WASHINGTON, DC – Rheumatoid arthritis (RA) is characterized by activated proinflammatory Th1 effector cells and abnormally low Th2 responses. The key molecule determining whether a precursor cell will follow the Th1 or Th2 pathway is IL-4, which shifts the balance away from Th1 and toward Th2. Alla Skapenko, MD, reported at the 2006 annual meeting of the American College of Rheumatology that RA patients who have a "loss-of-function" mutation in the IL-4 receptor, are rheumatoid factor positive (RF+), and have the HLA-DR shared epitope (SE), can with 90% accuracy be expected to develop erosive disease within the first 2 years after RA onset.¹

Dr. Skapenko and colleagues at the University of Erlangen in Germany and at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) in the US became interested in the possible role of IL-4 after a meta-analysis identified RA-related markers on the short arm of chromosome 16. "We became interested in this observation because the receptor for the cytokine IL-4 is encoded exactly in this region," Dr. Skapenko said.

The investigators analyzed the association of two single nucleotide polymorphisms (SNPs) within the IL-4 receptor  (I50V and Q551R) with susceptibility to RA and to rapidly erosive disease.

"The goal of our study was to delineate the association between SNPs in the IL-4 alpha receptor and susceptibility to and/or severity of RA," Dr. Skapenko said.  This was done in a case control study with a well-characterized cohort of 471 RA patients (353, RF+) and 371 healthy controls.

"Genotyping was performed by allele-specific polymerase chain reaction (PCR). To evaluate the association of IL-4R SNPs with disease progression, patients were stratified retrospectively according to radiological outcome at 2 years into an erosive and a nonerosive group," Dr. Skapenko said.

"When we analyzed the genotype of the I50V and the Q551R frequencies, we found no differences in the genotype frequencies, allele frequencies, and haplotype frequencies for either the intracellular I50V or the extracellular Q551R, which argues that these polymorphisms would not contribute to susceptibility for RA," Dr. Skapenko reported.

They conducted additional analyses, however, because "the important thing we fear as physicians is erosions. We analyzed x-rays of the hands and feet 2 years after disease onset, with the question of whether they had developed erosions," Dr. Skapenko said.

The Q551R SNP was not associated with differences in development of erosive disease. For the extracellular IL-4 I50V binding domain, the polymorphisms were associated with a "tremendous difference." Patients who were homozygous for the wild type I50 had much less frequent erosive disease. Those who were homozygous for the 150V mutation had almost 2-fold more erosive disease, arguing that this allele predisposes to erosive disease at 2 years.

"Heterozygous individuals have almost a 2-fold increased risk. Homozygous have almost a 4-fold greater risk of developing erosions within 2 years, compared to patients who did not have these markers," Dr. Skapenko said.

There were significant differences between the erosive and the nonerosive group of patients in the distribution of I50V IL-4R SNP genotypes (Chi square 15.68, P = .0004). Bone erosions were twice as common in the I50V homozygous patients at 2 years after disease onset (68.1%  vs 37.0%, OR 3.86, P <.0001).

Dr. Skapenko said that this association was independent of individual factors previously associated with severe disease, such as RF or the HLA-DR shared epitope. "Two copies of the alpha receptor alone are able to predict with a specificity of 4.85 the development of erosions within the first 2 years of RA," he said. Combined with one SE and the presence of RF, one can predict with an accuracy of more than 90% that this particular patient will develop erosive disease within 2 years.

This difference was not due to insufficient treatment, since patients who had developed erosive RA were more likely to have had treatment with one or more DMARDs compared with patients who had not developed erosive disease.

The investigators also analyzed the effect of the polymorphisms on IL–4-mediated cellular mechanisms. They found that the V50 allele conferred significantly reduced responsiveness to IL-4, as exemplified by reduced STAT6 phosphorylation in response to IL-4 stimulation.

"[This result] argues that this is, in fact, a loss-of-function mutation of the IL-4 receptor," Dr. Skapenko said. The result would likely be a shift in the Th1-Th2 balance, with reduction in IL–4-mediated inhibition of Th1 and increase in Th2 differentiation, suggesting a possible mechanism for the association of the I50V IL-4R polymorphism with early erosions in RA."

"Together, the data identify the I50V IL-4R SNP as a novel genetic marker in RA with high predictive value for early erosions," Dr. Skapenko concluded.

E-mail any comments to .

Reference