Targeting Tumor Necrosis Factor-alpha Research Articles

SAPHO syndrome: a review.

IntroductionSynovitis–acne–pustulosis–hyperostosis–osteitis (SAPHO) is an acronym for various osteoarticular and dermatological manifestations that can appear in the same patient. It is a rare syndrome, but since its awareness has increased, there have been more and more such reports in the literature.AimsThe objectives of this review are to summarize the current state of knowledge on pediatric and adult-onset SAPHO syndrome, and to discuss treatment strategies that should be considered.ResultsThe SAPHO syndrome can affect patients of any age, and its etiology is still not known. The syndrome has its cognizable radiological characteristics that are most important in making the diagnosis. There are several diagnostic criteria as well, but they need further validation. No standard treatment protocols are available and current treatment options are not evidenced-based due to the rarity of the syndrome. Therapy is empirical and aimed at easing pain and modifying the inflammatory process. It includes nonsteroidal anti-inflammatory drugs (NSAIDs) as the first-line agents. Antibiotics, corticosteroids, disease-modifying anti-rheumatic drugs, biologicals targeting tumor necrosis factor alpha or interleukin-1, and bisphosphonates have all been used with variable success. Surgery is reserved to treat complications. Even though it is a disease with good long-term prognosis, its treatment remains a challenge and the results are known to be disappointing, especially with the skin component of the disease.ConclusionIt is expected that these patients present at the time of diagnosis and the treatment should be as early, effective, and safe as possible in order to prevent osteoarticular progression and to limit the adverse events associated with pharmacological drugs.

Treatment of spondyloarthritis beyond TNF-alpha blockade.

The advent of biologics targeting tumor necrosis factor-alpha (TNF-alpha) has revolutionized the field of rheumatology in general and the treatment of spondyloarthritis (SpA) in particular, since - apart from non-steroidal anti-inflammatory agents - no disease modifying treatments are available for this frequent, inflammatory rheumatic condition. The significant improvements in signs and symptoms observed with TNF-blockers in this group of diseases, have raised the bar with regard to treatment goals, including clinical remission. Even if treatment failure with TNF-blocking agents may be a relatively rare phenomenon, cases of primary non-responders, secondary loss-of-efficacy and intolerance, have been described. Results with abatacept, rituximab and tocilizumab - all effective in the treatment of rheumatoid arthritis - were disappointing, especially in patients that had previously failed anti-TNF therapy. On the other hand, there is increasing evidence that targeting the cytokines of the Th-17 axis is associated with major improvements of skin psoriasis and its associated arthritis. In axial spondyloarthritis, preliminary proof-of-concept studies with ustekinumab and interleukin-17 targeting therapies suggest that these agents could become the first new treatment options, not targeting TNF. Finally, the advent of small molecules targeting inflammatory, intracellular signalling pathways, may further change our future therapeutic approach.

THU0164 Tnf-Alpha Bioactivity: A New Biomarker of Aspa Activity in Patients with Tnf-Alpha Blockers

BackgroundInfliximab is a chimeric monoclonal antibody targeting tumor necrosis factor alpha (TNFα) indicated in active axial sponsyloarthritis (aSpA).ObjectivesWe determine association between blood levels of infliximab, antibodies toward infliximab (ATI), TNFα,...

FRI0251 Liver Injury in Patients Receiving Infliximab: A Systematic Review

BackgroundInfliximab is a therapeutic monoclonal antibody that specifically targets Tumor Necrosis Factor alpha. In December 2004, the FDA conveyed an important drug warning on infliximab potential hepatotoxicity[1]. Several serious hepatic...

Su1397 Outpatients With Ulcerative Colitis Being Treated With Adalimumab and Infliximab Have Similar Rates of Loss of Response

Background: Biologic agents targeting tumour necrosis factor alpha (TNF-α), including infliximab and adalimumab, have been shown to be effective for induction and maintenance of remission in ulcerative colitis. However, during maintenance therapy response may be lost over time necessitating dose intensification, rescue corticosteroid therapy, or surgical intervention. A direct comparison of loss of response rates to adalimumab (ADA) and infliximab (IFX) during treatment of UC in a real-life IBD clinic has not been previously evaluated. Aims: The aim of this study was to compare, in UC patients treated with ADA or IFX, the proportion of patients who lost response during scheduled maintenance therapy, and to compare the time to loss of response for each agent. Methods: A retrospective cohort study evaluating anti-TNF Naive outpatients with UC entering into scheduled maintenance with ADA or IFX from 2004-2013 was conducted. All patients had completed the standard induction regimens for adalimumab and infliximab. Composite outcome for loss of response was defined by any one of: dose intensification (either increased dose or treatment frequency), surgical intervention, or rescue corticosteroid therapy. Kaplan-Meier analysis was used to assess maintenance of anti-TNF therapy over time. Logistic regression analysis was used to assess risk factors associated with loss of response. Results: 102 UC patients (60.8% male) met inclusion criteria. 36 patients (35.3%) were treated with adalimumab (ADA) and 66 patients (64.7%) were treated with infliximab (IFX). Disease distribution was pancolitic (73/ 102, 71.6%) or left-sided (29/102, 28.4%). Disease severity by mean partial Mayo score at anti-TNF induction was similar between the ADA (5.6±1.9) and IFX (6.2±2.3) groups. Mean follow-up duration was 139.0 weeks for ADA and 158.8 weeks for IFX. 21/36 (58.3%) ADA

The Heart and Pediatric Rheumatology

Recent advances in Kawasaki disease have included attempts to define genes involved in its pathogenesis. There have been recent advances in the studies of rheumatic carditis, leading to a better understanding of the mechanism of the disease. Histologic evaluation of patients with neonatal lupus erythematosus has revealed fibrosis with collagen deposition and calcification of the atrioventricular node. Therapy for cardiac involvement in systemic juvenile idiopathic arthritis should involve treatment of the underlying disease and systemic inflammatory state, and typically includes nonsteroidal antiinflammatory drugs, corticosteroids, disease-modifying drugs, and biologic therapies targeting tumor necrosis factor-alpha, interleukin-1, and interleukin-6.

PReS-FINAL-2064: Effect of Goloimumab a new anti-TNF, in patients with the diagnosis of juvenile idiopathic arthritis

Golimumab is a fully human monoclonal antibody targeting tumor necrosis factor-alpha (TNF-α), which plays an important role in the pathogenesis of juvenile idiopathic arthritis. Golimumab was approved for the treatment of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

Chemoprevention of Gastrointestinal Cancer: The Reality and the Dream

Despite substantial progress in screening, early diagnosis, and the development of noninvasive technology, gastrointestinal (GI) cancer remains a major cause of cancer-associated mortality. Chemoprevention is thought to be a realistic approach for reducing the global burden of GI cancer, and efforts have been made to search for chemopreventive agents that suppress acid reflux, GI inflammation and the eradication of Helicobacter pylori. Thus, proton pump inhibitors, statins, monoclonal antibodies targeting tumor necrosis factor-alpha, and nonsteroidal anti-inflammatory agents have been investigated for their potential to prevent GI cancer. Besides the development of these synthetic agents, a wide variety of the natural products present in a plant-based diet, which are commonly called phytoceuticals, have also sparked hope for the chemoprevention of GI cancer. To perform successful searches of chemopreventive agents for GI cancer, it is of the utmost importance to understand the factors contributing to GI carcinogenesis. Emerging evidence has highlighted the role of chronic inflammation in inducing genomic instability and telomere shortening and affecting polyamine metabolism and DNA repair, which may help in the search for new chemopreventive agents for GI cancer.

The SAPHO Syndrome

To review the epidemiology, presentation, diagnosis, treatment, pathogenesis, and genetics of the syndrome known under the acronym of SAPHO for Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis to heighten awareness of this entity. We conducted a Medline search using SAPHO syndrome, chronic recurrent multifocal osteitis/osteomyelitis, and related terms as keywords and extracted further relevant articles from the retrieved references. The SAHPO acronym identifies a syndrome encompassing a variety of osteoarticular disorders that are frequently accompanied by dermatoses characterized by neutrophilic pseudoabscesses, but can also occur in isolation. SAPHO syndrome is rare, although probably underrecognized because its diagnosis may be challenging because of the wide variability in its musculoskeletal and cutaneous manifestations. This is especially true when atypical sites are involved and when specific skin lesions are absent. There are no standardized treatment protocols available. Current treatments are empirical and have the objective of providing relief from the at times debilitating pain associated with SAPHO syndrome. They include nonsteroidal anti-inflammatory drugs and analgesics as first-line agents. Systemic corticosteroids, disease-modifying anti-rheumatic drugs, biologicals targeting tumor necrosis factor alpha and interleukin-1, and bisphosphonates have all been beneficial in some patients, but ineffective in others. This suggests that the pathogenesis of SAPHO syndrome is multifactorial, but this aspect remains poorly explored, although bacteria and immunological dysfunction are hypothesized to play a role. The early recognition, diagnosis, and prompt treatment of SAPHO syndrome can prevent the unnecessary use of long-term antibiotics or invasive procedures, while rapidly alleviating pain in a majority of affected patients.

1002 Overcoming Trastuzumab Resistance in Breast Cancer by Targeting Tumor Necrosis Factor Alpha

1002 Overcoming Trastuzumab Resistance in Breast Cancer by Targeting Tumor Necrosis Factor Alpha

Targeting tumor necrosis factor alpha (TNF-α) in diabetic rats could approve avenues for an efficient strategy for diabetic therapy

BackgroundSeveral studies held belief that downregulation of TNF-α may be effective for preventing diabetes and it's complications. However, it is not known whether TNF-α downregulation in long-term can generate any biological adverse. AimThe aim of the present study was to clarify what the impact is for such treatment with specific antibody for TNF-α on the other biological activities after 4weeks. MethodsUsing western blot, IHC, Elisa, biochemical assays and scanning electron microscope. ResultsResults show that TNF-α, FOXO-1, IL-6 and MPO, when expressed in diabetic rats, collectively induce dramatic changes in diabetic rats. Since, TNF-α is involved in activation of transcription factor FOXO1 along with oxidative stress mediated by neutrophils. On one hand, IL-6 mediates neutrophils activation leading to an augmentation in stress mediators. And FOXO1 is activated in order to eliminate these oxidative mediators, on the other hand. Data show also that the prominent defect in mucosal IgA and IL-2 secretions may be the leading reasons for digestive atrophy. Finally, Akt-1 inhibits the cleavage of caspase 3, so, it could prevent the incidence of apoptosis. ConclusionFindings of this study reveal how TNF-α can be mechanistically coupled to greater diabetic complications potential.

Etanercept‐induced cutaneous and pulmonary sarcoid‐like granulomas resolving with adalimumab

A 59-year-old female with rheumatoid arthritis on etanercept therapy presented with a 7-cm-large subcutaneous forearm mass. Multiple smaller nodules subsequently developed on the upper and lower extremities. Except for a new cough, the patient was systemically well. Biopsy of the mass showed sarcoidal type granulomatous inflammation with nodular aggregations of non-necrotizing epithelioid histiocytes in the subcutis. A chest computed tomography (CT) scan showed mediastinal adenopathy consistent with pulmonary sarcoidosis. Etanercept was discontinued, and the patient was started on adalimumab for rheumatoid arthritis control. The cutaneous nodules fully resolved in 6 months with no additional treatment. A 4-month follow-up CT scan showed significant regression of mediastinal adenopathy. The patient has since been maintained on adalimumab therapy for 2 years with no recurrence of sarcoid-like manifestations. Biologic response modifiers targeting tumor necrosis factor alpha (TNFα) are effective treatments of chronic inflammatory conditions such as rheumatoid arthritis and psoriasis. TNFα represents a major cytokine in granuloma formation, and TNFα inhibitors are sometimes efficacious in the treatment of sarcoidosis. Paradoxically, there is a small volume of literature implicating TNFα inhibitors in the development of sarcoid-like disease. We present this case to promote the recognition of TNFα inhibitor-induced sarcoidosis and to illustrate the wide clinicopathologic differential of sarcoidal type granulomas.

TNFα-mediated apoptosis in human osteoarthritic chondrocytes sensitized by PI3K-NF-κB inhibitor, not mTOR inhibitor

To investigate apoptosis of osteoarthritic (OA) chondrocytes stimulated with different inhibitors targeting tumor necrosis factor-alpha (TNFα) pathway, we isolated first passage chondrocytes from OA patients and then treated them with the inhibitors in combination with TNFα, and then collected the stimulated chondrocytes for Western blotting. Chondrocytes from OA patients expressed cleaved caspase-3 and PARP, suggesting apoptotic background. We here, validated that 10 ng/ml of TNFα couldn't induce more chondrocytes apoptosis. PI3K inhibitor LY294002 or NF-κB inhibitor CAPE, but not mTOR inhibitor rapamycin and MEK1/2 inhibitor U0126 in combination with TNFα could facilitate apoptosis. CAPE-induced more apoptosis could be explained by c-FLIP downregulation more than cIAP1 upregulation. And, we showed the first time that PI3K-NF-κB pathway, but not mTOR pathway could prevent chondrocytes apoptosis induced by a pro-apoptotic factor TNFα and call for attention while trying to inhibit NF-κB as a therapeutic target.

TNF alpha Inhibition as Treatment Modality for Certain Rheumatologic and Gastrointestinal Diseases

With the development of biologicals that specifically target tumor necrosis factor (TNF)alpha, our therapeutic approach to inflammatory diseases has dramatically changed. There are currently three anti-TNFalpha drugs available: etanercept, infliximab, and adalimumab. Etanercept is a recombinant fusion protein that can be used alone or in combination with other medications for conditions such as rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, psoriasis, and ankylosing spondylitis. Infliximab, a chimeric humanized monoclonal antibody and adalimumab, a fully human monoclonal antibody are approved for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and moderate to severe Crohn's disease. Infliximab is also approved for ulcerative colitis. Another anti-TNFalpha drug, certolizumab pegol, was declined approval as treatment option for active Crohn's disease due to a lack of sufficient efficacy. Phase III studies for the treatment of rheumatoid arthritis patients are still pending. It is the goal of this review article to summarize various therapeutic indications, underlying studies, safety, and use during pregnancy, as well as future directions for anti-TNF therapies.

Biologic Therapies for Psoriasis

Psoriasis is a common chronic inflammatory skin disease that may lead to disability and significant effects on patients' quality of life. A challenge in psoriasis management is to use an effective therapy early in the disease course in order to achieve a safe and well tolerated maintenance of remission with an improvement of both skin and joint manifestations. Recent advances in knowledge of the pathogenesis of psoriasis helped develop targeted treatment options that may be effective and well tolerated over long periods of administration, thus improving the patient's quality of life. These novel "biologic" agents specifically target tumor necrosis factor-alpha (infliximab, etanercept, and adalimumab) or T cells (efalizumab).

Japan College of Rheumatology 2009 guidelines for the use of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, in rheumatoid arthritis

The introduction of biological agents targeting tumor necrosis factor-alpha (TNF-α) has brought about a paradigm shift in the treatment of rheumatoid arthritis (RA). Although these anti-TNF agents have excellent efficacy against RA, a substantial number of patients still show inadequate responses. In Western countries, such patients are already being treated with new classes of antirheumatic drugs such as abatacept and rituximab. Tocilizumab (TCZ) is a humanized monoclonal antibody developed in Japan against the human interleukin-6 (IL-6) receptor. TCZ does not only alleviate the signs and symptoms of RA but also seems to prevent progressive bone and joint destruction. However, there is a concern that TCZ might increase the risk of adverse events such as infections since IL-6 plays a pivotal role in the immune system. Calculating the relative risks of specific adverse outcomes with TCZ use remains difficult, due to insufficient patient numbers enrolled in clinical trials to date. This review presents tentative guidelines for the use of TCZ for RA patients prepared by the Japan College of Rheumatology and based on results of clinical trials in Japan and Western countries. The guidelines are intended as a guide for postmarketing surveillance and clinical practice, and will be revised periodically based on the surveillance.

Biologics in the management of psoriasis

Psoriasis is a chronic inflammatory systemic disease for which there exist topical, ultraviolet, systemic, and biologic treatments. Biologic agents selectively interfere with the immune mechanisms responsible for psoriasis. Etanercept, infliximab, and adalimumab target tumor necrosis factor-alpha and have demonstrated efficacy in the treatment of psoriasis and psoriatic arthritis. Alefacept and efalizumab target T lymphocytes, are effective in the treatment of psoriasis, but are not approved for psoriatic arthritis. Finally, ustekinumab and ABT-874 target interleukin-12 and interleukin-23, and they have demonstrated efficacy in the treatment of psoriasis. The objective of this review is to present efficacy and safety data from randomized controlled trials of the biologic agents in the treatment of psoriasis.

Positioning biologic agents in the treatment of Crohnʼs disease

One decade after the emergence of biologic therapy for Crohn's disease (CD), our treatment algorithms are beginning to change. Once reserved for patients with refractory disease, disease unresponsive to conventional therapies, or those requiring multiple courses of corticosteroids, there is increasing evidence that early, aggressive interventions with immunosuppressants or biologic therapies targeting tumor necrosis factor-alpha or alpha-4 integrins can alter the natural history of CD by reducing the transmural complications of structuring and fistulization and the nearly inevitable requisite for surgical resections. More recent trials are beginning to suggest that intervention with combination therapy for selected patients with a poor prognosis may modify the long-term course of CD. Selection of patients with features predicting a complex or progressive course and early, combined intervention is now possible. Future studies are still needed to best identify predictors of response to individual agents with differing mechanisms of action, as well as to optimize the risk-benefit of long-term maintenance therapy.

Use of tumor necrosis factor-α (TNF-α) antagonists infliximab, etanercept, and adalimumab in patients with concurrent rheumatoid arthritis and hepatitis B or hepatitis C: a retrospective record review of 11 patients

An understanding of the cytokine cascade in a rheumatoid joint has led to the development of new therapeutic options, including drugs targeting tumor necrosis factor-alpha (TNF-alpha). The safety profile of these agents in patients with hepatitis-induced liver disease, however, remains a concern because of risks associated with immune suppression. To examine the effect of three different TNF-alpha antagonists, infliximab, etanercept, and adalimumab, on serum transaminases and hepatitis viral load in patients with rheumatoid arthritis (RA) and concurrent hepatitis B (HBV) or hepatitis C (HCV). Medical records of 11 patients with diagnosis of RA and documented seropositivity for hepatitis B or hepatitis C were retrospectively reviewed for worsening of hepatic inflammation and viral proliferation as measured by a rise in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and viral load while using these agents. Three patients had RA with concurrent chronic HBV and eight patients had RA with concurrent chronic HCV. Seven patients remained on a single anti-TNF-alpha agent and four patients switched to a second anti-TNF-alpha agent due to treatment failure. Two patients showed a transient elevation in AST and/or ALT from normal, but in all 11 patients, AST and ALT levels were within one time the upper range of normal at the conclusion of the study. No significant increase in viral load was seen except one patient who showed a fourfold increase from baseline. Our case series supports results obtained from previous studies examining the safety of anti-TNF-alpha agents in patients with underlying hepatic disease. Use of these agents in patients with HBV or HCV may be associated with a transient transaminitis but appears to be safe overall. In both groups, frequent monitoring of serum transaminase levels and viral load is essential.

Locally administered lentivirus-mediated siRNA inhibits wear debris-induced inflammation

To determine the safety and efficacy of local administration of lentivirus-mediated small interfering RNA (siRNA) targeting tumor necrosis factor-alpha (TNF-alpha) in murine air pouch model. From May 2007 to April 2008 a siRNA targeting TNF-alpha and a missense siRNA were designed, and recombine lentivirus which coexpressed the green fluorescent protein (GFP) as a marker gene was constructed. Air pouches were established and stimulated by Ti-6Al-4V particles. Pouches were divided into 3 groups randomly. Lentivirus-mediated siRNA targeting TNF-alpha (TNF-alpha group) or lentivirus-mediated missense siRNA (MS group), or virus-free saline (control group) were injected into pouches respectively. Pouch membrane, peripheral blood, heart, liver, spleen, kidney, lung and brain were harvested at 28 d after transfection, and assayed for markers of inflammation using histological, molecular, immunological techniques and Xenogen in vivo imaging system (IVIS) 50 vivo bioluminescent assay system. Xenogen IVIS 50 vivo image revealed strong expression of GFP localized in pouch areas and no expression in other parts of mice both in TNF-alpha group and MS group at 4 weeks after transfection, while no expression of GFP was found in control group. By RT-PCR and ELISA, the mRNA and protein levels of TNF-alpha in TNF-alpha group decreased by 81.6% and 82.6% respectively compared to control group (P < 0.01), and decreased by 78.9% and 84.0% respectively compared to MS group (P < 0.01), whereas TNF-alpha level in peripheral blood, heart, liver, spleen, kidney, lung and brain remained invariant (P > 0.05). Less inflammatory responses (thinner pouch membrane and decreased cellular infiltration) were observed in TNF-alpha group. Efficient local delivery of lentivirus-mediated siRNA targeting TNF-alpha into modified murine air pouch can inhibit debris-induced inflammation effectively, with no systemic adverse effects.