IMPACT Study: Preliminary results of a trial with a biologic to prevent preeclampsia in women with antiphospholipid syndrome

BackgroundPregnant women with antiphospholipid antibodies and/or lupus have higher rates of adverse pregnancy outcomes (APOs), such as fetal loss and preterm birth due to severe preeclampsia (PE) or placental insufficiency (PI). The presence of lupus anticoagulant (LAC) is the strongest predictor of an APO. At present, there is no effective treatment for women with these high-risk pregnancies, but in an animal model that mimics this human condition we found that TNF-α was a critical downstream effector of abnormal placental development and fetal damage, and that TNF-α blockade normalized placentation and spiral artery remodeling, and rescued pregnancies. We sought to determine whether TNF-α blockade during pregnancy, added to a regimen of heparin and low dose aspirin, reduces the rate of APOs in women with clinical APS and LAC.MethodsThe IMPACT Study (IMProve Pregnancy in APS with Certolizumab Therapy) is an open label single-stage Phase II trial to evaluate the effect of certolizumab, a TNF-α inhibitor that does not cross the placenta and has been shown to be well tolerated in pregnancy, to reduce the risk of adverse outcomes in this population. Patients with APS and LAC are referred to IMPACT by their physicians, consented and screened remotely by a study investigator, and medication is sent to the patient. They are treated with certolizumab from gestational week 8 through 28. Investigators contact patients every 2 weeks and receive medical reports and research blood samples monthly. The primary outcome is a composite of two APOs associated with poor placentation: fetal death >10 WG or severe preeclampsia/placental insufficiency requiring delivery prior to 34 weeks gestation. The target sample size is 45 evaluable subjects. We hypothesize that the rate of the primary outcome in these pregnancies will be reduced from ~40% based on historical data to 20% with certolizumab.ResultsSince May 2017 and despite the COVID-19 pandemic, we have enrolled 41 patients from ten states and 1 Canadian province. Characteristics: 56% previous PE or PI <34 weeks requiring delivery, 83% previous fetal death >10 weeks;61% thrombosis and/or stroke and 24% SLE in addition to APS. During the trial, no new clinical manifestations of SLE have been observed in participants who did not carry the SLE diagnosis. There were no instances of new anti-DNA antibodies or increases in autoantibody titres in those patients who were anti-DNA antibody positive. ACL or anti-β2GPI antibody titres did not change during the trial. There have been no serious adverse events attributable to the study medication.ConclusionWe are successfully using a "rare disease study” approach to conduct the first trial of a biologic therapy to prevent pregnancy complications in women with APS and LAC. Certolizumab appears to be safe in this small trial. Certolizumab appears to be safe so far in this small trial. IMPACT must be completed before we can draw any conclusions about efficacy, and its results must be confirmed in a future study.AcknowledgementsNIAMS, Lupus Research institute, Lupus Foundation of AmericaClinicalTrials. gov Identifier: NCT03152058Lay SummaryPregnancies in patients with antiphospholipid syndrome who have a lupus anticoagulant in their blood have a high likelihood of ending in fetal death or very premature delivery because of poor placental development and preeclampsia. At present, there is no effective treatment for women with these high-risk pregnancies, but our work in an animal model that mimics this human condition shows that blockade of TNF-α, a pivotal mediator of inflammation, prevents adverse outcomes. Our study will determine whether treatment during pregnancy with certolizumab, a TNF-α inhibitor that does not cross the placenta, reduces the rate of poor pregnancy outcomes in women with clinical antiphospholipid syndrome;and, if successful, it will provide a new approach to protecting pregnancies in women with antiphospholipid syndrome and a rationale for trials of TNF-α blockade in women with other conditions, like SLE, who are a risk for preeclampsia or placental insufficiency.

Impact of the first wave of the COVID-19 pandemic on systemic lupus erythematosus patients: Results from a multi-center prospective cohort.

OBJECTIVE: The aim of this study was to evaluate the initial impact of the COVID-19 pandemic on individuals with systemic lupus erythematosus (SLE). METHODS: Patients with SLE participating in a multi-center longitudinal cohort study in New York and Boston were invited to complete a supplemental web-based questionnaire in the summer of 2020. Participants completed standardized patient-reported outcome (PRO) measures and a combination of Likert scale and open-ended questions exploring the impact of the COVID-19 pandemic on their health and access to health care. Changes in PROs were evaluated with paired t-tests and frequencies of worsened symptoms were calculated. A thematic qualitative analysis was conducted on free text responses. RESULTS: Of 97 patients invited, 63 (65%) completed a supplemental questionnaire. Nearly 50% of respondents exhibited increases in anxiety (47.5%) and depression (48.3%) and over 40% scored worse in measures of pain interference, fatigue, and cognitive abilities. Respondents with pre-existing diagnoses of anxiety did not differ from other participants in PRO scores, but were more than three times as likely to report worsened health status. Patients denied difficulties accessing medications (85%) or medical care (84%) and over 50% participated in telehealth visits. Anxiety and increased health risks due to immunosuppression were recurring themes in free text responses. CONCLUSIONS: SLE patients experienced a significant physical and emotional toll in the initial months of the COVID-19 pandemic. Comprehensive patient-centered care, including monitoring and addressing anxiety and health-related quality of life, is critical to improving health outcomes in this population during the ongoing health crisis.

Pregnancy and Rheumatic Disease: Experience at a Single Center in New York City During the COVID-19 Pandemic.

OBJECTIVE: The present study was undertaken to evaluate the pregnancy experiences of women receiving care in the division of rheumatology at a major academic center in New York City during the COVID-19 pandemic. METHODS: A web-based COVID-19 survey was emailed to 26,045 patients who were followed in the division of rheumatology at a single center in New York City. Women ages 18-50 years were asked about their pregnancy. We compared the COVID-19 experience between pregnant and nonpregnant women and also explored the impact of the pandemic on prenatal care and perinatal outcomes. RESULTS: Among 7,094 of the 26,045 respondents, 1,547 were women ages 18-50 years, with 61 (4%) reporting being pregnant during the pandemic. The prevalence of self-reported COVID-19 was similar in pregnant and nonpregnant women (8% versus 9%, respectively; P = 0.76). Among women with COVID-19, pregnant women had a shorter duration of symptoms (P < 0.01) and were more likely to experience loss of smell or taste (P = 0.02) than nonpregnant women. Approximately three-fourths of women had a systemic rheumatic disease, with no differences when stratified by pregnancy or COVID-19 status. In all, 67% of pregnant women noted changes to prenatal care during the pandemic, and 23% of postpartum women stated that the pandemic affected delivery. CONCLUSION: Among women followed in the division of rheumatology at a major center in New York City, pregnancy was not associated with increased self-reported COVID-19. Pregnancy was associated with a shorter duration of COVID-19 symptoms and a higher prevalence of loss of smell or taste. The COVID-19 pandemic impacted prenatal care for the majority of pregnant patients.

Hydroxychloroquine and Chloroquine in COVID-19: A Survey of Prescription Patterns Among Rheumatologists.

OBJECTIVE: With hydroxychloroquine (HCQ) and chloroquine (CQ) emerging as potential therapies for coronavirus disease 2019 (COVID-19), shortages have been reported. We aimed to understand how rheumatologists, one of the most common prescribers of HCQ/CQ, prescribed these medications to manage COVID-19 and to understand if their patients are affected by shortages. METHODS: Between April 8 and April 27, 2020, an online survey was distributed to a convenience sample of rheumatologists who practice medicine in a diverse range of settings globally, resulting in 506 responses. Adjusted Poisson regression models were calculated. RESULTS: Only 6% of respondents prescribed HCQ/CQ for COVID-19 prophylaxis, and only 12% for outpatient treatment of COVID-19. Compared to the United States, the likelihood of prescribing HCQ/CQ for prophylaxis was higher in India (adjusted risk ratio [aRR], 6.7; 95% confidence interval [CI], 2.7-16.8; p < 0.001). Further, compared to the United States and those with 1 to 5 years of experience, rheumatologists in Europe (aRR, 2.9; 95% CI, 1.6-5.3; p < 0.001) and those with 10+ years of experience (11-20 years: aRR, 2.5; 95% CI, 1.2-5.3; p = 0.015; 21+ years: aRR = 3.3; 95% CI, 1.4-7.4; p = 0.004) had a higher likelihood of prescribing HCQ/CQ for outpatient treatment. Of note, 71% of all rheumatologists reported that their patients were directly affected by HCQ/CQ shortages. CONCLUSION: The results suggest that only a small percentage of rheumatologists are prescribing HCQ/CQ for prophylaxis or outpatient treatment of COVID-19. Medication shortages experienced by large numbers of autoimmune disease patients are concerning and should play a role in decisions, especially given poor efficacy data for HCQ/CQ in COVID-19.