Clinical trial NCT02748785: MTX Discontinuation and Vaccine Response
Official title: Effect of Methotrexate Discontinuation on Efficacy of Seasonal Influenza Vaccination in Patients With Rheumatoid Arthritis: A Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Arthritis, Rheumatoid
Lead sponsor: Seoul National University Hospital
Sponsor class: OTHER
First posted: 2016-04-22
Enrollment: 277
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Satisfactory Vaccination Responses Against 3 Antigens
timeFrame: 8 weeks
measure: Satisfactory Vaccination Responses Against > 2/3 Antigens
timeFrame: 8 weeks
measure: Satisfactory Vaccination Responses Against > 1/3 Antigens
timeFrame: 8 weeks
Secondary outcomes:
measure: Proportion of Seroprotection Against H1N1
timeFrame: 8 weeks
measure: Proportion of Seroprotection Against H3N2
timeFrame: 8 weeks
measure: Proportion of Seroprotection Against B-Yamagata
timeFrame: 8 weeks
measure: Change From Baseline in Antibody Titer Against H1N1
timeFrame: Day of and 4 weeks after vaccination
measure: Change From Baseline in Antibody Titer Against H3N2
timeFrame: Day of and 4 weeks after vaccination
measure: Change From Baseline in Antibody Titer Against B-Yamagata
timeFrame: Day of and 4 weeks after vaccination
measure: DAS28 Flare Rate at Visit 4
timeFrame: 20 weeks from enrollment.
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.