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Recent Advances in Rheumatoid Arthritis

Recent Advances in Rheumatoid Arthritis. Elizabeth D. Ferucci, MD, MPH, FACP May 22, 2010 ACP Alaska Chapter Meeting. Objectives. Summarize developments with respect to etiology of rheumatoid arthritis (RA) Review most recent information related to diagnosis of RA

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Recent Advances in Rheumatoid Arthritis

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  1. Recent Advances in Rheumatoid Arthritis Elizabeth D. Ferucci, MD, MPH, FACP May 22, 2010 ACP Alaska Chapter Meeting

  2. Objectives • Summarize developments with respect to etiology of rheumatoid arthritis (RA) • Review most recent information related to diagnosis of RA • Discuss options for management of RA

  3. Etiology of RA

  4. Genetics of RA • Genetic component to RA risk • Increased prevalence of RA in first-degree relatives (2-4x) • Twin studies suggest heritability of RA is 65%* • HLA DR4 and shared epitope 1970s-80s • New techniques identifying new loci • Genomewide association studies (GWAS) • Identifies single nucleotide polymorphisms (SNPs) associated with disease • Candidate gene/SNP studies Reviewed in: Raychaudhuri S. Curr Opin Rheumatol 2010;22:109. *MacGregor AJ. Arthritis Rheum 2000;43:30.

  5. October 2009: >30 RA Risk Loci Together explain ~35% of the genetic burden of disease REL BLK TAGAP CD28 TRAF0 PTPRC FCGR2A PRDM1 CD2-CD58 CD40 CCL21 CD244 IL2RB TNFRSF14 PRKCQ PIP4K2C IL2RA AFF3 TNFAIP4 STAT4 TRAF1-C5 IL2-IL21 “Shared epitope” hypothesis HLA DR4 PTPN22 CTLA4 PADI4 1978 1987 2003 2004 2005 2007 2008 2009 Plenge RM, ACR Annual Meeting Presentation, October 2009

  6. Contribution of Individual Genes/SNPs to Odds of RA Odds ratio % Variance Explained Raychaudhuri S. Curr Opin Rheumatol 2010;22:109.

  7. Anti-Citrullinated Peptide Antibodies (ACPA) • Rheumatoid factor (RF) has low specificity for RA • ACPA more specific than RF for RA • CCP is commercially available test • Sensitivity similar to RF (~60-80%) • More specific for RA (~96%) • Predicts poor prognosis

  8. RA defined by ACPA status • Genetics of RA • ACPA positive and negative RA both heritable • HLA shared epitope genes more important in ACPA-positive RA • HLA DRB1*04,*01,*10, and *14 • Different genes associated with ACPA-negative RA • HLA DRB1*03 with ACPA- RA1,2 1. Verpoort KN et al. Arthritis Rheum 2005;52:3058 2. Irigoyen P et al. Arthritis Rheum 2005;52:3813

  9. Interaction of Genetic and Environmental Factors: HLA and Smoking in RA A, Results in RA patients who are positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies. B, Results in RA patients who are negative for anti-CCP antibodies. Klareskog L, et al. Arthritis Rheum 2006;54:38-46.

  10. Oral Health and RA • Periodontal disease more common in people with RA than controls • Oral bacterium, Porphyromonas gingivalis, may be the connection • Associated with autoantibodies (CCP) • Could be part of causal pathway • Many ongoing studies of role in RA Rosenstein ED et al. Inflammation 2004;28:311-8

  11. Diagnosis of RA

  12. Diagnosis • Clinical diagnosis based on several different findings, primarily from joint exam • ACR 1987 criteria for classification for research studies • 4/7 required for diagnosis • RF and X-ray findings included • Remaining 5 criteria all exam or history-based Arnett FC, et al. Arthritis Rheum. 1988;31:315-324.

  13. Problems with old ACR Criteria • Work best in longstanding RA • But DMARDs work best in early RA and the goal is to prevent development of damage • Need criteria addressing earlier diagnosis given the benefits of early treatment • Need to include ACPA (CCP) • Balance with need for use in low resource settings where CCP not available • Goal of new criteria: predict who should be treated with DMARDs

  14. New ACR/EULAR Proposed Criteria • Initial screen: • 1+ swollen joints (if no, not RA) • Better explained by other dz? (if yes, not RA) • Typical RA erosion on X-ray? (if yes, RA) • Next step: • Pattern of joint involvement (more points for more joints and small joints) • Serology (RF and/or CCP, negative, low, high) • Duration (<6 wk, 6+ wk) • ESR and/or CRP (both normal vs. one abnormal)

  15. Normal labs do not rule out RA • Observational study of 2370 patients in Finland and US from 1980-2004 • Median ESR at presentation: 30 • ESR normal in 45-47% • CRP normal in 33-42% • All RF tests negative in 37-38% • 37% of patients had ESR < 28, normal CRP, or all negative RF tests Sokka T, Pincus T. J Rheumatol 2009;36:1387

  16. Management of RA

  17. Benefits of early detection and DMARD therapy • Decreased RA severity, disability and mortality with DMARDs • Less need for joint replacement surgery • May decrease risk of cardiovascular disease and mortality

  18. ACR Guidelines for Management • Summarize evidence for DMARDs and biologics in different settings • Incorporate the following in treatment decisions • Disease duration (<6mo, 6-24, >24 mo) • Disease activity (low, moderate, high) • Features of poor prognosis Saag KG et al. Arthritis Rheum 2008;59:762

  19. Measurement of Disease Activity: DAS28 as Example DAS28 = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.70 * ln(ESR) + 0.014 * GH • Includes: • Tender joint count • Swollen joint count • ESR (or CRP in different version) • GH: Patient global disease activity assessment • Categorized as low, moderate, or high

  20. Poor Prognostic Factors in RA • Presence of RF and/or CCP antibodies • Radiographic erosions • Functional limitation • Extraarticular disease

  21. Hydroxychloroquine (Plaquenil) Sulfasalazine Methotrexate Leflunomide (Arava) Less commonly used: Minocycline Azathioprine Gold, PO or IM Cyclosporine Etanercept (Enbrel) Infliximab (Remicade) Adalimumab (Humira) Golimumab (Simponi) Certolizumab Pegol (Cimzia) Anakinra (Kineret) Rituximab (Rituxan) Abatacept (Orencia) Tocilizumab (Actemra) DMARDs (Disease-Modifying Anti-Rheumatic Drugs) Traditional Biologics

  22. Role of MTX in RA • Methotrexate considered mainstay of RA therapy • Recommended first-line therapy in DMARD-naïve patients • All TNF inhibitors studied with/without MTX work better with MTX • New biologics studied in combination with MTX—incomplete response required for enrollment in most trials Katchamart et al. Ann Rheum Dis 2009;68:1105-12. Feely MG, O’Dell JR. Curr Opin Rheumatol 2010;22:316

  23. Benefits of Traditional DMARDs • Cost • Efficacy • Toxicity Profile

  24. TEAR Trial: RCT in early RA Immediate MTX+HCQ+SSZ (Triple Therapy) Immediate MTX+ etanercept Step up from MTX to triple therapy Step up from MTX to MTX+etanercept If DAS > 3.2 at 6 months Moreland LW et al. ACR Annual Meeting, October 2009, Abstract #1895.

  25. Limitations of traditional DMARDs • Lack of efficacy in some patients • May not slow radiographic progression • Toxicity (less common reason for discontinuation)

  26. SWEFOT Trial • Early RA • Start MTX first up to 20mg/wk • If DAS high after 3-4 months, randomized to add either SSZ+HCQ vs. infliximab • Open label • Primary outcome: 1 year EULAR good response • Achieved in 25% on SSZ+HCQ vs. 39% on infliximab (p=0.016) van Vollenhoven RF et al. Lancet 2009;374:459

  27. Major Paradigm Shift in RA • Treat early and aim for low disease activity • Many more options leading to: • New goal of treatment • REMISSION

  28. Cytokine Signaling Pathways Involved in RA RF IL-4 IL-10 IL-4 IL-6 IL-10 Th2 Macrophage Plasmacell Th0 IFNg IL-12 Interferon g B cell CD4 + T cell CD11 CD69 OPGL TNF IL-1 IL-6 CD11 CD69 Synovium Chondrocyte Osteoclast Fibroblast Production of metalloproteinases andother effector molecules Migration of polymorphonuclear cells Erosion of bone and cartilage Choy EH, Panayi GS. N Engl J Med 2001;344:907

  29. Biologics in RA • All recommended with methotrexate • Biologic agents target: • Tumor necrosis factor-a (TNF-a) • Co-stimulation between B and T cells • B cell surface proteins • Interleukin-6 (IL-6) • More likely to come soon….

  30. TNF inhibitors • Generally accepted as first-line biologics • Add to methotrexate when disease activity remains moderate to high after adequate trial • Five different agents available

  31. TNF Inhibitors

  32. TNF Antagonists: Contraindications • Current active infection • Chronic or recurrent infections • History of TB or positive PPD (untreated) • Congestive heart failure • Recent malignancy • Systemic lupus erythematosus • Multiple sclerosis, optic neuritis

  33. Cumulative incidence of tuberculosis (TB) following first exposure to anti-tumour necrosis factor (anti-TNF) therapy (most recent drug model, with person-years censored at death, last returned follow-up form, or date of switching to second anti-TNF). Dixon W G et al. Ann Rheum Dis 2010;69:522-528 ©2010 by BMJ Publishing Group Ltd and European League Against Rheumatism

  34. How long do I have to take this? • Goal: treat to remission • Next goal: drug-free remission • Can early aggressive treatment induce drug-free or biologic-free remission? • Treat early in disease • Obtain remission • Withdraw agents

  35. RRR Trial • Remission Induction by Remicade in RA • Low disease activity (DAS < 3.2) for 24 weeks on infliximab • 114 patients had infliximab discontinued • 102 re-evaluated at year 1 • 56 patients (55%) continued to have low DAS • In those who failed, retreatment with infliximab occurred Tanaka Y et al. Annals Rheum Dis 2010;online first as 10.1136/ard.2009.121491

  36. How to approach failure of TNFi • TNF inhibitors are not universally efficacious • Options after TNF inhibitor failure: • Within-class switching • TNF to non-TNF class biologic switch • Rituximab • Abatacept • Tocilizumab • Future direction: biomarkers to direct choice Buch MH. Curr Opin Rheumatol 2010;22:321

  37. Cautions with DMARDs • Most combinations are acceptable • Do not combine 2 biologic agents • Risk of infection • Use caution combining methotrexate and leflunomide • Risk of liver toxicity

  38. Vaccines and Biologics • Avoid live vaccines in patients on all biologics • FluMist (seasonal or H1N1 nasal) • Zoster • MMR • Other vaccines are recommended • Seasonal and H1N1 influenza • Pneumovax

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