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Molecular Pathway ofRHEUMATOID ARTHRITISHetty Rieskaliana1306343050OUTLINEPhysiology of normal synoviumMolecular pathophysiology of rheumatoid arthritisMolecular pharmacology of rheumatoid arthritis medications
Molecular Pathway ofRHEUMATOID ARTHRITISPhysiology of normal synoviumRheumatoid arthritis (RA)The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR):
RA is a chronic inflammatory disease characterized by joint swelling, joint tenderness, and destruction of synovial joints, leading to severe disability and premature mortality [1]
RA is considered an autoimmune diseaseRA affects 0.5-1% of the world populationThere are 2.5 times as many women as men with the diseaseLi YR, Kauffman JM (2014) Molecular Medicine of Rheumatoid Arthritis: From Molecular Pathphysiology to Novel Therapeutics and Evidence-Based Practice. Ann Orthop Rheumatol 2(2): 1014.4Normal joint (a) and a joint affected by RA(b)
Choy, Ernest 2012. Understanding the dynamics pathways involved in the pathogenesis of rheumatoid arthritis. www.rheumatology.oxfordjournals.orgNormal synoviumThe synovium is the soft tissue that lines diarthrodial jointsConsists of 2 distinct layers:Intima layer (lining)Subintima layer (sublining)
Normal synoviumLining/intimal layer containing 2 distinct cells:Macrophage-like type A synoviocytesFibroblast-like type B synoviocytes In RA, lining layer becomes hyperplastic and forms an aggrevive front term pannus
Sublining/ subintima layer consists of scattered blood vessels, fat cells, and fibroblasts residing in a matrix of fibrils and proteoglycans
Normal synoviumSynovial Macrophages Synovial Fibroblasts hyaluronan productionOther Sub-intimal Cell PopulationsCD3+ T cells, (including CD4+ and CD8+ cells), with some having a memory T cell phenotype, B cells and plasma cellsSynovial MacrophagesSynovial macrophages are present in both the intimal and subintimal layers in the normal synovium.Macrophages normally: a minority of cellsin inflammatory arthritis: macrophage numbers increase dramaticallyA small number of antigen presenting dendritic cells are also present in the normal synovium
Synovium in rheumatoid arthritis (x400 magnification) Synovial macrophages (normal synovium, x200 magnification)Macrophages are antigen presenting cells (APCs) and act as one of the first responders in the immune response process. Once activated, a macrophage releases cytokines and chemokines.Cytokines affect the way other cells act.Chemokines attract other leukocytes the area to battle the invaders in a process called chemotaxis.
Synovial Macrophages
Synovial fibroblastsSynovial fibroblasts are adapted to hyaluronan production, with UDPGD (uridine diphosphoglucose dehydrogenase) activity being a specific marker of this cell type. This enzyme converts UDP-glucose into UDP-glucoronate, which is one of the substrates required by hyaluronan synthase for assembly of the hyaluronan polymer. Disease states led to reduced UDPGD activity in synovial fibroblasts.Function of the Normal SynoviumMaintenance of tissue surface Lubrication the presence of a glycoproteinChondrocyte NutritionImmune System Innate immune systemThe innate immunity relies on receptors that detect common pathogenic features (ex: bacterial cell wall polysaccharides)
When it encounters a bacterium, a macrophage first engulfs it in a pouch (vesicle) called a phagosome. This vesicle is then taken inside the macrophage, where it fuses with another vesicle termed a lysosome.Lysosomes contain powerful chemicals and enzymes which can destroy bacteria.Adaptive immune systemThe receptors are designed to respond to only one feature, called an antigen. Saat ada invader yang teridentifikasi, hanya limfosit yang reseptornya cocok dengan invader saja yang teraktivasi. Antibodi dilepaskan oleh limfosit B dan mengandung reseptor yang sama dengan antigen.LymphocyteThere are two major types of lymphocytes:T lymphocytes B lymphocytes T lymphocytes (T cells) are so called because they mature in the thymus. B lymphocytes (B cells) are lymphocytes that develop in the bone marrow. Their primary job upon activation is to produce antibodies.LymphocytesUpon activation, B cells proliferate and then become plasma cells, secreting antibodiesT cells destroy infected cells
T Lymphocytes The T cells later develop into CD4 and CD8 T cellsCD8 has marked cytotoxic (cell-killer) T cells, and CD4 has marked whelper T cells, which further differentiate into two subclasses, TH1 and TH2 cells T cells do not produce an immune response by binding to an antigen. The antigen must be displayed by major histocompatibility complex (MHC). CD4 binds to MHC II, while CD8 binds to MHC I. When CD4 T cells bind to MHC II on B cells, they stimulate the B cell to produce antibodies. When they bind with MHC II on macrophages, they activate the macrophages to destroy the cells in their phagosomes. lymphocytes that bind with MHC too strongly could possibly cause autoimmune disease.Molecular Pathway ofRHEUMATOID ARTHRITISMolecular pathophysiology of rheumatoid arthritis
Molecular pathway of inflammatory The clinical manifestations of rheumatoid arthritis are initiated by lymphocytes that localize to synovial tissue where, when activated, they cause pain and swelling.These lymphocytes produce protein mediators (cytokines) that initiate inammation, attract other immune cells to the site, activate resident cells, and cause excess synovial uid production.Lymphocyte cells migration:
Tethering: aliran leukosit melambat dan menepi ke dinding pembuluh darahRolling: lekosit akan bergerak berputar-putar menepi dan tertambat pada sel-sel endotelial pada dinding pembuluh darahSel lekosit melekat pada sel endotelial, kemudian bermigrasi menuju jaringan dengan bantuan chemokine
Molecular pathway of inflammatory LFA =lymphocyte function antigen; ICAM = intercellular adhesion molecule;IFN = interferon; IL = interleukin;MHC = major histocompatibility complex;NO = nitricoxide;TNF = tumor necrosis factor
Molecular pathway of inflammatory Limfosit CD4+ dan makrofag teraktivasi, menghasilkan: IL-2, TNF dan IL-1.IL-2: memicu proliferasi limfosit, sehingga memperbanyak sitokin yang dihasilkan, menyebabkan inflamasiSelanjutnya, limfosit T akan mengaktifkan limfosit B menghasilkan autoantibodi, diantaranya rheumatoid factor (Ig M-RF) dan anti-cyclic citrullinated protein (anti-CCP)Diagnosis artritis rematoid awal:Ig M-RF > 40Anti-CCP >50Molecular pathway of inflammatory 26Molecular pathway of destruction of the cartilageDestruksi kartilago akan menyebabkan disfungsi sendi yang akan mempengaruhi kualitas hidup pasien rheumatoid arthtritisKartilago: sejenis jaringan ikat khusus yang terdiri atas satu tipe sel, yaitu chondrocyte, yang memproduksi extracelullar matrix (ECM)Normal: keseimbangan sintesis ECM dan degradasinyaRheumatoid arthtritis: degradasi ECM > sintesis ECM, sehingga terjadi dekstruksi kartilago.Enzim yang berperan dalam degradasi ECM: matrix metalloproteinase (MMP)MMP bersifat inducible, dipicu oleh antara lain: sitokin IL-1 dan TNF-Molecular pathway of destruction of the cartilageKlasifikasi MMPCollagenase (MMP-1, MMP-8, dan MMP-13)Gelatinase (MMP-2 dan MMP-9)Stromelysin (MMP-3 dan MMP-10)Metalloelastase (MMP-12, MMP-19)Enamelysin ((MMP-20 dan MMP-23)
Molecular pathway of destruction of the cartilageMMP diinaktivasi oleh suatu inhibitor, yaitu Tissue Inhibitors of Metallo Proteinases (TIMPs) regulator pada sirkulasi sistemik-2 macroglobulin (-2M) lokal di jaringanTarget pengembangan obat inhibitor selektif terhadap MMP-1, seperti cipemastat (uji klinik belum berhasil)Molecular Pathway ofRHEUMATOID ARTHRITISMolecular pharmacology of rheumatoid arthritis medicationsRheumatoid arthtritis therapySymptomatic therapy using non-steroid anti infamatory drugs (NSAID)Disease-modifying antirheumatic drugs (DMARD)
non-steroid anti infamatory drugs (NSAID)First line drugs in mild/early caseAfford symptomatic relief in pain, swelling, morning stiffnessDo not arrest disease processMechanism of action: competitive active site inhibitors of enzym (cyclooxigenase)AINSNon-selective cox inhibitorsNaproxen, piroxicam, diclofenacSelective cox-2 inhibitorsCelecoxib, etoricoxib
Disease-modifying antirheumatic drugs (DMARD)Current recomendation is to add DMARDs as soon as the diagnosis is confirmedSlow acting, take 6 weeks 6 months to show the effectsAlter disease progressionDisease-modifying antirheumatic drugs (DMARD)
MethotrexateConsidered first choice to treat RAMechanism of action: it probably relates to inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylaseMTX may act in RA through reducing cell proliferation, increasing the rate of apoptosis of T cells, increasing endogenous adenosine concentrations and altering cytokine production and humoral responsesMethotrexate
Adenosine is a purine nucleoside that binds four specific adenosine receptors, A1, A2a, A2b and A3Ligation of the A1-receptor leads to immuno stimulation of neutrophils, where as ligation of the A2a-receptor leads to immuno supressionMethotrexateBiology DMARDsAnti TNFAntagonis IL-1Antagonis IL-6Anti CD-20Cytotoxic T-lymphocyte-associated Antigen 4 (CTLA4)
1. Anti-TNFAnti-TNF:a. Infliximabb. Etanerceptc. Adalimumabd. Golimumabe. Certolizumab pegol
2. Antagonis reseptor IL-1Contoh: anakinraAnakinra block IL-1R (Interleukin-1 receptor)
3. Antagonis reseptor IL-6Obat yang dikembangkan dengan target IL-6 adalah toclizumab.Toclizumab bekerja dengan mengikat secara spesifik reseptor IL-6
Contoh: Rituximab
CD-20 is a phosphoprotein expressed in B cells3. Anti CD-20
5. CTLA4APC: CD80 and CD 86T lymphocyte: CD28 (activate) and cytotoxic T-lymphosyte-associated antigen 4 (inhibit)
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