1. Prof. Abdel-Azim Alhefny
Prof. of Internal Medicine, Rheumatology
& Clinical Immunology
Director of Rheumatology Unite
Ain Shams University

2.  A multi-system autoimmune connective
tissue disease that occurs most commonly in
women during their reproductive age
The most serious life threatening
frequent complication is lupus nephritis.

3. Alopecia
Oral ulcers
&Urinary abnormalities
Nonerosive
>4000
>100,000
Lymphopenia <1500
Systemic Lupus
Erythematosus

4. Sparing the nasolabial folds
Malar rash

5. 1) Malar rash
2) Discoid rash
3) Photosensitivity
(rash after exposure to UV-B radiation found in sunlight or
fluorescent lights.
It occurs in 60 – 100% of SLE patients)

6. Malar / Butter fly rash
 Erythema in a malar distribution over
the cheeks and bridge of the nose
(DD: sunburn, Chloasma ).
 The rash may precede or accompany
other manifestations of lupus.
 The involved skin feels warm and
edematous.
 The rash may last for hours or days, and
often recurs, particularly with sun
exposure (UV).
Spare the nasolabial
fold

7. Discoid rash
Sub acute Cutaneous Lupus

8. 4) Oral ulcers 5) Arthritis4) Oral ulcers 5) Arthritis (nonerosive)(nonerosive)

9. 6) Serositis:
 Pleurisy
 pericarditis
CXR : pleurisyCXR : pleurisy

11. 7) Renal:
Proteinuria >0.5gm/d,
Cellular casts
Red cell casts
Granular castGlomerulonephritis

12. 8) Neurological:
Seizures or psychosis
9) Hematological:
Hemolytic anemia
Leucopenia < 4000
Lymphopenia < 1500
Thrombocytopenia < 100 000
cerebral vasculitis

13. 10) Immunological:
Anti dsDNA ab
Anti –Sm ab
aCL ab
11) ANA antibodies
ANA testANA test
Anti dsDNA ab test (IFAnti dsDNA ab test (IF((

14. ACR
aCL -Antiboy
)1982with a 1997 revision(

15. Other common manifestations notOther common manifestations not
in the SLE classification criteriain the SLE classification criteria

16. Localized alopecia Wide spread non scaring
SLE- Clinical PresentationSLE- Clinical Presentation

17. SLE- ClinicalSLE- Clinical
PresentationPresentation
Vasculitis
Raynaud’s

18. 18
Pulmonary Involvement In SLE
Pleural disease
Acute lupus pneumonitis
Chronic interstitial lung disease
Pulmonary hemorrhage
Pulmonary embolism
Pulmonary vascular disease
Diaphragmatic dysfunction

19. 19
Cardiac manifestation of SLE
Pericardium ：• Pericarditis with or
without effusion
• Cardiac tamponade
(rare)
• Constrictive perecarditis
Myocardium ：• Myocarditis
Endocardium ：• Libman-Sacks
endocarditis
Coronary artery ：• Accelerated
atherosclerosis
• Vasculitis

21. Possible causes of
leukopenia in SLE
Possible causes of
anemia in SLE
 Immune destruction
 Marrow suppression
 Hypersplenism
 Drugs
 Auto-immune hemolytic
anemia
 Anemia of chronic
disease
 Marrow suppression
 Blood loss due to
thrombocytopenia or
NSAID use
 Hypersplenism
 Anemia of renal failure

22. 22
Serological Tests to Aid Diagnosis of SLESerological Tests to Aid Diagnosis of SLE

23.  SLICC group revised and validated the ACR
SLE classification criteria in order to:
 improve clinical relevance,
 meet efficient methodology requirements,
 incorporate new knowledge regarding the
immunology of SLE.
 The SLICC classification criteria provide
alternative classification criteria for use in
SLE clinical care and research.

24.  The new SLICC classification criteria
performed well in a large set of patient
scenarios rated by experts.
 According to the SLICC rule for the
classification of SLE, the patient must satisfy
at least 4 criteria, including at least:
 one clinical criterion and one immunologic
criterion
OR
 the patient must have biopsy-proven lupus
nephritis in the presence of ANA or anti-dsDNA
antibodies.
 Criteria are cumulative and need not be
present concurrently.

25. *** Clinical Criteria
1.Acute or subacute cutaneous lupus
2.Chronic cutaneous lupus
3.Oral/Nasal ulcers
4.Nonscarring alopecia
5.Inflammatory synovitis with physician-
observed swelling OR tenderness of > 2
joints+ MS > 30min
6.Serositis (pleural, pericardial)
7.Renal: Urine protein/creatinine
representing at least 500 mg protein/24
hr or RBC casts
8.Neurologic: seizures, psychosis,
mononeuritis multiplex, myelitis,
peripheral or cranial neuropathy
cerebritis (acute confusional state)
1.Hemolytic anemia
2. Leukopenia (<4000/mm3 at least once)
OR Lymphopenia (<1000/mm3 at least
once)
3.Thrombocytopenia (<100,000/mm3) at
*** Immunologic Criteria
• ANA above laboratory reference
range
• Anti-dsDNA above laboratory
reference
• Anti-Sm
• Antiphospholipid antibody
lupus anticoagulant,
false-positive test for syphilis,
anticardiolipin– at least 2x
normal or medium-high titer,
anti- b2 glycoprotein 1
• Low complement
low C3,
low C4,
low CH50
• Direct Coombs test in absence of
hemolytic anemia

26.  Renal involvement is common in SLE.
 The most frequently observed abnormality in
patients with lupus nephritis is proteinuria.
 In the US 35% of adults with SLE have clinical
evidence of nephritis at the time of diagnosis,
 50–60% will develop nephritis during the first 10
years of disease.
 It is more severe in blacks than it is in whites
& in men than in women.

27.  General
 Patients with active lupus nephritis often have other symptoms of
active SLE, including fatigue, fever, rash, arthritis, serositis, or CNS
disease.
 These are more common with Class III & IV L. nephritis.
 Occasionally, patients are asymptomatic (mesangial); yet, laboratory
abnormalities may be essential for diagnose.
 Nephritis
 Symptoms related to active nephritis may include peripheral edema
secondary to hypertension or hypoalbuminemia.
 Extreme peripheral edema is more common in persons with diffuse
proliferative or membranous lupus nephritis because of heavy
proteinuria (NS).
 Other symptoms directly related to hypertension that are commonly
associated with class II & IV lupus nephritis include headache,
dizziness, visual disturbances, and signs of cardiac decompensation.

28.  Patients with SLE should undergo testing for renal
involvement at regular intervals.
 Urinalysis with examination of the urinary sediment (≥5
red blood cells /HPF, casts),
 Urine protein excretion >0.5 g/day or 3+ on dipstick
(a spot urine protein/creatinine ratio>0.2),
 An elevated serum creatinine by at least 0.8 mg/dL
from pt. base line or to≥1.5 mg/dL
 Low estimated glomerular filtration rate ( or cr cl.).
 Elevated anti-DNA titers and
 Low complement (C3 and C4, anti-C1q antibodies )
levels often indicate active lupus, particularly LN.
 The diagnosis is confirmed by histopathologic
findings on renal biopsy.

29. 1. Increasing serum creatinine without alternative
causes (such as sepsis, hypovolemia, or medication)
2. Confirmed proteinuria of >1.0 gm/24 hours (either 24-
hour urine specimens or spot protein/creatinine ratios).
3. Combinations of the following, assuming the findings
are confirmed in at least 2 tests done within a short
period of time and in the absence of alternative causes:
a. Proteinuria > 0.5 gm/24 hours plus hematuria,
defined as > 5 RBCs/hpf
b. Proteinuria > 0.5 gm/24 hours plus cellular casts
RBCs: red blood cells; HPF: high-power field. (Hahn et al., 2012)

30. To detect transformation from one histologic pattern to another
 the emergence of an active sediment,
 a new elevation in serum creatinine, and/or
 worsening of proteinuria despite treatment
Among patients with membranous lupus:-
 Development of an active sediment since (transformation to a
proliferative lesion) which usually requires different treatment
In patients with treated proliferative LN
 Nephrotic syndrome may reflect a concurrent membranous
lesion
 Combined active sediment and a rapidly rising serum
creatinine, which might reflect crescentic disease that
requires more aggressive initial therapy.
Suspicion of possible renal disease unrelated to lupus
(eg, drug-induced acute interstitial nephritis).

31.  Most patients with LN have an immune complex-mediated
glomerular disease.
 Based upon clinicopathologic correlations, a LN classification
system was developed by a group of renal pathologists,
nephrologists, and rheumatologists in 2004.
 The ISN classification system divides glomerular disorders
associated with SLE into six different classes.
 Ideally, the biopsy specimen should contain at least 25
glomeruli.
 In addition, a significant percentage of patients evolve from
one class of LN to another, sometimes after therapy or
spontaneously
 However, no serum or urine marker of disease activity
provides the degree of information that is gained by
histopathology.
 Thus, classification of LN is determined by kidney biopsy.

32.  Minimal mesangial LN is characterized by mesangial immune
deposits identified either by immunofluorescence alone, or by
immunofluorescence and electron microscopy, but without
light microscopic abnormalities.
 Patients have a normal urinalysis and serum creatinine con.
 Mesangial proliferative LN is characterized by mesangial
hypercellularity or mesangial matrix expansion on LM.
 A few isolated subepithelial or subendothelial deposits may be
seen on IF or EM but no subendothelial deposits visible on
LM.
 Patients present with microscopic hematuria and/or
proteinuria; hypertension is uncommon, and NS and renal
insufficiency are virtually never seen.

34. Mild global mesangial hypercellularity within capillary loops

35.  Focal proliferative LN is defined by light microscopic
appearance of endocapillary or extracapillary
glomerulonephritis that involves <50 % of glomeruli.
 Lesions are associated with focal subendothelial deposits
on EM.
 Class III disease is further categorized depending on the
chronicity of the lesions.
 Hematuria and proteinuria are seen in almost all patients,
some have NS, HTN, and/or an elevated plasma creatinine.
 < 25% of glomeruli are affected and glomeruli show only
segmental areas of proliferation without necrosis.
 Progressive renal dysfunction is uncommon.

36. Focal endocapillary proliferative lesions on a background of focal
mesangial hypercellularity (arrow(

37.  Diffuse proliferative LN is defined by >50 % of
glomeruli displaying endocapillary with or without
extracapillary GN.
 Class IV disease is further categorized into segmental
(IV-S) and global (IV-G) depending on whether
affected glomeruli have segmental or global lesions.
 Additional subclasses of class IV disease are
categorized depending on the chronicity of the
lesions.
 Hematuria and proteinuria are present in all patients
with active disease, and NS, HTN, and renal
insufficiency are frequently observed.

38. Glomerular capillary walls are segmentally thickened by wire-loop
deposits. An intraluminal deposit forms a hyaline thrombus in one
capillary, and there is global endocapillary proliferation (arrow(

39.  Membranous LN is characterized by diffuse
thickening of the glomerular capillary wall on
LM and by subepithelial immune deposits on
IF or EM.
 Patients primarily present with NS although
hematuria and HTN may be seen.
 The plasma creatinine concentration is
usually normal or only slightly elevated.

40. There is regular thickening and rigidity of the glomerular capillary
walls accompanied by global mesangial hypercellularity

42.  Advanced sclerosing LN is characterized by
global sclerosis involving more than 90% of
glomeruli.
 It represents healing of prior inflammatory
injury, as well as the advanced stage of
chronic class III, IV, or V lupus nephritis.
 Patients display slowly progressive renal
dysfunction in association with proteinuria
and a relatively bland urine sediment.

45.  Some patients with renal disease have a histologic pattern
of injury that is indistinguishable from lupus nephritis, but
have no extrarenal symptoms, signs, or serologies
suggestive of SLE.
 ANA titers were negative or weakly positive, complement
levels were normal, and anti-DNA titers were negative.
 Other causes of glomerulonephritis were also excluded.
 All were treated with glucocorticoids with or without MMF
and CYC and, despite immunosuppression, 75% of the
patients required renal replacement therapy.
 Some patients, mostly children with lesions of class V
nephritis, initially presented with a "lupus-like" lesion and,
after a variable period, developed clinical and/or serological
features of SLE. In those cases, the glomerulonephritis
simply heralds the arrival of overt SLE

46.  In addition to the glomerulopathies, there
are three other forms of lupus renal disease:
tubulointerstitial nephritis;
vascular disease; and
drug-induced lupus

47.  In spite definition of LN according to ACR criteria when level of
proteinuria > 0.5 g / 24 hour (Tan et al., 1982)
 some Authors found that histopathological changes obtained from
renal biopsy in patients who have low level of proteinuria < 0.5
gram / 24 hour witout heamaturia or active urinary sediment with
normal kidney function and
 consider renal biopsy is mandatory for those types of patients to
improve outcome those groups are referred to silent lupus nephritis
(Mahajan et al., 2009)
 Renal biopsy is required for definitive diagnosis of LN. In the
absence of (ARF), low levels of proteinuria (below 0.5 g/24 h) have
been recommended by some to justify biopsy (Alhefny et al., 2010)
 Several studies, report that a delay in renal biopsy (and therapy) is
a strong dependent predictor of poor outcome (Fiehn et al., 2003)

49.  Renal biopsy is an important tool in assessing
patients with lupus nephritis and is often required
for definitive diagnosis of histopathological
subtypes and direction to proper treatment
(Christopher et al., 2007).
 The optimal treatment regimen in lupus nephritis
varies according to WHO class
(Hahn et al., 2012)

50.  Steroid & hydroxychloroquine
 They may not require the use of
immunosuppressants, but patients should
be monitored for deterioration in renal
parameters and may require repeated
biopsy
(Gordon et al., 2009).

51.  The Task Force Panel recommended
MMF=mycophenolate mofetyl (2–3 gm total daily
orally) or IV CYC= cyclophosphamide= endoxan,
along with glucocorticoids.
 MMF and CYC are considered equivalent based on
recent high-quality studies, a meta-analysis, and
expert opinion (Touma et al., 2011).
 Data showed good results for induction therapy
with MMF of 3 gm daily for 6 months, followed by
maintenance with lower doses of MMF for 3 years
(Dooley et al., 2011).

52.  For those with class III/IV without cellular crescents and
for those with proteinuria and a stable creatinine for
whom a renal biopsy sample cannot be obtained, both
2 gm and 3 gm MMF (cellcept 250, 500mg) total daily
doses were acceptable to the Task Force Panel,
 While a dose of 3 gm daily was favored for those with
class III/IV and crescents and for those with proteinuria
and a recent significant rise in creatinine (Hahn et al.,
2012).
 Some evidence suggests that Mycophenolic acid
(myfortic 180, 360mg) is less likely than MMF to cause
nausea and diarrhea

53. Low-dose “Euro-Lupus” CYC (500 mg IV once
every 2 weeks for a total of 6 doses), followed by
maintenance therapy with daily oral AZA. or daily
oral MMF .
High-dose CYC (500–1,000 mg/m2 IV once a
month for 6 doses), followed by maintenance
treatment with MMF or AZA
(Houssiau et al., 2010) .

54.  CYC was given monthly for 6 doses, then
quarterly for an additional 2 years, was
more effective in preventing renal flare
than the shorter 6 month regimen.
 However, the more current 3 to 6month
regimens followed by AZA or MMF
maintenance are showing good long-
term results & less gonadal failure
(Dooley et al., 2011).

55.  500–1,000 mg methylprednisolone (soluMedrol) daily
for 3 doses in combination with immunosuppressive
therapy, followed by daily oral glucocorticoids (0.5–1
mg/kg/ day), then taper to the minimal amount
necessary to control disease (Hahn et al., 2012).
 An extended follow up study has suggested benefit of
the combination of monthly IV methylprednisolone
and IV CYC over IV CYC alone (Illei et al., 2001).
 AZA treatment to induce improvement was less
effective than CYC combined with standard
glucocorticoid doses in one study (Houssiau et al.,
2010).

56.  A recent study showed that after 8 weeks of induction
treatment with either CYC or MMF, patients with LN
who showed ≥25% reduction in proteinuria and/or
normalization of C3 and/or C4 serum levels were likely
to show good clinical renal responses (Dall’Era et al.,
2011).
 Similarly, after 6 months of treatment, a decrease in
serum creatinine and in proteinuria to 1 gm/d predicts
a good long-term outcome (Mersereau and Dooley,
2010).
 Approximately 50% of SLE patients with serious LN
showed definite improvement in renal parameters
after 6 months of treatment with either MMF or CYC
and the proportion of responders increased to 65–80%
between 1-2yrs of treatment (Houssiau et al., 2010).

57.  Along with IV pulses of high-dose glucocorticoid and
initiation of oral glucocorticoids at the higher-range dosage,
1 mg/kg/day orally.
 Experts favored high-dose IV CYC for treatment of LN with
cellular crescents (Hahn et al., 2012).
 In general, the presence of crescents indicates a poorer
prognosis, even with appropriate treatment (Yu et al.,
2009).
 MMF (1 gm twice daily) is at least as effective as high doses
of CYC in crescentic class IV LN (Tang et al., 2008)

58.  Patients with pure class V LN and with Nephrotic
range proteinuria be started on prednisone (0.5
mg/kg/day) plus MMF 2–3 gm total daily dose. for 6
months resulted in improvement similar to that with
IV CYC (0.5–1.0 mg/kg IV monthly 6 doses) plus
prednisone,
(Radhakrishnan et al., 2010).

59.  Patients who improved after 6 months of either
high-dose CYC or MMF were randomized to be
maintained on either AZA 2 mg/kg/day or MMF 2
gm total daily dose.
 Prednisone up to 10 mg daily was permitted.
 Over 3 years of follow-up, MMF was statistically
better than AZA (regarding incidence of death,
ESRD, doubling of serum creatinine, and renal
flare). (Dooley et al., 2011).
 Severe adverse events occurred in significantly
more patients receiving AZA than receiving MMF.

60.  In patients who fail to respond after 6 months of treatment
with glucocorticoids plus MMF or CYC, the Task Force Panel
recommends a switch of the immunosuppressive agent from
either CYC to MMF, or from MMF to CYC, with these changes
accompanied by IV pulses of glucocorticoid 1gram for 3
days (Hahn et al., 2012) .
 In some cases rituximab can be used in patients whose
nephritis fails to improve or worsens after 6 months of one
induction therapy, or after the patient has failed both CYC
and MMF treatments (Terrier et al., 2011).
 The Task Force Panel did not reach consensus regarding the
use of calcineurin inhibitors (Cyclosporin A=sandimmune,
Tacrolimus=prograf) in this setting; however, there is
evidence for their efficacy as an induction agent and in
refractory disease (Ogawa et al., 2007).

61.  In a recent prospective trial, tacrolimus was equivalent to high-
dose IV CYC in inducing complete and partial remissions of LN
over a 6-month period (Chen et al., 2011).
 In another 4 year long prospective trial cyclosporine was similar
to AZA in preventing renal flares in patients receiving
maintenance therapy (Moroni et al., 2006).
 Combinations of MMF and calcineurin inhibitors and of
rituximab and MMF are being studied and might be considered
for those who have failed the recommended induction therapies
(Bao, 2008).
 If nephritis is worsening in patients treated for 3 months with
glucocorticoids plus CYC or MMF, the Task Force Panel
recommended that the clinician can choose any of the
alternative treatments discussed (Hahn et al., 2012).

62.  Several types of vascular involvement can occur in renal tissue of SLE,
including vasculitis, fibrinoid necrosis, thrombotic microangiopathy, and
renal vein thrombosis (Hahn et al., 2012).
 In general, vasculitis is treated similarly to LN discussed above.
 Vasculopathy is highly associated with hypertension; it is not clear
which comes first, SLE or hypertension.
 Thrombotic microangiopathy can be associated with a thrombotic
thrombocytopenia– like picture.
 The Task Force Panel recommended that thrombotic microangiopathy
be treated primarily with plasma exchange therapy (level C evidence)
(Kaplan and George, 2011).

63.  Class VI disease has a uniformly poor
prognosis for renal survival, reflecting
chronic damage;
 immunosuppressive treatment is not
recommended.
 Instead, therapies aiming to optimize blood
pressure control and stabilize protienuria
with the use of antihypertensives, ACE-I and
ARB are used to optimize renal survival
(Mangrum and Bakris, 2004).

64.  Approximately 20 % - 30% of patients with LN progress
to ESRD over a 10 year follow-up period.
 Up to 3% of cases of ESRD requiring dialysis or
transplantation, active lupus early in the dialysis
period may require treatment with CS and/or other
immuno-suppressive medication.
 Although controversial, it has been recommended
that patients with SLE should wait 6 to 12 months
while on dialysis prior to transplantation.
 Recurrence of active lupus nephritis in the transplant
occurs in 10 % to 30% of patients (West et al., 2007).

65.  MMF was preferable to CYC for patients who express a major
concern with fertility preservation, since high-dose CYC can
cause permanent infertility in both women and men (Touma
et al., 2011).
 6 months of high-dose IV CYC was associated with
approximately 17% sustained infertility in young women, and
higher rates in older women compared to 64% of those
treated with the additional quarterly doses (Hahn et al.,
2012).
 the physician should be sure that a patient is not pregnant
before prescribing MMF or MPA, and the medications should
be stopped for at least 6 weeks before pregnancy is
attempted (Hahn et al., 2012).

66.  In patients with prior LN but no current evidence of
systemic or renal disease activity, no nephritis
medications are necessary.
 Patients with mild systemic activity may be treated
with HCQ; this probably reduces activity of SLE
during pregnancy (Clowse et al., 2007).
 If clinically active nephritis is present, or there is
substantial extrarenal disease activity, the clinician
may prescribe glucocorticoids at doses necessary to
control disease activity, and if necessary AZA can
be added (Gordon, 2004)

67.  High-dose glucocorticoid therapy in patients with
SLE is associated with a high risk of maternal
complications such as hypertension and DM
(Gordon, 2004).
 MMF, CYC, and methotrexate should be avoided
because they are teratogenic in humans though AZA
is listed as pregnancy category D, cross sectional
studies have shown that the risk of fetal
abnormalities is low (Gordon, 2004).
 The dose of AZA should not exceed 2 mg/kg in a
pregnant woman.
 For patients with a persistently active nephritis
with documented or suspected class III or IV with
crescents, consideration of delivery is urgent (Hahn
et al., 2012).

68.  Rarely indicated nowadays because of
advances in patients monitoring and
availability of effective treatment, but can
be one of optional lines of therapy when
there is:-
sever lupus flare with major organ involvement
not responding to aggressive management,
sever uncontrolled hypertension and
vasculitis affecting major organs (Samadirad et
al., 2012).

69. Timing Suggested Lab. Tests Comments
Preconception
counseling
and/or first
prenatal visit
Urine analysis
Determination of proteinuria
CBC
Serum creatinine
Antiphospholipid antibodies
Anti-Ro and anti-La AB
Anti-ds DNA
Complement studies
Liver function tests
Obtain protein/creatinine
ratio, better:
24-hour urine protein
If positive, conduct weekly
fetal HR assessments from
16-24w of gestation and
every other week there after
until 32 week
Every month Urine analysis
Determination of proteinuria
Serum creatinine
If these test results are
abnormal, obtain lupus
serologies and complement
studies; consider a renal
biopsy before 32 weeks
gestation
Every trimester CBC
Anti-ds DNA - AB
Complement studies
Liver functions (for
Laboratory testing of LN patients during pregnancy

70. Pre-
Eclampsia
HELLP
Syndrome
Active Lupus
Nephritis
Timing in pregnancy After 20 wk
of gestation
After 20 wk of
gestation
All gestational ages
Complement (C3, C4) N N Typically decreased
Thrombocytopenia Absent present Present
Neutropenia Absent Absent Present
Active urine sediment Absent Absent Present
Other organ involvement Absent Absent Present
Anti-ds DNA Absent Absent Present
ANA antibodies Absent Absent Present
Anti-C1q antibodies Absent Absent Present
Abnormal liver function Absent present May be high
Serum uric acid Increased Increased (may be elevated
with reduced GFR)
Hypertension
(BP >140/90 mmHg)
present In 10–15% Variable
Elevation in creatinine
(>1.2 mg/dl)
Typically
absent
May occur in up
to 10%
Commonly present
Differentiation of Pre-eclampsia, HELLP syndrome &
Active LN

71.  During the 1950s, the 5-year survival rate among patients with lupus
nephritis was close to 0%.
 Recently, with the addition of immunosuppressive agents the 5- and
10-year survival rates are as high as 85% and 73%, respectively.
 Morbidity is related to the renal disease itself, as well as to treatment-
related complications and co-morbidities, including CVD and
thrombotic events.
 Progressive renal failure leads to anemia, uremia, and electrolyte and
acid-based abnormalities.
 Hypertension may lead to an increased risk of CAD and stroke.
 Nephrotic syndrome may lead to edema, ascites, and hyperlipidemia,
which add to the risk of CAD and the potential for thrombosis.
 Therapy with corticosteroids, cyclophosphamide, and other
immunosuppressive agents leads to increased risk of infection.
 Long-term corticosteroid therapy may lead to osteoporosis, avascular
necrosis, DM, and HTN, ……..
 Cyclophosphamide therapy may cause cytopenias, hemorrhagic
cystitis, infertility, and an increased risk of malignancy.
Mortality/MorbidityMortality/Morbidity

73. Class III/IV induction therapy

74. Treatment of class V without proliferative changes
and with nephrotic range proteinuria (>3gm/ day(.

75. Treatment of SLE patients
who are pregnant.

76. currently recommended therapeutic
regimens for the different classes of LN
(Dolff et al., 2011)

78.  Anti-DNA immune complex formation
 The pattern of glomerular injury seen in SLE is primarily
related to the site of formation of the immune deposits
 Deposits in the mesangium and subendothelial space
are proximal to the glomerular basement membrane
(GBM) and communicate with the vascular space.
 As a result, activation of complement with the
generation of the chemoattractants C3a and C5a results
in the influx of neutrophils and mononuclear cells.
 These changes manifest histologically by a mesangial or
focal or diffuse proliferative glomerulonephritis, and
 Clinically by an active urine sediment (red cells, white
cells, and cellular and granular casts), proteinuria, and
often an acute decline in renal function.

79.  Although deposits in the subepithelial space
can also activate complement, there is no
influx of inflammatory cells, since the
chemoattractants are separated from the
circulation by the GBM.
 Thus, injury is limited to the glomerular
epithelial cells and the primary clinical
manifestation is proteinuria, which is often
in the nephrotic range.
 Histologically, these patients most commonly
have membranous nephropathy.

80. Pathogenesis of lupus nephritis
Adapted from (Davidson & Aranow, Lupus nephritis, 2009)

81.  A kidney biopsy should be performed in most patients with SLE
who develop evidence for renal involvement in order to
establish the diagnosis and, determine the class of LN.
 Determining the class of lupus nephritis is important because:
 Treatment is guided by the histologic subtype (ie,WHO class, the
degree of activity and chronicity, and by complicating lesions such
as interstitial nephritis and thrombotic microangiopathy).
 The clinical presentation may not accurately reflect the severity of
the histologic findings.
 As an example, proliferative lupus may be present even if the
patient has minimal proteinuria and a normal serum creatinine.
 However, patients with proteinuria <500 mg/day and a
bland urine sediment do not need to undergo a kidney biopsy;
unlikely to have a class of nephritis that warrants
immunosuppressive therapy.

82.  Although subendothelial deposits can be
seen by IF or EM alone, the presence of
such deposits as detected by LM warrants a
combined diagnosis of class III/IV and V
disease.

84. Class I
Class II
Class III
III (A(:
III(A/C(:
III (C(:
Class IV
)IV-S) LN
)IV-G) LN
IV (A(:
IV (A/C(:
IV (C(:
Class V
Minimal mesangial LN
Mesangial proliferative LN
Focal proliferative LN (<50% of glomeruli(
active lesions
active and chronic lesions
chronic lesions
Diffuse proliferative LN (>50% glomeruli(
Diffuse segmental
Global LN
active lesions
active and chronic lesions
chronic lesions
Membranous LN†
Advanced sclerosing LN (90% globally sclerosed
glomeruli without residual activity(

85.  There is significant renal involvement (Class III, IV, or
V LN) in SLE patients with < 0.5 g proteinuria with or
without hematuria.
 These findings suggest that biopsy be strongly
considered in this patient population. (Lisa
Christopher Stine et al., 2007).
 Others have recommended biopsy only in patients
with higher levels of proteinuria (> 1000 mg/24 h) and
abnormal urine sediment (Salach and Cash,2007).
 However, several case series have suggested that
significant kidney damage may occur in the setting of
active proliferative LN without clinical signs of renal
involvement prevent end stage renal failure (Leehey
et al., 2006)

86.  Because early intervention is crucial to prevent poor
outcomes, it is imperative that kidney biopsies be
performed so that diagnoses can be made and
appropriate treatment initiated (Esdaile et al., 2010)
 Among the biopsy findings felt to be prognostic in
some studies are the presence of crescentic and
segmental lesions, global proliferative lesions (either
diffuse or focal), interstitial fibrosis, and high activity
and chronicity indices (Kashgarian, 2002).
 Several studies, report that a delay in renal biopsy
(and therapy) is a strong dependent predictor of poor
outcome (Fiehn et al., 2003)

87.  Patients receiving low-dose CYC, regardless
of initial response, were randomized for
maintenance therapy with either AZA, with a
goal of 2 mg/kg/day, or MMF, with a goal of
2 gm/day.
 Over a period of 4 years there were no
statistically significant differences in any
outcome measures, including death, renal
flares, end-stage renal disease, or doubling
of serum creatinine (Houssiau et al., 2010).

88. ,,,,,,