Disclosures Consultant - Abbvie Update in Rheumatoid Arthritis: - PDF document

Disclosures • Consultant - Abbvie Update in Rheumatoid Arthritis: Controversies in Women’s Health Jonathan Graf, M.D. Professor of Medicine, UCSF Division of Rheumatology, ZSFGH Director, UCSF RA Cohort Clinical features of RA Rheumatoid Arthritis • Most often insidious • Systemic disease whose predominant subacute onset manifestation involves a chronic, inflammatory, small joint arthritis • Small joint, symmetric inflammatory polyarthritis • Affects up to 1% of the US population of diarthrodial joints • Morning stiffness (hours) prevalent • Female:Male predominance of 3:1 • Improves with activity, worse with inactivity (gelling phenomenon) • Peak incidence: patients in their 30’s-40’s but • Joint swelling, joint pain are can occur at any stage of life common

RA: Clinical features Rheumatoid Arthritis: morbidity • Disease associated with • RA is a chronic and significant morbidity progressive disease • Disability costs are high, both in terms of direct and indirect • Chronic disease medical costs – 35% of patients with 10 years progression leads to disease duration are work- permanent joint disabled deformity, Arthritis Rheum. 2008 Mar 27;59(4):474-480 destruction, and disability • Significant increase in mortality (SMR 1.4) – Surprisingly consistent over 20 Humphreys et al. AC&R 2014 years of improved therapy Improving Outcomes in RA Improving Outcomes in RA • Improvement in timely and accurate • Improvement in timely and accurate diagnosis and prognosis diagnosis and prognosis • Treating to defined disease activity targets • Treating to defined disease activity targets • Improvements in therapy • Improvements in therapy • Issues of concern for women

Early RA: The Window of The Window of Opportunity Opportunity to Intervene 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 – More difficult to suppress activity and treat – More extra-articular disease? Rheumatoid arthritis: irreversible damage ACR Criteria for the Classification of can occur early in disease course Rheumatoid Arthritis 1987 (>4 criteria required; 1-4 must be present > 6 wks) • Morning stiffness > 1 hr • Arthritis of 3 or more joint areas • Arthritis of wrists, MCPs, and/or PIPs • Symmetric arthritis • Rheumatoid nodules 1 year prior to 6 months after 3 years after onset • Serum rheumatoid factor onset of RA onset of symptoms of symptoms • Radiographic changes Radiographic changes in the same joint over time

Limitations of ACR Classification ACR/Eular Classification Criteria 2010 Criteria for the diagnosis of early RA • Joint US-European effort to classify patients • Developed for the classification of patients with longstanding disease (for clinical studies, not diagnosis) with earlier disease for research – Many of these features (rheumatoid nodules, for ex) are seen with declining frequency • Lacks many of descriptive features of 1987 • For early RA, 1987 classification criteria: criteria – Specificity: 90% – Limited sensitivity: 40-65% • Not as practical for clinical practice: relies on • Relying on criteria to make a diagnosis of RA can lead to delayed or inappropriate diagnosis scoring system and algorithms START >10 joints (at least 2010 ACR/EULAR (eligible patient) one small joint) Rheumatoid arthritis No Yes No classification of rheumatoid arthritis Classification Criteria for RA 4-10 small joints Serology: JOINT DISTRIBUTION (0 ‐ 5) +/++ No Yes ≥ 6 = definite RA 1 large joint 0 Serology: 2 ‐ 10 large joints 1 No Yes 1-3 small joints ++ 1 ‐ 3 small joints (large joints not counted) 2 No Yes 4 ‐ 10 small joints (large joints not counted) 3 No Yes Duration: 2-10 large Serology: What if the score is <6? ≥ 6 weeks >10 joints (at least one small joint) 5 (no small) joints ++ Serology: No Yes SEROLOGY (0 ‐ 3) + Patient might fulfill the criteria… No Yes Negative RF AND negative ACPA 0 Serology: Duration: + ≥ 6 weeks No Yes No Yes Low positive RF OR low positive ACPA 2 Serology: ++  Prospectively over time No Yes High positive RF OR high positive ACPA 3 (cumulatively) Duration: APR: APR: No Yes ≥ 6 weeks Abnormal Abnormal SYMPTOM DURATION (0 ‐ 1) Duration: No Yes ≥ 6 weeks <6 weeks 0 Duration:  Retrospectively if data on all ≥ 6 weeks No Yes ≥ 6 weeks 1 four domains have been No Yes No Yes ACUTE PHASE REACTANTS (0 ‐ 1) No Yes adequately recorded in the past APR: APR: APR: Normal CRP AND normal ESR 0 Abnormal Abnormal Abnormal Abnormal CRP OR abnormal ESR 1 No Yes Yes No Yes No RA RA RA RA RA RA RA RA

START >10 joints (at least Diagnosis of early RA by 1987 ACR criteria one small joint) (eligible patient) Rheumatoid arthritis No Yes No classification of rheumatoid arthritis van Gaalen et al Arth Rheum 50: 709, 2004 4-10 small joints Serology: +/++ No Yes 936 patients with early inflammatory arthritis Serology: No Yes 1-3 small joints ++ No Yes Initial evaluation After 3 years No Yes Duration: 2-10 large Serology: ≥ 6 weeks (no small) joints ++ Serology: No Yes + No Yes 205 RA by ACR Serology: Duration: + ≥ 6 weeks No Yes Serology: No Yes criteria ++ No Yes Duration: APR: APR: No Yes ≥ 6 weeks Abnormal Abnormal No Yes Duration: ≥ 6 weeks Duration: 936 318 “undifferentiated 127 RA ≥ 6 weeks No Yes No Yes No Yes arthritis” No Yes APR: APR: APR: Abnormal Abnormal Abnormal No Yes 413 other diagnoses Yes No Yes No RA RA RA RA RA RA RA RA Factors predictive of progression Posttranslational modification of proteins: from undifferentiated arthritis to RA PADI converts arginine to citrulline van Gaalen et al Arth Rheum 50: 709, 2004 At initial evaluation OR (95% CI) Positive rheumatoid factor 1.7 (0.5-5.6) Positive anti-CCP antibody 38.6 (9.9-151.0)

Antibodies to citrullinated peptides RA-associated autoantibodies that in RA recognize peptides containing citrulline • Detected by ELISAs using synthetic cyclic Girbal-Neuhauser et al J Immunol 162: 585, 1999 citrullinated peptides (CCP) Peptide sequence Antibody recognition ESSRDGSRHPRSHD No • Sensitivity for very early RA: 50% • Sensitivity for early-later RA: 70-80% PADI • Specificity for RA: 95-98% ESSRDGScitHPRSHD Yes Actual citrullinated antigen(s) targeted in RA is/are not known RF and anti-CCP testing in a cohort Preclinical autoimmunity in RA: of 182 early RA patients appearance of anti-CCP abs and Quinn et al Rheumatology (Oxford) 45:478, 2006 RF prior to onset of arthritis RF-CCP- RF-CCP+ RF+CCP- RF+CCP+ Nielen et al Arth Rheum 50: 380, 2004

Summary: Clinical utility of the anti- Progression of joint damage in subgroups of early RA CCP antibody test Huizinga et al Arthritis Research& Therapy 7: 949, 2005 • Diagnosis: – Clinical suspicion of rheumatoid arthritis anti-CCP + – Early, undifferentiated inflammatory arthritis – Distinguish RA from other RF + polyarthritis radiographic joint damage • Not useful to monitor disease activity score • Best single predictor for destructive anti-CCP - disease in patients with early onset RA RA: Etiology/Genetics Gene-environment interaction in RA: Is smoking an environmental trigger? Klareskog et al Ann Rev Immunol 26:651. 2008 Anti-CCP negative Anti-CCP positive 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 Evidence for an interaction between smoking and the shared • Most of genetic contribution from Chromosome 6: HLA DR locus epitope in risk for anti-CCP-positive RA in a European cohort • More copies of HLA risk alleles, higher risk for RA and more severe disease

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 Is rheumatoid arthritis a single Improving Outcomes in RA disease? RA #1 RA#2 • Improvement in timely and accurate diagnosis and prognosis Genetic Risk + - (HLA DR SE) • Treating to defined disease activity targets ACPA + - • Improvements in therapy (? environmental citrullination) • Issues of concern for women Erosive dz + -

RA: Chronic Joint Destruction and Joint damage in RA: Disability – What We Try to Prevent progressive narrowing and erosion of a MCP joint At presentation: 1 year 5 years normal RA: Traditional Treatment Treatment of early RA Paradigm • Effective treatment should be started when • Pyramid of therapy the diagnosis is made – Start conservatively – Gradually ascend the – “Effective treatment” = therapies shown to pyramid in order of slow joint destruction potency and toxicity of therapy • Goal is to induce and then maintain – Only the most severely remission affected patients receive immuno- – Combination of drugs more effective than supressive, DMARDs monotherapy – DMARD therapy begun only after period of significant delay