Interstitial Pneumonia with Autoimmune Features (IPAF): time to redefine the classification criteria

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 rheumatology 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 revisions improved performance (mainly sensitivity) for ARDs classification, 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 pulmonologists 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 stochastically 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 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 largest prospective cohort of IPAF patients (191 subjects), followed 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 recognition 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