12. Inhaled corticosteroids (ICS) are now very widely
used in high doses in the management of COPD
patients , in sharp contrast to the situation in
asthma
12
13. (C)
(D)
(A) (B)
LAMA + LABA LABA + ICS
LAMA
Further
exacerbation(s)
Continue, stop or try
alternative class of
bronchodilator
A bronchodilator
Evaluate effect A long-acting
bronchodilator
(LABA or LAMA)
Persistent
symptoms
LAMA + LABA
LAMA +
LABA + ICS
Further
exacerbation(s)
Further
exacerbation(s)
Consider roflumilast
if FEV1 <50% pred.
and patient has
chronic bronchitis
Consider
macrolide
(in former
smokers)
Persistent
symptoms/further
exacerbation(s)
Treatment algorithm by GOLD groups:
Limited role of ICS containing treatment in Groups C & D
Preferred
treatment
LAMA + LABA
LABA +
ICS
LAMA
No
initiation
with ICS
containing
treatment
in GOLD
Groups C
and D*
*LABA/ICS may be the first choice in some patients. For example, those with
a history and/or findings suggestive of asthma-COPD overlap.
15. ICS/LABA combination therapy
Inhaled steroids not licensed for use in COPD
except as combination
ICS must be used in combination with LABA for
patients with COPD
ICS monotherapy only FDA approved for treatment
of asthma, not COPD
15
20. Inhaled corticosteroids (ICS) are the most effective controllers of
asthma.
They suppress inflammation mainly by switching off multiple
activated inflammatory genes through reversing histone acetylation
via the recruitment of histone deacetylase 2 (HDAC2).
21. ICS are the most effective anti-inflammatory therapy for
asthma but are relatively ineffective in COPD.
ICS fail to suppress inflammation in COPD patients because
there is a marked reduction in histone deacetylase-2 (HDAC) ,
the nuclear enzyme that corticosteroids require to switch off
activated inflammatory genes.
22. ICS provide much less clinical benefit in COPD & the inflammation
is resistant to the action of corticosteroids.
This appears to be due to a reduction in HDAC2 activity & expression
as a result of oxidative stress.
All patients with COPD show corticosteroid resistance.
23.
24. In patients with COPD, smoking asthmatics and severe asthma
there is a reduction in HDAC2 activity and expression, which
prevents corticosteroids switching off activated inflammatory
genes
25. FOR INTERNAL USE ONLY. STRICTLY CONFIDENTIAL.
DO NOT COPY, DETAIL OR DISTRIBUTE EXTERNALLY.
2
5
26. Recently ,much more has been learned about the molecular &
cell biology that account for switching on inflammatory genes &
even more about mechanisms for switching off those genes
that can be useful in therapy of inflammatory lung diseases
28. Modifications of core histone around which DNA is wound within the
chromosome plays a critical role in the regulation of all genes and
in determining which genes are active and which are silent.
Therefore, alteration of chromatin structure is the most important
in the regulation of inflammatory genes expression.
29.
30.
31. The structure of chromatin.
DNA is wound around nucleosomes, which are composed of eight
histone molecules with two copies of histones H2A, H2B, H3 and H4.
Each histone molecule has a long tail rich in lysine residues (K),
which are the sites of enzymatic modification, such as acetylation,
thus changing the charge of the molecule and leading to DNA
unwinding .
32.
33.
34.
35. Chromatin is made up of nucleosomes, which are particles consisting of
DNA associated with an octomer of core histone proteins (H2H, H2B, H3
and H4).
In the resting cells, DNA is wound tightly around those basic core
histones. This conformation of chromatin structure is described as closed
and is associated with suppression of gene expression
51. Coactivators, such as CREB-binding protein (CBP), have intrinsic
histone acetyltransferase (HAT) activity, resulting in opening up to
the chromatin structure, which allows binding of RNA polymerase II
and initiation of gene transcription.
Several transcription factors interact with CBP, including cyclic AMP
response element binding protein (CREB), nuclear factor (NF )- B,
activator protein (AP)-1 and signal transduction activated
transcription factors (STATs)
53. Gene activation & repression are regulated by acetylation of core
histones.
Histone acetylation is mediated by coactivators that have intrinsic histone
acetyltransferase (HAT) activity, opening up the chromatin structure to
allow binding of RNA polymerase II and transcription factors that were
unable to bind DNA in the closed chromatin configuration.
This is reversed by corepressors, which include histone deacetylases
(HDACs) and other associated corepressors that reverse this acetylation,
thereby causing gene silencing.
61. FOR INTERNAL USE ONLY. STRICTLY CONFIDENTIAL.
DO NOT COPY, DETAIL OR DISTRIBUTE EXTERNALLY.
Randomised
controlled trial
Observational
study
Systematic
review
Pneumonia X X X
Tuberculosis X
Bone fracture
(no effect on
fracture risk)
X X
Skin thinning/
easy bruising
X
Cataract X
Diabetes X
Oropharyngeal
candidiasis
X X X
Side effects of ICS in COPD and type of evidence
Price D. Prim Care Respir J 2013; 22: 92-100.
66. Stimulation of mild asthmatic alveolar macrophages activates nuclear
factor-κB (NF-κB) and other transcription factors to switch on histone
acetyltransferase leading to histone acetylation and subsequently to
transcription of genes encoding inflammatory proteins, such as tumour
necrosis factor-α (TNF-α), interleukin-8 (IL-8) and GM-CSF.
Corticosteroids reverse this by binding to glucocorticoid receptors (GR)
and recruiting histone deacetylase-2 (HDAC2).
This reverses the histone acetylation induced by NF-κB and switches off
the activated inflammatory gene
71. A reduction in HDAC activity in peripheral lung, airways, and in
alveolar macrophages is observed in patients with COPD.
This may account for the increased pulmonary inflammation and
resistance to corticosteroid treatment in those groups of patients.
There appears to be a selective reduction in HDAC2 expression
due to oxidative and nitrative stress. similar mechanism of steroid
resistance may also apply in severe asthma and smoking asthmatics
73. The molecular mechanism of corticosteroid resistance seems to be
due a defect in HDAC-2 .
There is increasing evidence that low concentrations of theophylline
are able to restore the activity and expression of HDAC-2 to normal
level in alveolar macrophages in COPD patients and to restore the
response of these cells to corticosteroids (theophylline is the
only activator of HDACs)
74. Similar mechanism of steroid resistance may also apply in severe
asthma and smoking asthmatics, theophylline may also be useful
in these patients and this may explain why theophlline appears
to be useful as an add-on therapy to inhaled steroids.
