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ATLANTA - Women with anti-SSA/Ro antibodies and a previous child who has heart block—a condition where the electrical signal that make the heart beat is damaged—may potentially decrease their risk of delivering another child with life threatening heart disease by taking hydroxychloroquine (Plaquenil®), according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Atlanta.

Systemic lupus erythematosus, also called SLE or lupus, is a chronic inflammatory disease that can affect the skin, joints, kidneys, lungs, nervous system, and/or other organs of the body. The most common symptoms include skin rashes and arthritis, often accompanied by fatigue and fever. Lupus occurs mostly in women, typically developing in individuals in their twenties and thirties - prime child-bearing age. Sjögren's syndrome is an inflammatory disease that can affect many different parts of the body, but most often affects the tear and saliva glands. Patients with this condition may notice irritation, a gritty feeling, or painful burning in the eyes. Dry mouth or difficulty eating dry foods, and swelling of the glands around the face and neck are also common. Some patients experience dryness of other mucous membranes (such as the nasal passages, throat, and vagina) and skin.

Anti-SSA/Ro antibodies are present in about one-third of women with systemic lupus erythematosus, almost all with Sjogren's syndrome, and even in some healthy women. Pregnancy in mothers with anti-SSA/Ro antibodies—whether they have a disease or not—can be challenging for patients and the doctors who treat them since, despite weekly monitoring, some children born to these women can have the heart complications of neonatal lupus, which are associated with additional diseases and even death. In addition, some children are born with the transient skin rash of cutaneous neonatal lupus.

Previous research suggested that fetal exposure to hydroxychloroquine may decrease the risk of heart problems associated with neonatal lupus in mothers with lupus and anti-SSA/Ro antibodies. Recently, researchers have taken this one step further and have studied the use of hydroxychloroquine as a way to lower the chances of these cardiac complications in subsequent pregnancies of women who have already given birth to a child with neonatal lupus.

Women who have one child with cardiac neonatal lupus are 10 times more likely to experience the same complications with additional children than women who have not had an affected child.

According to data from the Research Registry for Neonatal Lupus (a U.S. registry dedicated to collecting and analyzing neonatal lupus data) the recurrence rate of cardiac neonatal lupus after giving birth to one child is 18 percent and the occurrence of cardiac neonatal lupus after giving birth to one child with cutaneous neonatal lupus is 13 percent. Based on this information, researchers tried to find out whether this recurrence rate was lower in women taking hydroxychloroquine.

Twenty-four pregnancies of 22 women who had previously given birth to one child with lupus (either with or without cardiac complications) were followed. Sixty-eight percent of the mothers were Caucasian, 41 percent were diagnosed with lupus, and 32 percent were diagnosed with Sjogren's Syndrome. Nineteen of the 22 mothers had previously given birth to a child with cardiac neonatal lupus, and eight of those infants died of complications.

Researchers studied the effects of taking hydroxychloroquine daily (with an average dose of 352.6mg) started by six weeks of, and continued throughout the entire, pregnancy to determine if this would positively affect the outcomes of the pregnancies. In addition to taking hydroxychloroquine, 25 percent of the mothers received low dose intravenous immune globulin, 75 percent received non-fluorinated steroids (17 of these women were on prednisone), and 8.3 percent received fluorinated steroids (one of these women started taking these after the diagnosis of congenital heart block).

Based on the above recurrence/occurrence rates, researchers expected the rate of recurrent cardiac neonatal lupus among the study's participants to be 17.2 percent. Of the 24 pregnancies where the mothers took hydroxychloroquine, only one child with was born with cardiac neonatal lupus - a recurrence/occurrence rate of only 4.2 percent, about 75.7 percent less than expected.

These results led researchers to conclude that, in these high-risk pregnancies, hydroxychloroquine may decrease the risk for delivering a second child with cardiac neonatal lupus.

"This case series, made possible by the U.S. Research Registry for Neonatal Lupus and our collaborators in Europe, suggests that for women with anti-SSA/Ro antibodies who have had a previous child with neonatal lupus, the use of hydroxychloroquine during a subsequent pregnancy may reduce the risk of having a child with serious life-threatening heart disease," explains Peter M. Izmirly—assistant professor, New York University School of Medicine, New York and lead investigator in the study—who also notes that additional studies should be completed to confirm this observation.

Patients should talk to their rheumatologists to determine their best course of treatment.

The American College of Rheumatology is an international professional medical society that represents more than 8,000 rheumatologists and rheumatology health professionals around the world. Its mission is to advance rheumatology. The ACR/ARHP Annual Scientific Meeting is the premier meeting in rheumatology. Follow the meeting on twitter by using the official hashtag: #ACR2010.


Editor's Notes: Dr. Izmirly, will present this research during the ACR Annual Scientific Meeting at the Georgia World Congress Center at 5:45 PM on Monday, November 8 in Room B 402.

Learn more about living well with rheumatic disease as well as rheumatologists and the role they play in health care.

Presentation Number: 732

Hydroxychloroquine and Prevention of Anti-SSA/Ro Associated Cardiac Disease in Mothers with a Previous Child with Neonatal Lupus

Peter M Izmirly, MD
(New York University School of Medicine; New York, N.Y.)

Cecilia Pisoni, MD
(Lupus Research Unit, St Thomas' Hospital; London, England)

Mimi Y Kim, PhD
(Albert Einstein College of Medicine; Bronx, N.Y.)

Deborah Friedman, MD
(New York Medical College; Valhalla, N.Y.)

Carolina Llanos, MD, PhD
(Pontificia Universidad Catolica de Chile; Santiago, Chile)

Nathalie Costedoat-Chalumeau, MD, PhD
(Internal Medicine department, SLE and APS National Referral Center, Pitié-Salpíªtrií¨re Hospital; Paris, France)

Munther A Khamashta, MD, FRCP, PhD
(Lupus Research Unit, St Thomas' Hospital, King's College School of Medicine; London, England)

Jill P Buyon, MD
(New York University School of Medicine; New York, N.Y.)

Body: Purpose: Despite weekly monitoring of fetuses exposed to maternal anti-SSA/Ro antibodies, immediate treatment has never permanently reversed complete heart block. This irreversibility strongly supports an emphasis on preventative strategies. A recent case-control study revealed that fetal exposure to Hydroxychloroquine (HCQ), which prevents endosomal acidification and Toll-Like Receptor ligation (proposed pathway involved in cardiac inflammation and scarring), decreases the risk of cardiac manifestations of neonatal lupus (cardiac-NL) in Systemic Lupus Erythematosus (SLE) mothers with anti-SSA/Ro antibodies. That study did not address the effect of HCQ on the recurrence rate in subsequent pregnancies which is nearly 10 fold the frequency in anti-SSA/Ro positive women who have not had an affected child. Accordingly, this study explores whether HCQ prevents the development of cardiac-NL in these highest risk pregnancies.

Methods: Twenty-four pregnancies of 22 mothers satisfied the inclusion criterion: exposure to HCQ in a pregnancy of a mother whose previous child had either cardiac or cutaneous-NL. Exposure was defined as the sustained use of HCQ throughout pregnancy with initiation prior to 6 weeks gestation. In 19 of these 22 families the previous child had cardiac-NL (1- isolated cardiomyopathy and 18- advanced congenital heart block (CHB) 8 of whom died from complications of the disease) and in 3 families the prior child had cutaneous-NL. Of these 22 previous NL pregnancies, 15 were unexposed to HCQ (13 CHB, 1 cardiomyopathy and 1 rash), 6 were exposed to HCQ (4 CHB and 2 rash) and in 1 CHB child, exposure to HCQ was unknown.

Results: Sixty-eight percent of the mothers were Caucasian. The maternal health status was SLE in 41%, Sjogren's Syndrome (SS) in 32%, SLE with secondary SS in 18%, and Undifferentiated Autoimmune Syndrome in 9%. Sixty-four percent (14/22) of the mothers were positive for both anti-SSA/Ro and anti-SSB/La antibodies. The mean daily dose of HCQ was 352.6 mg. Using prospective data from the Research Registry for Neonatal Lupus, the recurrence rate of cardiac-NL following a child with cardiac-NL is 18% (based on 161 pregnancies following a previous child with CHB) and the occurrence rate of cardiac-NL following a child with cutaneous-NL is 13% (based on 39 pregnancies following a previous child with cutaneous-NL). These data suggest that the expected rate of cardiac-NL in this cohort should be approximately 17.2%. Of the 24 subsequent pregnancies exposed to HCQ in this study only one fetus developed cardiac-NL (3rd degree) and this mother's previous child had cutaneous-NL. Thus, the recurrence/occurrence rate was 4.2% (95% CI:(0.11% - 21.1%), a reduction of 75.7%. In addition to HCQ, 25% (6/24) of the mothers received intermittent low dose IVIG, 75% (18/24) non-fluorinated steroids, 17 of whom were on < 10="" mg="" of="" prednisone,="" and="" 8.3%="" (2/24)="" fluorinated="" steroids,="" one="" after="" the="" diagnosis="" of="" chb.="">

Conclusion: This case series suggests that in mothers with anti-SSA/Ro antibodies and a previous child with NL, exposure to HCQ during a subsequent pregnancy may decrease the risk for fetal development of cardiac-NL.

Disclosure: Peter Izmirly, nothing to disclose; Cecilia Pisoni, nothing to disclose; Mimi Kim, nothing to disclose; Deborah Friedman, Medtronics: Consulting fees; Carolina Llanos, nothing to disclose; Nathalie Costedoat-Chalumeau, nothing to disclose; Munther Khamashta, nothing to disclose; Jill Buyon: NIAMS-NIH: Research grants, NIH: Research grants.

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