Imaging of Articular Disorders in Children

Evaluating articular disorders in children differs from evaluating them in adults. In addition to articular cartilage and synovium, these disorders also affect the epiphyseal cartilage and the shape and contour of the epiphysis and growth plate. This article covers the range of joint diseases in children with a concentration on the aspects unique to the immature skeleton.

Radiographs can detect early and late arthritic changes. Accelerated maturation is an early finding that occurs in response to periarticular hyperemia. Later changes of inflammatory arthritis seen on x-ray include epiphyseal enlargement, bony erosion subchondral cyst formation, and joint surface deformity.

Ultrasound is more sensitive for evaluating cartilage damage, synovial thickening, or joint effusion, although it is less sensitive than magnetic resonance imaging (MRI). Ultrasound can also guide diagnostic and therapeutic aspiration of joint effusions.

MRI is the most sensitive imaging modality for evaluating arthritis in children. This includes early changes, such as synovial inflammation, and late manifestations, such as joint space narrowing resulting from cartilage loss. Contrast-enhanced MRI allows measurement of the degree of pannus formation and can be used before and after treatment. Decrease in pannus volume and enhancement is considered a favorable clinical outcome in juvenile rheumatoid arthritis. MRI also provides superior sensitivity for evaluating damage to cartilage.

Juvenile Rheumatoid Arthritis

Juvenile rheumatoid arthritis (JRA), the most common chronic arthropathy of childhood, is a systemic disease of unknown etiology. Characterized by arthritis that persists for more than 6 weeks before the age of 16 years, it has four subtypes: one form of seropositive disease and three subtypes of seronegative disease. Seropositive disease (5-15% of patients with JRA) has an onset in adolescence, primarily in females, and has a polyarticular distribution. It resembles adult rheumatoid arthritis. The majority of children have seronegative disease, making diagnosis a challenge because there are no diagnostic tests to confirm the diagnosis.

The knee is the most common joint with radiographic abnormalities. Early changes seen on x-ray include synovitis, joint effusion, soft tissue swelling, and osteopenia. Advanced skeletal maturation and epiphyseal enlargement are commonly seen in the knee, elbow, and hip. Both changes are secondary to hyperemia in the inflamed joint.

Radiographs are useful for diagnosis, staging, and follow-up, as well as for differential diagnosis. However, MRI and ultrasound provide the most helpful information in early disease because of the ability to directly image synovial pathology. On MRI, abnormal bone marrow signal precedes actual bone loss; this can help predict future erosive disease.

Juvenile Spondyloarthropathies

Seronegative spondyloarthropathies include ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, and arthritis associated with inflammatory bowel disease. These disorders have clinical similarities and a familial predisposition, as well as the presence of enthesitis, sacroiliitis, and human leukocyte antigen locus B27 (HLA-B27).

Juvenile ankylosing spondylitis involves few joints (usually fewer than 4) and begins in late childhood or early adolescence. Enthesitis (inflammation of a tendon insertion site) is more commonly seen in children than adults with ankylosing spondylitis. Sacroiliitis and disease of the spine may develop over many years.

Juvenile psoriatic arthritis is the only spondyloarthropathy that occurs more frequently in girls. Arthritis and nail pitting may appear years before development of a psoriatic rash (the opposite of the adult presentation). Most children have asymmetric pauciarticular joint involvement. Nail pitting and a positive family history are helpful for diagnosis because the radiographic changes may be indistinguishable from pauciarticular JRA.

In children with inflammatory bowel disease, arthritis is the most common extraintestinal manifestation. Arthritic symptoms can precede or follow diagnosis and parallel the clinical activity of the bowel disease. Most children have complete resolution of the arthritic symptoms.

Reiter's syndrome is a reactive arthritis after a gastrointestinal infection (Yersinis, Shigella, Salmonella, or Campylobacter) or a urethral infection (Chlamydia). This is a painful arthritis that is usually self-limited.

Lyme Arthropathy

Lyme arthritis develops in Stage 3 of Lyme disease, occurring in approximately 60% of untreated patients who have the hallmark rash (erythema chronicum migrans) in Stage 1. Arthritic pain can occur as early as several weeks after the rash or present years later. Radiographic features resemble an inflammatory arthropathy. Patients with Lyme arthritis may have asymmetric large joint involvement, particularly in the knee. Involvement of foot joints is uncommon.

Irritable Hip

In children who have an acutely irritable hip, it is essential to distinguish between septic arthritis and transient synovitis. Transient synovitis is usually self-limited (3-10 days) with a benign clinical course, whereas delay in diagnosis and treatment of septic arthritis can result in osteonecrosis, growth arrest, and sepsis.

Children with transient synovitis are young (5-10 years old) and present with acute hip pain, stiffness, and a limp. Ultrasound results are non-specific and may include a hip effusion and synovial thickening. Differential diagnoses include early Perthes' disease, JRA, and neoplasms, as well as septic arthritis.

Septic arthritis, an infection of the joint, also affects children younger than 10 years. Radiographs can rule out fracture or tumor, and ultrasound will detect an effusion. Aspiration must be performed to determine if sepsis is present, but four clinical symptoms are useful for distinguishing septic arthritis from transient synovitis: history of fever, non-weight-bearing status, erythrocyte sedimentation rate > 40 mm/hour, and white blood cell count > 12,000 cells/mm. MRI findings are nonspecific and cannot help to differentiate between transient synovitis and septic arthritis, but they may be helpful if there is no effusion and if osteomyelitis is a possible diagnosis.

Buchmann, R. F., & Jaramillo, D. (2004). Imaging of articular disorders in children. Radiologic Clinics of North America, 42 (1), 151-168.

New Drugs for Rheumatoid Arthritis

The cause of rheumatoid arthritis (RA) remains obscure, but greater understanding of the underlying mechanisms has revolutionized treatment. This article reviews the newest drugs available for treatment of this autoimmune disease. The drugs discussed all slow progress of the disease as measured radiologically and are thus classified as disease-modifying antirheumatic drugs. Methotrexate is the standard against which the newer drugs should be evaluated.

Specific CD4+ cells are involved in induction of the immune response in RA, with subsequent production of cytokines, such as tumor necrosis factor-[alpha] (TNF-[alpha]) and interleukin-1 within the synovial cavity. These cytokines trigger reactions that result in irreversible damage to soft tissues and bones. B-lymphocyte dysregulation is suggested by the association of erosive disease in the presence of rheumatoid factor, which mediates further damage through complement fixation.

Leflunomide

Leflunomide, an immunomodulatory drug, blocks the pyrimidine-synthesis pathway. It is a prodrug that rapidly converts after oral administration to its primary active metabolite. This metabolite is highly protein bound, with a half-life of 15-18 days. Therefore, without a loading dose, it may take up to 2 months to achieve steady-state concentrations. Because the drug undergoes extensive enterohepatic recirculation, it may take as long as 2 years for plasma levels to drop to undetectable levels. Renal excretion is limited.

The most serious adverse effect is hepatic; however, in clinical trials, increased transaminase levels were reversible after the drug was discontinued. However, patients with pre-existing liver abnormalities or a history of heavy alcohol intake or hepatitis should not take this drug. Weight loss and diarrhea can occur. During the first 2 months of treatment, blood pressure elevations can occur, so monitoring is important. Reversible alopecia, pancytopenia, peripheral neuropathy, and interstitial pneumonitis have also been reported.

Preclinical trials indicated that leflunomide causes fetal death or is teratogenic. Because of the drug's long half-life, discontinuing the drug is inadequate and the manufacturer suggests an elimination protocol. Men who wish to father a child, as well as potential mothers, should follow this protocol.

Leflunomide is an alternative for patients who cannot tolerate methotrexate, the most commonly used disease-modifying antirheumatic drug. A loading dose of 100 mg daily for 3 days can be given but is often omitted or reduced because of gastrointestinal disturbances. The usual daily dose (20 mg) is generally well tolerated by most patients. Leflunomide may be combined with methotrexate but increases the risk of hepatotoxicity. Patients on combination therapy must be monitored closely.

Tumor Necrosis Factor Antagonists

Patients with RA have high concentrations of TNF-[alpha], an inflammatory cytokine, in the synovial fluid; this is associated with bony erosion. Three TNF-blocking drugs are currently available: etanercept, infliximab, and adalimumab.

Etanercept is administered subcutaneously with concentrations peaking at about 50 hours. Half-life is about 4 days, with a weekly dose of 50 mg as effective as 25 mg twice a week.

Infliximab was first approved for the treatment of Crohn's disease. There are marked differences among patients in the pharmacokinetics of infliximab. However, a standard administration regimen has evolved. An IV infusion (3 mg/kg of body weight) is administered at 0, 2, and 4 weeks, then every 8 weeks. Half-life is 9 days. For patients with an inadequate response, maintenance dosage may be gradually increased (up to 10 mg/kg) or the interval between infusions decreased to every 4 to 6 weeks.

Adalimumab, a recombinant human monoclonal antibody, is administered subcutaneously and absorbed slowly, with concentrations peaking after 130 hours. Dosage is 40 mg every second week with a half-life of 2 weeks.

Initial studies report substantial efficacy, with almost no serious adverse effects. However, with wider use of TNF antagonists a range of adverse effects, including infections, cancer, vasculitis, lupus-like autoimmune disease, multiple sclerosis-like demyelinating disorders, liver disease, hematologic abnormalities (including aplastic anemia and lymphoma), severe allergy, and aseptic meningitis, have been linked to these drugs.

Several infections have occurred and may be more common in patients over 65 years old. Although the background risk of serious infection is approximately twice as high among all patients with RA, the risk of opportunistic infections is increased for patients receiving anti-TNF therapy. Tuberculosis has been reported in association with all TNF antagonists, and most often arises from the reactivation of latent infection usually within the first 2 to 5 months of treatment. Screening before treatment and lower doses have decreased the frequency of tuberculosis. Patients who test positive for latent tuberculosis should be treated before starting treatment with a TNF antagonist.

Lymphoma has been reported in association with all three TNF antagonists, but a causal relationship has not been established. There is no increased incidence of any other type of cancer. Exacerbation of previously quiescent multiple sclerosis and new-onset demyelinating neurologic disease has been reported; however, a causal relationship has not been established.

Injection site redness and itching are common in patients receiving etanercept and adalimumab. Antihistamines and slowing of the infusion rate control this local reaction, which can last several days.

TNF antagonists are among the most effective treatments available for treating RA. However, there is little information comparing the various TNF to each other or to other disease-modifying antirheumatic drugs. These drugs should not be started in patients with active infection and should be discontinued if a serious infection occurs. Other contraindications include any demyelinating disorder or heart failure; therapy should be discontinued if these problems develop.

Anakinra

Anakinra is a recombinant human interleukin-1-receptor antagonist. In patients with RA, levels of this antagonist are lower than the amount required to inhibit the levels of inter-leukin-1 (an inflammatory agent) present in inflamed joints. This drug must be administered daily by subcutaneous injection because of its short half-life (6 hours).

The most common adverse effect is skin irritation at the injection site. Most reactions, which are dose dependent, are mild and resolve within several weeks. Although risk of infection (primarily bacterial) is increased, no opportunistic infections were observed in clinical trials.

Anakinra may be useful in patients who do not respond to or cannot tolerate methotrexate, leflunomide, or the TNF antagonists. Monitoring complete blood counts is recommended, because neutropenia and thrombocytopenia have occurred in some patients. Do not combine anakinra and a TNF antagonist because this may increase infection risk.

Olsen, N. J., & Stein, C. M. (2004). New drugs for rheumatoid arthritis. The New England Journal of Medicine, 350 (21), 2167-2179.

Effect of Vitamin D on Falls

Falls are the largest single cause of injury-related mortality in the elderly. The primary goal of this meta-analysis was to determine the overall efficacy of vitamin D in preventing falls among older individuals through a systematic review of randomized controlled trials (RCTs) in the literature. The primary outcome measure was the relative risk of having at least one fall among persons receiving vitamin D compared with those not receiving vitamin D.

Only double-blind RCTs that studied any type of vitamin D were included. Studies had to include how falls were ascertained and how they were defined. The mean age of study participants had to equal or exceed 60 years to be included in this analysis. Studies that focused on patients with alcoholism or unstable health states, such as after acute hospitalization, were excluded.

Five studies met the inclusion criteria and collectively evaluated 1,237 individuals who had been treated with different vitamin D analogs for 2 months up to 3 years. The pooled results found a statistically significant 22% reduction in the risk of falling with vitamin D treatment compared with calcium or placebo. A physiologic explanation for this beneficial effect is that the active vitamin D metabolite binds to a specific nuclear receptor in muscle tissue, leading to improved muscle function and reduced risk of falling.

There were insufficient data to formally test which dose of vitamin D and which formulation would be most beneficial. The role of calcium and the optimal amount necessary in combination with vitamin D could not be clearly determined.

This meta-analysis suggests that vitamin D should reduce an older person's risk of falling by 22%, with the benefit most clearly established for women and with active vitamin D analogs. The pooled risk difference indicated that 15 people would need to be treated with vitamin D to prevent one person from falling.

Bischoff-Ferrari, H. A., Dawson-Hughes, B., Willett, W. C., Staehelin, H., Bazemore, M. G., Zee, R. Y., et al. (2004). Journal of the American Medical Association, 291 (16), 1999-2006.

Prevention of Bone Loss After Cardiac Transplantation

Osteoporosis is a well-known complication of cardiac transplantation. Rapid bone loss is reported consistently during the first year after transplantation. This study compared alendronate with calcitriol for prevention of bone loss during this critical period. The authors hypothesized that alendronate would be more effective than calcitriol.

This was a 1-year double-placebo double-blind study including 149 patients who had undergone cardiac transplantation within the previous 30 days. Study participants received either active alendronate (Fosamax, 10 mg daily) and a placebo matching the calcitriol or active calcitriol (Rocaltrol, 0.25 [mu]g twice daily) and a placebo matching the alendronate. All patients received calcium and vitamin D daily, as well as glucocorticoids and calcineurin inhibitors, primarily cyclosporine. Patients who declined to participate in the randomized study but who completed all study measurements served as the reference group (n = 27).

Baseline bone mineral density (BMD) measurement, spine radiographs, fasting serum, and 24-hour urine specimens were obtained immediately after transplantation. BMD was repeated at 6 and 12 months; radiography was repeated at 12 months. Primary efficacy end points were the percentage changes in the BMD of the lumbar spine and the femoral neck at 6 and 12 months.

Primary analysis revealed no significant differences between the intervention groups in terms of bone loss or fracture incidence. However, patients treated with either drug had significantly less bone loss at the hip than patients in the reference group. Those who received alendronate had less bone loss at the spine than those in the reference group. These findings suggest that both alendronate and calcitriol prevent bone loss after heart transplantation. Although fewer fractures occurred in patients in the intervention groups than in the referenced group, the differences were not significant.

There were no significant differences between the intervention groups in rates of transplantation-related or gastrointestinal adverse events. More patients in the calcitriol group than the alendronate group required adjustments of the calcium and calcitriol doses. Hypercalciuria and hypercalcemia also developed in more patients in the calcitriol group. The need to monitor serum and urinary calcium levels in patients taking calcitriol may make alendronate a more attractive choice in the early post-transplantation period.

Shane, E., Addesso, V., Namerow, P. B., McMahon, D. J., Lo, S., Staron, R. B., et al. (2004). Alendronate versus calcitriol for the prevention of bone loss after cardiac transplantation. The New England Journal of Medicine 350(8), 767-776.

Nurses Pass Certification Examination

ONCB congratulates the following nurses who passed the certification examination at test centers throughout the country in spring 2004. Since the first examination was offered in 1988, more than 5,000 orthopaedic nurses have passed this rigorous 4-hour examination to become board certified.

Danton Adair Jr.

Tamra Agayb

Joyce Allison

Kimberly Baltrip

Barbara Baugh

Alessandra Beers

Barbara Bennett

Michele Bennett

Jacqueline Bernat

Virginia Boesche

Suzanne Boltach

Paula Bonn

Wendy Boyer

Merla Brooks

Linda Brown

Leslie Bruns-Lamb

Michael Butts

Robin Calcaterra

Patricia Carabetta

Cresenciano Carandang

Deborah Childers

Teresa Cole

Cathy Colley

Cindy Collyott

Ellyn Colyer

Maureen Connors

Naomi Crockett

Anne Cross

Rebecca Crouse

Suzanne Crow

Leslie DaRonco

Edith Dauz

Robin Deem

Jacalyn Dixon

AnnaRita Dorais

Karen Durham

Kelly Edgell

Audrey Edwards

Suzanne Estes

Ellen Fiero

Theresa Foraker

Nancy Frank

Wanda Frederick

Paige Gannon

Preatta Gibbs

Cheryl Grain

Loretta Gray

Karen Gray

Nannette Grinnell

Tammy Hahn-Brown

Sabra Hamad

Kristen Heinig

Heidi Henson

Sharon Higgins

Karen Hightower

Robert Hobbs

Ramona Hunko

Lisa Hutchins

Eva Hyde

Harold Inocencio

Anita Jackson

Bonnie Jackson

Laura Jimenez

Helen Jones

Nancy Kise

Alice Klein

Sarah Kleiner

Penny Kohl

Sandra Kohler

Mary Koogler

J. Alanna Korda-Ackerson

Kathleen Kostas

Amy Kovar

Ellen Kraft

Margaret Kraft

Julie Kroll

Roberta Lake

Jeanne Larsen

Mary Laubach

Ellen Noonan Lenihan

Katrina Leonard

Karen Lewis

Susan Lilly

Sandy Love

Samantha Marsh

Lisa Martin

Robyn Miller

Jo-Ann Mittleman

Sara Moore

Sally Morelli

Michael Mormann

Teresa Nosek

Melissa Oswald

Neal Parish

Claudia Paternoster

Teresa Polly

Paula Polston

Nicole Pratt

Melanie Provencher

Ana Ramirez

Cynthia Reighard

Pia Rena

Audrey Rinscheid

Michelle Ripley

Deidra Ritter

Andre Roy

Elizabeth Rudins

Robert Sanchez Jr.

Florence Shields

Peggy Sommers

Kathy Sproule

Rebecca Stanton

Tammie Steinhard

Nancy Stickradt

Maria Stoute

Ellen Suerth

Christine Taber

Laurencito Tantengco

Kathryn Taylor

Kelli Tesler

Margaret Theisen

Stephanie Thomes

Mary Tolbert

Barbara Tommingo

Sanja Trajkovic

Lisa Turk

Kristel Vorpahl

Sharon Waggoner

Nancy Wagner

Carol Walker

Ellyn Weber

Linda Welch

Elizabeth White

Denise Whitmer

Nadina Whitsitt

Nancy Widman

Deanna Williams

Doris Williams

Sarah Wilson

Christy Yates

Downie Young

Theresita Yray