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 pericarditis

13 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: 13-20

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 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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