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LONDON – Tumor necrosis factor–inhibitor treatment improved refractory skin disease in juvenile dermatomyositis patients in the largest observational study of its kind from the United Kingdom and Ireland Juvenile Dermatomyositis Research Group.

Muscle disease in the juvenile dermatomyositis (JDM) patients largely had already improved with conventional therapies prior to treatment with anti–tumor necrosis factor (TNF)-alpha agents, but it did improve further with anti-TNFs.

The effect of TNF inhibitors was most notable for those with skin calcinosis, lead author Dr. Raquel Campanilho-Marques reported at the European Congress of Rheumatology on behalf of her colleagues in the Juvenile Dermatomyositis Research Group.

Some evidence suggests that TNF-alpha might be involved in the pathogenesis of idiopathic inflammatory myopathies, particularly in more prolonged courses of JDM.

But there is limited prior evidence for the efficacy of TNF inhibitors in JDM patients, where small observational studies and case series have shown improved core-set measures of disease activity in patients treated with anti-TNF agents, noted Dr. Campanilho-Marques, a pediatric rheumatologist in the infection, inflammation and rheumatology section at the University College London Institute of Child Health and the Great Ormond Street Hospital for Children NHS Trust in London.

The 67 patients in the study involved those who were enrolled in the JDM Cohort and Biomarker Study, met Bohan and Peter criteria for JDM, and were on anti-TNF therapy at the time of analysis because of nonresponse to conventional therapy, active skin disease, calcinosis, or muscle weakness. They had at least 3 months of anti-TNF therapy and received either infliximab 6 mg/kg every 4 weeks (after a standard initial induction regimen) or adalimumab (Humira) 24 mg/m² every other week.

A majority of the patients in the study were female (n = 41) and white (n = 54), with a mean age at disease onset of about 5 years. At the time of first use of anti-TNF agents, the patients had a mean age of about 10 years and a mean disease duration of 3.2 years. Treatment with TNF inhibitors lasted for a mean of about 2.5 years.

Of the 67 patients, data were not analyzed for 4 patients; there was insufficient information for 1 patient, while 3 patients had allergic reactions to their anti-TNF therapy on the first or second infusion. The remaining 63 patients included 43 who received infliximab, 4 on adalimumab, and 16 who used both.

Prior to anti-TNF treatment, 52 of 53 patients (98%) were taking methotrexate, azathioprine, hydroxychloroquine, or a combination of those. That declined to 45 of 56 (80%) at the start of anti-TNF therapy and then increased to 44 of 49 (89%) after 12 months of using an anti-TNF agent.

The use of cyclophosphamide declined markedly, from 26 of 65 patients (40%) to 3 of 65 (5%) at the start of TNF inhibition, and then to none after 12 months of anti-TNF therapy. Immunoglobulin therapy also declined, from use in 10%-12% of patients before and at the start of anti-TNF treatment to just 1 of 41 patients (2%) after 12 months of TNF inhibitor therapy.

The median modified Disease Activity Score for skin involvement significantly improved over the course of 12 months of treatment with infliximab, decreasing from 4 to 1. That was also the case for Physician Global Assessment score, as well as muscle outcome measurements on the Childhood Myositis Assessment Scale (CMAS) and the 8-item Manual Muscle Testing (MMT8).

For the 31 patients in the study who had calcinosis, lesions improved (reduced in number and/or size) in 17 patients, including 8 with complete resolution of their lesions. In the other 14 patients, lesions remained stable in 3 (fewer than three lesions) and were widespread or did not improve in 4; the other 7 patients had insufficient data to determine outcomes.

Most patients with muscle involvement already had improved with steroids prior to using anti-TNF drugs. Thus, the improvement in CMAS and MMT8 scores on anti-TNF treatment was not very large, going from about 45 to 53 and from about 74 to 79, respectively.

The investigators did not examine treatment response in relation to muscle-specific antibodies, but Dr. Campanilho-Marques said that it is something they would like to do in the future.

The main indication for anti-TNF agents was active skin disease that had not responded to conventional treatment, noted Dr. Campanilho-Marques, who is also with the departments of rheumatology at the Santa Maria Hospital and the Instituto Português de Reumatologia, both in Lisbon.

For 16 patients who switched from infliximab to adalimumab, the changes in outcome measures were not statistically significant. The switches occurred at a median of 2.35 months after starting infliximab; 10 patients switched because of inefficacy, 4 because of adverse events, and 2 because of patient preference.

After 12 months of anti-TNF therapy, the median prednisolone dose declined from 6 mg to 2.5 mg, but the decline appeared to be driven by five patients who sharply decreased their dose. Seven patients successfully stopped anti-TNF therapy after improvement occurred, Dr. Campanilho-Marques said.

Serious adverse events occurred 12 times during the year-long study period, including nine allergic reactions and three hospitalizations because of infection. Another 19 mild-to-moderate adverse events took place, which involved 15 infections and three local site reactions and skin rash, which led five patients to discontinue the biologic.

Overall, adverse events occurred at a rate of 13.3/100 patient-years, including 5.2 serious events/100 patient-years. One patient died because of a small bowel perforation that was probably secondary to disease-related damage. There were no malignancies or tuberculosis cases.

In a video interview at the meeting, Dr. Campanilho-Marques discussed the study findings and their implications.

The researchers had no relevant disclosures.

jevans@frontlinemedcom.com

LONDON – Tumor necrosis factor–inhibitor treatment improved refractory skin disease in juvenile dermatomyositis patients in the largest observational study of its kind from the United Kingdom and Ireland Juvenile Dermatomyositis Research Group.

Muscle disease in the juvenile dermatomyositis (JDM) patients largely had already improved with conventional therapies prior to treatment with anti–tumor necrosis factor (TNF)-alpha agents, but it did improve further with anti-TNFs.

The effect of TNF inhibitors was most notable for those with skin calcinosis, lead author Dr. Raquel Campanilho-Marques reported at the European Congress of Rheumatology on behalf of her colleagues in the Juvenile Dermatomyositis Research Group.

Some evidence suggests that TNF-alpha might be involved in the pathogenesis of idiopathic inflammatory myopathies, particularly in more prolonged courses of JDM.

But there is limited prior evidence for the efficacy of TNF inhibitors in JDM patients, where small observational studies and case series have shown improved core-set measures of disease activity in patients treated with anti-TNF agents, noted Dr. Campanilho-Marques, a pediatric rheumatologist in the infection, inflammation and rheumatology section at the University College London Institute of Child Health and the Great Ormond Street Hospital for Children NHS Trust in London.

The 67 patients in the study involved those who were enrolled in the JDM Cohort and Biomarker Study, met Bohan and Peter criteria for JDM, and were on anti-TNF therapy at the time of analysis because of nonresponse to conventional therapy, active skin disease, calcinosis, or muscle weakness. They had at least 3 months of anti-TNF therapy and received either infliximab 6 mg/kg every 4 weeks (after a standard initial induction regimen) or adalimumab (Humira) 24 mg/m² every other week.

A majority of the patients in the study were female (n = 41) and white (n = 54), with a mean age at disease onset of about 5 years. At the time of first use of anti-TNF agents, the patients had a mean age of about 10 years and a mean disease duration of 3.2 years. Treatment with TNF inhibitors lasted for a mean of about 2.5 years.

Of the 67 patients, data were not analyzed for 4 patients; there was insufficient information for 1 patient, while 3 patients had allergic reactions to their anti-TNF therapy on the first or second infusion. The remaining 63 patients included 43 who received infliximab, 4 on adalimumab, and 16 who used both.

Prior to anti-TNF treatment, 52 of 53 patients (98%) were taking methotrexate, azathioprine, hydroxychloroquine, or a combination of those. That declined to 45 of 56 (80%) at the start of anti-TNF therapy and then increased to 44 of 49 (89%) after 12 months of using an anti-TNF agent.

The use of cyclophosphamide declined markedly, from 26 of 65 patients (40%) to 3 of 65 (5%) at the start of TNF inhibition, and then to none after 12 months of anti-TNF therapy. Immunoglobulin therapy also declined, from use in 10%-12% of patients before and at the start of anti-TNF treatment to just 1 of 41 patients (2%) after 12 months of TNF inhibitor therapy.

The median modified Disease Activity Score for skin involvement significantly improved over the course of 12 months of treatment with infliximab, decreasing from 4 to 1. That was also the case for Physician Global Assessment score, as well as muscle outcome measurements on the Childhood Myositis Assessment Scale (CMAS) and the 8-item Manual Muscle Testing (MMT8).

For the 31 patients in the study who had calcinosis, lesions improved (reduced in number and/or size) in 17 patients, including 8 with complete resolution of their lesions. In the other 14 patients, lesions remained stable in 3 (fewer than three lesions) and were widespread or did not improve in 4; the other 7 patients had insufficient data to determine outcomes.

Most patients with muscle involvement already had improved with steroids prior to using anti-TNF drugs. Thus, the improvement in CMAS and MMT8 scores on anti-TNF treatment was not very large, going from about 45 to 53 and from about 74 to 79, respectively.

The investigators did not examine treatment response in relation to muscle-specific antibodies, but Dr. Campanilho-Marques said that it is something they would like to do in the future.

The main indication for anti-TNF agents was active skin disease that had not responded to conventional treatment, noted Dr. Campanilho-Marques, who is also with the departments of rheumatology at the Santa Maria Hospital and the Instituto Português de Reumatologia, both in Lisbon.

For 16 patients who switched from infliximab to adalimumab, the changes in outcome measures were not statistically significant. The switches occurred at a median of 2.35 months after starting infliximab; 10 patients switched because of inefficacy, 4 because of adverse events, and 2 because of patient preference.

After 12 months of anti-TNF therapy, the median prednisolone dose declined from 6 mg to 2.5 mg, but the decline appeared to be driven by five patients who sharply decreased their dose. Seven patients successfully stopped anti-TNF therapy after improvement occurred, Dr. Campanilho-Marques said.

Serious adverse events occurred 12 times during the year-long study period, including nine allergic reactions and three hospitalizations because of infection. Another 19 mild-to-moderate adverse events took place, which involved 15 infections and three local site reactions and skin rash, which led five patients to discontinue the biologic.

Overall, adverse events occurred at a rate of 13.3/100 patient-years, including 5.2 serious events/100 patient-years. One patient died because of a small bowel perforation that was probably secondary to disease-related damage. There were no malignancies or tuberculosis cases.

In a video interview at the meeting, Dr. Campanilho-Marques discussed the study findings and their implications.

The researchers had no relevant disclosures.

jevans@frontlinemedcom.com

LONDON – Tumor necrosis factor–inhibitor treatment improved refractory skin disease in juvenile dermatomyositis patients in the largest observational study of its kind from the United Kingdom and Ireland Juvenile Dermatomyositis Research Group.

Muscle disease in the juvenile dermatomyositis (JDM) patients largely had already improved with conventional therapies prior to treatment with anti–tumor necrosis factor (TNF)-alpha agents, but it did improve further with anti-TNFs.

The effect of TNF inhibitors was most notable for those with skin calcinosis, lead author Dr. Raquel Campanilho-Marques reported at the European Congress of Rheumatology on behalf of her colleagues in the Juvenile Dermatomyositis Research Group.

Some evidence suggests that TNF-alpha might be involved in the pathogenesis of idiopathic inflammatory myopathies, particularly in more prolonged courses of JDM.

But there is limited prior evidence for the efficacy of TNF inhibitors in JDM patients, where small observational studies and case series have shown improved core-set measures of disease activity in patients treated with anti-TNF agents, noted Dr. Campanilho-Marques, a pediatric rheumatologist in the infection, inflammation and rheumatology section at the University College London Institute of Child Health and the Great Ormond Street Hospital for Children NHS Trust in London.

The 67 patients in the study involved those who were enrolled in the JDM Cohort and Biomarker Study, met Bohan and Peter criteria for JDM, and were on anti-TNF therapy at the time of analysis because of nonresponse to conventional therapy, active skin disease, calcinosis, or muscle weakness. They had at least 3 months of anti-TNF therapy and received either infliximab 6 mg/kg every 4 weeks (after a standard initial induction regimen) or adalimumab (Humira) 24 mg/m² every other week.

A majority of the patients in the study were female (n = 41) and white (n = 54), with a mean age at disease onset of about 5 years. At the time of first use of anti-TNF agents, the patients had a mean age of about 10 years and a mean disease duration of 3.2 years. Treatment with TNF inhibitors lasted for a mean of about 2.5 years.

Of the 67 patients, data were not analyzed for 4 patients; there was insufficient information for 1 patient, while 3 patients had allergic reactions to their anti-TNF therapy on the first or second infusion. The remaining 63 patients included 43 who received infliximab, 4 on adalimumab, and 16 who used both.

Prior to anti-TNF treatment, 52 of 53 patients (98%) were taking methotrexate, azathioprine, hydroxychloroquine, or a combination of those. That declined to 45 of 56 (80%) at the start of anti-TNF therapy and then increased to 44 of 49 (89%) after 12 months of using an anti-TNF agent.

The use of cyclophosphamide declined markedly, from 26 of 65 patients (40%) to 3 of 65 (5%) at the start of TNF inhibition, and then to none after 12 months of anti-TNF therapy. Immunoglobulin therapy also declined, from use in 10%-12% of patients before and at the start of anti-TNF treatment to just 1 of 41 patients (2%) after 12 months of TNF inhibitor therapy.

The median modified Disease Activity Score for skin involvement significantly improved over the course of 12 months of treatment with infliximab, decreasing from 4 to 1. That was also the case for Physician Global Assessment score, as well as muscle outcome measurements on the Childhood Myositis Assessment Scale (CMAS) and the 8-item Manual Muscle Testing (MMT8).

For the 31 patients in the study who had calcinosis, lesions improved (reduced in number and/or size) in 17 patients, including 8 with complete resolution of their lesions. In the other 14 patients, lesions remained stable in 3 (fewer than three lesions) and were widespread or did not improve in 4; the other 7 patients had insufficient data to determine outcomes.

Most patients with muscle involvement already had improved with steroids prior to using anti-TNF drugs. Thus, the improvement in CMAS and MMT8 scores on anti-TNF treatment was not very large, going from about 45 to 53 and from about 74 to 79, respectively.

The investigators did not examine treatment response in relation to muscle-specific antibodies, but Dr. Campanilho-Marques said that it is something they would like to do in the future.

The main indication for anti-TNF agents was active skin disease that had not responded to conventional treatment, noted Dr. Campanilho-Marques, who is also with the departments of rheumatology at the Santa Maria Hospital and the Instituto Português de Reumatologia, both in Lisbon.

For 16 patients who switched from infliximab to adalimumab, the changes in outcome measures were not statistically significant. The switches occurred at a median of 2.35 months after starting infliximab; 10 patients switched because of inefficacy, 4 because of adverse events, and 2 because of patient preference.

After 12 months of anti-TNF therapy, the median prednisolone dose declined from 6 mg to 2.5 mg, but the decline appeared to be driven by five patients who sharply decreased their dose. Seven patients successfully stopped anti-TNF therapy after improvement occurred, Dr. Campanilho-Marques said.

Serious adverse events occurred 12 times during the year-long study period, including nine allergic reactions and three hospitalizations because of infection. Another 19 mild-to-moderate adverse events took place, which involved 15 infections and three local site reactions and skin rash, which led five patients to discontinue the biologic.

Overall, adverse events occurred at a rate of 13.3/100 patient-years, including 5.2 serious events/100 patient-years. One patient died because of a small bowel perforation that was probably secondary to disease-related damage. There were no malignancies or tuberculosis cases.

In a video interview at the meeting, Dr. Campanilho-Marques discussed the study findings and their implications.

The researchers had no relevant disclosures.

jevans@frontlinemedcom.com

LONDON – One of the largest studies of pregnancy outcomes after bisphosphonate exposure has found no evidence for major teratogenic effects in women with inflammatory diseases and glucocorticoid-induced osteoporosis and women with bone diseases.

However, the investigators for the French case-control study did find higher rates of neonatal complications and spontaneous abortion among infants of mothers with systemic inflammatory diseases and bisphosphonate use, but the results could be the result of confounding because of the severity of underlying disease and exposure to other medications.

“I think if a women is worried about bisphosphonate exposure during pregnancy, this study can bring her some reassuring news,” although it does not necessarily mean that bisphosphonates are safe during pregnancy, first author Aurélien Sokal said in an interview at the European Congress of Rheumatology. He is a medical student at Beaujon Hospital, Clichy, France, but conducted the study with colleagues during his time in training in the rheumatology department at Paris-Sud University.

“Very little is known about the effect of bisphosphonates on pregnancy outcomes and fetal development,” Mr. Sokal said, and they are feared for possible teratogenic effects in pregnancy because of their long half-life in bone – where they can be released even 1 year after their administration – as well as their ability to cross the placenta and high affinity for high-turnover bones, such as those in a growing fetus. He also noted that abnormalities in bone length, low birth weights, and bone diseases have been observed in rats exposed to bisphosphonates during gestation.

The study compared 23 patients with inflammatory diseases and bisphosphonate exposure during pregnancy against 92 controls with inflammatory diseases but no exposure, and 16 with bone diseases and exposure to bisphosphonates against 64 healthy controls with no underlying disease or bisphosphonate use. The patients came from a database assembled by the French Reference Center of Teratogenic Agents (CRAT) in Paris that has collected information since 1975 on patients referred for any drug exposure during pregnancy and followed their care through the end of pregnancy. The 39 patients who were exposed to bisphosphonates took the drugs during 1987-2014 within the 6 weeks preceding (n = 6) or during pregnancy (n = 33). They had a mean age of 33 years.

Systemic inflammatory diseases

The systemic inflammatory diseases found in women in the study included systemic lupus erythematosus (SLE), rheumatoid arthritis, antiphospholipid syndrome, systemic vasculitis, and other diseases. Of the 23 cases with systemic inflammatory diseases, 16 took risedronate, 5 took alendronate, 1 took etidronate, and the bisphosphonate was unknown in 1. Bisphosphonate exposure occurred before pregnancy in 2, during the first trimester in 21, second trimester in 4, third trimester in 4, and in all trimesters in 1.

Other types of medications were used significantly more often by patients with systemic inflammatory diseases than by controls: steroids (78% vs. 47%), methotrexate (26% vs. 5%), colchicine (17% vs. 2%), proton pump inhibitors (22% vs. 5%), and reproductive hormones (17% vs. 2%). Controls took antimalarials significantly more often (50% vs. 22%).

Voluntary abortions occurred at a similar rate in both exposed and unexposed women (12% vs. 9%), whereas significantly more therapeutic pregnancy terminations occurred among women exposed to bisphosphonates (17% vs. 1%). Live births occurred in 94% of the remaining exposed pregnant women, compared with 80% of controls.

Newborns were delivered at a mean of 38 weeks in both cases and controls, and there were no differences in birth weight, length, or rate of congenital malformation (9% vs. 2%).

The two malformations in neonates from exposed women had an uncertain link to bisphosphonates. One involved a neonate with severe malformative syndrome and advanced bone maturation who had a mother with SLE and was exposed to multiple drugs, including mycophenolate mofetil. The other neonate had ductus arteriosus, inguinal hernia, and negative otoacoustic emission; the baby’s mother had Crohn’s disease but had not taken known teratogenic drugs.

Two neonatal malformations among control women involved one neonate with severe malformative syndrome who had a mother with SLE but who was without exposure to known teratogenic drugs, and another with convulsant encephalopathy whose mother had systemic sclerosis and took pentoxifylline, cisapride, dihydroergocryptine, and colchicine.

However, cases had a 25% rate of neonatal complications, compared with a significantly lower 5% in controls. No infants had hypocalcemia.

Bone diseases

The 16 women with bone diseases included 9 with osteoporosis, 3 with malignancy, and 4 with miscellaneous bone conditions. A total of 5 received intravenous bisphosphonates and 11 received oral drugs (9 alendronate, 2 other). Most received a bisphosphonate in the first trimester (9 patients), but also 4 received it before pregnancy and 3 in the second trimester. More pregnancy terminations (voluntary or therapeutic) occurred among women with bone disease when compared with controls (19% vs. 3%), but the difference was not statistically significant. However in the remaining patients, live births occurred significantly less often in cases than in controls (69% vs. 100%). Birth weight, length, gestational age at birth, and the rates of congenital malformation and neonatal complications were otherwise similar.

The results of the study fall in line with those from the two major previous controlled studies on 24 women (Reprod Toxicol. 2006 Nov;22:578-9) and 21 women (Bone. 2009 Mar;44:428-30). Another series of 10 bisphosphonate-exposed pregnancies described 2 malformations, including 1 ventricular septal defect and 1 kidney and cardiac malformation (Autoimmun Rev. 2010 Jun;9:547-52). Another single case report described a neonate with bilateral talipes equinovarus (J Bone Miner Res. 2004 Oct;19:1742-5). A literature review of 78 cases of bisphosphonate exposure during or prior to pregnancy reported three malformations (Hormones [Athens]. 2011 Oct-Dec;10:280-91).

The study is ongoing and continues to collect data on the follow-up of children, Mr. Sokal said.

The study had no specific funding, and none of the investigators had disclosures to report.

jevans@frontlinemedcom.com

LONDON – One of the largest studies of pregnancy outcomes after bisphosphonate exposure has found no evidence for major teratogenic effects in women with inflammatory diseases and glucocorticoid-induced osteoporosis and women with bone diseases.

However, the investigators for the French case-control study did find higher rates of neonatal complications and spontaneous abortion among infants of mothers with systemic inflammatory diseases and bisphosphonate use, but the results could be the result of confounding because of the severity of underlying disease and exposure to other medications.

“I think if a women is worried about bisphosphonate exposure during pregnancy, this study can bring her some reassuring news,” although it does not necessarily mean that bisphosphonates are safe during pregnancy, first author Aurélien Sokal said in an interview at the European Congress of Rheumatology. He is a medical student at Beaujon Hospital, Clichy, France, but conducted the study with colleagues during his time in training in the rheumatology department at Paris-Sud University.

“Very little is known about the effect of bisphosphonates on pregnancy outcomes and fetal development,” Mr. Sokal said, and they are feared for possible teratogenic effects in pregnancy because of their long half-life in bone – where they can be released even 1 year after their administration – as well as their ability to cross the placenta and high affinity for high-turnover bones, such as those in a growing fetus. He also noted that abnormalities in bone length, low birth weights, and bone diseases have been observed in rats exposed to bisphosphonates during gestation.

The study compared 23 patients with inflammatory diseases and bisphosphonate exposure during pregnancy against 92 controls with inflammatory diseases but no exposure, and 16 with bone diseases and exposure to bisphosphonates against 64 healthy controls with no underlying disease or bisphosphonate use. The patients came from a database assembled by the French Reference Center of Teratogenic Agents (CRAT) in Paris that has collected information since 1975 on patients referred for any drug exposure during pregnancy and followed their care through the end of pregnancy. The 39 patients who were exposed to bisphosphonates took the drugs during 1987-2014 within the 6 weeks preceding (n = 6) or during pregnancy (n = 33). They had a mean age of 33 years.

Systemic inflammatory diseases

The systemic inflammatory diseases found in women in the study included systemic lupus erythematosus (SLE), rheumatoid arthritis, antiphospholipid syndrome, systemic vasculitis, and other diseases. Of the 23 cases with systemic inflammatory diseases, 16 took risedronate, 5 took alendronate, 1 took etidronate, and the bisphosphonate was unknown in 1. Bisphosphonate exposure occurred before pregnancy in 2, during the first trimester in 21, second trimester in 4, third trimester in 4, and in all trimesters in 1.

Other types of medications were used significantly more often by patients with systemic inflammatory diseases than by controls: steroids (78% vs. 47%), methotrexate (26% vs. 5%), colchicine (17% vs. 2%), proton pump inhibitors (22% vs. 5%), and reproductive hormones (17% vs. 2%). Controls took antimalarials significantly more often (50% vs. 22%).

Voluntary abortions occurred at a similar rate in both exposed and unexposed women (12% vs. 9%), whereas significantly more therapeutic pregnancy terminations occurred among women exposed to bisphosphonates (17% vs. 1%). Live births occurred in 94% of the remaining exposed pregnant women, compared with 80% of controls.

Newborns were delivered at a mean of 38 weeks in both cases and controls, and there were no differences in birth weight, length, or rate of congenital malformation (9% vs. 2%).

The two malformations in neonates from exposed women had an uncertain link to bisphosphonates. One involved a neonate with severe malformative syndrome and advanced bone maturation who had a mother with SLE and was exposed to multiple drugs, including mycophenolate mofetil. The other neonate had ductus arteriosus, inguinal hernia, and negative otoacoustic emission; the baby’s mother had Crohn’s disease but had not taken known teratogenic drugs.

Two neonatal malformations among control women involved one neonate with severe malformative syndrome who had a mother with SLE but who was without exposure to known teratogenic drugs, and another with convulsant encephalopathy whose mother had systemic sclerosis and took pentoxifylline, cisapride, dihydroergocryptine, and colchicine.

However, cases had a 25% rate of neonatal complications, compared with a significantly lower 5% in controls. No infants had hypocalcemia.

Bone diseases

The 16 women with bone diseases included 9 with osteoporosis, 3 with malignancy, and 4 with miscellaneous bone conditions. A total of 5 received intravenous bisphosphonates and 11 received oral drugs (9 alendronate, 2 other). Most received a bisphosphonate in the first trimester (9 patients), but also 4 received it before pregnancy and 3 in the second trimester. More pregnancy terminations (voluntary or therapeutic) occurred among women with bone disease when compared with controls (19% vs. 3%), but the difference was not statistically significant. However in the remaining patients, live births occurred significantly less often in cases than in controls (69% vs. 100%). Birth weight, length, gestational age at birth, and the rates of congenital malformation and neonatal complications were otherwise similar.

The results of the study fall in line with those from the two major previous controlled studies on 24 women (Reprod Toxicol. 2006 Nov;22:578-9) and 21 women (Bone. 2009 Mar;44:428-30). Another series of 10 bisphosphonate-exposed pregnancies described 2 malformations, including 1 ventricular septal defect and 1 kidney and cardiac malformation (Autoimmun Rev. 2010 Jun;9:547-52). Another single case report described a neonate with bilateral talipes equinovarus (J Bone Miner Res. 2004 Oct;19:1742-5). A literature review of 78 cases of bisphosphonate exposure during or prior to pregnancy reported three malformations (Hormones [Athens]. 2011 Oct-Dec;10:280-91).

The study is ongoing and continues to collect data on the follow-up of children, Mr. Sokal said.

The study had no specific funding, and none of the investigators had disclosures to report.

jevans@frontlinemedcom.com

LONDON – One of the largest studies of pregnancy outcomes after bisphosphonate exposure has found no evidence for major teratogenic effects in women with inflammatory diseases and glucocorticoid-induced osteoporosis and women with bone diseases.

However, the investigators for the French case-control study did find higher rates of neonatal complications and spontaneous abortion among infants of mothers with systemic inflammatory diseases and bisphosphonate use, but the results could be the result of confounding because of the severity of underlying disease and exposure to other medications.

“I think if a women is worried about bisphosphonate exposure during pregnancy, this study can bring her some reassuring news,” although it does not necessarily mean that bisphosphonates are safe during pregnancy, first author Aurélien Sokal said in an interview at the European Congress of Rheumatology. He is a medical student at Beaujon Hospital, Clichy, France, but conducted the study with colleagues during his time in training in the rheumatology department at Paris-Sud University.

“Very little is known about the effect of bisphosphonates on pregnancy outcomes and fetal development,” Mr. Sokal said, and they are feared for possible teratogenic effects in pregnancy because of their long half-life in bone – where they can be released even 1 year after their administration – as well as their ability to cross the placenta and high affinity for high-turnover bones, such as those in a growing fetus. He also noted that abnormalities in bone length, low birth weights, and bone diseases have been observed in rats exposed to bisphosphonates during gestation.

The study compared 23 patients with inflammatory diseases and bisphosphonate exposure during pregnancy against 92 controls with inflammatory diseases but no exposure, and 16 with bone diseases and exposure to bisphosphonates against 64 healthy controls with no underlying disease or bisphosphonate use. The patients came from a database assembled by the French Reference Center of Teratogenic Agents (CRAT) in Paris that has collected information since 1975 on patients referred for any drug exposure during pregnancy and followed their care through the end of pregnancy. The 39 patients who were exposed to bisphosphonates took the drugs during 1987-2014 within the 6 weeks preceding (n = 6) or during pregnancy (n = 33). They had a mean age of 33 years.

Systemic inflammatory diseases

The systemic inflammatory diseases found in women in the study included systemic lupus erythematosus (SLE), rheumatoid arthritis, antiphospholipid syndrome, systemic vasculitis, and other diseases. Of the 23 cases with systemic inflammatory diseases, 16 took risedronate, 5 took alendronate, 1 took etidronate, and the bisphosphonate was unknown in 1. Bisphosphonate exposure occurred before pregnancy in 2, during the first trimester in 21, second trimester in 4, third trimester in 4, and in all trimesters in 1.

Other types of medications were used significantly more often by patients with systemic inflammatory diseases than by controls: steroids (78% vs. 47%), methotrexate (26% vs. 5%), colchicine (17% vs. 2%), proton pump inhibitors (22% vs. 5%), and reproductive hormones (17% vs. 2%). Controls took antimalarials significantly more often (50% vs. 22%).

Voluntary abortions occurred at a similar rate in both exposed and unexposed women (12% vs. 9%), whereas significantly more therapeutic pregnancy terminations occurred among women exposed to bisphosphonates (17% vs. 1%). Live births occurred in 94% of the remaining exposed pregnant women, compared with 80% of controls.

Newborns were delivered at a mean of 38 weeks in both cases and controls, and there were no differences in birth weight, length, or rate of congenital malformation (9% vs. 2%).

The two malformations in neonates from exposed women had an uncertain link to bisphosphonates. One involved a neonate with severe malformative syndrome and advanced bone maturation who had a mother with SLE and was exposed to multiple drugs, including mycophenolate mofetil. The other neonate had ductus arteriosus, inguinal hernia, and negative otoacoustic emission; the baby’s mother had Crohn’s disease but had not taken known teratogenic drugs.

Two neonatal malformations among control women involved one neonate with severe malformative syndrome who had a mother with SLE but who was without exposure to known teratogenic drugs, and another with convulsant encephalopathy whose mother had systemic sclerosis and took pentoxifylline, cisapride, dihydroergocryptine, and colchicine.

However, cases had a 25% rate of neonatal complications, compared with a significantly lower 5% in controls. No infants had hypocalcemia.

Bone diseases

The 16 women with bone diseases included 9 with osteoporosis, 3 with malignancy, and 4 with miscellaneous bone conditions. A total of 5 received intravenous bisphosphonates and 11 received oral drugs (9 alendronate, 2 other). Most received a bisphosphonate in the first trimester (9 patients), but also 4 received it before pregnancy and 3 in the second trimester. More pregnancy terminations (voluntary or therapeutic) occurred among women with bone disease when compared with controls (19% vs. 3%), but the difference was not statistically significant. However in the remaining patients, live births occurred significantly less often in cases than in controls (69% vs. 100%). Birth weight, length, gestational age at birth, and the rates of congenital malformation and neonatal complications were otherwise similar.

The results of the study fall in line with those from the two major previous controlled studies on 24 women (Reprod Toxicol. 2006 Nov;22:578-9) and 21 women (Bone. 2009 Mar;44:428-30). Another series of 10 bisphosphonate-exposed pregnancies described 2 malformations, including 1 ventricular septal defect and 1 kidney and cardiac malformation (Autoimmun Rev. 2010 Jun;9:547-52). Another single case report described a neonate with bilateral talipes equinovarus (J Bone Miner Res. 2004 Oct;19:1742-5). A literature review of 78 cases of bisphosphonate exposure during or prior to pregnancy reported three malformations (Hormones [Athens]. 2011 Oct-Dec;10:280-91).

The study is ongoing and continues to collect data on the follow-up of children, Mr. Sokal said.

The study had no specific funding, and none of the investigators had disclosures to report.

jevans@frontlinemedcom.com

LONDON – Depression is relatively common among teenagers newly diagnosed with juvenile idiopathic arthritis, and adolescents with both disorders appeared to have a less complete response to their treatment in a study of 102 patients.

Juvenile idiopathic arthritis (JIA) that first manifests when a patient is a teenager comes at a “vulnerable time” that can drive the development and worsening of depression, and depression can potentially exacerbate inflammation and also interfere with treatment compliance, Dr. John Ioannou said at the European Congress of Rheumatology,

Depression and JIA can produce a “vicious cycle in which depression exacerbates the disease and the disease exacerbates depression,” explained Dr. Ioannou, a rheumatologist at University College Hospital in London.

Although no study results have yet identified an effective intervention for depression identified in teenagers with newly diagnosed JIA, the immediate message from these new findings is that clinicians must assess the psychological health of adolescents with JIA both when they are first diagnosed as well as at subsequent visits, and if depression is found it requires some sort of intervention, Dr. Ioannou said in an interview.

He and his associates studied 102 patients from the United Kingdom, who were newly diagnosed with JIA and were 11-16 years old at baseline and enrolled in the Childhood Arthritis Prospective Study (CAPS), a nationwide cohort of patients with childhood-onset arthritis of various types. The average age of the group they studied was just under 13 years old, 57% were girls, 52% had persistent oligoarticular arthritis, 30% had polyarticular arthritis, and 18% had enthesitis-related arthritis. All patients underwent assessment at baseline for depression using the Mood and Feelings Questionnaire and 15 (15%) had a score that flagged them as having “probable” depression.

This depression prevalence is about three- to fourfold higher than for an otherwise healthy group of similarly aged adolescents, Dr. Ioannou said.

At baseline, the subgroup of teens with depression had a significantly higher number of inflamed joints, restricted joints, and also more overall pain and disability as measured on the Childhood Health Assessment Questionnaire.

The 102 teens with JIA underwent follow-up assessment 1-3 years later, after they had received ongoing treatment for their JIA. At follow-up, standard JIA treatment had largely resulted in resolution of joint inflammation and movement restriction among all patients, including those with depression at baseline. However the adolescents who had both JIA and depression at entry continued to have significantly more pain and disability at follow-up than did the nondepressed JIA patients, suggesting a link between depression and refractory pain and disability in JIA patients, the researchers reported.

“We need to ensure that psychological assessments and support are available to all young people diagnosed with JIA, and that this is fully integrated into routine care” for newly diagnosed JIA patients, Dr. Ioannou said. He had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – Depression is relatively common among teenagers newly diagnosed with juvenile idiopathic arthritis, and adolescents with both disorders appeared to have a less complete response to their treatment in a study of 102 patients.

Juvenile idiopathic arthritis (JIA) that first manifests when a patient is a teenager comes at a “vulnerable time” that can drive the development and worsening of depression, and depression can potentially exacerbate inflammation and also interfere with treatment compliance, Dr. John Ioannou said at the European Congress of Rheumatology,

Depression and JIA can produce a “vicious cycle in which depression exacerbates the disease and the disease exacerbates depression,” explained Dr. Ioannou, a rheumatologist at University College Hospital in London.

Although no study results have yet identified an effective intervention for depression identified in teenagers with newly diagnosed JIA, the immediate message from these new findings is that clinicians must assess the psychological health of adolescents with JIA both when they are first diagnosed as well as at subsequent visits, and if depression is found it requires some sort of intervention, Dr. Ioannou said in an interview.

He and his associates studied 102 patients from the United Kingdom, who were newly diagnosed with JIA and were 11-16 years old at baseline and enrolled in the Childhood Arthritis Prospective Study (CAPS), a nationwide cohort of patients with childhood-onset arthritis of various types. The average age of the group they studied was just under 13 years old, 57% were girls, 52% had persistent oligoarticular arthritis, 30% had polyarticular arthritis, and 18% had enthesitis-related arthritis. All patients underwent assessment at baseline for depression using the Mood and Feelings Questionnaire and 15 (15%) had a score that flagged them as having “probable” depression.

This depression prevalence is about three- to fourfold higher than for an otherwise healthy group of similarly aged adolescents, Dr. Ioannou said.

At baseline, the subgroup of teens with depression had a significantly higher number of inflamed joints, restricted joints, and also more overall pain and disability as measured on the Childhood Health Assessment Questionnaire.

The 102 teens with JIA underwent follow-up assessment 1-3 years later, after they had received ongoing treatment for their JIA. At follow-up, standard JIA treatment had largely resulted in resolution of joint inflammation and movement restriction among all patients, including those with depression at baseline. However the adolescents who had both JIA and depression at entry continued to have significantly more pain and disability at follow-up than did the nondepressed JIA patients, suggesting a link between depression and refractory pain and disability in JIA patients, the researchers reported.

“We need to ensure that psychological assessments and support are available to all young people diagnosed with JIA, and that this is fully integrated into routine care” for newly diagnosed JIA patients, Dr. Ioannou said. He had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – Depression is relatively common among teenagers newly diagnosed with juvenile idiopathic arthritis, and adolescents with both disorders appeared to have a less complete response to their treatment in a study of 102 patients.

Juvenile idiopathic arthritis (JIA) that first manifests when a patient is a teenager comes at a “vulnerable time” that can drive the development and worsening of depression, and depression can potentially exacerbate inflammation and also interfere with treatment compliance, Dr. John Ioannou said at the European Congress of Rheumatology,

Depression and JIA can produce a “vicious cycle in which depression exacerbates the disease and the disease exacerbates depression,” explained Dr. Ioannou, a rheumatologist at University College Hospital in London.

Although no study results have yet identified an effective intervention for depression identified in teenagers with newly diagnosed JIA, the immediate message from these new findings is that clinicians must assess the psychological health of adolescents with JIA both when they are first diagnosed as well as at subsequent visits, and if depression is found it requires some sort of intervention, Dr. Ioannou said in an interview.

He and his associates studied 102 patients from the United Kingdom, who were newly diagnosed with JIA and were 11-16 years old at baseline and enrolled in the Childhood Arthritis Prospective Study (CAPS), a nationwide cohort of patients with childhood-onset arthritis of various types. The average age of the group they studied was just under 13 years old, 57% were girls, 52% had persistent oligoarticular arthritis, 30% had polyarticular arthritis, and 18% had enthesitis-related arthritis. All patients underwent assessment at baseline for depression using the Mood and Feelings Questionnaire and 15 (15%) had a score that flagged them as having “probable” depression.

This depression prevalence is about three- to fourfold higher than for an otherwise healthy group of similarly aged adolescents, Dr. Ioannou said.

At baseline, the subgroup of teens with depression had a significantly higher number of inflamed joints, restricted joints, and also more overall pain and disability as measured on the Childhood Health Assessment Questionnaire.

The 102 teens with JIA underwent follow-up assessment 1-3 years later, after they had received ongoing treatment for their JIA. At follow-up, standard JIA treatment had largely resulted in resolution of joint inflammation and movement restriction among all patients, including those with depression at baseline. However the adolescents who had both JIA and depression at entry continued to have significantly more pain and disability at follow-up than did the nondepressed JIA patients, suggesting a link between depression and refractory pain and disability in JIA patients, the researchers reported.

“We need to ensure that psychological assessments and support are available to all young people diagnosed with JIA, and that this is fully integrated into routine care” for newly diagnosed JIA patients, Dr. Ioannou said. He had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – Subcutaneous methotrexate monotherapy may be more effective at helping recently diagnosed patients with rheumatoid arthritis avoid biologic therapy, compared with similar patients on oral methotrexate, based on an analysis of data collected from 483 Canadian patients in routine care and enrolled in a national registry.

“This is a signal for improved efficacy with subcutaneous methotrexate, compared with oral methotrexate,” said Dr. Stephanie Gottheil, who reported these results at the European Congress of Rheumatology.

“In general, as long as patients with rheumatoid arthritis are under good control without a biologic drug, that is preferable” to initiating biologic treatment, said Dr. Gottheil, a researcher at Western University in London, Ont. Delaying the start of biologic treatment saves money, avoids the increased risk of infection that comes with biologic treatment, and defers a patient’s immune response to a biologic drug that can eventually compromise the biologic’s efficacy, she said in an interview.

“These data did not come from a randomized trial and so are by no means conclusive, but this is a signal that supports other data that subcutaneous methotrexate potentially puts patients into remission faster, and we know that earlier remission predicts more sustained remission,” she said.

“The biggest barrier to subcutaneous administration of methotrexate is patient preference to not inject themselves, but results from some studies have also shown that subcutaneous methotrexate is better tolerated,” compared with oral dosing, she added.

The study used data collected in the Canadian Early Arthritis Cohort (CATCH), which enrolls patients at several centers throughout Canada diagnosed with rheumatoid arthritis for less than 12 months. Dr. Gottheil and her associates particularly focused on 1,189 early RA patients with moderate to severe disease activity enrolled in CATCH during 2007-2012 who received methotrexate and had never previously received a biologic drug. The study’s primary endpoint was time to first treatment with a biologic during 3 years of follow-up after entry into the registry.

The patients’ average age at enrollment was 56 years, more than two-thirds were women, and their average methotrexate dosage was 20 mg/week. The cohort included 483 patients on methotrexate monotherapy – with virtually equal numbers on oral methotrexate and subcutaneous methotrexate – and 706 on a regimen that combined methotrexate with one or more additional (nonbiologic) drugs at baseline. The patients in each of the methotrexate monotherapy subgroups, those on oral or subcutaneous therapy, were very similar in their demographic and clinical profiles.

The analysis showed no statistically significant difference in time to first biologic use between the patients on a combination regimen and those on oral methotrexate monotherapy.

But when the researchers compared the time to first biologic among those on subcutaneous methotrexate monotherapy with those on oral methotrexate monotherapy, the subcutaneous patients showed a statistically significant, 47% reduced rate of starting any biologic drug during follow-up in an analysis that controlled for age, sex, education, comorbidities, disease duration, baseline disease activity, baseline corticosteroid use, joint erosions at baseline, and score on the health-assessment questionnaire at baseline, Dr. Gottheil reported.

The analysis also revealed three other variables that significantly linked with a slower progression to biologic treatment: older age, no use of corticosteroid treatment at baseline, and lower disease activity at baseline.

The CATCH registry research program is sponsored by AbbVie, Amgen, Bristol-Myers Squibb, Hoffmann-La Roche, Janssen, Pfizer, and UCB. Dr. Gottheil had no relevant disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – Subcutaneous methotrexate monotherapy may be more effective at helping recently diagnosed patients with rheumatoid arthritis avoid biologic therapy, compared with similar patients on oral methotrexate, based on an analysis of data collected from 483 Canadian patients in routine care and enrolled in a national registry.

“This is a signal for improved efficacy with subcutaneous methotrexate, compared with oral methotrexate,” said Dr. Stephanie Gottheil, who reported these results at the European Congress of Rheumatology.

“In general, as long as patients with rheumatoid arthritis are under good control without a biologic drug, that is preferable” to initiating biologic treatment, said Dr. Gottheil, a researcher at Western University in London, Ont. Delaying the start of biologic treatment saves money, avoids the increased risk of infection that comes with biologic treatment, and defers a patient’s immune response to a biologic drug that can eventually compromise the biologic’s efficacy, she said in an interview.

“These data did not come from a randomized trial and so are by no means conclusive, but this is a signal that supports other data that subcutaneous methotrexate potentially puts patients into remission faster, and we know that earlier remission predicts more sustained remission,” she said.

“The biggest barrier to subcutaneous administration of methotrexate is patient preference to not inject themselves, but results from some studies have also shown that subcutaneous methotrexate is better tolerated,” compared with oral dosing, she added.

The study used data collected in the Canadian Early Arthritis Cohort (CATCH), which enrolls patients at several centers throughout Canada diagnosed with rheumatoid arthritis for less than 12 months. Dr. Gottheil and her associates particularly focused on 1,189 early RA patients with moderate to severe disease activity enrolled in CATCH during 2007-2012 who received methotrexate and had never previously received a biologic drug. The study’s primary endpoint was time to first treatment with a biologic during 3 years of follow-up after entry into the registry.

The patients’ average age at enrollment was 56 years, more than two-thirds were women, and their average methotrexate dosage was 20 mg/week. The cohort included 483 patients on methotrexate monotherapy – with virtually equal numbers on oral methotrexate and subcutaneous methotrexate – and 706 on a regimen that combined methotrexate with one or more additional (nonbiologic) drugs at baseline. The patients in each of the methotrexate monotherapy subgroups, those on oral or subcutaneous therapy, were very similar in their demographic and clinical profiles.

The analysis showed no statistically significant difference in time to first biologic use between the patients on a combination regimen and those on oral methotrexate monotherapy.

But when the researchers compared the time to first biologic among those on subcutaneous methotrexate monotherapy with those on oral methotrexate monotherapy, the subcutaneous patients showed a statistically significant, 47% reduced rate of starting any biologic drug during follow-up in an analysis that controlled for age, sex, education, comorbidities, disease duration, baseline disease activity, baseline corticosteroid use, joint erosions at baseline, and score on the health-assessment questionnaire at baseline, Dr. Gottheil reported.

The analysis also revealed three other variables that significantly linked with a slower progression to biologic treatment: older age, no use of corticosteroid treatment at baseline, and lower disease activity at baseline.

The CATCH registry research program is sponsored by AbbVie, Amgen, Bristol-Myers Squibb, Hoffmann-La Roche, Janssen, Pfizer, and UCB. Dr. Gottheil had no relevant disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – Subcutaneous methotrexate monotherapy may be more effective at helping recently diagnosed patients with rheumatoid arthritis avoid biologic therapy, compared with similar patients on oral methotrexate, based on an analysis of data collected from 483 Canadian patients in routine care and enrolled in a national registry.

“This is a signal for improved efficacy with subcutaneous methotrexate, compared with oral methotrexate,” said Dr. Stephanie Gottheil, who reported these results at the European Congress of Rheumatology.

“In general, as long as patients with rheumatoid arthritis are under good control without a biologic drug, that is preferable” to initiating biologic treatment, said Dr. Gottheil, a researcher at Western University in London, Ont. Delaying the start of biologic treatment saves money, avoids the increased risk of infection that comes with biologic treatment, and defers a patient’s immune response to a biologic drug that can eventually compromise the biologic’s efficacy, she said in an interview.

“These data did not come from a randomized trial and so are by no means conclusive, but this is a signal that supports other data that subcutaneous methotrexate potentially puts patients into remission faster, and we know that earlier remission predicts more sustained remission,” she said.

“The biggest barrier to subcutaneous administration of methotrexate is patient preference to not inject themselves, but results from some studies have also shown that subcutaneous methotrexate is better tolerated,” compared with oral dosing, she added.

The study used data collected in the Canadian Early Arthritis Cohort (CATCH), which enrolls patients at several centers throughout Canada diagnosed with rheumatoid arthritis for less than 12 months. Dr. Gottheil and her associates particularly focused on 1,189 early RA patients with moderate to severe disease activity enrolled in CATCH during 2007-2012 who received methotrexate and had never previously received a biologic drug. The study’s primary endpoint was time to first treatment with a biologic during 3 years of follow-up after entry into the registry.

The patients’ average age at enrollment was 56 years, more than two-thirds were women, and their average methotrexate dosage was 20 mg/week. The cohort included 483 patients on methotrexate monotherapy – with virtually equal numbers on oral methotrexate and subcutaneous methotrexate – and 706 on a regimen that combined methotrexate with one or more additional (nonbiologic) drugs at baseline. The patients in each of the methotrexate monotherapy subgroups, those on oral or subcutaneous therapy, were very similar in their demographic and clinical profiles.

The analysis showed no statistically significant difference in time to first biologic use between the patients on a combination regimen and those on oral methotrexate monotherapy.

But when the researchers compared the time to first biologic among those on subcutaneous methotrexate monotherapy with those on oral methotrexate monotherapy, the subcutaneous patients showed a statistically significant, 47% reduced rate of starting any biologic drug during follow-up in an analysis that controlled for age, sex, education, comorbidities, disease duration, baseline disease activity, baseline corticosteroid use, joint erosions at baseline, and score on the health-assessment questionnaire at baseline, Dr. Gottheil reported.

The analysis also revealed three other variables that significantly linked with a slower progression to biologic treatment: older age, no use of corticosteroid treatment at baseline, and lower disease activity at baseline.

The CATCH registry research program is sponsored by AbbVie, Amgen, Bristol-Myers Squibb, Hoffmann-La Roche, Janssen, Pfizer, and UCB. Dr. Gottheil had no relevant disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler