Background
Immunoglobulin G4-related disease (IgG4-RD) is an increasingly recognized systemic fibroinflammatory disease characterized by lymphoplasmacytic infiltration with an abundance of IgG4-positive plasma cells [
1]. It can affect various organs including the pancreas, hepatobiliary system, kidney, retroperitoneum, and lacrimal and salivary glands [
2]. Lung involvement can either be the sole manifestation or part of multiple organ involvements [
3]. IgG4-related lung disease (IgG4-RLD) has heterogeneous presentations involving airway or interstitium, in addition to tumefactive parenchymal lesions, as reported previously [
4‐
9]. As a result, diagnosis is challenging, and the natural course of the disease is not well defined because most previous literature on this topic is based only on case reports.
Although IgG4-RLD has various manifestations, one previous study found common radiologic features of IgG4-RLD which correlated with pathologic specimens [
10]. Inoue et al. classified IgG4-RLD into four subtypes based on a predominant radiologic finding: solid nodular, bronchovascular, alveolar interstitial, and round ground glass opacity (GGO) [
10]. In addition to these four subtypes, several case reports suggested alveolar consolidative type as one of the imaging findings of IgG4-RLD [
11‐
13]. However, whether the clinical course of each subgroup is different from one another has not been investigated. Particularly, treatment responses with regards to radiological improvement and long-term pulmonary function changes according to the different radiologic subtypes are yet to be determined. Therefore, this study aimed to identify clinical characteristics, treatment outcomes, and longitudinal pulmonary function changes in patients with IgG4-RLD according to the radiologic classification.
Discussion
In the present study, we evaluated the characteristics of patients with IgG4-RLD, their long-term clinical course, and treatment outcomes according to the radiologic subtypes. CR or PR was achieved in 77.4% of the treated patients although relapse among them was frequent as 25.0%. Treatment outcomes differed according to the radiologic subtype; alveolar consolidative type showed the highest CR rate whereas alveolar interstitial type showed the lowest number of patients who achieved CR or PR.
IgG4-RD is a systemic inflammatory disease that can involve multiple organs. Lung involvement was first recognized in 2004 [
21,
22]. Given the rarity of the condition, it is difficult to ascertain the incidence or prevalence of IgG4-RLD [
3]. However, it has been reported that lung involvement is found in as many as 54% of patients with autoimmune pancreatitis [
23]. Notably, approximately 50% of the patients were diagnosed with IgG4-RLD without the involvement of any other organ in our study. If lung involvement is investigated in the presence of confirmed IgG4-RD in another organ, the diagnosis of IgG4-RLD may not be so difficult. However, when the lung is the only organ involved, diagnosis becomes much more challenging due to its multifarious radiologic manifestation [
3] and the difficulty in detecting a typical characteristic histopathologic feature such as storiform fibrosis in IgG4-RLD [
2,
14]. Thus, there is a possibility of underdiagnosis of the disease.
The purpose of IgG4-RLD treatment includes reducing respiratory symptoms and preventing disease progression that may lead to lung fibrosis and subsequent respiratory function decline [
24]. Nevertheless, long-term clinical course and treatment outcomes have not been evaluated to date, and differences in these according to the radiologic subtypes remain unclear. According to the results of our study, the prognosis was favorable overall although differences were noted between the subgroups with regards to radiologic improvement and maintenance of lung function. Given the favorable clinical course in IgG4-RLD shown in our study, differentiating from other disorders that mimic IgG4-RLD but have different outcomes should be emphasized. Sarcoidosis involves multiple organs and may have similar image findings such as lymphadenopathy and thickening of peribronchovascular bundles [
24,
25]. Lung lesions in multicentric Castleman’s disease and ANCA-associated vasculitis may show IgG4-positive lymphoplasmacytic infiltration [
24]. In particular, malignancy should be considered as a differential diagnosis because peritumoral IgG4-positive cell infiltration is often observed in the periphery of a cancer [
14].
In our study, five patients (13.5%) were categorized as alveolar interstitial type, of which four demonstrated lung involvement only. Isolated IgG4-related interstitial pneumonia has been reported previously [
26,
27]. The rate of patients achieving CR or PR was the lowest in the alveolar interstitial type (40.0%). However, no patients showed PD or relapse. Furthermore, when the lung function changes were assessed in this type (4 out of 5 patients), an improvement in lung function parameters was observed. The FVC was higher than the baseline value by more than 10% in all patients. Thus, alveolar interstitial type does not seem to convey a particularly worse prognosis when compared with the other types.
Baseline pulmonary function test results and their longitudinal changes were different according to the radiologic classification. Alveolar consolidative, bronchovascular, and alveolar interstitial types showed overall lower values at the time of diagnosis compared to the other types. In theory, these types may result in poorer lung function compared to the others due to a larger area involved in alveolar consolidative type, bronchial narrowing in bronchovascular type, and interstitial thickening in alveolar interstitial type. Despite the lower initial measurements at the time of diagnosis, the lung function parameters improved or at least remained stable in most patients after treatment, suggesting a favorable outcome.
In our study, azathioprine was administered in combination with prednisone in 15 patients. Although various steroid-sparing agents such as azathioprine have been used in the treatment of IgG4-RD [
28], evidence supporting their use is limited [
1]. As in the cases of our study, whether to use an additional immunosuppressive agent is often decided by the treating physician; it was reported that approximately a half of the experts (46%) suggested that some patients require steroid-sparing immunosuppressive agent in addition to glucocorticoids from the start of treatment whereas others did not agree with the combination treatment [
29]. It has also not been determined if immunosuppressive agents are required in patients who relapsed. Further studies are warranted to define the role of steroid-sparing immunosuppressive agents in the treatment of IgG4-RLD.
The strength of our study is that it involved the largest number of patients with IgG4-RLD with their long-term clinical outcomes. To the best of our knowledge, this is the only study that presents the long-term follow-up data with a median follow-up duration of 38 months. However, limitations should also be noted. First, this study was a retrospective study performed at two hospitals and this may question the generalizability of our findings. However, the demographic characteristics of patients [
24,
30] and relapse rate [
30,
31] were found to be similar to those of previous reports. Second, 10 patients with IgG4-RLD were diagnosed clinically without biopsy. Although there is a possibility that the lung lesions might have not been IgG4-RLD manifestations, lung involvement was confirmed only when there was a pathologically confirmed extrapulmonary IgG4-RD as well as compatible chest CT findings without alternative explanation. Third, some pathology specimens were obtained via bronchoscopic or percutaneous needle biopsy instead of surgical lung biopsy. One may argue non-surgical biopsy specimens are inadequate to make a pathological diagnosis of IgG4-RLD. The optimal biopsy method in IgG4-RLD is not determined. According to the consensus statement on the pathology of IgG4-related disease, needle biopsies often provide sufficient proof for the diagnosis of IgG4-RD and exclusion of competing diagnoses [
14]. In addition, the method of biopsy may vary among patients according to the location and radiologic manifestation of the target lesion [
2]. In fact, patients who underwent transbronchial lung biopsy in our study had alveolar consolidative (n = 3) and bronchovascular type (n = 1) for which the bronchoscopic approach may be appropriate to obtain tissue. Furthermore, other possible causes for the abnormalities in the lungs such as infection were excluded, and the observed steroid responsiveness supports the diagnosis. Fourth, patients with IgG4-RLD may present with other clinical manifestations which do not fit into the classification we used in this study. Previous case reports have shown that IgG4-RLD may have rare presentations such as pleural effusion [
32] and pulmonary vascular involvement [
33]. Because of the rarity of the disease, the clinical course and long-term outcomes of these subtypes could not be evaluated in this study.
In conclusion, most patients with IgG4-RLD showed favorable outcomes with regards to radiologic improvement and maintenance of pulmonary functions, although there was a difference according to the radiologic subtype. Further studies are warranted to identify an appropriate treatment strategy that maximizes remission and minimizes relapse in different radiologic subtypes.
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