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□ CASE REPORT □

Pulmonary Arterial Hypertension Associatedwith IgG4-related Disease

Motoko Ishida 1, Tomoya Miyamura 1, Shinji Sato 2, Daisaku Kimura 1 and Eiichi Suematsu 1

Abstract

A 22-year-old woman with generalized lymphadenopathy and symmetrical swelling of the lacrimal and

submandibular glands was diagnosed with IgG4-related disease. Biopsy specimens of the lips, lymph nodes,

gastrointestinal tract and bronchus showed IgG4-positive plasma cell infiltration. Echocardiography and right

heart catheterization revealed a high mean pulmonary arterial pressure. The patient was treated with 50 mg of

prednisolone daily and rapidly improved. This is the first reported case of pulmonary arterial hypertension as-

sociated with IgG4-related disease.

Key words: IgG4-related disease, pulmonary arterial hypertension

(Intern Med 53: 493-497, 2014)(DOI: 10.2169/internalmedicine.53.0154)

Introduction

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is

a recently described entity characterized by multiorgan

IgG4-positive plasma cell infiltration and high serum IgG4

concentrations (1). Umehara et al. described a consensus re-

garding the diagnostic criteria for IgG4-RD in 2011 (2).

IgG4-RD includes Mikulicz’s disease, orbital pseudotumors,

autoimmune pancreatitis, sclerosing cholangitis, prostatitis,

pulmonary disease, interstitial nephritis, hypophysitis and in-

flammatory aneurysms. We herein report a patient with

IgG4-RD with pulmonary arterial hypertension (PAH) and

multiple organ involvement who was successfully treated

with oral glucocorticoids.

Case Report

A 22-year-old woman was admitted to our hospital in

April 2011 due to generalized lymphadenopathy and hyper-

γ-globulinemia. She complained of shortness of breath on

effort. She had a history of bronchial asthma starting at 5

years of age; however, she had not experienced a clear epi-

sode of a severe asthma attack for several years. On a physi-

cal examination, there was symmetrical swelling of the lac-

rimal and submandibular glands and parotid glands that had

been present for several years. Chest auscultation revealed

coarse inspiratory crackles over the patient’s right upper

chest and abnormal increased splitting of the second heart

sound (IIA<IIP) on the second left sternal border with no

heart murmurs. The patient had generalized lymphadenopa-

thy, with lymph nodes measuring 5-20 mm in diameter in

the neck, bilateral axillae and bilateral inguinal regions.

There was no skin edema, eruptions, Raynaud’s phenome-

non or sclerodactyly. A urinalysis was normal. Blood testing

showed the following results: leukocytes, 9,000/μL; neutro-

phils, 3,501/μL; lymphocytes, 2,340/μL; eosinophils, 2,520/

μL; hemoglobin, 10.2 g/dL; platelets, 29.5×104/μL; total pro-

tein, 10.7 g/dL (normal range, 6.7-8.3 g/dL); albumin, 2.4 g/

dL (4.0-5.0 g/dL); CK, 161 IU/L (45-165 U/mL); KL-6,

283 U/mL (<500 U/mL); surfactant protein-D, 101 ng/mL

(<110 ng/mL); brain natriuretic peptide, 43.8 pg/dL; C-

reactive protein, 0.09 mg/dL (<0.30 mg/dL); CH50, <15 IU/

mL (30-45 IU/mL); C3, 30 mg/dL (63-134 mg/dL); C4, 2

mg/dL (13-36 mg/dL); IgE, 1,388 IU/mL (<300 IU/mL);

IgG, 7,183 mg/dL (870-1,700 mg/dL); IgG4, 3,230 mg/dL

(<108 mg/dL); and soluble interleukin 2 receptor, 1,490 U/

mL (124-466 U/mL). Serological data were negative for an-

tinuclear antibodies (ANA), anti-U1RNP antibodies, anti-SS-

A antibodies, anti-ds DNA antibodies, myeloperoxidase anti-

１Department of Internal Medicine and Rheumatology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Japan

and ２Department of Cardiology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Japan

Received for publication January 15, 2013; Accepted for publication September 17, 2013

Correspondence to Dr. Motoko Ishida, m-ishida@kyumed.jp

Intern Med 53: 493-497, 2014 DOI: 10.2169/internalmedicine.53.0154

494

Figure　1.　Chest computed tomography image showing consolidation, solid nodules and irregular thickening of bronchovascular bundles and interlobular septa (a, b) . A remarkable improvement was observed two months after the initiation of corticosteroid therapy (c, d) .

(a)

(c)

(b)

(d)

neutrophil cytoplasmic antibodies and proteinase 3 anti-

neutrophil cytoplasmic antibodies. However, the levels of

rheumatoid factor (RF) and complement-binding immune

complexes were elevated to 101 IU/mL (<15 IU/mL) and

3.9 μg/mL (<1.5 μg/mL), respectively. The results of a

blood gas analysis were almost within the normal ranges. A

chest X-ray showed bilateral infiltration, cardiac enlargement

and an enlarged left main pulmonary artery. Computed to-

mography (CT) revealed solid nodules with irregular thick-

ening of bronchovascular bundles and interlobular septa in

both lung fields (Fig. 1a, b). CT also disclosed enlargement

of the superficial, mediastinal, parabronchial and para-aortic

lymph nodes and thickening of the gastric wall. There was

no evidence of pancreatitis, biliary tract disease or interstitial

nephritis. Ga-67 scintigraphy disclosed a positive image of

the bilateral submandibular glands. We did not perform

fluorodeoxyglucose positron emission tomography.

A lymph node biopsy showed fibrosis; however, there

was no characteristic storiform fibrosis (Fig. 2a, b). Immu-

nohistochemical staining showed dense lymphoplasmacytic

infiltration with IgG4-positive plasma cells (Fig. 2c, d). The

ratio of IgG4-positive to IgG-positive plasma cells (IgG4+/

IgG+) was approximately 50%. A histopathological examina-

tion of subsequent lip biopsy, transbronchial lung biopsy

and esophageal and gastroduodenal biopsy specimens also

showed lymphoplasmacytic infiltration with IgG4-positive

plasma cells. The IgG4+/IgG+ plasma cell ratio was approxi-

mately 20% in the lip biopsy specimen (Fig. 2e, f) and 40%

in the biopsy specimens obtained from the esophagus, stom-

ach and duodenum (Fig. 2g); the ratio could not be deter-

mined in the lung biopsy specimen (Fig. 2h). The lip biopsy

specimen showed fibrosis; however, there was no oblitera-

tive phlebitis or eosinophil infiltration (Fig. 2i). Based on

these findings, we diagnosed the patient with IgG4-RD with

Mikulicz’s disease, gastrointestinal tract disease and lympha-

denopathy. We concluded that the findings of the lung bi-

opsy specimen were highly suspicious for IgG4-related pul-

monary disease (IgG4-PD).

The patient’s shortness of breath on effort was catego-

rized as World Health Organization class II. Her 6-minute

walking distance was 400 m. Respiratory function test re-

sults were almost normal, including the diffusing capacity

for carbon monoxide/alveolar volume (5.71 mL/min/mmHg/

L). Electrocardiography showed pulmonary P waves, a nor-

mal axis and normal T waves. Echocardiography disclosed

tricuspid regurgitation with an increased tricuspid pressure

gradient (52 mmHg); however, there were no signs of re-

traction of the ventricular septum. The chamber size, ejec-

tion fraction and valvular movements were normal (Fig. 3a).

Right heart catheterization showed a mean pulmonary arte-

rial pressure of 40 mmHg and a mean pulmonary capillary

wedge pressure of 17 mmHg. The pulmonary vascular resis-

tance index was 399 dyne/sec/cm-5/M2 (normal, 123±54

dyne/sec/cm-5/M2) and did not improve with supplemental

oxygen. These findings satisfied the criteria for PAH.

The patient was treated with 50 mg of prednisolone daily

Intern Med 53: 493-497, 2014 DOI: 10.2169/internalmedicine.53.0154

495

Figure　2.　Hematoxylin and Eosin (HE) staining and immunohistochemical staining of the biopsy specimens. HE staining of an inguinal lymph node biopsy specimen showing massive infiltration of plasma cells without malignant cells (a, original magnification, ×40; inset, ×400) . Masson trichrome staining of a lymph node biopsy specimen showing fibrosis (b, ×40) . IgG immunostaining (c, ×200) and IgG4 immunostaining (d, ×200) of the lymph node biopsy specimen showing infiltration of IgG- and IgG4-positive plasma cells (the IgG4+/IgG+ plasma cell ratio was approximately 50%) . IgG im-munostaining (e, ×400) and IgG4 immunostaining (f, ×400) of a lip biopsy specimen showing infiltra-tion of IgG- and IgG4-positive plasma cells (the IgG4+/IgG+ plasma cell ratio was approximately 20%) . IgG4 immunostaining of the stomach biopsy (g, ×200) and transbronchial lung biopsy (h, ×200) specimens showing IgG4-positive plasma cell infiltration. The lip biopsy specimen also exhibits fibrosis (i, Masson trichrome stain, ×100) .

(a)

(i)(h)

(g)(f)(e)

(d)

(b)

(c)

Intern Med 53: 493-497, 2014 DOI: 10.2169/internalmedicine.53.0154

496

Figure　3.　Echocardiography showing tricuspid regurgitation with a tricuspid pressure gradient of 52 mmHg (a) . One month after the initiation of treatment, the tricuspid pressure gradient had de-creased to <17 mmHg (b) .

(a) (b)

for pulmonary disease and PAH. The swelling of the lacri-

mal glands, submandibular glands and lymph nodes rapidly

decreased over the first week. After one month, the serum

IgG4 concentration decreased to 504 mg/dL. The serum

IgG, IgE and soluble interleukin 2 receptor concentrations

also decreased and the complement concentrations (CH50,

C3 and C4) increased after one month. Follow-up chest CT

showed a remarkable reduction in the abnormal areas in the

lung fields (Fig. 1c, d). Echocardiography demonstrated that

the tricuspid pressure gradient was normal (<17 mmHg)

(Fig. 3b).

Discussion

IgG4-RD was first described in 2001 as autoimmune pan-

creatitis with an elevated serum IgG4 concentration (1).

IgG4-RD has subsequently been found in various target or-

gans. Considering the histological and physiological findings

of our patient, we diagnosed her with IgG4-RD with

Mikulicz’s disease, pulmonary disease, lymphadenopathy,

gastrointestinal tract disease and PAH. The latest clinical

classification of pulmonary hypertension was published in

2009 (3). We concluded that the patient had PAH because

the laboratory data and results of the blood gas analysis, res-

piratory function tests and right heart catheterization did not

suggest pulmonary hypertension due to lung disease and/or

hypoxia and chronic thromboembolic pulmonary hyperten-

sion. In the present case, the mean pulmonary capillary

wedge pressure was 17 mmHg. We considered the possibil-

ity of cardiac dysfunction due to myocardial infiltration by

IgG4-positive plasma cells; however, we were unfortunately

unable to biopsy the myocardium. However, there was no

evidence of myocardial damage or left heart disease. We

concluded that the increased mean pulmonary capillary

wedge pressure was within the margin of error of the test

and excluded a diagnosis of pulmonary hypertension due to

left heart disease.

Galiè et al. reported that most patients with IgG4-PD are

positive for RF and ANA and many exhibit hypocomple-

mentemia with a high serum IgE concentration (4). The

presence of ANA, RF, IgG and complement fraction depos-

its in the walls of the pulmonary vessels suggests an immu-

nological mechanism. Some reports have indicated that pa-

tients with IgG4-PD demonstrate diffuse lymphoplasmacytic

infiltration with irregular fibrosis and obliterative vascular

changes, such as obliterating phlebitis and arteritis, with

eosinophil infiltration (5, 6). Abundant infiltration of IgG4-

positive plasma cells and the presence of obliterative phlebi-

tis have also been reported in patients with IgG4-related aor-

titis (7). Interestingly, our patient exhibited an increased

transpulmonary pressure gradient (>12 mmHg). A previous

report showed that such increases in pressure result from

structural changes in the pulmonary arteries and capillar-

ies (8). We speculate that this finding indicates damage to

the pulmonary arteries. The pathophysiological mechanisms

underlying the development of PAH remain unknown, even

in patients with connective tissue disease. Although it is dif-

ficult to prove the occurrence of PAH, we consider that

obliterative vasculitis of the pulmonary arteries due to an

immunological mechanism may have played a role in the

pathogenesis of PAH in our patient.

The primary aim of treatment was to improve the pa-

tient’s PAH and pulmonary disease associated with IgG4-

RD. Glucocorticoids are considered to be effective in treat-

ing IgG4-RD. Case reports and literature reviews have sug-

gested that glucocorticoid therapy combined with vasodila-

tors may be effective for the treatment of connective tissue

disease PAH, at least in the short term (9). Our patient re-

sponded well, and her abnormal test results normalized fol-

lowing glucocorticoid treatment. Furthermore, the PAH also

improved. Our findings suggest that the PAH was associated

with IgG4-RD.

Intern Med 53: 493-497, 2014 DOI: 10.2169/internalmedicine.53.0154

497

In summary, we herein described a patient with IgG4-RD

with multiorgan involvement, including PAH, who was suc-

cessfully treated with oral prednisolone. This is the first re-

ported case of PAH associated with IgG4-RD and is inter-

esting due to the presence of multiorgan plasma cell infiltra-

tion. Although we were unable to prove our speculation

with histological findings, a PAH mechanism is hypothe-

sized to involve obliterative arteritis of the pulmonary arter-

ies in the present patient. Her response to treatment supports

this possibility.

The authors state that they have no Conflict of Interest (COI).

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