Yi Zhao, MD & PhD, vice-director, associate professor

Department of Rheumatology & Immunology

Systemic Lupus Erythematosus

2018.04

• To establish a definition of SLE

• To introduce some background epidemiology

• To recognise the clinical features of SLE

• To develop an awareness of the drug therapy

related to SLE

• By the end of this session you will be able to

describe the presenting clinical features of SLE

• Outline the investigations required to confirm

the diagnosis

• Describe the drug therapy used in the

management of SLE

Definition Of SLE

a variety

of autoantibodies

damage of

multiple organs

SLE is a systemic autoimmune disease in which the body loses tolerance to self:

l More prevalent in African Americans, Caribbean populations, Hispanics and Asians

l Female > Male

l Most commonly seen in women of childbearing age

• Genetics

• Environment

• Hormones

— UVA and UVB light can stimulate/ up-regulate autoimmunity stimulating keratinocytes to produce cytokines -> activate B cells to produce ab—Viruses/Bacteria: molecular mimicry SLE patients have higher titers of antibodies to Epstein-Barr virus (EBV), increased circulating EBV viral loads; SSA ab has a sequence similar to EBV nuclear ag 1 Parvovirus B19—Drugs—Silica exposure, tobacco smoke, emotional stress

—High concordance in monozygotic twins

—5-12% or relatives with lupus have the disease

—No single lupus gene

—Disease is polygenic

—At least 30 susceptiblility genes identified

—HLADR2, HLADR3, HLADR4, HLADR8

(present in 75%)

•Two Stage Disease

§Loss of self-tolerance /Auto-Abs generation

§Immune complex formation, causes inflammation/disease

Stage One:• Loss of Self-tolerance§Involves self-antigen presentation by DCs

•Role of Apoptosis §Impaired clearance of apoptotic cells§Results from defective complement system• C2, C4, C1q defects • Reduced CR1 receptors §Cells serve as immunogens§ Induce auto-reactive T/B cells

•Aberrant DC activity —DC’s present self antigens from apoptotic cells

• Mostly nucleosomes, apoptotic blebs — DCs present to CD4 cells

•Aberrant Lymphocyte Activity —Unregulated T-cell dependent B-cell activation

•Aberrant Germinal Center Activity — Ligation between certain CD pairings —Somatic Hypermutation

•Autoantibody Production —95% are antinuclear Abs (anti-Sm, Anti-DNA)

Stage Two: Immune Complex Formation

o Auto-Abs bind to: Pieces of DNA Nucleosomes Proteoglycans

o Immune complex formation • Accumulate in organ basement membranes

Results of Immune Complexeso Local inflammationo Local complement activation o Local apoptosis

• Positive feedback loop

inflammatory response vascular abnormalities

the deposition of immune complexes

Direct invasion of antibodies

The inflammation and necrosis of the blood vessel walls

cause secondary thrombosis

ischemia and

dysfunction of

local tissue

• lupus cells

• Onion skin change in Arteriole

• fluorescence：Immunoglobulin and complement

deposition

lupus cells

• there are significantly centripetal fiber hyperplasia around the small artery，especially in the spleen central artery，this results from vasculitis.

Onion skin change

Immunoglobulin and complement deposition

• Different for each person.

• Myriad of symptoms

• Symptoms are often non-specific

• A disease that ranges from mild to life threatening.

• Characterized by flares and remissions.

What are the initial symptoms

• The initial manifestations of SLE are: fatigue,

fever, malaise, weight loss, musculoskeletal

manifestations similar to arthritis.

• SLE can affect multiple systems. Let’s take

a look at each of those systems.

Clinical Manifestations

What Are The Dermatological Signs?

– The client may have Cutaneous Lupus Erythematosus

– Malar "butterfly" rash – Photosensitivity – Vasculitis – Alopecia – Oral Ulcers

Malar Rash

• Fixed erythema, flat or raised, over the malar eminences

• Tending to spare the nasolabial folds

• 30-60 %

Photosensitivity

Rash over the sun exposed areas.

Face,neck and V shaped area of chest.

See rash varies in severity depending

on exposure.

Less under the orbit protected areas.

Erythematous hyper

pigmented margins

flat scarred hypo pigmented

centers

This can be seen in SLE and pure cutaneous lupus

Discoid lupus

Discoid Rash

• Erythematous raised patches

with adherent keratotic scaling

and follicular plugging

• Atrophic scarring may occur in older lesions

Subacute Cutaneous Lupus

SLE — Vasculopathy

¡ Small vessel vasculitis

¡ Raynaud’s phenomenon

¡ Antiphospholipid antibody

syndrome

Oral Lesions

• Erythema of hard and soft

palate, papules ,vesicles

and petechiae

• Erythematous rash of the

tongue

Oral Ulcers

Oral or nasopharyngeal

ulceration

usually painless

observed by physician

Neurological Symptoms

A client may have the following symptoms:

• Neuropathies (peripheral and central)

• Seizures• Depression• Psychosis

A client may have the following complications from an exacerbation of SLE:

• CVA• Organic Brain Syndrome

– Intellectual impairment

– Memory Loss– Personality Changes– Disorientation

Neuropsychiatric Systemic Lupus Erythematosus (NPSLE) CNS (diffuse & central)

• Acute confusional state• Psychosis• Anxiety• Depressive disorders• Cognitive dysfunction • Seizures• CVA• Chorea• Myelopathy• Demyelinating syndrome• Headaches

PNS • Neuropathies• Acute inflammatory

demyelination

Ocular Changes

• Conjunctivitis• Photophobia• Retinal vasculitis with transient blindness• Cotton-wool spots on retina

Cotton wool spots are small areas of yellowish white coloration in the retina. They occur because of swelling of the surface layer of the retina, which consists of nerve fibers. This swelling almost always occurs because the blood supply to that area has been impaired and in the absence of normal blood flow through the retinal vessels the nerve fibers are injured in a particular location resulting in swelling and the appearance of a "cotton wool spot. "

Musculoskeletal Changes

– Synovitis-90% patients, often the earliest sign

– Osteoporosis• From SLE itself and therapy

(usually steroids)– Osteonecrosis (avascular

necrosis)• Can occur with & without

history of steroid therapy

SLE Arthropathy

• Non erosive arthritis• Hand may show diffuse

soft tissue swelling,ulnar deviation,swan neck deformity,MCP subluxation.

努力要趁早

• Proteinuria• Cellular casts

Potential complications resulting from SLE are:

• Nephrotic syndrome• Renal failure

• Persistent proteinuria greater than 0.5 grams per

day or greater than 3+

• Cellular casts--may be red cell, hemoglobin,

granular, tubular, or mixed

• Impaired kidney function

• Lupus nephritis predict out come (prognosis)

• Major cause of mortality

How Does Lupus Damage The Kidneys

• Autoantibodies are formed against antigens

in the glomerulus basement membrane

• Circulating immune complexes bind to the

basement membrane of the glomeruli

• These result in inflammation of the

glomeruli (glomerulonephritis)

How Does Lupus Damage The Kidneys

– The basement membrane is damaged by the inflammation

– Appearance of protein, white and red blood cells and ‘casts’ in the urine

– Low albumin levels in the blood resulting in leakage of fluid from the vessels into the tissues (edema)

– Accumulation of waste proteins (uremia)– Hypertension

How can SLE effect the GI system?

– Uncommon – Severe abdominal pain often

indicate mesenteric vasculitis, resembling medium vessel vasculitis (PAN)

– Hepatic abnormalities more often due to therapy than to SLE itself

How can SLE effect the Cardiovascular system?

• Pericarditis

• Myocarditis

• Endocarditis

• Vasculitis

• Venous or arterial

thrombosis (anywhere

in the body)

hematologic system

• Anemia

• Leukopenia

• Thrombocytopenia

• Splenomegaly

Antiphospholipid Syndrome（APS）

thrombocytopenia

Arteriovenous thrombosis

recurrent spontaneous

abortions

APS

Respiratory System

n Pleuritis with or without effusion

n Life-threatening manifestations:

interstitial inflammation which

can lead to fibrosis and intra-

alveolar hemorrhage

n Also pneumothorax and

pulmonary HTN can occur

general inspection autoantibody complement lupus band test renal biopsy imaging tests

blood routineurinalysis

ESR

APL

antibody

ANA profile

AOCA

C3C4

CH50

diagnosis treatment prognosis

MRICT

SLE50%-70%（+）

Means disease

activity

Antinuclear antibody profile

antinuclear antibody

Anti-dsDNA antibody

Anti-ENA antibody

rRNP

SmRNP

SSB

SSA

Laboratory Findings in SLE• 97% positive ANA• 61% low complement levels (C3, C4)• 50% dsDNA ab• 46% leukopenia• 42% anemia• 40% proteinuria, nephritis• 35% anticardiolipin antibodies• 25% sjogren’s syndrome with positive SSA, SSB• 12% pleural effusion• Others: thrombocytopenia, anti SM, antiRNP, elevated LFTs,

splenomegaly, thrombophilia, miscarriages

ANA in Lupus• Sensitivity 93-99% in SLE• Sensitivity 95-100% in drug

induced Lupus• Specificity is not great• Higher the titer, higher the

specificity1:40- 30% normal population1:160- seen in 5% of the population

How is a diagnosis of SLE made?

SLE often a diagnostic challenge §Multisystem (cutaneous, renal, respiratory, CV,

CNS, GI)§Manifestations may characterize numerous other

conditions

• Use ACR classification criteria as a guide• Patients need to fulfil 4 of the 11 criteria to reach a

diagnosis of SLE

狼疮的诊断标准Diagnostic Criteria Of SLE

MD

SOAP

BRAIN

Malar rashDiscoid lesions

SerositisOral ulcerArthritisPhotosensitivity

Blood disorderdisorderRenal disorderAntinuclear antibodyImmunological disorderNeurological disorder

2012 SLICC Classification Criteria

• Need at least 4 criteria (1 clinical and 1 lab)

• Or biopsy proven Lupus Nephritis with Pos

ANA or pos dsDNA

Differential Diagnosis

• Rheumatic: RA, Sjogren’s syndrome, systemic sclerosis, dermatomyositis

• Nonrheumatic: HIV, endocarditis, viral infections, hematologic malignancies, vasculitis, ITP, other causes of nephritis

Treatment

• Individualized• Evaluate their risks for organ involvement

dsDNA ab: renal and neurologic SSA/SSB ab: rashes, pregnancy risksAPL ab: clottingRNP ab: may develop overlap diseases

Treatment: Patient Education

• 1. Avoidance sun• 2. Use of SPF > 35 sunblocks UVA and UVB• 3. Sun-protective clothing• 4. Promote exercise• 5. Healthy diet (low chol, low sugar, low salt)• 6. Smoking cessation• 7. Avoidance of stress (animal models)• 8. Good sleep hygiene

What medications are used to treat lupus?

ØGlucocorticoidsqFirst-line agents for most manifestations

qDosage and duration based on clinical experience

q don’t forget side effects, osteoporosis, atherosclerosis

ØAntimalarialsqHydroxychloroquine: cornerstone of SLE

treatment

q To prevent disease flares

What medications are used to treat lupus?

ØNSAIDs

Ø Immunosuppressive treatment （eg.cyclophosphamide/azathioprine/

cyclosporine ） q In lupus nephritis: based on histopathologic

classifications

q Other manifestations: treatment often includes immunosuppressives and a multidisciplinary approach

ØBiological agents

• How should clinicians initiate therapy in a stable patient who is not having a flare?

ØHydroxychloroquine and other antimalarials

qUsed to treat inflammatory arthritides

for >50 years

qPrevents relapses

qReduces risk for congenital heart block in neonatal SLE

qWell-tolerated with rare side effects (retinopathy; skin hyperpigmentation; neuromuscular or cardiac toxicity)

qNeed eye examination every 6 months

• How should clinicians choose therapy for a patient who is having a flare?

ØIV glucocorticoids + immunosuppressive medicationsq For severe manifestations (lupus nephritis, alveolar hemorrhage,

CNS vasculitis)

q Withdraw glucocorticoids once remission achieved

• Oral prednisone or methlyprednisolone

ØOverlap: lupus manifestations, glucocorticoid complications

q Osteoporosis, avascular bone necrosis, myopathy, psychosis

q Glucocorticoid dosage, duration: rely on clinical experience

• Prolonged medium-to-high dosing increases complications

• How should clinicians choose and dose drug therapy for lupus nephritis?

• Class I or II: no immunosuppressive therapy• Class III or IV: treat aggressivelyØStandard therapy: cyclophosphamide + IV glucocorticoids

qDose cyclophosphamide by total body surface area, adjusted for decreased creatinine clearance

qDose glucocorticoids using ACR recommendations

ØNewer regimen: mycophenolate mofetil + glucocorticoids

qGI and hematologic toxicity common

• Contraindicated in pregnancy (possibly teratogenic)

ØMaintenance therapyqMycophenolate mofetil qAzathioprineqBoth superior to cyclophosphamide

ØFor patients who don’t respond to either qCalcineurin inhibitors (cyclosporine, tacrolimus) qRituximab (monoclonal antibody against CD20) qEither in combination with glucocorticoids

How should clinicians choose therapy for neuropsychiatric lupus?

ØTreatment relatively empirical

qIV glucocorticoids, immunoglobulin,

cyclophosphamide

qRelapse may be more common in glucocorticoid

vs cyclophosphamide treatment

qRituximab may be beneficial, but relapse rate

seems high

• How should clinicians modify treatment for pregnant patients?

ØHigher flare rate in pregnancy + immediate post-partumqInitial presentation with hematologic or renal

manifestations during pregnancy not uncommonqConsider pregnancy-related abnormalities that mimic

SLE (eclampsia, HELLP syndrome)

ØTreat active lupus manifestationsq Use hydroxychloroquine and prednisoneq Discontinuation associated with increased flare risk

q If severe, consider IV glucocorticoids + azathioprine

q Contraindicated: mycophenolate mofetil, methotrexate, cyclophosphamide

Prognosis

Poor prognosis if the clients have：• high serum creatinine• hypertension• Myocardial damage associated with cardiac

insufficiency• Severe NP lupus

Prognosis

• Most SLE patients die from infection, probably related to therapy which suppresses immune system

• Recommend smoking cessation, yearly flu shots, pneumovax q 5years

Survival rate

1year

20 years

10 years

5 years96%

70%

80%

85%

Thank You for Your Attention