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 • Discuss options for management of RA
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.
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
Contribution of Individual Genes/SNPs to Odds of RA Odds ratio % Variance Explained Raychaudhuri S. Curr Opin Rheumatol 2010;22:109.
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
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
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.
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
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.
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
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)
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
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
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
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
Poor Prognostic Factors in RA • Presence of RF and/or CCP antibodies • Radiographic erosions • Functional limitation • Extraarticular disease
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
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
Benefits of Traditional DMARDs • Cost • Efficacy • Toxicity Profile
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.
Limitations of traditional DMARDs • Lack of efficacy in some patients • May not slow radiographic progression • Toxicity (less common reason for discontinuation)
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
Major Paradigm Shift in RA • Treat early and aim for low disease activity • Many more options leading to: • New goal of treatment • REMISSION
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
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….
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
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
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
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
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
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
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
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