Elevated Serum IgG4 Defines Specific Clinical Phenotype of Rheumatoid Arthritis

Abstract

Objectives. To explore the correlation of serum IgG4 (sIgG4) with clinical manifestations or therapeutic response in rheumatoid arthritis (RA). Methods. Consecutive 136 RA patients were recruited and followed up at regular interval. SIgG4 was detected by immunonephelometry. Serial synovial tissue sections from 46 RA patients were stained immunohistochemically for IgG4. Results. Forty-six percent of 136 RA patients had elevated sIgG4. Patients with elevated sIgG4 had higher sIgG4/sIgG ratio, C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and anticyclic citrullinated peptide antibodies than those with normal sIgG4 (all P < 0.05). Among 45 patients who received methotrexate and leflunomide therapy, 50% (9/18) of patients with elevated sIgG4 and 85% (23/27) of patients with normal sIgG4 reached therapeutic target (disease activity score of 28 joints < 3.2) at 6-month visit (χ 2 = 6.508, P = 0.011). IgG4-positive plasma cell count correlated positively with sIgG4, total synovitis score, and CD3-, CD20-, and CD38-positive cell counts (all P < 0.05). Conclusions. Our results showed that elevated sIgG4 in RA is common and disproportional to total IgG and RA with elevated sIgG4 may be a specific clinical phenotype with higher disease activity, higher level of autoantibodies, and poor response to methotrexate and leflunomide therapy.

Correlation of Lyme Disease–Associated IgG4 Autoantibodies With Synovial Pathology in Antibiotic‐Refractory Lyme Arthritis

“…As was seen here with synovial tissue in Lyme arthritis, antibodies of each IgG subclass were found in RA synovial tissue, and in some patients, IgG4 antibodies were particularly prominent (28). The subgroup of RA patients with elevated levels of serum IgG4 antibodies had higher disease activity, higher levels of rheumatoid factor and anti-citrullinated protein autoantibodies (ACPAs), and a poor response to diseasemodifying antirheumatic drugs (28), suggesting that serum IgG4 antibodies define a specific clinical phenotype with more severe disease. However, the specificities of these autoantibodies are different in RA from those in Lyme arthritis.…”

“…In RA, IgG1 antibodies are most prominent, as might be expected, but IgG4 antibodies are next most prominent 27,30 , which is surprising given that they are normally the least abundant subclass 13 . As was seen here with synovial tissue in Lyme arthritis, antibodies of each IgG subclass were found in RA synovial tissue, and in some patients, IgG4 antibodies were particularly prominent 28 . The subgroup of RA patients with elevated levels of serum IgG4 antibodies had higher disease activity, higher levels of rheumatoid factor and anti-citrullinated protein autoantibodies (ACPA), and a poor response to disease modifying anti-rheumatic drugs (DMARDs) 28 , suggesting that serum IgG4 antibodies define a specific clinical phenotype with more severe disease.…”

“…The overall profile of IgG antibody subclass responses in antibiotic-refractory Lyme arthritis has similarities with that in RA. The finding of increased levels of IgG antibodies in some RA patients was first noted years ago (26), but interest in the role of IgG4 autoantibodies in rheumatic diseases has increased recently (27)(28)(29). In RA, IgG1 antibodies are most prominent, as might be expected, but IgG4 antibodies are next most prominent (27,30), which is surprising given that they are normally the least abundant subclass (13).…”

The Immunobiology of Immunoglobulin G4

“…Elevated levels of serum IgG4 levels (>1.35 g/L) can be observed in a variety of disorders. 164,165 In particular, IgG4-RD-is characterized by an often (but not always) significantly elevated serum level of IgG4. 166 These disorders can affect almost any organ and share characteristics such as infiltration of the affected tissue by IgG4þ plasma cells, a characteristic pattern of fibrosis, and (in most cases) responsiveness to glucocorticoids.…”

IgG4-Related Disease and the Spectrum of Mimics in Rheumatology

“…However, it should be remembered that in some patients with IgG4-RD, an increase of serum IgG4 is observed. This percentage may be as high as 40% [46,47]. IgG4 production depends mainly on the action of interleukin 6 and 10.…”