Interferon-Regulated Chemokine Levels Predict Lupus Flare

BOSTON — Elevated levels of the three interferon-regulated chemokines that correlate with disease activity in systemic lupus erythematosus might prove useful for the prediction of disease flares.

Findings from research sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Lupus Research Institute “strongly suggest” monitoring interferon-regulated chemokines in lupus will be useful as a clinical tool to aid physician decision making, according to one of the investigators.

“Valid biomarkers of disease activity in systemic lupus erythematosus would have the potential to improve the management of this heterogeneous, multisystem autoimmune disease that is characterized by relapsing and remitting disease activity,” Jason W. Bauer, Ph.D., said during his presentation at the annual meeting of the American College of Rheumatology.

The interferon pathway has arisen as one of the more promising sources of biomarkers, with several interferon-regulated chemokines having been found at elevated levels in the serum of patients with systemic lupus erythematosus (SLE), he said.

Now, under the auspices of the Autoimmune Biomarkers Collaborative Network, researchers have analyzed serum samples from 288 patients from the Hopkins Lupus Cohort over the course of 1 year.

Patients were seen quarterly or whenever a flare occurred, for a total of approximately 1,300 visits. Detailed laboratory and clinical assessments including physician's global and SLE disease activity index (SLEDAI) scores also were obtained at each visit. Levels of the chemokines CXCL10, CC22, and CCL19 were measured using chemiluminescent multiplex enzyme-linked immunosorbent assays, and a normalized chemokine score was created to reflect the combined levels of all three.

“To provide evidence that interferon-regulated chemokines are biomarkers of SLE activity, we first used a cross-sectional approach to determine whether active lupus cases have higher levels of chemokines than inactive cases,” said Dr. Bauer of the University of Minnesota, Minneapolis.

Patients were classified as active if they had an SLEDAI score of 6 or greater, and inactive if the SLEDAI score was 2 or below and the physician's global assessment was 0.

Comparison of the chemokines from single visits of active patients with those of inactive patients found significant upregulation, particularly for CXCL10 and CCL19, in the active patients.

A cross-sectional approach also was used to compare chemokine scores according to SLEDAI scores. Patients with low chemokine scores were more likely to have SLEDAI scores of 0. Those with scores higher than 6 were more likely to have high levels of the three chemokines.

“We believe that these two cross-sectional approaches show these [chemokines] to be very robust markers of SLE disease activity,” said Dr. Bauer.

Similar findings were seen with serum chemokine levels over time, with elevated levels being associated with periods of flare and lower levels seen with remission. Moreover, levels of these biomarkers correlated much more closely with flare than did classic laboratory values such as sedimentation rate, complement levels, or anti-double-stranded DNA antibody titers, he said.

“Finally, we found that patients who had high baseline chemokine scores were more likely to experience a flare during the following year than were those with low baseline scores,” he said.

This approach also could provide a reliable measure of disease activity for use in clinical trials, but must be validated using samples from independent SLE cohorts, he added.

In an earlier study, Dr. Bauer and his colleagues wrote, “We hypothesize that high levels of systemic chemokines in active SLE, driven by type 1 interferon, lead to a state of 'chemokine confusion' that alters the normal trafficking and chemotaxis of leukocytes in the body, setting the stage for widespread, systemic autoimmunity.

High-level production of chemokines may also contribute to human SLE by recruiting immune and inflammatory cells into target tissues.” (PLoS Med. 2006;3[12]:e491).

BOSTON — Elevated levels of the three interferon-regulated chemokines that correlate with disease activity in systemic lupus erythematosus might prove useful for the prediction of disease flares.

Findings from research sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Lupus Research Institute “strongly suggest” monitoring interferon-regulated chemokines in lupus will be useful as a clinical tool to aid physician decision making, according to one of the investigators.

“Valid biomarkers of disease activity in systemic lupus erythematosus would have the potential to improve the management of this heterogeneous, multisystem autoimmune disease that is characterized by relapsing and remitting disease activity,” Jason W. Bauer, Ph.D., said during his presentation at the annual meeting of the American College of Rheumatology.

The interferon pathway has arisen as one of the more promising sources of biomarkers, with several interferon-regulated chemokines having been found at elevated levels in the serum of patients with systemic lupus erythematosus (SLE), he said.

Now, under the auspices of the Autoimmune Biomarkers Collaborative Network, researchers have analyzed serum samples from 288 patients from the Hopkins Lupus Cohort over the course of 1 year.

Patients were seen quarterly or whenever a flare occurred, for a total of approximately 1,300 visits. Detailed laboratory and clinical assessments including physician's global and SLE disease activity index (SLEDAI) scores also were obtained at each visit. Levels of the chemokines CXCL10, CC22, and CCL19 were measured using chemiluminescent multiplex enzyme-linked immunosorbent assays, and a normalized chemokine score was created to reflect the combined levels of all three.

“To provide evidence that interferon-regulated chemokines are biomarkers of SLE activity, we first used a cross-sectional approach to determine whether active lupus cases have higher levels of chemokines than inactive cases,” said Dr. Bauer of the University of Minnesota, Minneapolis.

Patients were classified as active if they had an SLEDAI score of 6 or greater, and inactive if the SLEDAI score was 2 or below and the physician's global assessment was 0.

Comparison of the chemokines from single visits of active patients with those of inactive patients found significant upregulation, particularly for CXCL10 and CCL19, in the active patients.

A cross-sectional approach also was used to compare chemokine scores according to SLEDAI scores. Patients with low chemokine scores were more likely to have SLEDAI scores of 0. Those with scores higher than 6 were more likely to have high levels of the three chemokines.

“We believe that these two cross-sectional approaches show these [chemokines] to be very robust markers of SLE disease activity,” said Dr. Bauer.

Similar findings were seen with serum chemokine levels over time, with elevated levels being associated with periods of flare and lower levels seen with remission. Moreover, levels of these biomarkers correlated much more closely with flare than did classic laboratory values such as sedimentation rate, complement levels, or anti-double-stranded DNA antibody titers, he said.

“Finally, we found that patients who had high baseline chemokine scores were more likely to experience a flare during the following year than were those with low baseline scores,” he said.

This approach also could provide a reliable measure of disease activity for use in clinical trials, but must be validated using samples from independent SLE cohorts, he added.

In an earlier study, Dr. Bauer and his colleagues wrote, “We hypothesize that high levels of systemic chemokines in active SLE, driven by type 1 interferon, lead to a state of 'chemokine confusion' that alters the normal trafficking and chemotaxis of leukocytes in the body, setting the stage for widespread, systemic autoimmunity.

High-level production of chemokines may also contribute to human SLE by recruiting immune and inflammatory cells into target tissues.” (PLoS Med. 2006;3[12]:e491).

BOSTON — Elevated levels of the three interferon-regulated chemokines that correlate with disease activity in systemic lupus erythematosus might prove useful for the prediction of disease flares.

Findings from research sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Lupus Research Institute “strongly suggest” monitoring interferon-regulated chemokines in lupus will be useful as a clinical tool to aid physician decision making, according to one of the investigators.

“Valid biomarkers of disease activity in systemic lupus erythematosus would have the potential to improve the management of this heterogeneous, multisystem autoimmune disease that is characterized by relapsing and remitting disease activity,” Jason W. Bauer, Ph.D., said during his presentation at the annual meeting of the American College of Rheumatology.

The interferon pathway has arisen as one of the more promising sources of biomarkers, with several interferon-regulated chemokines having been found at elevated levels in the serum of patients with systemic lupus erythematosus (SLE), he said.

Now, under the auspices of the Autoimmune Biomarkers Collaborative Network, researchers have analyzed serum samples from 288 patients from the Hopkins Lupus Cohort over the course of 1 year.

Patients were seen quarterly or whenever a flare occurred, for a total of approximately 1,300 visits. Detailed laboratory and clinical assessments including physician's global and SLE disease activity index (SLEDAI) scores also were obtained at each visit. Levels of the chemokines CXCL10, CC22, and CCL19 were measured using chemiluminescent multiplex enzyme-linked immunosorbent assays, and a normalized chemokine score was created to reflect the combined levels of all three.

“To provide evidence that interferon-regulated chemokines are biomarkers of SLE activity, we first used a cross-sectional approach to determine whether active lupus cases have higher levels of chemokines than inactive cases,” said Dr. Bauer of the University of Minnesota, Minneapolis.

Patients were classified as active if they had an SLEDAI score of 6 or greater, and inactive if the SLEDAI score was 2 or below and the physician's global assessment was 0.

Comparison of the chemokines from single visits of active patients with those of inactive patients found significant upregulation, particularly for CXCL10 and CCL19, in the active patients.

A cross-sectional approach also was used to compare chemokine scores according to SLEDAI scores. Patients with low chemokine scores were more likely to have SLEDAI scores of 0. Those with scores higher than 6 were more likely to have high levels of the three chemokines.

“We believe that these two cross-sectional approaches show these [chemokines] to be very robust markers of SLE disease activity,” said Dr. Bauer.

Similar findings were seen with serum chemokine levels over time, with elevated levels being associated with periods of flare and lower levels seen with remission. Moreover, levels of these biomarkers correlated much more closely with flare than did classic laboratory values such as sedimentation rate, complement levels, or anti-double-stranded DNA antibody titers, he said.

“Finally, we found that patients who had high baseline chemokine scores were more likely to experience a flare during the following year than were those with low baseline scores,” he said.

This approach also could provide a reliable measure of disease activity for use in clinical trials, but must be validated using samples from independent SLE cohorts, he added.

In an earlier study, Dr. Bauer and his colleagues wrote, “We hypothesize that high levels of systemic chemokines in active SLE, driven by type 1 interferon, lead to a state of 'chemokine confusion' that alters the normal trafficking and chemotaxis of leukocytes in the body, setting the stage for widespread, systemic autoimmunity.

High-level production of chemokines may also contribute to human SLE by recruiting immune and inflammatory cells into target tissues.” (PLoS Med. 2006;3[12]:e491).