Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiology of systemic lupus erythematosus (SLE) is unknown but genetic factors seem to play a role in the disease pathogenesis. The tumor necrosis factor alpha (TNFa) gene, encoded at the TNF locus in the MHC class III region, is now known to be an important candidate gene in SLE, due to the proinflammatory activities of the TNFa. The objectives of this study were to examine the role of the TNFa polymorphism for the susceptibility of Malaysian Chinese lupus patients to SLE and to determine its association with organ involvement. The allelic frequencies of the TNFa polymorphic variant (TNF2) of seventy lupus patients were determined during follow-up at the Medical Clinic of the National University Hospital Malaysia by PCR-RFLP technique. Sixty-four females and 6 males with a mean age of 33+/-12 years were included. Clinical data were obtained from case records. Autoantibody levels were measured by ELISA. Fifty-nine ethnically-matched blood donors were used as controls. The allelic frequency of the TNF2 variant was found to be significantly increased in the patients compared to the controls (52.8% vs 33.8%). SLE patients with the polymorphic TNF2 variant were found to be at increased risk of central nervous system involvement (p = 0.004, RR = 2.59) and to have an increased frequency of anti-La antibodies (p = 0.03). In view of these findings we suggest that TNF2 variant is playing a role in conferring susceptibility to SLE and in the disease pathogenesis.
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PMID:Association of the tumor necrosis factor alpha gene polymorphism with susceptibility and clinical-immunological findings of systemic lupus erythematosus. 1556 53

Cytokines, most particularly TNF and type I IFN (IFN-alphabeta), have been long considered essential elements in the development of autoimmunity. Identification of TNF in the pathogenesis of rheumatoid arthritis and TNF antagonist therapy represent successes of immunology. IFN-alphabeta plays a major role in systemic lupus erythematosus (SLE), a prototype autoimmune disease characterized by a break of tolerance to nuclear components. Here, we show that TNF regulates IFN-alpha production in vitro at two levels. First, it inhibits the generation of plasmacytoid dendritic cells (pDCs), a major producer of IFN-alphabeta, from CD34+ hematopoietic progenitors. Second, it inhibits IFN-alpha release by immature pDCs exposed to influenza virus. Neutralization of endogenous TNF sustains IFN-alpha secretion by pDCs. These findings are clinically relevant, as five of five patients with systemic juvenile arthritis treated with TNF antagonists display overexpression of IFN-alpha-regulated genes in their blood leukocytes. These results, therefore, might provide a mechanistic explanation for the development of anti-dsDNA antibodies and lupus-like syndrome in patients undergoing anti-TNF therapy.
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PMID:Cross-regulation of TNF and IFN-alpha in autoimmune diseases. 1572 81

Although far from complete, the picture of cytokines present in systemic lupus erythematosus (SLE) glomerulonephritis is already complex. Proinflammatory cytokines, such as TNF, IL-6, IL-1, and IL-18 are upregulated, as are both Th1 and Th2 cytokines, with different implications. In many instances, the local effects may be different from the systemic immunoregulatory ones. For some proinflammatory cytokines, and TNF in particular, the local proinflammatory ones may be more relevant to the disease. This may help solve discrepancies between different murine models of the disease and provide a better rationale for targeting certain cytokines in human SLE.
Lupus 2005
PMID:Cytokine expression in lupus kidneys. 1573 82

Crohn's disease is a T helper type 1 response immune disease characterized by increased production of interleukin-12 tumor necrosis factor-a (TNF-a), and interferon-g. Clinical trials have demonstrated that inhibition of TNF is effective for the treatment of Crohn's disease. Adverse events reported in patients treated with anti-TNF agents include immunogenicity, acute infusion reactions, delayed hypersensitivity-type reactions, autoimmune diseases including drug-induced lupus and demyelination, and infection. This article reviews new concepts in the treatment of Crohn's disease and ulcerative colitis with a variety of anti-TNF biologic therapies: infliximab, adalimumab, CDP870, CDP571, etanercept, and onercept.
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PMID:New concepts in anti-tumor necrosis factor therapy for inflammatory bowel disease. 1574 28

In the course of the disease, a wide variety of cytokines is dysregulated, many of which likely influence systemic lupus erythematosus (SLE) autoimmunity and/or lupus tissue inflammation. Proinflammatory cytokines in particular, such as TNF, IL-6, IL-18 or IFN-gamma, may play a major role in propagating the inflammatory processes responsible for tissue damage. These cytokines are overexpressed both systemically and locally, and preliminary results from open-label trials and/or animal studies suggest potential benefits of blocking either of these inflammatory mediators. Since new therapeutic agents may soon offer many ways to influence the process, controlled clinical trials following open-label safety studies are of central importance to arrive at optimized therapies for SLE patients.
Lupus 2005
PMID:Anti-cytokine therapy in systemic lupus erythematosus. 1580 94

The three licensed TNF(alpha) blocking agents (etanercept, infliximab, adalimumab) and the recombinant form of human interleukin-1-receptor antagonist (anakinra) have all been shown to be effective in patients with chronic rheumatic autoimmune diseases; they have also been associated with certain types of serious adverse events. As expected, much of the information on serious events have accumulated during the post-marketing period. Certain serious, but uncommon, adverse events have been observed with all three TNF(alpha) blocking agents, including serious bacterial infections, tuberculosis (TB) and certain opportunistic infections, demyelinating syndromes, and lupus-like reactions. These data suggest that these adverse reactions may be related to blockade of TNF(alpha) and may therefore represent class effects of these agents. However, the severity and degree of risk may not be the same with all three agents. Blockade of interleukin-1 activity with anakinra appears, at present, to be relatively safe. The safety profile of these products will continue to be developed through the use of the registry, periodic safety updates from the passive surveillance program, and safety data from controlled trials of biological therapy for other diseases. Physicians should minimize risks by patient selection and screening for opportunistic infections. Moreover, the choice of the biological agent must be tailored to minimize risks and maximize benefits.
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PMID:Safety of tumour necrosis factor and interleukin-1 blocking agents in rheumatic diseases. 1582 2

Targeted inhibition of tumour necrosis factor-alpha (TNF-alpha) is an effective therapy in rheumatoid arthritis and Crohn's disease (CD). Infliximab, a monoclonal murine-human chimeric antibody to TNF-alpha, and etanercept, a fusion protein of two p75 chains of the TNF receptor II and the Fc portion of IgG1, are generally well tolerated. Rarely does clinically significant autoimmunity, including drug-induced lupus and vasculitis occur. Immunologic mechanisms underlying the development of autoimmunity in the presence of such powerful immunosuppressants are unknown. We describe a patient with CD, who developed cutaneous vasculitis on etanercept, which worsened significantly with switch to infliximab. Investigation of the associated systemic and local immune response demonstrated the absence of human antichimera antibodies, but mRNA for T-helper 1 cytokines, chemokines and defensins in the skin and elevated angiogenesis factors in the serum, as determined by reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Histopathology revealed a lymphocytic vasculitis composed of T cells. A permanent B-cell line (MD-B) producing extremely high amounts of chemokines and interleukin-6 was established from this patient's peripheral blood. Lesions progressed despite discontinuation of the drugs and (40 mg/day) prednisone but almost completely resolved with single dose of (0.1 mg/kg) intravenous dexamethasone, which may be therapy of choice for this reaction. A few lesions (<10) have recurred intermittently over 4 years of follow-up, suggesting possible persistence of this TNF-inhibitor-triggered autoimmune disease.
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PMID:Immunology of cutaneous vasculitis associated with both etanercept and infliximab. 1585 15

DeltaBAFF is a novel splicing isoform of the regulator B cell-activating factor (BAFF, BLyS), a TNF family protein with powerful immunoregulatory effects. Overexpression of BAFF leads to excessive B cell accumulation, activation, autoantibodies, and lupus-like disease, whereas an absence of BAFF causes peripheral B cell immunodeficiency. Based on the ability of DeltaBAFF to multimerize with full-length BAFF and to limit BAFF proteolytic shedding from the cell surface, we previously proposed a role for DeltaBAFF in restraining the effects of BAFF and in regulating B lymphocyte homeostasis. To test these ideas we generated mice transgenic for DeltaBAFF under the control of human CD68 regulatory elements, which target expression to myeloid and dendritic cells. We also generated in parallel BAFF transgenic mice using the same expression elements. Analysis of the transgenic mice revealed that DeltaBAFF and BAFF had opposing effects on B cell survival and marginal zone B cell numbers. DeltaBAFF transgenic mice had reduced B cell numbers and T cell-dependent Ab responses, but normal preimmune serum Ig levels. In contrast, BAFF transgenic mice had extraordinarily elevated Ig levels and increases in subsets of B cells. Unexpectedly, both BAFF and DeltaBAFF appeared to modulate the numbers of B-1 phenotype B cells.
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PMID:deltaBAFF, a splice isoform of BAFF, opposes full-length BAFF activity in vivo in transgenic mouse models. 1597 64

The cytokine, tumour necrosis factor-alpha (TNF-alpha) plays a key role in the pathogenesis of many chronic inflammatory and rheumatic diseases, in particular, Crohn's disease, rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. Controlled trials have shown that the TNF inhibitors (etanercept, infliximab and adalimumab) significantly reduce symptoms and signs, improve function and quality of life, and reduce radiologically evident damage in patients with rheumatoid diseases. For reasons that are not entirely clear, etanercept does not work in Crohn's disease. Injection site and intravenous reactions and increased risk of infection (in particular, reactivation of tuberculosis) are associated with the use of these agents. Increased risk of lymphoproliferative disease, the development of lupus-like syndromes and demyelination, including optic neuritis and reactivation of multiple sclerosis, are under evaluation in long-term follow-up studies. The TNF inhibitors are expensive (about $18 000 per year), and in some patients need to be given continuously to maintain benefit, even in the presence of other immunosuppressive therapy.
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PMID:Tumour necrosis factor inhibitors. 1609 22

The purpose of this report is to provide suggested guidance concerning the monitoring of TNF blocker therapy. Since the completion of randomized trials, several new long-term safety concerns have arisen, involving mycobacterial and opportunistic infections, cytopenias, lymphoma, demyelinating disease, drug-induced lupus, congestive heart failure and hepatotoxicity. Since these serious events are rare, widespread post-marketing use and prolonged follow-up have been required to analyze their prevalence. Monitoring of TNF inhibitors is necessary to reassure physicians and patients of the continued efficacy and safety of these drugs. No published recommendations on monitoring are available. The clinician must weigh the potential clinical benefits of TNF inhibition against potential adverse effects. Patients should be evaluated carefully for the risk or presence of infection, tuberculosis and other serious adverse events by regular visits, careful clinical assessments, and an assiduous, high index of suspicion for these rare events. Tuberculin skin testing using PPD is recommended before starting treatment with any TNF inhibitor.
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PMID:Laboratory monitoring of biologic therapies. 1627 91


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