SLE
Epidemiology
15-40yrs, ♀:♂= 9:1, 2-3x in non-Caucasian. 15-20% in childhood (≈10yrs) and another 15-
20% >50yrs (“late-onset” lupus); in both cases ♀:♂= 2:1
The prevalence of SLE is 20/100.000 in Caucasians, 46/100.000 in Asians. African-
American, Asian and Hispanics have an excess morbidity from SLE (more hematological,
serosal, neurological and renal) and a younger age of onset than Europeans. In contrast,
Europeans have a higher prevalence of photosensitivity. Renal disease prevalence 0.5-
0.7/100.000.
25-35% of monozygotic twins and 2-5% of dizygotic twins. 10% of SLE patients have
an affected 1st-degree relative.
Causes
Although inheritance and the hormonal milieu may create a predisposition toward SLE, the
initiation of disease and its temporal variation in intensity likely result from:
-Environmental and other exogenous factors: tobacco, viral infection (EBV, CMV),
silica, UV light, pesticides, gut microbiome, drugs, female sex (loci in X chromosome and
female hormones [estrogen, progesterone, prolactin; mild/moderate hyperprolactinemia
has been demonstrated in 20-30% and is associated with active disease]).
UV light: induces DNA breaks that might alter gene expression or lead to
apoptotic or necrotic cell death. Even in the absence of cell death, DNA breaks or prolonged
maintenance of DNA-protein cross-links might provide an adjuvant or antigenic stimulus to
the immune system.
Genetics
Complement: the rare but high-risk deficiencies in complement pathway gene
products, including C2, C4 and C1q, are thought to contribute to lupus pathogenesis by
impairing clearance of cellular debris. C1q is the recognition protein for the classical pathway
and plays an additional role in inhibition of IFN-α production by directing stimulatory
immune complexes to monocytes rather than IFN-producing pDCs (→ C1q deficiency can
augment IFN-α and promote broad immune dysregulation).
DNases: two DNases (DNase1 and DNase1-Like 3) degrade DNA in NETs and the
absence of those enzymes is associated with vascular occlusions due to the accumulation of
intravascular NET clots.
-Genetic variants in DNase1 may contribute to SLE and families with a frame
shift mutation in the DNASE1L3 gene include patients with aggressive lupus and anti-DNA
antibodies (+ nephritis) or HUVS.
-TREX1 gene mutations, encoding a DNase (that degrades potentially
stimulatory reverse-transcribed DNA). The accumulation of cytosolic DNA results in an
activation of IFN-I genes through the STING-TBK1-IRF3 pathway. A functional connection
between TREX1 and control of IFN-I production was demonstrated in a murine model in
which TREX1 deficiency resulted in increased levels of IFN-β. Rare TREX1 variants, however,
have also been detected in 0.5-3% of individuals with “classical” SLE. Polymorphisms were
mostly located in genomic regions that are not crucial for the exonuclease activity of TREX1.
Of note, TREX1 polymorphisms in “classical” SLE increase the risk for neurological symptoms
and complications. Autosomal recessive or compound heterozygous variants in TREX1 are
found in many children with AGS who often, but not always, develop lupus, while cases of
autosomal dominant inheritance lead to familial chilblain lupus.
RNAses mutations
, STING mutations. STING (TLR-independent) is an ER transmembrane protein which
functions as an adaptor for the soluble sensor cGAMP (cytosolic dsDNA sensing),
intermediating IFN-I signaling. Increased transcription of IFN-β and IFN-stimulated genes and
constitutive phosphorylation of STAT1 (activated downstream of IFNAR, the IFN-I receptor).
HLA-DR3 (DRB1*03:01) (while in RA it’s HLA-DR4 [DRB1*04]), HLA-B8.
TLR7 de novo GoF mutation → monogenic lupus. This GoF mutation (on X
chromosome) causes aberrant TLR7 signalling in autoreactive B-cells, thereby giving them
the necessary 2nd signal for activation and survival (otherwise they’d die of anergy).
SNPs
-TLR7, TLR9. TLR7 is encoded on the X chromosome. Binds endosomal ssRNA
and activates IFN-I response via MyD88 → B-cell activation/proliferation.
-IRF5, IRF7: cytoplasmic proteins that translocate to the nucleus after
effective activation of the endosomal TLRs (by DNA or RNA) and then act as transcription
factors to initiate transcription of IFN-α and other proinflammatory mediators. IRF5 also
induces cell cycle arrest and cell death and is required for B-cell differentiation.
-STAT4 (Th1 signalling), STAT1 (IFN signalling). STAT4 gene polymorphisms
have an additive value with IRF5 for SLE-risk.
-TNFAIP3 gene: encodes A20 protein which functions as a negative regulator
of the NF-kB.
-FcγR cluster on chromosome 1 gene locus: low-affinity receptors for ICs.
-molecules mediating BCR, TCR signalling:
PTPN22 (both T and B cells)
BANK1, BLK, TNFAIP3 and others (B cells)
other loci on X chromosome: it has been proposed that epigenetic modifications in
the inactive X chromosome leading to increased inflammatory genes could explain the
female preponderance in SLE. Indeed, the X chromosome encodes several genes considered
relevant to SLE pathogenesis (CD40L, IRAK1, FOXP3, TLR7) that could be overexpressed in
females because of incomplete epigenetic X inactivation.
miRNAs: they regulate the expression of target genes
DNA methylation dysregulation (lower): action of DNMTs and miRNAs.
Partial chromosome 9 trisomy (involves the IFN-I gene cluster): chronically
elevated IFN-I and anti-RNP and anti-Ro60 autoantibodies production.
Of note, IRF5 and STAT4 have been reported to increase the risk of SLE in an additive
manner, implicating both innate and adaptive immunity in the development of SLE
pathogenesis. IRF5, TNFAIP3 and STAT4 control NET production.
Metrology
Disease activity scores
SLEDAI-2K (previous 10 days + ongoing/unchanged symptoms from the last
evaluation): “all-or-none” system, doesn’t capture improving or worsening and doesn’t
include severity within a specific organ system. Different organ involvement are weighted
differently, scores 1-8 (CNS and vascular weight more), total 0-105. Associated with survival
and chronic damage. The difference with old SLEDAI is that the old one doesn’t count the
persistent symptoms, so SLEDAI=0 could also mean persistent activity.
low activity SLEDAI = 1-4
moderate activity SLEDAI = 5-10
high activity SLEDAI >10
flare: increase ≥4, remission: reduction ≥4, in between = persistent activity.
,*There’s also SLEDAI-2K 30days (instead of 10, the previous 30 days) and SLEDAI-2KG (which
includes GC ≥5mg/d)
*There’s SELENA-SLEDAI (substituted by SLEDAI-2K) with includes PhGA and SELENA flare
index.
According to EULAR 2023 guidelines:
*Mild disease: constitutional symptoms, mild arthritis, rash ≤9% BSA, plts= 50-100,
SLEDAI≤6, BILAG-C or ≤1 BILAG-B manifestations.
*Moderate disease: moderate/severe arthritis (‘RA-like’), rash 10–18% BSA, plts=20-
50, serositis, SLEDAI 7-12, ≥2 BILAG-B manifestations).
*Severe disease: major organ threatening disease (encephalitis, myelitis,
pneumonitis, mesenteric vasculitis), plts=<20, TTP, MAS, rash>18% BSA, SLEDAI>12, ≥1
BILAG-A manifestations.
BILAG can assess single organs and is more sensitive, but more complex as it
scores by “not present, improving, same, worse, new” and categorizes organ disease activity
as A-E, based on an intent-to-treat principle. Doesn’t differentiate weighting for each
manifestation.
12 points → BILAG-A = active, severe (high-dose GC, immunosuppression)
8 points → BILAG-B=beware, moderate severity (low-dose GC≤20mg, topical)
1 point → BILAG-C=contentment, mild severity (symptomatic treatment, NSAIDs)
0 points → BILAG-D/E=inactive, with or without previous involvement.
DORIS definitions
- Low disease activity: SLEDAI-2K ≤4. Allowed: HCQ + GC ≤7.5mg + stable
immunosuppression.
- Remission: SLEDAI-2K= 0. Allowed: HCQ + GC ≤5mg + stable immunosuppression.
Damage indices
CLASI for skin damage measures erythema, scaling, hypertrophy and mucous
membrane disease, whereas the damage index measures the complications including
hyperpigmentation, atrophy and scarring alopecia.
SDI (SLICC/ACR Damage Index): scores irreversible damage (due to either disease
or medication AEs) accrual in 12 organ systems. The damage needs to be >6 months.
SDI 0 = no damage
SDI ≥1 = irreversible damage present
SDI ≥3 =severe damage present
Clinical response indices (for trials)
SRI: ≥4 SLEDAI reduction + no new BILAG flare + no worsening in PhGA.
BICLA: BILAG improvement in all systems + no new BILAG scores + no increase in
SLEDAI + no increase in PhGA + no treatment failure
Criteria
-ACR (1997) 83% sensitivity, 93% specificity
-SLICC (2012) 97% sensitivity, 84% specificity. No entry criterion with ANA (+).
-EULAR (2019) 96% sensitivity, 93% specificity. Positive ANA ≥1:80 and ≥10 points
, Note that the highest scoring are: renal biopsy, anti-dsDNA, anti-Sm, pericarditis/serositis,
MSK, seizure.
Pathophysiology
Causes
in a susceptible individual
i) ↑ autoantigens from:
- excessive production (accelerated cell apoptosis)
- defective clearance
- defective NET clearance (so more autoantigens remain presented)
ii) autoantibody production by:
- B-cell stimulation (by nucleic acids via endosomal TLR7/9) → antibody production
- antigen overload
iii) ↑ IFN-I by
-pDCs (activated via TLR7/9 by nucleic acid)
-abnormalities of endosomal or cytoplasmic nucleic acid sensors
iv) Defective clearance of autoantibodies and ICs
- defective phagocyte function
Epidemiology
15-40yrs, ♀:♂= 9:1, 2-3x in non-Caucasian. 15-20% in childhood (≈10yrs) and another 15-
20% >50yrs (“late-onset” lupus); in both cases ♀:♂= 2:1
The prevalence of SLE is 20/100.000 in Caucasians, 46/100.000 in Asians. African-
American, Asian and Hispanics have an excess morbidity from SLE (more hematological,
serosal, neurological and renal) and a younger age of onset than Europeans. In contrast,
Europeans have a higher prevalence of photosensitivity. Renal disease prevalence 0.5-
0.7/100.000.
25-35% of monozygotic twins and 2-5% of dizygotic twins. 10% of SLE patients have
an affected 1st-degree relative.
Causes
Although inheritance and the hormonal milieu may create a predisposition toward SLE, the
initiation of disease and its temporal variation in intensity likely result from:
-Environmental and other exogenous factors: tobacco, viral infection (EBV, CMV),
silica, UV light, pesticides, gut microbiome, drugs, female sex (loci in X chromosome and
female hormones [estrogen, progesterone, prolactin; mild/moderate hyperprolactinemia
has been demonstrated in 20-30% and is associated with active disease]).
UV light: induces DNA breaks that might alter gene expression or lead to
apoptotic or necrotic cell death. Even in the absence of cell death, DNA breaks or prolonged
maintenance of DNA-protein cross-links might provide an adjuvant or antigenic stimulus to
the immune system.
Genetics
Complement: the rare but high-risk deficiencies in complement pathway gene
products, including C2, C4 and C1q, are thought to contribute to lupus pathogenesis by
impairing clearance of cellular debris. C1q is the recognition protein for the classical pathway
and plays an additional role in inhibition of IFN-α production by directing stimulatory
immune complexes to monocytes rather than IFN-producing pDCs (→ C1q deficiency can
augment IFN-α and promote broad immune dysregulation).
DNases: two DNases (DNase1 and DNase1-Like 3) degrade DNA in NETs and the
absence of those enzymes is associated with vascular occlusions due to the accumulation of
intravascular NET clots.
-Genetic variants in DNase1 may contribute to SLE and families with a frame
shift mutation in the DNASE1L3 gene include patients with aggressive lupus and anti-DNA
antibodies (+ nephritis) or HUVS.
-TREX1 gene mutations, encoding a DNase (that degrades potentially
stimulatory reverse-transcribed DNA). The accumulation of cytosolic DNA results in an
activation of IFN-I genes through the STING-TBK1-IRF3 pathway. A functional connection
between TREX1 and control of IFN-I production was demonstrated in a murine model in
which TREX1 deficiency resulted in increased levels of IFN-β. Rare TREX1 variants, however,
have also been detected in 0.5-3% of individuals with “classical” SLE. Polymorphisms were
mostly located in genomic regions that are not crucial for the exonuclease activity of TREX1.
Of note, TREX1 polymorphisms in “classical” SLE increase the risk for neurological symptoms
and complications. Autosomal recessive or compound heterozygous variants in TREX1 are
found in many children with AGS who often, but not always, develop lupus, while cases of
autosomal dominant inheritance lead to familial chilblain lupus.
RNAses mutations
, STING mutations. STING (TLR-independent) is an ER transmembrane protein which
functions as an adaptor for the soluble sensor cGAMP (cytosolic dsDNA sensing),
intermediating IFN-I signaling. Increased transcription of IFN-β and IFN-stimulated genes and
constitutive phosphorylation of STAT1 (activated downstream of IFNAR, the IFN-I receptor).
HLA-DR3 (DRB1*03:01) (while in RA it’s HLA-DR4 [DRB1*04]), HLA-B8.
TLR7 de novo GoF mutation → monogenic lupus. This GoF mutation (on X
chromosome) causes aberrant TLR7 signalling in autoreactive B-cells, thereby giving them
the necessary 2nd signal for activation and survival (otherwise they’d die of anergy).
SNPs
-TLR7, TLR9. TLR7 is encoded on the X chromosome. Binds endosomal ssRNA
and activates IFN-I response via MyD88 → B-cell activation/proliferation.
-IRF5, IRF7: cytoplasmic proteins that translocate to the nucleus after
effective activation of the endosomal TLRs (by DNA or RNA) and then act as transcription
factors to initiate transcription of IFN-α and other proinflammatory mediators. IRF5 also
induces cell cycle arrest and cell death and is required for B-cell differentiation.
-STAT4 (Th1 signalling), STAT1 (IFN signalling). STAT4 gene polymorphisms
have an additive value with IRF5 for SLE-risk.
-TNFAIP3 gene: encodes A20 protein which functions as a negative regulator
of the NF-kB.
-FcγR cluster on chromosome 1 gene locus: low-affinity receptors for ICs.
-molecules mediating BCR, TCR signalling:
PTPN22 (both T and B cells)
BANK1, BLK, TNFAIP3 and others (B cells)
other loci on X chromosome: it has been proposed that epigenetic modifications in
the inactive X chromosome leading to increased inflammatory genes could explain the
female preponderance in SLE. Indeed, the X chromosome encodes several genes considered
relevant to SLE pathogenesis (CD40L, IRAK1, FOXP3, TLR7) that could be overexpressed in
females because of incomplete epigenetic X inactivation.
miRNAs: they regulate the expression of target genes
DNA methylation dysregulation (lower): action of DNMTs and miRNAs.
Partial chromosome 9 trisomy (involves the IFN-I gene cluster): chronically
elevated IFN-I and anti-RNP and anti-Ro60 autoantibodies production.
Of note, IRF5 and STAT4 have been reported to increase the risk of SLE in an additive
manner, implicating both innate and adaptive immunity in the development of SLE
pathogenesis. IRF5, TNFAIP3 and STAT4 control NET production.
Metrology
Disease activity scores
SLEDAI-2K (previous 10 days + ongoing/unchanged symptoms from the last
evaluation): “all-or-none” system, doesn’t capture improving or worsening and doesn’t
include severity within a specific organ system. Different organ involvement are weighted
differently, scores 1-8 (CNS and vascular weight more), total 0-105. Associated with survival
and chronic damage. The difference with old SLEDAI is that the old one doesn’t count the
persistent symptoms, so SLEDAI=0 could also mean persistent activity.
low activity SLEDAI = 1-4
moderate activity SLEDAI = 5-10
high activity SLEDAI >10
flare: increase ≥4, remission: reduction ≥4, in between = persistent activity.
,*There’s also SLEDAI-2K 30days (instead of 10, the previous 30 days) and SLEDAI-2KG (which
includes GC ≥5mg/d)
*There’s SELENA-SLEDAI (substituted by SLEDAI-2K) with includes PhGA and SELENA flare
index.
According to EULAR 2023 guidelines:
*Mild disease: constitutional symptoms, mild arthritis, rash ≤9% BSA, plts= 50-100,
SLEDAI≤6, BILAG-C or ≤1 BILAG-B manifestations.
*Moderate disease: moderate/severe arthritis (‘RA-like’), rash 10–18% BSA, plts=20-
50, serositis, SLEDAI 7-12, ≥2 BILAG-B manifestations).
*Severe disease: major organ threatening disease (encephalitis, myelitis,
pneumonitis, mesenteric vasculitis), plts=<20, TTP, MAS, rash>18% BSA, SLEDAI>12, ≥1
BILAG-A manifestations.
BILAG can assess single organs and is more sensitive, but more complex as it
scores by “not present, improving, same, worse, new” and categorizes organ disease activity
as A-E, based on an intent-to-treat principle. Doesn’t differentiate weighting for each
manifestation.
12 points → BILAG-A = active, severe (high-dose GC, immunosuppression)
8 points → BILAG-B=beware, moderate severity (low-dose GC≤20mg, topical)
1 point → BILAG-C=contentment, mild severity (symptomatic treatment, NSAIDs)
0 points → BILAG-D/E=inactive, with or without previous involvement.
DORIS definitions
- Low disease activity: SLEDAI-2K ≤4. Allowed: HCQ + GC ≤7.5mg + stable
immunosuppression.
- Remission: SLEDAI-2K= 0. Allowed: HCQ + GC ≤5mg + stable immunosuppression.
Damage indices
CLASI for skin damage measures erythema, scaling, hypertrophy and mucous
membrane disease, whereas the damage index measures the complications including
hyperpigmentation, atrophy and scarring alopecia.
SDI (SLICC/ACR Damage Index): scores irreversible damage (due to either disease
or medication AEs) accrual in 12 organ systems. The damage needs to be >6 months.
SDI 0 = no damage
SDI ≥1 = irreversible damage present
SDI ≥3 =severe damage present
Clinical response indices (for trials)
SRI: ≥4 SLEDAI reduction + no new BILAG flare + no worsening in PhGA.
BICLA: BILAG improvement in all systems + no new BILAG scores + no increase in
SLEDAI + no increase in PhGA + no treatment failure
Criteria
-ACR (1997) 83% sensitivity, 93% specificity
-SLICC (2012) 97% sensitivity, 84% specificity. No entry criterion with ANA (+).
-EULAR (2019) 96% sensitivity, 93% specificity. Positive ANA ≥1:80 and ≥10 points
, Note that the highest scoring are: renal biopsy, anti-dsDNA, anti-Sm, pericarditis/serositis,
MSK, seizure.
Pathophysiology
Causes
in a susceptible individual
i) ↑ autoantigens from:
- excessive production (accelerated cell apoptosis)
- defective clearance
- defective NET clearance (so more autoantigens remain presented)
ii) autoantibody production by:
- B-cell stimulation (by nucleic acids via endosomal TLR7/9) → antibody production
- antigen overload
iii) ↑ IFN-I by
-pDCs (activated via TLR7/9 by nucleic acid)
-abnormalities of endosomal or cytoplasmic nucleic acid sensors
iv) Defective clearance of autoantibodies and ICs
- defective phagocyte function
