artrite reumatoide: uma abordagem contemporânea

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Artrite Reumatoide: Uma abordagem contemporânea


  • Rheumatoid Arthritis in 2014Uzma Jalal Haque, MDAssistant Professor of MedicineDivision of RheumatologyJohns Hopkins Hospital

  • No Relevant Financial Relationships with Commercial Interests

    I will not reference an unlabeled or unapproved use of a drug or product in my presentation.Uzma Jalal HaqueTopics in clinical medicine 5/08/2014

  • ObjectivesHow Rheumatoid Arthritis (RA) in different in 2014 Diagnosis2010 diagnostic criteriaAnti-CCP antibodiesComorbidities and systemic consequences Treatment paradigms and therapeuticsFuture trajectory

  • RHEUMATOID ARTHRITISChronic Systemic inflammatory arthritis Loss of physical functionReduced Life ExpectancySystemic InvolvementLungs, eyes, nerves, nodulesSynovitisDestruction of cartilage/joints

  • Images courtesy of J. Cush, 2005.The Clinical Spectrum of RA

  • Rheumatoid Arthritis: Epidemiology and ImpactPrevalence 0.5-1%Peak incidence between 35 and 60 years of ageIncidence 2-4x greater in women than in menLeft untreated, 20% to 30% of RA patients become permanently unable to work within 3 years of diagnosis

    Associated with premature mortality 5-15 years less than non-RA populationIncreased cardiovascular mortality in RA: RR 2-4 times age- and sex-matched controls

  • PATHOGENESISRheumatoid Arthritis

  • Rheumatoid ArthritisFeldmann M, et al. Annu Rev of Immuno. 1996; 14:397-440.

  • DIAGNOSISRheumatoid Arthritis

  • A patient presents to your clinic42 year old female8 week history of joint pains in hands and feet, morning stiffness > 1 hour and fatigueJoint exam reveals R MCP 2,3 swelling, tenderness L PIP 2,3,4, L wrist swelling, L knee effusion and R ankle swelling Labs remarkable for Anti-CCP Ab 180 U, RF neg,ESR 52 mm/hr, CRP 1.5 mg/dl

  • Diagnosis of Rheumatoid Arthritis1987 Criteria

  • Additive RA Criteria 2010 ( 6)ACPA: Anti Citrullinated Peptide Antibody (e.g. anti-CCP); RF: Rheumatoid FactorAletaha D, et al, Arthritis Rheum 2010 Sep;62(9):2269-81. Designed to detect early features that predict a high likelihood of developing destructive disease

    Identify those in need of Disease Modifying Therapy

  • Your Clinic Patient. 1987 Criteria

    Hand InvolvementMorning stiffnessSwelling of 3 joints

    No erosionsNo nodulesNo RF

    3/7 criteria

    2010 Criteria

    6 small swollen joints- score 3 2 large swollen joint score 1High Titer CCP score 3Increased ESR or CRP score 1 6 weeks score 1

    Total score 8


    Rheumatoid Arthritis

  • In Your ClinicPatient with joint pain, morning stiffness in the small joints of hands and feetSingle swollen jointSend off ESR, CRP, RF and anti-CCPRefer to rheumatology

  • TREATMENTRheumatoid Arthritis

  • 1. TREAT EARLYRheumatoid Arthritis

  • Joint Damage Is Evident Early in RARadiographically evident joint damage is seenIn >67% of patients within the first 2 years1In >72% of patients within the first 5 years2Within months if sensitive MRI techniques are applied3

    Radiographic damage may progress at a more rapid rate early in disease than later in disease2,41. Pincus T, et al. J Rheumatol. 1998;41:1571-1582. 2. Wick MC, et al. Scand J Rheumatol. 2004;33:162-166.3. Mc Queen FM et al. Ann Rheum Dis 2001;60:859-8684. Welsing PM, et al. Arthritis Rheum. 2004;50:2082-2093.

  • Turning Back the RA Treatment ClockLaterEarly

  • NSAIDSSteroidsHydroxychloroquineSulfasalazineMethotrexate (lower dose)Initial RxThe Old RA Treatment PyramidStart Low and Go Slow(Gold)

  • DMARDSDisease-modifying anti-rheumatic drugsDrugs that suppress inflammation slow joint destructionImprove long term disability

  • 2. TREAT-TO-TARGETRheumatoid Arthritis

  • What is the treatment target?To achieveLow disease activity ORRemission

    To suppress inflammation, control disease, prevent joint damage, disability

  • How is the target defined?Several validated measures of disease activityCommonly used in clinical practiceWell defined cut-off pointsCDAI Clinical disease activity indexSDAI simple disease activity indexDAS disease activity score

  • TICORA = Tight Control for Rheumatoid ArthritisTSS = total Sharp score. Grigor C, et al. Lancet. 2004;364:263-269.Therapy Decisions Based on Measurement Are Superior to Gestalt: TICORA StudySingle-blind, 18-month, controlled trial, including 110 patients with RA
  • 3. Adjust Therapy if Target not met

    After starting a DMARD, if patient does not meet the target : low disease activity state or remissionAdjust / Escalate treatment

    till target is achieved


  • Rheumatoid Arthritis Therapy Leave the Pyramids in Egypt!Traditional DMARDsMethotrexateSulfasalazineLeflunomide

    What are NOT DMARDS:NSAIDS, Prednisone* hydroxychloroquine**adjunctive but not as monotherapyCombined with DMARDsBiologic therapiesTNF antagonistsAdalimumabEtanerceptInfliximabCertolizumab pegol*Golimumab*IL-1 antagonistAnakinraCostimulation modulationAbataceptB cell depletionRituximabIL-6 antagonistTocilizumabJAK inhibitorTofacitinib

    *Investigational agents

  • ABATACEPTPathogenesis & Targets of Approved RA TherapyMImmune complexesComplement fixationAttract inflammatory cell infiltratesIL-2IFNTNFIL-17RANKLPannusArticularcartilageTNF, IL-1, IL-6,MetalloproteinasesIL-4 IL-6 IL-10IL-6, TNF,IFN, IL-10, LymphotoxinAdapted from 1. Smolen JS et al. Nat Rev Drug Discov. 2003. 2. Choy EH et al N Engl J Med. 2001, 3. Silverman GJ et al Arthritis Res Ther 2003Antigen-presentingcells (APC)

    Production of metalloproteinases and other effector moleculesMigration of polymorphonuclear cellsErosion of bone and cartilageRF and anti-CCP antibodiesAPCRITUXIMABTNF INHIBITORSIL-1 INHIBITOR

  • In our ClinicEach VisitHistory joint pain, minutes of morning stiffness, medication toxicityCo-morbidityExamination assess joints for tenderness and swellingJoint scorePatient FormsPatient global assessment Pain assessmentAssessment of disabilityPhysician global assessment

  • In Our Clinic .each visitAssess disease activity calculating a score usually CDAI [TJC28 + SJC28 + (Patient GA VAS 10) + (Physician GA VAS 10)]High > 22Moderate > 10 - < 22Low < 10Remission < 2.8----- > Adjust DMARD if indicated------------ > Assess DMARD toxicity----------------- > Assess co-morbidity


  • Treatment Broad StrategiesInitiate therapy with ONE non-biologic DMARD (monotherapy)e.g., Methotrexate or LeflunomideIf target not met in 3 months, ADD another DMARD (combination therapy) dual therapyMTX + hydroxychloroquine (HCQ)MTX + Sulfasalazine (SSZ)Triple therapyMTX + SSZ + HCQLeflunomide + SSZ + HCQ

  • Treatment- Broad StrategiesMTX monotherapy achieves LDA/remission in 30% of patients with RACombination therapy more effective than monotherapyRole of Steroids in RAinitially to control disease as DMARDs take time to be effectivetreat flaresAvoid long term use

  • Treatment Broad StrategiesIf traditional DMARD combination does not achieve target or not toleratedAdd a biologic to a non-biologic DMARDAnti-TNF therapy typically first biologic usedAfter that, no particular order recommendedDriven by physician experience and insurance approval and toxicity profile

  • Assess disease activity in 3 monthsTreatment Algorithm for Rheumatoid ArthritisStart a DMARDAssess disease activity in 3 monthsAssess target (LDA or remission)Increase doseAdd DMARDSwitch DMARDContinue treatmentReassess in 3 monthsReassess in 3 to 6 monthsYesNo

  • At 5 yrs, 48% remission DAS < 1.614% in DFR

  • In Clinic Treatment Broad conceptsMTX is standard initial /anchoring therapy efficacy as monotherapylong term safety profile/well tolerateddose 15-25 mg/week add folic acid 1 mg daily to reduce side effectslow incidence of side effectsAdverse events: GI intolerance Headache fatigue - Alopecia Oral ulcers LFTs Anemia cytopenia - teratogenicity

    * May respond to switch to SQ administration# May respond to increased folate or folinic acid (Leukovorin) 5 mg 12-24 hr after MTX

  • Safety Concerns with TNF AntagonistsInjection/Infusion reactionsInfectious complications (low threshold for Abx)Serious bacterial infections (hold agent until infection resolves)Tuberculosis ( reactivation of latent TB, often systemic)Opportunistic (coccidiomycosis, histoplasmosis)Other potential safety concernsAvoid all live vaccinesNonmelanoma skin cancerincreased in several national registriesCongestive heart failureLymphoma (?) latest data shows no increase in risk above expected for RALupus-like syndromeDemyelinating diseaseCytopeniaOlsen and Stein. N Engl J Med. 2004;350:2167.

  • Screening and Evaluation for TB with TNF antagonistsIdeally perform PPD before steroids and other immunomodulatory therapyHistory suggestive of high TB risk exposure critical5 mm induration is considered positive in RAQuantiferon/TB-SPOT useful in detecting latent exposurePPD should be repeated every 1-2 years, or if travel to endemic areas, exposure, or high riskPatients with +PPD and negative CXR can have reactivationRisk reduced with INH initiation with/before TNF antagonistGreenberg JD, Reddy SM, Schloss SG, Kurucz OS, Bartlett SJ, Abramson SB, Bingham CO. J Rheumatol. 2008:35:770-5. ; Saag K, et al, Arthritis Rheum (Arthritis Care and Research) 2008; 59:76284.

  • Safety Concerns with AbataceptInfection risk increased Higher in patients with COPDThough very few cases of TB have been seen, screening is recommended No clear increase in malignancies except lung cancer


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