The Relationship Between Serum Chemokine Ligand 21 (CCL-21) Level and Disease Activity

NCT ID: NCT06540573

Last Updated: 2024-08-06

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

NOT_YET_RECRUITING

Total Enrollment

60 participants

Study Classification

OBSERVATIONAL

Study Start Date

2024-08-12

Study Completion Date

2024-11-30

Brief Summary

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Rheumatoid arthritis (RA) is a chronic systemic disease characterized by the development of new capillaries involved in the infiltration of inflammatory cells causing synovial hyperplasia and progressive destruction of cartilage and bone.Osteoarthritis (OA) is a degenerative joint disease that involves articular cartilage and other intra-articular structures.Although the pathological mechanisms involved in OA and RA are different, the onset and progression of both diseases are associated with inflammation, immune mechanisms and metabolic factors.C-C Motif Chemokine Ligand 21 (CCL21) is a CCR7-binding chemokine that plays an important role by modulating the circulation of T cells and dendritic cells in lymphoid and peripheral organs (9). Ligation of CCL21 in RA fibroblasts and macrophages induced the production of proangiogenic factors such as VEGF, Ang-1, and IL-8, suggesting that CCL21 plays an indirect role in RA angiogenesis.The aim of our study is to evaluate the serum levels of CCL21 in RA and OA patients by comparing them with healthy controls. In addition, the aim is to examine the correlation of serum CCL21 with disease degree/severity in both diseases and to determine whether it can be a biomarker of the disease state.

Detailed Description

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Rheumatoid arthritis (RA) is a chronic systemic disease characterized by the development of new capillaries involved in the infiltration of inflammatory cells causing synovial hyperplasia and progressive destruction of cartilage and bone. The synovial tissue layer consists of macrophages and fibroblasts, which have profound effects on the destructive process in RA through the production of pro-inflammatory cytokines, chemokines and pro-angiogenic factors (2,3). Osteoarthritis (OA) is a degenerative joint disease that involves articular cartilage and other intra-articular structures (4). OA leads to pain, stiffness, decreased joint function (5), and ultimately disability (6). Although the pathological mechanisms involved in OA and RA are different, the onset and progression of both diseases are associated with inflammation, immune mechanisms and metabolic factors (7,8). C-C Motif Chemokine Ligand 21 (CCL21) is a CCR7-binding chemokine that plays an important role by modulating the circulation of T cells and dendritic cells in lymphoid and peripheral organs (9). Ligation of CCL21 in RA fibroblasts and macrophages induced the production of proangiogenic factors such as VEGF, Ang-1, and IL-8, suggesting that CCL21 plays an indirect role in RA angiogenesis ( 10 ).

We determined that CCL21-mediated RA arthritis extends joint inflammation to bone erosion by coupling the differentiation of M1 macrophages with Th17 cells. Disease progression is further exacerbated by CCL21-induced neovascularization. We conclude that CCL21 is an attractive new target for the treatment of RA, as blocking its function can abolish erosive arthritis modulated by M1 macrophages and Th17 cell crosstalk. In short, CCL21 is a pleiotropic chemokine that shapes many aspects of RA pathology. We have not found a study that examined CCL21 blood serum levels in RA and OA patients and healthy controls and evaluated whether there is a relationship between CCL21 and these diseases.

The aim of our study is to evaluate the serum levels of CCL21 in RA and OA patients by comparing them with healthy controls. In addition, the aim is to examine the correlation of serum CCL21 with disease degree/severity in both diseases and to determine whether it can be a biomarker of the disease state.

Conditions

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Rheumatoid Arthritis Osteoarthritis

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

PROSPECTIVE

Study Groups

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Patients who were diagnosed with osteoarthritis and applied to outpatient clinic

Patients diagnosed with osteoarthritis (meeting the American College of Rheumatology (ACR) criteria

Laboratory tests (examination)

Intervention Type DIAGNOSTIC_TEST

Laboratory tests (examination) to be performed include complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), liver function tests and kidney function tests; rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (anti-CCP antibody) and C-C Motif Chemokine Ligand 21 (CCL21).

Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index

Intervention Type DIAGNOSTIC_TEST

Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) This questionnaire is used to assess the health status of osteoarthritis patients introduced in 1988 (13). It is consisted of 33 items which evaluates the health and function of the patient from various aspects including: clinical symptoms (5 questions), severity of joint stiffness (2 questions), degree of pain (9 questions), and activity of daily living (17 questions).The test questions are scored on a scale of 0-4, which correspond to: None(0),Mild (1),Moderate (2),Severe(3),and Extreme (4).The scores for each subscale are summed up, with a possible score range of 0-20 for Pain, 0-8 for Stiffness, and 0-68 for Physical Function. Usually a sum of the scores for all three subscales gives a total WOMAC score, however there are other methods that have been used to combine scores.Higher scores on the WOMAC indicate worse pain, stiffness, and functional limitations.

Patient global assessment (PGA)

Intervention Type DIAGNOSTIC_TEST

Patient global assessment (PGA) of disease activity will be reported by patients. PGA was developed in the late 1970s and was initially designed for the measurement of self-assessed pain in RA \[8\], although it has since been used to evaluate RA more globally. It is interesting to note that the way PGA is used in clinical practice covers, in fact, two very different concepts, one related to global health and the other to overall disease activity. They are both usually used under the heading of PGA without further specification for which is being assessed.

Physician global assessment (PhGA)

Intervention Type DIAGNOSTIC_TEST

Physician global assessment (PhGA)of disease activity will be reported by the physician.The Physician Global Assessment (PhGA) of treatment response measures the overall response to treatment as assessed by the physician. The PhGA is a well accepted and commonly used scale for evaluating treatment response in clinical trials both in adults and children. PhGA is a simple instrument and the result is easily understood. However, assigning a score for PhGA requires a very detailed evaluation. To perform this assessment a physician/health care provider would use extensive data from every aspect of ICF.

Health Assessment Questionnaire (HAQ)

Intervention Type DIAGNOSTIC_TEST

Functional impairment will be assessed with the Health Assessment Questionnaire (HAQ). It is a self-assessment tool used to measure functional ability in eight different areas: rising, dressing and grooming, hygiene, eating, walking, reach, grip, and activities of independent living. Each item or question is rated on a scale of 0 to 3, with 0 (normal/no difficulty), 1 (some difficulty), 2 (much difficulty), and 3 (unable to do). The 8 category scores are averaged, which represent an overall score from 0 (no disability) to 3 (completely disabled). If the questionnaire is slightly changed to reflect a certain disease, this does not affect the respective scoring.Scores 0-1 indicates mild to moderate disability, 1-2 indicates moderate to severe disability, and 2-3 indicates severe to very severe disability.

Knee Radiography

Intervention Type DIAGNOSTIC_TEST

Knee osteoarthritis (gonarthrosis) will be evaluated using Kellgren-Lawrence (KL) staging on direct radiographs (anteroposterior and lateral views).Numerous variations of the Kellgren and Lawrence classification system have been used in research. Grade 0 (none): definite absence of x-ray changes of osteoarthritis. Grade 1 (doubtful): doubtful joint space narrowing and possible osteophytic lipping.Grade 2 (minimal): definite osteophytes and possible joint space narrowing. Grade 3 (moderate): moderate multiple osteophytes, definite narrowing of joint space, some sclerosis and possible deformity of bone ends Grade 4 (severe): large osteophytes, marked narrowing of joint space, severe sclerosis and definite deformity of bone ends. Osteoarthritis is deemed present at grade 2 although of minimal severity

Patients who were diagnosed with rheumatoid arthritis and applied to outpatient clinic

Patients diagnosed with rheumatoid arthritis (meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010 criteria

Laboratory tests (examination)

Intervention Type DIAGNOSTIC_TEST

Laboratory tests (examination) to be performed include complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), liver function tests and kidney function tests; rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (anti-CCP antibody) and C-C Motif Chemokine Ligand 21 (CCL21).

The Disease Activity Score28 (DAS28)

Intervention Type DIAGNOSTIC_TEST

The Disease Activity Score (DAS) was created as a numerical tool for quantifying and assessing disease activity in rheumatoid arthritis (RA).The DAS28 (Disease Activity Score using 28 joint counts) was developed from the original DAS (Disease Activity Score).The DAS28 evaluates the disease activity by assessing the number of tender and swollen joints in a patient. Specifically, it considers 28 joints. The DAS28 also takes into account a blood marker of inflammation, typically the erythrocyte sedimentation rate (ESR) or the C-reactive protein (CRP) level.A patient with a DAS28 score of less than 2.6 is in remission; a score greater than or equal to 2.6 and less than 3.1 indicates low activity; a score greater than or equal to 3.1 and \<5.1 indicates moderate activity and a score 5.1 or more indicates high activity

Patient global assessment (PGA)

Intervention Type DIAGNOSTIC_TEST

Patient global assessment (PGA) of disease activity will be reported by patients. PGA was developed in the late 1970s and was initially designed for the measurement of self-assessed pain in RA \[8\], although it has since been used to evaluate RA more globally. It is interesting to note that the way PGA is used in clinical practice covers, in fact, two very different concepts, one related to global health and the other to overall disease activity. They are both usually used under the heading of PGA without further specification for which is being assessed.

Physician global assessment (PhGA)

Intervention Type DIAGNOSTIC_TEST

Physician global assessment (PhGA)of disease activity will be reported by the physician.The Physician Global Assessment (PhGA) of treatment response measures the overall response to treatment as assessed by the physician. The PhGA is a well accepted and commonly used scale for evaluating treatment response in clinical trials both in adults and children. PhGA is a simple instrument and the result is easily understood. However, assigning a score for PhGA requires a very detailed evaluation. To perform this assessment a physician/health care provider would use extensive data from every aspect of ICF.

Health Assessment Questionnaire (HAQ)

Intervention Type DIAGNOSTIC_TEST

Functional impairment will be assessed with the Health Assessment Questionnaire (HAQ). It is a self-assessment tool used to measure functional ability in eight different areas: rising, dressing and grooming, hygiene, eating, walking, reach, grip, and activities of independent living. Each item or question is rated on a scale of 0 to 3, with 0 (normal/no difficulty), 1 (some difficulty), 2 (much difficulty), and 3 (unable to do). The 8 category scores are averaged, which represent an overall score from 0 (no disability) to 3 (completely disabled). If the questionnaire is slightly changed to reflect a certain disease, this does not affect the respective scoring.Scores 0-1 indicates mild to moderate disability, 1-2 indicates moderate to severe disability, and 2-3 indicates severe to very severe disability.

Clinical disease activity index (CDAI)

Intervention Type DIAGNOSTIC_TEST

Clinical Disease Activity Index (CDAI) is a composite index (without acute-phase reactant) for assessing disease activity. CDAI is based on the simple summation of the count of swollen/tender joint count of 28 joints along with patient and physician global assessment on VAS (0-10 cm) Scale for estimating disease activity. The CDAI has range from 0 to 76

The Simplified Disease Activity Index (SDAI)

Intervention Type DIAGNOSTIC_TEST

The Simplified Disease Activity Index for Rheumatoid Arthritis (SDAI) is a scoring system that has been validated in both research and clinical settings. It has been shown to have the highest sensitivity and specificity for predicting a physicians' decisions to change DMARD therapy when compared to other scores.Remission is defined as an SDAI of \<3.3, low disease activity as ≤11, moderate disease activity as ≤26 and high disease activity as \>26. Response to therapy is considered moderate if SDAI decreases by ≥7 and major if decreases by ≥17

Healthy volunteers

Healthy who were volunteers applied to the physical treatment and rehabilitation outpatient clinic

Laboratory tests (examination)

Intervention Type DIAGNOSTIC_TEST

Laboratory tests (examination) to be performed include complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), liver function tests and kidney function tests; rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (anti-CCP antibody) and C-C Motif Chemokine Ligand 21 (CCL21).

Health Assessment Questionnaire (HAQ)

Intervention Type DIAGNOSTIC_TEST

Functional impairment will be assessed with the Health Assessment Questionnaire (HAQ). It is a self-assessment tool used to measure functional ability in eight different areas: rising, dressing and grooming, hygiene, eating, walking, reach, grip, and activities of independent living. Each item or question is rated on a scale of 0 to 3, with 0 (normal/no difficulty), 1 (some difficulty), 2 (much difficulty), and 3 (unable to do). The 8 category scores are averaged, which represent an overall score from 0 (no disability) to 3 (completely disabled). If the questionnaire is slightly changed to reflect a certain disease, this does not affect the respective scoring.Scores 0-1 indicates mild to moderate disability, 1-2 indicates moderate to severe disability, and 2-3 indicates severe to very severe disability.

Interventions

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Laboratory tests (examination)

Laboratory tests (examination) to be performed include complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), liver function tests and kidney function tests; rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (anti-CCP antibody) and C-C Motif Chemokine Ligand 21 (CCL21).

Intervention Type DIAGNOSTIC_TEST

Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index

Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) This questionnaire is used to assess the health status of osteoarthritis patients introduced in 1988 (13). It is consisted of 33 items which evaluates the health and function of the patient from various aspects including: clinical symptoms (5 questions), severity of joint stiffness (2 questions), degree of pain (9 questions), and activity of daily living (17 questions).The test questions are scored on a scale of 0-4, which correspond to: None(0),Mild (1),Moderate (2),Severe(3),and Extreme (4).The scores for each subscale are summed up, with a possible score range of 0-20 for Pain, 0-8 for Stiffness, and 0-68 for Physical Function. Usually a sum of the scores for all three subscales gives a total WOMAC score, however there are other methods that have been used to combine scores.Higher scores on the WOMAC indicate worse pain, stiffness, and functional limitations.

Intervention Type DIAGNOSTIC_TEST

The Disease Activity Score28 (DAS28)

The Disease Activity Score (DAS) was created as a numerical tool for quantifying and assessing disease activity in rheumatoid arthritis (RA).The DAS28 (Disease Activity Score using 28 joint counts) was developed from the original DAS (Disease Activity Score).The DAS28 evaluates the disease activity by assessing the number of tender and swollen joints in a patient. Specifically, it considers 28 joints. The DAS28 also takes into account a blood marker of inflammation, typically the erythrocyte sedimentation rate (ESR) or the C-reactive protein (CRP) level.A patient with a DAS28 score of less than 2.6 is in remission; a score greater than or equal to 2.6 and less than 3.1 indicates low activity; a score greater than or equal to 3.1 and \<5.1 indicates moderate activity and a score 5.1 or more indicates high activity

Intervention Type DIAGNOSTIC_TEST

Patient global assessment (PGA)

Patient global assessment (PGA) of disease activity will be reported by patients. PGA was developed in the late 1970s and was initially designed for the measurement of self-assessed pain in RA \[8\], although it has since been used to evaluate RA more globally. It is interesting to note that the way PGA is used in clinical practice covers, in fact, two very different concepts, one related to global health and the other to overall disease activity. They are both usually used under the heading of PGA without further specification for which is being assessed.

Intervention Type DIAGNOSTIC_TEST

Physician global assessment (PhGA)

Physician global assessment (PhGA)of disease activity will be reported by the physician.The Physician Global Assessment (PhGA) of treatment response measures the overall response to treatment as assessed by the physician. The PhGA is a well accepted and commonly used scale for evaluating treatment response in clinical trials both in adults and children. PhGA is a simple instrument and the result is easily understood. However, assigning a score for PhGA requires a very detailed evaluation. To perform this assessment a physician/health care provider would use extensive data from every aspect of ICF.

Intervention Type DIAGNOSTIC_TEST

Health Assessment Questionnaire (HAQ)

Functional impairment will be assessed with the Health Assessment Questionnaire (HAQ). It is a self-assessment tool used to measure functional ability in eight different areas: rising, dressing and grooming, hygiene, eating, walking, reach, grip, and activities of independent living. Each item or question is rated on a scale of 0 to 3, with 0 (normal/no difficulty), 1 (some difficulty), 2 (much difficulty), and 3 (unable to do). The 8 category scores are averaged, which represent an overall score from 0 (no disability) to 3 (completely disabled). If the questionnaire is slightly changed to reflect a certain disease, this does not affect the respective scoring.Scores 0-1 indicates mild to moderate disability, 1-2 indicates moderate to severe disability, and 2-3 indicates severe to very severe disability.

Intervention Type DIAGNOSTIC_TEST

Clinical disease activity index (CDAI)

Clinical Disease Activity Index (CDAI) is a composite index (without acute-phase reactant) for assessing disease activity. CDAI is based on the simple summation of the count of swollen/tender joint count of 28 joints along with patient and physician global assessment on VAS (0-10 cm) Scale for estimating disease activity. The CDAI has range from 0 to 76

Intervention Type DIAGNOSTIC_TEST

The Simplified Disease Activity Index (SDAI)

The Simplified Disease Activity Index for Rheumatoid Arthritis (SDAI) is a scoring system that has been validated in both research and clinical settings. It has been shown to have the highest sensitivity and specificity for predicting a physicians' decisions to change DMARD therapy when compared to other scores.Remission is defined as an SDAI of \<3.3, low disease activity as ≤11, moderate disease activity as ≤26 and high disease activity as \>26. Response to therapy is considered moderate if SDAI decreases by ≥7 and major if decreases by ≥17

Intervention Type DIAGNOSTIC_TEST

Knee Radiography

Knee osteoarthritis (gonarthrosis) will be evaluated using Kellgren-Lawrence (KL) staging on direct radiographs (anteroposterior and lateral views).Numerous variations of the Kellgren and Lawrence classification system have been used in research. Grade 0 (none): definite absence of x-ray changes of osteoarthritis. Grade 1 (doubtful): doubtful joint space narrowing and possible osteophytic lipping.Grade 2 (minimal): definite osteophytes and possible joint space narrowing. Grade 3 (moderate): moderate multiple osteophytes, definite narrowing of joint space, some sclerosis and possible deformity of bone ends Grade 4 (severe): large osteophytes, marked narrowing of joint space, severe sclerosis and definite deformity of bone ends. Osteoarthritis is deemed present at grade 2 although of minimal severity

Intervention Type DIAGNOSTIC_TEST

Eligibility Criteria

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Inclusion Criteria

* 20 RA patients, 20 Osteoarthritis patients and 20 healthy volunteers between the ages of 16-60.

Exclusion Criteria

* Age \< 16 years,
* Systemic Disorders (Diabetes, Hematological diseases (coagulopathies), serious cardiovascular diseases, chronic liver and kidney disease or malignancy.)
* Patients suffering from infectious disorders (septic arthritis, viral arthritis, fungal arthritis and other rheumatic diseases such as spondyloarthropathies, systemic lupus erythematosus or dermatomyositis and others.)
* Individuals with other autoimmune diseases, malignancy, cardiac or neurological deficits, end-stage organ failure and other conditions that may affect the serum level of CCL21, such as diabetes mellitus, concomitant inflammatory disease (acute infection or chronic inflammatory state), coronary artery disease and hepatitis, were excluded from the study. was left
* Lymphadenopathies
* OA patients who received intra-articular injection or systemic glucocorticoid therapy within 3 months were excluded from the study.
Minimum Eligible Age

16 Years

Maximum Eligible Age

60 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Gaziosmanpasa Research and Education Hospital

OTHER_GOV

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Ismail Dag

Role: STUDY_CHAIR

Eyup Sultan State Hospital

Central Contacts

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Deniz Oke, MD

Role: CONTACT

+90 532 430 69 50

Meryem Guneser Gulec, MD

Role: CONTACT

+90 530 567 88 32

References

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Li G, Zhao J, Li B, Ma J, Zhao Q, Wang X, Lv Z, Li K, Du Z, Ma X, Liu J. Associations between CCL21 gene polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. Rheumatol Int. 2017 Oct;37(10):1673-1681. doi: 10.1007/s00296-017-3784-4. Epub 2017 Aug 10.

Reference Type RESULT
PMID: 28799100 (View on PubMed)

Van Raemdonck K, Umar S, Palasiewicz K, Volkov S, Volin MV, Arami S, Chang HJ, Zanotti B, Sweiss N, Shahrara S. CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in rheumatoid arthritis. Cell Mol Life Sci. 2020 Apr;77(7):1387-1399. doi: 10.1007/s00018-019-03235-w. Epub 2019 Jul 24.

Reference Type RESULT
PMID: 31342120 (View on PubMed)

Other Identifiers

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450

Identifier Type: -

Identifier Source: org_study_id

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