The pathogenesis of rheumatoid arthritis

This etiologic model equates non-insulin-dependent diabetes mellitus (NIDDM) to chronic hypoxic stress hyperglycemia produced by increased stimulation of the sympathetic nervous system and hypothalamic–pituitary–adrenal axis. In the initial stages of the disease, hypoxia is believed to result from hemodilutional anemia precipitated by a reduction in vascular smooth muscle tone. The reduction increases lumen diameter necessitating an increased blood volume to maintain pressure.

Increased lumen diameter may also trigger atherosclerotic changes that characterize the later stages of NIDDM. The increased diameter decreases the shear stress experienced by endothelial cells and they respond by releasing endothelin, a smooth muscle constrictor and mitogen. The constricting action is hypothesized to be relatively ineffective in NIDDM leading to long-term endothelin release and activation of its mitogenic properties. The resulting increase in the number of smooth muscle cells may explain the intimal thickening of atherosclerosis. Restoration of vascular muscle tone is proposed as a treatment strategy for mild NIDDM.

Whether palisading granuloma formation occurs with leukocytoclastic vasculitis in rheumatoid nodules and in histopathologically similar conditions is debatable. Patients with high titers for rheumatoid factor and severe erosive rheumatoid arthritis are at risk for both rheumatoid vasculitis and rheumatoid nodules. A patient with all of these features developed a papular eruption. These papules showed clinicopathologic features both of leukocytoclastic vasculitis and of early palisading granuloma. Lesions resolved slowly with low-dose oral corticosteroid therapy. It is proposed that these lesions be called rheumatoid papules and that they may represent a link between vasculitis and the palisaded granulomatous reaction seen in rheumatoid nodules.

According to the original hypothesis, synovial tissue (ST) oedema and synovial fluid (SF) volume increase contribute to local hypoxia and metabolic alterations and to inflammation (A 1). Studies on biochemical mechanisms (A 2) in synovitides show that the SF volume correlates to SF hypoxia that correlates to lactate increase, acidosis and to some decrease in glucose. Normal ST produces lactate by glycolytic and pentose phosphate pathway activity, both, as well as the normally low oxygen utilization, being increased in synovitides. In ST very little carbohydrate seems to pass directly into the citric acid cycle and oxidation of fat may be involved, but it is not known if the fat is carried to ST by the blood or if it is synthetized locally (B). ST oedema and effusions may be most important as causes of local hypoxia (C). Acidosis alters physico-chemical properties of proteins, possibly changing their chemotactic and antigenic qualities, etc. Hypoxia and fuel supply might be related to fibroblast, macrophage and neutrophil reactions, and, in view of the high metabolic demands of villi, they may contribute to, e.g., ST necroses, and to erosions (D). I shall summarize some essentials of my present views on the pathogenesis (E 1 a) and causes in single cases (E 3 b) of synovitis, and comment on two other new hypotheses on rheumatoid arthritis (E 2) and on therapeutic (E 4) and other implications of this concept (E).

Dermatologists, while becoming increasingly involved in the diagnosis and management of patients with connective tissue diseases, have left rheumatoid arthritis relatively unexplored. An increased awareness of possible pathomechanisms of rheumatoid arthritis may allow for generalizations that lead to increased understanding of other connective tissue disorders. The types of cutaneous disorders that occur in association with rheumatoid arthritis include: vasoreactive dermatoses (e.g., various forms of vasculitis), which may occur secondary to the circulating immune complexes present in rheumatoid arthritis; autoimmune bullous disorders, which may occur in the setting of a suppressor T cell defect in rheumatoid arthritis; and various miscellaneous cutaneous associations. Hopefully, this review will lead to an increased understanding of both rheumatoid arthritis and the wide array of cutaneous associations of rheumatoid arthritis.

Past research into the pathogenesis of RA has generally concerned itself with established inflammation. The present review summarizes alterations in microvascular anatomy and function which occur during the hypoxic state, in various experimental and disease conditions. It further shows that tissue hypoxia is a common finding in RA and that the microvascular alterations of RA are similar to those produced by experimental hypoxia.

The available data suggest that microcirculatory compromise, concomitant with an increase in metabolic needs of synovial tissue, may initiate tissue injury via anoxia and acidosis, resulting in hydrolytic enzyme release, increased vascular permeability and acceleration of inflammatory processes. It is further believed that the microcirculatory abnormality may be generalized, accounting for the systemic manifestations often seen in RA.

Factors effecting arteriolar blood flow obstruction are reviewd to identify areas for future investigtion in RA and other disorders involving microvasculopathy. The multitude of longknown and newly recognized factors predisposing to vasospasm and vasodilatation have been outlined as a guide to possible mechanisms which may be operative in RA.

An attempt has been made to gather and synthesize the available data in the hope that it may stimulate other investigators to pursue more definitive research into specific areas which may show early microvascular abnormalities in the pathophysiology of RA. Identification of factors operative early in the pathogenesis of RA, before it becomes self-perpetuating, may well be a step in the direction of preventing the ravages of this disease, or providing insight to more effective control.