systemic lupus erythematosusccftp.scu.edu.cn/download/20180816195803730.pdf · 2018-08-16 · the...
TRANSCRIPT
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