SYSTEMIC LUPUS ERYTHEMATOSIS

SYSTEMIC LUPUS ERYTHEMATOSUSHistory Evolution Etiology pathopysiology Management & what is new Karunan KannampoyililSeethaprakashPictures by Little Darling K & Novakarun K2014 JanLupus NephritisSLE What is New 1.Introduction2.History3.Epidemiology4.Pathophysiology5.Pathology6.Autoimmunity7.Clinical features8.Diagnosis9.Management10.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 unknown & remains to be definedGeneticEnvironmental 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 diseaseTwin burden of Lupus

Physical burden of illness & it is potential seriousness

Intense fear which accompanies the illnessSeveral 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 5080%

Auto antibodies are exclusive to lupus.

SLE1.Introduction2.History3.Epidemiology4.Pathophysiology5.Pathology6.Autoimmunity7.Clinical features8.Diagnosis9.Management10.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)

Wolf (Lupus)

LupusWolf mutilates its 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.ISBN1550593323 They kill large prey by biting large chunks of flesh from the softperineumarea, causing massiveblood loss. Such bites can cause wounds 1015cm in length, with three such bites to the perineum usually being sufficient to bring down a large deer in optimum healthSLEsecond most common human autoimmune disease in the world.

Ref: Can morbidity and mortality of SLE be improved?AnurekhaBongu ElizabethChang RosalindRamsey-GoldmanBest 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.

SLESLE is the second most common autoimmune disorder (after thyroid disease) in women of childbearing age. Lupus is increasingly being recognized throughout the world's population. The incidence and prevalence of SLE varies among racial and ethnic groups. Lupus patient survival has significantly improved over the past five decades,But a three- to fivefold increased risk of death remains compared with the general population. As lupus patients survive longer, these individuals face a range of complications from the disease itself or consequent to its treatment.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; AnurekhaBongu Elizabeth

Prevalence of SLE IndiaA 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. LupusApril 1993vol. 2no. 2115-118INDIA - FEMALEMajority of the sufferers are females of the menstruating period.

It affects predominantly women in their reproductive years. The median age of onset in IndianSLE is 24.5 years and the sex ratio (F: M) is 11:1Ref: 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 patientsWhos destiny is to land in the dialysis room orKidney transplant arena with end stage Kidney failure and Those who escaped from suffering by reaching at the graveyards in the young age.AmericansAutoimmune diseases are common.

Aaffecting > 23.5 million Americans.

A Leading cause of death and disabilityUnfortunate?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: Bs, Ts, and tolls. Curr. Opin. Immunol.21, 626633 (2009).AutoimmunityBy 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. Rnnblom, V. Pascual, The innate immune system in SLE: Type I interferons and dendritic cells. Lupus 17, 394399 (2008). Organ specific expressionsThese 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

27Over the next 30 yearsPathologic 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 ERAHargraves (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 therapyPayne(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.INDIAFirst 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.

SLE 1.Introduction2.History3.Epidemiology4.Pathophysiology5.Pathology6.Autoimmunity7.Clinical features8.Diagnosis9.Management10.Future

EPIDEMIOLOGYIncidence2nd 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? AnurekhaB, ElizabethC ,RosalindR. Best Practice & Research Clinical Rheumatology 16: 2: 313-332, AprilPREVALENCE 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 REPORTNH, a previously healthy 11 yr old boyH/o fever- 2 wksgeneralized 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 cefotaximeand 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 raisedANA (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 dramaticHe 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 ofPrednisolone 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 ReportYoung Male with Systemic Lupus Erythematosus Presenting with Sensorineural Deafness with Immune Suppression Induced Miliary TuberculosisS Kundu, R Mitra, S Chatterjee, A Ghosh OCTOBER 2011VOL. 59AbstractA 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 Bhatand Iffat HassanEgyptian 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, 2010Summary :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 illnessMen 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 manA. Bertha,E. Tjandrajana, VM Srivastava, R. Subramanian,J. Mathew.Clinical Immunology and Rheumatology Department, CMC, Vellore, India

AbstractPreviously, 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, 870871.

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.

GENDERF: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 onsetMedian ages at diagnosisWhite F-7to50yrs M-50to59Black F-15 to 44 M 45 to 640 to 16yrs 16 to 55 yrs >56yrsETIOLOGYUnknown

Genetic

Hormonal

Immunologic

Environmental factors.GENETIC FACTORSHigh concordance rate (14 to 57 percent) in monozygotic twins.

Relatives (5-12 %) had disease& anti-C1q, anti-cardiolipin antibodies, C3,C4 abnormal

SLE chidrens 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.

AbstractWe 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 Sciences2005;59:347352.Rapid progression of atrioventricular nodal blockade in a patient with systemic lupus ErythematosisMakaryus 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 GENESSNP 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 FACTORSImmunoregulatory 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 SLEIn 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 endotheliumOTHER HORMONESProgesterone 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 erythematosusAnn Rheum Dis.1986 July;45(7): 579583.PMCID:PMC1001940K L Goh and F WangAbstractOf 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 studyThyroid disease in systemic lupus erythematosus and rheumatoid arthritisT. Y. Chan,Z. AlSaffar, C. Bucknall September 18, 2000. We determined the degree of overlap between autoimmune thyroid disease and two nonorganspecific autoimmune diseases, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Both SLE and RA are commonly encountered in our outpatient practice and were chosen because of their clinical relevance.Sixtynine 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/acutephase response for the RA group.All patients had thyroid function tests performed, which included the measurement of thyroidstimulating 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 Table1.

Thyroid disease in systemic lupus erythematosus and rheumatoid arthritisSLE patientsRA patientsNumber of patients6964Female:male ratio33.5:110.7:1Thyroid dysfunction17 (24.6%)7 (10.9%)TPO Abpositive16 (23.2%)7 (10.9%)Hypothyroid12 (17.4%)6 (9.4%)TPO Abpositive12 (17.4%)4 (6.3%)Clinical hypothyroidism3 (4.3%)2 (3.1%)TPO Abpositive3 (4.3%)1 (1.6%)Subclinical hypothyroidism9 (13.0%)3 (4.7%)TPO Abpositive9 (13.0%)4 (6.3%)Hyperthyroid4 (5.8 %)1 (1.6%)TPO Abpositive2 (2.9%)1 (1.6%)Clinical hyperthyroidism2 (2.9%)0TPO Abpositive2 (2.9%)0Subclinical hyperthyroidism2 (2.9%)1 (1.6%)TPO Abpositive01 (1.6%)Sick euthyroid disease1 (1.5%)0TPO Abpositive00Euthyroid52 (75.4%)57 (89.1%)TPO Abpositive2 (2.9%)2 (3.1%)Autoimmune thyroid disease in systemic lupus erythematosusD Pyne,D A Isenberg+Author AffiliationsCentre for Rheumatology, University College London, Arthur Stanley House, 4th Floor, 4050 Tottenham Street, London W1P 9PJ, UKCorrespondence to:Dr PyneAccepted30 May 2001AbstractBackground: The reported prevalence of autoimmune thyroid disease (3.924%) and antithyroid antibodies (1151%) 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 (p0.2).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 MellitusSebahat Tlpar1M. Hakan Poyrazolu1,Tahir E. Patrolu2,Mustafa Kendirci3,Funda Batu1,Zbeyde Gndz1,smail Dursun4andRuhan Dnsel14Kayseri 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 ABNORMALITIESRemains 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+ antigensAutoantibodies may be present for years before the first symptom of disease appears

SLESYMPOSIUM 08 12 20111.Introduction2.History3.Epidemiology4.Pathophysiology5.Pathology6.Autoimmunity7.Clinical features8.Diagnosis9.Management10.Future

PATHOPHYSIOLOGYPathogens and cell necrosis alert innate immunity.

Anders H JASN 2010;21:1270-12742010 by American Society of NephrologyPathogens 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-1, NF-Bdependent cytokines and chemokines, and IFN- and IFN-, the three dominant cytokine classes of innate immunity. NOD-like receptors and RIG helicases convert the recognition nucleic acids into cytokine release. Inflammasome-related sensors activate caspase 1, a necessary step for the secretion of IL-1. Activation of such sensors has additional cell typespecific effects (e.g., in dendritic cells [DC] or macrophages [M], 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.

.

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-B 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).IFNsHigh 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, 307336 (2005). M. J. Shlomchik, Activating systemic autoimmunity: Bs, Ts, and tolls. Curr. Opin. Immunol.21, 626633 (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 2008Additionally, 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 96B 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 CellB 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, Len B F, Rozas V MF, Gonzlez J P, Naves P R.SourceInstituto de Ciencias, Clnica Alemana, Facultad de Medicina, Universidad del Desarrollo.AbstractBAFF (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, Sjgren'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 RESEARCHThus, 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 RESEARCHSystemic Lupus Erythematosus and the NeutrophilXavier Bosch, M.D., Ph.D.N Engl J Med 2011; 365:758-760August 25, 2011Activation pd

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 microbesEven death doesnt 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).NETOSISIt 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-DNAantimicrobial 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-18s 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 .

LL 37

LL 37-FUNCTION

Neutrophil Extracellular Traps (Spiderman) NET & BACTERIA

NET &Bacteria

ScaningEMS view

Bacteria in Spidernet SEMS view

NET VideoNeutrophil Extracellular Traps: How to Generate and Visualize ThemVolker Brinkmann,Britta Laube,Ulrike Abu Abed,Christian goosmann,Arturo ZychlinskyCore Facility Microscopy, Max Planck Institute for Infection BiologyCellular Microbiology, Max Planck Institute for Infection Biology 02/24/2010

VICIOUS CYCLESLE 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.APOPTOSISSimilarly 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 cellsOne 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) 45:1203120DEFECTIVE CLEARANCE OF APOPTOTIC CELLSDelayed 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 cellsThere 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

122BCMAD-Elevated BAFF/IFNGenetic-HLA, X chromosome,Compliment defHormone - OestrogenPoor Adrenal functionLow blood levels of the hormone DHEAEnvironment- 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-IFNDefects -NETOSISDefective-ApoptosisNecrosisLeads to defective immune clearence.Increased rate of CD4/CD8

SLESYMPOSIUM 08 12 20111.Introduction2.History3.Epidemiology4.Pathophysiology5.Pathology6.Autoimmunity7.Clinical features8.Diagnosis9.Management10.Future

Activated pDC- IF

IF Demo

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-aIFN-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.129SLESYMPOSIUM 08 12 20111.Introduction2.History3.Epidemiology4.Pathophysiology5.Pathology6.Autoimmunity7.Clinical features8.Diagnosis9.Management10.Future

AUTO-ANTIBODIESANA: 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 nephritisImmune 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; doesnt track with disease, specific for lupus

131SSA/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-glycoproteinRENAL 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.

133SKIN 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 rareAnti-NMDA receptor antibodies may contribute to cerebral lupus phenotypesMicroinfarcts 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

135AUTOANTIBODIES ASSOCIATED WITH SLETARGET ANTIGENAPPROXIMATE FREQUENCYNUCLEAR ANTIGENS99dsDNA70RNP (U1-RNP)33RO (SSA)49LA (SSB)35Sm38PHOSPHOLIPIDS21RIBOSOMAL10SLESYMPOSIUM 08 12 20111.Introduction2.History3.Epidemiology4.Pathophysiology5.Pathology6.Autoimmunity7.Clinical features8.Diagnosis9.Management10.Future

Nervous SystemHeadache is the most common complaint

ADD, mood disorders, anxiety, delirium, psychosis, seizures (generalized or partial)Difficult to prove absolute causality

Generalized encephalopathiesFormal neuropsychiatric testing reveals deficits in 21-67% of patients with SLE139Cerebritis:

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, depressionCognitive dysfunctionPsychosisSeizuresStrokeChoreaPseudotumor cerebriTransverse myelitisPeripheral neuropathyTotal of 19 manifestations describedMay be difficult to distinguish from steroid psychosis or primary psychiatric diseaseNEUROLOGICOCULAR MANIFESTATIONSMucocutaneous lid involvement, secondary sjgren's syndrome, retinal vascular disease and neuroophthalmic disease . Retinopathy - usually consists of cottonwool spots with intraretinal haemorrhages. More severe form of lupus retinitis - retinal arteriolitis and vascular occlusion, resulting in capillary nonperfusion, 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 vasoocclusive disease

Hematologic SystemChronic anemia is present in up to 80% of patientsLeukopenia is present in up to 50% of patients (lymphopenia more common than neutropenia). Thrombocytopenia ranges from modest to severe with bleeding complicationsMay reflect disease activityMay be first sign of SLE; predating other signs and symptoms by years.Associated with the presence of anti-platelet antibodiesSecondary APS seen in about 40% of patients with SLE+

144

CV SystemPericarditis 6-45% of patients: low likelihood of tamponade or constrictive type. 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/mm3 on 2 occasions OR

c) Lymphopenia--< 1,500/ mm3 on 2 occasions OR

d) Thrombocytopenia-- 0.5 g/d proteinuria 3+ dipstick proteinuria B Cellular casts8. Neurologic disease. A SeizuresB Psychosis (without other cause)9. Hematologic disorders. A Hemolytic anemiaB Leukopenia (< 4000/uL) C Lymphopenia (< 1500/uL) D Thrombocytopenia (< 100,000/uL)10. Immunologic abnormalities. A Positive LE cell B Anti-ds- DNAC Anti- SmD Any antiphospholipid11. Positive ANA ( 95-100% )THE 1982 REVISED CRITERIA FOR CLASSIFICATION OF SLE (UPDATE)CLASSIFICATION CRITERIAMust have 4 of 11 for ClassificationSensitivity 96%Specificity 96%Like RA, diagnosis is ultimately clinicalNot all Lupus is SLEDiscoid LupusOverlap syndromeDrug induced lupusSubacute Cutaneous LupusLab FindingsComplete blood count

Anemia LeukopeniaLymphopeniaThrombocytopenia

Urine Analysis Hematuria ProteinuriaGranular castsLE CellThe 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 FINDINGSANA - 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 antibodiesAnti-Sm (Smith)Anti Ro/SSA-antibodyAnti La/SSB-antibodyAnti-RNPAntiphospholipid antibody

Biologic false + RPRLupus anticoagulant-antibodies tocoagulation factors. risk factor for venous and arterial thrombosis and miscarriage. Prolonged aPTTAnti-cardiolipin

Depressed serum complement

Anti histone antibodies

Total blood complement level: 41 to 90 hemolytic units

C1 level: 16 to 33 mg/dLC3 levels:Males: 88 to 252 mg/dLFemales: 88 to 206 mg/dLC4 levels:Males: 12 to 72 mg/dLFemales: 13 to 75 mg/dL

Increased complement activity may be seen in:CancerCertain infectionsUlcerative colitisDecreased complement activity may be seen in:CirrhosisGlomerulonephritisHereditary angioedemaHepatitisKidney transplantrejectionLupus nephritisMalnutritionSystemic lupus erythematosis

DIFFERENTIAL DIAGNOSISAlmost too broad to consider given number of clinical manifestationsRheumatic: RA, Sjogrens syndrome, systemic sclerosis, dermatomyositisNonrheumatic: HIV, endocarditis, viral infections, hematologic malignancies, vasculitis, ITP, other causes of nephritisOverlap Syndrome (UCTD, MCTD)LUPUS RELATED SYNDROMESAntiphospholipid 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

LUPUS RELATED SYNDROMESDrug 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 drugLUPUS RELATED SYNDROMESRaynauds Syndrome:-Not part of the diagnostic criteria for SLE.

-Does NOT warrant ANA if no other clinical evidence to suggest autoimmune diseaseSLESYMPOSIUM 08 12 20111.Introduction2.History3.Epidemiology4.Pathophysiology5.Pathology6.Autoimmunity7.Clinical features8.Diagnosis9.Management10.Future

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, methotrexateSLE 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: cyclosporineTREATMENTAntiphospholipid SyndromeAnticoagulation with warfarin (teratogenic) subcutaneous heparin and aspirin is usual approach in pregnancy

Lupus and PregnancyNo longer contraindicatedNo changes in therapy other than avoiding fetal toxic drugsComplications related to renal failure, antiphospholipid antibodies, SSA/SSBNephritisClass I-no RxClass II-Rx if proteinuria >1000 mg/dClass III and IV at high risk of progression so require aggressive immunosuppressive therapyClass V Rx with steroidsClass VI-dialysis or transplant189PROGNOSISUnpredictable course10 year survival rates exceed 85%Most SLE patients die from infection, probably related to therapy which suppresses immune systemRecommend 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 (0.51.0 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 mol/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 studiesWhile 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.

ConclusionsHigh-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.

RESULTSOf 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.

CONCLUSIONSIn 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 Frdric 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,Vronique le Guern12, Genevive Depresseux1, Loc Guillevin12, Ricard Cervera13, the MAINTAIN Nephritis Trial GroupAbstractBackground 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.

MethodsA 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 actionExamples of targetsT cellsCTLA4-Ig, modified CD40L, inhibition of ICOSRegulatory T cells: expanding CD4+CD25+, CD8+CD28-B cellsmAbs to CD20, CD22, BlyS, TACi-Ig, BAFF-RFcProteosome/plasma cellsCytokinesInhibition of IL-6, IL-10; TNF inhibitorsInnate immune systemInhibition of IFN- and IFN-, blockade of TLR-7 and/or TLR-9, C5a inhibitionToleragensPeptides derived from nucleosomes, splicosomesCell surface receptor activation inhibitionSyk kinase, sirolimusTargets for new therapies in systemic lupus erythematosusaThe 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 CrDecrease 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 yearsbut.. 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 alsoallow for the use of lower doses of glucocorticoids at the earlyphases 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 maintenanceRenal protection

Lupus nephritis: where are we now? Lupus nephritis: where are we now? Lightstone L Curr Opin Rheumatol. 2010 May;22(3):252-6.

BIOSIMILARS (Superman) Clinical 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.

SLESYMPOSIUM 08 12 20111.Introduction2.History3.Epidemiology4.Pathophysiology5.Pathology6.Autoimmunity7.Clinical features8.Diagnosis9.Management10.Future

How Understanding the Mechanism of SLE will influence therapyCurrently, 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

237How Understanding the Mechanism of SLE will influence therapyRemoval of B cells may improve disease controlpen 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 rituximabTrials of anti-IFN-a antibodies are underway

238Preliminary 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. AnakinraAnakinra 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 warriorsFutile Attempts- Nepotism?The futile attempt in search of various biosimilars (Superman) to protect from SLE still continued. -Hope for a good hope-

Galens 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

Quassia amaraThank youHowever, 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-astimulusTLR activation- pDc activation Inate Im-adaptive imNutrophil activation- NetosisCompliment activation-humoral imTiue injury-Apoptosis/NecrosisComplement 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-1. Activation of such sensors has additional cell typespecific effects (e.g., in dendritic cells [DC] or macrophages [M], 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 SummaryDefects 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)

253Mechanism SummaryOnce 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 neutrophils 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.

SpidermanThus 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.NETOSISIt 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-DNAantimicrobial 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 RoleToll-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

261Pathogens and cell necrosis alert innate immunityAll 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-1, NF-Bdependent cytokines and chemokines, and IFN- and IFN-, the three dominant cytokine classes of innate immunity. NOD-like receptors and RIG helicases convert the recognition nucleic acids into cytokine release.

CELL DEATHThere 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 PathologyPlasma 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 AssociationsHLAs are loci on genes that code for certain chain on the MHC complex

HLA-DR2

HLA-DR3

HLA-DQB1 Involved in mediating production of antibodies to ds-DNA.OVERACTIVE B-CELLSEstrogen is a stimulator of B-cell activity

Lupus is much more prevalent in females of ages 15-45Height 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 inflammationLactoferrin and hCAP-18 (the precursor of LL-37) are restricted to the neutrophils secondary (specific) granules

Lysozyme, another antimicrobial molecule, 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.

The following laboratory tests are suggested for monitoring in a patient with a previous history of renal involvement who is currently free of proteinuria and who has a normal creatinine clearance.Complete blood countErythrocyte sedimentation rateC-reactive proteinUrinalysis with examination of urinary sedimentSpot (untimed) urine protein and creatinineSerum creatinine and estimated glomerular filtration rate (eGFR)Serum albuminAnti-dsDNAComplement (CH50 or C3 and C4)For patients without a history of lupus nephritis, the spot (untimed) urine protein and creatinine and serum albumin are unnecessary.

The use of nontargeted agents: Important recent studiesThe overwhelming majority of agents in development are biologics. However, some nonbiological agents and drugs that are on the market for other disorders have been or are under study for SLE. A detailed discussion of these studies is beyond the scope of this minireview, but the salient points are summarized below:1. Fish oil is ameliorative in patients with mild activity [6].2. A large trial evaluating the efficacy of vitamin D is in progress (NCT 00418507).3. The Canadian Cooperative Consortium recently demonstrated that methotrexate is steroid sparing and has anti-inflammatory properties [7].4. Mycophenolate mofetil is equivalent to cyclophosphamide as induction therapy for SLE nephritis and is superior to azathioprine for maintenance [8,9].5. Topical pinecrolimus and tacrolimus are effective for chronic cutaneous SLE [10].6. Leflunomide improves SLE arthritis [11].7. Dehydroepiandrostrone has modest effects at best in mild SLE and may diminish fatigue and bone demineralization, as well as having steroid sparing properties [12].

In summary, none of the above agents are significantly ameliorative of SLE, and none have been shown to significantly influence its morbidity or mortality when compared to other agents currently available.

Ground rules: Requirements for a new SLE drugThe June 2010 FDA guidelines indicate that a candidate SLE drug should meet its primary endpoint in two adequate well-controlled trials demonstrating superiority [4]. Studies should be at least 1 year in duration, and enrollees should fulfill the American College of Rheumatology criteria for SLE. Steroid use variability should be minimized, and sparing effects, if any, should be defined. Study patients should be stratified by the severity of their SLE, with the British Isles Lupus Assessment Group (BILAG) 2004 [5] guidelines being the preferred index for measuring disease reduction (although the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), European Community Lupus Activity Measure (ECLAM) and Systemic Lupus Activity Measure (SLAM) are also acceptable). The docume