Transcript SYSTEMIC LUPUS ERYTHEMATOSUS

SYSTEMIC LUPUS
ERYTHEMATOSUS
DEFINITION AND
PREVALENCE
• Systemic lupus erythematosus (SLE) is
a disease of unknown etiology in which
tissues and cells are damaged by
pathogenic autoantibodies and immune
complexes
• Ninety percent of cases are in women
PATHOGENESIS AND
ETIOLOGY
• SLE results from tissue damage caused
by pathogenic subsets of autoantibodies
and immune complexes
• The abnormal immune responses
• polyclonal and antigen-specific T and B
lymphocyte hyperactivity
• inadequate regulation of that
hyperactivity
Etiology
• The etiology of SLE remains unknown. A
genetic predisposition, sex hormones, and
environmental trigger(s) likely result in the
disordered immune response that typifies
the disease.
A role for genetics is suggested by the increased percentage of two
histocompatibility antigens in patients with SLE, HLA-DR2 and HLADR3. In addition, there is an increased frequency of the extended
haplotype HLA-A1, B8, DR3. The role for heredity is further supported
by the concordance for this illness among monozygotic twins. The
polygenic nature, however, of this genetic predisposition as well as the
contribution of environmental factors is suggested by the only moderate
concordance rate which is reported to be between 25 and 60%.
The origin of autoantibody production in SLE is unclear but a role has
been suggested for an antigen driven process, spontaneous B-cell hyperresponsiveness, or impaired immune regulation. Regardless of the
etiology of autoantibody production, SLE is associated with the impaired
clearance of circulating immune complexes secondary to decreased CR1
expression, defective Fc receptor function, or deficiencies of early
complement components such as C4A.
• More is known about the pathogenic
cellular and molecular events which are
responsible for vascular lesions in SLE than
the origins of autoimmunity
• Disease manifestations result from recurrent
vascular injury due to immune complex
deposition, leukothrombosis, or thrombosis
• Additionally, cytotoxic antibodies can
mediate autoimmune hemolytic anemia and
thrombocytopenia, while antibodies to
specific cellular antigens can disrupt
cellular function. An example of the latter,
is the association between anti-neuronal
antibodies and neuropsychiatric SLE
SLE Subsets
• Discoid lupus is an illness characterized by
a non-photosensitive, chronic and
potentially scarring skin disease. This
illness is usually unaccompanied by ANA or
other autoantibodies. Perhaps 10% of
patients with discoid lupus will develop the
systemic illness
drug-induced
• Drugs such as procainamide or hydralazine can
induce the production of antinuclear antibodies,
especially anti-histone antibodies, and
occasionally a SLE-like illness. Drug induced
lupus is usually characterized by fever,
hematological abnormalities such as an
autoimmune hemolytic anemia or autoimmune
thrombocytopenia, or serositis. Skin, renal and
neurologic manifestations are uncommon
Neonatal
• Neonatal or congenital lupus occurs when
the transplacental acquisition of
autoantibodies, specifically anti-Ro (SS-A),
produce int he neonate a transient
photosensitive rash, confential complete
heart block, thrombocytopenia or rarely
hepatobiliary dysfunction
Ro (ANA negative) lupus
• ANA negative or Ro lupus is defined by the
absence of an ANA and the present of a lupus-like
illness. This disorder is manifest most often by a
partially photosensitive skin rash referred to as
subacute cutaneous lupus erythematosus. These
patients often demonstrate anti-Ro antibodies in
the serum and, given the cytoplasmic residence of
the Ro antigen, these patients may be ANA
negative
Signs and Symptoms
• 80% of patients with SLE will present with
involvement of the skin or joints
• A common presenting complaint is a
photosensitive rash often with alopecia
• Alternatively, patients may present with arthralgia
or frank arthritis. However, patients may present
with fever accompanied by single organ
involvement, such as inflammatory serositis,
glomerulonephritis, neuropsychiatric disturbance
or hematological disorder
Systemic Effects
•
•
•
•
•
•
•
•
•
•
•
Musculoskeletal
Mucocutaneous
Serositis
Hematological
Renal
Central Nervous System
Secondary Antiphospholipid Antibody Syndrome
Ocular
Lung
Cardiac
Gastrointestinal
Musculoskeletal
• Approximately 90% of patients with SLE have
musculoskeletal symptoms. The typical clinical
manifestation is arthralgia. The joints most
commonly involved are the proximal
interphalangeal, metacarpophalangeal, wrist, and
knees. In contrast to rheumatoid arthritis, however,
lupus is rarely accompanied by frank articular
erosions
• Myalgias are another common feature of
SLE. Less common is frank inflammatory
myositis which occurs occasionally during
the course of SLE
Mucocutaneous
• Mucosal ulcers are not an infrequent complication
of lupus, occurring in 30% of patients. They most
often occur on the hard or soft palate but also may
be found on the nasal septum
• The ulcers are usually painless and undetected by
the patient but may be painful when there is a
secondary infection, such as oral candidiasis. It is
controversial whether the ulcers represent a simple
inflammatory mucositis or a frank vasculitis of the
mucous membranes.
• Approximately 80% of patients with SLE have
dermatological manifestations during the course of
their illness. The acute cutaneous eruption is
manifest as a photosensitive rash which often has
a butterfly appearance by virtue of involving the
bridge of the nose and malar areas of the face. A
characteristic feature of this rash is sparing of the
nasolabial folds. Photosensitivity is less common
in patients of color but occurs in 50% of all
patients with SLE.
• The rash of subacute cutaneous lupus is observed in antiRo positive patients. This eruption is intermediately
photosensitive and can either have an annular, polycyclic
appearance or a more papulosquamous, pityriasiform, or
psoriasiform appearance. 25% of patients with SLE have
discoid skin lesions. These lesions are often on the face
with a predilection for the inner pinna of the ear but are not
photosensitive. These lesions are characterized clinically
by follicular plugging, skin atrophy, scaling, telangiectasia
and skin erythema
Alopecia occurs in 50% of patients. Typically this is manifest as
reversible hair thinning during periods of disease activity. This is
demonstrated by the ease with which hair can be plucked from the scalp
and the development of "lupus hairs" (i.e. short strands at the scalp line).
Following an acute, usually febrile, exacerbation of SLE patients may
experience precipitous generalized hair loss as part of a telogen
effluvium. This results from a period of arrested hair growth during the
acute episode. Discoid lesions involving the scalp leads to scarring
alopecia
• Unusual cutaneous manifestations of lupus include
urticaria, angioedema, bullae and panniculitis
known as lupus profundus
• Raynaudus phenomenon is observed in 30% of
patients
• Livedo reticularis occurs with increased incidence
in patients with SLE
• Digital purpura is another manifestation of SLE
and may occur as the consequence of vasculitis
• Palpable purpura with histologic evidence of
leukocytoclastic vasculitis is an occasional feature
of SLE
Serositis
• Inflammatory serositis of the pleura,
pericardium and peritoneum occurs in 50%
of patients with SLE. This may produce
pleuritis, pericarditis and medical
peritonitis.
Hematological
• Anemia of chronic inflammation is a common
feature of exacerbated SLE
• Coombs positive hemolytic anemia with an acute
declining hematocrit and reticulocytosis is a
characteristic but not especially common
occurrence in SLE
• Autoimmune thrombocytopenia purpura can be a
presenting feature of SLE
• Thrombocytopenia as a consequence of the
antiphopholipid antibody syndrome has also been
described in SLE
• Leukopenia with lymphopenia is also a
characteristic feature of SLE
Renal
• clinically relevant kidney disease occurs in about
50% of patients
• This is usually the consequence of the deposition
of immune complexes containing anti-DNA in the
kidney
• Mesangial lupus nephropathy is generally
associated with an excellent prognosis
• Proliferative lupus nephropathy, especially diffuse
proliferative, often has a nephritic picture with
hypertension, urinary red cell casts and can be
accompanied by significant deterioration in renal
function
Central Nervous System
• Neuropsychiatric complications occur in 50% of
SLE patients and include acute and chronic, as
well as focal and diffuse manifestations
• Cerebral vascular accidents are the consequence of
either inflammatory or non-inflammatory,
thrombotic vasculopathy in the central nervous
system
• Seizures complicate the course in 25% of patients
with lupus
• Diffuse cerebral dysfunction is manifest as an
organic effective disorders, personality disorder,
psychosis, or coma.
• Vascular or migraine headaches occur in 10% of
lupus patients
Secondary Antiphospholipid
Antibody Syndrome
• Patients with SLE have an increased incidence of
the antiphopholipid antibody syndrome
• This syndrome is defined by the co-occurrence of
thrombotic events and the presence of
autoantibodies against negatively charged
phospholipid, such as a biological false-positive
VDRL, lupus anticoagulant, or anti-cardiolipin
antibody
• This syndrome occurs most frequently in patients
with high titer IgG anti-cardiolipin antibodies or
lupus anticoagulant. Patients with this disorders
are at risk for recurrent arterial and venous
thrombosis, thrombocytopenia, and fetal wastage.
The mechanisms of this prothrombotic diathesis
are uncertain, but these autoantibodies, perhaps
interacting with co-factors, bind to target antigens
on endothelial cells, platelets or coagulation
factors producing a hypercoaguable state.
Ocular
• Patients with lupus may develop anterior
uveitis or iridocyclitis. Frank retinal
vasculitis has been described, as well as
central retinal artery occlusion, central
retinal vein occlusion and ischemic optic
neuropathy. Xerostomia with
keratoconjunctivitis sicca is seen in 10% of
patients.
Lung
• As mentioned, the most common
involvement of the lung is inflammatory
serositis producing pleuritis. However,
patients with lupus can also develop
transient hypoxia on the basis of pulmonary
leukosequestration, inflammatory
pneumonitis, interstitial pulmonary fibrosis,
pulmonary hypertension, diaphragmatic
dysfunction, and phrenic nerve palsy.
Cardiac
• The most common cardiac manifestation is
pericarditis with or without effusion.
Additionally, patients with lupus can
develop myocarditis. Nonbacterial
verrucous endocarditis or Libman-Sacks
endocarditis produces millimeter vegetation
on the mitral and aortic valve
Gastrointestinal
• Medical peritonitis with or without ascites
is a manifestation of lupus serositis
involving the peritoneum
• Less common manifestations of lupus
involving the gastrointestinal tract include
mesenteric ischemia from mesenteric
vasculitis and pancreatitis
Laboratory Procedures
•
•
•
•
•
complete blood count
erythrocyte sedimentation rate
Urinalysis
biochemical profile and antinuclear antibodies
In 90-95% of patients with SLE the serum ANA
will be positive typically with a speckled, diffuse,
or peripheral pattern.
• When the ANA is negative but the diagnosis is
still strongly suspected a test for anti-Ro (SS-A)
and anti-La (SS-B) can be used to identify the rare
patient with ANA negative, Ro lupus.
Additionally, a total hemolytic complement or
CH50 can be helpful. A CH50 of zero is consistent
with the unusual patient who has a homozygous
early complement component deficiency (e.g.
C1q, C2, C4), is at risk for developing a SLE-like
illness, but is ANA negative
• Once the diagnosis is more strongly suspected
because of the appropriate findings on history,
physical exam and screening laboratories (e.g.
positive ANA) additional tests are valuable. These
include anti-double stranded DNA, anti-RNP, antiSm, anti-Ro, anti-La, C3, and C4. 30-70% of
patients with SLE will be anti-DNA positive. 30%
of patients with SLE will be anti-Sm positive. The
presence of anti-double stranded DNA antibodies
and hypocomplementemia strongly suggests the
diagnosis of lupus and identifies the patient at
increase risk for glomerulonephritis
• In patients with a history of recurrent
thrombosis or recurrent fetal wastage, the
presence of the antiphopholipid antibody
syndrome is evaluated by a VDRL, PTT,
sensitive assay for lupus anticoagulant such
as the dilute Russell viper venom time, and
anti-cardiolipin antibodies.
Diagnostic Procedures
• X-rays
• MRI
• Chest x-rays and chest CT scans are used to
distinguish between infectious and inflammatory
lung disease
• Thoracentesis, pericardiocentesis and paracentesis
may be necessary to evaluate patients with
effusive serositis, especially in the presence of
fever
• Electrocardiograms (ECG) can demonstrate
changes indicative of pericarditis
• Echocardiograms are used to evaluate patients for
pericardial effusions or valvulitis
• Electroencephalograms (EEG) are useful in
evaluating patients with suspected
neuropsychiatric lupus
• Brain CT
• MRI
• Biopsies are infrequently required for the
diagnosis of SLE
THERAPEUTIC MODALITIES
•
•
•
•
•
STEROIDS
CYCLOPHOSPHAMIDE
AZATHIOPRINE
CYCLOSPORIN
Plasmapheresis