Checkpoint blockade and BRAF/MEK therapy in the therapeutic setting improved the overall survival after sentinel node biopsy: A retrospective study comparing patients with primary care between 1998-2009 and 2010-2017.

Immunotherapies using checkpoint blockade and BRAF/MEK therapies have improved overall survival (OS) in patients with unresectable melanoma metastases. In this retrospective study, we aimed to demonstrate the resulting increase in melanoma-specific survival (MSS) and OS after the excision of primary melanomas (≥1 mm thick) and sentinel lymph node (SN) biopsy (SNB). Using Kaplan-Meier estimates and Cox models, we compared two consecutive cohorts. Patients in cohort 1 (N = 518) underwent SNB between 1998 and 2009, and patients in cohort 2 (N = 460) between 2010 and 2017, when checkpoint blockade and BRAF/(MEK) inhibition became available for the treatment of unresectable relapses. The median follow-up times were 120 and 73 months, respectively. While recurrence-free and distant metastasis-free survival rates remained very similar, MSS and OS increased in favor of cohort 2. The estimated 5-year OS rate of SN-positive patients increased by 14.3% (78.5% vs 64.2%, logrank test: P = .005). The MSS benefit was significant even with low SN tumor burden (metastasis diameter < 1 mm). On multivariate analyses, the risk-reduction in favor of cohort 2 was significant in the total population and in the SN-negative and SN-positive subgroups. In SN-positive patients, besides the availability of modern therapies, SN metastasis diameter and ulceration were independent factors of MSS and OS. Treatment of unresectable melanoma recurrences with modern drug therapies results in significantly higher survival rates in a population with SNB. The survival benefit measured from primary melanoma affects both the SN-positive and SN-negative subpopulations.

Interleukin-19 Levels Are Increased in Palmoplantar Pustulosis and Reduced following Apremilast Treatment.

Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease characterised by neutrophilic granulocyte (neutrophil)-filled pustules on the palms and soles. The pathogenesis of PPP is poorly understood. This study conducted an identification of the immune mediators associated with PPP and an exploration of apremilast treatment effects on them. We screened for immune mediators elevated in blood taken from 68 patients with PPP versus control participants and included the most promising parameters in the protocol of phase the 2, multicentre study of apremilast (PDE4 inhibitor) in 21 patients with moderate-to-severe PPP (APLANTUS; EudraCT 2016-005122-11) for respective analysis of blood and skin samples of study patients. We investigated stimulated neutrophils and three-dimensional reconstituted epidermis cultures. Interleukin (IL)-19 was found to be the most upregulated immune mediator in the blood of PPP patients. IL-19 serum levels were independent of patients' age, gender, and BMI but were associated with strongly upregulated cutaneous IL-19 expression and correlated with the number of palmoplantar pustules. In patients participating in the APLANTUS study, apremilast reduced pustules more effectively than erythema and scaling. Moreover, this treatment significantly reduced IL-19 blood and skin levels. The reduction in IL-19 blood levels at week 4 correlated with the reduction in pustule counts at week 20 (end of treatment). IL-19 was expressed by neutrophils activated in vitro and induced CXCL6, a neutrophil-attracting chemokine, in epidermis models. This work demonstrates elevated IL-19 levels in the blood and skin of PPP patients and suggests a relevant role of this cytokine in the appearance of pustules in this disorder. It also suggests the suitability of IL-19 blood levels as a predictive biomarker for the treatment response of PPP patients, which should be validated in further studies.

Full-body blue light irradiation as treatment for atopic dermatitis: a randomized sham-controlled clinical trial (AD-Blue).

BACKGROUND: Visible blue light (wavelength 400-495 nm) is a promising new treatment option for both psoriasis and atopic dermatitis (AD). Whilst previous clinical trials featured various devices and blue light at a variety of wavelengths, none of these interventions were challenged in objective clinical criteria. PATIENTS AND METHODS: Eighty-seven patients diagnosed with AD were enrolled in AD-Blue, an international, prospective, double-blinded, three-armed (415 nm vs. 450 nm vs. sham control), randomized trial designed to investigate the safety and efficacy of prototype full-body blue light devices. RESULTS: Full-body irradiation with 450 nm blue light but not 415 nm had a significant impact on itch (Itch-VAS, -1.6 ± 2.3; p  =  0.023 vs. sham irradiation). PO-SCORAD values also decreased significantly in response to irradiation at 415 nm (-11.5 ± 18.4; p = 0.028 vs. sham irradiation). None of the other outcome measures (EASI, SCORAD, IGA, DLQI) changed significantly. No safety signals were observed. Evaluation of skin transcriptomes, cytokine levels in serum, and ELISpots from peripheral blood mononuclear cells isolated from a subset of patients revealed moderate decreases in IL-31 in response to irradiation with blue light. CONCLUSIONS: Despite its favorable safety profile and moderate reductions in itch and IL-31 levels, full-body blue light irradiation did not lead to an amelioration of any of the objective measures of AD.

Patient Preferences in Hidradenitis Suppurativa (APProach-HS): a discrete choice experiment.

BACKGROUND AND OBJECTIVES: Treatment options for moderate-to-severe hidradenitis suppurativa (HS) comprise antibiotics, biologics, and different surgical methods. These approaches differ substantially regarding the treatment process, success rates, and adverse events. However, information on patient preferences for HS therapies is hitherto scarce. Our aim was to assess patient preferences for medicamentous and surgical treatment of HS with conjoint analysis. PATIENTS AND METHODS: In this cross-section study, computerized discrete choice experiments were used to quantify patient preferences for HS therapies decomposed into treatment modality (tablets, subcutaneous injections, surgery with secondary-intention healing or primary closure), probability of sustained therapeutic success, probability of mild or severe adverse events, and duration of treatment or wound healing. RESULTS: Averaged over the cohort (n  =  216 patients with HS), sustained therapeutic success was considered as most important (Relative Importance Score [RIS]: 36.2), followed by the treatment modality (RIS: 24.0), and duration of treatment/wound healing (RIS: 19.9), whereas mild or severe adverse events (RIS: 10.7 or 9.3) were regarded as less relevant. Patients preferred tablets, followed by subcutaneous injections, and disliked surgery with primary closure. Preferences differed significantly dependent on age and affected body regions. CONCLUSIONS: Awareness of patient preferences is essential for patient-centered care in HS.

Drug survival in the treatment of generalized pustular psoriasis: A retrospective multicenter study.

Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening inflammatory skin disease. Our aim was to assess patient and disease characteristics and analyze drug survival rates in the treatment of GPP in a real-life setting. In this retrospective study, 201 treatment series of 86 patients with GPP treated at five University Medical Centers were analyzed. Overall, excellent response was reached in 41.3% of all treatment courses, partial response in 31.4%, and nonresponse in 27.3%. Biological treatment was significantly more effective than non-biological therapies (excellent response: 47.4% vs 35.9%; P = .02). Overall, the median drug survival was 14.0 months (biologicals: 36.0 months vs nonbiologicals: 6.0 months; P < .001). The crude probability of survival was highest for secukinumab (hazard ratio [HR] of drug discontinuation compared with acitretin: 0.22), followed by ixekizumab and ustekinumab (HR: 0.38 each), adalimumab (HR: 0.59), etanercept (HR: 0.62), infliximab (HR: 0.69), cyclosporine (HR: 1.00), acitretin (reference for HR), fumaric acid esters (HR: 1.06), methotrexate (HR: 1.26), and apremilast (HR: 3.44); no drug discontinuation with guselkumab. Our results reveal high efficacy and drug survival, particularly for IL-17 and IL-(12)/23 antagonists. Thus, these biologics may be considered early in the therapeutic algorithm of GPP.

Screening for depression in psoriasis patients during a dermatological consultation: A first step towards treatment.

BACKGROUND AND OBJECTIVES: Depression is a highly prevalent comorbidity in psoriatic patients. The aim of this prospective study was to follow up psoriasis patients at risk for depression and to evaluate individual pathways to mental health care and the efficacy of depression screening in a real-life setting. PATIENTS AND METHODS: In this prospective multicenter study, 355 patients with psoriasis were screened for depressive symptoms with the revised Beck Depression Inventory (BDI-II). General practitioners of patients at risk for depression were asked for further evaluation. One year later, information on mental health care provision was gathered. RESULTS: 130 patients were screened positive for depressive symptoms, and 71 patients were followed-up (follow-up rate: 54.6 %). Psychiatric treatment was recommended for 28.2 % and accepted by 23.9 % of patients. Parameters of disease activity of psoriasis (PASI: 3.1, ∆: -1.7, P = 0.018), quality of life (Dermatology Life Quality Index [DLQI]: 6.5, ∆: -2.8, P = 0.005), and depressive symptoms (BDI-II: 13.2, ∆: -8.3, P < 0.001) improved significantly. Decrease of the BDI-II score was more pronounced in patients with higher PASI decrease. CONCLUSIONS: Screening for depressive symptoms led to increased utilization of mental health care and improvement of psoriasis, depressive symptoms, and quality of life. Thus, such screening should be implemented in routine care to optimize patient management.

Dermatophyte infections in children compared to adults in Germany: a retrospective multicenter study in Germany.

BACKGROUND AND OBJECTIVE: Dermatophyte infections of the skin and nails are common worldwide and vary between geographical areas and over time. The aim of this study was to determine the epidemiological profile of dermatophytes in Germany with a focus on comparing children with adults. PATIENTS AND METHODS: In this retrospective multicenter study, mycological dermatophyte culture results in the period 01/2014 to 12/2016 were analyzed according to identified pathogen, age and gender of patients, and type of disease. RESULTS: Of 1,136 infections (children: n = 88, adults: n = 1,048), 50.8 % were clinically classified as onychomycosis, followed by tinea pedis (34.6 %), tinea corporis (16.2 %), tinea manus (16.2 %), tinea capitis (2.5 %), and tinea faciei (1.2 %). The most frequent pathogen was Trichophyton (T.) rubrum (78.6 %), followed by T. interdigitale (14.3 %), T. benhamiae (3.2 %), T. mentagrophytes (2.1 %), and Microsporum canis (1.7 %). The fungal spectrum differed particularly in tinea corporis and tinea capitis between children and adults with a more diverse pathogen spectrum in children. Trichophyton tonsurans was rarely identified as cause for tinea corporis (2.7 %) or tinea capitis (3.3 %). CONCLUSIONS: Differences in pathogens and frequency of fungal infections between age groups should be considered for optimal selection of the appropriate therapeutic regimen.

Response of eosinophilic fasciitis associated with Waldenström macroglobulinemia to rituximab.

Eosinophilic fasciitis (EF) and generalized morphea (GM) are rare and difficult-to-treat sclerosing skin diseases which may occur in association with hematologic disorders. We present a 66-year-old man with EF and associated Waldenström macroglobulinemia who received combination therapy with rituximab (375mg/m2 every other week, gradually extended to every eight weeks), prednisolone (1.25-30mg/d), and methotrexate (7.5-15mg/w). Three months after rituximab initiation, his skin condition improved steadily accompanied by a significant improvement in joint mobility with only mild and transitory flares (observation period: 59 months under treatment with rituximab). To date, there are five case reports on rituximab treatment of EF/GM with an association to hypergammaglobulinemia in three of those cases. Therapy effected significant improvement in four patients. Our case adds to the hitherto limited evidence that rituximab may be a promising therapeutic strategy for EF/GM in association with hypergammaglobulinemia.

Two questions may be enough - screening for depression in patients with psoriasis: a multicenter study.

BACKGROUND: Depression is frequently underdiagnosed and insufficiently treated in psoriatic patients in their daily routine. The aim of this study was to screen and analyze the impact of patient and disease characteristics on depression scores. PATIENTS AND METHODS: In this cross-sectional multicenter cohort study, adult psoriasis patients were screened for depression with two validated tools: the Whooley questions and the revised Beck Depression Inventory (BDI-II). RESULTS: Overall, 538 patients (median PASI 3.0, mean DLQI 5.3) were screened for depressive symptoms (mean BDI-II score 8.3). 24.2 % of all participants reached a BDI-II score ≥ 13, suggesting a depression that was at least mild. The results of the Whooley questions were positive for 28.2 % of the patients. There was a strong correlation between the two tools (p < 0.001). In the subgroup with a BDI-II score ≥ 13, disease activity (median PASI 3.8 vs. 2.8, p = 0.06) and DLQI scores (mean 10.1 vs. 3.7, p < 0.0001) were higher, and psoriatic arthritis and diabetes were more prevalent (52.6 % vs. 37.8 %, p = 0.002, and 16.2 % vs. 10.0 %, p = 0.04, respectively) than in the subgroup with a BDI-II score < 13. CONCLUSIONS: In specialized psoriatic outpatient clinics, a BDI-II score ≥ 13 was present in almost every fourth patient despite a low median PASI. The Whooley questions might be easy to use as a screening tool for depression in psoriasis patients.

Systemic therapies of pityriasis rubra pilaris: a systematic review.

Pityriasis rubra pilaris (PRP) is a rare papulosquamous disorder. Treatment is challenging; the armamentarium consists of topical corticosteroids, phototherapy, classic systemic treatments such as retinoids or immunosuppressive drugs, and most recently biologicals. However, the relative effectiveness of therapies is unclear. Our objective was to review the published literature on systemic treatment of PRP. A systematic review was conducted on PubMed and the Cochrane Library up to 5 September 2017. Studies evaluating any systemic treatments of PRP (except for historical treatments) were included. Overall, 182 studies met the predefined inclusion criteria, and reported on 475 patients and 652 courses of treatment. 42.0 % (225/514) of all patients treated with retinoids achieved an excellent response (isotretinoin: 61.1 % [102/167], etretinate: 47 % [54/115], and acitretin: 24.7 % [43/174]) compared to an excellent response rate of 33.1 % (53/160) with methotrexate. Therapy with biologicals was successful in 51.0 % of patients (71/133) (ustekinumab: 62.5 % [10/16], infliximab: 57.1 % [28/49], etanercept: 53.3 % [16/30], and adalimumab: 46.4 % [13/28]). This review balances effectiveness, side effects, experience, and drug costs in order to suggest a treatment regimen starting with isotretinoin as first-line, methotrexate as second-line and biologicals as third-line treatment for this difficult-to-treat dermatosis.

Diagnosis of mycobacterial skin infections.

The diagnosis of cutaneous mycobacterial infections may be challenging. Owing to the broad spectrum of their clinical presentations, mycobacterioses have to be considered as differential diagnoses to many inflammatory dermatoses. Diagnostic measures comprise histology including special staining, cultures and molecular microbiological examinations as well as the detection of cellular immune reactions of the patient by means of interferon-γ release assays and skin testing. Clinicians should know the appropriate use and combination of procedures to diagnose mycobacterioses quickly and correctly and to avoid costs and delays caused by unnecessary examinations. This mini review summarizes advantages, limitations, and pitfalls of diagnostic methods for mycobacterial skin infections.

Drug survival and reasons for drug discontinuation in palmoplantar pustulosis: a retrospective multicenter study.

BACKGROUND: Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease-related to psoriasis. Its treatment is challenging, and little is known about the sustainability of different medications. The aim of this study was to analyze drug survival rates and drug discontinuation in the treatment of PPP under real-world conditions. PATIENTS AND METHODS: Patients with PPP treated in the dermatology departments of five German university medical centers between 01/2005 and 08/2017 were included in our retrospective study. Drug survival of systemic therapies was assessed with Kaplan-Meier analysis and multivariate regression. RESULTS: Overall, 347 patients with 935 treatment courses were identified. Within the group of non-biologic systemic agents, apremilast showed the highest median drug survival (15 months), followed by cyclosporine (12 months), the combination of acitretin and topical PUVA (9 months), MTX (8 months), acitretin monotherapy (6 months), alitretinoin (5 months), and fumaric acid esters (3 months). Among biologicals, the highest maintenance rate was detected for certolizumab pegol (restricted mean: 47.4 months), followed by infliximab (median: 26 months), golimumab (22 months), ustekinumab (21 months), adalimumab (18 months), secukinumab (9 months), and etanercept (8 months). CONCLUSIONS: Biologicals and apremilast may serve as second-line options for treatment of PPP and should be further evaluated.

Behandlungspräferenzen für Biologika bei Psoriasis: erfahrene Patienten legen Wert auf Nachhaltigkeit.

HINTERGRUND UND ZIELE: Die Therapiezufriedenheit kann durch die Berücksichtigung von Patientenpräferenzen in der gemeinsamen Entscheidungsfindung verbessert werden. Kürzlich untersuchten wir Patientenpräferenzen für Eigenschaften von Biologika und fanden starke Präferenzen für Sicherheit und Wirksamkeit. Die vorliegende Studie hatte das Ziel, Auswirkungen von Therapieerfahrung auf diese Präferenzen zu erheben. PATIENTEN UND METHODEN: Präferenzen für Ergebnis- (Wahrscheinlichkeit einer 50%igen und 90%igen Verbesserung, Zeit bis zum Ansprechen, Nachhaltigkeit des Erfolgs, Wahrscheinlichkeit von leichten und schweren Nebenwirkungen und Wahrscheinlichkeit eines ACR-20-Ansprechens) und Prozesseigenschaften (Behandlungsort, Behandlungshäufigkeit, Zeitaufwand und Applikationsweise) wurden bei 200 Teilnehmern mit mittelschwerer bis schwerer Psoriasis mit Hilfe von Conjoint-Analyse ermittelt. Der Einfluss aktueller und früherer Therapien, der Krankheitsdauer und der Behandlungszufriedenheit auf die "Relative Importance Scores" wurde durch Varianz-analysen, Post-hoc-Tests und multivariate Regressionen bestimmt. ERGEBNISSE: Teilnehmer, die aktuell eine topische Therapie (p = 0,02) oder eine Phototherapie (p = 0,032) erhielten, hielten den Zeitaufwand der Behandlung für wichtiger als andere. Diejenigen, denen zuvor traditionelle Systemtherapien (p = 0,028) oder Biologika (p = 0,044) verordnet worden waren, legten mehr Wert auf die Nachhaltigkeit als andere. Diese Eigenschaft gewann mit steigender Anzahl zuvor verabreichter systemischer Therapien (p = 0,045) und längerer Krankheitsdauer (p = 0,018) an Bedeutung. FAZIT: Patientenpräferenzen für Biologika variieren abhängig von der Therapieerfahrung und Krankheitsdauer. Diese Aspekte sollten bei der gemeinsamen Entscheidungsfindung berücksichtigt werden.

Treatment preferences for biologicals in psoriasis: experienced patients appreciate sustainability.

BACKGROUND AND OBJECTIVES: Treatment satisfaction can be improved by integrating patients' preferences into shared decision-making. We recently investigated patients' preferences for attributes of biologicals, and showed high preferences for safety and efficacy. The objective of the present study was to assess the impact of treatment experience on these preferences. PATIENTS AND METHODS: Preferences for outcome (probability of 50 % and 90 % improvement, time until response, sustainability of success, probability of mild and severe adverse events, probability of ACR 20 response) and process attributes (treatment location, frequency, duration, and delivery method) were analyzed in 200 participants with moderate-to-severe psoriasis using conjoint analysis. The impact of current and previous therapies, disease duration, and treatment satisfaction on 'Relative Importance Scores' was determined by analysis of variance, post hoc tests, and multivariate regression. RESULTS: Participants presently on topical therapy (p = 0.02) or phototherapy (p = 0.032) placed more importance on treatment duration than others. Individuals who had previously been given traditional systemic agents (p = 0.028) or biologicals (p = 0.044) favored sustainability more than others. With an increasing number of systemic agents ever received (p = 0.045) and longer disease duration (p = 0.018), the latter attribute became increasingly important. CONCLUSIONS: Patients' preferences for biologicals vary in correlation with treatment experience and disease duration, aspects to be addressed in the context of shared decision-making.