The cause of RA is unknown but there are several hypotheses: an autoimmune mechanism; a superantigen-driven disease; an infection with an unusual pathogen (e.g. lentivirus); and a non-specific infectious stimulus acting on a particular genetic background. Whatever the cause(s) of RA, it would appear that cytokines are very important mediators of the pathology. Genetic polymorphisms with Mendelian inheritance have been characterized in regulatory regions of cytokines such as IL-1, TNF and related genes. It is possible, therefore, that whatever the initiating stimulus might be, the possession of different cytokine alleles may confer greater or lesser risk of developing a progressive disease.