tbuckley/cabot-search huggingface dataset:
P12 Paradoxal adalimumab induced palmoplantar pustulosis in a patient with Crohn’s disease
Journal: British Journal of Dermatology (2024)

Abstract In November 2023, a 25-year-old man presented with pustular lesions on his palms and soles bilaterally. The pustules were sterile and the biopsy was compatible with psoriasiform dermatitis. In the following days, the patient developed erythematous, scaly, indurated, plaques on his trunk. From the clinicopathological correlation, the diagnosis was palmoplantar pustular psoriasis. The patient was under the treatment of adalimumab from the summer of 2021 for Crohn’s disease (40 mg/2 weeks, subcutaneously), until he proceeded to our clinic with palmoplantar pustulosis. Adalimumab was discontinued. The patient was treated with topical cortisone and keratolytics, in combination with ustekinumab for Crohn’s disease, with a gradual improvement of his symptoms. Tumour necrosis factor (TNF) is a pro-inflammatory cytokine. Adalimumab is a fully human immunoglobulin G1 antibody, blocking TNF activity. In our case, we have another paradoxical adverse reaction of adalimumab. Despite the effectiveness of adalimumab in the treatment of psoriasis and Crohn’s d, our patient developed palmoplantar pustular psoriasis, though he was under adalimumab for his Crohn’s d. Ustekinumab is a biological agent targeting interleukine-12 and 23 and is widely used in the management of both psoriasis and Crohn’s d. Our patient switched from adalimumab to ustekinumab, which kept his Crohn’s d stable and improved his palmoplantar pustular psoriasis, after 1 month
P71 Bcl11b forms mutual connections with NF-κB1 and NF-κB2 in keratinocytes
Journal: British Journal of Dermatology (2024)

Abstract Psoriasis is a chronic inflammatory skin condition characterized by complex molecular interactions. Our earlier data showed that Bcl11b expression is downregulated in psoriasis, and that proinflammatory cytokines act differently on Bcl11b associated activity of the NF-κB pathways. Given the critical role of NF-κB1 in the canonical pathway and NF-κB2 in the non-canonical pathway, it prompted us to elucidate the mutual regulatory connections between Bcl11b, NF-κB1, and NF-κB2, which are critical in the inflammatory response in psoriasis. To investigate the regulatory interplay between Bcl11b, NF-κB1, NF-κB2 and other key genes in the NF-κB pathways. We employed a series of knockout (KO) experiments using CRISPR–Cas9 technology to target Bcl11b, NF-κB1 and NF-κB2 in HaCaT keratinocytes. Gene and protein expression levels were assessed using qPCR and western blot, respectively. Specifically, we examined the impact of Bcl11b KO on NF-κB1 and NF-κB2 expression, followed by evaluating the reciprocal effects of NF-κB1 KO on NF-κB2 and BCL11B and the effect of NF-κB2 KO on NF-κB1 and Bcl11b. Additionally, we investigated the expression of related genes, including RelA, TNF-α, TAK1 RelB, NIK, TRAF2, TRAF3 and TRAF6. Bcl11b KO leads to a downregulation of both NF-κB1 and NF-κB2 at the RNA and protein levels, along with a downregulation of related pathway genes such as, RelA, TNF-α, RelB, and NIK. Conversely, both NF-kB1 KO and NF-kB2 KO conditions also demonstrated a mutual connection among Bcl11b and these two transcription factors. To gain a deeper understanding of the role of Bcl11b in the regulation of the NF-κB pathways, we evaluated the expression levels of several upstream regulators. Our study indicates an upregulation of TRAF2 and TRAF3 in Bcl11b KO conditions, corroborating the downregulation of the non-canonical pathway via NIK. Additionally, we observed a downregulation of TRAF6 under Bcl11b KO conditions, explaining the inactivation of the canonical NF-κB pathway. Interestingly, TAK1 has upregulated in Bcl11b KO cells, indicating a complex regulatory role of Bcl11b within the NF-κB signalling pathway. These data suggest a regulatory network where Bcl11b plays a crucial role in modulating both the canonical and non-canonical NF-κB pathways via TRAF2, TRAF3, and TRAF6. The mutual regulation between Bcl11b, NF-κB1 and NF-κB2 highlights potential therapeutic targets for modulating inflammatory responses in psoriasis.
P15 Evaluating risankizumab for moderate-to-severe plaque psoriasis: real-world outcomes from an international study
Journal: British Journal of Dermatology (2024)

Abstract Risankizumab has shown high efficacy in Phase III randomized controlled trials (RCTs) for treating moderate-to-severe plaque psoriasis, outperforming ustekinumab and adalimumab in terms of skin clearance. However, there is limited data on its long-term effectiveness and safety in real-world settings. This study aims to bridge this gap by evaluating the 1-year real-world outcomes of risankizumab in adult patients with moderate-to-severe plaque psoriasis, focusing on both its efficacy and safety. We conducted an international, multicentre retrospective study involving five tertiary academic dermatology clinics in Canada and Portugal. The study included adult patients aged 18 years or older diagnosed with moderate-to-severe plaque psoriasis, characterized by a Physician’s Global Assessment (PGA) score of 3 or 4. One year after initiating risankizumab treatment, we assessed efficacy based on achieving a psoriasis area and severity index (PASI90) or PGA score of 0 (clear) or 1 (almost clear). Safety evaluations were based on the frequency and nature of adverse events reported by the patients. The study included 291 participants, with a mean age of 50.7 ± 15.0 years, of whom 62.5% were male. Of these, 56.4% (164/291) had not previously been treated with systemic biologic therapy, and the group had previously failed an average of 0.79 systemic biologics. After 1 year of treatment, 264 patients (90.7%) achieved PASI90 or a PGA score of 0/1. Furthermore, 90.7% attained a PASI ≤2, 56.4% achieved a PASI &amp;lt;1, and 72% reported a body surface area &amp;lt;1%. Adverse events were noted in 4.5% of the cohort (13/291), with fatigue being the most frequently reported, affecting 23% (3/13) of those with adverse events. None of the adverse events were considered severe, and all patients experiencing adverse events continued with the treatment. Treatment discontinuation occurred in 7.9% (23/291) of the patients, primarily due to insufficient efficacy (15/23, 65.2%). The findings from this study indicate that risankizumab provides substantial real-world efficacy and maintains a strong safety profile for treating moderate-to-severe plaque psoriasis, supporting the results seen in Phase III clinical trials. The treatment resulted in high levels of skin clearance over 1 year. However, further validation through larger real-world cohort studies with control groups is essential to confirm these results.
FC19 A global investigation of the aryl hydrocarbon receptor pathway reveals multiple levels of dysregulation amenable for therapeutic targeting in psoriasis
Journal: British Journal of Dermatology (2024)

Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and environmental sensor with homeostatic roles in the skin. We and others have shown that physiological AHR activation ameliorates inflammation in psoriasis models, leading to the development of the first-in-class AHR-modulating drug, Tapinarof, for mild-to-moderate psoriasis. The AHR pathway is regulated at multiple levels, including through the cytochrome P450 1 (CYP1) enzymes, which degrade AHR ligands providing critical negative feedback. Here we aim to deeply investigate the AHR pathway to identify dysfunctional checkpoints for therapeutic intervention in psoriasis. We performed a multi-model investigation in the blood and skin of White moderate-to-severe psoriasis patients (n = 51), not receiving systemic therapy, and age/sex/ethnicity-matched healthy volunteers (n = 28), assessing AHR ligand and precursor availability in serum, AHR and CYP1A1 bulk and spatial mRNA and protein in blood and skin, in vitro modulation of AHR expression in normal human epidermal keratinocytes (NHEK) by psoriasis-relevant cytokines, and CYP1 enzymatic activity. Serum levels of the ligand precursor tryptophan were significantly decreased in psoriasis patients (P &amp;lt; 0.001; n = 19) vs. healthy (n = 19). AHR mRNA expression was significantly decreased in psoriasis blood (P &amp;lt; 0.01; n = 30) and psoriasis lesional (PsL; P &amp;lt; 0.01; n = 17) skin vs. healthy, while CYP1A1 mRNA expression did not differ in blood but showed a downward trend in PsL (P = 0.0546; n = 16). While AHR and CYP1A1 protein were mostly co-expressed in the suprabasal skin layers, AHR mRNA predominantly localized in the basal layer in PsL (n = 5) compared with a more widespread expression in healthy skin (n = 7), with a reduction in AHR positive cells in the PsL dermis (P &amp;lt; 0.05). TNF (P &amp;lt; 0.001) and IFN-γ (P &amp;lt; 0.0001) significantly upregulated AHR mRNA in NHEK (n = 4). In vitro culture of skin epidermal sheets with the AHR agonist FICZ significantly upregulated CYP1A1 mRNA expression in healthy (q &amp;lt; 0.05; n = 8) and psoriasis epidermis (q &amp;lt; 0.05; n = 7); however, CYP1 enzymatic activity was not increased by AHR ligation in PsL. In contrast, FICZ-induced CYP1 enzymatic activity was enhanced in Th17 cells from the same patients (P = 0.0535; n = 8). Finally, exposure of NHEK to a psoriasis inflammatory cocktail containing TNF, IL-23 and IL-17A resulted in a significant reduction in induced CYP1 enzymatic activity (n = 3, P &amp;lt; 0.05), suggesting a potential mechanism for the lack of ligand-induced activity in PsL. Taken together, our data show that there is a multi-level dysregulation of the AHR pathway in psoriasis and suggests a failure of multiple pathway checkpoints that could be further targeted to restore AHR’s beneficial effects on skin.
P39 Outcomes after switching back to the originator adalimumab in psoriasis patients who previously switched to biosimilars
Journal: British Journal of Dermatology (2024)

Abstract Adalimumab is widely used for moderate-to-severe psoriasis, with many patients transitioning from the originator—Humira® to biosimilars. Limited evidence exists on outcomes for those switching back to Humira or other biologics after discontinuing biosimilars. This study aims to compare the risk of discontinuation, treatment effectiveness, and safety between patients switching back to Humira and those switching to other biologics after discontinuing biosimilars. Using data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), we conducted a cohort study including psoriasis patients who switched from Humira to biosimilars and then either back to Humira or to other biologics. Outcomes included the risk of discontinuation, psoriasis area and severity index (PASI) at 1 year, and the risk of serious adverse events (SAEs). We used fine stratification weights based on propensity score to balance patient characteristics. Patients were stratified as having less or more than 2 years of Humira® treatment before switching to biosimilars. In the result, the study included 187 patients who switched back to Humira and 177 patients who switched to other biologics. For patients who had &amp;lt;2 years of Humira treatment before transitioning to biosimilars, switching back to Humira resulted in a similar discontinuation rate [hazard ratio (HR): 1.21, 95% confidence interval (CI): 0.55–2.68] and comparable PASI at 1 year [3.0 (standard deviation, SD 5.8) vs. 3.3 (SD 4.6)] compared with switching to other biologics. Patients who had over 2 years of Humira® treatment before switching to biosimilars were less likely to discontinue treatment (HR: 0.52, 95% CI: 0.31–0.89), and had lower PASI at 1 year [2.4 (SD 4.7) vs. 3.6 (SD 6.3)] if they switched back to Humira® compared with those who switched to other biologics. SAEs were recorded in 12 out of 187 patients who switched back to Humira and in 12 out of 177 patients who switched to other biologics. In conclusion, among patients who switched back to Humira, those with &amp;lt;2 years of prior Humira treatment had similar outcomes compared with those who switched to other biologics. However, patients with over 2 years of prior Humira® treatment experienced better outcomes when switching back to Humira compared with switching to other biologics. Due to the limited data available in this study, further research with larger sample sizes is required to confirm these results.
Application and Expectations for Immune Checkpoint Blockade of LAG3 and TIGIT
Authors: Ecaterina Elena Dumbrava, Khaoula Ben Haj Frej, Elad Sharon, Hussein Tawbi
Journal: Annual Review of Medicine (2024)

Immune checkpoint blockade targeting the novel targets of the lymphocyte activation gene 3 (LAG3) and the T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) has marked a significant advancement in oncology, offering new therapeutic opportunities to fight diverse malignancies. This review covers the biological basis and clinical application of LAG3 and TIGIT inhibitors, highlighting pivotal trials and therapeutic outcomes. We underscore the use of dual therapy immune checkpoint blockade in enhancing antitumor immunity, particularly in settings where monotherapy has shown limited efficacy. Additionally, we address the emerging challenges such as treatment resistance and adverse effects. We explore the strategic integration of LAG3 and TIGIT blockade within the broader immunotherapy landscape, emphasizing innovative combinations and the quest for predictive biomarkers to optimize patient selection and treatment efficacy.
P64 Real-world durability of effectiveness through 24 months of anti-interleukin-17A biologics and other approved biologics in treating patients with moderate-to-severe psoriasis in the Psoriasis Study of Health Outcomes
Journal: British Journal of Dermatology (2024)

Abstract Introduction Patients with psoriasis (PsO) report that a quick and enduring response are key treatment goals. As such, more studies are needed to evaluate the treatment response of different biologics over long observation periods. To address this research gap, this analysis uses three different outcomes to evaluate the durability of treatment effectiveness of different biologics for patients with moderate-to-severe PsO from Week 12 through 2 years in a real-world setting. Methods The Psoriasis Study of Health Outcomes (PSoHO) is an ongoing, 3-year, international, prospective, non-interventional cohort study comparing the effectiveness of the anti-interleukin (IL)-17A cohort of ixekizumab (IXE) and secukinumab (SEC) to other approved biologics in patients with moderate-to-severe PsO initiating or switching to a newly approved biologic. The other biologics cohort includes adalimumab (ADA), brodalumab (BROD), certolizumab, etanercept, guselkumab (GUS), infliximab, risankizumab (RIS), tildrakizumab (TILD) and ustekinumab (UST). The first durability of effectiveness outcome was defined as the proportion of patients who achieved the primary endpoint of PASI90 and/or an sPGA score of 0 or 1 at Week 12, and who maintained a PASI75 score and/or an improvement of two points or more in sPGA from baseline at Months (M)6, M12 and M24. Two further analyses evaluated the proportion of patients who achieved PASI100 or PASI90 at Week 12 and maintained this result at M6, M12 and M24. Results Of the 1981 patients, 39.0% of patients were in the anti-IL-17A cohort and 61.0% received other biologics at baseline. A significantly higher proportion of patients in the anti-IL-17A cohort achieved each of the three outcomes measuring durability of effectiveness (P ≤ 0.001). For the individual treatments, 47.9% of IXE-treated patients, 46.3% of RIS-treated patients and 41.9% of SEC-treated patients achieved the first durability of effectiveness outcome. Over 14% of patients treated with BROD, RIS or IXE achieved a PASI100 response at Week 12 and maintained complete skin clearance through Month 24. Similarly, over 30% of patients treated with these biologics achieved the PASI90 durability response. As a non-interventional study, the number of patients varied across treatment groups and the small sample size of some biologics led to broader confidence intervals. Conclusion Evaluating PSoHO data at Week 12 and Months 6, 12, and 24, this analysis showed that the durability of treatment effectiveness in patients with moderate-to-severe PsO was significantly higher with anti-IL-17A biologics than other biologics in a real-world setting. Overall, this study highlights the importance of considering the durability of responses to treatments for patients with moderate-to-severe PsO.
P94 REX-7117 is a highly potent and selective oral STAT3 inhibitor that has demonstrated potential efficacy and safety differentiation versus JAK/TYK2 targeting in preclinical models of psoriasis
Journal: British Journal of Dermatology (2024)

Abstract Inhibition of key cytokine pathways, including IL-23 and IL-17, has translated into transformative efficacy in plaque psoriasis, psoriatic arthritis and other inflammatory diseases. There is a strong unmet need to develop oral medicines which match the efficacy of biologics. Additionally, current small molecule JAK/TYK2 inhibitors are associated with on-target safety signals, including opportunistic infections and dysregulated haematologic homeostasis (anaemia, thrombocytopenia). Oral selective STAT3 inhibitors represent an opportunity to target psoriatic pathogenesis by inhibiting clinically validated inflammatory mediators, such as IL-23 and IL-6 cytokines. The STAT3 SH2 domain mediates both binding to the cytokine receptor and transcriptional activity, and therefore is an attractive therapeutic target. Recludix has developed an innovative and proprietary SH2 domain platform that has enabled the discovery of a new class of small molecule inhibitors of these previously undruggable protein domains. REX-7117 is the first orally available, reversible, SH2 domain-targeting STAT3 inhibitor. REX-7117 demonstrates low nanomolar potency in biochemical and primary human cellular assays, is highly selective across the SH2 family, including other STAT proteins, and inhibits IL-6 and IL-23 driven Th17 cell function. Unlike JAK1/2 and TYK2 inhibitors, REX-7117 does not impair broader immune responses, such as Th1 cell activity, innate interferon-dependent anti-viral immunity, or growth factor signalling critical for haematologic homeostasis. In dogs and mice, REX-7117 achieves deep, durable, and selective STAT3 inhibition at clinically relevant oral doses and exhibits comparable efficacy to an IL-17 antibody in rodent models of plaque psoriasis. Selective STAT3 inhibition has the potential to combine the efficacy of clinically validated biologics with the convenience of oral administration, while avoiding known safety concerns observed with the broader activity of JAK and TYK2 inhibitors.
P109 Psoriasis care in a specialized academic psoriasis centre
Journal: British Journal of Dermatology (2024)

Abstract Psoriasis, currently referred to as psoriasis disease, is among the most frequent human chronic inflammatory skin diseases. Both pathogenic knowledge and clinical management are very much advanced over the last two decades and are superior compared with most other dermatological diseases. This is mirrored by several national and international clinical guidelines. Yet, patient care is still grossly varying among countries and regions within individual countries. Here data from a single psoriasis centre are presented including 869 inpatients and outpatients. Thirty percentage of the patients got their first diagnosis between the age of 18 and 40 years with plaque psoriasis at 79.3%, scalp psoriasis at 25%, inverse psoriasis 16.2% and pustular psoriasis 9%. The most affected area was the trunk (69.3%), followed by the extremities 58.1%; 21.3% of patients had confirmed Psoriasis-arthritis. Almost 50% had at least one comorbidity, arterial hypertension being most frequent with 30.7%, adiposities (17.3%), hyperlipidaemia (14.5%), hypothyroid disease (8.9%) and depression (6.7%). With regard to therapy, 38% of patients had topical treatment and 45.2% any ultraviolet therapy (narrowband UVB 23.8%, bath PUVA 14.8%). However, 45% used systemic biologic treatment, 12% were on conventional systemic agents and 5% were on small molecular antagonists. Among current systemic agents, ustekinumab was the most frequently used (11.9%), followed by secukinumab (10.6%), adalimumab 7.1% and methotrexate (5.5%). The most frequently used systemic drugs during the drug history were methotrexate (26.2%), fumarates (24.5%) and ustekinumab (20.4%). Compared with earlier data from this centre, there is a distinct increase in systemically treated patients and those on biologics over time. These data compare well with other published studies and reflect the patient composition and high portion of systemically treated patients of an academic medical centre.
P95 A systematic review of dual biologic or small molecule therapy in patients with psoriasis
Journal: British Journal of Dermatology (2024)

Abstract While many treatments exist for psoriasis, there remains a subset of patients who are refractory to conventional treatments, including biologic monotherapy. This patient population has necessitated alternate treatment regimes, including dual biologic and/or small molecule therapy. This systematic review aims to evaluate the efficacy and safety of dual biologic or small molecule therapy in patients with psoriasis and other comorbid inflammatory diseases, necessitating biologics and/or small molecules. Following PRISMA guidelines, Ovid’s Medline and Embase databases were searched, and a protocol was registered in PROSPERO. A total of 21 articles were ultimately included in the review, including 17 case reports, and 4 case series. The risk of bias was assessed using the Joanna Briggs Institute critical appraisal tool. This systematic review examined 38 patients with a mean age of 50.5 years (range: 27–78) who were predominantly female (56.7%). All cases with reported psoriasis duration had long-standing psoriasis with an average duration of 15.3 years. Prior to dual therapy, the most common treatments were biologic monotherapy (67.6%), topical corticosteroids (58.8%), and systemic immunosuppressors and/or immunomodulators (50.0%). The most commonly reported biologic combination was dupilumab and guselkumab (n = 13/38, 34.2%). There were two combinations of a biologic and a JAKi, baricitinib combined with infliximab and ixekizumab, respectively. Secondary indication for dual therapy was most commonly atopic dermatitis (AD) (50.0%) or psoriatic arthritis (26.3%). Dual biologic therapy was efficacious in 85.7% (n = 36/38) of patients, with a mean change in psoriasis area and severity index of 20.0 (P &amp;lt; 0.01). Adverse reactions to dual therapy were infrequent, with only four patients (9.52%) reporting non-dermatological events, three patients (7.14%) reporting dermatological events, and one patient reporting a loss of response to their psoriasis treatment (2.38%). Our findings highlight a cohort of patients with long-standing psoriasis, and other comorbid inflammatory diseases. The majority of patients had attempted conventional therapeutic options without adequate response. The efficacy of dual biologic and/or small molecule therapy offers a promising outlook for this patient population with comorbid inflammatory diseases with 95.2% of patients experiencing therapeutic benefit and a significant mean change in PASI reported. The various combinations of biologics utilized amongst the patients in this cohort highlight a need for individualized treatment approaches tailored to the specific clinical characteristics and comorbidities of each patient. It is important to acknowledge the limitations of the included studies, such as the small sample size and thus future studies with larger sample sizes are needed to examine the effectiveness and safety of combined biologic or small molecule therapy for this patient population.