CHAPTER 28: Rheumatology

DEFINITION

Most common pediatric inflammatory myopathy.

Bohan and Peter diagnostic criteria (definite JDM: heliotrope rash or Gottron’s papules plus at least three criteria; probable JDM: heliotrope rash or Gottron’s papules plus two criteria)

• Heliotrope rash (eyelids) or Gottron’s papules (extensor surfaces)

• Progressive symmetric proximal muscle weakness

• Elevated skeletal muscle enzymes (CK, AST, aldolase, LDH)

• EMG consistent with myopathy

• Biopsy evidence of myositis

• Updated criteria will likely include muscle abnormalities on MRI STIR or T2 sequence

EPIDEMIOLOGY

• Incidence: About 2–3 cases/million children

• Peaks at 6 years and 11–12 years of age; female:male is 2:1

• Comparable for blacks and whites, lower in Hispanics

• Unlike in adults, JDM has no definite associations with malignancy

ETIOLOGY

• Potential infectious triggers: Group A beta-hemolytic Streptococcus, coxsackie virus B, parvovirus, others

• HLA and TNF-α alleles may predispose a child to JDM

• Molecular mimicry is suspected

• Sun exposure may trigger onset of rash

DIFFERENTIAL DIAGNOSIS

• Rheumatologic:

  • ✓ Juvenile polymyositis is rare in children (2–8% of inflammatory myopathies), has similar age and sex distribution as JDM but includes proximal and distal weakness, muscle atrophy, lacks skin abnormalities, and calcinosis is rare

  • ✓ Systemic lupus erythematosus (SLE) and related conditions (e.g., mixed connective tissue disease, Sjögren syndrome)

  • ✓ Scleroderma

  • ✓ Juvenile idiopathic arthritis (JIA); polyarticular or systemic

  • ✓ Polyarteritis nodosa

  • ✓ Eosinophilic fasciitis

• Infectious:

  • ✓ Viral myopathies: Influenza A and B, coxsackie, Epstein–Barr virus, herpes, parainfluenza, adenovirus, enterovirus

  • ✓ Bacterial and parasitic myopathies: Staph, strep, toxoplasma

• Metabolic/Genetic:

  • ✓ Muscular dystrophies

  • ✓ Congenital myopathies

  • ✓ Myotonic disorders

  • ✓ Glycogen storage diseases

  • ✓ Periodic paralysis

  • ✓ Endocrinopathies

• Other:

  • ✓ Trauma

  • ✓ Toxins

  • ✓ Drug-induced myopathies

  • ✓ Disorders of neuromuscular transmission

PATHOPHYSIOLOGY

• Perivascular inflammation, mostly mononuclear cells

• Swelling and blockage of capillaries, tissue infarction, perifasicular atrophy

• Chronic inflammation ensues with fibrosis and microscopic calcification

CLINICAL MANIFESTATIONS

• Proximal muscle weakness (neck flexors, shoulders, abdomen, thighs): Gower sign, difficulty climbing stairs or combing hair

• Skin: Heliotrope rash (violaceous rash of eyelids); facial erythema, possibly in malar distribution; papulosquamous eruption on extensor surfaces (Gottron’s rash), particularly over interphalangeal joints (Gottron’s papules); shawl sign (erythematous rash in a shawl distribution); cutaneous calcinosis and ulceration

• Nailfolds: Capillary drop-out, capillary dilation, cuticular hypertrophy

• Arthritis: Effusions, limited range of motion, pain, deformity

• Mucocutaneous: Oral ulcers, gingival inflammation

• Pulmonary: Shortness of breath, cough, crackles can be consistent with interstitial lung disease or aspiration pneumonia

• Gastrointestinal: Dysphagia, ulceration, perforation, bleeding, constipation, diarrhea, abdominal pain

• Other manifestations: Lipodystrophy, polyneuropathies, retinal exudates, and cotton wool patches

• Other complications: Calcinotic lesions may spontaneously drain causing local inflammatory response and superinfection; can form exoskeleton; vasculitic ulcers; rare arrhythmias and cardiomyopathy; complications of chronic corticosteroid exposure (growth failure, hypertension, vertebral compression fractures, striae, avascular necrosis, cataracts, glaucoma)

DIAGNOSTICS

• CBC: Lymphopenia, anemia of chronic inflammation; iron deficiency anemia should raise concern for gastrointestinal blood loss

• ESR and CRP: Normal or high

• Elevated muscle enzymes: Creatine kinase, aldolase, AST, LDH

• ANA: Positive in 10–85% of cases; rheumatoid factor: negative

• Neopterin and vWF antigen: Elevations correlate with disease activity

• Anti-RNP (may indicate SLE overlap), anti-PM-SCL (associated with SLE or scleroderma), anti-Jo1 (associated with interstitial lung disease), anti-Mi2 (associated with lung disease)

• Urinalysis to rule out renal involvement (may indicate SLE overlap)

• MRI with T2 or STIR weighted images of muscles: Localizes active disease sites

• Chest x-ray: Evaluate for infiltrates

• High resolution chest CT: Evaluate for interstitial lung disease

• Modified barium swallow: Detect palato-esophageal dysfunction

• Plain films: Detect calcinosis, soft tissue, and muscle edema

• ECG: May see arrhythmias

• ECHO: may detect cardiomyopathy

• Muscle biopsy: Myositis, perifascicular necrosis with degenerating and regenerating fibers

• EMG: Fibrillations, insertional irritability

• Pulmonary function tests: Respiratory muscle weakness or interstitial lung disease cause a restrictive pattern

MANAGEMENT

• Mild disease: Corticosteroids (2 mg/kg/day then taper), methotrexate, +/− hydroxychloroquine if a significant rash is present

• Moderate–severe disease: Add pulse corticosteroids (methylprednisolone 30 mg/kg/day, up to 1000 mg) × 3 then oral (2 mg/kg/day then taper), IVIG (2g/kg IV every 3–4 weeks)

• Refractory disease: If active disease persists on a maximal regimen including methotrexate, IVIG, and hydroxychloroquine, other agents such as cyclophosphamide, rituximab, calcineurin inhibitors (cyclosporine A, tacrolimus), intermittent pulse methylprednisolone, and abatacept can be considered

• Interstitial lung disease: Cyclophosphamide, pulse corticosteroids

• Sunscreen: Minimum SPF 30 with UVA and UVB protection

• Nutritional supplements: Vitamin D and calcium

• Calcinosis: Decreased with early aggressive therapy, case reports of successful therapy with a variety of agents including bisphosphonates

• Physical and occupational therapy

• Immunizations:

  • ✓ No live vaccines for individuals on high-dose systemic corticosteroids or other immunosuppressive agents

  • ✓ Administer inactivated influenza (annually) and pneumococcal vaccines

  • ✓ Delay MMR until 11 months after last IVIG treatment if not otherwise contraindicated (e.g., on other immunosuppressants)

DEFINITION

Small vessel vasculitis affecting the skin, joints, GI tract, and kidneys. EULAR/PRINTO/PRES 2010 criteria: Purpura or petechiae (mandatory) with lower limb predominance and at least one of the four following criteria: abdominal pain, histopathology, arthritis or arthralgia, or renal involvement.

EPIDEMIOLOGY

• Most common childhood vasculitis in the United States

• Age range: 3–15 years; peak: 7 years

• Incidence: 3–17/100,000

• Typically occurs during winter preceded by upper respiratory tract infection

DIFFERENTIAL DIAGNOSIS

• Rheumatologic:

  • ✓ SLE and related conditions

  • ✓ ANCA-associated vasculitis

  • ✓ Hypersensitivity vasculitis

  • ✓ Cryoglobulinemia

  • ✓ Urticarial vasculitis

  • ✓ Polyarteritis nodosa

  • ✓ Sarcoidosis

• Hematologic/Oncologic:

  • ✓ Immune thrombocytopenic purpura

  • ✓ Leukemia

  • ✓ Hemophagocytic lymphohistiocytosis

  • ✓ Lymphoma

• Infectious/Post-infectious:

  • ✓ Sepsis

  • ✓ Viral and bacterial enterocolitis

  • ✓ Post-streptococcal glomerulonephritis

  • ✓ Hemolytic-uremic syndrome

• Gastrointestinal:

  • ✓ Crohn’s disease

  • ✓ Ulcerative colitis

  • ✓ Meckel diverticulum, polyps, lymphoid hyperplasia can cause intussusception

PATHOPHYSIOLOGY

• Small vessel vasculitis affecting capillaries and pre- and post-capillary vessels

• Mediated by immune complexes (typically IgA, can see IgG and activated complement C3) which are deposited in end-organs causing inflammation

• May be associated with antecedent respiratory infection (group A beta-hemolytic streptococcus, mycoplasma, parvovirus, other viral pathogens)

CLINICAL MANIFESTATIONS

• Classic presentation includes non-thrombocytopenic purpuric rash, musculoskeletal pain, and colicky abdominal pain

• Rash: Most common presenting symptom

  • ✓ Non-blanching, purpuric lesions developing in gravity- or pressure-dependent areas, usually distal to the elbows and below the waist

  • ✓ Early lesions may appear erythematous, petechial, or urticarial, evolving into hemorrhagic or ecchymotic lesions

  • ✓ Lesions may ulcerate

  • ✓ Koebner phenomenon may occur (lesions appear at sites of skin injury)

• Musculoskeletal pain: Second most common manifestation; symptoms may be persistent or intermittent

  • ✓ Periarticular or articular pain with impaired mobility and minimal joint warmth and effusion, typically affecting the ankles, knees, elbows, wrists, digits

• Gastrointestinal pain: Occurs in 2/3 of children within a week of rash onset; abdominal pain, hemorrhage, intussusception, bowel perforation possible; presents with colicky pain, vomiting, loose stool, melena, hematemesis; hepatosplenomegaly may be present

• Renal involvement: Occurs in 1/3 of patients and usually develops within the first 4–6 weeks; may lead to end-stage renal disease

  • ✓ Manifestations include microscopic or macroscopic hematuria with or without proteinuria, hypertension, glomerulonephritis, ureteritis, urethritis, and cystitis

• Rare manifestations:

  • ✓ GU: Scrotal swelling/hemorrhage mimicking testicular torsion, testicular torsion (rare)

  • ✓ CNS: Headache, seizures, hemorrhage, cerebrovascular thrombosis, focal deficits, and peripheral neuropathies

  • ✓ Pulmonary: Interstitial disease, alveolar hemorrhage, and respiratory failure

  • ✓ CV: Carditis, myocardial infarction

• Vital signs: Low-grade fevers; hypertension due to renal disease; tachycardia due to anemia or pain

• Duration of symptoms: Average 4 weeks if untreated, chronic HSP is unusual

• Recurrence: Up to 33%, usually within the first year after diagnosis

DIAGNOSTICS

• WBC (normal to slightly elevated); Hgb (normal to slightly low); platelet count (normal to elevated); PT/PTT (normal)

• ESR and CRP: Normal to elevated

• BUN and creatinine: Normal or possibly elevated with renal disease or volume depletion

• Albumin: Decreased with proteinuria and gastrointestinal losses, malnutrition, and inflammation

• Urinalysis: Proteinuria and/or hematuria; RBC casts

• Stool: May be hemoccult positive

• Immunological:

  • ✓ ANCA should be negative in HSP. If ANCA is positive, consider granulomatosis with polyangiitis (c-ANCA, positive anti-proteinase 3), and microscopic polyangiitis or rarely, Churg–Strauss (p-ANCA, anti-myeloperoxidase)

  • ✓ Elevated IgA levels in 50% (not routinely sent)

  • ✓ Cryoglobulins should be negative (not routinely sent)

• Abdominal x-ray barium studies, ultrasound, and CT may be useful for assessment of abdominal obstruction and intussusception

• Skin biopsy: May aid diagnosis in non-classic presentations; light microscopy demonstrates leukocytoclastic vasculitis and IgA deposition on immunofluorescence

• Renal biopsy: Useful if proteinuria/hematuria is significant or does not resolve; crescentic glomerulonephritis with IgA deposition may be seen

• Arthrocentesis: Perform, if necessary, to exclude infectious arthritis

MANAGEMENT

• Tylenol for analgesia; avoid NSAIDs if GI or renal involvement

• Monitor for hypertension; hematuria and proteinuria should present within 6 months

• Corticosteroids: Indicated for renal involvement, abdominal and musculoskeletal pain

  • ✓ For mild or moderate disease consider prednisone or methylprednisolone 2 mg/kg/day up to 60 mg/day for 1 week with 2-week taper

  • ✓ For severe disease, consider pulse methylprednisolone up to 30 mg/kg/day (maximum 1000 mg/day) up to 3 days then prednisone 2 mg/kg/day up to 60 mg/day for 1 week with a 2-week taper

• Immunosuppressive therapy (cyclophosphamide, azathioprine, methotrexate) should be considered in patients with complicated nephritis, pulmonary, cutaneous, and/or CNS manifestations

• Supportive care: Severe pain may require narcotics. Severe GI involvement may require NPO status, NG suction, and TPN, though response to corticosteroids is often dramatic with prompt initiation of therapy

DEFINITION

Chronic synovial inflammation of unknown etiology with onset prior to 16 years of age and leading to arthritis in one or more joints for at least 6 weeks. The 2001 International League Against Rheumatism (ILAR) criteria for JIA include seven specific subtypes.

• Oligoarthritis: Arthritis involving one to four joints during the first 6 months of disease. Persistent oligoarthritis affects no more than four joints throughout the course of disease. Extended oligoarthritis affects more than four joints after the first 6 months of disease

• Polyarthritis (rheumatoid factor negative): Involvement of five or more joints during the first 6 months of disease; rheumatoid factor test is negative

• Polyarthritis (rheumatoid factor positive): Involvement of five or more joints during the first 6 months of disease; two rheumatoid factor tests are positive at least 3 months apart during the first 6 months of disease

• Enthesitis-related arthritis: Arthritis and enthesitis (tenderness where a tendon inserts into a bone); or arthritis or enthesitis with at least two of the following: sacroiliac tenderness or inflammatory lumbosacral pain, HLA-B27 positive, onset of arthritis in a male greater than 6 years old, acute (symptomatic) anterior uveitis, history of ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, reactive arthritis, or acute anterior uveitis in a first-degree relative

• Psoriatic arthritis: Arthritis and psoriasis, or arthritis with two of the following: dactylitis, nail pitting or onycholysis, or psoriasis in a first-degree relative

• Systemic arthritis: Arthritis in one or more joints with or preceded by a fever of 2 weeks’ duration with a quotidian fever for at least 3 days plus at least one of the following: evanescent (non-fixed) erythematous rash, generalized lymphadenopathy, hepatomegaly, and/or splenomegaly, or serositis

• Undifferentiated arthritis: Arthritis that does not fulfill the above criteria based on subtype-specific exclusion criteria or fulfills criteria in two or more of the above categories

EPIDEMIOLOGY

• Most common chronic childhood rheumatologic disease

• Sex distribution is subtype-specific

• Incidence: 1–20/100,000 in children less than 16 years old

• Proportion of arthritis subtypes: Oligoarthritis (50–80%), polyarthritis (20%, of which 85% are rheumatoid factor negative), enthesitis-related arthritis (1–7%), psoriatric arthritis (1–11%), systemic arthritis (5–15%)

ETIOLOGY

• Genetic and environmental factors suspected

• HLA associations exist

• Associated with immunodeficiencies: IgA deficiency, 22q11 deletion

• Link between infectious triggers and arthritis is not fully established

DIFFERENTIAL DIAGNOSIS OF CHRONIC ARTHRITIS

• Critical to distinguish acute from chronic arthritis as a first step

• Other rheumatic and inflammatory diseases such as inflammatory bowel disease, sarcoidosis, SLE, and vasculitis can present with an acute or chronic oligo- or polyarthritis with or without fever

• Oligoarthritis: Trauma, reactive arthritis, septic arthritis, Lyme disease, foreign body, leukemia, bone or synovial tumor, Legg–Calve–Perthes disease, slipped capital femoral epiphysis, pigmented villonodular synovitis, cystic fibrosis arthropathy, congenital arthropathies, metabolic disorders such as gout

• Polyarthritis: Serum sickness, reactive arthritis, septic arthritis (Neisseria spp.), parvovirus B19 infection

• Systemic arthritis: Kawasaki disease, leukemia, lymphoma, primary hemophagocytic lymphohistiocytosis or secondary to infection or malignancy (e.g., lymphoma), septic arthritis, Lyme disease, Epstein–Barr virus, parvovirus B19, Bartonella henselae, mycoplasma, acute rheumatic fever, periodic fever syndromes such as neonatal-onset multisystem inflammatory disease, Langerhans cell histiocytosis, chronic recurrent multifocal osteomyelitis, Kikuchi disease, Castleman disease

PATHOPHYSIOLOGY

• Synovitis with villous hypertrophy and hyperplasia

• T-cell activation and recruitment into joint synovium leads to release of pro-inflammatory cytokines by multiple cell types

• Pannus formation in late disease, causing progressive erosion of cartilage and bone

• Systemic arthritis is currently considered to be an autoinflammatory condition with interleukin 1 being a key mediator

CLINICAL MANIFESTATIONS

• General: Fatigue, low- or high- grade fevers, anorexia, weight loss, failure to thrive, limp, joint swelling (may be asymptomatic) with morning stiffness, hepatosplenomegaly, pain with inactivity, evanescent urticarial rash, lymphadenopathy

• Oligoarthritis: Usually involves knees, ankles, fingers, wrists, elbows; systemic symptoms unusual

• Polyarthritis: May involve large and small joints, spares distal interphalangeal joints

• Systemic arthritis: High fevers 1–2 times/day for at least 2 weeks, temperature often returns to normal or subnormal accompanied by erythematous macular rash on trunk and proximal limbs; serositis (pericarditis and/or pleuritis); pericardial tamponade may ensue

• Musculoskeletal: Swelling/effusion; limited range of motion (including decreased cervical-spine motion); warmth; contracture/deformity; +/− limb length discrepancies and wasting of surrounding muscles (gastrocnemius or quadriceps)

• Arthritis of temporomandibular joint may cause failure to thrive secondary to pain. Micrognathia or jaw deviation may ensue

• Ophthalmologic: Pupil irregularities, synechiae, band keratopathy due to anterior uveitis; may lead to visual loss, cataract, glaucoma; uveitis is most common in ANA positive young females

• Macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis is a potentially life-threatening complication seen with systemic arthritis

  • ✓ Symptoms may include unremitting fever, hepatosplenomegaly, lymphadenopathy, bruising, mucosal bleeding, respiratory distress, encephalopathy, and renal involvement progressing to multi-system organ failure

• Other complications: Fractures, pseudoporphyria with NSAID use, if untreated can have contractures and limb-length discrepancy

DIAGNOSTICS

• No laboratory test can confirm the diagnosis of chronic arthritis

• ESR and CRP: Normal or high in oligoarthritis or polyarthritis; high with systemic arthritis

• CBC: Leukocyte count normal or high; platelets may be elevated

• ANA: Highest in younger girls, rarely positive in systemic arthritis; positive ANA associated with increased risk for developing uveitis in subtypes other than systemic arthritis

• Rheumatoid factor: Positive in minority of patients with polyarthritis, useful for prognostic purposes only

• Urinalysis: Abnormal results may suggest alternative diagnosis

• Joint fluid aspirate: Usually 2000–50,000 WBC/mm³ (but may be higher); neutrophils may predominate; glucose normal to slightly low; elevated protein

• Radiologic studies are helpful to rule out other disease processes such as tumors and to establish baseline for evaluation of joint erosions

• If cervical-spine range of motion limited, order cervical lateral flexion and extension spinal films to assess for atlantoaxial instability and subaxial ankylosis prior to surgery, intubation, sports participation

• Macrophage activation syndrome/secondary hemophagocytic lymphohistiocytosis: Fall in WBC and platelets, anemia, elevated liver enzymes, hypofibrinogemia, elevated D-dimer, prolonged PT and PTT, hypertriglyceridemia, hyperferritinemia, low ESR, evidence of macrophage hemophagocytosis on bone marrow biopsy

MANAGEMENT

• Oligoarthritis: Treatment of choice is intra-articular corticosteroid injections; NSAIDs (e.g., naproxen 20 mg/kg/day, divided twice per day) for symptomatic relief; if no response to intra-articular corticosteroid injections or manifestations are severe, then use methotrexate and/or biologic therapy

• Polyarthritis: Intra-articular corticosteroids, methotrexate, TNF-α inhibitors (e.g., etanercept, adalimumab, infliximab), CTLA-4 Ig (abatacept), IL-6 inhibitor (tocilizumab). Rheumatoid factor positive has poor prognosis and necessitates aggressive therapy

• Systemic arthritis: Corticosteroids, IL-1 inhibitors (anakinra or canakinumab), IL-6 inhibitor, cyclosporine (particularly with refractory MAS), intra-articular corticosteroids; cyclophosphamide for refractory disease

• Regular ophthalmology exams: Slit-lamp exam to diagnose asymptomatic uveitis

  • ✓ Frequency is every 3–6 months initially, depending on age at onset and ANA status, except in systemic arthritis, in which every 12-month screening is adequate

• Dietary evaluation: Ensure adequate calcium, vitamin D

• Physical and occupational therapy: To maintain and improve joint function and motion

• Immunizations:

  • ✓ Avoid live vaccines (varicella, MMR, intra-nasal influenza) for individuals on high-dose systemic corticosteroids or immunosuppressants

  • ✓ Administer inactivated influenza (annually) and pneumococcal vaccines

DEFINITION

An acute, febrile vasculitis of childhood defined by at least 5 days of fever and greater than or equal to four of the following: Conjunctivitis, mucous membrane changes, peripheral extremity changes, polymorphous rash, or cervical adenopathy. Incomplete Kawasaki disease may present with fewer than four criteria and coronary artery disease. It is more common in infants less than 6 months old.

EPIDEMIOLOGY

• Incidence: United States: about 12 per 100,000; Japan: about 112 per 100,000

• Median age = 2 years; 80% of cases occur before 5 years of age and 95% before 10 years

• Recurrence <1% in the United States but 3% in Japan

• Children <1 year have increased likelihood of developing coronary artery aneurysms

DIFFERENTIAL DIAGNOSIS

• Viral:

  • ✓ Measles

  • ✓ Epstein–Barr virus

  • ✓ Adenovirus

  • ✓ Enterovirus

  • ✓ Parvovirus B19

• Bacterial:

  • ✓ Scarlet fever

  • ✓ Staphylococcal scalded skin syndrome

  • ✓ Toxic shock syndrome

  • ✓ Yersinia pseudotuberculosis

  • ✓ Typhoid fever

  • ✓ Leptospirosis

  • ✓ Rocky Mountain spotted fever

• Allergic:

  • ✓ Drug reaction

  • ✓ Serum sickness

  • ✓ Stevens–Johnson syndrome

• Rheumatologic:

  • ✓ Systemic arthritis

  • ✓ Polyarteritis nodosa

  • ✓ Reactive arthritis

• Toxic:

  • ✓ Mercury poisoning

PATHOPHYSIOLOGY

• Vasculitis of medium-sized arteries

• Edema of endothelial and smooth muscle cells; inflammatory infiltration of vascular wall

• The etiology is unknown, but it may be due to a superantigen stimulation of immune system in genetically susceptible hosts

• Up to 1/3 have an identified infection

CLINICAL MANIFESTATIONS

• Three phases: Acute febrile phase (7–14 days), subacute phase (14–24 days), and convalescent phase (>24 days)

• Fever: High (can be >40°C) and spiking

• Conjunctival injection: Bilateral, bulbar (Limbic-sparing), generally non-purulent and painless

• Peripheral extremity changes: Edema (“sausage-like” digits), erythema; desquamation 2–3 weeks after fever onset

• Mucous membrane changes: Injected oropharynx, dry fissured, peeling, cracking lips, strawberry tongue

• Polymorphous rash: May be maculopapular, urticarial, scarlatiniform, erythema multiforme, prominence in groin area and groin desquamation may occur by end of first week

• Cervical adenopathy: ≥1.5cm, generally unilateral and may be tender

• Coronary artery aneurysms: Develop in 15–25% of patients not treated within 10 days of onset, but in fewer than 5% of treated patients

• Other manifestations: Extreme irritability, aseptic meningitis, cranial nerve palsy, transient sensorineural hearing loss, myocarditis, valvular disease, pleural effusions, gallbladder hydrops, hepatitis, jaundice, hepatosplenomegaly, abdominal pain, vomiting, diarrhea, arthralgias, arthritis of small and large joints, urethritis, uveitis, testicular swelling

DIAGNOSTICS

• Elevated ESR and CRP

• CBC: WBC normal or leukocytosis (WBC >15,000/mm³ in 50%); normocytic anemia; thrombocytosis (platelet count up to 1,000,000/mm³) after first week

• Mildly elevated ALT, AST, GGT, bilirubin, alkaline phosphatase but low albumin (<3g/dL)

• Urinalysis: Sterile pyuria in 70% (>10 leukocytes/hpf), catheter sample may miss urethritis

• CSF: Pleocytosis with lymphocyte predominance in 25–50% of patients who undergo LP

• Chest x-ray: May show pneumonitis, pleural effusion, cardiomegaly

• ECG: May show arrhythmia, ischemia, low voltages or ST-segment or T-wave changes

• Echocardiogram: Perform at time of diagnosis; may reveal coronary artery ectasia or aneurysms, pericardial effusion, valvular abnormalities, or diminished ventricular function

• Slit-lamp exam: Anterior uveitis is common (>85% of patients)

• Arthrocentesis: Synovial fluid WBC 50–300,000/mm³, normal glucose, negative Gram stain and culture

MANAGEMENT

• Intravenous immunoglobulin (IVIG): 2g per kg over 10–12 hours; if still febrile after approximately 36 hours, may consider a repeat dose of 2g per kg particularly if there is concern for persistent active disease

• Aspirin: 80–100 mg/kg/day divided into four oral doses; when afebrile for 48 hours, decrease dose to 3–5 mg/kg daily as a single oral dose for 6–8 weeks. Discontinue aspirin if follow-up echocardiogram and ESR are normal

• Corticosteroids: Conflicting clinical trial data on routine addition of corticosteroids to IVIG. Generally not recommended except in refractory cases (i.e., prednisone or methylprednisolone for persistent symptoms after two doses of IVIG)

• Refractory cases with persistent fevers

  • ✓ Systemic corticosteroids

  • ✓ Anti-TNF drugs such as infliximab

• Anticoagulants: Dipyridamole, clopidrogel, warfarin, or low molecular weight heparin, and abciximab can be used for the treatment of coronary aneurysms

• Other: Therapeutic apheresis and cyclophosphamide have been examined but data are lacking regarding their role in treatment

• Disposition: Close follow-up with pediatric cardiologist. Repeat echocardiogram is routinely performed 6–8 weeks after treatment and depending on the presence of coronary aneurysms

• Immunizations: Defer measles and varicella vaccinations for 11 months following high-dose IVIG. Those on long-term salicylate therapy should have an annual influenza vaccination

DEFINITION

Post-infectious manifestation of group A streptococcal (GABHS) pharyngitis. The diagnosis is based on the Jones criteria (Table 28-1)

• Should be distinguished from post-streptococcal reactive arthritis, a GABHS-associated reactive arthritis that does not fulfill Jones criteria, and is less likely to cause cardiac disease

EPIDEMIOLOGY

• Most common in 5–15 year olds

• Annual incidence was less than 1/100,000 until the mid to late 1980s when new outbreaks occurred. Outbreaks are common in overcrowded areas of people with low socioeconomic status

• Carditis more common in young children

• Arthritis more common in adults

ETIOLOGY

• Usually develops 2–3 weeks following an untreated GABHS pharyngitis

DIFFERENTIAL DIAGNOSIS

• Bacterial:

  • ✓ Septic arthritis

  • ✓ Lyme arthritis

  • ✓ Reactive arthritis (including post-streptococcal)

  • ✓ Osteomyelitis

  • ✓ Endocarditis

  • ✓ Mycoplasma pneumonia

• Viral:

  • ✓ Parvovirus

  • ✓ EBV

• Rheumatologic:

  • ✓ Systemic arthritis

  • ✓ Kawasaki disease

  • ✓ Systemic lupus erythematosus

  • ✓ Antiphospholipid syndrome (primary or secondary)

  • ✓ Behçet disease

• Immunologic:

  • ✓ Serum sickness

• Neurologic:

  • ✓ Hereditary disorders such as juvenile Huntington disease

  • ✓ Wilson disease

  • ✓ Benign hereditary chorea

  • ✓ Inborn errors or metabolism

  • ✓ Nutritional or electrolyte disturbance

  • ✓ Arteriovenous malformation

• Oncologic:

  • ✓ Leukemia

  • ✓ Lymphoma

• Hematologic:

  • ✓ Sickle cell arthropathy

PATHOPHYSIOLOGY

• Immune complexes may cause nondestructive synovitis and reversible reactions in basal ganglia that cause chorea

• Extracellular GAS toxin may target organs such as the heart and brain

• Autoimmunity and cell-mediated cytotoxicity may cause valvular inflammation

CLINICAL MANIFESTATIONS

• Arthritis: Migratory and/or additive, typically affects knees, ankles, elbows; joints may be swollen, warm, tender, limited range of motion; joint involvement more severe and common in teenagers

• Subcutaneous nodules: Firm and painless; over extensor surfaces of joints, occipital region, thoracic or lumbar spinous processes

• Erythema marginatum: Pink/red blanching rash with raised borders, central clearing, not pruritic or indurated; may worsen with fever

• Carditis: Affects mitral valve and aortic valve most commonly. It is a pancarditis that involves the endocardium, myocardium, and pericardium but congestive heart failure, if present, is most commonly due to valvular dysfunction

• Chorea: Involuntary, purposeless movements; associated with muscle weakness and emotional lability usually disappears over weeks to months; rarely recurs. “Milkmaid sign”: patient’s grip strengthens and weakens

DIAGNOSTICS

• Evidence of prior infection: Increased antistreptolysin O, anti-DNase B, positive throat culture, recent history of scarlet fever

• ESR and CRP: Usually elevated acutely

• CBC: Normocyctic, normochromic anemia

• Blood culture: Should be negative

• Joint fluid: Sterile, WBC count may be in septic range

• X-rays of affected joints: Normal or effusion present

• Chest x-ray: May see cardiomegaly

• ECG: May see heart block (usually 1st degree)

• Echocardiogram: May see mitral and/or aortic valve thickening and regurgitation. Stenotic lesions are associated with chronic valve disease in rheumatic fever

MANAGEMENT

• GABHS infection treatment (10 days duration)

  • ✓ Penicillin

  • ✓ Erythromycin or other macrolide antibiotic

  • ✓ Clindamycin

  • ✓ Cephalexin

• GABHS prophylaxis

  • ✓ Penicillin G benzathine every 4 weeks

    • ▪ Less than 27.3kg: 600,000 units

    • ▪ Greater than or equal to 27.3kg: 1.2 million units

  • ✓ Penicillin V 250 mg twice per day

  • ✓ Sulfadiazine or sulfisoxazole

    • ▪ Less than or equal to 27kg: 0.5g daily

    • ▪ Greater than 27kg: 1g daily

  • ✓ Macrolide if allergic to penicillin and sulfonamide

  • ✓ Duration

    • ▪ Without carditis: Treat for 5 years after last episode or until age 21, whichever is longer

    • ▪ With carditis: Treat for 10 years after last episode or until age 21, whichever is longer

    • ▪ With carditis and valvular disease: Treat for 10 years after last episode or until age 40, whichever is longer. Lifelong prophylaxis may be needed if risk of exposure is high

• Aspirin: 90–100 mg/kg/day divided 4 times per day for arthritis and carditis. Naproxen may be used for isolated joint disease

• Corticosteroid therapy may be used in cases of acute carditis and congestive heart failure (prednisone 2 mg/kg/day divided twice per day with slow taper or pulse dosing with methylprednisolone 30 mg/kg/day up to 1000 mg daily for 3 days) if critically ill

• Chorea: Diazepam, haloperidol, valproic acid, corticosteroids

DEFINITION

A multisystem autoimmune disease caused by pathologic production of autoantibodies and tissue deposition of immune complexes, and characterized by global immune dysregulation.

EPIDEMIOLOGY

• 15–25% present in first two decades of life, often after puberty

• Female:male = 9:1 after puberty and before menopause, otherwise 3:1

• African American:Caucasian = 3:1

• Incidence: 2–8 per 100,000; prevalence: 15–50 per 100,000

ETIOLOGY

• Genetic predisposition (HLA haplotype associations)

• Immune system dysregulation

• Environmental stimuli (UV light, drugs, herpes virus infections, diet)

• Hormonal factors

• Apoptosis abnormalities

DIFFERENTIAL DIAGNOSIS

• Rheumatologic:

  • ✓ Drug-induced lupus

  • ✓ Cutaneous lupus

  • ✓ Mixed connective tissue disease

  • ✓ Sjögren syndrome

  • ✓ Juvenile dermatomyositis

  • ✓ Scleroderma

  • ✓ JIA (systemic arthritis, polyarthritis)

  • ✓ Henoch–Schönlein purpura

  • ✓ Granulomatosis with polyangiitis

  • ✓ Microscopic polyangiitis

  • ✓ Churg–Strauss syndrome

  • ✓ Hypersensitivity vasculitis

  • ✓ Cryoglobulinemia

  • ✓ Polyarteritis nodosa

  • ✓ Kawasaki disease

  • ✓ Takayasu arteritis

  • ✓ Sarcoidosis

  • ✓ Primary antiphospholipid syndrome

  • ✓ IgG4-related disease

• Hematologic:

  • ✓ Thrombotic thrombocytopenic purpura

  • ✓ Immune thrombocytopenic purpura

  • ✓ Autoimmune hemolytic anemia

  • ✓ Evan syndrome

  • ✓ Aplastic anemia

• Immunologic:

  • ✓ Common variable immunodeficiency

• Oncologic:

  • ✓ Leukemia

  • ✓ Lymphoma

  • ✓ Malignancies metastatic to marrow or causing pleural or pericardial effusions

• Lymphoproliferative:

  • ✓ Autoimmune lymphoproliferative syndrome

  • ✓ Castleman disease

• Cardiac:

  • ✓ Viral or bacterial pericarditis

  • ✓ Autoinflammatory disease such as Familial Mediterranean Fever

• Renal:

  • ✓ Membranoproliferative glomerulonephritis

  • ✓ Minimal change disease

  • ✓ Focal segmental glomerulosclerosis

  • ✓ Tubulointerstitial nephritis

• Gastroenterologic:

  • ✓ Autoimmune hepatitis

  • ✓ Inflammatory bowel disease

  • ✓ Celiac disease

  • ✓ Protein-losing enteropathy

• Endocrine:

  • ✓ Hypothyroidism

• Viral:

  • ✓ Epstein–Barr virus

  • ✓ Cytomegalovirus

  • ✓ Enterovirus

  • ✓ Parvovirus B19

  • ✓ Viral hepatitis

  • ✓ Viral encephalitis

• Bacterial:

  • ✓ Lyme disease

  • ✓ Ehrlichiosis

  • ✓ Rocky Mountain Spotted Fever

  • ✓ Bartonella henselae

  • ✓ Acute rheumatic fever

PATHOPHYSIOLOGY

• Autoantibodies are directed against nuclear and cytoplasmic antigens. Organ-specific antibodies to cell surface antigens are also present

• Disease can be secondary to pathogenic autoantibodies (renal disease, thrombocytopenia, antiphospholipid antibody syndrome, neonatal lupus and fetal loss, CNS disease), pathogenic immune complexes (secondary to quantity and size, and tissue tropism), and T lymphocyte dysregulation (skin disease)

CLINICAL MANIFESTATIONS

Many children have nonspecific symptoms for months before diagnosis, often presenting with fatigue, malaise, easy bruising, arthritis, rash, Raynaud phenomenon, lymphadenopathy, and weight loss before other characteristic findings.

• Mucocutaneous: Malar rash, discoid rash, alopecia, photosensitivity, palatal ulceration (usually painless), Raynaud phenomenon, digital ulceration, or vasculitic rash

• Musculoskeletal: Arthralgia and arthritis are frequent at presentation. Arthritis is often polyarticular and non-erosive. Myositis may be seen, particularly in cases of mixed connective tissue disease

• Pleuropulmonary: Pleural effusion, pneumonitis, interstitial lung disease, shrinking lung syndrome, pulmonary hemorrhage, pulmonary embolus. Consider infection as a cause of pulmonary infiltrates in patients with SLE, particularly when immunocompromised

• Cardiovascular: Pericardial effusion, Libman–Sacks endocarditis, myocarditis, myocardial infarction

• Gastrointestinal: Hepatosplenomegaly, hepatitis, mesenteric vasculitis, pancreatitis, colitis. Esophageal dysmotility and reflux may be seen as part of mixed connective tissue disease

• Renal: Presentation of nephritis is variable and may cause hypertension and edema. It may be associated with interstitial nephritis and renal vein thrombosis

• Neurologic: Cognitive dysfunction, seizures, and psychosis are common. Also seen are severe headache, catatonia, chorea, ataxia, stroke (thrombotic or hemorrhagic), cranial nerve palsy, peripheral neuropathy, transverse myelitis. Neuropsychiatric testing may confirm cognitive impairment

• Hematologic: Anemia of chronic inflammation, autoimmune hemolytic anemia, microangiopathic hemolytic anemia, thrombocytopenia, and leukopenia (usually lymphopenia), secondary hemophagocytic lymphohistiocytosis, thrombosis (due to secondary antiphospholipid syndrome)

• Ocular: Retinal vasculitis, episcleritis, uveitis, optic neuritis, and sicca syndrome secondary to secondary Sjögren syndrome

• Endocrine: Autoimmune thyroid disease, short stature, delayed puberty, bone fragility

• Neonatal lupus: Congenital heart block, hepatitis, alloimmune cytopenias, erythema annulare

DIAGNOSTICS (TABLE 28-2)

Initial Evaluation

• CBC: Thrombocytopenia, anemia, leuko/lymphopenia. The following must be used to evaluate for the presence of autoimmune hemolytic anemia:

  • ✓ Peripheral smear: Schistocytes would suggest thrombotic microangiopathy rather than autoimmune hemolytic anemia

  • ✓ Reticulocyte count

  • ✓ Direct antiglobulin test (Coomb’s test)

  • ✓ LDH

  • ✓ Bilirubin

• Metabolic panel: Elevated creatinine, hypoalbuminemia suggests renal disease with proteinuria; may see hepatitis

• Urinalysis: Proteinuria, cellular casts suggests nephritis, gross hematuria suggests renal vein thrombosis

• Amylase/lipase if significant abdominal pain present

• Complement: Low CH50, C3, C4

• ANA profile: ANA rarely negative in an SLE patient

  • ✓ Anti-double stranded DNA is specific for SLE and suggests renal disease

  • ✓ Anti-Smith is SLE-specific

  • ✓ Anti-ribonuclear protein (RNP) is seen in SLE and in mixed connective tissue disease (high titer)

  • ✓ Anti-SCL 70 is seen in scleroderma and overlap syndromes

  • ✓ Anti-SSA and SSB are seen in Sjögren syndrome

  • ✓ Anti-Jo1 raises suspicion for interstitial lung disease in a variety of autoimmune disorders

• Antiphospholipid syndrome laboratory evaluation

  • ✓ Need an elevated functional lupus anticoagulant (PTT or dilute Russell viper venom time), anticardiolipin antibody or anti-β2-glycoprotein-1 antibody of IgG and/or IgM isotype on one or more occasions at least 12 weeks apart

  • ✓ Thrombosis (clinical or biopsy evidence) or recurrent fetal loss are required to fulfill criteria for antiphospholipid syndrome

• Renal biopsy if significant proteinuria (greater than 1g/24 hours or a urine protein/creatinine of greater than or equal to 1.0), hematuria, cellular casts, hypertension, or renal function impairment

  • ✓ Allows for characterization of nephritis and choice of therapy based on WHO classification

• Biopsy of skin rash if diagnostic precision required

• Arthrocentesis and culture if concerned about septic arthritis

• Blood culture if febrile. Patient may be functionally immunosuppressed secondary to hypocomplementemia and/or immunosuppressive medications

• Chest x-ray and PFTs if clinical concerns

• ECG and echocardiogram for baseline evaluation or if indicated clinically

• Brain imaging, EEG, and/or lumbar puncture may be required if focal CNS exam, severe headaches, psychiatric symptoms

  • ✓ In addition to routine CSF studies, CSF anti-neuronal antibodies, oligoclonal bands, and IgG synthesis rate are useful. Anti-neuronal antibodies have fair sensitivity and specificity for neuropsychiatric disease. In neuropsychiatric disease: oligoclonal bands may be positive (not specific) and IgG synthesis rate may be increased (evaluated using the IgG index: (CSF IgG/serum IgG)/(CSF albumin/serum albumin)

  • ✓ Serum anti-ribosomal P may be associated with psychosis

MANAGEMENT

Pharmacological Management

• Tailor to symptoms and balance benefits of therapy with adverse effects

• Corticosteroids: For ongoing disease activity

  • ✓ Initial dose is up to 2 mg/kg/day or 60–80 mg/day with a taper over 3–6 months, usually to maintenance dose or off as tolerated

  • ✓ Life- or organ-threatening disease: High dose (pulse) corticosteroids (30 mg/kg/day up to 1000 mg IV daily for 3 days)

• Cyclophosphamide: For severe organ-specific complications such as neuropsychiatric disease and proliferative glomerulonephritis

• Azathioprine or mycophenolate mofetil: For maintenance of renal remission or steroid sparing

• Rituximab (chimeric monoclonal antibody to CD20 on B cells): For severe, refractory disease or immune cytopenias

• Belimumab (human antibody targeting B cell activating factor): Recently approved for treatment, may be helpful in SLE patients in combination with standard therapy

• Methotrexate: For arthritis, refractory cutaneous disease, or immune thrombocytopenia

• IVIG: For immune thrombocytopenia or autoimmune hemolytic anemia

• Therapeutic apheresis: For severe, life-threatening disease such as thrombotic thrombocytopenic purpura or pulmonary hemorrhage

• NSAIDs: For arthralgia, arthritis, myalgia, serositis, headache. Use with care in individuals with renal disease

• Hydroxychloroquine (antimalarial): For dermatitis, constitutional symptoms, arthralgia, arthritis; regular ophthalmologic exams needed

• Topical or intralesional steroids: For skin lesions

• Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker: For hypertension and/or proteinuria

• Low-dose aspirin: For lupus anticoagulant or presence of antiphospholipid antibodies

• Anticoagulation: For thrombotic event (DVT, pulmonary embolus, arterial thrombus, recurrent fetal loss)

Health Maintenance

• Monitor serum cholesterol, LDL, HDL, and triglycerides

• Encourage regular exercise, weight loss, smoking cessation, and low-fat diet

• Calcium and vitamin D are recommended for patients on chronic corticosteroids. Regular DEXA scans to monitor bone density

• Obstetric/Gynecologic: Avoid estrogen-containing oral contraceptives particularly if antiphospholipid antibodies or lupus anticoagulant are present; awareness of neonatal lupus risk, particularly in patients positive for anti-Ro/SSA and anti-La/SSB

• Sun avoidance and protection (minimum SPF 30 with UVA/B protection)—this can flare the disease

• Avoid live vaccines if taking immunosuppressive medications

• Influenza and pneumococcal vaccination are recommended

• Specialized nursing, social work, physical and occupational therapy, psychology, and nutritional counseling