Rheumatoid Arthritis 2021 PDF - University of Ghana

RHEUMATOID ARTHRITIS Philip Debrah, Ph. D  COURSE OUTLINE Immune system characteristics of antigens and antibodies Humoral and cellular immunity Hypersensitivity Course will provide an awareness of the immunological basis of disease Immunotherap...

RHEUMATOID ARTHRITIS Philip Debrah, Ph. D  COURSE OUTLINE Immune system characteristics of antigens and antibodies Humoral and cellular immunity Hypersensitivity Course will provide an awareness of the immunological basis of disease Immunotherapy as an aspect of pharmaceutical science Types of immunity Active immunization: vaccines and toxoids Passive immunization: Human immune sera and animal immune sera 2  COURSE OBJECTIVES For students to appreciate what immunity is by way of definition Understand innate and adaptive immunity and the immune responses associated with these Also know what antibodies are, hematopoiesis and the precursors involved Lymphoid tissues and their distribution in the body Know what antigens are and their immunological characteristics Understand the humoral immune response Appreciate the immune system in health and disease Appreciate the immunological basis of allergy and hypersensitivity 3  RECOMMENDED TEXTS IMMUNOBIOLOGY: The Immune System in Health and Disease, Fourth Edition by Charles A. Janeway, Paul Travers, Mark Walport and Donald J. Capra Cellular and Molecular Immunology 6TH Edition (International Edition), by Abul K. Abbas, Andrew H. Lichtman and Shiv Pillai Medical Microbiology & Immunology, Seventh Edition by Warren Levinson and Ernest Jawetz Mi c robi olo g y : P ri nc i p l e s a nd E x plo rat ion s , 5 th Ed iti on by J a c q ue ly n G. B l a c k Founda tion s i n Mic robi olo g y, Six th Edit ion , by Kathle en Pa rk Ta l a ro 4  Concept and Definition ❖ Arthritis derives from two words “ARTH” which refers to JOINTS and “ITIS“ which refers to INFLAMMATION. ❖ Rheumatoid is derived from “RHEUMATISM” which broadly means musculoskeletal illness. ❖ Arthritis is a chronic inflammatory disorder that affects mostly the joints but sometimes other organ systems like the skin and lungs. ❖SYSTEMIC INFLAMMATORY AUTOIMMUNE DISORDER 5 REVIEW: SYNOVIAL JOINT 6  PATHOPHYSIOLOGY ❖ Rheumatoid arthritis is an AUTOIMMUNE CONDITION typically triggered by an interaction between a GENETIC FACTOR and the ENVIRONMENT. ❖For instance, a person with a certain gene for an immune protein like Human Leukocyte Antigen or HLA-DR1 & HLA-DR4 might develop rheumatoid arthritis when exposed to certain factors in the environment such as Cigarette smoke or specific pathogen like gut bacteria. ❖These exposures may result in modification of SELF ANTIGENS such as IgG antibodies or Type II collagen or Vimentin 7  PATHOPHYSIOLOGY ❖ 8  PATHOPHYSIOLOGY ❖Type II collagen and Vimentin may undergo CITRULLINATION ❖CITRULLINATION is the process of conversion of the amino acid ARGININE in these proteins (Type II collagen and Vimentin) to CITRULLINE, a different amino acid ❖These changes confuse the immune cells which no longer recognize these antigens as self. ❖The antigens are taken up by APC and carried to the lymph nodes for antigen processing and presentation. 9  PATHOPHYSIOLOGY ❖The APCs activate CD4 T-helper cells which stimulate B-Cell differentiation into PLASMA CELLS that produce SPECIFIC ANTIBODIES (AUTOANTIBODIES) against these antigens (AUTOANTIGENS). ❖The T-helper cells and autoantibodies enter circulation and reach the joints ❖In the joints, the T-Cells secrete CYTOKINES like IFN-γ and IL-17 ❖IFN-γ and IL-17 recruit more inflammatory cells like Macrophages into the joint space 10  PATHOPHYSIOLOGY ❖The macrophages further produce other cytokines like TNF-α, IL-1 and IL-6 and these together with the T-cells cytokines stimulate the SYNOVIAL CELLS TO PROLIFERATE resulting in PANNUS FORMATION ❖PANNUS is a thick, swollen synovial membrane with granulation or scar tissue that is made up of FIBROBLAST, MYOFIBROBLASTS and INFLAMMATORY CELLS ❖The pannus, over time can damage CARTILAGE, OTHER SOFT TISSUE and even ERODE BONE 11 PATHOPHYSIOLOGY 12 SYNOVIAL JOINT: NORMAL/HEALTHY 13 PATHOPHYSIOLOGY 14  PATHOPHYSIOLOGY ❖The inflammatory cytokines also increase a protein on the surface of T-cells known as RECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA B LIGAND (RANKL) ❖RANKL allows T-cells to bind with RANK, a receptor on the surface of OSTEOCLASTS to cause them to STOP BREAKING DOWN BONE 15  PATHOPHYSIOLOGY ❖ There is also antibodies infiltration into the joint space. ❖ These include RHEUMATOID FACTOR (RF) which is an IgM that targets the Fc domain of altered IgG. ❖ There is also ANTICYCLIC CITRULLINATED PEPTIDE ANTIBODY (ANTI-CCP) which targets citrullinated proteins. ❖ Binding of these antibodies to their targets result in IMMUNE COMPLEXES that accumulate in the 16 synovial fluids  PATHOPHYSIOLOGY ❖The chronic inflammation further promotes ANGIOGENESIS and the new blood vessels formed promote perfusion and arrival of more inflammatory cells. ❖As the disease progressed, multiple joints on both sides of the body get inflamed and gradually destroyed. ❖It usually affects five or more joints and tends to be SYMMETRICAL/BILATERAL. ❖Commonly affects the small joints such as the METACARPO-PHALANGEAL joints and PROXIMAL INTER-PHALANGEAL joints of the hand and the METATARSO- PHALANGEAL joints of the feet ❖Disease progression then has the large joints such as the SHOULDER, ELBOW, KNEES and ANKLES becoming affected 17  PATHOPHYSIOLOGY ❖ The inflammatory cytokines are not restricted to the joint spaces but may escape through the blood stream and affect MULTIPLE ORGAN SYSTEMS and cause EXTRA- ARTICULAR PROBLEMS. BLOOD VESSELS ❖ The walls of Blood vessels become inflamed resulting in various forms of VASCULITIS and an INCREASED PREDISPOSITION to ATHEROMATOUS PLACQUE FORMATION or DEPOSITION BRAIN ❖ IL-1 or IL-6 may travel to the brain and cause PYREXIA by acting as pyrogens 18  PATHOPHYSIOLOGY LIVER ❖The liver, in response to the inflammatory cytokines starts producing high amounts of HEPCIDIN, A PROTEIN THAT DECREASES SERUM PROTEIN LEVELS via inhibiting IRON ABSORPTION from the gut and TRAPPING it in MACROPHAGES and LIVER CELLS. LUNGS ❖There is activation and proliferation of FIBROBLASTS within the lung interstitium resulting in FIBROTIC SCAR TISSUE and subsequently affecting ALVEOLAR GAS EXCHANGE. ❖The Pleural cavities surrounding the lungs also become inflamed and fill up with PLEURAL EFFUSION which can mess with lung expansion 19  PATHOPHYSIOLOGY SKELETAL MUSCLES ❖There is promotion of protein breakdown which may result in cachexia. SKIN AND OTHER VISCERAL ORGANS ❖There is formation of RHEUMATOID NODULES. ❖These are ROUND SHAPED COLLECTIONS of Macrophages and Lymphocytes with a CENTRAL AREA of Necrosis. 20 PATHOPHYSIOLOGY 21 PATHOPHYSIOLOGY 22  DIAGNOSIS BLOOD TESTS ❖These immunological tests target and look for ❖RHEUMATOID FACTOR ❖ANTI-CITRULLINATED PEPTIDE (ANTI-CCP) ANTIBODY IMAGING ❖X- RAY: This is used to evaluate bone density around the affected joints; density usually decreases. ❖There is SOFT TISSUE SWELLING, NARROWING OF THE JOINT SPACE and BONE EROSIONS 23  TREATMENT ACUTE FLARES: These are managed with; ❖NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) and ❖Short term use of GLUCOCORTICOIDS LONG TERM: Management is through; ❖Use of DISEASE-MODIFYING ANTI-RHEUMATIC MEDICATIONS (DMARDs) such as; ❖LEFLUNOMIDE ❖METHOTREXATE ❖HYDROXYCHLOROQUINE Which suppress INFLAMMATION ❖SULFSALAZINE and ❖MINOCYCLINE ❖AZATHIOPRINE 24  TREATMENT CONTD. ❖Use of BIOLOGIC RESPONSE MODIFIERS (BIOLOGICS OR BRMs) ❖These are endogenous or exogenous substance that are able to modify the immune response either by enhancing or suppressing it. ❖They use different mechanisms of action depending on the type of BRM being used. ❖Some work by SUPPRESSING THE ACTIVITY OF T-CELLS example ABATACEPT ❖Others also wok via SUPPRESSION OF B-CELLS example RITUXIMAB ❖Others block various CHEMOKINES like TNF e.g. ADALIMUMAB, ETANERCEPT and INFLIXIMAB ❖Some like ANAKINRA block IL-1 while TOCILIZUMAB blocks IL-6 25 PATHOPHYSIOLOGY 26