Anti TNF-α Research Articles

Efficacy and safety of anti-tumor necrosis factor α monoclonal antibodies in 16 patients with severe/refractory vasculo Behcet's disease

Objective: To explore the efficacy and safety of anti-tumor necrosis factor alpha (TNFα) monoclonal antibodies (mAbs) for severe/refractory vasculo-Behcet's disease (BD). Method: The clinical data of severe/refractory vasculo-BD patients treated with anti-TNFα mAbs were retrospectively analyzed. Response of anti TNFα mAbs was analyzed. The dosage changes of glucocorticoid, the level of erythrocyte sedimentation rate (ESR) and hypersensitive C-reactive protein (hsCRP) before and after treatment were recorded, as well as side effects. Result: Sixteen patients were enrolled. Arterial lesions were reported in 12 patients, including 9 with arterial aneurysm, 6 with arterial dilation, 2 with stenosis and 2 with occlusion. Seven patients presented venous thrombosis, including lower extremity veins (n=6), cerebral venous sinus (n=2) and inferior vena cava system (n=2). Two cases had both arterial and venous involvement. Before the application of TNFα mAbs, all 16 patients failed to response to prednisone or its equivalent dose of 40 (7.5-90) mg/d in combination with cyclophosphamide, methotrexate, thalidomide or azathioprine for median 4 (0-156) months. After a mean duration of treatment for (17.1±6.5) months, 15 patients achieved complete remission and 1 patient achieved partial remission. Three patients received surgery without any postoperative complications. After using anti TNFα mAbs, the dosage of prednisone [5(0-12.5)mg/d vs. 40(7.5-90)mg/d, P<0.01], ESR [(7.3±4.6) mm/1h vs. (33.5±26.7) mm/1h, P<0.01] and hsCRP [1.9(0.2-11.4) mg/L vs. 24.3(0.4-113.9) mg/L, P<0.01] were significantly decreased. Side effects were observed in 2 patients. One developed pulmonary infection 12 months after adalimumab with conventional treatment. Another patient had allergy to infliximab then switched to adalimumab. Conclusion: In combination with corticosteroids and immunosuppressants, anti-TNF α mAbs are effective and well-tolerated in severe/refractory vasculo-BD, with a favorable steroid -sparing effect and rare postoperative complications.

Critical Issues on Diverticular Disease.

In this session diverse critical issues in diverticular disease were considered, including "In or outpatient management of uncomplicated diverticulitis?", "Segmental colitis associated with diverticulosis: what is it?"and "Diverticular inflammation is a risk factor for colorectal cancer?". The conclusions drawn are outlined in the statements but in summary, outpatient management is safe in selected patients, as long as correct diagnosis and stage are assured, and this can allow a cost effective treatment. Non-antibiotic management is also safe but should be confined as an outpatient treatment in carefully selected patients. Segmental colitis associated with diverticulosis (SCAD) is a defined pathological entity (only diagnosed on biopsy) characterized by an inflammatory bowel disease-like pathology, occurring principally in the sigmoid colon, with rectal and right colon sparing. The pathogenesis is unclear but may include a genetic predisposition, microbiome alteration and ischaemia. Treatment can last months, and depends on severity, options include antibiotics, 5 ASA and probiotics for mild cases. Severe disease needs systemic steroids or even anti TNFα treatment. Whether diverticular inflammation is a risk factor for colorectal cancer was debated and the conclusion that within the first eighteen months of diagnosis of diverticular disease associations with cancer are found, likely due to similar symptoms and misclassification of disease. After that time, diverticular disease does not increase the risk of colorectal cancer. Therefore, this is recommended to exclude cancer with imaging and colonoscopy after healing of the first episode of diverticulitis.

Management of Leprosy in the Context of COVID-19 Pandemic: Recommendations by SIG Leprosy (IADVL Academy).

Management of Leprosy in the Context of COVID-19 Pandemic: Recommendations by SIG Leprosy (IADVL Academy).

Effects of anti–TNF-alpha therapy on hemoglobin levels and anemia in patients with inflammatory bowel disease

BackgroundTumor necrosis factor-α (TNF-α) is involved in inducing inflammatory anemia. The potential effect of anti–TNF-α agents on anemia in inflammatory bowel diseases (IBD) is still unknown. MethodsAnalytical data and disease characteristics from 362 IBD patients [271 CD/91UC) treated with anti-TNF-α drugs were retrospectively collected. Effects on disease activity, blood markers and prevalence of anemia were assessed after 6 and 12 months of therapy. Results29.3% patients presented anemia at baseline, and significantly reduced to 14.4% and 7.8% after 6 and 12 months of therapy, respectively. Mean ± SD Hb levels increased significantly at month 6, and this increase was sustained at 12 months. Serum markers of iron metabolism increased significantly compared to baseline, as disease activity measured by C-reactive protein (CRP) was reduced. All these effects were observed independently for CD and UC, and were independent of iron supplementation during treatment. Anemia at baseline (OR 4.09; 95%CI 1.98–8.45) and elevated CRP (OR 3.45; 95CI 1.29–9.22) were independently associated with risk of persistent anemia, as well as iron replacement during therapy (OR 4.36; 95%CI 2.07–9.16). ConclusionsControlling disease activity with anti-TNF- α therapy significantly and independently associated with resolution of anemia in IBD, with no relevant role for iron replacement therapy.

Uhrf1-Mediated Tnf-α Gene Methylation Controls Proinflammatory Macrophages in Experimental Colitis Resembling Inflammatory Bowel Disease.

Macrophages drive the pathological process of inflammatory bowel diseases (IBD) mostly by secreting proinflammatory cytokines, such as Tnf-α. Recent studies have indicated the association between epigenetic modifications and macrophage functions. However, epigenetic mechanisms regulating macrophages' functional involvement in IBD remain unknown. In this study, we investigated whether the epigenetic regulator Uhrf1 plays a role in innate immunity by functionally regulating macrophages in intestines. We employed two transgenic strains of mice (one with Uhrf1 deficiency in macrophages [Uhrf1fl/flLyz2-Cre mice] and the other with the two mutations at Uhrf1's DNA methylation regulatory site [Uhrf1YP187/188AA mice]) to assess their susceptibility to dextran sodium sulfate-induced colitis. We examined the cytokines derived from Uhrf1fl/flLyz2-Cre and Uhrf1YP187/188AA macrophages in response to LPS stimulation. We also analyzed the effects of proinflammatory cytokines on Uhrf1 expression in macrophages. The data demonstrated that Uhrf1 deficiency and Uhrf1YP187/188AA mutation resulted in severe colitis in the dextran sodium sulfate-treated mice. In vitro analysis revealed the hypomethylation of Tnf-α promoter and the increased Tnf-α expression in Uhrf1fl/flLyz2-Cre and Uhrf1YP187/188AA macrophages in response to LPS stimulation, and anti-Tnf-α therapy implied the key role of Tnf-α to the aggravated colitis in Uhrf1-deficient mice. Exogenous Tnf-α destabilized Uhrf1 protein through ubiquitination-mediated protein degradation, triggering macrophage activation. In conclusion, we identified that Uhrf1-mediated DNA methylation controls Tnf-α expression of macrophages in the experimental colitis resembling IBD. The epigenetic mechanisms that activate macrophages may provide new therapeutic targets for IBD treatment.

High Levels of Platelet-Lymphocyte Complexes in Patients with Psoriasis Are Associated with a Better Response to Anti–TNF-α Therapy

Psoriasis is currently considered to be an immune-mediated disease whose patho-mechanisms involve platelet activation, which seems to correlate with the activity of the disease. Platelet activation is associated with the formation of platelet-lymphocyte complexes (PLyC), although their significance remains unknown. Moreover, biological treatments that target tumor necrosis factor-α (TNF-α) reduce platelet activation. To clarify the significance of PLyC, we compared their levels in patients with psoriasis with those of healthy donors and determined whether platelet binding modifies the secretion of IL-17A by T helper cells. Finally, we assessed the effect of anti-TNF-α treatment on PLyC in responder and non-responder patients with psoriasis. Ours results demonstrated an increase in PLyC in patients with psoriasis. Moreover, the percentage of IL-17-secreting cells was observed to be higher in the platelet-lymphocyte complex population, and these cells tended to secrete greater amounts of IL-17A. Psoriasis patients treated with anti-TNF-α normalized platelet-lymphocyte complex values, and the basal percentage of platelet-T helper lymphocyte complexes was significantly higher in the responder group. In conclusion, PLyC are increased in psoriasis patients, and the number of complexes decreases in response to anti-TNF-α treatment, specifically in the responder group of patients. This finding suggests that PLyC are a prognostic biomarker of response to anti-TNF-α therapy, but prospective studies are necessary to verify these results in patients with psoriasis.

Synthesis and evaluation of a novel series of 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylic acid-substituted amide derivatives as anticancer, antiangiogenic, and antioxidant agents

A series of novel indazole derivatives has been synthesized and evaluated for anticancer, antiangiogenic, and antioxidant activities. The capability of the synthesized compounds 11a–x to hinder the viability of three human cancer cells lines, HEP3BPN 11 (liver), MDA 453 (breast), and HL 60 (leukemia), were assessed by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Among the compounds 11a–x screened, 11c and 11d showed the higher inhibitory activity on the viability of HEP3BPN 11 (liver), when compared with the standard methotrexate. These compounds were further tested to evaluate their potential to inhibit the proangiogenic cytokines associated with tumor development. Compound 11c was found to be a potent antiangiogenic agent against TNFα, VEGF, and EGF, whereas 11d showed potent antiangiogenic activity against TNFα, VEGF, IGF1, TGFb, and leptin inhibition. All the compounds 11a–x were screened for their antioxidant activities using 2,2-diphenyl-1-picryl hydrazine (DPPH), hydroxyl (OH), and superoxide radical (SOR) scavenging activity. Compounds 11n, 11p, 11q, and 11v have shown significant OH radical scavenging activities, also compounds 11c, 11h, and 11k were found to have a DPPH radical scavenging activity and compounds 11a and 11m exhibited better SOR scavenging activity when compared with the reference compound ascorbic acid. In silico molecular docking analysis revealed important structural insights behind observed anti TNFα effect by present indazole compounds.

Therapeutic drug monitoring with vedolizumab in inflammatory bowel disease.

Therapeutic drug monitoring (TDM) is a useful tool for decision-making process in patients with inflammatory bowel disease (IBD) treated with anti TNF-α drugs, especially when experiencing loss of response. Growing evidences support the existence of exposure-response relationship with vedolizumab, but the utility and the appropriate use of TDM in clinical practice is still under debate. In this review, we summarize all evidences supporting a TDM-guided approach for patients treated with vedolizumab, suggesting three potential scenarios: 1) early prediction of long-term outcomes; 2) verifying the best strategy in case of loss of response; 3) maximizing therapeutic efficacy during maintenance treatment. Vedolizumab through concentrations <20 µg/mL at week 6 and >12 µg/mL seem to be associated with more favorable outcomes. No comparative studies have been conducted so far to demonstrate the advantage of adopting a TDM-guided versus an empirical approach for managing primary or secondary nonresponses. The frequency of antibodies to vedolizumab detection is quite low (up to 4% in pivotal trials), suggesting, unlike of anti TNF-α agents, a low probability of experiencing an immune-mediated pharmacokinetic failure in clinical practice. Future prospective and controlled studies are warranted to establish the guidance on the use of a TDM-guided approach with vedolizumab in clinical practice.

Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-α) inhibitors: a systematic review.

Tumour necrosis factor-α (TNF-α) inhibitors are increasingly being used as immunomodulators to manage inflammatory conditions such as rheumatoid arthritis and Crohn's disease. Reported serious side effects include an increased incidence of lymphoma and greater susceptibility to infections such as tuberculosis. The aim of this systematic review was to find out whether there is an associated risk of medication-related osteonecrosis of the jaw (MRONJ). Three authors independently searched PubMed, MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials for published reports of oral osteonecrosis (ONJ) or osteomyelitis (OM) in patients who took anti TNF-α drugs and had no history of antiangiogenic agents or antiresorptive treatment. All types of studies on humans treated with TNF-α inhibitors were considered. Only six were eligible for analysis, and all were independently assessed for risk of bias. They included six patients with ONJ or OM that was attributed solely to TNF-α inhibitors. The most common site of ONJ was the posterior mandible (n=5). The mean (SD) duration of anti-TNF-α treatment before the development of bony lesions was 62.5 (47.4) months. Invasive surgery was reported as a precipitating factor in five cases, and the ONJ/OM resolved with conservative management in five. Although all the studies were judged to be at high risk of bias, the limited data suggest that some patients will potentially develop ONJ/OM as a result of treatment with TNF-α inhibitors. Studies of higher quality are now needed to establish the relative risk of MRONJ in patients who take them.

P47 Successful treatment of two cases of refractory JIA uveitis with intravenous tocilizumab and subcutaneous methotrexate

Abstract Background There is a need for additional treatment options in refractory JIA uveitis which has responded inadequately to MTX and anti TNFα. There has been interest in the use of tocilizumab, the APTITUDE trial using SC tocilizumab in JIA uveitis and the STOP-Uveitis study comparing 2 dosing regimens of iv tocilizumab in adults. Anecdotal evidence reports JIA uveitis patients who were stable on IV tocilizumab flaring when switched to sc administration. We describe the successful use of IV tocilizumab and concurrent sc MTX in two cases. Methods Retrospective review of patient paper and electronic medical records. Results Case 1.: A five-year-old female presented with severe anterior uveitis in her right eye. She was diagnosed with idiopathic uveitis and treated with topical steroid, oral then SC MTX infliximab, mycophenolate and adalimumab, all with inadequate control of her uveitis. At the age of 12, on adalimumab, she developed arthritis and her diagnosis was changed to JIA uveitis. 7 years after initial diagnosis she was commenced on IV tocilizumab 8mgs/kg 4-weekly with improved control of her uveitis although initially still requiring some topical steroid. She required intra-articular steroids for active arthritis and agreed to restart SC MTX. On tocilizumab and MTX combined, her arthritis settled and her topical eye drops were weaned for the first time since diagnosis. From age 5 until 14 she was continually on topical steroids, consequently developing raised intraocular pressure and a dense cataract. With improved disease control she had cataract surgery aged 14. She has maintained good disease control for the last five years on the combination of IV tocilizumab and SC MTX and has not required any further steroids. Case 2: A 3 year old female with oligoarticular JIA had severe bilateral uveitis at presentation. Initial treatment was with oral prednisolone, topical steroid and SC MTX. 6 months after diagnosis her uveitis remained active and she was commenced on infliximab with additional IV methylprednisolone. Venous access was challenging, required a portacath to facilitate treatment. By the age of 6 she had developed a cataract requiring surgery and still had incomplete control of her uveitis. Infliximab was increased to 10mgs/kg 4 weekly with little further benefit and at the age of 7 she was changed to adalimumab. On this she developed macular oedema requiring pulse IV methylprednisolone. 5 years after diagnosis she was commenced on IV tocilizimab initially 4 weekly, increasing after three months to 2 weekly. Her methylprednisolone was weaned and she has subsequently maintained good disease control on IV tocilizumab 10mgs/kg 2 weekly with SC methotrexate. Conclusion We describe two cases of refractory JIA and uveitis in whom IV tocilizumab with SC methotrexate has provided good disease control. Further studies are required to determine the optimal dosing regimen. Conflicts of Interest The authors declare no conflicts of interest.

Effect of anti-TNF-α combined with p38MAPK antisense oligonucleotide combination preconditioning on TNF-α, p38MAPK mRNA expression in renal ischemia-reperfusion injury of rats

Objective To investigate the effect of anti-TNF-αcombined with p38MAPK antisense oligonucleotide on TNF-α, p38MAPK mRNA expression at different ischemia-reperfusion points. Methods One hundred and twenty normal male sprague-dawley(SD) rats were randomly divided into 4 groups: sham-operated (sham) group, ischemia-reperfusion(IR)group, anti-TNF-α+ ischemia-reperfusion(anti TNF-α+ IR)group, anti-TNF-αand p38MAPK antisense oligonucleotide + ischemia-reperfusion(combination preconditioning+ IR). Combination preconditioning+ IR group was subjected to ischemia-reperfusion injury with intravenous administration of anti-TNF-α(0.1 mg/kg) and p38-MAPK antisense oligonucleotide (5 mg/kg)5 min before reperfusion.IR group with the same injury was followed by saline administration in the same manner.Sham group was subjected to only anesthetization but not to ischemia.Pathomorphological changes of renal ischemia-reperfusion injury were observed by HE stain and RT-PCR were used to detect the changes of expression of TNF-α, p38MAPK mRNA. Results In IR group TNF-α mRAN, p38MAPK mRNA gradually upregulated with duration of ischemia-reperfusion, p38MAPK mRNA peaked at 6 h of reperfusion, TNF-α mRAN continue upregulating to 12 h of reperfusion, but these effects were offset by administration of anti-TNF-α(P<0.05) or anti-TNF-αcombined with p38MAPK antisense oligonucleotide(P<0.05). Conclusions Renal ischemia-reperfusion injury can be alleviated by anti-TNF-α and p38MAPK antisense oligonucleotide treatment. Key words: Reperfusion Injury; Kidney; Animals, Laboratory; Tumor Necrosis Factor-alpha; RNA, Messenger; Rats

Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease.

Prevention of clinical relapse (resumption of symptoms of active disease) and endoscopic relapse (signs of mucosal inflammation upon examination with an endoscope) are key objectives in the management of Crohn’s disease. There is no treatment currently available that completely prevents relapse and is without significant side-effects. The purpose of this systematic review was to examine the effectiveness and side effects of purine analogue medications (azathioprine and 6-mercaptopurine) used to prevent relapse in Crohn's patients in surgically-induced remission This review identified seven studies that included a total of 584 participants. One study compared azathioprine to placebo (e.g. a sugar pill). Another study compared 6-mercaptopurine to 5-aminosalicylic acid (5-ASA) or placebo. Three studies compared azathioprine to 5-ASA drugs. One small study compared azathioprine to both 5-ASA and adalimumab (a biological drug that is a tumour necrosis factor-alpha antagonist). One small study compared azathioprine to infliximab (a biological drug that is a tumour necrosis factor-alpha antagonist). The study that compared azathioprine to infliximab (22 patients) found that the effects on the proportion of patients who had a clinical or endoscopic relapse were uncertain. A small study (33 patients) found reduced clinical and endoscopic relapse rates favouring adalimumab over azathioprine. No firm conclusions can be drawn from the two small studies that compared azathioprine to infliximab or adalimumab. Adalimumab may be superior to azathioprine but further research is needed to confirm these results. A pooled analysis of two studies (168 patients) suggests that purine analogues may be superior to placebo for preventing clinical relapse in Crohn's patients in surgically-induced remission. One study (87 patients) found a reduction in endoscopic relapse rates favouring 6-mercaptopurine over placebo. A pooled analysis of five studies (425 patients) found no difference in clinical relapse rates between purine analogues and 5-ASA agents. One study (35 patients) found no difference in endoscopic relapse at 12 months between azathioprine and 5-ASA. Another study (91 patients) found reduced endoscopic relapse rates at 24 months favouring 6-mercaptopurine over 5-ASA patients. Patients taking purine analogues were more likely than 5-ASA patients to discontinue therapy due to side effects. Commonly reported side effects across the studies included leucopenia (a decrease in the number of white blood cells), arthralgia (joint pain), abdominal pain or severe epigastric intolerance, elevated liver enzymes, nausea and vomiting, pancreatitis (inflammation of the pancreas), anaemia (a decrease in the number of red blood cells), exacerbation (worsening) of Crohn's disease, nasopharyngitis (common cold), and flatulence. The results of this review need to be interpreted with caution as they are based on small numbers of patients and the overall quality of the evidence from the studies was rated as low or very low due to lack of precision of the results, inconsistent results across studies and the low methodological quality of some studies. Further research investigating the effectiveness and side effects of azathioprine and 6-mercaptopurine in comparison to other medications in patients with surgically-induced remission of Crohn's disease is warranted.

Fixed Drug Eruption to Biologics and Role of Lesional Patch Testing

A 40-year-old cashier with ankylosing spondylitis (AS) on anti–TNF-α therapy presented to the Immunology Clinic with an intermittent rash over her shin. She had been on regular subcutaneous adalimumab (AbbVie, North Chicago, IL) for the past 5 years and her AS was in remission. For the past 3 months, there was consistent recurrence of a solitary rash over her left anterior shin around 4 hours after every dose of adalimumab. Adalimumab was administered every 2 weeks to alternating thighs without history of local injection-site reactions. The lesions were well demarcated, beginning with an intense itch and burning sensation followed by a fixed erythematous oval plaque about 10 cm in diameter. The lesion would last for days with residual hyperpigmentation (Figure 1, A) and recurred after each dose. There was no interruption of her injections and no recent change in the “citrate-free” autoinjector formulation (confirmed with supplier). There were no new medications and she had no history of dermatological conditions. There was no history of trauma. The lesions got progressively worse with subsequent injections, and there was a localized vesicular eruption on her most recent episode (Figure 1, B). She declined a skin biopsy. Adalimumab was stopped and there was no recurrence of the rash. A fixed drug eruption (FDE) was suspected and drug patch testing was performed 2 months later after complete healing of the rash. Patch testing was performed using IQ Ultra chambers and adalimumab (directly extracted from the autoinjector and diluted 1:10 aqueous) with both control (uninvolved upper back skin) and lesional (residual pigmented lesion) patch test application. The patch tests were read on day 2 (D2) and day 4 (D4), in accordance with International Contact Dermatitis Research Group criteria. Patch testing result was negative at the control site at D2 and D4. Patch testing result was negative at the lesional site at D2 (Figure 2, A), but strongly positive (++) at D4 (Figure 2, B) with reactivation of the residual FDE lesion with a crescendo effect. Given the positive lesional patch test result and the suggestive clinical features, she was diagnosed with an FDE due to adalimumab. In view of her favorable response to TNF-α blockade, she consented to provocation testing with subcutaneous golimumab (another anti–TNF-α antagonist), which was well tolerated. Her AS continues to be in remission with golimumab. We previously reported on immediate-type hypersensitivity to adalimumab, and hypersensitivity reactions to biologics have been increasingly identified.1Li P.H. Watts T.J. Lui M.S. Lau C.S. Chung H.Y. Recall urticaria in adalimumab hypersensitivity.J Allergy Clin Immunol Pract. 2018; 6: 1032-1033Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 2Corominas M. Gastaminza G. Lobera T. Hypersensitivity reactions to biological drugs.J Investig Allergol Clin Immunol. 2014; 24: 212-225PubMed Google Scholar In this case, we report the first case of biologics-related FDE. An FDE is a delayed-type cutaneous hypersensitivity reaction to medication that recurs at the same site on further exposure and cross-reactivity is uncertain. In this case, tolerance to golimumab was demonstrated, suggesting a lack of cross-reactivity with an alternative anti–TNF-α antagonist. Adalimumab and golimumab are humanized IgG1 anti–TNF-α antibodies but likely structurally dissimilar, because both are complex macromolecules derived from different biological cell lines. We highlight the utility of lesional patch testing in biologics-related FDE and suggest that tolerance to other anti–TNF-α antagonists is possible, but more studies are required to determine the true rate of cross-reactivity.

Anticytokine Immune Therapy and Atherothrombotic Cardiovascular Risk.

Accumulating observations in humans and animals indicate that inflammation plays a key role in atherosclerosis development and subsequent complications. Moreover, the use of loss- or gain-of-function genetically modified, atherosclerosis-prone mice has provided strong experimental evidence for a causal role of innate and adaptive immunity in atherosclerosis and has revealed the pathogenic activity of proinflammatory cytokines, including TNF (tumor necrosis factor)-α, IL (interleukin)-1β, IL-6, and IL-18, and the atheroprotective effect of anti-inflammatory cytokines, including IL-10 and TGF-β. For the past 15 years, treatments using monoclonal antibodies specifically targeting cytokines, commonly referred as biological therapies, have transformed the treatment of chronic inflammatory diseases, such as rheumatoid arthritis or psoriasis, both conditions associated with increased cardiovascular risk. Analyzing the impact of anticytokine therapies on the cardiovascular outcomes of patients with chronic inflammatory diseases provides insight into the clinical relevance of experimental data on the role of inflammation in atherothrombotic cardiovascular diseases. CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) provided the first evidence that targeting inflammation in humans with atherosclerosis could improve clinical outcomes. Treatment with the anti-IL-1β antibody canakinumab significantly reduced recurrent cardiovascular events in individuals with stable coronary artery disease well-treated with standard-of-care measures. Other clinical studies support the protective effects of treatment with anti-TNF-α and anti-IL-6 receptor monoclonal antibodies on cardiovascular risk. Blockade of the IL-23/IL-17 axis, however, warrants caution as a cardiovascular intervention. Targeting this pathway has improved psoriasis but may augment cardiovascular risk in certain patients. Thus, careful consideration of the cardiovascular risk profile may influence the choice of the most appropriate treatment for patients with chronic inflammatory diseases.Visual Overview: An online visual overview is available for this article.

Abstract 352: The effect of anti-TNF-alpha Ab in AOM/DSS-induced colitic cancer mouse model

Abstract Aim: To reveal whether anti TNF-α antibody (Ab) induces colon carcinogenesis or not in colitic cancer models. Methods: The effects of TNF-α and anti TNF-α Ab were analyzed with cell-proliferation, migration, and invasion assays in human colon cancer cell lines, in vitro. Then, the effects of anti TNF-α Ab, infliximab (10 mg/kg, i.p.) were investigated with drug-induced colitis-associated colon cancer model by azoxymethane (AOM: 10 mg/kg, i.p.)/dextran sodium sulfate (DSS: 2.5%, oral) in vivo. Results: 50 ng/ml of TNF-α inhibited cell proliferation, migration, and invasion of HCT8 and COLO205, however, anti TNF-α Ab offset the TNF-α mediated-inhibition in vitro. Infliximab significantly attenuated the development of colon cancers in AOM/DSS treated mice. The microarray analyses revealed that mast cell related genes (mast cell protease1, mast cell protease 2, chymase 1, etc) were down-regulated in cancer tissues of the infliximab-treated AOM/DSS mice. The results of microarray were validated by real-time RT-PCR. Finally, the number of mast cells were also reduced in those mice. Conclusions: Mast cell may have a pivotal role in the development of colitic cancer. Anti TNF-α Ab may prevent colitic cancer in the patients with inflammatory bowel diseases. Citation Format: Shinobu Ohnuma, Wang Dang Yang, Hideyuki Suzuki, Keigo Kanehara, Hideaki Karasawa, Atsushi Kohyama, Kazuhiro Watanabe, Koh Miura, Takashi Kamei, Takeshi Naitoh, Michiaki Unno. The effect of anti-TNF-alpha Ab in AOM/DSS-induced colitic cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 352.

Potential Protective Effect of Pentoxifylline on Myocardial Injury Induced by Ischemia Reperfusion in Rat Model: A Histological and Immuno-Histochemical Study.

Background: Although, myocardial reperfusion is a pre-requisite to salvaging viable myocardium, the process of restoring coronary blood flow can paradoxically induce myocardial injury and cardiomyocyte death. A number of new therapeutic strategies are currently under investigation for preventing myocardial reperfusion injury and to improve clinical outcomes. Aim of the work: This study was performed to assess the potential benefit of pentoxifylline in the reduction of myocardial injury induced by ischemia/reperfusion . Material and Methods: In this study, 30 adult male albino rats were divided into 3 groups; control group, group II: subjected to ischemia (temporary occlusion of the left anterior descending coronary artery for 45 minutes) followed by reperfusion (for 120 minutes), and group III: single dose of pentoxifylline (40 mg/kg/bw) was injected intraperitoneal, 15 minutes before induction of ischemia/reperfusion. Samples from left ventricle from all animals were excised immediately, at the end of experimental time, and processed for examination by light and transmission electron microscopes. Also, immunohistochemical examination using caspase 3 and Anti TNF-α antibodies was performed. Results: Histological assessment revealed that the pretreatment with pentoxphilline protected the myocardium against ischemic/reperfusion induced injury; as demonstrated by improvement of histological structure of cardiac myocytes, minimal edema, hemorrage and fibrosis. No cellular inflammatory infiltration. Also, marked reduction of cardiomyocyte necrosis, indicating strong anti- apoptotic effect of pentoxphilline, and weak expression of TNF-α , indicating strong anti-inflammatory effect of pentoxphilline.

Anti-tumor necrosis factor α therapy associates to type 17 helper T lymphocytes immunological shift and significant microbial changes in dextran sodium sulphate colitis.

BACKGROUNDAnti-tumor necrosis factor α (TNFα) represents the best therapeutic option to induce mucosal healing and clinical remission in patients with moderate-severe ulcerative colitis. On the other side gut microbiota plays a crucial role in pathogenesis of ulcerative colitis but few information exists on how microbiota changes following anti-TNFα therapy and on microbiota role in mucosal healing.AIMTo elucidate whether gut microbiota and immune system changes appear following anti TNFα therapy during dextran sulfate sodium (DSS) colitis.METHODSEighty C57BL/6 mice were divided into four groups: “No DSS”, “No DSS + anti-TNFα”, “DSS” and “DSS + anti-TNFα”. “DSS” and “DSS + anti-TNFα” were treated for 5 d with 3% DSS. At day 3, mice whithin “No DSS+anti-TNFα” and “DSS+anti-TNFα” group received 5 mg/kg of an anti-TNFα agent. Forty mice were sacrificed at day 5, forty at day 12, after one week of recovery post DSS. The severity of colitis was assessed by a clinical score (Disease Activity Index), colon length and histology. Bacteria such as Bacteroides, Clostridiaceae, Enterococcaceae and Fecalibacterium prausnitzii (F. prausnitzii) were evaluated by quantitative PCR. Type 1 helper T lymphocytes (Th1), type 17 helper T lymphocytes (Th17) and CD4+ regulatory T lymphocytes (Treg) distributions in the mesenteric lymph node (MLN) were studied by flow cytometry.RESULTSBacteria associated with a healthy state (i.e., such as Bacteroides, Clostridiaceae and F. prausnitzii) decreased during colitis and increased in course of anti-TNFα treatment. Conversely, microorganisms belonging to Enterococcaceae genera, which are linked to inflammatory processes, showed an opposite trend. Furthermore, in colitic mice treated with anti-TNFα microbial changes were associated with an initial increase (day 5 of the colitis) in Treg cells and a consequent decrease (day 12 post DSS) in Th1 and Th17 frequency cells. Healthy mice treated with anti-TNFα showed the same histological, microbial and immune features of untreated colitic mice. “No DSS + anti-TNFα” group showed a lymphomononuclear infiltrate both at 5th and 12th d at hematoxylin and eosin staining, an increase of in Th1 and Th17 frequency at day 12, an increase of Enterococcaceae at day 5, a decrease of Bacteroides and Clostridiaceae at day 12.CONCLUSIONAnti-TNFα treatment in experimental model of colitis improves disease activity but it is associated to an increase in Th17 pathway together with gut microbiota alteration.

Treatment of Dactylitis and Enthesitis in Psoriatic Arthritis with Biologic Agents: A Systematic Review and Metaanalysis.

Biologic agents with different mechanisms of action [inhibitors of tumor necrosis factor-α (TNF-α), interleukin (IL)-12/23, and IL-17] showed efficacy in randomized controlled trials (RCT) in the treatment of psoriatic arthritis. We conducted a pooled metaanalysis of these agents for treatment of dactylitis and enthesitis and compared results with the American College of Rheumatology 20 (ACR20) response and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. A systematic literature search was performed and a pooled metaanalysis of RCT with anti-TNF-α (infliximab, golimumab, adalimumab), anti-IL-12/23 (ustekinumab), and anti-IL-17 (secu kinumab, ixekizumab) was conducted using the random-effects model. Bias was assessed using the Cochrane risk-of-bias tool. Eighteen RCT were included in the pooled analysis (n = 6981). Both TNF-α inhibitors and novel biologics (ustekinumab, secukinumab, ixekizumab) demonstrated significant resolution of dactylitis at Week 24 with pooled risk ratios (RR) versus placebo of 2.57 (95% CI 1.36-4.84) and 1.88 (95% CI 1.33-2.65), respectively. For resolution of enthesitis at Week 24, RR for TNF-α inhibitors was 1.93 (95% CI 1.33-2.79) versus 1.95 (95% CI 1.60-2.38) for novel biologics. Both biologic categories showed overlapping ranges of ACR20 responses (TNF-α inhibitors: RR = 2.23, 95% CI 1.60-3.11; pooled IL-12/23 and -17: RR = 2.30, 95% CI 1.94-2.72) and similar quality of life improvement scores with mean HAQ-DI score changes of -0.29 (95% CI -0.39 to -0.19) and -0.26 (95% CI -0.31 to -0.22), respectively. The pooled analysis demonstrated that anti-TNF-α agents have the same efficacy as novel agents (ustekinumab, secukinumab, and ixekizumab) in dactylitis and enthesitis.

Inflammation and Aortic Pulse Wave Velocity: A Multicenter Longitudinal Study in Patients With Inflammatory Bowel Disease.

BackgroundInflammatory bowel disease (IBD) is characterized by a low prevalence of traditional risk factors, an increased aortic pulse‐wave velocity (aPWV), and an excess of cardiovascular events. We have previously hypothesized that the cardiovascular risk excess reported in these patients could be explained by chronic inflammation. Here, we tested the hypothesis that chronic inflammation is responsible for the increased aPWV previously reported in IBD patients and that anti‐TNFa (anti‐tumor necrosis factor‐alpha) therapy reduce aPWV in these patients.Methods and ResultsThis was a multicenter longitudinal study. We enrolled 334 patients: 82 patients with ulcerative colitis, 85 patients with Crohn disease, and 167 healthy control subjects matched for age, sex, and mean blood pressure, from 3 centers in Europe, and followed them for 4 years (range, 2.5–5.7 years). At baseline, IBD patients had higher aPWV than controls. IBD patients in remission and those treated with anti–TNFa during follow‐up experienced an aortic destiffening, whereas aPWV increased in those with active disease and those treated with salicylates (P=0.01). Disease duration (P=0.02) was associated with aortic stiffening as was, in patients with ulcerative colitis, high‐sensitivity C‐reactive protein during follow‐up (P=0.02). All these results were confirmed after adjustment for major confounders. Finally, the duration of anti–TNFa therapy was not associated with the magnitude of the reduction in aPWV at the end of follow‐up (P=0.85).ConclusionsLong‐term anti–TNFa therapy reduces aPWV, an established surrogate measure of cardiovascular risk, in patients with IBD. This suggests that effective control of inflammation may reduce cardiovascular risk in these patients.

Evaluation of TNF alpha G308A promoter gene polymorphism and serum TNF alpha levels in patients with inflammatory bowel disease in Turkish population

Tumor necrosis factor alpha (TNF-α) plays an important role in the pathophysiology of Inflammatory bowel diseases (IBD). In this study, we aimed to investigate the role of TNF-α G308A promoter gene polymorphisms and TNF-α level in patients with IBD and their associations with clinical features of the patients. This study included 91 patients with inflammatory bowel disease (46 patients with ulcerative colitis (UC) and 45 patients with Crohn’s disease (CD)) and 129 healthy controls (HC). Polymerase chain reaction and restriction fragment length polymorphism techniques were both used to explain the frequency of TNF-α polymorphisms and the relationship about clinical outcomes of patients with IBD. There was no statistically significant difference about genotype frequencies and serum TNF-α level between the three groups (UC, CD, HC) (all p>0.05). TNF-α G308A genes polymorphisms were compared in terms of disease localization, behaviour, activity, the use of anti TNF-α treatment and operative status in patients with CD and UC. Similarly, there was no statistically significant difference about genotype frequencies in terms of all these parameters in patients with CD (p> 0.05). However, In patient with UC, the frequency of A allele and AG genotype was significantly increased in moderate and severe UC cases( p= 0.004). These findings suggest that TNF-α G308A gene polymorphism may be helpful in predicting the behavior of the disease in patients with ulcerative colitis but further studies are needed.