Tumor Necrosis Factor Alpha Inhibitors Research Articles

Coupled Neural–Glial Dynamics and the Role of Astrocytes in Alzheimer’s Disease

Neurodegenerative diseases such as Alzheimer’s (AD) are associated with the propagation and aggregation of toxic proteins. In the case of AD, it was Alzheimer himself who showed the importance of both amyloid beta (Aβ) plaques and tau protein neurofibrillary tangles (NFTs) in what he called the “disease of forgetfulness”. The amyloid beta forms extracellular aggregates and plaques, whereas tau proteins are intracellular proteins that stabilize axons by cross-linking microtubules that can form largely messy tangles. On the other hand, astrocytes and microglial cells constantly clear these plaques and NFTs from the brain. Astrocytes transport nutrients from the blood to neurons. Activated astrocytes produce monocyte chemoattractant protein-1 (MCP-1), which attracts anti-inflammatory macrophages and clears Aβ. At the same time, the microglia cells are poorly phagocytic for Aβ compared to proinflammatory and anti-inflammatory macrophages. In addition to such distinctive neuropathological features of AD as amyloid beta and tau proteins, neuroinflammation has to be brought into the picture as well. Taking advantage of a coupled mathematical modelling framework, we formulate a network model, accounting for the coupling between neurons and astroglia and integrating all three main neuropathological features with the brain connectome data. We provide details on the coupled dynamics involving cytokines, astrocytes, and microglia. Further, we apply the tumour necrosis factor alpha (TNF-α) inhibitor and anti-Aβ drug and analyze their influence on the brain cells, suggesting conditions under which the drug can prevent cell damage. The important role of astrocytes and TNF-α inhibitors in AD pathophysiology is emphasized, along with potentially promising pathways for developing new AD therapies.

Efficacy of targeted drugs for the treatment of adults with moderate-to-severe plaque psoriasis in the Russian Federation: a systematic literature review update

Background. A systematic literature review helps to identify the main treatment options, and evidence synthesis supports decision-making by comparing clinical efficacy of different treatments. Nowadays new drugs and clinical trials emerge rapidly, so previous network meta-analyses might need to be updated.Objective: to update the existing systematic review and network meta-analysis comparing efficacy of targeted drugs in adult patients with moderate-to-severe plaque psoriasis by adding randomized clinical trials (RCTs) on a new interleukin (IL) 23 inhibitor registered in the Russian Federation – risankizumab, and other RCTs published after 2019; to reassess the Psoriasis Area and Severity Index (PASI) 75/90 numbers of patients needed to treat to achieve clinical response to therapy and the costs per responder for 12–16 weeks and 1 year of therapy.Material and methods. We updated our systematic literature search in the PubMed/MEDLINE and Embase databases. Evidence synthesis included RCTs evaluating the efficacy of adalimumab (ADA), infliximab (INF), etanercept (ETN), certolizumab pegol (CZP), ixekizumab (IXE), netakimab (NTK), secukinumab (SEC), risankizumab (RIS), guselkumab (GUS), ustekinumab (UST), tofacitinib (TOFA), and apremilast (APR) after 12 weeks of therapy. The Bayesian meta-analyses with meta-regression models were performed in order to account for high heterogeneity in patient characteristics and significant differences in the placebo response rates. The considered drugs were ranked based on values of surface under the cumulative ranking curve (SUCRA). Additionally, drug class analyses were carried out.Results. Twenty three new RCTs were added to the network. IL-23 inhibitor RIS, recently approved in the Russian Federation, has joined the group of the most efficacious drugs, such as IL-17 inhibitors NTK and IXE, as well as IL-23 inhibitor GUS. In terms of PASI 75, RIS and IXE showed superiority compared to all tumor necrosis factor alpha (TNFα) inhibitors (INF, ADA, ETN), small molecules (TOFA and APR), and IL-12/23 inhibitor UST, while NTK and GUS were characterized by comparable efficacy with INF and outperformed the remaining drugs. There were no statistically significant differences in efficacy between all the TNFα inhibitors. GUS, IXE, INF, NTK, RIS and SEC demonstrated that no more than 2 patients need to be treated to achieve one PASI 75 response, and no more than 3 need to be treated for one PASI 90 response (according to the upper limit of 95% credible interval). Same as in the previously published study, NTK showed the lowest costs per responder for both 12-week and 1-year periods.Conclusion. The addition of head-to-head trials and increased statistical power of the network revealed previously unidentified significant differences between treatment options for moderate-to-severe plaque psoriasis.

Invasive squamous cell carcinoma arising from long‐lasting enterocutaneous fistula due to Crohn's disease

Chronic inflammation led to squamous cell carcinoma. We experienced squamous cell carcinoma from Crohn’s disease. A 53-year-old woman with Crohn's disease (CD) diagnosed more than 30 years earlier was referred to us because of a 4 month history of abdominal tumors. She underwent a total colectomy, small intestinal resection, and an eternal enterostomy 24 years earlier and had two enterocutaneous fistulous tracts with repeated inflammation on the lower-right side of her abdomen for 13 years. She had been treated with 5-aminosalicylic acid for more than 15 years, but did not receive immunosuppressants or tumor necrosis factor alpha inhibitors. Physical examination revealed a 6 × 3.5 cm reddish ulcerative tumor on the lower-right side of her abdomen surrounded by brownish pigmentation with indurations (Figure 1A). Histopathological examination of the tumor revealed atypical squamous cell proliferation with marked keratinization (Figure 1B,C). Histological continuity between the epidermis and atypical cells was not observed, and immunostaining of the cells was negative for human papillomavirus. Computed tomography and positron emission tomography/computed tomography demonstrated a large mass involving the abdominal walls and enlargement of the inguinal and right external iliac lymph nodes (Figure 1D). Her serum squamous cell carcinoma (SCC) antigen level was also elevated (5.4 ng/ml; normal range, <2.5 ng/ml). The patients were then diagnosed with SCC arising from an enterocutaneous fistula (ECF) related to CD. She was treated with radiation therapy (30 Gy) for a skin tumor and bilateral inguinal lymph nodes, followed by chemotherapy with pepleomycin. Unfortunately, her disease slowly progressed and she died 5 months after her initial visit. Crohn's disease is a chronic inflammatory bowel disorder characterized by transmural inflammation and fistula formation.1 Perianal fistulas are common complications of the disease, and patients with anal and/or perianal CD have a high risk of perianal fistula-related cancer.2 Fistula-related carcinoma develops in approximately 1% of patients with fistulizing perianal CD. More than half of these carcinomas are adenocarcinoma; most of the rest are SCC. Compared with perianal fistulas, ECF is rare, but it is associated with significant morbidity and mortality due to various complications.3 Late complications, such as late onset of malignancy, have been given little attention in the literature, with a limited number of patients with cancers arising from ECF and only one fistula-associated SCC patient, who was treated with long-lasting azathioprine followed by infliximab, being reported.4 The causes of malignancies arising from chronic fistulas are unclear, but chronic inflammation and immunosuppression are considered mechanisms of carcinogenesis in CD patients. Chronic inflammation, a feature of CD, induces constant epithelial regeneration, ulceration, and high cell turnover rates, leading to dysplasia and subsequently carcinoma. Our patient was not treated with immunosuppressants or biologics; however, so it is likely that her chronic inflammation led to carcinogenesis. The onset of malignancies arising from ECF in CD patients may increase in future because of the expanding use of immunosuppressants and/or biologics and improvements in the treatment of acute complications of ECF. Therefore, diagnosticians should be alert to early signs of fistula-associated malignancies. The authors declare no conflict of interest. Approval of the research protocol: N/A. Informed Consent: The written informed consent was obtained from the patient. Registry and the Registration No. of the study/trial: N/A. Animal Studies: N/A.

Cellular and Humoral Immune Responses to SARS-CoV-2 Vaccination in Inflammatory Bowel Disease Patients.

Background and AimsKnowledge on the immunogenicity of anti-SARS-CoV-2 vaccines in inflammatory bowel disease (IBD) patients is limited. Therefore, SARS-CoV-2-specific T-cell response and antibodies were analyzed in 60 IBD vaccine recipients and 30 controls.MethodsSARS-CoV-2 IgG antibodies against the viral spike protein were measured at baseline and at 8 and 26 weeks after the second vaccine dose. SARS-CoV-2 IgG antibodies against the nucleocapsid antigens were measured at week 26. SARS-CoV-2 interferon-gamma released assay (IGRA) was performed in all vaccinees at week 26.ResultsAt weeks 0 and 8, no differences were found in anti-spike antibodies between cohorts. At week 26, the decrease in antibody levels was more significant in the IBD cohort compared to the healthy cohort, and anti-nucleocapsid antibodies were not detected in either group. At week 26, 16 of 90 (18 %) vaccinated individuals had a negative IGRA test result, 7 of 90 (8 %) were borderline, and 67 (74 %) had a positive IGRA result; 22 of the 23 individuals with negative or borderline IGRA results belonged to the IBD cohort. However,the overall functional ability of T-lymphocytes to produce interferon-gamma after the unspecific mitogen stimulation was lower in IBD patients. In vaccinees with low or borderline IGRA, treatment with TNF-alpha inhibitors was the most frequent. In individuals with a significant drop in anti-spike antibody levels, plasmatic interferon-gamma concentrations after the specific SARS-CoV-2 stimulation were also insufficient.ConclusionsSimple humoral and cellular post-vaccination monitoring is advisable in IBD patients so that repeated vaccine doses may be scheduled.

Structural Insights from Molecular Modeling of Isoindolin-1-One Derivatives as PI3Kγ Inhibitors against Gastric Carcinoma.

The upregulation of phosphoinositol-3-kinase γ (PI3Kγ) is deemed to be positively correlated with tumor-associated-macrophage (TAM)-mediated gastric carcinoma (GC). PI3Kγ suppresses tumor necrosis factor-alpha (TNF-α) and interleukin-12 (IL-12) through activation of the AKT/mTOR pathway, which promotes the immunosuppressant phenotype of TAM. Unlike α and β isoforms, δ and γ isoforms are primarily distributed in leucocytes and macrophages. Dual inhibitors against PI3Kδ and PI3Kγ have been proven to have merits in targeting solid tumors. Furthermore, it has been found that PI3Kδ is activated by cytokines, while PI3Kγ is activated by G-protein-coupled receptors (GPCRs). This facilitates determining the functional difference between these two isoforms. For this goal, selective inhibitors would be immensely helpful. In the current manuscript, we conducted various molecular modeling studies with a series of isoindolin-1-one derivatives as potent PI3Kγ inhibitors by combining molecular docking, molecular dynamics (MD), molecular mechanics, Poisson–Boltzmann/generalized Born surface area (MM-PB/GBSA) binding free energy calculation, and three-dimensional structure–activity relationship (3D-QSAR) study. To evaluate the selectivity of γ isoform over δ, the molecular modeling studies of idelalisib analogs reported as PI3Kδ inhibitors were also investigated. The contour polyhedrons were generated from the comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) around the ligand-bound active site for both isoforms, which could emphasize plausible explanations for the physicochemical factors that affect selective ligand recognition. The binding modalities of the two isoforms using CoMFA and MD models were compared, which suggested some key differences in the molecular interactions with the ligands and could be summarized as three subsites (one affinity subsite near the C-helix and DFG and two hydrophobic subsites). In the context of the structure–activity relationship (SAR), several new compounds were designed using a fragment-substitution strategy with the aim of selectively targeting PI3Kγ. The pIC50 values of the designed compounds were predicted by the 3D-QSAR models, followed by the MM-PB/GBSA binding energy estimation. The overall findings suggest that the designed compounds have the potential to be used as PI3Kγ inhibitors with a higher binding affinity and selectivity.

Demyelinating events following anti-tumor necrosis factor alpha therapy: Rare but challenging to treat.

Demyelinating events are listed as adverse events with tumor necrosis factor alpha inhibitors (TNFi), but epidemiological studies have provided partly conflicting risk estimates. Furthermore, studies examining long-term outcomes of demyelinating events associated with TNFi are rare. This was a retrospective, observational study comprising validation and tracking of long-term outcomes in patients referred to a tertiary neurology referral center for suspected neurological complications associated with TNFi. Of 48 patients evaluated, only 14 showed signs of demyelinating disease on magnetic resonance imaging, where six fulfilled criteria for a clinically isolated syndrome (CIS) and eight were diagnosed with multiple sclerosis (MS). However, 13 patients had received an International Classification of Diseases code for MS at some stage. Mean follow-up from referral was 13 and 10.5years among subjects with MS and CIS, respectively. Continued disease activity was recorded among several of those fulfilling MS criteria, and two ultimately underwent autologous hematopoietic stem cell transplantation. In contrast, subjects with CIS showed no progression after cessation of TNFi. Our findings suggest that only a minority of those with suspected demyelinating disease following TNFi fulfill diagnostic criteria for MS and that MS diagnoses among those not fulfilling MS criteria may contribute to inflated epidemiological risk estimates. Nevertheless, in those fulfilling MS criteria, initiation of disease-modulating therapy, with escalation as needed, was important to suppress further disease activity.

Systemic interventions for treatment of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome.

Systemic interventions for treatment of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome.

Cost-Effectiveness of Tight Control for Crohn's Disease With Adalimumab-Based Treatment: Economic Evaluation of the CALM Trial From a Canadian Perspective.

Crohn’s disease (CD) is associated with reduced quality of life, increased absenteeism and high direct medical costs resulting from frequent hospitalizations and surgeries. Tumor necrosis factor–alpha inhibitors (TNFi’s) have transformed the therapeutic landscape and enabled a shift from a symptom control to a treat-to-target strategy. The Effect of Tight Control Management on Crohn’s Disease (CALM) trial demonstrated tight control (TC), with TNFi dose changes informed by biochemical markers of inflammation, achieved higher mucosal healing rates compared with conventional management (CM) based on symptoms. A Markov model compared TC and CM strategies from the perspective of the Canadian public payer using patient-observation data from the CALM trial. A regression model estimated weekly CD Activity Index–based transition matrices over a 5-year horizon and included covariates to improve extrapolation of outcomes beyond the 48-week trial assessment period. Costs of CD-related hospitalizations, biomarker tests and adalimumab injections were sourced from public data. Other direct medical costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. Absenteeism was monetized and included in a sensitivity analysis. Over the 5-year time horizon, TC reduced hospitalization costs by 64% compared with CM. Other direct medical costs were reduced by 22%; adalimumab costs increased by 38%, generating an ICER of $35,168 per QALY gained. Absenteeism costs were reduced by 54%, and, when that was included in the model, TC became dominant compared with CM. Management of CD with TC is cost-effective compared with CM in Canada and is dominant if indirect costs associated with absenteeism are included. Trial registration number: NCT01235689.

Effect of tumor necrosis factor alpha inhibition with etanercept on renal functions in L-NAME induced hypertensive rats: insights into the possible mechanisms

Effect of tumor necrosis factor alpha inhibition with etanercept on renal functions in L-NAME induced hypertensive rats: insights into the possible mechanisms

Adalimumab for the Treatment of Pediatric Populations With Non-Infectious Uveitis

&#x0D; Two systematic reviews, 1 economic evaluation, and 2 evidence-based guidelines were identified regarding the clinical effectiveness (including safety), cost-effectiveness, and use of adalimumab in pediatric populations with non-infectious uveitis.&#x0D; Pooled data of the SYCAMORE and ADJUVITE randomized controlled trials comparing adalimumab to placebo demonstrated that adalimumab significantly increased the likelihood of reducing or interrupting corticosteroid use (which is beneficial as long-term corticosteroid use can result in cataracts and glaucoma). Adalimumab significantly increased the event of a satisfactory response rate, but there was no difference in safety assessed as systemic adverse events and local adverse effects.&#x0D; Specific to the ADJUVITE trial, visual acuity slightly worsened before and after treatment with adalimumab and it was unclear if adalimumab increased control of intraocular inflammation.&#x0D; Specific to the SYCAMORE trial, adalimumab significantly lowered the risk of treatment failure and the rate and number of adverse events and serious adverse events were higher in the adalimumab group compared to the placebo group. For the adalimumab group, the most common adverse event type was infections and infestations and the most common serious adverse events were glaucoma, cataracts, injection site reactions, arthritis, and arthralgia.&#x0D; In the perspective of the health care system in the UK, adalimumab plus methotrexate was not found to be cost-effective compared to methotrexate alone (modelled by placebo data) in uveitis associated with juvenile idiopathic arthritis.&#x0D; Cost-effectiveness analyses of adalimumab at a discounted price lowered the incremental cost-effectiveness ratio, which supports the potential use of biosimilars in the future due to cost savings.&#x0D; Both guidelines recommended the use of treatment that blocks proteins that cause inflammation (tumour necrosis factor-alpha inhibitors) such as adalimumab in combination with an immunosuppressive agent such as methotrexate (i.e., adalimumab plus methotrexate) in patients with uveitis associated with juvenile idiopathic arthritis who are not responsive to initial treatment (e.g., topical corticosteroids) and are at risk for severe uveitis or vision threatening complications.&#x0D; The American College of Rheumatology/ Arthritis Foundation recommended the use of adalimumab and infliximab over etanercept with no preference between adalimumab and infliximab. Conversely, the guideline from multiple interdisciplinary German groups recommended that adalimumab and infliximab are the first- and second-choice tumour necrosis factor-alpha inhibiting drugs, respectively. They recommended a treatment switch to infliximab then golimumab when adalimumab is not effective or there is treatment failure with adalimumab.&#x0D;

Pulmonalis adenocarcinomaval társult dermatomyositis adalimumab terápiában részesülő beteg esetében – esetbemutatás

A 63-year-old woman is presented who was hospitalized with generalized skin lesions and progressive proximal muscle weakness. In her medical history there was a long term adalimumab treatment of psoriatic arthritis. Laboratory results presented high creatin kinase, lactate dehydrogenase and liver enzymes. Chest-, abdomen and pelvis CT scan showed a mass in the right lung and in the mediastinum. Histology verified adenocarcinoma of the lung. As clinical findings, laboratory results and medical imaging results confirmed tumor associated dermatomyositis, parenteral steroid and methotrexate medication was initiated. Further examniation and treatment were performed on pulmonology department. In the cases of dermatomyositis tumor search is crucial. Chronic inflammation is related to carcinogenesis. The relationship between tumor necrosis factor alpha inhibitor treatment and cancer risk is not clear, however patients with active or prior cancer, or those with high risk for developing cancer should be treated with special attention.

Occlusive retinal vasculitis: novel insights into causes, pathogenesis and treatment.

Occlusive retinal vasculitis (ORV) has a large differential diagnosis and varied therapeutic approaches. This review highlights existing and novel causes and treatment options for ORV. Mutations in CAPN5, TREX1, and TNFAIP3 have been associated with dominantly inherited forms of ORV. Various intraocular therapeutics have been shown to occasionally cause ORV; the most recent medications associated with ORV are vancomycin and brolucizumab. In cases of ORV linked to Behçet's disease, clinical trials support the use of tumor necrosis factor alpha inhibitors. Identification of the underlying etiology of ORV is critical to help guide treatment. Treatment in ORV involves both treatment any underlying infection or autoimmune condition, cessation of the any offending causative agent and local treatment of neovascular complications.

Gosha-jinki-Gan (GJG) shows anti-aging effects through suppression of TNF-α production by Chikusetsusaponin V.

Frailty develops due to multiple factors, such as sarcopenia, chronic pain, and dementia. Go-sha-jinki-Gan (GJG) is a traditional Japanese herbal medicine used for age-related symptoms. We have reported that GJG improved sarcopenia, chronic pain, and central nervous system function through suppression of tumor necrosis factor-alpha (TNF-α) production. In the present study, GJG was found to reduce the production of TNF-α in the soleus muscle of senescence-accelerated mice at 12weeks and 36weeks. GJG did not change the differentiation of C2C12 cells with 2% horse serum. GJG significantly decreased the expression of Muscle atrophy F-box protein (MAFbx) induced by TNF-α in C2C12 cells on real-time PCR. TNF-α significantly decreased the expression of PGC-1α and negated the enhancing effect of GJG for the expression of PGC-1α on digital PCR. Examining 20 chemical compounds derived from GJG, cinnamaldehyde from cinnamon bark and Chikusetsusaponin V (CsV) from Achyrantes Root dose-dependently decreased the production of TNF-⍺ in RAW264.7 cells stimulated by LPS. CsV inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB) p65 in RAW264.7 cells. CsV showed low permeability using Caco-2 cells. However, the plasma concentration of CsV was detected from 30min to 6h and peaked at 1h in the CD1 (ICR) mice after a single dose of GJG. In 8-week-old SAMP8 mice fed 4% (w/w) GJG from one week to four weeks, the plasma CsV concentration ranged from 0.0500 to 10.0ng/mL. The evidence that CsV plays an important role in various anti-aging effects of GJG via suppression of TNF-⍺ expression is presented.

Impact of Physical Activity Intensity Levels on the Cardiometabolic Risk Status of Children: The Genobox Study.

Childhood obesity has been related to metabolic syndrome and low-grade chronic inflammation. This study aimed to evaluate the impact of physical activity intensities and practice on inflammation, endothelial damage, and cardiometabolic risk factors in children. There were 513 participants, aged 6-14years, recruited for the study. Physical activity was measured by accelerometry, and the children were classified into four groups according to quartiles of moderate to vigorous physical activity (MVPA) practice as very low active, low active, moderate active, and high active. Anthropometric measures, blood pressure, and plasma metabolic and proinflammatory parameters were analyzed. Very low active group presented a worse lipid profile and higher insulin, leptin, adiponectin, resistin, matrix metallopeptidase-9, and tissue plasminogen activator inhibitor-1, while lower levels of tumor necrosis factor-alpha, Type 1 macrophages, and interleukin 8 than high-active children. Regression analyses showed that a higher MVPA practice was associated with lower levels of triacylglycerols (β: -0.118; p = .008), resistin (β: -0.151; p = .005), tPAI (β: -0.105; p = .046), and P-selectin (β: -0.160; p = .006), independently of sex, age, and body mass index (BMI). In contrast, a higher BMI was associated with higher levels of insulin (β: 0.370; p < .001), Homeostasis Model Assessment (β: 0.352; p < .001), triacylglycerols (β: 0.209; p < .001), leptin (β: 0.654; p < .001), tumor necrosis factor-alpha (β: 0.182; p < .001), Type 1macrophages (β: 0.181; p < .001), and tissue plasminogen activator inhibitor (β: 0.240; p < .001), independently of sex, age, and MVPA. A better anthropometric, metabolic, and inflammatory profile was detected in the most active children; however, these differences were partly due to BMI. These results suggest that a higher MVPA practice and a lower BMI in children may lead to a better cardiometabolic status.

Treatment Failure in Axial Spondyloarthritis: Insights for a Standardized Definition.

Axial spondyloarthritis is a chronic inflammatory rheumatic disease that affects the axial skeleton and causes severe pain and disability. It may be also associated with extra-articular manifestations. Early diagnosis and appropriate treatment can reduce the severity of the disease and the risk of progression. The biological disease-modifying antirheumatic drugs (bDMARDs) tumor necrosis factor alpha (TNFα) inhibitors (TNFi) and the anti-interleukin (IL)-17A antibodies secukinumab and ixekizumab are effective agents to reduce disease activity and minimize the inflammation that damages the joints. New alternatives such as Janus kinase (JAK) inhibitors are also available. Unfortunately, response rates to bDMARDs are far from optimal, and many patients experience so-called treatment failure. The definition of treatment failure definition is often vague and may depend on the rigorousness of the therapeutic goal, the inclusion or not of peripheral symptoms/extra-articular manifestations, or patients’ overall health. After an exhaustive bibliographic review, we propose a definition based on loss of the following status: low disease activity assessed by Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP, absence of extra-articular manifestations, and low disease impact on the patients’ general health. Apart from discontinuing the therapy because of safety or intolerance reasons, two types of treatment failure can be differentiated depending on when it occurs: primary failure (no response within 6 months after treatment initiation, or lack of efficacy) and secondary failure (response within 6 months but lost thereafter, or loss of efficacy over time). Physicians should carefully consider the moment and the reason for the treatment failure to decide the next therapeutic step. In the case of primary failure on a first TNFi, it seems reasonable to switch to another class of drugs, i.e., an anti-IL-17 agent, as phase III trials showed that the response to IL-17 blockade was higher than to placebo in patients previously exposed to TNFi. When secondary failure occurs, and loss of efficacy is suspected to be caused by antidrug antibodies (ADAs), it is advisable to analyze serum TNFi and ADAs concentrations, if possible; in the presence of ADAs and low TNFi levels, changing the TNFi is rational as it may restore the TNFα blocking capacity. If ADAs are absent/low with adequate drug therapeutic levels, switching to another target might be the best strategy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02064-x.

Antagonistic Antibody Targeting TNFR2 Inhibits Regulatory T Cell Function to Promote Anti-Tumor Activity.

Infiltration of regulatory T cells (Tregs) in the tumor microenvironment suppresses anti-tumor immune response, and promotes tumor progression. Tumor necrosis factor receptor‐2 (TNFR2), which is highly expressed on Tregs, activates Tregs through nuclear factor kappa B (NF-κB) pathway. Moreover, TNFR2+ Tregs have been shown to be most suppressive among all Tregs populations in tumor. Due to the unique expression pattern and function of TNFR2 on Tregs, a TNFR2 blocking antibody is expected to compromise Tregs function, relieve Tregs-mediated immunosuppression, and hence to enhance anti-tumor immune response. AN3025 is an antagonistic anti-human TNFR2 (hTNFR2) antibody that is currently under preclinical development. This study investigates the immunomodulatory and anti-tumor activity of AN3025. AN3025 was generated through rabbit immunization with extracellular domain of human TNFR2 and subsequent humanization by complementarity-determining regions (CDRs) grafting. AN3025 binds to the extracellular domain of both human and cynomolgus with sub-nanomolar affinity and specificity, but not mouse or rat TNFR2. AN3025 inhibited tumor necrosis factor alpha (TNFα) induced cell death of hTNFR2-overexpressing Jurkat cells by competing with TNFα for binding to hTNFR2. In the Tregs/T effector co-culture assay, AN3025 increased T effector proliferation and enhanced interferon gamma (IFNγ) production. As a monotherapy, AN3025 significantly inhibited MC38 tumor growth in TNFR2 humanized mouse model. Subsequent flow cytometry (FACS) and immunohistochemistry (IHC) analysis revealed that administration of AN3025 led to decreased Tregs population, increased CD4+ and CD8+ T cell numbers in the tumor. The anti-tumor activity of AN3025 was dependent on the existence of CD4+ and CD8+ T cells, as depletion of CD4+ and CD8+ T cells abolished the anti-tumor activity of AN3025. In addition, AN3025 in combination with anti-PD-1 antibody demonstrated stronger in-vivo anti-tumor activity. The potent anti-tumor efficacy of AN3025, either as a monotherapy or in combination with anti-PD-1 antibody, supports its further clinical development for the treatment of various human tumors.

Etanercept Prevents Endothelial Dysfunction in Cafeteria Diet-Fed Rats.

: BackgroundObesity is associated with endothelial dysfunction and this relationship is probably mediated in part by inflammation. Objective: The current study evaluated the effects of etanercept, a tumor necrosis factor-alpha (TNF-α) inhibitor, on endothelial and vascular reactivity, endothelial nitric oxide synthase (eNOS) immunoreactivity, and serum and aortic concentrations of TNF-α in a diet-induced rat model. Design and results: Male weanling Wistar rats were exposed to a standard diet and cafeteria diet (CD) for 12 weeks and etanercept was administered during CD treatment. Isolated aortas of the rats were used for isometric tension recording. Carbachol-induced relaxant responses were impaired in CD-fed rats, while etanercept treatment improved these endothelium-dependent relaxations. No significant change was observed in papaverine- and sodium nitroprusside (SNP)-induced relaxant responses. eNOS expression decreased in CD-fed rats, but no change was observed between etanercept-treated CD-fed rats and control rats. CD significantly increased both the serum and the aortic levels of TNF-α, while etanercept treatment suppressed these elevated levels. CD resulted in a significant increase in the body weight of the rats. Etanercept-treated (ETA) CD-fed rats gained less weight than both CD-fed and control rats.

Global Risk of Bacterial Skin Infections and Herpesviridae Infections with Ustekinumab, Secukinumab, and Tumour Necrosis Factor-alpha Inhibitors: Spontaneous Reports of Adverse Drug Reactions from the World Health Organization Pharmacovigilance Center.

Genetic defects in interleukin-12/23/17 immunity are associated with an increased risk of Staphylococcus aureus and herpesvirus skin infections. This study analysed spontaneous safety reports from the WHO Pharmacovigilance Center of bacterial skin or herpesvirus infections associated with secukinumab, ustekinumab and tumour necrosis factor-α inhibitors. Associations found in disproportionality analyses were expressed as reporting odds ratios (ROR). For bacterial skin infections, ustekinumab showed the strongest association (ROR 6.09; 95% confidence interval (95% CI) 5.44–6.81), and, among the tumour necrosis factor-α inhibitors, infliximab showed the strongest association (ROR 4.18; 95% CI 3.97–4.40). Risk was comparable between infliximab and secukinumab (ROR 3.51; 95% CI 3.00–4.09). Secukinumab showed the strongest association with herpes simplex infection (ROR 4.80; 95% CI 3.78–6.10). All biologics were equally associated with herpes zoster. Infliximab was the only biologic associated with cytomegalovirus infection (ROR 5.66; 95% CI 5.08–6.31) and had the strongest association with Epstein-Barr virus infection (ROR 6.90; 95% CI 6.03–7.90). All biologics evaluated were positively associated with bacterial skin infections, herpes simplex, and herpes zoster, compared with all other drugs in the WHO database for which individual case safety reports were collected. The possibility of under-reporting, reporting bias and difference in causality assessment between countries and reporters must be taken into account when interpreting the results of disproportionality analyses.

Childhood-onset Takayasu arteritis.

Takayasu arteritis is a rare chronic granulomatous large vessel vasculitis that predominantly affects the aorta and its branches. The purpose of this review is to unite the current knowledge regarding the pathophysiology, cause, and epidemiology as well as diagnosis, prognosis, and treatment of this condition in children. Although the etiopathogenesis is not fully understood, studies suggest an autoimmune basis for the disease as well as a genetic predisposition. It is a disease primarily affecting young women with up to a third of cases with onset in childhood. There are distinct features of childhood-onset Takayasu arteritis (cTA) that merit this separate review. Diagnostic criteria and clinical manifestations are unique in pediatric patients with renovascular hypertension being the most prevalent presentation. Traditional treatments involving high-dose corticosteroids and cytotoxic agents are being reconsidered for less toxic contemporary biologic agents. Current algorithms for treatment include early introduction of corticosteroid-sparing agents, such as methotrexate or mycophenolate as well as tumor necrosis factor-alpha (TNF-α) inhibitor (infliximab, adalimumab) and/or interleukin-6 (IL-6) receptor inhibitor (tocilizumab). Early diagnosis of cTA with goals to develop effective and well tolerated treatment paradigms are essential to improve the long-term prognosis of this rare and devastating disease.

Current Knowledge of Biologics in Treatment of Noninfectious Uveitis.

The arena of uveitis deals with a number of entities, which can be infectious or immune mediated. Noninfectious uveitis (NIU) has been managed with corticosteroids and immunosuppressives. However, their prolonged use has side effects limiting clinical utility in the long run. Improved knowledge regarding pathogenesis of uveitis and associated systemic disease has led to a new epoch in the development of treatment strategies, of which biologics are the recent ones. Biologics revolutionized the management of NIU especially uveitis associated with spondyloarthropathy and refractory uveitis. They target inflammation at a molecular level with less side effects. The most widely used are tumor necrosis factor-alpha inhibitors (infliximab and adalimumab). Other drugs include anti-CD20 inhibitors (rituximab), interleukin-6R-inhibitor (tocilizumab), Interleukin-1R-inhibitor (anakinra), Iinterleukin-2-inhibitor (daclizumab), and the list is further increasing. New advances in biologics are the biosimilar molecules, which are biological products that are highly similar to the reference product, and they include Infimab (biosimilar of infliximab), Exemptia or Adfrar (biosimilar of adalimumab), and Intacept or Etacept (biosimilar of etanercept). Other group of biologics are Janus Associated Kinase inhibitors (JAK-inhibitors), which are long-term oral treatment options of rheumatoid arthritis. They inhibit JAKs, which cause activation of signal transducer and activator of transcription (STAT) proteins, and initiate transcription of inflammatory genes. Many inflammatory cytokines that are implicated in pathogenesis of ocular inflammation are known to utilize the JAK/STAT-signaling pathway, including interleukin-2 (IL-2) and IL-6. Thus, biologics are the future of uveitis treatment with promising results. This article aims to summarize the current knowledge on biologics and their clinical utility in the management of NIU.