In the Journals

Complement activation linked to adverse pregnancy outcomes among women with SLE

Jane E. Salmon

Increased plasma levels of complements Bb and sC5b-9 early in pregnancy are strongly predictive of adverse outcomes among women with systemic lupus erythematosus and antiphospholipid antibodies, researchers noted.

“The complement activation pathway is involved in the pathogenesis of pregnancy complications in patients with lupus and antiphospholipid antibodies,” Jane E. Salmon, MD, from the Hospital for Special Surgery, in New York, told Healio Rheumatology. “Higher levels of complement activation products are associated with problems in pregnancy. The study is confirmatory of our mice studies that have implicated inflammation, particularly complement activation and recruitment of neutrophils, as a causative factor in placental insufficiency, fetal loss and growth restriction.”

To determine whether complement activation can predict adverse effects in early pregnancy among patients with erythematosus (SLE) or antiphospholipid (aPL) antibodies, Salmon and colleagues reviewed data from the Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus (PROMISSE) Study. The study comprised pregnant women at less than 12 weeks gestation, 487 of whom had SLE, aPL or both and 204 as healthy controls.

Researchers evaluated study participants monthly by measuring complement activation products on serial blood samples during each visit. Adverse pregnancy effects included fetal or neonatal death, preterm delivery at less than 36 weeks due to placental insufficiency, preeclampsia and growth restriction.

The investigators reported that adverse effects occurred in 20.5% of pregnant women with either SLE or aPL. Further, Bb and sC5b-9 levels were significantly higher in patients with adverse effects at 12 to 15 weeks, and remained elevated through 31 weeks compared with those with normal outcomes. Also, Bb and sC5b-9 plasma levels were significantly higher in patients with SLE or aPL without adverse effects, compared with the control group. Bb (adjusted OR = 1.41 per standard deviation increase; 95% CI, 1.06-1.89) and sC5b-9 (aOR = 1.37 per SD increase; 95% CI, 1.05-1.8) at 12 to 15 weeks remained significantly associated with adverse effects following logistic regression analyses, as well as after controlling for demographic and clinical risk factors. The association between Bb at 12 to 15 weeks and adverse effects in pregnancy were stronger among the161 patients with aPL (aOR = 2.01 per SD increase; 95% CI, 1.16-3.49).

“Our identification of Bb strongly argues that this alternative pathway to activate complement is very important in disease, supporting the mouse studies, but it also focuses a potential therapy on this pathway as opposed to some of the others,” Salmon said.

She noted that “although our findings cannot now be used to identify women at risk in the clinic, because the tests measuring complement activation products are only available for research and lack the sensitivity or specificity to be used alone to predict outcome, the identification of risk biomarkers in pregnant patients with lupus or aPL will allow identification of specific patients for trials targeting complement and downstream mediators.” – by Jason Laday

Disclosure: Salmon reports an investigator-initiated grant from UCB Pharmaceuticals and consulting fees from Alnylam and Alexion. Please see the full study for additional authors’ disclosures.

Jane E. Salmon

Increased plasma levels of complements Bb and sC5b-9 early in pregnancy are strongly predictive of adverse outcomes among women with systemic lupus erythematosus and antiphospholipid antibodies, researchers noted.

“The complement activation pathway is involved in the pathogenesis of pregnancy complications in patients with lupus and antiphospholipid antibodies,” Jane E. Salmon, MD, from the Hospital for Special Surgery, in New York, told Healio Rheumatology. “Higher levels of complement activation products are associated with problems in pregnancy. The study is confirmatory of our mice studies that have implicated inflammation, particularly complement activation and recruitment of neutrophils, as a causative factor in placental insufficiency, fetal loss and growth restriction.”

To determine whether complement activation can predict adverse effects in early pregnancy among patients with erythematosus (SLE) or antiphospholipid (aPL) antibodies, Salmon and colleagues reviewed data from the Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus (PROMISSE) Study. The study comprised pregnant women at less than 12 weeks gestation, 487 of whom had SLE, aPL or both and 204 as healthy controls.

Researchers evaluated study participants monthly by measuring complement activation products on serial blood samples during each visit. Adverse pregnancy effects included fetal or neonatal death, preterm delivery at less than 36 weeks due to placental insufficiency, preeclampsia and growth restriction.

The investigators reported that adverse effects occurred in 20.5% of pregnant women with either SLE or aPL. Further, Bb and sC5b-9 levels were significantly higher in patients with adverse effects at 12 to 15 weeks, and remained elevated through 31 weeks compared with those with normal outcomes. Also, Bb and sC5b-9 plasma levels were significantly higher in patients with SLE or aPL without adverse effects, compared with the control group. Bb (adjusted OR = 1.41 per standard deviation increase; 95% CI, 1.06-1.89) and sC5b-9 (aOR = 1.37 per SD increase; 95% CI, 1.05-1.8) at 12 to 15 weeks remained significantly associated with adverse effects following logistic regression analyses, as well as after controlling for demographic and clinical risk factors. The association between Bb at 12 to 15 weeks and adverse effects in pregnancy were stronger among the161 patients with aPL (aOR = 2.01 per SD increase; 95% CI, 1.16-3.49).

“Our identification of Bb strongly argues that this alternative pathway to activate complement is very important in disease, supporting the mouse studies, but it also focuses a potential therapy on this pathway as opposed to some of the others,” Salmon said.

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She noted that “although our findings cannot now be used to identify women at risk in the clinic, because the tests measuring complement activation products are only available for research and lack the sensitivity or specificity to be used alone to predict outcome, the identification of risk biomarkers in pregnant patients with lupus or aPL will allow identification of specific patients for trials targeting complement and downstream mediators.” – by Jason Laday

Disclosure: Salmon reports an investigator-initiated grant from UCB Pharmaceuticals and consulting fees from Alnylam and Alexion. Please see the full study for additional authors’ disclosures.