Systemic Lupus Erythematosus
Internist Update
Khaled Al Jarallah ,MD
FRCPC,FACP,FACR
Internist, Rheumatologist
Medical Department
Faculty of Medicine
Kuwait University
No disclosures related to the presentation
Learning objectives
• To highlight the natural history of SLE
• To develop a clinical approach to patient suspected
to have SLE
• To define your therapeutic strategies to each SLE
patient based upon activity, severity, organ damage,
and comorbidities
Multi-Systemic Autoimmune Disease
Heterogeneous disease
Lupus patient mind map !
Aetiology ?
Genetics
Hormonal
Environmental
Genetics
Moser K et al, Genes and Immunity 2009
Genetics
Criswell LA et al. The Rheumatologist 2011.
Environmental
•
•
•
•
•
Ultraviolet light
Drugs
Infection
Smoking
Silica dust
Pathogenesis
Innate
Adaptive
Ann Rheum Dis 2010;69:1603–11
Pathogenesis
www.dressage-de-chien.net
Natural history of SLE
Ann Rheum Dis 2010;69:1603–11
The 4 D’s clinical approach
• Diagnostic workup
• Disease activity assessment
• Damage assessment
• Design treatment goals
Diagnostic workup
• No gold standard test
• Clinical reasoning
• Classification criteria
Diagnostic workup
• Identify disease manifestations
• Perform Lab. Tests
• Exclude other diseases
• Distinguish activity from chronicity
• Prioritize active disease manifestations
SLE target
Which one is lupus rash ?
A
B
C
Lupus mimickers
 Dermatological conditions: Rosocea, dermatitis
 Chronic autoimmune disorders: sjogrens, MCTD , JIA
 Vasculitis either primary or secondary to infection
(Hep C, parvovirus B19 ,HIV, EB virus) or malignancy
 Kikuchi-Fujimoto disease
 Multiple Sclerosis
Case presentation
• A 25-year-old woman. Her disease
manifestations consists of :
• Fatigue
• Hemolytic anemia
• ANA +
• Anti-Sm +
• C3,C4,CH50 Low
Classification criteria for SLE
Year
1971
American College of Rheumatology (ACR)
classification
Criteria for SLE classification developed
1982
1997
Revised classification
Revised again
2012
SLICC SLE Criteria
1971 ACR criteria for classification of SLE
Clinical Criteria
1
Facial erythema
2
Discoid lupus
3
Clinical Criteria
9
Chronic false positive
seologic test for syphilis
Raynaud's phenomenon
10
Proteinuria (>3.5 gm/day)
4
Alopecia
11
Cellular casts
5
Photosensitivity
12
Pleuritis or pericarditis
6
Oral or nasal ulcers
13
Psychosis or convulsions
7
Arthritis without
deformity
14
8
L.E cells (2 or more)
Hemolytic anemia
or Leukocytopenia (<4,000
/m) or Thrombocytopenia
(<100,000 /m)
Any of four or more criteria should be
present , serially or simultaneously
1982 revised classification criteria
Clinical Criteria
1
Malar Rash
2
Discoid Rash
3
Photosensitivity
4
Oral ulcers
5
Arthritis
6
Serositis
7
Renal Disorder
8
Neurologic Disorder
9
Hematologic disorder
10
Immunologic disorder
11
Antinuclear Antibody
Any of four or more criteria should be present , serially or simultaneously
1997 Revised classification criteria
Clinical Criteria
Immunologic disorder
1
Malar Rash
a) Anti-DNA or
2
Discoid Rash
b) Anti- Sm or
3
Photosensitivity
4
Oral ulcers
5
Arthritis
c) Positive finding of
antiphospholipid antibodies
based on:
6
Serositis
7
Renal Disorder
8
Neurologic Disorder
9
Hematologic disorder
10
Immunologic disorder
11
Antinuclear Antibody
1.Abnormal IgG/ IgM
anticardiolipin
antibodies
2. Positive Lupus
anticoagulant
3. False positive seologic
test for syphilis for 6
months
Any of four or more criteria should be present , serially or simultaneously
2012-SLICC* classification criteria
At least 1 clinical + at least 1 immunologic
Criteria ( for a total of 4)
OR
Lupus Nephritis by biopsy
with ANA or anti-dsDNA antibodies
* Systemic Lupus International Collaborating Clinics
Petri M et al. Arthritis Rheum 2012;64(8):2677-86
2012-SLICC classification criteria
Clinical Criteria
1
Acute Cutaneous Lupus
2
Chronic Cutaneous Lupus
3
Oral or nasal ulcers
4
Non-scarring alopecia
5
Arthritis
6
Serositis
7
Renal Disorder
8
Neurologic Disorder
9
Hemolytic anemia
10
Leukopenia/ Lymphopenia
11
Thrombocytopenia
Lupus specific
Histopathologic findings of interface
dermatitis
Acute Cutaneous / Subacute Cutaneous Lupus
•
•
•
•
•
•
•
Malar rash
Bullous lupus
Toxic epidermal necrolysis
Maculopapular lupus rash
Photosensitive lupus rash
Nonindurated psoriasiform
Annular polycyclic rash
Chronic Cutaneous Lupus
•
•
•
•
•
•
•
Discoid rash, localized & generalized
Hypertrophic ( verrucous ) lupus
Lupus panniculitis ( profundus )
Lupus erythematosus tumidis
Chilblains lupus
Mucosal lupus
Lichen planus overlap
SLE- Cutaneous manifestations
2012-SLICC classification criteria
Clinical Criteria
1
Acute Cutaneous Lupus
2
Chronic Cutaneous Lupus
3
Oral or nasal ulcers
4
Non-scarring alopecia
5
Arthritis
6
Serositis
7
Renal Disorder
8
Neurologic Disorder
9
Hemolytic anemia
10
Leukopenia/ Lymphopenia
11
Thrombocytopenia
2012-SLICC classification criteria
Immunologic Criteria
1
ANA
2
Anti-DNA
3
Anti- Sm
4
Antiphospholipid antibodies
Lupus anticoagulant
False+ rapid plasma reagin
Anticardiolipin , IgA, IgG or IgM
Anti-B2-glycoprotein I ,IgA, IgG or IgM
5
Low complements (C3,C4 or CH 50)
6
Direct Coombs test ( in absence of hemolytic anemia)
Performance of the classifications as
compared to the current ACR criteria on
the sample based on 702 cases*
Rule
‘Sensitivity’
‘Specificity’
Misclassified
cases (n)
1997 ACR
criteria
267/310 (86%)
365/392 (93%)
70
SLICC criteria
292/310 (94%)
361/392 (92%)
49
*Petri M et al. Arthritis Rheum. 2012;64(8): 2677
Case presentation
• A 25-year-old woman. Her disease
manifestations consists of :
• Fatigue
• Hemolytic anemia
• ANA +
• Anti-Sm +
• C3,C4,CH50 Low
Cumulative SLE features in different ethnic groups
#European
N=1000
$Filipino
N=1,070
India*
N=1366
Kuwait**, Saudi@
N=732
Malar Rash
58
49
58
49
Discoid Rash
10
26
7
15
Photosensitivity
45
33
48
38
Oral ulcers
24
33
55
27
Arthritis
87
68
85
89
Serositis
29
12
22
41
Renal Disorder
37
47
73
49
Neurologic Disorder
23
13
51
24
Hematologic disorder
53
37
26
64
Immunologic disorder
Anti-DNA
Anti- Sm
VDRL
58
13
6
-
68
29
8
74
25
9
Antinuclear Antibody
94
-
98
96
*Lupus 1997; **1998; @2009; $Mod Rheumatol 2008; #Medicine (Baltimore) 1993
Cumulative frequencies of SLE features
Manifestation
Frequency
Constitutional symptoms
90%-95%
Mucocutaneous involvement
Musculoskeletal involvement
Serositis
Glomerulonephritis
Neuropsychiatric involvement
Autoimmune cytopenia
80%-90%
80%-90%
50%-70%
40%-60%
40%-60%
20%-30%
Vitali C et al.Clin Exp Rheumatol 1992
The 4 D’s clinical approach
• Diagnostic workup
• Disease activity assessment
• Damage assessment
• Design treatment goals
Disease activity assessment
• Which instrument to choose?
• SLEDAI ,BILAG ,SLAM, ECLAM, SRI
• Activity, severity, reversibility
SELENA-SLEDAI
SLEDAI
• Evaluates 24 lupus manifestations
• Parameters are scored √ if present
• Manifestation items are weighted with scores
ranging from 1 to 8
• Scores are totaled
– Mild: 0-5
– Moderate: 6-12
– Severe: 13-20
Bombardier C et al. Arthritis Rheum. 1992; 35:630-640
SLEDAI
SLEDAI
Score
Yes
No
Descriptor
Definition
8
1
 0
Seizure
Recent onset. Exclude metabolic, infectious, or drug causes.
8
1
 0
Psychosis
Altered ability to function in normal activity. Include
hallucinations, incoherence , marked loose associations, marked
illogical thinking, bizarre, disorganized, or catatonic behavior.
8
1
 0
Organic brain
syndrome
Altered mental function with impaired orientation, memory, or
other intellectual function, rapid onset and fluctuating clinical
features
8
1
 0
Visual
disturbance
Retinal changes of SLE. Include cytoid bodies, retinal
hemorrhages, serous exudate or hemorrhages in the choroid, or
optic neuritis.
8
1
 0
Cranial nerve
disorder
New onset of sensory or motor neuropathy involving cranial
nerves.
8
1
 0
Lupus headache
Severe, persistent headache; may be migrainous, but must
nonresponsive to narcotic analgesia.
8
1
 0
CVA
New onset of cerebrovascular accident(s). Exclude
arteriosclerosis.
8
1
 0
Vasculitis
Ulceration, gangrene, tender finger nodules, periungual
infarction, splinter hemorrhages, or biopsy or angiogram proof of
vasculitis.
SLEDAI
SLEDAI
Score
Yes
No
Descriptor
Definition
4
 1
0
Arthritis
More than 2 joints with pain and signs of inflammation
4
1
 0
Myositis
Proximal muscle aching/weakness, associated with elevated CPK/ aldolase
/EMG changes /biopsy showing myositis
4
1
 0
Urinary casts
Heme-granular or red blood cell casts
4
1
 0
Hematuria
>5 red blood cells/high power field. Exclude stone, infection, others
4
1
 0
Proteinuria
>0.5 gm/24 hours.
4
1
 0
Pyuria
> 5 white blood cells/high power field. Exclude infection.
2
 1
0
Rash
Inflammatory type rash.
2
 1
0
Alopecia
Abnormal, patchy or diffuse loss of hair.
2
1
 0
Mucosal ulcers
Oral or nasal ulcerations
2
1
 0
Pleurisy
Pleuritic chest pain with pleural rub or effusion, or pleural thickening.
2
1
 0
Pericarditis
Pericardial pain with at least 1 of the following: rub, effusion, or +ECG or echo
2
 1
0
Low complement
Decrease in CH50. C3. or C4 below the lower limit of normal for testing
laboratory.
2
 1
0
Increased DNA
binding
Increased DNA binding above normal range for
testing laboratory.
1
 1
0
Fever
>38°C. Exclude infectious cause.
1
 1
0
Thrombocytopenia
< 100x109 platelets/L. Exclude drug causes
1
 1
0
Leukopenia
< 3x109 WBC/L. Exclude drug causes
The 4 D’s clinical approach
• Diagnostic workup
• Disease activity assessment
• Damage assessment
• Design treatment goals
Damage assessment
• Which instrument to choose?
• SLICC/ACR damage index
• Chronicity, damage, irreversibility
SLICC/ACR damage Index
• Validated & used in clinical trails
• Records damage in 12 organs or systems
• The damage must present in the last 6 month
• High damage index correlate with poor
prognosis
SLICC/ACR damage Index
Item
Score
Ocular
•
Any cataract ever
•
Retinal change or optic atrophy
0,1
0,1
Neuropsychiatric
•
Cognitive impairment/ major psychosis
•
Seizures requiring therapy for 6 months
•
CVA ever (score 2 if >1)
•
Cranial or peripheral neuropathy
• Transverse myelitis
0,1
0,1
0,1
0,1
0,1
Renal
•
Estimated GFR <50%
•
Proteinuria >3.5 gm/24 h
•
ESRD
0,1
0,1
3
Pulmonary
• Pulmonary hypertension
• Pulmonary fibrosis and radiograph)
• Shrinking lung (radiograph)
• Pleural fibrosis (radiograph)
• Pulmonary infarction (radiograph)
0,1
0,1
0,1
0,1
0,1
Cardiovascular
• Angina or coronary artery bypass
• Myocardial infarction ever (score 2 if > 1)
• Cardiomyopathy (ventricular dysfunction)
• Valvular disease (murmur >3/6)
• Pericarditis for 6 months, or
pericardiectomy
0,1
0,1,2
0,1
0,1
0,1
Item
Score
Peripheral vascular
•
Claudication for 6 months
•
Minor tissue loss (pulp space)
•
Significant tissue loss ever ( loss of digit) (score 2 if >1 site)
•
Venous thrombosis, swelling, ulceration, or venous stasis
0,1
0,1,2
0,1
0,1
Gastrointestinal
•
Infarction or resection of bowel below duodenum spleen,
liver, or gall bladder ever, for cause any (score 2 if > 1 site)
•
Mesenteric insufficiency
•
Chronic peritonitis
•
Stricture or upper gastrointestinal tract surgery ever
0,1
0,1,2
0,1
0,1
Musculoskeletal
• Muscle atrophy or weakness
•
Deforming or erosive arthritis
•
Osteoporosis with fracture or vertebral collapse
•
Avascular necrosis (score 2 if >1)
•
Osteomyelitis
•
Tendon Rupture
0,1
0,1
0,1
0,1,2
0,1
0,1
Skin
• Scarring chronic alopecia
• Extensive scarring other than scalp and pulp space
• Skin ulceration (excluding thrombosis) for >6 months
0,1
0,1
0,1
Premature gonadal failure
0,1
Diabetes (regardless of treatment)
0,1
Malignancy (exclude dysplasia) (score 2 if > 1 site)
0,1,2
Damage (nonreversible change, not related to active inflammation) occurring since onset of lupus, ascertained by clinical assessment and present for at least 6
months unless otherwise stated. Repeat episodes must occur at least 6 months apart to score 2. The same lesion cannot be scored twice.
SLE Disease assessment
Disease Activity
SLEDAI
Disease Damage
SLICC/ACR
Damage Index
Health Status
Assessment
SF-36
The 4 D’s clinical approach
• Diagnostic workup
• Disease activity assessment
• Damage assessment
• Design treatment goals
Design treatment goals
• Do good
Control disease activity
Prevent organ damage
Prevent flares
• Do no harm
Safety profile Drugs
Drugs related damage
Mortality and Treatment
1950-1954
Corticosteroids
5 year survival , 50%
1940-1950
Antimalarials
1970-1990s
Methotrexate
Organ transplantation
Plasmapheresis
Cyclosporine
10 year survival >80%
1960-1970s
Cyclophosphamide
Azathioprine
‘dialysis’
10 year survival >60%
2011
Belimumab
2000-2010s
Mycophenolate mofetil
Biologics , Retuximab
Improvement in antibiotic
antihypertensive, and antithrombotic
therapies
Adapted from Manzi S ,ACR 2012
Hydroxychloroquine
•
•
•
•
•
•
•
•
Reduction in flares
N Engl J Med 1991;324:150
Reduction in lipids
Am J Med 1990;89:322
Reduction in thrombosis
Scand J Rheumatol 1996;25:191
Reduction in organ damage Arthritis Rheum 2005;52:1473
Improved survival Lupus 2005;14:220
Triples mycophenolate response
Lupus 2006;15:366
Prevents seizure
Ann Rheum Dis 2012;71:1502
Reduction in CHB in neonatal lupus Circulation 2012
Vitamin D
Improved vitamin D level positively affects:
• Disease activity (21% in odds in SLEDAI score 5or>)
• Urine protein/Cr (15% in odds in urine pr/cr >0.5)
• Systolic blood pressure
Low vitamin D is associated with venous thrombosis
Petri M et al. ACR abstracts 2012,2013
Overview of management of SLE
Establish diagnosis
Determine disease activity
No major organ involvement
• Antimalarials
• Low-dose steroids
• Azathioprine/methotrexate
Assess severity and organ involvement
Lifestyle (sun avoidance)
Topical agents
Symptomatic agents
Manage co-morbidities
Major organ involvement
• Cyclophosphamide (IV)
• Mycophenolate mofetil
• Calcineurin inhibitors (CyA/tarcolimus )
• Biologics (rituximab/belimumab) or
• Enroll in a clinical trial
Overview of the management of systemic lupus erythematosus -John A Reynolds, Ian N Bruce
Issue 2 (Topical Reviews Series 7) Spring 2013
Treatment targets for SLE
Adapted from Xiong W and Lahita RG. Ther Adv Musculoskelet Dis. 2011
Treatment targets for SLE
Ryo1m.cocolog-nifty.com
Types of Vaccinations
Inactivated or killed
vaccines
Toxoids
Live Attenuated Vaccines*
Cholera
Diphtheria
BCG
Meningococcal
Tetanus
Oral Typhoid
Pneumococcal
Typhoid
Hemophilus Influenza B
Herpes Zoster
Hepatitis A,B
Measles, Mumps, Rubella
HPV
Varicella
Polio ( Salk)
Polio (oral)
Seasonal influenza (IM)
Seasonal influenza (Intra
nasal)
Japanese Encephalitis
Yellow Fever
Endemic typhus
* Not recommended in SLE if on immunosuppressive or biologic medications, low immunoglobulins, hypocomplementemia
Conclusions “take home massages”
• SLE is a heterogeneous multisystem disease which
varies among races and ethnicities
• SLE pathogenesis is complex with dysregulation of
multiple arms of the immune system
• Early lupus diagnosis and disease monitoring remains
a challenge for treating physicians
• SLICC 2012 revised SLE criteria improved the
sensitivity and retained the specificity when
compared with 1997 ACR classification
Conclusions “take home massages”
• Set the treatment goals after Identifying disease
manifestations, comorbidities, distinguish activity
from chronicity and prioritize active disease
manifestations
• Use the least toxic medicine and lowest dose to
treat the most concerning disease manifestation
• Balance the treatment of active disease verses
the complications of the treatment
Learning Resources
• Bertsias GK et al .Diagnostic criteria for Systemic Lupus Erythematosus:
has the time come? Nat. Rev. Rheumatol.2013;9: 687-694
• Bertsias GK et al. EULAR recommendations for the management of
systemic lupus erythematosus. Report of a Task Force of the EULAR
Standing Committee for International Clinical Studies Including
Therapeutics Ann Rheum Dis 2008;67:195–205
• Hahn BH, et al; American College of Rheumatology. American College of
Rheumatology guidelines for screening, treatment, and management of
lupus nephritis. Arthritis Care Res . 2012;64:797-808
• www.rheumatolgy.org & www.eular.org
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