Autoimmune Diseases: Systemic Lupus Erythematosus & Graves’s Disease

1. PRESENTATION BY:
SHAH JITEN JAYPRAKASH
INDIAN ACADEMY DEGREE COLLEGE,
BANGALORE , KARNATAKA, INDIA.
➢ Systemic Lupus Erythematosus.
➢ Graves’s Disease.

2. Introduction
 Autoimmune diseases arise from an abnormal immune
response of the body against substances and tissues normally
present in the body (autoimmunity).
 This may be restricted to certain organs or involve a particular
tissue in different places.
 The treatment of autoimmune diseases is typically
with immunosuppression medication that decreases the
immune response.
 A large number of autoimmune diseases are recognized. A major
understanding of the underlying pathophysiology of
autoimmune diseases has been the application of genome wide
association scans that have identified a striking degree of genetic
sharing among the autoimmune diseases.
 About 2% of the population are affected by such diseases.
 There is a breakdown of self tolerance in these individuals.

3. Few Examples :-
1. Systemic Lupus Erythematosus.
2. Graves’s Disease.
3. Rheumatoid Arthritis.
4. Myasthenia Gravis.
5. Multiple Sclerosis.
6. Myocarditis.
7. Neuromyelitis Optica.
8. Addison’s Disease.
9. Thrombocytopenia.
10. Vasculitis.
11. Auto Immune Anameia.
12. Auto Immune Enteropathy.
13. Auto Immune Orchitis.

4. Systemic Lupus Erythematosus
 Systemic Lupus Erythematosus (SLE/ Lupus) is a systemic
autoimmune disease or autoimune connective tissue disease in
which the body’s immune system mistakenly attacks healthy
tissue.
 SLE which affects many internal organs in the body & most
often harms the heart, joints, skin, lungs, liver, kidneys, blood
vessels & nervous system.
 The course of the disease is unpredictable, with periods of illness
alternating with remissions.
 Approximately 1 in every 2000 individuals are affected.
 Age of onset is usually between 20 and 40 yrs of age.
 Etiology is unknown but may be due to genetic and
environmental factors.

5. Clinical Signs & Symptoms :-
 The first signs to appear are usually nonspecific such as fatigue,
weight loss, malaise, fever, and anorexia.
 Joint involvement of small joints of the hands, wrist and knees is
reported in over 90% of cases.
 A skin manifestation of an erythematous rash may appear in the
area of body exposed to UV light.
 A classic butterfly rash across the nose and cheeks which is
responsible for the name lupus may appear.
 Some patients may also exhibit renal involvement.
 Immune complexes may deposit in the subendothelial tissue and
thickening of the basement membrane results.
 All of these can result in renal failure and death.
 There might also be cardiac involvement with pericarditis and
ventricular enlargement.

8. Immunological Findings :-
 The LE (Lupus Erythematosus)cell was discovered by Malcolm
and Hargraves in 1948.
 The LE cell is a neutrophil that has engulfed the antibody-coated
nucleus of another neutrophil.
 The first anti-DNA antibody was discovered 9 years later.
 SLE is associated with more than 28 autoantibodies.
 Lupus patients appear to have overactive B cells especially the
subset with the CD5 marker which increase in number.
 The increased prevalence of the disease in women may be traced
to the fact that estrogen enhance B cell activity.
 Estrogen also suppresses regulator activities of T cells as a result,
there is a decrease in the absolute number of T cells.
 Complement is activated which results in decrease in the serum level
of complement components.

9.  IgG is most pathogenic and it forms complexes that are
deposited in the glomerular basement membrane.
 Accumulation of immune complex with complement activation is
responsible for the damage to the kidney.
 Drug induced lupus differs from the chronic form of the disease :
when the drug is withdrawn symptoms disappear.
 It is a milder form of the disease and manifest as arthritis or rashes.
 Drugs that have been implicated include procainamide hydrochloride,
hydralazine hydrochloride, methyldopa etc.

10. Causes :-
 SLE is presumably caused by an unknown environmental trigger,
acting on persons with genetic susceptibility and defects in the
immune system.
 SLE is associated with defects in apoptotic clearance, and the
pathogenic effect of apoptotic debris.
 People with SLE have intense polyclonal B-cell activation, with a
population shift towards immature B cells.
➢ Genetics
 The first mechanism may arise genetically. Research indicates
SLE may have a genetic link.
 SLE does run in families, but no single causal gene has been
identified. Instead, multiple genes appear to influence a
person's chance of developing lupus when triggered by
environmental factors.
 Some of the susceptibility genes may be population specific.

11. ➢ Drug reactions
 Drug Induced Lupus Erythematosus is a generally reversible
condition that usually occurs in people being treated for a
long-term illness.
 Drug-induced lupus mimics SLE. However, symptoms of
drug-induced lupus generally disappear once the medication
that triggered the episode is stopped.
 More than 38 medications can cause this condition, the most
common of which are procainamide, isoniazid,
hydralazine, quinidine, and phenytoin.
➢ Non-systemic forms of lupus
 Discoid (cutaneous) lupus is limited to skin symptoms and is
diagnosed by biopsy of rash on the face, neck, scalp or arms.
 Approximately 5% of people with DLE progress to SLE.

12. Pathophysiology :-
 One manifestation of SLE is abnormalities in Apoptosis, a type
of programmed cell death in which aging or damaged cells are
neatly disposed of as a part of normal growth or functioning.
➢ Abnormalities in cell death signaling
 Apoptosis is increased in monocytes and keratinocytes.
 Expression of Fas by B cells and T cells is increased.
 There are correlations between the apoptotic rates of
lymphocytes and disease activity.
 Necrosis is increased in T lymphocytes.
➢ Clearance deficiency
 Impaired clearance of dying cells is a potential pathway for the
development of this systemic autoimmune disease. This includes
deficient phagocytic activity and scant serum components in
addition to increased apoptosis.

13. ➢Accumulation in germinal
centers
 In healthy conditions, apoptotic
lymphocytes are removed in germinal
centres (GC) by specialized phagocytes,
the tingible body macrophages (TBM),
which is why no free apoptotic and
potential autoantigenic material can be
seen.
 In some people with SLE, accumulation of
apoptotic debris can be observed in GC
because of an ineffective clearance of
apoptotic cells.

14. ➢Anti-nRNP autoimmunity
 Autoantibodies to nRNP A and nRNP C initially targeted
restricted, proline-rich motifs. Antibody binding subsequently
spread to other epitopes.
 The similarity and cross-reactivity between the initial targets
of nRNP and Sm autoantibodies identifies a likely commonality
in cause and a focal point for intermolecular epitope spreading.
➢Others
 Elevated expression of HMGB1 was found in the sera of people
and mice with systemic lupus erythematosus, high mobility
group box 1 (HMGB1) is a nuclear protein participating
in chromatin architecture and transcriptional regulation.
 Recently, there is increasing evidence HMGB1 contributes to the
pathogenesis of chronic inflammatory and autoimmune
diseases due to its proinflammatory & immunostimulatory
properties.

15. Diagnosis :-
➢ Laboratory Diagnosis of SLE :-
 A screening test for antinuclear antibody (ANA) is usually the
first test done.
 Fluorescent antinuclear antibody (FANA) testing is most widely
used.
 The test is sensitive but the specificity is low because many of
the Abs are associated with other diseases.
 The test is an indirect IFA test which employs antihuman
globulin tagged with a fluorescent marker.
 About 5% of healthy individuals and between 10 and 30% of
elderly individual tests positive.
 If FANA is positive, then a profile testing should be done for
individual Abs.
 More than 99% of patients with SLE will have a positive result for one
or more tests.

16. ❖ Double-stranded DNA (ds-DNA) :-
 These Abs are the most specific for SLE and are seen only in
patients with SLE.
 Found in only 50 to 80% of cases but when seen, they are
diagnostic feature of the disease.
 Abs to ds-DNA produce a peripheral staining pattern in IFA.
 A positive test is indicated by a brightly stained kinetoplast with
a dilution of 1:10 or greater of patient serum.
❖ Anti-nRNP :-
 Anti-nRNP produces a finely speckled IFA pattern.
 RNP is a nuclear RNA which is found in association with seven to
eight nonhistone proteins.
 The antibody is also found in high titer in individuals with mixed
connective tissue disease and other autoimmune diseases.
 The antibody can be measured by double diffusion, passive
hemaglutination and EIA and IFA.

17. ❖ Antihistone Antibody :-
 Histone is a major component of chromatin.
 This antibody is found in lupus patients.
 It binds to DNA and may be found in all cases of drug induced
lupus.
 If no other Abs are present, this may support a diagnosis of drug
induced lupus.
 The Abs may be detected by IFA, RIA or EIA.
 Antibodies are also produced against DNA complexed to histone
known as deoxyribonucleoprotein (DNP).
 The antibody is thought to be identical to the LE factor or
phenomenon.
 It appears in 70 to 90% of patients with SLE.
 A slide method using latex particle coated with DNP have been
used in a simple slide agglutination test for SLE.

18. ❖ Anti-Sm antibody :-
 Antibody to extractable nuclear antigen was first described in a
patient named Smith hence it is called anti-Sm.
 Extractable nuclear Ags are small nuclear riboproteins that are
associated with uridine-rich ribonucleic acid (RNA).
 The Ab is specific for SLE and not found in other autoimmune
diseases.
 Anti-Sm can be measured by double diffusion, passive
hemagglutination, and EIA. Antibody to this appears in 25 to
40% of patients with SLE.
 It is found in patients with cutaneous manifestations of SLE.
 Antibodies are detected by the IFA test with the use of human
tissue culture cells e.g. (Hep-2) human epidermal.

19. Treatment :-
 The treatment of SLE involves preventing flares and reducing
their severity and duration when they occur.
 Treatment can include Corticosteroids and Topical steroids &
Anti-Malarial drugs may also use. Other drugs include
Cyclophosphamide, Methotrexate etc.
 If the primary symptom is fever or arthritis a high dose of Aspirin
or other Anti-inflammatory drug may bring relief.
 Some drugs approved for other diseases are used for SLE
'off-label'.
 In November 2010, an FDA advisory panel recommended
approving Belimumab (Benlysta) as a treatment for the pain and
flare-ups common in lupus.
 The drug was approved by the FDA in March 2011.

20. ➢ Medications :-
I. Disease-modifying anti-rheumatic drugs (DMARD).
II. Immuno suppressive drugs (ISD).
III. Analgesia. ( Analgesic drugs or pain killers).
IV. Intravenous Immunoglobulins (IVIGs).
➢ Lifestyle Changes :-
 Avoiding sunlight is the primary change to the lifestyle of people
with SLE, as sunlight is known to exacerbate the disease, as is the
debilitating effect of intense fatigue. These two problems can
lead to people becoming housebound for long periods of time.
 Drugs unrelated to SLE should be prescribed only when known
not to exacerbate the disease.
 Occupational exposure to silica, pesticides, and mercury can also
worsen the disease.

21. Prognosis :-
 No cure is available but there are many treatments for the SLE.
 In the 1950s, most people diagnosed with SLE lived fewer than five
years. Today, over 90% now survive for more than ten years, and
many live relatively asymptomatically. 80-90% can expect to live a
normal lifespan.
 Prognosis is typically worse for men & children than for women.
 Early mortality, within 5 years, is due to organ failure or
overwhelming infections, both of which can be altered by early
diagnosis and treatment.
Ongoing Research :-
 Research is geared towards finding a possible cause, a cure, & more
effective treatments for people with lupus.
 A study called BLISS-76 tested the drug, Belimumab, a fully human
monoclonal anti-BAFF Abs. BAFF stimulates and extends the life
of B lymphocytes, which produce antibodies against foreign and
self cells.It was approved by the FDA in March 2011.

22. Graves’s Disease
❖ Graves’s disease is another autoimmune disease that affects
the Thyroid gland.

23. INTRODUCTION : -
 It is also known as toxic diffuse Goiter and Flajani-Basedow-
Graves’s disease.
 Graves’ s disease produces Hyperthyroidism and Enlarged
Thyroid.
 It the most common cause of Hyperthyroidism and affects about
0.5% of the population.
 Women are more susceptible than men by a margin of 7:1 and
usually present between the ages of 30 and 40.
 In whites, the disease is associated with the HLA antigen DR3
while in Asians HLA Bw35 and Bw36 occur more frequently.
 HLA DQB1 appears to confer resistance to the disease.

24. Clinical Signs & Symptoms :-
 The signs and symptoms of Graves' disease virtually all result
from the direct and indirect effects of Hyperthyroidism, with
main exceptions being Graves' Ophthalmopathy & goiter.
 Disease is presented as Thyrotoxicosis with a diffusely enlarged
goiter that is soft instead of rubbery.
 Signs include nervousness, insomnia, weight loss, heat
intolerance, sweating, palpitations (rapid heart beat), increased
appetite, diarrhea, frequent defecation, muscle weakness, skin
warmth and moistness.
 Other symptoms include fatigue, cardiac dysrhythmias,
restlessness, and exopthalmus.
 People with hyperthyroidism may experience behavioral and
personality changes, including psychosis, mania, anxiety,
agitation, and depression.

25. Marty Feldman used his bulging eyes,
caused by Graves' disease, as a
comedian.
Hyperthyroidism
Bulging Eyes

28. Immunological Findings :-
 The thyroid presents with Hyperplasia with a patchy
infiltration of lymphocytes.
 Both CD4 and CD8 cells are present and the T cells appear
to play a central role in the pathogenesis of the disease.
 The most significant Ab present is thyroid stimulating
hormone receptor antibody (TRab).
 Ag-Ab combination result in the stimulation of the
receptor resulting in the release of the thyroid hormones.
 Another group of Abs called thyroid stimulating antibodies
or immunoglobulins (TSab or TSI) may have different
specificity .

29. Causes :-
 The exact cause is unclear; however, it is believed to involved a
combination of genetic and environmental factors.
 There is a genetic predisposition for Graves’s disease,
with some people are more prone to develop TSH receptor
activating antibodies due to a genetic cause.
 Since Graves’s disease is an autoimmune disease which appears
suddenly, often quite late in life, a viral or bacterial infection
may trigger antibodies which cross-react with the human TSH
receptor (a phenomenon known as antigenic mimicry, also seen
in some cases of type I diabetes).
 While a theoretical mechanism occurs by which stress could
cause an aggravation of the autoimmune response that leads to
Graves’s disease, more robust clinical data are needed for a firm
conclusion.

30. Pathophysiology :-
 Graves’s disease is an autoimmune disorder, in which the body
produces antibodies to the receptor for thyroid-stimulating
hormone (TSH). (Antibodies to thyroglobulin and to the thyroid
hormones T3 and T4 may also be produced.)
 These antibodies cause hyperthyroidism because they bind to
the TSHr and chronically stimulate it.
 TSHr is expressed on the follicular cells of the thyroid gland (the
cells that produce thyroid hormone), and the result of chronic
stimulation is an abnormally high production of T3 and T4. This,
in turn, causes the clinical symptoms of hyperthyroidism, and
the enlargement of the thyroid gland visible as Goiter.
 The infiltrative exophthalmos frequently encountered has been
explained by postulating that the thyroid gland and the
extraocular muscles share a common antigen which is
recognized by the antibodies. Antibodies binding to the
extraocular muscles would cause swelling behind the eyeball.

31. ❖ Histopathological image of diffuse Hyperplasia of the
Thyroid Gland (clinically presenting as hyperthyroidism).

32. Diagnosis :-
➢ Laboratory Diagnosis :-
❖ Graves' disease may present clinically with one of these
characteristic signs :-
I. Exophthalmos (protuberance of one or both eyes).
II. Fatigue, weight loss with increased appetite, and other
symptoms of Hyperthyroidism / Thyrotoxicosis.
III. Palpitations or Rapid heart beat.
IV. Muscular weakness.
 A key finding in Graves’s disease is elevated levels of total and
free T3 and T4 hormones.
 In addition, TSH levels are low due to Ab stimulation of the
thyroid.
 Measurement of the thyroid Abs may be undertaken if the above
assays are unclear.

33. Treatment :-
 Antithyroid medication may be employed, drugs which
can be used are Carbimazole, Methimazole, and
Propylthiouracil.
 Radioiodine which emits beta particles may be used, The
radioiodine treatment acts slowly (over months to years) to
destroy the Thyroid gland & Graves' disease-associated
hyperthyroidism is not cured in all persons by radioiodine,
but has a relapse rate that depends on the dose of
radioiodine which is administered.
 Surgery is also an option, A 2013 review article concludes
that surgery appears to be the most successful in the
management of Graves' disease, with total Thyroidectomy
being the preferred surgical option.

34. Prognosis :-
 If left untreated, more serious complications could result,
including birth defects in pregnancy, increased risk of
a miscarriage, bone mineral loss, and in extreme cases, death.
 Graves disease is often accompanied by an increase in heart rate,
which may lead to further heart complications including loss of
the normal heart rhythm (atrial fibrillation), which may lead to
stroke.
 If the eyes are proptotic (bulging) enough that the lids do not
close completely at night, dryness will occur with a risk of a
secondary corneal infection which could lead to blindness.
 Pressure on the optic nerve behind the globe can lead to visual
field defects and vision loss, as well.
 Prolonged untreated hyperthyroidism can lead to bone loss,
which may resolve when treated.

35. Epidemiology :-
 Graves' disease occurs in about 0.5% of people.
 It occurs about 7.5 times more often in women than men.
 Often it starts between the ages of forty and sixty.
 It is the most common cause of hyperthyroidism in the
United States (about 50% to 80% of cases).
Ongoing Research :-
 Agents that act as antagonists at thyroid stimulating
hormone receptors are currently under investigation as a
possible treatment for Graves’s disease.

36. Reference :-
 https://en.wikipedia.org/wiki/Autoimmune_disease.
 https://en.wikipedia.org/wiki/Systemic_lupus_
erythematosus .
 Bartels, Christie. "Systemic Lupus
Erythematosus". Medscape. Retrieved 7 February2015.
 "Common Symptoms of Lupus". Lupus Foundation of
America. Retrieved 7 June 2013.
 https://en.wikipedia.org/wiki/Graves%27_disease#Research.
 "Graves' Disease". www.niddk.nih.gov. August 10, 2012.
Retrieved 2015-04-0.
 Tomer Y, Davies T (1993). "Infection, thyroid disease, and
autoimmunity"(PDF).Endocr Rev 14 (1): 107–20.
 Brent, Gregory A. (Jun 12, 2008). "Clinical practice. Graves'
disease". The New England Journal of Medicine 358 (24): 2594–
2605.