Even in the absence of a defined CTD, 10 to 20% of patients with IIP have systemic symptoms (fever, arthralgias, Raynaud's phenomenon) and serologic abnormalities (elevated erythrocyte sedimentation rate, antinuclear antibodies, or rheumatoid factor) suggestive of an autoimmune process (25
). Following the 2002 ATS/ERS international consensus classification of the IIPs, it has been noted that most patients with these findings are classified among the patients with idiopathic NSIP (3
). In addition, it is now recognized that the vast majority of ILD associated with defined CTD is characterized by the histopathologic pattern of NSIP (11
) and a predominance of ground-glass opacities on HRCT (13
), especially in systemic sclerosis, Sjögren's syndrome, and dermatomyositis/polymyositis. A recent ATS working group described idiopathic NSIP as a distinct clinical entity that occurs mostly in middle-aged women who are never-smokers and who often have positive serologic tests for collagen vascular disease (31
). Fujita and coworkers recently reported in a case series that the clinical and pathologic features of patients with idiopathic NSIP and those with CTD-associated NSIP were qualitatively similar (32
). Given the above, we hypothesized that the clinical entity “idiopathic NSIP” is an autoimmune disease and the lung manifestation of UCTD, an increasingly recognized and distinct CTD. Our results provide strong evidence to support this hypothesis. In addition, the high prevalence (~ 10%) of these patients in a tertiary referral center population demonstrates the importance of this disorder.
Several characteristics of the current study enhance the validity of the results: the systematic prospective assessment for symptoms of CTD, detailed information on clinical and radiographic characteristics, and documentation of specific histopathologic findings. This study is the first to apply specific criteria for the diagnosis of UCTD to characterize patients with associated ILD. We show that patients with UCTD and ILD bear striking similarities to the more established CTDs in terms of clinical characteristics (female, younger, nonsmoker predilection, high titer-positive antinuclear antibodies (ANA), absence of clubbing), radiographic features (presence of significant ground-glass opacity and absence of honeycombing), and histopathologic patterns (NSIP predominant). We believe this study provides important insight into the underlying pathogenesis of these patients—that of autoimmunity.
Autoimmune disease predominantly affecting a single-organ system is well described (33
). The establishment of these diseases as autoimmune in nature has largely been based on clinical and laboratory evidence of autoimmunity, and histologic findings of a lymphocytic infiltrate in the affected organ (33
). In autoimmune pancreatitis, internationally recognized criteria are based on a combination of the findings of abdominal imaging, laboratory testing (positive autoantibodies), and histology (lymphoplasmacytic infiltrate) (35
). Other investigators have suggested the inclusion of a clinical response to steroids in the criteria (36
). In autoimmune hepatitis, the diagnosis is based on characteristic clinical features (e.g., female predilection, systemic symptoms such as arthralgias), circulating autoantibodies (e.g., ANA titer greater than 1:80), abnormal levels of serum globulins, and a compatible histologic picture (chronic hepatitis with a plasma cell infiltrate) (34
). Although the causes of autoimmune hepatitis and pancreatitis are unknown, aberrant autoreactivity is believed to have a role in its pathogenesis. Based on similar clinical, laboratory, and histopathologic criteria, we believe our findings suggest that idiopathic NSIP represents a form of autoimmune pneumonitis.
In the 2002 ATS/ERS international consensus statement on the classification of IIP, it was stated that, “the concept of an idiopathic form of NSIP presents a problem for the clinician because there is no recognized and distinctive clinical description for patients presenting with this histologic pattern on lung biopsy” (7
). Our study suggests that the application of diagnostic criteria for UCTD may be able to distinguish these patients based on a thorough systematic review of symptoms or signs of CTD and serologic studies before obtaining surgical lung biopsy.
It has been known for some time that the pulmonary manifestations of CTD occasionally precede the more typical systemic manifestations by months or years (especially in rheumatoid arthritis, systemic lupus erythematosus, and polymyositis/dermatomyositis) (37
). Consequently, we expect that some of the patients included in our UCTD cohort will go on to develop sufficient criteria to be classified as another disease entity. However, if patients with ILD behave similarly to those with UCTD in general, this is likely to be a minority of patients (e.g., 25%) (14
). Furthermore, among those patients with UCTD that does evolve into another disorder, the majority do so within the first year of follow-up (19
). It should be noted that our UCTD patients with ILD had mean disease duration (first pulmonary symptom onset until presentation) of approximately 3.5 years at the time of enrollment.
We have demonstrated that the most common clinical manifestations in patients with UCTD and ILD are diffuse arthralgias, Raynaud's phenomenon, and esophageal symptoms, whereas oral ulcerations, renal and neurologic disease (data not shown), alopecia, clubbing, and muscle weakness are uncommon. This relative frequency of findings are similar to what has been observed in other non-ILD UCTD cohorts (19
). These findings, if replicated, may inform subsequent development of more specific classification criteria for this form of CTD.
There are a number of limitations of this study. First, in keeping with the most recently published literature on the topic (19
), we chose to only require one connective tissue symptom for the diagnosis of UCTD. This approach may sacrifice some specificity and potentially lead to misclassification. If present, the direction of misclassification would be expected to bias our results toward the null hypothesis, because patients without true UCTD would have been misclassified as cases instead of control subjects. Importantly, the overwhelming majority of patients with UCTD-ILD had more than one symptom (86%) and most had at least three symptoms (67%). Second, although the study demonstrated several highly statistically significant associations, the sample size limited our power to examine some of the less dramatic but potentially insightful associations (e.g., mosaic perfusion on HRCT or germinal centers on histopathology). Third, the retrospective design limited our ability to acquire a complete serologic panel on all patients. Consequently, in our case definition, we had to include a requirement for at least one of several potential autoantibodies/inflammatory markers. In addition, we included sedimentation rate and C-reactive protein (in absence of infection) in our criteria to be as inclusive as possible because of the absence of prior description of UCTD in the setting of ILD. Although these tests are relatively nonspecific, they are frequently used to monitor disease activity of rheumatic diseases (38
). We would note again, however, that if misclassification occurred, it would have been expected to bias our results toward the null hypothesis. In future prospective studies, it will be important to perform comprehensive laboratory and serologic panels on all patients to more precisely elucidate these patterns.
In summary, we have demonstrated that most patients previously classified as having idiopathic NSIP have clinical, serologic, radiographic, and pathologic characteristics that are suggestive of autoimmune disease and meet criteria for UCTD. Future studies should confirm these findings in other cohorts of patients with ILD, define the natural history of UCTD-ILD, and identify appropriate targets for well-designed controlled studies of therapeutic interventions.