Low Complement Levels in IgG4-Related Disease

IgG4-related disease (IgG4-RD) is a systemic, immune-mediated disease, and little is known about the role of the complement system in disease pathogenesis. Up to 40% of patients with active IgG4-RD have low complement levels (C3 and C4) in the blood.¹ Historically, the hypocomplementemia in IgG4-RD has been considered specific to renal involvement with IgG4-related tubulointerstitial nephritis (TIN).

This single-center, cross-sectional study by Katz et al examined the phenotypic differences in patients with IgG4-RD with and without hypocomplementemia and assessed the association of low complement with disease features and other serologic markers of disease activity.¹ The study enrolled patients who fulfilled the 2019 American College of Rheumatology/European League Against Rheumatism IgG4-RD classification criteria and had data on complement components. Patients without complement data were excluded.

Researchers obtained data on disease features, organ involvement, and disease activity from the treating rheumatologist. Patients with pachymeningitis, hypophysitis, Reidel’s thyroiditis, fibrosing mediastinitis, retroperitoneal fibrosis, and sclerosing mesenteritis were combined into a single category of “fibrotic disease” for analysis, due to small sample sizes. Serologic data extracted from the medical records included serum concentrations of C3, C4, IgG1, IgG2, IgG3, IgG4, IgE, and peripheral blood absolute eosinophil count. Unadjusted and multivariable-adjusted logistic regression analyses were performed to identify factors associated with hypocomplementemia.

The study enrolled 249 patients with IgG4-RD who had complement data, with hypocomplementemia present in 32% of the cohort (n=90). Those with low complement levels had higher scores on classification criteria and a greater number of organs involved. Of interest, hypocomplementemia was not seen exclusively in patients with renal involvement. Even among the 94 patients with known renal involvement, only around half had hypocomplementemia. After adjusting for age, sex, and number of organs involved, only lymph node (odds ratio [OR], 2.59) and lung (OR, 2.56) involvement remained associated with hypocomplementemia. Patients with fibrotic disease manifestations and lacrimal gland involvement were less likely to have hypocomplementemia than those without these disease manifestations (OR, 0.43).

When evaluating disease characteristics, researchers found that patients with hypocomplementemia were more likely to be on immunosuppression (particularly rituximab) and to have active, untreated disease than those with normal complement levels. Hypocomplementemia was associated with higher concentrations of all IgG subclasses and IgE. After adjusting for serum IgG1 and IgG3, only IgG1 remained strongly associated with hypocomplementemia. Those with hypocomplementemia also tended to have higher eosinophil counts than those without.

This study provides novel and important data demonstrating that hypocomplementemia in IgG4-RD is not seen exclusively in patients with renal involvement, shifting the previously held paradigm regarding the role of complement in this disease. The authors demonstrated an association of hypocomplementemia with higher disease activity and greater organ involvement. Thus, the association between hypocomplementemia and TIN may be explained by other disease features and multiorgan involvement rather than TIN alone.

There are a few limitations of the study, including the single-center cohort, which limits potential generalizability, and the use of clinical laboratory results to define hypocomplementemia, which included external facilities and precludes knowing if complement activation also occurs at the tissue level. The exact mechanisms by which complement is activated in this disease also need further investigation. However, the study provides evidence of a strong association between disease activity and hypocomplementemia in IgG4-RD and highlights the importance of checking complement levels even in patients without renal involvement.

Reference

[1] Katz G, Perugino C, Wallace ZS, et al. Multiorgan involvement and circulating IgG1 predict hypocomplementaemia in IgG4-related disease. Ann Rheum Dis. 2024. doi:10.1136/ard-2024-225846