Acrokeratosis paraneoplastica (Bazex syndrome) – a systematic review on risk factors,diagnosis, prognosis and management

Acrokeratosis paraneoplastica Bazex (Bazex syndrome) is a rare paraneoplastic skin disease defined by erythematous, violaceous, scaly plaques on the hands and feet and on other acral locations such as nose and ears. Bazex syndrome is linked to a variety of underlying malignancies. Usually the skin lesions develop prior to the diagnosis of an internal malignant neoplasm with spontaneous remission after tumour removal. The objective of this study was to review the so far reported risk factors, diagnostic work‐up, prognosis and treatment options for Bazex syndrome in a systematic manner. This systematic review is based on a search in MEDLINE, EMBASE and Cochrane Central Register for English and German articles from 1990 to 2015. Evidence on the diagnosis and treatment of Bazex syndrome is limited predominately to case reports or to small case series. There are no randomized controlled trials. A number of underlying tumour entities, predominately oropharyngeal neoplasms and tumours of the gastroenterological tract, but other malignancies were reported. Treatment modalities including topical and systemic corticosteroids, salicylic acid, topical vitamin D analogues, etretinate and PUVA therapy are often ineffective. Due to the small number of patients and the frequent misdiagnosis of this clinical entity, the aim of this systematic review was to call attention to this rare condition and to help clinicians to diagnose and treat Bazex syndrome effectively. Because of the good prognosis of the skin lesions and the tendency to resolve spontaneously if the underlying tumour is treated early, the differential diagnosis of Bazex syndrome should be taken into consideration when dealing with atypical psoriasiform cutaneous lesions. An early diagnosis may improve the patient's prognosis substantially.     

Treatment of generalized granuloma annulare – a systematic review

Granuloma annulare (GA) is a benign inflammatory skin disease. Localized GA is likely to resolve spontaneously, while generalized GA (GGA) is rare and may persist for decades. GGA usually is resistant to a variety of therapeutic modalities and takes a chronic course. The objective of this study was to summarize all reported treatments of generalized granuloma annulare. This is a systematic review based on MEDLINE, Embase and Cochrane Central Register search of articles in English and German and a manual search, between 1980 and 2013, to summarize the treatment of generalized granuloma annulare. Most medical literature on treatment of GGA is limited to individual case reports and small series of patients treated without a control group. Randomized controlled clinical studies are missing. Multiple treatment modalities for GGA were reported including topical and systemic steroids, PUVA, isotretinoin, dapsone, pentoxifylline, hydroxychloroquine, cyclosporine, IFN‐γ, potassium iodide, nicotinamide, niacinamide, salicylic acid, dipyridamole, PDT, fumaric acid ester, etanercept, infliximab, adalimumab. While there are numerous case reports of successful treatments in the literature including surgical, medical and phototherapy options, well‐designed, randomized, controlled clinical trials are required for an evidence‐based treatment of GGA.     

Management of chronic hand eczema

Hand eczema (HE) is one of the most frequent skin diseases and has often a chronically relapsing course with a poor prognosis resulting in a high social and economic impact for the individual and the society. In this article, we highlight the results of an expert workshop on the 'management of severe chronic hand eczema' with the focus on the epidemiology, the burden of severe HE, its classification and diagnostic procedures, and the current status of treatment options according to an evidence-based approach (randomized controlled clinical trials, RCTs). We conclude that despite the abundance of topical and systemic treatment options, disease management in patients with severe chronic HE is frequently inadequate. There is a strong need for RCTs of existing and new treatment options based on clearly diagnosed subtypes of HE and its severity.     

Two novel mutations of the nicastrin gene in Chinese patients with acne inversa

Background Long‐term low‐level topical anti‐inflammatory therapy has been suggested as a new paradigm in the treatment of atopic eczema (AE). Objectives To determine the efficacy and tolerability of topical corticosteroids and calcineurin inhibitors for flare prevention in AE. Methods Systematic review of randomized controlled trials reporting efficacy of topical corticosteroids and/or topical calcineurin inhibitors for flare prevention in AE. Identification of relevant articles by systematic electronic searches (Cochrane Library, Medline) supplemented by hand search. Primary efficacy endpoint: proportion of participants experiencing at least one flare during proactive anti‐inflammatory treatment. Relative risks (RRs) and corresponding 95% confidence intervals (CIs) were calculated and pooled by pharmaceutical agent using random‐effects meta‐analysis. Sensitivity analysis included meta‐regression to explore the influence of study‐specific covariates. Results Nine articles reporting on eight vehicle‐controlled trials were included. Three, four and one trial(s) evaluated proactive therapy with topical tacrolimus, fluticasone propionate and methylprednisolone aceponate, respectively. Each agent under study was more efficacious to prevent flares than vehicle. Meta‐analysis suggested that topical fluticasone propionate (RR 0·46, 95% CI 0·38–0·55) may be more efficacious to prevent disease flares than topical tacrolimus (RR 0·78, 95% CI 0·60–1·00). Meta‐regression indicated robustness of these findings. Proactive anti‐inflammatory therapy was generally well tolerated. The trials identified, however, do not allow firm conclusions about long‐term safety. Conclusions Vehicle‐controlled trials indicate efficacy of proactive treatment with tacrolimus, fluticasone propionate and methylprednisolone aceponate to prevent AE flares. Indirect evidence from vehicle‐controlled trials suggests that twice weekly application of the potent topical corticosteroid fluticasone propionate may be more efficacious to prevent AE flares than tacrolimus ointment. Head to head trials should be conducted to confirm these results. Future studies are also needed to evaluate the long‐term safety of proactive treatment of AE.     

What's new in atopic eczema? An analysis of systematic reviews published in 2010–11

This review provides a summary of key findings from 24 systematic reviews of atopic eczema (AE) published or indexed between 1 August 2010 and 31 December 2011, updating published summaries from previous years. Epidemiological evidence points to the protective effects of early daycare, endotoxin exposure, consumption of unpasteurized milk, and early exposure to dogs, but antibiotic use in early life may increase the risk for AE. With regard to prevention of AE, there is currently no strong evidence of benefit for exclusive breastfeeding, hydrolysed protein formulas, soy formulas, maternal antigen avoidance, omega‐3 or omega‐6 fatty‐acid supplementation, or use of prebiotics or probiotics. With respect to AE treatments, the most compelling new systematic review evidence was for proactive treatment with topical anti‐inflammatory agents (topical corticosteroids and topical calcineurin inhibitors) for the prevention of AE flares in patients with moderate to severe AE. A meta‐analysis of 4 trials confirmed the superiority of tacrolimus 0.1% over pimecrolimus for the treatment of AE, and a review of 17 trials found that tacrolimus (0.1% or 0.03%) was broadly similar in efficacy to mild/moderate topical corticosteroids. Evidence for the role of education in the management of AE was less conclusive, with evidence from randomized controlled trials showing mixed results. Further work is needed in this area to conduct high‐quality trials of educational interventions that are clearly described and reproducible. There is no clear evidence for the efficacy of homeopathy, botanical extracts or Chinese herbal medicine in the treatment of AE, as large well‐designed trials are lacking in these areas.     

Impact of Topical Calcineurin Inhibitors on Quality of Life in Patients with Atopic Dermatitis

This review considers randomized trials of topical calcineurin inhibitors in atopic dermatitis that have included quality-of-life (QOL) data. Relatively few trials were identified and several different QOL measures have been used, partly because trial subjects included adults, children, and the parents of affected infants. Tacrolimus 0.1% and 0.03% ointment and pimecrolimus 1% cream were found to be superior to vehicle treatment in terms of QOL for active AD. In adults, tacrolimus 0.1% ointment provided a greater improvement in QOL than the 0.03% strength. Pimecrolimus 1% cream was superior to vehicle treatment for flare prevention in the studies that contained QOL outcomes but no data are available for tacrolimus ointment in this regard. QOL data comparing topical calcineurin inhibitors with other active treatments such as topical corticosteroids are sparse and it would be useful for future randomized trials to include QOL measures as a primary outcome.     

Therapeutic alternatives in cutaneous T-cell lymphoma.

Mycosis fungoides and Sézary syndrome, collectively referred to as cutaneous T-cell lymphoma, are non-Hodgkin's lymphomas that initially appear in the skin. Early-stage disease, limited to the skin, is best treated with sequential topical therapies such as topical nitrogen mustard, psoralen phototherapy (PUVA), or total-skin electron beam therapy. Photopheresis is the first line of therapy for the patient with erythroderma. Systemic therapy is generally reserved for patients with refractory disease and patients who initially present with extracutaneous involvement. Although there are several treatment options for cutaneous T-cell lymphoma, there have been few randomized comparative trials.     

Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome

BACKGROUND: Tacrolimus is a macrolide immunosuppressant approved in oral and intravenous formulations for primary immunosuppression in liver and kidney transplantation. Topical 0.1% tacrolimus ointment has recently been shown to be effective in atopic dermatitis for children as young as 2 years of age, with minimal systemic absorption. We describe 3 patients treated with topical 0.1% tacrolimus who developed significant systemic absorption. OBSERVATION: Three patients previously diagnosed as having Netherton syndrome were treated at different centers with 0.1% tacrolimus ointment twice daily. Two patients showed dramatic improvement. All patients were found to have tacrolimus blood levels within or above the established therapeutic trough range for oral tacrolimus in organ transplant recipients. None of these patients developed signs or symptoms of toxic effects of tacrolimus. CONCLUSIONS: Patients with Netherton syndrome have a skin barrier dysfunction that puts them at risk for increased percutaneous absorption. The Food and Drug Administration recently approved 0.1% tacrolimus ointment for the treatment of atopic dermatitis. Children with Netherton syndrome may be misdiagnosed as having atopic dermatitis. These children are at risk for marked systemic absorption and associated toxic effects. If topical tacrolimus is used in this setting, monitoring of serum tacrolimus levels is essential.     

Netherton syndrome: a case report and review of the literature

Netherton syndrome is a rare disorder inherited in an autosomal recessive pattern consisting of ichthyosiform dermatosis, hair shaft abnormalities (trichorrhexis invaginata), and an atopic diathesis. Patients with Netherton syndrome have been found to have a mutation on chromosome 5q32 in a gene named SPINK5 (serine protease inhibitor, Kazal type-5), which encodes an inhibitor of serine proteases called LEKTI. We report a female patient with previously undiagnosed Netherton syndrome who presented to participate in a clinical research trial investigating the benefit of topical tacrolimus 0.03% ointment [Protopic (Fujisawa Pharmaceutical Co. Ltd., Japan)] for the treatment of atopic dermatitis. This patient was confirmed to have a gene mutation in SPINK5. Current literature suggests a relative contraindication for use of topical tacrolimus in patients with Netherton syndrome owing to concern for increased systemic absorption of the drug. Our patient was not able to tolerate topical tacrolimus owing to local irritation, and did not derive any benefit from therapy. Though rare, when evaluating patients with a possible diagnosis of atopic dermatitis, an index of suspicion for Netherton Syndrome must be maintained. History and overall clinical findings, especially in regards to examination of the hair, will aid in diagnosis.     

Hailey–Hailey Disease: An Update Review with a Focus on Treatment Data

Hailey–Hailey disease is a rare blistering dermatosis first described in 1939 by the brothers Howard and Hugh Hailey. Its incidence is estimated at 1/50,000. The inheritance is autosomal dominant with complete penetrance, but a variable expressivity in affected family members. Clinically, Hailey–Hailey disease presents between the third and fourth decade as flaccid vesicles and blisters on erythematous skin, giving rise to erosions, fissures, and vegetations. Maceration and superinfections are frequent. The lesions are typically distributed symmetrically within intertriginous regions such as the retroauricular folds, lateral aspects of the neck, axillae, umbilicus, inguinal, and perianal regions. The disease is characterized by a chronic relapsing course with spontaneous remissions and multiple recurrences. Severe disease can be very frustrating and have a major psychological and social impact. Given the dearth of evidence-based guidelines and large clinical trials, the assessment of the efficacy and safety of treatments is difficult. Treatments include topical and systemic agents, and procedural therapy such as lasers and surgery. This review provides a systematic search of the literature with a focus on classical and emerging treatment options for Hailey–Hailey disease.

     

Mycosis fungoides und Sézary-Syndrom – Überblick und Ausblick

Mycosis fungoides and Sézary syndrome are the most important representatives of the heterogeneous group of cutaneous T-cell lymphomas. The diseases are rare and the diagnosis, which always requires a clinical-pathological correlation, is often delayed, especially in early forms of mycosis fungoides. The prognosis of mycosis fungoides depends on its stage and is usually favorable in the early stages. Clinically relevant prognostic parameters are missing and their development is the subject of current clinical research. Sézary syndrome, characterized by initial erythroderma and blood involvement, is a disease with a high mortality rate, in which good responses can now be achieved in many cases with new treatment options. The pathogenesis and immunology of the diseases is heterogeneous, with recent results pointing primarily to changes in specific signal transduction pathways that may be suitable as future treatment targets. Current therapy for mycosis fungoides and Sézary syndrome is primarily palliative with topical and systemic options either used alone or in combination. Only with allogeneic stem cell transplantation durable remissions can be achieved in selected patients. Similar to other areas of oncology, the development of new therapies for cutaneous lymphomas is currently changing from relatively untargeted empiricism to disease-specific, targeted pharmacotherapy based on knowledge from experimental research.     

Gram‐negative bacterial toe web infection – a systematic review

Gram‐negative bacterial toe web infection (GNBTWI) is a frequent therapeutic challenge in clinical practice with high recurrence rates and frequent need of systemic drugs. The aim of this systematic review was to provide an updated overview and evidence‐based data on pathogens, risk factors and treatment of GNBTWI along with promoting a consistent international terminology. This systematic review is based on a search in PubMed database for English and German articles published between 1980 and 2016. A total of seven articles were considered appropriate for inclusion in this review regarding to treatment and outcome. Throughout the medical literature, a variety of terms for bacterial toe web infections is used. Only few data on the incidence of GNBTWI were published. GNBTWI has been shown to have a significant male predominance. Pseudomonas aeruginosa is the most commonly identified organism beside a high mixed infection rate. We identified the following predisposing factors: interdigital tinea, occlusion and humidity, history of self‐medication with antifungals, antibiotics and glucocorticosteroids. As for treatment, debridement of macerated skin lesions and the hyperkeratotic rim showed good response in three published cases. Bacteriological workup of swabs including an antibiogram is recommended for identification of the proper topical and systemic therapy. Autosensitization dermatitis and frequent recurrences are common complications of GNBTWI. Despite the fact, that GNBTWI is an accepted disease entity, scarce data on GNBTWI exist in the medical literature. Randomized controlled trials are missing although needed for evidence‐based therapy. To facilitate communication and exchange of updates of GNBTWI, we promote the suggested terminology for bacterial toe web diseases.     

Chronic actinic dermatitis: treatment with topical tacrolimus (two cases)

BACKGROUND: Chronic actinic dermatitis is usually controlled under systemic immunosuppressive drugs. We report herein two patients successfully treated with topical tacrolimus. CASE REPORTS: Two men aged 60 and 70 years were treated for chronic actinic dermatitis for two years using systemic immunosuppressive drugs. Due to drug intolerance and treatment resistance, systemic treatment was substituted by topical tacrolimus. Cutaneous lesions improved dramatically within two months but withdrawal of daily application was immediately followed by recurrence of the lesions. DISCUSSION: Our cases, together with the 10 others reported in the literature, confirm the efficacy of topical tacrolimus in the treatment of chronic actinic dermatitis. Since tacrolimus chiefly targets activated T lymphocytes, it has been successfully deployed in various inflammatory dermatoses and its use is logical in the treatment of chronic actinic dermatitis. While dramatic improvement is achieved within a few weeks in this indication with twice-daily applications of tacrolimus ointment 0.1%, symptoms recur rapidly on dosage reduction, and extremely long-term, or even lifelong, treatment is thus probably needed. Topical tacrolimus application has been shown to be safe for periods of three years. However, the peculiar mechanism of chronic actinic dermatitis with a pronounced imbalance in T-cell subsets raises the question of theoretical risk of carcinogenicity of tacrolimus applications, and this, together with the prolonged duration of treatment, calls for long-term follow-up of chronic actinic dermatitis patients.     

皮肤T细胞淋巴瘤的治疗选择

皮肤T细胞淋巴瘤是一种少见的淋巴细胞增生性疾病,依据疾病的分类及分期不同,治疗选择有很大差异性。多数的皮肤T细胞淋巴瘤病程进展缓慢,诸如早期的蕈样肉芽肿和淋巴瘤样丘疹病,只需要选择皮肤局部治疗的方案。侵袭性或顽固性如Sézary综合征、复发性CTCL等,则需系统治疗,包括化疗。本文对国内现有药物及最新治疗方法进行综述。     

Erosive pustular dermatosis of the scalp: causes and treatments

Erosive pustular dermatosis of the scalp is a rare condition which primarily affects older women after local trauma and has historically been treated with topical steroids. As it is a rare entity and resembles other dermatologic conditions, it may easily be misdiagnosed. Identifying the causes and evaluating the efficacy of treatments of erosive pustular dermatosis of the scalp (EPDS) is of great importance to both avoid misdiagnosis and ensure optimal treatment of this rare condition. There are numerous causes. In addition to surgeries and physical injuries, topical and procedural treatments for actinic keratoses and androgenetic alopecia can trigger the development of lesions. There are also documented associations with several autoimmune and systemic conditions. Besides corticosteroids, topical tacrolimus and photodynamic therapy were the most commonly used treatments for EPDS. They were effective with few recurrences and adverse effects. Other successful treatment options were topical dapsone, silicone gels, calcipotriol, acitretin, and isotretinoin. Oral dapsone can be used in cases of disseminated disease. Zinc sulfate should be considered with low‐serum zinc levels. While cyclosporine was effective, there were adverse effects that may limit its use. It is important for dermatologists to be aware of the wide array of potential causes of erosive pustular dermatosis and include it on their differential. Additionally, although high‐potency topical steroids have been historically used as the first‐line treatment, there are many other effective treatments that may avoid recurrence and skin atrophy, particularly in the elderly population.     

Topical calcineurin inhibitors in the treatment of oral lichen planus: a systematic review and meta-analysis

Oral lichen planus (OLP) is a skin disease affecting the mouth, which can cause a burning or stinging discomfort in the mouth when eating or drinking. Ulcers may occur and these are especially painful. The cause of oral lichen planus is not known in most instances, but it is likely to be related to the body's immune system. In this study, the authors from China aimed to compare the efficacy and safety of drugs called topical calcineurin inhibitors (TCI) with medicines applied to the skin called topical corticosteroids (TCS), in the treatment of OLP. The authors looked at globally published randomized controlled trials (RCTs) reporting TCI (tacrolimus, pimecrolimus, and cyclosporine) compared with TCS for OLP from eight medical databases. Twenty-one RCTs with a total of 965 patients published between 1995 and 2017 were included (tacrolimus-TCS: 12 studies, 578 patients; pimecrolimus-TCS: 3 studies, 98 patients; cyclosporine-TCS: 6 studies, 289 patients). The authors found that TCI including tacrolimus, pimecrolimus and cyclosporine were similar to TCS in efficacy for the short-term treatment of OLP (3-8 weeks). In addition, tacrolimus 0.1% was similar to TCS in relapse rate. The blood levels of tacrolimus and cyclosporine were usually extremely low, while the few cases of patients with high levels may have been caused by swallowing the drug accidentally. Although a few adverse events (unwanted side effects) were observed in the tacrolimus and cyclosporine groups, no serious events were found. Therefore, TCI may be an alternative approach when OLP does not improve with use of TCS. Due to the limited trials of pimecrolimus and cyclosporine, as well as a few adverse events and high cost of cyclosporine, tacrolimus 0.1% should be the first drug of choice in TCI for the short-term treatment of OLP that is not improving with TCS. More well-designed RCTs are needed to evaluate the long-term efficacy and safety of TCI compared with TCS.     

S2k guideline for treatment of cutaneous lupus erythematosus – guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV)

Cutaneous lupus erythematosus (CLE) is a rare inflammatory autoimmune disease with heterogeneous clinical manifestations. To date, no therapeutic agents have been licensed specifically for patients with this disease entity, and topical and systemic drugs are mostly used ‘off‐label’. The aim of the present guideline was to achieve a broad consensus on treatment strategies for patients with CLE by a European subcommittee, guided by the European Dermatology Forum (EDF) and supported by the European Academy of Dermatology and Venereology (EADV). In total, 16 European participants were included in this project and agreed on all recommendations. Topical corticosteroids remain the mainstay of treatment for localized CLE, and further topical agents, such as calcineurin inhibitors, are listed as alternative first‐line or second‐line topical therapeutic option. Antimalarials are recommended as first‐line and long‐term systemic treatment in all CLE patients with severe and/or widespread skin lesions, particularly in patients with a high risk of scarring and/or the development of systemic disease. In addition to antimalarials, systemic corticosteroids are recommended as first‐line treatment in highly active and/or severe CLE. Second‐ and third‐line systemic treatments include methotrexate, retinoids, dapsone and mycophenolate mofetil or mycophenolate acid, respectively. Thalidomide should only be used in selected therapy‐refractory CLE patients, preferably in addition to antimalarials. Several new therapeutic options, such as B‐cell‐ or interferon α‐targeted agents, need to be further evaluated in clinical trials to assess their efficacy and safety in the treatment of patients with CLE.     

Treatment of Eosinophilic Annular Erythema: Retrospective multicenter study and literature review

BackgroundEosinophilic annular erythema (EAE) is a rare eosinophil-related skin disease which typically manifests with annular erythematous plaques and severe pruritus. Besides the diagnosis, the treatment of EAE is challenging since relevant published data are sparse.MethodsThe aim of this study was to assess the underlying diseases, treatments and outcomes of patients with EAE. To this end, we conducted a retrospective multicenter study and a systematic review of the MEDLINE database.ResultsWe included 18 patients with EAE followed in 8 centers. The MEDLINE database search yielded 37 relevant publications reporting 55 cases of EAE with 106 treatment sequences. The most common and efficient treatments included topical or systemic corticosteroids, hydroxychloroquine and dapsone. In refractory patients, a combination of systemic corticosteroids with hydroxychloroquine was associated with 88% of complete clinical response.DiscussionTo improve the management of EAE patients, we discuss the following treatment strategy: in topical steroid-resistant patients, hydroxychloroquine can be given as first-line systemic treatment. Dapsone, hydroxychloroquine or systemic corticosteroids are second-line options to consider. Last, monoclonal antibodies or JAK inhibitors targeting type 2 inflammation could represent promising last-resort options in refractory patients.     

The efficacy and safety of tacrolimus as mono- and adjunctive therapy for vitiligo: A systematic review of randomised clinical trials

There is currently no definitive treatment for vitiligo; various modalities include immune modulators phototherapy and skin camouflage. We investigated the efficacy and safety of topical tacrolimus either as monotherapy or combined therapy in the treatment of vitiligo. Electronic systematic search of the literature was carried out using four major databases. Randomised clinical trials (RCTs) that reported the use of topical tacrolimus in the treatment of human vitiligo have been included in a systematic review and meta-analysis. Meta-analysis was conducted via RevMan, and risk of bias was assessed through the Cochrane quality assessment tool. The protocol was published through PROSPERO (CRD42018112430). A total of 19 studies including 814 patients were included in our systematic review. The random-effects-model meta-analysis of two studies revealed that the tacrolimus and narrowband ultraviolet B (NB-UVB) combination therapy rates is better than NB-UVB alone in inducing >75% repigmentation [RR 1.34 (95% CI: 01.05–1.71), P = 0.02]. Tacrolimus and steroids had similar potency in acheiving >75% repigmentation [RR 1.02 (95% CI: 0.19–5.51), P = 0.98]. Meta-analysis of two studies revealed that the fractional laser and tacrolimus combination therapy is no better than tacrolimus alone in causing >75% repigmentation [RR 2.11 (95% CI: 0.87–5.09), P = 0.10]. Further investigating tacrolimus as mono- or adjuvant therapy for vitiligo is highly recommended. Combining tacrolimus to other treatment options such as steroids, phototherapy and laser may be superior to using tacrolimus alone.