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Pediatric Rheumatology
Basil M Fathalla, MD, ABP, FAAP
Consultant Pediatric Rheumatology
Al Jalila Children’s Specialty Hospital
Faculty Disclosure Statement
Basil Fathalla, MD discloses that he nor any
member of his immediate family does not have any
relevant financial arrangements or affiliations with
any corporate organization associated with the
manufacture, license, sale, distribution or
promotion of a drug or device.
Objectives
 Review the spectrum of clinical manifestations for
systemic autoimmune diseases
 Describe the diagnostic approach to children with
autoinflammatory disorders
 Describe management of children with unclassifiable
presentations of rheumatic entities
Case 1
Transit in DXB
• 9 years old Arabic boy at DXB coming
from Vienna in transit to Kuwait.
• Developed generalized seizures and
sustained head trauma from falling on the
ground in terminal 1
• Transfer to Latifa hospital
• Blood work revealed severe anemia and
head CT scan showed signs of old infarcts
Transit in DXB
• Systemic investigations for organ
involvement
• Rheumatologic work up for specific
diagnosis
• Spectrum of clinical manifestations of
systemic autoimmune connective tissue
diseases
The lupus, Latin for
Wolf, was used to
describe recurrent,
florid, facial
Ulcerations since the
13th century.
From "Diseases of the skin.
An Outline of the principles
and practice of Dermatology"
Malcolm Morris, Cassel &
Co., London, 1894
SLE: Historic review
 13th -19th centuries: the term lupus appeared in the
literature.
 1872: acute and chronic types of skin disease
described by Osler.
 1895: systemic nature of disease and characteristic
exacerbations / remissions described by Osler; the
term “erythema exudativum” suggested.
 1924: Libman and Sacks described detailed cardiac
involvement.
 1948: LE cell was described by Hargraves, Richmond
and Morton.
SLE : Definition / Classification
 An episodic, multi-system, autoimmune connective
tissue disease characterized by widespread
inflammation of blood vessels and connective tissues
and by the presence of anti-nuclear antibodies
especially to native DNA.
ACR Classification of SLE
ACR 1982 criteria:











Malar rash
Discoid-lupus rash
Photosensitivity
Mucocutaneous ulcers
Nonerosive arthritis
Nephritis
Encephalopathy
Serositis
Cytopenia
ANA
Immunoserology:




Anti-DsDNA
+ LE
+ ENA
False + VDRL
ACR 1997 criteria:


Same as 1982
Immunoserology:
 Anti-DsDNA
 + ENA
 + APL:
1)IgG or IgM for ACL
2)Lupus anticoagulant
3)False + VDRL
Epidemiology of Juvenile-SLE
 Estimated 5,000-10,000 U.S. children
 Incidence (early studies in USA): 0.53-0.6 per
100,000 per year
 SLE accounts for <1% of rheumatology clinics in
UK, 1.5-3% in Canada, & 4.5% in USA.
 15-17% of all SLE patients had onset in childhood
 Female to Male ratio
 < 12 yrs. of age: 3:1
 > 12 yrs. of age: 10:1
 All races affected
Etiology & Pathogenesis
 Immune dysregulation:




B cell function
Immune complex mediated disease
T cell function
Apoptosis
 Hormones:
 May play a role in disease predisposition and severity
 Environmental factors:
 Ultraviolet light
 Viral infections
 Drugs / chemicals
Clinical features of SLE:
Constitutional: fever, malaise, weight loss
Skin: malar rash, discoid lupus, photosensitivity,
alopecia, ulcers
MSK: arthritis, tenosynovitis, myositis, aseptic necrosis
Vascular: Raynaud’s, acrocyanosis, thrombosis
Cardiac: pericarditis, effusions, myocarditis,
Libman-Sacks endocarditis
Pulmonary: Pluritis, effusions, pneumonitis, hemorrhage
GI: peritonitis, pancreatitis, mesenteric vasculitis
Neuro: seizures, psychosis, CVA, neuropathy,
pseudotumor cerebri, cranial nerve palsies
Ocular: retinopathy, papilledema
Renal: glomerulonephritis
Copyright ©1972-2004. American College of Rheumatology Slide Collection. All rights reserved.
Copyright ©1972-2004. American College of Rheumatology Slide Collection. All rights reserved.
Copyright ©1972-2004. American College of Rheumatology Slide Collection. All rights reserved.
Lupus Nephritis in Children
 Uncommon disorder of childhood; most important
aspect of SLE.
 Typically presents after the age of 10 yrs; very rare
less than 5 yrs of age.
 F:M 4.5:1 (more males compared to adult onset).
 Present at time of disease onset in a higher percentage
than adults (82%).
 Usually develops in the first 2 years of disease onset.
Lupus Nephritis in Children
 Most common initial presentation is microscopic
hematuria (~ 79%) proteinuria including nephrotic
syndrome (~ 55%),
 WHO classification is used to classify lupus nephritis.
 Indicators of active disease on kidney biopsy: cellular
proliferation, necrosis, cellular crescents, hyaline
thrombi, leukocytic glomerular infiltration &
interstitial infiltration.
 Indicators of chronicity: glomerular sclerosis,
interstitial fibrosis, fibrous crescents, tubular atrophy.
Class
Type of GN
Description
I
Normal
No detectable disease
IIA
IIB
Minimal change
Mesangial glomerulitis
Normal LM, mesangial Ig & c by IFM,
mesangial deposits by EM, IIB: mesangial
hypercellularity.
III
Focal & segmental
proliferation
Focal cellular proliferation, necrosis,
leukocyte infiltrates in < 50% of
glomeruli. Subendothelial or mesangial
deposits. Focal tubular & interstitial
disease.
IV
Diffuse proliferative GN
Class III in >50% of glomeruli. Abundant
Subendothelial deposits. Marked
interstitial disease.
V
Membranous GN
No mesangial, endothelial or epithelial
proliferation Diffusely uniformly
thickened capillary walls. IFM & EM
show mesangial & subepithelial deposits.
VI
Glomerular sclerosis
Segmental or extensive sclerosis of
glomeruli; fibrous crescent are common.
SLE: Management
 General: team approach, counseling, education,, rest,
nutrition, sunscreen, immunization, management of
infection, growth monitoring.
 NSAIDs: for MSK problems, careful in presence of
renal disease.
 Preventive medications: Vit D + Ca, baby aspirin,
hydroxychloroquine.
 Immunosuppressives: Glucocorticosteroids,
DMARDs, cytotoxic drugs
SLE: system specific management
 Cutaneous disease: Topical Glucocorticosteroids,
hydroxychloroquine, sunscreen.
 Hematologic manifestations: Glucocorticosteroids,
IVIG.
 APL-syndrome: baby aspirin, warfarin, LMWH.
 CNS: Glucocorticosteroids, cyclophosphamide.
 Cardio-Pulmonary: Glucocorticosteroids,
hydroxychloroquine, mycophenolate mofetil,
cyclophosphamide.
SLE nephritis
 Mesangial glomerulitis: symptomatic, prednisone.
 Focal nephritis: Glucocorticosteroids, consider
mycophenolate mofetil.
 Diffuse nephritis: Glucocorticosteroids +
cyclophosphamide.
 Membranous nephritis: Glucocorticosteroids,
consider azathioprine, mycophenolate mofetil,
cyclophosphamide.
Case 2
Inflammation in the eye of the
beholder
• 7 years old Arabic girl
• Recurrent episodes of fever, abdominal
pain, and chest pain
• 2 years later seen by GI and diagnosed
with clinical entity classifiable as an
autoinflammatory disease
• Patient responsive to treatment
• Routine referral to rheumatology proved
beneficial
Inflammation in the eye of the
beholder
• Differential diagnosis for periodic fever
• Importance of systemic evaluation even
when diagnosis is known
• Practical approach to autoinflammatory
diseases
Case 3
The cytokine storm
• 14 month old ill looking Arabic boy with
high spikes of fever and rashes
• Very high acute phase reactants
• No arthritis
• Systemic evaluation was unremarkable
• Bone marrow ruled out leukemia
The cytokine storm
• Differential diagnosis for a prolong febrile
illness
• What to do if diagnosis is not conclusive
• Combination of DMRARDs vs. biologic
therapies: advantages and disadvantages
SoJIA
 Unique clinical features
with adult-onset
equivalent
 Monocyclic, polycyclic,
and persistent courses,
sometimes without
arthritis
 Marked role for innate
immunity
 Low risk for uveitis
Singh-Grewal D et al. Arthritis Rheum 2011
Maritini A. Ann Rheum Dis 2012
Distinctive Clinical Manifestations
 No gender bias or peak age at onset
 Geographic variation (North America 10% of JIA,
India & Japan ≈ 30-50% of JIA)
 Extra-articular features, including quotidian fever,
rash, lymphadenopathy, HSM, and polyserositis
 Elevated acute phase reactants reflecting systemic
inflammation
Fujikawa S et al. Acta Paediatr1997
Sawhney S et al. Best Pract Res Clin Rheumatol 2006
Singh-Grewal D et al. Arthritis Rheum 2011
Macrophage Activation Syndrome
 Clinically: febrile, ill looking, rapid hepatic failure
with encephalopathy, renal failure with hematuria &
proteinuria, DIC-like presentation; bruising, purpura,
& mucosal bleeding
 ↑ Nodes, liver & spleen
 May occur in infectious & neoplastic disorders
 Unknown etiology / cytokine storm
Sawhney S et al. Arch Dis Child. 2001
Stephan JL at al.Rheumatology (Oxford). 2001
Ravelli A et al. J Pediatr. 2005
Macrophage Activation Syndrome
 ↓ Blood cell count (Hgb. , WBC , Plts)
↓ ESR (hypofibrinogenemia: consumptive
coagulopathy & DIC)
Prolonged PT, PTT, fibrin-split products
↓ Fibrinogen, Vit K dependent clotting factors
BM: Reactive hematophagocytic lymphohistiocytosis
 Increased morbidity & mortality
 Treatment: IV glucocorticoid & cyclosporine
Sawhney S et al. Arch Dis Child. 2001
Stephan JL at al.Rheumatology (Oxford). 2001
Ravelli A et al. J Pediatr. 2005
PAMP / DAMP
IL-18R
IL-1R
MyD88
NFκB
Pro-inflammatory
cytokine
Adapted from: Mellins ED et al. Nat Rev Rheumatol 2011
IL-1b
IL-18R
IL-1R
IL-1b
ASC
Casp-1
Casp-1
Pro-IL-1
Adapted from: Mellins ED et al. Nat Rev Rheumatol 2011
?
MyD8
8
NFK
B
?
IL-6
TNF
M-CSF
IL-1
IL-18
Adapted from: Mellins ED et al. Nat Rev Rheumatol 2011
MyD8
8
NFK
B
IL-6
Vascular
endothelium:
Coagulopathy
TNF
M-CSF
IL-1
IL-18
Hypothalamus:
Liver:
Joints:
Bone marrow:
Fever
Increased
acute phase
reactants
Increased
inflammation
 Platelets
 Monocyte/n
eutrophils
 S 100
proteins
Adapted from: Mellins ED et al. Nat Rev Rheumatol 2011
MyD8
8
NFK
B
IL-6
TNF
M-CSF
IL-1
Pro-inflammatory molecules with cytokinelike action secreted by activated neutrophils
and monocytes. SoJIA have high levels of
S100 proteins in contrast to other febrile
illnesses
Wittkowski H et al. Arthritis Rheum 2008
Frosch M et al. Arthritis Rheum 2009
IL-18
Bone marrow:
 Platelets
 Monocyte/n
eutrophils
 S 100
proteins
Adapted from: Mellins ED et al. Nat Rev Rheumatol 2011
MyD8
8
NFK
B
IL-6
TNF
M-CSF
IL-1
Forms a complex that triggers TLR4 that
lead to  pro-inflammatory cytokines,
including IL-1β and increased S100 proteins
Wittkowski H et al. Arthritis Rheum 2008
Frosch M et al. Arthritis Rheum 2009
IL-18
Bone marrow:
 Platelets
 Monocyte/n
eutrophils
 S 100
proteins
Adapted from: Mellins ED et al. Nat Rev Rheumatol 2011
SoJIA
Arthritis
Rashes
Serositis
Leukocytosis
↑Platelets
↑ESR
↑CRP
↑Fibrinogen
MAS
Encephalopathy
Fever
Liver failure
HSM
Leukopenia
Lymphadenopathy↓Platelets
Hepatitis
↓ESR
Coagulopathy
↓Fibrinogen
↑Ferritin
DIC
↓Albumin
↑↑↑Ferritin
↑ sIL2Rα
NK
TNF
IL-1
IL-6
IFNγ
GM-CSF
Trigger
(? Virus)
CD8
APC
GM-CSF
CD8
Leukocytosis
Macrophage
activation
NK
IFNγ
GM-CSF
Trigger
(? Virus)
CD8
APC
GM-CSF
CD8
Leukocytosis
Macrophage
activation
NK
sIL2-R
↑ TNF
↑ IL-1
↑ IL-6
IL-18
IFNγ
GM-CSF
Trigger
(? Virus)
CD8
↑ Ferritin &
sCD163
APC
GM-CSF
CD8
Hemostatic
TF
Leukopenia
References
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