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 HLA-DR3. 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 hyper-responsiveness, 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 anti-Ro 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, anti-Sm, 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