1. Overview of Systemic Lupus Erythematosus
Pediatric Rheumatology
Red Team Resident
Teaching Series

2. Systemic Lupus Erythematosus
Episodic, heterogeneous, multisystem autoimmune disease
Widespread inflammation of vessels and connective tissues
Variable clinical manifestations and course
characterized by remissions and relapses
Incidence in children: /100,000 children/year
20% of adults have onset in childhood (<19 years old)
Female to male ratio: 9:1
Uncommon before 4 years of age
More common in African American and Hispanic children
Children have more aggressive disease with more organ involvement than adults
30% may progress to renal insufficiency depending on treatment
10 year survival 80-90%

3. Current Theories Of Pathogenesis In SLE
Etiology unknown
Multiple genes are associated with a predisposition towards developing lupus
Immune dysregulation of B and T cell responses
Immune complex deposition
Abnormalities of complement
Decreased clearance of apoptotic debris
Hormonal imbalance
Environmental triggers including UV B light, infection
Loss of tolerance to chromatin and other autoantigens
Cross reactivity between bacterial and mammalian DNA
Abnormal response to DNA?
These factors, acting alone or together, may trigger onset of disease in a genetically predisposed host.

4. Immune complex disease
Antibodies can be against self (e.g. nuclear components in SLE) or foreign antigens (i.e. drugs or microorganisms in serum sickness)
Antibodies and antigens combine to form immune complexes
Immune complexes deposit in blood vessels and tissues and activate inflammatory response leading to tissue destruction

5. ACR 1997 Revised Lupus Criteria
Need 4 of 11 criteria for a diagnosis of lupus (sensitivity of 96%
and a specificity of 100% in children). If a patient has lupus nephritis, then only a total of 3 of 11 criteria are needed.

6. 2012 SLICC Criteria
Click on this link for further details on individual criteria:

7. Clinical Features of SLE
Constitutional symptoms
Musculoskeletal disease
Mucocutaneous manifestations
Renal Disease
Central nervous system disease
Cardiopulmonary disease
Hematologic abnormalities
Gastrointestinal involvement
Constitutional: fever, fatigue, wt loss, anorexia (very nonspecific)

8. Musculoskeletal Disease
Incidence: 76%
Arthralgias
Arthritis
Non-erosive
Involves small joints of the hands, wrists, elbows, shoulders, knees, ankles
Can be migratory, lasting hours
Myalgias/ muscle weakness
Usually proximal
Muscle weakness/ myalgias usually in an acutely ill pt. Myositis often related to systemic vasculitis and visceral involvement.

9. Mucocutaneous Manifestations
Frequency: 76%
Malar rash
Discoid lupus
Vasculitis (purpura, petechiae)
Raynaud’s phenomenon
Nail involvement
Alopecia
Periungual erythema/ Livedo reticularis
Photosensitivity
Oral/ nasal ulcers
Rashes are common and varied!

10. Chronic discoid-type malar rash
Chronic discoid-type malar rash. Discoid lesions tend to be coin-shaped, red and raised with a scaly, sometimes hypopigmented center. This type of lesion can occur in both purely cutaneous (discoid) and systemic lupus.
Malar rash: classic butterfly rash, symmetric, sparing nasolabial folds. Can also include the chin and forehead. One third to one half of children have this at presentation. Can be photosensitive.

11. This is a typical photosensitive eruption involves the face, neck, and "V" of the chest. It occurs after exposure to UV light, and is found in 17-58% of patients with lupus. Crusting has developed following the breakdown of vesicular and bullous lesions.
This is livedo reticularis. While not a diagnostic criteria, it is a vasculitic-type rash often seen in individuals with lupus and other vasculitides. Note the mottled, lacey-type pattern.

12. This is a palatal ulcer. Oral and nasal ulcers occur in 30-40% of lupus patients. Oral ulcers tend to occur on the hard palate, but can occur on the buccal mucosa. They start as hyperemic areas that ulcerate. In the nose, they can precipitate nose bleeds. They are often painless, and are an indicator of active disease.
Raynaud’s (single digit): characterized by triphasic color change in an extremity to cold temperature or emotional upset: blanching (white), then cyanosis (blue), then reactive hyperemia (red), accompanied by ischemic pain. To meet a diagnosis of Raynaud’s, the blanching white phase and one other color phase need to be present. Primary Raynaud’s = patients without known autoimmune disease; Secondary Raynaud’s = with autoimmune disease.

13. Neuropsychiatric Manifestations
Frequency: 20-40%
Difficult to diagnose and treat
Second to nephritis as most common cause of morbidity & mortality
Can occur at any time; even at presentation
Standard lab examinations have not been helpful in diagnosing or managing CNS symptoms
COMMON: Depression, organic brain syndrome, functional psychosis, headaches, seizures, cognitive impairment, dementia, coma
OCCASIONAL: Cerebral vascular accidents (thrombosis or vasculitis), aseptic meningitis, peripheral neuropathy, cranial nerve palsies
RARE: Paralysis, transverse myelopathy, chorea
Depression: very common, hard to tease out from regular adol depression, worries about dz/ side effects/ appearance. Emotional lability, difficulty concentrating and remembering. Organic brain syndrome: disorientation, memory loss and progressive intellectual deterioration- grave prognostic sign. Psychosis: hallucinations, paranoia. Cognitive impairment: failing academically, lower IQ scores. Headache: many causes. Vascular migraine-like headaches are more freq in SLE pts than in controls. Sz: GTC usu. CVA: may occur independently or with venous sinus thrombosis or cerebral vein thrombosis; may be associated with HTN, antiphospholipid-related thrombosis or IVH 2/2 low plts.

14. Cardiovascular Findings
Pericarditis
Most common cardiac manifestation in children
Can be asymptomatic, or represented by chest pain worsened by lying down or deep breathing that is relieved by sitting up and leaning forward. Tamponade is rare but does occur.
Myocarditis
Sterile valvular vegetations (Libman-Sacks endocarditis – see photo below)
Less common in children than in adults.
Subclinical, it is a sterile nodule of fibrinoid necrosis of the collagenous tissue of the valve.
Risk of bacterial endocarditis
Arrhythmias
Cor pulmonale
Vasculitis (small vessels)
Atherosclerosis/ Coronary Heart disease
Dyslipoproteinemias

15. Pulmonary Findings Incidence: 5-67% May be subclinical (abnormal PFTs)
Pleuritis
unilateral or bilateral chest pain, exacerbated by deep inspiration
Pleural effusion
Usually small, can be asymptomatic
Pneumonitis
Pulmonary infiltrates, atelectasis, or rales; occurs in 10-15% of children
Pulmonary hemorrhage
Chest pain, hemoptysis, pallor, anemia
Pulmonary hypertension
Restrictive lung disease & diffusion defects most commonly observed abnormalities on PFTs

16. GI Involvement
Mild LFT elevation--not significant clinically--BUT NEED TO EXCLUDE AUTOIMMUNE HEPATITIS
Colitis
Mesenteric vasculitis
Protein-losing enteropathy
Pancreatitis
Exudative ascites

17. Hematologic Findings Leukopenia, especially lymphopenia Anemia
Neutropenia is rare except in the case of anti-neutrophil antibodies, or in the case of infections
Anemia
mild to moderate, common, due to chronic disease and mild hemolysis
Severe anemia is uncommon (5%), due to immune mediated hemolysis (Coombs +)
To meet lupus criteria, the anemia needs to be Coombs positive
Thrombocytopenia
Due to immune mediated damage
mild ( K) is common
severe (<20K) is uncommon (5-10%)
Bone marrow suppression/arrest (aplastic anemia)--very rare, due to antibodies against bone marrow precursors

18. Coagulopathy Hypocoagulable states: Hypercoagulable states:
Anti-platelet antibodies--decreased numbers of platelets or decreased function (increased bleeding time)
Other platelet dysfunction and thrombocytopenia
Anti-clotting factor antibodies
Hypercoagulable states:
Antiphospholipid Antibody Syndrome (APS)
Presence of antiphopholipid antibodies detected by one of the following tests:
Anticardiolipin antibodies
Beta 2-glycoprotein antibodies
Direct Russel Viper Venom Test
Lupus Anticoagulant
Protein C and S deficiencies
Thrombotic thrombocytopenic purpura

19. Renal Disease More common and more severe in children than in adults
Most common cause of morbidity & mortality
Can present as proteinuria (including nephrotic range), hematuria, cellular casts, hypertension, decreased GFR <-> renal failure
Glomerulonephritis – occurs in at least 75%
Glomerulonephritis class based on inflammation location and amount, and is predictive of potential for renal damage
Class I+II, III and IV GN (mesangial, focal and diffuse proliferative): result from immune complex deposition from the circulation
Class V GN (membranous): results from in situ formation of immune complexes
Microscopic or gross hematuria
Renal failure (up to 30-50% of children prior to 1980)

20. Laboratory Findings Cytopenias (anemia, thrombocytopenia, leukopenia)
Elevated ESR, CRP, Immunoglobulins (particularily IgG)
Hypoalbuminemia
Proteinuria; RBCs, casts in urine
Decreased creatinine clearance
Low complement levels (C3/ C4)
C4 depression is more specific than C3 depression
Autoantibodies (ANA, APL, Coombs, anti-platelet Ab, rheumotoid factor, etc.)
(Immune complexes)

21. Antinuclear Antibodies (ANA)
Sensitive but not specific, 95-98% patients positive
Against nuclear components of the cell
Titer specific- up to 10% of population have +ANA w/o disease; also see with infections, medications, malignancy
Subtypes:
dsDNA: high specificity for lupus (over 80%)
ENA (extractable nuclear antigens)
Smith: specific for SLE
U1RNP: associated with MCTD
SSA/SSB: Sjogren’s, neonatal lupus
Histone: drug induced lupus

22. SLE - Treatment
Treatment is usually based on organ system involvement and the severity of involvement
MILD DISEASE: Rashes, arthritis, leukopenia, anemia, arthritis, fever, fatigue
MODERATE DISEASE: Mild disease + mild organ system involvement such as: mild pericarditis, pneumonitis, hemolytic anemia, mild renal disease
SEVERE DISEASE: Severe, life-threatening organ system involvement
Sunscreen and UV avoidance
Immunizations and infections
Patients on immunosuppressive medications should avoid ALL LIVE VACCINES
Infections should be treated promptly due to immunosuppression and risk of disease flair
Unvaccinated patients exposed to VZV or measles should receive VZIG or IVIG
Physical and occupational therapy

23. Medications Used in Lupus
NSAIDs
Naproxen – often used with arthritis, mild serositis
Ibuprofen – can cause aseptic meningitis in lupus patients
Antimalarials (usually Hydroxychloroquine)
Used in all patients
Aspirin for patients with APLs
Corticosteroids
Used in all patients except those with very mild disease
Pulse dose
High dose (1-2 mg/kg/day)
Low maintenance dose (5-7.5 mg/day)

24. Medications Used in Lupus
DMARDs and Immunosuppressives
Azathioprine – hematologic disease, mild NP disease, general steroid-sparing agent
Methotrexate – arthritis, skin disease, general steroid-sparing agent
Cyclosporine/Prograf - nephritis
MMF – nephritis, general steroid-sparing agent
Cytoxan – nephritis, cerebritis, pulm HTN
Biologics
Rituximab
Benlysta
Theurapeutic Plasmaphresis
Stem Cell Transplantation

25. Emergencies in SLE Fever: always rule-out infection
Renal disease: uremia, hypertension
Cytopenias: acute hemolytic anemia, thrombocytopenia
CNS: seizures, coma
Pleural effusion (symptomatic)/ pneumonitis/ pulmonary hemorrhage
Pericarditis/ myocarditis/ tamponade
Peritonitis/ pancreatitis/ GI bleed
Raynaud's: digital necrosis
Ocular: retinal vein thrombosis, retinal vasculitis, hemorrhage, edema
Thrombotic events, catastrophic antiphospholipid antibody syndrome (CAPS), thrombotic thrombocytopenic purpura
“Lupus Crisis”

26. Practice Question
10-year-old girl with SLE for a health supervision visit. Initially presented at 8 years with ITP, found to have positive ANA, then arthritis and dsDNA. She is currently doing well in school. Malar rash noted on exam.
The MOST useful screening test for other organ involvement is:
A. Coombs test
B. ESR
C. Brain MRI
D. Urinalysis
E. VDRL