Rheumatology

I. Brief Overview of Clinical Characteristics of Rheumatologic Diseases

A. Juvenile Idiopathic Arthritis (JIA)1, 2, 3, 4

  1. 1. Most common rheumatologic condition in children
  2. 2. Classification criteria
    1. a. Arthritis of one or more joints defined as: joint swelling, limitation in range of motion, and/or tenderness
    2. b. Symptoms lasting at least 6 weeks
    3. c. Symptom onset less than 16 years of age
  3. 3. See Table 27.1 for information by JIA subtypes.5
  4. 4. Treatment varies based on JIA subtype, but can include:
    1. a. Nonspecific therapies: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), corticosteroids
    2. b. Disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, leflunomide, azathioprine
    3. c. Biologic agents, such as antitumor necrosis factor (anti-TNF), anti-interleukin 1 (IL-1), anti-interleukin 6 (IL-6), abatacept, and ustekinumab
  5. 5. Macrophage activation syndrome (MAS)6
    1. a. A severe disorder that develops in 7% to 17% of patients with systemic JIA
    2. b. Clinical features: Persistent fever, mental status changes, lymphadenopathy, hepatosplenomegaly
    3. c. Associated lab findings include severe and precipitous cytopenias with associated coagulopathies and hepatic dysfunction, marked hyperferritinemia with precipitous or paradoxical drop in erythrocyte sedimentation rate (ESR) and fibrinogen, elevated lactate dehydrogenase (LDH), and triglycerides, evidence of hemophagocytic macrophages in bone marrow or other tissue.
    4. d. MAS can also complicate other diseases, such as systemic lupus erythematosus and Kawasaki disease.
    5. e. First-line therapy includes pulse dose IV corticosteroids, IL-1 and IL-6 blockade. Cyclosporine A and Janus kinase (JAK) inhibitors can also be used in refractory disease.

B. Systemic Lupus Erythematosus (SLE)1,2,7, 8, 9, 10

  1. 1. Epidemiology
    1. a. 90% female, typically during reproductive years. However, F:M ratio closer to 5:1 for childhood onset disease
    2. b. Childhood onset accounts for up to 20% of cases
    3. c. Average age of onset: 12 years
    4. d. Higher prevalence in non-Caucasian individuals
  2. 2. Heterogeneous clinical manifestations. Patients with SLE may not fit all of the classification criteria. However, these classification criteria can be used to support a clinical diagnosis.
    1. a. American College of Rheumatology (ACR) criteria: Positive diagnosis requires at least four of the following:
      1. (1) Malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis (pleuritis or pericarditis), renal disorder (persistent proteinuria or cellular casts), neurologic disorder (seizures, psychosis), hematologic disorder (hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia), positive antinuclear antibody (ANA), other immunologic disorder (positive anti–double-stranded DNA [dsDNA], anti-Smith or antiphospholipid antibodies)
    2. b. Systemic Lupus International Collaborating Clinics (SLICC) criteria: Positive diagnosis requires four items (at least one clinical and one immunologic) OR biopsy-proven lupus nephritis with positive ANA or anti-dsDNA.
      1. (1) Clinical: Acute cutaneous, chronic cutaneous, oral ulcers, alopecia, synovitis, serositis, renal disorder, neurologic disorder, hemolytic anemia, leukopenia, thrombocytopenia
      2. (2) Positive immunologic testing: ANA, anti-dsDNA, anti-Smith, antiphospholipid, low C3/C4 complements or CH50, direct Coombs test in the absence of hemolytic anemia
  3. 3. Other clinical symptoms: Unexplained recurrent fever, weight loss, fatigue, anorexia, myalgia, arthralgia
  4. 4. Common autoantibodies
    1. a. ANAs are present in >99% of children with SLE.
    2. b. anti-dsDNA and anti-Smith are highly specific for SLE.
    3. c. anti-Ro (SSA) and anti-La (SSB) can be seen in SLE and can be associated with Sjögren syndrome and neonatal lupus (see Neonatal SLE).
  5. 5. Renal involvement
    1. a. 20% to 75% of children under 18 years will have renal involvement.
    2. b. 18% to 50% progress to end-stage kidney disease.
    3. c. Kidney biopsy can be helpful for both disease management and prognostication.
  6. 6. Treatment varies depending on disease severity and end-organ system involvement.
    1. a. NSAIDs
    2. b. Corticosteroids
    3. c. Hydroxychloroquine
    4. d. Methotrexate
    5. e. Azathioprine
    6. f. Leflunomide
    7. g. Cyclophosphamide
    8. h. Mycophenolate mofetil
    9. i. Biologics such as rituximab and belimumab
    10. j. Adjunctive therapy with antihypertensives and renoprotective agents

C. Drug-Induced SLE11

  1. 1. Some inciting drugs include: hydralazine, minocycline, procainamide, quinidine, isoniazid, interferon-alfa, chlorpromazine, ethosuximide, carbamazepine, anti-TNF therapy.
  2. 2. Usually with milder disease than idiopathic SLE
  3. 3. Presenting symptoms: Arthralgias, myalgias, fever, weight loss, serositis, polyarthritis
  4. 4. Rarely involves renal disorders and neuropsychiatric symptoms
  5. 5. More common lab findings: Positive ANA, anti-histone, anti-dsDNA
  6. 6. Treatment involves removal of the offending agent and, for severe disease, can include short-term immunosuppressive therapies.

D. Neonatal SLE12, 13, 14

  1. 1. Neonates born to mothers with positive anti-Ro (anti-SSA) or anti-La (anti-SSB) can develop a transient lupus-like syndrome due to transplacental passage of these autoantibodies.
  2. 2. Frequently, the mothers are healthy and do not have known autoimmune disease. The mothers may have isolated positive anti-Ro or anti-La, primary Sjögren syndrome, or SLE.
  3. 3. Clinical features in the neonate include: rash (annular erythema on eyelids and scalp, papular or plaque-like lesions), hepatomegaly, thrombocytopenia, hemolytic anemia, congenital atrioventricular heart block (1st, 2nd, or 3rd degree), and hydrops fetalis.
  4. 4. Neonates with heart block may require permanent pacemaker and are at continued risk for cardiac dysfunction later in life.
  5. 5. Other inflammatory features in the neonate resolve as maternal autoantibodies are cleared. Often within 6 months
  6. 6. Treatment for neonatal lupus is dependent on presenting symptoms and cardiac involvement.
  7. 7. Treatment may include steroids, cardiac pacing, and IVIG.

E. Vasculitis1,2,15,16

  1. 1. Refer to Table 27.2.
  2. 2. Treatment
    1. a. Note that treatment recommendations are largely based on adult studies because of limited clinical trials in pediatric patients.
    2. b. Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative first-line treatment recommendations for most severe vasculitis may include corticosteroids, cyclophosphamide, and/or plasma exchange. Rituximab may also be used.
      1. (1) In Table 27.2, this is referred to as “first-line vasculitis therapy.”

F. Sarcoidosis2,26,27

  1. 1. Epidemiology
    1. a. Prepubertal: Very rare
    2. b. During puberty and postpuberty: Peak onset at 13 to 15 years; males and females are equally affected
  2. 2. Multisystem, infiltrative, noncaseating granulomatous disease of unknown etiology; lung is the most commonly involved organ
    1. a. Pulmonary: Bilateral hilar adenopathy, restrictive and obstructive disease
    2. b. Ocular: Anterior uveitis, conjunctival granulomas
    3. c. Cutaneous: Erythema nodosum, plaques, alopecia
    4. d. CNS: Bilateral or unilateral Bell palsy (more common in postpubertal children, seizures (more common in prepubertal children), aseptic meningitis
  3. 3. Definitive diagnosis with lymph node biopsy; elevated angiotensin-converting enzyme (ACE) levels can be helpful but not diagnostic
  4. 4. Blau syndrome and early-onset sarcoidosis are two monogenic forms of sarcoidosis characterized by polyarthritis, uveitis, and dermatitis; symptom onset <4 years
  5. 5. Systemic immune suppression is often needed for treatment.

G. Scleroderma2,28

  1. 1. Both juvenile localized scleroderma and juvenile systemic sclerosis typically present in mid-childhood between 6 and 11 years of age, with a female predominance
  2. 2. In children, localized scleroderma is more common than systemic sclerosis and involves skin, muscle, and bone.
  3. 3. Treatment of localized scleroderma includes topical and systemic therapies such as corticosteroids, methotrexate, tacrolimus, imiquimod, and phototherapy.
  4. 4. Systemic sclerosis: Diffuse and limited disease; diffuse disease characterized by severe Raynaud syndrome, resulting in digital ulcers, pulmonary arterial hypertension (PAH), pulmonary fibrosis, esophageal dysmotility, renal disease
  5. 5. Treatment of systemic sclerosis involves management of the symptoms and underlying systemic inflammation.
    1. a. Raynaud syndrome: Nifedipine or PDE-5 inhibitors
    2. b. PAH: Endothelin receptor antagonist, PDE-5 inhibitors, riociguat, epoprostenol
    3. c. Skin and lung disease: Methotrexate, cyclophosphamide, and biologic therapy
    4. d. GI disease: Proton pump inhibitors, prokinetic medications
    5. e. Renal disease: ACE inhibitors

H. Sjögren Syndrome2,29

  1. 1. Female-to-male ratio 5:1 in children, age of onset 7 to 14 years old
  2. 2. Widespread lymphocytic infiltration of salivary and lacrimal glands with secondary atrophy and obliteration of secretory acini
  3. 3. Keratoconjunctivitis sicca: Dry eyes secondary to decreased tear production by lacrimal glands
  4. 4. Xerostomia: Dry mouth from decreased salivary gland production
  5. 5. May present as parotid gland swelling in children
  6. 6. Other possible system involvement: MSK, pulmonary, neurologic, renal
  7. 7. Treatment focuses mostly on symptomatic relief and management of chronic glandular changes.
    1. a. Keratoconjunctivitis sicca: Artificial tears
    2. b. Xerostomia: Sugar-free hard candies or chewing gum
    3. c. Systemic immune modulation and suppressing medications such as hydroxychloroquine, corticosteroids, methotrexate, and biologic therapy

I. Juvenile Dermatomyositis (JDM)2,30

  1. 1. More common in females (up to 2.5:1 female:male)
  2. 2. Median age of onset: 7 years old
  3. 3. Typically symmetric muscle weakness, involves more central musculature
  4. 4. Cutaneous findings: Gottron papules overlying knuckles and knees (91%), heliotrope rash (83%), malar rash (42%)
  5. 5. Treatment options depend on disease severity and prognosis and include the use of systemic immune modulation and suppressing medications such as intravenous immunoglobulins (IVIG), hydroxychloroquine, corticosteroids, methotrexate, mycophenolate mofetil, and biologic agents.

J. Other Rheumatologic Disorders2,31,32

  1. 1. Reactive arthritis
    1. a. Sterile inflammatory arthritis in response to a preceding (<4 weeks) bacterial infection, particularly of the gastrointestinal or genitourinary tracts
    2. b. Common triggers: Salmonella, Yersinia, Campylobacter, Shigella, Chlamydia trachomatis
    3. c. Involves acute asymmetrical oligoarticular arthritis of larger joints, often the lower extremities
    4. d. Can be associated with fever, weight loss, fatigue, tendinitis, bursitis, anterior uveitis, conjunctivitis, erythema nodosum, urethritis, and cervicitis
    5. e. Therapies include treatment of the precipitating infection, if needed, and supportive care for arthritis symptoms with NSAIDs. Can consider intraarticular or systemic steroids for NSAID-refractory arthritis
  2. 2. Reactive arthritis after a streptococcal infection
    1. a. Acute rheumatic fever (ARF)
      1. (1) Clinical features: Arthritis, carditis, erythema marginatum, nodules, Sydenham chorea
      2. (2) Pathogenesis: M protein from Group A Streptococcus induces production of autoimmune antibodies that are cross-reactive.
      3. (3) Typically occurs 2 to 3 weeks after tonsillopharyngitis infection
      4. (4) Treatment: Arthritis is responsive to NSAIDs, transient, and migratory.
        1. (a) Poststreptococcal reactive arthritis
          1. (i) Does not meet diagnostic criteria for ARF
          2. (ii) Typically occurs sooner after streptococcal infection (7–10 days)
          3. (iii) Can involve large and small joints and axial skeleton
          4. (iv) Arthritis is less responsive to NSAIDs, persistent, and additive.
          5. (v) Cardiac involvement is less common but can occur.

K. Multisystem Inflammatory Syndrome in Children (MIS-C)33, 34, 35

  1. 1. Emergence of MIS-C co-occurred with the 2019 SARS-CoV-2 pandemic. MIS-C is a postinfectious inflammatory syndrome after symptomatic or asymptomatic infection with the SARS-CoV-2 virus.
  2. 2. It is a rare complication of SAR-CoV-2 virus infection.
  3. 3. Case Definition for MIS-C was derived by the Centers for Disease Control and Prevention (CDC):
    • An individual aged <21 years who presents with fever (>38.0° C for >24 hours, or subjective fever lasting >24 hours), laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization affecting multiple organ systems (>2) AND without other plausible diagnosis AND positive for current or recent SARS-CoV-2 infection by reverse transcription polymerase chain reaction, serology, or antigen test or confirmed COVID-19 case within 4 weeks of onset of symptoms
  4. 4. Common clinical features include: fever, mucocutaneous lesions, conjunctivitis, mucositis, peripheral edema, lymphadenopathy, diarrhea, vomiting, abdominal pain, coronary artery aneurysm, myocarditis and cardiac dysfunction, altered mental status, seizures, focal neurologic deficits, respiratory failure, hypotension, and shock. Some develop acute renal failure and pancreatitis.
  5. 5. Common laboratory findings: Evidence of systemic inflammation including cytopenia, elevated ESR, C-reactive protein (CRP), elevated ferritin, coagulopathy with prolonged PTT/PT, and elevated d-dimer. Evidence of cardiac involvement with elevated pro-BNP and troponin
  6. 6. MIS-C can be complicated by macrophage activation syndrome (see section on Juvenile Idiopathic Arthritis).
  7. 7. The American College of Rheumatology provides continued guidance on evaluation and management of MIS-C.
    1. a. Suggested workup includes: complete blood count (CBC), comprehensive metabolic panel (CMP), PTT, PT, INR, CRP, ESR, ferritin, fibrinogen, d-dimer, troponin, Pro-BNP, EKG, echocardiogram.
    2. b. Evaluation for infectious and noninfectious causes during workup for MIS-C is recommended.
    3. c. Treatment includes: IVIG, systemic steroids, biologic therapy with agents such as anakinra (IL-1 blockade), or TNF inhibition with infliximab.
    4. d. Adjunctive therapies include: antiplatelet and anticoagulation with aspirin, enoxaparin, or warfarin for coronary artery involvement. Anticoagulation in patient with MIS-C and coronary artery aneurysms may be guided by the American Heart Association recommendations for Kawasaki disease (see Chapter 7 for a full discussion of cardiac involvement in MIS-C and Kawasaki disease). MIS-C patients with thrombosis should be on anticoagulation (low-dose aspirin and therapeutic) for 3 months or depending on resolution of thrombi on imaging at 4 to 6 weeks postdiagnosis.
  8. 8. Treatment teams should include input from Rheumatology, Cardiology, Infectious Disease, and Hematology, and if other organ systems involved, may also include: Nephrology, Neurology, Gastroenterology/Hepatology.

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