Efficacy and safety of fumaric acid esters in young patients aged 10-17 years with moderate-to-severe plaque psoriasis: a randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Apart from biologics, no systemic drugs are approved in Europe for children with moderate-to-severe psoriasis. Retrospective observational studies have shown promising results for fumaric acid esters (FAE) in this setting. OBJECTIVES: To show superiority of FAE over placebo in terms of treatment response after 20 weeks in children and adolescents aged 10-17 years. METHODS: In a multicentre, randomized, double-blind, placebo-controlled phase IIIb study, patients aged 10-17 years with moderate-to-severe plaque psoriasis requiring systemic therapy were randomized 2 : 1 to receive FAE (n = 91) or placebo (n = 43) over 20 weeks, followed by an open-label FAE treatment phase. The coprimary endpoints were ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and Physician's Global Assessment (PGA) score of 0 or 1 (clear or almost clear) at week 20. The study was registered with EudraCT number 2012-000035-82. RESULTS: At week 20, 55% [95% confidence interval (CI) 0·44-0·65] of FAE-treated patients achieved a PASI 75 response vs. 19% (95% CI 0·08-0·33) in the placebo group (absolute difference 36%, 95% CI 0·20-0·53; P < 0·001). In total, 42% (95% CI 0·32-0·53) in the FAE group vs. 7% (95% CI 0·01-0·19) in the placebo group achieved a PGA score of 0 or 1 at week 20 (absolute difference 35%, 95% CI 0·21-0·49; P < 0·001). During the double-blind period, drug-related adverse events occurred more frequently in patients receiving FAE compared with placebo (76% vs. 47%). Gastrointestinal disorders were the most common adverse events. CONCLUSIONS: FAE administered over a period of 20 weeks demonstrated a better response than placebo; the difference was statistically significant and clinically meaningful. Application up to 40 weeks was generally well tolerated. However, further studies are required.

A multicentre open-label study of apremilast in palmoplantar pustulosis (APLANTUS).

BACKGROUND: Palmoplantar pustulosis (PPP) is a chronic skin disease with painful erythematous scaly or crusty lesions and pustules on the palms and soles. Apremilast is a phosphodiesterase 4 inhibitor that has proven effective in the therapy of psoriasis, psoriatic arthritis and in oral ulcers associated with Behcet's disease. OBJECTIVE: To explore the efficacy of apremilast in PPP. METHODS: APLANTUS was a phase 2 single-arm multicentre study of apremilast in 21 subjects with moderate-to-severe PPP. Primary endpoint was the per cent change of the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at week 20 compared to baseline. RESULTS: 20 weeks of oral treatment with apremilast in patients with moderate-to-severe PPP resulted in a significant decrease of the PPPASI with a median reduction of 57.1% (p < 0.001), and 61.9% of patients achieved at least a 50% improvement of the PPPASI relative to baseline. The total number of pustules per patient decreased significantly relative to baseline with 76.2% of patients achieving at least a 50% reduction in total pustules count at week 20. Improvement of PPP was also apparent in a significant decrease of the dermatologic life quality index (DLQI). The median DLQI score dropped from 8.5 at baseline to 2.0 at week 20 (p = 0.030). Apremilast was generally well tolerated, and no serious adverse events occurred. CONCLUSIONS: Patients with PPP treated with apremilast showed benefit both in objective and subjective disease parameters. Apremilast should be investigated further in this difficult-to-treat skin condition. EudraCT number: 2016-005122-11.

[Management of plaque psoriasis in adults]. / Therapie der Psoriasis vulgaris im Erwachsenenalter.

In Germany, approximately 2% of the population suffers from psoriasis, which is no longer considered only a cutaneous, but rather a systemic disease. Accordingly, common comorbidities and potential joint involvement in psoriasis must be recorded. If necessary, interdisciplinary patient care has to be organized. The use of validated scores is recommended to complete the patient's medical history. The individual treatment should include intensified topical therapies as well as short-term phototherapy in case of an acute phase. In addition to conventional systemic therapies (e.g., fumarates, methotrexate), a number of new therapeutics for psoriasis are in development. Apart from the PDE­4 inhibitor apremilast, targeted therapies are currently available to block TNF-alpha, IL-17A, the IL-17 receptor and IL-23. Decisions on individualized, patient-centered psoriasis management should be based on assessment of disease severity and the existence of comorbidities. Furthermore, economic aspects should be taken into account.

Long-term follow-up of 22 psoriatic patients treated with ixekizumab after failure of secukinumab.

Switching of biologic agents in treatment of plaque psoriasis is a common strategy. Only a few studies are available on switching between IL17A-blockers. In a retrospective study, we identified 22 psoriasis patients who, after failing secukinumab as a first IL17A-blocker received ixekizumab with an observation period of at least 24 weeks. At last observation 10/22 patients had a good response (PASI75 or PASI<3) using ixekizumab therapy. None of five patients with primary non-response to secukinumab reached a good, durable response to ixekizumab. In conclusion, ixekizumab appears to be a therapeutic option as a second IL17A-blocker in psoriasis patients who did not show a primary non-response to secukinumab.

Long-term follow-up of 22 psoriatic patients treated with ixekizumab after failure of secukinumab.

The original article was published on February 15, 2020 and corrected on March 26, 2020. The revised version of the article amends the table and figure, while leaving the text largely unchanged. The changes appear in the revised online PDF copy of this article.

Prevalence, predictors and comorbidity of dry skin in the general population.

BACKGROUND: Dry skin is a frequent and multifaceted condition which can be associated with skin irritation, itch, patient discomfort and manifest skin disease. In spite of being frequent, little is known about the epidemiology of dry skin in the population. OBJECTIVE: To determine the prevalence of dry skin in the German adult population. METHODS: Data of 48 630 employed persons were assessed on a cross-sectional level in whole-body examinations by experienced dermatologists during company-based skin screenings conducted in 343 German companies. Next to the current dermatologic findings, age, gender, allergies, atopic diseases and the skin type were assessed. RESULTS: In total, n = 14 300 persons (29.4%) were rated as having xerotic skin. Older age but not gender was associated with xerosis. In the regression analyses controlling for age and gender, dry skin was a significant predictor for: axillary dermatitis (OR: 4.51; CI 2.70-7.54), atopic eczema (OR: 3.99; CI 3.42-4.65), exsiccation eczema (OR: 2.96; CI 2.40-3.65), psoriasis (OR: 1.57; CI 1.38-1.78), plantar warts (OR: 1.42; CI 1.26-1.60), seborrhoeic dermatitis (OR: 1.28; CI 1.16-1.42) and atopic disposition (OR: 1.17; CI 1.12-1.22). CONCLUSION: Dry skin is a frequent condition in the adult general population and needs special attention. Known risk factors may facilitate identifying patients at risk for deterioration.

ALIGNed on adherence: subanalysis of adherence in immune-mediated inflammatory diseases in the DACH region of the global ALIGN study.

BACKGROUND: Non-adherence to medication is a challenging problem in daily clinical practice. OBJECTIVE: To assess reasons for non-adherence in patients with chronic immune-mediated inflammatory diseases (IMIDs) in a direct comparison including evaluation of treatment necessity and concerns. METHODS: ALIGN was a non-interventional, multicountry, multicentre, self-administered, cross-sectional, epidemiologic survey study. Here, we investigate the German, Austrian and Swiss (DACH) cohort. Six hundred thirty-one patients with different IMIDs (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease and ulcerative colitis) under systemic therapies were evaluated concerning adherence, beliefs of necessity and concerns towards treatment in patients with IMIDs. RESULTS: The DACH cohort had significantly different levels of adherence depending on the IMID (P < 0.05) and the type of therapy (P < 0.05). Based on the significant influence of concerns on treatment adherence (P < 0.05) and the high belief of treatment necessity, patients could be classified in four attitudinal segments, which were unequally distributed throughout various IMIDs. High concerns had a significant influence on non-adherence, whereas necessity did not. Older age, female sex, TNFi mono-, conventional combination and TNFi combination therapy are positively associated with adherence. CONCLUSIONS: In the DACH region, patients are less concerned about medication and believe in the necessity of treatment. Therefore, we suggest adapting the communication in the various patient groups.

The genetic basis for most patients with pustular skin disease remains elusive.

BACKGROUND: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). OBJECTIVES: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. METHODS: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. RESULTS: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. CONCLUSIONS: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN.

Among the S100 proteins, S100A12 is the most significant marker for psoriasis disease activity.

BACKGROUND: Psoriasis is a chronic skin disease with deregulation of proteins in the immune system. These proteins include members of the heterogeneous S100 family, which have been discussed as potential biomarkers for disease severity. OBJECTIVE: The aim of this study was to evaluate the impact of S100A7, S100A8, S100A9 and S100A12 as possible markers for disease activity in patients with psoriasis skin disease. PATIENTS AND METHODS: S100A7, S100A8, S100A9 and S100A12 mRNA expression was determined in the skin of patients with psoriasis and controls (N = 341) by gene expression analyses. In addition, S100 serum levels were investigated by ELISA in an independent cohort of psoriasis patients (i) untreated, with different manifestations (skin/joints), (ii) under treatment (etanercept) and (iii) healthy controls, (N = 55). RESULTS: All S100-subtypes included are significantly upregulated in psoriasis skin lesions when compared with atopic dermatitis, lichen ruber and healthy donors. In untreated psoriasis patients, S100A12-serum levels showed the closest association with disease activity (PASI) (r = 0.542; P < 0.01). Serum levels decreased under treatment with etanercept (P < 0.05). CONCLUSION: Among the investigated S100-proteins, S100A12 showed the closest association with disease activity and therapeutic response and might therefore provide a valuable biomarker for psoriasis.

[Pustular psoriasis]. / Pustulöse Psoriasis.

A number of pustular skin diseases share clinical, pathogenetic, and epidemiological aspects with plaque-type psoriasis, and their classification as a separate clinical entity or as a subtype of psoriasis remains controversial, which is also reflected in the multitude of their names. They include generalized pustular psoriasis with its subtypes, acrodermatitis continua suppurativa (Hallopeau), acute pustulosis palmopantaris, palmoplantar pustular psoriasis, and pustular variants of a mostly TNF-blocker triggered paradoxical psoriasiform dermatitis. In this article, the epidemiology, clinical picture, pathogenesis, genetics, and therapy of these pustular skin diseases are described.

[Psoriasis and eczema on the scalp]. / Psoriasis und Ekzeme am Capillitium.

BACKGROUND: Diseases of the scalp are a severe burden for affected patients because they are often visible, frequently pruritic and hard to treat. Therefore, a proper diagnosis is extremely important. DIAGNOSIS: If the patient presents with erythematous, scaly skin lesions of the scalp, psoriasis has to be differentiated from atopic eczema, seborrheic eczema and contact eczema (allergic or toxic). The inspection of the entire body as well as a detailed history are essential for establishing the diagnosis. THERAPY: Topical corticosteroids are the therapeutic agents of choice for all of these scalp diseases. In individual cases immunosuppressive systemic treatments may be required. Azole antimycotics are not only used for seborrheic dermatitis but may also be indicated for treatment of atopic dermatitis or psoriasis of the scalp. OBJECTIVES: This review provides an overview of the clinical differences between scalp psoriasis and the various forms of eczema and of their therapeutic options. It also highlights the differential diagnosis between toxic and allergic contact eczema of the scalp.

Generation and functional analysis of human TNF-α/iNOS-producing dendritic cells (Tip-DC).

BACKGROUND: A unique type of CD11c(pos) dendritic cells (DC) is abundant in inflamed tissue, for example, in chronic inflammatory skin diseases. Due to their remarkable production of tumor necrosis factor (TNF)-α and inducible NO synthase (iNOS), these cells have been referred to as TNF and iNOS-producing DC (Tip-DC). While Tip-DC have been mainly characterized in murine models of infection, functional data about their human counterpart are lacking. OBJECTIVES: We sought to generate human Tip-DC in vitro und thus provide a new model for the investigation of their phenotype and function. METHODS: We generated human Tip-DC from monocytic precursor cells of healthy individuals, atopic and psoriatic patients using human serum. Resting and stimulated cells were analyzed by flow cytometry, real-time PCR, and by ELISA. INOS activity was measured by fluorometric detection of NO. RESULTS: Tip-DC closely resembled their in vivo counterparts by expressing CD11c, CD86, and CD40 while lacking CD1a, CD1c, or CD207/Langerin. Bacterial stimulation of Tip-DC from healthy donors, atopic dermatitis, or psoriasis patients resulted in a similar increase in iNOS activity and TNF-α production. In kinetic experiments, TNF-α, a putative activator of Tip-DC, could not induce NOS2. Upon bacterial stimulation, TNFA, IL6, IL12B, and IL23A mRNA appeared in a first wave, while IL12A and NOS2 mRNA were up-regulated later on but not blocked by anti-TNF-α agents, implying a biphasic pro-inflammatory response. CONCLUSIONS: We developed a new model for the study of human Tip-DC and provide the first evidence of their pro-inflammatory capacity.

New reasons for histopathological nail-clipping examination in the diagnosis of onychomycosis.

BACKGROUND: Onychomycosis is a common problem. Today, the gold standard in the diagnosis of onychomycosis is the direct microscopy and fungal culture. But direct microscopy is regarded as having a low sensitivity and fungal culture takes long time. In addition, in cases of controlling the antifungal treatment course, the present gold standard is often not a reliable tool because of the inhibition of the fungal growth in the culture. OBJECTIVE: The purpose of this study was to compare the present gold standard with histological examination with periodic acid-Schiff staining (PAS) of nail clippings in the diagnosis of onychomycosis in a large cohort. MATERIALS AND METHODS: We prospectively evaluated 1146 nail samples from 851 patients with clinical signs of onychomycosis using direct microscopy and fungal culture in comparison with PAS-stain. RESULTS: A total of 631 nail samples revealed a positive result in at least one test. The most sensitive single test for the diagnosis of onychomycosis was PAS with 82%, followed by culture (53%) and direct microscopy (48%). In 64 cases, in which a prediagnostic antimycotic treatment has been initiated, PAS showed to have by far the highest sensitivity (88%) in comparison with culture (33%) or direct microscopy (50%). CONCLUSIONS: Periodic acid-Schiff staining is the single method with the highest sensitivity in terms of detection of fungal elements (hyphae) in nail specimens. Especially in cases with prior antifungal treatment, histological analysis of PAS-stained nail clippings should be considered as an appropriate diagnostic tool.

Changing within the same class: efficacy of brodalumab in plaque psoriasis after treatment with an IL-17A blocker - a retrospective multicenter study.

INTRODUCTION: Biologic switching is common in psoriasis patients with non-response to or adverse events under therapy with a biologic. However, evidence on efficacy of switching between newly approved biologics of similar mode of action is scarce. The objective was to assess the efficacy of treating psoriasis patients with an IL-17-receptor A antagonist after failure of any IL-17A antagonist and to identify predictors of treatment response. METHODS: A retrospective multicenter chart review on psoriasis patients who received brodalumab after failure of ixekizumab or secukinumab therapy was conducted in five German University Medical centers. RESULTS: Overall, 23 patients were identified. PASI75 response to brodalumab was reached by 47.8% (11/23) of all patients at week 12 and at week 24. 3 patients experienced mild adverse events which did not lead to drug discontinuation. CONCLUSIONS: Brodalumab appears to be an efficacious and safe treatment option in psoriasis patients with prior exposure to IL-17A antagonists.

Introduction of a metabolic joint asymmetry score derived from conventional bone scintigraphy. A new tool to differentiate psoriatic from rheumatoid arthritis.

AIM: Clinical differentiation of psoriatic arthritis (PsA) and rheumatoid arthritis (rA) based on the pattern of joint involvement can be difficult; the frequent form of PsA with polyarthritis of the peripheral joints may sometime resemble rA. We investigated a metabolic joint asymmetry score (MJAS), reflecting the overall asymmetric joint involvement on conventional bone scintigraphy, for differentiating PsA from rA in patients presenting with peripheral polyarthritis. PATIENTS, METHODS: 106 patients (n = 61, PsA; n = 45, rA) with peripheral polyarthritis (≥ 5 joints) as well as 26 control subjects with no history of chronic joint disorders were analyzed. The intensity of articular 99mTc-MDP uptake in 40 peripheral joint pairs was scored regarding the bilateral difference of each joint based on a scale of 0-2 (no significant, moderate, and marked asymmetry, respectively). The patient's MJAS was defined as the sum of uptake difference scores of all joint pairs. The association of MJAS with the underlying condition (Psoriasis criteria, Revised Criteria of the ACR) was examined. RESULTS: 5280 peripheral joint pairs were investigated. There was no significant difference in the total number of involved joints in PsA 15.0 ± 8.2 versus rA 17.5 ± 8.8 patients (p = 0.132), but significantly less involvement in the control group (6.7 ± 5.0, p < 0.001). MJAS was markedly higher in PsA (17.0 ± 9.6) than in rA (4.8 ± 3.9, p < 0.001), and correlated with the total number of involved joints in PsA (r = 0.516, p < 0.001), but not in rA (r = 0.078, p = 0.380). The MJAS disparity between PsA and rA persisted after exclusion of the DIP joints (14.4 ± 7.7 vs. 4.4 ± 3.3; p<0.001). CONCLUSIONS: The new reproducible semi-quantification method for the asymmetry of metabolic joint involvement permits differentiation of psoriatic from rheumatoid peripheral arthritis with MJAS being markedly higher in patients with PsA as compared to rA patients. The score may offer an effective complementary tool for characterizing patients with peripheral polyarthritis.

[CT angiography hemodynamically relevant to renal artery stenosis. Evaluation of AXIAL, MPR, MIP and SSD reconstruction procedures under standard investigation conditions]. / CT-Angiographie hämodynamisch relevanter Nierenarterienstenosen. Evaluation der Rekonstruktionsverfahren AXIAL, MPR, MIP und SSD unter standardisierten Untersuchungsbedingungen.

PURPOSE: To evaluate the various reconstruction methods of helical-CT angiography for the assessment of hemodynamically relevant renal artery stenoses in comparison to i.a. DSA. METHODS: In 76 renal arteries the reconstruction modalities AXIAL, MRP, MIP and SSD of helical-CT angiography were compared with the results of i.a. DSA for the determination of the grade and location of the stenosis. RESULTS: The highest accuracy of stenosis grading was 76% with AXIAL reconstruction. In 8% of the cases grading of the stenosis was not evaluable by the AXIAL reconstruction. In these cases, a higher sensitivity in the detection of hemodynamically relevant stenoses (> grade II, > 50%) was achieved with the reconstruction mode MPR (96%) than with MIP (92%). In 51% of the cases the reconstruction mode SSD was not suitable for any diagnosis of renal artery stenosis because of overlying calcified plaques. CONCLUSIONS: The evidence of hemodynamically relevant stenosis in helical-CT angiography in comparison to i.a. DSA succeeds most reliable by using the reconstruction modality AXIAL in combination with MPR. The MIP reconstruction provides information about the anatomy of the renal arteries within one image.