tbuckley/cabot-search huggingface dataset:
P91 Bimekizumab-induced drug reaction with eosinophilia and systemic symptoms syndrome
Journal: British Journal of Dermatology (2024)

Abstract Drug reaction with eosinophilia and systemic symptoms syndrome (DRESSs) is a potentially life-threatening drug-induced reaction which can present with cutaneous, haematological and internal organ involvement. It is a T-cell-mediated delayed-type drug hypersensitivity reaction and although the pathogenesis is not yet fully understood, it has been recognized also to have significant genetic associations. Bimekizumab is the first monoclonal antibody to selectively inhibit IL-17F and IL-17A and has been approved for the management of plaque psoriasis and psoriatic arthritis in the UK and EU. We present a case of Bimekizumab-induced DRESS syndrome which, to our knowledge, has not yet been described in the literature. The patient is a 45-year-old male with chronic plaque psoriasis who presented with fevers, tachycardia, erythroderma, generalized oedema and lymphadenopathy 10 days after his first treatment with Bimekizumab. He had previously been established on Adalimumab but was still experiencing persistent flares of psoriasis. Laboratory results revealed eosinophilia, raised inflammatory markers and deranged liver function. Histology showed patchy interface dermatitis and moderate-to-severe perivascular chronic inflammatory infiltrate in the dermis with numerous eosinophils, but no psoriasiform changes. He fulfilled the diagnostic criteria for DRESSs, prompting discontinuation of Bimekizumab, treatment with fluid resuscitation, topical steroids and emollients. This resulted in an improvement in clinical picture and laboratory results over a 4-day hospital admission. However, upon tapering down the topical steroids, there was a worsening of his cutaneous symptoms. He developed a generalized eczematous rash on the trunk and limbs with acral oedema. This was further managed with oral ciclosporin and topical steroids. However, upon tapering down the topical steroids, there was worsening of his cutaneous symptoms. He developed a generalised erythematous scaly rash on trunk and limbs with acral oedema. This was further managed with oral ciclosporin and topical steroids. He was subsequently started on Rinsakizumab for the management of his psoriasis. This is a novel case report which demonstrates DRESSs in the context of Bimekizumab treatment for chronic plaque psoriasis. Generally, symptoms develop following a latency period of 3–8 weeks although studies have described ‘rapid-onset DRESSs’ which occurs &amp;lt;15 days following initiation of the culprit drug, which have primarily included antibiotics and contrast media. In this case, the onset of symptoms was earlier than is typically seen in DRESSs and the case highlights the importance of considering this established biologic as a potential cause of DRESSs in future cases.
FC21 Sexual dimorphism in keratinocyte response to IL-36 cytokines
Journal: British Journal of Dermatology (2024)

Abstract Pustular psoriasis is a devastating subtype of psoriasis associated with significant morbidity and mortality. Pustular psoriasis is the only form of psoriasis that shows prominent sex bias, with the majority of cases found in women. Pustular psoriasis, and to a lesser extent plaque psoriasis, is characterized by the prominent involvement of the IL-36 family of cytokines, which consists of three pro-inflammatory cytokines: IL-36A, IL-36B and IL-36G, and the IL-36 receptor antagonist (IL-36RA/IL36RN). All three IL-36 members and the IL-36 receptor antagonist are increased (5- to 10-fold) in psoriatic skin. Single-cell and spatial-seq data demonstrated that IL-36 responses are primarily localized to the supraspinous compartment of the epidermis and strongly correlate with and act downstream of both IL-17A and TNF responses. CRISPR/Cas9 targeted knocking out of each IL-36 family member in keratinocytes demonstrates that both IL36G and IL36R KOs, but not IL36A KO, suppress both IL-17A and TNF responses (P &amp;lt; 0.001). Notably, the suppressive role of IL36G KO occurred in the absence of neutrophil proteases, which have been considered primary activators of the IL-36 axis in the skin. Bulk RNA-seq data from primary keratinocytes (n = 47) showed marked sex bias in IL-36G response, with female keratinocytes having a more robust pro-inflammatory response to IL-36G compared with male keratinocytes (P &amp;lt; 0.001). Furthermore, female keratinocytes showed higher expression of the type I IFN, IFNK (P &amp;lt; 0.001; FC-3.84), and IFN signature genes, such as MX1 (P &amp;lt; 0.001; FC-4.78), indicating an association between IFN-κ and the IL-36 axis in female keratinocytes. These data provide novel insights into IL-36 biology, demonstrate its role in amplifying IL-17 and TNF responses in the epidermis, and suggest that the sex bias of IL-36 response may contribute to the marked female bias of pustular forms of psoriasis.
P28 The changes in the number and subsets of regulatory T cells in the skin of psoriasis mice: implications for the progression and outcome of psoriasis
Journal: British Journal of Dermatology (2024)

Abstract Regulatory T cells (Treg) are indispensable in immune suppression due to their suppressive function, which prevents autoimmunity and tissue damage caused by excessive or unnecessary immune activation. A significant increase in the number of Treg cells can be observed in the psoriatic lesions of mice; however, the underlying mechanism remains unclear. This study, based on the changes in the number of Treg cells, explored the variations in Treg numbers and phenotypic differences at different stages. It was found that the number of Treg cells increased with the progression of the disease and decreased during the remission phase, with their suppressive function being compromised. This is attributed to the fact that the proliferating Treg cells during the disease exacerbation are primarily a subset with impaired immune suppression. Therefore, we propose that methods to restore the number of Treg cells with high suppressive function could be beneficial for the amelioration of psoriasis.
P92 Efficacy and safety of infliximab biosimilars in the treatment of patients with moderate-to-severe psoriasis
Journal: British Journal of Dermatology (2024)

Abstract Increased expression of tumour necrosis factor-a (TNF-a) is related to the pathophysiology of psoriasis. Biosimilar agents of the anti-TNFa infliximab have been approved for treating psoriasis and psoriatic arthritis. There is increasing use and preference for biosimilar agents, because of the higher price of biologic agents and their impending expiration of efficacy for the patient. We report our experience regarding the efficacy and safety of the infliximab biosimilar agents (Inflectra, Zessly, Remsima) in treating patients with moderate-to-severe psoriasis. Data was collected by analysing the medical records of 79 patients with moderate-to-severe psoriasis. All patients switched infliximab with an infliximab biosimilar. Standard doses of 5 mg/kg were given as an intravenous infusion followed by additional 5 mg/kg doses at 2 and 6 weeks after the first infusion, then every 8 weeks. Effectiveness was assessed using the psoriasis area and severity index (PASI) and Dermatology Life Quality Index (DLQI) at Weeks 12, 24, and 52. The mean age was 55 years and the female-to-male ratio was 1:2.5. At baseline the mean PASI score was 19 and DLQI was 12. Twenty patients (25%) had psoriatic arthritis. Fifteen (19%), 22 (28%), 13 (16%), and 78 (99%) patients had failed after cyclosporine, methotrexate, acitretin, and other biologic systemic therapies, respectively. No side effects were reported. Eighty-nine percentage of patients achieved PASI75 (at least 75% improvement from baseline on PASI score) by Week 12 and 65% achieved PASI90 by Week 24. By Week 52, 60% of the patients achieved PASI90 AND 90% achieved DLQI 0/1. All patients with psoriatic arthritis had a significant improvement in their symptoms. According to our study, the infliximab biosimilars demonstrated a favourable efficacy and safety profile. The data provided by our experience contribute to the evidence needed for the clinical evaluation and appropriate incorporation of infliximab biosimilars in the standard treatment of patients with moderate-to-severe psoriasis.1,2
P17 Proteomic insights into the pathogenesis of psoriasis
Journal: British Journal of Dermatology (2024)

Abstract Psoriasis is a chronic immune-mediated inflammatory disease and is associated with numerous comorbidities such as psoriatic arthritis, cardiovascular disease, metabolic syndrome, and depression. Psoriasis causes a huge burden for both individuals and society worldwide. Although significant progress has been made in psoriasis research and treatment modalities over the last decades, there is currently no cure for psoriasis. The current psoriasis treatment options are intended to control symptoms and facilitate disease going into remission. Thus, a deep understanding of the complex molecular mechanism of psoriasis is required to develop novel molecular therapies that can prevent comorbidities. In this study, we investigated the proteomic profile of high-abundance protein-depleted plasma from 30 individuals to identify molecular signatures and pathways involved in psoriasis depending on the severity of the disease. Our initial findings show that 160 proteins are significantly upregulated in active disease compared with healthy individuals. These proteins are majorly involved in platelet aggregation, platelet activation, coagulation and cell adhesion. Interestingly, proteins involved in oxidative stress, cell adhesion and metabolic processes are downregulated in inactive disease compared with healthy volunteers. Overall, this study may provide insights into systemic proteomic response to inflammation in psoriasis.
FC11 Streptococcal tonsillopharyngitis triggers psoriasis by inducing a cross-reactive autoimmune response between B cells and melanocytes
Journal: British Journal of Dermatology (2024)

Abstract Psoriaiss is an HLA-C*06:02-associated T-cell-mediated autoimmune disease of the skin. Streptococcal tonsillopharyngitis caused by β-haemolytic streptococci is a common psoriasis trigger. The exact pathomechanism underlying the triggering event is unknown. We have investigated the relationship between streptococcal tonsillopharyngitis and psoriasis using a pathogenic Vα3S1/Vβ13S1 TCR that we had isolated from a lesional psoriatic CD8+ T-cell clone and expressed in a reporter mouse T-hybridoma cell line. With this TCR, we had previously shown that the major risk allele of psoriasis, HLA-C*06:02, mediates an autoimmune response of CD8+ T cells against melanocytes by presenting a melanocytic autoantigen as the pathomechanism underlying the HLA-association.1,2 We find in coculture experiments with cell suspensions from tonsils of HLA-C*06:02+ psoriasis patients who had undergone tonsillectomy for streptococcal-induced psoriasis that tonsillar B cells, as well as B cells from peripheral blood selectively activate the melanocyte-reactive Vα3S1/Vβ13S1 TCR in an IFN-γ-enhanced manner. B cells were further autostimulatory for CD8+ T cells from psoriasis patients. By matching the peptide recognition motif of the Vα3S1/Vβ13S1 TCR with the immunopeptidomes we had isolated from HLA-C*06:02 of B-cell lines homozygous for HLA-C*06:02 we identify several self-peptides that stimulate the Vα3S1/Vβ13S1 TCR as autoantigens. From the results of this unique approach for the identification of autoantigens in the immunopeptidome of a disease-mediating HLA-class I-molecule, we conclude that under the inflammatory conditions of streptococcal tonsillopharyngitis, B cells may stimulate potentially autoreactive CD8+ T cells that recognize different self-peptides presented by HLA-C*06:02 on B cells and melanocytes due to TCR polyspecificity. Streptococcal tonsillopharyngitis thus induces a cross-reactive autoimmune response between B cells in the tonsils and melanocytes in the skin that triggers psoriasis onset and relapses. These data call for a revision of the previous concept of molecular mimicry between streptococcal antigens and keratinocyte proteins as a pathomechanism of streptococci-induced psoriasis.
FC30 Precision biologic dosing in psoriasis: development, validation and beta-testing of a therapeutic drug monitoring dashboard
Journal: British Journal of Dermatology (2024)

Abstract Following the advent of biologic therapies for chronic plaque psoriasis, achieving clear/nearly clear skin (disease control) has become a realistic goal. Patients currently continue high-cost biologic therapy indefinitely once they have achieved disease control, which leads to a long-term drug and healthcare burden. Clinical trial data indicate that some individuals can maintain disease control with less frequent doses, especially those who have higher serum drug concentrations, indicating a role for therapeutic drug monitoring (TDM) in guiding dosing decisions. To enable real-world implementation of TDM-guided precision dosing of biologics, we developed, validated, and beta-tested an online interactive TDM dashboard, powered by a pharmacokinetic (PK) model. We searched for population PK models of the exemplar psoriasis biologic risankizumab in PKPDAI and PubMed databases. We externally validated the PK model using an independent multicentre real-world UK psoriasis dataset (n = 50 patients, BSTOP study) prior to embedding it within an online R Shiny interactive dashboard. Two rounds of beta-testing of the TDM dashboard were performed with healthcare professionals to assess usability. A two-compartment PK model with first-order absorption and elimination processes was identified. The PK model was based on Phase I–III trial data and adopted a nonlinear mixed effects approach (13 123 observations from 1899 patients; 71% male; median age, 47; median weight, 97 kg; Suleiman et al., Clin Pharmacokinet 2019). We integrated the model into an online R Shiny interactive dashboard, which generates a personalized dosing interval for risankizumab. The model is used as a Bayesian prior, to predict individual patient parameters using their serum drug concentrations, dose history and other covariates (weight, serum concentrations of anti-drug antibody, albumin and creatinine). Individual predictions were externally validated (mean absolute error 0.95 mg/L; mean percentage error 17.6%; root mean square error 1.7 mg/L; R2 0.8). Beta-testing sessions with 29 clinicians (58% female; mean age 41; 33% doctor; 42% nurse) from 8 UK dermatology centres showed above-average usability of the dashboard (mean System Usability Scale score 72/100, rating ‘good’). All participants evaluated the dashboard as user-friendly and rated it acceptable or completely acceptable. Mean time to generate a dosing interval using the dashboard was 1.9 min (SD 1.2). Mean time to generate a dosing interval using the dashboard was 1.9 min (SD 1.2). Our study provides a novel pipeline for the implementation of TDM-enabled precision dosing of biologics in real-world practice. Our user-friendly online TDM dashboard has the potential to incorporate other biologic therapies and can be extended across disease contexts (including non-response and other immune-mediated inflammatory diseases) for maximal real-world health benefits and cost saving.
P81 Study on the role of SLC7A11-mediated amino acid metabolism dysregulation in the pathogenesis of psoriasis
Journal: British Journal of Dermatology (2024)

Abstract Psoriasis is an inflammatory skin disease characterized by an abnormally activated immune response and excessive keratinocyte proliferation. Although metabolic disorders have been observed in psoriasis, the role of amino acid transporters in keratinocytes remains unclear. This study aimed to investigate the role and mechanism of the cystine/glutamate antiporter (SLC7A11) in psoriasis. To achieve this, we generated Cre and CreERT mice to specifically knock out the SLC7A11 gene in K14-expressing cells. We used the imiquimod (IMQ) model to induce skin inflammation and tested the effect of the SLC7A11 inhibitor, imidazole ketone erastin. Additionally, we analysed the resulting proteomic and metabolomic changes in SLC7A11 knockdown keratinocytes. Our findings revealed that SLC7A11 expression was increased in the keratinocytes of psoriatic lesions in both humans and mice. Deletion of SLC7A11 in keratinocytes reduced their proliferation and the inflammatory response induced by IMQ. SLC7A11 deletion or inhibition blocked the expansion of neutrophils and macrophages and reduced the release of CXCL2, CXCL5 and CCL20 in the IMQ-induced model. Furthermore, knocking down SLC7A11 expression blocked DNA synthesis, disrupted the cell cycle, and impaired intracellular signalling. Concurrently, intracellular amino acid metabolism, particularly cysteine metabolism, underwent dramatic changes, leading to a reduced inflammatory response. SLC7A11-mediated amino acid uptake plays a crucial role in the pathogenesis of psoriasis by regulating keratinocyte proliferation and inflammatory responses. Targeting SLC7A11 could be a promising immunosuppressive strategy for controlling psoriatic inflammation. This study provides new insights into the metabolic aspects of psoriasis and highlights the potential of SLC7A11 as a therapeutic target.
P128 Florid psoriasis in a patient with psoriatic arthritis and hidradenitis suppurativa: therapeutic challenges
Journal: British Journal of Dermatology (2024)

Abstract Hidradenitis suppurativa is a chronic inflammatory disorder that affects the skin. It causes recurring inflammatory lesions which may leave permanent scarring. The disease may be autoinflammatory. Hidradenitis suppurativa has been reported to emerge in patients with spondylarthritis, such as ankylosing spondylitis or psoriatic arthritis. The aim was to describe the case of a male patient who had psoriatic arthritis and developed hidradenitis suppurativa. A patient, male, aged 47 presented with psoriatic arthritis. He was on treatment with a TNFa inhibitor with good response as far as the arthritis was concerned. At the age of 51 he developed hidradenitis suppurativa with lesions in the axillary region bilaterally and under the lower ­mandible. Adalimumab was administered with partial remission of both psoriatic arthritis and hidradenitis suppurativa. However, as psoriatic arthritis was active in the axial skeleton with florid psoriasis and sacroiliitis was present bilaterally secukinumab 150 mg/month was initiated. Thereafter the dose of secukinumab was increased to 300 mg/month. Hidradenitis suppurativa lesions improved significantly. However, the pain in the axial skeleton remained intense. Hidradenitis suppurativa is a chronic inflammatory condition, which may be autoinflammatory in its pathogenesis. Hidradenitis suppurativa may appear in patients with spondylarthritis or psoriatic arthritis. Biologic agents are now applied in the management of hidradenitis suppurativa and appear to be effective. We describe the case of a patient with psoriatic arthritis and hidradenitis suppurativa who was treated effectively with biologic agents. The application of biologic agents in the treatment of hidradenitis suppurativa may shed light on the pathogenesis of the disease.
P82 Are nail, scalp and intergluteal cleft psoriasis really risk factors for psoriatic arthritis or are we just repeating previous studies?
Journal: British Journal of Dermatology (2024)

Abstract Psoriasis is a chronic, inflammatory, immune-mediated, systemic disease that primarily affects the skin and joints. In ∼70% of cases, the skin comes before the joints, and it is believed that ∼30% of patients with psoriasis will develop psoriatic arthritis (PsA). There is an ongoing effort to identify screening tools and biomarkers that detect joint disease early. Known risk factors include early onset and severity of disease, nail, scalp and intergluteal cleft involvement, family history of PsA, HLA-B27 positive, obesity, uveitis, biomechanical stress, and trauma. Observational, cross-sectional study with severe plaque psoriasis patients, aged between 18 and 70 years, of both genders. Non-probabilistic convenience sample: All patients were evaluated by the same board-certified dermatologist. Over 3 months, during the weekly shift of the severe psoriasis clinic, PEST was applied. Clinical and epidemiological variables were collected on medical records. PsA was defined by CASPAR criteria. It underwent an ethical assessment and was approved. Hundred and fifty-eight patients were studied: average age of 50.84 years, with a predominance of females (53.2%). The average duration of the disease was 15.89 years. Mean psoriasis area and severity index and body surface area were, respectively, 16.65 and 20.88%. Fifty patients (31.6%) with PsA were identified. Regarding PEST, a sensitivity of 84.61%, a specificity of 75.47%, with a negative predictive value of 90.90% were identified. Having a positive PEST made the presence of PsA almost seven times more frequent [PR: 6.914, P &amp;lt; 0.0001, 95% confidence interval (CI) = 3.486–13.714]. Scalp (80.9%) and intertriginous/intergluteal cleft psoriasis (55.1%) was frequent in the sample, but did not correlate with the presence of PsA (PR: 1.113, P = 0.794, 95% CI = 0.523–2.454; and PR: 0.881, P = 0.612, 95% CI = 0.565–1.375, respectively). However, nail involvement was significantly related to PsA (PR: 1.669, P = 0.026, 95% CI = 1.071–2.601). PEST performance was consistent with the literature and was especially valuable in ruling out PsA due to its high negative predictive value. A classic study that correlates the involvement of specific sites with joint disease may present a selection bias, since it was conducted within the scope of rheumatology, focusing on patients with seronegative chronic inflammatory arthritis, where the diagnosis of psoriasis was not obvious, being sought in ‘hidden’ areas. After all, apart from the involvement of the nail matrix as an extension of distal interphalangeal enthesitis, what would be the biological relationship between the involvement of the scalp or even the intergluteal cleft and the presence of arthritis? Small sample, cross-sectional design and the fact that only 66% of patients with PsA had the opportunity to confirm their diagnosis with a rheumatologist are recognized limitations.