Rheumatoid Arthritis Systemic disease whose predominant - PDF document

Rheumatoid Arthritis • Systemic disease whose predominant manifestation involves a chronic, inflammatory, Rheumatoid Arthritis: What’s old and small joint arthritis new in 2019 • Affects up to 1% of the US population Jonathan Graf, M.D. Professor of Medicine, UCSF Division of Rheumatology, ZSFGH • Female:Male predominance of 3:1 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 disability • Improves with activity, 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% • Rheumatoid nodules – Limited sensitivity: 40-65% • 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 à Prospectively over time High positive RF OR high positive ACPA 3 (cumulatively) SYMPTOM DURATION (0-1) <6 weeks 0 à 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 Normal CRP AND normal ESR 0 scoring system and algorithms 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 classification of rheumatoid arthritis No Yes No classification of rheumatoid arthritis No Yes 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 Yes Yes No Duration: No 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 No Serology: Yes Serology: Yes ++ ++ 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 Yes No Yes Yes No Yes No No 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 targeted in RA is not known 5

RF and anti-CCP testing in a cohort Antibodies to citrullinated peptides of 182 early RA patients in RA Quinn et al Rheumatology (Oxford) 45:478, 2006 • Detected by ELISAs using synthetic cyclic citrullinated peptides (CCP) RF-CCP- RF-CCP+ RF+CCP- • Sensitivity for very early RA: 50% • Sensitivity for early-later RA: 70-80% • Specificity for RA: 95-98% RF+CCP+ RA: Etiology/Genetics Preclinical autoimmunity in RA: appearance of anti-CCP abs and RF prior to onset of arthritis Manhattan plot from a genome-wide association study of RA Criswell, LA Immunological Reviews 233: 55, 2010 • 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 Nielen et al Arth Rheum 50: 380, 2004 6

HLA DRB1 alleles and rheumatoid arthritis: Gene-environment interaction in RA: Is smoking shared epitope hypothesis an environmental trigger? Note: most common serotype is HLA DR4 Klareskog et al Ann Rev Immunol 26:651. 2008 amino acid position on the DR b chain Anti-CCP negative Anti-CCP positive DRB1 allele 70 71 72 73 74 0101 Q R R A A 0401 Q K R A A 0404 Q R R A A 0405 Q R R A A 0408 Q R R A A 1402 Q R R A A 1001 R R R A A Evidence for an interaction between smoking and the shared CONSENSUS Q/R R/K R A A epitope in risk for anti-CCP-positive RA in a European cohort Possible culprits Periodontitis and the link to RA Konig et al. Science Translational Medicine 14 Dec 2016 P. Gingivalis can citrullinate proteins directly Aggregatibacter actinomycetemcomitans Exo-toxin causes host neutrophils to auto-citrullinate their proteins 7

Progression of joint damage in Among SE+ RA patients, CCP+ patients have subgroups of early RA those who are CCP+ have progression of damage radiographic progression whether SE+ or not Huizinga et al Arthritis Research& Therapy 7: 949, 2005 Huizinga, Criswell et al. Arthritis and Van Gaalen et al. Arthritis and Rheumatism 2005:52;11:3433-3438 Rheumatism 2004:50;7:2113-2121 anti-CCP + radiographic joint damage score anti-CCP - Is rheumatoid arthritis a single Anti-CCP status disease? • Anti-CCP positive RA patients are unique RA #1 RA#2 compared to anti-CCP negative patients – Shared epitope positive compared to controls SE + - • No additional contribution to risk of developing RA from SE independent of CCP status (data not shown) CCP + - (? environmental – More erosive disease citrullination) – More progressive course of disease Erosive dz + - (radiographically) 8