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?

What Is Rheumatoid Arthritis? 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?

synovitis of MCP & PIP joints 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

symmetrical joint involvement 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

bone & joint damage (erosions) 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

What Drugs Are Available? Drug therapy of RA What Drugs Are Available?

Drugs used to treat RA Disease-Modifying Drugs (DMARDs) biologic modifiers methotrexate Disease-Modifying Drugs (DMARDs) antimalarials sulfasalazine NSAID’s & Other Drugs steroids analgesics non-selective NSAIDs COX-2 selective inhibitors

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

Biologic Response Modifiers 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

TNF inhibition - approaches cell surface receptor antagonists soluble receptor antagonists antibodies to cytokines antibodies to cytokine receptors

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 -S-S- extracellular human TNF-receptor p75 monomer human IgG1 Fc domain soluble TNF receptor fusion protein

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 Clinical trials with infliximab provided the first direct evidence that TNF inhibitors might be useful therapeutic agents for patients with RA Human anti-chimeric antibody (HACA) responses to infliximab have been noted in many patients; this antibody response may be diminished by concomitant treatment with low dose methotrexate

Infliximab binds 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

TNF inhibition - approaches cell surface receptor antagonists soluble receptor antagonists antibodies to cytokines antibodies to cytokine receptors

T-cells – role in RA large number T cells in RA joints T cells from RA joints can transfer disease to immunodeficient mice depletion of pathogenic T cells prevent collagen-induced arthritis in mice

Activated T-cells – role in RA release chemical mediators that stimulate activity of other immune cells other immune cells release second set of mediators that induce inflammation & joint damage

Abatacept (Orencia®) selective T-cell co-stimulation modulator soluble fusion protein (CTLA-4 antigen + Fc of human IgG1)

Fusion Protein (CTLA4 + Fc Fragment) 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 anti-TNF adalimumab anti-TNF infliximab anti-TNF abatacept T-cell directed rituximab B-cell directed

Biologic modifier naming etanercept cept abatacept cept adalimumab mab infliximab mab rituximab 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? NSAID methotrexate leflunomide sulfasalazine antimalarial combination biologics gold

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