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Diagnostic and Treatment Innovations in Rheumatology Name of Speaker Credentials Date Site Target Audience This CME activity is intended for practicing physicians, and “physician extenders” There is no fee for participation in this CME activity. This program is made possible through an educational grant from Abbott Immunology Accreditation This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of CMEsolutions and Miller Professional Consulting. CMEsolutions is accredited by the ACCME to provide continuing medical education for physicians. CMEsolutions designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Disclosure of Significant Relationships with Relevant Commercial Interests Neither CMEsolutions nor Miller Professional Consulting has any commercial interests relevant to the content of this activity. The content of this CME activity will not contain discussion of off-label uses. Please consult the product prescribing information for full disclosure of labeled uses. CME Credit Statements To receive continuing education credit, please complete the evaluation and credit request form and submit following the meeting. Credit Statements will be mailed within two weeks of activity completion. Faculty Faculty Name and Degree Affiliation City and State Dr. XXXX’s Disclosure Statement indicates that he …: Dr. XXXX also discloses that there will be no discussion of off-label uses of any products during this presentation. Speaker Disclosures Objectives After this educational activity, participants will be able to: • Describe the pathophysiology of rheumatoid arthritis • Describe the differential diagnosis and the spectrum of clinical presentations of rheumatoid arthritis, and an improved ability to utilize applicable diagnostic tools in their daily practice • Describe the most current and innovative treatment approaches for rheumatoid arthritis. • Demonstrate that they are able to apply their increased understanding of the diagnosis and management of inflammatory arthritis through the successful completion of case reports. Program Outline What is rheumatoid arthritis? The importance of early diagnosis The critical role of the primary care provider Key Learning Points • Rheumatoid arthritis: • Is often an aggressive disease • May have potentially devastating consequences • Early, aggressive management can lead to successful control and remission Common Types of Arthritis Inflammatory arthritis Degenerative diseases Infectious arthritis Types of Inflammatory Arthritis Rheumatoid arthritis Seronegative spondyloarthropathies Psoriatic arthritis Ankylosing spondylitis Reactive arthritis Enteropathic arthritis Crystalline induced arthropathies Gouty arthritis (uric acid) Pseudogout (calcium pyrophosphate) Connective Tissue Diseases Systemic lupus erythematosus Polymyositis/dermatomyositis Systemic sclerosis Sjogren syndrome Sarcoidosis Infectious/Post infectious Lyme Disease Hepatitis C Post viral (Parvovirus, Echo, Coxsackie) Post streptococcal What is Rheumatoid Arthritis? Rheumatoid Arthritis: Is a chronic progressive systemic autoimmune disease Affects primarily joints Leads to cartilage and bone destruction Systemic disease: internal organ involvement common American College of Rheumatology Diagnostic Criteria for RA Must have at least 4 of the following 7 criteria: 6. Morning stiffness in joint for at least 1 hour* Arthritis in 3 or more joint areas (PIP, MCP, wrist, elbow, ankle, MTP)* Arthritis of the hand (wrist, MCP, PIP)* Symmetric arthritis* Rheumatoid nodules Rheumatoid factor 7. Radiographic changes 1. 2. 3. 4. 5. *Must be present at least 6 weeks Characteristics of Rheumatoid Arthritis Affects young people Peak age of onset: 20-45 years Affects approximately 1% of the population Affects 3 million Americans 2-3 times more common in women Loss of physical function and quality of life Life expectancy reduced The Pathogenesis of RA Why should a normal healthy immune system suddenly begin to destroy healthy joints? Answer not known Genetic predisposition in many instances Popular theories: environmental stimulus, hypothesis most likely viral; unproved Pathogenesis of Rheumatoid Arthritis Current Treatment Targets Rheumatoid Factors, anti-CCP B cell Immune complexes Complement T cell IFN- & Neutrophil Antigenpresenting cells B cell or macrophage Pannus other cytokines Synoviocytes Macrophage Mast cell TNF Chondrocytes IL-1 Osteoclast Articular cartilage Production of collagenase and other neutral proteases Bone Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15 Morbidity & Mortality of Rheumatoid Arthritis Average life expectancy shortened by 5-15 years Myocardial infarction: twice as likely Risk of stroke: increased Risk of infection: increased Risk of lymphoma: 3 times greater than general population Brown SL, et al. Arthritis Rheum. 2002;46:3151–3158; Bjornadal L, et al. J Rheumatol. 2002;29:906–912; Wolfe F, et al. J Rheumatol. 2003;30:36–40; Doran MF, et al. Arthritis Rheum. 2002;46:2287–2293; Asten P, et al. J Rheumatol. 1999;26:1705–1714; Jones M, et al. Br J Rheumatol. 1996;35:738–745; Baecklund E, et al. BMJ. 1998;317:180–181; Isomaki HA, et al. J Chronic Dis. 1978;31:691–696; Solomon DH, et al. Circulation. 2003;107:1303–1307. Disability in Rheumatoid Arthritis Disease progression in first 2 years determines long term disability Average work day loss/year = 30 Average lifetime earnings loss = 50% 40%-85% of RA patients will be unable to work within 8-10 years of disease onset 1 Allaire, SH et al. The costs of RA. PharmacoEconomics. 1994;6:513-522. 2. Wolfe, F et al. The prevalence and meaning of fatigue in RA. J Rheum 1996;23:1407-1417. 3 Verhoeven AC et al. Combination therapy in RA. Br J Rheum 1998; 37:612-619. 4. Lard LR et al. Early vs delayed treatment in RA. Am J Med 2001; 111:446-451. 5. Goldbach-Mansky R et al. New concepts in the treatment of RA. Annu Rev Med 2003; 54: 197-216. 6. Kirwan JR. J Rheumatol. 2001;28:881-886. Functional Decline Begins Early in RA Moderate loss of function* 0 2 Severe loss of function* 5 Years from Symptom Onset * 50% rates of loss of function based on HAQ scores Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306. Very severe loss of function* 10 Clinical Manifestations of RA Musculoskeletal manifestations Systemic manifestations Fatigue Fever Depression Weight loss Extra-articular manifestations Early Clinical Manifestations of RA Symmetric soft tissue swelling of joints Prolonged morning stiffness common Hand, wrist, foot involvement common Fatigue Late Clinical Manifestations of RA Joint destruction and deformity “Ulnar Drift” of MCP’s Rheumatoid nodules Extra-articular manifestations Clinical Spectrum of RA Images courtesy of J. Cush, 2002. Clinical Spectrum of RA Images courtesy of J. Cush, 2002. Swan Neck Deformities Metatarsal Head Protrusion Do the squeeze test Early Referral Algorithm for Newly Diagnosed RA Rapid evaluation advised with clinical suspicion of RA, which may be supported by the presence of any of the following: • 3 swollen joints • MTP/MCP involvement – Positive squeeze test • Morning stiffness 30 minutes Emery P et al. Ann Rheum. Dis. 2002:61:290-297 X-Rays Early on: may be normal Advancing disease: radiographic features more evident Earliest findings: soft-tissue swelling peri-articular osteopenia May not be as sensitive as MRI or ultrasound ExtraSkeletal Manifestations Of Rheumatoid Arthritis Nodulosis: Elbow Rheumatoid Nodules of Lung Laboratory Findings Rheumatoid Factor Early on: May be negative Eventually positive in 80% of patients Positive rheumatoid factor: 8% of the general population Anti-cyclic citrullinated peptide antibody (CCP) ANA: present in approximately 40% of RA patients Erythrocyte sedimentation rate C-reactive protein Anemia of chronic disease, thrombocytosis, leukocytosis Rheumatoid Factor: Not Unique to Rheumatoid Arthritis Aging Other connective tissue diseases (Sjogrens, SLE, dermatomyositis, etc) Chronic infections (endocarditis, hepatitis, etc.) Granulomatous diseases (Wegener’s, Crohn’s, sarcoidosis) Anti-Cyclic Citrullinated Peptide Antibody Specificity and Sensitivity Early RA (< 2 years) Anti-CCP 79% sensitivity Clinically Confirmed RA Anti-CCP 81% sensitivity Sero-negative RA Anti-CCP 40% sensitivity Specificity Sensitivity RF + 75% 60% Anti-CCP + 96% 75% Anti-CCP + RF + 99% 80% * High titer anti-CCP may predict aggressive erosive disease * Rarely anti-CCP reported in SLE, scleroderma, JRA Linn-Rasker SP, et al. Ann Rheum Dis 2006;65:366-71 Anti-Cyclic Citrullinated Peptide Antibody Specificity and Sensitivity Positive CCP antibody: almost always means RA If not: almost certainly a closely related auto immune connective tissue disease RA Is a Progressive Disease Severity Inflammation Disability Radiographs 0 5 10 15 20 25 Duration of Disease (years) Graph: Adapted from Kirwan JR. J Rheumatol. 2001;28:881-886. 30 CV Risk in Newly Diagnosed RA Patients 80 Study of patients with RA and conventional cardiac risk factors Given identical cardiac risk factors, patients with RA have a higher likelihood of having MI than non-RA patients 10-yr absolute CVD risk in 60-yr-old female RA 60 40 Non RA 20 Important to control both inflammatory disease and conventional risk factors DM, diabetes mellitus; DYS, dyslipidaemia; HTN, hypertension; OBE, obesity; SMO, smoker 1 Kremers HM, et al. 71st ACR, Boston 2007 #2185 0 Without risk factor SMO SMO HTN SMO HTN DM SMO HTN DM DYS SMO HTN DM DYS OBE SMO HTN DM DYS Low BMI Early Treatment Reduces the Cardiovascular Risk in Newly Diagnosed RA Patients Objective: Study sub-clinical atherosclerosis in early RA Methods: prospective cohort of 40 early RA patients tx with MTX and prednisone compared with 45 non-RA patients for cardiac risk parameters and carotid IMT by B-mode US after one year of treatment Result(s): CCA-IMT: Common carotid Artery intimamedia thickness CCA - IMT in mm 1 0.82 0.63 0.57 0 Baseline 12 Months eRA 0.57 Non RA Conclusion(s): Atherogenic lipid profile and subclinical atherosclerosis are features of early RA, which improved after therapy. Improvement in CCA-IMT .82mm to 0.63mm; p<.01-similar to non RA population. Georgiadis et al. ACR 2007 Abstract 1005 RR vs MTX Monotherapy Combination TNF-Inhibitor-MTX Therapy is Superior to MTX Monotherapy in Reducing the Risk of Acute MI in Patients with RA 2 1.78 p<0.03 1.10 0.88 1 0.93 0.20 0 Anti-TNF/MTX DMARD Anti-TNF DMARD/MTX Anti-TNF/DMARD Conclusion(s): Combined TNF-inhibitor and MTX therapy was associated with an 80% reduced risk of acute MI compared to MTX monotherapy in RA pts. “Such dramatic effect enhances the therapeutic gains of TNFinhibitor therapy in patients with RA and should be seriously considered, particularly in high-risk patients.” Singh et al. ACR 2007 Abstract 1339 Differentiating RA From Other Diseases Osteoarthritis Bouchard’s Nodes Heberden’s Nodes ©ACR Psoriatic Arthritis ©ACR Tophaceous Gout ©ACR The Treatment of Rheumatoid Arthritis Therapeutic Window of Opportunity Erosive changes occur early in disease Brief delay of therapy: significant impact years later Early DMARD treatment that suppresses inflammation: resets rate of progression for years to come O’Dell JR. Arthritis Rheum. 2002;46:283-285. Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78. Evolving Approaches in Treating RA 1980s Emphasis on treating symptoms of the disease Less treatment in early stages NSAIDs considered least toxic In US, MTX and corticosteroids considered most toxic Experimental drugs and procedures Immunosuppressants, gold-based drugs, and antibiotics Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics Self-management: education, rest, exercise Evolving Approaches in Treating RA 1990s to Present Emphasis on treating symptoms, limiting joint destruction Earlier use of DMARDs in higher doses MTX and SSZ considered first-choice DMARDs Combination therapy Early diagnosis Early treatment DMARDs and Biologics Preserve function and quality of life 2008 and On Even earlier use of biologic monotherapy or biologic with MTX Remission ACR Treatment Algorithm Rheumatologist Initial Establish diagnosis of RA early Multiple DMARD failure Initiate therapy Periodically assess disease activity Adequate response Inadequate response Change/add DMARDs MTX-naïve Combination MTX Other monotherapy Suboptimal MTX response Other Combination Biologics monotherapy Monotherapy Combination Multiple DMARD failure RA=rheumatoid arthritis; MTX=methotrexate; DMARDs=disease-modifying antirheumatic drugs. Adapted from ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46:328-346. Treatment Options in RA Non pharmacologic approaches: rest, exercise, PT Medications NSAIDs Disease modifying anti-rheumatic drugs (DMARDs) Biologic Agents Corticosteroids Surgery Disease Modifying Anti-Rheumatic Drugs (DMARDs) Generally slower acting Reduce signs and symptoms of inflammation Slow or retard rate of joint damage Oral or by injection Non-targeted Traditional DMARD’s Methotrexate (Rheumatrex) Hydroxychloroquine (Plaquenil) Sulfasalazine (Azulfidine) D-penicillamine Leflunomide (Arava) Azathioprine (Imuran) Gold (Solganol, Ridaura) Cyclosporine (Neoral) Minocycline (Minocin)* *Not FDA approved for RA Conventional DMARD Safety Considerations Hematologic Host Defense Hepatic Gastro-intestinal Malignancy & Lymphoma Reproductive Pulmonary Allergic Cutaneous Renal Ocular Problems with Old Approach Symptom control does not mean disease control1 Damage can occur early2 Risks of morbidity and mortality increase when disease is poorly controlled3,4 Toxicity References: 1. Mulherin D, et al. Br J Rheumatol. 1996;35:1263-1268. 2. McGonagle D, et al. Arthritis Rheum. 1999;42: 1706-1711. 3. Gabriel SE, et al. Arthritis Rheum. 2003;48:54-58. 4. Anderson JJ, et al. Arthritis Rheum. 2000;43:22-29. Evolving RA Treatment Paradigm Current Approach Initial treatment: traditional DMARDs Add traditional DMARD (Combination Therapy) Evolving Paradigm • Early aggressive treatment • Biologics • Combination therapy Biologic DMARD’s – Genetically Engineered Targeted Molecules Similar or Identical to Naturally Occurring Molecules TNFα antagonists: Interleukin-1 antagonist Anakinra (Kineret) Modulate T cell-antigen presenting cell interactions Adalimumab (Humira) Etanercept (Enbrel) Infliximab (Remicade) Abatacept (Orencia) Anti B-Cell monoclonal antibody Rituximab (Rituxan) Efficacy of Biologic Agents Combination therapy efficacy: equal or superior to DMARDs Targeted Mechanism of action identified Rapid onset of action Well tolerated: improved risk/benefit ratio Sustained response in many patients: prevention of structural damage control of symptoms prevention of disability Characteristics of Biologics Etanercept Enbrel Infliximab Remicade Adalimumab Humira Anakinra Kineret Abatacept Orencia Rituximab Rituxan Target TNF TNF TNF IL-1 Receptor T-Cell Activation B-Cell Half Life 3-5 Days 8-10 Days 10-20 Days 4-6 Hrs 13-16 Days 19 Days Construct Human Chimeric Human Human Human Chimeric Dosing Once Biweeklyweekly Once every 4-8 weeks Once every 1-2 weeks Once Daily Once Monthly Twice every 6-12 months Route Sub Q I.V. Sub Q Sub Q I.V. I.V. MEASURING DISEASE ACTIVITY Subjective—pain, morning stiffness, fatigue, limitation of function, PGAs Physical exam—swollen and tender joint count Lab evaluation—RF, anti-CCP, ESR, CRP Imaging—X-ray (Sharp Score), US, MRI Disease Activity and Outcome Scoring: ACR 20,50,70, DAS, HAQ, Global Arthritis Score (GAS) C-DAI, S-DAI, RAPID Better Outcomes in Patients Receiving Combination Therapy of MTX & Anti TNFα Patients (%) ACR50 Response 61 46 42 Patients (%) 70 60 50 40 30 20 10 0 Mean Change TSS 59 43 37 12 10.4 10 8 6 4 2 5.7 5.5 3 1.3 1.9 0 year 1 year 2 year 1 MTX Adalimumab MTX + Adalimumab Breedveld FC Arthritis Rheum 2006; 54(1): 26-37 year 2 Anti-TNF Monotherapy Improves Clinical Signs & Symptoms 70 Placebo (n = 30) Etanercept 25 mg (n = 78) 59* 60 50 40* 40 30 20 15* 11 5 10 1 0 ACR20 * p 0.001. ACR50 ACR70 Moreland LW et al. Ann Intern Med. 1999;130:478-486. Anti TNF + MTX Combination Slows Radiographic Progression 14 N = 428 12.6 30 Weeks 10 54 Weeks Mean Change in Total Sharp Score 12 102 Weeks 8 6 7 4.8 4 2 p < 0.001 p < 0.001 1.3 1.6 1 1 0.6 p < 0.001 p < 0.001 1.1 1 -0.5 0.2 -0.3 -0.7 -0.4 0 -2 Placebo + MTX Infliximab + MTX 3 mg/kg q8w 3 mg/kg q4w 10 mg/kg q8w 10 mg/kg q4w p values are versus placebo + MTX. Maini R et al. Lancet. 1999;354:1932-1939; Lipsky PE et al. N Engl J Med. 2000;343:1594-1602 B Cell Depleting Therapy in RA Patients Refractory to Anti TNFα Therapy: ACR Responses at 6 Months 60 p < 0.0001 51 % Patients 50 40 p < 0.0001 30 27 20 p < 0.0001 18 12 10 5 1 0 ACR20 ACR50 Placebo (N=201) Cohen S, et al. Arthritis and Rheumatism 2006:54(9):2793-2806 ACR70 Rituximab (N=298) B Cell Depleting Therapy in RA Patients Refractory to Anti TNFα Therapy: Radiographic Endpoints at 6 Months Mean Change 1.5 p=0.1693 1.2 p=0.2358 1 0.6 0.5 p=0.0156* 0.8 0.5 0.4 0.2 0 Total Genant-Modified Sharp Score Joint Space Narrowing Score Placebo (N=177) *Statistically significant Erosion Score Rituximab (N=268) 24 Placebo and 30 rituximab patients were missing x-rays at week 24 Cohen S, et al. Arthritis and Rheumatism 2006:54(9):2793-2806 Inhibition of T-Cell Activation by Co-Stimulatory Pathway Blockade in RA Patients With Inadequate MTX Response 100 ACR Response 90 80 68 70 Patients (%) Placebo + MTX 73 Abatacept + MTX 60 48 50 40 40 40 40 29 30 17 20 20 18 10 7 6 0 6 Mos 12 Mos ACR 20 6 Mos 12 Mos ACR 50 1. Kremer et al. Annals of Internal Medicine: 2006; 144:865-876 6 Mos 12 Mos ACR 70 Inhibition of T-Cell Activation by Co-Stimulatory Pathway Blockade in RA Patients: Radiographic Outcomes 2.5 2.3 2 Placebo + MTX * 1.5 1.2 Abatacept + MTX 1 *P<0.05 vs placebo 0.5 Change From Baseline 0 40 Abatacept 1 P=0.012 for Total Score X-Ray Progression 30 Placebo at 1 Year P=0.029 for Erosion Score 20 10 0 10 1. 2. P=0.009 for JSN Score 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Cumulative Probability2 Kremer, et al Annals of Internal Medicine: 2006; 144:865-876 Genant H, et al. Presented at: EULAR Annual Meeting; June 8-11, 2005; Vienna, Austria. Abstract OP0001. Figure courtesy of H. Genant, MD. Safety Considerations Morbidity and mortality of RA Safety of conventional DMARDs Safety of biologics Safety Considerations with Biologic DMARD’s Serious Infections Opportunistic infections (TB) Malignancies/lymphoma Demyelination Hematologic abnormalities Administration reactions Congestive heart failure Hepatic Autoantibodies and drug induced lupus Is Cancer More Aggressive on TNF-I? Mortality rate comparison in RA pts after cancer diagnosis between those treated and not treated with TNF-Is Swedish database (inpatient, outpatient and early RA registries) TNF naïve (n=61,585) and the Swedish Biologic Registry (n=6296) (1998–2005) Conclusion Preliminary results: no major difference in cancer survival between RA pts treated and not treated with TNF-antagonists Raaschou, P et al. 71st ACR, Boston 2007 #1344 All sites Mortality Anti-TNF No anti-TNF RR=0.8 (95% CI 0.5-1.2) Days Biologics: Relative Contraindications Active Hepatitis B Infection Multiple sclerosis, optic neuritis Active serious infections Chronic or recurrent infections Current neoplasia History of TB or positive PPD (untreated) Congestive heart failure (Class III or IV) Treatment Summary Early appropriately aggressive intervention in patients with inflammatory arthritis: critical to best possible outcome The combination of a biologic plus MTX is frequently more effective than either agent alone RA: Misperceptions Controlling symptoms = controlling the disease Early treatment should be conservative, eg, NSAIDs, COX-2 inhibitors Positive rheumatoid factor (RF) = RA RA is a disease of (postmenopausal) women and elderly people RA is inevitably progressive, regardless of therapy RA does not affect mortality rate Keys to Improving Outcomes and Slowing Disease Progression Early diagnosis-learn about the Anti-CCP test Irreversible joint destruction often begins within the first year after RA onset >70% of patients exhibit radiographic disease progression after only 2 years Joint damage strongly correlates with disability over the course of RA What can the Primary Care Provider do? Be mindful: serious nature of RA Remember early intervention is important Keep up to date on new developments Be an advocate for your patients Early referral to specialist Pick up the phone if necessary Warning Signs Morning stiffness 1 hour Joint pain lasting 3 months Symmetrical, bilateral painful and/or swollen joints 3 swollen joints MCP/MTP involvement Positive squeeze test RF+ CCP + Conclusion Rheumatoid Arthritis is a serious disease Early diagnosis is key to good outcomes Advent of new therapies have major impact in altering disease progression