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BackgroundThe diagnosis of psoriasis may be missed or delayed in primary care settings.AimTo examine trends in healthcare events before a diagnosis of psoriasis.Design and settingTwo matched case–control studies using electronic healthcare records delineated from the Clinical Practice Research Datalink (CPRD GOLD and Aurum) in the UK.MethodIndividuals 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.ResultsThere 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.ConclusionFindings 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 skin immune system is tightly regulated to prevent inappropriate inflammation in response to harmless environmental substances. This regulation is actively maintained by mechanisms including cytokines and cell surface receptors and its loss results in inflammatory disease. In the case of psoriasis, inappropriate immune activation leads to IL-17-driven chronic inflammation, but molecular mechanisms underlying this loss of regulation are not well understood.We reveal that immunoglobulin superfamily member CD200, and signalling via its receptor, CD200R1 are reduced in non-lesional psoriasis skin. To examine the consequences of this, CD200R1 was blocked in a mouse model of psoriasis demonstrating that the receptor limits psoriasis-like inflammation. Specifically, CD200R1 blockade enhances acanthosis, CCL20 production and neutrophil recruitment but surprisingly, macrophage function and IL-17 production were not affected, and neutrophil reactive oxygen species production was reduced.Collectively, our data show that CD200R1 affects neutrophil function and limits inflammatory responses in healthy skin by restricting neutrophil recruitment. However, the CD200 pathway is reduced in psoriasis, resulting in a loss of immune control, and increased neutrophil recruitment in mouse models. In conclusion, we highlight a pathway that might be targeted to dampen inflammation in patients with psoriasis.

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved by the US FDA for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Deucravacitinib was significantly more efficacious than placebo or apremilast and was well tolerated in previous reports from the phase 3 POETYK PSO-1 trial. Here, we examined response rates through Week 52 from this trial in subgroups defined by previous biologic, systemic (biologic/nonbiologic), and/or oral systemic treatment. Methods: PSO-1, a multicenter, double-blind trial, enrolled adults with moderate to severe plaque psoriasis. Patients with previous phototherapy, systemic treatment, and/or biologic treatment completed washout periods (4 weeks–6 months) before study entry, depending on treatment. Patients were randomized 2:1:1 to deucravacitinib 6 mg QD, placebo, or apremilast 30 mg BID; this analysis focused on deucravacitinib and placebo patients. Placebo patients switched to deucravacitinib at Week 16. PASI 75 and sPGA 0/1 were evaluated through Week 52 by prior treatment (biologic, systemic [biologic/nonbiologic], oral systemic) and by biologic- and systemic-naive patients. Nonresponder imputation was used for all reported endpoints. Results: 332 patients were randomized to deucravacitinib and 166 to placebo. At baseline, 34.3% of deucravacitinib patients and 44.0% of placebo patients received prior oral systemic treatment, 60.2% and 65.7% received prior systemic (biologic/nonbiologic) treatment, and 39.2% and 38.0% received prior biologic treatment, respectively. Week 52 PASI 75 response rates were similar in patients receiving deucravacitinib from baseline (65.1%) and placebo patients switching to deucravacitinib at Week 16 (68.3%). Findings with deucravacitinib were similar to those in placebo patients switching to deucravacitinib regardless of prior systemic (65.5%/68.1%), oral (70.2%/69.2%), or biologic (61.5%/61.8%) treatment, and in patients with no prior systemic (64.4%/68.6%) or biologic (67.3%/72.2%) treatment. Similarly, sPGA 0/1 response rates were comparable in deucravacitinib versus placebo patients in the overall population (52.7%/53.8%) and in the prior systemic (53.0%/55.3%), prior oral systemic (57.0%/53.8%), prior biologic (47.7%/45.5%), systemic-naive (52.3%/51.0%), and biologic-naive (55.9%/58.9%) cohorts. Conclusion: Deucravacitinib was effective through 52 weeks for moderate to severe plaque psoriasis regardless of previous systemic treatment. Placebo patients switching to deucravacitinib at Week 16 achieved PASI 75 and sPGA 0/1 similar to patients continuously treated with deucravacitinib.

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.To assess the evidence for effectiveness of antistreptococcal interventions including antibiotics and tonsillectomy in the management of acute guttate and chronic plaque psoriasis.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.Randomised trials of one or more antistreptococcal interventions in patients with guttate or chronic plaque psoriasis.Two reviewers independently examined each retrieved trial for eligibility and quality.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.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.

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.To assess the effectiveness of treatments for guttate psoriasis.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.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.Two reviewers independently assessed trial eligibility and quality.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.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.

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.

Christopher EM Griffiths speaks to Alisa Crisp, Commissioning Editor: Christopher EM Griffiths gained a first class BSc degree in Anatomy and qualified in Medicine from St Thomas‘ Hospital Medical School, London University (London, UK). He trained in Dermatology at St Mary‘s Hospital (London, UK), and at the University of Michigan (USA), where he was also on the Faculty for 4 years. He was appointed as the Foundation Chair in Dermatology at the University of Manchester (UK) in 1994 and is an honorary consultant dermatologist at Salford Royal NHS Foundation Trust (Salford, UK). Professor Griffiths developed the ‘hub-and-spoke‘ model of dermatology services for Greater Manchester and introduced a multidisciplinary clinic for severe psoriasis – the Manchester Psoriasis Service – awarded Hospital Doctor Dermatology Team of the Year in 2002. At the University of Manchester he has served in various roles as: Head of Medicine and Neuroscience, Head of the School of Translational Medicine, Research Dean and Direc...

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, β2microglobulin; reduced TGFβ2 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.

This international, double-blind study examined the effects of alefacept on circulating lymphocytes in 507 patients with chronic plaque psoriasis, and determined whether these effects were related to clinical improvement. Patients were randomized to intramuscular placebo, alefacept 10 mg, or alefacept 15 mg once weekly for 12 weeks followed by 12 weeks of observation. Alefacept dose-dependently reduced CD4+ and CD8+ memory T cells, while sparing the na ve population. The greatest reductions in disease activity occurred in patients with the largest decreases in memory T cells. For example, a 50 % reduction from baseline Psoriasis Area Severity Index at any time during treatment or follow-up was observed in 66 % of patients who had the greatest reductions in CD4+ memory T cells versus in 40 % of patients who had the smallest reductions in this T-cell subset. These results provide further support for the deleterious roles of CD4+ and CD8+ memory T-cell subpopulations in psoriasis pathogenesis.

Prolonged topical exposure of BALB/c strain mice to the contact allergen DNCB, or to the respiratory sensitiser trimellitic anhydride, results in T helper (h) 1 and Th2 cell polarisation, respectively. In addition, a single application of allergen results in discrete cutaneous cytokine profiles and the migration of Langerhans' cells (LC) with different tempos. Of note, DNCB only induced a rapid and transient increase in cutaneous IL-2. We have now explored the role of IL-2 in DNCB-induced LC migration. BALB/c mice received an intradermal injection of recombinant IL-2 or IL-1β (50ng/ear); the latter is known to provoke LC migration. LC densities were determined in epidermal sheets by immunofluorescence staining. Cytokine production by skin explants was measured by protein array. Intradermal injection of IL-1β decreased epidermal LC numbers significantly after 4 and 16h whereas IL-2 was without effect. Prior systemic administration of neutralising anti-IL-2 antibody failed to influence LC migration monitored 6h after DNCB treatment. Migration was blocked by treatment with an anti-tumor necrosis factor-α antibody, a cytokine regulator of LC migration. Administration of IL-2 did result in increased expression of cutaneous IL-17. These data show that IL-2 is not involved in LC migration, however, the selective up-regulation of IL-2 by DNCB may play a role in the subsequent polarisation of the immune response.