Use Of TNF-α Inhibitors Research Articles

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.

Quantification of longitudinal patient-reported burden of adverse drug reactions attributed to the use of TNF-α inhibitors in inflammatory rheumatic diseases: an observational prospective cohort study

ABSTRACT Background There is a lack of knowledge on patient perspectives on adverse drug reactions (ADRs) attributed to the use of biologics. The aim of this study is to quantify the burden over time of ADRs attributed to TNF-α inhibitors in patients with inflammatory rheumatic diseases (IRDs) and investigate whether the burden over time differs between different types of ADRs. Research design and methods Data were used from the Dutch Biologic Monitor (DBM), an observational prospective cohort study for patient-reported ADRs attributed to biologics. Patients with an IRD using a TNF-α inhibitor reporting an ADR, lasting for three consecutive questionnaires, were included. Questionnaires were sent every 2 months and the burden was scored on a 5-point Likert-type scale. Burden scores were analyzed using linear mixed models. Results Data from 166 unique patients reporting 274 ADRs were included. The burden score decreased every month by 0.29 points (95% CI −0.34 – −0.24) on average on a 5-point Likert-type scale. The burden score for infections and infestations decreased significantly faster than the burden score for injection site reactions. Conclusions Patient-reported burden of ADRs attributed to the use of a TNF-α inhibitor in patients with IRDs decreased significantly over time, especially for infections and infestations.

TNF-α inhibitor use during pregnancy and the risk of preeclampsia: population-based cohort study.

Although the clinical importance of preeclampsia is widely recognized, few treatment options are available for prevention. TNF-α inhibitors have been hypothesized to potentially prevent the disease. We aimed to examine whether exposure to TNF-α inhibitors during pregnancy reduces the risk of preeclampsia. We conducted a population-based pregnancy cohort study using nationwide samples of publicly (Medicaid data, 2000-2018) and commercially (MarketScan Research Database, 2003-2020) insured pregnant women linked to their liveborn infants. Exposure was ascertained based on a filled prescription or administration code for TNF-α inhibitors during the first and second trimester of pregnancy. The outcomes included early-onset preeclampsia, late-onset preeclampsia, and small-for-gestational age. For baseline confounding adjustment, we leveraged propensity score overlap weights to estimate risk ratios (RR). Among 4 315 658 pregnancies in the Medicaid and the MarketScan cohort, 2736 (0.063%) were exposed to TNF-α inhibitors during the first trimester and 1712 (0.040%) during the second trimester. After adjustment, the risk of early-onset preeclampsia was not decreased among mothers exposed during the first trimester compared with unexposed women with treatment indications [RR pooled : 1.25, 95% confidence interval (CI) 0.93-1.67]. Similarly, the risk of late-onset preeclampsia was not decreased among mothers exposed during the second trimester compared with unexposed women (RR pooled : 0.99, 95% CI 0.81-1.22). Contrary to the hypothesis, exposure to TNF-α inhibitors during pregnancy did not appear to be associated with a reduced risk of early-onset or late-onset preeclampsia. These findings do not support consideration of the use of TNF-α inhibitors for the prevention of preeclampsia.

TNF-α-positive patients with recurrent pregnancy loss: The etiology and management.

Elevated levels of tumor necrosis factor-alpha (TNF-α) have been associated with adverse pregnancy outcomes, specifically recurrent pregnancy loss (RPL). These elevated levels may be associated with the presence of autoantibodies. Although TNF-α inhibitors have shown promise in improving pregnancy rates, further research is needed to comprehend their impact and mechanisms in RPL patients. This study aims to investigate the association between elevated TNF-α levels and autoantibodies in RPL patients, as well as evaluate the effect of TNF-α inhibition on pregnancy outcomes. A total of 249 RPL patients were included in this study. Serum levels of TNF-α, autoantibodies, and complement were measured and monitored. Among these patients, 138 tested positive for TNF-α, while 111 tested negative. The medical records of these patients were retrospectively evaluated. Additionally, 102 patients with elevated TNF-α levels were treated with TNF-α inhibitors, and their pregnancy outcomes were assessed. TNF-α-positive RPL patients had higher levels of complement C1q, anti-cardiolipin (ACL)-IgA, ACL-IgM ,ACL-IgG, thyroglobulin antibody, and Anti-phosphatidylserine/prothrombin IgM antibody, as well as a higher positive rate of antinuclear antibodies compared to TNF-α-negative patients (23.19% vs. 12.6%, P< 0.05). Conversely, complement C3 were lower in TNF-α-positive patients (t test, P< 0.05). The use of TNF-α inhibitors led to a reduction in the early abortion rate (13.7% vs. 44.4%, P< 0.001) and an improvement in term delivery rate (52.0% vs. 27.8%, P= 0.012). Furthermore, patients who used TNF-α inhibitors before 5 weeks of pregnancy had a lower early abortion rate (7.7% vs. 24.3%, P= 0.033) and a higher term delivery rate (69.2% vs. 48.6%, P= 0.033). TNF-α plays a role in the occurrence and development of RPL, and its expression is closely associated with autoantibodies and complements. TNF-α inhibitors increase the term delivery rate in TNF-α-positive RPL patients, and their use before 5 weeks of pregnancy may more beneficial.

Paradoxical and bimodal immune-mediated dermatological side effects of TNF-α inhibitors: A comprehensive review.

Due to the increasing prevalence of immune-mediated diseases such as psoriasis, lichen planus, rheumatoid arthritis and inflammatory bowel disease, dermatologists have turned to new biologic drugs known as DMARDs (disease-modifying anti-rheumatic drugs) in recent years. In this study, we evaluate the immune-mediated dermatological side effects of DMARDS by reviewing and analyzing previous peer-reviewed research on the effects of TNF-α inhibitors in the treatment of skin diseases, as well as adverse effects of these drugs and some of the main causes of these effects. DMARDs are very effective in improving control of the above diseases. TNF-α inhibitors are an important group of DMARDs that are widely used. The paradoxical adverse events (PAEs) associated with the use of TNF-α inhibitors are divided into three categories: true paradoxical, borderline paradoxical, and non-paradoxical. True PAEs include conditions for which TNF-α inhibitors are approved for treatment. Borderline PAEs are considered to occur with this class of drugs for which there is no definite approval but for which there is sufficient evidence. Although these events are rare, early recognition of the accused drug and appropriate decision-making may prevent progression of complications and irreversible side effects.

Tumor necrosis factor-α inhibitor for successful treatment of toxic epidermal necrolysis with severe infection: a case series.

Toxic epidermal necrolysis (TEN) is a rare severe cutaneous adverse reaction that involves more than 30% of the body surface area. TEN can be accompanied by a series of systemic symptoms and has a high risk of death. Tumor necrosis factor (TNF)-α inhibitors such as adalimumab and etanercept have been shown to be safe and effective for the treatment of TEN in some cases. However, clinical data on the use of TNF-α inhibitors to treat TEN with severe systemic infection are scarce. In the present study, three adult patients who developed TEN with serious active infection were successfully treated with etanercept. One of the three patients had active open pulmonary tuberculosis, and the other two had septicemia and/or fungal sepsis. All patients' skin lesions significantly improved after several days, and none of the patients developed emerging or re-emerging infectious diseases, adverse reactions, or a similar rash during follow-up. TNF-α inhibitors may be an effective treatment choice for TEN with severe systemic infection. However, further studies with large samples are still required for validation because clinical experience is limited.

A multifunctional supramolecular hydrogel that rapidly binds TNF-α for efficient reduction of synovial inflammation and cartilage destruction in rheumatoid arthritis

TNF-α is a key inflammatory cytokine in the progression of rheumatoid arthritis (RA), which is the most common inflammatory joint disorder and is characterized by persistent synovitis and cartilage destruction. However, systematic use of TNF-α inhibitors may cause undesirable side effects and fail to repair damaged cartilage. Here we design a self-assembling Nap-DFDFDEGPIRRSDS (termed FP) peptide that can form injectable supramolecular hydrogels and inhibit TNF-α within 15 min. Following integration of metformin-loaded hollow copper sulfide (CuS/MET, termed CM) nanoparticles (NPs) into these FPCM hydrogels, invasion by RA synovial fibroblasts and polarization of pro-inflammatory M1 type macrophages is reduced by inhibiting TNF-α and releasing MET. In addition, CuS NPs are chondroinductive, allowing the hydrogels to provide a suitable microenvironment for cartilage regeneration. More importantly, intraarticular injection of FPCM hydrogels significantly alleviates synovial inflammation and promotes cartilage repair in an adjuvant-induced arthritis mouse model. The therapeutic mechanism was shown to involve inhibition of the PI3K/AKT signaling pathway. Our approach synergistically inhibits inflammation and promotes tissue repair, thus holding promise for treatment of many kinds of inflammatory arthritis where TNF-α is overexpressed.

Characteristic analysis of adverse reactions of five anti-TNFɑ agents: a descriptive analysis from WHO-VigiAccess.

Introduction: Tumor necrosis factor (TNF) inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab pegol) have revolutionized the treatment of severe immune-mediated inflammatory diseases, including rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis. This study assessed adverse drug reactions (ADRs) after the use of TNFα inhibitors in VigiAccess of the World Health Organization (WHO) and compared the adverse reaction characteristics of five inhibitors to select the drug with the least risk for individualized patient use. Methods: The study was a retrospective descriptive analysis method in design. We sorted out five marketed anti-TNFα drugs, and their ADR reports were obtained from WHO-VigiAccess. Data collection included data on the age groups, sex, and regions of patients worldwide covered by ADR reports, as well as data on disease systems and symptoms caused by ADRs recorded in annual ADR reports and reports received by the WHO. By calculating the proportion of adverse reactions reported for each drug, we compared the similarities and differences in adverse reactions for the five drugs. Results: Overall, 1,403,273 adverse events (AEs) related to the five anti-TNFα agents had been reported in VigiAccess at the time of the search. The results show that the 10 most commonly reported AE manifestations were rash, arthralgia, rheumatoid arthritis, headache, pneumonia, psoriasis, nausea, diarrhea, pruritus, and dyspnea. The top five commonly reported AE types of anti-TNFα drugs were as follows: infections and infestations (184,909, 23.0%), musculoskeletal and connective tissue disorders (704,657, 28.6%), gastrointestinal disorders (122,373, 15.3%), skin and subcutaneous tissue disorders (108,259, 13.5%), and nervous system disorders (88,498, 11.0%). The preferred terms of myelosuppression and acromegaly were obvious in golimumab. Infliximab showed a significantly higher ADR report ratio in the infusion-related reaction compared to the other four inhibitors. The rate of ADR reports for lower respiratory tract infection and other infections was the highest for golimumab. Conclusion: No causal associations could be established between the TNFα inhibitors and the ADRs. Current comparative observational studies of these inhibitors revealed common and specific adverse reactions in the ADR reports of the WHO received for these drugs. Clinicians should improve the rational use of these high-priced drugs according to the characteristics of ADRs.

Association between IL-17F, IL-17RA Gene Polymorphisms and Response to Biological Drugs in Psoriasis and Beyond.

Psoriasis is a systemic inflammatory disease that associates with multiple comorbidities. It involves complex interactions between environmental factors and polygenic predisposition. The IL-17 family is one of the main actors in the pathogenesis of psoriasis. Secondary nonresponse is common, especially during the long-term use of TNF-α inhibitors, but it is not uncommon even for newer biologics, such as IL-17 inhibitors. Identification of clinically useful biomarkers of treatment efficacy and safety would enable optimal treatment selection, improve patient quality of life and outcome, and reduce healthcare costs. To our knowledge, this is the first study to evaluate the relationship between genetic polymorphism of IL-17F (rs763780) and IL-17RA (rs4819554) and response to biological treatment and other clinical data in bio-naive and secondary non-responders psoriasis patients in Romania and Southeastern Europe. We performed a prospective, longitudinal, analytical cohort study of 81 patients diagnosed with moderate-to-severe chronic plaque psoriasis who received biological treatments for the first time. Of the 79 patients treated with TNF-α inhibitors, 44 experienced secondary nonresponse. All patients were genotyped for the two SNPs in IL-17F and IL-17RA genes. The rs763780 polymorphism in the IL-17F gene could be an attractive candidate biomarker for predicting which patients will respond to anti-TNF-α therapies. Another emergent association of rs4819554 in IL-17RA with the risk of nail psoriasis and a higher BMI in moderate-to-severe plaque psoriasis patients is described.

Alzheimer Disease Occurs More Frequently In Patients With Inflammatory Bowel Disease: Insight From a Nationwide Study.

Alzheimer disease (AD) affects 5 million Americans and early recognition improves cognitive function. Chronic inflammation and gut microbiome alteration are linked to cognitive decline which are common in inflammatory bowel disease (IBD). We investigated the association of IBD with development of AD. A commercial database (Explorys Inc., Cleveland, OH), an aggregate of electronic health records from 26 major US health care systems, was surveyed. Cohorts of patients with Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT) diagnoses of Crohn's disease (CD), ulcerative colitis (UC), and AD were identified. IBD patients with new diagnosis of AD were characterized based on demographic and traditional AD risk factors and IBD-related features. Among 342,740 IBD patients in the database, AD developed in 5750 IBD patients (1.55%). After adjusting for traditional AD risk factors, IBD was identified as an independent risk factor for development of AD [odds ratio (OR)=2.30, 95% confidence interval (CI)=2.10-2.51]. IBD patients with AD were younger in comparison to AD patients without IBD. On sub-group analysis, patients with CD had higher odds of developing AD (adjusted OR=3.34, 95% CI=3.25-3.42) than UC (adjusted OR=1.09, 95% CI=1.06-1.14). Use of tumor necrosis factor (TNF-α) inhibitors in IBD was associated with significantly lower odds of developing AD in both CD and UC. In this population based study, IBD was independently associated with development of AD. Among IBD; the association was stronger in patients with CD in comparison with UC. Use of TNF-α inhibitors was associated with lower odds of developing AD.

Bimekizumab in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor-α inhibitors: a randomised, double-blind, placebo-controlled, phase 3 trial (BE COMPLETE)

Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F and IL-17A. This study compared the efficacy and safety of bimekizumab with placebo over 16 weeks in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor-α (TNFα) inhibitors. BE COMPLETE was a phase 3, multicentre, randomised, double-blind, placebo-controlled trial conducted across 92 sites (including hospitals, clinics, and research centres) in 11 countries (Australia, Canada, Czech Republic, Germany, Hungary, Italy, Japan, Poland, Russia, the UK, and the USA). Eligible patients were aged 18 years or older with adult-onset psoriatic arthritis (meeting the Classification Criteria for Psoriatic Arthritis for at least 6 months before screening) with a history of inadequate response or intolerance to treatment with one or two TNFα inhibitors for either psoriatic arthritis or psoriasis. We stratified patients with active psoriatic arthritis by region and previous TNFα inhibitor use. Patients were randomly assigned (2:1) to receive subcutaneous bimekizumab 160 mg every 4 weeks or placebo by an interactive-voice and web-response system on the basis of a predetermined randomisation schedule. The primary endpoint was the proportion of patients with 50% or greater improvement in American College of Rheumatology criteria (ACR50) at week 16 (non-responder imputation). Efficacy analyses were done in the randomised population. The safety analysis set comprised patients who received one or more doses of study treatment. This trial was registered at ClinicalTrials.gov, NCT03896581, and is completed. Between March 28, 2019, and Feb 14, 2022, 556 patients were screened and 400 patients were randomly assigned to bimekizumab 160 mg every 4 weeks (n=267) or placebo (n=133). The primary and all hierarchical secondary endpoints were met at week 16. 116 (43%) of 267 patients receiving bimekizumab reached ACR50, compared with nine (7%) of 133 patients receiving placebo (adjusted odds ratio [OR] 11·1 [95% CI 5·4-23·0], p<0·0001). 121 (69%) of 176 patients with psoriasis affecting at least 3% body surface area at baseline who received bimekizumab reached 90% or greater improvement in the Psoriasis Area and Severity Index (PASI90), compared with six (7%) of 88 patients who received placebo (adjusted OR 30·2 [12·4-73·9], p<0·0001). Treatment-emergent adverse events up to week 16 were reported in 108 (40%) of 267 patients receiving bimekizumab and 44 (33%) of 132 patients receiving placebo. There were no new safety signals and no deaths. Bimekizumab treatment led to superior improvements in joint and skin efficacy outcomes at week 16 compared with placebo in patients with psoriatic arthritis and inadequate response or intolerance to TNFα inhibitors. The safety profile of bimekizumab was consistent with previous phase 3 studies in patients with plaque psoriasis, and studies of IL-17A inhibitors. UCB Pharma.

Anti-tumor Necrosis Factor-Alpha Therapy and Hypoglycemia: A Real-World Pharmacovigilance Analysis.

An association between tumor necrosis factor (TNF)-α inhibitors and hypoglycemia has been detected in a few case reports and small case series; however, no relevant pharmacovigilance data have been published yet. The objective of this study was to detect and characterize relevant safety signals between hypoglycemia and TNF-α inhibitor use. Indication-focused disproportionality analysis was conducted to detect increased reporting of TNF-α-associated hypoglycemia compared with all other reports with the same indication during the same time period. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated to determine disproportionality. To reduce potential confounding factors, adjusted RORs were further calculated by logistic regression to control for age, sex, diabetes status, and concomitant drugs that potentially affect blood glucose levels. In all, 1086 adverse drug reactions related to TNF-α inhibitors were reported as 'hypoglycemia'. There were no disproportionality signals of hypoglycemia in TNF-α inhibitor users with indication of inflammatory bowel disease. When TNF-α inhibitors were considered as a class, disproportion for hypoglycemia only emerged in indication of psoriasis (n=267, ROR 1.20, 95% CI 1.02-1.41). In further analyses of specific TNF-α inhibitor type, significant RORs for hypoglycemia were found in indication of rheumatic disease, including adalimumab in ankylosing spondylitis (n=37, ROR 1.97, 95% CI 1.28-3.04), psoriasis (n=160, ROR 1.64, 95% CI 1.37-1.97), and rheumatoid arthritis (n=230, ROR 1.35, 95% CI 1.16-1.56) and infliximab in psoriasis (n=18, ROR 2.14, 95% CI 1.33-3.42). After adjusting for confounding factors, only the signals of adalimumab were stable. Our study identified some potential pharmacovigilance signals between hypoglycemia and TNF-α inhibitors, which warrants further validation.

The Risk of Adverse Effects of TNF-α Inhibitors in Patients With Rheumatoid Arthritis: A Network Meta-Analysis.

ObjectivesTo evaluate the safety of each anti-TNF therapy for patients with rheumatoid arthritis (RA) and then make the best choice in clinical practice.MethodsWe searched PUBMED, EMBASE, and the Cochrane Library. The deadline for retrieval is August 2021. The ORs, Confidence Intervals (CIs), and p values were calculated by STATA.16.0 software for assessment.Result72 RCTs involving 28332 subjects were included. AEs were more common with adalimumab combined disease-modifying anti-rheumatic drugs (DMARDs) compared with placebo (OR = 1.60, 95% CI: 1.06, 2.42), DMARDs (1.28, 95% CI: 1.08, 1.52), etanercept combined DMARDs (1.32, 95% CI: 1.03, 1.67); certolizumab combined DMARDs compared with placebo (1.63, 95% CI: 1.07, 2.46), DMARDs (1.30, 95% CI: 1.10, 1.54), etanercept combined DMARDs (1.34, 95% CI: 1.05, 1.70). In SAEs, comparisons between treatments showed adalimumab (0.20, 95% CI: 0.07, 0.59), etanercept combined DMARDs (0.39, 95% CI: 0.15, 0.96), golimumab (0.19, 95% CI: 0.05, 0.77), infliximab (0.15, 95% CI: 0.03,0.71) decreased the risk of SAEs compared with golimumab combined DMARDs. In infections, comparisons between treatments showed adalimumab combined DMARDs (0.59, 95% CI: 0.37, 0.95), etanercept (0.49, 95% CI: 0.28, 0.88), etanercept combined DMARDs (0.56, 95% CI: 0.35, 0.91), golimumab combined DMARDs (0.51, 95% CI: 0.31, 0.83) decreased the risk of infections compared with infliximab combined DMARDs. No evidence indicated that the use of TNF-α inhibitors influenced the risk of serious infections, malignant tumors.ConclusionIn conclusion, we regard etanercept monotherapy as the optimal choice for RA patients in clinical practice when the efficacy is similar. Conversely, certolizumab + DMARDs therapy is not recommended.Systematic Review Registrationidentifier PROSPERO CRD42021276176.

TNFα Blockade Inhibits Both Initial and Continued Control of Pulmonary Coccidioides.

Tumor necrosis factor alpha (TNFα) is a pluripotent cytokine that is important in many infections, though its role in Coccidioides infection remains poorly understood. The need to understand TNFα in Coccidioides infection has increased recently with the widespread use of TNFα inhibitors for a wide variety of autoimmune conditions. Here, we couple the newly developed Coccidioides infection model using strain Cp1038 and C57BL/6 × DBA/2J F1 (B6D2F1) mice. B6D2F1 mice develop long-lasting control of Cp1038. Treatment of B6D2F1 mice with anti-TNFα antibodies permits significant fungal proliferation and death. Additionally, we show that antibody treatment limited to the first 2 weeks of infection was sufficient to induce this same loss of fungal control. Importantly, anti-TNFα antibody treatment initiated after fungal control leads to a loss of host control. These results highlight the importance of TNFα in both the initial control of murine Coccidioides and ongoing suppression of the fungal disease.

Association of tumor necrosis factor-α inhibitors and liver cirrhosis in patients with rheumatoid arthritis: A nationwide population-based nested case-control study.

Results from various studies are controversial regarding long-term hepatic effects of tumor necrosis factor (TNF)-α inhibitors. Here we aimed to investigate the development of liver cirrhosis with TNF-α inhibitors use in patients with rheumatoid arthritis (RA). This nested case-control study was based on the National Health Insurance Research Database (January 1, 2000 to December 31, 2008) of Taiwan. We identified 559 adult RA patients who developed liver cirrhosis, and 1055 matched control RA patients. TNF-α inhibitors of interest in the study period included adalimumab and etanercept. Multivariate logistic regression analysis for the development of liver cirrhosis with respect to use of TNF-α inhibitors was performed. The incidence rate of liver cirrhosis was 274 per 100000 person-years in newly diagnosed RA patients. We found the use of TNF-α inhibitors was not associated with the development of liver cirrhosis in RA patients (odds ratio 1.02, 95% confidence interval 0.61, 1.70) after adjustment for potential confounders. In addition, the finding was robust to an unobserved confounder. We found no association between the use of TNF-α inhibitors and development of liver cirrhosis in RA patients.

Фактор некроза опухоли α и его роль в патологии

Over the past years, the views on the role played by tumor necrosis factor α (TNF-α) in the body have changed. The aim of this review is to provide updates on TNF-α functions in various pathological conditions. While working on the review, the authors made search and analysis of full-text reviews and original articles in foreign (English) and Russian languages using such databases as eLIBRARY.RU, Google Scholar, Web of Science, Scopus and PubMed, mostly from 2018–2022. A priority was given to the original publications. TNF-α is a multifunctional pro-inflammatory cytokine which stimulates the production of other cytokines, chemokines, and interferon γ. Also, it is involved in the inflammatory processes during viral, bacterial, and autoimmune diseases. Its hypersecretion affects lipid, fat, and carbohydrate metabolism; promotes atherogenesis; leads to the development of arterial hypertension, type 2 diabetes mellitus, obesity, and non-alcoholic fatty liver disease; contributes to osteolysis; induces apoptosis of tumor cells in some types of cancer and stimulates metastatic spread and progression in other types. So far, the use of TNF-α inhibitors and the suppression of expression of TNF-α and its receptors has caused disappointment: approx. in 40–50% of cases the inhibition aggravated pathological conditions. The investigation of the cytokine activity is still going on. KEYWORDS: TNF-α, cytokines, inflammation, atherosclerosis, oncogenesis, obesity, diabetes mellitus, adipokines. FOR CITATION: Tereshchenko I.V., Kayushev P.E. Tumor necrosis factor α and its role in pathologies. Russian Medical Inquiry. 2022;6(9):523– 527 (in Russ.). DOI: 10.32364/2587-6821-2022-6-9-523-527.

Association between Carotid Intima-Media Thickness and the Use of Biological or Small Molecule Therapies in Patients with Rheumatoid Arthritis.

Objective: The objective of this study was to assess the association of carotid intima-media thickness (CIMT), and also the presence of atheromatous plaque, with biological and targeted synthetic disease-modifying antirheumatic drugs, in an established cohort of patients with rheumatoid arthritis (RA). Patients and Methods: We conducted a cross-sectional observational study based on a cohort of patients with RA and a registry of healthy controls, in whom the CIMT and presence of atheromatous plaque were assessed by ultrasound. Data were collected on disease activity, lab results and treatments. Descriptive and bivariate analyses were performed and two multivariate linear regression models (with CIMT as the dependent variable) were constructed to identify variables independently associated with CIMT in our sample of patients with RA. Results: A total of 176 individuals (146 patients with RA and 30 controls) were included. A higher percentage of patients than controls had atheromatous plaque (33.8% vs. 12.5%, p = 0.036), but no differences were found in terms of CIMT (0.64 vs. 0.61, p = 0.444). Compared to values in patients on other therapies, the CIMT was smaller among patients on tumour necrosis factor alpha (TNFα) inhibitors (mean [SD]: 0.58 [0.10] vs. 0.65 [0.19]; p = 0.013) and among those on Janus kinase inhibitors (mean [SD]: 0.52 [0.02] vs. 0.64 [0.18]; p < 0.001), while no differences were found as a function of the use of the other therapies considered. The multivariate linear regression analysis to identify factors associated with CIMT in our patients, adjusting for traditional cardiovascular risk factors such as hypertension, high levels of low-density lipoproteins, diabetes mellitus and smoking, showed that male sex, older age and having a greater cumulative erythrocyte sedimentation rate were independently associated with a larger CIMT, while patients on TNFα inhibitors had a CIMT 0.075 mm smaller than those on other treatments. Conclusions: The use of TNFα inhibitors may protect against subclinical atherosclerosis in patients with RA, patients on this biologic having smaller CIMTs than patients on other disease-modifying antirheumatic drugs. Nonetheless, these results should be confirmed in prospective studies with larger sample sizes.

Association of Tumor Necrosis Factor α Inhibitor Use with Diagnostic Features and Mortality of Tuberculosis in the United States, 2010-2017.

BackgroundAn elevated risk of tuberculosis (TB) disease in persons who have received tumor necrosis factor alpha inhibitor medications (TNF-α inhibitors) has been reported for nearly two decades, but clinical diagnostic features and outcomes of TB in this population remain poorly described.MethodsWe analyzed national surveillance data for TB cases among persons aged 15 years and older reported in the United States during 2010–2017 and associated mortality data reported through 2019 to describe the clinical characteristics of those receiving TNF-α inhibitors.ResultsOf 70 129 TB cases analyzed, 504 (0.7%) of the patients had TNF-α inhibitor use reported at TB diagnosis. Patients with TNF-α inhibitor use at TB diagnosis were more likely than TB patients not receiving TNF-α inhibitors to have TB diagnosed in extrapulmonary sites in conjunction with pulmonary sites (28.8% vs 10.0%, P < .001). Patients receiving TNF-α inhibitors were less likely to have acid-fast bacilli noted on sputum smear microscopy (25.6% vs 39.1%, P = .04), and more likely to have drug-resistant disease (13.5% vs 10.0%, P < .001). TB-attributed deaths did not significantly differ between patients receiving and not receiving TNF-α inhibitors (adjusted odds ratio, 1.46 [95% confidence interval, .95–2.26]).ConclusionsClinicians evaluating TNF-α inhibitor–treated patients should have a high index of suspicion for TB and be aware that extrapulmonary or sputum smear–negative TB disease is more common in these patients. No significantly diminished survival of TB patients treated with TNF-α inhibitor therapy before TB diagnosis was noted.

Absence of TNF-α Promotes Anemia of Inflammation and Inflammatory Bowel Disease

Anemia of inflammation (AI) is a hallmark of a multitude of disorders including infections, autoimmune diseases and malignancies. The pathophysiology of AI is currently under investigation. While the hematological aspect of AI and the involvement of cytokines such as IL6, IL1α, IL1 β has been subject to extensive study, the inflammatory and immunological arm has only recently begun to be explored. This involves a complex interplay of cytokine mediators both pro and anti-inflammatory, mediating a broader innate and ultimately adaptive immune response that could potentially be linked to the hematological deficiencies seen under AI. In particular, highly elevated levels of the cytokine TNF a have been noted in inflammatory conditions, including an established acute mouse model of AI induced by a single injection of the heat killed pathogen Brucella abortus (BA). The latter results observed by us prompted us to furtherinvestigate the role of this cytokine in BA induced AI.To study the above we injected mice lacking TNFα (TNFα-/-) with BA and studied hematological, inflammatory and immunological changes in our model. Following a single injection of BA, we found that TNFα -/- mice develop an irreversible macrocytic, hyperchromic anemia with hemoglobin levels dropping as low as 7 g/dL within two weeks of BA injection and not returning to normal even after eight weeks unlike their WT counterparts. This is further characterized by a complete abolition of Bone Marrow (BM) erythropoiesis and extra medullary erythropoiesis in the spleen (SPL). We also found elevated serum levels of erythropoietin and iron, indicating that the resulting anemia is not caused by a lack of these factors. The anemia was accompanied by a fall in the lifespan of RBCs in peripheral blood and a concurrent increase in production of reactive oxygen species by progenitors and terminally differentiated RBCs. Moreover, our experiments using WT GFP+ RBCs in BA treated TNFα-/- mice indicate that even the healthy GFP+ RBCs are cleared faster in the latter animals. Preliminary data, suggest that macrophages derived from BA treated TNFα-/- express pro-inflammatory markers and that the same cells can consume more RBCs than macrophages from control animals, suggesting increased macrophagocytosis. Subsequently, we looked at changes in serum cytokine levels over time after injection of BA. We found that unlike WT animals injected with BA, TNFα-/- mice show a sustained production of IFNγ, IL12-p40 and IL1β. We also found an expansion of splenic resident macrophages and T cells which are cell types implicated in the production of the cytokines mentioned previously. Finally, to extend the reach of this model to other disorders we treated TNFα-/- mice with low doses of dextran sodium sulfate (DSS) and found that only these animals developed inflammatory bowel disease (IBD) characterized by blood in the feces and severe anemia, unlike WT animals treated the same way.Our observations on the upregulation of IFNγ and IL12 is leading us to study macrophage activation and T helper cell polarization in the BM, SPL and lymph nodes. Moreover, we are also investigating the potential crosstalk between these effectors, cytokines and erythropoiesis looking at oxidative stress, survival and cell differentiation of erythroid progenitors. As a first step, we are investigating the recovery from BA of IFNγ-/- mice, as TNFα-/- mice with AI show a significant upregulation of IFNγ. Preliminary complete blood count of BA treated IFNγ -/- mice indicates that these animals do recover from an inflammatory insult and the anemia is reversible, unlike the TNFα-/- mice. These results suggest that absence of IFNγ could potentially rescue the severely impaired phenotype that we found in our TNFα-/- mice and the recovery in BA treated TNFα/IFNγ double knock out mice.Given the history of TNFα in enabling inflammatory reactions and promoting cell death, the view of this cytokine in supporting recover under AI as inferred from our results is relatively novel and suggest caution in the use of TNFα inhibitors. Furthermore, our data point to an important role in the crosstalk between TNFα and INFγ and in their effect on erythropoiesis. DisclosuresNo relevant conflicts of interest to declare.

Risk of hepatitis B virus reactivation in patients with autoimmune diseases undergoing non-tumor necrosis factor-targeted biologics.

Hepatitis B virus reactivation (HBVr) can occur in patients treated with immunosuppressive medications. Risk stratification for HBVr based on hepatitis B virus (HBV) serology and viral load is an important strategy to determine appropriate HBV monitoring and antiviral prophylaxis use. Recent advances in the understanding of pathophysiology of autoimmune diseases have led the development of cytokine-targeted therapies. Tumor necrosis factor (TNF)-α inhibitors have been widely used for patients with inflammatory bowel disease, psoriasis, and rheumatic diseases. Further, the clinical benefits of interleukin (IL)-12/23, IL-17, or Janus kinases inhibitors have been demonstrated in these patients. It is well known that TNF-α inhibitor use can lead to HBVr, however, the risk of HBVr in patients undergoing non-TNF-targeted biologics have not been fully understood. In this review, we discuss the risk of HBVr in patients treated with non-TNF-targeted biologics, and immunological mechanisms of these medications causing HBVr.