Features of IgG4-related sclerosing mesenteritis: A Chinese cohort study and literature review

Study Population

A total of 1, 409 patients were enrolled in the prospective IgG4-RD cohort established at Peking Union Medical College Hospital (PUMCH; ClinicalTrials. gov identifier NCT01670695). All patients in this cohort were consecutively enrolled at PUMCH between January 2011 and October 2024. No personally identifiable information was accessible after data collection. All patients in the cohort met the 2019 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for IgG4-RD and/or the 2020 revised Comprehensive Diagnostic Criteria for IgG4-RD. To identify patients with IgG4-SM within the prospective cohort, we systematically screened all 1, 409 patients with suspected mesenteric lesions based on imaging reports, which identified 61 potential cases. These records were then rigorously assessed against the predefined diagnostic criteria for IgG4-SM. A total of 32 records were excluded for: incomplete data; non-specific abnormalities; or other causes (e.g., malignancy, infection). After this eligibility assessment, 29 patients confirmed to have IgG4-SM were included in the final analysis, as illustrated in Figure 1A. For comparison, patients without IgG4-SM were randomly selected from the same prospective IgG4-RD cohort at a 1:3 ratio. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Peking Union Medical College Hospital (approval number S-442). Written informed consent was obtained from all patients.

Figure 1

Comparison of clinical characteristics between our cohort and reported cases of IgG4-SM. (A) Flowchart of case selection for IgG4-SM from the prospective IgG4-RD cohort at PUMCH. (B) Flowchart of case selection for IgG4-SM from the literature. (C) Proportion of biopsy types in patients of the two groups. (D) Age distribution of the two groups. (E) Comparison of erythrocyte sedimentation rate (ESR, mm/h) of the two groups (P = 0.002). (F) Comparison of IgG4 levels (mg/dL) of the two groups (P < 0.001). (G) Initial dose of glucocorticoid (mg/d).

This study employed a mixed-methods approach since we combined cases identified in PUMCH cohort with those previously reported. Therefore, we included reported cases with IgG4-SM available in the public database. A systematic literature search was performed in the PubMed database for articles published between 2000 and 2024, using the keywords “IgG4” and “sclerosing mesenteritis, ” which initially identified 609 records. After restricting the article type to case reports, 96 records underwent title and abstract screening. Following a full-text review of the remaining articles for eligibility, 32 cases from the literature were ultimately included for analysis (see Figure 1B).

Diagnosis of IgG4-SM

The diagnosis of IgG4-SM was based on the following criteria:(1) fulfillment of 2020 revised Comprehensive Diagnostic Criteria or the 2019 ACR/EULAR classification criteria for IgG4-RD. (2) imaging evidence of mesenteric involvement, such as hazy shadows, irregular soft tissue masses, or increased ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) uptake on positron emission tomography-computed tomography (PET-CT), and/or pathological evidence of focal or diffuse fibrosis and inflammatory changes in the small bowel mesentery.^[7,13] (3) exclusion of other causes, such as malignancy or infection.

Data Collection and Follow-up

The demographic and clinical characteristics of the study cohort were collected, including age, sex, disease duration, allergy history, symptom onset, affected organs, therapeutic strategy and follow-up duration. All laboratory test results were obtained at baseline, corresponding to the patients’ first clinic visit before the initiation of treatment. Laboratory data included complete blood count (CBC), liver function, renal function, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum IgG, IgA, IgM, total IgE, IgG subclass levels, and complement 3 and 4. When measuring serum IgG4 levels, a standardized procedure was used to mitigate the prozone effect.^[14] All patients underwent abdominal imaging examinations, including computed tomography (CT), magnetic resonance imaging (MRI), or PET-CT, as needed. Pathological biopsies of affected organs were performed in some patients for the diagnosis of IgG4-RD. Patients from the PUMCH cohort were followed until relapse, lost to follow-up, or March 2025, whichever occurred first.

For cases identified in the literature, key data was extracted, including demographics, clinical manifestations, laboratory findings, treatment modalities, and prognosis.

Disease Activity and Clinical Response

The IgG4-RD Responder Index (RI) score was used to evaluate disease activity with a score of 0–3 for each affected organ per visit.^[15] The Physician Global Assessment (PGA) is a subjective evaluation of overall disease activity. Disease relapse was defined as the recurrence or worsening of affected organs, new symptoms, or organ/site-specific radiological manifestations.^[16] Clinical and radiological remission of IgG4-SM were defined as follow: (1) Complete remission: Complete disappearance of symptoms (clinical) or lesions on imaging (radiological); (2) Partial remission: Improvement in symptoms (clinical) or reduction in lesion size on imaging (radiological); (3) No remission: No significant change in symptoms (clinical) or lesions on imaging (radiological); (4) Worsening: Increase in symptom severity (clinical) or enlargement of lesions on imaging (radiological).^[17]

Statistical Analysis

Variables were described using mean ± standard deviation or median with IQR (interquartile range) based on whether the data were normally distributed. Normally distributed data between two groups were analyzed using independent samples t-tests, while non-normally distributed data were analyzed using rank-sum tests. Categorical data were analyzed using chi-square tests or Fisher’s exact tests. Kaplan-Meier curves and Log-Rank tests were used to calculate and compare the cumulative relapse rates among different groups. Statistical analyses were performed using SPSS (version 23.0, IBM), R Studio (version 4.3.1, https://www.r-project.org), Adobe Illustrator CC 2015 (Adobe, Cal, USA), and Prism software version 6.1 (GraphPad Software, La Jolla, CA, USA). A two-tailed P-value < 0.05 was considered statistically significant.

Demographic and Clinical Characteristics

This study included 29 patients from PUMCH and 32 from the literature, totally 61 patients with IgG4-SM. The 29 IgG4-SM patients in PUMCH cohort were assigned as the case group, an additional 87 IgG4-RD patients without sclerosing mesenteritis were randomly selected at a 1: 3 ratio from the IgG4-RD cohort in PUMCH as controls, with no matching geographical features and other clinical parameters, to avoid bias. The demographic and clinical characteristics of IgG4-SM patients are summarized in Table 1.

In the overall cohort of IgG4-RD from PUMCH, the prevalence of IgG4-SM was 2.06% (29/1409), highlighting the rarity of sclerosing mesenteritis in IgG4-RD. The median age at diagnosis of IgG4-SM patients was 63 years (IQR 56–65), significantly higher than that of IgG4-RD patients without sclerosing mesenteritis (median 56, IQR 47–61, P = 0.001). Additionally, the IgG4-SM group had a higher proportion of males aged ≥ 60 years (41.4% vs. 19.5%, P = 0.019). IgG4-SM patients also presented with a greater number of involved organs (median 4, IQR 3–6) compared to those IgG4-RD patients without IgG4-SM (median 3, IQR 2–5, P = 0.019). However, there were no significant differences in the involvement of specific organs, such as the pancreas, lacrimal glands, and submandibular glands, between the two groups. Furthermore, IgG4-SM patients showed significantly higher IgG4-RD RI scores (8.00 [6.00–10.0] vs. 6.00 [4.00–10.0], P = 0.005) and PGA scores (6.26 ± 1.63 vs. 5.22 ± 2.45, P = 0.018) compared to those IgG4-RD patients without IgG4-SM.

We further compared the patients with IgG4-SM in our cohort to those identified through our systematic literature review (n = 32). Compared to the reported cases, no significant differences were observed in sex or age distribution between the two groups (Table 1, Figure 1D). In the aspect of the symptoms, less patients in our cohort presented with abdominal pain compared to reported cases (20.7% vs. 68.8%, P < 0.001). In contrast to the cases in the literature, who did not report symptoms of swollen salivary glands, patients in our cohort of exhibited considerable proportions to have enlargement of submandibular glands (44.8% vs. 0%, P < 0.001) and lacrimal glands (51.7% vs. 0%, P < 0.001). Furthermore, regarding biopsy types, the overall biopsy rate was lower in our cohort compared to that in the literature (65% vs. 97%, P < 0.001), with the majority undergoing biopsies of other affected organs and only a minority undergoing mesenteric biopsies (2/29 in our cohort), all of which were fine-needle aspirations. In contrast, in the reported cases, most of them (29/32) received mesenteric biopsies, where 21 received open surgery and 8 received core-needle aspiration. This contrast indicated the under-recognition of mesenteric involvement in IgG4-RD since its rarity. The detailed types of biopsies are shown in Figure 1C.

Baseline Laboratory Features

Baseline laboratory features (before treatment) of the 29 IgG4-SM patients and 87 IgG4-RD patients without sclerosing mesenteritis are summarized in Table 2. No significant differences were observed between the two groups in terms of hemoglobin (Hb), white blood cell count (WBC), high-sensitivity C-reactive protein (hsCRP), total IgG, IgA, IgM, IgG subclasses (IgG1, IgG2, IgG3), total IgE, complement C3, and C4 levels.

Compared with the 32 IgG4-SM in reported cases (see Table 3 or Figure 1E-F), patients in our cohort exhibited significantly lower levels of ESR (22.5 mm/h [11.2; 39.5] vs. 74.5 mm/h [53.5; 101], P = 0.002) and hsCRP (2.56 mg/L [0.97; 5.97] vs. 28.0 mg/L [22.0; 67.0], P < 0.001). Additionally, IgG4 levels were significantly higher in our cohort compared to the reported cases (6580 mg/L [3950; 15800] vs. 1693 mg/L [1190; 2898], P < 0.001).

Imaging Features

IgG4-SM exhibits characteristic imaging features. Abdominal CT axial images often reveal hazy shadows in the mesenteric region, indicative of mild inflammatory infiltration (see Figure 2A). In more severe cases, CT images may display irregular soft tissue masses, suggesting fibrosis and active inflammation (Figure 2B). PET-CT scans further reveal significant increases in ¹⁸F-FDG uptake within these soft tissue masses, reflecting high metabolic activity (Figure 2C-D).

Figure 2

Characteristic imaging findings of IgG4-SM before and after treatment. (A) Abdominal CT axial image of a patient with mild IgG4-SM showing hazy shadows in the mesenteric region. (B) Abdominal CT axial image of a patient with severe IgG4-SM showing irregular soft tissue masses in the mesenteric region. (C-D) PET-CT images of an IgG4-SM patient showing soft tissue masses in the mesenteric region with significantly increased ¹⁸F-FDG uptake, indicating high metabolic activity. (E-H) Post-treatment images corresponding to (A-D) demonstrate reduced lesion size, resolved hazy shadows, decreased soft tissue masses, and diminished ¹⁸F-FDG uptake, indicating a favorable treatment response.

Despite the potential difficulty in distinguishing IgG4-SM from malignancies on imaging, patients with IgG4-SM typically exhibit favorable radiological responses to corticosteroid therapy. Post-treatment imaging shows reduced lesion size, alleviation of hazy shadows, shrinkage of soft tissue masses, and decreased ¹⁸F-FDG uptake, indicating effective treatment (Figure 2E-H). Compared to previously reported cases of IgG4-SM, our cohort exhibits similar imaging characteristics.^[18]

Pathological Features

Histopathological features of IgG4-SM are consistent with those commonly affected organs. Typical mesenteric lesion from patients with IgG4-SM were shown in Figure 3, which revealed significant infiltration of lymphocytes and plasma cells, clearly demonstrated by hematoxylin and eosin (H& E) staining (Figure 3A). Fibrosis, characterized by dense collagen deposition and increased extracellular matrix, is a hallmark pathological feature of IgG4-SM, particularly in areas of active inflammation (Figure 3B).

Figure 3

Characteristic pathological features of IgG4-SM in a representative patient. (A) Hematoxylin and eosin (H& E) staining showing dense lymphoplasmacytic infiltration. (B) H&E staining revealing prominent fibrosis and periadipose inflammation. (C) CD19 staining highlighting B cell infiltration. (D) CD138 staining demonstrating abundant plasma cell infiltration. (E) IgG staining showing dense infiltration of IgG-positive plasma cell. (F) IgG4 staining revealing scattered IgG4-positive plasma cell infiltration.

Immunohistochemical staining showed dense infiltration of CD20^-positive B cells, CD138^-positive plasma cells, IgG-positive plasma cells, and IgG4-positive plasma cells (Figure 3C-F). Analysis of the staining results indicated that the ratio of IgG4-positive plasma cells to IgG-positive plasma cells (IgG4+/IgG+) exceeded 40%, with a density of IgG4-positive plasma cells greater than 10 cells per high-power field (HPF). The histopathological features observed in the mesenteric tissues from our cohort were consistent with those described in the literature-reported cases, demonstrating the characteristic lymphoplasmacytic infiltration, fibrosis, and immunohistochemical profile typical of IgG4-RD.

Treatment and Prognosis

In our cohort, the primary baseline treatment modality for IgG4-SM was corticosteroids, either alone or in combination with immunosuppressive agents (Figure 4A; treatment details are provided in Supplementary Table S1). Initial treatment typically involved prednisone at a dose of 30–40 mg/ day (Figure 1G). In contrast, surgical resection was less frequent in our patients compared to the reported cases (resection rate: 6.9% vs. 59.4%, P < 0.001, Table 3).

Figure 4

Comparison of treatment and prognosis among IgG4-RD without SM, IgG4-SM in our cohort, and IgG4-SM in reported cases. (A) Treatment modalities compared among the three groups. (B) Kaplan-Meier non-relapse survival curves for the three groups (log-rank test, P = 0.17). (C) Treatment outcomes in IgG4-SM patients from our cohort and reported cases.

After the treatment, the majority of IgG4-SM patients in our cohort exhibited favorable clinical and radiological responses, with significant symptom alleviation and reduced lesion size on imaging (Figure 4C). However, compared to the reported cases, our cohort had a lower radiological complete response rate (23.1% vs. 48.3%, P = 0.04), which may be attributed to differences in treatment approaches.

The median follow-up time in our cohort was 20 months (IQR 6–61), significantly longer than that in reported cases (median 6 months, IQR 4–12, P = 0.02). Despite this difference, Kaplan-Meier analysis showed no significant differences in cumulative relapse rates among the three groups (P = 0.17, Figure 4B).

Seven patients were followed for ≥ 5 years, including one patient for more than 10 years. All seven patients were alive at the last follow-up (overall survival rate, 100%). Five patients (71.4%) experienced relapse during follow-up, either in previously affected organs (for example, pancreas, sinus, or mesentery) or in newly involved sites such as the retroperitoneum and mediastinal lymph nodes. The remaining two patients maintained sustained remission throughout follow-up. Detailed clinical courses of these seven patients are presented in Supplementary Table S2. These findings indicate that IgG4-SM generally demonstrates a favorable long-term outcome but may relapse several years after initial remission, particularly following glucocorticoid tapering or discontinuation.