Association of subclinical atherosclerosis and leukopenia in systemic autoimmune diseases: Comment on the article by Huang et al (2010)

The data recently reported by Huang et al concerning their study of juvenile-onset systemic lupus erythematosus (SLE) appear to be of particular interest in clarifying the mechanisms by which the disease contributes to the acceleration of atherosclerosis (1). In their longitudinal study, they found that patients with juvenile-onset SLE had increased carotid intima-media thickness (IMT) compared with age-matched healthy controls at baseline and that lymphopenia was the only independent risk factor for the progression of IMT. These findings are similar to the data we recently reported from a study of a group of young women with another systemic autoimmune disease, primary Sjögren's syndrome (SS) (2). Approximately one-half of these patients had increased carotid IMT that was associated with leukopenia and anti-SSA antibodies; these 2 parameters were independent predictors of enhanced IMT in these patients. In a post hoc analysis, we also discovered that the great majority of our patients with leukopenia also had lymphopenia that, similar to the leukopenia, was associated with, and a predictor of, abnormal IMT. Although there are no conclusive data on the actual cardiovascular risk associated with SS, we chose to investigate subclinical atherosclerosis in this disease as a model of a systemic autoimmune disorder that shares several clinical features of SLE. Unlike SLE, however, primary SS often affords the opportunity to evaluate patients with longstanding disease, who are not previously or currently receiving treatments that may influence immunologic and vascular data. In this context, we think that these overlapping data in 2 different, but similar, systemic autoimmune diseases deserve particular attention and discussion. In Huang and colleagues' study, a high percentage of patients had dyslipidemia, which is a common characteristic of both SLE and SS patients (3, 4). However, the observation that this atherosclerosis risk factor was not related to increased IMT is consistent with the findings in SS and SLE reported by us and by other investigators (2, 3). Among SLE-related factors that may contribute to atherosclerosis progression, some are drug-related, and others, such as C-reactive protein, are present only during particular phases of the disease (5). This may interfere with the detection of a possible relationship to the pathologic IMT, a vascular index of subclinical structural damage not subject to fluctuations over time. In contrast, leukopenia and lymphopenia, typical features frequently encountered in both SLE and SS, are usually stable over time and are thus able to better characterize a subset of SLE and SS patients. The most critical question raised by Huang and colleagues' report is the possible mechanisms by which lymphopenia may induce atherosclerosis progression. In order to explain their finding, the authors suggested that lymphopenia may identify a patient subgroup with some features of SLE, such as those related to low lymphocyte count, that may favor the early development of atherosclerosis. Among these, anti-SSA antibodies, which are strictly associated with leukopenia/lymphopenia in both SLE and SS (2), were not analyzed in their study. The presence of these autoantibodies, however, may represent an interesting link between low white blood cell numbers and atherosclerosis. Similar to leukopenia, circulating anti-SSA antibodies remain permanently detectable over time in the great majority of patients. They can also induce a lowering of leukocyte levels by apoptotic processes that, in turn, are strongly implicated in the development of atherosclerosis (2). Moreover, the finding that both adolescent patients with SLE and young female patients with SS do not usually have alterations of nitric-oxide–mediated endothelium-dependent vasodilation, except for subsets of patients who have clinical evidence of inflammatory involvements (6, 7), is of particular interest. This reversible functional impairment of the endothelium that can precede the organic damage to the arterial wall is usually also associated with signs of inflammation in adult patients with SLE or with rheumatoid arthritis (5, 8). In contrast, the majority of SS patients have an isolated alteration of nitrate-mediated vasodilation that is associated with a low leukocyte count, and this may represent an expression of involvement of the muscle component in the intima-media layer of the arterial wall, probably due to cellular infiltration (7). Taken together, these observations suggest that some immunologic features shared by SLE and SS, such as leukopenia/lymphopenia and anti-SSA antibodies, may be associated with a precocious damage of the arterial wall induced by progressive structural injury. In this setting, however, it is intriguing that the higher prevalence of carotid plaques found in adult patients with SLE as compared with age-matched healthy controls is not detectable in patients with juvenile-onset SLE or in SS (1, 2). As suggested by Huang et al, it is possible that this discrepancy may depend on the patient's age. However, we also believe that additional factors, such as reversible and transient endothelial dysfunction, occurring in these conditions as a consequence of concomitant inflammatory events, may synergistically act on an already-damaged arterial wall and favor plaque formation and overt cardiovascular events. Roberto Gerli MD*, Elena Bartoloni Bocci MD*, Yehuda Shoenfeld MD, FRCP , * University of Perugia, Perugia, Italy, Chaim Sheba Medical Center Tel Hashomer, Israel.