Immunoglobulin G4 biomarkers and pathogenesis in immunoglobulin G4-related spinal pachymeningitis

Abstract

This letter to the editor highlights adding the diagnostic utility of immunoglobulin G4 (IgG4) measurements and its potential role in IgG4-related spinal pachymeningitis (IgG4-RSP) pathogenesis to the case reported by Chae TS et al, which focused on IgG4-RSP diagnosis based on magnetic resonance imaging findings and increased plasma IgG4 concentrations. A comprehensive understanding of both IgG4 serological and cerebrospinal fluid biomarkers is essential for managing this complex condition.

Key Words: IgG4-related spinal pachymeningitis; Serum IgG4; Cerebrospinal fluid IgG4; IgG4 indices; Pathogenesis

Core Tip: Immunoglobulin G4 (IgG4)-related spinal pachymeningitis is a rare inflammatory disorder affecting the spinal dura mater. Although increased serum IgG4 levels are commonly reported, they lack specificity when used in isolation. Cerebrospinal fluid-based biomarkers, such as the IgG4 indices and the presence of IgG4-specific oligoclonal bands, may provide a reliable alternative to meningeal biopsy, particularly when the latter is contraindicated or yields inconclusive results. These biomarkers offer advantages in terms of cost, accessibility, sensitivity, and specificity. Clarifying the pathogenic vs regulatory role of IgG4 is critical for both diagnosis and treatment.

TO THE EDITOR

In this issue of reported a case of immunoglobulin G4 (IgG4)-RSP, diagnosed primarily through elevated serum IgG4 levels (318 mg/dL) and whole-spine magnetic resonance imaging findings[1]. This paper highlights two critical aspects: The diagnostic utility of IgG4 measurements and its potential role in IgG4-RSP pathogenesis.

Plasma IgG4 levels exceeding 135 mg/dL are included in the diagnostic criteria for IgG4-related disease (IgG4-RD)[2]. Moreover, a plasma IgG4 concentration exceeding 280 mg/dL has proven valuable for differential diagnosis and prognosis in IgG4-RD[3], while a serum IgG4 level above 135 mg/dL, observed in 80% of individuals with active illness, serves as essential supportive evidence when only one histological feature is present[4]. Notably, maintenance rituximab therapy appears to markedly reduce serum IgG4 levels and promote both clinical and radiologic remission in patients with IgG4-related hypertrophic pachymeningitis[5]. However, clinicians should take into account the limitations of the serological test. Elevated plasma IgG4 levels may also occur in other immune-mediated forms of hypertrophic pachymeningitis, notably in cases associated with antineutrophil cytoplasmic antibody (ANCA)-related vasculitis[6]. Carruthers et al[7] further demonstrated that elevated serum IgG4 concentrations alone have reduced specificity for diagnosing IgG4-RD. Since plasma IgG4 levels vary depending on the extent of organ and tissue involvement, they may be unreliable and non-specific when used as a sole diagnostic marker. Therefore, meningeal biopsy and histopathological analysis are crucial for confirming hallmark dural morphological patterns, particularly dense lymphoplasmacytic infiltrates, storiform fibrosis, and obliterative phlebitis[8,9]. Immunohistochemical evidence, such as IgG4-positive plasma cell counts exceeding 10 per high-power field and an IgG4/IgG cell ratio greater than 40%[8,10], further supports a definitive diagnosis. Nonetheless, meningeal biopsy is invasive and may be complicated by technical challenges, including the infrequent detection of obliterative phlebitis in spinal lesions[11,12] and difficulties in obtaining an adequate number of IgG4-positive cells from small tissue samples[13].

In addition to plasma IgG4, cerebrospinal fluid (CSF) biomarkers, specifically the IgG4 indices and CSF-specific IgG4 oligoclonal bands, may enhance diagnostic specificity and serve as cost-effective, non-invasive alternatives for both diagnosis and monitoring of IgG4-RSP[14-16]. Quantitative assessment of intrathecal IgG4 synthesis has shown that an IgG4 Loc greater than 0.47 combined with CSF IgG4 levels above 2.27 mg/dL can perfectly distinguish IgG4-related hypertrophic pachymeningitis from other inflammatory pachymeningitides, achieving both 100% sensitivity and specificity[17]. Moreover, CSF IgG4 production correlates with disease activity[9], and normalization of CSF IgG4 levels following effective immunosuppressive treatment further reinforces their prognostic value[16]. Feldmann et al[15] have also shown that IgG4+ plasma cells determination in CSF via minimally invasive methods provides additional diagnostic confirmation. So, CSF biomarkers may serve as valuable alternatives to meningeal biopsy when the latter is contraindicated or less informative.

Several hypotheses have been proposed to clarify the potential role of IgG4 antibodies in IgG4-RSP. Several studies revealed the presence of ANCA in the serum from patients with IgG4-RSP[18,19]. Recently, neutralizing anti-IL-1 receptor antagonist (IL-1RA) autoantibodies have been identified in individuals with IgG4-RD[20]. Although there are no reports investigating these autoantibodies in IgG4-RSP, the observed increase in IL-1RA in CSF[21] does not necessarily exclude their involvement in the disease process. Moreover, the chronic nature of the disease and its clinical and serological responsiveness to steroids and rituximab[5] support the autoimmune nature of IgG4-RSP. However, since these autoantibodies are of IgG1 subtype, this mechanism is less convincing. A second hypothesis posits that T helper type 2 inflammation drives IgG4 responses in IgG4-RSP, as evidenced by significantly elevated CSF levels of interleukin (IL)-4, IL-5, IL-6, IL-9, and IL-10[21]. Even though the exact signal that triggers B-cell class switching to IgG4 remains to be fully elucidated, the concomitant increase in IL-4[21] appears to facilitate IL-10-mediated class switching in B lymphocytes, ultimately leading to the secretion of IgG4[22]. The observed reduction in serum IgG4 levels following treatment with IL-4/IL-13 inhibitors such as dupilumab further supports this hypothesis[23]. Additionally, activated B cells and macrophages release transforming growth factor-β1 (TGF-β1), which activates the TGF-βRI/SMAD2/3 pathway in dural fibroblasts, thereby contributing to fibrosis and inflammation[21,24]. This signalling pathway may represent a potential therapeutic target. Moreover, subjects with IgG4-RSP often exhibit heightened IgG4 reactivity against environmental antigens, such as those found in infective endocarditis[1], suggesting that IgG4 production may result from a pleiotropic stimulation of IgG4+ B lymphocytes, independent of antigen specificity. The third proposed mechanism speculates that IgG4 primarily acts as a regulator, mitigating ongoing immune activity or, ultimately, an epiphenomenon without directly influencing the pathogenesis of IgG4-RSP[25]. IgG4 has been reported to act as an anti-inflammatory antibody, regulating immune reactions by competing with other immunoglobulins and thereby preventing excessive immune activation[26]. Further studies are needed to confirm this hypothesis.

The optimal treatment for IgG4-related pachymeningitis remains to be established. Corticosteroids are the first-line therapy; however, relapsing cases may require immunosuppressive agents such as azathioprine, methotrexate, mycophenolate mofetil, or cyclophosphamide, as well as an anti-CD20 B-lymphocyte–depleting agent (e.g., rituximab). The efficacy of these treatments can be limited by advanced fibrotic changes and variable drug penetration through the blood–brain barrier[5,27,28]. Emerging therapeutic approaches targeting IL-4/IL-13 and TGF-β pathways (e.g., dupilumab and TGF-β blockers) also show potential as alternative strategies.

CONCLUSION

In summary, while serum IgG4 and CSF-based biomarkers such as the IgG4 indices and oligoclonal bands improve the non-invasive diagnosis and monitoring of IgG4-RSP, their interpretation should be integrated with clinical and histopathological findings to overcome diagnostic challenges. Further research is warranted to refine targeted therapies and clarify the multifaceted role of IgG4 in this complex disease.

ACKNOWLEDGEMENTS

We are indebted to Hanane Bouayad for his assistance and fruitful contribution.