1. BACKGROUND
and RATIONALE Autoimmune Rheumatic disease(AIRD) are chronic systemic inflammatory diseases requiring long term treatment
with DMARDS ,among which Methotrexate is an important drug for management (1,2).These patients are more
susceptible to infections because of their underlying immune dysfunction and
the treatment-induced immune suppression.(3,4) Consequently, they are
recommended to receive vaccines against preventable diseases, especially
against the current pandemic COVID 19. However, the
ability of the patients on MTX to adequately respond to vaccines and the differences in humoral and
cellular immune response to SARS-CoV-2 vaccination are not known, leaving a
significant gap in knowledge that prevents optimal management of this patient
population. Also, the period of time for which it should be discontinued is not
clear. It is known that in special circumstances, such as life-threatening
infections, vaccination or major surgery, use of MTX should be minimized to
restore treatment-associated immunosuppression [5,6].According to the ACR
guidelines it is advised to withhold
methotrexate 1 week after each vaccine dose, for those with well-controlled disease.
Our knowledge is confined to the data from influenza vaccine and pneumococcal
vaccine(7,8,9) which showed that holding MTX for 2 weeks is associated with
better vaccine response. The effects of temporary
discontinuation of methotrexate on antibody titers to the trivalent influenza
vaccine were investigated in a prospective, randomized, parallel-group,
single-blind, single-centre pilot study of 199 patients with rheumatoid
arthritis who were taking stable methotrexate doses Patients were randomly
assigned to continue methotrexate(group 1; 54 patients), suspend methotrexate 4
weeks before vaccination (group 2; 44 patients), suspend methotrexate 2 weeks
before and 2 weeks after vaccination(group 3; 49 patients); or suspend
methotrexate 4 weeks after vaccination (group 4; 52 patients).All groups showed
a similar frequency of satisfactory vaccine responses (≥4-times increase in
antibody titer); however, group 3 achieved significantly higher vaccine
responses compared with group 1. Withholding methotrexate 4 weeks before
influenza vaccination (group 2) was not associated with significantly different
antibody titers, whereas discontinuing methotrexate for 4 weeks after
vaccination (group 4) resulted in improvement compared with group 1. To reduce
the risk of rheumatoid arthritis flares while achieving an adequate vaccine
response, a shorter methotrexate discontinuation period was investigated in a prospective, multi-centre
study in which patients with rheumatoid arthritis on stable methotrexate doses
were randomly assigned to continue methotrexate (156 patients) or withhold
methotrexate for 2 weeks (160 patients) after the quadrivalent influenza
vaccine. Significantly more patients in the methotrexate-hold group achieved
satisfactory vaccine responses(≥4-times increase in antibody titre to at least
two of four influenza antigens) compared with the methotrexate-continue group
(75·5% vs 54·5%; p<0.001; difference 21·0%, 95% CI 10·6–31·7%). Neither of
these studies showed a significant increase in rheumatoid arthritis flares
after discontinuation of methotrexate. There are very few RCTs to prove this yet in COVID 19 vaccine except the
recent study on mRNA vaccine (BNT 17262) in patients
with immune mediated inflammatory diseases on methotrexate showed that MTX use
adversely affected humoral and cellular immune response to COVID-19 mRNA
vaccines(10) Hence it worthwhile
studying the immunogenicity to Covishield in stable subjects with vs without holding MTX . In a recent study done at our centre CARE, it was found that the humoral immunogenicity of Covishield in autoimmune
rheumatic diseases showed no statistically significant difference between the
patients on MTX with other DMARDs vs other DMARDs.As most of our patients
continued Methotrexate during their Covid-19 vaccination and produced similar
humoral response as in other DMARDS, the evidence for the recommendation for
discontinuation of Methotrexate one week after Covid-19 vaccination has to be
validated based on real world data with Randomized control trials Hence, we study the effect of
temporary discontinuation of MTX for 2 weeks post Covishield vaccine doses on
the humoral and cellular immunogenicity at the end of 1 month post 2nd
dose of vaccination . 2.
STUDY SITE: Dr.Shenoy’s
Care, Nettoor 3.
STUDY DESIGN:
single centre Randomized Controlled trial
4.
STUDY PERIOD: This
study will be conducted over a period of 6 months 5. STUDY
POPULATION ·
Patients diagnosed as Autoimmune Rheumatic disease(AIRD) who are on stable
dose of Methotrexate with or without
DMARDs for the last 2 months with stable liver function tests and blood counts and is scheduled for COVID 19 vaccination, with no evidence of
COVID infection ·
The baseline SARS CoV 2
anti Spike Ab titre will be measured to ensure that they are COVID 19 negative 6.
STUDY
OBJECTIVE Primary
Objective To compare the
immunogenicity of Covishield vaccination in patients with Autoimmune Rheumatic disease(AIRD)
on
methotrexate discontinuation temporarily for 2 weeks after each dose of vaccine
VS those continued on methotrexate . 7.
INCLUSION
AND EXCLUSION CRITERIA Inclusion Criteria ·
Patient above 18
years of age. ·
Patients willing
to give consent for the study ·
Patients with a
prior diagnosis of Autoimmune Rheumatic
disease(AIRD) stable dose for at least the past 2 months Exclusion Criteria ·
Patients who had
covid-19 infection in the past. ·
Patients with
history of allergy to vaccine components . ·
Prior
GBS/demyelinating syndromes
·
Any live vaccine
taken within prior 4 weeks or inactivated vaccine in last 2 weeks before study 1. METHODS: ·
In this prospective randomised single
centre study, patients with chronic stable Autoimmune
Rheumatic disease(AIRD) on
MTX with or without other DMARDs were randomly assigned at a ratio of 1:1 to
continue MTX or to hold MTX for 2weeks after each dose of Covishield vaccine .Randomization
shall be done using block randomisation chart. A prior COVID infection shall be
ruled out by baseline anti SARS CoV 2 Spike antibody assay, which should be
negative. .Baseline blood of about 7 ml would be withdrawn and will be stored
for future evaluation. A data collection form shall be used to capture details
about patients As primary objective the immunogenicity of Covishield vaccine
between the two groups will be compared using statistical analysis ·
After vaccination, patients in the
MTX-continue group continued their MTX in their current dose, whereas patients
inthe MTX-hold group suspended it for 2weeks after each dose of vaccine and then resumes it at previous dose. ·
1month after second dose of Covishield vaccine, the
serum of the patients will be collected and Covid19 antibody (spike antibody) /neutralising
Ab will be assessed using CLIA at CARE LAB to test humoral immune response, ELIspot
assay shall be done to test for cellular immune response ·
The patients will be further followed up
till the next 6 months. Any patient found positive after enrolment will be
withdrawn from the study. ·
Rescue
Therapy-In
case of flare of arthritis, short course low dose steroids and/or NSAIDs will
be considered till the second dose of vaccine ·
The study is
registered with CTRI, protocol number: CCR/RHEU /0003 /
2021.The study
will be conducted in accordance with the principles of the Declaration
of Helsinki and Good Clinical Practice guidelines. Written informed consent was
obtained from all patients before enrolment in the trial 2. Outcomes The primary outcome i.e., the anti spike/neutralizing antibody titre and
T cell ELIspot assay will be assessed
1 month after the second dose of
vaccine and to see if there is statistically significant difference among the
two groups studied 3. Statistical
analysis The primary
analysis population (per-protocol population) included all
study subjects who underwent the vaccination, discontinued or continued MTX
according to the allocated regimen, and whose
prevaccination and postvaccination titres were available The sample
sizing assumes that the expected percentage response in methotrexate hold group
is 75% and in methotrexate countinue group is 54%. To achieve 90% power to
detect this difference with a significance level of 5% it is estimated that 104
subjects per group would be required. With a withdrawal/non-evaluable subject
rate of 10% a total of 115 per group subjects will be recruited leading to a
total required sample size of 230 subjects. The data will be
assessed for the normality using Shapiro wilk test Countionous
variables will be assessed either with t test or mann Whitney test as
appropriately based on their normality . Categorical
variables will be assessed based on chi square test or fisher exact test
A P value lesser
than 0.05 will be considered as a statistically significant for our analysis
|