lecture 30 Flashcards
Learning objectives?
- 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
What is the biology of TNFα?
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)
What is the TNF-dependent cytokine cascade in RA (simplified)?
- 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
What have in vitro models demonstrated Re: the role of TNF in RA?
- 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
What have animal models revealed re: the role of TNF in RA?
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
What was the TNF blockage in Animal model of RA?
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
What was the first human clinical study of monoclonal anti-TNF antibodies?
- 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
What is the timeline of development of Anti-TNF therapy?
- 1975: identified
- 17 years of work leading to first human clinical trial
- latter part of 1990s that infliximab (infusion)
- adalimumab and etanercept
What are Anti-TNF bDMARDs?
- infliximab
- gollmumab
- adalimumab
- certollizumab pegol
- etanercept
What are bDMARDs for IL-1 in RA?
anakinra: IL-1 receptor blockade
what are bDMARDs for IL-6 in RA?
- tocillizumab
What are bDMARDs for CTLA4-blockade in RA?
- abatecept
- t cell costimulation blocker
What is anti-CD20 bDMARD in RA?
- rituximab
What is infliximab?
- first anti-tnf
- chimeric (mouse/human)
- human IgG1 constant region
- mouse variable region
- given at 8 weekly intervals in patients with arthritis
What is etanercept?
- fusion protein
- two p75 TNFα receptors
- human IgG1 constant region
- weekly injection
What is adalimumab?
- fully human mAb
- human IgG1 constant and variable regions
- humira
- fortnightly
What is certolizumab pegol?
- humanised mAb
- antigen binding fragment (Fab’)
- polyethylene glycol (PEG)
- administered at 28 day intervals
- good for people who don’t like frequent injections
What is golimumab?
- human IgG1 kappa mAb
- humanised form of infliximab
- 28/30 day intervals
What are outcome measures in RA?
American college of rheumatology 20% improvement criteria (ACR20)
At least 20% improvement in:
- swollen joint counts
- tender join count
and three of the following five variables:
- patient-assessed global disease activity (e.g. by VAS)
- evaluator-assessed global disease activity (e.g. by VAS)
- patient pain assessment (e.g. by VAS)
- functional disability (e.g. HAQ)
- 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)
What is the efficacy of bDMARD vs placebo (ACR50)?
- 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
What is an odds ratio?
- 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
What determines non-responders to TNF inhibitors?
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
What are bDMARD survival rates in biological naïve RA?
- 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
What are safety issues with TNF-inhibitors?
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)
What is the future of RA treatment?
‘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
What are head-to-head bDMARD trials?
- 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
Why is everyone comparing their drugs to ADA?
3rd most grossing drug in 2013
in 1/4 of the year accumulated $1.40b
- all new players want to compare to market leader
What is tofacitinib?
- 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
What are clinical trials involving tofacitinib?
- 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
What are take home messages?
- 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
