Research trends and hotspots in biologics for plaque psoriasis: A bibliometric study from 2004 to 2023.

Background and objective: Biologics have revolutionized the management of plaque psoriasis and are flourishing. We aimed to construct a knowledge structure in this field through bibliometrics, analyze research trends and cutting-edge hotspots to inspire future research directions, and provide valuable references for clinical decisions. Methods: Publications on biologics for plaque psoriasis in the Web of Science database core collection from 2004 to 2023 were searched. Bibliometric analysis and scientific knowledge mapping were performed with R, CiteSpace, and VOSviewer software. Results: 2,672 articles written by 9,474 authors from 67 countries were included in the study. The number of annual publications has steadily increased over the last 20 years. The most prolific countries, institutions, and authors were the United States, Novartis, and Prof. Reick K., respectively. Reference analysis categorized the research base of the field into 10 main clusters. "Efficacy" and "safety" were the most frequent keywords, and cluster analysis categorized the research in this area into four groups. Burst detection captured current hot keywords including interleukin (IL)-17 inhibitors, IL-23 inhibitors, "drug survival," "discontinuation," "Covid-19," "real-world," and "clinical features." Conclusion: Global publications on biologics research in plaque psoriasis have grown steadily and rapidly over the past two decades. Efficacy and safety are the highest topics of concern for researchers, and IL-17 inhibitors, IL-23 inhibitors, real-world studies, efficacy prediction, and retreatment after biologics failure or discontinuation are current research hotspots.

A Case of Cochlear Implantation in a Deaf Patient With Eosinophilic Otitis Media in Whom Post-implantation Hearing Threshold Improved After Introduction of Dupilumab.

Eosinophilic otitis media (EOM) is a rare, intractable, and chronic form of otitis media. The associated hearing loss often progresses to deafness, necessitating cochlear implantation (CI). EOM is associated with type 2 inflammatory conditions such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Dupilumab, a monoclonal antibody targeting the IL4Rα subunit, has shown efficacy in mitigating type 2 inflammatory diseases, including asthma and CRSwNP. Recent studies also suggest its effectiveness in treating EOM. We report a unique case of CI for EOM, in which the post-implant hearing threshold improved after the introduction of dupilumab. The patient was a 63-year-old man with a history of asthma and multiple nasal polypectomies. Eosinophils were detected in otorrhea samples from both ears, leading to an EOM diagnosis four years prior. Despite local corticosteroid therapy, his hearing gradually deteriorated. One month ago, he experienced sudden bilateral deafness and was referred to our hospital. The right tympanic membrane had a pinhole perforation but no otorrhea. CT showed a small amount of soft tissue density in the right middle ear, while the left side displayed cochlear osteolysis with soft tissue density. A right CI and myringoplasty were performed one and a half months after his visit. The cochleostomy revealed no perilymph leakage, confirming that the scala tympani was filled with granulation tissue. The electrode was inserted successfully despite the granulation, and all electrodes were placed correctly. Six months after CI, his hearing threshold with the cochlear implant remained poor at 67.5 dB. However, upon starting dupilumab therapy seven months postoperatively, his hearing threshold with the cochlear implant rapidly improved to 31.3 dB. Intraoperative findings suggested that the scala tympani was filled with granulation tissue, indicating significant cochlear inflammation due to EOM. The subsequent hearing improvement after introducing dupilumab may be attributed to the reduction or disappearance of granulation in the cochlea, allowing for effective electrical stimulation from the electrodes to the spiral ganglion. This case suggests the potential for improved postoperative hearing outcomes in CI for EOM when inflammation is effectively controlled with dupilumab.

Current status of pre- and retropectoral breast reconstructions worldwide: a narrative review.

Background and Objective: Advances in breast cancer research and technology contribute to conservative ablative surgical approach with emphasis on reconstruction. The introduction of biologic membranes in breast surgery facilitates a one-stage implant reconstruction while the importance of the pectoralis major muscle involvement in the procedure becomes debatable. A subsequent increase in prepectoral implant placement procedures seems to close a cycle of innovations in implant-based breast reconstructions. This sparks a debate that calls for a critical review of existing literature considering that new challenges tend to arise along with new perspectives. The authors seek to scope the present status of prepectoral and subpectoral implant reconstruction worldwide, and answer recurring questions, including the novelty of presented innovations in the context of existing literature. Methods: The article is based on a literature search in PubMed with the keywords "prepectoral" or "subpectoral" and "breast reconstruction", in addition to the authors' experience with a large number of patients. Key Content and Findings: Recent studies focus on the comparative safety of prepectoral vs. subpectoral placement debating the use of biologic vs. non-biologic sheets and implant texture. There seems to be more emphasis on early post-operative safety of the procedures, rather than any long-term prospects of their comparison, up to this point. Skin and nipple sparing mastectomy (SSM/NSM) together with biological membranes have played a key role in current practice and cannot be overlooked. Conclusions: After reading this paper, the reader should have a firm understanding of the key elements of implant-based breast reconstruction in historical context with emphasis on muscle planes and their pros and cons.

A comprehensive analysis on the safety of two biologics dupilumab and omalizumab.

Dupilumab was approved for the treatment of several dermatologic immune-mediated inflammatory diseases, such as atopic dermatitis and bullous pemphigoid; whereas omalizumab is the first biological agent which was approved to treat chronic spontaneous urticaria. None of the published meta-analyses has provided the sufficient data regarding the safety of these two biologics, especially regarding their potential serious adverse events (SAEs). The aim of this study was, to comprehensively evaluate the safety of the two biologics dupilumab and omalizumab. In this study, we included 32 randomized trials, and performed meta-analyses on 113 types of SAEs regarding dupilumab and 61 types of SAEs regarding omalizumab. We identified that: (1) use of dupilumab was significantly associated with the lower incidence of atopic dermatitis, while use of omalizumab was significantly associated with the lower incidence of asthma; and (2) use of dupilumab was not significantly associated with the incidences of 112 other kinds of SAEs including various infectious diseases, while use of omalizumab was not significantly associated with the incidences of 60 other kinds of SAEs including various infectious diseases. This meta-analysis for the first time assessed the association between use of dupilumab or omalizumab and incidences of various SAEs, and identified that neither dupilumab use nor omalizumab use was associated with the increased risks of any SAEs including various infectious diseases. These findings further confirm the general safety of the two biologics dupilumab and omalizumab. This informs clinicians that there is no need to worry too much about the safety issues of these two biologics.

The Efficacy and Safety of Biosimilars in Hidradenitis Suppurativa: A Comprehensive Review.

Hidradenitis Suppurativa (HS), also known as Acne Inversa, is a chronic, recurrent inflammatory skin condition primarily affecting apocrine gland-bearing areas, such as the axilla and groin. Characterized by painful nodules, abscesses, and scarring, and has a profound psychological impact on patients. Current treatments aim to manage symptoms and prevent new lesions with a combination of non-pharmacological and pharmacological approaches. Emerging biosimilars, which replicate the efficacy and safety profiles of known biologics at a lower cost, offer new options for treating this debilitating cutaneous disorder. The review summarizes recent studies to explain the role of biosimilars in HS, emphasizing their potential to expand effective treatment options.

Risk factors for interstitial lung disease in rheumatoid arthritis: a cohort study from the KOBIO registry.

Background: Interstitial lung disease (ILD) is a critical extra-articular manifestation of rheumatoid arthritis (RA). However, little is known about the risk factors of RA-ILD. Objectives: Here, we examined the effect of demographic, clinical, therapeutic, and environmental factors on the incidence of ILD in RA patients using the Korean College of Rheumatology Biologics and Targeted Therapy (KOBIO) registry. Design: We used data from the KOBIO registry, a multi-center, prospective, observational cohort that included RA patients in South Korea. Methods: RA patients who used biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) or conventional synthetic (cs)DMARDs, and were enrolled in the KOBIO registry, were examined. Demographic, clinical, and radiographic characteristics, as well as medications, were recorded at baseline and annually thereafter. Kaplan-Meier curves and the log-rank test were used to compare the incidence of ILD between RA patients taking different b/tsDMARDs. Hazard ratios (HRs) were calculated by Cox regression analyses. Results: In total, 2492 patients (1967 in the b/tsDMARDs group and 525 in the csDMARDs group) were analyzed. The b/tsDMARDs group showed longer disease duration, higher erythrocyte sedimentation rate/C-reactive protein, and higher disease activity score-28 (DAS28) than the csDMARDs group. The incidence of ILD was significantly higher in those taking tumor necrosis factor inhibitors and abatacept than in those taking csDMARDs (log ranked p < 0.001). Multivariate Cox regression analysis identified older age (HR = 1.057, p = 0.001), male sex (HR = 2.824, p = 0.007), time-averaged DAS28 (HR = 2.241, p < 0.001), and rheumatoid factor titer (HR = 1.009, p = 0.007) as having a significantly increased HR for ILD occurrence. Conclusion: ILD is a rare but critical extra-articular symptom of RA patients. Therefore, RA patients with the above risk factors should be monitored carefully for ILD development.

An in situ bioadhesive foam as a large intestinal delivery platform for antibody fragment to treat inflammatory bowel disease.

Biologics have been widely used as injectables in the treatment of inflammatory bowel disease (IBD). Different local treatment attempts have been developed in recent years. However, maintaining systemic levels of biologics is still crucial for achieving colitis remission. An equilibrium between systemic and local concentrations of biologics is therefore essential for treatment of colitis. Current formulations struggle to create optimal balance between drug concentrations in plasma and the colonic wall. Addressing this challenge, we developed a rectally delivered in situ foam that generates CO2via a reaction between potassium bicarbonate (PB) and citric acid (CA) without the aid of an external device. An anti-TNF-α antibody fragment (Fab) was loaded into the foam formulation, which promoted prolonged colon retention and improved Fab distribution up to proximal colon following rectal administration to mice. In addition, we observed increased plasma Fab concentrations in mice receiving the rectal Fab foam compared to a Fab solution. In a non-everted rat gut ex vivo model, a single exposure to the CO2-containing foam improved macromolecule transepithelial flux across colonic tissue by over ten-fold. Foam efficacy for Fab was investigated in a range of colitis mouse models, from acute to chronic. This non-invasive formulation platform demonstrates potential to overcome existing limitations in delivering biologics to inflamed colonic tissue.

Tralokinumab for the Treatment of Adult Atopic Dermatitis in Special Populations.

Introduction: Even if mild forms of atopic dermatitis (AD) are usually well controlled with topical prescription drugs and emollients, the management of severe forms of the disease may be challenging, especially in special populations (SPs). These patients include groups of disadvantaged people (elderly, patients with disabilities and serious medical conditions) who are usually excluded from clinical trials. As a consequence, most of the data about the efficacy and safety of a drug in these patients derives from post-marketing experiences. In this context, the aim of our study was to retrospectively investigate the effectiveness and safety of tralokinumab in the management of AD in SPs. Methods: A 24-weeks retrospective, dual-center study was performed enrolling patients with a diagnosis of moderate-to-severe AD undergoing treatment with tralokinumab at labelled dosage. Disease severity was assessed using Eczema Area Severity Index (EASI), Pruritus-Numerical Rating Scale (P-NRS), and Dermatology Life Quality Index (DLQI) score at baseline and after 4 weeks (W4), W16, and W24. Adverse events (AEs) were monitored at the same timepoints. Statistical significance of clinical improvement (EASI, P-NRS, DLQI) at week 4, week 16, and week 24 as compared with baseline was evaluated by using Student's t-test, considering significant a p-value <0.05. Results: Our study enrolling 27 SPs patients showed a significant improvement in EASI and P-NRS since week 4, continuing to improve up to week 24. Similarly, DLQI significantly decreases at each timepoint as compared with baseline. Finally, no AEs were reported during the study period. Of interest, our cohort included oncologic patients, a patient with a history of severe infection, as well as subjects affected by severe neurological, psychiatric, pulmonary, and/or cardiovascular disease. Discussion: Our experience showed that tralokinumab is effective and safe in elderly patients and subjects affected by severe comorbidities.

Comparative Effectiveness of Bimekizumab and Ustekinumab in Patients with Psoriatic Arthritis at 52 Weeks Assessed Using a Matching-Adjusted Indirect Comparison.

INTRODUCTION: A matching-adjusted indirect comparison (MAIC) was conducted to assess the relative efficacy at 52 weeks (Wk52) of bimekizumab 160 mg every 4 weeks (Q4W) and ustekinumab 45 or 90 mg every 12 weeks (Q12W) in patients with psoriatic arthritis (PsA) who were biologic disease-modifying anti-rheumatic drug naïve (bDMARD naïve) or who had a previous inadequate response or an intolerance to tumor necrosis factor inhibitors (TNFi-IR). METHODS: Relevant trials were systematically identified. Individual patient data from the bimekizumab trials BE OPTIMAL (NCT03895203; N = 431) and BE COMPLETE (NCT03896581; N = 267) were matched with summary data on patients receiving ustekinumab in the PSUMMIT 1 trial (NCT01009086; 45 mg, N = 205; 90 mg; N = 204) and a subgroup of TNFi-IR patients receiving ustekinumab in the PSUMMIT 2 trial (NCT01077362; 45 mg, N = 60; 90 mg, N = 58), respectively. Patients from the bimekizumab trials were re-weighted using propensity scores to match the baseline characteristics of the ustekinumab trial patients. Adjustment variables were selected based on expert consensus (n = 5) and adherence to established MAIC guidelines. Non-placebo-adjusted comparisons of recalculated bimekizumab and ustekinumab outcomes for the American College of Rheumatology (ACR) 20/50/70 response criteria (non-responder imputation) were analyzed. RESULTS: In patients who were bDMARD naïve, bimekizumab had a greater likelihood of response than ustekinumab at Wk52 for ACR20 (odds ratio [95% confidence interval] 45 mg: 2.14 [1.35, 3.40]; 90 mg: 1.98 [1.24, 3.16]), ACR50 (45 mg: 2.74 [1.75, 4.29]; 90 mg: 2.29 [1.48, 3.55]), and ACR70 (45 mg: 3.33 [2.04, 5.46]; 90 mg: 3.05 [1.89, 4.91]). In patients who were TNFi-IR, bimekizumab had a greater likelihood of response than ustekinumab at Wk52 for ACR20 (45 mg: 4.17 [2.13, 8.16]; 90 mg: 4.19 [2.07, 8.49]), ACR50 (45 mg: 5.00 [2.26, 11.05]; 90 mg: 3.86 [1.70, 8.79]), and ACR70 (45 mg: 9.85 [2.79, 34.79]; 90 mg: 6.29 [1.98, 20.04]). CONCLUSIONS: Using MAIC, bimekizumab showed greater efficacy than ustekinumab in achieving all ACR responses in patients with PsA who were bDMARD naïve and TNFi-IR at Wk52. TRIAL REGISTRATION: NCT03895203, NCT03896581, NCT01009086, NCT01077362.

Efficacy and Safety of Biologics in Polymyalgia Rheumatica: A Retrospective Study.

INTRODUCTION: The study aimed to determine the efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) in the treatment of polymyalgia rheumatica (PMR) complicated by rheumatoid arthritis (RA). METHODS: Patients with PMR which could be classified as RA and who were treated with bDMARDs were included in the analysis. The primary endpoint was the clinical Polymyalgia Rheumatica Activity Score (Clin-PMR-AS) after 26 weeks of treatment, and the secondary endpoint was adverse events during the observation period. RESULTS: A total of 203 patients with PMR which was resistant or intolerant to glucocorticoids and could be classified as RA were receiving bDMARDs and were enrolled in the study. There were 83, 82, and 38 patients in the tumor necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL-6Ri), and cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4-Ig) groups, respectively. Twenty-six weeks after bDMARD initiation, Clin-PMR-AS levels were significantly lower in the IL-6Ri group as compared to other groups. Multiple regression analysis was performed with Clin-PMR-AS as the objective variable. Body mass index (BMI), history of bDMARDs, and IL-6Ri use were identified as factors involved in Clin-PMR-AS. After adjustment for group characteristics using inverse probability of treatment weighting with propensity scores, the Clin-PMR-AS score at 26 weeks was significantly lower in the IL-6Ri group (9.0) than in both the TNFi (12.4, p = 0.004) and CTLA4-Ig (15.9, p = 0.003) group. CONCLUSION: IL-6Ri may potentially improve the disease activity of PMR compared to other bDMARDs.

Comparative Effectiveness of Bimekizumab and Risankizumab in Patients with Psoriatic Arthritis at 52 Weeks Assessed Using a Matching-Adjusted Indirect Comparison.

INTRODUCTION: The relative efficacy of bimekizumab and risankizumab in patients with PsA who were biologic disease-modifying anti-rheumatic drug naïve (bDMARD naïve) or with previous inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR) was assessed at 52 weeks (Wk52) using matching-adjusted indirect comparisons (MAIC). METHODS: Relevant trials were systematically identified. For patients who were bDMARD naïve, individual patient data (IPD) from BE OPTIMAL (NCT03895203; N = 431) were matched with summary data from KEEPsAKE-1 (NCT03675308; N = 483). For patients who were TNFi-IR, IPD from BE COMPLETE (NCT03896581; N = 267) were matched with summary data from the TNFi-IR patient subgroup in KEEPsAKE-2 (NCT03671148; N = 106). To adjust for cross-trial differences, patients from the bimekizumab trials were re-weighted to match the baseline characteristics of patients in the risankizumab trials. Adjustment variables were selected based on expert consensus (n = 5) and adherence to established MAIC guidelines. Recalculated bimekizumab Wk52 outcomes for American College of Rheumatology (ACR) 20/50/70 response criteria and minimal disease activity (MDA) index (non-responder imputation) were compared with risankizumab outcomes via non-placebo-adjusted comparisons. RESULTS: In patients who were bDMARD naïve, bimekizumab had a significantly greater likelihood of response than risankizumab at Wk52 for ACR50 (odds ratio [95% confidence interval]: 1.52 [1.11, 2.09]) and ACR70 (1.80 [1.29, 2.51]). In patients who were TNFi-IR, bimekizumab had a significantly greater likelihood of response than risankizumab at Wk52 for ACR20 (1.78 [1.08, 2.96]), ACR50 (3.05 [1.74, 5.32]), ACR70 (3.69 [1.82, 7.46]), and MDA (2.43 [1.37, 4.32]). CONCLUSIONS: Using MAIC, bimekizumab demonstrated a greater likelihood of efficacy in most ACR and MDA outcomes than risankizumab in patients with PsA who were bDMARD naïve and TNFi-IR at Wk52. TRIAL REGISTRATION: NCT03895203, NCT03896581, NCT03675308, NCT03671148.

Evolution of therapeutic strategy based on oxidant-antioxidant balance for fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD) stands as the most prevalent primary corneal endothelial dystrophy worldwide, posing a significant risk to corneal homeostasis and clarity. Corneal endothelial cells exhibit susceptibility to oxidative stress, suggesting a nuanced relationship between oxidant-antioxidant imbalance and FECD pathogenesis, irrespective of FECD genotype. Given the constrained availability of corneal transplants, exploration into non-surgical interventions becomes crucial. This encompasses traditional antioxidants, small molecule compounds, biologics, and diverse non-drug therapies, such as gene-related therapy, hydrogen therapy and near infrared light therapy. This review concentrates on elucidating the mechanisms behind oxidant-antioxidant imbalance and the evolution of strategies to restore oxidant-antioxidant balance in FECD. It provides a comprehensive overview of both conventional and emerging therapeutic approaches, offering valuable insights for the advancement of non-surgical treatment modalities. The findings herein might establish a robust foundation for future research and the therapeutic strategy of FECD.

Production and characterization of novel Anti-HIV Fc-fusion proteins in plant-based systems: Nicotiana benthamiana & tobacco BY-2 cell suspension.

Multifunctional anti-HIV Fc-fusion proteins aim to tackle HIV efficiently through multiple modes of action. Although results have been promising, these recombinant proteins are hard to produce. This study explored the production and characterization of anti-HIV Fc-fusion proteins in plant-based systems, specifically Nicotiana benthamiana plants and tobacco BY-2 cell suspension. Fc-fusion protein expression in plants was optimized by incorporating codon optimization, ER retention signals, and hydrophobin fusion elements. Successful transient protein expression was achieved in N. benthamiana, with notable improvements in expression levels achieved through N-terminal hydrophobin fusion and ER retention signals. Stable expression in tobacco BY-2 resulted in varying accumulation levels being at highest 2.2.mg/g DW. The inclusion of hydrophobin significantly enhanced accumulation, providing potential benefits for downstream processing. Mass spectrometry analysis confirmed the presence of the ER retention signal and of N-glycans. Functional characterization revealed strong binding to CD64 and CD16a receptors, the latter being important for antibody-dependent cellular cytotoxicity (ADCC). Interaction with HIV antigens indicated potential neutralization capabilities. In conclusion, this research highlights the potential of plant-based systems for producing functional anti-HIV Fc-fusion proteins, offering a promising avenue for the development of these novel HIV therapies.

Progression of Quality of Life in Patients with Plaque Psoriasis Who Achieved Three or More Years of Complete Skin Clearance with Guselkumab Treatment: a Post hoc Analysis of the VOYAGE 1 Clinical Trial.

INTRODUCTION: The interleukin-23p19 subunit inhibitor, guselkumab, has demonstrated improvements in clinical and patient-reported outcome (PRO) measures in patients with moderate-to-severe psoriasis. Understanding the relationship among clinical response, PRO measures and baseline characteristics could help clinicians individualize treatment plans. The objective of this analysis was to examine changes in signs, symptoms and quality-of-life (QoL) PRO measures in patients who maintained complete skin clearance through ≥ 3 years in the phase 3 VOYAGE 1 trial. METHODS: A descriptive post hoc analysis of data from VOYAGE 1 was conducted to compare baseline characteristics of patients who maintained complete skin clearance (Psoriasis Area and Severity Index [PASI] = 0 for ≥ 156 consecutive weeks) versus patients who did not. Mean scores for individual domains of the Dermatology Life Quality Index (DLQI) and Psoriasis Symptom and Sign Diary (PSSD) were evaluated in patients who maintained complete skin clearance, and baseline characteristics of patients who achieved PRO scores of DLQI = 0/1 and PSSD = 0 were compared with those who did not. RESULTS: Of the 329 patients included in this post hoc analysis, 73 (22.2%) maintained PASI = 0 for ≥ 156 weeks. This group had a numerically lower proportion of patients at baseline with obesity, depression or previous biologic treatment and a higher proportion who had never smoked. Patients who maintained PASI = 0 generally achieved positive DLQI and PSSD outcomes, though some impact of residual disease was observed, largely related to the DLQI "Symptoms and feelings" sub-scale and PSSD components "Dryness," "Redness" and "Itch." Patients reporting continued disease impact (despite sustaining PASI = 0) had greater disease severity at baseline versus those achieving DLQI = 0/1 and PSSD = 0. CONCLUSION: Clinical measures alone do not capture the full patient experience. While both QoL and clinical symptoms are responsive to highly effective treatment, a subset of patients with complete clinical response is still impacted by their psoriasis. Further investigation into this population is warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02207231.

General quasi-equilibrium multivalent binding model to study diverse and complex drug-receptor interactions of biologics.

Pharmacokinetics and pharmacodynamics of many biologics are influenced by their complex binding to biological receptors. Biologics consist of diverse groups of molecules with different binding kinetics to its receptors including IgG with simple one-to-one drug receptor bindings, bispecific antibody (BsAb) that binds to two different receptors, and antibodies that can bind to six or more identical receptors. As the binding process is typically much faster than elimination (or internalization) and distribution processes, quasi-equilibrium (QE) binding models are commonly used to describe drug-receptor binding kinetics of biologics. However, no general QE modeling framework is available to describe complex binding kinetics for diverse classes of biologics. In this paper, we describe novel approaches of using differential algebraic equations (DAE) to solve three QE multivalent drug-receptor binding (QEMB) models. The first example describes the binding kinetics of three-body equilibria of BsAb that binds to 2 different receptors for trimer formation. The second example models an engineered IgG variant (Multabody) that can bind to 24 identical target receptors. The third example describes an IgG with modified neonatal Fc receptor (FcRn) binding affinity that competes for the same FcRn receptor as endogenous IgG. The model parameter estimates were obtained by fitting the model to all data simultaneously. The models allowed us to study potential roles of cooperative binding on bell-shaped drug exposure-response relationships of BsAb, and concentration-depended distribution of different drug-receptor complexes for Multabody. This DAE-based QEMB model platform can serve as an important tool to better understand complex binding kinetics of diverse classes of biologics.

Advances in psoriasis research: From pathogenesis to therapeutics.

Psoriasis is a chronic inflammatory condition affecting approximately 2 % to 3 % of the global population. The pathogenesis of psoriasis is complex, involving immune dysregulation, hyperproliferation and angiogenesis. It is a multifactorial disease which is influenced by genetic and environmental factors. The development of various therapeutic agents, such as JAK inhibitors, small molecules, and biologics with potential anti-psoriatic properties was possible with the vast understanding of the pathogenesis of psoriasis. Various signalling pathways, including NF-κB, JAK-STAT, S1P, PDE-4, and A3AR that are involved in the pathogenesis of psoriasis as well as the preclinical models utilised in the research of psoriasis have been highlighted in this review. The review also focuses on technological advancements that have contributed to a better understanding of psoriasis. Then, the molecules targeting the respective signalling pathways that are still under clinical trials or recently approved as well as the latest breakthroughs in therapeutic and drug delivery approaches that can contribute to the improvement in the management of psoriasis are highlighted in this review. This review provides an extensive understanding of the current state of research in psoriasis, giving rise to opportunities for researchers to discover future therapeutic breakthroughs and personalised interventions. Efficient treatment options for individuals with psoriasis can be achieved by an extensive understanding of pathogenesis, therapeutic agents, and novel drug delivery strategies.

Comprehensive evaluation of disulfidptosis in intestinal immunity and biologic therapy response in Ulcerative Colitis.

Objective: Ulcerative Colitis (UC) manifests as a chronic inflammatory condition of the intestines, marked by ongoing immune system dysregulation. Disulfidptosis, a newly identified cell death mechanism, is intimately linked to the onset and advancement of inflammation. However, the role of disulfidptosis in UC remains unclear. Methods: We screened differentially expressed genes (DEGs) associated with disulfidptosis in multiple UC datasets, narrowed down the target gene number using lasso regression, and conducted immune infiltration analysis and constructed a clinical diagnostic model. Additionally, we explored the association between disulfidptosis-related key genes and disease remission in UC patients receiving biologic therapy. Finally, we confirmed the expression of key genes in FHC cells and UC tissue samples. Results: In the differential analysis, we identified 20 DEGs associated with disulfidptosis. Immune infiltration results revealed that five genes (PDLIM1, SLC7A11, MYH10, NUBPL, OXSM) exhibited strong correlations with immune cells and pathways. Using GO, KEGG and WGCNA analyses, we discovered that gene modules highly correlated with disulfidptosis-related gene expression were significantly enriched in inflammation-related pathways. Additionally, we developed a nomogram based on these five immune-related disulfidptosis genes for UC diagnosis, showing robust diagnostic capability and clinical efficacy. Kaplan-Meier survival analysis revealed a significant link between changes in the expression levels of these cell genes and disease remission in UC patients receiving biologic therapy. In line with previous studies, similar expression changes of the target gene were seen in both UC cell models and tissue samples. Conclusions: This study utilized bioinformatic analysis and machine learning to identify and analyze features associated with disulfidptosis in multiple UC datasets. This enhances our comprehension of the role disulfidptosis plays in intestinal immunity and inflammation in UC, providing new perspectives for developing innovative treatments for UC.

Limited predictive value of the gut microbiome and metabolome for response to biological therapy in inflammatory bowel disease.

Emerging evidence suggests the gut microbiome's potential in predicting response to biologic treatments in patients with inflammatory bowel disease (IBD). In this prospective study, we aimed to predict treatment response to vedolizumab and ustekinumab, integrating clinical data, gut microbiome profiles based on metagenomic sequencing, and untargeted fecal metabolomics. We aimed to identify predictive biomarkers and attempted to replicate microbiome-based signals from previous studies. We found that the predictive utility of the gut microbiome and fecal metabolites for treatment response was marginal compared to clinical features alone. Testing our identified microbial ratios in an external cohort reinforced the lack of predictive power of the microbiome. Additionally, we could not confirm previously published predictive signals observed in similar sized cohorts. Overall, these findings highlight the importance of external validation and larger sample sizes, to better understand the microbiome's impact on therapy outcomes in the setting of biologicals in IBD before potential clinical implementation.

Evaluation of dupilumab on the disease burden in children and adolescents with atopic dermatitis: A population-based cohort study.

BACKGROUND: Dupilumab is the first and only biologic agent approved for the treatment of atopic dermatitis (AD) in pediatric patients aged from 6 months to 17 years. The study aimed to evaluate the impact of dupilumab on the occurrence of comorbidities in pediatric patients with AD. METHODS: In this population-based cohort study, we utilized electronic health records from multiple healthcare organizations across the United States. Pediatric patients (<18 years of age) with a diagnosis of AD initiating dupilumab were propensity-score matched 1:1 to those initiating other systemic agents (azathioprine, cyclosporine, methotrexate, mycophenolate mofetil, or systemic corticosteroids). The primary outcomes were new-onset comorbidities emerging during the study period measured by the risk ratio (RR) and its confidence interval (CI). Subgroup analyses were stratified by age (0-5 years, 6-11 years, and 12-17 years), sex, and race. RESULTS: A total of 3575 pediatric patients with AD treated with dupilumab were matched to 3575 patients treated with other systemic agents. The dupilumab cohort was associated with a lowered risk of new-onset atopic comorbidities (including asthma [RR, 0.72; 95% CI, 0.59-0.89] and allergic rhinitis [RR, 0.62; 95% CI, 0.52-0.74]), infections (e.g., skin and soft tissue infection [RR, 0.70; 95% CI, 0.63-0.76] and respiratory tract infection [RR = 0.56; 95% CI, 0.51-0.61]), psychiatric disorders (e.g., mood disorder [RR, 0.52; 95% CI, 0.39-0.70] and anxiety [RR, 0.57; 95% CI, 0.46-0.70], sleep disturbance [RR, 0.60; 95% CI, 0.47-0.77]), neurologic and developmental disorders (e.g., attention deficit hyperactivity disorder [RR, 0.54; 95% CI, 0.38-0.75]). Furthermore, the positive effects are found to be more pronounced in younger children (aged 0-5 years) with AD. CONCLUSIONS: Treatment with dupilumab compared to systemic agents resulted in reductions in AD-related comorbidities in pediatric patients.

Predictors of initiating biologics in the treatment of psoriasis.

BACKGROUND: Biologics are among the most effective therapies for psoriasis. However, many patients are only introduced to them at advanced stages of the disease course. OBJECTIVES: Our aim was to identify predictors of initiating biologic therapy in patients with psoriasis and compare patients initiating biologics early versus late in their disease course. METHODS: Kaplan-Meier curves visualized time to biologic initiation, while Cox regression models further explored variables as predictors of biologic initiation. Mann-Whitney U and chi-squared tests compared patients who started biologics early with those who began biologics later in the disease course. RESULTS: Our primary analysis included 233 psoriasis patients. Cox regression showed that age at diagnosis (P = 0.007), general physical well-being (P = 0.02), and nail psoriasis severity (P = 0.02) were significantly associated with time to biologic initiation. Our secondary analysis, the comparisons between patients starting biologics early versus later in the disease course, included a total of 378 patients. The median (interquartile range [IQR]) age at diagnosis was 34.5 (25.0-51.2) years for patients initiating biologics within 5 years, compared to 22.0 (15.0-32.8) years for patients initiating biologics later (P < 0.0001). The median (IQR) age at initiation was 37.0 (27.0-53.2) and 45.0 (36.0-55.0) years for patients initiating biologics earlier versus later than 5 years (P = 0.04). CONCLUSIONS: Age at diagnosis, general well-being, and severity of nail psoriasis significantly predicted future initiation of biologic treatment. Patients initiating biologics early in their disease course were generally older at diagnosis but younger at the time of biologic initiation compared to patients initiating biologics later in their disease course.