State of the art in interstitial pneumonia with autoimmune features: a systematic review on retrospective studies and suggestions for further advances

Discussion

Classification criteria are standardised definitions with the primary aim of creating homogeneous cohorts for research [25]. In this way, they favour high specificity over sensitivity. In 2015, the IPAF criteria [6] were created via consensus opinion by an expert international panel of 13 pulmonologists, four rheumatologists, one thoracic radiologist and one pulmonary pathologist. Importantly, the panel was largely composed by the same investigators who had previously put forth criteria for ILD with autoimmune characteristics. The IPAF criteria, endorsed by the ATS and ERS proposed a research classification for interstitial pneumonia patients who presented at least one specific feature from at least two of the following three domains: clinical, serological and morphological. The proposed IPAF classification has the advantage of removing previous nomenclatures, creating a framework to study a more uniform population in a readily applicable manner worldwide.

Comparing the already reported IPAF cohorts, in our analysis we identified very different populations from the clinical, serological and morphological point of view. In addition, some differences were noted in terms of outcomes. As expected, mortality was higher in the Oldham et al. [18] cohorts, where more patients had a UIP pattern. However, in the other studies, mortality was not strictly related to the presence of a UIP pattern.

Obviously, comparison of different studies may have limitations. The first one is related to the retrospective nature of the reviewed cohorts, which can, at least in part, explain the numerous differences highlighted observed among them. In fact, IPAF criteria were proposed for prospective studies and data from these will be of pivotal interest. A second limitation is related to the lack of a rheumatologist clearly involved in the multidisciplinary team (MDT). Chartrand et al. [22] reported the presence of an expert rheumatologist in the diagnostic process, whereas in the other studies this role was not clearly involved in diagnosis. This difference may explain the reason why the cohort in the Chartrand et al. study has features and outcomes similar to CTD, whereas patients in the Oldham et al. cohort have features and outcomes more similar to IPF. A third weakness concerns treatment. Oldham et al. did not report any patient treatment. The other studies gave only a partial description of how patients were treated. In some cases, they were treated with steroids and/or immunosuppressant drugs according to the low prevalence of UIP pattern. Furthermore, despite the similarity of the HRCT pattern in the Ito et al. [24] and Chartrand et al. populations, a low percentage of treated patients and a worse prognosis was observed in the former cohort. These data may suggest the importance of treatment in the evolution and prognosis of IPAF patients.

Nevertheless, in the absence of proper prospective studies, the comparison and analysis of these four retrospective studies give some useful insights that may be helpful to improve the current IPAF classification.

As described, IPAF criteria overlap UCTD criteria as well as those criteria that identify early onset or incomplete forms of defined CTDs [16, 17, 26]. These disorders might be called “IPAF” inappropriately, while they represent different diseases at different stages. For instance, criteria for very early diagnosis of systemic sclerosis (VEDOSS) [26] are able to identify individuals with a high risk of developing a defined systemic sclerosis. These patients are of great interest, considering that their evident “sclerodermic flavour” allows the timing of onset of the disease to be studied, or whether the presence or even the absence of an item in the pathogenic behaviour influences complete disease manifestation.

Although criteria for very early diagnosis of other CTDs are not yet defined, IPAF criteria can capture all these forms under a unique definition. In this context, it should be considered that different CTDs, even at early stages, have different pathogenic pathways and varying evolution.

Moreover, IPAF criteria may include patients with ASS. Patients with a positive ATSA and ILD could be considered to have ASS by some clinicians and IPAF by others, despite the high risk of developing other clinical findings of the classic triad (arthritis and/or myositis) [21]. In this regard, it seems important to consider the mutual concept: ILD patients should be tested for all ATSA and other antibodies linked to inflammatory myopathies, although some of these antibodies are not widely available.

Thus, the current definition of IPAF is not probably able to select homogenous populations. On the contrary, in the context of the MDT follow-up, IPAF classification is useful in selecting subsets of ILD patients at risk of developing a defined CTD.

Another point of view could be that IPAF is a primary autoimmune disease, which mainly focuses on the lung. To sustain this hypothesis, it is necessary to satisfy Koch's postulate for autoimmune diseases [27] by demonstrating autoreactive T- or B-cells (specific antibodies). In support of this thesis, IPAF populations show higher proportions of ANA positivity than expected in the general population [28]. Moreover, antibodies useful for diagnosing CTD showed their primary autoantigen sources in the lung, such as Jo-1 and anti-citrullinated protein antibody (ACPA) [29–31]. In some other cases, antibodies are associated with prevalent lung involvement, such as ATSA and anti-Th/To [32, 33], and in IPF autoantibodies are less rare [34, 35].

In our opinion, IPAF criteria should follow the latter hypothesis to avoid the inappropriate inclusion of IPAF patients with several different clinical conditions.

In this light, the presence in these criteria of very specific items (such as Extractable Nuclear Antigen (ENA) specificities, anti-double stranded DNA, ACPA, distal digital tip ulceration, mechanic's hands) or even pathognomonic features, such as Gottron's sign [36], for definite CTDs appear to be not useful. Similarly, in spite of the lack of classification criteria for ASS, patients with ILD and myositis show positivity for ATSA up to 60% of cases [15]. Therefore, it may not be by chance that the Chartrand et al. [22] population showed simultaneously a higher prevalence of Gottron's sign, mechanic's hands, NSIP pattern and ATSA, four features all linked to inflammatory myopathies.

Conversely, other antibodies associated with a wide spectrum of autoimmune diseases and ILD such as anti-neutrophil cytoplasmic antibodies (ANCA) [37] and anti-Ku antibody should be considered [38, 39]. Furthermore, some reports described patients with ANCA-positive interstitial pneumonia. Currently, limited data are available for this subset of patients. Yamada [40] reviewed the reported cohorts, describing 92 patients with interstitial pneumonia generally classifiable as IPF with positivity for ANCA. In this cohort, 35.8% of patients showed concurrent ANCA-associated vasculitis (AAV), 17.4% developed an AAV with a delay of years compared to the interstitial pneumonia and the remaining 46.8% showed only ANCA-positive interstitial pneumonia. These patients had a prevalence of honeycombing in surgical lung biopsy with a prognosis similar to IPF. Few other patients had signs of bronchiolar or interstitial vasculitis. The author hypothesised two pathogenic mechanisms. The first is that subclinical alveolar haemorrhage can contribute to interstitial pneumonia in AAV. The second mechanism considered the high prevalence of anti-myeloperoxidase (MPO) ANCA in these patients. In response to inflammatory cytokines, MPO is shown to the surface of neutrophils, and can be bound by circulating ANCA, with subsequent neutrophil degranulation and release of reactive oxygen species, leading to injury and fibrosis. This second mechanism might explain ANCA-associated interstitial pneumonia without vasculitis.

In addition, this optimisation of the number of diagnostic items could avoid some confusion in classification. Particular attention should be paid to the possible association of autoimmune features during the classification of a single patient. In several cases, patients with combined positivity for high titre of rheumatoid factor and ACPA were considered to have IPAF. This combination exposes general and high-risk populations to a 100% likelihood of developing rheumatoid arthritis in 5 years [41]. Furthermore, in the Ahmad et al. [23] population, patients with sicca syndrome and minor salivary gland biopsy suggestive of Sjögren syndrome were classified as having IPAF. In these cases, the likelihood of developing technically detectable clinical impairment of salivary or lacrimal glands and fulfilling Sjögren syndrome criteria is very high. Besides, in the same study, patients with Raynaud's phenomenon, giant capillaries at nailfold videocapillaroscopy (NVC) and NSIP pattern were classified as having IPAF rather than VEDOSS. The authors specified that NVC was considered positive for minor alterations [42, 43], but giant capillaries, as reported in the manuscript, is one of the most specific items for CTD in NVC, with well documented significance in diagnosis and prognosis [44–47]. As such, abnormal NVC may be considered as an exclusion criterion for IPAF classification.

An improvement in specificity can be obtained with a more precise definition of the morphological domain. For example, it could be enriched adding a quantification cut-off in terms of PFTs. This may explain the frequent variability of ILD in CTDs reported in the literature. An interesting study on rheumatoid arthritis reported ILD in 19% of patients, but only 6% of these showed a restrictive PFT pattern [48]. In the remaining patients, it cannot be excluded that the aetiological cause of ILD may not be autoimmune and already solved at diagnosis. The use of thresholds may improve specificity at the expense of the sensitivity of the IPAF criteria, with more chances to create a homogeneous population.

Moreover, the concept of “unexplained intrinsic airways disease” could benefit from clarification, especially regarding bronchiectasis, reported as an example of unexplained intrinsic airways disease. Its finding is extremely common in the ILDs, especially in the UIP pattern [49], hence this parameter is not useful to discriminate among patients.

In the light of these considerations, IPAF criteria could be potentially refined as follows. 1) Exclusion of items extremely specific for CTD and simplification of criteria; 2) inclusion in the serological domain of ANCA and anti-Ku antibodies; 3) evaluation of positive NVC as an exclusion criterion of IPAF; 4) definition of a PFT cut-off to consider ILD as clinically significant/at risk of progression; 5) clarification of the multicompartment involvement section (mainly intrinsic airway disease); and 6) active involvement of a rheumatologist in the MDT.