HLA class II antigens in Croatian patients with pemphigus vulgaris and their correlation with anti-desmoglein antibodies.

Pemphigus vulgaris (PV) is an acquired autoimmune blistering disease characterized by the production of autoantibodies targeting desmosomal cadherins, primarily desmoglein 1 and desmoglein 3, leading to acantholysis. The etiology of PV is multifactorial, including genetic susceptibility. This retrospective study aimed to evaluate the association of HLA class II alleles and PV and to examine the impact of PV-associated HLA class II alleles on the concentration of anti-desmoglein antibodies. The study group included 30 patients in whom the diagnosis of PV was confirmed by histopathological analysis, immunofluorescence findings, and ELISA testing for detecting antibodies against desmoglein 1 and desmoglein 3. HLA class II alleles were typed by polymerase chain reaction with sequence-specific primers (PCR-SSP). The control group consisted of 190 healthy volunteer blood donors. Data analysis revealed a significantly higher frequency of HLA class II alleles in our population of patients with PV, including HLA-DRB1*04:02, HLA-DRB1*14:54, HLA-DQB1*03:02, HLA-DQB1*05:03, HLA- DQA1*03:01, and HLA-DQA1*01:04, as well as a significantly lower frequency of HLA-DQA1*05:01 compared to the control group. We have also investigated the influence of risk alleles for PV, recognized in almost all study populations, HLA-DRB1*04:02 and HLA-DQB1*05:03, on the concentration of antibodies against desmogleins 1 and 3 in relation to the presence of these alleles. The results showed significantly higher levels of antibodies directed against desmoglein 3 among patients with DRB1*04:02 compared to patients without this allele. No difference was found for anti-desmoglein 1 antibodies. Regarding DQB1*05:03 allele, statistical analysis showed no differences in the concentration of anti-desmoglein antibodies in patients carrying this allele versus those without it.

Histopathological Features of Time-Zero Kidney Biopsy Are Predictive Factors for Posttransplant Anemia.

INTRODUCTION: Posttransplant anemia (PTA) is a common complication of kidney transplantation, associated with reduced graft survival and higher mortality. We aimed to determine the association of PTA with histopathological characteristics of time-zero allograft biopsy and donor clinical characteristics. METHODS: We conducted a retrospective, observational cohort study that included 587 patients who underwent kidney transplantation in our center. Hemoglobin levels were assessed at 6 and 12 months after transplantation, and anemia was defined according to World Health Organization criteria. The kidney allograft time-zero biopsy has been done in all investigated cases. The evaluated histopathological parameters of the kidney allografts included glomerulosclerosis, arteriolar hyalinosis (AH), vascular fibrous intimal thickening (CV), interstitial fibrosis, tubular atrophy, and interstitial fibrosis and tubular atrophy. The Banff Classification of Allograft Pathology criteria were followed to assess the allograft histopathological changes. RESULTS: The prevalence of anemia was 31.3% at 6 months after transplantation and 23.5% at 12 months. There was an association between 20-50% glomerulosclerosis and PTA in both time points, independently from estimated glomerular filtration rate. AH and interstitial fibrosis were identified as independent risk factors for anemia 6 months after transplantation. CONCLUSION: Histopathological features of time-zero kidney biopsy may be predictors of PTA. Among them, our study recognized 20-50% degree of glomerulosclerosis, AH, and CV as the most significant risk factors for PTA.

Coexistence of Lichen Planus Pemphigoides, Palmoplantar Keratoderma of Unna-Thost, and Atopic Dermatitis.

Lichen planus pemphigoides (LPP) is a very rare autoimmune blistering disease associated with lichenoid skin changes. Unna-Thost palmoplantar keratoderma (PKK) is a type of diffuse palmoplantar keratoderma that mostly affects the palms of the hands and soles of the feet. It usually begins in early childhood. We present a unique case of coexistence of LPP, Unna-Thost PPK, and atopic dermatitis (AD). To our knowledge, there are three reported cases of both LPP and Unna-Thost PPK and a few reports of coexistence of Unna-Thost PKK and AD.

Stereological properties of seminiferous tubules in infertile men with chromosomal and genetic abnormalities.

BACKGROUND: Male infertility is caused by genetic anomalies in 15-30% of cases. This study aimed to determine stereological properties of seminiferous tubules in infertile men with genetic anomalies, including Klinefelter Syndrome (KS), Y chromosome microdeletions (MYC) and CFTR gene mutations (CFTR); and to compare them to seminiferous tubules of men with obstructive azoospermia of non-genetic origin (control group). METHODS: The study was conducted on 28 human testis biopsy specimens obtained from 14 patients with MYC, 18 samples from 9 patients with KS, and 6 samples from 3 patients with CFTR. Whenever possible, a bilateral biopsy was included in the study. The control group had 33 samples from 18 patients (3 of them with a solitary testis). Qualitative and quantitative (stereological) analysis of seminiferous tubules (including the status of spermatogenesis, volume, surface area, length and number of tubules) were performed in all groups. RESULTS: Qualitative histological analysis revealed significant impairment of spermatogenesis in KS and MYC, whereas testicular parenchyma was fully maintained in CFTR and control groups. Spermatogenesis was most seriously impaired in KS. All stereological parameters were significantly lower in KS and MYC, compared to the CFTR and control groups. The total volume, surface and length of seminiferous tubules were significantly lower in KS compared with MYC. CONCLUSIONS: Stereological analysis is valuable in evaluating male infertility, whereas qualitative histological analysis can be helpful in assessing sperm presence in testicular tissue of patients with KS or MYK undergoing TESE.

Diagnostic Delays for Non-melanoma Skin Cancers in Renal Transplant Recipients during the COVID-19 Pandemic: What is Hiding Behind the Mask?

Dear Editor, The ongoing pandemic of coronavirus disease 2019 (COVID-19) was declared by the World Health Organization on March 11, 2020, and remains a global challenge. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), transmitted primarily through respiratory droplets and aerosols. Even though the COVID-19 vaccine has become available since December 2020, the main preventive measures still include social distancing, hand washing, and the use of protective face masks. By May 22, 2021, 3,437,545 deaths caused by SARS-CoV-2 have been registered by WHO, confirming the burden of this disease (1). Consequently, the pandemic has become a challenge for health care systems, as they had to be focused on the care of patients with COVID-19. During the first lockdown from March to May 2020, it was advised to postpone clinical visits whenever this could be done without risk. This recommendation was mainly aimed at older patients and those with chronic diseases, as it has been shown that they are at greater risk for complications from COVID-19. Renal transplant recipients (RTRs) are at a greater risk for infections and different cancers due to their permanent immunosuppressive therapy. The most common malignancies in RTRs are skin cancers, particularly non-melanoma skin cancers. It has been estimated that RTRs have a 65-250 times higher risk for cutaneous squamous cell carcinoma (SCC), 10 times higher risk for basal cell carcinoma, and 2-5 times higher risk for melanoma when compared with the general population (2-4). RTRs are at a higher risk for complications from COVID-19, not only because of their immunosuppressive therapy but also because of different comorbidities, such as hypertension, cardiovascular disease, and diabetes mellitus (5). Therefore, RTRs tend to limit their medical visits and postpone clinical examinations for skin cancer screenings. Moreover, during clinical visits the patients are commonly asked to keep their protective masks on, increasing the risk of overlooking their facial skin changes. Herein we present two RTRs who developed skin cancers during the COVID-19 pandemic, and the tumors were diagnosed with a significant delay. Patient 1 A 67-year-old woman with unknown primary kidney disease received a renal allograft from a deceased donor in 2014. The immunosuppressive protocol included antithymocyte globulin induction with tacrolimus, mycophenolate mofetil, and steroid maintenance. In January 2020, she had noticed a reddish squamous lesion on her right cheek, which enlarged slowly. Since there were no other symptoms, she postponed the dermatologic examination. Additionally, she further postponed the visit to her physician during the pandemic as she wanted to avoid social contact as much as possible. One year later, at the nephrologist's examination, she was asked to take off her face mask for a skin check, and two skin tumors on her right cheek were noticed (Figure 1). One lesion was located at the angle of her mandible and presented as a hypertrophic, sharply marginated lesion with central crusting and a diameter of 2 cm. The other lesion was at the right zygomatic region and appeared as a scaly, erythematous lesion with a diameter of 7 mm. The patient was referred to a dermatologist, and a biopsy of both lesions was indicated. The pathohistological analysis revealed cutaneous SCC in situ for the mandibular lesion and actinic keratosis for the zygomatic lesion. SCC in situ has been excised, and actinic keratosis was treated by cryosurgery. Patient 2 A 66-year-old woman received a renal allograft from a deceased donor in 2010 due to chronic glomerulonephritis without biopsy. The immunosuppressive protocol included basiliximab induction with tacrolimus, mycophenolate mofetil, and steroid maintenance. In June 2020, an erosion occurred at her left infraocular area and did not heal but instead gradually enlarged. The patient suspected that the "wound" developed due to the friction from the rim of her eyeglasses. Six months later, the nephrologist noticed the erosion which was 10×5 mm in size with a slightly elevated, pearl-colored margin (Figure 2). The patient was referred to a dermatologist who indicated tumor excision due to suspected basal cell carcinoma. The pathohistological analysis confirmed the clinical diagnosis. DISCUSSION Both presented patients did not inform their family physicians about their skin changes because they avoided all non-nephrological medical visits during the pandemic. The additional reason for the diagnostic delay was the fact that they kept the masks on their faces during most examinations, with the skin lesions behind the mask consequently remaining unnoticed. The problem of diagnostic delay of skin cancers during the COVID-19 pandemic has been recognized by several studies. Canadian authors compared the number of biopsies for skin cancers during the first 15 weeks in 2020 and during the same period in 2019. They found a decrease in the number of biopsies for non-melanoma skin cancers (NMSC) and melanoma of 18% and 27%, respectively (6). A multicenter study performed in northern-central Italy showed that the number of skin cancer (NMSC and melanoma) diagnoses fell by 56.7% in weeks 11 to 20 of 2020 compared with the average number noted in the same periods of 2018 and 2019 (7). Furthermore, a single-center retrospective study in Italy demonstrated that the number of advanced skin cancers surgically treated between May 18 and November 18, 2020, was significantly higher than in the same period in 2019. These findings led the authors to conclude that the surgical excisions were postponed due to the delay in follow-ups, which resulted in increased incidence of advanced skin cancers (8). RTRs are at particular risk of severe consequences from diagnostic delay with regard to skin cancers. Namely, skin cancers in RTRs are more aggressive and are associated with a higher incidence rate of metastases and recurrences than in the general population (9). Therefore, RTRs should be advised to regularly check their skin for potential skin cancer, which includes self-examinations and dermatologic follow-ups.

Parotid metastases of cutaneous squamous cell carcinoma in renal transplant recipients: Case series and literature review.

Cutaneous squamous cell skin carcinoma (cSCC) is the most common skin cancer in renal transplant recipients (RTR). Metastatic potential of cSCC is significantly higher in RTR than in the general population. Parotid metastases (PM) of cSCC are rare, but their prognosis is poor. The present study aimed to investigate the frequency and characteristics of PM of cSCC in our renal transplant cohort. Among 1610 patients who received kidney allografts at our institution in the period from January 1999 to December 2019, 84 patients (5.2%) developed at least one cSCC. Three patients were identified to develop PM within 3 to 6 months after the occurrence of primary cSCC. All PM were discovered by clinical examination and in an advanced stage. Two of them died early after the diagnosis of PMs (after 4 months and 1 year, respectively). In conclusion, immunosuppression is one of the major risk factors for the development of cSCC and its metastases. It contributes to the poor survival of patients with PMs of the cSCC. Our experience emphasizes the need for the employment of the radiological tests in patients with primary high-risk cSCC to evaluate nonpalpable lymph node involvement.

The Role of the Skin Barrier in Periorificial Dermatitis.

Periorificial dermatitis, mostly known as perioral dermatitis, is a benign inflammatory facial dermatosis which can be a severe burden and even disfiguring and psychologically disturbing. The disease still presents a challenge for physicians when it comes to etiology and appropriate therapy. Although a variety of extrinsic and intrinsic factors have been proposed as etiopathogenetic factors, none of these fully explain complex pathogenesis of the disease. There is more evidence that supports beliefs that the epidermal barrier dysfunction is an underlying main pathogenic factor that contributes to persistent cutaneous inflammation in typical facial localizations. Patients with periorificial dermatitis are considered hyper-reactors who have impaired essential function of the skin barrier, especially the skin barrier of the perioral region, characterized by thin permeable stratum corneum and imbalance of intercellular lipids, which makes them more susceptible to various internal and external irritants that contribute to the development of the disease. The verification of this connection reinforces the need for clinicians to address this issue when approaching their patients and formulating the best treatment plan. Treatment should emphasize repairing the impaired skin barrier function to minimize associated skin inflammation and sensitivity, which results in resolution of the objective and subjective symptoms.

Do We Utilize Our Knowledge of the Skin Protective Effects of Carotenoids Enough?

Due to their potential health-promoting effects, carotenoids have drawn both scientific and public attention in recent years. The primary source of carotenoids in the human skin is diet, mainly fruits, vegetables, and marine product, but they may originate from supplementation and topical application, too. In the skin, they accumulate mostly in the epidermis and act as a protective barrier to various environmental influences. Namely, the skin is exposed to numerous environmental factors, including ultraviolet radiation (UVR), air pollution, and smoking, that cause oxidative stress within the skin with consequent premature (extrinsic) aging. UVR, as the most prominent environmental factor, may cause additional detrimental skin effects, such as sunburn, DNA damage, and skin cancer. Therefore, photoprotection is the first line intervention in the prevention of premature aging and skin cancer. Numerous studies have demonstrated that carotenoids, particularly ß-carotene, lycopene, lutein, and astaxanthin, have photoprotective effects, not only through direct light-absorbing properties, but also through their antioxidant effects (scavenging reactive oxygen species), as well as by regulation of UV light-induced gene expression, modulation of stress-dependent signaling, and/or suppression of cellular and tissue responses like inflammation. Interventional studies in humans with carotenoid-rich diet have shown its photoprotective effects on the skin (mostly by decreasing the sensitivity to UVR-induced erythema) and its beneficial effects in prevention and improvement of skin aging (improved skin elasticity and hydration, skin texture, wrinkles, and age spots). Furthermore, carotenoids may be helpful in the prevention and treatment of some photodermatoses, including erythropoietic protoporphyria (EPP), porphyria cutanea tarda (PCT) and polymorphous light eruption (PMLE). Although UVR is recognized as the main etiopathogenetic factor in the development of non-melanoma skin cancer (NMSC) and melanoma, and the photoprotective effects of carotenoids are certain, available studies still could not undoubtedly confirm the protective role of carotenoids in skin photocarcinogenesis.