Early disease intervention with guselkumab in psoriasis leads to a higher rate of stable complete skin clearance ('clinical super response'): Week 28 results from the ongoing phase IIIb randomized, double-blind, parallel-group, GUIDE study.

BACKGROUND: Guselkumab is an interleukin (IL)-23 inhibitor with demonstrated efficacy in patients with psoriasis. OBJECTIVES: Evaluate the impact of early disease intervention on clinical responses following 28 weeks of guselkumab treatment in patients with moderate-to-severe plaque psoriasis. Correlate clinical response and disease duration data with serum biomarker data. METHODS: GUIDE is a phase IIIb randomized, double-blind, parallel-group, multicentre study of adults with moderate-to-severe plaque psoriasis. In study part 1, patients with a short disease duration (SDD [≤2 years]) or a long disease duration (LDD [>2 years]) received guselkumab 100 mg at Week (W) 0, 4, 12, and 20. Those achieving complete skin clearance at W20 and W28 were defined as a super responder (SRe). A multivariable logistic regression analysed the association between baseline factors and the likelihood of becoming an SRe. The relationship between clinical response, disease duration and serum biomarker data was assessed at W0 and 4. RESULTS: In total, 880 patients were enrolled (SDD/LDD = 40.6%/59.4% of patients). More SDD than LDD patients achieved absolute Psoriasis Area and Severity Index (PASI) = 0 at W28 (51.8% vs. 39.4%) and were SRes (43.7% vs. 28.1% [overall 34.4%]). SDD patients also achieved PASI = 0 quicker than LDD patients (median 141 vs. 200 days). Disease duration and prior biologic use had the greatest impact on becoming an SRe, with no strong association among these independent variables. At baseline, there were no significant differences in the serum biomarker levels of IL-17A, IL-17F, IL-22 and ß-defensin 2 between SDD and LDD patients, or between SRe and non-SRe patients. Guselkumab rapidly decreased these markers of systemic inflammation across all patient groups analysed at W4. Guselkumab was well tolerated. CONCLUSIONS: Guselkumab efficacy was consistent across subpopulations, on the skin and systemically. The proportion of SRes was higher in SDD than LDD patients, indicating early treatment intervention may improve clinical outcomes.

Direct comparison of risankizumab and fumaric acid esters in systemic therapy-naïve patients with moderate-to-severe plaque psoriasis: a randomized controlled trial.

BACKGROUND: Fumaric acid esters (FAEs; Fumaderm® ) are the most frequently prescribed first-line systemic treatment for moderate-to-severe plaque psoriasis in Germany. Risankizumab (Skyrizi® ) is a humanized IgG1 monoclonal antibody that specifically binds to the p19 subunit of interleukin 23. OBJECTIVES: To compare risankizumab treatment to FAEs in patients with psoriasis. METHODS: This phase III randomized, active-controlled, open-label study with blinded assessment of efficacy was conducted in Germany. Patients were randomized (1 : 1) to subcutaneous risankizumab 150 mg (weeks 0, 4 and 16) or oral FAEs at increasing doses from 30 mg daily (week 0) up to 720 mg daily (weeks 8-24). Enrolled patients were adults naïve to and candidates for systemic therapy, with chronic moderate-to-severe plaque psoriasis. Phototherapy was not allowed within 14 days before or during the study. RESULTS: Key efficacy endpoints were met at week 24 for risankizumab (n = 60) vs. FAEs (n = 60) (P < 0·001): achievement of a ≥ 90% improvement in Psoriasis Area and Severity Index (PASI; primary endpoint 83·3% vs. 10·0%), ≥ 100% improvement in PASI (50·0% vs. 5·0%), ≥ 75% improvement in PASI (98·3% vs. 33·3%), ≥ 50% improvement in PASI (100% vs. 53·3%) and a Static Physician's Global Assessment of clear/almost clear (93·3% vs. 38·3%). The rates of gastrointestinal disorders, flushing, lymphopenia and headache were higher in the FAE group. One patient receiving risankizumab reported a serious infection (influenza, which required hospitalization). There were no malignancies, tuberculosis or opportunistic infections in either treatment arm. CONCLUSIONS: Risankizumab was found to be superior to FAEs, providing earlier and greater improvement in psoriasis outcomes that persisted with continued treatment, and more favourable safety results, which is consistent with the known safety profile. No new safety signals for risankizumab or FAEs were observed.

Patient-reported outcomes with risankizumab versus fumaric acid esters in systemic therapy-naïve patients with moderate to severe plaque psoriasis: a phase 3 clinical trial.

BACKGROUND: In a phase 3 clinical study, patients from Germany with moderate to severe psoriasis who were naïve to systemic treatment and received risankizumab had greater and more rapid disease improvements compared with those who received fumaric acid esters (FAEs). OBJECTIVE: To evaluate patient-reported outcomes (PROs) in patients treated with risankizumab compared with FAEs. METHODS: Adult patients were randomized 1:1 to receive either risankizumab 150 mg subcutaneous injections at weeks 0, 4 and 16 or FAEs (Fumaderm® ) provided according to the prescribing label. PRO secondary endpoints assessed were Psoriasis Symptom Scale (PSS), Dermatology Life Quality Index (DLQI), 36-Item Short Form Health Survey, version 2 (SF-36v2), Patient Benefit Index (PBI), Hospital Anxiety and Depression Scale (HADS), Patient Global Assessment (PtGA) and European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L). PROs were assessed at weeks 0, 16 and 24. RESULTS: Sixty patients each were randomized to receive risankizumab or FAEs. A significant PSS improvement was observed with risankizumab vs. FAEs at weeks 16 and 24 for total and psoriasis-associated redness, itching and burning scores (P < 0.001). DLQI scores were significantly lower (reflecting better health-related quality of life) with risankizumab vs. FAEs, with least squares (LS) mean differences of -7.4 and -7.6 at weeks 16 and 24, respectively (both P < 0.001). Patients randomized to risankizumab also had larger improvements in SF-36 Physical and Mental Component Summary scores, HADS anxiety and depression scores, PtGA, and EQ-5D-5L index and visual analogue scale scores (all P ≤ 0.002) at weeks 16 and 24 compared with FAEs. PBI was significantly higher, indicating greater benefit, with risankizumab vs. FAEs, with an LS mean difference of 1.1 and 1.3 at weeks 16 and 24, respectively (both P < 0.001). CONCLUSIONS: Risankizumab provides significant benefits over FAEs in improving PROs across several dimensions in patients with moderate to severe 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.

[Malignancies of the skin and immunomodulatory antirheumatic therapy]. / Hautmalignome und immunmodulierende Antirheumatikatherapie.

For the clinical practice there is uncertainty as to what degree the therapeutic immunomodulation of rheumatoid arthritis (RA) is associated with a weakening of protective tumor immunity. Neoplasms of the skin in particular are known to exhibit increased incidence rates in association with therapeutic immunosuppression in transplantation medicine; however, the immunosuppression required for the prevention of allogenic graft rejection is much more intensive and thus not directly transferable to the potential risks for an onset or relapse of melanoma or non-melanoma skin cancers (NMSC), e. g. spinocellular and basal cell carcinomas in association with the antirheumatic treatment of RA. This review covers the association of RA and its pharmacotherapy with conventional synthetic (cs) and biologic disease-modifying antirheumatic drugs (DMARD) on the basis of a systematic literature search. The incidence rates of NMSC are twice as high in biologic-naive RA patients compared to the general population, whereas the respective incidence rates for melanoma do not differ. A biologic treatment with tumor necrosis factor (TNF) blockers compared with administration of csDMARD only has a minor, if any effect on the increase of NMSC risk but is associated with a trend towards an elevated incidence rate of new onset melanoma although significance level was not reached in all of the reviewed studies. The data on non-TNF blocking biologics is sparse. Accordingly, it is inappropriate to draw any strong conclusions on potentially associated skin cancer risks from the present lack of safety signals. The consideration of individual risk factors, recommendations on sufficient UV protection and regular skin monitoring may serve to improve the safety of DMARD therapy in RA.

[Inverse psoriasis]. / Psoriasis inversa.

Inverse psoriasis is clinically defined by chronic inflammatory lesions in intertrigineous areas. Colonisation or infection with Candida ssp. or bacteria is common. The disease-related quality of life is significantly reduced especially regarding sexual behavior. After the exclusion of relevant differential diagnoses, therapy should be adapted to the clinical outcome and potential comorbidities. Substances which are efficacious in psoriasis vulgaris are generally efficacious in inverse psoriasis, but have to be used off-label. Controlled clinical studies are only available for topical ascomycin.

[Paradoxical skin reactions under therapy with TNF-alpha antagonists]. / Paradoxe Hautreaktionen unter Therapie mit TNF-α-Antagonisten.

Tumor necrosis factor α (TNF α) antagonists are an effective and established therapy option for chronic inflammatory diseases in rheumatology, gastroenterology and dermatology. However, some undesired but rare side effects of TNF α antagonists, so-called paradoxical skin reactions, have been observed. These are mostly in the form of psoriasiform skin alterations, including pustular variants, eczema, vasculitis and other rare skin diseases. This article provides an overview of the different variants of paradoxical skin reactions due to TNF α inhibitors and gives practical advice on the therapeutic consequences.

Deletion of the late cornified envelope genes LCE3B and LCE3C may promote chronic hand eczema with allergic contact dermatitis.

BACKGROUND: Genetically determined defects in epidermal skin barrier function may contribute to the development of irritant and/or allergic contact dermatitis in chronic hand eczema (CHE). OBJECTIVES: To assess whether a deletion in the late cornified envelope genes LCE3B and LCE3C may constitute a genetic predisposition for the development of CHE or any of its subtypes. PATIENTS AND METHODS: A total of 153 German patients with clearly defined CHE subtypes and 268 healthy individuals were screened for the deletion LCE3C_LCE3B-del by allele-specific polymerase chain reaction. RESULTS: Classification of the patients by etiologic subtypes revealed an association between the LCE3C_LCE3B-del allele and CHE due to allergic contact dermatitis. In this subtype, 19/37 patients (51.4%) were homozygous deletion carriers, 11/37 (29.7%) were heterozygous carriers, and just 7/37 (18.9%) were wild-type individuals. Compared to the other CHE subgroups and the healthy control group (homozygous, 88/268 [32.83%]; heterozygous, 133/268 [49.63%]; and wild-type, 47/268 [17.54%]), the prevalence of LCE3C_LCE3B-del in these patients reached statistical significance (P = .03977), as did homozygous deletion carrier status (P = .01044 for other subtypes and P = .02695 for controls). CONCLUSIONS: A deletion of LCE genes may promote the development of allergic contact dermatitis, which is a form of CHE involving delayed-type hypersensitivity.

Topical treatment of perianal eczema with tacrolimus 0.1%.

BACKGROUND: Perianal eczema is an inflammatory skin disease with a high prevalence in most industrialized countries. As general practitioners and dermatologists frequently see patients with perianal eczema the need for efficient, fast and safe therapies is high. Topical calcineurin inhibitors such as tacrolimus (FK506) ameliorate cutaneous inflammation and associated pruritus in an array of inflammatory dermatoses. OBJECTIVES: To investigate the effect of topical tacrolimus in perianal eczema. METHODS: Twenty-four patients with perianal eczema were treated with tacrolimus 0.1% ointment twice daily on the affected skin area for 2 weeks. RESULTS: All returning patients showed clinical improvement as assessed by macroscopic appearance and clinical score (modified SCORAD index). CONCLUSIONS: In this short-term trial we demonstrate that topical tacrolimus 0.1% is safe, efficient and well tolerated in patients with perianal eczema irrespective of the underlying cause.

Relevance of the low-affinity type of the Fcgamma-receptor IIIa-polymorphism in bullous pemphigoid.

Bullous pemphigoid (BP) is mediated by autoantibodies directed against molecules of the basement membrane zone. The biological function of antibodies involves binding to Fc-receptors expressed on human leucocytes. Recent studies suggested that a functional single-nucleotide-polymorphism of the Fcgamma-receptor IIIa (FcgammaRIIIa = CD16) at nucleotide 559 might predispose to the development of antibody-associated autoimmune disorders. This allelic difference affects the level of receptor affinity by predicting either a phenylalanine (F 158, low-affinity) or valine (V 158, high-affinity). We investigated if inherited frequencies of the high- and low-affinity FcgammaRIIIa polymorphism differed between patients with BP and healthy subjects. Genomic DNA from peripheral white blood cells was analyzed regarding FcgammaRIIIa polymorphism at nucleotide 559 by an established polymerase chain reaction. Sixty-seven Caucasian patients with BP and 88 healthy controls were included into the study. There was no significant difference in the distribution of the homozygous high-affinity FcgammaRIIIa-allotype (V/V) between BP-patients (14.9%) and healthy control subjects (20.5%). In contrast, 58.2% of the BP-patients were homozygous for the low-affinity FcgammaRIIIa-allotype (F/F), compared to 28.4% of the healthy controls (P = 0.001, OR 3.51). The frequencies of the polymorphism in the control group were in range of formerly published frequencies for healthy Caucasian subjects. Thus, the FcgammaRIIIa (158 F/V) polymorphism may modulate the susceptibility to acquire BP.

Incidental detection of S. pyogenes-DNA in psoriatic skin by PCR.

Psoriasis vulgaris is a T cell-mediated autoimmune skin disease. First disease onset and disease worsening are often triggered by tonsillar infection with Streptococcus pyogenes. Here we demonstrate the incidental detection of S. pyogenes DNA in samples of different biological origin from patients with chronic plaque-type psoriasis by PCR. These findings may support the model of molecular mimicry in psoriasis pathogenesis.

[Toxic mustard plaster dematitis and phototoxic dematitis after application of bergamot oil]. / Wenn die Natur zurückschlägt.

Two cases that illustrate the risks attendant on the therapeutic use of natural medications by laypersons are reported. In the first case, the application of a mustard plaster triggered toxic dermatitis. In the second case, a session in a solarium after the external application of bergamot oil resulted in a phototoxic reaction.

[Treatment of paraungual HPV73-positive Bowen disease with imiquimod cream]. / Therapie eines parungualen HPV-73-positiven Morbus Bowen mit Imiquimod-Creme.

Bowen disease - a squamous cell carcinoma in situ - is associated with oncogenic human papilloma viruses (HPV). The association is best established for genital Bowen disease but also holds for extragenital lesions. The immunomodulatory substance imiquimod is used for the treatment of HPV-induced skin disorders. In the case of paraungual Bowen disease, established treatment options as excision, cryosurgery, radiotherapy or laser treatment might cause persistent nail damage. We successfully treated HPV73-positive Bowen disease in this location with topical imiquimod.

Photodynamic therapy of genital condylomata in men.

Current treatments for genital condylomata are not completely satisfactory, as they fail to clear lesions in a proportion of patients, and relapses after successful treatment are frequently seen. Photodynamic therapy (PDT) using topical 5-aminolaevulinic acid (5-ALA) has been suggested as a novel treatment option. We performed a small open study using topical 5-ALA and red light (630 nm) in nine men with genital condylomata and a history of at least one previous unsuccessful conventional treatment. Complete cure was achieved in three patients, one of whom experienced a relapse after 3 weeks. Three patients showed partial responses, and three showed no response. Based on the currently available evidence, PDT is a viable treatment option for selected cases that fail to respond to other therapies.

Deep subcutaneous application of poly-L-lactic acid as a filler for facial lipoatrophy in HIV-infected patients.

INTRODUCTION: Facial lipoatrophy is a crucial problem of HIV-infected patients undergoing highly active antiretroviral therapy (HAART). Poly-L-lactic acid (PLA), provided as New-Fill/Sculptra, is known as one possible treatment option. In 2004 PLA was approved by the FDA as Sculptra for the treatment of lipoatrophy of the face in HIV-infected patients. While the first trials demonstrated relevant efficacy, this was to some extent linked to unwanted effects. As the depth of injection was considered relevant in this context, the application modalities of the preparation were changed. The preparation was to be injected more deeply into subcutaneous tissue, after increased dilution. MATERIAL AND METHODS: To test this approach we performed a pilot study following the new recommendations in 14 patients. RESULTS: While the efficacy turned out to be about the same, tolerability was markedly improved. The increase in facial dermal thickness was particularly obvious in those patients who had suffered from lipoatrophy for a comparatively small period of time. CONCLUSION: With the new recommendations to dilute PLA powder and to inject it into the deeper subcutaneous tissue nodule formation is a minor problem. However, good treatment results can only be achieved if lipoatrophy is not too intense; treatment intervals should be about 2-3 weeks.

[Quantitative dobutamine stress echocardiography in follow-up of heart transplantation: normal values and findings in patients with transplant vasculopathy]. / Quantitative Dobutamin-Stressechokardiographie in der Spätphase nach Herztransplantation: Normwerte und Befunde bei Patienten mit Transplantatvaskulopathie.

Cardiac allograft vasculopathy (CAV) remains a major problem after heart transplantation. This prospective study was performed to analyze the value of quantitative dobutamine stress echocardiography for the diagnosis of CAV compared with coronary angiography and intravascular ultrasound (IVUS). In 80 patients late (> or = 12 months) after cardiac transplantation, a total of 144 studies were evaluated. In addition to the usually performed regional wall motion analysis of 2D-echocardiograms, systolic thickening of septum and left ventricular posterior wall was quantified by M-mode echocardiography. In patients with CAV by invasive angiography and/or IVUS, systolic thickening of the septum and posterior wall was significantly lower at rest and at maximum dobutamine infusion than in patients without CAV. From a subgroup of 23 studies in transplant recipients without TVP or other cardiac complications, normal values for the M-mode parameters were calculated. The lower limits were: systolic thickening of septum at rest, > 17.2%, at maximum stress, > 45.9%; systolic thickening of left ventricular posterior wall at rest, > 41.6%, at maximum stress, > 67.6%. Regional wall motion analysis of 2D-echocardiograms had a sensitivity of 76% (specificity 82%) for diagnosis of CAV defined by invasive methods, evaluation of wall thickening by M-mode alone had a sensitivity of 63% (specificity 76%). The combined 2D- and M-mode-echocardiographic analysis yielded a sensitivity of 85% (specificity 71%). In summary, dobutamine stress echocardiography is a useful method for the noninvasive diagnosis of CAV. The quantitative M-mode analysis improves the sensitivity of the 2D-analysis. The calculated normal values for the M-mode parameters in heart transplant recipients may serve as reference for other studies.