Systemic lupus erythematosus - overview

Systemic lupus erythematosus - an overview: 

Systemic lupus erythematosus - an overview - Dr. Parvez Khan - Dr. Deepak Kapoor Assistant Professors, M - 1 Department of Internal Medicine Deccan College of Medical Sciences

Systemic Lupus Erythematosus Definition: 

Systemic Lupus Erythematosus Definition An inflammatory multi-system disease Immunologic aberrations: excessive auto-antibody production Tissue damage results from antibody and complement fixing immune complex deposition Wide spectrum of clinical presentations Characterized by remissions and exacerbations

Epidemiology: 

Epidemiology SLE - recognized worldwide Prevalence in USA: 15-50 \ 100,000 (1:2000) Incidence in USA: 1.8-7.6 \ 100,000\ year F:M 9:1 ( at age: 14-64 ) Racial predisposition: x 3 more common in blacks

Epidemiology in the young and elderly: 

Epidemiology in the young and elderly Peak incidence is at age 15-40 But: Onset may be at any age In pre-pubertal and post menopausal : female : male ratio 3:1

Genetic Epidemiology: 

Genetic Epidemiology SLE is a multi-genic disease In < 5% of patients a single gene is responsible Homozygous deficiencies of early components of complement (C1q, C1r, C1s, C4, C2) predispose to SLE A null allele for C4A is the HLA-linked gene most consistently associated with susceptibility to SLE

Genetic Epidemiology: 

Genetic Epidemiology HLA class II genes are associated with production of auto-antibodies TCR genes and Ig genes may contribute to susceptibility FC g RIIA, FC g RIIIA predispose to SLE in some ethnic groups (possibly responsible for impaired IC clearing)

Genetic Epidemiology: 

Genetic Epidemiology concordance for monozygotic twins: 24-58% relatives of SLE patients have increased incidence of: - SLE - other auto-immune diseases - auto-antibodies ~ 10% of SLE patients have relatives with SLE males need more susceptibility genes

Importance of Sex hormones : 

Importance of Sex hormones Female predominance (9:1) disease activity during menstrual period increased disease activity in pregnancy flares with oral contraceptive therapy abnormally rapid testosterone metabolism estrogenic metabolites persist longer

Environmental Factors: 

Environmental Factors Ultraviolet light ( UVB ) Alfalfa sprouts, chemicals ( hydrazines) ? Drugs (Resprim = Trimethoprim + sulphamethoxazole) Infections (parvovirus, CMV, HCV ) Smoking ( Discoid LE )

Defective Immune Regulation : 

Defective Immune Regulation B cell and T cell hyperactivity leads to: T cell dependent auto- Ab production made in high quantity Subsets of auto-Abs and the Immune Complexes they form with Ag mediate tissue damage Defective clearance of Immune Complexes Defects in immune tolerance and apoptosis Defects in T and natural killer regulatory cells

Pathogenic auto-antibodies Mechanisms of damage: 

Pathogenic auto-antibodies M echanisms of damage Direct binding to tissue via charge or cross-reactivity ( anti-DNA) Production of Immune Complexes leads to complement mediated damage Direct binding to cell membranes ( RBCs, Platelets)

Clinical Manifestations of SLE: 

Clinical Manifestations of SLE Constitutional non-specific but very common: - Fatigue - Fever - Weight Loss

Skin Manifestations LE-specific lesions: 

Skin Manifestations LE-specific lesions Acute : - malar “butterfly rash” - generalized erythema - bullous LE Subacute cutaneous lupus Chronic lupus : - localized discoid - generalized discoid - lupus profundus

Butterfly- malar rash: 

Butterfly- malar rash

Generalized, photosensitive erythema: 

Generalized, photosensitive erythema

Bullous rash: 

Bullous rash

Subacute cutaneous rash psoriatiform annular: 

Subacute cutaneous rash psoriatiform annular

Discoid rash: 

Discoid rash

Skin Manifestations LE-nonspecific lesions: 

Skin Manifestations LE-nonspecific lesions Panniculitis Urticarial lesions Vasculitis Livedo reticularis Oral lesions Non-scarring alopecia

Panniculitis: 

Panniculitis

Vasculitis with finger tip ulcers: 

Vasculitis with finger tip ulcers

Livedo reticularis: 

Livedo reticularis

Alopecia (diffuse or patchy) Non-scarring if part of SLE flare Scarring if results from discoid: 

Alopecia (diffuse or patchy) Non-scarring if part of SLE flare Scarring if results from discoid

Skin biopsy: Lupus band test = immunofluorescent staining of IgG and complement deposits in dermo-epidermal junction: 

Skin biopsy: Lupus band test = immunofluorescent staining of IgG and complement deposits in dermo-epidermal junction

Skin biopsy - SLE dermatitis Thickened epidermal basement membrane (large arrows) Inflammatory infiltrates (small arrow): 

Skin biopsy - SLE dermatitis Thickened epidermal basement membrane (large arrows) Inflammatory infiltrates (small arrow)

Skin biopsy - Discoid lesion Hyperkeratosis (small arrow) Lymphoid infiltrates (thick arrow) Fibrosis of deep dermis: 

Skin biopsy - Discoid lesion Hyperkeratosis (small arrow) Lymphoid infiltrates (thick arrow) Fibrosis of deep dermis F

Musculoskeletal Manifestations: 

Musculoskeletal Manifestations Arthritis : - the most common manifestation of SLE - non-erosive, rarely deforming (Jaccoud’s deformity) - synovial fluid- mild inflammation - tenosynovitis-may be early manifestation Myopathy : - myositis = true inflammation - myopathy 2nd to drugs: steroids, anti-malarials

Jaccoud’s arthropathy: 

Jaccoud’s arthropathy

Renal Disease in SLE : 

Renal Disease in SLE Proteinuria: 0.5 gr\ 24 hrs ( or > +3 ) Urinary casts: RBC,granular,tubular,mixed Hematuria: > 5 RBC / high power field Pyuria: > 5 WBC / high power field prevalence: 30-65% in 3-6% renal disease is first manifestation

WHO Classification of Lupus Nephritis J Am Soc Nephrol 15: 241-250, 2004: 

WHO Classification of Lupus Nephritis J Am Soc Nephrol 15: 241-250, 2004 Class I - Minimal mesangial LN (mesangial immune deposits seen by IF) Class II - Mesangial proliferative LN Class III - Focal proliferative LN (<50% of glomeruli with focal subendothelial immune deposits) Class IV - Diffuse proliferative segmental LN (IV-S) - Diffuse proliferative global LN (IV-G) ( > 50% of glomeruli with subendothelial immune deposits) Class V - Membranous LN (global or segmental subepithelial deposits) Class VI - Advanced sclerosing LN ( > 90% of glomeruli globally sclerosed) Activity index Chronicity Index

Renal disease in SLE: 

Renal disease in SLE Mild disease - Class II Serious disease - Class III, IV, V Clinical course: - Class II: hematuria, sub-nephrotic proteinuria, preserved GFR - Class III and IV: edema, HTN nephritic sediment, mild-mod proteinuria, acute GFR - Class V: features of nephrotic syndrome, preserved/ gradual GFR

Serositis in SLE: 

Serositis in SLE Pleuritis - occurs in 30-60% of patients Pericarditis - occurs in 20-30% Peritonitis

Cardiac Manifestations: 

Cardiac Manifestations Pericarditis Myocarditis Endocarditis (Libman -Sacks endocarditis) Coronary heart disease

Pulmonary Manifestations: 

Pulmonary Manifestations Pleuritis Pneumonitis - acute or chronic Pulmonary hemorrhage - due to vasculitis Pulmonary hypertension Pulmonary embolism

Hematologic Manifestations : 

Hematologic Manifestations Anemia: - in acute SLE: coomb’s positive hemolytic anemia - secondary to: chronic disease, CRF, blood loss, drugs. Leukopenia / Lymphopenia : - in active disease - secondary to drugs, infection

Hematologic Manifestations: 

Hematologic Manifestations Thrombocytopenia: - anti-platelet abs- common, not always associated with thrombocytopenia - occurs in active SLE - may be isolated finding ( ~ 50,000 without serious bleeding )

Neuropsychiatric SLE : 

Neuropsychiatric SLE Central nervous system Aseptic meningitis Cerebrovascular disease Demyelinating syndrome Headache (migraine, benign intracranial pressure) Movement disorder (chorea) Myelopathy Seizure disorder Acute confusional state Anxiety disorder Cognitive dysfunction Mood disorder Psychosis Peripheral nervous system Guillain - Barre’ syndrome Autonomic disorder Mononeuropathy, single/multiplex Myasthenia Gravis Neuropathy, cranial Plexopathyy Polyneuropathy The American College of Rheumatology Nomenclature and case definitions for Neuropsychiatric lupus syndromes . Arthritis & Rheumatism 1999

Anti-Nuclear Antibodies (ANA): 

Anti-Nuclear Antibodies (ANA) ANA : abs directed against nuclear antigens may occur in other systemic rheumatic diseases most frequent and highest in titer in SLE Positive in 98% of SLE patients detected by indirect immuno-fluorescence

Patterns of IF ANA staining: 

Patterns of IF ANA staining Homogenous (diffuse) - dsDNA , histone SLE, drug induced SLE, RA Speckled MCTD, SLE, Sjogren , Systemic Sclerosis Nucleolar Systemic Sclerosis, Sjogren , SLE Rim (peripheral) - dsDNA histones characteristic of SLE

Patterns of Immuno-fluorescence ANA staining: 

Patterns of Immuno -fluorescence ANA staining

ANAs : 

ANAs ANA’s can be divided into: those directed against dsDNA those directed against ssDNA those directed against histones those directed against non-histone nuclear proteins : nucleic acid-protein complexes

AUTOANTIBODIES IN SLE:: 

AUTOANTIBODIES IN SLE: Autoantibody anti- ds DNA anti- ss DNA anti- Histones anti- Sm ( Smith) anti- RNP anti- Ro ( SSA) anti- La ( SSB) Prevalence 50-60% 60-70% 70% 30% 35% 30% 15%

Anti DNA antibodies in SLE: 

Anti DNA antibodies in SLE Anti ss- DNA : nonspecific and not in clinical use Anti-ds DNA : specific for SLE Clinical use important : - levels correlate with disease activity - presence and level associated with risk for renal disease - pathogenic effect mediated through direct binding to glomeruli or immune-complex mechanisms.

Clinical Associations of Auto-antibodies in SLE: 

Clinical Associations of Auto-antibodies in SLE

Diagnosis of SLE: 

Diagnosis of SLE Based on a combination of clinical manifestations and laboratory findings which may occur simultaneously or serially Classification criteria are used for research

Classification criteria of SLE : 

Classification criteria of SLE Criterion Malar Rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurologic disorder Hematologic disorder Definition - Fixed erythema, malar distribution - Erythematous raised patches with scaling, atrophy, scarring - Skin rash as result of sunlight - Oral\ nasopharyngeal, usually painless - Nonerosive, 2 or more joints - Pleuritis OR Pericarditis -Proteinuria > 0.5gr or >+3 OR cellular casts - Seizures OR Psychosis - Hemolytic anemia OR Leukopenia < 4000/ mm 3 OR Lymphopenia <1500/mm 3 OR Thrombocytopenia < 100.000/mm 3

Classification criteria of SLE : 

Classification criteria of SLE Criterion 10. Immunologic disorder 11. Anti-nuclear antibody Definition - anti-dsDNA OR - anti- Sm OR - false positive VDRL / anti-phospholipid antibody Abnormal titer of ANA in absence of drugs known to cause DIL For diagnosis: any 4 of 11 criteria

Management of SLE: 

Management of SLE

The Challenge: 

The Challenge Treat Active Lupus Prevent Damage from: - Active lupus - Corticosteroids - Immunosuppressive agents

Treatment of active SLE Organ System Approach: 

Treatment of active SLE Organ System Approach Use the drug with the: - Least side effects - Lowest dose to control disease - Long term damage prevention Mild disease: Avoid Steroids Severe disease: Aggressive treatment

Treatments for SLE: 

Treatments for SLE NSAIDs Corticosteroids Hydroxychloroquine (Plaquenil) Chloroquine (Aralen) Antimalarials Quinacrine ( Mepacrine; Atabrine) Methotrexate Azathioprine Cyclophosphamide Cyclosporine Mycophenolate Mofetil (Cellcept) IVIG Thalidomide

Corticosteroids: 

Corticosteroids Effective for the suppression of all SLE manifestations NOT justified for Arthritis Moderate doses (20-30mg/d) sufficient for: pleuritis / pericarditis High doses (1mg/kg) required for: Nephritis, CNS disease, Severe hemolytic anemia or thrombocytopenia IV pulse 1g methylprednisolone sometimes used for refractory nephritis or life threatening disease

Corticosteroids- the price:: 

Corticosteroids- the price: Avascular Necrosis of Bone Osteoporosis with Fracture Hypertension, Hyperglycemia Premature Atherosclerosis Quality of life: Weight, Cushingoid Habitus, Mood changes

Anti-Malarials Hydroxychloroquine, Chloroquine, Quinacrine: 

Anti- Malarials Hydroxychloroquine , Chloroquine , Quinacrine Effective for the treatment of : Fatigue, Arthritis, Skin disease Prevents SLE flares Lowers cholesterol levels Anti-aggregant effect

Methotrexate: 

Methotrexate May be effective as a steroid sparing agent in the treatment of: - arthritis - skin disease

Immunosuppressive agents Azathioprine, Cyclophosphamide, Cyclosporine, Cellcept: 

Immunosuppressive agents Azathioprine , Cyclophosphamide , Cyclosporine, Cellcept Used mainly for nephritis May be used for major organ involvement - Azathioprine : P.O. 2-3mg\kg - Cyclophosphamide : IV pulses 0.5-1.0gr/m 2 q month than q3 months for 2-3 yrs - Cyclosporine: P.O. 1-3mg\kg\d - Mycophenolate Mofetil (Cellcept) : P.O. 1-3gr\d

Treatment of Lupus Nephritis: 

Treatment of Lupus Nephritis Induction : - Corticosteroids - IV Cyclophosphamide \ q month - Mycophenolate Mofetil ( Cellcept ) ? Maintenance: - IV Cyclophosphamide \ q 3 mo - Azathioprine - Mycophenolate Mofetil ( Cellcept ) - Cyclosporine

Cyclophosphamide side effects: 

Cyclophosphamide side effects Infection - frequency - 45% - sequential infusions - WBC < 3000 Premature ovarian failure - cumulative dose - age: < 25 yrs - 6% > 31 yrs - 67% Malignancy leukemia, gynecologic malignancies, bladder

Mycophenolate Mofetil ( MMF = Cellcept): 

Mycophenolate Mofetil ( MMF = Cellcept ) Immunosuppressive for: kidney, liver and heart transplant Inhibitor of : Inosine Monophosphate (IMP) dehydrogenase - key enzyme in de novo purine synthesis - glycosylation of adhesion molecules in T and B cells Inhibits: - proliferation of T and B lymphocytes - production of abs - generation of cytotoxic T cells - recruitment of leukocytes to sites of inflammation

MMF or IV Cyclophosphamide for Lupus Nephritis Ginzler et al. NEJM 2005: 

MMF or IV Cyclophosphamide for Lupus Nephritis Ginzler et al. NEJM 2005 140 pts class III, IV, V (24 week trial) MMF (71 pts) CTX (69 pts) At 12 weeks: - Complete remission 16 4 - Partial remission: 21 17 - Death 0 3 - Severe infections 1 6 - Diarrhea 15 2 Conclusion: - MMF more effective than CTX in inducing remission - severe infections : less with MMF

Sequential Therapies for proliferative LN Contreras G et al. NEJM 2004: 

Sequential Therapies for proliferative LN Contreras G et al. NEJM 2004 59 patients: class: III-12; IV-46; Vb-1 Induction: IV CYC (0.5-1gr/m 2 ) q mo for up to 7 pulses + steroids Maintenance (1-3 yrs): - IV CYC q 3 months - AZA 1-3 mg/kg/d - MMF 0.5-3 gr /d

Future possible treatments for SLE Treatments designed to effect specific processes: 

Future possible treatments for SLE Treatments designed to effect specific processes LJP 394 : B cell toleragen: cross links anti-DNA receptors on B cells Anti IL-10 : IL-10 is increased on correlates with disease activity Anti-CD40 ligand : prevents T cell activation CTLA4Ig : blocks CTLA4 on activated T cells from binding to B7 on B cells Anti C5 complement C1q immunoadsorption : removes immune complexes Anti CD 20 (Rituximab): CD20 is B cells restricted ag- leads to B cell depletion Anti-BLyS: anti B Lymphocyte Stimulator protein which is elevated in SLE

Prognosis: 

Prognosis Survival: 90-95% at 2 years 82-90% at 5 years 71-80% at 10 years 63-75% at 20 years Poor prognostic factors: - creatinine, nephrotic syndrome - hypertension - thrombocytopenia - African- American race - low socioeconomic status

Pregnancy and SLE: 

Pregnancy and SLE 1950s: - in SLE: pregnancy is not advised - termination should be offered 1990s: - 10-30% flare during pregnancy / postpartum - most flares are minor

Pregnancy Outcomes in SLE Johns Hopkins Cohort: 

Pregnancy Outcomes in SLE Johns Hopkins Cohort Fertility rates : normal 2-2.4 pregnancies\patient Preterm < 37 weeks 40.5% < 36 weeks 32.1% Pregnancy loss 10-30% 1st trimester 6.0% 2nd trimester 7.1%

The Mother in SLE: 

The Mother in SLE Risk factors for exacerbation : - active disease 3-6 months before conception - pre-existing renal disease Conception during remission: 10-30% risk of flare. Mild lupus rarely exacerbates in pregnancy Severe exacerbations: in 20% of pregnancies

Management of SLE flares in pregnancy: 

Management of SLE flares in pregnancy Prednisone IV Pulse methylprednisolone NSAIDs ( during 1st trimester ) Plaquenil Azathioprine Cyclosporine

Thank You: 

Thank You