Doxycycline compared with prednisolone therapy for patients with bullous pemphigoid: cost-effectiveness analysis of the BLISTER trial.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering skin disorder associated with significant morbidity and mortality. Doxycycline and prednisolone to treat bullous pemphigoid were compared within a randomized controlled trial (RCT). OBJECTIVES: To compare the cost-effectiveness of doxycycline-initiated and prednisolone-initiated treatment for patients with BP. METHODS: Quality-of-life (EuroQoL-5D-3L) and resource data were collected as part of the BLISTER trial: a multicentre, parallel-group, investigator-blinded RCT. Within-trial analysis was performed using bivariate regression of costs and quality-adjusted life-years (QALYs), with multiple imputation of missing data, informing a probabilistic assessment of incremental treatment cost-effectiveness from a health service perspective. RESULTS: In the base case, there was no robust difference in costs or QALYs per patient at 1 year comparing doxycycline- with prednisolone-initiated therapy [net cost £959, 95% confidence interval (CI) -£24 to £1941; net QALYs -0·024, 95% CI -0·088 to 0·041]. However, the findings varied by baseline blister severity. For patients with mild or moderate blistering (≤ 30 blisters) net costs and outcomes were similar. For patients with severe blistering (> 30 blisters) net costs were higher (£2558, 95% CI -£82 to £5198) and quality of life poorer (-0·090 QALYs, 95% CI -0·22 to 0·042) for patients starting on doxycycline. The probability that doxycycline would be cost-effective for those with severe pemphigoid was 1·5% at a willingness to pay of £20 000 per QALY. CONCLUSIONS: Consistently with the clinical findings of the BLISTER trial, patients with mild or moderate blistering should receive treatment guided by the safety and effectiveness of the drugs and patient preference - neither strategy is clearly a preferred use of National Health Service resources. However, prednisolone-initiated treatment may be more cost-effective for patients with severe blistering.

Updated evidence-based (S2e) European Dermatology Forum guideline on topical corticosteroids in pregnancy.

BACKGROUND: Topical corticosteroids may be needed for treating skin conditions in pregnancy. Nevertheless, only limited data on the fetal effects of topical corticosteroids are available. OBJECTIVE: To update an evidence-based guideline on the safe use of topical corticosteroids in pregnancy. METHODS: A guideline subcommittee of the European Dermatology Forum updated the guideline by adding and appraising new evidence. RESULTS: The current best evidence from 14 observational studies with 1 601 515 study subjects found no significant associations between maternal use of topical corticosteroids of any potency and some adverse pregnancy outcomes including mode of delivery, birth defect, preterm delivery and fetal death. However, maternal use of potent/very potent topical corticosteroids, especially in large amounts, is associated with an increase in the risk of low birthweight. CONCLUSION: Mild/moderate topical corticosteroids should be preferred to potent/very potent ones in pregnancy. The well-known topical side-effects of corticosteroids on the mother's side need to be considered as well.

Current practice in treatment approach for bullous pemphigoid: comparison between national surveys from the Netherlands and the UK.

Treatment approaches for bullous pemphigoid (BP), the most common autoimmune skin blistering disease, are largely based on national and international guidelines. We conducted a national survey among dermatologists in the Netherlands to explore the current treatment of BP, and compared the results with those of a previously published survey from the UK. Almost all responders in the Netherlands (n = 175) used very potent topical corticosteroids, both as monotherapy and as adjunctive therapy. In contrast to UK dermatologists, the majority recommended whole-body application rather than local application to lesions. Systemic antibiotics were used by > 70% of responders. Half of the responders in the Netherlands considered systemic steroids the first-choice treatment, with the majority also using adjunctive therapy as a routine. Despite many similarities in treatment approach between the two countries, these surveys provide an important insight into the gap between actual and recommended practice at a country level in relation to the best external evidence.

Evidence-based (S3) Guideline on (anogenital) Lichen sclerosus.

Lichen sclerosus (LS) is an inflammatory skin disease that usually involves the anogenital area. All patients with symptoms or signs suspicious of lichen sclerosus should be seen at least once initially by a physician with a special interest in the disease in order to avoid delay in diagnosis, as early treatment may cure the disease in some and reduce or prevent scarring. The diagnosis is made clinically in most cases. Biopsies should only be performed under certain circumstances. The gold standard for treatment remains potent to very potent topical steroids; however, mild and moderate disease in boys and men may be cured by circumcision. Certain triggers should be avoided. http://www.euroderm.org/images/stories/guidelines/2014/S3-Guideline-on-Lichen-sclerosus.pdf http://www.awmf.org/fachgesellschaften/mitgliedsgesellschaften/visitenkarte/fg/deutsche-gesellschaft-fuer-gynaekologie-und-geburtshilfe-dggg.html.

A randomized controlled trial to compare the safety and effectiveness of doxycycline (200 mg daily) with oral prednisolone (0.5 mg kg(-1) daily) for initial treatment of bullous pemphigoid: a protocol for the Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) Trial.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering disease in older people, and is associated with significant morbidity and mortality. Oral corticosteroids are usually effective but the side-effects are thought to contribute to the high morbidity and mortality rate. Treatment with oral tetracyclines may be effective but high-quality, randomized controlled trials (RCTs) are needed to confirm this. OBJECTIVES: To compare the effectiveness and safety of two strategies for treating BP. METHODS: This is a two-arm, parallel group, 52-week RCT comparing doxycycline with prednisolone for initial treatment of BP. Dose is fixed for the initial 6 weeks of treatment (doxycycline 200 mg daily; prednisolone 0.5 mg kg(-1) daily), after which it can be adjusted according to need. A total of 256 patients with BP will be recruited in the U.K. and Germany. RESULTS: The primary outcomes are: (i) effectiveness (assessor-blinded blister count at 6 weeks) and (ii) safety [proportion of patients experiencing ≥ grade 3 adverse events (i.e. severe, life: threatening or fatal) related to trial medication during the year of follow-up]. Primary effectiveness analysis will be an assessment of whether doxycycline can be considered noninferior to prednisolone after 6 weeks of treatment. Primary safety analysis is a superiority analysis at 12 months. Secondary outcomes include longer-term assessment of effectiveness, relapse rates, the proportion of patients experiencing any grade of adverse events related to treatment, quality of life and cost-effectiveness. CONCLUSIONS: The trial will provide good evidence for whether the strategy of starting BP treatment with doxycycline is a useful alternative to prednisolone.

Sebaceous carcinoma in patients receiving long-term immunosuppresive treatment: case report and literature review.

BACKGROUND: Sebaceous carcinoma (SC) is a very rare and aggressive malignant skin cancer that appears to occur with a greater frequency in the clinical setting of chronic immunosuppression; however, it is not reported in the literature as frequently as is squamous cell carcinoma (SCC). We report 2 cases of SC in organ transplant patients from clinical and histopathological points of view. METHODS: A 48-year-old patient after 3 renal transplantations (1986, 1986, and 1998) was presented to the Dermatology Department in 1999 because of a papillomatous lesion along her right upper eyelid. The lesion was excised. Histopathologically, it was diagnosed as a SC. There was no lymphovascular invasion and no metastasis; therefore no other treatment was included. No symptoms of recurrent disease were present 14 years since diagnosis. An 87-year-old patient after a renal transplantation in 1989 was referred to dermatologist in 1993 because of the lesion on his right temple. The lesion was excised; histopathologically, it was diagnosed as SC. Because of metastatic disease, he had a course of radiotherapy to the right side of the neck. The immunosuppressive drugs azathioprine and cyclosporine A were reduced. The patient died of metastatic disease 1 year later (3 years since diagnosis). Both patients had very high cumulative UV exposition during their lifetimes, and many skin cancers were diagnosed, especially SCC. RESULTS: It is necessary to realize that this cancer occurs more frequently in organ transplant patients, and its correct diagnosis is an essential issue because it has significantly more aggressive behavior than does SCC. In the 2 presented patients, we observed very rapid progression of disease. Despite aggressive treatment and reduction of immunosuppressive drugs, the second patient died 3 years after diagnosis. CONCLUSIONS: Regular dermatological follow-up is required in the population of organ transplant patients to identify all skin tumors in the early stage.

Immunopathological characteristics of patients with bullous pemphigoid and neurological disease.

BACKGROUND: The relationship between bullous pemphigoid (BP) and neurological disease has been the subject of numerous recent studies and BP antigens and their isoforms have been identified in the central nervous system (CNS). Whilst epidemiological data support this association, little is known about the pathomechanism behind this link and the immunological characteristics of patients with BP and neurological disease, other than multiple sclerosis (MS), has not been studied. OBJECTIVE: We aimed to compare the cutaneous immune response in BP patients with and without neurological disease, to investigate whether or not there is a distinctive immunopathological profile in patients with concomitant BP and neurological disease. METHODS: Seventy-two patients with BP were included and divided into two groups; those with neurological disease (BP+N, n = 43) and those without (BP-N, n = 29). Patients in BP+N group had a confirmed neurological disease by a hospital physician, neurologist or psychiatrist with positive neurological imaging where appropriate, or a Karnofsky score of 50 or less due to mental impairment. All sera were analysed with indirect immunofluorescence (IIF) using serial dilutions up to 1:120000, immunoblotting (IB) and Enzyme-linked immunosorbent assay (ELISA) for BP180 and BP230. RESULTS: Median antibody titres by IIF were 1:1600 vs. 1:800 for BP-N and BP+N, respectively, although the difference did not reach statistic significance (P = 0.93, Mann-Whitney U-test). ELISA values for both BP180 and BP230 did not differ significantly between the two groups. Similarly, autoantibodies to specific antigens as identified by ELISA and IB were not related to the presence of neurological disease. CONCLUSION: The results of this study indicate that patients with BP and neurological disease exhibit an immune response to both BP180 and BP230, thus the link between the CNS and the skin is not dependent on a specific antigen, but possibly both antigens or their isoforms may be exposed following a neurological insult, and play a role in generation of an immune response.

Epidermolysis bullosa acquisita and inflammatory bowel disease: a review of the literature.

We present a review of all previously reported cases of epidermolysis bullosa acquisita (EBA) and inflammatory bowel disease (IBD). We found 42 cases of coincident EBA and IBD in the literature: 35 cases of Crohn disease (CD) and 7 of ulcerative colitis (UC). The clinical and immunopathological features of the cases are described and the demographics collected. In the majority of cases, the diagnosis of IBD predated the development of the skin condition. The association between EBA and IBD was more common for CD than for UC. We discuss the immunopathogenesis of IBD and EBA, and also the link between them, namely type VII collagen.

Association between the subepidermal autoimmune blistering diseases linear IgA disease and the pemphigoid group and inflammatory bowel disease: two case reports and literature review.

We report two patients with subepidermal autoimmune blistering diseases and inflammatory bowel disease (IBD) [one with linear IgA disease (LAD) and ulcerative colitis (UC), and the other with mucous membrane pemphigoid (MMP) and Crohn disease (CD)], and present a review of all previously reported cases. We reviewed the literature, and found 48 cases of patients with autoimmune blistering diseases and IBD. The blistering diseases were LAD (25 patients), bullous pemphigoid (BP) (21), MMP (1) and pemphigoid gestationis (1), while the IBD types comprised UC (40) and CD (8). We describe the clinical and immunopathological features and demographic characteristics of the patients. In all but one case, the diagnosis of IBD predated the development of the skin condition. The association was more common with LAD than BP. The immunopathogenesis of IBD and autoimmune blistering diseases is discussed and a link between them hypothesized, namely, that the presentation of multiple antigens to the immune system during the unregulated inflammation in the bowel wall results in excitation of the immune system and recognition of autologous antigens.

Evidence-based (S3) guideline on topical corticosteroids in pregnancy.

Women with skin conditions may need topical corticosteroids during pregnancy. However, little is known about the effects of topical corticosteroids on the fetus. A guideline subcommittee of the European Dermatology Forum was organized to develop an evidence-based guideline on the use of topical corticosteroids in pregnancy (http://www.euroderm.org/edf/images/stories/guidelines/EDF-Guideline-on-Steroids-in-Pregnancy.pdf). The evidence from a Cochrane Review suggested that the major possible adverse effects on the fetus of topical corticosteroids were orofacial clefts when used preconceptionally and in the first trimester of pregnancy, and fetal growth restriction when very potent topical corticosteroids were used during pregnancy. To obtain robust evidence, a large population-based cohort study (on 84,133 pregnant women from the U.K. General Practice Research Database) was performed, which found a significant association of fetal growth restriction with maternal exposure to potent/very potent topical corticosteroids, but not with mild/moderate topical corticosteroids. No associations of maternal exposure to topical corticosteroids of any potency with orofacial cleft, preterm delivery and fetal death were found. Moreover, another recent Danish cohort study did not support a causal association between topical corticosteroid and orofacial cleft. The current best evidence suggests that mild/moderate topical corticosteroids are preferred to potent/very potent ones in pregnancy, because of the associated risk of fetal growth restriction with the latter.

Prevalence of benign cutaneous disease among Oxford renal transplant recipients.

BACKGROUND: The burden of malignant and benign cutaneous disease among renal transplant recipients (RTR) is substantial. Little attention is given to non-malignant skin problems in the literature despite their potential impact on quality of life or on aesthetics - which may contribute to poor compliance with immunosuppressive medications post-transplantation. OBJECTIVES: The aim of this study was to examine prevalence of benign cutaneous disease in a group of RTRs and identify risk factors for individual cutaneous conditions. METHODS: All cutaneous findings were recorded in a single full body skin examination of 308 RTRs. Data on medical, transplant and medication history were obtained from questionnaire and medical records. Odds ratios were calculated to look at associations between benign cutaneous diseases and various potential risk factors after controlling for gender, age, time since transplantation and skin type. RESULTS: Cutaneous infections such as viral warts (38%), fungal infection (18%) and folliculitis (27%) were common and usually chronic. A range of pilosebaceous unit disorders were observed with hypertrichosis being strongly associated with ciclosporin (P<0.0001). Other iatrogenic cutaneous effects included gingival hyperplasia (27%) and purpura (41%). We identified seborrhoeic warts and skin tags in 55% and 33% respectively. Inflammatory dermatoses were rare (<2%) apart from seborrhoeic dermatitis (9.5%). DISCUSSION: In this first comprehensive study on prevalence of benign cutaneous diseases in a UK transplant population, a wide range of skin disorders was identified. It is therefore important that RTRs have access to dermatology services post-transplantation for appropriate management of benign cutaneous conditions as well as early detection of cutaneous malignancy and education regarding risks of sun exposure.

Autoreactivity to bullous pemphigoid 180: is this the link between subepidermal blistering diseases and oral lichen planus?

Subepidermal blistering diseases are antibody-mediated diseases. The antigens differ between disease type, but bullous pemphigoid (BP)180 (collagen XVII) is a common finding in several clinical conditions. We report four patients with autoimmune blistering disease [linear Ig A disease (n=2), bullous pemphigoid (n=1), and epidermolysis bullosa acquisita (n=1)], all of whom also developed oral lichen planus (LP). In all cases, the diagnosis of the blistering disease predated the development of the oral lesions. All patients were under the care of dermatologists and of oral medicine/surgery doctors for the diagnosis and management of the oral LP. All had circulating antibodies to BP180 protein. To our knowledge, the association between blistering diseases and oral LP has not been reported previously, and may reflect autoimmunity to BP180.

Physiological changes in scalp, facial and body hair after the menopause: a cross-sectional population-based study of subjective changes.

BACKGROUND: Significant changes in scalp, facial and body hair occur after the menopause. These can have a significant negative impact on self-esteem and are also potential markers of endocrine or metabolic diseases. Knowledge of postmenopausal hair changes is important for clinicians to distinguish between normal physiological change and those that require further medical investigation. OBJECTIVES: To assess the subjective experience of scalp, facial and body hair change in a large cohort of normal postmenopausal females. METHODS: Postmenopausal females aged 45 years or over of northern European origin completed a questionnaire detailing scalp, facial and body hair changes following the menopause. Women with a history of thyroid disease, oophorectomy or premature menopause were excluded from the study. The Mann-Whitney U-test and the χ(2) test were used to assess the correlation between scalp, facial and body hair changes with age. RESULTS: Diffuse generalized hair loss was the most common form of scalp hair loss, reported by 26% of women. Frontal hair loss was reported by 9% of women. Facial hair gain was cited by 39% of females with the chin being the most frequent site for new growth (32% of women). Body hair loss was significantly correlated with older age (P < 0·001) and was most frequent at androgen-sensitive sites. We noted two patterns: (i) diffuse hair loss in which diffuse generalized scalp hair loss was significantly correlated with body hair loss and increasing age (P < 0·05); and (ii) frontal hair loss which was associated with higher facial hair scores and relatively younger age (P < 0·05) compared with women with diffuse hair loss. CONCLUSIONS: This is the first comprehensive study of the subjective hair changes in postmenopausal women. This study demonstrates two distinct patterns of hair change relating to age, which may reflect different underlying pathophysiological mechanisms and are of relevance to the medical management of these women as well as being possible predictors of health outcomes.

Childhood vulval lichen sclerosus: autoimmunity to the basement membrane zone protein BP180 and its relationship to autoimmunity.

Lichen sclerosus (LS) is associated with autoimmune disease in female children and adults. In adult women, there are antibody and T-cell responses to proteins in the basement membrane zone (BMZ). The aim of this study was to investigate reactivity to the BMZ in girls with LS. Nine girls with vulval LS were studied clinically and serologically. The presence of circulating BMZ autoantibodies was investigated. Autoimmunity was assessed by personal and family history of autoimmune diseases and autoantibodies. We detected circulating BMZ antibodies in four of the nine children, all with IgG responses. Three patients were positive by indirect immunofluorescence, one had a positive ELISA reaction to bullous pemphigoid antigen (BP)180, and three had a positive reaction on BP180 immunoblots. There was no association with autoimmune disease or clinical features. To our knowledge, this is the first study to find BMZ autoantibodies in children with vulval LS. The autoantibodies were directed at BP180 and were exclusively of the IgG class.

The high rate of familial lichen sclerosus suggests a genetic contribution: an observational cohort study.

BACKGROUND: Familial lichen sclerosus (LS) has been described in only 37 families. We feel that the association is under-reported. OBJECTIVES: To determine the percentage of patients with LS who have a positive family history. METHOD: A large observational-cohort study of a total of 1052 females at vulval clinics within a University Hospital with a diagnosis of LS of the vulva (clinical diagnosis was confirmed in 80% of cases by histology). Patients were questioned as to family history of LS or balanitis xerotica obliterans; male circumcision for medical reasons; vulval cancer; and routine medical and family history. The outcome was the presence or absence of personal or family history of LS, autoimmune disorder or vulval cancer. RESULTS: In total 1052 patients were investigated. Of these, 126 (12%) had a positive family history of LS. These patients belonged to 95 families. Vulval cancer was significantly increased in those with a family history of LS compared with those without (4.1% vs. 1.2%, P < 0.05). There was more associated autoimmune disease in familial LS than in sporadic LS, although this was not statistically significant. (7% vs. 5%, P > 0.2). CONCLUSION: Our data from a large cohort of patients with LS provide evidence of an increased risk for family members to develop LS. This indicates a likely genetic component in the aetiology of LS.

Association of seborrhoeic warts with skin cancer in renal transplant recipients.

BACKGROUND: Renal transplant recipients (RTR) have a well recognized increased risk of cutaneous malignancy. A clinical observation that RTR with skin cancer often had multiple seborrhoeic warts prompted an investigation in RTR into the relationship between seborrhoeic warts and skin cancer and an exploration into potential risk factors for seborrhoeic warts in this population, including infection with human papillomavirus (HPV). METHODS: This was a case control study involving 308 RTR. Clinical examinations identified seborrhoeic warts. Histological records reviewed to look for evidence of prior cutaneous malignancy. Seroprevalence of antibodies to 34 different HPV types tested using multiplex serology. Odds ratios (OR) calculated using unconditional logistic regression analysis to look for associations between skin cancer, HPV infection and seborrhoeic warts, controlling for potential confounding factors of gender, age and time since transplantation. RESULTS: Seborrhoeic warts were associated with non-melanoma skin cancer [OR = 3.7; 95% confidence intervals (CI) ranging from 1.6-8.9; P = 0.002] when confounding factors of gender, age and time since transplantation were controlled for. There was also an association between seborrhoeic warts and viral warts (OR = 3.0, CI: 1.6-5.4; P < 0.0001), but no association between seborrhoeic warts and infection with single or multiple HPV types. CONCLUSIONS: Seborrhoeic warts are associated with cutaneous malignancy, but not with any of the HPV types tested. The reasons for this association are unclear. RTR with multiple seborrhoeic warts may require more regular cutaneous examination to monitor for early signs of skin cancer.