Rheumatology 2020;59:1233–1240

RHEUMATOLOGY doi:10.1093/rheumatology/kez404
Advance Access publication 24 September 2019

Original article
Risk of progression of interstitial pneumonia with
autoimmune features to a systemic autoimmune
rheumatic disease
1
Michail K. Alevizos , Jon T. Giles1, Nina M. Patel2 and Elana J. Bernstein 1

Abstract
Objective. The aim of this study was to determine the risk of developing a systemic autoimmune rheumatic disease
(ARD) after an initial diagnosis of interstitial pneumonia with autoimmune features (IPAF).
Methods. We performed a retrospective cohort study of patients with interstitial lung disease (ILD) who were evaluated
at Columbia University Irving Medical Center from 2009 to 2017. We divided patients with idiopathic ILD into two groups:
those who met IPAF criteria and those who did not meet IPAF criteria at initial ILD diagnosis. We examined the asso-
ciation between IPAF and diagnosis of ARD during the follow-up period using a multivariable-adjusted logistic regression
model.
Results. Of the 697 patients with ILD who were screened, 174 met inclusion criteria (50 met IPAF criteria and 124 did
not). During a median follow-up period of 5.2 years, 16% (8/50) of subjects with IPAF were diagnosed with an ARD
compared with 1.6% (2/124) of subjects without IPAF (P = 0.001). Adjusting for age, sex, smoking status and use of
immunosuppressive therapy, the odds of progressing to an ARD were 14 times higher in subjects with IPAF than in those
without IPAF (odds ratio 14.18, 95% CI 1.44–138.95, P = 0.02).
Conclusion. The presence of IPAF confers an increased risk of developing an ARD. Patients with IPAF should therefore
be followed closely for the development of an ARD.

Key words: interstitial pneumonia with autoimmune features, progression to autoimmune disease

Rheumatology key messages

CLINICAL
SCIENCE
. Interstitial pneumonia with autoimmune features confers an increased risk of developing a systemic autoimmune
rheumatic disease.
. Patients with interstitial pneumonia with autoimmune features should be monitored by rheumatologists for de-
velopment of systemic autoimmune rheumatic diseases.

Introduction In 2015, the American Thoracic Society (ATS) and

Systemic autoimmune rheumatic diseases (ARDs) are a
relatively common cause of interstitial lung disease (ILD)
[1], and ILD may be the initial manifestation of an ARD [2].
In a retrospective cohort study of 50 patients presenting
to an ILD clinic for evaluation, 50% were subsequently
diagnosed with an ARD [3]. Therefore, it is important to
identify risk factors for progression to an ARD among pa-
tients with ILD as this could allow for early detection and
treatment of ARDs.
1
Division of Rheumatology and 2Division of Pulmonary and Critical
Care, Columbia University Irving Medical Center, New York, NY, USA
Submitted 29 April 2019; accepted 27 July 2019
Correspondence to: Elana J. Bernstein, Division of Rheumatology,
Columbia University Medical Center, 630 West 168th Street, Suite
3-450, New York, NY 10032, USA. E-mail: ejb2153@columbia.edu
European Respiratory Society (ERS) proposed the term
‘interstitial pneumonia with autoimmune features’ (IPAF)
to describe the 15–25% of ILD patients who have some
autoimmune features but do not meet classification cri-
teria for an ARD [4–6]. To meet classification criteria for
IPAF, a patient must have at least one feature from at least
two of the following three domains: clinical, serological
and morphological [6].
Data on progression of IPAF to ARDs are limited and
conflicting. Scire et al. found that 42% of individuals with
anti-synthetase antibodies who initially met IPAF criteria
ultimately developed myositis, RA or a myositis–RA over-
lap syndrome [7]. Ito et al. found that 12.2% of patients
who met the serological and morphological domain of
IPAF were later diagnosed with an ARD during a median
follow-up period of 4.5 years [8]. However, Chartrand et al.
found that none of 56 IPAF patients progressed to an ARD

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Michail K. Alevizos et al.
over a 4-year follow-up period [9]. Thus, it remains unclear
whether the risk of progression to an ARD is greater in
those with IPAF than in those with idiopathic ILD without
autoimmune features. The primary aim of this study was
to determine the risk of developing an ARD after an initial
diagnosis of IPAF. Our secondary aim was to identify risk
factors for the development of an ARD among patients
with idiopathic ILD. We hypothesized that adults with
IPAF would have a greater risk of developing an ARD
than those with idiopathic ILD who did not meet classifi-
cation criteria for IPAF.
Methods
Participants
We performed a retrospective cohort study of patients
with ILD who were evaluated at Columbia University
Irving Medical Center (CUIMC) between 1 January 2009
and 1 January 2017. Data were extracted from the elec-
tronic medical record. Patients were screened if they had
an ILD ICD-9 or ICD-10 code (516.3, 516.32, 516.35, 515,
J84.9, J84.111, J84.113, J84.10, J84.112, J84.116, J84.2,
J84.117) documented in at least six different clinic visits.
Patients were included if they were at least 18 years of age
at the time of ILD diagnosis; had at least one follow-up
clinic visit at least 6 months after initial pulmonary evalu-
ation at CUIMC; and had available data on rheumatologi-
cal serologies, imaging pattern on high resolution
computed tomography (HRCT) scan of the chest (as per
clinician and radiologist impression), pulmonary function
tests and work up for known causes of ILD at initial ILD
diagnosis. Patients were excluded if they had ILD due to a
known cause (e.g. hypersensitivity pneumonitis, estab-
lished ARD, sarcoidosis, familial pulmonary fibrosis). This
study was approved by the Institutional Review Board at
CUIMC (no. AAAR244).
Statistical analysis
We compared baseline characteristics between patients
with and without IPAF using Kruskal–Wallis, Fisher’s exact
and 2 tests, as appropriate. Our primary outcome was
diagnosis of an ARD by a rheumatologist in the follow-up
period. Via medical record review, we also determined
which of the ARD diagnoses would meet the following
sets of classification criteria: 2010 ACR/EULAR RA clas-
sification criteria [10], 2013 ACR/EULAR classification cri-
teria for SSc [11], 2017 EULAR/ACR classification criteria
for adult and juvenile idiopathic inflammatory myopathies
[12], and Chapel Hill Consensus Conference criteria for
systemic vasculitides [13].
To examine the association between IPAF at initial ILD
diagnosis and rheumatologist diagnosis of an ARD in the
follow-up period, we modelled IPAF as the independent
binary variable of interest in logistic regression models
where diagnosis of an ARD in the follow-up period was
the dependent binary variable. We initially estimated odds
ratios (ORs) for diagnosis of an ARD in the follow-up
period for adults with IPAF compared with those without
IPAF in a logistic regression model without adjustment for
1234
additional independent variables. We then constructed a
multivariable logistic regression model adjusting for age,
sex, smoking status and use of immunosuppressive ther-
apy. We also estimated hazard ratios for ARD diagnosis
for patients with vs without IPAF in a Cox proportional
hazards model without adjustment for additional inde-
pendent variables. We then constructed a multivariable
Cox model adjusting for age, sex, smoking status and
use of immunosuppressive therapy, and generated a
Kaplan–Meier curve. In exploratory analyses, we exam-
ined the association of (i) the IPAF clinical domain, (ii)
the IPAF serological domain, (iii) the IPAF morphological
domain, and (iv) female sex with progression to an ARD
[6]. We calculated the area under the receiver operating
characteristic curve (AUC) to estimate which combination
of covariates best predicted progression to an ARD
among patients with idiopathic ILD. All analyses were per-
formed using STATA version 13.1 (StataCorp, College
Station, TX, USA).
Results
Of the 697 patients screened, 419 met inclusion criteria.
Of these, 245 (58%) had ILD due to a known cause and
were excluded, while 174 (42%) patients had idiopathic
ILD at baseline. Of the 174 subjects with idiopathic ILD, 50
(29%) met ATS/ERS classification criteria for IPAF at initial
ILD diagnosis and 124 (71%) did not (Supplementary Fig.
S1, available at Rheumatology online).
Compared with subjects without IPAF, those with IPAF
were younger (median age 56 vs 66 years, P < 0.001) and
a greater proportion (i) were female (60% vs 36%,
P < 0.001); (ii) were non-smokers (48% vs 30%,
P = 0.03); (iii) had clinical features of autoimmunity (38%
vs 0, P < 0.001); (iv) had positive autoantibodies (98% vs
25%, P < 0.001); (v) had a non-specific interstitial pneu-
monia pattern on HRCT (82% vs 15%, P < 0.001) or
biopsy (73% vs 12%, P < 0.001); and (vi) had pulmonary
hypertension defined by right-sided heart catheterization
(14% vs 4%, P = 0.02) at initial ILD diagnosis (Tables 1–3).
A smaller proportion of subjects with IPAF than without
IPAF had a usual interstitial pneumonia (UIP) pattern on
HRCT (18% vs 75%, P < 0.001) or biopsy (20% vs 71%,
P < 0.001). The median [interquartile range (IQR)] duration
of observation was similar for both groups [6.3 (4.3–8.9)
years for IPAF vs 5.8 (3.0–8.5) years for non-IPAF,
P = 0.74]. During the observation period, a greater propor-
tion of subjects with IPAF than those without underwent
rheumatological evaluation (78% vs 19%, P < 0.001) and
received immunosuppressive therapy (96% vs 52%,
P < 0.001).
During the median follow-up period of 5.2 years, 8 of 50
(16%) subjects with IPAF were diagnosed with an ARD
compared with 2 of 124 (1.6%) subjects without IPAF
(P = 0.001; Table 4). A description of these patients’ initial
presentation as well as clinical features that arose in the
follow-up period is included in Supplementary Table S1,
available at Rheumatology online. Of the eight patients
with IPAF who were later diagnosed with an ARD, two
were diagnosed with RA, three with systemic sclerosis
https://academic.oup.com/rheumatology
 Risk of progression of interstitial pneumonia with autoimmune features

TABLE 1 Demographic, clinical, and treatment characteristics of patients with idiopathic ILD

Overall cohort IPAF Non-IPAF

Characteristic (n = 174) (n = 50) (n = 124) P-value

Age, median (IQR), years 63 (56–72) 56 (47–64) 66 (59–73) <0.001

Female sex, n (%) 74 (43) 30 (60) 44 (36) 0.003
Ever smoker, n (%) 111 (64) 25 (50) 86 (69) 0.03
BMI, median (IQR), kg/m2 28 (25–31) 28 (25–31) 27 (25–30) 0.38
FVC, mean (S.D.), % predicted 67 (20) 63 (20) 68 (19) 0.12
FEV1, mean (S.D.), % predicted 70 (20) 65 (20) 72 (20) 0.054
DLCO, mean (S.D.), % predicted 41 (14) 37 (11) 42 (14) 0.006
IPAF clinical domain, n (%) 19 (11) 19 (38) 0 <0.001
Mechanic’s hands, n (%) 2 (1) 2 (4) 0 0.14
Distal digital tip ulceration, n (%) 1 (0.6) 1 (2) 0 0.31
Inflammatory arthritis, n (%) 3 (1.7) 3 (6) 0 0.03
Palmar telangiectasias, n (%) 1 (0.6) 1 (2) 0 0.49
Raynaud’s phenomenon, n (%) 15 (8.6) 15 (30) 0 <0.001
Unexplained digital oedema, n (%) 0 0 0 —
Unexplained fixed rash on the digital extensor surfaces, n (%) 1 (0.6) 1 (2) 0 0.31
Rheumatological evaluation during the observation period, n (%) 62 (36) 39 (78) 23 (19) <0.001
Immunosuppression during the observation perioda, n (%) 112 (64) 48 (96) 64 (52) <0.001
Immunosuppression within first year of ILD diagnosis, n (%) 78 (45) 41 (82) 37 (30) 0.002

a
Immunosuppressive medications used: steroids, mycophenolate mofetil, azathioprine, cyclophosphamide, calcineurin inhibi-
tors. DLCO: diffusing capacity for carbon monoxide; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; IPAF:
interstitial pneumonia with autoimmune features; IQR, interquartile range.

(SSc), one with PM and two with ANCA-associated vas-
culitis. Both patients without IPAF who were later diag-
nosed with an ARD developed RA. Even though
diagnosis of an ARD was made by the patient’s rheuma-
tologist based upon clinical judgment—not necessarily
relying on classification criteria—review of medical re-
cords reveals that both ANCA-associated vasculitis diag-
noses would meet the Chapel Hill Consensus Conference
definition [13], all four RA diagnoses would meet the 2010
ACR/EULAR RA classification criteria [10], the one PM
diagnosis would be classified as definite myositis accord-
ing to the 2017 EULAR/ACR classification criteria for adult
and juvenile idiopathic inflammatory myopathies [12], and
two out of the three SSc diagnoses would meet the 2013
ACR/EULAR classification criteria for SSc [11]. The one
SSc patient who did not meet the 2013 ACR/EULAR clas-
sification criteria for SSc (case 9 in Supplementary Table
S1, available at Rheumatology online) presented with
oesophageal dysmotility and small intestinal bacterial
overgrowth as well as Raynaud’s phenomenon, and had
abnormal nailfold capillaries on nailfold capillaroscopy;
these manifestations, combined with the presence of
ILD, led to a multi-disciplinary consensus diagnosis of
SSc.
The multivariable-adjusted odds of progressing to an
ARD were 14-fold higher in patients with IPAF than in
those without IPAF (OR 14.18, 95% CI 1.44–138.95,
P = 0.02; Table 4), adjusting for age, sex, smoking
status, and use of immunosuppressive therapy. In a multi-
variable Cox regression analysis, the adjusted hazard of
progressing to an ARD was >20-fold higher in IPAF pa-
tients than in those without IPAF (hazard ratio 20.23, 95%
CI 1.90–214.70, P = 0.01; Fig. 1). In an exploratory ana-
lysis, the IPAF clinical domain was not statistically signifi-
cantly associated with progression to an ARD in univariate
(OR 3.96, 95% CI 0.93–16.85, P = 0.06) or multivariable
analyses (OR 3.27, 95% CI 0.62–17.21, P = 0.16). The
IPAF serological domain was statistically significantly
associated with progression to an ARD in univariate ana-
lysis (OR 11.22, 95% CI 1.30–90.60, P = 0.02), and
trended toward significance in multivariable analysis (OR
9.60, 95% CI 0.99–92.78, P = 0.051). The IPAF morpho-
logical domain was not statistically significantly asso-
ciated with progression to an ARD in univariate (OR
2.60, 95% CI 0.71–9.58, P = 0.15) or multivariable ana-
lyses (OR 1.04, 95% CI 0.23–4.70, P = 0.95). The multi-
variable-adjusted odds of progressing to an ARD were
9-fold higher in females with idiopathic ILD than in males
(OR 9.40, 95% CI 1.12–79.22, P = 0.04), adjusting for age,
IPAF status, smoking status and use of immunosuppres-
sion. The best predictors of progression to an ARD were (i)
the fully adjusted model (IPAF, age, sex, smoking status,
use of immunosuppressive therapy; AUC 0.87, 95% CI
0.80–0.94) or (ii) a combination of female sex and the
IPAF serological domain (AUC 0.83, 95% CI 0.74–0.92;
Table 5). The AUCs of these models were not statistically
different from one another (P = 0.40), indicating that the
two models were statistically similar in the prediction of
progression to an ARD.
Discussion
We found that patients with idiopathic ILD who met clas-
sification criteria for IPAF had 14-fold higher odds of

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Michail K. Alevizos et al.

TABLE 2 Baseline rheumatological serologies in patients with idiopathic ILD

Overall cohort IPAF Non-IPAF

Rheumatological serologies (n = 174) (n = 50) (n = 124) P-value

IPAF serological domain 80 (46) 49 (98) 31 (25) <0.001

ANA positivea 50 (29) 31 (62) 19 (15) <0.001
RF 52 upper limit of normal 15 (9) 7 (14) 8 (7) 0.11
Anti-CCP positive 7 (6) 4 (11) 3 (4) 0.09
(n = 112) (n = 37) (n = 75)
Anti-dsDNA positive 5 (4) 2 (5) 3 (4) 0.63
(n = 118) (n = 39) (n = 79)
Anti-Ro (SS-A) positive 20 (12) 18 (36) 2 (2) <0.001
(n = 167) (n = 50) (n = 117)
Anti-La (SSB) positive 2 (1.1) 1 (2) 1 (0.8) 0.49
(n = 167) (n = 50) (n = 117)
Anti-RNP positive 9 (5) 7 (14) 2 (2) 0.003
(n = 167) (n = 50) (n = 117)
Anti-Smith positive 3 (1.7) 2 (4) 1 (0.8) 0.19
(n = 167) (n = 50) (n = 117)
Anti-Scl-70 positive 1 (0.6) 1 (2) 0 0.30
(n = 167) (n = 50) (n = 117)
Anti-tRNA synthetase positiveb 9 (5.2) 9 (18) 0 <0.001
(n = 167) (n = 50) (n = 117)
Anti-PM-Scl positive 0 0 0 —
(n = 3) (n = 2) (n = 1)
Anti-MDA-5 positive 0 0 0 —
(n = 3) (n = 2) (n = 1)
c
Other serologies
Anti-RNA polymerase III positive 0 0 0 —
(n = 53) (n = 20) (n = 33)
Anti-centromere positive 1 (0.9) 0 1 (1.4) 0.99
(n = 106) (n = 36) (n = 70)
Anti-MPO positive 4 (3.5) 3 (8) 1 (1) 0.07
(n = 112) (n = 37) (n = 75)
Anti-PR3 positive 2 (2) 1 (3) 1 (1) 0.49
(n = 112) (n = 37) (n = 75)

Data presented as n (%). aANA 51: 320 titre, diffuse, speckled, homogeneous patterns or ANA nucleolar pattern (any titre) or
ANA centromere pattern (any titre). bIncludes anti-histidyl-tRNA synthetase (anti-Jo-1), anti-glycyl-tRNA synthetase (anti-EJ),
anti-threonyl-tRNA synthetase (anti-PL-7) and anti-alanyl-tRNA synthetase (anti-PL-12) antibodies. cSerologies not included in
the IPAF serological domain. dsDNA: double stranded DNA; IPAF: interstitial pneumonia with autoimmune features; MDA-5:
melanoma differentiation-associated protein; PR3: proteinase 3.

progression to an ARD compared with patients with idio-
pathic ILD who did not meet IPAF criteria, even when
controlling for important potential confounders such as
age, sex, smoking status and use of immunosuppressive
therapy. In an exploratory analysis, we also found that
among patients with idiopathic ILD, female sex was asso-
ciated with progression to an ARD, and the IPAF sero-
logical domain trended towards significance. In fact, the
combination of female sex and the IPAF serological
domain predicted progression to an ARD just as well as
the fully adjusted model. However, other autoimmune fea-
tures, such as the IPAF clinical or morphological domain,
were not associated with progression to an ARD. The pro-
portion of patients progressing to ARD among patients
who met the serological and morphological domain of
the IPAF criteria in the study of Ito et al. was similar to in
our study [8]. However, the study of Ito et al. did not in-
clude a control group for comparison. Chartrand et al.
reported that evolution to ARD may have been halted in
their cohort because all of the patients were on
immunosuppression [9]. The results of our study suggest
that IPAF criteria could be used to identify ILD patients at
high risk of developing an ARD. Previous studies have
shown the benefit of early immunomodulatory treatment
in preventing or delaying progression from undifferenti-
ated arthritis to RA [14]. Therefore, an important question
is whether immunomodulatory medication could similarly
prevent or delay progression to an ARD among patients
with IPAF.
The prevalence of the various ARDs in the IPAF group
was similar to one another, which is quite different from
the general population, in which RA is the most prevalent
ARD. This is likely due to the fact that ILD has differing
prevalences among different ARDs. For example, up to
90% of SSc patients exhibit some evidence of ILD on
HRCT and 40–75% of them have clinically significant
ILD [15, 16]. In contrast, a much lower percentage of RA
patients (33%) have radiographic ILD and only 10% have
clinically significant ILD [17, 18]. Castelino et al. also
observed a similar incidence of various ARDs in their

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 Risk of progression of interstitial pneumonia with autoimmune features

TABLE 3 Baseline morphological characteristics of patients with idiopathic ILD

Overall cohort IPAF Non-IPAF

Morphological characteristics (n = 174) (n = 50) (n = 124) P-value

IPAF morphological domain 74 (43) 46 (92) 28 (23) <0.001

HRCT pattern
NSIP 59 (34) 41 (82) 18 (15) <0.001
OP 7 (4.7) 3 (6) 4 (3.2) 0.41
NSIP with OP overlap 3 (1.7) 3 (6) 0 0.02
LIP 0 0 0 –
Biopsy pattern
NSIP 37 (34) 29 (73) 8 (12) <0.001
(n = 109) (n = 40) (n = 69)
OP 13 (11.9) 7 (17.5) 6 (8.7) 0.17
(n = 109) (n = 40) (n = 69)
NSIP with OP overlap 5 (4.6) 4 (10) 1 (1.4) 0.06
(n = 109) (n = 40) (n = 69)
LIP 0 0 0 –
(n = 109) (n = 40) (n = 69)
Histopathological feature
Interstitial lymphoid aggregates with germinal centers 3 (2.8) 3 (7.5) 0 0.02
(n = 109) (n = 40) (n = 69)
Diffuse lymphoplasmacytic infiltration (with or without lymphoid follicles) 7 (6.4) 6 (15.0) 1 (1.4) 0.01
(n = 109) (n = 40) (n = 69)
Unexplained pleural effusion or thickening 2 (1.1) 1 (2) 1 (0.8) 0.49
Unexplained pericardial effusion or thickening 0 0 0 –
Unexplained intrinsic airways disease 5 (2.9) 2 (4) 3 (2.4) 0.63
Unexplained pulmonary vasculopathy 5 (2.8) 4 (8) 1 (0.8) 0.02
HRCT pattern: UIP 102 (59) 9 (18) 93 (75) <0.001
Biopsy pattern: UIP 57 (52) 8 (20) 49 (71) <0.001
(n = 109) (n = 40) (n = 69)
Pulmonary hypertensiona 12 (7) 7 (14) 5 (4) 0.02

Data presented as n (%). aDiagnosed by right-sided heart catheterization. HRCT: high resolution computed tomography; IPAF:
interstitial pneumonia with autoimmune features; LIP: lymphocytic interstitial pneumonia; NSIP: non-specific interstitial pneu-
monia; OP: organizing pneumonia; UIP: usual interstitial pneumonia.

TABLE 4 Association between IPAF and diagnosis of ARD in the follow-up period

IPAF (n = 50) Non-IPAF (n = 124) P-value

Diagnosis of ARD in the follow-up period, n (%) 8 (16) 2 (1.6) 0.001

Type of ARD 2 RA, 3 SSc, 1 PM, 2 AAV 2 RA —
Total duration of observation, median (IQR), years 6.3 (4.3–8.9) 5.8 (3–8.5) 0.74
Time from ILD diagnosis to ARD diagnosis, median (IQR), years 3.4 (1.8–5.3) 7.8 (6.2–9.4) 0.19
Time from first rheumatological evaluation to ARD diagnosis, 0.9 (0.4–4.2) 2 (1–3) 0.51
median (IQR), years
Odds ratio, median (IQR)
Unadjusted 11.61 (2.37–56.90) 1 0.002
Adjusteda 14.18 (1.44–138.95) 1 0.02

a
Adjusted for age, sex, smoking status and use of immunosuppression. AAV: ANCA-associated vasculitis; ARD: systemic
autoimmune rheumatic disease; IPAF: interstitial pneumonia with autoimmune features; SSc: systemic sclerosis.

cohort of 50 ILD patients [3]. Interestingly, two of the ten
patients who progressed to an ARD in our study de-
veloped ANCA-associated vasculitis, but ANCAs are not
included in the serological domain of the IPAF criteria. If
the IPAF criteria ever undergo a revision, we suggest
including ANCAs in the serological domain.
ARDs evolve from an asymptomatic or minimally symp-
tomatic phase, during which specific autoantibodies are
present in the serum, to a clinically overt phase that mani-
fests with symptoms and signs that allow for diagnosis to
be made. For example, autoantibodies have been shown
to be present many years prior to the onset of clinical

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Michail K. Alevizos et al.
manifestations of both SLE and RA [19, 20]. During this
preclinical phase, autoantibodies are detected initially
against a single autoantigen but over time against add-
itional autoantigens (i.e. ‘epitope spread’). Clinical symp-
toms develop anywhere from 1 to 10 years after the
appearance of the first autoantibody [19–21]. In patients
with Raynaud’s phenomenon, the presence of SSc-spe-
cific autoantibodies has been associated with a signifi-
cantly higher risk of progression to SSc [22]. The
presence of both SSc-specific autoantibodies and abnor-
mal findings on nailfold capillaroscopy was associated
with an even greater risk of progression to SSc. Our find-
ings are consistent with the above studies and suggest
that the presence of a combination of autoimmune
FIG. 1 Kaplan-Meier estimates for progression to ARD
Kaplan–Meier curves for the risk of progression to an ARD
among patients with idiopathic ILD (IPAF and non-IPAF).
Risk estimates are adjusted for sex, age, smoking status
and use of immunosuppression. ARD: systemic autoim-
mune rheumatic disease; HR: hazard ratio; IPAF: intersti-
tial pneumonia with autoimmune features.
TABLE 5 Performance characteristics for baseline variables to predict progression to ARD
Variables
IPAF
IPAF, sex, age, smoker, use of immunosuppression (fully adjusted model)
Clinical domain
Serological domain
Morphological domain
Sex
Sex and serological domain
Clinical and serological domain
Serological and morphological domain
a
P-values for the comparison of AUCs of IPAF to a given variable or set of variables. bP-values for the comparison of AUCs of
the fully adjusted model to a given variable or set of variables. ARD: systemic autoimmune rheumatic disease; AUC: area
under the curve; IPAF: interstitial pneumonia with autoimmune features.
1238
features in ILD patients confers a significantly higher risk
of progression to an ARD.
IPAF shares common clinical features with the systemic
autoimmune rheumatic disease associated-interstitial
lung diseases (ARD-ILDs), which are complex, heteroge-
neous diseases. Similar to traditional ARD-ILD, patients
with IPAF may present with inflammatory forms of ILD
(e.g. organizing pneumonia, non-specific interstitial pneu-
monia) or more fibrotic disease (e.g. UIP). These
radiographic and histopathological patterns can be asso-
ciated with differing treatment responses and prognosis.
Oldham et al. showed that IPAF patients with UIP had a
similar prognosis to that of patients with idiopathic pul-
monary fibrosis, which was poorer than that of IPAF pa-
tients without UIP [23]. While clinical features may differ
among patients with different forms of ARDs or IPAF,
treatment of ILD in both settings is tailored to a patient’s
underlying radiographic and histopathologic ILD subtype.
Both rheumatologists and pulmonologists should be
involved in the care of patients with ARD-ILDs and IPAF.
Even though clinicians from these specialties approach
these diseases from different perspectives, we strive to
achieve consensus on diagnosis and treatment by sharing
our expertise during multi-disciplinary discussions. Such
multi-disciplinary consensus is critical to the proper clas-
sification of ARD-ILDs and IPAF.
There were some limitations of our study. First, it was
retrospective. However, as part of our inclusion criteria, all
subjects had ANA and RF testing and their HRCT pattern
available. Ninety-seven percent of the subjects had re-
sults of anti-SSA, anti-SSB, anti-RNP, anti-Smith, anti-
Scl-70 and anti-Jo-1 testing. Therefore, we were able to
assess uniformly for the serological and morphological
domains of the IPAF criteria. Second, it was conducted
at a single tertiary referral centre for ILD, which may limit
generalizability. Third, a small number of ARD cases were
observed in the follow-up period, which may be due to the
fact that the majority of IPAF patients received immuno-
suppression to treat their lung disease. However, as this
limitation would have biased our results toward the null
hypothesis, the true association between IPAF and ARD
AUC (95% CI) P-valuea P-valueb
0.77 (0.64–0.90) — 0.07
0.87 (0.80–0.94) 0.07 —
0.60 (0.45–0.75) 0.04 0.002
0.73 (0.62–0.83) 0.39 0.02
0.62 (0.45–0.75) 0.01 0.001
0.75 (0.65–0.86) 0.83 0.03
0.83 (0.74–0.92) 0.42 0.40
0.75 (0.62–0.88) 0.28 0.10
0.75 (0.61–0.89) 0.78 0.13
https://academic.oup.com/rheumatology
 Risk of progression of interstitial pneumonia with autoimmune features
unbiased by ILD treatment is likely even larger than the
large effect we detected. Fourth, a greater proportion of
patients with IPAF underwent rheumatological evaluation
than those without IPAF. However, the median observa-
tion time was similar between both groups, permitting
equal opportunity for referral for rheumatological evalu-
ation if an ARD was suspected. In addition, the higher
frequency of rheumatological evaluation among IPAF pa-
tients may be due to the fact that these patients de-
veloped an ARD at a higher frequency than the controls.
Our study has several strengths. Patients who are eval-
uated at the CUIMC ILD Program undergo a comprehen-
sive evaluation, which includes uniform testing of a broad
range of autoantibodies. Thus, we were able to collect
detailed information on the clinical phenotypes of these
patients, including rheumatological serologies, HRCT ima-
ging/lung biopsy patterns and pulmonary function tests.
Because we screened charts of patients with an ILD ICD-9
or ICD-10 code documented in at least six different clinic
visits, we were able to increase the specificity for ILD
diagnosis and establish a cohort of idiopathic ILD patients
with long-term follow-up at our institution.
In summary, the presence of IPAF confers an increased
risk of developing an ARD. Patients with IPAF should
therefore be followed by rheumatologists for the develop-
ment of an ARD. In particular, women with idiopathic ILD
and a positive autoantibody may be at increased risk for
the development of an ARD, and should be monitored
closely. Future work should aim to study the natural his-
tory of IPAF prospectively, as IPAF may represent a
‘window of opportunity’ for early diagnosis and manage-
ment, and perhaps even prevention of ARDs.
Acknowledgements
E.J.B. is supported by NIH/NIAMS K23AR075112.
Funding: This work was supported by the Bouncer
Foundation.
Disclosure statement: The authors have declared no
conflicts of interest.
Supplementary data
Supplementary data are available at Rheumatology online.
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