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BIOM30002 > lecture 30 > Flashcards

lecture 30 Flashcards

1
Q

Learning objectives?

A
  • evidence for a role of tumour necrosis factor alpha (TNF-α) in RA
    • in vitro and animal models
  • animal models: TNF α useful target in RA
  • TNF-inhibitors (TNFi)
    • different classes
    • efficacy
    • failure
  • human clinical trials of TNFi
  • future of RA treatment
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2
Q

What is the biology of TNFα?

A 
synthesised by: 
- activated macrophages 
- T cells 
→ transmembrane precursor protein 
→ cytoplasmic tail cleaved 
→ soluble TNF α (takes action at receptor site)
  • first described in 1975 (‘cachexin’)
    • ability to lyse tumours in vitro and in mouse models
  • binds one of two receptor types
    • TNFR1 (p55)
    • TNFR2 (p75)
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3
Q

What is the TNF-dependent cytokine cascade in RA (simplified)?

A
  • immune system
  • TNFα
  • stimulates release of pro-inflammatory cytokines inc. IL-1
  • both have downstream effects of promoting IL-6, 8, GM-CSF → pro-inflammatory
  • both also support production of anti-inflammatory cytokines such as IL-10, IL-1ra, sTNF-R
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4
Q

What have in vitro models demonstrated Re: the role of TNF in RA?

A
  • human rheumatoid synovium (cell mixtures) identified
    • abundance of T lymphocytes and macrophages
    • cytokines, destructive enzymes, prostaglandins (leading to joint damage)

TNF

  • role in production of pro-inflammatory cytokines supported by addition of neutralising TNFα antibody
    • decreased interleukin 1 (IL-1)
  • subsequent experiments
    • decreased IL-6
    • decreased granulocyte/macrophage colony stimulating factor (GM-CSF)

→ potential therapeutic target

  • however, TNFα inhibition downregulated production of effective cytokine inhibitors
    • decreased IL-10
    • decreased IL-1 ra
    • soluble TNF receptor
  • possible benefits of TNF blockade could be partially counterbalanced
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5
Q

What have animal models revealed re: the role of TNF in RA?

A

in animal model
- genetically susceptible DBA/1 mice
- collage type II-induced arthritis (CIA)
- administered hamster monoclonal anti-mouse TNF antibody
– therapeutically beneficial
→ reduced joint inflammation (cellular infiltration)
→ protective of joint architecture (cartilage, bone)
– supported hypothesis TNFα drives inflammation

  • further supportive data for anti-TNF therapy
    – TNFα expression in synovium
  • Human TNF Transgenic mice (hTNF.Tg mouse) TNF overexpression ‘all over the body’
    → erosive polyarthritis (major disease)
    → (colitis and skin pathology) → anti-TNF therapy in inflammatory bowel disease and psoriasis
  • experience with anti-TNF in CIA models replicated by several groups
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6
Q

What was the TNF blockage in Animal model of RA?

A

Model

  • genetically susceptible mice (DBA/1)
  • cia
  • about 21 days later arthritis appears and then spreads
  • joints destroyed
  • 50mg almost no effect
  • appeared to be dose dependent response
  • 500mg much better
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7
Q

What was the first human clinical study of monoclonal anti-TNF antibodies?

A
  • 1992
  • charing cross hospital
  • open, non-placebo-controlled design
  • twenty patients
  • long-standing RA
  • refractory to all existing therapy

→ improvement in symptoms
→ reduced signs of inflammation
→ no alarming adverse effects (AE)

dramatic reduction in macrophages

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8
Q

What is the timeline of development of Anti-TNF therapy?

A
  • 1975: identified
  • 17 years of work leading to first human clinical trial
  • latter part of 1990s that infliximab (infusion)
  • adalimumab and etanercept
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9
Q

What are Anti-TNF bDMARDs?

A
  • infliximab
  • gollmumab
  • adalimumab
  • certollizumab pegol
  • etanercept
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10
Q

What are bDMARDs for IL-1 in RA?

A

anakinra: IL-1 receptor blockade

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11
Q

what are bDMARDs for IL-6 in RA?

A
  • tocillizumab
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12
Q

What are bDMARDs for CTLA4-blockade in RA?

A
  • abatecept

- t cell costimulation blocker

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13
Q

What is anti-CD20 bDMARD in RA?

A
  • rituximab
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14
Q

What is infliximab?

A
  • first anti-tnf
  • chimeric (mouse/human)
  • human IgG1 constant region
  • mouse variable region
  • given at 8 weekly intervals in patients with arthritis
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15
Q

What is etanercept?

A
  • fusion protein
  • two p75 TNFα receptors
  • human IgG1 constant region
  • weekly injection
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16
Q

What is adalimumab?

A
  • fully human mAb
  • human IgG1 constant and variable regions
  • humira
  • fortnightly
17
Q

What is certolizumab pegol?

A
  • humanised mAb
  • antigen binding fragment (Fab’)
  • polyethylene glycol (PEG)
  • administered at 28 day intervals
  • good for people who don’t like frequent injections
18
Q

What is golimumab?

A
  • human IgG1 kappa mAb
  • humanised form of infliximab
  • 28/30 day intervals
19
Q

What are outcome measures in RA?

A

American college of rheumatology 20% improvement criteria (ACR20)

At least 20% improvement in:

  1. swollen joint counts
  2. tender join count

and three of the following five variables:

  1. patient-assessed global disease activity (e.g. by VAS)
  2. evaluator-assessed global disease activity (e.g. by VAS)
  3. patient pain assessment (e.g. by VAS)
  4. functional disability (e.g. HAQ)
  5. acute phase response (ESR or CRP)
VAS = visual analogue scale 
HAQ = health assessment questionairre 
ESR = erythrocyte sedimentation rate 
CRP = c-reactive protein

‘60-40-20’ rule
60% acr20
40% acr50 (of above)
20% acr70 (of above)

20
Q

What is the efficacy of bDMARD vs placebo (ACR50)?

A
  • used to only be able to compare bDMARD to gold standard (methotrexate)
  • forest plot
  • probably about 3x more likely to achieve ACR50 if you have RA and are exposed to one of these treatment agents
  • akanira confidence interval cross 1
  • etanercept is very efficacious
  • relative risk: different graph
  • certollizumab pegol much better than methotrexate
  • etanercept worse
  • adalimumab slightly better
  • other agents didn’t seem to work
  • but most clinicians do seem to accept that biological agents do work better than the standard
21
Q

What is an odds ratio?

A
  • measure of association between an exposure and an outcome
  • odds that an outcome will occur in a group exposed to a variable of interest, compared to the odds of the outcome occurring in a group not exposed to the same variable of interest

OR=1: exposure (TNFi) does not affect odds of outcome
OR>1: exposure (TNFi) associated with higher odds of outcome
OR<1: exposure (TNFi) associated with lower odds of outcome

22
Q

What determines non-responders to TNF inhibitors?

A

primary failure
- TNFα not their principle molecule

secondary failure

  • neutralising antibodies
    • human anti-chimaeric antibodies (HACA) e.g. infliximab
    • Human anti-human antibodies (HAHA) e.g. adalimumab
23
Q

What are bDMARD survival rates in biological naïve RA?

A
  • how long do these medications work for once you’ve started them?
  • this is for patients who’ve never been exposed to a biological agent
  • etanercept, adalimumab, infliximab
  • survival rates in the first 6 months are comparable
  • as time passes there is a separation of the lines
  • etanercept seems to be most well tolerated
  • 60 months: still effective in 60% of patients
24
Q

What are safety issues with TNF-inhibitors?

A

Administration

  • injection site reactions
  • infusion reactions

Cytopaenia
- neutropaenia

Infections

  • upper respiratory tract
  • soft tissue/skin

Demyelinating disease

  • neurodegenerative conditions e.g. MS
  • someone patients have developed MS while on treatment
  • tends to occur young women (who are the most at risk population)
  • hard to tease out the confounding factors

Heart failure
- new york heart association (NYHA) III and IV

Malignancy

  • non-melanoma skin cancers
  • lymphoma (very active RA already puts you at a risk of lymphoma)

Induction of autoimmunity

  • psoriasis (get a very specific time: normal clears, palm/foot covering, very uncommon in general population, causal relationship, even with cessation of therapy some get chronic psoriasis)
  • SLE (skin and joints, brain and kidneys)
25
Q

What is the future of RA treatment?

A

‘head-to-head’ trials of bDMARDs

  • direct comparisons of biological DMARDs
  • new therapeutic agents
    • small molecule inhibitors e.g. Tofacitinib (Janus Kinase (JAK)-inhibition)
    • intracellular
26
Q

What are head-to-head bDMARD trials?

A
  • Abatecept (ABA) vs Adalimumab (ADA)
  • methotrexate inadequate responders (MTX-IR), bDMARD-naïve
  • comparable efficacy
    • ACR20: ABA (64.8%) vs ADA (63.4%) at 12 months
    • inhibit radiographic progression
  • Adverse effects
  • ADA more injection site reactions
  • conclusions: ABA non-inferior to ADA at year 1

Tocilizumab (TOC) monotherapy IV vs. ADA monotherapy (subcutaneous)

  • MTX-IR
  • TOC superior for reduction in DAS28 at six months
  • AE
    • TOC more cytopaenieas (decreased platelets, neutrophils)
    • increased LDL cholesterol (maybe long term effect re: heart disease)
    • increased alanine transaminase (ALT)
  • conclusion: TOC superior to ADA but assoc. with more AE at 6 months
27
Q

Why is everyone comparing their drugs to ADA?

A

3rd most grossing drug in 2013
in 1/4 of the year accumulated $1.40b
- all new players want to compare to market leader

28
Q

What is tofacitinib?

A
  • novel, oral small molecule inhibitor
  • preferentially inhibits JAK 1 and 3 more than JAK 2, tyrosine kinase (lesser extent)
  • role in intracellular signal transduction critical for immune cell activation, proinflammatory cytokine production integral to lymphocyte function, cytokine signalling involved in RA pathophysiology
29
Q

What are clinical trials involving tofacitinib?

A
  • four phase III randomised controlled trials (RCT)
  • study outcomes:
  • ACR 20
  • DAS28-ESR <2.6 @ 3 months
  • health assessment questionnaire disability index (HAQ-DI)

efficacy

  • superior to placebo
  • effective as monotherapy MTX-IR
  • safe in combination with MTX
  • comparable efficacy to ADA
  • treatment alternative in RA patients TNFi-IR (non-TNFi-IR)

safety
AE
- headaches
- infection (upper respiratory tract, urinary tract)
- elevated LDL:HDL
- neutropaenia
- opportunistic infections (e.g. mucovacterium, tuberculosis)
- not for use in combination with bDMARD, cyclosporin, azathioprine

30
Q

What are take home messages?

A
  • benchtop to bedside story of TNF-inhibition: human tissue (in vitro models) complemented by animal models
  • five TNF agents available for RA treatment
    • effective
    • safety issues
  • first ‘head-to-head’ trials in bDMARDs
    • tocilizumab superior to adalimumab
    • abatacept non-inferior to adalimumab
  • new agents in development
    • small molecule inhibitors e.g. JAK inhibition

BIOM30002 (36 decks)

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