Expert consensus on the persistence of biological treatments in moderate-to-severe psoriasis.

BACKGROUND: Treatment persistence is becoming a useful measure to evaluate long-term effectiveness and safety of biological therapies in real-world settings. OBJECTIVE: The main objective of this study was to explore the scientific opinion of a panel of dermatologists and hospital pharmacists to reach a consensus about the impact, causes, and best strategies and interventions that might be associated with improved drug persistence in patients with psoriasis in Spain. METHODS: This research was conducted using a modified Delphi method organized in two rounds and involving a panel of 90 dermatologists and 34 hospital pharmacists. A questionnaire of 70 items was developed. The items proposed to reach a consensus included topics such as definitions and measures in the treatment of psoriasis, analysis of treatment persistence, factors that may influence treatment persistence, impact of treatment persistence and economic cost of treatment. RESULTS: Dermatologists reached a consensus on 77.1% of the items proposed, and hospital pharmacists reached a consensus on 71.4%. Both groups agreed that it is important to use standardized measures in the evaluation of treatment maintenance over time. Dermatologists agreed that treatment survival, persistence and retention are synonymous, but hospital pharmacists considered only treatment persistence as a valid term. In addition, panelists agreed that drug persistence is an indicator of success in the treatment of psoriasis that may be influenced by a drug's effectiveness and safety profile, as well as by patient satisfaction. They agreed that the different causes of treatment discontinuation should be considered in Kaplan-Meier analysis of treatment persistence. Moreover, treatment persistence was agreed to decrease the cost of therapy. CONCLUSION: This Delphi consensus highlights the different perspectives of dermatologists and hospital pharmacists regarding the interpretation of treatment persistence, and the challenge of harmonizing the results obtained.

The depth of follicular extension in actinic keratosis correlates with the depth of invasion in squamous cell carcinoma: implication for clinical treatment.

BACKGROUND: Actinic keratosis (AK) may show extension down follicles, not only in cases with full-thickness epidermal atypia ('bowenoid' AK), but also in cases with atypia limited to the epidermal basalis. Previous studies have demonstrated that, in bowenoid AK, follicular extension is usually superficial, being limited to the upper follicular segment. Little is known about the depth of follicular involvement in cases of invasive squamous cell carcinoma of the skin (iSCC) arising from AK and the role of the follicle in iSCC pathogenesis. OBJECTIVE: This study investigated the relationship between follicular extension of atypical keratinocytes in an AK and the development of iSCC from the follicular wall. The depth of follicular extension was correlated with the depth invasion of iSCC. Differences between the differentiated and classical pathways of iSCC were also examined. METHODS: We performed a retrospective histologic review of 193 biopsy specimens of iSCC with an associated AK. We assessed the presence and depth of follicular extension of atypical keratinocytes in the AK, using tumour (Breslow) thickness and the follicular unit level (infundibular, isthmic and subisthmic), as well as iSCC being present directly adjacent to the follicular basalis. RESULTS: Follicular extension was present in 25.9% of the cases (50 cases), usually extending into the lower follicular segment. The iSCC was present directly adjacent to the follicular basalis in 58% of the cases (29 cases), correlating highly with the depth of follicular extension (infundibular: 3/12; isthmic: 21/33; subisthmic 5/5). CONCLUSION: The depth of follicular extension of atypical keratinocytes in an AK correlates with the development of depth of invasion of an associated iSCC, irrespective of the pathway of origin. It is therefore important to note the presence and the depth of follicular extension when diagnosing an AK, as follicular extension likely accounts for a significant proportion of recurrent AK and the development of iSCC following superficial treatment modalities.

Epithelial-to-mesenchymal transition contributes to invasion in squamous cell carcinomas originated from actinic keratosis through the differentiated pathway, whereas proliferation plays a more significant role in the classical pathway.

BACKGROUND: Every actinic keratosis (AK) starts with atypia at the basal layers of the epidermis (AK I). Progression into invasive squamous cell carcinoma (iSCC) may occur following two main pathways, classical and differentiated. In the former, iSCC only occurs after involvement of the upper epidermal layers by atypical cells (AK III), while in the latter iSCC develops directly from AK I. In the anogenital mucosa, these two pathways are associated with differential expression of p53 and p16. OBJECTIVE: To explore differences between both pathways in the pathogenesis of AK, focusing on Ki67, p53, p16 and molecules that reveal epithelial-mesenchymal transition (EMT). METHODS: Tissue microarrays representative of superficial and deep portions of 80 consecutive iSCCs (53 DP/27CP) were studied immunohistochemically using antibodies against Ki67, p53, p16, vimentin, E-cadherin, ß-catenin and D2-40. The evaluation was performed by three researchers and the results compared to consensus. RESULTS: Invasive squamous cell carcinomas originated through the differentiated pathway exhibited significantly lower proliferative activity (Ki67) (30% vs 46%, P = 0.003) and significantly lower expression of vimentin (P < 0.001), E-cadherin (P < 0.001) and membranous ß-catenin (P < 0.001) than iSCCs developed through the classical pathway. The expression of E-cadherin and membranous ß-catenin was significantly correlated (Pearson's r = 0.386, Spearman's Rho < 0.001). There were no significant differences regarding the expressions of p53, p16 and D2-40. CONCLUSION: Epithelial-mesenchymal transition participates in transformation from AK I into iSCC (differentiated pathway), whereas a higher proliferative capacity facilitates intraepidermal extension in the classical pathway. Podoplanin, which is also involved in tumour invasion, does not seem to play a differential role in either pathway. Finally, the absence of differences in p53 and p16 expressions is at variance with other epithelia where the classical pathway is associated with human papillomavirus infection and can be explained by the fact that both AK pathways share identical mechanisms of actinic oncogenesis.

Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study.

BACKGROUND: It has been shown that the interleukin (IL)-23/IL-17 axis is critical in the pathogenesis of psoriasis. OBJECTIVES: To present the primary end point (week 12) and safety and efficacy data up to week 24 from a head-to-head trial (IXORA-S) of the IL-17A inhibitor ixekizumab (IXE) vs. the IL-12/23 inhibitor ustekinumab (UST). METHODS: Randomized patients received IXE (160-mg starting dose, then 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks, n = 136) or UST (45 mg or 90 mg weight-based dosing per label, n = 166). The primary end point was the proportion of patients reaching ≥ 90% Psoriasis Area and Severity Index improvement (PASI 90). Hommel-adjusted key secondary end points at week 12 included PASI 75, PASI 100, static Physician's Global Assessment (sPGA) score of 0 or 1, sPGA score of 0, Dermatology Life Quality Index (DLQI) score of 0 or 1, ≥ 4-point reduction on the itch numerical rating scale (NRS) and changes in itch NRS and skin pain visual analogue scale. RESULTS: At week 12, IXE (n = 99, 72·8%) was superior to UST (n = 70, 42·2%) in PASI 90 response (response difference 32·1%, 97·5% confidence interval 19·8-44·5%, P < 0·001). Response rates for PASI 75, PASI 100 and sPGA (0,1) were significantly higher for IXE than for UST (adjusted P < 0·05). At week 24, IXE-treated patients had significantly higher response rates than UST-treated patients for PASI, sPGA and DLQI (unadjusted P < 0·05). No deaths were reported, and the treatments did not differ with regard to overall incidences of adverse events (P = 0·299). CONCLUSIONS: The superior efficacy of IXE demonstrated at week 12 persisted up to week 24. The safety profiles were consistent with those previously reported for both treatments.

Phototoxic reaction to a combined oral contraceptive (levonorgestrel/ethinylestradiol).

We present the case of a phototoxic skin reaction due to the regular intake of a combined oral contraceptive (levonorgestrel/ethinylestradiol). Upon spectrophotometer testing, we demonstrated high absorption in the UV-B region of the solar spectrum of the combined product (Ovoplex®), especially for the estrogen compound (ethinylestradiol).

Adverse events associated with discontinuation of the biologics/classic systemic treatments for moderate-to-severe plaque psoriasis: data from the Spanish Biologics Registry, Biobadaderm.

BACKGROUND: Little is known about the adverse events (AEs) that lead to suspension of systemic treatments for psoriasis in clinical practice. OBJECTIVE: The study aimed to investigate AEs associated with discontinuation of systemic therapy in patients with psoriasis in a clinical setting (Biobadaderm). MATERIALS AND METHODS: Multicentre, prospective, cohort study of patients with moderate-to-severe plaque psoriasis receiving systemic therapies from January 2008 to November 2015, in 12 hospitals in Spain. The incidence rate (IR) was used to compare biologics and classic systemic therapies. RESULTS: A total of 4218 courses of treatment were given to 1938 patients. A total of 447 (11%) treatments were discontinued due to AEs. The IR of AE associated with discontinuation of systemic therapies was 13 events/100 patient-years (PY) (95% CI: 12.14-13.93), 9.34 events/100 PY (95% CI: 8.44-10.33) for biologics and 19.67 (95% CI: 17.9-21.6) events/100 PY for classics (P < 0.001). Of 810 discontinuation-related AEs, 117 (14%) were serious. The highest IRs were for cyclosporine [49.18/100 PY (95% CI: 41.91-57.72)] and infliximab [26.52/100 PY (95% CI: 20.98-33.51). Ustekinumab presented the lowest IR (2.6/100 PY (95% CI: 1.83-3.69). LIMITATIONS: Observational study with potential selection bias. CONCLUSION: Biologic therapies are associated with a lower rate of discontinuation-related AEs than are classic therapies in real clinical practice. Ustekinumab showed the lowest incidence.

Comparison of phenotype, comorbidities, therapy and adverse events between psoriatic patients with and without psoriatic arthritis. Biobadaderm registry.

BACKGROUND: There are a limited number of studies comparing psoriasis patients without psoriatic arthritis (PsA) to those with arthritis. Previous results are controversial. OBJECTIVES: To perform a comparative analysis of the phenotype, baseline comorbidities, therapeutic profile and incidence of adverse events (particularly overall adverse events, infections and infestations, malignancies and psychiatric disorders) among psoriatic patients with/without PsA. METHODS: All the patients on the Biobadaderm registry, a prospective inception cohort of psoriasis patients on systemic therapy, were included. Patients were divided into two groups: those with psoriasis without arthritis at the time of entry into the cohort (Pso group) and those with psoriasis and psoriatic arthritis (PsA group) at entry. Patients were followed until the censorship date (last visit in a lost-to-follow-up patient, or 10 November 2015, whichever occurred first). We excluded all the patients who developed any kind of signs and/or symptoms of joint involvement during the follow-up. A descriptive analysis was performed. We estimated incidence ratios (IRR) of adverse events during systemic treatment using a mixed-effects Poisson regression. RESULTS: We included 2120 patients: 1871 (88%) patients with psoriasis without arthritis and 249 (12%) with psoriasis and PsA. The follow-up time was 5020 patients-year in the Pso group and 762 patients-year in the PsA group. Patients with PsA had more comorbidities, particularly hypertension and liver disease; used a higher number of systemic therapies, particularly anti-TNFα drugs and combination therapy; and presented more adverse events (IRR adjusted = 1.29; 95% CI: [1.05-1.58]), particularly serious adverse events (IRR adjusted = 1.51; 95% CI: [1.01-2.26]) and infections/infestations (IRR adjusted = 1.88; 95% CI: [1.27-2.79]), independently of the associated comorbidities and present/past therapies. CONCLUSIONS: Given the differences between patients with psoriasis alone or with psoriasis associated with PsA, patients with psoriasis and PsA should be followed and managed more closely and with specific attention.

Precancerous Skin Lesions. / Precáncer cutáneo.

Certain clinically and histologically recognizable skin lesions with a degree of risk of progression to squamous cell carcinoma have been traditionally grouped as precancerous skin conditions but now tend to be classified as in situ carcinomas. This consensus statement discusses various aspects of these lesions: their evaluation by means of clinical and histopathologic features, the initial evaluation of the patient, the identification of risk factors for progression, and the diagnostic and treatment strategies available today.

Reliability of the MDi Psoriasis® Application to Aid Therapeutic Decision-Making in Psoriasis. / Fiabilidad de una aplicación de ayuda a la toma de decisiones terapéuticas en el paciente con psoriasis (MDi Psoriasis®).

BACKGROUND: Therapeutic decisions in psoriasis are influenced by disease factors (e.g., severity or location), comorbidity, and demographic and clinical features. OBJECTIVE: We aimed to assess the reliability of a mobile telephone application (MDi-Psoriasis) designed to help the dermatologist make decisions on how to treat patients with moderate to severe psoriasis. METHOD: We analyzed interobserver agreement between the advice given by an expert panel and the recommendations of the MDi-Psoriasis application in 10 complex cases of moderate to severe psoriasis. The experts were asked their opinion on which treatments were most appropriate, possible, or inappropriate. Data from the same 10 cases were entered into the MDi-Psoriasis application. Agreement was analyzed in 3 ways: paired interobserver concordance (Cohen's κ), multiple interobserver concordance (Fleiss's κ), and percent agreement between recommendations. RESULTS: The mean percent agreement between the total of 1210 observations was 51.3% (95% CI, 48.5-54.1%). Cohen's κ statistic was 0.29 and Fleiss's κ was 0.28. Mean agreement between pairs of human observers only, excluding the MDi-Psoriasis recommendations, was 50.5% (95% CI, 47.6-53.5%). Paired agreement between the recommendations of the MDi-Psoriasis tool and the majority opinion of the expert panel (Cohen's κ) was 0.44 (68.2% agreement). CONCLUSIONS: The MDi-Psoriasis tool can generate recommendations that are comparable to those of experts in psoriasis.

Management of Biologic Therapy in Moderate to Severe Psoriasis in Surgical Patients: Data From the Spanish Biobadaderm Registry. / Manejo de los tratamientos biológicos en pacientes con psoriasis moderada-grave sometidos a intervenciones quirúrgicas en el registro español Biobadaderm.

BACKGROUND AND OBJECTIVE: We now have considerable experience in the use of biologic agents to treat psoriasis, but doubts about management arise in certain clinical settings. Surgery is one of them. Although treatment guidelines advise that biologics be suspended before major surgery, data about actual clinical practices and associated complications are lacking. We aimed to analyze current practice in the clinical management of these cases. METHODS: Retrospective study of cases in the Biobadaderm database. We analyzed the management of biologic therapy in patients with psoriasis who underwent surgical procedures. RESULTS: Forty-eight of the 2113 patients registered in Biobadaderm underwent surgery. The largest percentage of procedures (31%) involved skin lesions. Biologic treatment was interrupted in 42% of the cases. No postsurgical complications were significantly related to treatment interruption. Likewise we detected no associations between treatment interruption and other variables, such as sex, age, or duration or severity of psoriasis. CONCLUSION: Continuity of biologic treatment and the risk of postsurgical complications were not associated in this study, although conclusions are limited by the small sample size.

Patient-relevant needs and treatment goals in nail psoriasis.

PURPOSE: Patient-centered health care implies that medical decisions are made jointly by physician and patient, based on patient needs. Aims were to (a) identify treatment goals for a new questionnaire on patient needs and benefits in nail psoriasis treatment; (b) analyze the importance of treatment goals in patients with nail psoriasis in general and in defined subgroups; and (c) determine the association between overall treatment goal importance and quality of life. METHODS: The study comprised the following steps: qualitative survey on needs and burdens in 120 patients; development of items by an interdisciplinary expert group; item testing in 55 patients in four countries; revision of the questionnaire and assessment in 203 patients in six countries (Germany, Denmark, Italy, Spain, USA, Japan). The percentage of patients rating the goals as 'quite/very important' was compared between various patient subgroups. RESULTS: Based on 692 free-text statements, 26 items were developed which were reduced to 24 items after pilot testing. Each of these treatment goals applied to the majority of patients in the multi-center study. Goal importance increased with severity of nail psoriasis, but not with age or disease duration. Manual dexterity and social interaction were of particular importance. Goal importance and quality of life were associated, but not redundant (r = 0.612, p < 0.001). CONCLUSIONS: Patients with nail psoriasis have manifold and specific treatment goals. Goal importance is a construct different from disease-specific quality of life and should be assessed separately. The new questionnaire can support goal setting in clinical practice.

Consensus document on the evaluation and treatment of moderate-to-severe psoriasis: Psoriasis Group of the Spanish Academy of Dermatology and Venereology.

Psoriasis is a highly prevalent disease with a major impact on quality of life; therefore, appropriate patient management is mandatory. Given that many issues in psoriasis are controversial and not clearly defined by evidence-based medicine, management of psoriasis is very variable. Expert consensus can generate practical guidelines for optimization of patient care. Much has changed since 2009, when the Consensus Document on the Evaluation and Treatment of Moderate to Severe Psoriasis was published by the Spanish Psoriasis Group (GEP) of the Spanish Academy of Dermatology and Venereology (AEDV). The objective of the present consensus document is to provide the dermatologist with updated recommendations for the evaluation and treatment of patients with moderate-to-severe plaque psoriasis. All active members of the GEP of the AEDV were invited to participate in the survey. The final group comprised 46 members from various areas of Spain and with substantial experience in managing psoriasis. A 3-round Delphi process was used to reach consensus. Consistent agreement and consistent disagreement (consensus) required the achievement of at least two of the following three criteria: Criterion 1, which was based on the position occupied by the mean on a scale of 1-9 and an SD <2; Criterion 2, which was based on the median and interquartile range (IQR) on a scale of 1-9; Criterion 3, which considered the percentage of the voting experts on a scale of 1-9. The items studied were definition of severity, therapeutic objectives, indications for systemic treatment and biologic therapy, induction and maintenance periods, therapeutic failure, loss of response, relapse and rebound, continuous and intermittent therapy, screening of patients before treatment, adherence to therapy, follow-up of treatment outcome, combination of drugs, transitioning and associated comorbidities. Consistent agreement or disagreement (consensus) was achieved for 198 items (agreement, 3 criteria 146 items, 2 criteria 43 items; disagreement, 3 criteria 9 items, 2 criteria 0 items) based on the criteria described above. Completion of the Delphi consensus process enabled a broad and experienced group of Spanish psoriasis experts to provide useful and practical guidelines for the management and treatment of patients with moderate-to-severe psoriasis, particularly in areas where evidence is lacking.

Survival of classic and biological systemic drugs in psoriasis: results of the BIOBADADERM registry and critical analysis.

BACKGROUND: Few reported studies compare drug survival in moderate-to-severe psoriasis vulgaris. OBJECTIVES: To describe and compare drug survival of systemic drugs, including biologic agents (infliximab, etanercept, adalimumab and ustekinumab) and classical drugs (acitretin, ciclosporin and methotrexate) in moderate-to-severe psoriasis. METHODS: This was a multicenter, prospective, cohort study of patients receiving systemic therapies between 2008 and 2013 in 12 hospitals in Spain. Baseline data and drug discontinuation were collected. Drug survival is presented using Kaplan-Meier survival curves. We compared adjusted risk ratios of serious adverse events (AEs) with results of survival analysis for AEs. RESULTS: A total of 1956 patients were included for analysis (1240 exposed to biologics during follow-up and 1076 to classic therapies). Median follow-up time was 3.3 years (0.0-5.1 years). There were 2209 discontinuations out of 3640 therapy cycles started. The main reason for discontinuation was lack of efficacy (36.4%) and remission (27.2%). Biologics showed a higher drug survival than classics and the pattern of survival results for all outcomes (positive or negative) were very similar. Adjusted risk ratios of serious AEs did not agree with results of survival analysis. LIMITATIONS: A limitation is that this is an observational study with potential selection bias. CONCLUSION: Survival as a proxy measure of drug safety in psoriasis is inadequate.

Prevalence of actinic keratosis among dermatology outpatients in Spain.

BACKGROUND: Actinic keratoses (AKs) are common skin lesions associated with an increased risk of developing squamous cell carcinoma. Few studies in Europe have focused on AK prevalence. AIM: To determine the point prevalence of AKs in a dermatology outpatient population in Spain, to describe the clinical characteristics of these lesions and to characterise the profile of AK patients. METHODS: Observational, cross-sectional, multicentre study conducted in 19 hospitals (dermatology outpatient services) around Spain. A total of 204 consecutive patients per hospital who were ≥45 years old were screened for the presence of AKs. RESULTS: 3877 patients were assessed and the overall AKs prevalence was 28.6%. Prevalence was significantly higher in men than women (38.4% vs. 20.8%, p<0.0001) and increased with age for both sexes (45.2% in 71-80 years). Scalp and ear lesion locations were significantly more frequent in men (51.9% vs. 2.7% and 16.9% vs. 2.4%, respectively, p<0.0001 both cases) and the cheek, nose and neckline in women (46.3% vs. 34.0% [p<0.0001], 43.0% vs. 24.8% [p<0.0001] and 5.3% vs. 1.8% [p=0.002]). Men showed a significantly higher frequency of ≥2 affected areas than women (42.7% vs. 20.3%, p<0.0001). Among patients with AK lesions, only 65% confirmed that they were the reason for the visit to the clinic. CONCLUSIONS: Approximately a quarter of the dermatology outpatient population in Spain aged ≥45 years old have AKs, with the prevalence rate being highest in men and in older age groups. AK is underdiagnosed and a proactive strategy is needed for the diagnosis and early treatment of these lesions.

Core Content for Undergraduate Medical Education in Spain: Recommendations of the Instructors' Group of the Spanish Academy of Dermatology and Venereology (AEDV).

BACKGROUND: Skin problems are among the most frequent reasons for seeking medical attention in primary care. In recent years, as a result of the process of adapting medical curricula to the requirements of the European Higher Education Area, the amount of time students spend learning the concepts of dermatology has been reduced in many universities. MATERIAL AND METHODS: In order to reach a consensus on core content for undergraduate education in dermatology, we sent a survey to the 57 members of the instructors' group of the Spanish Academy of Dermatology and Venereology (AEDV), asking their opinions on what objectives should be set for a dermatology course in Spain. A total of 131 previously selected objectives were listed. We then applied the Delphi method to achieve consensus on which ones the respondents considered important or very important (score≥4 on a Likert scale). RESULTS: Nineteen responses (33%) were received. On the second round of the Delphi process, 68 objectives achieved average scores of at least 4. The respondents emphasized that graduates should understand the structure and functions of the skin and know about bacterial, viral, and fungal skin infections, the most common sexually transmitted diseases (STDs), and the 4 main inflammatory dermatoses. Students should also learn about common complaints, such as itching and bald patches; the management of dermatologic emergencies; purpura and erythema nodosum as signs of internal disease; and the prevention of STDs and skin cancer. During clinical clerkships students should acquire the communication skills they will need to interview patients, write up a patient's medical history, and refer the patient to a specialist. CONCLUSIONS: The AEDV's group of instructors have defined their recommendations on the core content that medical faculties should adopt for the undergraduate subject of dermatology in Spain.

Association of the PDE3A-SLCO1C1 locus with the response to anti-TNF agents in psoriasis.

Psoriasis is a prevalent autoimmune disease of the skin that causes significant psychological and physical disability. Tumor necrosis factor (TNF)-blocking agents have proven to be highly efficacious in the management of moderate-to-severe psoriasis. However, a significant percentage of patients do not respond to this treatment. Recently, variation at the PDE3A-SLCO1C1 (phosphodiesterase 3A-SoLute Carrier Organic anion transporter family member 1C1) locus has been robustly associated with anti-TNF response in rheumatoid arthritis. Using a cohort of 130 psoriasis patients treated with anti-TNF therapy, we sought to analyze the association of this locus with treatment response in psoriasis. We found a highly significant association between PDE3A-SLCO1C1 and the clinical response to TNF blockers (P=0.0031). Importantly, the allele that was previously associated with the lack of response to rheumatoid arthritis (G allele, single-nucleotide polymorphism rs3794271) was associated with a higher anti-TNF efficacy in psoriasis. The results of this study are an important step in the characterization of the pharmacogenetic profile associated with anti-TNF response in psoriasis.

Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2).

BACKGROUND: Apremilast, an oral phosphodiesterase 4 inhibitor, regulates immune responses associated with psoriasis. OBJECTIVES: ESTEEM 2 evaluated the efficacy and safety of apremilast 30 mg twice daily for moderate-to-severe plaque psoriasis. METHODS: This phase III, double-blind, placebo-controlled trial randomized adults to apremilast or placebo (2 : 1). At week 16, placebo patients switched to apremilast. At week 32, apremilast patients achieving ≥ 50% reduction in Psoriasis Area and Severity Index (PASI 50) were rerandomized (1 : 1) to continue apremilast or receive placebo. Upon loss of 50% of PASI improvement obtained at week 32, patients rerandomized to placebo resumed apremilast. RESULTS: The modified intention-to-treat population (full analysis set) included 137 placebo and 274 apremilast patients. At week 16, significantly more apremilast patients achieved PASI 75 (28·8%), PASI 50 (55·5%) and static Physician's Global Assessment score of 0 or 1 (20·4%) vs. placebo (5·8%, 19·7%, 4·4%, respectively; P < 0·001). Most patients rerandomized to apremilast at week 32 had a PASI 50 response at week 52 (80%). Patients treated with apremilast showed significant improvements in quality of life (as assessed by the Dermatology Life Quality Index) and pruritus at week 16 compared with placebo (P < 0·001). The exposure-adjusted incidence of adverse events did not increase with continued apremilast treatment for up to 52 weeks. The most common adverse events were nausea, diarrhoea, nasopharyngitis and upper respiratory tract infection. CONCLUSIONS: Apremilast was effective in the treatment of moderate-to-severe plaque psoriasis over 52 weeks.

Lupus erythematosus tumidus: a clinical and histological study of 25 cases.

BACKGROUND: Lupus erythematosus tumidus (LET) is a subtype of cutaneous lupus erythematosus (CLE) that has been well characterized in recent years. However, some controversy still remains concerning the histological features of epidermal involvement. OBJECTIVES: The objective of this report is to describe the clinical and microscopic features of LET in patients diagnosed at Hospital Universitari Germans Trias i Pujol, Spain. METHODS: We conducted a retrospective study of 25 patients with a diagnosis of LET. RESULTS: All patients presented with typical LET lesions (smooth, erythematous plaques without macroscopic epidermal changes, such as follicular plugs or scale, that resolved without residual scarring or hypopigmentation). None of the patients fulfilled the criteria for systemic lupus erythematosus during follow-up. Test results for antinuclear antibodies were positive in five patients (20%), with titres below one of 320 in all cases. Twenty-two patients (88%) required antimalarial therapy; response was good in 70% and moderate response in 30%. Minor epidermal alterations were observed in 52% of biopsy specimens, with focal basal vacuolization being the most frequent. CONCLUSIONS: LET is a variant of CLE that has distinctive clinical, histologic and prognostic features. Unlike the patients in the case series previously described in the literature, most of our patients required treatment with antimalarials. Histology revealed mild epidermal alterations in a significant percentage of patients. Thus, in our opinion, the absence of microscopic epidermal alterations is not constant in LET.

Necrotizing and sarcoidal granulomas in the skin and synovial membrane, associated with common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinaemia, T-cell abnormalities and recurrent bacterial infections. Patients with CVID can present granulomatous lesions on both the skin and other organs. When these lesions are the first sign of the disease, the diagnosis can be very challenging. We report the case of a patient with undiagnosed CVID, who presented with necrotizing and sarcoidal granulomas on the skin and synovial membrane as the first appearance of immunodeficiency.

Actinic keratosis with atypical basal cells (AK I) is the most common lesion associated with invasive squamous cell carcinoma of the skin.

BACKGROUND: Progression from actinic keratosis (AK) to invasive squamous cell carcinoma (iSCC) of the skin is thought to occur after the development of full thickness epidermal neoplasia, as in the classic pathway of cervical cancer. Nevertheless, cutaneous iSCC may also directly arise from a proliferation of atypical basaloid cells limited mostly to the epidermal basal layer (AK I), akin to what happens in the 'differentiated pathway' of iSCC of the vulva, oral cavity and other locations. OBJECTIVE: To evaluate the prevalence of classic and differentiated pathways in the development of cutaneous iSCC. METHODS: The epidermis adjacent to and overlying iSCC, assumed to be representative of pre-existing lesions, was histologically studied in 196 skin biopsy specimens showing iSCC. RESULTS: AK I, AK II and AK III lesions overlying iSCC were present in 63.8%, 17.9% and 18.4% of cases respectively. The corresponding percentages in the epidermis adjacent to iSCC were 77.9%, 6.6% and 8.3% respectively (stage could not be assessed in 8.1% of cases). Focal epidermal ulceration overlying iSCC was seen in 32% of AK I, 28.6% of AK II and 33.3% of AK III instances. Adnexal involvement by atypical keratinocytes (proliferative AK) was present more frequently in cases with overlying AK I (39/125, 31.2%) than with AK II (8/35, 22.9%) and AKII I (5/36, 13.9%). CONCLUSION: Direct invasion from proliferating basaloid atypical keratinocytes limited to the epidermal basal layer (AK I), known as the differentiated pathway, was the most common form of progression to cutaneous iSCC in our series. On the other hand, stepwise progression from AK I to AK II and AK III (classic pathway) was seen to be operative in a substantial proportion of iSCC cases. All AK lesions, irrespective of intraepidermal neoplasia thickness, are therefore potentially invasive and tumour advance along adnexal structures might facilitate iSCC development from AK I lesions.