1. Systemic Lupus Erythematosus (SLE)
Dr.hanan alrayes,md
Consultant Rheumatology

2. Systemic Lupus Erythematosus (SLE)
Epidemiology
Pathogenesis of Lupus
Clinical manifestation
Discuss the clinical Course of SLE
Diagnostic criteria
Management

3. Systemic Lupus Erythematosus (SLE)
SLE is a chronic multisystem autoimmune inflammatory disease that is commonly diagnosed in women of childbearing age and it can affect any age group.
 Symptoms for each patient will be different, and this makes the disease difficult to diagnose

4. What is autoimmunity?
Diseases in which the pathology is caused by adaptive immune responses to self-antigens are called autoimmune disease
Basically, in autoimmune diseases, the human immune system recognizes parts of the body as harmful antigens and so builds a response, targeting self-cells. 
 Autoimmunity is very complex.  There are many different autoimmune diseases, each affecting the body in vastly different ways.
Even patients with the same autoimmune disease may show different symptoms. 
Autoimmune disease affect mostly women of childbearing age. 
While there is clear evidence of a genetic factor, environment, hormones, aging and chronic stress are also thought to play a role. 
 Generally, autoimmune diseases are lifelong conditions, although medication and treatment can make quality of life better for the patient

5. Epidemiology
The incidence and prevalence of SLE varies across the world by race and ethnicity as well as geography
Incidence is 1.8 to 7.6/100,000 per year
Prevalence reporting
average of 20/100,000 per year in the U.S
19.28 per 100,000 population in Qaseem region(Saudi Arabia)
AGE :
In female 80% present during childbearing years (20-45 years)
SLE can occur in all age groups, but it is uncommon before 8 years of age
Female: male 9:1 (in adults)
In prepubertal children as low as 2:1

6. Abnormal (control of) immune responses
SLE - Etiology
The etiology of SLE remains unknown
Yet, SLE is clearly multifactorial:
Genetic factors
Immunologic factors
Hormonal factors
Environmental factors
EBV?
Genetic predisposition
Baseline immunological abnormalities
Infection
Hormonal factors
Abnormal (control of) immune responses
SLE

7. Genetic susceptibility
Concordance of SLE is 25% among monozygotic twins but only 2% among dizygotic twins It is estimated that at least 4 susceptibility genes are needed for the development of SLE:
HLA-DR2 and HLA-DR3 confer relative risk of 2-5. DRB1*0301 and DRB1*1501
HLA class III genes
C1q deficiency results in high likelihood of developing SLE
Complement C4A deficiency: 80% of people with SLE have at least one null allele
C1r/s and C2 deficiency.
Mocc et al, J clininal pathology; Jul 2003
SNR signle-nucleotide polymorphisms

8. Risk factors The Complement Paradox
Deficiencies in C1,C2,C4 and CR1 predispose to the development of SLE
Complete lack of C1q or C % develop SLE
C3 deficiency % lupus like disease
Trouw, L.A. et al., Mol Immunology (2008) 45:

9. Risk factors SEX, Hormones and HPA axis
F:M ratio 9:1
Both physiological and supra physiological concentration of estrogen facilitate humoral responses , leading to increased B cell proliferation and antibodies production
The HPA axis is the chief component of the stress system:
Defective HPA axis ass with decrease in CRH mRNA expression
Increase in oestrogen metabolism to more potent metabolites
Low androgen values, as it correlate inversely with disease activity
Hyprprolactinaemia
Ulff et al ,J Rheumatol 2009;36:1903

10. Risk factors Environmental factors
Environmental factors such as ultraviolet light and sunlight, it can precipitate SLE flares, particularly skin disease
Infectious agents are thought to possibly induce autoimmune responses by molecular mimicry or another unknown mechanism
Silica dust, found in materials such as soil, cement and cigarette smoke, may increase the risk of SLE
Smoking is associated with a higher prevalence and greater severity of SLE

11. Source of the Auto-antigens in Lupus
The fundamental abnormality in SLE is selective loss of tolerance and self/non-self recognition and the development of auto-antibodies 11

13. Clinical Manifestations
Ranges from a relatively mild disorder to rapidly progressing, affecting many body systems
Most commonly affects the skin, joints, muscles, lining of lungs, heart, nervous tissue, and kidney.
Constitutional symptoms
Fever
Fatigue: mild to extreme fatigue
Lymphadenopathy
weight loss

14. What are the symptoms of SLE?
Skin rashes : 
Acute Butterfly rashes :Raised or flat malar rashes that occur across the bridge of the nose and on the cheeks. 
Suacute
Chronic Raised discoid rashes occur on the face, hand or other body parts.
 Sunlight usually aggravates these rashes.   

15. Clinical Manifestations
Oral /Nasopharyngeal ulcers Alopecia Raynaud's phenomena

16. Musculoskeletal Arthritis/Arthralgia
Symmetrical inflammatory polyarthritis
Non erosive
Swan neck like deformities called
Jaccoud's arthritis
Myositis/ myalgia

17. Neuropsychiatric symptoms
Seizures
Psychosis   
 Cognitive dysfunctions
Cranial nerves
Lupus headache
Transverse myelitis
Cerebrovascular accident ( CVA)
Neuropathy (mononeuritis multiplex, peripheral neuropathy)
Neurological manifestations are most likely due to the affect of autoantibodies on the central nervous system. 
Eye involvement :
Retinal hemorrhage
Optic neuritis

18. Respiratory/cardiovascular
Pleuritis (pleuritic chest pain )
Pleural effusion (Dyspnea )
Pneumonitis
Pulmonary hemorrhage
Interstitial lung fibrosis
Cardiovascular
Pericarditis
Pericardial effusion
Myocarditis
Pulmonary hypertension
Libman-Sacks endocarditis

19. Liver /Gastrointestinal
Kidney
Lupus Glomerulonephritis
Proteinuria > 0.5 gm/ day
Hematuria
Cellular cast
Liver /Gastrointestinal

20. Hematological involvement : Hemolytic Anemia Thrombocytopenia <100,000 / 𝑚𝑚 3 Neutropenia < 4000/ 𝑚𝑚 3 Lymphopenia < 1500/ 𝑚𝑚 3

21. The clinical spectrum of SLE is very broad
It make SLE both fascinating but potentially difficult to diagnose and manage 21 21 21

22. Laboratory testing
●Complete blood count and differential may reveal leukopenia, mild anemia, and/or thrombocytopenia ●Elevated serum creatinine may be suggestive of renal dysfunction ●Urinalysis with urine sediment may reveal hematuria, pyuria, proteinuria, and/or cellular casts ●Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels ●Urine protein-to-creatinine ratio SEROLOG ● ANA, Anti ds DNA , Anti Sm , anti SSA , anti SSB, Anti-U1 RNP antibodies ●Antiphospholipid antibodies: (lupus anticoagulant [LA], IgG and IgM anticardiolipin [aCL] antibodies; and IgG and IgM anti-beta2- glycoprotein [GP] I) ●C3 and C4 or CH50 complement levels

23. Clinical Course of SLE: Disease activity and Damage
GENES
Environment
PRE-CLINICAL
CLINICAL
Co-morbidities
TIME
Flares
Involvement of additional organs
Damage (SLICC)
Infections
Atheroscherosis
Malignancies
Autoantibodies
General- specific
Inflammatory
Involvement of first organ 23 23 23 23

24. diagnosis
The diagnosis of SLE is generally based on clinical judgment, after excluding alternative diagnoses.
Serological findings
ANA are important to suggesting the possibility of SLE
Anti-double-stranded DNA [dsDNA] and anti-Smith [Sm]) highly associated with SLE.
SLE classification criteria

25. Autoantibodies
ANA:
Against targets in the nucleus
The different types of ANAs are defined by their target antigen, including
double-stranded DNA,
individual nuclear histones,
other nuclear proteins
RNA-protein complex ………
THE central immunological disturbance in SLE is autoantibodies production

26. POSITIVE ANA SLE Other CTD (RA, SS, PSS, CREST, DM/PM) DRUG-INDUCED
NORMAL (FALSE POSTIVE) 5-20% of population LYMPHOPROLIFERATIVE DISORDER
CHRONIC INFECTION (HIV, Leprosy) 26

27. Autoantibodies Anti ds-DNA Anti ds-DNA is unique to SLE patients
It bind to conserved nucleic acid
Anti ds-DNA titer vary over time and disease activity:
Can correlate with nephritis
Immune complexes with anti-DNA ab/DNA can increase the expression of IFN-α via plamacytoid dendritic cells 27 27

28. Autoantibodies
SSA/Ro and SSB/La: detect ribonucleoproteins, associated with SICCA syndrome and photosensitivity
Anti-Sm: detects ribonucleoproteins involved in processing of mRNA
RNP

29. Why are autoantibodies so bad?
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

30. Renal disease
IgA, IgM, IgG and complement deposition in the mesangium and subendothelial and subepithelial of the GBM that results in complement activation and recruitment of inflammatory cells that result in tissue destruction.
Cross reactivity of anti-DS DNA antibodies with - actinin may also result in a direct focusing of complement activation 30

31. Why are autoantibodies so bad?
In the 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 may contribute to 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
NMDA (N methyl- D- Aspartate) 31

32. 1997 Acr Classification CRITERIA
Malar rash: butterfly-shaped rash across cheeks and nose
Discoid (skin) rash: raised red patches
Photosensitivity: skin rash as result of unusual reaction to sunlight
Mouth or nose ulcers: usually painless
Arthritis (nonerosive) in two or more joints, along with tenderness, swelling, or effusion. With nonerosive arthritis, the bones around joints don’t get destroyed.
Cardio-pulmonary involvement: inflammation of the lining around the heart (pericarditis) and/or lungs (pleuritis)
Neurologic disorder: seizures and/or psychosis
Renal (kidney) disorder: excessive protein in the urine, or cellular casts in the urine
Hematologic (blood) disorder: hemolytic anemia, low white blood cell count, or low platelet count
Immunologic disorder: antibodies to double stranded DNA, antibodies to Sm, or antibodies to cardiolipin
Antinuclear antibodies (ANA): a positive test in the absence of drugs known to induce it.
- See more at: diagnosis#sthash.9vPrenyo.dpuf

35. DIFFERENTIAL DIAGNOSIS
Rheumatoid arthritis
Mixed connective tissue disease
Drug induced lupus
Undifferentiated connective tissue disease
Dermatomyositis
Sjögren’s syndrome
Vasculitis
Adult Still’s disease (ASD)
Kikuchi’s disease
 Multiple sclerosis (MS)
Infection
malignancy

36. Management General measure Sun protection Diet and vitamin D Exercise
Immunization
Medications and/or therapies are often used to suppress the response of the immune system according to the severity and organ involved.
Treating comorbid conditions

37. The ‘traditional treatment armamentarium’
Benlysta

38. Biological Therapies
Proteins that affect cells or signals in the immune system
Usually need to be injected or infused (IV)

39. Biological Therapies APC Immune Stimulation IFN-α Rituximab
Rontalizumab
Sifalimumab
Immune Stimulation
IFN-α
pDC
Belimumab Atacicept
Rituximab
Ocrelizumab
Veltuzumab
Immune complexes containing nucleic acids
IPP
CD 20
Fostamatinib
Bly S
Apoptotic Material
T Cell
B Cell
APC
Antibodies
CD 22
IL6R
epratuzumabab
Abatacept
Tocilizumab
Abetimus 39

40. Prognosis Prognosis is variable, depending on the systems involved.
Mortality in the first 5 years tends to be from active SLE or infection.
Thereafter, mortality results from coronary heart disease, end- stage renal failure, or severe infection without active SLE

41. Key points
Systemic lupus erythematosus is a chronic multisystem autoimmune disease that predominantly affects the skin and joints, although any body system can be involved
The most common presentation is a butterfly rash on the face, low-grade fever, and non-deforming arthritis
The diagnosis is made on clinical grounds and based on the presence of antibodies to nuclear antigens such as anti- nuclear antibodies (ANA) and related serology, such as anti– double-stranded DNA (anti-dsDNA)

42. Case 1
A 26-year old female presented with generalized fatigue and pain and swelling of her hands, knees and feet with a MS of 60 minutes of 5 weeks duration. Associated with photosensitive skin rash
Examination:
Arthritis of small joints of hands,Knees
Facial rash.
Labs: ESR 70; Hb 11.5; WBC 4.2;lyhphocyte 1, plat 221; urine: proteinuria with casts on microscopy.

43. Inflammatory polyarthritis malar rash proteinuria
Summary:
26-y old female
Inflammatory polyarthritis
malar rash
proteinuria

44. Arthritis in a female 25-50 years of age:
Systemic lupus erythematosus
Rheumatoid arthritis
Other CT diseases: SS; DM; MCTD
Viral infection
……….

45. COMMONEST CAUSES OF POLYARTHRITIS
Inflammatory:
RA, SLE, DM/PM, SS, MCTD, seronegatives
Infectious:
Viral ,Some bacterial agents ( gonorrhea, brucellosis)
Neoplastic:
Leukemia, metastasis

46. Causes of erythematous rash over cheeks:
Systemic lupus erythematosus
Dermatomyositis

47. See more at:
- Davidson's Principles and Practice of Medicine, 22nd Edition

48. QUESTION