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| Megan Clowse, M.D.
Pathogenesis Treatment Clinical Outcomes | ||
| Pathogenesis | ||
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Abstract 1168: Tissue Factor: a Link Between Inflammation and Thrombosis in Antiphospholipid Antibody-Induced Pregnancy Loss Background: Antiphospholipid syndrome induced pregnancy loss was previously believed to be caused solely by thrombosis within the placenta. This group at Hospital for Special Surgery has demonstrated with a mouse model that complement activation and inflammation are essential to pregnancy loss from antiphospholipid antibodies. In a plenary session at the 2004 ACR meeting, Dr. Girardi presented data showing that heparin, which is commonly used to prevent pregnancy loss in women with APS, protected these pregnancies by decreasing complement activation, not just inhibiting thrombosis. Tissue factor activates the extrinsic coagulation cascade, leading to thrombosis, and is expressed by inflammatory cells and endothelial cells when stimulated by C5a. Purpose: To identify the link between complement activation and thrombosis in pregnancy loss caused by antiphospholipid antibodies in mice. Method: Human antiphospholipid IgG antibodies or a placebo infusion of human IgG were infused into pregnant mice. The fetal resorption rate and fetal weight were obtained on day 15 of gestation. The fetal and placental tissue was stained for tissue factor. This was performed on 3 sets of mice:
Results: The groups of mice with functional C5 and C5aR had an increase in fetal resorption, lower embryo weight, and intense tissue factor staining in the decidua. Mice without functional C5 or C5aR had normal pregnancy survival and weights, and had no tissue factor on the decidua. This demonstrates that working complement, in particular C5 and C5aR, are important mediators of pregnancy loss induced by antiphospholipid antibodies. They also prompt the deposition of tissue factor on the decidua. Without funtional C5 or C5aR, the pregnancies are not affected by the infusion of antiphospholipid antibodies. Mice with or without functional C6 had fetal resorption, lower embryo weights, and tissue factor staining on the decidua. This shows that C6 is not a mediator of pregnancy loss from antiphospholipid antibodies. Editorial Comment: This study demonstrates that C5a is an essential component of complement activation by antiphospholipid antibodies, tissue factor deposition at the decidua, and pregnancy loss. As tissue factor initiates the extrinsic coagulation cascade, leading to thrombosis, this is likely the link between complement and thrombosis. Using anti-C5 antibodies in women with antiphospholipid syndrome has been suggested, though not yet tried, to protect pregnancy from loss. This abstracts shows that this might help decrease both the inflammation and thrombosis that contributes to APS-associated pregnancy loss. Abstract 309: Prospective Study of Cell-free Fetal DNA and disease Activity in Women with Inflammatory Arthritis During Pregnancy Background: Rheumatoid Arthritis frequently improves during pregnancy and flares post-partum. Cell-free fetal DNA is DNA from the fetus that has been liberated from placental and fetal cells and is circulating in the pregnant mother. In the laboratory, it can be quantified and distinguished from maternal DNA. Though this technique is experimental, it is beginning to be used to detect some fetal genetic abnormalities and blood mismatching. The amount of cell-free fetal DNA may also be associated with preterm delivery and other pregnancy complications. Purpose: To assess for a correlation between cell-free fetal DNA and disease activity of rheumatoid arthritis during and after pregnancy. Method: 25 pregnancies in women with rheumatoid arthritis were studied, with identification and quantification of cell-free fetal DNA in each trimester and post-partum. A rheumatologist assessed disease activity throughout pregnancy. Results: The amount of cell-free fetal DNA found in the mothers blood increased in each trimester and quickly decreased after delivery. The women with less active rheumatoid arthritis had higher levels of cell-free fetal DNA in their blood. Editorial Comment: The cause for improvement in rheumatoid arthritis during pregnancy is poorly understood, with most theories revolving around either hormonal changes or immunologic shifts. This study demonstrates a new approach to this question and suggests that the presence of cell-free fetal DNA is protective against rheumatoid arthritis inflammation. Perhaps the increased exposure to fetal DNA induces tolerance in the mother, allowing her to carry her pregnancy and decreasing her immunologic attack against her joints. This is an interesting concept and deserves further study. | ||
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Background: Tumor Necrosis Factor-alpha inhibitors (TNF-inhibitors) are used commonly to control inflammatory arthritis. The FDA had labeled them as Class B for pregnancy risk, meaning that there is no evidence that they induce fetal malformations among humans or animals. There is not, however, significant evidence demonstrating their safety during pregnancy. Two studies addressed this issue. Abstract F12: Safety of TNF-inhibitors During Pregnancy in Patients with Inflammatory Arthritis Method: Two email surveys were sent to practicing rheumatologists about the use of TNF-inhibitors in pregnancy. Results: The 1st survey was sent to 3064 physicians and 1212 (40%) responded. This survey identified 463 pregnancies among women on TNF-inhibitors. Of these 387 resulted in full term births, 25 (5.4%) ended with a miscarriage, 5 were electively aborted, and there were no fetal malformations. The 2nd survey was sent to the 225 physicians who identified the 463 pregnancies in the 1st survey. Of these, detailed information was obtained on 95 pregnancies. Only 84 of the detailed pregnancies were exposed to a TNF-inhibitor during pregnancy, 23 (27%) of which were also exposed to another DMARD. Over 75% of the pregnancies were to women with RA. The TNF-inhibitor was continued throughout pregnancy in 27% of the pregnancies, but the rest were stopped within a few weeks of pregnancy identification in the 1st trimester. The main TNF-inhibitor used was etanercept (81% of pregnancies). Of the 84 pregnancies exposed to a TNF-inhibitor that were studied in detail, 93% resulted in a live birth. The other 7% suffered a miscarriage. The vast majority of these pregnancies resulted in a full term birth. Fetal malformations were identified in 2 offspring: one with a missing limb and one with a Vater association. These pregnancy outcomes measure favorably against those seen in the normal population. Abstract 884: Pregnancy in Women receiving Anti-TNF-alpha Therapy: Experience in Spain. Method: Data was collected from a Spanish registry for adverse events from biologic medications in rheumatologic disease. Results: Of 3550 women in the registry, 10 women had 11 pregnancies while on biologic therapy. One of these pregnancies resulted in a miscarriage at 9 weeks of gestation. Two pregnancies were electively terminated. Six pregnancies resulted in a fullterm birth, though 2 of these mothers had gestational diabetes. The outcome of 2 pregnancies was unknown. Only one pregnancy had exposure to a TNF-inhibitor beyond the first trimester and it was electively terminated at 14 weeks gestation. There were no fetal abnormalities reported. Editorial Comment: These reports of 95 pregnancies exposed to TNF-inhibitors are encouraging, showing no increase in pregnancy loss or fetal abnormalities. Though the outcomes of the 23 pregnancies that continued the TNF-inhibitor through pregnancy in the U.S. study were not shown specifically, this study shows that this may be safe. The OTIS registry, a group collecting pregnancies among women with rheumatoid arthritis and psoriatic arthritis, will be able to provide more information on the teratogenicity of TNF-inhibitors in the future. All pregnancies in women with inflammatory arthritis should be reported to the OTIS registry (otispregnancy.org) for careful examination of congenital abnormalities in the offspring. Abstract 994: Azathioprine Use in Lupus Pregnancy Background: The treatment of active lupus during pregnancy is difficult as the risks of both the medications and the disease activity to the mother and fetus must be balanced. Azathioprine can be effective treatment of active lupus and maintenance, especially in patients with prior lupus nephritis. It is also used in patients with prior solid organ transplants and inflammatory bowel disease. In these two groups of patients, the safety of azathioprine during pregnancy has been demonstrated. Azathioprine is metabolized by the fetal live into an inactive form of the drug, decreasing the impact of the immunosuppressant effects on the fetus. Methods: Cohort study of consecutive pregnancies in lupus patients seen from 1987 to 2002 at the Johns Hopkins Hospital. AZA use, pregnancy course and outcomes were determined through a prospective database and chart review. Results: 258 pregnancies were seen in 199 women. There were 236 pregnancies without AZA exposure. AZA was used to treat the mother in 31 pregnancies; 18 were using AZA at conception, 5 of whom discontinued its use in the 1st trimester. AZA was initiated in the 2nd or 3rd trimester in 11 pregnancies, and in the 1st trimester in 2 patients. Prior renal transplant was the indication for continuous AZA use in 3 pregnancies. There were no congenital anomalies identified in the infants exposed to AZA. Of the 166 pregnancies seen during the first trimester, 13 had AZA exposure. The miscarriage rate for women with early exposure to AZA was not statistically different from pregnancies without exposure (15% vs 9%, p=0.4). When adjusted for high activity lupus and the presence of APS, the miscarriage rates remained similar. 241 pregnancies survived past 20 weeks. Of these, 25 had exposure to AZA in the latter half of pregnancy. A higher rate of fetal demise occurred in pregnancies with AZA exposure. When adjusted for increased lupus activity and APS, odds ratio of 2.8 (95% CI 0.9 to 9.1, p=0.09) suggests a possible association of AZA with fetal loss after 20 weeks gestation. A comparison of the 17 pregnancies with severe lupus activity during pregnancy (PEA of 2.5 or 3) showed that those that did not receive AZA had a significantly improved rate of pregnancy survival over those treated with AZA (11% vs 63%, p=0.023). The pregnancies that did not receive AZA may have had less active lupus, though the two groups matched fairly well. The major difference between the 2 groups was timing: all but one of the pregnancies prior to 1995 did not receive AZA and all but one after 1995 did receive AZA. This suggests that the AZA use was based more on physician practice than on disease severity. Editorial Comment: The safety of continuing of Azathioprine among women already on the medication to control lupus activity or maintain a renal transplant is confirmed in this study. However, the use of Azathioprine to treat severely active lupus during pregnancy may put the fetus at increased risk. A randomized control trial of Azathioprine use during pregnancy is needed to establish the appropriate use of the drug. | ||
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Abstract 991: Obstetric hospitalizations in the U.S. for women with SLE and RA Background: Most of the data available about lupus and rheumatoid arthritis pregnancy outcomes come from cohorts at tertiary referral centers, possibly skewing the severity of disease and pregnancy outcomes. Methods: The 2002 Nationwide Inpatient Sample, a database of all admissions to a representative sample of 995 hospitals in the United States, was queried for pregnancies associated with SLE and RA. The diagnoses of SLE and RA as well as pregnancy complications were obtained from ICD-9 coding in the database. The SLE and RA pregnancies were compared with the general population. Results: Of 4.66 million obstetrical hospitalizations in 2002, 4480 occurred in women with SLE and 1670 occurred in women with RA. Women with SLE and RA had significantly longer hospital stays than the general population (SLE 4.3 days, RA 3.2 days, general population 2.6 days; p<0.001). Over a quarter of pregnancies affected by SLE had a non-delivery obstetrical admission, compared to 18% of those with RA and 12% in the general population. Hypertensive complications were found in a quarter of women with SLE, 12% with RA, and 8% of the general population, a difference that was highly significant. Intrauterine growth restriction occurred over twice as often in SLE and RA pregnancies, though this rate remained low (<5%). Premature rupture of membranes was not more common in women with SLE or RA. Editorial Comment: This is the largest collection of SLE and RA pregnancies yet published. The data on these pregnancies was not solely collected at tertiary centers, making it more applicable to the general SLE and RA patient. The high frequency of hypertension in pregnancies with SLE is not surprising, however the hypertension found in RA patients has not been previously reported. This may reflect the use of corticosteroids during pregnancy to control joint inflammation. Some prior reports have shown an increase in premature rupture of membranes among SLE pregnancies, but this is not borne out in this large study. A significant drawback of this study is that the diagnosis of SLE or RA was based solely on ICD-9 codes from the time of hospital discharge. It is not possible in this large anonymous database to confirm these diagnoses, which may lead to some inaccuracies. Abstract 445: In vivo Effects of Maternal Immunosuppression During Pregnancy on Childrens Immune Function Background: As most immunosuppressant medication cross into fetal blood flow, there is concern that offspring exposed to these medications in utero will have lasting immunosuppression. Method: The functioning of the immune system in 14 babies born to women with SLE or UCTD that were treated with immunosuppressants were compared to 14 babies born to women with SLE or UCTD who were not treated with immunosuppressant medications during pregnancy and 6 babies born to healthy mothers. The immunosuppressants used included cyclosporin (5 babies), azathioprine (3 babies), and dexamethasone (6 babies). Results: There was no difference in the levels of interferon? or IL-2 in babies exposed to immunosuppressants and those not exposed. There was also no difference found based on the type of immunosuppressant used. The percentages of 5 subpopulations of lymphocytes were also similar between all of the babies. Editorial Comment: Though there is significant theoretical concern about immunosuppression among offspring of rheumatologic pregnancies, there are very few reports of abnormalities identified. This abstract confirms that these medications do not produce significant changes in the immune system of the offspring. The oldest child tested in this study was 32 months old. It is possible that future immunologic abnormalities are yet to be uncovered. | ||
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