It's possible to control local inflammation in rheumatoid arthritis by interfering with protein changes in the joints, an international team of researchers found.

A phenomenon known as citrullination — the enzymatic conversion of the building block amino acid arginine into citrulline, which is structurally quite different — is characteristic of inflamed tissues in rheumatoid arthritis, explained Anca I. Catrina, MD, PhD, of the Karolinska Institute in Stockholm, and colleagues.

Local injections of the glucocorticoid triamcinolone decreased the expression of these citrullinated proteins, the researchers reported online in Arthritis Research & Therapy.

And the effect of glucocorticoid treatment on protein expression was accompanied by a significant decrease in the thickness of the synovial lining.

Protein citrullination takes place through catalysis by peptidylarginine deiminase (PAD) enzymes.

Many effective treatments for rheumatoid arthritis target systemic inflammation, but it has not been determined whether these treatments also can influence local citrullination in the synovium.

To explore potential direct effects of two commonly used therapies, glucocorticoids and methotrexate, Catrina and colleagues obtained biopsies from the knee joints of 26 patients with rheumatoid arthritis and from eight healthy controls.

One group of 11 patients with new-onset disease who had not previously been treated with a disease-modifying anti-rheumatic drug began therapy with methotrexate, 20 mg per week.

Biopsy specimens were obtained arthroscopically before and after eight weeks of treatment in these patients.

In another group of 15 patients with active knee arthritis, biopsy specimens were obtained before and two weeks after an intra-articular injection of 40 mg triamcinolone hexacetonide.

In both groups, patients were permitted to continue on nonsteroidal anti-inflammatory drugs and oral prednisone in doses up to 10 mg/day.

Antibodies to citrullinated proteins were found in 86 percent of biopsy samples from patients and in none of the healthy tissue samples, Catrina and colleagues found.

Expression of PAD2 and PAD4 also was higher in samples from patients compared with controls, the researchers reported.

Along with the analysis of the antibodies, the researchers also performed analyses of the samples, scoring the degree of inflammation on a four-point scale.

For the group receiving the intra-articular injections, they found significant correlations between the thickness of the synovial lining and all measures of citrullination and enzyme expression.

In contrast, methotrexate had no effect on the expression of citrullinated proteins, PAD expression, or inflammation in the synovium despite a good clinical response to methotrexate in most patients.

A potential explanation for the discrepancy in response for the two treatments could be that different time points were chosen for follow-up biopsy, according to the researchers.

However, they explained, eight weeks after starting methotrexate and two weeks after steroid injection were thought to be the time points most likely to reflect the greatest effects of the treatments.

"Despite major advances in understanding the central role of citrullination and anti-citrulline immunity in [rheumatoid arthritis] pathogenesis, we face a striking lack of knowledge regarding regulatory factors responsible for induction, perpetuation, and/or amelioration of the process of citrullination, both locally in the joint and generally in other tissues," wrote Catrina and colleagues.

Further research into these processes and the specific effects of other drugs on citrullination is needed, they concluded.