medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021.

The copyright holder for this

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Recommendations for COVID-19 Vaccination in People with Rheumatic Disease:

Developed by the Singapore Chapter of Rheumatologists

Short title : COVID-19 Vaccination in PRD

Santosa Amelia1,2, Xu Chuanhui3, Arkachaisri Thaschawee 4, Kong Kok Ooi3, Lateef

Aisha2,5, Lee Tau Hong6, Leong Keng Hong7, Low Andrea Hsiu Ling8, Sriranganathan

Melonie K9, Tan Teck Choon10, Teng Gim Gee1,2, Thong Bernard Yu-hor3, Fong Warren8,

Lahiri Manjari*1,2.

1 Division of Rheumatology, Department of Medicine, National University Hospital, Singapore

2 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

3 Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore

4 Rheumatology and Immunology Service, Department of Paediatric Subspecialties, KK Women's and Children's Hospital, Singapore

5 Department of Medicine, Woodlands Health Campus, Singapore

6 National Centre for Infectious Diseases, Singapore

7 Leong Keng Hong Arthritis and Medical Clinic, Singapore

8 Department of Rheumatology & Immunology, Singapore General Hospital, Singapore

9 Department of Medicine, Changi General Hospital, Singapore

10 Division of Rheumatology, Department of Medicine, Khoo Teck Puat Hospital, Singapore

*Correspondence:
Dr Manjari Lahiri
Division of Rheumatology, Department of Medicine, National University Hospital, Singapore
1E Kent Ridge Road, Singapore 119228
[email protected]

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Abstract

Aim

People with rheumatic diseases (PRD) remain vulnerable in the era of the COVID-19

pandemic. We formulated recommendations to meet the urgent need for a consensus for

vaccination against SARS-CoV-2 in PRD.

Methods

Systematic literature reviews were performed to evaluate (1) outcomes in PRD with COVID-

19; (2) efficacy, immunogenicity and safety of COVID-19 vaccination; and (3) published

guidelines/recommendations for non-live, non-COVID-19 vaccinations in PRD.

Recommendations were formulated based on the evidence and expert opinion according to the

Grading of Recommendations Assessment, Development and Evaluation methodology.

Results

The consensus comprises two overarching principles and seven recommendations. Vaccination

against SARS-CoV-2 in PRD should be aligned with prevailing national policy and should be

individualized through shared decision between the healthcare provider and patient. We

strongly recommended that eligible PRD and household contacts be vaccinated against SARS-

CoV-2. We conditionally recommended that the COVID-19 vaccine be administered during

quiescent disease if possible. Immunomodulatory drugs, other than rituximab, can be continued

alongside vaccination. We conditionally recommended that the COVID-19 vaccine be

administered prior to commencing rituximab if possible. For patients on rituximab, the vaccine

should be administered a minimum of 6 months after the last dose and/or 4 weeks prior to the

next dose of rituximab. Post-vaccination antibody titres against SARS-CoV-2 need not be
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

measured. Any of the approved COVID-19 vaccines may be used, with no particular

preference.

Conclusion

These recommendations provide guidance for COVID-19 vaccination in PRD. Most

recommendations in this consensus are conditional, reflecting a lack of evidence or low-level

evidence.

(words 247)

Keywords: COVID-19; SARS-CoV-2; vaccination; people with rheumatic diseases;

immunosuppression

Introduction

The global novel coronavirus disease 2019 (COVID-19) pandemic has posed many

uncertainties among physicians treating people with rheumatic diseases (PRD). Such patients

are considered high risk due to their diseases and the immunosuppressive nature of their

medications. A recent meta-analysis demonstrated that PRD had a two-fold risk of COVID-19

compared to control patients.1 In addition, PRD with COVID-19 had a higher fatality rate and

were at significant risk of suffering poor outcomes such as the need for hospitalization, care in

the intensive care unit (ICU) and mechanical ventilation.2,3

Various candidate vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-

CoV-2) are in development. The first three COVID-19 vaccines to receive Emergency Use

Authorisation (EUA) from the United States Food and Drug Administration (US FDA), the
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Pfizer-BioNTech® COVID-19 vaccine (BNT162b2), the Moderna® COVID-19 vaccine

(mRNA-1273) and the Johnson & Johnson® vaccine (JNJ-78436735), reported good vaccine

efficacy at 95%, 94.1% and 66.9%, respectively.4-6 However, patients on immunosuppressive

therapy were excluded from all three trials. Additionally, patients with autoimmune diseases

were excluded from two of the trials, and only 62 PRD (0.3% of the total study population, but

without detailed information) were included in the treatment arm of the Pfizer-BioNTech®

trial. Thus, there is a paucity of evidence for PRD and their managing physicians to guide

COVID-19 vaccination in this population.

The Singapore Health Sciences Authority (HSA) has approved the Pfizer-BioNTech® and

Moderna® COVID-19 mRNA vaccines via the Pandemic Special Access Route, and the

Ministry of Health, Singapore (MOH) Expert Committee on COVID-19 Vaccination (EC19V)

has published recommendations for their use 7,8 with other vaccines to be evaluated at a later

date. Worldwide, four additional vaccines, namely from Gamaleya Research Institute of

Epidemiology and Microbiology (Gam-COVID-Vac or Sputnik V®) 9, Oxford-Astra-Zeneca®

10
(AZD1222) , Novartis (Novavax® or NVX-CoV2373) 11
and Bharat Biotech (BB-152 or

Covaxin®) 12, have so far published or announced interim Phase 3 efficacy data and are either

already authorised or expected to apply for EUA in several countries. In this consensus

recommendation, the Chapter of Rheumatologists, College of Physicians, Academy of

Medicine, Singapore seeks to address questions regarding the suitability of COVID-19

vaccination in PRD and provide consensus recommendations on COVID-19 vaccination

among PRD.

Methods
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

A Core Working Group (CWG) was established (AS, CX, WF, ML). Members of the CWG

reviewed published primary clinical trials and performed a systematic literature review to

answer four research questions. Where appropriate, in lieu of a systematic review of the

primary literature, international best practice guidelines and recommendations from

rheumatology societies on vaccinations in PRD were reviewed. Other academic bodies’

recommendations for COVID-19 vaccination and other non-live, non-COVID-19 vaccinations

in PRD and / or immunocompromising conditions were also considered. The CWG developed

draft recommendations for rating by an invited task force panel (TFP). A modified Delphi

approach, similar to what has been applied by other organizations, was used.13,14 The TFP (TA,

KOK, AL, THL, KHL, AHLL, MKS, TCT, GGT, BYT) comprised eight locally recognized

adult rheumatologists from public and private healthcare institutions in Singapore, one

paediatric rheumatologist and one infectious diseases specialist. A conflict-of-interest

declaration was required from all members of the CWG and TFP prior to the consensus process.

All members declared no conflict of interest.

Review of the literature

The CWG sent out preselected topics to the TFP and sought their input on additional clinically

important topics. Considering the TFP's input, the CWG selected the following core topics

relevant to clinical decision-making for COVID-19 vaccination:

1. Are PRD at increased risk of adverse outcomes from COVID-19?

A recent systematic review and meta-analysis of global data showed that PRD remain

vulnerable, with substantial rates of severe outcomes.3 The overall rates of hospitalization,

oxygen support, ICU admission and fatality among COVID-19 infected patients with
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

rheumatic diseases were 58% (95% confidence interval (CI) 48% - 67%), 33% (95% CI 21%

- 47%), 9% (95% CI 5% - 15%) and 7% (95% CI 3% - 11%), respectively, which are

comparable with data from the COVID-19 Global Rheumatology Alliance (GRA) physician

registry. The fatality rate was higher both in this meta-analysis and the COVID-19 GRA (7.0%

and 6.7%, respectively) than that (3.4%) of general population infected with COVID-19 in the

WHO database, although age, gender and comorbidities were not matched.3 D’Silva et al

reported a higher risk of hospitalization, ICU admission, mechanical ventilation, acute kidney

injury, renal replacement therapy and death based on TriNetX, a multi-center research network

with real-time electronic health record data across 35 healthcare organizations in the US.15 The

authors concluded that these outcomes were likely mediated by a higher comorbidities burden

in PRD, such as hypertension, diabetes mellitus, chronic kidney disease and asthma.

2. Are existing approved vaccines against SARS CoV2 safe, immunogenic and efficacious in

PRD?

Two mRNA vaccines are currently approved by the US FDA and Singapore HSA. It is known

that selected DNA and RNA molecules have the unique property to activate the immune

system, through activation of Toll-like receptors.16 It has been shown that the innate immune

response would be suppressed by nucleoside modification of RNA, as the innate immune

system detects RNA lacking nucleoside modification as a means of selectively responding to

bacteria or viruses.17,18 Both mRNA COVID-19 vaccines from Pfizer/BioNTech® and

Moderna® are nucleoside-modified RNA. Thus, the risk of autoimmune disease flare after

receiving mRNA COVID-19 vaccine may more likely result from the adaptive immune

response to spike protein synthesized by mRNA, rather than the innate immune response to

nucleoside-modified RNA. Theoretically, this is no different from the risk from other protein /
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

conjugate vaccines, which have been in use for many years and have been confirmed to be safe

in PRD.

There were 62 (0.3%) participants who had rheumatic disease and received BNT162b2 mRNA

COVID-19 vaccine in the Pfizer/BioNTech® trial.4 No flare of autoimmune disease was

reported. Certainly, larger sample size and long-term follow-up studies are needed to further

ascertain the risk of flares in autoimmune diseases.

Other vaccine strategies, including inactivated virus vaccines (such as the CoronaVac

developed by Sinovac® 19 and Covaxin® developed by Bharat Biotech 12), virus vector vaccines

(such as the COVID-19 vaccines by AstraZeneca® 10, the Johnson and Johnson vaccine 6 and

the Sputnik V® Russian vaccine by Gamaleya 9) and protein subunit vaccines (such as the

Novavax® vaccine 11) similarly provide little data in PRD. Pertinent information from primary

COVID-19 vaccine trials to date are summarized in Table 1.4-6,9,10,12,19,20

There are currently no available data on the immunogenicity and efficacy of COVID-19

vaccination in PRD.

3. Are other (non-COVID-19) recommended non-live vaccines safe, immunogenic and

efficacious in PRD?

4. What is the effect of various drugs used in PRD on immunogenicity of (non-COVID-19)

vaccines in PRD?

To review the evidence in non-live, non-COVID-19 vaccinations in PRD, a systematic review

of international best practice guidelines and recommendations from rheumatology societies on

medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

vaccinations in PRD was performed, in lieu of a systematic review of the primary literature.

We searched PubMed for publications using the Medical Subject Headings (MeSH) terms

("Consensus"[MeSH] OR "Consensus Development Conference, NIH" [Publication Type] OR

"Consensus Development Conference" [Publication Type] OR "Consensus Development

Conferences, NIH"[MeSH] OR "Consensus Development Conferences"[MeSH]) OR

("Guidelines as Topic" [MeSH] OR "Practice Guidelines as Topic" [MeSH] OR "Guideline"

[Publication Type] OR "Health Planning Guidelines" [MeSH] OR "Standard of Care" [MeSH]

OR "Practice Guideline" [Publication Type] OR "Clinical Protocols" [MeSH] AND

((vaccine[MeSH Terms]) OR (vaccination[MeSH Terms])) OR (active immunization[MeSH

Terms]) AND ((((autoimmune disease[MeSH Terms]) OR (rheumatology[MeSH Terms])) OR

(host, immunocompromised[MeSH Terms])) OR (immunocompromised host[MeSH Terms]))

OR (immunocompromised patient[MeSH Terms]). The filters English (language) and Humans

were applied. This search yielded 191 citations. One member of the CWG (ML) screened

through the titles and/or abstracts and excluded those that were not a practice guideline, not

targeted to PRD, only addressed live vaccines, were only targeted to childhood vaccines, did

not undertake a systematic literature review, were duplicates, or were outdated

recommendations from the same body. Four additional citations were added from manual

search. We then reviewed the remaining 21 full text articles and excluded best practice

guidelines that did not undertake a consensus methodology and evidence grading or strength

of recommendations. Eleven full text articles were finally included (Figure 1, Table 2).21-31 The

definitions of PRD and immunomodulatory drugs considered in this recommendation are

summarized in Table 3.

Creation of preliminary statements and rating

medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

The CWG met to formulate and finalize preliminary statements for rating by the TFP, which

was conducted on an online survey platform. The TFP were provided with summarized

evidence from the reviewed trials and guidelines, a link to an online rating form and rating

instructions. Based on their expertise and the provided literature, each TFP member

independently rated each statement on a five-point Likert scale (1 = strongly disagree, 2 =

disagree, 3 = neutral, 4 = agree, 5 = strongly agree); an agreement was defined as a score of 4

or 5. A consensus was obtained if there was ≥70% agreement. The CWG and the TFP convened

via a teleconferencing platform, where the aggregated findings were presented and discussed.

Definitions were clarified and statements were reworded, if needed. As there was consensus

on all statements following the online voting round, no further round of voting was conducted.

The Grading of Recommendations Assessment, Development and Evaluation (GRADE)

32
methodology was used to determine the strength of recommendations. In determining the

strength of recommendations, the TFP considered the level of evidence available, as well as

the balance between the potentially expected benefits and risks from COVID-19 vaccination/

omission of vaccination in PRD. Recommendations were categorized as “strong” when

benefits/risks clearly outweighed the other, and “conditional” when benefits/risks were closely

balanced or uncertain.

Finalizing Consensus Statements

The final consensus statement was circulated to the TFP after the consensus meeting and was

approved by all members.

Results
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

The final consensus statements consist of two overarching principles and seven

recommendations. They are summarized in Table 4.

Overarching principles

1. Vaccination in PRD should be aligned with prevailing national policy.

The knowledge on COVID-19 vaccination is rapidly evolving with various candidate vaccines

still undergoing clinical trials. As new evidence becomes available, the landscape of vaccine

availability in each country will likely differ. It is important that healthcare professionals align

their recommendations to prevailing national policy, to ensure consistency of messages to

patients and maintain streamlined safety workflows. Vaccine safety monitoring systems, such

as the vaccine adverse event reporting system (VAERS) are in place to detect possible safety

signals in the vaccinated population. Locally, the HSA reviews all reports of post-vaccination

reactions, to inform national policy of vaccine eligibility, monitoring and precautions.

2. The decision for vaccination should be individualised, and should be explained to the

patient, to provide a basis for shared decision-making between the healthcare provider and

the patient.

The Rheumatologists’ decision for offering vaccinations to their patients should take into

account the individual patient’s disease state, medications, as well as their risk profile and

preferences. Patients should be provided with evidenced-based information to enable them to

participate in a shared decision-making process. Information should include the potential risks
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

and benefits from vaccination (or its omission), the vaccination schedule and a discussion of

the various available vaccines.

Recommendations

1. We strongly recommend that eligible patients be vaccinated against SARS-CoV2.

PRD are a vulnerable patient population at increased risk of acquiring COVID-191 and

suffering severe outcomes3,15. While there are little data on mRNA vaccination in PRD, there

are no reports of autoimmune disease flares in the small group of PRD included in the

Pfizer/BioNTech® trial.4 There is an isolated report of a healthy individual who was diagnosed

with fatal immune thrombocytopenia six days after COVID-19 vaccination with no clear

evidence of the development of a new autoimmune disease. While there was temporal

association, it could not be fully concluded that the vaccine was definitely the cause for the

patient’s presentation.33 To our knowledge, there are no other published reports of autoimmune

disease induction or flare after COVID-19 vaccination in the more than 300 million people

vaccinated worldwide to date. COVID-19 vaccination should therefore be strongly

recommended for PRD given the vulnerability of PRD along with good efficacy,

immunogenicity and favourable safety profile of COVID-19 vaccination in healthy patients.

This is in line with recommendations endorsed by the British Society of Rheumatology for

clinically extremely vulnerable (CEV) patients34, which includes PRD and the recent press

release from the American College of Rheumatology (ACR)35. The United States Centers for

Disease Control and Prevention (US CDC) similarly places immunocompromised persons at

an increased risk for severe COVID-19 and recommends that these patients receive vaccination

as long as there are no contraindications.36

medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

2. We conditionally recommend that the COVID-19 vaccine be administered during quiescent

disease, if possible.

This recommendation is extrapolated from other vaccine recommendations in PRD, and is

largely based on expert opinion, hence the conditional strength of recommendation.

28,29
Vaccination studies in PRD have been largely conducted during quiescent disease state

and thus have limited generalizability to the PRD population with active disease, though

isolated studies have shown similar vaccine immunogenicity regardless of disease state 37. The

decision for vaccination in patients whose disease is not quiescent should be considered on an

individual patient level.

3. We conditionally recommend that immunomodulatory drugs, other than rituximab, can be

continued alongside COVID-19 vaccination.

Vaccination studies in PRD on immunomodulatory drugs (other than B cell depleting therapy)

have shown sufficient protective efficacy with common non-live vaccines including influenza

and pneumococcal vaccines, despite somewhat reduced immunogenicity particularly with

methotrexate and abatacept.22,26,30

4. We conditionally recommend that the COVID-19 vaccine be administered prior to

commencing rituximab, if possible. For patients on rituximab, the vaccine should be

administered a minimum of 6 months after the last dose, and/or 4 weeks prior to the next

dose of rituximab.
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

B cell depleting therapy with rituximab is associated with significant reduction in

immunogenicity. Despite reduced humoral immune response, cellular immune response is still

preserved after influenza vaccination in patients who were treated with rituximab.38

Satisfactory immunogenicity has been shown in rituximab treated patients when influenza and

pneumococcal vaccines were administered 6 months after a previous dose 23,29,39 and at least 4

weeks prior to a subsequent dose 24,28, forming the basis of this conditional recommendation.

Of note, the British Arthritis and Musculoskeletal Alliance recommends that vaccination

should not be delayed in patients on or planned for rituximab, with an ideal interval of

vaccination 4-8 weeks after the last dose of rituximab or 2 weeks prior to a planned dose of

rituximab, if possible.34

5. We conditionally recommend that post-COVID-19 vaccination antibody titres need not be

measured.

Outside of paediatric care 27, post-vaccination antibody titre measurement is not part of routine

clinical practice and is not part of other vaccination guidelines in adult PRD. As the correlation

between antibody titres post COVID-19 vaccination and clinical protection is not well

established at present, we conditionally recommend that titres not be measured.

6. We strongly recommend that household contacts be vaccinated against SARS-CoV-2.

Vaccination of household contacts has been advocated by societies such as European Alliance
29
of Associations for Rheumatology (EULAR) and Infectious Diseases Society of America

(IDSA) 23 for a variety of inactivated and live vaccines (except for the oral polio vaccination
22,23,29
). Increasingly, epidemiologic studies have demonstrated SARS-CoV-2 transmission in
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

40-42
close contacts due to asymptomatic and pre-symptomatic infections , highlighting the

importance of extending vaccinations to household contacts in order to protect vulnerable

patients.

7. We conditionally recommend that any of the approved COVID-19 vaccines may be used,

with no particular preference.

The various SARS-CoV-2 vaccines in development are non-live vaccines. The anticipated risk

benefit ratio should therefore be similar for vaccinations to be recommended without

preference for any particular vaccine. However, long term follow-up in PRD will be needed to

ascertain longer term efficacy and safety of the various vaccines.

Discussion

The consensus recommendations for COVID-19 vaccination in PRD presented in this article

were based on review of the limited currently available literature with these vaccines,

supplemented by the more extensive knowledge that is available for other non-live vaccines in

PRD. It is noteworthy that the absence of evidence is not evidence of absence, and practical

recommendations for PRD need to be made despite the scarcity of literature in these vulnerable

patients. Experts in the specialty were consulted, in order to synthesize the available literature

into clinically meaningful recommendations. Available evidence on the risk of COVID-19 in

PRD was weighed against the potential risks / benefits of vaccination with a new vaccine

technology, borrowing from the principles of vaccination with non-live viruses in PRD and the

available knowledge on mRNA drug delivery systems.

medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

In formulating these recommendations, the TFP were cognizant of the heightened risk of

COVID-19 in our patients. Therefore, recommendations were formulated to aid practicing

rheumatologists in their decision making without being overly restrictive, while allowing

individualized decision making for each patient. These should take into account patient’s

disease status, ongoing treatment, risk profiles, preferences and local community transmission

risk.

Our consensus recommendations for COVID-19 vaccinations in PRD were developed

employing a systematic literature review and Delphi method. The process of recommendation

development incorporated all components of the Appraisal of Guidelines for Research &

Evaluation (AGREE) instrument43, other than patient/ allied health involvement, for

practicality. The AGREE framework was developed to ensure the rigor of guideline

formulation which are feasible for clinical practice. The only other consensus

recommendations developed using a standardised Delphi method for COVID-19 vaccination

in PRD were recently announced in a press release by the American College of

Rheumatology35. Importantly, the broad principles for COVID-19 vaccination in PRD in our

recommendations are similar to what the ACR has outlined, in spite of the vastly different

pandemic situation (and therefore the balance of risk/ benefit of the vaccine) in Asia versus

North America. Vaccination is strongly encouraged, may be given while on

immunomodulatory therapy, preferably during quiescent disease, and without the need for

testing for post-vaccination antibody titres. The ACR recommended that COVID-19

vaccination should be timed according to the dosing of certain immunomodulatory treatments

(rituximab, intravenous abatacept and intravenous cyclophosphamide) and that treatment with

methotrexate, Janus Kinase inhibitors and abatacept should be temporarily interrupted prior to

or after COVID-19 vaccination. However, as discussed, while there may be reduced vaccine
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

immunogenicity in patients on these medications, sufficient protective efficacy has been

demonstrated22,26,30, thus forming the basis of our recommendation to vaccinate without

treatment interruption or consideration for timing of doses.

As of the latest WHO update on March 5th, 2021, 79 candidate vaccines are in clinical

development, with a further 182 in pre-clinical development.44 Since the roll out of vaccination

campaigns in various regions in mid-December 2020 up to March 9th, 2021, more than 312

million vaccine doses have been administered worldwide45 and our collective experience with

the new vaccines continue to evolve. It is important that governing institutions and healthcare

providers continue to keep abreast of the latest evidence, so that recommendations can be

reviewed and/or revised as new knowledge emerges. Particularly, data on safety and efficacy

of vaccination in PRD are urgently needed to update recommendations in this vulnerable

population.

References

1. Akiyama S, Hamdeh S, Micic D, Sakuraba A. Prevalence and clinical outcomes of

COVID-19 in patients with autoimmune diseases: a systematic review and meta-analysis.
Ann Rheum Dis 2020 Oct 13 Online ahead of print.
2. D'Silva KM, Jorge A, Cohen A, et al. COVID-19 Outcomes in Patients with Systemic
Autoimmune Rheumatic Diseases (SARDs) Compared to the General Population: A US Multi-
Center Comparative Cohort Study. Arthritis Rheumatol 2020 Dec 10 Online ahead of print.
3. Xu C, Yi Z, Cai R, Chen R, Thong BY, Mu R. Clinical outcomes of COVID-19 in patients
with rheumatic diseases: A systematic review and meta-analysis of global data. Autoimmun
Rev 2021 Feb 18 Online ahead of print.
4. Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA
Covid-19 Vaccine. N Engl J Med 2020; 383(27): 2603-15.
5. Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-
CoV-2 Vaccine. N Engl J Med 2021; 384(5): 403-16.
6. FDA Briefing Document Janssen Ad26.COV2.S Vaccine for the Prevention of COVID-
19. 2021. https://www.fda.gov/media/146217/download. Accessed on March 9th, 2021.
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

7. Reccommendations on Singapore's COVID-19 Vaccination Strategy by the Expert

Committee on COVID-19 Vaccination. 2021.
https://www.moh.gov.sg/docs/librariesprovider5/pressroom/press-releases/annex-b-
ec19v-27-dec.pdf. Accessed on March 9th, 2021.
8. HSA Grants Interim Authorisation for Moderna COVID-19 Vaccine in Singapore. 2021.
https://www.hsa.gov.sg/announcements/press-release/hsa-grants-interim-authorisation-
for-moderna-covid-19-vaccine-in-singapore. Accessed on March 9th, 2021.
9. Logunov DY, Dolzhikova IV, Shcheblyakov DV, et al. Safety and efficacy of an rAd26
and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a
randomised controlled phase 3 trial in Russia. Lancet 2021; 397(10275): 671-81.
10. Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-
19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled
trials in Brazil, South Africa, and the UK. Lancet 2021; 397(10269): 99-111.
11. Novavax COVID-19 Vaccine Demonstrates 89.3% Efficacy in UK Phase 3 Trial. 2021.
https://ir.novavax.com/node/15506/pdf. Accessed on March 9th, 2021.
12. Bharat Biotech Announces Phase 3 Results of COVAXIN®:
India’s First COVID-19 Vaccine Demonstrates Interim Clinical
Efficacy of 81%. 2021. https://www.bharatbiotech.com/images/press/covaxin-phase3-
efficacy-results.pdf. Accessed on March 9th, 2021.
13. van der Heijde D, Aletaha D, Carmona L, et al. 2014 Update of the EULAR
standardised operating procedures for EULAR-endorsed recommendations. Ann Rheum Dis
2015; 74(1): 8-13.
14. American College of Rheumatology. Policy and Procedure Manual for Clinical
Practice Guidelines. Atlanta, Georgia: American College of Rheumatology., 2015.
15. D'Silva K, Jorge A, Lu N, Zhang Y, Wallace Z, Choi H. Outcomes of Coronavirus Disease
2019 Infection Among Patients Living with Rheumatic Diseases: A Matched Cohort Study
from a US Multi-Center Research Network [abstract]. Arthritis & rheumatology (Hoboken,
NJ) 2020; (72 (suppl 10)).
16. Jiménez-Dalmaroni MJ, Gerswhin ME, Adamopoulos IE. The critical role of toll-like
receptors — From microbial recognition to autoimmunity: A comprehensive review.
Autoimmunity reviews 2016; 15(1): 1-8.
17. Kariko K, Buckstein M, Ni H, Weissman D. Suppression of RNA recognition by Toll-like
receptors: the impact of nucleoside modification and the evolutionary origin of RNA.
Immunity 2005; 23(2): 165-75.
18. Koski GK, Kariko K, Xu S, Weissman D, Cohen PA, Czerniecki BJ. Cutting edge: innate
immune system discriminates between RNA containing bacterial versus eukaryotic
structural features that prime for high-level IL-12 secretion by dendritic cells. J Immunol
2004; 172(7): 3989-93.
19. Zhang Y, Zeng G, Pan H, et al. Safety, tolerability, and immunogenicity of an
inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-
blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis 2021; 21(2): 181-92.
20. Clinical study protocol of a phase 3, randomised, observer-blinded, placebo-
controlled trial to evaluate the efficacy and safety of a SARS-CoV-2 recombinant spike
protein nanoparticle vaccine (SARS-CoV-2 rS) with matrix-M1 TM adjuvant in adult
participants 18-84 years of age in the United Kingdom. 2021.
https://www.novavax.com/sites/default/files/2020-
11/2019nCoV302Phase3UKVersion2FinalCleanRedacted.pdf. Accessed on March 9th, 2021.
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

21. Singh JA, Saag KG, Bridges SL, Jr., et al. 2015 American College of Rheumatology
Guideline for the Treatment of Rheumatoid Arthritis. Arthritis care & research 2016; 68(1):
1-25.
22. Seo YB, Moon SJ, Jeon CH, et al. The Practice Guideline for Vaccinating Korean
Patients with Autoimmune Inflammatory Rheumatic Disease. Infection & chemotherapy
2020; 52(2): 252-80.
23. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for
vaccination of the immunocompromised host. Clin Infect Dis 2014; 58(3): e44-100.
24. Papp KA, Haraoui B, Kumar D, et al. Vaccination Guidelines for Patients with
Immune-mediated Disorders Taking Immunosuppressive Therapies: Executive Summary. J
Rheumatol 2019; 46(7): 751-4.
25. Keeling SO, Alabdurubalnabi Z, Avina-Zubieta A, et al. Canadian Rheumatology
Association Recommendations for the Assessment and Monitoring of Systemic Lupus
Erythematosus. J Rheumatol 2018; 45(10): 1426-39.
26. Holroyd CR, Seth R, Bukhari M, et al. The British Society for Rheumatology biologic
DMARD safety guidelines in inflammatory arthritis. Rheumatology 2019; 58(2): 372.
27. Heijstek MW, Ott de Bruin LM, Bijl M, et al. EULAR recommendations for vaccination
in paediatric patients with rheumatic diseases. Annals of the rheumatic diseases 2011;
70(10): 1704-12.
28. Guerrini G, Franzetti F, Giacomelli R, et al. Italian recommendations for influenza and
pneumococcal vaccination in adult patients with autoimmune rheumatic diseases. Clinical
and experimental rheumatology 2020; 38(2): 245-56.
29. Furer V, Rondaan C, Heijstek MW, et al. 2019 update of EULAR recommendations for
vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann
Rheum Dis 2020; 79(1): 39-52.
30. Buhler S, Eperon G, Ribi C, et al. Vaccination recommendations for adult patients
with autoimmune inflammatory rheumatic diseases. Swiss medical weekly 2015; 145:
w14159.
31. Centers for Disease Control and Prevention. Use of 13-Valent Pneumococcal
Conjugate Vaccine and 23-Valent Pneumococcal Conjugate Vaccine for Adults with
Immunocompromising Conditions: Recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR 2012; 61: 816-9.
32. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating
quality of evidence and strength of recommendations. BMJ 2008; 336(7650): 924-6.
33. Tarawneh O, Tarawneh H. Immune thrombocytopenia in a 22-year-old post Covid-19
vaccine. Am J Hematol. 2021 Jan 21. Online ahead of print.
34. Principles for COVID-19 Vaccination in Musculoskeletal and Rheumatology for
Clinicians. 2021. http://arma.uk.net/covid-19-vaccination-and-msk/. Accessed on March
9th, 2021.
35. American College of Rheumatology. COVID-19 Vaccine Clinical Guidance Summary
for Patients with Rheumatic and Musculoskeletal Diseases. 2021.
https://www.rheumatology.org/Portals/0/Files/COVID-19-Vaccine-Clinical-Guidance-
Rheumatic-Diseases-Summary.pdf. Accessed on March 9th, 2021.
36. Centres for Disease Control and Prevention. Interim Clinical Considerations for Use
of COVID-19 Vaccines Currently Authorized in the United States. 2021,
https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html.
Accessed on March 9th, 2021.
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

37. Campos LM, Silva CA, Aikawa NE, et al. High disease activity: an independent factor
for reduced immunogenicity of the pandemic influenza a vaccine in patients with juvenile
systemic lupus erythematosus. Arthritis care & research 2013; 65(7): 1121-7.
38. Arad U, Tzadok S, Amir S, et al. The cellular immune response to influenza
vaccination is preserved in rheumatoid arthritis patients treated with rituximab. Vaccine
2011; 29(8): 1643-8.
39. Singh JA, Saag KG, Bridges SL, Jr., et al. 2015 American College of Rheumatology
Guideline for the Treatment of Rheumatoid Arthritis. Arthritis & rheumatology 2016; 68(1):
1-26.
40. Pan X, Chen D, Xia Y, et al. Asymptomatic cases in a family cluster with SARS-CoV-2
infection. Lancet Infect Dis 2020; 20(4): 410-1.
41. Qian G, Yang N, Ma AHY, et al. COVID-19 Transmission Within a Family Cluster by
Presymptomatic Carriers in China. Clin Infect Dis 2020; 71(15): 861-2.
42. Mizumoto K, Chowell G. Transmission potential of the novel coronavirus (COVID-19)
onboard the diamond Princess Cruises Ship, 2020. Infect Dis Model 2020; 5: 264-70.
43. Collaboration A. Development and validation of an international appraisal
instrument for assessing the quality of clinical practice guidelines: the AGREE project.
Quality & safety in health care 2003; 12(1): 18-23.
44. World Health Organization: Draft landscape and tracker of COVID-19 candidate
vaccines. 2021. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-
candidate-vaccines. Accessed on March 9th, 2021.
45. Our World in Data. 2021. https://ourworldindata.org/grapher/cumulative-covid-
vaccinations?tab=chart&stackMode=absolute&time=earliest..latest&region=World.
Accessed on March 9th, 2021. .
46. Oxford Centre for Evidence-Based Medicine: Levels of Evidence (March 2009).
https://www.cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-evidence-
based-medicine-levels-of-evidence-march-2009. Accessed on March 9th, 2021.
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Figure 1: Flowchart for study selection

 Table 1: Primary COVID-19 vaccine trials
Pfizer-BioNTech® 4 Moderna® 5 Sinovac® 19 Oxford-Astra Gamaleya® 9 Johnson & Johnson® Novartis 20 Bharat Biotech12
Zeneca® 10 6

Trial Sites US, Brazil, Argentina, United States China UK, Brazil, South Russia US, Central & South UK, South Africa India
South Africa, Africa America, South
Germany, Turkey Africa
MOA Lipid nanoparticle–formulated, nucleoside- Adsorbed SARS- Replication deficient viral vector with SARS COV2 spike protein Adjuvant Whole-virion
modified mRNA CoV-2 (inactivated) recombinant protein inactivated SARS-
vaccine particle CoV-2 vaccine with
a toll-like
receptor 7/8 agonist
molecule adsorbed
to alum
Storage Freezer -70°C Freezer -15 to -25°C Refrigerator 2 to 8°C Refrigerator 2 to 8°C Freezer -18°C Refrigerator 2 to 8°C Refrigerator 2 to Refrigerator 2 to
8°C 8°C
Dosing Two 30ug (0.3ml) IM Two 100ug (0.5ml) Two doses 2 weeks Two doses 4-12 Two (0.5ml) IM doses Single dose Two (0.5ml) IM Two 6ug IM doses
doses 21 days apart IM doses 28 days apart weeks apart 21 days apart doses 21 days apart 28 days apart
apart
Inclusion Adults (>16yrs) Adults (≥18yrs) Adults (≥18yrs) Adults (≥18yrs) Adults (≥18yrs) Adults (≥18yrs) Adults (18-84yrs) Adults (18-98yrs)

Relevant Immunodeficient state Autoimmune disease Autoimmune disease Autoimmune disease Immunodeficient state Immunodeficient state Autoimmune NA
Exclusions and use of Immunodeficient state Immunodeficient state Immunodeficient state and use of and use of disease
immunosuppressant and use of and use of and use of immunosuppressant immunosuppressant Immunodeficient
medication. immunosuppressant immunosuppressant immunosuppressant medication within the medication. state and use of
medication within the medication within the medication within the past 3 months. immunosuppressant
past 6 months. preceding 3 months past 6 months. medication within
the preceding 3
months
N* 37,706 28,207 13,060 11,636 19,866 43,783 15,000 25,800
Follow up 2 months 64 days NA 2 months 27 days 8 weeks NA NA
(median) after
last dose
Asian 1608 (4.3%) 1382 (4.6%) NA 517 (4.4%) 286 (1.4%) 3.5% NA 100%
participants
Comorbidities 20.5% 22.3% NA 24.7% 24.8% 41% (including NA 17.4%
obesity)
PRD 62 (0.3%) Excluded NA Excluded Likely excluded Allowed, likely none NA NA
included
Elderly >55yrs (42.2%) >65yrs (25.3%) NA >55yrs (12.2%) >60yrs (10.8%) >65yrs (20.4%) >65yrs (27%) >60 yrs (9.4%)
Outcomes 8 vs 162 cases of 11 vs 185 cases of NA 30 vs. 101 cases of 16/14964 vs. 62/4902 116/19514 vs 6 vs. 56 cases of 7 vs. 36 cases of
symptomatic and PCR symptomatic and PCR symptomatic and PCR cases of symptomatic 348/19544 moderate / symptomatic and symptomatic and
confirmed COVID19, confirmed COVID19, confirmed COVID19, and PCR confirmed severe PCR PCR confirmed PCR confirmed
vaccine efficacy 95% vaccine efficacy vaccine efficacy COVID19, vaccine confirmed COVID19, COVID19, vaccine COVID19, vaccine
94.1% 70.4% efficacy 91.6% efficacy 89.3% efficacy 80.6%
 vaccine efficacy
66.9%

Common Expected Expected NA Not different from Injection site Expected NA Not different from
adverse events reactogenicity: reactogenicity: placebo arm. No reactions, flu-like reactogenicity: placebo arm. No
fatigue, headache. injection site pain, anaphylaxis illness, headache, injection site pain, anaphylaxis
Rare anaphylaxis, fatigue, headache, asthenia. No fatigue, headache,
lymphadenopathy muscle pain, joint anaphylaxis myalgia and fever. No
pain and chills. Rare anaphylaxis
lymphadenopathy and
hypersensitivity.
*Patients included in published interim analysis
MOA: Mechanism of action, PRD: Patients with rheumatic disease
NA: Not available
Table 2: Reviewed Practice Guidelines Citations, with focus on non-live vaccinations.

Article Vaccine type Patient Safety Immunogenicity Efficacy Timing / Post vaccination Vaccination of
Population DMARD Cessation Antibody Testing Household
Contacts
Good for Influenza Influenza (LOE
(LOE 1b-4) and PPSV23 2a-5), PPSV23
(LOE 1b-4) (LOE 1b-4)
Quiescent dx
Influenza (LOEa Influenza: reduced by No data for
Prior to IS, in particular B cell Yes, except for
29 PRD on IS/ 2b-4) and PCV RTX, ABA MTX, TNFi, B
Furer V, et al. Non-live depleting therapy (6mths post RTX, - oral polio (LOE
DMARD/ GC (LOE 4) deemed cell depletion,
4wks before next dose of RTX) NA)
safe PPSV23: reduced by belimumab,
No DMARD cessation
RTX, ABA, TOF, GOL tocilizumab,
abatacept,
PCV13: reduced by tofacitinib,
MTX glucocorticoids
Similar risk as Similar or slightly lower
general population than that of healthy Stable dx (LOE : very low)
PRD on IS/ (Influenza LOEb : individuals. Influenza and Prior to IS (LOE : very low)
Seo YB, et al. 22 Non-live - Yes
DMARD/ GC mod; pneumococcal Before ABA and ≥4 wks before RTX
Pneumococcal Pneumococcal: reduced No DMARD cessation
LOE : low) by MTX, RTX, ABA
Pneumococcal: reduced
by MTX, RTX, ABA,
Influenza and TOF, MMF, AZA, CyC,
Stable dx (LOE 2)
Influenza and PRD on IS/ Pneumococcal high dose GC (LOE 2)
Guerrini G, et al. 28 - Pneumococcal: before IS and ≥4 wks - -
pneumococcal DMARD/ GC deemed safe
before RTX (LOE 2)
(LOEc 2) Influenza: reduced by
RTX, ABA, high dose
GC (LOE 2)
2 wks before IS (LOE4 mod)
PRD on IS/
Papp KA, et al. 24 Non-live - - - RTX: 5 mths post RTX and ≥4 wk - -
DMARD/ GC
prior to RTX (LOE low)
Influenza: reduced by
ETN and INF, RTX,
ABA
No flare of RA
Holroyd CR, et al. 26 Non-live RA, PsA, axSpA - - - -
with Influenza Pneumococcal: reduced
by MTX, RTX, ABA

(LOEd 1C)
Trivial number of Influenza (LOE
25 SLE flares with mod)
Keeling SO, et al. Influenza SLE - - - -
Influenza (LOEe
mod)
Reduced by RTX and
RA on DMARD/ Killed vaccine No DMARD cessation needed (LOE
Singh JA, et al. 21 Non-live - possibly MTX (LOEd
GC (LOE very low) very low)
very low)
 When the IS is lowest (LOE low)
No flare nor
Reduced by DMARD/
PRD on IS/ trigger of Before ABA 4-6 wks post
Bühler S, et al. 30 Non-live GC especially MTX, - Yes (LOE NA)
DMARD/ GC rheumatic disease, RTX: 6 mths post RTX for vaccine (LOE NA)
RTX, ABA (LOE mod)
(LOEd low) revaccination, 12 mths post RTX for
primary vaccination
Influenza: reduced
Rubin LQ, et al. 23 Non-live IC - within 6 months of RTX - ≥2 wks before IS (LOE mod) - Yes (LOE high)
(LOE5 mod)
Centers for Disease
Control & Prevention Pneumococcal IC - - - -
31

Influenza and
Influenza: reduced by
pneumococcal: On
GC >10mg/day (LOEc
RTX (LOE 1b-2),
No flare of 3), AZA, HCQ, CYC
GC ≥2mg/kg or
rheumatic disease (LOE 2), RTX (LOE 2)
20mg/d for ≥ 2wks
PRD on DMARD or serious adverse
Heijstek MW, et al. 27 Non-live - Before RTX (LOE 1b-2) (LOE 3), ±TNFi -
/GC events in Pneumococcal: reduced
(LOE 2)
comparison to by MTX (LOE 2), RTX
healthy subjects (LOE 1b)
PPSV23: On MTX
(LOE 2)
a.
Oxford Centre for Evidence-Based Medicine – levels of evidence 46.
b.
Level of evidence as defined: High - Very unlikely to change confidence in the estimate of effect by an additional study; Moderate - Likely to change confidence in the estimate of effect by an additional study;
Low - Highly likely to change confidence in the estimate of effect by an additional study; Very low - Not sure about confidence in the estimate of effect
c.
Level of evidence as defined: 1a - Meta-analysis of randomised controlled trials (RCT); 1b - Randomised controlled trials; 2 - Prospective controlled intervention study without randomization; 3 -
Descriptive/analytic study (including case-control, cross-sectional, case series); 4 - Expert committee reports or opinion or clinical experience of respected authorities or both
d.
GRADE level of evidence 32.
e.
Level of evidence as defined: High - Consistent evidence from well performed RCTs or exceptionally strong evidence from unbiased observational studies; Moderate - Evidence from RCTs with important
limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from unbiased observational studies; Low - Evidence for at least 1 critical outcome from
observational studies, RCTs with serious flaws or indirect evidence; Very low - Evidence for at least 1 critical outcome from unsystematic clinical observations or very indirect evidence

Aza: azathioprine; ABA: abatacept; axSpA: axial spondyloarthritis; CYC: cyclophosphamide; dx: disease; DMARD: disease modifying anti-rheumatic drugs; GC: glucocorticoid; IS: immunosuppression; IC:
immunocompromised; JAKi: inhibitors of janus kinase; PsA: psoriatic arthritis; SLE: systemic lupus erythematosus; LOE: level of evidence; mths: months; MTX: methotrexate; MMF: mycophenolate mofetil; mod:
moderate; NA: non-available; PRD: people with rheumatic diseases; PCV: pneumococcal vaccination; RA: rheumatoid arthritis; RTX: rituximab; TNFi: tumor necrosis factor inhibitors; TOC: tocilizumab; wks: weeks.
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Table 3: Definition of PRD and Immunomodulatory treatment

PRD include, but are not limited to, those diagnosed with:

1. Chronic inflammatory arthritides (e.g. rheumatoid arthritis, psoriatic arthritis, spondyloarthritides,

juvenile idiopathic arthritis, adult onset stills disease)
2. Connective tissue diseases (e.g. systemic lupus erythematosus, immune mediated inflammatory myositis,
sjӧgrens syndrome, systemic sclerosis)
3. Primary systemic vasculitides
4. Autoinflammatory diseases

Immunomodulatory drugs considered for this guidance include:

1. Conventional synthetic disease modifying anti-rheumatic drugs (DMARDs) (methotrexate,

sulphasalazine, leflunomide, hydroxychloroquine)
2. Biologic DMARDs (anti-tumour necrosis factor, tocilizumab, rituximab, abatacept, secukinumab,
ixekizumab, anakinra, belimumab)
3. Targeted synthetic DMARDs (tofacitinib, baricitinib, upadacitinib*)
4. Immunosuppressive drugs (cyclophosphamide, mycophenolate mofetil, azathioprine, cyclosporin A,
tacrolimus)
5. Glucocorticoids

*not included in any of the searched literature on vaccines, hence recommendation is by extrapolation
medRxiv preprint doi: https://doi.org/10.1101/2021.03.01.21252653; this version posted March 12, 2021. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Table 4: Final Consensus Statements

Median % Agreement Strength of

Likert Score Recommendation
Overarching Principles

Vaccination in people PRD should be aligned

4.5 100 -
with prevailing national policy.

The decision for vaccination should be

individualised, and should be explained to the
patient, to provide a basis for shared decision- 5 100 -
making between the healthcare provider and
the patient.

Recommendations

1. We strongly recommend that eligible

5 100 Strong
patients be vaccinated against SARS-CoV2.
2. We conditionally recommend that the
COVID-19 vaccine be administered during 4.5 100 Conditional
quiescent disease, if possible.
3. We conditionally recommend that
immunomodulatory drugs, other than
5 80 Conditional
rituximab, can be continued alongside
COVID-19 vaccination.
4. We conditionally recommend that the
COVID-19 vaccine be administered prior to
commencing rituximab, if possible. For
patients on rituximab, the vaccine should 4 90 Conditional
be administered a minimum of 6 months
after the last dose, and/or 4 weeks prior to
the next dose of rituximab.
5. We conditionally recommend that post-
COVID-19 vaccination antibody titres need 4 90 Conditional
not be measured.

6. We strongly recommend that household

4.5 100 Strong
contacts be vaccinated against SARS-CoV2.

7. We conditionally recommend that any of

the approved COVID-19 vaccines may be 4 70 Conditional
used, with no particular preference.