1. SYSTEMIC LUPUS ERYTHEMATOSUS
Pardis Nematollahi MD,ACP
June,2014

2. 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

3. 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

4. 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

5. 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

6. 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

7. APOPTOSIS Death signal AUTOREACTIVITY Y Protease (caspase) cascade
Receptor ligation
ex: TNF, Fas
DNA fragmentation
Chromatin condensation
Cytoplasmic blebbing
Increased apoptosis or decreased clearance of apoptotic debris. SLE pts with increased apoptotic bodies, exposed for autoab production.
Clearance by phagocytes Y
AUTOREACTIVITY
Apoptotic bodies

8. C’ C’ C’ C’ Y Y Y Y Y Y Y Complement fixation Y Y Y Y Y Y Y Y Y Y Y Y
Immune complex formation Y C’ Y Y
RBC Y Y Y Y
Endo BM
Intima
Complement fixation
Release of inflammatory, vasoactive and chemotactic mediators
RBC Y C’
Disruption of endothelium Y Y Y Y C’ Y C’
Thickening of BM Y Y Y Y Y Y
Infiltration of inflammatory cells
Tissue damage

9. 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

10. Clinical Features of SLE
Constitutional symptoms
Musculoskeletal disease
Mucocutaneous involvement
Renal Disease
Central nervous system disease
Cardiopulmonary disease
Hematologic abnormalities
Gastrointestinal involvement
Constitutional: fever, fatigue, wt loss, anorexia (very nonspecific)

11. 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

12. General clinical manifestation
Severe fatigue
Fever
Weight loss
Anorexia
Lymphadenopathy

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

14. Fixed erythema, flat or raised, over the malar eminences
MALAR RASH
Fixed erythema, flat or raised, over the malar eminences
Tending to spare the nasolabial folds
30-60 %

15. Dermatologic Manifestations
Fig 65-10

16. MALAR RASH

17. 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.

18. DISCOID RASH
Erythematous raised patches with adherent keratotic scaling and follicular plugging
Atrophic scarring may occur in older lesions

19. Oral lesions of SLE
Erythema of hard and soft palate, papules ,vesicles and petechiae
Erythematous rash of the tongue.

21. Oral Ulcers
Oral or nasopharyngeal ulceration, usually painless, observed by physician

22. Joint
arthralgia, arthropathy, myalgia, frank arthritis, avascular necrosis
Joint involvement is typically a nonerosive synovitis with little deformity, which contrasts with rheumatoid arthritis

23. 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

24. 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
Pleuritis: uni or bilateral pleuritis chest pain, exacerbated by deep inspiration. Pleural effusions usu small volume, can by asx. Pnuemonitis: pulm infiltrates, atelectasis, rales occurs in 10-15% of SLE children. Pulm hemorrhage: chest pain, hemoptysis, pallor, anemia. pHTN resulting from pulm hemorrhage or PE’s from antiphospholipid syn.

25. 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
Pericarditis is the most common cardiac manifestation of SLE, 30% of children with acute dz…may be clinically silent, or represented by chest pain worsened by lying down or deep breathing, relieved by sitting up and leaning forward. Worry of the rare complication of pericardial constriction or tamponade. Myocarditis occurs in 10-15% of SLE children…CHF, cardiomegaly, arrhythmias, narrow pulse pressure, tachycardia in the absence of fever- get EKG. Valvulitis: classic cardiac lesion of SLE is Libman-Sacks endocarditis, is less common in children than in adults. Often subclinical, it is a sterile nodule of fibrinoid necrosis of the collagenous tissue of the valve, MV> AO>PV>TV.

26. Renal Findings In SLE Most 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
Renal involvement in children is more frequent and of greater severity than in adults. Significant renal disease usually develops within 2 yrs after onset of disease (although we do see it at onset), but occasionally appear many years later. WHO Classification: I:no dz, II: mesangial change, III: focal, segmental glomerulonephritis, IV: diffuse proliferative glomerulonephritis, V: membranous GN, VI: glomerular scerosis. 2004: revised ISN/ RPS classification

27. International Society of Nephrology/Renal
Pathology Society (ISN/RPS) Classification of Lupus Nephritis
Class I
Minimal mesangial lupus nephritis
Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence
Class II
Mesangial proliferative lupus nephritis
Purely mesangial hypercellularity or mesangial matrix expansion
Class III
Focal proliferative lupus nephritis
Active or chronic focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of all glomeruli
   

28. International Society of Nephrology/Renal
Pathology Society (ISN/RPS) Classification of Lupus Nephritis
Class IV
Diffuse proliferative lupus nephritis
    Active or chronic diffuse, segmental or global endo- or extracapillary glomerulonephritis involving  ≥ 50% of all glomeruli.

29. classification of lupus nephritis
International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003
classification of lupus nephritis
Class V
Membranous lupus nephritis
Global or segmental subepithelial immune deposits, with or without mesangial alterations
Class V lupus nephritis may occur in combination with class III or IV in which case both will be diagnosed
Class VI
Advanced sclerosis lupus nephritis
>90% of glomeruli globally sclerosed without residual activity

30. 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
50% of SLE pts have some evidence of CNS dz at onset. 40% of SLE pts has onset of CNS dz in first year of dz, or manifestations may appear many yrs later.

31. 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

32. 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
Depression: very common, hard to tease out from regular adol depression, worries about dz/ side effects/ appearance. Emotional lability, difficulty concentrating and remembering. Organic brain syndrome: disorientation, memory loss and progressive intellectual deterioration- grave prognostic sign. Psychosis: hallucinations, paranoia. Cognitive impairment: failing academically, lower IQ scores. Headache: many causes. Vascular migraine-like headaches are more freq in SLE pts than in controls. Sz: GTC usu. CVA: may occur independently or with venous sinus thrombosis or cerebral vein thrombosis; may be associated with HTN, antiphospholipid-related thrombosis or IVH 2/2 low plts.

33. 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 /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
Leukopenia, esp lymphocytopenia (<1500 cells/ mm3), is a hallmark of acute SLE.

34. 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
Lupus anticoagulant: PTT and PT prolonged, presence of an antibody (antiphospholipid ab) that acts at the junction of the extrinsic and intrinsic pathways (conversion of prothrombin to thrombin by thromboplastin is inhibited). Another antiphospholipid is responsible for the false-positive serologic test for syphilis. TTP: anemia, pupura, fever, changing CNS signs, nephritis, leukocytosis, MAHA, similar to HUS in children.

35. Infection
because of their underlying immune dysfunction and treatment with immunosuppressive drugs
Fever should be considered serious

36. Ocular Conjunctivitis Photophobia Monocular blindness
transient or permanent
Blurred vision
Cotton-Wool spots on retina
due to occlusion retinal blood vessels

37. 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

38. 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
Diagnosis of SLE: clinical diagnosis, supported by specific laboratory abnormalities

39. 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
Diagnosis of SLE: clinical diagnosis, supported by specific laboratory abnormalities

40. 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

41. The revised criteria for the classification of systemic lupus erythematosus
1. Serositis
2. Oral Ulcers
3. Arthritis
4. Photosensitivity
5. Blood disorders:
-Hemolytic anemia
-Leukopenia
(Lymphopenia)
-Thrombocytopenia
6. Renal disorders
7. 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

42. 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

43. 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

44. 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.

45. 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.

46. 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.

47. 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.

48. DIFFERENTIAL DIAGNOSIS
Rheumatic: RA, Sjogren’s syndrome, systemic sclerosis, dermatomyositis
Nonrheumatic: HIV, endocarditis, viral infections, hematologic malignancies, vasculitis, ITP, other causes of nephritis

49. Testing
The following are useful standard laboratory studies when SLE is suspected:
CBC with differential
Serum creatinine
Urinalysis with microscopy

50. 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

51. 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

52. Refrences
Robbins and Cotran,Pathologic basis of disease,8th edition,2010
Updated: Feb 19, 2014
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): [Medline]
American College of Rheumatology Update of the 1982 American College of Rheumatology revised criteria for classification of systemic lupus erythematosus. Available at Accessed March 15, 2012

53. Thank You