreen. In 20 patients with different subtypes of CLE and 10 HCs, defined areas on the upper back were treated with a broad-spectrum liposomal sunscreen 20 min prior to a combined standardized UVA/UVB irradiation. Immunohistological analyses using antibodies directed against MxA, CD11c, CD123 and CD68 were performed from skin biopsies taken from areas before UV irradiation as well as from sunscreen-treated and sunscreen-untreated areas 24 and 72 h after UV irradiation. The expression of MxA was completely prevented by the sunscreen applied prior to UV irradiation in CLE patients and HCs. Additionally, sunscreen protection significantly diminished the number of the CD11c- and CD123-positive dendritic cells, which are suggested to be a major source of type I/III IFNs, in UV-irradiated skin of patients with CLE. Moreover, the application of the sunscreen prevented the increase in CD68-positive macrophages in both groups 72 h after UV irradiation. The data of this study demonstrate that UV protection reduces lesional tissue damage and inhibits the typical IFN-driven inflammatory response in CLE.

Low-dose methotrexate - a therapeutical kick in TNF-alpha antagonist treatment for recalcitrant psoriasis vulgaris.

In contrast to the treatment of rheumatoid arthritis, there are few data in psoriasis vulgaris regarding the efficacy of combining tumor necrosis factor (TNF)-alpha inhibitors and methotrexate (MTX). Indeed, combination of MTX with different TNF-alpha inhibitors may enhance the therapeutic effects and reduce side effects because of less dosage of the single agent. The present authors present five cases in which low-dose MTX combined with TNF-alpha inhibitors led to impressive improvement in Psoriasis Area and Severity Index scores. Here, the present authors initiated very low-dose MTX treatment in addition to existing TNF-alpha inhibitor therapy to exhaust current therapy and prevent premature change of the biologic. These observations support the concept of combined treatment in recalcitrant cases of psoriasis, which need a systemically lifelong treatment when both first-line and second-line monotherapies fail to provide sufficient clinical response.

Real-time tissue elastography as promising diagnostic tool for diagnosis of lymph node metastases in patients with malignant melanoma: a prospective single-center experience.

BACKGROUND: Real-time tissue elastography is a new, noninvasive method in ultrasonography, differentiating tissues according to their stiffness. Earlier studies have highlighted this technique as a useful diagnostic tool for the detection of noncutaneous malignancies like breast, prostate and thyroid cancer based on the principle that tumor cells present a higher stiffness compared to the adjacent normal tissue. OBJECTIVE: The purpose of our study was to investigate the value of real-time tissue elastography for the differentiation of benign and metastatic peripheral lymph nodes (LN) in patients with cutaneous melanoma by comparing this technique with conventional B-mode sonography combined with power Doppler sonography (PDS). METHODS: In this prospective study, 36 melanoma patients (23 females and 13 males, mean age 62.7 ± 11.1 years) undergoing LN excision at the Department of Dermatology and Allergy, University of Bonn, were included between July 2011 and July 2012. Real-time tissue elastography was planned prior to surgery and histopathological examination. Elasticity images had been qualitatively scored for the proportion of stiff areas from pattern 1-5 (soft to stiff) on the basis of a newly defined system for LNs. RESULTS: A total of 42 LNs have been removed in 36 patients. Of these 42 LNs, 21 carried melanoma cells and 21 were benign LNs. Significant differences in elastographic patterns were found between metastatic and nonmetastatic LNs. In real-time tissue elastography, 19 (90.5%) of 21 metastatic LNs showed a pattern of 3, 4 or 5. Of all benign LNs, 76.2% had a pattern of 1 or 2 in their elastogram. Sensitivity and specificity of B-mode sonography combined with PDS were 80.9 and 76.2%, respectively, 90.5 and 76.2% for elastography and 95.2 and 76.2% for the combined evaluation. CONCLUSION: An elastography pattern ≥3 was identified as an independent significant factor, predicting a metastatic LN involvement. The combination of elastography with conventional B-mode sonography has the potential to further improve the differentiation between benign and metastatic peripheral LNs in melanoma patients.

Role of high-resolution ultrasound and PET/CT imaging for preoperative characterization of sentinel lymph nodes in cutaneous melanoma.

The purpose of our study was the comparison of high-resolution ultrasound (HRUS) and positron emission tomography combined with computerised tomography (PET/CT) in the preoperative characterization and identification of subclinical nodal metastases focusing on sentinel lymph nodes (SLN) in melanoma patients. Patients with cutaneous melanoma (CM) who received sentinel lymph node biopsy at the Department of Dermatology and Allergy, University of Bonn, between January 2009 and January 2011 had been evaluated with a retrospective computer-aided search concerning preoperative staging procedures. A combination of PET/CT and HRUS had been performed preoperatively in 20 of 123 patients. A total of 59 SLNs had been removed in those 20 patients followed by histopathologic examination. HRUS correctly identified two of 17 positive SLNs whereas PET/CT imaging identified none. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of HRUS were 11.8 % (95 % confidence interval [CI] = 3.3-34.3), 100 % (95 % CI = 91.6-100.0), 100.0 % (95 % CI = 34.2-100.0), and 73.7 % (95 % CI = 61.0-83.3), respectively. On the basis of this limited study cohort, HRUS had a better value than PET/CT in preoperative identification of positive SLNs, suggesting a possible diagnostic superiority of HRUS in general characterization of peripheral nodal disease in CM.

Suppression of UV-induced damage by a liposomal sunscreen: a prospective, open-label study in patients with cutaneous lupus erythematosus and healthy controls.

This study aimed to determine whether a broad-spectrum liposomal sunscreen with a very high sun protection factor (Daylong actinica) can prevent damage induced by ultraviolet (UV) irradiation in patients with cutaneous lupus erythematosus (CLE) and healthy controls (HCs) under standardised conditions. In 20 patients with CLE and 10 HCs, defined areas of sunscreen-untreated and sunscreen-treated skin on the upper back were irradiated with combined UVA/UVB light. Disease-specific skin lesions were induced by UVA/UVB light in the untreated areas of nine patients with CLE; no specific eruptions or any sun damage was observed in the sunscreen-treated areas in any of the CLE patients, nor in the HCs. Histological analysis of skin biopsy specimens confirmed the clinical results. In conclusion, the use of a high-protection, broad-spectrum sunscreen can prevent UV-induced damage in patients with CLE and HCs.

Sentinel lymph node status as most important prognostic factor in patients with high-risk cutaneous melanomas (tumour thickness >4.00 mm): outcome analysis from a single institution.

PURPOSE: Sentinel lymph node biopsy (SLNB) is considered the most powerful prognostic indicator of survival in patients with cutaneous melanoma of intermediate thickness (1-4 mm). The use of SLNB in patients with melanoma with a tumour thickness >4.0 mm is still controversial. The purpose of the current study was to determine the prognostic value of SLNB in patients with thick cutaneous melanomas (tumour thickness >4.0 mm) in terms of progression-free survival (PFS) and overall survival (OS). METHODS: A retrospective single-centre study was performed at the Department of Dermatology and Allergy, University of Bonn, and the Department of Nuclear Medicine, University of Bonn, based on data collected between September 2000 and January 2010. A total of 142 patients with cutaneous melanoma of thickness >4.00 mm were identified, and 63 of these patients underwent SLNB. RESULTS: Of the 63 patients in whom SLNB was performed, 25 (39.7 %) had a positive SLN. Ulceration was more frequent in SLN-positive patients (44 %) than in SLN-negative patients (18.4 %). The mean follow-up time for the 63 patients was 50.7 months. Positive SLN status predicted a significantly reduced life expectancy in the analyses of PFS and OS. In SLN-positive patients 5-year OS was 76 % and in SLN-negative patients was 84.2 % (p = 0.048). Patients with a combination of ulcerated tumour and positive SLN had the worst prognosis. CONCLUSION: On the basis of our follow-up data, SLNB has to be recommended in patients with a tumour thickness >4.00 mm after exclusion of lymph node macrometastases or distant metastases. SLN status is the most significant prognostic factor in this group of patients.

High-resolution ultrasound combined with power Doppler sonography can reduce the number of sentinel lymph node biopsies in cutaneous melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a widely accepted procedure to accurately stage patients with cutaneous melanoma. Disadvantages of the SLNB procedure are the overall costs and potential side effects of the operation [J Dtsch Dermatol Ges 2009;7:318-327; J Am Dermatol 2010;62:737-748]. OBJECTIVE: The purpose of our study was to evaluate whether high-resolution ultrasound combined with power Doppler sonography (PDS) is an appropriate tool for preoperative identification and characterization of sentinel lymph nodes (SLNs) in patients with cutaneous melanoma. METHODS: In a prospective study eighty-one consecutive patients with cutaneous melanoma (33 females and 48 males) in whom dissection of SLNs was indicated underwent ultrasound examinations before and after the preoperative lymphoscintigraphy. RESULTS: A total of 170 SLNs (mean 2.1 per patient) were removed and examined by histopathology. High resolution ultrasound combined with PDS correctly identified 2 of 9 positive SLNs. The sensitivity, specificity, positive predictive value, and negative predictive values of ultrasound were 22.2% (95% confidence interval (CI) = 2.8-60.0), 100% (95% CI = 97.7-100.0), 100.0% (95% CI = 15.8-100.0), and 95.8% (95% CI = 91.6-98.3), respectively. CONCLUSIONS: Although high-resolution ultrasound combined with PDS cannot substitute SLNB, this technique offers earlier diagnosis of lymph node involvement in a small subgroup of patients (with subcapsular location of metastases), and introduces the possibility to exclude those patients from SLN procedure and directly prepare them for complete lymph node dissection (CLND).