Lecture 30 - Rheumatoid Arthritis - TNF Flashcards Preview

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Flashcards in Lecture 30 - Rheumatoid Arthritis - TNF Deck (48):
1

Which cells synthesise TNF-α?
Describe its synthesis

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

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

2

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

1975
Called cachexin

Observed features:
• Lysis of tumour cells
• Wasting

3

What are the TNF-alpha receptors?

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

Both membrane bound

4

Describe the TNF-dependent cytokine cascade in RA

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

5

What was present in human rheumatoid synovium studies early on?

Cells:
• T cells
• Macrophages

Factors:
• Cytokines
• Destructive enzymes
• Prostaglandins

6

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

What is the conclusion that can thus be made?

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)

7

What is the inhibitory effect of TNF-alpha?

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

8

What is sTNF-R?

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

9

What were the worries with TNF blockade?

• TNF has anti-inflammatory effects

• TNF leads to death of tumour cells

10

Which animal models are used to study TNF-alpha?

Describe the studies

-- 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

11

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

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

12

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

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

With therapy: absence of most of the macrophages

13

Which was the first TNFi?
When was it introduced

Infliximab, late 90's

14

What is Anakinra?

Recombinant IL-1Ra
Competitive antagonist

15

What is Tocilizumab?

Humanised Anti-IL-6R mAb
IgG1

16

What is Abatacept?

Recombinant CTLA4 on IgG1 frame
Through blocking T cell co-stimulation from APCs, the T cell experiences anergy

17

What is Rituximab?

B cell depletion
Chimaeric mAb against CD20

18

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

Chimeric mAb against TNF

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

Administration:
• Every 8 weeks

19

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

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

Weekly injection

20

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

Fully human mAb
Both constant and variable regions are human

Fortnightly injections

21

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

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

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

22

What is Golimumab?

Structure:
• Human IgG1 kappa mAb against TNF

Administration:
• 30 days intervals

23

What are the big 5 anti-TNF mAbs?

• Infliximab
• Adalimumab
• Etanacept
• Golimumab
• Certolizumab pegol

24

What is ACR20?

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

What percent of patients achieve the ACR20?
What is the rule?

ACR20: 60%

ACR50: 40%

ACR70: 20%

This is the 60-40-20 rule

26

What is an Odds Ratio (OR)?

Explain what it means

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

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

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

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

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

Compare primary and secondary failure of TNFi's

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

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

30

Why is secondary failure observed?

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

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

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

32

What are the safety issues with TNFi's

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

What are some new themes in RA treatment

• Small molecule inhibitors (e.g. Tofacitinib)
• Head-to-head trials of bDMARDs

34

What are 'Head-to-Head' trials?

bDMARDs trialled head to head

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


1. ADA - ABA

2. TOC - ADA

35

Describe the ADA - ABA head to head trial

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

Describe the TOC - ADA head to head trial

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

Which anti-TNF drug is the market leader?

Adalimumab

US$1.4 billion in one quarter

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

38

What is Tofacitinib?
• Administration
• MOA

• Novel
• Oral
• Small molecule inhibitor

Inhibition of:
• JAK 1
• JAK 3
• JAK 2
• Tyrosine kinase (to a lesser extent)

39

What is JAK?

What does it have a role in?

Janus kinase

Role in intracellular signal transduction

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

40

Describe the JAK/STAT pathway

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

41

How does Tofacitinib disrupt intracellular signalling?

Inhibits JAK in the JAK/STAT pathway

Prevents gene transcription downstream

42

Describe RCTs of Tofacitinib
• Efficacy
• Safety

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

Which drug acts intracellularly?

Tofacitinib

44

What are the adverse effects of Tocilizumab?

• Cytopaenias
• Elevated LDL
• Headaches
• Opportunistic infections

45

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

Infammatory cytokines

Immunosuppressive cytokines / species

46

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

No alarming AEs

47

What are the sources of TNF in the RA synovium?

Activated synovial macrophages

Also:
Synovial fibroblasts
T cells

48

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

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