Rheumatoid arthritis (RA) is a prototype for a criterion-defined inflammatory disease, for which the aetiology and initial molecular pathogenesis has been elusive for a long time. We describe in this Review how studies on the interplay between specific immunity, alongside genetic and environmental predisposing factors, provide new tools to understand the molecular basis of distinct subsets of the disease. A particular emphasis is on the possibility that pathogenic immune reactions might be initiated at other sites than the joints, and that the lungs could harbour such sites. New data strengthen this concept, showing that local immunity towards citrullinated proteins and accompanying inflammation might be present in the lungs early during disease development. This progress makes RA an interesting case for the future development of therapies that might be directed against disease-inducing immunity even before inflammation and destruction of joints has begun.
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