Harrison’s Club

SYSTEMIC LUPUS
ERYTHEMATOSUS
ORCHID L. LOZANO MD
OUTLINE
A. PATHOGENESIS,
ETIOLOGY, AND
PATHOLOGY
 SYSTEMIC LUPUS ERYTHEMATOSUS

• an autoimmune disease in which organs and cells undergo damage caused

by tissue-binding autoantibodies and immune complexes
• 90% are women of child-bearing years
• highest in African-American and Afro-Caribbean women
• lowest prevalence in white men

Affects people of all genders, ages, and ethnic groups

PATHOGENESIS
 A. PATHOGENESIS, ETIOLOGY, AND
PATHOLOGY
• Underlying cause: Production of of increase quantity of immunogenic
forms of nucleic acids, their accompanying proteins, and self-antigens
leading to abnormal immune response.

Abnormal immune response:

 Autoimmunity-inducing activation of innate immunity (dendritic cells,
macrophages, neutrophils, NK cells)
 Partly through binding of DNS/RNA/Proteins by toll-like receptors
 Upregulation of genes by induced INFNs is a genetic signature in
peripheral blood cells of 50-80% of SLE patients
 A. PATHOGENESIS, ETIOLOGY, AND
PATHOLOGY
 Innate immune system interacts with B and T cells of adaptive immunity which further
drive the autoimmune response
 T lymphocytes- altered metabolism, increased glucose utilizationand pyruvate
production, activation of mTOR and increased autophagy.
 T and B cells- more easily activated and driven into apoptosis than normal cells
 Lupus phagocytic cells have reduce capacity to clear immune complexes, apoptotic
cells, and their DNA/RNA/Ro/La and phospholipid containing surface blebs
 A. PATHOGENESIS, ETIOLOGY, AND
PATHOLOGY
 RESULT: Persistence of large quantities of autoantigens and resultant large quantities of
autoantibodies with increased numbers of activated B cells and plasmablasts or plasma
cells and auto reactive T-cells --> Promote production of of autoantibodies and tissue
damage:
 Begins with deposition of autoantibodies/immune complexes followed by destruction of
mediated by complement activation and release of cytokines/chemokines
 Each processes depends on indivual’s genetic background, environmental influences and
epigenetics
ETIOLOGY AND RISK FACTORS
SLE is multigenic disease
• ~60% predisposing genes identified with HR of 1.5-3
• Accounts for only 18% of disease susceptibility (suggests environmental exposures and epigenetics
play a major role)
• Most common HLA: DRB1 *0301 and *1501 and DR3
Female sex is permissive for SLE
• Contributors: hormone effects, genes on x chromosome, epigenetic differences between genders
• Higher antibody production than males
• Exposure to estrogen-containing OCPs or HRTs: 1.2-2x increase risk
• People with Klinefelter’s syndrome (XXY karyotype): significant increased risk for SLE
ETIOLOGY AND RISK FACTORS
Environmental stimuli that may influence SLE
• UV light: causes SLE flares in about 70% of patients probably by increase in apoptosis in
keratinocytes and other cells or by altering DNA and intracellular protein to make them antigenic
• Infections: EBV-stimulates immune response
 EBV may trigger SLE in susceptible individuals
 Children and adults with SLE are more likely to be infected with EBV than matched controls
• Current tobacco smoking: HR=1.5
• Prolonged exposure to silica (inhalation of sopa podust, soil in farming activities: HR4.3
• Alcohol (2 glasses of wine/week of 1/2 of an alcoholic drink daily) reduces the risk of SLE
PATHOLOGY

• Skin Biopsy: Ig deposits in dermal-epidermal junction (DEJ), in basal keratinocytes,

and inflammation (dominated by T lymphocytes) in the DEJ and around blood vessels and
dermal appendages
• Blood vessels: histologic abnormalities are not specific but may indicate active disease
 Most common: leukocytoclastic vasculitis
• Lymph node: non specific diffuse chronic inflammation; used to rule out infection

• Renal biopsy:
 Pattern of severity of injury important in diagnosis and treatment selection
 ISN/RPS Classification of Lupus Nephritis (replacing WHO classification)
B. DIAGNOSIS
SLICC CRITERIA FOR CLASSIFICATION OF
SLE
• Bases for diagnosis: clinical features, autoantibodies

NOTE: renal biopsy read as systemic

lupus qualifies for classification as SLE if
any autoantibodies are present even if
the total criteria is <4.

Interpretation:
Presence of any 4 criteria (must have
at least 1 in each category) qualifies
patient to be classified as having SLE
with 93% specificity and 92% sensitivity.
B. DIAGNOSIS
B. DIAGNOSIS
ACR/EULAR 2019 CRITERIA FOR DIAGNOSIS OF
SLE
LABORATORY TESTS
General Utility:

• To establish or rule out diagnosis

• Follow the course of disease, particularly to suggest that a flare is occuring or
organ damage is developing
• Identify adverse effects of therapy
LABORATORY TESTS
Tests for Autoantibodies:

• ANA: most important for detection (positive in >95% of patients usually at the onset of symptoms)
 May be repeated if negative as some patients develop ANA within 1 year of syptom onset
 ANA-negative lupus: very rare in adults, usually associated with other autoantibodies (anti-Ro or
anti-DNA)

• High titer anti-dsDNA: specific for SLE

 Titers vary over time
 Some patients: Increase in anti ds-DNA, + decreased C3 or C4=flare (particulary of nephritis or
vasculitis)

• Anti-Sm antibodies: specific for SLE and assist in diagnosis

 Not correlated for disease activity or clinical manifestations
LABORATORY TESTS
Tests for Autoantibodies:
Antiphospholipid antibody (aPL): not specific for SLE
 Can identify patients at increase risk for venour or arterial clotting, thrombocytopenia,
and fetal loss
 Accepted tests for antiphospholipids (anticardiolipin, lupus anticoagulant, anti B2 glycoprotein)
-ELISA for anticardiolipin and anti B2 glycoprotein
-Sensitive phospholipid based activated prothrombin time (dilute Russell venom viper
test or DRVVT)
 Increased risk of clotting episodes:IgG anticardiolipin >40 IU, increased number of of different
aPL antibodies detected, at least 12 weeks apart
Anti-Ro antibodies: not used for diagnosis
 Indicator of increased increased risk for neonatal lupus , sicca syndrome, and SCLE
 Part of screening of women with child-bearing potential and SLE (together with screening for
aPL)
LABORATORY TESTS
Standard Tests for Diagnosis
• CBC, platelet count, urinalysis: detect abnormalities that contribute to diagnosis and
influence management decisions

Tests for Following Disease Couse

• Tests to indicate the status of organ involvement known to be present during

SLE flares: hemoglobin levels, platelet count, urinalysis, and serum levels of
creatinine or albumin
C. CLINICAL
MANIFESTATIONS
C. CLINICAL MANIFESTATIONS

• Autoantibodies are detectable at disease onset

• Severity varies from mild to intermittent to persistent and fulminant
• Most patients (~85%) have either continuing active disease or one or more flares of active
disease disease annually
• Systemic symptoms are present most of the time: fatigue,
myalgias/arthralgias
• Severe systemic illness requires GC therapy can occur with fever, prostration, weight loss,
and anemia +/- organ target manifestations
A. MUSCULOSCKELETAL
• Intermittent polyarthritis varying from mild to disabling
- common in hands, wrists and knees
• Presence of visible sinovitis suggests active systemic
disease
 Joint deformities ((hands and feet) develop in only 10%
 Erosions on joint x-rays are rare but can be identified by UTZ
in 10-50% of patients
 “Rhupus”: Individuals who have rheumatoid arthritis with
erosions and fulfill the criteria for both RA and SLE
 Joint pain is the most common reason for patient to increase
their dose of GC
 If pain persists in single joint (knee, shoulder, hip):
consider ischemic necrosis of bone particularly in there are
no other manifestation of active SLE
 myositis- patients treated with systemic glucocorticoids
B. CUTANEOUS
Classification of lupus dermatitis: acute, subacute, chronic
Forms: discoid lupus erythematosus (DLE), systemic rash,
subacute cutaneous lupus erythematosus (SCLE)

Discoid lupus erythematosus (DLE): most common

cutaneous chronic dermatitis in SLE

Lesions: roughly circular with slightly raised, scaly

hyperpigmented erythematous rims and depigmented, atrophic
centers in which all dermal appendages are permanently destroyed

Treatment: topical or locally injected glucocorticoids, systemic

antimalarials

NOTE: only 5% of people with DLE have SLE (although half have
positive ANA)
 Among people with SLE: ~20% have DLE
B. CUTANEOUS
Acute SLE rash:

• Photosensitive, slightly raised erythema,

ocassionally scaly, on the face (particularly the
cheeks and nose--the “butterfly” rash), ears, chin V
region of the neck, upper back, and extensor surface of
the arms

• Worsening of this rash often accompanies flare of

systemic disease
B. CUTANEOUS
Subacute cutaneous lupus erythematosus
(SCLE)
• consists of scaly red patches similar to psoriasis or
attacks of of circular, red-rimmed lesions
--exquisitely photosensitive, most have antibodies
to Ro (SS-A)
• Other rashes (less frequent): recurrent urticarian
planus like dermatitis, bullae, panniculitis (“lupus
profundus”)

 Small, painful ulcerations on oral or nasal mucosa:

common in LSE lesions resemble aphtous ulcers
C. RENAL
Nephritis:
--most serious manifestation of SLE

• Nephritis and infections-leading causes of mortality in the first decade of the disease
• Asymptomatic in most lupus patients thus urinalysis is a must in any person suspected in
LSE
• Renal biopsy required for all SLE patients with any clinical evidence of nephritis
• Indicators of dangerous proliferative glomerular damage: microscopic hematuria and
proteinuria (>500 mg/24H)
• Seen in ISN III and IV
• Half develop nephrotic syndrome, most dvelop hypertension
• If DPGN is untreated: ESRD within 2 years of diagnosis
• Requires aggressive immunosuppression UNLESS damage is irreversible
CLASSIFICATION OF LUPUS NEPHRITIS
C. RENAL

Aggresive immunosuppresion recommended for: Class III, class IV, Class V, accompanied
by III or IV disease
• With high risk for ESRD if patients are untreated or undertreated
Treatment of Nephritis NOT recommended: Class I, class II; presence of extensive irreversible disease

Membranous glomerular changes without proliferative changes on renal biopsy (seen in 20% of
SLE patients with nephrotic syndrome) portend better outcome than DPGN
 Treat the Class V and nephrotic proteinuria similar to ISN III and IV
 For most people with lupus nephritis, accelerated atherosclerosis becomes important after
several years of disease
D. NERVOUS SYSTEM
Diagnostic approach: determine if symptoms are from SLE or other condition ( i.e. infection in
immunosuppressed individuals or side effects of therapies)

For symptoms related to SLE, determine if due to a diffuse process of vascular occlusive disease

 Diffuse CNS Lupus: Most common manifestation is cognitive dysfunction (difficulties in

memory and reasoning)
 Other symptoms: Headache (when excruciating, often indicates SLE flare), seizures of any
time (often requires both anti-seizure and immunosuppresive therapies)
 Psychosis must be distinguished from glucocorticoid-induced psychosis
• GC induced psychosis: occurs in the first weeks of glucocorticoid therapy at doses of ≥40 mg of
prednison or equivalent, resolves over several days after stopping or decreasing GC
• Myelopathy: NOT rare, OFTEN disabling

 Standard of care: rapid initiation of immunosuppresive therapy starting with high dose of GC
E. VASCULAR
Vascular Occlusions

• TIAs, stroke and MI: increase prevalence

 Particularaly increased (but not exclusively) in SLE patients with antibodies to phospholipids
 Increase risk for vascular events by 3-10x: at higher risk = women <49 years
Chronic SLE +/- aPL antibodies: (+) accelerated atherosclerosis

Causes of Brain ischemia:

• Focal Occlusion: non-inflammatory, vasculitis
• Embolization: carotid artery plaque, fibrinous vegetations of Libman-Sachs endocarditis
• Myocardial Infarctions: primarily due to accelerated atherosclerosis
E. VASCULAR
Increased risk for atherosclerosis:
 male, old age, HTN, dyslipidemia, dysfunctional proinflammatory HDL, repeated high scores for
disease activity, high commulative daily doses of GC, high level of homocysteine and leptin

Treatment:
• high likelihood of clotting: long-term anticoagulation
• If due to vasculitis + bland vascular occlusions: anticoagulation+ immunosuppression
• Statin therapy to lower LDL-C: shown to reduce cardiac events in SLE patients with renal transplant
but not in other SLE cohorts
F. PULMONARY
• Pleuritis with or without pleural effusion: most common
• If mild: treat with NSAIDs
• If more severe: brief course of glucocorticoid therapy

• Pulmonary infiltrates: occur as manifestation of active SLE

• Difficult to distinguish form infection on imaging studies
• Life threatening pulmonary manifestations: interstitial inflammation leading to fibrosis, shrinking
lung syndrome, and intraalveolar hemorrhage
• Require early aggressive immunosuppression + supportive care
G. CARDIAC
• Pericarditis: Most frequent (Infrequently leads to Tamponade)
• Treatment: anti-inflammatory therapy

• Most serious Cardiac Manifestations: myocarditis and fibrinous endocarditis of Libman-Sachs

• Consequences of endocardial involvement: valvular insufficciencies (mitral or aortic), embolic
events
• No proven role for glucocorticoid or other immunosuppressive therapies

• Increased risk for myocardial infarction, usually due to accelerated atherosclerosis

H. HEMATOLOGIC
• Anemia of chronic illness (normochromic, normocytic): most frequent

• Others:
• Hemolysis: can be rapid in onset and severe, often effectively treated with high dose of GC

• Leukopenia: almost always lymphopenia, NOT granulocytopenia

-Rarely predisposes to infection, no therapy needed

• Thrombocytopenia
-If platelet count >40,000/mcL + no abnormal bleeding: NO therapy required
If severe: high dose glucocorticoid (1mkd of prednisione or equivalent) for the first few episodes
• Additional therapy for the following: recurring or prolonged hemolytic anemia or thrombocytopenia, or
disease
Treatment: Rituximab, platelet growth factors and/or splenectomy
I. GASTROINTESTINAL
• Possible manifestations of flare: nausea, vomiting, diarrhea, diffuse abdominal pain (due to
autoimmune peritonitis)

• Other findings in active SLE: increased AST and ALT (improved promptly during systemic GC therapy)
• Vasculitis involving the intestines: may be life threatening
• Frequent complications: perforations, ischemia, bleeding and sepsis
• Aggressive immunosuppresive therapy with high dose glucocorticoids for short-term control
J. OCULAR
• Serious manifestations: retinal vasculitis and optic neuritis
-blindness can develop over days to weeks
• Treatment: aggressive immunosupression

• Sicca syndrome (Sjogren’s syndrome) and non-specific conjunctivitis

-- common in SLE, rarely threaten vision
• Complications of Glucocorticoid therapy: cataracts, glaucoma
D. MANAGEMEN
T
 D. MANAGEMENT
• NO cure for SLE
• complete, sustained remissions are rare

Primary considerations: Induce remissions for acute flares, suppress symptoms to an

acceptable level, prevent organ damage

Therapeutic choices depend on:

• Whether disease manifestations are life-threatening or likely to cause organ damage to
justify aggressive thrapies
• Whether manifestations are potentially reversible
• Best approches to preventing complications of disease and its treatment
 D. MANAGEMENT
Conservative Therapies for Management of Non-life-threatening disease:
If NO major organ involvement but with fatigue, pain, and autoantibodies of SLE: give symptom relievers
• NSAIDS: analgesics/anti-inflammatories particularly for arthritis/arthralgias

CAUTIONS:
 SLE patients have increased risk for NSAID-induced aseptic meningitis, increased AST/ALT, HTN, renal
dysfunction
 All NSAIDS particularly the Coxibs may increase risk for AMI

• Antimalarials (hydroxychloroquine, chloroquine, and quinacrine): reduce dermatitis,and fatigue

-Hydroxychloroquine reduces the numbers of disease flares and the accrual of tissue damage o ver time
CAUTION: Retinal toxicity (requires annual ophthalmologic examinations while on treatment)
 D. MANAGEMENT
Conservative Therapies for Management of Non-life-threatening disease:
• Dehydroepiandrosterone: may reduce disease activity
• Low dose of systemic systemic glucocorticoids: if quality of life is inadequate, in spite of above conservative
measures
• Belimumab (anti-BLyS): for patients who had failed to respond to conservative therapies
 Likely to respond to belimumab: SLEDAI ≥ 10, (+) anti-dsDNA, decreased serum complement
• SLEDAI (SLE Disease Activity Index) > 3 reflects clinically active disease

• Management of lupus dermatitis: topical sunscreens, antimalarials, topical GCs, tacrolimus

• -If severe or unresponsive: systemic GC+/- mycophenolate mofetil, azathioprine or belimumab
 D. MANAGEMENT
Life-threatening SLE: proliferative form of lupus Nephritis
• Systemic Glucocorticoids: mainstay of treatment for inflammatory life-threatening or
organ-threatening manifestations
 Dose: 0.5 to 1 mg/kg/day PO or 500-1000 mg of methylprednisolone sodium
succinate IV x 3 days followed by 0.5-1 mg/kg of daily prednisone or equivalent

-Improves survival in DPGN compared to lower doses

-High dose of treatment maintained for about 4-6 weeks then doses are tapered as rapidly as
clinical situation permits, usually to a maintenance dose of 5-10 mg of prednisone,
prednisolone, or equivalent per day
Safety concerns for initial IV pulse therapy (500-1000mg daily for 3-5 days): infection,
hyperglycemia, hypertension, osteoporosis
 D. MANAGEMENT
Life-threatening SLE: proliferative form of lupus Nephritis
Cytotoxic/Immunosuppressive agents: added to GC for serious SLE
Indication: Lupus nephritis
• Options for induction in severely ill patients: cyclophosphamide (alkylating agent),
mycophenolate mofetil (lymphocyte-specific inhibitor od inosine monophosphate and purine
synthesis)
 Azathioprine (purine analogue anti-metabolite): slower onset and associated with
more flares
 Cyclophosphamide + GC: given early to patients with renal bipsy of ISN III or IV
disease --> reduces progresssion to ESRD and death
 Mycophenolate + GC: similar to cyclophosphamide + GC in achieving improvement
• Similar proportion of Asians respond to mycophenolate acyclophosphamide

Adverse Effects:
• More common with Cyclophosphamide: amenorrhea, leukopenia, and nausea
• More common with Mycophenolate: diarrhea
 D. MANAGEMENT
Life-threatening SLE: proliferative form of lupus Nephritis
• Mycophenolate, Azathioprine: similar efficacy and toxicity, safer than Cyclophosphamide
• Mycophenolate: superior to Azathioprine in maintaining renal function and survival among
those responded to to induction with Cyclophosphamide or Mycophenolate
• Azathioprine: can be used to control active SLE in pregnant patients ( the other 2 drugs
are teratogenic)
 If to be used: require screening for homozygous deficiency of TMPT
enzymes(required to metabolize the 6 mercaptopurine metabolite of azathioprine)
inceased risk of bone marrow suppression
Others: Chlorambucil, methotrexate, Leflunomide, Cyclosporine, Tacrolimus
• Hydroxychloroquine: should be given to SLE patients of any type since it prevents
damage in skin and kidneys and reduces all damage scores
• ACEIs or ARBS: reduce the chance of ESRD in patients with proteinuria >500mg/d
D. MANAGEMENT
D. MANAGEMENT
 D. MANAGEMENT
Management of Special Conditions in SLE

a. Crescentic Lupus nephritis

• Worse prognosis
• Therapies of choice: High dose Glucocorticoids + (High dose Cyclophosphamide or Mycophenolate
or Cyclosporine)
b. Membranous Lupus nephritis (INS-V)
• If with proliferative change: treat as if dealing with PROLIFERATIVE GN
• If with pure membranous changes + proteinuria: alternate-day glucocorticoids + (Cyclophosphamide
or Mycophenolate or Cyclosporine)
c. Pregnancy
• Increase fetal loss (approx 2-3fold)
• Higher risk: High disease activity, antiphospholipid antibodies, and/or nephritis
• Treatment: Hydroxychloroquine +/- Prednisone/prednisolone +/- Azathioprine i activity is not
suppressed
-Prednisone/Prednisolone at the lowest effective doses for shortest time required (Category A)
 D. MANAGEMENT
Management of Special Conditions in SLE
c. Pregnancy
• Adverse Effects of Prenatal Glucocorticoid exposure (primarily bethamethasone) on offspring:
low birth weight, developmental abnormalities in the CNS, and prediliction toward adult
Metabolic syndrome
• Other drugs for SLE are at least category C (may be teratogenic in animals)

d. SLE patients with aPL (on at least 2 occasions) and prior fetal losses:
• Treatment: heparin (standard or LMW) + low dose aspirin
• Aspirin alone may be used but less effective than combination with heparin
• Presence of Anti-Ro: associated with neonatal Lupus -rash +congenital heart block +/-
cardiomyopathy
 D. MANAGEMENT
Management of Special Conditions in SLE
e. Lupus and APS
• Requires long term anticoagulation with target INR of 2-2.5(if with one episode of
venous clotting) or 3-3.5 (if with recurrent clots or arterial clotting, particularly in the CNS)
• Microvascular thrombotic crisis (thrombotic thrompbocytopenic purpura, HUS)
 Syndrome: hemolysis, thrombocytopenia, and microvascular thrombosis in kidneys,
brain, and other tissues
 high mortality rate, occurs more commonly in younger individuals with lupus nephritis
 Most useful laboratory tests: identification of schistocytes in PBS and increase levels
of LDH and antibodies to ADAMS13
 Life saving treatment: plasma exchange or plasmapharesis (concomittant GC
recommended)
 D. MANAGEMENT
Management of Special Conditions in SLE

d. Lupus dermatitis

• Minimize exposure to UV light, use appropriate clothing, use sunscreen with spf at least
30
• Common treatment: topical glucocorticoids and antimalarias (hydroxychloroquine)
• Sytemic treatment: Retinoic acid (if patient have inadequate improvement with topical
glucocorticoids and antimalarials)
• Therapy-resistant lupus dermatitis: trial with topical tacrolimus or with systemic dapsone
or thalidomide)
PATIENT OUTCOME, PROGNOSIS, AND SURVIVAL
• Survival:

 5years: 95%

 10 years: 90%

 20 years: 78%
PATIENT OUTCOME, PROGNOSIS, AND SURVIVAL
• Poor prognosis: (50 % mortality in 10 years)
• Indicators:
• High S. Creatinine > 1.4 mg/dl
• Nephrotic syndrome (24 H urine protein excretion >2.6g)
• Hypoalbuminemia
• Antiphospholipid antibodies
• Ethnicity (African American, Hispanic with Mestizo heritage)
• Hypertension
• Anemia with hgb <124g/L
• Hypocomplementemia
• Male
• Low socioeconomic status
PATIENT OUTCOME, PROGNOSIS, AND SURVIVAL
• Causes of disability: chronic fatigue, arthritis, pain, renal disease
• NOTE: 30-50% of patients may achieve low disease activity (mild activity in HCQ +/- low dose
GCs), <10% experience remissions (no disease activity on no meds): BUT not permanent as flares
of SLE can occur
• Leading causes of death in the first decade of disease: systemic disease activity, renal failure,
infections
• Subsequent years: thromboembolic events
E. DRUG-INDUCED LUPUS
 E. DRUG-INDUCED LUPUS
• Causes: procainamide, disopyramide, propafenone, hydralazine, several ACEIs, BBs, PTU,
chlopromazine, lithium, carbamazepine, phenytoin, isoniazid, minocycline, nitrofurantoin, sulfasalazine,
HCTZ, lovastatin, simvastatin, biolokgics (IFN and TNF inhibitors)

• Procainamide and hydralazine-most frequent offender

• Manifestations: systemic complaints and arthralgias (most common), polyarthritis and
pleuropericarditis (25-50%)
• RARE: renal and CNS involvement
• Serology:
• All: (+) ANA, Most: (+) histone antibodies
• Rare: Anti-DsDNA and hypocomplementemia: distinguish drug induced from idopathic lupus
• Management:
• Initial: stop drug (most patients will improve in a few weeks)
• Short course (2-10 weeks) of glucocorticoids: if symptoms are severe
B. DIAGNOSIS
Reference: In Jameson, J. L., In Kasper, D. L., In Longo, D. L., In Fauci,
A. S., In Hauser, S. L., & In Loscalzo, J.
(2018). Harrison's principles of internal medicine 2Oth
ed.
Thank you!