Systemic Lupus Erythematosus Internist Update Khaled Al Jarallah ,MD FRCPC,FACP,FACR Internist, Rheumatologist Medical Department Faculty of Medicine Kuwait University
Feb 23, 2016
Systemic Lupus ErythematosusInternist Update
Khaled Al Jarallah ,MDFRCPC,FACP,FACRInternist, RheumatologistMedical DepartmentFaculty of MedicineKuwait 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
EnvironmentalHormonal
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
Ann Rheum Dis 2010;69:1603–11
Innate
Adaptive
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 American College of Rheumatology (ACR) classification
1971 Criteria for SLE classification developed1982 Revised classification1997 Revised again
2012 SLICC SLE Criteria
1971 ACR criteria for classification of SLEClinical Criteria
1 Facial erythema
2 Discoid lupus
3 Raynaud's phenomenon
4 Alopecia
5 Photosensitivity
6 Oral or nasal ulcers
7 Arthritis without deformity
8 L.E cells (2 or more)
Clinical Criteria
9 Chronic false positive seologic test for syphilis
10 Proteinuria (>3.5 gm/day)
11 Cellular casts
12 Pleuritis or pericarditis13 Psychosis or convulsions
14 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 Criteria1 Malar Rash2 Discoid Rash3 Photosensitivity4 Oral ulcers5 Arthritis6 Serositis7 Renal Disorder8 Neurologic Disorder9 Hematologic disorder
10 Immunologic disorder11 Antinuclear Antibody
Any of four or more criteria should be present , serially or simultaneously
1997 Revised classification criteriaClinical 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
Immunologic disorder
a) Anti-DNA orb) Anti- Sm orc) Positive finding of antiphospholipid antibodies based on:
1.Abnormal IgG/ IgM anticardiolipin antibodies 2. Positive Lupus anticoagulant3. 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 immunologicCriteria ( for a total of 4)
ORLupus 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
#EuropeanN=1000
$FilipinoN=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
58136
- 68298
74259
Antinuclear Antibody 94 - 98 96
Cumulative SLE features in different ethnic groups
*Lupus 1997; **1998; @2009; $Mod Rheumatol 2008; #Medicine (Baltimore) 1993
Cumulative frequencies of SLE features
Manifestation Frequency
Constitutional symptoms
90%-95%
Mucocutaneous involvement 80%-90% Musculoskeletal involvement 80%-90% Serositis 50%-70% Glomerulonephritis 40%-60% Neuropsychiatric involvement 40%-60% Autoimmune cytopenia 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: 13-20Bombardier 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 IndexItem Score
Ocular• Any cataract ever • Retinal change or optic atrophy
0,10,1
Neuropsychiatric • Cognitive impairment/ major psychosis • Seizures requiring therapy for 6 months • CVA ever (score 2 if >1) • Cranial or peripheral neuropathy • Transverse myelitis
0,10,10,10,10,1
Renal • Estimated GFR <50% • Proteinuria >3.5 gm/24 h • ESRD
0,10,13
Pulmonary• Pulmonary hypertension• Pulmonary fibrosis and radiograph) • Shrinking lung (radiograph) • Pleural fibrosis (radiograph) • Pulmonary infarction (radiograph)
0,10,10,10,10,1
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
0,10,1,20,10,10,1
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
0,10,1,20,10,1
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
0,10,1,2
0,10,1
Musculoskeletal • Muscle atrophy or weakness• Deforming or erosive arthritis • Osteoporosis with fracture or vertebral collapse • Avascular necrosis (score 2 if >1)• Osteomyelitis• Tendon Rupture
0,10,10,10,1,20,10,1
Skin• Scarring chronic alopecia• Extensive scarring other than scalp and pulp space
• Skin ulceration (excluding thrombosis) for >6 months
0,10,10,1
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 DamageSLICC/ACR
Damage Index
Health Status Assessment
SF-36
Disease ActivitySLEDAI
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
1950-1954Corticosteroids
5 year survival , 50%
1970-1990sMethotrexate
Organ transplantation Plasmapheresis
Cyclosporine10 year survival >80%
2011Belimumab
1940-1950Antimalarials
1960-1970sCyclophosphamide
Azathioprine‘dialysis’
10 year survival >60%
2000-2010sMycophenolate mofetilBiologics , 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
Assess severity and organ involvement
Lifestyle (sun avoidance)Topical agentsSymptomatic agentsManage co-morbidities
No major organ involvement• Antimalarials• Low-dose steroids• Azathioprine/methotrexate
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 VaccinationsInactivated or killed
vaccinesToxoids 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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