A 68-year-old Japanese male patient was previously referred to a hospital in November 2012 for further investigation of bilateral hilar lymphadenopathy detected on a chest radiograph, which had been brought to notice at every annual medical checkup for the past 10 years but had not been examined further. The patient had no health complaints or particular medical history. He had worked in sales and had a 15 pack-year smoking history. Chest radiography revealed bilateral hilar lymphadenopathy and reticular shadows in the lower lung fields (Figure 1(a)). CT of the chest showed bilateral hilar and mediastinal lymphadenopathy (Figure 1(b)), and ground-glass opacities and reticular shadows distributed predominantly in both lower lobes (Figure 1(c)).
The vital signs were as follows: body temperature, 36.3 C; blood pressure, 142/72 mmHg; pulse, regular at 72 beats/min; oxygen saturation, 97% (ambient air). Physical examination revealed no abnormalities except for fine crackles in the bilateral lower lung fields. An ophthalmic examination showed no findings of granulomatous uveitis.
Laboratory investigations showed that the C-reactive protein (CRP) level was 0.09 mg/dL (normal < 0.3 mg/dL). Increased levels of lactate dehydrogenase (LDH) (233 U/L, normal < 211 U/L) and Krebs von den Lungen-6 (KL-6) (1121 U/mL, normal < 500 U/mL) were observed. Serological tests showed an anti-cyclic citrullinated peptide (CCP) antibody level of <1.2 U/mL (normal < 4.5 U/mL) and rheumatoid factor (RF) of <1.0 IU/mL (normal < 10.0 IU/mL). The patient's serum angiotensin-converting enzyme (ACE) level was 24.6 U/L (normal < 25.0 U/L).
Pulmonary function test (PFT) revealed mild reduction in FVC, 2.96 L (87.3% predicted), forced expiratory volume in 1 s (FEV1.0), 2.38 L (91.9% predicted), and diffusion capacity of the lung for carbon monoxide (DLCO), 14.03 mL/min/mmHg (83.4% predicted). Although electrocardiography showed complete right bundle branch block, the transthoracic echocardiogram revealed no abnormality.
Bronchoscopy revealed no macroscopic abnormalities. Bronchoalveolar lavage fluid (BALF) analysis showed a cell count of 2.43 x 105/mL, with a cell differentiation of 39.0% macrophages, 61.0% lymphocytes, and a CD4/CD8 ratio of 1.9. Histopathological examination of the transbronchial lung biopsy (TBLB) specimens (right B3b, right B8a) revealed noncaseating epithelioid granulomas in the perivascular connective tissue with lymphocyte infiltration, which was consistent with sarcoidosis (Figure 2(a) and (b)). Alcian blue-positive intraluminal fibrosis with mural incorporation was also observed (Figure 2(c)). No microorganisms, including Mycobacterium spp. and Propionibacterium acnes, were detected in BALF, tissue smears, or lung specimen cultures.
In May 2016, the patient was referred to our hospital. Due to a progressive decline in FVC (>200 mL/year) accompanied by a deterioration of the radiological findings, 25 mg/day oral prednisolone (PSL) was initiated in November 2017 followed by gradual tapering (Figure 3). In March 2020, when PSL was reduced to 12 mg/day, the patient noticed arthralgia and swelling in the right wrist followed by the right third PIP and the left wrist, but not in ankle joints. No skin lesions were found. Although a giant cell tumor of the tendon sheath was tentatively suspected, histopathological examination of the joint lesion showed proliferative synovial tissues with massive infiltration of mononuclear cells, but not granuloma formation or giant cell tumor. Mgnetic resonance imagine (MRI) revealed bone marrow edema in the carpal bones and synovitis in the right wrist. In addition to these findings, a high anti-CCP antibody titer (>500 U/mL) led to the diagnosis of RA in August 2020, though the clinical joint findings were not necessarily typical. Salazosulfapyridine was initiated for the joint lesions.
Gradual progression of dyspnea had been accompanied by a total of 900 mL reduction in FVC during the 4 years until August 2020 (Figure 3). Concordantly, honeycomb changes gradually developed on a series of CT scans over 5 years (Figure 4). Nintedanib was initiated for PF-ILD in January 2021, resulting in a slowing of the FVC decline without the incidence of adverse events such as diarrhea or liver injury. Although home oxygen therapy was introduced in May 2021, FVC was maintained in follow-up pulmonary function tests with successful tapering of PSL to 10 mg/day (Figure 3). As of August 2021, the patient had stable symptoms and chest CT findings and was on regular monthly follow-up.