Sle by dr. tarun betha

Systemic lupus
erythematosus
Disease manifestations, diagnosis, management.
Updated EULAR criteria 2019.
Dr. Tarun Betha
Medicine resident
Poona hospital and research centre, Pune.
1

Outline
• Introduction
• Pathophysiology
• Clinical manifestations
• Criteria - 2019 EULAR
• Management
2

Introduction
• Systemic lupus erythematosus is a characterised
by abnormal immune response against body
organs and cells mediated by tissue binding
autoantibodies and immune complexes.
Source: Harrison textbook of internal Med, 20ed.
3

Etiology and pathogenesis
• Genetic factors
• Hormonal factors
• Immune abnormalities
• Environmental factors
4

Genetic factors
• High incidence in monozygotic twins ( 24 to 57
percent)
• Sibling risk for developing SLE is 29 fold higher
than general population.
• Deficiencies of C1q,C2,C4 (rare)
• TREX1 mutations affecting DNA degradation
(rare)
5

GENES FOR LUPUS NEPHRITIS
HLA-DR3, STAT4, APOL1 (African Americans),
FCGR3A, ITGAM, IRF5, IRF7, TNFSF4
(Ox40L), DNAse1.
EPIGENETICS
Hypomethylation of DNA: In CD4+T, B and
monocytes.
Histone modifications: increased producton of
IFN.
6

Hormonal factors
Estrogen
1. Stimulates thymocytes, CD8+ and CD4+ T cells,
B cells.
2. Increased macrophage Proto-oncogene
expression.
3. Reduces apoptosis in self reactive B cells, thus
promotes maturation of autoreactive B cells.
7

• Progesterone
1. Down regulates T cell proliferation.
2. Increases CD8+ T cells.
3. Promotes Th2 response ->
autoantibody production.
8

Immune abnormalities
• Loss of self-tolerance.
• Autoantibodies against self-antigens.
• Phagocytosis and immune complex clearing are
defective in SLE.
• B cells are persistently activated by T helper
cells. (IL-6 and IL-10).
9

Environmental factors
• Epstein-Barr virus (EBV), trypanosomiasis or
mycobacterial infections- anti-DNA antibodies.
• Ultraviolet light- stimulates keratinocytes to
secrete more IL-1, IL-3, IL-6, TNF-alpha.
• Uv light interferes with T cell DNA methylation
(auto reactive T cells)
10

• Silica dust (cleaning powders, soil, pottery
materials, cement and cigarette smoking)-
increases risk of SLE.
• Allergic to antibiotics are more frequently seen in
SLE patients.
11
Environmental factors - cont’d

Source: EULAR textbook of rheumatology
13

Clinical manifestations
• Clinical manifestations are mediated directly or
indirectly by antibody and immune complexes.
• These immune complexes will deposit in the
tissues with specific antigens.
• Compliment will act on these complexes causing
disease manifestations.
14

Major features
15
Constitutional symptoms
Fatigue is the most common complaint.
Fever - can be manifestation of active disease.
Myalgia and weight loss.
Arthritis and arthralgia occur in 90% of patients.

• Mucocutaneous involvement.
• Facial eruption (m/c) - acute cutaneous lupus.
• Oral and nasal ulcers.
• Non scarring alopecia.
• Scarring alopecia seen in discoid lupus.
16

Clinical manifestations- cont’d
Verrucous endocarditis with valvular vegetations
(arrows)
17
Cardiac manifestations.
Pericarditis
Endocarditis (libmann sach’s)
Myocarditis
Congenital heart block (anti-Ro,
anti-La/SSB)
Pericarditis, with or without an effusion, is the most common cardiac
manifestation of SLE, occurring in approximately 25 percent of patients at
some point during their disease course.

18
Vascular
Raynauds phenomenon
Vasculitis
Thromboembolic
Renal involvement

Vasculitis-
• small vessel involvement-
purpura, petechiae,
papulonodular lesions,
livedo reticularis, splinter
haemorrhages and
ulceration.
• Mesentric vasculitis, hepatic
vasculitis, retinal vasculitis.
19
Source: EULAR textbook of rheumatic diseases.

• Thromboembolic disease- arterial and venous
thrombosis.
• Gastrointestinal - esopagitis, intestinal
obstruction, protein losing enteropathy, lupus
hepatitis, acute pancreatitis, peritonitis.
• Pulmonary involvement- pleuritis, pneumonitis,
ILD, pulmonary hypertension, alveolar
haemorrhage.
21

Renal manifestations
• They are usually asymptomatic.
• Urine analysis should be advised for all SLE
patients.
• Protein-creat ratio >/= 0.5.
• RBC casts.
22

25
• Nephritis is most serious manifestation of SLE.
• Diagnosis is usually by HPE.

• Neuropsychiatric involvement- cognitive
dysfunction, delirium, psychosis, headache,
peripheral neuropathies.
• Haematological - anemia of chronic disease,
leukopenia (m/c), thrombocytopenia and
pancytopenia.
• Ophthalmological- keratoconjunctivits sicca
(m/c), retinal vasculitis, optic neuropathy,
episcleritis, uveitis.
26

27

28
Source: Harrison textbook of internal Med, 20ed. Source: visualdx.com

ACLE -
malar rash
Erythematous maculopapaular
eruption involving primarily sun
exposed skin, extensor surface of
arm and hands more commonly
involved
Type to enter a caption.
29

Discoid lupus erythematosus
Chillbains
Source: clinicaladvisor.com SLE pernio Source: visualdx.com
31

Diagnosis
Based on the clinical features.
Laboratory testing- supporting evidence of serositis.
elevated creatinine.
hypoalbuminemia.
proteinuria.
positive auto-antibodies (ANA, anti-dsDNA, anti-
sm).
32

33
Source: Harrison textbook of internal Med, 20ed.

Serological tests:
• antinuclear antibodies- ANA is screening test
because of its sensitivity (95%), low specificity.
• ANA negative lupus- other antibodies like anti-Ro
(SS-A), anti- ribosomal P.
• Typical features of lupus, negative ANA doesn’t
exclude diagnosis.
34

Antibodies to extractable nuclear antigens
(ENAs)
• Autoantibodies to ssDNA, histones common in
SLE and drug induced lupus.
• ds-DNA found in 70% of SLE patients at some
point in course of illness- 95% specific for SLE.
• anti-Sm (smith) detected in 10-30% and
pathognomonic for SLE.
• anti-ribosomal- specific for SLE but less
sensitive.
35

ACR criteria (1997)
36
Criteria Definition
alar rash
Fixed erythema, flat or raised, over malar eminences, sparing
nasolabial folds
iscoid rash
Erythematosus raised patches with adherent keratitis scaling
and follicular plugging.
erositis
Pleuritis: pleuritic pain or rub heard by physician or evidence of
pleural effusion
Pericarditis: documented ECG or rub or evidence of pericardial
effusion.
ral ulcers Oral or nasopharyngeal ulceration, usually painless.

37
Criteria Definition
rthritis
Non erosive arthritis involving two or more peripheral joints-
tenderness, swelling or effusion.
hotosensitivit
y
Skin rash as a result of unusual reaction to sunlight.
Neurological Seizures, psychosis in the abscence of othe causes like
metabolic derangements and offending drugs.
enal disorder
Persistent protenuria- 0.5g/ day or >3+ if quantification not
performed.
Cellular casts: red call, hemoglobin, granular , tubular or mixed.

38
Criteria Definition
NA
An abnormal titre of ANA by immunoflorescence or an
equivalent assay at any point in time and in the absence of
drugs associated with drug induced lupus.
mmunologic
Anti- DNA, Anti-Sm or positive findings of aPLs ( cardiolipin,
lupus anticoagulant)
aematologic
Haemolytic anemia with reticulocytosis
Leukopenia <4000/ mm3 total on two or more occasions.
Lymphopenia- <1500/ mm3 on two or more occasions.
Thrombocytopenia <100 000/ mm3 in the absence of
offending drugs.
Presence of any 4 out of 11 criteria is considered as SLE.
Sensitivity and specificity of 96%.

39
EULAR criteria- (2019)
- early or new onset SLE
• seven clinical and
three immunological
criteria. Each
weighted from 2 to
10.
• Sensitivity 96.1%,
specificity 93.4%.
• Classify as SLE with
score of 10 or more.
Criteria for diagnosis.
Source: 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus

• Definite SLE - ACR 4/11 criteria or 2012 SLICC
4/17 including one in 1 in 11 clinical and 1/6
immunological
• Probable SLE- 2 or 3 criteria in ACR plus one
other feature 1) optic neuritis 2) glomerular
haematuria 2) pneumonic is 3 ) myocarditis 4)
raynaud phenomenon 5) abdominal vasculitis 6)
elevated ESR and CRP
• Possible SLE- Any one ACR or SLICC plus any
one above feature
40

Undifferentiated connective
tissue disorder
• Systemic rheumatic diseases have several
common features, making specific diagnosis
difficult.
• Only 10-15% patients with symptoms suggestive
of connective tissue disease fulfill classification
criteria of SLE after 5 years of follow up.
42

Treatment of non-renal SLE—recommended drugs with respective grading of recommendation. aPL, antiphospholipid
antibodies; AZA, azathioprine; BEL, belimumab; BILAG: British Isles Lupus Assessment Group disease activity index;
CNIs, calcineurin inhibitors; CYC, cyclophosphamide; GC, glucocorticoids; HCQ, hydroxychloroquine; IM, intramuscular;
MMF, mycophenolate mofetil; MTX, methotrexate; Pre, prednisone; PO, per os; RTX, rituximab; PLTs: Platelets; SLEDAI,
Systemic Lupus Erythematosus Disease Activity Index.
Source: Fanouriakis A, et al. Ann Rheum Dis 2019
43

Mild Moderate Severe
MAJOR ORGAN THREATENING
DISEASE (nephritis, celebrities,
myelitis, pneumonitis, mesentric
vasculitis
thrombocytopenia with platelets <20
x 103/mm3
TTP like disease or acute
hemophagocytic syndrome
SLEDAI >12
Source: Fanouriakis A, et al. Ann Rheum Dis 2019
44

Managements SLE
• Pharmacological treatment
• Management of specific manifestations
• Comorbidities
45

Goals of treatment.
46
Recommendation LoE GoR
1 Treatment in SLE should aim at remission or low disease
activity and prevention of flares in all organs, maintained with the
lowest possible dose of glucocorticoids.
2b B
2 Flares of SLE can be treated according to the severity of
organ(s) involvement by adjusting ongoing therapies
(glucocorticoids, immunomodulating agents) to higher doses,
switching, or adding new therapies.
2b C
Source: 2018 EULAR recommendation for treatment

Pharmacologic treatment
47
Glucocorticoids
Antimalarials
Immunosuppressives/cytotoxics
(methotrexate, azathioprine, mycophenolate,
cyclophosphamide)
Calcineurin inhibitors (CNIs) (use in
renal and non-renal lupus)
Biologics

Glucocorticoids
48
Pharmacologic treatment- cont’d
1 Glucocorticoids can be used at doses and route of administration that depend
on the type and severity of organ involvement.
2b C
2 Pulses of intravenous methylprednisolone (usually 500–1000 mg per day, for
1–3 days) provide immediate therapeutic effect and enable the use of lower
starting dose of oral glucocorticoids.
3b C
3 For chronic maintenance treatment, glucocorticoids should be minimized to
less than 7.5 mg/day (prednisone equivalent) and, if possible, withdrawn.
1b B
4 Prompt initiation of immunomodulatory agents can expedite the
tapering/discontinuation of glucocorticoids.
2b B

Antimalarial- hydroxychloroquine
1 HCQ is recommended for all patients with SLE,
at a dose not exceeding 5 mg/kg/real BW.
1b A
3b C
2 In the absence of risk factors for retinal toxicity, ophthalmologic screening
(by visual fields examination and/or spectral domain-optical coherence
tomography) should be performed at baseline, after 5 years, and yearly
thereafter.
2b B
Source: 2018 EULAR recommendation for treatment 49

• Mild lupus (skin, joint, mucosal involvement)- HCQ with one
without prednisolone </= 7.5 mg/day.
• Moderate lupus (significant but non organ threatening-
constitutional , cutaneous, musculoskeletal or haematological) -
HCQ + prednisolone 5 to 15 mg/day +/- immunosuppressive Rx.
• Severe lupus (renal or CNS involvement)- methylprednisolone
0.5 to 1g/day for 3 days in acutely I’ll patients. Or 1 to
2mg/kg/day in stable patients.
50
Overview of Rx.
Source: Up-to-date

1 In patients not responding to HCQ (alone or in combination with glucocorticoids)
or patients unable to reduce glucocorticoids below doses acceptable for chronic
use, addition of immunomodulating/immunosuppressive agents such as
methotrexate 1b B
azathioprine 2b B
or mycophenolate should be considered. 2a B
2 Immunomodulating/immunosuppressive agents can be included in the initial
therapy in cases of organ-threatening disease.
2b C
3 Cyclophosphamide can be used for severe organ- or life-threatening SLE as well
as “rescue” therapy in patients not responding to other immunosuppressive agents.
2b C
Immunosuppressive treatment.
51

52
Methotrexate: Systemic lupus erythematosus, moderate to severe : Oral: Initial: 7.5
mg once weekly; may increase by 2.5 mg increments weekly (maximum: 20 mg once
weekly), in combination with prednisone.
source: Harrison 20ed, SLE, table 349-5
Azathioprine: 2–3 mg/kg per day PO for induction; 1–2 mg/kg per day for
maintenance; decrease frequency of dose if CrCl <50 mL/min
Mycophenolate mofetil: MMF: 2–3 g/d PO total given bid for induction therapy, 1-2
g/d total given bid for maintenance therapy; max 1 g bid if CrCl <25 mL/min.Begin with
low dose and increase every 1–2 weeks to minimize GI side effects. Start treatment at
0.5 g bid.
Cyclophosphamide: Low dose (for whites of northern European backgrounds):
500mg every 2 weeks for 6 doses, then begin maintenance with MMF or AZA. High
dose: 7–25 mg/kg q month × 6; consider mesna administration with dose.

53
Calcineurine inhibitors
Tacrolimus: Trough blood level should not exceed 5.5 ng/mL to minimise toxicity.
Begin dose at 2 mg bid.
S/E infection, nephrotoxicity, neural toxicity.
Cyclosporine inhibits T-cell activation of transcript. It is used in refractory skin
involvement, lupus Nephropathy, bone marrow hypoplasia.
Dose: 2.5 mg/kg/day in 2 divided doses.
source: Harrison 20ed, SLE, table 349-5

54
1 In patients with inadequate response to standard-of-care
(combinations of hydroxychloroquine, glucocorticoids, other
immunomodulating agents), defined as residual disease activity
not allowing tapering of glucocorticoids and/or frequent relapses,
add-on treatment with belimumab should be considered.
1a A
2 In organ-threatening disease refractory or with
intolerance/contra-indications to standard immunosuppressive
agents, rituximab can be considered.
2b C
Biologicals

55
Belimumab:
• human monoclonal antibody inhibits soluble form of B cell survival factor known
as BLyS or BAFF.
• Levels are elevated in patients of SLE in whom it keeps in formation and survival
of memory B cells and plasma blasts making autoantibodies.
• It is used in resistant cases of cutaneous and musculoskeletal disease.
• Contraindicated in lupus nephritis and active CNS involvement.
IV: Initial: 10 mg/kg every 2 weeks for 3 doses; Maintenance: 10 mg/kg every 4 weeks
SubQ: 200 mg once weekly
Switching from IV therapy: Administer the first SubQ dose 1 to 4 weeks after the last IV
dose.
Source: up-to-date

56
Rituximab
• chimeric B cell depleting monoclonal antibody.
• It is usually used in severe disease burden especially in lupus nephritis as
a last resort.
Dose: 375 mg/m2 q wk × 4 (or) 1 g q 2 wks × 2.
S/E: infusion reactions, Hep B reactivation, PML, mucocutaneous reaction.
Source: up-to-date

57
Management of specific
manifestations.
1 First-line treatment of skin disease in SLE includes
topical agents (glucocorticoids, calcineurin inhibitors) 2b B
antimalarials (HCQ, quinacrine) 1a A
systemic glucocorticoids. 4 C
2 In non-responsive cases or cases requiring high-dose
glucocorticoids,
methotrexate, 3a B
retinoids, dapsone, or mycophenolate can be added. 4 C
Skin manifestations.

58
Management of specific manifestations - cont’d
1 Attribution to SLE - as opposed to non-SLE - related neuropsychiatric
manifestations, can be facilitated by neuroimaging, investigation of
cerebrospinal fluid, consideration of risk factors [type and timing of the
manifestation in relation to the onset of lupus, patient age, non-neurological
lupus activity, presence of antiphospholipid antibodies (aPL)] and exclusion
of confounding factors.
2b C
2 Treatment of SLE-related neuropsychiatric disease includes
glucocorticoids/immunosuppressive agents for manifestations
considered to reflect an inflammatory process
1b A
and antiplatelet/anticoagulants for atherothrombotic/aPL-related
manifestations.
2b C
Neuropsychiatric manifestations.

59
1 Acute treatment of lupus thrombocytopenia includes high-dose
glucocorticoids (including pulses of intravenous methylprednisolone)
and/or intravenous immunoglobulin.
4 C
2 For maintenance of response, IS/GC-sparing agents such as
mycophenolate, azathioprine,
2b C
or cyclosporine can be used. 4 C
3 Refractory cases can be treated with rituximab 3a C
or cyclophosphamide. 4 C
Haematological manifestations.

60
1 Early recognition of signs of renal involvement and - when present -
performance of a diagnostic renal biopsy are essential to ensure
optimal outcomes.
2b B
2 Mycophenolate 1a A
or low-dose IV cyclophosphamide are recommended as initial
(induction) treatment, as they have the best efficacy/toxicity ratio.
2a B
3 In patients at high risk for renal failure (reduced glomerular filtration
rate, histologic presence of crescents or fibrinoid necrosis, or tubular
atrophy/interstitial fibrosis], mycophenolate
2b B
or high-dose IV cyclophosphamide can be used. 1b A
4 For maintenance therapy, mycophenolate or azathioprine should
be used.
1a A
Renal disease.

61
5 In cases with stable/improved renal function but incomplete renal
response (persistent proteinuria >1 g/24h after at least one year of
immunosuppressive treatment), repeat biopsy can distinguish chronic
from active kidney lesions.
4 C
6 Mycophenolate may be combined with low dose of a calcineurin
inhibitor in severe nephrotic syndrome
2b C
or incomplete renal response, 4 C
in the absence of uncontrolled hypertension, high chronicity index at
kidney biopsy, and/or reduced GFR.
Renal disease.

62
Comorbidities
1 All SLE patients should be screened at diagnosis for aPL. 1a A
2 SLE patients with high-risk aPL profile (persistently positive
medium/high titres or multiple positivity) may receive primary
prophylaxis with antiplatelet agents, especially if other
atherosclerotic/thrombophilic factors are present, after balancing the
bleeding hazard.
2a C
3 For secondary prevention (thrombosis, pregnancy
complication/loss), the therapeutic approach should be the same as
for primary anti-phospholipid syndrome.
1b B
Antiphospholipid antibody syndrome.

63
Comorbidities - cont’d
1 SLE patients should be assessed for general and disease-related
risk factors for infections such advanced age/frailty (–/D), comorbidities
(–/D), renal involvement (2b/B), immunosuppressive/biologic therapy
(1b-2b/B-C) and high-dose glucocorticoids (1a/A).
2 General preventative measures (including immunizations) and early
recognition and treatment of infection/sepsis are recommended (–/D).
- D
Infection and immunisation.

64
Source: up-to-date
Infection and immunisation.
Found to be safe in studies. Not safe in immunosuppressed.

65
1 Patients with SLE should undergo regular assessment for traditional
(1b/B-C) and disease-related risk factors for cardiovascular disease,
including persistently active disease (1b/B), increased disease duration
(1b/A), medium/high titres of aPL (1b/A), renal involvement (1b/B)
(especially, persistent proteinuria and/or GFR <60 ml/min) and chronic
use of glucocorticoids (1b/B).
2 Based on their individual cardiovascular risk profile, SLE patients may
be candidates for prevention with low-dose aspirin.
2b D
and/or lipid-lowering agents. (Atorvastatin or fluvastatin) 2b D
Cardiovascular.

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