Conditions: Rheumatoid Arthritis
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 32
Healthy volunteers: no

Brief summary:
The purpose of the study is to better understand the factors present in the cells of inflamed joints of patients with arthritis that may cause rheumatoid arthritis. Knowledge gained from this study may lead to new and better therapies for arthritis.

Detailed description:
Blood samples will be collected from patients that have been diagnosed with RA based on ACR classification criteria. The study will include 200 donors. The total number of subjects are divided into two groups to yield a power of 95% at a type I error 5% level \[determined based on the preliminary data\]. In the first group, 200 donors will be treated with methotrexate, plaquenil and/or prednisone (Disease modifying anti rheumatic drugs; DMARDs) that either achieve remission (Disease activity score, DAS28\<2.6) or do not achieve remission (DAS28\>2.6). 50 donor will be utilized as they respond to DMARDs and achieve remission (DAS28\<2.6) and 150 donors that do not respond to DMARDs will be transferred to second group. In the second group, 150 donors will be treated with methotrexate, plaquenil and/or prednisone and Cimzia® (provided to us by UCB).

In the first group of patients, blood samples will be obtained from RA patients treated with Disease modifying anti rheumatic drugs (DMARDs) such as methotrexate, plaquenil and/or prednisone that achieve remission (DAS28\<2.6). The patients that achieve remission (DAS28\<2.6), blood will only be taken once at the patients routine visit.

The second group will consist of RA patients that did not respond to "DMARDs". These patients will further receive (DMARDs) such as methotrexate, plaquenil and/or prednisone as well as Cimzia® (provided to us by UCB) free of charge. Cimzia® is a FDA approved drug and is a standard of care. Blood samples will be obtained from the patients treated with DMARDs including methotrexate, plaquenil, and/or prednisone and Cimzia® (provided to us by UCB) that have inactive remission (DAS28\<2.6). In this group, blood samples will be collected onset of the study as well as 3 and 6 months after treatment with Cimzia at patient's visit through our collaboration with the aforementioned rheumatologists. Patients receiving intra-articular steroid injections will be excluded from the study.

PB mononuclear cells will be isolated from RA whole blood and drawn into Blood collection tubes and isolated by Histopaque gradient centrifugation. Monocytes will be isolated from RA PB mononuclear cells by negative selection (as shown in the preliminary data) and half of the monocytes will be differentiated to macrophages for 7 days. The expression levels for IL-7 and IL-7R will be determined by real-time reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry analysis.

In our statistical analysis, we will first perform a stratified analysis to evaluate the differential expression levels in RA patients with active and inactive disease, controlling for the type of treatment. Data analysis will be performed in collaboration with an UIC Center for Clinical and Translational Science statistician. Specifically, we will perform the comparison of IL-7 and IL-7R expression among RA patients with active (DAS28\>2.6) vs. inactive disease (DAS28\<2.6) for DMARDs group (group 1). We will then perform a similar comparison for the DMARDs and Cimzia® therapy group (group 2). The stratified analysis can adjust for the potential confounding effect of treatment received and allows for the detection of the potential differential relationships between expression levels of IL-7 or IL-7R and disease status. We will also perform a pooled regression analysis in which the expression logarithm of IL-7 or IL-7R from patients is regressed on the treatment group indicator \[DMARDs (group 1) versus on DMARDs plus Cimzia® therapy (group 2)\] and disease status (active or inactive disease) which would demonstrate the interaction between treatment groups and disease activity. Such an analysis pools subjects from two treatment groups together and can therefore increase the sample size, and hence potentially the power of detecting the relationships between biomarkers and disease status. The RA samples will be collected over a 2 year period and the data will be analyzed in the last year of the proposal.

Arms:
arm 1: In the first group of subjects, blood samples will be obtained from (50) RA subjects with Disease modifying anti rheumatic drugs (DMARDs) such as methotrexate, plaquenil and/or prednisone that achieve remission (DAS28\<2.6). The subjects that achieve remission (DAS28\<2.6), blood will only be taken once at the subjects routine visit. Subject's that are non-responder to DMARDS will go onto group 2. arm 2: The second group will consist of (150) RA subjects that did not respond to "DMARDs". These patients will further receive (DMARDs) such as methotrexate, plaquenil and/or prednisone as well as Cimzia®. In this Arm, blood samples will be collected onset of the study as well as 3 and 6 months after treatment with Cimzia at subject's visit through our collaboration with the aforementioned rheumatologists.

Interventions: intervention 1: Lab Work intervention 2: Certolizumab pegol (CDP870, tradename Cimzia)(prefilled syringes at the dose of 200mg) intervention 3: Certolizumab pegol (CDP870, tradename Cimzia) intervention 4: Hydroxychloroquine intervention 5: Sulfasalazine intervention 6: Medrol intervention 7: Prednisone intervention 8: Triamcinolone intervention 9: Naproxen intervention 10: Leflunomide intervention 11: Methotrexate intervention 12: humira
Intervention descriptions: intervention 1: Lab work to measure IL-7 and IL-7R intervention 2: Certolizumab pegol (CDP870, tradename Cimzia) or is provided in prefilled syringes at the dose of 200mg.

Patients received 2x200mg at weeks 0, 2 and 4. Additionally a maintenance dose of 200mg is given every 2 weeks. Treatment is performed through subcutaneous injection. intervention 3: rtolizumab pegol (CDP870, tradename Cimzia) or is provided in prefilled syringes at the dose of 200mg.

Patients received 2x200mg at weeks 0, 2 and 4. Additionally a maintenance dose of 200mg is given every 2 weeks. Treatment is performed through subcutaneous injection. intervention 4: some patients are on 400mg/day of hydroxychloroquine. intervention 5: some patients are on 300 mg/day and some patients are on 1000 mg/day dose of sulfasalazine intervention 6: some patients are on 8mg/day of medrol intervention 7: some patients are on 10mg /day, some patients are on 20 mg/day, some patients are on 2.5 mg/day, some patients are on 30 mg/day, and some patients are on 5 mg/day of prednisone intervention 8: some patients are on Triamcinolone 40-80mg IM monthly (received 40mg dose 1 week before blood draw, off enbrel 50mg weekly and SSZ 1000mg bid for \~ 3 months) some patients are on Triamcinolone 40mg IM monthly intervention 9: some patients are on 1000 mg/day of naproxen intervention 10: some patients are on 20mg/day of leflunomide intervention 11: some patients are on 20mg weekly, some patients are on 25mg weekly, some patients are on 17.5 mg, some patients are on 15 mg weekly, some patients are on 7.5 mg weekly, and some patients are on 15 mg weekly dose of methotrexate intervention 12: some patients are on Humira 40mg q2weeks

Protocol document:
Prot_SAP_000.pdf: 
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IL-7 and IL-7R expression in PB mononuclear cells, PB monocytes or differentiated 
macrophages of RA patients with active vs. inactive disease treated with DMARD 
and/or CIMZIA. 
IRB# 2015-0117 
PI: Shiva, Shahrara, Ph.D. 
University of Illinois at Chicago 
Funding: Union Chimique Belge (UCB) 
Protocol Version 2.0 
3/2/2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Aim 1
IL-7/IL-7R
RA DAS28
 
 
 
1.  Background and Purpose 
 
Monocyte migration plays a key role in the pathogenesis of Rheumatoid arthritis (RA) since the 
number of monocyte derived macrophages is higher in RA synovial tissue compared to normal 
joints and is well correlated with radiological damage, joint pain and inflammation. However, the 
signaling pathway(s) responsible for enhanced recruitment of monocytes into the RA synovial 
joint space is unknown. To address this important issue, we performed microarray studies to 
identify differentially regulated genes in RA synovial fluid macrophages and identified IL-7 
Receptor (IL-7R) as one of the most highly upregulated genes in RA synovial fluid macrophages. 
Our preliminary data shows that IL-7R expression is elevated 45 fold in RA synovial fluid and 10 
fold in RA peripheral blood (PB) in vitro differentiated macrophages compared to normal PB 
macrophages by real-time RT-PCR and/or FACS analysis. Consistently, in RA synovial tissue, 
IL-7R is also elevated on macrophages in the lining and sublining compared to normal synovial 
tissue. We found that expression of IL-7R in RA PB monocytes and macrophages is modulated 
by TNF-α Interestingly, concentrations of IL-7R have a strong correlation with disease activity 
score as determined by 28 joint count (DAS28) and TNF-α levels in RA monocytes. Moreover, 
our preliminary data documents that IL-7 is secreted from TNF-α treated RA macrophages and 
can attract IL-7R+ monocytes from the circulation to the RA joint at concentrations of IL-7 
detected in RA synovial fluid. 
 
Based on our results we hypothesize that RA patients with a TNF-α driven active disease 
have elevated expression of IL-7/IL-7R and thereby response to anti-TNF-α therapy reduces IL-
7-mediated monocyte migration and the number of IL-7R+macrophages in the RA joint. To test 
our hypotheses, in aim 1 we will examine whether expression of IL-7 or IL-7R in RA PB cells 
correlates with RA disease severity and response to anti-TNF-α treatment (Fig. 1). To date the 
contribution of IL-7 and IL-7R to RA pathogenesis and its role as a TNF-α responsive gene has 
not been described.  
 
IL-7R is the top gene identified in synovial fluid macrophages and its expression in 
monocytes (R2=0.56 and p=8.4x10-5) and macrophages (R2=0.56 and p=2.4x10-6) strongly 
correlates with RA disease activity suggesting that IL-7R may be a predictor for disease severity. 
Hence in this proposal, novel translational studies will be performed in order to determine 
whether IL-7R and IL-7 are RA signature genes for disease activity and if these genes are 
markedly reduced in anti-TNF-α therapy responders compared to nonresponders. 
 
 
 
 
 
 
 
 
 
 
Figure 1. Specific aim is proposed to elucidate the significance of IL-7/IL-7R expression in 
peripheral blood cells to RA disease activity and response to anti-TNF-α treatment. 
 
To accomplish the proposed project we will: 


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Aim 1. Determine whether the levels of IL-7 and IL-7R are elevated in PB mononuclear cells, PB 
monocytes or differentiated PB macrophages of RA patients with active [disease activity score 
(DAS)28>2.6] and inactive disease (DAS28<2.6) treated with Disease modifying anti rheumatic 
drugs (DMARDs) alone and/or DMARDs plus Cimzia® (certolizumab Pegol). 
 
 
 
2.  Protocol Methodology 
Detection of IL-7 and IL-7R expression levels in RA patients with active and inactive 
disease: RA patients will be referred and informed written consent will be obtained by Latriese 
Sardine. Blood samples will be collected from patients that have been diagnosed with RA based 
on ACR classification criteria. The study will include 200 donors. The total number of subjects 
are divided into two groups to yield a power of 95% at a type I error 5% level [determined based 
on the preliminary data].  In the first group, 200 donors will be treated with  methotrexate, 
plaquenil and/or prednisone (DMARDs) that either achieve remission (DAS28<2.6) or do not 
achieve remission (DAS28>2.6). 50 donor will be utilized as they respond to DMARDs and 
achieve remission (DAS28<2.6) and 150 donors that do not respond to DMARDs will be 
transferred to second group. In the second group,  150 donors will be treated with  methotrexate, 
plaquenil and/or prednisone and Cimzia® (provided to us by UCB).  
In the first group of patients, blood samples will be obtained from RA patients treated with 
Disease modifying anti rheumatic drugs (DMARDs) such as methotrexate, plaquenil and/or 
prednisone that achieve remission (DAS28<2.6). The patients that achieve remission 
(DAS28<2.6), blood will only be taken once at the patients routine visit.  
The second group will consist of RA patients that did not respond to "DMARDs". These patients 
will further receive (DMARDs) such as  methotrexate, plaquenil and/or prednisone as well as 
Cimzia® (provided to us by UCB) free of charge. Cimzia® is a FDA approved drug and is a 
standard of care. Blood samples will be obtained from the patients treated with DMARDs 
including methotrexate, plaquenil, and/or prednisone and Cimzia® (provided to us by UCB) that 
have inactive remission (DAS28<2.6). In this group, blood samples will be collected onset of the 
study as well as  3 and  6 months after treatment with Cimzia at patient's  visit  through our 
collaboration with the aforementioned rheumatologists. Patients receiving intra-articular steroid 
injections will be excluded from the study. 
 
 
 
 
Group 1 
(200 donors)  
 
 
 
 
 
 
DMARDs 
Responders
150 donors 
DMARDs 
non-Responders 
50 donors 
Group 2 


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Group 2 
(150 donors 
DMARDs 
non-responders)  
 
 
PB mononuclear cells will be isolated from RA whole blood and drawn into EDTA or CPT tubes 
and isolated by Histopaque gradient centrifugation. Monocytes will be isolated from RA PB 
mononuclear cells by negative selection (as shown in the preliminary data) and half of the 
monocytes will be differentiated to macrophages for 7 days. The expression levels for IL-7 and 
IL-7R will be determined by real-time RT-PCR and FACS analysis.  
 
  
In our statistical analysis, we will first perform a stratified analysis to evaluate the differential 
expression levels in RA patients with active and inactive disease, controlling for the type of 
treatment. Data analysis will be performed in collaboration with an UIC Center for Clinical and 
Translational Science statistician. Specifically, we will perform the comparison of IL-7 and IL-7R 
expression among RA patients with active (DAS28>2.6) vs. inactive disease (DAS28<2.6) for 
DMARDs group (group 1). We will then perform a similar comparison for the DMARDs and 
Cimzia® therapy group (group 2). The stratified analysis can adjust for the potential confounding 
effect of treatment received and allows for the detection of the potential differential relationships 
between expression levels of IL-7 or IL-7R and disease status. We will also perform a pooled 
regression analysis in which the expression logarithm of IL-7 or IL-7R from patients is regressed 
on the treatment group indicator [DMARDs (group 1) versus on DMARDs plus Cimzia® therapy 
(group 2)] and disease status (active or inactive disease) which would demonstrate the interaction 
between treatment groups and disease activity. Such an analysis pools subjects from two 
treatment groups together and can therefore increase the sample size, and hence potentially the 
power of detecting the relationships between biomarkers and disease status. The RA samples will 
be collected over a 2 year period and the data will be analyzed in the last year of the proposal.  
 
Measure outcomes: For any of the genes that demonstrate at least 2.5 fold increase (89% 
sensitivity calculated based on our preliminary data) in active disease compared to remission, 
correlation coefficient will be calculated for that gene expression level, rheumatoid factor, Cyclic 
Citrullinated Peptide Antibody (anti-CCP), C-Reactive Protein (CRP), DAS28 and disease 
duration. 
 
3. Eligibility Criteria 
 
Subject inclusion criteria for RA blood: 
 1. Must meet 1987 Revised Criteria for the Classification of Rheumatoid Arthritis defined as the 
diagnosis of the referring physician. 
 2.. Persistent knee swelling (>ARA grade 2) for 2 weeks, and no recent intra-articular 
corticosteroid injection. 
 3. Age 18 years and older. 
 
4.  Exclusion Criteria:   
      
DMARDs + 
Cimzia 
Responders 
DMARDs + 
Cimiza 
non-Responders


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1. Patients having received intra-articular corticosteroid joint injection within the last 
2-4 weeks. 
2. Patients with active systemic or joint infections. 
3. Women who are pregnant (pregnancy status will be self-reported) 
4. Patients under 18 years of age 
5. Non-English speakers 
 
5.  Vulnerable Population Inclusion: 
     1. No vulnerable population will be included in this study. 
     2. RA patients treated with Cimiza have to practice abstinent. 
 
6.  Probable Duration of Protocol 
    The samples will be stored for 10 years or until total sample depletion.   
 
7. Location Where Research is to be Conducted 
Recruitment will be conducted at the Outpatient Care Center, 1801 West Taylor Street, 
Suite 3A, Chicago IL, 60612.  Research work done on samples will be conducted in the 
laboratory space in 835 S. Wolcott St, Room E807 MSB, University of Illinois at 
Chicago, Chicago IL, 60612. 
 
8. Special Precautions to be Taken by Researchers 
The potential risks are limited to that associated with routine blood draw, and the 
collection and storage of personal health information. 
 
A possible risk of the research is that your participation in the research or information 
about you and your health might become known to individuals outside the research. 
Latriese Sardine will obtain consent from patients with an informed consent document 
and authorization form.  Copies of these forms will be added to each patient's permanent 
medical record.  Drawn peripheral blood samples will be stored and a assigned a code, 
which will be identifiable only by the master list. The master list will be kept in a locked 
cabinet or a computer that would need a password to be accessed. Besides the PI and the 
key personnel, nobody will have access to the locked cabinet or the computer where the 
information is stored. The consent forms, authorization forms, and the coded index will 
be only available to the PI and key lab personnel involved in the project. The consent 
forms and authorization forms will be kept in a locked cabinet. The data will be kept on a 
secured server accessible only to the PI and key lab personnel involved in the project. 
The data recorded in the lab books and computer records will refer to the subject's code, 
not the name. Data shared with collaborators will be identified only by the code. The 
patients will never be identified in any publication. 
 
When the results of the research are published or discussed in conferences, no 
information will be included that would reveal your identity.   
 


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9. Type and Number of Experimental Subjects 
Subjects include patients over age 18, excluding pregnant women (self-reported), with an 
RA diagnosis, or other autoimmune disease to be used as a control. 200 donors will be 
treated with  methotrexate, plaquenil and/or prednisone (DMARDs) that either achieve remission 
(DAS28<2.6) or do not achieve remission (DAS28>2.6). 50 donor will be utilized as they 
respond to DMARDs and achieve remission (DAS28<2.6) and 150 donors that do not respond to 
DMARDs will be treated with DMARDs such as methotrexate, plaquenil and/or prednisone 
and Cimzia provided to us by UCB. Subjects that fulfill the eligibility criteria will be 
identified by their physician/rheumatologist to be consented in participating in the study.   
 
10. Description of Statistical Analysis to which the Data will be Subjected 
For RA blood, using paired t tests, a sample size of 200 subjects will have a 80% power 
to detect the difference with effect size of 1.25 or above.   
 
11. Potential Risks and Benefits to Subjects 
The risks associated with blood draw include fainting, pain, a bruise at the site of vein 
puncture, inflammation of the vein. Every care will be taken to avoid these 
complications. The side effect of the drug Cimzia are similar to other 3 TNF-blockers 
these include serious infections, Invasive fungal infections, cases of lymphoma and other 
malignancies,  Heart failure, Hepatitis B virus reactivation and  Lupus-like syndromes.  
 
Use of Cimzia may cause damage to the fetus. Therefore, it is recommended that patient 
practice abstinence.  
Measures taken to minimize these risks are detailed above in #8.  Samples and clinical 
information will be stored and cared for with every precaution taken to ensure 
confidentiality of participant information.  There will be no compensation except for a 
parking sticker and testing results will not be released to individual subjects.  However if 
the patients require to be treated with Cimzia (anti-TNFα), the medication will be 
provided to them free of charge up to 2 years. Subjects will not benefit directly, but 
receive medication. 
 
12. Monitoring and Safety of Subjects 
Possible adverse events that could be anticipated would be either complications arising 
from obtaining blood samples or breach of data security.  While these events are unlikely, 
they would be immediately reported to the IRB.  As above, all precautions will be taken 
to avoid adverse events, and any improvements in the sample collection and archival 
process that become available during the course of the study will be implemented (for 
example, new technology that allows the study of smaller amounts of blood sample, new 
widely available data security measures, etc.)  Referring physicians will be charged with 
the continued monitoring of study participants as part of their routine care.  
 
 
13. Procedures to Obtain and Record Informed Consent 


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Adult subjects will be provided with an informed consent and authorization form from 
study personnel, with full opportunity to ask questions and obtain clarification. This form 
will detail the study as described (please see consent form and authorization forms 
attached to this application). After description of the protocol, study staff will ask the 
subject to describe the study in their own words briefly to assess understanding of the key 
aspects, and any incomplete understanding will be addressed at that time also.  All adult 
subjects will then receive an informed consent form if they wish to participate.  The 
consent form will include phone numbers to contact study personnel if questions should 
arise in the future or if they should wish to discontinue their participation in the study.  
All original signed informed consent forms and authorization forms will be kept on file 
by Dr. Shahrara, and a copy will be given to the subject.  Subjects wishing to discontinue 
their participation will have their samples removed from storage, however data collected 
or generated prior to withdrawal of consent may still be used in keeping with the above 
guidelines of the study (fully Coded without identifier, etc.).   
 
14. Procedures which will be used to Maintain Confidentiality of Research 
and Study Subject Materials 
A number of procedures will be used to maintain confidentiality of subjects.  At 
enrollment, each subject will receive a designated study code number.  All consent forms 
will be stored in locked file cabinets.   
 
All personal health information will be stored in a secure database which only the PI and 
designated research staff can access.  This database will be password-protected, and will 
be stored in a computer or in a locked file cabinet.  Coded numbers will be generated for 
each subject, and these coded numbers will be used to label each specimen.  These coded 
numbers will be used to file the subject’s clinical information in an independent clinical 
database which is free of protected health information.  The clinical database will also be 
password-protected and stored on a computer in a locked office.  Only the PI and her 
designated staff will have access to the secure databases with protected health 
information and the link between anonymous specimen code numbers and patient 
identifying information.  Coded data may be shared with other investigators or included 
in publications, but no patient identifying information will be released.  Every precaution 
will be taken to ensure confidentiality of patient information.   
 
15. Description of Recruiting Methods 
No advertisements will be used.  Patients will be recruited through their physician.  If the 
patient is willing, then study personnel will discuss the study as described above in the 
informed consent section at a location and time that does not obstruct the clinical care of 
the potential subject or other patients in the outpatient area.   
 
16. Description of how the Patient’s Physician will be Notified or Involved in 
the Research 
The patient’s physician may be notified of whether the patient did or did not choose to 
participate in the study, if they are listed in the key personnel of the study and they obtain 
consent and authorization.  There will not be any further involvement of the patient’s 


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physician in the research after routine clinical care that provides the specimens.  Clinical 
care will not be impacted in any way by participation or non-participation in this study. 
 
17. References in the Text of the Narrative 
 
References 
1. 
Ohl L, Henning G, Krautwald S, Lipp M, Hardtke S, Bernhardt G, et al. 
Cooperating mechanisms of CXCR5 and CCR7 in development and organization of 
secondary lymphoid organs. J Exp Med 2003;197(9):1199-204. 
2. 
Forster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M. A putative 
chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and 
specific anatomic compartments of the spleen. Cell 1996;87(6):1037-1047. 
3. 
Burman A, Haworth O, Hardie DL, Amft EN, Siewert C, Jackson DG, et al. A 
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2005;174(3):1693-700. 
4. 
Pickens SR, Chamberlain ND, Volin MV, Pope RM, Mandelin AM, 2nd, 
Shahrara S. Characterization of CCL19 and CCL21 in rheumatoid arthritis. Arthritis 
Rheum 2011;63(4):914-22. 
5. 
Maruotti N, Cantatore FP, Crivellato E, Vacca A, Ribatti D. Macrophages in 
rheumatoid arthritis. Histol Histopathol 2007;22(5):581-6. 
6. 
Fujikawa Y, Sabokbar A, Neale S, Athanasou NA. Human osteoclast formation 
and bone resorption by monocytes and synovial macrophages in rheumatoid arthritis. 
Annals of the Rheumatic Diseases. 1996;55(11):816-22. 
7. 
Szekanecz Z, Koch AE. Macrophages and their products in rheumatoid arthritis. 
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Bar-Shavit Z. The osteoclast: a multinucleated, hematopoietic-origin, bone-
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Ming WJ, Bersani L, Mantovani A. Tumor necrosis factor is chemotactic for 
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11. 
Wengner AM, Hopken UE, Petrow PK, Hartmann S, Schurigt U, Brauer R, et al. 
CXCR5- and CCR7-dependent lymphoid neogenesis in a murine model of chronic 
antigen-induced arthritis. Arthritis Rheum 2007;56(10):3271-83. 
12. 
Muller G, Hopken UE, Lipp M. The impact of CCR7 and CXCR5 on lymphoid 
organ development and systemic immunity. Immunol Rev 2003;195:117-35. 
13. 
Worbs T, Forster R. A key role for CCR7 in establishing central and peripheral 
tolerance. Trends Immunol 2007;28(6):274-80. 
14. 
Campbell IK, Hamilton JA, Wicks IP. Collagen-induced arthritis in C57BL/6 (H-
2b) mice: new insights into an important disease model of rheumatoid arthritis. European 
Journal of Immunology 2000;30(6):1568-1575. 
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Campbell IK, Rich MJ, Bischof RJ, Hamilton JA. The colony-stimulating factors 
and collagen-induced arthritis: exacerbation of disease by M-CSF and G-CSF and 
requirement for endogenous M-CSF. J Leukoc Biol 2000;68(1):144-50. 


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16. 
Tak PP, Smeets TJ, Daha MR, Kluin PM, Meijers KA, Brand R, et al. Analysis of 
the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease 
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17. 
Mulherin D, Fitzgerald O, Bresnihan B. Synovial tissue macrophage populations 
and articular damage in rheumatoid arthritis. Arthritis Rheum 1996;39(1):115-24. 
18. 
Shahrara S, Pickens SR, Dorfleutner A, Pope RM. IL-17 induces monocyte 
migration in rheumatoid arthritis. J Immunol 2009;182(6):3884-91.