Elevated serum immunoglobulin G4 (IgG4) levels were more frequently observed in patients with C-reactive protein (CRP)-associated rheumatic diseases than in those with non-CRP-associated diseases, according to a recent study published in Medicine (Baltimore). The study also found no significant association between elevated serum IgG4 levels and autoantibody status.
IgG4 is the least abundant immunoglobulin G (IgG) subclass in human serum, accounting for approximately 5% of total IgG. Prolonged or repeated antigen exposure can promote IgG4 production through mechanisms involving a modified T-helper 2 (Th2) immune response. Elevated serum IgG4 levels have been reported in a range of inflammatory and autoimmune rheumatic diseases, including rheumatoid arthritis (RA), spondyloarthritis (SpA), vasculitis, and adult-onset Still disease (AOSD), which are commonly associated with elevated CRP levels. Elevations have also been reported in Sjögren syndrome (SS), systemic lupus erythematosus (SLE), retroperitoneal fibrosis (RPF), undifferentiated connective tissue disease (UCTD), and idiopathic inflammatory myopathy (IIM), in which CRP elevation may be less prominent. Because elevated serum IgG4 is not specific for IgG4-related disease (IgG4-RD), distinguishing IgG4-RD from other rheumatic diseases remains an important clinical challenge.
The retrospective, single-centre study included 255 patients with rheumatic diseases who underwent serum IgG4 testing between January 2017 and December 2022. Patients were categorised according to whether their rheumatic disease was typically associated with elevated CRP levels or without prominent CRP elevation. They were also classified according to the presence or absence of disease-specific autoantibodies.
Serum IgG4 levels of ≥1.35 g/L were considered elevated. Elevated IgG4 was more frequently observed among patients with RA than among those with SS (30.36% vs 11.83%; P=.005). Patients with CRP-associated rheumatic diseases had a significantly higher frequency of elevated serum IgG4 than those with non-CRP-associated diseases (30.23% vs 14.20%; P<.001). Among patients with RA, elevated serum IgG4 levels were associated with higher levels of immunoglobulin M, IgG, CRP, and erythrocyte sedimentation rate, as well as higher Disease Activity Score 28-CRP scores (all P<.05). However, the frequency of elevated IgG4 did not differ significantly according to autoantibody status.
The findings suggest that elevated serum IgG4 may be more common in rheumatic diseases characterised by prominent systemic inflammation and elevated CRP levels. In RA, the association between elevated IgG4 and markers of disease activity further suggests a potential relationship between IgG4 production and inflammatory activity.
However, the findings should be interpreted in the context of the study’s retrospective, single-centre design and the use of disease-level classification of CRP-associated versus non-CRP-associated conditions. Prospective studies incorporating patient-level inflammatory assessments are needed to determine whether serum IgG4 elevation has clinical or prognostic significance in individual rheumatic diseases.
Elevated serum IgG4 should not be considered diagnostic of IgG4-RD in isolation. Clinical features, organ involvement, imaging findings, histopathology, and other laboratory findings remain important when evaluating patients with suspected IgG4-RD.
References
- Dai J, Sun X, Yang J, Zhang J, Shi L. Factors associated with elevated serum IgG4 in rheumatic diseases: A retrospective single-center observational study. Medicine (Baltimore). 2026 Aug 28;105(35):e50240.
- Ebbo M, Grados A, Bernit E, et al. Pathologies associated with serum IgG4 elevation. Int J Rheumatol. 2012;2012:602809.
- Yu KH, Chan TM, Tsai PH, Chen CH, Chang PY. Diagnostic performance of serum IgG4 levels in patients with IgG4-related disease. Medicine (Baltimore). 2015;94:e1707.