SLE: A Guide to Systemic Lupus Erythematosus

SYSTEMIC LUPUS ERYTHEMATOSUS
History Evolution Etiology pathopysiology Management & what is new
Karunan Kannampoyilil
Seethaprakash
Pictures by Little Darling K & Novakarun K
2014 Jan
Lupus Nephritis

SLE What is New
1.Introduction
2.History
3.Epidemiology
4.Pathophysiology
5.Pathology
6.Autoimmunity
7.Clinical features
8.Diagnosis
9.Management
10.Future

INTRODUCTION
Systemic Lupus Erythematosus (SLE) is a
Chronic,usually life-long,
potentially fatal autoimmune disease
characterized by unpredictable exacerbations & remissions
with variable clinical manifestations.

• Clinical manifestations differ from
• one patient to another
• Heterogeneous disorder
• Over lap can occur
– Tissues & cells undergo damage due to binding of auto antibodies and immune complexes.
– Altered patterns of immuno regulations producing auto anti bodies and abnormalities of cell
mediated immunology(CMI)

Precise etiology
1. unknown & remains to be defined
2. Genetic
3. Environmental
4. Hormonal factors
These factors interact to form complex relations between the host, pathogens
& the environment
Recent advances in genetic research, newly discovered genes confirm, the
preexisting concept of pathogenesis.
New biologic insights

Burden of the disease
• Twin burden of Lupus
• Physical burden of illness & it is potential seriousness
• Intense fear which accompanies the illness

Several defects of immunological components play a
role
• Ability to produce pathogenic auto antibodies
• Lack of T&B-lymphocyte regulation
• Defective clearance of autoantigens & immune
complexes

• Majority of autoantibodies are directed at intracellular
nucleoprotein particles,
• Antinuclear antibodies(ANA) 98%
• Anti-double-stranded DNA (dsDNA) antibodies are
found in 50–80%
• Auto antibodies are exclusive to lupus.

SLE
1.Introduction
2.History
3.Epidemiology
4.Pathophysiology
5.Pathology
6.Autoimmunity
7.Clinical features
8.Diagnosis
9.Management
10.Future

HISTORY
• Hippocrates (~400BC) cutaneous ulcers (herpes esthiomenos.
• Biett 1833. first clear description of lupus erythematosus
• Cazenave and Clausit. 1850s coined 'Lupus Erythemateux‘
“They made the first description of the facial rash and skin
ulceration resembling 'a bite from a wolf', from which some
think lupus (Latin for wolf) derives its name”

Eurasian wolf (Canis lupus lupus)

Lupus
Wolf mutilates it’s prey before it
eats without killing,
in the similar way the SLE does.
Ref:. Graves, Will (2007). Wolves in Russia: Anxiety throughout the ages. Detselig Enterprises.ISBN 1550593323
“They kill large prey by biting large chunks of flesh from the soft perineum area, causing massive blood loss.
Such bites can cause wounds 10–15 cm in length, with three such bites to the perineum usually being sufficient
to bring down a large deer in optimum health”

SLE
second most common human autoimmune disease in the world.
Ref: Can morbidity and mortality of SLE be improved?
Anurekha Bongu Elizabeth Chang Rosalind Ramsey-Goldman
Best Practice & Research Clinical Rheumatology Volume 16, Issue 2,
April 2002, Pages 313-332 Northwestern University Medical School,
ArthritisChicago Ave, Chicago, IL, 60611, USA.
Available online 10 June 2002.

SLE
1. SLE is the second most common autoimmune disorder (after thyroid
disease) in women of childbearing age.
2. Lupus is increasingly being recognized throughout the world's
population.
3. The incidence and prevalence of SLE varies among racial and ethnic
groups.
4. Lupus patient survival has significantly improved over the past five
decades,
5. But a three- to fivefold increased risk of death remains compared with
the general population.
6. As lupus patients survive longer, these individuals face a range of
complications from the disease itself or consequent to its treatment.
7. Emerging data from epidemiological studies underscore the importance
of incorporating race and ethnicity in understanding the risk factors
leading to the significant burden of mortality and morbidity associated
with this disease; Anurekha Bongu Elizabeth

Prevalence of SLE India
A point prevalence of 3.2 per 100 000
(95% CI = 0-6.86 per 100 000).
Ref: Prevalence of Systemic Lupus Erythematosus in India(North)
A.N. Malaviyadoi: 10.1177/096120339300200209.
Lupus April 1993 vol. 2 no. 2 115-118

INDIA - FEMALE
Majority of the sufferers are females of the
menstruating period.
It affects predominantly women in their reproductive years. The median age of onset in Indian
SLE is 24.5 years and the sex ratio (F: M) is 11:1
Ref: A Kumar J: INDIAN GUIDELINES ON THE MANAGEMENT OF SLE. Indian Rheumatol Assoc 2002 : 10 : 80 - 96

• We are still in the dark to find out a cause for
this illness but we know that it is an
autoimmune disease.
• Large number of drugs that fight against the
illness was already there in the armamentarium
and more in the pipe line.

But alas!
• Nothing found to be use full for the majority of
SLE patients
• Who’s destiny is to land in the dialysis room or
• Kidney transplant arena with end stage Kidney
failure and
• Those who escaped from suffering by reaching
at the graveyards in the young age.

Americans
Autoimmune diseases are common.
Aaffecting > 23.5 million Americans.
A Leading cause of death and disability

Unfortunate?
Unable to cut short
Treatment cost
Sufferings
Morbidity
Mortality
Their future is bleak.

Some rays of hope
Lande, Christian Goosmann, and various others
Unveiling of the pathologic
Cellular mechanism of the autoimmunity
Ref: 1. Roberto Lande, et al.Peptide Complexes in Systemic Lupus Erythematosus Neutrophils Activate
Plasmacytoid Dendritic Cells by Releasing Self-DNA.Sci Transl Med 3, 73ra19 (2011
2. Volker Brinkmann, Britta Laube, Ulrike Abu Abed, Christian Goosmann, Arturo Zychlinsky.Neutrophil
Extracellular Traps: How to Generate and Visualize Them. www.youtube.com/poyilil . Video Article
3.M. J. Shlomchik, Activating systemic autoimmunity: B’s, T’s, and tolls. Curr. Opin. Immunol.21, 626–633
(2009).

Autoimmunity
By the breakdown of tolerance to
nuclear self-antigens, which leads
to activation of autoreactive
Bcells that produce utoantibodies
against self-nucleic acids and
associated proteins.

Autoimmunity in SLE
Results from hyper reactive B cells which
initiate the T Helper/ suppressor deregulation
results in the release of neutrophils characterized
by chronic activation of plasmacytoid Dendritic
Cells (pDCs) and production of autoantibodies
against nuclear self-antigens.
Ref: L. Rönnblom, V. Pascual, The innate immune system in SLE:
Type I interferons and dendritic cells. Lupus 17, 394–399 (2008).

Organ specific expressions
These autoantibodies bind self-
nucleic acids released by dying
cells, and form immune complexes
that are deposited in different
parts of the body, leading to
detrimental inflammation and
tissue damage.

Expressions of basic defects
• This results in various autoantibody
production and deposition of
immune complex in various organs.

Sir William Osler (1903) first mention
“He described 20 young ladies with skin rashes and chest pain
resulting from inflammation of the lining of the lung (pleurisy) or
heart (pericarditis)
In addition, these patients also had kidney disease, strokes and
brain involvement severe enough to be fatal so that 18 had died
within two years from presentation”

Over the next 30 years
• Pathologic studies documented the existence of
nonbacterial verrucous endocarditis (Libman-Sacks
disease) & wire-loop lesions in glomerulonephritis.
• Kemperer and colleagues in ( 1941) autopsy – termed
collagen vascular disease
• This terminology, persists in usage now fifty years after
its introduction

THE MODERN ERA
• Hargraves (1948) discovery of LE cell
• Friou, 1950s immunofluorescent test for ANA.
• Isenberg. Recognition of antibodies to DNA.
• The description of antibodies to extractable nuclear
antigens (nuclear ribonucleoprotein (nRNP, Sm, Ro, La).
• Hughes. Anticardiolipin antibodies.

Two other major advances in the
modern era
1. Development of animal models of lupus
The first animal model of systemic lupus was the F1 hybrid New Zealand Black/New
Zealand White mouse.16

RECOGNITION OF THE ROLE OF GENETICS
• Leonhardt in 1954 - familial occurrence
• studies by Arnett and Shulman at Johns
Hopkins.

Finally, no discussion of the history of lupus is complete
without a review of the development of therapy
• Payne(1894) quinine in lupus.
• Four years later, the use of salicylates in conjunction
with quinine.
• It was not until the middle of this century that
adrenocorticotrophic hormone and cortisone by Hench
revolutionized SLE treatment.

INDIA
• First case 1965 , Then a series of eight cases, till 1969.
• 1968- clinical immunology laboratory in New Delhi
• SLE was extensively studied and reported

• Based on these data, the present report
describes the clinical and laboratory
characteristics of 1366 SLE patients seen in
different regions of India
Ref A Kumar , INDIAN GUIDELINES ON THE MANAGEMENT OF SLE, J Indian Rheumatol
Assoc 10 : 80 – 96: 2002.
Ref:Malaviya AN, Chandrasekaran AN, Kumar A, Sharma PN. Occasional series-Lupus
round the world: systemic lupus Erythematosus in India. Lupus 1997; 6: 690-700.

EPIDEMIOLOGY
Incidence
• 2nd most common autoimmune disease in the world*
• Gen.population- 20 to 150 cases per 100,000 .
• Tripled - last 40 years
• Asia ,Europe & America - 1 to 25 per 100,000
• Geographic - more common in urban than rural.
*Ref: Can morbidity and mortality of SLE be improved? Anurekha B, Elizabeth C ,Rosalind R. Best Practice & Research Clinical Rheumatology 16: 2: 313-332, April
• PREVALENCE
– Higher- Asians, Afro-Americans, Afro-Caribbeans & Hispanic Americans compared with Americans of
European decent in US &Among Asian Indians compared with Caucasians in Britain
– 14-60 per lakh-highest in sweden
– Less in Blacks in Africa.
– Point prevalence in india is 3 per 1 lakh.
Rus,1. V, Maury, EE, Hochberg, MC. The epidemiology of systemic lupus erythematosus. In: Dubois' Lupus Erythematosus, Wallace, DJ, Hahn, BH (Eds), Lippincott Williams and Wilkins, Philadelphia 2002.
2.Peschken CA, Esdaile JM. Rheumatic diseases in North America's indigenous peoples. Semin Arthritis Rheum 1999; 28:368.
3.M. Epidemiology of systemic lupus erythematosus. Best Pract Res Clin Rheumatol 2002; 16:847.

CASE REPORT
• NH, a previously healthy 11 yr old boy
• H/o fever- 2 wks
• generalized fatigue ill-health.
• O/E - sick ,febrile (temp 39* C).
• PR- 110/ mt
• BP 110/60 mmHg
• No arthrlagias, myalagias or skin rash.
• Systemic examination - normal. No obvious
focus of infection was found

• . CBC - pancytopenia with
• WBC count of 1.9 x10*9/l, (neutrophils 0.8x10*9/l)
• Hb 8.9 g/l
• PC - 125x10*9/l.
• ESR - 117 mm/1st hour
• C R P normal
• ALT = 150 IU/l and AST =350 IU/l

• persistent fever –
• deteriorating clinical condition
• no identifiable focus of infection,
• treated empirically with IV cefotaxime
• and gentamycin,
• No noticeable bene f i t

• . A week later
• extensive erythematous rash on the malar area
of face,limbs ,palms and soles.
• developed oral ulcers and bleeding from the
buccal mucosa.
• he complained of generalized body aches,
there were no objective signs of any bone or
joint involvement

• . At this stage
• possibility of SLE was considered
• confirmed with findings of conspicuously raised
• ANA (2647.6 IU/ml)
• raised double stranded DNA antibody (2783.3 IU/ml)
titers.
• complement levels were also significantly reduced (C3
0.24g/l, C4 < 0.1 g/l)
• Serum protein electrophoresis showed polyclonal rise in
gammaglobulins.

• given pulse therapy with IV
methylprednisolone, 20 mg/kg/day for three
days.
• IV Immunoglobulin, 400 mg/kg for five days.
• The response was dramatic

• He soon became afebrile
• Erythematous rash disappeared-
• stopped complaining of generalized aches and
looked well
• was started on methotrexate and oral
glucocorticoid therapy (prednisolone 20
mg/day).

• Until the writing of this report (one year since
the diagnosis)
• The child continues to remain in remarkable
• Remission on a daily maintenance dose of
Prednisolone 10 mg on alternate days

• Q: Which is the most common infection
associated with SLE?
• Q:which is the parasitic infestation associated
with SLE?
• Q:which are the viral infections associated with
SLE?

SLE in Indian Men: Analysis of the Clinical and Laboratory Features with a Review of the
Literature. Ira Pande,A.N. Malaviya,N.G. Sekharan,S.S. Kailash,S. Uppal,A. Kumar,Clinical
Immunology and Rheumatology Unit, Department of Medicine
Abstract: Data on the clinical and laboratory profile of 39 male lupus
patients has been analysed. An attempt has been made to (1) delineate
the pattern of SLE in Indian males, (2) compare it with that reported in
the world literature, (3) find out differences, if any, between male
children and adults with the disease, and (4) compare it with our
previously published data on Indian females with SLE. Several
important points were brought out in this study.
A. 1. SLE in Indian males has an earlier age of disease onset,
2.a higher incidence of mucocutaneous and renal involvement and
3. a lower incidence of neuropsychiatric, gastrointestinal and
hematological disease in comparison to those published from the
developed countries.
B. 1. Leucopenia and lymphopenia, a reflection of disease severity, occur
significantly more in male children compared with adults.
2.Thrombocytopenia is exclusively noted in adult males and virtually
non-existent in children.
3. male patients overall have a less severe form of the disease in
comparison with their female counterpart,
as was evident by significantly less patients with hypocomplementemia,
diffuse proliferative lupus nephritis and psychosis.
Finally, a higher frequency of infection, particularly tuberculosis, was seen
in male patients, which was the cause of death in some.

Case Report
Young Male with Systemic Lupus Erythematosus Presenting with
Sensorineural Deafness with Immune Suppression Induced Miliary
Tuberculosis
S Kundu, R Mitra, S Chatterjee, A Ghosh OCTOBER 2011 VOL. 59
Abstract
A 32 year male presented with deafness and other classical symptoms
suggestive of SLE. Subsequent serological investigations confirmed the
diagnosis. Renal biopsy showed the presence of SLE induced Grade V
nephropathy. Patient was started on NIH protocol for lupus nephritis on
which he was doing well. After two years, he presented with symptoms
of miliary tuberculosis and was started on ATD. Subsequently, he
developed ATD induced hepatotoxicity and had to be switched over to
Inj. Streptomycin containing regimen. We thought to share this clinical
experience, as we found it a challenge to manage tuberculosis in such a
setting, where a fine balance had to be maintained between
immunosuppression for SLE and therapy of TB, and an ototoxic drug
had to be used in a patient with deafness induced by SLE.

Systemic Lupus Erythematosus in Male Masquerading as Pyrexia of Unknown Origin
Parvaiz A Shah, Hamed B Khan, Javed A Basu, Ghulam H Bardi, Tajamul H Bhat and Iffat Hassan
Egyptian Dermatology Online Journal 6 (1): 15Postgraduate Departments of Medicine, Dermatology, STD&
Leprosy, Government Medical College and Associated SMHS Hospital, Srinagar, Kashmir (J&K), 190010,
India. April 30, 2010
Summary :Systemic lupus erythematosus (SLE) is known to present with diverse
clinical features. The disease has a predilection for females. Here, we report a
case of SLE in a male patient masquerading as pyrexia of unknown origin and
culminating in multi-organ failure. The case is being reported for its unusual
presentation and rarity in male gender. High index of suspicion is required for
early diagnosis of the disease so as to avoid delay in initiation of treatment
and minimise mortality associated with the illness
“Men and women with SLE might have too much estrogenic and too little androgenic
hormone, shifting their immune system toward increased responses. Prolactin levels are
elevated in some individuals with SLE and may increase disease activity.”*
*Walker S.E., McMurray R.W., Houri J.M., et al: Effects of prolactin in stimulating disease
activity in systemic lupus erythematosus. Ann N Y Acad Sci 1998; 840: 762-772.

Klinefelter syndrome with systemic lupus erythematosus in an Indian man
A. Bertha,E. Tjandrajana, VM Srivastava, R. Subramanian,J. Mathew.
Clinical Immunology and Rheumatology Department, CMC, Vellore, India
Abstract
Previously, cases of systemic lupus erythematosus (SLE) and Klinefelter syndrome
(KS) in men have been reported in Western populations. We report the case of a 30-
year-old man from southern India with known infertility who was diagnosed to have
SLE and KS by fluorescence in-situ hybridization, as routine karyotype cultures failed.
The diagnosis has implications in management and highlights the need for strong
clinical suspicion and laboratory confirmation of KS by molecular methods when
suspected in all men with SLE. Quicker, long-term remission and genetic counseling
of such individuals can help in better management and coping with this chronic,
potentially fatal disease.
Lupus (2010) 19, 870—871.

Turner's syndrome women with SLE in a pedigree multiplex (46,X,del(X)(q13))
C M Cooney,G R Bruner,T Aberle,B Namjou-Khales,L K Myers,L Feo
Systemic lupus erythematosus (SLE) disproportionately affects
women. Recent work demonstrates that men with Klinefelter's
syndrome (47,XXY men) have a similar risk of developing SLE as do
women. We present an unusual African-American family with two
SLE-affected individuals in which one of the patients with SLE also
has Turner's syndrome (46,X,del(X)(q13)). Although not definitive,
this family raises interesting questions regarding the function of
genes located on the X chromosome in the development of SLE.
The paucity of case reports documenting the overlap of SLE with
Turner's syndrome while there is an association of male SLE with
Klinefelter's syndrome suggests a lower risk of SLE in women with
Turner's syndrome. These observations are consistent with a gene
dose effect at X with two X chromosomes (46,XX or 47,XXY)
conferring higher risk and one X chromosome (46,XY or 45,XO)
conferring lower risk of SLE.

GENDER
• F:M Children 3:1, Adults (Fertile)-7:1 to 15:1,PMW -
8:1
• Genes - X-chromosomes (IRAK1, MECP2, TLR7)
• Gene dose effect- XXY (Klinefelter)increased 14-fold
in men with SLE compared with the general
population of men,
• XO (Turner's syndrome)-under represented in
women
X-inactivation, imprinting, X or Y chromosome genetic modulators,
differential methylation of DNA & acetylation of histones bound
to DNA, intrauterine influences, chronobiologic differences,
pregnancy, and menstruation

Age at onset
Median ages at diagnosis
White F-7to50yrs M-50to59
Black F-15 to 44 M 45 to 64
0 to 16yrs 16 to 55 yrs >56yrs

ETIOLOGY
• Unknown
• Genetic
• Hormonal
• Immunologic
• Environmental factors.

GENETIC FACTORS
• High concordance rate (14 to 57 percent) in monozygotic twins.
• Relatives (5-12 %) had disease& anti-C1q, anti-cardiolipin antibodies, C3,C4 abnormal
• SLE chidren’s mothers (27%) had a positive test for ANA
• Genome-wide association studies (GWAS)- 30 to 40 gene loci.
Ref:1.Block SR, Winfield JB, Lockshin MD, et al. Studies of twins with systemic lupus erythematosus. A review of the
literature and presentation of 12 additional sets. Am J Med 1975; 59:533.
2.Deapen D, Escalante A, Weinrib L, et al. A revised estimate of twin concordance in systemic lupus erythematosus.
Arthritis Rheum 1992; 35:311.
3.Arnett FC, Reveille JD, Wilson RW, et al. Systemic lupus erythematosus: current state of the genetic hypothesis. Semin
Arthritis Rheum 1984; 14:24.

Congenital heart block,
Due to anti-Ro and anti-La,
is most often identified between 18 and 30 weeks gestation*
*Aust N Z J Obstet Gynaecol. 1999 Feb;39(1):26-7.
Recurrent miscarriage, congenital heart block and systemic lupus erythematosus.
Julkunen H, Kaaja R, Siren MK.
Abstract
We report the obstetric history of a woman, who between 15 spontaneous abortions, gave birth to a child with
congenital heart block. She later developed systemic lupus erythematosus, had antibodies to SS-A/Ro and
SS-B/La but was repeatedly negative for antiphospholipid antibodies.
One study from India reported a 40% prevalence of ACL among women with recurrent pregnancy loss.WHO
Velayuthaprabhu S, Archunan G. Evaluation of anticardiolipin antibodies and antiphosphatidylserine antibodies
in women with recurrent abortion. Indian Journal of Medical Sciences 2005;59:347–352.

Rapid progression of atrioventricular nodal blockade in a patient
with systemic lupus Erythematosis
Makaryus JN, Catanzaro JN, Goldberg S, Makaryus AN.
Am J Emerg Med. 2008 Oct;26(8):967.e5-7.
Abstract; Systemic lupus Erythematosis (SLE) is a multisystem disorder with
numerous potential adverse effects on the cardiovascular system. These
complications likely develop in most patients with SLE at some time during
the course of their disease, in part due to the decreased mortality associated
with SLE as a result of modem medical management. Conduction
disturbances have been reported in the literature to occur primarily from the
progression of SLE and secondarily from pharmacotherapy used to treat SLE
and may first be evident on the electrocardiogram in the emergency
department (ED) setting. Electrocardiogram abnormalities such as borderline
first-degree heart block may be clues to more significant cardiac disease
brought upon by years of chronic inflammation, myocarditis, vasculitis, and
fibrosis that are often the result of longstanding autoimmune disease. It is
essential that patients with autoimmune disease be screened carefully in the
ED setting for underlying myocardial disease, particularly given the increased
potential for atherosclerosis, ischemia, arrhythmias, and myocardial
conduction defects in these patients.

• Genetic factors confer the highest hazard ratios of 5 to 25.
• Deficiencies of the complement components C1q
(required to clear apoptotic cells) C 4A and B, C2, or the
presence of a mutated TREX1 gene (encodes the 3 prime
repair endonuclease1 enzyme that degrades DNA).
• The most common genetic predisposition-MHC.

• MHC - Genes for antigen presenting molecules
(class I -HLA-A,B, &-C and class II HLA molecules
[HLA-DR, -DQ, & DP]).
• MHC also contains genes- complement
components, cytokines, & heat shock protein.
• Predisposing loci- DR2 &DR3, are associated
with HR of approximately 2, but the region is
complex and involves multiple genes across the
entire 120-gene region in multiple ethnic groups

Genome-wide studies of up to 500,000 single-nucleotide polymorphisms (snps) have
identified at least 30 and perhaps up to 50 genetic associations for SLE

OTHER GENES
• Innate immunity (IRF5, Stat4, IRAK1, TNFAIP3,
SPP1), are associated with interferon alpha (IFNa)
pathways.
• Overexpression of IFNa-induced genes is found-
peripheral blood cells of 60% Lupus
• Polymorphisms in STAT4, PTPN22&IRF5 HR or
increased sensitivity to IFN-a .

• Furthermore, STAT4 and IRF5 may have additive
effect genes involve lymphocyte signaling
(PTPN22, OX40L, PD-1, BANK-1, LYN, BLK),
• Plays a role in activation or suppression of T/B
cell activation/survival.
• Clearance of immune complexes ( C1q, C4 &C2 ,
Fc gammaRIIA, RIIA and RIIIB, CRP, and integrin
alpha M [ITGAM]).
• IL-10 is conferred by a variation in gene copy
number rather than by different alleles eg, Fc
gamma R3&C4

IN SUMMARY
Except for the rare TREX1 mutation or deficiencies of
early components of complement, there is not a single
gene polymorphism that creates high risk.
Thus, a combination of susceptibility genes
OR
presence of susceptibility genes + absence of protective
genes (such as TLR5 polymorphism or loss-of-function
PTPN22 variant) are required to "achieve" enough
genetic susceptibility to permit disease development

• In addition to genome-encoded susceptibility
genes epigenetic modifications are likely to be
important in pathogenesis .
• Hypomethylation of DNA which influences
transcription into protein.
• Hypomethylation likely affects specific genes.
• The influence of micro RNAs (miRNA) on
transcription of several predisposing genes
identified

SINGLE NUCLEOTIDE POLYMORPHISM IN SLE
RISK GENES
• SNP in the third intron of STAT4 (which
predisposes to both rheumatoid arthritis and to
SLE in several ethnic groups) increases risk for
anti-DNA antibodies, nephritis and the
antiphospholipid syndrome .
• SNPs associated with LYN decrease risk for SLE
susceptibility and for hematologic manifestations
in European-American cohorts.

• A CRP-A allele is associated with SLE nephritis
but is inversely correlated with arthritis .
• Polymorphism of Fc gamma RIIa associated
with low binding of immune complexes
predisposes to lupus nephritis

• A coding variant of the ITGAM gene is associated with
the development of renal disease, discoid rash and
“immunological manifestations” in patients with
systemic lupus erythematosus with European
ancestry
• Stratification by disease phenotypes may be of
benefit in genetic analyses of molecular
pathogenesis.
• A GWAS of SLE patients identified several loci of
particular interest
• But none of the SNPs were strongly associated with
SLE in case-control analysis.

• Nephritis (2q34),
• Hemolytic anemia (11q14),
• Discoid lupus and thrombocytopenia (11p13),
• Vitiligo (17p12);
• production of certain autoantibodies (eg, anti-
ds DNA [19p13.2])
• Increased risk for end stage renal disease

HORMONAL FACTORS
• Immunoregulatory function of estradiol, testosterone,
progesterone, DHEA, and pituitary hormones, including
prolactin, has supported the hypothesis that they
modulate the incidence and severity .
As examples:
• Estrogen-containing contraceptive- associated with a
50% risk(age ≤10 years) orPMW
• SLE has been observed in some males with Klinefelter's
syndrome

• Altered sex hormone levels may predispose
SLE
• In women, plasma levels of the following
hormones are decreased:
testosterone,
progesterone, and
dehydroepiandrosterone (DHEA),
while estradiol and prolactin are increased.
• Breast feeding may decrease risk of
developing SLE

ROLE OF ESTROGEN IN SLE
• Stimulates thymocytes, CD8+ and CD4+ T cells, B
cells, macrophages
• Release of certain cytokines (eg, interleukin-1)
• Expression of HLA & endothelial cell adhesion
molecules (VCAM, ICAM)
• Increased macrophage proto-oncogene
expression and enhanced adhesion of peripheral
mononuclear cells to endothelium

OTHER HORMONES
• Progesterone downregulates T cell proliferation
and increases the number of CD8 cells
• while lupus flares have been associated with
hyperprolactinemia
• Progesterone & high levels of estrogen promote
a T cell response, which favors autoantibody
production

• Increased incidence of thyroid disease.
• Abnormalities of the hypothalamus-pituitary-
adrenal axis
• Patients appear to have an abnormal reaction
to stress characterized by a heightened
response to human corticotropin releasing
hormone (hCRH)

Thyroid disorders in systemic lupus erythematosus
Ann Rheum Dis. 1986 July; 45(7): 579–583.PMCID: PMC1001940
K L Goh and F Wang
Abstract
Of 319 patients with systemic lupus erythematosus (SLE), nine had
thyrotoxicosis, three had hypothyroidism, and two had thyroiditis.
This prevalence seems greater than that of similar thyroid disorders
seen in the general population. It is suggested that patients with
autoimmune thyroid disorders may develop SLE or vice versa. This
association requires confirmation by prospective study

Thyroid disease in systemic lupus erythematosus
and rheumatoid arthritis
A. T. Y. Chan,Z. Al‐Saffar , C. Bucknall
September 18, 2000.
We determined the degree of overlap between
autoimmune thyroid disease and two
non‐organ‐specific autoimmune diseases,
systemic lupus erythematosus (SLE) and
rheumatoid arthritis (RA). Both SLE and RA are
commonly encountered in our out‐patient
practice and were chosen because of their
clinical relevance.
Sixty‐nine SLE and 64 RA patients fulfilling the
American Rheumatism Association criteria for
SLE [1] and RA [2] were selected for this study.
Patients from both groups were found not to
be in a flare of their disease based on the SLE
disease activity index (SLEDAI) for the SLE
group and joint scores/acute‐phase response
for the RA group.
All patients had thyroid function tests performed,
which included the measurement of
thyroid‐stimulating hormone (TSH) and
thyroxine (T4) and/or total triiodothyronine (T3).
Thyroid peroxidase antibody (TPO Ab) was also
measured in all patients. The results are
summarized in Table 1⇔.

Thyroid disease in systemic lupus
erythematosus and rheumatoid arthritis
SLE patients RA patients
Number of patients 69 64
Female:male ratio 33.5:1 10.7:1
Thyroid dysfunction 17 (24.6%) 7 (10.9%)
TPO Ab‐positive 16 (23.2%) 7 (10.9%)
Hypothyroid 12 (17.4%) 6 (9.4%)
TPO Ab‐positive 12 (17.4%) 4 (6.3%)
Clinical hypothyroidism 3 (4.3%) 2 (3.1%)
TPO Ab‐positive 3 (4.3%) 1 (1.6%)
Subclinical hypothyroidism 9 (13.0%) 3 (4.7%)
TPO Ab‐positive 9 (13.0%) 4 (6.3%)
Hyperthyroid 4 (5.8 %) 1 (1.6%)
TPO Ab‐positive 2 (2.9%) 1 (1.6%)
Clinical hyperthyroidism 2 (2.9%) 0
TPO Ab‐positive 2 (2.9%) 0
Subclinical hyperthyroidism 2 (2.9%) 1 (1.6%)
TPO Ab‐positive 0 1 (1.6%)
Sick euthyroid disease 1 (1.5%) 0
TPO Ab‐positive 0 0
Euthyroid 52 (75.4%) 57 (89.1%)
TPO Ab‐positive 2 (2.9%) 2 (3.1%)

Autoimmune thyroid disease in systemic lupus erythematosus
D Pyne,
D A Isenberg
+Author Affiliations
Centre for Rheumatology, University College London, Arthur Stanley House, 4th Floor, 40–50 Tottenham Street, London
W1P 9PJ, UK
Correspondence to:
Dr Pyne
Accepted 30 May 2001
Abstract
Background: The reported prevalence of autoimmune thyroid disease (3.9–24%) and antithyroid antibodies (11–51%)
in SLE varies considerably. Early reports were mainly based on short term studies of small cohorts.
Objective: To report the prevalence of autoimmune thyroid disease and thyroid antibodies in 300 patients with SLE,
followed up at our centre between 1978 and 2000, by a retrospective analysis of case notes.
Results: The prevalence (5.7%) of hypothyroidism in our cohort was higher than in the normal population (1%), while
that of hyperthyroidism (1.7%) was not significantly different. Overall 42/300 (14%) of our cohort had thyroid
antibodies, rising to 15/22 (68%) in the subgroup who also had thyroid disease (p<0.001). Both antimicrosomal
and antithyroglobulin antibodies were detected. The antibodies were found in equally high frequency in the
hyperthyroid subgroup (80% patients), whereas in the hypothyroid subgroup antimicrosomal antibodies were
more frequent than antithyroglobulin antibodies (64% v 41%). There was no significant difference in the frequency
with which antimicrosomal or antithyroglobulin antibodies were detected between the hyperthyroid and
hypothyroid subgroups (p>0.2).
Conclusion: Our patients with SLE had a prevalence of hypothyroidism, but not hyperthyroidism, greater than that of
the normal population. The presence of either condition was associated with a higher frequency of both
antimicrosomal and antithyroglobulin antibodies.

Lupus Nephritis in a Child with Type I Diabetes Mellitus
Sebahat Tülpar1M. Hakan Poyrazoğlu1, Tahir E. Patıroğlu2,Mustafa Kendirci3,Funda Baştuğ1, Zübeyde
Gündüz1, İsmail Dursun4 and Ruhan Düşünsel1
4Kayseri Research and Education Hospital, Department of Pediatric Nephrology,
Erciyes University School of Medicine, Kayseri, Turkey
Patients with type 1 diabetes (T1D) are at
increased risk for developing other
autoimmune diseases, most commonly
autoimmune thyroiditis and celiac disease.
Few reports have described the association of
systemic lupus erythematosus and T1D in the
literature.
To the best of our knowledge, this is the first
report of lupus nephritis in a child with T1D.

IMMUNE ABNORMALITIES
• Remains unclear- primary- secondarily induced.
• A disease with abnormalities in immune
regulation secondary to a loss of self tolerance.
• Thus, affected patients are no longer totally
tolerant to all of their self-antigens-develop an
autoimmune response .
• The mediators are autoantibodies + immune
complexes+ antigens
• Autoantibodies may be present for years before
the first symptom of disease appears

SLE SYMPOSIUM
08 12 2011
1.Introduction
2.History
3.Epidemiology
4.Pathophysiology
5.Pathology
6.Autoimmunity
7.Clinical features
8.Diagnosis
9.Management
10.Future

Pathogens and cell necrosis alert innate immunity.
Anders H JASN 2010;21:1270-1274
©2010 by American Society of Nephrology

Stimulation of TLRs by PAMPs initiates signaling
cascades that involves a number of proteins, such
as MyD88, TRIF and IRAK
These signaling cascades lead to the activation of
transcription factors, such as AP-1, NF-κB and
IRFs inducing the secretion of pro-inflammatory
cytokines and effector cytokines that direct the
adaptive immune response
Medzhitov R. et al.A human homologue of the Drosophila Toll protein
signals activation of adaptive immunity. Nature, 388(6640):394-7. 1997.

• Self-antigens that are recognized are presented
primarily on cell surfaces
• particularly by cells that are activated or
undergoing apoptosis,
• where intracellular antigens access cell
surfaces where they can be recognized by the
immune system
• To form immune complexes, antigens have to
leave, versus be “released from”, cells.

• Phagocytosis and clearing of immune
complexes, of apoptotic cells, and of necrotic
cell-derived material are defective in SLE,
allowing persistence of antigen and immune
complexes .
• B cells/plasma cells that make autoantibodies
are more persistently activated and driven to
maturation by B cell activating factor (BAFF,
also known as B lymphocyte stimulator, BLyS)
and by persistently activated T helper cells
making B-supporting cytokines such as IL-6
and IL-10.

• BAFF (BLyS), serum levels - are elevated
promotes formation and survival of memory B
cells and plasmablasts.
• This increased autoantibody persistence is not
downregulated appropriately by anti-idiotypic
antibodies, or by CD4+CD25hi-Foxp3+
regulatory T cells, or by CD8+ suppressor T
cells.

• Antibody/antigen complexes, particularly those
containing DNA or RNA/proteins.
• Activate the innate immune system via TLR-9/ TLR-7.
• Dendritic cells are activated and release type 1
interferons and TNF-alpha.
• T cells release IFN-gamma, IL6, IL10, while NK and T
cells fail to release adequate quantities of TGF-beta.
• These cytokine patterns favour continued
autoantibody formation.

THE INNATE IMMUNE SYSTEM
• Activated by infections (bacteria or RNA/ DNA-
containing viruses).
• Thus both innate & adaptive immunity conspire
to continually produce autoantibodies;
• That response is regulated for a few years;
• If regulation fails, clinical disease results.

A key early event that triggers
autoimmunity in SLE is the
chronic innate activation of pDCs
to secrete type I interferons (IFNs).

IFNs
High levels of IFNs induce an unabated
differentiation of monocytes into Dendritic cells
that stimulate autoreactive B and T cells, and
lower the activation threshold of autoreactive B
cells, thereby promoting autoimmunity in SLE.
Ref: A. N. Theofilopoulos, R. Baccala, B. Beutler, D. H. Kono, Type I interferons (a/b) in immunity
and autoimmunity. Annu. Rev. Immunol. 23, 307–336 (2005).
M. J. Shlomchik, Activating systemic autoimmunity: B’s, T’s, and tolls. Curr. Opin. Immunol.21,
626–633 (2009).

B cell hyperactivity ("hypervigilant")
• hyperactive ("hypervigilant") immune system
that attacks a person's own protein as if it were
foreign matter.
• One reason for this is poor adrenal function.
Adrenal steroids modulate (slow down) the
immune system:
• when there is not enough of these steroids the
immune system goes berserk.

B-cell Disregulation
This contributes to the disregulation of the B-cell: increased levels of IFN-a differentiate
B-cells into antibody-producing plasmocytes and upregulates B-cell survival factors such
as BAFF.
Image taken from Barrat and Coffman 2008
Additionally, recent identification of a genetic linkage of an allele that suppresses B-lymphocyte
kinase levels in SLE emphasizes the importance of regulation of B cell proliferation and tolerance

B Cell Maturation Antigen Deficiency Exacerbates Lymphoproliferation and
Autoimmunity in Murine Lupus
J Immunol. 2011 Jun 1;186(11):6136-47. Epub 2011 May 2.
Chao Jiang*,1, William M. Loo*,1, Erin J. Greenley*, Kenneth S. Tung†‡ and Loren D. Erickson*‡
Abstract: Systemic lupus erythematosus and its preclinical lupus-prone mouse models are autoimmune disorders
involving the production of pathogenic autoantibodies. Genetic predisposition to systemic lupus
erythematosus results in B cell hyperactivity, survival of self-reactive B cells, and differentiation to
autoantibody-secreting plasma cells (PCs).

BCMA/BAFF/B Cell
• B Cell Maturation Antigen Deficiency .
• Enhanced BAFF expression leads to B cell hyperplasia and
autoimmunity
• BAFF –a cytokine implicated in the survival and maturation of
peripheral B lymphocytes And T & B cell activation.
• BAFF binds to 3 different receptors: TACI, BCMA and BAFF-R, whose
expression is restricted to B & T lymphocytes.
• Elevated BAFF levels have been detected in the serum of SLE
patients

[BAFF: A regulatory cytokine of B lymphocytes
involved in autoimmunity and lymphoid cancer].
[Article in Spanish]
Reyes S LI, León B F, Rozas V MF, González J P, Naves P R.
Source
Instituto de Ciencias, Clínica Alemana, Facultad de Medicina, Universidad del Desarrollo.
Abstract
BAFF (B cell activating factor belonging to the TNF family) is a cytokine implicated in the
survival and maturation of peripheral B lymphocytes and T and B cell activation. BAFF
binds to three different receptors: TACI, BCMA and BAFF-R, whose expression is restricted
to B and T lymphocytes. BAFF and BAFF-R-deficient mice show a dramatic loss of
peripheral B lymphocytes and a severely reduced immune response. In contrast, an
enhanced BAFF expression leads to B cell hyperplasia and autoimmunity in mice. In vivo,
administration of soluble decoy receptors for BAFF effectively decreases disease
progression in various autoimmune mouse models. These evidences render BAFF as a
potentially new therapeutic target. Elevated BAFF levels have been detected in the
serum of patients with autoimmune diseases, such as Systemic Lupus Erythematosus,
rheumatoid arthitis, Sjögren's syndrome, lymphoid cancers and HIV infection. In
addition to BAFF receptors, malignant B cells abnormally express BAFF, which attenuates
apoptosis through both autocrine and paracrine pathways. The data suggest that an
increase in the expression of BAFF induces an enhanced B and T cell activation and the
survival of pathologically active B cells. In this article, we review and discuss the
participation of BAFF and its receptors in the immune response and its involvement in
immunodeficiency, autoimmunity, infections and lymphoid cancers as well as the
currently investigated therapies using BAFF antagonists in the treatment of these
diseases.

CLINICAL IMPLICATIONS OF BASIC
RESEARCH
• Thus, identify the ability of neutrophils to activate pDCs through the
release of NETs and suggest that a dysregulation of this pathway
drives chronic pDC activation and autoimmunity in SLE.
Recent studies, such as those by Lande et al. @ and Garcia-Romo et
al., have pushed the neutrophil to the forefront of the pathogenesis
of SLE and have provided insight into how the implicated
biochemical and cellular events are linked.
Ref: CLINICAL IMPLICATIONS OF BASIC RESEARCH
Systemic Lupus Erythematosus and the Neutrophil
Xavier Bosch, M.D., Ph.D.
N Engl J Med 2011; 365:758-760August 25, 2011

The ability of neutrophils to ingest and kill bacteria and fungi
is an important component of innate immunity
The microbicidal prowess of human neutrophils emanates
from oxidative and nonoxidative mechanisms
The former results from activation of an enzyme complex that
oxidizes NADPH to produce copious amounts of superoxide
whose dismutation yields hydrogen peroxide, which can form
stronger oxidants by reacting with myeloperoxidase .

Casting NETs for microbes
• Even death doesn’t stop a neutrophil from
battling pathogens, as Fuchs et al.
• The infection-fighting cells often launch a
neutrophil extracellular trap (NET), a mesh of
DNA and enzymes that snares and kills bacteria
and fungi.
• The authors show that NET release involves a
unique type of cellular self-sacrifice and depends
on reactive oxygen species (ROS).

Neutrophil Extracellular Traps (NETs)
• Sera of SLE patients immunogenic complexes
composed of neutrophil-derived antimicrobial
peptides (LL37,HNP-1,2,3) and self-DNA.
• These complexes were produced by activated
neutrophils in the form of web-like structures
known as neutrophil extracellular traps (NETs)
and efficiently trigger innate pDC activation via
Toll-like receptor 9 (TLR9).

NETOSIS
It is proved that self-DNA in immune complexes of SLE patients contains
Neutrophil antimicrobial peptide LL37 and HNP.
These antimicrobial peptides were required for self-DNA to trigger TLR9 in
pDCs by forming complexes with the DNA that is protected from
extracellular degradation.
Such immunogenic self-DNA–antimicrobial peptide complexes were released
by dying neutrophils undergoing NETosis,
a cell death process in which activated neutrophils extrude large amounts of
nuclear DNA into the extracellular space in the form of web-like structures
called NETs

• The precursor of LL-37 is a 19.3-kDa prepropeptide
which, after losing its signal sequence, is called hCAP-
18
• The cathelin domain of hCAP-18 places it within the
cathelicidin family .
• Like other cathelicidins found in porcine, bovine,
rabbit , and mouse , neutrophils, hCAP-18’s cathelin
domain is highly conserved and precedes the domain
that encodes an antimicrobial peptide.
• Human hCAP-18 is expressed constitutively within
neutrophils and the testes and is inducibly
expressed by keratinocytes .

Neutrophil Extracellular Traps (Spiderman)

Bacteria in Spidernet SEMS view

NET Video
Neutrophil Extracellular Traps: How to
Generate and Visualize Them
Volker Brinkmann, Britta Laube, Ulrike Abu Abed, Christian
goosmann, Arturo Zychlinsky
Core Facility Microscopy, Max Planck Institute
for Infection Biology
Cellular Microbiology, Max Planck Institute for
Infection Biology 02/24/2010

VICIOUS CYCLE
• SLE patients were found to develop autoantibodies to
both the self-DNA and antimicrobial peptides in NETs
• Indicating that these complexes could also serve as
autoantigens to trigger B cell activation
• Circulating neutrophils from SLE patients released more
NETs than those from healthy donors.

APOPTOSIS
Similarly apoptosis the cell debris are
removed with out any immunological
reactions.
Ref:Hallmarks of the apoptotic and necrotic cell death process.(Pic)
Apoptosis includes cellular shrinking, chromatin condensation and margination
at the nuclear periphery with the eventual formation of membrane-bound
apoptotic bodies that contain organelles, cytosol and nuclear fragments and are
phagocytosed without triggering inflammatory processes.The necrotic cell swells,
becomes leaky and finally is disrupted and releases its contents into the
surrounding tissue resulting in inflammation. Modified from [Van Cruchten,
2002].

Defective clearance of apoptotic cells
• One common theme is defects in clearance of apoptotic cells
resulting in autoantibody production
– Phagocytes from lupus patients engulf far less during a 7 day
period in vitro than phagocytes from healthy patients
Image from Trouw et al., Mol Immunology (2008) 45:1203

DEFECTIVE CLEARANCE OF APOPTOTIC
CELLS
• Delayed or defective apoptosis then allows for
prolonged exposure of intracellular antigens,
“inflammatory cell death phenotype,”
Inflammatory cell recruitment and presentation
of normally protected intracellular components
as antigens allowing for autoantibody
production

Defective clearance of apoptotic cells
There may be a genetic component to defective
apoptosis.
• Concordance is 25% among monozygotic twins but only
2% among dizygotic twins suggesting a genetic
component
• HLA-DR2 and HLA-DR3 confer relative risk of 2-5.
• C1q deficiency results in high likelihood of developing
SLE

BCMAD-Elevated BAFF/IFN
• Genetic-HLA, X chromosome,Compliment def
• Hormone - Oestrogen
• Poor Adrenal function
• Low blood levels of the hormone DHEA
• Environment- UV rays,EB Virus,other inf.
• Neutrophils(NET)-Chronic activation of pDC -
hyperreactive B cells - Production of
autoantibodies against nuclear self-antigens.
• pDC-actB cells-IFN

1. Defects -NETOSIS
2. Defective-Apoptosis
3. Necrosis
4. Leads to defective immune clearence.
5. Increased rate of CD4/CD8

 IFN-a regulated genes are expressed at higher levels in
the blood of SLE patients
 Plasmacytoid DCs are the major producers of IFN-a.
SLE patients have 50-100 fold fewer in circulation as
they have migrated to lymph tissues where they
remain activated
 SNPs in interferon signaling related genes (Tyk2 and
interferon regulatory factor 5) also confer increased
likelihood of developing lupus
 SLE susceptibility polymorphism in STAT4 results in
increased sensitivity to IFN-a signaling.

IFN-a
IFN-a levels appear to correlate with disease
severity and levels of anti-DS DNA in SLE.
Patients with non-autoimmune diseases treated
with IFN-a can develop positive ANA, anti-DS
DNA abs and occasionally SLE.
Conditions that naturally increase IFN-a levels
(sunburn, viral infections) can induce SLE flares.

AUTO-ANTIBODIES
 ANA: targets - nucleus, but only those which have intrinsic
immunological activity: i.e.. They can activate the innate
immune system via Toll-like receptors
 Anti DS-DNA - recognizes DNA in complex with nucleosome
components (histone-derived peptides in particular)
Can correlate with nephritis
Immune complexes with anti-DNA ab/DNA can increase
the expression of IFN-a via plamacytoid dendritic cells
 Anti-Sm: detects ribonucleoproteins involved in processing
of mRNA; doesn’t track with disease, specific for lupus

SSA/Ro and SSB/La: detect ribonucleoproteins,
associated with SICCA syndrome and
photosensitivity
Anti NMDA: subunits NR2a and NR2b may be
associated with neuropsychiatric symptoms
“Antiphospholipid” antibodies are ab against
phospholipid-binding proteins or phospholipids
that are prothrombogenic. Ex: lupus
anticoagulant, anticardiolipin, and anti beta2-
glycoprotein

RENAL DISEASE:
• IgA, IgM, IgG and complement deposition in the
mesangium and subendothelial and subepithelial of the
GBM - complement activation and recruitment of
inflammatory cells - tissue destruction.
• Cross reactivity of anti-DS DNA antibodies with a-actinin
- direct focusing of complement activation.

SKIN DISEASE:
• Inflammation and breakdown of the dermal-epidermal
junction.
• UV exposure can worsen because it promotes
apoptosis in the skin resulting in autoantibody binding
and tissue injury via complement activation or
inflammatory cell activation
• Anti-Ro antibodies are associated with skin flares

• CNS
vasculitis is rare
– Anti-NMDA receptor antibodies may contribute to cerebral
lupus phenotypes
– Microinfarcts and degeneration or proliferative changes in
blood vessels, thought to be related to IC deposition
• ANTIPHOSPHOLIPID ABS
– thrombotic events anywhere in the body
– aPLs bind to endothelial cells, monocytes, neutrophils and
platelets causing inflammation and procoagulant release
– This process is dependent on complement activation

AUTOANTIBODIES ASSOCIATED WITH
SLE
TARGET ANTIGEN APPROXIMATE FREQUENCY
NUCLEAR ANTIGENS 99
dsDNA 70
RNP (U1-RNP) 33
RO (SSA) 49
LA (SSB) 35
Sm 38
PHOSPHOLIPIDS 21
RIBOSOMAL 10

Nervous System
Headache is the most common complaint
ADD, mood disorders, anxiety, delirium, psychosis,
seizures (generalized or partial)
Difficult to prove absolute causality
Generalized encephalopathies
Formal neuropsychiatric testing reveals deficits in 21-
67% of patients with SLE

Cerebritis:
 Degenerative changes in small vessel walls, often with
minimal or no inflammatory infiltrates
 May be related to immune complex deposition
Neuropathy secondary to vasculitis of vasa
nervorum (often with dermatomyositis overlap)

•Behaviour/Personality changes, depression
•Cognitive dysfunction
•Psychosis
•Seizures
•Stroke
•Chorea
•Pseudotumor cerebri
•Transverse myelitis
•Peripheral neuropathy
Total of 19 manifestations described
May be difficult to distinguish from steroid psychosis or primary
psychiatric disease
NEUROLOGIC

OCULAR MANIFESTATIONS
• Mucocutaneous lid involvement, secondary
sjögren's syndrome, retinal vascular disease
and neuro‐ophthalmic disease .
• Retinopathy - usually consists of cotton‐wool
spots with intraretinal haemorrhages.
• More severe form of lupus retinitis - retinal
arteriolitis and vascular occlusion, resulting in
capillary non‐perfusion, retinal haemorrhage
and venous stasis.

• When larger vessels are involved, branch or
central retinal artery or vein occlusion may
result, with secondary retinal
neovascularization and vitreous haemorrhage
• Lupus patients with raised concentrations of
antiphospholipid antibodies have a higher risk
of developing retinal vaso‐occlusive disease

Hematologic System
Chronic anemia is present in up to 80% of patients
Leukopenia is present in up to 50% of patients
(lymphopenia more common than neutropenia).
Thrombocytopenia ranges from modest to severe
with bleeding complications
 May reflect disease activity
 May be first sign of SLE; predating other signs and
symptoms by years.
 Associated with the presence of anti-platelet antibodies
Secondary APS seen in about 40% of patients with
SLE+

CV System
Pericarditis 6-45% of patients: low likelihood of
tamponade or constrictive type.
<10% with myocarditis
Libman-Sacks endocarditis
1-4 mm vegetations of accumulations of immune
complexes and mononuclear cells on mitral, tricuspid
or aortic valves
Risk of thromboembolism or secondary infective
endocarditis
Aortic insufficiency is the most common valvular
abnormality.

CARDIAC
– Cardiac failure
– Cardiac Arrythmias-common
– Coronary Artery Disease

Lupus - Endocarditis
Noninfective thrombotic endocarditis involving mitral valve in SLE.
Note nodular vegetations along line of closure and extending onto chordae tendineae.

Heart disease
 Contributes to bimodal pattern of mortality from lupus
 A study from U of Pittsburgh comparing rates of MI to
that of Framingham Offspring Study data showed that
risk of MI was 50x higher in woman with lupus ages 35-
44 and 2.5-4x higher in older age groups
 Autopsy data shows CAD in 40% of SLE patients as
opposed to only 2% of age matched controls.

 Atherosclerotic plaque burden (via carotid intima
media thickness measurements and by coronary
calcium scores) is higher in patients with SLE than in
controls.
 “Lupus dyslipoproteinemia” is low HDL, high TG,
normal or only slightly elevated LDL, increased
lipoprotein(a): this appears to correlate with
disease activity
 Means of prevention focus on risk factor
management and inflammation control, but no
clear guidelines are available as of yet.

LUNGS AND PLEURA
• Over 30% will have pleuritis or an effusion over
the course of their disease
– Fluid is exudative, normal glucose, high protein,
WBC <10,000 (neutrophilic or lymphocytic),
decreased complement
• Can have pneumonitis, pulmonary hemorrhage
(rare but often fatal), PE, pulmonary HTN
– Pulmonary HTN more likely to be associated with
Raynaud’s

PLEURO-PULMONARY
Infiltrates/ Discoid Atelectasis
“Shrinking lung” - diaphragm dysfunction
• Restrictive lung disease

MUSCULOSKELETAL
• Arthritis is NONEROSIVE, transient,
symmetrical, affecting small joints, seldom
deforming, less severe than RA
• Most common presenting feature of SLE

Jaccoud’s Arthopathy: Nonerosive, Reducible Deformities

– Synovitis-90% patients, often the earliest sign
– Osteoporosis
• From SLE itself and therapy (usually steroids)
– Osteonecrosis (avascular necrosis)
• Can occur with & without history of steroid therapy

RENAL (LUPUS NEPHRITIS)
• Usually asymptomatic
• Gross hematuria
• Nephrotic syndrome
• Acute renal failure
• Hypertension
• End stage renal failure

– Develops in up to 50% of patients
– 10% SLE patients go to dialysis or transplant
– Hallmark clinical finding is proteinuria
– Advancing renal failure complicates assessment of SLE
disease activity
Nephritis remains the most frequent cause of disease-
related death.

WHO CLASSIFICATION OF LUPUS NEPHRITIS
Class I Normal
Class II Mesangial
IIA Minimal alteration
IIB Mesangial glomerulitis
Class III Focal and segmental proliferative
glomerulonephritis
Class IV Diffuse proliferative glomerulonephritis
Class V Membranous glomerulonephritis
Class VI Glomerular sclerosis

Nephritis
 Class I Minimal mesangial lupus nephritis
Normal glomeruli by light microscopy, but mesangial immune
deposits by immunofluorescence
 Class II Mesangial proliferative lupus nephritis
Purely mesangial hypercellularity of any degree or mesangial matrix
expansion by lightmicroscopy, with mesangial immune deposits
May be a few isolated subepithelial or subendothelial deposits
visible by immunofluorescence or electron microscopy, but not by
light microscopy
Table from Weening et al., J Am Soc Nephrol 15: 241–250, 2004

 Class III Focal lupus nephritisa
Active or inactive focal, segmental or global endo- or
extracapillary glomerulonephritis involving 50% of all
glomeruli, typically with focal subendothelial immune
deposits, with or without mesangial alterations
Class III (A) Active lesions: focal proliferative lupus
nephritis
Class III (A/C) Active and chronic lesions: focal
proliferative and sclerosing lupus nephritis
Class III (C) Chronic inactive lesions with glomerular
scars: focal sclerosing lupus nephritis

 Class IV Diffuse lupus nephritisb
Active or inactive diffuse, segmental or global endo- or
extracapillary glomerulonephritis involving 50% of all glomeruli,
typically with diffuse subendothelial immune deposits, with or
without mesangial alterations. This class is divided into diffuse
segmental(IV-S) lupus nephritis when 50% of the involved
glomeruli have segmental lesions, and diffuse global (IV-G) lupus
nephritis when 50% of the involved glomeruli have global lesions.
Segmental is defined as a glomerular lesion that involves less than
half of the glomerular tuft.

This class includes cases with diffuse wire loop deposits but with
little or no glomerular proliferation
Class IV-S (A) Active lesions: diffuse segmental proliferative
lupus nephritis
Class IV-G (A) Active lesions: diffuse global proliferative lupus
nephritis
Class IV-S
(A/C)
Active and chronic lesions: diffuse segmental proliferative and
sclerosing lupus nephritis
Active and chronic lesions: diffuse global proliferative and
sclerosing lupus nephritis
Class IV-S (C) Chronic inactive lesions with scars: diffuse
segmental sclerosing lupus nephritis
Class IV-G (C) Chronic inactive lesions with scars: diffuse
global sclerosing lupus nephritis

 Class V Membranous lupus nephritis
Global or segmental subepithelial immune deposits or
their morphologic sequelae by light microscopy and by
immunofluorescence or electron microscopy, with or
without mesangial alterations
Class V lupus nephritis may occur in combination with
class III or IV in which case both will be diagnosed
 Class VI Advanced sclerosis lupus nephritis
90% of glomeruli globally sclerosed without residual
activity

GASTROINTESTINAL & HEPATIC
–Uncommon SLE manifestations
–Severe abdominal pain syndromes in SLE often
indicate mesenteric vasculitis, resembling
medium vessel vasculitis (PAN)
–Diverticulitis may be masked by steroids
–Hepatic abnormalities more often due to
therapy than to SLE itself

Lupus Diagnostic Criteria (need 4)
 1. Malar Rash: Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
 2. Discoid rash: Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring
may occur in older lesions
 3. Photosensitivity: Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
 4. Oral ulcers: Oral or nasopharyngeal ulceration, usually painless, observed by physician
From http://www.rheumatology.org/publications/classification/SLE/1997UpdateOf1982RevisedCriteriaClassificationSLE.asp?aud=pat

Lupus Diagnostic Criteria (need 4)
 5. Nonerosive Arthritis2 or more peripheral joints,
characterized by tenderness, swelling, or effusion
 6. Pleuritis or Pericarditis:
 a) Pleuritis--convincing history of pleuritic pain or
rubbing heard by a physician or evidence of pleural
effusion OR
 b) Pericarditis--documented by electrocardigram or
rub or evidence of pericardial effusion
From http://www.rheumatology.org/publications/classification/SLE/1997UpdateOf1982RevisedCriteriaClassificationSLE.asp?aud=pat

• 7. Renal Disorder:
– a) Persistent proteinuria > 0.5 grams per day or > than
3+ if quantitation not performed OR
– b) Cellular casts--may be red cell, hemoglobin, granular,
tubular, or mixed .
• 8.Neurologic Disorder:
– a) Seizures--in the absence of offending drugs or known
metabolic derangements; e.g., uremia, ketoacidosis, or
electrolyte imbalance OR
– b) Psychosis--in the absence of offending drugs or
known metabolic derangements, e.g., uremia,
ketoacidosis, or electrolyte imbalance

9. Hematologic Disorder:
a) Hemolytic anemia--with reticulocytosis OR
b) Leukopenia--< 4,000/mm
3
on ≥ 2 occasions OR
c) Lymphopenia--< 1,500/ mm
3
on ≥ 2 occasions OR
d) Thrombocytopenia--<100,000/ mm
3
in the absence
of offending drugs

10. Immunologic Disorder:
a) Anti-DNA: antibody to native DNA in abnormal titer
OR
b) Anti-Sm: presence of antibody to Sm nuclear
antigen OR
c) Positive finding of antiphospholipid antibodies on:
an abnormal serum level of IgG or IgM anticardiolipin
antibodies, a positive test result for lupus
anticoagulant using a standard method, or a false-
positive test result for at least 6 months confirmed by
Treponema pallidum immobilization or fluorescent
treponemal antibody absorption test

• 11. Positive Antinuclear Antibody:
An abnormal titer of antinuclear antibody by
immunofluorescence or an equivalent assay at
any point in time and in the absence of drugs

CLASSIFICATION
1. Malar rash
2. Discoid rash
3. Photosensitivity
4. Oral ulcers
5. Arthritis
6. Serositis
A Pleurits
B Pericarditis
7. Renal disease.
A > 0.5 g/d proteinuria
≥ 3+ dipstick proteinuria
B Cellular casts
8. Neurologic disease.
A Seizures
B Psychosis (without other cause)
9. Hematologic disorders.
A Hemolytic anemia
B Leukopenia (< 4000/uL)
C Lymphopenia (< 1500/uL)
D Thrombocytopenia
(< 100,000/uL)
10. Immunologic abnormalities.
A Positive LE cell
B Anti-ds- DNA
C Anti- Sm
D Any antiphospholipid
11. Positive ANA ( 95-100% )
THE 1982 REVISED CRITERIA FOR CLASSIFICATION OF SLE (UPDATE)

CLASSIFICATION CRITERIA
• Must have 4 of 11 for Classification
– Sensitivity 96%
– Specificity 96%
• Like RA, diagnosis is ultimately clinical
• Not all “Lupus” is SLE
– Discoid Lupus
– Overlap syndrome
– Drug induced lupus
– Subacute Cutaneous Lupus

Lab Findings
• Complete blood count
– Anemia
– Leukopenia
– Lymphopenia
– Thrombocytopenia
• Urine Analysis
– Hematuria
– Proteinuria
– Granular casts

LE Cell
• The LE cell is a neutrophil
that has engulfed the
antibody-coated nucleus of
another neutrophil.
• LE cells may appear in
rosettes where there are
several neutrophils vying for
an individual complement
covered protein.

IMMUNOLOGICAL FINDINGS
• ANA - 95-100%-sensitive but not specific for SLE
• Anti -ds DNA-specific(60%)-specific for SLE, but positive to
other non lupus conditions
• 4 RNA associated antibodies
– Anti-Sm (Smith)
– Anti Ro/SSA-antibody
– Anti La/SSB-antibody
– Anti-RNP

• Antiphospholipid antibody
–Biologic false + RPR
–Lupus anticoagulant-antibodies tocoagulation
factors. risk factor for venous and arterial
thrombosis and miscarriage. Prolonged aPTT
–Anti-cardiolipin
• Depressed serum complement
• Anti histone antibodies

Total blood complement level: 41 to 90
hemolytic units
• C1 level: 16 to 33 mg/dL
• C3 levels:
– Males: 88 to 252 mg/dL
– Females: 88 to 206 mg/dL
• C4 levels:
– Males: 12 to 72 mg/dL
– Females: 13 to 75 mg/dL

• Increased complement activity may be seen in:
• Cancer
• Certain infections
• Ulcerative colitis
• Decreased complement activity may be seen in:
• Cirrhosis
• Glomerulonephritis
• Hereditary angioedema
• Hepatitis
• Kidney transplant rejection
• Lupus nephritis
• Malnutrition
• Systemic lupus erythematosis

DIFFERENTIAL DIAGNOSIS
• Almost too broad to consider given number of
clinical manifestations
• Rheumatic: RA, Sjogren’s syndrome, systemic
sclerosis, dermatomyositis
• Nonrheumatic: HIV, endocarditis, viral
infections, hematologic malignancies,
vasculitis, ITP, other causes of nephritis
• “Overlap Syndrome” (UCTD, MCTD)

LUPUS RELATED SYNDROMES
• Antiphospholipid Syndrome (APS):
– Hypercoagulability with recurrent thrombosis of either venous or
arterial circulation
– Thrombocytopenia-common
– Pregnancy complication-miscarriage in first trimester
– Lifelong anticoagulation warfarin is currently recommended for patients
with serious complications due to common recurrence of thrombosis
– Antiphospholipid Antibodies
– Primary - without other SLE feature.
– Secondary - SLE features present

• Drug Induced Lupus
– Classically associated with hydralazine, isoniazid,
procainamide
– Male:Female ratio is equal
– Nephritis and CNS abnormalities rare
– Normal complement and no anti-DNA antibodies
– Symptoms usually resolve with stopping drug

Raynaud’s Syndrome:
-Not part of the diagnostic criteria for SLE.
- Does NOT warrant ANA if no other clinical
evidence to suggest autoimmune disease

SLE – treatment I.
• Mild cases (mild skin or joint involvement):
NSAID, local treatment, hydroxy-chloroquin
• Cases of intermediate severity (serositis,
cytopenia, marked skin or joint involvement):
corticosteroid (12-64 mg
methylprednisolone), azathioprin,
methotrexate

SLE – treatment II.
• Severe, life-threatening organ involvement (carditis, nephritis, systemic
vasculitis, cerebral manifestations):
high-dose intravenous corticosteroid + iv. cyclophosphamide
+ in some cases:
plasmapheresis or iv. immunoglobulin, or, instead of cyclophosphamide
mycophenolate mofetil (not registered in the EU)
• Some cases of nephritis (especially membranous), myositis,
thrombocytopenia: cyclosporine

TREATMENT
• Antiphospholipid Syndrome
– Anticoagulation with warfarin (teratogenic)
– subcutaneous heparin and aspirin is usual approach
in pregnancy
• Lupus and Pregnancy
– No longer “contraindicated”
– No changes in therapy other than avoiding fetal toxic
drugs
– Complications related to renal failure,
antiphospholipid antibodies, SSA/SSB

Nephritis
• Class I-no Rx
• Class II-Rx if proteinuria >1000 mg/d
• Class III and IV at high risk of progression so
require aggressive immunosuppressive therapy
• Class V Rx with steroids
• Class VI-dialysis or transplant

PROGNOSIS
• Unpredictable course
• 10 year survival rates exceed 85%
• Most SLE patients die from infection,
probably related to therapy which
suppresses immune system
• Recommend smoking cessation, yearly flu
shots, pneumovax q5years, and preventive
cancer screening recommendations

• ESR, CRP probably useful as general markers of
disease activity
• Complement and anti-DNA antibodies may
correlate to disease activity
• Patient history.

Early studies of corticosteroids &other
30 yrs ago, Donadio and colleagues published the results
of a randomized study in 50 DP GN and reduced
creatinine clearance, randomly assigned to either
prednisone alone or prednisone in combination with
oral cyclophosphamide (CTX).
CS-only group received 60 mg daily for 1 to 3 months, and
then tapered to receive 20 mg daily by 6 months.
second group received, in addition, oral CTX 2 mg/kg
body weight, which was subsequently titrated to the
peripheral white cell count.
The majority of patients in both groups improved with
therapy.

The patients who quickly progressed to ESRD were
equally divided between the two treatment
regimens.
It was in the long-term follow-up that the CTX
group appeared to do better:
after a mean of 43 months, 10 of 21 patients in the
prednisone-only group relapsed,
compared to 3 of 21 in the prednisone-CTX group.
• Joanne M. Bargman University Health Network
2University of Toronto, Toronto, Ontario, Canada
2008.

However, several other important
observations were made
Patients in both groups were equally likely to improve over the first 6
months.
This is an important lesson for treating an acutely ill lupus patient
Some physicians feel that there is an urgency to deliver intense
immunosuppressive therapy in the first few days of treatment of
lupus nephritis.
This can lead to serious infectious consequences.

In 1984 a pooled analysis of eight studies of lupus nephritis, comprising 250
patients (including children), 198 renal biopsies and 167 patients with
biopsy evidence of diffuse proliferative lupus nephritis, was published
Three of the studies came from the National Institutes of Health (NIH), and
the study by Donadio discussed above was also included.
Of the 250 patients, 113 received only corticosteroids, and the rest received
corticosteroid and other immunosuppressive agents (azathioprine and
CTX)
Patients receiving the corticosteroid and another agent had a lower rate of
deterioration of kidney function.
The New England Journal of Medicine [4].

None of these studies was a head-to-head comparison
of the two immunosuppressive agents
However, the pooled analysis added credence to Donadio's finding that prednisone in
combination with another immunosuppressive drug was more efficacious than
prednisone alone.
Within the limitations of this kind of analysis, azathioprine appeared to be a helpful
drug in the management of diffuse proliferative lupus nephritis without the risk of
increasing non-renal (?infective) deaths, as was suggested with CTX
The latter part of the 1980s was dominated by a series of publications from the
National Institutes of Health on the interim and final outcomes of different
treatment protocols for the treatment of lupus nephritis
Another follow-up report just 1 year later, focusing on histologic predictors of
outcome, was published in The New England Journal of Medicine in 1984 and did
not find a difference among the different cytotoxic-drug regimens and renal
outcome].

The NIH Publication and the
popularization of pulse CTX
Everything changed with the publication of another progress report,
again in The New England Journal of Medicine, in 1986
Patients who entered the lupus nephritis trials at the NIH between
1969 and 1981 were included. There were 107 patients in total, and
they were randomized into one of five treatment protocols
(1) High-dose prednisone (1 mg/kg);
(2) Azathioprine (up to 4 mg/kg) + low-dose prednisone;
(3) Oral CTX (up to 4 mg/kg) + low-dose prednisone;
(4) Combined oral azathioprine and oral CTX (up to 1 mg/kg of each)
and
(5) Intravenous CTX (0.5–1.0 g/m2 every 3 months titrated to a
peripheral white cell count nadir) + low-dose oral prednisone.

As mentioned, the protocol was changed in 1979 so that
immunosuppressive agents could be discontinued.
Furthermore, not all therapies were offered contemporaneously.
Groups 1, 2 and 3 were enrolled from 1969 to 1976, and groups 4 and
5 from 1973 to 1981
It is also important to note that the median serum creatinine was 1.0
mg/dl (88 μmol/l)
There has been criticism of subsequent lupus trials that the renal
disease in these trials was ‘too mild’
However, the serum creatinine was almost identical in these three
studies

While this was one of the largest cohorts of lupus patients to be examined,
the numbers were still quite small
At 120 months of follow-up, where the curves diverge, the number of
patients still in the study was 11 in the azathioprine, 8 in the oral CTX and
3 in the combined oral azathioprine/CTX groups.
There was just one patient in group 5 (IV CTX).
Despite the sizable methodological weaknesses outlined above, the ‘NIH
protocol’ of IV pulsed CTX became widely accepted as the gold standard
of treatment.

It was new therapy, carried the cache of the National Institutes of
Health and was the protocol to which all others were compared
thereafter
Furthermore, as Lewis observed: ‘The tendency to recommend
parenteral cyclophosphamide may in part reflect the mystique
associated with a more invasive intervention’
Finally, despite evidence that started to accrue suggesting that this
therapy may not necessarily lead to superior results compared to
other immunosuppressive regimens, it continued to be defended by
the original investigators].

The paper by Contreras et al. was a randomized controlled trial of pulse CTX,
mycophenolate mofetil (MMF) and azathioprine in the treatment of proliferative
lupus nephritis
Unfortunately, the water was muddied by the protocol, in which all groups received
induction therapy with up to seven monthly boluses of CTX before being
randomized to the three treatment arms.
Nonetheless, both azathioprine and MMF-treated subjects fared well in this trial. The
cumulative rate of renal survival was 95% in the MMF group, 80% in those
receiving azathioprine and 74% in the intravenous CTX.
Importantly, of the five patients who died during the trial, four were in the CTX arm
and died of sepsis (the fifth death was in a patient receiving MMF).
Again, similar to the observations of Felson's analysis 20 years before, no patient in
the azathioprine group died during the study.

The best thing about MMF
• is that it will convince people that there are therapies for lupus nephritis
other than pulse CTX
• The issue of induction of therapy was re-addressed by the study of Ginzler
and colleagues where patients were randomized to receive MMF versus
pulse CTX and was designed as a short-term (24 week) equivalency study
• The pregnant patient with lupus represents a special challenge.
Azathioprine is a D class drug, acknowledging that there is evidence of
human fetal risk, but the benefits from its use may be acceptable in the
pregnant patient with active lupus
• This is extrapolated from the pregnant transplant patient where this drug
is usually not discontinued [16].

Is the problem with CTX itself, or are
we using too high a dose?
The studies of the past 30 years have shown a worrisome trend of increased
incidence of severe infections and death in patients who received CTX
.
It would be hoped that the ‘payoff’ for the increased infections and deaths is
that the CTX is the more potent immunosuppressive agent and, therefore,
leads to a better control of the disease
Unfortunately, the same studies do not strongly support this contention.

The Euro-Lupus Nephritis Trial
examined the effects of ‘low-dose’ (3 g) versus ‘high-dose’ (mean of 8.5 g)
CTX in a randomized study of 90 patients with lupus nephritis.
Severe infections were more common in the high-dose group, although,
interestingly, the two deaths occurred in the patients taking low-dose CTX
There was a trend towards more renal remissions in the low-dose group (P =
NS), and the number of renal flares was no different
Of the 16 patients who experienced a renal flare in the high-dose group, 7
experienced the flare while being actively treated with the CTX pulses.

This interesting trial suggests that the same result can be reached with
lower rather than higher doses of CTX and with a lower risk of
severe infections
Despite the early switch to AZA at Month 3 in the ‘low-dose’ CTX
group, there were no more flares compared to the cohort
continuing CTX
So this study could also be construed as one comparing changing to
AZA at 3 months versus continuing CTX for another 9 months and,
once again, azathioprine comes out well.

Conclusions
High-dose corticosteroids remain the mainstay of therapy for the initial
treatment of severe lupus nephritis.
A second agent is recommended as it is associated with a lower rate of
relapse and, in most cases, better renal outcome.
The second drug should be approached as a ‘disease-modifying’ agent and
does not necessarily have to be started on the day of diagnosis, especially
if there is suspicion of intercurrent infection.
The renal prognosis is ultimately determined by the severity of disease and,
relatedly, the amount of fixed renal damage.

It is clear that the use of potent immunosuppressive agents may effectively
treat the lupus, but are themselves associated with worrisome short-
term and (perhaps unknown?) long-term side effects
.
All intensive immunosuppressive therapy can be associated with severe side
effects up to and including death.
In this regard, data from the recent ASPREVA Study are awaited with
interest
.
However, it is important to realize that CTX should not be considered the
only useful drug in the management of lupus nephritis.

Aspreva Lupus Management Study (ALMS):
Extra-Renal Activity Results from the
Maintenance Phase.
Isenberg4, David A., Appel1, Gerald B.,
Dooley6, Mary Anne, Ginzler3, Ellen M.,
Jayne2, David, Wofsy5, David,
Solomons7, Neil

• Background:
The 36-month maintenance phase of the ALMS study (NCT00377637) compared
the efficacy and safety of mycophenolate mofetil (MMF) with azathioprine
(AZA) in patients with lupus nephritis (LN) classes III, IV and V achieving a
clinical response in the induction phase with corticosteroids (CS) and either
MMF or cyclophosphamide (IVC).
• Methods:
Patients were re-randomized 1:1 to a double-blind comparison of either placebo
plus either oral MMF (2 g/day) or oral AZA (2 mg/kg/day). Patients were
permitted to receive corticosteroids (maximum dose: 10 mg/day prednisone
or equivalent). The primary efficacy outcome measure was time to treatment
failure (death, end-stage renal disease, sustained doubling of serum
creatinine, and/or renal flare [proteinuric or nephritic]). Patients who
withdrew before reaching the primary endpoint were censored at the time of
withdrawal. Although this was primarily an LN population, substantial extra-
renal assessments were performed. Extra-renal secondary parameters
included time to major extra-renal flare (British Isles Lupus Assessment
Group [BILAG] score category A in one extra-renal system or three systems
with concurrent category B scores) and the characterization of extra-renal
activity. Immunology secondary parameters (levels of complement proteins
C3 and C4, and titers of antibodies to double-stranded DNA [anti-dsDNA])
and adverse events (AEs) were also assessed.

RESULTS
• Of 227 patients randomized (intent-to-treat population), 127
completed the full 3 years (MMF, 73/116 [62.9%]; AZA, 54/111
[48.6%]): MMF was superior to AZA in the primary endpoint
(p=0.003). Extra-renal disease characteristics and immunology
parameters were similar across groups at baseline. There were very
few occurrences of major extra-renal flare in either group during the
study (8 [6.9%] for MMF, 7 [6.3%] for AZA), and time to major extra-
renal flare did not differ between groups (p=0.936). However, there
were differences in the characteristics of extra-renal activity. The most
common manifestation of major extra-renal flare in the MMF group
was mucocutaneous and in the AZA group was hematological. In the
MMF group, 75 subjects (65.2%) experienced lupus-related AEs
compared with 79 (71.2%) in the AZA group, with musculoskeletal
events being the most common in both groups (MMF, 39/115
[33.9%]; AZA, 37/111 [33.3%]). At the end of the study, in patients
who had completed 3 years, mean C3 and C4 levels were lower in the
AZA group and mean anti-dsDNA titers were lower in the MMF group;
differences were not statistically significant.

CONCLUSIONS
In this population of LN patients who had
responded to induction therapy, there were
low levels of extra-renal activity in the
maintenance phase in both MMF and AZA
groups.

Azathioprine versus mycophenolate mofetil for long-term
immunosuppression in lupus nephritis: results from the MAINTAIN
Nephritis Trial
Frédéric A Houssiau1,David D'Cruz2, Shirish Sangle2Philippe Remy3,
Carlos Vasconcelos4, Radmila Petrovic5, Christoph Fiehn6, Enrique de
Ramon Garrido7,
Inge-Magrethe Gilboe8, Maria Tektonidou9, Daniel Blockmans10, Isabelle
Ravelingien11,Véronique le Guern12, Geneviève Depresseux1, Loïc
Guillevin12,
Ricard Cervera13, the MAINTAIN Nephritis Trial Group
• Abstract
• Background Long-term immunosuppressive treatment does not
efficiently prevent relapses of lupus nephritis (LN). This investigator-
initiated randomised trial tested whether mycophenolate mofetil
(MMF) was superior to azathioprine (AZA) as maintenance treatment.

Methods
• A total of 105 patients with lupus with proliferative
LN were included.
• All received three daily intravenous pulses of 750
mg methylprednisolone, followed by oral
glucocorticoids and six fortnightly
cyclophosphamide intravenous pulses of 500 mg.
Based on randomisation performed at baseline,
AZA (target dose: 2 mg/kg/day) or MMF (target
dose: 2 g/day) was given at week 12.
• Analyses were by intent to treat.
• Time to renal flare was the primary end point.
Mean (SD) follow-up of the intent-to-treat
population was 48 (14) months.

• Results The baseline clinical, biological and pathological
characteristics of patients allocated to AZA or MMF did
not differ.
• Renal flares were observed in 13 (25%) AZA-treated and
10 (19%) MMF-treated patients.
• Time to renal flare, to severe systemic flare, to benign
flare and to renal remission did not statistically differ.
• Over a 3-year period, 24 h proteinuria, serum creatinine,
serum albumin, serum C3, haemoglobin and global
disease activity scores improved similarly in both groups.
Doubling of serum creatinine occurred in four AZA-treated
and three MMF-treated patients.
• Adverse events did not differ between the groups except
for haematological cytopenias, which were statistically
more frequent in the AZA group (p=0.03) but led only one
patient to drop out.
• Conclusions Fewer renal flares were observed in patients
receiving MMF but the difference did not reach statistical
significance.

Mechanism of action Examples of targets
T cells CTLA4-Ig, modified CD40L, inhibition of ICOS
Regulatory T cells: expanding CD4+CD25+,
CD8+CD28-
B cells mAbs to CD20, CD22, BlyS, TACi-Ig, BAFF-RFc
Proteosome/plasma cells
Cytokines Inhibition of IL-6, IL-10; TNF inhibitors
Innate immune system
Inhibition of IFN-α and IFN-γ, blockade of TLR-
7 and/or TLR-9, C5a inhibition
Toleragens
Peptides derived from nucleosomes,
splicosomes
Cell surface receptor activation inhibition Syk kinase, sirolimus
Targets for new therapies in systemic lupus erythematosusa

The management of LN at the
beginning of the decade
Steroids alone not enough. Need for IST
Induction and maintenance therapy. Need for along-term follow-up ( more than
5 years)
The choice highly debatable: AZA, CY, CsA
Two sides: always CY vs never CY (Then the new kid came in the block: MMF )
Chan, Contreras and Ginzler studies all inNEJM)
Strong pro-MMF movement.
Official declaration of the end of the CY era!!

The management of LN at the end of
the decade
ALMS ( induction-maintenance) and MAINTAIN ( maintenance)
studies
Induction: AZA, MMF or IV-CY (high or low- dose) or CsA for
membranous
depending upon severity
MMF equal to CY for moderate proliferative LN ( ALMS)
Maintenance: AZA or MMF (contradicting results)

Prognostic factors-biomarkers
Prognostic markers at disease onset
- Poor: Anti-DNA, anti-phospholipids (APA), IFN-a
signature( in some ethnic groups)
Good: other DNAs (ie Ro/La/Sm/RNP)
•Biomarkers for early response (8 weeks)
- improvement in proteinuria by at least 25%
- normalization of C3, C4 or both, increase in Hct
•Intermediate biomarkers ( 24 weeks)
- remission of proteinuria and normalization of Cr
Decrease in anti-DNA unreliable alone. Better if combined
with C3

ROLE OF CYCLOSPORINE
• Induction for severe LN or LN non-responding to
AZA or MMF
• Impaired renal function/Adverse histology/Failure
to respond after 3-6 mo of initial RX

• With current immunosuppressive therapies only
a small percentage of LN patients reach ESRD at
10 years
• but…..
• Flares are common….
• up to 30% of patients will flare with 20% of these
flares being major flares requiring intensification
of IST
Significant morbidity - related to steroids

IV-MP pulses during the induction
The use of IV-MP pulses in current treatment protocols cannot
be overemphasized.
There is circumstantial data to support the use of one to three
IV-MP pulses especially for patients with moderate or severe
nephritis.
In addition to expediting remission, IV-MP pulses may also
allow for the use of lower doses of glucocorticoids at the early
phases of the induction period.

Steroid -Free Imperial College Study
Steroid -Free Imperial College Study
Day 1: 500 mg IV MP and 1g IV RTX
Day 15 500 mg IV MP and 1g IV RTX
Maintenance: MMF 500 mg bd titrated (1-3 mg/L) steroid
free maintenance
Renal protection
Lupus nephritis: where are we now? Lupus nephritis: where
are we now?
Lightstone L Curr Opin Rheumatol. 2010 May;22(3):252-6.

Clinical<Failure> Basic
• Once we failed to prevent the formation
autoantibodies by the NET, search
continued to produce biologics
(Superman) against the antibodies
produced by the SLE.
One biologic fails
try another it fails
try another.....

• CD20 antibody. Rituximab, in SLE, reported an
unexpected negative results.
• Belimumab, the monoclonal antibody against B-
lymphocyte stimulator (BLyS), showed significant
clinical benefit.
• Studies of a co-stimulation blocker (abatacept),
tumor necrosis factor inhibitor (infliximab), and
interleukin-6 inhibitor (tocilizumab)
• were either negative Studies of T cell and interferon
inhibition remain in the early development phase.

How Understanding the Mechanism of
SLE will influence therapy
 Currently, general immunosuppressants and
antimalarials are the therapy of choice for lupus
(steroids, plaquenil) and lupus nephritis
(cyclophosphamide –cellcept may become an
approved option)
 Current therapies are limited by side effects
 No new FDA approved drug for lupus have surfaced
in 40 years!
 Research into the underlying mechanisms will allow
for more directed therapies that may provide better
control of SLE with fewer side effects

How Understanding the Mechanism of
SLE will influence therapy
Removal of B cells may improve disease control
pen label trials of rituximab (anti CD-20) have shown up
to 80% response, 50% with sustained response after 12
months. A recent RCT (EXPLORER) did not show a
benefit with rituximab but patients were very sick and
both control and study patients received high doses of
steroids which may have undercut the benefit seen in
patients given rituximab
Trials of anti-IFN-a antibodies are underway

 Preliminary trials of inhibitory DNA sequences to
block immune complex binding to TLRs suggest
that preventing aberrant TLR 7 and 9 activation
decreases IFN-a levels and disease flares
 Anti-IL-10 trials are ongoing. Preliminary trials
suggest improvement in skin and joint symptoms
 Trials are also ongoing to block other B-cell
stimulating signals (anti-BlyS=Belimumab,
atacicept (soluble fusion protein that inhibits Blys
ligand) and to block helper T cell activation.

hope@
• Among the important ones are Tocilizumab a
humanised monoclonal antibody that binds
interleukin -6 (IL-6) receptors.
• Ustekunumab is a human immunoglobulin (Ig)
G1 antibody that neutralizes IL-12 and IL-23
mediated common response.

Fusion proteins*
• Alefacept a Fusion protein of the CD-2 binding
region of leukocyte function associated
antigen -3 and the CH2 and CH3 domain lgG1
inhibit T-cells activation and induces apoptosis
of memory T-cells.
• Abatacept modulates CD 80/CD86: CD28 Co-
stimulatory signal needed for activation of T-
cells.

Anakinra
Anakinra competitively inhibit IL-1 binding to IL-
1 type -1 receptor Rituximab.
CD 20 directed cytotoxic antibody.
Ref: Joanna m. Do biologics cause cancer? University of
Michigan.17.08.2011.

Conclusion
The war continues and warriors

Futile Attempts- Nepotism?
•The futile attempt in
search of various
biosimilars (Superman)
to protect from SLE still
continued.

Galen’s saying
‘All who drink of this remedy
recover in a short time except
those whom it does not help, who
all die. Therefore it is obvious
that it fails only in incurable
cases’

However, immune complexes are taken up by
cells with FcgRIIa and taken to the endosome
where they can activate TLR 7 and 9.
 This results in signaling cascade activation that
increases production of IFN-a

stimulus
1. TLR activation- pDc activation Inate Im-
adaptive im
2. Nutrophil activation- Netosis
3. Compliment activation-humoral im
4. Tiue injury-Apoptosis/Necrosis

• Complement C4a deficiency: 80% of people with
SLE have at least one null allele
Can lead to decreased clearance of apoptotic cells and
increased inflammation and presentation of self antigens
• Patients with SLE may also develop
autoantibodies against adaptor molecules
which facilitate phagocytosis of apoptotic cells
(C1q, MBL) resulting in defective clearance,
classical pathway complement activation,
and recruitment of inflammatory cells.

• Inflammasome-related sensors activate caspase 1,
a necessary step for the secretion of IL-1β.
• Activation of such sensors has additional cell
type–specific effects (e.g., in dendritic cells [DC] or
macrophages [MØ], mesangial cells [MC],35
glomerular endothelial cells [EC],36 or
podocytes.37,38
• Cell necrosis can trigger identical effects because
some intracellular molecules can act as DAMPs on
the same receptors.
• Apoptotic cell death and rapid clearance by
phagocytes avoids unnecessary immune
activation.

Mechanism Summary
 Defects in clearance of apoptotic cells
can lead to exposure of intracellular
immunogenic components which can
be taken up by DC and presented to
autoreactive B cells (made this way
during random somatic hypermutation).
 In the right genetic environment, these
B cells may become activated to
produce autoantibodies.
 Polymorphisms or mutations in genes
in numerous steps of B-cell regulation or
IFN-a responsiveness can predispose to SLE (FcgRIIa, IRF5,
STAT4, BLK)

Mechanism Summary
• Once autoantibodies (particularly anti-DS DNA)
are present, they can complex with DNA exposed
on dying cells and then bind to the FcgRIIa on
PDCs, activate TLR 7 and 9, and result in high
levels of IFN-a production.
• IFN-a encourages a feed-forward mechanism of
continued plasma cell activation to produce
increased amounts of autoantibodies and
encourage further disease progression and
tissue destruction.

The nonoxidative mechanisms of human neutrophils are mediated by antimicrobial peptides (AMP)& proteins
stored within its various cytoplasmic granules
.
Cathepsin G,
azurocidin (also called CAP37),
BPI (also called CAP57),
and defensins are restricted to the primary (azurophil) granules,
which also contain
myeloperoxidase,
elastase, and
proteinase 3
Lactoferrin
and hCAP-18 (the precursor of LL-37) are restricted to the neutrophil’s secondary (specific)
granules .
Lysozyme, another AMP, occurs in both primary and secondary granules
Whereas azurophil granule contents are delivered preferentially to intracellular phagolysosomes, the specific granule contents are largely secreted
extracellularly.

Spiderman
Thus playing a wonderful role by the NET (Spiderman).
In the case of autoimmune diseases and SLE
Either the apoptosis is defective or
after apoptotic cell death the removal of the debris are defective.

NETOSIS
• It is proved that self-DNA in immune complexes
of SLE patients contains Neutrophil antimicrobial
peptide LL37 and HNP.
• These antimicrobial peptides were required for
self-DNA to trigger TLR9 in pDCs by forming
complexes with the DNA that is protected from
extracellular degradation.

• Such immunogenic self-DNA–antimicrobial
peptide complexes were released by dying
neutrophils undergoing NETosis, a cell death
process in which activated neutrophils extrude
large amounts of nuclear DNA into the
extracellular space in the form of web-like
structures called NETs
• The ability of neutrophils to ingest and kill
bacteria and fungi is an important component of
innate immunity.

The Innate Immune System May Also
Play a Role
• Toll-Like Receptors recognize molecular patterns
(double stranded RNA, DNA, LPS etc) in order to
provide rapid response to invading pathogens. They
use defined signaling pathways to result in
production of inflammatory cytokines and initiate
inflammatory reactions.
• TLR7 and 9 are selectively expressed on PDCs
• Regulation in endosomes may regulate control of
NFkB vs. IRF7 activation in human plasmacytoid
dendritic cells

Pathogens and cell necrosis alert
innate immunity
• All classes of pathogens release pathogen-
associated molecular patterns that can activate
TLRs on the cell surface or in intracellular
endosomes.
• TLR activation induces the expression of pro-IL-
1β, NF-κB–dependent cytokines and chemokines,
and IFN-α and IFN-β, the three dominant
cytokine classes of innate immunity.
• NOD-like receptors and RIG helicases convert the
recognition nucleic acids into cytokine release.

CELL DEATH
• There are two ways of cell death either by
necrosis or by apoptotic.
• In case of necrotic or inflammatory cell death
various cell debris like DNA, nucleolus,
chromatids etc are released in to the
extracellular space which normally cached in the
NET and removed from the tissues.

• Garcia-Romo et al. also show that these NETs
potently activate dendritic cells, leading to
secretion of requires FcRIIa, signaling through the
pattern recognition receptor Toll-like receptor 7,
and formation of reactive induce NETosis, and
the released NETs contain LL37 and another
neutrophil protein, HMGB1.
• Induction of NETosis neutrophils undergo
accelerated cell death in culture.

Main Pathology
• Plasma cells - produce antibodies that are specific for self
proteins, namely ds-dna.
• Overactive B-cells.
• Suppressed regulatory function in T-cells.
• Lack of T-cells.
• Activation of the Complement system

Genetic Associations
• HLA’s are loci on genes that code for certain β
chain on the MHC complex
• HLA-DR2
• HLA-DR3
• HLA-DQB1 – Involved in mediating production of
antibodies to ds-DNA.

OVERACTIVE B-CELLS
• Estrogen is a stimulator of B-cell activity
– Lupus is much more prevalent in females of ages 15-
45
• Height of Estrogen production
• IL-10, also a B-cell stimulator is in high concentration in
lupus patient serum.
– High concentration linked to cell damage caused by
inflammation

SLE: A Guide to Systemic Lupus Erythematosus

SLE: A Guide to Systemic Lupus Erythematosus

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