Topical Treatment of Psoriasis Vulgaris: The Swiss Treatment Pathway.

Topical treatment is crucial for the successful management of plaque psoriasis. Topicals are used either as a stand-alone therapy for mild psoriasis or else in combination with UV or systemic treatment for moderate-to-severe disease. For the choice of a suitable topical treatment, the formulation matters and not just the active substances. This expert opinion paper was developed via a non-structured consensus process by Swiss dermatologists in hospitals and private practices to illustrate the current treatment options to general practitioners and dermatologists in Switzerland. Defining treatment goals together with the patient is crucial and increases treatment adherence. Patients' personal preferences and pre-existing experiences should be considered and their satisfaction with treatment and outcome regularly assessed. During the induction phase of "classical" mild-to-moderate psoriasis, the fixed combination of topical calcipotriol (Cal) 50 µg/g and betamethasone dipropionate (BD) 0.5 mg/g once daily is frequently used for 4-8 weeks. During the maintenance phase, a twice weekly (proactive) management has proved to reduce the risk of relapse. Of the fixed combinations, Cal/BD aerosol foam is the most effective formulation. However, the individual choice of formulation should be based on a patient's preference and the location of the psoriatic plaques. Tailored recommendations are given for the topical management of specific areas (scalp, facial, intertriginous/genital, or palmoplantar lesions), certain symptoms (hyperkeratotic or hyperinflammatory forms) as well as during pregnancy or a period of breastfeeding. As concomitant basic therapy, several emollients are recommended. If topical treatment alone does not appear to be sufficient, the regimen should be escalated according to the Swiss S1-guideline for the systemic treatment of psoriasis.

Incidence and predictors of cutaneous manifestations during the early course of systemic sclerosis: a 10-year longitudinal study from the EUSTAR database.

OBJECTIVES: To longitudinally map the onset and identify risk factors for skin sclerosis and digital ulcers (DUs) in patients with systemic sclerosis (SSc) from an early time point after the onset of Raynaud's phenomenon (RP) in the European Scleroderma Trials and Research (EUSTAR) cohort. METHODS: 695 patients with SSc with a baseline visit within 1 year after RP onset were followed in the prospective multinational EUSTAR database. During the 10-year observation period, cumulative probabilities of cutaneous lesions were assessed with the Kaplan-Meier method. Cox proportional hazards regression analysis was used to evaluate risk factors. RESULTS: The median modified Rodnan skin score (mRSS) peaked 1 year after RP onset, and was 15 points. The 1-year probability to develop an mRSS ≥2 in at least one area of the arms and legs was 69% and 25%, respectively. Twenty-five per cent of patients developed diffuse cutaneous involvement in the first year after RP onset. This probability increased to 36% during the subsequent 2 years. Only 6% of patients developed diffuse cutaneous SSc thereafter. The probability to develop DUs increased to a maximum of 70% at the end of the 10-year observation. The main factors associated with diffuse cutaneous SSc were the presence of anti-RNA polymerase III autoantibodies, followed by antitopoisomerase autoantibodies and male sex. The main factor associated with incident DUs was the presence of antitopoisomerase autoantibodies. CONCLUSION: Early after RP onset, cutaneous manifestations exhibit rapid kinetics in SSc. This should be accounted for in clinical trials aiming to prevent skin worsening.

Swiss S1 Guidelines on the Systemic Treatment of Psoriasis Vulgaris.

Psoriasis vulgaris is a common, chronic inflammatory skin disease with a prevalence of 1.5-2% in Western industrialized countries. A relevant percentage of patients suffer from moderate-to-severe psoriasis and experience a significant reduction in quality of life. The choice of an adequate therapy could help to prevent disease and exacerbation of comorbidity, which could increase quality of life, avoid hospitalization and avoid reduction of working days. The present guidelines are focused on the initiation and management of systemic therapies in cases of moderate-to-severe plaque-type psoriasis in adults to optimize treatment response, adherence and quality of life. This first version of the Swiss S1 guidelines presents therapeutic recommendations which are based on a systematic literature search as well as an informal expert consensus of dermatologists in Switzerland.

Superiority in Quality of Life Improvement of Biologics over Conventional Systemic Drugs in a Swiss Real-Life Psoriasis Registry.

BACKGROUND: Randomized controlled trials have shown the efficacy of systemic treatments in moderate-to-severe psoriasis. Clinical outcomes in psoriasis patients under real-world conditions are less well understood. OBJECTIVE: This study compared Psoriasis Area and Severity Index (PASI) and Dermatological Life Quality Index (DLQI) improvement in all psoriasis patients registered in the Swiss Dermatology Network for Targeted Therapies. We asked whether outcomes differed between 4 treatment strategies, namely biologic monotherapy versus conventional systemic monotherapy, versus combined biologic and conventional systemic drugs, and versus therapy adaptation (switching from one type to another). METHODS: PASI and DLQI within 1 year after onset of systemic treatment, measured at 3, 6, and 12 months, were compared among the 4 groups using generalized linear mixed-effects models. RESULTS: Between March 2011 and December 2014, 334 patients were included; 151 received conventional systemic therapeutics, 145 biologics, 13 combined treatment, and 25 had a therapy adaptation. With regard to the absolute PASI, neither the biologic cohort nor the combined treatment cohort significantly differed from the conventional systemic therapeutics cohort. The odds of reaching PASI90 was significantly increased with combined therapy compared to conventional systemic therapeutics (p = 0.043) and decreased with a higher body mass index (p = 0.041). At visits 3 and 4, the PASI was generally lower than at visit 2 (visit 3 vs. visit 2, p = 0.0019; visit 4 vs. visit 2, p < 0.001). After 12 months, patients with biologic treatment had a significantly lower DLQI than those with conventional systemic therapeutics (p = 0.001). CONCLUSION: This study suggests that after 1 year of treatment, biologics are superior in improving the subjective disease burden compared to conventional systemic drugs.

Efficacy and Survival of Systemic Psoriasis Treatments: An Analysis of the Swiss Registry SDNTT.

BACKGROUND: The Swiss psoriasis registry SDNTT (Swiss Dermatology Network for Targeted Therapies) records the long-term safety and effectiveness of systemic treatment regimens for psoriasis. PATIENTS AND METHODS: Patients with moderate to severe psoriasis are included in the SDNTT when treatment with a conventional systemic agent or biologic is initiated that was not previously used by the respective patient. Patients are followed over a 5-year period. Clinical data are obtained every 3-6 months using standardized case report forms. Here, baseline data and follow-up data for 1 year of patients included from October 2011 until December 2014 were analyzed. RESULTS: Within 39 months, 323 patients from 7 tertiary dermatology centers in Switzerland were recruited in the SDNTT; 165 patients received biologics and 158 conventional systemic therapies. Patients treated with biologics had a significantly higher severity (PASI 11.3 vs. 9.2, BSA 15.6 vs.11.9, psoriatic arthritis 36.4 vs. 10.8%; p ≤ 0.005, p ≤ 0.013, p ≤ 0.001) and a longer duration of illness (19.2 vs. 14.4 years, p ≤ 0.003) compared to patients starting a conventional systemic treatment. PASI reduction was satisfying in both treatment groups, with 60.6% of patients treated with biologics achieving PASI75 after 1 year compared to 54.2% of patients receiving conventional systemic drugs (nonsignificant). On average, the drug survival in patients receiving a biologic therapy was significantly longer than those receiving conventional systemic treatments (30.5 vs. 19.2 months, p ≤ 0.001). CONCLUSIONS: In the real-world setting of a prospective national therapy registry, the application of current therapeutic guidelines for patients with moderate to severe psoriasis resulted in a PASI reduction of approximately 70% within the first year of treatment, but current therapeutic targets of PASI75 and PASI90 were reached in only 58 and 36% of patients, respectively, at 1 year, highlighting a gap in efficacy between selective clinical trials and the real-world setting.

The dermatologists' role in managing psoriatic arthritis: results of a Swiss Delphi exercise intended to improve collaboration with rheumatologists.

BACKGROUND: Psoriatic arthritis (PsA) substantially impacts the management of psoriatic disease. OBJECTIVE: This study aimed to generate an interdisciplinary national consensus on recommendations of how PsA should be managed. METHODS: Based on a systematic literature search, an interdisciplinary expert group identified important domains and went through 3 rounds of a Delphi exercise, followed by a nominal group discussion to generate specific recommendations. RESULTS: A strong consensus was reached on numerous central messages regarding the impact of PsA, screening procedures, organization of the interaction between dermatologists and rheumatologists, and treatment goals. CONCLUSION: These recommendations can serve as a template for similar initiatives in other countries. At the same time, they highlight the need to take into account the impact of the respective national health care system.

Unilesional follicular mycosis fungoides: report of two cases with progression to tumor stage and review of the literature.

Mycosis fungoides (MF) is the most common type of cutaneous lymphoma and has protean clinicopathological manifestations. Follicular or folliculotropic MF (FMF) is a rare variant, which histopathologically is characterized by pronounced folliculotropism of neoplastic T cells, with or without follicular mucinosis, and clinically by an impaired prognosis compared to classic MF. In contrast, unilesional MF is a very rare variant with an excellent prognosis, with a single case of large-cell transformation reported to date. The combination of folliculotropic and unilesional MF is very unusual, with only two cases reported to date. Here we report two patients with unilesional folliculotropic MF with progression to tumor stage in both patients. To the best of our knowledge, this is the first report on the disease evolution with large-cell transformation and progression of unilesional FMF. Complete remission was achieved by local radiation therapy in both patients. The differential diagnoses, classification and implications for the treatment of unilesional FMF as well as the pertinent literature are discussed.

Secukinumab for the treatment of psoriasis, psoriatic arthritis, and axial spondyloarthritis: Physical and pharmacological properties underlie the observed clinical efficacy and safety.

Psoriasis, psoriatic arthritis, and axial spondyloarthritis are systemic inflammatory diseases, each commonly manifesting as a spectrum of symptoms, complications, and comorbidities that arise differently in individual patients. Drugs targeting inflammatory cytokines common to the pathogenesis of each of these conditions have been developed, although their specific actions in the different tissues involved are variable. For a drug to be effective, it must be efficiently delivered to and locally bioactive in disease-relevant tissues. Detailed clinical data shed light on the therapeutic effects of individual biologics on specific domains or clinical manifestations of disease and assist in guiding treatment decisions. Pharmacologic, molecular, and functional properties of drugs strongly impact their observed safety and efficacy, and an understanding of these properties provides complementary insight. Secukinumab, a fully human monoclonal IgG1/κ antibody selectively targeting interleukin (IL)-17A, has been in clinical use for >6 years in the treatment of moderate to severe psoriasis, psoriatic arthritis, and both radiographic (also known as ankylosing spondylitis) and nonradiographic axial spondyloarthritis. In this review, we discuss pharmacokinetic and pharmacodynamic data for secukinumab to introduce clinicians to the pharmacological properties of this widely used drug. Understanding how these properties affect the observed clinical efficacy, safety, and tolerability of this drug in the treatment of IL-17A-mediated systemic inflammatory diseases is important for all physicians treating these conditions.

Homozygosity for the c.917A→T (p.N306l) polymorphism in the EVER2/TMC8 gene of two sisters with epidermodysplasia verruciformis Lewandowsky-Lutz originally described by Wilhelm Lutz.

BACKGROUND: Epidermodysplasia verruciformis Lewandowsky-Lutz (EV) is a rare genodermatosis, characterised by development of numerous verrucous skin lesions caused by specific genotypes of human papillomaviruses belonging to the ß-papillomavirus genus. The EV loci were mapped to chromosome 2p21-p24 (EV2) and 17q25 (EV1). On chromosome 17, 2 adjacent related genes--EVER1/TMC6 and EVER2/TMC8--were identified. We reinvestigated 2 patients originally described by Wilhelm Lutz in 1946 with the aim to document the natural course of the disease and confirm his diagnosis. METHODS: PCR fragments specific for exons with short flanking intron sequences of EVER1/TMC6 and EVER2/TMC8 genes from patients' DNA were amplified using sequence information. The single-nucleotide polymorphism (SNP) rs7208422 was studied, using restriction fragment length polymorphism analysis. RESULTS: In the index patient, we identified a homozygous TT genotype in exon 8 of the EVER2/TMC8 gene (c.917A→T, p.N306I). The same mutation could thereafter be detected in her sister from paraffin-embedded skin. CONCLUSION: We have followed one of the first patients described with EV in Basel, Switzerland, in 1930 until today and demonstrated the TT genotype (SNP rs7208422) in the EVER2/TMC8 gene in this index patient and her sister. The results underline the possible relevance of SNP rs7208422 by influencing the susceptibility to ß-papillomaviruses and their oncogenic potential.

Symmetrical Facial Giant Plaque-Type Juvenile Xanthogranuloma: Case Report and Review of the Literature.

Juvenile xanthogranuloma (JXG) is the most common type of non-Langerhans cell histiocytosis. JXG is a rare benign tumor, which may be present at birth or develop later. The classical form of JXG is characterized by a red-yellowish benign papule or nodule with predilection sites on the head, neck, and trunk, although lesions can appear on extremities or extracutaneous sites. In most cases there is only one lesion, whereas numerous papules or nodules may occur. Special forms of JXG such as mixed, giant, subcutaneous, eruptive, clustered, and plaque-like have been reported and associations between JXG and systemic diseases have been made. Diagnosis mainly relies on the clinical appearance, and histology usually can confirm the disease. Here we present a very rare case of symmetrical giant facial plaque-type juvenile xanthogranuloma (SGFP-JXG) and compare it with classical JXG, variations of JXG, and discuss the differential diagnosis. A 4-year-old Caucasian female presented with plaque-like lesions composed of yellowish confluent papules on both the cheeks. The histological evaluation revealed a histiocytic lesion with a formation of Touton giant cells and immunohistochemistry results confirmed the diagnosis of the SGFP-JXG. In comparison to classical JXG, the onset of SGFP-JXG sometimes occurs later and the spontaneous resolution period may be prolonged. No associated diseases and no systemic involvements were observed. Histopathology is required to differentiate this form of JXG from other histiocytosis. To the best of our knowledge, only four cases of SGFP-JXG have been reported in the literature so far.

Management of dupilumab-associated ocular surface diseases in atopic dermatitis patients.

Atopic dermatitis is a chronic inflammatory skin disease characterised by eczematous skin lesions and intense pruritus. It is often associated with other atopic diseases such as allergic rhinitis and conjunctivitis, bronchial asthma and eosinophilic oesophagitis. Dupilumab is the first biologic approved for the treatment of moderate-to-severe atopic dermatitis in Switzerland. Dupilumab targets the interleukin (IL)-4/IL-13 receptor and thus inhibits the signalling of IL-4 and IL-13, two key mediators of type 2 inflammation, resulting in an improvement of clinical signs and symptoms of atopic dermatitis. Patients with atopic dermatitis present more often with ocular surface diseases (OSDs), such as allergic conjunctivitis, blepharitis and keratitis as well as infectious conjunctivitis and keratoconus compared with the general population. Upon dupilumab therapy, increased rates of ocular surface diseases have been reported in clinical trials. Interestingly, dupilumab-associated (da) OSD is restricted to atopic dermatitis patients and has not been observed in asthma and chronic rhinosinusitis trials. Fortunately, most cases of dupilumab-associated OSD are mild-to-moderate and transient. Thus, ocular surface disease presents a particular adverse event of treatment with dupilumab in dermatology. This article aims at providing a practical guide for physicians, with a special focus on dermatologists, allergists and ophthalmologists in Switzerland, to the diagnosis and management of dupilumab-associated OSD in atopic dermatitis patients.For this purpose, an expert group of dermatologists and ophthalmologists from university and cantonal hospitals in Switzerland reviewed data on ocular surface diseases published in clinical trial and real-life reports of dupilumab therapy, published case reports and case series on the management of dupilumab-associated OSD, as well as recent recommendations provided by experts of national and international boards. Based on the observations of dupilumab-associated OSD and practical experiences in identifying and treating OSD, an algorithm has been developed that is specific to the needs in Switzerland. Considering concomitant ocular diseases and differential diagnoses, the clinical presentation of dupilumab-associated OSD and its response to therapeutic measures, a stepwise approach is recommended. Mild dupilumab-associated OSD can be managed by dermatologists and allergists, whereas patients with moderate-to-severe OSD requiring corticosteroid or calcineurin inhibitor therapy should necessarily be referred to an ophthalmologist. The effects of preventive measures, such as artificial tears, are uncertain. The recommendations provided here should guarantee a prompt and effective treatment of OSD for patients under dupilumab therapy in order to prevent that an otherwise potent therapy has to be ceased because of ocular adverse events.

ITIM-dependent endocytosis of CD33-related Siglecs: role of intracellular domain, tyrosine phosphorylation, and the tyrosine phosphatases, Shp1 and Shp2.

The leukocyte CD33-related sialic acid-binding Ig-like lectins (Siglecs) are implicated in glycan recognition and host defense against and pathogenicity of sialylated pathogens. Recent studies have shown endocytosis by CD33-related Siglecs, which is implicated in clearance of sialylated antigens and antigen presentation and makes targeted immunotherapy possible. Using CD33 as a paradigm, we have now investigated the reasons underlying the comparatively slow rate of endocytosis of these receptors. We show that endocytosis is largely limited and determined by the intracellular domain while the extracellular and transmembrane domains play a minor role. Tyrosine phosphorylation, most likely through Src family kinases, increases uptake of CD33 depending on the integrity of the two cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Simultaneous depletion of the protein tyrosine phosphatases, Src homology-2-containing tyrosine phosphatase 1 (Shp1) and Shp2, which bind to phosphorylated CD33, increases internalization of CD33 slightly in some cell lines, whereas depletion of spleen tyrosine kinase (Syk) has no effect, implying that Shp1 and Shp2 can dephosphorylate the ITIMs or mask binding of the phosphorylated ITIMs to an endocytic adaptor. Our studies show that restraint of CD33 internalization through the intracellular domain is relieved partly when the ITIMs are phosphorylated and show that Shp1 and Shp2 can modulate this process.

Unifocal Langerhans cell histiocytosis of the oral mucosa.

A 24-year-old man was admitted for a painful gingival ulcer. Histology and immunohistochemistry of a lesional biopsy revealed the diagnosis of Langerhans cell histiocytosis (LCH). To rule out multifocal disease, a complete staging was performed. There was no evidence of bony lesions or any other organ involvement. The diagnosis of LCH restricted to the oral mucosa was established. The complete oral lesion was ablated by CO(2) laser and subsequently treated topically with triamcinolone acetonide. The patient is still in remission after one year of follow-up. LCH confined to the oral mucosa is rare. It presents usually as an inflammatory or ulcerative lesion, easily leading to misinterpretation and delayed diagnosis. Patients with limited unifocal mucocutaneous disease, as in the present case, usually have an excellent prognosis. However, the oral lesion may represent an early sign of LCH, predating and progressing to an aggressive life-threatening multiorgan disease.

Effectiveness of methotrexate in moderate to severe psoriasis patients: real-world registry data from the Swiss Dermatology Network for Targeted Therapies (SDNTT).

Methotrexate (MTX) is a frequently used anti-psoriatic drug that is commonly recommended in international psoriasis guidelines. It is effective in treating skin lesions, nail changes and psoriatic arthritis. In 2017 a prospective, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial, commonly known as the METOP trial, was published assessing the effectiveness and safety of subcutaneous administration of methotrexate. Because trial data do not always relate to real-life data with unselected patient populations, we wanted to determine whether the data obtained in the METOP-trial correspond to real-life registry data from our Swiss Dermatology Network for Targeted Therapies (SDNTT). Data of 449 patients with moderate to severe psoriasis who participated in the SDNTT registry between 2011 and 1st of July 2017 were analyzed. Only patients receiving methotrexate s.c. were included. 66 patients under MTX were included into this study. Baseline PASI was 6.3 ± 3.8 (SDNTT) compared to 15.9 ± 5.9 in the METOP trial. In our cohort, only 18% of all patients reached PASI 75 after 12 weeks, 6% showed a complete remission (PASI 100) compared to 41% and 4% in the METOP trial after 16 weeks. 22.7% of all patients showed increased liver enzymes in either study and nausea was seen in 15% (SDNTT) versus 22% (METOP) of patients. No severe adverse events were observed in our cohort. Compared to the METOP-trial, the response rates seen our real-world cohort were distinctly lower.