Tumor Necrosis Factor Receptor Fusion Research Articles

Effects of etanercept, a tumor necrosis factor receptor fusion protein, on primary cell cultures prepared from intact human intervertebral disc tissue.

The aim of the present study was to investigate the effects of etanercept (ETA), a tumor necrosis factor (TNF) inhibitor, on human cell cultures prepared from intact intervertebral disc tissue. ETA is used as a treatment for cases of rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis and ankylosing spondylitis accompanied by moderate or severe joint pain. ETA was applied to primary cell cultures [annulus fibrosus and nucleus pulposus (NP) from intact intervertebral disc tissue]. Cell cultures without ETA treatment served as the control group. Morphological and quantitative molecular analyses of the two groups were performed. The number of viable cells and cell proliferation decreased in the ETA-treated cultures as compared with those in the control group. Furthermore, in the treatment group, the chondroadherin gene, an NP-specific marker, was not expressed after 24 h. By contrast, the cartilage oligo matrix protein was expressed 24, 48 and 72 h post-ETA treatment, while its expression was significantly lower than that in the control group. In addition, the expression of interleukin-1β, as well as matrix metallopeptidase-7 and −19, was markedly decreased. Overall, the cell proliferation and gene expression in the ETA-treated cells were significantly different from those in the control group (P<0.05). These results suggest that the treatment duration and dosage of TNF inhibitors, which are used to suppress active inflammation, should be considered in the clinical setting. These biological agents may delay the healing of intervertebral disc tissue damage by slowing cell proliferation and altering gene expression via anabolic and catabolic pathways.

Clinical analysis of 6 patients with drug-induced lupus

To improve the understanding of drug-induced lupus (DIL) and the differences from systemic lupus erythematosus (SLE). Clinical manifestation and treatment of patients with definite DIL were retrospectively analyzed. Six patients with DIL were enrolled in this study, including 4 females and 2 males. Two patients were diagnosed after receiving interferon, one after soluble tumor necrosis factor receptor fusion protein, one after propylthiouracil, one after penicillamine, and one after levofloxacin. High titer of antinuclear antibody was identified in all six patients, including 3 with positive anti-dsDNA antibody. One patient had positive anti-Sm antibody. One patient had positive anti-RNP antibody. One patient had anti-nucleosome antibody. One patient had anti-histone antibody. One patient had antimitochondrial antibodies-M2, and one patient had anticardiolipin antibodies. Patients with DIL are not as severe as those with SLE. After cessation of suspected drugs and administration of standard treatment, the clinical outcome of DIL is satisfying.

Potential Application of Biological Products for the Treatment of Ocular Surface Inflammation.

Various biological products have been introduced for the treatment of autoimmune diseases. The injection of tocilizumab [anti-interleukin (IL)-6R antibody] and a tumor necrosis factor receptor fusion protein (TNFR-Fc) has been approved for the treatment of rheumatoid arthritis. We investigated the effect of the anti-IL-6R antibody and TNFR-Fc on corneal inflammation. Topical instillation of the anti-IL-6R antibody (MR16-1, 2 μg/μL; anti-IL-6R group) or TNFR1-Fc (100 μg/mL; TNFR1 group) was performed after corneal wounds were induced in BALB/c mice by alkali burns. The injured eye was analyzed on day 14 or 28 after injury, and topical instillation was performed until day 14 or day 28. Corneal stromal sections were made using a laser capture microdissection system, and total RNA from the specimens was subjected to quantitative polymerase chain reaction array analysis. Topical instillation of phosphate-buffered saline (PBS) served as a control. The vascularized area was significantly reduced in the anti-IL-6R (day 14) and TNFR1 groups (day 28) compared with that in the PBS group. In the anti-IL-6R group, the expression levels of matrix metalloproteinase-13, monocyte chemotactic protein-1, and C-C motif ligand-22 were downregulated compared with those in the PBS group. In the TNFR1 group, expression of mitogen-activated protein kinase 8 was downregulated. These results indicate the possible application of biological products for topical instillation for the treatment of corneal inflammation.

Population pharmacokinetics of rhTNFR-Fc in Chinese patients with rheumatic arthritis.

We aimed to investigate the population pharmacokinetics (PK) of soluble recombinant human tumor necrosis factor receptor fusion protein (rhTNFR- Fc) in Chinese patients with rheumatic arthritis (RA). The PK differences between Chinese patients with RA and healthy Chinese subjects were also compared. 40 patients were randomized to a single subcutaneous (SC) injections of 12.5 mg (n = 10), 25 mg (n = 10), and 50 mg (n = 10) of rhTNFR-Fc, and six SC injection of rhTNFR- Fc at 25 mg once in 3 days (n = 10) respectively. A total of 550 serum concentration data points were collected in the RA patients. The population PK analysis was performed by NONMEM. Based on the population PK parameters obtained herein and those reported in healthy Chinese subjects, simulation was conducted to compare the difference of rhTNFR-Fc exposure between these populations. The PK data of Chinese patients with RA were best described by a one compartment model with lag time. A higher CL/F was noted in RA patients compared with that of the healthy Chinese subjects (1.64 L/h vs. 1.10 L/h), and a lower Ka was noticed in the RA patients compared with that of the healthy subjects (0.0317 h-1 vs. 0.0605 h-1). The simulate results showed that rhTNFR-Fc exposure in Chinese patients with RA was significantly lower than that in healthy subjects. The mean patients/healthy subjects C(max) and AUC(ss) ratios were 0.870 and 0.890, respectively. A population PK model of rhTNFR- Fc was developed in Chinese patients with RA. Statistical difference was noted in the PK of rhTNFR-Fc between Chinese patients with RA and healthy Chinese subjects.

Zymographic analysis using gelatin‐coated film of the effect of etanercept on the extracellular matrix‐degrading activity in synovial fluids of rheumatoid arthritis patients

Rheumatoid arthritis (RA) is a chronic inflammatory disease. Most RA patients develop cartilage and bone destruction, and various proteinases are involved in the destruction of extracellular matrix of cartilage and bone. The aim of this study is to evaluate the utility of our newly developed method to measure total gelatinolytic activity. We adopted this method for measurement in synovial fluid from RA patients treated by the anti-rheumatic drug etanercept (ETN), a recombinant human soluble tumor necrosis factor receptor fusion protein, and compared the findings with clinical and laboratory data. Enzymatic activity of synovial fluid was analyzed by zymography using gelatin-coated film, and compared with the index of Disease Activity Score of 28 joints - C-reactive protein (DAS28-CRP), CRP and matrix metalloproteinase (MMP)-3 level before and after ETN therapy. Synovial fluids of 19 patients were collected before and after administration of ETN therapy. In nine of 19 patients, who showed a decrease in gelatin-degrading activity in synovial fluid, the index of DAS28-CRP (4.85-2.85, ΔDAS=-2.00) and CRP (3.30-0.94mg/dL, ΔCRP=-2.36) was alleviated after ETN therapy, while cases with no change or an increase in gelatin-degrading activity showed a modest improvement in clinical data: DAS28-CRP (4.23-3.38, ΔDAS=-0.85) and CRP (1.70-0.74mg/dL, ΔCRP=-0.96). Our newly developed method for measurement of gelatin-degrading activity in synovial fluid from RA patients is highly practicable and useful for predicting the effect of ETN therapy.

OHP-037 Evaluation of Change of Etanercept Subcutaneous Administration Device

BackgroundEtanercept is a soluble tumour necrosis factor receptor fusion protein used in a variety of arthropathies. A new administration device (pen) has recently been marketed.Purpose To evaluate pain differences and...

A Case of Etanercept Induced Palmoplantar Pustular Psoriasis

Observations: Etanercept is a human recombinant soluble tumor necrosis factor  (TNF-α) receptor fusion protein. Etanercept has been used successfully to treat a wide range of inflammatory disorders including psoriasis and psoriatic arthritis resistant to classical disease-modifying treatments. The widespread use of TNF-α antagonists led to the recognition of adverse effects. Herein, we report a case of palmoplantar pustular psoriasis in a 37-year-old man during the etanercept therapy.

Etanercept for Steroid-Refractory Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation.

AbstractAbstract 4548 Background:Treatment strategy for steroid-refractory acute graft versus host disease (aGvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to be standardized. We report our clinical experience of Etanercept, recombinant human soluble tumor necrosis factor receptor fusion protein, on steroid-refractory aGvHD, retrospectively. Method:A total of 18 patients who received allo-HSCT and presented with steroid-refractory aGvHD in Ajou University Hospital were studied retrospectively. Twenty five miligram of Etanercept was given subcutaneously twice weekly for 4 weeks. Clinical responses were checked with regard to the severity of aGvHD. Results:Median age was 43.5 years. Patients with AML, myeloma, ALL, aplastic anemia, myelodysplastic syndrome and idiopathic myelofibrosis were studied. The engraftment kinetics was adequate and no one failed to engraft. Before Etanercept, grade 4, grade 3, grade 2 and grade 1 of aGvHD occurred in 7, 6, 5, and zero patients, respectively however the number of patients were changed to 4, 5, 5, and 4 after Etanercept, respectively (p = .005). Eighty percent of grade II and 57% of grade IV patients showed partial response, so did in 14% of grade III patients. Skin and gut aGvHD was well controlled with Etanercept, whereas hepatic GvHD was not. Three patients died of severe infection. There was no factor affecting clinical outcome of Etanercept. All the non-responders died but 56.6% of the responders survived (p = 0.003). Conclusion:Etanercept can be one of the effective anti-aGvHD drugs for steroid-refractory cases after allo-HSCT considering tolerable side effects and tolerable cost. Disclosures:No relevant conflicts of interest to declare.

Guilt by association - what is the true risk of malignancy in children treated with etanercept for JIA?

Recently, the Food and Drug Administration placed a "black box" label on etanercept, and other tumor necrosis factor inhibitors used to treat childhood arthritis, warning of the risk of malignancies. The Food and Drug Administration made their decision based on a review of 48 cases of malignancies identified worldwide in children treated with tumor necrosis factor inhibitors for inflammatory bowel disease, sarcoidosis, and juvenile idiopathic arthritis. Recently, an article in Pediatric Rheumatology demonstrated that there may not be an increased risk of cancer in children with juvenile idiopathic arthritis treated specifically with the tumor necrosis factor receptor fusion protein, etanercept. There are many confounding issues regarding whether or not etanercept increases the risk of malignancy, specifically lymphomas, above the background rate of cancer in children with juvenile idiopathic arthritis who are not being treated with biologic agents. Whether or not it was appropriate for the Food and Drug Administration to lump cancer patients with underlying granulomatous diseases (inflammatory bowel disease and sarcoidosis) with children with juvenile idiopathic arthritis is explored herein. Moreover, the amalgamation of etanercept with anti-tumor necrosis factor monoclonal antibodies (adalimumab and infliximab) is another point of contention. What is clear is that there is much that is currently unknown to be able to convincingly demonstrate a substantial risk of cancer in children with juvenile idiopathic arthritis treated with etanercept. Conversely, there is ample evidence demonstrating remarkable benefit of etanercept in treating juvenile idiopathic arthritis. Physicians treating childhood arthritis should weigh these potential risks and benefits with patients and their families discussing the current limitations in available data regarding the risk of cancer in children treated with etanercept for juvenile idiopathic arthritis.

Adalimumab for psoriasis patients who are non‐responders to etanercept: open‐label prospective evaluation

Targeted biologic therapies have made a significant impact on the treatment for moderate to severe psoriasis. In the United Kingdom, the National Institute for Health and Clinical Excellence recommends etanercept, a human recombinant tumour necrosis factor (TNF) receptor fusion protein, for moderate to severe psoriasis patients who have failed conventional therapies. There is, however, no data available on the role of other TNF antagonists for patients who have failed etanercept. Adalimumab, a fully human, anti-TNF monoclonal antibody, is approved for treatment of moderate to severe psoriasis. To assess the efficacy and safety of adalimumab (40 mg weekly) in psoriasis patients who were non-responders to high-dosage etanercept (50 mg twice weekly). All patients attending a tertiary referral service for severe psoriasis who were non-responders to high-dosage etanercept [i.e. failed to achieve >or= 50% improvement in Psoriasis Area and Severity Index (PASI 50) after 12 weeks of treatment] were considered for open-label adalimumab therapy for 12 weeks. Details on clinical course, PASI, Dermatology Life Quality Index (DLQI) and adverse events were recorded at baseline and weeks 2, 4, 8, and 12. Results Four of five patients in this study had reached at least PASI 50 by week 12. Of these, two patients achieved a 75% improvement in PASI (PASI 75). No serious adverse events were reported. Initial data from this open-label prospective evaluation suggests that weekly adalimumab therapy is an effective treatment for patients with severe psoriasis who had failed to respond to at least 3 months of high-dosage etanercept.

Afebriles Erysipel unter Etanercept-Therapie

Bei einer 67-jährigen Patientin, die aufgrund einer rheumatoiden Arthritis mit Etanercept behandelt wird, kam es unter der Etanercept-Therapie zum Auftreten eines afebrilen Erysipels. Nach Absetzen des Tumor-nekrosefaktor-alpha (TNF-α)-Fusionsproteins erfolgte der Temperaturanstieg. Das Erysipel wurde erfolgreich mit einem Kombinationspräparat, bestehend aus Amoxicillin und Flucloxacillin behandelt. Nach Abheilung konnte die Etanercept-Therapie fortgesetzt werden. Patienten, die mit einem TNF-α-Blocker behandelt werden, können trotz tiefer Infektionen – wie dem Erysipel – afebril bleiben und diagnostische Schwierigkeiten bereiten.

Effects of therapy with soluble tumour necrosis factor receptor fusion protein on pulmonary cytokine expression and lung injury following haemorrhage and resuscitation.

Acute lung injury frequently develops following haemorrhage, and is characterized by increased proinflammatory cytokine levels and massive neutrophil accumulation in the lung. Blood loss produces rapid increases in tumour necrosis factor-alpha (TNF-alpha) mRNA expression among pulmonary cell populations which precede the development of lung injury. In order to examine the role of TNF-alpha in producing acute inflammatory lung injury, we treated mice following haemorrhage and resuscitation with a TNF antagonist, composed of soluble dimeric human p80 TNF receptor linked to the Fc region of human IgG1 (sTNFR:Fc). Therapy with sTNFR:Fc prevented the post-haemorrhage increases in circulating and pulmonary TNF-alpha levels normally found following blood loss. Administration of sTNFR:Fc also diminished the increase in IL-1 beta, IL-6, TNF-alpha and interferon-gamma (IFN-gamma) mRNA normally found in the lungs following haemorrhage. However, therapy with sTNFR:Fc was not associated with improvement in the histologic parameters of post-haemorrhage lung injury, such as neutrophil infiltration and interstitial oedema. In contrast to the effects of sTNFR:Fc on cytokine mRNA levels among intraparenchymal pulmonary mononuclear cells, such therapy following haemorrhage was associated with increased amounts of mRNA for TNF-alpha among peripheral blood mononuclear cells, as well as increased IFN-gamma titres in serum and bronchoalveolar lavage (BAL) specimens. These results indicate that therapy with sTNFR:Fc in the post-haemorrhage period, although capable of decreasing proinflammatory cytokine expression in the lungs, does not prevent the development of acute lung injury in this setting.

Etanercept-related Cutaneous Nodulosis in a Patient with Rheumatoid Arthritis

Etanercept is a recombinant human tumor necrosis factor (TNF) receptor fusion protein, which inhibits the biological activity of TNF-α. The common side effects of TNF-α inhibitors are injection site reactions, infusion reactions and infection. Rheumatoid nodules are the most common extraarticular manifestation of rheumatoid arthritis. Drugs such as methotrexate were reported to be associated with rheumatoid nodules, but etanercept-related nodules were uncommonly observed. We report the new formation of cutaneous rheumatoid nodules in a 58-year-old man during anti-TNFα therapy with etanercept. He had 2-year history of seropositive rheumatoid arthritis, and been treated with methotrexate, hydroxychloroquine, sulfasalazine, prednisolone and nonsteroidal anti-inflammatory drugs before etanercept regimen. Rheumatoid nodules developed on the palmar surface of fingers 4 month after treatment of etanercept, although his disease activity was maintained low. One month later, we decided to stop etanercept because his nodulosis extended to elbow. Since then, he has been followed up without any progression of rheumatoid nodules or aggravation of arthritis.

Differences in Reactivation of Tuberculosis Induced from Anti-TNF Treatments Are Based on Bioavailability in Granulomatous Tissue

The immune response to Mycobacterium tuberculosis (Mtb) infection is complex. Experimental evidence has revealed that tumor necrosis factor (TNF) plays a major role in host defense against Mtb in both active and latent phases of infection. TNF-neutralizing drugs used to treat inflammatory disorders have been reported to increase the risk of tuberculosis (TB), in accordance with animal studies. The present study takes a computational approach toward characterizing the role of TNF in protection against the tubercle bacillus in both active and latent infection. We extend our previous mathematical models to investigate the roles and production of soluble (sTNF) and transmembrane TNF (tmTNF). We analyze effects of anti-TNF therapy in virtual clinical trials (VCTs) by simulating two of the most commonly used therapies, anti-TNF antibody and TNF receptor fusion, predicting mechanisms that explain observed differences in TB reactivation rates. The major findings from this study are that bioavailability of TNF following anti-TNF therapy is the primary factor for causing reactivation of latent infection and that sTNF—even at very low levels—is essential for control of infection. Using a mathematical model, it is possible to distinguish mechanisms of action of the anti-TNF treatments and gain insights into the role of TNF in TB control and pathology. Our study suggests that a TNF-modulating agent could be developed that could balance the requirement for reduction of inflammation with the necessity to maintain resistance to infection and microbial diseases. Alternatively, the dose and timing of anti-TNF therapy could be modified. Anti-TNF therapy will likely lead to numerous incidents of primary TB if used in areas where exposure is likely.

Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft‐versus‐host disease following allogeneic hematopoietic stem cell transplantation

Etanercept is a recombinant human soluble tumor necrosis factor (TNF-alpha) receptor fusion protein that inhibits TNF-alpha, a major mediator in the pathogenesis of graft-versus-host disease (GVHD). The purpose of our study was to evaluate the safety and efficacy of etanercept therapy in 21 patients with steroid-refractory acute GVHD (aGVHD) (n = 13) and chronic GVHD (cGVHD) (n = 8). Etanercept 25 mg was given subcutaneously twice weekly for 4 weeks followed by 25 mg weekly for 4 weeks. At the time of initiation of etanercept, 14 patients had skin, 13 had gastro-intestinal, 5 had liver, 5 had pulmonary, and 4 had oral involvement. Twelve patients (57%) completed 12 doses of therapy. Overall, 11 of 21 patients (52%) responded to the treatment with etanercept, including 6 patients (46%) with aGVHD [n = 4 complete response (CR), n = 2 partial response (PR)] and 5 patients (62%) with cGVHD (n = 1 CR, n = 4 PR). Clinical responses were most commonly seen in patients with refractory gut aGVHD with 55% of the patients having a CR and 9% having a PR. CMV reactivation occurred in 48% of patients, bacterial infections in 14% of patients, and fungal infections in 19% of patients. Fourteen patients (67%) were alive after a median follow-up of 429 days (range 71-1007 days) since initiation of etanercept. Seven patients died, 3 of infections, 2 of refractory aGVHD, and 2 of disease progression. In conclusion, our preliminary data indicate that etanercept is well tolerated and can induce a high response rate in patients with steroid-refractory aGVHD and cGVHD, particularly in the setting of GI involvement.

Once-Weekly Administration of High-Dosage Etanercept in Patients with Plaque Psoriasis: Results of a Pilot Experience (Power Study)

Etanercept is a soluble tumour necrosis factor receptor fusion protein which is approved for the treatment of plaque psoriasis at the dose of either 25mg twice weekly (BIW) or, for the initial 12 weeks, 50mg BIW. Alternative dosing regimens have not been evaluated in psoriasis. In this study, we compare the efficacy and tolerability of two etanercept dosing regimens--50mg BIW and 100mg once weekly (OW)--for 12 weeks in 108 patients with moderate-to-severe recalcitrant psoriasis. Efficacy measures included Psoriasis Area and Severity Index (PASI), severity of pruritus recorded on a visual analogue scale (VAS) and the influence on quality of life assessed by means of Dermatology Life Quality Index (DLQI). Both etanercept regimens caused a significant change in all the efficacy parameters after 4 weeks and 12 weeks, at a comparable rate. At week 12, a PASI improvement of at least 50% from baseline (PASI 50) was achieved by 74% of patients treated with 50mg BIW and 78% of patients treated with 100mg OW. A PASI 75 response was obtained in 54% and 50% of patients treated with 50mg BIW and 100mg OW, respectively. Treatment was well tolerated with similar type and frequency of adverse events between the two groups.

Outcome of patients with active ankylosing spondylitis after two years of therapy with etanercept: Clinical and magnetic resonance imaging data

To examine the long-term outcome of patients with active ankylosing spondylitis (AS) clinically and by magnetic resonance imaging (MRI) after continuous treatment with the tumor necrosis factor (TNF) receptor fusion protein etanercept over 2 years. Overall, 26 patients with active AS were treated with etanercept 25 mg twice daily subcutaneously, twice weekly with no concomitant disease-modifying antirheumatic drugs (DMARDs) or steroids. The clinical response was assessed by standardized parameters. Inflammatory spinal lesions were quantified by the ASspiMRI-a rating gadolinium-enhanced (T1-weighted gadolinium diethylenetriaminepentaacetic acid) and STIR MRI sequences. The primary outcome was a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) improvement > or =50% after 2 years of etanercept therapy compared with the baseline value of the study. Overall, 21 (70%) of 30 patients completed year 2. In the intent-to-treat analysis, 54% of the patients showed a 50% improvement according to the BASDAI and a 40% improvement according to the Assessment in Ankylosing Spondylitis (ASAS) criteria. In the completer analysis, 9 (43%) of 21 patients were in partial remission according to ASAS criteria. Mean +/- SD BASDAI scores, which were elevated at baseline (6.3 +/- 1.6), remained low: 2.7 +/- 2.4 after 2 years compared with 2.6 +/- 2.2 at week 54. In accordance, all other clinical parameters showed sustained improvement during year 2. The majority of patients had no disease activity flares. MRI evaluation showed a 75% improvement of active spinal lesions, but minor spinal inflammation was still present in 64% of the patients after 2 years. There were 2 serious adverse events leading to discontinuation of etanercept. The clinical efficacy and safety of etanercept in patients with active AS without simultaneous administration of DMARDs or steroids over 2 years of continuous treatment is confirmed. Spinal inflammation as depicted by MRI decreased significantly, but a few patients still had some spinal inflammation even after long-term anti-TNF therapy.

Sepsis and Myocardial Depression in a Young Woman

Severe sepsis may be associated with depression of myocardial function, attributed to various inflammatory mediators. Myocardial dysfunction in sepsis is characterized by biventricular failure and complicates usual therapy with high-volume fluid resuscitation and vasopressors. However, in patients who survive septic shock, myocardial dysfunction can improve rapidly. We describe a young woman with septic shock due to Streptococcus pneumoniae, complicated by severe but reversible biventricular dysfunction.

Differential Expression of Phosphorylated NF-κB/RelA in Normal and Psoriatic Epidermis and Downregulation of NF-κB in Response to Treatment with Etanercept

Etanercept, a recombinant human tumor necrosis factor (TNF) receptor fusion protein, is FDA approved for psoriasis and psoriatic arthritis. TNFalpha increases the synthesis of proinflammatory cytokines and leads to the activation of multiple signaling pathways, including nuclear factor kappa B (NF-kappaB). The Rel/NF-kappaB transcription factors play a central role in numerous cellular processes, including the stress response and keratinocyte proliferation and differentiation. Utilizing a phosphorylation-specific antibody, we examined the expression of active nuclear NF-kappaB/RelA via immunohistochemistry in normal skin, non-lesional psoriatic skin, lesional psoriatic skin, and lesional skin from patients treated with etanercept. There was no expression of active nuclear NF-kappaB in the normal epidermis, whereas a basal level of constitutive active phosphorylated NF-kappaB/RelA was present in uninvolved epidermis from psoriasis patients. There was also significant upregulation of active phosphorylated NF-kappaB/RelA in the epidermis from psoriatic plaques. Serial biopsies from psoriasis patients treated with etanercept at 1, 3, and 6 mo demonstrated a significant downregulation of phosphorylated NF-kappaB/RelA, which correlated with decreases in epidermal thickness, restoration of normal markers of keratinocyte differentiation, and clinical outcomes. These data suggest that activation of NF-kappaB plays a significant role in the pathogenesis of psoriasis and that a potential mechanism of action for TNF-targeting agents is downregulation of NF-kappaB transcriptional activity.

Clinical Pharmacokinetics of Etanercept: A Fully Humanized Soluble Recombinant Tumor Necrosis Factor Receptor Fusion Protein

Etanercept, a fully humanized soluble recombinant tumor necrosis factor receptor fusion protein, is an approved treatment for rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis. Etanercept is absorbed slowly from the site of subcutaneous injection, with time to peak concentration at approximately 48 to 60 hours, and is cleared slowly from the body with a t(1/2) of 70 to 100 hours. The absolute bioavailability of etanercept was 58% in healthy subjects following subcutaneous administration. The 25-mg twice-weekly dosage regimen generates systemic exposures comparable to 50 mg once weekly, as predicted by pharmacokinetic modeling and simulation and later confirmed by clinical studies. The pharmacokinetics of etanercept in patients with rheumatoid arthritis are comparable to those in healthy individuals and patients with ankylosing spondylitis, congestive heart failure, and psoriasis. In children with polyarticular-course juvenile rheumatoid arthritis, after subcutaneous doses of 0.4 mg/kg twice weekly, the clearance of etanercept may be slightly reduced in children aged 4 to 8 years. Pharmacokinetic simulation predicts that a dose of 0.8 mg/kg once weekly generates comparable systemic exposure as 0.4 mg/kg twice weekly. No requirement for etanercept dosage adjustment is needed when etanercept is coadministered with warfarin, digoxin, or methotrexate.