Rheumatoid Arthritis Update in Rheumatology Systemic disease - PDF document

Rheumatoid Arthritis Update in Rheumatology • Systemic disease whose predominant Selected Topics 2017: manifestation involves a chronic, inflammatory, small joint arthritis Rheumatoid Arthritis Polymyalgia Rheumatica/Giant Cell Arteritis • Affects up to 1% of the US population Jonathan Graf, MD • Female:Male predominance of 3:1 Professor of Medicine, UCSF 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: irreversible damage Early RA: The Window of can occur early in disease course Opportunity to Intervene • 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? 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 2

Limitations of 1987 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 with declining frequency • Arthritis of 3 or more joint areas • Arthritis of wrists, MCPs, and/or PIPs • For early RA, 1987 classification criteria: – Specificity: 90% • Symmetric arthritis – Limited sensitivity: 40-65% • Rheumatoid nodules • Relying on criteria to make a diagnosis of RA can lead to • Serum rheumatoid factor delayed or inappropriate diagnosis • Radiographic changes • Criteria revised in 2010 to accommodate patients with earlier disease – but not practical to use 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 3

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 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 4

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 Development of better tools to Possible culprits predict disease severity Konig et al. Science Translational Medicine 14 Dec 2016 P. Gingivalis can citrullinate proteins directly Is it possible to predict which patients require more aggressive therapy up front? Aggregatibacter actinomycetemcomitans Exo-toxin causes host neutrophils to auto-citrullinate their proteins 5

Classic (ABIM!) Predictors of Progression of joint damage in subgroups of early RA Disease Severity Huizinga et al Arthritis Research& Therapy 7: 949, 2005 • More difficult to treat, destructive, extra- anti-CCP + articular disease: – Rheumatoid factor positive radiographic joint damage – Erosive disease score – Genetic factors • HLA class II DR4 and other molecules that contain anti-CCP - “shared epitope” – Correlates with number of alleles (homozygous>heterozygous) • Not practical to genotype all patients 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 – Genetic risk: carry shared epitope SE + - – More erosive disease CCP + - – More progressive course of disease Erosive dz + - (radiographically) 6

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 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 7

Re-Thinking the RA Treatment ACR RA Practice Guidelines 2002 Pyramid • Most patients with Rheumatoid Arthritis should be evaluated expeditiously • Treatment with DMARD instituted within 3 months of diagnosis • Goals are to prevent or control joint damage, prevent loss of function, • Emphasizes earlier diagnosis and initiation of and decrease pain therapy with disease modifying anti-rheumatic drugs T ight C ontrol for R heumatoid A rthritis TICORA Patients Grigor C, Porter D, et al. Lancet 2004;364(9430):263-9. • Pre-biologic era study • Early disease (<2 years) • Randomly assigned 110 • Active disease patients to “intensive” vs. – Mean SJC 11-12 usual management – Mean CRP 38-44 mg/L • Every three months, independent blinded metrologist assessed disease activity Change in disease activity assessed at 18 months 8

What does “Intensive Therapy” Look Like? Mean Disease Activity Standard Therapy Intensive therapy • Follow up visits q 3 mo • Follow up visits q 1 mo • DMARD monotherapy used for • DMARD monotherapy used for active disease active disease • Intra-articular injections of TAC • Intrarticular injections of TAC allowed allowed • Changes or additions to • Changes or additions to therapy were made based therapy were based on formal upon gestalt disease activity (score) > moderate D isease A ctivity S core 28 Joints ACR Treatment Guidelines 2008 • Building evidence from trials like TICORA suggests better long term outcomes when treating to a defined 1. Tender Joint count target early in disease 2. Swollen Joint Count • ACR guidelines encourages regular, formal assessments of disease activity 3. Patient global disease assessment (visual analog – Similar to hemoglobin A1C for diabetes scale from 0-100mm) – Several formal disease scores available: • DAS28 4. Serum measure of • CDAI, SDAI, etc… inflammation (ESR/CRP) • Vectra-DA biomarker assay • ACR: Treat to target of mild disease activity or better 9

DAS: Treating to target Improving Outcomes in RA • DAS 28 disease activity cutoffs: • Improvement in timely and accurate diagnosis and prognosis – DAS28 <2.6 Remission – DAS28 2.6-3.2 Mild Activity • Treating to defined disease activity targets – DAS28 3.21-5.1 Moderate Activity • Improvements in therapy – DAS28 >5.1 High Disease Actiivty Families of Biologic Therapies DMARD Therapies • Anti-Tnf medications (5 total) • Methotrexate – Etanercept (TNF decoy receptor fusion protein) – Infliximab, Adalimumab, certolizumab, golimumab • Leflunomide (Arava) (variations of anti-TNF antibodies or Fab’) • Sulfasalazine • B-cell depleting agents – Rituximab • Azathioprine • T-cell costimulation inhibitors (receptor-ligand ) • Mycophenolate Mofetil – Abatacept • “Corticosteroids” • Inhibitors of Il-6 signaling • “Hydroxychloroquine” – Tocilizumab (anti Il-6 receptor antibody) • “Minocycline” • Il-1 Inhibitors (Il-1 cytokine receptor decoy) – Anakinra 10