Secrets – Pediatric: Rheumatology

CLINICAL ISSUES

1. What is an ANA?

Antinuclear antibody (ANA) is made up of circulating γ-globulins directed against several known and unknown nuclear proteins. Unfortunately, the classic immunofluorescence technique is being replaced by a still nonvalidated enzyme-linked immunosorbent assay (ELISA) technique in order to save costs. When it is measured by an immunofluorescent technique, it is also called fluorescent antinuclear antibody (FANA). It is expressed as a titer, usually with a cutoff of 1:40. It is positive in 97% of patients with systemic lupus erythematosus (SLE), usually at a titer at or above 1:320, and in 60% to 80% of patients with juvenile idiopathic arthritis (JIA), usually at a lower titer. It is also positive in 10% to 30% of normal children, and because of that should not be used as a screening test when the child does not present objective physical findings of arthritis.

2. What is an ANA profile?

Out of the many nuclear antigens that can make the FANA test positive, there are some with clinical value in pediatrics. They are grouped under the so-called ANA profile. These are individual antibodies measured by ELISA (commercial laboratories) or Western blot (specialized laboratories).

3. Should I order a profile instead of an ANA because it has more specificity?

No. This test has value only in the right clinical context (see later) and when there is a documented positive ANA by immunofluorescence.

4. What is the significance of the various antibodies included in the ANA profile?

• Anti–double-stranded DNA: Associated with SLE. This test has to be ordered separately; it is not usually part of the profile.
• Antihistone: Associated with drug-induced lupus
• Anti-Ro (also called anti-SS A): Associated with Sj€ogren syndrome and neonatal lupus
• Anti-La (also called anti-SS B): Associated with Sj€ogren syndrome and neonatal lupus
5. A 6-year-old girl with a 2-month history of joint pain (onset after a viral illness) has a normal physical examination, complete blood cell count, and erythrocyte sedimentation rate (ESR), but a positive ANA titer of 1:160. What are some of the possible explanations for this positive ANA?
• Laboratory variation
• Nonspecific response to viral illness
• Preclinical state of SLE (least likely)
• Normal population frequency (about 8% at that titer)
• Other autoimmune or paraneoplastic conditions

Tan EM, Feltkamp TE, Smolen JS, et al: Range of antinuclear antibodies in “healthy” individuals, Arthritis Rheum
40:1601–1611, 1997.

6. Is Raynaud phenomenon a disease?
In 1874, Maurice Raynaud, while still a medical student, described a triad of episodic pallor, cyanosis, and erythema after exposure to cold stress; the term Raynaud phenomenon describes
this clinical triad. When this phenomenon is associated with a disease such as scleroderma or lupus, it is called Raynaud syndrome; when the phenomenon is seen as an isolated condition without
any other rheumatic disorder, it is called Raynaud disease, although some patients on long-term

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follow-up may develop an associated disease (e.g., CREST syndrome [a limited form of systemic sclerosis]). Rheumatologists are commonly consulted for adolescents with blue dusky hands and feet. If there is no pallor, it is probably acrocyanosis (Crocq disease), a benign variant of no clinical relevance. It may occur in association with weight loss in athletes or children treated with amphetamine derivatives for attention-deficit/hyperactivity disorder.

Nigrovic PA, Fuhlbrigge RC, Sundel RP: Raynaud’s phenomenon in children: a retrospective review of 123 patients,
Pediatrics 111:715–721, 2003.

7. When is a child considered to have hypermobile joints?
The presence of three of the following features suggests true hypermobility:
• Apposition of the thumb to the flexor aspect of the forearm (Fig. 17-1)
• Hyperextension of the fingers so that they lie parallel to the dorsum of the forearm
• Hyperextension at the elbow of >10 degrees
• Knee hyperextension of >10 degrees
• Ability to touch the floor with the heel and also with the palms of the hands from a standing
position without flexing the knee

Figure 17-1. Abnormal contact between the thumb and forearm in a young girl with benign hypermobility joint syndrome.

8. Which children can demonstrate a Gorlin sign?
Gorlin sign is the ability to touch the tip of the nose with the tongue. It is seen in conditions associated with hypermobility syndromes, such as Ehlers-Danlos syndrome.

9. In what settings can reactive arthritis occur?
REACTIVE arthritis in its broadest sense refers to a pattern of arthritis associated with a nonarticular (remote) infection. By definition, it is an inflammatory arthritis, but a live organism cannot be isolated by culture of synovial fluid or synovial biopsy. A restricted definition of the syndrome includes arthritis after enteric (e.g., Salmonella, Shigella, Yersinia, Campylobacter, Giardia) or genitourinary infections (e.g., Chlamydia).

Morris D, Inman RD: Reactive arthritis: developments and challenges in diagnosis and treatment, Curr Rheumatol Rep 14:390–394, 2012.

10. What conditions are associated with gastrointestinal symptoms and arthritis?
Noninfectious
• Ulcerative colitis
• Crohn disease
• Behçet disease
• Henoch-Sch€onlein purpura
• Celiac disease

Infectious
• Salmonella
• Shigella
• Yersinia
• Campylobacter
• Tuberculosis
• Giardiasis
11. One week after mild trauma, an 8-year-old girl has pain and tenderness in the right foot and leg, both of which are cold, exquisitely tender to the touch, with mottled discoloration. What is the likely diagnosis?
Complex regional pain syndrome, type 1. More commonly called reflex sympathetic dystrophy, or reflex neurovascular dystrophy, this poorly understood entity is often confused with arthritis because of localized severe pain in one of the extremities. However, several features separate
it from arthritis. The pain is not confined to a single joint; it is regional in nature, involving portions of an extremity; and it often follows minor trauma (+/ immobilization or walking aid use).
The pain is very severe, and even light touch causes pain (i.e., hyperesthesia). Several dysautonomic changes (e.g., mottling, color changes, sweating) may occur but not always. Laboratory findings are normal. Imaging techniques or nerve conduction studies are not needed unless the diagnosis is in question. Regional osteopenia as a result of disuse may develop in very severe cases.
Because the role of the sympathetic nervous system is unclear and dystrophy may not occur in all cases, the terminology change has been revised by the International Association for the Study of Pain. In type 1, all of the features of the complex are present without definable nerve injury.
In type 2, a definable nerve injury is present.

Rajapakse D, Liossi C, Howard RF: Presentation and management of chronic pain, Arch Dis Child
5:474–480, 2014.
Merskey H, Bogduk N, editors: Classification of Chronic Pain. IASP Press, 2002, Seattle, pp 41–43.

12. How is complex regional pain syndrome managed?
Although many children are casted because of suspected hairline fractures, immobilization is contraindicated. Treatment is aimed at providing pain relief using analgesics and other nonmedical modalities. It is important that families be given a good explanation of the mechanism of pain
and assurance that this condition is controllable. A physical therapy program should be started immediately, with emphasis on passive and active range of motion exercises and the maintenance of function and pain desensitization. Aquatic therapy is particularly useful in these children to initiate therapy. Desensitization of the painful area using one of several modalities (e.g., biofeedback, transcutaneous electrical nerve stimulation, visualization, acupuncture) can be part of the program. A positive attitude on the part of physicians and therapists is essential.

Katholi BR, Daghstani SS, Banez GA, et al: Noninvasive treatments for pediatric complex regional pain syndrome: a focused review, PM&R 6(10): 926–933, 2014.
Lee BH, Scharff L, Sethna NF, et al: Physical therapy and cognitive-behavioral treatment for complex regional pain syndromes, J Pediatr 141:135–140, 2002.

13. Do children develop fibromyalgia?
Children as young as 9 years of age have been diagnosed with this syndrome. Fibromyalgia is a condition that is characterized by musculoskeletal aches and pains, fatigue, variable disturbed sleep patterns, and tenderness over various parts of the body. These tender points are useful for the diagnosis (Fig. 17-2). There should be tenderness over at least 4 of these 11 points for proper classification of individuals. In addition, there should be no tenderness over nonspecific sites such as the forehead or the pretibial region.
Aches and pains are extremely common in children and may be the result of serious medical diseases (e.g., leukemia), mental illness (e.g., depression), and psychosocial stress. Differentiation of chronic musculoskeletal pain of nonorganic origin may be difficult in children and adolescents.

Criteria for diagnosis of fibromyalgia (American College of Rheumatology)

1. History of widespread pain
Pain is considered widespread when it occurs on both sides of the body above and below the waist. Axial skeletal pain must be present.
2. Pain in 11 of 18 bilateral tender point sites on digital palpation
(using about 4 kg of pressure).

Occiput
Suboccipital muscle
insertions

Trapezius
Midpoint of upper border

Supraspinatus Origins, above the scapula spine near the medial border
Gluteal Upper outer quadrants of buttocks in anterior
fold of muscle

Greater Trochanter
Posterior to trochanteric
prominence

Low cervical Anterior aspects of intertransverse spaces at C5–C7

Second rib
Second costochondral junction, just lateral to junction on upper surfaces
Lateral epicondyle 2 cm distal to epicondyles

Knee
Medial fat pad proximal to joint line

Figure 17-2. American College of Rheumatology criteria for the diagnosis of fibromyalgia. (From Ballinger S, Bowyer S: Fibromyalgia: the latest “great” imitator, Contemp Pediatr 14:147, 1997.)

DERMATOMYOSITIS AND POLYMYOSITIS
14. What are the criteria used for the diagnosis of juvenile dermatomyositis and polymyositis?
• Symmetric proximal muscle weakness (e.g., Gowers sign)
• Elevated serum enzymes in muscle (creatine kinase [CK], lactic dehydrogenase [LDH], aspartate transaminase [AST], and/or aldolase)
• Abnormal electromyogram (increased insertional activity, myopathic pattern, polymorphic potentials)
• Inflammation and/or necrosis on muscle biopsy
• Characteristic skin eruption
The presence of rash distinguishes dermatomyositis from polymyositis. Three out of four criteria plus a pathognomonic rash establish the diagnosis of dermatomyositis, and a confirmatory biopsy is not necessary. If fewer criteria are met, a biopsy may be needed for diagnosis.

Huber A, Feldman BM: An update on inflammatory myositis in children, Curr Opin Rheumatol 25:630–635, 2013.

15. What skin changes are pathognomonic for dermatomyositis?
Gottron patches (Fig. 17-3). These begin as inflammatory papules over the dorsal aspect of interphalangeal joints and the extensor aspect of the elbows and knee joints. The papules become violaceous and flat topped and may coalesce to become patches. Eventually, the lesions show atrophic changes and become hypopigmented.

Figure 17-3. Gottron papules. (From Fitzpatrick JE, Aeling JL: Dermatology Secrets, ed 2.
Philadelphia, 2001, Hanley & Belfus, p 257.)

16. What are the other classic cutaneous findings of dermatomyositis among children?
• Periorbital edema and erythema with violaceous color of the upper eyelid (heliotrope rash)
• Rash over the upper chest in the shawl distribution
• Photosensitivity
• Cutaneous vasculitis with ulceration
• Nail-fold capillary abnormalities
17. Which infectious agents are known to cause myositis?
• Viral: Notably Coxsackie (named after Coxsackie, NY) and influenza A and B
• Bacterial: Staphylococcus and Yersinia (causing pyomyositis)
• Protozoal: Toxoplasma and trichinosis
• Spirochetal: Borrelia
The most common cause of acute muscle disease associated with pain, difficulty walking, and a high level of creatine kinase is VIRAL myositis.

JUVENILE IDIOPATHIC ARTHRITIS
18. Why is JRA becoming juvenile idiopathic arthritis (JIA)?
The Europeans and Canadians have never liked the term “rheumatoid” embedded in JRA, which has been used in the United States since 1977, because it suggests homology with the adult disease (rheumatoid arthritis). In the same year of 1977 in the city of Basel, European investigators coined the term JCA, which included pretty much all forms of primary childhood arthritis. The International League of Associations of Rheumatology (ILAR) ended the transatlantic dispute and has come up with the new name— JIA (juvenile idiopathic arthritis). At least there is some consistency because the “J” and the “A” remain unchanged. “J” stands for juVEnile (before the seventeenth birthday for disease onset), and “A” for arthritis, meaning joint inflammation. The new classification went through multiple revisions and is still a work
in progress. The potential advantages are (1) an end to the confusion and (2) the hopeful beginning of a solution by at least recognizing that we do not know what causes the disease (it may pay to be humble).
19. What is synovitis, and at what point is it considered chronic?
SYNOVIAL inflammation (synovitis) is the primary pathologic lesion in JIA. It is chronic at 6 weeks in the United States and at 3 months in Europe.
20. What is the most common chronic arthritis seen in children?
JIA, with a point prevalence of about 1:1000.
21. What are the diagnostic criteria for the classification of JIA?
JIA is a diagnosis of exclusion. Features include the following:
• Onset at 16 years of age
• Clinical arthritis with joint swelling or effusion, increased heat, and limitation of range of motion with tenderness
• Duration of disease of ≤6 weeks

22. What are the characteristics of the seven main subsets of JIA? The seven major subgroups are distinguished by the number of joints, presence of rheumatoid factor, and different combination of extra-articular manifestations (Table 17-1).

Table 17-1. Subsets of Juvenile Idiopathic Arthritis
NO. OF
SUBSET JOINTS
AGE
UVEITIS HLA- RF ANA B27 RE- MISSION OTHER SYMPTOMS
Systemic Any 0-16 mo — — — — 50% Fever,
visceromegaly, serositis, rash
Oligopersistent 1–4 2 yr ++++ — ++++ — 60% None
Oligoextended* >5
2 yr ++++ — ++++ — 20% None
Polyarticular >5 RF(—) 3 yr +++ — +++ — 15% Subcutaneous nodules (small)
Polyarticular >5 RF(+) 12–17 yr None + ++ — 0% Subcutaneous nodules (large)
Enthesitis- Any
related number arthritis 8–16 Acute — — + Unknown Tendinous involvement
Enthesitis†

Psoriatic Any
arthritis number Any + — +/— Low Dactylitis, psoriasis of nails and skin, tendinous involvement
Other arthritis{
N/A N/A N/A N/A N/A N/A N/A
ANA Antinuclear antibody; HLA human leukocyte antigen; RF rheumatoid factor.
*After a typical oligoarticular onset with an oligoarticular course for 6 months, the new joints become recruited.
†Inflammation at the insertion point of tendons, capsule, and ligaments.
{Any form of chronic arthritis that fails to meet criteria for any of the other subsets.

23. What percent of pediatric JIA presents as systemic JIA? Five percent to 15% of JIA presents as systemic in North America and Europe. In Asia, however, systemic JIA appears to account for a greater percentage of JIA cases with 25% in India and 50% in Japan.
24. What is the pattern of fever and characteristic rash of the systemic-onset subset of JIA?
Systemic-onset JIA (Still disease) accounts for about 15% of cases of children with JIA. Affected individuals typically have fever of unknown origin with once- or twice-daily (i.e., quotidian) temperature spikes, often higher than 40 °C. Shaking chills often precede the fever. The temperature characteristically returns to 37 °C or lower; continuous fever should suggest other diagnoses.
A blotchy, light pink, evanescent rash that blanches on compression and that may show perimacular pallor accompanies the fever in more than 90% of cases (Fig. 17-4). The rash of systemic JIA is diagnostic

Figure 17-4. Typical rash of systemic-onset juvenile rheumatoid arthritis. (From West S: Rheumatology Secrets, ed 2. Philadelphia, 2002, Hanley & Belfus, p 493.)

only after the diagnosis is made (by exclusion). Arthritis may not be present during the first several weeks of illness. Serositis, hepatosplenomegaly, and lymphadenopathy are other significant findings in patients with this form of the disease.

Prakken B, Albani S, Martini A: Juvenile idiopathic arthritis, Lancet 377:2138–2149, 2011.

25. In addition to different clinical features, how is systemic JIA distinguished from other subgroups of JIA?
• Equal sex distribution (other subgroups more commonly occur in females)
• Rarely familial
• Lack of autoantibodies (e.g., rheumatoid factor, ANA) and autoreactive T-cells
• Lack of HLA associations
• Greater responsiveness to interleukin-1 and interleukin-6 inhibition
• Autoinflammatory, rather than autoimmune, disease (See question 101.)

Prakken B, Albani S, Martini A: Juvenile idiopathic arthritis, Lancet 377:2138–2149, 2011.

26. Why is it sometimes difficult to distinguish systemic JIA (sJIA) from leukemia?
Up to 20% of patients with acute lymphoblastic leukemia (ALL) have some degree of musculoskeletal symptoms, including joint pain and occasional swelling that can mimic sJIA. In both diseases,
there is anemia, fever, and weight loss. Both can involve hepatosplenomegaly and lymphadenopathy.
In ALL, however, the fever is not usually spiking, and platelets and white blood cell counts tend to be low to low normal. In ALL, compared with sJIA, pain occurs more commonly at nighttime. A good examination of a peripheral smear is crucial. A high lactic dehydrogenase level is very suggestive of leukemia, and the technetium-99 bone scan shows a different pattern of uptake. More than one bone marrow biopsy may be necessary.

Marwaha RK, Kulkarni KP, Bansal D, Trehan A: Acute lymphoblastic leukemia masquerading as juvenile rheumatoid arthritis: diagnostic pitfall and association with survival, Ann Hematol 89:249–254, 2010.
Jones OY, Spencer CH, Bowyer SL, et al: A multicenter case-control study on predictive factors distinguishing childhood leukemia from juvenile rheumatoid arthritis, Pediatrics 117:e840–e844, 2006.

27. In a patient with suspected rheumatic disease, what clinical features are more suggestive of malignancy?
Particularly concerning are nonarticular bone pain, back pain as the principal symptomatic feature, bone tenderness, and severe constitutional symptoms. Children with rheumatic joint problems are typically stiff, and they may complain about pain. The pain of malignancy is out of proportion to the amount of swelling around the joint, and it tends to be worse at night. It is vital to think about the possibility of malignancy in children with rheumatic complaints.

Cabral DA, Tucker LB: Malignancies in children who initially present with rheumatic complaints, J Pediatr 134: 53–57, 1999.

28. What is the value of measuring ANA and rheumatoid factor (RF) in patients with JIA?
After JIA has been diagnosed on clinical grounds, results of these tests help assign the patient to the appropriate category (e.g., oligoarticular or RF-positive polyarticular). These tests are also useful as prognostic indicators. Because ANA can be present in 10% to 30% of normal children, this test should not be used as a screening test to diagnose JIA in children who experience noninflammatory pain. The presence of ANA increases the risk for uveitis, thereby making ophthalmologic surveillance more important. RF is valuable as a marker of poor functional prognosis in adolescents with polyarticular arthritis.

29. Are radiographs helpful for diagnosing JIA? No. There are no characteristic radiographic changes at onset. The value of radiology is to rule out other skeletal conditions and to provide a documented baseline status.

30. A patient with JIA who becomes ill with thrombocytopenia, profound anemia, and markedly elevated transaminases probably has what complication?
Macrophage activation syndrome (MAS). This new conceptualization of an old problem is seen in children with systemic-onset JIA both at onset (even at presentation) and late during the course of disease. It is characterized by a massive upregulation of T-cell and macrophage function, with vast release of proinflammatory cytokines leading to hemophagocytosis (the hallmark). It is believed that, in most cases, MAS is triggered by a viral infection. MAS is the single most important contributor
of mortality, together with gastrointestinal bleeding and infection among patients with systemic JIA. The name and nosologic classification of this entity are currently being debated by experts in the field.

Bennett TD, Fluchel M, Hersh AO, et al: Macrophage activation syndrome in children with systemic lupus erythematosus and children with juvenile idiopathic arthritis, Arthritis Rheum 64:4135–4142, 2012.

31. What are the main features of the macrophage activation syndrome?
• Worsening of fever and rash
• Anemia, frequently severe (due in part to hemophagocytosis), leukopenia, and thrombocytopenia
• Disseminated intravascular coagulation with hypofibrinogenemia and pseudonormalization of ESR
• Liver dysfunction
• Hypertriglyceridemia
• Hyponatremia (pseudo)
• Massive increase in ferritin levels
• Occasional central nervous system involvement
• Generalized musculoskeletal pain

Ramanan AV, Schneider R: Macrophage activation syndrome—what’s in a name! J Rheum 30:2513–2516, 2003.

KEY POINTS: JUVENILE IDIOPATHIC ARTHRITIS
1. Sine qua non: Persistence for ≤6 weeks
2. Seven subtypes differentiated by number of involved joints, presence of rheumatoid factor, and
extra-articular involvement
3. Characteristic finding: Morning stiffness or soreness that improves during the day
4. No laboratory tests are diagnostic.
5. Patients <7 years old with antinuclear antibody–positive oligoarticular juvenile idiopathic arthritis at highest risk for uveitis

32. What is the traditional first-line approach to JIA medical management?
The so-called first-line therapy consists of nonsteroidal anti-inflammatory drugs (NSAIDs). Given at the correct dose, they exert pain relief and suppress inflammation (decrease in morning stiffness), with a peak action at 4 to 6 weeks. The classic members of this group are aspirin, ibuprofen, naproxen, tolmetin, and indomethacin. Choice among them is made on the basis of availability in liquid form, half-life, side-effect profile, individual doctor preferences, and results of an individual trial. Most of their action is through inhibition of cyclooxygenase. About one-third of patients have their symptoms controlled through the use of NSAIDs; two-thirds require more aggressive drug therapy. For patients with oligoarticular disease, intra-articular injection of corticosteroids is also considered first-line therapy.
33. What second-line agents have been used in the treatment of JIA?
• Gold salts
• Penicillamine
• Hydroxychloroquine
• Sulfasalazine
• Methotrexate

Of these, only methotrexate has been proved beneficial in a randomized, double-blind, placebo- controlled trial.

Giannini EH, Brewer EJ, Kuzmina N, et al.: Methotrexate in resistant juvenile rheumatoid arthritis: results of the USA-USSR double blind placebo controlled trial, N Engl J Med 326:1043–10499, 1992.

34. When are corticosteroids indicated for children with JIA?
• Life-threatening disease (e.g., pericarditis, myocarditis)
• Unremitting fever not responsive to NSAIDs
• Unrelenting polyarthritis with severe limitations requiring intensive physical therapy to achieve ambulatory status
• Topical therapy for uveitis (systemic steroids are rarely needed for children with aggressive uveitis unresponsive to topical therapy)
• As intra-articular injections to treat unresponsive joints or single joint disease in the context of intolerance to or lack of efficacy of NSAIDs. Triamcinolone hexacetonide is the drug of choice.

35. What are the most common side effects of prolonged corticosteroid therapy?
Effects can be minimized by alternate-day therapy, but sometimes the treatment is worse than the disease. Commonly encountered problems associated with high-dose corticosteroid use in children can be remembered using the mnemonic CUSHINGOID MAP:
• Cataracts
• Ulcers
• Striae
• Hypertension
• Infectious complications
• Necrosis of bone (avascular)
• Growth retardation
• Osteoporosis
• Increased intracranial pressure (pseudotumor cerebri)
• Diabetes mellitus
• Myopathy
• Adipose tissue hypertrophy (obesity, “buffalo hump”)
• Pancreatitis

36. What are biologic agents?
These are genetically engineered products that act by blocking specific immune pathways, such
as cytokine signaling, to lessen inflammation. Etanercept, the first biologic agent used in the treatment of JIA, blocks the actions of tumor necrosis factor-α, a proinflammatory cytokine. A growing variety
of other agents are used, including adalimumab, another antibody to tumor necrosis factor, and abatacept, which is a costimulation blocker that acts by blocking receptors on antigen-presenting cells. Newer biologics have been developed to control up-regulated IL-1 (anakinra, rilonacept and canakinumab) and IL-6 (tocilizumab). Canakinumab is approved for the treatment of systemic-onset JIA and tocilizumab for both systemic and polyarticular JIA. Biologic agents have become important therapeutic options for patients with JIA resistant to or intolerant of conventional treatments.

Sen ES, Ramanan AV: New age of biological therapies in paediatric rheumatology, Arch Dis Child 99:679–685, 2014.

37. Which children with JIA require the most frequent monitoring for uveitis? Uveitis (also called iridocyclitis) is inflammation of the iris and the ciliary body. It occurs on average in 20% of patients with pauciarticular JRA and in 5% of patients with polyarticular
disease. Table 17-2 summarizes the American Academy of Pediatrics guidelines for frequency of slit-lamp examination developed by the sections of ophthalmology and rheumatology. Patients at high risk require quarterly examinations; those at moderate risk need biannual examinations;
and those at low risk can be examined annually.

Qian Y, Acharya NR: Juvenile arthritis-associated uveitis, Curr Opin Ophthalmol 21:468–472, 2010.

Table 17-2. Frequency of Ophthalmologic Examination in Patients with JIA
EYE
AGE DURATION EXAMINATION
ANTINUCLEAR AT OF DISEASE RISK FREQUENCY
TYPE ANTIBODIES ONSET (YEARS) CATEGORY (MONTHS)
Oligo- or
polyarthritis + ≤6 ≤4 High 3
+ ≤6 >4 Moderate 6
+ ≤6 >7 Low 12
+ >6 ≤4 Moderate 6
+ >6 >4 Low 12
– ≤6 ≤4 Moderate 6
– ≤6 >4 Low 12
– >6 N/A Low 12
Systemic N/A N/A N/A Low 12
disease
(fever,
rash)
JIA juvenile idiopathic arthritis.
Frequency of Ophthalmologic Examination in Patients with JIA. (Data from Cassidy J, KIVLIN J, Lindsley C, Nocton J: Ophthalmologic examinations in children with JUVENIle rheumatoid arthritis. Pediatrics 117:1843-1845, 2006.)

38. What is the earliest sign of uveitis among patients with JIA?
When the anterior chamber of the eye is examined with a slit lamp, a “flare” is the earliest sign. This is a hazy appearance as a result of an increased concentration of protein and inflammatory cells. Later signs can include a speckled appearance of the posterior cornea (as a result of keratic precipitates), an irregular or poorly reactive pupil (as a result of synechiae between the iris and lens), band keratopathy, and cataracts (Fig. 17-5).

Figure 17-5. Uveitis. A slit-lamp examination shows “flare” in the fluid of the anterior chamber (caused by increased protein content) and keratic precipitates on the posterior surface of the cornea, representing small collections of inflammatory cells). (From Cassidy JT, Laxer RM, Petty RE, Lindsley CB, editors: Textbook of Pediatric Rheumatology, ed 6. Philadelphia, 2011,
Saunders, pp 305–314.)

39. What are the juvenile spondyloarthropathies under the revised classification system? The spondyloarthropathies are now considered one of the subsets of JIA and are recognized under the heading enthesitis-related arthritis (ERA).

40. What are the characteristic clinical features of the juvenile spondyloarthropathies?
• Affect males >8 years of age
• Enthesitis (inflammation of tendon, capsule, and ligament insertion sites) is characteristic
• Prodromal oligoarthritis involving large joints of the lower extremities including the hip
• Involvement of the sacroiliac joints and the back, which is manifested as pain, stiffness, and reduced range of motion (Fig. 17-6)
• Associated with human leukocyte antigen (HLA-B27) ( 90% in children with ankylosing spondylitis and 60% of those with other spondyloarthropathies)
• Seronegativity: ANA and rheumatoid factors typically negative

Ramanathan A, Srinivasalu H, Colbert RA: Update on juvenile spondyloarthritis, Rheum Dis Clin North Am
39:767–788, 2013.

Figure 17-6. Fifteen-year-old boy shown in the position of maximal forward flexion. Note the flattened back (arrow). Radiographs demonstrated bilateral sacroiliac arthritis but no abnormality of the lumbosacral spine. (From Casssidy JT, Laxer RM, Petty RE, Lindsley CB, editors: Textbook of Pediatric Rheumatology, ed 6. Philadelphia, 2011, Saunders, pp 272–286.)

41. How is enthesitis diagnosed clinically?
The enthesis is the site of attachment of ligaments, tendons, capsule, and fascia to bone. Enthesopathy is unique to the spondyloarthropathies and appears as painful localized tenderness at the tibial tubercle (which may be mistaken for Osgood-Schlatter disease), the peripheral patella, and the calcaneal insertion of the Achilles tendon and plantar fascia (which may be mistaken for Sever disease). Thickening of the Achilles tendon and tenderness of the metatarsophalangeal joints are associated findings. Magnetic resonance imaging (MRI) can be extremely helpful. The T2-weighted image may show bone marrow edema adjacent to the enthesis.

42. Why is the diagnosis of ankylosing spondylitis difficult to make in children? A child may have undifferentiated spondyloarthritis (an enthesitis-related arthritis) that is characterized by enthesitis and recurrent episodes of lower-extremity oligoarthritis for several
years before he or she develops back symptoms. To fulfill the criteria for ankylosing spondylitis, clinical features of lumbar spine pain, limitation of lumbar motion, and radiographic signs of sacroiliitis must be present. The average time from onset of symptoms to diagnosis in an
adult with ankylosing spondylitis is 5 years; many adolescents are adults before they fulfill the criteria (Fig. 17-7). MRI (STIR [short T1 inversion recovery] or T2W [T2-weighted]) is very helpful to document early sacroiliitis. For sacroiliitis, no gadolinium is necessary.

Figure 17-7. Periarticular sclerosis in a boy with chronic sacroiliitis and a diagnosis of spondyloarthropathy.

43. Where are the dimples of Venus?
The dimples of Venus are used to define a baseline for the Schober test. The dimples are prominent paravertebral indentations in the lower back of some individuals. A line drawn between the dimples marks the lumbosacral junction and this is the point from which one measures 10 cm above for an upper limit and 5 cm below for the lower limit to assess anterior flexion of the lumbosacral spine.
After the patient bends over without flexing the knees one takes a second measurement of the distance. The change in length between the upper and the lower point should be now >5 cm from the baseline measurement.

LYME DISEASE
44. What criteria are used to diagnose Lyme disease?
Classification criteria (i.e., case definition) as determined by the Centers for Disease Control and Prevention include the following:
• Erythema migrans: enlarging circular erythematous lesion (minimum size, 5 cm), or
• At least one clinical manifestation (arthritis, cranial neuropathy, atrioventricular block,
aseptic meningitis, radiculoneuritis) and isolation or serologic evidence of Borrelia burgdorferi
infection

45. What is the typical rash seen in Lyme disease?
The classic rash of erythema migrans (EM), believed to be pathognomonic for Lyme disease, is an expanding erythematous skin lesion (round or oval; 5 cm) that begins as a small macule or papule at the bite site. As the lesion expands over days to weeks, central or paracentral clearing gives the lesion an annular or targetlike appearance (Fig. 17-8). However, EM is not always classic. About 60% of cases have homogenous erythema, 30% with central erythema, 9% with central clearing, 7%
with central vesicles or ulcerations, and 2% with central purpura.

Dandache P, Nadelman RB: Erythema migrans, Infect Dis Clin North Am 22:235–260, 2008.

Figure 17-8. Erythema migrans (EM) with punctum (arrow). (From Dandache P, Nadelman RB: Erythema migrans, Infect Dis Clin North Am 22:237, 2008.)

46. How long after a tick bite does the rash of Lyme disease appear?
Median time is 7 to 10 days, but the rash can appear with a range of 1 to 36 days.
47. How is Lyme disease confirmed in the laboratory?
Although attempts to demonstrate borrelial DNA in infected tissues by polymerase chain reaction has met with some success and cultures occasionally render positive results, the main diagnostic tool continues to be serology. Immunoglobulin M (IgM) peaks about 4 weeks after infection, and IgG peaks at 6 weeks. This is the main reason why antibodies may not be detected during the early dermatologic and neurologic stages.
There are two detection techniques: ELISA and Western blot. Both are available for IgG and IgM. ELISA measures whole components of Borrelia. It is a very sensitive test, but with many
false-positive results. A negative ELISA requires no further investigation at a given time. All positive ELISAs—particularly those with borderline positivity—should be confirmed by Western blot. This is the so-called two-tier system. The C6 peptide ELISA measures IgG to a relatively invariant lipoprotein on the spirochete, and as a single test, has been shown to be as sensitive and almost as specific
as the two-tier system.

Steere AC, McHugh G, Damle N, et al: Prospective study of serologic tests for Lyme disease, Clin Infect Dis
47:188–195, 2008.

48. If infection ensues after a tick bite, how does Lyme disease progress?
• Early localized disease: 2 to 30 days. Sixty percent to 80% of children will develop EM. Some may have a flulike illness with fever, myalgia, headache, fatigue, arthralgia and malaise.
• Early disseminated disease: 3 to 12 weeks. Clinical manifestations reflect hematogenous spread to other sites; these include secondary EM (multiple lesions), cranial nerve palsies (primarily facial nerve), and aseptic meningitis. Much more rarely seen in children (compared with adults) are radiculoneuritis and carditis (with varying degrees of heart block).
• Late disease: 2 to 12 months. In children, the most common manifestation is arthritis. Rarely, encephalomyelitis can develop. There is controversy regarding chronic Lyme disease.

Shapiro ED: Lyme disease, N Engl J Med 370:1724–1731, 2014.
Feder HM Jr, Johnson BJB, O’Connell S, et al: A critical appraisal of “chronic Lyme disease.” N Engl J Med
357:1422–1430, 2007.

49. How is the diagnosis of Lyme meningitis established?
The diagnosis is often inexact and is commonly made on the basis of the finding of cerebrospinal fluid pleocytosis and the presence of EM and/or positive serology. Both ELISA and Western blot testing may be negative or indeterminate early during the course of infection, when dissemination to the central nervous system has occurred. Testing of the cerebrospinal fluid for intrathecal production of specific antibody and demonstration of B. burgdorferi DNA by polymerase chain reaction testing is not readily available, and the latter is relatively insensitive.
50. How are Lyme disease and viral meningitis clinically differentiated?
Both are predominantly summertime illnesses, but the distinction is critical because Lyme
meningitis requires weeks of intravenous antibiotics. In addition to the possible presence of EM, other areas of clinical distinction in patients with signs and symptoms of meningitis include the following:
• Cranial neuropathy, especially peripheral seventh-nerve palsy, is strongly suggestive of Lyme meningitis.
• Papilledema is more commonly seen in patients with Lyme meningitis.
• Longer duration (7 to 12 days versus 1 to 2 days) of symptoms, including headache before lumbar puncture, is more typical of Lyme meningitis.
• Rash of EM
• Cerebrospinal fluid pleocytosis should not have more than 10% neutrophils in Lyme meningitis Either the rash of EM, papilledema, or a cranial nerve palsy is seen in more than 90% of
patients with Lyme meningitis but in almost none with viral meningitis.

Avery RA, Frank G, Glutting, Eppes SC: Prediction of Lyme meningitis in children from a Lyme disease-endemic region: a logistic-regression model using history, physical, and laboratory findings, Pediatrics 117:e1–e7, 2006.
Shah SS, Zaoutis TE, Turnquist JL, et al: Early differentiation of Lyme from enteroviral meningitis, Pediatr Infect Dis J
24:542–545, 2005.

51. Should lumbar punctures be done for patients with facial palsy and suspected Lyme disease? This remains debated because studies in the late 1990s revealed “occult meningitis” (i.e., cerebrospinal fluid [CSF] pleocytosis) in patients without meningeal signs but with Lyme facial palsy. However,
the clinical significance of an abnormal CSF is unclear, and there has been no apparent increase in late-stage Lyme disease in those treated with oral antibiotics alone. Consequently, most experts advise no lumbar puncture for suspected or confirmed Lyme facial palsy, unless there is severe or prolonged headache, nuchal rigidity, or other meningeal signs.
52. How is Lyme arthritis differentiated from septic arthritis?
The inflammation generated by Lyme arthritis is significantly less intense than septic arthritis. Lyme arthritis typically involves a single large joint (knee 90%), range of motion is less limited than septic arthritis, and weight bearing is sometimes possible. On joint aspiration, septic arthritis more typically shows >100,000 cells/mL3. Septic arthritis is more commonly associated with an elevated peripheral white blood cell count and elevated sedimentation rate.

Deanehan JK, Kimia AA, Tan Tanny SP, et al: Distinguishing Lyme from septic knee monoarthritis in Lyme disease-endemic areas, Pediatrics 131:e695–e701, 2013.

53. What is the prognosis for children diagnosed with Lyme arthritis?
Multiple studies have shown that the long-term prognosis for treated patients is excellent, with little morbidity. Clinicians should be aware that persistent synovitis after the completion of a single course of 4 weeks of antibiotics is not rare and not the result of antibiotic failure. In fact, up to
two-thirds of patients with Lyme arthritis require 3 months to achieve resolution, and 15% have symptoms of their arthritis for more than 12 months.

Smith BG, Cruz Al Jr, Milewski MD, Shapiro ED: Lyme disease and the orthopaedic implications of Lyme arthritis,
J Am Acad Orthop Surg 19:91–100, 2011.
Gerber MA, Zemel LS, Shapiro ED: Lyme arthritis in children: clinical epidemiology and long-term outcome,
Pediatrics 102:905–908, 1998.

54. What should be suspected if a patient with Lyme disease develops fever and chills after starting antibiotic treatment?
The Jarisch-Herxheimer reaction. This reaction consists of fever, chills, arthralgia, myalgia, and vasodilation, and it follows the initiation of antibiotic therapy in certain illnesses (most typically syphilis). It is thought to be mediated by endotoxin release as the organism is destroyed. A similar reaction occurs in 40% or less of patients treated for Lyme disease, and it may be mistaken for an allergic reaction to the antibiotic.
55. Should we follow Lyme disease course and response to therapy with titers?
No! As a result of the continued secretion of antibodies by memory cells, serology (particularly with ultrasensitive commercial kits) may remain positive for up to 10 years after microbial eradication. The misinterpretation of positive serology as a proxy for active infection is responsible for many unnecessary antibiotic courses in endemic areas.

Kalish RA, McHugh G, Granquist J, et al: Persistence of immunoglobulin M or immunoglobulin G antibody responses after active Lyme disease, Clin Infect Dis 33:780–785, 2001.

56. Is antibiotic prophylaxis indicated for all tick bites?
No. In most regions, the rate of tick infestation is low, and thus the likelihood of transmission is also low. Even in endemic areas, the risk for Lyme disease to a placebo group after tick bites was only 1.2%. The tick has to be attached for at least 24 to 48 hours before the transmission of infection occurs. Treating all tick bites with antibiotics is impractical (some children would be on oral antibiotics throughout the summer). One study did show that a single 200-mg dose was effective for preventing Lyme disease if it was given within 72 hours of the tick bite. Consequently, antibiotic prophylaxis is not routinely recommended, but, in unique circumstances (e.g., endemic areas, prolonged attachment, pregnancy), prophylaxis could be considered.

Nadelman RB, Nowakowski J, Fish D, et al, Tick Bite Study Group: Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite, N Engl J Med 345:79–84, 2001.
Shapiro ED, Gerber MA, Holabird NB, et al: A controlled trial of antimicrobial prophylaxis for Lyme disease after deer-tick bites, N Engl J Med 327:1769–1773, 1992.

57. What are other means of preventing Lyme disease?
• Avoidance of tick-infested areas
• Use of light-colored, long-sleeved clothing, with pants tucked into sneakers
• Insect repellents (N,N-diethyl-meta-toluamide [DEET]; permethrin)
• “Tick checks” after potential exposures
• Proper tick removal: Pulling straight out, with tweezers close to skin

Hayes EB, Piesman J: How can we prevent Lyme disease? N Engl J Med 348:2424–2430, 2003.

KEY POINTS: LYME DISEASE
1. Spirochete Borrelia burgdorferi is the culprit.
2. Only one-third of patients recall the tick bite.
3. The erythema migrans rash is virtually diagnostic.
4. Enzyme-linked immunosorbent assay testing has a high false-positive rate; confirm with Western blot analysis.
5. Potential complications include arthritis, aseptic meningitis, and cranial nerve palsies, and atrioventricular block.
6. Lyme meningitis (compared with viral meningitis): Cranial neuropathy and papilledema are more common, with longer duration of symptoms before diagnosis.

RHEUMATIC FEVER
58. What is acute rheumatic fever?
Rheumatic fever is a postinfectious, immune-mediated, inflammatory reaction that affects the connective tissue of multiple organ systems (heart, joints, central nervous system, blood vessels, subcutaneous tissue) and that follows infection with certain strains of group A β-hemolytic streptococci (GABHS).
The major manifestations are carditis, polyarthritis, chorea, erythema marginatum, and subcutaneous nodules. In the developing world, acute rheumatic fever and rheumatic heart diseases are the leading causes of cardiovascular death during the first 5 decades of life.
59. What are the major Jones criteria for rheumatic fever?
The mnemonic J ‘ NES may be useful:
• Joints: Migratory arthritis
• ‘: Heart disease
• Nodules: Subcutaneous nodules
• Erythema: Erythema marginatum
• Sydenham: Sydenham chorea
60. What is acceptable proof of antecedent streptococcal pharyngitis when diagnosing acute rheumatic fever?
• Throat culture: This is the gold standard for diagnosis of GABHS. Positive cultures, however, do not distinguish GABHS pharyngitis from a carrier state.
• Streptococcal antigen tests: Rapid diagnostic tests for the detection of GABHS antigens in pharyngeal secretions are acceptable evidence of infection because they are highly specific. Again, positive tests do not distinguish true infection from a carrier state.
• Antistreptococcal antibodies: At the time of clinical presentation with rheumatic fever, throat cultures are usually negative. It is reasonable to assess the levels of antistreptococcal antibodies in all cases of suspected rheumatic fever because the antibodies should be elevated at the time of presentation.

Gerber MA, Baltimore RS, Eaton CB, et al: Prevention of rheumatic fever and diagnosis of acute streptococcal pharyngitis, Circulation 119:1541–1551, 2009.

61. Which antistreptococcal antibodies are most commonly measured?
The most commonly employed test measures antibodies to anti-streptolysin O. The cutoff for a positive test in a school-age child is 320 Todd units (240 in an adult); levels peak 3 to 6 weeks

after infection. If the test is negative—as may be the case in 20% or less of patients with acute rheumatic fever (ARF) and in 40% of those with isolated chorea—other antistreptococcal antibodies may be detected. The most practically available of these identifies antibodies to deoxyribonuclease B (positive cutoff, 240 units in children, 120 in adults). Alternatively, subsequent convalescent samples run simultaneously with the acute sample may detect rising titers of either antistreptolysin O or antideoxyribonuclease B.
62. What are the common manifestations of carditis in patients with ARF?
In his Etudes Médicales du Rhumatisme, Lasègue remarked that “rheumatic fever licks the joints .. . and bites the heart,” meaning that the severity of the two manifestations tends to be inversely related. In more recent outbreaks of ARF, 80% or less of patients have had evidence of carditis.
ARF causes a pancarditis, which potentially affects all layers (from the pericardium through the endocardium) and may include the following:
• Valvulitis: This is heralded by a new or changing murmur. The most common manifestation is isolated mitral regurgitation, and this is followed in frequency by a mid-diastolic rumble
of unclear pathophysiology (Carey-Coombs murmur), and then by aortic insufficiency in the presence of mitral regurgitation. Isolated aortic insufficiency is uncommon, and so are stenotic lesions.
• Dysrhythmias: Electrocardiogram abnormalities typically involve some degree of heart block.
• Myocarditis: When mild, this may manifest as resting tachycardia out of proportion to fever. However, when it is clinically more severe and in combination with valvular damage, myocarditis may lead to congestive heart failure.
• Pericarditis: Patients may have chest pain or friction rub. Pericarditis and myocarditis virtually never occur in isolation.

Messeloff CR: Historical aspects of rheumatism, Med Life 37:3–56, 1930.

63. How quickly can valvular lesions occur in children with ARF?
New murmurs appear within the first 2 weeks in 80% of patients, and they rarely occur after the second month of illness. Hence, during an episode, one normal echocardiogram in the first
2 weeks should be sufficient to eliminate carditis.
64. What are the typical characteristics of arthritis in patients with ARF?
Migratory polyarthritis is usually the earliest symptom of the disease, and it typically affects the large joints, the knees, the ankles, the elbows, and the wrists (hips are not commonly involved).
The joints are extraordinarily painful; weight bearing may not be possible. Physical
examination discloses warmth, erythema, and exquisite tenderness such that the weight of even bedclothes and sheets may not be tolerable. This tenderness is typically out of proportion with the degree of swelling.
65. What is the effect of aspirin therapy on the arthritis of rheumatic fever?
This type of arthritis is exquisitely sensitive to even modest doses of salicylates, which effectively arrest the process within 12 to 24 hours. If aspirin or other NSAIDs are employed early during the course of the condition, the arthritis will not migrate, and a delay in diagnosis may result. Such medications should be withheld until the clinical course of the illness has become clear. Conversely, if there is not a dramatic response to aspirin, a diagnosis other than rheumatic fever should be considered.
66. What is the rash of rheumatic fever?
Erythema marginatum. This rash occurs in less than 5% of cases of ARF. If you see it and call a colleague to the bedside to confirm it, it is likely to have disappeared in the meantime. It is an evanescent, pink to slightly red, non-pruritic eruption with pale centers and serpiginous borders; it may be induced by the application of heat, and it always blanches when palpated. The outer edges of the lesion are sharp, whereas the inner borders are diffuse (Fig. 17-9). It is most often found on the trunk and proximal extremities (but not the face). Erythema marginatum is seen almost solely in patients with carditis.

Figure 17-9. Classic rash of erythema marginatum on the arm of a child with acute rheumatic fever.

67. What is Sydenham chorea?
Purposeless, involuntary, irregular movements of the extremities that are associated with muscle weakness and labile emotional behavior. These symptoms are believed to result from inflammation of the cerebellum and of the basal ganglia.

Wei F, Wang J: Sydenham’s chorea or St. Vitus’s dance, N Engl J Med 369:e25, 2013.

68. Who was Saint Vitus?
Saint Vitus was a Sicilian youth who was martyred in the year 303 at the age of 14. In the Middle Ages, individuals with chorea would worship at shrines dedicated to this saint. Accordingly, Sydenham chorea is also known as “Saint Vitus dance.” Saint Vitus is the patron saint of dancers and comedians. And chorea, by the way, means dance in Greek! St. Vitus was one of the 14 Holy Helpers. He was invoked to help people with epilepsy, nervous disorders, and Sydenham’s chorea although at the time of Vitus, there was no Sydenham. Thomas Sydenham (the “British Hippocrates”) was born in 1624.
69. Are corticosteroids of benefit for the treatment of ARF?
Controlled studies in the 1950s failed to show any definite benefit of corticosteroids for the treatment of rheumatic carditis. Nonetheless, it is generally recommended that patients with severe carditis (e.g., congestive heart failure, cardiomegaly, third-degree heart block) receive prednisone (2 mg/kg/day) in addition to conventional therapy for their heart failure. The unusual patient with well-documented rheumatic arthritis that does not respond to salicylates or NSAIDs will benefit symptomatically from prednisone.
70. Can antibiotic prophylaxis for rheumatic fever ever be discontinued?
The optimal duration of antistreptococcal prophylaxis after documented ARF is the subject of some debate. It is clear that the risk for recurrence decreases after 5 years have elapsed from the most recent attack. Most clinicians therefore recommend discontinuing prophylaxis in patients who have not had carditis after 5 years or on the twenty-first birthday (whichever comes later). Those at high risk for contracting streptococcal pharyngitis (e.g., school teachers, health care professionals, military recruits, others living in crowded conditions) and anyone with a history of carditis should receive antibiotic prophylaxis for longer periods. Recommendations vary, ranging from 10 years to the fortieth birthday (whichever is longer) to lifelong prophylaxis, depending on the extent of residual heart disease.
71. Where do PANDAS live in the world of pediatric rheumatology?
In 1989, Swedo and colleagues characterized the psychiatric abnormalities found in children with Sydenham chorea, noting a high prevalence of obsessive-compulsive disorder (OCD) behaviors. They also described a syndrome, which they dubbed PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection), in which OCD and Tourette syndrome in some children appeared to be triggered or exacerbated by streptococcal infections in the absence of classic chorea or other manifestations of rheumatic fever. PANDAS has been expanded into PANS (pediatric acute-onset neuropsychiatric syndrome), which theorizes a wider possibility of antecedent triggers for acute OCD symptoms.
The existence of PANDAS (and PANS) remains controversial. There has been no prospective study of group A streptococcal infection to confirm the association of streptococcal pharyngitis with

these behavioral abnormalities. The symptoms of tic disorders and OCD tend to fluctuate spontaneously and may be nonspecifically exacerbated by illness. In some cases, the only link to streptococcal infection has been a single throat culture or serologic test, thereby bringing the specificity of the condition into question. PANDAS (the syndrome) currently remains an unproven hypothesis,
PANDA the mammal (Ailuropoda melanoleuca) can be found both in central China and in zoos around the world.

Murphy TK, Gerardi DM, Leckman JF: Pediatric acute-onset neuropsychiatric syndrome, Psychiatr Clin North Am
37:353–374, 2014.
Swedo SE, Rapaport JL, Cheslow DL, et al: High prevalence of obsessive-compulsive symptoms in patients with Sydenham chorea, Am J Psychiatry 146:246–249, 1989.

SYSTEMIC LUPUS ERYTHEMATOSUS
72. What is systemic lupus erythematosus (SLE)?
SLE is a multisystem autoimmune disorder characterized by the production of autoantibodies and a wide variety of clinical and laboratory manifestations.

Lupus Foundation of America: www.lupus.org. Accessed Jan. 13, 2015.

73. What laboratory tests should be ordered in a child who is suspected of having SLE?
A useful study for SLE is the ANA test. Up to 97% of patients with SLE have positive ANAs at some point during their illness. In a patient with characteristic signs and symptoms, a positive
ANA may help confirm suspicions of SLE. Unfortunately, however, around 10% of the normal childhood population may also have a positive ANA. Therefore, a positive ANA in the absence of any objective findings of SLE means very little. Other autoantibodies are much more specific, but they are less sensitive for SLE. These include antibodies to double-stranded DNA and the extractable nuclear antigen Sm. Complement levels are often depressed in patients with active SLE, and sedimentation rates are often elevated. The combination of a positive anti–double-stranded DNA antibody level
and a low C3 level is nearly 100% specific for SLE. Anemia, leukopenia, lymphopenia, and/or thrombocytopenia may also be seen.

Levy DM, Kamphuis S: Systemic lupus erythematosus in children and adolescents, Pediatr Clin North Am
59:345–364, 2012.
Tsokos GC: Systemic lupus erythematosus, N Engl J Med 365:2110–2121, 2011.

KEY POINTS: SYSTEMIC LUPUS ERYTHEMATOSUS
1. The hallmark of systemic lupus erythematosus (SLE) is the presence of autoantibodies at intermediate to high titers.
2. About 15% to 20% of SLE patients have the onset of disease during childhood.
3. Clinical presentations vary, but the most common presenting symptoms are arthritis, rash, and renal disease.
4. Neonatal SLE is caused by maternal autoantibodies; this leads to complete congenital heart block.
5. The presence of antiphospholipid antibodies predisposes the patient to venous thrombosis.

74. What are the most common manifestations of SLE in children?
• Arthritis: 80% to 90%
• Rash or fever: 70%
• Renal disease, such as proteinuria or casts (every patient with SLE is likely to have some abnormality demonstrated on renal biopsy): 70%
• Serositis: 50%
• Hypertension: 50%

• Central nervous system disease (psychosis/seizures): 20% to 40%
• Anemia, leukopenia, thrombocytopenia: 30% each

Iqbal S, Sher MR, Good RA, Cawkwell GD: Diversity in presenting manifestations of systemic lupus erythematosus in children, J Pediatr 135:500–505, 1999.

75. What are the neurologic manifestations of SLE?
Lupus cerebritis is a term that implies an inflammatory etiology of central nervous system disease. Microscopically, however, widely scattered areas of microinfarction and noninflammatory vasculopathy are seen in brain tissue; actual central nervous system vasculitis is rarely observed. A lumbar puncture may reveal cerebrospinal fluid pleocytosis or an increased protein concentration, but it
can be normal as well. Neuropsychiatric manifestations (e.g., psychoses, behavioral changes, depression, emotional lability) or seizures are most commonly observed. An organic brain syndrome with progressive disorientation and intellectual deterioration can be seen. Cranial or peripheral motor or sensory neuropathies, chorea, transverse myelitis, and cerebellar ataxia are less common manifestations of central nervous system lupus. Severe headaches and cerebral ischemic events have also been seen.

Steinlein MI, Blaser SI, Gilday Dl, et al: Neurological manifestations of pediatric systemic lupus erythematosus,
Pediatr Neurol 13:191–197, 1995.

76. Which diseases should be considered in the differential diagnosis of children with a butterfly rash?
A malar rash is present in 50% of children with SLE. The typical butterfly rash involves the malar areas and crosses the nasal bridge, but it spares the nasolabial folds; occasionally, it is difficult to distinguish from the rash of dermatomyositis. See Fig. 17-10. (Erythematous papules on the extensor surfaces of the metacarpophalangeal and proximal interphalangeal joints are common in dermatomyositis, but these are not generally seen in patients with SLE.) Seborrheic dermatitis or
a contact dermatitis may be similar to the rash of SLE. Vesiculation should suggest another disease, such as pemphigus erythematosus. A malar flush is clinically distinct and may be seen in children with mitral stenosis or hypothyroidism.

Figure 17-10. Malar rash of a 14-year-old patient with SLE. The distribution of this typical “butterfly” or malar rash includes the cheeks and crosses the nasal bridge but spares the nasolabial folds. (From Firestein GS, editor: Kelley’s Textbook of Rheumatology, ed 9. Philadelphia, 2013, Saunders, pp 1771–1800.)

77. Should children with SLE undergo a renal biopsy?
This is an area of controversy because nearly all children with SLE will have some evidence of renal involvement. Usually, clinical disease (e.g., abnormal urine sediment, proteinuria, renal function changes) correlates with the severity of renal disease on biopsy, but this is not always the case. Extensive glomerular abnormalities can be found on biopsy with minimal concurrent clinical manifestations.

For this reason, many authorities are aggressive with early biopsy. Three circumstances in particular warrant biopsy:
• A child with SLE and nephrotic syndrome—to distinguish membranous glomerulonephritis from diffuse proliferative glomerulonephritis (which would warrant more aggressive therapy)
• Failure of high-dose corticosteroids to reverse deteriorating renal function—to determine the likelihood of benefit from cytotoxic therapy
• A prerequisite to entry into clinical therapeutic trials

Silverman E, Eddy A: Systemic lupus erythematosus. In Cassidy JT, Petty RE, Laxer R, Lindsley C, editors:
Textbook of Pediatric Rheumatology, ed 6, Philadelphia, 2011, WB Saunders, pp 315–343.

78. How can the result of renal biopsy affect treatment of SLE?
Biopsy can reveal a spectrum of renal pathology, ranging from a normal kidney (rare) to mesangial nephritis or glomerulonephritis (focal or diffuse, proliferative or membranous). Histologic transformation from one group to another over time is not unusual. Treatment of lupus nephritis
is based on the severity of the lesion. Mesangial disease may require little or no intervention. Patients with membranous nephropathy commonly have nephrotic syndrome and usually respond to prednisone. Focal proliferative glomerulonephritis is often controlled with corticosteroids alone, but diffuse proliferative glomerulonephritis often requires corticosteroids, intravenous pulse cyclophosphamide, and possibly other immunosuppressives. Among the latter group is mycophenolate mofetil and rituximab (a monoclonal antibody that depletes B cells). Because of the detrimental effects on fertility observed with cyclophosphamide, many investigators feel that mycophenolate should be used instead of cyclophosphamide (including children with diffuse proliferative glomerulonephritis).
79. When should high-dose corticosteroid therapy be considered for SLE management? High-dose corticosteroids usually consist of either intravenous pulse methylprednisolone (30 mg/kg per dose with a maximal dose of 1 g given daily or on alternate days given as an intravenous bolus for up to 3 doses) or oral prednisone (1 to 2 mg/kg/day). Often, intravenous pulses are then
followed by high-dose oral steroids. The main indications for high-dose steroids in cases of SLE are as follows:
• Lupus crisis (widespread acute multisystem vasculitic involvement)
• Worsening central nervous system disease (as long as steroid psychosis is not thought to be the etiology)
• Severe lupus nephritis
• Acute hemolytic anemia
• Acute pleuropulmonary disease
80. What is the association of antiphospholipid antibodies and lupus?
Antiphospholipid antibodies can cause recurrent arterial and/or venous thromboses (e.g., stroke, phlebitis, renal vein thrombosis, placental thrombosis leading to fetal demise). Antiphospholipid antibodies are usually detected as anticardiolipin antibodies or lupus anticoagulant. These antibodies are often seen in patients with SLE, but their prevalence among patients with pediatric lupus varies widely (30% to 87% for anticardiolipin antibodies and 6% to 65% for lupus anticoagulant), depending on the study cited.
The pathogenesis of thrombosis in patients with antiphospholipid antibodies remains unclear.

Von Scheven E, Athreya BH, Rosé CD, et al: Clinical characteristics of antiphospholipid antibody syndrome in children,
J Pediatr 129:339–345, 1996.

81. Which laboratory tests are useful for monitoring the effectiveness of therapy in patients with SLE?
Serologic studies can provide useful information about the activity of SLE. The ANA titer does not correlate with disease activity. However, anti–double-stranded DNA titers (if present) often drop, and complement levels may increase and return to normal with effective therapy. Sedimentation rates usually decrease, and complete blood cell counts may return to normal (or at least improve) with effective therapy and decreased disease activity.

82. What are the most common manifestations of neonatal lupus erythematosus? The syndrome of neonatal lupus erythematosus (NLE) was first described in babies born to mothers with SLE or Sj€ogren syndrome; however, it has now been found that 70% to 80% of mothers with these conditions are asymptomatic. NLE is most likely caused by the transmission of maternal IgG autoantibodies. The main manifestations are as follows:
• Cutaneous: Skin lesions are found in about 50% of babies with NLE. Although the rash may be present at birth, it usually develops within the first 2 to 3 months of life. The lesions include macules, papules, and annular plaques, and they may be precipitated by exposure to sunlight. The lesions are usually transient and nonscarring.
• Cardiac: Complete congenital heart block (CCHB) is the classic cardiac lesion of NLE; 90% of all CCHB is due to neonatal lupus. Most cases of CCHB appear after the neonatal period, and 40% to 100% of these patients eventually require a pacemaker, usually before they are
18 years old.
• Hepatic: Hepatic involvement is seen in at least 15% of babies with NLE. Hepatomegaly with or without splenomegaly is usually seen. Hepatic transaminases are either mild or moderately elevated, or they may be normal. Clinically and histologically, the appearance is often one of idiopathic neonatal giant cell hepatitis.
• Hematologic: Thrombocytopenia, hemolytic anemia, and/or neutropenia may be seen.

Izmirly PM, Rivera TL, Buyon JP: Neonatal lupus syndromes, Rheum Dis Clin North Am 33:267–285, 2007.

83. What is the pathophysiology of the CCHB of NLE?
CCHB is caused by maternal autoantibodies that cross the placenta and deposit themselves in the conducting system—usually the atrioventricular node—of the fetal heart. This leads to a
localized inflammatory lesion, which may then be followed by scarring with fibrosis and calcification. The autoantibodies found are usually anti-Ro antibodies, but anti-La antibodies can also be the etiologic agents.

84. What are the common features of drug-induced lupus?
Fever, arthralgias and arthritis, and serositis can be seen in patients with drug-induced lupus. ANA and antihistone antibodies are often positive, but antibodies to double-stranded DNA are usually negative, and complement levels remain normal. Renal involvement, central nervous system disease, malar rash, alopecia, and oral ulcers are not usually seen in patients with drug-induced lupus, and their presence should raise suspicion for SLE.

85. What are the most common causes of drug-induced lupus in children? Antiepileptic medications (especially ethosuximide, phenytoin, and primidone) are the most common causes, and at least 20% of children taking antiepileptic drugs will develop a positive ANA. Minocycline, hydralazine, isoniazid, α-methyldopa, and chlorpromazine are also associated with drug-induced lupus, as are a variety of antithyroid medications and β-blockers. Actually,
all the tetracyclines have been associated with a peculiar lupuslike syndrome that includes the following:
• Acute symmetric polyarthritis
• Positive ANA
• Mild liver dysfunction
Perhaps the most common agent associated with lupus currently is chronic use of minocycline (and other tetracyclines) in association with the treatment of acne. Drug-induced lupus usually resolves within 2 weeks of discontinuation of the medication, but it may last longer (months). It is characterized by arthritis, lupus rash, and hepatitis (persistent “transaminitis”). Other
autoantibodies in addition to ANA can be seen as well.

El-Hallak M, Giani T, Yeniay BS, et al: Chronic minocycline-induced autoimmunity in children, J Pediatr
153:314-319, 2008.

VASCULITIS
86. What clinical features suggest a vasculitic syndrome?
A multisystem disease with fever, weight loss, and rash is often the presenting picture of a vasculitic disorder, which is characterized by the presence of inflammation in a blood vessel wall. Many different types of rashes may be seen, the more common of which are palpable purpura, urticarial vasculitis, and dermal necrosis. Central nervous system involvement, arthritis, myositis, and/or serositis may be seen.

Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, Garcia-Fuentes M: Cutaneous vasculitis in children and adults: associated diseases and etiologic factors in 303 patients, Medicine 77:403–418, 1998.

87. How are the primary systemic vasculitides classified?
One scheme proposed by an international consensus (EULAR/PRES: European League against Rheumatism/Paediatric Rheumatology European Society) has classified vasculitides on the basis of the size of the vessels that are predominantly affected as well as “other vasculitides,” which do not fit well into a vessel size category. In the list below, conditions in italics are common pediatric diseases.
Conditions marked with an asterisk (*) are not uncommon in pediatric rheumatology centers.
Predominantly large vessel vasculitis
• Takayasu arteritis*
Predominantly medium-sized vessel vasculitis
• Kawasaki disease
• Polyarteritis nodosa and its limb-limited variant*
Predominantly small vessel vasculitis
• Microscopic polyangiitis*
• Granulomatosis with polyangiitis (formerly Wegener granulomatosis)*
• Eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome)*
• Leukocytoclastic vasculitides
• Immune complex mediated: Henoch-Schönlein purpura, lupus VASCULITIS, serum-sickness VASCULITIS, drug-induced immune-complex VASCULITIS, infection-induced immune-complex VASCULITIS, Sj€ogren syndrome vasculitis,* hypocomplementemic urticarial vasculitis*
Other vasculitides
• Behçet disease*
• Paraneoplastic small vessel vasculitis (mostly with acute myelocytic leukemia, acute lymphoblastic leukemia, or asparaginase treatment)*
• Inflammatory bowel disease vasculitis, particularly ulcerative colitis–associated stroke and polyarteritis nodosa–like syndrome associated with Crohn disease*

Ozen S, Ruberto N, Dillon MJ, et al: EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides, Ann Rheum Dis 65:936–941, 2006.

88. What are the two most common pediatric vasculitides?
Henoch-Schönlein purpura and Kawasaki disease are the two most common pediatric vasculitides.
89. Which infectious agents are associated with vasculitis?
• Viral: Human immunodeficiency virus, hepatitis B and C viruses, cytomegalovirus, Epstein-Barr virus, varicella virus, rubella virus, and parvovirus B19
• Rickettsial: Rocky Mountain spotted fever, typhus, rickettsialpox
• Bacterial: Meningococcus, disseminated sepsis as a result of any organism, subacute bacterial endocarditis
• Spirochete: Syphilis
• Mycobacterial: Tuberculosis
90. What are the conditions that are grouped under the term pulmonary-renal syndromes?
These are medical syndromes with alveolar hemorrhage plus glomerulonephritis, which can occur spontaneously or weeks to months apart, and are usually manifestations of autoimmune conditions. Serum autoantibody patterns are helpful in distinguishing the causes (e.g., Goodpasture syndrome is

typically positive for antiglomerular basement membrane antibodies). Symptoms can include dyspnea, fever, and hemoptysis in combination with signs of glomerulonephritis (e.g., edema, hematuria).
• Goodpasture syndrome
• Granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis)
• Eosinophilic granulomatosis with polyangiitis (EGP, formerly Churg-Strauss syndrome)
• SLE

91. What is the clinical triad of Behçet disease?
Aphthous stomatitis, genital ulcerations, and uveitis. Behçet disease is a vasculitis of unclear etiology. In two-thirds of cases in children, polyarthritis and inflammatory gastrointestinal lesions occur, which can confuse the diagnosis with inflammatory bowel disease, particularly if the patient is younger than 5 years. Aseptic meningitis, sinus vein thrombosis, and other forms of deep vein thrombosis are characteristic of this disease.

92. Should it be “Henoch-Scho€nlein purpura” or “Scho€nlein-Henoch purpura”?
In 1837, Johann Sch€onlein described the association of purpura and arthralgia. Edward Henoch later added the other clinical features including gastrointestinal in 1874 and renal in 1899. Thus, purists would say that, more properly, the term should be “Sch€onlein-Henoch purpura.” However, in 1801, William Heberden described a 5-year-old boy with joint and abdominal pains, petechiae, hematochezia, and gross hematuria in his Commentaries on the History and Cure of Disease, so the true purists might say that, most properly, the condition should be “Heberden syndrome.”

93. What are the characteristic laboratory findings of patients with Henoch-Scho€nlein purpura (HSP)?
Acute-phase reactants, including the ESR and C-reactive protein, are commonly elevated, and there is frequently a mild leukocytosis. Thrombocytopenia is never seen. Microscopic hematuria and proteinuria are indicators of renal involvement. HSP purpura appears to be an IgA-mediated illness; elevated serum IgA has been noted and has been demonstrated by immunofluorescence in skin and renal biopsies. (The renal histology is indistinguishable from Berger disease.) Circulating immune complexes and cryoglobulins containing IgA are also commonly seen.

94. What kinds of skin lesions are noted in patients with HSP?
HSP is one of the HYPERSENSITIVITY VASCULITIDES and, as such, is characterized by leukocytoclastic inflammation of arterioles, capillaries, and venules. Initially, urticarial lesions predominate, and they may itch or burn; these develop into pink maculopapules (Fig. 17-11). With damage to the

Figure 17-11. Numerous purpuric macules and papules on the legs and feet of a child with Henoch-Sch€onlein purpura. (From Gawkrodger DJ: Dermatology: An Illustrated Colour Text, ed 3. Edinburgh, 2002, Churchill LIVINGSTONe, p 78.)

vessel walls, there is bleeding into the skin, which results in nonthrombocytopenic petechiae and palpable purpura. A migrating soft tissue edema is also commonly seen in younger children.
95. In addition to the skin, what other organ systems are typically involved in HSP?
Classically, HSP involves the musculoskeletal system, the gastrointestinal tract, and/or the kidneys.
• The most common abdominal finding is gastrointestinal colic (70%). This is frequently associated with nausea, vomiting, and gastrointestinal bleeding. These findings may precede the skin rash in 30% of cases or less. Intussusception occurs in 5% of cases or less.
• Renal involvement occurs in about 50% of reported cases, and it is usually apparent early during the course of the illness. It ranges in severity from microscopic hematuria to nephrotic syndrome.
• Joint involvement is very common (80%) and can be quite painful. Periarticular swelling of the knees, ankles, wrists, and elbows—rather than a true arthritis—is usually seen.
• Up to 15% of males can have scrotal involvement with epididymitis, orchitis, testicular torsion, and scrotal bleeding.
• Pulmonary hemorrhage is a rare complication of HSP that is mainly seen among adolescents and adults. It is associated with significant mortality.

Trnka P: Henoch-Sch€onlein purpura in children, J Paediatr Child Health 49:995–1003, 2013.
Tizard EJ, Hamilton-Ayres MJJ: Henoch-Sch€onlein purpura, Arch Dis Child Educ Pract Ed 93:1–8, 2008.

96. How often does chronic renal disease develop in children with HSP?
The long-term prognosis of patients with HSP depends mainly on the initial renal involvement. Overall,
<5% of patients with HSP develop end-stage renal disease. However, up to two-thirds of children who have severe crescentic glomerulonephritis documented on biopsy will develop terminal renal failure within 1 year. Of those with nephritis or nephrotic syndrome at the onset of illness, almost half may
have long-term problems with hypertension or impaired renal function as adults. Microscopic hematuria as the sole manifestation of HSP is common and is associated with a good long-term outcome.

Bogdanovi´c R: Henoch-Sch€onlein purpura nephritis in children: risk factors, prevention and treatment, Acta Paediatr
12:1882–1889, 2009.
Coppo R, Andrulli S, Amore A, et al: Predictors of outcome in Henoch-Sch€onlein purpura in children and adults, Am J Kidney Dis 47:993–1003, 2006.

KEY POINTS: HENOCH-SCH O€N LEIN PURPURA
1. A small vessel vasculitis
2. The classic clinical triad is as follows: purpura, arthritis, and abdominal pain.
3. Half of patients have abnormal urinalyses (hematuria, proteinuria; usually mild).
4. Steroid therapy is debated, but it should be considered for painful arthritis, abdominal pain, nephritis, edema, and scrotal swelling.
5. A few patients have long-term renal complications.

97. Why is the diagnosis of intussusception often difficult in patients with HSP?
• Intussusception can occur suddenly, without preceding abdominal symptoms.
• Nearly half of cases of HSP intussusception are ileoileal (compared with non-HSP intussusceptions, of which 75% are ileocolic). This increases the likelihood of a false-negative barium enema.
• The variety of possible gastrointestinal complications in patients with HSP (e.g., pancreatitis, cholecystitis, gastritis) can confuse the clinical picture.
• The common occurrence (50% to 75%) of melena, guaiac-positive stools, and abdominal pain in HSP without intussusception may lead to a lowered index of suspicion.
98. When are corticosteroids indicated for the treatment of HSP?
The precise indication for corticosteroids in patients with HSP remains controversial. Prednisone, 1 to 2 mg/kg/day (maximum: 80 mg/kg/day) for 5 to 7 days, is often used for severe intestinal symptoms and

may decrease the likelihood of intussusception. Corticosteroids may be helpful in the settings of significant pulmonary, scrotal, or central nervous system manifestations to minimize vasculitic inflammation; they are sometimes used if severe joint pain is present and NSAIDs are contraindicated. Steroids do not prevent the recurrence of symptoms, and symptoms may flare when steroids are discontinued. Controversy has arisen regarding the use of corticosteroids in all patients with HSP. Some epidemiologic studies have shown that the use of corticosteroids may shorten hospital course and prevent surgical complications. There is no controversy in the fact that corticosteroids make children with HSP feel a lot better rather quickly. However, the issue is whether to use a toxic medication for a disease that is benign most of the time. There is a great deal of controversy as
well with regards to the early use of corticosteroids (oral or intravenous pulses) in patients with
renal disease and their ability to improve long-term outcomes; no benefit has yet been demonstrated in randomized controlled trials.

Jauhola O, Ronkainen J, Koskimies O, et al: Outcome of Henoch-Sch€onlein purpura 8 years after treatment with a placebo or prednisone at disease onset, Pediatr Nephrol 27:933–939, 2012.
Weiss PF, Feinstein JA, Luan X, et al: Effects of corticosteroid on Henoch-Sch€onlein purpura: a systematic review,
Pediatrics 120:1079–1087, 2007.

99. What is acute hemorrhagic edema of infancy (AHEI)?
A simplistic answer is that AHEI is an infantile version of HSP, appearing during the first year of life. Erythematous, palpable, large purpuric lesions develop and when confluent are quite
dramatic in appearance. (The French call it the “rosette” and the English call it the “knot of ribbons.”) Skin lesions are seen in the upper and lower extremities and on the face, particularly in the ears. IgA deposition is common around the vasculitic lesions. Renal and gastrointestinal involvements are rare, and recovery is the rule in 2 to 3 weeks. It is also known as
Finkelstein syndrome.

McDougall CM, Ismail SK, Ormerod A: Acute haemorrhagic oedema of infancy, Arch Dis Child 90:316, 2005.

100. In which rheumatic diseases can “cauliflower ears” be seen?
In babies with AHEI and in older children with relapsing polychondritis—a potentially serious disease primarily affecting cartilage of the ears, airways, sclera, and aortic valve ring.

101. What is the difference between autoinflammatory and autoimmune diseases? Autoinflammatory diseases are a group of conditions that involve deregulation of the inflammatory cascade in the absence of autoantibodies (such as ANA, RF, and ANCA). The autoinflammatory problem is believed to involve dysregulation of innate immunity. This is the branch of the immune system characterized by nonspecific immune defenses (e.g., neutrophils and monocytes).
Autoimmune diseases result from problems with ADAPTIVE (or acquired) immunity, which refers to the more complex antigen-specific immune response (e.g., lymphocytes). Both conditions result in the immune system attacking the body’s own tissues.
Autoinflammatory diseases are incompletely understood, but many are characterized by genetic mutations, which result in increased and frequent activation of inflammatory pathways. Inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), are overproduced. Unlike autoimmune diseases, autoantibodies are not driving the inflammation. Autoinflammatory diseases are characterized by chronic and recurrent episodes of systemic and organ-specific inflammation with fever, particularly recurrent, as a prime symptom.

Hausmann JS, Dedeoglu F: Autoinflammatory diseases in children, Dermatol Clin 31:481–494, 2013.

102. Are all autoinflammatory diseases characterized by periodic fever and genetic mutations?
No, and this can make the diagnostic process difficult. More than 20 monogenetic auto-inflammatory diseases have been identified. These include familial Mediterranean fever, TNF-associated periodic

fever syndrome (TRAPS), and hyperimmunoglobulin D syndrome (HIDS). However, PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) syndrome, also known as Marshall syndrome, has no known genetic basis although it has many of the features of an auto-inflammatory disorder. In addition, Behçet syndrome (discussed previously) and systemic-onset JIA, both without a specific single gene mutation, are suspected to be autoinflammatory diseases.

Russo RAG, Brogan RA: Monogenic autoinflammatory diseases, Rheumatology 53:1927–1939, 2014.