IgG4 related mesenteritis

IgG4 Related Mesenteritis (IgG4 Related Sclerosing Mesenteritis)

Overview and nomenclature

IgG4-related mesenteritis is a rare fibroinflammatory disorder of the small-bowel mesentery that belongs to the spectrum of IgG4-related disease (IgG4-RD) and presents histologically as sclerosing mesenteritis with IgG4-rich inflammation. Orphanet defines it as a subtype of sclerosing mesenteritis, a disease characterized by chronic inflammation and fibrosis of the mesenteric adipose tissue, with clinical manifestations such as abdominal pain, diarrhea, nausea, weight loss, bloating, and anorexia. When the histologic pattern of sclerosing mesenteritis shows dense lymphoplasmacytic infiltrates enriched in IgG4-positive plasma cells, storiform fibrosis, and often elevated serum IgG4 levels, the condition is labeled IgG4-related sclerosing mesenteritis (IgG4-RSM).[^1][2][^3][4]

Synonymous or closely related terms in the literature include:

• IgG4-related mesenteritis
• IgG4-related sclerosing mesenteritis (IgG4-RSM)
• IgG4-related disease with mesenteric involvement
• A mesenteric manifestation of systemic IgG4-RD[^2][5][^1]

Relationship to sclerosing mesenteritis and IgG4-RD

Sclerosing mesenteritis

Sclerosing mesenteritis (SM) is an uncommon, chronic fibroinflammatory condition affecting the mesenteric fat of the small intestine, with overlapping histologic subtypes: mesenteric panniculitis (inflammation and fat necrosis predominating) and retractile mesenteritis (marked fibrosis and retraction). Traditionally considered idiopathic, SM has been associated with prior abdominal surgery or trauma, autoimmune conditions, and malignancy.[^6][4]

IgG4-related disease spectrum

IgG4-RD is a systemic immune-mediated fibroinflammatory disease characterized by tumefactive lesions, dense IgG4-positive lymphoplasmacytic infiltrates, storiform fibrosis, and often obliterative phlebitis, usually accompanied by elevated serum IgG4 levels. Commonly involved organs include the pancreas (autoimmune pancreatitis), biliary tree, salivary and lacrimal glands, retroperitoneum, kidneys, and lymph nodes.[^7][5][^8][9]

Mesenteric involvement is rare but increasingly recognized as part of this spectrum. Case reports and small series document sclerosing mesenteritis with classic IgG4-RD histopathologic features and systemic or serologic evidence of IgG4-RD, supporting the concept of IgG4-related mesenteritis as a distinct organ manifestation of IgG4-RD.[^3][8][^1][2]

Epidemiology

Sclerosing mesenteritis itself is rare, with an estimated prevalence of <1% in abdominal CT series; IgG4-related mesenteritis is rarer still and has been described mainly in isolated case reports and small case series. Orphanet notes that the overall prevalence of sclerosing mesenteritis is unknown, and no separate population figures are available for the IgG4-related subset.[^4][1][^2][3]

Published cases span a wide adult age range (from the third to eighth decade), with a slight predominance among middle-aged and older adults. Both sexes are affected; some series suggest male predominance in generic SM, but IgG4-RSM cases include both men and women.[^1][2][^3][6]

Pathogenesis and histopathology

IgG4-RD pathophysiology

The pathogenesis of IgG4-RD involves a Th2- and regulatory T-cell–skewed immune response, expansion of IgG4-secreting plasmablasts, and activation of fibroblasts, leading to progressive fibrosis. Key cytokines include IL-4, IL-10, IL-13, and TGF-β, which promote class switching to IgG4 and extracellular matrix deposition.[^5][9][^7]

Mesenteric involvement

When IgG4-RD involves the mesentery, the histologic triad characteristic of IgG4-RD overlaps with the features of sclerosing mesenteritis:[^2][3][^1]

• Dense lymphoplasmacytic infiltrate, often nodular, with numerous IgG4-positive plasma cells (typically >10–50 IgG4+ cells per high-power field and an IgG4+/IgG+ ratio >40%).
• Storiform (cartwheel-like) fibrosis affecting mesenteric fat and connective tissue.
• Variable obliterative phlebitis, in which veins within the lesion are destroyed and replaced by inflammatory/fibrotic tissue.
• Background of fat necrosis, chronic inflammation, and fibrosis, overlapping with classic SM histology.[^6][1][^2]

Immunohistochemical staining confirms increased IgG4-positive plasma cells and helps distinguish IgG4-RSM from non-IgG4-related sclerosing mesenteritis and from malignancies such as lymphoma or desmoplastic metastatic carcinoma.[^3][1][^2]

Clinical presentation

Symptoms

IgG4-related mesenteritis often presents non-specifically and may mimic malignancy. Common symptoms reported across case series and reviews include:[^10][1][^2][3]

• Abdominal pain (often chronic or colicky, sometimes localized to the right lower quadrant or periumbilical region).
• Abdominal distension or a palpable mass.
• Weight loss and decreased appetite.
• Nausea, vomiting, and altered bowel habits, sometimes with diarrhea.

Some patients are incidentally diagnosed when mesenteric abnormalities are detected during imaging for other reasons, such as evaluation of systemic IgG4-RD or suspected malignancy.[^10][7]

Systemic features and organ associations

In many cases, mesenteritis is part of multisystem IgG4-RD, with involvement of other organs such as:[^8][7][^5]

• Pancreas (autoimmune pancreatitis).
• Biliary tree and liver (sclerosing cholangitis, hepatic lesions).
• Retroperitoneum (retroperitoneal fibrosis).
• Salivary and lacrimal glands (Mikulicz disease).
• Lungs and pleura.

However, some reports document isolated IgG4-related sclerosing mesenteritis without other organ involvement, making it more difficult to distinguish clinically from idiopathic SM or malignancy.[^2][3]

Laboratory findings

Laboratory abnormalities may include:[^7][3][^2]

• Elevated serum IgG4 levels, though this is not universal.
• Mild elevation of acute-phase reactants (ESR, CRP) in some patients.
• Non-specific laboratory changes related to nutritional compromise or associated organ involvement.

Negative tumor markers and absence of clonal populations on immunophenotyping support a non-neoplastic diagnosis when malignancy is suspected.[^10][2]

Imaging features

CT and MRI

Imaging plays a central role in detection but is not specific for IgG4-RSM and often raises suspicion for malignancy. Common CT/MRI findings include:[^8][1][^3][2]

• Lobulated or ill-defined soft-tissue mass in the root of the mesentery or small bowel mesentery.
• Increased density or “misty” mesentery with fat stranding.
• Encasement of mesenteric vessels without overt vascular occlusion (the “fat-ring” or “halo” sign may be less prominent than in classic mesenteric panniculitis).
• Calcifications or cystic/necrotic areas within the mass in some cases.[^1]
• On FDG-PET/CT, hypermetabolic activity in the mass can mimic malignancy.[^3][7]

Differentiation from malignancy

Given this imaging overlap, IgG4-RSM is often initially interpreted as lymphoma, carcinoid, desmoplastic metastasis, or mesenteric desmoid tumor. Definitive distinction typically requires histologic examination obtained via surgical excision or image-guided core biopsy.[^8][1][^2][3]

Diagnosis

Diagnostic criteria

There are no separate formal criteria specific to IgG4-related mesenteritis, so diagnosis relies on the general IgG4-RD classification framework (e.g., the 2019 ACR/EULAR classification criteria) applied to the mesentery. Key components include:[^9][5]

1. Compatible clinical and radiologic presentation:
   1. Mesenteric mass or inflammatory lesion consistent with sclerosing mesenteritis.
2. Histopathology showing:
   1. Dense lymphoplasmacytic infiltrate.
   1. Storiform fibrosis.
   1. Obliterative phlebitis (when evaluable).
   1. Abundant IgG4-positive plasma cells on immunostaining.[^1][2][^3]
3. Serologic support:
   1. Elevated serum IgG4 (>135 mg/dL) strengthens the diagnosis but is not mandatory.[^5][7]
4. Evidence of systemic IgG4-RD (other organ involvement) further supports classification when present.[^7][5]

Exclusion of mimickers

A critical part of diagnosis is excluding other entities that can mimic IgG4-RSM:[^2][3][^8][1]

• Malignancies: lymphoma, metastatic carcinoma (e.g., from small bowel, colon, or pancreas), carcinoid tumors.
• Non-IgG4 sclerosing mesenteritis and other inflammatory panniculitides.
• Infectious processes (e.g., tuberculosis, fungal infections) involving the mesentery.

Histopathology with immunohistochemical staining for IgG4 and IgG, as well as special stains for organisms and clonality studies, is essential to differentiate these conditions.[^6][1][^2]

Differential diagnosis

The differential diagnosis of a mesenteric mass or “misty mesentery” includes:

• Idiopathic sclerosing mesenteritis without IgG4 features.[^4]
• Mesenteric panniculitis and retractile mesenteritis not related to IgG4-RD.[^4]
• Malignancies: non-Hodgkin lymphoma, desmoplastic metastatic carcinoma (e.g., neuroendocrine tumor), gastrointestinal stromal tumor with mesenteric extension.
• Metastatic carcinoid with mesenteric fibrosis.
• Infectious granulomatous diseases (TB, fungal, Whipple’s disease).
• Vasculitides or other systemic inflammatory diseases affecting the mesentery.[^8][1][^2]

Clinical context (systemic IgG4-RD manifestations, serum IgG4), imaging, and, most importantly, histology help refine the diagnosis.

Management

General principles

Treatment of IgG4-related mesenteritis follows general IgG4-RD management principles, with glucocorticoids as first-line therapy and additional immunosuppressive or biologic agents (e.g., rituximab) used in refractory or relapsing disease.[^9][5][^7]

Glucocorticoid therapy

Multiple case reports document dramatic symptom relief and radiologic regression of mesenteric lesions with systemic corticosteroids:[^11][3][^2]

• Typical induction regimens mirror those used in other IgG4-RD manifestations, such as prednisone 0.6 mg/kg/day for 2–4 weeks, followed by a gradual taper over several months.[^5][9]
• Response is monitored clinically (pain, weight, GI symptoms), biochemically (serum IgG4 and inflammatory markers), and radiologically (CT/MRI/PET).[^3][7]

Steroid-sparing agents and biologics

For patients who are steroid-dependent, relapse upon tapering, or have contraindications to long-term steroids:

• Conventional immunosuppressants such as azathioprine, mycophenolate mofetil, or methotrexate have been used with variable success as maintenance therapy in IgG4-RD.[^9][5]
• Rituximab (anti-CD20 monoclonal antibody) is increasingly recognized as an effective option for IgG4-RD, including abdominal manifestations, by depleting B cells and reducing plasmablasts. While specific data for IgG4-RSM are limited to case reports and small series, responses appear consistent with other organ disease.[^5][9]
• A recent case described successful treatment of IgG4-RSM with prednisolone plus thalidomide, resulting in significant regression of the mesenteric mass, though this approach remains experimental.[^11]

Role of surgery

Many patients with IgG4-RSM undergo surgery before diagnosis because imaging strongly suggests malignancy and tissue is needed for histology. Once diagnosis is established, surgery is generally reserved for:[^1][2][^3]

• Diagnostic biopsy when less invasive methods are not feasible.
• Management of complications, such as bowel obstruction, ischemia, or perforation.

Routine extensive resection is avoided whenever possible, given the responsiveness of IgG4-RSM to medical therapy.[^11][2]

Prognosis and follow-up

Short- and medium-term outcomes

Case reports and small series indicate that most patients with IgG4-related mesenteritis who receive appropriate therapy have good symptomatic and radiologic responses, with regression or stabilization of mesenteric lesions. Nevertheless, relapse is possible, especially if steroids are tapered too rapidly or maintenance therapy is not used.[^9][11][^2][3][^5]

Because IgG4-RD is a chronic relapsing condition, ongoing follow-up is recommended to monitor for:

• Recurrence or progression of mesenteric disease.
• New involvement of other organs (e.g., pancreas, biliary tree, retroperitoneum).
• Treatment-related adverse effects (steroid complications, immunosuppression risks).[^7][5]

Long-term outlook

Long-term, IgG4-RD generally has a favorable prognosis if recognized early and treated appropriately; chronic organ damage from progressive fibrosis is the main concern. For IgG4-RSM specifically, data are sparse but suggest that mortality is more often related to complications of undiagnosed or untreated disease (bowel obstruction, ischemia) or comorbid conditions, rather than the mesenteritis itself when treated.[^2][3][^7][5][^8][9]

Practical points for clinicians and writers

• IgG4-related mesenteritis should be considered in adults with mesenteric masses or “misty mesentery” on imaging, especially when accompanied by elevated serum IgG4, other features of IgG4-RD, or histology showing storiform fibrosis with IgG4-rich plasma cells.[^5][1][^2]
• Because imaging findings often mimic malignancy, histologic confirmation with IgG4 immunostaining is crucial to avoid unnecessary extensive surgery and to guide appropriate immunosuppressive treatment.[^8][1][^2]
• First-line therapy is systemic glucocorticoids, with excellent short-term responses in most reported cases; rituximab and other steroid-sparing agents are reserved for relapsing or refractory disease.[^9][2][^5]
• Multidisciplinary management involving gastroenterology, rheumatology, radiology, pathology, and surgery is often needed, particularly in complex presentations or when differentiating from malignancy.[^10][11][^7]

Authoritative references to support educational and clinical writing include the Orphanet summary on IgG4-related mesenteritis, case series and reviews from NIH/PMC on IgG4-RSM, radiologic overviews of abdominal IgG4-RD, and recent comprehensive reviews of IgG4-related digestive diseases.[^4][7][^1][2][^5][9]

References

1. IgG4-Related Sclerosing Mesenteritis – PMC – NIH – by SJ Lee · 2016 · Cited by 26 — In particular, if the histologic and immunologic features are assoc…
2. A Case of IgG4-related Sclerosing Mesenteritis – PMC – NIH – by Z Butt · 2018 · Cited by 14 — Immunoglobulin G4 (IgG4)-related sclerosing mesenteritis is one of …
3. A Case Report With an Updated Review of the Literature – PMC – by M Bertoni · 2022 · Cited by 8 — Our case report describes a patient with symptomatic sclerosing m…
4. IgG4-related mesenteritis – IgG4-related mesenteritis … Sclerosing mesenteritis (SM) is a rare pathological disease causing in…
5. IgG4-Related Disease With Gastrointestinal Involvement – PMC – IgG4-related disease is an immune-mediated chronic, systemic, and autoinflammatory disease that can …
6. IgG4-related sclerosing mesenteritis and its possible … – This report describes a woman with an IgG4 related Sclerosing mesenteritis. Among the implicated eti…
7. IgG4-Related Disease: A Constellation of Abdominal Manifestations – IgG4-related disease is an autoimmune condition that results in inflammation and fibrosis throughout…
8. Atypical Manifestations of IgG4-Related Sclerosing Disease in … – Sclerosing mesenteritis can be associated with IgG4-related sclerosing disease [3, 14]. In a previou…
9. IgG4-related digestive diseases: diagnosis and treatment – IgG4-related digestive diseases encompass a group of chronic inflammatory disorders characterized by…
10. A Case of Rare IgG4-Related Disease – Introduction: Immunoglobulin G4 Related Diseases (IgG4RD) are systemic disorders characterized by or…
11. Diagnostic Dilemma: IgG4-Related Sclerosing Mesenteritis … – IgG4-related disease is a newly recognized fibroinflammatory condition characterized by the above fe…