M.M. van Rossum

Quality of life and sexual health in patients with genital psoriasis

Background  Knowledge about quality of life and sexual health in patients with genital psoriasis is limited.

Genital psoriasis: A systematic literature review on this hidden skin disease.

It is well known that the genital skin may be affected by psoriasis. However, little is known about the prevalence and clinical appearance of genital psoriasis, and genital skin is often neglected in the treatment of psoriatic patients. We performed an extensive systematic literature search for evidence-based data on genital psoriasis with respect to epidemiology, aetiology, clinical and histopathological presentation, diagnosis and treatment. Three bibliographical databases (PubMed, EMBASE and the Cochrane Library) were used as data sources. Fifty-nine articles on genital psoriasis were included. The results show that psoriasis frequently affects the genital skin, but that evidence-based data with respect to the efficacy and safety of treatments for genital psoriasis are extremely limited. An advised treatment paradigm for genital psoriasis, based on the levels of evidence, is: first-line: (weak) topical corticosteroids; second-line: vitamin D preparations or tar-based treatments.

Changes in keratin 6 and keratin 10 (co-)expression in lesional and symptomless skin of spreading psoriasis.

Background: Keratin 6 (K6) and keratin 10 (K10) are markers for epidermal hyperproliferation and differentiation, respectively, and are both expressed in the suprabasal layers of the epidermis. They may be co-expressed in different stages of the spreading psoriatic lesion, but single expression can also occur. Objective: To investigate to what extent keratinocytes express K6 and K10, and to what extent they co-express K6 and K10 in different stages of the psoriatic lesion. We studied this in spreading psoriatic plaques. Methods: Three 3-mm punch biopsies were obtained from the inner involved margin of a spreading lesion, from the uninvolved skin immediately adjacent to the spreading plaque, and from the distant uninvolved skin of 8 patients with incipient psoriasis. From 9 healthy volunteers, 3-mm punch biopsies were obtained as controls. After preparation of single cell suspensions of these biopsies, a triple staining protocol was performed with markers for K6 (monoclonal antibody LHK6B), K10 (monoclonal antibody RKSE60) and DNA content (TO-PRO-3 iodide). Subsequently, cells were measured with a flow cytometer and the proportion of the markers was calculated using specific software. Results: We observed a population of K6/K10-co-expressing cells, but also populations expressing only K6. These subpopulations varied with the involvement of the lesion. There was a statistically significant difference between the inner margin and the outer margin with respect to the proportion of K6- and K10-expressing cells, whereas more K6-positive and K10-negative cells were detected in the inner margin of the lesions. The proportion of K6/K10-co-expressing cells in the inner margin was significantly different from the distant uninvolved skin. Conclusion: We confirmed that individual keratinocytes in psoriasis can express K6 or K10 depending on their localization in involved or uninvolved skin. There is a unique subpopulation of cells in the psoriatic plaques which co-express K6 and K10. More studies are required to fully understand the pathogenic relevance of co-expression and single expression of K6 and K10.

HPV-related (pre)malignancies of the female anogenital tract in renal transplant recipients.

Renal transplantations (RTs) are performed routinely in many countries. After RT, the administration of lifelong immunosuppressive therapy is required. As a consequence, renal transplant recipients (RTRs) have a high risk to develop virus-associated (pre)malignancies, such as Human papillomavirus (HPV) related anogenital (pre)malignancies. It is known that the majority of the RTRs are infected with HPV and that these women have a 14-fold increased risk of cervical cancer, up to 50-fold of vulvar cancer and up to 100-fold of anal cancer. Often, treatment of these lesions requires concessions and may be suboptimal as radiation therapy and extensive surgery may damage the renal transplant. Therefore, prognosis may be compromised due to inadequately treated malignancies. Especially for these immunocompromised patients prevention is of utmost importance. Yearly cervical cancer screening for RTRs is advised, but appears to be executed poorly. For the future, optimizing screening and prevention of anogenital (pre)malignancies is an important issue for women after RT. This review gives a broad overview of all aspects regarding HPV-related (pre)malignancies of the female anogenital tract in RTRs.

Early identification of antigen-specific immune responses in vivo by [18F]-labeled 3′-fluoro-3′-deoxy-thymidine ([18F]FLT) PET imaging

Current biomarkers are unable to adequately predict vaccine-induced immune protection in humans with infectious disease or cancer. However, timely and adequate assessment of antigen-specific immune responses is critical for successful vaccine development. Therefore, we have developed a method for the direct assessment of immune responses in vivo in a clinical setting. Melanoma patients with lymph node (LN) metastases received dendritic cell (DC) vaccine therapy, injected intranodally, followed by [18F]-labeled 3′-fluoro-3′-deoxy-thymidine ([18F]FLT) PET at varying time points after vaccination. Control LNs received saline or DCs without antigen. De novo immune responses were readily visualized in treated LNs early after the prime vaccination, and these signals persisted for up to 3 wk. This selective [18F]FLT uptake was markedly absent in control LNs, although tracer uptake in treated LNs increased profoundly with as little as 4.5 × 105 DCs. Immunohistochemical staining confirmed injected DC dispersion to T-cell areas and resultant activation of CD4+ and CD8+ T cells. The level of LN tracer uptake significantly correlates to the level of circulating antigen-specific IgG antibodies and antigen-specific proliferation of T cells in peripheral blood. Furthermore, this correlation was not observed with [18F]-labeled fluoro-2-deoxy-2-d-glucose. Therefore, [18F]FLT PET offers a sensitive tool to study the kinetics, localization, and involvement of lymphocyte subsets in response to vaccination. This technique allows for early discrimination of responding from nonresponding patients in anti-cancer vaccination and aid physicians in individualized decisionmaking.

Genital psoriasis: a questionnaire-based survey on a concealed skin disease in the Netherlands.

Background  Psoriatic lesions may involve nearly all sites of the body. Involvement of the genital skin is frequently classified as part of intertriginous psoriasis without special awareness and treatment for this presentation of the disease. Gaining knowledge about the frequency of the involvement of genital skin in these patients will improve the overall care for patients with psoriasis.

Treatment of psoriasis with a new combination of calcipotriol and betamethasone dipropionate: a flow cytometric study.

Background: Calcipotriol and corticosteroids are established topical antipsoriatics. Previous studies have shown that combined therapy with calcipotriol and betamethasone dipropionate was more effective than monotherapy. In the present study, a recently developed combination product of calcipotriol and betamethasone dipropionate was compared with both monotherapies and the vehicle. Methods: Twenty-five psoriatic patients were treated twice daily with the combination product, monotherapy or vehicle during 4 weeks. Skin biopsies, taken before and after treatment, were analysed using a multi-parameter flow cytometric method. Parameters of inflammation (vimentin-positive cells), normal differentiation (keratin-10-positive cells) and proliferation (cells in SG2M-phase) were assessed. Results: Flow cytometric analysis showed that the combination product turned out to be more effective in reducing inflammation compared with the other treatments. Restoration of normal differentiation was more advanced in patients treated with the combination product or betamethasone dipropionate compared to the vehicle. The highest number of normally differentiated cells was seen after use of the combination product. All treatments, except for the vehicle, decreased hyperproliferation. Conclusion: This study shows that the combination product is a valuable new approach to the treatment of psoriasis.Background: Calcipotriol and corticosteroids are established topical antipsoriatics. Previous studies have shown that combined therapy with calcipotriol and betamethasone dipropiona

Patients’ Experience of Psoriasis in the Genital Area

Background: Psoriasis in the genital area is often neglected, although it bothers a substantial number of patients. Objective: To study both the role of the physician in the treatment of genital psoriasis and the symptom intensity of these lesions as experienced by the patients. Methods: A detailed self-administered questionnaire (containing items on the role of the physician and genital symptom intensity, range 0–10) was filled in by members of the Dutch Psoriasis Society. Results: Data of 277 patients with genital psoriasis were analyzed. A total of 45.8% did not discuss the presence of genital psoriasis with their physician, 25% believed that the physician paid sufficient attention to genital lesions, and 67.8% never applied treatment for genital lesions. Mean symptom intensity ranged from 2.4 to 5.1, all scores being significantly higher for women compared to men. Severe symptoms were present in up to 43.5% of patients. Of these patients, up to 38.1% did not discuss the symptoms with their physician. Conclusion: The consultation rate for genital lesions is low, while numerous patients report a significant burden of disease.

Immunofluorescent surface labelling, flow sorting and culturing of putative epidermal stem cells derived from small skin punch biopsies

Basal keratinocytes of human epidermis strongly express the cell surface glycoprotein beta(1)-integrin, and putatively harbour epidermal stem cells. Selective sorting and culturing of keratinocyte stem cells forms the basis for studies on the role of these cells as targets for therapeutic intervention and gene therapy. Here we have studied variables which affect cell surface labelling for beta(1)-integrin, flow sorting and subsequent culturing of beta(1)-integrin-positive and beta(1)-integrin-negative keratinocytes. Keratinocytes were derived from small human skin punch biopsies (3 or 4 mm in diameter), and we tested a number of variables such as choice of proteolytic enzyme for cell isolation, cell concentration, fixation, storage of fixed cell suspensions and labelling conditions. In contrast to thermolysin treatment for cell isolation, trypsin treatment left most cell surface beta(1)-integrin molecules intact. Ethanol and paraformaldehyde fixation interfered with beta(1)-integrin detection, and unfixed cells gave the best results. Optimisation of all the individual steps resulted in a labelling protocol for reproducible staining and sorting of the cells. Sorted cells were seeded in 96-well plates (300 cells/well) and colonies were obtained in more than 50% of the wells with beta(1)-integrin-positive keratinocytes. In plates with beta(1)-integrin-negative cells, only 10% of the wells contained keratinocyte colonies. Flow sorted keratinocytes obtained by trypsin formed numerous colonies in cell culture experiments. In cell suspensions obtained with thermolysin, only sparse colonies were formed. We conclude that our methodology permits the use of small human tissue samples for cell labelling and sorting, while preserving the clonogenic potential.

VML 295 (LY-293111), a novel LTB4 antagonist, is not effective in the prevention of relapse in psoriasis

Leukotriene B4 (LTB4) receptor antagonists have been the subject of several studies in the treatment of inflammatory diseases, including psoriasis. A novel oral LTB4 antagonist, VML 295 (LY‐293111) has recently been developed and has a pronounced effect on epidermal inflammatory parameters. However, oral treatment of psoriasis for 4 weeks did not result in a decrease in disease severity. The present study was performed in order to investigate whether prolonged treatment with VML 295 up to 8 weeks has a beneficial effect on the overall severity of psoriasis. Moreover, we studied to what extent VML 295 is able to prevent relapse in psoriasis. In the present study, 35 patients with stable chronic plaque psoriasis were included. A representative plaque of at least 16 cm2 was initially treated with clobetasol‐17‐propionate lotion under hydrocolloid occlusion in all patients. Clearance was achieved within 6 weeks in 31 patients. After clearance, the patients were randomized to treatment and received oral VML 295 capsules 200 mg twice daily or placebo for 8 weeks. Twenty‐five patients completed the study. The psoriasis area and severity index (PASI) was assessed before treatment, at clearance, and on days 15, 29, 43 and 57 of the treatment period. Biopsies were taken from the treated lesion before treatment, after clearance and at relapse, and cells were analysed by flow cytometry with markers for differentiation (keratin 10), inflammation (vimentin), and proliferation (DNA content). After 8 weeks of treatment, 14 of 15 VML 295‐treated patients had relapsed and 11 of 16 placebo‐treated patients had relapsed. A total of six patients were withdrawn. The time to relapse and the number of relapsed patients was not significantly different comparing the treatment groups. There was no significant difference in PASI scores between VML 295‐treated patients and placebo‐treated patients after 8 weeks of treatment. Flow cytometric parameters for differentiation, inflammation and proliferation did not show significant differences between VML 295‐ and placebo‐treated patients. We conclude that oral VML 295 (LY‐293111) is not effective in preventing relapse in psoriasis, either clinically or at the cellular level, and that in our group of patients VML 295 had no beneficial effect on overall psoriasis severity. Moreover, we conclude that further development of LTB4 modulating drugs for the treatment of psoriasis is not indicated.