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Guidelines on COVID-19 vaccination in patients with immune-mediated rheumatic diseases: a Brazilian Society of Rheumatology task force

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Objective To provide guidelines on the coronavirus disease 2019 (COVID-19) vaccination in patients with immune-mediated rheumatic diseases (IMRD) to rheumatologists considering specific scenarios of the daily practice based on the shared-making decision (SMD) process. Methods A task force was constituted by 24 rheumatologists (panel members), with clinical and research expertise in immunizations and infectious diseases in immunocompromised patients, endorsed by the Brazilian Society of Rheumatology (BSR), to develop guidelines for COVID-19 vaccination in patients with IMRD. A consensus was built through the Delphi method and involved four rounds of anonymous voting, where five options were used to determine the level of agreement (LOA), based on the Likert Scale: (1) strongly disagree; (2) disagree, (3) neither agree nor disagree (neutral); (4) agree; and (5) strongly agree. Nineteen questions were addressed and discussed via teleconference to formulate the answers. In order to identify the relevant data on COVID-19 vaccines, a search with standardized descriptors and synonyms was performed on September 10th, 2021, of the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and LILACS to identify studies of interest. We used the Newcastle–Ottawa Scale to assess the quality of nonrandomized studies. Results All the nineteen questions-answers (Q&A) were approved by the BSR Task Force with more than 80% of panelists voting options 4—agree—and 5—strongly agree—, and a consensus was reached. These Guidelines were focused in SMD on the most appropriate timing for IMRD patients to get vaccinated to reach the adequate covid-19 vaccination response. Conclusion These guidelines were developed by a BSR Task Force with a high LOA among panelists, based on the literature review of published studies and expert opinion for COVID-19 vaccination in IMRD patients. Noteworthy, in the pandemic period, up to the time of the review and the consensus process for this document, high-quality evidence was scarce. Thus, it is not a substitute for clinical judgment.
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Tavaresetal. Advances in Rheumatology (2022) 62:3
https://doi.org/10.1186/s42358-022-00234-7
POSITION ARTICLE AND GUIDELINES
Guidelines onCOVID-19 vaccination
inpatients withimmune-mediated rheumatic
diseases: aBrazilian Society ofRheumatology
task force
Anna Carolina Faria Moreira Gomes Tavares1, Ana Karla Guedes de Melo2* , Vítor Alves Cruz3,
Viviane Angelina de Souza4, Joana Starling de Carvalho1, Ketty Lysie Libardi Lira Machado5,
Lilian David de Azevedo Valadares6, Edgard Torres dos Reis Neto7, Rodrigo Poubel Vieira de Rezende8,
Maria Fernanda Brandão de Resende Guimarães1, Gilda Aparecida Ferreira1, Alessandra de Sousa Braz2,
Rejane Maria Rodrigues de Abreu Vieira9, Marcelo de Medeiros Pinheiro7, Sandra Lúcia Euzébio Ribeiro10,
Blanca Elena Gomes Rios Bica11, Kátia Lino Baptista8, Izaias Pereira da Costa12, Claudia Diniz Lopes Marques13,
Maria Lúcia Lemos Lopes14, José Eduardo Martinez15, Rina Dalva Neubarth Giorgi16,
Lícia Maria Henrique da Mota17, Marcos Antônio Araújo da Rocha Loures18, Eduardo dos Santos Paiva19,
Odirlei André Monticielo20, Ricardo Machado Xavier20, Adriana Maria Kakehasi1 and
Gecilmara Cristina Salviato Pileggi7
Abstract
Objective: To provide guidelines on the coronavirus disease 2019 (COVID-19) vaccination in patients with immune-
mediated rheumatic diseases (IMRD) to rheumatologists considering specific scenarios of the daily practice based on
the shared-making decision (SMD) process.
Methods: A task force was constituted by 24 rheumatologists (panel members), with clinical and research expertise
in immunizations and infectious diseases in immunocompromised patients, endorsed by the Brazilian Society of
Rheumatology (BSR), to develop guidelines for COVID-19 vaccination in patients with IMRD. A consensus was built
through the Delphi method and involved four rounds of anonymous voting, where five options were used to deter-
mine the level of agreement (LOA), based on the Likert Scale: (1) strongly disagree; (2) disagree, (3) neither agree nor
disagree (neutral); (4) agree; and (5) strongly agree. Nineteen questions were addressed and discussed via teleconfer-
ence to formulate the answers. In order to identify the relevant data on COVID-19 vaccines, a search with standardized
descriptors and synonyms was performed on September 10th, 2021, of the MEDLINE, EMBASE, Cochrane Central Reg-
ister of Controlled Trials, ClinicalTrials.gov, and LILACS to identify studies of interest. We used the Newcastle–Ottawa
Scale to assess the quality of nonrandomized studies.
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
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licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.
Open Access
Advances in Rheumatology
*Correspondence: anakarlagmelo@gmail.com
2 Hospital Universitário Lauro Wanderley, Universidade Federal da
Paraíba, R. Tab. Stanislau Eloy, 585 - Castelo Branco, João Pessoa, Paraíba
58050-585, Brazil
Full list of author information is available at the end of the article
Page 2 of 11
Tavaresetal. Advances in Rheumatology (2022) 62:3
Background
e pandemic of severe acute respiratory syndrome cor-
onavirus-2 (SARS-CoV-2), whose first case was described
in Wuhan, China, in December 2019 [1], is the most sig-
nificant health crisis being faced by humanity currently,
and this has motivated efforts by the scientific com-
munity to seek ways to combat the transmission of this
new virus. e virus has spread rapidly worldwide, with
more than 228 million confirmed cases. In Brazil, it has
resulted in more than 591,000 cumulative deaths, consti-
tuting one of the largest, if not the greatest, epidemiologi-
cal tragedies in our history [2, 3].
Nowadays, four vaccines against SARS-CoV-2 are
approved for use in Brazil: CoronaVac/Butantan Insti-
tute—inactivated –, ChAdOX1 nCoV19/Oxford/Astra-
Zeneca/Oswaldo Cruz Foundation—viral vector—,
BNT162b2mRNA/Pfizer—messenger RNA—and Janssen
Vaccine—viral vector.
Although reports from several cohorts of patients
with IMRD published around the world do not show
an increased risk of unfavorable outcomes associated
with coronavirus disease 2019 (COVID-19) compared
to the general population [4], new data from population
registries [5], including the Brazilian Registry of IMRD
patients infected by the SARS-CoV-2 named ReumaCov,
showed that patients with a moderate to a high degree of
immunosuppression and those with an uncontrolled dis-
ease, especially systemic lupus erythematosus, systemic
vasculitis and systemic sclerosis with pulmonary involve-
ment, are at increased risk for COVID-19 outcomes or
death (pulse therapy with methylprednisolone or cyclo-
phosphamide [prevalence ratio, PR 2.86; 95% CI 1.59 to
5.14; p < 0.018]) [6].
Vaccination is the best way to avoid immune-prevent-
able infectious diseases. Patients with IMRD may have
a reduced immune response due to the underlying dis-
ease or immunosuppressive treatment. erefore, they
have a higher risk of infections, the leading causes of
hospitalizations and deaths in this group of patients [7].
For this reason, the discussion on immunization against
SARS-CoV-2 has become an urgent and relevant issue
[8]. e concern is shared about the effectiveness of dif-
ferent vaccines in patients with IMRD due to the dis-
ease itself and immunosuppressive drugs. Regarding
the vaccine response, it is essential to emphasize that
cellular and humoral immune responses are essential,
and isolated response measures can lead to a mistaken
idea of ineffectiveness [7].
Considering the uncertainties and the scarcity of data
on the safety and efficacy of COVID-19 vaccination
in patients with IMRD, the BSR Committee for Infec-
tious and Endemic Diseases formed a task force com-
posed of 24 rheumatologists to reach a consensus on
COVID-19 vaccination using the Delphi method. is
task force produced a consensus-based practical frame-
work for COVID-19 vaccination in patients with IMRD.
ese recommendations are not intended to replace
clinical judgment, and the vaccination decision should
be individualized and shared between patients and
rheumatologists.
Methods
Taskforce
e BSR first formed the task force with a steering
committee that included the endemic and infectious
diseases committee members and the executive board
of the BSR. e task force was convened until July to
August 2021 and comprised twenty-four rheumatolo-
gists: twenty rheumatologists specialized in treating
diseases in adults and four pediatric rheumatologists
from the BSR. e coordinator group, composed of
nine rheumatologists, formulated a list of potential
questions and a literature review. All nineteen con-
cept questions were discussed and refined during two
rounds of anonymous voting with other task force
members. After questions approval, all  nineteen
answers were formulated by the coordinator group
and then discussed in one round (3rd) with the whole
group. In the last round (4th), all nineteenQ&A were
voted. Each round consisted of the completion of a
structured questionnaire to achieve a consensus.
Results: All the nineteen questions-answers (Q&A) were approved by the BSR Task Force with more than 80% of
panelists voting options 4—agree—and 5—strongly agree—, and a consensus was reached. These Guidelines were
focused in SMD on the most appropriate timing for IMRD patients to get vaccinated to reach the adequate covid-19
vaccination response.
Conclusion: These guidelines were developed by a BSR Task Force with a high LOA among panelists, based on the
literature review of published studies and expert opinion for COVID-19 vaccination in IMRD patients. Noteworthy, in
the pandemic period, up to the time of the review and the consensus process for this document, high-quality evi-
dence was scarce. Thus, it is not a substitute for clinical judgment.
Keywords: Covid-19 vaccination, Task force, Guidelines, Immune-mediated rheumatic diseases, Immunosuppression
Page 3 of 11
Tavaresetal. Advances in Rheumatology (2022) 62:3
Literature review
e research questions were defined according to the
efficacy, immunogenicity, and safety of available COVID-
19 vaccines in adult IMRD patients and the influence of
immunosuppressive therapy on vaccine immunogenicity.
We searched MEDLINE, EMBASE, Cochrane Central
Register of Controlled Trials (CENTRAL), and LILACS,
using relevant descriptors and synonyms, adapting the
search to the specifics of each database (Fig.1). We also
searched the Open Grey database, the World Health
Organization International Clinical Trials Registry Plat-
form (WHO ICTRP), and ClinicalTrials.gov to identify
published, ongoing, and unpublished studies. All studies
published before September 10th, 2021, were included,
and no language restrictions were implemented for elec-
tronic search. Other papers that were considered relevant
in the opinion of the experts could be added.
e search descriptors used for the Pubmed database
were: "Rheumatic Diseases"[Mesh] OR "Autoimmune
Diseases"[Mesh] OR "Connective Tissue Diseases"[Mesh]
OR "Collagen Diseases"[Mesh] OR "Hereditary
Autoinflammatory Diseases"[Mesh] OR (chronic immune
inflammatory diseases) OR (immune-mediated inflam-
matory diseases) AND "COVID-19 Vaccines"[Mesh] OR
"mRNA-1273 vaccine" [Supplementary Concept] OR
"ChAdOx1 COVID-19 vaccine" [Supplementary Con-
cept] OR "Ad5-nCoV vaccine" [Supplementary Concept]
OR "Ad26.COV2.S vaccine" [Supplementary Concept]
OR "BNT162 vaccine" [Supplementary Concept]. e
search descriptors were adapted for each database used
in this literature review.
e database search yielded 780 records. We also
included two additional records. After removing dupli-
cates, titles and abstracts were examined. We retrieved
52 full-text articles for further scrutiny; of those, 25 stud-
ies were excluded due to: ineligible population (n = 10),
preprint (n = 2), not reporting patient data (n = 11), or no
full text available (n = 2) (Fig. 1). We finally included 27
studies in this review [930].
Studies were eligible if they presented data on the
immunogenicity, effectiveness, and/or safety of the
COVID-19 vaccine in patients with IMRD. We used e
Recordsidentifiedthrough
database searching
(n=780)
Additional recordsidentified
throughother sources
(n =2)
Recordsafter duplicates removed
(n =248)
Recordsscreened
(n =534)
Recordsexcluded
(n =482)
Full-textarticlesassessed
foreligibility
(n =52)
Full-textarticlesexcluded, with
reasons
(n =25)
Wrongpopulation:10
Preprint:2
No reported patientdata: 11
No full textavailable:2
Studies included in the
review
(n =27)
Fig. 1 Study flow diagram
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Tavaresetal. Advances in Rheumatology (2022) 62:3
Newcastle–Ottawa Scale (NOS) [31] (Additional file1) to
assess the methodological quality of the included studies.
Consensus building
e entire process was conducted following the Delphi
method, a well-established method for consensus-build-
ing [32, 33], and included four rounds of anonymous vot-
ing. Each round consisted of voting a structured online
questionnaire built on the Google® Forms platform, and
task force members received the questionnaire by e-mail.
Based on the Likert Scale, all members should indicate
their LOA for question–answer: 1. Strongly disagree;
2. Disagree, 3. Neither agree nor disagree (neutral); 4.
Agree; and 5. Strongly agree. e first round consisted
in discussing all questions with all members justifying
agreement or disagreement to the questions. In the sec-
ond round, the convener and collaborators made modi-
fications considered plausible. All questions were voted
according to the LOA mentioned above. In the third
round, questions and answers were voted, and task force
members had to justify agreement or disagreement for
each Q&A; in the last round (4th), the coordinator group
applied suggested modifications, and task force members
voted statements-answers according to the LOA. More
than 80% of panelists voted for options 4—agree—and
5—strongly agree in all scenarios, and the consensus was
achieved, considering the LOA previously established by
the coordinator group and following Delphi methodol-
ogy. e manuscript was drafted and revised by all the
task force members, and seventeen recommendations
(Table1)were established.
Recommendations
Questions toexplore
1. Should patients with IMRD receive COVID-19 vac-
cines?
Table 1 Recommendations related to COVID-19 vaccination in patients with immune-mediated rheumatic diseases
IMRD: immune-mediated rheumatic diseases
Recommendations LOA
1. Based on their risk for COVID-19, patients with IMRD should be encouraged to get their COVID-19 vaccination in a shared-making decision
process 100%
2. The decision on the best timing to be vaccinated with COVID-19 vaccines should be individualized, considering the patient’s age, the under-
lying IMRD, and its treatment, aiming to optimize the vaccine response 100%
3. COVID-19 vaccination should ideally occur in the setting of stable disease activity in patients with IMRD and absence or low immunosuppres-
sion 95.9%
4. The rheumatologist should inform their patients on the possibility of not effective vaccine response, especially those under high immuno-
suppression 100%
5. Immunomodulatory or immunosuppressive treatment in patients with IMRD should not be discontinued before and or after receiving
COVID-19 vaccines, except for B-cell depleting agents (e.g., rituximab) 95.8%
6. COVID-19 vaccination should be ideally done 6 months after the last dose of rituximab and four weeks before the next one considering the
complete vaccination schedule
*If this is not possible, this recommendation should be followed at least for the first dose
95.8%
7. IMRD patients should receive the same COVID-19 vaccine platform in the complete schedule
*In cases of severe adverse events (anaphylaxis) or immediate reactions (urticaria, angioedema, or respiratory distress) to any vaccine platform,
an alternative approach is recommended for additional doses following local availability
95.8%
8. An additional dose of the COVID-19 vaccine should be considered for patients with IMRD who completed their vaccination schedule 100%
9. The additional dose should preferably be with a COVID-19 vaccine platform different than that used in the primary COVID-19 vaccination
schedule 95.8%
10. Temporary interruption of immunomodulatory drugs before an additional dose of COVID-19 vaccines for patients with IMRD should not be
recommended 91.7%
11. Temporary interruption of rituximab should not be recommended concerning the COVID-19 vaccine additional dose
*Until high-quality evidence is available 83.4%
12. COVID-19 vaccines can be administered simultaneously with the other vaccines 92.3%
13. Assessment for seroconversion after COVID-19 vaccination is not recommended 95.9%
14. Seasonal influenza and pneumococcus vaccination are strongly recommended for patients with IMRD
* It is essential to keep vaccination cards updated 92.3%
15. Vector viral COVID-19 vaccine should be recommended for patients with IMRD and thrombocytopenia or previous thrombotic events 95.9%
16. Pregnant patients with IMRD should receive only non-vector viral COVID-19 vaccines
*Until new safety evidence is available for this scenario 100%
17. Children and adolescents (12–17 years) with IMRD should receive COVID-19 vaccination 95.8%
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Tavaresetal. Advances in Rheumatology (2022) 62:3
Yes. Rheumatologists should be familiar with and be
up to date on the characteristics, efficacy, and safety of
COVID-19 vaccines to better guide their patients, con-
sidering both the local epidemiological situation and the
risks and benefits of this SMD process.
LOA: 95.8% Strongly agree; 4.2% Agree
2. Should the decision on the best timing to get
COVID-19 vaccination for patients with IMRD be
individualized and preferably shared with the rheu-
matologist, considering the patient’s age, the underly-
ing IMRD, and its treatment, aiming to optimize the
vaccine response?
Yes. Some factors, such as old age and comorbidities
(mainly heart disease and chronic lung disease), are asso-
ciated with unfavorable outcomes and a worse prognosis
of COVID-19. e attending physician should consider
IMRD activity and the degree of immunosuppression to
determine the most appropriate time for COVID-19 vac-
cination in this population. In addition, rheumatologists
should determine whether the patient fits the risk group
for priority vaccination, as defined by the Public Health
Agencies.
LOA: 83.3% Strongly agree; 16.7% Agree
3. Should the rheumatologist discuss with their patients
the possibility of lower vaccine response, especially
those under a high degree of immunosuppression?
Yes. Despite the scarcity of studies and the significant
variability of immunosuppressants used in clinical prac-
tice, recent evidence suggests that patients under intense
immunosuppression may have a lower vaccine response.
Particular attention should be given to patients using
doses greater than 20 mg/day of glucocorticoids and
those using abatacept or rituximab due to their negative
impact on vaccine response [3437].
LOA: 83.3% Strongly agree; 16.7% Agree
4. Should the IDEAL timing get COVID-19 vaccina-
tion in patients with IMRD be when in remission or
absence or low degree of immunosuppression?
Yes. Aiming for better vaccine response, IMRD patients
should be vaccinated when in remission or under con-
trol with a low degree of immunosuppression or without
immunosuppressive treatment [3840]. In other situa-
tions, it is worth discussing with the attending rheuma-
tologist on the best timing for vaccination, considering
the epidemiological situation and the inclusion in the
priority groups defined by the Ministry of Health and the
associated factors specific to IMRD that are described
above.
LOA: 79.2% Strongly Agree; 16.7% Agree
5. Based on the available literature data, should immu-
nomodulatory/immunosuppressive treatment in
patients with IMRD not be discontinued before
and or after receiving COVID-19 vaccines? Should
COVID-19 vaccination in IMRD patients be post-
poned while under treatment with a B-cell depleting
agent (e.g., rituximab)?
Yes. To date, there are no available data to guide the
management of immunosuppressive therapy in the
context of COVID-19 vaccination. All the currently
approved vaccines are non-live, and there is no risk of
vaccine-related infection. It is also necessary to consider
the risk of reactivation of the underlying disease with
the interruption of a specific treatment and the potential
negative effect of using immunosuppressive medications
on vaccine response. Two studies recently published
addressed COVID-19 vaccination in patients with IMRD.
Braun-Moscovici etal. conducted a phase IV, prospec-
tive open-label trial to assess the humoral response after
two doses of mRNA COVID-19 vaccine in patients with
IMRD treated with immunomodulatory drugs and the
impact on IMRD activity [34]. After multivariate logistic
regression analysis, rituximab (RTX) and abatacept were
related to decreased humoral response to a vaccine. e
authors concluded that most disease-modifying antirheu-
matic drugs (DMARDs), including methotrexate (MTX),
biologics, and Janus Kinase (Jak) inhibitors, can be con-
tinued with BNT162b2mRNA/Pfizer COVID-19 vaccine.
Delaying treatment with RTX, when possible, should be
considered in individual cases. Mrak etal. [35] evaluated
humoral and cellular immune responses in RTX treated
patients following COVID-19 vaccination. Twenty-nine
(39%) out of 74 RTX treated patients seroconverted
with BNT162b2mRNA/Pfizer immunization. Twenty-
six out of 45 patients (58%) had a detectable cellular
response. ese data suggest that vaccination can induce
SARS-CoV-2 specific antibodies in RTX-treated patients
regardless of humoral response and may lead to new vac-
cination strategies in patients treated with RTX. A Brazil-
ian study evaluated the immunogenicity and safety of the
CoronaVac inactivated vaccine in patients with IMRD in
a phase IV trial [36]. Lower anti-SARS-CoV2 IgG sero-
conversion (70.4 versus 95.5%, p < 0,001) and neutralizing
antibodies positivity (NAbs) (56.3 versus 79.3%, p < 0.001)
in the IMRD group compared to the control group were
evidenced. e use of MTX (OR 0.42; 95% CI 0.29–0.61,
p < 0.001), mycophenolate mofetil (OR 0.15; 95% CI 0.09–
0.24, p < 0.001), tumor necrosis factor-alpha inhibitors
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Tavaresetal. Advances in Rheumatology (2022) 62:3
(OR 0.41; 95% CI 0.26–0.64, p < 0.001), abatacept (OR
0.24; 95% CI 0.13–0.46, p < 0.001) and RTX (OR 0.34;
95% CI 0.13–0.93, p = 0.036) were associated with lower
seroconversion in patients with IMRD. MTX (OR 0.67,
95% CI 0.47–0.95, p = 0.024), mycophenolate mofetil (OR
0.33; 95% CI 0.21–0.53, p < 0.001) and RTX (OR 0.28; 95%
CI 0.09–0.87, p = 0.028) were associated with the absence
of neutralizing activity in patients with IMRD. Together,
these data provided evidence of humoral and cellu-
lar immunogenicity in a short-term follow-up of IMRD
patients vaccinated with mRNA and inactivated COVID-
19 vaccines. Long-term data is required. COVID-19 vac-
cination should be ideally done 6months after the last
dose of RTX and four weeks before the next one consid-
ering the complete schedule. If this is not possible, this
recommendation should be followed, at least for the first
dose.
LOA: 50% Strongly Agree; 45.8% Agree
6. Should COVID-19 vaccination be recommended for
patients with IMRD even if they have already been
infected with this virus?
Yes. Regardless of the scarcity of evidence about
acquired immunity duration due to SARS-CoV-2 infec-
tion and the formal recommendation for vaccination of
recovered patients from the general population, we rec-
ommend following the local health agencies’ guidelines
until new evidence or recommendations are available.
Cases of reinfection in humans or infection with new
virus variants have been reported a few months after
initial infection, challenging the idea of long-lasting pro-
tective immunity [4143]. In addition, it is crucial to con-
sider the scenario of the emergence of new virus variants.
LOA: 87.5% Strongly agree; 8.3% Agree
7. Should all platforms of COVID-19 vaccines be con-
sidered potentially safe for vaccination of patients
with IMRD?
Yes. None of the platforms used to produce vaccines
contain live viruses. Recently published studies [3437]
that assessed efficacy and safety of vaccines in patients
with IMRD showed a low incidence of adverse events,
most of them being local and self-limited. Guidelines
from local health agencies should be followed until new
evidence are available.
LOA: 70.8% Strongly agree; 29.2% Agree
8. Should the choice of COVID-19 vaccine for IMRD
patients follow the recommendations of local regula-
tory agencies and availability?
Yes. e choice should follow the requirements of local
public health agencies and the local availability of the
vaccines. We recommend that all individuals, including
patients with IMRD, receive a COVID-19 vaccine that
has undergone a rigorous national regulatory process and
is approved.
LOA: 83.3% Strongly agree; 16.7% Agree
9. Should IMRD patients receive the same platform
in the complete schedule of COVID-19 vaccination
until new evidence about interchangeability is avail-
able?
Yes. e entire vaccination schedule must follow
the same platform initially used and should follow the
national and local health regulatory agencies’ guide-
lines. In cases of severe adverse events (anaphylaxis) or
immediate reactions (urticaria, angioedema, or respira-
tory distress) to any vaccine platform [44], an alternative
approach is recommended for additional doses follow-
ing local availability. Recently the National Immuniza-
tion Program (NIP) recommended an additional dose of
COVID-19 vaccine for immunocompromised patients,
whose platform choice should be guided by local avail-
ability but should be different from the platform of the
initial schedule [45].
LOA: 62.5% Strongly agree; 33.3% Agree
10. Should an additional dose of the COVID-19 vac-
cine be considered for patients with IMRD who
completed their vaccination schedule?
Yes. To date, studies indicated that individuals with
moderately to severely compromised immune systems
may not build the same level of immunity to a 2-dose vac-
cine schedule compared to people who are not immuno-
compromised [3235]. erefore, they may benefit from
an additional dose to ensure better protection against
COVID-19. In addition, data on breakthrough infections
have accounted for a large proportion of the hospitali-
zation rate from fully vaccinated immunocompromised
subjects [46].
LOA: 83.3% Strongly agree; 16.7% Agree
11. Should the additional dose preferably be with a
COVID-19 vaccine platform different than that
used in the primary COVID-19 vaccination sched-
ule?
Yes. Available data on the responses to heterologous
COVID-19 vaccination, especially in countries using
inactivated and vector viral vaccines, showed higher
spike RBD-IgG (receptor binding domain) and neutral-
izing activities than the homologous vaccine recipients
[4749].
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Tavaresetal. Advances in Rheumatology (2022) 62:3
LOA: 62.5% Strongly agree; 33.3% Agree
12. Should a temporary interruption of immunomod-
ulatory drugs be recommended before an addi-
tional dose of COVID-19 vaccines for patients with
IMRD?
No. Long-term data are required to guide recommen-
dations for immunomodulatory/immunosuppressive
drugs interruption and COVID-19 vaccination. So far,
the literature data is conflicting and does not allow to
take a definitive position.
LOA: 37.5% Strongly agree; 54.2% Agree
13. Should rituximab be interrupted concerning
COVID-19 vaccine additional dose?
No. Regarding rituximab or other anti-CD20 thera-
pies, the best period for vaccination must be discussed
through an SMD process between the patient and assis-
tant rheumatologist. Assessing serum CD19 levels [40]
could be a tool to guide the best timing for the additional
dose of the vaccine and subsequent dose of rituximab. If
this is not available, it is recommended to perform the
additional dose 2 to 4weeks before the next dose of RTX.
e available literature points out a possible influence of
rituximab in seroconversion [3236, 50], but more infor-
mation is required.
LOA: 29.2% Strongly agree; 54.2% Agree
14. Is there a risk that the underlying disease will
worsen or reactivate after COVID-19 vaccination?
Yes. Natural viral infection or vaccination have been
noted as potential triggering events for inflammatory
diseases for many decades. Regarding disease activity of
IMRD and vaccination, it is suggested that promoting
vaccination in quiescent disease phases avoids disease
flare-up and favors a better immune response. However,
due to COVID-19 severity, a rapid COVID-19 immuniza-
tion is strongly recommended, and the patients included
in most trials were vaccinated in different activity phases
of their disease. Concerning the possibility of inducing or
enhancing the autoimmune response through molecu-
lar mimicry between the viral antigen and host antigen,
Rotondo etal. showed a low rate (5.7%) of disease relapse
of IMRD after the first dose of vaccine, the rate of disease
flare-up observed after BNT162b2mRNA/Pfizer vaccina-
tion could be due to the higher frequency of this vaccine
administration. However, no significant differences in
adverse events (AEs) between BNT162b2mRNA/Pfizer
and ChAdOx1 nCoV19 were found in this study [51].
Watad etal. reported that the average time between vac-
cination and new-onset or flare of symptoms was four
days (median of 4days [1–25days] in those who devel-
oped an IMRD after the first dose and a median of 4days
[1–7days] in those after the second dose) with most cases
occurring after the first inoculation (77.8%) [52]. Despite
the high population exposure in the regions served by
these centers, the authors concluded that IMRDs flares or
onset temporally associated with COVID-19 vaccination
appear rare. Most are moderate events and respond to
therapy; although some severe flares occurred, new stud-
ies could be necessary.
LOA: 66.7% Strongly agree; 29.2% Agree
15. Is it recommended to assess for seroconversion
after COVID-19 vaccination?
No. It is not recommended to assess the post-vaccina-
tion humoral response against SARS-CoV-2. e level
of seroconversion varies among individuals, especially
those immunocompromised. In addition, humoral
immunity is not the only protective barrier against
SARS-CoV-2, and the durability of the protection pro-
vided by natural infection and vaccination is not well-
defined [35]. Individuals that received COVID-19
vaccines or those who recovered from infection should
be informed that the durability of the protection is still
to be determined.
LOA: 79.2% Strongly agree; 16.7% Agree
16. Should patients with IMRD also receive influenza
and pneumococcus vaccines?
Yes. Vaccination against seasonal influenza and pneu-
mococcus is strongly recommended for patients with
IMRD, considering the risk of severe pneumonia in
immunocompromised patients. COVID-19 vaccines
can be administered with other vaccines at the same
time, accordingly to National Immunization Program
and the Ministry of Health [53]. We emphasize that it
is important to keep IMRD patients vaccination card
updated.
LOA: 73.1% strongly agree; 19.2% agree
17. Should vector viral vaccine be recommended for
patients with IMRD and thrombocytopenia or
previous thrombotic events?
Yes. romboembolic events related to viral vec-
tor vaccines are rare, with an average of 2 to 4 cases
reported per million doses applied. Its immunological
mechanism is described in immune-mediated throm-
botic thrombocytopenia induced by heparin (HITT or
HIT type 2), where thrombosis and thrombocytopenia
are associated with anti-platelet factor IV antibodies.
Although the risk factors for developing this adverse
reaction are unknown, most cases were observed in
women under 50 years old, without comorbidities or
risk factors for thrombosis. ere is no evidence of
greater risk among IMRD patients and no plausible
Page 8 of 11
Tavaresetal. Advances in Rheumatology (2022) 62:3
reason to contraindicate COVID-19 vaccination in this
group. Vector viral vaccines should be avoided in indi-
viduals with a previous history of HITT and venous
and or arterial thrombosis cases with thrombocytope-
nia after any vaccine [5458].
LOA: 54.2% Strongly agree; 41.7% Agree
18. Should pregnant patients with IMRD receive only
non-vector COVID-19 vaccines until new safety
evidence is available for this scenario?
Yes. Vaccination should be encouraged in pregnant
women [59], following guidelines of national health
authorities. Since the notification of a fatal case of throm-
bosis with thrombocytopenia in a pregnant woman after
the ChAdOx1- nCoV19 vaccine, the National Health Sur-
veillance Agency and the Brazilian Ministry of Health
discontinued the administration of vector viral vaccines
in pregnant and postpartum women. Until such asso-
ciation is definitively clarified, Brazilian regulatory agen-
cies recommended only m-RNA and inactivated virus
COVID-19 vaccines for this group of individuals.
LOA: 58.3% Strongly agree; 41.7% Agree
19. Should children and adolescents (12–17years old)
with IMRD be vaccinated against SARS-CoV-2?
Yes. On June 23rd, 2021, the Center for Disease Con-
trol and Prevention reported an increased number of
post-mRNA vaccine myocarditis/pericarditis cases (pos-
sibly hypersensitivity eosinophilic myocarditis). ese
are considered rare events, with no reported fatal out-
comes. e majority of cases occurred in adolescents
and young adults (under 30years old), mainly boys over
12 to 17years old. ere are no long-term data on this
outcome yet [60]. e BSR considers the benefits to out-
weigh the risks and recommends COVID-19 vaccina-
tion for this age group.LOA: 70.8% Strongly agree; 25%
Agree.
Discussion
is document presents the result of a BSR Task Force
Delphi consensus-building to provide guidelines for
COVID-19 vaccination in IMRD patients based on
clinical scenarios. e consensus process considered
potential concerns and was elaborated according to evi-
dence-based information and expert opinion. e BSR
developed these guidelines with a high LOA among their
panelists regarding COVID-19 vaccination in patients
with IMRD. ese recommendations(Table1) included
discussion about particularities of safety and immuno-
genicity of vaccination in immunocompromised patients,
considering adverse events and guidance for managing
immunosuppressive treatment.
Vaccination is the most effective strategy to reduce
and mitigate the SARS-CoV-2 pandemic. In randomized
studies, COVID-19 vaccines proved efficacy in reducing
SARS-CoV-2 infection rates and severe disease. How-
ever, the pivotal studies did not include IMRD patients
who have an immune dysfunction related either to the
underlying disease or the use of immune-modulating
drugs, which could interfere in COVID-19 vaccination
response. Both humoral and T-cell immune response
following vaccination are relevant to evaluate effective-
ness. Understanding of the development and durability
of these responses determines the necessity for booster
dosing schedules [3437]. Currently, data have shown a
lower response rate in IMRD patients when compared to
healthy controls. It is unclear whether this is attributable
to the underlying disease or its different treatments [38,
61].
e decision to vaccinate IMRD patients should be
individualized and preferably shared between health pro-
fessionals and patients, considering the epidemiologi-
cal setting, the immunosuppression degree, and disease
activity. Immunization should not be delayed in epidem-
ics and pandemics such as COVID-19 since the benefits
outweigh the risks. Misinformation negatively affects
the decision to vaccinate, reduces the population’s con-
fidence, and decreases adherence to vaccination. SDM
process should be based on highest scientific evidence
and on persuasive and motivational approach strategies
especially among pregnant women, children, adoles-
cents and immunocompromised patients. is could be
made discussing with patients risks and benefits of vac-
cines, listening to their doubts, clarifying their concerns
and providing them ways to get high-quality information
from confident sources. It seems to be the most suitable
way to overcome barriers to vaccine hesitation, especially
in vulnerable populations [6265].
Vaccination hesitancy is a complex and multifacto-
rial phenomenon defined as a delay in the acceptance
of vaccination despite the availability of vaccination
services. A study recently published by our group ana-
lyzed data from 1,000 patients with IMRD and evi-
denced a high vaccine acceptance rate (81.9%), but also
found out that 25% of patients who hesitated to receive
the COVID vaccine linked their decision to the lack of
a definitive recommendation for vaccination against
COVID-19, suggesting that physicians should be more
engaged in disseminating information demystifying
issues related to vaccination [64, 65].
All four COVID-19 vaccines approved in Brazil are
non-live, and thus, there is no risk of inducing vaccine-
related disease [51, 52]. Several studies confirmed that
other non-live vaccines, such as those against influenza,
pneumococcus, hepatitis A, hepatitis B, and human
Page 9 of 11
Tavaresetal. Advances in Rheumatology (2022) 62:3
papillomavirus, are effective and safe for this popula-
tion [66, 67]. Influenza and pneumococcus vaccinations
are strongly recommended for IMRD patients because
of an increased risk of developing severe pneumonia
and its complications such as severe respiratory dis-
tress and respiratory failure [39, 6669].
Some international Rheumatology Societies have
released recommendations for COVID-19 vaccination
in IMRD patients. e American College of Rheuma-
tology (ACR) and the European Alliance of Associa-
tions for Rheumatology (EULAR) suggested that SMD
process is essential in defining the best timing for vac-
cination and stand out the absence of safer and more
effective vaccine platform for individuals with IMRD.
e ACR pointed to temporary interruption of immu-
nosuppressive agents before and/or after immuniza-
tion, such as abatacept, MTX, and Jak inhibitors. is
clinical guidance was based on observational studies
assessing vaccination responses against other micro-
organisms, such as pneumococcus and influenza, and
in the growing knowledge about the impact of immu-
nosuppressants in COVID-19 vaccines responses.
e use of new technologies, such as mRNA and viral
vector-based, is relatively new, and the impact of the
underlying disease and immune-modulating drugs on
serological and T-cell responses are uncertain [7, 34
37]. e authors recognized that there is limited high-
quality evidence to base these recommendations [39,
40].
Given this scenario of uncertainty, we performed a
systematic literature review on the safety and efficacy
of COVID-19 vaccines. Only non-randomized studies
were found with heterogeneous subtypes of IMRD and
diverse treatments regimens, absence of a well-defined
control group, and differences in outcomes, leading
to difficulties in interpreting the results and compar-
ing the studies. We performed critical judgment of the
included studies based on the selection of the study
groups, the comparability of the groups, and the ascer-
tainment of either the exposure or outcome using the
Newcastle–Ottawa Scale.
Systematic reviews of prospective cohort studies
could be the key to better understanding the effec-
tiveness and safety of the COVID-19 vaccine in IMRD
patients. We believe that the results of our review and
recommendations may help decision-making processes
and guide Brazilian rheumatologists in daily practice.
Conclusion
e BSR task force approved a twenty Q&A with more
than 80% LOA, considering scenarios of daily prac-
tice to help the decisions on COVID-19 vaccination in
IMRD patients based on the SMD process and estab-
lished seventeen recommendations(Table1).
Although these guidelines are based on the best
evidence available on the safety and immunogenic-
ity of COVID-19 vaccines in patients with IMRD, we
emphasize that there is still no high-quality evidence
to guide the temporary withdrawal of immunomodu-
latory or immunosuppressive medications before or
after COVID-19 vaccination and further research is
required. It is noteworthy that the current consensus
was built based on expert opinion and thus, do not
intend to substitute clinical judgment. ese Guidelines
will be updated, As soon as new evidence about the
COVID-19 vaccines’ safety and efficacy emerges.
Abbreviations
ACR : American College of Rheumatology; BSR: Brazilian Society of Rheuma-
tology; CG: Control group; COVID 19: Coronavirus disease 2019; DMARDs:
Disease-modifying rheumatic drugs; EULAR: European Alliance of Associations
for Rheumatology; IgG: Immunoglobulin G; IMRD: Immune-mediated rheu-
matic diseases; JAK: Janus kinase; LOA: Level of agreement; MTX: Methotrex-
ate; mRNA: Ribonucleic acid messenger; NAb: Neutralizing antibody; NIP:
National Immunization Programme; PR: Prevalence ratio; Q&A: Questions-
answers; RBD: Receptor binding domain; ReumaCoV: Brazilian Registry of IMRD
patients infected by the SARS-CoV-2; RTX: Rituximab; SARS-CoV-2: Severe
acute respiratory syndrome coronavirus 2; SMD: Shared-making decision
process; YF: Yellow fever.
Supplementary Information
The online version contains supplementary material available at https:// doi.
org/ 10. 1186/ s42358- 022- 00234-7.
Additional le1. Newcastle–Ottawa Quality Assessment Scales.
Acknowledgements
Not applicable.
Authors’ contributions
All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Nor applicable.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1 Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte,
Brazil. 2 Hospital Universitário Lauro Wanderley, Universidade Federal da
Paraíba, R. Tab. Stanislau Eloy, 585 - Castelo Branco, João Pessoa, Paraíba
Page 10 of 11
Tavaresetal. Advances in Rheumatology (2022) 62:3
58050-585, Brazil. 3 Hospital das Clínicas, Universidade Federal de Goiás,
Goiânia, Brazil. 4 Universidade Federal de Juiz de Fora, Juiz de Fora, Brazil. 5 Hos-
pital Universitário Cassiano Antônio Moraes, Universidade Federal do Espírito
Santo, Vitória, Brazil. 6 Hospital Getúlio Vargas, Recife, Brazil. 7 Universidade
Federal de São Paulo, São Paulo, Brazil. 8 Universidade Federal Fluminense,
Niterói, Brazil. 9 Hospital Geral, Fortaleza, Brasil. 10 Universidade Federal do Ama-
zonas, Manaus, Brazil. 11 Universidade Federal do Rio de Janeiro, Rio de Janeiro,
Brazil. 12 Faculdade de Medicina, Universidade Federal do Mato Grosso do Sul,
Campo Grande, Brazil. 13 Universidade Federal de Pernambuco, Recife, Brazil.
14 Universidade Federal de Ciências da Saúde, Porto Alegre, Brazil. 15 Pontifícia
Universidade Católica, São Paulo, Brazil. 16 Instituto de Assistência Médica ao
Servidor Público Estadual, São Paulo, Brazil. 17 Hospital Universitário, Brasília,
Brazil. 18 Universidade Estadual, Maringá, Brazil. 19 Hospital das Clínicas, Univer-
sidade Federal do Paraná, Curitiba, Brazil. 20 Hospital das Clínicas, Universidade
Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Received: 16 March 2021 Accepted: 8 January 2022
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... The Committee of Endemic and Infectious Diseases and the Executive Board of the Brazilian Society of Rheumatology (SBR) proposed an update to the "Guidelines on COVID-19 vaccination in patients with immune-mediated rheumatic diseases: a Brazilian Society of Rheumatology task force" [1] based on recently published scientific evidence [2] and on the new recommendations of the Brazilian National Immunization Program (NIP) for vaccination of immunocompromised persons [3,4]. According to the NIP documents [3,4], the primary vaccination series is composed of three doses of Coronavac or ChAdOx-1 (AstraZeneca) or mRNA BNT162b2 (Pfizer), or two doses of Ad26.COV2.S (Janssen). ...
... Несмотря на ряд нерешённых проблем, связанных с иммуногенностью и безопасностью вакцинации против SARS-CoV-2, эксперты всех международных и национальных ревматологических ОБЗОРЫ научных обществ [49,[52][53][54][55][56], включая Ассоциацию ревматологов России [57], поддерживают положение о том, что польза от вакцинации значительно превосходит потенциальный вред, связанный с развитием нежелательных явлений, поскольку вакцинация, несомненно, снижает риск инфицирования SARS-CoV-2 и тяжёлого течения COVID-19. Решение о проведении вакцинации против SARS-CoV-2 должно быть индивидуализированным, с учётом текущей эпидемической ситуации, активности ИВРЗ, характера проводимой терапии, основываться на достижении взаимопонимания между врачом и пациентом и происходить при обязательном подписании пациентом информированного согласия. ...
... Some studies have shown a lower response in in this group of patients compared to healthy controls. It is unclear whether this is attributable to the underlying disease or its treatments [1]. ...
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Objectives To identify potential predictors of COVID-19 vaccine hesitancy (C19-VH) in adults with immune-mediated inflammatory diseases (IMID). Methods A total of 1000 IMID patients were enrolled in this web-based cross-sectional study. A standardised and self-administered survey was designed by members of the Brazilian Society of Rheumatology Steering Committee for Infectious and Endemic diseases and distributed to IMID patients spread across Brazil. Results Of the 908 (90.8%) respondents eligible for analysis, 744 (81.9%) were willing to get vaccinated against COVID-19. In our multivariable logistic regression model, concurrent malignancy, fibromyalgia, hydroxychloroquine use, and recent corticosteroid pulse therapy were independently associated with higher odds of C19-VH. The short duration of COVID-19 vaccine clinical trials was the main reason for C19-VH. Conclusion We identified novel characteristics potentially associated with C19-VH among adults with IMID. Greater awareness on the safety and efficacy of COVID-19 vaccines is needed for both IMID patients and attending physicians.
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Background We describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine. Methods From 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination. Results We analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%. Conclusion Among adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring.
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Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were launched in December 2020. Vaccination of patients with rheumatic diseases is recommended, as they are considered at higher risk of severe COVID-19 than the general population. Patients with rheumatic disease have largely been excluded from vaccine phase 3 trials. This study explores the safety and reactogenicity of BNT162b2 among patients with rheumatic diseases. Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), median age 58.8 years, 285 subjects in total, were vaccinated twice with the BNT162b2 (Pfizer/BioNTech). Questionnaires on reactogenicity matching the original phase 3 study were answered seven days after completed vaccination. The majority of SLE and RA patients experienced either local (78.0%) or systemic reactions (80.1%). Only 1.8% experienced a grade-4 reaction. Compared to the original study, we found more frequent fatigue [Odds ratio (OR) 2.2 (1.7–2.8)], headache [OR 1.7 (1.3–2.2)], muscle pain [OR 1.8 (1.4–2.3)], and joint pain [OR 2.3 (1.7–3.0)] in patients. In contrast, the use of antipyretics was less frequent [OR 0.5 (0.3–0.6)]. Patients with SLE and RA experience reactogenicity to the Pfizer-BioNTech BNT162b2 COVID-19 vaccine. Reactogenicity was more frequent in patients, however, not more severe compared with healthy controls.
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Patients with rheumatoid arthritis (RA) are treated with drugs that may impact their immune responses to SARS-CoV-2 vaccines. We describe here the anti-Spike (anti-S) IgG and neutralizing antibody responses induced by the mRNA-1273 SARS-CoV-2 vaccine in a 78-years-old patient with RA, who received a low-dose combination therapy of methotrexate and adalimumab, shortly before vaccine administration. Both near-normal and impaired immune responses to vaccines have been reported previously in patients treated with these drugs. Our case report shows that, even at low doses, combined methotrexate-adalimumab therapy can be associated with a weak immune response to the mRNA1273 vaccine in elderly patients.
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Objective: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination. Methods: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases. Results: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy. Conclusion: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.
Article
Objectives To assess the kinetics of humoral response after the first and second dose of messenger RNA (mRNA) vaccines in patients with inflammatory joint diseases compared with healthy controls (HC). To analyse factors influencing the quantity of the immune response. Methods We enrolled patients with rheumatoid arthritis (RA) and seronegative spondyloarthritis (SpA), excluding those receiving B-cell depleting therapies and assessed the humoral response to mRNA vaccines after the first and the second dose of the vaccine in terms of seroconversion rate and titre. We compared the results to a HC group and analysed the influence of therapies as well as other characteristics on the humoral response. Results Samples from 53 patients with RA, 46 patients with SpA and 169 healthy participants were analysed. Seroconversion rates after the first immunisation were only 54% in patients with inflammatory arthritis compared with 98% in the HC group. However, seroconversion rates were 100% in all groups after second immunisation. Patients developed reduced antibody titres after the first vaccination compared with HC, but there was no difference after the second dose. While disease modifying anti-rheumatic drug (DMARD) monotherapy did not affect antibody levels, seroconversion rates as well as titre levels were reduced in patients receiving a combination of DMARDs compared with HC. Conclusions Patients with inflammatory joint diseases under DMARD therapy show impaired humoral responses to the first vaccine dose but excellent final responses to vaccination with mRNA vaccines. Therefore, the full course of two immunisations is necessary for efficient vaccination responses in patients with inflammatory arthritis under DMARD therapy.
Article
Objectives Current treatments are effective only in 30% of lupus nephritis patients emphasizing the need for novel therapeutic strategies. To develop mechanistic hypotheses and explore novel biomarkers, we analyzed the longitudinal urinary proteomic profiles in patients with lupus nephritis undergoing treatment. Methods We quantified 1,000 urinary proteins in 30 patients with lupus nephritis at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single cell transcriptomics of renal biopsies from lupus nephritis patients. Results Our analysis revealed multiple biological pathways including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization that could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with lupus nephritis as compared to controls without SLE. IL-16, CD163, and TGF-β mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction of urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in lupus nephritis kidneys. IL-16 producing cells were found at key sites of kidney injury. Conclusion Urine proteomics may profoundly change the diagnosis and management of lupus nephritis by noninvasively monitor active intrarenal biological pathways. These findings implicate IL-16 in lupus nephritis pathogenesis designating it as a potentially treatable target and biomarker.
Article
Objectives The treatment for COVID-19 often utilizes immune-modulating drugs. These drugs are also used in immune mediated inflammatory diseases (IMIDs). We performed a systematic review about seroconversion after SARS-CoV-2 vaccination in patients with IMIDs and impact of various drugs on seroconversion rates. Methods Electronic databases were searched to identify relevant studies reporting seroconversion rates following SARS-CoV-2 vaccination in IMIDs. We calculated the pooled seroconversion rates after a single or two doses of vaccination, pooled seroconversion rates in patients with specific IMIDs, and rates in patients on various drugs/drug classes. Results Twenty-five studies were included in the systematic review. The pooled seroconversion rates after two doses of mRNA vaccination were higher (83.1, 95%CI: 74.9–89.0, I2 = 90%) as compared to a single dose (69.3, 52.4–82.3, I2 = 95%). The odds of seroconversion were lower in IMIDs as compared to healthy controls (0.05, 0.02–0.13, I2 = 21%). The seroconversion rates in patients with inflammatory bowel disease (95.2, 95%CI: 92.6–96.9, I2 = 0%), spondyloarthropathy (95.6, 95% CI: 83.4–98.9, I2 = 35%), and systemic lupus erythematosus (90.7, 95%CI: 85.4–94.2, I2 = 0%) were higher as compared to rheumatoid arthritis (79.5, 95% CI: 65.1–88.9, I2 = 85%), and vasculitis (70.5, 95% CI: 52.9–83.5, I2 = 51%). The seroconversion rates following double dose of mRNA were excellent (>90%) in those on anti-tumour necrosis factor (TNF), anti-integrin (vedolizumab), anti-IL 17 (secukinumab), anti-IL6 (Tocilizumab) and anti-IL12/23 (Ustekinumab) therapies but attenuated (<70%) in patients on anti-CD20 (Rituximab) or anti-cytotoxic T lymphocyte associated antigen (CTLA-4) therapies (Abatacept). The seroconversion rates were good (70–90%) with steroids, hydroxychloroquine, JAK inhibitors, mycophenolate mofetil and leflunomide. Combination of anti-TNF with immunomodulators (azathioprine, 6-meracptopurine, methotrexate) resulted in an attenuated vaccine response as compared to anti-TNF monotherapy. Conclusion Seroconversion rates after SARS-CoV-2 vaccination are lower in patients with IMIDs. Certain therapies (anti-TNF, anti-integrin, anti-IL 17, anti-IL6, anti-12/23) do not impact seroconversion rates while others (anti-CD20, anti-CTLA-4) result in poorer responses.