Rheumatoid Arthritis. Outline. Treatment Goal 4/10/2013. Clinical evaluation New treatment options Future research Discussion

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1 Rheumatoid Arthritis Robert L. Talbert, Pharm.D., FCCP, BCPS University of Texas at Austin College of Pharmacy University of Texas Health Science Center at San Antonio Outline Clinical evaluation New treatment options Future research Discussion Treatment Goal No known cure for RA Control disease activity Alleviate pain Maintain function of essential activity daily living and work Maximize quality of life Slow the rate of joint damage 1

2 RA Composite Endpoint (ACR20) Patient has a response to therapy if shows at least: 20% improvement in tender joints 20% improvement in swollen joints At least a 20% improvement in 3 of the 5 following; Patient pain assessment Patient global assessment Physician global assessment Patient self-addressed disability Acute phase reactant (ESR or C-Reactive Protein) Treatment Options Non-pharmacological therapy i.e., rest, occupational and physical therapy, assistive devices, surgery Pharmacotherapy NSAIDs: symptoms and pain relief Disease modifying anti-rheumatic drugs (DMARDs): slow disease progression, prevent irreversible joint damage Corticosteroids: symptoms and pain relief Selection of treatment Aggressiveness and timing of treatment based on prognosis Features of poor prognosis Early onset, high titer of RF, elevated ESR, swelling of > 20 joints, boney erosions and extraarticular manifestations of RA Rheumatoid nodules, Sjogren s syndrome, RA vasculitis, Felty s syndrome, RA lung disease Functional limitation-various scales Treatment algorithm 2

3 RA Disease Activity Saag KG, et al. Arth Rheum 2008;59: Early RA (< 6 months) Singh JA, et al. Arth Care Res 2012;64: Established RA 3

4 Disease-Modifying Antirheumatic Drugs (DMARDs) Goal: remission or control of disease progression prevent irreversible damage Use: persistent synovitis despite NSAIDs use Limitations May not prevent damage despite clinical control May not have lasting efficacy May not be tolerated due to toxicity DMARDs Factors for selecting drugs Efficacy, side effects, cost, convenience, monitoring program, time to onset Monitoring efficacy Clinical symptoms Radiographic changes Monitoring toxicity DMARDs Conventional agents Hydroxychloroquine Sulfasalazine Methotrexate Gold (oral and injection) Azathioprine D-penicillamine Chlorambucil Cyclophosphamide Cyclosporin Minocycline Newer agents Leflunomide (Arava ) Etanercept (Enbrel ) Infliximab (Remicade ) Anakinra or rhil-1ra (Kineret ) Adalimumab (D2E7, Humira -Abbott) Abatacept (CTLA4-Ig, Orencia ) Rituximab (Rituxan ) Tocilizumab (Actemra ) Certolizumab (Cimzia ) 4

5 Conventional DMARDs Common characteristics Slow onset of action (1-6 months) Efficacy varied in different patients Response to treatment may decrease over time Can only slow down the rate of joint damage Additive/synergistic when used in combination Many are contraindicated in pregnancy and lactation DMARD Combinations Randomized controlled clinical trials have shown that triple-dmard combination of MTX, HCQ, and SSZ has increased efficacy compared to MTX alone without increased toxicity Showed less radiographic progression, fewer withdrawals due to lack of efficacy Leflunomide (Avara ) Inhibit pyrimidine (uridine and cytidine nucleotide) de novo synthesis through inhibition of dihydroorotate dehydrogenase (DHODH) crucial for proliferation of lymphocytes Active metabolite: A Metabolized in liver, excreted by kidney Good GI absorption Dose: 100 mg x 2-3 days then mg/day 5

6 Leflunomide (Avara ) Adverse reactions Common: GI upset, weight loss, alopecia (dose related), skin rash (dose related) Uncommon but serious Hepatotoxicity (dose related) FDA prescribing information warning updated Oct 2003 Thrombocytopenia, hypersensitivity, sepsis Teratogenic Does NOT produce bone marrow toxicity (CBC monitoring not necessary) Monitoring parameter ALT/AST q 4 wks x 6 mo, then q 6-8 wks Leflunomide (Avara ) Place in therapy Efficacy comparable to methotrexate but with fewer side effects Combination with methotrexate is superior than methotrexate alone Cost: 100 mg PO once daily: $ /day 10 mg or 20 mg PO once daily: $ /mo. Etanercept (Enbrel ) Fusion monoclonal antibody = recombinant human p75 TNF-alpha receptor fused with Fc portion of human IgG1 Binds to TNF-alpha neutralize activity of TNF-alpha in the inflammatory process Extracellular Domain of Human p75 TNF Receptor Fc Region of human IgG1 6

7 Role of TNF-alpha in RA 7

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