Cutaneous findings following COVID-19 vaccination: review of world literature and own experience.

There is growing evidence that not only the novel coronavirus disease (COVID-19) but also the COVID-19 vaccines can cause a variety of skin reactions. In this review article, we provide a brief overview on cutaneous findings that have been observed since the emerging mass COVID-19 vaccination campaigns all over the world. Unspecific injection-site reactions very early occurring after the vaccination are most frequent. Type I hypersensitivity reactions (e.g. urticaria, angio-oedema and anaphylaxis) likely due to allergy to ingredients may rarely occur but can be severe. Type IV hypersensitivity reactions may be observed, including delayed large local skin lesions ("COVID arm"), inflammatory reactions in dermal filler or previous radiation sites or even old BCG scars, and more commonly morbilliform and erythema multiforme-like rashes. Autoimmune-mediated skin findings after COVID-19 vaccination include leucocytoclastic vasculitis, lupus erythematosus and immune thrombocytopenia. Functional angiopathies (chilblain-like lesions, erythromelalgia) may also be observed. Pityriasis rosea-like rashes and reactivation of herpes zoster have also been reported after COVID-19 vaccination. In conclusion, there are numerous cutaneous reaction patterns that may occur following COVID-19 vaccination, whereby many of these skin findings are of immunological/autoimmunological nature. Importantly, molecular mimicry exists between SARS-CoV-2 (e.g. the spike-protein sequences used to design the vaccines) and human components and may thus explain some COVID-19 pathologies as well as adverse skin reactions to COVID-19 vaccinations.

Prompt response of advanced cutaneous squamous cell carcinoma to cemiplimab in a kidney transplant patient receiving treatment with everolimus.

The safety and efficacy of immune checkpoint inhibitors in solid organ transplant recipients (SOTR) are unclear, as SOTR are usually excluded from clinical investigations due to their high risk for irreversible allograft rejection. We observed a kidney transplant patient with metastatic cutaneous squamous cell carcinoma who experienced complete response under anti-tumour therapy using cemiplimab and prevention of transplant rejection by fixed dose everolimus.

Medium-dose ultraviolet (UV) A1 vs. narrowband UVB phototherapy in atopic eczema: a randomized crossover study.

BACKGROUND: Ultraviolet (UV) A1 and narrowband (NB)-UVB have been reported to be effective treatments for atopic eczema (AE). OBJECTIVES: We aimed to compare the efficacy of medium-dose UVA1 and NB-UVB mono-phototherapy in patients with AE. METHODS: A randomized double-blind controlled crossover trial (ClinicalTrials.gov Identifier: NCT00419406) was conducted in which patients with AE received a 6-week course of both medium-dose UVA1 and NB-UVB. Clinical efficacy was assessed using the Six Area, Six Sign, Atopic Dermatitis (SASSAD) score and a visual analogue scale for pruritus. Assessment of health-related quality of life was performed using the Skindex-29. Total immunoglobulin E (IgE) and eosinophilic cationic protein (ECP) were evaluated at baseline and after each phototherapy course. RESULTS: Twenty-eight patients who completed both UVA1 and NB-UVB phototherapy courses on an intention-to-treat basis were analysed according to the crossover design. Both interventions were associated with significant clinical improvement but there was no significant difference between treatments with respect to the mean +/- SD relative reduction (RR) of the clinical scores (SASSAD, 43.7 +/- 31.4% vs. 39.4 +/- 24.1%, P = 0.5; pruritus score, 16 +/- 61.8% vs. 25.2 +/- 30.5%, P = 0.5, respectively). There was no significant difference in the mean +/- SD RR of the Skindex-29 after UVA1 and NB-UVB phototherapy (12.7 +/- 18.8% vs. 16.5 +/- 17.6%, P = 0.1). Changes in the total IgE and ECP levels following UVA1 and NB-UVB did not differ significantly (P = 0.3 and P = 0.9, respectively). CONCLUSIONS: A 6-week course of NB-UVB and UVA1 phototherapy of AE resulted in significant clinical improvement. With regard to efficacy and tolerability, both phototherapeutic modalities may be considered comparably good.

[First manifestation of psoriasis vulgaris in tumor necrosis factor receptor-associated periodic syndrome during treatment with etanercept]. / Erstmanifestation einer Psoriasis vulgaris bei Tumornekrosefaktor-Rezeptor-1-assoziiertem periodischem Syndrom unter Therapie mit Etanercept.

Drugs antagonizing tumor necrosis factor (TNF) alpha have been increasingly and successfully used in the treatment of psoriasis vulgaris and psoriatic arthritis. We report a patient with TNF receptor 1-associated periodic syndrome (TRAPS) who received TNF-alpha antagonist etanercept. A month later, the patient developed for the first time generalized psoriasis vulgaris. This paradoxical phenomenon has been reported sporadically in patients receiving TNF-alpha antagonists for other inflammatory diseases. The cause of psoriasis induced by TNF-alpha antagonists is still obscure.

Increased expression of TGF-beta/Smad proteins in basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer in humans placing a significant burden on healthcare services worldwide. There is an increasing evidence that the development of cutaneous epithelial tumours is pathogenetically linked to dysregulations of the transforming growth factor beta (TGF-beta) and its signalling molecules, the Smads. OBJECTIVE: In the present study we aimed to investigate the mRNA as well as protein expression of TGF-beta/ Smad signalling proteins in patients with BCC and healthy controls. METHODS: In this prospective pilot study, 24 patients with BCC were recruited. Punch biopsies were harvested from the centre of the tumour (lesional) as well as an adjacent healthy skin site (non-lesional controls). In addition to the specimens of BCC patients, skin samples (healthy controls) were obtained from subjects who had no history of skin cancer (n = 25). Real-time RT-PCR as well as immunohistochemistry was performed. - RESULTS: The mRNA levels of TGF-b/Smad transducers observed in healthy controls did not significantly differ from TGF-beta/Smad levels observed in non-lesional skin of BCCs patients (P > 0.05). RT-PCR revealed significant mRNA overexpression of TGF-beta1, Smad3, and Smad7 in BCCs as compared to non-lesional skin (P < 0.05). TGF-beta1 mRNA expression significantly correlated with Smad3 (r = 0.60; P < 0.05) and Smad7 (r = 0.76; P < 0.05) levels. Immunohistochemistry demonstrated marked protein overexpression of Smad3 in tumour tissue as compared to non-lesional skin. CONCLUSIONS: Our data suggest a possible role of TGF-beta/Smad signalling in the pathogenesis of BCC.

Quantification of ultraviolet protective effects of pityriacitrin in humans.

Pityriacitrin (PIT), produced by Malassezia yeasts, is an UV absorbing substance that might cause hypopigmentation in pityriasis versicolor alba. We aimed to investigate the UV protective effect of PIT in humans using in vitro and in vivo test methods. Spectrophotometry of PIT cream and the vehicle was performed in the wavelength range from 290 to 400 nm. UV transmission and the sun protection factor (SPF) were assessed for different cream formulations. Using colorimetry we evaluated erythema and pigmentation following irradiation of cream-protected and non-protected skin of healthy subjects. UVB as well as UVA transmission decreased with increasing PIT concentrations. An increase of PIT concentration of 1.25, 2.5, and 5% was associated with slightly increasing SPFs of 1.4, 1.5, and 1.7, respectively. Our in vivo tests confirmed the validity of the SPF of PIT 5% cream determined in vitro. In conclusion, the UV protective effect of PIT is all in all very weak suggesting that PIT is likely only an inferior cofactor in the development of hypopigmentation in pityriasis versicolor alba lesions following sun exposure.

Optical coherence tomography of cutaneous lupus erythematosus correlates with histopathology.

Diagnosis of cutaneous forms of lupus erythematosus (LE), including chronic discoid LE (CDLE) and subacute cutaneous LE (SCLE), is usually based on characteristic clinical and histopathological findings. We aimed to visualize morphological changes in lesions of cutaneous LE using optical coherence tomography (OCT), and to correlate the OCT findings with histopathology. Six patients with CDLE and five patients with SCLE were investigated. Prior to skin biopsy, OCT assessment was performed on previously marked lesions. The images of OCT and corresponding histology were evaluated side-by-side on the PC screen. The thickening and disruption of the entrance signal in OCT images correlated with the hyperkeratosis which was observed in the histological sections. Atrophy of the epidermis, which was demonstrated by histology, could also be detected in the OCT pictures showing a thinned layer below the entrance signals. On OCT, a patchy reduction of reflectivity was observed in the upper dermis corresponding to dense patchy, partly lichenoid, lymphocytic infiltrates and oedema of the upper dermis. Furthermore, OCT images displayed increased signal-free cavities which histopathologically corresponded to dilated vessels in the upper dermis. All OCT parameters studied significantly (P < 0.05) correlated with histopathological features as indicated by coefficients of correlation ranging from 0.55 to 0.94. OCT enables to demonstrate micromorphological changes in cutaneous LE which correlate with histopathological findings. Nevertheless, the current technique does not allow one to visualize definite diagnostic features of cutaneous LE. However, OCT may be a promising method for objective monitoring of LE activity and treatment effects over time in vivo.

Immunohistology of amicrobial pustulosis of the folds.

Amicrobial pustulosis of the folds (APF), is a rare pustular eruption, predominantly involving the cutaneous folds, the external auditory canals and the scalp, occurring in patients who exhibit a wide spectrum of autoimmune abnormalities. There is a lack of data on the immunohistology of APF. We report a new case of APF associated with features of systemic lupus erythematosus (LE). Extensive immunohistological examinations of lesional and nonlesional skin were performed. The results of our immunohistological studies indicate that immunostaining with p53, Bcl-2, and CD8 antigens could be useful in differentiating APF from closely related inflammatory conditions such as psoriasis and cutaneous LE. However, studies on a larger sample size including controls are needed to substantiate our findings.

Epidermal thickness assessed by optical coherence tomography and routine histology: preliminary results of method comparison.

BACKGROUND: Optical coherence tomography (OCT) is a promising non-invasive imaging technique for studying the epidermis and upper dermis in vivo. As proposed previously by Welzel et al. (J Am Acad Dermatol 1997; 37: 958-963), distance measurements between the entrance peak and the second peak of the A-scan seem to correspond to epidermal thickness (ET). However, there is a lack of systematic studies comparing OCT with histology. METHODS: Sixteen healthy subjects were included in this pilot study. OCT assessments were conducted on the upper back. To determine ET by OCT, the distance between the entrance peak and the second peak of the A-scan was calculated (ET-OCT). After OCT measurement a 4 mm punch biopsy was taken on each subject from the same site previously assessed. The maximum thickness of the epidermis (ET-Histo) was determined microscopically using routine histological slices (formalin-paraffin technique, haematoxylin-eosin staining). Correlation and agreement between the two methods were assessed by means of the Pearson correlation procedure and Bland-Altman plots, respectively. RESULTS: ET-Histo was 79.4 +/- 21.9 microm, including a stratum corneum thickness of 20 +/- 12.1 microm. OCT measurements resulted in an ET of 106 +/- 15.4 microm. No correlation between ET-Histo and ET-OCT was observed (r = 0.29, P = 0.27). There was a considerable lack of agreement between histology and OCT measurements as expressed in a high bias of 26.63 microm [95% confidence interval (CI) 14.49-38.77]. Furthermore, the lower 95% limits of agreement were -18.03 microm (95% CI -37.11 to 1.05) and the upper 95% limits of agreement were 71.28 microm (95% CI 52.2-90.36) indicating that ET-OCT may be 71.28 microm above or 18.03 microm below ET-Histo. CONCLUSIONS: Our preliminary data suggest that the above-described OCT algorithm is probably not a valid measure for the evaluation of ET. The second peak of the A-scan seems not to correspond to the dermo-epidermal junction zone, but rather to fibrous structures in the upper dermis. Nevertheless, further systematic comparison studies between OCT and histology are warranted, using different OCT algorithms for ET determination and cryopreparation, which has a higher reliability than the formalin-paraffin technique.

UVA1 and UVB irradiated skin investigated by optical coherence tomography in vivo: a preliminary study.

In histological studies, it has frequently been demonstrated that ultraviolet (UV) exposure, in particular UVB, can induce significant thickening of the viable epidermis and/or stratum corneum. Since skin biopsy alters the original skin morphology and always requires an iatrogenic trauma, we aimed to introduce optical coherence tomography (OCT) in vivo for the investigation of changes of epidermal thickness (ET) following UVA1 and UVB irradiation. Twelve healthy subjects received daily 60 J/cm2 of UVA1 and 1.5 minimal erythema doses UVB on their upper back over 3 consecutive days. Twenty-four hours after the last irradiation, OCT assessments were performed on UV exposed and adjacent nonirradiated control sites. Data of ET as expressed by comparison of the averaged A-scans differed significantly between nonirradiated (94.2 +/- 15.7 microm), UVA1 (105.4 +/- 12.8 microm) and UVB (125.7 +/- 22.1 microm) exposed sites. In comparison to the nonirradiated sites, UVA1 exposed skin showed significant (P = 0.022) increase of ET of 11% and UVB exposed sites a significant (P < 0.001) increase of 25%. ET of UVA1 and UVB exposed skin sites differed significantly (P =0.005). Our results obtained from OCT in vivo measurements confirm data of previous histological studies indicating that not only erythemogenic doses of UVB, but also suberythemogenic doses of UVA1 may have a significant impact on ET. OCT appears to be a promising bioengineering technique for photobiological studies. However, further studies are needed to establish its measurement precision and validity, and to investigate in vivo spectral dependence on UV induced skin changes such as skin thickening.

Immunohistochemical investigation of mid-dermal elastolysis.

We report a 31-year-old Caucasian woman presenting with remarkable wrinkling on her trunk and proximal extremities. Diagnosis of mid-dermal elastolysis (MDE) was confirmed by Van Gieson's staining. Immunohistochemical investigations revealed enhanced expression of CD34+ and CD68+ cells accompanied by slightly increased expression of CD3+ and CD4+ lymphocytes in lesional skin. Furthermore an elevated cellular expression of matrix metalloproteinase (MMP)-1 and slightly increased presence of MMP-12 positive cells combined with a decrease of tissue inhibitor of metalloproteinases 1 (TIMP-1) positive cells was observed in lesional skin as compared with a control specimen obtained from nonlesional skin. Our data may indicate inflammatory processes and an altered balance between MMPs and TIMPs in MDE. Furthermore CD34+ dendritic fibroblasts and/or histiocytes are possibly involved in the pathogenesis of MDE.

Hepatitis B-assocciated adult-onset Still's disease presenting with neutrophilic urticaria.

Adult-onset Still's disease (AOSD) is an uncommon systemic inflammatory disorder that is characterized by quotidian fever, articular manifestations, neutrophilic leukocytosis, and maculopapular rash. The aetiology of the disease is unknown, however, an infectious cause has been suggested. Here we describe a patient in whom neutrophilic urticaria was the cutaneous manifestation of AOSD. In addition, the patient suffered from chronic hepatitis B infection that may be a potential trigger factor of AOSD. In patients with AOSD, serological investigations for detection of infection should include hepatitis serology. Further, we suggest that urticarial lesions may be a more common cutaneous manifestation of AOSD than has been recognized previously. Thus it is important to include AOSD in the differential diagnosis of urticaria.

Antibodies to human recombinant tissue transglutaminase measured by radioligand assay: evidence for high diagnostic sensitivity for celiac disease.

Celiac disease is associated with endomysial antibodies (EmA), which have recently been reported to be directed to tissue transglutaminase (tTG). To demonstrate binding of antibodies to recombinant tTG, human tTG was cloned, expressed by in vitro transcription/translation and used to develop novel radioligand assays for combined and single detection of immunoglobulin A (IgA) and G (IgG)-specific antibodies. IgA and IgG-tTGA were found in 43 (95.6%) of 45 patients with newly-diagnosed celiac disease verified by biopsy. In addition, all 30 sera from patients with gastrointestinal symptoms and positive EmA were positive for IgA-tTGA, and all but one serum (96.7%) had antibodies of the IgG class. Receiver-operating characteristic analysis including 574 sera from healthy controls revealed a specificity of 99.5%. By means of these new assays, we identified all patients with endomysial antibodies and achieved, at equal specificity, an even improved sensitivity (95.6%) as compared to EmA (91.1%) detected by the standard immunofluorescence test. Here, we have provided direct evidence that recombinant tTG is a major target of antibodies in celiac disease. Our data suggest that tTGA measured by radioligand assay have the power to overcome the limitations of the EmA-test. This new strategy may considerably facilitate large-scale screening for silent and latent celiac disease.