Systemic lupus

erythematosus

Prof.Univ.Dr. Zorilă Corina

 Definition
• Systemic lupus erythematosus (SLE) is a
multisystem autoimmune disease
characterized by autoimmune-mediated
tissue alterations (by autoantibodies or
circulating immune complexes).
• Disease prevalence is between 15-
50/100.000.
• The disease is more common in young
women
• Clinical manifestations involve multiple organ
impairment:
• Ex. joints, skin, kidney, central nervous system,
cardiovascular system, hematology and immune
systems ,
• patients have variable combinations of distinct
clinical signs of evolution in general sinusoidal
one with exacerbations and remissions.
 Etiopathogenesis
• LES results from the interaction of
environmental factors - infection, UV
radiation and certain drugs - and a
genetically susceptible land.
• Predisposing genetic constellation
common theme is that they involve a
hyperactivity or decrease immune control.
 Genes
• Genes that influence susceptibility to the
disease are:
• parts of the genes encoding the complement
pathway: C1q, C2, C4a, reduction of the
synthesis of such components decreases the
clearance of apoptotic cells growing tank
autoantigens;
• some alleles of the major histocompatibility
complex: HLA-DR2 and HLA-DR3.
• The genes involved in regulating the activity of
interferon, TNF receptor or Fc receptor.
 The environmental factors
-Epstein-Barr virus infection;
-UV radiation - abnormal epithelial DNA with
increasing availability of autoantigens;
-drugs: procainamide, hydralazine (di-
methylation and "immuno-gendering"
DNA), interferon α, anti-TNF agents;
• Consequently there is in LES aberrant immune reactivity
(both humoral and cellular) whose consequence is the
appearance of autoantibodies and circulating immune
complexes that cause multiorgan injury
• Antibodies:
• Ac anti-DNA dc (anti-dsDNA) specific for SLE,
• ANA (anti-nuclear Ac) occur in 95% of cases of SLE, is
the best method of screening
• Ac anti-Sm are also specific but rare (25%) did not
correlate with disease activity
 Clinical manifestations
General symptoms refer to: asthenia,
fatigue, weight loss, headache,
lymphadenopathy, arthralgia generalized
The onset is usually insidious with arthragia,
low grade fever, generalized
micropoliadenopathy
The disease follows a general trend
characterized by exacerbations and
remissions.
• 15-20% of cases of SLE begins in
childhood.
• Disease activity of children is higher and
achieved kidney impairment is more
common and more severe.
 Cutaneous manifestations
- Flat or uneven malar rash ("butterfly") that respects naso-
labial folds;
- Farms maculopapular lesions may occur on other areas
exposed to the sun;
- Photosensitivity - 40% of patients;
- Mucosal ulceration - buccal mucosa, gums, nasal septum;
- Subcutaneous panniculitis nodular lesions may occur;
- Generalized or focal alopecia;
- Vasculitic lesions: purpura, urticaria;
- Petechiae secondary to thrombocytopenia
 Musculoskeletal manifestations :
• polyarthralgias intermittent
• Lupus arthritis, non-erosive, non-deforming
without geodes and erosions;
• ischemic necrosis (femoral head), particularly in
patients corticosteroid dependent ;
• myalgia or myositis (CPK ↑ weakness belts with
necrosis and inflammation in biopsy material);
• cortisone myopathy;
• LES may be accompanyed by fibromyalgia
contributing to depression and fatigue
 Renal Manifestations
• Lupus nephritis is usually the most serious manifestation
of SLE with infection due to it being princeps mortality
cause in the first decade of the disease
• Patients with lupus nephritis shows:
• microscopic hematuria (dysmorphic RBCs and RBC
cylinder)
• rank nephritic proteinuria (50% had nephrotic syndrome
with> 3.5 g/24h)
• hypertension and accelerated atherosclerosis.
 Lupus nephritis
• Represents the classic picture of immune complex
glomerulonephritis.
• Usually affects young women, 90% of patients are
women in the third decade of life.
• Patients with SLE can develop any type of glomerular
syndrome.
• Two thirds of patients presenting nephrotic syndrome:
Nephrotic proteinuria rank with hypertension and renal
function limiting variable.
• In severe cases is present telescoped urinary sediment:
Dysmorphic erythrocytes, leukocytes, hyaline and
granular cylinders considered typical for the disease
 Lupus nephritis(2)
• Is classified into six grades (WHO) according to
histological lesions:
• I-st degree - without histological changes in optical
microscopy (immune deposits in fluorescence);
• II-nd degree-restricted proliferative changes in the
mesangium;
• III-rd degree -focal proliferative changes (in 10-50% of
glomeruli);
• IV-th degree- diffuse proliferative glomerulonephritis in
50% of glomeruli;
• V-th degree -lesions predominantly membranous with
varying degrees of proliferation;
• VI-th degree-glomerulosclerosis
WHO
class Type of nephritis Morphological characteristics
type
Normal aspect Normal optic glomeruli in MO, sometimes
I fine deposits in ME or IF
Mesangial MO: increased mesangial matrix with
II proliferative GN hypercellularity
ME: IgA deposits + C
Focal and segmental MO: diffuse mesangial hypercellularity,
GN segmental proliferation and focal
III segmental necrosis, hyaline thrombi
ME: IgA deposits + C
IV Diffuse proliferative MO: hypercellularity extensive mesangial
GN (> 50%) cells, endothelial capillary walls thickened
appearance of "wire loops" PMN intra-and
extraluminal.
IF: large granular deposits of Ig (IgG>
IgM> IgA) and complement, especially
subendothelial, deposits of fibrin in the
urinary space
ME: electronodense subendothelial
deposits, epi-,mesangial and
intramembranous
membranous GN MO: mesangial hypercellularity,
extramembranoase deposits with diffuse
V thickening of the capillary walls regular
Describe four types depending on
proliferative lesions associated
Glomerular sclerosis MO: diffuse or focal glomerular sclerosis,
VI proliferative without associated lesions
Studies have shown the phenomenon of
transformation iterated biopsy histological types of
nephropathy in SLE ​(10-45% of cases), so that a
histological form may develop into another class,
more frequently in grade II or grade III to IV a
possibility of regression of the lesions and renal
therapy.
Specific lesions indicative of disease activity and
possible reversibility are:
-endo-capillary proliferation,
-cariorexis nuclear
-presence of crescents,
-fibrinoid necrosis,
-look "wire loops"
-mononuclear cell infiltrate,
-hyaline thrombi
 Cardiovascular manifestations :
• Lupus pericarditis, generalized component of
serositis;
• warty lesions sterile valve (Libman-Sacks
endocarditis), nodular inflammatory lesions that
may be associated with antiphospholipid
syndrome;
• premature and accelerated atherosclerosis;
• Raynaud's phenomenon: paroxysmal and
episodic vasospasm of digital arteries (60% in
SLE);
 Pulmonary manifestations :
• pleural effusion to 30% of SLE patients at
some point in the disease;
• parenchymal damage is rare: pneumonia,
alveolar hemorrhage, pulmonary embolism
or pulmonary hypertension with impaired
diffusing capacity;
Gastrointestinal manifestations :
vasculitis in the digestive tract (ischemia,
perforation, hemorrhage, and Sepsa)
peritonitis (rare);
pancreatitis (10%) due to vascular pathology
(or therapy with cortisone and
azathioprine);
sometimes splenomegaly;
 Hematologic manifestations :
• anemia (50%), multifactorial hemolysis (Coombs
+ or microangiopathic) or reflect chronic
(normocytic normochromic);
• leukopenia, most commonly lymphopenia
(<1500/μl) reflects the increase apoptosis and
Ac antilymphocytic, rarely neutropenia;
• thrombocytopenia (idiopathic or autoimmune)
syndrome can cause severe bleeding, especially
in the context of Ac directed against coagulation
factors.
 Antiphospholipidic syndrome
• refers to recurrent vascular thrombosis (arterial
or venous) that may be associated with
miscarriages, impaired glomerular thrombotic
microangiopathic hemolytic anemia,
thrombocytopenia, valvular disease, CNS
disease in a context of antiphospholipid Ac
(occurring in one third of patients with SLE
• Screening tests: antiphospholipid antibodies
(aPL) are not specific enough to predict
thrombotic events and morbidity especially in
pregnancy
 Generalized lymphadenopathy
• By follicular hyperplasia sometimes occurs
with lymphoma imposing differential
diagnosis;
• However, in SLE ​there is an increased
incidence of hematological malignancies
(especially non-Hodgkin lymphoma)
 Ocular manifestations

• Sjogren's syndrome (sicca) and

•   nonspecific conjunctivitis associated with
lupus but usually do not affect vision.
• retinal vasculitis and optic neuritis can lead
to blindness.
• Complications of corticosteroid therapy
include cataract and glaucoma rarely.
 Neurological manifestations:
• Can be an expression of the disease itself (diffuse
process or vascular occlusion) or infections in
immunosuppressed patients is:
• cognitive dysfunction;
• headache;
• seizures;
• psychotic manifestations (to be distinguished from
glucocorticoid-induced psychosis);
• myelopathy;
• manifestations of PNS damage: acute inflammatory
demyelinating poliradiculopatie, mononeuropathy (even
multiplex), autonomic dysfunction, plexopathies;
 Autoantibodies
• ANA (anti-nuclear Ac) occur in 95% of cases of SLE, is the best
method of screening;

• Ac dc anti-DNA (anti-dsDNA) -70% specific for SLE; their titer

correlates with disease activity (nephritis or vasculitis);

• Ac anti-Sm are also specific but rare (25%) did not correlate with
disease activity;

• Ac anti-phospholipid (anticardiolipin and lupus anticoagulant) are

not features but is one of the diagnostic criteria of the disease and
identify patients at risk of arterial or venous thrombosis,
thrombocytopenia or miscarriages;

• Anti-Ro in neonatal lupus (congenital AV block), but also in systemic

sclerosis and Sjogren's syndrome, more common in ANA negative
patients, their presence indicates a low risk of lupus nephritis;
 Blood tests
• ESR is elevated C-reactive protein (CRP)
normal= hallmark for SLE
• leukopenia,
• Lupus cells present in 50-75% of cases
• Low serum complement with all its components.
• Circulating immune complexes are elevated
pathognomonic
 Other tests :
• False positive VDRL,
• Coombs test positive
• possible presence of rheumatoid factor
(RF),
• cryoglobulins,
• fibrin degradation products (PDF).
 Direct immunofluorescence test of
the skin
• It is made with IgG
antibodies
• Note the linear deposit in
the epidermal basement
membrane

• The nuclei are deposits

within the epidermis
• (anti-nuclear atc. present)
 Diagnostic Criteria (ACR)
1. Malar rash erythema flat or supradenivelat over eminent cheek;
2. Discoid Lupus: circular erythematous areas, raised edges and center
hyperpigmented atrophic, depigmented;
3. Photosensitivity: Exposure to UV radiation generates rash;
4. Oral ulcers: ulcers in the oral mucosa or nasopharynx, seen by a doctor;
5. Arthritis: non-erosive arthritis of two or more peripheral joints with tenderness
swelling and exudation;
6. Serosity: pleural effusion or pericarditis documented clinically (friction rub) or ECG
or imaging evidence of effusion;
7. Renal disease: proteinuria> 0.5 g / day or cellular cylinders;
8. Hematologic manifestations (leukopenia <4000/ul, lymphopenia <1500/ul,
hemolytic anemia, or thrombocytopenia <100.000/ul;
9. Neurological manifestations: seizures or psychosis without other causes;
10. Immune manifestations: Ac dc anti-DNA or anti-Sm or Ac Ac anti-phospholipid;
11. ANA in high titer;
 DIAGNOSIS

• Any combination of four of the 11 criteria,

occurring at any time in history makes the
diagnosis of lupus in patients most likely
(specificity 95%, sensitivity 75%);
 PROGNOSIS
• The disease is chronic, unpredictable with
recurrent activity.
• Survival at 10 years is 85%. Renal and
neurological complications dictates prognosis.
• Causes of mortality include early and
generalized atherosclerosis, IRC, infections,
complications of therapy with cortisone and
increased incidence of non-Hodgkin lymphomas
 TREATMENT
• It is different depending on the clinical
manifestations: Supportive and symptomatic
conservative in mild disease and in case of
severe complications is more aggressively.
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
are sufficient to control arthritis / arthralgia.
• Antimalarials (hydroxychloroquine, chloroquine
and quinacrine) are effective for skin and joint
manifestations, hydroxychloroquine 200-400mg /
day (attention retinal toxicity);
• Aspirin (as antiplatelet-80-325mg / day) in
patients with thrombotic tendencies;
 Corticosteroids
• Corticosteroids alone or in combination with
immunosuppressive agents are first-line medication in
CNS lupus, vasculitis, and reversible kidney damage;
• Prednisone 0.5-2 mg / kg / day or parenteral
methylprednisolone 1 g iv / day for 3 days followed by
0.5-1 mg / kg / day per os;
• progressively lower doses until maintenance dose (5-10
mg / day or 10-20 mg / 2 days to prednisone).
• It is contraindicated in lupus GN with IRC
• Side effects of long-term corticosteroid therapy include
opportunistic infections, diabetes, osteoporosis,
hypertension;
 Immunosuppressants agents
• azathioprine 1-2.5 mg / kg / day per os or
cyclophosphamide 1-4 mg / kg / day may be
associated corticosteroid therapy in severe
illness.
• In lupus nephritis (gr III, IV and V) may be
administered parenterally cyclophosphamide
500mg-1g/m2 month 3 months 6 months
then for another 18 months (watch
hemorrhagic cystitis, testicular or ovarian
failure at cumulative doses);
 Studiul EURO-LUPUS
• Has demonstrateg the effectiveness of the mini-
bolus cyclophosphamide (500 mg / infusion
every 15 days, six injections total) compared to
the conventional monthly intravenous
cyclophosphamide (CYC) (bolus of 0.7 g/m2
monthly for 6 months) regression proliferative
lupus nephropathy. Survival and renal function
data were collected prospectively over a period
of 10 years from 90 patients randomized to the
study EURO-LUPUS.

The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing

low-dose and high-dose intravenous cyclophosphamide.
Houssiau FA et coll. Ann Rheum Dis. 2010;69:61-4.
 Biologic therapy
• Rituximab and systemic lupus erythematosus:
• results of a randomized phase II / III
(EXPLORER study) Rituximab (RTX) is a
chimeric monoclonal antibody whose target is
the CD20 B cell marker.
• This drug is widely used in refractory lupus to
conventional treatments.
 Systemic Scleroderma
• systemic scleroderma, progressive, or
"systemic sclerose" is a disseminated
disease of connective tissue, making part
of the collagenoses.
• It caracterized by cutaneous and vascular
fibrosis.
• Rare, 5-20 new cases / year / 1 million
inhabitants.
 Systemic Scleroderma
• The term derives from the Greek words skleros (hard or
indurated = hard, tough, rough) and derma (skin).
• Hippocrates first described this condition as thickened
skin clinic.
• Carlo Curzio (1752) made ​the first detailed description of
these conditions, when a patient presented with
thickened skin.
• The term scleroderma was given by Giovambattista
Fantonetti in 1836. This disease is a rheumatologic
disorder because it affects the connective tissue of the
body (1).
 Systemic Scleroderma
• Scleroderma is a systemic disease characterized by
inflammation especially subcutaneous tissue, followed by
progressive fibrosis, leading to atrophy of skin,
subcutaneous fat and skin vessel arteritis.
• Scleroderma can affect several organs (gastrointestinal,
respiratory, renal, cardiovascular, genitourinary), as well
as vascular structures are frequently involved
• Is associated with thyroiditis, primary biliary cirrhosis and
rarely neuropathy.
•   Rarely, it may meet failure and pulmonary damage
without affecting skin.
 Pathophysiology
• Scleroderma manifestations result from
• progressive tissue fibrosis and occlusion of the
microcirculation by excessive production and storage of
collagen type I and III.
• Other molecules found in the connective tissue (e.g..,
Glycosaminoglycans, tenascin, fibronectin) were also
elevated.
• Vascular alterations indicate a predilection for affecting small
arteries, arterioles and capillaries.
•   The cytoskeleton of small vessels is affected by the
structural defects that lead to collapse.
• As a result, the joints are no longer functional, allowing the
endothelium to have vascular lumen.
• In scleroderma, there is an autoimmune
response and an inflammatory response.
•   The inflammatory response is reflected by the
moderate increase in ESR and serum globulins.
• The role of the immune system in the
pathogenesis of scleroderma remains unclear,
although patients with scleroderma shows
changes in humoral and cell-mediated immunity.
• Autoimmune response includes T cells and B. A
primary factor in the autoimmune antibodies are
termed autoantibodies (5).
 Antibodies
• Antinuclear antibodies and antinucleolar are present at
about 95% of patients with scleroderma.
• These autoantibodies include anti-centromere, anti-
topoisomerase I, anti-Th RNP and anti-PM-Scl, which
are usually accepted as markers of scleroderma.
• Anti-RNA polymerase III (described in 1993) are a
specific marker for scleroderma. These autoantibodies
identify a group of patients with progressive skin damage
and increased risk of renal impairment. Recent research
has demonstrated a link between the gene for the
protein fibrillin 1 and the appearance of scleroderma.
 Clinical symptoms
• Raynaud syndrome frequently onset
• Appears thickened skin, especially on the
face, neck, trunk and limbs
• The fingers are tapered, with thickened
skin with no elasticity finger flexion occurs
fixing "sclerodactyly"
• Extremity ulcers may appear , limited
fingertips
 Cutaneous manifestations
There are features and key elements of diagnosis:
CREST syndrome
-Calcifications sous cutanées
-Raynaud syndrome
-Esophagial affection
-Sclerodactyly
-Télangectasies

Affectation of the face can create a layout property with the

disappearance of wrinkles, the appearance of "Byzantine
icon“.
 The locomotor system

• osteoarticular: inflammatory polyarthritis,

tendonitis, osteolysis of the extremities.
• Muscle: Muscle weakness belts, may be
accompanied by enzymatic and electrical
anomalies myogenic reached.
• Neurological: mononeuropathies, trigeminal or
carpal tunnel or polyneuropathy
 The Visceral injuries
Digestive sistem
Esophageal impairment affects 75% of patients, more or
less on long term.
A progressive paralysis of the lower part of the esophagus
causes dysphagia.
  There is a reflux causing esophagitis, sometimes
ulcerated.
There may be more rarely with the same type at the
stomach and small intestine, which can cause
malabsorption. It also describes digestive telangiectasia
wich can be a bleeding source.
 The pulmonary impairement
• Scleroderma can reach the lung with
changes of interstitial fibrosis, more or less
frequently depending on the series and the
published diagnostic mode.
•   There may also be pulmonary
hypertension, isolated or not.
 Cardiovascular sistem

• Their frequency varies depending on the type of

series published clinical, echocardiographic and
anatomical.
• There are currently no endocardial reached.
• The pericardial events are classic, but it is
especially myocardial involvement is frequent
and severe.
• Note the possibility of a coronary spasm, the so
called "Raynaud of the coronary."
 The renal sistem
The "scleroderma renal crisis" performs a
vital emergency with acute renal failure
and hemolysis.
  But most of the time it is, however, a slowly
progressive chronic renal failure with
hypertension.
 Treatment
Line treatments.
Include the corticosteroids, D-penicillamine, factor
XIII, interferon.
It seems that prolonged conventional
immunosuppressants may be useful in slowing the
progression of the disease.
Symptomatic treatments.
They are likely to be adapted to each case,
depending on the visceral affection and their
complications.
 Clinical forms
• Patients with scleroderma may present :
• localized form or
• systemic form.

• Localized scleroderma usually affects only the skin on the hands

and face. Evolves slowly and rarely becomes systemic.
• There are two types of localized scleroderma:
• morphea and
• Linear scleroderma.

• In systemic scleroderma (also called systemic sclerosis) affects the

internal organs.
• This form has 2 versions: Limited (the CREST syndrome, calcinosis,
Raynaud's phenomenon, esophageal motor disorder, sclerodactyly,
telangiectasia) and diffuse scleroderma.
• Both forms evolves slowly.