systemic lupus erythematosus (sle ) dr.hanan alrayes,md consultant rheumatology

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

DR.HANAN ALRAYES,MD

CONSULTANT RHEUMATOLOGY

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

Epidemiology

Pathogenesis of Lupus

Clinical manifestation

Discuss the clinical Course of SLE

Diagnostic criteria

Management

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

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

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

SLE - Etiology• The etiology of SLE remains unknown• Yet, SLE is clearly multifactorial:

– Genetic factors– Immunologic factors– Hormonal factors– Environmental factors

EBV?

Genetic predisposition

InfectionAbnormal (control of) immune responses

Hormonal factors

Baseline immunological abnormalities

SLE

GENETIC SUSCEPTIBILITYConcordance 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*1501HLA class III genesC1q deficiency results in high likelihood of developing SLEComplement C4A deficiency: 80% of people with SLE have at least one null alleleC1r/s and C2 deficiency. Mocc et al, J clininal pathology; Jul 2003

RISK FACTORS THE COMPLEMENT PARADOX

Deficiencies in C1,C2,C4 and CR1 predispose to the development of SLE

Complete lack of C1q or C4 90% develop SLE

C3 deficiency 23% lupus like disease

Trouw, L.A. et al., Mol Immunology (2008) 45:1199-1207.

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

RISK FACTORSENVIRONMENTAL 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

The fundamental abnormality in SLE is selective loss of tolerance and self/non-self recognition and the development of auto-

antibodies

SOURCE OF THE AUTO-ANTIGENS IN LUPUS

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

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.

CLINICAL MANIFESTATIONS

Oral /Nasopharyngeal ulcers

Alopecia

Raynaud's phenomena

MUSCULOSKELETAL

Arthritis/Arthralgia

Symmetrical inflammatory polyarthritis

Non erosive

Swan neck like deformities called

Jaccoud's arthritis

Myositis/ myalgia

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

Respiratory

Pleuritis (pleuritic chest pain )

Pleural effusion (Dyspnea )

Pneumonitis

Pulmonary hemorrhage

Interstitial lung fibrosis

Cardiovascular

Pericarditis

Pericardial effusion

Myocarditis

Pulmonary hypertension

Libman-Sacks endocarditis

RESPIRATORY/CARDIOVASCULAR

Kidney

Lupus Glomerulonephritis

Proteinuria > 0.5 gm/ day

Hematuria

Cellular cast

Liver /Gastrointestinal

Hematological involvement :

Hemolytic Anemia

Thrombocytopenia <100,000 /

Neutropenia < 4000/

Lymphopenia < 1500/

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

Clinical Course of SLE: Disease activity and Damage

TIMETIME

PRE-CLINICAL CLINICAL Co-morbidities

GENES Environment

AutoantibodiesGeneral- specific

AutoantibodiesGeneral- specific

•Inflammatory•Involvement of first organ

•Inflammatory•Involvement of first organ

•Flares•Involvement of additional organs•Damage (SLICC)

•Flares•Involvement of additional organs•Damage (SLICC)

•Infections•Atheroscherosis•Malignancies

•Infections•Atheroscherosis•Malignancies

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

AutoantibodiesANA: 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 proteinsRNA-protein complex

………

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)

Autoantibodies

Anti ds-DNA is unique to SLE patients

It bind to conserved nucleic acidAnti ds-DNA titer vary over time and disease activity:

Can correlate with nephritisImmune complexes with anti-DNA ab/DNA can increase the expression of IFN-α via plamacytoid dendritic cells

ANTI DS-DNA

AUTOANTIBODIES SSA/Ro and SSB/La: detect ribonucleoproteins,

associated with SICCA syndrome and photosensitivity

Anti-Sm: detects ribonucleoproteins involved in processing of mRNA

RNP

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

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

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

1997 ACR CLASSIFICATION CRITERIA

1. Malar rash: butterfly-shaped rash across cheeks and nose

2. Discoid (skin) rash: raised red patches

3. Photosensitivity: skin rash as result of unusual reaction to sunlight

4. Mouth or nose ulcers: usually painless

5. Arthritis (nonerosive) in two or more joints, along with tenderness, swelling, or effusion. With nonerosive arthritis, the bones around joints don’t get destroyed.

6. Cardio-pulmonary involvement: inflammation of the lining around the heart (pericarditis) and/or lungs (pleuritis)

7. Neurologic disorder: seizures and/or psychosis

8. Renal (kidney) disorder: excessive protein in the urine, or cellular casts in the urine

9. Hematologic (blood) disorder: hemolytic anemia, low white blood cell count, or low platelet count

10. Immunologic disorder: antibodies to double stranded DNA, antibodies to Sm, or antibodies to cardiolipin

11. Antinuclear antibodies (ANA): a positive test in the absence of drugs known to induce it.

- See more at: http://www.lupusresearchinstitute.org/lupus-facts/lupus-diagnosis#sthash.9vPrenyo.dpuf

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

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

The ‘traditional treatment armamentarium’

FDA Approved drugs glucocorticoids hydroxychloroquine low dose ASA

‘Off - label’ but standard of care azathioprine cyclophosphamide NSAIDs

Immunosuppressives developed for other diseases mycophenolate mofetil methotrexate cyclosporin leflunomide tacrolimus fludarabine

Benlysta

Biological Therapies

• Proteins that affect cells or signals in the immune system

• Usually need to be injected or infused (IV)

IFN-α

Apoptotic Material

Apoptotic Material APC T Cell B Cell

Antibodies

CD 22IL6R

CD 20

Bly S

Immune complexes containing nucleic acids

pDC

Immune Stimulation

RontalizumabSifalimumab

IPP 201101

Fostamatinib

Belimumab Atacicept

RituximabOcrelizumabVeltuzumab

Abatacept Tocilizumab

epratuzumababAbetimus

Biological Therapies

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

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)

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.

26-y old femaleInflammatory polyarthritis

malar rash proteinuria

Summary:

Arthritis in a female 25-50 years of age:

1. Systemic lupus erythematosus2. Rheumatoid arthritis3. Other CT diseases: SS; DM; MCTD4. Viral infection5. ……….

Inflammatory:

RA, SLE, DM/PM, SS, MCTD, seronegativesInfectious: Viral ,Some bacterial agents ( gonorrhea, brucellosis)

Neoplastic:

Leukemia, metastasis

COMMONEST CAUSES OF POLYARTHRITIS

Causes of erythematous rash over cheeks:

Systemic lupus erythematosus

Dermatomyositis

See more at:

- http://www.lupus.org

- http://www.lupus.com

- Davidson's Principles and Practice of Medicine, 22nd Edition

QUESTION