A RESIDENT'S GUIDE TO PEDIATRIC RHEUMATOLOGY

A RESIDENT’S GUIDE TO

PEDIATRIC RHEUMATOLOGY

Revised Edition - 2019

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

This guide is intended to provide a brief introduction to basic topics in pediatric rheumatology.

Each topic is accompanied by at least one up-to-date reference that will allow you to explore the

topic in greater depth.

In addition, a list of several excellent textbooks and other resources for you to use to expand

your knowledge is found in the Appendix.

We are interested in your feedback on the guide! If you have comments or questions, please

feel free to contact us via email at pedrheumguide@gmail.com.

Supervising Editors:

 Dr. Ronald M. Laxer, SickKids Hospital, University of Toronto

 Dr. Tania Cellucci, McMaster Children’s Hospital, McMaster University

 Dr. Evelyn Rozenblyum, St. Michael’s Hospital, University of Toronto

Section Editors:

 Dr. Michelle Batthish, McMaster Children’s Hospital, McMaster University

 Dr. Roberta Berard, Children’s Hospital – London Health Sciences Centre, Western

University

 Dr. Liane Heale, McMaster Children’s Hospital, McMaster University

 Dr. Clare Hutchinson, North York General Hospital, University of Toronto

 Dr. Mehul Jariwala, Royal University Hospital, University of Saskatchewan

 Dr. Lillian Lim, Stollery Children’s Hospital, University of Alberta

 Dr. Nadia Luca, Alberta Children’s Hospital, University of Calgary

 Dr. Dax Rumsey, Stollery Children’s Hospital, University of Alberta

 Dr. Gordon Soon, North York General Hospital and SickKids Hospital Northern Clinic in

Sudbury, University of Toronto

 Dr. Rebeka Stevenson, Alberta Children’s Hospital, University of Calgary

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

TABLE OF CONTENTS

Section

Topic

Page #

Pediatric Rheumatology Clinical Assessment

Approaches and Differential Diagnoses for Common

Complaints Referred to Pediatric Rheumatology

Juvenile Idiopathic Arthritis

Systemic Lupus Erythematosus and Related Conditions

Systemic Vasculitis

Idiopathic Inflammatory Myopathies

Scleroderma and Related Syndromes

Autoinflammatory Diseases

Uveitis

Inflammatory Brain Diseases

Infection and Infection-Related Conditions

Pain Syndromes

Pediatric Rheumatology Emergencies

Medications

107

Appendix

Helpful Resources in Pediatric Rheumatology

115

Notes:

Please consider that all treatment regimens discussed in the guide are

suggestions based on evidence-based guidelines and/or common practices by

the pediatric rheumatologists who are Section Editors of the Guide. Alternative

treatment approaches may be used in other centres.

More detailed information on medications (class, action, dose, side effects, monitoring)

may be found in the Medications section.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 1 – PEDIATRIC RHEUMATOLOGY CLINICAL ASSESSMENT

1A. Pediatric Rheumatologic History

An appropriate rheumatologic history for a new patient should cover the following areas:

History of presenting complaint

Onset, duration, pattern

Potential triggers, such as trauma, infection or immunizations

Severity and impact on function, including school and activities of daily living

Associated symptoms

Factors that improve or worsen symptoms

Previous investigations

Previous treatment, including effectiveness and adverse reactions

Past medical history

Chronic medical conditions

Admissions to hospital, surgeries

Eye examinations

Development

Brief review of all domains - gross motor, fine motor, speech, language, hearing, social

Immunizations

All childhood vaccinations

Varicella – Infection or vaccination?

Medications

Prescribed medications – dose, route, frequency, adherence

Over-the-counter medications, vitamins, herbal supplements

Allergies

Travel history (especially risk factors for tuberculosis or Lyme infections)

Family history

Ethnicity and consanguinuity

Rheumatologic diseases: Juvenile idiopathic arthritis (JIA), rheumatoid arthritis (RA)

Ankylosing spondylitis (AS)

Premature osteoarthritis

Inflammatory bowel disease (IBD)

Psoriasis

Systemic lupus erythematosus (SLE)

Vasculitis

Autoinflammatory diseases, including early hearing loss and early

renal failure

Other autoimmune diseases: Diabetes mellitus type I, Celiac disease, Thyroid disease

Social history

Parents marital status, occupations, care providers, drug coverage, adolescent psychosocial

assessment (e.g. HEEADSSS)

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Review of systems

General: Energy level, fatigue, poor sleep, non-restful sleep

Anorexia, weight loss

Fevers → frequency, duration, pattern, associated symptoms

Functioning → home, social, school, extra-curricular activities, work

HEENT: Photophobia, blurred vision, redness, pain

Sicca symptoms (dry eyes, dry mouth)

Nasal and/or oral ulcers (painful or painless)

Epistaxis

Dysphagia

Otalgia, hearing difficulties

CVS: Chest pain, orthopnea, syncope

Peripheral acrocyanosis

Raynaud phenomenon

Respiratory: Difficulty breathing, shortness of breath

Pleuritic chest pain

Prolonged cough, productive cough, hemoptysis

GI: Recurrent abdominal pain, “heartburn”

Diarrhea, constipation, bloody stools, melena

Nausea, vomiting

Skin: Any type of skin rash on face, scalp, trunk, limbs

Petechiae, purpura

Nodules

Ulcers (includes genital/perineal)

Photosensitivity

Alopecia, hair changes

Nail changes (pits, onycholysis) and nail fold changes

Joints: Pain (day and/or night), swelling, redness, heat, decreased range of motion

Loss of function, reduced activities, pain waking from sleep

Inflammatory → morning stiffness or gelling, improves with activity or exercise

Mechanical → improves with rest, “locking”, “giving away”

Muscles: Pain

Muscle weakness (proximal vs. distal)

Loss of function, reduced activities

CNS: Headaches

Psychosis, visual distortions

Cognitive dysfunction, drop in school grades

Seizures

PNS: Motor or sensory neuropathy

GU: Dysuria, change in urine volume or colour

Irregular, missed or prolonged menstrual periods, heavy menses

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

1B. Pediatric Rheumatologic Examination

Vital signs (including blood pressure percentiles)

Height, weight, BMI (percentiles, recent changes)

General appearance

HEENT: Conjunctival injection or hemorrhage, pupils (shape and reaction)

Complete ophthalmoscope examination from cornea to fundus

Nasal mucosa, nasal discharge, sinus tenderness

Oropharyngeal mucosa, tongue, tonsils

Thyroid

CVS: Heart sounds, murmurs, rubs, precordial examination

Vascular bruits (if indicated)

Peripheral pulses, peripheral perfusion, capillary refill

Lungs: Respiratory excursion, percussion, breath sounds, adventitious sounds

Abdomen: Tenderness, peritoneal signs, masses, bowel sounds, bruits (if indicated)

Hepatomegaly, splenomegaly

LN: Assess all accessible lymph node groups

Skin: Any type of skin rash, including petechiae, purpura, nodules, and ulcers

Alopecia, hair abnormalities

Nails: Nail pits, clubbing, onychonychia

Nail fold capillaries – thickening, branching, drop-out, hemorrhages

Digital ulcers, splinter hemorrhages, loss of digital pulp

CNS: Mental status

Cranial nerves

Motor: muscle bulk, tone, power/strength, tenderness, deep tendon reflexes

Cerebellar

Gait (walking, running, heels, toes, and tandem)

Sensory (if indicated), allodynia borders (if indicated)

Joints: Begin with a screening exam, such as the Pediatric Gait Arms Legs Spine

(pGALS)

Assess all joints for heat, swelling, tenderness, stress pain, active and passive

range of motion, deformity

Enthesitis sites

Localized bony/joint tenderness

Leg length (functional and/or actual)

Thigh, calf circumference difference (if indicated)

Back: Range of motion, tenderness, stress pain from repetitive motion

Scoliosis

Modified Schober test (if indicated)

Other: Fibromyalgia tender points (if indicated)

References:

1. Foster HE, Jandial S. pGALS – paediatric Gait Arms Legs and Spine: a simple

examination of the musculoskeletal system. Pediatr Rheumatol Online J 2013; 11(1):44.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

1C. Laboratory Testing in Pediatric Rheumatology

General Principles

 Interpret all laboratory results in context of specific patient

 Consider the clinical rationale and potential impact of all laboratory tests that are ordered,

especially for autoantibody testing

 Review all laboratory test results to guide interpretation of abnormalities

 Trends in laboratory values may be more important than isolated abnormalities

Complete blood cell count and differential

 Hemoglobin, red blood cell count and mean corpuscular volume

o Normocytic or microcytic anemia in chronic inflammatory disease

o Autoimmune hemolytic anemia in systemic lupus erythematosus (SLE)

o Non-immune hemolytic anemia in macrophage activation syndrome (MAS)

o Iron deficiency anemia if chronic blood loss (e.g. due to NSAIDs, inflammatory bowel

disease)

 White blood cell count and differential

o High white blood cell counts may be due to infection, systemic inflammation, or side-

effect of corticosteroids

o Leukopenia with lymphopenia and/or neutropenia may be due to systemic inflammation

or medications

 Platelet count

o Active inflammation may lead to increased platelet counts (e.g. subacute phase of

Kawasaki disease, systemic juvenile idiopathic arthritis (JIA), or Takayasu arteritis)

o Active disease may also lead to reduced platelet counts (e.g. SLE)

Acute phase response to systemic inflammation

 Acute phase reactants are plasma proteins produced by the liver that change production

during acute phase of inflammation

 Acute phase response mediated by cytokines, such as IL-1, IL-6 and TNF (which are the

target of many biologic agents used in childhood rheumatic diseases)

 Substantial acute phase response may be seen in infection, trauma, burns, tissue infarction,

advanced cancer and immune-mediated disease

 Mild elevation may be seen in conditions such as obesity, pregnancy, and strenuous

exercise

 Overall effect of acute phase response is to protect host from damage

 Excessive or prolonged acute phase response may be deleterious itself (e.g. septic shock,

MAS, malignancy)

C-reactive protein (CRP)

 Direct measure of inflammation (sensitive but not specific)

 Level rises rapidly in response to inflammation and falls quickly with appropriate treatment

 May reflect severe disease more closely than other acute phase reactants, although this

may be patient-specific and/or disease-dependent (e.g. CRP typically rises in patients with

SLE when there is infection, serositis or MAS, but may be normal with active disease)

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Erythrocyte sedimentation rate (ESR)

 Indirect measure of acute phase reaction

 Changes more slowly than CRP

 Measure rate at which red blood cells settle in a tube of anticoagulated blood in one hour

 Depends on fibrinogen, gamma globulins

Ferritin

 Protein central to iron homeostasis

 Serum ferritin levels increase in setting of inflammation

 Very high levels suggestive of macrophage activation syndrome

 May not function as a reliable measure of iron status in setting of inflammatory disease

Summary of laboratory changes in acute phase response to systemic inflammation:

Increase in acute phase response

Decrease in acute phase response

CRP, ESR

Complement proteins

Fibrinogen, coagulation proteins

Ferritin

Ceruloplasmin

Haptoglobin

G-CSF

IL-1 receptor antagonist

Serum amyloid A

Albumin

Transferrin

IGF-1

Complement

 Increased levels of complement components frequently seen in inflammation

 Low complement levels present in SLE, acute post-infectious glomerulonephritis,

membrano-proliferative glomerulonephritis, or liver disease

 Congenital complement deficiencies predispose either to recurrent infections (mainly

encapsulated organisms) or to unusual autoimmune disease (“lupus-like” disease)

 In SLE, serial measurements of C3 and C4 are useful to monitor disease activity

o Complement levels tend to fall during a flare and return to normal concentration after

appropriate therapy

o Persistently low C3 associated with lupus nephritis

Autoantibodies

Antinuclear antibodies (ANA)

 Autoantibodies directed against nuclear, nucleolar or perinuclear antigens

 ANA should not be used as a screening tool

o Low titres of ANA (e.g. ANA ≤ 1:80) may be present in up to 30% of normal healthy

population and may revert to negative over time

o ANA may also be present in non-rheumatologic diseases (e.g. infection, malignancy,

medications)

 No need to repeat ANA regularly once positive titre established (from Choosing Wisely:

Pediatric Rheumatology Top 5 by American College of Rheumatology)

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Low titres of non-specific ANA may be seen in JIA patients, but positive ANA titres ≥ 1:160

in JIA patients are associated with younger age at onset, higher risk of uveitis, asymmetric

arthritis and lower number of affected joints over time

 Persistent higher titres of ANA > 1:160 suggest connective tissue diseases, such as SLE

o Negative ANA makes diagnosis of SLE unlikely

 Specific antibodies (e.g. anti-double stranded DNA) should only be requested if ANA is

positive and there is evidence of rheumatic disease (highlighted in Choosing Wisely:

Pediatric Rheumatology Top 5 by American College of Rheumatology)

Anti-double stranded DNA (Anti-dsDNA)

 Anti-dsDNA autoantibody targets DNA in nucleus of cell

 Highly specific for SLE

 Titres are affected by disease activity and may be used to monitor disease progression and

response to therapy

Autoantibodies to extractable nuclear antigen (ENA)

Specific ENA antibodies

Characteristic disease associations

Anti-Ro/SSA

SLE, Neonatal lupus erythematosus, Sjögren

Anti-La/SSB

SLE, Neonatal lupus erythematosus, Sjögren

Anti-Sm (Anti-Smith)

SLE

Anti-RNP

Mixed connective tissue disease, SLE, Systemic sclerosis

Anti-histone

Drug-induced lupus, SLE

Anti-Scl 70

Diffuse systemic sclerosis

Anti-centromere

Limited systemic sclerosis (CREST)

Anti-Jo1

Polymyositis with interstitial lung disease, juvenile

dermatomyositis (JDM)

Anti-SRP

Anti-Mi-2

JDM with profound myositis & cardiac disease

JDM with good prognosis

Rheumatoid factor (RF)

 IgM autoantibody that reacts to Fc portion of IgG

 Present in 85% of adults with rheumatoid arthritis

 Present in only 5-10% of children with JIA

o Helpful in classification and prognosis of JIA, but should not be used as a screening test

since arthritis is a clinical diagnosis

o Children with RF-positive polyarthritis are at higher risk of aggressive joint disease with

erosions and functional disability

 RF may also be detected in chronic immune-complex mediated diseases, such as SLE,

systemic sclerosis, Sjögren, mixed connective tissue disease, cryoglobulinemia and chronic

infection (subacute bacterial endocarditis, hepatitis B and C, TB)

Anti-citrullinated peptide antibodies (ACCP)

 Antibodies to citrullinated peptides found in inflamed synovium

 Highly specific for rheumatoid arthritis, but often positive in older children with polyarticular

Rheumatoid factor positive JIA

 Indicates increased risk of aggressive disease and progressive joint damage

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Antiphospholipid antibodies

 Heterogeneous group of antibodies directed against cell membrane phospholipids

 Include lupus anticoagulant, anticardiolipin, anti-β

-glycoprotein I

 Associated with increased risk of arterial or venous thrombosis (but lupus anticoagulant

paradoxically prolongs laboratory PTT)

 May be produced due to primary antiphospholipid antibody syndrome (APS) or secondary to

SLE, other autoimmune diseases, malignancy, infection or drugs

Antineutrophil cytoplasmic antibodies (ANCA)

 Antibodies target antigens in cytoplasmic granules of neutrophils

 May be pathogenic by activating neutrophils, leading to perpetuation of chronic inflammation

 High sensitivity and specificity for primary small vessel systemic vasculitides

ANCA

Immunofluorescence

pattern

Antigen specificity

(ELISA)

Disease associations

c-ANCA

Cytoplasmic

Proteinase-3 (PR3)

Granulomatosis with polyangiitis

p-ANCA

Perinuclear

Myeloperoxidase

(MPO)

Microscopic polyangiitis

Eosinophilic granulomatosis with

polyangiitis

Ulcerative colitis

Primary sclerosing cholangitis

SLE

Anti-Glomerular Basement Membrange (Anti-GBM) antibodies

 Antibodies target alpha-3 chain of type IV collagen, which is normally present in glomerular

and alveolar basement membranes

 Antibody binding to basement membranes in lungs and kidneys activates classical

complement pathway and neutrophil-dependent inflammation, leading to small vessel

vasculitis with immune complex formation

 Production of antibodies may be triggered by environmental factors (e.g. infection, cigarette

smoking)

Human Leukocyte Antigen (HLA) Genetics

 Many genes of the major histocompatibility complex (especially HLA class I and II genes)

have been associated with rheumatic disorders

HLA-B27

 HLA class I gene that is present in only 7-10% of the general population (may be higher in

some First Nations groups)

 Found in 90-95% of Caucasians with ankylosing spondylitis and many patients with JIA

(particularly enthesitis related arthritis and psoriatic arthritis), inflammatory bowel disease,

isolated acute anterior uveitis, and reactive arthritis

 HLA-B27 may play a role in the pathogenesis of inflammatory disease

HLA-B51

 May be associated with Behçet disease

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Additional tests:

Urinalysis

 Routinely used to assess for proteinuria and hematuria associated with renal involvement in

autoimmune and autoinflammatory diseases

Fecal calprotectin

 May be measured as an indicator of underlying gastrointestinal inflammation

Genetic testing

 Often ordered to confirm diagnosis of genetic fever syndromes and other autoinflammatory

disorders

Cytokine profiling

 May be used in research contexts to qualify the inflammatory response and guide therapy

 May become more widely available in upcoming years

References:

1. Mehta J. Laboratory testing in pediatric rheumatology. Pediatr Clin N Am 2012; 59:263-

84.

2. Pilania RK, Singh S. Rheumatology panel in pediatric practice. Indian J Pediatr 2019;

56(5):407-14.

1D. Diagnostic Imaging in Pediatric Rheumatology

General Principles

 Interpret all imaging results in context of specific patient

 Consider the clinical rationale and potential impact of all imaging that is ordered, including

risks of sedation, radiation and contrast administration

 Imaging alone is not sufficient to confirm any rheumatic disease

 Repeat imaging may be helpful to assess response to therapy, disease progression and

development of damage or to screen for specific organ involvement in systemic conditions

 Review of questionable or unexpected imaging findings with a pediatric radiologist who has

specific expertise (e.g. musculoskeletal or neuroradiology training) is recommended

X-ray

 Bone and joint X-rays

o Often ordered as initial testing for pain and deformity

o May be used to rule out bony abnormalities or injuries, such as fracture, that may

explain symptoms

o Helpful to image both affected and non-affected sides to assess for subtle changes

o May be normal at disease onset

o Most likely to be ordered in assessment of patients with possible JIA or other

inflammatory arthritis, non-bacterial osteomyelitis, or systemic sclerosis

o Findings in JIA may include effusion, soft tissue swelling, periarticular osteopenia,

joint space narrowing, erosions, subchondral cysts, osteophytes, bone deformity,

fusion, or accelerated bone development in young children

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Chest X-rays

o May be used to assess for heart and lung involvement in systemic autoimmune or

autoinflammatory diseases

Ultrasound

 May be used to assess for effusions and other findings of synovitis or to facilitate joint

injections

 May also be used with Doppler to assess vasculature for obstruction of blood flow, which

may be due to thrombosis or vasculitis in rheumatic diseases

 Highly operator dependent and requires specific skill and experience, especially with

pediatric patients

 Many rheumatologists are currently performing point-of-care ultrasonography to aid clinical

assessment of disease activity and joint injection

Computed tomography (CT)

 Chest CT may be useful to identify findings of interstial lung disease and pulmonary

hemorrhage in connective tissue diseases

 CT angiograms may be used to assess for findings of vasculitis when magnetic resonance

or conventional angiograms are not easily accessible

 While CT may identify findings for a number of rheumatic diseases, it is often not the first

imaging of choice because of the associated radiation.

 If CT is deemed necessary, radiation may be reduced with high resolution techniques

Magnetic resonance imaging

 Ideal imaging modality for synovitis in specific joints (e.g. temporomandibular, sacroiliac and

cervical spine) and may identify early signs of disease and/or damage in JIA

 Whole body MRI protocols have been developed to assess for enthesitis and chronic non-

bacterial osteomyelitis

 Specialized protocols have been developed to identify findings in inflammatory myositis

 Ideal imaging modality to identify findings of brain inflammation (especially if 3T or higher

strength magnet available) and may also be used to assess for inflammation in aorta, blood

vessels and other organs (e.g. gastrointestinal tract); MR angiography should be requested

for more accurate imaging of blood vessels

 Limitations are that MRI is expensive and less accessible and longer scan times often

require sedation for younger children

Echocardiography

 Typically used to assess for coronary artery aneurysms in Kawasaki disease and for carditis

or other cardiopulmonary involvement in systemic autoimmune or autoinflammatory

diseases

 Antenatal use of echocardiography is important in babies at risk of neonatal lupus

erythematosus to assess for myocarditis and endocardial fibroelastosis

 Some centres may require consultation with cardiologist in conjunction with imaging

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Dual Energy X-ray Absorptiometry (DEXA) scan

 Measures bone mineral density

 Used most often in patients on chronic steroid therapy at baseline and at regular intervals to

monitor for development of osteopenia/osteoporosis

References

1. Pilania RK, Singh S. Rheumatology panel in pediatric practice. Indian J Pediatr 2019;

56(5):407-14.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 2 – APPROACHES TO AND DIFFERENTIAL DIAGNOSES FOR COMMON

COMPLAINTS REFERRED TO PEDIATRIC RHEUMATOLOGY

2A. Approach to Childhood Joint Pain

Differential diagnosis for pain involving a single joint:

Traumatic

Fracture

Soft tissue injury (e.g. strains, sprains)

Foreign body synovitis

Infection-related

Septic arthritis

Osteomyelitis

Chronic infections, such as tuberculosis or Lyme disease

Reactive arthritis including post-Streptococcal reactive arthritis

Acute rheumatic fever

Inflammatory

Juvenile idiopathic arthritis (JIA)

Chronic non-bacterial osteomyelitis

Inflammatory bowel disease

Genetic autoinflammatory syndromes (e.g. familial Mediterranean fever,

pyogenic arthritis pyoderma gangrenosum and acne)

Behçet disease

Neoplastic

Musculoskeletal tumors (e.g. osteoid osteoma, osteosarcoma)

Hematologic malignancy

Hemarthrotic

Traumatic

Coagulopathy (e.g. hemophilia)

Pigmented villonodular synovitis

Arteriovenous malformation

Hematologic

Sickle cell disease (e.g. pain crisis, dactylitis)

Mechanical

Overuse or repetitive strain injury

Tendon/ligament/meniscal injury

Apophysitis

Joint damage (e.g. prior trauma, infection, congenital anomaly)

Orthopedic

Avascular necrosis (AVN)

Slipped capital femoral epiphysis (SCFE)

Osteochonditis dissecans

Pain syndrome

Complex regional pain syndromes (CRPS)

Potential investigations for pain involving a single joint:

 X-rays

 Joint aspiration and synovial fluid analysis and/or culture

 Blood work: CBC and differential, ESR, CRP

 Consider, if indicated:

o Further infectious testing (e.g. blood culture, Lyme serology, TB skin test)

o Further imaging (e.g. ultrasound, MRI)

o Autoimmune serology (e.g. ANA, HLA B27)

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Differential diagnosis for pain involving multiple joints:

Inflammatory

Juvenile idiopathic arthritis (JIA)

Systemic lupus erythematosus (SLE)

Juvenile dermatomyositis

Scleroderma/mixed connective tissue disease/overlap syndromes

Systemic vasculitis (e.g. Henoch-Schönlein purpura / IgA vasculitis)

Inflammatory bowel disease (IBD)

Genetic autoinflammatory syndromes

Sarcoidosis

Chronic non-bacterial osteomyelitis / chronic recurrent multifocal

osteomyelitis

Serum sickness

Infection-related

Acute infections (e.g. parvovirus B19, EBV, Neisseria gonorrheae)

Chronic infections (e.g. tuberculosis (Poncet arthritis), Lyme disease)

Subacute bacterial endocarditis (SBE)

Reactive arthritis, including acute rheumatic fever (ARF)

Osteomyelitis and septic arthritis may rarely present with multifocal

involvement

Immunological

Immunodeficiency associated with arthritis (e.g. Wiskott-Aldrich)

Neoplastic

Leukemia, lymphoma, neuroblastoma, cancers with systemic

involvement

Mechanical

Overuse injuries, repetitive strain injuries

Apophysitis

Hypermobility – benign or due to connective tissue disease (e.g. Ehlers-

Danlos)

Skeletal dysplasias

Metabolic

Rickets

Vitamin C deficiency (scurvy)

Glycogen storage disease, mucopolysaccharidoses

Pain syndrome

Fibromyalgia

Potential investigations for pain involving multiple joints:

 Blood work: CBC and differential, blood film, ESR, CRP

 Infectious testing (e.g. Parvovirus B19 serology, EBV serology, throat culture, ASOT)

 Consider, if indicated:

o Autoimmune serology (e.g. ANA, Rheumatoid factor, HLA B27)

o Imaging (e.g. X-rays, ultrasound, MRI)

o Urinalysis

o Bone marrow aspirate and biopsy

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

What do clinical features associated with joint pain tell you about underlying diagnosis?

Signs/symptoms

Associated conditions

Severe joint pain

Infection-related, malignancy, trauma, AVN, pain syndrome

Pinpoint tenderness

Osteomyelitis, trauma, AVN, malignancy, enthesitis, chronic non-

bacterial osteomyelitis

Night pain

Malignancy, osteoid osteoma, benign nocturnal limb pain

Redness

Septic arthritis, acute rheumatic fever, reactive arthritis

Migratory joint pain

Leukemia, acute rheumatic fever

Non weight bearing

Infection, malignancy, discitis, myositis, pain syndrome

Hip pain

Infection-related, AVN, SCFE, malignancy, chondrolysis, transient

synovitis, JIA (particularly enthesitis related arthritis)

Back pain

Usually benign, but consider bone or spinal cord tumour, discitis,

spondylolysis/spondylolisthesis, JIA (enthesitis related arthritis),

myositis, osteoporosis, CNO, pain syndrome

Periarticular pain

Malignancy, hypermobility, pain syndrome, CNO

Dactylitis

JIA (particularly enthesitis related arthritis and psoriatic arthritis),

sickle cell, trauma

Clubbing

Cystic fibrosis, IBD, malignancy (especially lung), familial,

hypertrophic osteoarthropathy

Weight loss

Malignancy, systemic autoimmune rheumatologic diseases, IBD

Muscle weakness

Myositis, overlap syndromes, malignancy, pain-related weakness

Rash

Systemic autoimmune rheumatologic diseases, vasculitis, JIA

(particularly systemic arthritis and psoriatic arthritis), acute

rheumatic fever, Lyme disease, serum sickness, autoinflammatory

syndromes

Oral ulcers

Vasculitis, Behçet disease, SLE, IBD, autoinflammatory

syndromes

Eye pain and redness

Reactive arthritis, enthesitis related arthritis. IBD, Behçet disease

Nail or nail fold changes

Systemic autoimmune rheumatologic diseases, psoriasis,

subacute bacterial endocarditis

Raynaud phenomenon

Systemic autoimmune rheumatologic diseases

School withdrawal

Pain syndrome, chronic fatigue

Travel

Infection-related (e.g. tuberculosis, Lyme disease, viral)

Consanguinity

Genetic or metabolic diseases (e.g. autoinflammatory diseases)

References:

1. Nannery R, Heinz P. Approach to joint pain in children. Paediatr and Child Health 2018;

28(2):43-49.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

2. Tse SM, Laxer RM. Approach to acute limb pain in childhood. Pediatr Rev 2006; 27:170-

80.

3. Sen ES, et al. The child with joint pain in primary care. Best Pract & Res Clin Rheumatol

2014; 28:888-906.

2B. Approach to Childhood Back Pain

Differential diagnosis for back pain in children

Inflammatory

Juvenile idiopathic arthritis (JIA)

Inflammatory bowel disease (IBD)

Chronic non-bacterial osteomyelitis, chronic recurrent multifocal

osteomyelitis

Transverse myelitis (e.g. SLE)

Infection-related

Acute infections (e.g. osteomyelitis, septic arthritis, discitis, epidural

abscess)

Chronic infections (e.g. tuberculosis (Pott disease))

Reactive arthritis

Neoplastic

Musculoskeletal tumors (e.g. osteoblastoma, osteosarcoma, spinal cord

tumors, metastases)

Leukemia, lymphoma

Mechanical

Spondylolysis, spondylolisthesis

Scoliosis

Scheuermann disease

Disc prolapse

Degenerative disc disease

Trauma

Fracture

Hematologic

Sickle cell pain crisis

Pain syndrome

Other

Fibromyalgia

Neurofibromatosis

Potential investigations for back pain in children:

 Investigations may not be needed and depend on clinical assessment

 Consider, if indicated:

o Imaging (e.g. X-rays, MRI)

o Autoimmune serology (e.g. ANA, Rheumatoid factor, HLA B27)

o Blood work (e.g. CBC and differential, ESR, CRP)

References:

1. Altaf F, et al. Back pain in children and adolescents. Bone Joint J 2014; 96B:717-23.

2. Nigrovic PA. Evaluation of the child with back pain. UpToDate. Updated December

2018. URL: https://www.uptodate.com/contents/evaluation-of-the-child-with-back-pain.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

2C. Approach to Fevers

Definition of fever of unknown origin:

 Temperature > 38 degrees Celsius lasting ≥ 8 days with no clear source of fever

Differential diagnosis for fever of unknown origin in children

Infectious

Bacterial (e.g. abscess, mastoiditis, osteomyelitis, pyelonephritis,

sinusitis, typhoid fever, tuberculosis)

Viral (e.g. Adenovirus, CMV, EBV, Enterovirus, HIV)

Other infections including parasitic and fungal (e.g. malaria, Lyme

disease, Toxoplasma, Blastomycosis)

Inflammatory

Serum sickness

Systemic vasculitis (e.g. Kawasaki disease)

Systemic lupus erythematosus

Juvenile dermatomyositis

Systemic arthritis/JIA

Behçet disease

Inflammatory bowel disease

Genetic autoinflammatory syndromes

Castleman syndrome

Hemophagocytic lymphohistiocytosis (primary or secondary HLH/MAS)

Sarcoidosis

Drug-induced

Drug fevers or intoxication

Neoplastic

Leukemia, lymphoma

Langerhans cell histiocytosis

Neuroblastoma

Endocrinologic

Hyperthyroidism

Thyroiditis

Diabetes insipidus

Other

Pancreatitis

Factitious fevers

Potential investigations for fever of unknown origin in children:

 Investigations will depend on clinical assessment and serial re-examination

 Initial blood work: CBC and differential, blood film, electrolytes, urea, creatinine, glucose,

ESR, CRP, ferritin, liver enzymes, albumin, LDH

 Urinalysis

 Initial infectious work-up: blood culture, urine culture, nasopharyngeal swab for viruses

 Consider, if indicated:

o Imaging (e.g. X-rays, abdominal ultrasound)

o Further infectious testing (e.g. ASOT, Monospot, cerebrospinal fluid testing)

o Testing for immunodeficiency (e.g. complement and immunoglobulin levels)

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Definition of recurrent fevers:

 ≥ 3 episodes of unexplained fever within 6 months separated by ≥ 7 days of good health

Differential diagnosis for recurrent fevers

Infectious

Repeated viral or bacterial infections

Viral (e.g. CMV, EBV, Parvovirus, hepatitis viruses, HIV)

Bacterial (e.g. Typhoid fever, occult dental abscess, endocarditis,

Mycobacteria)

Parasitic or fungal (e.g. malaria, Borrelia, Brucellosis, Yersinia)

Inflammatory

Genetic autoinflammatory syndromes

Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA)

Systemic lupus erythematosus

Systemic arthritis/JIA

Inflammatory bowel disease

Behçet disease

Polyarteritis nodosa

Sarcoidosis

Hemophagocytic lymphohistiocytosis (primary or secondary HLH/MAS)

IgG4 disease

Hematologic

Cyclic neutropenia

Neoplastic

Leukemia, lymphoma

Immunologic

Drug-induced

DiGeorge syndrome

Chediak-Higashi

Combined immunodeficiency syndrome

Drug fevers or intoxication

Other

CNS abnormality (e.g. hypothalamic dysfunction)

Castleman disease

Factitious fevers

Potential investigations for recurrent fevers:

 Clinical assessment during episode of fever and when well

 Fever diary including pattern of fever and associated symptoms

 Blood work during episode and when well: CBC and differential, ESR, CRP, ferritin, liver

enzymes, albumin, LDH, immunoglobulins (including IgD)

 Urinalysis

 Consider, if indicated:

o Infectious testing (e.g. blood culture, viral serology)

o Autoimmune serology (e.g. ANA)

o Genetic testing

References:

1. Antoon JW, et al. Pediatric fever of unknown origin. Pediatr Rev 2015; 36(9):380-91.

2. Soon GS, Laxer RM. Approach to recurrent fever in childhood. Can Fam Physician

2017; 63(10):756-62.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

2D. Approach to Recurrent Oral Ulcers

Differential diagnosis for recurrent oral ulcers in children

Inflammatory

Inflammatory bowel disease

Celiac disease

Behçet disease

Systemic lupus erythematosus (SLE)

Hyperimmunoglobulinemia D syndrome (HIDS)

Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA)

A20 haploinsufficiency (HA20)

Sarcoidosis

Infectious

Viral (e.g. Herpes simplex, Coxsackie)

Reactive arthritis

Hematologic

Cyclic neutropenia

Drugs

Azathioprine, Methotrexate, Sulfasalazine

Other

Aphthous stomatitis

What are the characteristics of oral ulcers in different inflammatory conditions?

SLE

Painless shallow oral ulcers, typically located on roof of mouth

where hard and soft palate meet

Inflammatory bowel

disease

Painful aphthous ulcers anywhere in oropharynx, sometimes

associated with cheilitis

Behçet disease

Painful aphthous ulcers or punched-out ulcers on tongue, lips,

gingiva and/or buccal mucosa

Celiac disease

Painful recurrent aphthous ulcers

PFAPA

Painful aphthous ulcers with discrete margins, typically on

buccal mucosa, associated with febrile episodes

HIDS

Painful aphthous ulcers with discrete margins, typically on

buccal mucosa, associated with febrile episodes

Sarcoidosis

Painless well-circumscribed brownish red or violaceous lesions

(sometimes nodular), erythematous gingival enlargement,

submucosal swelling of palate

References:

1. Siu A, et al. Differential diagnosis and management of oral ulcers. Semin Cutan Med

Surg 2015; 34(4):171-7.

2. Le Doare K, et al. Fifteen-minute consultation: a structured approach to the management

of recurrent oral ulceration. Arch Dis Child Educ Pract Ed 2014; 99(3):82-6.

3. Stoopler ET, Al Zamel G. How to manage a pediatric patient with oral ulcers. J Can Dent

Assoc 2014; 80:e9.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

2E. Additional differential diagnoses

Differential diagnosis for lymphadenopathy in children

Inflammatory

Systemic lupus erythematosus

Systemic arthritis/JIA

Kawasaki disease

Hemophagocytic lymphohistiocytosis (primary or secondary HLH)

Kikuchi-Fujimoto disease

Castleman disease

Rosai-Dorfman disease

Monogenic autoinflammatory diseases

Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA)

Serum sickness

Sarcoidosis

Infectious

Viral (e.g. EBV, CMV, HIV)

Bacterial (e.g. Bartonella, tuberculosis)

Bacterial spirochete/tick bourne (e.g. Lyme disease)

Neoplastic

Lymphoma, leukemia

Langerhans cell histiocytosis

Neuroblastoma

Other

Drug-induced

Differential diagnosis for erythema nodosum in children

Infectious

Viral (e.g. EBV, CMV, HIV)

Bacterial (e.g. Group A Streptococcus, Mycoplasma, Bartonella, Yersinia,

tuberculosis)

Inflammatory

Inflammatory bowel disease

Systemic lupus erythematosus

Behçet disease

Systemic vasculitis (e.g. polyarteritis nodosa, granulomatosis with

polyangiitis)

Sarcoidosis

Neoplastic

Lymphoma, leukemia

Hepatocellular carcinoma

Renal cell carcinoma

Drug-related

Oral contraceptives

Antibiotics (e.g. sulpha drugs, penicillins, macrolides)

Other

Idiopathic

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Differential diagnosis for recurrent parotitis

Infectious

Viral: HIV (diffuse infiltrative lymphocytosis), Influenza B, mumps, EBV,

CMV, Parvovirus, Paramyxovirus, Adenonvirus

Bacterial: Streptococcal infections, Staphylococcus aureus, Bartonella,

Haemophilus

Tuberculosis

Inflammatory

Systemic lupus erythematosus

Sjögren syndrome

IgG4 related disease

Neoplastic

Parotid tumours

Lymphoma

Other

Sialolithiasis

Juvenile recurrent parotitis

Pneumoparotid

Differential diagnosis for muscle weakness

Inflammatory

Juvenile dermatomyositis

Juvenile polymyositis

Systemic lupus erythematosus

Mixed connective tissue disease

Juvenile idiopathic arthritis

Systemic sclerosis

Overlap myositis

Inclusion-body myositis

Focal myositis

Orbital myositis

Granulomatous myositis

Eosinophilic myositis

Inflammatory bowel disease

Autoinflammatory diseases (e.g. TNF-receptor associated periodic

syndrome, Chronic atypical neutrophilic dermatosis with lipodystrophy

and elevated temperature, Familial Mediterranean fever)

Infectious

Viral (e.g. Enterovirus, Influenza, Coxsackievirus, Echovirus, Parvovirus,

Hepatitis B, HTLV)

Bacterial/Spirochetal (e.g. Staphylococcus, Streptococcus, Borrelia)

Parasitic (e.g. Toxoplasmosis, Trichinosis)

Genetic

Muscular dystrophy (e.g. Duchenne, Becker)

Congenital myopathies (e.g. Spinal muscular atrophy)

Metabolic

Metabolic diseases (e.g. mitochondrial, glycogen storage)

Other

Endocrinopathies (e.g. thyroid-associated myopathies)

Trauma

Toxins

Neuromuscular transmission disorders (e.g. myasthenia gravis)

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Differential diagnosis for chorea and abnormal movements in children

Inflammatory

Autoimmune encephalitis

Systemic lupus erythematosus

Antiphospholipid antibody syndrome

Behçet disease

Hashimoto encephalitis

Polyarteritis nodosa

Sjögren syndrome

Celiac disease

Sarcoidosis

Infectious

Acute rheumatic fever

Lyme disease

Malaria

Neurosyphilis

Tuberculosis

Creutzfeld-Jacob disease

Neurologic

Benign hereditary chorea

Huntington disease

Idiopathic basal ganglia calcification

Ataxia telengiectasia

Tic disorder

Neoplastic

Paraneoplastic syndromes

Tumors with basal ganglia involvement

Drug-related

Dopaminergic and other drugs

Other

Porphyria

Wilson disease

Liver failure

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Differential diagnosis for stroke-like presentations in children

Inflammatory

CNS vasculitis (primary angiography-positive or secondary vasculitis)

Systemic vasculitis (e.g. polyarteritis nodosa)

Systemic lupus erythematosus

Antiphospholipid antibody syndrome

Structural

Arterial dissection

Fibromuscular dysplasia

Moyamoya disease

Hematologic

Thromboembolic disease (e.g. prothrombotic condition, atherosclerosis)

Hemoglobinopathies (e.g. sickle cell disease)

Vasospastic

Reversible vasoconstrictive syndromes

Drug-induced (e.g. cocaine)

Genetic

Deficiency of adenosine deaminase 2 (DADA2)

Channelopathies

Connective tissue disorders (e.g. Ehlers-Danlos syndrome, Marfan

syndrome)

Neurofibromatosis

Metabolic

CADASIL (cerebral autosomal dominant arteriopathy with subcortical

infarcts and leukoencephalopathy), MELAS (mitochondrial

encephalopathy, lactic acidosis, stroke-like episodes)

References:

1. Hambleton L, et al. Lymphadenopathy in children and young people. Paediatr and Child

Health 2016; 26(2):63-7.

2. Penn E, Goudy S. Pediatric inflammatory adenopathy. Otolaryngol Clin North Am 2015;

48(1):137-51.

3. Leung AKC, et al. Erythema nodosum. World J Pediatr 2018; 14(6):548-54.

4. Baszis K, et al. Recurrent parotitis as a presentation of primary pediatric Sjögren

syndrome. Pediatrics 2012; 129:179-82.

5. Huber AM. Juvenile idiopathic inflammatory myopathies. Pediatr Clin North Am 2018;

65(4):739-56.

6. Gilbert DL. Acute and chronic chorea in childhood. Semin Pediatr Neurol 2009; 16(2):71-

7. Tsze DS, Valente JH. Pediatric stroke: a review. Emerg Med Int 2011; 734506.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 3 – JUVENILE IDIOPATHIC ARTHRITIS

3A. Introduction to Juvenile Idiopathic Arthritis (JIA)

 Arthritis is diagnosed in the presence of joint effusion OR two or more of the following:

limited range of movement with joint line tenderness or painful range of movement

 Currently, the most widely-used classification criteria for JIA is by the International League of

Associations for Rheumatology (ILAR) from the late 1990’s

o Definition: JIA is arthritis of unknown etiology that begins before the 16th birthday

and persists for at least 6 weeks and in which other causes of arthritis are excluded

o Classification: Recognizes 7 distinct subtypes of JIA, based on their presentation

within the first 6 months

1. Oligoarthritis

2. Polyarthritis (Rheumatoid Factor Negative)

3. Polyarthritis (Rheumatoid Factor Positive)

4. Systemic arthritis

5. Enthesitis-related arthritis

6. Psoriatic arthritis

7. Undifferentiated arthritis

 A recent re-classification of JIA was proposed by Pediatric Rheumatology International

Trials Organization (PRINTO) in 2019, but has not been validated

o Most prominent changes proposed in the new PRINTO criteria are that JIA is

considered a group of distinct clinical phenotypes (rather than a single disease) that

begin before the 18

birthday and are not classified by the number of joints involved

Oligoarthritis

ILAR Classification Criteria for Oligoarthritis *

Definition: Arthritis affecting 1 to 4 joints during the first 6 months of disease

Subcategories:

1. Persistent oligoarthritis: Affects not more than 4 joints throughout disease course

2. Extended oligoarthritis: Affects more than 4 joints after the first 6 months of disease

Exclusions:

o Psoriasis or a history of psoriasis in the patient or first degree relative

o Arthritis in an HLA-B27 positive male beginning after 6

birthday

o Ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with IBD, or acute anterior uveitis,

or history of one of these disorders in 1

degree relative

o Presence of IgM Rheumatoid Factor on at least 2 occasions at least 3 months apart

o Presence of systemic JIA

* Classification criteria are designed to identify a homogeneous population for research studies

and are not diagnostic criteria, although they are often used for diagnosis in practice

 Oligoarthritis is the most common subtype of JIA

 Typical patient is a young girl with positive ANA who presents with a small number of swollen

joints

 Most frequent joints to be involved are knees, ankles, wrists, or elbows

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Hip involvement is distinctly uncommon, especially early in disease, unless the disease

develops into extended oligoarthritis or is really part of enthesitis-related arthritis

 ANA is positive in 60-80% of patients (antigenic specificity is unknown for ANA in JIA)

 Oligoarticular JIA with positive ANA is associated with a higher risk of asymptomatic uveitis

(see Section 9)

Polyarthritis (Rheumatoid Factor Negative)

ILAR Classification Criteria for Polyarthritis (Rheumatoid Factor Negative) *

Definition:

 Arthritis affecting 5 or more joints during first 6 months of disease

 Negative testing for RF

Exclusions:

o Psoriasis or a history of psoriasis in the patient or first degree relative

o Arthritis in an HLA-B27 positive male beginning after 6

birthday

o Ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with IBD, or acute anterior uveitis,

or history of one of these disorders in 1

degree relative

o Presence of IgM Rheumatoid Factor on at least 2 occasions at least 3 months apart

o Presence of systemic JIA

* Classification criteria are designed to identify a homogeneous population for research studies

and are not diagnostic criteria, although they are often used for diagnosis in practice

 Children with RF negative polyarthritis are frequently younger and have a better prognosis

than those with RF positive disease

 ANA is positive in about 25% of patients

 Joint involvement is frequently symmetrical, affecting large and small joints alike

 Less than 50% of patients go into spontaneous remission, and long-term sequelae are

frequent, especially with hip and shoulder involvement

Polyarthritis (Rheumatoid Factor Positive)

ILAR Classification Criteria for Polyarthritis (Rheumatoid Factor Positive) *

Definition:

 Arthritis affecting 5 or more joints during first 6 months of disease

 2 or more positive tests for RF at least 3 months apart during first 6 months of disease

Exclusions:

o Psoriasis or a history of psoriasis in the patient or first degree relative

o Arthritis in an HLA-B27 positive male beginning after 6

birthday

o Ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with IBD, or acute anterior uveitis,

or history of one of these disorders in 1

degree relative

o Presence of systemic JIA

* Classification criteria are designed to identify a homogeneous population for research studies

and are not diagnostic criteria, although they are often used for diagnosis in practice

 All patients are RF positive, many are positive for anti-CCP antibodies, and ANA is positive in

40-50%

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 RF positive polyarthritis mostly affects adolescent girls

 Patients with RF positive polyarthritis share many characteristics with adults with rheumatoid

arthritis, including symmetrical polyarthritis especially involving the PIP joints and MCP joints

 Children may develop rheumatoid nodules and similar complications to adult disease,

including joint erosions and Felty syndrome (neutropenia and splenomegaly)

 RF positive polyarthritis is associated with more joint erosion and damage and with worse

radiographic outcome

 Remission rates (off medications) are lowest among RF positive patients

Systemic Arthritis

ILAR Classification Criteria for Systemic Arthritis *

Definition:

 Arthritis affecting 1 or more joints

 Associated with or preceded by fever of at least 2 weeks duration that is documented to be

daily, or “quotidian” for at least 3 days

 Accompanied by 1 or more of:

 Evanescent (non-fixed) erythematous rash

 Generalized lymph node enlargement

 Hepatomegaly and/or splenomegaly

 Serositis

Exclusions:

o Psoriasis or a history of psoriasis in the patient or first degree relative

o Arthritis in an HLA B27 positive male beginning after 6

birthday

o Ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with IBD, or acute anterior uveitis,

or history of one of these disorders in 1

degree relative

o Presence of IgM Rheumatoid Factor on at least 2 occasions at least 3 months apart

* Classification criteria are designed to identify a homogeneous population for research studies

and are not diagnostic criteria, although they are often used for diagnosis in practice

 Typical symptoms of systemic arthritis include:

o Once or twice daily fever spikes to >38.5°C, which then return to baseline or below

o Salmon-coloured, evanescent rash accompanying the fever, occasionally pruritic, and

lesions may be elicited by scratching the skin (Koebner phenomenon)

o Lymphadenopathy (common), splenomegaly (10%) and hepatomegaly (less common)

o Arthritis may develop later (usually within first year of fever) and is usually polyarticular,

affecting knees, wrists and ankles, but cervical spine and hip involvement also occurs

 An infectious work-up should be done and bone marrow aspirate to exclude malignancy

strongly considered before starting corticosteroid treatment

 Systemic JIA is associated with macrophage activation syndrome, a potentially life

threatening inflammatory complication (see Section 13)

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Enthesitis Related Arthritis (ERA)

ILAR Classification Criteria for Enthesitis Related Arthritis *

Definition:

 Arthritis and enthesitis

 Or, arthritis or enthesitis with at least 2 of the following:

 Presence or history of sacroiliac joint tenderness or inflammatory back 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, or acute anterior uveitis in a first-degree relative

Exclusions:

o Psoriasis or a history of psoriasis in the patient or first degree relative

o Presence of IgM Rheumatoid Factor on at least 2 occasions at least 3 months apart

o Presence of systemic JIA

* Classification criteria are designed to identify a homogeneous population for research studies

and are not diagnostic criteria, although they are often used for diagnosis in practice

 Hallmark of ERA is enthesitis (inflammation of the insertion sites of tendons, ligaments and

fascia) and asymmetrical oligoarthritis, predominantly affecting the lower extremities

Entheses by anatomic region

Region

Enthesitis exam

Chest

Costernal junctions (1

and 7

)

Shoulder

Acromioclavicular junction

Supraspinatus insertion into greater tubercle of

humerus

Elbow

Common flexor insertion into medial epicondyle

of humerus

Common extensor insertion into lateral

epicondyle of humerus

Pelvis

Abdominal muscle insertions into iliac crest

Sartorius insertion into anterior superior iliac

spine

Posterior superior iliac spine

Gracilis and adductor insertion into pubis

symphysis

Hamstring insertion into ischial tuberosity

Hip extensor insertion into greater trochanter of

femur

Knee

Quadriceps tendon insertion to patella

Infrapatellar ligament insertion to patella and

tibial tuberosity

Ankle

Achilles tendon insertion into calcaneus

Foot

Plantar fascia insertion into calcaneus,

metatarsal heads and base of 5

metatarsal

Image adapted with permission from: Jariwala M, Burgos-Vargas R, “Juvenile Spondyloarthropathies” in Pediatric

Rheumatology: A Clinical Viewpoint, 2017, Pages 229-46, Copyright Springer Singapore (2017).

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Common sites of enthesitis in the lower body

A B C

A. Insertions of

plantar fascia

B. Insertions of

quadriceps and

patellar tendons

C. Insertion of

Achilles tendon

Images were published in “Spondyloarthropathies of childhood” in Pediatrics Clinics of North America, 1995,

Volume 42, Pages 1051-1070, Copyright Elsevier (1995).

 ERA typically occurs in boys, usually over 6 years of age with familial predilection

 Axial involvement (involvement of the sacroiliac joints and/or spine) typically develops later

 Other manifestations include tarsitis (diffuse inflammation of tarsal joints and surrounding

tendon sheaths) and dactylitis (sausage-shaped swelling of entire digit)

 Symptomatic anterior uveitis may develop in children with ERA and this usually presents

with significant eye pain and redness, which may be unilateral

 Gastrointestinal symptoms (e.g. chronic abdominal pain, diarrhea, hematochezia) should be

carefully evaluated for possible inflammatory bowel disease

Psoriatic Arthritis

ILAR Classification Criteria for Psoriatic Arthritis *

Definition:

 Arthritis and psoriasis

 Or, arthritis and at least 2 of the following:

 Dactylitis

 Nail-pitting or onycholysis

 Psoriasis in a first-degree relative

Exclusions:

o Arthritis in an HLA B27 positive male beginning after 6

birthday

o Ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with IBD, or acute anterior uveitis,

or history of one of these disorders in 1

degree relative

o Presence of IgM Rheumatoid Factor on at least 2 occasions at least 3 months apart

o Presence of systemic JIA

* Classification criteria are designed to identify a homogeneous population for research studies

and are not diagnostic criteria, although they are often used for diagnosis in practice

 Psoriasis may develop after arthritis and may lead to reclassification of JIA type as psoriatic

 Typically asymmetric, and involves both large and small joints

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Clinical hallmark is dactylitis, which is caused by simultaneous inflammation of the flexor

tendon and synovium, leading to the typical “sausage digit” appearance

Undifferentiated Arthritis

ILAR Classification Criteria for Undifferentiated Arthritis *

Definition: Arthritis that fulfils criteria in no category or in 2 or more of above categories

* Classification criteria are designed to identify a homogeneous population for research studies

and are not diagnostic criteria, although they are often used for diagnosis in practice

References:

1. Crayne CB, Beukelman T. Juvenile idiopathic arthritis: Oligoarthritis and polyarthritis.

Ped Clin North Am 2018; 65(4):657-74.

2. Weiss PF, Colbert RA. Juvenile spondyloarthritis: A distinct form of juvenile arthritis. Ped

Clin North Am 2018; 65(4):675-90.

3. Lee JJY, Schneider R. Systemic juvenile idiopathic arthritis. Ped Clin North Am 2018;

65(4):691-709.

4. Petty RE, et al. ILAR classification of juvenile idiopathic arthritis: Second revision,

Edmonton 2001. J Rheumatol 2004; 31(2):390-2.

5. Martini A, et al. Toward new classification critieria for juvenile idiopathic arthritis: First

steps, Pediatric Rheumatology International Trials Organization International

Consensus. J Rheumatol 2019; 46(2):190-7.

3B. Approach to Management of JIA

 Goals of therapy

1. Eliminate inflammation with goal to achieve clinical remission

2. Prevent joint damage

3. Promote normal growth and development

4. Maintain normal function and optimize quality of life

5. Minimize medication toxicity

 Timing of assessments:

o Children with suspected JIA should be reviewed by a pediatric rheumatologist in 4-6

weeks and those with possible systemic JIA within 7 days

o Follow-up is recommended at intervals of 3-4 months in patients with controlled

disease and more often in those with uncontrolled disease

 Disease monitoring:

o Assessments of disease activity by a pediatric rheumatologist and multidisciplinary

team are essential for disease monitoring

o Laboratory monitoring is often an essential part of management, especially during

disease flares and medication changes (escalation and weaning)

o Surveillance joint X-rays should not be ordered routinely to monitor disease activity,

but may be used as needed to assess for joint damage (highlighted in Choosing

Wisely: Pediatric Rheumatology Top 5 by American College of Rheumatology)

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o Ultrasound and/or MRI could be considered to detect early or subclinical disease

activity or damage and MRI is usually indicated for monitoring of temporomandibular,

sacroiliac, hip, and subtalar joints

o Careful monitoring by an eye care provider is essential to assess for chronic anterior

uveitis, especially in patients with oligoarthritis and positive ANA

o Screening for asymptomatic uveitis should take place within 4 weeks of diagnosis

 Multidisciplinary approach:

o Multidisciplinary team is part of comprehensive JIA management

o Occupational and physical therapists play an important role in treating JIA

o Psychosocial aspects of disease must be recognized and addressed

 Treat-to-Target Strategy for JIA:

o Target of treatment is complete remission, which means absence of signs and

symptoms of inflammatory disease activity, including extra-articular manifestations

(e.g. uveitis)

o Minimal or low disease activity may be an alternative target, particularly in patients

with longstanding or difficult-to-treat disease

o Setting the target and therapeutic decisions should be based on individual patient

characteristics and agreed on with the patient/parents

o Rapid escalation and changes in therapy may be required until target is achieved

o In all patients, at least a 50% improvement in disease activity should be reached

within 3 months and the target within 6 months; however, patients with systemic JIA

should be fever-free within 1 week

 Medications:

o Initial therapy with an NSAID may be started by a patient’s primary care physician;

however, further therapy should be directed by a pediatric rheumatologist

o Intra-articular corticosteroids and methotrexate remain key medications for JIA

o Potential algorithms for treatment of oligoarthritis, polyarthritis and systemic JIA are

included in the following pages

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

An Algorithm for Treatment of Oligoarthritis

Persistent oligoarticular

arthritis

Inadequate response

Oligoarticular arthritis

NSAID or Intra-Articular Corticosteroid injection (IAC) withTriamcinolone hexacetonide

Improvement

Inadequate response

Follow and, if no IAC, continue NSAID

Recurrence

Remission

Evolves into polyarticular

arthritis

Intermittent IAC, or

consider adding disease-

modifying drug

Management same as

polyarticular JIA

(see next algorithm)

Inadequate response

Remission

Consider biologic agent

Repeat or first IAC

Remission

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

An Algorithm for Treatment of Polyarthritis

Inadequate

response

If inadequate

response, consider

switch to different

anti-TNF agent or

other biologic agent

(e.g. abatacept,

tocilizumab)

Consider adding

anti-TNF therapy

Continue therapy

and follow

Remission

Recurrence

Optimise disease-modifying drug

Consider IAC or low dose oral

corticosteroids as bridging therapy

Continue therapy and follow

Polyarthritis

NSAID with or without Intra-Articular Corticosteroid injections (IAC)

Consider using disease-modifying drug, such as methotrexate, as part of initial

therapy for moderate to severe polyarthritis

Improvement

Inadequate response

Add disease-modifying drug, such as

methotrexate or leflunomide

Continue NSAID and follow

Recurrence

Remission

Improvement

Recurrence

Remission

Improvement

Inadequate

response

N.B. A limited course of Corticosteroids

(< 3 months) during initiation or

escalation of therapy may be added in

patients with high-moderate disease

activity

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

An Algorithm for Treatment of Systemic JIA

References

1. Giancane G, et al. Recent therapeutic advances in juvenile idiopathic arthritis. Best Pract

Res Clin Rheumatol 2017; 31(4):476-87.

2. Ravelli A, et al. Treating juvenile idiopathic arthritis to target: recommendations of an

international task force. Ann Rheum Dis 2018; 77(6): 819-28.

3. Beukelman T, et al. 2011 American College of Rheumatology recommendations for the

treatment of juvenile idiopathic arthritis... Arthritis Care Res 2011; 63(4):465-82.

4. Ringold S, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline

fot the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-

Systemic Polyarthritis, Sacroilitis, and Enthesitis. Arthritis Care Res 2019; 71(6):717-34.

5. Cellucci T, et al. Management of Juvenile Idiopathic Arthritis 2015: A Position Statement

from the Pediatric Committee of the Canadian Rheumatology Association. J Rheumatol

2016; 43(10):1773-6.

Systemic arthritis

Mild to moderate disease

Moderate to severe disease

NSAID and/or Corticosteroidsand/or

Anakinra

Corticosteroids and/or biologic agent,

such as anti-IL-1 or anti-IL-6 therapy

Improvement

Inadequate

response

Improvement

Inadequate

response

Continue therapy

and follow

Continue therapy

and follow

Add or change

biologic anti-IL-1 or

anti-IL-6 agent

Remission Recurrence

Recurrence

Remission

Recurrence

Remission

Change biologic therapy or

consider methotrexate,

leflunomide, or anti-TNF

agent, or abatacept if

prominent arthritis

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 4. SYSTEMIC LUPUS ERYTHEMATOSUS & RELATED CONDITIONS

4A. Systemic Lupus Erythematosus (SLE)

 Multi-system inflammatory disease characterized by autoantibody and immune-complex

mediated inflammation of blood vessels and connective tissues

 Pediatric-onset SLE accounts for 10-20% of all cases of SLE

 Female predominance, especially in adolescence and adulthood

 Ethnic predilection in Blacks, Hispanics, and Asians

 Positive family history of SLE in 10%

1997 American College of Rheumatology (ACR) Classification Criteria for SLE *

Patients are classified as having SLE if they have ≥ 4/11 of following criteria:

 Malar rash (butterfly rash sparing nasolabial folds)

 Discoid lupus rash **

 Photosensitivity

 Oral or nasal mucocutaneous ulcerations (typically painless)

 Non-erosive arthritis involving two or more peripheral joints

 Nephritis (characterized by proteinuria and/or cellular casts)

 CNS involvement (characterized by seizures and/or psychosis)

 Serositis (pleuritis or pericarditis)

 Cytopenia (thrombocytopenia, lymphopenia, leukopenia, hemolytic anemia with

reticulocytosis)

 Positive ANA

 Positive immunoserology (anti-dsDNA, anti-Sm (anti-Smith), antiphospholipid antibodies)

* Classification criteria are designed to identify a homogeneous population for research studies

and are not diagnostic criteria, although they are often used for diagnosis in practice

** Uncommon in children

 1997 ACR classification criteria are not diagnostic criteria and were designed to identify a

homogeneous population of SLE patients for research studies; however, the presence of ≥ 4

criteria is specific for SLE (>93%) and so the criteria have been widely used for diagnosis

 In 2012, newer Systemic Lupus International Collaborating Clinics (SLICC) classification

criteria for SLE were developed that incorporated more immunologic criteria and were more

sensitive (>95%) but less specific (83%) than the 1997 ACR criteria

 New EULAR/ACR classification criteria for SLE have been developed in 2019 and may be

adopted in the future since they are both sensitive (>95%) and specific (>93%) for SLE

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

2019 Proposed European League Against Rheumatism (EULAR) and American College

of Rheumatology (ACR) Classification Criteria for SLE *

Clinical domains

Points**

Constitutional domain

 Fever

Cutaneous domain

 Non-scarring alopecia

 Oral ulcers

 Subacute cutaneous or discoid lupus

 Acute cutaneous lupus

Arthritis domain

 Synovitis or tenderness in at least 2 joints

Neurologic domain

 Delirium

 Psychosis

 Seizure

Serositis domain

 Pleural or pericardial effusion

 Acute pericarditis

Hematologic domain

 Leukopenia

 Thrombocytopenia

 Autoimmune hemolysis

Renal domain

 Proteinuria >0.5 g/24 hours

 Class II or V lupus nephritis

 Class III or IV lupus nephritis

Immunological domains

Points**

Antiphospholipid antibody domain

 Anti-cardiolipin IgG >40 GPL

Or anti-β

-glycoprotein I IgG >40 units

Or lupus anticoagulant

Complement proteins domain

 Low C3 or low C4

 Low C3 and low C4

Highly specific antibodies domain

 Anti-dsDNA antibody

 Anti-Sm (Anti-Smith) antibody

* In order to be classified as having SLE, patients must have all of the following: (a) ANA

≥1:80 (entry criterion); (b) ≥10 points in total; and (c) at least one clinical criterion

N.B. Classification criteria are designed to identify a homogeneous population for research

studies and are not diagnostic criteria, although they are often used for diagnosis in practice

** Only the highest criterion in a given domain is counted toward total number of points

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Other clinical features of SLE not included in any of the above classification criteria:

o Additional constitutional symptoms (i.e. fatigue, weight loss, anorexia)

o Other rashes (e.g. annular erythema, maculopapular or linear (nonspecific) rash, bullous

lupus (rare), palmar/plantar/periungual erythema, livedo reticularis, or vasculitic rash)

o Myalgia, and/ or myositis

o Raynaud phenomenon (see Section 7E)

o Lymphadenopathy

o Hepatomegaly, splenomegaly

o Decreased concentration and cognitive dysfunction, stroke, mood disorder, headache

o Pneumonitis, pulmonary hemorrhage

o Myocarditis, Libman-Sacks endocarditis

 Other common laboratory features of SLE:

o Elevated ESR with normal CRP (except high CRP in infection and/or serositis)

o Elevated IgG levels

o Other autoantibodies: anti-Ro, anti-La, anti-RNP, Rheumatoid factor

 May be accompanied by macrophage activation syndrome (MAS) at onset or anytime during

course

 Treatment

o Use minimum required treatment to maintain clinical and laboratory quiescence

o More aggressive treatment used for more severe organ involvement

o Hydroxychloroquine (Plaquenil™)

 Considered standard therapy for SLE

 Proven efficacy in decreasing frequency and severity of disease flares

 Improves serum lipid profile

 May be helpful in lowering antiphospholipid antibody titres and preventing thrombotic

recurrences in patients with SLE

o Corticosteroids

 Often used in initial therapy for SLE with dose depending on severity and organ

involvement

 Pulse (very high dose) therapy is used for severe lupus nephritis, hematologic crisis,

CNS disease or other life or organ-threatening manifestations

o Azathioprine

 Typically used for hematologic and renal manifestations

o Mycophenolate mofetil

 Used for hematologic, renal and CNS manifestations

o Cyclophosphamide

 Used for severe renal and CNS manifestations

o Rituximab

 Used for resistant thrombocytopenia and in other specific scenarios, such as when a

patient is unresponse to other therapies

o Belimumab

 Adjunctive therapy for mild/moderate SLE (trials excluded those with severe CNS

and renal involvement)

 Course and Outcomes

o Relapsing and remitting course of disease

o 10-year survival >90%

o Most deaths related to infection, renal, CNS, cardiac, and pulmonary disease

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o Additional morbidity related to disease and/or treatment:

 Early-onset coronary artery disease

 Bone disease → osteopenia, osteoporosis, avascular necrosis

 Malignancy

 Infection

 Childhood-onset SLE vs. adult-onset SLE

 Children have more active disease at presentation and over time

 Children more likely to have active renal disease (~70% vs. 30-60% in adults)

 Children receive more intensive drug therapy and sustain more long-term damage

References:

1. Harry O, et al. Childhood-onset systemic lupus erythematosus: a review and update. J

Pediatr 2018; 196:22-30.

2. Tarvin SE, O’Neil KM. Systemic lupus erythematosus, Sjögren syndrome, and mixed

connective tissue disease in children and adolescents. Ped Clin North Am 2018;

65(4):711-37.

3. Weiss JE. Pediatric systemic lupus erythematosus: More than a positive antinuclear

antibody. Pediatr Rev 2012; 33(2):62-73.

4. Tedeschi SK, et al. Multicriteria decision analysis process to develop new classification

criteria for systemic lupus erythematosus. Ann Rheum Dis 2019; 78(5):634-40.

4B. Neonatal Lupus Erythematosus (NLE)

 Disease of developing fetus and newborn characterized by transplacental passage of

maternal autoantibodies

 Pathogenesis linked to maternal anti-Ro and anti-La antibodies

 Presence of autoantibodies is necessary but not sufficient to cause NLE since many

mothers with autoantibodies deliver healthy, unaffected infants

 Mothers of infants with NLE may have SLE, Sjögren syndrome, or another autoimmune

disease; however, many mothers are healthy with no known autoimmune disease

 Incidence of NLE is 1-2% in children of mothers with anti-Ro and/or anti-La antibodies

 Higher risk for subsequent children once one child has been affected (e.g. 16% of

subsequent siblings of child with congenital heart block)

 Clinical features

o Cardiac

 Most important and severe manifestation is complete congenital atrioventricular (AV)

heart block

 Complete heart block is associated with significant morbidity and mortality

(congestive heart failure, fetal hydrops, intrauterine death)

 Other manifestations include less severe conduction abnormalities, carditis and risk

of endocardial fibroelastosis

o Skin

 Classic NLE rash is annular, erythematous papulosquamous rash with fine scale and

central clearing

 Predilection for face and scalp (not malar distribution)

 Typically photosensitive

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Dermatitis may be present at birth, but commonly develops in first 6 weeks of life

 New lesions appear for several months, but rarely develop after 6 months and

typically heal without scarring

 Telangiectasias may develop starting at 6-12 months of age, may not be in areas

affected by previous rash

o Hematologic

 Thrombocytopenia is most common

 Neutropenia and anemia are less common

 Usually resolve without sequelae and rarely require treatment

 Neutropenia is not typically associated with increased risk of infection

o Hepatic

 Asymptomatic cholestatic hepatitis with mildly to moderately elevated liver enzymes

 Hepatomegaly and less commonly splenomegaly

 May be the only manifestation(s) of NLE

 Typically resolves before 6 months without treatment

o Neurologic

 Reported CNS manifestations include macrocephaly, hydrocephalus, spastic

paraparesis, asymptomatic neuroimaging abnormalities, and vasculopathy

 Clinical significance still unclear

 Important to monitor head circumference

 Treatment

o If fetal bradycardia found during pregnancy, require fetal echocardiography to assess for

heart block and endocardial fibroelastosis (EFE) and may require treatment with

Dexamethasone/Betamethasone ± sympathomimetics

o Pacemaker may be required soon after birth for neonates with complete heart block

o Classic NLE rash does not require treatment (although sun avoidance and sunscreen

are recommended) since rash will completely resolve; Corticosteroids may hasten

healing, but may increase risk of telengiectasias

o Severe cytopenias may require treatment with IVIG

o Future pregnancies require expectant management with fetal heart rate monitoring and

mothers with autoantibodies may be treated with Hydroxychloroquine (Plaquenil)

References:

1. Vanoni F, et al. Neonatal systemic lupus erythematosus syndrome: a comprehensive

review. Clin Rev Allergy Immunol 2017; 53(3):469-76.

2. Johnson B. Overview of neonatal lupus. J Pediatr Health Care 2014; 28(4):331-41.

4C. Drug-Induced Lupus

 Development of lupus-like symptoms that is temporally related to continuous drug exposure

(>1 month) and that resolves with cessation of the offending drug

 Usually accompanied by serologic findings of positive ANA as well as anti-histone

antibodies (in approximately 90% of patients)

 Variable time from drug exposure to onset of symptoms

 Onset generally insidious

 Patients commonly present with fever, arthralgias or arthritis, myalgias and serositis

 Usually mild, although life threatening disease has been reported

 Rarely involve classic malar or discoid rash, oral ulcers or major organ involvement

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Laboratory findings may include mild cytopenias, high ESR

 Drugs that have been implicated in drug-induced lupus include: Minocycline,

anticonvulsants, Hydralazine, and biologic agents that target tumor necrosis factor (TNF)

 Treatment

o Stop the offending drug

o Corticosteroids and/or Hydroxychloroquine (Plaquenil™) may be used for moderate to

severe manifestations (e.g. cardiac tamponade)

References:

1. Vaglio A, et al. Drug-induced lupus: Traditional and new concepts. Autoimmun Rev

2018; 17(9):912-8.

4D. Antiphospholipid Syndrome (APS)

 Systemic autoimmune disorder characterized by recurrent arterial and/or venous thrombosis

and elevated levels of one or more antiphospholipid antibodies

 Primary APS if occurs without apparent underlying disease

 Secondary APS due to SLE, other autoimmune diseases, drugs or viral infections (e.g. HIV)

 Venous thrombosis in ~60%, arterial thrombosis in ~30%, small vessel thrombosis in ~5%,

and mixed thrombosis in ~2%

 Thrombotic manifestations are most common, followed by hematologic, skin and non-

thrombotic neurologic manifestations

Adaptation of the Updated Sapporo Classification Criteria for Pediatric APS Patients *

Definite APS is considered to be present if the clinical criterion and at least 1 of the laboratory

criteria are met

Clinical criterion:

 Vascular thrombosis: ≥1 clinical episode(s) of arterial, venous, or small vessel thrombosis

in any tissue or organ confirmed objectively by validated criteria

Laboratory criteria:

 Lupus anticoagulant on ≥ 2 occasions at least 12 weeks apart

 Anticardiolipin antibody (IgG and/or IgM isotype) in medium or high titre (>40 GPL or MPL,

or >99

percentile) on ≥ 2 occasions at least 12 weeks apart

 Antibodies to β

-glycoprotein I (IgG and/or IgM isotype) in medium or high titre (>99

percentile) on ≥ 2 occasions at least 12 weeks apart

* Classification criteria are designed to identify a homogeneous population for research

studies and are not diagnostic criteria, although they are often used for diagnosis in practice

 Higher risk of thrombosis associated with higher antibody titres, IgG isotype and specific

antibodies (e.g. anti-cardiolipin and lupus anticoagulant)

 Deep venous thrombosis is the most common type of venous thrombosis, while stroke is the

most common type of arterial thrombosis (see Section 2: Differential Diagnosis of stroke-like

presentations in children)

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Additional clinical features of APS:

o Livedo reticularis, Raynaud phenomenon, and skin ulcers

o Cardiac valve disease (Libman-Sachs endocarditis)

o Chorea

o Seizures

o Transient cerebral ischemia

o Transverse myelopathy

 Additional laboratory features of APS:

o Thrombocytopenia

o Hemolytic anemia

o Additional antibodies to prothrombin, annexin, and/or other phospholipids

o False positive VDRL

 Treatment

o If primary, treat as a disorder of coagulation

o If secondary (most commonly due to SLE), treat underlying disorder (often using

Corticosteroids and/or Hydroxychloroquine)

o Anticoagulation using heparin (e.g. low molecular weight heparin (LMWH)) is usually

required at least initially, but patients could require LMWH or warfarin therapy lifelong

o Consider anti-platelet agents (e.g. ASA)

o May consider Rituximab as direct therapy to target pathogenic autoantibodies in APS

References:

1. Rumsey DG, et al. Diagnosis and treatment of antiphospholipid syndrome in childhood:

A review. Blood Cells Mol Dis 2017; 67:34-40.

2. Aguiar C, et al. Pediatric antiphospholipid syndrome. Curr Rheumatol Rep 2015;

17(4):27.

3. Avcin T, et al. Pediatric antiphospholipid syndrome: Clinical and immunologic features of

121 patients in an international registry. Pediatrics 2008; 122(5):e1100-7.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 5 – SYSTEMIC VASCULITIS

5A. Introduction to Vasculitis

 Group of multi-system inflammatory diseases characterized by inflammation and necrosis of

blood vessels, resulting in vessel occlusion and tissue ischemia

 Consider vasculitis when:

o Unexplained prolonged constitutional symptoms (fever, weight loss, fatigue)

o Multiple organ system involvement – see table below:

Organ System

Clinical features that suggest possible systemic vasculitis

Head and Neck

Chronic sinusitis

Epistaxis

Chronic otitis

Hearing loss

Chondritis

Ophthalmologic

Episcleritis

Iritis

Panuveitis

Retinitis

Central nervous system

Headaches

Seizures

Strokes

Cardiac

Pericarditis

Myocarditis

Myocardial infarction

Pulmonary

Hemorrhage

Nodules

Cavities

Infiltrates

Renal

Nephritis

Nephrotic syndrome

Hypertension

Rapidly progressive renal failure

Gastrointestinal

Ischemic abdominal pain

Dermatologic

Palpable purpura

Nodules

Livedo reticularis

Ulcers

Vascular

Chronic vascular insufficiency

Vascular bruits

Claudication

Peripheral nervous system

Mononeuritis

Musculoskeletal

Arthritis, arthralgia

Myalgia, calf pain

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Classification of vasculitis based on size of vessel (predominantly) involved

Large vessel vasculitis

Takayasu arteritis

Giant cell arteritis (older adults)

Medium vessel vasculitis

Kawasaki disease

Polyarteritis nodosa (systemic, cutaneous)

Small vessel vasculitis

Immune complex vasculitis

 IgA vasculitis (Henoch-Schönlein purpura)

 Cryoglobulinemia

 Hypocomplementemic urticarial vasculitis

ANCA-associated vasculitis

 Microscopic polyangiitis

 Granulomatosis with polyangiitis (previously Wegener

granulomatosis)

 Eosinophilic granulomatosis with polyangiitis (previously

Churg-Strauss Syndrome)

Variable vessel vasculitis

Behçet disease

Cogan syndrome

Other vasculitis

Primary CNS vasculitis (see Section 10)

Primary cutaneous vasculitis

Vasculitis secondary to drugs, infection (e.g. hepatitis B virus,

Parvovirus), or malignancy

Monogenic disease causing vasculitis (e.g. Deficiency of

Adenosine Deaminase 2)

 Investigations

o Look for end-organ damage (eyes, skin, heart, lungs, kidneys, nervous system)

o Look for triggers or underlying disease (drugs, malignancy, infection, CTD)

o Inflammatory markers (CRP, ESR)

o Immune serology (ANA, ANCA)

o Tissue biopsy (histopathology & immunofluorescence)

o Angiography (conventional; magnetic resonance; computed tomography); vessel wall

itself may be assessed using magnetic resonance or computed tomography

 Treatment

o Depends on specific disease, organ involvement, severity

o Immunosuppressive agents plus supportive therapy

 Potential complications

o Acute: organ failure (renal, pulmonary, cardiac), hemorrhage (pulmonary, GI), thrombus

(renal, pulmonary, coronary, cerebral, GI vessels), infection (often treatment-related)

o Chronic: hypertension, renal failure, pulmonary insufficiency, hearing loss, saddle nose

deformity, subglottic stenosis, hemiplegia, neuropathy

References:

1. Barut K, et al. Pediatric Vasculitis. Curr Opin Rheumatol 2016; 28:29-38.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

2. Jennette JC, et al. 2012 Revised International Chapel Hill Consensus Conference

Nomenclature of Vasculitides. Arthritis Rheum 2013; 65(1):1-11.

3. Weiss P. Pediatric Vasculitis. Pediatr Clin North Am 2012; 59(2):407-23.

5B. Takayasu arteritis

2008 EULAR/PRINTO/PRES Classification Criteria for Childhood Takayasu arteritis *

Angiographic abnormalities of the aorta or its main branches and pulmonary arteries showing

aneurysm/dilatation, narrowing, or thickened arterial wall (mandatory criterion)

Plus ≥ 1/5 of the following:

 Peripheral pulse deficit or claudication (focal muscle pain induced by physical activity)

 Discrepancy of four limb systolic BP >10 mm Hg in any limb

 Bruits or thrills over the aorta and/or its major branches

 Hypertension (>95

percentile for height)

 Acute phase reactants (ESR >20 or increased CRP)

* Classification criteria are designed to identify a homogeneous population for research studies

and are not diagnostic criteria, although they are often used for diagnosis in practice

 Large vessel vasculitis involving the aorta and its branches (thoracic, abdominal, carotid)

 Chronic, relapsing disease

 Initially can present as non-specific inflammatory illness with fever

 Evolution to chronic, fibrotic phase with signs and symptoms of chronic vascular

insufficiency (pulse deficit, claudication, BP discrepancy, bruits)

 Investigations

o Magnetic resonance angiography useful to show extension of disease and vessel wall

inflammation; often used to follow disease (less invasive than conventional angiography)

o Rule out associated TB infection (PPD, chest X-ray)

 Treatment

o Depends on degree of inflammation

o If “active” disease (by acute phase reactants +/- wall enhancement on MRA):

 Corticosteroids plus second line agent

 Second line agents include Methotrexate, Mycophenolate mofetil, Infliximab or

Adalimumab

 May also use Tocilizumab, Cyclophosphamide, or Rituximab if refractory disease

o If “inactive” disease:

 Manage end-organ manifestations (medical therapy +/- vascular surgery)

References:

1. Ozen S, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood

polyarteritis nodosa, childhood Wegener’s granulomatosis and childhood Takayasu

arteritis: Ankara 2008. Ann Rheum Dis 2010; 69(5):798-806.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

2. Brunner J, et al. Takayasu arteritis in children and adolescents. Rheumatology 2010;

49:1806-14.

3. de Ranieri D. Great vessels of children: Takayasu’s arteritis. Pediatr Ann 2015;

44(6):e148-52.

5C. Kawasaki disease (KD)

Diagnostic Criteria for Kawasaki disease *

Fever persisting for ≥5 days

Plus ≥4/5 of the following:

 Changes in peripheral extremities (edema/erythema) or perineal area (erythema/peeling)

 Polymorphous exanthem

 Bilateral conjunctival injection, non-exudative

 Changes of lips and oral cavity (injection of oral and pharyngeal mucosa, fissured lips,

strawberry tongue)

 Cervical lymphadenopathy (frequently unilateral, ≥1.5 cm)

* Other ways to make diagnosis of KD:

a) In presence of fever and coronary artery involvement on echo, <4/5 criteria sufficient

b) Incomplete KD diagnosed if ≥5 days of fever with 2 or 3 features (common in infants,

who are at higher risk of coronary artery involvement)

c) Atypical KD diagnosed if KD with an unusual manifestation (e.g. renal failure)

 Medium vessel vasculitis, with predilection for coronary arteries

 Most common between 1 and 5 years of age

 Most common cause of acquired heart disease in children in developed countries

 May be triggered by infectious agent (viral and/or bacterial super-antigen implicated)

 Polygenic with genes identified that influence risk of KD and coronary artery involvement

 Clinical features

o Common: irritability (aseptic meningitis), arthritis (at onset or delayed), sterile pyuria

(urethritis), gastroenteritis (abdominal pain, vomiting, diarrhea), uveitis, periungual

desquamantion in weeks 2 or 3 (subacute phase)

o Uncommon: gallbladder hydrops, GI ischemia, jaundice

o Cardiac involvement: myocarditis, pericarditis, cardiac failure, valvular regurgitation

 Complications

o Coronary artery disease

 Major concern is the development of coronary artery aneurysms, which most

commonly occurs at 4-6 weeks after the acute illness

 Risk factors: males, infants <1 year or >9 years of age, prolonged fever, Asian or

Hispanic ethnicity, thrombocytopenia, hyponatremia

o KD shock syndrome (characterized by hypotension or poor perfusion)

o Macrophage activation syndrome (MAS)

o Dissemeniated intravascular coagulation

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Investigations

o Leukocytosis with left shift, normocytic anemia, elevated ESR/CRP, hypoalbuminemia,

hyponatremia, may have elevated transaminases

o Thrombocytosis in second week of illness with return to normal by 4-8 weeks

o Echoardiogram required at the time of diagnosis and 6 weeks later

 Treatment

o See treatment algorithm on next page

o Target treatment within 10 days of fever onset

o IVIG

o Unequivocally reduces the occurrence of coronary artery aneurysms

 Recommended dose 2 g/kg

 If still febrile 24-36 hours after IVIG → second dose of IVIG

 Consider monitoring for IVIG-related hemolysis with CBC, blood film, reticulocytes

and direct antiglobulin test initially at 24-92 hours and then at 5-7 days after IVIG

o ASA

 Historically, started with high-dose ASA 80-100 mg/kg/day (anti-inflammatory) until

afebrile x 24 hours, then switched to low-dose 3-5 mg/kg/day (anti-platelet)

 Many centres now start with low-dose ASA 3-5 mg/kg/day

 Low-dose ASA (and/or other antiplatelet agents) may be continued longer than 6

weeks in patients with coronary artery aneurysms

o Corticosteroids

 May be used with first dose of IVIG in patients at high risk of coronary artery disease

(see risk factors above) or may be reserved for patients with refractory fever after

two doses of IVIG

 Additional indications: myocarditis, MAS, Kawasaki shock-syndrome

 Common treatment regimens include IV Methylprednisolone for 1-3 days or

Prednisone PO 2 mg/kg/day for 3 days or for a longer course with slow wean in high-

risk patients

o If large coronary aneurysm → Abciximab (glycoprotein IIb/IIIa receptor inhibitor) in acute

or subacute phase; long-term antiplatelet (+ Heparin or Warfarin if giant aneurysm)

 Prognosis

o In-hospital mortality 0.17% (all cardiac-related)

o ~ 2% risk of recurrent KD

o Without treatment, coronary artery aneurysms occur in ~25% of patients → reduced to

~4% if IVIG treatment within 10 days

o If coronary artery aneurysm → risk for thrombosis, obstruction and stenosis, ventricular

dysfunction/arrhythmia, early atherosclerosis, myocardial infarction (highest if ≥8 mm)

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

An algorithm for treatment of Kawasaki disease

References:

1. McCrindle BW, et al. Diagnosis, treatment, and long-term management of Kawasaki

disease: A scientific statement for health professionals from the American Heart

Association. Circulation 2017; 135:e927-99.

2. Yellen ES, et al. Performance of 2004 American Heart Association recommendations for

treatment of Kawasaki disease. Pediatrics 2010; 125(2): e234-e241.

3. Scuccimarri R. Kawasaki disease. Ped Clin North Am 2012; 59(2):425-445.

5D. Polyarteritis nodosa (PAN)

 Necrotizing vasculitis in medium or small size muscular arteries

 Very rare in childhood

Corticosteroids (see text)

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

2008 EULAR/PRINTO/PRES Classification Criteria for Childhood PAN *

Systemic illness characterized by:

 Histological findings of necrotizing vasculitis in medium or small sized muscular arteries,

 Angiography showing aneurysm, stenosis or occlusion of medium or small sized arteries

Plus ≥1/5 of the following:

 Skin involvement (livedo reticularis, tender subcutaneous nodules, superficial skin

infarctions, or deep skin infarctions)

 Myalgia or muscle tenderness

 Hypertension (>95

percentile for height)

 Peripheral neuropathy (motor mononeuritis multiplex, sensory peripheral neuropathy)

 Renal involvement (proteinuria >0.3 g in 24 hrs, hematuria, red blood cell casts, impaired

renal function)

* Classification criteria are designed to identify a homogeneous population for research studies

and are not diagnostic criteria, although they are often used for diagnosis in practice

Systemic PAN

 Additional clinical features

o Constitutional symptoms, including prolonged fever

o Testicular pain or tenderness

o Stroke or coronary artery disease

o Bruits

o Ischemic abdominal pain

 Laboratory features

o Leukocytosis, thrombocytosis, and elevation of ESR and CRP

o Positive hepatitis B serology can occur although it is unusual

 Treatment

o Prednisone plus second line agent (e.g. Methotrexate, Cyclophosphamide, Azathioprine,

Mycophenolate mofetil)

o Plasma exchange may be considered in acute life-threatening disease

Cutaneous PAN

 Clinical syndrome characterized by absence of major organ involvement, but may involve

skin, joints, muscles and peripheral nervous system

 Skin findings (tender subcutaneous nodules, livedo reticularis, superficial or deep ulcers)

 Additional clinical features

o Constitutional features

o Myalgia, arthralgia, non-erosive arthritis

o Peripheral neuropathy

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Investigations

o Diagnosis requires deep skin biopsy to get small muscular arteries showing necrotizing,

non-granulomatous vasculitis

o Negative testing for ANCA

o May be associated with serological (ASOT) or culture evidence of Streptococcal

infection

 Treatment

o Corticosteroids with rapid wean or another second line agent (e.g. IVIG, Methotrexate)

o Penicillin treatment (if proven associated Streptococcal infection) and prophylaxis

Deficiency of Adenosine Deaminase 2 (DADA2)

 Consider in differential diagnosis of polyarteritis nodosa

 Recently identified monogenic autoimmune recessive disease (mutations in ADA2 gene)

leading to vasculitis

 Clinical features are variable, depending on mutation type and number of affected alleles

 Common features:

o Recurrent lacunar stroke (ischemic or hemorrhagic) with onset at young age

o Fever

o Vasculitis, including polyarteritis nodosa

o Livedo reticularis

o Hepatosplenomegaly

o Various ophthalmologic manifestations

 Investigations

o Elevated inflammatory markers

o Diagnosis confirmed through genetic testing

o MRI brain to assess for stroke

 Treatment

o TNF-inhibitors have been successful in suppressing fever, vasculopathy and strokes

o Hematopoetic stem cell transplantation may offer definitive treatment

o Future therapies may include recombinant ADA2 protein or gene therapy

References:

1. Ozen S, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood

polyarteritis nodosa, childhood Wegener’s granulomatosis and childhood Takayasu

arteritis: Ankara 2008. Ann Rheum Dis 2010; 69(5):798-806.

2. Beckum KM, et al. Polyarteritis nodosa in childhood: recognition of early dermatologic

signs may prevent morbidity. Pediatr Dermatol 2014; 31(1):e6-9.

3. Falcini F, et al. Clinical overview and outcome in a cohort of children with polyarteritis

nodosa. Clin Exp Rheumatol 2014; 32(3 Suppl 82):S134-7.

4. Ombrello AK, et al. Treatment strategies for deficiency of adenosine deaminase 2. N

Engl J Med. 2019; 380(16):1582-84.

5E. IgA Vasculitis (also known as Henoch-Schönlein Purpura, or HSP)

 Most common vasculitis in children

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Often follows a respiratory infection, most commonly Group A Streptococcus

 Predominantly small vessel vasculitis, characterized by IgA deposition and leukocytoclastic

vasculitis

2008 EULAR/PRINTO/PRES Classification Criteria for Childhood HSP *

Purpura (commonly palpable and in crops) or petechiae with lower limb predominance **

Plus ≥1/4 of the following:

 Diffuse abdominal colicky pain with acute onset (may include intussusceptions and

gastrointestinal bleeding)

 Skin biopsy showing leukocytoclastic vasculitis with predominant IgA deposits, or kidney

biopsy showing proliferative glomerulonephritis with predominant IgA deposits

 Arthritis or arthralgias of acute onset

 Renal involvement (proteinuria >0.3 g in 24 hrs, hematuria, or red blood cell casts,

impaired renal function)

* Classification criteria are designed to identify a homogeneous population for research

studies and are not diagnostic criteria, although they are often used for diagnosis in practice

** If purpura in atypical distribution, demonstration of IgA deposition is required

 Clinical features

o Cutaneous purpura (100% of patients) with palpable lesions 2-10 mm in diameter,

usually concentrated on lower extremities

o Arthritis (75%) usually affecting knees and ankles, associated with painful oedema

o GI involvement (50-75%), including abdominal pain and intussusception

o Renal involvement (40-50%)

 Most commonly microscopic hematuria

 Proteinuria accompanies hematuria in 25%

 Nephrotic syndrome in 5%

 Renal abnormalities may not manifest initially, thus must regularly monitor blood

pressure and urinalysis x 6 mos after acute illness

o Orchitis (10-20% of males) associated with pain and swelling

 Investigations

o No distinctive or diagnostic laboratory abnormalities

o May have elevated WBC, platelets, ESR and/or CRP

o Coagulation profile must be normal and thrombocytopenia should be absent

o Serum IgA increased in 50% of patients

o Biopsy of skin or kidneys may be needed (see classification criteria above)

 Treatment

o Largely supportive

o NSAIDs may be used for joint pain (caution required due to potential renal involvement)

o Prednisone in select patients

 May decrease severity and duration of GI symptoms and may help bullous lesions

 Unclear impact on risk of persistent renal disease (controversial)

 No definite benefit for prevention of HSP recurrence

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o If severe nephritis (e.g. nephrotic syndrome, decreased renal function, crescentic

nephritis): pulse IV Methylprednisolone ± second line agent (e.g. Azathioprine,

Mycophenolate mofetil, Cyclophosphamide)

 Prognosis

o Usually a self-limited condition that resolves within 4 weeks (average)

o Recurrence occurs in about 1/3 of patients

o Long-term prognosis depends on severity of nephritis (poorer prognosis with nephrotic

syndrome or if >50% crescent formation on biopsy)

o End-stage renal disease occurs in 1-3% of patients; in ~20% of those with nephritic or

nephrotic syndrome (N.B. % varies among different studies)

References:

1. Gonzalez-Gay MA, et al. IgA vasculitis: Genetics and clinical and therapeutic

management. Curr Rheumatol Rep 2018; 20(5):24.

2. Ozen S, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood

polyarteritis nodosa, childhood Wegener’s granulomatosis and childhood Takayasu

arteritis: Ankara 2008. Ann Rheum Dis 2010; 69(5):798-806.

3. Hahn D, et al. Interventions for preventing and treating kidney disease in Henoch-

Schönlein Pupura (HSP). Cochrane Database of Systematic Reviews 2015;

8:CD005128.

4. Weiss PK, et al. Corticosteroids may improve clinical outcomes during hospitalization for

Henoch-Schönlein purpura. Pediatrics 2010; 126(4):674-81.

5F. Granulomatosis with Polyangiitis (GPA, formerly Wegener Granulomatosis)

 Predominantly small vessel vasculitis, characterized by granulomatous inflammation

 Generally occurs in the second decade of life, with a female preponderance

 Hallmark of GPA is triad of upper and lower respiratory tract inflammation and renal disease

2008 EULAR/PRINTO/PRES Classification Criteria for Childhood GPA *

At least 3 of the 6 following criteria:

 Histopathology showing granulomatous inflammation within wall of artery or in

perivascular or extravascular area

 Upper airway involvement (chronic purulent or bloody nasal discharge, recurrent

epistaxis, nasal septum perforation, saddle nose deformity, chronic or recurrent sinus

inflammation)

 Laryngo-tracheo-bronchial involvement (subglottic, tracheal or bronchial stenoses)

 Pulmonary involvement (nodules, cavities, or fixed pulmonary infiltrates)

 ANCA positive by immunofluorescence or ELISA

 Renal involvement (proteinuria >0.3 g in 24 hrs, hematuria, or red blood cell casts,

impaired renal function)

* Classification criteria are designed to identify a homogeneous population for research studies

and are not diagnostic criteria, although they are often used for diagnosis in practice

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Clinical features (in order of decreasing frequency)

o Constitutional: fatigue, malaise, fever, weight loss

o Pulmonary: dyspnea, chronic cough, hemoptysis/alveolar hemorrhage, lung

nodules/cavitations/fixed infiltrates

o Ear, nose and throat: nasal involvement (epistaxis, ulcers), sinusitis, otitis/mastoiditis,

hearing loss, subglottic involvement

o Renal: abnormal urinalysis, biopsy-proven glomerulonephritis, elevated creatinine, acute

renal failure

o Musculoskeletal: arthralgia/myalgia, arthritis

o Gastrointestinal: nonspecific abdominal pain, chronic nausea

o Eye: nonspecific red eye, conjunctivitis, scleritis

o Cutaneous: palpable purpura/petechiae

o Neurological: severe headache, dizziness

 Investigations

o ANCA positive in ~90% of patients (~80% are c-ANCA positive with anti-PR3 positivity)

 Treatment

o Initial therapy involves combination of Corticosteroids and a second-line agent, such as

Cyclophosphamide, Rituximab or Methotrexate (choice depends on disease severity)

o Plasma exchange may be used as part of induction therapy for children with life-

threatening disease

o Maintenance therapy with Methotrexate, Azathioprine, Rituximab, plus tapering doses of

Corticosteroids

o May consider endoscopic intervention for subglottic stenosis and endobronchial disease

 Prognosis

o Significant morbidity associated with disease and medications

o Rare complications include mechanical ventilation and dialysis in around 10% of patients

References:

1. Jariwala MP, Laxer RM. Primary vasculitis in childhood: GPA and MPA in childhood. Front

Pediatr 2018; 16(6):226.

2. Ozen S, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood

polyarteritis nodosa, childhood Wegener’s granulomatosis and childhood Takayasu

arteritis: Ankara 2008. Ann Rheum Dis 2010; 69(5):798-806.

3. Villa-Forte A. EULAR /European vasculitis study group recommendations for the

management of vasculitis. Curr Opin Rheumatol 2010; 22:49-53.

4. McGeoch L, et al. CanVasc recommendations for the management of antineutrophil

cytoplasm antibody (ANCA)-associated vasculitides. Can J Kidney Health Dis 2015;

2(43):1-6.

5G. Microscopic Polyangiitis (MPA)

 Pauci-immune, necrotizing, non-granulomatous small vessel vasculitis

 Rare in childhood

 No classification criteria have been developed

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Clinical features

o Rapidly progressive, necrotizing, crescentic glomerulonephritis (90% of patients)

o Pulmonary capillaritis leading to hemorrhage (30-60%)

o Pulmonary-renal syndrome (30-50%)

o Hypertension (50-60%)

o Palpable purpura (common)

o May have refractory anemia

 Diagnosis

o Serology: 50-75% p-ANCA positive with anti-MPO on ELISA

o Renal biopsy with immunofluorescence: pauci-immune glomerulonephritis

 Treatment

o Induction: Corticosteroids + Cyclophosphamide, Methotrexate or Rituximab

o Maintenance: Azathioprine, Methotrexate, or Rituximab

References:

1. Jariwala MP, Laxer RM. Primary vasculitis in childhood: GPA and MPA in childhood. Front

Pediatr 2018; 16(6):226.

2. Cabral D, et al. Comparing presenting clinical features in 48 children with microscopic

polyangiitis to 183 children who have granulomatosis with polyangiitis (Wegener's): An

ARChiVe Cohort Study. Arthritis Rheumatol 2016; 68(10):2514-26.

3. Sun L, et al. Clinical and pathological features of microscopic polyangiitis in 20 children.

J Rheumatol 2014; 41(8):1712-9.

5H. Eosinophilic Granulomatosis with Polyangiitis (formerly Churg-Strauss Syndrome)

 Granulomatous small vessel vasculitis

 No EULAR/PRINTO/PRES classification criteria – very rare in children

 Characterized by:

o Preceding history of “difficult to control” chronic asthma

o Paranasal sinus abnormalities

o Peripheral eosinophilia (≥10%) + eosinophilic infiltration on biopsy

o Non-fixed pulmonary infiltrates

o Peripheral neuropathy

 Additional clinical features

o Cardiovascular (50%): myocardial ischemia, pericarditis, cardiac failure

o Ischemic abdominal pain

o Cutaneous nodules

 Diagnosis

o Biopsy (lung, skin) showing eosinophilic infiltrates and granulomas

o Peripheral eosinophilia and increased IgE levels

o ANCA, usually anti-MPO, present in less than 50% patients

 Treatment

o Prednisone plus second line agent

o Cyclophosphamide or Rituximab if cardiac, GI or neurologic involvement

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

References;

1. Gendelman S, et al. Childhood-onset eosinophilic granulomatosis with polyangiitis

(formerly Churg-Strauss syndrome) : a contemporary single-center cohort. J Rheumatol

2013; 40(6):929-35.

2. Boyer D, et al. Churg-Strauss syndrome in children: A clinical and pathologic review.

Pediatrics 2006; 118:e914-20.

5I. Behçet Disease

 Systemic vasculitis with characteristic oral and genital ulcers, vasculopathy and uveitis

 Among the systemic vasculitides, Behçet disease is remarkable for its ability to involve

arteries and veins of all sizes (small, medium, large)

 More common in certain ethnic groups along the “Silk Road” (Turks, Greeks)

 Uncommon in children

1990 International Study Group for Behçet Disease Criteria for Diagnosis

 Recurrent oral ulcers (major or minor aphthous ulcers, or herpetiform ulceration recurring

at least 3 times in 12 months)

Plus ≥ 2 of the following criteria:

 Recurrent genital ulcers (aphthous ulceration or scarring)

 Eye lesions (including anterior or posterior uveitis, cells in vitreous on slit lamp

examination, or retinal vasculitis, observed by an ophthalmologist)

 Skin lesions (including erythema nodosum, pseudofolliculitis, papulopustular lesions, or

acneiform nodules consistent with Behçet)

 Pathergy (skin papule 2 mm or more in size developing 24 to 48 hours after oblique

insertion of a 20-25 gauge needle 5 mm into the skin, generally of the forearm)

2014 International Classification Criteria for Behçet Disease *

 Ocular lesions (anterior or posterior uveitis or retinal vasculitis)

 Genital aphthosis

 Oral aphthosis

 Skin lesions (erythema nodosus, pseudofolliculitis, skin aphthosis)

 Neurologic manifestations (peripheral and central)

 Vascular manifestations (arterial and/or venous thrombosis, phlebitis)

 Positive pathergy test

2 points

1 point

Bonus point

* Patients with total score ≥4 are classified as having Behçet disease

N.B. Classification criteria are designed to identify a homogeneous population for research

studies and are not diagnostic criteria, although they are often used for diagnosis in practice

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Other clinical features include:

o CNS: aseptic meningitis, encephalitis, cerebral venous sinus thrombosis, or

pseudotumour cerebri

o MSK: oligoarthritis or polyarthritis

o GI: abdominal pain, diarrhea, colitis

o Vascular: arterial and/or venous thrombosis

 Diagnosis

o Currently made clinically

o Several sets of diagnostic criteria have been proposed (see above)

o No pathognomonic clinical finding or laboratory test to provide definitive diagnosis

o Genetics may be helpful – HLA-B51 (more prevalent in Mediterranean and Far East) and

HLA-B51 (more prevalent in East Asian)

 Treatment

o No controlled studies have been performed on children

o Corticosteroids, Colchicine, Thalidomide, and Anti-TNF agents (e.g. Infliximab) have

been shown to be helpful

o May treat isolated oral and/or genital ulcers with topical therapy, including analgesics

and/or steroids

o Apremilast (an oral phosphodiesterase 4 inhibitor) has recently been demonstrated to be

effective for treatment of oral ulcers in Behçet disease

References:

1. Demir S, et al. Vasculitis in systemic autoinflammatory diseases. Front Pediatr 2018;

6:377.

2. Koné-Paut I. Behçet’s disease in children, an overview. Pediatr Rheumatol Online J

2016; 14(1):10.

3. Ozen S, Eroglu FK. Pediatric-onset Behçet disease. Curr Opin Rheumatol 2013;

25(5):636-42.

4. Hatemi G, et al. EULAR recommendations for the management of Behçet disease. Ann

Rheum Dis 2008; 67: 1656-1662.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 6 – IDIOPATHIC INFLAMMATORY MYOPATHIES

6A. Juvenile Dermatomyositis (JDM)

 JDM is an autoimmune myopathy characterized by capillary vasculopathy primarily affecting

skin and muscle

 Not associated with cancer in children, unlike dermatomyositis in adults

Bohan and Peter Criteria for Diagnosis of Juvenile Dermatomyositis

 Symmetrical proximal muscle weakness

 Characteristic skin changes, including Gottron papules on the dorsal surface of the

knuckles and heliotrope rash over the eyelids

 Elevated muscle enzymes, including CK, AST, LDH, aldolase

 Abnormal EMG demonstrating denervation and myopathy

 Abnormal muscle biopsy demonstrating necrosis and inflammation

 Recently, MRI has become an important diagnostic tool to look for muscle inflammation and

to direct a site for biopsy (if needed)

 Please see Section 2E for other diagnoses to consider when assessing a child with muscle

weakness

 Clinical features

o Proximal muscle weakness (which is present in 95% of patients) may be described on

history as difficulty getting up from sitting or lying, difficulty climbing stairs, and frequent

falls; also, children may demonstrate a Gower sign on physical exam (see

https://www.youtube.com/watch?v=IpoT46EAuCU)

o It is important to assess for 3D’s – dysphagia, dysphonia and dyspnea – that indicate

severe disease

o Nasal voice, difficulty swallowing and choking on foods (18-44%) may indicate weakness

of the palate and cricopharyngeal muscles

o Characteristic skin rashes include:

 Gottron papules (57-100%, but may be confused with psoriasis given location on

extensor surfaces, see https://www.nejm.org/doi/full/10.1056/NEJMicm1002816)

 Heliotrope rash (66-100%)

 Malar rash (42-73%)

 Photosensitive rashes

 Skin ulceration in severe cases.

o Capillary vasculopathy can be seen using capillaroscopy to look at changes in the nail

fold capillaries (91%) such as tortuosity, dilatation, and dropout

o Other organ systems may also be involved:

 Arthritis (23-58%)

 GI tract symptoms (22-37%), including dysphagia, GI ulceration, perforation

 Lungs (interstitial lung disease)

 Heart (cardiomyopathy) – very rare

o Constitutional features, such as fever and fatigue, are common

o Anasarca can be a rare initial manifestation and is associated with treatment resistance

and poor prognosis

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o Amyopathic JDM (skin features without muscle involvement) is rare in children and may

represent JDM with mild muscle involvement that has not yet been identified; however,

treatment to prevent future complications (e.g. calcinosis) is recommended

 Investigations

o Muscle enzymes (CK, AST, ALT, LDH, aldolase) and inflammatory markers (ESR, CRP)

likely to be elevated

o Positive ANA is common (up to 70% of patients) but not specific

o Myositis-specific antibodies (MSA) are identified in up to 2/3 of children with JDM, but

are not routinely available in all laboratories

MSA

Frequency

Associated Clinical Characteristics

Anti-p155/p140

60%

Rash (Gottron papules, malar rash, “shawl-sign” rash)

Photosensitivity

Low CK levels

Chronic illness course

Generalized lipodystrophy

Anti-MJ

20%

Muscles cramps

Dysphonia

High rate of hospitalization

Monocyclic disease course

Anti-synthetase

5-10%

Interstitial lung disease

“Mechanic’s hands”

Arthralgia

Older age at diganosis

Anti-Mi2

Hispanic ethnicity

Rash (Gottron papules, heliotrope rash, malar rash)

High CK

Low mortality

Anti-SRP

**In patients with

polymyositis

25%

Black race

Severe onset

Distal weakness

Raynaud phenomenon

Cardiac involvement

High CK levels

Chronic disease course, may require wheelchair use

Anti-MDA5

7.4%

Japanese and East Asian patients

Skin ulceration

Milder muscle disease

Arthritis

May have progressive interstitial lung disease

 Complications

o Long delays in diagnosis or insufficiently aggressive treatment may put patients at higher

risk for complications and poor outcome

o Muscle weakness and pain can lead to joint contractures

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o Soft tissue calcification, or calcinosis, can develop within a few years of diagnosis or

may be seen at presentation of longstanding disease (see

https://www.dermnetnz.org/topics/calcinosis-cutis/)

o Lipoatrophy may occur accompanied by hyperinsulinism, hypertriglyceridemia, liver

dysfunction, acanthosis nigricans, and type 2 diabetes

o Medication-related side effects from Corticosteroid toxicity (see Section 14) can include

infection, osteoporosis, growth delay, cataracts and glaucoma, type 2 diabetes, and

hypertension

 Monitoring disease activity

o Clinical: skin rash; periungual capillaroscopy; muscle strength and function as measured

by the Childhood Myositis Activity Scale (CMAS)

o Laboratory: muscle enzymes (CK, AST, ALT, LDH, aldolase), inflammatory markers

(ESR), lipid abnormalities & organ involvement

 Treatment

o Supportive: adequate nutrition, physiotherapy, exercise, sunscreen for photosensitive

rash

o Medications:

 Induction therapy using Corticosteroids starting from 1-2 mg/kg/day with slow taper

and subcutaneous Methotrexate

 Cyclophosphamide may be used for interstitial lung disease, gastrointestinal disease

and vasculitis

 IVIG, Cyclosporine, Mycophenolate mofetil or Rituximab if resistant or refractory

 Topical therapies may also be considered for resistant skin disease

 Course and Outcomes

o 40-60% of patients have a chronic course, 40-60% have a monophasic course, and <5%

have a polyphasic course

o Ongoing rash and nail fold abnormalities in first 6 months are best predictors of longer

time to remission

o Persistent skin and nail fold changes may represent ongoing inflammatory disease and

should be treated accordingly

o Outcomes are favourable, since most children have no functional disability and <10%

have moderate-to-severe disability

References:

1. Huber AM. Juvenile idiopathic inflammatory myopathies. Pediatr Clin North Am 2018;

65(4):739-56.

2. Huber A, Feldman BM. An update on inflammatory myositis in children. Curr Opin

Rheumatol 2013; 25(5):630-5.

3. Rider LG, et al. Developments in the classification and treatment of the juvenile

idiopathic inflammatory myopathies. Rheum Dis Clin North Am 2013; 39(4):10.

4. Rider LG, et al. The myositis autoantibody phenotypes of the juvenile idiopathic

inflammatory myopathies. Medicine (Baltimore) 2013; 92(4):223.

5. Huber AM, et al. Validation and clinical significance of the Childhood Myositis

Assessment Scale for assessment of muscle function in the juvenile idiopathic

inflammatory myopathies. Arthritis Rheum 2004; 50(5):1595-603.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

6B. Juvenile Polymyositis

 Uncommon in children

 Characterized by proximal and distal muscle weakness

 No associated skin findings and normal nail fold capillaries

 Myositis is typically more severe than in juvenile dermatomyositis or in other connective

tissue diseases

 Resistant to treatment

 Anti-signal recognition particle (SRP) autoantibodies are seen in children with polymyositis

and are associated with black race, severe onset, distal weakness, Raynaud phenomenon,

cardiac involvement, high CK levels, chronic disease course and wheelchair use

References:

1. Huber AM. Juvenile idiopathic inflammatory myopathies. Pediatr Clin North Am 2018;

65(4):739-56.

2. Huber A, Feldman BM. An update on inflammatory myositis in children. Curr Opin

Rheumatol 2013; 25(5):630-5.

3. Rider LG, et al. The myositis autoantibody phenotypes of the juvenile idiopathic

inflammatory myopathies. Medicine (Baltimore) 2013; 92(4):223.

6C. Myositis in other connective tissue diseases

 Myositis may be present in other connective tissue diseases, such as systemic lupus

erythematosus, systemic sclerosis, mixed connective tissue diseases and overlap

syndromes

 Please see Section 2E for other diagnoses to consider when assessing a child with muscle

weakness

 Typically accompanied by other features of the various connective tissue diseases, such as

arthralgia, malar rash, Raynaud phenomenon, interstitial lung disease

 Laboratory findings include high titres of ANA and myositis-associated antibodies

o Anti-PM-Scl and anti-Ku associated with scleroderma-myositis overlap syndrome

o Anti-U1-RNP associated with mixed connective tissue disease and overlap

syndromes

 Associated with higher mortality than other categories of myositis

References:

1. Huber AM. Juvenile idiopathic inflammatory myopathies. Pediatr Clin North Am 2018;

65(4):739-56.

2. Shah M, et al. The clinical phenotypes of the juvenile idiopathic inflammatory

myopathies. Medicine 2013; 92(1):25-41.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 7 – SCLERODERMA & RELATED SYNDROMES

7A. Classification of Scleroderma and Scleroderma-like Disorders

Morphea/ Localized scleroderma

(See Section 7B)

Circumscribed morphea

Linear scleroderma

Generalized morphea

Pansclerotic morphea

Mixed morphea

Systemic sclerosis

(See Section 7C)

Diffuse cutaneous *

Limited cutaneous **

Overlap syndromes

Scleroderma-like disorders

Graft versus host disease

Drug or toxin induced (e.g. L-tryptophan,

vinyl chloride, bleomycin)

Diabetic cheiroarthropathy

Phenylketonuria

Eosinophilia-myalgia syndrome

Eosinophilic fasciitis

Nephrogenic systemic fibrosis

Premature aging syndromes

*Diffuse cutaneous systemic sclerosis characterized by skin sclerosis extending proximal to

wrists and ankles and involving trunk and face; associated with internal organ involvement and

earlier organ dysfunction

Limited cutaneous systemic sclerosis (formerly known as CREST syndrome – calcinosis,

Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) progresses

more slowly, but has higher risk for later development of pulmonary hypertension

7B. Localized Scleroderma or Morphea

 Morphea refers to a group of autoimmune disorders with sclerotic skin and subdermal

connective tissue changes due to excessive accumulation of collagen

 25% of children can have extracutaneous manifestations: arthritis, uveitis, neurologic

findings (e.g. seizures, headache), Raynaud phenomenon

 Circumscribed morphea

o Includes superficial lesions sometimes referred to as “plaque” morphea

o May involve superficial and deep dermis as well as subcutaneous tissues

o Early lesions are firm, ivory-coloured oval lesions surrounded by reddish-lilac coloured

ring suggesting active inflammation

o Later, there is atrophy, hyper- ( or rarely hypo-) pigmentation and softening of lesions

o More common on trunk than extremities

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Generalized morphea

o When ≥4 individual circumscribed lesions become confluent and affect ≥2 anatomic sites

o Often rapid onset over months

 Linear scleroderma

o Most common form in children and adolescents

o Characterized by ≥ 1 linear streaks (often following dermatomal distribution) extending

over face, head, trunk and/or extremities

o Unilateral in greater than 85% cases

o Complications include joint flexion contractures, limb atrophy, leg length discrepancy

o Facial Linear Variants: may be associated with intracranial lesions, seizures, uveitis, and

dental abnormalities.

 En coup de sabre: involves face or scalp, usually forehead; often with alopecia

 Parry-Romberg syndrome: progressive hemi-facial atrophy; often involves face

below the forehead; more disfiguring; no epidermal involvement

 Pansclerotic morphea

o Least common subtype, but most disabling

o Circumferential changes (often affecting a limb) that extend into tissues below dermis

including muscle, tendon and bone; frequently spares the fingers and toes

 Mixed morphea

o Morphea of ≥ 2 subtypes in an individual patient

 Diagnosis

o Clinical, although skin biopsy may be performed (to exclude other disorders or to assess

if lesion actively inflamed or “burnt out”)

o MRI may be useful to determine extent of deep lesions

 Treatment

o Topical: Corticosteroids, Calcipotriene (vitamin D), Imiquimod 5%, Tacrolimus

o Systemic: Corticosteroids, Methotrexate, Mycophenolate mofetil, Cyclosporine, Biologic

therapy may be considered in recalcitrant disease

o Other: Phototherapy with Ultraviolet A rays

o Supportive: physiotherapy, occupational therapy, psychosocial support

o Surgery for facial lesions, tendo-achilles lengthening

References

1. Li SC. Scleroderma in children and adolescents. Ped Clin North Am 2018:757-781.

2. Zulian F. Scleroderma in children. Best Pract Res Clin Rheumatol 2017; 31:576-595.

7C. Systemic Sclerosis (SSc)

 Rare autoimmune disease in children, characterized by symmetrical skin thickening or

hardening and fibrosis of internal organs

 Sexes equally affected until onset age of 8 years, followed by 3:1 ratio of females:males

 90% of pediatric patients have diffuse cutaneous subtype and 10% have limited cutaneous

subtype (formerly known as CREST syndrome – calcinosis, Raynaud phenomenon,

esophageal dysmotility, sclerodactyly, and telangiectasia)

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

2013 ACR/EULAR Classification Criteria for SSc *

Items

Score

Skin thickening **

 Skin thickening of fingers of both hands extending proximal to

metacarpophalangeal (MCP) joints

 Skin thickening of whole finger distal to MCP joints

 Puffy fingers

Finger tip lesions **

 Digital tip ulcers

 Pitting scars in fingertips

Telengiectasia

Abnormal nailfold capillaries (enlarged capillaries and/or capillary loss with

or without peri-capillary hemorrhages)

Pulmonary arterial hypertension and/or interstitial lung disease

Raynaud phenomenon

Scleroderma related antibodies (any of anti-centromere, anti-Scl70 (also

known as anti-topoisomerase I), or anti-RNA polymerase III)

* Patients with total score of ≥ 9 are classified as having definite systemic sclerosis

N.B. Classification criteria are designed to identify a homogeneous population for research

studies and are not diagnostic criteria, although they are often used for diagnosis in practice

** Only include highest score from these categories in calculation of total score

2007 PRES/ACR/EULAR Provisional Classification Criteria for Juvenile SSc *

Major criterion (mandatory): Sclerosis/induration of skin proximal to MCP joints

Plus ≥ 2 of the following minor criteria:

 Cutaneous (sclerodactyly)

 Peripheral vascular (Raynaud phenomenon, nail fold capillary abnormalities, digital tip

ulcers)

 Gastrointestinal (dysphagia, gastroesophageal reflux)

 Cardiac (arrhythmias, heart failure)

 Renal (renal crisis, new-onset arterial hypertension)

 Respiratory (pulmonary fibrosis, decreased DLCO, pulmonary arterial hypertension)

 Neurologic (neuropathy, carpal tunnel syndrome)

 Musculoskeletal (tendon friction rubs, arthritis, myositis)

 Serologic (antinuclear antibodies, SSc-selective autoantibodies including anti-

centromere and anti-Scl70 (also known as anti-topoisomerase I))

* Classification criteria are designed to identify a homogeneous population for research studies

and are not diagnostic criteria, although they are often used for diagnosis in practice

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Common clinical features of SSc:

Raynaud

Phenomenon

Common in children with SSc

Associated with abnormal nail fold capillaries

Can lead to digital pitting and gangrene

Dermatologic

Non-pitting edema and/or induration of skin resulting in restricted range

of motion, usually in fingers; later evolves to skin thickening causing

joint contractures (sclerodactyly)

Calcium deposits under the skin, often develop over bridge of nose and

extensor surfaces

Telangiectasias

Abnormal nail fold capillaries

Musculoskeletal

Arthralgias

Polyarthritis with minimal joint effusion

Joint contractures often secondary to skin changes

Subclinical myositis with mild weakness and slight elevation in muscle

enzymes

Gastrointestinal

Major cause of morbidity

Severe gastroesophageal reflux disease (GERD) due to dysfunction of

lower esophageal sphincter

Dysmotility leads to stasis, bacterial overgrowth and malabsorption with

diarrhea; may also result in severe constipation and megacolon

Respiratory

Major cause of mortality

Pulmonary arterial hypertension (most severe)

Interstitial lung disease (most common, usually bibasilar)

Inflammatory alveolitis (precedes fibrosis)

Cardiac

Pericarditis (small pericardial effusions are very common)

Micro-infarction of cardiac vasculature leads later to cardiomyopathy

Arrhythmias (from fibrosis of conducting system)

Renal

Major cause of morbidity prior to development of ACE inhibitors

Renal vasculopathy leads to renal hypertension (may be life-

threatening)

Proteinuria (may precede hypertension)

Glomerular disease is unusual

Neurologic

Rare (e.g. trigeminal neuropathy, carpal tunnel syndrome)

 Investigations

o Blood work to assess for evidence of systemic inflammation and organ involvement

o Serology helpful for diagnosis and classification: ANA (common), Rheumatoid factor

(rare), anti-Scl 70 (also known as anti-topoisomerase1, usually associated with diffuse

cutaneous SSc), anti-centromere (usually associated with limited cutaneous SSc)

o Blood pressure and urinalysis to evaluate renal involvement

o ECG and echocardiogram to evaluate possible cardiac involvement and screen for

pulmonary arterial hypertension; consider cardiac MRI

o Chest X-ray, pulmonary function tests with DLCO and high resolution CT chest to

assess for lung disease, especially alveolitis and interstitial pulmonary fibrosis

o Upper GI series to look for dysmotility and GERD

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Treatment

o Primarily supportive care

 Avoid cold, stress, caffeine and nicotine (to prevent Raynaud phenomenon)

 Eat small meals, avoid foods that exacerbate gastric acidity, remain upright after

eating and elevate head of bed (for dysmotility and GERD)

 Physiotherapy and occupational therapy

o Symptomatic treatment

 GERD: Proton pump inhibitors (e.g. Omeprazole)

 Raynaud phenomenon: peripheral vasodilators (e.g. Nifedipine)

 Hypertension, renal disease: ACE Inhibitors (e.g. Enalapril)

 Pulmonary hypertension: endothelin-1 receptor antagonists (e.g. Bosentan),

prostacyclin analogs (Epoprostenol)

o Systemic therapy

 Methotrexate or Mycophenolate mofetil (MMF) for active skin disease

 Cyclophosphamide, MMF and Corticosteroids for alveolitis and interstitial lung

disease

 Other immunomodulatory agents have unclear efficacy in treatment of SSc

 Autologous stem cell transplantation has been demonstrated to be efficacious and

best cadidates appear to be patients with severe disease of short duration before

irreversible damage has occurred

 Prognosis and outcome

o Prognosis depends on degree of organ dysfunction, which either later stabilizes or

progresses to significant morbidity and mortality

o Survival much better in children (5 year survival approximately 90%) compared to adults

References

1. Li SC. Scleroderma in children and adolescents. Ped Clin North Am 2018:757-781.

2. Zulian F. Scleroderma in children. Best Pract Res Clin Rheumatol 2017; 31:576-595.

3. Zulian F, et al. The Pediatric Rheumatology European Society/American College of

Rheumatology/European League against Rheumatism provisional classification criteria

for juvenile systemic sclerosis. Arthritis Rheum 2007; 57(2):203-12.

7D. Mixed Connective Tissue Disease (MCTD)

 Autoimmune disorder characterized by several clinical and laboratory features:

o High titre anti-U1 RNP antibodies

o Swollen hands

o Raynaud phenomenon

o Arthritis

o Myositis

o Skin rashes (may include malar rash, Gottron-like papules, sclerosis)

 Children may also develop over time GI manifestations (similar to SSc), interstitial lung and

renal diseases

 Multiple different diagnostic criteria for MCTD exist (e.g. Sharp, Alarcon-Segovia, Kasukawa,

Kahn), but no single set of criteria is validated in children

 Investigations should be directed to assess for multi-organ involvement

 Treatment depends on severity of clinical manifestations and organ involvement

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Reference

1. Berard RA, Laxer RM. Pediatric mixed connective tissue disease. Curr Rheumatol Rep

2016; 18(5):28.

2. Mier RJ, et al. Pediatric-onset mixed connective tissue disease. Rheum Dis Clin North

Am 2005; 31(3):483-96.

7E. Raynaud Phenomenon

 Vascular spasm in extremities leading to triphasic colour sequence: white (blanching due to

ischemia), blue (cyanosis, related to desaturation), then red (erythema due to reperfusion)

 Well-demarcated areas of colour change

 Usually affects fingers and toes, but may also involve other areas (lips, tongue, tip of nose,

earlobes)

 Precipitated by cold, physical or emotional stress, caffeine, medications or smoking

 Raynaud phenomenon may be primary or secondary

o Primary

 No underlying etiology, but often positive family history

 No peripheral ulcerations

o Secondary

 Due to underlying autoimmune disease (scleroderma, overlap syndromes, MCTD,

SLE, JDM), mechanical obstruction (thoracic outlet syndrome, cervical rib),

hyperviscosity (polycythemia), cryoglobulinemia, drugs/toxins, or vibration-induced

phenomenon

 In isolated Raynaud phenomenon, two best predictive factors for future development of

autoimmune diseases are:

1. Positive ANA

2. Abnormal nail fold capillaries

 Investigations

o Blood work – complete blood count and differential, inflammatory markers, complement

levels, serology (ANA, specific autoantibodies, RF)

o Urinalysis

 Treatment

o Preventive (avoid triggers; warm mittens, socks and boots in winter etc)

o Systemic therapy may be used to prevent ischemic tissue injury

 Peripheral vasodilator, such as Nifedipine, may be titrated to alleviate the Raynaud

episodes; avoid medication-related hypotension, headaches or dizziness

 If severe, may require IV prostaglandins

o Topical therapy (e.g. nitroglycerin 2% ointment) may be used for digital ulcers

References

1. Nigrovic PA, et al. Raynaud’s phenomenon in children: a retrospective review of 123

patients. Pediatrics 2003; 111(4):715-721.

2. Gargh K, et al. A retrospective clinical analysis of pharmacological modalities used for

symptomatic relief of Raynaud’s phenomenon in children treated in a UK paediatric

rheumatology centre. Rheumatology 2010; 49(1):193-4.

3. Wigley FM, Flavahan NA. Raynaud’s phenomenon. N Engl J Med 2016; 375(6):556-65.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

7F. Sjögren Syndrome

 Multisystem autoimmune disease characterized by decreased secretion of lacrimal and

salivary glands leading to dry eyes (keratoconjunctivitis sicca) and xerostomia (dry mouth)

 Most common presentation in children is parotid swelling or parotitis

 Clinical diagnosis, given lack of validated pediatric criteria

 Diagnosis in adults based on weighted scoring system, including the following:

o Presence of focal lymphocytic sialadenitis in labial salivary gland biopsy (higher weight)

o Positivity for anti-SSA/Ro (higher weight)

o Ocular staining score (see below)

o Schirmer’s test (see below)

o Unstimulated whole saliva flow

 Sjögren syndrome may be primary or secondary

o Primary (idiopathic) has no underlying etiology

o Secondary occurs in the context of an autoimmune disease, such as systemic lupus

erythematosus

 Investigations

o Ocular: Schirmer’s test (tear production ≤ 5 mm in 5 minutes is abnormal), tear break-up

time, Rose Bengal staining of devitalized areas

o Salivary glands: scintigraphy, biopsy

o Blood work: complete blood count and differential, inflammatory markers,

immunoglobulin levels, serology (ANA, anti-Ro/SSA, anti-La/SSB, specific

autoantibodies, RF)

 Treatment

o Supportive (artificial tears for dry eyes; increase fluid intake, chewing gum for dry mouth)

o Hydroxychloroquine (Plaquenil) may be helpful

 Complications

o Increased risk of eye irritation and conjunctivitis

o Oral problems (dental caries, gingivitis, and infections such as Candida)

o Increased risk of non-Hodgkin lymphoma

References

1. Baszis K, et al. Recurrent parotitis as a presentation of primary pediatric Sjögren

syndrome. Pediatrics 2012; 129(1):e179-82.

2. Shiboski SC, et al. 2016 American College of Rheumatology/European League Against

Rheumatism classification criteria for primary Sjogren’s syndrome. Arthritis Rheumatol

2017; 69(1):35-45.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 8 – AUTOINFLAMMATORY DISEASES

8A. Periodic Fever/Autoinflammatory Syndromes

 The recurrent or periodic fever syndromes are defined by ≥3 episodes of unexplained fever

in a 6-month period, occurring at least 7 days apart, separated by at least one week of good

health

 Fevers are typically associated with a constellation of symptoms, including ocular,

oropharyngeal, gastrointestinal, dermatologic, musculoskeletal, and neurologic

manifestations

 Interval between attacks of fever may be irregular or regular

 Patients typically feel well between episodes

Characteristic Features of the Periodic Fever Syndromes

Features

FMF

TRAPS

HIDS

CAPS

PFAPA

FCAS

MWS

NOMID

Age of

onset

< 20 yrs

< 1 yr

Often < 1yr

At birth or

within first

months

< 5 yrs

Duration of

attack

1-3 days

1-4 weeks

3-7 days

1-3 days

1-3 days to

continuous

Hours or

continuous

3-6 days

Interval of

attacks

Weeks to

months

Weeks to

months

Weeks to

months

Variable;

cold-induced

Variable

Days

3-6 weeks

Skin rash

Erysipelas-

like in ~40%

Migratory

rash; may be

painful

Maculopapular

in 90%

Cold-induced;

urticarial

Urticarial

Adenopathy

Not typical

Common; may

be generalized

Not typical

Yes

Oral ulcers

May occur

Yes

Abdominal

pain

In ~95%;

pain,

peritonitis,

constipation

Common;

colicky

Often present;

can be severe

with diarrhea

May occur

MSK

Arthralgia;

oligoarthritis;

myalgia

Localized

myalgia;

arthralgia;

arthritis

Symmetric

oligoarthritis of

large joints;

arthralgia

Arthralgia

Arthralgia;

arthritis;

clubbing

Arthralgia;

osseous

overgrowth;

clubbing

Arthralgia

Serositis

Peritonitis;

pleuritis;

pericarditis

Pleuritis;

peritonitis

Pericarditis

(uncommon)

Not typical

Amyloidosis

Occurs in

60% if

untreated

Occurs in

~25% if

untreated

Uncommon,

<5-10%

May occur

Occurs in

~30% if

untreated

May occur

Other

Scrotal

swelling and

pain

Periorbital

edema;

conjunctivitis;

headache;

testicular

pain

Headache

Conjunctivitis

Conjunctivitis;

episcleritis;

sensorineural

hearing loss

Conjunctivitis;

episcleritis;

papilledema;

chronic

meningitis;

sensorineural

hearing loss

Inheritance

AD / de novo

None

Mutation

Chromosome

Gene

Protein

16p13

MEFV

Pyrin

12p13

TNFRSF1A

TNF receptor

P55

12q24

MVK

Mevalonate

kinase

1q44

NLRP3

Cryopyrin

1q44

NLRP3

Cryopyrin

1q44

NLRP3

Cryopyrin

No gene

identified

AD: autosomal dominant, AR: autosomal recessive

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Familial Mediterranean fever (FMF)

 Most common hereditary autoinflammatory disease

 Typically autosomal recessive inheritance but occasionally autosomal dominant

transmission; linked to genetic mutation in MEFV gene encoding pyrin

 Ethnic predilection among Sephardi and Ashkenazi Jewish, Arab, Armenian, and Turkish

populations with carrier rates as high as 1:3 to 1:5

 Usually presents in childhood with 60% of patients presenting prior to 10 years of age

 Clinical features

o Fever episodes last for 1-3 days and occur at irregular intervals

o Clinical hallmark is serositis (e.g. peritonitis, pleuritis, pericarditis)

o Skin: Erysipelas-like rash on shins and dorsum of feet

o MSK: Monoarthritis or oligoarthritis, arthralgia, myalgia

 Morbidity is associated with amyloidosis, especially renal amyloidosis

 Treatment

o Colchicine is highly effective therapy for most patients with FMF

o Anti-IL-1 therapy with Anakinra, Canakinumab or Rilonacept is effective in Colchicine-

resistant or intolerant FMF

TNF-Receptor Associated Periodic Syndrome (TRAPS)

 Rare recurrent fever syndrome

 Originally known as Familial Hibernian Fever

 Autosomal dominant inheritance; linked to genetic mutation in TNFRSF1A gene that

encodes TNF receptor

 Age of onset ranges from early childhood to later adulthood

 Clinical features

o Distinguishing feature is relatively long duration of most attacks, which can last 3-4

weeks and occur at irregular intervals

o Skin: Migrating erythematous, maculopapular rash that spreads from trunk to extremities

o MSK: Severe migratory myalgias associated with rash, arthralgias, arthritis

o Ocular: Conjunctivitis, periorbital edema

o GI: Severe abdominal pain

o Other: oral ulcers, lymphadenopathy

 Treatment

o Corticosteroids provide symptomatic relief but do not diminish frequency of attacks

o Anti-TNF agents (e.g. Etanercept) thought to be promising, but results of studies

disappointing

o Anti-IL-1 therapy may be beneficial

Mevalonate kinase deficiency- Hyperimmunoglobulinemia D Syndrome (HIDS)

 Rare recurrent fever syndrome

 Autosomal recessive inheritance; linked to genetic mutations in MVK gene encoding

mevalonate kinase

 More than 90% of patients show symptoms within first year of life

 Clinical features

o Fever episodes lasting 3-7 days that recur every 4-8 weeks

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o Fever typically associated with abdominal pain, vomiting, diarrhea and a diffuse

maculopapular or urticarial rash

o Other common features include tender cervical lymphadenopathy, oral ulcers,

headaches, arthralgias, and large joint symmetric arthritis

o May have a striking elevation of serum IgD and IgA during fever episodes

o Elevation of urinary mevalonic acid during episodes

o Often triggers are identified, especially immunizations

 Treatment

o NSAIDs and corticosteroids often limit symptoms

o Biologic agents (Anti-IL-1 and Anti-TNF) may be more effective

Cryopyrin Associated Periodic Syndrome (CAPS)

 Group of autoinflammatory syndromes that are associated with genetic mutations involving

NLRP3 gene encoding cryopyrin

 FCAS and NOMID characterized by disease onset in infancy; MWS may develop later

 Spectrum of 3 diseases on a continuum of increasing disease severity

1. Familial Cold Autoinflammatory Syndrome (FCAS)

 Autosomal dominant inheritance of NLRP3 mutations

 Children develop fever, chills and generalized, non-pruritic urticarial skin lesions

within 30 minutes to 6 hours of exposure to cold

 Symptoms persist up to 24 hours

 Associated symptoms during attacks include conjunctivitis and arthralgias

 Amyloidosis extremely rare

2. Muckle Wells Syndrome (MWS)

 Autosomal dominant inheritance of NLRP3 mutations

 Frequent episodes of fever lasting 24-48 hours

 Characterized by generalized urticarial-like rash, arthralgias, myalgias, arthritis, and

conjunctivitis

 Progressive sensorineural hearing loss emerges in adolescence

 Higher risk of amyloidosis (25%)

3. Neonatal Onset Multisystem Inflammatory Disease (NOMID)

 Spontaneous NLRP3 mutations

 Nearly continuous clinical features that develop shortly after birth

 Frequent fever episodes lasting 24-48 hours several times per week

 Distinguishing features from other autoinflammatory syndromes are poor growth or

failure to thrive, severe neuroinflammation and deforming arthropathy

 Skin: Nearly-constant generalized urticarial-like rash

 CNS: Aseptic meningitis, intellectual disability, neurosensory hearing loss, optic

nerve atrophy

 MSK: Deforming arthropathy with epiphyseal overgrowth, clubbing

 Ocular: Conjunctivitis, episcleritis, uveitis, papilledema, visual loss

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Hepatomegaly, splenomegaly

 Poor long-term prognosis with high morbidity and mortality

 Treatment

o Anti-IL-1 therapy with Anakinra, Canakinumab, or Rilonacept are highly effective

o Early treatment may reduce risk of amyloidosis and improve functional outcome

Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis (PFAPA)

 Most common recurrent fever syndrome in children in North America

 No known genetic association or inheritance pattern

 Typically starts before 5 years and is self-limited (usually resolves within 5 years)

 Clinical features

o Episodes of high fever that occur with regular periodicity every 3-6 weeks

o Fever episodes generally last up to 3-6 days

o Characteristic findings of small non-scarring aphthous ulcers, non-exudative pharyngitis,

and cervical adenitis

o May have associated nausea, vomiting, abdominal pain and headache

o Throat cultures are consistently negative

 Treatment

o No consensus regarding treatment

o Single dose of prednisone at onset of symptoms and, if necessary, the following day can

abort the attack; however, interval between fever attacks may shorten

o Other options include cimetidine and tonsillectomy +/- adenoidectomy

References:

1. Ostring GT, Singh‐Grewal D. Periodic fevers and autoinflammatory syndromes in

childhood. J Paediatr Child Health 2016; 52:865-71.

2. Soon GS, Laxer RM. Approach to recurrent fever in childhood. Can Fam Physician

2017; 63(10):756-62

3. Tsoukas P, Laxer RM. Follow the complex bread crumbs: A review of autoinflammation

for the general paediatrician. Paediatr and Child Health [published online ahead of print,

July 2019].

4. Federici S, Gattorno M. A practical approach to the diagnosis of autoinflammatory

diseases in childhood. Best Pract Res Clin Rheumatol 2014; 28(2):263-76.

5. Goldsmith DP. Periodic fever syndromes. Pediatr Rev 2009; 30(5):e34-41.

8B. Other Inherited Autoinflammatory Diseases

 The term ‘autoinflammatory’ has been used to distinguish disorders of innate immune

system characterized by recurrent, seemingly unprovoked episodes of inflammation from

more common ‘autoimmune’ diseases characterized by dysregulation of the adaptive

immune system (with high-titre autoantibodies and proliferation of antigen-specific T cells)

 Hereditary periodic fever syndromes (described above) were first group of monogenic

disorders to be classified as autoinflammatory

 New monogenic autoinflammatory diseases continue to be discovered (described below)

 Spectrum of autoinflammatory diseases is now thought to include disease, such as systemic

juvenile idiopathic arthritis, Behçet disease, and chronic non-bacterial osteomyelitis (CNO),

which may prove to be polygenic in origin

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome

 Rare autosomal dominant autoinflammatory syndrome

 Clinical features

o Recurrent episodes of sterile, erosive arthritis in early childhood

o As patients progress to puberty, skin involvement may predominate

o Characterized by cystic acne, recurrent and often debilitating aggressive ulcerative skin

lesions of the lower extremities indistinguishable from pyoderma gangrenosum

 Treatment

o Arthritis may respond to corticosteroids, but adverse effects often limit their use

o Reports of successful treatment with Anti-IL-1 and Anti-TNF therapy

Deficiency of the Interleukin-1 Receptor Antagonist (DIRA)

 Rare autosomal recessive autoinflammatory syndrome

 Clinical features

o Systemic inflammation in the perinatal period

o Bone pain with characteristic radiographic findings of multifocal sterile osteolytic bone

lesions, widening of multiple anterior ribs, and periostitis

o Pustular skin lesions

 Treatment

o Patients treated with Anakinra have shown rapid clinical and immunological responses

Deficiency of the Interleukin-36 Receptor Antagonist (DITRA)

 Rare life-threatening multisystem disease with repeated flares of sudden onset

 Clinical features

o High-grade fever, malaise

o Generalized pustular psoriasis

 Treatment

o Treatment with anakinra has been described

Deficiency of Adenosine Deaminase 2 (DADA2) (also see Section 5D)

 Newly recognized autosomal recessive syndrome with presentation very early in life

 Clinical features

o Recurrent fevers, livedoid skin rash and vascular involvement

o Vascular involvement may include recurrent lacunar strokes, cerebral haemorrhage,

polyarteritis nodosa

o May have hypertension, hepatosplenomegaly and cutaneous vasculitis

 Treatment

o Reports of successful treatment with Anti-TNF therapy

o Hematopoeitic stem cell transplantation considered for severe phenotypes

Type 1 Interferonopathies

 Rare diseases characterized by mutations in interferons, which are molecules that represent

the cell’s first lines of defence again pathogens, mainly viruses

 Type I interferon (INFαß) signalling defects can phenotypically manifest as a group of

heterogeneous autoinflammatory diseases

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Common clinical features in type 1 Interferonopathies

o Lupus-like symptoms during infancy or prepubertal age

o Signs of vasculopathy such as chilblains or strokes

 Specific conditions

o Aicardi-Goutières syndrome

 Prototypic type 1 interferonopathy

 Characterized by neonatal onset

 Clinical features include progressive congenital encephalopathy, intracranial

calcification, white matter disease, chilblain-like skin lesions, glaucoma,

hypothyroidism, cardiomyopathy, demyelinating peripheral neuropathy

o Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature

(CANDLE) syndrome, also known as Nakajo-Nishimura syndrome (NNS)

 Diagnosis

o Gene studies are the most accurate diagnostic test

o Interferon gene signature test

 Treatment

o Unlike other fever syndromes, general immunosuppression with Corticosteroids,

Methotrexate, or anti-IL1 (e.g. Anakinra or Canakinumab which are effective in other

periodic fever syndromes) are not effective

o Anti-IL6 and Jak inhibitors have been effective in these conditions

References:

1. Federici S, Gattorno M. A practical approach to the diagnosis of autoinflammatory

diseases in childhood. Best Pract Res Clin Rheumatol. 2014; 28(2):263-76.

2. Hashkes PJ, Toker O. Autoinflammatory syndromes. Pediatr Clin North Am 2012;

59(2):447-70.

3. Davidson S, et al. An Update on Autoinflammatory Diseases: Interferonopathies. Curr

Rheumatol Rep 2018; 20(7):38

8C. Role of Genetic Testing in Suspected Autoinflammatory DIsease

 Genetic testing may be used to confirm a diagnosis when the clinical pattern fits with one of

the autoinflammatory diseases

 A genetic diagnosis should be pursued in a logical manner recognizing the cost and

limitations of testing, although panels of genetic mutations associated with these conditions

are now more accessible and cost-effective

 While genetic testing may help to confirm a diagnosis, it is important to consider the

differential diagnosis and potential investigations for recurrent fevers outlined in Section 2C

 A simple interactive tool is available online (https://www.printo.it/eurofever/scoreCriteria.asp)

to guide ordering of genetic tests for recurrent fever syndromes

References:

1. Gattorno M, et al. A diagnostic score for molecular analysis of hereditary

autoinflammatory syndromes with periodic fever in children. Arthritis Rheum 2008;

58(6):1823-32.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

8D. Chronic Non-Bacterial Osteomyelitis (CNO)

 A non-infectious, autoinflammatory disease involving bone

 Pathophysiology poorly understood, neutrophil mediated

 CNO affects females > males and is more common in children and adolescents

 Known as chronic recurrent multifocal osteomyelitis (CRMO) if multiple bony sites

 Some cases (20-30%) are unifocal at diagnosis and many have non-recurrent disease

 Clinical and radiographic findings initially mimic septic osteomyelitis; however, no abscess

formation is noted, cultures are negative, and there is a poor response to antibiotic therapy

 Must consider bone malignancy, infection, and histiocytosis in work-up as CNO is a

diagnosis of exclusion

 There are no validated diagnostic criteria for CNO/CRMO, but Jansson et al proposed a

clinical score (see table below) that may aid in differentiating non-bacterial osteitis from

other bone lesions and may guide the diagnostic approach

Proposed clinical score for nonbacterial osteitis (Jansson et al)

Risk factor

Score

Normal blood count

Symmetrical bone lesions

Lesions with marginal sclerosis

Normal body temperature

Vertebral, clavicular or sternal lesions

Radiographically proven lesions ≥ 2

CRP ≥ 1 mg/dL (10 mg/L)

Total clinical score *

* Total clinical score

Recommended diagnostic approach

1 lesion on whole body imaging

>1 lesion on whole body imaging

≤ 28

Bone biopsy with culture

Clinical monitoring

28-38

Clinical monitoring

≥ 39

Consistent with CNO diagnosis

Adapted from Jansson et al, Arthritis Rheum 2009.

 Clinical features

o Presents with acute or insidious onset of bone pain often associated with localized

swelling, tenderness and warmth; some patients also have fever and malaise

o Typical sites of involvement include the clavicles, pelvis, vertebral bodies and

metaphyses of long bones

o CNO is associated with inflammatory disorders of skin (e.g. palmoplantar pustulosis,

psoriasis, generalized pustulosis, severe acne, pyoderma gangrenosum), disorders of

the gastrointestinal tract (e.g. inflammatory bowel disease), and arthritis adjacent to

active bone lesions and (less commonly) distant to the osteitis

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o The term SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is often

used in adults -- SAPHO may represent a later presentation of childhood CNO or may

be a distinct disorder within the same disease spectrum

o Clinical course characterized by periods of exacerbation with symptom-free intervals

 Imaging

o X-Rays:

 Mixed osteolytic and sclerotic bone lesions localized in the metaphyses close to the

growth plate

 Periosteal reaction may be present

 Cortical thickening may occur later in disease course

o MRI (whole body, if available): sensitive to assess extent and activity of lesions, as well

as asymptomatic lesions

o Bone scan: may be helpful to assess the extent of lesions, but is associated with

significant radiation exposure and may not distinguish inflammatory lesions from

metabolically active growth plates

 Treatment

o Most lesions resolve without significant sequelae and spontaneous remission can occur;

however severe pain, recurrences, and functional limitations may necessitate therapy

o First-line therapy: NSAIDs provide symptomatic relief in up to 80% of patients

o Corticosteroids may sometimes be used for brief periods of time to provide symptomatic

relief or as a bridge to second-line therapy

o Second-line agents include Bisphosphonates (e.g. Pamidronate, Zolendronate),

Sulfasalazine, Methotrexate, anti-TNF agent (e.g. Infliximab)

References:

1. Zhao Y, Ferguson PJ. Chronic nonbacterial osteomyelitis and chronic recurrent

multifocal osteomyelitis in children. Pediatr Clin North Am 2018; 65(4):783-800.

2. Twilt M, Laxer RM. Clinical care of children with sterile bone inflammation. Curr Opin

Rheumatol 2012; 23(5):424-31.

3. Jansson AF, et al. Clinical score for nonbacterial osteitis in children and adults. Arthritis

Rheum 2009; 60(4):1152-9.

4. Zhao Y, et al. Consensus treatment plans for chronic nonbacterial osteomyelitis

refractory to Nonsteroid anti-inflammatory drugs and/or with active spinal lesions.

Arthritis Care Res 2018; 70(8):1228-37.

8E. Relapsing Polychondritis

 A rare immune-mediated condition associated with inflammation in cartilage and other

tissues (particularly ears, nose, eyes, joints, respiratory tract, and heart valves)

 Children have similar clinical features to adults, but are more likely to have family history of

autoimmunity and less likely to have associated inflammatory diseases

 Early manifestations often remain unrecognized until emergence of classic features, such as

auricular inflammation and saddle-nose deformity

 Associated with high morbidity and mortality

 Screening for complications (e.g. aortic dilatation, cardiac lesions) is mandatory

 Diagnosis based on clinical criteria – all 3 sets of criteria were established based on single-

centre cohort studies and none have been validated in an independent cohort

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

1976 McAdam et al Criteria for Relapsing Polychondritis

≥ 3 of the following clinical features:

 Bilateral auricular chondritis

 Non-erosive, seronegative inflammatory polyarthritis

 Nasal chondritis

 Ocular inflammation (conjunctivitis, keratitis, scleritis/episcleritis, uveitis)

 Respiratory tract chondritis (laryngeal and/or tracheal cartilages)

 Cochlear and/or vestibular dysfunction (neurosensory hearing loss, tinnitus, vertigo)

1979 Damiani and Levine Criteria for Relapsing Polychondritis

≥ 1 of the clinical features proposed by McAdam plus positive histologic confirmation

≥ 2 of the clinical criteria proposed by McAdam plus response to Corticosteroids or Dapsone

1989 Modified Michet et al Criteria for Relapsing Polychondritis

Proven chondtritis in at least 2/3 cartilage sites of:

 Auricular cartilage

 Nasal cartilage

 Laryngotracheal cartilage

Proven inflammation in at least 1/3 of the above cartilage sites (auricular, nasal,

laryngotracheal) plus 2 other minor criteria:

 Occular inflammation

 Vestibular dysfunction

 Seronegative inflammatory arthritis

 Hearing loss

 Treatment

o No evidence-based guidelines for treatment

o In adults, largely empiric and based on disease severity

o Options include NSAIDs, corticosteroids, Methotrexate, Dapsone, Azathioprine and

anti-TNF therapy

References:

1. Belot A, et al. Pediatric-onset relapsing polychondritis: case series and systematic

review. J Pediatr 2010;156(3):484-9.

2. Kemta LF, Chevalier X. Refractory relapsing polychondritis: Challenges and solutions.

Open Access Rheumatology: Research and Reviews 2018; 1-11.

3. Borgia F, et al. Relapsing polychondritis: An updated review. Biomedicines 2018;

6(3):E84.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 9 – UVEITIS

9A. Uveitis

 Inflammation of the uvea, which is the middle layer of the eye

 May be asymptomatic or symptomatic

 Classification based on anatomic location of inflammation:

o Anterior uveitis involves the iris and/or ciliary body

o Intermediate uveitis involves the pars plana between the ciliary body and retina

o Posterior uveitis involves the choroid and/or retina

o Panuveitis describes the presence of inflammation in all three anatomic locations in

which there is no predominant site of inflammation

* Image published in “Facts About Uveitis” by the National Eye Institute: https://nei.nih.gov/health/uveitis/uveitis

 Complications of uncontrolled uveitis include:

o Cataracts

o Glaucoma

o Band keratopathy

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o Synechiae (adhesion of iris to lens)

o Cystoid macular edema

o Vision loss

 Treatment

o Prompt and aggressive treatment to prevent or minimize visual complications

o Minimize chronic use of topical corticosteroids (due to side effects such as cataract

formation and glaucoma)

o Close collaboration between rheumatologists and ophthalmologists is essential

o Options include topical (corticosteroids, cycloplegics, mydriatics, anti-glaucoma agents)

and systemic (Methotrexate, Infliximab, Adalimumab, other) therapies

9B. Systemic Inflammatory Diseases Associated with Uveitis

Disease

Acute/Chronic

Location

Associated clinical

features

Investigations

Juvenile

idiopathic arthritis

(except enthesitis

related arthritis)

Chronic, recurrent,

asymptomatic

Anterior >

Posterior

Oligoarthritis >>

Polyarthritis

ANA

Enthesitis related

arthritis

Acute symptomatic,

often recurrent

Enthesitis, sacroiliitis;

often associated with

reactive arthritis, IBD, or

a family history of these

conditions

HLA-B27

Behçet disease

Acute or chronic

Posterior

Recurrent oral and/or

genital ulcers, arthritis,

skin rash

Pathergy

Blau syndrome

(Infantile

sarcoidosis)

Chronic

Posterior,

Anterior,

Panuveitis

Skin rash, arthritis

Consider genetic

testing (NOD2/

CARD15

mutations)

Kawasaki disease

Acute,

asymptomatic

Consider if patient

presents with severe

conjunctivitis and

photophobia

Echocardiogram

Sarcoidosis

Chronic

Posterior,

Anterior,

Panuveitis

Skin rash, arthritis, lung

involvement,

lymphadenopathy

Biopsy, consider

genetic testing

(NOD2/CARD15

mutations)

Tubulo-interstitial

nephritis and

uveitis (TINU)

Acute

Fever, arthralgias,

fatigue, abdominal pain,

and nephritis; uveitis may

present before or after

renal disease

U/A, renal function

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

9C. Infectious Causes of Uveitis

Disease

Acute/Chronic

Location

Associated clinical

features

Investigations

Cat scratch

(Bartonella

henselae)

Chronic

Anterior,

Posterior

Fever of unknown origin,

regional lymphadenopathy,

abdominal pain, weight

loss, hepatosplenomegaly

Cat exposure

Serology

Cytomegalovirus

Chronic

Posterior

Congenital; fever, malaise

Immunocompromised host

Serology, viral PCR

Herpes virus

Acute or chronic

Anterior,

posterior

Keratouveitis, fever,

gingivostomatitis

Serology, viral

culture and/or PCR

Lyme disease

Chronic

Anterior,

Posterior

Erythema migrans, arthritis,

CNS symptoms

Tick bites in endemic areas

Serology

Toxoplasmosis

Chronic, acute

recurrences

Posterior

Congenital exposure

(chorioretinitis,

hydrocephalus, intracranial

calcifications); bilateral

symmetric non-tender

cervical lymphadenopathy,

constitutional symptoms,

headaches, myalgias and

hepatosplenomegaly

Immunocompromised host;

cat exposure

Serology

Tuberculosis

Chronic

Chronic cough, fever,

weight loss, multi-organ

manifestations

Travel/exposure history

PPD,

Chest X-ray

References:

1. Krishna U, et al. Uveitis: a sight-threatening disease which can impact all systems.

Postgrad Med J 2017; 93(1106);766-73.

2. Heilingenhaus A, et al. Update of the evidence based, interdisciplinary guideline for anti-

inflammatory treatment of uveitis associated with juvenile idiopathic arthritis. Semin

Arthritis Rheum 2018; Epub ahead of print.

3. Sen ES, et al. Uveitis associated with juvenile idiopathic arthritis. Nat Rev Rheumatol

2015; 11(6):338-48.

4. Angeles-Han ST, et al. 2019 American College of Rheumatology/Arthritis Foundation

Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis-

Associated Uveitis. Arthritis Care Res 2019; 71(6):703-16.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 10 – INFLAMMATORY BRAIN DISEASES

10A. Introduction to Inflammatory Brain Diseases

 Inflammatory brain disease encompasses a wide range of disorders

 Clinical and diagnostic features vary depending on the underlying disease

 A broad differential diagnosis should be considered when a child presents with newly

acquired neurological or psychiatric deficits

Types of inflammatory brain diseases in children:

Vasculitis

Primary Angiitis of the Central Nervous System in childhood (cPACNS)

 Angiography-positive cPACNS: progressive and non-progressive

 Angiography-negative cPACNS

Secondary CNS vasculitis

Non-vasocentric

neuroinflammatory

disorders

Demyelinating disorders

 Multiple sclerosis, acute demyelinating encephalomyelitis (ADEM),

optic neuritis, transverse myelitis

Antibody mediated inflammatory brain disease

 Autoimmune encephalitis, neuromyelitis optica, Hashimoto

encephalopathy

Systemic inflammatory diseases with CNS involvement

 Systemic lupus erythematosus, antiphospholipid syndrome, celiac

disease, Beçhet disease, sarcoidosis

Post-infectious or infection-associated inflammatory encephalopathy

 Post-Streptococcal neuropsychiatric disorders (including acute

rheumatic fever, Pediatric Acute-onset Neuropsychiatric Syndrome

(PANS) and Pediatric Autoimmune Neuropsychiatric Disorders

Associated with Streptococcal infections (PANDAS)), post-

Mycoplasma basal ganglia encephalitis, post-Herpes Simplex Virus

encephalitis, Febrile infection-related epilepsy syndrome (FIRES)

Other neuroinflammatory disorders

 Rasmussen encephalitis

10B. Childhood Primary Angiitis of the Central Nervous System (cPACNS)

 Currently defined by modified Calabrese criteria:

o Clinical evidence of a newly-acquired focal or diffuse neurologic and/or psychiatric deficit

in child <18 years of age, plus

o Angiographic or histologic evidence of CNS vasculitis, plus

o Absence of an underlying systemic condition

 2 clinically and radiologically distinct types of cPACNS

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

1. Angiography positive cPACNS (Large-medium vessel CNS vasculitis)

o Clinical features: stroke presentation with headache, acute hemiparesis, hemisensory

deficits, and/or fine motor deficits

o Inflammatory markers: often normal

o CSF: often normal

o MRI: unilateral focal areas of acute ischemia in a vascular distribution

o Evidence of vasculitis on angiography (conventional angiography or MRA)

o Brain biopsy not required

o Further divided into progressive and non-progressive subtypes

o Non-progressive cPACNS

 Defined by absence of progression on imaging 3 months after initial angiography (i.e.

monophasic disease)

 More common than progressive cPACNS

o Progressive cPACNS

 Defined by progression on neuroimaging 3 months after initial angiography

 Presents with both focal and diffuse neurologic deficits

 Multifocal T2 lesions on MRI, proximal and distal stenosis on angiography

2. Angiography negative cPACNS (Small vessel CNS vasculitis)

o Clinical features: systemic symptoms (fever, malaise), headache, seizures, ataxia,

cognitive decline and/or behaviour changes

o Inflammatory markers: may be elevated

o CSF: more likely to have pleocytosis, elevated protein and/or elevated opening pressure

compared to angiography-positive disease; oligoclonal bands may also be present

o MRI: multifocal T2 hyperintensities in both white and grey matter, lesions do not conform

to large-vessel vascular territory

o By definition, angiography is negative

o Brain biopsy (ideally lesional): non-granulomatous, intramural and perivascular T

lymphocytes in small arteries, arterioles, capillaries or venules

 Treatment

o Based on type of cPACNS

o Angiography positive cPACNS

 Anti-coagulation with or without anti-platelet agent

 Corticosteroids in non-progressive cPACNS may improve outcome

 Progressive cPACNS treated with same protocol as for angiography negative

cPACNS

o Angiography negative cPACNS

 Induction (first 6 months) using Cyclophosphamide and Corticosteroids

 Maintenance (up to 24 months) using Mycophenolate mofetil and Corticosteroids

o Rehabilitation addressing cognitive, behavioural, physical and psychological deficits

o Adjunctive therapy: PJP prophylaxis while on Cyclophosphamide; Vitamin D

supplementation and ensure adequate calcium intake while on steroids

 Prognosis

o Complications: persistent neurological deficits, seizures, cognitive disability

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

References:

1. Gowdie P, et al. Primary and secondary CNS vasculitis. J Child Neurol. 2012;

27(11):1448-59.

2. Van Mater H. Pediatric inflammatory brain disease: a diagnostic approach. Curr Opin

Rheumatol 2014; 26(5):553-61.

10C. Secondary Central Nervous System Vasculitis

 Occurs in context of an underlying systemic illness

 Can occur in context of infections, as well as other systemic inflammatory and autoimmune

diseases

 Treatment may involve Corticosteroids as well as medications directed to underlying cause

Causes of secondary CNS vasculitis:

Infections

Bacteria: Mycobacterium tuberculosis, Mycoplasma pneumonia,

Streptococcus pneumonia

Virus: Epstein-Barr virus, Cytomegalovirus, Enterovirus, Varicella zoster

virus, Hepatitis C virus, Parvovirus B19, West Nile virus

Fungus: Candida albicans, Actinomycosis, Aspergillus

Spirochete: Borrelia burgdorferi, Treponema pallidum

Inflammatory

diseases

Systemic vasculitis: granulomatosis with polyangiitis, microscopic

polyangiitis, Kawasaki disease, polyarteritis nodosa, Behçet disease

Systemic lupus erythematosus

Juvenile dermatomyositis

Morphea

Autoinflammatory syndromes

Inflammatory bowel disease

Hemophagocytic lymphohistiocytosis

Other

Drug-induced vasculitis

Malignancy-associated vasculitis

References:

1. Gowdie P, et al. Primary and secondary CNS vasculitis. J Child Neurol. 2012;

27(11):1448-59.

10D. Pediatric autoimmune encephalitis (AE)

 Brain inflammation caused by antibodies directed against intracellular neuronal antigens,

synaptic receptors, ion channels and other neuronal proteins

 Most common autoantibodies in children target the N-methyl-D-aspartate (NMDA) receptor,

myelin oligodendrocyte glycoprotein (MOG) and glutamic acid decarboxylase 65 (GAD65)

 Addional antibody targets identified in children include aquaporin 4, dopamine-2 receptor,

gamma-aminobutyric acid (GABA) (A) receptor, GABA(B) receptor, and glycine receptor

 Better prognosis if antibody target is extracellular or synaptic protein

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Clinical features of pediatric AE include seizures, memory deficits, behaviour changes,

psychiatric symptoms, altered mental state, and focal neurological deficits

 Investigations

o MRI may be normal or abnormal (findings often depend on antibody)

o Serum testing may show inflammatory changes or may be normal

o CSF may show increased white blood cell counts

o EEG is often abnormal with seizures, epileptiform discharges and/or slowing

o Psychoeducational testing often shows cognitive dysfunction, including impaired

memory and slow cognitive processing speeds

 Diagnosis confirmed by identification of anti-neuronal antibodies in CSF or serum

 Management in collaboration with pediatric neurologist is recommended

 Treatment typically involves Corticosteroids, IVIG and other immunosuppressants, such as

Rituximab

Anti-NMDA receptor encephalitis

 Most common neuronal antibody mediated encephalitis syndrome in children

 Clinical features

o Typically evolves in stages

o Prodrome of fever and headache

o Subsequent development of psychiatric or behavioral manifestations, speech changes,

decreased consciousness, seizures, choreoathetoid movements and autonomic

instability (tachycardia, fever, hypertension, hypoventilation)

 Investigations

o Diagnosed by presence of anti-NMDA receptor antibodies in CSF or serum (testing more

sensitive in CSF)

o MRI: frequently normal

o CSF: usually abnormal (lymphocytic pleocytosis, increased protein, or oligoclonal bands)

o EEG: often abnormal with diffuse slowing in children and more focal findings in

teenagers and adults

o Consider imaging for ovarian or testicular teratoma (association between anti-NMDA

receptor encephalitis and tumor in adults)

 Treatment

o First line therapy includes Corticosteroids, IVIG and/or plasma exchange

o Rituximab may also be considered

 Outcome

o Over 80% of patients have full recovery

o Recovery may be slow with continued improvement seen up to 2 years after onset of

symptoms

Autoimmune encephalitis associated antibodies to MOG

 Most common antibody associated with autoimmune demyelination

 Antibodies more common in children than adults

 Clinical features

o Typically patients have symptoms consistent with ADEM, including encephalopathy,

weakness, ataxia, sensory changes and/or seizures

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o Also associated with optic neuritis (especially bilateral) and transverse myelitis

 Investigations

o Diagnosed by presence of anti-MOG antibodies in CSF or serum (testing more sensitive

in serum)

o MRI: focal or multifocal white matter lesions, longitudinally extensive myelitis and/or optic

neuritis

o CSF: neutrophilic pleocytosis may be present

o EEG: non-specific slowing

 Treatment

o First line therapy with Corticosteroids

o IVIG and/or plasma exchange added for severe disease

o Chronic immunotherapy, including IVIG, Azathioprine and//or Mycophenolate mofetil,

may be considered for relapsing disease

 Outcome

o Significant improvement expected within three months of initiating therapy

o Disappearance of antibodies associated with monophasic course, whereas persistent

antibodies are associated with relapsing course

Neuromyelitis Optica (NMO)

 Neuroinflammation due to antibodies to aquaporin-4

 Inflammation and demyelination mostly affecting the spinal cord and optic nerves

 Clinical features

o Commonly present with acute optic neuritis and transverse myelitis

o Other reported clinical features: encephalopathy, ophthalmoparesis, vertigo, nausea and

vomiting, hyponatremia, inappropriate diuresis, intractable hiccups

o Reported in association with Sjögren syndrome

 Investigations

o Diagnosis requires identification of antibodies to aquaporin-4 in serum or CSF

o CSF: pleocytosis and elevated protein

o MRI: lesions in the periventricular regions of the third and fourth ventricles and in the

periaqueductal grey matter

 Treatment

o Initial therapy: Corticosteroids, IVIG and/or plasma exchange

o Maintenance with second line agent should be considered (e.g. Azathioprine, Rituximab)

 Outcome

o Frequent relapsing course with accumulation of neurological deficits

References:

1. Dalmau J, Graus F. Antibody-mediated encephalitis. N Eng J Med 2018; 378:840-51.

2. Armangue T, et al. Autoimmune encephalitis in children. J Child Neurol 2012; 27(11):

1460-9.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

3. Van Mater H. Pediatric inflammatory brain disease: a diagnostic approach. Curr Opin

Rheumatol 2014; 26(5):553-61.

4. Co DO, et al. Immune-mediated diseases of the central nervous system. Pediatr Clin

North Am 2017; 64(1):57-90.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 11 – INFECTION & INFECTION-RELATED CONDITIONS

11A. Bone and Joint Infections

Osteomyelitis

 Intraosseous infection with bacteria or rarely, fungi

 Classified as acute, subacute, or chronic

o Acute osteomyelitis is of recent onset and short duration

 Most often hematogenous in origin but may result from trauma such as a compound

fracture or puncture wound

 Can be metaphyseal, epiphyseal, or diaphyseal in location

o Subacute osteomyelitis is of longer duration and is usually caused by less virulent

organisms

o Chronic osteomyelitis results from ineffective treatment of acute osteomyelitis and is

characterized by necrosis and sequestration of bone

 Source may be (1) hematogenous (2) local invasion from contiguous source (3) direct

invasion of bone

 Usually blood-borne to metaphysis, slow blood flow allows organisms to pass through

fenestrations in vessel wall, migrate through haversian canal to sub-periosteal space

 Unique features:

o Neonates may present with pseudoparalysis or sepsis; fever is common; organisms

frequently cross the physis and cause growth arrest

o Patients with hemoglobinopathy frequently have Salmonella and other gram-negative

organisms

 Key symptoms:

o Fever, severe bone pain, and tenderness with or without local swelling should suggest

the possibility of acute osteomyelitis

 Bones involved:

o Femur, tibia, humerus, fibula, calcaneus, pelvis

 Organisms:

o Staphylococcus most common

o Group A Streptococcus, MRSA, atypical Gram negative bacteria and Salmonella

 Investigations

o Blood work: Elevated WBC, ESR, CRP are non-specific

o Blood cultures (sensitivity 60%), bone biopsy culture (sensitivity 80%)

o Imaging:

 X-rays important for exclusion of other diagnoses

 X-ray signs include soft-tissue swelling, soft tissue edema, subperiosteal changes

and bone destruction (diagnostic findings may not be clear until days 10 to 21)

 Bone scan has positive predictive value of 83% (MRI 85%) and allows detection of

other sites

 Treatment

o For the treatment of uncomplicated osteomyelitis, in which fever and symptoms resolve

rapidly, 2 to 4 days of intravenous antibiotics can be followed by high dose oral

antibiotics, for a total antibiotic course of 3 weeks.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Septic Arthritis

 Intra-articular infection with bacteria or rarely, fungi

 Medical emergency (surgical emergency if hip or shoulder involved)

 Key symptoms:

o Usually accompanied by systemic signs of illness (e.g., fever, vomiting, headache)

o May be a component of a more generalized infection that may include meningitis,

cellulitis, osteomyelitis, or pharyngitis

o Joint pain is usually severe, and the infected joint and periarticular tissues are swollen,

hot, and sometimes erythematous; often difficulty weight bearing if lower extremities are

involved

 Joints involved:

o Joints of lower extremity are most commonly the sites of infection

o Knees, hips, ankles, and elbows account for 90% of infected joints in children

 Organisms:

o Staphylococcus aureus and non–Group A β Streptococcus are most common overall

o Streptococcus pneumoniae is common in children younger than 2 years

o Neisseria gonorrheae in sexually active adolescents

o Salmonella is commonly associated with sickle cell disease

o Mycobacterium tuberculosis is an unusual cause of septic monarthritis in childhood

o Kingella kingae is emerging as an important pathogen in children with septic arthritis

and

may also account for a significant portion of culture negative cases

 Investigations

o Joint aspiration - need to aspirate joint prior to antibiotics

 Synovial fluid usually appears cloudy

 Very high WBC count (50,000-300,000, > 75% neutrophils)

 Gram stain positive

o Blood work

 Elevated WBC with neutrophilia, CRP and ESR are non-specific

o Cultures

 Synovial fluid culture (sensitivity 80%), blood culture (sensitivity 10%)

 Require special handling if suspect Neisseria or Mycobacterium tuberculosis

 Kingella kingae may require cultures for 7 days to isolate the organism

o Imaging

 Plain X-rays are not diagnostic, but may be helpful in excluding other disorders; may

show an underlying osteomyelitis as the etiology of the septic arthritis; may

demonstrate only increased soft tissue and capsular swelling

 Ultrasound may be helpful in identifying/quantifying joint effusions and in joint

aspiration for diagnostic purposes

 MRI superior to CT in delineation of soft tissue structures and MRI changes may be

seen as soon as 24 hours following infection; synovial enhancement detected in

virtually all patients

 Bone scans are not used for diagnositic evaluation

 Treatment

o Antibiotics

 Choice of antibiotics depends on presence of predisposing factors, age of child and

suspected organism

 Cefazolin often first line antibiotic or Clindamycin for penicillin allergic patients

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Course of antibiotics typically 2 to 7 days of intravenous therapy (depending on

organism) followed by high dose oral antibiotics for a total duration of 2 weeks

o Surgical

 May require surgical debridement, joint irrigation, drainage or recurrent aspiration for

infections in deep joints (e.g. hips)

References:

1. Paakkonen M, Peltola H. Bone and Joint Infections. Ped Clinic North Am 2013;

60(2);425-436.

2. Castellazzi L, et al. Update on the management of pediatric acute osteomyelitis and

septic arthritis. Int J Mol Sci 2016; 17(6):855-63.

3. Montgomery NI, Rosenfeld S. Pediatric osteoarticular infection update. J Pediatr Orthop

2015; 35(1):74-81.

4. Kocher MS, et al. A clinical practice guideline for treatment of septic arthritis in children:

efficacy in improving process of care and effect on outcome of septic arthritis of the hip.

J bone Joint Surg Am 2003; 85(6):994-9.

11B. Reactive Arthritis

 A form of non-septic arthritis developing after an extra-articular infection

 Arthritogenic bacteria:

o GI: Salmonella, Shigella, Yersinia, Campylobacter

o GU: Chlamydia, Ureaplasma

 Clinical manifestations

o Several stages involved:

1. Clinical infection precedes appearance of arthritis and/or enthesitis by 1 to 4 weeks

2. Active period of weeks to months

3. Sustained remission or recurrent episodes which may evolve to ERA, especially in

patients that are positive for HLA B27

o Acute arthritis (marked pain, sometimes erythema over affected joint) and/or enthesitis

o May see tenosynovitis, bursitis, dactylitis

o Patients may continue to have fever, weight loss, fatigue and muscle weakness

o Painless, shallow mucosal ulcers are common

o Urethritis and cervicitis are rare

o Conjuctivitis occurs in about two thirds of children at onset

o Skin lesions include erythema nodosum, circinate balanitis and keratoderma

blennorrhagicum

 Investigations

o Mild decrease in hemoglobin, mild leukocytosis with neutrophilia

o Elevated inflammatory markers (platelets, immunoglobulins, ESR and CRP)

o Autoantibodies (RF and ANA) are usually absent, but reactive arthritis is more common

in HLA-B27 positive individuals

o Synovial fluid is sterile

o Cultures (blood, urine, stool) obtained at the time of infection may be positive

 Treatment:

o NSAIDs

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o No clear evidence that antibiotics during inflammatory phase alter course of disease

o Rarely, Corticosteroids (oral or intra-articular) may be required

o Sulfasalazine is recommended in the management of resistant arthritis and enthesitis

References:

1. Carter JD, Hudson AP. Reactive arthritis: clinical aspects and medical management.

Rheum Dis Clin North Am 2009; 35(1):21-44.

2. Rihl M, et al. Infection and musculoskeletal conditions: Reactive arthritis. Best Pract Res

Clin Rheumatol 2006; 20(6):1119-37.

11C. Acute Rheumatic Fever (ARF)

 Inflammatory illness following Group A Streptococcus (GAS) infection

 Diagnosis of ARF using Jones Criteria

o Most recent revision of Jones Criteria in 2015 developed distinct criteria for low and

moderate-high risk populations to increase sensitivity for patients at higher risk

2015 Revised Jones Criteria for Diagnosis of Acute Rheumatic Fever

For all patient populations with evidence of preceding GAS infection, diagnosis of initial ARF

requires 2 major criteria or 1 major plus 2 minor criteria

Population

risk

Low risk populations

Cases of ARF ≤ 2/100,000 in school-

aged children or rheumatic heart

disease in ≤ 1/1000 at any age

Moderate- and high-risk populations

Cases of ARF > 2/100,000 in school-

aged children or rheumatic heart

disease in > 1/1000 at any age

Major

criteria

1. Carditis (clinical and/or subclinical)

2. Polyarthritis

3. Chorea

4. Erythema marginatum

5. Subcutaneous nodules

1. Carditis (clinical and/or subclinical)

2. Monoarthritis, polyarthritis or

polyarthralgia

3. Chorea

4. Erythema marginatum

5. Subcutaneous nodules

Minor

criteria

1. Polyarthralgia

2. Fever ≥ 38.5 degrees Celsius

3. ESR ≥ 60 and/or CRP ≥ 3.0 mg/dL

(30 mg/L)

4. Prolonged PR interval (unless

carditis is a major criterion)

1. Monoarthralgia

2. Fever ≥ 38 degrees Celsius

3. ESR ≥ 30 and/or CRP ≥ 3.0 mg/dL

(30 mg/L)

4. Prolonged PR interval (unless

carditis is a major criterion)

Adapted from Gewitz et al, Revision of Jones Criteria for the diagnosis of ARF, Circulation 2015.

 Clinical features

 Arthritis in ARF has characteristics that help differentiate it from other causes

 Characteristically migratory and additive starting with monoarthritis of large joints

 Short duration of arthritis (hours to days)

 Dramatic response to ASA/NSAIDs

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Chorea often occurs as a late manifestation; may be diagnosed as being due to ARF

without accompanying evidence of GAS infection if other causes (e.g. tic disorder,

encephalitis, familial chorea, etc…) have been excluded

 Subcutaneous nodules not often present as sole major manifestation

 Investigations

 Infectious testing

 Diagnosis of ARF requires supporting evidence of antecedent GAS infection with

positive throat culture or elevated/rising streptococcal antibody titres

 Echocardiography

 Echo should be performed in all suspected cases of ARF

 Common cardiac findings of ARF include pathological mitral valve regurgitation,

pathologic aortic regurgitation, acute/chronic mitral or aortic valve changes

 Treatment

o Antibiotic therapy: 10 days oral antibiotics, usually Penicillin

o Anti-inflammatory therapy:

 ASA 100 mg/kg/day divided QID PO for 3–5 days, then 75 mg/kg/day divided QID

PO for 4 weeks (or may consider Naproxen instead)

 Prednisone may be used for carditis/cardiomegaly and heart failure +/- Digoxin

o Carbamazepine, Phenobarbital, Haloperidol, or Chlorpromazine for chorea

o Prophylaxis for recurrence:

 Without carditis: Up to age 21 or 5 years post initial attack, whichever is later

 With carditis, but without residual heart disease: Up to age 21 or 10 years post initial

attack, whichever is later

 With carditis and residual heart disease: Up to age 40 or 10 years post initial attack,

whichever is later

References:

1. Karthikeyan G, Guilherme L. Acute rheumatic fever. Lancet 2018; 392(10142):161-74.

2. Gewitz MH, et al. Revision of the Jones Criteria for the diagnosis of acute rheumatic

fever in the era of doppler echocardiography: a scientific statement from the American

Heart Association. Circulation 2015;131(20):1806-18.

3. Gerber MA, et al. Prevention of rheumatic fever and diagnosis and treatment of acute

streptococcal pharyngitis. Circulation 2009;119:1541-51.

11D. Post-Streptococcal Reactive Arthritis (PSRA)

 PSRA defined as inflammatory arthritis of ≥1 joint (with poor response to NSAID) associated

with a recent Group A Streptococcus (GAS) infection, but not meeting the Jones criteria to

diagnose acute rheumatic fever (ARF) (see Section 12C)

 Characteristics that help distinguish PSRA from ARF include the following:

PSRA

ARF

Age distribution

Bimodal: 8-14 years and 21-

37 years

5-15 years with peak around

12 years

Timing of disease onset

following GAS infection

7-10 days

10-28 days

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Pattern of joint involvement

Additive and persistent, non-

migratory arthritis involving

large, small and axial joints

Migratory, transient arthritis

involving mainly large joints

Response to ASA/NSAID

Poor to moderate

Dramatic improvement

Carditis

Uncommon

Occurs in 60-70% of ARF

patients

 Treatment

o Antibiotic therapy: 10 days oral antibiotics, usually Penicillin

o Anti-inflammatory therapy:

 ASA or NSAID

 Corticosteroids may be used in refractory cases

o Prophylaxis for recurrence:

 Controversial

 Antibiotic prophylaxis may be given for up to 1 year after onset of symptoms with

close monitoring for development of carditis; if clinically well after one year and

echocardiogram remains normal, then may discontinue prophylaxis

 Prognosis

o Most cases resolve spontaneously within a few weeks, but some recurrent or prolonged

Reference:

1. Bawazir Y, et al. Post-streptococcal reactive arthritis (PSRA). Curr Rheumatol Rev 2019

[Epub ahead of print].

2. Van der Helm-van Mil AH. Acute rheumatic fever and poststreptococcal reactive arthritis

reconsidered. Curr Opin Rheumatol 2010; 22(4):437-42.

11E. Lyme Disease

 Complex tic-borne disease with multiple organ involvement (skin, joint, neurologic)

 Most common vector-borne infection in North America and Europe

o Borrelia burgdorferi spirochete transmitted by hard-bodied ticks of the genus Ixodes

o Found in the temperate zones of the northern hemisphere

 Incidence continues to rise

 Clinical manifestations divided into early and late manifestations

o Early manifestations develop within weeks or few months of tick bite

o Late manifestations begin several months or even years later

Organ system

Early Lyme disease

Late Lyme disease

Skin

Nervous system

Musculoskeletal system

Cardiovascular system

Erythema migrans

Cranial nerve palsy

Lymphocytic meningitis

Arthralgia or arthritis

Carditis*

Acrodermatitis chronic

atrophicans*

Chronic encephalomyelitis

Arthritis

*Rare in childhood

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o Erythema migrans usually begins as a round, erythematous macule or papule that

rapidly expands, often with central clearing, to a diameter of at least 5 cm and resolves

within four weeks if untreated

o Arthritis is typically monoarthritis, but may sometimes be polyarthritis

 Investigations

o Elevated ESR

o CSF lymphocytic pleocytosis

o Serologic confirmation (initial screening performed with ELISA, then positive or

equivocal tests confirmed with Western blot)

o Do not test for Lyme disease as a cause of musculoskeletal symptoms without an

exposure history and appropriate examination findings (highlighted in Choosing Wisely:

Pediatric Rheumatology Top 5 by American College of Rheumatology)

 Treatment

o Varies according to disease manifestations

o Erythema migrans only:

 Amoxicillin or Doxycycline (only if >10 years of age) PO x 14-21 days

o Early Lyme disease (except isolated rash) or Late Lyme disease:

 Ceftriaxone or Cefotaxime IV x 2-4 weeks, or

 Amoxicillin or Doxycycline (only if >10 years of age) PO x 4 weeks

o Post-exposure prophylaxis:

 If tick removed (while in endemic area) and was engorged, may benefit from

Doxycycline 200 mg (or 4.4 mg/kg) PO as a single dose within 72 hours of removing

tick (however, not enough data to recommend amoxicillin prophylaxis)

 Prevention

o Appropriate clothing (e.g. long pants and sleeves)

o Tick repellents (e.g. DEET, permethrim) applied to clothing

o Search for and remove ticks promptly with tweezers

References:

1. Shapiro ED. Lyme disease. New Engl J Med 2014; 370(18):1724-31.

2. Sood SK. Lyme disease in children. Infect Dis Clin North Am 2015: 29(2);281-94.

3. Eldin C, et al. Review of European and American guidelines for the diagnosis of Lyme

borreliosis. Med Mal Infect 2019;49(2):121-32.

4. Onyett H, et al. Lyme disease in Canada: Focus on children. Canadian Pediatric Society

position statement. Paediatr Child Health 2019. [Epub ahead of print]

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 12 – PAIN SYNDROMES

12A. Chronic Pain Syndromes

 Primary pain syndromes may have a greater impact on patients’ and families’ quality of life

than inflammatory disease

 Many children with chronic musculoskeletal (MSK) pain do not have an identified cause

 Potential role of psychosocial stress in development of chronic pain syndromes

Growing Pains

 Onset usually between 4 and 10 years of age

 Typical history is deep aching cramping pain in bilateral thighs or calves, usually at night

and intermittently waking the patient from sleep

 Improve with gentle massage, heat and/or analgesia

 Symptoms disappear by morning

 Normal physical examination

 Investigations not necessary for diagnosis

Fibromyalgia (aka Generalized Amplified Musculoskeletal Pain)

 Chronic generalized pain syndrome

 May be triggered by change in physical activity due to injury or chronic illness

 Clinical features

o Widespread pain with gradual onset and chronic course lasting at least 3 months

o Associated with fatigue, poor sleep and waking feeling unrefreshed

o Pain may be affected by anxiety, stress, activities and weather

o Symptoms may wax and wane over time

o Absence of physical findings that indicate another condition (caveat – fibromyalgia may

occur in context of another medical condition (e.g. JIA) but would be disproportionate

for that condition and would involve pain at sites that are not affected by the disease)

 Diagnosis

o No confirmatory blood or imaging investigations, as these are typically normal

o Tender points are no longer included in most recent diagnostic criteria due to

inconsistencies in examination

o Most recent criteria for juvenile fibromyalgia were adapted from adult 2010 ACR criteria

for fibromyalgia (sensitivity 83.8%, specificity 89.4%) and published in 2016

Adapted Juvenile Fibromyalgia Diagnostic Criteria

Diagnosis requires all 3 of the following criteria:

1. Widspread pain index (WPI) ≥7 points and symptom severity (SS) scale ≥5 points or WPI

3-6 points and SS scale ≥9 points (see next page for WPI and SS scale)

2. Symptoms have been present at a similar level for at least 3 months

3. Patient does not have a disorder that would otherwise explain the pain

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Widespread Pain Index

(1 point per check box; score range 0-19 points)

Patient instructed to indicate if they have had pain or

tenderness during the past 7 days in the areas

shown below and to check the boxes in the diagram

for each area in which they have had pain or

tenderness.

Symptom Severity Scale

(Score range 0-12 points)

Patient instructed to indicate the severity of the following

symptoms during the past 7 days using the scale below:

Severity

Description

No problem

Slight or mild problem: generally mild or

intermittent

Moderate problem: often present and/or at

moderate level of intensity

Severe problem: continuous, life-disturbing

symptoms

Symptoms

Severity

Fatigue

Trouble thinking or remembering

Waking up tired (unrefreshed)

Somatic symptoms* in general

* Somatic symptoms include: muscle pain, irritable bowel

syndrome, fatigue, thinking or remembering problem,

weakness, headache, abdominal pain or cramps, nausea,

loss of appetite, numbness or tingling, dizziness, insomnia,

depression, constipation, chest pain, shortness of breath,

blurred vision, dry mouth, dry eyes, itching, wheezing,

ringing in ears, heartburn, hair loss, easy bruising, frequent

or painful urination, bladder spasms.

Final SS score is sum of severity of first 3 symptoms

(fatigue, waking unrefreshed and cognitive symptoms

each on a scale of 0-3 points) plus the score of

severity of somatic symptoms in general (0-3 points).

Criteria and scales adapted from:

1. Zemel L, Blier PR. Juvenile fibromyalgia: A primary pain or pain processing disorder. Semin Pediatr

Neurol 2016; 23:231-41.

2. Clauw, DJ. Fibromyalgia: A clinical review. JAMA 2014. 311(15):1547-55.

 Treatment strategies for chronic pain in children and adolescents that are supported by

research evidence include:

o Education about chronic pain

o Progressively increasing aerobic physical activity over time to a target of 60 minutes

daily

o Improving sleep hygiene, including consistent bed and waking times, and eliminating

long naps during the day

o Learning coping strategies for chronic pain

o Counselling, cognitive behavioural therapy (CBT), other psychotherapy and/or

biopsychosocial approaches to manage anxiety, low mood, and other consequences

and contributors to pain

o Intensive interdisciplinary pain treatment, including physiotherapy, recommended for

more severe pain-related disability

 Medications less effective in childhood fibromyalgia

 Better outcomes in children compared to adults

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

Complex Regional Pain Syndrome (CRPS) Type I (previously known as Reflex

Sympathetic Dystrophy)

 Chronic pain often involving peripheral extremity (lower extremities more common in kids)

 Initiating mild injury or cause of immobilization can lead to CRPS Type I

 Continuing pain, allodynia, and/or hyperalgesia in which pain is disproportionate to inciting

event

 Associated autonomic signs, including swelling, changes in skin blood flow leading to

discolouration, and/or abnormal sweating in the region of pain

 Diagnosis using Budapest clinical criteria (see below) involves exclusion, therefore no other

condition should account for the degree of pain and dysfunction

 Treatment involves intense physiotherapy with manipulation of extremity with goal to restore

function; another potential treatment option is desensitization

Complex Regional Pain Syndrome Type II

 Pain caused by nerve injury, but not limited to distribution of injured nerve

 Similar to type I in symptoms and treatment

References:

1. Weiss JE, Stinson JN. Pediatric pain syndromes and non-inflammatory musculoskeletal

pain. Pediatr Clin North Am 2018; 65(4):801-26.

2. Zemel L, Blier PR. Juvenile fibromyalgia: A primary pain or pain processing disorder.

Semin Pediatr Neurol 2016; 23:231-41.

3. Sherry DD, et al. The treatment of juvenile fibromyalgia with an intensive physical and

psychosocial program. J Pediatr 2015; 167(3):731-7.

4. Hechler TH, et al. Systematic review on intensive interdisciplinary pain treatment of

children with chronic pain. Pediatrics 2015; 136(1):115-27.

5. Kashikar-Zuck S, et al. Longitudinal evaluation of patient-reported outcomes

measurement information systems measures in pediatric chronic pain. Pain 2016;

157(2):339-47.

6. Weissmann R, Uziel Y. Pediatric complex regional pain syndrome: a review. Pediatr

Rheumatol 2016; 14(29):1-10.

Budapest Clinical Criteria for Complex Regional Pain Syndrome

Diagnosis requires all 4 of the following critieria:

1. Continuing pain, disproportionate to inciting event

2. At least 1 symptom (reported) in 3 or more categories*

3. At least 1 sign (at evaluation) in 2 or more categories*

4. No other diagnosis can better explain the patient’s signs and symptoms

* Categories

 Sensory: hyperesthesia, hyperalgesia or allodynia

 Vasomotor: temperature or skin colour asymmetry

 Sudomotor/Edema: edema or sweating asymmetry

 Motor/Trophic: decreased range of motion, motor dysfunction, trophic changes in skin,

hair and nails

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

12B. Hypermobile Joint Syndrome

 Joint pain caused by idiopathic increased flexibility – may be generalized or local

 Pain typically occurs after activity

 More common in females

 Need to consider and exclude syndromes associated with generalized joint hypermobility

(e.g. Ehlers-Danlos, Marfan, Down, Turner, Stickler and osteogenesis imperfecta

syndromes)

 Several different sets of criteria for diagnosis

Beighton Criteria for Hypermobile Joint Syndrome

 Able to touch thumb to volar surface of forearm (1 point each for left and right)

 Able to hyperextend 5

finger MCP joint to 90 degrees (1 point each for left and right)

 Able to hyperextend elbows >10 degrees (1 point each for left and right)

 Able to hyperextend knees >10 degrees (1 point each for left and right)

 Able to touch palms to floor with knees extended (1 point)

Diagnosis requires ≥6/9 points prior to puberty and ≥5/9 points after puberty

 Additional features consistent with hypermobility include:

o Flat feet

o Able to sit in “W” position

o Able to touch elbows behind back

o Able to put heel behind head

 Treatment

o Education and reassurance

o Activity modification (avoid exacerbating activity)

o Physiotherapy to strengthen muscles around affected joints

o Orthotics and supportive footwear

o Cognitive behavioural therapy for more severely affected individuals

 Course

o Can predispose to injuries in sports

o Does not seem to increase prevalence of joint dislocations in early teens

o In general, quality of life may be lower due to frequent joint pain

References:

1. Weiss JE, Stinson JN. Pediatric pain syndromes and non-inflammatory musculoskeletal

pain. Pediatr Clin North Am 2018; 65(4):801-26.

2. Cattalini M, et al. When flexibility is not necessarily a virtue: a review of hypermobility

syndromes and chronic or recurrent musculoskeletal pain in children. Pediatr Rheumatol

Online J 2015; 13(1):40.

3. Pacey V, et al. Joint hypermobility syndrome: A review for clinicians. J Paediatr Child

Health 2015; 51(4):373-80.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 13 – PEDIATRIC RHEUMATOLOGY EMERGENCIES

13A. Introduction to Pediatric Rheumatologic Emergencies

 Can present with a wide spectrum of clinical illness, affecting virtually any organ

 Prompt recognition and treatment may be organ and even life saving

 May occur in the context of a pre-existing rheumatic disease or may be the initial

presentation

13B. Neonatal Lupus Erythematosus with Complete Heart Block (CHB)

 85% of neonates with CHB have transplacentally acquired maternal antibodies to Ro/SSA or

La/SSB

 Prevalence of CHB is 0.65-2% in infants of anti-Ro/SSA women; in affected mother,

likelihood of recurrence is 19%

 1 year mortality up to 54% if untreated

 Rheumatology consultation may be requested urgently for complete heart block with signs

of active inflammation (such as pericardial effusion or carditis), congestive heart failure or

antenatal fetal hydrops

 Clinical Presentation

o Bradycardia with potential congestive heart failure (CHF)

o May already have been diagnosed antenatally

o May manifest other findings typical of NLE such as rash, hepatitis and cytopenias

 Diagnostic Investigations

o Confirm CHB with electrocardiogram

o Cardiology assessment with echocardiogram to assess for active inflammation or

endocardial fibroelastosis (EFE)

o Presence of antinuclear antibodies, specifically those against Ro/SSA and La/SSB in

maternal and neonatal serum

o Elevated troponin levels may indicate secondary myocardial ischemia

 Treatment

o Infants with complete heart block may need pacemaker soon after birth

o If active inflammation is seen on echocardiogram, may consider steroids +/- IVIG

(treatment will depend on presence of CHF/myocarditis and EFE)

References:

1. Izmirly PM, et al. Progress in the pathogenesis and treatment of cardiac manifestations

of neonatal lupus. Curr Opin Rheumatol 2017: 29(5):467-72.

2. Hornberger LK, Al Rajaa N. Spectrum of cardiac involvement in neonatal lupus. Scan J

Immunol 2010;72(3):189-97.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

13C. Macrophage Activation Syndrome

 Macrophage activation syndrome (MAS) is a potentially life-threatening multisystem

inflammatory condition

 Consider in the broad differential of an unexplained persistently febrile child, especially in

the presence of pancytopenia – a high index of suspicion is required

 MAS may complicate a number of autoimmune diseases (e.g. systemic arthritis/JIA, SLE,

Kawasaki disease most commonly)

 May occur at any time during the disease course (especially following a change in therapy)

or may be part of the initial presentation

 Classified as a form of secondary hemophagocytic lymphohistiocytosis (HLH)

o Primary HLH is an inherited multi-system inflammatory disease caused by genetic

abnormalities affecting natural killer cell, macrophage and T cell function

o Similar abnormalities have recently been identified in patients with systemic JIA

o Secondary HLH in children can also be associated with malignancy or infection,

especially EBV

o Primary and secondary HLH share similar clinical and biochemical features

o Recent development of an MAS/HLH score to discriminate between primary HLH and

MAS includes age, splenomegaly, neutrophil count, platelet count, hemoglobin and

fibrinogen

 Diagnostic clinical and laboratory features of MAS

o Fever (continuous/persistent)

o Splenomegaly

o Cytopenias (anemia, thrombocytopenia, neutropenia) or, in systemic JIA, may see

decrease in previously elevated cell counts

o Elevated triglycerides

o Decreased fibrinogen

o Elevated ferritin

o Hemophagocytosis on bone marrow, lymph node, liver or spleen biopsy

 Other important clinical and laboratory features

o Bleeding, bruising, petechiae, due to DIC-like picture with prolonged INR/PTT, elevated

D-dimers

o Hepatic dysfunction with hepatomegaly, elevated bilirubin and liver enzymes

o Elevated LDH

o Persistently raised CRP, but decreasing ESR (due to consumption of fibrinogen)

o CNS dysfunction, including headache, confusion, seizures, and coma

o Respiratory distress including ARDS, pulmonary dysfunction

o Lymphadenopathy

o Changes in blood pressure and heart rate

o MAS may be life-threatening and can result in death

o Critically important to monitor clinical features and trends in laboratory investigations

 Diagnostic criteria

o No single universally-accepted diagnostic criteria for MAS

o Different criteria using a range of abnormal laboratory values have been proposed for

various diseases

o Most criteria involve a combination of the features listed above

o A high index of suspicion is needed to make the diagnosis

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Additional urgent investigations prior to starting treatment (especially prior to IVIG)

o Cultures of blood, urine and throat should be ordered to rule out an underlying bacterial

infection since it will take time to receive results

o Infectious serology and PCR (e.g. EBV, CMV, Parvovirus B19, Herpes viruses) may

be helpful to diagnose an underlying viral infection in primary or secondary HLH

o If the child does not have an established diagnosis and a systemic rheumatologic

condition is suspected, autoantibodies (e.g. ANA, ENA panel, rheumatoid factor,

ANCA) and direct antiglobulin test should be ordered

o Soluble CD163, soluble IL-2 receptor, NK cell function and lymphocyte typing may be

helpful to identify underlying immune dysfunction and/or monitor inflammation

 Treatment

o Very close monitoring of labs, vital signs, and fluid input/output

o All patients require supportive management

 Fluids for hypotension

 Blood products (platelets, red blood cells)

 Respiratory support

o Consider informing and/or involving the pediatric intensive care unit early – if site does

not have ability to provide critical care, consider transfer to a different institution

o If patient is critically ill and complete evaluation is not possible, additional treatment

should be commenced without delay

o If infection suspected, concurrent treatment with appropriate antimicrobial therapy

should be started

o Immunosuppressive therapy

 IVIG often used initially during diagnostic work-up, but is rarely sufficient

 Current HLH protocol involves a step-wise algorithm starting with high-dose or

pulse IV Corticosteroids (may use Dexamethasone or Methylprednisolone) and

followed by addition of Cyclosporine and then Etoposide if there is no improvement

 Plasmapheresis has been used in life-threatening disease

 Case series suggest that biologic agents, in particular Anakinra (anti-IL-1), may be

effective treatments for MAS

 In children with primary HLH or refractory HLH, bone marrow transplant is definitive

treatment

References:

1. Sen ES, et al. Macrophage activation syndrome. Indian J Pediatr 2016; 83(3):248-53.

2. Minoia F, et al. Development and initial validation of the macrophage activation

syndrome/primary hemophagocytic lymphohistiocytosis score, a diagnostic tool that

differentiates primary hemophagocytic lymphohistiocytosis from macrophage activation

syndrome. J Pediatr 2017;187:72-8.

3. Borgia RE, et al. Features, treatment, and outcomes of macrophage activation syndrome

in childhood-onset systemic lupus erythematosus. Arthritis Rheumatol 2018;70(4):616-

624.

4. Ravelli A, et al. 2016 Classification criteria for macrophage activation syndrome

complicating systemic juvenile idiopathic arthritis: a European league against

rheumatism/American College of rheumatology/paediatric rheumatology international

trials organization collaborative initiative. Ann Rheum Dis 2016;75(3):481-9.

5. Wang W, et al. Macrophage activation syndrome in Kawasaki disease: more common

than we thought? Semin Arthritis Rheum 2015; 44(4):405-10.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

13D. Pulmonary Renal Syndrome

 Should be considered in any child presenting with respiratory distress and renal involvement

 Clinical presentation of diffuse alveolar hemorrhage in combination with rapidly progressive

glomerulonephritis

 May be rapidly fatal from devastating pulmonary hemorrhage or progressive renal failure

Causes of pulmonary renal syndrome

Specific

Systemic lupus erythematosus (SLE)

Granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis)

Microscopic polyangiitis (MPA)

Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-

Strauss)

Henoch-Schönlein purpura (HSP, now also known as IgA vasculitis)

Goodpasture syndrome

Non-

specific

Pulmonary edema

Pulmonary embolism in a child with renal disease

Pulmonary infection

Renal disease in a child with pulmonary disease, usually infection

Hemolytic uremic syndrome

IgA nephropathy

 Clinical Presentation

o Dyspnea and cough associated with hypoxemia in room air

o Frank hemoptysis may not be present in all cases

o Renal involvement/failure: oliguria, hypertension, nephritic syndrome, nephrotic

syndrome

 Diagnostic Investigations

o Tests to assess presence of pulmonary hemorrhage or vasculitis

 Complete blood count showing anemia (often microcytic) or decreasing hemoglobin,

elevated reticulocyte count

 Chest X-ray may show diffuse alveolar infiltrates

 Chest CT may show patchy ground glass opacities or nodules

 Pulmonary function tests may show an increase in DLCO consistent with intra-

alveolar bleeding

 Bronchoscopy may demonstrate fresh blood and bronchalveolar lavage (BAL)

demonstrates presence of red blood cells and hemosiderin-laden macrophages; fluid

should also be sent for culture to exclude infection

o Tests to assess presence of renal involvement

 Urinalysis demonstrating proteinuria, hematuria, cellular casts and/or elevated urine

protein:creatinine ratio

 Increases in creatinine and/or urea

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o Tests to determine underlying cause of pulmonary renal syndrome

 Autoantibodies and immune markers:

 Positive ANCA in GPA, MPA, EGPA (see Section 5)

 ANA, anti-dsDNA, antibodies to extractable nuclear antigens, and

antiphospholipid antibodies may be positive in SLE

 Anti-glomerular basement membrane (GBM) antibodies seen in Goodpasture

syndrome

 Complement levels decreased in SLE

 Renal biopsy:

 ANCA-associated vasculitis: pauci-immune necrotizing crescentic

glomerulonephritis

 SLE: glomerular immune deposits with histologic changes of lupus nephritis

 Goodpasture syndrome: IgG deposition along glomerular basement membrane

with crescentric changes

 HSP: deposition of IgA-containing immune complexes in glomeruli with

mesangial cell proliferation, glomerular sclerosis and crescent formation

 Skin biopsy:

 HSP: leukocytoclastic vasculitis with IgA deposits

 SLE: immunofluorescence demonstrates immunoglobulins and complement at

the dermal-epidermal junction; may see damage of keratinocytes, follicular

plugging, basal layer vacuolation, perivascular infiltrates and dermal mucin

deposition

 Treatment

o Early recognition and management of pulmonary renal syndrome is critical

o Initial therapy is identical for any underlying cause of pulmonary renal syndrome and

should be started promptly

o Supportive therapy may include oxygen, intubation, ventilation and/or dialysis

o Initial immunomodulatory therapy with pulse IV methylprednisolone followed by high

dose prednisone (1-2 mg/kg/day)

o Cyclophosphamide or Rituximab may be used depending on the underlying disease

o Addition of plasmapheresis may be considered; commonly done for anti-GBM disease

but benefits less clear for ANCA-associated vasculitis (PEXIVAS trial)

o If concurrent infection cannot be excluded, appropriate anti-microbial coverage should

be considered

References:

1. West SC, et al. Pulmonary Renal Syndrome: a life threatening but treatable condition.

Postgrad Med J 2013: 89(1051):274-83.

13E. Catastrophic Antiphospholipid Syndrome (APS)

 A severe variant of the classic APS, characterized by:

o Multiple organ dysfunction and failure developing over short period of time

o Histopathological evidence of multiple small vessel occlusions, although the patient may

not have obvious thrombosis

o Laboratory confirmation of the presence of antiphospholipid antibodies (aPL), usually in

high titre

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Multisystem microvascular thrombosis with a secondary systemic inflammatory response

syndrome (SIRS) due to tissue damage

 2/3 of patients have an underlying trigger (infection, surgery, trauma, malignancy, and flares

of SLE) and children are more likely to have infectious trigger compared to adults

 Catastrophic APS more likely to be first manifestation of APS in children compared to adults

 Majority of catastrophic APS patients do not have underlying rheumatic disease

 Occurs in <1% of patients with APS; mortality rate of 33-50%

 Clinical Presentation

o May be mistaken for overwhelming sepsis

o Cardiopulmonary manifestations are the most frequent at presentation

 May look like acute respiratory distress syndrome

 Pulmonary embolus or alveolar hemorrhage may occur

o CNS features are next most common

 Cerebral infarction, seizures, and encephalopathy

 Cerebral venous sinus thrombosis

o Renal and abdominal involvement is common

 Renal failure, proteinuria, significant abdominal pain

 80% of patients experience an intra-abdominal thrombotic event over the course of an

episode

o Clinical signs of systemic inflammation and lab features of DIC

Diagnostic Criteria for Catastrophic Antiphospholipid syndrome

Definite diagnosis requires all of the following criteria:

 Evidence of vessel occlusion, or effect of vessel occlusion, in ≥3 organs or tissues

 Occurrence of diagnostic features simultaneously or in <1 week

 Histopathologic evidence of small vessel occlusion in at least one affected organ or tissue

 Presence of antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin) persistent

over at least 6 weeks

Probable diagnosis if:

 Only 2 organ systems affected, or

 Occurrence of two diagnostic features in <1 week and another within 4 weeks, or

 Histopathologic demonstration of small vessel occlusion not possible

 Unable to demonstrate persistence of antibodies due to death

 Diagnostic Investigations

o Tests to confirm presence of thrombotic disorder

 Look for organ infarction (kidney, spleen, or bowel) on imaging or organ failure

(cardiac or renal) with markers of DIC, coagulation dysfunction, and/or peripheral

destruction of blood elements

 May require tissue sample

o Tests to confirm presence of aPL antibodies

 Lupus anticoagulant, anti-cardiolipin, anti-β2-glycoprotein I

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Novel aPL antibodies (e.g. anti-phosphatidylserine-prothrombin antibodies) also

reported in catastrophic APS cases but testing not widely available

o Investigate underlying triggers for the episode

 Cultures and infectious serology to assess for infection (respiratory, skin, urinary tract)

 Bone marrow biopsy or imaging may be needed to assess for an underlying

malignancy

 Investigations for a systemic inflammatory condition, such as SLE, may be indicated if

the child does not have a previous diagnosis

 Treatment

o Patients are often critically ill

o ICU support should be available and anticipated

o May need acute measures such as mechanical ventilation or dialysis

o Treatment aimed at removing triggering factor, if known, eliminating existing thrombus,

and controlling SIRS

o Empiric antibiotics until infection ruled out

o Targeting two main pathologic processes may reduce mortality

 Thrombosis: treated acutely with Heparin; may also need vasodilators, fibrinolytics,

and embolectomy; long-term anticoagulation with either Low Molecular Weight

Heparin or Warfarin

 SIRS: treated with systemic corticosteroids, therapeutic plasma exchange (TPE) and

IVIG (should be given after TPE)

o Other agents for severe or refractory cases include Rituximab and Eculizumab (anti-C5

agent)

References:

1. Go EJL, O'Neil KM. The catastrophic antiphospholipid syndrome in children. Curr Opin

Rheumatol 2017; 29(5):516-22.

2. Rodríguez-Pintó I, et al. CAPS Registry Project Group (European Forum on

Antiphospholipid Antibodies). Catastrophic antiphospholipid syndrome (CAPS):

descriptive analysis of 500 patients from the International CAPS Registry. Autoimmun

Rev 2016; 15:1120-24.

3. Asherson RA, et al. Catastrophic antiphospholipid syndrome: international consensus

statement on classification criteria and treatment guidelines. Lupus 2003; 12(7):530-4.

4. Litvinova E, et al. Prevalence and signification of non-conventional antiphospholipid

antibodies in patients with clinical APS criteria. Front immunol 2018;9:2971

13F. Cardiac Tamponade

 Uncommon but life-threatening complication of pericarditis with effusion

 Autoimmune cause identified in 13-30% of children with tamponade

 May occur in children with known rheumatologic disease or as part of initial presentation

 Clinical Presentation

o Typically presents with dyspnea, tachypnea and chest pain

o May have elevated jugular venous pressure, facial edema or plethora, tachycardia,

pulsus paradoxus, muffled heart sounds, and if advanced, hypotension

o Fever is common

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o May see clinical features suggestive of associated rheumatic disease (e.g. SLE,

systemic JIA)

 Diagnostic Investigations

o ECG typically shows sinus tachycardia and may also show low voltage QRS complexes,

ST elevation/PR segment depression, and electrical alternans

o Chest X-ray may show a large cardiac silhouette

o Echocardiography may demonstrate a moderate to large pericardial effusion, findings of

chamber collapse, respiratory variation in volumes and flows, IVC dilatation due to

increased central venous pressure

 Treatment

o Initial priority is to stabilize cardiorespiratory status and to restore adequate cardiac

output by removal of pericardial fluid (pericardiocentesis)

o Temporizing measures can be used such as IV fluids or sympathomimetics

o Corticosteroids are the mainstay of acute treatment for life-threatening conditions

o Other immunosuppressive agents may be added if there is insufficient improvement or if

required to treat an underlying rheumatic disease and may include NSAIDs, Colchicine,

and Anti-IL-1 agents

References:

1. Imazio M, et al. Contemporary management of pericardial effusion: practical aspects for

clinical practice. Postgrad Med 2017; 129(2):178-186.

2. Mok GC, Menahem S. Large pericardial effusions of inflammatory origin in childhood.

Cardiol Young 2003; 13(2):131-6.

3. Maharaj SS, Chang SM. Cardiac tamponade as the initial presentation of systemic lupus

erythematosus: a case report and review of the literature. Pediatr Rheumatol Online J

2015; 13:9.

13G. Kawasaki Disease (KD) Shock Syndrome (KDSS)

 Uncommon but life-threatening complication of KD

 Occurs in <10% of children diagnosed with KD; older age of onset

 Children often present with shock before the KD diagnosis is made and more likely to have

incomplete presentation

 May have more prominent inflammatory markers in early phase and higher risk of coronary

artery dilatation

 Clinical Presentation

o Hemodynamic instability with tachycardia, hypotension and poor peripheral perfusion

o May have muffled heart sounds or gallop rhythm

o Typically associated with more severe manifestations of KD, although not necessarily

longer duration of fever

o KDSS is a multisystem disease with impaired cardiac function, gastrointestinal

symptoms (e.g. vomiting), respiratory failure, encephalopathy, and acute renal injury

o More likely to demonstrate IVIG resistance

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Diagnostic Investigations

o Compared to children with KD who are hemodynamically stable, children with KDSS are

more likely to have:

 Higher CRP and ESR

 Higher white blood cell and neutrophil counts with bands

 Lower hemoglobin and platelet counts

 Lower sodium and albumin levels

 Consumptive coagulopathy with low platelet counts, increased D-dimers and

prolonged PTT

 Emerging data shows higher levels of IL-6, IL-10 and IFN-ᵞ (if testing available at

center) may be useful to distinguish KDSS from KD

o ECG typically shows sinus tachycardia

o Echocardiography:

 Impaired left ventricular systolic function with a lower ejection fraction and mitral

regurgitation

 More likely to develop coronary artery abnormalities

 Treatment

o Initial priority is to stabilize cardiorespiratory status

o Require careful fluid resuscitation – large fluid boluses not recommended as these may

precipitate congestive heart failure

o May require inotropic and/or vasopressor support

o IVIG and ASA remain mainstay of therapy; however, IVIG resistance is more common

and may need to progress to further therapies, such as corticosteroids (see Section 5C)

o If treated early and aggressively, most children survive without sequelae

References:

1. Ma L, et al. Clinical Manifestations of Kawasaki Disease Shock Syndrome. Clin Pediatr

(Phila) 2018; 57(4):428-35.

2. Kanegaye JY, et al. Recognition of a Kawasaki Shock Syndrome. Pediatrics 2009;

123(5):e783-9.

3. Li Y, et al. Kawasaki disease shock syndrome: clinical characteristics and possible use

of IL-6, IL-10 and IFN-γ as biomarkers for early recognition. Pediatr Rheumatol Online J

2019; 17(1):1.

13H. Renal Crisis in Systemic Sclerosis (SSc)

 Rare and potentially life-threatening complication of SSc

 High rate of mortality and progression into end-stage renal disease (ESRD)

 Incidence of 4-6% in SSc patients, primarily in diffuse SSc

 Usually develops within the first 4 years of onset of the disease

 Risk factors: presence of anti-RNA polymerase antibodies, rapid progression of skin

thickening, congestive heart failure, high dose glucocorticoids,

 Clinical Presentation

o Reflects thrombotic microangiopathy of kidney similar to thrombotic thrombocytopenic

purpura/hemolytic uremic syndrome

o Acute renal failure without warning signs

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o Sudden onset of moderate to severe hypertension (normal blood pressure in 10% of

renal crisis cases)

o May be accompanied by hypertensive encephalopathy, congestive heart failure,

arrhythmia, or acute cerebrovascular event

 Diagnostic Investigations

o Elevated creatinine, proteinuria and hematuria

o Thrombotic microangiopathy: hemolytic anemia and thrombocytopenia

o Renal biopsy findings include proliferation and thickening of arcuate and interlobar

arteriole intima, leading to narrowing or full obliteration of vessels

o CXR may demonstrate pulmonary edema

o Eye exam may identify retinal hemorrhages or exudates

o MRI/CT head may show signs of stroke

 Treatment

o Rapid (within 72 hr) control of blood pressure

 Provides stabilization of renal function in 70% of patients

o ACE inhibitors (Captopril most widely studied)

o Plasma exchange to be considered if intolerant to ACE inhibitor or concomitant

hemolytic microangiopathy

o Adjunctive treatment with endothelin receptor antagonist (e.g. Bosentan) or Eculizumab

(anti-C5a) if refractory

o If ESRD: dialysis and possibly transplantation

References:

1. Gordon SM, et al. Risk Factors for Future Scleroderma Renal Crisis at Systemic

Sclerosis Diagnosis. J Rheumatol 2019;46(1):85-92.

2. Zanatta E, et al. Therapy of Scleroderma Renal Crisis: State of the Art. Autoimmun Rev

2018;17(9):882-9.

3. Guillevin L and Mouthon L. Scleroderma Renal Crisis. Rheum Dis Clin N Am 2015;

41:475-88.

13I. Acute Adrenal Crisis

 Many children with rheumatic diseases are treated with systermic glucocorticosteroids in

high doses to achieve disease control or lower doses for prolonged periods of time to

maintain remission

 Adrenal crisis may occur during withdrawal of therapy or at times of stress (e.g. illness,

disease flare) requiring additional steroids

 Patients at risk of adrenal suppression include those who have used corticosteroids for more

than a 2 week period at >2mg/kg or multiple courses totalling >3 weeks in the previous 6

months

 Associated with higher mortality in the pediatric population

 Clinical Presentation

o May be variable

o Many signs and symptoms are non-specific and can be mistaken for symptoms of an

intercurrent illness or the underlying condition being treated

o Signs and symptoms include:

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Arthralgias, myalgias, generalized weakness

 Headache

 Abdominal pain, nausea, vomiting, diarrhea

 Fever

 Hypotension

 Decreased level of consciousness, lethargy

 Unexplained hypoglycemia

 Hyponatremia

 Seizures, coma

 Treatment

o Hydrocortisone injection 100 mg/m2 (maximum 100 mg) IV/IM stat with IV normal

saline volume expansion, followed by hydrocortisone 25 mg/m2 every 6 hours

(maximum 25 mg every 6 hours)

o Consult endocrinologist on call for further advice

 Prevention

o Stress dosing with hydrocortisone during illness, fever or surgery

o Education of patient and family

References:

1. Levy-Shraga Y, Pinhas-Hamiel O. Novel insights into adrenal insufficiency in childhood.

Minerva Pediatr 2014; 66(6):517-32.

2. Shulman DI, et al. Adrenal insufficiency: still a cause of morbidity and death in childhood.

Pediatr 2007; 119(2):e484-94.

3. Huber BM, et al. Adrenal insufficiency after glucocorticoid withdrawal in children with

rheumatic diseases. Acta Paediatr 2010; 99(12):1889-93.

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

SECTION 14 – MEDICATIONS

Medications are listed in alphabetical order by their generic names with the exception of

Corticosteroids and NSAIDs, which are listed by their categories. A table summarizes the

mechanisms of action of the monoclonal antibody (mAb) and fusion protein biologic agents.

 Abatacept

o Class: biologic agent (see Biologic agents for summary table)

o Mechanism of action: Selectively inhibits co-stimulatory signal for T-cell activation

o Dose: 10 mg/kg/dose if <75 kg; 750 mg if 75-100 kg; or 1000 mg if >100 kg via IV every

2 weeks for 3 doses then every 4 weeks thereafter

o Side effects: infusion reactions, anaphylaxis, GI upset, bronchospasm, infections,

potential risk of future malignancy (very rarely)

 Adalimumab

o Class: biologic agent (see Biologic agents for summary table)

o Mechanism of action: recombinant mAb that binds to circulating and cell surface TNFα

o Dose: 24 mg/m

/dose if <15 kg; 20 mg if 15-30 kg; or 40 mg if >30 kg via SC injection

every 2 weeks (can be given weekly when clinically indicated)

o Side effects: injection site reactions, headaches, infections, cytopenias, potential risk of

future malignancy, demyelinating disease, new or worsening heart failure (adult patients)

o Monitoring: CBC, differential, AST, ALT, creatinine every 3-6 months

 Anakinra

o Class: biologic agent (see Biologic agents for summary table)

o Mechanism of action: human recombinant form of IL-1 receptor antagonist (IL-1Ra)

o Dose: 1-2 mg/kg/dose (max 100 mg) SC daily; in sJIA, may titrate up to 4 mg/kg/dose

(max 200 mg) SC daily

o Side effects: injection site reactions, flu-like symptoms, infections

o Monitoring: Neutrophil count prior to initiating; monthly for 3 months; then quarterly

 Azathioprine

o Class: antimetabolic agent; purine analogue

o Mechanism of action: interferes with DNA synthesis; inhibits T cells and monocytes

o Dose: 2-3 mg/kg/day (max 150 mg) PO daily

o Side effects: nausea, diarrhea, oral ulcers, rash, cytopenias, pancreatitis, hepatotoxicity

o Monitoring: CBC, differential and liver enzymes every 2 weeks until achieve stable dose

then every 2 months; consider thiopurine methyltransferase (TPMT) genetic testing if

abnormally low CBC (e.g., neutropenia) unresponsive to dose reduction

 Belimumab

o Class: biologic agent (see Biologic agents for summary table)

o Mechanism of action: human IgG1 neutralizing monoclonal antibody against B-

lymphocyte stimulating factor (also known as B-lymphocyte simulator [BLyS])

o Dose: 10 mg/kg via IV every 2 weeks for 3 doses then every 4 weeks

o Side effects: infusion reactions, nausea, diarrhea, headaches, infections, potential risk of

future malignancy (very rarely)

o Monitoring: CBC (e.g., leukopenia) and liver enzymes with each infusion

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Biologic agents

Biologic Class

Medication

Mechanism of Action

Approved

pediatrics

(Health

Canada)

B cell depletion

Belimumab

 Human monoclonal antibody directed against BLyS

 Inhibits BLyS-induced proliferation of B cells and decreases

survival of autoreactive B cells

Yes

Rituximab

 Chimeric mouse-human monoclonal antibody directed

against CD20 on pre-B and mature B cells

 Selectively depletes B cells

IL-1 inhibitors

Anakinra

 IL-1 receptor antagonist

 Blocks IL-1 receptor to prevent pro-inflammatory signaling

(both IL-1α and IL-1β)

Yes

Canakinumab

 Human monoclonal antibody directed against IL-1β

 Binds to IL-1β to prevent pro-inflammatory signaling

Yes

Rilonacept

 Fully human dimeric fusion protein consisting of extracellular

portion of IL-1 receptor and constant region of human

immunoglobulin

 Binds to IL-1 to prevent pro-inflammatory signaling

IL-6 inhibitor

Tocilizumab

 Humanized monoclonal antibody against IL-6 receptor

 Blocks IL-6 mediated pro-inflammatory signaling

Yes

IL-12/IL-23

inhibitor

Ustekinumab

 Humanized monocloncal antibody against IL-12 and IL-23

 Blocks IL-12/23 to prevent pro-inflammatory signaling

IL-17A inhibitor

Secukinumab

 Humanized monocloncal antibody against IL-17A

 Blocks IL-17A mediated pro-inflammatory signaling, which is

mainly produced by T helper 17 cells

T cell

co-stimulatory

modulator

Abatacept

 Fusion protein consisting of extracellular portion of CTLA-4

and constant region of human immunoglobulin

 Blocks co-stimulation and activation of T cells

Yes

TNF inhibitors

Adalimumab

 Human monoclonal antibody directed against circulating and

membrane-bound TNFα

 Binds to TNFα to block pro-inflammatory signaling

 May result in cell lysis in presence of complement

Yes

Certolizumab

 PEGylated Fab fragment of humanized monoclonal antibody

directed against TNFα

 Binds to TNFα to block pro-inflammatory signaling

Etanercept

 Soluble fusion protein consisting of extracellular portion of

TNFα receptor and the constant region of human

immunoglobulin

 Binds to circulating (but not membrane-bound) TNFα to block

pro-inflammatory signaling

Yes

Golimumab

 Human monoclonal antibody directed against TNFα

 Binds to TNFα to block pro-inflammatory signaling

Infliximab

 Monoclonal human-mouse antibody directed against

circulating and membrane-bound TNFα

 Binds to TNFα to block pro-inflammatory signaling

 Enables antibody-dependent and complement-dependent

cytotoxicity

Yes

TNF: tumor necrosis factor; IL: interleukin; BLyS: B-lymphocyte stimulator; CTLA-4: cytotoxic T lymphocyte-

associated antigen-4; Note: suffix of monoclonal antibody (mAb) = -mab

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Biosimilars

o A biosimilar is a newer type of biologic medication that is designed to be identical to an

existing biologic medication, but is created using a different process

o Uncertain whether biosimilars will have identical effects to reference biologic product

since even minor modifications may alter pharmacokinetic, immunogenetic,

glycosylation, sialylation, stability, safety, and efficacy

o Biosimilars often more cost-effective than the biologic agents that they replicated

o Rare events and long-term safety will be assessed in postmarketing surveillance studies

o Currently approved Anti-TNF biosimilars

 Infliximab biosimilars: Remsina, Inflectra and Renflexis are approved for adults in

Canada, but not yet mandated for use in children

 Adalimumab biosimilar: Hadlima approved for adults in Canada

 Etanercept biosimilars: Brezys and Erelzi are approved for adults in Canada, while

Erelzi is mandated for use by certain Canadian provinces for children over 62 kg

(dose 50 mg SC weekly)

 Canakinumab

o Class: biologic agent (see Biologic agents for summary table)

o Mechanism of action: fully human mAb targeting IL-1β

o Dose: sJIA  4 mg/kg/dose SC every 4 weeks; CAPS  2-4 mg/kg if 15-40 kg; or 150

mg (may consider 300 mg) if >40 kg via SC injection every 8 weeks

o Side effects: injection site reactions, headache, flu-like symptoms, GI upset, infections

 Colchicine

o Class: alkaloid

o Mechanism of action: binds to microtubules to prevent activation, proliferation and

functioning of inflammatory cells

o Dose: 0.6-1.8 mg/day; may divide into twice daily doses if side effects

o Side effects: nausea, vomiting, diarrhea, cytopenias, rhabdomyolysis, renal failure

o Monitoring: CBC, differential, renal function

 Corticosteroids

o Potent anti-inflammatory agents

o Mechanism of action: multiple anti-inflammatory actions including binding to transcription

factors (such as NF-κB) to block production of pro-inflammatory proteins; binding to

enzymes to block function of inflammatory cells; and direct inhibition of cytokines

o Commonly used corticosteroids

 Prednisone (PO tablets), prednisolone (PO liquid) – equivalent

 Methylprednisolone (IV) – very similar to prednisone/prednisolone

 Dexamethasone (PO or IV) – superior blood-brain barrier penetration, more potent

 Triamcinolone hexacetonide (intra-articular)

o Dose: depends on indication and severity of inflammation

o Side effects:

 Early: increased appetite, GI upset, gastritis, mood and behaviour changes

 Late: infections, Cushing syndrome (truncal obesity, moon facies, cutaneous striae),

acne, growth suppression, osteoporosis, AVN, psychosis, hypertension,

dyslipidemia, hyperglycemia, myopathy, cataracts, glaucoma

o Monitoring: clinical (including blood pressure); consider monitoring bone health carefully

if long-term corticosteroids are used

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Cyclophosphamide

o Class: cytotoxic alkalating agent

o Mechanism of action: alkylating metabolites prevent cell division by crosslinking DNA

and RNA strands, particularly affecting lymphocytes (B and T cells)

o Dose: 500-1000 mg/m

/dose IV every 2 to 4 weeks up to 6 months

o Side effects:

 Short-term: nausea, vomiting, anorexia, alopecia, oral ulcers, cytopenias,

opportunistic infections, hemorrhagic cystitis, SIADH, teratogenicity, gonadal

dysfunction

 Long-term: bladder fibrosis, bladder carcinoma, fertility issues, malignancy

o Monitoring: CBC, differential on day of infusion and then days 7, 10 and 14 after infusion

to monitor cytopenias

o Special consideration: prophylaxis

 Mesna administered with infusion to prevent hemorrhagic cystitis

 Cotrimazole (trimethoprim-sulfamethoxazole) given 3 times weekly to prevent

opportunistic infection by Pneumocystis jirovecii

 Cyclosporine

o Class: immunomodulatory agent

o Mechanism of action: inhibits calcineurin leading to inhibition of nuclear factor of

activated T cells (NF-AT) resulting in profound inhibition of T cell proliferation and

cytokine production

o Dose: 3-5 mg/kg/day PO divided twice daily; may be given by IV in MAS

o Side effects: hypertension, headache, nausea, vomiting, myalgias, renal toxicity,

hepatotoxicity, GI upset, tremor, paresthesias, gingival hyperplasia, hirsutism

o Monitoring: BP, renal function, urinalysis, CBC, differential, and liver enzymes monthly

 Etanercept

o Class: biologic agent (see Biologic agents for summary table)

o Mechanism of action: fully human dimeric fusion protein that binds to circulating TNFα

o Dose: 0.4 mg/kg/dose (max 25 mg) twice weekly or 0.8 mg/kg/dose (max 50 mg) weekly

via SC injection

o Side effects: injection site reactions, headaches, flu-like symptoms, infections,

cytopenias, potential risk of future malignancy, demyelinating disease, new or worsening

heart failure (adult patients)

o Monitoring: CBC, differential, AST, ALT, creatinine every 3-6 months

 Hydroxychloroquine

o Class: disease-modifying antirheumatic drug (DMARD); antimalarial agent

o Mechanism of action: interferes with antigen processing and antigen-antibody

interactions, inhibits nucleic acid and protein synthesis

o Dose: up to 6.5 mg/kg/day (max 400 mg) PO daily

o Side effects: nausea, anorexia, skin rash, headache, dizziness, photosensitivity, retinal

toxicity

o Monitoring: eye examinations every 12 months to assess for retinal deposits

 Infliximab

o Class: biologic agent (see Biologic agents for summary table)

o Mechanism of action: monoclonal chimeric human-mouse antibody that binds to

circulating and cell surface anti-TNFα

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o Dose: 6-10 mg/kg/dose on week 0, 2, 6 then every 4 to 8 weeks (may occasionally

require higher doses)

o Side effects: injection site reactions, headaches, infections, cytopenias, potential risk of

future malignancy, demyelinating disease, new or worsening heart failure

o Monitoring: CBC, differential, AST, ALT, creatinine every 3-6 months

o Special consideration: human anti-chimeric antibodies (HACAs) can develop and

decrease efficacy and increase risk of infusion reactions; incidence is lower in patients

receiving continuous (rather than intermittent) therapy and concomitant

immunosuppressive therapy (e.g., methotrexate)

 IVIG

o Class: biologic agent; plasma-derived protein

o Mechanism of action: multiple anti-inflammatory mechanisms including inhibition of

antibody-mediated cytotoxicity; attenuation of complement-mediated damage;

modulation of cytokine production; and neutralization of superantigens

o Dose: 2 g/kg/dose IV

o Side effects: infusion reactions, haemolysis, aseptic meningitis 18-36 hours post infusion

(headache and vomiting), cough, acute renal failure

o Special consideration: need to delay future immunizations with live-virus vaccines by 11

months due to possible inefficacy of subsequent vaccines for this time period

 Leflunomide

o Class: disease-modifying antirheumatic drug (DMARD)

o Mechanism of action: inhibits enzyme involved in DNA synthesis and interferes with

lymphocyte proliferation

o Dose: 10 mg PO every other day for patients <20 kg, 10 mg PO daily for patients 20-40

kg, 20 mg PO daily for patients >40 kg

o Side effects: oral ulcers, nausea, vomiting, allergic rash, alopecia, leukopenia,

hepatotoxicity, teratogenicity

o Monitoring: CBC, differential, liver enzymes, creatinine at baseline, in 2-4 weeks after

starting and then every 8-12 weeks

o Special consideration: need to discuss alcohol avoidance and birth control

 Methotrexate

o Class: disease-modifying antirheumatic drug (DMARD)

o Mechanism of action: inhibitor of dihydrofolate reductase enzyme (folate pathway) and

DNA synthesis

o Dose: 10-15 mg/m

/dose (max 25 mg) PO or SC weekly (note: often better response

and fewer side effects with SC route)

o Side effects: GI upset, oral ulcers, hepatotoxicity, bone marrow suppression,

teratogenicity

o Monitoring: CBC, differential, liver enzymes, creatinine at baseline, in 2-4 weeks and

then every 8-12 weeks

o Special considerations: need to discuss alcohol avoidance and birth control; administer

with folic or folinic acid to minimize side effects

 Mycophenolate mofetil

o Class: antimetabolic agent

o Mechanism of action: inhibits enzyme in DNA synthesis leading to inhibition of B and T

cell proliferation

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

o Dose: 800-1200 mg/m

/day (max 3000 mg/day) PO divided twice daily

 Typical starting dose is 250 mg daily

 May use drug levels (MMF kinetics) to optimize dose where available

o Side effects: GI upset, headaches, cytopenias, infections, teratogenicity

o Monitoring: CBC, differential, liver enzymes, creatinine at baseline, in 2-4 weeks and

then every 8-12 weeks

 Non-steroidal anti-inflammatory drugs (NSAIDs)

o First-line anti-inflammatory agents for arthritis

o Mechanism of action: inhibit cyclooxygenase (COX) to block production of pro-

inflammatory prostaglandins

o Dose: see table below for doses of commonly used NSAIDs

o Side effects: abdominal pain, nausea, vomiting, diarrhea, constipation, pseudoporphyria

(Naprosyn), gastritis, GI bleeding, rare renal toxicity, rare hepatotoxicity, rare ototoxicity

o Monitoring: no routine monitoring necessary if NSAIDs used as monotherapy, but

hemoglobin, renal function and liver enzymes with clinic visits

NSAID

Dose

Comments

Aspirin/ASA

High dose (anti-inflammatory): 50-100 mg/kg/day

PO div QID

Low dose (anti-platelet): 3-5 mg/kg/day PO OD

Used mostly in the setting of

Kawasaki disease and acute

rheumatic fever

Celecoxib

50 mg PO BID if 10-25 kg

100 mg PO BID if >25 kg

Selective COX-2 inhibitor;

expensive

Ibuprofen

20-40 mg/kg/day PO div TID or QID

Commonly used in childhood JIA

Indomethacin

2-3 mg/kg/day (max 150 mg/day) PO div TID

Commonly used in ERA and sJIA,

can be compounded into liquid

Meloxicam

0.125 mg/kg (max 15 mg/day) PO daily

Used in JIA, can be compounded

into liquid

Naproxen

20 mg/kg/day (max 500 mg/dose) PO div BID

Frequently used in childhood JIA

Piroxicam

0.4 mg/kg (max 20 g/day) PO daily

Used in JIA, capsule may be

opened and sprinkled on food

ERA: enthesitis related arthritis; sJIA: systemic juvenile idiopathic arthritis; COX = cyclooxygenase

 Pamidronate

o Class: bisphosphonate

o Mechanism of action: inhibits bone resorption, decreases mineralization by inhibiting

osteoclast activity

o Dose: 1 mg/kg/day if >3 yrs (max 60 mg/day) monthly for 3 months (note: first dose to be

given over 2 days)

o Side effects: bone pain, fever, headaches, lethargy, fetal toxicity, unclear risk of

osteonecrosis of the jaw

o Monitoring: calcium, phosphate, creatinine, ALP and PTH prior to each infusion

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Rilonacept

o Class: biologic agent (see Biologic agents for summary table)

o Mechanism of action: fully human dimeric fusion protein that blocks IL-1 by acting as a

soluble decoy receptor; also known as “IL-1 Trap”

o Dose: loading dose 4.4 mg/kg/dose (max 320 mg) then 2.2 mg/kg/dose SC weekly (max

160mg)

o Side effects: injection reactions, infections, dyslipidemia, potential risk of future

malignancy

o Monitoring: CBC and liver transaminases after 4 weeks and then every 3 months; serum

lipid monitoring added 8-12 weeks after initiation

 Rituximab

o Class: biologic agent (see Biologic agents for summary table)

o Mechanism of action: chimeric mouse-human monoclonal antibody that binds to the B

cell CD20 receptor (on pre-B and mature B cells but not on stem cells or plasma cells)

o Dose: dosing may depend on indication; 375 mg/m

once weekly for 2-4 doses or 750

mg/m

on days 1 and 15; for polyarticular RF-positive JIA patients 500 mg/m

(max 1000

mg) every 2 weeks for 2 doses or 375 mg/m

once weekly for 4 doses

o Side effects: infusion reactions, allergic reaction, hypogammaglobulinemia, infection,

potential risk of future malignancy, progressive multifocal leukoencephalopathy (PML)

o Monitoring: screen for hepatitis B; check B cell numbers before and 1 month after

infusion; quantitative immunoglobulins every 3 months; follow liver transaminases

o Special considerations:

 Prophylaxis with cotrimazole (trimethoprim-sulfamethoxazole) given 3 times weekly

to prevent opportunistic infection by Pneumocystis jirovecii

 Human anti-chimeric antibodies (HACAs) can develop and decrease efficacy and

increase risk of infusion reactions

 Recommend screening for hepatitis status

 Recommend pre-medication with Hydrocortisone

 Sulfasalazine

o Class: disease-modifying antirheumatic drug (DMARD); analogue of 5-ASA linked to a

sulfonamide

o Mechanism of action: inhibits enzymes and transcription factors involved in production of

pro-inflammatory cytokines

o Dose: 50 mg/kg/day (max 3 g daily) PO divided twice daily; typically start at 10

mg/kg/day and increase weekly over 4 weeks to target dose

o Side effects: nausea, vomiting, rash, oral ulcers, photosensitivity, cytopenias,

hypogammaglobulinemia, hepatotoxicity, allergy (Stevens-Johnson syndrome)

o Monitoring: CBC, differential and liver enzymes every 2 months, immunoglobulin levels

every 6 months

o Special consideration: contraindicated if history of allergy to sulfonamide antibiotics

 Tocilizumab

o Class: biologic agent (see Biologic agents for summary table)

o Mechanism of action: humanized monoclonal antibody that binds both soluble and

membrane-bound IL-6 receptor

o Dose:

 Systemic JIA: 12 mg/kg/dose if <30 kg; or 8 mg/kg/dose (max 800 mg) if ≥ 30 kg via

IV every 2 weeks

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

 Polyarticular JIA: 10 mg/kg/dose if <30 kg; or 8 mg/kg/dose (max 800 mg) if ≥ 30 kg

via IV every 4 weeks

o Side effects: infusion reactions, headaches, GI upset, hepatotoxicity, dyslipidemia,

neutropenia, thrombocytopenia, GI perforation, infection, potential risk of future

malignancy

o Monitoring: AST, ALT, absolute neutrophil count at baseline, at second infusion and then

every 2-4 weeks; lipid panel 4-8 weeks after start of treatment then every 6 months

 Tofacitinib

o Class: Janus Kinase inhibitor

o Mechanism of action: interferes with Jak-stat system (Jak 3 and Jak 1) and subsequent

production of selective interleukins and interferons

o Dose: dosing in adult rheumatoid arthritis 5 mg PO twice daily

o Side effects: infections, viral reactivation, anemia, thrombocytopenia, neutropenia,

lymphopenia, hypercholesterolemia, increased liver transaminases, GI perforation,

potential risk of future malignancy

 Secukinumab

o Class: biologic agent (see Biologic agents for summary table)

o Mechanism of action: humanized monoclonal antibody that binds soluble and membrane

bound IL-17A

o Dose: for ankylosing spondylitis and psoriatic arthritis 150 mg SC every week for 4

weeks and then every 4 weeks

o Side effects: infections, flu-like symptoms, injection site reactions, potential risk of future

malignancy, may un-mask or lead to flares of inflammatory bowel disease

 Ustekinumab

o Class: biologic agents (see Biologic agents for summary table)

o Mechanism of action: humanized monoclonal antibody that binds soluble and membrane

bound IL-12 and IL-23

o Dose: for psoriasis 0.75 mg/kg if <60 kg, 45 mg if 60-100 kg or 90 mg for >100 kg; given

by SC injection at baseline, in 4 weeks and then every 12 weeks

o Side effects: infections, injection site reactions, potential risk of future malignancy, rare

reports of posterior reversible encephalopathy syndrome

A RESIDENT’S GUIDE TO PEDIATRIC RHEUMATOLOGY

APPENDIX – HELPFUL RESOURCES IN PEDIATRIC RHEUMATOLOGY

Textbooks

Petty RE, Laxer RM, Lindsley CB, Wedderburn L. Textbook of Pediatric Rheumatology, Seventh

Edition. 2015: Saunders Elsevier Publishing.

Foster HE, Brogan P. Paediatric Rheumatology. 2018: Oxford University Press.

Laxer RM, Sherry DD, Hashkes PN Pediatric Rheumatology in Clinical Practice. 2

edition.

2016: Springer-Verlag.

Hashkes PJ, Laxer RM, Simon A. Textbook of Autoinflammation. 2019: Springer Nature

Switzerland.

Monographs

Li SC, Higgins GC, Eds. Pediatric Rheumatology. Pediatr Clin North Am 2018; 65(4).

Laxer RM, Sherry DD, Eds. Pediatric Rheumatology. Pediatr Clin North Am 2012; 59(2).

Rouster-Stevens KA, et al. Choosing Wisely: The American College of Rheumatology’s Top 5

for Pediatric Rheumatology. Arthritis Care Res 2014; 66(5):649-57.

Internet Resources for Images in Rheumatology

American College of Rheumatology Image Bank: http://images.rheumatology.org/

Rheumatlas website: http://rheumexamatlas.com/atlas/

Internet Resources for Patients

Paediatric Rheumatology InterNational Trials Organisation (PRINTO) – provides information on

all childhood rheumatic diseases in many languages:

https://www.printo.it/pediatric-rheumatology/IE/info/IE

RheumInfo – provides easy-to-read pictopamphlets on medications

https://rheuminfo.com/

About Kids Health – provides information on multiple childhood rheumatic diseases from a

general pediatric perspective

https://www.aboutkidshealth.ca/

Teens Taking Charge (Managing JIA Online) – provides resources for adolescent JIA patients

https://www.aboutkidshealth.ca/Article?contentid=1087&language=English

Arthritis Australia - provides information on JIA and chronic pain in children

https://arthritisaustralia.com.au/managing-arthritis/arthritis-and-children/

We are interested in your feedback on the guide! If you have comments or questions,

please feel free to contact us via email at pedrheumguide@gmail.com.