Pharmacological Management for Rheumatoid Arthritis

Pharmacological Management for Rheumatoid Arthritis APC e.g. macrophage encounters some unknown antigen It presents unknown antigen to CD4+ T-helper cell Immune chain reaction occurs including cytokine overproduction Immune system gets confused and attacks own tissue with proteins similar to this antigen Immune cells including lymphocytes are activated and pro-inflammatory cytokines, such as the following, are expressed in the inflamed area: o TNF o IL-1 o IL-6 Reduce joint inflame Reduce joint pain Maximum joint function Prevent joint destruction and deformity First-line, fast-acting: to reduce pain and inflammation o NSAIDs e.g. aspirin o Corticosteroids Second-line, slow acting: DMARDs, promotes disease remission, prevents progressive destruction o Gold o Methotrexate (MTX) o Hydroxychloroquine New second-line: biological DMARDs ( BioDMARDs ) or biological response modifiers (BRMs) o Anti-IL-1 o Ant-TNF DMARDs Unrelated chemical structures and mechanisms Common types o Sulfasalazine o Gold compounds o Penicillamine o Hydroxychloroquine o Methotrexate (MTX) o Leflunomide DMARD therapy can be started as soon as diagnosis is achieved Takes months to show effects o NSAIDs given as carer in the meantime If therapy successful, conmittant NSAIDs or glucocorticosteroids can be reduced Effects o Reduce number of swollen joints o Reduction in pain and disability scores o Articular index on radiology o Serum concentration of acute phase proteins and RhF (IgM antibody against host IgG) Combination of sulphonamide (sulphapyridine) with a salicylate Its split into its components by colonic bacteria Usually used to treat IBM including UC and Crohn’s but also effective in RA The 5-aminosalicylic acid (5-ASA) part may act by scavenging free radicals produced by neutrophils ? ?Oxidative Stress and inflammation signalling In the form of organic complexes o Sodium aurothiomalate o Auronofin Max effect 3-4 months delay Pain, joint swelling subside, bone damage diminishes Mechanism not clear but auronofin inhibits induction of IL-1 and TNF-? Penicillamine Also known as Dimethylcysteine Hydrolysis of penicillin 75% of patients with RA respond to penicillamine Effects seen within weeks, reach plateau after several months Penicillamine decreases immune-response, IL-1 generation, prevents maturation of collagen Mostly used to treat malaria but also used for RA One mechanism involves blocking toll-like receptors (TLR) on dendritic cells Hydroxychloroquine ? ?TLR signalling ? ?dendritic cell activation ? ?inflammation process Second mechanism: hydroxychloroquine ? ?pH of intracellular vacuoles ? interferes with antigen processing in macrophages and other APCs Have an anti-inflammatory and immunosuppressant effects via several mechanisms o Inhibition of PG and leukotrienes synthesis o ?In macrophage phagocytosis, IL-1 secretion and number of circulating monocytes Inhibition of release of collagenase and lysozymal enzymes Supresses activity of immune cells to reduce inflammation Suppresses immune cells by inhibiting dihydroorotate dehydrogenase, an enzyme needed for DNA and RNA production Recent or concurrent treatment with hepatotoxic or haemotoxic DMARDs e.g. The active metabolite of leflunomide, A771726, has a long half life (1-4wks) Serious adverse effects may occur even if treatment with leflunomide has been stopped. If toxicity occurs, A771726 needs to be cleared from body using colestryramine or charcoal Originally used for chemotherapy Effect and infrequent side effects Used for Ra, juvenile arthritis, SLE, psoriatic arthritis, polymyositis ? MTX in cancer: MTX inhibits dihydrofolate reductase (DHFR, an enzyme involved in tetrahydrofolate synthesis) DHFR catalyses conversion of dihydrofolate to active tetrahydrofolate o THF needed for synthesis of nucleoside thymidine required for DNA synthesis Folate is needed for purine synthesis so all purine synthesis is inhibited by MTX Therefore, MTX inhibits DNA and RNA synthesis ? MTX in RA: Much smaller dose than in cancer (1/1000 th ) 4 possible mechanisms o MTX inhibits proliferation of cells responsible for synovial inflammation in RA (T-cells) MTX inhibits synthesis of toxic compounds (spermine and spermidine) that accumulates in chronically inflamed tissue MTX reduces intracellular glutathione levels by an oxidant associated mechanism leading to limited macrophage recruitment and function Adenosine, released in high concentration from cells and tissue after treatment with MTX mediates the antiinflammatory effects of MTX Subcutaneous methotrexate (SCMTX) weekly self-injection now available Current BioDMARDs inhibit cytokines IL-1, TNF or IL-6 IL-1 and TNF are produced in large amounts in RA and other forms of inflammation The first BioDMARDs attach to TNF or IL-1 and inhibit or inactivate them More recently, IL-6 and its cell surface receptors have become new targets In RA, the natural IL-1 receptor antagonist in too low concentration in synovium to counteract elevated IL-1 Anakinra competitively inhibits IL-1 binding to IL-1 receptor ? blocks activity of Now removed from PBS Etanercept (soluble TNF-receptor fused to Fc domain of IgG) Infliximab and adalimumab: chimeric mouse/human monoclonal antibodies against TNF All bind and neutralise TNF Etanercept o Human gene for soluble TNF-receptor 2 fused to the gene for the Fc component of IgG1 MW of 150kDa Binds to TNF and decreases its plasma concentration ? less available for binding to TNF-receptors on cells Can be used with other arthritis medications including Other DMARDs including MTX Steroids e.g. prednisolone NSAIDs Pain killers e.g. paracetamol Monoclonal antibody against TNF? Used in autoimmune disease including RA Combination treatment o Usually combined with other DMARDs like MTX o Steroids: prednisolone or cortisone o NSAIDs Pain killer e.g. paracetamol Cannot be combined with other BioDMARDs Almost same regime as etanercept Tocilizumab is a recombinant humanised monoclonal antibody that inhibits signalling mediated by soluble and membrane bound IL-6 receptors IL-6 is a cytokine produced by many types of cells involved in paracrine function as well as regulation of systemic processes such as: Induction of Ig secretion o T-cell activation o Induction of hepatic acute phase proteins o Stimulation of haematopoiesis IL-6 has been implicated in the pathogenesis of inflammatory diseases like RA Tocilizumab improves tender and swollen joint counts, pain assessment, CRP, disability index scores CD80/86 – CD28 costimulatory pathway and MHC-TCR complex leads to T-cell activation by APC Orencia binds to CD80-86, blocking T-cell activation RA was through to be T-cell mediated o Professional APC encounters unknown antigen o APC presents antigen to CD4 T-helper cell o In a genetically predisposed individual, this starts an immune chain reaction Immune system is confused and targets healthy tissue which expresses proteins similar to encountered antigen B-cell also plays role as APC and anti-body producing cell B-cell depletion therapy o B-cells can’t act as APC to activate T-cells o B-cells can’t produce RhF o B-cells can’t release cytokines Rituximab binds to cell surface markers of CD20 Rituximab induces B-cell destruction through 3 mechanisms o Antibody-dependent cell mediated cytotoxicity (ADCC) NK cells, T cells and macrophages are involved in recognising and killing antibody-labelled target cells o Complement-dependent cytotoxicity (CDC) Binding of antibody recruits complement which punches holes in cell membrane, flooding cell ? lysis Apoptosis: binding of the antibody signals cell to self-destruct Upper Limb Conditions Often due to compressive force or traction injury following anterior dislocation of the shoulder Involves a loss of movement or lack of sensation in the shoulder area of the body ? affecting deltoid and skin on shoulder Presentation o Mild, dull or achy pain to the deep or lateral shoulder with some radiation to the proximal arm Numbness and tingling of the lateral arm Instability and weakness with flexion, abduction and external rotation Neuropathy of the musculocutaneous branch innervating the anterior compartment of the muscles Presentation Weakness of flexion of the elbow, poor power supination or numbness of lateral forearm, loss of power in biceps and brachialis Motor dysfunction of anterior compartment muscles and sensory dysfunction of lateral cutaneous branch of the forearm Entrapment of the ulnar nerve near the elbow region, in the cubital tunnel or the epicondylar groove, or the wrist Presentation o Numbness and tingling o Motor function dysfunction of the hand, except thenar and two lateral lumbricals Sensory dysfunction of the anterior and posterior surfaces of the medial one and half fingers and associated palm areas Entrapment of median nerve in arm, forearm or wrist Carpal tunnel Presentation o Loss of flexor muscle function (abduction of forearm) and loss of ability to oppose the thumb Ape hand deformity Wrist drop: patients cannot extend wrist Reconstruction o Nerve conduits ? tubes to bridge small nerves o Nerve allograft ? processed human cadaver nerve to bridge small to intermediate large nerve gaps Nerve autograft ? nerve from patient used to reconstruct the critical nerve Tendon transfers o Tendon is cut at its normal insertion, rerouted and connected to another bone Multiple tendon transfer procedure