Advances In Rheumatoid Arthritis 2020: Diagnosis, Assessment, And Novel .
Advances in Rheumatoid Arthritis2020: Diagnosis, Assessment, andNovel Oral therapiesJonathan Graf, M.D.Professor of Medicine, UCSFDivision of Rheumatology, ZSFGHDirector, UCSF RA Cohort
Rheumatoid Arthritis Systemic disease whose predominantmanifestation involves a chronic, inflammatory,small joint arthritis Affects up to 1% of the US population Female:Male predominance of 3:1 Peak incidence: patients in their 30’s-40’s butcan occur at any stage of life
Clinical features of RA Most often insidioussubacute onset Small joint, symmetricinflammatory polyarthritisof diarthrodial joints Morning stiffness (hours)prevalent Improves with activity,worse with inactivity(gelling phenomenon) Joint swelling, joint pain arecommon
RA: Clinical features RA is a chronic andprogressive disease Chronic diseaseprogression leads topermanent jointdeformity,destruction, anddisability
Rheumatoid Arthritis: morbidity Disease associated withsignificant morbidity Disability costs are high, both interms of direct and indirectmedical costs– 35% of patients with 10 yearsdisease duration are workdisabledArthritis Rheum. 2008 Mar27;59(4):474-480 Significant increase in mortality(SMR 1.4)– Surprisingly consistent over 20years of improved therapyHumphreys et al. AC&R 2014
Improving Outcomes in RA Improvement in timely and accuratediagnosis and prognosis Treating to defined disease activity targets Improvements in therapy
Improving Outcomes in RA Improvement in timely and accuratediagnosis and prognosis Treating to defined disease activity targets Improvements in therapy
Early RA: The Window ofOpportunity to Intervene
The Window of OpportunityEventually Closes for Many . Chronic diseaseprogression leads topermanent jointdeformity, destruction,and disability Empirically, RA is adifferent disease thelonger disease activityprogresses withouteffective control– More difficult to suppressactivity and treat– More extra-articulardisease?
Rheumatoid arthritis: irreversible damagecan occur early in disease course1 year prior toonset of RA6 months afteronset of symptoms3 years after onsetof symptomsRadiographic changes in the same joint over time
ACR Criteria for the Classification ofRheumatoid Arthritis 1987( 4 criteria required; 1-4 must be present 6 wks) Morning stiffness 1 hrArthritis of 3 or more joint areasArthritis of wrists, MCPs, and/or PIPsSymmetric arthritisRheumatoid nodulesSerum rheumatoid factorRadiographic changes
Limitations of ACR ClassificationCriteria for the diagnosis of early RA Developed for the classification of patients withlongstanding disease (for clinical studies, not diagnosis)– Many of these features (rheumatoid nodules, for ex) are seenwith declining frequency For early RA, 1987 classification criteria:– Specificity: 90%– Limited sensitivity: 40-65% Relying on criteria to make a diagnosis of RA can lead todelayed or inappropriate diagnosis
ACR/Eular Classification Criteria 2010 Joint US-European effort to classify patientswith earlier disease for research Lacks many of descriptive features of 1987criteria Not as practical for clinical practice: relies onscoring system and algorithms
2010 ACR/EULARClassification Criteria for RAJOINT DISTRIBUTION (0‐5) 6 definite RA1 large joint02‐10 large joints11‐3 small joints (large joints not counted)24‐10 small joints (large joints not counted)3 10 joints (at least one small joint)5What if the score is 6?Negative RF AND negative ACPA0Patient might fulfill the criteria Low positive RF OR low positive ACPA2High positive RF OR high positive ACPA3SEROLOGY (0‐3)SYMPTOM DURATION (0‐1) 6 weeks0 6 weeks1ACUTE PHASE REACTANTS (0‐1)Normal CRP AND normal ESR0Abnormal CRP OR abnormal ESR1 Prospectively over time(cumulatively) Retrospectively if data on allfour domains have beenadequately recorded in the past
START 10 joints (at leastone small joint)(eligible patient)Rheumatoid arthritisNoNo classification of rheumatoid arthritisYes4-10 small jointsNoSerology: / YesSerology: 1-3 small jointsNoYesDuration: 6 weeksNoSerology: NoDuration: 6 weeksSerology: YesSerology: YesNoSerology: NoNoNoYesDuration: 6 weeksAPR:AbnormalNoDuration: 6 weeksDuration: 6 weeksYesNo YesNoNo sYes2-10 large(no small) jointsNoNoYesRANoRAAPR:AbnormalNoYesRARAYesRARARA
START 10 joints (at leastone small joint)(eligible patient)Rheumatoid arthritisNoNo classification of rheumatoid arthritisYes4-10 small jointsNoSerology: / YesSerology: 1-3 small jointsNoYesDuration: 6 weeksNoSerology: NoDuration: 6 weeksSerology: YesSerology: YesNoSerology: NoNoNoYesDuration: 6 weeksAPR:AbnormalNoDuration: 6 weeksDuration: 6 weeksYesNo YesNoNo sYes2-10 large(no small) jointsNoNoYesRANoRAAPR:AbnormalNoYesRARAYesRARARA
Diagnosis of early RA by 1987 ACR criteriavan Gaalen et al Arth Rheum 50: 709, 2004936 patients with early inflammatory arthritisInitial evaluationAfter 3 years205 RA by ACRcriteria936318 “undifferentiatedarthritis”413 other diagnoses127 RA
Factors predictive of progressionfrom undifferentiated arthritis to RAvan Gaalen et al Arth Rheum 50: 709, 2004At initial evaluationOR (95% CI)Positive rheumatoid factor1.7 (0.5-5.6)Positive anti-CCP antibody38.6 (9.9-151.0)
Posttranslational modification of proteins:PADI converts arginine to citrulline
RA-associated autoantibodies thatrecognize peptides containing citrullineGirbal-Neuhauser et al J Immunol 162: 585, 1999Peptide sequenceESSRDGSRHPRSHDAntibody recognitionNoPADIESSRDGScitHPRSHDYesActual citrullinated antigen(s) targeted in RA is/are not known
Antibodies to citrullinated peptidesin RA Detected by ELISAs using synthetic cycliccitrullinated peptides (CCP) Sensitivity for very early RA: 50% Sensitivity for early-later RA: 70-80% Specificity for RA: 95-98%
Preclinical autoimmunity in RA:appearance of anti-CCP abs andRF prior to onset of arthritisNielen et al Arth Rheum 50: 380, 2004
RF and anti-CCP testing in a cohortof 182 early RA patientsQuinn et al Rheumatology (Oxford) 45:478, 2006RF-CCP-RF-CCP RF CCP-RF CCP
Progression of joint damage insubgroups of early RAHuizinga et al Arthritis Research& Therapy 7: 949, 2005anti-CCP radiographicjoint damagescoreanti-CCP-
Summary: Clinical utility of the antiCCP 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 destructivedisease in patients with early onset RA
RA: Etiology/GeneticsManhattan plot from a genome-wide association study of RACriswell, LA Immunological Reviews 233: 55, 2010 15‐20% concordance in monozygotic twinsRA: 60% heritable contributionMost of genetic contribution from Chromosome 6: HLA DR locusMore copies of HLA risk alleles, higher risk for RA and more severe disease
Gene-environment interaction in RA: Is smokingan environmental trigger?Klareskog et al Ann Rev Immunol 26:651. 2008Anti-CCP positiveAnti-CCP negativeEvidence for an interaction between smoking and the sharedepitope in risk for anti-CCP-positive RA in a European cohort
Periodontitis and the link to RA
Possible culpritsKonig et al. Science Translational Medicine 14 Dec 2016P. Gingivalis cancitrullinate proteins directlyAggregatibacter actinomycetemcomitansExo-toxin causes host neutrophils toauto-citrullinate their proteins
Is rheumatoid arthritis a singledisease?Genetic RiskRA #1RA#2 - - -(HLA DR SE)ACPA(? environmentalcitrullination)Erosive dz
Improving Outcomes in RA Improvement in timely and accuratediagnosis and prognosis Treating to defined disease activity targets Improvements in therapy
RA: Chronic Joint Destruction andDisability – What We Try to Prevent
Joint damage in RA:progressive narrowing and erosion of a MCP jointAt presentation:normal1 year5 years
Treatment of early RA Effective treatment should be started whenthe diagnosis is made– “Effective treatment” therapies shown toslow joint destruction Goal is to induce and then maintainremission– Combination of drugs more effective thanmonotherapy
RA: Traditional TreatmentParadigm Pyramid of therapy– Start conservatively– Gradually ascend thepyramid in order ofpotency and toxicity oftherapy– Only the most severelyaffected patientsreceive immunosupressive, DMARDs– DMARD therapy begunonly after period ofsignificant delay
Re-Thinking the RA TreatmentPyramid Emphasizes earlier diagnosis and initiation oftherapy with disease modifying anti-rheumaticdrugs
ACR RA Practice Guidelines 2002 Most patients withRheumatoid Arthritisshould be evaluatedexpeditiously Treatment with DMARDinstituted within 3 monthsof diagnosis Goals are to prevent orcontrol joint damage,prevent loss of function,and decrease pain
Tight Control for Rheumatoid ArthritisGrigor C, Porter D, et al. Lancet 2004;364(9430):263-9. Pre-biologic era study Randomly assigned 110patients to “intensive” vs.usual management Every three months,independent blindedmetrologist assesseddisease activityChange in disease activity assessed at 18 months
TICORA Patients Early disease ( 2 years) Active disease– Mean SJC 11-12– Mean CRP 38-44 mg/L
What does “Intensive Therapy” Look Like?Standard TherapyIntensive therapy Follow up visits q 3 mo Follow up visits q 1 mo DMARD monotherapy used foractive disease DMARD monotherapy used foractive disease Intra-articular injections of TACallowed Intrarticular injections of TACallowed Changes or additions totherapy were made basedupon gestalt Changes or additions totherapy were based on formaldisease activity (score) moderate
Mean Disease Activity
ACR Treatment Guidelines 2008 Building evidence from trials like TICORA suggestsbetter long term outcomes when treating to a definedtarget early in disease ACR guidelines encourages regular, formal assessmentsof disease activity– Similar to hemoglobin A1C for diabetes– Several formal disease scores available: DAS28 CDAI, SDAI, etc Vectra-DA biomarker assay ACR: Treat to target of mild disease activity or better
Disease Activity Score 28 Joints1.Tender Joint count2.Swollen Joint Count3.Patient global diseaseassessment (visual analogscale from 0-100mm)4.Serum measure ofinflammation (ESR/CRP)
DAS: Treating to target DAS 28 disease activity cutoffs:– DAS28 2.6Remission– DAS28 2.6-3.2Mild Activity– DAS28 3.21-5.1Moderate Activity– DAS28 5.1High Disease Actiivty
Improving Outcomes in RA Improvement in timely and accuratediagnosis and prognosis Treating to defined disease activity targets Improvements in therapy
DMARD Therapies MethotrexateLeflunomide (Arava)SulfasalazineAzathioprineMycophenolate ��“Minocycline”
RA: Targeted Therapy Approach Start with traditional DMARD Check to see if low disease activity or better hasbeen attained Advance therapy (dose), switch from oral to SQMTX, or add combination Good data that combination DMARDs orcombination DMARD biologic both effective(TEAR trial & CSP 551 RACAT trial)
Families of Biologic Therapies for RA Anti-TNF medications– Etanercept (TNF decoy receptor fusion protein)– Infliximab, Adalimumab, certolizumab, golimumab(variations of anti-TNF antibodies or Fab’)– Biosimilar drugs (infliximab-dyyb) B-cell depleting agents– Rituximab T-cell costimulation inhibitors (receptor-ligand )– Abatacept Inhibitors of Il-6 signaling– Tocilizumab (anti IL6 receptor antibody)– Sarilumab (anti IL6 receptor antibody)
Why Move Towards Combination Regimenswith Biologics? Klareskog L. et al. TEMPO Lancet 2004
The Current Pyramid Paradigm Early initiation and titration of DMARD If incomplete response to DMARD alone, after reasonabletitration, addition of combination therapy recommended
“Doc, can I ever stop my RA medicines?”OPTIMA 2014Smolen J et al. Lancet. 2014.PRIZE 2014Emery P, et al. N Eng J Med. 2014 Short answer: probably no for most patients Long answer: Possibly, for a few lucky patients with RA Longer answer: A significant percentage of RA patients may be able tosuccessfully taper their medicines
Tapering or discontinuing antiTNF therapyEmery P, et al. N Eng J Med. 2014 Nov 6;371(19):1781-92 PRIZE study of early upfrontetanercept MTX followed by taper Those who achieved low dz activity(DAS 3.2) at wk 39 and remission atwk 52 (open label phase) enteredrandomized double blinded phase 1:1:1 tapered etanercept (1/2 dose) MTX, PBO MTX, or double PBO Those with DAS 3.2 at wk 39 had alldrug withdrawn through wk 65
PRIZE Results:Emery P, et al. N Eng J Med. 2014 Nov 6;371(19):1781-92 Tapering anti-TNF works for some. Sustained remission off therapy achievable in small percentage
Oral Small Molecule Inhibitors: ? Newwave of RA therapy Not proteins but are small molecules Taken orally and can act intracellularly “Biologic‐like” effects by blocking downstream eventsinitiated by cytokine‐receptor engagement Emerging term: “Biologic response modifiers”– Not organic, complex macromolecules but have similar effectsto biological molecules First class of kinase inhibitors for RA: JAK inhibitors– JAK 1, JAK 2, JAK 3, TYK 2
Cytokine Signaling through KinasesCytokine:eg. TNF/IL6Current Biologic TherapiesKinasesTranscriptionBiologic Effect:ProliferationActivationCytokine production
Cytokine Signaling through KinasesCytokine:eg. TNF/IL6Current Biologic TherapiesKinasesNew Kinase Inhibitors
Overview of cytokine signaling through Jakand selective inhibition by JAKi’s Pan selective JAKi’shave advantage ofknocking downmultiple cytokinepathways vs moreselctive JAKi’s orsingle anti-cytokinetherapy (eg. AntiTNF) Also come with riskof inhibitingimportantconstituitivefunctions (JAK2 andhematopoesis)Schwartz, O’Shea et al. Nat Rev Drug Discov. 2017 Dec;16(12):843-862.
Pipeline of Oral Small MoleculeInhibitors Tofacitinib (PAN JAKi: JAK 1/3 2 kinase inhibitor)– Rheumatoid Arthritis (FDA approved 2012; Failed twice to get approval inEurope until 2017)– Now also approved for psoriatic arthritis and ulcerative colitis (2018)– Potential future indications: psoriasis, atopic dermatitis, and alopecia areata Baricitinib (Pan JAKi: JAK 1/2 kinase inhibitor) FDA approved for RA 2018* Upadacitinib (more JAK 1 selective inhibitor) FDA approved 2019In development– Filgotinib (JAK 1 selective: approval expected in 2020)
40% of MTX naïvepatients with activeRA achieved a 70%response onTofacitinib 10 mg vs.10% on MTX. Predictable adverseevents similar to anti‐iL6 therapy––Lee EB et al. N Engl J Med 2014;370:2377‐2386.Liver, neutropenia,lipids, infections, etc.Caution that JAKsignaling morewidespread than forIL6 alone
Baricitnib: RABEACONGenovese et al. NEJM 2016Active RA refractory to conventional DMARDs and biological DMARDs
Baricitinib: RA-BEAMTaylor et al. NEJM 2017Active RA despite MTX: Comparing Baricitinib to Adalimumab and
Baricitinib: A cautionary taleFDA approval blocked 2017
Baricitinib: Analysis of VTE/PEeventsScott et al. Drug Safety July 2018, Volume 41, Issue 7, pp 645–6536/997 patients 4 mg @24 wkvs. 0 PBO/2 mg @ 24 wkTaylor et al. Arth & Rheum 2019 in press
FDA approves amendedapplication for Baricitinib 2018 FDA originally required new clinical safetytrial but changed its mind and acceptedamended application with additionalsecondary analyses of existing clinical trialdata Black box warning for serious infectionsand VTE/PE risk Only 2 mg (low dose) approved in US. 2 &4 mg doses already approved in Europesince 2017 and safety surveillance ongoing Based upon additional data: Baricitinibshould be used with caution in patients withrisk factors for DVT/PE :– older age, obesity, a medical history ofthrombosis, hypercoagulable state, recentsurgery or immobilization
Brighter Future for Patients with RA
EXTRA SLIDES
longstanding disease (for clinical studies, not diagnosis) - Many of these features (rheumatoid nodules, for ex) are seen with declining frequency For early RA, 1987 classification criteria: - Specificity: 90% - Limited sensitivity: 40-65% Relying on criteria to make a diagnosis of RA can lead to delayed or inappropriate diagnosis
What is rheumatoid arthritis? Rheumatoid arthritis is a type of arthritis where your immune system mistakenly targets your own body. It especially affects the lining of the joints between your bones. Early symptoms include swelling, heat, tenderness, pain or stiffness in your joints. Rheumatoid arthritis (RA) can occur at any age and is the second
The pathogenic role of rheumatoid factor in rheumatoid arthritis The first autoantibody in rheumatoid arthritis (RA), rheumatoid factor (RF), was described by Waaler in 1940, who reported the hemag glutinating activity of a serum from a patient with RA [1]. RFs were named by Pike in 1949 due to their association with RA [2] and were
the diagnosis of early Rheumatoid Arthritis. Rheumatoid factors (RFs) are antibodies specific enough to be used as diagnostic and prognostic markers of rheumatoid arthritis (RA). They often appear many years before the onset of clinical RA. Rheumatoid factors are antibodies directed against the Fc portion of IgG. Rheumatoid factors (RF) are .
matoid arthritis afflicts approximately three times more women than men. Certainly, of all forms of arthritis, rheumatoid arthritis is the most crippling. It is this subtype of dis-order which will be the concern in this paper. Although the term "rheumatoid arthritis" was first used in the middle of the nineteenth century, a detailed descrip-
Rheumatoid Arthritis Diagnosis and Management Lydia Gedmintas, MD, MPH Associate Physician Division of Rheumatology, Department of Medicine . Sparks JA, et al. Rheumatoid arthritis and mortaliyt among women during 36 years of oprospective follow-up: results from the Nurses' Health Study. Arthritis Care Res (Hoboken), 2016: 68(6): 753-62.
Rheumatoid arthritis affects different people in different ways. In some cases, the disease may disappear, or may come and go ('flare') for many years. For other people, the symptoms and disability may slowly worsen over time. If left untreated, rheumatoid arthritis may lead to damage to joints that cannot be repaired. Other parts
Each benefit program defines which services are covered. The conclusion that a particular service or supply is medically . M05.279 Rheumatoid vasculitis with rheumatoid arthritis of unspecified ankle and foot M05.29 Rheumatoid vasculitis with rheumatoid arthritis of multiple sites . Orencia (abatacept) Last review: January 1, 2020
What Is Rheumatoid Arthritis? Rheumatoid arthritis, or RA, is a chronic (long-term) disease that causes inflammation of the joints and other tissues. Joints become stiff, swollen and painful. If the inflammation is not controlled, it can damage joints and organs. That's why it's important to get prompt diagnosis and proper treatment of RA.
