The natural history of IPAF is still not well known IPAF is a heterogeneous entity in its own definition. Moreover, there are few retrospective studies, from a single center and with a short follow-up time. This study is the first observational multicenter study to date that has evaluated the effect of corticoids and immunomodulatory therapy on IPAF in terms of pulmonary functional impairment and in the long term. Moreover, we confirm previously identified risk factors of progression in IPAF, and propose new ones such as prognostic biomarkers.
As in other studies, IPAF NEREA patients were predominantly women, in their sixties, being NSIP the most frequent radiological pattern, and the most common clinical and serological manifestations were joint symptoms, Raynaud's phenomenon, and seropositive ANA antibodies [16, 26, 27].
In ILDs, a decline of pulmonary function is expected over time. Whereas DLCO% is highly sensitive for predicting the presence of ILD, lung volumes might be more useful for assessing disease extent [28]. Recent publications suggest that a 5% difference in FVC% is clinically meaningful in the short term [29]. Thereby, the current study has assessed the incidence rate of functional impairment as a decline in relative FVC% ≥ 5% over 6-month periods [21]. In our study, 63% of IPAF suffered deterioration over the study course, with an incidence rate of 23.9 per 100 patients-semester. Moreover, it is also important to note that our IPAF progressed during the first years of disease, as 50% of them developed functional deterioration at 16 months after IPAF diagnosis. To date, there are no studies that analyze long-term pulmonary functional progression, although as in other ILDs, this is a determining factor in the definition of a progressive phenotype with prognostic and therapeutic implications [30, 31]. Our results are similar to those shown in patients with rheumatoid arthritis-related ILD from the NEREA registry [32].
Another relevant matter we have addressed, is the identification of factors related to pulmonary functional impairment in IPAF. UIP pattern entailed a poorer prognosis regardless other factors, as it has been shown in patients with other CTD-ILD [32, 33]. Similarly, UIP pattern has been reported to be associated with an increased mortality risk both in IPAF [15, 16, 34, 35] and CTD-ILD [36, 37]. Regarding therapeutic management, we were not able to show differences among glucocorticoids nor inmunomodulatory therapy in the entire IPAF population. This could reflect the variability among patients and therapies. “It is important to note that therapeutic decisions in our patients were multidisciplinary, considering the patient health status, the extra-pulmonary disease, the ILD severity, and patient’s preferences in all cases.”
In order to study treatment effect in detail, we stratified the patients according to radiographic patterns and found that systemic glucocorticoids were associated with better outcome in UIP pattern. This points out the existence of different pathogenetic mechanisms in autoimmune-related UIP as compared to idiopathic forms [38]. This finding does occur in other CTD-ILDs [39], which have led to propose the use of glucocorticoids in progressive fibrosing phenotypes [19, 32]. Joerns et al. showed that the combination of glucocorticoids and MMF was associated with less functional progression after adjustment for radiological patterns [19]. In our study and regarding NSIP patients, it seemed that azathioprine and MMF didn´t influence, but with tacrolimus and cyclosporine, the statistical significance was reached. In the case of UIP pattern, a possible benefit of rituximab was found (p = 0.1). However, a small number of events supported our findings, and they need to be interpreted with caution.
In most studies, older age in IPAF can be considered a poor prognosis independent factor [34, 35, 40], although they were related to mortality. In our study we achieved statistical significance in those with UIP pattern, losing significance in the entire IPAF population and in those with NSIP pattern.
As a novelty, this study was able to evaluate the role of different antibodies on prognosis. Interestingly, the presence of Anti-Ro antibodies was independently associated with a lower risk of functional progression, both in NIU pattern and in the entire IPAF population. Whereas, the presence of ANA at titers ≥ 1/320 increased the risk of bad outcome in UIP subgroup. All these findings, need to be replicated in larger studies, in order to confirm their potential role as biomarkers in IPAF.
Taking the long period of inclusion into consideration, the analysis was adjusted for time calendar to elude bias. Intriguingly, a more recent diagnosis was associated study with greater functional progression, both in IPAF population and in UIP patterns. It is known that these patients are difficult to classify, mainly those with UIP pattern, which could have been previously diagnosed with idiopathic pulmonary fibrosis instead of IPAF, remaining outside this population in those earlier periods, but not in the most recent ones.
As major limitations of our study, is the retrospective nature of the design until 2017 and also the small sample size. Nevertheless, the inclusion of non-selected patients from seven hospitals with a long-term follow-up provides important strengths, giving an overall vision of real world evidence in this field. Moreover, all the patients were recruited and attended at special CTD-ILD multidisciplinary units, implicating standardized and homogeneous evaluations. All data were available for analysis, allowing adjustment for confounders to elude possible bias.
Our results support that patient with IPAF suffer pulmonary functional impairment that can be comparable to other ILD-CTD. The effect of certain treatments, as well as the identification of associated factors on pulmonary deterioration in patients with IPAF, may help clinicians in daily practice. Notwithstanding, our findings need to be replicated in additional prospective studies to gain further insight into the management of IPAF.
