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BIOM30002 - M2M > Lecture 30 - Rheumatoid Arthritis - TNF > Flashcards

Lecture 30 - Rheumatoid Arthritis - TNF Flashcards

1
Q

Which cells synthesise TNF-α?

Describe its synthesis

A

Activated macrophages
(as well as synovial fibroblasts and T cells)

Production:
• Initially transmembrane
• Cytoplasmic tail cleaved
• Soluble TNF-alpha released

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2
Q

When was TNF-alpha first discovered?
What was it called then?
What were the observed features?

A

1975
Called cachexin

Observed features:
• Lysis of tumour cells
• Wasting

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3
Q

What are the TNF-alpha receptors?

A
  • TNFR1 + p55 (constitutive)
  • TNFR2 + p75 (induced)

Both membrane bound

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4
Q

Describe the TNF-dependent cytokine cascade in RA

A

TNF-alpha release

Proinflammatory: i.e. stimulates the release of other pro-inflammatory cytokines:
• IL-1
• IL-6
• GM-CSF

Anti-inflammatory: stimulates the release of suppressive cytokines
• IL-10
• IL-1ra
• sTNF-R

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5
Q

What was present in human rheumatoid synovium studies early on?

A

Cells:
• T cells
• Macrophages

Factors:
• Cytokines
• Destructive enzymes
• Prostaglandins

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6
Q

What were the observations in vitro of TNF-alpha neutralising antibody?

What is the conclusion that can thus be made?

A
  1. Cells from RA synovium in culture
  2. Treatment with TNFi
  3. Observations:
    • Decreased IL-1
    • Decreased IL-6
    • Decreased GM-CSF

However, also decreased:
• IL-10, sTNF-R and IL-1Ra

Conclusion:
TNF-alpha is pro-inflammatory and leads to the release of other pro-inflammatory cytokines (as well as the release of some anti-inflammatory cytokines)

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7
Q

What is the inhibitory effect of TNF-alpha?

A

TNF-alpha stimulates the release of suppressive cytokines (IL-10, IL-1Ra, sTNF-R)

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8
Q

What is sTNF-R?

A

Soluble TNF receptor

It is a decoy receptor that binds TNF in the extracellular space so that it can’t bind the membrane bound receptor

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9
Q

What were the worries with TNF blockade?

A
  • TNF has anti-inflammatory effects

* TNF leads to death of tumour cells

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10
Q

Which animal models are used to study TNF-alpha?

Describe the studies

A

– DBA/1 mice –
1. Genetically susceptible to RA were injected with collagen which induced arthritis (CIA)
2. TNFi administered to mice
3. Observations:
• Decreased joint inflammation
• Protection of joint architecture (cartilage and bone)
compared to the control group

NB In lower doses of anti-TNF mAb there was no significant improvement. Higher doses were required

Conclusion:
TNF-alpha drives disease in arthritis

– h.TNF.Tg mice –

  1. Mice over-expressing human TNF-alpha
  2. Treatment with TNFi
  3. Similar results to CIA mice
Furthermore, these mice also experienced
 • Polyarthritis
 • Colitis
 • Skin pathology
i.e. not just RA

With anti-TNF therapy:
• Lead to improvements in these diseases

Conclusion:
Anti-TNF therapy may be effective in other inflammatory disorders

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11
Q

When was the first human trial for anti-TNF therapy?

Describe the trial and the results

A

1992, Charing Cross Hospital

20 patients
Long-standing RA
Weren’t responding to all other therapy

Given anti-TNF mAbs

Outcomes:
• Improvement in symptoms
• Reduced signs of inflammation
• No alarming adverse events

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12
Q

Describe the histological changes seen in synovial tissue with and without anti-TNF therapy

A

W/o therapy: many macrophages present (which are producing TNF)

With therapy: absence of most of the macrophages

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13
Q

Which was the first TNFi?

When was it introduced

A

Infliximab, late 90’s

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14
Q

What is Anakinra?

A

Recombinant IL-1Ra

Competitive antagonist

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15
Q

What is Tocilizumab?

A

Humanised Anti-IL-6R mAb

IgG1

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16
Q

What is Abatacept?

A

Recombinant CTLA4 on IgG1 frame

Through blocking T cell co-stimulation from APCs, the T cell experiences anergy

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17
Q

What is Rituximab?

A

B cell depletion

Chimaeric mAb against CD20

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18
Q

What is Infliximab?
Describe these features:
• Structure
• Administration

A

Chimeric mAb against TNF

Chimeric:
• Mouse: variable regions
• Human: constant regions

Administration:
• Every 8 weeks

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19
Q

What is Etanercept?
Describe these features:
• Structure
• Administration

A

Fusion protein:
• Two p75 TNF-alpha receptors
• Human: constant region

Weekly injection

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20
Q

What is Adalimumab/Humira?
Describe these features:
• Structure
• Administration

A

Fully human mAb
Both constant and variable regions are human

Fortnightly injections

21
Q

What is Certolizumab pegol?
Describe these features:
• Structure
• Administration

A

Structure:
• Humanised mAb
• Solely Fab fragment
• PEG (to increase half life)

Administration:
• Reduced frequency of injections (due to longer half life)

22
Q

What is Golimumab?

A

Structure:
• Human IgG1 kappa mAb against TNF

Administration:
• 30 days intervals

23
Q

What are the big 5 anti-TNF mAbs?

A
  • Infliximab
  • Adalimumab
  • Etanacept
  • Golimumab
  • Certolizumab pegol
24
Q

What is ACR20?

A

American College of Rheuamtology 20 Percent

Criteria:
At least 20% improvement in:
• Swollen joint count
• Tender joint count
and three of the following:
• Parient-assessed global disease activity
• Evaluator-assessed global disease activity
• Patient pain assessment
• Functional disability (picking things up, turning on taps etc.)
• Acute phase response (ESR or CRP)

25
Q

What percent of patients achieve the ACR20?

What is the rule?

A

ACR20: 60%

ACR50: 40%

ACR70: 20%

This is the 60-40-20 rule

26
Q

What is an Odds Ratio (OR)?

Explain what it means

A

Measure of association between an exposure and an outcome

Comparing those who are exposed, and those who aren’t

OR = 1: Exposure does not affect outcome

OR > 1: exposure is more likely to achieve outcome

OR < 1: exposure is detrimental

27
Q

What was seen in the recent studies comparing bDMARDs with placebos?

A

Patients on bDMARDs are 3 (i.e. OR = 3.35) times more likely to achieve ACR50 than those receiving a placebo

NB different agents had varying Ors

Conclusion:
bDMARDs have better outcomes than placebo

28
Q

What have clinical trials determined about the relative efficacies of bDMARDs against synthetic DMARDs?

A

In one analysis, most of the biologics weren’t much better, or they were worse, than synthetic DMARDs (especially etanercept)

However in this analysis, certolizumab pegol had a far greater efficacy than any other

Despite this analysis, clinicians generally hold that bDMARDs work better than conventional agents (DMARDs)

29
Q

Compare primary and secondary failure of TNFi’s

A
  1. Primary failure:
    Exposure to medication, and no improvement at all

This may be because TNF is not the main molecule in this case of RA

  1. Secondary failure:
    • Start out really well on a medication
    • After a while ( a couple of years) it stops working
30
Q

Why is secondary failure observed?

A

Due to:
• Human anti-chimeric Abs (HACA)
e.g. against infliximab

• Human anti-human Abs (HAHA)
e.g. against Adalimumab

These are neutralising Abs against the drugs

31
Q

Compare time spent on these various drugs:
• Adalimumab
• Infliximab
Ethanacept

A

In order of time spent on the drug (most to least)
• Ethanacept
• Adalimumab
• Infliximab

32
Q

What are the safety issues with TNFi’s

A
  1. Administration
    • Injection site reactions
    • Infusion reactions
  2. Cytopaenia
    • Neutropenia
  3. Infections
    • Upper respiratory tract
    • Soft tissue (skin)
  4. Demyelinating disease
    • MS
  5. Heart failure
    • NYHA Type III and Type IV
  6. Malignancy
    • Non-melanoma
    • Lymphoma
  7. Induction of autoimmune disease
    • SLE
    • Psoriasis

Thus, patients must give consent before therapy

NB There are some confounding factors

33
Q

What are some new themes in RA treatment

A
  • Small molecule inhibitors (e.g. Tofacitinib)

* Head-to-head trials of bDMARDs

34
Q

What are ‘Head-to-Head’ trials?

A

bDMARDs trialled head to head

Subjects:
• Had never had bDMARDs before
• Had poor response on Methotrexate

  1. ADA - ABA
  2. TOC - ADA
35
Q

Describe the ADA - ABA head to head trial

A

Abatacept (ABA) vs. Adalimumab (ADA)

Efficacy, ACR20 %:
• ABA: 64.8%
• ADA: 63.4%

Adverse effects:
• ADA more injection site reactions

Conlusions:
• ABA non-inferior to ADA after one year

36
Q

Describe the TOC - ADA head to head trial

A

TOC: Tocilizumab
ADA: Adalimumab

Efficacy:
• TOC superior in reduction in DAS28 after 6 months

Adverse effects:
• TOC has more cytopaenias
• Increased LDL
• Increased Alanine Transaminase

Conclusion:
TOC is superior to ADA, but there is a trade off because of the AE

37
Q

Which anti-TNF drug is the market leader?

A

Adalimumab

US$1.4 billion in one quarter

Other drug companies want to show that their drugs are as effective as Adalimumab

38
Q

What is Tofacitinib?
• Administration
• MOA

A
  • Novel
  • Oral
  • Small molecule inhibitor
Inhibition of:
 • JAK 1
 • JAK 3
 • JAK 2
 • Tyrosine kinase (to a lesser extent)
39
Q

What is JAK?

What does it have a role in?

A

Janus kinase

Role in intracellular signal transduction

Role in:
• Immune cell activation
• Pro-inflammatory cytokine production
• Cytokine signalling

40
Q

Describe the JAK/STAT pathway

A
  1. Ligand binds to receptor
  2. JAK activation
  3. STAT activation
  4. STAT enters nucleus and turns on gene transcription
41
Q

How does Tofacitinib disrupt intracellular signalling?

A

Inhibits JAK in the JAK/STAT pathway

Prevents gene transcription downstream

42
Q

Describe RCTs of Tofacitinib
• Efficacy
• Safety

A

There have been four Phase III RCTs

Efficacy:
 • Superior to placebo
 • Superior to Methatrexate mono therapy
 • Safe in combination with Methatrexate
 • Comparable efficacy to Adalimumab
 • Viable therapy for patients who are not responding to anti-TNF therapy
Safety:
Some adverse effects:
 • Headaches
 • Infection
 • Elevated LDL
 • Neutropaenia
 • Opportunistic infection
Can not be used in combination with other bDMARDs

(so AEs similar to Tocilizumab)

43
Q

Which drug acts intracellularly?

A

Tofacitinib

44
Q

What are the adverse effects of Tocilizumab?

A
  • Cytopaenias
  • Elevated LDL
  • Headaches
  • Opportunistic infections
45
Q

In general, which classes of cytokines does TNF stimulate the release of?

A

Infammatory cytokines

Immunosuppressive cytokines / species

46
Q

What were the adverse effects seen in the first clinical trial of TNFi?

A

No alarming AEs

47
Q

What are the sources of TNF in the RA synovium?

A

Activated synovial macrophages

Also:
Synovial fibroblasts
T cells

48
Q 
Compare the structure of the following:
 • Adalimumab
 • Certolizumab pegol
 • Etanercept
 • Golimumab
 • Infliximab
A

Adalimumab:
• Human monoclonal IgG1

Certolizumab pegol:
• Humanised Fab fragment, pegylated

Etanercept:
• Recombinant TNF receptor (p75) with IgG1 frame

Golimumab:
• Human monoclonal IgG1

Infliximab:
• Chimaeric monoclonal IgG1

BIOM30002 - M2M (36 decks)

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