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Introduction : Definition, epidemiology
Pathogenesis : Etiology, Risk factors, pathology.
Diagnosis : SLICC 2012 v/s ACR 1997.
Autoantibodies in Lupus.
Systemic Manifestations : overview and life
Management : Therapies old and new, special
conditions, monitoring disease activity, Flare
definition and management, pipeline therapies.
• Inflammatory multisystem disease.
• Women>Men- 9:1 ratio.
• 90% cases are women of childbearing age.
• African Americans>Whites.
• Onset usually between ages 15 and 45 years, but
can occur in childhood or later in life.
• Highly variable course and prognosis, ranges from
mild to life threatening.
• Characterized by flares and remissions.
• Tissue-binding autoantibodies and immune
• Incidence & Prevalence : increasing
– Improved survival, diagnosing milder cases.
• Geographical variability :
•African-Americans > Caucasians (3x)
•Asian-American and Hispanics > Caucasians
•Age at diagnosis:
•16-55 years of age: 65% of cases
•< 16: 20%
•> 65: 15%
US UK Japan
(per 100000 per
5.1 3.8 2.9
52.2 26.2 28.4
Lupus : History
• Lupus means “wolf” in Latin.
• 10th century- 1st used medically in case reports.
• Described clinically in the 19th century
• Butterfly rash in 1845
• Arthritis in 1892
• Nephritis in 1895 by Osler
• Serologic tests become available in the 20th century
• LE cell in 1948
• Lupus anticoagulant in 1952
• ANA in 1954
• 1971- First set of classification criteria.
• UV light (A2 and B component)
• Gender ( female > male, Estrogen)
• Vitamin D deficiency
• Other organic compounds.
– Silica dust, solvents, petroleum products, Smoking.
– Long list : Sulfonamide, Hydralazine, Isoniazid, d-
Penicillamine, Antiarrhythmic drugs : Propafenone,
– Interferons and TNF inhibitors.
• Activation of innate immunity.
• Lowered activation thresholds and abnormal
• Ineffective regulation of CD4+ and CD8+ T
cells, B cells and myeloid derived suppressor
• Reduced clearance of immune complexes and
Development of Autoantibodies
cells engulf and
Release “find me”
• Cytokines involved in tissue injury / organ
damage in lupus include :
– B cell maturation/survival cytokines B-Lymphocyte
– Interlukin 6, 17, 18.
– Proinflammatory type 1 and 2 interferons (IFNs)
Autoantibodies in SLE
Antibody Prevalence Antigen recognized
ANA 98 % Multiple nuclear antigens
Anti-dsDNA 70 Double stranded DNA
Anti-Sm 25 Protein complexed to 6 species of nuclear U1 RNA
Anti-RNP 40 Protein complexed to U1 RNA
Anti-Ro (SS-A) 30 Protein complexed to hY RNA (60kDa and 52 kDa)
Anti-La (SS-B) 10 Protein complexed to hyRNA (47 –kDa)
Antihistone 70 Histone proteins associated with DNA.
Antiphospholipid 50 β2G1, Phospholipids, prothrombin
Antierytherocyte 60 RBC membrane
Antiplatelet 30 Surface and altered cytoplasmic antigens on
Antineuronal 60 Neuronal and lymphocyte surface antigens
Antiribosomal P 20 Ribosomal protein
Clinical relevance : Autoantibodies
– High sensitivity, low specificity.
– Best screening test
– Repeated negative tests makes
– Can be positive in upto 10-15%
of normal individuals.
– Immunofluorescent technique
(IF) more reliable than ELISA
and/or bead assays.
Clinical relevance : Autoantibodies
• Anti dsDNA
– High titers : Specific
– 60% sensitivity.
– In some, Correlates with disease activity
• Anti- Sm
– Specific to SLE.
– More common in Blacks and Asians.
– No definite clinical correlation.
Clinical relevance : Autoantibodies
• Antiphospholipid Antibodies
– Ig G Anticardiolipin : High titres(>40 IU), Increased
risk for clotting
– Anti β2 glycoprotein.
– Lupus anticoagulant (By DRVVT)
• Anti Ro/SS-A
– Non Specific
– Associated with : Sicca syndrome, Neonatal Lupus,
Subacute cutaneous lupus
– Decreased risk for nephritis
Women with childbearing potential and
SLE should be screened for both
Antiphospholipid and anti-Ro antibodies
Clinical relevance : Autoantibodies
• Anti RNP
– Non Specific, association with RA (Rhupus), black > white.
• Anti La/SS-B
– Decreased risk for nephritis, associated with anti Ro.
• Anti histone
– Drug induced lupus.
– Measured by DCT
– Not useful clinically
– Positivity in CSF : Active CNS Lupus
• Antiribosomal P
– Positivity in Serum : Depression, Psychosis in Lupus.
Diagnosis : SLE
• American Rheumatism Association (ARA) in
1982 (revised in 1997) proposed “criteria for
classification "and not for diagnosis.
• Pitfalls of ACR 1997.
– Overly biased and weighted toward cutaneous
lupus, with four cutaneous criteria.
– Omission of Hypocomplementemia.
– Only psychosis and seizure were included.
– Biopsy-proven nephritis compatible with SLE was
Systemic Lupus International
Collaborating Clinics (SLICC) classification
• 11 clinical and 6 immunological criteria
• The patient should satisfies atleast four of the
criteria including at least one clinical criterion
and one immunologic criterion.
• Biopsy-proven nephritis compatible with SLE
in the presence of ANA or anti-dsDNA
antibodies in the absence of other lupus
features is regarded as sufficient for a patient
to be diagnosed as having lupus.
Acute Cutaneous Lupus OR Subacute
• Acute cutaneous lupus: lupus malar rash, bullous
lupus, TENvariant of SLE, maculopapular lupus rash,
photosensitive lupus rash (in the absence of
• Subacute cutaneous lupus: nonindurated psoriaform
and/or annular polycyclic lesions that resolve
Lupus affecting the fat
underlying skin aka ‘lupus
lupus erythematosus tumidus
• Tumidus dermal form of lupus.
• Characteristically photosensitive
• Red, swollen, urticaria-like
bumps and patches
• Ring-shaped (Annular)
Oral OR Nasal Ulcers
• Oral: palate, buccal, tongue
• Nasal ulcers
• In the absence of vasculitis, Behcet’s disease,
infection (herpesvirus), inflammatory bowel
disease, reactive arthritis, and acidic foods.
• Nonscarring alopecia
– Diffuse thinning or hair fragility with visible broken
• Synovitis involving 2 or more joints
– Characterized by swelling or effusion OR
tenderness in 2 or more joints and at least 30
minutes of morning stiffness
– Typical pleurisy for > 1 day OR pleural effusions OR
– Typical pericardial pain (pain with recumbency
improved by sitting forward) for > 1 day OR
pericardial effusion OR pericardial rub OR
pericarditis by electrocardiography.
– Urine PCR (or 24-hour urine protein) > 500 mg
protein/24 hours OR RBC casts.
• ANA > reference negative value.
• Anti-ds DNA
• Anti phospholipid
• Low serum complement
• Positive direct Coomb’s test
SLICC : What's new
• Non scarring alopecia added as new entity.
• Old Hematological divided into 3.
• Inclusion of mononeuritis multiplex, myelitis,
and acute confusional state in CNS
• Biopsy proven lupus nephritis
• Addition of Low complement levels in immune
• Antiphospholipid antibodies.
Performance of the SLICC as compared
to old ACR criteria
• SLICC : Sensitivity and specificity were 94% and
• ACR 1997: Sensitivity and specificity were 86%
• The new criteria retain the specificity while being
• The new criteria retains the goal of simplicity of
use, yet reflects current knowledge of SLE
obtained in 29 years since the initial ACR criteria.
• Intermittent polyarthritis
• soft tissue swelling and tenderness in joints
and/or tendons (hand, wrist, knee)
• Joint deformities develop in only 10%
• Individuals having rheumatoid-like arthritis
with erosions who fulfill criteria for both RA
and SLE ("rhupus") may be coded as having
• One of most serious manifestation.
• Classification of Lupus Nephritis is purely
• Renal biopsy indicated in every SLE patient
with evidence of nephritis.
• UPCR >0.5, RBC casts.
• Nephrotic Syndrome
ISN/RPS classification of lupus nephritis
Class I Minimal mesangial lupus nephritis (Light microscopy : Normal glomeruli)
Class II Mesangial proliferative LN (few isolated subepithelial/endothelial deposits visible by IF or
Class III Focal lupus nephritis (<50% glomerulli, sub endothelial deposits)
III A Active lesions
III A/C Active and Chronic Lesions
III C Chronic Lesions
Class IV Diffuse lupus nephritis( >50% glomeruli involved, Segmental and Global lesions)
IV – S (A) Active lesions - Diffuse segmental proliferative lupus nephritis
IV – G (A) Active lesions - Diffuse global proliferative lupus nephritis
IV – S (A/C) Active & chronic lesions - Diffuse segmental proliferative & sclerosing lupus nephritis
IV – G (A/C) Active & chronic lesions - Diffuse global proliferative & sclerosing lupus nephritis
IV – S (C) Chronic inactive lesions with scars - Diffuse segmental sclerosing lupus nephritis
IV – G (C) Chronic inactive lesions with scars - Diffuse segmental global lupus nephritis
Class V Membranous lupus nephritis
Class VI Advanced sclerosing lupus nephritis
• Cognitive dysfunction
• Difficulty with memory and reasoning
• Headaches, when excruciating, often indicates
• Psychosis : must be distinguished from
glucocorticoid induced psychosis.
• Disabling myelopathy.
• Stroke, TIAs
• Aseptic meningitis.
Management : SLE
• No cure.
• Complete sustained remission, rare.
• Mainstay : Supress symptoms and prevent
• Depends on severity of disease.
• Prevention of complications of disease and its
Management : Algorithm
• Symptom complex suggestive of SLE
• Order tests : ANA, CBC, Urine Me, Platelets
• All results normal, Symptoms subside: No SLE
• Results normal, symptoms persist : Repeat ANA & anti dsDNA, anti Ro. (3)
• ANA positive : SLICC criteria, ≥4: Definite SLE, <4 : Probable SLE (Treatment)
• Repeat ANA, Anti dsDNA and Anti Ro : All negative. NO SLE
• Some Positive : SLICC ≥4 : Definite SLE (Treatment)
Management : SLE
• Non life- or organ –threatening.
– Non Pharmacological conservative, Risk factor
– Addition of Low dose Corticosteroids, belimumab.
• Life- or organ –threatening.
– Nephritis, Myelitis, vasculitis.
– High dose iv steroids + Immunosuppressant.
• Special conditions
– Pregnancy, Dermatitis, Thrombotic crisis.
• NSAIDs (Asprin)
• Mycophenolate mofetil
• IV Ig
“Off label” but
standard of care
– For minor symptoms.
– Arthralgia, musculoskeletal, fever, headaches and
– Short periods only.
– Adverse effects : Aseptic meningitis, Transaminitis,
Decreased renal function, GI bleed, Vasculitis.
– All esp. COX 2 inhibitors : increase risk of MI
– Rapidly reduce inflammation.
– Modulate innate and adaptive immune response.
– Dosages : depend on severity.
Low dose prednisone (0.1–0.2
Mild SLE cutaneous and musculoskeletal
Medium dose prednisone (0.5
High dose oral prednisone (1.0–1.5
mg/kg) or IV methylprednisolone (1
g or 15 mg/kg)
renal or neuropsychiatric
manifestations or vasculitis
– MOA : Inhibit endosome function ? Disrupt
class II MHC Decreasing antigen presentation.
– Activates endosomal TLR: decrease IFN α.
– Use : constitutional, musculoskeletal, skin and
mild pleuritic symptoms.
– Dose : 200-400 mg daily.
– Adverse effects :Retinal damage, agranulocytosis,
aplastic anemia, cardiomyopathy, myopathy,
peripheral neuropathy, pigmentation of skin,
Quinacrine : diffuse yellow skin.
• Alkylating agent, Cross-links DNA and suppress
DNA synthesis, Prevents division of cells.
• For lupus nephritis, neuropsychiatric lupus,
severe systemic vasculitis.
• Dosing Protocols.
– NIH : I/V CPM (0.5–1.0 g/m2 bsa) once /month X
6 months, f/b once / 3 months for 2 years.
– Euro Lupus : I/V CPM 500 mg / 2 weeks X
3 months, f/b AZA or NIH regimen as
• In comparative study no significant difference
between NIH and Euro Lupus.
• Adverse reactions : Severe infections, alopecia,
lymphomas and bladder Ca and infertility.
• I/V mesna decrease risk of bladder Ca.
• Gonadotropin releasing hormone use prevents
premature ovarian failure.
• Purine analogue, inhibits synthesis of xanthylic
and adenylic acids, supress DNA synthesis.
• Use : systemic features of lupus, &
maintenance dose for Lupus Nephritis, ISN
class III & IV.
• Option as induction agent in patients with LN,
concerned with risk of infertility with CPM.
• Dosage : For Induction : 2 - 3 mg/kg/day PO;
• For maintenance : 1 -2 mg/kg/day;
• If CrCI <50 ml/min, decrease frequency.
• Adverse effects : BM suppression, GI
intolerance, hypersensitivity and
hepatotoxicity. induction therapy for selected
• Monophosphate dehydrogenase Inhibitor,
blocks synthesis of guanosine nucleotides and
proliferation of T and B cells.
• Use : Induction and maintenance therapy in
lupus nephritis & moderate to severe SLE.
• NB : More effective in Hispanic, African-
Americans and non-Asians, non white races
with lupus nephritis, compared to CPM.
• Folate antimetabolite, inhibits DNA synthesis.
• Use : for musculoskeletal manifestations, also
good for serositis and to some extent for skin
• Dosage : 10-25 mg/week PO or SC along with
folic acid. Requires dose modification renal
• Adverse Effects : stomatitis, bone marrow
suppression, hepatitis, alopecia and
pneumonitis, pulmonary fibrosis.
• Fully human monoclonal antibody against B
lymphocyte stimulator (BLyS), important for
survival of B cells. FDA approved.
• Use : reduce disease activity in SLE patients
with mild–moderate disease, without severe
renal or central nervous system. (FDA
• Dose : 10 mg/kg IV wks 0, 2 and 4, then
• Generally, well tolerated, not associated with
a high rate of adverse events.
• Chimeric mouse/human monoclonal antibody
specific for human CD20.
• Selectively Depletes CD20+ mature B cells
• Use : For non responders to above therapy.
• Currently, not approved for SLE.
• Only in patients with refractory disease esp.
cytopenia, nephritis or neuropsychiatric lupus.
• Dose : 375 mg/m2/wk x 4 or 1g/2 wks x 2,
along with corticosteroids and other
• Infection (including PML), infusion reactions,
headache, arrhythmias, allergic responses.
• Off -label use in catastrophic antiphospholipid
• Mechanism of action of IVIG in SLE t/t not
• Small clinical trials, have reported variable
efficacy of IVIG.
• Off label : in patients with refractory SLE,
• Mainstay of treatment for any inflammatory
life-threatening or organ-threatening
manifestations of SLE is systemic
• Pulse, 1 g of methylprednisolone IV daily for 3
days followed by high dose (0.5- 1 mg/kg/day)
prednisone or equivalent.
• In Mild disease : Start with
hydroxychloroquine, RAAS blockers, manage
proteinuria and hypertension.
• Treatment with hydroxychloroquine have
higher rates of renal response, fewer relapses,
and reduced accrual of renal damage.
• Patients with ISN grade III or IV disease,
treatment with GCs and CPM reduce
progression to ESRD and death.
• For Induction : GCs + CPM or MMF
– Both CPM and MMF were found to be equally
– MMF preferred in Hispanic, African-Americans
and non-Asians, non white races .
• Azathioprine (AZA) may be effective for
induction but is slower to influence response
and associated with more flares.
• For Maintenance : either MMF or AZA can be
used, in some studies MMF was found more
• For Refractory cases : consider rituximab /
Crescentic Lupus Nephritis
• Crescents in glomeruli have got worse
• Currently only High dose CPM with High-Dose
GC, in induction phase is recommended.
Membranous Lupus Nephritis
• Classified as ISN class V, have proliferative
• In pure Membranous variant,
immunosuppression is not recommended
unless proteinuria in nephrotic range.
• ACE inhibitors and ARB’s are recommended.
• Alternate day GC’s plus CPM/ MMF /
Cyclosporine all effective in reducing
Pregnancy and Lupus
• Lupus does not affects fertility.
• Rate of fetal loss increased.
• Demise is higher in mothers with
– high disease activity
– SLE nephritis
• Women with AntiRo SSA need additional
monitoring, high risk for neonatal Lupus.
• APLA with SLE treated with heparin and low dose
Pregnancy and Lupus
• Glucocorticoids are Category A
• Cyclosporin, Tacrolimus Rituximab in Category C
• AZA, HCQs, MMF, CPM as category D (benefits
• MTX is Cat X (risk outweighs benefits)
• Mgx : HCQs and if required prednisone at lowest dose
for short time.
• AZA may be added.
• Breast feeding should be avoided ( glucocorticoids and
immunosuppressants get into breast milk).
• Rare condition
• Not true lupus, passively transferred
• Transplacental transfer of IgG anti SSA or SSB
• 5-7% transient rash, resolves by 6-8 months
• 2% cardiac complications, congenital heart
• Trans-placental fluorinated corticosteroids,
dexamethasone and betamethasone.
• Hydroxychloroquine during pregnancy associated
with reduced rates of NLS.
• IVIg was reported to prevent recurrence of CHB in
one study, but two large RCTs failed to show any
Drug Induced Lupus
• Appears during therapy.
• Fever, malaise, arthritis, intense arthralgia, myalgia,
serositis, and or rash (less common).
• ANA positivity very high.
• Differs from SLE
– White predominance, less female predilection, rare
involvement of kidneys or brain.
– Commonly antihistone antibody positive, Anti dsDNA and
– Withdraw offending drug
– Low doses of systemic corticosteroids if severe disease.
Microvascular Thrombotic Crisis
• Hemolysis, thrombocytopenia, and
microvascular thrombosis in kidneys, brain
and other tissues.
• High mortility.
• LAB : PS shows schistocytes, LDH is
elevated, Antibodies to ADAMS13.
• Management : Plasma exchange, along with
Lupus and antiphospholipid
• Repeated fetal losses, venous or arterial clotting,
with atleast 2 positive tests for APLA(12 weeks
• Target INR
– Between 2.0 – 2.5 (One episode of venous clotting).
– Between 3.0 – 3.5 (recurring clots or arterial clotting)
• Heparin and Warfarin.
• Statins, hydroxychloroquine, and rituximab might
Disease Activity Assessment
• For quantification of lupus disease activity
primarily to check effectiveness of a new
• Not used in routine medical practice.
Disease Activity Assessment
Most commonly used disease activity
– SLEDAI, SLEDAI-2000, SRI-50
– Classic and BILAG 2004
• Composite indices
• 24 lupus manifestations
• Parameters scored only if present ( ie active lupus)
• 16 Clinical, 8 lab parameters.
• Manifestation items are weighted with scores 1 to
• Total score is sum
– Mild : 0-5
– Moderate : 6-12
– Severe: 13-20
• Score reduction requires complete resolution.
• 3 to 7 point reduction = clinically meaningful
• Cannot measure partial improvement of
• Cannot measure worsening of an existing
• Some items are “unfairly” scored (eg
• Seizures that are due to past irreversible
central nervous system damage are excluded.
• Some other descriptors were modified like
“cerebrovascular accident” was modified to
exclude hypertensive cause.
• Detects less severe items than SLEDAI 2K.
• Easy to use.
• Measures improvement/ worsening in disease
activity by organ system domain.
• Individual parameters grouped into 9 organ
domains and scored: 0,1,2,3,4 meaning “not
present”, “improving” , “same” , “worse” and
• made with intention to treat.
• Scores A to E, A = severe disease activity; E =
Composite Responder Indices
• For assessing disease activity in response to
• Identify both improvement and worsening in
same and different organ system.
Take home message
• SLE : Multifactorial disease.
• No cure, but disease activity can be limited if
detected early and remissions can be reached.
• Management : requires both lifestyle
modification and pharmacotherapy.
• Severe disease : managed by GC’s and
• Disease activity assessment : For future