Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove.

Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6-36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.

Mapping opportunities for the earlier diagnosis of psoriasis in primary care settings in the UK: results from two matched case-control studies.

BACKGROUND: The diagnosis of psoriasis may be missed or delayed in primary care settings. AIM: To examine trends in healthcare events before a diagnosis of psoriasis. DESIGN AND SETTING: Two matched case-control studies using electronic healthcare records delineated from the Clinical Practice Research Datalink (CPRD GOLD and Aurum) in the UK. METHOD: Individuals aged ≥18 years with an incident diagnosis of psoriasis (case group) between 1 January 2010 and 29 December 2017 were identified and matched by age, sex, and general practice with six individuals without psoriasis (control group). Healthcare activities were examined and annual incidence rates and incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for 10 years before the index date were compared between case and control groups. RESULTS: There were 17 320 people with psoriasis and 99 320 controls included from CPRD GOLD, and 11 442 people with psoriasis and 65 840 controls extracted from CPRD Aurum. Data from CPRD GOLD showed that people with psoriasis were up to eight times more likely to be diagnosed with pityriasis rosea at 6 months (IRR 7.82, 95% CI = 4.09 to 14.95) before the index date than the control group. The case group were twice as likely to be diagnosed with eczema (IRR 1.90, 95% CI = 1.76 to 2.05) or tinea corporis (IRR 1.99, 95% CI = 1.74 to 2.27) 1 year before the index date. The case group were more likely to report dry skin, rash, skin texture changes, and itching than the control group up to 5 years before the index date. The most frequently reported clinical feature was rash with an IRR of 2.71 (95% CI = 2.53 to 2.92) at 1 year before the index date. The case group were prescribed topical corticosteroids (IRR 1.97, 95% CI = 1.88 to 2.07) or topical antifungals (IRR 1.92, 95% CI = 1.78 to 2.07) in the year before the index date twice as often as those in the control group. CONCLUSION: Findings suggest that the diagnosis of psoriasis may be missed or delayed in a UK primary care setting for up to 5 years for some individuals, hence leading to a potentially detrimental delay in establishing an appropriate treatment regimen.

The systemic influence of chronic smoking on skin structure and mechanical function.

One of the major functions of human skin is to provide protection from the environment. Although we cannot entirely avoid, for example, sun exposure, it is likely that exposure to other environmental factors could affect cutaneous function. A number of studies have identified smoking as one such factor that leads to both facial wrinkle formation and a decline in skin function. In addition to the direct physical effects of tobacco smoke on skin, its inhalation has additional profound systemic effects for the smoker. The adverse effects on the respiratory and cardiovascular systems from smoking are well known. Central to the pathological changes associated with smoking is the elastic fibre, a key component of the extracellular matrices of lungs. In this study we examined the systemic effect of chronic smoking (>40 cigarettes/day; >5 years) on the histology of the cutaneous elastic fibre system, the nanostructure and mechanics of one of its key components, the fibrillin-rich microfibril, and the micromechanical stiffness of the dermis and epidermis. We show that photoprotected skin of chronic smokers exhibits significant remodelling of the elastic fibre network (both elastin and fibrillin-rich microfibrils) as compared to the skin of age- and sex-matched non-smokers. This remodelling is not associated with increased gelatinase activity (as identified by in situ zymography). Histological remodelling is accompanied by significant ultrastructural changes to extracted fibrillin-rich microfibrils. Finally, using scanning acoustic microscopy, we demonstrated that chronic smoking significantly increases the stiffness of both the dermis and the epidermis. Taken together, these data suggest an unappreciated systemic effect of chronic inhalation of tobacco smoke on the cutaneous elastic fibre network. Such changes may in part underlie the skin wrinkling and loss of skin elasticity associated with smoking. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Efficacy of Dupilumab in Different Racial Subgroups of Adults With Moderate-to-Severe Atopic Dermatitis in Three Randomized, Placebo-Controlled Phase 3 Trials

Dupilumab, a monoclonal antibody that blocks the shared receptor subunit for interleukin (IL)-4 and IL-13, is currently approved for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis (AD). The efficacy and safety of dupilumab for AD among racial subgroups is unknown. This post hoc analysis from three phase 3 trials assessed the efficacy and safety of dupilumab vs placebo by racial subgroup (White, Asian, Black/African American). Data from LIBERTY AD SOLO 1 (NCT02277743), SOLO 2 (NCT02277769), and CHRONOS (NCT02260986) were pooled. Outcomes included mean and percent change from baseline to week 16 in the key therapeutic domains Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (NRS), Dermatology Life Quality Index (DLQI), and Patient-Oriented Eczema Measure, as well as Investigator's Global Assessment and pain or discomfort assessed by the European Quality of Life-5 Dimensions 3 level questionnaire. A total of 2,058 patients (White n=1,429, Asian n=501, Black/African American n=128) were included in the current analysis. Baseline demographics and disease characteristics were balanced between treatment groups and racial subgroups. In the three trials, dupilumab significantly (P<0.0001) improved all assessed outcomes compared with placebo in the White and Asian subgroups. In the smaller Black/African American subgroup, dupilumab significantly (P<0.0001) improved EASI endpoints and mean changes in Peak Pruritus NRS and DLQI vs placebo, with positive numeric trends favoring dupilumab in all other endpoints. Dupilumab was generally well tolerated, with an acceptable safety profile in all racial subgroups. Serious adverse events occurred more frequently with placebo; treatment discontinuations due to adverse events were rare in all treatment groups. Significant clinical improvement and a favorable benefit-risk profile can be achieved with dupilumab treatment in patients of White, Asian, and Black/African American racial subgroups with moderate-to-severe AD inadequately controlled with topical medications. ClinicalTrials.gov identifiers: NCT02277743, NCT02277769, NCT02260986

WITHDRAWN: Interventions for guttate psoriasis.

BACKGROUND: Guttate psoriasis is a distinctive acute form of psoriasis which characteristically occurs in children and young adults. Very little specific evidence-based guidance is available in standard texts to help make rational decisions about treatment options. OBJECTIVES: To assess the effectiveness of treatments for guttate psoriasis. SEARCH METHODS: We searched the Cochrane Clinical Trials Register (Cochrane Library, Issue 3, 1999), Medline (1966- September 1999), Embase (1988-September 1999), Salford Database of Psoriasis Trials (to November 1999) and European Dermato-Epidemiology Network (EDEN) Psoriasis Trials Database (to November 1999) for terms GUTTATE and PSORIASIS. We also searched 100 unselected RCTs of psoriasis therapy and all 112 RCTs of phototherapy for psoriasis in the Salford Database of Psoriasis Trials for separate stratification for guttate psoriasis. SELECTION CRITERIA: Randomised trials in which patients with acute guttate psoriasis were randomised to different treatments, except those trials examining antistreptococcal interventions which are addressed in a separate Cochrane review. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility and quality. MAIN RESULTS: No published report could be found to support or to challenge current commonly used methods of management.Only one trial which met the selection criteria was identified. In this small study of 21 hospitalised patients with guttate psoriasis, intravenous infusion of an n-3 fatty acid rich lipid emulsion was compared with placebo emulsion containing n-6 fatty acids. The n-3 preparation appeared to be of some benefit for patients with guttate psoriasis. AUTHORS' CONCLUSIONS: There is currently no firm evidence on which to base treatment of acute guttate psoriasis. Studies comparing standard treatment modalities, including phototherapy and topical regimens, are required to enable informed decisions on treatment choices to be made.

WITHDRAWN: Antistreptococcal interventions for guttate and chronic plaque psoriasis.

BACKGROUND: Guttate psoriasis is a distinctive acute form of psoriasis which characteristically occurs in children and young adults. It is closely associated with preceding streptococcal sore throat or tonsillitis. Some authorities have claimed that ordinary (chronic plaque) psoriasis may also be made worse by infection at distant sites. Although many dermatologists have recommended using antibiotics for guttate psoriasis in particular, it is not clear whether they influence the course of either form of psoriasis. Some dermatologists have also recommended tonsillectomy for psoriasis in patients with recurrent streptococcal sore throat. OBJECTIVES: To assess the evidence for effectiveness of antistreptococcal interventions including antibiotics and tonsillectomy in the management of acute guttate and chronic plaque psoriasis. SEARCH METHODS: We searched the Cochrane Clinical Trials Register (Cochrane Library, Issue 3, 1999), Medline (1966- September 1999), Embase (1988-September 1999), the Salford Database of Psoriasis Trials (to November 1999) and the European Dermato-Epidemiology Network (EDEN) Psoriasis Trials Database (to November 1999) for terms [STREPTOCOCC* or ANTIBIOTIC* or TONSIL*] and PSORIASIS using the Cochrane Skin Group search strategy. SELECTION CRITERIA: Randomised trials of one or more antistreptococcal interventions in patients with guttate or chronic plaque psoriasis. DATA COLLECTION AND ANALYSIS: Two reviewers independently examined each retrieved trial for eligibility and quality. MAIN RESULTS: The one eligible trial we identified compared the use of two oral antibiotic schedules in 20 psoriasis patients, predominantly of guttate type, who had evidence of beta-haemolytic streptococcal colonisation. Either rifampicin or placebo was added to the end of a standard course of antistreptococcal antibiotic (phenoxymethylpenicillin or erythromycin). No patient in either arm of the study improved during the observation period.No randomised trials of tonsillectomy for psoriasis were identified. AUTHORS' CONCLUSIONS: Although it is well known that guttate psoriasis may be precipitated by streptococcal infection, there is no firm evidence to support the use of antibiotics either in the management of established guttate psoriasis or in preventing the development of guttate psoriasis following streptococcal sore throat.Although both antibiotics and tonsillectomy have frequently been advocated for patients with recurrent guttate psoriasis or chronic plaque psoriasis, there is to date no good evidence that either intervention is beneficial.

Greater improvement in quality of life outcomes in patients using fixed-combination calcipotriol plus betamethasone dipropionate aerosol foam versus gel: results from the PSO-ABLE study.

BACKGROUND: Health-related quality of life (HRQoL) measures provide patient-centred evaluations of response to treatment. In the 12-week, Phase III PSO-ABLE study, fixed-combination calcipotriol 50 µg/g as hydrate (Cal) plus betamethasone 0.5 mg/g as dipropionate (BD) aerosol foam was significantly more effective for the treatment of psoriasis than Cal/BD gel. OBJECTIVE: To compare HRQoL in mild-severe psoriasis vulgaris patients (involving 2-30% body surface area) over 12 weeks of treatment with Cal/BD foam or gel. METHODS: HRQoL was assessed using: Dermatology Life Quality Index (DLQI), EuroQoL-5D-5L-PSO (EQ-5D), and Psoriasis QoL (PQoL-12) questionnaires (baseline, Weeks 4, 8 and 12); DLQI score of 0/1 (range: 0-30) and weighted EQ-5D utility index score of 1 (range: 0-1) indicates there is no impact on a patient's QoL and perfect health, respectively. Itch, itch-related sleep loss, and work impairment were also assessed. RESULTS: In total, 463 patients were randomized to the study (Cal/BD foam, n = 185; Cal/BD gel, n = 188; foam vehicle, n = 47; gel vehicle, n = 43). Significantly more Cal/BD foam patients achieved DLQI scores of 0/1 at Weeks 4 (45.7% vs 32.4%; p = 0.013) and 12 (60.5% vs 44.1%; p = 0.003) than Cal/BD gel patients. Cal/BD foam significantly improved EQ-5D utility index (0.09 vs 0.03; p<0.001) and PQoL-12 scores (-2.23 vs -2.07; p = 0.029) from baseline to Week 4 versus Cal/BD gel. Itch, itch-related sleep loss, and work impairment improved more with Cal/BD foam than gel. CONCLUSION: Cal/BD foam demonstrated greater HRQoL improvement in patients with psoriasis than Cal/BD gel over 12 weeks of treatment.

Feeding filaggrin: effects of l-histidine supplementation in atopic dermatitis.

Atopic dermatitis (AD), also known as eczema, is one of the most common chronic skin conditions worldwide, affecting up to 16% of children and 10% of adults. It is incurable and has significant psychosocial and economic impacts on the affected individuals. AD etiology has been linked to deficiencies in the skin barrier protein, filaggrin. In mammalian skin, l-histidine is rapidly incorporated into filaggrin. Subsequent filaggrin proteolysis releases l-histidine as an important natural moisturizing factor (NMF). In vitro studies were conducted to investigate the influence of l-histidine on filaggrin processing and barrier function in human skin-equivalent models. Our further aim was to examine the effects of daily oral l-histidine supplementation on disease severity in adult AD patients. We conducted a randomized, double-blind, placebo-controlled, crossover, nutritional supplementation pilot study to explore the effects of oral l-histidine in adult AD patients (n=24). In vitro studies demonstrated that l-histidine significantly increased both filaggrin formation and skin barrier function (P<0.01, respectively). Data from the clinical study indicated that once daily oral l-histidine significantly reduced (P<0.003) AD disease severity by 34% (physician assessment using the SCORingAD tool) and 39% (patient self-assessment using the Patient Oriented Eczema Measure tool) after 4 weeks of treatment. No improvement was noted with the placebo (P>0.32). The clinical effect of oral l-histidine in AD was similar to that of mid-potency topical corticosteroids and combined with its safety profile suggests that it may be a safe, nonsteroidal approach suitable for long-term use in skin conditions that are associated with filaggrin deficits such as AD.

Inhibition of IL-17A by secukinumab shows no evidence of increased Mycobacterium tuberculosis infections.

Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-17A), has been shown to have significant efficacy in the treatment of moderate to severe psoriasis, psoriatic arthritis and ankylosing spondylitis. Blocking critical mediators of immunity may carry a risk of increased opportunistic infections. Here we present clinical and in vitro findings examining the effect of secukinumab on Mycobacterium tuberculosis infection. We re-assessed the effect of secukinumab on the incidence of acute tuberculosis (TB) and reactivation of latent TB infection (LTBI) in pooled safety data from five randomized, double-blind, placebo-controlled, phase 3 clinical trials in subjects with moderate to severe plaque psoriasis. No cases of TB were observed after 1 year. Importantly, in subjects with a history of pulmonary TB (but negative for interferon-γ release and receiving no anti-TB medication) or positive for latent TB (screened by interferon-γ release assay and receiving anti-TB medication), no cases of active TB were reported. Moreover, an in vitro study examined the effect of the anti-tumor necrosis factor-α (TNFα) antibody adalimumab and secukinumab on dormant M. tuberculosis H37Rv in a novel human three-dimensional microgranuloma model. Auramine-O, Nile red staining and rifampicin resistance of M. tuberculosis were measured. In vitro, anti-TNFα treatment showed increased staining for Auramine-O, decreased Nile red staining and decreased rifampicin resistance, indicative of mycobacterial reactivation. In contrast, secukinumab treatment was comparable to control indicating a lack of effect on M. tuberculosis dormancy. To date, clinical and preclinical investigations with secukinumab found no evidence of increased M. tuberculosis infections.

Lichen planopilaris is characterized by immune privilege collapse of the hair follicle's epithelial stem cell niche.

Lichen planopilaris (LPP) is a chronic inflammatory disease of unknown pathogenesis that leads to permanent hair loss. Whilst destruction of epithelial hair follicle stem cells (eHFSCs) that reside in an immunologically protected niche of the HF epithelium, the bulge, is a likely key event in LPP pathogenesis, this remains to be demonstrated. We have tested the hypotheses that bulge immune privilege (IP) collapse and inflammation-induced eHFSC death are key components in the pathogenesis of LPP. Biopsies of lesional and non-lesional scalp skin from adult LPP patients (n = 42) were analysed by quantitative (immuno)histomorphometry, real-time quantitative polymerase chain reaction (qRT-PCR), laser capture microdissection and microarray analysis, or skin organ culture. At both the protein and transcriptional level, lesional LPP HFs showed evidence for bulge IP collapse (ie increased expression of MHC class I and II, ß2microglobulin; reduced TGFß2 and CD200 expression). This was accompanied by a Th1-biased cytotoxic T cell response (ie increased CD8(+) GranzymeB(+) T cells and CD123(+) plasmacytoid dendritic cells, with increased CXCR3 expression) and increased expression of interferon-inducible chemokines (CXCL9/10/11). Interestingly, lesional LPP eHFSCs showed both increased proliferation and apoptosis in situ. Microarray analysis revealed a loss of eHFSC signatures and increased expression of T cell activation/binding markers in active LPP, while bulge PPARγ transcription was unaltered compared to non-lesional LPP HFs. In organ culture of non-lesional LPP skin, interferon-γ (IFNγ) induced bulge IP collapse. LPP is an excellent model disease for studying and preventing immune destruction of human epithelial stem cells in situ. These novel findings raise the possibility that LPP represents an autoimmune disease in whose pathogenesis IFNγ-induced bulge IP collapse plays an important role. Therapeutically, bulge IP protection/restoration may help to better manage this highly treatment-resistant cicatricial alopecia.

So you want to be a clinical academic.

A career as a clinical academic combines the immense rewards of being a clinician with the potential to make groundbreaking discoveries which can deepen our understanding of disease, develop new therapies and impact upon national and international health-care policy through research. As a medical academic, you will regularly engage with a wide range of colleagues at the frontiers of science and clinical practice and have an unparalleled opportunity to travel, to educate others nationally and internationally, and to become a world authority in your discipline.

Chemical consequences of cutaneous photoageing.

Human skin, in common with other organs, ages as a consequence of the passage of time, but in areas exposed to solar ultraviolet radiation, the effects of this intrinsic ageing process are exacerbated. In particular, both the severity and speed of onset of age-related changes, such as wrinkle formation and loss of elasticity, are enhanced in photoaged (also termed extrinsically aged) as compared with aged, photoprotected, skin. The anatomy of skin is characterised by two major layers: an outer, avascular, yet highly cellular and dynamic epidermis and an underlying vascularised, comparatively static and cell-poor, dermis. The structural consequences of photoageing are mainly evident in the extracellular matrix-rich but cell-poor dermis where key extracellular matrix proteins are particularly susceptible to photodamage. Most investigations to date have concentrated on the cell as both a target for and mediator of, ultraviolet radiation-induced photoageing. As the main effectors of dermal remodelling produced by cells (extracellular proteases) generally have low substrate specificity, we recently suggested that the differential susceptibility of key extracellular matrix proteins to the processes of photoageing may be due to direct, as opposed to cell-mediated, photodamage.In this review, we discuss the experimental evidence for ultraviolet radiation (and related reactive oxygen species)-mediated differential degradation of normally long lived dermal proteins including the fibrillar collagens, elastic fibre components, glycoproteins and proteoglycans. Whilst these components exhibit highly diverse primary and hence macro- and supra-molecular structures, we present evidence that amino acid composition alone may be a useful predictor of age-related protein degradation in both photoexposed and, as a consequence of differential oxidation sensitivity, photoprotected, tissues.

Genetic susceptibility to psoriasis: an emerging picture.

Psoriasis is recognized as a complex disease for which multiple genetic and non-genetic factors influence susceptibility. The major susceptibility locus resides in the MHC class I region and, until relatively recently, evidence for non-MHC loci was inconsistent. Like many common diseases, knowledge of the genetic basis of this condition has been advanced dramatically in recent times with the advent of genome-wide association studies using single nucleotide polymorphisms. Here, we give an overview of current knowledge of genetic risk factors for psoriasis and consider emerging studies that may further add to our understanding of the genetic basis of the disease.

Pathogenesis and clinical features of psoriasis.

Psoriasis, a papulosquamous skin disease, was originally thought of as a disorder primarily of epidermal keratinocytes, but is now recognised as one of the commonest immune-mediated disorders. Tumour necrosis factor alpha, dendritic cells, and T-cells all contribute substantially to its pathogenesis. In early-onset psoriasis (beginning before age 40 years), carriage of HLA-Cw6 and environmental triggers, such as beta-haemolytic streptococcal infections, are major determinants of disease expression. Moreover, at least nine chromosomal psoriasis susceptibility loci have been identified. Several clinical phenotypes of psoriasis are recognised, with chronic plaque (psoriasis vulgaris) accounting for 90% of cases. Comorbidities of psoriasis are attracting interest, and include impairment of quality of life and associated depressive illness, cardiovascular disease, and a seronegative arthritis known as psoriatic arthritis. A more complete understanding of underlying pathomechanisms is leading to new treatments, which will be discussed in the second part of this Series.

Current and future management of psoriasis.

Management of psoriasis begins with identification of the extent of cutaneous disease. However, a holistic, contractual approach to treatment is encouraged, with particular reference to psychosocial disability and quality-of-life issues. The presence of psoriasis on palms, soles, body folds, genitals, face, or nails, and concomitant joint disease, are also important when considering treatment options. An evidence-based approach is essential in delineating differences between the many available treatments. However, archaic approaches, especially combinational ones, are routinely used by some clinicians, with inadequate prospective or comparative evidence. Treatments currently available are: topical agents used predominantly for mild disease and for recalcitrant lesions in more severe disease; phototherapy for moderate disease; and systemic agents including photochemotherapy, oral agents, and newer injectable biological agents, which have revolutionised the management of severe psoriasis. Other innovative treatments are undergoing clinical studies, with the aim of maintaining safe, long-term control of the condition.