Dr. I Nyoman Suarjana, SpPD-KRSMF Ilmu Penyakit DalamRSUD Ulin/FK UNLAMRHEUMATOID ARTHRITIS(RA)

Pre testLaboratory examination to support diagnosis of RA is follows, except :C-reactive proteinRheumatoid factorAnticyclic citrullinated peptide antibody (anti-CCP)Anti-RA 33Anti-ds DNA

Pre testIf diagnosis of RA was established, the basic therapy must be given immediately :SteroideNon steroide antiinflammatory drugs (NSAIDs)Disease modifying antirheumatic drugs (DMARDs)CalciumPhysioterapy

IntroductionRA is a common chronic inflammatory joint conditionmultifactorial aetiologyvariable course with exacerbations and remissions of activityinflammation leads to joint damage (erosions)can result in severe disability

Rheumatoid Arthritis: DefinitionProgressive, systemic, inflammatory disorderUnknown etiologyCharacterized by Symmetric synovitisJoint erosionsMultisystem extra-articular manifestations

The Importance of Early DiagnosisRA is progressive, not benignStructural damage/disability occurs within first 2 to 3 years of diseaseSlower progression of disease linked to early treatment

HistoryRheumatoid first used in 1859 by Garrod Little evidence for RA prior to 16th CenturyPossibly earlier in New WorldIn contrast to OA and Gout

EpidemiologyIncidence1.4/10000 male, 3.6/10000 femalesPrevalence 0.5-2 %male:female 1:3Worldwide distributionhigher in native Americansabsent in some parts of AfricaOnset any age but maximum40 - 70 years in women60 - 70 years in men

Etiology of Rheumatoid ArthritisAutoimmunity Normal antibodies become autoantibodies and attack the tissue. Infectious agents Genetic FactorGender Female : Male ( 2:1- 4:1) Endocrine (CRH, estrogen synthase)Stressful eventsSmoking

Possible Infectious Causes of RAInfectious Agent Potential Pathogenic MechanismMycoplasma Direct synovial infection, superantigensParvovirus B19 Direct synovial infectionRetroviruses Direct synovial infectionEnteric bacteria Molecular mimicry (QKRAA)Mycobacteria Molecular mimicry (QKRAA, proteoglyc.) Immunostimulatory DNAEBV Molecular mimicry (QKRAA)Bacterial cells wall Macrophage activation

Q = glutamine, K = leucine, R = arginine, A = alanineHLA-DR4 amino acids sequence 70 - 74

Potential Autoantigens in RACartilage antigens Type II collagen, gp39, Cartilage link protein, Proteoglycans, AgrecanCitrullinated peptidesGlucose-6-phosphoisomeraseHLA-DR (QKRAA)Heat-shock proteinsHeavy-chain binding protein (BiP)hnRNP-A2Immunoglobulin (IgG)

Genetic factorsSmall increased risk in siblingsMonozygotic twins15% concordanceDizygotic twins4% concordanceHLA DR4

Clinical featuresSymmetrical deforming polyarthritisaffects synovial lining of joints, bursae and tendonsmore then just joint diseasePresentationVariableGradual or acute/subacutePalindromicMonoarticularSymmetrical, diffuse small joint involvement

RA Is Characterised by Synovitis and Joint DestructionNORMALRASynovial membraneCartilageCapsuleSynovial fluidInflamed synovial membranePannusMajor cell types:T lymphocytesmacrophagesMinor cell types:fibroblastsplasma cellsendotheliumdendritic cellsMajor cell type:neutrophilsAdapted from Feldmann M, et al. Annu Rev Immunol. 1996;14:397-440.Cartilage thinning

Progression of joint involvementSpread occurs within months to years to other jointsAlmost any joint may be involvedSpontaneous remission can occur (after acute onset)Poor prognosis factors existSymptomsOf inflammationstiffness, pain, swelling, warmth, redness

Pattern of joint involvementsymmetricalsmall joints of hands - DIP sparedcharacteristic featuresBoutonniereSwan neckZ thumbVolar subluxationUlnar deviation

Functional impairmentrelated to underlying disease activity and joint damage due to previous activity

Extra articular diseasenoduleseyelungkidneyvasculitisnervesFeltys

InvestigationsHaematologyHb, wcc, plts, ESRBiochemistryU+E, LFT, CRPImmunologyRhF, ANAMicrobiologyviral titresRadiologyXR, bone scan, MRI

Differential diagnosisPost viral (parvo, rubella)Reactive arthritisSLEPolyarticular GoutPolyarticular OA

ACR 1987 Criteria for DiagnosisFour or more of the following criteria must be present:Morning stiffness > 1 hourArthritis of > 3 joint areasArthritis of hand joints (MCPs, PIPs, wrists)Symmetric swelling (arthritis)Serum rheumatoid factorRheumatoid nodulesRadiographic changesFirst four criteria must be present for 6 weeks or more

ManagementEducationPhysical therapiesDrugsanalgesicsNSAIDsDMARDsImmunotherapiesSteroids ia, po, im, ivSurgery

Rheumatoid Arthritis:Treatment PrinciplesConfirm the diagnosisDetermine where the patient stands in the spectrum of disease When damage begins early, start aggressive treatment early Use the safest treatment plan that matches the aggressiveness of the diseaseMonitor treatment for adverse effectsMonitor disease activity, revise Rx as needed

Goals of TherapyControl disease activityAlleviate painMaintain function for essential daily activitiesMaximize quality of lifeSlow progression/rate of joint damage

Non-Pharmacological Management of Rheumatoid ArthritisRestExerciseFlexibility/stretchingMuscle conditioningCardiovascular/aerobicDiet/weight controlPhysical/occupational therapy

Pharmacological treatment of RA can bedivided into :

Disease-modifying antirheumatic drugs (DMARDs) Anti-inflammatory agents Analgesics

Anti-inflammatory agents and analgesicsAnti-inflammatory agents include:Glucocorticoids Non-steroidal anti-inflammatory drugs (NSAIDs, most also act as analgesics)

Analgesics include:Acetaminophen Opiates Diproqualone Lidocaine topical

DMARDs can be further subdivided into : - Traditional small molecular mass drugs synthesised chemically - Newer 'biological' agents produced through genetic engineering.

Traditional small molecular mass drugs:Azathioprin Ciclosporin (cyclosporine A) D-penicillamineGold saltHydroxychloroquine LeflunomideMethotrexate (MTX) Minocycline Sulfasalazine (SSZ)

Tumor necrosis factor (TNF) blockers : etanercept (Enbrel), infiximab (Remicade), adalimumab (Humira), Certolizumab pegol (Cimzia)sc (CDP-870)Anti-B cell (CD20) antibody : rituximab (Rituxan, MabThera), OcrelizumabInterleukin-1 blockers : anakinra (Kineret) Blockers of T cell activation (costimulation blockers) : abatacept (Orencia)Anti-Blys antibody : BelimumabAnti-IL-6 receptor MAb : Tocilizumab (ActemraTM)Protein tyrosine kinase inhibitor : Imatinib (Gleevec)CPH82 (influences the cell cycle & cell proliferation) : Reumacon

Biological agents :

Combination therapy is well tolerated and associated with no significant increase in the rate of adverse events compared with monotherapy.

Methotrexate-sulfasalazine, Methotrexate-chloroquine, Methotrexate- ciclosporin, Methotrexate-leflunomide, Methotrexate-intramuscular-gold Methotrexate-doxycycline are effective combination regimens.

Nat Clin Pract Rheumatol.2007; 3(8):450-458.

Triple DMARD therapy is better than various DMARD monotherapy and dual therapy regimens. Methotrexate and hydroxychloroquine may have synergistic anti-inflammatory properties. Clinical trial evidence to support the use of other methotrexate and sulfasalazine combinations is often weak or lacking. Nat Clin Pract Rheumatol.2007; 3(8):450-458.

Disease-Modifying antirheumatic Drugs (DMARDs)Drug Mechanisms Common Usual of action adverse effects Dosing regimensInjectable gold Inhibits: macorphg, Mucocutan.eruptions 50 mg/wk i.m to total Aurothioglucose angiogenesis,prot. Proteinuria dose of 1000 mg then Gold sodium kinase C Thrombocytopenia 50 mg i.m q 2-4 wk thiomalateOral gold Inhibits: macrophg, Diarrhea, Mucocutan. 3 mg p.o.b.i.d Auranofin PMN function eruptionsAntimalarials Hydroxychlorqn Inhibits: cytokine Diarrhea, mucocutan. 400 mg p.o.,q.d Chlorqn phosphat secretion,lysoso- eruptions 250 mg p.o.,q.d mal enzymes, ma crophg.functionD-Penicillamine Inhibits: helper T Mucocutan.eruptions 500-1000 mg p.o.,q.d cell function, angio Proteinuria genesis Thrombocytopenia

Disease-Modifying antirheumatic Drugs (DMARDs)Drug Mechanisms Common Usual of action adverse effects Dosing regimensSulfasalazine Inhibits: B cell Nausea, abd.pain, 1000 mg p.o.,b.i.d responses, angio- diarrhea, rash or t.i.d genesisMethotrexate Dihydrofolate Mucocutan.eruptions 7.5-25 mg/wk p.o. reductase inhibitor, Bone marrow (may also be admi- Antiinflammatory via Nausea, diarrhea, nistered parente- induction of adeno- Hepatic abnormalities rally SC or IM) sine release,inhibits chemotaxisLeflunomide Inhibits pyrimidine Hepatic abnorm. 20 mg/day p.o. synthesis Diarrhea,nausea (initial loading dose of 100 mg/day for 3 days

Disease-Modifying antirheumatic Drugs (DMARDs)Drug Mechanisms Common Usual of action adverse effects Dosing regimensAnakinra IL-1 receptor Injection site 100 mg s.c. antagonist reactions, injection daily Infections Adalimumab TNF antibody Injection site 40 mg s.c. inj. (human) reaction, q. 14 days Opportunistic infectionsInfiximab TNF antibody Infusion reactions 3 mg/kg i.v. slow (chimeric) Opportunistic infusion wk 0,2,6, infection then every 8 wk Etanercept Soluble TNF Injection site 25 mg s.c. inj. receptor reactions twice weekly or Opportunistic 50 mg/wk s.c. infections

Disease-Modifying antirheumatic Drugs (DMARDs)Drug Mechanisms Common Usual of action adverse effects Dosing regimensCyclosporine Inhibits: synthesis Hypertension 2.5-4 mg/kg p.o. of IL-2 & other T Renal insuff. q.d. cell cytokines HirsutismAzathioprine Inhibits DNA Bone marrow 1-2 mg/kg p.o,q.d synthesis supprression Mycophenolate Inhibits lymphocyte GI, leukopenia 1.0-1.5 g p.o,b.i.dMofetil proliferation nausea,hepatic abnormalities Cyclophos- Crosslinks DNA Nausea, emesis 1-2 mg/kg p.o,q.dphamide & inhibits cellular Bone marrow proliferation suppression Ovarian failure Hemorrhagic cystitis risk of cancer

Disease-Modifying antirheumatic Drugs (DMARDs)Drug Mechanisms Common Usual of action adverse effects Dosing regimensMinocycline Inhibits biosyn- Diarrhea,nausea 100 mg p.o, b.i.d thesis & activity Photosensitivity of MMPsRituximab Anti-CD20 mono- Hypotension 1 g IV q.14 days clonal antibody Hypertension (chimeric) RA exacerb.

STEM CELL THERAPYHematopoietic stem cells may be beneficial as a treatment for rheumatoid arthritis Bingham SJ, Moore JJ. Stem cell transplantation for autoimmune disorders. Rheumatoid arthritis. Best Pract Res Clin Haematol 2004; 17(2): 263-76.

Hematopoietic stem cell transplantation is being investigated as a treatment for patients with severe refractory rheumatoid arthritis that is unresponsive to conventional therapies. The stem cells are well tolerated in patients with rheumatoid arthritis. The authors review the research and suggest future protocols for treatments.

PrognosisLife expectancy reduced by7 years in men3 years in womenSevere morbiditysudden onset do better than gradualearly knee involvement badBad RA has a worse prognosis than IHD or Hodgkins

Risk Factors for Increased Morbidity and Mortality in RASocial factorsLow socioeconomic statusLack of formal educationPsychosocial stressLow HAQ scoresPhysical factorsExtra-articular manifestationsElevated CRP and ESRHigh titers of RFErosions on x-rayDuration of disease

Rheumatoid Arthritis: Treatment Plan SummaryA variety of treatment options are availableTreatment plan should matchThe current disease activity The documented and anticipated pace of joint destructionConsider a rheumatology consult to help design a treatment plan

************Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease, characterised by synovitis and joint destruction,1 and often results in significant disability and premature mortality.2 The pathogenesis of this chronic autoimmune disease is mediated by an interdependent network of cytokines, prostanoids, and proteolytic enzymes.3 Cytokines possess proinflammatory and immunosuppressive anti-inflammatory properties that regulate immune responses.1An imbalance between proinflammatory and anti-inflammatory effects is thought to contribute to the chronic nature of RA. Hence, the current pathogenetic model for RA is one of a chronic, tissue-specific inflammatory process to which a variety of immune responses can contribute.1 This slide depicts the unique pathophysiological elements of RA that arise from interactions between the variety of leucocytes that invade the joint, andthe native cellular components of joint tissue.

1. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14:397-440.2. Pincus T. The underestimated long term medical and economic consequences of rheumatoid arthritis. Drugs. 1995;50(suppl 1):1-14.3. Tak PP, Bresnihan B. The pathogenesis and prevention of joint damage in rheumatoid arthritis. Advances from synovial biopsy and tissue analysis. Arthritis Rheum. 2000;43:2619-2633.******************************