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and it is essential that these are then evaluated by a multidisciplinary team with experience in interstitial lung diseases to ensure an accurate diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">1&#44;4&#8211;8</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">This manuscript is the outcome of a multidisciplinary meeting in which pulmonology&#44; radiology&#44; and pathology clinicians came together to debate topics related to the use of antifibrotic drugs in the treatment of IPF&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">IPF treatment&#58; a recent &#40;r&#41;evolution</span><p id="par0015" class="elsevierStylePara elsevierViewall">IPF was initially considered to be a chronic inflammatory process and therefore early treatment strategies aimed to eliminate or suppress the inflammatory component&#46; In 2000&#44; the first international guidelines on IPF diagnosis and treatment recommended corticosteroids and immunosuppressive&#47;cytotoxic agents &#40;azathioprine or cyclophosphamide&#41; as &#8220;standard treatment&#8221;&#44; despite the weak evidence available&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">9</span></a> This targeting of inflammatory pathways&#44; however&#44; produced disappointing results&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">4&#44;10&#8211;12</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Understanding of IPF pathobiology improved significantly following the publication of the 2000 IPF guidelines and it was proposed that the disease might be the result of an aberrant healing response to recurrent alveolar epithelial cell injury&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">13&#44;14</span></a> Guidelines published in 2011 concluded there was insufficient evidence to continue to recommend corticosteroid and immunomodulatory agents as standard therapy for IPF&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">15</span></a> The results of the IFIGENIA study&#44; a double-blind clinical trial designed to investigate the potential role of antioxidant pathways in IPF&#44; were published in 2005&#46; The trial&#44; which compared prednisolone plus azathioprine with prednisolone plus azathioprine plus N-acetylcysteine &#40;NAC&#41;&#44; showed a significantly reduced decline in forced vital capacity &#40;FVC&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#41; and diffusion capacity of the lung for carbon monoxide &#40;DLCO&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41; in patients treated with NAC combined with prednisolone and azathioprine after 52 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">16</span></a> Although the trial had some methodological pitfalls&#44; this triple therapy became the new standard treatment for IPF&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Around the same time&#44; pirfenidone&#44; an orally bioavailable synthetic compound with antifibrotic&#44; anti-inflammatory&#44; and antioxidant effects&#44; was being studied in clinical trials in Japan&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">17&#44;18</span></a> Although the exact mechanism of action of pirfenidone in IPF is not yet completely understood&#44; its anti-inflammatory effects are believed to result from the suppression of tumor necrosis factor &#945; &#40;TNF-&#945;&#41;&#44; interleukin &#40;IL&#41;-6&#44; IL-12&#44; and IL-8&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">19</span></a> while its anti-fibrotic effect is thought to result primarily from inhibition of expression of transforming growth factor beta &#8211; a profibrotic cytokine &#8211; although other pathways have been suggested&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">20</span></a> The first Japanese trial&#44; a phase II&#44; multicenter&#44; randomized&#44; double-blind trial&#44; showed no significant treatment effect for pirfenidone on the primary endpoint&#44; which was a change from baseline in the lowest oxygen saturation by pulse oximetry &#91;SpO<span class="elsevierStyleInf">2</span>&#93; during a 6-min exercise test&#46; It did&#44; however&#44; show that the high-dose treatment &#40;1800<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; had a positive effect in reducing VC decline&#44; a secondary endpoint&#44; at 9 months&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">17</span></a> In addition&#44; acute exacerbations were only observed in the placebo group during the same period&#46; A subsequent multicenter&#44; randomized&#44; double-blind phase III clinical trial of 275 IPF patients randomly assigned to pirfenidone 1800<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; pirfenidone 1200<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; or placebo for 52 weeks&#44; showed a significantly slower decline in FVC and better progression-free survival in the two pirfenidone groups compared with placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">18</span></a> Based on the results of these two studies&#44; pirfenidone was approved for IPF treatment by the Japanese authorities in 2008&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Meanwhile&#44; pirfenidone was also being studied in Europe and in the United States of America &#40;USA&#41; in the CAPACITY trials&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">21</span></a> The placebo-controlled phase III trials&#44; CAPACITY 004 and 006&#44; showed contradictory results&#44; and the primary endpoint of a significant reduction in FVC decline at week 72 was only met in study 004&#46; However&#44; the pooled analysis revealed a significant reduction in the mean decline of absolute and percent predicted FVC and the number of patients with an FVC decline &#8805;10&#37; at week 72 in the 2403<span class="elsevierStyleHsp" style=""></span>mg&#47;day pirfenidone group&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">21</span></a> In relation to the secondary endpoints&#44; the patients in the 2403<span class="elsevierStyleHsp" style=""></span>mg&#47;day group also had longer progression-free survival and a lower rate of decline in mean 6-min walk distance &#40;6MWD&#41; than patients in the placebo group&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">21</span></a> The results of this pooled analysis led to the approval of pirfenidone for IPF treatment by the European Medicines Agency &#40;EMA&#41; in 2011&#44; although they were not sufficient to convince the US Food and Drug Administration &#40;FDA&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Despite the approval of pirfenidone in Japan and Europe&#44; the triple therapy persisted as the treatment regimen of choice in many countries until the results of the PANTHER study were published&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">11</span></a> The PANTHER study was a randomized clinical trial with three arms&#58; a triple therapy arm&#44; an NAC arm&#44; and a placebo arm&#46; The triple therapy arm was stopped after a mean follow-up of 32 weeks because of higher mortality and hospitalization rates than in the other two groups&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Despite some initial controversy&#44; this event marked the end of triple therapy&#46; Moreover&#44; on completion of the PANTHER study in 2014&#44; no significant differences were detected between NAC and placebo for changes in FVC &#40;primary endpoint&#41; or for death rates or frequency of acute exacerbations &#40;secondary endpoints&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">22</span></a> Recent publications describing a therapeutic effect for NAC in a subgroup of IPF patients expressing the <span class="elsevierStyleItalic">TOLLIP</span> gene polymorphism rs3750920<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">23</span></a> and a potential benefit of inhaled acetylcysteine&#44;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">24</span></a> have rekindled the discussion about the potential therapeutic role of NAC and antioxidants as a therapeutic group in IPF&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">After the evaluation of the CAPACITY trials&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">19</span></a> the ASCEND trial&#44; which included 555 patients from the USA&#44; Europe&#44; and Australia randomly assigned to receive 2403<span class="elsevierStyleHsp" style=""></span>mg&#47;day of pirfenidone or placebo for 52 weeks showed that the treatment group had a significantly reduced absolute FVC decline&#44; fewer patients with an FVC decline &#8805;10&#37;&#44; better progression-free survival &#40;defined as the time to occurrence of a confirmed absolute decrease of &#8805;10 percentage points in percent predicted FVC&#44; a confirmed decrease of &#8805;50<span class="elsevierStyleHsp" style=""></span>m in the 6MWD&#44; or death&#41;&#44; and fewer patients with a decrease of &#8805;50<span class="elsevierStyleHsp" style=""></span>m in the 6MWD&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">25</span></a> Moreover&#44; pooled data from the CAPACITY and ASCEND trials evidenced a reduction in both all-cause and IPF-related mortality after one year&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">25</span></a> These results further supported the efficacy of pirfenidone in IPF and led to FDA approval in 2014&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In the same year&#44; nintedanib also received FDA approval after the INPULSIS trials&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">26</span></a> Nintedanib is a small molecule tyrosine kinase inhibitor that targets the receptors of platelet-derived growth factor&#44; fibroblast growth factor&#44; and vascular endothelial growth factor&#46; Blockage of these receptors may inhibit downstream signaling cascades of fibroblasts and myofibroblasts&#44; attenuating the development of aberrant fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">27</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In the phase II nintedanib trial TOMORROW&#44; which included 432 IPF patients randomized to one of four doses of nintedanib &#40;50<span class="elsevierStyleHsp" style=""></span>mg od&#44; 50<span class="elsevierStyleHsp" style=""></span>mg bid&#44; 100<span class="elsevierStyleHsp" style=""></span>mg bid&#44; and 150<span class="elsevierStyleHsp" style=""></span>mg bid&#41; or placebo&#44; a significant reduction in FVC decline after 52 weeks was seen in the 150<span class="elsevierStyleHsp" style=""></span>mg bid group compared with placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">28</span></a> This subgroup of patients also had significantly fewer acute exacerbations and a smaller mean decrease in the St&#46; George&#39;s Respiratory Questionnaire score&#46; Two subsequent large phase III trials&#44; INPULSIS 1 and 2&#44; comparing 150<span class="elsevierStyleHsp" style=""></span>mg bid of nintedanib with placebo in 1066 patients&#44; showed a reduction in the annual rate of decline in absolute and percent predicted FVC &#40;primary endpoint&#41; and an increase in time to the first acute exacerbation for nintedanib&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">26</span></a> With these results&#44; the EMA few months after the FDA approved nintedanib for the treatment of IPF in January 2015&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">A new era emerged for patients with IPF following the INPULSIS<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">26</span></a> and ASCEND<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">25</span></a> trials and the approval of nintedanib and pirfenidone&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">29</span></a> The two drugs were identified in national and international guidelines on the diagnosis and treatment of IPF as being efficacious in slowing functional decline and disease progression in IPF patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">1&#44;30&#8211;33</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The nintedanib and pirfenidone trials showed similar efficacy results but raised logical questions related to how the drugs would perform in the real world&#44; outside the restrictions of the trials&#46; The inclusion criteria varied somewhat between the INPULSIS &#40;nintedanib&#41; and ASCEND &#40;pirfenidone&#41; trials&#46; The pirfenidone trials<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">21&#44;25</span></a> included patients with percent predicted FVC 50&#8211;90&#37;&#44; predicted DLCO 30&#8211;90&#37; and high-resolution computed tomography &#40;HRCT&#41; images indicating either definite or possible UIP&#44; however with confirmation by surgical lung biopsy&#46; The nintedanib trials&#44;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">26&#44;28</span></a> by contrast&#44; included patients with percent predicted FVC &#62;50&#37;&#44; predicted DLCO 30&#8211;79&#37;&#44; and HRCT images indicating definite or possible UIP&#46; Following publication of the trials&#44; several post-marketing surveillance studies and subgroup analyses investigating effects according to age or stage of disease were undertaken in order to answer several questions&#58; If these drugs are efficacious in slowing the progression of IPF&#44; should they be used earlier&#63; How will they behave in patients with more severe disease&#63; Will their effects extend beyond the trial period&#63;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">29&#44;34</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">When should IPF treatment be started&#63;</span><p id="par0070" class="elsevierStylePara elsevierViewall">The most controversial question currently surrounding IPF treatment is probably when it should be started&#46; We know that IPF is a progressive disease and that both pirfenidone and nintedanib slow functional decline&#46; However&#44; some patients remain stable for several months and it has been argued that in a stable patient with mild disease&#44; treatment should be postponed until functional decline begins&#46; Nevertheless&#44; it is impossible to predict the rate or severity of disease progression in each patient or to know when they will experience an acute exacerbation&#46; Moreover&#44; we cannot be sure that deleterious subclinical changes are not taking place in patients without signs of significant functional deterioration&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">In a recent post hoc subgroup analysis of pooled data from the INPULSIS trials&#44; Kolb et al&#46; described similar rates of FVC decline in nintedanib-treated patients with percent predicted FVC &#62;90&#37; and &#8804;90&#37; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">35</span></a> Other pre-specified subgroup analyses have shown similar results&#44; with a consistent effect observed for nintedanib in patients with FVC &#8804;70&#37; and &#62;70&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">36</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">In a post hoc analysis of pooled data from the CAPACITY and ASCEND trials&#44; Albera et al&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">37</span></a> showed similar clinically significant disease progression &#40;decline in FVC&#44; 6MWD&#44; and dyspnea measured by the University of California&#44; San Diego Shortness of Breath Questionnaire&#41; at 12 months in pirfenidone-treated patients with more preserved lung function &#40;FVC &#8805;80&#37; or GAP stage I&#41; and less preserved lung function &#40;FVC &#60;80&#37; or GAP stage II&#8211;III&#41; at baseline&#46; The GAP index is a multidimensional IPF staging model that takes into account gender &#40;G&#41;&#44; age &#40;A&#41;&#44; and 2 lung physiology variables &#40;P&#41; &#40;FVC and DLCO&#41;&#59; it distinguishes between stages I&#44; II&#44; and III&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">38</span></a> The magnitude of the pirfenidone treatment effect was comparable between the subgroups&#44; regardless of whether lung function was classified as using FVC or the GAP model &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">37</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The above data suggest that patients diagnosed in early stages of disease experience significant functional deterioration and that both nintedanib and pirfenidone have a positive effect in terms of slowing progression in these early stages &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; clearly supporting the recommendation to initiate treatment immediately after IPF diagnosis and highlighting the importance of prompt diagnosis&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Severe disease</span><p id="par0090" class="elsevierStylePara elsevierViewall">Percent predicted FVC &#60;50&#37; is usually associated with severe disease&#46; As stated earlier&#44; this was an exclusion criterion in both the pirfenidone and nintedanib trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">21&#44;25&#44;26&#44;28</span></a> Information about the potential effects of antifibrotic agents in patients with severe disease is thus scarce&#44; and overall&#44; the treatment indications outlined by the health authorities exclude patients with this grade of functional impairment&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Some interesting data in this respect&#44; however&#44; have emerged from post-marketing surveillance studies&#46; In the open-label INPULSIS-ON extension trial&#44; patients who started treatment with nintedanib 150<span class="elsevierStyleHsp" style=""></span>mg bid with percent predicted FVC &#8804;50&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24&#41; showed a similar absolute mean change in FVC from baseline to week 48 as those with FVC &#62;50&#37; at baseline &#40;&#8722;62&#46;3<span class="elsevierStyleHsp" style=""></span>mL vs&#46; &#8722;87&#46;9<span class="elsevierStyleHsp" style=""></span>mL&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">39</span></a> suggesting that nintedanib may have a similar therapeutic effect in advanced forms of the disease&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In a real-life retrospective study of pirfenidone in several Italian interstitial lung disease centers&#44; Harari et al&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">40</span></a> evaluated 128 IPF patients stratified according to FVC and GAP stage&#44; and reported a greater reduction in decline in percent predicted FVC in patients with moderate to severe disease&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">In Japan&#44; a retrospective evaluation of 1371 patients who began pirfenidone in the first year after its approval for IPF treatment detected functional and symptomatic stabilization&#44; regardless of degree of functional impairment&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">41</span></a> Two-thirds of the patients were considered to have advanced disease &#40;stage III&#8211;IV&#44; according to a four-stage Japanese IPF staging model based on partial pressure of arterial oxygen at rest and SpO<span class="elsevierStyleInf">2</span> during the 6<span class="elsevierStyleHsp" style=""></span>MW test&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">41</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">At the recent 2016 European Respiratory Congress&#44; Costabel and colleagues<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">42</span></a> reported on the results of a comparison of 54 patients with percent predicted FVC &#8804;50&#37; with 530 patients with FVC &#62;50&#37; in the RECAP trial&#44; which was an extension of the CAPACITY trials&#46; Although a higher treatment discontinuation rate was observed in the subgroup with more advanced disease&#44; long-term treatment with pirfenidone resulted in a similar rate of FVC decline in both groups&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Despite the relatively small number of patients&#44; the above data suggest that both nintedanib and pirfenidone have a positive effect in patients who have advanced disease at diagnosis &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Is the treatment effect maintained after 52 weeks&#63;</span><p id="par0120" class="elsevierStylePara elsevierViewall">Another question that post-marketing surveillance studies and extension trials such as RECAP<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">43</span></a> and INPULSIS-ON<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">44&#44;45</span></a> have attempted to answer is whether or not the positive effect observed for nintedanib and pirfenidone in terms of slowing FVC decline is maintained after 52 weeks&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In 2014&#44; Valeyre et al&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">46</span></a> published the results of a long-term safety assessment of patients treated with pirfenidone in the CAPACITY trials&#46; Although safety was the primary focus of the study&#44; the authors demonstrated that treatment with pirfenidone for up to 7&#46;7 years &#40;median&#44; 2&#46;6 years&#59; range&#44; 1 week&#8211;7&#46;7 years&#41; was not only well tolerated but also showed a persistent positive therapeutic effect&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">46</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">More recently&#44; in an oral communication at the 2016 ERS Congress &#40;London&#44; 3&#8211;9 September 2016&#41;&#44; Noble et al&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">47</span></a> presented data from the RECAP extension study on the long-term effects of pirfenidone on percent predicted FVC and showed that the drug maintained its effect over more than 3 years&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Finally&#44; in a recent presentation of results from the INPULSIS-ON extension study&#44; Crestani showed that FVC decline was similar to that observed in the original INPULSIS trials&#44; suggesting that like pirfenidone&#44; nintedanib also maintained its effect for over 3 years&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">44&#44;45</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">What should be done once disease progression is confirmed&#63;</span><p id="par0140" class="elsevierStylePara elsevierViewall">Disease progression in IPF is defined as a sustained decline of more than 10&#37; in FVC and&#47;or of 15&#37; in DLCO&#46; Lung function is usually evaluated every 6 months following initiation of treatment&#46; Once disease progression has been established&#44; the treating physician&#40;s&#41; can choose to suspend the drug and administer palliative care only&#59; suspend the drug and switch to an alternative therapy&#59; add an alternative therapy&#59; or continue the drug despite the functional decline&#46; There is insufficient evidence&#44; however&#44; to support any of these options&#46; In May 2016&#44; Nathan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">48</span></a> published the results of a pooled analysis of patients from the CAPACITY and ASCEND trials showing that in the subgroup of patients who experienced a functional decline in FVC &#62;10&#37; after 6 months&#44; those who continued to receive pirfenidone had a lower risk of subsequent FVC decline or death&#46; These results suggest that maintaining antifibrotic therapy may confer benefits even after disease progression is confirmed&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Bonella et al&#46;&#44; <a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">49</span></a> in a German multicenter observational study of nintedanib in IPF&#44; reported that a subgroup of patients who had shown disease progression under pirfenidone&#44; achieved clinical and functional stability when switched to nintedanib&#46; A combination regimen of pirfenidone and nintedanib has also been proposed&#44; as theoretically it would allow synergistic activity in different fibrotic pathways&#46; One safety and pharmacokinetics study reported acceptable tolerability for nintedanib administered alone or with pirfenidone and also showed that nintedanib bioavailability may decrease with the co-administration of pirfenidone&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">50</span></a> Despite these findings&#44; more data and studies are needed to guide treatment strategies in patients with disease progression&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">What is the impact of adverse events induced by nintedanib or pirfenidone&#63;</span><p id="par0150" class="elsevierStylePara elsevierViewall">The most common adverse events reported for nintedanib in the TOMORROW<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">28</span></a> and INPULSIS trials<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">26</span></a> were diarrhea&#44; nausea&#44; and vomiting&#44; which were more prevalent in the 150<span class="elsevierStyleHsp" style=""></span>mg dose group&#46; Although 60&#37; of patients in the INPULSIS trials developed diarrhea&#44; only 4&#37; discontinued treatment for this reason&#46; In a pooled analysis from the TOMORROW and INPULSIS trials&#44; Richeldi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">51</span></a> found that 20&#46;6&#37; of patients in the nintedanib group prematurely discontinued treatment due to overall adverse events versus 15&#46;0&#37; in the placebo group&#46; Nearly 30&#37; of patients in both groups experienced one or more serious adverse events&#46; Adverse events due to nintedanib&#44; however&#44; are usually mild or moderate and can be easily managed in most patients&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">An interim safety analysis of the INPULSIS-ON extension study<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">44&#44;45</span></a> showed that patients who completed 96 weeks of nintedanib treatment experienced fewer adverse events &#40;316&#46;8 events per 100 patient-years&#41; than those who completed the initial 52-week evaluation &#40;632&#46;6 events&#41; and those who initiated treatment after 52 weeks on placebo &#40;550&#46;6 events&#41;&#46; A similar situation was observed for serious adverse events &#40;33&#46;9 vs&#46; 36&#46;7 and 38&#46;3 events per 100 patient-years&#41; and events leading to treatment discontinuation &#40;14&#46;6 vs&#46; 21&#46;4 events per 100 patient-years in the other two groups&#41;&#46; The author concluded that these interim results from the INPULSIS-ON trial support the long-term efficacy and safety of nintedanib in patients with IPF&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The most common adverse events during the pirfenidone CAPACITY<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">19</span></a> and ASCEND trials<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">25</span></a> were gastrointestinal events &#40;nausea&#44; dyspepsia&#44; vomiting&#44; and anorexia&#41; and skin disorders &#40;rash&#44; photosensitivity&#41;&#46; The events were generally mild or moderate&#44; reversible with dose reductions&#44; and without clinically significant consequences&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">In a comprehensive analysis of safety across four clinical trials evaluating pirfenidone in patients with IPF&#44; the more frequent adverse events reported were also mild to moderate nausea &#40;40&#37;&#41;&#44; dyspepsia &#40;21&#37;&#41;&#44; vomiting &#40;18&#37;&#41;&#44; and rash &#40;26&#37;&#41;&#46; These events rarely led to treatment discontinuation&#44; despite the longer median duration of exposure to pirfenidone &#40;2&#46;6 years&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">46</span></a> This study also showed that while gastrointestinal and skin-related adverse events are relatively common at the beginning of treatment&#44; they decrease considerably after the first 6 months and remain low during the course of treatment&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Ogura et al&#46;&#44; <a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">41</span></a> in a prospective post-marketing surveillance study of patients with IPF administered pirfenidone in the first year after its launch in Japan&#44; found a similar safety profile to that reported in the Japanese phase II and III trials&#44; with 64&#46;6&#37; of patients experiencing at least one adverse event&#46; The most common events were decreased appetite&#44; photosensitivity&#44; and nausea&#44; and these resolved or improved in the majority of cases&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">The results of the RECAP open-label extension study of pirfenidone showed that the type and frequency of adverse events after 60 weeks of treatment were similar to those observed in the initial 72-week phase III CAPACITY trials and rarely resulted in early discontinuation of therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">43</span></a> The incidence of nausea and photosensitivity was 35&#46;4&#37; and 11&#46;9&#37; in the CAPACITY trials versus 32&#46;0&#37; and 11&#46;8&#37; in the RECAP study&#46; Rash and diarrhea&#44; by contrast&#44; were less common in RECAP &#40;18&#46;0&#37; and 16&#46;9&#37; vs&#46; 31&#46;0&#37; and 27&#46;0&#37;&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">21&#44;43</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="par0180" class="elsevierStylePara elsevierViewall">Based on the available data from clinical trials and extension studies&#44; we can conclude that both pirfenidone and nintedanib have a significant effect on FVC decline&#44; regardless of disease stage assessed by FVC or GAP&#46; Moreover&#44; the RECAP and INPULSIS-ON extension trials showed that the effect was maintained over time&#46; Both nintedanib and pirfenidone were found to prolong survival&#44; with a reduction in both IPF-related and all-cause mortality&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Despite the relatively high rates of adverse events&#44; which are mostly gastrointestinal in nature&#44; the existing data support the recommendation that treatment with nintedanib or pirfenidone should be considered when IPF is diagnosed&#44; regardless of disease stage&#46; Since IPF is a progressive lung disease&#44; early diagnosis and treatment are crucial for slowing functional decline&#44; reducing symptoms&#44; and improving quality of life&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Ethical disclosures</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Protection of human and animal subjects</span><p id="par0190" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Confidentiality of data</span><p id="par0195" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Right to privacy and informed consent</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflicts of interest</span><p id="par0205" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "IPF treatment&#58; a recent &#40;r&#41;evolution"
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          "titulo" => "Is the treatment effect maintained after 52 weeks&#63;"
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          "titulo" => "What should be done once disease progression is confirmed&#63;"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Idiopathic pulmonary fibrosis &#40;IPF&#41; is a progressive and fatal lung disease that up to now has been associated with a poor prognosis&#46; However&#44; the results of the INPULSIS and ASCEND trials and the approval of nintedanib and pirfenidone have marked the beginning of a new era for IPF patients&#46; Questions remain&#44; however&#46; Should these drugs be used earlier&#63; What effect will they have on more severe disease&#63; Will their effects last beyond the trial period&#63; This manuscript is the outcome of a multidisciplinary meeting between pulmonology&#44; radiology&#44; and pathology clinicians on the use of antifibrotic agents in IPF&#46; In our opinion&#44; the existing data show that pirfenidone and nintedanib slow functional decline in early stages of disease&#46; These drugs also appear to result in therapeutic benefits when administered to patients with advanced disease at diagnosis and maintain effective over time&#46; The data also suggest that continuing antifibrotic therapy after disease progression may confer benefits&#44; but more evidence is needed&#46; Early diagnosis and treatment are crucial for reducing functional decline&#44; slowing disease progression&#44; and improving quality of life&#46;</p></span>"
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