Expert Review of Clinical Immunology

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Interstitial Pneumonia with Autoimmune Features

(IPAF): time to redefine the classification criteria

Gianluca Sambataro, Carlo Vancheri & Domenico Sambataro

To cite this article: Gianluca Sambataro, Carlo Vancheri & Domenico Sambataro
(2023) Interstitial Pneumonia with Autoimmune Features (IPAF): time to redefine
the classification criteria, Expert Review of Clinical Immunology, 19:2, 131-133, DOI:
10.1080/1744666X.2023.2134119

To link to this article: https://doi.org/10.1080/1744666X.2023.2134119

Published online: 11 Oct 2022.

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EXPERT REVIEW OF CLINICAL IMMUNOLOGY
2023, VOL. 19, NO. 2, 131–133
https://doi.org/10.1080/1744666X.2023.2134119
EDITORIAL
Interstitial Pneumonia with Autoimmune Features (IPAF): time to redefine the
classification criteria
Gianluca Sambataroa,b, Carlo Vancheria and Domenico Sambatarob
a
Department of Clinical and Experimental Medicine, Regional Referral Centre for Rare Lung Disease, A.O.U. “Policlinico-San Marco,” University of
Catania, Catania, Italy; bRheumatology Outpatient Clinic, Artroreuma SRL, Mascalucia, Italy
ARTICLE HISTORY Received 6 September 2022; Revised 22 September 2022; Accepted 4 October 2022
KEYWORDS Interstitial pneumonia with autoimmune features; undifferentiated connective tissue disease; diagnosis; autoantibodies; idiopathic inflammatory
myopathies
The research classification named ‘Interstitial Pneumonia with
Autoimmune Features’ (IPAF) was proposed to include
patients with Interstitial Lung Disease (ILD) associated with
clinical and/or serological characteristics that are not sufficient
to meet classification criteria for any specific Autoimmune
Rheumatic Disease (ARD) [1]. IPAF criteria were proposed by
an expert consensus, serving as a potential common platform
for further improvements.
IPAF resembles the concept of Undifferentiated Connective
Tissue Disease (UCTD), which is widely debated in rheumatol­
ogy settings [2], with the interesting difference that IPAF does
not necessarily require seropositivity. The UCTD criteria were
proposed in 1999, showing a progression toward ARDs in 20–
60% of patients over 3–10 years, mainly toward Systemic
Lupus Erythematosus and Rheumatoid Arthritis (RA) [2]. Over
the last 20 years, the classification criteria for ARDs have been
revised several times considering research findings. These revi­
sions improved performance (mainly sensitivity) for ARDs clas­
sification, reducing the number of patients considered UCTD,
and also the UCTD rate of progression, as some patients were
already classifiable for a definite ARD.
This data could be explained, at least in part, by a selection
bias: a nuanced, if not totally absent, autoimmune clinical
picture, could be underestimated by physicians and the
patient, who tend to seek out the specialist deemed most
useful for the management of the main clinical problem
(ILD). A tight collaboration between rheumatologists and pul­
monologists could be useful for diagnostic purposes, allowing
for the correct classification of patients, and could also be
useful in research, highlighting ARD patients in which ILD is
the first, the main, or even the sole clinical manifestation. It is
quite surprising that the sole ARD for which ILD is included in
the validated classification criteria is systemic sclerosis (SSc).
As currently proposed, IPAF criteria allow the inclusion of
patients in which the ‘autoimmune feature’ could be stochas­
tically associated: clearly if ANA positivity with a titer of 1:320
can be recognized in about 3% of healthy subjects [3],
a similar proportion of patients with Nonspecific Interstitial
Pneumonia (NSIP) could be seropositive with the same ANA
titer, without this being related to the ILD. Conversely, the
CONTACT Gianluca Sambataro dottorsambataro@gmail.com Department of Clinical and Experimental Medicine, Regional Referral Centre for Rare Lung
Disease, A.O.U. ‘Policlinico-San Marco,’ University of Catania, Catania, Italy
© 2022 Informa UK Limited, trading as Taylor & Francis Group
autoimmune feature could be the expression of an early/
incomplete form of ARD. An overhaul of IPAF criteria could
limit the first possibility and improve recognition of
the second. The studies have shown that patients enrolled
with the current IPAF criteria progress toward ARDs in 20–
30% [4–6]. In particular, a recent manuscript reports the lar­
gest prospective cohort of IPAF patients (191 subjects), fol­
lowed for a mean time of 31 months, proving a progression
toward ARDs in 24.1% [4]. The rate of progression can be
a possible ‘gold standard’ to evaluate the actual effectiveness
of IPAF criteria in including patients with early (or at least
incomplete) ARDs, and a revision of IPAF criteria could
increase this proportion.
Below, we suggest modifications to the IPAF criteria.
The clinical domain is composed of inflammatory arthritis
or polyarticular morning stiffness >60 minutes, Raynaud’s
Phenomenon (RP), digital edema, distal digital tip ulcerations,
palmar telangiectasias, Mechanic’s Hands (MH), Gottron’s Sign
(GS). Firstly, these clinical items might be difficult to recognize
for not trained physicians, and a close collaboration between
rheumatologists and pulmonologists could be needed.
Moreover, IPAF criteria showed a progression mainly toward
Idiopathic Inflammatory Myopathies (IIMs) and primary
Sjögren’s Syndrome (pSS) [4-,6]. A symptomatic ILD preceding
myositis or sicca syndrome is relatively common for IIMs and
pSS [7,8]. While IIMs could be recognized by some clinical
signs such as MH and GS, the main pSS symptom (sicca
syndrome) is not mentioned. Its introduction would probably
improve the recognition of pSS patients presenting with ILD
as the first clinical symptom [8]. Another important point is to
balance the level of sensitivity and specificity when enrolling
patients. Myalgia was defined as nonspecific for the recogni­
tion of ARDs [1], however ILD patients with myalgia showed
a high proportion of positivity for Myositis Specific and
Myositis Associated Antibodies (MSA/MAA), therefore this
symptom could merit inclusion [9]. Morning stiffness is also
quite nonspecific, although included. Since 2016, we have
considered this item present if associated with an increase in
Erythrosedimentation Rate or C Reactive Protein level [10]. On
the other hand, distal digital tip ulcerations, as well as digital
132 EDITORIAL
edema and palmar telangiectasias are generally very specific
for SSc [11]. Their recognition in ILD patients is more likely to
be associated with a definite diagnosis. To confirm this, pro­
spective studies on IPAF cohorts involving rheumatologists did
not report this item [5,6,10,12,13], and almost never report the
presence of GS. Considering the mean age of IPAF patients
(and ILD patients in general) the presence of GS associated
with ILD should be considered for classification at least as
a probable IIM, according to the 2017 criteria of Lundberg IE
et al. [14].
The serological domain includes almost all the known auto­
antibodies. However, a cytoplasmic ANA pattern is not
included. This pattern is quite common in patients with IIM
[15], and in our opinion, it could have the same weight as
a nucleolar or anti-centromere pattern, therefore the inclusion
of patients at any titer, if present, should be allowed. The
presence of anti-La is not useful, as it has been proved that
the presence of this autoantibody without anti-Ro is not asso­
ciated with autoimmune conditions [16]. The serological
domain also includes anti-tRNA synthetase antibodies
(AtRSA), but it is well-recognized that antisynthetase syn­
drome can be present with ILD as the sole clinical manifesta­
tion [7]. Therefore, these autoantibodies are not useful to the
aims of the IPAF criteria, and they should be substituted with
other non-AtRSA MSA/MAAs, such as Tif1γ, anti Ku, NXP2,
SAE1 and Mi2. The major concern is that these autoantibodies
are evaluated, at least in clinical practice, using immunoblot­
ting, with the risk of false positivity. Finally, Anti-Neutrophil
Cytoplasm Antibodies (ANCA) were excluded due to their
specificity in recognizing vasculitides. However, the IPAF cri­
teria are useful as they suggest an autoimmune pathway and
can recognize autoimmune conditions with potential systemic
involvement, therefore the exclusion of vasculitides can be
questioned. As a final point on the serological domain, the
authors of the IPAF criteria stated that reevaluating autoanti­
bodies during the follow-up of these patients may not be
useful [1]. It is generally true that autoantibody positivity
precedes the diagnosis of ARDs, however the possibility of
some fluctuations in seropositivity should be taken into
account. These are generally possible for autoantibodies asso­
ciated with disease activity, and cannot be excluded for other
antibodies of which our current knowledge is limited (e.g.
MSA/MAA). To confirm this, prospective studies on IPAF
patients proved the progression of patients toward ARDs in
patients that were seronegative at the first assessment and
with specific seropositivity during the follow-up [5].
The Morphological Domain of IPAF, while not excluding the
possibility, limits the enrollment of patients with a Usual
Interstitial Pneumonia (UIP) pattern, deemed by the authors
not to be sufficiently associated with ARDs. However, UIP is
the most common radiological pattern in RA-ILD, in long­
standing SSc-ILD and in vasculitis, ILD preceding sicca syn­
drome in pSS commonly shows a UIP pattern, and it can also
be recognized in up to 20% of IIMs [17]. We studied UIP
patients with and without only one IPAF domain (clinical or
serological), calling this group ‘UIPAF.’ Our UIPAF patients
progressed toward ARDs in a proportion similar to classic
IPAF, and significantly higher than Idiopathic Pulmonary
Fibrosis [5,18]. For these reasons, we suggest completely
removing the morphological domain, and substituting it with
an ‘instrumental domain.’
The instrumental domain could include some very simple,
rapid and inexpensive tools for the diagnosis of ARDs.
Functional gland impairment (mainly with unstimulated
whole saliva test and Schirmer’s test) can be positive in pSS
patients without significant symptoms, so may be suggestive
of the disease [19]. Nailfold videocapillaroscopy is also a useful
tool, assessing RP as possibly associated with scleroderma
spectrum disorders (SSD). However, it could show alterations
(bushy capillaries or even a scleroderma pattern) also in IIM,
regardless of the presence of RP [20,21]. In our opinion, NVC
should be performed on all ILD patients, in order to exclude
the presence of a defined SSD in RP patients, but also to find
elements suggesting IIM in patients without RP.
In conclusion, IPAF is a research classification, and it cannot
be considered a diagnosis. This classification has the great
merit of stimulating close collaboration between pulmonolo­
gists and rheumatologists, sharing knowledge that contributes
to clear improvements not only in research, but also in daily
practice. IPAF criteria need an overhaul, in light of the current
literature. The clinical and serological domains can be
reviewed, the morphological domain could be substituted
with an ‘instrumental’ domain, including NVC and tests for
gland impairment, that ideally should be performed on all
ILD patients A potential revision of these criteria could be
started in late 2023, after the upcoming publication of the
classification criteria for Antisynthetase Syndrome by the
CLASS project [22]. New IPAF criteria could be validated by
examining the rate of progression toward ARDs and compared
with the current criteria (24.1%) [4].
Conflict of Interest: GS reports personal fees from
Boehringer Ingelheim outside the submitted work; CV is part
of the F. Hoffmann-La Roche Ltd. and Boehringer Ingelheim
Scientific board. He has received consulting fees and/or
speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi,
F. Hoffmann-La Roche Ltd and Menarini. DS declares no con­
flict of interest.
Funding
This paper was not funded.
Declaration of interest
G Sambataro reports personal fees from Boehringer Ingelheim outside the
submitted work; C Vancheri is part of the F. Hoffmann-La Roche Ltd. and
Boehringer Ingelheim Scientific board. He has received consulting fees
and/or speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi,
F. Hoffmann-La Roche Ltd and Menarini. The authors have no other
relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from those
disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.

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