Pirfenidone, an orally administered pyridine, demonstrated combined anti-inflammatory, anti-oxidant and anti-fibrotic actions both in vitro and in animal models of pulmonary fibrosis, consisting in the regulation of the expression of TGF-β and inhibition of fibroblast and collagen synthesis. However, the precise mechanism of action remains unknown.
Four placebo-controlled randomized trials [
82‐
84] explored and confirmed the beneficial effect of pirfenidone in IPF patients. The results of a pre-specified pooled data analysis incorporating data from the phase 3 trials supported the efficacy of pirfenidone towards the reduction of overall and IPF-related mortality, although rates of death did not differ significantly in the individual prospective trials. Overall, the use of pirfenidone in the reported studies was associated with adverse events of generally mild to moderate intensity, such as gastrointestinal symptoms (nausea, dyspepsia), raised liver function tests and photosensitivity. The favourable safety profile and good tolerability of pirfenidone have been confirmed by post-authorization data provided by recent interim reports from international open-label extension studies [
85,
86]. Findings from several single-center European and Japanese studies have also contributed to confirm long-term tolerability and also efficacy, sometime showing a trend toward stabilization of the disease in a significant proportion of treated patients [
87‐
90].
Nintedanib is a multiple inhibitor of tyrosine kinase receptors implicated in lung fibrosis pathogenesis, including PDGF receptors α and β, VEGF receptors 1, 2 and 3, and FGF receptors 1, 2 and 3 [
91], which was shown to prevent the development of lung fibrosis in the bleomycin murine model [
92]. Nintedanib at a dose of 150 mg given twice daily showed efficacy in reducing in the rate of functional loss in phase 2 an 3 trials [
93,
49],prompting the approval of the drug for use in patients with mild-to-moderate IPF. Gastrointestinal side effects (diarrhoea, nausea, and vomiting) and increase in the levels of liver enzymes were the most common side effects in the treated groups.
Therapeutic approach of IPF: A practical guide
For the first time after decades of disappointing results, physicians have now two equally effective treatment options to offer to patients with IPF. Translating the results of the trials into clinical practice proved to be not straightforward though, and some uncertainties are still limiting the management of the heterogeneous IPF population.
The timing for starting treatment might represent the first challenge for physicians approaching those patients newly diagnosed with IPF who are asymptomatic and have little or no functional impairment. In fact, it is unclear whether they might benefit from any treatment since there is no marker to ascertain the future clinical course of these patients. Recent post-hoc analyses of pooled data from the late phase trials on the efficacy of both nintedanib and pirfenidone showed that in the placebo arms subgroups of patients with more preserved lung function at baseline had a similar rate of progression of the disease as compared to patients with more impaired lung function, while the treated subgroups showed to receive the same benefit from both drugs [
95,
96]. This evidence would suggest that an early commencement of anti-fibrotic therapy in patients with IPF is advisable regardless of their functional impairment at baseline. Indeed, until effective markers for predicting disease course are validated, risks and potential benefits of an early start of treatment should be evaluated in the single individual, also keeping an eye on the high costs of the available therapies.
Duration of treatment represents a matter of debate, as it is unknown whether pirfenidone or nintedanib maintain their efficacy for periods longer than 2 years and whether they should be discontinued in those patients experiencing significant disease progression, as there are no markers of response to treatment available yet. A subgroup analysis of data from the CAPACITY and the ASCEND trials showed that in patients who progressed significantly during treatment (predicted FVC decline > 10% after 6 months), those who continued pirfenidone had a lower risk of subsequent FVC decline or death [
97]. As for Nintedanib, first evidence on the efficacy of long-term treatment has been recently provided by the open-label INPULSIS-ON trial, evaluating the safety and efficacy of nintedanib 150 mg twice daily in patients who completed an INPULSIS trial. Such analysis suggested that patients continuing or starting nintedanib in INPULSIS-ON declined similarly to patients treated with nintedanib in INPULSIS, suggesting that the efficacy of nintedanib is kept for up to 3 years [
98].
This trial also allowed to enter patients with more severe disease (i.e., FVC ≤ 50% predicted, and exclusion criteria for most randomized trials in IPF) and will hopefully clarify whether the beneficial effects of these drugs may be generalized to the whole IPF population. The interim analysis showed that patients with FVC ≤ 50% and > 50% predicted at baseline had a similar decline in FVC to week 48, suggesting that nintedanib may offer similar benefits in patients with advanced disease [
98]. However, only 24 patients with FVC ≤ 50% predicted were included in the analysis, as such these finding are not conclusive. Nevertheless, with the sole exception of the America Food and Drug Administration Agency, regulatory health agencies excluded this population from the indication to treat with pirfenidone and nintedanib, and stronger post-marketing surveillance evidence is needed to change the current regulations.
With two drugs available, which should be chosen when starting treatment? Indeed, pirfenidone and nintedanib appear to have comparable efficacy and tolerability, as well as a partially overlapping spectrum of potential side effects [
49,
99]. As such, the initial choice should be based on the careful consideration of the patient’s features, including comorbidities, concomitant medications, and personal preferences. The replacement of the first agent should be considered when side effects are not tolerable, while it does not seem convenient to interrupt either anti-fibrotic treatment when disease progression is evident, as both pirfenidone and nintedanib seem to maintain efficacy over several years. Very few data are available on patients experiencing such therapy shift. Retrospectively, a small population of patients switching to nintedanib from pirfenidone treatment has shown that nintedanib may be better tolerated, but no conclusions can be drawn from this limited evidence [
100].
When available and appropriate, the option of participating in a clinical trial should always be considered and discussed with the patient. This can give access to new, potentially beneficial therapies and gives the patients the opportunity to play an active role in their management and to be followed by expert medical staffs in specialized centers.
Following the example of most fields of respiratory medicine, such as asthma, chronic obstructive pulmonary disease, pulmonary hypertension and lung cancer, combination therapy that includes the use of different molecules in a synergic has a strong rationale [
101]. Indeed, the association of drugs with proven efficacy or, alternatively, the addition of a promising agent to a background effective therapy are likely to represent the future of pharmacological therapy in IPF. To date however not much is known about the interactions between the two approved drugs when administered together, both in terms of tolerability and efficacy. The combination seemed safe in a small Japanese study in a small cohort of 50 patients [
102], which suggested that exposure to nintedanib decreased when added to pirfenidone, while the latter was not affected. More recently, the safety and tolerability of a combination regimen has been supported by open-label, 12 weeks-randomized trial of nintedanib with add-on pirfenidone, compared with nintedanib alone. Interestingly, no pharmacokinetic interaction between nintedanib and pirfenidone was observed [
103]. Favourable safety profiles have also been observed in an interimanalysis from a 24-week single-arm study on the safety and tolerability of pirfenidone with add-on nintedanib after at least 12 weeks of combined treatment [
104].
A larger, multicenter phase 2 open-label, multiple dosing trial to investigate the pharmacokinetics of nintedanib and pirfenidone when administered separately or in combination has been recently conducted in the UK (
https://clinicaltrials.gov/ct2/show/NCT02606877 Identifier: NCT02606877). For the time being, it is advisable to avoid the concomitant use of the two drugs given the risk associated with the partly overlapping side effect profiles.
Supportive care
Neither pirfenidone or nintedanib succeeded to demonstrate a survival benefit in IPF, nor they proved to improve the symptoms of these patients, often burdened by a heavily impaired quality of life and repercussions on psychological and emotional levels [
105,
106]. Whilst there is no definite evidence regarding the best timing for initiation of supportive care in IPF [
107], the unpredictability of the disease would suggest that palliative care should be integrated early and regarded as a standard of care to provide relief from the symptoms and anxiety related to fear of these symptoms [
108]. Indeed, the level of provision of supportive care seems to be not adequate in IPF. A retrospective investigation of decedents patients with IPF showed that only a minority of patients who died in a hospital actually received palliative care before admission [
109]. Recently, a few well-designed qualitative studies found significant gaps between the perceived needs of patients and their carers and the quality and timing of information provided by physicians about the meaning of the disease-centered assessments, disease prognosis and its management. Such evidence highlights the requirement of a pragmatic, continued needs assessment and the identification of triggers to refer patients to supportive and palliative care [
110,
111]. A supportive approach to these patients might be best delivered through the joint efforts of a well-coordinated multidisciplinary team including doctors, nurses and social workers, with the main goal of improving the quality of life of these patients [
112].
Chronic cough affects up to 80% of patients and has a significant impact on quality of life [
113]. Physicians should identify possible triggering factors or comorbidities, such as gastroesophageal reflux disease (GERD), obstructive sleep apnoea (OSA), infections or ACE inhibitor use. This symptom is often refractory to conventional anti-tussive treatments [
114]. Oral corticosteroids and opiates are often used in clinical practice, but the benefit is unclear [
115]. A single center double-blinded study of thalidomide showed an improvement in quality of life, but the significant side effects reported - such as dizziness and neuropathy - seem to exclude the routine use of this agent for treating cough in IPF [
116]. A subgroup analysis of a phase 3 trial of pirfenidone in Japan showed the potential efficacy of the anti-fibrotic drug in reducing cough, and the evaluation of this symptom through validated measurements could be an endpoint in future trials [
117].
Functional de-conditioning is also very common in patients with IPF. As such, respiratory rehabilitation has been proposed as a valid intervention in these patients and demonstrated to improve 6-min walk distance and shortness of breath [
118], and seems to reduce anxiety and depression and enhance the quality of life, other than to maintain musculoskeletal conditioning [
119]. Nevertheless, the beneficial effect does not seem to persist after 6 months [
120]. A study showed that subjects did not keep on with exercise at home following a rehabilitation program of 3 months, which highlights the importance of compliance in rehabilitation [
121].
Patients with IPF may present with hypoxemia during exercise, sleep or even at rest as a result of impaired gas exchange due to disease progression with or without concomitant conditions such as pulmonary hypertension. Despite there is no definite evidence of its beneficial effects in IPF [
122], supplemental long-term oxygen therapy is required to contrast the detrimental effects of low oxygen levels, that may impact on symptoms, the performance of daily activities and therefore overall quality of life [
123].
The need of psychological support in IPF patients is considered to be comparable to that of cancer patients, with depression related to shortness of breath, fatigue, and cough being reported in up to 25% of IPF patients. Nevertheless, the impact of interventions aimed to reduce emotional disturbance such as psychological counselling, support groups or mindfulness programs has never been measured in clinical studies, and the provision of such services in clinical practice is poor [
123,
124]. In patients with advanced lung disease, psycho-educational intervention and cognitive behavioural therapy seem to help develop coping strategies and feel less isolated, as described in a pilot study of a psycho-educational intervention program (PRISIM) [
106]. Participation to support groups might help patients and carers reduce the psychological burden of the disease through sharing feelings and experiences, and represent a compelling opportunity for providing practical information about IPF and its management. Support networks have been recently developed in IPF thanks to the foundation of regional networks of specialist centers [
124].
Another area of interest in supportive care is represented by mindfulness techniques, originally developed by J Kabat – Zinn in 1979 to integrate meditation with clinical and psychological practice. Mindfulness is a term indicating a state of mental presence and attention to the present moment, which can help discriminate positive thoughts and emotions from the negative ones often leading to repercussions on the emotional level. In patients with breast cancer, mindfulness-based programs have demonstrated to be effective in reducing anxiety and depression [
125]. In asthmatic patients, this programs showed to improve quality of life by promoting coping strategies and reducing reactivity to dyspnoea, irrespectively to impairment of lung function [
126]. Recently, a single-center pilot study suggested that Mindfulness-based programs are feasible in patients with ILD and might have a positive effect on mood [
127].
In conclusion, non-pharmacological interventions and supportive care might help reduce the burden of illness in IPF patients and their carers and should be promoted since the earlier stages of the disease. A better knowledge of the impact of such strategies and their standardization is warranted though to deliver an appropriate, individualized approach.
Treatment of comorbidities
Multi-morbidity is frequent among IPF patients, who have a median age of 66 years at diagnosis and present risk factors shared with several health conditions. Most common respiratory comorbidities include chronic obstructive pulmonary disease (COPD), lung cancer, pulmonary hypertension, obstructive sleep apnoea, while non-respiratory comorbidities include ischemic heart disease and gastro-oesophageal reflux [
128] The greatest challenge for clinicians is probably to understand to which extent these comorbidities might impact the clinical course of the disease and affect prognosis. Unfortunately, little is known about the real prevalence and burden of comorbidities in patients with IPF although a recent systematic review tried to clarify the prevalence and prognostic implications of various comorbidities in IPF patients across 126 studies [
129]. Data are also limited as to the correct management of comorbidities in IPF, and more robust evidence from prospective multicenter studies are required to determine the impact of conventional treatment of comorbidities in IPF population and to evaluate effects of new anti-fibrotic medications [
130].
The prevalence of COPD in IPF ranges from 6% to 67% across 23 different studies [
129]. A syndrome called combined pulmonary fibrosis and emphysema (CPFE) has been recently described in patients with fibrosis in lower pulmonary lobes and coexisting emphysema in the upper regions [
131]. Although pulmonary fibrosis seems to be the major determinant of the clinical course in these patients [
132], CPFE has been proposed as a distinct disease entity for having different features as compared to both IPF and emphysema. Pulmonary function tests are usually characterized by relatively preserved lung volumes, due to the compensating effect of hyperinflation of emphysema on the reduced compliance produced by fibrosis, while the two conditions contribute together in producing a severe impairment of diffusing capacity of the lung for carbon monoxide (DLco). Most importantly, the prevalence of pulmonary arterial hypertension is higher in CPFE than in IPF alone (47–90% versus 31–46%) [
133], with significant impact on mortality [
134]. Should airflow limitation coexist in these patients, use of bronchodilators should be considered, although there is no definite evidence on their efficacy.
Lung cancer is more frequent in patients with IPF than in the general population, suggesting a predisposition to developing neoplasm in IPF. This could be explained both by common risk factors such as tobacco-smoking and by the sharing of pathogenic pathways and molecular alterations [
135]. The prevalence varies from 3% to 48% across different studies, and it significantly affects prognosis, shortening survival by 2 years [
136]. Remarkably, most patients with IPF and lung cancer are excluded from surgical options due to limited lung functionality and reduced exercise tolerance. Moreover, surgical procedures would also increase the risk of acute exacerbations of IPF, known to have a short-term mortality of approximately 50% [
137].
Pulmonary hypertension (PH), usually defined as mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg, is one of the conditions more frequently associated to IPF and has been widely demonstrated to increase mortality in this population [
138,
139]. The absence of direct correlation between severity of PH and the extent of the underlying fibrotic disease implies that mechanisms other than hypoxia contribute to pulmonary vascular disease in IPF [
140]. Despite the clear prognostic implications, the benefits of treating this condition in IPF patients remain unknown. Overall, studies investigating PH-directed therapies failed so far to prove efficacy in IPF [
141‐
144], although Sildenafil, a phosphodiesterase-5 inhibitor, showed some positive effects on DLco, quality of life and symptoms in patients with advanced IPF [
145,
146]. Indeed, the negative results obtained so far might also be due to intrinsic limitations of trial design rather than to a real lack of efficacy of the drugs being tested [
147], and further evidence is needed to clarify the potential benefit of these treatments in a more targeted population of patients where PH is the primary driver of poor outcome.
Moderate to severe OSA affects up to 65% IPF patients [
148,
149]. Patients with IPF, OSA and sleep-related hypoxemia had a worse prognosis and disease progression rates than patients with IPF alone [
150]. Small, nonrandomized studies demonstrated improved quality of life in patients with IPF, and concomitant OSA treated with continuous positive airway pressure (CPAP) [
151,
152].
GERD is common in IPF patients, and the use of proton pump inhibitors (PPI) demonstrated to improve survival in retrospective studies [
153,
154]. Based on such evidence and the low cost of therapy and risk of side-effects, in the most recent update of the guidelines for the treatment of IPF [
52], anti-acid treatment was recommended in most IPF patients.
The coexistence of coronary artery disease deserves attention is observed in up to 30% of patients with IPF and increases mortality [
155]. The management of coronary artery is challenging since complications of invasive therapy are more frequent in IPF patients due to their performance and respiratory status [
156]. Consequently, the majority of these patients are being treated with standard medical therapies. However, patients with IPF should be evaluated for coronary artery disease from the clinical and radiological point of view. Coronary artery calcification at chest CT scan represents a useful tool and a potential screening tool to detect at-risk patients [
157].
Anxiety-depressive disorder considerably affects patients with IPF with a prevalence of 11–50% [
158]. Depression has a harmful impact on quality of life and reduces adherence to treatment of these patients [
159]. For this reason, patients with a new diagnosis of IPF should be screened for depression and anxiety and merit an early referral to a psychiatric consultation [
160].