Association of elevated transcript levels of interferon-inducible chemokines with disease activity and organ damage in systemic lupus erythematosus patients

Abstract

Introduction: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with a heterogeneous course and varying degrees of severity and organ damage; thus, there is increasing interest in identifying biomarkers for SLE. In this study we correlated the combined expression level of multiple interferon-inducible chemokines with disease activity, degree of organ damage and clinical features in SLE, and we investigated their roles as biomarkers.

Methods: Peripheral blood cells obtained from 67 patients with SLE patients, 20 patients with rheumatoid arthritis (RA) and 23 healthy donors were subjected to real-time PCR in order to measure the transcriptional levels of seven interferon-inducible chemokines (RANTES, MCP-1, CCL19, MIG, IP-10, CXCL11, and IL-8). The data were used to calculate a chemokine score for each participant, after which comparisons were performed between various groups of SLE patients and control individuals.

Results: Chemokine scores were significantly elevated in SLE patients versus RA patients and healthy donors (P = 0.012 and P = 0.002, respectively). Chemokine scores were correlated positively with SLE Disease Activity Index 2000 scores (P = 0.005) and negatively with C3 levels (P < 0.001). Compared with patients without lupus nephritis and those with inactive lupus nephritis, chemokine scores were elevated in patients with active lupus nephritis, especially when their daily prednisone dosage was under 30 mg (P = 0.002 and P = 0.014, respectively). Elevated chemokine scores were also associated with the presence of cumulative organ damage (Systemic Lupus International Collaborating Clinics/American Society of Rheumatology Damage Index >or= 1; P = 0.010) and the occurrence of anti-Sm or anti-RNP autoantibodies (both P = 0.021).

Conclusions: The combined transcription level of interferon-inducible chemokines in peripheral blood leucocytes is closely associated with disease activity, degree of organ damage, and specific autoantibody patterns in SLE. The chemokine score may serve as a new biomarker for active and severe disease in SLE.

Figure 1

Comparison of chemokine and IFN scores between SLE and RA patients, and healthy donors. The methods employed to calculate the chemokine score and the IFN score are described in Materials and methods. (a) Chemokine scores were significantly elevated in SLE patients versus RA patients and healthy donors. (b) IFN scores were significantly elevated both in SLE and RA patients versus healthy donors. (c) Chemokine scores were positively correlated with IFN scores in SLE patients. Each symbol represents an individual patient; horizontal lines indicate median values. IFN, interferon; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

Figure 2

Association of chemokine and IFN scores with disease activity in SLE patients. Each symbol represents an individual patient; horizontal lines indicate median values. (a) SLE patients with a moderate-to-severe flare of disease (SLEDAI-2K score > 10) had significantly higher chemokine scores than did those without a disease flare (SLEDAI-2K score < 4) at the time of blood donation. (b) Chemokine scores were positively correlated with SLEDAI-2K. (c) Chemokine scores were significantly elevated in SLE patients with a reduced level of complement C3 (<80 mg/dl) compared with those with normal levels of C3. (d) A significantly negative correlation was observed between the chemokine score and C3 level. In addition, IFN scores were also correlated (e) positively with SLEDAI-2K and (f) negatively with C3 level. IFN, interferon; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000.

Figure 3

Elevated chemokine scores in SLE patients with organ damage. Each symbol represents an individual patient; horizontal lines indicate median values. (a) Chemokine scores exhibited a positive trend toward elevation in patients with active lupus nephritis (LN; n = 26) relative to patients with inactive LN (n = 10) and those with no history of LN (n = 31). (b) In the cohort, 30 patients were receiving daily doses of prednisone under 30 mg at the time of blood draw. Among them, eight patients had current LN, seven had inactive LN and 15 had never experienced renal manifestations of SLE. Patients with active renal disease had significantly higher chemokine scores than those with inactive LN or without LN. (c) Chemokine scores were significantly elevated in SLE patients with chronic and irreversible organ damage (SDI score 1 to 2 or more) compared with those with no damage. (d) Among those patients whose daily dosage of prednisone was less than 30 mg, chemokine scores were also significantly higher in those with versus those without chronic organ damage. (e) Chemokine scores were calculated in four active LN patients at the beginning of and after 12 weeks of treatment. In patient (p) 1, p2 and p3 (who achieved significant clinical improvement after treatment) chemokine scores were notably decreased, whereas in p4 (who had rapidly progressed into renal failure) chemokine score was dramatically increased. LN, lupus nephritis; SDI, Systemic Lupus International Collaborating Clinics/American Society of Rheumatology Damage Index; SLE, systemic lupus erythematosus.