Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease

AUTREV-01767; No of Pages 10 Autoimmunity Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev

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Clodoveo Ferri a,⁎, Andreina Manfredi a, Marco Sebastiani a, Michele Colaci a, Dilia Giuggioli a, Caterina Vacchi a, Giovanni Della Casa c, Stefania Cerri b, Pietro Torricelli c, Fabrizio Luppi b

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Article history: Received 28 August 2015 Accepted 8 September 2015 Available online xxxx

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Keywords: ILD IPAF UCTD CTD NSIP UIP Interstitial pneumonia

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Chair and Rheumatology Unit, Centre for Rare Pulmonary Diseases (MaRP), University of Modena and Reggio Emilia, Medical School, Azienda Ospedaliero-Universitaria, Policlinico di Modena, Modena, Italy b Respiratory Disease Unit, Centre for Rare Pulmonary Diseases (MaRP), University of Modena and Reggio Emilia, Medical School, Azienda Ospedaliero-Universitaria, Policlinico di Modena, Modena, Italy c Radiology Unit, Centre for Rare Pulmonary Diseases (MaRP), University of Modena and Reggio Emilia, Medical School, Azienda Ospedaliero-Universitaria, Policlinico di Modena, Modena, Italy

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Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease Our interdisciplinary rheumatology–pneumology experience, and review of the literature

a b s t r a c t

Background: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the lungs, varying from idiopathic interstitial pneumonias to secondary variants, including the ILDs associated to connective tissue diseases (CTDs). In addition, a number of patients are recognized as unclassifiable ILD (U-ILD), because of the inability to reach a definite diagnosis; some of them show autoimmune manifestations not fulfilling the classification criteria of a given CTD. The term interstitial pneumonia with autoimmune features (IPAF) has been recently proposed for this particular ILD subset. Methods: Here, we report our experience resulting from the integrated — pneumology/rheumatology — approach to patients with suspected ILDs or CTDs referred to our university-based Center for the Rare Pulmonary Diseases and Rheumatology Unit, from January 2009 to June 2015, with particular attention to the above-mentioned U-ILD, IPAF, and undifferentiated connective tissue disease (UCTD). The comparative analysis of these clinical variants was carried out; moreover, the observed findings were compared with the results of the updated review of the literature. Results: After the first clinical assessment, the U-ILD were identified in 50 patients; afterwards, on the basis of clinico-serological and radiological findings U-ILD group was subdivided into 2 subgroups, namely U-ILD without any clinical extra-thoracic manifestations and/or immunological alterations (15 pts) and IPAF according to the above-mentioned classification criteria (35 pts). Patients with either IPAF or U-ILD were compared with a series of 52 stable UCTD (disease duration ≥3 years), followed at our Rheumatology Unit. Some important differences were evidenced among the 3 series of U-ILD, IPAF, and UCTD: firstly, female gender was more frequent in patients with UCTD (86%) or IPAF (69%) compared with U-ILD (60%) or idiopathic pulmonary fibrosis (24%; p = 0.001). In addition, UCTD patients were younger and showed longer disease duration. More interestingly, both UCTD and IPAF series show a comparable prevalence of various clinical manifestations, with the exception of the interstitial lung involvement detectable in a very small percentage of UCTD patients. Concordantly, the review of the literature evidenced two main subsets of U-ILD, one is characterized by isolated unclassifiable interstitial pneumonia and another one composed by subjects with clinically prevalent lung involvement in the setting of not definite CTD, the recently proposed IPAF. Conclusion: We hypothesize that IPAF and UCTD might represent two clinical variants of the same systemic autoimmune disorders. The marked difference regarding the prevalence of ILD, which is the clinical hallmark of IPAF but very rare in UCTD, may at least in part reflect a selection bias of patients generally referred to different specialist centers, i.e. pneumology or rheumatology, according to the presence/absence of clinically dominant ILD, respectively. Well-integrated, interdisciplinary teams are recommended for the assessment and management of these patients in the clinical practice. Finally, the cooperation between multidisciplinary groups with

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⁎ Corresponding author at: Chair and Rheumatology Unit, Dept of Internal Medicine, University of Modena and Reggio E., Policlinico di Modena, Via del Pozzo, 71, 41100 Modena Italy. Tel.: +39 059 4224053; fax: +39 059 4224178. E-mail address: [email protected] (C. Ferri).

http://dx.doi.org/10.1016/j.autrev.2015.09.003 1568-9972/© 2015 Published by Elsevier B.V.

Please cite this article as: Ferri C, et al, Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.09.003

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C. Ferri et al. / Autoimmunity Reviews xxx (2015) xxx–xxx

different experiences may be advisable for a validation study of the proposed nomenclature and classification 58 criteria of these indefinable ILD/CTD variants. 59 © 2015 Published by Elsevier B.V.

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Introduction . . . . . . . . . . . . . . . . . . . . . . 1.1. Patients and methods . . . . . . . . . . . . . . 1.1.1. Review of the literature . . . . . . . . . 1.1.2. Statistical analysis . . . . . . . . . . . . 1.2. Results . . . . . . . . . . . . . . . . . . . . . 1.2.1. Our experience . . . . . . . . . . . . . 1.2.2. Review of the literature . . . . . . . . . 1.2.3. Suggestions for ongoing classification criteria 1.3. Discussion . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .

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Table 1 Clinical assessment of patients with interstitial lung diseases (ILDs).

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General data

Signs/symptomsa

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Demografic Occupational Environmental Avocational Medication Smoking

Arthralgias Arthritis Morning stiffness Puffy fingers Raynaud's phen. Myalgias Muscle weakness Rash Photosensitivity Alopecia Dermatitis Mechanics' hand Gottron's sign Skin ulcers Oral/genital ulceration Oral dryness Ocular dryness Dysphagia Recurrent fever Weight loss Serositis Dyspnoea on exertion Dry cough

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challenging problem in the clinical practice in term of correct diagnosis and patients' management [4–8]. Thus, several authors emphasized the importance of a multidisciplinary approach to the complex of ILDs, including U-ILD [4,9,10]. In addition to clinical, radiological, and pathological features of lung involvement, the patient's assessment should also include a clinico-immunological evaluation by expert rheumatologists, considering the incidence of phenotypes with overlapping features of both ILDs and systemic autoimmune disorders [4,9,10]. Very recently, a task force of pulmonologists and rheumatologists was formed to develop a consensus regarding these difficulties; the team of investigators proposed the introduction of a novel entity termed interstitial pneumonia with autoimmune features (IPAF), along which the preliminary classification criteria based on the combination of features from clinical, serological, and morphological domains [11]. At our university-based Center for Rare Lung Diseases (MaRP), a similar multidisciplinary approach have been directed at patients referred to our tertiary units because of the presence of suspected ILDs and/or systemic autoimmune diseases. The

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Interstitial lung diseases (ILDs) represent a heterogeneous group of clinical conditions characterized by inflammation and/or fibrosis of the lungs; it encompasses a spectrum of different subtypes and phenotypes [1–3]. In particular, ILDs include idiopathic interstitial pneumonias, and a number of variants secondary to environmental and occupational exposures, sarcoidosis, pulmonary Langherans cell hystiocytosis, lymphangioleiomyomatosis, connective tissue diseases (CTDs), as well as a miscellanea of less frequent forms such as ILDs associated with systemic vasculitides, including diffuse alveolar hemorrhage, eosinophilic pneumonia, etc [1–3]. In addition, various clinico-pathological studies on ILD patients' series referred at tertiary respiratory units focused on the presence of unclassifiable ILD (U-ILD); this is a newly proposed and poorly definite entity that seems to represent 10–15% of the whole ILDs [4–8]. Some inconsistencies in the U-ILD definition and the lack of conclusive classification criteria represent a

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Laboratory examinations First line ANA ≥1:160 titer Anti-ENA ESR (N2 times normal) Abnormal CRP Routine blood chemistry Urinalysis Infections (HCV, HBV, HIV, EBV) RF Second line Anti-CCP Complement C3/C4 AMA ASMA ANCA Anti-phospholipid Ab/LAC Organ-specific autoAb 24 h-proteinuria

Instrumental investigations Chest HRCT PFTs (including DLco)

Surgical lung biopsy Doppler echocardiography Joint echography Nailfold capillaroscopy Schirmer's test Salivary gland echography Minor salivary gland biopsy Muscle biopsy Electromyography Skin biopsy

ANA: anti-nuclear antibodies; anti-ENA: anti-extractable nuclear antigen; (antibodies: anti-Scl-70, anti-Ro, anti-La, anti-dsDNA, anti-Smith, anti-RNP, anti-PM-Scl, and/or anti-tRNA synthetase); ESR: eritrocyte sedimentation rate; CRP: C-reactive protein; HCV: hepatitis C virus; HBV: hepatitis B virus; HIV: human immudeficiency virus; EBV: Epstein-Barr virus; RF: rheumatoid factor; anti-CCP: anti-cyclic citrullinated peptide antibodies; AMA: anti-mitochondrial antibodies; ASMA: anti-smooth muscle antibodies; ANCA: antineutrophil cytoplasmic antibodies; LAC: lupus anticoagulant; HRCT: high-resolution computed tomography; PFTs: pulmonary function tests; DLco: diffusion lung capacity for carbon monoxide. a Past and/or present.

Please cite this article as: Ferri C, et al, Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.09.003

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C. Ferri et al. / Autoimmunity Reviews xxx (2015) xxx–xxx

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Since 2009 our multidisciplinary team of the university-based Center for Rare Pulmonary Diseases (MaRP: Malattie Rare del Polmone) is cooperating in the classification, clinical assessment, and management

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Table 2 Nomenclature of primary/secondary ILDs and related rheumatic disorders.

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Nomenclature

t2:4 t2:5

Pulmonary diseases ILD (interstitial lung disease)

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IPF (idiopathic pulmonary fibrosis)

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U-ILD (unclassifiable interstitial lung dis)

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UCTD-ILD (UCTD-UIP/UCTD-NSIP) (undifferentiated connective tissue dis-interstitial lung dis) AIF-ILD (autoimmune featured ILD)

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IPAF (interstitial pneumonia with autoimmune features)

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Lung dominant CTD (lung dominant connective tissue dis)

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CTD-ILD (connective tissue disease-interstitial lung dis) Miscellanea

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Rheumatic diseases CTDs (connective tissue diseases)

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UCTD (undifferentiated CTD)

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Incomplete/very early CTD

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RA (rheumatoid arthritis)

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Miscellanea

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Heterogeneous group of diseases that cause fibrosis or inflammation of the pulmonary parenchyma. Chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of UIP. ILD without definite diagnosis because of inadequate data or major discordance between clinico-radiologic and pathologic findings. Patients who meet classification criteria for UCTD and concomitant ILD (UIP or NSIP pattern).

Ryerson CJ, 2013 [3] Raghu G, 2011 [50]

Travis WD, 2013 [2], Skolnik K, 2015 [4] Kinder BW, 2007, 2010 [41,44], Corte TJ, 2012 [38]

Clinical subset of ILD with features of CTD (signs, symptoms, and/or immunological alterations) that do not meet specific classification criteria for a given autoimmune disease. Interstitial pneumonia and features (clinical, serological, and/or morphological) suggestive of a CTD that do not meet established classification criteria for a given autoimmune disease. Patient with clinically prevalent interstitial pneumonia associated to different autoimmune features suggestive for underlying CTD, but not fulfilling the classification criteria for definite CTD. ILD in the setting of well defined CTD

Vij R, 2011 [42]

Exposure related ILD (occupational, environmental, avocational, medication, smoking), sarcoidosis, idiopathic ILD (RB-ILD, DIP, COP, AIP, LIP), others (Langherans cell histiocytosis, eosinophilic pneumonia, neurofibromatosis, lymphangioleiomyomatosis)

Ryerson CJ, 2013 [3], Travis WD, 2013 [2]

A group of definite systemic autoimmune disorders, mainly systemic lupus erythematosus, inflammatory idiopathic myopathies, Sjögren's syndrome, systemic sclerosis, antiphospholipides syndrome, and mixed connective tissue disease. Signs and symptoms suggestive of CTD, but not fulfilling the criteria for any of definite CTDs, with serum antinuclear antibodies detected on two different occasions, clinically present ≥3 years Patient with clinical features suggesting a prodromic or very early stage of CTD. For example see VEDOSS criteria for a very early diagnosis of systemic sclerosis: the presence of Raynaud's phenomenon, puffy fingers, and ANA positivity plus disease-specific autoantibodies (ACA, anti-Scl70), and/or microvascular alterations detected by nailfold videocapillaroscopy. Chronic inflammatory autoimmune disease characterized by swelling, tenderness, and destruction of synovial joints, frequent seropositivity for rheumatoid factor and anti-CCP; possible association with ILD (mainly UIP). Systemic vasculitides (including diffuse alveolar hemorrhage syndrome), spondyloarthropathies, Behçet's disease

Van den Hoogen F 2013 [25], Vitali C 2002 [26], Bohan A 1975 [27,28], Petri M 2012 [29], Miyakis S 2006 [30], Mosca M 1999 [16], Sharp GC 1972 [31]

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of patients affected by either ILDs, with possible extra-pulmonary rheumatic manifestations, or systemic autoimmune disorders potentially complicated by lung involvement. Trained pulmonologists and rheumatologists are involved in the center, where other specialists, i.e. radiologists, cardiologists, thoracic surgeon, and pathologists actively collaborate; the involved specialists have a long-term experience on clinical aspects and treatment of both ILDs and CTDs, including specific diagnostic procedures, especially radiological, histopathological, and immunological investigations, nailfold capillaroscopy, and joint echography. All patients referred to our tertiary care center because of respiratory manifestations of ILDs underwent to a core set of clinicoserological and laboratory investigations, including therapeutical decisions. The initial patient's assessment is followed by periodical patient's re-evaluation. Table 1 summarizes the first patients' clinical work-up that includes: a) recording of demographic findings and specific patients' exposures potentially responsible for some variants of secondary ILDs [1,2]; b) a wide panel of signs and symptoms of either lung involvement and possible underling CTDs or rheumatoid arthritis [25–32]; c) laboratory, and d) instrumental investigations, directed at the better definition of both lung disease and CTDs [25–37; Table 1]. At the first evaluation all patients underwent to first line laboratory and instrumental investigations, repeated periodically during the follow-up according

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integrated clinical evaluation of these individuals allows to better classify a variety of disorders, ranging from idiopathic pulmonary fibrosis to ILDs secondary to other conditions, mainly CTDs, with specific consideration of the gray zone of unclassifiable disorders. This latter comprises different phenotypes varying from U-ILD [4–8] or the recently proposed IPAF [11] to undifferentiated connective tissue disease (UCTD). In the field of systemic rheumatic diseases, UCTD represents a challenging entity because of the discrepancies in the symptom composition among published patients' series, together with the lack of well-recognized classification criteria [12–24]. Here we report our experience resulting from the integrated — pneumology/rheumatology — approach to patients with idiopathic and secondary ILDs, including the above-mentioned IPAF and UCTD, as well as our attempt to better define these latter conditions on the basis of observed findings and throughout the updated review of the literature.

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Fischer A, 2015 [11]

Fischer A, 2010 [45]

Ryerson CJ, 2013 [3]

Mosca M, 1999 [16], Clegg DO 1991 [13], Doria A 2005 [20] Matucci-Cerinic M 2009 [46], Avouac J 2011 [47]

Aletaha D, 2010 [32]

Ryerson CJ, 2013 [3]

UIP: usual interstitial pneumonia; NSIP: Non specific interstitial pneumonia; VEDOSS: very early diagnosis of systemic sclerosis; ANA: anti-nuclear antibodies; ACA: anti-centromere antibodies; anti-CCP: anti-cyclic citrullinated peptide antibodies.

Please cite this article as: Ferri C, et al, Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.09.003

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1.1.1. Review of the literature A throughout search in PubMed, Embase, Scopus, Web of Science, Asian Science Citration Index (ASCI), IranMedex, Scientific Information Database (SID), PaKMediNet, IndMed, and Index Medicus for the World Health Organization Eastern Mediterranean Region (IMEMR) regarding patients with ILDs, CTDs, and CTD-associated ILDs up to August 2015 was done, using the key words lung fibrosis, ILD, IPF, IPAF, UCTD, and/or CTD.

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1.2.1. Our experience During the last years, from January 2009 to June 2015, at our Center for Rare Pulmonary Diseases (MaRP) we evaluated a large population of patients referred because of the presence of signs and symptoms of suspected ILD. Besides established — idiopathic and secondary — ILD, a significant number of U-ILD patients (50 pts) with or without autoimmune features was recorded. In U-ILD patients the presence of interstitial pneumonia was invariably confirmed by the analysis of imaging features of high-resolution computed tomography (HRCT) evaluated by trained pulmonologists and radiologists. A careful analysis of this particular patients' subset revealed the presence in 26 U-ILD individuals of clinicoserological autoimmune features not fulfilling the classification criteria for a given CTD. These 26 patients were classified by rheumatologists as having UCTD according to previously published classification criteria [12,13,16,20]. Following the recent proposal by the task force of pulmonologists and rheumatologists [11], we re-evaluated our series of U-ILD patients confirming the presence of IPAF in 35 subjects; this subset is composed by the above-mentioned UCTD (26 pts) and another fraction of the former 50 U-ILD (9 pts). The Table 3 shows the characteristics of these two patients' subsets, i.e. 35 IPAF and 15 U-ILD, respectively. The latter 15 patients with true U-ILD were classified according to standard criteria [1,2,4], and always in the absence of any clinicoserological features of autoimmune disease. Patients with either IPAF or U-ILD were compared with a series of 52 stable UCTD (disease duration ≥ 3 years) classified according current criteria [12,13,16,20]. The UCTD patients belong to a large series of various inflammatory systemic rheumatic disorders referred to our Rheumatology Unit and carefully investigated for possible lung involvement. Patients with pulmonary clinico-radiological and/or function testing alterations were further evaluated and classified by the MaRP team. Therefore, a number of important differences can be evidenced among the 3 series of UCTD, IPAF, and U-ILD (Table 3). Firstly, the female gender is particularly frequent in UCTD (86%) and IPAF (69%), and statistically significant higher compared to our IPF series (24%; p =

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Table 3 t3:1 Demographic, clinical, and serological features of our patients' series with UCTD, IPAF, and t3:2 U-ILD. t3:3

Demographic features Females % (F/M) Pts mean age (yrs SD)b Dis dur (mean yrs SD)a Follow-up (mean yrs SD)

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1.1.2. Statistical analysis Data were expressed as mean ± standard deviation (SD) unless otherwise noted. Categorical variables were analyzed by chi square test or Fisher's exact test as appropriate; Wilcoxon test was used to compare repeated measurements in paired groups, while differences between the means were determined using Mann–Whitney U-test for unpaired samples. p values ≤ 0.05 were considered statistically significant.

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1.2.2. Review of the literature Table 4 summarizes the main reports regarding a number of clinical investigations [5–8,38–43] and consensus studies with proposals of classification criteria for both U-ILD and UCTD [1,2,11–13,16,20,44,45]: two clinical entities of uncertain contours and definition. The U-ILD represents a heterogeneous number of disorders with clinically prevalent ILD but without definite classification because of inadequate data or major discordance between clinico-radiologic and pathologic findings [1–3; Table 2]. The clinical and/or classification studies included numerically variable patients' series (from 23 to 132 pts; ref. 5–8,38–43). Some reports focused on pulmonary clinico-radiological and pathological

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0.001). In addition, UCTD patients were younger and showed longer disease duration; these differences are more pronounced by comparing UCTD with U-ILD. Interestingly, both UCTD and IPAF series show a comparable prevalence of various clinical manifestations, with the exception of the interstitial lung involvement detectable in a very small percentage of UCTD patients.

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to the patient's clinical status. Clinical signs and symptoms of both respiratory and extra-pulmonary manifestations were obtained on the basis of patients' physical examination and specific questionnaire elaborated according to guidelines and classification criteria of international scientific societies [25–37; Table 1]. Similarly, laboratory and instrumental investigations were carried out according to standardized methodologies [25–38; Table 1]. Given the continuing evolution of proposed ILD subtypes, we report in the Table 2 the nomenclature, definition, and classification criteria, when available, of primary and secondary ILDs as well as of CTDs with correlated ILDs.

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IPAF

U-ILD

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Pts no. 35

Pts no. 15 p

86% (44/8) 55 ± 13 12.1 ± 8.4 6.1 ± 4.4

69% (24/11) 63 ± 12 7.1 ± 3.1 3.9 ± 2.9

60% (9/6) 68 ± 8.9 5.3 ± 2.6 3.5 ± 2.2

b vs c

t3:5

p

p

t3:6

ns 0.001 0.003 0.027

ns ns 0.009 0.019

ns ns ns ns

a vs c a vs b

Clinical features Arthralgias Arthritis Morning stiffness Puffy fingers Myalgias Proximal muscle weakness Rash Phosensitivity Alopecia Dermatitis Mechanics' hand Gottron's sign Skin ulcers Oral ulceration Oral dryness Ocular dryness Dysphagia Recurrent feverc Weight loss Raynaud's phen. Serositis

91.4% 34.3% 40% 0% 20% 0%

66.7% 12.9% 17.8% 0% 40.6% 0%

57.1% 0% 0% 0% 30.4% 0%

0.05 0.009 0.004 ns ns ns

0.04 ns ns ns ns ns

ns ns ns ns ns ns

54.3% 37.1% 2.9% 2.9% 0% 0% 2.9% 5.7% 62.9% 65.7% 19.4% 10.3% 3.6% 77.1% 14.3%

23.3% 3.7% 0.0% 3.6% 0% 0% 0% 0% 48.2% 45.2% 0% 0% 2.9% 66.7% 15.4%

0% 0% 0% 0% 0% 0% 0% 0% 40% 25% 0% 0% 6.7% 0.0% 6.7%

≤0.001 0.005 ns ns ns ns ns ns ns 0.01 ns ns ns ≤0.001 ns

0.02 ≤0.001 ns ns ns ns ns ns ns ns 0.01 ns ns ns ns

ns ns ns ns ns ns ns ns ns ns ns ns ns ≤0.001 ns

Interstitial lung disease

4%

100%

100%

≤0.001 ≤0.001 ns

Immunological features ANA ≥1:320 titer Anti-ENAd Rheumatoid factor Anti-CCP Low-complement

90% 67.6% 9.7% 15.4% 11.8%

81.3% 31.4% 14.3% 0% 7.6%

0%f 0% 0% 0% 0%

≤0.001 ≤0.001 ns ns ns

ns 0.002 ns ns ns

≤0.001 ≤0.001 ns ns ns

UCTD: undifferentiated connective tissue diseases; IPAF: interstitial pneumonia with autoimmune features; U-ILD: unclassifiable interstitial lung diseases; Dis Dur: disease duration; ANA: anti-nuclear antibodies; anti-ENA: anti-extractable nuclear antigen antibodies; anti-CCP: anti–cyclic citrullinated peptides. a From disease onset. b At the onset of the follow-up. c Of unexplained origin. d Anti-Scl-70, anti-Ro, anti-La, anti-dsDNA, anti-Smith, anti-RNP, anti-PM-Scl, or antitRNA synthetase. e With disease duration ≥3 years. f 41.7% were ANA-positive but with titer b1:320.

Please cite this article as: Ferri C, et al, Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.09.003

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Table 4 Review of the literature on U-ILD/IPAF, and UCTD patients' series. U-ILD

Classification

Clinical studies

UCTD

Classification

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studies

Pts no.

Authors, year (ref. no.)

studies

Pts no.

t4:5 t4:6 t4:7 t4:8 t4:9 t4:10 t4:11 t4:12 t4:13 t4:14 t4:15 t4:16 t4:17 t4:18 t4:19 t4:20 t4:21 t4:22 t4:23

Not considering autoimmune features: Xaubet A, 2004 [39] − Morell F, 2008 [40] − Zhang D, 2010 [5] U-ILD Ryerson CJ, 2013 [6] U-ILD ATS/ERS, 2002 [1] U-ILD Travis WD, 2013 [2] U-ILD Hyldgaard C, 2014 [7] − Troy L, 2014 [8] −

26 73 38 132 − − 62 23

Considering autoimmune features: Kinder BW, 2007 [44] Kinder BW, 2010 [41] Fischer A, 2010 [45] Vij R, 2011 [42] Corte TJ, 2012 [38] Pan L, 2013 [43] Fischer A, 2015 [11] Present series

28 29 − 63 52 65 − 102

LeRoy EC, 1980 [12] Clegg DO, 1991 [13] Danieli MG, 1999 [14] Dijkstra S, 1999 [15] Mosca M, 1999 [16] Cavazzana I, 200 [17] Mosca M, 2002 [18] Bodolay E, 2003 [19] Doria A, 2005 [20] Vaz CC, 2009 [21] Conti V, 2010 [22] Guerrero LF, 2013 [23]

+ + − − + − − − + − − −

− 410 165 22 − 148 64 435 − 184 41 94

O

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UCTD-ILD − Lung dominant CTD AIF-ILD − − IPAF UCTD; IPAF, U-ILD

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ILD: interstitial lung diseases; CTD: connective tissue diseases; U-ILD: unclassifiable interstitial lung diseases; UCTD: undifferentiated connective tissue diseases; AIF-ILD: autoimmune featured interstitial lung diseases; IPAF: interstitial pneumonia with autoimmune features.

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features with the purpose of better define the borders and the distinctive features of U-ILD. Other studies underlined the association of interstitial pneumonia with a variable number of autoimmune features — clinical and/or serological — suggesting the presence of systemic immune-mediated disorder with prevalent lung involvement. In all cases the presence of autoimmune components was not sufficient to classify the underlying disorder as definite CTD. The authors proposed different terms evidencing the coexistence of unclassifiable interstitial lung involvement and undifferentiated autoimmune disorders; namely, ‘autoimmune featured ILD’, ‘lung dominant CTD’, ‘UCTD-ILD’, or the recently IPAF (Table 4). Although these terms seem to refer to the same clinical entity, there are important differences in the composition of patients' series recruited at various tertiary care centers, in the employed assessment methodologies, and consequently in the proposed classification criteria. However, taken together these previous studies seem to identify two main subsets of U-ILD, one regarding patients with isolated unclassifiable interstitial pneumonia and another one composed by subjects with clinically prevalent lung involvement in the setting of not definite CTD. This dichotomy seems to be confirmed by the results of our study showing the presence of two distinct phenotypes of U-ILD, namely the true U-ILD and the IPAF [11]. On the other hand, published studies in the field of autoimmune rheumatic diseases, focusing on UCTD patients (Table 4), are quite concordant as regards the definition and clinical characteristics of this disorder, including the rarity of clinically overt interstitial lung involvement [16–24]. Patients with stable UCTD show clinical features, lasting ≥3 years, and serological markers suggestive of CTDs but not fulfilling the criteria for any of definite CTDs. With regards to UCTD classification criteria available data are generally limited to the results of consensus or expert opinion reports [12,13,16,20] in the absence of validation studies.

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1.2.3. Suggestions for ongoing classification criteria The analysis of previous literature on U-ILD patients' series revealed a number of proposals for a better definition and classification criteria of this condition [1–3,5–8,11,38–45]. The term U-ILD was initially referred to a patients' subset characterized by interstitial pneumonia without epidemiological and clinic-pathological features of definite ILD [1–3]. Therefore, an increasing number of studies focused on the presence of a particular U-ILD phenotype associated to one or more clinicserological features suggesting a possible underlying autoimmune disorder [11,38,41–45]. A number of above-mentioned definitions

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have been proposed for this peculiar entity (Tables 2, 4); by adopting the lastly suggested IPAF, we observed a clear overlapping of clinicoepidemiological features between IPAF, recruited at our Center for Rare Pulmonary Diseases, and UCTD patients, referred to our Rheumatology Unit, with the exception of interstitial pneumonia. This important difference can be explained at least in part by a selection bias in the patients' referral: subjects with clinically dominant respiratory symptoms are invariably referred to tertiary pulmonary care unit, while patients with a variable composition of autoimmune features but without or mild/subclinical respiratory symptoms are commonly referred to rheumatologists (Fig. 1). In this context, the three patients' series reported in Table 3 constitute a spectrum of undifferentiated/ unclassifiable conditions (Fig. 2) that can be observed in the settings of either ILDs or CTDs, referred to different tertiary centers such as Pneumology and Rheumatology Units, respectively. From one side there are patients with U-ILD, a condition characterized by the absence of environmental exposures or immune-mediated disorders and apparently isolated interstitial pneumonia [1–3], from the opposite side there are the so-called UCTD with prevalent autoimmune features and rare lung involvement [12,13,16,20]. While the IPAF that is characterized by both ILD and autoimmune features may represent a transitional condition between U-ILD and UCTD. Moreover, both IPAF and UCTD could be classified in the setting of CTDs, a group of multifaceted autoimmune disorders with frequent phenotypic variations during the time; consequently, we cannot exclude that in some individuals they may represent a prodromic condition or very early phase of a given CTD [46,47]. The evolution into definite CTDs is more likely during the first years of disease; at the first evaluation or during the follow-up period, it is possible to identify patients with specific clinico-serological findings suggestive of a given CTD. Therefore, a multidisciplinary clinical assessment and monitoring may be decisive for the prognostic and therapeutical implications (Fig. 3). The initial IPAF patient's evaluation should be based on a core set of standard clinico-serological and instrumental investigations, including signs and symptoms of possible underlying CTDs or other autoimmune systemic rheumatic diseases (Tables 1, 5; 48–66). Consequently, second line laboratory/instrumental investigations should be decided on the basis of specific clinical aspects that might characterize individual IPAF patients. As example, those with Raynaud's phenomenon and/or puffy fingers, and/or typical serological markers (anti-Scl70, anticentromere, anti-nucleolar antibodies), suggesting the presence of early systemic sclerosis, can be further investigated for microangiopatic alterations by nailfold capillaroscopy [35,36,46,47]. While patients with

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individuals with concomitant interstitial pneumonia and autoimmune features, fulfilling the recently proposed classification criteria for IPAF [11]; their clinico-serological findings were also compared with a series of UCTD patients belonging to a large series of systemic autoimmune diseases followed at our Rheumatology Unit. In addition, we describe our model of integrated approach — pneumology/rheumatology — aiming at a better definition of these still unclear conditions [2–4,11, 13,16,20,38,42,44,45]. The proposed model was based on our clinical practice as well as on the data emerging from updated review of the world literature on this topic (see references in Table 2; 10). During the last years we evaluated with systematic, multidisciplinary approach a large series of patients with suspected ILDs and/or rheumatic autoimmune disorders potentially complicated by pulmonary manifestations, namely CTDs and AIDs (Table 5). In the setting of established ILDs, we identified a group of patients with U-ILD, classified according to current criteria [2,4. In particular, we focused on individuals with U-ILD and clinico-immunological manifestations of systemic autoimmune disorders, but not fulfilling the classification criteria of a given disease [2–4,42,44,45; Tables 2, 5]. Moreover, we recently reclassified these patients according to the proposed criteria for IPAF [11]; the comparative analysis of IPAF and stable UCTD, recruited at our Rheumatology Unit, revealed a clear-cut overlap of clinical symptoms and immunological alterations between these two disorders, excepting the presence of interstitial pneumonia. This latter organ manifestation represents the main clinical hallmark of IPAF, while it was rarely observed in our UCTD patients (Table 3), confirming the data of the previous literature [16–24]. In order to explain this particular discrepancy, we hypothesize that both IPAF and UCTD may belong to unique unclassifiable systemic autoimmune disorder, but patients are generally referred to different tertiary care centers, namely Pneumology or Rheumatology Units, based on the presence/absence of clinically overt lung involvement, respectively. In this scenario, the IPAF may be regarded as the bridging condition between the U-ILD without extrathoracic manifestations and UCTD; all together these disorders constitute the spectrum of undifferentiated variants of definite ILDs, CTDs, and other autoimmune systemic diseases (Fig. 2, Tables 2, 5). The development of standardized nomenclature and validated classification criteria for the U-ILD [2,4] in general, and in particular for patients with IPAF [11] should be taken into account also the so-called UCTD, a woolly condition in the field of systemic autoimmune rheumatic diseases still awaiting for a better clinico-prognostic definition [16–24]. In this respect, a clear clinico-epidemiological overlap between apparently idiopathic interstitial pneumonia with one or more autoimmune features of CTDs, classified according to rheumatologists' current criteria (Table 5), has been previously underlined by other authors [38,41,44]. The extent of overlapping area between different ILDs with suspected underlying autoimmune diseases and UCTD may vary because of the heterogeneity of adopted classification criteria [10,38,41,44]. A number of terms and classification criteria for U-ILD, mainly for autoimmune ‘flavored’ variants, have been proposed during the last years (Table 2; 3,11,38,41–45). Often, the suggested definitions are referred to limited ILD patients' series and/or expert opinions, with important differences of methodological approach and/or clinical experience (Table 2). In order to improve and uniform the current nomenclature and classification criteria, well-balanced teams of pulmonologists and rheumatologists, with the contribution of other specialists, mainly radiologists and pathologists, should deal with this important topic. As regards the possible bias of patients pre-selection before the referral to different tertiary care centers could be avoided by means of assessment and long-term follow-up of patients with either ILDs and CTDs carried out by the same multidisciplinary team. In this setting, continual discussion regarding potential clinical phenotypes may allow to early identify the possible autoimmune features associated to ILDs, from one side, as well as potential interstitial lung involvement complicating established CTDs and other autoimmune rheumatic diseases, from the other side (Fig. 3, Table 5). Moreover, long-term clinical follow up of U-ILD, mainly

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Fig. 1. At our center for the Rare Pulmonary Diseases there are referred patients with suspected interstitial lung diseases (ILDs) because of isolated/prevalent respiratory manifestations. They are evaluated by means of wide clinical work-up (Table 1) by trained pulmonologists and rheumatologists, with the contribution of other specialists, i.e. radiologists, cardiologists, thoracic surgeon, and pathologists; the involved specialists have a long-term experience on the diagnosis and treatment of ILDs as well of CTDs and other autoimmune diseases (AIDs) referred to our Rheumatology Unit. Patients were finally classified according to guidelines and classification criteria of international scientific societies (ref. 25–37). Besides established ILDs, CTDs, and AIDs, there are subjects with unclassifiable interstitial lung diseases (U-ILD). These latter include a number of patients that fulfill the recently proposed ‘interstitial pneumonia with autoimmune features’ (IPAF). The IPAF patients were compared with unclassifiable connective tissue diseases (UCTD) recruited among different CTDs and other AIDs referred to our Rheumatology Unit. There is a clear-cut clinic-serological overlapping between these two patients' series, with the exception of ILD detectable in a very small percentage of UCTD patients (see Table 3). This difference can be correlated to a selection bias in the patients' referral: subjects with clinically dominant respiratory symptoms are invariably referred to tertiary pulmonary care unit, while patients with prevalent autoimmune features, with/without respiratory symptoms, are commonly referred to rheumatologists (see also Fig. 2). *Exposure related ILD (occupational, environmental, avocational, medication, smoking), sarcoidosis, idiopathic ILD [respiratory bronchiolitis-associated-ILD (RB-ILD), desquamative interstitial pneumonia (DIP), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), lymphocytic interstitial pneumonia (LIP)], others (Langherans cell histiocytosis, eosinophilic pneumonia, neurofibromatosis, lymphangioleiomyomatosis); IPF: idiopathic pulmonary fibrosis; °other systemic autoimmune diseases (AIDs): see Table 5.

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sicca syndrome with/without specific autoantibodies (anti-Ro, anti-La) of suspected Sjögren's syndrome may undergo to Schirmer's test, salivary gland echography, and/or minor salivary gland biopsy [26]. Finally, subjects with arthritis should be deeply evaluated for possible rheumatoid arthritis by means of specific serological examinations (rheumatoid factor and anti-cyclic citrullinated peptide antibodies), with some limitations [67,68], echographic, and/or x-ray examinations of inflamed joints [32,37].

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The present study reports our interdisciplinary experience on the clinical evaluation of patients with U-ILD. In particular, it focuses on

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Fig. 2. The spectrum of undifferentiated/unclassifiable conditions that can be observed in the field of interstitial lung diseases (ILDs), connective tissue diseases (CTDs), and other autoimmune diseases (AIDs; see Table 5) includes unclassifiable interstitial lung diseases (U-ILD), interstitial pneumonia with autoimmune features (IPAF), and unclassifiable connective tissue diseases (UCTD). The IPAF may represent a transitional phenotype in the middle of U-ILD and the UCTD; IPAF are characterized by the presence of both interstitial lung involvement and autoimmune features. *Exposure related ILD (occupational, environmental, avocational, medication, smoking), sarcoidosis, idiopathic ILD [respiratory bronchiolitis-associated-ILD (RB-ILD), desquamative interstitial pneumonia (DIP), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), lymphocytic interstitial pneumonia (LIP)], others (Langherans cell histiocytosis, eosinophilic pneumonia, neurofibromatosis, lymphangioleiomyomatosis); IPF: idiopathic pulmonary fibrosis.

Fig. 3. The figure summarizes the activity of our multidisciplinary, integrated pneumology–rheumatology center, devoted to patients with idiopathic and secondary interstitial lung diseases (ILDs), with particular attention to ILDs associated to connective tissue diseases (CTDs) or other autoimmune diseases (AIDs, see Table 5). These disorders are characterized by multifactorial and multistep etiopathogenesis that can be responsible for the production of different phenotypes. Our standardized model takes into account these complex scenario in order to correctly classify the clinical subtypes and to early detect possible predictive factors of specific CTD/AID development: 1) Initial assessment and classification, according to current criteria, of patients referred to the Center for Rare Pulmonary Diseases (patients with suspected ILDs) or Rheumatology Unit (patients with suspected CTDs/AIDs) of our university-based hospital. 2) Patients with established ILDs and CTDs/AIDs, as well as individuals with unclassifiable ILDs (U-ILD), interstitial pneumonia with autoimmune features (IPAF), and undifferentiated connective tissue diseases (UCTD) were carefully monitored. 3) Long-term follow-up allows to early observe possible variations of patients' clinico-serological manifestations with impact on classification/diagnosis. This is particularly important for patients with unclassifiable/undifferentiated disorders (U-ILD, IPAF, UCTD); the detection of clinico-serological features suggesting the presence of possible/incomplete or very early disease may be critical to define emerging specific phenotypes of ILDs (example: patients with IPF developing a CTD-associated ILD) or of CTDs/AIDs (example: rare cases of SSc or RA patients originally referred with apparently isolated ILD as presenting symptom). This approach can be crucial in some cases for targeted therapeutical decisions, particularly in the very early phase of a given disease (see text, Figs. 1, 2; Tables 1, 3). °Exposure related ILD (occupational, environmental, avocational, medication, smoking), sarcoidosis, idiopathic ILD [respiratory bronchiolitis-associated-ILD (RB-ILD), desquamative interstitial pneumonia (DIP), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), lymphocytic interstitial pneumonia (LIP)], others (Langherans cell histiocytosis, eosinophilic pneumonia, neurofibromatosis, lymphangioleiomyomatosis); IPF: idiopathic pulmonary fibrosis; SSc: systemic sclerosis; SLE: systemic lupus erythematous; SS: Sjögren's syndrome; DM/PM: dermatomyositis/polymyositis; RA: rheumatoid arthritis; *other systemic autoimmune diseases (AIDs): see Table 5.

Please cite this article as: Ferri C, et al, Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.09.003

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Table 5 Prevalence of interstitial lung diseases in systemic autoimmune rheumatic diseases.

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Diseases

ILDs

Comment

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Classical connective tissue diseases Systemic sclerosis (SSc) Systemic lupus erythematosus (SLE) Sjögren's syndrome (SS) Inflammatory myopathies (DM/PM) Mixed connective tissue disease Undifferentiated connective tissue disease (UCTD)

55–65% 34, 48 1–15% 51 2–45% 53–55 up to 75% 56 35–66% 57, 58 n.a.

Clinically overt ILD; mainly in diffuse cutaneous SSc subset 49; NSIP pattern more frequently reported 50 Mainly in long-lasting disease duration and older patients; possible evolution from SLE pneumonitis 52 ILD prevalence directly correlated with SS duration55 Anti-synthetase antibodies mark the presence/development of ILD 56

Other systemic autoimmune diseases Rheumatoid arthritis

4–68% 59

t5:14 t5:15

Ankylosing spondylitis Behçet's disease

35–65% 61 n.a.

t5:16 t5:17

Cryoglobulinemic vasculitis ANCA-associated vasculitidesa

Anecdotal 63 ~366

Smoking, male gender, and long-standing disease are frequently reported as risk factors for ILD59; UIP pattern present in 2/3 cases 60 data from small case series nodular or reticular opacities have been occasionally described and considered residuals of lung hemorrhage/infarcts 62 Subclinical lymphocytic alveolitis (BAL) 64, 65 Association with MPO-ANCA antibodies 66

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ILDs: interstitial lung diseases; NSIP: Non Specific Interstitial Pneumonia; UIP: Usual Interstitial Pneumonia; DM/PM: dermatomyositis/polymyositis; n.a.: not available; BAL: bronchoalveolar lavage; MPO-ANCA: anti-myeloperoxidase-antineutrophil cytoplasmic autoantibodies. a Granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis.

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of patients with IPAF or UCTD, may reveal signs and symptoms suggestive of a given systemic autoimmune disorder in its very early stage (Fig. 3). This approach can be decisive for early, targeted therapeutical strategy in the single patient with specific clinical phenotype. In the clinical practice, it is possible to find patients with presenting ILD who develop during the follow-up one or more features of early systemic sclerosis, the CTD with high prevalence of ILD (Table 5;), or early rheumatoid arthritis, two pathogenically different conditions needing distinct, specific treatments (Table 5; 34,48–50). In similar circumstances, the detection of typical, but often subtle symptoms should be decisive for the early diagnosis, when pathogenetic treatments may have the highest likelihood to positively affect the overall disease outcome. Another example may be the case of a patient with apparently isolated interstitial pneumonia (UIP pattern) who developed after 12-month follow-up a sensory neuropathy at the lower limbs due to biopsy-proven vasculitic (p-ANCA positive) peripheral nerve involvement (personal observation). Longer clinical follow up of this patient may permit a better disease definition; however, such clinical observations underline the needing of careful patient's long-term monitoring to better classify individuals with apparently ‘idiopathic’ interstitial pneumonia as expression of underlying autoimmune disorders. Patients with ILDs, including IPF, may clinically develop with an insidious onset characterized by dyspnea on exertion and bibasilar inspiratory crackles. Therefore, various etiopathogenetic factors, namely environmental exposures, drug toxicity, or systemic autoimmune diseases, especially classical CTDs (Table 5), must be considered in order to correctly classify idiopathic and secondary ILDs [1–3]. Some features can be usefully employed for a correct patient's assessment; in particular, individuals with underlying CTDs are more frequently young female with multisystem disease [48–66]; they may present one or more extrathoracic manifestations such as Raynaud phenomenon, arthralgias/arthritis, sicca syndrome, skin, muscle, and/or mucosal manifestations, with serum immunological alterations (Table 1). Moreover, pulmonary manifestations of patients with ILD-CTD are generally multicompartmental, showing various degrees of lung, pleura, airway, pericardium, and/or pulmonary vascular involvement. The clinically heterogeneous manifestations of ILD-CTD are mirrored by the pathological lung patterns, including NSIP, the most prevalent, UIP, lymphocytic interstitial pneumonitis, cryptogenic organizing pneumonitis, or diffuse alveolar hemorrhage, as well as the combination of the above patterns [69]. Classical CTDs, other autoimmune diseases (Table 5), as well as the associated ILDs, are characterized by multifactorial and multistep etiopathogenesis. These conditions may clinically manifest with a variable, often unpredictable symptom composition during the natural

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course of the disease; therefore, a careful long-term monitoring is recommendable in all cases. In this scenario, we agree with the proposal of multidisciplinary approach by ERS/ATS Task Force [11], with the adoption of the term IPAF that is more inclusive compared to previous nomenclature (Table 2). Accordingly, we suggest to cover the complete spectrum of systemic autoimmune diseases (Table 5) in the clinical work-up and differential diagnosis of ILD patients with autoimmune and/or rheumatologic ‘flavor’ [11]. Moreover, clinico-serological monitoring of patients with IPAF or UCTD may allow to deeply investigate specific pathogenetic mechanisms as well as possible parameters able to predict the evolution to definite disease phenotypes (Fig. 3). In the same time, validated classification criteria may warrant the correct patient's selection for clinicotherapeutical trials. Finally, the cooperation between multidisciplinary groups with different experiences may be the next step for the consensus study on the nomenclature and classification criteria of still indefinable variants of ILDs and CTDs [10,11]. The ILDs and CTDs represent two wide heterogeneous groups of disorders in the fields of pneumology and rheumatology, respectively. The ILDs may be correlated to a wide number of triggering factors or other well-known diseases, in the absence of these conditions some individuals are classified as having IPF [70]. Similarly, CTDs and other systemic autoimmune rheumatic diseases may be complicated in variable percentage by ILD [71,72] which is particularly frequent and severe in some conditions such as systemic sclerosis (Table 5; 34,48–50), or uncommon, often subclinical in others (see references in Table 5). Nevertheless, interstitial pneumonia can be regarded as the intersection between ILDs and CTDs; the different prevalence of this specific organ involvement in CTDs, as well as of different CTD phenotypes, may be the results of a variable combination of genetic and/or environmental etiopathogenetic co-factors in individual patients. Likely, a comparable process can be ascribed to ILDs, especially to clinical variants with associated autoimmune features suggestive of underlying CTDs [10,11]. This marked difference can be correlated to a clear-cut selection bias in the patient's referral: those with clinically dominant respiratory symptoms are invariably referred to tertiary pulmonary care unit, while patients with a variable composition of autoimmune features but without or subclinical respiratory symptoms are commonly referred to the Rheumatology Care Center (Fig. 1). The three patients' series reported in Table 3 constitute the spectrum of undifferentiated/unclassifiable conditions that can be observed in the field of ILDs or CTDs commonly referred to our two tertiary care units (Fig. 2): from one side there are patients without any possible cause of interstitial

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• Interstitial lung diseases (ILDs) may be associated to connective tissue diseases (CTDs) or other systemic autoimmune diseases (AIDs). • In some ‘autoimmune flavored’ ILDs the possible underlying disorder does not fulfill the classification criteria of a given CTD. • For these patients the term interstitial pneumonia with autoimmune features (IPAF) has been recently proposed. • IPAF share several clinico-serological features with undifferentiated connective tissue diseases (UCTD), except for ILD that is rarely found in UCTD. • This difference might be due to pre-selection bias in the patient's referral depending on the presence/absence of clinically dominant ILD. • Our model of interdisciplinary pneumology–rheumatology evaluation and management of IPAF/UCTD patients is proposed.

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pneumonia such as environmental exposures or immune-mediated disorders, i.e. U-ILD, from the opposite side there are the so-called UCTD, while the IPAF may represent a transition between U-ILD and UCTD, being characterized by the presence of both ILD and autoimmune features not fulfilling the diagnosis of definite CTD [11]. While U-ILD remain stable after the initial patients' assessment, a number of patients with IPAF might develop overt ILD-CTD; similarly, the majority of stable UCTD represent a durable condition during the time. However, both IPAF and UCTD may be a prodromic condition or very early phase of a given CTD; the evolution into definite CTD is more likely during the first years of follow-up. At the first assessment and during the initial follow-up period, it is important to identify patients with specific clinico-serological characteristics suggestive of definite CTD, with important implications on the therapeutical strategies (Fig. 3). The parceling of internal medicine into several specialties and subspecialties has been the natural consequence of the vast growing of the medical knowledge during the last decades. At the same time, there is an increasing needing in the clinical practice of rediscovery the ‘whole’ and the interdependence of single components for a correct patient's assessment and management. The holistic approach is particularly recommendable for patients with complex, multiorgan disorders such as systemic autoimmune diseases, but also for apparently isolated organ-specific diseases, among which the ILDs that not rarely may be the presenting symptom of the above-mentioned systemic disorders.

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