Tumor Necrosis Factor Blockers Research Articles

A rare case of disseminated histoplasmosis with oral manifestations in a rheumatoid arthritis patient treated with rituximab: Diagnostic and management challenges – A review

Disseminated histoplasmosis happens to be a rare complication that rheumatologists come across in their clinical practice. Biologics, mainly tumor necrosis factor blockers, have been mentioned as one of the causative factors in invasive histoplasmosis, and there are few case reports to support that. However, rituximab use has not been reported with histoplasmosis infection frequently. The association of such novel biologic agents with serious infections such as histoplasmosis needs further exploration as timely management and intervention can be life-saving for the patient. We report about a 69-year-old female, diagnosed with rheumatoid arthritis, who was treated with rituximab and subsequently developed disseminated histoplasmosis. She was successfully managed with antifungals. Here, we discuss the latest evidence-based treatment modalities for such patients with special reference to rheumatoid patients on biologic therapy.

A Study of Cecal Ligation and Puncture-Induced Sepsis in Tissue-Specific Tumor Necrosis Factor Receptor 1-Deficient Mice.

Sepsis is a complex syndrome resulting from a dysregulated immune response to an infection. Due to the high prevalence, morbidity, and mortality, there is a lot of interest in understanding pathways that play a role in sepsis, with a focus on the immune system. Tumor necrosis factor (TNF) is a pleiotropic pro-inflammatory cytokine and a master regulator of the immune system but clinical trials with TNF blockers in sepsis have failed to demonstrate significant protection. Since TNF stimulates two different receptors, TNF receptor 1 (TNFR1) and TNFR2, pan-TNF inhibition might be suboptimal since both receptors have opposite functions in polymicrobial sepsis. Therefore, we hypothesized that TNF has a dual role in sepsis, namely a mediating and a protective role, and that protection might be obtained by TNFR1-specific inhibition. We here confirmed that TNFR1−/− mice are protected in the sterile endotoxemia model, whereas TNFR1 deficiency did not protect in the cecal ligation and puncture (CLP)-induced polymicrobial sepsis model. Since whole body TNFR1 blockage might be deleterious because of the antibacterial function of TNF/TNFR1 signaling, we focused on the potential devastating role of TNF/TNFR1 signaling in specific cell types. We were interested in the gut epithelium, the endothelium, and hepatocytes using conditional TNFR1−/− mice, as these cell types have been shown to play a role in sepsis. However, none of these conditional knockout mice showed improved survival in the CLP model. We conclude that cell-specific targeting of TNFR1 to these cell types has no therapeutic future in septic peritonitis.

How do dose reduction and discontinuation of tumor necrosis factor-blocking (anti-TNF) agents affect people with low disease activity rheumatoid arthritis?

How do dose reduction and discontinuation of tumor necrosis factor-blocking (anti-TNF) agents affect people with low disease activity rheumatoid arthritis?

Progranulin autoantibodies in systemic sclerosis and autoimmune connective tissue disorders: A preliminary study.

ObjectiveThe present study aimed to investigate progranulin autoantibodies in systemic sclerosis and autoimmune connective tissue disorders. Progranulin is a physiologic tumor necrosis factor (TNF) antagonist. Progranulin antibodies decrease progranulin levels.MethodsSerum samples of 123 patients with systemic sclerosis and various autoimmune connective tissue disorders (Sjoegren's syndrome [SjS], mixed connective tissue disorder, polymyositis [PM] and dermatomyositis [DM], antiphospholipid syndrome [APLS], and undifferentiated connective tissue disease [UCTD]) were tested for progranulin antibodies using enzyme‐linked immunosorbent assay.ResultsProgranulin antibodies were found in 34 of 123 (27.6%) patients at least once during their disease. In detail, 2 of 8 (25%) patients with limited cutaneous systemic sclerosis, 10 of 31 (32.3%) patients with diffuse cutaneous systemic sclerosis, 9 of 22 (40.9%) patients with SjS, 1 of 3 (33.33%) patients with mixed connective tissue disease, 4 of 33 (12.1%) patients with DM or PM, 6 of 15 (40%) patients with APLS, and 2 of 11 (18.2%) patients with UCTD were positive for progranulin antibodies during the course of disease.ConclusionsProgranulin antibodies are frequently present in patients with systemic sclerosis and other autoimmune connective tissue disorders. Despite the lack of specificity for a given autoimmune disease, progranulin antibodies might not only indicate a potential subtype but also play a pathogenic role in patients with autoimmune connective disorders. Given the important role of TNF‐α in inflammatory processes in autoimmune connective tissue disorders, progranulin antibodies might support the proinflammatory environment by neutralizing the TNF blocker progranulin.

A novel specific peroxisome proliferator-activated receptor γ (PPARγ) modulator YR4-42 ameliorates hyperglycaemia and dyslipidaemia and hepatic steatosis in diet-induced obese mice.

AimsTo evaluate a novel tetrahydroisoquinoline derivative YR4‐42 as a selective peroxisome proliferator‐activated receptor γ (PPARγ) modulator (SPPARM) and explore its anti‐diabetic effects in vitro and in vivo.Materials and methodsUsing two standard full PPARγ agonists rosiglitazone and pioglitazone as controls, the PPARγ binding affinity and transactivation action of YR4‐42 were evaluated using biochemical and cell‐based reporter gene assays. The capacity of YR4‐42 to recruit coactivators of PPARγ was also assessed. The effects of YR4‐42 on adipogenesis and glucose consumption and PPARγ Ser273 phosphorylation were investigated in 3T3‐L1 adipocytes. The effects of YR4‐42 and pioglitazone, serving as positive control, on glucose and lipids metabolism were investigated in high‐fat diet‐induced obese (DIO) C57BL/6J mice. The expression of PPARγ target genes involved in glucose and lipid metabolism was also assessed in vitro and in vivo.Results In vitro biochemical and cell‐based functional assays showed that YR4‐42 has much weaker binding affinity, transactivation, and recruitment to PPARγ of the coactivators thyroid hormone receptor‐associated protein complex 220 kDa component (TRAP220) and PPARγ coactivator 1‐α (PGC1α) compared to full agonists. In 3 T3‐L1 adipocytes, YR4‐42 significantly improved glucose consumption without a lipogenesis effect, while blocking tumour necrosis factor α‐mediated phosphorylation of PPARγ at Ser273, thereby upregulating the expression of the PPARγ Ser273 phosphorylation‐dependent genes. Furthermore, in DIO mice, oral administration of YR4‐42 ameliorated the hyperglycaemia, with a similar insulin sensitization effect to that of pioglitazone. Importantly, YR4‐42 also improved hyperlipidaemia‐associated hepatic steatosis without weight gain, which avoids a major side effect of pioglitazone. Thus, YR4‐42 appeared to selectively modulate PPARγ responses. This finding was supported by the gene expression analysis, which showed that YR4‐42 selectively targets PPARγ‐regulated genes mapped to glucose and lipid metabolism in DIO mice.ConclusionsWe conclude that YR4‐42 is a novel anti‐diabetic drug candidate with significant advantages compared to standard PPARγ agonists. YR4‐42 should be further investigated in preclinical and clinical studies.

Clinical and therapeutic management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: RADAR study.

To describe the clinical and therapeutic management of rheumatoid arthritis (RA) patients with biological disease-modifying antirheumatic drugs (bDMARDs), alone or in combination with conventional synthetic DMARDs (csDMARDs), as well as analysing changes over time in bDMARD use. An observational, retrospective, multicentre study was conducted in the rheumatology departments of 10 public Spanish hospitals. Patients with RA treated with bDMARDs at baseline who had medical records available in the data collection period 2013-2016 were included. All visits to rheumatology departments recording any type of bDMARD modification (dose, etc.) were collected. Clinical characteristics, concomitant treatment, resource use, work productivity and quality of life (QoL) were recorded. 128 patients were included: 81 received first-line bDMARD treatment, 28 second-line bDMARD treatment and 19 received third or later lines. Mean study follow-up was 4.1years. Assessment of DAS28 was available in 54.6% of visits. At baseline, 48.7% of patients had moderate-high disease activity. At final observation, 69.5% of patients continued with the first bDMARD. Tumour necrosis factor blockers were administered to 85.2% of patients in first line, 45.7% in second line and 18.1% in third or later lines. At final observation, 80.2% of patients still felt pain/discomfort. As expected, those with higher disease activity had higher loss of work productivity and lower QoL, as assessed by DAS28, than patients with lower disease activity. Drugs represented 82.6% of the total cost. In this Spanish cohort of 128 patients, most patients remained on the first prescribed bDMARD, despite remaining signs and symptoms.

Behçet's syndrome: clinical presentation and prevalence in Switzerland.

Behçet's syndrome is a rare systemic autoimmune/autoinflammatory disease affecting mucocutaneous tissues, the skin and the eyes, as well as the joints, the central nervous system, the gastrointestinal tract and blood vessels. Because of the lack of clinical data in Switzerland, the aims of this cohort study were to calculate the disease prevalence and to analyse the disease manifestations and the immune-suppressive medication. Data were extracted from 52 patient charts. Thereafter, all patients were interviewed with a questionnaire and 46 had an additional physical examination and laboratory analyses. For calculation of prevalence, data of the national statistical bureau were used. A disease prevalence of 4.03/100,000 inhabitants was calculated. The mean delay between first disease manifestation and diagnosis was 8 years. It was 2 years longer for Swiss than for non-Swiss individuals (p = 0.45). The time intervals between diagnosis and occurrence of different organ manifestations ranged from +8 to -11 years. There was no difference in organ involvement between different ethnicities. Colchicine was prescribed for 52% of patients only, whereas tumour necrosis factor (TNF) inhibitors and glucocorticoids were most frequently prescribed (80 and 64%, respectively). In almost half of the patients, TNF blockers could be stopped and replaced by conventional immunosuppressive drugs. The data from this cohort of Behçet's syndrome patients, the largest in Switzerland, documents a prevalence higher than anticipated. The diagnostic delay underlines an urgent need to improve awareness of the disease and allow timely treatment.

Comparative efficacy and safety of biosimilar rituximab and originator rituximab in combination with methotrexate in patients with active rheumatoid arthritis: A Bayesian network meta-analysis .

We aimed to assess the relative efficacy and safety of biosimilar rituximab and originator rituximab plus methotrexate (MTX) compared to those of placebo plus MTX in patients with active rheumatoid arthritis (RA). We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) that examined the efficacy and safety of biosimilar+MTX and rituximab+MTX versus placebo+MTX (MTX group) in patients with active RA despite treatment with MTX and/or tumor necrosis factor (TNF) blockers. Six RCTs involving 1,747 patients met inclusion criteria. The American College of Rheumatology 20% (ACR20) response rate was significantly higher in the biosimilar+MTX (odds ratio (OR) 4.30, 95% credible interval (CrI) 1.75-10.91) and rituximab+MTX (OR 4.07, 95% CrI 2.51-7.18) groups than in the MTX group, with no difference in the ACR20 response rate between the biosimilar+MTX and rituximab+MTX groups. The biosimilar+MTX group had the highest probability of being the best treatment based on the ACR20 response rate (surface under the cumulative ranking curve (SUCRA) = 0.7832), followed by rituximab+MTX (SUCRA = 0.7134) and MTX groups (SUCRA = 0.0034). ACR50 and ACR70 response rates showed a distribution pattern similar to ACR20 response rate. Safety based on number of adverse events did not differ significantly among the three interventions after 24 weeks. Biosimilar and originator rituximab, combined with MTX, represent an effective intervention for active RA despite treatment with MTX or TNF blockers. No significant difference was found between biosimilar and originator rituximab regarding efficacy and safety.

Pulmonary involvement in rheumatoid arthritis

Pulmonary involvement in patients with rheumatoid arthritis, in particular interstitial lung diseases (RA-ILD) is of great clinical importance. Patients should be asked about symptoms of pulmonary involvement and the lungs should be clinically examined even during the diagnostic procedure and regularly during the course of the disease. Before initiation of a basic pharmacological treatment an X‑ray examination of thoracic organs is obligatory. In cases of conspicuous clinical or radiological findings, extended diagnostic procedures with lung function testing (body plethysmography with diffusion measurement) and high resolution computed tomography (CT) should be performed, depending on the findings. The differential diagnosis of interstitial lung alterations in patients with RA is broad and should consider side effects of the basis medication in addition to infectious causes. The optimal pharmacological treatment of RA-ILD is not sufficiently clarified. The value of methotrexate (MTX) has changed because, in contrast to previous assumptions, a better course could be observed under MTX treatment, at least in mild to moderate courses of RA-ILD. In the case of a clinically relevant RA-ILD, tumor necrosis factor (TNF) blockers should be avoided because a dramatic deterioration of pulmonary function has sometimes been observed. Among biological disease-modifying antirheumatic drugs (DMARD), rituximab and abatacept are currently preferred. The role of Janus kinase (JAK) inhibitors in RA-ILD is currently being discussed but limited data are available. Patients with RA-ILD benefit from aclose collaboration between pulmonologists and rheumatologists.

Sympatholytic and Anti-Inflammatory Effects of Ropivacaine and Bupivacaine After Infraclavicular Block in Arterio Venous Fistula Surgery.

BackgroundVarious mechanisms have been suggested for analgesic effects of drugs used in infra-clavicular block and each has contributed to pain relief.ObjectivesThe aim of this study was to compare the degree of sympathetic block and measure tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1 levels before and after infra-clavicular block with ropivacaine and bupivacaine in patients undergoing arterio venous fistula (AVF) surgery.MethodsForty-eight patients undergoing AVF surgery were randomly divided to two groups, undergoing infra-clavicular block with ropivacaine and bupivacaine. The bupivacaine group was blocked with 30 mL of 0.5% bupivacaine and in the ropivacaine group, the blockage was done with 30 mL of 0.5% ropivacaine. Infra-clavicular block was carried out by ultrasound in a vertical manner. Blood samples were taken before the block and one hour after the block to measure IL-1, IL-6, and TNF-alpha. Data were analyzed by covariance analysis and correlation t-test.ResultsT-correlation analysis showed that in both ropivacaine and bupivacaine groups, the TNF-alpha, IL-6, and IL-1 levels decreased after the block. Also, the increase in arterial diameter was significantly greater in ropivacaine group.ConclusionsThe present study showed that peripheral block with any single drug could reduce pre-inflammatory factors. On the other hand, ropivacaine significantly increased the diameter of the artery compared to the bupivacaine group.

Serum miR-214 as a novel biomarker for ankylosing spondylitis.

Serum microRNA (miR) in ankylosing spondylitis (AS) patients has been rarely identified. The objective of this study was to find AS-specific miR in sera of patients with AS. Total RNAs were isolated from whole sera of patients with AS, patients with rheumatoid arthritis (RA), and healthy controls (HC) using miRNeasy Serum/Plasma Kit. The presence of miR was assayed using Agilent 2100 Bioanalyzer Small RNA assay. Each RNA sample was used for miR microarray. To verify microarray results, candidate circulating miRs were validated by quantitative polymerase chain reaction (qPCR) using samples from patients with AS (n=65), patients with RA (n=25), and HCs (n=39). Cycle threshold values were converted to copy numbers by drawing a standard curve using a synthetic chemical standard. All clinical values were also evaluated at the time of miR isolation. A total of 887 miRs were screened for three groups. Lower expression of miR-214 in AS than in HC and RA was observed after normalization of raw data. Finally, lower expression of serum miR-214 was confirmed in AS after validation by qPCR. Correlation analysis showed that the level of miR-214 of AS was significantly associated with Ankylosing Spondylitis Disease Activity Score-C-reactive protein (r=0.299, P=0.02). However, other disease-specific variables showed no statistical significance: gender (P=0.286), peripheral arthritis (P=0.634), enthesitis (P=0.464), dacylitis (P=0.750), psoriasis (P=0.552), inflammatory bowel disease (P=0.369), human leukocyte antigen-B27 positivity (P=0.473), use of non-steroidal anti-inflammatory drugs (P=0.448), and use of tumor necrosis factor-blocker in the last 3months (P=0.505). miR-214 may serve as a noninvasive biomarker for diagnosis of AS. In addition, expression level of miR-214 was associated with disease activity.

The Impact of Ramadan Fasting on the Reduction of PASI Score, in Moderate-To-Severe Psoriatic Patients: A Real-Life Multicenter Study.

Fasting during the month of Ramadan consists of alternate abstinence and re-feeding periods (circadian or intermittent fasting). Nothing is currently known on the impact of this kind of fasting on psoriasis. A sample of 108 moderate-to-severe plaque psoriasis patients (aged 42.84 ± 13.61 years, 62 males, 46 females) volunteered to take part in the study. A significant decrease in the “Psoriasis Area and Severity Index” (PASI) score after the Ramadan fasting (mean difference = −0.89 ± 1.21, p < 0.0001) was found. At the multivariate regression, the use of cyclosporine (p = 0.0003), interleukin-17 or IL-17 blockers (p < 0.0001), and tumor necrosis factor or TNF blockers (p = 0.0107) was independently associated with a low PASI score, while the use of apremilast (p = 0.0009), and phototherapy (p = 0.0015) was associated with a high PASI score before the Ramadan fasting. Similarly, the consumption of cyclosporine (p < 0.0001), IL-17 blockers (p < 0.0001), mammalian target of rapamycin or mTOR inhibitors (p = 0.0081), and TNF blockers (p = 0.0017) predicted a low PASI score after the Ramadan fasting. By contrast, narrow band ultraviolet light B or NB-UVB (p = 0.0015) was associated with a high PASI score after Ramadan fasting. Disease duration (p = 0.0078), use of apremilast (p = 0.0005), and of mTOR inhibitors (p = 0.0034) were independent predictors of the reduction in the PASI score after the Ramadan fasting. These findings reflect the influence of dieting strategy, the biological clock, and circadian rhythm on the treatment of plaque psoriasis.

The role of progranulin (PGRN) in the modulation of anti-inflammatory response in asthma.

Asthma is one of the most common chronic diseases. Epidemiological studies show that asthma will develop among around 40% of children under six years old with symptoms of bronchial obstruction. Diagnosis of asthma is complicated, especially in the paediatric population. As a result, a lot of research is being carried out to establish the pathophysiology and to find new biomarkers of this disease. Progranulin (PGRN) is a recently discovered growth factor with many biological functions. PGRN has anti-inflammatory properties because it inhibits neutrophil degranulation and blocks tumor necrosis factor α (TNF-α) transmission. The underlying mechanisms are still being researched, but TNF-α is considered to be a cytokine responsible for neutrophilic inflammation in the airways and bronchial hyperresponsiveness. Therefore, PGRN, by lowering TNF-α concentration and stimulating regulatory T-cell (Treg) proliferation, relieves symptoms of bronchial inflammatory diseases. This article attempts to verify the current knowledge about basic pathophysiological mechanisms in asthma. We also summarise the most recent research advances in the role of PGRN in the respiratory system.

Comparative Effectiveness of Ustekinumab Versus Adalimumab in Induction of Clinical Response and Remission in Crohn's Disease: Experience of a Real-World Cohort at a Tertiary Care Inflammatory Bowel Disease Referral Center.

BackgroundThere is paucity of head-to-head studies comparing the effectiveness of ustekinumab (UST) and adalimumab (ADA) in Crohn’s disease (CD). Here we provide a real-world comparison of these two agents.MethodsWe conducted an ambidirectional cohort study. Each patient included had moderate to severe active CD. Clinical response and remission were assessed between 4 and 16 weeks after induction.ResultsOf a total of 163 patients, 97 were induced with ADA and 66 were induced with UST. Logistic regression model analysis adjusted based on effect size showed that ADA when compared to UST induced clinical response (73.2% vs. 50% (odds ratio (OR): 2.40; 95% confidence interval (CI): 1.14 - 5.07; P = 0.02)) and remission (44.3% vs. 27.7% (OR: 2.35; 95% CI: 1.07 - 5.16; P = 0.034) in a statistically significantly higher proportion of patients. Among tumor necrosis factor (TNF)-naive patients, when comparing ADA vs. UST, ADA was superior in inducing clinical response (69/89 (77.5%) vs. 4/10 (40%) (OR: 4.26; 95% CI: 1.08 - 16.84; P = 0.04)), but not remission (41/89 (46%) vs. 3/9 (33%) (OR: 1.64; 95% CI: 0.39 - 6.97; P = 0.503)). Among TNF-experienced patients, ADA was numerically inferior in inducing clinical response (2/8 (25%) vs. 29/56 (52%) (OR: 0.38; 95% CI: 0.07 - 1.94; P = 0.24)) and remission (2/8 (25%) vs. 15/56 (27%) (OR: 1.22; 95% CI: 0.22 - 6.81; P = 0.82)), but neither of these differences were statistically significant.ConclusionsIn a real-world setting, the rate of clinical response and remission was higher among patients with CD who received ADA compared to UST. Of note, however, despite the small sample sizes of TNF-experienced patients who received ADA and TNF-naive patients who received UST, the higher effectiveness of ADA in inducing clinical response and indeed remission among patients with CD with active disease appears to primarily be driven by those who are TNF-naive. Among TNF-experienced patients, UST may be superior in inducing clinical response and equally effective in inducing clinical remission when compared to ADA. Based on this study, one may infer that among TNF-experienced patients with CD with active disease, one could consider switching to an agent such as UST instead of a second approved TNF blocker. However, larger studies comparing the two agents are required.

Upside and Downside of Tumor Necrosis Factor Blockers for Treatment of Immune/Inflammatory Diseases.

Tumor necrosis factor (TNF)-α, the most potent proinflammatory cytokine discovered to date, was first isolated in 1984 from human macrophage cells. Initially, it was thought to be a protein that was cytotoxic to tumor cells. But later, it was regarded as an agent that promotes inflammation and other chronic diseases found in humans. Currently, we know that the TNF superfamily (TNFS) has 19 members that perform a wide variety of functions via > 40 TNF receptors. Of TNFS members, TNF-α has been studied extensively and was found to be implicated in numerous autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, systemic lupus erythematosus, juvenile idiopathic arthritis, and diabetes. Thus, agents that can inhibit TNF-α have great potential for prevention and treatment of chronic diseases. To date, the U.S. Food and Drug Administration has approved many TNF-α blockers, such as etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab. These agents can block TNF-α actions and be used to treat different diseases. However, the uses of TNF-α blockers are not without serious adverse effects. Therefore, natural TNF-α blockers are best for developing safe, efficacious, and affordable agents for prevention and treatment of chronic diseases. The current review details the TNFS, functions of TNF-α in normal and disease conditions, roles of TNF-α blockers, and advantages and disadvantages.

Etanercept protects ovarian reserve against ischemia/reperfusion injury in a rat model

IntroductionEtanercept has been widely used in autoimmune diseases for blocking tumor necrosis factor α (TNF-α), which is an inflammatory cytokine. The anti-apoptotic and anti-inflammatory effects of etanercept against ischemia/reperfusion (I/R) injury have been shown for several tissues in rat studies, but to the best of our knowledge, there are no reports on its protective effects following similar injury in ovarian tissue. The aim of this study was to investigate whether etanercept has beneficial effects on ovarian I/R injury, as well as on ovarian reserve.Material and methodsTwenty-four rats were randomly divided into four groups (n = 6/group): sham (laparotomy only); sham + etanercept; I/R; and I/R + etanercept. Ischemia was induced for 3 h by twisting the ovary, and 24 h after detorsion the ovarian tissues were collected to evaluate histopathologic changes, glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), and superoxide dismutase (SOD) concentrations for oxidative stress, 8-hydroxy-2′-deoxyguanosine (8-OHdG) for DNA damage, caspase-3 activity for apoptosis and ovarian follicle counts. To measure anti-Mullerian hormone (AMH), serum samples were drawn before and after surgery.ResultsTissue GSH and SOD levels were significantly higher, while MDA and MPO levels were significantly lower in the I/R + etanercept group than in the I/R group (p < 0.05, p < 0.01, respectively). Tissue 8-OHdG and caspase-3 activity were significantly lower in the I/R+etanercept group than in the I/R group (p < 0.05, p < 0.01, respectively). Preoperative and postoperative AMH levels were compared and there was a significant reduction in the I/R and I/R + etanercept groups (p < 0.001, p < 0.001). The reduction of AMH in the I/R + etanercept group was significantly lower than in the I/R group. The primordial, preantral and small antral follicle numbers were also significantly higher in the I/R + etanercept group compared to the I/R group (p < 0.001, p < 0.001, p < 0.005, respectively).ConclusionsEtanercept attenuated inflammation and related oxidative stress and also helped to preserve ovarian reserve following ovarian I/R damage.

Tumor necrosis factor receptor 1 inhibition is therapeutic for neuropathic pain in males but not in females.

Tumor necrosis factor (TNF) is a proinflammatory cytokine, which is involved in physiological and pathological processes and has been found to be crucial for pain development. In the current study, we were interested in the effects of blocking Tumor necrosis factor receptor 1 (TNFR1) signaling on neuropathic pain after peripheral nerve injury with the use of transgenic mice and pharmacological inhibition. We have previously shown that TNFR1 mice failed to develop neuropathic pain and depressive symptoms after chronic constriction injury (CCI). To investigate the therapeutic effects of inhibiting TNFR1 signaling after injury, we delivered a drug that inactivates soluble TNF (XPro1595). Inhibition of solTNF signaling resulted in an accelerated recovery from neuropathic pain in males, but not in females. To begin exploring a mechanism, we investigated changes in N-methyl-D-aspartate (NMDA) receptors because neuropathic pain has been shown to invoke an increase in glutamatergic signaling. In male mice, XPro1595 treatment reduces elevated NMDA receptor levels in the brain after injury, whereas in female mice, NMDA receptor levels decrease after CCI. We further show that estrogen inhibits the therapeutic response of XPro1595 in females. Our results suggest that TNFR1 signaling plays an essential role in pain induction after CCI in males but not in females.

High Rate of Drug-Free Remission After Induction Therapy With Golimumab in Early Peripheral Spondyloarthritis.

New treatment algorithms using tumor necrosis factor (TNF) blockers in early stages of spondyloarthritis (SpA) induce high rates of clinical remission or low disease activity. It could be anticipated that such early intervention strategies in peripheral SpA may induce drug-free remission. We undertook this study to evaluate drug-free clinical remission after induction therapy with golimumab inpatients with very early active peripheral SpA, and to identify patient characteristics that predict sustained drug-free remission. Eligible patients were age ≥18 years and fulfilled the Assessment of SpondyloArthritis international Society criteria for peripheral SpA. All patients had symptom durationof <12 weeks. Sustained clinical remission wasdefined as the absence of arthritis, enthesitis, and dactylitis at 2 consecutive major visits, after which treatment was withdrawn. Patients were prospectively followed up to assess the rate of sustained drug-free clinical remission and clinical relapse. Eighty-two percent of patients (49 of 60) fulfilled sustained clinical remission criteria after a regimen of induction therapy with golimumab. The majority of patients already reached this status at week 24 (n = 30), with an additional 11 and 8 patients at weeks 36 and 48, respectively. All patients had a follow-up period of at least 18 months after drug withdrawal. Fifty-three percent of patients (26 of 49) still have drug-free remission of their disease.Inability to sustain drug-free remission was associated with the presence of psoriasis and polyarticular disease (swollen joint count >5). Anti-TNF treatment in very early peripheral SpA results in a remarkably high rate of sustained clinical remission. More than 50% of patients continue to have remission of their disease after withdrawal of therapy, which highlights a defined window of opportunity permitting induction of drug-free remission.

ANALYSIS OF RISK FACTORS AND POSTOPERATIVE COMPLICATIONS IN PATIENTS WITH CROHN'S DISEASE.

The post-operative complications rate is greater in patients with Crohn's disease than in other abdominal surgeries due to other benign conditions. Prevention and management of such complications are important factors in the care of these patients. The objectives of this research are to analyze the rate of postoperative complications and the major risk factors in patients with Crohn's disease. A descriptive and retrospective study based on analysis of medical records of patients with Crohn's disease undergoing ileal and/or colonic resection, which analyzed the main surgical complications and their major risk factors. Forty-four surgical procedures and thirty-seven patients were analyzed. Most were female (56.7%). Postoperative complications were observed in 18 (40.9%) surgeries. The disease duration (P=0.04), the penetrating behavior (P=0.013), the time between diagnosis and the first surgery (P=0.04), malnutrition with low body mass index (BMI), duration of surgery (P=0.016), and the size of the removed specimen (P=0.014) were associated with higher rates of complications. The use of drugs blocking tumor necrosis factor up to eight weeks before surgery was not significantly associated with higher complications rates or increased need for reoperation. The complication rate observed in this study is similar to published data. The duration of the disease, the penetrating behavior, the size of the removed specimen, the duration of the surgery, and BMI are important risk factors for perioperative complications in Crohn's disease.

An explorative study on deep profiling of peripheral leukocytes to identify predictors for responsiveness to anti-tumour necrosis factor alpha therapies in ankylosing spondylitis: natural killer cells in focus

BackgroundTherapeutic targeting of tumour necrosis factor (TNF)-α is highly effective in ankylosing spondylitis (AS) patients. However, since one-third of anti-TNF-treated AS patients do not show an adequate clinical response there is an urgent need for new biomarkers that would aid clinicians in their decision-making to select appropriate therapeutic options. Thus, the aim of this explorative study was to identify cell-based biomarkers in peripheral blood that could be used for a pre-treatment stratification of AS patients.MethodsA high-dimensional, multi-parametric flow cytometric approach was applied to identify baseline predictors in 31 AS patients before treatment with the TNF blockers adalimumab (TNF-neutralisation) and etanercept (soluble TNF receptor).ResultsAs the major result, the frequencies of natural killer (NK) cells, and in particular CD8-positive (CD8+) NK cell subsets, were most predictive for therapeutic outcome in AS patients. While an inverse correlation between classical CD56+/CD16+ NK cells and reduction of disease activity was observed, the CD8+ NK cell subset behaved in the opposite direction. At baseline, responders showed significantly increased frequencies of CD8+ NK cells compared with non-responders.ConclusionsThis is the first study demonstrating that the composition of the NK cell compartment has predictive power for prediction of therapeutic outcome for anti-TNF-α blockers, and we identified CD8+ NK cells as a potential new player in the TNF-α-driven chronic inflammatory immune response of AS.