TNF-a inhibitors

Etanercept is a fully human dimeric fusion protein composed of human TNF-a p75 receptor fused to the Fc portion of human IgG 1.41 It acts as a tumor necrosis factor-a (TNF-a) inhibitor by binding to and inactivating TNF-a, thus preventing interactions with its cell surface receptors.41 This agent is useful for chronic moderate to severe plaque psoriasis and for psoriatic... 

Adalimumab is a TNF-a inhibitor initially approved for the treatment of rheumatoid arthritis in 2003. It is approved for treatment of psoriatic arthritis and off-label uses and clinical... 

Biologic agents useful in treating adult patients with moderate to severe chronic plaque psoriasis include the T-cell modulators alefacept and efalizumab, and the TNF-a inhibitors etanercept, infliximab, and adalimumab. TNF-a inhibitors are also discussed in Chapter 55. 

Adverse Side Effects. Patients taking TNF-a inhibitors may be prone to upper respiratory tract infections and other serious infections, including sepsis.48,51,83 This increased risk of infection probably occurs because the drug inhibits a key component of the immune response—namely, TNF-a. These drugs... 

FIGURE 16-2 T Schematic diagram illustrating the effects of tumor necrosis factor-alpha (TNF-a) inhibitors. Drugs such as etanercept, infliximab, and adalimumab attach directly to TNF-a, thereby preventing this destructive cytokine from reaching joint tissues. See text for more details. 

IL-1, IL-6, TNF-a inhibitors, and NO inhibitors prepared by Tamura (5) consisting of 3,4-dihydro-2H-pyran derivatives, (IV), were effective in the treatment of autoimmune and inflammatory diseases including septic shock. 

Te use of NSAIDS and other anti-inflammatory therapies are similar to those used in other autoimmune arthritic disorders. Corticosteroid injections for severe pain and inflammation at specific joints are standard therapy. For severe forms of the disease immunomoduladng and-rheumatic drugs such as methodexate and sulfasalazine are effecdve. As with other similar disorders, the biologic TNF a inhibitors are currently prescribed for severe Reiter s synchome. 

Fig. 13.5 How IL-1 andTNF-a cause inflammation, (a) IL-1 function. IL-1 induces the secretion of TNF-a to enhance its actions. The major effect of IL-1 is on capillary endothelial cells (see text). IL-1 causes keratinocytes and endothelial cells to proliferate and secrete other interleukins, especially IL-8, which acts like IL-1 on capillary endothelial cells (b) TNF-afunction. TNF-a usually acts as a proinflammatory growth and survival factor (see text). Its induction of vascular endothelial growth factor (VEGF) promotes greater capillary proliferation and permeability. VEGF contains a cysteine knot domain like von Willebrand factor (Fig. 11.2) [a Based on Fig. 1 in Dinarello CA (2000) Proinflammatory Cytokines. Chest 118(2) 503-508 b Slightly modified Fig. 1 from Jackson JM (2007) TNF-a inhibitors, Dermatologic Therapy, 20 251-261]...

TNF-a inhibitors are associated with increased risk of severe infections, for example with TB, and septicaemia. Adverse effects are many and include nausea, abdominal pain, worsening heart failure, hypersensitivity reactions, headache, depression and blood disorders. 

Brown ER, Charies KA, Hoare SA, Rye RL, Jodrell DI, Aird RE, Vora R, Prabhakar U, Nakada M, Corringham RE, DeWitte M, Sturgeon C, Propper D, Balkwill FR, Smyth JF. A clinical study assessing the tolerability and biological effects of infliximab, a TNF-a inhibitor, in patients with advanced cancer. Ann Oncol 2008 19(7) 1340-6. 

TNF-a inhibitors have also been utilized to treat pulmonary fibrosis. In one study, IFF patients stabilized while receiving etanercept compared with progressive disease seen in the placebo-treated patients (250). In another report of symptomatic scleroderma patient with pulmonary fibrosis, quality of life improved while treated with infliximab, but the treatment did not affect the progression of pulmonary fibrosis or pulmonary hypertension (251). Case series suggest infliximab can improve RA-associated pulmonary fibrosis (252-254). However, other studies suggest that both infliximab (255,256) and etanercept (257) can be associated with development or progression of pulmonary fibrosis. Additionally, both drugs have been associated with the subsequent development of sarcoidosis (258-262). 

Tumor necrosis factor-a (TNF-a) inhibitors (particularly infliximab) have been used, with anecdotal success, to treat refractory sarcoidosis (particularly lupus pernio) (166,189-192). Data in pulmonary sarcoidosis are limited (193—195). In a recent multicenter trial, 138 patients with chronic pulmonary sarcoidosis were randomized to placebo or infliximab (3 mg/kg) or infliximab (5 mg/kg) (194). At 24 weeks, the primary endpoint AFVC% predicted was shghtly higher among infliximab-treated patients (2.5% above baseline) compared to placebo-treated patients (no change). This difference, although statistically significant, is of doubtful chnical significance. 

AAV. However, all TNF-a inhibitors have potential serious toxicities including opportunistic infections lymphoproliferative and sohd malignancies (20,158) induction of autoimmune disorders, vasculitis, or interstitial lung diseases (186). Placebo-controlled trials are necessary to ascertain the role of infliximab or other TNF-ot inhibitors for WG or AAV. 

Ethyl 2-(p-fluorobenzyl)trifluoroacetoacetate reacted with resorcinol in 70 % sulfuric acid at 100 °C to provide coumarin 315a. Upon treatment with N,N-dimethylcarbamoyl chloride in the presence of NaH, this compound was readily converted into the corresponding iV,A -dimethylcarbamate 316a, which was tested as a TNF-a inhibitor [175]. A similar reaction of resorcinol with diethyl... 

Cheng J-F, Chen M, Wallace D, Tith S, Arrhenius T, Kashiwagi H, Ono Y, Ishikawa A, Sato H, Kozono T, Sato H, Nadzan AM (2004) Discovery and structure-activity relationship of coumarin derivatives as TNF-a inhibitors. Bioorg Med Chem Lett 14 2411-2415... 

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