Comparison of Pathological Findings Between Relapsed and Non-Relapsed IgG4-RD

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Comparison of Pathological Findings Between Patients with Relapsed and Non-Relapsed Immunoglobulin G4-Related Disease

Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterized by elevated serum IgG4 levels, multi-organ involvement, and distinct histopathological features. These features include dense lymphoplasmacytic infiltrates, storiform fibrosis, obliterative phlebitis, and a significant infiltration of IgG4-positive plasma cells in affected tissues. Despite advancements in understanding the clinical and serological predictors of relapse, such as demographics, treatment regimens, and laboratory markers, the role of histopathological characteristics in predicting disease recurrence remains unexplored. This study aimed to investigate whether specific pathological features correlate with relapse in IgG4-RD patients, providing insights into potential biomarkers for disease prognosis.

Study Design and Patient Characteristics

The study enrolled 15 relapsed and 30 non-relapsed IgG4-RD patients from a prospective cohort (ClinicalTrials.gov ID: NCT01670695). All patients met the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-RD and underwent diagnostic biopsies at Peking Union Medical College Hospital. The relapse and non-relapse groups were rigorously matched for age, sex, biopsied organ, baseline clinical parameters, and serological profiles to minimize confounding variables. A relapse was defined as the recurrence or worsening of symptoms or imaging findings, with or without elevated serum IgG4 levels, while isolated increases in IgG4 without clinical deterioration were excluded from the relapse definition.

Disease activity was assessed using the IgG4-RD Responder Index (RI). Treatment response criteria included a ≥50% reduction in the IgG4-RD RI within six months or successful glucocorticoid (GC) tapering to a maintenance dose without relapse. Patients received standard therapy with GCs alone or in combination with immunosuppressants (IMs), with comparable initial and maintenance GC doses between groups.

Pathological Evaluation

Tissue samples were fixed in formalin, embedded in paraffin, and sectioned for hematoxylin and eosin (H&E), Elastica van Gieson, Masson’s trichrome, and immunohistochemical (IHC) staining. Histopathological features evaluated included:

  1. Fibrosis: Graded as 3+ (>50% of the field replaced by fibrous tissue), 2+ (33–50%), 1+ (<33%), or absent.
  2. Lymphoplasmacytic Infiltration: Quantified by the density of plasma cells and lymphocytes.
  3. Obliterative Phlebitis: Assessed by the presence of venous occlusion due to inflammation.
  4. Lymphoid Follicle Formation: Counted as ectopic germinal centers.
  5. IgG4+/IgG+ Plasma Cell Ratios: Evaluated using IHC staining with anti-IgG4 (EP138) and anti-IgG antibodies. Positive cells were counted in five high-powered fields (HPFs; 0.034 mm² per field), and the IgG4+/IgG+ ratio was calculated.

Clinical and Serological Parameters

Baseline clinical and laboratory data, including disease duration, organ involvement, complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum immunoglobulins (IgG, IgA, IgM), IgG subclasses, total IgE (T-IgE), and eosinophil counts, were analyzed. No significant differences were observed between relapsed and non-relapsed groups in these parameters, ensuring comparability.

Key Findings

Absence of Pathological Differences Between Relapse and Non-Relapse Groups

Despite thorough evaluation, no significant differences were identified in histopathological features between relapsed and non-relapsed patients:

  • IgG4+ Plasma Cells/HPF: Median counts were 68.3 (relapse) vs. 65.1 (non-relapse), P = 0.789.
  • IgG+ Plasma Cells/HPF: 102.4 (relapse) vs. 98.7 (non-relapse), P = 0.882.
  • IgG4+/IgG+ Ratio: 0.67 (relapse) vs. 0.66 (non-relapse), P = 0.642.
  • Fibrosis Grade: 2.1 (relapse) vs. 2.0 (non-relapse), P = 0.734.
  • Lymphoid Follicles/HPF: 3.2 (relapse) vs. 3.0 (non-relapse), P = 0.581.
  • Obliterative Phlebitis and Eosinophil Infiltration: No significant differences (P > 0.05).

Correlations Between Pathological and Clinical Variables

In the pooled cohort, several correlations emerged:

  1. IgG4+ Plasma Cells and Serum IgG4 Levels: Positive correlation (r = 0.32, P = 0.032).
  2. IgG4+ Plasma Cells and Disease Activity: Strong correlation with IgG4-RD RI (r = 0.492, P < 0.001) and number of involved organs (r = 0.389, P = 0.008).
  3. IgG4+/IgG+ Ratio and Serum IgG2: Negative correlation (r = -0.402, P = 0.006).
  4. IgG+ Plasma Cells and Serum IgG4: Positive correlation (r = 0.297, P = 0.048).

Discussion

This study represents the first comprehensive comparison of histopathological features in relapsed versus non-relapsed IgG4-RD patients. The absence of significant pathological differences between groups suggests that traditional markers, such as IgG4+ plasma cell density or fibrosis severity, may not predict relapse risk. However, the correlations between IgG4+ plasma cells and disease activity metrics (IgG4-RD RI, organ involvement) underscore the role of tissue-level IgG4 responses in driving systemic inflammation.

The negative correlation between the IgG4+/IgG+ ratio and serum IgG2 levels is intriguing, as IgG2 is associated with antimicrobial responses. This inverse relationship may reflect an immune dysregulation where excessive IgG4 production suppresses protective IgG2 responses, potentially contributing to disease chronicity.

Clinical Implications

The findings highlight the complexity of IgG4-RD pathophysiology, where clinical relapse may arise from mechanisms independent of classical histopathological features. Factors such as residual subclinical inflammation, genetic predisposition, or microenvironmental cues in affected organs might influence relapse risk. The study also reinforces the utility of the IgG4-RD RI as a robust tool for monitoring disease activity and treatment response.

Limitations and Future Directions

The study’s retrospective design and small sample size limit the generalizability of findings. Additionally, the exclusion of lymph node biopsies (due to nonspecific lymphoid hyperplasia) may have omitted relevant data. Future prospective studies with larger cohorts, multi-organ biopsies, and advanced techniques (e.g., transcriptomics, single-cell sequencing) are needed to identify novel histopathological or molecular relapse predictors.

Conclusion

While this study did not identify specific pathological predictors of IgG4-RD relapse, it elucidated critical relationships between tissue IgG4+ plasma cells and systemic disease activity. These insights pave the way for integrating histopathological and clinical data to refine prognostic models and personalize therapeutic strategies.

doi.org/10.1097/CM9.0000000000001713

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