Nintedanib: New indication for systemic sclerosis-associated interstitial lung disease

Abstract

Nintedanib (Ofev™), an oral triple kinase inhibitor targeting pro-fibrotic pathways, has been used for treatment of idiopathic pulmonary fibrosis (IPF). Based on positive results from phase III, placebo-controlled, randomized comparative clinical trial conducted in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib received marketing approval in the United States and Japan for the treatment of SSc-ILD. Nintedanib significantly reduced the annual rate of decline in forced vital capacity over 52 weeks compared with placebo. The safety profiles observed in this trial were consistent with those reported in IPF patients, and the most common adverse events were gastrointestinal disorders, including diarrhea, nausea, and vomiting, which sometimes lead to discontinuation or permanent dose reduction of nintedanib. In contrast, serious adverse events were infrequent and were related mostly to worsening of cardiopulmonary involvement of SSc. This review summarizes the milestones in development of nintedanib leading to the approval for the treatment of SSc-ILD, and covers mechanisms of action, efficacy results and safety profiles, and future perspectives of nintedanib.

Keywords:

• Interstitial lung diseases
• lung function
• nintedanib
• scleroderma
• systemic sclerosis

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Introduction

Nintedanib (Ofev™) is a small molecule inhibitor of tyrosine kinases, including platelet-derived growth factor (PDGF) receptor αβ, fibroblast growth factor (FGF) receptor 1–3, and vascular endothelial growth factor (VEGF) receptor 1–3 [1]. In addition, nintedanib inhibits Fms-like tyrosine-protein kinase, lymphocyte-specific tyrosine-protein kinases Lck and Lyn, proto-oncogene tyrosine-protein kinase Src, and colony stimulating factor-1 receptor [2]. This multi-kinase inhibitor binds competitively to the ATP binding pocket of these kinases and blocks the intracellular signaling cascades. Nintedanib has initially been developed for treatment of malignancies, including non-small cell lung cancer, advanced renal cell cancer, and hepatocellular carcinoma [3], but does not have indication in Japan. Nevertheless, clinical trials of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) had been conducted because of its potential to inhibit processes involved in the fibrotic pathogenesis [4], resulting in approval for indication of IPF in the United States in 2014, and in Europe and Japan in 2015, and currently in more than 65 countries. Interstitial lung disease (ILD), including IPF, is a group of conditions with heterogeneous clinical presentation and prognosis, but has common underlying pathophysiologies, such as excessive fibrosis and subsequent structural distortion of the lungs. Expansion of indication of nintedanib has been continuously investigating, and nintedanib has now received new indication for systemic sclerosis (SSc)-associated ILD (SSc-ILD), based on the efficacy and safety evaluation by Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial [5]. This review features mechanisms of action, efficacy and safety profiles, and future perspectives of nintedanib, which would contribute to adequate use of nintedanib in clinical practice.

Roles of nintedanib in mechanisms of pathologic fibrosis

A series of experiments have reported that nintedanib shows anti-fibrotic effects in vitro and in vivo [6]. Experiments with cultured human lung and skin fibroblasts demonstrated inhibition of proliferation, down-regulation of extracellular matrix proteins, and suppression of myofibroblast differentiation by treatment with nintedanib. Nintedanib also inhibited release of pro-fibrotic mediators from peripheral blood monocytic cells, and modulate macrophage polarization and resultant suppression of their pro-inflammatory responses. The anti-fibrotic activity has been demonstrated in several animal models of lung fibrosis, irrespective of preventative and therapeutic treatment. On the other hand, nintedanib demonstrated significant efficacy in 4 independent animal models of SSc, covering different aspects of the disease [6–8]. In particular, nintedanib suppressed fibrotic tissue remodeling in Fra-2 transgenic mouse model, which demonstrated vascular, inflammatory, and fibrotic histologic findings in the skin, lung, and myocardium, comparable with SSc patients [9,10]. This effect is partially explained by prevention of accumulation in M2 macrophages in the affected organs, suggesting that anti-fibrotic effects of nintedanib are associated, in part, with suppression of M2 polarization [8]. Additionally, nintedanib effectively attenuated pulmonary vascular remodeling in Fra-2 transgenic mice by reducing the number of vascular smooth muscle cells and occlusive pulmonary vessels [8]. Thus, nintedanib exerts a variety of mechanisms to suppress fibrotic tissue remodeling, and underlying mechanisms responsible for anti-fibrotic effects are variable among pathologic conditions.

Progressive fibrosing ILD, such as IPF, is characterized by alveolar epithelial cell injury and subsequent dysregulated repair machinery, leading to excessive deposition of extracellular matrix and loss of normal parenchymal architecture and lung function. In this process, myofibroblasts is considered the hallmark cell in the development of lung fibrosis [11]. A number of growth factors, cytokines, and chemokines are implicated in the proliferation, migration, and myofibroblast differentiation from resident mesenchymal cells, as well as epithelial-mesenchymal transdifferentiation (EMT) and endothelial-mesenchymal transdifferentiation (Endo-MT). PDGF is a potent mitogen for fibroblasts and plays an essential role in the expansion of myofibroblasts by stimulating their proliferation, migration, and survival [12]. Upregulation of PDGF has consistently been observed in the fibrotic lesions of various organs [13]. Tyrosine kinase inhibitors that inhibit a PDGF receptor, such as imatinib, have been shown to reduce fibrosis of the lungs and skin in various animal models [14,15]. Enhanced FGF levels as well as increased expression of FGF receptors on epithelial, endothelial, smooth muscle cells, and myofibroblasts were detected in the lungs of IPF patients [16]. In vivo abrogation of FGF signaling reduced pulmonary fibrosis and improved survival in bleomycin-treated mice [17]. On the other hand, VEGF is critical for angiogenesis and vasculogenesis and its roles in tissue fibrosis remains controversial, while experimental evidence in rats suggests that inhibition of VEGF receptors may reduce tissue fibrosis [18].

Efficacy of nintedanib in patients with IPF

IPF is a chronic, progressive fibrosing ILD of unknown cause, occurring mainly in older males, and is associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP) [19]. IPF is principally a fatal disease, with a median survival of 2 to 3 years after diagnosis, but the natural course is variable among the patients. Disease progression is manifested by increasing respiratory symptoms, worsening pulmonary function, i.e. forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLco), acute respiratory decline termed ‘acute exacerbation’, and, ultimately, death. The efficacy of nintedanib in IPF was demonstrated in phase II dose-finding trial (TOMORROW) [20] and subsequent two identical, placebo-controlled confirmatory phase III clinical trials (INPULSIS-1 and INPULSIS-2) [4], which included a total of 1231 patients for a randomized treatment period of 52 weeks. These trials provided substantial evidence that treatment with nintedanib 150 mg twice daily resulted in a clinically meaningful reduction in the annual rate of decline of FVC by 49% compared with placebo, indicating slowing disease progression. In the pooled analysis of two phase III clinical trials, the risk of first acute exacerbation was significantly reduced in patients receiving nintedanib compared with placebo. Overall mortality over 52 weeks and other survival-related endpoints consistently showed a numerical difference in favor of nintedanib, with hazard ratios ranging from 0.68 to 0.80. The open-label extension studies demonstrated a sustained effect of nintedanib on lung function in the long term [21]. Since sildenafil may provide benefits regarding oxygenation and quality of life in patients with IPF and severely impaired gas change, an additional, randomized, double-blind, parallel-group clinical trial was conducted to investigate the efficacy of nintedanib in combination with sildenafil, compared with nintedanib alone, in 273 patients with IPF and advanced lung function impairment [22]. Results for the primary endpoint of St. George’s Respiratory Questionnaire (SGRQ) total score showed that the addition of sildenafil to nintedanib did not provide significant benefit in terms of quality of life versus nintedanib alone, while treatment with nintedanib in combination with sildenafil was associated with a reduction in the risk of disease progression as defined as ≥5% decline of FVC% predicted or death, compared with nintedanib alone.

Efficacy of nintedanib in patients with SSc-ILD

SSc is a multi-system connective tissue disease (CTD) characterized by excessive fibrosis, wide-spread vascular abnormalities, and dysregulated immune system [23]. Patients suffer from fibrosis of the skin and multiple organs, leading to chronic disability and premature death. ILD is the leading cause of death amongst patients with SSc [24]. Immunosuppressive agents (e.g. mycophenolate mofetil, cyclophosphamide, methotrexate) are used to treat SSc manifestations, including skin thickening and ILD. The recommendations of European League against Rheumatism Scleroderma Trials and Research group (EUSTAR) recommend cyclophosphamide for treatment of SSc-ILD [25]. Nonetheless, consensus from a worldwide group of SSc experts recommends mycophenolate mofetil for induction and maintenance therapy for ILD [26], because it had similar efficacy compared with cyclophosphamide and had a more favorable safety profile [27]. In comparison with IPF, SSc-ILD shows several differences in clinical, radiologic, and pathologic characteristics, including slower decline of FVC, almost lack of acute exacerbation, predominant histopathologic and/or radiologic pattern of nonspecific interstitial pneumonia (NSIP) rather than UIP, and at least partial efficacy of immunosuppressants in SSc-ILD [28]. Although the initiating and amplifying mechanisms of SSc-ILD and IPF are different, both share the final pathways of pathologic fibrosis, characterized by fibroblast activation and myofibroblast accumulation.

SENSCIS was a randomized, placebo-controlled, double-blind, phase III trial to investigate the efficacy and safety of nintedanib 150 mg twice daily in patients with SSc-ILD [5]. This trial randomized a total of 580 patients diagnosed as having SSc-ILD with disease duration from the first non-Raynaud’s symptom ≤7 years, extent of fibrotic changes related to ILD ≥10% on a high-resolution computed tomography (HRCT) scan, FVC ≥40% predicted, and DLco of 30–89% predicted, irrespective of disease subsets (diffuse cutaneous SSc [dcSSc] versus limited cutaneous SSc [lcSSc]). This is a global trial involving 32 countries, and 71 patients (12% of the entire subjects) participated from Japan. In patients enrolled in this trial, the mean disease duration was 3.5 years, 52% of patients had dcSSc, and 61% was positive for anti-topoisomerase I antibody. A stable dose of mycophenolate was used for at least 6 months by 49% of patients at baseline. As a result, nintedanib significantly reduced the annual rate of decline in FVC over 52 weeks compared with placebo. The FVC decline in the nintedanib group was 44% lower than in the placebo group, which was in the same range as that previously observed in IPF, although the adjusted difference between the treatment groups was 41 mL/year. The mean FVC change from baseline showed a gradual separation of curves between the treatment groups over 52 weeks. Since decline of FVC has been shown to be associated with morbidity and mortality in patients with SSc-ILD [29,30], slowing decline of FVC would contribute to improved survival. The effects of nintedanib on preventing FVC decline were consistent across patient subgroups stratified by gender, age, race, region, anti-topoisomerase I antibody status, SSc subtype, and mycophenolate use. It was of note that an additive effect of nintedanib was observed in patients who were already treated with mycophenolate. In contrast, there was no difference between the treatment groups in the changes from baseline in modified Rodnan total skin thickness score (mRSS) and SGRQ. Patients who completed the trial on treatment continue treatment of nintedanib in an open-label extension study to evaluate long-term safety and tolerability. Since the SENSCIS trial was designed aiming primarily to assess efficacy on ILD, it was difficult to assess efficacy of nintedanib on other manifestations of SSc, such as progressive skin thickening in early dcSSc.

Safety profile of nintedanib

The major route of elimination of nintedanib is excretion using a biliary-fecal system, and contribution of renal excretion is neglectable (<1%) [31]. The drug exposure is increased in patients with impaired hepatic function, and therefore, treatment with nintedanib should not be considered in patients with liver cirrhosis and moderate or severe hepatic impairment (Child-Pugh grade B and C), who were excluded from clinical trials. Patients with Child-Pugh grade A might be treated with a reduced dose of nintedanib, i.e. 100 mg twice daily. Since nintedanib is a substrate of P-glycoprotein, co-administration with a P-glycoprotein inhibitor (e.g. ketoconazole) or inducer (e.g. refampicin) may lead to increase or decrease of nintedanib exposure, respectively. Besides this, metabolic drug-drug interactions of nintedanib resulting from induction or inhibition of cytochrome P450 enzymes are not expected based on in vitro studies. There is no clinically relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone, bosentan, or sildenafil. Nintedanib is contraindicated during pregnancy, since it causes embryo/fetal lethality and teratogenic effects in rats at the drug exposure comparable with that obtained at the recommended human dose. Therefore, females of childbearing age should be advised to avoid pregnancy while receiving nintedanib and at least 3 months after the last dose. There is no evidence for impairment of male fertility.

The safety profile of nintedanib in patients with IPF has been investigated comprehensively in phase II/III clinical trials [4,20], and data from long-term extension programs were consistent with safety profile observed in the parent trials [21,32]. In addition, all-case post-marketing surveillance in IPF patients is still ongoing in Japan, and collected data now exceed 60000 patient-years exposure. The safety profile observed in phase III clinical trial of SSc-ILD was principally consistent with those in IPF patients [5]. In all clinical trials, the most commonly reported adverse events in patients receiving nintedanib treatment were gastrointestinal (GI) disorders, including diarrhea, nausea, and vomiting. The adverse events leading to discontinuation or permanent dose reduction were more frequent in the nintedanib than in the placebo group, and the most common reasons were GI disorders [4,5]. On the other hand, serious adverse events were balanced between the nintedanib and placebo groups, and were mostly related to pulmonary complications of the underlying disease, including worsening of ILD and/or pulmonary hypertension (PH). Almost equal frequencies of patients died in nintedanib and placebo arms in the SENSCIS trial over 52 weeks (3.5% and 3.1%, respectively), and there was no difference in the events leading to death between the groups [5]. In summary, known safety profile of nintedanib is generally favorable due to infrequent serious adverse events suspected to be related to nintedanib, but mild or moderate GI disorders are fairly common. Considering the mechanisms of action and efficacy of nintedanib for preventing the progression of lung function decline, long-term continuation of the treatment is critical for obtaining maximal therapeutic effects of nintedanib on SSc-ILD. For this purpose, management of adverse events, especially GI symptoms, is essential.

Diarrhea is the most common adverse event. In most patients, the event occurs within the first 3 months of treatment. Most of the events are of mild or moderate intensity and were managed by symptomatic treatment, but temporary interruption and/or dose reduction of the nintedanib dose are required in some patients. In the INPULSIS trials in patients with IPF, diarrhea was reported in 62% versus 18% of patients treated with nintedanib and placebo, respectively [4]. Diarrhea led to dose reduction of nintedanib in 11% of the patients and to discontinuation of nintedanib in 4%. In the SENSCIS trial in patients with SSc-ILD, diarrhea was reported in 76% versus 32% of patients treated with nintedanib and placebo, respectively [5]. Diarrhea led to dose reduction of nintedanib in 22% and to discontinuation of nintedanib in 7%. Although there is no clear correlation between pharmacokinetics of nintedanib and diarrhea, dose reduction often improves the symptom. The frequency of diarrhea was higher in patients with SSc-ILD than in those with IPF in both treatment groups, probably because of underlying GI involvement in SSc patients, and concomitant use of mycophenolate in almost half of the patients. Diarrhea should be treated at first signs with adequate hydration and anti-diarrheal medications, e.g. loperamide and pro-biotics. If symptomatic treatment does not relief the symptom, nintedanib should be reduced in the dosage or interrupted. Nintedanib may be resumed, but start at a reduced dose (100 mg twice daily) is preferable. In case of persisting severe diarrhea despite symptomatic treatment, nintedanib should be discontinued.

Nausea and vomiting are also frequently reported adverse events. In most patients with nausea and vomiting, the event is of mild to moderate intensity. In clinical trial data, approximately 3% of the patients required discontinuation of nintedanib because of these adverse events in patients with IPF and SSc-ILD [4,5]. If symptoms persist despite appropriate supportive care including anti-emetic therapy, dose reduction or treatment interruption may be considered. The treatment may be resumed, but start at a reduced dose is preferable. In case of persisting severe symptoms, nintedanib should be discontinued. It was of note that more patients in the nintedanib group than in the placebo group reported weight and appetite decrease as adverse events. This is especially relevant to SSc patients who intrinsically have GI involvement, and it is clinically difficult to discriminate GI manifestations of SSc from adverse events of nintedanib. Careful monitoring of GI symptoms as well as body weight is mandatory during treatment with nintedanib.

In clinical trials of patients with IPF and SSc-ILD, cases of elevation in liver enzymes to at least 3 times the upper limit of the normal range have been reported with nintedanib treatment in approximately 5% of the patients, but serious liver dysfunction was reported <1% [4,5]. The majority of hepatic events were reported within the first 3 months of the treatment, but this adverse event occurs anytime during the treatment. Therefore, hepatic transaminase and bilirubin levels should be monitored carefully during treatment with nintedanib. Elevation of liver enzymes is reversible upon dose reduction or interruption in the majority of cases. If transaminases elevated to >3 times upper limit of the normal range, interruption or dose reduction of nintedanib is recommended. Once transaminases have returned to baseline levels, nintedanib may be re-increased or resumed at a reduced dose, which may be subsequently increased to the full dose. If any liver test elevations are associated with clinical signs or symptoms of liver insufficiency, e.g. jaundice, treatment with nintedanib should be permanently discontinued. Patients with low body weight (<65 kg), and Asian and female patients have a higher risk of elevations in liver enzymes. A small single-center study reported that low body surface area was associated with hepatotoxicity of nintedanib in IPF patients [33]. In addition, nintedanib exposure increased linearly with patient age, which may also result in a higher risk of developing liver dysfunction. Close monitoring is recommended in patients with risk factors for nintedanib-induced liver dynfunction. Although the regimen initiating at a reduced dose (100 mg twice daily) and subsequent increase to the full dose might be an option [34], it is of note that there is no evidence of efficacy in patients treated with such dose-escalating regimen. Of course, exclusion of other causes for liver dysfunction, including liver injury induced by concomitant drugs (e.g. mycophenolate mofetil, methotrexate), and concomitant liver diseases (e.g. autoimmune hepatitis) is necessary in clinical setting.

Arterial thromboembolism is considered as an important potential risk of nintedanib treatment in IPF patients; myocardial infarction was more frequently reported in the nintedanib than in the placebo group [35]. On the other hand, risk of thromboembolism was not increased in nintedanib over placebo groups in the SENSCIS [5]. We should consider the high background rate of cardiovascular events in the IPF population [36].

VEGF signal inhibition might be associated with an increased risk of bleeding, mediated through dysregulated vascular formation and repair, leading to fragility of blood vessels [37]. In clinical trials with nintedanib in patients with IPF and SSc-ILD, the frequency of patients who experienced bleeding adverse events was slightly higher in the nintedanib than placebo arm [4,5]. Non-serious epistaxis was the most frequent, and serious bleeding events occurred in approximately 1% with similar frequencies in the nintedanib- and placebo-treated groups. Patients at known risk for bleeding including patients with inherited predisposition to bleeding or patients receiving a full dose of anticoagulative treatment were not included in clinical trials. Therefore, these patients should only be treated with nintedanib if the anticipated benefit outweighs the potential risk.

Development or worsening of pulmonary hypertension (PH) is another concern due to VEGF inhibition. Patients with IPF and SSc are known to have significant risk for development of PH, including group 1 pulmonary arterial hypertension and group 3 PH due to respiratory diseases and/or hypoxia [38,39]. Therefore, patients with significant PH were excluded in the clinical trials. In animal model, VEGF inhibition followed by exposure to hypoxia lead to development of PH with a plexiform lesion, a histologic feature typical of pulmonary arterial hypertension [40]. New occurrence of PH was observed in both nintedanib and placebo arms in the clinical trials of IPF and SSc-ILD [4,5], although the number of patients who developed PH was too small to draw any conclusion. Nevertheless, in Fra-2 transgenic mice, treatment with nintedanib prevented developing histologic features of pulmonary arterial hypertension [8]. Further studies are necessary to investigate potential roles of nintedanib in development or worsening of this devastating complication.

Based on the mechanism of action that inhibits tissue remodeling, nintedanib may impair wound healing, although no increased frequency of impaired wound healing in nintedanib over placebo arm was observed in the clinical trials [4,5]. Particular caution should be exercised in treating patients with previous abdominal surgery or history of peptic ulceration, diverticular disease, or receiving concomitant corticosteroids or non-steroidal anti-inflammatory drugs. Nintedanib should not be used for SSc patients with advanced GI involvement, such as intestinal pseudo-obstruction, since cases of GI perforation have been reported. It has been advised the nintedanib should only be initiated at least 4 weeks after major surgery, and perioperative interruption of nintedanib should be considered.

In SSc patients, increased onset or delayed healing of digital ulcer (DU) might be associated with nintedanib treatment. This concern is primarily based of the mechanism of action that potentially impairs angiogenesis and wound healing. In the SENSCIS trial, the number of new DU was comparable between nintedanib and placebo groups [5], but patients with >3 digital ulcers at baseline were excluded in the trial. Specific care should be taken in patients with the presence of multiple active DU and/or a history of repeated DU.

Respiratory tract infection was reported in both nintedanib- and placebo-treated patients in clinical trials of IPF and SSc-ILD. In the SENSCIS, occurrence of pneumonia was reported as a serious adverse event in numerically greater in nintedanib over placebo groups (2.8% versus 0.3%, respectively) [5]. The presence of advanced ILD and concomitant use of corticosteroids and/or mycophenolate apparently increased the risk of pneumonia. A potential risk of infection in association with modulation of macrophage function by nintedanib remains unanswered.

Future perspectives

Nintedanib treatment showed a favorable benefit-risk balance in clinical trials for patients with SSc-ILD. Since nintedanib has a different mode of action from immunosuppressants, which are currently available for treatment of SSc-ILD, it should be an encouraging treatment option. However, the treatment difference (nintedanib minus placebo) for the adjusted annual rate of decline in FVC from baseline over 52 weeks was only 41.0 mL. The eligibility criteria allowed for a wide range of patients to be enrolled by a simple definition of the extent of fibrosis by HRCT ≥10%, which suggests that the findings may be largely generalizable to clinical practice of patients with SSc-ILD. On the other hand, this inclusion criteria resulted in the high level of variability in the adjusted annual rate of decline in FVC. It has been known that clinical course of SSc-ILD is highly variable [29,41]. Findings from observational cohort studies showed that less than one-third of patients with SSc-ILD at diagnosis progressed to end-stage lung disease, with the remaining patients exhibiting stable lung function throughout the disease course [29]. Heterogeneous clinical course of SSc-ILD is confirmed by the SENSCIS trial: patients with absolute decline in FVC >5% and >10% predicted at week 52 were only 28% and 8%, respectively, in the placebo arm [5]. However, findings from the prespecified subgroup analyses showed no significant differences between patients stratified by background characteristics. We definitely need to know which patients with SSc-ILD benefit from nintedanib treatment. For this purpose, it is critical to identify predictors for progressive decline of lung function, treatment response to nintedanib, and tolerability of nintedanib. Additional post-hoc analysis of the SENSCIS for identifying those predictors using a variety of clinical and imaging features as well as biomarkers should answer these questions. Another issue to be solved is whether nintedanib has disease-modifying effects on SSc in general or nintedanib is effective only for preventing progression of ILD, just like selective pulmonary vasodilators for SSc-associated pulmonary arterial hypertension [42]. Characteristics of the patients enrolled in the SENSCIS were apparently different from those of the patients enrolled in other clinical trials for evaluating disease-modifying effects on early dcSSc [43–45]. Future independent prospective studies to assess efficacy of nintedanib on mRSS and other manifestations of SSc may provide a further understanding of therapeutic benefits of nintedanib in SSc patients.

Based on clinical experience, there is a group of patients with ILD who, at some point in time, develop a progressive fibrosing course, independent from the ILD classification. In this group of patients, the natural history appears to follow a course similar to IPF with worsening of respiratory symptoms, lung function, quality of life and functional status, as well as mortality despite treatment with currently available immunosuppressive therapies. The terminology for describing this group of ILD is proposed as ILD with progressive fibrosing phenotype [46]. It is postulated that targeted anti-fibrotic therapy may slow the progression of ILD with progressive fibrosing phenotype based on clinical trial experiences in IPF and SSc-ILD. Thus, a phase III clinical trial INBUILD was initiated to investigate the efficacy and safety of nintedanib in patients with ILD with progressive fibrosing phenotype, including those with ILD associated with CTD, such as rheumatoid arthritis, SSc, dermatomyositis/polymyositis, mixed connective tissue disease, Sjögren’s syndrome, and even anti-synthetase syndrome. The primary results have just been published, and showed that nintedanib significantly reduced the annual rate of decline in FVC over 52 weeks compared with placebo [47]. The FVC decline in the nintedanib group was 57% lower than in the placebo group, which was in the same range as that previously observed in IPF and SSc-ILD. Indication of nintedanib is expanding from IPF to various forms of ILD with progressive fibrosing phenotype. In particular, underlying mechanisms of CTD-associated ILD involve immune activation and inflammation in various extents, this exciting result poses an important question on how to optimize the treatment of CTD-associated ILD from a variety of selections of nonspecific immunosuppressants, biologics targeting cytokines and immune cells, and targeted anti-fibrotic therapy.

Conflicts of interest

M.K. has received research grants from Actelion, and consulting fees from Bayer, Boehringer-Ingelheim, Chugai, Corbus, Galapagos, GlaxoSmithKline, and CSL Behring, and serves on the speaker bureaus for Actelion, Boehringer-Ingelheim, and Chugai.

A.A. has received research grants from Boehringer-Ingelheim, Shionogi, GlaxoSmithKline, aTyr Pharma, Norbel Pharma, Abbie, and Taiho, and consulting fees from Toray, Asahikasei, Kowa, Kyorin, and Nippon Kayaku.