Treatment of psoriasis with biologic and non-biologic targeted therapies in patients with latent tuberculosis infection or at risk for tuberculosis disease progression: Recommendations from a SPIN-FRT expert consensus.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a significant global health problem. In immunocompetent individuals, the microorganism can remain in a latent, non-contagious form, however, it may become active under conditions of immunosuppression. Tumour necrosis factor (TNF) inhibitors, which are frequently used for the management of immune-mediated disorders like psoriasis, have been associated with a significantly increased risk of reactivating latent TB. Consequently, international guidelines recommend TB screening and preventive treatment before starting anti-TNF therapy. These recommendations have extended to IL-12/23, IL-17, IL-23 and TYK2 inhibitors under a caution principle, despite their different mechanisms of action. However, current evidence suggests that some of these agents are arguably not associated with an increased risk of TB reactivation or development of TB disease after infection, which calls for a critical reassessment of these guidelines. We have conducted a literature search evaluating the risk of TB reactivation associated with these innovative therapies, integrating findings from both randomized clinical trials and real-world evidence. The identified evidence is limited but the low number of identified cases of reactivation with IL-17 and IL-23 inhibitors prompts reconsidering the need for preventive treatment for latent TB in all cases, regardless of biologic class or individual patient's risk of TB reactivation or drug toxicity. This review, along with the clinical insight of a panel of experts on behalf of the SPIN-FRT, led to the development of these consensus recommendations for managing psoriasis treatment in patients with latent TB infection or at risk of TB infection, who are receiving or are intended to receive biologic and non-biologic targeted therapies. These recommendations highlight the need for updates to the existing guidelines, aiming to provide a more differentiated approach that reflects the evolving landscape of psoriasis treatment and its implications for TB management.

Lesional activation of Tc 17 cells in Behçet disease and psoriasis supports HLA class I-mediated autoimmune responses.

BACKGROUND: Behçet disease (BD) presents with lymphocytic and neutrophilic vasculitis of unknown aetiology. HLA-B*51, the endoplasmic reticulum aminopeptidase 1 (ERAP1), and interleukin 23 receptor (IL23R)/IL12R are genetic risk factors. IL-23 regulates IL-17A, which controls the recruitment and activation of neutrophils. OBJECTIVES: To determine pathological changes in BD skin lesions related to the complex genetic predisposition. METHODS: We characterized the expression of IL-17A and IL-23A in various cell types by immunohistological double staining of sections from papulopustular skin lesions of acute attacks of BD and psoriasis vulgaris lesions, another HLA-class I-associated T-cell-mediated autoimmune disease in which excessive T-cell-derived IL-17A production promotes neutrophil activation. RESULTS: We found that in BD lesions, as in psoriasis, actively expanding CD8+ T cells were the predominant source of IL-17A. IL-17A+ CD8+ T (Tc 17) cells outnumbered infiltrating IL-17A+ CD4+ T cells. Unlike the epidermal localization of CD8+ T cells in psoriasis, Tc 17 cells in BD lesions mainly infiltrated the perivascular tissue and the blood vessel walls of dermis and subcutaneous tissue. They co-localised with a marked IL-23A expression by CD11c+ dendritic cells and CD68+ macrophages. IL-17A expression was associated with extensive recruitment of neutrophils around blood vessels that formed neutrophil extracellular traps (NETs). CONCLUSIONS: In BD, the genetic predisposition may mediate antigen-specific activation and differentiation of a Tc 17 response, possibly targeting endothelial (auto)antigens. Neutrophils recruited by IL-17A in this process may enhance tissue damage by extensive NET formation (NETosis). Thus, the IL-23/IL-17 axis presumably controls neutrophilic inflammation in BD vasculitis in the context of a predominant antigen-specific CD8+ T-cell response.

[Psoriasis in dupilumab-treated atopic dermatitis]. / Psoriasis bei Dupilumab-behandeltem atopischem Ekzem.

Dupilumab is a monoclonal antibody that binds to the common alpha chain of the IL­4 and IL-13 receptor and blocks the Th2 signaling pathway, which plays a key role in the development of atopic dermatitis. We report on the case of a 40-year-old man, who developed histologically confirmed psoriasis after 6 weeks of dupilumab therapy. The arbitrary, abrupt stopping of the unusual, not guideline-based oral steroid therapy, together with the blockade of the Th2 signaling pathway by dupilumab were apparently the relevant trigger factors for the newly developed psoriasis in our patient.

Genetics and Crime: Integrating New Genomic Discoveries Into Psychological Research About Antisocial Behavior.

Drawing on psychological and sociological theories of crime causation, we tested the hypothesis that genetic risk for low educational attainment (assessed via a genome-wide polygenic score) is associated with criminal offending. We further tested hypotheses of how polygenic risk relates to the development of antisocial behavior from childhood through adulthood. Across the Dunedin and Environmental Risk (E-Risk) birth cohorts of individuals growing up 20 years and 20,000 kilometers apart, education polygenic scores predicted risk of a criminal record with modest effects. Polygenic risk manifested during primary schooling in lower cognitive abilities, lower self-control, academic difficulties, and truancy, and it was associated with a life-course-persistent pattern of antisocial behavior that onsets in childhood and persists into adulthood. Crime is central in the nature-nurture debate, and findings reported here demonstrate how molecular-genetic discoveries can be incorporated into established theories of antisocial behavior. They also suggest that improving school experiences might prevent genetic influences on crime from unfolding.

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

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

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.

Treatment of psoriasis with etanercept: the typical patient profile.

The chronic nature of psoriasis means that patients often require lifetime treatment. Over this time, treatment frequently has to be adapted to meet variable demands resulting from changes in life course and life events. Biological drugs used to treat psoriasis vary in their dosing regimens, convenience and flexibility. Dermatologists need to understand which biologic agent is best suited for each individual patient. A wealth of evidence supports the safe and effective use of etanercept, which offers a rapid and sustained response, flexibility of dosing, maintenance of response after dose reduction or interruption, and efficacy against non-skin manifestations such as psoriatic arthritis. An expert panel met to agree the typical patient profile of a psoriasis patient treated with etanercept, the main benefits of etanercept in psoriasis, and the patient group most likely to benefit from its use. They agreed that flexibility of dosing, the potential to individualize therapy by stopping and starting treatment while maintaining efficacy, and the possibility of cost saving through the use of flexible treatment regimens were important benefits supporting the use of etanercept in many patients with psoriasis.

[Autoimmune reactions in psoriasis : Spotlight]. / Autoimmunreaktionen bei Psoriasis : Spotlight.

BACKGROUND: Psoriasis is a human leukocyte antigen (HLA)-associated T­cell-mediated disorder. OBJECTIVES: The role of the main psoriasis risk allele HLA-C*06:02 in disease manifestation and the mechanisms which activate the pathogenic T­cell response in the skin of psoriasis patients remained elusive. MATERIALS AND METHODS: Key to the immune pathogenesis of psoriasis was the analysis of the specificity of the infiltrating lesional psoriatic CD8(+) T cells RESULTS AND CONCLUSION: Analyses of the lesional psoriatic T­cell reactivity demonstrate that psoriasis is an autoimmune disease. It is based on an autoimmune response against melanocytes which is preferentially mediated by HLA-C*06:02 through autoantigen presentation. Here we discuss the mechanisms of this autoimmune response in the context of the polygenic psoriatic predisposition.

[Psoriasis migrans : Erythema migrans as Koebner phenomenon in psoriasis]. / Psoriasis migrans : Erythema migrans als Köbner-Phänomen bei Psoriasis.

Psoriasis is a chronic inflammatory disorder of the epidermis, which can be induced by systemic factors, such as streptococci infections or drugs. In addition, psoriasis can be caused by a local cutaneus trauma, known as Koebner phenomenon. Here, we describe a woman with psoriasis in remission, who developed a new psoriatic lesion due to a cutaneous infection with Borrelia burgdorferi. After causal therapy with doxycycline, the erythema migrans and psoriasis lesions disappeared.

Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE).

BACKGROUND: Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, demonstrated efficacy and safety in moderate-to-severe plaque psoriasis when administered via subcutaneous injection. Self-administration by pre-filled syringe (PFS) can offer patients clinical benefits of a drug, with increased convenience. OBJECTIVES: To assess efficacy, safety and usability of secukinumab administration via PFS in subjects with moderate-to-severe plaque psoriasis. MATERIALS AND METHODS: Subjects in this phase 3 trial were randomized 1 : 1 : 1 to secukinumab 300 or 150 mg or matching placebo. Results to week 12 are presented here. Each treatment was delivered using a PFS once weekly to week 4, and again at week 8. Co-primary endpoints were secukinumab superiority over placebo for week 12 PASI 75 (≥ 75% reduction in Psoriasis Area and Severity Index) and IGA mod 2011 (2011 modified Investigator's Global Assessment) 0/1 response rates. Secondary endpoints included PFS usability, determined by observer rating of successful, hazard-free self-injection and subject rating of acceptability by the Self-Injection Assessment Questionnaire (SIAQ). RESULTS: Co-primary endpoints were met, with demonstration of superiority for each secukinumab dose vs. placebo at week 12 (PASI 75: 75·9%, 69·5% and 0% for secukinumab 300 mg, 150 mg and placebo; IGA mod 2011 0/1: 69·0%, 52·5% and 0%, respectively; P < 0·0001 for all comparisons vs. placebo). PFS usability was high: 100% of subjects successfully self-administered treatment at week 1, and subjects reported high SIAQ-assessed acceptability of the PFS throughout the trial. No new/unexpected safety signals were observed. CONCLUSIONS: Secukinumab administration by PFS was effective, with an acceptable safety profile and high usability. The PFS provides a reliable, convenient form of secukinumab administration in subjects with moderate-to-severe plaque psoriasis.

Long-term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate-to-severe psoriasis: results from the PHOENIX 2 study through 5 years of follow-up.

BACKGROUND: Evaluation of the dosing flexibility and long-term efficacy of biological agents is limited. OBJECTIVES: To evaluate the long-term efficacy and safety of ustekinumab with and without dosing adjustment in the 5-year PHOENIX 2 study. METHODS: Patients were randomized to placebo or ustekinumab (45 or 90 mg) at weeks 0, 4, then every 12 weeks; patients receiving placebo crossed-over at week 12. Dosing adjustments were permitted at/beyond week 28 for early adjusters (weeks 28 or 40 per response); late adjusters (during long-term extension per investigator judgement); and nonadjusters (maintained randomized treatment throughout the study). Efficacy and safety were evaluated through weeks 244 and 264, respectively. RESULTS: In the overall population, 70% (849 of 1212) of ustekinumab-treated patients completed treatment through week 244, with high proportions of patients responding to the 45-mg and 90-mg doses, respectively: 75% improvement in Psoriasis Area and Severity Index (PASI 75) (76·5% and 78·6%) and PASI 90 (50·0% and 55·5%). Approximately 20% of patients were early adjusters, 30% were late adjusters and 50% were nonadjusters. Approximately half of the late adjusters initiated adjustments after already achieving PASI 75. Improved response was generally observed following dosing adjustments. Through week 264, safety event rates did not increase and event rates were generally comparable between dose groups and between patients with and without dosing adjustment. CONCLUSIONS: Treatment with ustekinumab for up to 5 years was safe and effective. Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify actual incremental benefits. The results also suggest that some patients may desire treatment goals beyond PASI 75.

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.

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.

Clinical relevance of immunogenicity of biologics in psoriasis: implications for treatment strategies.

Biological drugs such as the tumour necrosis factor inhibitors have revolutionized the treatment of psoriasis, but some have the potential to induce an unwanted immune response. This immunogenicity may be associated with low trough drug levels, reduced clinical efficacy, reduced drug survival and an increased risk for adverse events. This article presents a literature review of the evidence on immunogenicity of biologics used in the treatment of psoriasis and considers the implications for therapeutic decision-making in the management of patients with moderate-to-severe psoriasis.

Cost-effectiveness evaluation of clobetasol propionate shampoo (CPS) maintenance in patients with moderate scalp psoriasis: a Pan-European analysis.

BACKGROUND: Scalp psoriasis is a difficult to treat and usually chronic manifestation of psoriasis. The CalePso study showed that CPS (Clobex(®) Shampoo) in maintenance therapy of scalp psoriasis (twice weekly) significantly increases the probability of keeping patient under remission during 6 months, compared with vehicle (40.3% relapses vs. 11.6% relapses, ITT). OBJECTIVE: The objective of the study was to assess the cost-effectiveness of a maintenance therapy with CPS vs. its vehicle in nine European countries. METHODS: A 24-week decision tree model was developed with 4-weekly time steps. The considered population has moderate scalp psoriasis successfully treated with a daily application of CPS up to 4 weeks. Data were taken from the CalePso study and from national experts' recommendations for alternative treatment choices, with their probabilities of success taken from literature to develop country-specific models. Health benefits are measured in disease-free days (DFD). The economic analysis includes drug and physician costs. A probabilistic sensitivity analysis (PrSA) assesses the uncertainty of the model. RESULTS: Depending on the country, the mean total number of DFDs per patient is 21-42% higher with CPS compared with vehicle, and the mean total cost is 11-31% lower. The mean costs per DFD are 30-46% lower with CPS compared with the vehicle. The PrSA showed in 1000 simulations that CPS is more effective vs. vehicle in 100% of the cases and less expensive than its vehicle in 80-99% of the cases. CONCLUSION: This model suggests that CPS is cost-effective in maintaining the success achieved in moderate scalp psoriasis patients.

Expression of Mucins in Different Entities of Salivary Gland Cancer: Highest Expression of Mucin-1 in Salivary Duct Carcinoma : Mucin-1 - highest expression in Salivary Duct Carcinoma.

Therapeutic options for advanced salivary gland cancer (SGC) are rare. Therefore, it was the aim of this study to investigate the extent and intensity of Mucin-1 (MUC1), Mucin-16 (MUC16), and Mucin-5AC (MUC5AC) as potential molecular targets using immunohistochemistry. The medical records of all patients who underwent primary surgery for salivary gland cancer with curative intent in a tertiary referral center between 1990 and 2018 were reviewed. Immunohistochemical staining for MUC1, MUC16, and MUC5AC was performed for all patients with sufficient formalin-fixed paraffin-embedded material, and a semi-quantitative combined score derived from the H-score for the cytoplasmatic, the membranous and the apical membrane was built for the most common entities of SGC. 107 patients with malignancies of the parotid (89.7%) and the submandibular gland (10.3%) were included. The most common entities were mucoepidermoid carcinoma (MuEp; n = 23), adenoid cystic carcinoma (AdCy; n = 22), and salivary duct carcinoma (SaDu; n = 21). The highest mean MUC1 combined score was found in SaDu with 223.6 (±91.7). The highest mean MUC16 combined score was found in MuEp with 177.0 (±110.0). The mean MUC5AC score was low across all entities. A higher MUC1 combined score was significantly associated with male gender (p = 0.03), lymph node metastasis (p < 0.01), lymphovascular invasion (p = 0.045), and extracapsular extension (p = 0.03). SaDu patients with MUC16 expression showed a significantly worse 5-year progression-free survival than those without MUC16 expression (p = 0.02). This is the first study to give a comprehensive overview of the expression of MUC1, MUC16, and MUC5AC in SGC. Since advanced SGCs lack therapeutic options in many cases, these results warrant in vitro research on therapeutic targets against MUC1 in SaDu cell lines and xenograft models.

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.