TNF Receptor Fusion Protein Research Articles

P36 Crohn’s-associated inflammatory arthritis treated successfully with upadacitinib

Introduction/BackgroundEnteropathic arthritis is inflammatory arthritis which is associated with inflammatory bowel disease such as Crohn’s disease and ulcerative colitis. The optimal treatment for patients is one which is effective for both arthritis and bowel disease. First line treatments include DMARDs such as methotrexate and sulfasalazine. Second line options include anti-TNF biologics such as infliximab and adalimumab, and the anti-IL-12/23 biologic ustekinumab. There is currently little guidance on choice of treatment if these options fail. We present a case of Crohn’s-associated inflammatory arthritis which did not respond to two anti-TNFs but was successfully treated with the JAK inhibitor upadacinitib.Description/MethodA 30-year-old male was referred to gastroenterology with a 4 month history of diarrhoea and weight loss. His faecal calprotectin was raised at 982µg/g. He had a history of seronegative inflammatory arthritis diagnosed 5 years previously. He had been treated initially with methotrexate and sulfasalazine, which were discontinued due to side effects and inefficacy, and his arthritis was subsequently well-controlled on etanercept for the last year.Colonoscopy showed patchy colitis at the rectum which was continuous in the transverse and ascending colon and caecum. The appearances and mucosal biopsy were consistent with moderately active Crohn’s colitis. In view of this, etanercept was switched to adalimumab, which was administered using the accelerated loading regimen used in IBD.Five weeks after switching the patient developed a flare of arthritis with knee and ankle inflammation and CRP 30. He was given oral steroids and reviewed in a combined rheumatology/gastroenterology clinic. The frequency of adalimumab was increased to 40mg weekly and subcutaneous methotrexate 10mg weekly was introduced.Despite this, the patient’s arthritis remained active, although with some improvement in his bowel symptoms and a fall in faecal calprotectin to 117µg/g. Adalimumab was switched to certolizumab and methotrexate increased to 15mg weekly with intra-muscular steroids. On certolizumab he developed progressively more active arthritis with CRP 83, bilateral ankle inflammation and large knee effusions requiring aspiration and steroid injection.After 8 weeks of certolizumab, there was no improvement and the decision was made to switch to upadacitinib 15mg daily. Within 4 weeks of treatment with upadacitinib he noticed a significant improvement in his arthritis and after 12 weeks was in clinical remission with normal CRP and faecal calprotectin. Methotrexate was later discontinued due to nausea. Over 12 months later the patient remains in remission for both bowel disease and arthritis on upadacitinib monotherapy.Discussion/ResultsIn enteropathic arthritis, joint symptoms may precede or follow bowel disease. Etanercept, a recombinant TNF-receptor fusion protein, is not an effective treatment for IBD. Indeed, there are case reports and observational data to suggest that etanercept may be associated with an increased risk of developing IBD in some patients. In our case the patient developed Crohn’s disease while taking etanercept and the switch to adalimumab precipitated a flare of his arthritis which was not controlled by treatment intensification. The failure of two anti-TNF biologics, adalimumab and certolizumab, may point to the activation of alternative cytokine inflammatory pathways as the driver of the patient’s disease.Our patient was managed in a combined rheumatology/gastroenterology clinic which enabled an inter-specialty approach to managing both aspects of his disease. After the failure of certolizumub we made the decision to trial upadacitinib, a selective JAK1 inhibitor, owing to our experience of its effectiveness in rheumatoid and psoriatic arthritis, and its promising results in Phase 3 trials in Crohn’s disease. We considered ustekinumab but opted against it as in our experience it may be suboptimal in patients in whom arthritis is the most troublesome symptom. Upadacitinib worked quickly and effectively to control our patient’s arthritis alongside his bowel disease and was well tolerated.There are currently limited treatments which are effective for both IBD and arthritis, and there is little guidance on treatment strategies in enteropathic arthritis if anti-TNF and ustekinumab are unsuccessful. Tofacitinib, a JAK1/3 inhibitor, is licensed for rheumatoid and psoriatic arthritis and ulcerative colitis, but is not effective for Crohn’s disease. Upadacitinib is undergoing Phase 3 trials in Crohn’s disease and our case highlights its potential role in the treatment of patients with Crohn’s disease and inflammatory arthritis in whom anti-TNF therapy is unsuccessful.Key learning points/Conclusion1. Etanercept is not an effective treatment for inflammatory bowel disease and may necessitate a change to another anti-TNF biologic such as infliximab or adalimumab.2. Upadacitinib, a selective JAK1 inhibitor, was successfully used in our case to treat both arthritis and bowel disease. Although this was just one case, the results of Phase 3 trials suggest a promising role for upadacitinib in Crohn’s disease and it is already used in the treatment of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.3. Patients with enteropathic arthritis may be best managed in a specialist combined gastroenterology and rheumatology clinic where a holistic approach to the management of both aspects of their disease can be undertaken.

Risk of herpes zoster (shingles) in patients with rheumatoid arthritis under biologic, targeted synthetic and conventional synthetic DMARD treatment: data from the German RABBIT register

ObjectiveTo compare event and incidence rates of herpes zoster (HZ), also known as shingles, in patients with rheumatoid arthritis under treatment with conventional synthetic (cs), targeted synthetic (ts) or biologic...

Inhibitory effect of tumor necrosis factor-α on the basolateral Kir4.1/Kir5.1 channels in the thick ascending limb during diabetes.

Diabetic nephropathy is a major contributor to the morbidity and mortality of patients with diabetes. TNF-α expression is elevated during diabetes and is implicated in the pathogenesis of diabetic nephropathy; however, its underlying molecular mechanisms remain unclear. The present study aimed to investigate the effect and molecular mechanism of TNF-α on the basolateral inwardly rectifying potassium (Kir)4.1/Kir5.1 channels in the thick ascending limb (TAL) of rat kidneys using western blotting and the patch clamp technique to provide a theoretical basis for the cause of the decrease in kidney concentrating capacity during diabetes. The results demonstrated that urinary TNF-α excretion and protein TNF-α expression in the TAL increased and basolateral Kir4.1/Kir5.1 channel activity decreased during diabetes; however, diabetic rats exhibited amelioration of Kir4.1/Kir5.1 activity with a soluble TNF-α antagonist, TNF receptor fusion protein (TNFR:Fc). These results suggested that TNF-α inhibited the activity of the basolateral Kir4.1/Kir5.1 channel in the TAL of rat kidneys during diabetes. In addition, the protein expression levels of phospholipase A2 (PLA2) and cyclooxygenase-2 (COX2) increased in diabetic rats, the effects of which deceased following treatment with TNFR:Fc compared with the diabetic group. Furthermore, an agonist of PLA2 (melittin) and COX2 production [prostaglandin E2 (PGE2)] inhibited the basolateral Kir4.1/Kir5.1 channels. Taken together, the results of the present study suggested that the inhibitory effect of TNF-α on the basolateral Kir4.1/Kir5.1 channels in the TAL during diabetes is mediated by the PLA2/COX2/PGE2 signaling pathway.

Single-Stranded DNA Aptamers Against TNF and Their Potential Applications.

Aptamers are short, single-stranded RNA or DNA sequences, which can bind to protein ligands with high affinity and specificity. Applications of aptamers are broad, ranging from drugs and drug delivery vehicles to biosensors. Tumor necrosis factor (TNF) is an inflammatory cytokine that plays a critical role in the pathogenesis of several autoimmune inflammatory diseases. Blocking TNF activity by monoclonal antibodies or TNF receptor fusion protein has been tremendously successful in treating these diseases. However, manufacturing these biological TNF inhibitors is expensive and a significant proportion of patients do not respond to TNF blockade. Here we describe selection of single-stranded DNA aptamers for TNF blockage, and their bioactivity in blocking TNF-mediated cytotoxicity in vitro. These TNF-binding aptamers have the potential to serve as alternatives to biological TNF inhibitors and to be used as in vivo probes for TNF detection.

Risk Assessment of Etanercept in Mice Chronically Infected With Toxoplasma gondii.

Toxoplasma gondii (T. gondii) is a zoonotic parasite that severely harms the health of the host. The cysts of T. gondii can reactivate from bradyzoites to tachyzoites, if the individual develops low or defective immunity, causing lethal toxoplasmosis. The host resists T. gondii infection by mediating Th1-type cellular immunity to generate pro-inflammatory cytokines. Tumor necrosis factor (TNF) is an important pro-inflammatory cytokine, which can induce lysosomal fusion of parasitophorous vacuole (PV) to kill parasites. Etanercept is a soluble TNF receptor fusion protein, which is widely used clinically to cure autoimmune diseases. The effects and specific molecular mechanisms of etanercept treatment on patients co-infected with autoimmune diseases and chronic toxoplasmosis are rarely reported. In our study, a mouse model of chronic infection with T. gondii and murine macrophages RAW264.7 cells infected with T. gondii were employed to investigate the impact of etanercept on the status of chronic infection. The cytokines levels and a series of phenotypic experiments in vivo and in vitro were measured. In the present study, the expression levels of TNF, IL-1β, and IL-6 were decreased and the brain cysts number was increased in mice chronically infected with T. gondii after being treated with etanercept. In vivo experiments confirmed that etanercept caused a decrease in the immune levels of the mice and activated the brain cysts, which would lead to conversion from chronic infection to acute infection, causing severe clinical and pathological symptoms. Murine macrophages RAW264.7 cells were pretreated with etanercept, and then infected with T. gondii. In vitro experiments, the expression levels of cytokines were decreased, indicating that etanercept could also reduce the cells’ immunity and promote the transformation of bradyzoites to tachyzoites, but did not affect the intracellular replication of tachyzoites. In summary, etanercept treatment could activate the conversion of bradyzoites to tachyzoites through reducing host immunity in vivo and in vitro. The results obtained from this study suggest that the use of etanercept in patients co-infected with autoimmune diseases and chronic toxoplasmosis may lead to the risk of activation of chronic infection, resulting in severe acute toxoplasmosis.

Preventive effect of tumor necrosis factor inhibitors versus nonsteroidal anti-inflammatory drugs on uveitis in patients with ankylosing spondylitis.

To compare the preventive effect of tumor necrosis factor (TNF) inhibitors (anti-TNF antibody and soluble TNF receptor fusion protein (TNFR)) and nonsteroidal anti-inflammatory drugs (NSAIDs) on uveitis in patients with ankylosing spondylitis (AS). This retrospective cohort study included all AS patients (n = 1055) who have been treated with either TNF inhibitor or NSAIDs at the Seoul National University Hospital from 2004 to 2016. Treatment episodes of each patient were assigned to anti-TNF antibody (n = 517), TNFR (n = 341), and NSAID (n = 704) groups. The incidence of uveitis in each group was compared using a Cox proportional hazard model. The incidence rates of uveitis before and after initiation of TNF inhibitors were also assessed. A propensity score-matched (PSM) comparison was performed for a sensitivity analysis. Uveitis was significantly less common in the anti-TNF antibody group than the NSAID group (adjusted hazard ratio (HR) 0.53; 95% confidence interval (CI) 0.29-0.96) while it was higher in the TNFR group (adjusted HR 2.25, 95% CI 1.43-3.53). Anti-TNF antibody further reduced the incidence of uveitis when prescribed with NSAIDs (combination therapy) (adjusted HR 0.39; 95% CI 0.19-0.79). Combination therapy was preventive in AS patients with a history of uveitis (adjusted HR 0.31; 95% CI 0.12-0.81), but not in those without history of uveitis. The incidence rate of uveitis fell from 6.36 to 2.60 per 100 person-years when anti-TNF antibody was added to NSAIDs. Anti-TNF antibody plus NSAIDs reduces the risk of uveitis to a greater extent than NSAIDs alone in AS patients with a history of uveitis. Combination therapy may be an effective secondary prevention measure.

Etanercept for treating axial spondyloarthritis

ABSTRACTIntroduction: Axial spondyloarthritis is an inflammatory rheumatic disease causing back pain, functional impairment and potential ankylosis in the advanced stage. In this context, TNF blockers have been a major therapeutic advance. Etanercept is a soluble recombinant TNF receptor fusion protein in this vain.Areas covered: The aim of this review is to summarize the current published data concerning the efficacy and tolerance of etanercept in axial spondyloarthrits. The authors performed a systematic review on PubMed, using ‘etanercept’ and ‘spondyloarthritis’, ‘axial spondyloarthritis’ or ‘ankylosing spondylitis’ keywords.Expert opinion: Etanercept showed clinical efficacy on the axial (non-radiographic and radiographic) and peripheral manifestations (peripheral arthritis and enthesitis) of axial spondyloarthritis (Ax-SpA). Among the extra-articular manifestations, it works on psoriasis but not on inflammatory bowel disease, with a lack of efficacy data in anterior uveitis. Etanercept also demonstrated an interesting tolerance profile and good drug survival rates after 5 years. Etanercept was also shown to reduce MRI inflammation on the spine and the sacroiliac joints. However, like other TNF blockers, its impact on radiographic progression could not be fully demonstrated. In the context of upcoming new biologic targeted treatments, head-to-head and longer-term randomized controlled trials are now required to further define the role of etanercept in spondyloarthritis treatment strategies.

Reduced skin blistering in experimental epidermolysis bullosa acquisita after anti-TNF treatment.

Epidermolysis bullosa acquisita (EBA) is a difficult-to-treat subepidermal autoimmune blistering skin disease (AIBD) with circulating and tissue-bound anti-type VII collagen antibodies. Different reports have indicated an increased concentration of tumor necrosis factor alpha (TNF) in the serum and blister fluid of patients with subepidermal AIBDs. Furthermore, successful anti-TNF treatment has been reported for individual patients with AIBDs. Here, we show that in mice, induction of experimental EBA by repeated injections of rabbit-anti mouse type VII collagen antibodies led to increased expression of TNF in skin, as determined by real-time PCR and immunohistochemistry. To investigate if the increased TNF expression is of functional relevance in experimental EBA, we inhibited TNF function using the soluble TNF receptor fusion protein etanercept (Enbrel®) or a monoclonal antibody to murine TNF. Interestingly, mice receiving either of these two treatments showed significantly milder disease progression than controls. In addition, immunohistochemical staining demonstrated reduced numbers of macrophages in lesional skin in mice treated with TNF inhibitors compared to controls. Furthermore, etanercept treatment significantly reduced the disease progression in immunization-induced EBA. In conclusion, the increased expression of TNF in experimental EBA is of functional relevance, as both the prophylactic blockade of TNF and the therapeutic use of etanercept impaired the induction and progression of experimental EBA. Thus, TNF is likely to serve as a new therapeutic target for EBA and AIBDs with a similar pathogenesis.

Intrinsic and chemo-sensitizing activity of SMAC-mimetics on high-risk childhood acute lymphoblastic leukemia.

SMAC-mimetics represent a targeted therapy approach to overcome apoptosis resistance in many tumors. Here, we investigated the efficacy of the SMAC-mimetic BV6 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In ALL cell lines, intrinsic apoptosis sensitivity was associated with rapid cIAP degradation, NF-κB activation, TNF-α secretion and induction of an autocrine TNF-α-dependent cell death loop. This pattern of responsiveness was also observed upon ex vivo analysis of 40 primograft BCP-ALL samples. Treatment with BV6 induced cell death in the majority of ALL primografts including leukemias with high-risk and poor-prognosis features. Inhibition of cell death by the TNF receptor fusion protein etanercept demonstrated that BV6 activity is dependent on TNF-α. In a preclinical NOD/SCID/huALL model of high-risk ALL, marked anti-leukemia effectivity and significantly prolonged survival were observed upon BV6 treatment. Interestingly, also in vivo, intrinsic SMAC-mimetic activity was mediated by TNF-α. Importantly, BV6 increased the effectivity of conventional induction therapy including vincristine, dexamethasone and asparaginase leading to prolonged remission induction. These data suggest SMAC-mimetics as an important addendum to efficient therapy of pediatric BCP-ALL.

Fc Receptor-mediated Effector Function Contributes to the Therapeutic Response of Anti-TNF Monoclonal Antibodies in a Mouse Model of Inflammatory Bowel Disease.

Anti-tumour necrosis factor [TNF] monoclonal antibodies [infliximab, adalimumab] induce complete mucosal healing in a proportion of patients with Crohn's disease whereas a TNF receptor fusion protein [etanercept] is not effective and the anti-TNF F[ab']2 fragment [certolizumab] shows a very low rate of complete mucosal healing. In contrast, all four TNF-neutralising drugs have demonstrated efficacy in the treatment of rheumatoid arthritis. These observations suggest that factors other than neutralisation of TNF may contribute to clinical outcomes in Crohn's disease. Here we tested the hypothesis that Fc receptor [FcR]-mediated effects may contribute to the therapeutic response of anti-TNF antibodies in inflammatory bowel disease. We modified an IgG2c mouse anti-TNF antibody that binds the high-affinity FcRs to generate an IgG1 isotype with strongly diminished binding. We examined the therapeutic effects of both antibodies in the T cell transfer model of inflammatory bowel disease and the collagen-induced arthritis model. The IgG2c anti-TNF antibody prevented colonic inflammation in the T cell transfer model of colitis, whereas the IgG1 anti-TNF did not. Conversely, both the IgG2c and IgG1 anti-TNFs were similarly effective in reducing the severity of articular inflammation in mouse collagen-induced arthritis. These data support the concept that the mechanism of action for TNF-neutralising drugs may differ across immune-mediated diseases and, potentially, between therapeutics within a particular disease. Our data suggest a specific role of Fc-mediated immune regulation in the resolution of intestinal inflammation by anti-TNF monoclonal antibodies.

Biologic therapy for refractory scleritis: a new treatment perspective.

Scleritis is an umbrella term for a heterogeneous group of ocular diseases that can be associated with autoimmune or systemic disorders. The purpose of this article was to review the literature regarding the use of biologic drugs to treat refractory scleritis. A search of the MEDLINE, Embase, and LILACS electronic databases was conducted, and the reference lists of published articles were hand-searched. No language filters were used. This search strategy yielded no randomized trials of the use of biologic therapies to treat scleritis; only case reports and retrospective studies were retrieved. These studies suggest that monoclonal antibodies (infliximab and adalimumab) are superior to the soluble TNF receptor fusion protein etanercept for the treatment of scleritis in patients that do not respond to corticosteroids and/or to immunosuppressive treatment. Rituximab seems to be the best option for scleritis associated with vasculitis.

Effect of TNF-alpha blockade on coagulopathy and endothelial cell activation in xenoperfused porcine kidneys.

Following pig-to-primate kidney transplantation, endothelial cell activation and xenogenic activation of the recipient's coagulation eventually leading to organ dysfunction and microthrombosis can be observed. In this study, we examined the effect of a TNF-receptor fusion protein (TNF-RFP) on endothelial cell activation and coagulopathy utilizing an appropriate ex vivo perfusion system. Using an ex vivo perfusion circuit based on C1-Inhibitor (C1-Inh) and low-dose heparin administration, we have analyzed consumptive coagulopathy following contact of human blood with porcine endothelium. Porcine kidneys were recovered following in situ cold perfusion with Histidine-tryptophan-ketoglutarate (HTK) organ preservation solution and were immediately connected to a perfusion circuit utilizing freshly drawn pooled porcine or human AB blood. The experiments were performed in three individual groups: autologous perfusion (n = 5), xenogenic perfusion without any further pharmacological intervention (n = 10), or with addition of TNF-RFP (n = 5). After perfusion, tissue samples were obtained for real-time PCR and immunohistological analyses. Endothelial cell activation was assessed by measuring the expression levels of E-selectin, ICAM-1, and VCAM-1. Kidney survival during organ perfusion with human blood, C1-Inh, and heparin, but without any further pharmacological intervention was 126 ± 78 min. Coagulopathy was observed with significantly elevated concentrations of D-dimer and thrombin-antithrombin complex (TAT), resulting in the formation of multiple microthrombi. Endothelial cell activation was pronounced, as shown by increased expression of E-selectin and VCAM-1. In contrast, pharmacological intervention with TNF-RFP prolonged organ survival to 240 ± 0 min (max. perfusion time; no difference to autologous control). Formation of microthrombi was slightly reduced, although not significantly, if compared to the xenogenic control. D-dimer and TAT were elevated at similar levels to the xenogenic control experiments. In contrast, endothelial cell activation, as shown by real-time PCR, was significantly reduced in the TNF-RFP group. We conclude that although coagulopathy was not affected, TNF-RFP is able to suppress inflammation occurring after xenoperfusion in this ex vivo perfusion model.

Autocrine TNF-α Signaling in Hematopoietic Stem Cells Promotes Myeloproliferative Disease Progression through Activation of TNFR2

The JAK2V617F mutation is a unifying feature in the majority of patients with myeloproliferative neoplasms (MPNs). The presence of JAK2V617 in a hematopoietic stem (HSC) or progenitor cell confers a proliferative advantage over native JAK2 counterparts. Several inflammatory cytokines are elevated in MPN patients and in murine models of JAK2V617F-driven MPN. In particular, expression of tumor necrosis factor alpha (TNF-α) is increased by constitutive JAK2 kinase activity and imparts a competitive advantage on JAK2V617Fexpressing cells.To identify cell types responsible for increased levels of TNF-α we performed intracellular cytokine staining in leukocytes from myelofibrosis (MF) patients and normal controls. Using a panel of markers to define cellular subsets we found expression of TNF-α was uniformly low in unstimulated cells. However, when cells were treated with lipopolysaccharide (LPS), TNF-α expression was 16-fold higher in HSCs of MF patients compared to normal controls (p<0.005), while expression in mature populations was not different. In a murine model of JAK2V617F driven MPN, where JAK2V617F cells are identified by GFP, TNF-α expression was 3-fold higher in JAK2V617F-expressing HSCs (GFP+) compared to GFP-controls (p<0.005), irrespective of LPS stimulation.To evaluate anti-TNF therapy in MPNs, we treated JAK2V617F mice with etanercept, a soluble TNF receptor fusion protein that binds and inactivates TNF-α. Etanercept did not significantly restrain JAK2V617F-associated WBC or hematocrit increases over a 10-week period, despite suppression of TNF-α activity in plasma. As TNF-α may activate pro-apoptotic (predominantly through TNF receptor 1, TNFR1) and pro-survival pathways (predominantly through TNF receptor 2, TNFR2), we reasoned that global blockade of TNF-α may not shift the balance in favor of normal hematopoiesis. To investigate this we sorted primitive (Lin-, cKit+) cells from mice with JAK2V617F-induced MPN by TNF receptor expression. TNFR2+ cells showed significantly increased colony formation compared to TNFR1+ cells, demonstrating that TNFR2 expression is associated with increased clonogenic potential. Additionally we treated these primitive cells with specific antibodies blocking TNFR1 or TNFR2. Colony assays performed after 3 days in liquid culture with TNFR-blocking antibodies confirmed that interrupting TNFR2-mediated survival signaling resulted in decreased colony formation (61% reduction) while blocking TNFR1 increased colony formation (5% increase). In addition we tested CD34+ cells from MF patient samples with TNFR-blocking antibodies. As seen with the murine MPN cells, colony formation was decreased with the TNFR2 blocking antibody (30% reduction) and increased with the TNFR1 blocking antibody (48% increase) consistent with a differential activation of survival signals by TNF-α in MPN cells. These studies were performed without addition of exogenous TNF-α, which confirms the ability and requirement for these primitive JAK2V617Fcells to utilize TNF-α production to actively support survival.Our data suggest that TNF-α generated by primitive MPN cells promotes their survival through activation of TNFR2, while TNFR1 activation is suppressive. If selective inhibition of TNFR2 shifts the equilibrium toward normal hematopoietic cells, this would support the use of TNFR2 blockade to treat MF and other myeloproliferative neoplasms. Genotyping of human MF and murine MPN colonies cultured with TNF receptor blocking antibodies and experiments in normal human CD34+ cells are ongoing and will be presented. DisclosuresDeininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMA, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy.

Tumour necrosis factor-α levels are elevated in adolescent patients with juvenile idiopathic arthritis on etanercept therapy

The use of etanercept, a tumor necrosis factor (TNF) inhibitor, has revolutionized the treatment of juvenile idiopathic arthritis (JIA). TNF is a key cytokine implicated in the pathogenesis of inflammatory arthritis and etanercept, which is a soluble TNF receptor fusion protein, binds and inactivates TNF-α and lymphotoxin-A.

Immediate Neurological Recovery Following Perispinal Etanercept Years After Brain Injury

Positron emission tomographic brain imaging and pathological examination have revealed that a chronic, intracerebral neuroinflammatory response lasting for years after a single brain injury may occur in humans. Evidence suggests the immune signaling molecule, tumor necrosis factor (TNF), is centrally involved in this pathology through its modulation of microglial activation, role in synaptic dysfunction, and induction of depressive symptoms and neuropathic pain. Etanercept is a recombinant TNF receptor fusion protein and potent TNF inhibitor that has been found to reduce microglial activation and neuropathic pain in multiple experimental models. We report that a single dose of perispinal etanercept produced an immediate, profound, and sustained improvement in expressive aphasia, speech apraxia, and left hemiparesis in a patient with chronic, intractable, debilitating neurological dysfunction present for more than 3 years after acute brain injury. These results indicate that acute brain injury-induced pathologic levels of TNF may provide a therapeutic target that can be addressed years after injury. Perispinal administration of etanercept is capable of producing immediate relief from brain injury-mediated neurological dysfunction.

Etanercept therapy in Behçet’s disease

The goal of the present study was to investigate patient outcome when using the TNF receptor fusion protein etanercept in addition to conventional immunosuppressive drugs in ameliorating disease intensity and reducing relapses in refractory Behçet's disease (BD). A single center, prospective study was conducted over 1year. A total of 15patients with the established diagnosis of BS were enrolled (mean age: 36.5 ± 6.75years, mean disease duration: 3.86 ± 1.30years). Clinical features were classified as refractory if the patients failed to achieve the desired response within 6 months of immunosuppressive and oral glucocorticoid therapy or flare of lesions developed while on the maximum tolerable doses of these drugs. The study included 2patients who were on previous infliximab therapy for refractory disease. Inflammatory biomarkers (ESR and CRP) were investigated. Baseline clinical features in the study prior to inclusion showed recurrent oro-genital ulcers were observed in 100 % of patients, the pathergy test was positive in 17.6 %, ocular involvement was observed in 86.7 %, and acne lesions were recorded in 73.3 %. The following values were also recorded: mean ESR 22 ± 16.97mm/h, mean CRP level 6.87 ± 4.44mg/l, mean visual analog score 5.46 ± 1.55, and mean patient global score 5.13 ± 1.30. At the beginning of the study, all patients were on oral prednisolone (mean dose: 20.16 ± 11.81mg/day), azathioprine (mean dose: 126.66 ± 25.81mg/day), and oral colchicine (mean dose: 1.08 ± 0.10mg/day), then etanercept was added at a regular weekly dose of 50mg subcutaneously for 1year. By 8weeks, 100 % of the patients achieve the primary endpoint, which included clinical resolution of refractory mucocutaneous, joint, and active ocular lesions with normalization of the acute phase symptoms. Patients with refractory BD who received a 12-month treatment with etanercept in addition to conventional immunosuppressive therapy achieved a good therapeutic response with successful reduction of oral prednisolone to a mean dose of 6.66 ± 2.24mg/day. No serious infections or drug-related adverse events reported.

Etanercept reduces thermal and mechanical orofacial hyperalgesia following inflammation and neuropathic injury

This study evaluated the involvement of tumour necrosis factor α (TNF-α) in orofacial thermal and mechanical hyperalgesia induced by an inflammatory stimulus or by chronic constriction of the infraorbital nerve (CION) using etanercept (Eta), a TNF-receptor fusion protein that inhibits TNF-α action. Animals were treated with Eta (0.5 and 5.0 mg/kg, s.c.) or dexamethasone (Dex, 0.5, 1.0 and 2.0 mg/kg, s.c.) and orofacial thermal (cold and heat) and mechanical hyperalgesia induced by an inflammatory stimulus (carrageenan, Cg 50 and 100 μg/lip) or by chronic CION, a model of neuropathic pain in the orofacial region was evaluated. Treatments with Dex or Eta were carried out before Cg or before or after CION. Eta or Dex abolished inflammatory thermal and mechanical hyperalgesia. Also, each drug, when given at the day of the surgery and the subsequent day, was effective to abolish thermal and mechanical hyperalgesia induced by CION, assessed on day 4 and on day 13 after the surgery, respectively. However, Eta, but not Dex, given after the CION, abolished thermal and mechanical hyperalgesia and reduced TNF-α level in the trigeminal ganglion. These results suggest that TNF-α has an important role in cold, heat and mechanical hyperalgesia induced by inflammation or neuropathy in the orofacial region and this may contribute for the establishment of new therapeutic strategies to treat orofacial pain.

Biologic Treatment of Pediatric Rheumatic Diseases: Are we Spoilt for Choice?

Approximately 15 years ago the first biological treatment for juvenile idiopathic arthritis (JIA) was introduced. Since the introduction of the TNF receptor fusion protein etanercept in 1998, now more than seven biologics are now registered, or under study for JIA. Notably, these biologics were initially not developed for JIA but derived from the experience in the treatment of adult rheumatic diseases. This simple fact still has major consequences on the prescription and reimbursement of biological treatments in pediatric rheumatic diseases (PRD). As an endorsement for clinical research in pediatric diseases, the EU launched a new act in 2006, the Pediatric Rule [101]. This rule states that drugs tested for a specific condition in adults are also required to be tested in related pediatric diseases [101]. Therefore, when pharmaceuticals submit a registration proposal to EMA, a Pediatric Investigational Plan must be included. This means increased efforts and costs for pharmaceutical companies. Despite the efforts of the EMA, many national and local institutional review boards are still reluctant to approve medication studies in children. In The Netherlands, therapeutic trials in children are only allowed under strict regulations. Children should benefit from the study, risks have to be negligible and the burden minimal. A proposal to amplify these strict regulations encountered a lot of resistance among members of the College of Human Rights, claiming to protect young children for medical trials. So the question arises: are pediatric rheumatologists convinced that therapeutic trials in children with rheumatic diseases are required in order to enlarge the spectrum of biological therapy, or do the current therapies provide s ufficient choices in the treatment of PRD?

AB1149 Biologics in the management of pediatric autoimmune and autoinflammatory diseases: Side effects

BackgroundThe last 20 years have seen an evolution in the approach to therapy of many chronic pediatric diseases such as autoimmune, cardiological, neoplastic and infectious disorders. However, persisting treatment failures...

OP0062 Safety and Efficacy of Etanercept in Children with the JIA Categories Extended Oligoarthritis, Enthesitis Related Arthritis and Psoriasis Arthritis

BackgroundThe approval of the recombinant TNF receptor fusion protein etanercept for the treatment of the JIA categories resistant extended Oligoarthritis (ExOA), enthesitis related arthritis(ERA) and psoriasis arthritis (PSA) was actually...