Plasma adrenomedullin level in systemic lupus erythematosus

B. M. Y. Cheung, C.-S. Lau, R. Y. H. Leung, K. K. Tong and C. R. Kumana

Department of Medicine, The University of Hong Kong, Hong Kong, SAR, China

SIR, Human adrenomedullin (AM) is a 52-amino acid peptide hormone first isolated from phaeochromocytoma and the adrenal medulla [1]. AM-like immunoreactivity is also found in the heart, lungs and kidneys, as well as in plasma. The physiological role of AM is not well understood, but the plasma AM level is elevated in a number of disease states, including essential hypertension, coronary artery disease, congestive heart failure and renal failure [2]. AM is a vasodilator, through its direct action on vascular smooth muscle to increase intracellular cAMP and the stimulation of endothelial nitric oxide release. AM immunoreactivity is present in the brain, consistent with a role as a neurotransmitter. Recent studies have shown that leucocytes and macrophages are major sites of AM production [3]. Cytokines, including tumour necrosis factor-{alpha} (TNF-{alpha}) and interleukin-1ß (IL-1ß) stimulate the secretion of AM in vitro [4], suggesting that AM interacts with the immune system. Disruption of the cytokine network may play a role in the development and disease manifestations of systemic lupus erythematosus (SLE) [5]. Both TNF-{alpha} and IL-1 have been implicated in SLE. Furthermore, vasculitis and endothelial damage are commonly found during active disease [6]. As AM interacts with the immune system and the endothelium is a major source of AM, we studied the plasma AM level in a cohort of SLE patients and compared the results with those from controls.

Forty-seven consecutive patients with SLE were recruited from the outpatient SLE clinic. All were ethnic Chinese. Twenty-three normal healthy subjects participated as controls. Clinical and laboratory data and the SLE Disease Activity Index (SLEDAI) [7] were recorded. Plasma immunoreactivity of AM was measured with a radioimmunoassay kit (Peninsula Laboratories, Belmont, CA, USA) [2]. Data were analysed using SPSS for Windows (version 7.5, SPSS Inc., Chicago, USA).

Clinical characteristics of patients and AM results are summarized in Table 1Go. Plasma AM concentration was significantly lower in patients with SLE than in controls (P < 0.0001). None of the subjects was pregnant or had heart failure, respiratory disease or diabetes. Systolic and diastolic blood pressures of patients with SLE (mean ± S.D.) were 124 ± 20 and 76 ± 10 mmHg respectively. Plasma creatinine concentration (mean ± S.D.) was 85 ± 60 µmol/l (normal range 56–110 µmol/l). Thirty-four and 13 patients had SLEDAI <4 and >= 4 respectively at the time of study. Exclusion of patients with hypertension (n = 7), renal impairment (n = 2) and liver disease (n = 1) did not affect the highly significant elevation in plasma AM level in patients (27.5 ± 4.4 pmol/l, P < 0.0001 vs controls).


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TABLE 1. Plasma adrenomedullin level in control subjects and patients with SLE

 
Plasma AM level in SLE patients correlated with anti-double-stranded DNA (anti-dsDNA) titre (r = 0.39, P = 0.008) (Fig. 1) and SLEDAI (r = 0.35, P = 0.04). Plasma AM level in patients with active disease (SLEDAI >=4) on immunosuppressive drugs (prednisolone, azathioprine and cyclophosphamide) tended to be lower than in those who were not (mean ± S.E.; 33.3 ± 13.7 vs 55.2 ± 17.8 pmol/l; P = 0.06), whilst immunosuppressive drugs did not affect the plasma AM level in patients with inactive disease (mean ± S.E.; SLEDAI <4, 21.2 ± 3.9 pmol/l; SLEDAI >= 4, 21.2 ± 2.3 pmol/l; not significant). Plasma AM level did not correlate with age.

Our preliminary study has shown that the plasma level of AM is elevated in patients with SLE and that it correlates with disease activity. However, the reason for this elevated AM level is not clear. It was not explained by known confounding factors, including cardiopulmonary disorders, diabetes, renal and liver diseases, and pregnancy. AM is secreted in stress, and exercise and glucocorticoids [8] both stimulate the secretion of AM. It was therefore possible that the use of corticosteroids and other immunosuppressive agents accounted for the elevation in plasma AM. However, further analysis did not confirm this hypothesis. Indeed, patients with active disease receiving immunosuppressive agents tended to have lower levels of plasma AM. As cytokines stimulate AM secretion, the elevation in plasma AM level in SLE may be secondary to the increase in inflammatory cytokines such as TNF-{alpha} in SLE. Previous studies have shown that SLE is characterized by endothelial damage. It was therefore probable that the elevated plasma levels of AM found in our patients were a consequence of endothelial damage. Further studies are needed to explore the relationship between vasculitis and AM. If the relationship between AM and SLE activity is confirmed, AM may be a useful marker for monitoring disease activity.

The relationship between AM and the development and progression of nephritis in patients with SLE is worthy of further investigation. First, calcitonin gene-related peptide, a potent vasodilator neuropeptide which shares a common amino acid sequence with AM, is present in increased quantities in the inflamed kidneys of SLE mice and may be partly responsible for the altered immune response [9]. Secondly, AM lowers systemic vascular resistance, and is natriuretic and diuretic [10]. These properties resemble those of atrial natriuretic peptide (ANP) which has an important role in the progression of renal failure [9]. Interestingly, plasma concentrations of AM and ANP are correlated [11].

In conclusion, the plasma level of AM is elevated in patients with SLE and correlates with disease activity; patients with active disease (but not those in remission) receiving immunosuppressive drugs tend to have lower levels. Collectively, these findings suggest that AM is involved in the pathophysiology of SLE.

Notes

Correspondence to: Dr C.-S. Lau, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, SAR, China. Back

References

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Accepted 10 January 2000