Platelet C4d Predicts Cardiovascular Events and Mortality in Lupus

NEW YORK – The 18%-20% of systemic lupus erythematosus patients who test positive for platelet C4d face a much greater likelihood of having a future cardiovascular event, stroke, or death than those who are not platelet C4d positive, according to Dr. Susan M. Manzi, who presented the results at a rheumatology meeting sponsored by New York University.

"The only factor that predicted mortality greater than being positive for P-C4d [platelet C4d] was having cancer," said Dr. Manzi, chair of the department of medicine and codirector of the Lupus Center of Excellence at West Penn Allegheny Health System, Pittsburgh.

In the study of 356 patients with systemic lupus erythematosus (SLE), which was carried out between July 2001 and August 2009, 70 tested positive for P-C4d (20%) and 286 tested negative. This confirms a previous study that found that P-C4d was present in 18% of SLE patients and that P-C4d was highly specific for SLE (Arthritis Rheum. 2006;54:670-4). "P-C4d carries a 95% specificity for SLE," said Dr. Manzi, who is also vice chair and professor of medicine at Temple University, Philadelphia.

Patients who were P-C4d positive had twice as many cardiovascular events (36 vs. 18, P = .001). The odds ratio of having a cardiovascular event was 2.09 for positive P-C4d (P = .02), which was much higher than for smoking (OR 1.36), SLE disease duration (0.99), or the presence of renal disease (1.42). The odds ratio for aPL antibodies was 2.30 (P = 0.004).

The results for stroke were even more striking. Thirteen patients with P-C4d had stroke, compared with three in those who tested negative for P-C4d (P = .002). There was nearly a fivefold increased risk of stroke in this group (OR 4.96, CI 1.75-14.06, P = .003). Almost three times as many patients had a pulmonary embolism in the P-C4d group, compared with controls (11 vs. 4, P = .007).

Fourteen SLE patients (4%) died during the follow-up. Of those, more P-C4d-positive patients died compared with those who tested negative for P-C4d (11% vs. 2%, P = .002). Causes of death included infection (4), cardiac arrest (2), congestive heart failure (1), cancer (2), hemorrhage (1), and unspecified (4). The risk of all-cause mortality was increased almost eightfold in those who were P-C4d positive (OR 7.92, CI 2.13-29.48, P = .002). Only cancer (OR 19.74) surpassed being P-C4d as a risk for all-cause mortality in multivariate regression analysis.

"Usually when we measure complement in the circulation, we measure the parent protein C4 in the plasma. When complement is activated, it breaks down into fragments and we see that one fragment, C4d, can covalently bind to cell surfaces. So, as we study how these fragments of complement activation bind to cells, we are exploring their potential use as disease biomarkers and prognostic indicators," Dr. Manzi said.

Dr. Manzi serves on the advisory boards of Bristol-Myers Squibb, Human Genome Sciences, and Cephalon. She receives funding for research from Amgen USA, Aspreva Pharmaceuticals, Bristol-Myers Squibb, Cephalon, Genentech, Human Genome Sciences, and Immunomedics.

NEW YORK – The 18%-20% of systemic lupus erythematosus patients who test positive for platelet C4d face a much greater likelihood of having a future cardiovascular event, stroke, or death than those who are not platelet C4d positive, according to Dr. Susan M. Manzi, who presented the results at a rheumatology meeting sponsored by New York University.

"The only factor that predicted mortality greater than being positive for P-C4d [platelet C4d] was having cancer," said Dr. Manzi, chair of the department of medicine and codirector of the Lupus Center of Excellence at West Penn Allegheny Health System, Pittsburgh.

In the study of 356 patients with systemic lupus erythematosus (SLE), which was carried out between July 2001 and August 2009, 70 tested positive for P-C4d (20%) and 286 tested negative. This confirms a previous study that found that P-C4d was present in 18% of SLE patients and that P-C4d was highly specific for SLE (Arthritis Rheum. 2006;54:670-4). "P-C4d carries a 95% specificity for SLE," said Dr. Manzi, who is also vice chair and professor of medicine at Temple University, Philadelphia.

Patients who were P-C4d positive had twice as many cardiovascular events (36 vs. 18, P = .001). The odds ratio of having a cardiovascular event was 2.09 for positive P-C4d (P = .02), which was much higher than for smoking (OR 1.36), SLE disease duration (0.99), or the presence of renal disease (1.42). The odds ratio for aPL antibodies was 2.30 (P = 0.004).

The results for stroke were even more striking. Thirteen patients with P-C4d had stroke, compared with three in those who tested negative for P-C4d (P = .002). There was nearly a fivefold increased risk of stroke in this group (OR 4.96, CI 1.75-14.06, P = .003). Almost three times as many patients had a pulmonary embolism in the P-C4d group, compared with controls (11 vs. 4, P = .007).

Fourteen SLE patients (4%) died during the follow-up. Of those, more P-C4d-positive patients died compared with those who tested negative for P-C4d (11% vs. 2%, P = .002). Causes of death included infection (4), cardiac arrest (2), congestive heart failure (1), cancer (2), hemorrhage (1), and unspecified (4). The risk of all-cause mortality was increased almost eightfold in those who were P-C4d positive (OR 7.92, CI 2.13-29.48, P = .002). Only cancer (OR 19.74) surpassed being P-C4d as a risk for all-cause mortality in multivariate regression analysis.

"Usually when we measure complement in the circulation, we measure the parent protein C4 in the plasma. When complement is activated, it breaks down into fragments and we see that one fragment, C4d, can covalently bind to cell surfaces. So, as we study how these fragments of complement activation bind to cells, we are exploring their potential use as disease biomarkers and prognostic indicators," Dr. Manzi said.

Dr. Manzi serves on the advisory boards of Bristol-Myers Squibb, Human Genome Sciences, and Cephalon. She receives funding for research from Amgen USA, Aspreva Pharmaceuticals, Bristol-Myers Squibb, Cephalon, Genentech, Human Genome Sciences, and Immunomedics.

NEW YORK – The 18%-20% of systemic lupus erythematosus patients who test positive for platelet C4d face a much greater likelihood of having a future cardiovascular event, stroke, or death than those who are not platelet C4d positive, according to Dr. Susan M. Manzi, who presented the results at a rheumatology meeting sponsored by New York University.

"The only factor that predicted mortality greater than being positive for P-C4d [platelet C4d] was having cancer," said Dr. Manzi, chair of the department of medicine and codirector of the Lupus Center of Excellence at West Penn Allegheny Health System, Pittsburgh.

In the study of 356 patients with systemic lupus erythematosus (SLE), which was carried out between July 2001 and August 2009, 70 tested positive for P-C4d (20%) and 286 tested negative. This confirms a previous study that found that P-C4d was present in 18% of SLE patients and that P-C4d was highly specific for SLE (Arthritis Rheum. 2006;54:670-4). "P-C4d carries a 95% specificity for SLE," said Dr. Manzi, who is also vice chair and professor of medicine at Temple University, Philadelphia.

Patients who were P-C4d positive had twice as many cardiovascular events (36 vs. 18, P = .001). The odds ratio of having a cardiovascular event was 2.09 for positive P-C4d (P = .02), which was much higher than for smoking (OR 1.36), SLE disease duration (0.99), or the presence of renal disease (1.42). The odds ratio for aPL antibodies was 2.30 (P = 0.004).

The results for stroke were even more striking. Thirteen patients with P-C4d had stroke, compared with three in those who tested negative for P-C4d (P = .002). There was nearly a fivefold increased risk of stroke in this group (OR 4.96, CI 1.75-14.06, P = .003). Almost three times as many patients had a pulmonary embolism in the P-C4d group, compared with controls (11 vs. 4, P = .007).

Fourteen SLE patients (4%) died during the follow-up. Of those, more P-C4d-positive patients died compared with those who tested negative for P-C4d (11% vs. 2%, P = .002). Causes of death included infection (4), cardiac arrest (2), congestive heart failure (1), cancer (2), hemorrhage (1), and unspecified (4). The risk of all-cause mortality was increased almost eightfold in those who were P-C4d positive (OR 7.92, CI 2.13-29.48, P = .002). Only cancer (OR 19.74) surpassed being P-C4d as a risk for all-cause mortality in multivariate regression analysis.

"Usually when we measure complement in the circulation, we measure the parent protein C4 in the plasma. When complement is activated, it breaks down into fragments and we see that one fragment, C4d, can covalently bind to cell surfaces. So, as we study how these fragments of complement activation bind to cells, we are exploring their potential use as disease biomarkers and prognostic indicators," Dr. Manzi said.

Dr. Manzi serves on the advisory boards of Bristol-Myers Squibb, Human Genome Sciences, and Cephalon. She receives funding for research from Amgen USA, Aspreva Pharmaceuticals, Bristol-Myers Squibb, Cephalon, Genentech, Human Genome Sciences, and Immunomedics.