Systemic Lupus Erythematosus

Definition
Causes and Influences
Pathology
Clinical features
The joints
The skin
Cardiovascular
Pulmonary
Gastrointestinal
Renal / Kidney
Central Nervous System
Reticuloendothelial
The Laboratory investigations
Antibodies in SLE
Criteria for SLE
Assessment of severity
Principles of therapy

Index:

Definition - SYSTEMIC LUPUS ERYTHEMATOSUS - SLE / LUPUS

SLE is a chronic inflammatory illness characterised by a immunoregulatory disturbance and producing a multisystem disorder including skin, joints, blood, kidney, lung, brain, and other organs.


It was originally described by BIETT in 1822.
The term LE was given by CAZANAVE in 1851
The systemic manifestations were described by KAPOSI and OSLER
HARGRAVES first described an unusual cell type on histology in these patients - the LE CELL. HASERICK associated this LE CELL with ANTINUCLEAR ANTIBODIES - antibodies found present in the lupus patients.


Various influences are associated with the disease. These include:
GENETIC
HORMONAL
ENVIRONMENTAL


Epidemiology

The prevalence is between 2.9-400 / 100000
The disease is much more common in females - Female to male ratio is 9 : 1, and occurs also in greater numbers in Blacks and Asians.
However , certain communities are found to have high prevalence rates.
There is a high prevalence in the Western Cape of South Africa - for example amongst persons of mixed ancestry, whilst it is noted to be rare amongst the rural black population of South Africa.

Definite FAMILIAL relationships are noted and genetic profiles have been described.
HLA A1 B8 DR3
NULLC4 ALLELE
ACETYLATOR STATUS - a mechanism of enzyme degradation of certain nitrogenous chemicals in the liver.
REDUCED C3 complement receptors on Red blood cells

ENVIRONMENTAL factors are also found :
Sunlight.
Dietary.
Drugs :
Especially : Hydrallazine, Procainamide, INH, and Certain Anticonvulsants- hydantoins, Aldomet, Certain anti-thyroid drugs, Quinidine, Penicillin and Sulphonamides These have been noted to occasionaly cause a drug induced Lupus like syndrome. (Note : This does NOT prevent their use in patients with SLE).

HORMONAL Influences are also considered important in pathogenesis. These include especially estrogenic influences.

Perhaps the major mechanism of disease however is the Immunological abnormalities. These are manifested in several ways

LYMPHOPENIA
REDUCED SUPPRESSOR FUNCTION
REDUCED PRODUCTION / RESPONSE TO IL2 REDUCED KILLER CELL ACTIVITY
REDUCED PRODUCTION IL1
INCREASED B CELL STIMULATING FACTORS
AUTOANTIBODY PRODUCTION
POLYCLONAL B CELL ACTIVATION
ANTI-CELLULAR ANTIBODY
PLATELETS
RBC
LYMPHOCYTES
MEMBRANE PHOSPHOLIPID
IMMUNE COMPLEX FORMATION / DEPOSITION
ABERRANT IMMUNOREGULATION


The Pathological changes that one sees on histology of the tissues is largely non specific

MONOCYTIC INFILTRATE
LYMPHOCYTIC INFILTRATES
PERIVASCULAR INFILTRATES
MUSCLE CELL DAMAGE

But some specific changes are seen - including :

HAEMATOXYLIN BODIES AND INCLUSION BODIES OF LE CELLS:
ANTIBODY TO CELLULAR NUCLEOPROTEIN.
GLOBULAR MASS OF BLUISH HOMOGENOUS MATERIAL ON H&E STAIN
CONCENTRIC FIBROSIS “ONION SKIN LESIONS” IN THE SPLEEN
VERROUCOUS ENDOCARDITIS LESIONS IN THE HEART VALVES


Clinical Features of SLE :

It is a MULTIPLE ORGAN DISEASE characterised by EXACERBATIONS AND REMISSIONS.


Joint and Musculoskeletal manifestations


ARTHRALGIA - This is common and is pain in the joints with little to find on examination -other than regional tenderness. The pain can be severe and is often worse in the morning, and associated with some stiffness-especially in the hands. However the patient often complains of continuous pain ALL over.

ARTHRITIS - This is characterised by the presence of swelling of the synovial joint lining and is SYMMETRICAL and usually NON EROSIVE

JOINT DEFORMITY may be seen - although uncommon. A variety of ulnar deviation which is reversible is seen in the hands called Jaccouds arthropathy.

TENOSYNOVITIS - this is a tendonitis and is often seen in particular in the flexor hand tendons, but may manifest also as regional enthesitis or bursitis problems.

AVASCULAR NECROSIS is an orthopaedic problem which is associated with the disease but also with use of medications in the disease - especially STEROIDS


The Skin:


Clearly the most visible and common manifestation of SLE is the skin disease :
This is characterised by inflammation at the DERMAL EPIDERMAL JUNCTION with :
OEDEMA - swelling
VACUOLISATION
PERIVASCULAR INFILTRATES of inflammatory cells
FOLLICULAR PLUGGING - plugging and blocking of the follicles
DERMAL ATROPHY - thinning of the dermal skin layer
IMMUNOFLUORESCENCE GRANULAR IgG DEPOSITS - immune antibody fixation in the skin and dermis layer.

The skin disease has several subtypes - classified according to the severity and type of rash.


ACUTE CUTANEOUS L.E - This is characterised by the classical BUTTERFLY RASH. It tends to EXACERBATE WITH FLARES of the SLE and is characterised by
ERYTHEMA
OEDEMA
PHOTOSENSITIVITY


SUBACUTE CUTANEOUS L.E :
This is a rash seen in patients and is described as SYMMETRICAL SUPERFICIAL NON SCARRING It is distributed especially on the
NECK,
CHEST,
SHOULDERS,
BACK,
ARMS.
There are circular ANNULAR LESIONS NON SCARRING ALOPECIA - hair loss, which is patchy in the scalp is seen in 50% of cases. PHOTOSENSITIVITY is VERY common finding.
An ASSOCIATION with certain genetic markers are seen - HLAB8 DR3 ENA(Ro)
Interestingly , in this variety of SLE there is a
LOW INCIDENCE of LUPUS NEPHRITIS


DISCOID L.E

This is characterised by ERYTHEMATOUS PLAQUES with SCALING of the skin surface.
It affects the SCALP EAR FACE NECK.

EARLY: changes seen include OEDEMA and the skin is INFLAMED and HYPERPIGMENTED. LATER: The skin develops CENTRAL DEPIGMENTATION and ATROPHY with DEPRESSED SCARS. TELANGIECTASIA - prominent spidery like superficial blood vessels become prominent.
SEVERE ALOPECIA is common In discoid LE.
90% of patients have disease RESTRICTED TO THE SKIN and there is a LOW INCIDENCE of SEVERE COMPLICATIONS and systemic disease.
Positive antibody serology is usually seen but is USUALLY a LOW TITRE


Cardiovascular manifestations:


PERICARDITIS - inflammation of the lining around the heart is seen in 30% and presents with chest pain , malaise and sometimes breathlessness.
The clinical findings may be absent with a pericardial effusion identified on an XRAY or cardiac ultrasound..ie it can be ASSYMPTOMATIC.
However a pericardial RUB may be heard on auscultation of the heart on examination.
Occasionally the fluid in the pericardial space can increase in volume, and rarely the fluid in the confined space can compress the heart itself and result in CARDIAC TAMPONADE- with heart failure. In addition, scarring down of the pericardium can result in CARDIAC CONSTRICTION, another cause of right heart failure.
MYOCARDITIS occurs in 25% of patients and is manifested by persistent TACHYCARDIA, ST-T CHANGES on electrocardiogram, congestive heart failure with breathlessness, and ARRHYTHMIA with palpitations or tachycardia complications.
ENDOCARDITIS implies involvement of heart valves with inflammation and sterile VEGETATIONS called LIBMAN SACKS VEGETATIONS.
The MITRAL and AORTIC valves are most commonly involved.
The problem ranges from MILD to SEVERE.
There is an association between the valvular lesions and the ANTI PHOSPHOLIPID ANTIBODY / Lupus anticoagulant.
EMBOLI are a potential complication of clots to the brain and there is a potential for stroke. Involvement of BLOOD VESSELS, may cause significant morbidity. This can be the result of a vasculopathy or vasculitis, or due to accelerated atherosclerosis - a potential complication of steroid therapy.
CORONARY ARTERITIS and STEROID related ATHEROGENESIS may cause myocardial infarction.
PERIPHERAL VASCULOPATHY is also well documented.
There are several manifestations of this:
RAYNAUDSsyndrome
LIVEDO RETICULARIS- a lace like rash on the body, which is cold sensitive.
ANTIPHOSPHOLIPID ANTIBODY is seen more commonly in patients with lupus and used to be called the lupus anticoagulant. This is associated with, mid-trimester abortions, thrombosis of blood vessels- arterial and venous, central nervous system disease and headaches / migraine, mitral valve lesions and also thrombocytopenia - low platelet counts.
PERIPHERAL VASCULITIS
PURPURA
URTICARIAL VASCULITIS
ANGIOEDEMA associated with C2 / C4 DEFICIENCY and C1 ESTERASE INHIBITOR DEFICIENCY
LARGE VESSEL VASCULITIS - a process which is relatively INFREQUENT
VASCULITIS of small and medium vessels may be seen more commonly and LYMPHOCYTES/GRANULOCYTES are seen in the walls of the vessels.
LEUKOCYTOCLASTIC CHANGE is more frequent with RUPTURED CELLULAR DEBRIS.
IMMUNOGLOBULIN / C3 DEPOSITS may be identified in the walls of the blood vessels.


SLE : Pulmonary disease


PLEURITIS / PLEURAL EFFUSION - inflammation of the lining of the lung.
PNEUMONITIS - inflammation within the lung tissue - similar to pneumonia.
PULMONARY HAEMORRHAGE - pulmonary bleeding.
INTERSTITIAL LUNG DISEASE - a progressive scarring of the lung tissue.
SHRINKING LUNG SYNDROME - an interesting feature where the lung volumes decrease. This is felt to relate to elevation of the diaphragms as a consequence of weakness of the muscular diaphragm. INFECTIONS - with pneumonia and sinusitis must be distinguished by disease activity. STEROIDS / IMMUNE THERAPY may reduce the host defences, and infection may follow rapidly.
PULMONARY EMBOLISM - occurs with the development of clot in the leg, which dislodges and travels to the lung vessels - obstructing them. The result is chest pain and breathlessness. PULMONARY HYPERTENSION
. - With the occlusion and narrowing of the blood vessels, and with the scarring and fibrosis of the lung tissue, as well as a general increase in tone of the blood vessels within the lung, the pulmonary pressures rise, resulting in breathlessness, and potential progressive right sided heart failure - COR PULMONALE.


Gastrointestinal Involvement


The gastrointestinal tract can be involved in several ways. Most commonly are :

ORAL ULCERS. These are usually PAINLESS and tend to occur in CROPS. They tend to increase with flares of disease activity.
ESOPHAGEAL DYSMOTILITY - results in dysphagia - difficulty swallowing food with a tendency for the food to get “stuck”. There is an association with this and RAYNAUDS.
ABDOMINAL PAIN : One of the most interesting and difficult management problems in SLE. This can be ACUTE/SUBACUTE and has several mechanisms:
SEROSITIS - inflammation of the peritoneum - the lining of the abdominal wall.
PANCREATITIS
VASCULITIS: which can result in visceral BOWEL GANGRENE
VENOUS OCCLUSIONS
PEPTIC ULCERATION - especially related to DRUGS: - the Nonsteroidal anti-inflammatories and high dose cortisone.
HEPATITIS
- and inflammation of the lining around the liver -peri-hepatitis, is an additional potential problem, although generally uncommon.


Kidney / Renal disease :


This is perhaps the most vital organ involved in lupus and frequently, it’s involvement determines the outcome of the disease in the majority of patients.
Inflammation in the kidney is called
nephritis. This can be renal GLOMERULAR involvement or INTERSTITIAL involvement .
50% OF PATIENTS develop renal disease.

Several subtypes are known.

Several classification systems exist - but the best and most recognised is the World Health Organisation
(W.H.O) CLASSIFICATION These are :
1. NORMAL
2. PURE MESANGIAL NEPHRITIS with MESANGIAL CELL PROLIFERATION AND MATRIX THICKENING
3. FOCAL SEGMENTAL Glomerulonephritis (GN) - with SEGMENTAL PROLIFERATION
4. DIFFUSE PROLIFERATIVE GN with PROLIFERATION /CRESCENTS / and FIBRINOID MATERIAL visible in the glomeruli
5. MEMBRANOUS GN. - with BASEMENT MEMBRANE THICKENING
6. ADVANCED SCLEROSING GN. - with END STAGE FIBROSIS and scarring

Mortality from renal disease has improved dramatically over the past few years with identification of the more severe subtypes and appropriate therapy.
DIALYSIS has also offered patients with end stage renal failure an opportunity for prolongation of life, and RENAL TRANSPLANTATION has where available, given these patients a totally improved quality of life, although immunosupression is required, as well as ongoing follow up in these patients. SURVIVAL in Lupus Nephritis is now approximately
85% over 5 YEARS and
65% over 10 YEARS.

Therefore an examination of the urine for blood and protein is vital as well as an examination of the urine sediment with a microscope. An increase in the protein or blood in the urine is a possible indication for renal biopsy to determine the subtype of renal disease and determination of aggression and type of therapy.


CNS - Central Nervous System disease


CNS disease Is extremely common and has a wide spectrum of involvement.
DEPRESSION
PSYCHOSIS
EPILEPSY
HEADACHES
MIGRAINE
TIA
- transient ischaemic attack with transient weakness or neurological deficit.
STROKE - established neurological deficit.
CHOREA - an involuntary movement disorder
MYELOPATHY - spinal cord disease.
POLYNEUROPATHY
- peripheral nerve disease - with weakness or sensation disturbance in the limbs.


Reticuloendothelial involvement.


LYMPHADENOPATHY - enlarged lymph nodes are seen in 50% of patients.
HEPATOMEGALY - an enlargement of the liver.
SPLENOMEGALY
- an enlarged spleen


The laboratory investigations in SLE.


I generally do a Blood Count, ESR (Sedimentation rate) and a CRP - C-Reactive Protein.
The CRP is usually not elevated in lupus unless there is coincidental infection or inflammation from another cause. The ESR is usually elevated in active disease or inflammation and infection.

ANAEMIA : is seen in 40% of cases and is usually the anaemia of chronic disorder.
HAEMOLYTIC ANAEMIA - due to antibody destruction of Red blood cells as part of the autoimmune process is a potentially serious problem and possibly requires Corticosteroids or more potent immunosuppression for more severe involvement.
LEUCOPENIA - a low white cell count is frequent, and in particular a low lymphocyte count fraction may be noted.
THROMBOCYTOPENIA - a low platelet count is seen in 25% of patients.
This is either due to marrow suppression - either from the disease or drugs used, especially the cytotoxic drugs, or peripheral consumption with destruction of platelets in the circulation.
A bone marrow examination is required to distinguish which source the problem is from. The peripheral destruction of the platelets is due to antibody against the platelets themselves part of the autoimmune process.

I also then do a spectrum of antibody tests - including, antinuclear antibody ANA, anti DNA antibody, extractable nuclear antibodies - especially ENA sm, ENA rnp, and antihistone antibody if drug induced lupus is suspected.
These are further discussed below.
A measurement of
IMMUNE COMPLEXES may give an assessment of the level of circulating antibody - antigen complexes
COMPLEMENT- These
Immune molecules involved in inflammation are consumed by these complexes and their levels drop, and also can be measured as an index of disease activity.


A renal function assessment should include a test for blood and protein and microscopy. A blood Urea nitrogen and Creatinine, as well as a 24 hour urine collection to investigate the Creatinine clearance and protein production over 24 hours is necessary. Where appropriate, a liver function is done.


A chest Xray, Electrocardiogram and Pulmonary function tests are done as deemed appropriate.


Antibody tests include :
ANA
DS DNA (Double stranded DNA)
ENA
ANTI HISTONE antibody.


The Antinuclear antibodies :
An antibody is a protein made by the B cell lymphocyte of the body, under the stimulus of the T lymphocyte cell. The initial T cell response follows presentation to the T Cell of antigen, by an “antigen presenting cell” - usually a macrophage.
The original stimulating antigen in lupus is not known, but felt by many to be an infective agent - possibly a virus or retroviral particle.
The T Cell requires a particular “self” gene marker to respond to the cell presenting the antigen to it. If it does not see these self gene markers - no reaction will occur.
The “self” gene marker is related to the HLA gene series - that provides markers for risk factor of disease.
The antibodies in Lupus are associations with the disease and not necessarily causal.
Thus damage to an organ may expose tissue antigens to the macrophage, and antibodies may therefore be produced as a result of damage, rather than causing the damage in the first place.
These antibodies are antibodies to “self” and hence the terminology -
autoimmune - “immune to self”


The tests done are :

FLUORESCENT ANTIBODY TEST : These bind to Nucleic acid, Chromatin, Histones and Ribonuclear proteins. Positive titres are seen in a number of conditions other than lupus :
Chronic active hepatitis
Primary Biliary cirrhosis
Pulmonary fibrosis
Sjogren syndrome
Drug induced lupus
Bacterial endocarditis
Old age


Anti DNA antibody : Antibodies to double-stranded DNA are more specific to SLE and are measured using the CRITHIDIA ASSAY. The METHOD of this assay uses a Crithidia organism.
This is a FLAGELLATE WITH A KINETOPLAST CONTAINING HELICAL double stranded DNA WITHOUT HISTONES.
Antibody can be made to detect this.
DNA BOUND TO KINETOPLAST IS DETECTED BY FLUORESCENT ANTIGLOBULIN SERUM.


Extractable Nuclear Antibody :
These antibodies are directed against RNA EXTRACTED FROM THE NUCLEUS WITH SALINE.
They are LABELLED WITH PHOSPHOROUS AND PRECIPITATED WITH ANTIBODY.
Several are described:
ANTI -U1 RNP Other than SLE may be seen in
Mixed connective tissue disorder :MCTD
MAY IDENTIFY PRECURSORS TO SYSTEMIC SCLEROSIS
They also identify a subset of lupus patients with LESS RENAL DISEASE

ANTI-Ro (SS-A) Seen in:
SLE
SJOGREN syndrome
Associated with increased PHOTOSENSITIVITY in SLE patients
Identify risk of NEONATAL HEART BLOCK in babies of SLE patients

ANTI-Sm Seen in SLE


The Fluorescent Staining characteristics of the antibodies are as follows


Staining Characteristics

Ab TO NUCLEAR PROTEIN :

HOMOGENOUS / DIFFUSE STAIN

Ab TO DNA :

PERIPHERAL / RIM STAIN

Ab TO RNA :

NUCLEOLAR PATTERN

Ab TO EXTRACTABLE ANTIGEN :

SPECKLED PATTERN


The Diagnostic Criteria

IN FACT : There are multiple clinical manifestations and therefore Criteria are identified for diagnosis by the American College of Rheumatology (ACR) These criteria are more for the classification of the disease and do not mean that therapy must be withheld because not all criteria have been fulfilled.
However they ensure that patients entered on studies are definite cases and improve the validity of trials.
They also, of course, increase diagnostic certainty, if all criteria are fulfilled.

CRITERIA FOR DIAGNOSIS SLE : Revised Criteria For Classification (Require 4/11)

Criteria for the diagnosis of SLE

1. MALAR RASH: FIXED ERYTHEMA
2. DISCOID RASH: KERATOSIS PLUGGING ATROPHY
3. PHOTOSENSITIVITY BY PATIENT HISTORY OR CLINICAL OBSERVATION.
4. ORAL ULCERS USUALLY PAINLESS
5. ARTHRITIS NONEROSIVE >1 JOINTS
6. SEROSITIS PLEURA/PERICARDIAL
7. RENAL PROTEIN >3+ / >0.5g CELLULAR CASTES
8. NEUROLOGICAL SEIZURE PSYCHOSIS
9. HAEMATOLOGICAL HAEMOLYTIC ANAEMIA OR LEUKOPENIA OR LYMPHOPENIA OR THROMBOCYTOPENIA
10. IMMUNOLOGICAL +LE CELL PREPARATION OR ANTI DNA OR SM ANTIBODY OR FALSE +VE SYPHILIS
11. ANTINUCLEAR ANTIBODY BY IMMUNOFLUORESCENCE OR EQUIVALENT ASSAY

Once the diagnosis is made , it is important to evaluate the severity of disease and establish the degree of organ involvement This is done clinically and with laboratory tests.
I still believe that many aspects of Lupus therapy is also an
art rather than only a science.
The distinguishing of activity flare from infection for example is often extremely difficult, as often a source of infection is not identifiable, and Lupus patients are more susceptible to severe infections. Indeed - this is where the experience of the Rheumatologist or Physician is so critical - and therein lies the
ART of lupus therapy
. Of course the lab and science is equally important and many new advances are discovered with research.


Assessment of disease Severity


CLINICAL

The presence of severe ORGAN INVOLVEMENT Especially :
NEPHRITIS
CVS
SKIN
SEROSITIS
FEVER / FATIGUE / WEIGHT LOSS

IMMUNOLOGICAL

High levels of antibodies ANF / ANTI DNA
LOW levels of COMPLEMENT
High levels of immune complexes


SLE : The Principles of Therapy


Once an assessment is made of disease activity - a plan can be made for therapy. Always remember that Lupus patients also get all the common minor illnesses seen with non-lupus individuals. Not every problem is due to the Lupus, and not every problem represents a complication thereof.
There is a tendency for some Doctors and Medical personel to fear the disease, which is a problem that is lessened with the experience of the practitioner.
It is however very important to remain vigilant.
Therefore it is recommended that a Rheumatologist see the patients and hopefully coordinate therapy, but involve the Family physician, and other paramedical staff - including Physical therapists, Occupational therapists, other involved staff and certainly, the patient and family concerned.
EDUCATION is very important


The principles are :

1. CONTROL the ACUTE DISEASE / FLARE / ACTIVITY
2. MANAGEMENT of the CHRONIC DISEASE

For mild disease a conservative approach is required but for severe disease an aggressive approach becomes necessary.

For the joint manifestations - judicial use of Nonsteroidal anti-inflammatories (NSAIDS) are almost always required - especially if there is swelling and stiffness of the joints. Analgesics are useful for pain control - and should be used depending on severity of the discomfort. Antimalarials ie plaquenil, are particularly useful for joint and skin disease and should be seen as a controller of the underlying process, rather than symptomatic therapy alone. For the skin disease, topical cortisone preparations in different strengths are useful. For the face, topical steroids should be avoided unless in dilute format as they can cause skin thinning. However severe disease sometimes warrants usage under guidance of a dermatologist if necessary. Antimalarials are useful for skin disease control. Monitoring of eye toxicity is required for long term use of the antimalarials.

Use of corticosteroid tablets should be used for severe disease, where function is impaired and NSAIDS are not helping for joint problems, and for major organ involvement. Corticosteroids can be used in oral form or in intravenous “pulse therapy” for severe organ disease.


Immunosupression is used for severe internal organ involvement and to reduce requirement for the steroids - “steroid sparing agents”. Their usage requires expert knowledge as monitoring is required for side effects.
Examples include
CYCLOPHOSPHAMIDE
AZATHIOPRINE
METHOTREXATE
CHLORAMBUCIL


OTHER
Therapeutic measures sometimes employed include
Dapsone
PLASMAPHORESIS
TOTAL LYMPHOID IRRADIATION


DIALYSIS has altered the prognosis of millions of patients in end stage renal failure, as has transplantation for thousands of individuals.


For chronic disease the aim of therapy is :

PATIENT EDUCATION
PERIODIC EVALUATION
PREVENT ORGAN DETERIORATION
MINIMISE DISABILITY
MINIMISE COMPLICATIONS OF THERAPY
It is important to establish a maintenance disease modifying therapy regimen if possible - including antimalarials and if severe disease, as minimal doses of NSAIDS, analgesics, cortisone and immunosupression drugs as the cost - benefit side effect profile ratio will allow.


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Original Article - copyright
Dr D Gotlieb : drdoc on-line
Rheumatologist
Cape Town
December 1998
Updated Oct 2001