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1
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Introduction

A

• Hello everyone, my name is My-Linh Ho and I am working with Dr. Kristen Demoruelle. Our study explores the presence of Sputum Anti-Citrullinated Protein Antibodies, aka ACPAS in Subjects At-Risk for RA. Before I talk to you further this, I would first like to review what Rheumatoid Arthritis is.

2
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What is Rheumatoid Arthritis?

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• Rheumatoid arthritis is an autoimmune, systemic inflammatory disease that affects about 1.5 million adults in the US. Major features associated with the disease are the familiar inflammatory arthritis that is often symmetrical and polyarticular. Xray imaging include erosions and joint space narrowing, while lab characteristic findings include an increase in RA-related autoantibodies. These features are important when diagnosing RA.

3
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Development of RA

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• Now, we don’t know the exact etiology of RA, but we know that it develops in multiple phases. Before RA can get diagnosed (press button) there are phases that lead up to that- as we like to call- the preclinical period of RA. As you can see here, RA is initiated by some genetic and environmental risk factors. This contributes to development of autoimmunity marked by the presence of circulating ACPAs. Notice here too that there are no signs of IA. Some change with the autoantibodies then occurs that causes inflammatory arthritis, where we then classify it as RA.

4
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ACPAs

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• Of course there are also other RA-Related autoantibodies such as RF, but we focused on ACPAs because it is more specific and common in majority of RA patients. These autoantibodies direct against citrullinated peptides, which are simply a result of post-translational modification of arginine to citrulline.

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Importance of Understanding

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• It is important to understand the development of RA for several reasons. 1) Early intervention makes a difference. If we can identify the risk factors and biomarkers in someone earlywith the disease, we can reduce joint inflammation and damage. 2) RA is progressive. There currently is no cure, and we only have drugs to slow it down and reduce systemic side effects. 3) If we can target early along the pathway of RA development, we could potentially prevent RA altogether.

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Pre-Clinical Period

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• Let’s take another look at the development of RA again. If we want to prevent the development of RA, we first need to identify where these ACPAs are generated. Previous studies have already demonstrated that these RA-related autoantibodies are initiated outside of the joints. And it has been suggested that they are generated along the mucosal sites such as oral, urogenital, and respiratory tract.

7
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RA in Lung

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• Our study hypothesizes that the autoantibodies may generate in the lungs for a few reasons.
o 1) One of the strongest risk factors for RA is smoking, which is inhaled.
o 2) There is high prevalence of lung disease in early RA.
o 3) Inflammatory airways disease is highly prevalent on HRCT in subjects with serum RA-related Abs in the absence of joint inflammation.
o 4) There are known mechanisms of generation of Abs in the lungs of subjects with RA.

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Hypothesis and Aims

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• In order to test our hypothesis, we aim to examine the levels of ACPAs and the specific isotypes in the sputum.

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Subjects

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  • For this study, we recruited our subjects from the Studies of the Etiology of RA Cohort, which is a prospective cohort study established to investigate the natural history of RA. We’ve also recruited subjects through the local community.
  • From this, we’ve included 34 RA subjects who are seropositive and has the classified the disease, 140 at risk subjects who have no inflammatory arthritis but have either serological risk meaning they are seropositive for CCP3.1 or familial risk meaning they have a first degree relative that has RA. We’ve also included 56 controls to compare.
10
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Induced Sputum

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• For this study, we looked at Ab levels in the sputum because it is a good representation of the lungs. It is also safer, easier, and cheaper than Broncho alveolar lavage, which is very invasive. After the sputum is obtained, we homogenize it for ELISA testing. We also excluded and sputum sample with a >10 squamous epithelial cell count to make sure that it is a good representation of sputum and not saliva.

11
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Study Visit

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  • During the study visit, questionnaires are given to the patients that asks about their joint, lung, and smoking history. Serum and sputum are also collected and undergo ELISA testing for Anti-CCP3.1 IgA/IgG both, and then Anti-CCP IgA and IgG separately.
  • The sputum positivity cut-off was determined by the level that is positive in less than 5% of the controls.
12
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Subject Characteristics

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  • Listed here are the subject characteristics.
  • As you can see, most of our subjects are women (RA is known to affect more women than men). The control subjects are a lot younger and the RA subjects have a more significant history.