American Journal of Respiratory and Critical Care Medicine

The recognition by Katzenstein and Fiorelli (1) that nonspecific interstitial pneumonia (NSIP) was a separate histopathologic entity from idiopathic pulmonary fibrosis (IPF) created great excitement because it helped to explain why some patients with IPF have more cellular inflammation on biopsy and/or more lymphocytes in bronchoalveolar lavage fluid and respond to corticosteroid therapy. NSIP has all these features (2), in addition to unique histopathology with spatial and temporal homogeneity of fibrosis as well as a better prognosis than IPF (2, 3). However, this new diagnostic category also raised questions and generated debate; the NSIP pattern has been found in association with various underlying diseases, including hypersensitivity pneumonitis, drug-related lung diseases, following an episode of acute respiratory distress syndrome, and in the context of connective tissue diseases, as first noted by Katzenstein and Fiorelli (1). Another concern was that NSIP may not be one entity because the histologic pattern has been split into three subtypes—that is, cellular, mixed, and fibrotic—in both the original description and other reports (13), whereas the radiologic findings are also heterogeneous (4). Furthermore, patient series showed that a subset of patients with fibrotic NSIP have a clearly unfavorable prognosis similar to that of IPF during long-term follow-up (5, 6). There was also debate as to whether NSIP is an early stage of IPF rather than a distinct entity (7).

NSIP was categorized as a provisional diagnosis in the 2002 American Thoracic Society and the European Respiratory Society consensus classification of idiopathic interstitial pneumonia (8), and a special workshop was organized to address its characterization. The NSIP workshop consisted of expert pathologists, radiologists, and clinicians, and concluded that idiopathic NSIP is a distinct clinico-radiologic and pathologic entity; the final report will come out soon. However, there is still a possibility that NSIP may not be a single entity and may overlap with different conditions. Among these, connective tissue diseases are the most intriguing, because NSIP has been recognized as a major histopathologic pattern of lung involvement in scleroderma, polymyositis-dermatomyositis, or Sjögren's syndrome (911). In addition, in some patients, lung involvement precedes other systemic manifestations, making the distinction between idiopathic NSIP and lung involvement of connective tissue disease impossible at the time of diagnosis.

Many studies, including the NSIP workshop, reported that a substantial number of patients with idiopathic NSIP have positive autoantibodies (12). In this context, the study by Kinder and colleagues in this issue of the Journal (pp. 691–697) is timely and provides important information (13). The authors hypothesized that idiopathic NSIP is the lung manifestation of undifferentiated connective tissue disease (UCTD), a clinical entity with symptoms and/or signs suggestive of a connective tissue disease, but not fulfilling the classification criteria for any specific diagnostic entity (14). From their medical records, they identified 28 patients with idiopathic interstitial pneumonia (IIP) who met the criteria for UCTD and compared these patients with the control group of patients with IIP (n = 47) who did not meet the UCTD criteria. Compared with the control group, the patients with UCTD–interstitial lung disease were more likely to have ground-glass opacity on high-resolution computed tomography (HRCT) and NSIP pattern on biopsy, and less likely to have honeycombing on HRCT or usual interstitial pneumonia (UIP) on biopsy. The authors also analyzed their biopsy-proven NSIP cases and found that a majority (88%) of patients previously classified as idiopathic NSIP met the criteria for UCTD. Based on these findings, Kinder and colleagues suggest that the clinical entity of idiopathic NSIP actually appears to be a lung manifestation of UCTD.

This study has several limitations, which makes it difficult to accept the conclusion that idiopathic NSIP is UCTD. First, this clinical series was retrospective and performed in one center with a small number of subjects. The total number of evaluable patients with IIP was 75, including 28 with UCTD, and surgical lung biopsy was performed in only 53% of the subjects. Second, there was uncertainty in the diagnosis of UCTD. Even though UCTD is a relatively new entity with no definitive consensus criteria for diagnosis yet available, the classification criteria used in rheumatology are as follows: (1) signs and symptoms suggestive of a connective tissue disease, but not satisfying the criteria of any defined disease entity; (2) positive result for antinuclear antibody test; and (3) disease duration of at least 3 years (14). Because a significant proportion of the patients initially diagnosed as UCTD eventually evolve into a defined connective tissue disease, longer follow-up might permit correct classification of many patients initially given this diagnosis. The authors' criterion for UCTD was duration of 1 year, which may be too short a follow-up period and may increase the number of false-positive cases. Furthermore, the authors modified the second criterion of the presence of antinuclear antibodies to include nonspecific inflammatory markers, such as C-reactive protein, creatine kinase, aldolase, or sedimentation rate, which are not specific for connective tissue diseases. This modification might also result in more false-positive cases. A third limitation of this study is that autoantibodies were not tested for in all subjects, especially in the control group, and, even among those tested, uniform serologic panels were not performed.

Because 12% of the patients included in this study with biopsy-proven idiopathic NSIP did not have UCTD even in terms of the authors' extended diagnostic criteria, their conclusion characterizing idiopathic NSIP as a form of UCTD seems to be an overstatement. Of note, other studies have proposed a similar possibility that IIPs, such as NSIP, are manifestations of connective tissue diseases, such as systemic sclerosis sine scleroderma, or anti-aminoacyl-tRNA synthetase antibody syndrome, that may escape proper diagnosis when only chest physicians are involved in the evaluation of such cases (15, 16). Nevertheless, it is plausible that a significant proportion of idiopathic NSIP is UCTD or another atypical connective tissue disease. Further prospective and cooperative work between chest physicians and rheumatologists is warranted to classify idiopathic NSIP into a novel disease entity.

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