Background
Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a recently recognized fibroinflammatory condition that is characterized by tumefactive involvement of single or multiple organs, marked lymphoplasmacytic infiltrates and fibrosis with abundant IgG4-positive plasma cells. IgG4-RD is often associated with elevated serum IgG4 concentrations [
1]. Since Hamano and colleagues (2001) first reported elevated serum IgG4 concentration in autoimmune pancreatitis [
2], IgG4-RD has been diagnosed in virtually every organ system.
IgG4-RD lung involvement was first reported in 2004 by Taniguchi and colleagues in a patient with interstitial pneumonia, autoimmune pancreatitis and IgG4-positive plasma cells in the interstitium [
3]. Although lung involvement has been reported in many IgG4-RD studies since then, the majority of them were not confirmed by lung biopsies. To our knowledge, the only two biopsy-proven studies of IgG4-related lung disease (IgG4-RLD) were retrospective and performed in Japan [
4,
5]. However, both studies included patients diagnosed via transbronchial lung biopsy. In our opinion, the lung specimen from transbronchial lung biopsy is too small to make a pathological diagnosis of IgG4-RLD. Therefore, we made this study including 17 cases of biopsy-proven IgG4-RLD, with specimens obtained via thoracotomy, video-assisted thoracoscopic surgery (VATS) or percutaneous transthoracic core-needle lung biopsy, to better understand this rare disease.
Discussion
As a newly recognized disease, IgG4-RLD is still not well understood. In this retrospective study, we analyzed 17 cases of biopsy-proven IgG4-RLD in Chinese to identify the characteristics of this rare disease.
It is still unclear how often lung involvement occurs in patients with IgG4-RD. A retrospective study of 90 patients with autoimmune pancreatitis revealed that 54 % of patients had lung lesions [
8], but another study of 116 patients with biopsy-proven IgG4-RD revealed that biopsy-proven IgG4-RLD accounted for only approximately 10 % of the cases [
9]. The difference might be explained by following reasons: (i) In IgG4-RD patients with multiple organs involvement, lung specimen is less probably obtained because it is more invasive; (ii) Infection, aspiration pneumonia, pulmonary congestion, etc., also contribute to lung lesions in IgG4-RD patients, which might be misdiagnosed as lung involvement. Therefore, IgG4-RLD should be cautiously diagnosed without a pathological confirmation.
Compared with typical IgG4-RD involving two or more organs, this study showed uncommon extrapulmonary involvement in biopsy-proven IgG4-RLD, even with the help of PET. Although selection bias exists because patients with only lung involvement are more prone to receive a lung bi,opsy, this association indicates that lung involvement is probably over-estimated in IgG4-RD patients. Thus, pathological confirmation seems crucial for the diagnosis of IgG4-RLD.
The etiology of IgG4-RLD is still unknown. Autoimmunity is currently considered as the main pathogenic mechanism [
10]. Two patients were simultaneously diagnosed with primary Sjogren syndrome in this study, proving the relationship between IgG4-RLD and CTDs. An antibody against plasminogenbinding protein of
Helicobacter pylori has been identified in more than 90 % of patients with autoimmune pancreatitis [
11], proposing that infectious agents may play a role in the pathogenesis of IgG4-RD. But in our study, the association between IgG4-RLD and infection was not identified.
The clinical symptoms of IgG4-RLD depend on the lesion locations and are usually nonspecific [
12]. In our study, cough, dyspnea, chest pain and hemoptysis were the primary respiratory symptoms. Fever was observed in nearly half of the patients in this study indicating that constitutional symptoms are not as rare as previously thought [
13]. Although asymptomatic patients were also noted in our study, this phenomenon was not as common as reported in a previous Japanese study [
4].
One study of IgG4-RD patients demonstrated that serum IgG4 concentrations > 1350 mg/L and serum IgG4/IgG ratios > 8 % had a sensitivity of 97.0 and 95.5 %, respectively [
14]. However, in our study, the above criteria had a sensitivity of only 53.8 and 38.5 %, respectively, in IgG4-RLD patients. Serum IgG4 concentrations tend to be higher in patients with multiple organ involvement [
15]. Most patients in this study had only lung involvement, which may explain the discrepancy. Therefore, it is not appropriate to exclude a diagnosis of IgG4-RLD due to a normal serum IgG4 concentration. Inflammatory marker concentrations are higher in IgG4-RLD patients with fever, suggesting that constitutional symptoms are associated with disease severity. This phenomenon has been previously reported by our team [
16]. More aggressive treatment is usually necessary in these patients.
Inoue and colleagues summarized four patterns of CT findings: solid nodular, round-shaped ground glass opacity, alveolar interstitial, and bronchoalveolar [
17]. However, in our study, lobar or segmental consolidation was commonly seen. Ground glass opacity was patchy or diffuse. A bronchoalveolar manifestation was usually mixed with other more prominent patterns. Therefore, we prefer the following categories based on the main manifestation: (i) nodule or mass with spiculated margins; (ii) lobar or segmental consolidation with air bronchograms; (iii) ground glass opacity; (iv) alveolar interstitial; and (v) bronchovascular. However, a mixed pattern is commonly seen in IgG4-RLD patients. Mediastinal and/or hilar lymphadenopathy have been described in 40 to 90 % of patients with IgG4-RD in literature [
13], however, a lower rate of mediastinal or hilar lymph node involvement is found in this study, which may be explained by the reason that a restricted definition of lymphadenopathy is applied in this study, and might be associated with only one organ involvement in most cases.
The use of
18F-FDG PET uncovers more organ involvement than conventional evaluations in IgG4-RD patients [
18]. In IgG4-RD patients with involvement of two or more organs detected by PET, lung involvement occurs in approximately 25 % of cases [
18,
19]. However, abnormal uptake is not always associated with IgG4-RD involvement [
19], as demonstrated in our study. Therefore, the explanation of a high SUV should be cautious in IgG4-RD patients.
Although lung tissue obtained via a less-invasive, CT-guided, transthoracic core-needle biopsy is convenient, it failed to yield a definitive diagnosis in about one third of patients in this study. Thoracotomy or VATS can obtain more lung tissue, and are usually required to make a pathological diagnosis of IgG4-RLD. Transbronchial cryobiopsy is a new technique that allow to obtain larger and more qualified specimen than forceps biopsy. The use of cryobiopsy in diagnosing interstitial lung disease has been proved to be proper and promising [
20,
21]. However, the value of cryobiopsy in IgG4-RLD is still to be investigated.
To treat IgG4-RLD, corticosteroids are still the cornerstone therapy. The exact regimen for corticosteroids is still not detailed, but a regimen similar to extrapulmonary IgG4-RD therapy, such as during autoimmune pancreatitis, is recommended [
1]. In this study, all patients treated with steroids achieved remission, which confirmed the effectiveness of steroids for IgG4-RLD patients. Data regarding the use of immunosuppressants for IgG4-RLD is still sparse. Limited data and our study demonstrated positive results. Self-limitation has been occasionally observed in some IgG4-RLD patients [
22], and was also observed in our study. We recommend medical treatment in most patients. Only some specific patients can watch and wait, and long-term follow-ups are necessary.
The value of this study is limited by the small number of included patients. Our study show that although IgG4-RLD and typical IgG4-RD share common features, IgG4-RLD has its own distinct characteristics.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
XS participated in the design, summarized the data and drafted the manuscript. HL and RF performed the pathological examination of all specimens, and helped to draft the manuscript. MP, XH, PW, HW and WX collected data, and helped to draft the manuscript. JS participated in the design, and revised the manuscript critically. All authors read and approved the final manuscript.