Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01889 (ankylosing spondylitis)
 5,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-alpha is a major effector and regulatory cytokine, which seems to have an outstanding position in rheumatic and other inflammatory states. Because TNF-alpha has been detected in the inflamed gut and sacroiliac joints of patients with chronic inflammatory bowel diseases and spondyloarthritides, like ankylosing spondylitis, there was need for studies of the efficacy of the modern biologic anti-TNF agents infliximab and etanercept in these diseases. Infliximab is approved for the treatment of Crohn disease. In addition, there are now also positive data for infliximab in the treatment of ankylosing spondylitis and for etanercept and infliximab in the treatment of psoriatic arthritis.
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PMID:New treatment options in spondyloarthropathies: increasing evidence for significant efficacy of anti-tumor necrosis factor therapy. 1155 23

Tumor necrosis factor (TNF)-alpha is one of the oldest known cytokines in human physiology. It is involved in both normal and pathologic states. Virtually every cell and organ in the body are affected by TNF-alpha. Though TNF-alpha is usually involved in inflammation as a normal host defense response, when overproduced, it can become pathologic and affect almost every organ system. In this article, we address the role of TNF-alpha in diseases such as rheumatoid arthritis, Crohn's disease, psoriasis, and ankylosing spondylitis as well as the drugs used to modulate TNF-alpha. Specifically, we look at the structure, mechanism of action, and clinical use for etanercept, infliximab, and adalimumab. Historically, we also review the drug lenercept, another TNF-alpha modulator. These drugs offer alternative effective treatments to rheumatologic and dermatologic diseases without as many of the toxic side effects of some of the traditional therapies. The traditional agents target TNF-alpha in addition to several other modes of action (disease modifying anti-rheumatic drugs [DMARDS] such as cyclosporine and methotrexate) (Table 1). Though TNF-alpha immunomodulation seems to be a very effective, promising treatment in several TNF-alpha mediated disease processes, long-term studies need to be performed to assess the risk-benefit ratio of using these drugs over an extended period of time.
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PMID:Focus on: biologics that affect therapeutic agents in dermatology. 1577 86

Tumor necrosis factor (TNF)-alpha inhibitors have proven efficacy in various autoimmune diseases such as Crohn disease, rheumatoid arthritis, psoriasis, and ankylosing spondylitis. Indeed, some TNFalpha inhibitors have already been approved for the management of the inflammatory manifestations associated with Crohn disease and rheumatoid arthritis. These agents are increasingly used for treatment of corticosteroid-resistant graft-versus-host disease after bone marrow transplantation, and case reports have documented their efficacy in treating corticosteroid- and muromonab-resistant rejection after intestinal transplantation. Thus, the potential role of TNFalpha inhibitors in transplantation of other vascularized solid organs is worthy of investigation. Experimental evidence indicates that TNFalpha plays a key role in mediating ischemia/reperfusion (IR) injury after liver, kidney, intestine, heart, lung, and pancreas transplantation. TNFalpha was also identified as a marker cytokine during organ rejection. Single-center studies evaluating the role of TNFalpha inhibitors in kidney transplantation have been initiated but the results are not yet available. TNFalpha is known to be a contributing factor in kidney allograft rejection, and may have value in predicting the onset of steroid-resistant acute rejection after liver transplantation. Experimental and preliminary clinical data have shown that circulating levels of TNFalpha are increased during cardiac graft rejection, and indicate that TNFalpha plays a role in the pathogenesis of acute cardiac allograft rejection. Anti-TNFalpha therapy was shown to prolong cardiac allograft survival when used alone or in combination with other drugs. TNFalpha genotype has been strongly associated with mortality in humans due to acute cell-mediated heart transplant rejection. In addition, there is evidence for a genetic predisposition toward acute rejection after kidney and simultaneous kidney-pancreas transplantation. TNFalpha inhibition has been used successfully as part of an induction therapy for pancreatic islet cell transplantation. Apart from IR injury and acute rejection after lung transplantation, TNFalpha was also found to be involved in the pathoimmunology of obliterative bronchiolitis. In conclusion, a substantial body of experimental evidence and preliminary clinical data suggest that TNFalpha inhibitors may play an important role in solid-organ transplantation, both in the amelioration of IR injury and in the treatment and prevention of acute rejection. Pharmacodynamic monitoring and pharmacogenetic screening may help to identify patients most likely to benefit from TNFalpha blockade. Randomized controlled trials in patients undergoing solid-organ transplantation are needed to further elucidate the clinical value of TNFalpha inhibition.
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PMID:Biologics in the treatment of transplant rejection and ischemia/reperfusion injury: new applications for TNFalpha inhibitors? 1612 5

Chronic low-grade inflammation is associated with insulin resistance. The aim of this study was to determine insulin response to intravenous glucose load and insulin sensitivity in patients with ankylosing spondylitis (AS). Fourteen nonobese male patients with AS and 14 matched healthy controls underwent frequent-sampling intravenous glucose tolerance test (FSIVGTT). Insulin secretion and insulin sensitivity were calculated using the computer-minimal and homeostasis-model assessment 2 (HOMA2) models. Fasting glucose, insulin, cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, triglyceride levels, HOMA2, glucose effectiveness, insulin sensitivity and insulin response to FSIVGTT did not differ between patients and controls. Tumor necrosis factor-alpha and interleukin (IL)-6 concentrations tended to be higher in AS patients than in controls. Second-phase beta-cell responsiveness was 37% lower (p = 0.05) in AS patients than in controls. A negative correlation was found between the percentage of beta-cell secretion and IL-6 in all subjects (r = -0.54, p = 0.006). We found normal insulin sensitivity but attenuated glucose utilization in the second phase of FSIVGTT in AS patients. Our results indicate that elevated IL-6 levels may play a pathophysiological role in attenuating beta-cell responsiveness, which may explain the association between elevated IL-6 levels and increased risk for type 2 diabetes.
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PMID:Attenuated insulin response and normal insulin sensitivity in lean patients with ankylosing spondylitis. 1636 18

Joint involvement is the most frequent extra-intestinal manifestation of chronic inflammatory bowel disease (IBD). Arthralgias are common and spondylarthropathy may affect peripheral joints, the spine as well as tendons. Clinical assessment has the greatest impact on diagnostics and therapy. In particular, a history of "inflammatory back pain" should lead to further investigations. HLA-B27 may be indicative of ankylosing spondylitis in IBD. Ultrasound and magnetic resonance imaging are preferred diagnostic modalities for the assessment of inflammation. Arthralgia often improves during treatment of IBD. In contrast, polyarticular arthritis, sacroiliitis, ankylosing spondylitis and enthesitis often require additional continuous therapy. Baseline therapy includes analgesics, intra-articular corticosteroid administration, and physiotherapy. Disease-modifying antirheumatic drugs such as sulfasalazine and methotrexate are used in polyarticular arthritis. Sulfasalazine may be effective in patients with early axial disease as well. Tumor necrosis factor (TNF) blocking agents may be employed in patients with active disease not responding to conventional treatment. For patients who fail to respond to TNF blockade, the emergence of other targets of the inflammatory cascade may provide more treatment choices in the future.
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PMID:[Joint involvement in chronic inflammatory bowel disease--current diagnostics and treatment options]. 1677 16

Tumor necrosis factor (TNF) antagonists are widely used to reduce disease activity and joint damage, and to improve health-related quality of life in patients suffering from rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis. To date, no increased risk of embryotoxicity or teratogenicity, or adverse pregnancy outcome (such as birth defects, premature birth, and low birth weight) has been reported in patients with inflammatory arthropathies treated with anti-TNF therapy, compared with the general population. However, the available data are limited, and methotrexate, which is commonly used in combination with anti-TNF drugs, is teratogenic. Until more data are available, no firm conclusions can be reached regarding the safety of anti-TNF therapy in pregnancy. Nevertheless, in selected cases where there is high disease activity, anti-TNF therapy might be recommended, depending on the results of individual risk-benefit analyses. Fully informed consent from the mother is needed in such cases. Anti-TNF agents are not usually used during lactation, although the risk of toxicity is probably negligible.
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PMID:Drug insight: Anti-tumor necrosis factor therapy for inflammatory arthropathies during reproduction, pregnancy and lactation. 1733 38

Tumor necrosis factor is a potent cytokine involved in the inflammatory process of many diseases. Agents that block tumor necrosis factor have been used in the treatment of various immune-mediated diseases, including rheumatoid arthritis, Crohn disease, psoriatic arthritis, and ankylosing spondylitis. Sarcoidosis is an immune-mediated inflammatory disorder of unknown etiology characterized by the formation of noncaseating granulomas. Tumor necrosis factor plays a major role in the inflammatory process seen in sarcoidosis. Sarcoidosis therapies with activity against tumor necrosis factor and specific anti-tumor necrosis factor therapies have been used with variable success. The long-term safety and efficacy of such therapies are yet to be determined in well-designed clinical trials with long-term follow-up.
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PMID:Sarcoidosis, role of tumor necrosis factor inhibitors and other biologic agents, past, present, and future concepts. 1756 Mar 12

Tumor necrosis factor (TNF)-targeted therapies are increasingly used for a rapidly expanding number of rheumatic and autoimmune diseases. With this use and longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. We have analyzed the clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy found through a MEDLINE search of articles published between January 1990 and December 2006. We identified 233 cases of autoimmune diseases (vasculitis in 113, lupus in 92, interstitial lung diseases in 24, and other diseases in 4) secondary to TNF-targeted therapies in 226 patients. The anti-TNF agents were administered for rheumatoid arthritis (RA) in 187 (83%) patients, Crohn disease in 17, ankylosing spondylitis in 7, psoriatic arthritis in 6, juvenile RA in 5, and other diseases in 3. The anti-TNF agents administered were infliximab in 105 patients, etanercept in 96, adalimumab in 21, and other anti-TNF agents in 3. We found 92 reported cases of lupus following anti-TNF therapy (infliximab in 40 cases, etanercept in 37, and adalimumab in 15). Nearly half the cases fulfilled 4 or more classification criteria for systemic lupus erythematosus (SLE), which fell to one-third after discarding preexisting lupus-like features. One hundred thirteen patients developed vasculitis after receiving anti-TNF agents (etanercept in 59 cases, infliximab in 47, adalimumab in 5, and other agents in 2). Leukocytoclastic vasculitis was the most frequent type of vasculitis, and purpura was the most frequent cutaneous lesion. A significant finding was that one-quarter of patients with vasculitis related to anti-TNF agents had extracutaneous involvement. Twenty-four cases of interstitial lung disease associated with the use of anti-TNF agents were reported. In these patients, 2 specific characteristics should be highlighted: the poor prognosis in spite of cessation of anti-TNF therapy, and the possible adjuvant role of concomitant methotrexate. In conclusion, the use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, SLE, and interstitial lung disease.
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PMID:Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. 1763 66

Tumor necrosis factor-alpha (TNFalpha) is a key proinflammatory cytokine involved in chronic inflammatory diseases. Infliximab, a chimeric (human-murine) monoclonal IgG1 anti-TNFalpha antibody, is used in the treatment of Crohn's disease (including fistulising disease) and rheumatoid arthritis (in combination with methotrexate) if standard treatments have failed. The indications for infliximab have recently been expanded to include ankylosing spondylitis, psoriatic arthritis, psoriasis and ulcerative colitis. The biological agent infliximab is given by multiple intravenous infusions in a dosage of 3-5 mg/kg (initially at weeks 0, 2 and 6; subsequently in intervals of 4-8 weeks). In controlled trials, clinical response rates of 20-40% have been achieved with such regimens in Crohn's disease and rheumatoid arthritis. However, the therapeutic benefits must be balanced against the risks of a variety of severe adverse events (e.g. severe infections including tuberculosis, hepatotoxicity, infusion reactions, serum sickness-like disease and lymphoma). Following single and multiple infusions of infliximab, no relevant differences in median concentration-time profiles have been observed between patients with Crohn's disease, patients with rheumatoid arthritis and patients with psoriasis. The apparent volume of distribution of the high-molecular-weight infliximab (149.1 kDa) is low (3-6L) and represents the intravascular space. The long persistence in this compartment (elimination half-life 7-12 days, mean residence time 12-17 days) is due to the very low systemic clearance of about 11-15 mL/hour (0.18-0.25 mL/minute). Elimination of infliximab is most probably accomplished through degradation by unspecific proteases. During multiple infusions (every 4-8 weeks), no accumulation was observed, and serum concentrations and the area under the plasma concentration-time curve of infliximab increased in proportion to the infused dose, indicating linear pharmacokinetics. Co-medication with methotrexate delayed the decline in the serum concentrations of infliximab. When relating serum concentrations to the clinical response in patients with rheumatoid arthritis and patients with Crohn's disease, it can be assumed that trough concentrations above 1 microg/mL could be used as a kind of therapeutic target. In the future, identification of biomarkers for (non-)response and risk factors for adverse drug reactions would be very helpful. Furthermore, combined biological, pharmacokinetic, pharmacogenomic and clinical studies have not yet been performed and are needed to optimise the therapeutic potential of infliximab, which is currently established as a rescue treatment in refractory patients.
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PMID:Clinical pharmacokinetics and use of infliximab. 1765 72

Immunosuppressive therapies, in particular cyclosporine, are known to induce the development of lymphoproliferative malignancies. In general, the lymphomas that occur in the setting of impaired immune function are B cell non-Hodgkin's lymphomas, often large cell lymphomas. Mycosis fungoides (MF) is the most common form of cutaneous T cell lymphomas, which can require persistent antigen and superantigen stimulation by way of chronic immunosuppression and HIV. Tumor necrosis factor antagonists, which are novel immunomodulatory agents, might produce significant adverse effects, including an increased risk of malignancy. Currently available data do not show whether these agents were the proximate cause of the reported lymphomas. We present a 32-year-old male with ankylosing spondylitis treated with infliximab who developed MF during the second year of therapy.
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PMID:Mycosis fungoides in a patient with ankylosing spondylitis during infliximab therapy. 1776 16


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