In this study, we evaluated the short-term longitudinal changes in pulmonary function in individuals with the recently described distinct rheumatologic entity, UCTD-ILD [14
], and compared their course to that found in patients with IPF. Our study shows that patients with UCTD-ILD have a more favorable clinical course than do patients with IPF (as measured by change in forced vital capacity)—a parameter associated with increased mortality in patients with IPF, the ILD with the most robust clinical outcome data available [19
Patients with idiopathic NSIP have features suggestive of an autoimmune disease [5
]. Recently, we showed that patients with the histopathological pattern of NSIP, in the absence of a defined classic CTD, had considerable, if not complete, overlap with the clinical diagnosis of undifferentiated connective tissue disease [14
]. This is consistent with findings showing the NSIP pattern to be the most common histopathological pattern found in patients with the “classic” CTDs, such as scleroderma, rheumatoid arthritis, Sjögren’s disease, systemic lupus erythematosus, and polymyositis/dermatomyositis. Importantly, patients with “classic” CTDs have a better prognosis compared with patients with IPF [2
]. Our findings show that UCTD-ILD similarly seems to have a better prognosis than IPF, at least in the short term.
We chose an improvement of at least 5% in predicted FVC as our threshold for physiologic improvement because recent prospective clinical studies of ILD suggest that such a magnitude of change in FVC is appropriate given the typical annual change in this parameter [22
], even with effective therapy [24
]. Indeed, large multicenter, clinical trials, recently enrolling (IPFnet, CAPACITY), were powered to detect differences of this magnitude in longitudinal change of FVC percent predicted. Furthermore, in a recent clinical trial of IPF, a change of 5% in predicted FVC was shown to be strongly associated with mortality [27
Our study demonstrates that patients with UCTD-ILD were more likely to receive immunomodulatory treatments than were patients with IPF. This likely represents a temporal trend away from the use of these agents in IPF [28
]. A higher number of patients with UCTD-ILD than IPF had an improvement in functional parameters while on therapy, but our study was not powered to demonstrate the full range of clinically significant differences regarding treatment. Whether the difference in outcome is secondary to a different underlying natural disease course for UCTD-ILD or responsiveness to therapy cannot be determined from our study. Based on our data, we cannot recommend any specific treatment course for these patients. However, the signals in the data suggest the possibility of a treatment response to immunomodulatory therapy in patients with UCTD-ILD and should be rigorously evaluated in future studies.
There are several limitations of this study; most are related to its retrospective design. First, approximately one-third of potentially eligible patients with IPF or UCTD at the study center did not have more than one set of pulmonary function tests available for evaluation and thus could not be included in this study. We attempted to mitigate this limitation by assessing whether these patients were systematically different from the patients who were included in the study in terms of demographic factors or baseline pulmonary function tests. There were no significant differences in baseline pulmonary function tests (including FVC and DLCO); however, the non-study patients were older, as described above. Second, patients had follow-up pulmonary function tests at different time intervals. Although the standard clinical practice was to recommend repeat tests every 3–6 months, there were no formal protocols in place to ensure that this occurred. We addressed this limitation in the analysis phase by using regression techniques. Lastly, the single-center design and heterogeneity in treatment recommendations by the individual providers limited our power to observe differential effects of treatment between these populations and within the population of UCTD-ILD.
Our findings of a demonstrably different disease course in functional changes between IPF and UCTD-ILD is an important first step. These results demonstrate the importance of identifying an underlying undifferentiated connective tissue disorder when patients present with incipient interstitial lung disease. Equipped with these data, the clinician can provide better prognostic advice for patients with UCTD-ILD.
These results will need to be confirmed in prospective studies with more standardized and complete follow-up. Additionally, it will be important to demonstrate whether the differences in functional parameters seen between these two populations are accompanied by differences in the most meaningful of outcomes—mortality—and patient-centered outcomes, such as change in dyspnea. In addition, there is much to be learned about the underlying pathogenesis of UCTD-ILD and to identify appropriate targets for well-designed intervention trials. Lastly, it will be important to establish whether any clinical, biologic, or serologic features can identify which patients are most at risk for progressive disease and lung-related death.