Long-Term Etanercept Use in Children With RA Appears Safe

Etanercept appears safe through 8 years of continuous use in children with polyarticular-course juvenile rheumatoid arthritis without any incidence of cancers or serious opportunistic infections.

That is the conclusion of a multicenter, randomized, controlled trial, later extended into an open-label study, looking at the long-term safety of the anti-tumor necrosis factor-α drug. “Etanercept [Enbrel] was the first of the anti-TNF agents tested in children with JRA, and thus we have the longest and most clinical experience with it,” said Dr. Daniel Lovell of the Cincinnati Children's Hospital Medical Center, in an interview.

Of 69 patients originally randomized into the trial, Dr. Lovell and Dr. Andreas Reiff and colleagues followed 58 into the open-label extension; all had taken at least one etanercept dose.

In the original trial, all patients initially received etanercept for 3 months. Those who responded were randomized to etanercept or placebo. Corticosteroids and anti-inflammatory drugs were allowed in both the randomized trial and the extension, but few patients were allowed to take methotrexate again, said Dr. Reiff, head of the division of rheumatology and rehabilitation at Children's Hospital Los Angeles. In the ongoing safety study, 42 of the original patients (61%) received at least 4 years of etanercept, and 16 (23%) received at least 8 continuous years of the drug. All used the recommended dosage for the subcutaneous injection formulation (0.4 mg/kg twice per week). Overall, 16 patients (23%) reported adverse events. Long-term use did not significantly increase the rate of adverse events. Between years 4 and 8 of follow-up, only one severe adverse event (pyelonephritis) occurred. No lupus, demyelinating disorders, tuberculosis, opportunistic infections, malignancy, or deaths were reported.

Three cases of varicella infection occurred in follow-up, according to Dr. Reiff. Although Dr. Lovell said etanercept had a good safety profile, he expressed caution about an increased risk of varicella in children on etanercept who lack protective antibodies to this virus.

Dr. Lovell recommended all children be tested for varicella antibodies (IgG) before etanercept treatment. Precautions should be taken to avoid exposing nonimmune children on etanercept to active varicella.

Even patients on immunosuppressive drugs who were vaccinated may not have a protective antibody level, said Dr. Reiff, who noted he serves as an adviser and speaker for Amgen Inc. and Wyeth, which comarket etanercept.

“There is definitely a possibility that varicella can be more severe on these drugs,” Dr. Reiff said in an interview. But since etanercept has a half-life of nearly 5 days, it takes 3–4 weeks before it is cleared from the body after stopping. “We watch these patients very carefully. We treat them for their chicken pox, and if we see that their course is aggressive or prolonged, we admit them for IV treatment.”

Dr. Lovell noted when parents vaccinate or revaccinate nonimmune children against varicella, initiation of etanercept is delayed by 3 months. Prophylactic acyclovir is needed in children on etanercept with known exposure to varicella.

Nonimmune children on etanercept should not be exposed to varicella because of increased susceptibility. DR. LOVELL

Etanercept appears safe through 8 years of continuous use in children with polyarticular-course juvenile rheumatoid arthritis without any incidence of cancers or serious opportunistic infections.

That is the conclusion of a multicenter, randomized, controlled trial, later extended into an open-label study, looking at the long-term safety of the anti-tumor necrosis factor-α drug. “Etanercept [Enbrel] was the first of the anti-TNF agents tested in children with JRA, and thus we have the longest and most clinical experience with it,” said Dr. Daniel Lovell of the Cincinnati Children's Hospital Medical Center, in an interview.

Of 69 patients originally randomized into the trial, Dr. Lovell and Dr. Andreas Reiff and colleagues followed 58 into the open-label extension; all had taken at least one etanercept dose.

In the original trial, all patients initially received etanercept for 3 months. Those who responded were randomized to etanercept or placebo. Corticosteroids and anti-inflammatory drugs were allowed in both the randomized trial and the extension, but few patients were allowed to take methotrexate again, said Dr. Reiff, head of the division of rheumatology and rehabilitation at Children's Hospital Los Angeles. In the ongoing safety study, 42 of the original patients (61%) received at least 4 years of etanercept, and 16 (23%) received at least 8 continuous years of the drug. All used the recommended dosage for the subcutaneous injection formulation (0.4 mg/kg twice per week). Overall, 16 patients (23%) reported adverse events. Long-term use did not significantly increase the rate of adverse events. Between years 4 and 8 of follow-up, only one severe adverse event (pyelonephritis) occurred. No lupus, demyelinating disorders, tuberculosis, opportunistic infections, malignancy, or deaths were reported.

Three cases of varicella infection occurred in follow-up, according to Dr. Reiff. Although Dr. Lovell said etanercept had a good safety profile, he expressed caution about an increased risk of varicella in children on etanercept who lack protective antibodies to this virus.

Dr. Lovell recommended all children be tested for varicella antibodies (IgG) before etanercept treatment. Precautions should be taken to avoid exposing nonimmune children on etanercept to active varicella.

Even patients on immunosuppressive drugs who were vaccinated may not have a protective antibody level, said Dr. Reiff, who noted he serves as an adviser and speaker for Amgen Inc. and Wyeth, which comarket etanercept.

“There is definitely a possibility that varicella can be more severe on these drugs,” Dr. Reiff said in an interview. But since etanercept has a half-life of nearly 5 days, it takes 3–4 weeks before it is cleared from the body after stopping. “We watch these patients very carefully. We treat them for their chicken pox, and if we see that their course is aggressive or prolonged, we admit them for IV treatment.”

Dr. Lovell noted when parents vaccinate or revaccinate nonimmune children against varicella, initiation of etanercept is delayed by 3 months. Prophylactic acyclovir is needed in children on etanercept with known exposure to varicella.

Nonimmune children on etanercept should not be exposed to varicella because of increased susceptibility. DR. LOVELL

Etanercept appears safe through 8 years of continuous use in children with polyarticular-course juvenile rheumatoid arthritis without any incidence of cancers or serious opportunistic infections.

That is the conclusion of a multicenter, randomized, controlled trial, later extended into an open-label study, looking at the long-term safety of the anti-tumor necrosis factor-α drug. “Etanercept [Enbrel] was the first of the anti-TNF agents tested in children with JRA, and thus we have the longest and most clinical experience with it,” said Dr. Daniel Lovell of the Cincinnati Children's Hospital Medical Center, in an interview.

Of 69 patients originally randomized into the trial, Dr. Lovell and Dr. Andreas Reiff and colleagues followed 58 into the open-label extension; all had taken at least one etanercept dose.

In the original trial, all patients initially received etanercept for 3 months. Those who responded were randomized to etanercept or placebo. Corticosteroids and anti-inflammatory drugs were allowed in both the randomized trial and the extension, but few patients were allowed to take methotrexate again, said Dr. Reiff, head of the division of rheumatology and rehabilitation at Children's Hospital Los Angeles. In the ongoing safety study, 42 of the original patients (61%) received at least 4 years of etanercept, and 16 (23%) received at least 8 continuous years of the drug. All used the recommended dosage for the subcutaneous injection formulation (0.4 mg/kg twice per week). Overall, 16 patients (23%) reported adverse events. Long-term use did not significantly increase the rate of adverse events. Between years 4 and 8 of follow-up, only one severe adverse event (pyelonephritis) occurred. No lupus, demyelinating disorders, tuberculosis, opportunistic infections, malignancy, or deaths were reported.

Three cases of varicella infection occurred in follow-up, according to Dr. Reiff. Although Dr. Lovell said etanercept had a good safety profile, he expressed caution about an increased risk of varicella in children on etanercept who lack protective antibodies to this virus.

Dr. Lovell recommended all children be tested for varicella antibodies (IgG) before etanercept treatment. Precautions should be taken to avoid exposing nonimmune children on etanercept to active varicella.

Even patients on immunosuppressive drugs who were vaccinated may not have a protective antibody level, said Dr. Reiff, who noted he serves as an adviser and speaker for Amgen Inc. and Wyeth, which comarket etanercept.

“There is definitely a possibility that varicella can be more severe on these drugs,” Dr. Reiff said in an interview. But since etanercept has a half-life of nearly 5 days, it takes 3–4 weeks before it is cleared from the body after stopping. “We watch these patients very carefully. We treat them for their chicken pox, and if we see that their course is aggressive or prolonged, we admit them for IV treatment.”

Dr. Lovell noted when parents vaccinate or revaccinate nonimmune children against varicella, initiation of etanercept is delayed by 3 months. Prophylactic acyclovir is needed in children on etanercept with known exposure to varicella.

Nonimmune children on etanercept should not be exposed to varicella because of increased susceptibility. DR. LOVELL