Rheumatoid Arthritis Work performed by: Raquel Costa Ricardo Abreu Rúben Carvalho Sara Petronilho Tiago Branco Cellular and Molecular Biology II Medicine 2009/2010

Rheumatoid arthritis an autoimmune disease Rheumatoid arthritis (RA) is a chronic multisystem disease of unknown cause. The characteristic feature of RA is persistent inflammatory synovitis, usually involving peripheral joints in a symmetric distribution. However, there are a variety of sistemic manifestations.

Synovial inflamation Cartilage damage Bone erosion Changes in joint integrity The hallmark of the disease

The course of RA can be quite variable: Some patients may experience only a mild oligoarticular illness of brief duration with minimal joint damage; Whereas others will have a relentless progressive polyarthritis with marked functional impairment.

RA,rheumatoid arthritis; PMR, polymyalgia rheumatica; SLE,systemic lupus rythematosus; JRA, juvenile rheumatoid arthritis; DM,dermatomyositis; PM, polymyositis

Juvenile Rheumatoid Arthritis Juvenile rheumatoid arthritis (JRA), or juvenile arthritis, is not a single disease, but a group of diseases. What they all have in common is chronic joint inflammation. Besides this common feature, these diseases are very different in their symptoms, their treatments, and their outcomes. JRA is also called juvenile idiopathic arthritis (JIA) because it is very different from adult rheumatoid arthritis.

Symptoms Fatigue Loss of energy Low-grade fever Muscle and joint aches Stiffness Inflamed tissues Disease inactive Non- Inflamed tissues

Dyagnosis Search the skin for rheumatoid nodules (most often around the elbows and fingers); Examine the joints for inflammation and deformity; Blood and X-ray tests.

Dyagnosis joint inflammation The lining tissue of the joint (synovium) becomes inflamed, resulting in the production of excessive joint fluid (synovial fluid). The synovium also thickens with inflammation (synovitis).

Dyagnosis Blood Tests Rheumatoid factor Citrulline antibody Antinuclear Antibody Test (ANA) Sedimentation Rate (Erythrocyte Sedimentation Rate or ESR) C-Reactive Protein (CRP)

Dyagnosis Rheumatoid factor is present in about 80% of adults with rheumatoid arthritis. Rheumatoid factor Is most helpful when the traditional blood test for rheumatoid arthritis, rheumatoid factor, is not present. Citrulline antibody Is common blood test that is used to detect and monitor inflammation in the body Sedimentation Rate CRP is classified as an acute phase reactant, which means that its levels will rise in response to inflammation. C-Reactive Protein

Dyagnosis The American College of Rheumatology has developed a system for classifying rheumatoid arthritis that is primarily based upon the X-ray appearance of the joints. This system helps medical professionals classify the severity of rheumatoid arthritis.

Prognosis Variable and difficult to predict Risk factors:

Treatment

Treatment Physical therapy Drugs: 1.NSAIDs 2.DMARDs Glucocorticoid Therapy Anti-Cytokine Agents Immunosuppressive Therapy Surgery

Treatment NSAIDInhibition of COX enzymesAnalgesic, anti- inflammatory and antipyretic properties; COX-1 iihnbits clotting Toxicity Gastroduodenal ulceration CoxibInhibition of COX-2Increased risk of cardiovascular problems Sodium Retention Hypertension DMARDDeacrese inflamation and RA’s destructive capacity Toxicity Gastrointestinal upset, oral ulceration, liver function abnormalities Methotrexate (DMARD) Folic Acid Antagonist (Inhibition of DHFR) Inhibition of T-Cell activation Rapid onset of action, retards the development of bone erosion and facilitates healing Toxicity (decreased by giving a suplement of folic acid) Glucocorticoid therapy (prednisone) Involved in the feedback mechanism in the immune system (regulation) Inhibition of products of inflamation (prostaglandins, leukotrienes) Inhibition of COX Inhibition of genes which code for citokynes (IL-1 to IL-8) Decreased T-cell proliferation (enhanced production of IkB) Decreases signs and symptoms of inflammation, slows the progression of bone erosion (used as an aditive therapy)

Treatments Anti-TNF-alfa (anti-citokyne agent) Binds to tumor necrosis factor-alpha (TNF- α ) Blunts the activity of Th1 cells Controls signs and symptoms, decreases disability and the rate of progression of joint damage Reactivation of dormant tuberculosis, development of autoantibodies, injection site reactions Anakinra (anti-citokyne agent) IL-1 receptor antagonist, so it inhibits proinflammatory citokynes (IL1 alfa and beta), which (when active) help to activate T-cells, stimulate the release of prostaglandins and the synthesis and secretion of other interleukins Improves signs and symptoms, decreases disability, progression of articular damage and inflammation Injection site reactions Immunosupress ive therapy (Leflunomide) Inhibition of the proliferation of T-cells (decreases the immune system’s response) Decreases inflammation Severe Toxicity Used as a last resort

Evidence relating to its pathogenesis are… A genetic link with HLA-DR4 Problems with the Major Histocompatibility Complex Class II and the T cell-associated protein PTPN22 A dramatic response that leads to: ◦ Release of the cytokine TNF and other cytokines ◦ Abnormal B cell - T cell interaction The presence of autoantibodies to IgGFc, known as rheumatoid factors, and antibodies to citrullinated peptides (ACPA). Cigarette smoking that appears to be fundamental A more or less random pattern of predisposed individuals are affected.

Possible infectious triggers The "mistaken identity" theory suggests that an infection triggers an immune response, leaving behind antibodies that should be specific to that organism. e.g. Infections with Epstein-Barr virus and Human Herpes Virus 6.

Molecular mimicry The antibodies are not sufficiently specific. This begin an immune attack against part of the host. But the normal host molecule "looks like" a molecule on the offending organism, that triggered an autoimmune reaction. ??????

Continued abnormal immune response The genetic association with HLA-DR4, with the gene PTPN22 and with two additional genes implicate altered regulation of the immune response. These genetic factors may interact with environmental risk factor, like: ◦ Smoking cigarette ◦ Hormonal factors

Once the abnormal immune response has become established… Rheumatoid factors and ACPA were produced in large quantities Activate macrophages Inflammation get worse Synovial macrophages and dendritic cells further function as antigen Leading to an established local immune reaction in the tissue Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate.

Researchs “Decreased number and impaired functions of endothelial progenitor cells (EPCs) leading to impaired vasculogenesis have been associated with rheumatoid arthritis (RA). Defective vasculogenesis has also been implicated in premature atherosclerosis in RA.” in

Researchs “This study investigated five confirmed rheumatoid arthritis (RA) susceptibility genes/loci (HLA-DRB1, PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5) for association with susceptibility and severity in an inception cohort. (…) These findings support the mounting evidence that different genetic loci are associated with autoantibody positive and negative RA, possibly suggesting that many of the genes identified to date are associated with autoantibody production.” in

Researchs “Currently, statin-mediated reduction of LDL- cholesterol levels is considered to be the cornerstone of cardiovascular disease prevention. In addition to their lipid-lowering capabilities, statins exert immunomodulatory effects, which could be of dual benefit in the treatment of RA.” in

Conclusion Management of rheumatoid arthritis (RA) has radically changed over the last decade. The current aim of management is to achieve remission and prevent joint damage to provide a better quality of life. In order to achieve this goal, inflammation is suppressed as much as possible during the early phase of the disease before onset of joint damage.

Bibliography Braunwald E, et. al., (ed.) Harrison's Principles of Internal Medicine, 15th ed. New York, New York: McGraw Hill ncas/doencas+reumaticas/artritereumatoide.htm medications?page= eumatoidArthritis