RA STEVE DARBY Flashcards
what is RA?
chronic inflammatory disorder affecting approximately 0.5-1% of the UK population
inflammation within synovial joints, causing pain, swelling and stiffness and progressing to erosion and eventually joint destruction. .
what kind of disorder is RA?
systemic autoimmune inflammatory disorder and may cause extra-articular manifestations affecting blood vessels, bone marrow, GI tract, skin, lungs and eyes.
when do people usually develop RA?
symptom onset > 25 years of age - usually 5th decade of life
what ethnicity are most likely to get ra?
caucasions
what are RA symptoms?
swelling, stiffness, pain and redness
why does swelling occur in RA?
Synovial tissue in the caps of joints becomes damaged in rheumatoid arthritis sufferers, causing the tissue to thicken and swell.
why does stiffness occur in RA?
Inflamed joints tend to stiffen and are difficult to move correctly. People who have RA experience stiff joints, especially in the mornings or after long periods of rest. This can last for hours at a time.
why does pain occur in RA?
Cartilage and bone within the joints will wear down over time. Joints are supported by surrounding muscles, ligaments and tendons, but, with RA, these will weaken and no longer stabilize joints. This causes intense pain and joint damage as a result.
why does redness occur in RA?
joints can be warm and may appear pink (or even red) on the outside during a flare or when inflamed.
what symptoms would you get in early stage RA in your hands?
fixed flexion (buttonhole or boutonnière deformity) or fixed hyperextension(swan-neck deformity) of the PIP joints, which impairs hand function.
•Swelling and dorsal subluxation of the ulnar styloid, which causes wrist pain. It may also cause rupture of the finger extensor tendons, leading to a sudden drop of the little and ring fingers that requires urgent surgical repair.
what would a healthy bone and joint look like?
- Articular cartilage provides a lubricated surface for the opposing bones of the joint
- The synovial membrane produces and contains synovial fluid for the joint
- The synovial fluid helps remove debris and provide lubrication
what causes RA?
•Precise Cause remains largely unknown •Genetic / Environmental trigger •Combination of genetics and environmental •Leads to generation of AUTOANTIGENS •Autoantigens >autoimmune response
how does a persons genetics influence their sucebalility to RA?
Human Leukocyte Antigen (HLA) – a complex of genes on chr6 that regulate the immune system
•MHC I and MHC II complex
•Patients with genetic alterations to HLA-DR1 and / or HLA-DR4 alleles are associated with increased risk of RA
•PTP2N22mutation - encodes a protein tyrosine phosphatase, which participates in activation and control of inflammatory cells, including T cells.
what are some of the environmental factors that lead to environmental arthritogen?
- EBV, retroviruses, parvoviruses
- M.tuberculosis
- Mycoplasma
- Gut Bacterium
- Smoking
- Airborne pollutants
- Gum disease..!!•Obesity
- Hormones
- Diet
- Citrullinated proteins
what is cutrullination of proteins?
Citrullination is a post translational conversion of arginine to citrulline in proteins by an enzyme called Peptidyl Arginine Deminiase(PA D)
what happens in RA with cutrullination of proteins?
In RA this is pathological and it becomes dysregulated and can lead to alterations of proteins in the synovium >HYPER-citrullination
Citrullination can lead to autoantigens being formed which are then no longer recognised as self antigens by the immune system
what contributes to the citrullination of proteins and arthritogens?
periodontal infetion
smoking
genetics
these all activated cells an ACPA production
how does periodontal infection lead to citrullination of proteins and arhritogens?
inflamation, apoptosis and necrosis in gingiva, PPAD and PAD release> citrullination of human and bacterial proteins
how does smoking contribute to citrullination of proteins and arthritogens?
inflamation, apoptosis and necrosis in lungs, PAD release
> citrullination of proteins
what is MHC’s role in the immune response?
presents antigens to T cells to activate immune response
HLA-DRβ1 thought to contain a binding site of the arthritogen that initiates the inflammatory synovitis
how does inflammation occur in RA?
auto antigen activates T helper cells
this causes macrophages and fibroblast like synoviocytes to release cytokines, autoantibodies, innate immunity and proteases
how does destruction occur in RA?
T helper cells stimulate fibroblast like synoviocytes and macrophages to release:
pannus, osteoclast activation, somatic mutations, proteases
what is a cytokine?
Cytokines are small secreted proteins released by cells have a specific effect on the interactions and communications between cells.
what do cytokines do?
Bind to cytokine Receptors
•Cytokines have very prominent roles in regulating both the innate and adaptive immune systems, and in the process of inflammation.
how are cytokines released?
•Can be autocrine, paracrine or endocrine
what are the main cytokines we are concerned about because of RA?
IL-1,IL-6
INF-y
TNFa
how do antigens present themselves?-MOA NB
autoantigens bind to antigen presenting cells -APCs
APCs couple to T-cells
T cells release cytokines to recruit macrophages and B cells- INFY, INF17
Macrophages also release cytokines to stimulate synovial cells to proliferate- TNFa, IL1,6
synovial cells release MMPs and RANKl
what is the difference between a healthy joint an an RA joint?
RA:
Synovial Membrane is inflamed
•Thick Pannus
•Bone and Cartilage is eroded
•Macrophages release cytokines–TNF-α–IL1–IL6•Increases fibroblast like synoviocytes
•Macrophage Like Synoviocytes(MLS) line the membran
what causes RA pannus?
Thick swollen inflamed membrane–Fibroblasts–Myofibroblasts–Inflammatory cells
•Can lead to scar tissue
•Leads to cartilage damage
•Bone erosion
how do you diagnose RA?
- Family history:
- Pain history and examination of joints:
- Blood tests:
- Positive Rheumatoid Factor(RF)
- Positive anti-cyclic citrullinated peptide(anti-CCP)
- High Erythrocyte Sedimentation Rate(ESR)
- Positivec-reactive protein(CRP)
- Imaging scans: x-rays, ultrasounds, and magnetic resonance imaging scans to examine the joints and determine if RA is the cause of erosion
what is the prognosis for RA?
decreases life expectancy by 3 to 7 years, mainly caused by –heart disease–Infection–gastrointestinal bleeding
why should RA be controlled?
to lower CV riisk in all patients with CA
how does synovial inflammation occur?
- enhanced chemokine production by synobiocytes, endothelial cells and monocytes
- synovial fibroblast proliferation
- increased VEGF production my synovial fibroblasts
how does cartilage degration occur?
- chondrocyte release of MMPs
- reduced proteoglycan production by chondrocytes
how does subchondral bone resorption?
enhancement of RANKL expression on osteoblasts and synovial fibroblasts
what provides the IL6 cytokines?
CNS- due to depression and fatigue
CV system- accelerated CVD, increased MI electric instability
adipose tissue- insulin resistance
liver- hepicin mediated anemia or chronic diseases
how do NSAIDs work to treat RA?
immediate relief but not for long term
at high doses- GI s/e, headache, hpt
what are the two types of DMARDs?
traditional- sulfasalazine, leflunomide
biologic- rutuzimab, abatacept, tofacitnib
how do traditional DMARDs work?
immunosuppressants- methotrexate, azathiopurine
antimaraials- hydroxychloroquine
how do biologic DMARDs work?
TNF antagonists- infliximab
IL6 inhibitor- tocilizumab
how long to DMARDs take to have an effect?
may take weeks or months to have an effect
how do DMARDS work?
block release of cytokines from macrophages- not exactly known
what is an aminosalicylate and how doe sit work?
Common First choice DMARD produces remission in active RA
amino analogue of salicylic acid- given as sulfasalizine
what kind of release does 5-ASA have?
delayed release -useful in RA
what is the MOA of 5-ASA
Inhibition of leucocyte movement
•Reduces cytokine levels and TNF
Inhibition of inflammatory mediators
what is methotrexate?
Methotrexate is an antifolate approved for the treatment of severe active rheumatoid arthritis in adults who are intolerant to, or have had an insufficient response to, first-line therapy
how does methotrexate work?
Methotrexate blocks the pyrimidine/Purine biosynthetic pathway and the proliferation of B-cells by interfering with DNA synthesis, repair, and replication
how does leflunomide work?
Multi use immunosuppressive drug, in animals it prevents –Skin–Heart–kidney graft rejection
when is leflunomide effective?
Effective in autoimmune diseases
–Being examined for use in systemic lupus erythematosus
–myasthenia gravis in rats
–Use in RA and psoriatic arthritis
what is the MOA of leflunomide?
through metabolism to teriflunomide
Specifically inhibiting dihydroorotate dehydrogenase (DHODH)
what does inhibiting of the pyrimidine biosynthetic pathways with leflunomide result in?
ecreasing DNA and RNA nitrogen-containing bases, and arresting the B-cell and T-cell proliferation cycles and production of antibodies
how does hydroxychloroquine work?
The mechanism of antirheumatic action is currently unknown; however, it is largely accepted that it accumulates in and stabilizes lysosomes •Impacts Antigen Presentation
•Causes suppression of T cells
what is hydroxychlorquine used for?
RA, lupus erythematus and malaria
how does DMARDs biologic work?
centre around the use of Monoclonal Antibodies (suffix with “MAB”) to inhibit key components of the RA pathogenesis
T-Cell Co-Stimulation Modulator –abatacept
anti-CD20 B-Cell Depleter- rituximab
what does TNF a do?
-proinflam cytokine response chemokine release hepcidin induction PGE production osteoclast activation chondrocyte activation anigiogenesis leukocyte accumulation endothelial cell activation chemokine release
how does anakinra work?
Anakinrais a recombinant human IL-1 receptor antagonist
•Competitively inhibits IL-1 binding to the interleukin-1 type I receptor expressed in a wide variety of tissues and organs
what is IL1 needed for?
IL -1 production is induced in response to inflammatory stimuli and mediates various physiologic responses –Inflammatory –Immunological responses
•Patients with rheumatoid arthritis have elevated levels of IL-1
what is tocilzumab?
Tocilizumabis a recombinant humanised monoclonal antibody that acts as a competitive antagonist at the IL-6 receptor
•IL -6 is a proinflammatory cytokine produced by a variety of cell types, including T-and B-lymphocytes, monocytes and fibroblasts
what is a t cell co-stumulation modulator?
T cell activation requires recognition of a specific antigen carried by an antigen-presenting cell (APC) •The “co-stimulatory signal” involves binding of CD80/CD86 molecules on the surface of APCto the CD28 receptor on T-cells
what is abatacept and how does it work?
Abataceptis a monoclonal antibody that selectively binds to CD80 / CD86 and blocks the co-stimulatory signal. •Abataceptis given by intravenous infusion. Its metabolism is unknown, and it has a very long half-life of about 14 days.
what is Anti-CD20 B-Cell Depleter and how does it work?
CD20 is a cell marker on B Cells during B cell differentiation
•Rituximab specifically depletes CD20+ B cells by binding to the CD20 antigen expressed on the cell surface
•Blockade of CD20 leads to B cell death (via apoptosis and lysis)
