Arthritis, Rheumatoid
Conditions
Brief summary
To investigate whether a short term discontinuation of methotrexate (MTX) will improve the vaccination efficacy to seasonal influenza vaccination without deteriorating RA disease activity in a randomized clinical trial.
Detailed description
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that affects the joints as the main target of the inflammation. Patients with RA require chronic treatment with disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX), which constitutes the mainstay of treatment. Underlying immune dysfunction and the additional immune suppression associated with treatment render patients with RA more susceptible to infection. Thus, vaccination against preventable diseases including influenza, pneumococcal pneumonia and hepatitis B is recommended for all RA patients who are subject to treatment with immunesupprssive drugs, unless there is a contraindication to the use of vaccination. However, low dose of glucocorticoids, conventional DMARDs and biological DMARDs including tumor necrosis factor inhibitors have been reported to substantially decrease vaccine response (4); MTX has been reported to be associated with a decreased response to seasonal influenza vaccination by up to 15%. To optimize a vaccine response, vaccination should be administrated before the treatment with immunesuppressive medications is initiated. However, most patients with RA are already on stable dose of DMARDs at the time of when vaccinations, especially vaccine against seasonal influenza that needs annual administration, are considered. Alternatively, temporarily discontinuation of DMARDs might restore normal immune response to and so improve the efficacy of vaccination. Although a short term discontinuation of DMARDs during perioperative period has not been associated with increased disease activity the longer discontinuation of DMARDs might lead to a significant aggravation of RA disease activity. To optimize the vaccine response, a short term discontinuation of DMARDs could be considered if this approach proves to be safe and effective.
Interventions
DRUGMethotrexate
Methotrexate will be continued
BIOLOGICALSeasonal Influenza vaccine
all subjects will be vaccinated with a seasonal influenza vaccine
Sponsors
Seoul National University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females \> 18 years at time of consent * Have a diagnosis of RA per ACR criteria * Must understand and voluntarily sign an informed consent form including writing consent for data protection * Stable doses of methotrexate over the preceding 6 weeks
Exclusion criteria
* Pregnant or lactating females * Previous anaphylactic response to vaccine components or to egg. * Acute infection with T \>38°C at the time of vaccination * History of Guillain-Barre syndrome or demyelinating syndromes * Previous vaccination with any live vaccine 4 weeks before or any inactivated vaccine 2 weeks before the study * Blood transfusion within 6 months * Active rheumatoid arthritis necessitating a recent change in the drug regimen * Any other rheumatic disease such as systemic lupus erythematosus, mixed connective tissue disease, dermatomyositis/polymyositis, and vasculitis except for secondary Sjogren's disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Satisfactory Vaccination Responses Against 3 Antigens | 8 weeks | Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers |
| Satisfactory Vaccination Responses Against > 2/3 Antigens | 8 weeks | Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers |
| Satisfactory Vaccination Responses Against > 1/3 Antigens | 8 weeks | Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Antibody Titer Against H1N1 | Day of and 4 weeks after vaccination | Fold change = post-vaccination titer/pre-vaccination titer |
| Change From Baseline in Antibody Titer Against H3N2 | Day of and 4 weeks after vaccination | Fold change = post-vaccination titer/pre-vaccination titer |
| Proportion of Seroprotection Against H1N1 | 8 weeks | Seroprotection is defined as antibody titers of ≥40 |
| DAS28 Flare Rate at Visit 4 | 20 weeks from enrollment. | DAS28 flare rate at visit 4 as compared to visit 1. RA flare was defined as an increase in DAS28 of \>1.2 (or \>0.6 if the baseline DAS28 was ≥3.2). |
| Change From Baseline in Antibody Titer Against B-Yamagata | Day of and 4 weeks after vaccination | Fold change = post-vaccination titer/pre-vaccination titer |
| Proportion of Seroprotection Against H3N2 | 8 weeks | Seroprotection is defined as antibody titers of ≥40 |
| Proportion of Seroprotection Against B-Yamagata | 8 weeks | Seroprotection is defined as antibody titers of ≥40 |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Group 1 will continue MTX
Methotrexate: Methotrexate will be continued
Seasonal Influenza vaccine: all subjects will be vaccinated with a seasonal influenza vaccine | 54 |
| Group 2 Group 2 will hold MTX 4 weeks before vaccination and resume MTX on the day of vaccination
Methotrexate: Methotrexate will be continued
Seasonal Influenza vaccine: all subjects will be vaccinated with a seasonal influenza vaccine | 44 |
| Group 3 Group 3 will hold MTX 2 weeks before vaccination and resume MTX 2 weeks after vaccination
Methotrexate: Methotrexate will be continued
Seasonal Influenza vaccine: all subjects will be vaccinated with a seasonal influenza vaccine | 49 |
| Group 4 Group 4 will hold MTX on day of vaccination and resume MTX 4 weeks after vaccination.
Methotrexate: Methotrexate will be continued
Seasonal Influenza vaccine: all subjects will be vaccinated with a seasonal influenza vaccine | 52 |
| Total | 199 |
Baseline characteristics
| Characteristic | Group 1 | Group 2 | Group 3 | Group 4 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 59.1 years STANDARD_DEVIATION 13.1 | 58.5 years STANDARD_DEVIATION 113.3 | 58.1 years STANDARD_DEVIATION 10.9 | 58.1 years STANDARD_DEVIATION 11.7 | 58.5 years STANDARD_DEVIATION 11.7 |
| Disease Activity Score (DAS)-28 | 2.5 units on a scale (0-10) STANDARD_DEVIATION 1.1 | 2.8 units on a scale (0-10) STANDARD_DEVIATION 1.2 | 2.6 units on a scale (0-10) STANDARD_DEVIATION 1 | 2.6 units on a scale (0-10) STANDARD_DEVIATION 1 | 2.6 units on a scale (0-10) STANDARD_DEVIATION 1.1 |
| Disease duration | 5.2 years STANDARD_DEVIATION 4.5 | 6.1 years STANDARD_DEVIATION 4.9 | 4.9 years STANDARD_DEVIATION 4.4 | 6.2 years STANDARD_DEVIATION 5.5 | 6.2 years STANDARD_DEVIATION 5.5 |
| Sex: Female, Male Female | 45 Participants | 39 Participants | 42 Participants | 43 Participants | 169 Participants |
| Sex: Female, Male Male | 9 Participants | 5 Participants | 7 Participants | 9 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 33 / 54 | 23 / 44 | 23 / 49 | 17 / 52 |
| serious Total, serious adverse events | 0 / 54 | 2 / 44 | 0 / 49 | 0 / 52 |
Outcome results
Primary
Satisfactory Vaccination Responses Against > 1/3 Antigens
Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers
Time frame: 8 weeks
Population: Per Protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Satisfactory Vaccination Responses Against > 1/3 Antigens | 77.8 percentage of responders |
| Group 2 | Satisfactory Vaccination Responses Against > 1/3 Antigens | 81.8 percentage of responders |
| Group 3 | Satisfactory Vaccination Responses Against > 1/3 Antigens | 87.8 percentage of responders |
| Group 4 | Satisfactory Vaccination Responses Against > 1/3 Antigens | 88.5 percentage of responders |
Primary
Satisfactory Vaccination Responses Against > 2/3 Antigens
Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers
Time frame: 8 weeks
Population: Per Protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Satisfactory Vaccination Responses Against > 2/3 Antigens | 53.7 percentage of responders |
| Group 2 | Satisfactory Vaccination Responses Against > 2/3 Antigens | 52.3 percentage of responders |
| Group 3 | Satisfactory Vaccination Responses Against > 2/3 Antigens | 71.4 percentage of responders |
| Group 4 | Satisfactory Vaccination Responses Against > 2/3 Antigens | 65.4 percentage of responders |
Primary
Satisfactory Vaccination Responses Against 3 Antigens
Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers
Time frame: 8 weeks
Population: Per Protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Satisfactory Vaccination Responses Against 3 Antigens | 31.5 percentage of responders |
| Group 2 | Satisfactory Vaccination Responses Against 3 Antigens | 22.7 percentage of responders |
| Group 3 | Satisfactory Vaccination Responses Against 3 Antigens | 51 percentage of responders |
| Group 4 | Satisfactory Vaccination Responses Against 3 Antigens | 46.2 percentage of responders |
Secondary
Change From Baseline in Antibody Titer Against B-Yamagata
Fold change = post-vaccination titer/pre-vaccination titer
Time frame: Day of and 4 weeks after vaccination
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Group 1 | Change From Baseline in Antibody Titer Against B-Yamagata | 2.9 Fold change |
| Group 2 | Change From Baseline in Antibody Titer Against B-Yamagata | 2.8 Fold change |
| Group 3 | Change From Baseline in Antibody Titer Against B-Yamagata | 4.7 Fold change |
| Group 4 | Change From Baseline in Antibody Titer Against B-Yamagata | 6.1 Fold change |
Secondary
Change From Baseline in Antibody Titer Against H1N1
Fold change = post-vaccination titer/pre-vaccination titer
Time frame: Day of and 4 weeks after vaccination
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Group 1 | Change From Baseline in Antibody Titer Against H1N1 | 5.1 Fold change |
| Group 2 | Change From Baseline in Antibody Titer Against H1N1 | 5.0 Fold change |
| Group 3 | Change From Baseline in Antibody Titer Against H1N1 | 8.7 Fold change |
| Group 4 | Change From Baseline in Antibody Titer Against H1N1 | 8.1 Fold change |
Secondary
Change From Baseline in Antibody Titer Against H3N2
Fold change = post-vaccination titer/pre-vaccination titer
Time frame: Day of and 4 weeks after vaccination
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Group 1 | Change From Baseline in Antibody Titer Against H3N2 | 5.9 Fold change |
| Group 2 | Change From Baseline in Antibody Titer Against H3N2 | 6.1 Fold change |
| Group 3 | Change From Baseline in Antibody Titer Against H3N2 | 12.2 Fold change |
| Group 4 | Change From Baseline in Antibody Titer Against H3N2 | 10.0 Fold change |
Secondary
DAS28 Flare Rate at Visit 4
DAS28 flare rate at visit 4 as compared to visit 1. RA flare was defined as an increase in DAS28 of \>1.2 (or \>0.6 if the baseline DAS28 was ≥3.2).
Time frame: 20 weeks from enrollment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | DAS28 Flare Rate at Visit 4 | 7.5 percentage of flare patients |
| Group 2 | DAS28 Flare Rate at Visit 4 | 14.0 percentage of flare patients |
| Group 3 | DAS28 Flare Rate at Visit 4 | 19.1 percentage of flare patients |
| Group 4 | DAS28 Flare Rate at Visit 4 | 12.0 percentage of flare patients |
Secondary
Proportion of Seroprotection Against B-Yamagata
Seroprotection is defined as antibody titers of ≥40
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Proportion of Seroprotection Against B-Yamagata | 72 percentage of patients w/ seroprotection |
| Group 2 | Proportion of Seroprotection Against B-Yamagata | 71 percentage of patients w/ seroprotection |
| Group 3 | Proportion of Seroprotection Against B-Yamagata | 94 percentage of patients w/ seroprotection |
| Group 4 | Proportion of Seroprotection Against B-Yamagata | 81 percentage of patients w/ seroprotection |
Secondary
Proportion of Seroprotection Against H1N1
Seroprotection is defined as antibody titers of ≥40
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Proportion of Seroprotection Against H1N1 | 74 percentage of patients |
| Group 2 | Proportion of Seroprotection Against H1N1 | 86 percentage of patients |
| Group 3 | Proportion of Seroprotection Against H1N1 | 96 percentage of patients |
| Group 4 | Proportion of Seroprotection Against H1N1 | 86 percentage of patients |
Secondary
Proportion of Seroprotection Against H3N2
Seroprotection is defined as antibody titers of ≥40
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Proportion of Seroprotection Against H3N2 | 100 percentage of patients w/ seroprotection |
| Group 2 | Proportion of Seroprotection Against H3N2 | 96 percentage of patients w/ seroprotection |
| Group 3 | Proportion of Seroprotection Against H3N2 | 98 percentage of patients w/ seroprotection |
| Group 4 | Proportion of Seroprotection Against H3N2 | 96 percentage of patients w/ seroprotection |