SYSTEMIC LUPUS ERYTHEMATOSUS

Pardis Nematollahi MD,ACP

June,2014

SYSTEMIC LUPUS ERYTHEMATOSUS

Autoimmune multisystem disease characterized by widespread microvascular inflammation and production of autoantibodies

This means wide spectrum of presentation

Chronic with relapsing and remitting course

Ranging from indolent to fulminant

The classic presentation of a triad of fever, joint pain, and rash in a woman of childbearing age should prompt investigation into the diagnosis of SLE

Etiology

Etiology is unknown Most probable causes Genetic influence At least 35 genes are known to increase the risk of SLE. A genetic predisposition is supported by 40% concordance in

monozygotic twins; if a mother has SLE, her daughter's risk of developing the disease has been estimated to be 1:40, and her son's risk, 1:250.

Immunological factors Many immune disturbances, both innate and acquired, occur in SLE

Studies of human leukocyte antigens (HLAs) reveal that HLA-A1, HLA-B8, and HLA-DR3 are more common in persons with SLE than in the general population. The presence of the null complement alleles and congenital deficiencies of complement (especially C4, C2, and other early components) are also associated with an increased risk of SLE

Etiology

Environmental and exposure-related causes of SLE are Silica dust and cigarette smoking Administration of estrogen to postmenopausal women Photosensitivity is clearly a precipitant of skin disease

Ultraviolet light stimulates keratinocytes, which leads not only to overexpression of nuclear ribonucleoproteins

Vitamin D deficiency Drugs Numerous studies have investigated the role of infectious

etiologies that may also perpetuate autoimmunity. Patients with SLE have higher titers of antibodies to Epstein-Barr virus (EBV), have increased circulating EBV viral loads, and make antibodies to retroviruses

Pathophysiology

Systemic lupus erythematosus (SLE) is characterized by a global loss of self-tolerance with activation of autoreactive T and B cells leading to production of pathogenic autoantibodies and tissue injury.

Autoimmune reactions directed against constituents of cell nucleus, DNA

Receptor ligation ex: TNF, Fas

Protease (caspase) cascade

DNA fragmentationChromatin condensation

Cytoplasmic blebbing

Apoptotic bodies

APOPTOSIS

Clearance by phagocytesY

Y

Y

YY

YAUTOREACTIVITY

Y

YYY

Y

YY

YY

Y

Y

Y

Y

YY

Y

Y

Y

Y

C ’ C ’

C ’Immune complex formation

C ’

EndoBM

Intima

Complement fixation

Release of inflammatory, vasoactive and chemotactic

mediatorsDisruption of endothelium

Thickening of BM

Infiltration of inflammatory

cellsTissue damage

RBC

RBC

EPIDEMIOLOGY

Age : peak 20s and 30s but any age can be affected before 8 yrs unusual Sex :more women affected ,10:1 during childbearing

age Prevalence:1/2500 1 in 700 among women of childbearing age . By

comparison, the female-to-male ratio is only 2 : 1 for disease developing during childhood or after the age of 65

Clinical Features of SLE

Constitutional symptoms Musculoskeletal disease Mucocutaneous involvement Renal Disease Central nervous system disease Cardiopulmonary disease Hematologic abnormalities Gastrointestinal involvement

Clinical Manifestations

Ranges from a relatively mild disorder to rapidly progressing, affecting many body systems

Most commonly affects the skin/muscles, lining of lungs, heart, nervous tissue, and kidneys

General clinical manifestation

Severe fatigue Fever Weight loss Anorexia Lymphadenopathy

Mucocutaneous manifestation

Frequency: 76% Malar rash Discoid lupus Vasculitis (purpura, petechiae) Raynaud’s phenomenon Nail involvement Alopecia Photosensitivity Oral/ nasal ulcers

MALAR RASH

Fixed erythema, flat or raised, over the malar eminences

Tending to spare the nasolabial folds

30-60 %

Dermatologic Manifestations

Fig 65-10Fig 65-10

MALAR RASH

Photosensitivity

Rash over the sun exposed areas.Face,neck and V shaped area of chest.See rash varies in severity depending on exposure.Less under the orbit protected areas.

DISCOID RASH

Erythematous raised patches with adherent keratotic scaling and follicular plugging

Atrophic scarring may occur in older lesions

Oral lesions of SLE

Erythema of hard and soft palate, papules ,vesicles and petechiae

Erythematous rash of the tongue.

Oral Ulcers

Oral or nasopharyngeal ulceration, usually painless, observed by physician

Joint

arthralgia, arthropathy, myalgia, frank arthritis, avascular necrosis

Joint involvement is typically a nonerosive synovitis with little deformity, which contrasts with rheumatoid arthritis

Serositis

Pleuritis : convincing history of pleuritic pain ,pleural

rub heard by a physician or evidence of pleural effusion or

Pericarditis: documented by ECG ,pericardial rub or

evidence of pericardial effusion

Pulmonary Findings In SLE

Incidence: 5-67% May be subclinical (abnormal PFTs) Pleuritis Pleural effusion Pneumonitis Pulmonary hemorrhage Pulmonary hypertension Restrictive pulmonary disease & diffusion

defects most commonly observed abnormalities on PFTs

Cardiovascular Findings In SLE

Pericarditis Myocarditis Sterile valvular vegetations (rarely

clinically significant except for risk of bacterial endocarditis)

Arrhythmias Cor pulmonale Vasculitis (small vessels) Atherosclerosis/ Coronary Heart disease Dyslipoproteinemias

Renal Findings In SLEMost common cause of morbidity & mortality

Lupus nephritis affects up to 50% of SLE patients. The principal mechanism of injury is immune complex deposition in the glomeruli, tubular or peritubular capillary basement membranes, or larger blood vessels

A variety of clinical findings may point toward renal involvement, including hematuria, red cell casts, proteinuria, and in some cases the classic nephrotic syndrome

Neuropsychiatric Manifestations Of SLE

Frequency: 20-40% Difficult to diagnose and treat Second to nephritis as most common cause of

morbidity & mortality Can occur at any time; even at presentation

Pathophysiology of CNS involvement

The pathologic basis of central nervous system symptoms is not entirely clear, but antibodies against a synaptic membrane protein have been implicated. Neuropsychiatric symptoms of SLE have often been ascribed to acute vasculitis, but in histologic studies of the nervous system in such patients significant vasculitis is rarely present. Instead, noninflammatory occlusion of small vessels by intimal proliferation is sometimes noted, which may be due to endothelial damage by antiphospholipid antibodies

Neuropsychiatric Manifestations Of SLE

COMMON: Depression, organic brain syndrome, functional psychosis, headaches, seizures, cognitive impairment, dementia, coma

OCCASIONAL: Cerebral vascular accidents (thrombosis or vasculitis), aseptic meningitis, peripheral neuropathy, cranial nerve palsies

RARE: Paralysis, transverse myelopathy,chorea

Hematologic Findings In SLE

Leukopenia, especially lymphopenia Anemia

mild to moderate, common, due to chronic disease and mild hemolysis

severe, uncommon (5%), due to immune mediated hemolysis (Coombs

+) Thrombocytopenia

mild 100-150/micoL, common due to immune mediated damage

severe <20/microL, uncommon (5-10%), immune mediated damage

Bone marrow suppression/arrest--very rare, due to antibodies against precursors

Coagulopathy In SLE

Hypocoagulable states: Anti-platelet antibodies--decreased numbers of

platelets or decreased function (increased bleeding time)

Other platelet dysfunction and thrombocytopenia Anti-clotting factor antibodies

Hypercoagulable states: Antiphospholipid Antibody Syndrome (APS): more

later Protein C and S deficiencies

Thrombotic thrombocytopenic purpura

Infection

because of their underlying immune dysfunction and treatment with immunosuppressive drugs

Fever should be considered serious

Ocular

ConjunctivitisPhotophobiaMonocular blindness transient or permanentBlurred visionCotton-Wool spots on retina due to occlusion retinal blood vessels

GI INVOLVEMENT IN SLE Uncommon SLE manifestations Mild LFT elevation--not significant

clinically--BUT NEED TO EXCLUDE AUTOIMMUNE HEPATITIS

Colitis Mesenteric vasculitis Protein-losing enteropathy Pancreatitis Exudative ascites

1997 ACR CRITERIA FOR THE CLASSIFICATION OF SLE

Malar (butterfly) rash: Fixed erythema, flat or raised, sparing the nasolabial

folds

Discoid lupus rash: Raised patches, adherent keratotic scaling,

follicular plugging; may cause scarring

Photosensitivity: Rash as a result of unusual reaction to sunlight, by

patient history or physician observation

Oral or nasal mucocutaneous ulcerations: Usually painless

1997 ACR CRITERIA FOR THE CLASSIFICATION OF SLE (cont)

Inflammatory arthritis: Nonerosive, in two or more peripheral joints

Pleuritis or pericarditis Pleuritis—convincing history of pleuritic pain or rub heard by a physician or

evidence of pleural effusion, or Pericarditis—documented by electrocardiogram or rub or evidence of

pericardial effusion

Cytopenias: Hemolytic anemia with reticulosis or leukopenia (<4,000/mm3) or lymphopenia (<1,500/mm3) or thrombocytopenia (<100,000/mm3)

Nephritis: Proteinuria >0.5 gm/dL or >3+ or Cellular casts

1997 CRITERIA FOR THE CLASSIFICATION OF SLE (cont)

Encephalopathy: Seizures Psychosis

Positive ANA

Positive immunoserology:Anti-DNA antibody to native DNA in abnormal titer, or Anti-Sm, or Positive finding of antiphospholipid antibodies based on (1)

an abnormal serum level of IgG or IgM anticardiolipin antibodies, (2) a positive test for lupus anticoagulant using a standard test, or (3) a false-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by negative Treponema pallidum immobilization or fluorescent treponemal antibody absorption test

The revised criteria for the classification of systemic lupus erythematosus

1. Serositis 2. Oral Ulcers3. Arthritis4. Photosensitivity5. Blood disorders: -Hemolytic anemia -Leukopenia (Lymphopenia) -Thrombocytopenia 6. Renal disorders7. ANA positive

8. Immunologic abnormalities:

-Anti-ds- DNA -Anti- Sm -Antiphospholipid -False +ve VDRL 9. Neurologic

abnormalities 10. Malar rash 11. Discoid rash – rimmed

with scaling, follicular plugging

CLASSIFICATION CRITERIA

Must have 4 of 11 for Classification Sensitivity 96% Specificity 96%(In children 100%)

Not all “Lupus” is SLE Chronic discoid Lupus erythematosus Drug induced lupus Subacute Cutaneous Lupus

erythematosus

Chronic Discoid Lupus Erythematosus

Chronic discoid lupus erythematosus is a disease in which the skin manifestations may mimic SLE, but systemic manifestations are rare.

It is characterized by the presence of skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated erythematous border.

The face and scalp are usually affected, but widely disseminated lesions occasionally occur

Chronic Discoid Lupus Erythematosus

The disease is usually confined to the skin, but 5% to 10% of patients with discoid lupus erythematosus develop multisystem manifestations after many years.

Approximately 35% of patients show a positive ANA test, but antibodies to double-stranded DNA are rarely present.

Immunofluorescence studies of skin biopsy specimens show deposition of immunoglobulin and C3 at the dermoepidermal junction similar to that in SLE.

Subacute Cutaneous Lupus Erythematosus.

This condition also presents with predominant skin involvement and can be distinguished from chronic discoid lupus erythematosus by several criteria.

The skin rash in this disease tends to be widespread, superficial, and nonscarring, although scarring lesions may occur in some patients.

Most patients have mild systemic symptoms consistent with SLE. Furthermore, there is a strong association with antibodies to the SS-A antigen and with the HLA-DR3 genotype.

Thus, the term subacute cutaneous lupus erythematosus seems to define a group intermediate between SLE and lupus erythematosus localized only to skin.

Drug-Induced Lupus Erythematosus

A lupus erythematosus–like syndrome may develop in patients receiving a variety of drugs, including hydralazine, procainamide, isoniazid, and d-penicillamine, Many of these drugs are associated with the development of ANAs, but most patients do not have symptoms of lupus erythematosus.

For example, 80% of patients receiving procainamide test positive for ANAs, but only one third of these manifest clinical symptoms, such as arthralgias, fever, and serositis.

Drug-Induced Lupus Erythematosus,cont.

Although multiple organs are affected, renal and central nervous system involvement is distinctly uncommon.

There are serologic and genetic differences from classical SLE, as well. Antibodies specific for double-stranded DNA are rare, but there is an extremely high frequency of antibodies specific for histone

Persons with the HLA-DR4 allele are at a greater risk of developing lupus erythematosus after administration of hydralazine.

The disease remits after withdrawal of the offending drug.

DIFFERENTIAL DIAGNOSIS

Rheumatic: RA, Sjogren’s syndrome, systemic sclerosis, dermatomyositis

Nonrheumatic: HIV, endocarditis, viral infections, hematologic malignancies, vasculitis, ITP, other causes of nephritis

Testing

The following are useful standard laboratory studies when SLE is suspected:

CBC with differential Serum creatinine Urinalysis with microscopy

Other laboratory tests that may be used in the diagnosis of SLE are as follows

ESR or CRP results Complement levels Liver function tests Spot protein/spot creatinine ratio Autoantibody tests

PROGNOSIS

Unpredictable course The outcome has improved significantly, and an

approximately 90% 5-year and 80% 10-year survival can be expected

Most SLE patients die from renal failure and infection, probably related to therapy which suppresses immune system

Recommend smoking cessation, yearly flu shots, pneumovax q5years

Refrences

1. Robbins and Cotran,Pathologic basis of disease,8th

edition,2010

2. http://emedicine.medscape.com/article Updated: Feb 19, 2014

3. Livingston B, Bonner A, Pope J. Differences in clinical manifestations between childhood-onset lupus and adult-onset lupus: a meta-analysis. Lupus. Nov 2011;20(13):1345-55. [Medline]

4. American College of Rheumatology. 1997 Update of the 1982 American College of Rheumatology revised criteria for classification of systemic lupus erythematosus. Available at http://tinyurl.com/1997SLEcriteria. Accessed March 15, 2012

Thank You