Rheumatoid arthritis symposium Flashcards
What is autoimmunity?
Immune response to self-antigens
Represents a breakdown of immunological tolerance
What is the consequence of chronic cytokine release?
Tissue destruction
What is rheumatoid arthritis?
Inflammation of synovial joints
Systemic inflammation
Who is affected by RA?
1% of population
3X more common in women
Diagnosis common at 40-50 years
What are some long-term complications of rheumatoid arthritis?
Acute-phase response in liver Production of free fatty acids and adipoctokines leading to insulin resistance Low bone mineral density and fractures Low stress tolerance and depression Atherogenesis, MI, stroke
Describe the pattern of joint damage in RA
Usually multiple joints in a symmetrical fashion
Morning stiffness
Swelling, heat, redness, pain
Loss of funciton
What is synovitis?
Swelling over extensor tendons, wrist and MCP joints
Synovium hyperplasia
Describe synovial fibroblasts in synovitis
Reduced apoptosis
Enhanced anchorage
Upregulated adhesion molecules
Increased proliferation
What is the pathology of rheumatoid arthritis?
Pannus Synovial fluid rich in neutrophils Synovitis Cartilage erosion Bone erosion Cartilage loss
What is pannus?
Inflammed synovial membrane due to cells infiltrating from blood
What is the composition of synovial tissue?
Macrophages - 40%
Fibroblast and endothelial cells -10-15%
T-lymphoctes - 40%
B lymphocytes and plasma cells - 5%
What are the key populations of T cells in RA synovial?
Th17 and Th1 cells
What is IL-17 known to do?
Activate synovial fibroblasts and osteoclasts which remove bone
Favour cartilage resorption
Describe B-cells in RA
B cells form diffuse or follicular infiltrates in synovium
Produce cytokines and are important for antigen presentation e.g. IL-6
What does monoclonal anti-CD20 do to B cells?
Depletes B-cells and is an effective treatment
Describe cartilage erosion
Fibroblasts make matrix metalloproteases which break down collagen network in cartilage
Chondrocytes undergo apoptosis
Fibroblasts adhere to and invade cartilage leading to biochemical dysfunction and joint space narrowing.
What cytokines produce osteoclast differentiation and activation?
IL-17 RANKL TNF-alpha IL-1 IL-6
What percentage of patients are affected by bone erosion within 1 year of diagnosis?
80%
What are the clinical markers of RA?
Elevated ESR
Elevated CRP
Rheumatoid factor
Cyclic citrullinated peptide antibodies
What is rheumatoid factor?
Made by B cells and directed against Fc portion of another antibody to form immune complex
2 varies: IgM or IgG
Why is rheumatoid factor not that useful for diagnosis of RA?
Not specific for RA
Also present in other autoimmune diseases and in some healthy individuals
Some RA patients are seronegative
Levels don’t correlate with disease activity
Describe use of CCP antibody for diagnosis of RA
Antibodies directed against CCP found in 60-70% of patients with RA
Rarely found in healthy people who don’t go on to develop RA
Detectable in blood many years before disease onset
Anti-CCP positive RA has a more aggressive clinical course of disease
What is citrullination?
Process of replacing protein arginine residues with citrulline residues
Occurs normally in body but if it occurs on an unusual part of the protein they may be recognised as foreign leading to antibody response
What citrullinated self-proteins are most likely in RA?
alpha-enolase Keratin Fibrinogen Fibronectin Collagen Vimentin
What are the possible mechanisms for anti-CCP antibodies enhancing development and severity of inflammation when mild synovitis is already present?
Activation of inflammatory cells by anti-CCP immune complexes
Anti-CCP mediated neutrophil cell death producing NETs
Direct binding of anti-CCPs to drive osteoclastogenesis
Describe the incidence of RA worldwide
1%
Less common in South America and asia
high incidence in North Americans in north america
What polymorphisms are associated with RA?
HLA-DRB1 SE PTPN22 CTLA4 STAT4 TRAF1
What is HLA-DRB1 SE?
Human leucocyte antigen
What is PTPN22?
Protein tyrosine phosphatase 22 which regulates T-cell activation
What is CTLA4?
Co-stimulation suppressor that regulates interactions between T cells and APCs
What is STAT4?
Transducer of cytokine signals that regulate proliferation, survival and differentiation of lymphocytes
What is TRAF1?
Regulator of TNF-alpha receptor superfamily signalling
Describe the incidence of RA in twins
Monozygotic twins: 12-15%
Dizygotic twins: 3-5%
Suggests there is a genetic component but it is only weak
Describe the influence of hormones on developing RA
Testosterone considered protective against autoimmune diseases
Risk of developing RA is increased during period just after giving birth
RA patients often experience remission during pregnancy
Risk of developing RA after menopause isn’t influence by HRT
Describe the influence of smoking on developing RA
Heavy smoking increases risk of RA among people with susceptibility genes of HLA-DR4 alleles
2TCDD in cigarette smoke activates synovial fibroblasts which induce pro-inflammatory cytokines
Describe the suggestion of an infectious trigger of RA
Evidence is hard to find as infection may no longer be present once disease is established
Bacterial components identified in joint tissue in both RA and healthy joint tissue
Give examples of infections that could trigger RA
Human parvovirus B19 Human retrovirus 5 Alphaviruses Hepatitis Chronic hepatitis C virus Epstein-Barr virus Mycoplasma E.coli Rubella virus Porphyromonas gingivitis
What are the 2 groups of pharmacological therapies for RA?
Anti-inflammatory drugs which provide symptom relief
Disease-modifying anti rheumatic drugs which slow clinical and radiographic progression of RA
What are some synthetic agents of DMARDs?
Methotrexate
Sulfasalazine
Hydroxychloroquine
Leflunomide
What are some non-selective COX 1/2 inhibitors?
Aspirin
Ibuprofen
Diclofenac
Give an example of an NSAID COX-2 selective inhibitor
Celecoxib
What are the 2 types of anti-inflammatory drugs used?
NSAIDs
Steroid anti-inflammatory drugs, immunosuppressants
Give examples of steroids used
Prednisolone
Depomedrone
Triamcinolone
Why should long-term use of steroids be avoided?
Due to risk of infections and osteoporosis
What is the mechanism of methotrexate?
Inhibits cell proliferation Increases adenosine level Reduces production of polyamines Induces apoptosis of activated CD4 and CD8 T-cells Reduces inflammation
What are the 2 components of sulfasalazine?
Sulfapyridine
5-amino salicylic acid
What is hydroxychloroquine used to treat?
Malaria
SLE
What is a possible mechanism of hydroxychloroquine?
Increases lysosomal pH
What is the mechanism of leflunomid?
Lymphocyte inhibitor
Inhibits de novo pyrimidine synthesis
Most effective in reducing B-cell populations (also has an effect on T-cells)
Describe DMARD combination therapy
More effective than single drug without extra side effects
What is the most effective DMARD combination?
MTX
Sulfasalazine
Hydroxychloroquine
What are the adverse effects of synthetic DMARDs?
Nausea Loss of appetite Diarrhoea Rash, allergic reaction Headache Hair loss Risk of infections Hepatotoxicity Kidney toxicity
What is TNF blockade used to treat?
RA
Crohn’s disease
Ankylosing spondylitis
Psoriasis
When is biological therapy recommended?
If patient failed to respond to at least 2 standard DMARDs
RA disease activity score measured ≥5 on 2 or more occasions
Give examples of TNF blockers
Etanercept Infliximab Adalimumab Certolizumab pegol Golimumab
What does Infliximab do?
Neutralises free, membrane and receptor bound TNA-alpha leading to antibody dependent cell-mediated cytotoxicity
What is infliximab also used for?
Crohn’s disease
UC
Plaque psoriasis
Ankylosing spondylitis
What does Etanercept do?
Binds free and membrane bound TNF reducing accessible TNF
What is etanercept also used for?
Juvenile idiopathic arthritis
Plaque psoriasis
Psoriatic arthritis
Ankylosing spondylitis
What is adalimumab also used for?
Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Ankylosing spondylitis Crohn's disease
What is golimumab also used in?
Psoriatic arthritis
Ankylosing spondylitis
What should patients be screened for before starting TNF therapy?
History of TB Multiple sclerosis Recurrent infections Leg ulcers Past history of cancer
What is rituximab?
Monoclonal antibody against B cells
How does rituximab work?
Depletes B cells
Opsonises B cells which are attacked and killed via:
- complement mediated cytotoxicity
- antibody dependent cell-mediated cytotoxicity
- apoptosis
What is rituximab also used to treat?
SLE
What is abatacept?
T-cell co stimulation blocker
How does abatacept work?
T-cell co stimulation blocker which increases threshold for T-cell activation
Competitive inhibitor of Cd28
Suppresses proliferation of synovial recirculating T cells
Reduces level of inflammatory mediators
What is tociluzimab?
IL-6R blocker
What is tociluzimab also used in?
Systemic juvenile idiopathic arthritis
What is anakinra?
IL-1R antagonist
Recombinant IL-1ra
How does anakinra work in RA?
Reduces bone erosion
Decreases osteoclast production
Blocks IL-1 induced MMP release from synovial cells
What are the adverse effects of biological therapies?
Increased risk of infections Nausea Headache Hypertension Allergic reactions
When are biological therapies contraindicated?
Pregnancy
Breastfeeding
