Amy Rothman Schonfeld

Many physicians who care for children feel that selective cyclooxygenase-2 nonsteroidal anti-inflammatory agents have equivalent or greater safety, efficacy, or tolerability and fewer side effects than do coventional NSAIDs. However, in the years since the voluntary withdrawal of rofecoxib and valdecoxib from the market, few practitioners aside from rheumatologists prescribe selective COX-2 NSAIDs for children, according to a report of survey results published in Pediatric Rheumatology.

Investigators e-mailed a link to a 22-question survey to 1,289 pediatricians, pediatric rheumatologists, sports medicine physicians, pediatric surgeons, and pediatric orthopedic surgeons. In all, 84 e-mails were returned as “undeliverable.” Despite reminders and incentives, only 338 (28%) of the 1,205 e-mail recipients completed the surveys. Response rate varied by specialty, with the highest response rates from pediatric rheumatologists (100 of 247, 40%) and the lowest for sports medicine specialists (12 of 106, 11%).

Indeed, one limitation of the study was that it was skewed to include a large percentage of pediatric rheumatologists, since investigators were particularly interested in hearing from those who often prescribe NSAIDs, according to Dr. Deborah M. Levy, a pediatric rheumatologist at the Hospital for Sick Children in Toronto, and Dr. Lisa F. Imundo, a pediatric rheumatologist at the Morgan Stanley Children's Hospital of New York–Presbyterian, Columbia University.

Nonrheumatologists frequently (more than once a week) prescribed ibuprofen, naproxen, and ketorolac, but they rarely prescribed any other NSAID. Rheumatologists used a wider variety of medications, most notably ibuprofen, diclofenac, indomethacin, naproxen, celecoxib, and rofecoxib.

About half of the respondents (164 of 330) had never prescribed a selective COX-2 NSAID. By specialty, 72% of pediatricians, 52% of orthopedic surgeons, 79% of pediatric surgeons, and 4% of rheumatologists had never prescribed a selective COX-2 NSAID. The most common reasons for prescribing a selective COX-2 NSAID were for arthritis, musculoskeletal pain, soft-tissue injury, and fracture. Use of these agents was more likely after failure of an NSAID.

Pediatric rheumatologists reported that certain adverse events were more common with conventional NSAIDs than with selective COX-2 agents. Abdominal pain (81% vs. 23%), epistaxis (13% vs. 2%), easy bruising (64% vs. 8%), headaches (21% vs. 1%), and fatigue (12% vs. 1%) were more common with conventional NSAIDs (n = 99), compared with the selective COX-2 medications (n = 95).

COX-2 NSAIDs were rated as equivalent or superior to conventional NSAIDs for safety (66%), pain relief (72%), relief of inflammation (74%), and tolerability (83%) in the opinion of physicians who had prescribed the agents.

Eleven physicians reported that one or more patients had a cardiovascular event while taking an NSAID, all of which were attributed to the patients' underlying diseases, and not to the use of either a conventional or selective COX-2 NSAID, according to the investigators.

Rofecoxib was voluntarily withdrawn from the market in September 2004, and valdecoxib was withdrawn in April 2005, and these events affected physician prescribing habits. For pediatric rheumatologists, 57% said they prescribed selective COX-2 NSAIDs less frequently and 26% said they no longer prescribed them. Consequently, 44% increased their prescriptions of conventional NSAIDs.

Nine conventional NSAIDS (aspirin, etodolac, ibuprofen, indomethacin, ketorolac, meloxicam, naproxen, oxaprozin, and tolmetin) and one selective COX-2 NSAID (celecoxib) currently have Food and Drug Administration–approved pediatric indications. At the time of the survey, no COX-2 NSAID had a pediatric indication. The authors suggest that phase IV, open-label postmarketing studies of conventional and selective COX-2 NSAIDs in children are needed to more accurately assess the risks and benefits of these medications (Pediatr. Rheumatol. Online J. 2010 Feb. 4 [doi:10.1186/1546-0096-8-7]).

Disclosures: Dr. Levy received support through an independent research grant from Pfizer, manufacturer of valdecoxib. Dr. Imundo reported that she has no financial conflicts of interest.

Many physicians who care for children feel that selective cyclooxygenase-2 nonsteroidal anti-inflammatory agents have equivalent or greater safety, efficacy, or tolerability and fewer side effects than do coventional NSAIDs. However, in the years since the voluntary withdrawal of rofecoxib and valdecoxib from the market, few practitioners aside from rheumatologists prescribe selective COX-2 NSAIDs for children, according to a report of survey results published in Pediatric Rheumatology.

Investigators e-mailed a link to a 22-question survey to 1,289 pediatricians, pediatric rheumatologists, sports medicine physicians, pediatric surgeons, and pediatric orthopedic surgeons. In all, 84 e-mails were returned as “undeliverable.” Despite reminders and incentives, only 338 (28%) of the 1,205 e-mail recipients completed the surveys. Response rate varied by specialty, with the highest response rates from pediatric rheumatologists (100 of 247, 40%) and the lowest for sports medicine specialists (12 of 106, 11%).

Indeed, one limitation of the study was that it was skewed to include a large percentage of pediatric rheumatologists, since investigators were particularly interested in hearing from those who often prescribe NSAIDs, according to Dr. Deborah M. Levy, a pediatric rheumatologist at the Hospital for Sick Children in Toronto, and Dr. Lisa F. Imundo, a pediatric rheumatologist at the Morgan Stanley Children's Hospital of New York–Presbyterian, Columbia University.

Nonrheumatologists frequently (more than once a week) prescribed ibuprofen, naproxen, and ketorolac, but they rarely prescribed any other NSAID. Rheumatologists used a wider variety of medications, most notably ibuprofen, diclofenac, indomethacin, naproxen, celecoxib, and rofecoxib.

About half of the respondents (164 of 330) had never prescribed a selective COX-2 NSAID. By specialty, 72% of pediatricians, 52% of orthopedic surgeons, 79% of pediatric surgeons, and 4% of rheumatologists had never prescribed a selective COX-2 NSAID. The most common reasons for prescribing a selective COX-2 NSAID were for arthritis, musculoskeletal pain, soft-tissue injury, and fracture. Use of these agents was more likely after failure of an NSAID.

Pediatric rheumatologists reported that certain adverse events were more common with conventional NSAIDs than with selective COX-2 agents. Abdominal pain (81% vs. 23%), epistaxis (13% vs. 2%), easy bruising (64% vs. 8%), headaches (21% vs. 1%), and fatigue (12% vs. 1%) were more common with conventional NSAIDs (n = 99), compared with the selective COX-2 medications (n = 95).

COX-2 NSAIDs were rated as equivalent or superior to conventional NSAIDs for safety (66%), pain relief (72%), relief of inflammation (74%), and tolerability (83%) in the opinion of physicians who had prescribed the agents.

Eleven physicians reported that one or more patients had a cardiovascular event while taking an NSAID, all of which were attributed to the patients' underlying diseases, and not to the use of either a conventional or selective COX-2 NSAID, according to the investigators.

Rofecoxib was voluntarily withdrawn from the market in September 2004, and valdecoxib was withdrawn in April 2005, and these events affected physician prescribing habits. For pediatric rheumatologists, 57% said they prescribed selective COX-2 NSAIDs less frequently and 26% said they no longer prescribed them. Consequently, 44% increased their prescriptions of conventional NSAIDs.

Nine conventional NSAIDS (aspirin, etodolac, ibuprofen, indomethacin, ketorolac, meloxicam, naproxen, oxaprozin, and tolmetin) and one selective COX-2 NSAID (celecoxib) currently have Food and Drug Administration–approved pediatric indications. At the time of the survey, no COX-2 NSAID had a pediatric indication. The authors suggest that phase IV, open-label postmarketing studies of conventional and selective COX-2 NSAIDs in children are needed to more accurately assess the risks and benefits of these medications (Pediatr. Rheumatol. Online J. 2010 Feb. 4 [doi:10.1186/1546-0096-8-7]).

Disclosures: Dr. Levy received support through an independent research grant from Pfizer, manufacturer of valdecoxib. Dr. Imundo reported that she has no financial conflicts of interest.

Many physicians who care for children feel that selective cyclooxygenase-2 nonsteroidal anti-inflammatory agents have equivalent or greater safety, efficacy, or tolerability and fewer side effects than do coventional NSAIDs. However, in the years since the voluntary withdrawal of rofecoxib and valdecoxib from the market, few practitioners aside from rheumatologists prescribe selective COX-2 NSAIDs for children, according to a report of survey results published in Pediatric Rheumatology.

Investigators e-mailed a link to a 22-question survey to 1,289 pediatricians, pediatric rheumatologists, sports medicine physicians, pediatric surgeons, and pediatric orthopedic surgeons. In all, 84 e-mails were returned as “undeliverable.” Despite reminders and incentives, only 338 (28%) of the 1,205 e-mail recipients completed the surveys. Response rate varied by specialty, with the highest response rates from pediatric rheumatologists (100 of 247, 40%) and the lowest for sports medicine specialists (12 of 106, 11%).

Indeed, one limitation of the study was that it was skewed to include a large percentage of pediatric rheumatologists, since investigators were particularly interested in hearing from those who often prescribe NSAIDs, according to Dr. Deborah M. Levy, a pediatric rheumatologist at the Hospital for Sick Children in Toronto, and Dr. Lisa F. Imundo, a pediatric rheumatologist at the Morgan Stanley Children's Hospital of New York–Presbyterian, Columbia University.

Nonrheumatologists frequently (more than once a week) prescribed ibuprofen, naproxen, and ketorolac, but they rarely prescribed any other NSAID. Rheumatologists used a wider variety of medications, most notably ibuprofen, diclofenac, indomethacin, naproxen, celecoxib, and rofecoxib.

About half of the respondents (164 of 330) had never prescribed a selective COX-2 NSAID. By specialty, 72% of pediatricians, 52% of orthopedic surgeons, 79% of pediatric surgeons, and 4% of rheumatologists had never prescribed a selective COX-2 NSAID. The most common reasons for prescribing a selective COX-2 NSAID were for arthritis, musculoskeletal pain, soft-tissue injury, and fracture. Use of these agents was more likely after failure of an NSAID.

Pediatric rheumatologists reported that certain adverse events were more common with conventional NSAIDs than with selective COX-2 agents. Abdominal pain (81% vs. 23%), epistaxis (13% vs. 2%), easy bruising (64% vs. 8%), headaches (21% vs. 1%), and fatigue (12% vs. 1%) were more common with conventional NSAIDs (n = 99), compared with the selective COX-2 medications (n = 95).

COX-2 NSAIDs were rated as equivalent or superior to conventional NSAIDs for safety (66%), pain relief (72%), relief of inflammation (74%), and tolerability (83%) in the opinion of physicians who had prescribed the agents.

Eleven physicians reported that one or more patients had a cardiovascular event while taking an NSAID, all of which were attributed to the patients' underlying diseases, and not to the use of either a conventional or selective COX-2 NSAID, according to the investigators.

Rofecoxib was voluntarily withdrawn from the market in September 2004, and valdecoxib was withdrawn in April 2005, and these events affected physician prescribing habits. For pediatric rheumatologists, 57% said they prescribed selective COX-2 NSAIDs less frequently and 26% said they no longer prescribed them. Consequently, 44% increased their prescriptions of conventional NSAIDs.

Nine conventional NSAIDS (aspirin, etodolac, ibuprofen, indomethacin, ketorolac, meloxicam, naproxen, oxaprozin, and tolmetin) and one selective COX-2 NSAID (celecoxib) currently have Food and Drug Administration–approved pediatric indications. At the time of the survey, no COX-2 NSAID had a pediatric indication. The authors suggest that phase IV, open-label postmarketing studies of conventional and selective COX-2 NSAIDs in children are needed to more accurately assess the risks and benefits of these medications (Pediatr. Rheumatol. Online J. 2010 Feb. 4 [doi:10.1186/1546-0096-8-7]).

Disclosures: Dr. Levy received support through an independent research grant from Pfizer, manufacturer of valdecoxib. Dr. Imundo reported that she has no financial conflicts of interest.

Pregnant women with rheumatoid arthritis face an increased risk of adverse obstetric outcomes, and they deserve heightened prenatal attention, according to a recent report.

Specifically, mothers with rheumatoid arthritis (RA) were 1.47 times more likely than unaffected mothers to have a low-birth-weight baby and 1.20 times more likely to have a baby deemed small for gestational age. Women with RA also had a higher risk for developing preeclampsia (adjusted odds ratio 2.22) or having to undergo a cesarean section (adjusted OR 1.19), according to investigators (Ann. Rheum. Dis. 2010 Feb. [doi:10.1136/ard.2008.105262]).

“Our findings suggest a need for more intensive prenatal care among pregnant women with RA. In addition, early intervention should be considered to counter potential adverse obstetric outcomes for pregnant women with RA,” said Herng Ching Lin, Ph.D., and associates at Taipei (Taiwan) Medical University.

Investigators used two data bases in their analysis: the Taiwan National Health Insurance Research Dataset (NHIRD), which included inpatient and ambulatory care claims for 1996-2003, and the second was the 2001-2003 National Birth Certificate Registry (NBCR), which is maintained by the government of Taiwan. From the almost 500,000 women who had live singleton births in Taiwan between 2001 and 2003, the investigators identified 1,912 mothers with RA (International Classification of Disease, Version 9-CM, code 714.0) and compared their pregnancy outcomes with those of 9,560 controls who were matched to the cases by age, parity, and year of delivery.

Pregnant women with rheumatoid arthritis face an increased risk of adverse obstetric outcomes, and they deserve heightened prenatal attention, according to a recent report.

Specifically, mothers with rheumatoid arthritis (RA) were 1.47 times more likely than unaffected mothers to have a low-birth-weight baby and 1.20 times more likely to have a baby deemed small for gestational age. Women with RA also had a higher risk for developing preeclampsia (adjusted odds ratio 2.22) or having to undergo a cesarean section (adjusted OR 1.19), according to investigators (Ann. Rheum. Dis. 2010 Feb. [doi:10.1136/ard.2008.105262]).

“Our findings suggest a need for more intensive prenatal care among pregnant women with RA. In addition, early intervention should be considered to counter potential adverse obstetric outcomes for pregnant women with RA,” said Herng Ching Lin, Ph.D., and associates at Taipei (Taiwan) Medical University.

Investigators used two data bases in their analysis: the Taiwan National Health Insurance Research Dataset (NHIRD), which included inpatient and ambulatory care claims for 1996-2003, and the second was the 2001-2003 National Birth Certificate Registry (NBCR), which is maintained by the government of Taiwan. From the almost 500,000 women who had live singleton births in Taiwan between 2001 and 2003, the investigators identified 1,912 mothers with RA (International Classification of Disease, Version 9-CM, code 714.0) and compared their pregnancy outcomes with those of 9,560 controls who were matched to the cases by age, parity, and year of delivery.

Pregnant women with rheumatoid arthritis face an increased risk of adverse obstetric outcomes, and they deserve heightened prenatal attention, according to a recent report.

Specifically, mothers with rheumatoid arthritis (RA) were 1.47 times more likely than unaffected mothers to have a low-birth-weight baby and 1.20 times more likely to have a baby deemed small for gestational age. Women with RA also had a higher risk for developing preeclampsia (adjusted odds ratio 2.22) or having to undergo a cesarean section (adjusted OR 1.19), according to investigators (Ann. Rheum. Dis. 2010 Feb. [doi:10.1136/ard.2008.105262]).

“Our findings suggest a need for more intensive prenatal care among pregnant women with RA. In addition, early intervention should be considered to counter potential adverse obstetric outcomes for pregnant women with RA,” said Herng Ching Lin, Ph.D., and associates at Taipei (Taiwan) Medical University.

Investigators used two data bases in their analysis: the Taiwan National Health Insurance Research Dataset (NHIRD), which included inpatient and ambulatory care claims for 1996-2003, and the second was the 2001-2003 National Birth Certificate Registry (NBCR), which is maintained by the government of Taiwan. From the almost 500,000 women who had live singleton births in Taiwan between 2001 and 2003, the investigators identified 1,912 mothers with RA (International Classification of Disease, Version 9-CM, code 714.0) and compared their pregnancy outcomes with those of 9,560 controls who were matched to the cases by age, parity, and year of delivery.

PHILADELPHIA — Women with rheumatic disease who took etanercept during pregnancy were three times more likely to have a child with a major malformation than a disease-matched comparison group, judging from interim results from a small sample.

Most of the malformations were isolated, and no patterns of birth defect were apparent, according to Christina Chambers, Ph.D., who presented the findings from the Autoimmune Diseases in Pregnancy Project being conducted by the Organization of Teratology Information Specialists (OTIS) at the annual meeting of the American College of Rheumatology.

The OTIS Study is a prospective observational cohort study with the purpose of evaluating effects of autoimmune diseases and their treatment on pregnancy outcomes and fetal development. Recruitment of pregnant women began in 2000, and is projected to continue through 2015. Current recruitment stands at 944, with a goal of 1,500, explained Dr. Chambers, an associate professor of pediatrics and family and preventive medicine at the University of California in San Diego.

To be enrolled, the women must have current diagnoses of rheumatoid arthritis (RA), juvenile rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, or Crohn's disease. After birth, the infants are followed for up to a year.

“Evaluating pregnancy outcomes following medication exposure is a not a situation that lends itself to conducting a randomized controlled trial for obvious ethical reasons,” said Dr. Chambers. While the literature contains case reports, the OTIS Project is designed to give clinicians the evidence-based information they need to counsel patients who are pregnant or considering becoming pregnant.

At the time of this progress report, outcome was available for 115 women with RA who had been exposed to etanercept, compared to 55 disease-comparison controls. Outcome was available for 42 women with RA who were exposed to adalimumab, compared with 58 disease-matched women and 84 healthy controls.

The percent of live births was higher in those treated with etanercept compared with those with similar rheumatic diseases (92% vs. 85%) and fewer spontaneous abortions occurred in the etanercept-treated group (4% vs. 11%). There were no ectopic pregnancies in either group. One stillbirth was reported in the etanercept cohort and none in the controls. Preterm deliveries were more common in women who were taking etanercept (23% vs. 13%). Taking the drug did not seem to be related to the average birth weight in full-term infants.

Of the major malformations among all pregnancies enrolled in OTIS, 12% (14 of 114) were reported in the etanercept group, compared with 3.8% (2 of 53) in the disease-matched controls. “Typically we would see a specific pattern of malformation with a medication that truly causes defects, but our results indicate that most of the defects were isolated with no apparent patterns,” she said.

For those exposed to adalimumab, the percentage of live births was lower in those receiving the drug (88%) compared with those with similar autoimmune illnesses (93%) and healthy controls (92%). The rate of spontaneous abortions also was higher in the adalimumab-treated cohort (12%) compared with the disease-matched (5%) and healthy cohorts (1%).

Preterm delivery was higher in both the adalimumab-treated (14%) and disease-matched comparison (17%) groups versus healthy controls (4%). Mean birth weight was approximately 300 grams less in full term infants whose mothers had received adalimumab compared with healthy controls but similar to full-term infants in the disease-matched comparison group. Rates of major malformations were similar (4%–5%) in all groups.

“Firm conclusions await the accumulation of target sample size for adalimumab and etanercept and multivariate analysis,” she said.

Most of the malformations were isolated, and no patterns of birth defect were apparent.

Source DR. CHAMBERS

PHILADELPHIA — Women with rheumatic disease who took etanercept during pregnancy were three times more likely to have a child with a major malformation than a disease-matched comparison group, judging from interim results from a small sample.

Most of the malformations were isolated, and no patterns of birth defect were apparent, according to Christina Chambers, Ph.D., who presented the findings from the Autoimmune Diseases in Pregnancy Project being conducted by the Organization of Teratology Information Specialists (OTIS) at the annual meeting of the American College of Rheumatology.

The OTIS Study is a prospective observational cohort study with the purpose of evaluating effects of autoimmune diseases and their treatment on pregnancy outcomes and fetal development. Recruitment of pregnant women began in 2000, and is projected to continue through 2015. Current recruitment stands at 944, with a goal of 1,500, explained Dr. Chambers, an associate professor of pediatrics and family and preventive medicine at the University of California in San Diego.

To be enrolled, the women must have current diagnoses of rheumatoid arthritis (RA), juvenile rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, or Crohn's disease. After birth, the infants are followed for up to a year.

“Evaluating pregnancy outcomes following medication exposure is a not a situation that lends itself to conducting a randomized controlled trial for obvious ethical reasons,” said Dr. Chambers. While the literature contains case reports, the OTIS Project is designed to give clinicians the evidence-based information they need to counsel patients who are pregnant or considering becoming pregnant.

At the time of this progress report, outcome was available for 115 women with RA who had been exposed to etanercept, compared to 55 disease-comparison controls. Outcome was available for 42 women with RA who were exposed to adalimumab, compared with 58 disease-matched women and 84 healthy controls.

The percent of live births was higher in those treated with etanercept compared with those with similar rheumatic diseases (92% vs. 85%) and fewer spontaneous abortions occurred in the etanercept-treated group (4% vs. 11%). There were no ectopic pregnancies in either group. One stillbirth was reported in the etanercept cohort and none in the controls. Preterm deliveries were more common in women who were taking etanercept (23% vs. 13%). Taking the drug did not seem to be related to the average birth weight in full-term infants.

Of the major malformations among all pregnancies enrolled in OTIS, 12% (14 of 114) were reported in the etanercept group, compared with 3.8% (2 of 53) in the disease-matched controls. “Typically we would see a specific pattern of malformation with a medication that truly causes defects, but our results indicate that most of the defects were isolated with no apparent patterns,” she said.

For those exposed to adalimumab, the percentage of live births was lower in those receiving the drug (88%) compared with those with similar autoimmune illnesses (93%) and healthy controls (92%). The rate of spontaneous abortions also was higher in the adalimumab-treated cohort (12%) compared with the disease-matched (5%) and healthy cohorts (1%).

Preterm delivery was higher in both the adalimumab-treated (14%) and disease-matched comparison (17%) groups versus healthy controls (4%). Mean birth weight was approximately 300 grams less in full term infants whose mothers had received adalimumab compared with healthy controls but similar to full-term infants in the disease-matched comparison group. Rates of major malformations were similar (4%–5%) in all groups.

“Firm conclusions await the accumulation of target sample size for adalimumab and etanercept and multivariate analysis,” she said.

Most of the malformations were isolated, and no patterns of birth defect were apparent.

Source DR. CHAMBERS

PHILADELPHIA — Women with rheumatic disease who took etanercept during pregnancy were three times more likely to have a child with a major malformation than a disease-matched comparison group, judging from interim results from a small sample.

Most of the malformations were isolated, and no patterns of birth defect were apparent, according to Christina Chambers, Ph.D., who presented the findings from the Autoimmune Diseases in Pregnancy Project being conducted by the Organization of Teratology Information Specialists (OTIS) at the annual meeting of the American College of Rheumatology.

The OTIS Study is a prospective observational cohort study with the purpose of evaluating effects of autoimmune diseases and their treatment on pregnancy outcomes and fetal development. Recruitment of pregnant women began in 2000, and is projected to continue through 2015. Current recruitment stands at 944, with a goal of 1,500, explained Dr. Chambers, an associate professor of pediatrics and family and preventive medicine at the University of California in San Diego.

To be enrolled, the women must have current diagnoses of rheumatoid arthritis (RA), juvenile rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, or Crohn's disease. After birth, the infants are followed for up to a year.

“Evaluating pregnancy outcomes following medication exposure is a not a situation that lends itself to conducting a randomized controlled trial for obvious ethical reasons,” said Dr. Chambers. While the literature contains case reports, the OTIS Project is designed to give clinicians the evidence-based information they need to counsel patients who are pregnant or considering becoming pregnant.

At the time of this progress report, outcome was available for 115 women with RA who had been exposed to etanercept, compared to 55 disease-comparison controls. Outcome was available for 42 women with RA who were exposed to adalimumab, compared with 58 disease-matched women and 84 healthy controls.

The percent of live births was higher in those treated with etanercept compared with those with similar rheumatic diseases (92% vs. 85%) and fewer spontaneous abortions occurred in the etanercept-treated group (4% vs. 11%). There were no ectopic pregnancies in either group. One stillbirth was reported in the etanercept cohort and none in the controls. Preterm deliveries were more common in women who were taking etanercept (23% vs. 13%). Taking the drug did not seem to be related to the average birth weight in full-term infants.

Of the major malformations among all pregnancies enrolled in OTIS, 12% (14 of 114) were reported in the etanercept group, compared with 3.8% (2 of 53) in the disease-matched controls. “Typically we would see a specific pattern of malformation with a medication that truly causes defects, but our results indicate that most of the defects were isolated with no apparent patterns,” she said.

For those exposed to adalimumab, the percentage of live births was lower in those receiving the drug (88%) compared with those with similar autoimmune illnesses (93%) and healthy controls (92%). The rate of spontaneous abortions also was higher in the adalimumab-treated cohort (12%) compared with the disease-matched (5%) and healthy cohorts (1%).

Preterm delivery was higher in both the adalimumab-treated (14%) and disease-matched comparison (17%) groups versus healthy controls (4%). Mean birth weight was approximately 300 grams less in full term infants whose mothers had received adalimumab compared with healthy controls but similar to full-term infants in the disease-matched comparison group. Rates of major malformations were similar (4%–5%) in all groups.

“Firm conclusions await the accumulation of target sample size for adalimumab and etanercept and multivariate analysis,” she said.

Most of the malformations were isolated, and no patterns of birth defect were apparent.

Source DR. CHAMBERS

PHILADELPHIA — Drinking water or skim milk can improve gout control, according to findings from two studies that highlight the important contribution of lifestyle factors on gout prevention and management.

“Our results show that drinking water is a simple, safe, and effective means of trying to reduce recurrent gout attacks,” Dr. Tuhina Neogi said at the annual meeting of the American College of Rheumatology.

The study included 535 people who had had a gout attack within the past year (78% male; mean age, 53 years) and who provided information via the Internet about food, drink, medications, physical activity, and other possible gout risk factors during periods preceding the attack and during attack-free periods. By using a case crossover study design, the participants acted as their own controls. Medical records were accessed to verify gout diagnosis, explained Dr. Neogi of Boston University.

The findings showed that increasing water intake was associated with decreased risk for recurrent gout attacks. Compared with those who drank no or one 8-ounce glass of water per day, those who drank five to eight glasses had a 40% lower chance of a gout attack and those who drank more than eight glasses had a 46% lower chance.

In the second study, researchers from New Zealand measured the acute effects of skim milk consumption on serum urate concentrations in 16 healthy male volunteers, in light of reports that skim milk was beneficial in gout prevention. The randomized controlled crossover study was designed to assess the effects of skim milk that was from the early season and the late season, as well as MPC85, a milk protein concentrate that contains 85% protein. The effects of soy milk consumption also were assessed, and it was considered the control.

“Late-season” skim milk, primarily available from countries where milking is seasonal and cows are grass fed, is high in orotic acid, a substance known to promote uric acid removal by the kidneys, explained Dr. Nicola Dalbeth, a senior lecturer in clinical medicine at the University of Auckland (New Zealand). MPC85 skim milk is ultrafiltered and contains very low concentrations of orotic acid, purines, and lactose.

Each participant received a single dose of each product in a random order, with each study visit separated by a week. The amount consumed was equal to about 3.5 8-ounce glasses of milk in one sitting (80 g of protein in 800 mL). Serum and urine were obtained immediately before ingestion and then hourly over the next 3 hours.

Drinking soy milk led to a 10% increase in serum urate. In contrast, all skim milks decreased serum urate by about 10% (P less than .0001). All products, including soy, led to an increase in the fractional excretion of uric acid (FEUA).

Interestingly, there were differences among the types of skim milk, which may shed light on the underlying mechanism. Late-season skim milk led to a greater increase in FEUA, compared with either ultrafiltered skim milk or early-season skim milk, suggesting that the acute urate-lowering effect of orotic acid may explain these effects.

“We cannot necessarily extrapolate these results from [healthy individuals] to those with gout,” Dr. Dalbeth acknowledged. “Furthermore, I am not saying drinking milk should replace allopurinol. But one of the key things we do is spend a lot of time telling people with gout what not to do, such as do not eat red meat. It is very useful to have some positive information.”

“Even though gout has been known since antiquity, and we have had treatments around for decades, it is not a well-managed disease. Medical management is still the cornerstone. Still, there are a lot of lifestyle and behavioral aspects that people with gout can do for themselves to reduce their risk,” Dr. M. Elaine Husni, vice chair of rheumatology and director of the arthritis and musculoskeletal center at the Cleveland Clinic, said when she was asked to comment on the results of both studies.

Dr. Neogi reported having no conflicts of interest. Dr. Dalbeth said that her study was funded in part by the Fonterra Dairy Cooperative, and that one of the study authors was an employee of Fonterra.

Elsevier Global Medical News

PHILADELPHIA — Drinking water or skim milk can improve gout control, according to findings from two studies that highlight the important contribution of lifestyle factors on gout prevention and management.

“Our results show that drinking water is a simple, safe, and effective means of trying to reduce recurrent gout attacks,” Dr. Tuhina Neogi said at the annual meeting of the American College of Rheumatology.

The study included 535 people who had had a gout attack within the past year (78% male; mean age, 53 years) and who provided information via the Internet about food, drink, medications, physical activity, and other possible gout risk factors during periods preceding the attack and during attack-free periods. By using a case crossover study design, the participants acted as their own controls. Medical records were accessed to verify gout diagnosis, explained Dr. Neogi of Boston University.

The findings showed that increasing water intake was associated with decreased risk for recurrent gout attacks. Compared with those who drank no or one 8-ounce glass of water per day, those who drank five to eight glasses had a 40% lower chance of a gout attack and those who drank more than eight glasses had a 46% lower chance.

In the second study, researchers from New Zealand measured the acute effects of skim milk consumption on serum urate concentrations in 16 healthy male volunteers, in light of reports that skim milk was beneficial in gout prevention. The randomized controlled crossover study was designed to assess the effects of skim milk that was from the early season and the late season, as well as MPC85, a milk protein concentrate that contains 85% protein. The effects of soy milk consumption also were assessed, and it was considered the control.

“Late-season” skim milk, primarily available from countries where milking is seasonal and cows are grass fed, is high in orotic acid, a substance known to promote uric acid removal by the kidneys, explained Dr. Nicola Dalbeth, a senior lecturer in clinical medicine at the University of Auckland (New Zealand). MPC85 skim milk is ultrafiltered and contains very low concentrations of orotic acid, purines, and lactose.

Each participant received a single dose of each product in a random order, with each study visit separated by a week. The amount consumed was equal to about 3.5 8-ounce glasses of milk in one sitting (80 g of protein in 800 mL). Serum and urine were obtained immediately before ingestion and then hourly over the next 3 hours.

Drinking soy milk led to a 10% increase in serum urate. In contrast, all skim milks decreased serum urate by about 10% (P less than .0001). All products, including soy, led to an increase in the fractional excretion of uric acid (FEUA).

Interestingly, there were differences among the types of skim milk, which may shed light on the underlying mechanism. Late-season skim milk led to a greater increase in FEUA, compared with either ultrafiltered skim milk or early-season skim milk, suggesting that the acute urate-lowering effect of orotic acid may explain these effects.

“We cannot necessarily extrapolate these results from [healthy individuals] to those with gout,” Dr. Dalbeth acknowledged. “Furthermore, I am not saying drinking milk should replace allopurinol. But one of the key things we do is spend a lot of time telling people with gout what not to do, such as do not eat red meat. It is very useful to have some positive information.”

“Even though gout has been known since antiquity, and we have had treatments around for decades, it is not a well-managed disease. Medical management is still the cornerstone. Still, there are a lot of lifestyle and behavioral aspects that people with gout can do for themselves to reduce their risk,” Dr. M. Elaine Husni, vice chair of rheumatology and director of the arthritis and musculoskeletal center at the Cleveland Clinic, said when she was asked to comment on the results of both studies.

Dr. Neogi reported having no conflicts of interest. Dr. Dalbeth said that her study was funded in part by the Fonterra Dairy Cooperative, and that one of the study authors was an employee of Fonterra.

Elsevier Global Medical News

PHILADELPHIA — Drinking water or skim milk can improve gout control, according to findings from two studies that highlight the important contribution of lifestyle factors on gout prevention and management.

“Our results show that drinking water is a simple, safe, and effective means of trying to reduce recurrent gout attacks,” Dr. Tuhina Neogi said at the annual meeting of the American College of Rheumatology.

The study included 535 people who had had a gout attack within the past year (78% male; mean age, 53 years) and who provided information via the Internet about food, drink, medications, physical activity, and other possible gout risk factors during periods preceding the attack and during attack-free periods. By using a case crossover study design, the participants acted as their own controls. Medical records were accessed to verify gout diagnosis, explained Dr. Neogi of Boston University.

The findings showed that increasing water intake was associated with decreased risk for recurrent gout attacks. Compared with those who drank no or one 8-ounce glass of water per day, those who drank five to eight glasses had a 40% lower chance of a gout attack and those who drank more than eight glasses had a 46% lower chance.

In the second study, researchers from New Zealand measured the acute effects of skim milk consumption on serum urate concentrations in 16 healthy male volunteers, in light of reports that skim milk was beneficial in gout prevention. The randomized controlled crossover study was designed to assess the effects of skim milk that was from the early season and the late season, as well as MPC85, a milk protein concentrate that contains 85% protein. The effects of soy milk consumption also were assessed, and it was considered the control.

“Late-season” skim milk, primarily available from countries where milking is seasonal and cows are grass fed, is high in orotic acid, a substance known to promote uric acid removal by the kidneys, explained Dr. Nicola Dalbeth, a senior lecturer in clinical medicine at the University of Auckland (New Zealand). MPC85 skim milk is ultrafiltered and contains very low concentrations of orotic acid, purines, and lactose.

Each participant received a single dose of each product in a random order, with each study visit separated by a week. The amount consumed was equal to about 3.5 8-ounce glasses of milk in one sitting (80 g of protein in 800 mL). Serum and urine were obtained immediately before ingestion and then hourly over the next 3 hours.

Drinking soy milk led to a 10% increase in serum urate. In contrast, all skim milks decreased serum urate by about 10% (P less than .0001). All products, including soy, led to an increase in the fractional excretion of uric acid (FEUA).

Interestingly, there were differences among the types of skim milk, which may shed light on the underlying mechanism. Late-season skim milk led to a greater increase in FEUA, compared with either ultrafiltered skim milk or early-season skim milk, suggesting that the acute urate-lowering effect of orotic acid may explain these effects.

“We cannot necessarily extrapolate these results from [healthy individuals] to those with gout,” Dr. Dalbeth acknowledged. “Furthermore, I am not saying drinking milk should replace allopurinol. But one of the key things we do is spend a lot of time telling people with gout what not to do, such as do not eat red meat. It is very useful to have some positive information.”

“Even though gout has been known since antiquity, and we have had treatments around for decades, it is not a well-managed disease. Medical management is still the cornerstone. Still, there are a lot of lifestyle and behavioral aspects that people with gout can do for themselves to reduce their risk,” Dr. M. Elaine Husni, vice chair of rheumatology and director of the arthritis and musculoskeletal center at the Cleveland Clinic, said when she was asked to comment on the results of both studies.

Dr. Neogi reported having no conflicts of interest. Dr. Dalbeth said that her study was funded in part by the Fonterra Dairy Cooperative, and that one of the study authors was an employee of Fonterra.

Elsevier Global Medical News

PHILADELPHIA — Women with rheumatic disease who took etanercept during pregnancy were three times more likely to have a child with a major malformation than a disease-matched comparison group, judging from interim results from a small sample.

Most of the malformations were isolated, and no patterns of birth defect were apparent, according to Christina Chambers, Ph.D., who presented the findings from the Autoimmune Diseases in Pregnancy Project being conducted by the Organization of Teratology Information Specialists (OTIS) at the annual meeting of the American College of Rheumatology.

The OTIS study is a prospective observational cohort study with the purpose of evaluating effects of autoimmune diseases and their treatment on pregnancy outcomes and fetal development. Recruitment began in 2000, and is projected to continue through 2015. Current recruitment stands at 944, with a goal of 1,500, said Dr. Chambers, an associate professor of pediatrics and family and preventive medicine at the University of California in San Diego.

Pregnant women are typically enrolled in the study before they reach 20 weeks of gestation. To be enrolled, the women must have current diagnoses of rheumatoid arthritis (RA), juvenile rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, or Crohn's disease.

Many participants are referred to the OTIS coordinating center, where they undergo multiple interviews and review of their symptom management. After birth, the infants are followed for up to a year, during which time they are assessed by their pediatricians, undergo blinded dysmorphological examination by OTIS physicians, and are photographed.

“Evaluating pregnancy outcomes following medication exposure is a not a situation that lends itself to conducting a randomized controlled trial for obvious ethical reasons,” said Dr. Chambers. While the literature contains case reports, the OTIS Project is designed to give clinicians the evidence-based information they need to counsel patients who are pregnant or considering becoming pregnant.

At the time of this progress report, outcome was available for 115 women with RA who had been exposed to etanercept, compared with 55 disease-comparison controls. Outcome was available for 42 women with RA who were exposed to adalimumab, compared with 58 disease-matched women and 84 healthy controls.

The percent of live births was higher in those treated with etanercept, compared with those with similar rheumatic diseases (92% vs. 85%) and fewer spontaneous abortions occurred in the etanercept-treated group (4% vs. 11%). One stillbirth was reported in the etanercept cohort and none in the controls. Preterm deliveries were more common in women who were taking etanercept (23% vs. 13%).

Of the major malformations among all pregnancies enrolled in OTIS, 12% (14 of 114) were reported in the etanercept group, compared with 3.8% (2 of 53) in the disease-matched controls. The defects included displaced stomach with epispadias and congenital eye defect; ventricular septal defect with peripheral pulmonic stenosis; pyloric stenosis; hypospadias; ventricular septal defect with patent foramen ovale and patent ductus arteriosus; volvulus; patent foramen ovale; atrial septal defect with patent ductus arteriosus; microcephaly; congenital hypothyroidism; and an unspecified heart defect. Three abnormalities—Noonan syndrome, Turner syndrome, and Down syndrome—were genetic or chromosomal. “Typically we would see a specific pattern of malformation with a medication that truly causes defects, but our results indicate that most of the defects were isolated with no apparent patterns,” Dr. Chambers said.

For those exposed to adalimumab, the percentage of live births was lower in those receiving the drug (88%) compared with those with similar autoimmune illnesses (93%) and healthy controls (92%). The rate of spontaneous abortions also was higher in the adalimumab-treated cohort (12%) compared with the disease-matched (5%) and healthy cohorts (1%). There were no ectopic pregnancies or stillbirths in the drug-treated group.

Preterm delivery was higher in both the adalimumab-treated (14%) and disease-matched comparison (17%) groups compared with healthy controls (4%). Mean birth weight was approximately 300 grams less in full term infants whose mothers had received adalimumab compared with healthy controls but similar to full-term infants in the disease-matched comparison group.

Rates of major malformations were similar (from 4% to 5%) in all groups and within the range of expected numbers in the general population, said Dr. Chambers.

My Take

Answering Your Patient's Questions

There are really sparse data on the safety of biologic agents in women who are pregnant. We currently are in a situation where controlled randomized trials typically are not appropriate, yet pregnant women are using these medications. The OTIS project is a prospective, observational cohort study that should shed light on whether biologics are safe for women who are pregnant. However, it will still be several years before all results are in and the data can be statistically analyzed. In the meantime, what can you tell your patients about the use of biologics if they are pregnant or plan to become pregnant?

Q: If I take a biologic, will it be more difficult to become pregnant?

A: Information is very limited, but to date neither preclinical data nor clinical data indicate that becoming pregnant is more difficult.

Q. If I do become pregnant while on a biologic drug, do I have a chance of having a baby with a birth defect?

A. One of the principles of teratology is that known teratogens tend to cause specific patterns of malformations. To date with the limited information available, neither animal nor human data suggest that the risk for a specific pattern of defects is increased over baseline if you take a biologic agent while pregnant. While preliminary results from the OTIS project have noted that more malformations occurred in the offspring of women taking etanercept, the defects were varied and isolated.

Q. If I do become pregnant while taking this drug, will my child's immune system be compromised?

A. There are limited human data available for rituximab. To date, the results of the OTIS study do not indicate an increase in opportunistic infections, hospitalizations, or malignancies in the infants of women who have taken etanercept or adalimumab.

Q. If I do become pregnant while taking a biologic agent, do I have to discontinue the drug or can I safely continue to take the drug throughout pregnancy?

A. We really don't know the answer. In the OTIS project, approximately half of women on etanercept or adalimumab remain on the medication into the second or third trimester.

Disclosures: Dr. Chambers has received research grants from Sandoz, Kali Labs, Apotex, Barr Labs, Teva Pharmaceuticals, Amgen, Bristol Myers Squibb, Abbott Laboratories, Sanofi-Aventis Pharmaceutical, and Sanofi-Pasteur.

BY CHRISTINA CHAMBERS, Ph.D.

PHILADELPHIA — Women with rheumatic disease who took etanercept during pregnancy were three times more likely to have a child with a major malformation than a disease-matched comparison group, judging from interim results from a small sample.

Most of the malformations were isolated, and no patterns of birth defect were apparent, according to Christina Chambers, Ph.D., who presented the findings from the Autoimmune Diseases in Pregnancy Project being conducted by the Organization of Teratology Information Specialists (OTIS) at the annual meeting of the American College of Rheumatology.

The OTIS study is a prospective observational cohort study with the purpose of evaluating effects of autoimmune diseases and their treatment on pregnancy outcomes and fetal development. Recruitment began in 2000, and is projected to continue through 2015. Current recruitment stands at 944, with a goal of 1,500, said Dr. Chambers, an associate professor of pediatrics and family and preventive medicine at the University of California in San Diego.

Pregnant women are typically enrolled in the study before they reach 20 weeks of gestation. To be enrolled, the women must have current diagnoses of rheumatoid arthritis (RA), juvenile rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, or Crohn's disease.

Many participants are referred to the OTIS coordinating center, where they undergo multiple interviews and review of their symptom management. After birth, the infants are followed for up to a year, during which time they are assessed by their pediatricians, undergo blinded dysmorphological examination by OTIS physicians, and are photographed.

“Evaluating pregnancy outcomes following medication exposure is a not a situation that lends itself to conducting a randomized controlled trial for obvious ethical reasons,” said Dr. Chambers. While the literature contains case reports, the OTIS Project is designed to give clinicians the evidence-based information they need to counsel patients who are pregnant or considering becoming pregnant.

At the time of this progress report, outcome was available for 115 women with RA who had been exposed to etanercept, compared with 55 disease-comparison controls. Outcome was available for 42 women with RA who were exposed to adalimumab, compared with 58 disease-matched women and 84 healthy controls.

The percent of live births was higher in those treated with etanercept, compared with those with similar rheumatic diseases (92% vs. 85%) and fewer spontaneous abortions occurred in the etanercept-treated group (4% vs. 11%). One stillbirth was reported in the etanercept cohort and none in the controls. Preterm deliveries were more common in women who were taking etanercept (23% vs. 13%).

Of the major malformations among all pregnancies enrolled in OTIS, 12% (14 of 114) were reported in the etanercept group, compared with 3.8% (2 of 53) in the disease-matched controls. The defects included displaced stomach with epispadias and congenital eye defect; ventricular septal defect with peripheral pulmonic stenosis; pyloric stenosis; hypospadias; ventricular septal defect with patent foramen ovale and patent ductus arteriosus; volvulus; patent foramen ovale; atrial septal defect with patent ductus arteriosus; microcephaly; congenital hypothyroidism; and an unspecified heart defect. Three abnormalities—Noonan syndrome, Turner syndrome, and Down syndrome—were genetic or chromosomal. “Typically we would see a specific pattern of malformation with a medication that truly causes defects, but our results indicate that most of the defects were isolated with no apparent patterns,” Dr. Chambers said.

For those exposed to adalimumab, the percentage of live births was lower in those receiving the drug (88%) compared with those with similar autoimmune illnesses (93%) and healthy controls (92%). The rate of spontaneous abortions also was higher in the adalimumab-treated cohort (12%) compared with the disease-matched (5%) and healthy cohorts (1%). There were no ectopic pregnancies or stillbirths in the drug-treated group.

Preterm delivery was higher in both the adalimumab-treated (14%) and disease-matched comparison (17%) groups compared with healthy controls (4%). Mean birth weight was approximately 300 grams less in full term infants whose mothers had received adalimumab compared with healthy controls but similar to full-term infants in the disease-matched comparison group.

Rates of major malformations were similar (from 4% to 5%) in all groups and within the range of expected numbers in the general population, said Dr. Chambers.

My Take

Answering Your Patient's Questions

There are really sparse data on the safety of biologic agents in women who are pregnant. We currently are in a situation where controlled randomized trials typically are not appropriate, yet pregnant women are using these medications. The OTIS project is a prospective, observational cohort study that should shed light on whether biologics are safe for women who are pregnant. However, it will still be several years before all results are in and the data can be statistically analyzed. In the meantime, what can you tell your patients about the use of biologics if they are pregnant or plan to become pregnant?

Q: If I take a biologic, will it be more difficult to become pregnant?

A: Information is very limited, but to date neither preclinical data nor clinical data indicate that becoming pregnant is more difficult.

Q. If I do become pregnant while on a biologic drug, do I have a chance of having a baby with a birth defect?

A. One of the principles of teratology is that known teratogens tend to cause specific patterns of malformations. To date with the limited information available, neither animal nor human data suggest that the risk for a specific pattern of defects is increased over baseline if you take a biologic agent while pregnant. While preliminary results from the OTIS project have noted that more malformations occurred in the offspring of women taking etanercept, the defects were varied and isolated.

Q. If I do become pregnant while taking this drug, will my child's immune system be compromised?

A. There are limited human data available for rituximab. To date, the results of the OTIS study do not indicate an increase in opportunistic infections, hospitalizations, or malignancies in the infants of women who have taken etanercept or adalimumab.

Q. If I do become pregnant while taking a biologic agent, do I have to discontinue the drug or can I safely continue to take the drug throughout pregnancy?

A. We really don't know the answer. In the OTIS project, approximately half of women on etanercept or adalimumab remain on the medication into the second or third trimester.

Disclosures: Dr. Chambers has received research grants from Sandoz, Kali Labs, Apotex, Barr Labs, Teva Pharmaceuticals, Amgen, Bristol Myers Squibb, Abbott Laboratories, Sanofi-Aventis Pharmaceutical, and Sanofi-Pasteur.

BY CHRISTINA CHAMBERS, Ph.D.

PHILADELPHIA — Women with rheumatic disease who took etanercept during pregnancy were three times more likely to have a child with a major malformation than a disease-matched comparison group, judging from interim results from a small sample.

Most of the malformations were isolated, and no patterns of birth defect were apparent, according to Christina Chambers, Ph.D., who presented the findings from the Autoimmune Diseases in Pregnancy Project being conducted by the Organization of Teratology Information Specialists (OTIS) at the annual meeting of the American College of Rheumatology.

The OTIS study is a prospective observational cohort study with the purpose of evaluating effects of autoimmune diseases and their treatment on pregnancy outcomes and fetal development. Recruitment began in 2000, and is projected to continue through 2015. Current recruitment stands at 944, with a goal of 1,500, said Dr. Chambers, an associate professor of pediatrics and family and preventive medicine at the University of California in San Diego.

Pregnant women are typically enrolled in the study before they reach 20 weeks of gestation. To be enrolled, the women must have current diagnoses of rheumatoid arthritis (RA), juvenile rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, or Crohn's disease.

Many participants are referred to the OTIS coordinating center, where they undergo multiple interviews and review of their symptom management. After birth, the infants are followed for up to a year, during which time they are assessed by their pediatricians, undergo blinded dysmorphological examination by OTIS physicians, and are photographed.

“Evaluating pregnancy outcomes following medication exposure is a not a situation that lends itself to conducting a randomized controlled trial for obvious ethical reasons,” said Dr. Chambers. While the literature contains case reports, the OTIS Project is designed to give clinicians the evidence-based information they need to counsel patients who are pregnant or considering becoming pregnant.

At the time of this progress report, outcome was available for 115 women with RA who had been exposed to etanercept, compared with 55 disease-comparison controls. Outcome was available for 42 women with RA who were exposed to adalimumab, compared with 58 disease-matched women and 84 healthy controls.

The percent of live births was higher in those treated with etanercept, compared with those with similar rheumatic diseases (92% vs. 85%) and fewer spontaneous abortions occurred in the etanercept-treated group (4% vs. 11%). One stillbirth was reported in the etanercept cohort and none in the controls. Preterm deliveries were more common in women who were taking etanercept (23% vs. 13%).

Of the major malformations among all pregnancies enrolled in OTIS, 12% (14 of 114) were reported in the etanercept group, compared with 3.8% (2 of 53) in the disease-matched controls. The defects included displaced stomach with epispadias and congenital eye defect; ventricular septal defect with peripheral pulmonic stenosis; pyloric stenosis; hypospadias; ventricular septal defect with patent foramen ovale and patent ductus arteriosus; volvulus; patent foramen ovale; atrial septal defect with patent ductus arteriosus; microcephaly; congenital hypothyroidism; and an unspecified heart defect. Three abnormalities—Noonan syndrome, Turner syndrome, and Down syndrome—were genetic or chromosomal. “Typically we would see a specific pattern of malformation with a medication that truly causes defects, but our results indicate that most of the defects were isolated with no apparent patterns,” Dr. Chambers said.

For those exposed to adalimumab, the percentage of live births was lower in those receiving the drug (88%) compared with those with similar autoimmune illnesses (93%) and healthy controls (92%). The rate of spontaneous abortions also was higher in the adalimumab-treated cohort (12%) compared with the disease-matched (5%) and healthy cohorts (1%). There were no ectopic pregnancies or stillbirths in the drug-treated group.

Preterm delivery was higher in both the adalimumab-treated (14%) and disease-matched comparison (17%) groups compared with healthy controls (4%). Mean birth weight was approximately 300 grams less in full term infants whose mothers had received adalimumab compared with healthy controls but similar to full-term infants in the disease-matched comparison group.

Rates of major malformations were similar (from 4% to 5%) in all groups and within the range of expected numbers in the general population, said Dr. Chambers.

My Take

Answering Your Patient's Questions

There are really sparse data on the safety of biologic agents in women who are pregnant. We currently are in a situation where controlled randomized trials typically are not appropriate, yet pregnant women are using these medications. The OTIS project is a prospective, observational cohort study that should shed light on whether biologics are safe for women who are pregnant. However, it will still be several years before all results are in and the data can be statistically analyzed. In the meantime, what can you tell your patients about the use of biologics if they are pregnant or plan to become pregnant?

Q: If I take a biologic, will it be more difficult to become pregnant?

A: Information is very limited, but to date neither preclinical data nor clinical data indicate that becoming pregnant is more difficult.

Q. If I do become pregnant while on a biologic drug, do I have a chance of having a baby with a birth defect?

A. One of the principles of teratology is that known teratogens tend to cause specific patterns of malformations. To date with the limited information available, neither animal nor human data suggest that the risk for a specific pattern of defects is increased over baseline if you take a biologic agent while pregnant. While preliminary results from the OTIS project have noted that more malformations occurred in the offspring of women taking etanercept, the defects were varied and isolated.

Q. If I do become pregnant while taking this drug, will my child's immune system be compromised?

A. There are limited human data available for rituximab. To date, the results of the OTIS study do not indicate an increase in opportunistic infections, hospitalizations, or malignancies in the infants of women who have taken etanercept or adalimumab.

Q. If I do become pregnant while taking a biologic agent, do I have to discontinue the drug or can I safely continue to take the drug throughout pregnancy?

A. We really don't know the answer. In the OTIS project, approximately half of women on etanercept or adalimumab remain on the medication into the second or third trimester.

Disclosures: Dr. Chambers has received research grants from Sandoz, Kali Labs, Apotex, Barr Labs, Teva Pharmaceuticals, Amgen, Bristol Myers Squibb, Abbott Laboratories, Sanofi-Aventis Pharmaceutical, and Sanofi-Pasteur.

BY CHRISTINA CHAMBERS, Ph.D.

PHILADELPHIA — Vertebral fractures are present in a significant percentage of children with rheumatic diseases, and these fractures appear prior to prolonged glucocorticoid exposure, according to Dr. Leanne M. Ward.

“Vertebral fractures are an underrecognized complication of steroid-treated rheumatic disorders,” said Dr. Ward, director of the Pediatric Bone Health Clinical and Research Programs at University of Ottawa. “The question is when the fractures first occur—in the course of the disease or steroid treatment.”

Investigators from the Canadian STOPP (Steroid-Associated Osteoporosis in the Pediatric Population) Consortium evaluated the spine health of 134 children (89 girls; median age, 10 years) with rheumatic conditions.

In all, 30 children had juvenile dermatomyositis (JDM), 28 had juvenile idiopathic arthritis excluding systemic JIA, and 76 were diagnosed with other rheumatic disorders (systemic lupus erythematosus, systemic vasculitides, systemic JIA, and others).

The children underwent thoracolumbar spine x-rays and lumbar spine areal bone mineral density (LS aBMD) evaluation within 30 days of beginning glucocorticoid therapy.

A total of 7% of the group (9 of 134) had vertebral fractures. In these nine children, six patients had a single vertebral fracture and three patients had 2-5 fractures, for a total of 13 fractures. Three of the fractures (23%) were moderate and the rest were mild. Most fractures were located in the midthoracic and upper lumbar regions, said Dr. Ward at the annual meeting of the American College of Rheumatology. Although the mean LS aBMD scores for the group were lower than the norm (−0.6 plus or minus 1.22; P less than .001), LS aBMD did not predict the development of vertebral fractures. The odds for fracture were increased 10-fold if the child reported back pain.

The STOPP Consortium was founded in 2003 as a Canadian national pediatric bone health working group of investigators from 12 tertiary children's hospitals.

Dr. Ward recommends that children with rheumatic diseases undergo baseline spine radiographs at diagnosis and then annually, or more frequently if they have new-onset back pain. Children with vertebral fractures who have back pain may be candidates for bisphosphonate therapy, said Dr. Ward.

Dr. Ward reported having a business relationship with Novartis.

This image shows a fracture at L1 in a girl with JDM who takes glucocorticoids.

Source Courtesy Dr. Leanne M. Ward

PHILADELPHIA — Vertebral fractures are present in a significant percentage of children with rheumatic diseases, and these fractures appear prior to prolonged glucocorticoid exposure, according to Dr. Leanne M. Ward.

“Vertebral fractures are an underrecognized complication of steroid-treated rheumatic disorders,” said Dr. Ward, director of the Pediatric Bone Health Clinical and Research Programs at University of Ottawa. “The question is when the fractures first occur—in the course of the disease or steroid treatment.”

Investigators from the Canadian STOPP (Steroid-Associated Osteoporosis in the Pediatric Population) Consortium evaluated the spine health of 134 children (89 girls; median age, 10 years) with rheumatic conditions.

In all, 30 children had juvenile dermatomyositis (JDM), 28 had juvenile idiopathic arthritis excluding systemic JIA, and 76 were diagnosed with other rheumatic disorders (systemic lupus erythematosus, systemic vasculitides, systemic JIA, and others).

The children underwent thoracolumbar spine x-rays and lumbar spine areal bone mineral density (LS aBMD) evaluation within 30 days of beginning glucocorticoid therapy.

A total of 7% of the group (9 of 134) had vertebral fractures. In these nine children, six patients had a single vertebral fracture and three patients had 2-5 fractures, for a total of 13 fractures. Three of the fractures (23%) were moderate and the rest were mild. Most fractures were located in the midthoracic and upper lumbar regions, said Dr. Ward at the annual meeting of the American College of Rheumatology. Although the mean LS aBMD scores for the group were lower than the norm (−0.6 plus or minus 1.22; P less than .001), LS aBMD did not predict the development of vertebral fractures. The odds for fracture were increased 10-fold if the child reported back pain.

The STOPP Consortium was founded in 2003 as a Canadian national pediatric bone health working group of investigators from 12 tertiary children's hospitals.

Dr. Ward recommends that children with rheumatic diseases undergo baseline spine radiographs at diagnosis and then annually, or more frequently if they have new-onset back pain. Children with vertebral fractures who have back pain may be candidates for bisphosphonate therapy, said Dr. Ward.

Dr. Ward reported having a business relationship with Novartis.

This image shows a fracture at L1 in a girl with JDM who takes glucocorticoids.

Source Courtesy Dr. Leanne M. Ward

PHILADELPHIA — Vertebral fractures are present in a significant percentage of children with rheumatic diseases, and these fractures appear prior to prolonged glucocorticoid exposure, according to Dr. Leanne M. Ward.

“Vertebral fractures are an underrecognized complication of steroid-treated rheumatic disorders,” said Dr. Ward, director of the Pediatric Bone Health Clinical and Research Programs at University of Ottawa. “The question is when the fractures first occur—in the course of the disease or steroid treatment.”

Investigators from the Canadian STOPP (Steroid-Associated Osteoporosis in the Pediatric Population) Consortium evaluated the spine health of 134 children (89 girls; median age, 10 years) with rheumatic conditions.

In all, 30 children had juvenile dermatomyositis (JDM), 28 had juvenile idiopathic arthritis excluding systemic JIA, and 76 were diagnosed with other rheumatic disorders (systemic lupus erythematosus, systemic vasculitides, systemic JIA, and others).

The children underwent thoracolumbar spine x-rays and lumbar spine areal bone mineral density (LS aBMD) evaluation within 30 days of beginning glucocorticoid therapy.

A total of 7% of the group (9 of 134) had vertebral fractures. In these nine children, six patients had a single vertebral fracture and three patients had 2-5 fractures, for a total of 13 fractures. Three of the fractures (23%) were moderate and the rest were mild. Most fractures were located in the midthoracic and upper lumbar regions, said Dr. Ward at the annual meeting of the American College of Rheumatology. Although the mean LS aBMD scores for the group were lower than the norm (−0.6 plus or minus 1.22; P less than .001), LS aBMD did not predict the development of vertebral fractures. The odds for fracture were increased 10-fold if the child reported back pain.

The STOPP Consortium was founded in 2003 as a Canadian national pediatric bone health working group of investigators from 12 tertiary children's hospitals.

Dr. Ward recommends that children with rheumatic diseases undergo baseline spine radiographs at diagnosis and then annually, or more frequently if they have new-onset back pain. Children with vertebral fractures who have back pain may be candidates for bisphosphonate therapy, said Dr. Ward.

Dr. Ward reported having a business relationship with Novartis.

This image shows a fracture at L1 in a girl with JDM who takes glucocorticoids.

Source Courtesy Dr. Leanne M. Ward

PHILADELPHIA — Six of eight patients with anti–signal recognition peptide myopathy that was refractory to standard immunosuppressive therapy showed clinical improvement with rituximab, according to findings from recent research.

Presenting the data at the annual meeting of the American College of Rheumatology, Dr. Ritu Valiyil noted that patients who responded to rituximab were able to lower their doses of corticosteroids.

Myopathy associated with anti–signal recognition peptide (anti-SRP) autoantibody is a severe, necrotizing, immune-mediated disease characterized by rapidly progressive proximal muscle weakness, myalgia, dysphagia, and markedly elevated serum creatine kinase (CK) levels. Patients generally respond poorly to conventional immunosuppressive therapies such as azathioprine, methotrexate, or intravenous immunoglobulin, says Dr. Valiyil, a rheumatology fellow at Johns Hopkins University, Baltimore.

A chart review identified eight patients who had failed standard immunosuppressive therapies who were then given two doses of rituximab, an anti-CD20 monoclonal antibody. The eight patients' mean age was 37 years; six were women, and four were black.

As soon as 2 months after receiving two doses of rituximab, six of the eight patients demonstrated improved muscle strength in their hands. Prior to treatment with rituximab, the mean creatine kinase was 1,835 IU/L, which declined to a mean of 777.5 IU/L after treatment. Three patients sustained the response for 12-18 months after initial dosing.

All patients on rituximab continued on adjunctive steroid therapy but were able to reduce their corticosteroid dose. The mean highest prednisone dose prior to receiving rituximab was 75 mg/day; the mean lowest dose after rituximab was 21 mg/day.

Autoantibodies were detected and quantitated in the serum samples collected before and after rituximab treatment in five patients. Four of the five patients showed a decrease in serum anti-SRP antibodies. The substantial decrease in anti-SRP antibody levels after rituximab suggest that B cells and anti-SRP antibodies may play a role in the pathogenesis of this myopathy, commented Dr. Valiyil.

“It should be noted that [many] of our patients were African American and we cannot rule out the possibility that there may be more of a response in this particular group of patients,” explained Dr. Lisa Christopher-Stine, a rheumatologist at Hopkins who is the principal investigator of the study.

Dr. Valiyil and Dr. Christopher-Stine reported having no financial conflicts of interest to disclose.

PHILADELPHIA — Six of eight patients with anti–signal recognition peptide myopathy that was refractory to standard immunosuppressive therapy showed clinical improvement with rituximab, according to findings from recent research.

Presenting the data at the annual meeting of the American College of Rheumatology, Dr. Ritu Valiyil noted that patients who responded to rituximab were able to lower their doses of corticosteroids.

Myopathy associated with anti–signal recognition peptide (anti-SRP) autoantibody is a severe, necrotizing, immune-mediated disease characterized by rapidly progressive proximal muscle weakness, myalgia, dysphagia, and markedly elevated serum creatine kinase (CK) levels. Patients generally respond poorly to conventional immunosuppressive therapies such as azathioprine, methotrexate, or intravenous immunoglobulin, says Dr. Valiyil, a rheumatology fellow at Johns Hopkins University, Baltimore.

A chart review identified eight patients who had failed standard immunosuppressive therapies who were then given two doses of rituximab, an anti-CD20 monoclonal antibody. The eight patients' mean age was 37 years; six were women, and four were black.

As soon as 2 months after receiving two doses of rituximab, six of the eight patients demonstrated improved muscle strength in their hands. Prior to treatment with rituximab, the mean creatine kinase was 1,835 IU/L, which declined to a mean of 777.5 IU/L after treatment. Three patients sustained the response for 12-18 months after initial dosing.

All patients on rituximab continued on adjunctive steroid therapy but were able to reduce their corticosteroid dose. The mean highest prednisone dose prior to receiving rituximab was 75 mg/day; the mean lowest dose after rituximab was 21 mg/day.

Autoantibodies were detected and quantitated in the serum samples collected before and after rituximab treatment in five patients. Four of the five patients showed a decrease in serum anti-SRP antibodies. The substantial decrease in anti-SRP antibody levels after rituximab suggest that B cells and anti-SRP antibodies may play a role in the pathogenesis of this myopathy, commented Dr. Valiyil.

“It should be noted that [many] of our patients were African American and we cannot rule out the possibility that there may be more of a response in this particular group of patients,” explained Dr. Lisa Christopher-Stine, a rheumatologist at Hopkins who is the principal investigator of the study.

Dr. Valiyil and Dr. Christopher-Stine reported having no financial conflicts of interest to disclose.

PHILADELPHIA — Six of eight patients with anti–signal recognition peptide myopathy that was refractory to standard immunosuppressive therapy showed clinical improvement with rituximab, according to findings from recent research.

Presenting the data at the annual meeting of the American College of Rheumatology, Dr. Ritu Valiyil noted that patients who responded to rituximab were able to lower their doses of corticosteroids.

Myopathy associated with anti–signal recognition peptide (anti-SRP) autoantibody is a severe, necrotizing, immune-mediated disease characterized by rapidly progressive proximal muscle weakness, myalgia, dysphagia, and markedly elevated serum creatine kinase (CK) levels. Patients generally respond poorly to conventional immunosuppressive therapies such as azathioprine, methotrexate, or intravenous immunoglobulin, says Dr. Valiyil, a rheumatology fellow at Johns Hopkins University, Baltimore.

A chart review identified eight patients who had failed standard immunosuppressive therapies who were then given two doses of rituximab, an anti-CD20 monoclonal antibody. The eight patients' mean age was 37 years; six were women, and four were black.

As soon as 2 months after receiving two doses of rituximab, six of the eight patients demonstrated improved muscle strength in their hands. Prior to treatment with rituximab, the mean creatine kinase was 1,835 IU/L, which declined to a mean of 777.5 IU/L after treatment. Three patients sustained the response for 12-18 months after initial dosing.

All patients on rituximab continued on adjunctive steroid therapy but were able to reduce their corticosteroid dose. The mean highest prednisone dose prior to receiving rituximab was 75 mg/day; the mean lowest dose after rituximab was 21 mg/day.

Autoantibodies were detected and quantitated in the serum samples collected before and after rituximab treatment in five patients. Four of the five patients showed a decrease in serum anti-SRP antibodies. The substantial decrease in anti-SRP antibody levels after rituximab suggest that B cells and anti-SRP antibodies may play a role in the pathogenesis of this myopathy, commented Dr. Valiyil.

“It should be noted that [many] of our patients were African American and we cannot rule out the possibility that there may be more of a response in this particular group of patients,” explained Dr. Lisa Christopher-Stine, a rheumatologist at Hopkins who is the principal investigator of the study.

Dr. Valiyil and Dr. Christopher-Stine reported having no financial conflicts of interest to disclose.

PHILADELPHIA — Results from the largest registry of children with juvenile idiopathic arthritis who are taking etanercept indicate that the number of serious adverse events was low and seems not to increase with prolonged treatment.

Adverse events (including serious infections, malignancies, and deaths) were documented, according to Dr. Gerd Horneff, who presented the latest data from the German etanercept registry for the treatment of JIA at the annual meeting of the American Society of Rheumatology.

The significance of the findings was reflected by the overflow crowd that came to hear Dr. Horneff's presentation. Considerable attention to this issue was raised by a Food and Drug Administration alert issued in August that requires manufacturers of tumor necrosis factor (TNF) blockers to update boxed warnings in prescribing information to notify health care professionals of an increased risk of lymphoma and other malignancies in children and adolescents who are treated with infliximab, etanercept, adalimumab, certolizumab pegol, or golimumab.

The FDA identified 48 cases of malignancies in children and adolescents who were exposed to TNF inhibitors, and 20 malignancies in pediatric rheumatology patients. In all, 14 were in children or adolescents taking etanercept. The malignancy reporting rate for etanercept (2.2 per 10,000 patient-years in aged 17 years or younger) was higher than background rates for lymphomas, but similar to background rates for all malignancies. The FDA concluded that because of the relatively rare occurrence of these cancers and the limited number of pediatric patients treated with TNF blockers, as well as the possible role of other immunosuppressive therapies used along with TNF blockers, it was unable to fully characterize the strength of the association between TNF blockers and development of a malignancy, and that more data were needed from long-term studies.

Dr. Horneff presented the safety results for the largest group of children who had been exposed to etanercept to date (1,139), yielding more than 3,300 patient-years of observation. In comparison, only 69 children taking etanercept have been studied in randomized, controlled trials. The German registry includes 43% of children who are taking etanercept and are enrolled in registries around the world, explained Dr. Horneff of the department of pediatrics at Asklepios Clinic in Sankt Augustin, Germany.

The registry contained reports of serious adverse events (SAEs) in 9% of children. These included, but were not limited to, 34 infections, 21 autoimmune/uveitis reactions, 11 disease flare-ups, 11 neuropsychiatric reactions, and 11 other types of reactions. Five children had allergic/skin reactions. One child had a fatal macrophage activation syndrome reaction 6 months after etanercept discontinuation.

Four children developed malignancies including thyroid carcinoma (diagnosed during the 10th month of treatment), yolk sac carcinoma (diagnosed after 3 weeks of treatment), non-Hodgkin's lymphoma (in a patient exposed to many biologic and nonbiologic agents), and Hodgkin's lymphoma (diagnosed 19 months after discontinuing etanercept following 1.5 years of treatment). These data are consistent with the observation reported by the FDA, although the risk of malignancy was still quite low, said Dr. Horneff.

The background incidence of malignancy in children with JIA has not been well defined. It remains unclear whether the risk of malignancy is increased in JIA. Long-term inflammation may increase the cancer risk. Numerous different types of cancers have been observed, but lymphoma is the most common, he said.

Infections were the most common serious adverse event in this registry. There were no reports of tuberculosis or opportunistic infections. The 0.01 infectious SAEs per patient-year reported in the German registry are similar to the 0.02 SAEs per patient-year reported in the U.S. registry and the 0.04 rate reported in open-label, long-term extension studies, according to Dr. Horneff. Taking steroids with etanercept tripled the risk of developing a serious infection (odds ratio, 2.9; P = .007), but adding methotrexate did not significantly increase the risk of infection (P = .085). Autoimmunopathies occurred in 2% of children, the equivalent of 0.007 SAEs per patient-year of observation.

The average age of enrollees in the German registry was 12.5 years, and about 70% were female. The average disease duration was 4.3 years. The primary diagnoses were polyarthritis (42%) and extended oligoarthritis (17%). In all, 11% had systemic JIA.

“Randomized controlled trials showed that polyarticular JIA can successfully be treated with TNF inhibitors etanercept, adalimumab, and infliximab, and open-label extension studies demonstrated long-term efficacy,” Dr. Horneff said.

“Although no causative relationship can be concluded between etanercept and malignancies, the use of TNF inhibitors should be limited to those patients with severe polyarticular JIA who do not respond to previous treatment. Furthermore, combination treatment with methotrexate or other immunosuppressants may increase clinical efficacy but may also increase risk, and should, therefore, be indicated with caution.

Nevertheless, the extensive use of immunosuppressants other than methotrexate as alternative treatment or pretreatment before considering TNF-inhibitors may also affect the risk for malignancies and should be avoided.”

Dr. Horneff disclosed having financial relationships with a number of companies, including Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Chugai, Lilly, MedImmune, Merck Serono, Novartis, Nycomed, Pfizer, Roche, Sandoz, and Wyeth.

PHILADELPHIA — Results from the largest registry of children with juvenile idiopathic arthritis who are taking etanercept indicate that the number of serious adverse events was low and seems not to increase with prolonged treatment.

Adverse events (including serious infections, malignancies, and deaths) were documented, according to Dr. Gerd Horneff, who presented the latest data from the German etanercept registry for the treatment of JIA at the annual meeting of the American Society of Rheumatology.

The significance of the findings was reflected by the overflow crowd that came to hear Dr. Horneff's presentation. Considerable attention to this issue was raised by a Food and Drug Administration alert issued in August that requires manufacturers of tumor necrosis factor (TNF) blockers to update boxed warnings in prescribing information to notify health care professionals of an increased risk of lymphoma and other malignancies in children and adolescents who are treated with infliximab, etanercept, adalimumab, certolizumab pegol, or golimumab.

The FDA identified 48 cases of malignancies in children and adolescents who were exposed to TNF inhibitors, and 20 malignancies in pediatric rheumatology patients. In all, 14 were in children or adolescents taking etanercept. The malignancy reporting rate for etanercept (2.2 per 10,000 patient-years in aged 17 years or younger) was higher than background rates for lymphomas, but similar to background rates for all malignancies. The FDA concluded that because of the relatively rare occurrence of these cancers and the limited number of pediatric patients treated with TNF blockers, as well as the possible role of other immunosuppressive therapies used along with TNF blockers, it was unable to fully characterize the strength of the association between TNF blockers and development of a malignancy, and that more data were needed from long-term studies.

Dr. Horneff presented the safety results for the largest group of children who had been exposed to etanercept to date (1,139), yielding more than 3,300 patient-years of observation. In comparison, only 69 children taking etanercept have been studied in randomized, controlled trials. The German registry includes 43% of children who are taking etanercept and are enrolled in registries around the world, explained Dr. Horneff of the department of pediatrics at Asklepios Clinic in Sankt Augustin, Germany.

The registry contained reports of serious adverse events (SAEs) in 9% of children. These included, but were not limited to, 34 infections, 21 autoimmune/uveitis reactions, 11 disease flare-ups, 11 neuropsychiatric reactions, and 11 other types of reactions. Five children had allergic/skin reactions. One child had a fatal macrophage activation syndrome reaction 6 months after etanercept discontinuation.

Four children developed malignancies including thyroid carcinoma (diagnosed during the 10th month of treatment), yolk sac carcinoma (diagnosed after 3 weeks of treatment), non-Hodgkin's lymphoma (in a patient exposed to many biologic and nonbiologic agents), and Hodgkin's lymphoma (diagnosed 19 months after discontinuing etanercept following 1.5 years of treatment). These data are consistent with the observation reported by the FDA, although the risk of malignancy was still quite low, said Dr. Horneff.

The background incidence of malignancy in children with JIA has not been well defined. It remains unclear whether the risk of malignancy is increased in JIA. Long-term inflammation may increase the cancer risk. Numerous different types of cancers have been observed, but lymphoma is the most common, he said.

Infections were the most common serious adverse event in this registry. There were no reports of tuberculosis or opportunistic infections. The 0.01 infectious SAEs per patient-year reported in the German registry are similar to the 0.02 SAEs per patient-year reported in the U.S. registry and the 0.04 rate reported in open-label, long-term extension studies, according to Dr. Horneff. Taking steroids with etanercept tripled the risk of developing a serious infection (odds ratio, 2.9; P = .007), but adding methotrexate did not significantly increase the risk of infection (P = .085). Autoimmunopathies occurred in 2% of children, the equivalent of 0.007 SAEs per patient-year of observation.

The average age of enrollees in the German registry was 12.5 years, and about 70% were female. The average disease duration was 4.3 years. The primary diagnoses were polyarthritis (42%) and extended oligoarthritis (17%). In all, 11% had systemic JIA.

“Randomized controlled trials showed that polyarticular JIA can successfully be treated with TNF inhibitors etanercept, adalimumab, and infliximab, and open-label extension studies demonstrated long-term efficacy,” Dr. Horneff said.

“Although no causative relationship can be concluded between etanercept and malignancies, the use of TNF inhibitors should be limited to those patients with severe polyarticular JIA who do not respond to previous treatment. Furthermore, combination treatment with methotrexate or other immunosuppressants may increase clinical efficacy but may also increase risk, and should, therefore, be indicated with caution.

Nevertheless, the extensive use of immunosuppressants other than methotrexate as alternative treatment or pretreatment before considering TNF-inhibitors may also affect the risk for malignancies and should be avoided.”

Dr. Horneff disclosed having financial relationships with a number of companies, including Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Chugai, Lilly, MedImmune, Merck Serono, Novartis, Nycomed, Pfizer, Roche, Sandoz, and Wyeth.

PHILADELPHIA — Results from the largest registry of children with juvenile idiopathic arthritis who are taking etanercept indicate that the number of serious adverse events was low and seems not to increase with prolonged treatment.

Adverse events (including serious infections, malignancies, and deaths) were documented, according to Dr. Gerd Horneff, who presented the latest data from the German etanercept registry for the treatment of JIA at the annual meeting of the American Society of Rheumatology.

The significance of the findings was reflected by the overflow crowd that came to hear Dr. Horneff's presentation. Considerable attention to this issue was raised by a Food and Drug Administration alert issued in August that requires manufacturers of tumor necrosis factor (TNF) blockers to update boxed warnings in prescribing information to notify health care professionals of an increased risk of lymphoma and other malignancies in children and adolescents who are treated with infliximab, etanercept, adalimumab, certolizumab pegol, or golimumab.

The FDA identified 48 cases of malignancies in children and adolescents who were exposed to TNF inhibitors, and 20 malignancies in pediatric rheumatology patients. In all, 14 were in children or adolescents taking etanercept. The malignancy reporting rate for etanercept (2.2 per 10,000 patient-years in aged 17 years or younger) was higher than background rates for lymphomas, but similar to background rates for all malignancies. The FDA concluded that because of the relatively rare occurrence of these cancers and the limited number of pediatric patients treated with TNF blockers, as well as the possible role of other immunosuppressive therapies used along with TNF blockers, it was unable to fully characterize the strength of the association between TNF blockers and development of a malignancy, and that more data were needed from long-term studies.

Dr. Horneff presented the safety results for the largest group of children who had been exposed to etanercept to date (1,139), yielding more than 3,300 patient-years of observation. In comparison, only 69 children taking etanercept have been studied in randomized, controlled trials. The German registry includes 43% of children who are taking etanercept and are enrolled in registries around the world, explained Dr. Horneff of the department of pediatrics at Asklepios Clinic in Sankt Augustin, Germany.

The registry contained reports of serious adverse events (SAEs) in 9% of children. These included, but were not limited to, 34 infections, 21 autoimmune/uveitis reactions, 11 disease flare-ups, 11 neuropsychiatric reactions, and 11 other types of reactions. Five children had allergic/skin reactions. One child had a fatal macrophage activation syndrome reaction 6 months after etanercept discontinuation.

Four children developed malignancies including thyroid carcinoma (diagnosed during the 10th month of treatment), yolk sac carcinoma (diagnosed after 3 weeks of treatment), non-Hodgkin's lymphoma (in a patient exposed to many biologic and nonbiologic agents), and Hodgkin's lymphoma (diagnosed 19 months after discontinuing etanercept following 1.5 years of treatment). These data are consistent with the observation reported by the FDA, although the risk of malignancy was still quite low, said Dr. Horneff.

The background incidence of malignancy in children with JIA has not been well defined. It remains unclear whether the risk of malignancy is increased in JIA. Long-term inflammation may increase the cancer risk. Numerous different types of cancers have been observed, but lymphoma is the most common, he said.

Infections were the most common serious adverse event in this registry. There were no reports of tuberculosis or opportunistic infections. The 0.01 infectious SAEs per patient-year reported in the German registry are similar to the 0.02 SAEs per patient-year reported in the U.S. registry and the 0.04 rate reported in open-label, long-term extension studies, according to Dr. Horneff. Taking steroids with etanercept tripled the risk of developing a serious infection (odds ratio, 2.9; P = .007), but adding methotrexate did not significantly increase the risk of infection (P = .085). Autoimmunopathies occurred in 2% of children, the equivalent of 0.007 SAEs per patient-year of observation.

The average age of enrollees in the German registry was 12.5 years, and about 70% were female. The average disease duration was 4.3 years. The primary diagnoses were polyarthritis (42%) and extended oligoarthritis (17%). In all, 11% had systemic JIA.

“Randomized controlled trials showed that polyarticular JIA can successfully be treated with TNF inhibitors etanercept, adalimumab, and infliximab, and open-label extension studies demonstrated long-term efficacy,” Dr. Horneff said.

“Although no causative relationship can be concluded between etanercept and malignancies, the use of TNF inhibitors should be limited to those patients with severe polyarticular JIA who do not respond to previous treatment. Furthermore, combination treatment with methotrexate or other immunosuppressants may increase clinical efficacy but may also increase risk, and should, therefore, be indicated with caution.

Nevertheless, the extensive use of immunosuppressants other than methotrexate as alternative treatment or pretreatment before considering TNF-inhibitors may also affect the risk for malignancies and should be avoided.”

Dr. Horneff disclosed having financial relationships with a number of companies, including Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Chugai, Lilly, MedImmune, Merck Serono, Novartis, Nycomed, Pfizer, Roche, Sandoz, and Wyeth.

PHILADELPHIA —Women with rheumatic disease who took etanercept during pregnancy were three times more likely to have a child with a major malformation than was a disease-matched comparison group, judging from interim results from a small sample.

Most of the malformations were isolated, and no patterns of birth defect were apparent, according to Christina Chambers, Ph.D., who presented the findings from the Autoimmune Diseases in Pregnancy Project being conducted by the Organization of Teratology Information Specialists (OTIS) at the annual meeting of the American College of Rheumatology.

“Although outcomes were presented for these pregnancies, I always caution health care providers and patients that these are ongoing studies with a target sample size that is intended to have sufficient power to answer our research questions. For that reason, we have not performed any formal interim statistical analysis nor have we adjusted for differences between groups, such as maternal smoking or folic acid use, that may affect pregnancy outcomes,” said Dr. Chambers of the department of pediatrics and family and preventive medicine at the University of California, San Diego.

OTIS is a prospective observational cohort study with the purpose of evaluating the effects of autoimmune diseases and their treatment on pregnancy outcomes and fetal development. Recruitment began in 2000 and is projected to continue through 2015. Current recruitment stands at 944, with a goal of 1,500.

Pregnant women are typically enrolled in the study before they reach 20 weeks of gestation. To be enrolled, the women must have current diagnoses of rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, or Crohn's disease. Many participants are referred by their rheumatologists to the OTIS coordinating center, where they undergo multiple interviews and review of their symptom management. After birth, the infants are followed for up to a year, during which time they are assessed by their pediatricians, undergo blinded dysmorphological examination by OTIS physicians, and are photographed.

“Evaluating pregnancy outcomes following medication exposure is a not a situation that lends itself to conducting a randomized controlled trial for obvious ethical reasons,” said Dr. Chambers. Although the literature contains case reports, the OTIS project is designed to give clinicians the evidence-based information they need to counsel patients who are pregnant or considering becoming pregnant.

At the time of this progress report, outcome was available for 115 women with RA who had been exposed to etanercept, compared with 55 disease-comparison controls. Outcome was available for 42 women with RA who were exposed to adalimumab, compared with 58 disease-matched women and 84 healthy controls. The percentage of live births was higher in those treated with etanercept, compared with those with similar rheumatic diseases (92% vs. 85%), and fewer spontaneous abortions occurred in the etanercept-treated group (4% vs. 11%). There were no ectopic pregnancies in either group. One stillbirth was reported in the etanercept cohort and none in the controls. Preterm deliveries were more common in women who were taking etanercept (23% vs. 13%).

Of the major malformations among all pregnancies enrolled in OTIS, 12% (14 of 114) were reported in the etanercept group, compared with 3.8% (2 of 53) in the disease-matched controls.

The defects included displaced stomach with epispa-dias and congenital eye defect; ventricular septal defect with peripheral pulmonic stenosis; pyloric stenosis; hypospadias; ventricular septal defect with patent foramen ovale and patent ductus arteriosus; volvulus; patent foramen ovale; atrial septal defect with patent ductus arteriosus; microcephaly; congenital hypothyroidism; and an unspecified heart defect. Three abnormalities—Noonan syndrome, Turner syndrome, and Down syndrome—were genetic or chromosomal. No cases of the malformation patterns VATER or VACTERL were found.

“Typically we would see a specific pattern of malformation with a medication that truly causes defects, but our results indicate that most of the defects were isolated with no apparent patterns,” Dr. Chambers said.

For those exposed to adalimumab, the percentage of live births was lower in those receiving the drug (88%) compared with those with similar autoimmune illnesses (93%) and healthy controls (92%). The rate of spontaneous abortions also was higher in the adalimumab-treated cohort (12%) compared with the disease-matched (5%) and healthy (1%) cohorts. There were no ectopic pregnancies or stillbirths in the drug-treated group.

Preterm delivery was higher in both the adalimumab-treated (14%) and disease-matched comparison (17%) groups, compared with healthy controls (4%). Mean birth weight was approximately 300 g less in term infants whose mothers had received adalimumab, compared with healthy controls, but similar to term infants in the disease-matched comparison group. Rates of major malformations were similar (4% to 5%) in all groups and within the range of expected numbers in the general population, said Dr. Chambers.

“Firm conclusions await the accumulation of target sample size for adalimumab and etanercept and multivariate analysis.

“It is important to recognize that many differences between medication-exposed and comparison groups can be accounted for by other maternal risk factors, and so until these are addressed in multivariate analysis, we are dealing with very preliminary results. We also will be evaluating minor anomalies, 1-year growth, and developmental screening data,” Dr. Chambers said.

'Firm conclusions await the accumulation of target sample size' needed for multivariate analysis.

Source DR. CHAMBERS

PHILADELPHIA —Women with rheumatic disease who took etanercept during pregnancy were three times more likely to have a child with a major malformation than was a disease-matched comparison group, judging from interim results from a small sample.

Most of the malformations were isolated, and no patterns of birth defect were apparent, according to Christina Chambers, Ph.D., who presented the findings from the Autoimmune Diseases in Pregnancy Project being conducted by the Organization of Teratology Information Specialists (OTIS) at the annual meeting of the American College of Rheumatology.

“Although outcomes were presented for these pregnancies, I always caution health care providers and patients that these are ongoing studies with a target sample size that is intended to have sufficient power to answer our research questions. For that reason, we have not performed any formal interim statistical analysis nor have we adjusted for differences between groups, such as maternal smoking or folic acid use, that may affect pregnancy outcomes,” said Dr. Chambers of the department of pediatrics and family and preventive medicine at the University of California, San Diego.

OTIS is a prospective observational cohort study with the purpose of evaluating the effects of autoimmune diseases and their treatment on pregnancy outcomes and fetal development. Recruitment began in 2000 and is projected to continue through 2015. Current recruitment stands at 944, with a goal of 1,500.

Pregnant women are typically enrolled in the study before they reach 20 weeks of gestation. To be enrolled, the women must have current diagnoses of rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, or Crohn's disease. Many participants are referred by their rheumatologists to the OTIS coordinating center, where they undergo multiple interviews and review of their symptom management. After birth, the infants are followed for up to a year, during which time they are assessed by their pediatricians, undergo blinded dysmorphological examination by OTIS physicians, and are photographed.

“Evaluating pregnancy outcomes following medication exposure is a not a situation that lends itself to conducting a randomized controlled trial for obvious ethical reasons,” said Dr. Chambers. Although the literature contains case reports, the OTIS project is designed to give clinicians the evidence-based information they need to counsel patients who are pregnant or considering becoming pregnant.

At the time of this progress report, outcome was available for 115 women with RA who had been exposed to etanercept, compared with 55 disease-comparison controls. Outcome was available for 42 women with RA who were exposed to adalimumab, compared with 58 disease-matched women and 84 healthy controls. The percentage of live births was higher in those treated with etanercept, compared with those with similar rheumatic diseases (92% vs. 85%), and fewer spontaneous abortions occurred in the etanercept-treated group (4% vs. 11%). There were no ectopic pregnancies in either group. One stillbirth was reported in the etanercept cohort and none in the controls. Preterm deliveries were more common in women who were taking etanercept (23% vs. 13%).

Of the major malformations among all pregnancies enrolled in OTIS, 12% (14 of 114) were reported in the etanercept group, compared with 3.8% (2 of 53) in the disease-matched controls.

The defects included displaced stomach with epispa-dias and congenital eye defect; ventricular septal defect with peripheral pulmonic stenosis; pyloric stenosis; hypospadias; ventricular septal defect with patent foramen ovale and patent ductus arteriosus; volvulus; patent foramen ovale; atrial septal defect with patent ductus arteriosus; microcephaly; congenital hypothyroidism; and an unspecified heart defect. Three abnormalities—Noonan syndrome, Turner syndrome, and Down syndrome—were genetic or chromosomal. No cases of the malformation patterns VATER or VACTERL were found.

“Typically we would see a specific pattern of malformation with a medication that truly causes defects, but our results indicate that most of the defects were isolated with no apparent patterns,” Dr. Chambers said.

For those exposed to adalimumab, the percentage of live births was lower in those receiving the drug (88%) compared with those with similar autoimmune illnesses (93%) and healthy controls (92%). The rate of spontaneous abortions also was higher in the adalimumab-treated cohort (12%) compared with the disease-matched (5%) and healthy (1%) cohorts. There were no ectopic pregnancies or stillbirths in the drug-treated group.

Preterm delivery was higher in both the adalimumab-treated (14%) and disease-matched comparison (17%) groups, compared with healthy controls (4%). Mean birth weight was approximately 300 g less in term infants whose mothers had received adalimumab, compared with healthy controls, but similar to term infants in the disease-matched comparison group. Rates of major malformations were similar (4% to 5%) in all groups and within the range of expected numbers in the general population, said Dr. Chambers.

“Firm conclusions await the accumulation of target sample size for adalimumab and etanercept and multivariate analysis.

“It is important to recognize that many differences between medication-exposed and comparison groups can be accounted for by other maternal risk factors, and so until these are addressed in multivariate analysis, we are dealing with very preliminary results. We also will be evaluating minor anomalies, 1-year growth, and developmental screening data,” Dr. Chambers said.

'Firm conclusions await the accumulation of target sample size' needed for multivariate analysis.

Source DR. CHAMBERS

PHILADELPHIA —Women with rheumatic disease who took etanercept during pregnancy were three times more likely to have a child with a major malformation than was a disease-matched comparison group, judging from interim results from a small sample.

Most of the malformations were isolated, and no patterns of birth defect were apparent, according to Christina Chambers, Ph.D., who presented the findings from the Autoimmune Diseases in Pregnancy Project being conducted by the Organization of Teratology Information Specialists (OTIS) at the annual meeting of the American College of Rheumatology.

“Although outcomes were presented for these pregnancies, I always caution health care providers and patients that these are ongoing studies with a target sample size that is intended to have sufficient power to answer our research questions. For that reason, we have not performed any formal interim statistical analysis nor have we adjusted for differences between groups, such as maternal smoking or folic acid use, that may affect pregnancy outcomes,” said Dr. Chambers of the department of pediatrics and family and preventive medicine at the University of California, San Diego.

OTIS is a prospective observational cohort study with the purpose of evaluating the effects of autoimmune diseases and their treatment on pregnancy outcomes and fetal development. Recruitment began in 2000 and is projected to continue through 2015. Current recruitment stands at 944, with a goal of 1,500.

Pregnant women are typically enrolled in the study before they reach 20 weeks of gestation. To be enrolled, the women must have current diagnoses of rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, or Crohn's disease. Many participants are referred by their rheumatologists to the OTIS coordinating center, where they undergo multiple interviews and review of their symptom management. After birth, the infants are followed for up to a year, during which time they are assessed by their pediatricians, undergo blinded dysmorphological examination by OTIS physicians, and are photographed.

“Evaluating pregnancy outcomes following medication exposure is a not a situation that lends itself to conducting a randomized controlled trial for obvious ethical reasons,” said Dr. Chambers. Although the literature contains case reports, the OTIS project is designed to give clinicians the evidence-based information they need to counsel patients who are pregnant or considering becoming pregnant.

At the time of this progress report, outcome was available for 115 women with RA who had been exposed to etanercept, compared with 55 disease-comparison controls. Outcome was available for 42 women with RA who were exposed to adalimumab, compared with 58 disease-matched women and 84 healthy controls. The percentage of live births was higher in those treated with etanercept, compared with those with similar rheumatic diseases (92% vs. 85%), and fewer spontaneous abortions occurred in the etanercept-treated group (4% vs. 11%). There were no ectopic pregnancies in either group. One stillbirth was reported in the etanercept cohort and none in the controls. Preterm deliveries were more common in women who were taking etanercept (23% vs. 13%).

Of the major malformations among all pregnancies enrolled in OTIS, 12% (14 of 114) were reported in the etanercept group, compared with 3.8% (2 of 53) in the disease-matched controls.

The defects included displaced stomach with epispa-dias and congenital eye defect; ventricular septal defect with peripheral pulmonic stenosis; pyloric stenosis; hypospadias; ventricular septal defect with patent foramen ovale and patent ductus arteriosus; volvulus; patent foramen ovale; atrial septal defect with patent ductus arteriosus; microcephaly; congenital hypothyroidism; and an unspecified heart defect. Three abnormalities—Noonan syndrome, Turner syndrome, and Down syndrome—were genetic or chromosomal. No cases of the malformation patterns VATER or VACTERL were found.

“Typically we would see a specific pattern of malformation with a medication that truly causes defects, but our results indicate that most of the defects were isolated with no apparent patterns,” Dr. Chambers said.

For those exposed to adalimumab, the percentage of live births was lower in those receiving the drug (88%) compared with those with similar autoimmune illnesses (93%) and healthy controls (92%). The rate of spontaneous abortions also was higher in the adalimumab-treated cohort (12%) compared with the disease-matched (5%) and healthy (1%) cohorts. There were no ectopic pregnancies or stillbirths in the drug-treated group.

Preterm delivery was higher in both the adalimumab-treated (14%) and disease-matched comparison (17%) groups, compared with healthy controls (4%). Mean birth weight was approximately 300 g less in term infants whose mothers had received adalimumab, compared with healthy controls, but similar to term infants in the disease-matched comparison group. Rates of major malformations were similar (4% to 5%) in all groups and within the range of expected numbers in the general population, said Dr. Chambers.

“Firm conclusions await the accumulation of target sample size for adalimumab and etanercept and multivariate analysis.

“It is important to recognize that many differences between medication-exposed and comparison groups can be accounted for by other maternal risk factors, and so until these are addressed in multivariate analysis, we are dealing with very preliminary results. We also will be evaluating minor anomalies, 1-year growth, and developmental screening data,” Dr. Chambers said.

'Firm conclusions await the accumulation of target sample size' needed for multivariate analysis.

Source DR. CHAMBERS

PHILADELPHIA — Children followed for an average of 14 years after diagnosis of juvenile idiopathic arthritis showed no increased risk of invasive cancers, according to Dr. Ann Clarke.

Studies have shown an increased risk of malignancy—particularly lymphoma and lung cancer—in adult rheumatoid arthritis patients. This is the first assessment of cancer risk in children, she said at the annual meeting of the American College of Rheumatology.

In this study, the investigators analyzed juvenile idiopathic arthritis (JIA) registries maintained at two pediatric rheumatology centers located in Saskatoon, Sask., and Winnipeg, Man., between 1974 and 2006. Clinic patients were linked to regional tumor registries to determine any cancer occurrence. The observed malignancy incidence was compared with the expected incidence, based on general population cancer data, said Dr. Clarke of McGill University, Montreal.

The sample included 1,168 children with JIA (67.3% girls), most of whom were diagnosed when they were about 9 years old. Children were followed from the time of diagnosis until their death, their development of cancer, or the completion of the study interval at the end of 2006, for a total of 16,396 patient-years.

On the basis of regional age- and sex-specific general population cancer rates, the researchers expected six invasive cancers to be identified during the average 14 years of follow-up. In actuality, no cancers were found.

The investigators noted that the potential effect of medications on possible cancer risk is still not precisely known. In this cohort, about one-quarter of the children had been exposed to disease-modifying antirheumatic drugs, most commonly methotrexate. In all, 19 children had taken anti–tumor necrosis factor medications.

The U.S. Food and Drug Administration required stronger black boxed warnings in prescribing information that use of anti–tumor necrosis factor agents seemed to be associated with an increased risk for cancer among children

Dr. Thomas J.A. Lehman said in an interview that Dr. Clark's study illustrates that the risk of cancer in children receiving anti-TNF agents for JIA is very low. However, the anti-TNF warning by the FDA applies to children who received an anti-TNF agent for any reason not only children with juvenile arthritis.

A significant proportion of the children with reported malignancies noted by the FDA had inflammatory bowel disease, not juvenile arthritis. At the same time the FDA was able to draw on a much larger population of patients than the present study, said Dr. Lehman, chief of the division of pediatric rheumatology at the Hospital for Special Surgery in New York.

“Our obligation as physicians is to make sure families understand that the benefits of anti-TNF agents are very great and the risk to the individual child of developing a malignancy is almost vanishingly small. This study had no cases in all the children seen. We don't have adequate data to guarantee that there might not be a small increase in the risk of malignancies, but we do have adequate data demonstrating the dramatic benefits of anti-TNF agents.

Dr. Lehman, who is also professor of clinical pediatrics at New York Weill Cornell Medical Center, is on the speakers bureau for Wyeth Pharmaceuticals and Amgen Inc., which market etanercept, and Abbott Laboratories, manufacturer of adalimumab.

Dr. Clark noted that one limitation of the study was its predominantly white (80.5%) and First Nations/Inuit (16.9%) enrollment. She reported no conflicts.

PHILADELPHIA — Children followed for an average of 14 years after diagnosis of juvenile idiopathic arthritis showed no increased risk of invasive cancers, according to Dr. Ann Clarke.

Studies have shown an increased risk of malignancy—particularly lymphoma and lung cancer—in adult rheumatoid arthritis patients. This is the first assessment of cancer risk in children, she said at the annual meeting of the American College of Rheumatology.

In this study, the investigators analyzed juvenile idiopathic arthritis (JIA) registries maintained at two pediatric rheumatology centers located in Saskatoon, Sask., and Winnipeg, Man., between 1974 and 2006. Clinic patients were linked to regional tumor registries to determine any cancer occurrence. The observed malignancy incidence was compared with the expected incidence, based on general population cancer data, said Dr. Clarke of McGill University, Montreal.

The sample included 1,168 children with JIA (67.3% girls), most of whom were diagnosed when they were about 9 years old. Children were followed from the time of diagnosis until their death, their development of cancer, or the completion of the study interval at the end of 2006, for a total of 16,396 patient-years.

On the basis of regional age- and sex-specific general population cancer rates, the researchers expected six invasive cancers to be identified during the average 14 years of follow-up. In actuality, no cancers were found.

The investigators noted that the potential effect of medications on possible cancer risk is still not precisely known. In this cohort, about one-quarter of the children had been exposed to disease-modifying antirheumatic drugs, most commonly methotrexate. In all, 19 children had taken anti–tumor necrosis factor medications.

The U.S. Food and Drug Administration required stronger black boxed warnings in prescribing information that use of anti–tumor necrosis factor agents seemed to be associated with an increased risk for cancer among children

Dr. Thomas J.A. Lehman said in an interview that Dr. Clark's study illustrates that the risk of cancer in children receiving anti-TNF agents for JIA is very low. However, the anti-TNF warning by the FDA applies to children who received an anti-TNF agent for any reason not only children with juvenile arthritis.

A significant proportion of the children with reported malignancies noted by the FDA had inflammatory bowel disease, not juvenile arthritis. At the same time the FDA was able to draw on a much larger population of patients than the present study, said Dr. Lehman, chief of the division of pediatric rheumatology at the Hospital for Special Surgery in New York.

“Our obligation as physicians is to make sure families understand that the benefits of anti-TNF agents are very great and the risk to the individual child of developing a malignancy is almost vanishingly small. This study had no cases in all the children seen. We don't have adequate data to guarantee that there might not be a small increase in the risk of malignancies, but we do have adequate data demonstrating the dramatic benefits of anti-TNF agents.

Dr. Lehman, who is also professor of clinical pediatrics at New York Weill Cornell Medical Center, is on the speakers bureau for Wyeth Pharmaceuticals and Amgen Inc., which market etanercept, and Abbott Laboratories, manufacturer of adalimumab.

Dr. Clark noted that one limitation of the study was its predominantly white (80.5%) and First Nations/Inuit (16.9%) enrollment. She reported no conflicts.

PHILADELPHIA — Children followed for an average of 14 years after diagnosis of juvenile idiopathic arthritis showed no increased risk of invasive cancers, according to Dr. Ann Clarke.

Studies have shown an increased risk of malignancy—particularly lymphoma and lung cancer—in adult rheumatoid arthritis patients. This is the first assessment of cancer risk in children, she said at the annual meeting of the American College of Rheumatology.

In this study, the investigators analyzed juvenile idiopathic arthritis (JIA) registries maintained at two pediatric rheumatology centers located in Saskatoon, Sask., and Winnipeg, Man., between 1974 and 2006. Clinic patients were linked to regional tumor registries to determine any cancer occurrence. The observed malignancy incidence was compared with the expected incidence, based on general population cancer data, said Dr. Clarke of McGill University, Montreal.

The sample included 1,168 children with JIA (67.3% girls), most of whom were diagnosed when they were about 9 years old. Children were followed from the time of diagnosis until their death, their development of cancer, or the completion of the study interval at the end of 2006, for a total of 16,396 patient-years.

On the basis of regional age- and sex-specific general population cancer rates, the researchers expected six invasive cancers to be identified during the average 14 years of follow-up. In actuality, no cancers were found.

The investigators noted that the potential effect of medications on possible cancer risk is still not precisely known. In this cohort, about one-quarter of the children had been exposed to disease-modifying antirheumatic drugs, most commonly methotrexate. In all, 19 children had taken anti–tumor necrosis factor medications.

The U.S. Food and Drug Administration required stronger black boxed warnings in prescribing information that use of anti–tumor necrosis factor agents seemed to be associated with an increased risk for cancer among children

Dr. Thomas J.A. Lehman said in an interview that Dr. Clark's study illustrates that the risk of cancer in children receiving anti-TNF agents for JIA is very low. However, the anti-TNF warning by the FDA applies to children who received an anti-TNF agent for any reason not only children with juvenile arthritis.

A significant proportion of the children with reported malignancies noted by the FDA had inflammatory bowel disease, not juvenile arthritis. At the same time the FDA was able to draw on a much larger population of patients than the present study, said Dr. Lehman, chief of the division of pediatric rheumatology at the Hospital for Special Surgery in New York.

“Our obligation as physicians is to make sure families understand that the benefits of anti-TNF agents are very great and the risk to the individual child of developing a malignancy is almost vanishingly small. This study had no cases in all the children seen. We don't have adequate data to guarantee that there might not be a small increase in the risk of malignancies, but we do have adequate data demonstrating the dramatic benefits of anti-TNF agents.

Dr. Lehman, who is also professor of clinical pediatrics at New York Weill Cornell Medical Center, is on the speakers bureau for Wyeth Pharmaceuticals and Amgen Inc., which market etanercept, and Abbott Laboratories, manufacturer of adalimumab.

Dr. Clark noted that one limitation of the study was its predominantly white (80.5%) and First Nations/Inuit (16.9%) enrollment. She reported no conflicts.