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Illnesses: Autoimmune Rheumatological Diseases
I Illnesses: Autoimmune Rheumatological Diseases J B Soep and J R Hollister, University of Colorado at Denver and Health Sciences Center, Denver, CO, USA ã 2008 Elsevier Inc. All rights reserved.
Glossary Aneurysm – Localized dilation or ballooning of a blood vessel. Antibody – A protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses. In autoimmune diseases, antibodies are directed against self tissues and/or organs. Arthritis – Swelling of one or more joints with associated pain, warmth, limited range of motion, and/or tenderness. Autoimmune – When the immune system attacks itself by mistake and causes harm to the involved cells or tissues. Autoimmune diseases can affect many parts of the body, including the skin, joints, muscles, nerves, brain, and kidney. Inflammation – A response of body tissues to injury or irritation, characterized by pain, swelling, redness, and heat. Intravenous immunoglobulin (IVIG) – Pooled antibodies extracted from the plasma of blood donors, used to suppress inflammation in several autoimmune diseases. Pauciarticular – Arthritis involving four or fewer joints. Polyarticular – Arthritis involving five or more joints. Purpura – Reddish/purplish discoloration of the skin, caused by small bleeding vessels underneath the skin. Rheumatoid factor – An antibody that can bind to other antibodies that is measurable in the blood and is positive in a subset of juvenile rheumatoid arthritis. Rheumatology – The study of diseases of inflammation and autoimmunity with special interests in causes of rash, fever, arthritis, weakness, weight loss, fatigue, joint and muscle pain.
Synovitis – When the synovium becomes thickened, inflamed, and engorged with fluid, causing joint pain, swelling, and warmth. Synovium – The soft tissue that lines the noncartilaginous surfaces of joints. Systemic – Spread throughout the body, affecting many organs or body systems. Uveitis – Inflammation of the middle layer of the eye, termed the uvea, which includes the iris (the colored part of the eye), the ciliary body (behind the iris), and choroid (the lining under the retina). Vasculitis – A group of diseases featuring inflammation of the wall of blood vessels.
Introduction The immune system normally protects the body from infection. In autoimmune diseases, the immune system is directed against the host, attacking the body’s own organs and tissues. Rheumatologic diseases develop when this autoimmune response causes inflammation involving the musculoskeletal system, skin, and blood vessels. Pediatric rheumatology is the medical subspeciality focused on caring for children with these conditions (Table 1). Because rheumatologic conditions are often associated with chronic joint pain and impaired function, pediatric patients may experience gross-motor and fine-motor delays. Fortunately, with appropriate treatment, the majority of young children with rheumatic diseases can eventually have normal growth and development.
Arthritis Nomenclature There are three classification systems for chronic arthritis in childhood (Table 2); each has attempted to categorize
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this heterogeneous group of patients to improve communication among caregivers, standardize research, and improve patient care. While each classification takes a slightly different approach to dividing the patients with chronic arthritis, they all contain three common subtypes: systemic, polyarticular (five or more joints), and pauciarticular/oligoarticular (four or fewer joints). Epidemiology Juvenile idiopathic arthritis ( JIA) is the most common rheumatic illness in pediatrics. Arthritis is defined as swelling of one or more joints with associated pain, Table 1
Pediatric rheumatologic diseases
Genetics While the cause of JIA in childhood is currently unknown, there appears to be a genetic predisposition. Multiple genes related to inflammation and immunity seem to be involved. Children with arthritis often have family members with a history of other autoimmune diseases such as lupus and rheumatoid arthritis.
Juvenile idiopathic arthritis Systemic Polyarticular Oligoarticular Enthesitis-related arthritis Psoriatic arthritis Systemic lupus erythematosus Scleroderma Dermatomyositis Sarcoidosis Vasculitis Polyarteritis nodosa Henoch-Scho¨nlein purpura Wegener’s granulomatosis Takayasu’s arteritis Behcet’s syndrome Kawasaki disease
Table 2
warmth, limited range of motion, and/or tenderness. Symptoms must be present for at least 6–12 weeks. Diagnostic criteria also include disease onset before the age of 16 years and exclusion of other causes of arthritis. The systemic, polyarticular rheumatoidn factor-negative and oligoarticular subtypes may all present between the ages of 0 and 3 years. The peak age of onset for oligoarticular disease is 2 years. There is a bimodal age distribution for polyarticular arthritis with a peak in toddlers and then again in school-age and adolescent children. The systemic form of JIA has a more uniform age distribution, presenting anytime between infancy and adulthood. In general, girls are affected with chronic arthritis more frequently than boys.
Pathophysiology The synovium, or joint lining, is the target organ for inflammation in JIA. The inflammation results in proliferation of the synovial tissue and secretion of increased amounts of joint fluid. The net result is joint swelling, increased blood flow, and increased inflammatory cells within the joint. If the synovitis persists long enough in
Classification of pediatric chronic arthritis
Juvenile rheumatoid arthritis (American College of Rheumatologya)
Juvenile chronic arthritis (European League Against Rheumatismb)
Juvenile idiopathic arthritis (International League of Associations for Rheumatologyc)
Systemic Polyarticular
Systemic Polyarticular, rheumatoid factor negative Juvenile rheumatoid arthritis (Polyarticular, rheumatoid factor positive) Pauciarticular
Systemic Polyarticular, rheumatoid factor negative Polyarticular, rheumatoid factor positive
Pauciarticular
Juvenile ankylosing spondylitis Juvenile psoriatic arthritis
a
Oligoarthritis Persistent Extended Enthesitis-related arthritis Psoriatic arthritis Undifferentiated arthritis Fits no other category Fits more than one category
Brewer EJ, Jr., Bass J, Baum J, et al. (1977). Current proposed revision of JRA criteria. Arthritis and Rheumatism 20(supplement): 195–199. b European League Against Rheumatism (EULAR) Bulletin No. 4 (1977) Nomenclature and classification of arthritis in children. Basel. National Zeitung AG. c Petty RE, Southwood TR, Baum J, et al. (1998) Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban 1997. Journal of Rheumatology 25: 1991–1994. Reproduced from Cassidy JT and Petty RE (2001) Textbook of Pediatric Rheumatology, 4th edn., p. 215. Philadelphia, PA: Elsevier Saunders, with permission from Elsevier.
Illnesses: Autoimmune Rheumatological Diseases
a particular joint, permanent destruction of the cartilage, underlying bone, and other surrounding joint structures such as ligaments and tendons may occur. Clinical Characteristics Pauciarticular
Oligoarticular or pauciarticular arthritis is the most common form of chronic arthritis in childhood, representing approximately 50% of patients. This form of arthritis involves four or fewer joints and typically affects the large joints in an asymmetric pattern. Extra-articular disease is unusual except for uveitis, chronic inflammation in the anterior chamber of the eye. Uveitis is asymptomatic and affects approximately 10–20% of children with pauciarticular arthritis. Risk factors for uveitis include female gender, disease onset under 7 years, and a positive antinuclear antibody (ANA). Uveitis may cause blindness if untreated. The activity of the eye disease does not correlate with the activity of the arthritis and the risk remains elevated for at least 4 years after the initial diagnosis of arthritis. Therefore, routine ophthalmology examinations, including a slit lamp examination, are required to evaluate for uveitis and if present, necessitates treatment with antiinflammatory eye drops or systemic medications. Patients with pauciarthritis are generally otherwise well and frequently remain very active. Based on the frequent asymmetric distribution, patients who develop arthritis before the age of 3 years may develop muscle atrophy and a leg length discrepancy with the affected leg overgrowing because of increased growth factors in areas of increased blood flow. Polyarticular
Polyarticular disease is defined as arthritis involving five or more joints within 6 months of diagnosis. The arthritis often involves both large and small joints in a symmetric pattern. Polyarthritis comprises approximately 35% of all patients with JIA. There are two subgroups within this category: rheumatoid factor-negative disease (25%) and rheumatoid factor-positive disease (10%). The rheumatoid factor is an antibody associated with more chronic, severe arthritis. Rheumatoid factor-positive disease is typically not seen until late school-age or adolescence. Systemic features of polyarthritis may include fatigue, anemia, and growth failure. Systemic
Systemic arthritis, also known as Still’s disease after George Still who made some of the early observations about juvenile arthritis, makes up approximately 15% of children with JIA. The arthritis is generally polyarticular, affecting both large and small joints. The hallmark is a high spiking fever, often as high as 39 to 40 C with rapid return to baseline or subnormal temperatures. The fever
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typically occurs 1–2 times per day, frequently in the late afternoon or evening. There is also a characteristic rash that consists of salmon-pink flat lesions of different sizes. The rash moves all over the body, not lasting in one location for more than minutes to hours. It is most often seen over pressure areas and when the fever is present. The rash is occasionally itchy. Patients frequently have other systemic features including enlarged liver and spleen, swollen glands, inflammation of the lining of the heart and/or lungs, tendonitis, and hepatitis. Impact on Growth and Development JIA is often associated with abnormalities of growth and development. Due to the chronic joint symptoms, including pain, swelling, and stiffness, patients may have delayed motor skills. Patients may present with delays in fine and gross motor development. Young children may have difficulty pulling to a stand and cruising or parents may note an abnormal gait once the child learns to walk. Toddlers may have trouble with coordination and may have difficulty keeping up with their peers. Occasionally children are diagnosed with cerebral palsy due to the asymmetric abnormalities in range of motion and function. Alternatively, patients may be noted to lose developmental milestones, coinciding with the onset of their joint symptoms. Proper treatment of the disease should allow the patient to ‘catch-up’ and again meet their normal milestones. The disease has no significant impact on cognitive development. Chronic systemic inflammation is frequently associated with retardation in linear growth. In addition, treatment with steroids, at doses of greater than 3 mg per day, are growth suppressing. During remission, patients usually return to their baseline growth velocity. If patients continue to be significantly below the fifth percentile in height, even when their disease is adequately controlled and after they have tapered down on their steroids, they can be treated successfully with growth hormone. There may also be localized growth abnormalities. Increased blood flow and growth factors can lead to accelerated linear growth surrounding an involved joint with a resultant leg length discrepancy or may lead to localized bony overgrowth. Alternatively, patients may have premature closure of the growth plates or destruction of a growth center leading to shortening of a limb or digit. Micrognathia, shortening of the jaw, may be seen when there is long-standing inflammation of the temporomandibular joint and can lead to significant pain, facial deformity, difficulty opening the mouth, and chewing. Laboratory Tests There are no specific or diagnostic laboratory tests for JIA. Markers of systemic inflammation, such as
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sedimentation rate and c-reactive protein, are typically quite elevated with active systemic illness and may be mildly elevated with polyarticular involvement. Most commonly all of the laboratory tests are normal in the case of oligoarticular disease. Synovial fluid analysis, if performed, typically demonstrates a white blood cell count between 5000 and 60 000 cells ml 1with a normal to slightly decreased glucose.
Radiologic Studies Standard radiographs are not diagnostic of early juvenile arthritis. Early nonspecific findings include osteoporosis and soft-tissue swelling. The primary purpose of X-rays in early disease is to exclude other conditions that may be associated with bony changes. Late changes of chronic arthritis include joint space narrowing due to thinning of the cartilage and erosions of the underlying bone. Magnetic resonance imaging may demonstrate joint damage earlier than standard X-rays and, if performed with contrast, can help identify areas of active synovitis.
Table 3 0–3 years
Common causes of joint pain in children aged
Mechanical/orthopedic Trauma Hypermobility Growing pains Infectious diseases Bacterial Osteomyelitis Septic arthritis Viral Parvovirus Epstein Barr Virus Reactive arthritis Other Lyme disease Malignancy Leukemia Lymphoma Neuroblastoma Osteoid osteoma Rheumatic diseases Dermatomyositis Vasculitis Sarcoidosis
Differential Diagnosis Because there are no diagnostic tests for JIA and because it is a diagnosis of exclusion, it is important to rule out other causes of the clinical findings prior to making the diagnosis. Often the differential diagnosis is quite broad, including orthopedic abnormalities, infectious etiologies, and malignancy (Table 3). There are a few key features that can help distinguish these different entities. Characterizing the timing of the pain can be very helpful. In inflammatory conditions such as arthritis, patients frequently have increased symptoms in the morning with associated morning stiffness and gelling–stiffness after periods of inactivity. In contrast, patients with a mechanical problem typically have the least pain in the morning and have worsening symptoms throughout the day and with activity. Orthopedic problems may also be associated with popping, locking, and giving out of the joint. The classic features of growing pains are poorly localized pain occurring at night, waking the child from sleep with no objective signs of inflammation, and absence of symptoms during the day. Patients with growing pains usually like to have the affected area massaged, while this is typically not seen in arthritis. When considering infectious causes, we need to observe for the presence of focal symptoms, usually in association with significant pain, swelling, warmth, and possibly redness of the involved area. Patients often have a persistent fever. Bacterial infections may involve the joint, as in septic arthritis, or the bone, as in osteomyelitis, or both. If infection is being considered it is important to obtain appropriate
cultures. In cases of postinfectious or reactive arthritis, a preceding illness is identified in approximately 50% of cases. Typically the onset of arthritis is acute and severe and may affect one or multiple joints and may have a migratory pattern. A very important distinction between reactive arthritis and chronic arthritis is the duration of symptoms. In order to meet criteria for chronic arthritis, symptoms must be present for at least 6–12 weeks. In contrast, the symptoms associated with reactive arthritis typically resolve completely within 4–6 weeks with a low rate of recurrence. Features that may suggest an underlying malignancy include pain out of proportion to physical findings, pain and swelling around the joint instead of the joint itself, enlarged liver or spleen, swollen glands, and an elevated lactate dehydrogenase (LDH) or uric acid. X-rays may demonstrate direct bone infiltration or nonspecific findings including increased or decreased density lines in the broad portion of the bone called metaphyseal bands. Treatment Goals of treatment are to control pain; preserve range of motion, strength and function; manage systemic complications; and facilitate normal nutrition, growth, and physical and psychological development. The traditional approach is to begin with the safest, simplest, and most
Illnesses: Autoimmune Rheumatological Diseases
conservative measures and then intensify treatment as needed to manage the signs and symptoms of the disease. Nonsteroidal anti-inflammatory medications (NSAIDs), such as ibuprofen and naproxen, are the mainstay of therapy. Steroids are reserved for the severely affected child, primarily patients with systemic disease. Monoarticular or oligoarticular disease can be treated with local steroid joint injections. Other disease-modifying, anti-rheumatic medications include methotrexate, leflunomide, and cyclosporine. Newer biologic medications, such as etanercept, infliximab, adalimumab, and anakinra, inhibit specific cytokines – proteins that are known to play a significant role in the inflammation and chronic bone and cartilage changes seen in chronic arthritis. Rehabilitation services, such as physical and occupational therapy, are very important to minimize pain, maintain and restore function, and prevent deformity and disability. Splinting and special exercises to prevent deformity and contractures may be needed. Treatments include heat and cold, water therapy, ultrasound, range of motion and strengthening exercises, gait training, joint protection, serial casting, and shoe lifts. Prognosis The course and prognosis for JIA is variable. With oligoarticular disease, many patients eventually go into remission within a few years without any long-term sequelae. Patients rarely have permanent cartilage or bone damage. However, patients may have fixed flexion contractures or leg length discrepancies that can impact their normal gait and function. In addition, these patients may be at higher risk for osteoarthritis in the future. There is a subgroup of patients, those with extended oligoarticular disease, who have a progressive increase in the number of involved joints so that they ultimately have a polyarticular course and may have more chronic or severe disease. The prognosis for chronic anterior uveitis has been improving with the current options for treatment. However, visual loss may still occur. Other complications include glaucoma and cataracts that may lead to increased visual impairment. The rheumatoid factor-negative polyarticular disease seen in young patients generally goes into remission within several years without permanent joint damage. Patients in this age group with the worst prognosis include those who have been referred late in their course and those with early involvement of the small joints of the hands and feet. The systemic features associated with systemic arthritis, including the fever and rash, tend to remit within months to years. However, these symptoms may recur with subsequent exacerbations of the arthritis. The ultimate prognosis in this form of chronic arthritis is
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determined by the extent of their arthritis. Those patients with a more polyarticular course of arthritis have a worse functional outcome.
Lupus Pediatric systemic lupus erythematosus is very rare under the age of 5 years, more typically presenting in schoolage children and adolescents. However, neonatal lupus erythematosus is a form of lupus that occurs in infancy. This condition is associated with specific maternal antibodies that cross the placenta and attack fetal and neonatal tissues. It most commonly affects the heart, skin, blood, and liver.
Pathophysiology Specific maternal antibodies, anti-Ro and anti-La, are required for the development of neonatal lupus. Mothers may have an underlying autoimmune condition such as systemic lupus erythematosus or Sjogren’s syndrome or may be asymptomatic. These antibodies cross the placenta and react with fetal and neonatal tissues, causing an inflammatory reaction. Findings become apparent at birth or in the early postnatal period. Aside from the congenital heart block (CHB), the other clinical features are transient, coinciding with the presence of the antibodies and usually resolving by 6–12 months as the antibodies are broken down.
Clinical Manifestations Cardiac The most significant manifestation of neonatal lupus is CHB in which the electrical impulses fail to conduct normally through the heart. This may become apparent either in utero or soon after birth. To date, third-degree atrioventricular block, when the atria and ventricles beat independently, is irreversible. CHB is associated with significant complications and risk of mortality. A majority of patients require pacemakers during their entire lives. Other less common cardiac manifestations include structural abnormalities and inflammatory processes such as myocarditis (inflammation of the heart muscle), or pericarditis (inflammation of the lining of the heart). Skin The rash associated with neonatal lupus consists of oval, red lesions on the face, scalp, trunk, and extremities. The rash is typically found in sun-exposed areas and is strongly photosensitive. The lesions may be present at birth or develop
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postnatally. Patients often present after being exposed to the fluorescent lights in the newborn nursery or after beginning phototherapy for high bilirubin. Generally the rash resolves without a scar. Blood
Neonatal lupus can be associated with immune-mediated low platelet, white blood cell, and red blood cell counts. Occasionally, these effects on the blood lines are severe enough to require transfusions. Liver
Infants with neonatal lupus may present with liver dysfunction. Typically patients have an enlarged liver, with or without an enlarged spleen, bile stasis, and increased liver function tests. The liver function abnormalities usually resolve without any permanent dysfunction. Treatment The majority of the manifestations of neonatal lupus resolve without any specific treatment once the maternal antibodies are broken down, typically within 6–12 months. Severe systemic manifestations occasionally require treatment with steroids or intravenous immunoglobulin (IVIG). Prognosis The blood, liver, and skin manifestations typically resolve without any long-term sequelae. Babies with associated heart block have a more guarded prognosis as they are at risk for congestive heart failure and generally require long-term pacemakers.
Vasculitis Nomenclature Vasculitides, autoimmune conditions associated with inflammation of blood vessels, are often classified based on involved vessel size (Table 4).
Table 4
Classification of vasculitides
Large vessel Takayasu’s arteritis Giant cell arteritis Medium vessel Kawasaki disease Wegener’s granulomatosis Polyarteritis nodosa Churg-Strauss syndrome Small vessel Henoch-Scho¨nlein purpura Microscopic polyarteritis
Henoch-Scho¨nlein purpura Epidemiology
Henoch–Scho¨nlein purpura (HSP) is one of the most common forms of systemic vasculitis in children. Onset of HSP is most common in the winter. Often there is a preceding, viral, upper respiratory infection or streptococcal disease. Clinical manifestations
The common clinical characteristics include purpura, arthritis, abdominal pain with or without gastrointestinal bleeding, blood and protein in the urine, and inflammation of the testicles. The typical rash consists of palpable, purple, nonblanching lesions, most commonly on the lower extremities. They often begin as red, flat spots or hive-like lesions that become purpuric in nature, turning purple, then brown, and then slowly resolving. Young children with HSP frequently have significant swelling of the scalp, extremities, scrotum, and around the eyes. Patients may also have vasculitis and swelling of the lining of the intestine, leading to crampy abdominal pain, with or without hemorrhage. Small intestine intussusception, when the intestine telescopes on itself, is one of the most common gastrointestinal complications, presenting with colicky pain, a distended abdomen, and vomiting. Kidney disease, manifested as blood and protein in the urine and high blood pressure and less commonly renal failure, occurs in approximately one-third of patients. The kidney findings generally develop within 3 months of the onset of symptoms. Joint pain and/or frank arthritis occur in most patients. Less common manifestations include central nervous system vasculitis and hemorrhage into the lungs. Acute hemorrhagic edema, a variant of HSP in children less than 2 years of age, is manifested as fever, purpura, and significant swelling of the face and extremities. Kidney and gastrointestinal involvement in this form is uncommon. Laboratory tests
There are no diagnostic laboratory tests for HSP. General markers of inflammation, including sedimentation rate and c-reactive protein, are typically elevated. The antinuclear antibody and rheumatoid factor are usually negative. Antibodies associated with vasculitis, antineutrophil cytoplasmic antibodies (ANCA), may be present. Serum immunoglobulin A levels may be elevated. Treatment
Treatment of HSP is supportive, focusing on maintaining hydration and managing pain. Generally, management with acetaminophen or NSAIDs such as ibuprofen is sufficient to control the pain. Systemic steroids are indicated to manage severe abdominal pain and/or hemorrhage. If steroids are discontinued abruptly, patients often experience a rapid return of symptoms. Therefore, once
Illnesses: Autoimmune Rheumatological Diseases
steroids have been started, it is recommended to taper them over several weeks to avoid this rebound of symptoms. Severe renal disease may also be managed with highdose steroids with or without chemotherapeutic agents such as cyclophosphamide.
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frequently reveal blood and protein in the urine with abnormal kidney function tests. A positive P-ANCA is seen in a majority of patients. Angiograms are typically negative because these imaging studies usually cannot detect small vessel disease. A biopsy of involved tissue demonstrates vasculitis of small vessels.
Prognosis
Generally, the signs and symptoms of HSP are self-limiting, with complete resolution within 1 month. However, it is not unusual to have at least one recurrence, often within the first couple of months after the first occurrence. Typically, subsequent episodes are briefer and less severe. When children have multiple episodes of HSP, it is important to screen for streptococcal disease; if this is identified as a trigger, preventive antibiotics may be helpful in preventing subsequent episodes. The renal disease associated with HSP has a more variable outcome. Patients who present with isolated mild blood and/or protein in the urine generally do well, with no long-term sequelae. Patients with more severe kidney inflammation, manifested as high blood pressure and decreased kidney function, have a higher rate of chronic renal disease with a small percentage of children developing end-stage renal failure.
Treatment
Treatment of both forms of polyarteritis includes systemic steroids to manage the acute manifestations. Additional immunosuppressive agents such as cyclophosphamide, azathioprine, or methotrexate may be indicated for more severe disease or for those patients who need a steroidsparing agent. Prognosis
The prognosis of polyarteritis is variable. Patients with cutaneous PAN generally have a good outcome; however, they may have relapses over a period of several years. In general, patients with classic PAN and microscopic polyangiitis require long-term treatment with immunosuppressive medications. With these treatments, patients may have significant complications, such as kidney failure, high blood pressure, and seizures, but appear to have relatively low mortality.
Polyarteritis Clinical manifestations
There are two main types of polyarteritis. Polyarteritis nodosa (PAN) typically presents with fatigue, weight loss, fever, rash, abdominal pain, and arthritis. Patients may also have muscle pain; testicular pain; kidney involvement such as high blood pressure and blood in the urine; and neurologic symptoms such as seizures, focal deficits, and visual loss. The skin lesions include lumps under the skin called nodules, purpura, or ulcerated areas. Laboratory testing typically reveals anemia, increased white blood cell counts, platelet counts, and other markers of inflammation. In classic PAN, the ANCA is generally negative. Angiograms, special imaging studies that evaluate blood vessels, may demonstrate areas of dilated or narrowed vessels, particularly involving the kidney and intestine. Biopsies of involved areas confirm the presence of segmental vasculitis of small and medium arteries. There is a cutaneous form of PAN that is limited to fever, rash, and joint symptoms. The most characteristic finding is purpura, most commonly of the lower extremities and sometimes on the soles of the feet. The lesions are often quite tender and can interfere with walking. Outbreaks can be triggered by streptococcal infections and in these cases, may be prevented by using prophylactic antibiotics. Microscopic polyangiitis, in contrast, generally presents with pulmonary hemorrhage and rapidly progressive kidney inflammation. Patients may also have muscle pain, arthritis, abdominal pain, and purpura. Laboratory tests demonstrate increased inflammatory markers and
Kawasaki disease Epidemiology
Kawasaki disease (KD) is another common form of vasculitis in young children, with a peak incidence between 6 and 11 months. Infants may not present with typical characteristics and therefore may have a delay in diagnosis and treatment and ultimately a worse outcome. The cause of this multisystem, inflammatory condition is unknown. Many features of this disease suggest an infectious etiology; however, no single agent has been identified. There are reports of seasonal peaks and clusters in different geographical areas. Clinical manifestations
The fever is typically 39–40 C, for 5 or more days. The fever is unresponsive to antibiotics and usually poorly responsive to acetaminophen and ibuprofen. Patients often have bilateral conjunctivitis without eye drainage and sparing the area closest to the iris. The swollen glands, also known as lymphadenopathy, seen with KD, are typically located on one side of the neck and are greater than 1.5 cm in diameter. The rash is variable and may consist of red, flat, or raised areas, may be purpuric, or can resemble the rash of scarlet fever. The rash may involve the trunk, face, extremities, and diaper area. As the rash resolves, there is often peeling of the affected areas. While the fever is present, children frequently have red, dry, cracked, swollen lips and/or a ‘strawberry’ tongue. The typical extremity changes include swelling
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of the hands and feet in the early phases of the disease and later peeling of the tips of the fingers and toes. The most serious manifestation of KD is heart disease. There is a predilection for involvement of the coronary arteries, the arteries feeding the heart. The vasculitis may lead to aneurysms of involved vessels. Severe sequelae may include impaired heart function, heart attack and abnormal heart rhythm. Patients may also have dilation of other vessels such as arteries in the arm and leg. Other manifestations include sterile meningitis with headache and extreme irritability, uveitis, joint pain, arthritis, muscle inflammation, inflammation of the gallbladder, and white blood cells in the urine with negative urine cultures. Laboratory and imaging studies
During the acute phase of KD, patients typically have significant elevation of inflammatory markers including sedimentation rate, c-reactive protein, and white blood cells. The platelet count often rises 2–4 weeks into the illness. As with other forms of vasculitis, patients may have a positive ANCA. Patients may also have mild elevation in the liver function tests, anemia, white blood cells in the urine and spinal fluid with negative bacterial and viral cultures. Echocardiograms are necessary to diagnose and monitor coronary artery abnormalities. Biopsies of involved tissue demonstrate vasculitis of medium-sized arteries. Treatment
Standard treatment for KD includes IVIG 2 g kg 1 as a single dose. Administration of IVIG within the first 10–12 days of illness is usually associated with improvement in all clinical manifestations and reduction in the frequency and severity of coronary artery abnormalities. Occasionally, patients will have a recurrence of symptoms such as fever, rash, and the lip and tongue changes, and in these cases, they often benefit from a second dose of IVIG. Patients should also be treated with aspirin, at anti-inflammatory doses during the acute phase of the disease and then at lower doses to achieve antiplatelet effects to decrease the risk of blood clots in the abnormal vessels. The role of steroids in the treatment of KD is controversial and usually reserved for patients with severe or resistant disease. In addition, stronger immunosuppressive medications such as cyclophosphamide and infliximab have been used for recalcitrant cases. Generally, patients should have an echocardiogram at the time of diagnosis and then have a repeat study within 2–6 weeks. No additional studies are needed for patients who have no evidence of coronary involvement on the repeat scan. Patients who have evidence of coronary abnormalities, however, require regular follow-up studies to monitor for evolution of their disease and to screen for premature cardiovascular disease that may be a late sequelae of KD.
Prognosis
In general, the clinical manifestations of KD resolve with appropriate treatment without any long-term sequelae. The major exception is in those with coronary involvement who may have significant complications and some risk of early and late mortality.
Dermatomyositis Epidemiology Dermatomyositis is the most common inflammatory muscle disease of childhood. This condition may present at any age, with a peak age of onset around 7 years of age and a second peak in adulthood. The cause of dermatomyositis is unknown and likely multifactorial, involving a genetic predisposition, environmental factors such as sun exposure, and possibly, in at least some cases, a viral trigger. Pathophysiology The clinical features of dermatomyositis are caused by abnormalities of small blood vessels, ultimately leading to decreased blood flow and damage to the end organs, including striated muscle, skin, and gastrointestinal tract. Clinical Manifestations Constitutional Poor appetite, weight loss, fatigue, fever, and malaise may be present. Musculoskeletal Patients have symmetrical weakness, primarily affecting the muscles of the neck, abdomen, shoulders, and hips. Children frequently have difficulty climbing stairs, getting up from a chair, and combing their hair. The muscles in the larynx, pharynx, and palate can be involved, causing nasal speech, weakness of the voice, and regurgitation of liquids through the nose and increasing the risk of aspiration of fluids into the lungs. Patients frequently have a positive Gower’s sign; when asked to get up from sitting on the floor, they use their hands to walk up the anterior aspects of their thighs to compensate for their pelvic muscle weakness. Neck flexor weakness is a particularly sensitive indicator of muscle impairment. Patients may also have muscle pain, as well as swelling and tightness over the muscles. After long-standing disease, patients may eventually develop muscle atrophy. The position of comfort is flexion of the limbs, promoting the development of flexion contractures. Patients may have arthritis, usually symmetric, involving both large and small joints.
Illnesses: Autoimmune Rheumatological Diseases
Skin
The typical rashes may precede or follow the onset of muscle weakness and may occur in the absence of elevated muscle enzymes. Swelling around the eyes and dilated, tortuous, superficial vessels over the eyelid are often seen. One of the classic findings in dermatomyositis is the heliotrope rash, manifested as a purple discoloration of the eyelids. The rash is frequently photosensitive. Sun exposure may exacerbate the rash alone, or may activate the muscle inflammation as well. Another pathognomonic rash is Gottron’s papules, thickened, pale, or red raised plaques over the knuckles, elbows, and knees. Patients may also develop a red rash on the cheeks and nasal bridge, on the chest (‘V’ rash), or upper back (‘shawl rash’). Diffuse vasculitis, manifested as abnormal blood vessels along the cuticle edge and ulcers of the skin around the mouth or on the finger tips, may be associated with more severe disease. Calcinosis, calcium deposits under the skin, occurs in up to 70% of patients. Calcinosis frequently develops months to years after the onset of disease and is often located at sites exposed to trauma. While the cause of calcinosis is unknown, it appears to be related to disease severity and duration. Patients treated early and aggressively have a decreased risk of developing soft tissue calcifications. Gastrointestinal
Patients may have esophageal hypomotility that can contribute to the swallowing dysfunction. Vasculitis can affect any part of the gastrointestinal tract and may impair absorption, cause weight loss, and progress to ulceration with perforation of the intestine. Cardiopulmonary
Patients may have electrocardiogram abnormalities, most commonly asymptomatic changes in the electrical conduction within the heart. Decrease in ventilatory capacity in the absence of respiratory symptoms may occur due to muscular weakness. Pulmonary inflammation and scarring may also occur. Diagnostic Criteria There are five diagnostic criteria for dermatomyositis, including characteristic rash, symmetrical proximal muscle weakness, elevated muscle enzymes, typical muscle pathology on biopsy, and inflammatory changes in the muscle by electromyography (EMG), a technique to study the physiologic properties of muscles. In order to make a definitive diagnosis of dermatomyositis, patients need rash and 3 or 4 other criteria. Patients have probable disease if they have rash with two criteria and possible dermatomyositis with rash and one criterion. Usually, the diagnosis is made based on the physical and laboratory findings. An EMG and/or biopsy are usually not necessary unless the features are atypical.
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Laboratory and Radiologic Data Muscle-derived enzymes (creatine kinase, LDH, aspartate transaminase (AST), alanine aminotransferase (ALT), aldolase) may all be elevated, or a single value may be abnormal. Usual indications of inflammation, such as sedimentation rate and white blood cell count, are often normal, despite widespread inflammation. A magnetic resonance imaging study of the involved muscles may be helpful in confirming the presence of muscle inflammation, monitoring disease activity, or assisting in locating an appropriate location for biopsy. Pathology Biopsy of involved areas includes vasculitis and noninflammatory blood vessel abnormalities affecting arterioles, capillaries, and venules. Muscle biopsy findings reveal atrophy of the muscle fibers surrounding the involved blood vessels, vascular inflammation with muscle fiber degeneration, cell death, and regeneration. Treatment There are several emergent issues that need to be assessed when the patient presents. Children should be evaluated for any evidence of respiratory compromise, keeping in mind that patients may not exhibit all of the typical signs of respiratory distress because of their significant weakness. Patients also need to be assessed for intestinal vasculitis if they have any abdominal pain or diarrhea since this complication is associated with significant complications and mortality. Evaluations to consider include checking the stool for blood and an abdominal computed tomography scan. In addition, any patient who has voice changes and/or reports of swallowing difficulty should not be allowed to take anything by mouth until appropriate swallowing evaluations can be performed to assess for risk of aspiration. Steroids are the therapy of choice. Because patients may have some degree of intestinal inflammation, intravenous dosing may be indicated for moderate-to-severe disease to improve absorption. Steroids are gradually tapered to a low maintenance dose while monitoring the physical examination and muscle enzymes. Children usually require treatment with these small doses of steroids for at least 2 years since stopping this medication sooner is associated with an increased risk of an exacerbation in their disease. It is important to monitor for long-term side effects of steroids, including osteoporosis, glaucoma, cataracts, growth retardation, and steroid myopathy that can contribute to muscle weakness and atrophy. In patients with more resistant disease or with significant steroid side effects, additional medications may be added, such as methotrexate and cyclosporine. IVIG and
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hydroxychloroquine are particularly good for managing rash. Sun protection, using sunscreen with greater than or equal to sun protection factor (SPF) 30, is very important. Physical and occupational therapy should be used to prevent loss of range of motion and development of contractures by implementing passive range of motion exercises in the early phases of disease and more intensive, graded exercises at later stages focused on stretching and strengthening. Prognosis At least 80% of patients have a unicyclic course. Therefore, only a small percentage of children have resistant disease with more continuous or recurrent courses. It is difficult to predict the outcome at the onset of illness. Factors that have been associated with a poor prognosis include persistent, severe disease activity, extensive vasculitis, calcinosis, difficulty swallowing, and voice changes. There are certain muscle-specific antibodies that are associated with more severe disease. Also, delay in treatment or inadequate treatment, is associated with a worse prognosis.
Sarcoidosis
Laboratory and Pathologic Findings Laboratory abnormalities include increased markers of inflammation, increased immunoglobulins, and elevated calcium in the blood and urine. Pathologic specimens demonstrate granulomas – nodular collections of inflammatory cells. Angiotensin-converting enzyme (ACE) is produced by cells within the granulomas; therefore, serum levels are often elevated, although this is less common in young children. It is important to recognize that serum ACE levels are higher in children and therefore it is necessary to use appropriate normal values to interpret the results of this test. Treatment Treatment generally involves systemic steroids and additional immunosuppressive agents, such as methotrexate, azathioprine, and infliximab may be used to achieve better disease control and to minimize the side effects of prednisone. Prognosis Children with sarcoidosis tend to have chronic symptoms and may suffer from long-term complications of this disease. Specifically, the joint disease can lead to severe growth delay as well as destruction of cartilage and bone. Patients with uveitis may develop significant visual impairment.
Clinical Manifestations Sarcoidosis is a multisystem autoimmune condition. There are two patterns of presentation, including a group of patients who present before the age of 4 years. These patients with early-onset sarcoid typically have skin, joint, and eye disease. The rash may be flat, raised, or nodular. The arthritis associated with sarcoidosis is typically quite proliferative with significant thickening of the synovium and large collections of fluid in the joints. The physical findings are often out of proportion to the joint symptoms with minimal pain, decreased range of motion, and stiffness. Patients may develop uveitis, involving the anterior and/or posterior areas. The collections of white blood cells seen in the eye can produce a ‘snowbank’ appearance when examined by an ophthalmologist. Other manifestations, such as swollen glands, enlarged liver and spleen, and lung involvement, seen in older-onset sarcoidosis are rare in young children.
Conclusions/Future Directions Pediatric rheumatic diseases are rare autoimmune conditions that may have significant impacts on development and quality of life and can be associated with long-term sequelae. Clinical and basic science research is now focused on standardizing diagnostic criteria and outcome measures, validation of quality of life instruments, further investigations of possible genetic and environmental triggers, and novel therapies that will hopefully improve the overall outcomes of affected children. See also: Allergies; Asthma; Colic; Crying; Failure to Thrive; Feeding Development and Disorders; Immune System and Immunodeficiency; Physical Growth; Prenatal Development; Screening, Newborn and Maternal Well-being; Screening, Prenatal; Vision Disorders and Visual Impairment.
Genetics There have been familial cases of patients with early-onset disease. Some of these cases have a specific gene mutation and have been classified as having Blau syndrome. The relationship between sarcoidosis and Blau syndrome is not entirely clear but they appear to be along a similar spectrum of disease.
Suggested Readings Cassidy JT and Petty RE (2001) Textbook of Pediatric Rheumatology, 4th edn, p. 215. Philadelphia, PA: Elsevier Saunders. Cassidy JT, Petty RE, Laxer RM, and Lindsley CB (2005) Textbook of Pediatric Rheumatology, 5th edn. Philadelphia, PA: Elsevier Saunders.
Imagination and Fantasy Compeyrot-Lacassagne S and Feldman BM (2005) Inflammatory myopathies in children. Pediatric Clinics of North America 52: 493–520. Dedeoglu F and Sundel RP (2005) Vasculitis in children. Pediatric Clinics of North America 52: 547–575. European League Against Rheumatism (EULAR) Bulletin No. 4 (1997) Nomenclature and classification of arthritis in children Basel: National Zeitung AG. Klippel JH (1997) Primer on the Rheumatic Diseases, 11th edn. Atlanta: Arthritis Foundation. Ravelli A and Martini A (2007) Juvenile idiopathic arthritis. Lancet 369: 767–778. Tse SML and Laxer RM (2006) Approach to acute limb pair in childhood. Pediatric in Review 27: 170–180.
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Weiss JE and Ilowite NT (2005) Juvenile idiopathic arthritis. Pediatric Clinics of North America 52: 413–442.
Relevant Websites http://www.aap.org – American Academy of Pediatrics. http://www.rheumatology.org – American College of Rheumatology. http://www.arthritis.org – Arthritis Foundation. http://www.niams.nih.gov – NIAMS, National Institute of Arthritis and Musculoskeletal and Skin diseases. http://www.myositis.org – The Myositis Association, Juvenile Dermatomyositis.
Imagination and Fantasy J D Woolley and A Tullos, The University of Texas, Austin, TX, USA ã 2008 Elsevier Inc. All rights reserved.
Glossary Fantasy – A subset of imagination in which the imagined entity, object, or scenario is more extravagant or less constrained by reality. Imagination – The formation of mental imagines of entities or events that are not present to the senses. Individual differences – Characteristics of children’s biological, social, environmental, or genetic makeup that make them different from other children the same age. Without individual differences, all children of the same age would develop similarly. Object substitution – Involves using one object to stand for another. For example, children might pretend that a cardboard box is a castle. Pretend play – An activity in which children’s behavior involves some form of nonreality. It often involves some or all of the following six behaviors: (1) self-pretense, (2) object substitution, (3) animation of objects, (4) pretending about imaginary objects, (5) pretending to be another person or entity, and (6) pretending to have imaginary companions. Pretense – Involves mental, verbal, or physical engagement in nonreality. Role play – Involves imagining and acting out the role of another person or creature. It can involve acting like another person, behaving toward a toy as if it is really what it represents, or interacting with a pretend being, such as an imaginary companion.
Introduction Walk into any preschool classroom, and evidence of young children’s imagination abounds. In one corner of the room you might observe children playing dress-up, in another the products of a finger-painting project, and in another a child building a castle out of colorful blocks. Many consider the preschool years to represent the peak of imaginative and fantastical thinking. In this article we explore the origins and development of imagination and fantasy from its earliest observable manifestations in older infants and toddlers through its peak in the later preschool years. We must begin by considering what we mean by imagination and fantasy. The word ‘imagination’ is certainly used in a multitude of ways to mean many things: ‘‘use your imagination,’’ ‘‘she or he’s got a good imagination,’’ ‘‘I can’t imagine what it would be like,’’ are some common examples. In its most basic sense, imagination is the formation of a mental image of something that is not present to the senses; it is the act of conceiving of an alternative to reality. Imagination is the ability to think of things as otherwise than we see them or as different from how they exist in the world. Imagination can include thinking about the immediate future (e.g., imagining how good a cookie would taste) and the distant future (e.g., imagining being a grown-up), as well as the more prototypical uses found in the quotes above. Fantasy is most often taken to be a subset of imagination, or imagination that is somehow farther removed or less restricted by reality. For example, a fantasy may involve slaying dragons or time travel,
Glossary Aneurysm – Localized dilation or ballooning of a blood vessel. Antibody – A protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses. In autoimmune diseases, antibodies are directed against self tissues and/or organs. Arthritis – Swelling of one or more joints with associated pain, warmth, limited range of motion, and/or tenderness. Autoimmune – When the immune system attacks itself by mistake and causes harm to the involved cells or tissues. Autoimmune diseases can affect many parts of the body, including the skin, joints, muscles, nerves, brain, and kidney. Inflammation – A response of body tissues to injury or irritation, characterized by pain, swelling, redness, and heat. Intravenous immunoglobulin (IVIG) – Pooled antibodies extracted from the plasma of blood donors, used to suppress inflammation in several autoimmune diseases. Pauciarticular – Arthritis involving four or fewer joints. Polyarticular – Arthritis involving five or more joints. Purpura – Reddish/purplish discoloration of the skin, caused by small bleeding vessels underneath the skin. Rheumatoid factor – An antibody that can bind to other antibodies that is measurable in the blood and is positive in a subset of juvenile rheumatoid arthritis. Rheumatology – The study of diseases of inflammation and autoimmunity with special interests in causes of rash, fever, arthritis, weakness, weight loss, fatigue, joint and muscle pain.
Synovitis – When the synovium becomes thickened, inflamed, and engorged with fluid, causing joint pain, swelling, and warmth. Synovium – The soft tissue that lines the noncartilaginous surfaces of joints. Systemic – Spread throughout the body, affecting many organs or body systems. Uveitis – Inflammation of the middle layer of the eye, termed the uvea, which includes the iris (the colored part of the eye), the ciliary body (behind the iris), and choroid (the lining under the retina). Vasculitis – A group of diseases featuring inflammation of the wall of blood vessels.
Introduction The immune system normally protects the body from infection. In autoimmune diseases, the immune system is directed against the host, attacking the body’s own organs and tissues. Rheumatologic diseases develop when this autoimmune response causes inflammation involving the musculoskeletal system, skin, and blood vessels. Pediatric rheumatology is the medical subspeciality focused on caring for children with these conditions (Table 1). Because rheumatologic conditions are often associated with chronic joint pain and impaired function, pediatric patients may experience gross-motor and fine-motor delays. Fortunately, with appropriate treatment, the majority of young children with rheumatic diseases can eventually have normal growth and development.
Arthritis Nomenclature There are three classification systems for chronic arthritis in childhood (Table 2); each has attempted to categorize
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this heterogeneous group of patients to improve communication among caregivers, standardize research, and improve patient care. While each classification takes a slightly different approach to dividing the patients with chronic arthritis, they all contain three common subtypes: systemic, polyarticular (five or more joints), and pauciarticular/oligoarticular (four or fewer joints). Epidemiology Juvenile idiopathic arthritis ( JIA) is the most common rheumatic illness in pediatrics. Arthritis is defined as swelling of one or more joints with associated pain, Table 1
Pediatric rheumatologic diseases
Genetics While the cause of JIA in childhood is currently unknown, there appears to be a genetic predisposition. Multiple genes related to inflammation and immunity seem to be involved. Children with arthritis often have family members with a history of other autoimmune diseases such as lupus and rheumatoid arthritis.
Juvenile idiopathic arthritis Systemic Polyarticular Oligoarticular Enthesitis-related arthritis Psoriatic arthritis Systemic lupus erythematosus Scleroderma Dermatomyositis Sarcoidosis Vasculitis Polyarteritis nodosa Henoch-Scho¨nlein purpura Wegener’s granulomatosis Takayasu’s arteritis Behcet’s syndrome Kawasaki disease
Table 2
warmth, limited range of motion, and/or tenderness. Symptoms must be present for at least 6–12 weeks. Diagnostic criteria also include disease onset before the age of 16 years and exclusion of other causes of arthritis. The systemic, polyarticular rheumatoidn factor-negative and oligoarticular subtypes may all present between the ages of 0 and 3 years. The peak age of onset for oligoarticular disease is 2 years. There is a bimodal age distribution for polyarticular arthritis with a peak in toddlers and then again in school-age and adolescent children. The systemic form of JIA has a more uniform age distribution, presenting anytime between infancy and adulthood. In general, girls are affected with chronic arthritis more frequently than boys.
Pathophysiology The synovium, or joint lining, is the target organ for inflammation in JIA. The inflammation results in proliferation of the synovial tissue and secretion of increased amounts of joint fluid. The net result is joint swelling, increased blood flow, and increased inflammatory cells within the joint. If the synovitis persists long enough in
Classification of pediatric chronic arthritis
Juvenile rheumatoid arthritis (American College of Rheumatologya)
Juvenile chronic arthritis (European League Against Rheumatismb)
Juvenile idiopathic arthritis (International League of Associations for Rheumatologyc)
Systemic Polyarticular
Systemic Polyarticular, rheumatoid factor negative Juvenile rheumatoid arthritis (Polyarticular, rheumatoid factor positive) Pauciarticular
Systemic Polyarticular, rheumatoid factor negative Polyarticular, rheumatoid factor positive
Pauciarticular
Juvenile ankylosing spondylitis Juvenile psoriatic arthritis
a
Oligoarthritis Persistent Extended Enthesitis-related arthritis Psoriatic arthritis Undifferentiated arthritis Fits no other category Fits more than one category
Brewer EJ, Jr., Bass J, Baum J, et al. (1977). Current proposed revision of JRA criteria. Arthritis and Rheumatism 20(supplement): 195–199. b European League Against Rheumatism (EULAR) Bulletin No. 4 (1977) Nomenclature and classification of arthritis in children. Basel. National Zeitung AG. c Petty RE, Southwood TR, Baum J, et al. (1998) Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban 1997. Journal of Rheumatology 25: 1991–1994. Reproduced from Cassidy JT and Petty RE (2001) Textbook of Pediatric Rheumatology, 4th edn., p. 215. Philadelphia, PA: Elsevier Saunders, with permission from Elsevier.
Illnesses: Autoimmune Rheumatological Diseases
a particular joint, permanent destruction of the cartilage, underlying bone, and other surrounding joint structures such as ligaments and tendons may occur. Clinical Characteristics Pauciarticular
Oligoarticular or pauciarticular arthritis is the most common form of chronic arthritis in childhood, representing approximately 50% of patients. This form of arthritis involves four or fewer joints and typically affects the large joints in an asymmetric pattern. Extra-articular disease is unusual except for uveitis, chronic inflammation in the anterior chamber of the eye. Uveitis is asymptomatic and affects approximately 10–20% of children with pauciarticular arthritis. Risk factors for uveitis include female gender, disease onset under 7 years, and a positive antinuclear antibody (ANA). Uveitis may cause blindness if untreated. The activity of the eye disease does not correlate with the activity of the arthritis and the risk remains elevated for at least 4 years after the initial diagnosis of arthritis. Therefore, routine ophthalmology examinations, including a slit lamp examination, are required to evaluate for uveitis and if present, necessitates treatment with antiinflammatory eye drops or systemic medications. Patients with pauciarthritis are generally otherwise well and frequently remain very active. Based on the frequent asymmetric distribution, patients who develop arthritis before the age of 3 years may develop muscle atrophy and a leg length discrepancy with the affected leg overgrowing because of increased growth factors in areas of increased blood flow. Polyarticular
Polyarticular disease is defined as arthritis involving five or more joints within 6 months of diagnosis. The arthritis often involves both large and small joints in a symmetric pattern. Polyarthritis comprises approximately 35% of all patients with JIA. There are two subgroups within this category: rheumatoid factor-negative disease (25%) and rheumatoid factor-positive disease (10%). The rheumatoid factor is an antibody associated with more chronic, severe arthritis. Rheumatoid factor-positive disease is typically not seen until late school-age or adolescence. Systemic features of polyarthritis may include fatigue, anemia, and growth failure. Systemic
Systemic arthritis, also known as Still’s disease after George Still who made some of the early observations about juvenile arthritis, makes up approximately 15% of children with JIA. The arthritis is generally polyarticular, affecting both large and small joints. The hallmark is a high spiking fever, often as high as 39 to 40 C with rapid return to baseline or subnormal temperatures. The fever
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typically occurs 1–2 times per day, frequently in the late afternoon or evening. There is also a characteristic rash that consists of salmon-pink flat lesions of different sizes. The rash moves all over the body, not lasting in one location for more than minutes to hours. It is most often seen over pressure areas and when the fever is present. The rash is occasionally itchy. Patients frequently have other systemic features including enlarged liver and spleen, swollen glands, inflammation of the lining of the heart and/or lungs, tendonitis, and hepatitis. Impact on Growth and Development JIA is often associated with abnormalities of growth and development. Due to the chronic joint symptoms, including pain, swelling, and stiffness, patients may have delayed motor skills. Patients may present with delays in fine and gross motor development. Young children may have difficulty pulling to a stand and cruising or parents may note an abnormal gait once the child learns to walk. Toddlers may have trouble with coordination and may have difficulty keeping up with their peers. Occasionally children are diagnosed with cerebral palsy due to the asymmetric abnormalities in range of motion and function. Alternatively, patients may be noted to lose developmental milestones, coinciding with the onset of their joint symptoms. Proper treatment of the disease should allow the patient to ‘catch-up’ and again meet their normal milestones. The disease has no significant impact on cognitive development. Chronic systemic inflammation is frequently associated with retardation in linear growth. In addition, treatment with steroids, at doses of greater than 3 mg per day, are growth suppressing. During remission, patients usually return to their baseline growth velocity. If patients continue to be significantly below the fifth percentile in height, even when their disease is adequately controlled and after they have tapered down on their steroids, they can be treated successfully with growth hormone. There may also be localized growth abnormalities. Increased blood flow and growth factors can lead to accelerated linear growth surrounding an involved joint with a resultant leg length discrepancy or may lead to localized bony overgrowth. Alternatively, patients may have premature closure of the growth plates or destruction of a growth center leading to shortening of a limb or digit. Micrognathia, shortening of the jaw, may be seen when there is long-standing inflammation of the temporomandibular joint and can lead to significant pain, facial deformity, difficulty opening the mouth, and chewing. Laboratory Tests There are no specific or diagnostic laboratory tests for JIA. Markers of systemic inflammation, such as
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sedimentation rate and c-reactive protein, are typically quite elevated with active systemic illness and may be mildly elevated with polyarticular involvement. Most commonly all of the laboratory tests are normal in the case of oligoarticular disease. Synovial fluid analysis, if performed, typically demonstrates a white blood cell count between 5000 and 60 000 cells ml 1with a normal to slightly decreased glucose.
Radiologic Studies Standard radiographs are not diagnostic of early juvenile arthritis. Early nonspecific findings include osteoporosis and soft-tissue swelling. The primary purpose of X-rays in early disease is to exclude other conditions that may be associated with bony changes. Late changes of chronic arthritis include joint space narrowing due to thinning of the cartilage and erosions of the underlying bone. Magnetic resonance imaging may demonstrate joint damage earlier than standard X-rays and, if performed with contrast, can help identify areas of active synovitis.
Table 3 0–3 years
Common causes of joint pain in children aged
Mechanical/orthopedic Trauma Hypermobility Growing pains Infectious diseases Bacterial Osteomyelitis Septic arthritis Viral Parvovirus Epstein Barr Virus Reactive arthritis Other Lyme disease Malignancy Leukemia Lymphoma Neuroblastoma Osteoid osteoma Rheumatic diseases Dermatomyositis Vasculitis Sarcoidosis
Differential Diagnosis Because there are no diagnostic tests for JIA and because it is a diagnosis of exclusion, it is important to rule out other causes of the clinical findings prior to making the diagnosis. Often the differential diagnosis is quite broad, including orthopedic abnormalities, infectious etiologies, and malignancy (Table 3). There are a few key features that can help distinguish these different entities. Characterizing the timing of the pain can be very helpful. In inflammatory conditions such as arthritis, patients frequently have increased symptoms in the morning with associated morning stiffness and gelling–stiffness after periods of inactivity. In contrast, patients with a mechanical problem typically have the least pain in the morning and have worsening symptoms throughout the day and with activity. Orthopedic problems may also be associated with popping, locking, and giving out of the joint. The classic features of growing pains are poorly localized pain occurring at night, waking the child from sleep with no objective signs of inflammation, and absence of symptoms during the day. Patients with growing pains usually like to have the affected area massaged, while this is typically not seen in arthritis. When considering infectious causes, we need to observe for the presence of focal symptoms, usually in association with significant pain, swelling, warmth, and possibly redness of the involved area. Patients often have a persistent fever. Bacterial infections may involve the joint, as in septic arthritis, or the bone, as in osteomyelitis, or both. If infection is being considered it is important to obtain appropriate
cultures. In cases of postinfectious or reactive arthritis, a preceding illness is identified in approximately 50% of cases. Typically the onset of arthritis is acute and severe and may affect one or multiple joints and may have a migratory pattern. A very important distinction between reactive arthritis and chronic arthritis is the duration of symptoms. In order to meet criteria for chronic arthritis, symptoms must be present for at least 6–12 weeks. In contrast, the symptoms associated with reactive arthritis typically resolve completely within 4–6 weeks with a low rate of recurrence. Features that may suggest an underlying malignancy include pain out of proportion to physical findings, pain and swelling around the joint instead of the joint itself, enlarged liver or spleen, swollen glands, and an elevated lactate dehydrogenase (LDH) or uric acid. X-rays may demonstrate direct bone infiltration or nonspecific findings including increased or decreased density lines in the broad portion of the bone called metaphyseal bands. Treatment Goals of treatment are to control pain; preserve range of motion, strength and function; manage systemic complications; and facilitate normal nutrition, growth, and physical and psychological development. The traditional approach is to begin with the safest, simplest, and most
Illnesses: Autoimmune Rheumatological Diseases
conservative measures and then intensify treatment as needed to manage the signs and symptoms of the disease. Nonsteroidal anti-inflammatory medications (NSAIDs), such as ibuprofen and naproxen, are the mainstay of therapy. Steroids are reserved for the severely affected child, primarily patients with systemic disease. Monoarticular or oligoarticular disease can be treated with local steroid joint injections. Other disease-modifying, anti-rheumatic medications include methotrexate, leflunomide, and cyclosporine. Newer biologic medications, such as etanercept, infliximab, adalimumab, and anakinra, inhibit specific cytokines – proteins that are known to play a significant role in the inflammation and chronic bone and cartilage changes seen in chronic arthritis. Rehabilitation services, such as physical and occupational therapy, are very important to minimize pain, maintain and restore function, and prevent deformity and disability. Splinting and special exercises to prevent deformity and contractures may be needed. Treatments include heat and cold, water therapy, ultrasound, range of motion and strengthening exercises, gait training, joint protection, serial casting, and shoe lifts. Prognosis The course and prognosis for JIA is variable. With oligoarticular disease, many patients eventually go into remission within a few years without any long-term sequelae. Patients rarely have permanent cartilage or bone damage. However, patients may have fixed flexion contractures or leg length discrepancies that can impact their normal gait and function. In addition, these patients may be at higher risk for osteoarthritis in the future. There is a subgroup of patients, those with extended oligoarticular disease, who have a progressive increase in the number of involved joints so that they ultimately have a polyarticular course and may have more chronic or severe disease. The prognosis for chronic anterior uveitis has been improving with the current options for treatment. However, visual loss may still occur. Other complications include glaucoma and cataracts that may lead to increased visual impairment. The rheumatoid factor-negative polyarticular disease seen in young patients generally goes into remission within several years without permanent joint damage. Patients in this age group with the worst prognosis include those who have been referred late in their course and those with early involvement of the small joints of the hands and feet. The systemic features associated with systemic arthritis, including the fever and rash, tend to remit within months to years. However, these symptoms may recur with subsequent exacerbations of the arthritis. The ultimate prognosis in this form of chronic arthritis is
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determined by the extent of their arthritis. Those patients with a more polyarticular course of arthritis have a worse functional outcome.
Lupus Pediatric systemic lupus erythematosus is very rare under the age of 5 years, more typically presenting in schoolage children and adolescents. However, neonatal lupus erythematosus is a form of lupus that occurs in infancy. This condition is associated with specific maternal antibodies that cross the placenta and attack fetal and neonatal tissues. It most commonly affects the heart, skin, blood, and liver.
Pathophysiology Specific maternal antibodies, anti-Ro and anti-La, are required for the development of neonatal lupus. Mothers may have an underlying autoimmune condition such as systemic lupus erythematosus or Sjogren’s syndrome or may be asymptomatic. These antibodies cross the placenta and react with fetal and neonatal tissues, causing an inflammatory reaction. Findings become apparent at birth or in the early postnatal period. Aside from the congenital heart block (CHB), the other clinical features are transient, coinciding with the presence of the antibodies and usually resolving by 6–12 months as the antibodies are broken down.
Clinical Manifestations Cardiac The most significant manifestation of neonatal lupus is CHB in which the electrical impulses fail to conduct normally through the heart. This may become apparent either in utero or soon after birth. To date, third-degree atrioventricular block, when the atria and ventricles beat independently, is irreversible. CHB is associated with significant complications and risk of mortality. A majority of patients require pacemakers during their entire lives. Other less common cardiac manifestations include structural abnormalities and inflammatory processes such as myocarditis (inflammation of the heart muscle), or pericarditis (inflammation of the lining of the heart). Skin The rash associated with neonatal lupus consists of oval, red lesions on the face, scalp, trunk, and extremities. The rash is typically found in sun-exposed areas and is strongly photosensitive. The lesions may be present at birth or develop
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postnatally. Patients often present after being exposed to the fluorescent lights in the newborn nursery or after beginning phototherapy for high bilirubin. Generally the rash resolves without a scar. Blood
Neonatal lupus can be associated with immune-mediated low platelet, white blood cell, and red blood cell counts. Occasionally, these effects on the blood lines are severe enough to require transfusions. Liver
Infants with neonatal lupus may present with liver dysfunction. Typically patients have an enlarged liver, with or without an enlarged spleen, bile stasis, and increased liver function tests. The liver function abnormalities usually resolve without any permanent dysfunction. Treatment The majority of the manifestations of neonatal lupus resolve without any specific treatment once the maternal antibodies are broken down, typically within 6–12 months. Severe systemic manifestations occasionally require treatment with steroids or intravenous immunoglobulin (IVIG). Prognosis The blood, liver, and skin manifestations typically resolve without any long-term sequelae. Babies with associated heart block have a more guarded prognosis as they are at risk for congestive heart failure and generally require long-term pacemakers.
Vasculitis Nomenclature Vasculitides, autoimmune conditions associated with inflammation of blood vessels, are often classified based on involved vessel size (Table 4).
Table 4
Classification of vasculitides
Large vessel Takayasu’s arteritis Giant cell arteritis Medium vessel Kawasaki disease Wegener’s granulomatosis Polyarteritis nodosa Churg-Strauss syndrome Small vessel Henoch-Scho¨nlein purpura Microscopic polyarteritis
Henoch-Scho¨nlein purpura Epidemiology
Henoch–Scho¨nlein purpura (HSP) is one of the most common forms of systemic vasculitis in children. Onset of HSP is most common in the winter. Often there is a preceding, viral, upper respiratory infection or streptococcal disease. Clinical manifestations
The common clinical characteristics include purpura, arthritis, abdominal pain with or without gastrointestinal bleeding, blood and protein in the urine, and inflammation of the testicles. The typical rash consists of palpable, purple, nonblanching lesions, most commonly on the lower extremities. They often begin as red, flat spots or hive-like lesions that become purpuric in nature, turning purple, then brown, and then slowly resolving. Young children with HSP frequently have significant swelling of the scalp, extremities, scrotum, and around the eyes. Patients may also have vasculitis and swelling of the lining of the intestine, leading to crampy abdominal pain, with or without hemorrhage. Small intestine intussusception, when the intestine telescopes on itself, is one of the most common gastrointestinal complications, presenting with colicky pain, a distended abdomen, and vomiting. Kidney disease, manifested as blood and protein in the urine and high blood pressure and less commonly renal failure, occurs in approximately one-third of patients. The kidney findings generally develop within 3 months of the onset of symptoms. Joint pain and/or frank arthritis occur in most patients. Less common manifestations include central nervous system vasculitis and hemorrhage into the lungs. Acute hemorrhagic edema, a variant of HSP in children less than 2 years of age, is manifested as fever, purpura, and significant swelling of the face and extremities. Kidney and gastrointestinal involvement in this form is uncommon. Laboratory tests
There are no diagnostic laboratory tests for HSP. General markers of inflammation, including sedimentation rate and c-reactive protein, are typically elevated. The antinuclear antibody and rheumatoid factor are usually negative. Antibodies associated with vasculitis, antineutrophil cytoplasmic antibodies (ANCA), may be present. Serum immunoglobulin A levels may be elevated. Treatment
Treatment of HSP is supportive, focusing on maintaining hydration and managing pain. Generally, management with acetaminophen or NSAIDs such as ibuprofen is sufficient to control the pain. Systemic steroids are indicated to manage severe abdominal pain and/or hemorrhage. If steroids are discontinued abruptly, patients often experience a rapid return of symptoms. Therefore, once
Illnesses: Autoimmune Rheumatological Diseases
steroids have been started, it is recommended to taper them over several weeks to avoid this rebound of symptoms. Severe renal disease may also be managed with highdose steroids with or without chemotherapeutic agents such as cyclophosphamide.
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frequently reveal blood and protein in the urine with abnormal kidney function tests. A positive P-ANCA is seen in a majority of patients. Angiograms are typically negative because these imaging studies usually cannot detect small vessel disease. A biopsy of involved tissue demonstrates vasculitis of small vessels.
Prognosis
Generally, the signs and symptoms of HSP are self-limiting, with complete resolution within 1 month. However, it is not unusual to have at least one recurrence, often within the first couple of months after the first occurrence. Typically, subsequent episodes are briefer and less severe. When children have multiple episodes of HSP, it is important to screen for streptococcal disease; if this is identified as a trigger, preventive antibiotics may be helpful in preventing subsequent episodes. The renal disease associated with HSP has a more variable outcome. Patients who present with isolated mild blood and/or protein in the urine generally do well, with no long-term sequelae. Patients with more severe kidney inflammation, manifested as high blood pressure and decreased kidney function, have a higher rate of chronic renal disease with a small percentage of children developing end-stage renal failure.
Treatment
Treatment of both forms of polyarteritis includes systemic steroids to manage the acute manifestations. Additional immunosuppressive agents such as cyclophosphamide, azathioprine, or methotrexate may be indicated for more severe disease or for those patients who need a steroidsparing agent. Prognosis
The prognosis of polyarteritis is variable. Patients with cutaneous PAN generally have a good outcome; however, they may have relapses over a period of several years. In general, patients with classic PAN and microscopic polyangiitis require long-term treatment with immunosuppressive medications. With these treatments, patients may have significant complications, such as kidney failure, high blood pressure, and seizures, but appear to have relatively low mortality.
Polyarteritis Clinical manifestations
There are two main types of polyarteritis. Polyarteritis nodosa (PAN) typically presents with fatigue, weight loss, fever, rash, abdominal pain, and arthritis. Patients may also have muscle pain; testicular pain; kidney involvement such as high blood pressure and blood in the urine; and neurologic symptoms such as seizures, focal deficits, and visual loss. The skin lesions include lumps under the skin called nodules, purpura, or ulcerated areas. Laboratory testing typically reveals anemia, increased white blood cell counts, platelet counts, and other markers of inflammation. In classic PAN, the ANCA is generally negative. Angiograms, special imaging studies that evaluate blood vessels, may demonstrate areas of dilated or narrowed vessels, particularly involving the kidney and intestine. Biopsies of involved areas confirm the presence of segmental vasculitis of small and medium arteries. There is a cutaneous form of PAN that is limited to fever, rash, and joint symptoms. The most characteristic finding is purpura, most commonly of the lower extremities and sometimes on the soles of the feet. The lesions are often quite tender and can interfere with walking. Outbreaks can be triggered by streptococcal infections and in these cases, may be prevented by using prophylactic antibiotics. Microscopic polyangiitis, in contrast, generally presents with pulmonary hemorrhage and rapidly progressive kidney inflammation. Patients may also have muscle pain, arthritis, abdominal pain, and purpura. Laboratory tests demonstrate increased inflammatory markers and
Kawasaki disease Epidemiology
Kawasaki disease (KD) is another common form of vasculitis in young children, with a peak incidence between 6 and 11 months. Infants may not present with typical characteristics and therefore may have a delay in diagnosis and treatment and ultimately a worse outcome. The cause of this multisystem, inflammatory condition is unknown. Many features of this disease suggest an infectious etiology; however, no single agent has been identified. There are reports of seasonal peaks and clusters in different geographical areas. Clinical manifestations
The fever is typically 39–40 C, for 5 or more days. The fever is unresponsive to antibiotics and usually poorly responsive to acetaminophen and ibuprofen. Patients often have bilateral conjunctivitis without eye drainage and sparing the area closest to the iris. The swollen glands, also known as lymphadenopathy, seen with KD, are typically located on one side of the neck and are greater than 1.5 cm in diameter. The rash is variable and may consist of red, flat, or raised areas, may be purpuric, or can resemble the rash of scarlet fever. The rash may involve the trunk, face, extremities, and diaper area. As the rash resolves, there is often peeling of the affected areas. While the fever is present, children frequently have red, dry, cracked, swollen lips and/or a ‘strawberry’ tongue. The typical extremity changes include swelling
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of the hands and feet in the early phases of the disease and later peeling of the tips of the fingers and toes. The most serious manifestation of KD is heart disease. There is a predilection for involvement of the coronary arteries, the arteries feeding the heart. The vasculitis may lead to aneurysms of involved vessels. Severe sequelae may include impaired heart function, heart attack and abnormal heart rhythm. Patients may also have dilation of other vessels such as arteries in the arm and leg. Other manifestations include sterile meningitis with headache and extreme irritability, uveitis, joint pain, arthritis, muscle inflammation, inflammation of the gallbladder, and white blood cells in the urine with negative urine cultures. Laboratory and imaging studies
During the acute phase of KD, patients typically have significant elevation of inflammatory markers including sedimentation rate, c-reactive protein, and white blood cells. The platelet count often rises 2–4 weeks into the illness. As with other forms of vasculitis, patients may have a positive ANCA. Patients may also have mild elevation in the liver function tests, anemia, white blood cells in the urine and spinal fluid with negative bacterial and viral cultures. Echocardiograms are necessary to diagnose and monitor coronary artery abnormalities. Biopsies of involved tissue demonstrate vasculitis of medium-sized arteries. Treatment
Standard treatment for KD includes IVIG 2 g kg 1 as a single dose. Administration of IVIG within the first 10–12 days of illness is usually associated with improvement in all clinical manifestations and reduction in the frequency and severity of coronary artery abnormalities. Occasionally, patients will have a recurrence of symptoms such as fever, rash, and the lip and tongue changes, and in these cases, they often benefit from a second dose of IVIG. Patients should also be treated with aspirin, at anti-inflammatory doses during the acute phase of the disease and then at lower doses to achieve antiplatelet effects to decrease the risk of blood clots in the abnormal vessels. The role of steroids in the treatment of KD is controversial and usually reserved for patients with severe or resistant disease. In addition, stronger immunosuppressive medications such as cyclophosphamide and infliximab have been used for recalcitrant cases. Generally, patients should have an echocardiogram at the time of diagnosis and then have a repeat study within 2–6 weeks. No additional studies are needed for patients who have no evidence of coronary involvement on the repeat scan. Patients who have evidence of coronary abnormalities, however, require regular follow-up studies to monitor for evolution of their disease and to screen for premature cardiovascular disease that may be a late sequelae of KD.
Prognosis
In general, the clinical manifestations of KD resolve with appropriate treatment without any long-term sequelae. The major exception is in those with coronary involvement who may have significant complications and some risk of early and late mortality.
Dermatomyositis Epidemiology Dermatomyositis is the most common inflammatory muscle disease of childhood. This condition may present at any age, with a peak age of onset around 7 years of age and a second peak in adulthood. The cause of dermatomyositis is unknown and likely multifactorial, involving a genetic predisposition, environmental factors such as sun exposure, and possibly, in at least some cases, a viral trigger. Pathophysiology The clinical features of dermatomyositis are caused by abnormalities of small blood vessels, ultimately leading to decreased blood flow and damage to the end organs, including striated muscle, skin, and gastrointestinal tract. Clinical Manifestations Constitutional Poor appetite, weight loss, fatigue, fever, and malaise may be present. Musculoskeletal Patients have symmetrical weakness, primarily affecting the muscles of the neck, abdomen, shoulders, and hips. Children frequently have difficulty climbing stairs, getting up from a chair, and combing their hair. The muscles in the larynx, pharynx, and palate can be involved, causing nasal speech, weakness of the voice, and regurgitation of liquids through the nose and increasing the risk of aspiration of fluids into the lungs. Patients frequently have a positive Gower’s sign; when asked to get up from sitting on the floor, they use their hands to walk up the anterior aspects of their thighs to compensate for their pelvic muscle weakness. Neck flexor weakness is a particularly sensitive indicator of muscle impairment. Patients may also have muscle pain, as well as swelling and tightness over the muscles. After long-standing disease, patients may eventually develop muscle atrophy. The position of comfort is flexion of the limbs, promoting the development of flexion contractures. Patients may have arthritis, usually symmetric, involving both large and small joints.
Illnesses: Autoimmune Rheumatological Diseases
Skin
The typical rashes may precede or follow the onset of muscle weakness and may occur in the absence of elevated muscle enzymes. Swelling around the eyes and dilated, tortuous, superficial vessels over the eyelid are often seen. One of the classic findings in dermatomyositis is the heliotrope rash, manifested as a purple discoloration of the eyelids. The rash is frequently photosensitive. Sun exposure may exacerbate the rash alone, or may activate the muscle inflammation as well. Another pathognomonic rash is Gottron’s papules, thickened, pale, or red raised plaques over the knuckles, elbows, and knees. Patients may also develop a red rash on the cheeks and nasal bridge, on the chest (‘V’ rash), or upper back (‘shawl rash’). Diffuse vasculitis, manifested as abnormal blood vessels along the cuticle edge and ulcers of the skin around the mouth or on the finger tips, may be associated with more severe disease. Calcinosis, calcium deposits under the skin, occurs in up to 70% of patients. Calcinosis frequently develops months to years after the onset of disease and is often located at sites exposed to trauma. While the cause of calcinosis is unknown, it appears to be related to disease severity and duration. Patients treated early and aggressively have a decreased risk of developing soft tissue calcifications. Gastrointestinal
Patients may have esophageal hypomotility that can contribute to the swallowing dysfunction. Vasculitis can affect any part of the gastrointestinal tract and may impair absorption, cause weight loss, and progress to ulceration with perforation of the intestine. Cardiopulmonary
Patients may have electrocardiogram abnormalities, most commonly asymptomatic changes in the electrical conduction within the heart. Decrease in ventilatory capacity in the absence of respiratory symptoms may occur due to muscular weakness. Pulmonary inflammation and scarring may also occur. Diagnostic Criteria There are five diagnostic criteria for dermatomyositis, including characteristic rash, symmetrical proximal muscle weakness, elevated muscle enzymes, typical muscle pathology on biopsy, and inflammatory changes in the muscle by electromyography (EMG), a technique to study the physiologic properties of muscles. In order to make a definitive diagnosis of dermatomyositis, patients need rash and 3 or 4 other criteria. Patients have probable disease if they have rash with two criteria and possible dermatomyositis with rash and one criterion. Usually, the diagnosis is made based on the physical and laboratory findings. An EMG and/or biopsy are usually not necessary unless the features are atypical.
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Laboratory and Radiologic Data Muscle-derived enzymes (creatine kinase, LDH, aspartate transaminase (AST), alanine aminotransferase (ALT), aldolase) may all be elevated, or a single value may be abnormal. Usual indications of inflammation, such as sedimentation rate and white blood cell count, are often normal, despite widespread inflammation. A magnetic resonance imaging study of the involved muscles may be helpful in confirming the presence of muscle inflammation, monitoring disease activity, or assisting in locating an appropriate location for biopsy. Pathology Biopsy of involved areas includes vasculitis and noninflammatory blood vessel abnormalities affecting arterioles, capillaries, and venules. Muscle biopsy findings reveal atrophy of the muscle fibers surrounding the involved blood vessels, vascular inflammation with muscle fiber degeneration, cell death, and regeneration. Treatment There are several emergent issues that need to be assessed when the patient presents. Children should be evaluated for any evidence of respiratory compromise, keeping in mind that patients may not exhibit all of the typical signs of respiratory distress because of their significant weakness. Patients also need to be assessed for intestinal vasculitis if they have any abdominal pain or diarrhea since this complication is associated with significant complications and mortality. Evaluations to consider include checking the stool for blood and an abdominal computed tomography scan. In addition, any patient who has voice changes and/or reports of swallowing difficulty should not be allowed to take anything by mouth until appropriate swallowing evaluations can be performed to assess for risk of aspiration. Steroids are the therapy of choice. Because patients may have some degree of intestinal inflammation, intravenous dosing may be indicated for moderate-to-severe disease to improve absorption. Steroids are gradually tapered to a low maintenance dose while monitoring the physical examination and muscle enzymes. Children usually require treatment with these small doses of steroids for at least 2 years since stopping this medication sooner is associated with an increased risk of an exacerbation in their disease. It is important to monitor for long-term side effects of steroids, including osteoporosis, glaucoma, cataracts, growth retardation, and steroid myopathy that can contribute to muscle weakness and atrophy. In patients with more resistant disease or with significant steroid side effects, additional medications may be added, such as methotrexate and cyclosporine. IVIG and
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hydroxychloroquine are particularly good for managing rash. Sun protection, using sunscreen with greater than or equal to sun protection factor (SPF) 30, is very important. Physical and occupational therapy should be used to prevent loss of range of motion and development of contractures by implementing passive range of motion exercises in the early phases of disease and more intensive, graded exercises at later stages focused on stretching and strengthening. Prognosis At least 80% of patients have a unicyclic course. Therefore, only a small percentage of children have resistant disease with more continuous or recurrent courses. It is difficult to predict the outcome at the onset of illness. Factors that have been associated with a poor prognosis include persistent, severe disease activity, extensive vasculitis, calcinosis, difficulty swallowing, and voice changes. There are certain muscle-specific antibodies that are associated with more severe disease. Also, delay in treatment or inadequate treatment, is associated with a worse prognosis.
Sarcoidosis
Laboratory and Pathologic Findings Laboratory abnormalities include increased markers of inflammation, increased immunoglobulins, and elevated calcium in the blood and urine. Pathologic specimens demonstrate granulomas – nodular collections of inflammatory cells. Angiotensin-converting enzyme (ACE) is produced by cells within the granulomas; therefore, serum levels are often elevated, although this is less common in young children. It is important to recognize that serum ACE levels are higher in children and therefore it is necessary to use appropriate normal values to interpret the results of this test. Treatment Treatment generally involves systemic steroids and additional immunosuppressive agents, such as methotrexate, azathioprine, and infliximab may be used to achieve better disease control and to minimize the side effects of prednisone. Prognosis Children with sarcoidosis tend to have chronic symptoms and may suffer from long-term complications of this disease. Specifically, the joint disease can lead to severe growth delay as well as destruction of cartilage and bone. Patients with uveitis may develop significant visual impairment.
Clinical Manifestations Sarcoidosis is a multisystem autoimmune condition. There are two patterns of presentation, including a group of patients who present before the age of 4 years. These patients with early-onset sarcoid typically have skin, joint, and eye disease. The rash may be flat, raised, or nodular. The arthritis associated with sarcoidosis is typically quite proliferative with significant thickening of the synovium and large collections of fluid in the joints. The physical findings are often out of proportion to the joint symptoms with minimal pain, decreased range of motion, and stiffness. Patients may develop uveitis, involving the anterior and/or posterior areas. The collections of white blood cells seen in the eye can produce a ‘snowbank’ appearance when examined by an ophthalmologist. Other manifestations, such as swollen glands, enlarged liver and spleen, and lung involvement, seen in older-onset sarcoidosis are rare in young children.
Conclusions/Future Directions Pediatric rheumatic diseases are rare autoimmune conditions that may have significant impacts on development and quality of life and can be associated with long-term sequelae. Clinical and basic science research is now focused on standardizing diagnostic criteria and outcome measures, validation of quality of life instruments, further investigations of possible genetic and environmental triggers, and novel therapies that will hopefully improve the overall outcomes of affected children. See also: Allergies; Asthma; Colic; Crying; Failure to Thrive; Feeding Development and Disorders; Immune System and Immunodeficiency; Physical Growth; Prenatal Development; Screening, Newborn and Maternal Well-being; Screening, Prenatal; Vision Disorders and Visual Impairment.
Genetics There have been familial cases of patients with early-onset disease. Some of these cases have a specific gene mutation and have been classified as having Blau syndrome. The relationship between sarcoidosis and Blau syndrome is not entirely clear but they appear to be along a similar spectrum of disease.
Suggested Readings Cassidy JT and Petty RE (2001) Textbook of Pediatric Rheumatology, 4th edn, p. 215. Philadelphia, PA: Elsevier Saunders. Cassidy JT, Petty RE, Laxer RM, and Lindsley CB (2005) Textbook of Pediatric Rheumatology, 5th edn. Philadelphia, PA: Elsevier Saunders.
Imagination and Fantasy Compeyrot-Lacassagne S and Feldman BM (2005) Inflammatory myopathies in children. Pediatric Clinics of North America 52: 493–520. Dedeoglu F and Sundel RP (2005) Vasculitis in children. Pediatric Clinics of North America 52: 547–575. European League Against Rheumatism (EULAR) Bulletin No. 4 (1997) Nomenclature and classification of arthritis in children Basel: National Zeitung AG. Klippel JH (1997) Primer on the Rheumatic Diseases, 11th edn. Atlanta: Arthritis Foundation. Ravelli A and Martini A (2007) Juvenile idiopathic arthritis. Lancet 369: 767–778. Tse SML and Laxer RM (2006) Approach to acute limb pair in childhood. Pediatric in Review 27: 170–180.
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Weiss JE and Ilowite NT (2005) Juvenile idiopathic arthritis. Pediatric Clinics of North America 52: 413–442.
Relevant Websites http://www.aap.org – American Academy of Pediatrics. http://www.rheumatology.org – American College of Rheumatology. http://www.arthritis.org – Arthritis Foundation. http://www.niams.nih.gov – NIAMS, National Institute of Arthritis and Musculoskeletal and Skin diseases. http://www.myositis.org – The Myositis Association, Juvenile Dermatomyositis.
Imagination and Fantasy J D Woolley and A Tullos, The University of Texas, Austin, TX, USA ã 2008 Elsevier Inc. All rights reserved.
Glossary Fantasy – A subset of imagination in which the imagined entity, object, or scenario is more extravagant or less constrained by reality. Imagination – The formation of mental imagines of entities or events that are not present to the senses. Individual differences – Characteristics of children’s biological, social, environmental, or genetic makeup that make them different from other children the same age. Without individual differences, all children of the same age would develop similarly. Object substitution – Involves using one object to stand for another. For example, children might pretend that a cardboard box is a castle. Pretend play – An activity in which children’s behavior involves some form of nonreality. It often involves some or all of the following six behaviors: (1) self-pretense, (2) object substitution, (3) animation of objects, (4) pretending about imaginary objects, (5) pretending to be another person or entity, and (6) pretending to have imaginary companions. Pretense – Involves mental, verbal, or physical engagement in nonreality. Role play – Involves imagining and acting out the role of another person or creature. It can involve acting like another person, behaving toward a toy as if it is really what it represents, or interacting with a pretend being, such as an imaginary companion.
Introduction Walk into any preschool classroom, and evidence of young children’s imagination abounds. In one corner of the room you might observe children playing dress-up, in another the products of a finger-painting project, and in another a child building a castle out of colorful blocks. Many consider the preschool years to represent the peak of imaginative and fantastical thinking. In this article we explore the origins and development of imagination and fantasy from its earliest observable manifestations in older infants and toddlers through its peak in the later preschool years. We must begin by considering what we mean by imagination and fantasy. The word ‘imagination’ is certainly used in a multitude of ways to mean many things: ‘‘use your imagination,’’ ‘‘she or he’s got a good imagination,’’ ‘‘I can’t imagine what it would be like,’’ are some common examples. In its most basic sense, imagination is the formation of a mental image of something that is not present to the senses; it is the act of conceiving of an alternative to reality. Imagination is the ability to think of things as otherwise than we see them or as different from how they exist in the world. Imagination can include thinking about the immediate future (e.g., imagining how good a cookie would taste) and the distant future (e.g., imagining being a grown-up), as well as the more prototypical uses found in the quotes above. Fantasy is most often taken to be a subset of imagination, or imagination that is somehow farther removed or less restricted by reality. For example, a fantasy may involve slaying dragons or time travel,