Integrated neuroendocrine immune risk factors in relation to rheumatoid arthritis: should rheumatologists now adopt a model of a multiyear, presymptomatic phase?

An integrative perspective of neuroendocrine immune (NEI) and related risk factors for the onset of rheumatoid arthritis (RA) is presented, based upon studies of the long-term presymptomatic phase. Besides the recognized genetic markers and familial predisposition, multiple immunological precursors of RA have been identified many years before the clinical onset of inflammatory manifestations. Rheumatoid factors and related antibodies occur in approximately one-half of presymptomatic susceptibles. Cigarette smoking in sufficient amount and duration is a major risk factor for RA, particularly for postmenopausal-onset women and for men. In premenopausal-onset RA, subtle insufficiency of adrenal cortical function is less well recognized. In such women, cytokine imbalance may also precede inflammatory onset of RA. In males alone, multiple hormonal and cytokine correlations were found many years before the onset of RA, implying long-term activation or perturbation of this NEI system. The proposed physiopathogenetic model of RA requires further controlled, prospective studies for validation of the multiyear presymptomatic phase of RA. Such studies promise to clarify the currently unknown causal and sequential chains in this enigmatic disease.