Case presentation
A 67-year-old man was admitted to our hospital complaining of repeated cough, hemoptysis, anorexia and fatigue. He has a significant medical history for hypertension and was a heavy smoker. Five months prior to admission, the patient was diagnosed with pneumonia at the local hospital on the basis of cough, hemoptysis and diffuse lesions in both lungs that were observed through the chest computed tomography (CT) scan. At that time, his serum IgG was 16.35 g/L (normal range: 7–16 g/L), while his hemoglobin, serum creatinine and C-reactive protein (CRP) levels were in the normal range. In addition, urinalysis yielded negative results for proteinuria and hematuria. Two months before admission, he experienced ear stuffiness due to mixed hearing loss, after which a CT scan revealed bilateral middle ear mastoiditis, bilateral ethmoid sinusitis. The month before admission, he complained about anorexia and fatigue, and developed severe anemia with hemoglobin concentration at only 59 g/L. Rapid deterioration of renal function was observed with serum creatinine level at 717.2 µmol/L. The test for serum anti-MPO antibody showed positive result, while anti-PR3 antibody was weakly positive. The diagnosis of AAV was made and methylprednisolone 40 mg/d was prescribed. Serum creatinine level decreased to 548.1µmol/L 6 days after treatment.
Later on, the patient was admitted to our hospital. Doppler ultrasound examination revealed that the mean length of the left kidney amounted to 90.4mm, and the right kidney 104.4 mm. CT scan showed right maxillary sinusitis and multiple subpleural small nodules (approximately 2 to 3 mm in diameter) could be seen in both lungs (shown in Fig. 1. A, B). The right upper lung had shown inflammation, while bilateral ground-glass opacity was displayed by the lower lung (shown in Fig. 1. C). Serum IgG was 19.7 g/L (normal range:7–16 g/L), IgG4 was 4.07 g/L (normal range: 0.030–2.010 g/L), and the IgG4: IgG ratio was 20.7%. Serum IgE was 406 IU/mL (normal range: 0-100 IU/mL) and CRP was 12.6 mg/L (normal range: < 5.0 mg/L). No hypocomplementemia was apparent, with C3 and C4 levels at 790 and 147 mg/L, respectively. The levels of serum creatinine was 481 µmol/L (normal range: 44–133 µmol/L), urinary red blood cells 6 to 10/high-power field, urine microalbumin 129.0 mg/L and 24-hour urine protein quantitation at 0.16 to 0.32g. Peripheral white blood cells were 8.97 x109/L with normal eosinophils, and hemoglobin was 89 g/L. A test for serum perinuclear-ANCA had shown positive result, and MPO-ANCA level was 275.27 U/mL (normal range 0–15 U/mL). The PR3-ANCA level was 2.181U/mL (normal range 0–15 U/mL). A renal biopsy was then performed with the following results: immunofluorescence examination showed fibrinoid necrosis, IgM (+) and C3 (+/-), tubular basement membrane (TBM) deposits showed granular staining for IgG (shown in Fig. 2. A); under light microscopy, fifteen glomeruli could be seen in the specimen, among which two were observed with cellular crescents and eight with cell fibrotic crescents (shown in Fig. 3. A); multifocal inflammatory cell infiltration was evident in the tubulointerstitial area (shown in Fig. 3. B). Immunohistochemical staining showed that IgG4 positive plasma cells were more than 10/HPF, and the ratio of IgG4-positive to IgG-positive plasma cells was more than 40% (shown in Fig. 3. C, D). Ultrastructural examination reveals electron-dense deposits, without substructure, in the TBM (shown in Fig. 2. B, C)
The patient was finally diagnosed with IgG4-RD based on the IgG4-positive plasma cell-enriched TIN, increased serum IgG4, TBM deposits and pulmonary nodules. The findings of pauci-immune crescentic GN, ground-glass opacities in the lower lungs, middle ear mastoiditis, paranasal sinusitis and increased MPO-ANCA led to a concurrent diagnosis of systemic ANCA-associated vasculitis in the form of MPA (shown in Table 1). The patient received methylprednisolone pulse therapy of 0.5 g/d for 3 consecutive days followed by 40 mg/d intravenous drip. Later, oral prednisone was tapered to 20 mg/d due to complication of pulmonary inflammation. The patient responded partially to this regime of treatment. His serum creatinine and IgG level decreased to 319 µmol/L and 10.4 g/L respectively; while his serum IgG4 and IgG4: IgG ratio dropped to 1.53 g/L and 14.71% respectively.
Four months later, re-examination through CT showed improvement in bilateral interstitial changes (shown in Fig. 1. D), but ground-glass nodules were still seen in the right middle lobe with multiple subpleural small nodules. However, the bronchial lavage fluid examination revealed no evidence of fungus or tuberculosis. Changes in the lungs were thought to be caused by IgG4-RD, but biopsy could not be performed due to the location of upper lobe and the high risk it bears. After 6 months of treatment, the level of serum IgG4 was 0.323 g/L, and serum creatinine was maintained at 230 µmol/L (shown in Fig. 4). Five months ago, the patient received intravenous cyclophosphamide at 0.2–0.4 g every two weeks in local hospital. His latest serum creatinine level was at 187.2 µmol/L. Regular follow-up is still ongoing.
Literature review
Clinical profile
Through the literature review (from 1976 to 2020), 52 patients who met IgG4-RD and AAV criteria based on histopathological investigation were identified, which were defined as having overlap syndrome according to the previous researches [6,7]. 10 patients without detailed data were excluded [6] and 42 patients were included. Among them, 34 cases showed concurrent IgG4-RKD and AAV, and 29 cases (85.3%) were IgG4-RKD concomitant AAV associated glomerulonephritis (ANCA-GN) with mild to moderate renal impairment (shown in Table 2–3).
Among the 42 patients ranged in age from 31 to 73 years old with a median age of 60 at diagnosis, 14 (33.3%) patients were women, and 28 (66.7%) patients were men. Serological tests of CRP were showed in 20 patients. 16 of them (80.0%) has an elevated level of CRP ranging from 2.11 to 17.9 mg/dl. Serum IgG4 concentration increased in 41 (97.6%) patients (median:395 mg/dl; range:177-876mg/dl). Forty-one patients (97.6%) tested positive for ANCA with 37 (90.2%) patients showing a specificity for MPO and 4 (9.8%) patients with a specificity for PR3. The identification of IgG subclasses of MPO-ANCA was performed in three studies involving 17 patients [15-17] and all patients were positive for IgG4-MPO-ANCA in overlap syndrome. The main organs involved in both AAV and IgG4-RD are kidney and lung. The ear, nose and throat (ENT) and peripheral nervous system (PNS) involvement were prevalent in AAV (21.4%, 19.0%, respectively), while pancreas involvement appeared mainly in IgG4-RD cases (9.5%) (shown in Table 2–3).
In the 34 patients with concurrent IgG4-RKD and AAV, the average of serum creatinine level was 302.7±193.5 µmol/L. In 15 patients with recorded proteinuria level, 14 exhibited ~2 g/day proteinurea level, with no nephrotic syndrome. Microhematuria was either absent or low in most patients (0-15 erythrocytes/high power field in light microscopy of urine sediments) (Table 3).
Pathological profile
A total of 48 biopsies were performed in 42 patients. The biopsy site with the highest frequency was the kidneys (75.0%), followed by the lungs (8.3%). Evidence of necrotizing vasculitis lesions, leukocytoclastic vasculitis lesions and necrotizing granulomatous inflammation was respectively observed in 3 patients, while necrotizing glomerulonephritis in 9 patients, and crescentic glomerulonephritis in 12 patients. Lymphoplasmacytic infiltrate was noted in all IgG4-RD patients, with an IgG4/IgG ratio of > 40% in 8 (19.0%) patients and the number of IgG4-positive plasma cells >10 per HPF was observed in 33 (78.6%) patients. Storiform fibrosis was present in 23 (54.8%) patients (shown in Table 2–4).
Regarding to the 33 patients manifested as IgG4-RKD and ANCA-GN overlap syndrome, kidney histology presented pauci-immune necrotizing or crescentic glomerulonephritis and IgG4-related TIN. IgG4-related TIN could be seen in all the cases. Typical storiform fibrosis was noticed in 16 (48.5%) patients. Pauci-immune necrotizing and or crescentic glomerulonephritis could be diagnosed in 23 (69.7%) patients. Glomerulonephritis with crescents or segmental necrosis was presented in 10 patients (30.3%). Among these specimens, the average percentage of crescents were 39.1 ± 20.8%. Fibrinoid necrosis could be seen in 15 (45.5%) specimens. Most immunoglobulins and complements could not be detected along the glomerular capillary loops by immunofluorescence test. Based on the ANCA-GN classification proposed by Berden et al. [18], 23 patients with available data were classified respectively as follows: 9 (39.1%) focal, 12 (52.2%) crescentic, 1 (4.3%) sclerotic and 1 (5.3%) mixed ANCA-GN (shown in Table 4).
Treatment and outcome
From the data, 42 patients received immunosuppressive therapy, among which 7 (16.7%) patients were treated with oral glucocorticoids alone, 30 (71.4%) patients with glucocorticoids in combination with cyclophosphamide, 3 (7.1%) patients with glucocorticoids in combination with rituximab, and t 2 (4.8%) patients w with oral glucocorticoids in combination with azathioprine. Additionally, 22 (52.4%) patients received intravenous methylprednisolone pulse therapy and 5 (11.9%) patients received additional plasmapheresis. 3 (7.1%) patients experienced relapse of AAV or treatment resistance during treatment with glucocorticoids in combination with cyclophosphamide or azathioprine, and were then being treated with rituximab and achieved remission thereafter. During follow-up, 36 (85.7%) out of 42 patients achieved remission within 3 months, while relapse occurred in 2 (4.8%) cases. Treatment resistance occurred in 6 (14.3%) patients, with 5 of them proceeded to routine hemodialysis. No fatality was recorded. In regards to IgG4-RKD, 30 (88.2%) out of 34 patients achieved renal improvement with lower serum creatinine levels as serum IgG4 concentration decreased (shown in Table 2–3).