IgG4 Subtype Identified for First Time in Graves' Disease

Nancy A. Melville

October 21, 2013

SAN JUAN, Puerto Rico — A small but significant percentage of patients with Graves' disease show elevated plasma levels of immunoglobulin G4 (IgG4), suggesting the presence of a novel subtype of the disease, according to a new study presented here at the 2013 Annual Meeting of the American Thyroid Association.

"We found that about 6% of Graves' disease patients had elevated levels of serum IgG4," said lead author Ken Takeshima, MD, from Wakayama Medical University, Japan.

"IgG4-related disease has been associated with other thyroid conditions, including Hashimoto's thyroiditis or Riedel's thyroiditis; however, an association with Graves' disease has not been previously established," he observed.

Endocrinologist Emad Kandil, MD, FACS, from the endocrine surgery section at Tulane University School of Medicine, New Orleans, Louisiana, who moderated the session, said: "This was an interesting paper with the potential for clinical significance in managing patients with Graves' disease." Additional research will be needed to help better understand the nature of the IgG4 subtype in Graves' disease, he noted.

For example, it will be of interest to discover whether patients with this subtype might benefit from treatment strategies that other IgG4-related disease patients appear to respond to, such as steroids, he explained.

Graves' Disease Patients With Elevated IgG4 Are Older

Graves' disease is an autoimmune thyroid disorder and is the most common cause of endogenous hyperthyroidism. Thyroid-stimulating immunoglobulins (TSIs) bind to and activate thyrotropin receptors, causing the thyroid gland to grow and the thyroid follicles to increase synthesis of thyroid hormone. The cause is unknown; current treatment of thyrotoxicosis in patients with Graves' disease involves long-term use of antithyroid agents (such as methimazole), radioactive iodine therapy, or thyroidectomy.

IgG4-related disease has only recently been identified as a fibroinflammatory condition, with consensus reached on 2 diagnostic criteria: serum IgG4 concentration greater than 135 mg/dL and more than 40% of IgG+ plasma cells being IgG4+. Clinical diagnostic criteria include diffuse/localized swelling or masses in single or multiple organs (Mod Rheumatol. 2012;22:21-30).

To investigate whether there was any evidence of elevated IgG4 in Graves' disease, Dr. Takeshima and colleagues evaluated serum IgG4 concentrations in 109 Graves' disease patients. There were 7 patients (6.4%) who showed elevated serum levels, with a mean value of 175.0 mg/dL, and elevated ratios of IgG4/IgG, at 12.7%.

The remaining patients had mean serum IgG4 levels of 39.6 mg/dL and IgG4/IgG ratios of 3.2%.

Those with higher IgG4 levels were significantly older than the patients without elevated levels (mean ages 54.7 and 43.4 years, respectively), a novel finding.

"This was different from studies on Hashimoto disease, in which patients with elevated IgG4 were younger than those with nonelevated levels," Dr. Takeshima explained.

Graves' disease patients with higher IgG4 levels also had significantly increased low echogenic areas in the thyroid, compared with the nonelevated-IgG4 group (low echo scoring 1.66 vs 0.61, respectively; P = .005).

More Research Needed in New Subtype

Among the patients with elevated IgG4 levels, the elevations were successfully controlled with a small dosage of antithyroidal drug in 4 patients; a combination of antithyroidal drug and levothyroxine (L-T4) in 1 patient; or L-T4 administration only after 1 year from the first visit in 2 patients.

But "there was no discussion in the paper for managing these patients with steroids," Dr. Kandil noted, adding that it would be interesting to see whether steroid therapy could be useful in managing this specific subset of patients, because "in other autoimmune diseases, elevated IgG4 levels can be managed with steroids," he told Medscape Medical News.

Future multicenter trials are warranted to discover more about this subset of patients — for instance, it would be useful to compare outcomes among patients with this subtype who did and did not undergo surgical intervention for Graves' disease, he concluded.

Dr. Takeshima and Kandil have reported no relevant financial relationships.

2013 Annual Meeting of the American Thyroid Association. Abstract 12, presented October 17, 2013.

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