Prof. Dr. Somaya Anwar Hussein Prof. Dr. Hala Zaki Raslan Dr. Reem Ismail El Shazly

20 Pages·2015·0.33 MB·English

ANTI MUTATED CITRULLINATED VIMENTIN
ANTIBODIES IN RHEUMATOID ARTHRITIS
PATIENTS: RELATION TO DISEASE ACTIVITY
AND MANIFESTATIONS
Thesis
Submitted for partial fulfillment of Master Degree
in Rheumatology and Rehabilitation
By:
Amira Ahmed ElGogary
(M.B., B.Ch.)
Supervised by:
Prof. Dr. Somaya Anwar Hussein
Professor of Rheumatology and Rehabilitation
Faculty of Medicine
Cairo University
Prof. Dr. Hala Zaki Raslan
Professor of Internal Medicine
National Research Center
Dr. Reem Ismail El Shazly
Lecturer of Rheumatology and Rehabilitation
Faculty of Medicine
Cairo University
Faculty of Medicine
Cairo University
2012
ABSTRACT
Background: Numerous serological markers of RA have been described
over the past 50 years. Among all these, Anti Citrullinated Protein/Peptide
Antibodies (ACPA) have been proven to be specific, diagnostic and
prognostic markers in RA. The newest member of this autoantibody family
is Anti- Mutated Citrullinated Vimentin (MCV).
Aim of work: The aim of this work was to evaluate the prevalence of Anti-
Mutated Citrullinated Vimentin Antibodies (MCV) in rheumatoid arthritis
patients and to correlate it with disease activity, various disease
manifestations and prognosis.
Patients and methods: 50 RA patients (94% females and 6% males)
fulfilling the 1987 ACR revised classification criteria for RA having mean
disease duration of 8.33±7.22 years and 30 healthy controls (40% females
and 60 % males) were included. All RA patients were subjected to: Clinical
assessment of disease activity by taking full history, general and local
examination, measurement of 28 joint count of tender and swollen joints
with calculation of disease activity score (DAS-28) for each patient together
with assessing functional ability with Modified Health Assessment
Questionnaire (MHAQ). Complete blood count, erythrocyte sedimentation
rate and rheumatoid factor were performed. Anti-MCV and anti-CCP assays
were performed by ELISA in patients and controls. RA patients were then
classified into; anti-MCV positive and anti-MCV negative groups for
statistical comparison. Plain X-ray was performed on the hands and wrists
and scored by Sharp score.
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Results: A highly significant elevation of serum anti-MCV in RA patients
was detected when compared to controls. Anti-MCV was detected in 42
patients (84%) and in 6 healthy controls (20%) giving a specificity of 84%
and a sensitivity of 80%. There was no significant difference between anti-
MCV positive and anti-MCV negative patients as regard parameters of
disease activity represented in ESR and DAS 28, however, there was a
significant difference between anti-MCV positive and anti-MCV negative
patients as regards MHAQ and Sharp scores. In addition, there were no
significant differences between RA patients who were anti-MCV negative
and those who were anti-MCV-positive with respect to age, sex, disease
duration. On the other hand, there was a highly significant elevation of
serum anti-CCP in RA patients when compared to controls, as anti-CCP was
detected in 35 patients (70%) and in none of the healthy controls giving a
sensitivity of 70% and a specificity of 100%. However, there was no
significant correlation with either anti-MCV or anti-CCP as regards to
neither the qualitative nor the quantitative data except for RF which was
significantly more frequent with anti-CCP than anti-MCV.
Conclusion: Anti-MCV antibodies bore a sensitivity of 84 % and a
specificity of 80% while anti-CCP bore a sensitivity of 70 % and a
significantly higher specificity of 100 %. And according to these findings,
the anti-MCV assay did not provide significant additional diagnostic value
over the already established anti-CCP assay nor did it correlate with disease
activity. For now, it seems that the only obvious advantage of positive anti-
MCV test is a significantly closer association with radiologic progression,
thus making the anti-MCV a good predictor of more aggressive and erosive
disease.
Key words: Rheumatoid arthritis, anti-MCV antibodies.
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Acknowledgement
First and foremost, all thanks to God, the most merciful and gracious,
for giving me the will and strength to fulfill this study, then to my family,
especially, my sister and my husband that encountered a lot to help guide
and support me.
I owe my deepest gratitude to Prof. Dr. Somaya Anwar, Professor of
Rheumatology and Rehabilitation, Faculty of medicine, Cairo University, for
her kind support, scientific remarks and keen interest in the progress of this
work.
I am heartily thankful and indebted to Prof. Dr. Hala Raslan,
Professor of Internal Medicine, National Research Center, for her sincere
guidance, precious advice, continuous encouragement throughout this work
and for advocating much of her time and effort to make this work at its best.
Sincere thanks to Dr. Reem El Shazly, Lecturer of Rheumatology and
Rehabilitation, Faculty of medicine, Cairo University for her great patience
in reading and revising the manuscript, and her great help and valuable
ideas throughout the work.
Special thanks to Dr. Maha Abdel Hadi, Lecturer of Rheumatology
and Rehabilitation, National Research Center, Dr. Mohamed Shaker
Lecturer of Radiology, National Research Center and Dr. Mohamed El
Tohamy, Lecturer of Medical Anthropology, National Research Center for
there assistance and precious guidance.
I'll never forget all the help and support I got from my dear
colleagues at the Rheumatology and Rehabilitation Department, Cairo
University without their assistance I wouldn't have been able to complete
this work.
Last but not least, my mother, without your support, encouragement
and prayers, I would’ve never been able to accomplish anything throughout
my whole life. You are my idol.
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CONTENTS
Page
LIST OF ABBREVIATIONS vi
LIST OF FIGURES xi
LIST OF TABLES xiv
INTRODUCTION 1
AIM OF WORK 3
REVIEW OF LITERATURE
Chapter (1): Rheumatoid arthritis 4
Chapter (2): Autoantibodies in Rheumatoid arthritis 25
Chapter (3): Anti-CCP and Anti-MCV 41
PATIENTS AND METHODS 64
RESULTS 74
DISCUSSION 94
SUMMARY 106
RECOMMENDATIONS 108
REFERENCES 109
ARABIC SUMMARY
v
LIST OF ABBREVIATIONS
aCL Anti-cardiolipin
ACPA anti-Citrullinted peptide antibodies
ACR American College of Rheumatology
AFA antifilaggrin antibody
AKA antikeratin antibody
ALT Alanine transaminase
ANCA Anti Neutrophil Cytoplasmic Antibodies
anti-CCP anti-Cyclic Citrullinted peptide
anti-CII Anti-type II collagen
Anti-Sm anti-smith
anti-β2GPI anti-β2-glycoprotein I
APC antigen-presenting cells
APF antiperinuclear factor
aPL Antiphospholipid antibodies
aPT anti-prothrombin
AS Ankylosing Spondylitis
AST Aspartate transaminase
BiP Binding immunoglobulin protein
C1q first complement component
cANCA cytoplasmic anti neutrophil cytoplasmic antibodies
CBC Complete Blood Count
cIMT carotid intima-media thickness
CMC carpometacarpal
CRP C- reactive protein
vi
CV Citrullinated Vimentin
CVD Cardiovascular disease
DAS Disease Activity Score
DCs Dendritic Cells
DMARDs Disease modifying anti-rheumatic drugs
DNA Deoxyribonucleic acid
EBV Epstein Barr virus
EIM Extraintestinal manifestation
ELISA Enzyme-linked immunosorbent assay
ESR Erythrocyte sedimentation rate
EULAR European League Against Rheumatism
Fc Fragment crystalizable region
FGF fibroblast growth factor
FLS Fibroblast-like Synoviocytes
GIT Gastrointestinal tract
GM-CSF Granulocyte-Macrophage-colony-stimulating Factor
Gp39 cartilage glycoprotein 39
GPI glucose-6-phosphate isomerase
Hb Hemoglobin
HCV Hepatitis C virus
HLA Human Leucocyte Antigen
hnRNP Heterogeneous Nuclear Ribonucleoprotein
HOMA-IR Homeostasis model assessment for insulin resistance
HRP horse radish perioxidase
hsCRP High sensitivity C-reactive protein
hsp heat shock proteins
vii
IBD Inflammatory bowel disease
IC Immune complexes
ICAM-1 intercellular adhesion molecule-1

IFN- Interferon-gamma
Ig immunoglobulin
IL Interleukin
IL-1Ra Interleukin 1 receptor antagonists
IL-1RacP Interleukin 1 receptor accessory protein
IU International unit
JIA Juvenile idiopathic arthritis
JSN Joint space narrowing
LA lupus anticoagulants
LDL Low density lipoprotein
MCB metacarpal base
MCP metacarpo-phalangeal
MCP-1 monocyte chemotactic protein-1
MCV Mutated Citrullinated Vimentin
MHAQ Modified health assessment questionnaire
MMPs matrix metallo-proteinases
mPAN microscopic polyarteritis nodosa
MPO Myeloperoxidase
MTP metatarso-phalangeal
MTX Methotrexate
NFκB Nuclear Factor κBetta
NH3 ammonia
NO Nitric oxide
viii
NOS Nitric oxide synthases
NPV Negative predictive value
NS Non significant
NSAID Non-steroidal anti-inflammatory drugs
OPG Osteoprotegerin
OPG-L Osteoprotegerin – ligand
PAD Peptidyl Arginine Deaminase
pANCA perinuclear anti neutrophil cytoplasmic antibodies
PDF platelet-activating derived factor
PGE2 Prostaglandin E2
PIP Proximal interphalangeal
PMNs Polymorphoneuclear neutrophils
PPV Positive predictive value
PR3 neutral proteinase 3
PsA Psoriatic arthritis
PTPN 22 protein tyrosine phosphatase nonreceptor type 22
R range
RA Rheumatoid arthritis
RANKL Receptor activator of nuclear factor kappa-B ligand
RBCs Red blood cells
RF Rheumatoid Factor
RPGN rapidly progressive segmental necrotizing and crescentic
glomerulonephritis
S Significant
SD Standard deviation
SLE Systemic Lupus Erythromatosis
ix
SPSS Statistical Package for the Social Science
TCR T cell receptor
TIMPs Tissue inhibitors of metalloproteinases
TNF- Tumor Necrosis Factor-alpha
U1-snRNP small nuclear ribonucleoproteins U1
UA Undifferentiated arthritis
VCAM-1 Vascular cell adhesion protein 1
WG Wegener's granulomatosis
x