Smoking and Rheumatoid Arthritis

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Rheumatoid arthritis (RA) is one of the most common systemic

autoimmune diseases, and one of the least understood. Smoking is the

major known environmental risk factor for RA, though little is known

about the mechanisms involved. HLA-DR shared epitope (SE) genes are a

widely recognized genetic risk factor for RA, though little is known

about how these genes affect autoimmune reactions that lead to

chronic inflammation and progressive joint and organ damage.

 

To better understand the interactions between smoking and HLA-DR SE

genes in RA, a team of researchers in Sweden focused on the disease's

distinctive autoimmune hallmark: citrulline, an amino acid not

normally present in protein. While extremely rare in healthy

individuals and relatively rare in other inflammatory conditions,

citrulline-modified proteins are common in about two-thirds of RA

patients and may be an underlying factor in the development of the

disease. To investigate whether smoking and SE genes trigger immune

reactions to citrullinated proteins, the team conducted a case-

control study involving patients with recent-onset RA. The results,

featured in the January 2006 issue of Arthritis & Rheumatism

(http://www.interscience.wiley.com/journal/arthritis), suggest that

smokers with SE genes are more susceptible to anticitrulline antibody-

positive RA.

 

The study's 930 early RA patients, drawn from the Epidemiological

Investigation of Rheumatoid Arthritis Study Group, ranged in age from

18 to 70 years. 383 healthy controls, drawn from the blood bank of

northern Sweden, were matched for age, gender, and residential area.

All participants completed questionnaires about their past and

present smoking habits, as well as genotyping profiles. In addition,

bronchial fluid was obtained from a representative sample of RA

patients, including both current heavy smokers and lifelong non-

smokers, and tested with immunostaining for the presence of

citrullinated protein in cells.

 

Based on their series of experiments and comparisons, the researchers

found that a history of smoking increases the risk for RA, but only

for individuals who test positive for anticitrulline antibodies,

regardless of the presence of SE genes. Similarly, inheriting HLA-DR

SE genes in a single copy, as well as in double copies, increases the

risk for RA, but only for individuals who test positive for

anticitrulline antibodies, including individuals who have never

smoked. Yet, for individuals who test positive for anticitrulline

antibodies, the interaction of smoking and carrying 2 copies of the

SE gene dramatically increases the risk for developing RA--by 21

times.

 

" The remarkable gene-environment interaction observed in the case-

control study, together with the immunostaining for citrullinated

proteins, might now provide a clue to the molecular mechanisms of

importance for disease development in a subset of RA patients, " notes

team spokesperson Dr. Lars Klareskog of Karolinska Institutet,

Stockholm. " We may thereby be given some new opportunities to both

predict and understand the onset of RA and to interfere with RA-

inducing events before clinical symptoms are apparent. "

 

Article: " A New Model for an Etiology of Rheumatoid Arthritis:

Smoking May Trigger HLA-DR (Shared Epitope)-Restricted Immune

Reactions to Autoantigens Modified by Citrullination, " Lars

Klareskog, Patrik Stolt, Karin Lundberg, Henrik Källberg, Camilla

Bengtsson, Johan Grunewald, Johan Rönnelid, Helena Erlandsson Harris,

Ann-Kristin Ulfgren, Solbritt Rantapää-Dahlqvist, Anders Eklund,

Leonid Padyukov, Lars Alfredsson, and the Epidemiological

Investigation of Rheumatoid Arthritis Study Group, Arthritis &

Rheumatism, January 2006, 54:1, pp. 53-61.

 

John Wiley & Sons, Inc.

www.interscience.wiley.com