Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Psoriasis is a chronic inflammatory disease of the skin affecting approximately 2% of the world's population. Traditional systemic treatments, including methotrexate, ciclosporin, psoralen plus UVA (PUVA), oral retinoids and fumaric acid esters, are widely used for severe disease and are effective in the short term. Severe psoriasis is a chronic disease and patients and physicians have expressed concerns about possible harm from organ toxicity, such as skin cancer (PUVA), hyperlipidaemia (retinoids), renal (ciclosporin) or hepatotoxicity (methotrexate). Long-term monitoring is required and may not detect early organ damage. The pathophysiology of psoriasis remains to be clarified, but advances toward the understanding of the immunological basis of psoriasis have uncovered the involvement of immunological pathways; for example, the role of tumour necrosis factor (TNF)-alpha, T cell proliferation and T cell activation, and migration to the epidermis. This advancement in knowledge combined with developments in recombinant technologies has led to the development of target-specific therapies. Biological agents are defined as proteins that can be extracted from animal tissue or produced via recombinant DNA technologies and possess pharmacological activity. Adalimumab, alefacept, infliximab, efalizumab and etanercept are examples of biological agents currently used for the treatment of psoriasis. Some of these are also therapy for other autoimmune conditions, such as rheumatoid arthritis and Crohn's disease. These biological agents are effective in psoriasis but raise new safety concerns. Information on the safety of biological agents in conditions such as rheumatoid arthritis and Crohn's disease can not be directly extrapolated to psoriasis. An increased incidence of lymphomas has been postulated to be associated with etanercept, infliximab and adalimumab; serious infections, such as tuberculosis, have also been reported with these three biologicals, all of which target TNF-alpha. Demyelinating disorders, such as multiple sclerosis, have been reported with some biologicals as has congestive heart failure. Alefacept, because of its mechanism of action of lowering the number of active T cells, is associated with low T cell counts. Efalizumab has been associated with thrombocytopenia and haemolytic anaemia. Data on the safety of >2.5 years' continuous treatment with efalizumab are reassuring and a valuable beginning to understanding the role and risk of harm of long-term therapy for a chronic disease. Longer follow-up studies and safety databases, for each of the biologicals used in psoriasis, are needed to ensure both prolonged efficacy and minimal risk of harm.
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PMID:Fulfilling an unmet need in psoriasis : do biologicals hold the key to improved tolerability? 1645 34

Progressive multifocal leucoencephalopathy (PML) is a serious and usually fatal CNS infection caused by JC polyoma virus. CD4+ and CD8+ T lymphopenia, resulting from HIV infection, chemotherapy, or immunosuppressive therapy, are the primary risk factors. The immune modulatory monoclonal antibodies rituximab, natalizumab, and efalizumab have received regulatory approval in the USA and Europe for treatment of non-Hodgkin lymphoma, rheumatoid arthritis, and chronic lymphocytic leukaemia (Europe only); multiple sclerosis and Crohn's disease; and psoriasis, respectively. Efalizumab and natalizumab administration is associated with CD4+ T lymphopenia and altered trafficking of T lymphocytes into the CNS, and rituximab leads to prolonged B-lymphocyte depletion. Unexpected cases of PML developing in people who receive these drugs have been reported, with many of the affected individuals dying from this disease. Herein, we review clinical findings, pathology, epidemiology, basic science, and risk-management issues associated with PML infection developing after treatment with these monoclonal antibodies.
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PMID:Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project. 1964 2

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the white matter of the human brain caused by lytic infection of oligodendrocytes with the human polyomavirus JCV. Although the majority of PML cases occur in severely immune-suppressed individuals, with HIV-1 infection as the predominant factor, PML has been increasingly diagnosed in patients treated with biological therapies such as monoclonal antibodies that modulate immune system functions. Monoclonal antibodies that target the cell adhesion molecules VLA-4 (natalizumab; Tysabri for multiple sclerosis and Crohn's disease) or LFA-1 (efalizumab; Raptiva for severe forms of plaque psoriasis) to prevent extravasation of inflammatory T cells into tissues, or target the cell surface marker CD20 (rituximab; Rituxan for hematologic malignancies and rheumatoid arthritis) to deplete peripheral circulating B cells, have all been associated with PML. The link between the effects of these therapies on the immune system and the occurrence of PML has prompted investigations on JCV sites of latency in the bone marrow, the migration of bone marrow derived cells into the circulation, and intracellular virus entry into the brain.
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PMID:Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. 1971 97

A 49-year-old female was started on efalizumab for severe psoriasis. Three weeks later, she developed rapidly progressive inflammatory polyarthritis associated with high titers of both rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) antibody. To our knowledge, this is the first reported case of efalizumab-induced anti-CCP-positive rheumatoid arthritis (RA). The polyarticular form of psoriatic arthritis (PsA) is associated with HLA-DR4, an antigen also associated with RA, and the presence of shared epitope alleles in PsA patients correlates with erosive disease, indicating a possible common mechanism of disease. CD4 T-cells play a prominent role in the pathogenesis of RA and PsA. Efalizumab theoretically modulates that role, appearing clinically to precipitate arthritis in a subset of PsA patients. On April 8, 2009, the makers of efalizumab announced a phased voluntary withdrawal of the drug from the US market because of progressive multifocal leukoencephalopathy cases. Further research using animal models of inflammatory polyarthritis is needed to determine the exact relationship between efalizumab and inflammatory arthritis, as well as to further explore the apparent connection between the inflammatory polyarticular form of PsA and RA.
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PMID:Efalizumab-induced inflammatory polyarthritis: what are the implications? 2022 9

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disorder of the central nervous system, caused by the reactivation of the ubiquitous JC virus. PML usually occurs during severe immunosuppression, and the most common causes are represented by human immunodeficiency virus infection, lymphoproliferative disorders and other forms of cancer. Recently, the introduction of monoclonal antibodies (e.g. natalizumab, rituximab, efalizumab) in the treatment of several dysimmune diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis and systemic lupus erythematosus, has led to an increased incidence of PML. This phenomenon has had severe consequences, leading, for example, to the withdrawal from the market of Efalizumab, and important restrictions in the use of the other compounds, all of which are characterized by high efficacy in improving prognosis and quality of life. In this review we will discuss clinical, laboratory and imaging findings of PML. In addition, proposed pathogenetic mechanisms promoting the reactivation of JC virus in the context of treatment with monoclonal antibodies will be described.
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PMID:Progressive multifocal leukoencephalopathy: an unexpected complication of modern therapeutic monoclonal antibody therapies. 2208 8