Rheumatoid Arthritis. Advances in Biologic Therapies: What the Family Practitioner Should Know. Ra: Traditional Treatment Paradigm

Transcription

1 Rheumatoid Arthritis Advances in Biologic Therapies: What the Family Practitioner Should Know Jonathan Graf, M.D. Assistant Professor of Medicine, UCSF Division of Rheumatology, SFGH April, 2008 No Conflicts of Interest Chronic, inflammatory, predominantly small joint arthritis Affects up to 1% of the US population Female:Male predominance of 3:1 Disability costs are high, both in terms of direct and indirect medical costs 35% of patients with 10 years disease duration are work-disabled Decline from 50% rate reported in 1987 Arthritis Rheum Mar 27;59(4): RA: Chronic Joint Destruction and Disability What We Try to Prevent Ra: Traditional Treatment Paradigm Pyramid of therapy Start conservatively Gradually ascend the pyramid in order of potency and toxicity of therapy Only the most severely affected patients receive immunosupressive, DMARDs DMARD therapy begun only after period of significant delay 1

2 Re-Thinking the RA Treatment Pyramid Early RA: The Window of Opportunity to Intervene Emphasizes earlier diagnosis and initiation of therapy with disease modifying anti-rheumatic drugs The Window of Opportunity Eventually Closes for Many. Chronic disease progression leads to permanent joint deformity, destruction, and disability Empirically, RA is a different disease the longer disease activity progresses without effective control More difficult to suppress activity and treat More extra-articular disease? ACR RA Practice Guidelines 2002 Most patients with Rheumatoid Arthritis should be evaluated expeditiously Treatment with DMARD instituted within 3 months of diagnosis Goals are to prevent or control joint damage, prevent loss of function, and decrease pain 2

3 DMARD Therapies Methotrexate Leflunomide (Arava) Sulfasalazine Azathioprine Mycophenolate Mofetil Corticosteroids Hydroxychloroquine Minocycline Combination DMARD Therapies: Some Step Up, Others Step Down Methotrexate +SSZ +Plaquenil +/- Prednisone Arava + SSZ + Plaquenil +/- Prednisone Methotrexate X Arava Generally not done More and more, combination therapies of DMARDs and Biologic medications being used earlier in the course of treatment Why Move Towards Combination Regimens with Biologics?? The Current Pyramid Paradigm Early initiation and titration of DMARD If incomplete response to DMARD alone, after reasonable titration, addition of biologic recommended 3

4 Biologic Therapies What is meant by the term Biologic Therapy? Double meaning: Organic compounds made by living cells As opposed to products from a chemistry lab Modify biologic responses Antibody-antigen interactions Cytokine-receptor interactions (both ends) Cell signaling proteins, inhibitors, or ligands Families of Biologic Therapies Anti-Tnf medications Etanercept (cytokine receptor fusion protein) Infliximab (anti-cytokine antibody) Adalimumab (anti-cytokine antibody) B-cell depleting agents (monoclonal antibody) Rituximab T-cell costimulation inhibitors (receptor-ligand ) Abatacept Il-1 Inhibitors (Il-1 cytokine receptor decoy) Anakinra Biologic Therapies: The Class Anti-TNF Family of Biologics Anti-Tnf medications Etanercept (cytokine receptor fusion protein) Infliximab (anti-cytokine antibody) Adalimumab (anti-cytokine antibody) B-cell depleting agents (monoclonal antibody) Rituximab T-cell costimulation inhibitors (receptor-ligand ) Abatacept Il-1 Inhibitors (Il-1 cytokine receptor decoy) Anakinra 4

5 TNF Where does it come from? TNF genes located on chromosome 6 (MHC) Primarily Macrophage and Monocyte derived Some also produced in T Cells and Synoviocytes (T Cells make more TNF-b) TNF Forms Two forms of TNF bind TNF receptors TNF-a (cachexin) and TNF-b (lymphotoxin) Both membrane bound and soluble forms of TNF-a Soluble TNF derived from cleavage of membrane bound TNF (TACE TNF converting enzyme) 5

6 TNF-α and TNF-β (LT) Forms and Receptor Binding TNF Where does TNF act?? Like TNF, the TNF receptors are both membrane bound and soluble Activating (membrane bound) P55 and p75 receptor Decoy receptor (cleaved from membrane) Mutations inhibiting cleavage implicated in period fever syndromes (TRAPS) TNF Effects: The Good and the Bad Good: TNFa and TNFb regulate biological functions necessary for normal inflammatory and immune responses. TMF-a absolutely essential for granulomatous host defenses against intracellular bacteria MTb, fungal infections, listeria Bad: TNF-a binds membrane-bound TNF receptors and mediates pro-inflammatory processes implicated in inflammatory arthritis. The arbiter: soluble TNF receptor mediates delicate balance between TNF activity and inhibition (natural antiinflammatory ) Man-Made Advances in TNF Biology The family of anti-tnf therapies Etanercept (Enbrel) Infliximab (Remicade) Adalimumab (Humira) Etanerceot Infliximab Adalimumab 6

7 Etanercept recombinant, dimeric fusion protein Consists of the soluble human p75 tumor necrosis factor (TNF) receptor coupled to the Fc fragment of human IgG1 lacking the CH1 domain. Binds soluble TNF-a and TNF-b and prevents activation of TNF-Rs Etanercept Infliximab Infliximab is a humanized monoclonal antibody TNF binding region derived from mouse anti- TNF monoclonal antibody Attached to constant region of human IgG1 kappa antibody. Chimeric molecule not 100% human Adalumimab The Anti-TNF Clan Adalimumab is a recombinant, fully human monoclonal IgG1 kappa antibody. All monoclonal anti-tnfs bind membrane bound and soluble TNF (May have added benefit leading to clearance or apoptosis of cells expressing surface TNF) All monoclonals bind only TNF-alpha (not TNF-b) May explain differential effects of anti-tnf medications in IBD Differences between agents: Enbrel Remicade Humira Ab N Y Y Tnf a/b Y N N Crohn s N Y Y Human Y N Y T ½ S L L 7

8 Pharmacokinetics Bioavailability Etanercept (subcutaneous) 60% adalimumab (subcutaneous) 64% Infliximab is administered intravenously. Half life Important for duration of biologic effect/sideeffects Etanercept 4.25 days Infliximab 8-12 days Adalimumab 14 days Clearance The exact mechanisms have not been definitively determined The reticuloendothelial system may play a role No formal studies have been done to determine the effects of hepatic or renal impairment on clearance. FDA Approved TNF Uses Etanercept: Rheumatoid Arthritis Psoriatic Arthritis Ankylosing Spondylitis Juvenile Idiopathic Arthritis Infliximab Rheumatoid Arthritis (subtleties to approval) Ankylosing Spondylitis Psoriatic Arthritis Crohn s Disease Severe Ulcerative Colitis Adalimumab Rheumatoid Arthritis Psoriatic Arthritis Ankylosing Spondylitis (July 31, 2006) Crohn s Disease (February 27,2007) Indication for JIA on the way.. Etanercept (Arthritis Rheum 2002;46: ), infliximab (N Engl J Med 2000;343: ), and adalimumab (Ann Rheum Dis 2002;61:311-8) have been shown to slow or inhibit the radiographic progression of joint destruction in rheumatoid arthritis. Off Label Uses Other spondyloarthropathies IBD Reactive Arthritis Undifferentiated Adult Still s Disease Vasculitis Wegeners no (at least with Etanercept) Behcet s maybe growing use (especially eye disease) Anti-TNF agents - Practical Stuff: Dosing Etanercept (formulation and dosing have been constantly changing) 50 mg SQ injection once weekly or as a 25 mg SQ injection twice weekly Originally formulated as powder Powder must be refrigerated and reconstituted in sterile solution before being administered Now available in pre-filled syringe or autoinjector 8

9 Infliximab Dosing Infusion is given in a doctor s office or infusion center and takes approximately 2-3 hours to complete. Administered as an intravenous infusion beginning with a loading dose of 3 mg/kg at time intervals 0,2,6 weeks. Dosing is usually maintained at 3 mg/kg every eight weeks Flexibility in dosing allows for the dose to be increased up to 10 mg/kg and/or the interval decreased to as little as every 4 weeks, depending on response to therapy. Adalimumab - Dosing Given as a single, 40 mg subcutaneous injection once every other week Medication comes preloaded in a syringe, does not need to be reconstituted, and should be refrigerated before use. Now has automated delivery system, too (Humira Pen) Some dosing flexibility allows the medication to be given as often as 40 mg every week as clinical conditions warrant What to do When Starting Therapy. Assess risk of reactivation of latent tuberculosis with a baseline PPD +/- CXR prior to initiation of therapy The risk of latent infection with histoplasmosis and coccidiomycosis should be considered in patients from endemic regions. No baseline or routine laboratory testing is officially recommended. Age appropriate cancer screening, while not officially recommended, may be of benefit prior to initiating therapy. Patients are recommended not to receive live vaccinations after initiating or continuing therapy. Contraindications History of latent tuberculosis unless/until they have completed an adequate courses of prophylactic therapy (Duration up for debate) Active acute or chronic infections (HCV may become exception) Active or suspected malignancies. Hypersensitivity to an anti-tnf agent or mouse product (infliximab) Anti-TNF agents in the setting of hepatic disease or renal failure has not been studied. Anti-TNFs are generally contraindicated in patients with moderate or severe congestive heart failure (some have black box warning) History of demyelinating disease 9

10 Anti-TNFs: Like all success stories, there are always complications Increased risk of infections! (OR of 2.0 for serious infection in large meta analysis published in JAMA 2006) Increased malignancy risk: Always thought of as a theoretical risk, now controversial evidence that RA patients may be at increased risk of lymphoma and/or solid tumors May worsen symptoms of congestive heart failure. Anti-TNFs, Less common associations Associated with the development of antinuclear antibodies, other autoantibodies and, rarely, a lupus-like syndrome Rarely, a demylenating syndrome has been developed in patients using anti-tnf agents. Cytopenias and aplastic anemia have been reported in sporadic cases of patients on anti-tnf agents Hepatitis reported in some patients Anti-Tnf Therapy: Allergic and Idiopathic Reactions Dermatologic reactions Localized: Mild-moderate injection site reactions erythema, pruritis, pain, and/or swelling reactions are commonly self-limiting early in the course of therapy. FDA has recent case reports of Steven s Johnson and TEN with all 3 Infusion reactions, especially with infliximab within 1-2 hours after receiving the therapy fever, chills, urticaria, and cardio-pulmonary symptoms antibody mediated serum-sickness type of syndrome also reported that s separate than from typical infusion reaction Specifics: Anti-TNF and TB Reviews of the FDA Adverse Events Reporting System (First of which published by Keane et al., NEJM 2001) Incidence of TB 4X background rate in US general and RA populations (24.4 cases/100,000 pts/year) 56% Extra Pulmonary TB 24% Disseminated disease Average onset 12 weeks after initiation (3-4 th dose) Wolfe published separate study with rate as high as 60/100,000 pts/year) 10

11 Best Practice & Research Clincial Rheumatology 2006 Counsel Risks of TB Screen with PPD +/- CXR (we do both) Treatment of latent disease for 6-9 months with INH. Duration of time before using anti-tnf not established (1 wk-6 mo.) Be alert to atypical presentations of TB Specifics: Hepatitis B TNF KO mice have impaired proilferative capacity of CTL response to HBV TNF-A may play role in clearing and/or containing HBV infection As of 2006, 11 reported cases of chronic HBV treated with infliximab (not just with RA) 1 pt with adult stills Fulminate hepatitis 2 cases with MTX Reactivation (increase in transaminases and/or HBV DNA) 3 cases without MTX Reactivation 4 cases with 3TC Stable without HBV reactivation 1 pt reverted from HBV DNA+ to negative Hepatitis B Recommendations: 2006 No official recommendations regarding screening or treatment All patients should be screened with HBV serologies I Avoid TNF-A agents in chronic HBV patients (HBV sag pos >6 months +/- abnormal LFTs +/- Detectable HBV DNA) If must use anti-tnfs, consider 3TC. This is actually formal recommendation of GI literature Specifics: Hepatitis C TNF appears to be implicated in chronic liver injury rather than having protective anti-viral effects Some clinical evidence to support benefit in HCV cirrhosis Interval monitoring of LFTs and HCV viral load recommended 11

12 Specifics: Endemic Fungal Infections No clear guidelines Incidence of fungal infections/listeria appears to be lower than for TB Counsel about risk Avoid high risk behavior where possible (cave exploring, cleaning bird cages, farming in the central valley, etc.) Consider drawing Cocci titers. If positive, some recommend empiric prophylaxis with fluconazole Follow carefully for first few months after initation of therapy and consider fungal infecton if ill. Specifics: Anti-TNFs and Malignancy Elevated risk of lymphoma in patients with RA with some likely relation to disease activity and duration Large meta-analysis suggested an OR 3.3 for all malignancies in patients using anti-tnf, especially high doses). Only studied anti-tnf antibodies (Bongartz et al., JAMA 2006) Longitudinal analysis of 20,000 patients from the National Databank of Rheumatic Diseases found no increased risk of lymphoma compared to general population or those with RA (Wolfe et al., A&R 2007) ACR Hotline Update: 5/06 No need to be overly alarmed, although safety of patients on immunosupressive therapy always of paramount concern Counsel patients about risks JAMA: number needed to harm 154 ACR published information sheet on website No study has established new or incr. risk of TNF-inhibitor solid tumors No guidance on safety of use in patients with prior malignancies Specifics: CHF Guidelines Furst et al. Best Practice & Research Clinical Rheumatology 2006 Patients without history of CHF do not need baseline Echo Patients with mild compensated CHF (NYHA class I&II) should receive ECHO prior to starting Rx. Normal EF, counsel about risks Abnormal EF, would avoid use Contraindicated in NYHA class III&IV Discontinue if new onset CHF develops unexplained by other events 12

13 The Sun is Rising for Patiens with RA: The Future is Bright Other considerations Patients receiving infliximab should have baseline screening for infection, including temperature and symptom assessment, prior to each infusion. Infliximab infusion steps up slowly to minimize infusion reactions Patients should be instructed to contact their physician and hold medication if any symptoms of acute infection develop. All anti-tnf agents are pregnancy category B. 13

14 Infliximab Infusion Reactions 1-2 hours after receiving therapy (as opposed to serum sickness) Fever, Chills, Urticaria, Cardio-pulmonary symptoms Treated first by stopping the infusion!!! Then, oxygen, benadryl, Solumedrol, Epi. If needed for anaphylaxis Anti-TNF agents, especially infliximab, can lead to the development of antibodies to the agent. Whether these antibodies influence efficacy or adverse reactions is uncertain 14