Etiology of IgG4-Related Pulmonary Hypertension

Dear Editor,

IgG4-related disease (IgG4-RD) affects every single organ of the body [1-6], but little is known about pulmonary hypertension associated with IgG4-RD. Appropriate treatment is generally crucial for the prevention of irreversible organ damage in IgG4-RD [7-10], but especially with pulmonary hypertension because it is frequently serious and fatal.

We conducted a literature review of IgG4-related pulmonary hypertension and identified a total of 7 patients [1, 11-15], who satisfied the IgG4-RD comprehensive diagnostic criteria [16] (Fig. 1a). Their age ranged from 22 to 69 years. Four were male and 3 were female. All patients presented with dyspnea. Pulmonary hypertension was assessed by right heart catheterization in 5 patients and by echocardiography in 2 patients (Fig. 1a). Remarkably, those cases could be classified into two types based on imaging possibly related to causal etiology: (i) “IgG4-related fibrosing mediastinitis type” or (ii) “IgG4-related lung disease type” as shown in Figure 1a.

IgG4-related fibrosing mediastinitis lesion was determined by tumefactive mediastinal lesions in the images. All 5 patients with IgG4-related fibrosing mediastinitis showed no evidence of IgG4-related lung disease lesions (Fig. 1a). On the other hand, the 2 patients with IgG4-related lung disease did not show any evidence of IgG4-related mediastinitis lesions as well as pulmonary large-vessel compression in the images (Fig. 1a). This suggests that there are 2 different etiologies of IgG4-related pulmonary hypertension (Fig. 1b). In the IgG4-related fibrosing mediastinitis type, the proximal medium-to-large-sized pulmonary artery was mechanically compressed from the outside by tumefactive mass lesions within the mediastinal space. In the IgG4-related lung disease type, the intense lymphoplasmacytic infiltration secondary to obliterative phlebitis or obliterative arteritis in the lungs occupied distal pulmonary microvessels as a causal etiology of pulmonary hypertension [1].

While IgG4-related fibrosing mediastinitis has recently been proposed as a possible etiology of idiopathic fibrosing mediastinitis [5], fibrosing mediastinitis itself is classically known as a cause of pulmonary hypertension by compressing the medium-to-large-sized proximal pulmonary artery [17]. IgG4-related fibrosing mediastinitis shows elevated levels of serum C-reactive protein without multi-organ involvement [4], in line with the cases with pulmonary hypertension of “IgG4-related fibrosing mediastinitis type” (Fig. 1a). On the other hand, IgG4-related lung disease causes obliterative vasculitis of microvessels, which can lead to pulmonary hypertension. A study examined the tissue sections from patients with IgG4-related lung disease and revealed the frequent presence of obliterative vasculitis lesions in the lungs [18].

IgG4-related lung disease frequently presents with multiple organ involvements and normal serum C-reactive protein, which is consistent with the IgG4-related lung disease type in our present study (Fig. 1a). Moreover, we need to note that there is the possibility of another etiology of pulmonary hypertension which has yet to be reported; pulmonary vasculitis due to IgG4-RD. Pulmonary vasculitis has been reported to cause pulmonary hypertension in other vasculitic diseases [19, 20], and IgG4-RD causes systemic vasculitis [6]. The reason for no previous reports with this etiology might be the difficulty in obtaining specimens of pulmonary vessels for histopathological confirmation.

Glucocorticoid treatment is usually effective for patients with IgG4-RD [2]. Importantly, all 7 patients with IgG4-related pulmonary hypertension responded well to immunosuppressive treatments including glucocorticoid without pulmonary vasodilators such as prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors (Fig. 1a). Therefore, we need to be attentive to clinical manifestations of IgG4-related pulmonary hypertension to avoid a delay in diagnosis and immunosuppressive treatment initiation for this serious but treatable organ involvement. Echocardiography, right heart catheterization, and biopsy should be considered in cases of unexplained dyspnea complicated with IgG4-related mediastinitis or lung disease.

IgG4-RD frequently relapses during glucocorticoid tapering [21], and long-term outcome remains unclear particularly in IgG4-related pulmonary hypertension. Further accumulations of cases and longitudinal studies are needed for a better understanding of the disease and for establishing treatment strategies for patients with IgG4-related pulmonary hypertension.