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Airways Abnormalities May Represent Preclinical Rheumatoid Arthritis


 

EXPERT ANALYSIS FROM A SYMPOSIUM SPONSORED BY THE AMERICAN COLLEGE OF RHEUMATOLOGY

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.

Dr. William F.C. Rigby

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It’s even possible such therapy would be curative rather than suppressive, such that the medication could eventually be withdrawn.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]).

"This is a great paper, profound in its implications," Dr. Rigby commented.

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). Earlier work with the Armed Forces cohort had established that this serologic profile is 96% specific for RA.

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, indicating that RA isn’t smoldering preclinically in their joints for a long time prior to the time they show up in a rheumatologist’s office with joint symptoms. The prevalence of CT airways changes in the early RA group was similar to that in the preclinical seropositive group.

Of note, none of the subjects with preclinical RA had CT evidence of interstitial lung disease; it was all airways disease, Dr. Rigby observed.

The lung is quite plausible as the site where tolerance is broken (that is, autoantibodies against self-proteins such as cyclic citrullinated peptides are first formed), in light of the fact that smoking is a well-established environmental risk factor for RA, associated with a greater than five-fold increased risk of the rheumatologic disease in epidemiologic studies. Infectious respiratory illness could also hypothetically serve as a trigger for the breaking of tolerance, the rheumatologist said.

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. At this time, however, Dr. Rigby considers the evidence for the lung as the major player to be further along and more persuasive.

He reported having no financial conflicts.

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