EULAR: Identify Arthritis Early, Treat it Effectively

BERLIN—Research into factors surrounding prearthritis is uncovering genetic and environmental factors at play at the earliest stages of development of rheumatoid arthritis (RA), giving doctors and patients more hope for earlier interventions, Iain McInnes, PhD, professor of medicine at the University of Glasgow, Scotland, said at the European League Against Rheumatism (EULAR) 2012 Annual European Congress of Rheumatology, held June 6–9.

In a session dedicated to highlighting the latest research in early arthritis and in juvenile disease, Dr. McInnes said he found 23,000 papers in the last year when he searched for the terms “early” and “arthritis.”

“Genome-wide association studies have dominated the literature,” he said.

One retrospective study looking at the genetic studies already done—and comprising 5,000 RA cases and 15,000 controls—found that three proteins at five amino-acid positions account for almost all of the link between the major histocompatibility complex and seropositive RA. They are HLA-DRB1 at positions 11, 71, and 74, HLA-B at position 9, and HLA-DPB1 at position 9.¹

Dr. McInnes said the findings mean that we are “closer to understanding what the underlying autoreactive peptides might be.”

He also highlighted studies focusing on environmental factors. A study featuring the sequencing of the microbiome of the mouth in new-onset, never-treated RA patients found that advanced forms of periodontal disease are prevalent in RA and that Porphyromonas gingivalis exposure was similar in RA and controls. Perhaps most interesting, the researchers found that Prevotella and Leptotrichia were the only species in early RA that do not appear to be associated with periodontal disease—a finding that calls for more study.²

Another study found that the number of pack years smoked, together with a single- or double-shared epitope, “exponentially increases the odds ratio of developing rheumatoid arthritis,” clearly showing a gene and environment interaction, Dr. McInnes said.³

One study found that lung abnormalities, including thickening of the bronchial walls, was more common in anticitrullinated protein autoantibody (ACPA)–positive patients than in subjects who were ACPA negative. The abnormalities were also elevated in those with early arthritis compared to controls.⁴

Dr. McInnes also highlighted two studies in epigenetics, including one that looked at microRNA 146, which is suppressed by smoking. In miR146 knockout mice, autoimmunity arose, with the mice developing an enlarged spleen and lymph nodes.⁵

“This is an exciting clue that there might now be a link between smoking and immune function and arthritis development,” he said.

Another study found, conversely, that a miR155 deficiency in mice led to a reduction in collagen-induced arthritis.⁶

“It works two ways: A microRNA can also promote inflammation, or rather its absence may be allowing inflammation,” Dr. McInnes said.

Juvenile Idiopathic Arthritis

Albert Martini, MD, professor of Pediatrics at the University of Genova in Italy, spent much of his talk reviewing the latest on juvenile idiopathic arthritis (JIA). There’s a need to identify early predictors of outcome more effectively, he said, pointing to a study of 440 Nordic cases of JIA. In cases with the last follow-up visit at least seven years after onset of disease, 48.7% of the patients were still not in remission, and 22.9% had sustained damage as a result of the disease.⁷

A study comparing groups of methotrexate users, with withdrawal of the drug at either six or 12 months after remission, found no difference in relapse rate, but higher concentrations of myeloid-related protein 8/14 was found to be linked with a higher risk of relapse after methotrexate was stopped.⁸

In a subsequent study, it was found that serum levels of myeloid-related protein 8/14 greater than 740 ng/ml predicted disease flares accurately.⁹

Dr. Martini noted one study that illuminated the high rate of intolerance to methotrexate among JIA patients. A 297-patient cohort study found that 44.5% of those on oral methotrexate, and 67.5% of those on parenteral doses, experienced methotrexate intolerance.¹⁰

“Classic conditioning plays an important role in methotrexate intolerance,” Dr. Martini said.

TNF blockers have produced very good results. A study using the Dutch Register found that, out of 262 biological treatment–naive patients, 32% had an excellent response to etanercept, while 36% had an intermediate response, and 32% had a poor response.¹¹ Excellent responses were linked with low baseline disability scores, few disease-modifying antirheumatic drugs used before starting etanercept, and young age at JIA onset. Poor responses were linked with system JIA and female gender.

There are some concerns about the safety of TNF blockers in children, though how serious they are remains unclear.

A U.S. Food and Drug Administration report said that 48 children with JIA had developed malignancies after taking TNF blockers, but the cases were confounded by the potential risk of malignancy associated with underlying illnesses and by the use of concomitant immunosuppression.¹²

A subsequent study, using U.S. Medicaid data from 2000 to 2005, found that children with JIA appear to have an increased risk of malignancy, but that treatment, including TNF blockers, was not significantly associated with that malignancy risk.¹³

Dr. Martini noted the start of PharmaChild, a European initiative to follow, long-term, thousands of JIA patients on biological agents. “Only long-term observation on many thousands of patients can establish the safety of a drug,” he said.

Thomas Collins is a freelance medical writer based in Florida.

References

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