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Biologics for the respiratory
physician
Nidhi Sofat
Clinical Senior Lecturer
St George’s, University of London
What is a biologic?
1. Review of what they are/ their pharmacology/
classification
2. Brief overview of how and when used for
rheumatological disease
3. The role of the resp physician - ruling out TB before use
- protocol/ guidelines for doing this, evidence of TB
- reactivation, immunology and science underlying this
4. Horizon scanning - are biologics ever likely to be
useful for respiratory disease
1. Review of what they are/ their
pharmacology/ classification
How were biologics discovered? - 1
• 1980s, new molecular tools enabled the biology of cytokine
expression and regulation to be studied
• TNF-dependent cascade in active rheumatoid synovium,
suggesting that TNF might be a therapeutic target
• This concept was supported in an animal model of the
disease
Biology of TNF production,
receptor interaction and signaling
Tracey et al. Pharmacology & Therapeutics 117 (2008) 244–279
Tracey et al. Pharmacology & Therapeutics 117 (2008) 244–279
How were biologics discovered? - 2
• The proof of concept was a series of clinical
trials, which have led to marked changes in
the therapy of human rheumatoid arthritis
and subsequently of other diseases
• The work with TNF clearly demonstrated the
importance of cytokines in medicine
• Capacity of mAbs (or receptor fusion proteins)
to be used long-term in large populations,
thus changing the therapeutic landscape.
TNF tumour necrosis factor
Pharmacokinetics simulation of serum concentrations of infliximab, etanercept and adalimumab
at steady state in patients with RA treated with each drug at the doses and schedules shown
Tracey et al. Pharmacology & Therapeutics 117 (2008) 244–279
Tracey et al. Pharmacology & Therapeutics 117 (2008) 244–279
2. Brief overview of how and when
used for rheumatological disease
Rheumatoid arthritis
Osteoarthritis
Degenerative joint disease
Burden of disease
• RA affects ~1% of the population worldwide, was a major clinical problem.
• With anti-cytokine therapy, RA is far from curable, but it is much more
manageable, less crippling, and less lethal
• RA is an autoimmune disease with chronic inflammation leading to joint
destruction.
• The classical autoantibodies, or rheumatoid factors, have long been
known; more recently discovered are IgG Abs to deiminated citrullinated
proteins.
• Cytokines augment HLA expression and Ag presentation to T cells in local
autoimmune disease sites like synovial joints
• Cytokine research was propelled by the successful biochemical
purification and cloning of cytokine cDNAs.
• Molecular biology techniques also helped provide key therapeutics, such
as engineered mAbs and receptor fusion proteins.
Anti-TNF therapies

Basic science data showed TNF may be
key regulator in inflammation (Brennan et al.
1992)

Infliximab, etanercept and adalimumab
undergone extensive clinical trials for
efficacy and safety

Share common properties, but also have
distinct pharmacologic and
pharmacokinetic profiles

Absence of direct comparison trials

Clinicians need to compare efficacy
First studies of TNF inhibitors
• First clinical trial of infliximab in RA was in 1992, at Charing Cross Hospital
(London, U.K.)
• Open-label trial due to concerns about safety of a blinded clinical trial.
Infliximab was well tolerated with no short-term safety signals and
impressive efficacy, but as the Ab metabolized, all patients relapsed by 12–
18 wk
• Next, a formal double-blind placebo-controlled randomized trial was
conducted
• A single infusion, with either a previously used effective dose (10 mg/kg)
or a tenth of that, was used; both were accompanied by dramatic doserelated efficacy over 4 wk compared with placebo
• From this trial, we were able to perform a series of studies on the
mechanism of action of the anti-TNF Ab.
ATTRACT study
• 2 year, multicentre, multinational trial in
428 patients with active RA despite
treatment with methotrexate
• Randomized to one of 5 treatments
• Infliximab 3 to 10 mg/mg every 4 to 8
weeks or placebo
• Followed up over 2 years
• All patients received stable dose of MTX
mean 15mg/kg/week
Maini et al, Lancet 1999
Main findings of ATTRACT
• At 30 weeks, 50% met ACR50 criteria at infliximab 3mg/kg
every 8 weeks, compared with 20% of placebo group
• At 54 weeks, higher percentage of treatment group
(3mg/kg) reached ACR20, ACR50 and ACR70 criteria
compared with placebo group:
• ACR 20 (42 VS 17%)
P < 0.05
• ACR 50 (21 VS 8%)
• ACR 70 (10 VS 2% )
• Effects sustained for up to 102 weeks
Modified Sharp score and Infliximab (ATTRACT)
Maini et al, Lancet 1999
Etanercept trials
Genovese et al. 2001
Adalimumab study
De Putte et al. 2003
Learning points
• Within hours of anti-TNF administration, elevated levels of IL-6 in serum
plummet virtually to baseline, thus confirming the existence of a TNFdependent cytokine network in RA patients in vivo
• Rapid normalization of low hemoglobin, high platelet counts, and
fibrinogen concentration and restoration of abnormal regulatory T cell
function
• Destructive enzymes (e.g., matrix metalloproteinase 3) are reduced, and
osteoprotegerin levels are restored
• Although there is a falloff of response to anti-TNF with time
• Some patients have remained responsive to anti-TNF for over 5 yr.
• This indicates that cytokine networks in RA evolve slowly, if at all, and if
TNF is blocked, its pivotal role in orchestrating the inflammatory response
is not displaced by another proinflammatory cytokine.
From new discovery to protocol development
Current TNF inhibitors in clinical
practice
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Adalimumab
Certolizumab pegol
Etanercept
Golimumab
Infliximab
Drugs used to treat inflammatory arthritis
Immunotherapy
DMARDS
Corticosteroids,
Cyclophosphamide
Anti-TNFα therapies
Rituximab
Anti-IL-6 tocilizumab
Combination
DMARDS
Methotrexate,
sulphasalazine,
azathioprine
NSAIDS and analgesics
Traditional treatment Paradigm- Rheumatoid Arthritis
Nice
guideline
Criteria common to many
trials in RA
• Effects on symptoms
• ACR response criteria
• Structure (joint space narrowing, erosions,
Sharp scores)
• Physical function/Quality of Life e.g. HAQ
scores
• WHY SO IMPORTANT
• The total cost of RA in the UK has been
estimated at between £3.8 and £4.75 billion
per year.
• 3. The role of the resp physician - ruling out TB
before use - protocol/ guidelines for doing
this, evidence of TB reactivation, immunology
and science underlying this
As Clinician – how do we
treat?
• Weigh evidence and experience
with different agents
• E.g. iv versus sc
• Post-marketing surveillance
• Risk factors e.g. TB
• Long-term data:
• BSR biologics register (10,000
patients)
Why are trials important
• They can change clinical practice
• May allow comparisons between
different treatments
• May give rise to the discovery of
new phenomena post-treatment
e.g. incidence of TB post TNF
therapy
Models for attributing tuberculosis (TB) to drug treatment.
Dixon W G et al. Ann Rheum Dis 2010;69:522-528
Cumulative incidence of tuberculosis (TB) following first exposure to anti-tumour necrosis
factor (anti-TNF) therapy (most recent drug model, with person-years censored at death, last
returned follow-up form, or date of switching to second anti-TNF).
Dixon W G et al. Ann Rheum Dis 2010;69:522-528
Cumulative incidence of tuberculosis (TB) following first exposure to antitumour necrosis factor (anti-TNF) therapy
• To April 2008, 40 cases of TB were reported, all in the anti-TNF cohort.
• The rate of TB was higher for the monoclonal antibodies ADA (144 events/100 000
person-years) and INF (136/100 000 person-years) than for ETA (39/100 000 personyears).
• After adjustment, the incidence rate ratio compared with ETA-treated patients was 3.1
(95% CI 1.0 to 9.5) for INF and 4.2 (1.4 to 12.4) for ADA.
• The median time to event was lowest for INF (5.5 months) compared with ETA (13.4
months) and ADA (18.5 months).
• 13/40 cases occurred after stopping treatment. 25/40 (62%) cases were
extrapulmonary, of which 11 were disseminated.
• Patients of non-white ethnicity had a sixfold increased risk of TB compared with white
patients treated with anti-TNF therapy.
Mechanisms of TB reactivation after TNF Inhibitor therapy
Source: The Lancet Infectious Diseases 2003; 3:148-155 (DOI:10.1016/S1473-3099(03)00545-0)
Interactions with infliximab and etanercept.
Infliximab binds more avidly than etanercept does to transmembrane TNFα and forms
a more stable complex
More infliximab than etanercept binds to transmembrane TNFα. Infliximab is more
effective at inhibiting transmembrane TNF -mediated activation of endothelial cells.
Infliximab binds both the monomeric and trimeric form of soluble TNFα, whereas
etanercept effectively binds only to the trimeric form. Etanercept–TNFα complexes are
unstable, resulting in the release of soluble TNFα
Source: The Lancet Infectious Diseases 2003; 3:148-155
(DOI:10.1016/S1473-3099(03)00545-0)
• Thorax 2005;60:800-805 doi:10.1136/thx.2005.046797
• BTS guidelines
• BTS recommendations for assessing risk and for managing
Mycobacterium tuberculosis infection and disease in
patients due to start anti-TNF-α treatment
• British Thoracic Society Standards of Care Committee*
• Correspondence to:
Professor L P Ormerod
Professor of Respiratory Medicine, Blackburn Royal Infirmary,
Blackburn, Lancashire BB2 3LR, UK;
[email protected]
Algorithm for management of TB in patients scheduled for anti-TNF-α treatment.
Copyright © BMJ Publishing Group Ltd & British Thoracic Society. All rights reserved.
False-positive PPD test in a patient with psoriasis due to
koebnerization
Screening tests
Characteristics
Advantages/Disadvantages
Suggested use
Tuberculin Skin Test (TST)
Not as sensitive or specific as QTF
More widely available
Requires a follow-up exam after placement
within 48–72 h
False positive with BCG vaccination
Best tested before start of
methotrexate or biologics
More sensitive and specific than TST
Best tested before the initiation of
biologics
Interferon gamma tests e.g. QTF / T spot
Requires a blood draw and less widely
available
False positive with exposure to
Mycobacterium
marinum
Possibility of pathergy to cause a
false positive
May lead to false negative during
ongoing biologic therapy.
Use in conjunction with
exposure/travel history and
symptomology
Exposure and travel history
Travel to endemic areas or exposure to
known TB contacts elevate risk for
Especially important after initiation
of biologics as positive
exposure or travel history should
prompt a chest X-ray, even with
negative TST or QFT
Chest X ray
Exposure to radiation
Use in those with history concerning
for possible TB exposure as
TST and QTF are less reliable in
ongoing biologic therapy
Can follow internal lung changes in time
Consider annual testing in those that
are already on biologic therapy
Mantoux versus Interferon gamma tests
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Diagnosis of latent TB
1. Mantoux/TST testing should be performed
2. Interferon-gamma (IFN γ)– tests, if available, should
be considered for those in whom Mantoux testing is positive
or is less reliable.
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Type of tests Number of labs
Mantoux test
Quantiferon test
T-spot test
BTS recommendations for assessing risk and for managing Mycobacterium
tuberculosis infection and disease in patients due to start anti-TNF-α
treatment
Table 3 Annual risk of TB disease/100 000 in England and Wales: effect of age
(to the nearest whole number)
Age (years)
White
Black African
0–14
1
47
15–34
2
314
35–54
4
168
55–74
7
204
>75
11
Not available
•4. Horizon scanning - are biologics
ever likely to be useful for
respiratory disease
Lessons learnt from biologic use in non-rheumatic diseases
• The pharmacodynamics of most biologics is incompletely understood; for
example, etanercept is ineffective in Crohn’s disease, whereas other antitumor necrosis factor (TNF) drugs are highly potent.
• Induction of immune tolerance may be achievable in the early stages of
autoimmunity
• Biologic therapies have occasionally been associated with reactivation of
latent viruses such as Epstein–Barr virus and JC virus. This may be
inseparable from their mode of action, and highlights the need for careful
post-marketing surveillance.
• Many inflammatory diseases exist as several phenotypes, which respond
differently to therapy.
• As highlighted by asthma studies, it is essential to identify and consider
these factors during clinical trial design in order to advance the field of
stratified medicine, which is currently in its infancy.
Nature Reviews Rheumatology 7, 507-516 (September 2011) | doi:10.1038/nrrheum.2011.106
Biologic therapies in non-rheumatic diseases: lessons for rheumatologists?
Gillian M. Bell, Gary Reynolds & John D. Isaacs
Summary
• Monoclonal antibody technology has
revolutionised rheumatology in the last 10
years
• New therapeutic targets emerging in other
specialties
• Pathway development critical for optimal
efficacy
Acknowledgements
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People, St George’s
Dr Alison Davis
Ms Cori Smee
Dr Monika Hermansson
Dr Tom Barrick
Dr Franklyn Howe
Dr Julekha Wajed
Dr Kaushik Sanyal
Miss Saralili Dipa Robertson
Mr Ray Moss
Dr Matt Szarko
Miss Caroline Hing
Prof John Axford
Prof Emma Baker
Dr Patrick Kiely
Dr Vivian Ejindu
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The Kennedy Institute of Rheumatology
Dr Robin Wait
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Heatherwood and Wexham Park NHS Trust
Mr Jonathan Jones
Funding
Rosetrees’ Trust
St George’s Charitable Trust
The Wellcome Trust
South London AHSC
NIHR
CLRN