NYU Annual Pediatric Rheumatology Update

NEW YORK – A timely diagnosis of a child presenting with a limp is essential because of the wide variety of possible causes, including benign disease such as a mild injury, a chronic disabling disease such as juvenile idiopathic arthritis, or a life-threatening infection or malignancy. It may be up to the pediatric rheumatologist to discriminate among the possible causes of the limp, distinguish pathology from normal, call for the proper consults and tests, as well as manage any identified rheumatic diseases, Dr. Philip J. Kahn said at a meeting sponsored by New York University.

By the time the rheumatologist sees a child presenting with a limp, the child may have already seen a pediatrician, emergency physician, and even an orthopedist.

Dr. Kahn, a pediatric rheumatologist at New York University Langone Medical Center, said he is concerned when a limp is associated, with fever, rash, weakness, joint swelling, and bearing weight. "If the child has fever and severe musculoskeletal pain, even with a normal platelet count, you should think of malignancy."

One of the first questions to ask is "Does it hurt?" A child with an antalgic gait (a gait that has adapted to counter or avoid pain) may refuse to bear weight. In this case, inquire whether the child has walked into the office or hospital or had to be carried. Nonpainful limp is usually insidious in onset, Dr. Kahn said, and may be suggestive of a rheumatic condition, weakness, stiffness, or deformity. Question the child as well as the parent, even though young patients may not be able to verbalize pain, and older children may deny it.

Other important clues about the limp are the time of onset; association with any known event, injury, or time of day; duration of pain (constant pain is suggestive of infection or malignancy); and location of pain (focal or diffuse, bone or joint). The physician should inquire about fever, anorexia, weight loss, or night sweats, which should raise suspicion of malignancy, infection, or rheumatologic problems. If fever is present, determine whether it is continuous, nocturnal, or quotidian (appearing daily, often at the same time). Delayed motor development or regression of achieved milestones, such as when a child who has walked independently suddenly asks to be carried around, may suggest neurologic or rheumatic disease. While a child may deny joint stiffness, a parent may notice the child cannot move easily in the morning or after long car rides or sitting in a classroom (Best Pract. Res. Clin. Rheumatol. 2009;23:625-42). Age is also an important consideration when evaluating the child with a limp.

Because observation is key during the physical exam, Dr. Kahn said to allow time to watch the child move around freely, looking for aberrations in gait. The child should be unclothed, barefoot, and observed during motion and at rest. While palpating the legs, be alert to areas of tenderness, suggestive of contusion, fracture, malignancy, or infection. Joints should be inspected for effusion, warmth, and tenderness, keeping in mind the possibility of referred pain from the hip or back, and range of motion should be assessed. He noted that the Childhood Myositis Assessment Scale (CMAS) can be helpful for assessing weakness (Arthritis Care Res. 2011;63 [Suppl. 11]:S118-57).

"Laboratory and radiographic evaluation will depend on what is discovered from the history and physical," Dr. Kahn said. Initial work-up may include complete/full blood count with differential, routine serum chemistries (including creatinine and liver and muscle enzymes), acute phase reactants (erythrocyte sedimentation rate [ESR] and C-reactive protein), and urinalysis. Testing synovial fluid for white blood cells is appropriate if septic arthritis is suspected, although the test is not highly sensitive or specific. "Elevated ESR in the presence of a normal or low platelet count in a child with musculoskeletal pain, especially if the child is febrile, is concerning for malignancy," he said. Dr. Kahn is somewhat reluctant to order antinuclear antibody testing unless there is a compelling reason because he says parents often panic upon hearing that.

The American College of Radiology in 2012 issued Appropriateness Criteria for evaluating limping children aged 0 to 5 years and selecting an imaging study (J. Am. Coll. Radiol. 2012;9:545-53). The criteria are categorized according to three variants: trauma; no trauma and no sign of infection; or possible presence of infection. With possible infection, imaging protocols are described for patients with localized pain to the hip, localized pain to the nonhip and lower extremity, and nonlocalized pain. Each imaging modality is given an appropriateness rating and an assessment of the relative radiation level. In brief, the criteria suggest that localized radiographs or tibial radiographs are appropriate following trauma. With an atraumatic and noninfectious history, hip ultrasound may be the initial study of choice, followed by radiography if the ultrasound is negative. Ultrasound of the hip allows a quick and accurate diagnosis of joint effusion, and aspiration can differentiate septic arthritis – an emergency situation – from transient synovitis. When long-term infection is suspected, MRI is the study of choice to demonstrate osteomyelitis or soft-tissue abscess.

Dr. Kahn presented a series of case studies, illustrating some key differentiating features that can help make the diagnosis:

• Case 1: A 2.5-year-old girl is carried into the emergency department (ED) after limping for 2 days. She began limping after coming home from the playground. She has no fever, rash, or constitutional features, and appears happy and smiling. Her hips, knees, ankles, and feet are not swollen, warm, or tender. There is tenderness at a point along her right tibia. The diagnosis is toddler’s fracture.

• Case 2: A 2.5-year-old girl is carried into the ED after limping for 2 days. There is no history of trauma, but the pain has become so severe that it awakens her at night. She refuses to walk, has constant pain not controlled by NSAIDS, and is cranky, febrile, tachycardic, and appears sick. She holds her right hip in a FABER (flexion, abduction, and external rotation) position. Her labs are C-reactive protein of 100 mg/L and a white blood cell of 30,000. The diagnosis is septic arthritis, with immediate referral to an orthopedist.

• Case 3: A 2.5-year-old girl walks into the ED after limping for 3 months. She denies having any pain, and her mother says she is lazy. She no longer alternates her feet when ascending steps and has fallen once when descending the stairs. When you examine her, she shows edematous and purple eyelids and a rash over her knuckles, as well as proximal weakness. Her muscle enzymes are elevated. The diagnosis is juvenile dermatomyositis.

• Case 4: A 2.5-year-old girl walks into the ED after limping for 3 months. An active girl, she fell off a slide the previous day and developed a large effusion after scraping her knee. She is smiling and running around the ED. She has no fever, malaise, joint swelling, or nocturnal wakening, although her mother says her limp is worse in the morning but lessens after breakfast. Inflammatory markers are normal and rheumatoid factor is absent. The diagnosis is oligoarticular juvenile idiopathic arthritis.

• Case 5: A 2.5-year-old girl walks into the ED after complaining that her legs have bothered her for 3 months. At night, she complains of lower leg pain in both legs and awakes sometimes at night from the pain but seems fine in the morning. No erythema or swollen joints are seen. She has been taken three times to the ED over the last few weeks, but blood tests and x-rays are said to be normal. Fever, rash, or constitutional symptoms are absent. The diagnosis is growing pains.

Dr. Kahn reported having no relevant financial disclosures.

NEW YORK – A timely diagnosis of a child presenting with a limp is essential because of the wide variety of possible causes, including benign disease such as a mild injury, a chronic disabling disease such as juvenile idiopathic arthritis, or a life-threatening infection or malignancy. It may be up to the pediatric rheumatologist to discriminate among the possible causes of the limp, distinguish pathology from normal, call for the proper consults and tests, as well as manage any identified rheumatic diseases, Dr. Philip J. Kahn said at a meeting sponsored by New York University.

By the time the rheumatologist sees a child presenting with a limp, the child may have already seen a pediatrician, emergency physician, and even an orthopedist.

Dr. Kahn, a pediatric rheumatologist at New York University Langone Medical Center, said he is concerned when a limp is associated, with fever, rash, weakness, joint swelling, and bearing weight. "If the child has fever and severe musculoskeletal pain, even with a normal platelet count, you should think of malignancy."

One of the first questions to ask is "Does it hurt?" A child with an antalgic gait (a gait that has adapted to counter or avoid pain) may refuse to bear weight. In this case, inquire whether the child has walked into the office or hospital or had to be carried. Nonpainful limp is usually insidious in onset, Dr. Kahn said, and may be suggestive of a rheumatic condition, weakness, stiffness, or deformity. Question the child as well as the parent, even though young patients may not be able to verbalize pain, and older children may deny it.

Other important clues about the limp are the time of onset; association with any known event, injury, or time of day; duration of pain (constant pain is suggestive of infection or malignancy); and location of pain (focal or diffuse, bone or joint). The physician should inquire about fever, anorexia, weight loss, or night sweats, which should raise suspicion of malignancy, infection, or rheumatologic problems. If fever is present, determine whether it is continuous, nocturnal, or quotidian (appearing daily, often at the same time). Delayed motor development or regression of achieved milestones, such as when a child who has walked independently suddenly asks to be carried around, may suggest neurologic or rheumatic disease. While a child may deny joint stiffness, a parent may notice the child cannot move easily in the morning or after long car rides or sitting in a classroom (Best Pract. Res. Clin. Rheumatol. 2009;23:625-42). Age is also an important consideration when evaluating the child with a limp.

Because observation is key during the physical exam, Dr. Kahn said to allow time to watch the child move around freely, looking for aberrations in gait. The child should be unclothed, barefoot, and observed during motion and at rest. While palpating the legs, be alert to areas of tenderness, suggestive of contusion, fracture, malignancy, or infection. Joints should be inspected for effusion, warmth, and tenderness, keeping in mind the possibility of referred pain from the hip or back, and range of motion should be assessed. He noted that the Childhood Myositis Assessment Scale (CMAS) can be helpful for assessing weakness (Arthritis Care Res. 2011;63 [Suppl. 11]:S118-57).

"Laboratory and radiographic evaluation will depend on what is discovered from the history and physical," Dr. Kahn said. Initial work-up may include complete/full blood count with differential, routine serum chemistries (including creatinine and liver and muscle enzymes), acute phase reactants (erythrocyte sedimentation rate [ESR] and C-reactive protein), and urinalysis. Testing synovial fluid for white blood cells is appropriate if septic arthritis is suspected, although the test is not highly sensitive or specific. "Elevated ESR in the presence of a normal or low platelet count in a child with musculoskeletal pain, especially if the child is febrile, is concerning for malignancy," he said. Dr. Kahn is somewhat reluctant to order antinuclear antibody testing unless there is a compelling reason because he says parents often panic upon hearing that.

The American College of Radiology in 2012 issued Appropriateness Criteria for evaluating limping children aged 0 to 5 years and selecting an imaging study (J. Am. Coll. Radiol. 2012;9:545-53). The criteria are categorized according to three variants: trauma; no trauma and no sign of infection; or possible presence of infection. With possible infection, imaging protocols are described for patients with localized pain to the hip, localized pain to the nonhip and lower extremity, and nonlocalized pain. Each imaging modality is given an appropriateness rating and an assessment of the relative radiation level. In brief, the criteria suggest that localized radiographs or tibial radiographs are appropriate following trauma. With an atraumatic and noninfectious history, hip ultrasound may be the initial study of choice, followed by radiography if the ultrasound is negative. Ultrasound of the hip allows a quick and accurate diagnosis of joint effusion, and aspiration can differentiate septic arthritis – an emergency situation – from transient synovitis. When long-term infection is suspected, MRI is the study of choice to demonstrate osteomyelitis or soft-tissue abscess.

Dr. Kahn presented a series of case studies, illustrating some key differentiating features that can help make the diagnosis:

• Case 1: A 2.5-year-old girl is carried into the emergency department (ED) after limping for 2 days. She began limping after coming home from the playground. She has no fever, rash, or constitutional features, and appears happy and smiling. Her hips, knees, ankles, and feet are not swollen, warm, or tender. There is tenderness at a point along her right tibia. The diagnosis is toddler’s fracture.

• Case 2: A 2.5-year-old girl is carried into the ED after limping for 2 days. There is no history of trauma, but the pain has become so severe that it awakens her at night. She refuses to walk, has constant pain not controlled by NSAIDS, and is cranky, febrile, tachycardic, and appears sick. She holds her right hip in a FABER (flexion, abduction, and external rotation) position. Her labs are C-reactive protein of 100 mg/L and a white blood cell of 30,000. The diagnosis is septic arthritis, with immediate referral to an orthopedist.

• Case 3: A 2.5-year-old girl walks into the ED after limping for 3 months. She denies having any pain, and her mother says she is lazy. She no longer alternates her feet when ascending steps and has fallen once when descending the stairs. When you examine her, she shows edematous and purple eyelids and a rash over her knuckles, as well as proximal weakness. Her muscle enzymes are elevated. The diagnosis is juvenile dermatomyositis.

• Case 4: A 2.5-year-old girl walks into the ED after limping for 3 months. An active girl, she fell off a slide the previous day and developed a large effusion after scraping her knee. She is smiling and running around the ED. She has no fever, malaise, joint swelling, or nocturnal wakening, although her mother says her limp is worse in the morning but lessens after breakfast. Inflammatory markers are normal and rheumatoid factor is absent. The diagnosis is oligoarticular juvenile idiopathic arthritis.

• Case 5: A 2.5-year-old girl walks into the ED after complaining that her legs have bothered her for 3 months. At night, she complains of lower leg pain in both legs and awakes sometimes at night from the pain but seems fine in the morning. No erythema or swollen joints are seen. She has been taken three times to the ED over the last few weeks, but blood tests and x-rays are said to be normal. Fever, rash, or constitutional symptoms are absent. The diagnosis is growing pains.

Dr. Kahn reported having no relevant financial disclosures.

NEW YORK – A timely diagnosis of a child presenting with a limp is essential because of the wide variety of possible causes, including benign disease such as a mild injury, a chronic disabling disease such as juvenile idiopathic arthritis, or a life-threatening infection or malignancy. It may be up to the pediatric rheumatologist to discriminate among the possible causes of the limp, distinguish pathology from normal, call for the proper consults and tests, as well as manage any identified rheumatic diseases, Dr. Philip J. Kahn said at a meeting sponsored by New York University.

By the time the rheumatologist sees a child presenting with a limp, the child may have already seen a pediatrician, emergency physician, and even an orthopedist.

Dr. Kahn, a pediatric rheumatologist at New York University Langone Medical Center, said he is concerned when a limp is associated, with fever, rash, weakness, joint swelling, and bearing weight. "If the child has fever and severe musculoskeletal pain, even with a normal platelet count, you should think of malignancy."

One of the first questions to ask is "Does it hurt?" A child with an antalgic gait (a gait that has adapted to counter or avoid pain) may refuse to bear weight. In this case, inquire whether the child has walked into the office or hospital or had to be carried. Nonpainful limp is usually insidious in onset, Dr. Kahn said, and may be suggestive of a rheumatic condition, weakness, stiffness, or deformity. Question the child as well as the parent, even though young patients may not be able to verbalize pain, and older children may deny it.

Other important clues about the limp are the time of onset; association with any known event, injury, or time of day; duration of pain (constant pain is suggestive of infection or malignancy); and location of pain (focal or diffuse, bone or joint). The physician should inquire about fever, anorexia, weight loss, or night sweats, which should raise suspicion of malignancy, infection, or rheumatologic problems. If fever is present, determine whether it is continuous, nocturnal, or quotidian (appearing daily, often at the same time). Delayed motor development or regression of achieved milestones, such as when a child who has walked independently suddenly asks to be carried around, may suggest neurologic or rheumatic disease. While a child may deny joint stiffness, a parent may notice the child cannot move easily in the morning or after long car rides or sitting in a classroom (Best Pract. Res. Clin. Rheumatol. 2009;23:625-42). Age is also an important consideration when evaluating the child with a limp.

Because observation is key during the physical exam, Dr. Kahn said to allow time to watch the child move around freely, looking for aberrations in gait. The child should be unclothed, barefoot, and observed during motion and at rest. While palpating the legs, be alert to areas of tenderness, suggestive of contusion, fracture, malignancy, or infection. Joints should be inspected for effusion, warmth, and tenderness, keeping in mind the possibility of referred pain from the hip or back, and range of motion should be assessed. He noted that the Childhood Myositis Assessment Scale (CMAS) can be helpful for assessing weakness (Arthritis Care Res. 2011;63 [Suppl. 11]:S118-57).

"Laboratory and radiographic evaluation will depend on what is discovered from the history and physical," Dr. Kahn said. Initial work-up may include complete/full blood count with differential, routine serum chemistries (including creatinine and liver and muscle enzymes), acute phase reactants (erythrocyte sedimentation rate [ESR] and C-reactive protein), and urinalysis. Testing synovial fluid for white blood cells is appropriate if septic arthritis is suspected, although the test is not highly sensitive or specific. "Elevated ESR in the presence of a normal or low platelet count in a child with musculoskeletal pain, especially if the child is febrile, is concerning for malignancy," he said. Dr. Kahn is somewhat reluctant to order antinuclear antibody testing unless there is a compelling reason because he says parents often panic upon hearing that.

The American College of Radiology in 2012 issued Appropriateness Criteria for evaluating limping children aged 0 to 5 years and selecting an imaging study (J. Am. Coll. Radiol. 2012;9:545-53). The criteria are categorized according to three variants: trauma; no trauma and no sign of infection; or possible presence of infection. With possible infection, imaging protocols are described for patients with localized pain to the hip, localized pain to the nonhip and lower extremity, and nonlocalized pain. Each imaging modality is given an appropriateness rating and an assessment of the relative radiation level. In brief, the criteria suggest that localized radiographs or tibial radiographs are appropriate following trauma. With an atraumatic and noninfectious history, hip ultrasound may be the initial study of choice, followed by radiography if the ultrasound is negative. Ultrasound of the hip allows a quick and accurate diagnosis of joint effusion, and aspiration can differentiate septic arthritis – an emergency situation – from transient synovitis. When long-term infection is suspected, MRI is the study of choice to demonstrate osteomyelitis or soft-tissue abscess.

Dr. Kahn presented a series of case studies, illustrating some key differentiating features that can help make the diagnosis:

• Case 1: A 2.5-year-old girl is carried into the emergency department (ED) after limping for 2 days. She began limping after coming home from the playground. She has no fever, rash, or constitutional features, and appears happy and smiling. Her hips, knees, ankles, and feet are not swollen, warm, or tender. There is tenderness at a point along her right tibia. The diagnosis is toddler’s fracture.

• Case 2: A 2.5-year-old girl is carried into the ED after limping for 2 days. There is no history of trauma, but the pain has become so severe that it awakens her at night. She refuses to walk, has constant pain not controlled by NSAIDS, and is cranky, febrile, tachycardic, and appears sick. She holds her right hip in a FABER (flexion, abduction, and external rotation) position. Her labs are C-reactive protein of 100 mg/L and a white blood cell of 30,000. The diagnosis is septic arthritis, with immediate referral to an orthopedist.

• Case 3: A 2.5-year-old girl walks into the ED after limping for 3 months. She denies having any pain, and her mother says she is lazy. She no longer alternates her feet when ascending steps and has fallen once when descending the stairs. When you examine her, she shows edematous and purple eyelids and a rash over her knuckles, as well as proximal weakness. Her muscle enzymes are elevated. The diagnosis is juvenile dermatomyositis.

• Case 4: A 2.5-year-old girl walks into the ED after limping for 3 months. An active girl, she fell off a slide the previous day and developed a large effusion after scraping her knee. She is smiling and running around the ED. She has no fever, malaise, joint swelling, or nocturnal wakening, although her mother says her limp is worse in the morning but lessens after breakfast. Inflammatory markers are normal and rheumatoid factor is absent. The diagnosis is oligoarticular juvenile idiopathic arthritis.

• Case 5: A 2.5-year-old girl walks into the ED after complaining that her legs have bothered her for 3 months. At night, she complains of lower leg pain in both legs and awakes sometimes at night from the pain but seems fine in the morning. No erythema or swollen joints are seen. She has been taken three times to the ED over the last few weeks, but blood tests and x-rays are said to be normal. Fever, rash, or constitutional symptoms are absent. The diagnosis is growing pains.

Dr. Kahn reported having no relevant financial disclosures.

NEW YORK – Tailoring the frequency of vision screening for children with juvenile idiopathic arthritis is an important step to getting uveitis symptoms treated effectively before permanent morbidity occurs, according to Dr. Sanjay R. Kedhar.

"We know that children with JIA [juvenile idiopathic arthritis] who have chronic inflammation of the eye have a threefold increase in the risk of blindness. We also know that immunosuppressive therapy reduces the risk of blindness by 60%. I believe that physicians should feel the time pressure to identify uveitis in children and treat them aggressively to preserve vision and reduce morbidity," said Dr. Kedhar, an ophthalmologist at The New York (N.Y.) Eye and Ear Infirmary and associate professor of ophthalmology at New York Medical College in Valhalla, N.Y. Uveitis-associated morbidity includes cataracts, glaucoma, band keratopathy, phthisis bulbi, and vision loss.

Uveitis is the third most common cause of blindness in children, and JIA-associated uveitis is the most common cause of uveitis in children. About one in four children with JIA uveitis presents with blindness. Early detection, awareness of risk factors, and prompt and effective treatment can slow or prevent vision loss in children with JIA-associated uveitis, he said at the meeting, sponsored by New York University.

Uveitis associated with JIA most commonly affects the anterior portions of the eye, between the cornea and iris. Symptoms of anterior uveitis include blurred vision, pain, redness, photophobia, floaters, flashing lights, and distorted vision (metamorphopsia). The problem is that symptoms may be absent in children or, alternatively, children may not be able to verbalize what they see. "By the time symptoms are detected in school screening, it may be too late," Dr. Kedhar said.

That is why it is important to make sure children with JIA have regular ophthalmologic examinations as recommended by the American Academy of Pediatrics (Pediatrics 2006;117:1843-5). Screening frequency depends upon the presence of risk factors, such as type of arthritis (oligoarticular), age at onset, antinuclear antibody (ANA) seropositivity, and RF seronegativity. Children with JIA who have oligoarticular and polyarticular joint involvement and who are ANA positive and RF negative generally are at highest risk of developing uveitis, with 33%-70% affected.

"These are the kids we have to worry about the most," Dr. Kedhar said. If the joint symptoms appear before 7 years of age, the children should be seen every 3-4 months. Those children who have oligoarticular and polyarticular joint involvement beginning before age 7 but are ANA negative are considered at intermediate risk and should be seen every 6 months. Those who have a systemic onset of disease require screening every 12 months, reflecting the low risk of uveitis in this group.

Other risk factors for JIA-associated uveitis vision loss include female sex, anterior chamber flare seen on first exam, and abnormal intraocular pressure. The Systemic Immunosuppressive Therapy for Eye Diseases Study, a multicenter, retrospective cohort study of 327 patients with JIA-associated uveitis, showed that posterior synechiae, active uveitis, and intraocular surgery were associated with worse visual acuity outcomes (Ophthalmology 2013;120:186-92).

Another predictor of poor visual outcome is the onset of ocular symptoms before or soon after arthritis symptoms. Generally, having one ocular complication increases the risk of developing another.

Dr. Kedhar strongly suggested having an ophthalmologist be a part of the JIA patient’s medical team, along with the pediatrician and pediatric rheumatologist. A characteristic sign of anterior uveitis is an abnormal, irregular pupil. Ciliary flush is often not present in cases of JIA. In the acute setting, the red reflex may be diminished in the uveitis-affected eye. Keratic precipitates are white blood cells that accumulate on the posterior corneal surface and may indicate long-standing inflammation. Flare is another classic finding, and can be attributed to protein leakage into the aqueous humor. "In some studies, flare is used to monitor response of uveitis to treatment," Dr. Kedhar said. Uveitis is not typically associated with discharge or itching.

While topical corticosteroids are considered the first line of treatment, their use generated quite a bit of discussion from audience members. One of the main concerns is the conundrum that cataracts and glaucoma can occur because of uncontrolled inflammation associated with uveitis or as side effects of topical corticosteroids. Dr. Kedhar said that in his practice, he tries to limit the chronic use of corticosteroid drops to four times a day or less, generally switching patients to immunomodulatory therapy if they are corticosteroid dependent. He says that side effects are related to cumulative dose. He acknowledges that some ophthalmologists avoid topical steroids altogether but he believes they can be used safely for limited times. Because of greater concern for systemic side effects in children, systemic corticosteroids are used for only the short term.

Immunosuppressive therapy has been shown to reduce the risk of blindness in the better eye by 60% (Am. J. Ophthalmol. 2007;143:840-6). The most widely used immunomodulatory agent for children is methotrexate. Anti–TNF-alpha agents may be used in patients who fail to respond to conventional immunosuppressive therapy. A recent study in Italy that compared infliximab and adalimumab for refractory uveitis in 91 patients with JIA found higher remission rates after 1 year with adalimumab (67% vs. 43%, P = .025) (J. Rheumatol. 2013;40:74-9). Adalimumab has the convenience of subcutaneous administration, stable serum concentrations, and a more favorable safety profile, whereas infliximab offers fast onset and potent anti-inflammatory effects (J. Ophthalmic Vis. Res. 2011;6:259-69).

The anti–TNF-alpha agent golimumab was found to be helpful in three cases of refractory JIA uveitis. Golimumab offers the advantage of subcutaneous once-a-month dosing and avoids the expense and time commitment of outpatient infliximab infusions, Dr. Kedhar noted (J. Ophthalmic. Inflamm. Infect. 2012;2:231-3).

"Uveitis may require higher doses of immunomodulatory agents than those used for rheumatologic manifestations," Dr. Kedhar said. "The activity of uveitis associated with JIA may be independent from the rheumatologic disease. Although we used to recommend treating uveitis for 1 year once quiescence is established, many uveitis specialists now recommend treating until 2 years of quiescence to minimize the risk of recurrence."

[email protected]

NEW YORK – Tailoring the frequency of vision screening for children with juvenile idiopathic arthritis is an important step to getting uveitis symptoms treated effectively before permanent morbidity occurs, according to Dr. Sanjay R. Kedhar.

"We know that children with JIA [juvenile idiopathic arthritis] who have chronic inflammation of the eye have a threefold increase in the risk of blindness. We also know that immunosuppressive therapy reduces the risk of blindness by 60%. I believe that physicians should feel the time pressure to identify uveitis in children and treat them aggressively to preserve vision and reduce morbidity," said Dr. Kedhar, an ophthalmologist at The New York (N.Y.) Eye and Ear Infirmary and associate professor of ophthalmology at New York Medical College in Valhalla, N.Y. Uveitis-associated morbidity includes cataracts, glaucoma, band keratopathy, phthisis bulbi, and vision loss.

Uveitis is the third most common cause of blindness in children, and JIA-associated uveitis is the most common cause of uveitis in children. About one in four children with JIA uveitis presents with blindness. Early detection, awareness of risk factors, and prompt and effective treatment can slow or prevent vision loss in children with JIA-associated uveitis, he said at the meeting, sponsored by New York University.

Uveitis associated with JIA most commonly affects the anterior portions of the eye, between the cornea and iris. Symptoms of anterior uveitis include blurred vision, pain, redness, photophobia, floaters, flashing lights, and distorted vision (metamorphopsia). The problem is that symptoms may be absent in children or, alternatively, children may not be able to verbalize what they see. "By the time symptoms are detected in school screening, it may be too late," Dr. Kedhar said.

That is why it is important to make sure children with JIA have regular ophthalmologic examinations as recommended by the American Academy of Pediatrics (Pediatrics 2006;117:1843-5). Screening frequency depends upon the presence of risk factors, such as type of arthritis (oligoarticular), age at onset, antinuclear antibody (ANA) seropositivity, and RF seronegativity. Children with JIA who have oligoarticular and polyarticular joint involvement and who are ANA positive and RF negative generally are at highest risk of developing uveitis, with 33%-70% affected.

"These are the kids we have to worry about the most," Dr. Kedhar said. If the joint symptoms appear before 7 years of age, the children should be seen every 3-4 months. Those children who have oligoarticular and polyarticular joint involvement beginning before age 7 but are ANA negative are considered at intermediate risk and should be seen every 6 months. Those who have a systemic onset of disease require screening every 12 months, reflecting the low risk of uveitis in this group.

Other risk factors for JIA-associated uveitis vision loss include female sex, anterior chamber flare seen on first exam, and abnormal intraocular pressure. The Systemic Immunosuppressive Therapy for Eye Diseases Study, a multicenter, retrospective cohort study of 327 patients with JIA-associated uveitis, showed that posterior synechiae, active uveitis, and intraocular surgery were associated with worse visual acuity outcomes (Ophthalmology 2013;120:186-92).

Another predictor of poor visual outcome is the onset of ocular symptoms before or soon after arthritis symptoms. Generally, having one ocular complication increases the risk of developing another.

Dr. Kedhar strongly suggested having an ophthalmologist be a part of the JIA patient’s medical team, along with the pediatrician and pediatric rheumatologist. A characteristic sign of anterior uveitis is an abnormal, irregular pupil. Ciliary flush is often not present in cases of JIA. In the acute setting, the red reflex may be diminished in the uveitis-affected eye. Keratic precipitates are white blood cells that accumulate on the posterior corneal surface and may indicate long-standing inflammation. Flare is another classic finding, and can be attributed to protein leakage into the aqueous humor. "In some studies, flare is used to monitor response of uveitis to treatment," Dr. Kedhar said. Uveitis is not typically associated with discharge or itching.

While topical corticosteroids are considered the first line of treatment, their use generated quite a bit of discussion from audience members. One of the main concerns is the conundrum that cataracts and glaucoma can occur because of uncontrolled inflammation associated with uveitis or as side effects of topical corticosteroids. Dr. Kedhar said that in his practice, he tries to limit the chronic use of corticosteroid drops to four times a day or less, generally switching patients to immunomodulatory therapy if they are corticosteroid dependent. He says that side effects are related to cumulative dose. He acknowledges that some ophthalmologists avoid topical steroids altogether but he believes they can be used safely for limited times. Because of greater concern for systemic side effects in children, systemic corticosteroids are used for only the short term.

Immunosuppressive therapy has been shown to reduce the risk of blindness in the better eye by 60% (Am. J. Ophthalmol. 2007;143:840-6). The most widely used immunomodulatory agent for children is methotrexate. Anti–TNF-alpha agents may be used in patients who fail to respond to conventional immunosuppressive therapy. A recent study in Italy that compared infliximab and adalimumab for refractory uveitis in 91 patients with JIA found higher remission rates after 1 year with adalimumab (67% vs. 43%, P = .025) (J. Rheumatol. 2013;40:74-9). Adalimumab has the convenience of subcutaneous administration, stable serum concentrations, and a more favorable safety profile, whereas infliximab offers fast onset and potent anti-inflammatory effects (J. Ophthalmic Vis. Res. 2011;6:259-69).

The anti–TNF-alpha agent golimumab was found to be helpful in three cases of refractory JIA uveitis. Golimumab offers the advantage of subcutaneous once-a-month dosing and avoids the expense and time commitment of outpatient infliximab infusions, Dr. Kedhar noted (J. Ophthalmic. Inflamm. Infect. 2012;2:231-3).

"Uveitis may require higher doses of immunomodulatory agents than those used for rheumatologic manifestations," Dr. Kedhar said. "The activity of uveitis associated with JIA may be independent from the rheumatologic disease. Although we used to recommend treating uveitis for 1 year once quiescence is established, many uveitis specialists now recommend treating until 2 years of quiescence to minimize the risk of recurrence."

[email protected]

NEW YORK – Tailoring the frequency of vision screening for children with juvenile idiopathic arthritis is an important step to getting uveitis symptoms treated effectively before permanent morbidity occurs, according to Dr. Sanjay R. Kedhar.

"We know that children with JIA [juvenile idiopathic arthritis] who have chronic inflammation of the eye have a threefold increase in the risk of blindness. We also know that immunosuppressive therapy reduces the risk of blindness by 60%. I believe that physicians should feel the time pressure to identify uveitis in children and treat them aggressively to preserve vision and reduce morbidity," said Dr. Kedhar, an ophthalmologist at The New York (N.Y.) Eye and Ear Infirmary and associate professor of ophthalmology at New York Medical College in Valhalla, N.Y. Uveitis-associated morbidity includes cataracts, glaucoma, band keratopathy, phthisis bulbi, and vision loss.

Uveitis is the third most common cause of blindness in children, and JIA-associated uveitis is the most common cause of uveitis in children. About one in four children with JIA uveitis presents with blindness. Early detection, awareness of risk factors, and prompt and effective treatment can slow or prevent vision loss in children with JIA-associated uveitis, he said at the meeting, sponsored by New York University.

Uveitis associated with JIA most commonly affects the anterior portions of the eye, between the cornea and iris. Symptoms of anterior uveitis include blurred vision, pain, redness, photophobia, floaters, flashing lights, and distorted vision (metamorphopsia). The problem is that symptoms may be absent in children or, alternatively, children may not be able to verbalize what they see. "By the time symptoms are detected in school screening, it may be too late," Dr. Kedhar said.

That is why it is important to make sure children with JIA have regular ophthalmologic examinations as recommended by the American Academy of Pediatrics (Pediatrics 2006;117:1843-5). Screening frequency depends upon the presence of risk factors, such as type of arthritis (oligoarticular), age at onset, antinuclear antibody (ANA) seropositivity, and RF seronegativity. Children with JIA who have oligoarticular and polyarticular joint involvement and who are ANA positive and RF negative generally are at highest risk of developing uveitis, with 33%-70% affected.

"These are the kids we have to worry about the most," Dr. Kedhar said. If the joint symptoms appear before 7 years of age, the children should be seen every 3-4 months. Those children who have oligoarticular and polyarticular joint involvement beginning before age 7 but are ANA negative are considered at intermediate risk and should be seen every 6 months. Those who have a systemic onset of disease require screening every 12 months, reflecting the low risk of uveitis in this group.

Other risk factors for JIA-associated uveitis vision loss include female sex, anterior chamber flare seen on first exam, and abnormal intraocular pressure. The Systemic Immunosuppressive Therapy for Eye Diseases Study, a multicenter, retrospective cohort study of 327 patients with JIA-associated uveitis, showed that posterior synechiae, active uveitis, and intraocular surgery were associated with worse visual acuity outcomes (Ophthalmology 2013;120:186-92).

Another predictor of poor visual outcome is the onset of ocular symptoms before or soon after arthritis symptoms. Generally, having one ocular complication increases the risk of developing another.

Dr. Kedhar strongly suggested having an ophthalmologist be a part of the JIA patient’s medical team, along with the pediatrician and pediatric rheumatologist. A characteristic sign of anterior uveitis is an abnormal, irregular pupil. Ciliary flush is often not present in cases of JIA. In the acute setting, the red reflex may be diminished in the uveitis-affected eye. Keratic precipitates are white blood cells that accumulate on the posterior corneal surface and may indicate long-standing inflammation. Flare is another classic finding, and can be attributed to protein leakage into the aqueous humor. "In some studies, flare is used to monitor response of uveitis to treatment," Dr. Kedhar said. Uveitis is not typically associated with discharge or itching.

While topical corticosteroids are considered the first line of treatment, their use generated quite a bit of discussion from audience members. One of the main concerns is the conundrum that cataracts and glaucoma can occur because of uncontrolled inflammation associated with uveitis or as side effects of topical corticosteroids. Dr. Kedhar said that in his practice, he tries to limit the chronic use of corticosteroid drops to four times a day or less, generally switching patients to immunomodulatory therapy if they are corticosteroid dependent. He says that side effects are related to cumulative dose. He acknowledges that some ophthalmologists avoid topical steroids altogether but he believes they can be used safely for limited times. Because of greater concern for systemic side effects in children, systemic corticosteroids are used for only the short term.

Immunosuppressive therapy has been shown to reduce the risk of blindness in the better eye by 60% (Am. J. Ophthalmol. 2007;143:840-6). The most widely used immunomodulatory agent for children is methotrexate. Anti–TNF-alpha agents may be used in patients who fail to respond to conventional immunosuppressive therapy. A recent study in Italy that compared infliximab and adalimumab for refractory uveitis in 91 patients with JIA found higher remission rates after 1 year with adalimumab (67% vs. 43%, P = .025) (J. Rheumatol. 2013;40:74-9). Adalimumab has the convenience of subcutaneous administration, stable serum concentrations, and a more favorable safety profile, whereas infliximab offers fast onset and potent anti-inflammatory effects (J. Ophthalmic Vis. Res. 2011;6:259-69).

The anti–TNF-alpha agent golimumab was found to be helpful in three cases of refractory JIA uveitis. Golimumab offers the advantage of subcutaneous once-a-month dosing and avoids the expense and time commitment of outpatient infliximab infusions, Dr. Kedhar noted (J. Ophthalmic. Inflamm. Infect. 2012;2:231-3).

"Uveitis may require higher doses of immunomodulatory agents than those used for rheumatologic manifestations," Dr. Kedhar said. "The activity of uveitis associated with JIA may be independent from the rheumatologic disease. Although we used to recommend treating uveitis for 1 year once quiescence is established, many uveitis specialists now recommend treating until 2 years of quiescence to minimize the risk of recurrence."

[email protected]

The Centers for Disease Control and Prevention announced on April 1 the availability of funding opportunities to expand newborn screening for severe combined immunodeficiency, also known as SCID.

Currently, only 12 states regularly test for SCID as part of their newborn screening programs. With the availability of a highly specific and low-cost test that measures a biomarker for a T-cell deficiency associated with SCID that can easily be added to current routine newborn screening, patient advocacy groups as well as state and federal governments are working to spur more widespread adoption of newborn SCID screening.

"Severe combined immunodeficiency is a pediatric emergency," medical geneticist Amy Brower, Ph.D., said at the NYU Annual Pediatric Rheumatology Update. "We need to get the message out to pediatricians and ob.gyns. that talking about newborn screening should begin prenatally. ... Unfortunately, surveys find that ob.gyns. do not have time for that conversation, and parents don’t remember it. We want physicians to know that there is a new test for SCID that has been vetted, is evidence based, and is available that can identify children before they become gravely ill."

Dr. Brower also suggests that parents should be made aware that even if their state does not offer SCID screening, they can request to have a newborn dried blood spot sample sent to a commercial lab for SCID analysis.

SCID is known colloquially as "bubble boy syndrome" because poor immune systems make these children vulnerable to infections. While babies born with SCID appear normal at birth, they stand a high risk of developing life-threatening viral, bacterial, and fungal infections. Right after birth, they are still protected by transplacentally derived maternal IgG antibodies, but soon lose that protection. If the condition is detected early and treated, survival rates are excellent. If treated before 3.5 months of age, 95% of affected babies will have long-term survival, but the survival rate falls below 70% if SCID is diagnosed after 3.5 months, even with intensive care and intervention (Public Health Rep. 2010;125:88-95).

Treatments include hematopoietic cell transplantation, enzyme replacement in cases of adenosine deaminase (ADA) deficiency, and gene therapy.

"Newborn screening for SCID is cost-effective, leads to years of productive life, and prevents the real negative outcomes associated with having one of this group of conditions," said Michael Watson, Ph.D., director of the American College of Medical Genetics and Genomics (ACMG) and principal investigator of the Newborn Screening Translational Research Network (NBSTRN). "Bone marrow transplant costs about $50,000-plus, but when these babies start getting infections and need hospitalization, the costs can be $1 to 1.2 million."

Using an estimated cost of SCID screening of $7.10 per baby, a medical model developed by the Washington State Department of Health reported a potential benefit:cost ratio of 4.93, meaning that almost $5 in benefits would accrue from every dollar of costs to provide SCID screening (Thompson JD, Glass M. Guide to the newborn screening cost-benefit model for adding severe combined immunodeficiency, 2012).

In January 2010, the U.S. Secretary of Health and Human Services approved SCID as the 30th core condition of the Recommended Uniform Screening Panel and the first immunological disorder. In May 2010, HHS Secretary Kathleen Sebelius endorsed newborn screening for SCID as the standard of care. However, there has been a wide disparity of adoption among states. "Currently no states are doing all newborn screening recommended by the secretary of HHS’s Advisory Committee, which now consists of 31 core conditions, including SCID and congenital heart screening," said Dr. Brower, project manager for the NBSTRN.

States that have screening programs in place for SCID are California, Colorado, Connecticut, Delaware, Florida, Massachusetts, Michigan, Minnesota, Mississippi, New York, Texas, and Wisconsin (also Puerto Rico).

Figure 1 from the NBSTRN shows the estimated number of newborns screened throughout the United States up until Dec. 31, 2012. Screening in the small area of New Mexico and Arizona reflects the high rate of SCID in Navajo Native Americans: In 2012, about 45% of all newborns were screened for SCID, and the hope is to reach 65% by 2014, Dr. Brower said at the meeting sponsored by New York University.

The Centers for Disease Control and Prevention (CDC) has been instrumental in trying to expand SCID newborn screening capability to more states, and contributed funding to pilot projects in Massachusetts and Wisconsin. The new CDC program is known as the Program to Support New Implementation of State or Territorial Public Health Laboratory Capacity for Newborn Bloodspot Screening of Severe Combined Immunodeficiency (SCID). Eligibility is restricted to states, special districts, and territorial governments that do not currently conduct SCID newborn screening. The total funds available are $1.8 million and it is anticipated that three awards will be made of $300,000 each year for 2 years. The application deadline is May 28, 2013, for funding that can begin on Aug. 1.

"Implementation of newborn screening for SCID is going slowly," agreed Dr. Watson. One challenge is the disparity of processes necessary for approval. Some states require legislative action, some need approval by the governor, and others require a go-ahead from the state’s department of health, which sometimes requires completion of a pilot program despite evidence collected from other states. Funding to properly outfit labs to carry out the new technology also can be a barrier.

Dr. Watson says that most of the states that initially began offering SCID screening already had the molecular assay technology in place from other programs, such as second-tier testing for cystic fibrosis. But even labs with the technical capability to conduct limited testing were not prepared to handle the high volume necessary for newborn screening. A possible cost-saving solution is that instead of having testing facilities available in every state, Dr. Watson suggests regionalized test centers, as is now done in New England, state partnerships, or even the use of commercial labs. Once a lab becomes equipped to handle SCID newborn screening, it often has the capacity to handle more than its own state’s needs, said Dr. Brower. Right now, Wisconsin and Massachusetts have the capacity to offer screening for other states.

Another limiting factor facing states considering adding SCID newborn screening can be the lack of a proper response mechanism. If a child screens positive for SCID, the child’s pediatrician must be prepared to shepherd the family through the next steps of diagnosis and arrange for immediate treatment, said Dr. Brower. To better inform pediatricians and other primary care physicians about SCID, the American College of Medical Genetics and Genomics offers an ACT sheet on SCID management aimed for the primary care provider. Dr. Watson also advises primary care providers to establish relationships with specialists in immunology, so that if a SCID baby is identified, the primary care provider can reach out for support regarding medical management, as well as for dealing with parental concerns.

The SCID newborn screening test is effective. Wisconsin was the first state to begin newborn screening for SCID. Between January 2008 and December 31, 2012, 5 infants with SCID or other forms of severe T-cell lymphopenia were detected out of almost 208,000 infants screened. No infants with SCID were missed during the screening period. The specificity of the assay used was 99.98%, with a false-positive rate of 0.018%. (Pediatrics 2012;130:S50-1). In California, the test had 99.91% specificity. Of 11 infants identified with SCID, all were able to be treated, with more than 90% alive at 6-21 months. In Colorado, a child with SCID was identified within the first week the SCID screening program began.

As part of the ACMG, the NBSTRN (www.nbstrn.org) maintains several SCID resources for investigators, including links to patient registries, a virtual repository of dried blood spot samples, and a longitudinal pediatric data resource. It also was involved with the National SCID Pilot Study that screened newborns in California, Louisiana, New York, and Puerto Rico. The ACMG operates the NBSTRN as part of funding it receives from the Eunice Kennedy Shriver National Institute of Child Health and Human Development for research into new therapeutics, technologies, and other aspects of newborn screening.

The NBSTRN also holds monthly conference calls for stakeholders, including scientists, clinicians, public health specialists, administrators, and patient advocates, to discuss SCID-related developments. "After decades of living with SCID children, some of whom we have already lost, mothers with children like mine who are older and were late transplants understand the urgency. They push us to think, what else can we be doing?" said Dr. Brower. Those interested in helping to broaden SCID screening may consult the Immune Deficiency Foundation’s SCID Newborn Screening Toolkit for Advocates or attend its national conference in Baltimore on June 27-29.

Screening for SCID

SCID is a group of conditions characterized by blocks in T-cell development, leading to functional deficiencies in both T cells and B cells.

Fortunately, a screening test able to detect low levels of a DNA biomarker of normal T-cell development has proven successful at identifying individuals before symptoms appear. The test, developed by Dr. Jennifer M. Puck of the University of California, San Francisco, measures T-cell receptor excision circles (TRECs) using a polymerase chain reaction (PCR) process in samples of dried blood spots commonly taken from infants that are used for other screening purposes. Infants with SCID or related disorders have very low or undetectable levels of TRECs.

Being able to measure TRECs "was a real game changer for SCID," said Dr. Brower. It fit well into ongoing public health programs that utilized dried blood spot collections. "This was a technology developed at [the National Institutes of Health] that was developed and translated into clinical care with clear public health benefits." At the NBSTRN, Dr. Brower leads similar efforts to take genomic advances from bench to bedside.

The Wisconsin screening program uses a cutoff of 25 TRECs/mcL. Most screening programs have an algorithm in place for dealing with abnormal results. In Wisconsin, the first step is to redo the TREC assay. If the results are still positive, a physician member of the screening program is notified, who then contacts the newborn’s primary care physician. A decision is then made to either do another filter-paper specimen analysis or have a whole-blood specimen sent for T-cell enumeration by flow cytometry. A full workup for SCID is then recommended if results are still abnormal. (Curr. Opin. Pediatr. 2011;23:667-73).

In the first 18 months of the California screening program, 116 babies had samples sent for flow cytometry. Of those, 81 were normal. There were 10 cases of typical SCID, 1 child with Omenn syndrome (leaky SCID), 4 with variants of SCID, 8 with low T cell syndromes, and 7 with secondary causes of low T cells. There were 5 preterm births.

Children with leaky SCID may have a later onset of symptoms, with rash, adenopathy, and poorly functioning T cells. SCID variants include cartilage-hair hypoplasia, CHARGE syndrome (coloboma, heart defect, atresia choanae [also known as choanal atresia], retarded growth and development, genital abnormality, and ear abnormality), Down syndrome, or DiGeorge syndrome.

SCID newborn screening also could be helpful to children with non-SCID, secondary causes of T-cell lymphopenia who might also be vulnerable to serious opportunistic infections. Just recently, abnormal TREC findings led investigators to diagnose ataxia telangiectasia in two infants (J. Clin. Immunol. 2013;33:540-9).

Dr. Brower and Dr. Watson both said that they had no relevant financial disclosures.

[email protected]

The Centers for Disease Control and Prevention announced on April 1 the availability of funding opportunities to expand newborn screening for severe combined immunodeficiency, also known as SCID.

Currently, only 12 states regularly test for SCID as part of their newborn screening programs. With the availability of a highly specific and low-cost test that measures a biomarker for a T-cell deficiency associated with SCID that can easily be added to current routine newborn screening, patient advocacy groups as well as state and federal governments are working to spur more widespread adoption of newborn SCID screening.

"Severe combined immunodeficiency is a pediatric emergency," medical geneticist Amy Brower, Ph.D., said at the NYU Annual Pediatric Rheumatology Update. "We need to get the message out to pediatricians and ob.gyns. that talking about newborn screening should begin prenatally. ... Unfortunately, surveys find that ob.gyns. do not have time for that conversation, and parents don’t remember it. We want physicians to know that there is a new test for SCID that has been vetted, is evidence based, and is available that can identify children before they become gravely ill."

Dr. Brower also suggests that parents should be made aware that even if their state does not offer SCID screening, they can request to have a newborn dried blood spot sample sent to a commercial lab for SCID analysis.

SCID is known colloquially as "bubble boy syndrome" because poor immune systems make these children vulnerable to infections. While babies born with SCID appear normal at birth, they stand a high risk of developing life-threatening viral, bacterial, and fungal infections. Right after birth, they are still protected by transplacentally derived maternal IgG antibodies, but soon lose that protection. If the condition is detected early and treated, survival rates are excellent. If treated before 3.5 months of age, 95% of affected babies will have long-term survival, but the survival rate falls below 70% if SCID is diagnosed after 3.5 months, even with intensive care and intervention (Public Health Rep. 2010;125:88-95).

Treatments include hematopoietic cell transplantation, enzyme replacement in cases of adenosine deaminase (ADA) deficiency, and gene therapy.

"Newborn screening for SCID is cost-effective, leads to years of productive life, and prevents the real negative outcomes associated with having one of this group of conditions," said Michael Watson, Ph.D., director of the American College of Medical Genetics and Genomics (ACMG) and principal investigator of the Newborn Screening Translational Research Network (NBSTRN). "Bone marrow transplant costs about $50,000-plus, but when these babies start getting infections and need hospitalization, the costs can be $1 to 1.2 million."

Using an estimated cost of SCID screening of $7.10 per baby, a medical model developed by the Washington State Department of Health reported a potential benefit:cost ratio of 4.93, meaning that almost $5 in benefits would accrue from every dollar of costs to provide SCID screening (Thompson JD, Glass M. Guide to the newborn screening cost-benefit model for adding severe combined immunodeficiency, 2012).

In January 2010, the U.S. Secretary of Health and Human Services approved SCID as the 30th core condition of the Recommended Uniform Screening Panel and the first immunological disorder. In May 2010, HHS Secretary Kathleen Sebelius endorsed newborn screening for SCID as the standard of care. However, there has been a wide disparity of adoption among states. "Currently no states are doing all newborn screening recommended by the secretary of HHS’s Advisory Committee, which now consists of 31 core conditions, including SCID and congenital heart screening," said Dr. Brower, project manager for the NBSTRN.

States that have screening programs in place for SCID are California, Colorado, Connecticut, Delaware, Florida, Massachusetts, Michigan, Minnesota, Mississippi, New York, Texas, and Wisconsin (also Puerto Rico).

Figure 1 from the NBSTRN shows the estimated number of newborns screened throughout the United States up until Dec. 31, 2012. Screening in the small area of New Mexico and Arizona reflects the high rate of SCID in Navajo Native Americans: In 2012, about 45% of all newborns were screened for SCID, and the hope is to reach 65% by 2014, Dr. Brower said at the meeting sponsored by New York University.

The Centers for Disease Control and Prevention (CDC) has been instrumental in trying to expand SCID newborn screening capability to more states, and contributed funding to pilot projects in Massachusetts and Wisconsin. The new CDC program is known as the Program to Support New Implementation of State or Territorial Public Health Laboratory Capacity for Newborn Bloodspot Screening of Severe Combined Immunodeficiency (SCID). Eligibility is restricted to states, special districts, and territorial governments that do not currently conduct SCID newborn screening. The total funds available are $1.8 million and it is anticipated that three awards will be made of $300,000 each year for 2 years. The application deadline is May 28, 2013, for funding that can begin on Aug. 1.

"Implementation of newborn screening for SCID is going slowly," agreed Dr. Watson. One challenge is the disparity of processes necessary for approval. Some states require legislative action, some need approval by the governor, and others require a go-ahead from the state’s department of health, which sometimes requires completion of a pilot program despite evidence collected from other states. Funding to properly outfit labs to carry out the new technology also can be a barrier.

Dr. Watson says that most of the states that initially began offering SCID screening already had the molecular assay technology in place from other programs, such as second-tier testing for cystic fibrosis. But even labs with the technical capability to conduct limited testing were not prepared to handle the high volume necessary for newborn screening. A possible cost-saving solution is that instead of having testing facilities available in every state, Dr. Watson suggests regionalized test centers, as is now done in New England, state partnerships, or even the use of commercial labs. Once a lab becomes equipped to handle SCID newborn screening, it often has the capacity to handle more than its own state’s needs, said Dr. Brower. Right now, Wisconsin and Massachusetts have the capacity to offer screening for other states.

Another limiting factor facing states considering adding SCID newborn screening can be the lack of a proper response mechanism. If a child screens positive for SCID, the child’s pediatrician must be prepared to shepherd the family through the next steps of diagnosis and arrange for immediate treatment, said Dr. Brower. To better inform pediatricians and other primary care physicians about SCID, the American College of Medical Genetics and Genomics offers an ACT sheet on SCID management aimed for the primary care provider. Dr. Watson also advises primary care providers to establish relationships with specialists in immunology, so that if a SCID baby is identified, the primary care provider can reach out for support regarding medical management, as well as for dealing with parental concerns.

The SCID newborn screening test is effective. Wisconsin was the first state to begin newborn screening for SCID. Between January 2008 and December 31, 2012, 5 infants with SCID or other forms of severe T-cell lymphopenia were detected out of almost 208,000 infants screened. No infants with SCID were missed during the screening period. The specificity of the assay used was 99.98%, with a false-positive rate of 0.018%. (Pediatrics 2012;130:S50-1). In California, the test had 99.91% specificity. Of 11 infants identified with SCID, all were able to be treated, with more than 90% alive at 6-21 months. In Colorado, a child with SCID was identified within the first week the SCID screening program began.

As part of the ACMG, the NBSTRN (www.nbstrn.org) maintains several SCID resources for investigators, including links to patient registries, a virtual repository of dried blood spot samples, and a longitudinal pediatric data resource. It also was involved with the National SCID Pilot Study that screened newborns in California, Louisiana, New York, and Puerto Rico. The ACMG operates the NBSTRN as part of funding it receives from the Eunice Kennedy Shriver National Institute of Child Health and Human Development for research into new therapeutics, technologies, and other aspects of newborn screening.

The NBSTRN also holds monthly conference calls for stakeholders, including scientists, clinicians, public health specialists, administrators, and patient advocates, to discuss SCID-related developments. "After decades of living with SCID children, some of whom we have already lost, mothers with children like mine who are older and were late transplants understand the urgency. They push us to think, what else can we be doing?" said Dr. Brower. Those interested in helping to broaden SCID screening may consult the Immune Deficiency Foundation’s SCID Newborn Screening Toolkit for Advocates or attend its national conference in Baltimore on June 27-29.

Screening for SCID

SCID is a group of conditions characterized by blocks in T-cell development, leading to functional deficiencies in both T cells and B cells.

Fortunately, a screening test able to detect low levels of a DNA biomarker of normal T-cell development has proven successful at identifying individuals before symptoms appear. The test, developed by Dr. Jennifer M. Puck of the University of California, San Francisco, measures T-cell receptor excision circles (TRECs) using a polymerase chain reaction (PCR) process in samples of dried blood spots commonly taken from infants that are used for other screening purposes. Infants with SCID or related disorders have very low or undetectable levels of TRECs.

Being able to measure TRECs "was a real game changer for SCID," said Dr. Brower. It fit well into ongoing public health programs that utilized dried blood spot collections. "This was a technology developed at [the National Institutes of Health] that was developed and translated into clinical care with clear public health benefits." At the NBSTRN, Dr. Brower leads similar efforts to take genomic advances from bench to bedside.

The Wisconsin screening program uses a cutoff of 25 TRECs/mcL. Most screening programs have an algorithm in place for dealing with abnormal results. In Wisconsin, the first step is to redo the TREC assay. If the results are still positive, a physician member of the screening program is notified, who then contacts the newborn’s primary care physician. A decision is then made to either do another filter-paper specimen analysis or have a whole-blood specimen sent for T-cell enumeration by flow cytometry. A full workup for SCID is then recommended if results are still abnormal. (Curr. Opin. Pediatr. 2011;23:667-73).

In the first 18 months of the California screening program, 116 babies had samples sent for flow cytometry. Of those, 81 were normal. There were 10 cases of typical SCID, 1 child with Omenn syndrome (leaky SCID), 4 with variants of SCID, 8 with low T cell syndromes, and 7 with secondary causes of low T cells. There were 5 preterm births.

Children with leaky SCID may have a later onset of symptoms, with rash, adenopathy, and poorly functioning T cells. SCID variants include cartilage-hair hypoplasia, CHARGE syndrome (coloboma, heart defect, atresia choanae [also known as choanal atresia], retarded growth and development, genital abnormality, and ear abnormality), Down syndrome, or DiGeorge syndrome.

SCID newborn screening also could be helpful to children with non-SCID, secondary causes of T-cell lymphopenia who might also be vulnerable to serious opportunistic infections. Just recently, abnormal TREC findings led investigators to diagnose ataxia telangiectasia in two infants (J. Clin. Immunol. 2013;33:540-9).

Dr. Brower and Dr. Watson both said that they had no relevant financial disclosures.

[email protected]

The Centers for Disease Control and Prevention announced on April 1 the availability of funding opportunities to expand newborn screening for severe combined immunodeficiency, also known as SCID.

Currently, only 12 states regularly test for SCID as part of their newborn screening programs. With the availability of a highly specific and low-cost test that measures a biomarker for a T-cell deficiency associated with SCID that can easily be added to current routine newborn screening, patient advocacy groups as well as state and federal governments are working to spur more widespread adoption of newborn SCID screening.

"Severe combined immunodeficiency is a pediatric emergency," medical geneticist Amy Brower, Ph.D., said at the NYU Annual Pediatric Rheumatology Update. "We need to get the message out to pediatricians and ob.gyns. that talking about newborn screening should begin prenatally. ... Unfortunately, surveys find that ob.gyns. do not have time for that conversation, and parents don’t remember it. We want physicians to know that there is a new test for SCID that has been vetted, is evidence based, and is available that can identify children before they become gravely ill."

Dr. Brower also suggests that parents should be made aware that even if their state does not offer SCID screening, they can request to have a newborn dried blood spot sample sent to a commercial lab for SCID analysis.

SCID is known colloquially as "bubble boy syndrome" because poor immune systems make these children vulnerable to infections. While babies born with SCID appear normal at birth, they stand a high risk of developing life-threatening viral, bacterial, and fungal infections. Right after birth, they are still protected by transplacentally derived maternal IgG antibodies, but soon lose that protection. If the condition is detected early and treated, survival rates are excellent. If treated before 3.5 months of age, 95% of affected babies will have long-term survival, but the survival rate falls below 70% if SCID is diagnosed after 3.5 months, even with intensive care and intervention (Public Health Rep. 2010;125:88-95).

Treatments include hematopoietic cell transplantation, enzyme replacement in cases of adenosine deaminase (ADA) deficiency, and gene therapy.

"Newborn screening for SCID is cost-effective, leads to years of productive life, and prevents the real negative outcomes associated with having one of this group of conditions," said Michael Watson, Ph.D., director of the American College of Medical Genetics and Genomics (ACMG) and principal investigator of the Newborn Screening Translational Research Network (NBSTRN). "Bone marrow transplant costs about $50,000-plus, but when these babies start getting infections and need hospitalization, the costs can be $1 to 1.2 million."

Using an estimated cost of SCID screening of $7.10 per baby, a medical model developed by the Washington State Department of Health reported a potential benefit:cost ratio of 4.93, meaning that almost $5 in benefits would accrue from every dollar of costs to provide SCID screening (Thompson JD, Glass M. Guide to the newborn screening cost-benefit model for adding severe combined immunodeficiency, 2012).

In January 2010, the U.S. Secretary of Health and Human Services approved SCID as the 30th core condition of the Recommended Uniform Screening Panel and the first immunological disorder. In May 2010, HHS Secretary Kathleen Sebelius endorsed newborn screening for SCID as the standard of care. However, there has been a wide disparity of adoption among states. "Currently no states are doing all newborn screening recommended by the secretary of HHS’s Advisory Committee, which now consists of 31 core conditions, including SCID and congenital heart screening," said Dr. Brower, project manager for the NBSTRN.

States that have screening programs in place for SCID are California, Colorado, Connecticut, Delaware, Florida, Massachusetts, Michigan, Minnesota, Mississippi, New York, Texas, and Wisconsin (also Puerto Rico).

Figure 1 from the NBSTRN shows the estimated number of newborns screened throughout the United States up until Dec. 31, 2012. Screening in the small area of New Mexico and Arizona reflects the high rate of SCID in Navajo Native Americans: In 2012, about 45% of all newborns were screened for SCID, and the hope is to reach 65% by 2014, Dr. Brower said at the meeting sponsored by New York University.

The Centers for Disease Control and Prevention (CDC) has been instrumental in trying to expand SCID newborn screening capability to more states, and contributed funding to pilot projects in Massachusetts and Wisconsin. The new CDC program is known as the Program to Support New Implementation of State or Territorial Public Health Laboratory Capacity for Newborn Bloodspot Screening of Severe Combined Immunodeficiency (SCID). Eligibility is restricted to states, special districts, and territorial governments that do not currently conduct SCID newborn screening. The total funds available are $1.8 million and it is anticipated that three awards will be made of $300,000 each year for 2 years. The application deadline is May 28, 2013, for funding that can begin on Aug. 1.

"Implementation of newborn screening for SCID is going slowly," agreed Dr. Watson. One challenge is the disparity of processes necessary for approval. Some states require legislative action, some need approval by the governor, and others require a go-ahead from the state’s department of health, which sometimes requires completion of a pilot program despite evidence collected from other states. Funding to properly outfit labs to carry out the new technology also can be a barrier.

Dr. Watson says that most of the states that initially began offering SCID screening already had the molecular assay technology in place from other programs, such as second-tier testing for cystic fibrosis. But even labs with the technical capability to conduct limited testing were not prepared to handle the high volume necessary for newborn screening. A possible cost-saving solution is that instead of having testing facilities available in every state, Dr. Watson suggests regionalized test centers, as is now done in New England, state partnerships, or even the use of commercial labs. Once a lab becomes equipped to handle SCID newborn screening, it often has the capacity to handle more than its own state’s needs, said Dr. Brower. Right now, Wisconsin and Massachusetts have the capacity to offer screening for other states.

Another limiting factor facing states considering adding SCID newborn screening can be the lack of a proper response mechanism. If a child screens positive for SCID, the child’s pediatrician must be prepared to shepherd the family through the next steps of diagnosis and arrange for immediate treatment, said Dr. Brower. To better inform pediatricians and other primary care physicians about SCID, the American College of Medical Genetics and Genomics offers an ACT sheet on SCID management aimed for the primary care provider. Dr. Watson also advises primary care providers to establish relationships with specialists in immunology, so that if a SCID baby is identified, the primary care provider can reach out for support regarding medical management, as well as for dealing with parental concerns.

The SCID newborn screening test is effective. Wisconsin was the first state to begin newborn screening for SCID. Between January 2008 and December 31, 2012, 5 infants with SCID or other forms of severe T-cell lymphopenia were detected out of almost 208,000 infants screened. No infants with SCID were missed during the screening period. The specificity of the assay used was 99.98%, with a false-positive rate of 0.018%. (Pediatrics 2012;130:S50-1). In California, the test had 99.91% specificity. Of 11 infants identified with SCID, all were able to be treated, with more than 90% alive at 6-21 months. In Colorado, a child with SCID was identified within the first week the SCID screening program began.

As part of the ACMG, the NBSTRN (www.nbstrn.org) maintains several SCID resources for investigators, including links to patient registries, a virtual repository of dried blood spot samples, and a longitudinal pediatric data resource. It also was involved with the National SCID Pilot Study that screened newborns in California, Louisiana, New York, and Puerto Rico. The ACMG operates the NBSTRN as part of funding it receives from the Eunice Kennedy Shriver National Institute of Child Health and Human Development for research into new therapeutics, technologies, and other aspects of newborn screening.

The NBSTRN also holds monthly conference calls for stakeholders, including scientists, clinicians, public health specialists, administrators, and patient advocates, to discuss SCID-related developments. "After decades of living with SCID children, some of whom we have already lost, mothers with children like mine who are older and were late transplants understand the urgency. They push us to think, what else can we be doing?" said Dr. Brower. Those interested in helping to broaden SCID screening may consult the Immune Deficiency Foundation’s SCID Newborn Screening Toolkit for Advocates or attend its national conference in Baltimore on June 27-29.

Screening for SCID

SCID is a group of conditions characterized by blocks in T-cell development, leading to functional deficiencies in both T cells and B cells.

Fortunately, a screening test able to detect low levels of a DNA biomarker of normal T-cell development has proven successful at identifying individuals before symptoms appear. The test, developed by Dr. Jennifer M. Puck of the University of California, San Francisco, measures T-cell receptor excision circles (TRECs) using a polymerase chain reaction (PCR) process in samples of dried blood spots commonly taken from infants that are used for other screening purposes. Infants with SCID or related disorders have very low or undetectable levels of TRECs.

Being able to measure TRECs "was a real game changer for SCID," said Dr. Brower. It fit well into ongoing public health programs that utilized dried blood spot collections. "This was a technology developed at [the National Institutes of Health] that was developed and translated into clinical care with clear public health benefits." At the NBSTRN, Dr. Brower leads similar efforts to take genomic advances from bench to bedside.

The Wisconsin screening program uses a cutoff of 25 TRECs/mcL. Most screening programs have an algorithm in place for dealing with abnormal results. In Wisconsin, the first step is to redo the TREC assay. If the results are still positive, a physician member of the screening program is notified, who then contacts the newborn’s primary care physician. A decision is then made to either do another filter-paper specimen analysis or have a whole-blood specimen sent for T-cell enumeration by flow cytometry. A full workup for SCID is then recommended if results are still abnormal. (Curr. Opin. Pediatr. 2011;23:667-73).

In the first 18 months of the California screening program, 116 babies had samples sent for flow cytometry. Of those, 81 were normal. There were 10 cases of typical SCID, 1 child with Omenn syndrome (leaky SCID), 4 with variants of SCID, 8 with low T cell syndromes, and 7 with secondary causes of low T cells. There were 5 preterm births.

Children with leaky SCID may have a later onset of symptoms, with rash, adenopathy, and poorly functioning T cells. SCID variants include cartilage-hair hypoplasia, CHARGE syndrome (coloboma, heart defect, atresia choanae [also known as choanal atresia], retarded growth and development, genital abnormality, and ear abnormality), Down syndrome, or DiGeorge syndrome.

SCID newborn screening also could be helpful to children with non-SCID, secondary causes of T-cell lymphopenia who might also be vulnerable to serious opportunistic infections. Just recently, abnormal TREC findings led investigators to diagnose ataxia telangiectasia in two infants (J. Clin. Immunol. 2013;33:540-9).

Dr. Brower and Dr. Watson both said that they had no relevant financial disclosures.

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