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LSU Clinical Pharmacology Drug Therapy of Rheumatoid Arthritis (RA) Reginald D Sanders, MD Drug therapy of RA - overview •what is rheumatoid arthritis (RA)? •what happens to patients with RA? •what drugs are available? •how are those drugs used? •where are we going with therapy? Drug therapy of RA What Is Rheumatoid Arthritis? Drug therapy of RA Case Presentation Case presentation •25 years old dental hygienist •6 months history of pain & swelling in the MCP & PIP joints of both hands •recent onset swelling in knees, wrists, elbows & ankles •very stiff for 2 hours in the morning •very stiff after sitting Case presentation •pain present daily but varies day to day •hurts when weather changes abruptly •with worsening pain, is missing work •exam shows multiple swollen joints •incomplete fist formation bilaterally •small olecranon nodules Case presentation •laboratory studies sedimentation rate = 66 mm/hr rheumatoid factor + (1:2560) antibody to CCP + (>200 units) •hand X-rays show small, discrete bony erosions Case presentation What does she have? What do we do? RA - clinical picture synovitis of MCP & PIP joints RA - clinical picture •persistent arthritis •hands & feet usually involved •morning stiffness •rheumatoid factor & antibody to CCP •sedimentation rate •extra-articular disease RA - joint involvement symmetrical joint involvement RA - essential features normal abnormal synovial inflammation RA - extra-articular disease rheumatoid nodule RA - extra-articular disease rheumatoid vasculitis RA - extra-articular disease rheumatoid (epi)scleritis RA - severe arthritis disabling arthritis RA - severe arthritis bone & joint damage (erosions) RA - severe arthritis “arthritis mutilans” RA - outcome with inadequate treatment, a significant number of patients with RA will experience significant disability due to joint destruction Drug therapy of RA What Drugs Are Available? Drugs used to treat RA NSAID’s & Other Drugs non-selective NSAIDs COX-2 selective inhibitors steroids analgesics Disease-Modifying Drugs (DMARDs) antimalarials sulfasalazine methotrexate biologic modifiers Traditional DMARDs •hydroxychloroquine (anti-malarial) •sulfasalazine •methotrexate •leflunomide Biologic response modifiers •etanercept (Enbrel®) •infliximab (Remicade®) •adalimumab (Humira®) •anakinra (Kineret®) •abatacept (Orencia®) •rituximab (Rituxan®) DMARDs - characteristics •no direct analgesic effect •no direct anti-inflammatory effect •delayed onset of benefits •narrow range of effectiveness •unique adverse effect profiles •able to prevent progression of RA Antimalarial agents •main drug - hydroxychloroquine •excellent safety profile •minor side effects •best-known side effect - retinopathy •mechanism of action unknown Antimalarial agents •slow, gradual improvement (8-16 weeks) •effective in mild-to-moderate RA •effective in other conditions •often used in combination therapy Antimalarial agents - toxicity •rash •marrow suppression •headache, diarrhea •retinopathy •transient muscle weakness Sulfasalazine •useful in mild-to-moderate RA •side effects frequent, but usually mild •alternative to hydroxychloroquine •usually takes 8-16 weeks to begin working •mechanism of action unknown Sulfasalazine - toxicity •rash •abdominal pain •marrow suppression •allergic reaction Methotrexate •most widely used remittive agent for RA •advantages •disadvantages •favored drug for severe RA •mechanism of action in RA unknown (inhibits folic acid metabolism) Methotrexate - toxicity •hepatic toxicity •pneumonitis •bone marrow suppression •nausea, stomatitis •“the yucks” Methotrexate - toxicity •accelerated rheumatoid nodulosis RA - extra-articular disease rheumatoid nodule Methotrexate - toxicity •accelerated rheumatoid nodulosis •susceptibility to infection •induction of malignant disease Leflunomide ® (Arava ) •immunomodulatory drug •inhibits pyrimidine synthesis •retards progression of RA erosions •loading dose first three days (100 mg) •once daily therapy thereafter (20 mg) Leflunomide ® (Arava ) •common side effects diarrhea, nausea alopecia rash, toxic epidermal necrolysis hepatic toxicity •contraindicated in pregnancy Drug therapy of RA Biologic Response Modifiers Reginald D Sanders, MD Biologic response modifiers •targeted therapy for rheumatoid arthritis •result of better understanding of disease processes •parenteral administration (IV or SQ) •akin to chemotherapy Cytokines •mediate immune functions •produced by activated immune cells •actions enhance immune response or inhibit immune response •anticytokine therapy in RA? Tumor necrosis factor alpha •produced by macrophages (cytokine) •stimulates synovial cells to produce collagenases •found in increased amounts in RA synovium •must attach to cell receptor to work Inhibitors of TNF alpha etanercept (Enbrel®) infliximab (Remicade®) adalimumab (Humira®) inhibits TNF alpha activity Etanercept ® (Enbrel ) •biologic modifier •recombinant human tumor necrosis factor receptor fusion protein •binds & inactivates soluble TNF •subcutaneously, once or twice a week •retards erosive disease Etanercept (Enbrel®) soluble TNF receptor fusion protein -SS-SS-SS S- S S S S S S S extracellular human TNF-receptor p75 monomer human IgG1 Fc domain Soluble TNF receptor binding synovial cell macrophage Etanercept (Enbrel®) •low incidence of side effects •may truly help fatigue •marked improvement in RA symptoms •used in combination with methotrexate Etanercept - side effects •local injection site reactions •headache •increased risk of infections •increased risk of autoimmune disease? •increased risk of malignancy? Infliximab (Remicade®) chimeric anti-TNF monoclonal antibody human IgG1 mouse binding sites for TNF Infliximab binds TNF alpha infliximab TNF alpha Infliximab ® (Remicade ) •chimeric monoclonal antibody •binds to human TNF alpha •retards erosive disease •best when used with methotrexate •intravenous dosing (q 6-8 weeks) Infliximab - side effects •activation of latent tuberculosis •activation of latent histoplasmosis •increased risk of other infections •increased risk of demyelinating disease? •increased risk of malignancy? Adalimumab ® (Humira ) •fully human recombinant anti-TNF alpha monoclonal antibody •subcutaneous every 2 weeks •side effects similar to other TNF inhibitors Abatacept ® (Orencia ) •selective T-cell co-stimulation modulator •soluble fusion protein (CTLA-4 antigen + Fc of human IgG1) Abatacept ® (Orencia ) Fusion Protein (CTLA4 + Fc Fragment) Abatacept ® (Orencia ) •selective T-cell co-stimulation modulator •soluble fusion protein (CTLA-4 antigen + Fc of human IgG1) •binds to CD80 & CD86 •blocks interaction with CD28 •attenuates T-cell activation Co-stimulatory modulation Antigen Presentation Generates Signal #1 Co-stimulatory modulation CD28 Costimulation Provides Signal #2 Co-stimulatory modulation Without Abatacept With Abatacept Abatacept - indications •reduce signs & symptoms of RA •slow progression of structural damage •improve physical function •used if inadequate response to methotrexate and/or TNF inhibitors •not used with TNF inhibitors Abatacept – adverse events •infections •malignancy? •infusion reactions (headaches, dizziness, hypertension) B-cells – role in RA B-cells – role in RA Rituximab ® (Rituxan ) •monoclonal antibody •B-cell lymphoma therapy •binds to & depletes C-20+ cells Rituximab – CD20 targeting Biologic modifiers •etanercept •adalimumab •infliximab •abatacept •rituximab anti-TNF anti-TNF anti-TNF T-cell directed B-cell directed Biologic modifier naming •etanercept •abatacept •adalimumab •infliximab •rituximab cept cept mab mab mab RA – changing approaches •earlier use of remittive drugs in patients at risk for erosive disease •majority of joint damage within 5 years •typical patient has severe functional impairment within 2 years •at 10 years 40% of patients disabled Erosive RA - risk factors •female sex •synovitis resistant to therapy •positive rheumatoid factor •high sedimentation rate •polyarthritis •elderly onset of disease RA - new approaches •earlier use of remittive drugs in patients at risk for erosive disease •combination of remittive drugs RA - new approaches •earlier use of remittive drugs in patients at risk for erosive disease •combination of remittive drugs •targeted therapy (biologic response modifiers) Therapeutic wheel of fortune? RA - choosing a remittive agent Mild RA hydroxychloroquine sulfasalazine Moderate RA hydroxychloroquine sulfasalazine methotrexate Severe RA methotrexate azathioprine leflunomide biologic modifiers combinations Toxicity - NSAIDs vs DMARDs •lowest toxicity with salsalate •DMARDs comparable to most toxic NSAIDs •hydroxychloroquine very safe DMARD Drug therapy of RA Case Presentation Therapy - current choices •NSAIDs •“disease-modifying” anti-rheumatic drugs •corticosteroids •“biologic agents” •no “cure”, only “control” •limitations Case presentation - therapy NSAID low dose prednisone methotrexate biologic weeks 0-3 weeks 4-16 weeks 17+ LSU Clinical Pharmacology Drug Therapy of Rheumatoid Arthritis Reginald D Sanders, MD
