Outcome and long-term treatment protocol for topical tacrolimus in oral lichen planus.

BACKGROUND AND OBJECTIVE: Topical tacrolimus has been shown to be beneficial in the treatment of oral lichen planus (OLP). However, long-term effects and its optimal application protocol with gradual reduction have not been studied. Accordingly, we analysed the clinical response of OLP to tacrolimus in our daily clinical practice with a focus on the optimal long-term therapeutic scheme. METHODS: Retrospective analysis of all consecutive patients diagnosed with OLP and treated with topical tacrolimus (0.03% oral rinse) in a clinical setting between 2015 and 2020. The objective clinical response was measured by a 4-point scale (complete remission, major remission, partial remission and no response), and subjective impairment by a 3-point scale (severe, moderate and none). RESULTS: Fifty-seven patients (74% women; median age: 66 years) were included. Fifty-six (98%) patients had prior treatment with topical steroids. After introduction of tacrolimus, objective remission (major or complete) was reached by 28%, 62%, 87% and 97% of patients after 3, 6, 12 and 24 months respectively. Subjective remission was reported by 16%, 48%, 69% and 83% after 3, 6, 12 and 24 months of treatment respectively. The treatment frequency could be gradually reduced from initially twice daily to once daily or less in 28%, 61%, 78% and 87% after 3, 6, 12 and 24 months respectively; 41% of patients completely suspended the treatment at one point, but 67% of them experienced a relapse after a median time of 3.3 months. Four patients (7%) developed a squamous cell carcinoma (SCC) during the observation period. Otherwise, there were only few and minor side-effects. CONCLUSION: Topical tacrolimus can be an effective second-line therapy for OLP refractory to potent topical corticosteroids. The therapy frequency can often be reduced during the maintenance period. Both signs of clinical activity and subjective impairment should guide therapy. Regular follow-up is necessary to recognize possible SCC.

European Guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part II.

This guideline has been initiated by the task force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology, including physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline that systematically reviewed the literature on mucous membrane pemphigoid (MMP) in the MEDLINE and EMBASE databases until June 2019, with no limitations on language. While the first part of this guideline addressed methodology, as well as epidemiology, terminology, aetiology, clinical presentation and outcome measures in MMP, the second part presents the diagnostics and management of MMP. MMP should be suspected in cases with predominant mucosal lesions. Direct immunofluorescence microscopy to detect tissue-bound IgG, IgA and/or complement C3, combined with serological testing for circulating autoantibodies are recommended. In most patients, serum autoantibodies are present only in low levels and in variable proportions, depending on the clinical sites involved. Circulating autoantibodies are determined by indirect IF assays using tissue substrates, or ELISA using different recombinant forms of the target antigens or immunoblotting using different substrates. The major target antigen in MMP is type XVII collagen (BP180), although in 10-25% of patients laminin 332 is recognized. In 25-30% of MMP patients with anti-laminin 332 reactivity, malignancies have been associated. As first-line treatment of mild/moderate MMP, dapsone, methotrexate or tetracyclines and/or topical corticosteroids are recommended. For severe MMP, dapsone and oral or intravenous cyclophosphamide and/or oral corticosteroids are recommended as first-line regimens. Additional recommendations are given, tailored to treatment of single-site MMP such as oral, ocular, laryngeal, oesophageal and genital MMP, as well as the diagnosis of ocular MMP. Treatment recommendations are limited by the complete lack of high-quality randomized controlled trials.

The evolving field of Dermato-oncology and the role of dermatologists: Position Paper of the EADO, EADV and Task Forces, EDF, IDS, EBDV-UEMS and EORTC Cutaneous Lymphoma Task Force.

BACKGROUND: The incidence of skin cancers has been increasing steadily over the last decades. Although there have been significant breakthroughs in the management of skin cancers with the introduction of novel diagnostic tools and innovative therapies, skin cancer mortality, morbidity and costs heavily burden the society. OBJECTIVE: Members of the European Association of Dermato-Oncology, European Academy of Dermatology and Venereology, International Dermoscopy Society, European Dermatology Forum, European Board of Dermatovenereology of the European Union of Medical Specialists and EORTC Cutaneous Lymphoma Task Force have joined this effort to emphasize the fundamental role that the specialist in Dermatology-Venereology has in the diagnosis and management of different types of skin cancer. We review the role of dermatologists in the prevention, diagnosis, treatment and follow-up of patients with melanoma, non-melanoma skin cancers and cutaneous lymphomas, and discuss approaches to optimize their involvement in effectively addressing the current needs and priorities of dermato-oncology. DISCUSSION: Dermatologists play a crucial role in virtually all aspects of skin cancer management including the implementation of primary and secondary prevention, the formation of standardized pathways of care for patients, the establishment of specialized skin cancer treatment centres, the coordination of an efficient multidisciplinary team and the setting up of specific follow-up plans for patients. CONCLUSION: Skin cancers represent an important health issue for modern societies. The role of dermatologists is central to improving patient care and outcomes. In view of the emerging diagnostic methods and treatments for early and advanced skin cancer, and considering the increasingly diverse skills, knowledge and expertise needed for managing this heterogeneous group of diseases, dermato-oncology should be considered as a specific subspecialty of Dermatology-Venereology.

Pushing and loss of elastic fibers are highly specific for melanoma and rare in melanocytic nevi.

The histopathological differentiation of melanocytic nevi from malignant melanoma (MM) is based on well-known criteria, and is straightforward in the vast majority of cases. However, there are few cases of melanocytic lesions (ML), the diagnosis of which is very challenging or even impossible. Here we have studied several morphological characteristics with particular focus on elastic fibers (EF) to identify features, helpful for the distinction between nevi and MM. In a monocentric retrospective study we have analyzed 14 morphological histological characteristics in 30 MMs and 90 nevi, encompassing 30 compound/dermal nevi, 30 junctional nevi, 30 dysplastic nevi. All consecutive cases were retrieved from the archives of our tertiary referral centre during the 6-month study period. Nine characteristics including loss of EF in the ML, loss of EF in lesional fibrosis, pushing of the EF, UV-elastosis, loss of rete ridges of the epidermis, regression of the ML, atrophy of the epidermis, pigment incontinence, and concentric eosinophilic fibroplasia (CEF) showed a statistical significant difference (p < 0.05 and at least an OR > 2) distinguishing nevi from MM. Loss of EF was found in 73.1% of MM cases, but in less than 2.5% of nevi. We identified nine morphological characteristics that are helpful to differentiate melanocytic nevi from MM. A loss of the EF in a ML appeared to be highly associated with MM.

Rituximab and bilateral HSV epithelial keratitis in a patient with mucous membrane pemphigoid.

BACKGROUND: B cell depleting therapy is widely used for lymphoproliferative diseases and immune-mediated disorders, including mucous membrane pemphigoid. The latter is an autoimmune blistering disease affecting predominantly the mucosae potentially associated with devastating complications. METHODS: A 71-year-old patient with severe mucous membrane pemphigoid involving ocular, oral pharyngeal and laryngeal involvement is described. To control the disease, the patient was given rituximab therapy in combination with oral corticosteroids. He subsequently experienced an epithelial herpes simplex virus keratitis in one eye and 3 months later in his fellow eye. Topical treatment with ganciclovir resulted in prompt recovery. RESULTS: For the first time, a correlation between rituximab and bilateral epithelial herpes simplex virus keratitis is described. CONCLUSIONS: Although rituximab is a promising biologic agent for the treatment of autoimmune diseases, it bears the risk of reactivation of viral infections, including the onset of herpes simplex virus keratitis.

Distinct interferon-gamma and interleukin-9 expression in cutaneous and oral lichen planus.

BACKGROUND: Cutaneous (CLP) and oral lichen planus (OLP) as the main subtypes of lichen planus (LP) present with different clinical manifestation and disease course, although their histopathologic features such as the band-like lymphocyte infiltrate and keratinocyte apoptosis are similar. So far, the underlying cellular and molecular mechanisms remain poorly understood. OBJECTIVE: The aim of this study was to characterize and compare the in situ cellular infiltrates, cytokine expression profiles and apoptosis markers in CLP and OLP. METHODS: Using immunofluorescence staining and laser scanning microscopy, we evaluated the cellular infiltrate (CD1a, CD3, CD4, CD8, CD21, CD57, CD123), cytokine expression (interleukin (IL)-1, IL-6, IL-9, IL-10, IL-17, IL-22, IL-23, tumour necrosis factor-α, transforming growth factor-ß, interferon (IFN)-γ), and apoptosis markers (Fas, Fas ligand, cleaved caspase-3, TUNEL) of 21 anonymized biopsy specimens of LP (11 CLP, 10 OLP). RESULTS: Among infiltrating cells mainly T cells and natural killer (NK) cells as well as plasmacytoid dendritic cells (DC) were observed. A predominance of CD8+ T cells was noted in OLP. In both CLP and OLP, T helper (Th)1, Th9, Th17, and Th22-type cytokines were expressed. The expression of IL-9, IFN-γ and IL-22 was higher in CLP compared to that of OLP (P = 0.0165; P = 0.0016; P = 0.052 respectively). Expression of Fas and Fas ligand as well as cleaved caspase-3-positive cells was observed in the epithelium of all LP samples. CONCLUSIONS: The cell and cytokine patterns of CLP and OLP were partially distinct and generally resembled those reported for autoimmune diseases. The presence of CD8+ and NK cells as well as Fas/Fas ligand expression suggested that various pathways involved in keratinocyte apoptosis are relevant for LP. These results might help to establish targeted therapies for LP.

Treatment of sporadic port-wine stains: a retrospective review of 17 cases consecutively treated by pulsed sequential dual wavelength 595 and 1064 nm laser.

BACKGROUND: Port-wine stains (PWS) are relatively common and often cause cosmetic and psychological concerns. The pulsed dye laser is currently the treatment of choice for PWS. OBJECTIVE: To assess the effectiveness of the pulsed sequential dual wavelength 595 and 1064 nm laser as first-line treatment for PWS and to identify prognostic factors for treatment outcome in a retrospective series of 17 consecutive previously untreated patients. METHODS: The response to treatment was evaluated 2 months after treatment utilizing comparative photographs and a standard physician global assessment (PGA) grading system. Furthermore, measurement of the normalized erythema index (NEI) reduction (ΔNEI%) was carried out using an image analysis system. The subjective improvement was assessed using a patient's satisfaction questionnaire. Multiple linear regression models were finally used to identify factors associated with ΔNEI% and patients' satisfaction. RESULTS: Seventeen patients, with PWS, including 12 children were included. The average PGA assessment was 2.5 ± 1.3 corresponding to an amelioration of 50% with a high intraclass correlation coefficient among the experts. The before-after NEI showed a statistically significant mean reduction of 3.5 ± 2.6 units, corresponding to a relative reduction of 31%. Questionnaires showed that the satisfaction was very good with an average score of 6.1 points on a scale ranging from -10 to 10 points. Multiple regression analysis revealed that location in the frontotemporal area was associated with a significant reduction in ΔNEI% (38.4%; 95% CI 4.3, 72.6). Presence of PWS on the neck was associated with a lower patient satisfaction (-3.7 points; 95% CI -6.5, -0.9). There were no significant side-effects, except for transient discomfort and purpura. CONCLUSIONS: Based on the results obtained in the largest reported series so far, the pulsed sequential dual wavelength 595 and 1064 nm laser represents an effective and safe first-line therapeutic option for the treatment of PWS.

Bowen disease of the nail unit: a retrospective study of 12 cases and their association with human papillomaviruses.

BACKGROUND: Bowen disease is the most frequent nail malignancy, usually seen as a verrucous plaque of the nail in men. OBJECTIVE: To characterize the affected patient population, the clinical manifestations, the diagnostic delay and diagnostic steps, and presence of human papilloma virus (HPV) infection. METHODS: We retrospectively evaluated all cases of Bowen disease of the nail unit over a period of 9 years. Data were obtained from our electronic database. Human papilloma virus genotype was assessed in biopsy specimens by polymerase chain reaction (PCR) sequencing. RESULTS: We identified 12 cases of Bowen disease of the nail unit in 10 patients. Mean age at onset was 52 years, with a male predominance of 90%. The thumb and middle finger were the most frequently affected (66%). Fifty percent of the lesions presented as periungual and subungual verrucous tumours. Patients sought medical evaluation after a mean delay of 5.7 years; histopathological diagnosis was made after a mean delay of 3.2 years. HPV infection was identified in 75% of the cases. CONCLUSIONS: Any recently appeared verrucous lesion of the nail unit in men above the age of 40 years should raise the suspicion of Bowen disease and lead to further histopathological diagnostic procedures.

Diagnostic value of immunohistochemistry on formalin-fixed, paraffin-embedded skin biopsy specimens for bullous pemphigoid.

BACKGROUND: Direct immunofluorescence microscopy (DIF) studies constitute the gold standard for diagnosis of bullous pemphigoid (BP) but depend on the availability of specialized laboratories and often on an additional skin biopsy specimen. OBJECTIVES: To assess the value of immunohistochemical analyses (IHCA) in the diagnosis of BP using formalin-fixed, paraffin-embedded skin biopsy specimens as an alternative to DIF; and to study the correlation between the results of IHCA and the presence of histological subepidermal blister formation and of circulating autoantibodies by indirect immunofluorescence studies using split skin or by enzyme-linked immunosorbent assays. METHODS: We included all patients newly diagnosed with BP evaluated between 2008 and 2010. There were 51 consecutive skin biopsy specimens obtained from 38 patients with BP with positive DIF. RESULTS: By IHCA, deposits of immunoreactants were found in 45% of all tested cases. Deposits of C3d, IgG, IgM, IgE and IgA were found in 37%, 23%, 2%, 0% and 0% of cases, respectively. Deposits of C3d and/or IgG were found in 79% of the 24 cases with a blister and in 83% of the 12 cases with subepidermal blistering and positive immunoserological analyses, respectively. CONCLUSIONS: In contrast to previous studies, our findings in an unselected patient cohort indicate that IHCA are not sufficiently sensitive to replace DIF studies for confirming the diagnosis of BP. IHCA sensitivity significantly increases in the presence of histological blistering and/or of circulating autoantibodies. IHCA represents a potential rescue diagnostic technique only if specialized laboratories and/or a second biopsy specimen for DIF are unavailable.

Treatment of lower extremity telangiectasias in women by foam sclerotherapy vs. Nd:YAG laser: a prospective, comparative, randomized, open-label trial.

BACKGROUND: Telangiectasias of the lower extremities are very common. There are no blinded, randomized, controlled clinical trials comparing laser modalities with the gold standard sclerotherapy, while the few available studies encompass small patients cohorts. OBJECTIVE: This prospective, randomized, open-label trial compares the efficacy of sclerotherapy with polidocanol vs. long-pulsed neodymium-doped yttrium aluminium garnet (Nd:YAG) laser in the treatment of leg telangiectasias. PATIENTS AND METHODS: Fifty-six female patients with primary leg telangiectasias and reticular veins (C1A or SEpAS1PN) were included in the study. One leg was randomly assigned to get treatment with the multiple synchronized long-pulsed Nd:YAG laser, while the other received foam sclerotherapy with polidocanol 0.5%. The patients were treated in two sessions at intervals of 6 weeks. The patients were evaluated by the handling physician after 6 weeks and 6 months. Two investigators assessed blindly at the end of the study the photographs for clearing of the vessels using a six-point scale from 1 (no change) to 6 (100% cleared). Patients reported about pain sensation and outcome satisfaction. RESULTS: According to the handling dermatologist, at the last follow-up, there was an improvement of 30-40% with a median of 3 (IQR 2) and a good improvement of 50-70% with a median of 4 (IQR 2) after laser treatment and sclerotherapy respectively. In contrast, according to the blinded investigators, there was a median of 5 (IQR 1) with a very good improvement of >70% after both therapies. Improvement was achieved more quickly by sclerotherapy, although at the last follow-up visit there was no difference in clearance between the two groups as assessed by the blinded experts (P-value 0.84). The degree of patient's satisfaction was very good and similar with both therapeutic approaches. There was a significant difference (P-value 0.003) regarding pain perception between the types of therapy. Laser was felt more painful than sclerotherapy. CONCLUSION: Telangiectasias of the lower extremities can be successfully treated with either synchronized long-pulsed Nd:YAG laser or sclerotherapy. The 1064-nm long-pulsed Nd:YAG laser is associated with more pain and is suitable especially in case of needle phobia, allergy to sclerosants and in presence of small veins with telangiectatic matting, while sclerotherapy can also treat the feeder veins.

Systemic light-chain amyloidosis revealed by progressive nail involvement, diffuse alopecia and sicca syndrome: report of an unusual case with a review of the literature.

Immunoglobulin light-chain (AL) amyloidosis is a form of systemic amyloidosis in which the fibrils are derived from monoclonal light chains. We report a case of a 66-year-old woman presenting with nail changes, parchment-like hand changes, progressive alopecia and sicca syndrome. Histopathological studies of biopsy specimens of the scalp, the nail, minor labial salivary glands and abdominal skin revealed deposits of AL κ-type amyloid. Urine protein electrophoresis exhibited a weak band of κ-type light chains. Based on this striking case, we here review the characteristic nail and hair manifestations associated with systemic amyloidosis. Knowledge of these signs is important for an early diagnosis of systemic amyloidosis, identification of the underlying disease and patient management.

Cutaneous reactive angiomatosis with combined histological pattern mimicking a cellulitis.

Cutaneous reactive angiomatoses (CRA) encompass a distinct group of rare benign reactive vascular proliferations that include reactive angioendotheliomatosis, diffuse dermal angiomatosis and reactive intralymphatic histiocytosis. The etiology of these conditions, often associated with either localized or systemic diseases, is poorly understood. We report a 72-year-old woman who presented giant diffuse cellulitis-like plaques on the right lower limb and the pelvis and a reduction of her general condition with fever. Light microscopy studies revealed combined features of reactive angioendotheliomatosis, diffuse dermal angiomatosis and reactive intralymphatic histiocytosis. A small arteriovenous fistula of the right lower leg was thought to act as trigger. Systemic corticosteroids resulted in the clinical remission of the skin lesions. Our observation provides strong evidence that reactive angioendotheliomatosis, diffuse dermal angiomatosis and reactive intralymphatic histiocytosis, previously regarded as distinct forms of CRA, may show overlapping histopathological features and most likely represent facets of the same disease.

Laboratory diagnosis of paraneoplastic pemphigus.

BACKGROUND: Paraneoplastic pemphigus (PNP) is a multiorgan disease characterized by antibodies against plakins, desmogleins and the α2-macroglobulin-like-1 (A2ML1) protein, in association with an underlying neoplasm. Accurate diagnosis relies on the demonstration of these autoantibodies in serum. OBJECTIVES: To evaluate the value of different laboratory techniques in the serological diagnosis of PNP. METHODS: We performed immunoblotting, envoplakin (EP) enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence (IIF) on rat bladder, radioactive immunoprecipitation and a nonradioactive combined immunoprecipitation-immunoblot assay. Additional assays included BP180 ELISA and BP230 ELISA. We included the sera of 19 patients with PNP and 40 control subjects. RESULTS: The sensitivities were 63% for anti-EP ELISA, 74% for rat bladder IIF, 89% for immunoblotting, 95% for radioactive immunoprecipitation and 100% for nonradioactive immunoprecipitation. Specificities ranged from 86% to 100%. The BP180 and BP230 ELISAs had low sensitivity and specificity for PNP. The combination of rat bladder IIF and immunoblot showed 100% sensitivity and specificity. The analysis of sequential PNP sera showed that antibody titres may decrease over time, possibly resulting in negative outcomes for EP ELISA and rat bladder IIF studies. CONCLUSIONS: The detection of autoantibodies against EP and periplakin, or A2ML1 by immunoprecipitation is most sensitive for PNP. The combination of rat bladder IIF and immunoblotting is equally sensitive and highly specific, and represents an alternative valuable and relatively easy approach for the serological diagnosis of PNP.

Mortality rate in bullous pemphigoid: a retrospective monocentric cohort study.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease and is associated with an increased mortality. The end points of our study were to evaluate the mortality rate in a retrospective cohort of BP patients followed up to 5 years after the diagnosis and to determine prognostics factors. METHODS: All new cases of BP diagnosed between 1990 and 2003 in the University Hospital of Geneva were retrospectively collected. 60 patients were included, 47 (88.6%) of whom were treated with a combination of corticosteroids and chlorambucil. RESULTS: The 1-year, 2-year and 5-year probabilities of death were 26.7, 37.1 and 60.8%, respectively. Old age, dementia and use of chlorambucil at initial doses of 6 mg/day, but not at lower doses, were associated with poor prognosis in multivariate analysis. CONCLUSION: Our study confirms that BP is associated with a high mortality. The observed mortality rates are however higher than those of previous studies, which is probably related to the inclusion of more debilitated patients.