Clinical Follow-up of Anti-Carbamylated Antibody Status in Rheumatoid Arthritis

Sponsor
Universidad Autonoma de Nuevo Leon (Other)
Overall Status
Completed
CT.gov ID
NCT02958319
Collaborator
(none)
278
1
29.8
9.3

Study Details

Study Description

Brief Summary

Patients with rheumatoid arthritis (RA) with positive antibodies against carbamylated proteins (anti-CarP) have a more severe clinical course. The primary objective of this study in adult subject with RA is as follows: To explore the clinical differences in activity indexes (Disease Activity Score of 28 joints with Erythro Sedimentaion Rate (DAS28-ESR)) at 6, 12 and 18 months of follow up according the anti-CarP antibodies status.

Condition or Disease Intervention/Treatment Phase

    Detailed Description

    Clinical follow-up of Anti-Carbamylated Antibody Status in Rheumatoid Arthritis patients at 6, 12 and 18 months.

    Concept

    Patients with rheumatoid arthritis (RA) with positive antibodies against carbamylated proteins (anti-CarP) have a more severe clinical course.

    Background

    The immune based pathophysiology of RA is one of the most studied. We already know that the citrullinated peptide antigen inducing antibody formation and subsequent anti-cyclic citrullinated peptide (anti-CCP) antibodies. In some patients can explain the clinical manifestations. However it is also apparent that some groups of patients with rheumatoid arthritis who do not have anti-CCP antibodies. It is possible then the presence of a variety of antigens exposed during the disease, and perhaps different clinical presentations associated with each.

    The use of anti-CCP antibodies has been included in the classification criteria of RA developed by the American College of Rheumatology (ACR) in 2010 and generated the presence of two sub-groups of patients with RA, the positive and negative for anti-CCP. It is very important to study the presence of anti-CCP antibodies in RA population because it influences the clinical behavior and response to treatment. In very early or undifferentiated arthritis, the presence of anti-CCP antibodies can predict the presence of erosions in the course of the disease. On the other hand, patients with negative anti-CCP antibodies tend to have better responses to treatment with methotrexate.

    Initially it was thought that the obvious pathophysiological link between RA and citrullinated peptides leading to formation of antibodies was the apparent cause of the clinical manifestations, but soon it was demonstrated that there were groups of patients with clinical manifestations of RA that did not had anti-CCP antibodies so its genesis was not explained by citrullination. Then it is possible a diversity of antigens exposed during the illness and perhaps different clinical presentations associated with each one or its combinations. So actually, some studies are attempting to show other possible antigens involved in RA and one of them uses homocitrulline as an antigenic basis to RA pathophysiology. The carbamylation or homocitrullination is a posttranslational modification of proteins that occurs when the amino acid lysine reacts with cyanate in a non-enzyme-mediated process generating homocitrulline. Mydel, Bokarewa and cols. demonstrated that immunization of mice with homocitrulline- and citrulline-containing peptides leads to development of erosive arthritis following intra-articular injection of homocitrulline-containing peptides and proposed that homocitrulline induced activation of T cells is a key mechanism in the pathogenesis of autoimmune arthritis as it serves as an initial triggering event for neo-epitope recognition of citrulline containing peptides. Recently It has been shown that rheumatoid arthritis patients has homocitrullinated proteins in his joints which can trigger an inflammatory response with formation of antibodies against homocitrulline.

    Shi et al. showed in a study of 571 RA patients and 350 healthy subjects the following statements:

    • The anti-carbamylated peptide (Anti-CarP) antibodies are different from Anti-CCP antibodies and they do not cross-react.

    • The Anti-CarP antibodies are present in sera of patients with RA.

    • Anti-CarP antibodies are found in sera of patients without anti-CCP.

    • The Anti-CarP antibodies are associated with increased progression to radiographic damage.

    Thus, autoantibodies recognizing anti-CarP are a promising new serological marker for anti CCP antibodies negative RA and are associated with a more severe clinical course.

    Hypothesis

    Patients with RA with positive antibodies against anti-CarP have a more severe clinical course and elevated cardiovascular risk.

    Design

    It is a parallel study for clinical follow-up , observational.

    Description of Subject Population(s)

    • Patients older than 18 years old, both gender, with RA diagnosis according to ACR European Leage Against Rheumatism (EULAR) 2010 classification that accepted and signed informed consent that were seen at the Rheumatology Clinic in Hospital Universitario "Dr. José Eleuterio González", Monterrey, NL. México.

    • Exclusion: Chronic kidney disease and pregnant patients Assessment Tools and Procedures

    • DAS-28 ESR

    • Lipid profile Length of Study in Months

    • 18 Primary Endpoints

    • Clinical activity measured by DAS28-ESR in patients with RA according to antibodies against anti-CarP status at 6, 12 and 18 months Secondary Endpoints

    • Number and accumulative dose of Disease Modifying Anti-Rheumatic Drugs (DMARD) according to antibodies against anti-CarP status at 6, 12 and 18 months

    • Cardiovascular risk according to antibodies against anti-CarP status at 6, 12 and 18 months Clinical Information

    • Total number of subjects 262

    • Number of subjects for each treatment arm 131

    • Study Duration Per Patient (in Months) 18

    Primary Objective

    The primary objective of this study in adult subject with RA is as follows:
    1. To explore the clinical differences in activity indexes (DAS28-ESR) at 6, 12 and 18 months of follow up according the anti-CarP antibody status

    Study Secondary Objective(s)

    One secondary objective is as follows:
    • To investigate the remission rate (DAS28-ESR) according the anti-CarP antibody status

    • Other secondary objectives are as follows:

    • To compare the percentage of subjects with DAS28-ESR Low Disease Activity (LDA) at 6, 12 and 18 months according the anti-CarP antibody status

    • To compare the accumulative dose of prednisone between groups according the anti-CarP antibody status

    • To compare the number and doses of DMARD´s used to treat RA between groups according the ant CarP antibody status

    Study Design

    • Prospective, Non-Randomized, Open Label

    • Inception Cohort Study

    Study Primary Efficacy Endpoints

    The primary efficacy endpoitns is as follows:
    • The percentage of subjects who meet DAS28-ESR < 2.6 at 6, 12 and 18 months in the Anti CarP positive antibody arm compared Anti CarP negative antibody arm

    Study Secondary Efficacy Endpoints

    The secondary efficacy endpoints are as follows:
    • Percentage of subjects with DAS28-ESR LDA at 6, 12 and 18 months at 6, 12 and 18 months in the Anti CarP positive antibody arm compared Anti CarP negative antibody arm

    • Median of the accumulative dose of prednisone at 18 months at 6, 12 and 18 months in the Anti CarP positive antibody arm compared Anti CarP negative antibody arm

    • Mean of the number and doses of DMARD´s used to treat RA at enrollment at 6, 12 and 18 months in the Anti CarP positive antibody arm compared Anti CarP negative antibody arm

    • Cardiovascular risk according to anti-CarP antibody status

    Study Sample Size Calculation

    A total of 262 subjects will be followed in this study. According the pilot study it was found a 12 month remission rate in the Anti CarP positive antibody of 33% arm compared Anti CarP negative antibody arm of 50%, with a difference of 17% in remission rate at 12 month follow-up. One hundred and thirty-three patients are needed per group. A 2 group continuity corrected chi square test with a 2-sided significance level (alpha) of 0.05 was used to compare sample size and a 0.2 (beta) to power.

    Study Statistical Methods

    Descriptive statistic for categorical and numerical variables will be used. Categorical variables will be expressed in frequency and percentage; comparisons will be done by chi square test. Numerical variables, after normality test we will describe them as mean and median with standard deviation (SD) and interquartile range (IQR) as corresponds, respectively.

    For the primary end point, chi square test the percentage of DAS28-ESR remission by group will be compared.

    For the secondary end points we will compared by t test or Mann Whitnney U the mean o median of the accumulative dose of prednisone and number of DMARD used.

    Study Design

    Study Type:
    Observational
    Actual Enrollment :
    278 participants
    Observational Model:
    Cohort
    Time Perspective:
    Prospective
    Official Title:
    Clinical Follow-up of Anti-Carbamylated Antibody Status in Rheumatoid Arthritis Patients at 6, 12 and 18 Months
    Study Start Date :
    Jun 1, 2016
    Actual Primary Completion Date :
    Nov 26, 2018
    Actual Study Completion Date :
    Nov 26, 2018

    Arms and Interventions

    Arm Intervention/Treatment
    Anti P Carb negative RA patients

    RA patients negative for antibodies against the carbamylated proteins

    Anti P Carb positive RA patients

    RA patients positive for antibodies against the carbamylated proteins

    Outcome Measures

    Primary Outcome Measures

    1. DAS28-ESR [6, 12 and 18 Months]

      To explore the clinical differences in activity indexes (DAS28-ESR) at 6, 12 and 18 months of follow-up according the anti-CarP status. The DAS28 is a composite score derived from 4 measures, one of them can be the erythrocyte sedimentation rate (ESR). We will be using the DAS28-ESR version. To calculate the DAS28-ESR the rheumatologist or specialist nurse will:- count the number of swollen joints (out of the 28), count the number of tender joints (out of the 28), take blood to measure ESR, ask participants to make a 'global assessment of health' (indicated by marking a 10 cm line between very good and very bad). DAS28-ESR is calculated with classic calculators and resulting values are interpreted as follows: <2.6: disease remission 2.6 - 3.2: low disease activity 3.2 - 5.1: moderate disease activity >5.1: high disease activity

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Rheumatoid arthritis patients according to ACR EULAR 2010 classification that accepted and signed informed consent
    Exclusion Criteria:
    • Chronic kidney disease and pregnant patients

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Servicio de Reumatología, Departamento de Medicina Interna, Facultad de Medicina y Hospital Universitario, Universidad Autonoma de Nuevo León Monterrey Nuevo León Mexico 64460

    Sponsors and Collaborators

    • Universidad Autonoma de Nuevo Leon

    Investigators

    • Study Chair: Jose Gerardo Garza Leal, PhD, Universidad Autónoma de Nuevo León

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    David Vega Morales, MD, MsSc, Doctorate, Universidad Autonoma de Nuevo Leon
    ClinicalTrials.gov Identifier:
    NCT02958319
    Other Study ID Numbers:
    • RE16-00001
    First Posted:
    Nov 8, 2016
    Last Update Posted:
    Jan 4, 2022
    Last Verified:
    Dec 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail 278 patients were recruited in the study because they fullfilled the four follow-up visits in a retrospective/prospective manner after the informed consent signature and blood sample collection. After antibody analysis, 145 patients were found to be anti-CarP negative and 133 to be anti-CarP positive.
    Arm/Group Title Anti P Carb Negative RA Patients Anti P Carb Positive RA Patients
    Arm/Group Description RA patients negative for antibodies against the carbamylated proteins RA patients positive for antibodies against the carbamylated proteins
    Period Title: Overall Study
    STARTED 145 133
    COMPLETED 145 133
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title Anti P Carb Negative RA Patients Anti P Carb Positive RA Patients Total
    Arm/Group Description RA patients negative for antibodies against the carbamylated proteins RA patients positive for antibodies against the carbamylated proteins Total of all reporting groups
    Overall Participants 145 133 278
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    49.5
    (11.4)
    55.8
    (10.64)
    51.09
    (11.13)
    Sex: Female, Male (Count of Participants)
    Female
    135
    93.1%
    119
    89.5%
    254
    91.4%
    Male
    10
    6.9%
    14
    10.5%
    24
    8.6%
    Race and Ethnicity Not Collected (Count of Participants)
    Count of Participants [Participants]
    0
    0%
    Region of Enrollment (participants) [Number]
    Mexico
    145
    100%
    133
    100%
    278
    100%
    SMOKE (Count of Participants)
    Count of Participants [Participants]
    55
    37.9%
    59
    44.4%
    114
    41%
    DIABETES MELLITUS (Count of Participants)
    Count of Participants [Participants]
    17
    11.7%
    21
    15.8%
    38
    13.7%
    CARDIOVASCULAR HISTORY (Count of Participants)
    Count of Participants [Participants]
    6
    4.1%
    3
    2.3%
    9
    3.2%
    HYPERTENSION (Count of Participants)
    Count of Participants [Participants]
    27
    18.6%
    26
    19.5%
    53
    19.1%
    HYPOTHYROIDSM (Count of Participants)
    Count of Participants [Participants]
    11
    7.6%
    9
    6.8%
    20
    7.2%
    OSTHEOARTHRITIS (Count of Participants)
    Count of Participants [Participants]
    4
    2.8%
    4
    3%
    8
    2.9%
    FIBROMYALGIA (Count of Participants)
    Count of Participants [Participants]
    3
    2.1%
    1
    0.8%
    4
    1.4%
    DEPRESSION (Count of Participants)
    Count of Participants [Participants]
    2
    1.4%
    2
    1.5%
    4
    1.4%

    Outcome Measures

    1. Primary Outcome
    Title DAS28-ESR
    Description To explore the clinical differences in activity indexes (DAS28-ESR) at 6, 12 and 18 months of follow-up according the anti-CarP status. The DAS28 is a composite score derived from 4 measures, one of them can be the erythrocyte sedimentation rate (ESR). We will be using the DAS28-ESR version. To calculate the DAS28-ESR the rheumatologist or specialist nurse will:- count the number of swollen joints (out of the 28), count the number of tender joints (out of the 28), take blood to measure ESR, ask participants to make a 'global assessment of health' (indicated by marking a 10 cm line between very good and very bad). DAS28-ESR is calculated with classic calculators and resulting values are interpreted as follows: <2.6: disease remission 2.6 - 3.2: low disease activity 3.2 - 5.1: moderate disease activity >5.1: high disease activity
    Time Frame 6, 12 and 18 Months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Anti P Carb Negative RA Patients Anti P Carb Positive RA Patients
    Arm/Group Description RA patients negative for antibodies against the carbamylated proteins RA patients positive for antibodies against the carbamylated proteins
    Measure Participants 145 133
    6 MONTHS
    3.75
    (1.31)
    3.72
    (1.3)
    12 MONTHS
    3.59
    (1.46)
    3.69
    (1.28)
    18 MONTHS
    3.65
    (1.35)
    3.77
    (1.32)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Anti P Carb Negative RA Patients, Anti P Carb Positive RA Patients
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.82
    Comments p < 0.05 was considered statistically significant
    Method GENERAL LINEAL MODEL
    Comments GENERAL LINEAL MODEL OF REPEATED MEASURES
    Method of Estimation Estimation Parameter Median Difference (Final Values)
    Estimated Value 4.1
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame 18 MONTHS
    Adverse Event Reporting Description
    Arm/Group Title Anti P Carb Negative RA Patients Anti P Carb Positive RA Patients
    Arm/Group Description RA patients negative for antibodies against the carbamylated proteins RA patients positive for antibodies against the carbamylated proteins
    All Cause Mortality
    Anti P Carb Negative RA Patients Anti P Carb Positive RA Patients
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/145 (0%) 0/133 (0%)
    Serious Adverse Events
    Anti P Carb Negative RA Patients Anti P Carb Positive RA Patients
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/145 (0%) 0/133 (0%)
    Other (Not Including Serious) Adverse Events
    Anti P Carb Negative RA Patients Anti P Carb Positive RA Patients
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/145 (0%) 0/133 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title David Vega-Morales MD
    Organization Servicio de Reumatología del Hospital Universitario
    Phone 52 81 80485210
    Email drdavidvega@yahoo.com.mx
    Responsible Party:
    David Vega Morales, MD, MsSc, Doctorate, Universidad Autonoma de Nuevo Leon
    ClinicalTrials.gov Identifier:
    NCT02958319
    Other Study ID Numbers:
    • RE16-00001
    First Posted:
    Nov 8, 2016
    Last Update Posted:
    Jan 4, 2022
    Last Verified:
    Dec 1, 2021