Tumor Necrosis Factor Alpha Blockade Research Articles

Impact of Adalimumab Treatment on Interleukin-17 and Interleukin-17 Receptor Expression in Skin and Synovium of Psoriatic Arthritis Patients with Mild Psoriasis.

Interleukin (IL)-17 and tumor necrosis factor-alpha (TNF)-α are key players in psoriatic arthritis (PsA) pathogenesis. While both cytokines can be therapeutically targeted with beneficial clinical outcome, it is unclear whether inhibiting one cytokine will affect the other at sites of inflammation. If both act independently, this might provide a rationale for dual or combined inhibition of both cytokines. Here, we evaluated the effect of TNF blockade in PsA patients on IL-17 levels in both skin and synovial tissue biopsies. PsA patients with mild psoriatic skin lesions were randomized to receive either adalimumab or placebo for four weeks. Synovial and skin biopsies were obtained at weeks zero and four. Skin from healthy donors (HDs) was used for comparison. Expression of IL-17A, IL-17F, IL-17RA and IL-17RC was assessed by immunohistochemistry and analyzed with digital image analysis. We found relatively low levels of IL-17 and its receptors in the skin of PsA patients compared to HD, and only IL-17F in the dermis of lesional psoriatic skin was significantly higher compared to HD skin (p = 0.0002). Histologically IL-17A, IL-17F, IL-17RA and IL-17RC in skin and synovial tissue were not downregulated by adalimumab treatment. Thus, in this cohort of PsA patients with mild psoriasis, TNF blockade did not affect the protein levels of IL-17 cytokines and its receptors in skin and synovium, despite reduced cellular inflammation and improved clinical outcome for joint involvement.

Membranous nephropathy complicating relapsing polychondritis: A case report

Background: Relapsing polychondritis is a rare systemic disease characterized by recurrent inflammation, and often destruction, of cartilaginous tissues. Renal manifestations are rare. Membranous nephropathy complicating relapsing polychondritis has been reported only once previously, and there is no standardized treatment for membranous nephropathy associated with relapsing polychondritis. Case presentation: A 67-year-old Caucasian man with a history of chronic renal disease presented with 9 months of progressive dyspnea on exertion and 5 months of erythema, pain, and collapse of auricular cartilage. Imaging studies confirmed active inflammation of laryngeal, auricular, and costal cartilage and he was diagnosed with relapsing polychondritis. Patient had longstanding proteinuria and renal biopsy demonstrated membranous nephropathy. Patient initially showed renal and respiratory improvement with etanercept, a tumor necrosis factor alpha inhibitor, treatment. However, subsequent disease and treatment-related complications led to a progressive overall clinical decline and patient died approximately 1 year following relapsing polychondritis diagnosis. Conclusion: Membranous nephropathy may rarely complicate relapsing polychondritis. In our case, both the cartilaginous inflammation and the renal disease improved after treatment with tumor necrosis factor alpha blockade, however complications of existing airway disease led to recurrent hospitalizations and eventually death.

Management of Multisystem Inflammatory Syndrome in Children Associated with COVID-19 Infection.

Purpose of reviewThe purpose of this review is to summarize what is known about multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 infection.Recent findingsThe timing of presentation and features of diagnosis are described. Cardiac involvement is common and is the focus of this review. Arrhythmias, heart block, acute heart failure, shock, cardiac dysfunction, and coronary dilation have all been reported. Therapies used to treat children with this hyperinflammation syndrome include supportive care and agents that modulate the immune system. Therapies commonly described include intravenous immunoglobulin, steroids, and cytokine-directed agents, particularly tumor necrosis factor-alpha blockade and interleukin receptor blockade. The threshold for diagnosing coronary involvement in MIS-C is coronary artery dimensions indexed to body surface that exceed the normative values (Z score >2). Those hospitalized with MIS-C are evaluated by electrocardiogram and echocardiogram; outpatient assessment by a cardiologist is indicated prior to sports clearance.SummaryThe prognosis of treated MIS-C patients is good. Future work is needed to understand the scope of cardiac involvement associated with acute COVID-19 and MIS-C in children and to define the optimal therapeutic targets for these distinct entities.

Tumor necrosis factor alpha blockade prevents immune checkpoint inhibitor therapy-related cardiotoxicity

Abstract Background Increasing use of immune checkpoint inhibitor (ICI) therapy has recently been associated with latent left ventricular dysfunction as a common cardiotoxic side effect during early therapy. Considering the potential impact on morbidity and mortality, strategies to prevent ICI-related cardiotoxicity are urgently needed, but established immunosuppressive measures prevent the anti-tumor effect of the ICI therapy, thereby limiting its applicability to severe, life-threatening cases. Recently, tumor necrosis factor alpha (TNFα) blockade was shown to prevent ICI-related gut toxicity while preserving, or even enhancing, anti-tumor efficacy. Purpose This study aims to investigate a cardioprotective effect of TNFα blockade during anti programmed death 1 (PD1) ICI therapy in a preclinical model as a basis for a potential new, preventive therapeutic approach for ICI-related cardiotoxicity. Methods A melanoma mouse model was established as the basis to study PD1 blocking therapy and protective measures in a preclinical setting. Mice were subcutaneously transplanted with a syngeneic melanoma cell line and treated with anti-PD1 antibodies for 15 days. Response to therapy was monitored by assessment of tumor size. Cardiotoxicity was confirmed by mouse echocardiography. Mice were then simultaneously treated with anti-PD1 antibodies and TNFα-blocking antibodies. A cardioprotective effect was evaluated by echocardiography and flow cytometry was used to characterize myocardial immune cells. Results Mice receiving anti-PD1 showed smaller tumor sizes with increased immune cell infiltration compared to control littermates as a sign for a profound response to therapy. Cardiotoxicity was confirmed as demonstrated by reduced left ventricular ejection fraction and reduced global radial strain in anti-PD1-treated mice. Mice receiving anti-PD1 ICI therapy showed 2-fold elevated concentrations of CD4+ and CD8+ T-lymphocytes in the murine heart as determined by flow cytometry. CD44 expression was upregulated in cytotoxic T-cells as a marker of enhanced T-cell activity in anti-PD1 treated mice. Administration of TNFα-blocking antibodies did not alter tumor sizes during anti-PD1 treatment as a sign for a sustained response to therapy. Remarkably, mice receiving TNFα-blocking antibodies together with anti-PD1 ICI therapy showed increased left ventricular function compared to mice receiving anti-PD1 monotherapy. Flow cytometry revealed increased expression of T cell exhaustion markers in mice receiving TNFα blockade as a potential underlying mechanism. Conclusions ICI therapy targeting PD1 induces latent cardiotoxicity with left ventricular dysfunction. TNFα blockade may serve as a novel cardioprotective treatment without compromising the anti-tumor efficacy of ICI therapy. Prospective studies are needed to further characterize ICI-related cardiotoxicity in patients and to evaluate the cardioprotective effect of TNFα blockade. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): IFORES research grant, Medical Faculty, University Duisburg-Essen, Essen, Germany

Tumor necrosis factor alpha (TNF-α) blockade improves natural killer cell (NK) activation, hypertension, and mitochondrial oxidative stress in a preclinical rat model of preeclampsia

ABSTRACT The RUPP rat model of Preeclampsia exhibits hypertension (MAP), cytolytic natural killer (cNK) cells, tumor necrosis factor alpha (TNF-α) and mitochondrial Reactive Oxygen Species (mt ROS). Objective: Does TNF-α blockade with ETAN (Etanercept) decrease cNK cell and mt ROS in RUPP rats. Methods: On gestational day 14, RUPP surgery was performed, ETAN (0.4 mg/kg) was administered on day 18, MAP, blood and tissues collected on 19. Results:MAP, cytolytic NK cells and mt ROS were elevated in RUPP vs. NP and normalized with ETAN. Conclusion: TNF-α blockade lowered blood pressure and improve inflammation and organ function in response to placental ischemia.

Functional and phenotypic heterogeneity of Th17 cells in health and disease.

Th17 cells have nonredundant roles in maintaining immunity, particularly at mucosal surfaces. These roles are achieved principally through the production of cytokines and the recruitment of other immune cells to maintain the integrity of mucosal barriers and prevent the dissemination of microorganisms. Th17 cells are heterogeneous and exhibit a considerable degree of plasticity. This allows these cells to respond to changing environmental challenges. However, Th17 cells also play pro-inflammatory roles in chronic autoimmune diseases. The trigger(s) that initiate these Th17 responses in chronic autoimmune diseases remain unclear. In this report, we provide an overview of studies involving animal models, patient data, genome wide association studies and clinical trials targeting IL-17 for treatment of patients to gain a better understanding of the pathogenic roles of Th17 cells play in a range of autoimmune diseases. The report sheds light on likely triggers that initiate or perpetuate Th17 responses that promote chronic inflammation and autoimmunity. The divergent effects of tumour necrosis factor alpha blockade on Th17 cells in patients, is explored. Furthermore, we highlight the role of Th17 cells in inducing autoreactive B cells, leading to autoantibody production. Pathogenic bacterial species can change Th17 cell phenotype and responses. These findings provide insights into how Th17 cells could be induced to promoting autoimmune disease pathogenesis. This article provides an overview of the distinct roles Th17 cells play in maintaining immunity at mucosal surfaces and in skin mucosa and how their functional flexibility could be linked with chronic inflammation in autoimmune rheumatic diseases.

1,25(OH)2D3 and dexamethasone additively suppress synovial fibroblast activation by CCR6+ T helper memory cells and enhance the effect of tumor necrosis factor alpha blockade

BackgroundDespite recent improvements in the treatment of rheumatoid arthritis (RA), an insufficient treatment response and the development of treatment resistance in many patients illustrates the need for new therapeutic strategies. Chronic synovial inflammation could be suppressed by targeting RA synovial fibroblast (RASF) activation by, for example, interleukin (IL)-17A-producing CCR6+ T helper memory (memTh) cells. Here, we modulated this interaction by combining the active vitamin D metabolite 1,25(OH)2D3 with dexamethasone (DEX) and explored the potential therapeutic applications.MethodsCCR6+ memTh cells from peripheral blood mononuclear cells (PBMCs) of healthy donors or treatment-naive early RA patients were cultured alone or with RASF from established RA patients for 3 days and treated with or without 1,25(OH)2D3, DEX, or etanercept. Treatment effects were assessed using enzyme-linked immunosorbent assay (ELISA) and flow cytometry.Results1,25(OH)2D3, and to lesser extent DEX, reduced production of the pro-inflammatory cytokines IL-17A, IL-22, and interferon (IFN)γ in CCR6+ memTh cells. Tumor necrosis factor (TNF)α was only inhibited by the combination of 1,25(OH)2D3 and DEX. In contrast, DEX was the strongest inhibitor of IL-6, IL-8, and tissue-destructive enzymes in RASF. As a result, 1,25(OH)2D3 and DEX additively inhibited inflammatory mediators in CCR6+ memTh-RASF cocultures. Interestingly, low doses of mainly DEX, but also 1,25(OH)2D3, combined with etanercept better suppressed synovial inflammation in this coculture model compared with etanercept alone.ConclusionThis study suggests that 1,25(OH)2D3 and DEX additively inhibit synovial inflammation through targeting predominantly CCR6+ memTh cells and RASF, respectively. Furthermore, low doses of DEX and 1,25(OH)2D3 enhance the effect of TNFα blockade in inhibiting RASF activation, thus providing a basis to improve RA treatment.

Heterogeneity of the Type I Interferon Signature in Rheumatoid Arthritis: A Potential Limitation for Its Use As a Clinical Biomarker.

An increased expression of interferon (IFN)-responding genes (IRGs), the so-called IFN signature, has been reported in rheumatoid arthritis (RA). However, some controversy exists concerning its clinical relevance. The main aim of this study is to evaluate whether quantitative and qualitative differences in the activation of the IFN pathway may account for these findings. The expression of IFN-induced protein 44 (IFI44), IFN-induced protein 44 like (IFI44L), IFN alpha inducible protein 6, and MX dynamin-like GTPase 1 (MX1) was determined in peripheral blood in 98 RA patients (IFI6) and 28 controls. RA patients were classified into groups according to their clinical stage and treatments received: very early RA (VERA), biological disease-modifying antirheumatic drug (bDMARD) naive, and bDMARD. An additional group of 13 RA patients candidates for tumor necrosis factor alpha (TNFα) blockade was also recruited. The associations among IRGs were evaluated by network and principal component analyses. The expression of all IRGs was increased in RA to different levels. The IFN score was increased in all RA groups (VERA, bDMARD-naïve, and bDMARD), but important differences in their degree of activation and in the relationships among IRGs were observed. The IFN score correlated with the accumulated disease activity score 28-joints, and it was found to be a predictor of clinical outcome in VERA. No differences in the IFN score were observed between the bDMARD-naive and bDMARD groups, but opposite associations with the clinical parameters were noted. Interestingly, the correlations among IRGs delineate different pictures between these two groups. The IFN score at baseline predicted poor clinical outcome upon TNFα blockade. Although no absolute changes in the IFN score were found, TNFα-blockade shifted the associations among IRGs. A certain heterogeneity within the IFN signature can be recognized in RA, depending on the clinical stage. The structure of the IFN signature may be a potential explanation for the controversy in this field and must be considered to decipher its clinical relevancein RA.

Tumor Necrosis Factor-Alpha Targeting Can Protect against Arthritis with Low Sensitization to Infection.

Tumor necrosis factor-alpha (TNF-α) blockade is an effective treatment for rheumatoid arthritis (RA) and other inflammatory diseases, but in patients, it is associated with reduced resistance to the infectious agents Mycobacterium tuberculosis and Listeria monocytogenes, among others. Our goal was to model infection and arthritis in mice and to compare etanercept, a currently used anti-TNF-α inhibitor, to an anti-TNF-α vaccine. We developed a murine surrogate of the TNF-α kinoid and produced an anti-murine TNF-α vaccine (TNFKi) composed of keyhole limpet hemocyanin conjugated to TNF-α, which resulted in anti-TNF-α antibody production in mice. We also used etanercept (a soluble receptor of TNF commonly used to treat RA) as a control of TNF neutralization. In a mouse model of collagen-induced arthritis, TNFKi protected against inflammation similar to etanercept. In a mouse model of acute L. monocytogenes infection, all TNFKi-treated mice showed cleared bacterial infection and survived, whereas etanercept-treated mice showed large liver granulomas and quickly died. Moreover, TNFKi mice infected with the virulent H37Rv M. tuberculosis showed resistance to infection, in contrast with etanercept-treated mice or controls. Depending on the TNF-α blockade strategy, treating arthritis with a TNF-α inhibitor could result in a different profile of infection suceptibility. Our TNFKi vaccine allowed for a better remaining host defense than did etanercept.

Abstract P389: Post-traumatic Stress-induced Sensitization of Angiotensin II Hypertension is Reversed by Blockade of Angiotensin-converting Enzyme or Tumor Necrosis Factor-alpha

Using an Induction-Delay-Expression experimental paradigm, our previous studies demonstrated that post-traumatic stress disorder (PTSD) sensitizes angiotensin (ANG) II-elicited hypertension, which was associated with upregulation of central renin-angiotensin system (RAS) components and proinflammatory cytokines (PICs). The present study investigated whether inhibition of angiotensin-converting enzyme (ACE) or tumor necrosis factor-α (TNF-α) prior to PTSD blocks sensitization of ANG II-elicited hypertensive response. The resident-intruder paradigm was used to model PTSD. Each intruder rat (male Sprague-Dawley) was pretreated with ACE inhibitor (captopril, 0.5 mg/Ml) or with TNF-α inhibitor (pentoxifylline, PTX, 100 mg/kg/day) in the drinking water for two weeks and then exposed to a different resident (male Long-Evans) for 2 hours on three days with each session separated by 1 day. Beginning 3 days after the last exposure, the intruder (PTSD) rats and unstressed control rats received a subcutaneous infusion of ANG II (120 ng/kg/min) for 2 weeks. The PTSD rats had a significantly enhanced hypertensive response to the ANG II infusion and an upregulation of mRNA expression of RAS and PIC components and of a microglial marker in the lamina terminalis (LT) when compared to control rats. Both the sensitized hypertensive response and enhanced gene expression were blocked by pre-treatment with either ACE inhibitor or TNF-α antagonist. These results suggest that upregulation of the brain RAS and PICs produced by a severe stress contribute to PTSD-induced sensitization of the hypertensive response to ANG II.

MP81-01 CENTRAL TUMOR NECROSIS FACTOR-ALPHA BLOCKADE INCREASED NNOS EXPRESSION IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS AND IMPROVED SEXUAL BEHAVIOR DISORDER IN MALE DIABETIC RATS

You have accessJournal of UrologySexual Function/Dysfunction: Basic Research & Pathophysiology II1 Apr 2017MP81-01 CENTRAL TUMOR NECROSIS FACTOR-ALPHA BLOCKADE INCREASED NNOS EXPRESSION IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS AND IMPROVED SEXUAL BEHAVIOR DISORDER IN MALE DIABETIC RATS Ting Long, Huanhuan Wang, Xiaohong Ye, Wenwen Lin, Yuanyuan Zhang, and Danian Qin Ting LongTing Long More articles by this author , Huanhuan WangHuanhuan Wang More articles by this author , Xiaohong YeXiaohong Ye More articles by this author , Wenwen LinWenwen Lin More articles by this author , Yuanyuan ZhangYuanyuan Zhang More articles by this author , and Danian QinDanian Qin More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2527AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Sexual dysfunction, including decreased libido, sexual behavior disorder and erectile dysfunction (ED), is common in male patients with diabetes mellitus (DM). We previously demonstrated that increased peripheral tumor necrosis factor alpha (TNF-a) expression, associated with inflammation in DM, contributes to ED in the rat corpus cavernosum. However, the role of TNF-a in the central pathophysiology of DM-associated male sexual dysfunction is unknown. In this study, we examined the effects of TNF-a inhibition, i.e. etanercept (ETN) via chronic intra-cerebroventricular (ICV) infusion on neuronal nitric oxide synthase (nNOS) expression in the hypothalamic paraventricular nucleus (PVN) and sexual behavior disorder in male diabetic rats. METHODS Type II male DM rats were divided into 4 groups (G), n= 12/G, and subjected to chronic ICV infusion of artificial cerebrospinal fluid (aCSF) or ETN (10 μg/kg/day) by Osmotic Pumps, with and without induction of DM: G1: non-diabetic+ICV aCSF as control; G2: non-diabetic+ICV ETN; G3: DM+ICV aCSF; and G4: DM+ICV ETN. After 4 weeks of treatments, sexual behavior, expression of TNF-a, TNFR-1, and nNOS proteins, nNOS activity, and reactive oxygen species (ROS) generation within the PVN were assessed. RESULTS Male diabetic rats with ICV aCSF treatment displayed significantly severe sexual disorder accompanied with blunted nNOS expression and activity in the PVN in addition to local upregulated TNF-a and TNFR-1 expression, and increased ROS generation compared with non-diabetic controls. The sexual behavioral parameters including mounting latency, intromission latency, the number of mountings and the number of intromissions until ejaculation, induced by the introduction of receptive females, were significantly improved in the treated group with ETN. ICV ETN significantly inhibited TNF-a and TNFR-1 expression and reduced ROS generation in the PVN in diabetic rats. In addition, ICV ETN appeared to induce marked increased in nNOS expression in the PVN of diabetic animals compared with ICV aCSF-treated diabetic rats. Activity of nNOS in the PVN was also significantly increased in ICV ETN-treated versus ICV aCSF-treated diabetic rats. CONCLUSIONS Increased TNF-a and TNFR1 expression in the hypothalamic PVN associated with DM contributes to male sexual disorder by centrally inhibiting nNOS expression and activity in the PVN via promoting local ROS generation. Central TNF-a blockade may have beneficial effects on the male sexual disorder in diabetes through improvement of NO pathway within the PVN. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1089 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Ting Long More articles by this author Huanhuan Wang More articles by this author Xiaohong Ye More articles by this author Wenwen Lin More articles by this author Yuanyuan Zhang More articles by this author Danian Qin More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Tumor necrosis factor-alpha blockade in recurrent and disabling chronic sciatica associated with post-operative peridural lumbar fibrosis: Results of a two-year, double-blind, placebo randomized controlled study

To assess the efficacy and safety of tumor necrosis factor (TNF)-α inhibition with infliximab (IFX) in treating recurrent and disabling chronic sciatica pain associated with post-operative peridural lumbar fibrosis. A double-blind, randomized, placebo controlled study randomized 35 patients presenting sciatica pain associated with post-operative peridural lumbar fibrosis to 2 groups: IFX ( n = 18), a single intravenous injection of 3 mg/kg IFX; and placebo n = 17), a single saline serum injection. The primary outcome was a 50% reduction in sciatica pain on visual analog scale (VAS) at day 10. Secondary outcomes were radicular and lumbar VAS pain at day 0 and radicular and lumbar VAS pain, Québec disability score, drug sparing effect and tolerance at days 10, 30, 90, and 180. At day 10, the placebo and IFX groups did not differ in the primary outcome (50% reduction in sciatica pain observed in 3 [17.6%] vs 5 [27.8%] patients, p = 0.69). The number of patients reaching the Patient Acceptable Symptom State for radicular pain was significantly higher in the placebo than IFX group after injection (12 [70.6%] vs 5 [27.8%], p = 0.01). The 2 groups were comparable for all other secondary outcomes. Treatment with a single 3-mg/kg IFX injection for post-operative peridural lumbar fibrosis-associated sciatica pain does not significantly reduce radicular symptoms at day 10 after injection.

Chronic constriction injury-induced nociception is relieved by nanomedicine-mediated decrease of rat hippocampal tumor necrosis factor.

Neuropathic pain is a chronic pain syndrome that arises from nerve injury. Current treatments only offer limited relief, clearly indicating the need for more effective therapeutic strategies. Previously, we demonstrated that proinflammatory tumor necrosis factor-alpha (TNF) is a key mediator of neuropathic pain pathogenesis; TNF is elevated at sites of neuronal injury, in the spinal cord, and supraspinally during the initial development of pain. The inhibition of TNF action along pain pathways outside higher brain centers results in transient decreases in pain perception. The objective of this study was to determine whether specific blockade of TNF in the hippocampus, a site of pain integration, could prove efficacious in reducing sciatic nerve chronic constriction injury (CCI)-induced pain behavior. Small inhibitory RNA directed against TNF mRNA was complexed to gold nanorods (GNR-TNF siRNA; TNF nanoplexes) and injected into the contralateral hippocampus of rats 4 days after unilateral CCI. Withdrawal latencies to a noxious thermal stimulus (hyperalgesia) and withdrawal to innocuous forces (allodynia) were recorded up to 10 days and compared with baseline values and sham-operated rats. Thermal hyperalgesia was dramatically decreased in CCI rats receiving hippocampal TNF nanoplexes; and mechanical allodynia was transiently relieved. TNF levels (bioactive protein, TNF immunoreactivity) in hippocampal tissue were decreased. The observation that TNF nanoplex injection into the hippocampus alleviated neuropathic pain-like behavior advances our previous findings that hippocampal TNF levels modulate pain perception. These data provide evidence that targeting TNF in the brain using nanoparticle-protected siRNA may be an effective strategy for treatment of neuropathic pain.

Spectral domain-optical coherence tomographic findings in patients with ankylosing spondylitis under anti-tumor necrosis factor-alpha therapy

Objective: To evaluate the effect of tumor necrosis factor-alpha (TNF-α) blockade on the thickness of the peripapillary retinal nerve fiber layer (RNFL), the ganglion cell-inner plexiform layers (GCIPL), and the macula in ankylosing spondylitis (AS) patients under anti-TNF-α therapy.Materials and methods: Twenty-one patients with AS received etanercept, or adalimumab, or infliximab for at least 6 months. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores were measured before and 6 months after the beginning of the treatment. Peripapillary RNFL, four regional fields (superior, inferior, nasal, and temporal), GCIPL, and macular thicknesses of the patients were analyzed by optical coherence tomography before the treatment, at 3 months and 6 months after the beginning of the treatment.Results: The mean BASDAI, ESR, and CRP values were 5.2 ± 1.5, 31.6 ± 21.7, and 15.7 ± 13.9, respectively, at the beginning of the treatment and 2.3 ± 1.7, 21.3 ± 15.1, and 10.1 ± 10.3, respectively, 6 months after the beginning of treatment. There were significant differences among the mean BASDAI, ESR, and CRP values at the beginning of treatment and 6 months later (p < 0.001, p = 0.007, and p = 0.009, respectively). There were no significant differences among peripapillary RNFL (p = 0.24), four regional fields (p = 0.98, p = 0.23, p = 0.09, p = 0.47), GCIPL (p = 0.25), or macular (p = 0.33) thicknesses of the patients during anti-TNF-α treatment. In addition, the mean intraocular pressure levels throughout the follow-up did not show significant variation on repeated-measures ANOVA (p = 0.77).Conclusions: TNF-α blockade does not seem to influence RNFL, GCIPL, or macular thickness of patients with AS in the short term.

Intravesical Application of Rebamipide Promotes Urothelial Healing in a Rat Cystitis Model

Rebamipide is used as a topical therapeutic agent for various organs. We examined the healing effects of intravesical rebamipide on damaged urothelium in a rat model of chemically induced cystitis. Hydrochloride was injected in the bladder of female Sprague Dawley® rats to induce cystitis. On days 1 and 4 rebamipide (1 or 10mM) or vehicle was administered in the bladder and maintained for 1 hour. Histopathology, urothelial permeability, cystometrogram and nociceptive behaviors were evaluated on day 7. Also, tissue rebamipide concentrations after the 1-hour bladder instillation were quantified using high performance liquid chromatography. Intravesically administered rebamipide permeated the bladder, particularly in hydrochloride treated rats, and the pharmacologically effective tissue dose remained for greater than 6 hours. Bladder histological evaluation revealed polymorphological inflammatory cell infiltration and decreased positive staining for uroplakin 3A in hydrochloride treated rats. Scanning electron microscopy showed damaged tight junctions in the hydrochloride group. Evans blue absorption in the bladder wall was increased in hydrochloride treated rats. These findings, which were associated with urothelial injury and increased permeability, were dependently suppressed by the rebamipide treatment dose. Cystometrogram demonstrated that the intercontraction interval was shorter in hydrochloride treated rats but prolonged by rebamipide. The increased nociceptive behaviors observed after intravesical resiniferatoxin administration werealso suppressed by rebamipide. Intravesical rebamipide accelerated the repair of damaged urothelium, protected urothelial barrier function and suppressed bladder overactivity and nociception.

AB0931 Anti-TNF Agents in Intractable Familial Mediterranean Fever with Axial Spondylarthropathy: Four Cases

BackgroundFamilial Mediterranean Fever (FMF) is an autoinflammatory disease characterized by recurrent attacks of fever and serositis. A relation between FMF and Ankylosing Spondylitis (AS) has been suggested in small cohort...

THU0508 Sparing Methotrexate Results in a Less Stringent Control of Plasma Cell and Immunoglobulin Free Light Chain Production in Seropositive Patients with Rheumatoid Arthritis

BackgroundClinical trials revealed that tumor necrosis factor alpha (TNF-α) blockade is more effective if administered with concomitant methotrexate (MTX).ObjectivesBased on an observation made when studying B cell subsets in patients...

Beneficial effects of tumour necrosis factor-alpha (TNF-alpha) blockade in rheumatoid arthritis (RA)

The biological properties of TNF-alpha make it a candidate therapeutic target in RA. Our studies have demonstrated that TNF-alpha and its receptors are up-regulated and co-expressed in the synovium and cartilage-pannus junction of RA joints. Neutralizing TNF-alpha antibodies reduce the production of the many pro-inflammatory cytokines, including IL-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF), produced by mononuclear cells from RA in culture. When injected into DBA/1 mice with collagen-induced arthritis and TNF-alpha transgenic mice with arthritis, anti-TNF MoAbs decrease inflammatory damage of joints. Clinical trials employing cA2, a chimaeric anti-TNF-alpha MoAb, in open-label and randomized placebo-controlled studies have demonstrated a dose-dependent efficacy with impressive improvement in disease activity and acute-phase responses lasting several weeks. We conclude that TNF-alpha is a critical mediator of inflammation in RA, and is an important therapeutic target in this disease.

Intravesical Application of Rebamipide Suppresses Bladder Inflammation in a Rat Cystitis Model

We examined the effects of intravesical application of rebamipide (Otsuka Pharmaceutical, Tokyo, Japan) on bladder inflammation and overactivity in a chemically induced cystitis model. Female Sprague Dawley® rats under isoflurane anesthesia were injected with 150 mg/kg cyclophosphamide in the peritoneum, and 1 mM or 10 mM rebamipide or vehicle was administered in the bladder and remained for 1 hour. Control rats were injected with saline in the peritoneum and vehicle was administered in the bladder. The bladder was harvested at 48 hours. Hematoxylin and eosin staining was performed and the inflammation grade was assessed. The amount of myeloperoxidase was measured using enzyme-linked immunosorbent assay. Proinflammatory cytokines were quantified using reverse transcriptase-polymerase chain reaction. Cystometrogram was done in awake rats 48 hours after cyclophosphamide treatment to measure voiding reflex parameters. Histological evaluation revealed that bladder inflammation in cyclophosphamide treated rats was suppressed by rebamipide in a dose dependent manner. Up-regulated myeloperoxidase, IL-1β, IL-6 and TNF-α expression in cyclophosphamide treated rats was also suppressed in rebamipide treated rats. Cystometrogram demonstrated that the intercontraction interval decreased in cyclophosphamide treated rats but was prolonged by rebamipide. Intravesical application of rebamipide suppressed bladder inflammation and overactivity in a dose dependent manner. This may provide a new treatment strategy for chemotherapy associated cystitis.

P01-010 – Anti-TNF agents in intractable FMF: four cases

Familial Mediterranean Fever (FMF) is an autoinflammatory disease characterized by recurrent attacks of fever and serositis. A relation between FMF and Ankylosing Spondylitis (AS) has been suggested in small cohort studies, although there is no consensus regarding the role of HLA B27. Colchicine, the mainstay treatment in FMF, does not improve the axial or peripheral symptoms due to spondylarthropathy. There are controversial data about the efficacy of Tumor Necrosis Factor Alpha (TNF α) blockade in FMF patients [1].