Rheumatoid arthritis is a systemic autoimmune disease characterised by chronic joint inflammation

117 Pages·2008·1.79 MB·English

The Islamic University – Gaza
Deanship of Graduate Studies
Faculty of Science
Biological Science Master Program
Medical technology

Comparison of Anti Cyclic Citrullinated Protein 2 Serum
Levels with Rheumatoid Factor for the Diagnosis of
Rheumatoid Arthritis in Gaza Strip

Prepared by
Bushra M. Skaik

Supervisor
Prof. Mohammad E. Shubair

Submitted in Partial Fulfillment of Requirement for the degree of
Master of Life Sciences/Medical Technology

م2008 - ه1429
Declaration

“I herby declare that this submission is my own work and that, to the best of my
knowledge and belief, it contains no material previously published or written by
another nor material which to a substantial extent has been accepted for the
award of any other higher degree or diploma of the university or other institute of
higher learning, except where due acknowledgement is made in the text"

Author

Bushra Mohammed Skaik

Signature: bushra Date: Feb- 2008

.

All Rights Reserved © 2008. No part of this work can be copied, translated or
stored in retrieval system, without prior permission of the author.

I
Comparison of Anti Cyclic Citrullinated Protein 2 Serum Levels
with Rheumatoid Factor for the Diagnosis of Rheumatoid
Arthritis in Gaza Strip

Abstract

Background: Rheumatoid Arthritis (RA) is the most common autoimmune
disease. Howevere, specific and practicable tests for its specific diagnosis

are lacking. Therefore, a good marker should ideally not only indicate the

development of the disease, but also be able to differentiate RA from other

similar diseases and to help early diagnosis. The new marker which has
been tested in this study is the anti citrullinated protein antibody "ACCP2A".

Objective: To compare the diagnostic value and clinical utility of (ACCP2A)

with IgM rheumatoid factor (IgM RF) in patients with RA in Gaza Strip.

Methods: In cross sectional study; ACCP2A and IgM RF were determined in
142 serum samples; 67 patients suffering from arthritis, and 75 healthy

controls. All patients were diagnosed according to the guidelines of

American College of Rheumatology (ACR) and by rheumatologist. Both tests

were assessed by enzyme linked immunosorbent assay (ELISA). C-reactive
protein (CRP) and erythrocyte sedimentation rate (ESR) were also assayed

as inflammatory parameters for all subjects. All clinical features (onset for

RA, early symptoms, classification criteria, extra-articular disease, and

radiographic manifestations) and medications were investigated by
questionnaire interviews. And all results were analyzed by SPSS version

"15" .

Results: At a cutoff value of (>5 U/ml) for ACCP2A; sensitivity was 56% and

specificity was 99% and at a cutoff value of (>6 IU/ml) for IgM RF; it had a
higher sensitivity (85%) and a lower specificity (69%) than ACCP2A. The

area under the receiver operating characteristics (ROC) curve (AUC) for

ACCP2A was 0.80 (95% confidence interval, 0.70 – 0.90) and for IgM RF
was 0.83 (95% confidence interval, 0.74 – 0.92). In addition, there were
II
significant differences in the mean levels of ACCP2A (34.5 v 1.4) and IgM RF
(98 v 20) between RA patients and healthy plus other patient groups. Although
the concordance between both tests was significant (p= 0.000), IgM RF as the
single positive marker was found in 35% and ACCP2A as a single marker in 6%.
However, when the two markers were tested simultaneously, sensitivity and
specificity reached 88% and 100%. There was no significant correlation between
ACCP2A and personal characters such as age, gender, family history and
smoking. IgM RF didn’t show significant correlation with these characters except
with gender. A correlation with extra-articular manifestations, severity of
erosions and CRP was observed for both tests. ACCP2A didn't show significant
correlation with ESR but IgM RF showed a significant correlation with it.
Conclusion: ACCP2A was more specific than IgM RF in diagnosis of RA. So it
could be a useful serological assay in establishing the diagnosis of RA
especially in ambiguous cases or RF negative patients with RA. However, a
combination of both assays acts as "gold standard" in diagnosis of RA patients
in Gaza Strip. And both assays are also a better predictor of disease severity.

Keywords; Rheumatoid Arthritis, anti cyclic citrullinated peptide 2 antibody,
rheumatoid factor, Gaza Strip

III
ﺺﻴﺨﺸﺗ ﻲﻓ مﺰﺗﺎﻣوﺮﻟا ﻞﻣﺎﻋ ﻊﻣ 2 ﻦﻴﻟوﺮﺘﻴﺴﻟا ﻦﻴﺗوﺮﺑ ﺪﺿ ةدﺎﻀﻤﻟا مﺎﺴﺟﻷا يﻮﺘﺴﻣ ﺔﻧرﺎﻘﻣ
ةﺰﻏ عﺎﻄﻗ ﻲﻓ ﻲﻣﺰﺗﺎﻣوﺮﻟا ﻞﺻﺎﻔﻤﻟا بﺎﻬﺘﻟا

ﺔﺻﻼﺨﻟا

ﺔ(cid:1127)(cid:1127)ﻋﺎﻨﻤﻟا زﺎ(cid:1127)(cid:1127)ﻬﺟ مﻮ(cid:1127)(cid:1127)ﻘﻳ ﺚ(cid:1127)(cid:1127)ﻴﺣ ﺎﻋﻮﻴ(cid:1127)(cid:1127)ﺷ ﺔ(cid:1127)(cid:1127)ﻴﻋﺎﻨﻤﻟا ضاﺮ(cid:1127)(cid:1127)ﻣﻷا ﺮ(cid:1127)(cid:1127)ﺜآأ ﻦ(cid:1127)(cid:1127)ﻣ ﻲﻣﺰﺗﺎ(cid:1127)(cid:1127)ﻣوﺮﻟا ﻞ(cid:1127)(cid:1127)ﺻﺎﻔﻤﻟا بﺎ(cid:1127)(cid:1127)ﻬﺘﻟا ﺮ(cid:1127)(cid:1127)ﺒﺘﻌﻳ :ﺔ(cid:1127)(cid:1127)ﻣﺪﻘﻣ

ﻦ(cid:1127)(cid:1127)ﻋ ﺮﻤﺘ(cid:1127)(cid:1127)ﺴﻣ ﺚ(cid:1127)(cid:1127)ﺤﺒﻟا نﺈ(cid:1127)(cid:1127)ﻓ ﻚﻟﺬ(cid:1127)(cid:1127)ﻟ ،ﻪ(cid:1127)(cid:1127)ﺼﻴﺨﺸﺘﻟ ﻖﻴﻗﺪ(cid:1127)(cid:1127)ﻟا ﺺ(cid:1127)(cid:1127)ﺤﻔﻟا ﺪ(cid:1127)(cid:1127)ﻘﺘﻔﻳ ضﺮ(cid:1127)(cid:1127)ﻤﻟا اﺬ(cid:1127)(cid:1127)ه و ﻞ(cid:1127)(cid:1127)ﺻﺎﻔﻤﻟا ﺔ(cid:1127)(cid:1127)ﻤﺟﺎﻬﻤﺑ ﻢ(cid:1127)(cid:1127)ﺴﺠﻠﻟ
ﺔﻬﺑﺎ(cid:1127)ﺸﻤﻟا ى ﺮ(cid:1127)ﺧﻷا ضاﺮﻣﻷا ﻦﻋ ﻩﺰﻴﻤﺗ ﻲﻠﻋ و ضﺮﻤﻟا رﻮﻄﺗ ﻲﻠﻋ فﺮﻌﺘﻟا ﻲﻠﻋ ةردﺎﻗ نﻮﻜﺗ ةﺪﻳﺪﺟ تﺎﺻﻮﺤﻓ
ﻲ(cid:1127)ﻓ ﺎً(cid:1127)ﻣﺎه ﻼً ﻣﺎﻋ ﺮﺒﺘﻌﻳ ﺮﻜﺒﻤﻟا ﺺﻴﺨﺸﺘﻟا نإ ﺚﻴﺣ اﺮﻜﺒﻣ ﻪﺼﻴﺨﺸﺗ ﻲﻠﻋ ﺎًﻀﻳأ اًردﺎﻗ نﻮﻜﻳو ﻞﺑ ضاﺮﻋﻷا ﻲﻓ ﻪﻟ

.اًﺮﻜﺒﻣ جﻼﻌﻟﺎﺑ ءﺪﺒﻠﻟ مﺰﺗﺎﻣوﺮﻟا ضاﺮﻣأ ﻢﻠﻋ

ﻦﻴﻟوﺮﺘﻴ (cid:1127)ﺴﻟا ﻦﻴﺗوﺮ(cid:1127)ﺑ ﺪ(cid:1127)ﺿ ةدﺎ(cid:1127)ﻀﻤﻟا مﺎ(cid:1127)ﺴﺟﻷا ﺺ(cid:1127)ﺤﻓ ﻦ(cid:1127)ﻣ ﻞﻜﻟ ﺔﻴﺒﻄﻟا ةﺪﺋﺎﻔﻟا و ﺔﻴﺼﻴﺨﺸﺘﻟا ﺔﻤﻴﻘﻟا ﺔﻧرﺎﻘﻣ :فﺪﻬﻟا

.ةﺰﻏ عﺎﻄﻗ ﻲﻓ ﻲﻣﺰﺗﺎﻣوﺮﻟا ﻞﺻﺎﻔﻤﻟا بﺎﻬﺘﻟا ضﺮﻣ ﻲﻓ مﺰﺗﺎﻣوﺮﻟا ﻞﻣﺎﻋو

ﺔﻴﻠ(cid:1127)ﺼﻣ ﺔ(cid:1127)ﻨﻴﻋ ﻲﻓ مﺰﺗﺎﻣوﺮﻟا ﻞﻣﺎﻋو ﻦﻴﻟوﺮﺘﻴ ﺴﻟا ﻦﻴﺗوﺮﺑ ﺪﺿ ةدﺎﻀﻤﻟا مﺎﺴﺟﻷا ﻦﻣ ﻞآ ﺺﺤﻓ ﻢﺗ :ﺔﻘﻳﺮﻄﻟا
142

ﻊ(cid:1127)(cid:1127)ﻴﻤﺟ . ﺔﻄﺑﺎ(cid:1127)(cid:1127)ﺿ ﺔ(cid:1127)(cid:1127)ﻨﻴﻌآ ﻢهرﺎ(cid:1127)(cid:1127)ﻴﺘﺧا ﻢ(cid:1127)(cid:1127)ﺗ و ﻞ(cid:1127)(cid:1127)ﺻﺎﻔﻤﻟا تﺎ(cid:1127)(cid:1127)ﺑﺎﻬﺘﻟا ﻦ(cid:1127)(cid:1127)ﻣ نﻮﻧﺎ(cid:1127)(cid:1127)ﻌﻳ ﺎً(cid:1127)(cid:1127)ﻀﻳﺮﻣ ﻞﻤ(cid:1127)(cid:1127)ﺸﺗ تﺎ(cid:1127)(cid:1127)ﻨﻴﻌﻟا ﻩﺬ(cid:1127)(cid:1127)هو
75 67

ﺔ(cid:1127)ﻴﻜﻳﺮﻣﻷا ﺔ(cid:1127)ﻄﺑاﺮﻟا ﺎﻬﺘﻌ(cid:1127)ﺿو ﻲ(cid:1127)ﺘﻟا ﺮﻴﻳﺎ(cid:1127)ﻌﻤﻠﻟ ﺎ(cid:1127)ﻌﺒﺗو مﺰﺗﺎﻣوﺮﻟا ﻲﺋﺎﺼﺧأ ﺔﻄﺳاﻮﺑ ﺎًﻴﻜﻴﻨﻴﻠآإ ﻢﻬﺼﻴﺨﺸﺗ ﻢﺗ ﻲﺿﺮﻤﻟا
ﺎً(cid:1127)ﻀﻳأ ﻢ(cid:1127)ﺗ ﺎ(cid:1127)ﻤآ . اﺰ(cid:1127)ﻴﻟﻹا ﺔ(cid:1127)ﻘﻳﺮﻃ ﺔﻄ(cid:1127)ﺳاﻮﺑ ﻦﻴ(cid:1127)ﺼﺤﻔﻟا ﻼﻜﺑ ﺔﺻﺎﺨﻟا ﻞﻴﻟﺎﺤﺘﻟا ءاﺮﺟإ ﻢﺗ ﺪﻗو . م 1987 مﺎﻋ مﺰﺗﺎﻣوﺮﻠﻟ
ﺮﻴﻳﺎ(cid:1127)(cid:1127)ﻌﻤآ ءاﺮ(cid:1127)(cid:1127)ﻤﺤﻟا مﺪ(cid:1127)(cid:1127)ﻟا تاﺮ(cid:1127)(cid:1127)ﻜﻟ ﺐﻴ(cid:1127)(cid:1127)ﺳﺮﺘﻟا ﺔﻋﺮ(cid:1127)(cid:1127)ﺳ و "ﻲ(cid:1127)(cid:1127)ﺳ" ﻂ(cid:1127)(cid:1127)ﺸﻨﻟا ﻲ(cid:1127)(cid:1127)ﻨﻴﺗوﺮﺒﻟا بﺎ(cid:1127)(cid:1127)ﻬﺘﻟﻻا ﻞ(cid:1127)(cid:1127)ﻣﺎﻋ تﺎ(cid:1127)(cid:1127)ﺻﻮﺤﻓ ءاﺮ(cid:1127)(cid:1127)ﺟإ

.ﺔﻨﻴﻋ ﻞآ ﻲﻓ تﺎﺑﺎﻬﺘﻟﻼﻟ

ﺔ(cid:1127)ﻄﺑاﺮﻟا ﺎﻬﺘﻌ(cid:1127)ﺿو ﻲ(cid:1127)ﺘﻟا ﺮﻴﻳﺎ(cid:1127)ﻌﻤﻟا ،ةﺮ(cid:1127)ﻜﺒﻤﻟا ضاﺮ(cid:1127)ﻋﻷا ،ضﺮ(cid:1127)ﻤﻟا ءﺪ(cid:1127)ﺑ ﻞ(cid:1127)ﺜﻣ ضﺮﻤﻟﺎ(cid:1127)ﺑ ﺔ(cid:1127)ﻘﻠﻌﺘﻤﻟا تﺎ(cid:1127)ﻣﻮﻠﻌﻤﻟا ﻢﻴﻘﺗ ﻢﺗ

ﻢ(cid:1127)ﺗ ﺞﺋﺎ(cid:1127)ﺘﻨﻟا ﻞ(cid:1127)آو نﺎﻴﺒﺘ(cid:1127)ﺳا ﺔﻄ(cid:1127)ﺳاﻮﺑ ﺔ(cid:1127)ﻳودﻷا و ﺔﻴﻋﺎﻌ(cid:1127)ﺷﻹا تاﺮ(cid:1127)ﻴﻐﺘﻟا ،ﻞﺻﺎﻔﻤﻟا جرﺎﺧ ضﺮﻤﻟا ﺮهﺎﻈﻣ ،ﺔﻴﻜﻳﺮﻣﻷا
SPSS "15"ماﺪﺨﺘﺳﺎﺑ ﺎﻬﻠﻴﻠﺤﺗ

ﻲ(cid:1127)ﻓ ﻩرﺎ(cid:1127)ﺸﺘﻧا مﺪ(cid:1127)ﻋو ﻲ(cid:1127)ﺿﺮﻤﻟا ﻲ(cid:1127)ﻓ %56 ﻲ(cid:1127)ه ﻦﻴﻟوﺮﺘﻴ(cid:1127)ﺴﻟا ﻦﻴﺗوﺮ(cid:1127)ﺑ ﺪ(cid:1127)ﺿ ةدﺎﻀﻤﻟا مﺎﺴﺟﻷا رﺎﺸﺘﻧا ﺔﺒﺴﻧ :ﺞﺋﺎﺘﻨﻟا

لوﺮ(cid:1127)(cid:1127)ﺘﻨﻜﻟا ﻲ(cid:1127)(cid:1127)ﻓ ﻩرﺎ(cid:1127)(cid:1127)ﺸﺘﻧا مﺪ(cid:1127)(cid:1127)ﻋو %85 ﻲ(cid:1127)(cid:1127)ه ﻲ(cid:1127)(cid:1127)ﺿﺮﻤﻟا ﻲ(cid:1127)(cid:1127)ﻓ مﺰﺗﺎ(cid:1127)(cid:1127)ﻣوﺮﻟا ﻞ(cid:1127)(cid:1127)ﻣﺎﻋ رﺎ(cid:1127)(cid:1127)ﺸﺘﻧا ﺔﺒ(cid:1127)(cid:1127)ﺴﻧو %99 ﻲ(cid:1127)(cid:1127)ه لوﺮ(cid:1127)(cid:1127)ﺘﻨﻜﻟا

نأ ﺎﻧﺪ(cid:1127)ﺟﻮﻓ ROC ﻲ(cid:1127)ﻨﺤﻨﻣ ﺖ(cid:1127)ﺤﺗ ﺔﺣﺎ(cid:1127)ﺴﻤﻟا سﺎ(cid:1127)ﻴﻘﺑ ﺎ(cid:1127)ﻨﻤﻗ ﺎ(cid:1127)ﻨﻧﺈﻓ ﻦﻴﺼﺤﻔﻟا ﻼﻜﻟ ﺔﻴﺼﻴﺨﺸﺘﻟا ﺔﻤﻴﻘﻟا ﺔﻓﺮﻌﻤﻟو .%69
ﻲ(cid:1127)ه مﺰﺗﺎ(cid:1127)ﻣوﺮﻟا ﻞ(cid:1127)ﻣﺎﻌﻟ ﺔﺒﺴﻨﻟﺎﺑ ﺔﺣﺎﺴﻤﻟاو 0.80 ﻲه ﻦﻴﻟوﺮﺘﻴﺴﻟا ﻦﻴﺗوﺮﺑ ﺪﺿ ةدﺎﻀﻤﻟا مﺎﺴﺟﻸﻟ ﺔﺒﺴﻨﻟﺎﺑ ﺔﺣﺎﺴﻤﻟا

. لوﺮ(cid:1127)ﺘﻨﻜﻟا و ﻲﺿﺮﻤﻟا ﻦﻴﺑ ﻦﻴﺼﺤﻔﻟا ﺔﻤﻴﻗ ﻂﺳﻮﺘﻣ ﻲﻓ ﺔﻴﺋﺎﺼﺣإ ﺔﻟﻻد وذ فﻼﺘﺧا دﻮﺟو ﻲﻟإ ﺔﻓﺎﺿﻹﺎﺑ ، 0.83

ﻲﺿﺮﻤﻟا ﻲﻓ ﻩﺪﺣﻮﻟ مﺰﺗﺎﻣوﺮﻟا ﻞﻣﺎﻋ دﻮﺟو نﺈﻓ ﺔﻴﺋﺎﺼﺣإ ﺔﻟﻻد ﺎﻬﻟ ﻦﻴﺼﺤﻔﻟا ﻦﻴﺑ ﺔﻗﻼﻌﻟا نأ ﻦﻣ ﻢﻏﺮﻟا ﻲﻠﻋو
IV
ﻢﻏﺮ(cid:1127)ﻟا ﻲﻠﻋ ﻦﻜﻟ .%6 نﺎآ ﻩﺪﺣﻮﻟ ﻦﻴﻟوﺮﺘﻴﺴﻟا ﻦﻴﺗوﺮﺑ ﺪﺿ ةدﺎﻀﻤﻟا مﺎﺴﺟﻷا ﺺﺤﻓ دﻮﺟوو %35 ﻲﻟاﻮﺣ نﺎآ

مﺪ(cid:1127)ﻋ تﺎ(cid:1127)ﺒﺛاو %88 ﻲ(cid:1127)ه ﻲ(cid:1127)ﺿﺮﻤﻟا ﻲ(cid:1127)ﻓ ضﺮ(cid:1127)ﻤﻟا تﺎ(cid:1127)ﺒﺛإ ﻲﻠﻋ ﺎًﻌﻣ ﻦﻴﺼﺤﻔﻟا ةرﺪﻗ نأ ﺖﺘﺒﺛأ ﺔﺳارﺪﻟا نﺈﻓ ﻚﻟذ ﻦﻣ

.%100 ﻲه لوﺮﺘﻨﻜﻟا ﻲﻓ ﻢهدﻮﺟو
و ﻦﻴﻟوﺮﺘﻴ(cid:1127)(cid:1127)ﺴﻟا ﻦﻴﺗوﺮ(cid:1127)(cid:1127)ﺑ ﺪ(cid:1127)(cid:1127)ﺿ ةدﺎ(cid:1127)(cid:1127)ﻀﻤﻟا مﺎ(cid:1127)(cid:1127)ﺴﺟﻷا ﻦﻴ(cid:1127)(cid:1127)ﺑ ﺔﻴﺋﺎ(cid:1127)(cid:1127)ﺼﺣإ ﺔ(cid:1127)(cid:1127)ﻗﻼﻋ دﻮ(cid:1127)(cid:1127)ﺟو مﺪ(cid:1127)(cid:1127)ﻋ ﺎً(cid:1127)(cid:1127)ﻀﻳأ ﺔ(cid:1127)(cid:1127)ﺳارﺪﻟا تﺮ(cid:1127)(cid:1127)ﻬﻇأ ﺎ(cid:1127)(cid:1127)ﻤآ
مﺰﺗﺎ(cid:1127)(cid:1127)ﻣوﺮﻟا ﻞ(cid:1127)(cid:1127)ﻣﺎﻋ ﺺ(cid:1127)(cid:1127)ﺤﻓ نأ ﺎ(cid:1127)(cid:1127)ﻤآ و .ﻦﻴﺧﺪ(cid:1127)(cid:1127)ﺘﻟا ،ﻲﻠﺋﺎ(cid:1127)(cid:1127)ﻌﻟا ﺦﻳرﺎ(cid:1127)(cid:1127)ﺘﻟا ،ﺲﻨ(cid:1127)(cid:1127)ﺠﻟا ،ﺮ(cid:1127)(cid:1127)ﻤﻌﻟا ﻞ(cid:1127)(cid:1127)ﺜﻣ ضﺮ(cid:1127)(cid:1127)ﻤﻠﻟ ﺔﺒﺒ(cid:1127)(cid:1127)ﺴﻤﻟا ﻞ(cid:1127)(cid:1127)ﻣاﻮﻌﻟا

.ﺲﻨﺠﻟا ﻊﻣ ﻪﺘﻗﻼﻋ اﺪﻋ تاﺮﻴﻐﺘﻤﻟﺎﺑ ﺔﻗﻼﻋ ﻲﻄﻋأ

ﺖ(cid:1127)ﻈﺣﻮﻟ " ﻲ(cid:1127)ﺳ" ﻂ(cid:1127)ﺸﻨﻟا ﻦﻴﺗوﺮﺒﻟا و ﻞﺻﺎﻔﻤﻟا ﻞآﺂﺗ ةﺪﺷو ﻞﺻﺎﻔﻤﻟا جرﺎﺧ ض اﺮﻋﻷا ﻊﻣ ﺔﻗﻼﻌﻟا نأ ﻢﻏﺮﻟا ﻲﻠﻋو
ﺔﻋﺮ(cid:1127)ﺳ ﻊ(cid:1127)ﻣ ﺔﻴﺋﺎ(cid:1127)ﺼﺣإ ﺔ(cid:1127)ﻗﻼﻋ ﻲ(cid:1127)ﻄﻌﻳ ﻢ(cid:1127)ﻟ ﻦﻴﻟوﺮﺘﻴ(cid:1127)ﺴﻟا ﻦﻴﺗوﺮ(cid:1127)ﺑ ﺪﺿ ةدﺎﻀﻤﻟا مﺎﺴﺟﻷا ﺺﺤﻓ نﺈﻓ ﻦﻴﺼﺤﻔﻟا ﻼآ ﻊﻣ
.ﺔﻴﺋﺎﺼﺣإ ﺔﻗﻼﻋ ﻲﻄﻋأ مﺰﺗﺎﻣوﺮﻟا ﻞﻣﺎﻋ ﺺﺤﻓ ﻦﻜﻟ ءاﺮﻤﺤﻟا مﺪﻟا تاﺮﻜﻟ ﺐﻴﺳﺮﺘﻟا

ﻲ(cid:1127)ﻓ مﺰﺗﺎ(cid:1127)ﻣوﺮﻟا ﻞ(cid:1127)ﻣﺎﻋ ﺺ(cid:1127)ﺤﻓ ﻦ(cid:1127)ﻣ ﺔ(cid:1127)ﻗد ﺮ(cid:1127)ﺜآأ ﺮ(cid:1127)ﺒﺘﻌﻳ ﻦﻴﻟوﺮﺘﻴﺴﻟا ﻦﻴﺗوﺮﺑ ﺪﺿ ةدﺎﻀﻤﻟا مﺎﺴﺟﻷا ﺺﺤﻓ :جﺎﺘﻨﺘﺳﻻا
ﺺﻴﺨ(cid:1127)(cid:1127)ﺸﺗ تﺎ(cid:1127)(cid:1127)ﺒﺛإ ﻲ(cid:1127)(cid:1127)ﻓ ﺔ(cid:1127)(cid:1127)ﻣﺎﻬﻟا ﺔﻴﺟﻮﻟوﺮﻴ(cid:1127)(cid:1127)ﺴﻟا تﺎ(cid:1127)(cid:1127)ﺻﻮﺤﻔﻟا ﻦ(cid:1127)(cid:1127)ﻣ ﺮ(cid:1127)(cid:1127)ﺒﺘﻌﻳ و . ﻲﻣﺰﺗﺎ(cid:1127)(cid:1127)ﻣوﺮﻟا ﻞ(cid:1127)(cid:1127)ﺻﺎﻔﻤﻟا بﺎ(cid:1127)(cid:1127)ﻬﺘﻟا ﺺﻴﺨ(cid:1127)(cid:1127)ﺸﺗ
ﻲ(cid:1127)ﺻﻮﺗ و . مﺰﺗﺎ(cid:1127)ﻣوﺮﻟا ﻞ(cid:1127)ﻣﺎﻋ ﻲ(cid:1127)ﻠﻋ ﻢهؤﺎ(cid:1127)ﻣد يﻮﺘﺤﺗ ﻻ ﻦﻳﺬﻟا ﻲﺿﺮﻤﻟا وأ ﺔﻀﻣﺎﻐﻟا تﻻﺎﺤﻟا ﻲﻓ ﺔﺻﺎﺧ ضﺮﻤﻟا

ﻲ(cid:1127)ﻓ ﻲﻣﺰﺗﺎ(cid:1127)ﻣوﺮﻟا ﻞﺻﺎﻔﻤﻟا بﺎﻬﺘﻟا ﺺﻴﺨﺸﺗ ﻲﻓ ﻲﺒهﺬﻟا رﺎﻴﻌﻤﻟا ﺮﺒﺘﻌﻳ اﺬه نأ ﺚﻴﺣ ﺎًﻌﻣ ﻦﻴﺼﺤﻔﻟا ﻞﻤﻌﺑ ﺔﺳارﺪﻟا

.ةﺰﻏ عﺎﻄﻗ

V
Dedication

This thesis is dedicated to
Palestinian people
My fathers, pure soul
My family (mother, sisters and brothers)

VI
Acknowledgment

I wouId like to acknowledge all of the people who have assisted me with my

work presented in this thesis. My deepest gratitude goes to my supervisor,

Prof. Mohammad Eid Shubair, who has given me his utmost support,

guidance in all steps through this project.
I would also like to thank Dr. Mrwan El Hinde (head of rheumatism section

in EL SHIFA hospital), who helped me to recruit and assess the patients in

the study and for providing facilities for sample collection from them. So my

sincere thanks go out also to all of the patients that agreed to participate in
this study, without them this study would not have been possible.

I wish to gratefully acknowledge to the engineer Hani Mater for helping me

in buying and preparing the material and kits from outside of Gaza strip.

I am very grateful to Mr. Yosif El Arkan for helping me in the practical part
of research and for his permission for me to make part of work in his lab.

And I wish also to express my thanks to Mr. Naser Abu Shaban for his

useful advice in the practical part of research.

I owe my thanks to Dr. Samir Safi (Assistant Professor of Statistics) for
teaching and helping me in doing statistical analysis.

I want to mention with thanks Mr. Abdel Karim El Asele (technologist

assistant) for helping me in blood collection from healthy control.

I wish to present my thanks to the people who served as healthy controls in
my study.

In addition, I express my thanks to my aunt and Public Aid hospital for

preserving the samples during electricity cut off from the university.

Finally, I would like to thank my friends and relatives for their ongoing
support and encouragement.

VII
Table of Contents

Items Page

Declaration I
Abstract (English) II

Abstract (Arabic) IV
Dedication VI

Acknowledgment VII
Table of contents VIII

List of tables XI
List of figure XII

List of abbreviation XIV

Chapter
Chapter I Introduction 1

1.1 Overview 1
1.2 Objectives 4

1.3 Significance 4
Chapter II Literature Review 5

2.1 Background 5
2.2 History 5

2.3 Epidemiology 6
2.4 Etiology 8

2.4.1 Genetic risk factors 8
2.4.1.1 HLA genes 8

2.4.1.2 Non HLA genes 9
2.4.2 Other risk factors 9

2.4.2.1 Gender 10
2.4.2.2 Smoking 10

2.4.2.3 Infection 10
2.4.2.4 Miscellaneous factors 10

2.4.3 Gene-environmental interaction 10
2.5 Pathogenesis 11

2.6 Onset, course, clinical manifestation 16
2.6.1 Onset and course 16

2.6.2 Non specific symptoms 16
2.6.3 Clinical manifestation 16

2.6.3.1 Articular manifestation 16
2.6.3.2 Extra-articular manifestation 18

2.7 Mortality 20
2.8 Diagnosis 20

2.8.1 Diagnostic criteria 20
2.8.2 Laboratory diagnosis 22

2.8.2.1 Ab in the diagnosis of RA 22
s
A. RF :A non specific Ab for RA 22
B. New markers specific for RA 23
C. ACCP2A: specific Ab for RA 23
VIII
D. Citrullination 24
E. Genetic association between citrullination and RA 25
F. ACCPA assays 27
G. Clinical utility of ACCP2A 28
H. Future trends of ACCP2A 31
2.8.2.2 Inflammatory markers in RA 32
A. ESR 32
B. CRP 32
C. The importance of ESR and CRP in RA 33
2.9 Imaging studies 33
2.10 Treatment 33
Ch apter III Materials and Methods 35
3.1 Materials 35
3 .1.1 Reagents kits 35
3.1.2 Instruments and disposable 35
3.2 Study population 35
3.2.1 Patients group 36
3 .2.2 Healthy control 36
3.2.3 Questionnaire 36
3 .2.4 Permission and ethical consideration 36
3.3 Methods 36
3 .3.1 Sample collection 36
3.3.2 Sample processing 37
3.3.2.1 ACCP2A assay 37
A. Principle of assay 37
B. Kit components 37
C. Procedure (semi quantitative protocol) 38
D. Calculation of results 38
3.3.2.2 IgM RF assay 39
A. Principle of assay 39
B. Kit components 40
C. Procedure (semi quantitative protocol) 40
D. Calculation of results 40
3.3.2.3 CRP assay 41
A. Principle of assay 41
B. Kit components 41
C. Procedure (qualitative method) 41
D. Interpretation of result 42
3.3.2.4 ESR assay 42
A. Principle of method 42
B. Method components 42
C. Procedure 42
3.4 Statistical methods 43
Ch apter IV Results 44
4.1 Characteristic of study population 44
44..42 TSheen sciotinvcitoyr adnadn csep ebceitfwiceiteyn o Af ACCCCPP2A2A a nadn dIg IMgM R RFF for diagnosis of RA 5416
4.3 Comparison between the mean levels of ACCP2A and IgM RF in RA, 48
controls plus others groups
IX