Idiopathic Pulmonary
Fibrosis: Is There Anything New To Offer?
Chris Hatzis
Pathophysiology
lIPF is felt to begin after an
initial insult to the lung
lIPF has been associated with
smoking and occupational exposures (farming, glass cutting, etc)
lThis injury causes fibrogenic
cytokines to be released from alveolar macrophages such as TGF-b1, PDGF, TNF-a,
IL-1, and basic fibroblast growth factor
lFibroblasts differentiate,
making them more resistant to apoptosis and leading to an unremitting fibrotic
response
Azathioprine and
Prednisone
lA RCT was performed by Raghu et al. in 1991 with 27 previously untreated IPF
patients comparing prednisone plus placebo to prednisone plus azathioprine
lThere were no significant
differences in the changes in patients’ lung function parameters at one year
between the two groups, but a nonsignificant trend towards better FVC, DLCO,
and resting PaO2 did occur in the azathioprine group
lThere was also a trend towards
decreased mortality in the azathioprine group (43% [6/14] at nine years versus
77% [10/13] for the prednisone alone group), but this was not statistically
significant (p = 0.16)
lThere have been no larger RCTs since this trial
lThis combination has become
the standard of care for IPF therapy
Gamma-interferon 1b
lIn 2004, Raghu
et al. performed a RCT to compare the effect of gamma interferon 1b versus placebo
in corticosteroid nonresponders
lThere were no
differences between the placebo and treatment groups in the time to disease
progression, and there were no differences in TLC, DLCO, and resting PaO2
between the groups
lRisk of dying 17% in placebo
group and 10% in treatment group, however, difference was not statistically
significant
lA large RCT is underway to
determine if interferon gamma 1b may work in patients with less severe disease
Pirfenidone
lAzuma et al. performed a
double blind RCT in 2004 on 107 UIP patients randomized to either oral
pirfenidone or placebo
lThere was no statistically
significant difference between the groups in lowest SaO2 seen during 6 minute
walk
lHowever, there was a
significant improvement in the treatment group in lowest SaO2 during 6 minute
walk compared to the placebo group in patients who had SaO2 that remained >
80% on baseline 6 minute walk
lAt nine months the VC and TLC
decline was significantly less in the pirfenidone group
lNo acute
exacerbations occurred in the pirfenidone group in the 9 months studied, while 14%
of the placebo group had IPF exacerbations – this caused the study to be
aborted early
lPirfenidone may be of greater
benefit in patients with less severe disease
lCurrently undergoing phase
Anticoagulation
lKubo et al. (2005) enrolled 56
patients who were randomized to receive prednisolone alone or prednisolone plus
anticoagulation
lThe survival rate of the
anticoagulation group was significantly better than that of the steroid-only
group at 1 year and 3 years
lMortality from acute IPF exacerbations was significantly less in the group that received LMWH at the time of admission versus the prednisolone only group
lBoth long
term survival and IPF exacerbation survival were improved by anticoagulation
lUnblinded study, and intention
to treat analysis not used
lHowever, this is a promising
treatment pathway
N-acetylcysteine
lUsed currently as mucolytic,
for renal protection around the time of IV contrast administration, and
acetaminophen toxicity
lMultinational RCT by Demedts et al. (2005) with 182 patients randomized to
either 600 mg tid of oral NAC vs placebo
lThere was no significant
difference in survival between the two groups at 12 months
lNAC did slow deterioration of
primary endpoints (DLCO and VC)
lTrials with oral NAC alone
without standard therapy are needed
GERD and IPF
lRecent
studies have shown a high prevalence of GERD in IPF patients
lIs GERD a
risk factor for the development and progression of IPF?
lRaghu
et al. (2006) performed a case series of four patients with treatment naive IPF
who refused conventional treatment and were merely treated with PPI and
lifestyle changes
lIn this study, the patients with IPF with coincident GERD had stable or improving DLCO/FVC while compliant with GERD therapy
lAn RCT is needed to better
characterize if acid suppression can successfully halt IPF progression
Summary
lIPF is a progressive disorder
with a poor prognosis
lThere have been no
well-performed RCT showing a significant survival benefit for any therapy
lCytotoxic therapy has shown
some benefit in RCTs, but the risks of therapy may
outweigh the benefits
lNewer, less toxic treatment
strategies may be the future of IPF therapy