Tumor Necrosis Factor Alpha Inhibitors Research Articles

Impact of adalimumab on erectile dysfunction, sperm parameters and hormonal profile in male psoriasis patients: a six-month observational study.

Psoriasis, a chronic inflammatory skin disease, is associated with systemic complications that extend beyond cutaneous lesions, including cardiovascular risks and sexual dysfunction. Erectile dysfunction (ED) is notably more prevalent in male psoriasis patients, likely driven by both systemic inflammation and psychological stress. Adalimumab (ADA), a tumor necrosis factor-alpha (TNF-α) inhibitor, has been shown to effectively reduce psoriasis severity, but its effects on sexual and reproductive health remain underexplored. This study investigates the impact of ADA on erectile function, sperm parameters, and hormonal profiles in male psoriasis patients. This six-month prospective observational study included 33 biologic-naïve male patients aged 18-50 years with moderate-to-severe plaque psoriasis (Psoriasis Area and Severity Index [PASI] > 10). Patients received ADA according to standard clinical protocols. Erectile function was assessed using the International Index of Erectile Function (IIEF-5). Sperm parameters, including ejaculate volume, sperm concentration, total sperm count, motility, vitality, and morphology, were analyzed following World Health Organization (WHO) 2010 criteria. Hormonal profiles (testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and prolactin) were measured via standardized assays. Statistical analyses were performed using paired t-tests or Wilcoxon signed-rank tests, with p-values < 0.05 considered significant. ADA significantly improved erectile function, as the mean IIEF-5 score increased from 21.3 ± 2.2 to 22.2 ± 1.9 (p = 0.03). The percentage of patients with ED decreased from 51.5% at baseline to 36.4% post-treatment (p < 0.001). Progressive sperm motility and vitality showed statistically significant improvement post-treatment (p = 0.02 and p = 0.04, respectively), while other sperm parameters remained unchanged. Total testosterone levels significantly increased from 3.4 ± 0.4 ng/ml to 3.5 ± 0.4 ng/ml (p = 0.02), while LH, FSH, estradiol, and prolactin levels showed no significant changes. The anti-inflammatory properties of adalimumab, through the inhibition of TNF-α, not only reduce psoriasis severity but also appear to exert positive effects on male sexual and reproductive health. Our study demonstrated significant improvements in erectile function, sperm motility, vitality, and testosterone levels in male psoriasis patients after adalimumab therapy. These findings suggest that beyond its role in controlling psoriatic skin lesions, adalimumab may help mitigate the systemic inflammatory burden that contributes to sexual dysfunction and impaired spermatogenesis. Future long-term studies are essential to further explore the sustained impact of TNF-α inhibition on male fertility and reproductive outcomes.

Infusion Reactions to Infliximab in Pediatric Patients with Inflammatory Bowel Disease

Infliximab (IFX) is a recombinant DNA-derived chimeric IgG monoclonal antibody protein that inhibits tumor necrosis factor alpha (TNF-α). IFX, like other agents derived from foreign proteins, can cause infusion reactions both during and after the infusion. The incidence of infusion reactions ranges between 0% and 15% in pediatric patients. The potential underlying mechanisms for these reactions may include anaphylaxis and anaphylactoid reactions, cytokine release syndrome, serum sickness-like reactions, and the development of antibodies against IFX. Several precautions can help reduce the risk of a new infusion reaction, such as a gradual increase in the infusion rate, scheduled infusions, and administering premedication or immunomodulators alongside IFX. Acute mild to moderate reactions often resolve spontaneously after a temporary cessation of the infusion or reduction in the infusion rate. Strategies like graded dose challenges and premedication can be utilized to prevent recurrence. In cases of severe reactions, desensitization or switching to an alternative biologic may be considered. This article aims to review the most recent guidelines for managing IFX-related infusion reactions in pediatric patients with inflammatory bowel disease (IBD), relying on the best available evidence.

TissueGene-C induces anti-inflammatory activity and M2 macrophage polarization via activation of prostaglandin E2 signaling

Osteoarthritis (OA) is the most common form of degenerative joint disease that commonly affects the knees, hips, and hands. OA is a mechano-inflammatory disease characterized by low-grade inflammation, which results in the breakdown of the cartilage extracellular matrix (ECM) within joints, leading to pain, stiffness, and inflammation. TissueGene-C (TG-C) is a cell and gene therapy investigational drug for treating knee OA that comprises human allogenic chondrocytes and an irradiated modified cell line stably expressing transforming growth factor-β1 (TGF-β1). Previous preclinical animal studies have shown that TG-C provides pain relief via its anti-inflammatory effects and cartilage structural improvement in rat OA model. The goal of this study was to investigate the mechanism of action of TG-C, explore its anti-inflammatory activity, and identify the TG-C-derived active factor(s) responsible for its efficacy. Our results showed that TG-C induces the polarization of M2 macrophages and the upregulation of interleukin-10 (IL-10) and interleukin-1 receptor antagonist (IL-1ra) while inhibiting tumor necrosis factor alpha (TNF-α) expression. Additionally, this study identified prostaglandin E2 (PGE2) as the main bioactive factor responsible for the anti-inflammatory activity of TG-C. Our results demonstrated that PGE2 is expressed by the TG-C chondrocyte component and modulated by TGF-β1 derived from the second component of TG-C. Finally, the present study provides insight into the mechanism of action of TG-C in the treatment of OA.

Autoimmune diseases and cardiovascular risk: Mendelian randomization analysis for the impact of 19 autoimmune diseases on 14 cardiovascular conditions

BackgroudAutoimmune diseases (AIDs) have been associated with various cardiovascular diseases (CVDs) in observational data. However, the causality of these associations remains uncertain. Therefore, a systematic assessment of the impact of AIDS on cardiovascular risk is required. ResultsWe assessed the impact of 19 common AIDs on 14 CVDs using bidirectional Mendelian randomization (MR). Celiac disease (odds ratio [OR] = 2.949, 95 % confidence interval [CI]: 1.111–7.827, P = 0.030) and type 1 diabetes mellitus (T1DM) (OR = 1.044, 95 % CI: 1.021–1.068, P = 1.82e-4) were associated with an increased risk of peripheral arterial disease (PAD). Additionally, celiac disease was linked to an increased risk of arrhythmia (OR = 1.008, 95 % CI: 1.002–1.013, P = 0.004), multiple sclerosis to venous thromboembolism (OR = 1.001, 95 % CI: 1.000–1.001, P = 0.010), and psoriasis to heart failure (OR = 1.048, 95 % CI: 1.021–1.077, P = 0.001). Sensitivity analyses were conducted to enhance the robustness of these findings. Predominantly, immune response and inflammation-related pathways were enriched in the aforementioned associations. Mediation analysis identified human leukocyte antigen-DR positive myeloid dendritic cells as partially mediating the effect of T1DM on PAD, with a mediated proportion of 16.61 % (P = 0.028). Potential therapeutic agents, such as tumor necrosis factor-alpha inhibitors and interferon, may have efficacy in treating AID-related CVDs. ConclusionsThis study presents genetic evidence of certain AIDs impacting specific CVDs and identifies potential mediators and drugs.

Tumor Necrosis Alpha (TNF-α) Antagonists Used in Chronic Inflammatory Rheumatic Diseases: Risks and their Minimization Measures.

Tumor necrosis factor alpha (TNF- α) inhibitors are widely employed for the management of chronic inflammatory rheumatism. However, their usage carries significant risks, including site and infusion reactions, serious infections, malignancy, heart failure autoimmune and demyelinating disorders. These risks are comprehensively outlined in risk management plans (RMPs) associated with these molecules. RMP provides information on the safety profile of a medicinal product as well as the measures that will be taken to minimize risks; these are known as risk minimization measures. These measures are divided into routine measures related to elements, such as the summary of product characteristics, labeling, pack size, package leaflet, or legal supply status of the product, while additional measures may include educational programs, including tools for healthcare providers and patients, controlled access or pregnancy prevention programs, among others. Additional measures can consist of one or more interventions that need to be implemented in a sustainable way in a defined target group, while respecting the timing and frequency of any intervention and procedures to reach the target population. An evaluation of the effectiveness of these measures is required to determine whether or not an intervention has been effective. This comprehensive review offers an in-depth exploration of the current treatment, uses, and associated risks of TNF-α inhibitors. Additionally, it provides a detailed account of risk minimization measures and risk management practices while shedding light on their real-world implementation and effectiveness.

Rationale design and synthesis of new roflumilast analogues as preferential selective and potent PDE-4B inhibitors

In this study, we designed and synthesized novel analogues of roflumilast that exhibit selective inhibition of PDE-4B. To accomplish this target; synthesis of novel series (4a-u, 5a-i, and 6) was done, aiming at obtaining new PDE-4B inhibitors hits based on the proposed pharmacophore, 1-(cyclopropylmethoxy)-2-(difluoromethoxy) benzene moiety. Enzyme assay was used to measure the IC50 values for the PDE-4B inhibition of all the synthesized compounds along with roflumilast as a reference drug. The results demonstrated that most of the examined candidates exhibited considerable inhibitory activity against the PDE-4B enzyme. The four compounds (4i, 4k, 4p, and 4q) exhibited the highest potency (IC50 = 7.25, 7.15, 5.50, 7.19 nM, respectively) with no significant inhibition difference from roflumilast (no statistical difference at p < 0.05). Interestingly, compound 4p with 3-OH and 4-OCH3 substituents was found to be the most potent against PDE-4B enzyme (IC50 = 5.50 nM), compared to that of roflumilast (IC50 = 2.36 nM). Moreover, the most potent derivatives 4i, 4k, 4p, and 4q were further tested for PDE-4D inhibitory activity to investigate their PDE-4D/PDE-4B selectivity ratio. Compound 4k showed the highest selectivity towards PDE-4B isozyme more than the reference drug roflumilast (PDE-4D/4B IC50 ratio for compound 4k and roflumilast = 3.22 and 3.02, respectively). Additionally, compound 4p was chosen to test its selectivity for PDE-4B over PDE-8A, PDE-11A, and PDE-1B compared to thereference drug roflumilast. Compound 4p showed approximately 6-fold selectivity for PDE-4B over PDE-8A, about 5-fold selectivity for PDE-4B over PDE-11A, and about 11-fold selectivity of PDE-4B over PDE-1B. Compound 4p showed a higher selectivity towards PDE-4B than PDE-1B, more than the reference compound roflumilast. Furthermore, the most potent compounds (4i, 4k, 4p, 4q) were subjected to further investigation, and their effects on the cAMP level and percentage of inhibition of tumor necrosis factor-alpha (TNF-α) were studied and compared with reference drug roflumilast. Compound 4q showed the highest increase in the level of intracellular cAMP (6.55 ± 0.37 pmol/mL) and compound 4i showed the highest % of TNF-α inhibition (77.22 %). On the other side, a molecular docking study against PDE-4B clarified that all the examined candidates achieved nearly similar binding modes with similar orientations to that of the native roflumilast ligand and showed higher docking scores than roflumilast.

17β-Estradiol Abrogates TNF-α-Induced Human Brain Vascular Pericyte Migration by Downregulating miR-638 via ER-β.

Pericytes (PCs) contribute to brain capillary/BBB integrity and PC migration is a hallmark for brain capillary leakage following pro-inflammatory insults. Estradiol promotes endothelial barrier integrity by inhibiting tumor necrosis factor-alpha (TNF-α)-induced PC migration. However, the underlying mechanisms remain unclear. Since micro-RNAs (miRs) regulate BBB integrity and increases in miR638 and TNF-α occur in pathological events associated with capillary leakage, we hypothesize that TNF-α mediates its capillary disruptive actions via miR638 and that estradiol blocks these actions. Using quantitative reverse transcription PCR, we first assessed the modulatory effects of TNF-α on miR638. The treatment of PCs with TNF-α significantly induced miR638. Moreover, transfection with miR638 mimic induced PC migration, whereas inhibitory miR638 (anti-miR) abrogated the pro-migratory actions of TNF-α, suggesting that TNF-α stimulates PC migration via miR638. At a molecular level, the pro-migratory effects of miR638 involved the phosphorylation of ERK1/2 but not Akt. Interestingly, estradiol downregulated the constitutive and TNF-α-stimulated expression of miR638 and inhibited the TNF-α-induced migration of PCs. In PCs treated with estrogen receptor (ER) ER-α, ER-β, and GPR30 agonists, a significant downregulation in miR638 expression was solely observed in response to DPN, an ER-β agonist. DPN inhibited the pro-migratory effects of TNF-α but not miR638. Additionally, the ectopic expression of miR638 prevented the inhibitory effects of DPN on TNF-α-induced PC migration, suggesting that interference in miR638 formation plays a key role in mediating the inhibitory actions of estradiol/DPN. In conclusion, these findings provide the first evidence that estradiol inhibits TNF-α-induced PC migration by specifically downregulating miR638 via ER-β and may protect the neurovascular unit during injury/stroke via this mechanism.

Difficult-to-treat Takayasu arteritis: a case-based review.

Takayasu arteritis is a rare chronic inflammatory large vessel vasculitis which affects the aorta and its large branches. The diagnosis is based on the 2022 ACR/EULAR classification criteria for Takayasu arteritis. The management of this vasculitis is challenging. Although it is corticosteroid-responsive, relapses and disease progression are common. Thus, it is possible to resort to alternative conventional synthetic disease-modifying anti-rheumatic drugs and biologics, as second-line such as tumor necrosis factor-alpha inhibitors, tocilizumab, or JAK inhibitors as second-line agents is possible. Nevertheless, in some complex cases, the vasculitis remains active despite different proposed therapeutic lines, and a multitarget approach could induce sustained remission. We report herewith a case of 33-female patient with a refractory Takayasu arteritis which remained active after three different therapeutic lines with tocilizumab, then infliximab, then Upadacitinib. Finally, we consider a successful multitarget approach with a combination of infliximab, Upadacitinib, and methotrexate.

Diagnostic and Therapeutic Insights Into Pediatric Neurosarcoidosis: Observations From French Pediatric Rheumatology Centers

BackgroundThe diagnosis and management of neurosarcoidosis (NS) in pediatric patients remain challenging, with limited case documentation to guide clinicians. Most existing reports focus on initial presentations. This study aimed to outline the clinical features, management, and medium-term outcomes of pediatric NS MethodsIn this retrospective, multicentric, observational study, we collected data from pediatric patients followed in French pediatric rheumatology centers with a diagnosis of NS between January 2001 and June 2023. ResultsWe identified 11 patients diagnosed with NS, comprising eight girls and three boys. The mean age at diagnosis of sarcoidosis was 10 (5 to 15) years, and the mean age of diagnosis of NS was 11.5 (5 to 17) years. Predominant neurological symptoms included headache (nine of 11 patients), papilledema (6 of 11 patients), facial palsy (two patients), seizures (one patient), and motor deficit (two patients). Nine of 11 patients had eye involvement, which consisted of granulomatous and bilateral uveitis. All patients exhibited meningitis, with cerebrospinal fluid white blood cell counts ranging from 6 to 70 cells/mm3. Six individuals presented neurological abnormalities on imaging, detailed in this study. Treatment primarily involved corticosteroids, methotrexate, and tumor necrosis factor alpha (TNF-alpha) inhibitors. Biologics targeting TNF-alpha were necessary to achieve remission in eight of 11 patients. In two patients who did not receive this treatment initially, it was required later in the course of evolution. ConclusionsThis study enhances understanding of the clinical course of pediatric NS and supports the early use of TNF-alpha biologics for improved management in affected children.

Rheumatoid Arthritis and COVID-19 at the Intersection of Immunology and Infectious Diseases: A Related PRISMA Systematic Literature Review.

Rheumatoid arthritis (RA) patients face different health challenges when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than the general population, due to both their immunocompromised state and the immunosuppressive therapies they receive. This systematic literature review, which follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) paradigm, explores the interactions between RA and SARS-CoV-2 infection, focusing on immunologic issues, disease management, vaccination, and adverse outcomes. In order to obtain the most relevant information, we systematically reviewed the specific literature from 1 January 2021 to 31 December 2023, based on the PRISMA method, by which we eventually selected 35 eligible articles, to which we added other ISI-indexed studies to enrich our results further. Consequently, we performed a funnel analysis to evaluate the potential for publication bias. Firstly, the data collected revealed the impact of the pandemic on RA diagnoses and the fear of face-to-face medical consultations that delayed adequate treatment. Secondly, cardiovascular and metabolic comorbidities increase the risk of prolonged COVID-19 symptoms, hospitalization, and severe COVID-19 outcomes for RA patients. With respect to immunosuppressive treatment used to control RA, it was observed that glucocorticoids (especially high-dose usage) and Rituximab (RTX) predispose the patients to poor SARS-CoV-2 outcomes, as opposed to Baricitinib and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) inhibitors. COVID-19 vaccination has proven effective and generally safe for RA patients in some studies, although therapies with Methotrexate (MTX), Abatacept (ABA), and RTX have been associated with impaired vaccine immune response. This systematic literature review brings updated and thorough information with respect to the immunological, clinical, and management of a complex immune-mediated inflammatory disease (IMID) like RA in the setting of COVID-19 and underlines the challenges faced by this group of patients. The lessons learned can be extended beyond the pandemic in shaping a more informed and compassionate healthcare system and offering long-term medical care for patients with RA.

Review article: Optimisation of biologic (monoclonal antibody) therapeutic response in inflammatory bowel disease.

There are a plethora of therapeutic options for the management of inflammatory bowel disease (IBD). Despite this, clinical outcomes with standard dosing often fall short of established targets. While efforts centre on developing novel therapies, there is an ongoing need to optimise the use of existing agents. To focus on strategies to optimise response to biologic (monoclonal antibody) therapies in IBD, including use of therapeutic drug monitoring (TDM). An extensive review of the published literature. TDM is a strategy aimed at enhancing the effectiveness of drugs with variable exposure-response relationships by measuring serum concentrations of biologic therapies and detecting neutralising antibodies. Reactive TDM is performed when therapeutic goals have not been achieved. Tumour necrosis factor alpha (TNF) inhibitors are the treatment class most frequently associated with immunogenicity and loss of response. Immunogenicity can be reduced through avoidance of low serum drug concentrations by dose optimisation or use of concomitant immunomodulator therapy. Subtherapeutic dosing in the absence of antidrug antibodies is best managed by dose escalation or dose interval reduction. Persistent neutralising drug antibodies necessitate switching to an alternative therapy. Proactively ensuring adequate serum trough levels might help sustain treatment durability and prevent loss of response. Newer non-TNF inhibitors demonstrate less robust exposure-response relationships, and TDM may not prove as beneficial. In the treat-to-target paradigm of IBD treatment, optimising treatment effect with dose optimisation, which may involve strategies including TDM, increases the likelihood of achieving clinical remission and may accomplish deeper levels of remission beyond symptom control.

Ophthalmic Use of Targeted Biologics in the Management of Intraocular Diseases: Current and Emerging Therapies.

Monoclonal antibodies (mAbs) have demonstrated substantial potential in the treatment of intraocular diseases. This review aimed to comprehensively evaluate the applications, efficacy, and safety of mAbs in the management of intraocular conditions. A comprehensive literature search was conducted in major medical databases through July 2024. Relevant studies on monoclonal antibodies for intraocular diseases were included. Two independent researchers screened the literature, extracted data, and assessed study quality. Cost-effectiveness analyses were also reviewed. Anti-vascular endothelial growth factor (VEGF) antibodies, such as bevacizumab, ranibizumab, and aflibercept, showed significant therapeutic effects in neovascular age-related macular degeneration (NVAMD), diabetic macular edema (DME), and retinal vein occlusion (RVO). Tumor necrosis factor-alpha (TNF-α) inhibitors demonstrated promising results in treating noninfectious uveitis. Complement system-targeted therapies like pegcetacoplan offered new options for geographic atrophy. Anti-VEGF antibodies showed potential in managing retinopathy of prematurity (ROP). However, challenges persist, including high costs, potential drug resistance, and limited long-term safety data in certain scenarios. Monoclonal antibodies are vital for treating intraocular diseases, but continuous innovation and rigorous clinical evaluation are essential. Future research should focus on developing novel delivery systems, exploring combination therapies, conducting long-term follow-up studies, and investigating personalized treatment strategies to provide safer, more effective, and cost-effective therapeutic solutions.

TNF-α inhibitors for type 1 diabetes: exploring the path to a pivotal clinical trial.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreas. This destruction leads to chronic hyperglycemia, necessitating lifelong insulin therapy to manage blood glucose levels. Typically diagnosed in children and young adults, T1D can, however, occur at any age. Ongoing research aims to uncover the precise mechanisms underlying T1D and to develop potential interventions. These include efforts to modulate the immune system, regenerate β-cells, and create advanced insulin delivery systems. Emerging therapies, such as closed-loop insulin pumps, stem cell-derived β-cell replacement and disease-modifying therapies (DMTs), offer hope for improving the quality of life for individuals with T1D and potentially moving towards a cure. Currently, there are no disease-modifying therapies approved for stage 3 T1D. Preserving β-cell function in stage 3 T1D is associated with better clinical outcomes, including lower HbA1c and decreased risk of hypoglycemia, neuropathy, and retinopathy. Tumor Necrosis Factor alpha (TNF-α) inhibitors have demonstrated efficacy at preserving β-cell function by measurement of C-peptide in two clinical trials in people with stage 3 T1D. However, TNF-α inhibitors have yet to be evaluated in a pivotal trial for T1D. To address the promising clinical findings of TNF-α inhibitors in T1D, Breakthrough T1D convened a panel of key opinion leaders (KOLs) in the field. The workshop aimed to outline an optimal clinical path for moving TNF-α inhibitors to a pivotal clinical trial in T1D. Here, we summarize the evidence for the beneficial use of TNF-α inhibitors in T1D and considerations for strategies collectively identified to advance TNF-α inhibitors beyond phase 2 clinical studies for stage 3 T1D.

Clinicopathologic features, demographics, disease burden, and therapeutics in alopecic sarcoidosis: a case series and systematic review.

Alopecic sarcoidosis is an uncommon cutaneous manifestation of sarcoidosis. Scarring and nonscarring alopecic sarcoidosis have been reported; however, information on the epidemiology, systemic disease associations, and treatment efficacy is limited. To address these gaps, we conducted a retrospective chart review and systematic literature review of alopecic sarcoidosis cases. Full-text English publications from PubMed, Scopus, and Google Scholar from inception to August 2023 were analyzed. Treatment evidence quality was assessed using the modified Oxford Centre for Evidence-Based Medicine rating scale. Three patients with biopsy-proven alopecic sarcoidosis were included as a case series, all demonstrating systemic sarcoidosis and 2 requiring multiple therapies. Among 1778 search results, 60 articles representing 77 cases of alopecic and scalp sarcoidosis were included. Patients were categorized into 4 distinct alopecic subgroups. Black patients constituted the majority of all subgroups. Extracutaneous sarcoidosis burden was high across all alopecic subgroups, with ocular disease appearing overrepresented. Topical and oral corticosteroids were the main treatments. Though scarring alopecia patients had poor outcomes despite receiving immunomodulators/cx, limited data suggest potential efficacy of tumor necrosis factor-alpha inhibitors. This study has a small sample size. Our findings underscore the importance of evidence-based strategies for improving alopecic sarcoidosis management. Prompt diagnosis and systemic evaluation, especially for scarring alopecia, are essential for timely intervention to optimize patient outcomes.

Proactive therapeutic drug monitoring of biologic drugs in patients with inflammatory bowel disease, inflammatory arthritis, and psoriasis: systematic review and meta-analysis

ObjectiveTo address the efficacy and safety of proactive therapeutic drug monitoring of biologic drugs for patients with inflammatory bowel disease, inflammatory arthritis, and psoriasis.DesignSystematic review and meta-analysis.Data sourcesMedline, Embase, Central,...

Optic Atrophy Occurring with Anti‐Tumor Necrosis Factor Alpha Therapy: A Case Report

Ocular involvement related to treatment with tumor necrosis factor alpha inhibitors is a rare adverse effect that may lead to irreversible outcomes. We illustrate through this report a case of optic atrophy under Etanercept in a patient with spondyloarthritis. The diagnosis was suspected due to visual acuity impairment, and was confirmed by ophthalmological examination. Although the TNF-blockers were discontinued and corticosteroids were administered, the follow-up examination did not reveal any improvement in visual acuity. This is a potential serious complication of TNF inhibitors that rheumatologists should recognize when monitoring patients with rheumatic diseases.

Treatment efficacy and patient satisfaction of ustekinumab compared with tumor necrosis factor-alpha inhibitors in Chinese patients with moderate-to-severe psoriasis: a real-world study

Background Ustekinumab is an interleukin (IL)-12/IL-23 inhibitor for the treatment of moderate-to-severe psoriasis. Objective This real-world study compared ustekinumab and tumor necrosis factor-alpha inhibitors (TNFis) in Chinese moderate-to-severe psoriasis patients. Methods Patient health records of 110 moderate-to-severe psoriasis patients initiating or switching biologics were reviewed, with 31 patients receiving ustekinumab (ustekinumab group) and 79 patients receiving TNFis (TNFi group). Results Compared with TNFi group, psoriasis area and severity index (PASI)-75 response rate at month 6 (M6) were elevated (87.1% versus 65.8%, p = 0.026) in the ustekinumab group, whereas the rates at month 1 (M1) and month 3 (M3) and PASI-90 response rates at M1, M3, and M6 only showed an increasing trend (all p > 0.050) in the ustekinumab group than the TNFi group. By subgroup analyses, ustekinumab (versus TNFi) was more effective in patients with biologics therapy history than those without. Compared with the TNFi group, the ustekinumab group had lower dermatology life quality index scores and higher patient satisfaction scores at M3 and M6 (all p < 0.050). Conclusion Chinese moderate-to-severe psoriasis patients treated with ustekinumab have a better treatment response at 6 months with improved quality of life and patient satisfaction after 3–6 months of treatment when compared to TNFi.

Glucoraphanin and sulforaphane mitigate TNFα-induced Caco-2 monolayers permeabilization and inflammation

Intestinal permeabilization is central to the pathophysiology of chronic gut inflammation. This study investigated the efficacy of glucoraphanin (GR), prevalent in cruciferous vegetables, particularly broccoli, and its derivative sulforaphane (SF), in inhibiting tumor necrosis factor alpha (TNFα)-induced Caco-2 cell monolayers inflammation and permeabilization through the regulation of redox-sensitive events. TNFα binding to its receptor led to a rapid increase in oxidant production and subsequent elevation in the mRNA levels of NOX1, NOX4, and Duox2. GR and SF dose-dependently mitigated both these short- and long-term alterations in redox homeostasis. Downstream, GR and SF inhibited the activation of the redox-sensitive signaling cascades NF-κB (p65 and IKK) and MAPK ERK1/2, which contribute to inflammation and barrier permeabilization. GR (1 μM) and SF (0.5–1 μM) prevented TNFα-induced monolayer permeabilization and the associated reduction in the levels of the tight junction (TJ) proteins occludin and ZO-1. Both GR and SF also mitigated TNFα-induced increased mRNA levels of the myosin light chain kinase, which promotes TJ opening. Molecular docking suggests that although GR is mostly not absorbed, it could interact with extracellular and membrane sites in NOX1. Inhibition of NOX1 activity by GR would mitigate TNFα receptor downstream signaling and associated events. These findings support the concept that not only SF, but also GR, could exert systemic health benefits by protecting the intestinal barrier against inflammation-induced permeabilization, in part by regulating redox-sensitive pathways. GR has heretofore not been viewed as a biologically active molecule, but rather, the benign precursor of highly active SF. The consumption of GR and/or SF-rich vegetables or supplements in the diet may offer a means to mitigate the detrimental consequences of intestinal permeabilization, not only in disease states but also in conditions characterized by chronic inflammation of dietary and lifestyle origin.

Abstract 09: Leucine Rich Repeat Containing 8A Anion Channels Modulate Vascular Reactivity in ApoE Knockout Mice

Volume-regulated anion channels (VRACs) are comprised of Leucine Rich Repeat Containing 8 (LRRC8) family proteins which include LRRC8A, B, C, D and E. We have proposed that these channels may allow influx of extracellular superoxide to drive inflammation and modulate cultured vascular smooth muscle cell (VSMC) inflammation. We previously demonstrated that LRRC8A knockdown or inhibition inhibits tumor necrosis factor alpha (TNFα)-induced inflammation. Mesenteric arteries from male smooth muscle-specific LRRC8A knockout (KO) mice displayed enhanced responsiveness to both endothelium-dependent (acetylcholine, ACh), and independent (sodium nitroprusside, SNP) vasodilators compared to vessels from WT mice. KO vessels were also protected from vascular dysfunction induced by TNFα in tissue culture (48hr exposure). We hypothesized that reduced VSMC inflammation in LRRC8A KO mice would protect vascular function in ApoE knockout (ApoE -/- ). We created ApoE -/- mice lacking LRRC8A only in VSMCs and assessed vascular reactivity of isolated mesenteric arteries by wire myography in female and male WT, Heterozygous (HET) and KO tissues after 14 weeks of high fat diet. WT vessels displayed enhanced in contraction compared to LRRC8A KO or HET (male PE max contraction of KCL (%), WT 177 ± 4.6 vs. KO 152 ± 3.3 or HET 153 ± 3.0, p &lt; 0.05, n=6-7). Relaxation responses to ACh were increased in female KO or HET compared to WT (ACh LogEC 50 , WT -7.2 ± 0.09 vs. KO -7.5 ± 0.09 or HET -7.4 ± 0.07, p &lt; 0.05, n=5-6). SNP-mediated relaxation were increased in male KO vessels compared to WT (SNP LogEC 50 , WT -8.1 ± 0.06 vs. KO -8.3 ± 0.06, p &lt; 0.05, n=7). These results demonstrate that loss (KO) or reduction (HET) of LRRC8A expression preserves vascular function in the face of the inflammatory response induced by hypercholesterolemia in ApoE -/- mice. These channels may represent a novel therapeutic target for preservation of vascular function and this may only require partial inhibition of current.

Cancer and hidradenitis suppurativa

Patients with hidradenitis suppurativa (HS) have an increased risk of developing cancer. This includes not only hematologic malignancies and solid tumors but also cutaneous squamous cell carcinoma (SCC) originating within the HS lesions. The development of SCC is most commonly associated with Caucasian men who smoke and have severe gluteal or perianal lesions of more than 25 years. Other factors that have occasionally been associated with HS-related SCC include treatment with a tumor necrosis factor-alpha inhibitor (such as infliximab and adalimumab), genodermatoses (such as keratitis-ichthyosis-deafness syndrome and Dowling-Degos disease), and paraneoplastic syndromes (such as hypercalcemia, hypercalcemia-leukocytosis, and paraneoplastic neuropathy). The tumor may demonstrate the presence of human papillomavirus; even after treatment, patients have a poor prognosis because cancer metastasis, recurrence, or both commonly occur. The potential role of human papillomavirus vaccination for cancer prevention and early treatment of SCC with targeted therapy (with an epidermal growth factor inhibitor such as cetuximab) and/or checkpoint inhibitor immunotherapy (such as cemiplimab and pembrolizumab) remains to be determined. Rarely, HS lesions have mimicked cutaneous metastases in patients with visceral malignancy by demonstrating an increased uptake of fluorine-18 fluorodeoxyglucose on positron emission tomography and/or computed tomography scans. Primary cancers (such as cutaneous SCC and mucinous adenocarcinoma) and breast cancer skin metastases can masquerade as HS lesions. When a lesion is located at a current or earlier site of HS that is new or rapidly growing and/or does not respond to HS-directed therapy, prompt evaluation to establish or exclude the diagnosis of cancer should be considered.