Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infliximab, a chimeric monoclonal antibody to tumour necrosis factor-alpha, contains murine protein elements and targets the immune system, raising concerns about the potential for immune sensitization and immunosuppressive sequelae. However, long-standing inflammatory disease with high activity and chronic immunosuppressant therapy can also predispose patients to immunosuppressive sequelae. Patients with Crohn's disease, rheumatoid arthritis and other indications received single or multiple doses of infliximab and their condition was followed for up to 3 years. Adverse events, most frequently headache, nausea, and upper respiratory tract infection, were generally mild and occurred in 76% of infliximab-treated patients vs. 57% of placebo-treated recipients. Human antichimeric antibodies developed in 13% of patients, increasing the potential for subsequent infusion reactions. Antibodies to double-stranded DNA developed in a small percentage of patients. Other antinuclear antibodies characteristic of serum lupus erythematosus were not found; no patient developed a true lupus syndrome and no other autoimmune disorders were reported. Infliximab is not associated with typical immunosuppressive sequelae, such as infections and malignancy, or with autoimmune disorders. Infliximab therapy was well tolerated, serious adverse events were infrequent, successfully managed with medication and without sequelae, and overall mortality was within the expected incidence for this patient population.
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PMID:Review article: safety of infliximab in clinical trials. 1059 35

Infliximab is a chimeric anti-tumour necrosis factor-alpha monoclonal antibody that has been studied for the treatment of Crohn's disease and rheumatoid arthritis. In several placebo controlled, randomized clinical trials and open trials, 771 patients have been given infliximab (a further 192 received placebo). Follow-up for safety has included the time of study (12 weeks after the last infusion), plus three additional years. Acute infusion reactions (headache, fever, chills, urticaria, chest pain) were seen in 17% of patients receiving infliximab compared with 7% of those receiving placebo. While infections were reported more frequently overall in the patients given infliximab (26% over 27 weeks of follow-up versus 16% of placebo-treated patients over 20 weeks of follow-up), there was no increased risk of serious infections. There was no difference in the overall mortality rate between the groups. While low titres of autoantibodies developed in less than 10% of patients, drug-induced lupus was seen in less than 1%, with these cases resolving upon discontinuation of the drug. Overall, infliximab showed an acceptable safety profile.
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PMID:Long term safety of infliximab. 1102 58

Most disease modifying antirheumatic drugs (DMARD) are discontinued within 5 years because of loss of clinical efficacy or toxicity. As a result, there has been a concerted effort to develop new immunomodulatory agents, particularly biological agents, that block the putative proinflammatory cytokines. Among the agents developed thus far, inhibitors of tumor necrosis factor (TNF) have shown perhaps the greatest promise as therapeutic agents for rheumatoid arthritis (RA). Two TNF-blocking agents, etanercept (Enbrel) and infliximab (Remicade), have been approved in the US and more recently in Europe, for the treatment of patients with RA. The results of randomized placebo controlled trials have shown that both agents significantly decrease the intensity of synovitis and prevent or retard the progression of cartilage destruction, especially when combined with methotrexate. Their side effect profiles appear to be acceptable, although rare cases of lupus-like diseases and of severe infections have been reported. Although the early clinical experience with these agents has been encouraging, their longterm safety and continuing efficacy in the general population with RA, as well as in high risk patient subsets (i.e., patients with malignancies or chronic infections), remain to be determined. In addition, the costs of these newer agents must be justified on clinical grounds. Because of the questions still surrounding these new treatment principles, several consensus conferences have been held in Europe and the US to address the role of the new biologicals in the current RA armamentarium.
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PMID:How do the biologics fit into the current DMARD armamentarium? 1140 55

In the last decade, there have been substantial advances in the treatment of rheumatoid arthritis with the addition of several new disease-modifying agents to the therapeutic armamentarium. Biological agents targeting tumour necrosis factor (TNF) represent one such important addition. Infliximab, a chimeric anti-TNF monoclonal antibody, has shown remarkable promise in alleviating the signs and symptoms of rheumatoid arthritis in addition to retarding radiographic disease progression when used in combination with methotrexate. In its pivotal phase III trial, the addition of infliximab to patients with methotrexate-refractory disease was associated with substantial clinical benefit. Using American College of Rheumatology criteria for improvement, one-half of patients receiving infliximab (3 mg/kg every 8 weeks) plus methotrexate showed at least 20% improvement compared with only 20% of those receiving placebo plus methotrexate (p < 0.001) with over one-half of eventual responders obtaining criteria for improvement by the second week of observation. Although its use has been met with much deserved enthusiasm, recent reports have highlighted several potential serious adverse effects associated with infliximab (and other TNF antagonists), including infusion reactions, congestive heart failure, drug-induced lupus, and CNS demyelination. In addition, recent reports have cited the potential for reactivation of mycobacterial and fungal infection in patients receiving infliximab, mandating appropriate tuberculosis screening prior to drug initiation. Although the frequency of serious drug-related toxicity (requiring discontinuation of the agent) appears to be quite low, these reports underscore the need for caution and close surveillance with the administration of TNF inhibitors, particularly given that strategies aimed at preventing toxicity remain unproven. Despite its potential for toxicity, infliximab remains a valuable alternative for patients with rheumatoid arthritis.
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PMID:Benefit-risk assessment of infliximab in the treatment of rheumatoid arthritis. 1249 61

Tumour necrosis factor (TNF) plays an important role in mediating the inflammation of inflammatory bowel disease, in particular, Crohn's disease. Strategies aimed at reducing tumour necrosis factor in patients with inflammatory bowel disease include the mouse/human chimeric monoclonal antibody infliximab, the humanized monoclonal antibody CDP571, the human soluble TNF p55 receptor onercept, the human monoclonal antibody D2E7 (adalimumab), the anti-TNF human antibody Fab' fragment-polyethelene glycol (PEG) conjugate CDP870, and the small molecules thalidomide and CNI-1493 (MAP-kinase inhibitor). Infliximab is effective for treating active Crohn's disease, maintaining remission, closing fistulas, maintaining fistula closure, and treating ankylosing spondylitis. Infliximab is also being investigated for the treatment of ulcerative colitis. Side-effects occurring in patients treated with infliximab include human anti-chimeric antibodies, infusion reactions, delayed hypersensitivity reactions, formation of autoantibodies, and, in rare circumstances, drug-induced lupus and serious infections, including tuberculosis. CDP571 is effective for treating active Crohn's disease, steroid sparing, and possibly for closing fistulas and maintaining remission. Side-effects occurring in patients treated with CDP571 include anti-idiotype antibodies, infusion reactions and the formation of autoantibodies. A controlled trial of etanercept in patients with Crohn's disease was negative. Pilot studies with onercept, thalidomide, and CNI-1493 have suggested benefit for Crohn's disease. There are no published data on the efficacy of adalimumab (D2E7) or CDP870 for either Crohn's disease or ulcerative colitis. Anti-tumour necrosis factor therapies are effective for the treatment of Crohn's disease and are being investigated for ulcerative colitis.
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PMID:Strategies for targeting tumour necrosis factor in IBD. 1261 86

Infliximab, a chimeric monoclonal antibody targeting tumor necrosis factor alpha (TNF-alpha), is efficacious in the treatment of rheumatoid arthritis and Crohn's disease. We report in detail an unusual adverse reaction to infliximab therapy, a drug-induced lupus-like clinical syndrome. A 45-year-old woman with steroid-dependent Crohn's colitis, successfully managed with maintenance infliximab infusions and methotrexate, developed a lupus-like syndrome eight months after her initial infusion. This was characterized by inflammatory arthritis and an urticarial and papulosquamous rash and was accompanied by high titers of antinuclear, double-stranded DNA, glomerular-binding, and histone antibodies and by reduced levels of the C4 component of complement. After discontinuance of infliximab infusions and treatment of symptoms with intermittent courses of prednisone, the patient's arthritis progressively improved, with accompanying decrements in autoantibody titers. One year later, she has minimal joint discomfort and no rash or gastrointestinal symptoms despite also discontinuing prednisone and methotrexate. Infliximab therapy may cause a lupus-like syndrome that is reversible upon discontinuing this agent. These findings support recent evidence identifying TNF-alpha as an inhibitor of autoantibody formation.
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PMID:A lupus-like syndrome associated with infliximab therapy. 1279 23

The introduction of infliximab, a mouse/human chimeric monoclonal antibody to tumor necrosis factor (TNF), is an important advance in the treatment of Crohn's disease. Infliximab is effective for induction and maintenance of remission in patients with inflammatory luminal and fistulizing disease. The development of human antichimeric antibodies (HACAs) has led to infusion reactions and loss of efficacy in patients treated with infliximab. Strategies to reduce the frequency of HACA formation include induction of immunologic tolerance with a three-dose regimen at 0, 2, and 6 weeks followed by systematic maintenance dosing every 8 weeks; concomitant immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate; and premedication with intravenous corticosteroids. Humanized or fully human anti-TNF biotechnologic agents, including CDP571, CDP870, etanercept, adalimumab, and onercept, are theoretically less immunogenic than the chimeric antibody infliximab. Etanercept is not effective for Crohn's disease. CDP571 is not effective in unselected patients with active Crohn's disease, but it may be effective in patients with elevated C-reactive protein. The efficacy of CDP870, adalimumab, and onercept is under investigation. The different mechanisms of action of these anti-TNF agents may account for their variable efficacy. Their benefits, however, must be considered in the context of their risks, including infusion reaction; delayed hypersensitivity-like reaction; new onset of autoimmunity, with rare cases of drug-induced lupus and new-onset demyelination; and the potential for rare but serious infections.
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PMID:Optimizing anti-tumor necrosis factor strategies in inflammatory bowel disease. 1460 60

Infliximab is a tumour necrosis factor (TNF)-alpha antagonist that has revolutionised the treatment of Crohn's disease and rheumatoid arthritis. However, infliximab therapy can be complicated by a variety of adverse reactions. Acute infusion reactions occur during or shortly after infusion and typically consist of fever, chills, nausea, dyspnoea and headaches. Delayed reactions, characterised by myalgias, arthralgias, fever, rash, pruritus, facial, hand or lip oedema, dysphagia, urticaria, sore throat and headache may occur 3-12 days after infusion. Although the mechanisms of these reactions are not yet clearly defined, emerging evidence indicates that these reactions may be associated with the immune response against infliximab and the development of antibodies to infliximab.A number of studies have identified protective factors that may minimise adverse reactions, presumably related to the immune response against infliximab. Factors that may be protective by helping to establish immune tolerance for the foreign infliximab protein include concomitant administration of immunomodulators or corticosteroids, starting infliximab therapy with a 0, 2, 6-week induction regimen, maintenance dose administration with infusions every 8 weeks or less, and avoiding long periods between infusions. Infliximab therapy also may have other immunological consequences. There is evidence that infliximab may impede the appropriate immune response to a number of pathogens, prohibiting its use in patients with active infections. In addition, patients should be screened and appropriately treated for tuberculosis before initiating infliximab therapy. The development of autoantibodies, such as antinuclear antibody or anti-ds-DNA, has also been described with infliximab therapy, although the development of clinical lupus-like syndrome is rare. While there is a theoretical risk of increased rate of malignancies due to antagonism of TNFalpha, to date there is no clear evidence of such an effect. In addition, cardiac and neurological adverse events associated with infliximab therapy have been described. The mechanism for these adverse events is unclear. In summary, infliximab therapy can be an effective treatment for Crohn's disease; however, a number of immunological consequences and adverse events may complicate the infusion of this agent. Appropriate prophylaxis and therapy of these adverse reactions will allow infliximab to be used safely in the vast majority of patients.
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PMID:Managing immunogenic responses to infliximab: treatment implications for patients with Crohn's disease. 1530 61

The treatment of rheumatoid arthritis (RA) has changed dramatically over the past 15 years with the realisation that earlier, aggressive therapy limits progression. There is evidence that biological response modifiers (BRMs), which target specific cytokines such as TNF-alpha and IL-1, are more effective than traditional disease-modifying antirheumatic drugs (DMARDs), especially in combination with methotrexate. Four therapies are approved for use in RA; three target TNF-alpha (etanercept [Enbrel, Amgen Inc.], infliximab [Remicade, Centocor Inc.], and adalimumab [Humira, Abbott]), and one targets IL-1 (anakinra [Kineret, Amgen Inc.]). It is clear from both the clinical trials and postmarketing reports that all four agents have a different safety profile compared with traditional DMARDs. There are several areas of concern with the use of the BRMs, which include serious and opportunistic infections, malignancy/lymphoma, congestive heart failure, demyelination, injection/infusion reactions, development of autoantibodies and lupus-like disease. It is important to be fully aware of the safety profile and differences between BRMs in order to use them appropriately.
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PMID:Considerations with the use of biological therapy in the treatment of rheumatoid arthritis. 1533 95

The anti-TNF-alpha antibody infliximab (Remicade) is highly effective in the treatment of Crohn's disease. A subset of patients experience allergic reactions as a result of antibodies to infliximab (ATIs). The purpose of the current study is to describe the safety and efficacy of adalimumab (Humira) in patients previously allergic or intolerant to infliximab. Adalimumab is an anti-TNF-alpha agent containing only human peptide sequences. Seven patients have been treated with adalimumab who had experienced immediate- or delayed-hypersensitivity reactions to infliximab and one with infliximab-induced lupus. Except for injection site discomfort, adalimumab was well tolerated without signs or symptoms of allergic reactions. One patient who had previously received pooled human immunoglobulin developed a pruritic rash after each dose of adalimumab. Patients with active disease who had previously experienced a robust response to infliximab responded to adalimumab as reflected by an improvement in Harvey-Bradshaw index and inflammatory markers. Based on these preliminary data, adalimumab may be a safe and effective substitute for infliximab-allergic patients. Individuals who have been exposed to human antibodies may be sensitized to other human antibodies such as adalimumab.
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PMID:A pilot study of adalimumab in infliximab-allergic patients. 1547 39


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