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Oct 23, 2013 (3 years and 9 months ago)

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Medical Biotechno
logy (BIOT 412) Human Diseases Assignment Muhammad Adeel

Department of
Biological Sciences


FORMAN CHRISTIAN COLLEGE LAHORE

(A CHARTERED UNIVERSITY)








Assignment # 1

Human Diseases (Rheumatoid Arthritis)



Name
: Muhammad Adeel

Roll

No
: 12
-
10004

Course
:

BIOT 412

Instructor
:
Dr. Leslye Johnson



Medical Biotechno
logy (BIOT 412) Human Diseases Assignment Muhammad Adeel

Human
Disease:
Rheumatoid Arthritis (RA)

Section A: What is it?

In a very simple manner, Rheumatoid Arthritis can be described as
a
chronic

multisystem

disease that causes the inflammation of joints and its surrounding tissues as well. The area of
infection can spread to other areas than the joints as well.

It is a well known example of
auto
immune disorders
, in which the body’s own cells are attacked by

the immune system. In this
case the lymphocytic infiltration of the
synovium

(soft tissue lining the non cartilaginous surface
in joints) takes place.

Since the disease can spread to other areas of the body, it has been labeled
as a
systemic

disease.

1.

Path
ogenesis

While it has been known that the disease is mediated immunologically, the actual mechanism
of triggering it is unknown. Some have labeled pathogens like virus and bacteria for the
initiation, but no tangible study has been formed.
However b
oth, ge
netic and environmental
factors are involved in this disease. The role of human leukocyte antigen has been recognized in
the pathogenesis. A serotype of this major histocompatibility complex,
HLA DR 4

is known to
be involved. Initially the disease would af
fect the
synovial membrane and destroy the joint
system symmetrically. On a systemic level, it goes on to affect the pulmonary, ocular, vascular
and other organs as well.

Th
e figure below shows a normal

joint:



Medical Biotechno
logy (BIOT 412) Human Diseases Assignment Muhammad Adeel

As the disease progresses, it can lead to disruption of the tendons, and that of course, would
limit the movement of joints.
On another level, a certain level of deformity would exist.

(Fauci et
al., 2009)


The deformation is caused by the release of a sig
nificant number of cytokines. Apart
from this
effector molecules

are also released, which increase the inflammation.
The method of
inflammation can be direct or indirect. In both cases, the end result is the degradation of collagen
and preteoglycans.
Macro
phages release enzymes that have increase number of neutrophils in the
area, adding to the pathogenesis process.
The autoantibody released in the process is known as
the
Rheumatoid Factor (RhF)
.

These factors and an immunoglobulin (Ig G) form complexes
tha
t lead to the disease process.
Citrulline antibody

is another factor involved in the process.

The figure below shows a deformed hand that has been affected with RA. The other figure is of
an inflamed joint.

(
Marshall & Haynes,
2005)


2.

Parts of Body
Affected

As mentioned earlier, it is a systemic illness, so all major organs of the body would be
infected if the inflammation spread.
However the major regions include: wrists, hands, elbows,
shoulders, knees, ankles, etc

Apart from this, the skin, lungs
and heart can also be affected.

3.

Genetic or Environmental?

After much study on RA, it has been shown that both genetic and environmental factors are
involved. Research has shown that factors like genetic variance, incomplete penetrance and
Medical Biotechno
logy (BIOT 412) Human Diseases Assignment Muhammad Adeel

multiple gene inv
olvement do play a role in RA. As hinted earlier, HLA genes have a major role
to play in the progress of this disease.

(Nakaoka et.al, 2011)

Research has also shown that environmental factors can also make people vulnerable to
RA. A research has shown that

habits like smoking can lead to RA. The reason cited is that the
smoking causes change in the proteins related to the immune system and this can lead to the
settling in of an auto immune disorder like RA.

(John, 2009)

As mentioned earlier Rheumatoid
factors are released against body’s own tissues. This
factor is basically a part (Fc) of an immunoglobin, IgG.

Together they form
immune complexes

that cause pathogenesis. This factor can be precipitated on cooling the blood sample and are
therefore referred to as
cryoglobulin.



4.

Symptoms

RA is basically characterized by a symmetrical inflammation of the joints. This means that
joints on the both s
ide of the body would be equally affected.

The major thing to be understood
about the symptoms of the disease is that they are dependent on the type of inflammation.
RA
has tow levels:
active
and
inactive
. In active type, the inflammation is very much ther
e and so
are the symptoms. In case of inactive, the inflammation is less and the symptoms go into
remission. The return of inflammation can happen any time and is known as a relapse or
flare
.
During the active state of the disease, the symptoms are as foll
ows:



Fatigue, loss in hunger, low intensity fever, pain in muscles & joints, stiffness (this
symptom is quite notable during the morning time).
Due to the inflammation, the joints
would turn red, become swollen and cause extreme pain.
Similar symptoms woul
d
include difficulty in turning door knobs or twisting your hand,

presence of nodule on the
posterior side of the skin, numbness, chest pain among others. Since it is a systemic
illness, burning in eyes, drying of mouth and pleurisy are also symptoms of RA
.

Section B) Understanding from Genetics’ Perspective

Using the genetics perspective, researchers were able to understand the role of a serotype
of HLA, HLA DR4 in the causing of the immune
response

against bodies own antigens. They
Medical Biotechno
logy (BIOT 412) Human Diseases Assignment Muhammad Adeel

were also able to use
techniques like DNA sequencing and molecular based typing to conclude
the role of D region in the disease. The research pointed out,



Using DNA sequencing and

molecular
-
based typing, it has been demonstrated

that the
disease
-
conferring portion of the D re
gion is

confined to a short sequence within the third
hypervariable

region of HLA
-
DRB1 gene which includes

the amino acid positions 67 through
74. The

HLA genes and gender constitute about 30% of the genetic

risk in RA, while other
genetic factors such as

cytokine genes, germline genes, and T
-
cell receptors

also account for
some of the genetic predisposition

to RA
.


(Marshall & Haynes, 2005)

Section C) Population Effected


It is now a well established fact that women are affected at least three times more t
han
men. As per statistics available, it occurs in 0.8% of the population.
Majority of the people
affected from RA are in their 40’s and 50’s. However this doesn’t mean that only old people are
affected by it, since RA can occur at any age. Juvenile RA is
a term referred to young people
affected by RA.
The prevalence of this disease progresses with age.


In Pakistan, at least 8% of the population suffers from joint pain. The exact numbers who
suffer from RA is unknown owing to various reasons. Surveys have

not been much beneficial
here, since people often are unwilling to reveal illnesses. However, the data collected via cross
sectional studies has shown that a major portion of the elderly population suffers. Women, of
course, face the major brunt of it. Ho
wever, the ratio is less or equal to developed nations like
U.K or U.S.A.

(Akhtar et al., 2011)

Section D) Diagnostics, Prevention and Treatment

1.

Diagnostics

It is imperative to know that a single standard test has not been made for detecting RA at its
initial stage. Usually a combination of imaging and blood tests is done to arrive at a standard
conclusion. Rheumatoid Factor presence cannot be taken as a yard
stick for any immunological
study pertaining to RA since it is present in other diseases like HCV, so the specificity of such a
Medical Biotechno
logy (BIOT 412) Human Diseases Assignment Muhammad Adeel

test would be significantly low. An assay has been developed, which would be discussed in the
last section. Let us take a look a
t these diagnostics:

A)

Blood Tests

Blood tests can be used to measure the degree of inflammation. Most often used tests include:



Erythrocyte sedimentation rate (ESR) and C
-
reactive Protein (CRP)

When the value of both these factors is high, inflammation is p
resent.
Also the color of
synovial fluid during inflammation changes, and can be viewed in the figure below:


B)

Imaging

An X
-
ray would also show if the joint has been inflamed by RA. It has been shown that x ray
of feet is more effective in showing the pres
ence of RA. Doctors have also agreed that better
imaging techniques like magnetic resonance imaging and ultrasound scans produce better
diagnosis.

2.

Treatment

A permanent cure for RA has not been found yet, however advancement in usage of antibody
therapy
is there. It would be discussed in the last section. The goal of treatment is to lessen the
pain and improve the function of joints. Doctors are resilient on the fact that earlier diagnosis can
lead to lessening of pain to a great extent. The range of trea
tment can be divided into four
segments:

Medical Biotechno
logy (BIOT 412) Human Diseases Assignment Muhammad Adeel

A)

Drugs


B)Physical Therapy


C) Surgery


D)Biological Therapy

We shall take a look at each aspect now.

A)

Drugs


For quite some time, drugs have been in use for the treatment of RA.
Mostly doctors would
prescribe a
combination of 2
, 3

drugs to lessen the pain.

The dosage and the kind of drug
depend

on the activeness of the RA in the patient.
Major classes of drug being used in such cases are
analgesics and non steroidal anti
-
inflammatory drugs

(NSAID’s)
. Pain Killer
s

are

basically given
to help the other drug to its task by lessening the pain in the patient.
NSAID’s are quite effective
in terms of relieving pain, but their efficacy is short term.

These can be in the form of capsules or
gel that can be applied on

affec
ted areas. Another class of drug being used these days is the
disease modifying anti
-
rheumatic drugs (DMARD’s).
The basic target of these drugs is not to
lessen pain but to address the main disease. Examples would include gold injections and
sulfasalazine
among others. Some of them are i
mmunosuppressant

as well, and limit the RF
production.

Steroids are also given to reduce inflammation; however they should be used with
care owing to their side effects.

(Fauci et al., 2009)

B)

Physical Therapy

In places where drugs can be harmful owing to side effects, physical therapy can be used.
In
this procedure the working of joints is maintained with exercise.
In such cases, patients are
assigned
a physiotherapist

who would suggest different exercises over

a specific period of time.

C)

Surgery

If the disease has been detected in an earlier stage, the doctor would opt for a surgery. The
scope and magnitude of surgery varies from patient to patient. In certain cases, the synovium is
removed to prevent further in
flammation.
In old patients,
joint replacement surgery

can also be
performed.

D)

Biological Therapy

Biological therapies were developed during the last

two

decade
s

and are focused on addressing
the immune system’s involvement in the disease.
The therapy invol
ves the usage of molecules
Medical Biotechno
logy (BIOT 412) Human Diseases Assignment Muhammad Adeel

that can target immune system factors.
A known class of molecule being used these days is

the
anti
-
TNF

drugs and they are being used against tumor necrosis factor (involved in
inflammation).

Other classes target other factors like CD3 or CD 22.

The principle is that they
would inhibit the release of such auto immune factors.

(Takeuchi,

2011)

Section E) Recent Development (Major Research Questions)


A major research question that can be though
t of in terms of recent therapeutic revolution
is that
“Is the cure of RA a realistic goal
?”

A paper published in 2009, indicated to the fact that
disease remission is an actual possibility. Apart from this, it also suggested that advances in
molecular bio
logy have lead to understanding of the disease and developing a possible cure. In
this section, we would take a look at these research innovations:

1.

Innovation in Diagnosis

Advancement in molecular biology has lead to a very specific diagnostic measure for RA,
which is now known as
Anti MCV Antibody Test
.
It focuses on detecting the autoantibodies
produced against a protein family known as
citrullinated vimentin
.

It is
basically a point of care
testing immunoassay that would detect a mutated form of these proteins. The specificity of this
test is as high as 99.7%, which is quite great.

2.

Innovation in Treatment

As mentioned earlier, biological molecules are now being appli
ed against the immune
response. Another region of innovation that can lead to a permanent cure or at least remission of
the disease is the
antibody therapy

(Hay & Olewyn, 2004)
.
These monoclonal antibodies can be
divided into four categories:

1.

Chimeric

2. H
umanized


3. Fully Human

4. Fusion Proteins

Their function is limiting the effect caused by the immune system against its own body
tissues. Further development is now being made in these monoclonal antibodies by altering their
glycobiology. It is now known

that by altering the sugar structure of the antibody, better
molecules can be made. This has been implemented in the case of a molecule
rituximab
, which
has been glycol
-
engineered for enhancing its activity.
(Isaac, 2009)

Medical Biotechno
logy (BIOT 412) Human Diseases Assignment Muhammad Adeel

References

Akhtar, E, Bilal, S & H
aque, U (2011) “Prevalence of Arthritis in India & Pakistan”,
Rheumatology International
,
33:
849
-
55


Bartold, PM, Marshall, RI and Haynes D.R (2005) “Peridontitis & Rheumatoid Arthritis”,
J
Periodontal
,
76:
2066
-
74

Fauci, AS, Braunwald, E, Kasper DL, Hauser, SL, Longo, DL, Jameson JL, Loscalzo, J. (2009)
Harrison’s Manual Of Medicine
. McGraw Hill: New York, 886
-
888

Hameed, K & Gibson, T (1997). “A comparison of the prevalence of rheumatoid arthritis and
other rheumat
ic diseases amongst Pakistanis living in England & Pakistan”.
British Journal of
Rheumatology

36
: 781
-
185

Hay, FC & Westwood MR Olwyn, (2002)
Practical Immunology
, 4
th

Edition. Blackwell
Science: New York: 76

Isaacs, D John (2009) “Antibody engineering to
develop new antirheumatic therapies”,
Arthritis
Research & Therapy
.
11
:

225
-
229

Nakaoka, H, Cui, T, Tajima A, Oka, A, Mitsunaga, S, Kashiwase, K, Homma, Y, Sato, S,
Suzuki, Y, Inoko, H & Inoue, I (2011) “ A systems genetics approach provides a bridge from
discovered genetic variants to biological pathways in rheumatoid arthritis”.
PLoS One
: 9: 1
-
16

Takeuchi, T (2011) “Revolutionary change in rheumatoid arthritis management with biological
therapy”
Keio Med

60:
75
-
81

Web Resource Used:

Statistics of RA in
Pakistan:

http://www.mendeley.com/research/prevalence
-
arthritis
-
india
-
pakistan
-
review/

On immunoassay of RA:

http://acr.confex.com/acr/2008/webprogram/Paper2009.html

Figures

from
:
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001467/