7: Selected topics in pediatric rheumatology

Selected Topics in Pediatric Rheumatology


Sampath Prahalad, Sheila Angeles-Han, Kelly A. Rouster-Stevens, Larry Vogler


Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, USA


Introduction


Rheumatic diseases in pediatric populations require special considerations. While some features are similar in adult populations, others such as the juvenile idiopathic arthritides have different classification criteria and approaches to diagnosis. Manifestations in young patients have unique features as well as pediatric-specific treatment considerations. This chapter will review considerations in juvenile idiopathic arthritis, pediatric systemic lupus erythematosus, juvenile dermatomyositis, and the childhood vasculitides.


Juvenile Idiopathic Arthritis (JIA)



  • Juvenile idiopathic arthritis refers to a collection of chronic arthropathies in children
  • Several clinically and genetically distinct subtypes are recognized
  • While the pathophysiology of JIA is complex, both genetic and environmental factors are believed to play a role in the susceptibility to JIA

    • JIA is a heterogeneous collection of chronic arthritis in children
    • All subtypes of JIA have in common arthritis in one or more joints for at least 6 weeks in a child under the age of 16 years
    • Different subtypes of JIA have different clinical features, genetic associations, comorbidities, and outcomes

Epidemiology



  • JIA is the most common childhood rheumatic disease encountered in pediatric rheumatology clinics
  • The incidence of JIA is 1 in 10,000 children; prevalence is approximately 1 in 1000 children under 16 years
  • Most subtypes of JIA are more common in girls than in boys

Classification and Diagnosis



  • JIA is a heterogeneous disease with several subtypes
  • Historically the terms juvenile rheumatoid arthritis (JRA) and juvenile chronic arthritis (JCA) have been used to describe and classify chronic arthritis in childhood

    • Each of these classifications included different subtypes, which resulted in difficulties in comparing studies from Europe and the US
    • Consequently the International League of Associations for Rheumatology (ILAR) criteria were developed which are comprehensive and more uniform

  • The American College of Rheumatology Criteria defined juvenile rheumatoid arthritis (JRA) as arthritis in one or more joints for at least 6 weeks in a child under 16 years

    • Pauciarticular JRA is arthritis in four or fewer joints in the first 6 months of disease
    • Polyarticular JRA is arthritis in five or more joints in the first 6 months of disease
    • Systemic JRA is daily (quotidian) fever spiking to more than 39 °C for at least 2 weeks in association with arthritis in one or more joints

  • The European League Against Rheumatism (EULAR) criteria recognized juvenile chronic arthritis (JCA) as arthritis in one or more joints for at least 3 months in a child under 16 years

    • Systemic JCA is arthritis with characteristic fever
    • Polyarticular JCA is arthritis in more than four joints with negative rheumatoid factor
    • Juvenile rheumatoid arthritis is arthritis in more than four joints with positive rheumatoid factor
    • Pauciarticular JCA is arthritis in fewer than five joints
    • Juvenile ankylosing spondylitis is the presence of features of ankylosing spondylitis in a child younger than 16 years
    • Juvenile psoriatic arthritis is the presence or psoriatic arthritis in a child younger than 16 years

  • The International League of Associations for Rheumatology (ILAR) criteria form the most current classification system for JIA

    • The ILAR criteria define JIA as arthritis in one or more joints for at least 6 weeks in a child under 16 years
    • The ILAR criteria specified exclusion criteria to define homogeneous, mutually exclusive subtypes of JIA as follows:

      • Psoriasis or a history of psoriasis in the patient or first-degree relative
      • Arthritis in an HLA-B27 positive male after the 6th birthday
      • Ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome or acute anterior uveitis, or a history of one of these disorders in a first-degree relative
      • The presence of IgM rheumatoid factor on at least two occasions at least 3 months apart
      • The presence of systemic JIA

    • The ILAR criteria classify JIA into seven subtypes:

      • In systemic JIA there is arthritis in one or more joints with fever of at least 2 weeks’ duration accompanied by one of the following: evanescent rash, serositis, lymphadenopathy or hepatosplenomegaly

        • Exclusions: a, b, c, d
        • Systemic JIA affects boys and girls equally
        • Systemic JIA makes up 4–17% of all JIA

      • Oligoarticular JIA affects one to four joints during the first 6 months of disease

        • Exclusions: a, b, c, d, e
        • Two subcategories are recognized

          • Persistent oligoarthritis affects up to four joints throughout the course of the disease
          • Extended oligoarthritis affects more than four joints after the first 6 months of disease

        • Oligoarticular JIA affects girls more often than boys
        • It is the most common subtype of JIA, 27–56% of all JIA
        • Onset is typically in early childhood, peak 2–4 years

      • Polyarthritis (rheumatoid factor (RF)-negative) presents with arthritis affecting five or more joints during the first 6 months of disease

        • Exclusions: a, b, c, d, e
        • A test for RF is negative
        • RF-negative polyarticular JIA affects girls more often than boys
        • It is the second most common subtype of JIA, 11–28% of all JIA
        • Onset is biphasic, early peak at 2–4 and later peak at 6–12 years
        • Uveitis can be seen with this subtype as well

      • Polyarthritis (RF positive) affects five or more joints during the first 6 months of disease

        • Exclusions: a, c, d, e
        • This is typically seen in older children and teens
        • It is much more common among females
        • Two or more tests for RF at least 3 months apart during the first 6 months of disease are positive
        • Most children are also positive for anti-CCP antibodies
        • This subtype makes up ∼2–7% of all JIA
        • It can be associated with rheumatoid nodules
        • This subtype has the potential for aggressive disease and poor outcome
        • Uveitis is rare with this subtype

      • Psoriatic arthritis is arthritis and psoriasis, or arthritis and at least two of the following:




          • Dactylitis
          • Nail pitting
          • Onycholysis
          • Family history of psoriasis (in a first-degree relative)

        • Exclusions: b, c, d, e
        • This subtype makes up 2–11% of all JIA

      • Enthesitis-related arthritis (ERA) is diagnosed if there is arthritis and/or enthesitis with at least two of the following:




          • Presence of or history of sacroiliac joint tenderness with or without inflammatory lumbosacral pain
          • Presence of HLA-B27 antigen
          • Onset of arthritis in a male over 6 years of age
          • Acute (symptomatic) anterior uveitis
          • History of ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, or acute anterior uveitis in a first-degree relative

        • Exclusions: a, d, e
        • This subtype affects boys much more than girls
        • This subtype is associated with acute, painful uveitis
        • ERA makes up 3–11% of all JIA, and typically presents in late childhood or adolescence

      • Undifferentiated arthritis is arthritis that does not fulfill criteria in any of the above categories or that fulfills criteria for two or more of the above categories

        • About 11–21% of children in various series have been reported to have undifferentiated JIA

Comorbid Conditions



  • Chronic anterior uveitis

    • Chronic anterior uveitis is seen in about 10–20% of children with JIA
    • Onset is insidious and often asymptomatic
    • Risk of chronic anterior uveitis is higher in those children with positive ANA, and younger age of onset, and in the first 4 years of disease
    • Children with JIA are advised to undergo regular slit lamp examinations by an ophthalmologist to detect and treat uveitis promptly
    • Untreated uveitis can lead to irregular pupils, glaucoma, cataracts, and vision loss
    • The risk of chronic anterior uveitis is highest among those children with oligoarticular and JIA, affecting up to 30% of patients
    • Children with RF-negative polyarthritis and psoriatic arthritis are also at risk of chronic anterior uveitis, especially if they are ANA positive
    • Children with systemic JIA seldom develop uveitis
    • Treatment includes topical steroids initially, and, for refractory disease, systemic medications are used

  • Acute uveitis

    • In contrast to children with chronic anterior uveitis, children with acute uveitis tend to be symptomatic
    • It presents typically with eye pain, photophobia, redness
    • Unless promptly seen by an ophthalmologist, symptoms are often attributed to foreign body, infection or allergy
    • It is usually unilateral and often recurrent
    • Typically uveitis resolves without leaving sequelae
    • Visual prognosis is typically excellent
    • In a large series, 7.8% of children with ERA had acute uveitis

  • Macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH)

    • This is a rare and potentially lethal condition
    • Up to 7% of children with systemic JIA may develop MAS/HLH over the course of their illness
    • MAS often follows an infection, particularly by members of the herpesvirus family such as Epstein Barr virus
    • Clinically characterized by rapid development of an unremitting fever, hepatosplenomegaly, lymphadenopathy, hepatic dysfunction, encephalopathy, purpura, bruising, and mucosal bleeding
    • More severely affected children can develop multi-organ failure
    • Laboratory features include the following

      • Leukopenia
      • Thrombocytopenia
      • Anemia
      • A sudden and paradoxical drop in erythrocyte sedimentation rate (ESR), with an elevated C-reactive protein (CRP)
      • Abnormal prothrombin time (PT), partial thromboplastin time (PTT)
      • Elevated fibrin degradation products and fall in fibrinogen
      • Elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
      • Significant elevation of ferritin and soluble IL2 receptor levels

    • Demonstration of prominent phagocytosis of other hematopoietic cells by macrophages in the bone marrow, lymph nodes, liver, or spleen is diagnostic
    • Treatment includes high-dose intravenous steroids and cyclosporine
    • Cases refractory to treatment or severe presentations should prompt treatment according to the HLH protocol with corticosteroids, cyclosporine, and etoposide

  • Long-term sequelae: children who have a delayed diagnosis or have poorly controlled JIA are at risk for some long-term sequelae

    • Leg length disturbances

      • Typically seen in children with asymmetric oligoarticular JIA with unilateral knee involvement
      • The affected limb tends to be longer due to hyperemia
      • This requires shoe-lift or orthotics to correct gait abnormalities

    • Micrognathia

      • Children with JIA who have disease of the temporomandibular joints are at risk for micrognathia

    • Cervical spine fusion

      • Children with involvement of cervical spine joints can develop fusion of the posterior elements of the cervical spine
      • This results in decreased range of motion of the neck, and a potential for cervical spine subluxation with hyperextension of the neck such as during anesthesia

    • Erosions

      • Poorly controlled or active arthritis can result in cartilage loss, which presents as joint space narrowing on radiographs, and later bony erosions
      • This can cause pain and disability

    • Growth retardation

      • Although rare, long standing active arthritis, in particular systemic JIA, can result in growth delays and retardation

Laboratory Tests in JIA



  • Anti-nuclear antibodies (ANA)

    • ANA may be positive in ∼60% of children with JIA
    • ANA tend to be higher among children with oligoarticular JIA and RF-negative polyarticular JIA
    • ANA are rare among children with systemic JIA or ERA
    • Positive ANA are associated with a higher risk for chronic anterior uveitis
    • Most often the ANA, when positive, are of low to moderate titer
    • Tests for Smith, RNP, SSA, SSB, and ds-DNA are typically negative
    • ANA-positive JIA patients have been reported to constitute a homogeneous population despite differences in ILAR-recognized subtypes

  • Rheumatoid factor (RF)

    • Children with RF-positive polyarticular JIA by definition have positive tests for IgM-RF
    • The ILAR criteria require the presence of two positive tests for RF in the first 6 months, at least 3 months apart
    • Positive RF is associated with potential for poor outcome
    • False-positive IgM-RF can be seen with infections, but these typically resolve; hence the requirement for two positive RF tests

  • Anti-citrullinated peptide antibodies (ACPA)

    • Antibodies to citrullinated peptide antibodies are highly specific for adult-seropositive RA
    • The most widely available commercial test assays for antibodies to cyclic citrullinated peptides (CCP)
    • Most children with RF-positive JIA are also positive for anti-CCP antibodies
    • Anti-CCP antibodies may appear prior to clinical manifestation of inflammatory arthritis

  • HLA-B27

    • HLA-B27 is a polymorphic form of the gene encoding human leukocyte antigen class I molecule – HLA B
    • HLA-B27 is associated with ankylosing spondylitis or spondyloarthropathy
    • A positive test for HLA-B27 is observed in ∼7% of white northern European population in the US
    • The frequency of HLA-B27 is lower among African and African-American individuals
    • A positive HLA-B27 is found in 80–90% of children with enthesitis-related arthritis

  • Complete blood count (CBC)

    • CBC is often obtained as a baseline lab test in children with JIA
    • With oligoarticular JIA and many children with RF-negative polyarticular JIA, CBC is often normal
    • Children with systemic JIA typically present with leukocytosis, thrombocytopenia, and anemia
    • Children with ERA might have anemia

  • Comprehensive metabolic panel (CMP)

    • CMP is also obtained as a baseline lab test in children with JIA
    • Children with systemic JIA may have hypoalbuminemia
    • Most children with JIA do not have abnormal CMP
    • Since there can be alterations of AST and ALT with some of the medications used to treat JIA, a baseline evaluation is recommended
    • Elevated AST and ALT in systemic JIA could indicate macrophage activation syndrome

Treatment



  • Non-steroidal anti inflammatory drugs (NSAIDs)

    • NSAIDs are often the first line of treatment of JIA
    • Ibuprofen is used at a dose of 30 mg/kg/day in three divided doses
    • Naproxen is one of the commonly used NSAIDs at doses of 15–20 mg/kg/day in two divided doses with a maximum of 500 mg BID
    • Meloxicam can also be used as a single daily dose at 0.25 mg/kg/day with a maximum of 15 mg daily
    • Other agents used are nabumetone (30 mg/kg/day in one to two doses; maximum 2000 mg/day) and indocin (1.5–3 mg/kg/day; maxi­mum 200 mg/day)
    • Celecoxib is a COX-2 inhibitor that can also be used in some children intolerant to the other NSAID agents
    • All NSAIDs can cause gastritis, so it is recommended that they be taken with food, and if indicated be used with H2-receptor blockers or proton pump inhibitors
    • NSAIDs can also case acute renal papillary necrosis, which can present with hematuria
    • Naproxen can cause pseudoporphyria and increased skin fragility, especially in fair-skinned individuals

  • Steroids

    • Steroids are often used as bridge agents to achieve short-term disease control
    • They are most useful in the setting of systemic JIA
    • For serositis or MAS, intravenous steroids are indicated
    • Low-dose steroids may also have a role in polyarticular JIA, especially with positive RF
    • Steroids have many side effects with prolonged usage including notably weight gain, osteoporosis, hypertension, hyperglycemia, cataracts, striae
    • Prednisone is often used at doses ranging from 0.5–2 mg/kg/day
    • For children with oligoarticular JIA, and for some children with other types of JIA, intra-articular injection of steroids is a very effective form of treatment
    • The most commonly employed agent is triamcinolone hexacetonide which has a long half-life
    • Children with uveitis/iritis typically are treated with topical ster­oid drops, and in some instances intra-ocular depot steroid prep­arations

  • Methotrexate

    • Methotrexate is the preferred agent employed as a disease-modifying antirheumatic drug (DMARD)
    • It is indicated in polyarticular JIA, systemic JIA with predominantly articular features, extended oligoarticular JIA, and in persistent oligoarticular JIA with poor response to NSAIDs and/or intra-articular steroids
    • It is available as tablets for oral form or injection for parenteral use, typically administered subcutaneously
    • The usual starting dose of 0.5 mg/kg given once weekly, and increased as tolerated to 1 mg/kg/week; we recommend using up to a maximum of 25 mg/wk in most children
    • Beyond 20 mg/week, most clinicians prefer to use it subcutaneously
    • Adverse effects

      • Most children tolerate methotrexate without problems
      • In some children methotrexate can cause nausea which can occur from just before the dose up to 24–48 hours after the dose.
      • Methotrexate can also cause oral mucosal ulcers (mucositis) at higher doses

        • Folic acid given daily at 1 mg can minimize oral ulcers

      • Methotrexate can also cause elevations in AST and ALT, as well as leukopenia

    • The ACR recommends CBC, CMP prior to initiating methotrexate, 1–2 months after starting or after dose change, and every 2–3 months on stable doses
    • Methotrexate is potentially teratogenic and female patients taking this drug should be counseled against getting pregnant while on it

  • Leflunomide

    • Leflunomide is an immunomodulatory agent that inhibits pyrimidine synthesis
    • It is considered for patients who do not tolerate methotrexate
    • Usually administered with a loading dose, followed by every day or every other day dosing depending on the weight of the child
    • Improvement should be notable by 6–12 weeks
    • CBC, WBC count, differential, platelet count, AST, ALT, and albumin should be monitored every 4–12 weeks
    • Leflunomide is teratogenic

      • It has a long half-life, and it has been recommended that cholestyramine be administered and drug levels be verified to be less than 0.02 mg/L on at least two occasions, 2 weeks apart in individuals wishing to conceive

  • Biological response modifiers

    • TNF inhibitors

      • Tumor necrosis factor (TNF-α) is a pro-inflammatory cytokine found in elevated levels in individuals with JIA and RA as well as other inflammatory disorders
      • Biological agents that antagonize TNF-α have been shown to be effective in the treatment of JIA
      • Currently two anti-TNF agents are approved for use in JIA

        • Etanercept is given once or twice weekly subcutaneously at 0.8 mg/kg/week
        • Adalimumab is given once every other week subcutaneously at 0.4 mL (20 mg) for children <30 kg and 0.8 mL (40 mg) for children >30 kg
        • In addition, infliximab is also used by many clinicians, given as intravenous infusions at doses 3–10 mg/kg given every 4–8 weeks
        • Other anti-TNF agents approved for use in adults with RA are being investigated in children at this time

      • All TNF inhibitors have potential to increase susceptibility to serious infections including mycobacterial and fungal infections
      • A test for tuberculosis (PPD or Quantiferon gold) is recommended prior to initiating anti-TNF therapy and annual screening for TB is recommended
      • Children with serious infections are advised to hold TNF inhibitors until their primary infection has been adequately treated
      • Most children tolerate anti-TNF agents well; some develop injection site or infusion reactions

    • Tocilizumab

      • Tocilizumab is a monoclonal antibody directed against IL-6, which is a potent proinflammatory cytokine
      • Tocilizumab has been approved for the treatment of systemic JIA and polyarticular JIA
      • It is given as an intravenous infusion every 2 weeks for systemic JIA and every 4 weeks for polyarticular JIA
      • The dose is 8 mg/kg/dose, and for children less than 30 kg, the dose is 12 mg/kg/dose
      • Major adverse events include infusion reactions, cyto­penias, increased liver transaminases, and hyper­cholesterolemia
      • Tocilizumab can be given with methotrexate
      • Tocilizumab is also effective in treating adult RA

    • Anakinra

      • Anakinra is a human recombinant form of IL-1 receptor antagonist produced by recombinant technology in Escherichia coli
      • Anakinra has shown improvement in features of JIA compared to placebo, although the improvements were not as dramatic as with TNF inhibitors
      • Anakinra appears to be particularly effective in the treatment of systemic JIA especially in children with predominantly systemic features
      • The commonly used dose for anakinra is 1 mg/kg increased to 2 mg/kg (maximum of 100 mg)
      • Side effects include injection site reactions and increased susceptibility to infections
      • Although not associated with reactivation of latent TB, docu­menting a negative PPD before initiating treatment is rec­om­mended
      • Improvement is often seen with within 2 weeks
      • Neutrophil count should be monitored at baseline, monthly for 3 months and then quarterly

    • Abatacept

      • Abatacept is a fully human, soluble fusion protein which prevents a co-stimulatory signal necessary for T cell activation
      • It binds to CD80 and CD86, thereby blocking interaction with CD28, which results in downregulation of the antigen presenting cell–T lymphocyte interaction
      • It is available as an infusion which has a pediatric indication for JIA
      • Recently a subcutaneous formulation of abatacept has been marketed
      • Most common side effects are headaches, upper respiratory tract infections, nasopharyngitis, and nausea
      • Dose: for patients less than 75 kg, the dose is 10 mg/kg IV, 75–100 kg dose is 750 mg IV, and >100 kg: 1000 mg
      • It is given intravenously over 30 minutes on week 0, 2, 4, and every 4 weeks
      • Abatacept is generally effective and well tolerated
      • Abatacept also showed efficacy in a trial of subjects that failed previous biological therapy
      • Can be administered with methotrexate

    • Rituximab

      • Rituximab is a chimeric monoclonal mouse–human antibody targeting the CD20 receptor on mature B cells and pre B cells, but not stem cells of plasma cells
      • Rituximab exerts its effects by removing B cells from circulation and is theoretically beneficial in diseases where autoantibodies may be pathogenically important
      • It is indicated for adults with RA
      • It is commonly used for children with RF-positive polyarticular JIA who are refractory to treatment with other agents
      • The dose is 375–500 mg/m2 (maximum 1000 mg) intravenously at weeks 0 and 2, 50 mg/hr initially
      • Premedication with methylprednisolone, antihistamine, and acetaminophen is recommended
      • Adverse effects include infusion reactions, and progressive multifocal leukencephalopathy
      • Improvement should be seen within 1 month of first infusion
      • B cell counts should be checked before and 1 month after infusion
      • Quantitative immunoglobulins should be checked every 3 months

Prognosis



  • Most studies that have evaluated long term outcomes of JIA done in the pre-biologic era
  • Persistent oligoarticular JIA has generally the best outcome, with up to 50% of children achieving long-term remission, and <5% with moderate to severe limitation of function
  • One third of those with oligoarticular JIA have an extended course over time
  • Systemic JIA and RF-positive polyarticular JIA often have the worst prognosis, with up to 20% reporting moderate to severe limitation of function
  • Fewer than 10% of children with RF-positive JIA achieve long-term remission
  • It is unusual for children with JIA diagnosed in the recent years to end up in wheelchairs or need to use crutches for the most part
  • With more aggressive therapy, use of DMARDs earlier, and the use of biological response modifiers, the long-term outcome is anticipated to improve for the next generation of children with JIA

Pediatric Systemic lupus Erythematosus (pSLE)


Epidemiology



  • pSLE is the second most common disease encountered in pediatric rheumatology clinics, while JIA is the most common
  • The incidence rates for pSLE range from 0.36–2.5 per 100,000 children-years
  • There is wide variation in prevalence of pSLE in the literature, ranging from 1.89–25.7 per 100,000 children
  • Females are affected more than males

    • In younger children the female-to-male ratio is approximately 4:3
    • During the second decade of life the female-to-male ratio is 4:1

Diagnosis



  • The American College of Rheumatology classification criteria are useful in pSLE, although they are not diagnostic criteria and are validated only in adults
  • Pediatric patients often present with constitutional symptoms, including fever, weight loss, and malaise
  • Prepubertal children present more often with renal disease and hemolytic anemia, while postpubertal patients present with musculoskeletal and cutaneous features
  • At least half of patients with pSLE have hematologic involvement at presentation
  • Similar to adults, pSLE is associated with anti-dsDNA, anti-Smith, anti-RNP, anti-SSA(Ro), and anti-SSB(La)

Disease Course



  • Over time patients with pSLE have more active disease compared to adults
  • Studies have suggested that pSLE compared to adults is:

    • More often associated with renal disease, encephalopathy, chilblains, cutaneous vasculitis, malar rash, hemolytic anemia, leukopenia
    • Less often associated with discoid rash, arthalgias, myalgias, and sicca symptoms

      • <5% of isolated discoid lupus are encountered in patients under 15 years

  • Race, ethnicity, and environmental influences are likely related to variations in disease expression over time
  • Table 7.1 shows comparison of organ involvement in pSLE and adult SLE










































Organ/tissue pSLE Adult SLE
Musculoskeletal Trend toward more overt arthritis (non-erosive) and tenosynovitis
More than 90% of children who develop arthritis have presentation of joint symptoms within first year of disease
40% of children have osteopenia (defined as a Z score ≤-1)
6–10% of children have fractures related to osteopenia		 Myalgias more common
Jaccoud arthropathy
Drug-induced myopathy
Among premenopausal adult women, 40% have osteopenia and 5% have osteoporosis
Mucocutaneous Malar rash more frequent
60–80% of children have skin involvement at diagnosis
Raynaud phenomenon is seen in 15–20% of children		 Photosensitivity and discoid lesions more frequent
Subacute cutaneous lupus more common
Raynaud phenomenon is seen in 20–40% of adults
Renal Lupus nephritis (LN) often presenting feature
Up to 70% of children develop LN
Approximately 40% of children with LN develop hypertension
Proteinuria and urinary sediment abnormalities more common
5–10% of children with proliferative LN progress to end-stage renal disease within 5–10 years		 LN affects 30–50% of adults
Studies vary on renal survival rates in adults, depending on WHO class, race, presence of hypertension, and age at onset, 5 year renal survival rate ranges from 50–95%
Neuropsychiatric (NPSLE) Large variation in reports of children affected with NPSLE, but occurence at least as common as in adults
Within the 1st year of diagnosis, 70% of children develop NPSLE features
Most common mood disorder is depression
Cerebrovascular disease has been reported in up to 25% of pediatric patients
Cerebral vein thrombosis occurs in 15–25% of children, particularly lupus anticoagulant-positive patients
More children develop encephalopathy
Standardized assessments are being developed and validated in children		 Cranial nerve abnormalities more common
Within the 1st year of diagnosis, approximately 30% develop NPSLE features
Hematologic Almost all children develop hematologic involvement
Anemia of chronic disease is most common anemia
Hemolytic anemia is more prevalent in pediatric patients
Up to three quarters of children develop leukopenia
Neutropenia occurs in up to 15% of children
Overall, thrombocytopenia is more prevalent in children		 Up to 80% of adults develop hematologic involvement
Similarly, anemia of chronic disease is most common anemia
Up to one quarter of adults develop leukopenia
Neutropenia occurs in up to 20% of adults
Antiphospholipid antibody
syndrome (APS)		 Anti-phospholipid antibodies and/or lupus anticoagulant occur in 30–50% of patients
Children with the presence of lupus anticoagulant have 28-fold increased risk of thrombosis compared to children that persistently tested negative		 Similarly, up to 50% of adults develop antiphospholipid antibodies and/or lupus anticoagulant
Development of APS is more common in adults
Cardiovascular Pericarditis with pericardial effusion most common
Myocarditis, endocarditis, and conduction system abnormalities less common
In contrast to adults, transthoracic echocardiograms are often sufficient to diagnose Libman-Sacks disease
Premature athersclerosis is a concern, although studies supporting the use of statins is lacking		 Up to half of patients have evidence of pericardial thickening and/or effusion
Myocardial dysfunction has been reported in 5–60% of adults
Depending on the definition of abnormality, conduction defects affect 10 to 75% of adults
Increased risk of premature atheroslcerotic disease among premenopausal women
Pulmonary Involvement occurs in 25–75% of children
Wide range of manifestations from asymptomatic to life-threatening disease
Pleuritis most common
Chronic interstitial lung disease and pulmonary hypertension are rare		 Involvement occurs in up to 90% of adults
Pleuritis most common
3–15% have chronic interstitial lung disease
5–15% have mild subclinical pulmonary hypertension
Gastrointestinal (GI) Approximately 20% have GI involvement
Younger children are more susceptible
Although uncommon, pancreatitis may be present at diagnosis
Splenomegaly occurs in 20–30%
Hepatomegaly occurs in 40–50%		 GI involvement varies depending on the definition of manifestation, but may occur in up to 70%
Hepatomegaly occurs in 10–30%

Table 7.1 Comparison of organ involvement in pSLE and adult SLE.


Management



  • General

    • Psychosocial support is important

      • Assist with school issues and resources for children

    • Sun protection (sunscreen, sun avoidance, sun-protective clothing)
    • Growth

      • Growth failure occurs in approximately 15% of children
      • Puberty may be delayed
      • Although not well investigated, growth hormone may be associated with an increased risk of lupus flare

    • Bone health

      • 50% of bone mass is accrued during adolescence
      • Encourage exercise to promote bone density
      • Calcium and vitamin D

        • Prepubertal children should receive 1000 mg/day of calcium and postpubertal children should receive 1300–1500 mg/day of calcium
        • Children should receive 600–1000 units/day of vitamin D

          • Intermittently monitor 25-hydroxy vitamin D levels and adjust dose (maximum of 5000 units/day)

      • Dual-energy X-ray absorptiometry (DXA)

        • Precise use is in evolution
        • Recent pediatric reference data sets have been published for bone density measurements in children
        • Z scores of total body, lumbar spine, total hip, and femur may provide some indication of bone density
        • T scores are not useful in children, as they pertain to mean bone mineral density (BMD) at age 30, and should not be applied to growing children

    • Vaccinations

      • Generally recommended, with the exception of live viral vaccines during times of active disease or while on immunosuppression
      • Pneumococcal, meningococcal, Haemophilus influenzae type B, and annual inactivated influenza vaccine are recommended

    • Provide counseling regarding sexually transmitted disease, pregnancy, and contraception
    • Review risk factors for cardiovascular disease
    • Non-adherence is common and should be considered if a child is experiencing a lupus flare

  • Medications

    • Corticosteroids

      • Cornerstone of treatment
      • Optimal dose and route have not been defined

        • Oral prednisone up to 2 mg/kg/day
        • Intravenous methylprednisolone pulse 30 mg/kg/dose (to maximum of 1000 mg)

      • Comparisons of adult SLE and pSLE suggest that children are more often prescribed prednisone and receive intravenous methylprednisolone more frequently

    • Antimalarials

      • Similar to adult SLE, most children receive hydroxychloro­quine

        • 5–7 mg/kg/day
        • Emphasize the importance of routine ophthalmologic evaluation

      • Chloroquine is rarely prescribed

    • Azathioprine

      • Dose of 2–3 mg/kg/day
      • Consider thiopurine methyltransferase testing prior to initiation

    • Mycophenolate mofetil

      • 600 mg/m2/dose twice per day (maximum of 3 g/day)
      • In contrast to adults, there are no randomized controlled trials of mycophenolate in pSLE

    • Cyclophosphamide

      • Monthly pulse therapy of 500–1000 mg/m2/dose used for lupus nephritis, neuropsychiatric lupus, or severe life-threatening manifestations
      • Safety and efficacy of gonadotropin releasing hormone agonists for ovarian preservation has not been established in pSLE

    • B cell depleting therapy

      • Case reports of benefit of rituximab in pSLE, particularly for refractory hemolytic anemia and thrombocytopenia
      • Ongoing trial of belimumab in pSLE
      • Identifying the developmental stages of B cells in pSLE versus adult SLE may enhance therapies in the future

Prognosis



  • Overall the prognosis has improved in recent years, but compared to adults, disease control and damage are poorer in children

    • In the 1950s, 5-year survival was 30–40%
    • In the 1980s, 5-year survival improved to >90%
    • Data from the University of California Lupus Outcomes Study (LOS) examined a cohort of patients with childhood-onset disease and found that 12% had died during the first 5 years of the study follow-up period

  • Survival rates in children are associated with socioeconomic status, access to health care, educational background, ethnic background, infection, and active disease
  • Children with renal or CNS involvement have increased mortality
  • Morbidity due to lupus damage remains extensive

    • In a nested case–control study within the LUMINA (Lupus in MInorities, NAture versus nurture) trial, patients diagnosed during adolescence had a trend toward increased musculoskeletal and neuropsychiatric damage, while adult-onset disease trended toward more diabetes and peripheral vascular damage
    • In the LOS childhood-onset disease cohort, at the time of follow-up 68% of patients reported active disease

Juvenile Dermatomyositis

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Jul 3, 2016 | Posted by in RHEUMATOLOGY | Comments Off on 7: Selected topics in pediatric rheumatology

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