Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations

Abstract

Introduction: Systemic sclerosis (SSc) (scleroderma) is a complex autoimmune disease that clinically manifests as progressive fibrosis of the skin and internal organs. Anti-centromere antibodies (ACAs), anti-topoisomerase antibodies (ATAs), and anti-RNA polymerase III antibodies (ARAs) are three mutually exclusive SSc-associated autoantibodies that correlate with distinct clinical subsets characterized by extent of cutaneous involvement and pattern of organ involvement. The current report sought to determine whether plasma cytokine profiles differ in SSc patients grouped according to these SSc-associated autoantibody subsets.

Methods: Plasma from 444 SSc patients and 216 healthy controls was obtained from the Scleroderma Family Registry and University of Texas Rheumatology Division. Patients were classified according to the presence of ACAs, ATAs, ARAs, or none of the above (antibody-negative). Levels of 13 cytokines were determined using multiplex assays.

Results: Compared with females, healthy control males had higher plasma levels of IL-2 (P = 0.008), IL-5 (P = 0.01) and IL-8 (P = 0.01). In addition, in controls, IL-6 (P = 0.02) and IL-17 (P = 0.01) levels increased with advancing age. After adjusting for age and gender, SSc patients had higher circulating levels of TNFalpha (P < 0.0001), IL-6 (P < 0.0001), and IFNgamma (P = 0.05) and lower IL-17 (P = 0.0005) and IL-23 (P = 0.014). Additional analyses demonstrated that disease duration also influenced these cytokine profiles. IL-6 was elevated in ATA-positive and ARA-positive patients, but not in ACA-positive patients. IL-8 was uniquely increased in the ATA-positive subset while both ATA-positive and ACA-positive subsets had elevated IFNgamma and IL-10. IL-5 was only significantly increased in the ACA-positive subset. Lastly, patients with interstitial lung disease had elevated IL-6 and patients with pulmonary hypertension had elevated IL-6 and IL-13.

Conclusions: Plasma cytokine profiles differ in SSc patients based on the presence of SSc-associated autoantibodies. Plasma cytokine profiles in SSc patients may also be affected by disease duration and the pattern of internal organ involvement.

Figure 1

Gender effects on plasma cytokine levels. Male healthy controls have higher circulating levels of IL-2 (P = 0.008), IL-5 (P = 0.01) and IL-8 (P = 0.01), and lower circulating levels of IL-13 (P = 0.03) and IL-23 (P = 0.006). Plasma cytokine levels (in pg/ml) were log_n-transformed. Data presented as mean ± standard error of the mean.

Figure 2

Age effects on plasma cytokine levels. IL-6 (P = 0.02) and IL-17 (P = 0.01) levels increased with advancing age. There was also a trend for increasing levels of IL-8 with age (P = 0.07). Plasma cytokine levels (in pg/ml) were log_n-transformed. Data presented as mean ± standard error of the mean.

Figure 3

Effect of disease duration on plasma cytokine profiles in scleroderma patients compared with controls. Plasma cytokine levels (in pg/ml) were log_n-transformed. Data presented as mean ± standard error of the mean. *P < 0.05. **P < 0.01. ****P < 0.0001.

Figure 4

Four plasma cytokine profiles in systemic sclerosis-association autoantibody subsets of scleroderma patients compared with controls. Plasma cytokine levels (in pg/ml) were log_n-transformed. Data presented as mean ± standard error of the mean. *P < 0.05. **P < 0.01. ***P < 0.001. ****P < 0.0001.

Figure 5

Nine plasma cytokine profiles in systemic sclerosis-association autoantibody subsets of scleroderma patients compared with controls. Plasma cytokine levels (in pg/ml) were log_n-transformed. Data presented as mean ± standard error of the mean. *P < 0.05. **P < 0.01.