Rheumatoid Arthritis Advances in Rheumatoid Arthritis • Systemic disease whose predominant 2019: Diagnosis, Assessment, and manifestation involves a chronic, inflammatory, small joint arthritis Novel Oral therapies • Affects up to 1% of the US population Jonathan Graf, M.D. Professor of Medicine, UCSF • Female:Male predominance of 3:1 Division of Rheumatology, ZSFGH Director, UCSF RA Cohort • Peak incidence: patients in their 30’s-40’s but can occur at any stage of life Clinical features of RA RA: Clinical features • Most often insidious subacute onset • RA is a chronic and progressive disease • Small joint, symmetric • Chronic disease inflammatory polyarthritis progression leads to of diarthrodial joints permanent joint • Morning stiffness (hours) deformity, prevalent destruction, and • Improves with activity, disability worse with inactivity (gelling phenomenon) • Joint swelling, joint pain are common 1
Rheumatoid Arthritis: morbidity Improving Outcomes in RA • Disease associated with • Improvement in timely and accurate significant morbidity diagnosis and prognosis • Disability costs are high, both in terms of direct and indirect medical costs • Treating to defined disease activity targets – 35% of patients with 10 years disease duration are work- disabled Arthritis Rheum. 2008 Mar 27;59(4):474-480 • Improvements in therapy • Significant increase in mortality (SMR 1.4) – Surprisingly consistent over 20 Humphreys et al. AC&R 2014 years of improved therapy Early RA: The Window of Improving Outcomes in RA Opportunity to Intervene • Improvement in timely and accurate diagnosis and prognosis • Treating to defined disease activity targets • Improvements in therapy 2
The Window of Opportunity Rheumatoid arthritis: irreversible damage can occur early in disease course 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 1 year prior to 6 months after 3 years after onset – More difficult to suppress onset of RA onset of symptoms of symptoms activity and treat – More extra-articular Radiographic changes in the same joint over time disease? Limitations of ACR Classification ACR Criteria for the Classification of Criteria for the diagnosis of early RA Rheumatoid Arthritis 1987 (>4 criteria required; 1-4 must be present > 6 wks) • Developed for the classification of patients with longstanding disease (for clinical studies, not diagnosis) • Morning stiffness > 1 hr – Many of these features (rheumatoid nodules, for ex) are seen • Arthritis of 3 or more joint areas with declining frequency • Arthritis of wrists, MCPs, and/or PIPs • For early RA, 1987 classification criteria: • Symmetric arthritis – Specificity: 90% – Limited sensitivity: 40-65% • Rheumatoid nodules • Serum rheumatoid factor • Relying on criteria to make a diagnosis of RA can lead to • Radiographic changes delayed or inappropriate diagnosis 3
2010 ACR/EULAR ACR/Eular Classification Criteria 2010 Classification Criteria for RA JOINT DISTRIBUTION (0-5) • Joint US-European effort to classify patients ≥6 = definite RA 1 large joint 0 2-10 large joints 1 with earlier disease for research 1-3 small joints (large joints not counted) 2 4-10 small joints (large joints not counted) 3 What if the score is <6? >10 joints (at least one small joint) 5 SEROLOGY (0-3) Patient might fulfill the criteria… • Lacks many of descriptive features of 1987 Negative RF AND negative ACPA 0 Low positive RF OR low positive ACPA 2 criteria Prospectively over time High positive RF OR high positive ACPA 3 (cumulatively) SYMPTOM DURATION (0-1) <6 weeks 0 Retrospectively if data on all ≥6 weeks 1 four domains have been • Not as practical for clinical practice: relies on ACUTE PHASE REACTANTS (0-1) adequately recorded in the past scoring system and algorithms Normal CRP AND normal ESR 0 Abnormal CRP OR abnormal ESR 1 START START >10 joints (at least >10 joints (at least (eligible patient) one small joint) (eligible patient) one small joint) Rheumatoid arthritis Rheumatoid arthritis No Yes No Yes No classification of rheumatoid arthritis No classification of rheumatoid arthritis 4-10 small joints 4-10 small joints Serology: Serology: +/++ +/++ No Yes No Yes Serology: Serology: No Yes No Yes 1-3 small joints 1-3 small joints ++ ++ No Yes No Yes No Yes No Yes Duration: Duration: 2-10 large Serology: 2-10 large Serology: ≥6 weeks ≥6 weeks (no small) joints ++ (no small) joints ++ Serology: Serology: No Yes No Yes + + No Yes No Yes Serology: Duration: Serology: Duration: + ≥6 weeks + ≥6 weeks No Yes No Yes No Yes No Yes Serology: Serology: ++ ++ No Yes No Yes Duration: APR: APR: Duration: APR: APR: No Yes No Yes ≥6 weeks Abnormal Abnormal ≥6 weeks Abnormal Abnormal Duration: Duration: No Yes No Yes ≥6 weeks ≥6 weeks Duration: Duration: ≥6 weeks ≥6 weeks No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes APR: APR: APR: APR: APR: APR: Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal No Yes No Yes No Yes No Yes No Yes No Yes RA RA RA RA RA RA RA RA RA RA RA RA RA RA RA RA 4
Factors predictive of progression Diagnosis of early RA by 1987 ACR criteria from undifferentiated arthritis to RA van Gaalen et al Arth Rheum 50: 709, 2004 van Gaalen et al Arth Rheum 50: 709, 2004 At initial evaluation OR (95% CI) 936 patients with early inflammatory arthritis Initial evaluation After 3 years Positive rheumatoid factor 1.7 (0.5-5.6) Positive anti-CCP antibody 38.6 (9.9-151.0) 205 RA by ACR criteria 936 318 “undifferentiated 127 RA arthritis” 413 other diagnoses Posttranslational modification of proteins: RA-associated autoantibodies that PADI converts arginine to citrulline recognize peptides containing citrulline Girbal-Neuhauser et al J Immunol 162: 585, 1999 Peptide sequence Antibody recognition ESSRDGSRHPRSHD No PADI ESSRDGScitHPRSHD Yes Actual citrullinated antigen(s) targeted in RA is/are not known 5
Preclinical autoimmunity in RA: Antibodies to citrullinated peptides appearance of anti-CCP abs and in RA RF prior to onset of arthritis • Detected by ELISAs using synthetic cyclic citrullinated peptides (CCP) • Sensitivity for very early RA: 50% • Sensitivity for early-later RA: 70-80% • Specificity for RA: 95-98% Nielen et al Arth Rheum 50: 380, 2004 RF and anti-CCP testing in a cohort Progression of joint damage in of 182 early RA patients subgroups of early RA Quinn et al Rheumatology (Oxford) 45:478, 2006 Huizinga et al Arthritis Research& Therapy 7: 949, 2005 anti-CCP + RF-CCP- RF-CCP+ RF+CCP- radiographic joint damage score anti-CCP - RF+CCP+ 6
Summary: Clinical utility of the anti- RA: Etiology/Genetics CCP antibody test • Diagnosis: – Clinical suspicion of rheumatoid arthritis – Early, undifferentiated inflammatory arthritis – Distinguish RA from other RF + polyarthritis • Not useful to monitor disease activity • Best single predictor for destructive Manhattan plot from a genome-wide association study of RA Criswell, LA Immunological Reviews 233: 55, 2010 disease in patients with early onset RA • 15-20% concordance in monozygotic twins • RA: 60% heritable contribution • Most of genetic contribution from Chromosome 6: HLA DR locus • More copies of HLA risk alleles, higher risk for RA and more severe disease Gene-environment interaction in RA: Is smoking Periodontitis and the link to RA an environmental trigger? Klareskog et al Ann Rev Immunol 26:651. 2008 Anti-CCP negative Anti-CCP positive Evidence for an interaction between smoking and the shared epitope in risk for anti-CCP-positive RA in a European cohort 7
Is rheumatoid arthritis a single Possible culprits disease? Konig et al. Science Translational Medicine 14 Dec 2016 P. Gingivalis can RA #1 RA#2 citrullinate proteins directly Genetic Risk + - (HLA DR SE) ACPA + - (? environmental citrullination) Aggregatibacter actinomycetemcomitans Exo-toxin causes host neutrophils to auto-citrullinate their proteins Erosive dz + - RA: Chronic Joint Destruction and Improving Outcomes in RA Disability – What We Try to Prevent • Improvement in timely and accurate diagnosis and prognosis • Treating to defined disease activity targets • Improvements in therapy 8
Joint damage in RA: Treatment of early RA progressive narrowing and erosion of a MCP joint • Effective treatment should be started when the diagnosis is made – “Effective treatment” = therapies shown to slow joint destruction • Goal is to induce and then maintain remission – Combination of drugs more effective than monotherapy At presentation: 1 year 5 years normal RA: Traditional Treatment Re-Thinking the RA Treatment Paradigm Pyramid • Pyramid of therapy – Start conservatively – Gradually ascend the pyramid in order of potency and toxicity of therapy – Only the most severely affected patients receive immuno- supressive, DMARDs – DMARD therapy begun • Emphasizes earlier diagnosis and initiation of only after period of therapy with disease modifying anti-rheumatic significant delay drugs 9
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