The impact of lesional inflammatory cellular infiltrate on the phenotype of bullous pemphigoid.

BACKGROUND: The influence of cutaneous cellular infiltration on the phenotype of bullous pemphigoid (BP) remains to be established. OBJECTIVES: To evaluate the main histopathological characteristics of patients with BP and to assess the association between the composition of lesional inflammatory infiltrate and the various clinical, immunological and immunopathological aspects of the disease. METHODS: Retrospective study encompassing patients diagnosed with BP throughout the years 2009-2020 in a specialized tertiary referral centre. RESULTS: The study encompassed 136 patients with BP, of whom 27 (19.9%) demonstrated a cell-poor inflammatory infiltrate in lesional skin specimens. Overall, 78 (57.4%), 71 (52.2%) and 5 (3.7%) specimens were found to include eosinophil-predominant, lymphocyte-predominant and neutrophil-predominant inflammatory infiltrates, respectively. Relative to the remaining patients with BP, those with an eosinophil-predominant inflammatory infiltrate had higher (90.8% vs. 77.2%; P = 0.030) whilst those with a cell-poor inflammatory infiltrate lower (70.3% vs. 88.7%; P = 0.017) seropositivity of anti-BP180 NC16A IgG. The latter subgroup presented with higher prevalence of mucosal involvement (25.9% vs. 8.3%; P = 0.011) and a non-inflammatory clinical phenotype (50.0% vs. 17.1%; P = 0.041). Patients with lymphocyte-predominant inflammatory infiltrate manifested with higher severity BPDAI scores and a lower frequency of the non-inflammatory subtype (11.1% vs. 36.4%; P = 0.035), whilst those with a neutrophilic infiltrate presented with lower mean (SD) levels of anti-BP180 NC16A IgG [269.3 (227.6) vs. 722.7 (1499.6) U/mL; P = 0.003]. CONCLUSIONS: Eosinophil-predominance and high cellularity in the lesional inflammatory infiltrate of BP skin are associated with increased seropositivity of anti-BP180 NC16A IgG. Lymphocyte-predominant infiltrates predict a more severe phenotype, pointing towards a pathogenic role of autoreactive lymphocytes.

Expression of PD-1 and Tim-3 is increased in skin of patients with bullous pemphigoid and pemphigus vulgaris.

BACKGROUND: Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are common autoimmune bullous dermatoses (AIBD) characterized by blisters and erosions. Treatment options are limited and often insufficient. Immune checkpoint receptors play critical roles in immune homoeostasis and self- tolerance. Targeting checkpoint receptors is highly efficient in treatment of various cancers, but often also associated with autoimmune side effects. OBJECTIVES: We therefore aimed to investigate the expression of immune checkpoint receptors in patients with BP and PV. METHODS: We analysed expression of the checkpoint receptors programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain 3 (Tim-3) and lymphocyte activation gene 3 (Lag-3) in lesional skin of patients with BP and PV compared to healthy control skin as well as the expression patterns of PD-1 and Tim-3 on various infiltrating immune cells in skin sections of AIBD by immunohistochemistry and immunofluorescence. We also measured serum levels of soluble PD-1, Tim-3 and Lag-3 in AIBD patients by ELISA. RESULTS: We report on increased expression of PD-1 and Tim-3, but not Lag-3, in lesional skin of patients with BP and PV. Investigating the expression pattern of PD-1 and Tim-3 on different cutaneous immune cells, we observed significant upregulation of PD-1 predominantly on infiltrating CD8 T cells and upregulation of Tim-3 on CD8 T cells as well as macrophages. CONCLUSIONS: Our results suggest exploring immune checkpoint receptors as novel therapeutic targets using an agonistic approach in autoimmune bullous diseases.

Differentiation between lymphomas and pseudolymphomas of the skin by computerized DNA-image cytometry.

The histologic and immunohistologic differential diagnosis between pseudolymphomas (PL) and malignant lymphomas (ML) of the skin can be difficult. Since DNA cytometry has been found to be of both diagnostic and prognostic value in various neoplasms, its ability to discriminate between ML and PL in Feulgen-stained imprints of 17 PL and 49 ML skin biopsies was examined by high-resolution image analysis. The reliability of the following algorithms of DNA distribution was evaluated: 1) 2cDI (2c-deviation index), which reflects the variation of the nuclear DNA values around the diploid DNA peak; 2) percentage of cells having a DNA value greater than or equal to 5c (5cER; 5c-exceeding rate); 3) percentage of cells presenting with a DNA value greater than or equal to 4c (4cER). A 2cDI of 0.1 was found to be the most reliable marker for the differentiation between PL and ML. On the basis of this feature, 16 of 17 cases of PL and 46 of 49 cases of ML were correctly classified. The sensitivity, specificity, and efficiency of this feature were 94%. A 5cER greater than or equal to 1% had a specificity of 100%, but the sensitivity was only 43%. For the 4cER, a sensitivity of 61% and a specificity of 94% were found. In conclusion, the calculation of the 2cDI and the 5cER based on high-resolution image analysis provided additional helpful diagnostic features, and therefore should be included as a diagnostic tool. If the 5cER is at least 1%, the diagnosis of a ML can be confirmed with a specificity of 100%.

Primary and secondary cutaneous Ki-1+ (CD30+) anaplastic large cell lymphomas. Morphologic, immunohistologic, and clinical-characteristics.

Skin biopsies were collected from 15 patients with cutaneous tumors morphologically similar to Ki-1+ anaplastic large cell (ALC) lymphoma of the lymph nodes, including Ki-1+ ALC lymphoma of childhood. The histology and immunophenotype of these cutaneous tumors are reported and follow-up data on the patients are given. The tumorous infiltrates were composed of large, sometimes very bizarre cells with one nucleolus or multiple nucleoli. All tumor cells expressed the lymphoid cell activation antigen Ki-1 (CD30) in conjunction with CD25 and the beta-chain of the T cell receptor. In 11 patients, Ki-1+ cutaneous tumors developed primarily in the skin. In nine patients, these were restricted to the skin in follow-up periods ranging from 3 months to 6 years. Two patients developed lymph node involvement after 2 months and 2 years, indicating the spreading potential of these cutaneous tumors. Morphologic and immunophenotypical identity of the atypical cells found in primary cutaneous ALC lymphoma, in regressing atypical histiocytosis (RAH), and in lymphomatoid papulosis (LyP) of type A, together with the protracted clinical course in all three conditions, suggests that primary cutaneous ALC lymphoma, RAH, and LyP of type A represent clinical variants of the same lymphoma entity. Secondary development of Ki-1+ ALC skin tumors was observed in two patients with cutaneous T cell lymphomas of mycosis fungoides type. These secondary Ki-1+ ALC lymphomas of the skin showed rapid systemic progression similar to the primary lymphonodal Ki-1+ ALC lymphomas. Concomitant or subsequent occurrence of Ki-1+ ALC tumors in cutaneous T cell lymphomas thus may be a bad prognostic sign.

[Urea in combination with dithranol in treating psoriasis vulgaris]. / Harnstoff in Kombination mit Dithranol zur Therapie der Psoriasis vulgaris.

Dithranol (anthralin) is one of the basic compounds used in the treatment of psoriasis vulgaris. However, in outpatients its use is largely restricted as it may cause discoloration of skin, clothes, and bedding as well as significant skin irritation. The combination of dithranol with urea results in a better benefit/side-effect ratio. Even at relatively low dithranol concentrations (0.1%/0.2%) combined preparations have been found to be effective over several weeks of application. The therapeutic results of such treatment are comparable to those of topical glucocorticosteroid preparations.

Night-time plasma cortisol secretion is associated with specific sleep stages.

Polysomnographic recordings were obtained in 16 healthy male subjects in order to evaluate temporal interrelationships between concentrations of plasma cortisol and sleep at night. The pattern of nocturnal cortisol secretion appeared to be synchronized with the periodicity of sleep: rapid eye movement (REM) sleep was found to be primarily present when cortisol concentrations were decreasing, indicating a diminished or absent secretory activity of the adrenals at that time; wakefulness and Stage 1 sleep, by contrast, were associated with increasing plasma cortisol concentrations. Furthermore, the enhanced adrenal secretory activity usually preceded the occurrence of light sleep or wakefulness, which is in accord with a wakening effect of plasma cortisol. Just prior to the onset of the first pronounced rise in plasma cortisol during sleep, episodes of slow wave sleep (SWS) became more frequent. This suggests that the offset of episodes of SWS may act as a trigger for the first pronounced nocturnal rise in plasma cortisol.

Relationships between sleep stages and plasma cortisol: a single case study.

The relationship between the plasma cortisol level and sleep stages was investigated in a single male subject across 17 nights. Blood samples were taken every 30 min from 11.00 p.m. until 02.30 a.m. and every 15 min during the rest of the night. Data analyses performed for the whole nights did not give evidence for strong relations between plasma cortisol and sleep stages. Analyses on data of the second part of the night, beginning with the onset of the first cortisol peak, revealed that plasma cortisol was primarily decreasing when rapid eye movement sleep (REM) was present. Sleep stage I and periods of wakefulness were associated with increasing cortisol levels. There was no evidence for a particular EEG event triggering the first rise of plasma cortisol during the night.

[Possible prevention of adriamycin-induced cardiomyopathy by verapamil. Results of a pilot study]. / Mögliche Prävention der Adriamycin-induzierten Kardiomyopathie durch Verapamil. Ergebnisse einer Pilotstudie.

An increased cytoplasmatic calcium level seems to play an important role in the pathogenesis of Adriamycin (ADM)-induced cardiomyopathy. Experiments have shown that calcium channel blockers such as verapamil may prevent this type of cardiomyopathy in animals, but data are contradictory. In a clinical pilot trial, the left ventricular function of 22 patients undergoing ADM-chemotherapy in combination with verapamil was examined. M-mode echocardiograms were performed parallel to every chemotherapy course. Left ventricular function was determined by fractional shortening rate (FS) and peak fibre shortening velocity (V ef max.). Three 40-mg doses of verapamil were given p.o./day continuously. Data of these patients were compared with a control group of 61 patients treated and checked equally without additional verapamil therapy. In the course of therapy parameters of left ventricular function remained almost constant in the verapamil group but decreased significantly in the control group. In the verapamil group FS changed by -0.05 FS %/100 mg ADM/m2, V ef max. by +0.015 circ./s/100 mg ADM/m2 compared with -2.31 FS % and -0.33 circ./s in the control group (P 0.01 and 0.001, respectively). In the verapamil group no congestive heart failure occurred and no patient showed FS below 30%, whereas in the control group in 23% (14) of the cases ADM therapy had to be stopped because FS fell below 30%. One congestive heart failure was observed. These clinical results suggest that verapamil may be a useful drug for preventing ADM-induced cardiomyopathy but further investigations are necessary.