NATIONAL QUALIFICATIONS CURRICULUM SUPPORT
Human Biology
Autoimmune Disorders
Case Study on Rheumatoid Arthritis
Student’s Notes
[HIGHER]
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Acknowledgement
Learning and Teaching Scotland gratefully acknowledges this contribution to the National
Qualifications support programme for Human Biology.
The publisher gratefully acknowledges permission to use the following sources: image Joints
frequently affected by rheumatoid arthritis, reproduced with kind permission of Arthritis
Research UK; table Rheumatoid arthritis patient demography, treatment and disease activity
from Nature Medicine, Vol 2, No 2, February 1996, p 176, reprinted by permission from
Macmillan Publishers Ltd, Nature Medicine © 1996; image and table from ‘The Role of
interleukin-15 in T-cell migration and activation in rheumatoid arthritis’, Nature Medicine, Vol
2, No 2, February 1996, p 177, reprinted by permission from Macmillan Publishers Ltd, Nature
Medicine © 1996; a hand affected by rheumatoid arthritis © James Heilman, MD
Every effort has been made to trace all the copyright holders but if any have been inadvertently
overlooked, the publishers will be pleased to make the necessary arrangements at the first
opportunity.
© Learning and Teaching Scotland 2011
This resource may be reproduced in whole or in part for educational purposes by educational
establishments in Scotland provided that no profit accrues at any stage.
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Contents
Part 1: Background
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Part 2: Analysis of clinical data
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Scenario
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CASE STUDY ON RHEUMATOID ARTHRITIS
Images of rheumatoid arthritis
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CASE STUDY ON RHEUMATOID ARTHRITIS
Part 1: Background
All the images on page 4 have one thing in common: they illustrate a range of
different physical deformities that are caused by rheumatoid arthritis (RA).
You may know someone who suffers from this disease . Although the severity
of the symptoms varies enormously between individuals, the lifestyle of any
person suffering from any of the symptoms wi ll be affected to some extent.
Rheumatoid arthritis does not discriminate, although more women are
affected than men.
Task 1
Examine the images on page 4 and give thought to how these deformities
would cause difficulties for both the individual and their immediate families.
Within your group, discuss and list any examples of how daily life could be
adversely affected and what support could be provided to overcome any of
these problems. You should remember to take age, gender and different
lifestyles into consideration. A useful website can be accessed at:
http://www.umm.edu/patiented/articles/what_lifestyle_changes_can_help_ma
nage_rheumatoid_arthritis_000048_10.htm
Rheumatoid arthritis is an example of an autoimmune disease. This case study
will illustrate the symptoms and possible, although still unclear, causes of the
disease. The first part of the study requires a good understanding of both the
immune system and autoimmunity. The second part involves you carrying out
analysis on real data acquired from subjects who have been diagnosed with
the disease.
Task 2
In pairs, construct a mind map to the immune system and autoimmunity
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CASE STUDY ON RHEUMATOID ARTHRITIS
Main points:
The immune system
The inflammatory response
This kind of defence attacks all invading organisms, ie it is not specific.
When organisms damage tissue, pain and swelling results, b lood flow is
increased and special cells called neutrophils (most abundant white blood
cells in mammals) are brought to the site of infection. The neutrophils then
engulf and destroy the invading organisms by the process of phagocytosis. If
infection is not overcome, then specific immune responses can be activated.
Specific Immune responses
T- lymphocytes and B- lymphocytes
Bone marrow produces lymphocytes. A population of these, the T
lymphocytes, enter the thymus and the lymph nodes. Others remain in the
bone marrow, becoming B lymphocytes.
What do B lymphocytes do? When B cells are stimulated by the presence of
an antigen, they will rapidly multiply. Some of them will become memory
cells or mass produce antibodies. The antigens then combine with the
antibodies at the receptor sites and the whole complex is engulfed by
phagocytes.
What do the T- lymphocytes do? When a cell becomes infected, microbial
proteins are released by the host cell, move to the cell surface and act as
antigens. A type of T lymphocyte called a killer T cell recognises the antigen
and destroys the infected cell. A chemical is released that perforates the
membrane. This is called the cell-mediated response.
Helper T cells (another type of T lymphocytes) patrol the body and when they
recognise antigens they activate the B lymphocytes, killer T cells and
macrophages, as illustrated in Figure (1).
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CASE STUDY ON RHEUMATOID ARTHRITIS
Figure 1 The Immune Response
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CASE STUDY ON RHEUMATOID ARTHRITIS
Autoimmunity
The principal function of the immune system is to defend against infe ction by
attacking and eliminating harmful pathogens, whilst not attacking the body’s
own cells and tissues.
A state of autoimmunity may develop when the immune system recognises
and reacts to one or more of the body’s proteins. When this happens, the
immune reaction that develops may have a serious impact on health.
The immune system distinguishes only between ‘self’ and ‘non-self’. Proteins
that are produced by the body are self and trigger a state of immunological
tolerance; proteins from viruses, bacteria, parasites, plants, animals and other
humans are non-self and can potentially trigger an immune response.
In simple terms, when autoimmunity develops, the immune system will attack
the body’s own cells and tissues.
A faulty immune system can initiate the development of chronic, disabling
autoimmune diseases. More than 80 clinically distinct autoimmune diseases
have been discovered and diagnosed to date.
Task 3
Name at least six examples of autoimmune diseases.
Task 4
Find out about the incidence of autoimmune disease in Scotland
All autoimmune diseases are chronic, disabling disorders that have the ability
to inflict a poor quality of life. The range of more than 80 identified diseases
comprises a heterogeneous family of disorders exhibiting a wide variety of
clinical symptoms.
It is well known that T cells play an important role in cell-mediated
autoimmunity. T cells are known to mediate tissue damage in type I diabetes
and multiple sclerosis. Cytokines and chemokines are biological mediators
secreted by immune cells. They influence the type of immune response
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generated in autoimmunity. Pro-inflammatory cytokines, such as Tumour
Necrosis Factor Alpha(TNFa), have a well-established role in the mediation
of autoimmune disease.
This knowledge has been used to design therapy for some autoimmune
diseases, for example TNFa blocking treatments have led to a reduction in
inflammation in some RA patients.
Arthritis is a group of conditions involving joints in the body. There are
more than 100 forms of arthritis but this study will involve two commonly
known types, namely osteoarthritis (OA) and RA.
What are the differences between OA and RA?
 OA is a much more common condition than RA.
 OA is a degenerative joint disease caused by the breakdown of cartilage. It
can result from injury or simply be a side effect of increasing age, ie wear
and tear.
 RA is a chronic inflammatory autoimmune condition that causes stiffness
in joints and difficulties in movement. In RA, the body’s own immune
system starts to attack its own tissues. Many parts of the body can be
affected.
Task 5
What is a chronic disease?
 OA patients tend to be older; their condition mainly a consequence of
ageing.
 In contrast, RA can afflict people of all ages , although the most common
age of onset is 30–50 years. RA can also affect children (juvenile RA).
 The synovial fluid contained in the synovium is responsible for the
lubrication of a joint and allows smooth movement. In people who suffer
from RA, antibodies are produced against the synovial tissue and this
ultimately results in inflammation in and around the joints.
 Patients suspected of having arthritis whether OA or RA need to be tested
to find out which form of the disease they have and are therefore required
to provide biopsy samples of their joint tissue and synovial fluid.
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Task 6
What is a Biopsy?
 In clinical research, as illustrated in the analysis section of this study,
synovial joint samples from OA patients are often used for comparison
with samples from RA patients. This is because clinicians have access to
biopsy samples from OA patients, whereas it would be very invasive and
ethically difficult to acquire samples of this kind from normal, healthy
individuals.
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Rheumatoid arthritis-some background to the disease
RA is an inflammatory autoimmune disorder characterised by symmetrical
inflammation of freely moveable joints. In addition to the observed external
features of this disease, systemic inflammation is commonly exhibited in RA.
Task 7
Find out about systemic inflammation and write a brief description of it in
your own words.
A booklet called Target Rheumatoid Arthritis, produced by the Association of
the British Pharmaceutical Industry, is a particularly useful and appropriate
resource for background information on this disease (abpi@abpi.org.uk,)
http://www.abpi.org.uk).
Introductory video: the following websites give an overview of the symptoms
and basic understanding of how RA affects the joints in a human body.
http://www.arthritisresearchuk.org/arthritis_information/arthritis_types__sym
ptoms/rheumatoid_arthritis.aspx
http://www.goldagegroup.com/rheumatoid_arthritis.htm
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Synovial joints
A joint is where two bones meet. Joints allow the movement and flexibility of
various parts of the body.
Revise the structure of the synovial joint by labelling Figure 2
Bone
Synovial membrane
Capsule
Bone
Synovial fluid
Tendon
Cartilage
Muscle
Figure 2 A normal synovial joint.
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How does the disease develop?
The progression of RA is not the same in every person.Common symptoms
include joint pain and swelling, stiffness (especially in the morning or after
sitting for long periods) and fatigue.
The development of the disease can be divided into three stages:
 the inflammatory stage: pain, swelling, stiffness and early bone loss
 the proliferative stage: tissues around the joint thicken and form pannus
 the destructive stage: cartilage and bone degenerate, giving the physical
symptoms of RA.
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CASE STUDY ON RHEUMATOID ARTHRITIS
Figure 3 shows a comparison of a healthy joint with one showing typical
signs of RA.
Figure 3 A healthy joint (left) and one showing typical signs of RA (right) (Target
Rheumatoid Arthritis).
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Figure 4 shows the joints frequently affected by RA.
50–60%
80%
80%
80%
90%
Figure 4 Joints affected by RA. The figures represent the frequency of distribution
of affected joints. Adapted from: Arthritis Research UK. Figures from Target
Rheumatoid Arthritis.
In approximately 20% of RA patients the disease develops very rapidly, with
pain and inflammation in several joints, severe morning stiffness and great
difficulty doing everyday tasks.
Although arthritis means ‘inflammation of the joints’, it’s not just the joints
that are affected. Along with pain and swelling in the joints , patients may feel
tired, depressed or irritable, even with mild arthritis. Fatigue can be one of
the most difficult aspects of RA for people to deal with.
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CASE STUDY ON RHEUMATOID ARTHRITIS
Current immunological understanding of RA
RA is characterised by a chronic inflammation of the synovial joints . T cells,
B cells and macrophages all infiltrate the joints and have a n effect (ie elicit
an immune response).
Because of its chronically disabling pathology and relatively high pre valence
(approximately 1%), RA has been a major focus of biomedical research for
many years.
RA has been found to be induced by a strong T cell -mediated inflammatory
immune response. The inflammation exhibited in RA is associated with
enhanced circulating levels of activated immune cells and pro-inflammatory
cytokines.
Task 8
Find out about cytokines and write a brief description of them in your own
words.
http://arthritis.about.com/od/inflammation/f/cytokines.htm
Task 9
Find out about interleukins and write a brief description of them in your own
words.
Task 10
Find out about interleukin-15 (IL-15) and write a brief description of it in
your own words.
Task 11
What is a pannus? Write a brief description of it in your own words.
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Task 12
Briefly describe the significance of the following blood tests, which are used
in the detection and diagnosis of RA.
(a)
(b)
Erythrocyte sedimentation rate.
CRP blood test.
http://arthritis.about.com/od/arthqa/f/arthbloodtests.htm.)
Task 13
What is meant by rheumatoid factors?
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Part 2: Analysis of clinical data
The next stage of this study will focus on the analysis of actual results
obtained from patients who have been diagnosed with RA. The data are real
and have been extracted from a paper(McInnes, Iain, B et al (1996) ‘The Role
of IL-15 in T-cell migration and activation in Rheumatoid Arthritis,Nature
2(2)pp175-182)
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Table 1 shows the data provided by 17 subjects who have had RA for
different periods of time. Your job is to analyse this data and form valid
conclusions from the information provided.
Table 1 RA patient demography, treatment and disease activity
Patient
Age
Disease
duration
(years)
Rheumatoid
factor (+ or
–)
ESR
(mm/h)
Drug
profile
4
CRP
levels
(mg
ml –1 )
10
RA1
89
6
+
RA2
36
5
+
36
58
Gold
RA3
34
4
+
28
57
SASP
RA4
44
9
+
15
14
SASP
RA5
44
10
+
16
5
Pred,MTX
RA6
57
3
+
46
50
SASP
RA7
60
8
+
51
39
Gold
RA8
59
33
+
89
161
MTX
RA9
75
50
+
30
74
SASP
RA10
49
11
+
46
59
MTX
RA11
56
16
+
8
30
Gold
RA12
65
7
+
71
66
SASP
RA13
74
20
+
22
44
SASP
RA14
73
3
+
58
86
Gold
RA15
54
25
–
23
66
SASP
RA16
31
5
+
45
16
Gold
RA17
57
15
+
80
93
Gold
ESR, erythrocyte sedimentation rate; CRP, C -reactive protein.
 Clinical details and blood samples of RA patients were collected at the
time of synovial fluid collection.
 ESR is a test that indirectly measures how much inflammation is in the
body (<20 mm h –1 is normal).
 Blood levels of CRP are normally <10 mg ml –1 .
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CASE STUDY ON RHEUMATOID ARTHRITIS
Task 14
Examine the data in Table 1 and answer the following questions.
(a)
What conclusion can be made on the basis of the se rheumatoid factor
results?
(b)
What steps could be taken to support this conclusion?
Use two different colours to identify any patients in Table 1 whose results
were higher than normal for either ESR rates or CRP levels.
Task 15
Construct a bar chart based on the age of the patients diagnosed with RA
Task 16
(a)
Calculate the mean age of the patients.
(b)
What is the range of ages?
(c)
Construct a suitable chart to illustrate the age of each patient along with
the duration of the disease.
(d)
From this data, can you conclude that there is a direct relationship
between the age of the patient and the duration of the disease? Give
evidence to support your conclusion.
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Figure 5 compares the ESR with the levels of CRP in RA patients as shown in
Table (1)
Figure 5 A comparison of ESR and CRP levels in RA patients.
Task 17
(a)
Using the data in Figure (5) calculate the mean ESR rate of the RA
patients.
(b)
Calculate the mean CRP level of the RA patients .
(c)
What valid conclusions can be made from these results?
(d)
Can you suggest any ways in which the survey of these patients could
be improved to provide more valid conclusions?
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The next stage of the analysis involves a comparison of IL -15 levels in
synovial fluid from OA and RA patients.
Figure 6 IL15 levels in OA patients
Figure 7 IL levels in RA patients
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Task 18
Compare Figures 6 and 7 and write down what conclusions can be drawn
from them.
Quantification of IL-15 in synovial tissues
Figure 8 Image of synovial tissue. Sections of syno vial tissue stained to show the
presence of IL15. Positive staining is shown in red.
Task 19
What does the slide shown in Figure 8 confirm?
Comment on the distribution of the red stained area.
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The data were quantified for each patient sample and the summarised results
are shown in Table 2.
Percentage(%) of positively stained cells were counted
in different areas of the synovial tissue
Diagnosis
Area 1
Area 2
Area3
RA (n = 9)
54 ± 13.1
24 ± 12.3
12 ± 7.7
OA (n = 5)
6.5 ± 4.5
2 ±1.1
Table (2) A comparison of synovial Tissue samples in OA and RA patients
Task 20
Construct a pie chart to show the distribution of positively stained cells in the
RA patients.
What does this pie chart show?
A second sample of synovial tissue was stained to show the presence of
CD68, a macrophage antigen (Figure 9). Again, positively stained cells are
shown in red.
Would you expect this sample to represent a patient with RA or OA? Provide
a full explanation to support your view.
Figure 9 A second sample of synovial tissue was stained to show the presence of
CD68, a macrophage antigen. Positively stained cells are shown in red.
Task 21
Would you expect this sample Fig (9) to represent a patient with RA or OA?
Provide a full explanation to support your view
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Scenario
Read the following scenario and answer the questions.
A 37-year-old woman gradually developed painful wrists over 3 months . She
consulted her doctor only when the pain and early morning stiffness stopped
her from gardening.
Question 1
What questions should the doctor ask the woman?
The doctor suspects that the woman may have developed RA.
Question 2
What physical signs should he look for?
On examination, the doctor found that the wrists and joints of both the
woman’s hands were swollen and tender but not deformed.
Question 3
From what you have learned through this study, can you suggest what clinical
tests should be carried out at this stage?
The results of blood tests showed that the woman had a raised CRP level (27
mg –1 , normal <10) but a normal haemoglobin and white-cell count. A test for
rheumatoid factor was negative and antinuclear antibodies were not detected.
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Question 4
Based on the result of the rheumatoid factor test, can the doctor assume that
the woman does not have RA? Explain you answer.
The clinical diagnosis was early RA and ibuprofen was prescribed. Despite
some initial improvement in the pain, the stiffness and swelling of the hands
persisted and 1 month later both knees became similarly affected. The woman
was referred to a rheumatologist.
Six months after initial presentation, the woman developed two nodules on
the left elbow; these were small, painless, firm and immobile , but not tender.
A test for rheumatoid factor was now positive .
At this point she was sent to the local hospital for further tests.
X-rays of the hands showed bony erosions in the metacarpals (Figure 10). She
still had a raised CRP (43 mg l –1 ). A biopsy showed that a pannus had
developed.
Figure 10 X Ray image of Rheumatoid Arthritis in hands
There was now definite X-ray evidence of RA in the patient. If one
metacarpal joint (MCP) is involved with RA, then typically all of the joints
are involved. The X Ray image Figure (10) shows that every MCP joint is
affected.
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The doctor recommended that treatment should be a weekly low dose of
methotrexate.
Question 5
How does the methotrexate work? What other drugs are available and how do
they work? What other forms of treatment are available and how successful
are they likely to be?
(Target Rheumatoid Arthritis)
The good news for this particular woman is that the drug has controlled the
arthritis for several years and no further symptoms have developed.
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