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204-theme 1 > rheumatoid arthirits Symposium > Flashcards

rheumatoid arthirits Symposium Flashcards

1
Q

describe the aetiology of RA

A

RA is an autoimmune disease

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2
Q

describe how autoimmunity is mediated by cytokines

A
  • Autoimmunity (or autoreactivity)= immune responses to self-antigens
    Represents a breakdown of immunological tolerance

-Immune reactions to ‘self’ can occur as part of a controlled inflammatory reaction e.g. tissue repair

  • They are mediated by cytokines: - acute-Removal of pathogen/
    Tissue repair

chronic -Tissue destruction

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3
Q

is inflammation constant in RA

A

Inflammation naturally fluctuates over time above the threshold for pathological inflammation.

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4
Q

what is the goal of treatment

A

Goal of treatment: restore natural fluctuations below threshold

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5
Q

describe the characteristics of RA

A
  • Inflammation of the synovial joints
  • 3x more women than men with RA
  • Affects 1% of the worldwide population

-Diagnosis most commonly around
age 40-50

  • Systemic inflammation
  • Reduced quality of life
  • Disability
  • Increased mortality – decreased life expectancy
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6
Q

what are the systemic Clinically Observed Long-Term Complications in Patients with Rheumatoid Arthritis.

A

1- Il-6- liver- acute- phase response (CRP)

  • Iron redistribution
    2. TNF-alpha- Il-6 - Free fatty acids & adipocytes
    3. Muscle- TNF-alpha IL-1, insulin resistance

4- bone- low bone mineral density- fractures- TNF-alpha, RANK L ligand

5- Liver leads to fat and blood vessels: at thermogenesis, myocardial infarction and stroke- TNF-alpha

6- Brain- SERT and HPA axis - low stress tolerance

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7
Q

describe the appearance of joint damage in RA

A

Usually multiple joints in a symmetrical fashion:
- Morning stiffness

  • Swelling, heat, redness and pain
  • Loss of function
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8
Q

what are the destructive processes involved in joint damage

A

Destructive process:

  • Bone erosion
  • Synovial and cartilage damage
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9
Q

what is Synovitis

A

Swelling over extensor tendons, wrist and MCP joints

Synovium hyperplasia (an increase in cell numbers)

Synovial fibroblasts have reduced apoptosis, enhanced anchorage, upregulated adhesion molecules and increased proliferation

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10
Q

what is the pathology of RA in the make up of joints

A

-Pannus-

(inflamed synovial membrane)

-Synovial fluid
rich in neutrophils

  • Synovitis
  • Cartilage erosion

-Cartilage
loss

-Bone erosion

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11
Q

what is the composition of the synovial tissue RA

A
  • macrophages (40%)
  • T lymphocytes (40%)
  • B lymphocytes
    and plasma cells
    (5%)
- fibroblast and 
endothelial cells       (10 -15%)
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12
Q

what is the disequilibrium in the cytokine of RA

A
  • proinflamm-more Il-1, TNF-alpha, Il-7, IL-17

- less antiinflam: il-4,13

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13
Q

describe the Innate immune cells involved in RA

A
  • Infiltrating macrophages, mast cells, NK cells in synovium
  • Infiltrating neutrophils in synovial fluid (enhanced NETosis)
  • Macrophages appear to be key effectors:

–Phagocytosis

–Antigen presentation

–TNF, IL-1 and IL-6

  • Most therapies decrease macrophage cytokine production
  • Decreased macrophage infiltration strongly correlates with the degree of clinical improvement to therapies
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14
Q

what is the function of T cells in RA

A
  • Human leukocyte antigen (HLA) associations suggest T cell role
  • RA synovium is rich in activated T cells
    • Th17 cells and Th1 cells predominate
  • Increasingly, Th17 cells have been suggested as a major pathogenic subset. IL-17 is known to:
  • -Activate synovial fibroblasts and osteoclasts
  • -Favour cartilage resorption

-T regulatory cells are enriched in the RA joint but appear to be have a defect that can be reversed by blocking TNF

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15
Q

what are the roles of B cells in RA

A

Auto-antibodies associated with disease are usually present before onset of symptom

B cells form diffuse or follicular infiltrates in the RA synovium

B cell depletion using monoclonal anti-CD20 is effective treatment

B cells also produce cytokines and are important for antigen presentation

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16
Q

what interleukins are involved in the complex cellular interaction and what cells are they released by

A
  • synovial fibroblast prolif and activation- RANK L, M-CSF- osteoclast formation and activation also via il-6,1beta and TNF- activates synovial fibroblast from macrophages
  • macrophages < IL-1beta, iL-8,TNF, CCl2> monocyte and neutrophils
  • macrophages release Il-23 which activates TH17
  • macrophages TH1
  • B cells, autoantibodies and immune complexes- activate macrophages
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17
Q

describe the cartilage erosion that occurs with RA

A

1- Fibroblasts adhere to and invade the cartilage

2-Leads to biomechanical dysfunction and joint space narrowing

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18
Q

describe the normal maintenance of cartilage

A

1-Fibroblasts make matrix metalloproteases (MMPs) which break down the collagen network in the cartilage

2-Chondrocytes undergo apoptosis

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19
Q

what is the timeline for structural joint damage in RA

A

5 years- early and progressive

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20
Q

describe the cytokine mediated process of bone erosion

A

Cytokines including IL-17, RANKL, TNF-alpha, IL-1 and IL-6 promote osteoclast differentiation and activation

Deep bone resorption pits develop, which become filled with inflammatory tissue

Worse at mechanically vulnerable sites, such as the 2nd/ 3rd metacarpal

Little repair as cytokines inhibit the differentiation of osteoblasts

Affects 80% RA patients within 1 year of diagnosis

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21
Q

what are the clinical markers for RA

A
  • Elevated ESR
  • Elevated CRP
  • Rheumatoid factor (RF)
  • Cyclic citrullinated peptide (CCP) antibodies
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22
Q

describe the rheumatoid factor interaction with RA & evaluate use

A
  • Rheumatoid factors are antibodies directed against the Fc portion of another antibody, leading to immune complex formation
  • Of some use in diagnosis, but:
  • Not specific for RA (only 86%), also present in other autoimmune diseases, infectious diseases and some healthy individuals
  • Some RA patients are ‘seronegative’
  • Levels do not correlate with disease activity
  • RF +ve patients have a more severe disease
  • Role in pathogenesis is unclear
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23
Q

describe the Cyclic citrullinated peptide (CCP) antibody in RA

A

Also known as ACPA (anti-citrullinated peptide antibodies)

Antibodies directed against CCP are found in 60-70% of patients with RA (anti-CCP +ve)

Very rarely found in healthy people who do not go on to develop RA (high specificity 98%)

Detectable in the blood many years before disease onset

Anti-CCP +ve RA has a more aggressive clinical course of disease

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24
Q

describe the interaction of Citrullination as a marker with RA

A
  • process of replacing protein arginine residues with citrulline residues
  • Occurs normally in the body but if occurs on an unusual part of the protein, they may be recognised as foreign, leading to an antibody response
  • Cirullinated self proteins; α-enolase, keratin, fibrinogen, fibronectin, collagen and vimentin are detected in RA patients
25
Q

Do anti-CCP antibodies have a pathogenic role?

A

Unable to induce arthritis alone, but can enhances the development and severity of inflammation in mice when a mild synovitis is already present.

Possible mechanisms:

1) Activation of inflammatory cells by anti-CCP immune complexes
2) Anti-CCP mediated neutrophil cell death producing NETs
3) Direct binding of anti-CCPs to drive osteoclastogenesis.

26
Q

what is the Etiology of RA

A

genes- predisp- autoimmune disease- immune function & environment

(incidence in UK (0.8-1% of pop)

27
Q

what are the polymorphisms associated with RA

A

1) HLA-DRB1 SE -Human leukocyte antigen, account for 30-50% of the overall genetic risk
2) PTPN22 - (protein tyrosine phosphatase 22) Regulates T cell activation
3) CTLA4 -co-stimulation suppressor that regulates interactions between T cells and antigen presenting cells
4) STAT4-Transducer of cytokine signals that regulates proliferation, survival and differentiation of lymphocytes
5) TRAF1 -Regulator of TNFα receptor superfamily signalling

28
Q

what is the RA disease occurrence

A

-Monozygotic
‘identical’
- Monozygotic twins 12-15%

-Dizygotic
‘non-identical’-Dizygotic twins 3-5%

29
Q

describe in general how genetics influence RA

A
  • Susceptibility and severity of disease is determined by a combination of genes
  • No particular gene is necessary or sufficient for disease
  • Most genes show a relatively low gene penetrance. Variants are not found in many of the individuals who have RA.
  • Thus there must be other factors that in addition to genetics that have a role in the susceptibility and severity of autoimmune diseases.
  • The genes identified as risk factors are likely to regulate the immune response to environmental agents important in the induction of disease
30
Q

what are the hormones involved in RA

A
  • Testosterone is considered to protect against autoimmune disease. Men who get RA usually have low testosterone levels
  • Risk of developing RA is increased during the period just after giving birth
  • RA risk related to breast feeding after the first pregnancy
  • RA patients often experience remission during pregnancy. Patients show less disease activity and have increased numbers of T-regulatory cells that can suppress inflammation
  • However, the risk of developing RA after menopause is not influenced by hormone replacement therapy.
31
Q

how can smoking influence RA

A

-Heavy smoking of both sexes increase the risk of RA among persons with susceptibility HLA-DR4 alleles.

-Heavy smoking of both sexes increase the risk of RA among persons with susceptibility HLA-DR4 alleles.
Twin studies have demonstrated the gene–environment interaction by showing that the effect of smoking is greater in genetically susceptible individuals, particularly if HLA DRB1+

  • Smoking and HLA-DRB1 alleles increase the risk of being anti-CCP +ve
  • 2,3,7,8-tetrachlorodibenzop dioxin (TCDD) in cigarette smoke, has been shown to activate synovial fibroblasts to induce pro-inflammatory cytokines.
32
Q

what are the Suggested infectious trigger of RA

A

-Viral/bacterial infections have been suggested for many decades as an initiating cause of autoimmunity

-Hepatitis
,Chronic hepatitis C virus,Mycoplasma

  • Bacterial components have been identified in joint tissue from RA patients but also in healthy joint tissue
  • In argument against an infectious trigger, there has been no evidence of a seasonal influence on incidence of autoimmune diseases
33
Q

describe Periodontitis

A

Periodontitis is inflammation of the gums and supporting structures of the teeth. It is one of the most common human diseases.

Early Periodontal Disease
Periodontitis is caused by certain bacteria (known as periodontal bacteria) and by the local inflammation triggered by those bacteria. Although these periodontal bacteria are naturally present in the mouth, they are only harmful when the conditions are right for them to increase dramatically in numbers. This happens when a layer of bacteria and food debris, known as plaque, builds up and is left undisturbed on the teeth, commonly in hard-to-reach areas such as between the teeth.

34
Q

describe pathology of periodinitis

A
  • involves the genetic susceptibility of HLA-DRB1 shared epitope
  • Activated T cells via APCs
  • B cells activated, releasing antibodies
  • cause ACPA-based immune complexes
  • cause complement activation via C5AR and (FcyR) directly activates leucocytes which release inflammatory mediators
35
Q

what are the different types of therapies used for RA

A
  • Anti-inflammatory drugs
    Symptoms relief

-Disease-modifying antirheumatic drugs (DMARDs)
Slow the clinical and radiographic progression of RA:

Synthetic agents: MTX, sulfasalazine, hydroxychloroquine, leflunomid

Biologic agents: TNF-blockers,
Drugs targeting IL-1, IL-6 , B-cells and T-cells

36
Q

what are some examples of the anti-inflammatory drugs used for symptom relief

A

1)- Non-steroid anti-inflammatory drugs (NSAIDs)
- Non-selective COX-1/2 inhibitors: aspirin, ibuprofen, diclofenac
COX-2 selective inhibitor: celecoxib

2) - Steroid anti-inflammatory drugs (glucocorticoids), immunosuppressants
- prednisone, prednisolone, depomedrone, triamcinolone

Short-term use

Intramuscular injection/ injected into inflamed joints/ per os

Slow down disease progression, preventing further damage to the joints

Long-term use should be avoided: adverse effects can outweigh their therapeutic benefit over time even at low dose → risk of infections and osteoporosis

37
Q

describe the gold standard of treatment for RA

A

Synthetic DMARDs – Methotrexate (MTX)

  • Antimetabolite (folate analogue), inhibits cell proliferation
  • Increases adenosine level (anti-inflammatory)
  • Reduces the production of damaging polyamines
  • Induces apoptosis of activated CD4+ and CD8+ T-cells
  • Administered between 7.5 and 25mg weekly per os or s.c. – at this dose no significant anti-cancer or immunosuppressive effect
  • Reduces inflammation quickly and keeps it under tight control
  • Reduces the risk of death from cardiovascular disease in people with RA
  • Taking supplements of folic acid reduces side-effects caused by folic acid depletion
  • “Anchor drug” in combination therapies
38
Q

name some other synthetic DMARDS

A

Sulfasalazine (SSZ) – 2-component drug
Sulfapyridine (antibiotic) + 5-amino salicylic acid (anti-inflammatory)
Also used in ulcerative colitis

Hydroxychloroquine (HCQ) – antimalarial drug
Used in combination with other DMARDs
A possible mechanism of action: increases lysosomal pH in (immune) cells
Also used for the treatment of SLE

Leflunomid – lymphocyte inhibitor
Inhibits de novo pyrimidine synthesis
Most effective in reducing B-cell populations (but significant effect on T-cells too)

39
Q

describe DMARD combination therapy

A

Combinations of DMARDs – more effective in treating early active RA than the use of single drugs

Helpful when not possible to use biologic drugs e.g. in patients with recent cancer or chronic infection

Well tolerated, with no more side effects than the single drug

Methotrexate – “anchor drug” to which others should routinely be added:
+ sulfasalazine
hydroxychloroquine
leflunomide

  • Triple combination of MTX + SSZ + HCQ
    most effective which Uses steroids in some form
40
Q

what are the adverse effects of synthetic DMARDS

A
  • 8-12 weeks treatment required to achieve improvement of symptoms
  • MTX – 30% of patients experience adverse effects
-Side effects expected by DMARDs:
Nausea
Loss of appetite
Diarrhoea
Rash, allergic reactions
Headache

systemic side effects:
Additional side effects:

Hydroxychloroquine – accumulation of the drug in the eye
Leflunomid – hypertension

41
Q

describe how biologic is used to treat RA

A

Abstract
The effect of tumour necrosis factor (TNF alpha) antibodies on synovial cell interleukin-1 (IL-1) production was investigated in 7 patients with rheumatoid arthritis and in 7 with osteoarthritis. Synovial cell IL-1 production was significantly reduced by anti-TNF alpha antibody in cultures from patients with rheumatoid arthritis, but antilymphotoxin antibody did not have this effect (except in 1 culture). In cultures from patients with osteoarthritis spontaneous IL-1 production was low, despite high concentrations of TNF alpha, and IL-1 production was not inhibited by anti-TNF alpha antibody. In rheumatoid arthritis, TNF alpha may be the main inducer of IL-1, and anti-TNF alpha agents may be useful in treatment.
PMID: 2569055

42
Q

what type of role does TNF play in RA

A

-TNF released by macrophages causes:

1- endothelial cells to be activated by upregulation of ICAM-1,

causing leukocyte adhesion and diapedesis via Il-8 from synovial fibroblasts

2- activation of synovial fibroblasts to release Il-8, & matrix metalloproteases PGE2, Il-6

3- recruiting of monocytes which through interaction with Il-1 via synovial fibroblasts activate T cells- B cells which release RF and antibodies causing cartilage degradation

43
Q

describe anti-TNF therapy

A
  • TNF blockade both effective and relatively safe, has dramatically changed therapy for RA, Crohn’s disease, ankylosing spondylitis and psoriasis.
  • comparing a TNF-a blocker with a placebo. Almost 80 percent of patients receiving a high dose of the TNF-a blocker responded to treatment, compared to just 8 percent on placebo
44
Q

what are the targets of biologic agents

A

Il-1, Il-6, T cells and B cells

45
Q

how are the biological agents protein drugs administered & when are they used for treatment

A
  • parenterally

1- Patient has failed to respond to treatment with at least two standard (synthetic) DMARDs, one of which must be MTX (unless patient cannot take MTX for medical reason)

2-Patient’s RA disease activity score (DAS 28) is measured as 5.1 or over, on two occasions, one month apart

46
Q

name some currently licensed biologics

A

TNF-blockers: etanercept, infliximab, adalimumab, certolizumab pegol, golimumab

Monoclonal antibody against B cells: rituximab

T cell co-stimulation blocker: abatacept

IL-6 blocker: tocilizumab

47
Q

describe the TNF-blockers (usually combined with MTX)

A

Infliximab – partially humanized mouse monoclonal anti-hTNF-a antibody

Etanercept – soluble TNF receptor dimer

Adalimumab – human IgG1 monoclonal anti-TNF-a antibody

Certolizumab pegol – PEGylated anti-TNF-a monoclonal antibody fragment

Golimumab – human IgG1 monoclonal anti-TNF-a antibody

48
Q

describe how infliximab works & admin

A

Neutralizes free, membrane and receptor-bound TNF-a → antibody-dependent cell-mediated cytotoxicity (ADCC)

(IV)

49
Q

describe how Eqtanercept works & admin

A

Extracellular domain of the hu p75 TNFR fused with the Fc domain of hu IgG1

Binds free and membrane-bound TNF reducing the accessible TNF in RA → ADCC

Also used for the treatment of juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis

(SUBCUT)

50
Q

describe how Certolizumab pegol – The Fab’ fragment

works & admin

A

PEGylated Fab’ fragment of humanized anti-TNF-a mAb – no Fc portion

Also used for the treatment of Chron’s disease

400mg by subcutaneous injection at

When Polyethylene glycol (PEG)
covalently attached to drugs, it reduces antigenicity, immunogenicity.

Prolongs circulatory time of the drug.

SUBCUT

51
Q

what are the side effects of ANTI-TNF therapy

A

Patients screened before starting treatment to exclude an increased risk of side effects, in particular for a past history of tuberculosis (TB), multiple sclerosis, recurrent infection, leg ulcers and a past history of cancer

Chest X-ray to be taken to exclude signs of previous TB and to exclude signs of heart failure

Anti-TNF therapy can be administered for as long as 10 years.

Patients can stay on the drug for as long as they continue to respond well to it.

Increased risk of infections, reactivation of TB

Live vaccines, against e.g. yellow fever or live polio, should be avoided

52
Q

describe how Rituximab – The B-cell depleting agent

works & admin

A

Partially humanized anti-CD20 mAb

Rituximab opsonized B-cells are attacked and killed by three mechanisms:

Complement mediated cytotoxicity

2-3) Antibody-dependent cell mediated cytotoxicity (ADCC) – FcgR/ CR mediated opsonic phagocytosis

4) Apoptosis

used for Also used for the treatment of SLE

IV

53
Q

adverse effect of biological therapies

A

Increased risk of infections:
Upper respiratory tract infections (nasopharyngitis)
Pneumonia
Urinary tract infections
It is recommended to receive influenza and pneumococcal vaccines before embarking on biological therapy

Avoid life vaccines

Nausea

Headache

Hypertension

Allergic reactions

Contraindicated in pregnancy and while breast feeding (rituximab, tocilizumab, abatacept, anakinra)

54
Q

describe how Anakinra works

A

Recombinant IL-1ra

Differs from native human IL-1ra: it has the addition of a single methionine residue at its amino terminus

In RA: 
	Reduces bone erosion
	Decreases osteoclast production
	Blocks IL-1 induced MMP release 
	from synovial cells

Not used in the UK to treat RA, but licensed in the US

55
Q

describe how Tociluzimab works

& admin

A

The IL-6R blocker

Also used in systemic juvenile idiopathic arthritis

IV

56
Q

describe how Abatacept works & admin

A

The T-cell co-stimulation blocker

CTLA-4/ hu IgG1 soluble receptor fusion protein

Competitive inhibitor of CD28

Increases threshold for T-cell activation

Suppresses the proliferation of synovial recirculating T cells

Reduces the level of inflammatory mediators

Intravenous infusion of 500mg, 750mg

57
Q

describe the other diseases that biologic agents affect

A

Also used in juvenile idiopathic arthritis,

plaque psoriasis,

psoriatic arthritis,

ankylosing spondylitis,

Crohn’s disease

58
Q

how is Adalimumab, golimumab – Fully human anti-TNF-a mAbs

administrated

A

40-50mg subcutaneous injection every other week- monthly

204-theme 1 (15 decks)

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