Fine-tune screening for adverse pregnancy outcome biomarkers in antiphospholipid syndrome

NEW YORK – What you screen and where you send your samples can have a tremendous impact on the usefulness of biomarkers to predict adverse pregnancy outcomes in patients with antiphospholipid syndrome, according to Dr. Michael D. Lockshin.

Women who have antiphospholipid antibodies are at high risk of developing adverse pregnancy outcomes (APOs), including preeclampsia, restricted fetal growth, prematurity, and fetal neonatal death. Antiphospholipid syndrome (APS) is defined by a clinical event (either thrombosis and/or recurrent pregnancy loss) plus the presence of an antiphospholipid antibody (either IgG or IgM anticardiolipin [aCL] and/or beta-2-glycoprotein I [beta-2 GPI]).

To see which serologic variables associated with APS may best identify women at highest risk of APO, researchers enrolled 144 pregnant patients with antiphospholipid antibodies (aPL) between 2003 and 2011 in the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus) study. Twenty-eight (19%) had an APO. The results showed that 39% of the patients with lupus anticoagulant (LAC) had an APO, compared with 3% who did not have LAC (P = .0001).

A small percentage (5%) of women who were LAC negative but had high titers of IgG aCL antibody (at least 40 units/mL) had APOs. IgM aCL, IgG anti-beta-2 GPI, and IgM anti-beta-2 GPI were not predictive of APOs, according to Dr. Lockshin and his colleagues (Arthritis Rheum. 2012;64:2311-8).

Among women with high titers of IgG aCL, 8% of those who were LAC negative had an APO, compared with 43% who were LAC positive (P = .002).

"The only tests that made a difference in predicting APOs were lupus anticoagulant and IgG aCL," said Dr. Lockshin, director of the Barbara Volcker Center for Women and Rheumatic Disease and professor of medicine and of obstetrics and gynecology at Weill Cornell Medical College, New York.

Similar patterns were seen in women with lupus who also had APS. In that population, 55% of those who were LAC positive and 12% who were LAC negative/high titer IgG aCL had an APO.

Dr. Lockshin then asked whether LAC screening methods differed in predicting the risk of APOs. He compared the positive and negative predictive values of the dilute prothrombin time test (dPT), the dilute Russell viper venom test (dRVVT), and the activated partial thromboplastin time test (APTT), as well as all tests combined, and found that using the results of all three tests together yielded the highest positive predictive value (all, 0.926; dPT, 0.808; dRVVT, 0.560; aPTT, 0.630). The test with the best negative predictive value was the dRVVT (0.910).

Making appropriate risk assessments for women with APS depends on accurate serological measurement. Dr. Lockshin reported that in a group of 610 women who were referred for SLE and/or aPL, 279 were found to be aPL positive by a referral laboratory. Upon reanalysis of the samples by a core laboratory, 147 of those deemed aPL positive by the referral laboratory were deemed to be aPL negative, yielding a 52% false positive rate. In a group of 196 referred as healthy controls, 2 were found to be aPL positive by the core lab, meaning that 2% of the controls were false negative for aPL. "Don’t just casually accept a commercial laboratory’s determination," Dr. Lockshin said at the meeting, sponsored by New York University.

In multivariate analysis, having SLE significantly increased the risk of having an APO (23% vs. 17%). Patients with prior thrombosis also were more likely to have an APO than were those without prior thrombosis (52% vs. 13%, P = .00005). Age, race, or prior pregnancy loss were not determinants of pregnancy problems.

Dr. Lockshin also addressed the question as to whether heparin mitigates the risk of an APO. He found that in patients who were LAC positive, there was no difference in the number of APOs in those given heparin (49%), compared with those not treated with heparin (50%). The rate of APOs was actually higher in women who were LAC negative but treated with heparin, compared with those who did not receive heparin (29% vs. 18%, no significant difference). Aspirin did reduce the occurrence of APOs (14% vs. 30%, P = .04), but neither hydroxychloroquine nor steroids had any protective effects.

At the meeting, Dr. Lockshin also reported the results of a pilot 12-month open-label phase II trial of rituximab for the noncriteria manifestations of APS (thrombocytopenia, cardiac valve disease, skin ulcers, aPL nephropathy, and/or cognitive dysfunction). After two doses of rituximab (1,000 mg) on days 1 and 15, dramatic improvements in leg ulcers were seen, and, for the first time ever, possible improvement in cognitive function, said Dr. Lockshin. No changes were noted in serology, cardiac valves, or abnormal imaging findings (Arthritis Rheum. 2013;65:464-471).

To encourage further investigation of APS, an international research network has been launched to organize well-designed, large-scale, multicenter clinical trials in aPL-positive patients, said Dr. Lockshin. The AntiPhospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) has initiated two collaborative projects, one looking into the use of hydroxychloroquine for primary thrombosis prevention and the other a web-based registry of aPL-positive patients with or without systemic autoimmune diseases. For more information, go to www.apsaction.org.

Dr. Lockshin reported no financial disclosures.

NEW YORK – What you screen and where you send your samples can have a tremendous impact on the usefulness of biomarkers to predict adverse pregnancy outcomes in patients with antiphospholipid syndrome, according to Dr. Michael D. Lockshin.

Women who have antiphospholipid antibodies are at high risk of developing adverse pregnancy outcomes (APOs), including preeclampsia, restricted fetal growth, prematurity, and fetal neonatal death. Antiphospholipid syndrome (APS) is defined by a clinical event (either thrombosis and/or recurrent pregnancy loss) plus the presence of an antiphospholipid antibody (either IgG or IgM anticardiolipin [aCL] and/or beta-2-glycoprotein I [beta-2 GPI]).

To see which serologic variables associated with APS may best identify women at highest risk of APO, researchers enrolled 144 pregnant patients with antiphospholipid antibodies (aPL) between 2003 and 2011 in the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus) study. Twenty-eight (19%) had an APO. The results showed that 39% of the patients with lupus anticoagulant (LAC) had an APO, compared with 3% who did not have LAC (P = .0001).

A small percentage (5%) of women who were LAC negative but had high titers of IgG aCL antibody (at least 40 units/mL) had APOs. IgM aCL, IgG anti-beta-2 GPI, and IgM anti-beta-2 GPI were not predictive of APOs, according to Dr. Lockshin and his colleagues (Arthritis Rheum. 2012;64:2311-8).

Among women with high titers of IgG aCL, 8% of those who were LAC negative had an APO, compared with 43% who were LAC positive (P = .002).

"The only tests that made a difference in predicting APOs were lupus anticoagulant and IgG aCL," said Dr. Lockshin, director of the Barbara Volcker Center for Women and Rheumatic Disease and professor of medicine and of obstetrics and gynecology at Weill Cornell Medical College, New York.

Similar patterns were seen in women with lupus who also had APS. In that population, 55% of those who were LAC positive and 12% who were LAC negative/high titer IgG aCL had an APO.

Dr. Lockshin then asked whether LAC screening methods differed in predicting the risk of APOs. He compared the positive and negative predictive values of the dilute prothrombin time test (dPT), the dilute Russell viper venom test (dRVVT), and the activated partial thromboplastin time test (APTT), as well as all tests combined, and found that using the results of all three tests together yielded the highest positive predictive value (all, 0.926; dPT, 0.808; dRVVT, 0.560; aPTT, 0.630). The test with the best negative predictive value was the dRVVT (0.910).

Making appropriate risk assessments for women with APS depends on accurate serological measurement. Dr. Lockshin reported that in a group of 610 women who were referred for SLE and/or aPL, 279 were found to be aPL positive by a referral laboratory. Upon reanalysis of the samples by a core laboratory, 147 of those deemed aPL positive by the referral laboratory were deemed to be aPL negative, yielding a 52% false positive rate. In a group of 196 referred as healthy controls, 2 were found to be aPL positive by the core lab, meaning that 2% of the controls were false negative for aPL. "Don’t just casually accept a commercial laboratory’s determination," Dr. Lockshin said at the meeting, sponsored by New York University.

In multivariate analysis, having SLE significantly increased the risk of having an APO (23% vs. 17%). Patients with prior thrombosis also were more likely to have an APO than were those without prior thrombosis (52% vs. 13%, P = .00005). Age, race, or prior pregnancy loss were not determinants of pregnancy problems.

Dr. Lockshin also addressed the question as to whether heparin mitigates the risk of an APO. He found that in patients who were LAC positive, there was no difference in the number of APOs in those given heparin (49%), compared with those not treated with heparin (50%). The rate of APOs was actually higher in women who were LAC negative but treated with heparin, compared with those who did not receive heparin (29% vs. 18%, no significant difference). Aspirin did reduce the occurrence of APOs (14% vs. 30%, P = .04), but neither hydroxychloroquine nor steroids had any protective effects.

At the meeting, Dr. Lockshin also reported the results of a pilot 12-month open-label phase II trial of rituximab for the noncriteria manifestations of APS (thrombocytopenia, cardiac valve disease, skin ulcers, aPL nephropathy, and/or cognitive dysfunction). After two doses of rituximab (1,000 mg) on days 1 and 15, dramatic improvements in leg ulcers were seen, and, for the first time ever, possible improvement in cognitive function, said Dr. Lockshin. No changes were noted in serology, cardiac valves, or abnormal imaging findings (Arthritis Rheum. 2013;65:464-471).

To encourage further investigation of APS, an international research network has been launched to organize well-designed, large-scale, multicenter clinical trials in aPL-positive patients, said Dr. Lockshin. The AntiPhospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) has initiated two collaborative projects, one looking into the use of hydroxychloroquine for primary thrombosis prevention and the other a web-based registry of aPL-positive patients with or without systemic autoimmune diseases. For more information, go to www.apsaction.org.

Dr. Lockshin reported no financial disclosures.

NEW YORK – What you screen and where you send your samples can have a tremendous impact on the usefulness of biomarkers to predict adverse pregnancy outcomes in patients with antiphospholipid syndrome, according to Dr. Michael D. Lockshin.

Women who have antiphospholipid antibodies are at high risk of developing adverse pregnancy outcomes (APOs), including preeclampsia, restricted fetal growth, prematurity, and fetal neonatal death. Antiphospholipid syndrome (APS) is defined by a clinical event (either thrombosis and/or recurrent pregnancy loss) plus the presence of an antiphospholipid antibody (either IgG or IgM anticardiolipin [aCL] and/or beta-2-glycoprotein I [beta-2 GPI]).

To see which serologic variables associated with APS may best identify women at highest risk of APO, researchers enrolled 144 pregnant patients with antiphospholipid antibodies (aPL) between 2003 and 2011 in the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus) study. Twenty-eight (19%) had an APO. The results showed that 39% of the patients with lupus anticoagulant (LAC) had an APO, compared with 3% who did not have LAC (P = .0001).

A small percentage (5%) of women who were LAC negative but had high titers of IgG aCL antibody (at least 40 units/mL) had APOs. IgM aCL, IgG anti-beta-2 GPI, and IgM anti-beta-2 GPI were not predictive of APOs, according to Dr. Lockshin and his colleagues (Arthritis Rheum. 2012;64:2311-8).

Among women with high titers of IgG aCL, 8% of those who were LAC negative had an APO, compared with 43% who were LAC positive (P = .002).

"The only tests that made a difference in predicting APOs were lupus anticoagulant and IgG aCL," said Dr. Lockshin, director of the Barbara Volcker Center for Women and Rheumatic Disease and professor of medicine and of obstetrics and gynecology at Weill Cornell Medical College, New York.

Similar patterns were seen in women with lupus who also had APS. In that population, 55% of those who were LAC positive and 12% who were LAC negative/high titer IgG aCL had an APO.

Dr. Lockshin then asked whether LAC screening methods differed in predicting the risk of APOs. He compared the positive and negative predictive values of the dilute prothrombin time test (dPT), the dilute Russell viper venom test (dRVVT), and the activated partial thromboplastin time test (APTT), as well as all tests combined, and found that using the results of all three tests together yielded the highest positive predictive value (all, 0.926; dPT, 0.808; dRVVT, 0.560; aPTT, 0.630). The test with the best negative predictive value was the dRVVT (0.910).

Making appropriate risk assessments for women with APS depends on accurate serological measurement. Dr. Lockshin reported that in a group of 610 women who were referred for SLE and/or aPL, 279 were found to be aPL positive by a referral laboratory. Upon reanalysis of the samples by a core laboratory, 147 of those deemed aPL positive by the referral laboratory were deemed to be aPL negative, yielding a 52% false positive rate. In a group of 196 referred as healthy controls, 2 were found to be aPL positive by the core lab, meaning that 2% of the controls were false negative for aPL. "Don’t just casually accept a commercial laboratory’s determination," Dr. Lockshin said at the meeting, sponsored by New York University.

In multivariate analysis, having SLE significantly increased the risk of having an APO (23% vs. 17%). Patients with prior thrombosis also were more likely to have an APO than were those without prior thrombosis (52% vs. 13%, P = .00005). Age, race, or prior pregnancy loss were not determinants of pregnancy problems.

Dr. Lockshin also addressed the question as to whether heparin mitigates the risk of an APO. He found that in patients who were LAC positive, there was no difference in the number of APOs in those given heparin (49%), compared with those not treated with heparin (50%). The rate of APOs was actually higher in women who were LAC negative but treated with heparin, compared with those who did not receive heparin (29% vs. 18%, no significant difference). Aspirin did reduce the occurrence of APOs (14% vs. 30%, P = .04), but neither hydroxychloroquine nor steroids had any protective effects.

At the meeting, Dr. Lockshin also reported the results of a pilot 12-month open-label phase II trial of rituximab for the noncriteria manifestations of APS (thrombocytopenia, cardiac valve disease, skin ulcers, aPL nephropathy, and/or cognitive dysfunction). After two doses of rituximab (1,000 mg) on days 1 and 15, dramatic improvements in leg ulcers were seen, and, for the first time ever, possible improvement in cognitive function, said Dr. Lockshin. No changes were noted in serology, cardiac valves, or abnormal imaging findings (Arthritis Rheum. 2013;65:464-471).

To encourage further investigation of APS, an international research network has been launched to organize well-designed, large-scale, multicenter clinical trials in aPL-positive patients, said Dr. Lockshin. The AntiPhospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) has initiated two collaborative projects, one looking into the use of hydroxychloroquine for primary thrombosis prevention and the other a web-based registry of aPL-positive patients with or without systemic autoimmune diseases. For more information, go to www.apsaction.org.

Dr. Lockshin reported no financial disclosures.