Development of Nephritis and Abnormal Lung Shadow in a Patient with IgG4-related Hypertrophic Pachymeningitis with MPO-ANCA Positivity after Unplanned Interruption of Maintenance Glucocorticoid Therapy

Abstract

We herein report a patient with immunoglobulin (Ig)G4-related hypertrophic pachymeningitis (HP) with myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) positivity without renal dysfunction at the time of the diagnosis who subsequently developed nephritis after an unplanned interruption of maintenance glucocorticoid therapy. A renal biopsy specimen obtained at the time of the development of renal dysfunction revealed the possibility of both ANCA-associated nephritis and IgG4-related tubulointerstitial nephritis, with no HP relapse. The present case highlights the need to monitor other organ complications, including renal damage, in patients with IgG4-related HP with MPO-ANCA positivity, even after achieving remission.

Introduction

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated disorder characterized by elevated serum IgG4 levels, plasmacyte infiltration, and fibrosis (1-3). Hypertrophic pachymeningitis (HP) is an intracranial manifestation of IgG4-RD or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Some patients with IgG4-related HP tests are positive for ANCA (4,5), a serological marker for the diagnosis of granulomatous polyangiitis or microscopic polyangiitis (MPA) (6-10). IgG4-RD can affect any organ, including the kidney (11,12) and lung (13), whereas IgG4-related HP positive for myeloperoxidase (MPO)-ANCA has been reported to localize to the head and neck (5). To our knowledge, there are currently no reports of renal and lung involvement in IgG4-related HP with MPO-ANCA positivity wherein both the dura mater (DM) and kidney were biopsied.

We herein report a patient with IgG4-related HP with MPO-ANCA positivity who developed renal involvement and an abnormal lung shadow after unplanned interruption of maintenance glucocorticoid (GC) therapy.

Case Report

A man in his 60s developed headaches and dizziness (July, year X-8) and visited a neighboring clinic, where magnetic resonance imaging (MRI) showed dural thickening compatible with HP. He was treated for presumed idiopathic HP, with prednisolone (PSL) 20 mg/day initiated, tapered, and then discontinued (January, year X-7). Upon PSL discontinuation, his C-reactive protein (CRP) and MPO-ANCA levels increased to 0.90 mg/dL and 3.6 IU/mL, respectively, while proteinase-3 (PR3)-ANCA levels were within normal limits (1.4 IU/mL). Immune-mediated disease was suspected, and the patient was referred to our department.

His serum creatinine level and estimated glomerular filtration rate (eGFR) were both within normal limits (0.59 mg/dL and 102.9 mL/min/1.73 m², respectively). Urine protein and occult blood tests were negative, and a microscopic examination of urine sediment showed no red or white blood cells. The serum levels of IgG, IgG4, and MPO-ANCA were elevated at 2,585, 416, and 5.7 IU/mL, respectively. Gadolinium-enhanced MRI showed diffuse thickening of the DM (Fig. 1A). Computed tomography (CT) of the trunk showed a nodular shadow in the upper lobe of the right lung (Fig. 2A), with no other abnormalities in organs typically affected by IgG4-RD, such as the pancreas and kidney. A biopsy specimen from the DM showed infiltration of lymphocytes and plasma cells, along with fibrosis, but there was no evidence of vasculitis. Immunological staining of the DM for IgG4 revealed many IgG4-expressing plasma cells, and the amount of IgG4 as a percentage of the total IgG was 64% (Fig. 1B). Based on the clinical symptoms, the patient was diagnosed with isolated IgG4-associated HP without extrameningeal organ involvement.

Figure 1.

(A) Gadolinium-enhanced magnetic resonance imaging of the brain showing diffuse thickening of the dura mater. (B) Pathological findings of the dura mater showing infiltration of the lymphocytes and plasma cells along with fibrosis. Immunological staining for immunoglobulin (Ig)G4 shows many IgG4-expressing plasmacytes; the amount of IgG4 as a percentage of total IgG was 64%.

Figure 2.

Chest computed tomography. (A) A nodular shadow in the upper lobe of the right lung observed at admission. (B) A newly developed ground-glass opacity in the right middle lobe and a persistent nodular shadow in the right upper lobe, observed in October X-2. (C) Left pleural effusion, persistence of the nodular shadow in the right upper lobe, and a newly developed 20-mm nodular shadow in the left upper lobe of the lung observed during the second admission to our department. (D) Disappearance of the left pleural effusion and nodular shadow in the left upper lobe one month after the second admission.

PSL (35 mg/day) was initiated, and the patient's symptoms improved, along with normalization of the serum IgG, IgG4, and MPO-ANCA levels. The PSL dose was gradually reduced to 5 mg/day and continued as a maintenance dose. On the day of the outpatient clinic visit (October, year X-2), tests revealed an elevated serum CRP level (1.61 mg/dL) with no pyrexia and no subjective respiratory symptoms, such as cough or sputum. The white blood cell count and neutrophil value were within normal limits (7,750 /μL and 68%, respectively). A few days later, CT revealed a newly developed ground-glass opacity in the right middle lobe, while nodular opacity remained in the right upper lobe (Fig. 2B). No abnormalities were found in the abdominal organs.

Considering the possibility of bacterial pneumonia due to ground-glass opacity, oral antibiotics were administered. Subsequently, the patient's serum IgG4 level increased to 152 mg/dL. However, at the next scheduled outpatient visit (November, year X-2), the patient did not attend the follow-up on his own because of the absence of subjective symptoms.

In July X, at 75 years old, the patient developed general malaise and visited another hospital. Given his medical history, he was referred to our department the following day. He complained of a loss of appetite but denied having headaches. Bilateral dorsal fast edema was observed. An elevated serum creatinine level and decreased eGFR were found (2.38 mg/dL and 21.8 mL/min/1.73 m², respectively). The urine dipstick result for hematuria was 3+, his protein/creatinine ratio was 0.63 g/gCre, and his β2-microglobulin level was 12,727 μg/L. No eosinophilia or hypocomplementemia was observed (white blood cell count, 8,690 /μL; eosinophils, 0.9%; CH50, 53 U/mL; C3, 82 mg/dL; and C4, 12 mg/dL). CT of the trunk showed left pleural effusion, persistent nodular opacity in the right upper lobe, and a newly developed 20-mm nodular opacity in the left upper lobe, whereas the ground-glass opacity in the right middle lobe had disappeared (Fig. 2C); however, no abnormal kidney morphology was noted. A 12-lead electrocardiogram revealed atrial fibrillation. Echocardiography revealed dilatation of the left atrial cavity (42.1 mm) without a thrombus and a low ejection fraction (45%). Repeated MRI of the head revealed no DM thickening.

Considering the possibility of bacterial pneumonia and renal dysfunction due to dehydration, the patient was hospitalized and started on intravenous infusion of extracellular fluid, antibacterials, and 10 mg/day intravenous PSL, which did not improve the renal function or CRP levels. Serum IgG, IgG4, and MPO-ANCA levels increased to 2,856 mg/dL, 835, and 27.5 IU/mL, respectively. After admission, he developed numbness of the toes, which was diagnosed as peripheral neuropathy according to the nerve conduction study.

Considering the possibility of IgG4-related renal disease and ANCA-associated glomerulonephritis, we increased the GC dose to 50 mg/day of oral PSL. A renal biopsy revealed cellular crescents, tuft necrosis, and fibrinoid necrosis of the arterioles, consistent with ANCA-associated glomerulonephritis (Fig. 3). There were eight glomeruli, four of which had global sclerosis. One glomerulus exhibited segmental sclerosis and fibrous crescents. One glomerulus exhibited segmental endocapillary hypercellularity and tuft necrosis. Two glomeruli collapsed, one of which was associated with a cellular crescent. tubulointerstitium was severely affected by lymphocytes, plasma cells, and few eosinophils and neutrophil infiltration, with storiform fibrosis surrounding inflammatory cells (bird's eye pattern) in approximately 80% of the cortex. Peritubular capillaritis and tubulitis were also observed. Fibrinoid necrosis was found in some of the arterioles. Mild tubular atrophy was observed (10% of the cortex). These findings were compatible with the sclerotic class of the Berden classification (14); however, the small number of biopsied glomeruli did not guarantee the validity of this classification.

Figure 3.

Renal biopsy findings suggestive of ANCA-associated glomerulonephritis. (A) A glomerulus (thin arrow), identical to that shown in (C), exhibiting tuft necrosis, suggesting an active lesion. Segmental sclerosis and fibrous crescents (thick arrows), suggesting chronic lesions. Appearance of tubulitis (dotted arrows). Overall, both active and chronic lesions were abundant, a characteristic of ANCA-related nephritis. (B) The glomerulus showing disruption of the basement membrane (arrow) of Bowman’s capsule, surrounded by inflammatory cells, suggesting severe glomerulitis. (C, D) Hematoxylin and Eosin staining; the glomerulus, identical to that shown in (A), showing tuft necrosis with fibrin in the Bowman’s space and karyorrhexis. Fibrin (thick arrow) in Bowman’s space and karyorrhexis (thin arrow). The inset shows disruption of glomerular tuft in PAM staining. Masson’s trichrome staining; fibrinoid necrosis of the arterioles. Bar: 50 μM. ANCA: antineutrophil cytoplasmic antibody, HE: Hematoxylin and Eosin staining, MT: Masson’s trichrome staining, PAS: periodic acid-Schiff staining, PAM: periodic acid–methenamine silver staining

Immunofluorescence staining revealed a pauci-immune pattern (Fig. 4), as electron-dense deposits were not observed by electron microscopy. In addition, findings consistent with IgG4-related tubulointerstitial nephritis were also identified, including infiltration of plasma cells, IgG-positive cells infiltrating the interstitium (48% of which were IgG4-positive), and mild fibrosis (Fig. 5).

Figure 4.

Immunofluorescence staining showing a pauci-immune pattern.

Figure 5.

Renal biopsy findings of lesions suggestive of IgG4-related nephritis. (A) Plasma cell infiltration and storiform fibrosis. (B) The amount of IgG4 as a percentage of the total IgG was 48%. Bar: 50 μM. IgG4-RD: immunoglobulin G4-related disease, HE: Hematoxylin and Eosin staining, PAM: periodic acid–methenamine silver staining

Warfarin was initiated to inhibit left atrial thrombus formation, mecobalamin to treat peripheral neuropathy, and darbepoetin alpha to treat renal anemia. Following PSL elevation, serum CRP levels normalized and IgG, IgG4, and MPO-ANCA levels decreased. Hematuria and proteinuria also improved, but the eGFR decreased. Chest CT performed after the increase in the PSL dose showed the disappearance of the left pleural effusion and a nodular shadow in the left upper lobe; ground-glass opacity in the right middle lobe was no longer present (Fig. 2D). The PSL dose was tapered, and the patient was discharged with PSL 25 mg/day. As the PSL dose was gradually tapered in our outpatient clinic, the patient developed sputum and an elevated CRP level, suggestive of a respiratory infection, which was treated with oral antibacterial agents. Although renal dysfunction persisted, the serum IgG4 and MPO-ANCA levels were normal at 10 mg/day PSL (Fig. 6).

Figure 6.

Clinical course. ABPC/SBT: ampicillin/sulbactam, ANCA: antineutrophil cytoplasmic antibody, AZM: azithromycin, CRP: C-reactive protein, eGFR: estimated glomerular filtration rate, ECF: extracellular fluid, Hb: hemoglobin, IgG4: immunoglobulin G4, LVFX: levofloxacin, MPO: myeloperoxidase, O.B.: occult blood, PSL: prednisolone, Prot: protein

Discussion

ANCA positivity is included in the 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR, currently European Alliance of Associations for Rheumatology) classification criteria for IgG4-RD (1,2). Although there has been debate regarding whether or not IgG4-RD and AAV co-occur (15), a certain proportion of patients with IgG4-RD are positive for ANCA. Martín-Nares et al. reported that 56% of patients with IgG4-RD who were tested for ANCA were positive based on the results of indirect immunofluorescence microscopy (16). Mizushima et al., in a study of 162 patients with IgG4-RD, found that 18 of them were positive for autoantibodies, including 4 exhibiting PR3 ANCA. Based on this finding, they concluded that the autoantibodies included in the exclusion criteria of the 2019 ACR/EULAR classification criteria for IgG4-RD were of limited clinical significance (4).

Considering the presence of HP, elevated serum IgG4 levels, and histological findings of DM in which fibrosis, infiltration of lymphocytes, and IgG4-expressing plasmacytes were observed, the present case was compatible with steps 1 and 3 of the 2019 ACR/EULAR classification criteria for IgG4-RD (1,2). Positive MPO-ANCA and necrotizing vasculitis, which were included in step 2 of the exclusion criteria, were also identified. However, considering necrotizing vasculitis in the kidney and positive MPO-ANCA, the present case was compatible with more than five points of the 2022 ACR/EULAR classification criteria for MPA (8,9), with IgG4-RD one of its differential diagnoses. Gautier et al. reviewed 13 patients with IgG4-related HP positive for c-ANCA (PR3-ANCA) or p-ANCA (MPO-ANCA) and found that HP with IgG4-positive ANCA tended to localize to the head and neck (5). While cases similar to the present one have been reported, where necrotizing vasculitis suggests MPA and IgG4-RD in the kidney (17), the prominent feature of the present case was pathological multi-organ involvement. Kawashima et al. reported a case wherein a Japanese woman with an elevated serum IgG4 level (407 mg/dL) developed thickened DM (identified via MRI without a biopsy), granulomas, and necrotizing vasculitis suggestive of granulomatosis with polyangiitis, a form of AAV, in the lung tissue, along with tubulointerstitial nephritis and necrotizing vasculitis with infiltration of IgG4-positive cells (18).

To our knowledge, the present case is the first involving IgG4-related HP positive for MPO-ANCA that subsequently developed renal involvement and abnormal lung shadows after unplanned interruption of maintenance GC; both dural and kidney biopsy results suggested the coexistence of IgG4-RD and MPA. Although ANCA positivity was included in the exclusion criteria of the 2019 ACR/EULAR classification criteria for IgG4-RD, as mentioned previously (1,2), these reports and ours suggest that the pathology of AAV and IgG4-RD can coexist in one patient. As no re-thickening of the DM was found on MRI at the onset of renal dysfunction, it was presumed that pachymeningitis was in remission in our case, suggesting that multi-organ involvement does not always occur simultaneously. Considering the common features of IgG4-RD and MPA, such as their predominance in older people, involvement of various anatomical sites, including the HP and kidney, and responsiveness to immunosuppressive therapy, it would be worth determining whether or not the two disease entities share common genetic factors.

HLA-DRB1*0901 has been reported to be associated with MPA in a Japanese population (19). For IgG4-RD, HLA-DRB1 was recently identified as a susceptibility locus in a genome-wide association study in a Japanese population (20). HLA typing for IgG4-RD or AAV not covered by the Japanese Health Insurance System was not performed in this case. Further studies are thus required to clarify whether or not specific genetic factors are associated with the coexistence of IgG4-RD and MPA. In addition, no pathological examination was performed, and the nodular and relapsing-remitting shadows in the lungs may suggest IgG4-related lung disease, considering the revised diagnostic criteria for IgG4-related respiratory disease, including other organ involvement as a diagnostic factor (13), or represent an aspect of the AAV. In addition, although a sural nerve biopsy was not performed, peripheral neuropathy in the lower extremities at the second visit was attributed to AAV- or IgG4-related neuropathy (21).

Serum IgG and ANCA levels have been used to differentiate IgG4-related renal disease from AAV (22). The significantly elevated serum IgG and IgG4 levels observed at the second visit were highly predictive of IgG4-RD. Baker et al. reported that serum IgG4 levels greater than 5 times the upper limit of normal were highly predictive of IgG4-RD, whereas 25% of patients with serum IgG4 levels greater than five times the upper limit of normal were referred for diagnoses other than IgG4-RD (23). However, serum ANCA positivity was also predictive of renal involvement in AAV. Cohen et al. analyzed 507 patients who underwent a renal biopsy and serum ANCA measurement and found that the serum ANCA level had high diagnostic value for pauci-immune glomerulonephritis; regardless of the ANCA titer, with 97.6% sensitivity and 71.2% specificity achieved (24).

HP and latent nephritis may have developed simultaneously in the present patient, with the clinical manifestations of nephritis appearing only after sudden, unplanned cessation of GC. In addition, the fact that the clinical manifestations of nephritis were masked at the time of initial referral to our department because of short-term GC therapy in a neighboring hospital cannot be ignored. From a clinical perspective, we were unable to assess whether the renal dysfunction observed at the second admission to our department was rapidly progressive or chronic because the patient had not visited any hospital for approximately 20 months before the second admission. In addition, ANCA-associated renal vasculitis does not always progress rapidly; indeed, in some cases, it progresses slowly (25,26). Thus, nonrapidly progressive renal dysfunction does not necessarily exclude the possibility of AAV. We considered the clinical course to be within one week of the second admission. No significant change in the renal function was observed with low-dose PSL during this short period, which was inconsistent with the signs of rapidly progressive glomerulonephritis. The renal biopsy specimen showed findings compatible with AAV but also suggestive of IgG4-RD; therefore, we could not distinguish IgG4-related renal disease from renal involvement by AAV either clinically or pathologically. Nevertheless, immunosuppressive therapy with PSL was administered based on the possibility of IgG4-related renal disease, renal involvement by AAV, or the previously mentioned pulmonary symptoms.

IgG4-RD and AAV share many of the common features mentioned previously; however, the therapeutic strategies for these two diseases are different. GC is the mainstay of therapy for IgG4-RD (27). In contrast, combination therapy of rituximab or cyclophosphamide with GC is recommended as remission induction therapy in the Japanese clinical practice guidelines for AAV 2023 (28,29). Danlos et al. reported the efficacy of rituximab for relapse in overlapping IgG4-RD and AAV cases (30). However, the pre-revised version of the 2023 guidelines (31) recommended that GC monotherapy be considered for high-risk patients, such as older patients and those at a high risk of infection, which has been incorporated into the 2023 guidelines (28). Thietart et al. reported that rituximab was effective in both induction and maintenance therapy for AAV; however, a significantly elevated risk of severe infection was found with induction therapy of rituximab in combination with high-dose GC in patients ≥75 years old (32). The efficacy and safety of reduced-dose GC regimen in combination with rituximab in Japanese population were shown in the LoVAS trial (33,34), however, whether or not the reduction rate of PSL is applicable to patients with both AAV and IgG4-RD, like the present case, is unclear. We chose moderate-dose GC monotherapy based on the findings of the DM biopsy, which was pathologically compatible with IgG4-RD at the first admission to our hospital, and high-dose GC monotherapy at the second admission, considering the patient's age, risk of infection, and possibility of multiple organ involvement in IgG4-RD (35).

We reported a patient with IgG4-related HP and MPO-ANCA positivity who developed abnormal lung shadows and renal involvement. Renal biopsy results suggested both IgG4-RD and AAV. Thus, clinicians should be aware of the potential complications affecting other organs, including the kidneys, in patients with IgG4-related HP with MPO-ANCA positivity, even after achieving remission following immunosuppressive therapy.

Written informed consent was obtained from the patient for publication.

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