Chapter 17: Autoimmune Diseases, Systemic Lupus erythematosus (SLE)
This is the prototype of autoimmune diseases.
Osler described in detail in 1895.
Typical features: These are mostly young females (childbearing age) with butterfly rashes, fever, pain in joints, and photosensitivity. Sometimes the sign and symptoms are puzzling and the patient may come with only fever and proteinuria.
The onset of SLE may be:
- Acute or insidious
Major Immunologic Features
- The lupus erythematosus cell phenomenon is positive.
- Increase concentration (titer) of Antinuclear Antibody (ANA).
- Positive anti-DNA Ab particularly double-stranded DNA (dsDNA).
- The complement level is low.
- The deposition of immune complexes (Ag + Ab) can be demonstrated.
- Detection of other autoantibodies.
Age:- This may occur at any age but the peak is second to the third decade. This may be seen in children.
Sex:- It is most common in females with a male: female ratio of 1:9.
One out of 700 white females develops SLE while black females are 1:245.
One out of 2500 females may have SLE during their lifetime.
HLA:- DR3 in Caucasians and DR2 in orientals has susceptibility to SLE. Monozygotic twin Caucasians have a higher incidence.
Types of Autoantibodies
- Anti-nuclear antibodies.
- Anti -DNA
- Against RNA.
- against RNA-associated proteins.
- against Histones.
- against the nuclear antigen.
Antinuclear antibodies (ANA) are virtually positive in all patients. But these are not specific. When ANA is negative then doubt about the diagnosis.
DNA and anti-DNA from the immune-complex and leads to pathological lesions.
- Autoantibodies against formed elements of blood like-RBC, platelets, and neutrophils.
- C. Smith antigen(sm):- Anti-smith antibody is strongly suggestive of the disease.
- D. Anti-cardiolipin antibodies are present and are nonspecific.
Etiology of SLE (Pathogenesis)
SLE may be due to the following factors or these are the hypotheses favoring the emergence of this disease.
1. Genetic Factors
- This disease is 60% in monozygotic twins in comparison to dizygotic twins where it is only 3%.
- There is an increase familial risk and even normal family members show autoantibodies in 20% of them.
- 60% has inherited low complement (particularly C2 and C4).
- There is an increase incidence in DR2 and DR3. Also more common in HLA-A1 and B8.
2. Nongenetic Factors (or Environmental Factors)
- There is a history of a man associated animal like a dog that shows dsDNA and his master has SLE.
- Viruses: -It is disputed but viral particles are positive in affected tissue.
- Drugs: – Some of the drugs are also blamed for this disease like hydralazine, procainamide, and D-penicillamine.
- Sex-hormones: – There are certain pieces of evidence that suggest the role of sex-hormones particularly female hormones. e.g. during reproductive life, the incidence of the disease is 10 times more common. This disease is also more common in pregnancy and in the normal menstrual period.
- Estrogen:- It is found that estrogen increases antibodies formation. So female hormones accelerate the disease while male hormones suppress the disease.
- U-V-light: – This can stimulate keratinocytes and the stimulated cells produce IL-1 which in turn stimulates the B-lymphocytes and T-L.
3. Immunologic Factors
This disease is definitely due to a defect in the immune system.
- Some believe that defect is in both B-L and T-L. But this has a lot of controversies.
- B-lymphocytes defect is accepted because there is an increased concentration of immunoglobulins. Also, there is 8-10 times more proliferation of B-L and this B-L reacts with self and non-self-antigens.
- Hyperactivity of B-L:- This hyperactivity may be due to inherited defect and these cells are refractory to immune regulation.
- There is overactivity of T-helper cells.
- There may be a decreased activity of T-suppressor cells.
- Infectious agents may give rise to polyclonal activation.
Mechanism of Injury
The injury to various organs and cells may be due to:
- Type III: – Immune complex disease that may involve almost all organs and common sites are blood vessels, kidneys, and skin.
- Type II: – Cytotoxic reaction which will destroy RBC, platelets, neutrophils, and lymphocytes, etc.
American Rheumatism Association Criteria
American Association of rheumatism gave certain criteria for the diagnosis of SLE. These were revised in 1982. When four or more of the following signs and symptoms present, they can label as a case of SLE.
- Malar Rash: – There are butterfly rashes and these are flat or may be raised. These are present in 1/3 of the cases.
- Discoid Rash: – These are erythematous raised patches. There are keratotic scaling and follicular plugging and in severe cases may see atrophic scarring.
- Photosensitivity: – There is an appearance of skin rashes when exposed to sunlight.
- Oral ulcers: – There are painless ulcers in the oral cavity or nasopharynx.
- There is non-erosive arthritis involving 2 or more peripheral joints. These are tender, edematous, and may see effusion.
- Serositis: – There is pleuritis with rub and pain. There may be pericarditis with rub or effusion.
- Renal disorder: – There is proteinuria more than 0.5G / 24 hours or 3+. There are cellular casts like RBC, hemoglobin, or granular casts.
- Neurological disorders:- These patients may have seizures. It has to exclude abscess, drugs, or metabolic disorders, or electrolyte imbalance. Sometimes these patients come with psychosis.
- Hematological disorders:- These patients may have:
- Autoimmune hemolytic Anaemia with increased reticulocytes.
- There is no evidence of offending drugs.
- Immunologic disorders: These patients may show:
- L-E cell phenomenon is positive.
- dsDNA-Ab presence.
- Anti-smith-Ab presence.
- False test positive for syphilis.
- ANA: There is an increased titer of ANA.
If 4 of the above criteria present at any time during the course of the disease, a diagnosis of SLE can be made with 90% specificity and 97% sensitivity.
In SLE, almost all the organs are involved. The most common organs are:-
|Disease||% occurrence of the disease|
|Skin||80 to 90|
|Joints||80 to 90|
|Lungs||10 to 20|
The characteristic lesion is seen in:
- Blood vessels.
- Connective tissue.
1. Blood Vessels
There is necrotizing vasculitis with the presence of fibrinoid necrosis and accompanied by perivascular lymphocytic infiltrate.
The chronic stage is followed by fibrosis. These affected blood vessels can show the presence of Ig, C3, and DNA.
60-70% shows no changes on light microscope while 100% shows evidence on E/M and immunofluorescence.
This involvement of the kidney may be monitored by:-
- Abnormal urine analysis.
- Increase the concentration of dsDNA antibodies.
- Low complement level especially C4.
WHO has given the classification of lupus nephritis as follows.
Class – I:
This is a rare condition where on light microcopy, E/M and immunofluorescence are normal where there will be biochemical evidence of the renal involvement.
Class-II – Mesengial lupus glomerulonephritis:
This is 25% of the cases and is the mildest form with minimal S/S. There are mild haematuria and proteinuria.
Microscopically there is an increase in mesengium, increased mesengial cells. Granular deposits of Ig and complement can be demonstrated.
Class III – Focal proliferative glomerulonephritis
This is seen in 20% of the cases. There is 50% involvement of the glomeruli and also there is partly involvement of the glomeruli. The patient will have proteinuria and haematuria.
Microscopically there is partly involvement of glomeruli, increased endothelial and mesengial cells. There is neutrophils infiltration. Sometime fibrinoid necrosis and thrombosis may be seen.
Class IV – Diffuse proliferative glomerulonephritis
This is seen in 35-40% of the case. This is the most serious condition. Patients show gross haematuria and proteinuria. 50% have hypertension and these patients develop nephrotic syndrome.
Microscopically there is diffuse involvement of the glomeruli with an increase in endothelial cells, mesengial cells, and sometimes epithelial cells leading to the crescent formation. There may be fibrinoid necrosis and thrombosis.
Class V- Membranous glomerulonephritis
This is seen in 15% of the cases. Patients have severe proteinuria and become nephrotic.
Microscopically there is a widespread thickening of capillary walls.
Mechanism of injury:
In the kidney is mainly typed III immune complex disease and the complexes are (DNA + Anti-DNA).
3. Cardiovascular System
These patients may have pericarditis. Another common lesion is non-bacterial verrucous endocarditis, which shows vegetations of 1-4mm in diameter. These vegetations microscopically show fibrinoid necrosis, neutrophil infiltration, and fibroblastic proliferation. There is the presence of hematoxylin bodies (Bacterial vegetations are larger measuring 0.5-2cm in diameter).
These patients may have anginal attacks due to coronary thickening.
There is the involvement of the peripheral joints which are characterized by tenderness, swelling, or effusion.
Microscopically there is non-erosive synovitis with little deformity. There are fibrinous exudates and mainly neutrophil infiltrate. If the joint fluid is aspirated, it will show mainly neutrophils.
There is erythema, butterfly rashes (on nose and cheek). Extremities and trunk show urticaria and bullae. There are hypopigmented areas and without the presence of a scar called sub-acute lupus.
Microscopically there is basal cell degeneration, perivascular mononuclear infiltrate. Dermis shows fibrosis. Ig can be demonstrated at the dermo-epidermal junction.
There are interstitial pneumonitis and diffuse fibrosing alveolitis. This may be acute or chronic or subacute. There is pleuritis and in 50% of the cases, there is pleural effusion.
There are increased capillary thickening and follicular hyperplasia. The infiltrate by plasma cells increases.
Microscopically there is perivascular fibrosis and it gives “onion skin” appearance.
8. Central Nervous System:
The patient may have a presentation of psychosis and seizures. 25% of signs are related to acute vasculitis which leads to infarct and hemorrhage.
9. Chronic Discoid Lupus Erythematosus:
There is only skin manifestation.
The course of the disease: – This is unpredictable.
- The patient may go into remission.
- 90% of survival is seen for one year.
- 80% of survival is seen for 5 years.
- 76% of survival is seen for 10 years.
The most common cause of death is Renal Failure followed by:-
- Intercurrent infection.
- Cardiac failure.
- Pulmonary diseases.
- Involvement of CNS.
- Blood shows normochromic and normocytic anemia.
- Occasionally Coomb’s test is positive and indicates hemolytic anemia.
- There are lymphopenia and thrombocytopenia.
- Urine analysis shows haematuria and proteinuria with the presence of renal cast.
- Typically ESR is raised while CRP will be negative.
- ANA-Antinuclear antibodies are positive in 99% of the cases. If these are negative then SLE diagnosis is in doubt.
- ANA may be positive in other diseases like:
Sjogren syndrome = 68%.
Scleroderma = 60-70%.
Rheumatoid arthritis = 20-40%
- Immunofluorescence techniques on the frozen section:
There are four patterns that are seen and specific for SLE is RIM formation.
- dsDNA—Antibodies are specific for SLE diagnosis and these are positive in 70% of the cases.
- Smith—Ag-Ab is diagnostic but positive in 30% of the cases.
- Lupus-Erythematous cell phenomenon (LE Cell).
This was described by Hargreave in 1948. The blood of the patients shows hematoxylin bodies in the monocytes/neutrophils pushing the nucleus to the periphery.
Procedure and Mechanism of LE cell phenomenon:
Take the blood of patients 5-10ml.
It is traumatized by glass beads or glass rods to expose the nucleus to antinuclear antibodies in the serum of patients. Complement is activated and it causes the death of the nucleus and it becomes a homogenous hematoxylin color body and the nucleus is pushed to the periphery.
- Patients are treated according to the manifestation of the disease.
- For arthritis, Nonsteroidal anti-inflammatory drugs and aspirin may be used.
- For cutaneous manifestation, anti-malarial (Hydrochloroquin) can be used.
- Corticosteroid alone or in combination with cytotoxic drugs like cyclophosphamide, and azathioprine may be used in case of life-threatening manifestation.