RHEUMATOLOGY - McGraw-Hill Specialty Board Review Pediatrics, 2nd Edition

McGraw-Hill Specialty Board Review Pediatrics, 2nd Edition

Chapter 17. RHEUMATOLOGY

CASE 140: A 5-YEAR-OLD BOY WITH FEVERS AND JOINT SWELLING

A 5-year-old previously healthy boy has had a daily spiking fever up to 104°F (40°C) in the evenings for 4 weeks. His temperature is normal between spikes. When febrile, the child is irritable, has malaise, and does not want to play or move. He is often active and playful when afebrile. He appears stiff in the morning. His mother is concerned that his finger and knee joints appear swollen.

SELECT THE ONE BEST ANSWER

1. This child’s diagnosis is most likely

(A) rheumatic fever

(B) systemic arthritis

(D) Kawasaki disease (KD)

(E) systemic lupus erythematosus (SLE)

2. Which of the following laboratory results is not expected in this disease?

(A) decreased platelet count

(B) increased white blood cell count

(D) increased erythrocyte sedimentation rate

(E) negative antinuclear antibody (ANA)

3. Which of the following is true about the skin rash in this entity?

(A) it is evanescent, salmon colored, and often accompanies the fever

(B) biopsy shows a leukocytoclastic vasculitis

(D) the lesions frequently ulcerate

(E) in some patients, the rash is fixed, lasting up to 3 days

4. Commonly described extra-articular involvement in this disease includes

(A) eye inflammation

(B) nephritis

(D) mitral insufficiency

(E) myositis

5. The first medication usually given to treat the fevers and joint symptoms of this disease is

(A) a systemic corticosteroid (CS)

(B) acetaminophen

(D) methotrexate

(E) an antitumor necrosis factor drug

6. Systemic CS should not be expected to

(A) stop the progression of joint disease

(B) improve the anemia

(D) decrease symptoms of pericarditis

(E) decrease joint pain and swelling

7. Patients on methotrexate therapy should be monitored regularly for

(A) hematuria

(B) muscle enzyme elevation

(D) liver enzyme elevation

(E) hyperlipidemia

8. Potential long-term complications of this disease include

(A) growth delay, short stature, and osteoporosis

(B) micrognathia

(D) risk of neurologic problems related to cervical spine arthritis

(E) all of the above

9. A 4-year-old boy has had recurrent fevers up to 40ºC documented for the past year. The fevers occur every 4-6 weeks, last up to 5 days, and are associated with sore throat and occasional mouth sores. Workup for an acute infectious etiology during the fevers has been negative, and he never has had neutropenia. Between febrile episodes he is an active child without physical complaints, and he is growing well. His pediatrician gave him a diagnosis of PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis). Which of the following is true about PFAPA?

(A) it is a benign entity in which most patients have resolution of the cyclic fevers by the age of 10 years

(B) it is associated with defects of the innate immune system

(D) inheritance pattern is autosomal recessive

(E) patients frequently have polyserositis during the febrile episodes

10. A 7-year-old girl was well until 3 months ago when she developed pain in her left knee. Her mother notes that she occasionally limps. There is no history of trauma or fevers. Her physical examination reveals left knee swelling and a mild loss of flexion and extension. She has mild guarding on ranging. She has left quadriceps atrophy. Her other joints are normal. Which of the following should be considered in the differential diagnosis?

(A) pauciarticular arthritis

(B) osteosarcoma

(D) Lyme disease

(E) all of the above

11. Diagnostic workup in the patient from question 10 should include

(A) rheumatoid factor

(B) plain film radiograph

(D) uric acid

(E) HLA-B27 serotyping

12. Which is a true statement about laboratory results in children with oligoarthritis?

(A) complete blood count (CBC) and erythrocyte sedimentation rate may be normal

(B) ANA is positive in all patients

(D) leukocyte count and complement levels are often decreased

(E) rheumatoid factor is present in approximately 25% of these patients

13. The best way to detect early uveitis in children with arthritis is to

(A) assess visual acuity

(B) perform visual field testing

(D) perform a slit lamp examination

(E) refer patient to ophthalmology immediately if eye symptoms develop

14. All of the following statements are true about special school needs for children with chronic arthritis except

(A) a school district can transfer the child to another district if it is unable to provide the requested special services

(B) a public school must evaluate the child for special services if the parent requests them for the child

(C) services that may be requested if needed by the child to ensure proper education within the public school system include transportation between home and school, an extra set of books for home use, homebound instruction if unable to attend school, consultation by physical and occupational therapy services, and adaptive physical education

(D) Congress has passed legislation requiring that public school districts provide services to children with special needs

(E) none of the above

15. Potential long-term problems in a child with oligoarticular disease include

(A) flexion contracture of the involved joint

(B) blindness secondary to uveitis

(D) progression to polyarticular disease in a small percentage of these children

(E) more of the above

16. A 9-year-old boy has had right hip pain for 1-2 weeks, sometimes making ambulation difficult. Your differential diagnosis could include all but which of the following?

(A) Legg-Calvé-Perthes disease

(B) bone tumor

(D) oligoarticular arthritis

(E) early juvenile ankylosing spondylitis

17. Which of the following is true regarding juvenile ankylosing spondylitis?

(A) arthritis is limited to the hip and axial (spine and sacroiliac) joints

(B) females are affected more frequently than males

(D) enthesitis (inflammation at tendon insertion sites) may be present

(E) patients are always HLA-B27 positive

18. Benign hypermobility syndrome is a common cause of joint pain in children. Which of these statements is not true regarding this syndrome?

(A) it is most common in children 3-10 years of age and decreases in frequency with age

(B) a criterion for diagnosis is hyperextension at elbows and knees by 10 degrees or more

(D) a criterion for diagnosis is the ability to touch the thumb to the volar forearm

(E) it occurs more often in girls than boys

19. “Growing pains” is a diagnosis commonly given to children with musculoskeletal pain. All of the following are true about this entity except

(A) it most commonly involves the lower extremities, often with cramping discomfort behind the knee, in the calves, thighs, or along the tibiae

(B) the pain often awakens the child in the middle of the night and may be associated with increased activity the day before

(D) these children often have morning stiffness and achiness

(E) treatment includes massage and reassurance to the parents

Match each entity that is associated with joint symptoms in questions 20 through 28 with one descriptive characteristic A through I.

20. Psoriatic arthritis	(A) mutation of gene encoding for pyrin
21. Rheumatoid factor	(B) conjunctivitis and positive arthritis urethritis
22. Gonococcal arthritis	(C) vesiculopustular lesions on extremities and tenosynovitis
23. Lyme disease	(D) resolves by 6-12 weeks
24.Familial Mediterranean fever	(E) nail pitting and fever dactylitis
25. Reiter syndrome	(F) erythema chronicum migrans
26. Postinfectious arthritis	(G) arthritis may precede abdominal symptoms
27. Rheumatic fever	(H) erythema marginatum
28. Inflammatory bowel	(I) rheumatoid nodules, disease scleritis and vasculitis

ANSWERS

1. (B) Systemic arthritis is the most likely diagnosis in a child with a daily spiking fever. Known as a quotidian fever, this fever pattern is characterized by 1 or 2 daily spikes higher than 102.2°F (39°C) with a rapid return to baseline (98.6°F [37°C]) or below for the rest of the day. The fever spike classically occurs in the late afternoon or evening hours, but it can occur any time of day. The child often appears well when afebrile.

Systemic arthritis is 1 of 3 types of arthritis included in the juvenile rheumatoid arthritis (JRA) classification system:

• Systemic onset

• Pauciarticular (or oligoarticular): 4 or fewer joints involved

• Polyarticular: 5 or more joints involved

• Rheumatoid factor negative

• Rheumatoid factor positive

In 1998, a new classification was proposed for chronic childhood arthritis. It also includes systemic arthritis as one of the categories, along with several other types of childhood arthritis that were not included in the JRA classification. This new nomenclature is juvenile idiopathic arthritis (JIA), and the new classification is

• Systemic

• Oligoarthritis: persistent

• Oligoarthritis: extended (progression in number of joints involved to 5 or more, occurring 6 or more months after initial diagnosis)

• Polyarticular: rheumatoid factor negative

• Polyarticular: rheumatoid factor positive

• Psoriatic arthritis

• Presence of arthritis and psoriasis or

• Presence of arthritis and at least 2 of the following: dactylitis, nail abnormalities, psoriasis in a first-degree relative

• Enthesitis-related arthritis:

• Presence of arthritis and enthesitis or

• Presence of either arthritis or enthesitis with at least 2 of the following: positive HLA-B27; onset of arthritis in male more than 8 years of age; sacroiliac or inflammatory back pain; +ve family history (ankylosing spondylitis, enthesitis-related arthritis; sacroiliitis with inflammatory bowel disease; reactive arthritis or acute anterior uveitis in a first- or second-degree relative)

• Undifferentiated arthritis (fits no other category, or fits into more than 1 category)

This newer classification system includes the 2 spondyloarthropathies, specifically enthesitisrelated and psoriatic arthritis. The JIA system should increase the homogeneity of the subgroups of childhood arthritis patients, which should promote improved recognition of the disease presentation, course, response to treatment, and long-term outcomes of each arthritis subgroup. Research projects, such as studies on disease pathogenesis or genetic markers, may yield more information and result in changes to the classification system in the future. Literature published after 1998 often refers to JIA instead of JRA.

2. (A) The CBC in active systemic arthritis usually has a marked elevation of the leukocyte count (can be >30,000/mm³) and platelets (frequently >500,000/mm³), as well as anemia (hemoglobin often <10 g/dL). Low normal or below normal platelet counts should raise concern of malignancy, especially leukemia, which can present with clinical and laboratory features (eg, hepatosplenomegaly, lymphadenopathy, joint pain, fevers, anemia, and increased erythrocyte sedimentation rate) similar to those seen in systemic arthritis. (Note: A rare complication of systemic arthritis, macrophage activation syndrome [MAS], is associated with depressed platelet levels. This acute illness is characterized by disseminated intravascular coagulation, purpura, hepatic failure, encephalopathy, and other features. MAS has a high mortality rate if not treated rapidly and aggressively. High-dose intravenous CS are the first line of treatment.) Children with systemic arthritis almost always have a negative ANA.

3. (A) The classic systemic rash is migratory and so evanescent that it resolves within a few hours or less (Figure 140-1). There is no need (nor time!) to biopsy it. This precipitous resolution of the rash would not be expected in a leukocytoclastic vasculitis lesion. The systemic rash is usually more prominent during the fever spikes. It appears most often on the trunk and extremities but may be present also on the face, palms, and soles. It may occasionally be pruritic.

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FIGURE 140-1. Evanescent salmon-colored, macular, or maculopapular rash of systemic arthritis. See color plates.

4. (C) Eye involvement, common in other subtypes of childhood arthritis, is typically absent in systemic arthritis. Extra-articular features include the quotidian fever and evanescent rash previously described, as well as polyserositis, hepatosplenomegaly, lymphadenopathy, pneumonitis, and anemia of chronic disease.

5. (C) The first-line medication for systemic arthritis is a NSAID, such as ibuprofen (35-40 mg/kg per day; maximum dose of 2400 mg/day) or naproxen (15-20 mg/kg per day; maximum dose of 1000 mg/day), both of which are approved for children and available in liquid form. Note that anti-inflammatory doses are higher than those recommended for analgesia and antipyrexia. Other NSAIDs approved for children include tolmetin, diclofenac, and sulindac, as well as indomethacin, which may control fevers and polyserositis symptoms better than other NSAIDs but frequently causes epigastric pain and headaches. CS are often used to treat systemic features not responding to NSAIDs. Before starting CS treatment, the physician must be certain that no other diagnosis, such as leukemia, is being overlooked. Methotrexate may help decrease systemic symptoms and is often effective in treating active joint inflammation. Methotrexate is approved for and commonly given to children with systemic and other JIA subtypes who have persistent arthritis despite NSAID treatment. Antitumor necrosis factor alpha (anti-TNF alpha) drugs, the first class of biologics to be used widely for treatment of rheumatoid arthritis, are used to treat active joint disease in children that has not responded adequately to methotrexate. This class of medication may be less efficacious in systemic arthritis compared with other subtypes of childhood arthritis. Five anti-TNF alpha medications are available: etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol; only the first 2 are approved for use in JIA. The biologic medications are targeted therapies. Many of them directed against proinflammatory cytokines and are used in several diseases including JIA, adult rheumatoid arthritis, inflammatory bowel disease, psoriasis, SLE, severe uveitis, Behçet, sarcoidosis, and various vasculitides, although their use is often off-label. Two of the anticytokine biologics, anti-interleukin (IL)1 (anakinra; canakinumab), and anti-IL6 (tocilizumab) appear to have special efficacy in treating systemic features of systemic JIA. Many of the biologic medications are in phase 2/3 testing in pediatric and adult rheumatic diseases.

6. (A) Although systemic CS are effective in controlling systemic features and usually decrease joint pain and swelling, they do not halt the progression of the joint disease and destruction in childhood arthritis.

7. (D) Liver enzymes should be monitored regularly (every 1-2 months) in patients on methotrexate therapy. The concern for significant hepatotoxicity in patients with high cumulative methotrexate doses after years of treatment does exist but has yet to be substantiated in studies evaluating liver biopsies in these patients. Alcohol consumption is contraindicated in patients on methotrexate. Other complications of low-dose weekly methotrexate include marrow toxicity, which is generally mild and reversible, as well as mouth sores and nausea. Supplementation with folic acid may decrease these side effects. Immunosuppression tends to be mild at the low methotrexate doses given for childhood arthritis, so severe or opportunistic infections rarely occur. The infection risk may be increased if the child is also receiving CS. It is recommended that children on methotrexate not be immunized with live attenuated vaccines. Methotrexate is highly teratogenic; therefore, patients who are sexually active must use effective birth control methods while on this medication.

8. (E) Delayed growth, short stature, and osteoporosis are attributable to chronic illness, CS treatment, and poor nutrition. Decreased weightbearing and limited participation in physical activities contribute further to the osteoporosis. Micrognathia develops in many patients and may cause chewing difficulties, orthodontic problems, and even obstructive sleep apnea. Patients with significant cervical spine arthritis that results in C1-C2 instability or ankylosis of posterior vertebral processes are at risk for spinal cord injury (Figure 140-2). Functional disabilities historically occurred in 15-30% of children; however, with early aggressive treatment and the availability of biologic medications, the prognosis has improved greatly.

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FIGURE 140-2. A. Cervical spine radiograph showing fusion of the spinous processes of C2-C4 and C5-C7 in a 9-year-old boy with systemic arthritis since 18 months of age. B. MRI of the same patient showing cervical cord impingement at the C4-C5 level; note that impingement is only at the cervical level which is not fused and where all neck flexion and extension takes place.

9. (A) PFAPA is a benign syndrome, although frustrating to the family. The symptoms are primarily those described in the name, as well as fatigue and occasional joint or stomach pain during the fever episode. The etiology is unknown. Treatment includes antipyretics and reassurance to the parents. A recent study showed that a significant proportion of children have improvement or resolution of fever after tonsillectomy. When considering a diagnosis of PFAPA, it is important to exclude other causes of periodic fevers, including cyclic neutropenia and the known hereditary periodic fevers. Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation related to inborn errors of the innate immune system, with no evidence of autoimmune dysfunction. They have Mendelian patterns of inheritance, either autosomal recessive or dominant. Gene mutations for the 4 main hereditary periodic fevers have been identified over the last 15 years. The most common of these syndromes is familial Mediterranean fever, an autosomal recessive disorder most often occurring in individuals of eastern Mediterranean origin. It usually presents during young childhood with monthly fevers lasting up to 3 days, associated with polyserositis, arthritis of lower extremity joints, myalgias, and an erysipelas-like rash. Treatment with colchicine is usually effective in preventing the fevers and the long-term complication of amyloidosis. The other hereditary periodic fevers include: hyperimmunoglobulin-D with periodic fever syndrome (HIDS), which is autosomal recessive, tumor necrosis receptor–associated periodic syndrome (TRAPS), which is autosomal dominant and often treated with the anti-TNF medication etanercept, cryopyrinopathies, which include familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal onset multisystem inflammatory disease (NOMID), all of which may respond to treatment with anti-IL 1 biologics.

10. (E) The differential diagnosis of monoarticular arthritis is broad and influenced by several factors, including the duration and severity of joint symptoms, presence of extra-articular symptoms, and the patient’s age and gender. The differential can be divided into 5 main categories: rheumatologic, orthopedic, infectious, tumor, and miscellaneous entities. Rheumatologic diseases include oligoarticular arthritis (which involves ≤4 joints), psoriatic arthritis, juvenile ankylosing spondylitis (or enthesitis-related arthritis) and sarcoidosis, with the first 2 diagnoses more likely in this patient. Orthopedic problems affecting the knee include repetitive stress injuries, trauma, Osgood-Schlatter disease, osteochondritis desiccans, and patellofemoral syndrome, all of which, except trauma, are unlikely in a child this young. The main infectious cause to consider in a patient with a 3-month history of knee swelling is Lyme disease. Septic arthritis and osteomyelitis are unlikely in this case, considering the long duration of symptoms and the relatively mild clinical findings. Possible tumors are osteosarcoma, Ewing sarcoma, and pigmented villonodular synovitis. Although these tumors tend to occur in an older child, the clinician must always maintain a level of suspicion when the patient’s complaints are unifocal. Concern for a malignant process increases if the child has pain that is out of proportion to findings on physical examination and/or has a history of frequent focal bone pain, especially pain that awakens the child from sleep.

11. (B) A plain radiograph is essential in a monoarticular presentation to rule out a bone tumor. Rheumatoid factor is negative in more than 90% of patients with childhood arthritis. When present, it is usually found in older children with polyarticular disease. Furthermore, false-positive results can occur, making rheumatoid factor a very poor screening test for childhood arthritis. A joint aspiration for synovial fluid culture is not indicated in this child. The main reason to perform a joint aspiration is to rule out an acute bacterial infection, which is not expected in this case based on the long duration of relatively mild symptoms. Synovial fluid cultures aimed at recovering Borrelia burgdorferi are usually unsuccessful. Polymerase chain reaction of synovial fluid, and especially synovial tissue, has a much higher yield for identifying the presence of the Lymecausing spirochete. Furthermore, if Lyme disease is suspected because the patient resides in, or has traveled to a Lyme-endemic region, serologic studies (Lyme titers/Western blot) are usually performed, rather than joint aspiration.

12. (A) The CBC, erythrocyte sedimentation rate and CRP are often normal in oligoarticular arthritis. The ANA is positive in 40-60% of these children, usually in relatively low titer (≤1:320). It is important to recognize that the diagnosis of JIA is a clinical diagnosis, based on history and physical findings. Laboratory studies are frequently normal in multiple arthritis syndromes including oligoarticular JIA, rheumatoid factor-negative polyarticular, enthesitisrelated, and psoriatic JIA. When laboratory results are abnormal, they are often nonspecific, such as an increase in acute-phase reactants, mild anemia, or a positive ANA. The 2 notable exceptions are systemic JIA (anemia, and increased leukocyte count, platelets, erythrocyte sedimentation rate, and CRP); and rheumatoid factor positive JIA, which, by definition, has a positive rheumatoid factor and also frequently a positive anticyclic citrullinated peptide (anti-CCP), a new, more specific but less sensitive marker for this disease. Laboratory studies in children with suspected JIA may be helpful in decreasing the likelihood of other diagnoses, such as SLE, leukemia, inflammatory bowel disease, and sarcoidosis.

13. (D) By performing a slit lamp examination, the ophthalmologist can detect inflammatory cells in the aqueous humor of the anterior chamber of the eye. This is the best examination to detect early uveitis, an insidious eye disease in which most young patients lack eye symptoms. Later complications, such as cataracts, band keratopathy, and synechiae, can be seen by examination with an ophthalmoscope. However, by then, irreversible injury to the eye may have already taken place. High risk factors associated with chronic uveitis in childhood arthritis are female gender, young age (<6 years), positive ANA, disease duration less than 4 years, oligoarticular arthritis, and, less commonly, polyarticular (rheumatoid factor negative) arthritis and psoriatic arthritis. Children at high risk for uveitis should have a slit lamp examination every 3 months. Initial treatment for children with uveitis includes topical steroids and mydriatics. If inflammation persists, treatment with systemic CS, methotrexate, or monoclonal anti-TNF alpha medications may be indicated.

14. (A) The local public school district is required by Congress (Individuals with Disabilities Education Act 1975, amended in 1997, and the Disabilities Act Section 504) to provide special services to children with disabilities, including arthritis. It may not transfer this responsibility to other school districts.

15. (E) Although oligoarticular arthritis has a good prognosis in most patients, a significant percentage of patients may have long-term morbidity secondary to this disease. Appropriate management during periods of active disease can minimize morbidity.

16. (D) Isolated hip pain is extremely rare in oligoarticular arthritis. Tumor should always be included in the differential diagnosis of focal bone or joint pain. Orthopedic conditions involving the hip include Legg-Calvé-Perthes disease (idiopathic avascular necrosis) in younger children and slipped capital femoral epiphysis in adolescents. Hip arthritis occurs commonly in spondyloarthropathy. Transient or toxic synovitis of the hip is a self-limited process (usually ≤2 weeks’ duration), often noted to follow an upper respiratory infection. The child with toxic synovitis is generally 3-10 years of age, may limp, complain of pain in the hip, thigh, or knee, and may have limited hip range of motion. If there is any clinical suspicion that the patient may have septic arthritis, the hip joint must be aspirated immediately.

17. (D) Juvenile ankylosing spondylitis falls under the category of enthesitis-related arthritis in the JIA classification system. Enthesitis is inflammation at tendon insertion sites, for example, the Achilles insertion. Patients commonly have involvement of hip and axial joints, but they may also have arthritis of peripheral, especially lower extremity, joints. Ankylosing spondylitis is considered one of the spondyloarthropathies. The term spondyloarthropathy has historically referred to a group of entities that have certain clinical and laboratory characteristics in common: inflammation of spinal and sacroiliac joints, association with HLA-B27, absence of rheumatoid factor, occurrence of acute iritis, increased occurrence in males, and frequent positive family history of ankylosing spondylitis, inflammatory bowel disease, psoriatic arthritis, and Reiter syndrome. The presence of HLA-B27 is associated with an increased risk of developing ankylosing spondylitis, but it need not be positive to make this diagnosis. It is present in approximately 90% of whites but only 60% of African Americans with ankylosing spondylitis.

18. (C) The diagnosis of benign hypermobility syndrome is made by the presence of certain physical findings. These include answers B and D, as well as the ability to hyperextend the metacarpophalangeal joints when the wrist is in extension so that the fingers are parallel to the forearm, and the ability to touch the floor with the palms of the hands with the knees straight. Look for these physical findings in young children (especially between the ages of 3 and 10 years) who have increased pain after activity, as well as intermittent night pain. The incidence of benign hypermobility syndrome is increased in girls (female-to-male ratio is 2:1). It is more common in Asians and West Africans than in whites. Rarely, a small joint effusion in the ankles or knees may be observed; otherwise, there is absence of any clinical or laboratory signs of inflammation. Treatment includes parental and patient reassurance, education about this entity, avoidance of high-impact activities that increase joint symptoms, physical therapy to work on muscle strengthening, joint protection education, supportive footwear, and evening acetaminophen or ibuprofen on occasion.

19. (D) Growing pains, perhaps more appropriately called “benign nocturnal pain of childhood,” are characterized by lower extremity pain that frequently awakens the child (usually between ages 4 and 10 years) at night and may be associated with increased activity the day before. Laboratory and radiologic studies, if performed, are normal. Parents should be reassured. Massage may be helpful during episodes. If night awakening occurs regularly, then bedtime treatment with acetaminophen or a nonsteroidal anti-inflammatory medication, as well as a passive stretching program are helpful to decrease occurrence of symptoms. The child with this diagnosis should have no morning stiffness or other significant joint or bony pain during the day because these symptoms, in association with night awakening secondary to pain, could raise concern for an inflammatory process or malignancy.

20. (E) nail pitting and dactylitis

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FIGURE 140-3. Dactylitis of the 2nd and 4th toes in a patient with psoriatic arthritis.

21. (I) rheumatoid nodules, scleritis, and vasculitis

22. (C) vesiculopustular lesions on extremities and tenosynovitis

23. (F) erythema chronicum migrans

24. (A) mutation of gene encoding for pyrin

25. (B) conjunctivitis and urethritis

26. (D) resolves by 6-12 weeks

27. (H) erythema marginatum

28. (G) arthritis may precede abdominal symptoms

SUGGESTED READING

Burgos-Vargas R. Juvenile onset spondyloarthritides. Rheumatic Disease Clinics of North America. 2002;28:531-60.

Hashkes PJ, Laxer RM. Update on the medical treatment of juvenile idiopathic arthritis. Current Rheum Reports. 2006;8:450-458.

Petty RE, Cassidy JT. Chronic arthritis. In: Cassidy JT, Petty RE, Laxer RM, Lindsley CB, eds. Textbook of Pediatric Rheumatology. 5th ed. Philadelphia, PA: Elsevier Saunders; 2005:206-323.

Petty RE, Southwood TR, Baum J, et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban 1997. J Rheumatol. 1998;25:1991-1994.

Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369:767-778.

CASE 141: A 15-YEAR-OLD GIRL WITH FATIGUE, FEVER, AND ARTHRITIS

A previously healthy 15-year-old girl has had fatigue, low-grade fevers, sore throat, joint pain and stiffness for the past few weeks. On physical examination, she has cervical adenopathy and mild swelling of her finger joints. Her throat culture is negative for group A streptococcus. CBC: leukocyte count 3.9/mm³with a normal differential; the platelets are 165,000/mm³and the hemoglobin is 10.5 g/dL.

SELECT THE ONE BEST ANSWER

1. The differential diagnosis for this patient includes

(A) EBV infection

(B) leukemia

(D) A and C

(E) A, B, and C

2. Her ANA titer is 1:320. In addition to SLE, ANAs can be found in which of the following?

(A) patients taking phenytoin

(B) healthy individuals

(D) A and C

(E) A, B, and C

3. Autoantibodies that are specific for SLE include

(A) anti-double-stranded DNA (anti-dsDNA) and antiribonuclear protein (anti-RNP)

(B) anti-dsDNA and anti-Smith (anti-Sm)

(D) antihistone antibodies and anti-dsDNA

(E) anti-SS-A and anti-RNP

4. Which of the following skin findings is not included in the classification criteria used for the diagnosis of SLE?

(A) erythema marginatum

(B) photosensitivity

(D) discoid lesions

(E) mucocutaneous ulcerations (oral and/or nasal)

5. Which of the following complications does not occur in SLE?

(A) platelet counts less than 5000/mm³(B) psychosis, seizures, or cognitive dysfunction

(D) progressive erosive arthritis in most patients who have joint swelling

(E) pericarditis, myocarditis, or valvular dysfunction

6. Which statement regarding renal disease in pediatric SLE is true?

(A) a normal urinalysis rules out lupus nephritis

(B) lupus nephritis usually recurs in a transplanted kidney

(D) patients with mesangial disease on biopsy are at increased risk for progression to renal failure compared with those with proliferative lesions

(E) the presence of anti-Sm antibodies increases the risk of lupus nephritis

7. All of the following are true regarding laboratory evaluation in SLE except

(A) the erythrocyte sedimentation rate and CRP are good markers for subsequent SLE disease activity

(B) an elevated leukocyte count is associated with the use of high-dose CS or may be secondary to infection

(D) increases in anti-dsDNA levels may indicate impending exacerbation of disease

(E) patients with SLE may have a combination of a Coombs positive hemolytic anemia and thrombocytopenia, known as Evans syndrome

8. Which statement is false regarding antiphospholipid antibodies (APLA)?

(A) the risk of both venous and arterial thrombosis is increased in patients with APLA

(B) all patients with SLE should be checked for the presence of APLA

(D) the presence of APLA increases the risk of miscarriage

(E) more than 90% of patients with APLA have an underlying rheumatic disease

9. Which statement regarding the treatment of SLE in children is not true?

(A) hydroxychloroquine is often used to treat skin, joint, and muscle inflammation

(B) complications of CS treatment include avascular necrosis, osteoporosis, hypertension, and diabetes

(D) cyclophosphamide treatment may cause gonadal injury and may increase the risk of oncogenesis

(E) stress doses of CS may be necessary 6-12 months after cessation of chronic CS treatment

10. All of the following statements are true about childhood SLE except

(A) infection is a major cause of early mortality in children with SLE

(B) cardiovascular disease, including myocardial infarction and stroke, is a major long-term cause of morbidity and mortality

(D) 10-year survival rates have increased since the availability of CS from less than 50% to more than 90%

(E) 20% of adults with SLE were either diagnosed with SLE or developed initial SLE symptoms during childhood

11. All are true about neonatal lupus except

(A) the risk of having a baby with neonatal lupus increases if the mother has active lupus during pregnancy

(B) most children with congenital atrioventricular heart block require a pacemaker

(D) neonatal lupus is strongly associated with the presence of anti-Ro (SS-A) and/or anti-La (SS-B)

(E) a mother may have a baby with neonatal lupus even if she has never had a diagnosis or symptoms of a rheumatic illness

12. Which statement is correct regarding drug-induced lupus?

(A) all patients require treatment with CS to control symptoms

(B) renal involvement is common

(D) minocycline is one of several drugs known to cause drug-induced lupus

(E) complement levels are usually depressed in drug-induced lupus

13. Which of the following statements is true about Raynaud?

(A) the order of the triphasic color change is red → white → blue

(B) primary Raynaud, which is not associated with any underlying rheumatic disease, is more common in children than adults

(C) Raynaud phenomenon occurs in approximately a third of children with SLE and in more than 90% of children with systemic sclerosis (diffuse scleroderma)

(D) Raynaud is seen more often in males than females

(E) the order of the triphasic color change is red → blue → white

14. Approximately 4 weeks ago, a mother noticed that her 7-year-old son had a rash on his face and knuckles. Two weeks later, she noted he had decreased endurance and was having difficulty running and climbing at the playground. His teacher reported to his mother that he was having problems ascending 2 flights of stairs to go to music class. Which of the following would you not expect to find on initial physical examination of this child?

(A) dystrophic calcification

(B) violaceous discoloration of the upper eyelids

(D) muscle tenderness

(E) diffuse cutaneous vasculitis

15. Which of the following is not helpful in diagnosing juvenile dermatomyositis (JDM)?

(A) presence of Gottron papules and a heliotrope rash over the eyelids

(B) presence of ANA and an elevated sedimentation rate

(D) proximal muscle weakness

(E) muscle biopsy showing inflammatory cell infiltrate, perifascicular atrophy, and necrosis

16. Which statement is not true regarding the complications and outcome of JDM?

(A) calcinosis may cause limitation in joint range and cosmetic problems

(B) more than two-thirds of patients have good to excellent functional outcomes

(D) lower esophageal dysfunction often leads to dysphagia

(E) in severe cases, dysphonia may be present

17. For the past few days, a 5-year-old child has been complaining of intermittent abdominal pain. No emesis or diarrhea has been reported. Then her mother noted a red rash on her legs and brought her to your office. Your examination reveals a nontoxic child who is afebrile. She has palpable purpuric lesions, coalescing by the ankles, and ascending up to the buttocks. Her abdominal examination reveals mild diffuse tenderness but no rebound. You suspect that she has Henoch-Schönlein purpura (HSP). Which of the following statements regarding HSP is not true?

(A) the rash may recur during the first 6 weeks after presentation, often increasing after physical activity

(B) arthritis, especially of the ankles and knees, is common

(D) edema of the scalp, hands, and feet is not uncommon, especially in affected children younger than 4 years old

(E) skin biopsy will show a leukocytoclastic vasculitis with immune globulin (Ig)A deposition

18. All the following are true about GI involvement in HSP except

(A) GI hemorrhage is common and may be occult or gross, presenting as melena

(B) GI symptoms can present before the rash

(D) complications include bowel wall infarction and perforation

(E) ultrasonography may show edema of bowel wall and may identify an intussusception

19. Which statement is true for renal involvement secondary to HSP?

(A) most children who have hematuria during the acute phase of HSP illness have progression of renal disease

(B) it is associated with a membranous lesion on renal biopsy

(D) it may persist in 1-5% of children and may progress to end-stage disease in approximately 1%

(E) it occurs more commonly in patients younger than 8 years old at the time of HSP diagnosis

20. An 18-month-old boy was healthy until the acute onset of persistent fevers 4 days ago. He has been irritable but alert. His mother brings him to the emergency department and you note an exanthem on the trunk. You suspect Kawasaki disease (KD). You may expect to see all but which of the following findings on your admission physical?

(A) desquamation of the skin on the palms and soles

(B) cervical adenopathy

(D) edema on the dorsum of hands and feet

(E) conjunctivitis

21. A 15-year-old girl has had Raynaud symptoms for 1 year, and she occasionally develops sores on her fingertips. Previous laboratory assessment by her pediatrician revealed a normal CBC, C3, C4, and UA but a positive ANA (1:2560 nucleolar pattern). Over the past 6 months, she developed fullness of her fingers with skin tightening and decreased finger-joint range of motion. A diagnosis of systemic sclerosis (scleroderma) is suspected. Further workup should include

(A) renal biopsy

(B) brain magnetic resonance imaging (MRI)

(D) 24-hour urine collection for protein and creatinine clearance

(E) pulmonary function tests

22. In the past 6-12 months, an 8-year-old boy developed an altered appearance of his lower right leg including tautness and shininess of the skin and decreased ankle range of motion. He was diagnosed by the rheumatologist to have linear scleroderma. Which of the following physical findings does not occur in this entity?

(A) muscle atrophy

(B) Raynaud

(D) occasional patches of morphea at distant locations

(E) flexion contractures on the involved limb

Match each entity in questions 23 through 33 to one descriptive characteristic, A-K.

23. Polyarteritis nodosa	(A) large vessel vasculitis
24. Sjögren syndrome	(B) + cANCA (antineutrophil cytoplasmic antibodies)
25. En coup de sabre	(C) severe uveitis of anterior and posterior uveal tracts
26. Wegener	(D) a type of panniculitis granulomatosis
27. KD	(E) sicca complaints (dry eyes and ↓ oral secretions)
28. Serum sickness	(F) vasculitis of small and medium-sized vessels
29. Behçet disease	(G) presents 7-14 days after antigen exposure
30. Sarcoidosis	(H) elevated anti-DNase B titers
31. Takayasu arteritis	(I) linear scleroderma of the face
32. Erythema nodosum	(J) noncaseating granulomas
33. Rheumatic fever	(K) treatment with intravenous gammaglobulin (IVIG)

ANSWERS

1. (E) The patient’s clinical complaints, physical findings, and CBC results are all nonspecific and are not diagnostic for any particular disease. It is important to have a broad differential when first assessing this type of patient. Malignancy, such as leukemia, should be considered in children with this clinical history and depressed cell lines on CBC. Children with leukemia may present with musculoskeletal pain that is frequently out of proportion to the physical findings. This diagnosis may be overlooked in those who do not have blasts on peripheral smear (approximately 15% of children). SLE should be considered in any patient who presents with multisystem complaints. Constitutional symptoms such as fever, fatigue, and weight loss are common in SLE, as is joint involvement, which is present in approximately 75% of patients. Mild cytopenias are common laboratory findings in SLE. EBV infection, especially in the teenager, can present with multisystem complaints similar to those seen in SLE, including constitutional symptoms, arthralgias/ arthritis, and adenopathy. Children with EBV infections often have cytopenias and positive ANAs, which can add to the challenge of differentiating between SLE and EBV. Further laboratory evaluation (EBV antibody profile, complement levels, autoantibodies such as anti-Sm and anti-double stranded DNA, UA) may help guide the clinician to the correct diagnosis.

2. (E) ANAs are found in many clinical settings, even among healthy individuals (especially among those who have primary relatives with autoimmune disease or in the elderly). They may be detected in infections (eg, EBV, streptococcal, subacute endocarditis, hepatitis C), autoimmune disease (SLE, mixed connective tissue disease, dermatomyositis, scleroderma, juvenile idiopathic arthritis, adult rheumatoid arthritis, Sjögren syndrome), druginduced processes (eg, secondary to anticonvulsants, isoniazid, penicillamine, hydralazine, procainamide, minocycline), and organ-specific autoimmune disease (autoimmune hepatitis, thyroiditis). ANA is present in almost all patients with SLE (>98%). Titers are variable in SLE but are usually 1:320 or higher. It is important to recognize that although virtually all patients with SLE have a positive ANA, most people with a positive ANA do not have SLE.

3. (B) Anti-dsDNA and anti-Sm are specific for SLE and are present in approximately 70% and 20% of SLE patients, respectively. Other autoantibody subtypes may be present but are not specific for SLE, and they may be identified with other autoimmune entities:


SPECIFIC AUTOANTIBODY	CLINICAL ASSOCIATIONS

Anti-dsDNA	SLE
Anti-Sm	SLE
Anti-U1-RNP	Mixed connective tissue disease; SLE
Anti-Ro/SS-A	SLE; Sjögren syndrome; neonatal lupus; C2 and C4 deficiencies
Anti-La/SS-B	Sjögren syndrome; SLE; neonatal lupus
Anti-Scl 70	Systemic sclerosis
Anti-Jo-1	Polymyositis, especially with interstitial lung disease
Antihistone	Drug-induced lupus; SLE
Anticentromere	Limited scleroderma (CREST)

Abbreviation: CREST, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, telangiectasia.

4. (A) The American College of Rheumatology 1997 criteria for classification of SLE are helpful diagnostic tools for SLE diagnosis. The criteria are

• Malar rash (Figure 141-1)

• Discoid rash

• Photosensitivity

• Oral or nasal ulcerations

• Nonerosive arthritis

• Polyserositis

• Nephritis (proteinuria >0.5 g/day or cellular casts)

• Encephalopathy (seizures or psychosis)

• Cytopenia

• Positive ANA

• Positive immunoserology: +anti-dsDNA or +anti-Sm, or presence of antiphospholipid antibodies

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FIGURE 141-1. Malar rash in a teenage boy with systemic lupus erythematosus. See color plates.

The presence of 4 of these 11 criteria has a sensitivity and a specificity of more than 95% for the diagnosis of SLE. SLE should be considered in children who present with multisystem complaints and signs. Although not included in the criteria just listed, several other features may be present that increase suspicion for SLE, such as constitutional symptoms (fatigue, weight loss, fevers), alopecia, myalgias/myositis, Raynaud phenomenon, lymphadenopathy, hepatosplenomegaly, myocarditis, and thrombosis. Decreased C3 and C4 levels in a patient with a positive ANA associated with any of the symptoms just listed raise concern of a diagnosis of SLE. In 1999, the American College of Rheumatology (ACR) developed expanded nomenclature for neuropsychiatric SLE when it described 19 central and peripheral neurologic syndromes, including cognitive dysfunction, headaches, and cranial and polyneuropathies. Answer A, erythema marginatum, is a skin finding in acute rheumatic fever.

5. (D) The arthritis in SLE patients is rarely erosive, and joint deformity is uncommon. A small percentage of patients with SLE may develop Jaccoud arthropathy, which is a nonerosive but deforming arthropathy.

6. (C) Lupus nephritis occurs in more than 60% of children with SLE. The risk of renal involvement is increased among those with antibodies to dsDNA but not among those with anti-Sm antibodies. Although some patients may present with nephrotic syndrome, hypertension, and renal insufficiency, the majority initially have no clinical symptoms of renal disease. Therefore, it is important to perform frequent urinalyses, assess protein excretion (the easiest way is by performing a protein-to-creatinine ratio on a spot urine), and follow the serum creatinine and albumin. Rarely, patients with a normal UA may have renal involvement. Because urine and blood studies are indirect assessments of renal status in SLE patients, a kidney biopsy is often necessary to provide important information to help with treatment decisions. The 2004 International Society of Nephrology (ISN) classification system, which replaced the World Health Organization (WHO) classification system, categorizes renal lesions based on light (and occasionally electron) microscopy, and immunofluorescence. The ISN classification describes 6 classes, which are then further subdivided to provide more detail of the renal pathology:

• Class I: minimal mesangial lupus nephritis

• Class II: mesangial proliferative lupus nephritis

• Class III: focal proliferative glomerulonephritis

• Class IV: diffuse proliferative glomerulonephritis

• Class V: membranous nephritis

• Class VI: advanced sclerosing lupus nephritis

Patients with class I or II lesions generally respond well to CS, often low dose, or treatment only with hydroxychloroquine and continued observation of renal status. Class III is potentially a more significant lesion that may improve with CS treatment alone or with cytotoxic treatment, but it may also progress to a more severe renal lesion, such as class IV. Classes IV and V require aggressive medical management to decrease progression to renal insufficiency and failure. Class VI has marked glomerular sclerosis, suggesting an end-stage kidney. In addition to histologic classification, activity (inflammation) and chronicity (scarring) indexes are also assessed, which have a further impact on medical treatment decisions and renal prognosis. Lupus nephritis is associated with increased morbidity and decreased long-term survival. The poorer outcome is related to renal complications such as hypertension, nephrotic syndrome, and renal failure. Treatment of severe renal disease (cytotoxic drugs and high CS doses) may further contribute to morbidity and mortality. To help protect inflamed and compromised kidneys, blood pressure management is essential. Treatment with an angiotensin inhibitor is recommended. If progression to renal failure occurs, the patient undergoes dialysis until a transplant can be performed. A renal transplant is generally postponed until the patient’s SLE is quiescent. Fortunately, clinically significant lupus nephritis occurs in less than 5% of transplanted kidneys.

7. (A) The erythrocyte sedimentation rate and CRP are not helpful markers for SLE disease activity. Both are nonspecific studies affected by infection and other inflammatory conditions. The complement levels and anti-dsDNA titers reflect disease activity more reliably.

8. (E) The presence of APLA is associated with venous or arterial thrombosis, recurrent fetal loss, hemolytic anemia, thrombocytopenia, and livedo reticularis. Approximately half of patients with APLA do not have an underlying rheumatologic disease (primary APLA syndrome); the rest have secondary APLA syndrome, usually related to a rheumatic disease (especially SLE). It is important to test for the presence of APLA in any individual who presents with an unexplained venous or arterial thrombosis and also in patients diagnosed with SLE. APLA studies include lupus anticoagulant, anticardiolipin antibodies, and anti-beta₂-glycoprotein.

9. (C) CS treatment is necessary to help control multisystem involvement in the vast majority of children with SLE. Unfortunately, prolonged use can lead to multiple complications. These include growth suppression (starting at doses equivalent to ≥3 mg/day in small children), musculoskeletal (osteoporosis, avascular necrosis, muscle wasting, myopathy), cardiovascular (hypertension, hyperlipidemia), ophthalmologic (cataracts, glaucoma), skin (striae, impaired healing), diabetes, secondary adrenocortical insufficiency, and immunosuppression. A major goal of medical therapy is to minimize the CS dose given. This, in part, is accomplished by using combination therapy. Hydroxychloroquine is often effective in treating skin, muscle, and joint involvement. It may also decrease the incidence of SLE exacerbations. Immunosuppressive therapy (including cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, cyclosporine A, and rituximab) is often given to patients whose disease is not controlled by CS or who have major organ system involvement, especially involving the renal and central nervous systems. Unfortunately, current treatment for SLE is not specific and usually involves global immunosuppressive therapy. Preventive measures employed in the management of SLE include treatment of hypertension, hyperlipidemia, osteoporosis, and administration of vaccines to decrease the risk of certain infections, especially pneumococcal or influenza.

10. (C) Although the prognosis for SLE has improved, most children with SLE are unable to discontinue all medications. Ten-year survival has increased from less than 50% in the 1950s to more than 90% currently. The most common cause of death is infection, followed by renal failure. Mortality occurring more than 10 years after SLE diagnosis is often secondary to cardiovascular complications such as myocardial infarction and stroke.

11. (A) Anti-Ro (SS-A) and/or anti-La (SS-B) antibodies are present in virtually all mothers who have babies with neonatal lupus erythematosus (NLE). These autoantibodies may be present in individuals with SLE, Sjögren syndrome, rheumatoid arthritis, and even in women with no rheumatologic symptoms or diagnosis. In women with SLE, only the presence or absence of anti-Ro and anti-La has an impact on the risk of having a baby with NLE, not the status of SLE disease activity. (However, women with active and severe SLE may be at increased risk of premature delivery, miscarriage, and other pre- and perinatal complications.) Clinical manifestations of NLE include rash, hepatitis, thrombocytopenia, and permanent congenital heart block (CHB). Except for CHB, the NLE manifestations resolve by 6 months of age, corresponding to the disappearance of maternal autoantibodies from the baby’s circulation. Some children may have residual scarring from skin lesions. Most children with CHB require pacemakers, many needing insertion during the first few weeks of life.

12. (D) Most patients with drug-induced lupus (DIL) have milder symptoms and less organ-system involvement than those with idiopathic SLE. The most common clinical manifestations in DIL are arthralgias/arthritis, myalgias, serositis, rash, and constitutional symptoms (such as fatigue and fever). Renal and neurologic involvement is rare. Antibodies to histones are often present; anti-dsDNA antibody is usually absent. Complement levels tend to be normal. The most commonly implicated drugs causing DIL in children include anticonvulsants (especially hydantoins and ethosuximide), isoniazid, and minocycline. Reported cases of DIL secondary to minocycline have increased greatly in the past decade, corresponding to its increased use in teenagers for the treatment of acne. In adults, hydralazine and procainamide are the most frequent triggers of DIL. Definitive treatment for DIL is discontinuation of the suspected triggering medication. NSAIDs are useful to treat fever, musculoskeletal involvement, and serositis. Although most patients do not require CS, some may require treatment for rare major organ system involvement or persistence of symptoms.

13. (C) Raynaud may occur in patients with rheumatologic disease (secondary Raynaud or Raynaud phenomenon) and in individuals without an underlying rheumatologic process (primary Raynaud or Raynaud disease). Primary Raynaud is most common in adult women, usually during their third and fourth decades of life. It may occur in teenage girls but is rare in prepubertal children and teenage boys. In both primary and secondary Raynaud, the triphasic color change, in order, is white → blue → red. The pathogenesis is arterial vasoconstriction with subsequent reduction in local blood flow, particularly to the hands, the toes, and occasionally the ears, nose tip, and lips. It is usually triggered by cold temperature or emotional stress. It is important to know if a child with Raynaud has a primary or secondary process. The history, physical examination, and laboratory evaluations are all essential to help determine this. The history may reveal multisystem complaints. The presence of pitting or scarring of the distal digital pulp, finger edema, sclerodactyly, or changes in the nail-fold vessels suggest a secondary Raynaud process, as does the presence of a high ANA titer. Raynaud’s phenomenon occurs in systemic sclerosis (>90% of patients), mixed connective tissue disease (about 50%), and SLE (about 35%). Treatment includes patient education to keep the extremities warm and the core temperature up, vasodilators (such as calcium channel blockers), and biofeedback.

14. (A) Dystrophic calcification, or calcinosis, is a late feature of juvenile dermatomyositis (JDM), usually developing months to years after the initial symptoms of rash and muscle weakness. Proximal muscle weakness, muscle tenderness, and active skin lesions, including diffuse cutaneous vasculitis and erythema over the extensor aspects of the elbows and knees may be present.

15. (B) ANA and the erythrocyte sedimentation rate are nonspecific laboratory studies that do not help with the diagnosis of JDM. The diagnosis requires the presence of the classic rash consisting of Gottron papules that are scaly, erythematous lesions over the dorsal aspects of the metacarpophalangeal and interphalangeal joints (Figure 141-2), and a heliotrope discoloration over the upper eyelids, often with mild periorbital edema. The presence of at least 2 of the 4 following criteria is also needed to make the diagnosis: (1) symmetric proximal muscle weakness, (2) increase in the serum of one or more skeletal muscle enzymes (creatine kinase, aldolase, aspartate aminotransferase, lactic dehydrogenase), (3) electromyography (EMG) demonstrating myopathy and denervation, and (4) a muscle biopsy showing inflammation and necrosis. If the first 2 criteria are present, the invasive studies, specifically EMG and muscle biopsy, are rarely needed. A noninfused MRI of the gluteal and thigh muscles may show areas of edema, consistent with muscle inflammation. This tool is being employed more commonly to help in the diagnosis of JDM. It may be difficult to evaluate the presence of muscle weakness in a child younger than 7 years of age in whom it is often not possible to perform formal muscle strength grading. Therefore, assessment of gross motor skills (such as the ability to squat and arise, balance, jump, hop, get on and off the floor, and ascend stairs) is an essential part of the physical examination. Look for a positive Gower sign (the use of the arms to assist in transitioning from a kneeling or prone position to standing, by “walking” the hands up the thighs).

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FIGURE 141-2. Erythematous, scaly lesions (Gottron’s papules) over the dorsal aspects of the metacarpophalangeal and interphalangeal joints in a 10-year-old girl with dermatomyositis. Nailfold telangiectasias can also be seen. See color plates.

16. (D) In JDM, weakness of the skeletal muscles employed in swallowing (proximal esophageal, palatal, pharyngeal, and hypopharyngeal muscles) may lead to dysphagia, regurgitation of liquids through the nose, and dysphonia with nasal speech. The risk of aspiration is quite real in these patients who require aggressive medical management and may need protection of the airway. Overall, the prognosis of JDM has improved greatly since the availability of CS, which is the first line of treatment. In the pre-steroid era, at least a third of patients died (usually secondary to respiratory failure or GI vasculitis), and another third had major morbidity (significant residual weakness and/or severe calcinosis). Currently, CS treatment is given to all JDM patients, with duration of therapy lasting more than 1 year, often 18-24 months, depending on the clinical response. A rapid taper of CS or total treatment duration less than 6 months is often associated with disease exacerbation. Some JDM patients require additional medications. Methotrexate is the most commonly used second-line agent. Cyclosporin and IVIG also have demonstrated efficacy. JDM treatment with biologics is being evaluated. Currently, long-term survival is more than 95%, and more than two-thirds of patients have good to excellent outcomes. Calcinosis is still a major cause of morbidity and reflects prolonged periods of poorly controlled disease (Figure 141-3). Early diagnosis and appropriate treatment of JDM are essential because they have been shown to decrease mortality and morbidity.

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FIGURE 141-3. Radiograph showing extensive calcinosis in the lower leg muscles and fascial planes of an adolescent with long-standing, poorly controlled dermatomyositis.

17. (C) HSP, the most common vasculitic syndrome of childhood, is characterized by the presence of a palpable purpuric rash (Figure 141-4). Distribution is primarily over the dependent areas of legs (especially prominent by the ankles) and buttocks, but it may also occur on the hands and arms. Ulceration of the lesions may occasionally occur. Recurrence of the purpuric rash, especially after increased physical activity, is common during the first 6 weeks. The rash is never associated with thrombocytopenia. Skin biopsy shows a leukocytoclastic vasculitis with IgA deposition. Subcutaneous edema may be present in younger children and occurs on the dorsum of hands and feet, periorbital areas, scalp, and scrotum. Arthritis, most commonly involving ankles and knees, occurs in 60-80% of children. Treatment of the arthritis is usually not necessary, although NSAIDs may be helpful. However, they should be used with caution because of the possible GI and renal involvement seen in HSP.

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FIGURE 141-4. Palpable, purpuric lesions on the legs of a child with Henoch-Schönlein purpura. See color plates.

18. (C) GI involvement occurs in more than two-thirds of patients and can be mild or severe. It is usually characterized by colicky pain and may be associated with emesis and GI hemorrhage, either occult or gross. Abdominal pain is thought to be secondary to bowel wall edema. Mucosal ulceration may occur. When the GI symptoms are present before the rash (15-35% of cases), the diagnosis may be unclear and an acute surgical abdomen may be suspected. GI complications include intussusception (2-4%), and, rarely, bowel infarction, bowel wall perforation, pancreatitis, and hydrops of the gallbladder. Intussusception in HSP is usually ileoilial, as opposed to the more common ileocolic location seen in idiopathic intussusception. A barium enema, thus, will not often detect intussusception in HSP. A more helpful study to evaluate GI involvement in HSP is ultrasonography, which demonstrates bowel wall edema in children with GI symptoms, as well as complications such as intussusception and perforation. Although placebo-controlled studies are lacking, children with severe GI manifestations are often given CS. A reasonable treatment regimen is 1-2 mg/kg per day for 1 week, tapering off over the next few weeks. Intravenous CS administration may be required initially to assure systemic absorption.

19. (D) Renal involvement occurs in 20-40% of patients and generally presents within 3 months of the HSP diagnosis with microscopic hematuria. Mild proteinuria may also be present, but nephrotic syndrome, renal insufficiency, and hypertension are uncommon. UA should be performed weekly initially, and then at least monthly for the first 3 months after HSP diagnosis, and perhaps beyond in those with increased risk factors for renal disease: older age (>8 years of age); persistent rash; history of severe abdominal symptoms, initial abnormal urinalyses. Renal involvement progresses in 1-5% of patients and may result in renal failure. Early renal characteristics associated with persistent nephropathy or renal failure include proteinuria more than 1 g/day, nephrotic syndrome, and renal insufficiency. Renal biopsy findings range from mild mesangial proliferation in those with mild UA changes to severe crescentic glomerulonephritis in patients with more severe renal involvement. IgA deposition is present on immunofluorescence. Treatment of renal disease in HSP is controversial because of a lack of prospective multicenter trials. However, recent studies suggest improved outcomes of HSP renal disease with CS, alone or combined with an immunosuppressive medication such as cyclophosphamide, azathioprine, mycophenolate mofetil, or cyclosporine.

20. (A) KD is one of the most common vasculitides of childhood. Its pathology includes vasculitis and fibrinoid necrosis of medium-size arteries, especially the coronary arteries. The clinical characteristics for the KD classification criteria are well known and include the presence of persistent fever 39ºC or higher for 5 or more days with at least 4 of the following 5 features: nonspecific exanthema primarily on the trunk; oral changes (“strawberry” tongue and/or red, swollen, cracked lips); conjunctivitis (bilateral, bulbar, and nonsuppurative); cervical lymphadenopathy; extremity changes (edema and erythema of the hands and feet during the acute phase and/or desquamation of the palms and soles starting at the fingertips and toes during the subacute phase, approximately 2 weeks after clinical presentation). Some children, especially infants, may have incomplete or atypical KD, making the diagnosis more challenging and delaying treatment. Because children younger than 1 year of age are at increased risk for coronary aneurysms, any very young child with unexplained fever longer than 5 days associated with some features of KD should have an echocardiogram performed. In addition to the diagnostic features described, other common findings in KD include irritability (in part related to aseptic meningitis that occurs in 40% of patients), hydrops of the gallbladder, arthritis, and uveitis. Laboratory studies show markedly elevated acute phase reactants, white blood count and platelet counts, the presence of anemia, mild liver enzyme elevation, and negative cultures and ANA. Once the diagnosis of KD is made, or is highly suspected, IVIG, 2 g/kg, should be administered. This treatment is especially effective when given within 10 days of presentation, usually resulting in immediate defervescence and a marked decrease in the risk of developing coronary aneurysms (from >20% to <5%). If clinical symptoms persist, retreatment with IVIG is indicated. Some patients require further treatment, usually high-dose intravenous methylprednisolone. High-dose aspirin (80-100 mg/kg/day) is also given during the acute phase and then decreased to antiplatelet dosing (3-5 mg/kg) until acute-phase reactants and platelet levels return to normal. Low-dose aspirin is continued indefinitely in those with coronary aneurysms. An echocardiogram should be performed when the KD diagnosis is made and then repeated 6-8 weeks later. De novo aneurysms rarely develop more than 8 weeks after disease onset. Long-term sequelae occur most often in patients who were diagnosed with giant aneurysms (internal vessel diameter ≥8 mm) during the acute illness. These patients may develop vessel stenosis and occlusion, leading to ischemia and/or infarction. In industrialized countries, KD is the leading cause of acquired heart disease in children.

21. (E) Scleroderma is classified as (1) systemic disease that includes diffuse cutaneous systemic scleroderma (DCSS, or systemic sclerosis) and limited scleroderma (or CREST, which is very rare in pediatrics); (2) localized disease (see answer 22). The pathology of systemic and localized scleroderma is similar, with early inflammatory infiltrate in the skin and other involved tissues, followed by increased fibroblast and collagen deposition. A vasculopathy with endothelial cell injury is prominent in this disease. The etiology is unclear. DCSS is a very rare but potentially devastating illness in children. Raynaud, present in more than 90%, is often severe, resulting in digital ulcerations and gradual loss of distal tufts (Figure 141-5). Initially, tense swelling with subcutaneous edema, especially of the fingers and arms, is prominent. Then the skin gradually tightens down, resulting in marked limitation in finger and large joint range. Telangiectasias and subcutaneous calcification are common. Arthritis, especially of the small joints, and myositis can occur. Pulmonary disease is present in most patients and can be asymptomatic or characterized by dyspnea on exertion or dry cough. Lung involvement may be primarily parenchymal with fibrosis, vascular leading to pulmonary hypertension, or a combination of both. Serial pulmonary function tests are indicated during the course of the disease to evaluate for restrictive disease and decreased diffusion. DCSS can affect the entire GI tract, but the most prominent problems are lower esophageal dysfunction resulting in reflux, gut hypotonia, and malabsorption. Radiographic studies, especially to assess esophageal function, may be helpful in guiding treatment. Renal disease is primarily vascular and can lead to renal crisis with malignant hypertension. Cardiac involvement may be primary or may be secondary to pulmonary hypertension. Periodic echocardiograms should be performed. Laboratory studies are not helpful in making a diagnosis of DCSS or in assessing disease status. Most patients do have a high-titer positive ANA. Management of DCSS is challenging and often customized based on clinical involvement. Treatment generally includes intensive rehabilitation (especially occupational therapy), H2 blockers and proton pump inhibitors for reflux, calcium channel blockers for Raynaud, angiotensin-converting enzyme inhibitors for hypertension, and various anti-inflammatory and immunosuppressive medications (which are, unfortunately, frequently not very efficacious) to treat the fibrotic and vascular complications of this disease.

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FIGURE 141-5. (left) Diffuse cutaneous systemic scleroderma: taut, shiny and thickened skin on hands/fingers with small ulcerations and early loss of distal tufts. (right) Same patient 2 years later with large distal ulcers and further loss of distal tufts.

22. (B) Localized scleroderma is more common than systemic sclerosis and limited scleroderma (or CREST), which is rare among children. Often referred to as morphea, this group of disorders is characterized by involvement of skin and subdermal tissues. There is absence of systemic complications and Raynaud. Several subtypes of morphea are described, varying from mild and scattered superficial plaques to more severe generalized and deep morphea. Linear scleroderma, the most common form of localized scleroderma/morphea, usually involves one limb, although 2 or more limbs may be involved. Lower extremities are affected more often than upper. Involvement extends through subcutaneous tissue and muscle to underlying bone, leading to inhibited growth of the affected limb, severe muscle atrophy, and flexion contractures (Figure 141-6). Linear scleroderma of the face, or en coup de sabre, may result in facial hemiatrophy, dental/orthodontic problems, and major cosmetic concerns. Parry-Romberg syndrome refers to progressive facial hemiatrophy without the classic “en coup de sabre” lesion, often complicated by seizures and trigeminal neuralgia. Laboratory studies in localized scleroderma are not diagnostic, although the ANA is often positive, as is singlestranded DNA. No treatment is indicated for superficial morphea, whose lesions often regress over a few years. Deep and generalized morphea, as well as linear scleroderma, often respond to treatment with systemic CS and methotrexate. Physical and/or occupational therapy is indicated in children with linear scleroderma.

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FIGURE 141-6. (top) Linear scleroderma (LS) involving the left leg. (bottom) Right foot of the same patient demonstrating an LS streak starting at the 2nd toe and extending over the dorsum of the distal foot.

23. (F) vasculitis of small and medium-size vessels

24. (E) sicca complaints (dry eyes and decreased oral secretions)

25. (I) linear scleroderma of the face

26. (B) positive cANCA (antineutrophil cytoplasmic antibodies)

27. (K) treatment with IVIG

28. (G) presents 7-14 days after antigen exposure

29. (C) severe uveitis of anterior and posterior uveal tracts

30. (J) noncaseating granulomas

31. (A) large-vessel vasculitis

32. (D) a type of panniculitis

33. (H) elevated anti-DNase B titers