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 different experiences may be advisable for a validation study of the proposed nomenclature and classification criteria of these indefinable ILD/CTD variants.