pharma fouda 2_p34-36.pdf

Part 4: Drug g therap py of rhe eumatoid arthrritis (RA)) Definittion RA is a chronic inflammato ory diseasse characteerized by symmetricc small join nt infla- mmatioon, swelling g, and deformity. Ext...

Part 4: Drug g therap py of rhe eumatoid arthrritis (RA)) Definittion RA is a chronic inflammato ory diseasse characteerized by symmetricc small join nt infla- mmatioon, swelling g, and deformity. Ext xtra-articula ar manifesttations aree also com mmon. Pathop physiology y The ex xact aetiollogy is un nclear howwever; gen netic facto ors play a n importa ant role. Activated T cells,, B cells, polymorpho p onuclear le eukocytes (PMLs), m macrophag ges, and comple ement systtem lead to productiion of solu uble mediaators (lysossymes, cyttokines, e.g. TNNF-α, IL-1, etc.) tha at cause jjoint inflam mmation, cartilage c d destruction n, bone erosionn, and defformity. Why W the im mmune sys stem attac cks the jooint structu ures as "foreign n" antigens, is unkno own. Clinica al manifes stations Artticular manifestation ns: Thee disease affects a mainly small jjoints of the hands anda toes in a sym metrical fash hion. In se evere case es, large jo oints are also o affected.. Affected joints j are sswollen, painful and d with limited m mobility. Symmptoms area especia ally worsee in the moorning. In late case es, chara acteristic ms of joint deformity are prese nt. form Exttra-articular manifestations: The e spectrumm of clinical manifesstations off RA can extend e to include sy ystemic gans e.g. pleural effus org sion, perica mia, vasculitis, etc. arditis, anem 133  Diagnosis  Serological: – Abnormal blood antibodies "rheumatoid factor" can be found in 80% of RA patients. – Detection of Cyclic Citrullinated Peptide antibodies (anti-CCP antibodies): more specific than RF and can be detected up to 10 years before the development of RA.  Joint X-ray can show joint swelling and bony erosions typical of RA. █ Management of RA ▌Symptomatic treatment NSAIDs: large doses of NSAIDs are usually required. They offer symptomatic relief of pain and inflammation but don't prevent joint destruction. Corticosteroids: they are given as short-term therapy till DMARDs give their effect. ▌Disease-Modifying Antirheumatoid Drugs (DMARDs)  They are the most important and should be started as early as possible because their effect may take 3 weeks to 3 months to be evident.  They prevent progression of the disease and slow joint destruction by modifying the immune reactions.  Combinations of two or more DMARDs are more effective than a single drug. Biologic DMARDs: TNF-α inhibitors TNF-α plays a crucial role in the pathogenesis of RA, and these drugs became the most important DMARDs. – Adalimumab and infliximab: they are monoclonal antibodies that complex with TNF-α and prevent its interaction with T cells and macrophages. – Etanercept: it is a recombinant protein that interferes with TNF-α and prevents it from binding to its receptors. – Acute and chronic infections, live virus vaccination, demyelinating disorders, class III or IV heart failure, and recent malignancies are contraindications to the use of TNF inhibitors. – Because these drugs are expensive, recent guidelines do not recommend their use until at least one nonbiologic DMARD, usually methotrexate, has been administered without sufficient success. 134  Methotrexate – It is a folic acid antagonist with cytotoxic and immunosuppressant properties. It is one of the first line drugs being used in more than 60% of RA cases. – It inhibits multiple intracellular enzymes needed for activation of PMLs, T cells, and macrophages. – It is given once weekly orally. Folic acid 5mg must be given 24h after methotrexate dose to compensate for folic acid deficiency. – Common adverse effects: hepatotoxicity is common (monitoring liver functions is essential), myelosuppression (bone marrow), teratogenicity. Hydroxychloroquine (antimalarial drug) – It decreases synthesis of DNA and RNA in the inflammatory cells and decrease response of T cells to antigens. – It also stabilizes lysosomal membranes. Sulfasalazine It is metabolized into sulfapyridine and 5-aminosalicylic acid. 5-ASA causes inhibition of IgA and IgM production, and suppresses T and B cell functions. Immunosuppressant drugs – Cyclophosphamide and azathioprine: suppress immune function by their cytotoxic action through a variety of mechanisms, particularly inhibition of DNA synthesis. – Cyclosporine: It is a potent and specific inhibitor of T cells. It inhibits phosphorylation of calcineurin, a protein that regulates nuclear transcription factors in the T cells. Gold salts Gold salts could be given i.m. or orally. Gold inhibits the functions of human macrophages and decrease the release of inflammatory cytokines and growth factors from inflammatory cells. Leflunomide – It suppresses pyrimidine synthesis and suppresses T cell and B cell functions. – It is effective as methotrexate in inhibition of bone damage. Anakinra – It is a competitive IL-1 receptor antagonist. – It has a relatively short half-life and must be administered subcutaneously daily. 135