A Case of IgG4-Related Disease Manifesting as Extensive Abdominal Periarteritis and Membranous Nephropathy, Successfully Controlled with Low-Dose Steroid Therapy without Relapse or Complications

IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition characterized by tumor-like mass formation in many affected organs [1]. IgG4-RD can affect nearly every organ system, including the pancreas, salivary glands, lacrimal glands, biliary tree, kidneys, thyroid gland, lungs, and aorta [2]. The major histopathological features associated with IgG4-RD include a dense lymphoplasmacytic infiltrate that is enriched with IgG4-positive plasma cells and storiform fibrosis [1].

Vascular manifestations have been reported to be present in 10%–30% of patients with IgG4-RD [3]. Although some patients with IgG4-related vascular lesions present with chest or back pain, fever, and edema, many patients have no vascular-related symptoms and are diagnosed radiologically [3]. IgG4-related vascular lesions mainly involve the aorta, called periaortitis, and in rare cases include medium-sized arteries, such as the celiac, mesenteric, iliac, coronary, pulmonary, and vertebral arteries, called periarteritis [2].

The kidney is one of the major targets of IgG4-RD, and 7.0%–24.6% of patients with IgG4-RD have renal manifestations [4]. The most dominant renal feature is tubulointerstitial nephritis (TIN), characterized by rich IgG4-positive plasma cells and fibrosis. Renal involvement is detected by renal dysfunction, or by some radiographic abnormalities such as renal enlargement, soft tissue infiltrative lesions encasing the renal pelvis or sinus, and multiple cortical hypodense lesions on contrast-enhanced computed tomography (CT) images, during systemic screening of extrarenal lesions by chance [5, 6]. Moreover, some glomerular lesions such as membranous nephropathy (MN) have been reported [7, 8]. Clinical manifestations of IgG4-RD vary depending on the affected organs, severity, and timing of onset [9]. In addition, IgG4-RD is a great mimicker of many neoplastic, inflammatory, and infectious diseases, which sometimes makes the diagnosis of IgG4-RD challenging. IgG4-RD can lead to irreversible organ failure due to swelling, obstruction, or fibrosis of the organs without appropriate therapy, but it is highly treatable and responds promptly to glucocorticoids [10]; therefore, prompt diagnosis and early initiation of treatments are essential. Herein, we present a case of IgG4-RD with extensive abdominal periarteritis and MN successfully controlled with low-dose steroid therapy without relapse or complications.

A 71-year-old man was referred to our hospital with a 1-month history of edema. He had a history of diabetes mellitus, duodenal ulcer, and hypertension and was a current heavy smoker. His family history was unremarkable. The patient’s serum albumin level was low at 1.8 g/dL with a urinary protein level of 6.1 g/day. Serum creatinine level had slightly increased to 1.0 mg/dL from 0.8 mg/dL at baseline 3 months before admission. Based on these laboratory results, he was diagnosed with nephrotic syndrome and admitted to our hospital for further evaluation and treatment. However, on hospital day 3, the patient presented with acute abdominal pain and was diagnosed with generalized peritonitis due to duodenal perforation; he underwent laparoscopic drainage and omental patch repair on the same day. The postoperative course was uneventful, and the patient was readmitted to the nephrology department on hospital day 21.

On readmission, sitagliptin 50 mg, rosuvastatin 2.5 mg, amlodipine 10 mg, lansoprazole 15 mg, cilnidipine 10 mg, nifedipine 80 mg, and losartan potassium 50 mg daily were administered. The patient’s body temperature was 36.4°C, heart rate was 71 beats/minute, and blood pressure was 133/77 mm Hg. A physical examination revealed bilateral pitting edema in the lower extremities and a weight gain of 3 kg in the last 1 month. He had no salivary or lacrimal swelling, lymphadenopathy, or skin rashes. No obvious neurological findings were noted, and the abdominal bruit was unremarkable.

Laboratory data are shown in Table 1. Laboratory tests revealed hypoalbuminemia (1.8 g/dL), severe proteinuria (6.1 g/day), and high creatinine levels (1.0 mg/dL), consistent with nephrotic syndrome with mild acute kidney injury. Although the IgG level was normal (967 mg/dL), the IgG4 level was 435 mg/dL (reference range 11–121 mg/dL), and the IgG4/IgG ratio was high. The Immunoglobulin E level was also high at 5,500 IU/mL (reference range <170 IU/mL). Antinuclear antibody, myeloperoxidase, anti-neutrophil cytoplasmic antibodies, proteinase 3 (PR3)-anti-neutrophil cytoplasmic antibodies, and anti-Sjögren’s syndrome-related antigen A and B antibodies were all negative.

Chest radiography results were normal. Ultrasonography revealed no vascular stenosis or occlusions. CT scan did not show the typical radiographic findings of IgG4-RD, such as enlarged salivary glands and pancreas, cortical hypodense lesions, or enlarged renal pelvis. Soft tissue mass around the superior mesenteric artery, inferior mesenteric artery, splenic artery, and common iliac arteries was observed (Fig. 1a, b). Coronary periarteritis was not evident. Notably, the extensive periarteritis was confined only to a major branch of the abdominal aorta. The thickened perivascular tissue showed slight enhancement in the delayed phase (Fig. 1c, d), consistent with the characteristics of IgG4-related periarteritis [11]. Other potential etiologies, including malignancies, lymphoma, Cogan’s syndrome, and medium-vessel vasculitis, including polyarteritis nodosa and Behçet’s disease, were incompatible with the laboratory examinations and clinical findings.

On hospital day 21, the patient underwent renal biopsy for massive proteinuria. There were 21 glomeruli in the biopsy specimens, five of which were globally sclerotic (24%). No cellular crescent was present. Twenty percent of the interstitium showed fibrosis (Fig. 2a). Spike formation on the glomerular basement membrane (GBM) was also detected (Fig. 2b). Infiltration of inflammatory cells, composed of lymphocytes and plasma cells, was observed only focally in the interstitium. There is no storiform interstitial fibrosis or obliterative phlebitis (Fig. 2a, c). The IgG4/IgG-positive plasma cell ratio was 76%, and the number of IgG4-positive plasma cells was 71/high-power field (Fig. 2d, e). Immunofluorescence staining for IgG showed positive granular staining in the capillary walls. On IgG subclass staining, IgG1 deposition along the capillary walls was dominant, IgG4 deposition was second dominant, and staining for IgG2 and IgG3 was very weak (Fig. 2f–i). Deposits of kappa and lambda light chains were slightly observed in similar granular patterns with equal intensity. Staining for C1q and PLA2R was negative. Staining for NELL-1 and exostosin 1/exostosin 2 was also negative (online suppl. Fig. 1a–c; for all online suppl. material, see https://doi.org/10.1159/000542414). Electron microscopy showed subepithelial deposits along the GBM (Fig. 2j), consistent with stage II MN. Finally, the findings of periarteritis, high serum IgG4 levels, and focal interstitial inflammation with rich IgG4-positive plasma cells led to the diagnosis of IgG4-RD.

The clinical course of the patient is shown in Figure 3. We chose low-dose steroid therapy because this patient had a peptic ulcer, and a high dose of prednisolone can promote aneurysm formation in IgG4-related periarteritis. Complete remission of proteinuria was achieved after the initiation of prednisolone and angiotensin receptor blockers. After 1 year of continuous low-dose steroid therapy, urinary protein levels remained in remission, serum creatinine levels did not deteriorate, and IgG4 levels remained low (Fig. 3). The soft tissue mass lesions had reduced by 25% 4 months after treatment and remained stable 1 year after treatment (Fig. 4). We successfully controlled IgG4-RD without the aneurysm formation that can be induced by treatments, and prevented recurrence of the peptic ulcer.

This case represents a presentation of IgG4-RD, demonstrating extensive abdominal periarteritis and nephrotic syndrome without typical manifestations such as pancreatitis or sialadenitis. The findings of periarteritis on contrast-enhanced CT images, high serum IgG4 levels, and focal interstitial inflammation with rich IgG4-positive plasma cells led to the diagnosis of IgG4-RD. We successfully controlled IgG4-related kidney disease (IgG4-RKD) and periarteritis with low-dose steroid therapy without aneurysm formation induced by treatments.

IgG4-related vascular lesions pathologically exhibit significant fibrous adventitial thickening and numerous IgG4-positive plasma cell infiltrations [12], which show soft tissue mass around arteries with homogeneous enhancement in the late phase of contrast-enhanced CT [13]. In this case, the radiological features and clinical were consistent with IgG4-related periarteritis. In previously reported cases of IgG4-related periaortitis/periarteritis, the proportion of patients with elevated CRP levels varied from 29% to 90% [14], with even those showing elevated CRP exhibiting only mild increases. In this case, despite the extensive vascular lesions, CRP levels were normal, suggesting IgG4-RD rather than other vasculitis such as Takayasu’s aortitis, polyarteritis nodosa, or Behçet’s disease. Moreover, this case is unique in that the extensive periarteritis was confined to a major branch of the abdominal aorta (superior mesenteric artery, inferior mesenteric artery, splenic artery, and common iliac arteries), rather than to the aorta itself. Ozawa et al. [15] reported that the infra-renal abdominal aorta was most frequently involved (81.5%), whereas cases with involvement only of the medium-sized arteries, as described in our case, were rare (9.2%). The difference in pathophysiology among distribution types of affected vascular lesions remains unclear, and a more comprehensive investigation needs to be conducted. IgG4-related periaortitis and periarteritis are reportedly associated with older age at onset of IgG4-RD and highly active disease state and less linked to the well-known risk factors of atherosclerosis [15, 16]. No statistical relevance between IgG4-related periarteritis and IgG4-RKD has been reported [17].

The most dominant feature of IgG4-RKD is TIN with rich IgG4-positive plasma cells and fibrosis. MN is a rare manifestation of IgG4-RKD [18]. Kawano et al. [4] reported a literature review of 34 cases of IgG4-related MN; of those patients, 38% had only MN without TIN, whereas 62% had MN complicated with TIN. The radiological findings of diffuse bilateral renal enlargement on radiological images [5] and the high IgG4/IgG-positive plasma cell ratio in the interstitium are diagnostically important for IgG4-TIN. In IgG4-related MN, the characteristic radiographic features are seen in rare cases [18]. Moreover, the dominant deposition of IgG subclasses on the GBM can vary from IgG1 to IgG4 [4, 8], which suggests the dominant deposition of IgG subclass is not necessarily diagnostic for IgG4-related MN [8]. Therefore, further evaluation of extrarenal manifestations and serum IgG4 levels is essential to distinguish between MN associated with IgG4-RD and idiopathic MN. In addition, recent advancements in MN pathobiology have identified novel antigens, including PLA2R, NELL-1, and EXT1/EXT2. NELL-1-positive MN is associated with malignancy, and EXT1/EXT2-positive MN is associated with active systemic autoimmunity, predominantly SLE [19]. In our case, all these antigens were negative, and there were no clinical findings of cancer or SLE. The accumulation of reports on the association of IgG4-MN with specific antigens is needed.

One of the characteristics of our case is that the patient developed duodenal perforation after the onset of IgG4-RKD. Because we did not obtain tissue from the ulcer site, we could not prove whether it was a simple recurrence of duodenal ulcer or whether IgG4-RD caused the duodenal perforation. Duodenal ischemia due to IgG4-related periarteritis could make the duodenal mucosa vulnerable. However, to the best of our knowledge, no report has shown a direct link between duodenal ischemia and IgG4-related periarteritis.

Notably, we controlled the rare IgG4-related extensive periarteritis and MN using low-dose steroid therapy, without any complications. Early diagnosis and treatment are essential to prevent irreversible organ dysfunction. Glucocorticoids are the first-line treatment for IgG4-RD, particularly for inducing remission. IgG4-related vascular lesions have been treated with medium- to high-dose glucocorticoids [3, 17] and were shown to improve in 70%–100% of cases treated with corticosteroids alone or in combination with immunosuppressants (azathioprine, cyclophosphamide, rituximab, etc.). Exacerbation of luminal dilatation after treatment occurs in 7%–21% of cases [14‒16, 20‒23]. In this case, we initiated low-dose steroid therapy (prednisolone 10 mg, 0.2 mg/kg/day) to minimize the risk of peptic ulcer recurrence and to safely manage the potential for arterial rupture, which can occur with the rapid improvement after medium- to high-dose prednisolone. After treatment, the soft tissue mass lesions gradually improved and remained stable without arterial rupture or luminal dilatation. The patient has remained in renal remission during the year following steroid therapy without complications. A previously published retrospective study divided IgG4-RKD into two groups based on initial steroid doses: ≤0.6 mg/kg/day (ranging from 0.2 to 0.6 mg/kg/day, mean 0.47 mg/kg/day) and >0.6 mg/kg/day (ranging from 0.61 to 1.1 mg/kg/day, mean 0.81 mg/kg/day). The study reported no significant difference in eGFR improvement or relapse rate between the two groups [24]. Although low-dose treatment is not generally recommended due to a lack of sufficient evidence, it may be considered for patients with potential risk of treatment complications, as in this case. In high-risk cases for steroid use, but only in the absence of acute organ damage from IgG4-RD, it might be an option to start steroid therapy at a low dose and carefully reduce the dose based on imaging and laboratory test results. If the initial response is inadequate, the dose can be increased to a standard dose. Furthermore, in this case, complete remission of nephrotic syndrome was achieved using the least intense treatment. In previous reports of MN associated with IgG4-RD, multiple treatments such as glucocorticoid alone or in combination with immunosuppressants (cyclophosphamide, rituximab, and mycophenolate mofetil), in addition to renin-angiotensin system inhibitors, have been implemented [4, 5]. However, the response to treatment and prognosis in MN associated with IgG4-RD are not clear because of the lack of evidence, and further investigation is required.

We report a case of IgG4-RD manifesting as extensive abdominal periarteritis and MN. The characteristic radiological features seen on contrast-enhanced CT images, serum IgG4 levels, and pathological findings led to the accurate diagnosis of IgG4-RD, which we successfully controlled with low-dose steroid therapy without relapse or any complications. Although various clinical manifestations of IgG4-RD sometimes make the correct diagnosis challenging, clinicians should diagnose it using serological, radiological, and pathological evaluations and treat patients to prevent irreversible organ failure.

The authors would like to thank Dr. Koyama for his help with image preparation. This case was presented and discussed in “Online case conference by Japanese association of IgG4-related disease.” The authors are grateful for useful comments at the conference.

This study was approved by the Ethics Committees of Kyoto University Hospital, Approved No. [562]. This case report was written in compliance with the Declaration of Helsinki. The patient has signed the informed consent for publication.

The authors have no conflicts of interest to declare.

None.

Minami Matsumoto and Shinya Yamamoto performed primary manuscript preparation; Minami Matsumoto and Shinya Yamamoto wrote the manuscript. Shigeo Hara and Takahiro Tsuji performed staining for specific antigens of membranous nephropathy. Shinya Yamamoto had primary responsibility for the final content; and Minami Matsumoto, Shinya Yamamoto, Hideki Yokoi, Sho Koyasu, Shigeo Hara, Takahiro Tsuji, Minamiguchi Sachiko, and Motoko Yanagita reviewed the manuscript and revised it critically. Minami Matsumoto, Shinya Yamamoto, Hideki Yokoi, Sho Koyasu, Shigeo Hara, Takahiro Tsuji, Minamiguchi Sachiko, and Motoko Yanagita read and approved the final manuscript.

Minami Matsumoto and Shinya Yamamoto contributed equally to this work.

The dataset supporting the conclusions of this article is included within the article.