Clinical Therapeutics and Manufacturing (5LMS2015) - Rheumatoid Arthritis Lecture 2 PDF

Clinical Therapeutics and Manufacturing (5LMS2015) Rheumatoid arthritis Lecture 2: treatment for rheumatoid arthritis Dr C. Keating [email protected] Treatment General outlines ✓Patient education ✓Health care professional management...

Clinical Therapeutics and Manufacturing (5LMS2015) Rheumatoid arthritis Lecture 2: treatment for rheumatoid arthritis Dr C. Keating [email protected] Treatment General outlines ✓Patient education ✓Health care professional management ✓Medication ✓Surgery Most of the disability in RA is due to the initial impact of the disease: THEREFORE THE GOAL IS TO CONTROL THE DISEASE EARLY ON Drugs for RA 1) Anti-inflammatory drugs Compounds that have little effect upon disease progression: ✓NSAIDs ✓COX-2 inhibitors ✓Glucocorticoids such as prednisolone 2) DMARDS (Disease Modifying Anti-Rheumatic Drugs) Compounds that may be useful in limiting the progression of the disease: ✓Conventional DMARDs (cDMARDs) ✓Biologics  Anti inflammatory drugs: Glucocorticoids (eg, prednisolone). Useful ‘bridging’ drug Oral, intramuscular or intra articular admin Anti inflammatory and immune suppression actions: Inhibitors of cytokine gene expression ✓ potent transcriptional inhibitors of variety of cytokines, (IL-1, IL-2, IL-6, and TNFα) Inhibitors of inflammatory cell action ✓ Decrease activity of T cells ✓ Decrease proliferation of T cells Side effects of glucocorticoids: Cushing Syndrome Adapted from Baxter & Rousseau, 1979  Steroid formulations Lodotra (prednisone) Modified release formulation Activated approx 6 h post ingestion of tablet ✓Take with water, after food ✓Do not chew Prednisone released to coincide with circadian rhythms of endogenous cortisol and disease symptoms which peak in the early morning hours Studies showed significant improvement in early- morning joint stiffness symptoms in patients on Lodotra. Drugs for RA: the DMARDS ✓Conventional DMARDS (Disease Modifying Anti- Rheumatic Drugs) ✓Biologic DMARDs These compounds may be useful in limiting the progression of the disease: 90% of joints involved in RA occur in 1st year: treat aggressively & EARLY DMARDS Shown to ✓Reduce swelling ✓Reduce pain ✓Improve function cDMARDS Methotrexate* Azathioprine Cyclosporin Immunosuppressant Leflunomide* Sulfasalazine* Anti inflammatory Sodium aurothiomalate Gold complexes Penicillamine Penicillin metabolite Hydroxychloroquine sulfate Antimalarials  Immunosuppressant drugs Important drugs They induce and maintain remission But they impair immune responses (this makes them quite hazardous in that patients become susceptible to infection) Drugs used are methotrexate and leflunomide. Azathioprine and ciclosporin are NOT used as much anymore due to better drugs being available  Methotrexate Folic acid antagonist and inhibitor of dihydrofolate reductase. Inhibits DNA synthesis BUT: Also interferes with proinflammatory actions of IL-1 Also promotes release of adenosine (anti- inflammatory) Side effects: myelosuppression, mucositis; GI disorders hepatotoxicity; pneumonitis, teratogenic Co-administration of folic acid supplements reduces myelosupression; mucositis  Leflunomide Prodrug converted to teriflunomide in the body Leflunomide is a pyrimidine synthesis inhibitor through blocking dihydroorotate dehydrogenase. Leflunomide targets rapidly dividing cells (T-cells) Used for moderate to severe rheumatoid arthritis. Side effects: GI disturbances, peripheral neuropathy risk of hepatic failure Long half life  Anti-inflammatory drugs : Sulfasalazine Pro drug broken down by gut bacterial azoreductase to 5-aminosalicylate (5-ASA) & sulfapyridine 5-ASA Acts in the lumen Absorbed into systemic circulation ANTI -INFLAMMATORY EFFECTS Adverse side effects  Sulfasalazine Therapeutic use through inhibition of PGs and LTs. Also inhibits pro inflammatory cytokines IL-1 and TNFα Side effects GI disturbances, malaise and headache. Severe ADRs include reduced wbc counts (caused by sulfapyridine).  Hydroxychloroquine sulfate Weak cDMARD. Slow onset of action Act by preventing antigen processing by immune cells, thereby preventing immune response developing Effective against autoimmune responses Used in mild RA and with methotrexate and sulfasalazine in triple therapy Serious side effects if overdosed. CV side effects and psychiatric effects also observed. Care if used  Biological DMARDs Many options for RA (see additional reading in Canvas) Recommended when conventional therapy options are not working Target many pathways in RA but broadly ✓ Anti TNF alpha ✓ Other cytokines involved in RA pathophysiology (IL-6) ✓ Other targets!! International non-proprietary names (INNs) for antibodies Common INN substem Example antibody origin Chimeric -xi- Infliximab Humanised -zu- Tocilizumab Human -u- Sarilumab Immunogenicity Callaghan, NHS Lothian Scotland Biological therapy for rheumatoid arthritis See hand-out PDF to lecture a, used in conjunction with methotrexate Drug Type Target Indication Etanercept Fusion protein (soluble TNF (decoy receptor) RA (mod- severe) TNF receptor/lg) Infliximab Chimeric Ab TNF (neutralises) RA (mod- severe)a Anakinra Recombinant protein IL-1 (receptor RA (mod-severe)a antagonist) Abatacept Fusion Protein B7(antigen presenting RA (mod-severe)a cells) Tocilizumab Humanised monoclonal IL-6 receptor RA (mod – antibody severe)a Sarilumab Human monoclonal IL-6 receptor RA (mod- severe)a antibody Rituximab Chimeric monoclonal CD20 receptor on B Treatment of RA in antibody cells patients non responsive to anti TNF therapy Treatment flowchart: NICE Mono therapy with cDMARD (MTX, Leflu, Sulfasalazine. Hydroxychloroquine for mild cases) MTX with Biological drugs (TNFalpha inhibitors) Other biological drugs +\- MTX (i.e. rituximab) Other biological drugs +\- MTX (i.e. sarilumab, tocilizumab) Other compounds? Synthetic DMARDs (tofacitinib, baricitinib,upadacitinib) Janus kinase (JAK) inhibitors Used under expert supervision across a range of chronic inflammatory diseases Risks include: cardiovascular events, venous thromboembolism, malignancies, serious infections, increased mortality. New guidelines on their use NICE. Rheumatoid arthritis versus osteoarthritis  Summary RA is an aggressive autoimmune disease of the synovial joints. Associated with gradual onset over days to weeks with early moderate symptoms. Chronic inflammation eventually leads to joint remodeling and erosion RA is a Th1 immune response involving T-cells and macrophages Important cytokines involved in RA include TNFα, IL-1 and IL-6. RA is incurable and treatment is lifelong in order to limit progression of the disease Typical drug therapy involves using DMARD drugs such as methotrexate and newer biologics such as infliximab. Self assessment Questions A 50yr old woman presents to her GP with pain in her joints. She complains that for the past 2 months she has had a lot of difficulty getting dressed in the morning because her hands are always stiff and painful, but this improves as the day goes on. Which investigation is most specific for the most likely diagnosis? A. X-ray B. Anti-CCP antibodies C. Rheumatoid factor D. MRI E. c-ANCA antibodies Q1) List three cytokines that are implicated in the pathogenesis of rheumatoid arthritis? Q2) What is a key difference between anti-inflammatory drugs and immunosuppressant drugs? Q3) List three biological drugs used to treat rheumatoid arthritis?