IgG4-related diseases
I. Overview
IgG4-associated disease is a newly recognized disease of unknown etiology that can involve multiple organs or tissues and is a chronic, progressive autoimmune disease with the following characteristics: tumor-like damage, dense lymphoplasmacytic infiltration enriched with IgG4(+) plasma cells, matted fibrosis, and usually accompanied by elevated serum IgG4 levels. IgG4RD is seen in almost any organ system: biliary tract, salivary glands, periocular tissues, kidneys, lungs, lymph nodes, meninges, aorta, breast, prostate, thyroid, pericardium and skin.1-5 And regardless of which organ is involved, the histopathological features are highly similar.
With the recognition of IgG4RD, a number of diseases long considered as single organ involvement have been classified into the spectrum of IgG4-related diseases, such as Mikulicz syndrome, Kuttner tumor, Riedel’s thyroiditis, and retroperitoneal fibrosis. The two most common clinical manifestations of IgG4RD are.
1, type I autoimmune pancreatitis (IgG4-associated pancreatitis).
2, salivary gland diseases (e.g. Mikulicz syndrome, sclerosing salpingitis or Kuttner’s tumor). In fact, many empirical findings regarding IgG4RD have been derived from studies of these two types of diseases.
Because IgG4RD was not recognized as a systemic disease until 2003 and there were no uniform diagnostic criteria for a long time, little is known about its incidence, and only Japan has reported an incidence of IgG4RD in Japan of about 0.28-1.08/100, 0006.
II. Pathological characteristics
Histopathologic analysis of biopsy specimens is the cornerstone of the diagnosis of IgG4RD, which is characterized by dense lymphoplasmacytic infiltrates with a mats-like distribution, occlusive phlebitis, and mild to moderate eosinophilic infiltrates. The inflammatory damage usually forms tumor-like masses within the tissue, thereby destroying the affected organ. Neutrophils with granulomas are generally extremely rare in IgG4RD tissues, except in some exceptional cases.
In addition to morphology, immunohistochemistry is required to aid in the diagnosis of IgG4RD. The inflammatory infiltrate consists of a mixture of T and B lymphocytes, with T cells in a scattered distribution and B cells usually clustered in the germinal center. Various isoforms of immunoglobulins can be seen in the affected tissue, but IgG4 accounts for the major part. As many inflammatory infiltrates can also be seen with a small number of IgG4(+) cells, a quantitative definition of IgG4 is also needed. On the one hand, in absolute numbers, the threshold for the number of IgG4(+) plasma cells identified in the literature fluctuates between 10 and 50/HPF; on the other hand, in relative numbers, the ratio of Ig4(+) plasma cells to IgG(+) plasma cells is more useful for the diagnosis of IgG4RD if it is greater than 50%. especially in the advanced stages of the disease, when only a small number of plasma cells are present in the tissue and fibrosis The ratio of IgG4 to IgG will play a key role in the diagnosis, especially in advanced stages of the disease when only a small number of plasma cells are present in the tissue and fibrosis becomes the main component.
Clinical features of organ involvement
IgG4-related diseases usually have a subacute onset, and most patients do not have systemic symptoms, are not usually accompanied by fever or elevated C-reactive protein, and are often inadvertently diagnosed during routine imaging or pathological analysis. Some patients are confined to a single organ, while others have other organ involvement in addition to the main organ involvement. Very few patients have spontaneous improvement or remission, while others require pharmacological treatment.
IgG4RD usually has two clinical manifestations.
1. tumor-like damage: it can lead to tumor-like enlargement of organs, such as pancreatic enlargement in autoimmune pancreatitis and salivary gland enlargement in Mikulicz syndrome.
2. allergic diseases: many patients with IgG4RD have allergic features such as atopy, eczema, asthma and elevated blood eosinophils. In patients with IgG4RD, up to 40% have a combination of allergic diseases such as bronchial asthma or chronic sinusitis. Although IgG4RD develops subacutely, if left untreated, it can still lead to tissue damage and even organ failure.
IV. , serum blood characteristics
In the normal population, IgG4 accounts for less than 5% of total IgG and is the subtype with the lowest proportion. Most patients with IgG4-related diseases have elevated serum IgG4 levels, but there are still about 30% of patients with pathologically confirmed IgG4RD who have normal serum IgG4 levels. A series of monitoring of patients with elevated serum IgG4 levels showed that although the majority of patients had lower serum IgG4 levels after hormone therapy than before treatment, most still had above normal values. About 30% of patients with persistently elevated serum IgG4 levels had relapses, while those with normal serum IgG4 levels also had a relapse rate of about 10%; some studies also reported that there was no clear relationship between relapse and IgG4 recovery levels.
In addition, elevated serum IgG4 levels are not specific to IgG4RD, but can also be seen in a number of other diseases, including allergic diseases, bacterial, fungal and parasitic infections, Rosai-Dorfman disease, ANCA-associated vasculitis, polymyositis/dermatomyositis, pancreatic cancer, hepatobiliary cancer and lung cancer. Clinical use of 1350 mg/L is generally used as the threshold for whether serum IgG4 levels are elevated, but caution is needed in interpreting its significance.
V. Treatment and prognosis
Not all IgG4RD requires treatment; for example, IgG4-associated lymphadenopathy can persist for decades without significant progression, and follow-up is sufficient for these patients; however, if important organs are involved, they should be treated aggressively. The use, dosage, and duration of corticosteroids as the drug of choice remain controversial. Consensus guidelines in Japan recommend the initial administration of prednisolone 0.6 mg/kg.day for 2-4 weeks in autoimmune pancreatitis, followed by a reduction to 5 mg/day over 3-6 months, and then 2.5-5 mg/day for maintenance for up to 3 years. The literature also suggests that hormones be tapered off within 3 months. Immunosuppressive agents such as azathioprine, morte-macrolimus and methotrexate are usually used in combination with hormone tapering or as maintenance therapy after remission.
Rituximab, a CD20 monoclonal antibody, is widely used in the treatment of non-Hodgkin’s lymphoma and is now also tried in relapsed or refractory IgG4RD. studies have found that IgG4RD treatment with rituximab resulted in a rapid reduction in serum IgG4 levels and a significant improvement in clinical symptoms within a few weeks.
Patients with IgG4RD are more likely to develop malignant tumors, including lung cancer, colon cancer and lymphoma, compared to the normal population, for reasons that are currently unknown. Therefore, patients with IgG4RD always need to be alert to the possibility of combined malignancies, both at the time of diagnosis and during follow-up.
IgG4-related lung diseases
I. Overview
IgG4-associated lung disease is a manifestation of IgG4-associated disease involving the lung or pleura. Taniguchi et al. first reported autoimmune pancreatitis combined with interstitial pneumonia in 2004, which was the earliest report of IgG4RLD. From 2004 to 2012, only a few dozen cases of IgG4RLD could be found in the English literature in its entirety. Although fewer cases have been reported in the literature, the incidence of IgG4RLD may not be as low as expected as the understanding of IgG4 increases. In fact, in a study involving 114 IgG4RD, 14% of patients had combined pulmonary or pleural lesions, while another imaging study of 90 autoimmune pancreatitis showed the combined presence of pulmonary damage in 54% of patients, with intrathoracic lymphadenopathy being the most common presentation.The forms of intrathoracic involvement in IgG4-related disease are shown in Table 1.
II. Clinical features
Approximately half of the patients with IgG4RLD have concomitant respiratory symptoms, including cough, chest pain, bloody sputum, and shortness of breath after activity, while the other half have only imaging abnormalities without respiratory symptoms. Similar to IgG4RD of other organs, systemic symptoms such as fever, weight loss, and sweating are less common. Overall, the clinical pulmonary manifestations of IgG4RLD are rather nonspecific, and it is difficult to distinguish it from other pulmonary diseases by this.
Histopathology
A summary of the histopathology of the few cases of IgG4RLD reveals the following characteristics of the lung tissue: diffuse lymphoplasmacytic infiltration, irregular fibrosis, intimal inflammation without necrosis, and a significant increase in the absolute and relative number of IgG4(+) plasma cells. In terms of cellular composition, plasma cells are the main component, followed by lymphocytes and histiocytes; in some patients eosinophils can be evident, but granulomas are extremely rare. As can be seen, the pathological features of IgG4RLD are basically similar to those of other sites, but also slightly different: compared to the histopathology of autoimmune pancreatitis, the matting-like changes in lung tissue are less pronounced, while collagen fibrosis and fibroblast proliferation are more prominent; in addition, only phlebitis is seen in pancreatic tissue, while arterial and venous involvement is often seen in lung tissue.
In patients with parenchymal lung involvement, the histopathology can sometimes be consistent with organizing pneumonia (OP) or nonspecific interstitial pneumonia (NSIP). When the pleura is involved, the pathology shows significant pleural thickening due to sclerosing inflammation. In the mural pleura, sclerosing inflammation may extend to the subpleural fibrous and adipose tissue, while subpleural lung tissue may be involved when the dirty pleura is compromised.
IV. Imaging features
Intrathoracic involvement of IgG4RLD includes the lung parenchyma, airways, pleura, and mediastinum, and may involve only one site or multiple sites simultaneously.
The images of lung parenchymal involvement may show the following four patterns.
1, solid nodular mass type.
2, rounded ground glass type.
3, alveolar interstitial type.
4, bronchial vascular bundle type.
The first two are alveolar cavity lesions with increased density, varying in size, and may be solitary or multiple, without a clear lobar tendency. The solid nodular mass type is to be distinguished from malignancy, while the ground glass style is to be distinguished from alveolar cell carcinoma. These two forms are often clinically confirmed by wedge resection or lobectomy because they are indistinguishable from tumors and eventually pathologically confirmed. The latter two are interstitial lesions that can present as lattices, honeycombs, irregular cords, and thickening of lobular septa with bronchial vascular bundles. In fact, it is impossible to distinguish from certain idiopathic interstitial pneumonias, such as idiopathic interstitial pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), cryptogenic mechanized pneumonia (COP), and nodular disease, on imaging alone.
Airway involvement is rare. Ito et al. described a 63-year-old woman diagnosed with autoimmune pancreatitis in whom tracheobronchial stenosis with mucosal congestion and edema was seen on tracheoscopy; and mediastinal lymph node enlargement and thickened bronchial vascular bundles were also seen on CT. Another condition is the narrowing of the airway following compression and traction, such as compression of the airway by mediastinal fibrosis and traction bronchiectasis due to interstitial lung lesions.
In some patients, the pleura is the main site of involvement, manifesting as nodular damage on the dirty pleura or mural pleura, with the combination of pleural effusion being less common.17 Pathologic features are as described previously.
Mediastinal or hilar lymph node enlargement may be present in 40-90% of patients with IgG4RD and is often confirmed by CT or PET. A proportion of fibrosing mediastinitis is eventually confirmed as IgG4-related disease.
V. Diagnostic criteria
Among the organs involved in IgG4RD, only IgG4-related Mikulicz disease, IgG4-related type I autoimmune pancreatitis and IgG4-related kidney disease have their own diagnostic criteria. In view of this, the Japanese IgG4 group released universal clinical diagnostic criteria for IgG4-related diseases in 2011. Since IgG4RLD does not yet have its own organ-specific diagnostic criteria, this diagnostic criteria can be referred to for clinical diagnosis. The core of this diagnostic criteria is the combination of clinical manifestations, serum IgG4 levels and pathological features, and the distinction between diagnosis as confirmed (clinical, serum and pathological are available), probable (lack of serum) and suspicious (lack of pathology). Importantly, it must be differentiated from malignant tumors and similar diseases.
VI. Treatment and prognosis
IgG4RLD usually responds well to hormonal therapy, similar to IgG4RD in other sites. There are no relevant studies on hormonal treatment regimens, but the initial dose of 30 mg/day to 1 mg/kg.day is generally given, and if the treatment is effective, significant symptomatic relief is seen within 2 weeks. The hormone can be tapered over the following months, with close monitoring for symptom relief and recurrence. Once the hormone dose is reduced to ≤10 mg/day, maintenance for several months may be considered to reduce the recurrence rate. In patients who have complete surgical resection of a limited lesion, hormone therapy may no longer be required, but there are patients who have relapsed after surgical resection.
Similar to other sites of IgG4RD, there is still a lack of experience with immunosuppressive therapy in IgG4RLD. In the literature, cyclosporine A and bortezomib have each been used in IgG4RLD, and we have clinically tried morte-macrolimus in combination with morte-macrolimus in IgG4RLD where hormonal therapy has been ineffective, but given the short history of IgG4RLD, there is a lack of experience with the prognosis of this disease. Similar to other sites of IgG4RD, the incidence of malignancy is also increased in IgG4RLD and needs to be taken into account.