Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus.

BACKGROUND: Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. OBJECTIVES: Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. METHODS: Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. RESULTS: Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. CONCLUSIONS: We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.

Healthcare utilization and management of actinic keratosis in primary and secondary care: a complementary database analysis.

BACKGROUND: The high prevalence of actinic keratosis (AK) requires the optimal use of healthcare resources. OBJECTIVES: To gain insight in to the healthcare utilization of people with AK in a population-based cohort, and the management of AK in a primary and secondary care setting. METHODS: A retrospective cohort study using three complementary data sources was conducted to describe the use of care, diagnosis, treatment and follow-up of patients with AK in the Netherlands. Data sources consisted of a population-based cohort study (Rotterdam Study), routine general practitioner (GP) records (Integrated Primary Care Information) and nationwide claims data (DRG Information System). RESULTS: In the population-based cohort (Rotterdam Study), 69% (918 of 1322) of participants diagnosed with AK during a skin-screening visit had no previous AK-related visit in their GP record. This proportion was 50% for participants with extensive AK (i.e. ≥ 10 AKs; n = 270). Cryotherapy was the most used AK treatment by both GPs (78%) and dermatologists (41-56%). Topical agents were the second most used treatment by dermatologists (13-21%) but were rarely applied in primary care (2%). During the first AK-related GP visit, 31% (171 of 554) were referred to a dermatologist, and the likelihood of being referred was comparable between low- and high-risk patients, which is inconsistent with the Dutch general practitioner guidelines for 'suspicious skin lesions' from 2017. Annually, 40 000 new claims representing 13% of all dermatology claims were labelled as cutaneous premalignancy. Extensive follow-up rates (56%) in secondary care were registered, while only 18% received a claim for a subsequent cutaneous malignancy in 5 years. CONCLUSIONS: AK management seems to diverge from guidelines in both primary and secondary care. Underutilization of field treatments, inappropriate treatments and high referral rates without proper risk stratification in primary care, combined with extensive follow-up in secondary care result in the inefficient use of healthcare resources and overburdening in secondary care. Efforts directed to better risk differentiation and guideline adherence may prove useful in increasing the efficiency in AK management. What's already known about this topic? The prevalence of actinic keratosis (AK) is high and, in particular, multiple AKs are a strong skin cancer predictor. The high prevalence of AK requires optimal use of healthcare resources. Nevertheless, (population based) AK healthcare utilization and management data are very rare. What does this study add? Although AK-related care already consumes substantial resources, about 70% of the AK population has never received care. Primary care AK management demonstrated underutilization of topical therapies and high referral rates without proper risk stratification, while in secondary care the extensive follow-up schedules were applied. This inefficient use of healthcare resources highlights the need for better harmonization and risk stratification to increase the efficiency of AK care.

Cumulative exposure to biological therapy and risk of cancer in patients with psoriasis: a meta-analysis of Psonet studies from Israel, Italy, Spain, the U.K. and Republic of Ireland.

BACKGROUND: Cancer risk following long-term exposure to systemic immunomodulatory therapies in patients with psoriasis is possible. OBJECTIVES: To assess a dose-response relationship between cumulative length of exposure to biological therapy and risk of cancer. METHODS: Four national studies (a healthcare database from Israel, and prospective cohorts form Italy, Spain and the U.K. and Republic of Ireland) collaborating through Psonet (European Registry of Psoriasis) participated in these nested case-control studies, including nearly 60 000 person-years of observation. 'Cases' were patients who developed an incident cancer. Patients with previous cancers and benign or in situ tumours were excluded. Four cancer-free controls were matched to each case on year of birth, sex, geographic area and registration year. Follow-up for controls was censored at the date of cancer diagnosis for the matched case. Conditional logistic regression was performed by each registry. Results were pooled using random-effects meta-analysis. RESULTS: A total of 728 cases and 2671 controls were identified. After matching, differences between cases and controls were present for the Charlson Comorbidity Index in all three registries, and in the prevalence of previous exposure to psoralen-ultraviolet A and smoking (the British Association of Dermatologists Biologic Interventions Register only). The risk of first cancers was not significantly associated with cumulative exposure to biologics (adjusted odds ratio per year of exposure 1·02, 95% confidence interval 0·92-1·13). Results were similar if squamous and basal cell carcinomas were included in the outcome. CONCLUSIONS: Cumulative length of exposure to biological therapies in patients with psoriasis in real-world clinical practice does not appear to be linked to a higher risk of cancer after several years of use.

Biologics combined with conventional systemic agents or phototherapy for the treatment of psoriasis: real-life data from PSONET registries.

BACKGROUND: Biologics have greatly improved psoriasis management. However, primary and secondary non-response to treatment requires innovative strategies to optimize outcomes. OBJECTIVE: To describe the use of combined treatment of biologics with conventional systemic agents or phototherapy in daily clinical practice. METHODS: We collected data on frequency of use, demographics, treatment characteristics and drug survival of biologics combined with conventional systemic agents or phototherapy in five PSONET registries. RESULTS: Of 9922 biologic treatment cycles, 982 (9.9%) were identified as combination treatment. 72.9% of treatment cycles concerned concomitant use of methotrexate, 25.3% concerned concomitant UVB therapy, acitretin or cyclosporin and 1.8% concerned combined treatment with PUVA, fumaric acids or a second biologic. Substantial variation was detected in type and frequency of combination treatments prescribed across registries. Patients initiated on combined treatment had generally severe disease and were affected with psoriasis for many years. The extent to which patients had been priory treated with biologic monotherapy and the proportion of patients affected with psoriatic arthritis differed between registries. Survival rates for etanercept, adalimumab, infliximab and ustekinumab with methotrexate ranged between 43 and 92%, 28 and 83%, 65 and 87% and 53 and 77%, respectively, across registries after one year with no consistent superior survival for a particular biologic. Longest survival on a biologic combined with methotrexate, acitretin or cyclosporin was 103, 78 and 34 months, respectively. CONCLUSION: Methotrexate was the most commonly used concomitant treatment for patients on a biologic. Wide geographical variations in treatment selection and persistence of combination treatment exist. Data derived from ongoing studies may help to determine whether combined treatment is superior to biologic monotherapy.

National registries of systemic treatment for psoriasis and the European 'Psonet' initiative.

About 11 million people suffer from psoriasis in Europe. This chronic condition may have a dramatic impact on quality of life. About 20% of patients may need systemic treatment to effectively control their disease activity. The introduction of biological agents greatly increased the options of systemic therapies for psoriasis. However, clinical experience with newer systemic therapies is relatively limited, and available data are mostly derived from short-term phase III trials. Except for PUVA and ciclosporin, long-term safety data from formal postmarketing studies are also largely lacking conventional treatment options. Registries provide one mechanism to monitor the long-term safety and effectiveness of treatment in the 'natural environment'. Several European countries have established registries to collect data on systemic psoriasis treatment. Even though different in some aspects of study design and monitoring, the registries share a number of common features: they include all the biological drugs and sometimes all the licensed systemic agents for psoriasis, and they observe the patients for a defined period of time irrespective of the drug given. Combining the results from these registries would increase their power and impact. We are developing an international collaboration called 'Psonet' that will perform a joint analysis of data from 9 individual national psoriasis registries.

Refinement and reduction of the Impact of Psoriasis Questionnaire: classical test theory vs. Rasch analysis.

BACKGROUND: Quality of life instruments are increasingly important in assessing disease severity. However, some of these measurements have been developed on a more or less ad hoc basis. Although not well standardized, psychometric analyses can be used to retest, refine and shorten existing quality of life instruments. OBJECTIVES: To psychometrically test and refine the Impact of Psoriasis Questionnaire (IPSO) and to compare the results of two different statistical approaches. PATIENTS AND METHODS: Among 792 psoriasis patients who were included in the PUVA Follow-up Study, we used classical test theory (CTT) and Rasch analysis to test and optimize the IPSO. Thereafter, two shortened versions of the IPSO derived from these models were compared. RESULTS: CTT analyses of the original IPSO demonstrated suboptimal item performance for six of 16 items and inappropriate subscaling. In contrast to the original four subscales, factor analysis of the CTT version yielded three subscales (mental functioning, mental wellbeing and stigmatization). The Rasch approach, which included ordering of thresholds, differential item functioning and item fit, resulted in a unidimensional 11-item questionnaire. Although the two new versions of the IPSO shared only six items, both reflected the original IPSO well. However, several arguments such as lower correlation coefficients, higher Cronbach's alpha, ordered thresholds, unidimensionality and fewer differences among subgroups of patients suggested that the Rasch version of the IPSO may be the preferred instrument to use. CONCLUSIONS: The IPSO can be improved and shortened and the Rasch-reduced version of this instrument is likely to assess the psychosocial impact of moderate to severe psoriasis on patients' lives best because it is a short, reliable and unidimensional measurement.

Squamous-cell cancer of the skin in patients given PUVA and ciclosporin: nested cohort crossover study.

BACKGROUND: Immunosuppressive treatments have been associated with an increased risk of skin cancer, especially in patients who have had organ transplants. We aimed to assess the risk of skin cancer in patients taking the ciclosporin who had been exposed to psoralen and ultraviolet-A light (PUVA) and other treatments for severe psoriasis. METHODS: We did a nested cohort crossover study of 28 participants in the PUVA follow-up study who were on ciclosporin to compare the frequency of squamous-cell carcinoma before and after first use of ciclosporin. We also analysed the entire PUVA study cohort (1380) to assess the relation between use of this drug and frequency of squamous-cell carcinoma. FINDINGS: In the 5 years before first use, six of 28 (21%) ciclosporin users developed a total of 20 squamous cell cancers. After ciclosporin use (average follow-up 6 years), 13 (46%) developed a total of 169 squamous-cell carcinomas. In the nested cohort, after adjustment for amount of exposure to PUVA and methotrexate, incidence of tumours was seven times higher after first ciclosporin use than in the previous 5 years (incidence rate ratio 6.9 [95% CI 4.3-11]). Multivariate analysis of the entire cohort showed that risk of squamous-cell carcinoma after any use of ciclosporin is close to that recorded for at least 200 PUVA treatments (3.1 [2.6-3.7] and 2.8 [2.6-3.2], respectively). INTERPRETATION: The risk of squamous cell cancer of the skin is increased by ciclosporin in patients with psoriasis who have been exposed to PUVA. Such risks should be balanced against the effectiveness of the drug and possible newer immunosuppressive agents.

The risk of melanoma in association with long-term exposure to PUVA.

BACKGROUND: Oral methoxsalen (psoralen) and ultraviolet A radiation (PUVA) is a highly effective therapy for psoriasis and many other skin conditions. It is carcinogenic. Previously we reported an increased risk of melanoma that first emerged 15 years after first treatment. OBJECTIVE: Our purpose is to present additional data concerning the associations of previous exposure to PUVA, the passage of time, and the risk of malignant melanoma. METHODS: We have prospectively studied a cohort of 1380 patients first treated with PUVA in 1975 and 1976. We have documented the occurrence of melanoma and in this report compare the observed and expected incidence of melanoma in this cohort, particularly melanomas developing since our earlier report (ie, after March 1996). RESULTS: Since 1975, 23 patients have developed 26 invasive or in situ cutaneous melanomas. In an average of 2.25 years since our last report, we detected 7 additional invasive melanomas (incidence rate ratio, 8.4; 95% confidence interval, 3.4-17.3). CONCLUSION: Beginning 15 years after first exposure to PUVA, an increased risk of melanoma is observed in our cohort of PUVA-treated patients. This risk is greater in patients exposed to high doses of PUVA, appears to be increasing with the passage of time, and should be considered in determining the risks and benefits of this therapy.

The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-membership survey.

BACKGROUND: Psoriasis can have a profound impact on a patient's quality of life. OBJECTIVES: To assess patients' perspectives on the impact of psoriasis on their lifestyle and emotional well-being and the social ramifications of living with the disease; to determine the range of therapies available; and to ascertain patients' satisfaction with the management of their disease. DESIGN: A 4-page, self-administered questionnaire was mailed on July 13 and 14, 1998, to the entire membership of the National Psoriasis Foundation (N = 40 350), and followed by a telephone survey of responders with severe psoriasis. MAIN OUTCOME MEASURES: Patients' perspectives on the psychosocial impact of psoriasis and the effectiveness of the management of their disease. RESULTS: Of the 40 350 questionnaires mailed out, a response rate of 43% was realized. The most frequent symptoms experienced by the mail-survey respondents were scaling (94%), itching (79%), and skin redness (71%); 39% reported that psoriasis covered 10% or more of their bodies. A total of 6194 patients with severe psoriasis were entered into the database for the telephone survey. Of these, 79% reported that psoriasis had a negative impact on their lives, 40% felt frustrated with the ineffectiveness of their current therapies, and 32% reported that treatment was not aggressive enough. CONCLUSIONS: The unprecedented response to the survey provides compelling evidence that individuals with psoriasis believe that the disease has a profound emotional and social as well as physical impact on their quality of life. Many patients with psoriasis, particularly those with severe disease, are frustrated with the management of their disease and by the perceived ineffectiveness of their therapies. Physicians may need to improve communication with their patients and should reevaluate their management of psoriasis.

Medication and medical service utilization for acne 1995-1998.

BACKGROUND: Acne occurs in most persons sometime during adolescence or early adulthood and is a frequent reason for visits to dermatologists and for prescription drug therapy. OBJECTIVE: The purpose of this study was to analyze changes in the utilization of physician services and medications for the treatment of acne. METHODS: An analysis was performed of data from two US federal surveys of outpatient physician services and prescribing for the years 1980 to 1997 and two commercial sources of drug prescription data for 1996 to 1998. From these data, I estimated visits for acne and drugs prescribed during these visits. RESULTS: Visits for women principally for acne are about 80% more frequent than those for men. Each year 5 million prescriptions for oral antibiotics and 1.4 million prescriptions for isotretinoin are dispensed for the treatment of acne. CONCLUSION: Substantial health care resources are devoted to the treatment of acne, with women particularly likely to continue to frequently utilize these services after 19 years of age.

Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanoma skin cancer: a critical review of the literature and meta-analysis.

OBJECTIVE: To assess the risk of developing a basal cell carcinoma (BCC), and/or a squamous cell carcinoma (SCC), and/or Bowen disease (SCC in situ) after a nonmelanoma skin cancer (NMSC) of a specific type. DATA SOURCES: Four electronic databases were searched from January 1, 1966, to October 21, 1999. STUDY SELECTION: We included all studies published in English, identified by standard search strategies, that provided original data quantifying the risk of an NMSC among persons with a previous NMSC. DATA EXTRACTION: For each study and separate histological type of index skin tumor and subsequent skin tumor (SCC, BCC, NMSC, or Bowen disease), we determined the 3-year cumulative risk and the incidence rate of second tumors per 100 000 person-years. In cases where more than 1 study was assessing the risk of one specific tumor type after another, we undertook a formal meta-analysis. We compared the incidence of a subsequent SCC after an index SCC and of a subsequent BCC after an index BCC with the incidence of the first occurrence of such tumors in the comparable general population. DATA SYNTHESIS: We identified and reviewed 17 studies that included data for 26 tumor combinations. Overall, the 3-year cumulative risk of a subsequent SCC after an index SCC is 18%, at least a 10-fold increase in incidence compared with the incidence of first tumors in a comparable general population. For BCCs, the 3-year cumulative risk is 44%, also at least a 10-fold increase in incidence compared with the rate in a comparable general population. The risk of developing a BCC in patients with a prior SCC is about equal to that risk among persons with a prior BCC, but the risk of developing an SCC in patients with a prior BCC is low (6%). CONCLUSIONS: Although these studies vary in their study type, location, and biases, their results are consistent. The risk of developing a subsequent skin cancer of a specific type depends on the type of prior NMSC and number of prior skin tumors of that type. Based on these findings, follow-up strategies for patients with BCC and SCC are suggested.

Incidence of skin cancer in 5356 patients following organ transplantation.

BACKGROUND: Skin cancer following solid organ transplantation is an important cause of morbidity in long-term survivors. This risk is well known but imprecisely quantified. OBJECTIVES: We aimed to determine: (i) the skin cancer risks in transplant patients more precisely; (ii) whether the risk of malignant melanoma is altered; and (iii) whether the risk of epithelial cancers occurring at non-exposed sites is comparable with that seen in sun-exposed sites. METHODS: We linked a population-based cohort of 5356 patients who had received organ transplants in Sweden between 1970 and 1994 with the compulsory Swedish Cancer Registry, to identify all cancer cases except basal cell carcinomas, which are not registered. RESULTS: After a mean follow-up of 5.6 years post-transplantation, 172 of 5356 patients developed 325 non-melanoma skin cancers (excluding basal cell carcinomas) and six malignant melanomas. The relative risk of non-melanoma skin cancer was 108.6 [95% confidence interval (CI) 94.6-123.1] for men and 92.8 (95% CI 73.2-116.0) for women. The highest risks were noted for upper limbs, and the risk increased with time. No significant increase in malignant melanomas was noted: the relative risk was 1.6 (95% CI 0.5-3.7) for men and 0.5 (95% CI 0. 0-2.6) for women. Except for the lip, which is also sun-exposed, other epithelial sites did not show comparable increases in cancer risk. CONCLUSIONS: We conclude that organ transplant recipients are at a highly increased risk for non-melanoma skin cancer and must be closely followed throughout their lives. Cancer risk associated with transplantation is higher for sun-exposed than for non-sun-exposed epithelial tissues, even among populations living in regions with low solar insolation.

Top-cited dermatology authors publishing in 5 "high-impact" general medical journals.

BACKGROUND: In addition to publishing in the dermatologic literature, some dermatologists also publish articles in the general medical journals, which enjoy wide circulation and whose articles are often cited. OBJECTIVE: To identify articles and citations to these articles that the most frequently cited authors in the dermatologic literature published in highly cited general medical journals. DESIGN: We obtained a citation database from the Institute of Scientific Information, Philadelphia, Pa, that identified all articles published by the top-cited authors in the dermatologic literature in 5 "high-impact" general medical journals. SETTING: The 5 high-impact general medical journals with the historically highest impact factors. SUBJECTS: Two hundred top-cited authors in dermatology journals and their coauthors. MAIN OUTCOME MEASURE: Number of citations to articles published in 5 high-impact general medical journals. RESULTS: From 1981 to 1998, 120 of the 200 top-cited dermatology authors published a total of 674 papers in the 5 most highly cited general medical journals. Original articles published in these high-impact general medical journals were cited an average 7.5 times more often than articles published in dermatology journals. CONCLUSIONS: Top-cited authors in dermatology journals also frequently publish in the leading 5 high-impact general medical journals. Publications in these journals by dermatologists are often highly cited.