Let s talk about Arthritis Osteoarthritis Rheumatoid Arthritis Kam Shojania, MD, FRCPC Clinical Professor and Head, St. Paul s, UBC and VGH Divisions of Rheumatology Slides with thanks to: Cheryl Koehn and The Arthritis Society BC and Yukon Division Progressive Volunteer-led Not-for-profit Providing hope through Education, Support and Solutions Education programs Research support Fundraising programs hope through education, support & solutions The Arthritis Research Centre of Canada Leading edge arthritis research right here in BC Osteoarthritis Rheumatoid Arthritis Psoriatic Arthritis Systemic Autoimmune Diseases www.arthritisresearch.ca Today s Presentation Agenda Different types of arthritis New therapies for rheumatoid arthritis (RA) By extension, therapies for ankylosing spondylitis, SLE, Discussion
Did you know 1 in 6 Canadians have arthritis 60% are under 65 years of age Every 10 years, the number grows by 1 million Arthritis costs over $9 billion annually Arthritis is the most common cause of long-term disability What is Rheumatism? Any painful disorder affecting joints, muscles, or connective tissue More than 120 different forms Can be divided into joint or non joint problem Mild to chronic debilitating pain Affects small children to the elderly What is Arthritis? Arthritis has a high prevalence in Canada arth = joint itis - inflammation 2 main categories: 1. Inflammatory Arthritis e.g. rheumatoid, psoriatic etc. 2. Degenerative Arthritis osteoarthritis (OA) a. primary no known cause b. secondary due to trauma or underlying inflammatory diseases Arthritis is not confined to older adults Prevalence varies in Canada
Ostearthritis: The most common arthritis Research into Etiology (cause) Early diagnosis Treatment Joint replacement ARC is at the forefront of OA research Many different types of arthritis and autoimmune diseases Rheumatoid Arthritis 2% Juvenile rheumatoid arthritis -rare Osteoarthritis - most common 50% at age 50 Systemic lupus erythematosus 0.1% Ankylosing spondylitis (0.1%) Gout (2-4%) Scleroderma (rare) Vasculitis (rare) Sarcoidosis Behcets disease Rheumatoid Arthritis (RA) Most common inflammatory arthritis Affects 1 in 100 people An auto-immune disease Causes lining around joints to be inflamed - continuous inflammation leads to joint deformity RA can affect joints, eyes, internal organs, mouth & skin Rheumatoid Arthritis (RA) Who gets it? Twice as many women get RA as men Most often developed between 25 50yrs but can effect people of all ages Why?? Infection? Genes ARC is looking into population studies of RA as well as clinical trials into RA treatment Normal vs. RA Joint Joint Affected in RA vs OA
Early Mortality Arthritis Books Suggested Web Sites www.arthritis.ca/bc www.arthritisresearch.ca www.arthritis.org www.quackwatch.com www.arc.org.uk www.fda.gov www.nlm.nih.gov www.mayoclinic.com www.nccam.nih.gov The Arthritis Society B.C. Research happening in BC! USA Arthritis Foundation Independent try it! United Kingdom USA Food & Drug Admin USA huge medical library Mayo Clinic National Centre for complementary & alternative medicine Medications for Rheumatoid Arthritis Medications for Rheumatoid Arthritis Can be loosely classified into: 1) Medications that treat symptoms of RA The Faster the better!! Structural joint damages begins within the first two years of the disease 2) Medications that treat the underlying disease process Treatment of RA with drugs that both modify the course of the disease and reduce inflammation has greatest impact within 3 6 mths of diagnosis Importance of Early Aggressive Treatment of RA Disease onset Early 70% of patients have X-ray evidence of damage within the first 3 years Established: increasing disability Critical window of opportunity End Stage RA Complications RA doesn t just affect the joints Can cause rheumatoid nodules Heart and lung Eye disease Can affect the nervous system Skin including leg ulcers Blood including low white blood cell count or anemia Osteoporosis & fractures Lymphomas Stomach ulcers and gut bleeds from anti-inflammatories (NSAIDs)
New information Rheumatoid arthritis patients, like those with diabetes or lupus, need to control their cardiac risk factors smoking, lipids, blood sugar, blood pressure. General Classification of Antirheumatic Drugs Antirheumatic drugs can be broadly classified into 3 major categories We hopethat good control of RA will reduce the risk of heart disease. Disease Modifying Antirheumatic Drugs (DMARDs) Slow to work Need to see a rheumatologist to get them More than 1 drug may be required Side effects of the drugs May lose benefit Traditional DMARD Selection Agent Time to Benefit Potential for Toxicity Toxicities to Monitor Methotrexate 3-8 wk Moderate Myelosuppression, hepatic fibrosis and cirrhosis, pulmonary infiltrates Anti-malarials 1 6 mo Low Retinal damage (v. rare with HCQ) Leflunomide 2-10 wk Moderate / High Diarrhea, alopecia, rash, headache, risk of immunosuppression, infection, weight loss, BP Sulfasalazine 1 3 mo Moderate Myelosuppression Traditional DMARD Selection (con t) Agent Time to Benefit Potential for Toxicity Toxicities to Monitor Cyclosporine 2-4 mo High Renal insufficiency, anemia, hypertension Gold, parenteral 3 4 mo Moderate Myelosuppression, proteinuria Azathioprine 2 3 mo Moderate Myelosuppression, hepatotoxicity, lymphoproliferative disorders Minocycline 2 3 mo Moderate Hyperpigmentation, dizziness, vaginal yeast infections Why is methotrexate so important in RA? Best benefit/side effect ratio of all DMARDs prebiologics Best drug survival of all DMARDs Massive international data re benefit and safety Confirmed in recent trials comparing MTX to biologics Easy to administer and monitor Inexpensive
RA Treatment: Historical Overview Empirical Treatment Aspirin Gold Salts SAS Glucocorticoids Antimalarials NSAIDs Evidencebased Treatment Mechanism-based Treatment MTX Biologics TNF Inhibitors 1900 1925 1939 1950s 1956 1975 2000 2006 SAS = Sulfasalazine MTX = Methotrexate TNF = Tumour necrosis factor NSAID = Nonsteroidal anti-inflammatory drug Treatment Focus 1980s Mortality Morbidity Disability Emerging Biologics T-cell costimulation Inhibition B-cell Depletion 1990s Radiographic progression Quality of life What is a biologic? Designer drugs based on molecular science Proteins which often look like antibodies if they are an antibody their name ends in - mab (short for monoclonal antibody) The biologic drug blocks a specific molecule which is critical in the inflammation pathway Modified from Smolen JS, Steiner G. Nat Rev Drug Discov. 2003;2:473-488. Biological Therapy Highly specific in their action Very expensive to produce Require injection don t work by mouth For RA, currently available biologics target the cytokines TNF (Tumor Necrosis Factor) or IL-1 (interleukin-1) and recently, other targets have been approved. Generic name Examples of biologics Enbrel Humira Remicade Orencia Rituxan Actemra Etanercept Adalimu mab Blocks TNF TNF TNF T-cell signal Route SC 2/wk SC q2 wk IV q5-9wks IV q monthly Body weight Cost ($/yr) + DMARD 0/MTX/an y Approved for BC Pharm. No effect No effect Dose Dose adjust Infliximab Abatacept Rituximab Tocilizuma b B-cells 2IV q6-9mth No effect IL-6 IV monthly No effect + 17,000 + 17,000 12-96,000 + 17,000 depends + 15,000 JRA, RA, AS, PsA 0/MTX/a ny RA, AS MTX/lef/aza RA, AS, PsA, Crohn's RA PsA ** RA** RA**, Crohn's 0/MTX/an y RA MTX RA, Lymphom a 0/any RA RA** RA** RA** ** On Special Authority Proven Benefits: BIOLOGICS Inflamed joints: best single agents available Joint destruction reduced even if joint inflammation Disability rapid and sustained improvement Morning Stiffness rapid relief Fatigue relief often dramatic All biologics work better when combined with methotrexate! e.g. TEMPO trial Lancet Feb 28, 2004 (MTX vs. Enbrel vs. both combined) Remission rate at 1 year: MTX 13% Enbrel 16% Combined 35%
Etanercept: Mechanism of action Infliximab and Adalimumab: Mechanism of action Click here to run the animation Click here to run the animation Mechanisms in Rheumatology 2001 Mechanisms in Rheumatology 2001 TNF inhibitors in RA Rare but Serious Adverse Effects Infections Reactivation of TB (all, esp Remicade, Humira) Induction of autoimmunity e.g. lupus (Remicade) Exacerbations of multiple sclerosis (Enbrel) Exacerbation of CHF (all) Pancytopenia (low blood cell counts): (Enbrel) Orencia (abatacept) Approved August, 2006 by Health Canada Used alone or combination with methotrexate Targets 2 nd signal that stimulates T cells Injection every 4 weeks, 30 min, at home Similar costs to anti-tnf drugs Research being done at ARC Not yet covered by BC Pharmacare Abatacept Selectively Modulates Co-Stimulation via CD80/86:CD28 Pathway Rituxan (Rituximab) APC MHC CD80/86 Abatacept TCR CD28 T-cell Approved June 20, 2006 by Health Canada Use in combination with methotrexate Targets B-cells Injection or injection; two infusions 2 weeks apart. Additional course after 6 mths depending on signs & symptoms $1000 - $2000/mth Linsley PS, et al. J Exp Med 1991;174(3):561 569
Rituximab Selective B-Cell Depletion Newer Biologics? Rituximab is a genetically engineered anti-cd20 therapeutic monoclonal antibody that selectively depletes CD20+ B cells IL-6 inhibitor tociluzimab (Actemra) More anti-tnf agents Golimumab (Simponi) Certolizumab (Cimzia) Keystone EC. Rheumatology 2005;44(Suppl.2):ii8-ii12. RISKS OF BIOLOGICS What about Malignancy? Our experience thus far No increase in cancer No increase in lymphoma No increased risk of recurrent cancer in RA patients starting Enbrel or Remicade after treatment of a prior cancer.. What am I doing for early severe RA? Triple therapy (MTX, SS, HCQ) Short course of prednisone This protocol may be equivalent to a biologic. If not, I am much closer to getting a biologic approved in BC If you SMOKE, try to stop Why? Smokers develop rheumatoid arthritis or SLE twice as often as nonsmokers do Smokers respond less well to RA DMARDs Smoking contributes significantly to the increased incidence of heart disease, ulcers, lung disease, pneumonia and osteoporosis RA patients are at risk for all of the usual smoking-relating diseases Key Points for RA patients Current shift to early and aggressive treatment of rheumatoid arthritis Early use of combinations Increasing use of biologics
Exercise Regularly People with arthritis can exercise safely: Exercise is a natural remedy The correct balance of exercise can relieve stiffness, improve strength and energy level Exercise increases strength of muscles which, in turn, protect joints Consult with your doctor before beginning an exercise routine Questions? Arthritis Answers Line 1-800-321-1433 or visit www.arthritis.ca/bc