Eculizumab for the treatment of preeclampsia/HELLP syndrome

Burwick, Richard M.; Feinberg, Bruce B.

doi:10.1016/j.placenta.2012.11.014

Cited by 175 publications

(124 citation statements)

References 17 publications

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“…Higher concentrations of complement anaphylatoxins (eg, C5a) may cause recurrent spontaneous abortion, 20,32 preterm birth, 33,34 and preeclampsia, 21,22 whereas treatment with the C5 inhibitor eculizumab may have therapeutic relevance in these conditions. 35 Importantly, eculizumab seems to be administrable safely in pregnancy in the long term. 36,37 In our study, we found similar C5a levels in healthy pregnant and non-pregnant women and could not detect any association between C5a levels and obstetric parameters, such as fetal birthweight or gestational week at delivery; of note, these pregnancies were without complications.…”

Section: Discussionmentioning

confidence: 99%

Relationship of Circulating C5a and Complement Factor H Levels With Disease Control in Pregnant Women With Asthma

et al. 2016

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BACKGROUND: Asthma often complicates pregnancy and represents a risk of serious pregnancy complications. The complement system contributes to asthma pathogenesis and is up-regulated in healthy gestation as well. The anaphylatoxin C5a has a major pro-inflammatory role, and the complement factor H is a main soluble regulator protein both in asthma and during pregnancy; however, peripheral levels of these complement factors and their relationship to disease control have not yet been evaluated in pregnant subjects with asthma. METHODS: The present study aimed to investigate circulating C5a and complement factor H levels in asthma (non-pregnant subjects with asthma; n ‫؍‬ 19) and in pregnancy with asthma (pregnant subjects with asthma; n ‫؍‬ 22), compared with healthy non-pregnant (n ‫؍‬ 21) and healthy pregnant women (n ‫؍‬ 13) and to test their relationship to clinical parameters of asthma (lung function, airway inflammation, and symptoms). RESULTS: Circulating C5a levels were higher in the pregnant asthma subject group compared with the healthy non-pregnant, healthy pregnant, and non-pregnant asthma groups: median 2.629 (interquartile range [IQR] 2.257-3.052) ng/mL versus 1.84 (IQR 1.576 -2.563), 1.783 (IQR 0.6064 -2.786), and 2.024 (IQR 1.232-2.615) ng/mL, respectively (P ‫؍‬ .02 in all cases). C5a correlated negatively with FEV 1 (r ‫؍‬ ؊0.44, P ‫؍‬ .039) and FVC values (r ‫؍‬ ؊0.64, P ‫؍‬ .001) in the pregnant asthma group and positively with fraction of exhaled nitric oxide levels in the nonpregnant asthma group (n ‫؍‬ 12, r ‫؍‬ 0.78, P ‫؍‬ .004). Complement factor H levels were elevated in both the healthy pregnant and pregnant asthma subject groups compared with the healthy non-pregnant group (median 1,082 [IQR 734.9 -1,224] and 910.7 [IQR 614.5-1076] g/mL vs 559.7 [IQR 388.7-783.1] g/mL, P ‫؍‬ .002 and P ‫؍‬ .004, respectively) but not in the pregnant asthma group compared with the non-pregnant asthma group (median 687.4 [IQR 441.6 -947.6] g/mL, P ‫؍‬ .10). CONCLUSIONS: Asthma during pregnancy increases the circulating level of pro-inflammatory C5a, which is accompanied by impaired lung function and partly counteracted by the gestation-specific elevation of regulatory complement factor H level (detected in pregnancy both in healthy and subjects with asthma).

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Section: Discussionmentioning

confidence: 99%

Relationship of Circulating C5a and Complement Factor H Levels With Disease Control in Pregnant Women With Asthma

et al. 2016

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“…Recently, a case report was published, where treatment with the C5 inhibitor eculizumab prolonged HELLP (hemolysis, elevated liver enzymes, and low platelets)/PE pregnancy by 17 days. The treatment resulted in a clinical improvement of the patient and normalization of her lab parameters supporting the role of C in the pathogenesis of PE (11). Up to our knowledge, however, the C system has never been described in its entirety in the PE placentae in comparison with healthy control placentae.…”

Section: Introductionmentioning

confidence: 85%

Complement activation and regulation in preeclamptic placenta

et al. 2014

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† Anna Inkeri Lokki and Jenni Heikkinen-Eloranta have contributed equally to this work.Preeclampsia (PE) is a common disorder of pregnancy originating in the placenta. We examined whether excessive activation or poor regulation of the complement system at the maternal-fetal interface could contribute to the development of PE. Location and occurrence of complement components and regulators in placentae were analyzed. Cryostat sections of placentae were processed from 7 early-onset PE (diagnosis <34 weeks of gestation), 5 late-onset PE, 10 control pregnancies, and immunostained for 6 complement activators and 6 inhibitors. Fluorescence was quantified and compared between PE and control placentae. Gene copy numbers of complement components C4A and C4B were assessed by a quantitative PCR method. Maternal C4 deficiencies (≥1 missing or nonfunctional C4) were most common in the early-onset PE group (71%), and more frequent in late-onset PE compared to healthy controls (60 vs. 38%). Complement C1q deposition differed significantly between control and patient groups: controls and early-onset PE patients had more C1q than late-onset PE patients (mean p = 0.01 and p = 0.005, respectively). C3 activation was analyzed by staining for C3b/iC3b and C3d. C3d was mostly specific to the basal syncytium and C3b/iC3b diffuse in other structures, but there were no clear differences between the study groups. Activated C4 and membrane-bound regulators CD55, CD46, and CD59 were observed abundantly in the syncytiotrophoblast. Syncytial knots, structures enriched in PE, stained specifically for the classical pathway inhibitor C4bp, whereas the key regulator alternative pathway, factor H (FH) showed a wider distribution in the placenta. Differences in C1q deposition between late-and early-onset PE groups may be indicative of the different etiology of PE symptoms in these patients. Irregular distribution of the complement regulators C4bp and FH in the PE placenta and a higher frequency of C4A deficiencies suggest a disturbed balance between complement activation and regulation in PE.

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“…После введения экулизумаб связывается с С5 и предотвращает дальнейшую активацию комплемента и образование терминального комплекса комплемента, предотвращая его разрушающее действие. В настоящее время в литературе имеются лишь единичные наблюдения применения экулизумаба при «акушерском» аГУС [30][31][32]. У тех 5 родильниц из 8, которым лечение было начато в течение недели от дебюта аГУС, к моменту окончания курса индукционной терапии (через 1 мес от начала) удалось не только купировать гематологические признаки ТМА, но и полностью восстановить функцию поврежденных органов, включая почки, головной мозг, легкие.…”

Section: таблица 3 основные лабораторные показатели в острый период unclassified

Atypical hemolytic-uremic syndrome in obstetric practice: The first Russian experience of diagnosis and treatment

Kozlovskaya¹,

Korotchaeva²

2016

Ross. vestn. akush.-ginekol.

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1 Кафедра нефрологии и гемодиализа Первого Московского государственного медицинского университета им. И.М. Сеченова Минздрава россии, Москва, россия; 2 научно-исследовательский отдел нефрологии Первого Московского государственного медицинского университета им. И.М. Сеченова Минздрава россии, Москва, россия атипичный гемолитико-уремический синдром в 12-31% случаев связан с беременностью или родами и может опреде-лять прогноз жизни как матери, так и ребенка. Цель работы -анализ клинических проявлений, особенностей течения и исходов атипичного гемолитико-уремического синдрома у беременных и родильниц. Материал и методы. С 2012 по 2016 г. наблюдались 20 пациенток в возрасте от 19 до 38 лет, у которых атипичный гемолитико-уремический синдром развился во время беременности или непосредственно после родов. Результаты. развитию указанного синдрома предше-ствовали преимущественно преэклампсия и/или hEllP-синдром и другие акушерские осложнения, диарея. Все пациентки имели полный симптомокомплекс тромботической микроангиопатии: резкое снижение уровня гемоглобина (66±16,77 г/л) с признаками микроангиопатического гемолиза (повышение уровня лДг -2953,16±3185,17 ед/л, шизоцитоз), тромбо-цитопению (52,5±33,2 тыс. в мкл), острое повреждение почек (гиперкреатининемия -466,3±212,4 мкмоль/л, олигурия или анурия). у 16 (80%) из 20 пациенток впервые отмечена артериальная гипертензия. у всех пациенток тромботическая микроангиопатия носила системный характер: признаки поражения печени и легких имели по 75% женщин (15 из 20) соответственно, поражение цнС отмечалось у 70% (14 из 20), сердца -у 40% (8 из 20). При анализе течения ати-пичного гемолитико-уремического синдрома в зависимости от сроков беременности на момент развития заболевания клинико-лабораторные показатели были измененными в большей степени у женщин с манифестацией синдрома в III три-местре и после родов. лечение состояло преимущественно из плазмотерапии в режимах инфузий свежезамороженной плазмы и плазмообмена -у 16 (80%) пациенток из 20, 8 пациенткам было начато лечение экулизумабом -препаратом, являющимся моноклональным антителом против компонента С5 системы комплемента. Материнская летальность соста-вила 35%. Выводы. «акушерский» атипичный гемолитико-уремический синдром характеризуется развитием полиорган-ной недостаточности у большинства пациенток. развитию синдрома предшествуют различные комплемент-активирующие состояния. По-видимому, именно осложнения беременности, а не сама беременность при нормальном ее течении явля-ются триггерами атипичного гемолитико-уремического синдрома у женщин с генетической предрасположенностью к его развитию.авторы информируют об отсутствии конфликта интересов.Ключевые слова: тромботическая микроангиопатия, атипичный гемолитико-уремический синдром, беременность, преэклампсия, HELLP-синдром.

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Eculizumab for the treatment of preeclampsia/HELLP syndrome

Cited by 175 publications

References 17 publications

Relationship of Circulating C5a and Complement Factor H Levels With Disease Control in Pregnant Women With Asthma

Relationship of Circulating C5a and Complement Factor H Levels With Disease Control in Pregnant Women With Asthma

Complement activation and regulation in preeclamptic placenta

Atypical hemolytic-uremic syndrome in obstetric practice: The first Russian experience of diagnosis and treatment

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