Biologic drug survival rates in the era of anti-interleukin-17 antibodies: a time-period-adjusted registry analysis.

BACKGROUND: Drug survival rates reflect efficacy and safety and may be influenced by the availability of alternative treatment options. Little is known about time-dependent drug survival in psoriasis and the effect of increasing numbers of biologic treatment options. OBJECTIVES: To determine whether drug survival is influenced by the availability of treatment options and by factors such as gender, psoriatic arthritis or previous biologic treatment. METHODS: This observational, retrospective, multicentre cohort study analysed data from patients registered in the Austrian Psoriasis Registry (PsoRA) who were treated with biologics between 1 January 2015 and 30 November 2019. RESULTS: A total of 1572 patients who received 1848 treatment cycles were included in this analysis. The highest long-term Psoriasis Area and Severity Index improvement was observed after treatment with ixekizumab, followed by ustekinumab and secukinumab, adalimumab and etanercept. Overall, ustekinumab surpassed all other biologics in drug survival up to 48 months. However, when adjusted for biologic naïvety, its superiority vanished and drug survival rates were similar for ixekizumab (91·6%), secukinumab (90·2%) and ustekinumab (92·8%), all of them superior to adalimumab (76·5%) and etanercept (71·9%) at 12 months and beyond. Besides biologic non-naïvety (2·10, P < 0·001), the introduction of a new drug such as secukinumab or ixekizumab (relative hazard ratio 1·6, P = 0·001) and female gender (1·50, P = 0·019) increased the risk of treatment discontinuation overall, whereas psoriatic arthritis did not (1·12, P = 0·21). CONCLUSIONS: The time-dependent availability of drugs should be considered when analysing and comparing drug survival. Previous biologic exposure significantly influences drug survival. Women are more likely to stop treatment.

[Chronic, refractory ulcer on the ring finger : Manifestation of distal epithelioid sarcoma]. / Chronisches, therapieresistentes Ulkus am Ringfinger : Manifestation des epitheloiden Sarkoms vom distalen Typ.

The epithelioid sarcoma classic, "distal" type was first published in 1970. It is a very rare, malignant, aggressive subcutaneous soft tissue sarcoma that shows characteristic positivity for both epithelial and mesenchymal immunohistochemical markers. It grows very slowly and mostly presents in young men. Clinically the tumor is characterized as a coarse cutaneous or subcutaneous nodular induration that often ulcerates in the course of the disease. An association with trauma is often described and can lengthen time to diagnosis. Most frequently it is found on the flexural side of fingers, the back of the hands, soles of the feet, and extensor sides of arms and legs. Specific for this type of sarcoma is the progression along nerves, tendons, and fasciae. Treatment of choice should be wide excision of the tumor, sentinel node biopsy, and possibly even localized postoperative radiation therapy. Unfortunately the epithelioid sarcoma is very likely to recur and is then associated with metastases in the lung and lymph nodes.

The role of IL-23 and the IL-23/TH 17 immune axis in the pathogenesis and treatment of psoriasis.

Psoriasis is a chronic, immune-mediated disease affecting more than 100 million people worldwide and up to 2.2% of the UK population. The aetiology of psoriasis is thought to originate from an interplay of genetic, environmental, infectious and lifestyle factors. The manner in which genetic and environmental factors interact to contribute to the molecular disease mechanisms has remained elusive. However, the interleukin 23 (IL-23)/T-helper 17 (TH 17) immune axis has been identified as a major immune pathway in psoriasis disease pathogenesis. Central to this pathway is the cytokine IL-23, a heterodimer composed of a p40 subunit also found in IL-12 and a p19 subunit exclusive to IL-23. IL-23 is important for maintaining TH 17 responses, and levels of IL-23 are elevated in psoriatic skin compared with non-lesional skin. A number of agents that specifically inhibit IL-23p19 are currently in development for the treatment of moderate-to-severe plaque psoriasis, with recent clinical trials demonstrating efficacy with a good safety and tolerability profile. These data support the role of this cytokine in the pathogenesis of psoriasis. A better understanding of the IL-23/TH 17 immune axis is vital and will promote the development of additional targets for psoriasis and other inflammatory diseases that share similar genetic aetiology and pathogenetic pathways.

[Wound management with enzyme alginogels : Expert consensus]. / Wundbehandlung mit Enzym-Alginogelen : Expertenkonsens.

BACKGROUND: The challenges of modern wound management, such as the treatment of chronic wounds and their phase-specific handling, are demanding and require optimally adapted therapeutic measures. The principles of moist wound care as well as an adequate debridement have priority here. To support these necessary measures, different options are available, e.g., a new product group operating across several wound phases. OBJECTIVE: A new treatment principle in modern wound management based on an expert consensus is presented. METHODS: On the basis of clinical experience reports and published evidence, the current and new principles of wound treatment were discussed in a panel of experts and formulated as a consensus statement. RESULTS: Enzyme alginogels represent a combination of agents that allow phase-specific wound care. They exhibit autolytic, absorbent, and antimicrobial properties and simultaneously cover three components of wound management based on the TIME framework. Thus, according to the experts, they differ from other wound healing products and can be classified in a distinct product group. Clinical studies, as well as clinical experiences, provide evidence for the efficacy of enzyme alginogels. DISCUSSION: According to the experts, the potential of enzyme alginogels used considering the principles of moist wound care, comprises the three-fold effect (continuous and significantly simplified debridement, maintaining a moist wound environment and antimicrobial effect without cytotoxicity), the ease of use, and the flexible application. In addition, the flexibility of the product class regarding frequency of application, duration of treatment and combinability with secondary dressings, are of economic benefit in the health care sector.

The quality of European dermatological guidelines: critical appraisal of the quality of EDF guidelines using the AGREE II instrument.

Clinical practice guidelines are systematically developed tools to assist clinicians and health policy makers in decision making for clearly defined clinical situations. In the light of the demand for evidence-based medicine and quality in health care and the increasing methodological requirements concerning guidelines development, it is important to evaluate existing practice guidelines to systematically identify strengths and weaknesses. Currently, the most accepted tool for the methodological evaluation of guidelines is the Appraisal of Guidelines for Research & Evaluation (AGREE) Instrument. Intention of this assessment is to identify and critically appraise clinical practice guidelines commissioned by the European Dermatology Forum (EDF). A quality assessment of a predefined set of guidelines, including all available clinical practice guidelines published on the EDF guidelines internet site, was performed using the AGREE II instrument. To assure an objective assessment, four independent assessments were performed by evaluators situated in different European countries. Twenty-five EDF guidelines covering different dermatological topics were identified and evaluated. The assessment included seven guidelines developed on the highest methodological standard (systematic literature search and structured consensus conference, S3). Eighteen guidelines were identified that were based on either a structured consensus process (S2k), a systematic literature assessment (S2e) or on informal consensus only (S1). The methodological and reporting quality among the evaluated guidelines was heterogeneous. S3 guidelines generally received the highest scores. The domains 'clarity of presentation' and 'scope and purpose' achieved the highest mean ratings within the different domains of assessment, whereas the domains of 'applicability', 'stakeholder involvement' and 'editorial independence' scored poorly. Considering the large variations in the achieved scores, there is need for methodological harmonization within the EDF guidelines to achieve comparable methodological standards.

A patient-centred approach to biological treatment decision making for psoriasis: an expert consensus.

BACKGROUND: Each individual psoriasis patient has different expectations and goals for biological treatment, which may differ from those of the clinician. As such, a patient-centred approach to treatment goals remains an unmet need in psoriasis. OBJECTIVE: The aim of this study was to review available data on patients' and physicians' decision criteria and expectations of biological treatment for moderate-to-severe psoriasis with the aim of developing a core set of questions for clinicians to ask patients routinely to understand what is important to them and thus better align physicians' and patients' expectations of treatment with biologics and its outcomes. METHODS: A literature search was conducted to identify key themes and data gaps. Aspects of treatment relevant when choosing a biological agent for an individual patient were identified and compared to an existing validated instrument. A series of questions aimed at helping the physician to identify the particular aspects of treatment that are recognised as important to individual psoriasis patients was developed. RESULTS: Key findings of the literature search were grouped under themes of adherence, decision-making, quality of life, patient/physician goals, communication, patient-reported outcomes, satisfaction and patient benefit index. Several aspects of treatment were identified as being relevant when choosing a biological agent for an individual patient. The questionnaire is devised in two parts. The first part asks questions about patients' experience of psoriasis and satisfaction with previous treatments. The second part aims to identify the treatment attributes patients consider to be important and may as such affect their preference for a particular biological treatment. The questionnaire results will allow the physician to understand the key factors that can be influenced by biological drug choice that are of importance to the patient. This information can be used be the physician in clinical decision making. CONCLUSION: The questionnaire has been developed to provide a new tool to better understand and align patients' and physicians' preferences and goals for biological treatment of psoriasis.

Successful treatment of PASH syndrome with infliximab, cyclosporine and dapsone.

BACKGROUND: The group of autoinflammatory syndromes associated with Pyoderma gangrenosum, Acne, and Suppurative Hidradenitis are poorly defined and difficult to control with currently available treatment modalities. OBJECTIVES: We describe a patient with PASH syndrome and report about the successful multimodal treatment with infliximab, cyclosporine, and dapsone. METHODS: A review of the available literature to date about this group of autoinflammatory diseases was performed. We performed genetic analysis for PSTPIP1 mutations associated with PAPA syndrome. RESULTS: A 22-year-old woman presented to our department with pyoderma gangrenosum, concomitant acne, and suppurative hidradenitis. She had previously been treated unsuccessfully with etanercept, adalimumab, fumaric acid and the IL-1 receptor antagonist (IL-1RA) anakinra without prolonged remission. Treatment with intravenous infliximab in combination with cyclosporine and dapsone lead to sudden and prolonged improvement of the clinical symptoms that we classified as PASH syndrome. We review the literature about this group of diseases and report the third case of PASH syndrome to date. CONCLUSION: PASH syndrome and associated diseases should be considered whenever hidradenitis suppurativa is found in association with pyoderma gangrenosum. We provide a systematic overview about PASH syndrome and suggest a novel multimodal therapeutic regimen beyond isolated inhibition of TNF or IL-1.

Psoriasis beyond the skin: an expert group consensus on the management of psoriatic arthritis and common co-morbidities in patients with moderate-to-severe psoriasis.

BACKGROUND: Psoriatic arthritis (PsA) and co-morbidities of psoriasis represent a significant clinical and economic burden for patients with moderate-to-severe psoriasis. Often these co-morbidities may go unrecognized or undertreated. While published data are available on the incidence and impact of some of them, practical guidance for dermatologists on detection and management of these co-morbidities is lacking. OBJECTIVE: To prepare expert recommendations to improve the detection and management of common co-morbidities in patients with moderate-to-severe psoriasis. METHODS: A systematic literature review was conducted on some common co-morbidities of psoriasis-cardiovascular (CV) diseases (including obesity, hypertension, hyperglycaemia and dyslipidaemia), psychological co-morbidities (including depression, alcohol abuse and smoking) and PsA-to establish the incidence and impact of each. Data gaps were identified and a Delphi survey was carried out to obtain consensus on the detection and management of each co-morbidity. The expert panel members for the Delphi survey comprised 10 dermatologists with substantial clinical expertise in managing moderate-to-severe psoriasis patients, as well as a cardiologist and a psychologist (see appendix) with an interest in dermatology. Agreement was defined using a Likert scale of 1-7. Consensus regarding agreement for each statement was defined as ≥75% of respondents scoring either 1 (strongly agree) or 2 (agree). RESULTS: The expert panel members addressed several topics including screening, intervention, monitoring frequency, and the effects of anti-psoriatic treatment on each co-morbidity. Consensus was achieved on 12 statements out of 22 (3 relating to PsA, 4 relating to psychological factors, 5 relating to CV factors). The panel members felt that dermatologists have an important role in screening their psoriasis patients for PsA and in assessing them for psychological and CV co-morbidities. In most cases, however, patients should be referred for specialist management if other co-morbidities are detected. CONCLUSION: This article provides useful and practical guidance for the detection and management of common co-morbidities in patients with moderate-to-severe psoriasis.

An updated overview and clarification of the principle role of debridement.

Routine care of non-healing acute and chronic wounds often comprises either cleaning or debridement. Consequently, debridement is a basic necessity to induce the functional process of tissue repair, which makes it a central medical intervention in the management of acute and chronic, non-healing wounds.

Comparison of PHMB-containing dressing and silver dressings in patients with critically colonised or locally infected wounds.

OBJECTIVE: This study compares treatment with a polihexanide-containing biocellulose wound dressing (BWD+PHMB) versus the best local standard of silver dressings (Ag) in painful, critically colonised (wounds-at-risk) or locally-infected wounds. METHOD: Patients with wounds of various aetiologies, a baseline VAS pain score >4 and a semi-quantitative bacterial load of ++ or higher were randomly allocated to receive treatment with either BWD+PHMB or Ag. Patients with systemic infections and/or using systemic antibiotics were excluded. The primary endpoint, patient-reported pain (VAS total pain, including the sub-scores pain at night, during the day, before, and 15min after dressing changes), was compared between treatment groups and scored on days 0, 1, 3, 7, 14, 21 and 28. Secondary outcomes of bacterial load, wound bed and periwound skin condition, quality of life and dressing handling were assessed at the same visits. RESULTS: Thirty-eight patients (BWD+PHMB, n=21 [24 wounds]; Ag, n=17 [18 wounds]) were included in the analyses. Baseline variables showed no significant differences. Wound pain was reduced significantly in both groups, with a better pain reduction noted for BWD+ PHMB (p<0.001) before dressing changes. Compared with Ag, in the BWD+PHMB group critical colonisation and local wound infection had been reduced significantly faster and better (p<0.001) over the 28-day study period. Improved quality of life, good tolerability and no adverse events were demonstrated for both groups. CONCLUSION: Both BWD+PHMB and AG were effective in reducing pain and bacterial burden. However, that BWD+PHMB was significantly faster and better in removing the critical bacterial load, makes this dressing an attractive therapeutic option to treat critically colonised and locally-infected wounds.

Chronic wounds treated with cold atmospheric plasmajet versus best practice wound dressings: a multicenter, randomized, non-inferiority trial.

The use of phase-adapted wound dressings represents best practice (BP) in chronic wound treatment. However, efficacy is often limited and associated care requirements are high. Cold atmospheric plasmajet (CAP-jet) is a promising new therapeutic tool for these wounds. In the present multicenter, randomized, open-label, prospective, clinical trial, non-inferiority of the CAP-jet versus BP was assessed in 78 patients with infected or non-infected chronic wounds of different etiology. Primary outcome measure was the sum of granulation tissue, furthermore wound area reduction, healing rate, time to complete healing, changes in wound pH value, infection score, exudate level and local tolerability were assessed. In CAP-jet treated wounds compared to control, the sum of granulation tissue was significantly higher (p < 0.0001) and wound area reduced significantly faster (p < 0.001). Furthermore, wound pH value decreased significantly faster (p = 0.0123) and local infection was overcome more rapidly by CAP-jet therapy. In 58.97% CAP-jet- vs. 5.13% BP-treated patients, complete healing of chronic ulcers was documented after 6 weeks. Treatment with CAP-jet appeared not only non-inferior, but even superior to BP in all wound entities analyzed with a favorable tolerability profile. Thus, treatment with the CAP-jet provides beneficial effects in chronic wound treatment regarding promotion of the wound healing process.

Early detection of renal damage caused by fumaric acid ester therapy by determination of urinary ß2-microglobulin.

BACKGROUND: Fumaric acid esters are considered efficacious and safe drugs for the treatment of psoriasis. Renal damage, caused either by acute renal injury or Fanconi syndrome, is a recognized side-effect of this therapy. OBJECTIVES: To investigate whether the measurement of urinary excretion of ß2-microglobulin, a marker of renal proximal tubular dysfunction, allows early detection of kidney damage before an increase in serum creatinine or significant proteinuria occurs. METHODS: Urinary ß2-microglobulin excretion was measured regularly in 23 patients undergoing fumaric acid ester therapy. RESULTS: Urinary ß2-microglobulin remained normal in all 10 male patients. Three (23%) out of 13 female patients experienced an increase in urinary ß2-microglobulin excretion. In two of these patients a sharp increase was observed in association with high doses. One further patient had moderately elevated levels on rather low doses of fumaric acid esters. After discontinuing treatment, urinary ß2-microglobulin levels returned to normal within a few weeks. CONCLUSION: Determination of urinary ß2-microglobulin possibly allows early detection of renal damage by fumaric acid esters. Female patients seem to be prone to this side-effect, especially when taking high doses.

Classification of wounds at risk and their antimicrobial treatment with polihexanide: a practice-oriented expert recommendation.

Currently, there are no generally accepted definitions for wounds at risk of infection. In clinical practice, too many chronic wounds are regarded as being at risk of infection, and therefore many topical antimicrobials - in terms of frequency and duration of use - are applied to wounds. Based on expert discussion and current knowledge, a clinical assessment score was developed. The objective of this wounds at risk (W.A.R.) score is to allow decision-making on the indication for the use of antiseptics on the basis of polihexanide. The proposed clinical classification of W.A.R. shall facilitate the decision for wound antisepsis and allow an appropriate general treatment regimen with the focus on the prevention of wound infection. The W.A.R. score is based on a clinically oriented risk assessment using concrete patient circumstances. The indication for the use of antiseptics results from the addition of differently weighted risk causes, for which points are assigned. Antimicrobial treatment is justified in the case of 3 or more points.

A practice-oriented recommendation for treatment of critically colonised and locally infected wounds using polihexanide.

UNLABELLED: The problem of wound infection presents a special challenge in the treatment of acute as well as chronic wounds. Typical complications not only jeopardise the successful outcome of treatment modalities as a whole; they may result in amputation or even become life-threatening. Polihexanide is an antimicrobial substance which is highly appropriate for use in critically colonised or infected acute and chronic wounds. This finding is based primarily on the broad antimicrobial spectrum and good cell and tissue compatibility of polihexanide, its capability of binding to organic matrix, the low risk of contact sensitisation, and the fact that it promotes wound healing. Furthermore, there has been no conclusive evidence to date of any pathogens developing resistances under the use of polihexanide. SUMMARY: Wound infections are special and challenging situations in therapy of acute and chronic wounds. Typical complications are risky not only for therapeutic process but also for amputation and viability of patients. Polihexanide is an exceedingly appropriate antimicrobial substance for using in critical colonised and local infected acute and chronic wounds. This evaluation is based on different properties of the compound like the broad antimicrobial spectrum, the excellent cell and tissue tolerability, the binding capacity to organic matrix, low risk of contact sensitisation and adjuvant effects to wound healing. Up to now there are no microbial resistances observed.

Immunoglobulin kappa light chain variable region gene complex organization and immunoglobulin genes encoding anti-DNA autoantibodies in lupus mice.

We have investigated the genetic origin of autoantibody production in several strains of mice that spontaneously develop a systemic lupus erythematosus-like disease. Restriction fragment length polymorphism analyses of gene loci encoding kappa light chain variable regions (Igk-V) demonstrated, as shown previously for the Ig heavy chain locus, that autoantibody production and disease occur in different Igk-V haplotypes. Moreover, autoimmune mice with known genetic derivation inherited their Igk-V loci essentially unaltered from their nonautoimmune ancestors. New Zealand black lupus mice, with unknown genetic derivation, had a possibly recombinant Igk-V haplotype, composed of V kappa loci that were primarily indistinguishable from those of nonautoimmune strains from either of the two potential donor haplotypes. The heavy and light chain gene segments (variable, diversity, joining) encoding anti-DNA antibodies were diverse and often closely related, or even identical, to those found in antibodies to foreign antigens in normal mice. Only 1 of 11 sequenced variable region genes could not be assigned to existing variable region gene families; however, corresponding germline genes were present in the genome of normal mice as well. These data argue against abnormalities in the genes and mechanisms generating antibody diversity in lupus mice and suggest a remarkable genetic and structural diversity in the generation of anti-DNA binding sites.

T-cell receptor repertoire of lymphocytes infiltrating cutaneous melanoma is predominated by V alpha specificities present in T-cells of normal human skin.

Lymphocytes infiltrating solid tumors can be propagated in vitro with interleukin 2 and are then capable, as CD8+ cytotoxic T-cells, of specific lysis of autologous tumor targets in a class I-restricted manner. Since the specificity of these cells is determined by their T-cell receptor (TCR) configuration, the aim of this study was to delineate the TCR V alpha repertoire of tumor-infiltrating lymphocytes within 24 melanoma specimens and to compare these data with the TCR expression pattern of unaffected peritumoral and normal human skin. While lymphocytes within all skin specimens tested expressed a substantial, albeit limited, heterogeneity of V alpha specificities with an average number of 9.0 different V alpha gene segments, the V alpha repertoire within cutaneous melanoma lesions was significantly more restricted (mean of V alpha expression, 3.86; P < 0.001) with a predominance of only 3 V alpha families (V alpha 13, V alpha 15, and V alpha 16), all of which were also found to be expressed within normal skin. Collectively, the fact that the TCR V alpha repertoire in melanoma is skewed toward the predominance of only a few V alpha regions may be indicative of a limited number of melanoma-associated antigenic determinants being involved in the anti-tumor immune response.

The role of fetal epithelial tissues in the maturation/differentiation of bone marrow-derived precursors into dendritic epidermal T cells (DETC) of the mouse.

Our attempts to clarify the contribution of the thymic vs. the cutaneous microenvironment in the maturation of dendritic epidermal T cell (DETC) precursors into DETC gave diverse results. In one series of experiments, we found that i.v. injection of fetal thymocytes (containing a TCR V gamma 3-expressing subpopulation), but not of adult thymocytes (containing no TCR V gamma 3+ cells) results in the appearance of CD3/TCR V gamma 3+ dendritic epidermal cells (=DETC). In other experiments, we have obtained evidence that transplantation of day 16 fetal skin onto a Thy-1-disparate recipient results in the appearance of donor-type DETC. Our further observation that the transplanted skin contains CD45+/Thy-1+/CD3- lymphocytes, but no mature T cells, therefore implies that fetal skin can provide stimuli promoting the expression of CD3/TCR genes in immature (CD3-) DETC precursors. It remains to be seen whether both or only one of these maturational pathways are (is) followed under physiological conditions.

Nanocrystalline silver dressings as an efficient anti-MRSA barrier: a new solution to an increasing problem.

The emergence of multi-drug-resistant strains of bacteria represents a particular challenge in the field of wound management. The aim of the current study was to investigate whether nanocrystalline silver dressings possess the physical properties to act as a barrier to the transmission of methicillin-resistant Staphylococcus aureus (MRSA) in the laboratory setting and in a clinical setting. Initially, MRSA suspension and colony culture experiments were performed showing that nanocrystalline silver dressings act as potent and sustained antimicrobial agents, efficiently inhibiting MRSA penetration. Subsequently, a double-centre clinical trial was initiated using nanocrystalline silver dressings as a cover for 10 MRSA colonized wounds in a total of seven patients. By delineating the MRSA load on the upper side of the dressing and the wound bed each time the dressing was changed (i.e. after 1, 24, 48 and 72 h), nanocrystalline silver dressings were found to provide a complete, or almost complete, barrier to the penetration/spread of MRSA in 95% of readings. In addition, 67% of all wound observations showed a decrease in the MRSA load with an eradication rate of 11%. We believe that nanocrystalline silver dressings may become an important part of local MRSA management, with cost benefits to both patients and the healthcare system.

In vivo cytokine expression in normal and perturbed murine skin--analysis by competitive quantitative polymerase chain reaction.

Although cells from both epidermis and dermis have been shown to produce a variety of soluble mediators in vitro, it is not clear whether this reflects the in vivo situation. To study in vivo cytokine expression, whole skin as well as dispase-separated epidermis and dermis from normal adult mice were prepared and snap-frozen immediately. RNA was then extracted and analyzed both by conventional and by competitive quantitative polymerase chain reaction. Molecular analysis showed that murine skin in vivo constitutively expresses several cytokine genes at moderate (e.g., interleukin-1 alpha) or low (e.g., interleukin-6 and granulocyte-macrophage colony-stimulating factor) abundance. A striking, rapid upregulation was observed for some of these cytokines in the process of tissue separation. Of interest, the epidermal and dermal compartments exhibited different induction patterns: interleukin-1 alpha, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-alpha expression were detected preferentially in the epidermis, whereas upregulation of interleukin-6 was found to be most prominent in the dermis. This pattern of cytokine expression was also reflected in supernatants generated from the respective single-cell suspensions. Thus, this study determines the baseline in vivo cytokine expression in the skin and the occurrence of immediate, compartment-specific alterations on perturbation. These data should contribute to our understanding of both skin homeostasis and the host-defense mechanisms initiated following injury to this organ.