Alitretinoin as a Treatment Modality for Ichthyosis in Women of Childbearing Age: A Case Series and Review of the Literature.

BACKGROUND: Acitretin, a synthetic vitamin A derivative, is the most studied and widely used oral retinoid for ichthyoses. Its major disadvantage is the need for contraceptive measures during 3 years after discontinuation. An alternative is needed for women of childbearing age. With alitretinoin, another retinoid, pregnancy is considered safe 1 month after discontinuation. OBJECTIVES: The aim of this study was to provide evidence for alitretinoin as an alternative for acitretin for ichthyosis in women of childbearing age. Our experience is shared in a case series combined with an overview of the current literature. METHODS: Nine women of childbearing age (19-31 years, median 21) with different subtypes of ichthyosis (autosomal recessive congenital ichthyosis, (superficial) epidermolytic ichthyosis, erythrokeratoderma variabilis, and epidermolytic epidermal nevi, a mosaic form of epidermolytic ichthyosis) were included and treated with 30 mg alitretinoin during 2-28 months. Severity was measured by Ichthyosis Area Severity Index (IASI) and Investigator Global Assessment (IGA). A literature search in Pubmed using the Mesh terms "alitretinoin," "skin diseases, genetic" and "ichthyosis" was performed. RESULTS: Significant reduction in the mean scores of IGA, IASI-erythema, IASI-scaling, and IASI-total was seen. Seven patients are still being treated, 1 patient stopped to become pregnant, 1 patient discontinued due to financial reasons. Observed side effects were reversible headache (n = 6), asteatotic eczema (n = 1), "not feeling well" temporarily (n = 1), and easier blistering of the feet (n = 1). The literature search resulted in six case reports and case series about alitretinoin in ichthyosis and ichthyosis syndromes with in total 29 patients. The vast majority of articles (21/29) reported significant improvement or even complete remission of skin symptoms. However, validated outcome measures to support these results were lacking. Side effects (n = 16) were relatively mild, except for benign intracranial hypertension (n = 1) and autoimmune hypothyroidism (n = 1). CONCLUSION: Our study shows, with validated outcome measures, that alitretinoin is effective to mitigate the symptoms of ichthyosis in women of childbearing age and a suitable alternative to acitretin.

Paraneoplastic pemphigus: A detailed case series from the Netherlands revealing atypical cases.

BACKGROUND: Paraneoplastic pemphigus (PNP) is an extremely rare life-threatening blistering autoimmune disease that is associated with an underlying neoplasm. There is a set diagnostic criterion for PNP, which is primarily based on a severe stomatitis and the detection of specific antibodies against envoplakin, periplakin and alpha-2-macroglobulin-like protein 1. However, it has become increasingly evident that there are patients with PNP that do not meet all the diagnostic criteria requirements. OBJECTIVES: The aim of this study was to analyse our cohort of Dutch patients and to define the atypical cases that did not meet the diagnostic criteria. METHODS: A retrospective case study of all known Dutch PNP patients of the past 25 years. Patients' clinical and immunological variables were thoroughly analysed and described. RESULTS: Twenty-four patients were included in this study. The results revealed several atypical patient cases that did not completely meet the set diagnostic criteria. Of the 24 patients, two patients presented without stomatitis, in three patients an underlying neoplasm could not be detected, and in two patients the presence of specific autoantibodies could not be demonstrated, although all other criteria for PNP were met. Finally, three of the 24 patients survived the disease. CONCLUSION: Although our findings showed similarities to previous studies and most of the patients met the criteria, there were a few atypical patient cases; highlighting the importance of not strictly adhering to the set criteria when making a diagnosis, as this can lead to a missed or late diagnosis. Thus, it is of crucial importance to combine clinical and elaborate laboratory results to confirm the diagnosis of PNP in suspected patients. Although PNP harbours an unfavourable prognosis in most cases, it might be resolved by timely treatment of the underlying cause.

Patients' and parents' experiences during wound care of epidermolysis bullosa from a dyadic perspective: a survey study.

BACKGROUND: Epidermolysis bullosa is a rare, often severe, genetic disorder characterized by fragility of the skin and mucous membranes. Despite the important role of parents during wound care, an essential factor in adapting to this disease, studies focusing on the parent-child relationship during wound care are scarce. The current study is aimed at addressing this gap. METHODS: A quantitative study among 31 children (n = 21 ≤ 17 years; n = 10 17-25 years) and 34 parents (including 27 parent-child dyads) was conducted to examine the relationship between pain, itch, anxiety, positive and negative feelings, and coping strategies assessed with the newly developed Epidermolysis Bullosa Wound Care List. The majority of the analyses were descriptive and the results were interpreted qualitatively because of the small sample size. RESULTS: Children and parents both showed significantly more positive (i.e. 'protected', 'proud', 'calm', 'connected to each other' and 'courageous') than negative feelings (i.e. 'helpless', 'angry', 'insecure', 'guilty', 'gloomy' and 'sad') during wound care, with parents reporting both feelings more than children. The more children experienced pain, the more they were anxious, had negative feelings, were inclined to use distraction, to postpone wound care and to cry. The more parents experienced feelings (either positive or negative), the more likely they sought distraction. With regard to child-parent dyads the results showed that the more children expressed anxiety, the more parents experienced negative feelings. Furthermore, those who reported more negative feelings were more likely to hide their feelings, while those who reported more positive feelings were more inclined to show their feelings. Pain, itch and anxiety in the child were associated with more distraction or postponement of wound care by the parent. CONCLUSION: This study underlines the importance of paying attention to the relationship between feelings and coping strategies in child-parent dyads in the management of pain and anxiety during wound care. Further research could provide more insight how these feelings and coping strategies are related to the psychological well-being of both the child and the parent in the short term as well as in the long term.

Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa.

Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types. The subtype and severity of EB is linked to the gene involved and the specific variants in that gene, which also determine its mode of inheritance. Current treatment is mainly focused on symptomatic relief such as wound care and blister prevention, because truly curative treatment options are still at the preclinical stage. Given the current level of understanding, the broad spectrum of genes and variants underlying EB makes it impossible to develop a single treatment strategy for all patients. It is likely that many different variant-specific treatment strategies will be needed to ultimately treat all patients. Antisense-oligonucleotide (ASO)-mediated exon skipping aims to counteract pathogenic sequence variants by restoring the open reading frame through the removal of the mutant exon from the pre-messenger RNA. This should lead to the restored production of the protein absent in the affected skin and, consequently, improvement of the phenotype. Several preclinical studies have demonstrated that exon skipping can restore protein production in vitro, in skin equivalents, and in skin grafts derived from EB-patient skin cells, indicating that ASO-mediated exon skipping could be a viable strategy as a topical or systemic treatment. The potential value of exon skipping for EB is supported by a study showing reduced phenotypic severity in patients who carry variants that result in natural exon skipping. In this article, we review the substantial progress made on exon skipping for EB in the past 15 years and highlight the opportunities and current challenges of this RNA-based therapy approach. In addition, we present a prioritization strategy for the development of exon skipping based on genomic information of all EB-involved genes.

Cannabinoid use and effects in patients with epidermolysis bullosa: an international cross-sectional survey study.

BACKGROUND: Epidermolysis bullosa (EB) patient anecdotes and case reports indicate that cannabinoid-based medicines (CBMs) may alleviate pain and pruritus and improve wound healing. CBM use has not been characterized in the EB patient population. OBJECTIVES: To evaluate CBM use among EB patients, including CBM types, effects on symptoms (e.g., pain and pruritus), disease process (e.g., blistering, wounds, and inflammation), well-being (e.g., sleep, appetite) and concomitant medications. METHODS: English-speaking EB patients or caregivers completed an online international, anonymous, cross-sectional survey regarding CBM use. Respondents reported the types of CBMs, subsequent effects including perceived EB symptom alteration, changes in medication use, and side effects. RESULTS: Seventy-one EB patients from five continents reported using or having used CBMs to treat their EB. Missing question responses ranged between 0 (0%) and 33 (46%). Most used more than one CBM preparation (mean: 2.4 ± 1.5) and route of administration (mean: 2.1 ± 1.1). Topical and ingested were the most common routes. Pain and pruritus were reported retrospectively to decrease by 3 points (scale: 0-10; p < 0.001 for both) after CBM use. Most reported that CBM use improved their overall EB symptoms (95%), pain (94%), pruritus (91%) and wound healing (81%). Most participants (79%) reported decreased use of pain medications. The most common side-effect was dry mouth (44%). CONCLUSIONS: CBMs improve the perception of pain, pruritus, wound healing, and well-being in EB patients and reduced concomitant medication use. Nevertheless, a direct relation between the use of CBMs and reduction of the above-mentioned symptoms cannot be proven by these data. Therefore, future controlled studies using pharmaceutically standardised CBM preparations in EB are warranted to delineate the risks and benefits of CBMs.

Paraneoplastic pemphigus associated with post-transplant lymphoproliferative disorder after small bowel transplantation.

BACKGROUND: PNP is a malignancy-associated autoimmune mucocutaneous syndrome due to autoantibodies against plakins, desmogleins, and other components of the epidermis and basement membrane of epithelial tissues. PNP-causing malignancies comprise mainly lymphoproliferative and hematologic neoplasms. PNP is extremely rare, especially in children. METHODS: Here, we present the first case of a child who developed PNP on a PTLD after small bowel transplantation because of a severe genetic protein-losing enteropathy. RESULTS: The patient in this case report had a severe stomatitis, striate palmoplantar keratoderma, and lichenoid skin lesions. In addition, she had marked esophageal involvement. She had lung pathology due to recurrent pulmonary infections and ventilator injury. Although we found no evidence of BO, she died from severe pneumonia and respiratory failure at the age of 12 years. CONCLUSION: It is exceptional that, despite effective treatment of the PTLD, the girl survived 5 years after her diagnosis of PNP. We hypothesize that the girl survived relatively long after the PNP diagnosis due to strong T-cell suppressive treatments for her small bowel transplantation.

The relationship between quality of life and coping strategies of children with EB and their parents.

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare genetic skin disorders that primarily manifest as blisters and erosions following mild mechanical trauma. Despite the crucial role of the parents of children with EB in managing the disease, studies focusing on the parent-child relationship remain a gap in the literature. To address this gap, the current quantitative study, involving 55 children with all types of EB and 48 parents, assessed the relationship between their quality of life and coping strategies. Quality of life was measured with the Pediatric Quality of Life Inventory and TNO-AZL Questionnaire for Adult's Health- related Quality of Life, and coping strategies were assessed with the Coping with a Disease Questionnaire. The majority of the analyses were descriptive and the results were interpreted qualitatively because of the small sample size. RESULTS: Overall, the quality of life of children with EB and that of their parents was somewhat lower compared with the quality of life of healthy children and adults. Children with EB who more frequently used emotional reactions and cognitive-palliative strategies to cope with the disease demonstrated lower levels of emotional and social functioning, while children who showed more acceptance and distancing showed higher levels of functioning on all domains. Parents who frequently demonstrated emotional reactions reported lower levels of social functioning and experienced more depressive emotions and anger. Parents who used more avoidance showed higher levels of positive emotions. Within parent-child dyads, acceptance, cognitive-palliative strategies and distancing were positively related. Children's emotional and social functioning were negatively associated with their parents' depressive emotions. Parents' acceptance was linked to higher physical functioning in children, whereas children's avoidance was linked to a lower level of anger in parents. CONCLUSION: Children who are able to accept the disease or distance themselves from it appear to be better off in contrast to those who tend to engage in the cognitive-palliative strategies and expressing emotional reactions. Parents seem to be better off when they are able to use avoidance in contrast to those who tend to show emotional reactions. Further research is needed to substantiate these findings.

Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19).

Angiotensin-converting enzyme 2 (ACE2) has been established as the functional host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the current devastating worldwide pandemic of coronavirus disease 2019 (COVID-19). ACE2 is abundantly expressed in a variety of cells residing in many different human organs. In human physiology, ACE2 is a pivotal counter-regulatory enzyme to ACE by the breakdown of angiotensin II, the central player in the renin-angiotensin-aldosterone system (RAAS) and the main substrate of ACE2. Many factors have been associated with both altered ACE2 expression and COVID-19 severity and progression, including age, sex, ethnicity, medication, and several co-morbidities, such as cardiovascular disease and metabolic syndrome. Although ACE2 is widely distributed in various human tissues and many of its determinants have been well recognised, ACE2-expressing organs do not equally participate in COVID-19 pathophysiology, implying that other mechanisms are involved in orchestrating cellular infection resulting in tissue damage. Reports of pathologic findings in tissue specimens of COVID-19 patients are rapidly emerging and confirm the established role of ACE2 expression and activity in disease pathogenesis. Identifying pathologic changes caused by SARS-CoV-2 infection is crucially important as it has major implications for understanding COVID-19 pathophysiology and the development of evidence-based treatment strategies. Currently, many interventional strategies are being explored in ongoing clinical trials, encompassing many drug classes and strategies, including antiviral drugs, biological response modifiers, and RAAS inhibitors. Ultimately, prevention is key to combat COVID-19 and appropriate measures are being taken accordingly, including development of effective vaccines. In this review, we describe the role of ACE2 in COVID-19 pathophysiology, including factors influencing ACE2 expression and activity in relation to COVID-19 severity. In addition, we discuss the relevant pathological changes resulting from SARS-CoV-2 infection. Finally, we highlight a selection of potential treatment modalities for COVID-19. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure. METHODS: We screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] <0.001) between patients and controls. To assess the frequency of rare variants in the control population, we evaluated the rare coding variants (MAF <0.001) found in the European cohort of the Exome Aggregation Database. We further evaluated plectin localization by immunofluorescence in a subset of patients with and without a PLEC variant. RESULTS: Forty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants. CONCLUSIONS: Although PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development.