SYSTEMIC LUPUS

ERYTHEMATOSUS
Errol Latag
Orlyn Claire Lavilla
BLOCK 5A
 SYSTEMIC LUPUS ERYTHEMATOSUS 1

 autoimmune
 organ damage mediated by autoantibodies and immune complexes
 90% of patients are women of childbearing age
 highest prevalence in African Americans
 Pathogenesis and Etiology 2

 Abnormal immune responses

 activation of innate immunity (dendritic cells)
 lowered activation of adaptive immunity cells (T and B lymphocytes)
 ineffective regulatory and inhibitory CD4+ and CD8+ T cells
 reduced clearance of apoptotic cells and immune complexes
 Pathogenesis and Etiology
3

Gene-environment interactions  abnormal immune responses  pathogenic

autoantibodies and immune complexes  tissue deposition, complement
activation, inflammation  irreversible organ damage
 Pathogenesis and Etiology
4

 Factors influencing SLE

 female sex
 exposure to estrogen-containing oral contraceptives or hormone
replacement
 exposure to UV light
 infection, EBV
 PATHOLOGY
5

 Skin biopsy
 Ig deposition at dermal-epidermal junction
 basal keratinocyte injury
 T-lympocyte dominated inflammation in DEJ, around blood vessels and
dermal appendages
 PATHOLOGY: Renal biopsy

Light microscopy Immunoflourescence

Class I (minimal mesangial Normal glomeruli Mesangial immune
LN) deposits
Class II (mesangial Mesangial hypercellularity Few isolated subepithelial
proliferative LN) or subendothelial deposits
 PATHOLOGY: Renal biopsy

Light microscopy Immunoflourescence

Class III (focal LN) Focal, segmental or global Focal subendothelial
endo- or extracpillary GN deposits
involving <50% of all
glomeruli
Class IV (diffuse LN) Diffuse, segmental or global Diffuse subendothelial
endo- or extracapillary GN deposits
involving 50% of all glomeruli
 PATHOLOGY: Renal biopsy

Class V (membranous LN)
- May occur in combination
with Class II or IV
Class VI (advanced sclerotic
LN)
8
Light microscopy Immunoflourescence
Global or segmental immune Global or segmental
deposits subepithelial deposits
>90% of glomeruli globally
sclerosed
 PaTHOLOGY

 Blood vessels
 Patterns of vasculitis not specific for SLE 9
 Leukocytoclastic vasculitis – most common

 Lymph nodes
 Nonspecific diffuse chronic inflammation
 DIAGNOSis

 Diagnostic criteria for SLE (2006)

 Specificity 95% 10
 Sensitivity 75%
 ≥ 4 of 11 criteria
 Diagnostic criteria

11

Systemic Lupus Erythematosus

Malar rash Fixed erythema, flat or raised, over the malar
eminences
Discoid rash Erythematous circular raised patches with adherent keratotic
scaling and follicular plugging; may have atrophic scarring
Photosensitivity Rash after exposure to UV light
 DIAGNOSTIC CRITERIA

12

Systemic Lupus Erythematosus

Oral ulcers Oral, nasopharyngeal
Arthritis Nonerosive arthritis of 2 or more peripheral joints
Antinuclear Abnormal titer of ANA
antibodies
 DIAGNOSTIC CRITERIA

13

Systemic Lupus Erythematosus

Renal Proteinuria >0.5g/d
disorder or ≥3+; cellular casts
Neurologic Seizures or psychosis without other causes
disorder
Hematologic Hemolytic anemia or leukopenia (<4000/ul); lymphopenia (<1500/ul);
disorder thrombocytopenia (<100,000/ul) in the absences of offending drugs
Immunologic Anti-dsDNA, anti-Sm, anti-phospholipid
disorder
 CLINICAL MANIFESTATIONS

14
 Musculoskeletal
 Cutaneous
 Renal
 Neurologic
 Vascular
 Pulmonary
 Cardiologic
 Hematologic
 Gastrointestinal
 Ocular
 musculoskeletal MANIFESTATIONS

15
 Intermittent polyarthritis (soft-tissue swelling, tenderness; commonly in
hands, wrists, and knees)
 Joint deformities – in 10%
 Erosions on joint xrays?
 Increased prevalence of ischemic necrosis of bone
 Myalgia vs. muscle weakness secondary to glucocorticoid and antimalarial
therapies
 CUTANEOUS MANIFESTATIONS

16
 Lupus Dermatitis
 DLE: slightly raised, scaly hyperpigmented erythematous rims with
depigmented, atrophic centers
 Systemic rash: photosensitive, slightly raised erythema, “butterfly rash”,
accompanies flares
 SCLE: scaly red patches or circular flat red-rimmed lesions
 “other”: urticaria, lichen planus-like dermatitis, bullae, panniculitis
(lupus profundus)
 RENAL MANIFESTATIONS
17

 Lupus Nephritis
 Usually asymptomatic in most patients  do U/A
 Renal biopsy helpful in therapeutic planning
 Class III, IV – microscopic hematuria, proteinuria; half develop nephrotic syndrome,
hypertension
 If DPGN left untreated, ESRD develops from 2 yrs of diagnosis
 NEUROLOGIC MANIFESTATIONS
18

 Evaluate first: secondary to SLE vs. another condition?

 If related to SLE: diffuse vs. occlusive?
 Cognitive dysfunction, headache, seizure, mono-, polyneuropathy,
psychosis, myelopathy
 VASCULAR MANIFESTATIONS 19

 Increased prevalence of TIA, stroke, MI

 aPL antibodies associated with hypercoagulability and acute thrombotic events
 Cerebral ischemia
 Focal occlusion (noninflammatory vs. vasculitic)
 Embolization (from carotid artery plaque of Libman-Sacks endocarditis)
 Myocardial ischemia
 Manifestation of accelerated atherosclerosis
 7-10x risk of vascular events, even higher in women <45 yo with SLE
 PULMONARY MANIFESTATIONS 20

 Pleuritis ± pleural effusion – most common

 Pulmonary infiltrates
 Interstitial inflammation
 Fibrosis
 Shrinking lung syndrome
 Intraalveolar hemorrhage
 CARDIAC MANIFESTATIONS 21

 pericarditis
 most frequent cardiac manifestation
 usually responds to anti-inflammatory therapy and infrequently leads to
tamponade
 more serious cardiac manifestations
 myocarditis and fibrinous endocarditis of Libman-Sacks
 endocardial involvement can lead to valvular insufficiencies, most
commonly of the mitral or aortic valves, or to embolic events
 increased risk for myocardial infarction
 HEMATOLOGIC MANIFESTATIONS 22

 anemia
 most frequent hematologic manifestation
 usually normochromic normocytic
 hemolysis
 can be rapid in onset and severe
 leukopenia
 almost always consists of lymphopenia
 rarely predisposes to infections
 thrombocytopenia
 may be a recurring problem
 therapy may not be required
 GASTROINTESTINAL MANIFESTATIONS 23

 can be manifestations of an SLE flare

 nausea, vomiting, diarrhea, diffuse abdominal pain
 increases in AST and ALT
 vasculitis involving the intestine may be life-threatening; perforations,
ischemia, bleeding, and sepsis are frequent complications.
 OCULAR MANIFESTATIONS 24

 Sicca syndrome (Sjögren's syndrome)

 nonspecific conjunctivitis
 retinal vasculitis
 optic neuritis
 LABORATORY TESTS
25

 to establish or rule out the diagnosis

 to follow the course of disease
 to identify adverse effects of therapies
 TESTS FOR AUTOANTIBODIES
26

 ANA
 positive in >95% of patients
 ANA-negative lupus exists but is very rare in adults and is usually associated with
other autoantibodies (anti-Ro or anti-DNA).
 usually at the onset of symptoms
 A few patients develop ANA within 1 year of symptom onset; repeated testing may
thus be useful.
 TESTS FOR AUTOANTIBODIES
27

 Anti-dsDNA
 high-titer IgG antibodies are specific for SLE
 correlates with disease activity

 Anti-Sm
 also specific for SLE
 does not usually correlate with disease activity or clinical manifestations
 TESTS FOR AUTOANTIBODIES

28
 aPL
 not specific for SLE
 presence fulfils one classification criterion
 Identifies patients at increased risk for venous or arterial clotting,
thrombocytopenia, and fetal loss

 Anti-Ro
 not specific for SLE
 associated with sicca syndrome, subacute cutaneous lupus, and
neonatal lupus with congenital heart block
 associated with decreased risk for nephritis
Autoantibodies
TESTS FOR AUTOANTIBODIES

29
 TESTS FOR FOLLOWING DISEASE
COURSE

 hemoglobin levels 30
 platelet counts
 urinalysis
 serum levels of creatinine or albumin
 Anti-dsDNA
 titers vary over time
 in some patients, increases in quantities herald a flare, particularly of
nephritis or vasculitis
 TREATMENT

 no cure for SLE

 complete sustained remissions are rare 31
 goals of treatment
 to control acute, severe flares
 to suppress symptoms to an acceptable level
 to prevent organ damage
 therapeutic choices depend on
 whether disease manifestations are life-threatening or likely to cause
organ damage
 whether manifestations are potentially reversible
 best approaches to preventing complications of disease and its
treatments
 Treatment: Conservative Therapies for Management of Non-
Life-Threatening Disease

 NSAIDs
 useful analgesics/anti-inflammatories, 32
particularly for arthritis/arthralgias
 caution in using NSAIDs
 SLE patients are at increased risk for NSAID-induced aseptic meningitis, elevated
serum transaminases, hypertension, and renal dysfunction
 NSAIDs, particularly cox-2 inhibitors, may increase risk for myocardial infarction
Treatment: Conservative Therapies for Management of Non-
Life-Threatening Disease

 Antimalarials (hydroxychloroquine, chloroquine, and quinacrine)

 often reduce dermatitis, arthritis, and fatigue 33
 potential retinal toxicity
 annual ophthalmologic examinations
 Treatment: Conservative Therapies for Management of Non-
Life-Threatening Disease

 Dehydroepiandrosterone 34
 may reduce disease activity
 recent review of scientific literature found that DHEA supplements may
allow lower dose of prescription medication inn SLE patients and may
also reduce the frequency of flare-ups*

 Methotrexate
 may have a role in the treatment of arthritis and dermatitis

 If the quality of life is inadequate in spite of these conservative measures,

treatment with low doses of systemic glucocorticoids may be necessary.

* University of Maryland Medical Center Online Medical Encyclopedia

Treatment: Life-Threatening SLE (Proliferative Forms of Lupus
Nephritis)

 Systemic glucocorticoids 35
 0.5 – 2 mg/kg per day PO or 1000 mg of
methylprednisolone sodium succinate IV daily for 3 days followed by
0.5 – 1 mg/kg of daily prednisone or equivalent
 survival is significantly better in people with DPGN treated with high-
dose daily glucocorticoids (40–60 mg of prednisone daily for 4–6
months) versus lower doses
 currently, high doses are recommended for much shorter periods
 has become standard practice to initiate therapy for active, potentially
life-threatening SLE with high-dose IV glucocorticoid pulses
Treatment: Life-Threatening SLE (Proliferative Forms of Lupus
Nephritis)

36
 Cytotoxic/immunosuppressive agents
 (added to glucocorticoids) are recommended to treat serious SLE
 either cyclophosphamide (an alkylating agent) or mycophenolate
mofetil (a relatively lymphocyte-specific inhibitor of inosine
monophosphatase and therefore of purine synthesis) is an acceptable
choice for induction of improvement in severely ill patients
 recommended dose is 500 – 750 mg/m2 intravenously, monthly for 3 – 6 months,
then discontinuation with introduction of mycophenolate or azathioprine
 gonadotropin-releasing hormone agonist prior to each cyclophosphamide dose can
reduce incidence of ovarian failure, a common effect of cyclophosphamide therapy
Treatment: Life-Threatening SLE (Proliferative Forms of Lupus
Nephritis)

37
 Cytotoxic/immunosuppressive agents
 azathioprine (a purine analogue and cycle-specific antimetabolite) may
be effective but is slower to influence response
 Treatment: Special Conditions in SLE that May Require
Additional or Different Therapies

38
 Pregnancy
 rate of fetal loss is increased (approximately two- to threefold) in
women with SLE
 fetal demise is higher in mothers with high disease activity, antiphospholipid
antibodies, and/or nephritis
 suppression of disease activity can be achieved by administration of
systemic glucocorticoids
 maternal SLE should be controlled with prednisone/prednisolone at the lowest
effective doses for the shortest time required
 adverse effects of prenatal glucocorticoid exposure (primarily betamethasone) on
offspring may include low birth weight, developmental abnormalities in the CNS,
and predilection toward adult metabolic syndrome.
 Treatment: Special Conditions in SLE that May Require
Additional or Different Therapies
39

 Pregnancy
 In SLE patients with aPL (on at least two occasions) and prior fetal
losses, treatment with heparin (standard or low-molecular-weight) plus
low-dose aspirin has been shown in prospective controlled trials to
increase significantly the proportion of live births
 Treatment: Special Conditions in SLE that May Require
Additional or Different Therapies 40

 Antiphospholipid Antibody Syndrome

 Patients with SLE who have venous or arterial clotting, and/or repeated
fetal losses, and at least two positive tests for aPL have APAS and should
be managed with long-term anticoagulation
 target international normalized ratio (INR) of 2.0 – 2.5 is recommended for patients
with one episode of venous clotting; an INR of 3.0 – 3.5 is recommended for patients
with recurring clots or arterial clotting
 Treatment: Special Conditions in SLE that May Require
Additional or Different Therapies 41

 Microvascular Thrombotic Crisis (Thrombotic Thrombocytopenic Purpura,

Hemolytic Uremic Syndrome)
 carries a high mortality rate and occurs most commonly in young
individuals with lupus nephritis
 most useful laboratory tests are identification of schistocytes on
peripheral blood smears and elevated serum levels of lactate
dehydrogenase
 plasma exchange or extensive plasmapheresis is usually life-saving
 there is no evidence that cytotoxic drugs are effective
 Treatment: Special Conditions in SLE that May Require
Additional or Different Therapies
42

 Lupus Dermatitis
 minimize exposure to ultraviolet light, employing appropriate clothing
and sunscreens with a sun protection factor of at least 15
 topical glucocorticoids and antimalarials (such as hydroxychloroquine)
are effective in reducing lesion severity in most patients and are
relatively safe
 systemic treatment with retinoic acid is a useful strategy in patients
with inadequate improvement on topical glucocorticoids and
antimalarials
 Treatment: Special Conditions in SLE that May Require 43
Additional or Different Therapies

 Lupus Dermatitis
 extensive, pruritic, bullous, or ulcerating dermatitides usually improve
promptly after institution of systemic glucocorticoids
 tapering may be accompanied by flare of lesions, thus necessitating use of a second
medication such as hydroxychloroquine, retinoids, or cytotoxic medications such as
methotrexate or azathioprine
 in therapy-resistant lupus dermatitis there are reports of success with
topical tacrolimus or with systemic dapsone or thalidomide
 Treatment: Preventive Therapies 44

 providing appropriate vaccinations

 suppressing recurrent urinary tract infections
 strategies to prevent osteoporosis should be initiated in most patients likely
to require long-term glucocorticoid therapy
 control of hypertension and appropriate prevention strategies for
atherosclerosis, including monitoring and treatment of dyslipidemias,
management of hyperglycemia, and obesity, are recommended
 PROGNOSIS 45

 survival in patients with is approximately 95% at 5 years, 90% at 10 years,

and 78% at 20 years
 poor prognosis (~50% mortality in 10 years) in most series is associated with
(at the time of diagnosis)
 high serum creatinine levels [>124 mol/L (>1.4 mg/dL)]
 hypertension
 nephrotic syndrome (24-h urine protein excretion >2.6 g)
 anemia [hemoglobin <124 g/L (<12.4 g/dL)]
 hypoalbuminemia
 hypocomplementemia
 aPL
 male sex
 ethnicity (African American, Hispanic, and mestizo heritage)
 DRUG-INDUCED LUPUS 46

 syndrome of positive ANA associated with symptoms such as fever, malaise,

arthritis or intense arthralgias/myalgias, serositis, and/or rash
 appears during therapy with certain medications and biologic agents, has
less female predilection than SLE, rarely involves kidneys or brain, is rarely
associated with anti-dsDNA, is commonly associated with antibodies to
histones, and usually resolves over several weeks after discontinuation of the
offending medication.
 ANA usually appears before symptoms
 DRUG-INDUCED LUPUS
47

 the substances that most frequently induce lupus

 the antiarrhythmics procainamide, disopyramide, and propafenone
 the antihypertensive hydralazine
 several ACE inhibitors and beta blockers
 the antithyroid propylthiouracil
 the antipsychotics chlorpromazine and lithium
 the anticonvulsants carbamazepine and phenytoin
 the antibiotics isoniazid, minocycline, and macrodantin
 the antirheumatic sulfasalazine
 the diuretic hydrochlorothiazide
 the antihyperlipidemics lovastatin and simvastatin
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