MTX Discontinuation and Vaccine Response

Study Overview
=================
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.

Official Title
-----------------
Effect of Methotrexate Discontinuation on Efficacy of Seasonal Influenza Vaccination in Patients With Rheumatoid Arthritis: A Randomized Clinical Trial

Conditions
-----------------
Arthritis, Rheumatoid

Intervention / Treatment
-----------------
* Drug: Methotrexate
* Biological: Seasonal Influenza vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (No MTX Hold before Vaccination)<br>Group 1 will continue MTX | Drug: Methotrexate<br>* Methotrexate will be continued<br>Biological: Seasonal Influenza vaccine<br>* all subjects will be vaccinated with a seasonal influenza vaccine<br>|
| Experimental: Group 2 (MTX hold 4 Weeks before vaccination)<br>Group 2 will hold MTX 4 weeks before vaccination and resume MTX on the day of vaccination | Drug: Methotrexate<br>* Methotrexate will be continued<br>Biological: Seasonal Influenza vaccine<br>* all subjects will be vaccinated with a seasonal influenza vaccine<br>|
| Experimental: Group 3 (MTX hold 2 Weeks before Vaccination)<br>Group 3 will hold MTX 2 weeks before vaccination and resume MTX 2 weeks after vaccination | Drug: Methotrexate<br>* Methotrexate will be continued<br>Biological: Seasonal Influenza vaccine<br>* all subjects will be vaccinated with a seasonal influenza vaccine<br>|
| Experimental: Group 4 (MTX hold on Day of Vaccination)<br>Group 4 will hold MTX on day of vaccination and resume MTX 4 weeks after vaccination. | Drug: Methotrexate<br>* Methotrexate will be continued<br>Biological: Seasonal Influenza vaccine<br>* all subjects will be vaccinated with a seasonal influenza vaccine<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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. |