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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group 1 (No MTX Hold before Vaccination) | Experimental | Group 1 will continue MTX |
|
| Group 2 (MTX hold 4 Weeks before vaccination) | Experimental | Group 2 will hold MTX 4 weeks before vaccination and resume MTX on the day of vaccination |
|
| Group 3 (MTX hold 2 Weeks before Vaccination) | Experimental | Group 3 will hold MTX 2 weeks before vaccination and resume MTX 2 weeks after vaccination |
|
| Group 4 (MTX hold on Day of Vaccination) | Experimental | Group 4 will hold MTX on day of vaccination and resume MTX 4 weeks after vaccination. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methotrexate | Drug | Methotrexate will be continued |
|
| Measure | Description | Time Frame |
|---|---|---|
| Satisfactory Vaccination Responses Against 3 Antigens | Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers | 8 weeks |
| Satisfactory Vaccination Responses Against > 2/3 Antigens | Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers | 8 weeks |
| Satisfactory Vaccination Responses Against > 1/3 Antigens | Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers | 8 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of Seroprotection Against H1N1 | Seroprotection is defined as antibody titers of ≥40 | 8 weeks |
| Proportion of Seroprotection Against H3N2 | Seroprotection is defined as antibody titers of ≥40 |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Seoul National University Hospital | Seoul | 110-744 | South Korea |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 12355475 | Background | Doran MF, Crowson CS, Pond GR, O'Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum. 2002 Sep;46(9):2287-93. doi: 10.1002/art.10524. | |
| 25587634 | Background | McMahan ZH, Bingham CO 3rd. Effects of biological and non-biological immunomodulatory therapies on the immunogenicity of vaccines in patients with rheumatic diseases. Arthritis Res Ther. 2014 Dec 23;16(6):506. doi: 10.1186/s13075-014-0506-0. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | 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 |
| FG002 | 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 |
| FG003 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Visit 1- Visit 2 |
| |||||||||||||
| Visit 2-Visit 3 |
| |||||||||||||
| Visit 3- Visit 4 |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | Group 2 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Satisfactory Vaccination Responses Against 3 Antigens | Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers | Per Protocol | Posted | Number | percentage of responders | 8 weeks |
|
At each visit
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lung cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Upper respiratory infection | Infections and infestations | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Eun Bong Lee | Seoul National University Hospital | +82-2-2072-4399 | leb7616@snu.ac.kr |
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| ID | Term |
|---|---|
| D001172 | Arthritis, Rheumatoid |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
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| ID | Term |
|---|---|
| D008727 | Methotrexate |
| ID | Term |
|---|---|
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
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| Seasonal Influenza vaccine | Biological | all subjects will be vaccinated with a seasonal influenza vaccine |
|
| 8 weeks |
| Proportion of Seroprotection Against B-Yamagata | Seroprotection is defined as antibody titers of ≥40 | 8 weeks |
| Change From Baseline in Antibody Titer Against H1N1 | Fold change = post-vaccination titer/pre-vaccination titer | Day of and 4 weeks after vaccination |
| Change From Baseline in Antibody Titer Against H3N2 | Fold change = post-vaccination titer/pre-vaccination titer | Day of and 4 weeks after vaccination |
| Change From Baseline in Antibody Titer Against B-Yamagata | Fold change = post-vaccination titer/pre-vaccination titer | Day of and 4 weeks after vaccination |
| 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). | 20 weeks from enrollment. |
| 25795907 | Background | Winthrop KL, Silverfield J, Racewicz A, Neal J, Lee EB, Hrycaj P, Gomez-Reino J, Soma K, Mebus C, Wilkinson B, Hodge J, Fan H, Wang T, Bingham CO 3rd. The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis. Ann Rheum Dis. 2016 Apr;75(4):687-95. doi: 10.1136/annrheumdis-2014-207191. Epub 2015 Mar 20. |
| 28468794 | Derived | Park JK, Lee MA, Lee EY, Song YW, Choi Y, Winthrop KL, Lee EB. Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial. Ann Rheum Dis. 2017 Sep;76(9):1559-1565. doi: 10.1136/annrheumdis-2017-211128. Epub 2017 May 3. |
| COMPLETED |
|
| NOT COMPLETED |
|
| COMPLETED |
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| NOT COMPLETED |
|
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
| BG002 | 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 |
| BG003 | 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 |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Disease duration | Mean | Standard Deviation | years |
|
| Disease Activity Score (DAS)-28 | The Disease Activity Score (DAS) is a combined index to measure the disease activity in patients with Rheumatoid Arthritis (RA). The DAS will provide a number between 0 and 10, indicating how active the rheumatoid arthritis is at this moment, whereas a higher values represent a worse disease activity. 0.. minimum score 10..maximum score | Mean | Standard Deviation | units on a scale (0-10) |
|
| OG002 | 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 |
| OG003 | 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 |
|
|
| Secondary | Proportion of Seroprotection Against H1N1 | Seroprotection is defined as antibody titers of ≥40 | Posted | Number | percentage of patients | 8 weeks |
|
|
|
| Secondary | Proportion of Seroprotection Against H3N2 | Seroprotection is defined as antibody titers of ≥40 | Posted | Number | percentage of patients w/ seroprotection | 8 weeks |
|
|
|
| Secondary | Proportion of Seroprotection Against B-Yamagata | Seroprotection is defined as antibody titers of ≥40 | Posted | Number | percentage of patients w/ seroprotection | 8 weeks |
|
|
|
| Secondary | Change From Baseline in Antibody Titer Against H1N1 | Fold change = post-vaccination titer/pre-vaccination titer | Posted | Geometric Mean | 95% Confidence Interval | Fold change | Day of and 4 weeks after vaccination |
|
|
|
| Secondary | Change From Baseline in Antibody Titer Against H3N2 | Fold change = post-vaccination titer/pre-vaccination titer | Posted | Geometric Mean | 95% Confidence Interval | Fold change | Day of and 4 weeks after vaccination |
|
|
|
| Secondary | Change From Baseline in Antibody Titer Against B-Yamagata | Fold change = post-vaccination titer/pre-vaccination titer | Posted | Geometric Mean | 95% Confidence Interval | Fold change | Day of and 4 weeks after vaccination |
|
|
|
| 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). | Posted | Number | percentage of flare patients | 20 weeks from enrollment. |
|
|
|
| Primary | Satisfactory Vaccination Responses Against > 2/3 Antigens | Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers | Per Protocol | Posted | Number | percentage of responders | 8 weeks |
|
|
|
| Primary | Satisfactory Vaccination Responses Against > 1/3 Antigens | Seroresponse is defined as serconversion or ≥4-fold increase in antibody titers | Per Protocol | Posted | Number | percentage of responders | 8 weeks |
|
|
|
| 0 |
| 54 |
| 33 |
| 54 |
| EG001 | 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 | 2 | 44 | 23 | 44 |
| EG002 | 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 | 0 | 49 | 23 | 49 |
| EG003 | 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 | 0 | 52 | 17 | 52 |
| Fracture | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Dizziness | General disorders | Systematic Assessment |
|
| Injection site reaction | General disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
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| D003240 |
| Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D000072471 |
| Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |