Rheumatoid Arthritis PDF

Rheumatoid Arthritis Prof.Dr.Ahmet ÖZGÜL YDU-UoKyrenia Dept.PM&R Rheumatoid Arthritis  A chronic, progressive and systemic inflammatory disease with autoimmun characteristics primarily affecting the joints  Inflammation of synovial joints (joints lined by synovium: [synovitis...

Rheumatoid Arthritis Prof.Dr.Ahmet ÖZGÜL YDU-UoKyrenia Dept.PM&R Rheumatoid Arthritis  A chronic, progressive and systemic inflammatory disease with autoimmun characteristics primarily affecting the joints  Inflammation of synovial joints (joints lined by synovium: [synovitis]) is the hallmark of the disease  Rheumatoid Inflammation Tissue injury Proinflammatory mediators Infl cell activation The synovium is a thin membrane derived from cells of the embryonic mesenchyme. It lines the joint capsule Gravallase EM, Monach PA. Rheumatology 100, 811-831  Rheumatoid Inflammation Tissue injury Proinflammatory mediators Infl cell activation In RA,however, a chronic and clinically significant synovial inflammation develops and eventually leads to destruction of cartilage and bone  Rheumatoid Arthritis Which cells colonize? Inflammatory synovial infiltrate in patients with established RA is heterogeneous: It is composed of  T cellsi CD4+ > CD8 +; Treg, Th17  B-cells  Plasma cells  Macrophages  Dendritic cells  Mast cells  Natural killer cells (NK)  Neutrophiles Rheumatoid Arthritis  B-cells role have multiple roles.  Cytokine production,  Antigen presentation,  T-cell response modulation  Antibody production.  Direct role in inflammation by activating macrophages through TNF-a and IL-6  IL-6 is a differentiation factor for B-cells.  Rheumatoid Inflammation Tissue injury Proinflammatory mediators Infl cell activation Adhesive moleculs (active leucocyte, endothelial cells, synovial fibroblasts These cells will pursue an inflammatory reaction. After serving their purpose at a site of injury, these cells are normally cleared via apoptosis or emigration from the site. Maintenance of inflammation In RA, however, chronic inflammation persists through continuous penetration because of an imbalance between cell recruitment, of inflammatory cells into proliferation, and retention on the one hand and cell synovium death and emigration from the tissue on the other hand. In the case of RA, interactions between T cells and Increased IL-6 stromal cells in synovial tissue favor inhibition of T-cell apoptosis production Decreased IgG solubility Rheumatoid Arthritis Passing of high number of cells into the joint and increase of cytokines etc driving them to stay These cells secrete cytokines and chemokines. Followingly, the medium changes so much the increased cytokine level results in activation of synovial fibroblast and osteoclasts which finally cause the destruction of bone and cartilage. During Rheumatoid Inflammation  Rheumatoid Arthritis  Synovium is composed of 1-2 cell layers  It may reach up to 10-12 cell layers through rheumatoid inflammation.  This thickening does not ensue only from synovial cells, but also from immigrating and colonizing cells.  IL-1 TNF-a MMP1[Collagenase] Cartilage Proteases for MMP2[Gelatinase] Ligament tissue destruction MMP3[Stromelysin-1] Tendon MMP8 [Neutrophile Collagenase] + MMP13[Collagenase 3] Cells of Pannus Serin proteases Cells in synovial fluid Cathepsins Chondrocytes Rheumatoid Arthritis RA is characterized by bone and cartilage destruction. Two main mechanisms causing are: : a- Synovioum turns in to pannus tissue, which causes synovial destruction b- Osteoclast evolution and activation Rheumatoid Arthritis One of the characteristic findings is formation of ‘pannus’ tissue which contains cells and cytokines, proteases able to destruct extracellular matrix. Pannus is caused by proliferating synovial cells and immigrating cells like mononuclear cells of lymphocyte and monocyte lineage being able to secrete inflammatory mediators. Multinuclear cells covering TRAP, katepsins K, and mRNA exist also in pannus (a) Low-power view, demonstrating abundant expression of mRNA (black dots) for MMP-3 (stromelysin-1). (b) High-power view, demonstrating that MMP-3 mRNA expression is limited to cells within the synovial lining layer. Gravallese et al. In situ hybridization studies of stromelysin and collagenase mRNA expression in rheumatoid synovium, Arthritis Rheum, 1991.  Rheumatoid Inflammation Tissue injury Proinflammatory mediators Infl cell activation Adhesive moleculs (active leucocyte, endothelial cells, Synovial pannus synovial fibroblasts Localized Osteopenia Bone erosions Joint swelling Periarticular destruction Maintenance of inflammation through continuous penetration of inflammatory cells into synovium Increased IL-6 Activation of production compleman and Immune complex leucocytes presipitation in synovial tissue Decreased IgG solubility  Cytokines Cartilage destruction Chemokines Inflammation Bone destruction Compleman Effector cell entrance Cartilage degr. products ACPA + ACPA - Enviromental factors Genetic predisposition HLA-DRB1, PTPN22,CTLA-4, IL- 10,PADI… Scherer-Burmester 2007 Rheumatoid Arthritis Pathogenesis The emergence of rheumatoid arthritis is particularly (50%) is caused on genetic ground. It may have familial clustering! HLA-DRB1 MHC IIb Shared Epitope (SE) [QKRAA-QKRRA veya RRRAA] Homozigot Heterozigot Compound Heterozigot ACPA RF Rheumatoid Arthritis Pathogenesis Anti-citrullinated protein antibodies (ACPAs) and antibodies to the Fc portion of IgG (RF), are found in about 80% of persons with RA. Because ACPAs are highly specific for RA and usually precede development of joint pain, it is likely that they are central to pathogenesis. Breaking of immunologic tolerance to citrullinated epitopes is facilitated by genetic predisposition to autoimmunity in general and to ACPA in particular via HLA alleles featuring the “shared epitope” motif by exposures such as smoking and periodontitis. Rheumatoid Arthritis Pathogenesis 3 main risk factors for RA emergence Shared Epitope [SE] PTPN22 Smoking As the apoptotic cells are cleared through macrophages, smoking may cause presentation of cytrullinated peptides to the alveolar macrophages. Enviromental Factors Smoking ++ Coffee consumption + Alcool - BMI + Synthetic lipids + Female sex +  The shared epitope (SE) accelerates endogenous reactive oxygen species (ROS) production. (a) Time-course ROS levels in representative SE-positive (red line) and SE-negative (blue line) B- lymphocyte cell lines. (b) ROS production rates in B lymphocytes. Results are shown as the mean ± standard error of the mean fluorescent units per minute (FU/minute) during the linear late phase of the ROS curve (80 to 200 minutes). Ling S et al.Arthritis Research & Therapy 2007, 9:R5 (doi:10.1186/ar2111 Finally: The destruction of joints, soft tissue, bone and cartilage  Dysability Joint damage Disease activity  Rheumatoid Arthritis: RA has different forms of onset. Insidious onset is the main appearance. Insidiously, mainly symmetric morning stiffness , and difficulty in making a fist are main symptoms. Monoarticular appearance: It begins in one or two joints and later develops clinically Very acute onset with florid morning stiffness, polyarthritis and pitting edema. (RS3PE?). A benign, senile type RA) Acute monoarthritis Palindromic rheumatism with remitting and relapsing episodes of pain that last shortly (weeks) Local extra-articular Systemic extra-articular The peak age of emergence is not exactly known but, it is in reproductive period. There is a female preponderance of 2-3 fold than men Its prevalence is 1% with an annual incidence of 30/100.000. The disease has a genetic background. The prevalence increases approaching North pole. 0.8-2 % Frequency in closed communties may change.  Rheumatoid Arthritis Long-lasting disease mainly results in disease-specific deformities: Boutonniere’s deformity Swanneck deformity Ulnar deviation Z-deformity of thumb. Dorsal subluxation of MTP joints (cock-up deformity)  The ligament laxity and natural tilt o Zigzag deformity radius caused by chronic synovitis lets Radial deviation of the wrist + the volar subluxation of carpals over MCP ulnar deviation radius.  Rheumatoid Arthritis: Extra- articular findings: (Commonly in long lasting, seropositive erosive disease) Harrison’s: Rheumatoid Arthritis  RA Clinic Early disease: None joint destruction, X-Ray finding; bone-catilage erosion (mild disease). Spontaneous remission possible Progressive disease: In despite of treatmens activity, ESR and RF protects their levels.. Late disease: Joint destruction is imminent. The history may be of years. Generally resistent to treatments. Sometimes resolution possible.  1987 revised ARA Criteria Morning stiffness lasting more than 1 hour Arthritis with swelling/effusion in at least 3 joint areas Hand joint arthritis ( et least in one of wrist, MCP or PIP joints) Symmetric joint involvement and effusion Subcutaneous Nodules Radiographic changes typical for RA Positive Romatoid Factor 2010 ACR/EULAR Criteria for RA  Radiologic Changes in RA Early RA Early-Late RA Loss of Joint space – Symmetric soft tissue Shrinking of of soft tissue swelling swelling Subchondral erosion Subluxations – Juxta-articular Ulnar drift osteoporosis Fibrous ankylosis of fingers – Erosion in Bar area Very late RA pancompartmental Joint space loss Great subchondral erosions Osseous ankylosis of wrist joints RA systemic involvement: Lab High ESR Anemia Thrombocytosis Increased SGOT and ALP  Systemic Involvement Nodules: 20-30%, mostly in RF + patients. Associated with disease activity; seen generally in moderate-advanced patients. Subsides with Treatment Muscular involvement – Muscle atrophy associated with infl disese Renal Involvement: seldom; generally drug side effect – Mezengial GN, – Amiloidosis: Emerges in longlasting RA. SAA is associated with inflammatory activity. All systems may be involved Diagnosis by biopsy.  Ocular Keratokonjunktivitis sicca: Most frequent (%10-15). Not associated with symptom severity. Eye burning, mucoid discharge and, yabancı cisim duyusu Diagnosis Schirmer testi Treatment: Symptomatic  Ocular Episcleritis Catarakt (Associated with Glucocorticoids) Glaucome (Associated with Glucocorticoids) Retinopathy (Chloroquin) Brown Snd. RA Sistemik tutulum Vaskulit – Subclinic vasculitis: May be frequent in seropositive RA. – ICAM-1, ICAM-3 have been found to be high in RA. Vasculitis, occurs frequently in long-lasting (> 10 y) seropositive patientes.  Vasculitis Vasculitic patients may share – High RF – Low serum complement – Cryoglobulin Additionally – Circulating immun High ESR complexes Thrombocytosis Anemia Low serum albumin may accompany  Anemia in RA: Associated with severity of inflammation, decreases ts severity with treatment. Fe replacement may be incufficient as the synthesis of Hb is decreased because of inflammation. Fe utilization decreases. Decreased Chronic inflammation erythropoietin level causes: Decreased resonse of – Ferritin synthesis BM to erythropoietin – Hemosiderin Primary destruction of – Abnormal Fe retantion in RBC + inhibition of RE production of RBC – Inreased Lactoferrin precursors which binds Fe causing RESULT: its decrease Ineffective Erithropoesis  Felty Syndrome The association of RA, Splenomegali and Leucopenia. It characteristically occurs in ‘longlasting, seropositive, nodular and deformig RA. – If Leucocyte count is < 1000, bacterial inf. – Ulcers – Hypocomplementemia  – Increased immun complex level  Attacks granulocytes causes increased granulocyte segmentation  Granulocyte life  Specific bacterial infection and inadequate response of Bone Marrow Leucopenia – Appropriate DMARD treatment decreases the infection risk – Splenectomy generrally an effective treatment  Systemic Inolvement in RA Pulmonary involvement is frequent. Autopsy studies reveal 50% involvement. Caplan snd. (Pulmonary nodulosis + pneumoconiosis. Characterized with multiple peripheral lung nodes greater than 1 cm. frequently seen in people exposured to silica, coal dust etc.  RA Sistemik Involvement Cardiac Involvement Most frequently pericarditis. Rarely symptomatic. Nodule occurs through +, seropositive patients mechanisms of presents more – Vasculitis Pericardial involvement 30% in – Nodule emergence ECHO studies but, frequently – Amiloidosis hemodynamically not important – Serousity – Valvulitis – Fibrosis