Tumor Necrosis Factor Antibody Research Articles

Micronutrient supplementation as an interventional therapy for growth faltering in children with environmental enteric dysfunction

Background Environmental enteric dysfunction (EED) is a subclinical disorder which affects the small bowel of children, mainly living in developing countries. Zinc acts a major function in intestinal cells proliferation and crypt-villus structure preservation. Omega-3 fatty acids modulate some enzymes implicated in intestinal inflammation. Objective This research was performed to assess the effect of receiving both zinc and omega-3 supplements on anthropometric parameters and serum markers levels of EED [high sensitive C-reactive protein (hsCRP), Alpha-1-acid glycoprotein (AGP), tumor necrosis factor alpha (TNF-α), zonulin, and antibody of endotoxin core (EndoCAb)]. In those stunted kids with EED, this evaluation may lead to enhancing the nutritional composition of complementary food introduced to stunted and malnourished children having EED. Materials and methods This interventional study included 105 stunted and/or underweight children who were diagnosed as EED patients. They were subdivided into two groups; group I: 55 children receiving zinc sulphate and group II: 50 children receiving omega-3. Quantification of serum markers of EED (hsCRP, AGP, TNF-α, zonulin, antibody of endotoxin core) in addition to serum vitamin D, along with assessment of anthropometric parameters were performed to those children 6 months after zinc and omega-3 supplementation Results and conclusion In all subjects postintervention group, anthropometric parameters [height for age z-score (HAZ) score, weight for age z-score (WAZ) score and arm circumference] increased significantly 6 months after supplementation, however serum markers of EED (AGP, hsCRP, TNF-α and zonulin) decreased significantly 6 months after supplementation. Vitamin D level correlated positively with weight for age z-score and height for age z-scores. Conclusion Oral zinc sulphate and omega-3 may be added to EED management protocol to improve anthropometric parameters and decrease serum markers of EED.

Neutrophil-activating therapy for the treatment of cancer.

Despite their cytotoxic capacity, neutrophils are often co-opted by cancers to promote immunosuppression, tumor growth, and metastasis. Consequently, these cells have received little attention as potential cancer immunotherapeutic agents. Here, we demonstrate in mouse models that neutrophils can be harnessed to induce eradication of tumors and reduce metastatic seeding through the combined actions of tumor necrosis factor, CD40 agonist, and tumor-binding antibody. The same combination activates human neutrophils invitro, enabling their lysis of human tumor cells. Mechanistically, this therapy induces rapid mobilization and tumor infiltration of neutrophils along with complement activation in tumors. Complement component C5a activates neutrophils to produce leukotriene B4, which stimulates reactive oxygen species production via xanthine oxidase, resulting in oxidative damage and Tcell-independent clearance of multiple tumor types. These data establish neutrophils as potent anti-tumor immune mediators and define an inflammatory pathway that can be harnessed to drive neutrophil-mediated eradication of cancer.

Pre-injection of Zebrafish (Danio rerio) tnfb Polyclonal Antibody Decreases the Mortality of Vibrio vulnificus Infected Zebrafish.

Tumor necrosis factor (TNF) plays an important role in an inflammatory cytokine storm. Over-secretion of TNF by the host in response to infection aggravates the disease. TNF expression level is positively correlated with the mortality caused by some bacterial infections. Therefore, using TNF antibody may alleviate the inflammation to resist bacterial infections. The function of fish TNF-b antibody in bacterial infection is still unclear. In this study, infection models of Vibrio vulnificus FJ03-X2 strain with high pathogenicity and strong virulence were established in zebrafish (Danio rerio) fibroblast cell line (ZF4 cells) and zebrafish. Zebrafish tnfb (Zetnf-b) gene was cloned and expressed by Escherichia coli BL21 (DE3), and Zetnf-b polyclonal antibody was prepared. Pre-injection of Zetnf-b polyclonal antibody and AG-126 before infecting with V. vulnificus could increase the survival rate of zebrafish by 36.6 and 46.7%, respectively. Pre-injection of Zetnf-b polyclonal antibody could effectively decrease the mortality of zebrafish infected by V. vulnificus. Thus, TNF polyclonal antibody therapy could be considered as an effective strategy to control V. vulnificus in fish.

Increased serum levels of interleukin-6 in erythema nodosum leprosum suggest its use as a biomarker.

Erythema nodosum leprosum (ENL) is a frequent complication of multibacillary leprosy that can result in significant morbidity, including peripheral nerve damage and physical disability. The identification of possible serum markers could be a valuable tool for the early detection of ENL. The purpose of this study was to evaluate selected serum mediators involved in the innate and adaptive immune responses to identify possible immunomarkers for ENL. The levels of interleukin-2, interleukin-4, interleukin-6, interleukin-10, interleukin-17, interferon-γ, tumor necrosis factor, nitric oxide and anti-phenolic glycolipid-I antibodies were measured in the sera of leprosy patients with ENL [at the beginning of reaction (M0) and 1 month later (M1)], and then compared with the levels of the same markers in patients with untreated multibacillary leprosy without ENL (controls with leprosy: CTRL) and healthy individuals (healthy controls: CTRH). Significantly higher levels of serum interleukin-6 were observed in M0 than in CTRL. In addition, pairwise comparisons showed higher levels of interleukin-6 in M0 compared to M1. Levels of tumor necrosis factor were higher in M0 than in CTRL, with no significant difference between M0 and M1. There were no differences in the levels of interleukin-2, interleukin-4, interleukin-10, interleukin-17 or interferon-γ between groups. The CTRL group had higher levels of nitric oxide compared to M0 and M1. High levels of anti-phenolic glycolipid-I were observed in M0, M1 and CTRL than in CTRH. Three patients were not assessed at M1, decreasing the number of evaluated patients from 14 to 11. High-serum levels of interleukin-6 were observed during ENL, primarily in patients with more severe reactions; levels decreased after specific therapy, suggesting a role for this cytokine in pathogenesis and its utility as an ENL biomarker. Further studies should explore whether interleukin-6 could also be used as a predictive marker for ENL or as a specific target for its treatment.

Suppression of Rheumatoid Arthritis by Enhanced Lymph Node Trafficking of Engineered Interleukin-10 in Murine Models.

Rheumatoid arthritis (RA) is a major autoimmune disease that causes synovitis and joint damage. Although clinical trials have been performed using interleukin-10 (IL-10), an antiinflammatory cytokine, as a potential treatment of RA, the therapeutic effects of IL-10 have been limited, potentially due to insufficient residence in lymphoid organs, where antigen recognition primarily occurs. This study was undertaken to engineer an IL-10-serum albumin (SA) fusion protein and evaluate its effects in 2 murine models of RA. SA-fused IL-10 (SA-IL-10) was recombinantly expressed. Mice with collagen antibody-induced arthritis (n = 4-7 per group) or collagen-induced arthritis (n = 9-15 per group) were injected intravenously with wild-type IL-10 or SA-IL-10, and the retention of SA-IL-10 in the lymph nodes (LNs), immune cell composition in the paws, and therapeutic effect of SA-IL-10 on mice with arthritis were assessed. SA fusion to IL-10 led to enhanced accumulation in the mouse LNs compared with unmodified IL-10. Intravenous SA-IL-10 treatment restored immune cell composition in the paws to a normal status, elevated the frequency of suppressive alternatively activated macrophages, reduced IL-17A levels in the paw-draining LN, and protected joint morphology. Intravenous SA-IL-10 treatment showed similar efficacy as treatment with an anti-tumor necrosis factor antibody. SA-IL-10 was equally effective when administered intravenously, locally, or subcutaneously, which is a benefit for clinical translation of this molecule. SA fusion to IL-10 is a simple but effective engineering strategy for RA therapy and has potential for clinical translation.

Golimumab in adolescents with Crohn's disease refractory to previous tumour necrosis factor antibody.

AimAnti‐tumour necrosis factor (TNF)‐α drugs are effective treatments for the management of moderate/severe Crohn's disease (CD), but treatment failure is common. In the treatment of paediatric CD, there are no data about the use of a third introduced subcutaneous TNF antibody golimumab.MethodsWe evaluated the efficacy of golimumab for adolescents with moderate/severe CD. Retrospective analyses were done in all 7 (5 girls) adolescents who received golimumab at a median age of 17 years for a median of 7.2 months. Paediatric Crohn's disease activity index (PCDAI), full blood count, inflammatory markers, use of corticosteroids and adverse events were recorded.ResultsWith golimumab, 5 of the 7 children were PCDAI responders and 2 entered remission (PCDAI <10). Faecal calprotectin was significantly reduced after 4 weeks compared to baseline. Out of five children, steroid withdrawal was possible in one and steroid reduction in two cases. There were no serious side effects.ConclusionIn moderate/severe CD, golimumab induced clinical remission with PCDAI response. Golimumab may be an effective rescue therapy in refractory CD.

Clinical outcomes with ustekinumab as rescue treatment in therapy-refractory or therapy-intolerant ulcerative colitis.

Recently, ustekinumab a monoclonal antibody targeting interleukin-12 and -23 and successfully used in Crohn's disease also has been shown to be effective in induction and maintaining remission in patients with moderate to severe ulcerative colitis in a large phase 3 trial. However, no observational data on the use of ustekinumab in ulcerative colitis in daily clinical practice is available. The purpose of this study was to assess the clinical outcomes achieved with ustekinumab as rescue treatment in therapy-refractory or -intolerant ulcerative colitis in a real-life setting. A retrospective data analysis was performed in 19 ulcerative colitis patients who were intolerant or refractory to all of the following drugs: steroids, purine-analogues, tumour necrosis factor antibodies and vedolizumab. To all patients ustekinumab was provided as a rescue treatment (intravenous induction with 6 mg/kg, followed by week subcutaneous injection once every eight weeks of 90 mg). The primary outcome was achievement of clinical remission at one year, defined as score of ≤ 3 points in the Lichtiger score (colitis activity index). Patients were evaluated regularly and a colonoscopy was performed before the start and at the end of the observation. Ethical approval was provided by Ethikkommission Ärztekammer Hamburg (PV 5539). In five patients, therapy was stopped due to refractory disease or side effects. In all remaining 14 patients the median colitis activity index dropped from 8.5 points (range 1-12) at start to 2.0 points at one year (range 0-5.5) and Mayo endoscopy scores fell from a median of two points (range 1-3, mean of 2.3) at start to a median of one point (range 1-3, mean of 1.4) at one year. Including the five drop-outs, clinical remission was achieved in 53% of the 19 patients at one year. In accordance with the UNIFI (A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis) trial our real-life data support ustekinumab as an effective and safe treatment option in therapy refractory moderate to severe ulcerative colitis with a history of biological therapies.

Ameliorating the effects of Adalimumab on rabbits with experimental cerebral vasospasm after subarachnoid hemorrhage.

Adalimumab (ADA), which is a new-generation recombinant human monoclonal antibody for tumor necrosis factor α (TNFα), has strong anti-inflammatory effects. The role of enhanced inflammation is well established for the development and progression of cerebral vasospasm. Investigated in the present study is the probable ameliorating and neuroprotective effects of ADA in rabbits using a cerebral vasospasm model with biochemical and histopathological methods. Thirty male New-Zealand white rabbits were randomly divided into control, subarachnoid hemorrhage (SAH) only and SAH plus ADA treatment groups. SAH was established as a single cisterna magna autologous arterial blood injection. ADA treatment was started just after intracisternal blood injection and continued for 72 hours once a day. The animals were sacrificed 72 hours after the induction of SAH, serum and brainstem tissue obtained for investigations. Brainstem tissue and plasma levels of tumor necrosis factor-alpha and Interleukin-1β, brainstem tissue Matrix metalloproteinase-9 levels increased after SAH and partly decreased after treatment. Plasma levels of brain-derived neurotrophic factor decreased after SAH and partly restored after treatment. ADA treatment significantly increased the mean cross-sectional area of the vasospastic basilar arteries, reduced the basilar artery wall thickness and also ameliorates enhanced endothelial apoptosis. Findings obtained in this study suggest that ADA is an effective neuroprotective agent for ameliorating cerebral vasospasm in experimental rabbit vasospasm.

Profile of Tofacitinib in the Treatment of Ulcerative Colitis: An Evidence-Based Review of Recent Data.

Recent advances in the understanding of the pathophysiology of ulcerative colitis (UC) have led to the expansion of our therapeutic arsenal. Conventional treatment options, including aminosalicylates, corticosteroids, thiopurines, and calcineurin inhibitors, fail to control the disease in a significant proportion of patients. Approximately 25–50% of the patients treated with tumor necrosis factor antibodies (anti-TNFα) are primary and secondary non-responders to therapy. Tofacitinib is a novel orally administered small synthetic molecule that inhibits a homologous family of enzymes, termed Janus kinases that modulate multiple key cytokines involved in the pathogenesis of UC. Phase II and III trials showed promising results in UC, leading the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to approve its administration for the induction and maintenance of remission in moderate-to-severe UC. Herein, we review tofacitinib for the management of UC, its mechanism of action pharmacokinetic properties, efficacy, and safety.

Retuning the immune system in myelodysplastic syndromes: from immunomodulatory approaches to vaccination strategies and non myeloablative hemopoietic cell transplant.

Several findings suggest that the pathogenesis and clinical history of myelodysplastic syndromes (MDS) is influenced by a variety of immune pathways and mechanisms. Coherently several therapeutic approaches based on the idea of modulating the immune system have been exploited in this clinical setting. The present review will first consider more consolidated strategies such as antithymocyte globulin and immunomodulatory (IMiDs) analogues. Less explored approaches, such as anti tumor necrosis factor antibodies, cyclosporin and bortezomib will be also evaluated. Finally the potential impact of anti-tumour vaccination or hemopoietic cell transplantation on the outcome of MDS patients will be addressed.

The role of kinins in the proliferation of fibroblast primed with TNF in scratch wound assay: Kinins and cell proliferation

The aim of this study was to evaluate the involvement of both B1 and B2 kinins receptors (B1R and B2R) in the fibroblast proliferation induced by the cytokine tumour necrosis factor (TNF) attempting to establish an in vitro model of wound healing. Murine fibroblasts L-929 were cultivated in 24 wells plaque until total confluence (DMEM (Vitrocell®); 5% fetal bovine serum, 5% CO2, 37 °C) and then submitted to the scratch assay. The cells were treated with PBS, TNF (2 ng/mL) and/or mr-TNF antibody (200 μg/mL), or PDTC. The cells received the second set of treatment (3 h later): PBS; 1 μM HOE-140; 1 μM des-Arg9-Leu8-BK (DALBK) or 100 μM PDTC. TNF was able to increase the cell proliferation when compared with the group treated with PBS. The co-treatment with the TNF antibody completely reversed the TNF effect. The TNF-proliferative effect was blocked by B1 (DALBK) and B2 (HOE-140) kinin receptor antagonists administered separately or along, suggesting the involvement of both receptors in the TNF mechanism of action. Furthermore, the treatment with a NF-ĸB inhibitor PDTC completely blocked the cell proliferation. The TNF cell proliferation was incremented with BK (1 μM) treatment, and its effect was totally reversed by HOE-140 treatment. No effect was observed for TNF plus DABK. Eventually, TNF treatment was able to increase TNF level in the growing medium; however, this increase was suppressed by BK treatment. These results suggest that TNF induces cell proliferation and the induced signalling cascade has the B2R participation. All these events seem to be totally dependent on the NF-ĸB activation. These inflammatory mediators can improve the wound healing in the resolution of inflammation.

Abatacept blocks anti-citrullinated protein antibody and rheumatoid factor\xa0mediated cytokine production in human macrophages in IDO-dependent manner

BackgroundThe anti-inflammatory effect of abatacept is most pronounced in patients with high-titer autoantibodies (including anticitrullinated protein antibodies [ACPA] and rheumatoid factor [RF]). Considering that autoantibodies trigger inflammatory cytokine production by monocytes and that abatacept binds to monocytes, influencing their functional state, we hypothesized that abatacept may effectively inhibit the production of several different cytokines by ACPA- or RF-challenged monocytes.MethodsPeripheral blood CD68+ monocytes stimulated with macrophage colony-stimulating factor for 24 h were exposed to random immunoglobulin G alone (negative control), purified ACPA, purified RF, or lipopolysaccharide (positive control) in cell culture plates coated with citrullinated vimentin (to allow ACPA immune complex formation). Stimulations were done in the presence or absence of abatacept or tumor necrosis factor (TNF) antibody (adalimumab) with or without indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-d-tryptophan. Supernatants were analyzed for key proinflammatory cytokines TNF-α, interleukin (IL)-1β, IL-6, IL-8, and chemokine (C-C motif) ligand 2 (CCL2) after 24 h.ResultsExposure to ACPA or RF significantly induced the production of TNF-α (20-fold and 27-fold, respectively), IL-1β (each 4-fold), IL-6 (12-fold and 11-fold, respectively), IL-8 (43-fold and 30-fold, respectively), and CCL2 (each 4-fold) in human monocytes. Abatacept inhibited this autoantibody-mediated upregulation of cytokines, reducing TNF-α by > 75%, IL-1β by > 65%, IL-6 and IL-8 by > 80%, and CCL2 by > 60%. In contrast, a TNF inhibitor did not influence autoantibody-induced proinflammatory cytokine production. IDO inhibition reversed the effect of abatacept and again permitted the induction of cytokine production by ACPA and RF.ConclusionsThese data show that abatacept interferes with autoantibody-mediated cytokine production by monocytes through induction of IDO. This inhibitory effect on the production of several effector cytokines in RA may explain the fast anti-inflammatory effect of abatacept as well as its preferential efficacy in patients with high-titer ACPA and RF.

Anti–Tumor Necrosis Factor With a Glyco-Engineered Fc-Region Has Increased Efficacy in Mice With Colitis

Although tumor necrosis factor (TNF) antagonists reduce many clinical features of inflammatory bowel disease, complete mucosal healing occurs in fewer than 50% of patients. The Fc-region of monoclonal antibodies against TNF has immunosuppressive properties via effects on macrophage polarization. We examined the interaction between the anti-TNF Fc-region and Fcγ receptors (FcγR), and whether the absence of the Fc core fucose (which increases binding to FcγRIIIa) increases the efficacy of anti-TNF in mice with colitis. We generated Rag1-/- mice that lackall activating FcγRs (FcγRI, FcγRIII, and FcγRIV; called FcγR-/-Rag1-/- mice). We produced hypo-fucosylated antibodies against mouse and human TNF (adalimumab). Colitis was induced in mice by transfer of CD4+CD45RBhi to FcγR-/-Rag1-/- or Rag1-/- littermates; mice were given different antibodies against TNF or isotype (control) antibodies and disease activity index scores were determined. Colon tissues were collected and analyzed by histology. Human peripheral blood mononuclear cells (PBMCs) were isolated from blood of healthy donors. T-cell proliferation and proportions of CD206+ (immune regulatory) macrophages were measured in mixed lymphocyte reactions. Human PBMCs were genotyped for FCGR3A158 (the FcγRIIIa-158F allotype displays a lower Fc binding affinity) using the TaqMan single nucleotide polymorphism genotype assay. Rag1-/- mice with colitis given anti-TNF had near complete mucosal healing and Rag1-/- mice given an isotype control antibody developed severe colitis. In contrast, FcγR-/-Rag1-/- mice were refractory to the effects of anti-TNF: their histological colitis scores were as severe as those from FcγR-/-Rag1-/- mice given a control antibody. Colons from Rag1-/- mice that received anti-TNF had an increased number of CD206+ macrophages compared with Rag1-/- mice given control antibody; in FcγR-/-Rag1-/- mice given anti-TNF these numbers were as low as FcγR-/-Rag1-/- given the control antibody. In human PBMCs, anti-TNF increased the number of CD206+ macrophages: this required expression of FcγRIIIa; numbers of these cells were reduced in PBMCs with the low-affinity FcγRIIIa-158F genotype. A hypo-fucosylated form of adalimumab bound human FcγRIIIa with a higher affinity than control adalimumab. When hypo-fucosylated adalimumab was added to PBMCs, a larger number of CD206+ macrophages formed and T-cell proliferation was reduced, compared with addition of a control adalimumab. Hypo-fucosylated adalimumab increased the number of CD206+ macrophages in PMBCs that expressed the low-affinity FcγRIIIa. In mice with colitis, hypo-fucosylated anti-TNF significantly increased the number of CD206+ macrophages in the colon compared with control anti-TNF and was more effective in reducing colitis severity as measured by histology. In a study of the invitro and invivo mechanisms of anti-TNF, we found FcγR engagement by anti-TNF to be required for reduction of colitis in mice and development of CD206+ macrophages. A hypo-fucosylated form of anti-TNF binds FcγRIIIa with higher affinity and induces development of CD206+ macrophages in human PBMCs, especially PBMCs that express low-affinity FcγRIIIa. Hypo-fucosylated anti-TNF might be more effective in patients with inflammatory bowel disease.

Appropriateness of Testing for Anti-Tumor Necrosis Factor Agent and Antibody Concentrations, and Interpretation ofResults.

The availability of tests for blood concentrations of anti-tumor necrosis factor (TNF) agents and antibodies against these drugs could improve dose selection for patients with inflammatory bowel disease (IBD). However, there is little consensus on when to test and how to interpret test results. We used the RAND/UCLA Appropriateness Method to determine when these tests are appropriate and how to clinically interpret their results. We conducted a systematic literature search in November 2013 to identify observational or experimental studies of the measurement of anti-TNF drug and antibody concentrations in patients with IBD and interpretation of their results. We developed 35 scenarios that assessed the appropriateness of testing and 143 scenarios that addressed clinical strategies in response to test results, and presented the findings to an expert panel. The appropriateness of each scenario was rated before and after an in-person meeting with the panel. Panelists rated the appropriateness of various clinical management options including changing therapy within class, switching out of class, adjusting drug dose or interval, adding or adjusting concomitant immune modulators, and doing nothing for each of 6 permutations of high versus low drug concentrations and high, low, or undetectable antibody concentrations. Disagreement was assessed using a validated index. Assessment of anti-TNF drug and antibody concentrations was rated appropriate at the end of induction therapy in primary nonresponders, in secondary nonresponders, at least once during the first year of maintenance therapy, and following a drug holiday. Routine assessment in responders at the end of induction was rated uncertain. In nearly all scenarios, escalation of drug dosing was rated appropriate when drug concentration was low in the absence of antibodies, and switching within class was rated appropriate when antibodies were present. Other recommendations depended on the specific clinical scenario for which the test was obtained. Based on the RAND/UCLA Appropriateness Method of analysis, an expert panel recommends testing for drug and antibody concentrations in many clinical scenarios. The appropriate timing and best way to respond to anti-TNF drug and antibody testing for IBD depends on the specific clinical scenario. These recommendations can help guide clinicians to best optimize anti-TNF therapy.

Rational design of antirheumatic prodrugs specific for sites of inflammation.

ObjectiveBiologic drugs, such as the anti–tumor necrosis factor (anti‐TNF) antibody adalimumab, have represented a breakthrough in the treatment of rheumatoid arthritis. Yet, concerns remain over their lack of efficacy in a sizable proportion of patients and their potential for systemic side effects such as infection. Improved biologic prodrugs specifically targeted to the site of inflammation have the potential to alleviate current concerns surrounding biologic anticytokine therapies. The purpose of this study was to design, construct, and evaluate in vitro and ex vivo the targeting and antiinflammatory capacity of activatable bispecific antibodies.MethodsActivatable dual variable domain (aDVD) antibodies were designed and constructed to target intercellular adhesion molecule 1 (ICAM‐1), which is up‐regulated at sites of inflammation, and anti‐TNF antibodies (adalimumab and infliximab). These bispecific molecules included an external arm that targets ICAM‐1 and an internal arm that comprises the therapeutic domain of an anti‐TNF antibody. Both arms were linked to matrix metalloproteinase (MMP)–cleavable linkers. The constructs were tested for their ability to bind and neutralize both in vitro and ex vivo targets.ResultsIntact aDVD constructs demonstrated significantly reduced binding and anti‐TNF activity in the prodrug formulation as compared to the parent antibodies. Human synovial fluid and physiologic concentrations of MMP enzyme were capable of cleaving the external domain of the antibody, revealing a fully active molecule. Activated antibodies retained the same binding and anti‐TNF inhibitory capacities as the parent molecules.ConclusionThe design of a biologic prodrug with enhanced specificity for sites of inflammation (synovium) and reduced specificity for off‐target TNF is described. This construct has the potential to form a platform technology that is capable of enhancing the therapeutic index of drugs for the treatment of RA and other inflammatory diseases.

Extraintestinal Manifestations of Inflammatory Bowel Disease.

Extraintestinal manifestations (EIM) in inflammatory bowel disease (IBD) are frequent and may occur before or after IBD diagnosis. EIM may impact the quality of life for patients with IBD significantly requiring specific treatment depending on the affected organ(s). They most frequently affect joints, skin, or eyes, but can also less frequently involve other organs such as liver, lungs, or pancreas. Certain EIM, such as peripheral arthritis, oral aphthous ulcers, episcleritis, or erythema nodosum, are frequently associated with active intestinal inflammation and usually improve by treatment of the intestinal activity. Other EIM, such as uveitis or ankylosing spondylitis, usually occur independent of intestinal inflammatory activity. For other not so rare EIM, such as pyoderma gangrenosum and primary sclerosing cholangitis, the association with the activity of the underlying IBD is unclear. Successful therapy of EIM is essential for improving quality of life of patients with IBD. Besides other options, tumor necrosis factor antibody therapy is an important therapy for EIM in patients with IBD.

Efficacy of anti-tumor necrosis factor therapy for extra-articular manifestations in patients with ankylosing spondylitis: a meta-analysis.

BackgroundWe performed a meta-analysis to evaluate the effect of anti–tumor necrosis factor (TNF) therapy on the frequency of extra–articular manifestations (EAMs) in patients with ankylosing spondylitis (AS).MethodsWe searched with the terms ‘ankylosing spondylitis’, ‘infliximab’, ‘etanercept’, ‘adalimumab’, ‘golimumab’, ‘certolizumab’, ‘TNF inhibitor/blocker/antagonists’ or ‘anti-TNF’ on MEDLINE, EMBASE and Cochrane Library for randomized controlled trials (RCTs) of ≥12 weeks with parallel or crossover design of TNF inhibitor versus placebo to treat uveitis, inflammatory bowel disease (IBD) and/or psoriasis of AS, published before February 2014.ResultsWe found 8 RCTs that fit our criteria. Anti–TNF therapy was associated with less uveitis than placebo in patients with AS (OR: 0.35, 95% CI: 0.15–0.81, P = 0.01). Subgroup analysis showed receptor fusion proteins were more efficacious for uveitis than placebo (OR: 0.30, 95% CI: 0.09–0.94, P = 0.04), but monoclonal antibodies were not (OR: 0.43, 95% CI: 0.12–1.49, P = 0.18). Anti–TNF therapy and placebo group did not significantly differ in treating IBD in AS patients (OR: 0.75, 95% CI: 0.25–2.29, P = 0.61). In subgroup analysis, neither monoclonal antibodies (OR: 0.45, 95% CI: 0.10–1.92, P = 0.28) nor receptor fusion proteins (OR: 1.52, 95% CI: 0.25–9.25, P = 0.65) significantly differed from placebo in treating IBD. We found no suitable reports on psoriasis.ConclusionsAnti–TNF therapy was preventive for flares or new onset of uveitis in AS patients, and might be an alternative for these patients. However, monoclonal anti–TNF antibodies and TNF receptor fusion proteins were not efficacious for IBD in AS patients.

Growth and bone health in paediatric patients with Crohn's disease receiving subcutaneous tumor necrosis factor antibody.

To study whether adalimumab (ADA) was associated with improvement in growth, bone mineral density (BMD) and bone metabolism. In children with Crohn's disease (CD) there is a high prevalence of growth failure and reduced BMD. Treatment with infliximab is associated with an improvement in growth. Anthropometry, paediatric CD activity index (PCDAI), bone markers and BMD was measured in 18 patients (72% females) one year before and after start of ADA with a median age of 14.4 years (range: 5-19 years) at treatment start. Outcomes were indicators of growth with treatment as well as interval growth. Eleven (61%) children experienced catch-up growth after ADA. PCDAI significantly decreased from 52.1 ± 16 to 30.4 ± 23 (P ≤ 0.001). Post ADA, body mass index (BMI) standard deviation score (SDS) 0.1[range: 2.7-(-0.8)] vs -1 [range: 0.1-(-3.6)], P = 0.04 and ∆BMI SDS in children 0.3 [range: 0.7-(-0.2)] vs -1.1 [range: 1.2-(-2.3)], P = 0.01 in remission were significantly higher compared to those with moderate to severe inflammation. The main predictors for growth were 25-hydroxycholecalciferol and for bone mineralisation weight and height SDS. ADA had no significant influence on bone markers and BMD. Next to improvement of PCDAI, half of the children achieved a positive catch-up growth. A better nutritional status with improvement in BMI and weight is positive predictor for improved growth and bone mineralisation.

O-037 Modulation of Inflammatory Processes in DSS-induced Colitis Models versus Gastrointestinal Acute Radiation Syndrome with AVX-470m, an Oral Polyclonal Anti-TNF Antibody

Development of improved therapies for inflammatory bowel disease (IBD) requires animal models that elucidate underlying mechanisms of disease. Acute radiation syndrome (ARS) has devastating consequences in the gastrointestinal (GI) tract driven in part by cytokine-mediated inflammation that closely resembles the pathophysiology of IBD. Tumor Necrosis Factor (TNF) is central to the dysregulated inflammatory response in IBD, and is strongly implicated in GI ARS. In this study AVX-470 m, a bovine polyclonal neutralizing antibody for murine TNF, is used to characterize the pathogenesis of GI damage in models of GI ARS and IBD. Colitis was induced in C57BL/6 mice by including 3% DSS in drinking water for 5 days. Other C57BL/6 mice were irradiated with 15.9 Gy (∼LD80/30) from a 60Co gamma source, with partial bone marrow shielding. Animals were dosed BID with AVX-470 m (10 mg/day) or saline by oral gavage for up to 14 days. In colon and jejunum tissues, relative mRNA expression levels of cytokines and immune markers was measured by qPCR (Taqman), and protein expression was analyzed by immunohistochemistry (IHC) in paraffin embedded, formalin fixed tissue sections. Both mRNA and protein levels of TNF were increased in colon and jejunum tissue, respectively, in the colitis and GI ARS models. IL-1β, IL-6, MMP9, ICAM-1, and TNFR2 mRNA levels were increased in both models, but IL12p40 was increased only in the colitis model, and no change in TNFR1 mRNA levels was detected in either model. Protein expression of MPO was increased in both the colitis and GI ARS models. These data show a remarkable correlation of inflammatory responses between these 2 models of GI injury. In contrast, CD68 and CD3 protein were increased in colon tissue in the colitis model, but neither protein was detected in jejunum in the GI ARS model, suggesting a reduced T-cell component in GI ARS, perhaps due to destruction of these cells by the high levels of ionizing radiation. In both colitis and GI ARS models, treatment with AVX-470 m resulted in a significant decrease in TNF mRNA and protein expression in colon and jejunum tissues, respectively. AVX-470 m also decreased MPO protein expression, and reduced MMP9 mRNA expression, in both models. In the colitis model, IL-6 mRNA levels were decreased by AVX-470 m treatment in colon tissue, while in the GI ARS model IL-6 mRNA levels were transiently increased in jejunum tissue. No change in mRNA levels for ICAM-1 or TNFR1 were seen in either model following AVX-470 m treatment. These studies show that inflammatory responses in colitis and GI ARS models share a common TNF-mediated neutrophilic component in the colon and jejunum, respectively, but differ with respect to immune cell involvement in response to injury. Further studies will reveal whether these differences reflect variability in timing, tissue localization, or response to the different insults. The fact that AVX-470 m is effective in both models highlights the central role of TNF in inflammation in the GI tract, and supports the therapeutic potential of an oral anti-TNF antibody as a gut-targeted treatment for multiple GI inflammatory diseases.

Comprehensive tuberculosis screening program in patients with inflammatory arthritides treated with golimumab, a human anti–tumor necrosis factor antibody, in Phase III clinical trials

Reactivation of Mycobacterium tuberculosis infection is a major complication in patients treated with anti-tumor necrosis factor (anti-TNF) agents. We report on the 5 cases of active tuberculosis (TB) that developed in the Golimumab Phase III Program (3 with rheumatoid arthritis, 1 with psoriatic arthritis, and 1 with ankylosing spondylitis) through 1 year among 2,210 patients receiving golimumab. Data from global studies were used for an in-depth evaluation of the 5 cases of TB through week 52. Integrated safety data were evaluated for potential hepatotoxicity in patients treated with anti-TB therapy. No active TB developed among 317 patients receiving golimumab and treated for latent TB with isoniazid. Active TB occurred in 5 patients not treated with isoniazid by week 52 (in 2 patients by week 24); all of the patients had negative TB screening tests (per the local guidelines) and resided in countries with high background rates of TB. No deaths were due to TB. Across all of the groups (placebo and golimumab), alanine aminotransferase and aspartate aminotransferase elevations occurred in greater proportions of patients treated for latent TB infection versus not treated; elevations were largely mild (<3 times the upper limit of normal). Comprehensive TB screening kept the number of active TB cases relatively low despite conducting the studies in TB-endemic regions. Treatment for latent TB infection appeared effective, since no patients treated for latent TB had TB reactivation. Concurrent treatment with golimumab and anti-TB medication was generally well tolerated. Clinicians should remain vigilant for development of active TB after initiation of TNF inhibitors, since prompt diagnosis and treatment can improve outcomes.