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RA autoimmunity may smolder in the lungs.


SNOWMASS, COLO.--One of the most interesting questions in all of rheumatology is this: Where does rheumatoid arthritis hang out in the body preclinically during the years following autoantibody formation but before symptomatic joint involvement?

Increasing evidence suggests that RA is smoldering in the lungs during this preclinical stage, which can last a decade or more. Indeed, bronchiole-associated lymphoid tissue may actually be the site where tolerance is broken and RA-related autoimmunity and systemic inflammation are generated, according to Dr. William F.C. Rigby, professor of medicine and professor of microbiology and immunology at Dartmouth Medical School, Hanover, N.H.

The great hope is that as this preclinical seropositive phase of RA becomes more fully understood, it will be possible to develop an autoantibody/cytokine biomarker profile in affected individuals that reliably predicts time to diagnosis. Efforts are well underway in this regard (Arthritis Rheum. 2010;62:3161-72). If such studies are validated, it will be time to launch randomized trials with the aim of preventing RA via drug therapy using methotrexate or other candidate medications while individuals are still in the preclinical stage. It's even possible such therapy would be curative rather than suppressive, such that the medication could eventually be withdrawn.

"If methotrexate can be used to prevent the vascular complications of atherosclerosis, why can't we use it to prevent RA? There is now [a National Institutes of Health] clinical trial proposing this. Because once the joint gets targeted, damage can happen very, very quickly. Many people have erosions on x-ray after only weeks of symptoms," the rheumatologist observed.

He credited the discovery of the existence of a lengthy preclinical seropositive phase of RA to landmark studies involving U S military personnel with centrally stored blood samples that were available for many years prior to their being diagnosed with RA (Ann. Rheum. Dis. 2008;67:801-7). The existence of this years-long preclinical lag time has since been confirmed in multiple other populations.

Recently, investigators at the University of Colorado at Denver, Aurora, identified the lung as an early site of autoimmune-related injury in subjects with what is being called preclinical seropositive RA (Arthritis Rheum. 2011 Dec. 19 [doi:10.1002/art.34344]).

By conducting mass screenings at an annual Colorado health fair, the investigators identified a cohort of 45 subjects with preclinical RA (defined by elevated anti-cyclic citrullinated peptide antibodies and/or two or more rheumatoid factor isotypes, along with no evidence of arthritis on a 68-joint examination).

All 45 subjects underwent chest CT with blinded scan readings. So did 16 seronegative healthy controls matched for age, sex, and smoking status, as well as 12 patients with early RA diagnosed less than 1 year before.

The prevalence of airways disease on CT (air trapping, bronchial wall thickening, bronchiectasis, and/or centrilobular opacities) was 77% in the autoantibody-positive preclinical RA group, compared with 31% of controls. Moreover, none of the seropositive preclinical RA subjects with CT lung abnormalities had any evidence of synovitis of their joints on MRI.

Some research groups are homing in on the gut or periodontal colonization by Porphyromonas gingivalis as possible key sites where tolerance is broken in individuals who will years later be diagnosed with RA. He reported having no financial conflicts.

If methotrexate can be used to prevent vascular complications, why can't we use it to prevent RA? DR. RIGBY
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Title Annotation:RHEUMATOLOGY
Author:Jancin, Bruce
Publication:Internal Medicine News
Geographic Code:1U8CO
Date:Apr 1, 2012
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