Clinical Rheumatology (2019) 38:2673–2681

https://doi.org/10.1007/s10067-019-04720-0

REVIEW ARTICLE

Progressive fibrosing interstitial lung disease associated

with systemic autoimmune diseases
Aryeh Fischer 1 & Jörg Distler 2

Received: 26 March 2019 / Revised: 12 July 2019 / Accepted: 30 July 2019 / Published online: 19 August 2019
# The Author(s) 2019

Abstract
Interstitial lung disease (ILD) is a common manifestation of systemic autoimmune diseases and a leading cause of death in these
patients. A proportion of patients with autoimmune ILDs develop a progressive fibrosing form of ILD, characterized by
increasing fibrosis on high-resolution computed tomography, worsening of lung function, and early mortality. Autoimmune
disease–related ILDs have a variable clinical course and not all patients will require treatment, but all patients should be
monitored for signs of progression. Apart from systemic sclerosis–associated ILD, the limited evidence to support the efficacy
of immunosuppression as a treatment for ILDs is based mainly on small retrospective series and expert opinion. Non-clinical data
suggest that there are commonalities in the mechanisms that drive progressive fibrosis in ILDs with an immunological trigger as
in other forms of progressive fibrosing ILD. This suggests that nintedanib and pirfenidone, drugs known to slow disease
progression in patients with idiopathic pulmonary fibrosis, may also slow the progression of ILD associated with systemic
autoimmune diseases. In the SENSCIS® trial, nintedanib reduced the rate of ILD progression in patients with systemic
sclerosis–associated ILD. The results of other large clinical trials will provide further insights into the role of anti-fibrotic
therapies in the treatment of autoimmune disease–related ILDs.

Keywords Connective tissue diseases . Mortality . Pulmonary fibrosis . Rheumatic diseases . Systemic sclerosis

Introduction (HRCT), worsening of lung function, and early mortality

[6–8]. The proportion of patients with autoimmune ILDs
Interstitial lung disease (ILD) is a common manifestation of who develop progressive fibrosis is not known, but in an on-
systemic autoimmune diseases (also referred to as connective line survey, rheumatologists and pulmonologists with experi-
tissue diseases) including systemic sclerosis (SSc) [1], rheu- ence in managing patients with ILDs estimated it to be 24–
matoid arthritis (RA) [2], mixed connective tissue disease 31% of patients [9]. Combining information from this survey
(MCTD) [3], polymyositis/dermatomyositis [4], and with a systematic review of published literature, it was esti-
Sjögren’s syndrome [5]. The reported prevalence of ILD in mated that 13–40% of patients with autoimmune ILDs devel-
patients with systemic autoimmune disease varies widely de- op a progressive fibrosing phenotype [10].
pending on the methodology used and the population studied. In this article, we will describe the impact of ILD in patients
A proportion of patients with systemic autoimmune diseases with systemic autoimmune diseases, the current management
develop a progressive fibrosing form of ILD, characterized by of autoimmune ILDs, and the potential role of anti-fibrotic
increasing fibrosis on high-resolution computed tomography therapy in the treatment of autoimmune ILDs with a progres-
sive fibrosing phenotype.

* Aryeh Fischer
[email protected] ILDs in autoimmune diseases
1
University of Colorado School of Medicine, 1635 Aurora Court, Systemic autoimmune diseases are associated with a range of
Denver, CO 80045, USA pulmonary manifestations including pleural disease (pleuritis,
2
University of Erlangen-Nuremberg, Krankenhausstrasse 12, pleural effusion, and pleural thickening), airways disease, pul-
91054 Erlangen, Germany monary hypertension, vasculitis, diffuse alveolar hemorrhage,
2674 Clin Rheumatol (2019) 38:2673–2681

and ILD [11]. ILD often appears early in the course of sys- HRCT while 24% had NSIP [26]. It is important to note that
temic autoimmune disease and may even be the first manifes- patterns evident on HRCT are not fixed but may evolve over
tation of the disorder [11–13]. In addition, there exists a group time; for example, patients who have a largely non-fibrotic
of patients with interstitial pneumonia who show some fea- pattern on HRCT at the time of diagnosis may later develop
tures of autoimmunity but do not meet diagnostic criteria for a more fibrotic form of the disease [27].
any recognized autoimmune disease [14, 15]. The symptoms of cough, dyspnea, and fatigue associated
ILD is particularly common in patients with SSc; indeed, with ILD can contribute to the impairment of quality of life in
ILD (defined as pulmonary fibrosis seen on HRCT or chest patients with systemic autoimmune diseases. A survey of 50
radiography, most pronounced in the basilar portions of the patients with RA-ILD at a US center found that the severity of
lungs, or the occurrence of idiopathic “Velcro” crackles on fatigue and dyspnea were the strongest predictors of physical
auscultation) is included in the classification criteria for SSc health impairment, while the severity of cough, fatigue, and
[16]. In the Canadian Scleroderma Research Group registry, dyspnea were the strongest predictors of mental health impair-
ILD was evident on HRCT in 64% of patients who had HRCT ment [28]. Dyspnea has been reported by patients with SSc as
scans available, while 26% of patients had ILD according to one of the main factors driving their functional disability [29].
the presence of basilar “Velcro” crackles on auscultation and
22% had ILD based on chest X-ray [1]. In a recent analysis of
data from 21 referral centers in Spain, 43% of 1374 patients Progression of fibrosing ILDs
with SSc had evidence of pulmonary fibrosis on chest radio-
graph or HRCT [17]. ILD is a rarer occurrence in patients with Progression of autoimmune ILDs is characterized by deterio-
RA, but still affects a large number of patients. The prevalence ration in lung function, which may be assessed through mea-
of ILD in patients with RA varies across studies due to differ- surement of forced vital capacity (FVC) (lung volume) and
ences in the populations studied and the criteria used to define diffusion capacity of the lungs for carbon monoxide (DLco)
ILD. In an analysis of data from 150 consecutive outpatients (the lungs’ capacity for gas exchange) [30]. Lung function
with RA (irrespective of signs/symptoms of ILD) at a single may decline rapidly after ILD is diagnosed. In a study of
UK center, 28 (6.2%) had ILD on HRCT [18], while a multi- 695 patients with SSc in the European Scleroderma Trials
center study of 1460 patients with early RA (< 2 years of and Research (EUSTAR) cohort, approximately one-third of
symptoms) found that 52 patients (3.6%) had ILD at baseline patients had DLco < 50% predicted within 3 years of the onset
or developed it within 3 years of follow-up [19]. In a retrospec- of Raynaud’s phenomenon [31]. In an analysis of 167 patients
tive analysis of medical records from 582 patients with RA, the with RA-ILD referred to a tertiary care center, the proportion
lifetime risk of developing ILD was estimated to be 7.7%, of patients with FVC < 50% predicted increased from 14% at
compared with 0.9% in a matched cohort without RA [2]. diagnosis to 22% after 5 years, while the proportion of patients
Patients with more active RA, measured using Disease with DLco < 40% predicted increased from 29% at diagnosis
Activity Score using 28 joints (DAS28) or based on markers to 40% after 5 years; patients with a UIP pattern on HRCT
of disease activity such as erythrocyte sedimentation rate, ap- were more likely to progress to DLco < 40% predicted than
pear to be at increased risk of developing ILD [2, 19, 20]. A those with NSIP [8]. The course of ILD progression in patients
prospective analysis of 1419 patients with RA at a US center with other autoimmune diseases is not well documented, but it
found that patients with high or moderate disease activity de- is clear that ILD progresses in a significant proportion of pa-
fined by DAS28 had a 2-fold increased risk of developing ILD tients with these diseases. Among 107 patients with ILD as-
compared with those in remission or with low disease activity sociated with polymyositis/dermatomyositis treated with im-
over a mean follow-up of 5.6 years. For every unit increase in munosuppressants, 16% had a decline in FVC of ≥ 10% pre-
the DAS28, the risk of ILD increased by 35% [20]. dicted and/or a decline in DLco of ≥ 15% predicted over a
Radiological and histopathological patterns are observed at median follow-up of 34 months [32]. In an analysis of 18
varying frequencies across different forms of autoimmune patients with Sjögren’s syndrome and ILD followed for a me-
disease–associated ILD. In SSc-ILD, the typical pattern on dian of 38 months, 5 (28%) had a decline in FVC of ≥ 10%
HRCT or histology is non-specific interstitial pneumonia predicted or a decline in DLco of ≥ 15% predicted despite
(NSIP) pattern, although a usual interstitial pneumonia (UIP) immunosuppression [33]. In an analysis of 75 patients with
pattern may also be observed [21, 22]. NSIP is also the pre- anti-synthetase syndrome-ILD receiving anti-inflammatory
dominant pattern on HRCT or biopsy in patients with ILD therapy, 6 patients (8.0%) had a decline in FVC of > 10%
associated with Sjögren’s syndrome or polymyositis/ predicted and/or a decline in DLco of > 15% predicted 1 year
dermatomyositis [23–25]. In contrast, the most common pat- after diagnosis of ILD. Of 36 patients who had an increase in
tern seen on HRCT or lung biopsy in patients with RA-ILD is FVC of > 10% predicted and/or increase in DLco of > 15%
UIP [2, 13, 26]. In an analysis of 230 patients with RA-ILD in predicted after 1 year, 12 (33%) had a deterioration over the
the BRILL network in the UK, 65% of patients had UIP on following 2 years [34].
Clin Rheumatol (2019) 38:2673–2681 2675

ILD is a major cause of death in patients with systemic may remain untreated but should be monitored closely for
autoimmune diseases. In an analysis of 1072 deaths in patients signs of progression. There is no agreed definition of disease
with SSc in the EUSTAR database, ILD was listed as the progression in ILD, but in practice, assessment of disease
cause of death in 16.8% of cases, followed by pulmonary progression is likely to be based on clinicians’ assessment of
arterial hypertension (14.7%) and cancer (13.1%) (Fig. 1) symptoms, pulmonary function tests, and/or imaging. With
[35]. A greater extent of fibrosis on HRCT and decline in this in mind, and considering the other manifestations of the
FVC or DLco are established predictors of mortality in pa- disease that need to be considered when managing patients
tients with SSc-ILD [7, 36–38]. A seminal study found that with autoimmune diseases, cross-disciplinary collaboration
patients with extensive disease, defined as > 30% extent of between pulmonologists and rheumatologists is key to identi-
fibrosis on HRCT, or 10–30% extent of fibrosis on HRCT fying patients with autoimmune disease-ILD who require
plus FVC < 70% predicted, had much greater mortality than treatment and deciding on the therapy that should be given
patients with more limited disease (HR 3.46) [36]. The pres- [47].
ence of ILD also markedly increases mortality in patients with Immunosuppressants are the standard of care for systemic
RA [2, 39, 40]. Among 679 patients in a Danish registry, one- autoimmune diseases and may be effective in slowing the
year mortality in patients with RA-ILD was 14%, compared progression of ILD in some patients. However, other than in
with 4% in RA patients without ILD who were matched for SSc-ILD, there is no evidence from randomized double-blind
age, gender, and time since diagnosis of RA (Fig. 2) [40]. Ten- trials to support the efficacy of immunosuppressants in
year mortality in these groups was 60% and 35%, respectively treating ILD. In the absence of a robust evidence base to
[40]. Predictors of mortality in patients with RA-ILD include inform therapeutic decision-making, the choice of therapy
the presence of a UIP pattern on HRCT (Fig. 3), a greater for autoimmune ILD is based on clinical experience rather
extent of fibrosis on HRCT, and lower FVC or DLco [26, than data.
41–44]. In an analysis of 137 patients with RA-ILD at a single Data from randomized controlled trials support the use of
US center, a baseline FVC below the mean of the cohort cyclophosphamide (CYC) and mycophenolate mofetil
(68.7% predicted) and a decline from baseline in FVC ≥ (MMF) to treat SSc-ILD. In the Fibrosing Alveolitis in
10% predicted at any time over the follow-up period (median Scleroderma Trial (FAST), subjects were randomized to re-
4.8 years) were predictors of mortality (HRs 1.46 and 2.57, ceive low-dose prednisolone plus CYC for 6 months followed
respectively) after controlling for age, sex, smoking, and by oral azathioprine for 6 months, or placebo for 1 year. At the
HRCT pattern [41]. A greater extent of fibrosis on HRCT end of the treatment period, there was an improvement of
has also been associated with worse survival in patients with 2.4% in FVC % predicted with active treatment versus a de-
MCTD [3]. cline of 3.0% with placebo [48]. In Scleroderma Lung Study I
(SLS I), among 145 patients with SSc who completed
6 months of treatment, the mean decline from baseline in
Treatment of autoimmune ILDs FVC % predicted at 1 year was 1.0% in patients treated with
CYC versus 2.6% in those treated with placebo [49]. Based on
Not all patients with autoimmune disease–related ILD require the results of these trials, guidelines for the treatment of SSc-
treatment. Pharmacotherapy with immunosuppression is gen- ILD issued by the European League Against Rheumatism
erally reserved for patients with clinically significant, progres- Collaborative Initiative (EULAR) recommend the use of tai-
sive disease [45, 46], while those with non-progressive ILD lored CYC therapy, in particular for patients with progressive

Fig. 1 Causes of death in patients

with SSc in the European
Scleroderma Trials and Research
(EUSTAR) cohort. Adapted from
[35]. Republished with permis-
sion of Ann Rheum Dis, from
Mapping and predicting mortality
from systemic sclerosis, Elhai
et al., 76(11), 2017; permission
conveyed through Copyright
Clearance Center, Inc.
2676 Clin Rheumatol (2019) 38:2673–2681

Fig. 2 Kaplan–Meier estimate of

mortality in patients with RA-ILD
compared with patients with RA
without ILD (matched by age,
sex, and time since diagnosis of
RA). Adapted from [40].
Republished with permission of
Ann Rheum Dis, from A
population-based cohort study of
rheumatoid arthritis-associated
interstitial lung disease: comor-
bidity and mortality, Hyldgaard C
et al., 76(10), 2017; permission
conveyed through Copyright
Clearance Center, Inc.

disease [50, 51]. However, the toxicity of CYC limits it to BRILL network, 21 had received pulsed CYC for progressive
short-term use. The latest EULAR guidelines did not consider ILD; survival time was 72 months in patients treated with
the findings of SLS II, which showed that treatment with oral CYC compared with 43 months in patients with better base-
MMF for 2 years resulted in the same improvement in FVC as line lung function who did not receive CYC [61]. In an obser-
oral CYC for 1 year followed by placebo for 1 year (absolute vational study at a single UK center, lung function changes
changes of 2.19% and 2.88% predicted, respectively), with were assessed in 44 patients with RA-ILD treated with ritux-
better tolerability [52]. However, MMF is now the most wide- imab between 2004 and 2015 (total follow-up 195 patient-
ly used therapy for SSc-ILD and has been endorsed as first- years) [62]. The median relative change in FVC was 1.2%
line therapy by consensus panels of experts [46, 53, 54]. predicted in the 6–12 months after initiation of rituximab com-
Rituximab and azathioprine are also used in the treatment of pared with a decline of 2.4% predicted in the 6–12 months
SSc-ILD, but the evidence that these drugs may preserve or before treatment [62]. At the latest time point with evaluable
improve lung function in these patients comes solely from data, 30 patients (68%) did not meet the criteria for ILD pro-
retrospective or open-label studies [55–58]. gression (i.e., did not have a decline in FVC of > 10% predict-
Beyond SSc-ILD, more robust trial data are needed to de- ed or DLco of > 15% predicted, worsening of ILD score on
termine the role of immunosuppressant therapy for HRCT, or death from progressive lung disease) [62]. In an
autoimmune-associated ILDs. Although CYC, MMF, rituxi- uncontrolled open-label Spanish registry, of 63 patients with
mab, and azathioprine are also commonly used in the treat- RA-ILD treated with abatacept for 12 months, FVC % pre-
ment of RA-ILD, the evidence to support their use comes dicted remained stable in approximately two-thirds of patients
solely from retrospective or observational studies [59–62]. In and improved by ≥ 10% from baseline in approximately one-
a retrospective analysis of 206 patients with RA-ILD in the fifth of patients [63]. A number of other retrospective/

Fig. 3 Kaplan–Meier estimate of

survival in patients with RA-ILD
and UIP or NSIP patterns on
HRCT. Adapted from [41].
Reproduced with permission of
the © ERS 2019. European
Respiratory Journal Feb 2016, 47
(2) 588–596; DOI: https://doi.org/
10.1183/13993003.00357-2015.
This material has not been
reviewed prior to release;
therefore, the European
Respiratory Society may not be
responsible for any errors,
omissions or inaccuracies, or for
any consequences arising
therefrom, in the content
Clin Rheumatol (2019) 38:2673–2681 2677

observational studies have shown preservation or improve- Potential role of anti-fibrotic therapy
ment in lung function in patients with other autoimmune in fibrosing autoimmune ILDs
ILDs treated with immunosuppressants including with a progressive phenotype
polymyositis/dermatomyositis [59, 64] and anti-synthetase
syndrome [65, 66]; however, these studies were uncontrolled Research is ongoing into whether the addition of anti-
and lung function was measured over limited time periods (1 fibrotic therapies that have been shown to slow the pro-
to 4 years). gression of lung fibrosis in patients with IPF might be
There is some evidence linking the use of DMARDs such added to immunosuppressant therapy to slow the progres-
as methotrexate to the development or worsening of ILD in sion of fibrosing ILD in patients with systemic autoim-
rare cases [67], but a causal relationship has not been mune diseases. Non-clinical studies suggest that there are
established. In a retrospective analysis of 78 patients with commonalities in the mechanisms that drive progressive
RA-ILD at a Mexican referral center, patients taking metho- fibrosis between ILDs associated with immunological dis-
trexate prescribed to treat ILD had better survival compared eases and ILDs with other causes [69–72]. Progressive
with those not receiving methotrexate [68]. fibrosing ILDs are believed to be triggered by repetitive

Table 1 Ongoing and recently completed trials in patients with ILDs related to systemic autoimmune diseases

Trial name (ClinicalTrials.gov Patient population Sample Treatment groups Primary endpoint
identifier) size

SENSCIS® (NCT02597933) [94] SSc-ILD 580 Nintedanib versus Rate of decline in FVC over
placeboa 52 weeks (mL/year)
INBUILD® (NCT02999178) [96] Progressive fibrosing ILDs other than 663 Nintedanib versus Rate of decline in FVC over
IPF placebob 52 weeks (mL/year)
TRAIL1 (NCT02808871) RA-ILD 270 Pirfenidone versus Proportion of patients with a
placeboc decline in FVC ≥ 10%
predicted or death at week 52
SLS III (NCT03221257) SSc-ILD 150 Pirfenidone added to Change in FVC % predicted at
MMF month 18
versus MMF aloned
NCT03856853 SSc-ILD 144 Pirfenidone versus Change in FVC % predicted at
placeboe week 52
EvER-ILD (NCT02990286) CTD-ILD or IPAF or idiopathic ILD, 122 Rituximab added to Change in FVC % predicted at
plus NSIP based on HRCT or MMF week 24 (primary endpoint)
histology, plus lack of response to (versus MMF alone) and change in DLco at week 24
immunosuppressant therapy for (secondary endpoint)
ILD
RECITAL (NCT01862926) [97] Severe and/or progressive ILD asso- 116 Rituximab versus IV Changes in FVC (mL) at week 24
ciated with SSc, idiopathic in- CYC (primary endpoint) and 48
flammatory myositis (including (secondary endpoint)
anti-synthetase syndrome), or
MCTD
APRIL (NCT03084419) RA-ILD 30 Abatacept Change in FVC over 28 weeks
a
Patients receiving prednisone ≤ 10 mg/day and/or stable therapy with mycophenolate (mofetil or sodium) or methotrexate (≥ 6 months) were eligible for
inclusion. Patients were not eligible if they had received azathioprine ≤ 8 weeks, or CYC, cyclosporine, or rituximab ≤ 6 months prior to randomization.
Immunosuppressants were allowed during the trial in cases of clinically significant deterioration
b
Patients were not eligible if they had received azathioprine, CYC, MMF, tacrolimus, oral corticosteroids > 20 mg/day, or a combination of oral
corticosteroids, azathioprine, and N-acetylcysteine within 4 weeks; CYC within 8 weeks; or rituximab within 6 months prior to randomization. These
drugs were allowed after 6 months of study treatment in case of worsening of ILD or autoimmune disease
c
Patients were not eligible if they had an introduction or dose modification of corticosteroids (except prednisone or equivalent maintained at ≤ 20 mg/
day) or any cytotoxic, immunosuppressive, or cytokine modulating or receptor antagonist agent for the management of pulmonary manifestations of RA
≤ 3 months prior to screening
d
Patients were not eligible if they had received oral CYC, MMF, azathioprine, or other putative disease-modifying medications ≤ 12 weeks prior to
screening; had received ≥ 3 intravenous doses of CYC, rituximab, or other injectable medication with putative disease-modifying activity ≤ 6 months
prior to screening; or had received prednisone (or equivalent) > 10 mg/day ≤ 30 days prior to their baseline visit
e
Patients were not eligible if they had received prednisone > 10 mg/day within 2 weeks; had received azathioprine, hydroxychloroquine, colchizine, D-
penicillamine, and sulfasalazine within 8 weeks; or had received CYC, rituximab, tocilizumab, abatacept, leflunomide, tacrolimus, newer anti-arthritic
treatments like tofacitinib and ciclosporine A, or potassium para-aminobenzoate within 6 months
2678 Clin Rheumatol (2019) 38:2673–2681

injuries at alveolar epithelial or microvascular endothelial to systemic autoimmune diseases are ongoing (Table 1). The
sites, which lead to cell destruction and unregulated re- INBUILD® trial (NCT02999178) is investigating the effects
pair. Fibroblasts orchestrated to the sites of injury are of nintedanib versus placebo in patients with progressive
activated to become myofibroblasts, which secrete exces- fibrosing ILDs other than IPF, including those associated with
sive amounts of extracellular matrix (ECM), resulting in autoimmune diseases [96]. SLS III (NCT03221257) is study-
increased tissue stiffness, which in turn further activates ing the efficacy and safety of pirfenidone added to MMF
and stimulates fibroblasts [69, 70]. Macrophages and lym- versus MMF alone in patients with SSc-ILD, while the effects
phocytes recruited to the site of injury release pro-fibrotic of pirfenidone versus placebo in patients with RA-ILD are
mediators, and vascular damage leads to the activation being investigated in TRAIL I (NCT02808871). Based on
and degranulation of platelets, which release pro-fibrotic their metabolism [98, 99], drug-drug interactions between
mediators. These mediators further promote fibroblast ac- anti-fibrotic therapies and immunosuppressant therapies are
tivation, driving a self-sustaining process of progressive not expected, but further data are needed.
fibrosis [70, 73, 74]. Coagulation pathways that are acti-
vated by tissue damage may also drive fibrosis [75, 76].
As fibrosis progresses, the accumulation of ECM in-
creases the diffusion distances between blood vessels Conclusions
and cells, reducing the oxygen supply to tissues [77].
Vascular alterations and reduced capillary density may ILD is a major cause of morbidity and mortality in patients
also reduce oxygen supply [77]. In a self-sustaining loop, with systemic autoimmune diseases. Immunosuppressant
tissue hypoxia may stimulate further production of ECM therapy is the mainstay of therapy for these diseases, but there
proteins [78, 79]. Several epigenetic modifications have is very limited evidence to support its efficacy in treating ILD
also been implicated in the activation of fibroblasts in apart from SSc-ILD. Clinical and mechanistic similarities
fibrosing lung diseases [80, 81]. among progressive fibrosing ILDs suggest that drugs known
The commonalities in the pathogenic mechanisms that to slow disease progression in patients with IPF may also slow
drive fibrosis with different triggers suggest that drugs that the progression of ILD associated with systemic autoimmune
slow disease progression in patients with IPF might also in- diseases. In the SENSCIS trial, nintedanib reduced the annual
hibit the progression of other ILDs. Nintedanib and rate of decline in FVC in a broad range of patients with SSc-
pirfenidone reduce the rate of decline in lung function in pa- ILD, including those taking mycophenolate, suggesting that in
tients with IPF [82, 83]. The mechanism of action of future, the paradigm for treating autoimmune ILDs may shift
pirfenidone remains unclear, but it has been shown to reduce to a combination of immunosuppressant and anti-fibrotic
the proliferation of fibroblasts and myofibroblasts and to in- therapy.
hibit ECM synthesis and deposition [84, 85]. Nintedanib has
demonstrated anti-fibrotic, anti-inflammatory, and vascular re- Acknowledgments Medical writing assistance, supported financially by
Boehringer Ingelheim, was provided by Elizabeth Ng and Wendy Morris
modelling effects in several animal models resembling aspects
of FleishmanHillard Fishburn, London, UK, during the preparation of this
of fibrosing ILDs [72, 86–93]. In Fra2 mice, a model of the manuscript. The authors were fully responsible for all content and edito-
fibrotic and vascular manifestations of SSc, nintedanib re- rial decisions, were involved at all stages of development, and have ap-
duced hydroxyproline levels and myofibroblast counts in the proved the final version.
lung, as well as reducing the thickening of the walls of pul- Data availability Not applicable to this article as no datasets were gener-
ated or analyzed.
monary arteries [90]. In transgenic SKG mice, a model resem-
bling aspects of RA-ILD, nintedanib reduced hydroxyproline
Compliance with ethical standards
levels and α-smooth muscle actin staining in the lungs [93].
The Phase III SENSCIS® trial assessed the efficacy and The manuscript does not contain clinical studies or patient data.
safety of nintedanib in 576 patients with SSc-ILD [94].
Nintedanib reduced the annual rate of decline in FVC versus Conflict of interest Aryeh Fischer reports grants and personal fees from
placebo in a broad range of patients, including those with Boehringer Ingelheim and personal fees from Genentech-Roche, Pfizer,
and Genentech. Jörg Distler has nothing to disclose. The authors have
diffuse cutaneous SSc and limited cutaneous SSc and patients received no payment for this article.
who were and were not taking mycophenolate at baseline. The
safety profile of nintedanib was similar to that observed in Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://
patients with IPF, characterized mainly by mild or moderate
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
gastrointestinal events, particularly diarrhea [94], and the gas- distribution, and reproduction in any medium, provided you give appro-
trointestinal adverse event profile was similar in patients who priate credit to the original author(s) and the source, provide a link to the
were and were not taking mycophenolate [95]. Other large Creative Commons license, and indicate if changes were made.
trials of anti-fibrotic therapies in patients with ILDs related
Clin Rheumatol (2019) 38:2673–2681 2679

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