OBJECTIVE: Increasing evidence demonstrates a link between the chronic inflammatory state in patients with rheumatoid arthritis (RA) and the development of insulin resistance. It is thought that anti-TNF-α biologic therapy may improve insulin sensitivity and ameliorate insulin resistance by the downregulation of inflammatory cytokines, however, pre-clinical and clinical studies have yielded conflicting results. A meta-analysis on this topic is necessary to summarize current evidence and generate hypotheses for future research.
METHODS: Literature search was performed in four databases, namely PubMed, EMBASE, Scopus, and The Cochrane Library, from inception till April 9, 2023, querying studies reporting peripheral insulin resistance with and without anti-TNF-α use in patients with RA. Peripheral insulin resistance or sensitivity was quantified by the Homeostasis Model Assessment of Insulin Resistance (HOMA) index or the Quantitative Insulin Sensitivity Check Index (QUICKI) respectively. The difference in insulin resistance or sensitivity between the treatment and control group was calculated using standardized mean difference (SMD) for the purposes of the meta-analysis.
RESULTS: Twelve articles were reviewed, with 10 longitudinal studies with a total of 297 patients included in the meta-analysis. The pooled standardized mean difference (SMD) from baseline HOMA was -0.82 (95% CI: -1.38 to -0.25) suggesting significant beneficial effects of anti-TNF-α therapy on insulin resistance.
CONCLUSIONS: Current evidence supports the significant clinical efficacy of anti-TNF-α biologics in alleviating insulin resistance and improving insulin sensitivity in patients with active RA.

Osteoarthritis (OA) affects the entire joint, causing structural changes in articular cartilage, subchondral bone, ligaments, capsule, synovial membrane, and periarticular muscles that afflicts millions of people globally, leading to persistent pain and diminished quality of life. The intra-articular use of platelet-rich plasma (PRP) is gaining recognition as a secure therapeutic approach due to its potential regenerative capabilities. However, there is controversial clinical data regarding efficacy of PRP for OA treatment. In this context, gathering scientific evidence on the effects of PRP in treating OA in animal models could provide valuable insights into understanding its impact on aspects like cartilage health, synovial tissue integrity, and the inflammatory process in affected joints. Thus, the objective of this study was to assess the effects of PRP injections on inflammation and histopathological aspects of cartilage and synovium in animal models of OA through a comprehensive systematic review with meta-analysis.
A electronic search was conducted on Medline, Embase, Web of Science, The Cochrane Library, LILACS, and SciELO databases for relevant articles published until June 2022. A random-effects meta-analysis was employed to synthesize evidence on the histological characteristics of cartilage and synovium, as well as the inflammatory process. The GRADE approach was utilized to categorize the quality of evidence, and methodological quality was assessed using SYRCLE\'s RoB tool.
Twenty-one studies were included in the review, with twelve of them incorporated into the meta-analysis. PRP treatment demonstrated superior outcomes compared to the control group in terms of cartilage histology (very low quality; p = 0.0002), synovium histology (very low quality; p < 0.0001), and reductions in proinflammatory markers, including IL-1 (low quality; p = 0.002), IL-6 (very low quality; p < 0.00001), and TNF-α (very low; p < 0.00001). However, PRP treatment did not yield a significant impact on PDGF-A levels (very low quality; p = 0.81).
PRP appears capable of reducing proinflammatory markers (IL-1, IL-6, TNF-α) and mitigating cartilage and synovium damage in animals with OA. However, the levels of evidence of these findings are low to very low. Therefore, more rigorous studies with larger samples are needed to improve the quality of evidence.
CRD42022250314.

BACKGROUND: Chronic low back pain (CLBP) is a prevalent and debilitating condition, leading to significant challenges to both patients and the governmental healthcare system. Non-pharmacologic interventions have received increasing attention as potential strategies to alleviate chronic low back pain and improve patient outcomes. The aim of this systematic review was to comprehensively assess the changes in blood inflammatory biomarkers after non-pharmacologic interventions for CLBP patients, thus trying to understand the complex interactions between non-pharmacologic interventions and inflammatory biomarker changes in CLBP.
METHODS: A thorough search (from January 1st, 2002 to October 5th, 2022) of PubMed, Medline (platform Web of Science), and the Cochrane Library (platform Wiley Online Library) were conducted, and inclusion criteria as well as exclusion criteria were refined to selection of the studies. Rigorous assessments of study quality were performed using RoB 2 from Cochrane or an adaptation of the Downs and Black checklist. Data synthesis includes alterations in inflammatory biomarkers after various non-pharmacologic interventions, including exercise, acupressure, neuro-emotional technique, and other modalities.
RESULTS: Thirteen primary studies were included in this systematic review, eight randomized controlled trials, one quasi-randomized trial, and four before-after studies. The interventions studied consisted of osteopathic manual treatment (one study), spinal manipulative therapy (SMT) (three studies), exercise (two studies), yoga (two studies) and acupressure (two studies), neuro-emotional technique (one study), mindfulness-based (one study) and balneotherapy study (one study). Four studies reported some changes in the inflammatory biomarkers compared to the control group. Decreased tumor necrosis factor-alpha (TNF-α) after osteopathic manual treatment (OMT), neuro-emotional technique (NET), and yoga. Decreased interleukin (IL)-1, IL-6, IL-10, and c-reactive protein (CRP) after NET, and increased IL-4 after acupressure. Another five studies found changes in inflammatory biomarkers through pre- and post-intervention comparisons, indicating improvement outcomes after intervention. Increased IL-10 after balneotherapy; decreased TNF-α, IL-1β, IL-8, Interferon-gamma, interferon-γ-induced protein 10-γ-induced protein 10 after exercise; decreased IL-6 after exercise and SMT; decreased CRP and chemokine ligand 3 after SMT.
CONCLUSIONS: Results suggest a moderation of inflammatory biomarkers due to different non-pharmacologic interventions for CLBP, generally resulting in decreased pro-inflammatory markers such as TNF-α and IL-6 as well as increased anti-inflammatory markers such as IL-4, thus revealing the inhibition of inflammatory processes by different non-pharmacologic interventions. However, a limited number of high-quality studies evaluating similar interventions and similar biomarkers limits the conclusion of this review.

Strokes are the second leading cause of death and disability worldwide. The brain injury resulting from stroke produces a persistent neuroinflammatory response in the brain, resulting in a spectrum of neurologic dysfunction affecting stroke survivors chronically, also known as post-stroke pain. Excess production of tumor necrosis factor alpha (TNF alpha) in the cerebrospinal fluid (CSF) of stroke survivors has been implicated in post-stroke pain. Therefore, this literature review aims to assess and review the role of perispinal etanercept in the management of post-stroke pain. Several studies have shown statistically significant evidence that etanercept, a TNF alpha inhibitor, can reduce symptoms present in post-stroke syndrome by targeting the excess TNF alpha produced in the CSF. Studies have also shown improvements in not only post-stroke pain but also in traumatic brain injury and dementia. Further research is needed to explore the effects of TNF alpha on stroke prognosis and determine the optimal frequency and duration of etanercept treatment for post-stroke pain.

Background and Objectives: Sudden Sensorineural Hearing Loss (SSNHL) is a quite common clinical finding in otolaryngology. Most cases are classified as idiopathic and there is a dearth of information on factors able to predict the response to treatment and hearing recovery. The main aim of this systematic review and meta-analysis was to assess and critically discuss the role of circulating inflammatory biomarkers in SSNHL. Materials and Methods: A search was conducted of the English literature published between 1 January 2009 and 7 July 2022 on Pubmed, Scopus, Web of Science, ScienceDirect, and Cochrane following PRISMA guidelines. Results: A total of 256 titles were retrieved from the search. After full-text screening and application of inclusion/exclusion criteria, 13 articles were included. Twelve out of thirteen studies reported significant differences in biomarkers values in SSNHL patients, of which Tumor Necrosis Factor alpha (TNF-α) and C-reactive Protein (CRP) were the most analyzed. Our meta-analysis for CRP\'s mean values in SSNHL groups vs. controls showed significantly higher CRP levels with a pooled overall difference of 1.07; confidence interval (CI) at 95%: 0.03; 2.11. For TNF-α, discordant results were found: three studies showed significantly higher levels in SSNHL patients vs. controls, whereas other three investigations showed lower levels in the SSNHL groups (overall pooled difference 1.97; 95% CI: -0.90; 4.84). A high between-study heterogeneity was found. Conclusions: This systematic review pointed out that, although there exists a growing literature in the field of circulatory biomarkers identification in SSNHL, there is a high heterogeneity of results and low quality of evidence. CRP resulted to be higher in SSNHL patients than in controls, while TNF-α showed more heterogeneous behavior. The data reported herein needs to be confirmed in well-designed prospective multicenter randomized studies, with the objective of improving SSNHL treatment and outcome and thereby reducing the social burden of hearing loss.

Multiple sclerosis (MS) is one of the most prevalent causes of nontraumatic neurological impairment in young adults. This review aims to determine the impact of exercise on cytokine and adipokine profile levels as inflammatory markers in MS patients across various exercise paradigms. We used specific keywords in PubMed, Web of Science, The Cochrane Library, and Scopus to find randomized clinical trials addressing the effects of physical activity and exercise training on inflammatory markers levels in MS patients. The majority of the research showed no considerable changes in IL-6 levels, while three studies reported declining levels after the intervention. Approximately half of the trials observed a change in TNF-α and IL-10 levels after exercise interventions, while the other half showed no meaningful changes. Other markers such as IL-17, IL-4, IL-12, adipokines, and BDNF showed fluctuations in levels. We found no universal agreement on the effects of different exercise training protocols on the serum level of inflammatory markers in patients with MS. More research is needed to fully identify the effects of exercise on cytokines in MS patients.

Recurrent spontaneous abortion (RSA) is a troublesome pregnancy disorder that manifests as sequential early pregnancy losses; its causes are diverse and complex. Among the known possible causes of RSA, the development of an immune disorder in response to the embryo appears to be the most pronounced. The imbalance between immune rejection and immune tolerance contributes to pregnancy loss in females with RSA, wherein the abnormal ratio of T helper (Th)1 cell‑related cytokines [predominantly tumor necrosis factor (TNF)‑α] and Th2 cell‑related cytokines is a strong risk factor for RSA. TNF‑α is a pro‑inflammatory cytokine and TNF inhibitors have been effective in the treatment of various autoimmune diseases, such as ankylosing spondylitis, and inflammatory diseases, such as ulcerative colitis. Based on their immunomodulatory properties, TNF inhibitors have been used in the treatment of RSA to reduce the immune rejection rate and improvement in pregnancy outcomes has been observed in females suffering from RSA who were treated with TNF inhibitors. The aim of the present review was to interpret the involvement of TNF‑α in the immunological disorder underlying RSA and summarize the clinical outcomes of TNF inhibitor treatment in patients with RSA.

BACKGROUND: Tumor necrosis factor alpha (TNF-α) is a cytokine with a key role in proinflammation and multiple diseases, including cancer. The gene encoding TNF-α is located within a highly polymorphic region on chromosome 6p21.3; two polymorphisms -308G/A (rs1800629) and -238G/A (rs361525) have been associated with occurrence of human diseases. There is a debate in recent meta-analyses that reached discrepant conclusions regarding the potential role of TNF-α polymorphisms in multiple myeloma (MM) risk. The aim of this systematic review and meta-analysis is to investigate the association between the aforementioned two polymorphisms with the risk and survival of MM.
METHODS: Eligible articles were identified through an extensive search in PubMed database (end of search: June 18, 2020). The pooled effect estimates were calculated following the random-effects models by Der Simonian and Laird. Separate analyses were conducted by ethnicity. Between-study heterogeneity was quantified, and the deviation of genotype frequencies in controls from the Hardy-Weinberg equilibrium was evaluated.
RESULTS: Eighteen studies (2934 cases, 4291 controls) have been included in the quantitative synthesis examining risk and 5 studies for survival (557 cases). No association was found between -308G/A and -238G/A TNF-α polymorphisms and MM susceptibility in all genetic models for both Caucasian and East Asian populations. There was no association between -308G/A and -238G/A TNF-α polymorphisms and survival (overall or progression-free) of MM.
CONCLUSIONS: This systematic review and meta-analysis did not reveal a significant effect of -308G/A and -238G/A TNF-α polymorphisms upon risk or survival of MM.

The level of immunoglobulins and cytokines changes with an ageing immune system. This review summarizes findings from studies that have examined the impact of acute and chronic exercise on immunoglobulins and cytokines in the elderly. Our literature analysis revealed that acute endurance exercise resulted in increased secretory salivary immunoglobulin A (SIgA), while acute bouts of muscle strengthening exercise (i.e., isokinetic, eccentric, knee extensor exercise) increased plasma/muscle interleukin (IL)-6, IL-8 and tumor necrosis factor alpha (TNF-α) levels. Chronic exercise in the form of short-term endurance training (i.e., 12-16 weeks) and long-term combined endurance and resistance training (i.e., 6-12 months) induced increases in salivary SIgA concentration. We additionally identified that short-term endurance training at moderate intensities and the combination of endurance, strength, balance, and flexibility training increase plasma IL-10 and reduce plasma IL-6 and TNF-α in healthy elderly adults and male patients with chronic heart failure. Strength training for 6-12 weeks did not alter plasma IL-1β, IL-2, IL-6 and TNF-α concentration in healthy elderly adults and patients with chronic-degenerative diseases, while 12 weeks of resistance training decreased muscle TNF-α mRNA in frail elderly individuals. Short-term (i.e., 10-24 weeks) moderate- to high-intensity strength training reduced LPS-IL-6, LPS, IL-1β, LPS-TNF-α and circulating concentrations of TNF-α and increased IL-10 in healthy elderly women and older people with cognitive impairment, respectively. In conclusion, it appears that acute bouts of endurance exercise and short-term chronic exercise training exercise are appropriate methods to enhance mucosal immune function, reduce systemic markers of inflammation, and promote anti-inflammatory processes in elderly individuals.

Frailty is a geriatric syndrome defined as a status of extreme vulnerability to stressors, leading to a higher risk of negative health-related outcomes. \"Inflammaging\", an age-related state of low-grade chronic inflammation, is characterized by an increased concentration of pro-inflammatory cytokines and acute phase proteins. Inflammaging has been postulated as an underlying mechanism of frailty, and several studies tested the relationship between frailty and concentration of inflammatory mediators. The aim of this systematic review and meta-analysis was to test whether inflammatory mediators are overproduced in frail older adults. Among the 758 articles identified in the literature search, 50 were included in the systematic review, and 39 in the three meta-analyses, i.e., C-reactive protein (CRP), interleukin 6 (IL6), and tumor necrosis factor α. To reduce heterogeneity, meta-analyses were restricted to studies identifying frailty by the Fried et al. [1] [J. Gerontol. A. Biol. Sci. Med. Sci. 56, M146-56] phenotypic criteria. Quantitative analyses measuring the association between frailty and biomarker concentrations showed significant differences when frail subjects were compared to non-frail and pre-frail subjects for CRP and IL6. This work established strong association between inflammatory biomarkers and frailty, confirming the role of age-related chronic inflammation in frailty development.