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Idiopathic Pulmonary Fibrosis: An overview
of the disease, current and developing
treatments
Idiopathic Pulmonary Fibrosis (IPF) is a progressive fibrotic Interstitial
Lung Disease (ILD) of unknown cause. Extensive scarring of lung tissue
impairs function and as there is no curative treatment prognosis is very
poor [1]. It is difficult to diagnose and is not well understood as there are
very limited resources dedicated to research when comparing to cancer
research [2]. After a brief introduction on IPF, this paper will discuss
current therapies, recent clinical developments, and future developments
through pre-clinical evaluations.
Pathophysiology
The epithelium becomes activated in the lungs in IPF which can trigger
epithelial to mesenchymal transition (whereby epithelial cells behave like
mesenchymal cells) and the release of TGF-β [3]. The differentiation and
migration of fibroblasts and myofibroblasts is triggered by:
• clotting factors
• mediators released by activated epithelial cells (e.g. TGF-β, PDGF, Wnt)
• cells which have undertaken epithelial to mesenchymal transition
Fibroblasts and myofibroblasts may even differentiate directly from
epithelial cells and are altered by mutations, often involving epigenetic
changes [4]; they evade apoptosis, proliferate and generate extracellular
matrix at a rapid rate.
Myofibroblasts are more fibrotic than fibroblasts. These secrete large
amounts of extracellular matrix rich in type I collagen. As the excess
extracellular matrix is deposited this may act as a positive feedback
mechanism for further deposition of collagen. Myofibroblasts also disrupt
the basement membrane and the lung architecture through matrix
metalloproteinases [5]. The result of fibroblast activation is the
development of dispersed areas of fibrosis known as fibroblastic foci.
Underlying this is an inability of the lung to remove the damaged tissue as
it develops. Abnormalities in the immune system may enhance fibrosis and
this is currently under investigation.
Diagnosis
The American Journal of Respiratory and Critical Care Medicine has
defined evidence based guidelines for diagnosing IPF [6]. As is the case
with many idiopathic conditions, diagnosing IPF is not straightforward and
usually requires a multidisciplinary team (MDT) involving a chest
physician, a radiologist, a histopathologist, a lung surgeon and a specialist
nurse [7]. The difficulty lies in the fact that this is essentially a differential
diagnosis. The MDT must establish that the patient suffers from ILD that
is not caused by any known cause such as environmental exposure to
irritants, connective tissue disease or drug toxicity. Further investigations
should include High-Resolution Computed Tomography (HRCT) and, in
some cases, a surgical lung biopsy; showing a pattern of Usual Interstitial
Pneumonia (UIP), a subtype of ILD that includes IPF and is characterised
by fibrosis in specific patterns [6].
Clinical Features
The main features found in IPF patients are (in decreasing order of
relevance): age > 45, persistent breathlessness on exertion, persistent
cough, bilateral inspiratory crackles and finger clubbing. History taking
and examination, lung function testing and blood testing are essential in
diagnosing ILD and finding known causes of ILD hence ruling out IPF [7].
Typical features of clinical presentation for IPF patients
Name of study authors
Age
Sex (M/F)
Smoker
PRESENTING SYMPTOMS
Cough
Sputum
Dyspnoea
Fatigue
Haemoptysis
Chest pain
Recurrent unexplained fever
Leg/foot swelling
Lin Pan et. al. [8]
Clinical findings were recorded on clinical presentation for 75 patients
diagnosed with IPF [8].
Imaging
The next step in investigation should be referring the patient for a chest Xray and an HRCT scan. X-rays are often done first and provide a basis for
referring to an HRCT scan, looking for evidence of honeycombing, a
common feature in most IPF patients [6].
Typical HRCT and Chest X-RAY for an IPF patient [9]
Figure 1. HRCT scan(left) showing the subtle difference between honeycombing (*, posterior part
of the right lung) and emphysematous lesions (arrowhead, lateral left lung). The X-RAY(right)
shows signs of reticular opacity (blurring caused by an intraparenchymal process [9]) which is
also indicative of UIP [5]. Reproduced with permission from [9], Copyright Massachusetts Medical
Society.
At this stage there can be a diagnosis. However, often the investigations
are inconclusive and further testing is required [7].
Lung Biopsies
Bronchoscopic and transbronchial biopsies are also tools that help make
alternative diagnoses, but the most accurate diagnostic tool is a surgical
lung biopsy. A surgeon obtains tissue directly from the lung which is then
analysed by a histopathologist who will look for UIP-specific patterns [7].
Typical histological slides for an IPF patient [9]
Figure 2. (A) shows the presence of heavily fibrosis tissue. (B) is further magnified and shows the
close anastomosis of a fibroblastic focus (*) with normal alveolar tissue (arrow). These features
are characteristic of IPF. Reproduced with permission from [9], Copyright Massachusetts Medical
Society.
The added information from performing a surgical biopsy is usually
enough for the MDT to reach a conclusion. However not all patients are
eligible for a surgical biopsy and diagnosis can be very challenging [7].
In order to exclude other potential causes of observed ILD such as
sarcoidosis, a bronchioalveolar lavage, yielding differential cell count and
analysis, may be performed [7].
Survival
Median survival from diagnosis is 3 years but is closer to 7 years if
measured from the onset of symptoms. Survival is very heterogeneous
with some patients surviving more than a decade while others decline
much more rapidly. Mortality increases with age and cigarette
consumption during illness. Not all patients with IPF die from the disease,
and there are some comorbidities which can influence survival such as
emphysema [1]. The proportion of patients with IPF who die from the
disease is disputed with one study suggesting it could be less than half.
Other causes of death include cardiovascular disease, cancer and infection
[11]. Individuals with IPF have higher prevalence of vascular disease [12].
Incidence
The standardised mortality rate in the UK has increased from 1968 to 2008
and this is not explained solely by an ageing population but may partly
reflect increasing awareness of the disease. IPF accounts for more deaths
in the UK than ovarian cancer, lymphoma or leukaemia [13].
The reported incidence and prevalence of IPF can vary greatly between
countries [11] [13] [14]. Whilst there is likely to be a degree of
international variation, research is also dependant on the methodology
used. Changes in classification have occurred over recent years and IPF
was only formally classified as a unique disease state in 2000, discrete
from the other idiopathic interstitial pneumonias [15].
The incidence of IPF in the UK was predicted to be 8.0/ 100,000 person
years in 2008 [13]. In some countries such as Taiwan the incidence is
much lower [11], however, higher estimates of 16.3/100,000 person years
have been suggested in studies in the USA. Such findings occurred when a
broader diagnostic classification was used. The results of epidemiological
studies depend significantly on the breadth of criteria used [14] and are
rarely based on biopsy findings [16].
Incidence is higher in males and increases with age; hence we can expect
to see a rise in prevalence in the future due to the aging population. Very
few cases are seen in individuals younger than 55 [13]. There is some
geographical variation within the UK and it appears that incidence rates
may be higher in rural areas [13], perhaps due to environmental and
occupational risk factors (see below).
Risk Factors
As IPF is a rare disease, the majority of research into epidemiology
involves case control studies which often do not provide particularly
strong evidence of a causal link and are especially prone to recall bias.
Individuals with certain genotypes may have a predisposition to the
disease. Exposure to environmental risk factors may then cause injury and
further modify the genetic make-up of the epithelial cells, often through
epigenetic changes.
Tobacco smoking is an established risk factor of IPF. Smoking trends may
help explain the discrepancy of incidence between the sexes. Abnormal
acid gastro-oesophageal reflux shows higher prevalence in those with IPF
(87%) than asthma and has been strongly associated with the disease [17].
A wide variety of environmental and occupational exposures have been
attributed as potential risk factors for IPF. These include agriculture (from
exposure to dust such as feeding grains or faecal material), livestock, wood
dust and stone/sand [16].
Viruses may play a role and research suggests that herpes virus can trigger
endoplasmic reticulum stress, a key feature in the pathophysiology of the
disease [5].
Genetics also play a role in pathogenesis. Patients with IPF have
significantly shorter telomeres in the alveolar epithelium than is expected
which may prevent effective regeneration in the lung. Mutations in the
telomerase enzyme (TERC and TERT) are present in some familial cases
of IPF [18], and surfactant protein (C and A2) may also be mutated and
accumulate.
A mucin 5B gene promotor polymorphism in epithelial cells of the lung is
associated with approximately 35% of sporadic cases [5]. This may be due
to reduced clearance of toxic agents which contribute to the disease [19].
Using this knowledge of IPF a variety of treatments have been
developed, aiming to improve the survival rate of patients.
Traditional Pharmacological Therapy
The traditional pharmacological therapy for IPF is an anti-inflammatory
agent used together with an immunomodulatory or anti-fibrotic agent. The
anti-inflammatory agent is usually a corticosteroid, and the current
recommended drug of choice is prednisone. The immunomodulatory agent
recommended is usually either azathioprine or cyclophosphamide [20].
Azathioprine is a purine analogue converted to its active form in body
tissues. It acts by inhibiting adenine deaminase, thus inhibiting de novo
purine synthesis and therefore impairing cell proliferation, especially
leukocytes and lymphocytes. Cyclophosphamide is an alkylating agent of
the nitrogen mustard group. It is given orally and is activated in the liver to
several cytotoxic compounds that suppress lymphocyte function [21].
Figure 3. Chemical Structure of Azathioprine
Figure 4. Chemical Structure of Cyclophosphamide
The benefits of the traditional therapy, however, remain debatable. As
reviewed in Mapel et al.’s paper, some older trials evaluating
corticosteroid therapy in IPF suggested favourable corticosteroid response
with improvements in factors associated with a better prognosis, but these
improvements are only seen in a small percentage of patients.
Furthermore, the improvement is seen primarily in patients who have a
better outlook, with less advanced pulmonary fibrosis [22]. The lack of
useful, high-quality clinical data evaluating the benefits of corticosteroid
therapy makes it difficult to derive from these studies a distinction
between causation and correlation.
Similarly, there is no consensus that a combined corticosteroid therapy
with azathioprine or cyclophosphamide improves outcomes. Schwartz et
al.’s paper in 1994 suggests that cyclophosphamide therapy is beneficial;
however, it had a small sample size and was designed as an observational
study rather than a treatment intervention trial [23]. Other trials [24, 25]
show combined corticosteroid and cyclophosphamide therapy to be
unhelpful in delaying disease progression, listed in Table 1. These trials
also cannot be taken to be conclusive: in addition to a small sample size in
Riha et al.’s paper, retrospective trials are less able to take into account all
the pertinent risk factors involved as risk factors would have been recorded
before-hand, and there is likely to be minimal standardisation of the
recorded data for accuracy and consistency as compared to randomised
prospective controlled trials [26].
Study
Schwartz et
al., 1994 (4)
Riha et al.,
2002 (5)
Collard et al.,
2004 (6)
Therapy
Sample Size,
Trial Type
corticosteroids 39: 14
VS
corticosteroids,
cyclophospham 7
ide VS no
cyclophosphami
treatment
de, 18
untreated.Prospe
ctive
observational
study
corticosteroids 42: 27
VS
corticosteroids,
corticosteroids 7 corticosteroids
and
and
cyclophospham cyclophosphami
ide VS no
de, 8
treatment
untreated.Retros
pective review
prednisone and 164: 82
cyclophospham prednisone and
ide VS no
cyclophosphami
treatment
de, 82
untreated.Retros
pective review
Outcome
Patients on
cyclophospham
ide had better
outcome
No difference
in survival
No difference
in survival
Consensus Recommendation
The current consensus recommendation is to use prednisone, azathioprine
and N-acetylcysteine (NAC). NAC is a precursor of the major antioxidant
glutathione and thus acts as a powerful antioxidant and cellular
detoxifying agent. It was shown to restore depleted pulmonary glutathione
levels and to improve lung function in patients with fibrotic lung disease
[27]. It has been proposed more recently that an oxidant / antioxidant
imbalance is involved in alveolar epithelial cell injury and thereby
contributes to progressive fibrosis in IPF [5]; if this were true, the use of
NAC in managing IPF would appear to have some scientific basis. This is
backed up by a 2005 randomised parallel-group intervention trial with a
sample size of 182 patients, which showed statistically significant
improvement for patients on NAC compared to patients on traditional
therapy: patients on NAC + traditional therapy had less deterioration in
VC and single-breath DLCO at 6 and 12 months than patients only on
placebo + traditional therapy [28].
Figure 5. Chemical Structure of N-acetylcysteine
Clinically, the use of any drug combination would have to take into
account not only the benefit to the patient, but also possible adverse
effects. The common adverse effects of NAC include nausea, vomiting,
and other GI complaints. Rarely, rash and / or fever may occur. These
adverse effects are rather common among drugs and are, in most cases,
quite benign. Not only was there no significant additional toxicity seen
with use of NAC, NAC seemed to protect against azathioprine-induced
myelotoxicity [29].
However, there are as of now no published trials evaluating the mortality
and / or morbidity of patients on NAC therapy versus patients who are not
on any therapy. Therefore while the use of NAC in addition to traditional
therapy may be established as better than that of traditional therapy, the
question of whether pharmacological agents really do help IPF patients
still remains.
To Give, or Not to Give?
Given that there is little reliable, quality evidence-based data to support the
use of combined corticosteroid therapy, should it still be given to patients
with IPF? Corticosteroids are used pharmacologically to treat patients with
inflammatory disorders, but recent research evidence suggests that chronic
inflammation plays only a minimal role in the progression of IPF [5].
Furthermore, corticosteroids are known to have many adverse effects,
including, but not limited to, osteoporosis, hypertension, infertility, and a
heightened risk of catching infections. Do the questionable benefits of
pharmacological agents really justify their usage? To answer this question,
we looked at and evaluated alternative approaches to the treatment of IPF.
The Surgical Approach
Due to the poor prognosis of IPF, patients with end-stage IPF are often
considered for lung transplantation [30]. However, the efficacy of this
procedure has long since been debated. Lung transplantation involves
donation of one or two healthy lungs to an individual with IPF; these lungs
will be free from fibrosis and should therefore give a better prognosis to
those who receive them. Lung transplant has been found to decrease risk
of death by around 75% [31], showing that statistically, it is an option
worth considering at end-stage IPF. Lung transplants can be done
unilaterally or bilaterally depending on severity of bronchiectasis [31].
However, evidence suggests that there is no significant survival benefit
between patients receiving unilateral or bilateral transplantation [32].
Out of all patients awaiting lung transplantation, IPF patients have the
poorest prognosis [33]. Even when considering other conditions requiring
lung transplant, IPF has the highest percentage of people dying while on
the waiting list [34]. While this means they are prioritised by transplant
teams over some other conditions, receiving a transplant will still depend
upon organ availability, ABO blood group matching to avoid chronic
rejection and cytomegalovirus status [31]. Despite this, transplant teams
may well prioritise patients with other conditions such as Cystic Fibrosis
because of their higher survival benefit from the transplantation [34].
Another cause of prioritisation over end-stage IPF sufferers is that IPF
often develops in people age 50+ [13]. Transplant teams may be more
likely to give organs to younger patients because of the associated survival
benefit.
Time on the waiting list has to be very short as prognosis is so poor.
Waiting times for transplantation depend on the centre, availability of
organs and prioritisation, and IPF patients can find themselves waiting
anytime from 2-12 months for a transplant [31, 33, 34]. Even though
transplants are quickly prioritised, death on the waiting list for IPF remains
shockingly high, stretching from 30-40% in some centres [31, 34]. This
high death rate on quite often a short waiting time could suggest that
patients are being referred for transplant too late into the disease process
[33]. Earlier referral for transplantation may see better survival rates in IPF
patients and could provide better outcomes for a lot of people currently
suffering.
Are Transplants our Answer?
Although, survival rates are a lot higher for patients who have received
transplant [31, 34], the 5 year survival rate of patients is still only around
50% [30-33]. A lot of patients die from sepsis after the operation has
occurred, and there is always the risk of chronic rejection in all
transplantations. Some patients also died of cancer before 5 years.
Although there is no established link between carcinoma and IPF, it has
been suggested that whatever is causing the fibrosis in IPF could also be
damaging and mutating the p53 gene, a mutation important in
carcinogenesis. On top of this IPF and cancer share several risk factors
such as smoking [9].
As stated earlier giving transplant earlier in the disease may be a good
option to combat the high death rates associated with end-stage IPF [9].
But even as death from organ rejection and sepsis decreases there will
always be a limited supply of organ donors and therefore prioritisation of
IPF and other diseases will still go on, and death will occur in some cases.
Considering transplant for IPF earlier in the disease will also mean there
will be more people on the waiting list for transplants and waiting times
will increase for all diseases.
As current pharmacological therapies and surgeries have limited benefit in
IPF, the answer lies with identifying the underlying fibrotic process in IPF,
and developing new clinical options to combat or reverse the disease
process to improve prognosis for patients.
Tralokinumab Monoclonal Antibodies
N-acetylcysteine Antioxidants
Warfarin Anticoagulation
Aerosol Interferon-gamma (cytokine)
Thalidomide (immunomodulatory drug)
Losartan (angiotensin-II receptor antagonist) Other
Antifibrotics Pirfenidone Nintedanib
Endothelin Receptor Antagonists Macitentan Bosentan
Combination Therapies Azathioprine, Prednisolone & N-acetylcysteine
PEX, Rituximab & Steroids
Current Clinical Trials for IPF Treatment
The current pharmacological treatments for IPF are relatively ineffective at
improving the disease prognosis or slowing the disease progression.
Current treatment options focus on anti-inflammatory mechanisms [6]
however multiple drugs, many of which are anti-fibrotic, are in clinical
trials.
Pirfenidone
Pirfenidone is an anti-fibrotic and anti-inflammatory agent that is currently
used as a treatment for mild-to-moderate IPF in most of the world. It was
first approved in 2008 for use in Japan and has since been approved for
use in India, Europe, China, Canada, and the USA with the FDA
approving its use in October this year.
Figure 6. Chemical Structure of Pirfenidone
The exact mechanism of action of pirfenidone is unknown; however it has
been shown to reduce fibroblast formation, inhibit TGF-β stimulated
collagen production and down-regulate pro-fibrotic cytokines.
After dealing with problems such as acute exacerbations from IPF leading
to patient death, some early clinical trials for pirfenidone [35] showed that
it preserved vital capacity, and this justified the CAPACITY phase III
studies. [36] The two CAPACITY trials had the primary endpoint of
change in percent predicted (FVC) at Week 72 after starting a course of
pirfenidone. Only one of the studies met this with statistical significance,
however. The results of this paper followed by a Cochrane review of nonsteroid treatments for IPF [37] was considered sufficient evidence to
approve the drug for use in Europe, however the FDA required more
evidence to prove pirfenidone’s effectiveness, and this prompted the 2014
ASCEND study [38].
The ASCEND study went on to meet its primary endpoint (change in
FVC) and both of its key secondary endpoints (6MWD, PFS) with
statistical significance. Following a pre-specified analysis of the ASCEND
study [39] the FDA approved pirfenidone for treatment of mild-tomoderate IPF.
The use of pirfenidone as IPF treatment is currently under scrutiny as it is
only slightly slowing down disease progression, and is not curative or
proving to increase quality of life.
Nintedanib (BIBF 1120)
Figure 7. Chemical Structure of Nintedanib
Nintedanib, previously known as BIBF 1120, is a tyrosine kinase
antagonist which targets pro-fibrotic growth factor receptors including
those for FGF, VEGF and PDGF. Following successful mouse studies,
nintedanib was advanced to a randomised, double-blind, placebocontrolled Phase II clinical trial. [40]
Figure 8: Graph shows the effect of different nintedanib doses on lung function, measured using
FVC. A dose of 150mg of nintedanib twice daily was shown to reduce annual FVC decline by ⅔
compared to the placebo. Reproduced with permission from [40], Copyright Massachusetts
Medical Society.
The TOMORROW trial reported three main effects of nintedanib on IPF:
• decrease the frequency of acute exacerbations
• potentially slow decline in lung function
• improve quality of life [41]
However, these improvements can be mainly attributed to the treatment of
some secondary effects of IPF, instead of the IPF cause itself. [40]
Despite this, nintedanib has a lot of potential regarding IPF treatment and
it might not be long before it is licensed for use, having been given priority
review by the FDA and accelerated assessment by the European Medicine
Agency.
Endothelin Receptor Antagonists
Endothelin receptor antagonists (ERAs) work by blocking endothelin
receptors which are activated by endothelin (ET-1). ET-1 is a potent,
endogenous vasoconstrictor and acts via proliferation of smooth muscle
cells, fibrosis, inflammation, and endothelial dysfunction. In addition, ET1 is a profibrotic molecule that can increase collagen synthesis and
decrease interstitial collagenase production. It is thought that by blocking
the actions of ET-1 that prognosis of patients with IPF might improve.
ERAs also have anti-angiogenic effects, as increased vasculature is caused
by IL-8 release [42] and this is thought to contribute to fibrosis. [43] It is
therefore hypothesised that a reduction in angiogenesis would reduce
fibrosis.
Bosentan
Another ERA being investigated for the treatment of IPF is bosentan.
After the first BUILD trials showed a trend to delayed IPF worsening or
death, as well as improvements in some measures of dyspnoea and healthrelated quality of life, [44] further BUILD trials looked to demonstrate
these trends further. Both of these trials failed to achieve their primary
outcomes, however. BUILD-2 suggested its failure related to its primary
outcome, 6MWD, not being appropriate to assess treatment effects in
parenchymal lung disease. [45] BUILD-3 used IPF worsening for its
primary outcome, [46] however this did not aid the success of the study.
Macitentan
Macitentan is an ERA approved for the treatment of pulmonary arterial
hypertension, but is now being investigated for its potential benefit in IPF
treatment. The MUSIC trial was a phase II study that compared macitentan
versus placebo to assess its effect on FVC in IPF patients. [47] Neither the
primary or secondary endpoint of the study was met, and this meant the
follow-up study (MUSIC OL) was withdrawn prior to enrolment as it was
not justified.
Other Therapies
Losartan
Losartan is an angiotensin II receptor antagonist used mainly to treat
hypertension, however its effectiveness in treating IPF is currently being
trialed. A phase I clinical trial published in 2012 [48] showed a potential
association between regular losartan intake and attenuation of disease
progression in IPF patients. The only other study pursued for use of
losartan in treating IPF was by the University of Iowa in 2011, however it
was withdrawn in the recruitment phase.
Tralokinumab (monoclonal antibody)
Monoclonal antibodies bind to specific target cells or proteins, which are
then attacked by the patient’s immune system. Tralokinumab is a human
IgG4 recombinant monoclonal antibody (mAb) for interleukin-13 (IL-13),
a cytokine that is thought to possibly play a role in the pathogenesis of IPF
through the promotion of inflammation, fibrosis, and mast cell activation.
Targeting IL-13 is also believed to enhance repair processes in the lungs.
[49] There is an ongoing phase II trial currently evaluating the efficacy and
safety of tralokinumab in patients with mild-to-moderate (IPF) over a 72week treatment period. Recruitment for a clinical trial to evaluate the
efficacy of tralokinumab in adults with IPF is also underway.
Warfarin
As an anticoagulant, warfarin was proposed as a potential treatment option
for IPF as previous studies have linked IPF to thrombosis-related clinical
events, such as an increased risk of acute coronary syndrome and deep
vein thrombosis. [50] The first study to look at the use of warfarin to treat
IPF [51] was stopped due to a low probability of benefit based on an
increase in mortality seen in the subjects randomised to warfarin (14
warfarin versus 3 placebo deaths).
N-acetylcysteine (NAC)
The PANTHER-IPF trials recently analysed the effectiveness of NAC as a
monotherapy compared to the current three-drug regimen. [52] However
these trials had to be halted due to severe adverse effects and an excess
number of deaths in the combination-therapy group. Further research is
therefore required for a conclusion on the effectiveness of NAC as a
monotherapy to be drawn.
Aerosol interferon gamma (IFN-γ)
Interferon gamma (IFN-γ) is a Th1 cytokine which inhibits collagen
production. In fibrosis, the balance of cytokines is shifted towards
promoting collagen, thus inhibiting collagen production should decrease
the levels of fibrosis. The effectiveness of IFN-γ in IPF treatment remains
unclear however. A 1999 study found that IFN-γ and prednisolone
significantly improved pulmonary function tests in patients who had
previously been unresponsive to treatment. [53] However, another study in
2004 found no significant difference when IFN-γ was administered
compared to a placebo. [54] Further studies are therefore required to
investigate the therapeutic potential of IFN-γ.
Thalidomide
Thalidomide is an immunomodulator with anti-inflammatory effects and
anti-angiogenic properties. It has been shown to suppress TNF-α levels,
[42] which may slow the deterioration of lung function in IPF patients as
TNF-α plays a crucial role in fibrosis. The anti-angiogenic properties of
thalidomide are of interest as they may cause a reduction in fibrosis,
however further studies are required to determine whether thalidomide
might be a viable treatment for IPF.
Combination therapies
Future pharmacological treatments of IPF may lie in the use of
combinations of drugs instead of one single drug, following the successful
results of some trials.
Azathioprine, Prednisone and NAC
This combination is currently recommended for IPF treatment, having
been shown to stabilise the condition of IPF patients, slow their disease
progression and decrease the deterioration rate of VC and DLCO. [28] In
2011, the American Thoracic Society recommended against this three-drug
regimen as a routine treatment for IPF, [5] however it may be appropriate
in some cases.
PEX, Rituximab and Steroids
Two clinical studies are currently in progress investigating the effects of
combined PEX, rituximab (mAb) and corticosteroids in the United States.
[55, 56]
Figure 9. Table comparing two clinical studies investigating the combination therapy of PEX,
rituximab and steroids.
This page gives an overview of some of the drugs currently in clinical
trials, however more potential options are being explored – many of which
are through pre-clinical trials.
TRIAL NAME
A
PHASE
Multicenter 2
ESTIMATED
COMPLETION
DATE
July 2015
AIM
Effects
EXPERIMENTAL ARM EXPERIMENTAL
A
ARM B
of
this Standard
Steroid Standard
Steroid
Study
of
Combined PEX,
Rituximab and
Steroids
in
Acute Idiopathic
Pulmonary
Fibrosis
Combined PEX, 1/2
Rituximab and
Steroids
in
Acute
IPF
Exacerbations
combined
treatment
Treatment:
Treatment
+
Rituximab + PEX
Intravenous
Methylprednisolone
December 2014 Feasibility, safety
and efficacy in
hospitalised
patients
with
acute
IPF
exacerbations
Standard
Treatment:
Steroid Standard Steroid
Treatment
+
Rituximab + PEX
Intravenous
Methylprednisolone
Preclinical Studies for IPF
The only drug currently approved for IPF treatment, pirfenidone, received
a ‘weak no’ recommendation from four well-respected medical
groups.[57] Pirfenidone can produce photosensitivity side-effects in more
than 50% of patients, with little clinical benefit.[58] Therefore a new
treatment for IPF is needed to improve the poor disease prognosis.
Preclinical trials are underway to try and find a new alternative. Most
commonly used is the bleomycin model in mice.
Figure 10. Masson’s stain of mice lungs showing the fibrotic effects of Bleomycin. Reproduced
with permission from [68], Copyright Massachusetts Medical Society.
Bleomycin refers to a family of structurally related compounds, used in
anti-cancer chemotherapy via DNA breakdown.[59] It causes single and
double-strand breaks in tumour cells, interrupting the cell cycle. However
this produces DNA-cleaving superoxide and hydrogen-free radicals which
lead to an inflammatory response causing pulmonary toxicity, activation of
fibroblasts and subsequently, fibrosis. Bleomycin was chosen for animal
use because of the major adverse effect that results: fibrosis. Since its first
use modelling IPF, numerous agents have been shown to inhibit its
fibrosis. However, very few have been used clinically in IPF management
and their efficacy is significantly reduced in humans compared to animal
models.[60]
Bleomycin causes rapid inflammatory and fibrotic reactions giving
elevation of inflammatory cytokines and pro-fibrotic markers, peaking at
around day 14. Certain histological hallmarks, such as mural incorporation
of collagen, intra-alveolar buds and obliteration of alveolar space, leads to
the assumption that it is very similar to the human disease. The bleomycin
model is advantageous due to its ease of performance, making it accessible
and reproducible. Instillation is normally through intratracheal
administration resulting in fast inflammatory reactions causing
bronchiocentric accentuated fibrosis. Techniques such as intravenous or
intrapleural administration cause subpleural scarring, which is more
similar to the human disease. All methods of instillation have a control
group subjected to the same procedure but using saline.[59]
Bleomycin has contributed largely toward understanding of IPF,
elucidating roles of cytokines, growth factors and signalling pathways.
Now we can identify multiple limitations with the model. To start, single
bleomycin injection into a mouse causes pathogenesis resembling acute
lung disease, because the injury sustained comes at one point in time,
rather than the continuous and progressive deterioration in IPF; a chronic
disease. A recurring problem is that all these trials test the drug’s effect
over a short time – less than 31 days – therefore results obtained are for
minimizing acute injury and repair.[61] Human IPF lasts much longer and
therefore this has minimal relevance.[62] Additionally, fibrotic
development induced by Bleomycin is partially reversible, independent
from intervention, which isn’t the case in humans. This is demonstrated in
the graph below from a 2009 paper[63]; at 28days Lactate Dehydrogenase
(LDH) – a fibrosis level marker – levels in the lungs were similar in the
control and bleomycin-exposed mice. This shows mice lungs can
somewhat recover from bleomycin-induced lung fibrosis even without
treatment.
Figure 11. This graph shows the ability of mice lungs to partially recover from the fibrosis caused
by bleomycin, void of any intervention. Reproduced with permission from [63], Copyright
Massachusetts Medical Society.
Studies also often start treatment immediately after injury is sustained,
whereas in humans significant damage will have developed before
symptoms and subsequent treatment are initiated. Therefore, even with
promising results in mice in preclinical trials, success may not replicate in
humans.
Further studies have been conducted recently, refining the bleomycin
mouse model. For instance, bleomycin injected biweekly models the
chronic disease nature more closely as their lungs receive continuous
injury for 16 weeks.[64] Ten weeks following this, mice lungs still display
significant fibrosis. However, issues occur such as gaining ethical consent
and a very high mortality rate.
Although bleomycin is the most ubiquitous current model, there are
alternatives. One study used Silicon Dioxide to induce pulmonary fibrosis
in mice. Silicon Dioxide, also known as Silica, is the second commonest
element in the Earth’s crust, found in many rocks. Breaking it down
produces silica dust which, if deposited in the lungs is phagocytosed by
macrophages which are unable to differentiate between pathogens and
silica particles. This initiates an inflammatory response, releasing multiple
cytokines and subsequently fibrosis as fibroblasts proliferate, producing
collagen around silica particles.[65]
The 2009 paper used bleomycin to induce pulmonary fibrosis to
investigate the effectiveness of vascular endothelial growth factor (VEGF)
receptor tyrosine kinase inhibitor SU5416 as a treatment. It was considered
a potential therapy because of VEGF’s role in angiogenesis, which is
important in fibrotic development. This study aimed to see if VEGF
pathway disruption might significantly reduce pulmonary fibrosis in the
mice. The results, although showing a strong correlation between
increased VEGF expression and heightened angiogenesis and therefore
higher pulmonary fibrosis, did not show a decrease of lung fibrosis on
treatment of SU5416.
Group
Day 7
Control
BLM
E-SU5416
L-SU5416
Microvessels number (vessels/HPF)
Day 14
Day 28
Table 1: SU5416 inhibits angiogenesis response in bleomycin-induced
pulmonary fibrosis, measured by microvessel density.[63]
A more recent study[57], from Japan, looked into using carbon monoxidebound haemoglobin vesicles. The use of carbon monoxide (CO) was based
on its potent anti-inflammatory, anti-oxidant and anti-proliferative effects.
Two obstacles of using CO are its extremely short half-life (1-21min) and
the high risk of toxicity when administered via inhalation. However, using
haemoglobin-vesicles solves both issues, and it is itself promptly
metabolized to ensure there is no accumulation in the body. Finally, it is
believed to carry CO to the lungs efficiently, making it a potential therapy
for IPF.
Some studies have used Transforming Growth Factor (TGF)-B1 as an
alternative chemical to induce lung fibrosis in mice. This is a natural
protein which appears to be critical in healing due to its role in
angiogenesis, its anti-inflammatory and anti-fibrotic effects. However, on
closer examination this is partially contradicted as TGF-B1 induces tissue
injury, stimulates apoptosis of cells and decreases epithelisation; all of
which inhibit healing.[66]
Even still, if TGF-B1 levels are elevated chronically, there is increased
collagen deposition and consequently excessive fibrosis results.[67] This
has been demonstrated by increased collagen staining in Ad-TGFB lungs
compared to the control (Ad-con) by a study from 2012; see image
below.[68]
Figure 12. Increased collagen staining in Ad-TGFB lungs compared to Ad-con, the control.
Reproduced with permission from [68], Copyright Massachusetts Medical Society.
Although initially earlier studies struggled with using TGF-B1 due to the
critical role it plays in airway development, causing problems with fetallethality.[57] However, having created live lung-specific TGF-B1 mice, an
exciting opportunity has arisen to study adult lung fibrosis. In the paper
previously mentioned, from 2012, TGF-B1 was instilled intratracheally
into anaesthetised mice.[66]
Another method of inducing pulmonary fibrosis in an animal model is the
use of a skin sensitising hapten fluorescein isothiocyanate (FITC) Single
intratracheal instillation of FITC leads to reproducible lung injury,
quantifiable increases in the lung collagen content and evidence of specific
immunity to fluorescein hapten.[69] It has several advantages over the
bleomycin model; it produces chronic persistent inflammation that leads to
an altered fibroblast phenotype resulting in increased collagen deposition
rather than transient fibrosis, which occurs in the bleomycin model.[69,
70] FITC also enables identification of injured areas by fluorescence,
which enables tracking of an area of initial injury at a time remote from the
injury. It is also less expensive than the bleomycin model.[69]
The aetiology of IPF is not well understood, meaning that any
pharmacological developments do not address the primary cause of IPF,
instead merely treating the associated pathology. Considering the extent of
our research, we have realised the very limited number of potential
treatments and the relatively unpromising results that clinical and preclinical trials have yielded. Therefore in order to advance treatment of this
disease and improve the prognosis for patients, the underlying cause needs
to first be identified.
In our first meeting, it became apparent that none of our group had much
knowledge about IPF. As the project progressed and consequently our
understanding of IPF developed, we realised the debilitating consequences
of the disease on a sufferer’s life. Simple daily tasks which are normally
carried out with ease are complicated by the significant lung destruction in
IPF and this leads to a severely reduced quality of life. The lack of
awareness of IPF also shocked us, particularly when we learnt of the poor
prognosis and survival time that accompanies a diagnosis. However, our
group were reassured that most of the papers we referenced were very
recent, demonstrating that there are many ongoing attempts to find a
successful treatment. Hopefully a significant advancement will be made in
the near future.