Molnár, Katalin MD.

Systemic Lupus Erythematosus

1. Definition, incidence, prevalence2. Etiology and pathogenesis3. Clinical manifestations4. Diagnosis5. Treatment6. Clinical course and prognosis

Definition Systemic Lupus Erythematosus (SLE) is an autoimmune disease in which organs and cellsundergo damage mediated by tissue‐bindingautoantibodies and immune complexes.

SLE The etiology is unknown. Virtually any organ of the body may be involved. Results from interactions among genetic, hormonal, environmental, and immunologic factors.

Typically the course of the disease is a series of remissions and exacerbations.

With good management, the ten years survival may be over 90%.

Epidemiology Prevalence: 2‐140/100,000 worldwide

Incidence: 1‐10/100,000 worldwide. Population at highest risk:

Women in their reproductive years Female: male ratio is approximately 9:1 More common in Black (3‐6x), Hispanic and NativeAmerican (2‐3x), and Asian (2x).

Pathogenesis and etiologyInteractions between susceptibility genes and environmental factors result in abnormal immune responses.  Activation of innate immunity (DC) by 

CpG DNA, DNA in IC, RNA in RNA/protein self‐antigens;

Lowered activation thresholds of adaptive immunity cells (Tly, Bly); 

Uneffective regulatory and inhibitory CD4+ and CD8+ T cells; 

Reduced clearance of apoptotic cells and of immune complexes;

Pathogenesis and etiology Ag, Ab, IC persist for prolonged periods of time, allowing inflammation and disease to develop.

Immune activation of circulating and tissue‐bound cells is accompanied by increased secretion of proinflammatory TNFα and type 1 and 2 IFNs, and the B cell– driving cytokines BLyS, IL‐10.

Upregulation of genes induced by interferons is a genetic “signature” of SLE.

„Interferon signature”

Hormons Female sex is permissive for SLE; Females make higher antibody responses than

males; Women exposed to estrogen-containing oral

contraceptives or hormone replacement have an increased risk of developing SLE (1.2-2x);

Estradiol binds to receptors on Tly and Blyincreasing activation and survival;

Favoring prolonged immune responses.

UV light Exposure to ultraviolet light causes flares of SLE in

approximately 70% of patients, possibly by increasing apoptosis in skin cells or by altering DNA and intracellular proteins to make them antigenic.

Infections Infections induce a normal immune response that

matures to contain some T and B cells that recognize self-antigens;

Such cells are not appropriately regulated, and autoantibody production occurs.

Most SLE patients have autoantibodies for 3 years or more before the first symptoms of disease.

Infections Epstein-Barr virus (EBV) may be one infectious

agent that can trigger SLE in susceptible individuals. Children and adults with SLE are more likely to be

infected by EBV; EBV activates and infects B lymphocytes and survives

in those cells for decades; It also contains amino acid sequences that mimic

sequences on human spliceosomes (RNA/protein antigens often recognized by autoantibodies in people with SLE).

Harrison’s 17th Retail

Pathogenesis and Etiology

Pathology Skin: deposition of Ig et the dermal‐epidermaljunction (DEJ), injury to basal keratinocytes, infl. dominated by T ly (in the DEJ, vessels), unaffectedskin may also show.

Kidney: lupus nephritis (Class I‐VI.) Blood vessels: not specific, but leukocytoclasticvasculitis is most common.

Lymph node: to role out infection or malignancies, nonspecific diffuse chronic inflammation.

The natural clinical history of SLEOnset

Slow beginning (NDC)

Full‐blown way

Course

Moderate

Wavering

Chronic progressive

Crisis

Clinical features Constitutional ( unexplained fever, fatigue, wgt loss, synovitis, 

anaemia) Joints Cutaneous Serosal Cardiopulmonary Vascular Hematologic Renal Neurologic Gastrointestinal Ocular Antiphospholipid antibody syndrome

SYMPTOMSSYMPTOMS PERCENTAGE (%)

Achy joints / arthralgia 95 

Fever of more than 100 degrees F / 38 degrees C  90

Arthritis / swollen joints  90

Prolonged or extreme fatigue  81

Skin Rashes  74

Anemia 71

Kidney Involvement  50

Pain in the chest on deep breathing / pleurisy 45

Butterfly‐shaped rash across the cheeks and nose   42

Sun or light sensitivity / photosensitivity  30

Hair loss  27

Abnormal blood clotting problems 20

Fingers turning white and/or blue in the cold 17

Mouth or nose ulcers 12

Arthritis

Arthritis

Jaccoud’s arthropathy (JA) is a condition characterised clinically by ‘reversible’ jointdeformities such as swan neck, thumb subluxation, ulnar deviation, ‘boutonniere’and hallux valgus, along with an absence of articular erosions on a plain radiograph.JA was initially described in patients with rheumatic fever (RF), but as this disorderhas become rare the main clinical entity associated to JA at present is SLE. JA hasalso been described in other connective tissue diseases, infections and neoplasia. Ingeneral, its prevalence in either SLE or RF is around 5%.

Jaccoud’s arthropathy (JA)

Arthropathy

Classification of the cutaneous manifestations of SLE

Lupus specificA. Acut cutan LE /ACLE/

Malar erythemaGeneralised ACLE, photosens.

B. Subacut cutan LE /SCLE/AnularPsoriasiform

C. Chronicus cutan LE /CCLE/Classic discoidHypertrophic DLELupus panniculitisMucosal ulcerationOthers (L.tumidus, Lichenoid)

Lupus aspecificA. Cutan vascular symptoms

VasculitisVasculopathyRaynaud syndromeLivedo reticularis

B. Non scarring diffuse alopeciaC. UrticariaD. Erythema exsudativum

multiforme

Sontheimer RD. Lupus. 1997;6(2):84‐95

Malar rash

Mouth ulcers

Scarring hypopigmented alopecia, with DLE, 29‐year‐old African‐American woman

Subacute cutaneous lupus erythematosus (SCLE), 29‐year‐old African‐American woman

Livedo reticularis

Erythemamultiforme

Erythema exudativummultiforme

Vasculitis in SLE

Nail‐fold vasculitis

Acut vasculitis in lupus

Subacute cutaneous lupuserythematosus (SCLE)

Raynaud syndrome

Nervous system manifestations

CNS

Aseptic meningitis Cerebrovascularis laesion Demyelination syndroma Headache (Migrain) Chorea Myelopathy Epilepsy Psychosis Acut confuse statement Cognitiv dysfunction

PNS

Acut Guillain‐Barré sy. Disturbance of Autonomic

nervous sy.  Mononeuritis simplex/multiplex Myasthenia gravis like Cranial neuropathy Polyneuropathy

Renal manifestations Proteinuria (> 500mg/24h) and cellular casts:  50% Nephrotic syndrome: 25% Renal failure: 5‐10%Pathology:

I. ‐no histologic changesII. proliferative changes confined to the mesangiumIII. proliferative changes in tufts of 10‐50% of glomeruliIV.  Diffuse prolif.GN affecting >50% of glomeruliV.  Predominantly membranous changes with various degrees of prolif.VI.  End stage (cicatrized)+ report the extent of inflammatory/or chronic changes

Classification of Lupus nephritis ISN/RPS(2003)

Class I. Minimal mesangial lupus nephritisClass II. Mesangial proliferative lupus nephritisClass III. Focal lupus nephritis (involving 50% of glomeruli)

Diffuse segmental (IV‐S), or diffuse global GN (IV‐G) lupus N  

IV‐S (A), IV‐G (A), IV‐S (A/C),  IV‐G (C),IV‐S (C), 

Class V. Membranous lupus nephritisClass VI.  Advanced sclerosing lupus nephritis

(≥90% globally sclerosed glomeruli without residualactivity)

Renal manifestations 50‐70% of all lupus patients experience renal developments.

Most dangerous: Glomerulonephritis where at least 50% of the glomeruli have cellular proliferation

Renal failure because of GNis the leading cause of death among lupus patients.

Normal

Glomerulonephritis

Cardiac and vascular manifestations Pericarditis

Exsudate Constriction Tamponade

Myocarditis Malignant arrythmias Cardiac failure

Endocarditis Valvulopathy Embolisation Arrythmias Cardiac failure Subacut infective endocarditis

Coronarias Coronaritis Coronariasclerosis Acut coronaria syndrome, MI

Pericardial fluid on X‐rayAnd on echocardiography

Subacut verrucosusnon‐infective endocarditis

Extensiv anterior AMI

Pulmonary manifestations Pleuritis, hydrothorax Pneumonitis, alveolitis Bronchiolitis obliterans Pulmonal hypertension Pulmonal embolism Pulmonal haemorrhage ARDS Pneumonia

Pleural effusionX‐ray and CT images

Alveolitis (HRCT)

Pulmonal embolism(autopsy)

Vascular occlusionsVenous thrombosis 10%Arterial thrombosis 5%

Vascular events are increased in patients withantiphospholipid AB.

Brain ischemia can be caused by focal vasculitis ornoninflammatory occlusion, or by embolization of carotid artery plaque or Libman‐Sachs endocarditis.

Myocardial infarctions are primarily manifestations of accelerated art.scler. or +vasculitis

Pathology:small vessel leukocytoclastic vasculitis

Hematologic manifestations

Anemia (of chronic disease) 70% Hemolitic anemia 10% Leukopenia (

Gastrointestinal manifestations

Nonspecific 30%(anorexia, nausea, mild pain, diarrhea)

Vasculitis with bleeding or perforation 5% Ascites

Other manifestations in SLE• Vasculitis• Pancreatitis, lupus hepatitis• Pepetic ulcer/GI-bleeding• Mesenterial

thrombosis/vasculitis• Thrombosis of A./V.

Centralis retinae• Optic neuritis• Chorioretinitis• Sicca sy.

Ocular manifestations

Retinal vasculitis, optic neuritis 5% Conjunctivitis/episcleritis 10% Sicca sy 15%

(cataracts, glaucoma‐ complications of glucocorticoidtherapy)

Scleritis anteriorRetinopathy (fundoscopy) „Cotton‐wool spots”.

Thrombosis of Vena Centralisretinae

Opctic neuritis

Kerato‐conjunctivitis sicca

Oculardisorders

Subgroups of SLE Neonatal LE

Subacute cutan LE

Drug induced LE

SLE in Elderly

SLE with secondary APS

Neonatal LE 1% of newborns of anti‐SS‐A+ mothers, Symptoms: 

skin lesions, hepato‐splenomegaly, thrombocytopenia, AIHA, congenital heart block

Laboratory: aSSA/aSSB antibodies, ANA positivity, high cc. of a‐dsDNA

Therapy: Corticosteroid, HIVIG, pacemaker

Subacute cutan lupus (SCLE) Symptoms:

• Annular or psoriasiform lesions,• Photosensitivy (60‐70%),• Rare renal complications (10%),• Rare CNS involvement (20%)

Laboratory: aSS‐A/aSS‐B antibody (60‐70%)

Therapy:  Sunscreen Lotion,  Local steroids, Low dose systemic steroid, Antimalarials

Drug‐induced SLE Symptoms:

More common in the elderly, Reversible, Minor symptoms: rare renal and CNS complications, rare DLE Frequent respiratory symptoms

Laboratory: aSS‐A/aSS‐B antibody (60‐70%) Slow acetylators Association with HLA DR4 H2A, H2B anti‐histon antibodies

Therapy:  Withdrowal of provoking drug, Steroid

SLE in elderly patients Onset after 60 years of age, lower range of women Frequency appx. 10% Symptoms:

Serositis, musculo‐skeletal, pulmonal manifestations: pulm. fibrosis, Skin rashes, Sicca sy.

Moderate symptoms

Laboratory:  Anaemia, increased ESR

Differential diagnosis: Exclude neoplasms

Therapy:  NSAIDs, Low dose steroid

SLE with secondary APS Antiphospholipid syndrome or antiphospholipidantibody syndrome (APS or APLS or), often also Hughes syndrome, is an autoimmune, hypercoagulable state caused by antiphospholipidantibodies.

APS provokes blood clots, thrombosis in both arteriesand veins as well as pregnancy‐related complications such as miscarriage, stillbirth, preterm delivery, orsevere preeclampsia.

The mechanisms of antiphospholipidantibodies

It reduces the production of prostacyclin in endothelial cells and release

It inhibits the fibrinolysis It inhibits the natural anticoagulants

It interfers with the thrombomodulin inendothelial cells

It increases platelet activation and aggregation

It inhibits the beta‐2‐GPI function

• Vasoconstriction• Thrombosis• Inhibition of trophoblast

invasion

Diagnosis/Laboratory tests To establish or rule out the diagnosis To follow the disease (flare, organ damage) To identify adverse effects of therapies

Updated American College of RheumatologyDiagnostic Criteria for SLE

1. Malar rash2. Discoid rash3. Photosensitivity4. Oral ulcers5. Arthritis6. Renal disorder

a. Persistent proteinuria >0.5 g/dayor >3+ if quantitation not performedb. Cellular casts

7. Serositisa. Pleuritisb. Pericarditis

8. Neurologic disordera. Seizuresb. Psychosis

9. Haematologic disturbancesa. Hemolytic anemiab. Leukopenia (4.0 G/l)c. Lymphopenia (1.5G/l)d. Thrombocytopenia (100G/l)

10. Immunologic disurbancesa. Anti‐dsDNA positivityb. Anti‐Sm ppositivityc. Anti‐KL/LA positivity

11. ANA positivitity

SLE can be diagnosed if any 4 ormore of thefollowing 11 criteria are present, serially orsimultaneously, during any interval of observation. Specificity is ~ 95%, Sensitivity is   ~75%.

• Nuklear antigens: ssDNA, dsDNA, histon(H1, H2A, H2B, H3, H4), Sm, RNP

• Cytoplasmic antigen: SS‐A (Ro), SS‐B (La), ribosomal p‐protein, ANCA (atypic)

• Surface antigen: endothel, red blood cell, granulocyte, lymphocyte, thrombocyte ag.

• Others, plasmatic factors: beta‐2‐glikoprotein I, fospholipids.  

Targets of autoantibodies in SLE

Diagnostic Studies No single test can determine whether a person has lupus, but several laboratory tests may help make a diagnosis.

SLE is diagnosed primarily on criteria relating to patient history, physical examination, and laboratory findings.

Laboratory tests Complete blood count Urinalysis Blood chemistries Erythrocyte sedimentation rate Complement levels (C3, C4, CH50):

Low levels indicates possible presence of disease. FANA – Fluorescent antinuclear antibody Immune tests: Anti‐DNA and anti‐Smith antibody tests most specific for SLE

Diagnostic Tests Laboratory tests X‐rays of affected joints Chest x‐ray for pulmonary problems ECG + echocardiography for cardiac problems Abdominal ultrasound

Differential diagnosis Skin:  rosacea (seborrhoic papular erythema), Erythemamultiforme (allergic vasculitis) Urticaria, Lichen planus(papulosis erythema, necrosis, edema)

Arthritis: Lyme arthritis, reactive arthritis Infections: infective endocarditis, menigococcal‐, gonococcal septicemias, tuberculosis, leptospirosis, AIDS...

Granulomatosus disease: sarcoidosis Tumors Hematologic: ITP, AIHA Neurologic disorders: multiple sclerosis, idiopathicepilepsy, stroke

Other autoimmun diseases: RA, scleroderma, polymyositis

Positive ANA SLE Non SLE CTD (RA, SS, PSS, CREST, DM/PM) Normals (false positive) Lymphoproliferative disorder Chronic infection (HIV, Leprosy)

Therapy

There is no cure for SLE, and complete sustained remissions are rare.

The physician should plan to control acute, severe flares and then develop maintenance strategies that suppress symptoms to an acceptable level and prevent organ damage.

Therapeutic choices depend on Whether disease manifestations are life‐threateningor likely to cause organ damage, justifying aggressive therapies; 

Whether manifestations are potentially reversible; and 

The best approaches to preventing complications of disease and its treatments.

Therapy for non‐major organ involvements

Arthralgias, myalgias, fever, mild serositis NSAID  (GI and renal side effects!)

Salicylates (ototoxicity, tinnitus) Skin lesions, arthritis

Antimalarials ‐chloroquine‐200‐400mg/die(agranulocytosis, neuropathy, retinal tox.)

Dehydroepiandrosteron 200mg/die(acne, menstrual irregularities)

Topical glucocorticoids, sunscreen Methotrexat‐10‐25mg/week with folic acid

(bone marrow suppression, hepato‐nephrotoxicity, pneumonitis) Antiphospholipid sy‐ warfarin, LMWH

Major organ involvement Glomerulonephritis ( grad III‐V) CNS AIHA marked ITP Severe granulocytopenia,Myocarditis PneumonitisMesenteric vasculitis

Treatment for major organ involvement Life threatening SLE‐ 1g Methylprednisolon i.v./die for 3days followed by 0,5‐1mg/kg/day prednisone or equivalent for 4‐6 month, recently for 4‐6 weeks, thereafter doses are tapered as rapidly as possible to 5‐10mg/d prednisone

(hypertension, hyperglycemia, infection, osteoporosis) Severe SLE‐ 0,5mg/kg/day prednisolon p.os+ intermittentcyclophosphamid 500‐1000mg/m² surface area monthly i.v. for 6‐12 month

(Bone marrow suppression, infection, VZV, alopecia, sterility)‐ prednisolon p.os+2‐3mg/kg/die azathioprine p.os

(side effects as in cyclophosphamid therapy, without sterility)‐ prednisolon p.os +mycophenolate mofetil (ly‐specificinhibitor approved for SLE nephritis) 2‐3g/die p os.

(Infection, bone marrow suppression, lymphoma)

Preventive therapies Vaccinations (influenza and pneumococcal vaccines)‐flare rates are similar to control

Osteoporosis : Ca +vitamin D3 Control and treat hypertension, hyperglycemia, obesity, dyslipidaemias and hyperglycemia

Novel therapy Immunoablative chemotherapy with or withoutautologous stem cell transplant

B‐cell tolerogen (Single signal anergy) Complement inhibitors (anti‐C5, soluble CR1) Adhesion molecule inhibitors (anti‐ICAM 1, antiCD11b/CD18)

Co‐stimulatory pathway inhibitors (anti‐CTLA‐4, anti‐CD40 ligand)

Targeted therapeutic approaches in SLE

New therapies

Possible anti‐citokin treatment in SLE

Cytokine Clinical trial results

IL‐1 Small open label trials of recombinant IL‐1ra, with improvement in arthritis

IL‐6 Ongoing clinical trial with human anti–IL‐6 RmAb

IL‐10 Small trial with murine anti–IL‐10 mAb with benefit in cutaneous and arthritic symptoms

TNF Small open label trial of Infliximab with benefit in arthritis and proteinuria

Type I IFN Clinical trial planned BLyS Some clinical efficacy of 

human anti‐BLyS mAbJennifer H. Anolik J.H., Aringer M.: New treatments for SLE: cell‐depleting and anti‐cytokine therapies. Best Practice & Research Clinical Rheumatology Vol. 19, No. 5, pp. 859–878, 2005

Patient outcomes

Survival in patients with SLE in the United States, Canada, Europe, and China is approximately 95% at 5 years, 90% at 10 years, and 78% at 20 years.

In the United States, African Americans and Hispanic Americans with a mestizo heritage have a worse prognosis than Caucasians, whereas Africans in Africa and Hispanic Americans with a Puerto Rican origin do not.

Thank you for attention!

Additional slides

DNA is the Main man DNA is the main antigen for which antibodies are formed.

Extracellular DNA has an affinity for basement membrane where it is bound by autoantibodies.

Classical thickening of the basement membrane.

LE Cell The LE cell is a neutrophil that has engulfed the antibody‐coated nucleus of another neutrophil. 

LE cells may appear in rosettes where there are several neutrophils vying for an individual complement covered protein. 

Arthritis Foundation Issues Top Ten Research Advances inArthritis and Related Musculoskeletal Diseases for 2003

Lupus gene patterns activated by interferon identified: Using a multiple gene analysis technique, two different research teams haveprovided strong evidence that virus‐fighting substances called type I interferons play a key role in systemic lupus erythematosus (lupus) and therefore could be important targets for new therapies. 

„Interferon signature”

IgG Pathogen IgG is the most “pathogenic” because it forms intermediate sized complexes that can get to the small places and block them.

The role of IFN‐γ IFN‐γ plays a crucial role in provoking kidney damage by promoting the formation of pathogenic complement‐fixing antibodies as well as by increasing major histocompatibility complex class II antigen expression.

IFN‐γ may contribute to the pathogenesis of diffuse proliferative glomerulonephritis by both up‐regulation of CD40 and activation of the cellular immune response in human lupus.

IFN‐γ is known to enhance integrin expression including both intercellular adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 (VCAM‐1), on glomerular cells, which in turn may facilitate influx of inflammatory cells.

Calvani N et al: Clin. Exp. Immunol. 2004, 138: 171-178.

Pathogenesis and etiology Lupus T and natural killer (NK) cells fail to produce enough IL‐2 and transforming growth factor (TGF) to induce regulatory CD4+ and inhibitory CD8+ T cells. pathogenic Ab, IC ↑ activation of complement, phagocytic cells leads to release of chemotaxins, cytokines, chemokines, vasoactive peptides, and destructiveenzymes,

In the setting of chronic inflammation, accumulation of growth factors and products of chronic oxidation contribute to irreversible tissue damage.

Genes SLE is a multigenic disease.  Homozygous deficiencies of early components of complement (C1q,r,s; 

C2; C4) confer strong predisposition to SLE, but such deficiencies are rare. 

Other genes increase risk for  SLE by only 1.5‐ to 3‐fold.Some gene alleles probably contribute to disease susceptibility by: Influencing clearance of apoptotic cells (C1q, MBL)  Immune complexes (FcR 2A and 3A), Antigen presentation (HLA‐DR2,3,8),  B cell maturation IL‐10, also a B‐cell stimulator is in high 

concentration in lupus patient serum, T cell activation (PTPN22),  Chemotaxis (MCP‐1). 

Activation of Complement System Complement system is activated by the binding of antibodies to foreign debris. In this case its over activation

RBCs lack CR1 receptor Decreasing the affective removal of complexes

Diagnostic StudiesAntinuclear antibodies ANA and other antibodies indicate autoimmune disease

Anti‐DNA and anti‐Smith antibody tests most specific for SLE

LE prep can be positive with other rheumatoid diseases

ESR & CRP are indicative of inflammatory activity

Musculoskeletal manifestations Arthralgias, myalgias 95% Nonerosive polyarthritis 60% Hand deformities 10% Myopathy/myositis 40/5%(but glucocorticoid, antimalarial drugs!)

Ischemic necrosis of bone 15%

Cutaneous manifestations Malar rash 50% Discoid rash 15% Photosensitivity 40% Oral ulcers 40% Other rashes 40% (maculopapular, urticarial, bullous, subacute cutaneouslupus)

Alopecia 40% Vasculitis 20% Panniculitis 5%

Pathology: deposition of Ig at dermal‐epidermal junction, injury to basalkeratinocytes, inflammation dominated by T lymphocytes

Cutaneous manifestations of SLE

Malar rash(Butterfly Rash)

DLE

SCLE

Scarring alopeciaErythema exsudativum

multiforme

DLE

Pictures from Dr. Emese Kiss

Raynaud sy.

Typical vascular laesions in SLE

Plantar vasculitis

Pictures from Dr. Emese Kiss

Nervous system manifestations Cognitive disorders 50% Mood disorders 40% Headache 25% Seizures 20% Mono‐polyneuropathy 15% Stroke, TIA 10% Acute confusional state/ movement disorder 2‐5% Aseptic meningitis, myelopathy

Bronchiolitis obliterans

Cardiopulmonary manifestations Pleural, pericardial effusions 30‐50%Myocarditis, endocarditis 10%(Libman‐Sachs)

Coronary artery disease 10% Lupus pneumonitis 10% Interstitial fibrosis 5% Pulm. hypertension, ARDS, hemorrhage

Provoking drugs High risk: 

hydralazine, procainamide, izoniazid Moderate risk: 

INH, hydantoin, succinimid Low risk: 

sulphonamid, penicillin, phenothiasin, thiouracil, oestrogen

Targets of antiphospholipidantibodies

Fospholipids: Phosphatidil‐serin Ph.‐inositol Ph.‐ethanolamin Ph.‐cholin Ph.‐sav

Protein cofactors: beta‐2‐glikoprotein I annexin V prothrombin Prot. C Prot. S heparan sulphat HMW kininogen

Laboratory tests

Tests for antibodiesAntibody % AG recognized Clinical utilityANA 98 Multiple nuclear Best screening test, repeat

Anti-dsDNA 70 Double-stranded Specific, correlates with activityAnti-Sm 25 Prot.complex to

6 species of small nucl.RNA

Specific, no definite clinicalcorrelations

Anti-Ro (SS-A)

30 Prot.complex to hY RNA

Associated with sicca, neonatallupus, decreased risk with nephritis

Antihistone 70 H associated with DNA

More frequent in drug-inducedSLE

Antiphospholipid

50 Phlp,β2glycoprot1cofact.,prothtro.

Predisposes to clotting, fetal loss, thrombocytopenia

A-erythrocyt 60 E membrane directCoombs-small overt hemolys.A-platelet 30 Surface,cytopl. Sens. and spec. not goodA-neuronal 60 Neuron,ly In some series correlate with active

CNS lupus

Conservative therapies formanagement of non‐life‐

threatening disease

Among patients with fatigue, pain, and autoantibodies of SLE, but without major organ involvement, management can be directed to suppression of symptoms.

Analgesics and antimalarials are mainstays. NSAIDs are useful analgesics/anti‐inflammatories,particularly for arthritis/arthralgias.

Conservative therapies for management of non‐life‐threatening disease Antimalarials (hydroxychloroquine, chloroquine, and quinacrine) often reduce dermatitis, arthritis, and fatigue.

Hydroxychloroquine reduces the number of disease flares; it may also reduce accrual of tissue damage over time.

Because of potential retinal toxicity, patients receivingantimalarials should undergo ophthalmologic examinations at least annually.

A placebo‐controlled prospective trial suggests that administration of dehydroepiandrosteronemay reduce disease activity. 

If quality of life is inadequate in spite of these conservative measures, treatment with low doses of systemic glucocorticoids may be necessary.

CAUTION! SLE patients compared with the general population are at increased risk for NSAID‐induced aseptic meningitis, elevated serum transaminases, hypertension, and renal dysfunction. 

All NSAIDs, particularly those that inhibit cyclooxygenase‐2 specifically, may increase risk for myocardial infarction.

Life‐threatening SLE: proliferativforms of lupus nephritis Systemic glucocorticoids (0.5–2 mg/kg per day PO or 1000 mg of methylprednisolone sodium succinate IV daily for 3 days followed by 0.5–1 mg/kg of daily prednisone or equivalent).

Currently, high doses are recommended for much shorter periods; recent trials of interventions for severe SLE employ 4–6 weeks of these doses.

Thereafter, doses are tapered as rapidly as the clinical situation permits, usually to a maintenance dose varying from 5 to 10 mg of prednisone or equivalent per day or from 10 to 20 mg every other day.

Life‐threatening SLE: proliferativforms of lupus nephritis Prospective controlled trials in active lupus nephritis show that administration of high doses of glucocorticoids (1000 mg of methylprednisolone daily for 3 days) by IV routes compared with daily oral routes shortens the time to maximal improvementby a few weeks but does not result in better renal function.

Monitor advers effects: infection, hyperglycemia, hypertension, osteoporosis, etc.

Life‐threatening SLE: proliferativforms of lupus nephritis

Cytotoxic/immunosuppressive agents added to glucocorticoids are recommended to treat serious SLE. 

Almost all prospective controlled trials in SLE involving cytotoxic agents have been conducted in patients with lupus nephritis, and always in combination with glucocorticoids.

Life‐threatening SLE: proliferativforms of lupus nephritis

Cyclophosphamide (an alkylating agent) or  Mycophenolate mofetil (a relatively lymphocyte‐specific inhibitor of inosine monophosphatase and therefore of purine synthesis) is an acceptable choice for induction of improvement in severely ill patients; 

Azathioprine (a purine analogue and cycle‐specific antimetabolite) may be effective but is slower to influence response.

Life‐threatening SLE: proliferativforms of lupus nephritisCyclophosphamide treatment: (1) once monthly IV for 6 months followed by 2 more years of quarterly doses, 

(2) for 12 weeks followed by azathioprine, and (3) for 6 months followed by azathioprine or mycophenolate.

May be discontinued when it is clear that a patient is improving; possibility of disease flare is reduced by continuing therapy with one of the cytotoxic/immunosuppressive drugs.

Life‐threatening SLE: proliferativforms of lupus nephritis

The adverse effects of Cyclophosphamide are: a high rate of irreversible ovarian or testicular failure with increasing cumulative doses,

nausea and malaise that often accompany each IV dose,  alopecia,  frequent infections.

Special conditions (that mayrequire additional or different

therapies)

Pregnancy and Lupus Lupus and Antiphospholipid Antibody Syndrome Microvascular Thrombotic Crisis (TTP, HUS) Lupus dermatitis

Special conditions (that mayrequire additional or different

therapies)Pregnancy and Lupus:  Rate of fetal loss is increased (2‐3x). Fetal demise is higher in mothers with high disease activity, 

antiphospholipid antibodies, and/or nephritis. Adverse effects of prenatal glucocorticoid exposure (primarily 

betamethasone) on offspring may include low birth weight, developmental abnormalities in the CNS, and predilection toward adult metabolic syndrome.

The presence of antibodies to Ro, sometimes associated with neonatal lupus consisting of rash and congenital heart block.

Poor maternal outcomes are highest in women with active nephritis or irreversible organ damage in kidneys, brain, or heart.

Special conditions (that mayrequire additional or different

therapies)Lupus and Antiphospholipid Antibody Syndrome: Should be managed with long‐term anticoagulation. A target international normalized ratio (INR) of2.0–2.5 is recommended for patients with one episode of venous clotting;

An INR of 3.0–3.5 is recommended for patients with recurring clots or arterial clotting, particularly in the central nervous system.

Special conditions (that mayrequire additional or different

therapies)

Microvascular Thrombotic Crisis (TTP, HUS): This syndrome of hemolysis, thrombocytopenia, and microvascular thrombosis in kidneys, brain, and other tissues carries a high mortality rate and occurs mostcommonly in young individuals with lupus nephritis.

Plasma exchange or extensive plasmapheresis is usually life‐saving.

Special conditions (that may requireadditional or different therapies)

Lupus dermatitis: Patients with any form of lupus dermatitis should minimize exposure to ultraviolet light, employing appropriate clothing and sunscreens with a sun protection factor of at least 15.

Extensive, pruritic, bullous, or ulcerating dermatitidesusually improve promptly after institution of systemic glucocorticoids.

Antimalarials, retinoic acid, methotrexate, azathioprine, topical tacrolimus, systemic dapsone or thalidomide can be usefull. 

Prognosis In societies where modern medical care (and organ 

transplantation) is available only to those who can pay, glucocorticoid therapies are usually the sole therapy for severe lupus; prognosis is worse than in the developed world. 

Poor prognosis (~50% mortality in 10 years) in most series is associated with (at the time of diagnosis): high serum creatinine levels [>124 μmol/L (>1.4 mg/dL)], hypertension,  nephrotic syndrome (24‐h urine protein excretion >2.6 g), anemia [hemoglobin 

SLE: Health Status Disease activity (SLEDAI, SLAM, BILAG) Damage Index (SLICC DI) disease treatment or co‐morbidity

Treatment/iatrogenic induced illness( e.g. avascular necrosis of bone, acceleratedatherosclerosis, cataracts, striae, immunosupression, etc.)

Infection