Can rheumatism patients get vaccinated?

*Only for medical professionals to read and use hormones, can not be vaccinated? According to unofficial statistics that are not rigorous, the public's demand for different vaccines has increased in recent years
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Vaccines, as one of the most important applications of immunology, enable the body to obtain a certain protective ability by initiating a complex immune process
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In the fight against the novel coronavirus pneumonia (hereinafter referred to as the "new crown") epidemic, China has now received more than 800 million doses of the new crown vaccine
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It sounds wonderful, but not everyone can "miaomiaomiaomiaomiao" together
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In particular, immunosuppressants and other drugs used to treat rheumatism may suppress the body's immune system and affect the production of antibodies.
This makes patients very confused: Can I get the vaccine? In the sharing at the 2021 European League Against Rheumatism (EULAR) conference, a team from Oregon shared a special case, which may be able to answer this problem that plagues both doctors and patients with rheumatism
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Case sharing The psoriatic arthritis patient, 50 years old, female, has a history of chronic obstructive pulmonary disease (COPD), has used many biological agents, including infliximab and etanercept, the treatment is ineffective.
Snuzumab treatment can only improve the symptoms of skin involvement and is not effective for joint symptoms; adalimumab treatment was effective at first, but the current condition has not continued to improve
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In addition, treatment with methotrexate (20 mg/week, oral) is not completely effective, and treatment with prednisone (5 mg/day) is effective, but the disease worsens after the dose is reduced
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Although the patient has tried and is using a variety of drugs to control the condition, psoriatic arthritis is still in the active stage.
The patient has worsening pain, morning stiffness lasts for 90 minutes, and plaque rash with itching on both knees.

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At present, there is synovitis in the wrist and ankle joints, as well as toe inflammation and plaque psoriasis in both knees
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Figure 1: The patient is currently in the active stage of the disease.
The patient has an international travel plan after the epidemic, so he wants to replace the biological agent with an oral JAK inhibitor to facilitate travel
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In accordance with the health and safety practices of international travel, the patient consulted the entry-exit quarantine personnel, and the relevant departments recommended that they be vaccinated with hepatitis A vaccine, typhoid vaccine, cholera vaccine and yellow fever vaccine (the latter two are all live vaccines)
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The patient himself should be vaccinated against herpes zoster in accordance with local medical and health recommendations because he is over fifty years old
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At this time, the patient is really guilty: Can she start international travel if she wants to be vaccinated in accordance with the regulations? As the party being consulted, the core issues that doctors are concerned about are nothing more than the following: ①Can the patient receive live vaccines (cholera vaccine and yellow fever vaccine)? ②Can the patient be vaccinated against herpes zoster, and if it can be vaccinated, which one is more suitable for her? ③During the period of vaccination, how to manage the medication regimen for the treatment of psoriatic arthritis and how to arrange the timing of medication? how about it? After reading the related questions of this case, do you feel that your eyes are black? It doesn't matter, Professor Winthrop of Oregon Health and Science University in Oregon will help you to answer your questions
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Everyday: The new crown epidemic has not been controlled.
How can patients adapt to the dangerous "jungle" Professors face the doubts of patients.
The first reaction is the same as that of domestic counterparts who are sticking to the front line of the epidemic: Is the epidemic really suitable for international travel? If you really need to be vaccinated, for this patient, the new crown vaccine should be the most appropriate.
The new crown vaccine currently being vaccinated in the United States is mainly the mRNA vaccine of Pfizer and Modena
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Figure 2: The mechanism of action of the mRNA vaccine [1] In view of the fact that the patient's willingness to vaccinate the new crown vaccine does not seem to have a strong willingness to vaccinate other vaccines, the professor listed the phase III data (safety and effectiveness data) of several new crown vaccines.
Among them: Pfizer's BNT162b2 mRNA vaccine was given two doses at an interval of 21 days, with a total of 38,955 subjects, and the interim analysis was 90% effective in 94 subjects; Modena's mRNA vaccine was given two doses at an interval of 28 days.
A total of 25,645 participants, 95 subjects in the interim analysis, the effectiveness of 94%; AstraZeneca adenovirus vaccine was given two doses at 28 days intervals, in the UK trial, more than 2700 subjects tested the effectiveness of 90%
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The effectiveness of more than 8,900 subjects in Brazil was 62%, and the effectiveness of the interim analysis in the United States was 76% (Note: the effectiveness of the United Kingdom was obtained by combining the results of two different doses, and the dose was halved.
It is better than the original dose, so this data is for reference only); One dose of Johnson & Johnson adenovirus vaccine Ad26.
COV2.
S, the effectiveness of the US trial is 72%, and the effectiveness of South Africa is 57%; Novavac's NVX-CoV2373 recombinant The vaccine was given 2 doses 21 days apart.
The effectiveness of the British trial was 89%, and the effectiveness of South Africa was 60%
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The purpose of enumerating these data is very straightforward-it is recommended that the patient should be given the new crown vaccine first
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At the same time, Professor Winthrop also elaborated on the adverse reaction literature of the new crown vaccine, emphasizing the relevant data of immune thrombotic thrombocytopenia: the incidence of AstraZeneca vaccine is 1 in 100,000, and most of them are age Female subjects younger than 60 years old, and the overall incidence of Johnson & Johnson vaccine is 1/1000000, the main population is young women, but if the subjects are grouped into females younger than 50 years old, this probability will increase by 7 times
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Regarding the "female unfriendliness" of this data, the professor's advice is also very simple-change to a new crown vaccination
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In general, Professor Winthrop believes that there are endless variants of the new coronavirus and is worried that this may make the virus more spread
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Therefore, in the face of the progress of the new crown epidemic, Professor Winthrop used "jungle" to describe the environment in which patients are currently living
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As we all know, survival of the fittest is the core concept of the law of the jungle.
Patients with rheumatism and immune diseases also live in this crisis-ridden jungle.
Whether they need to be vaccinated with the new crown vaccine to enhance their adaptability, the answer is obvious! "Insufficiency of internal strength": other defenses for patients with rheumatism.
In most cases, patients with rheumatism are in a state of "deficiency of internal strength" where martial arts have been abandoned: they need to use disease-improving anti-rheumatic drugs (DMARDs) and glucocorticoids.
And immunosuppressive drugs to regulate the immune system in a disorder
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The favorite words mentioned in the novel, "How can one not get a knife while floating in the rivers and lakes" is very vivid on them.
The body's defensive ability declines, but they still have to face the dangers in the environment
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Therefore, Professor Winthrop believes that in addition to the new crown vaccine, this category of patients also needs other vaccines as a "defense thing" to ensure that they have a certain degree of self-protection: ①Vaccines that need to be vaccinated in daily life: influenza vaccine, Pneumonia vaccine, shingles vaccine, hepatitis B vaccine (for those at risk of infection), whooping cough vaccine
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②Vaccines that may need to be vaccinated during international travel: typhoid vaccine (patients in an immunosuppressed state cannot choose oral dosage forms), yellow fever vaccine (depending on the travel destination, immunosuppressed persons cannot be vaccinated), hepatitis A vaccine, Japanese encephalitis vaccine , Rabies vaccine
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The professor believes that when patients with rheumatism are considering many vaccines that need to be vaccinated during travel, they can consider the specific vaccination according to the destination
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And the vaccination of patients with rheumatism immune disease, will the vaccination be affected by the treatment medication? Know what you need to know: Rheumatism patients understand these test results and then vaccination.
It is correct to say so much.
Will the treatment of rheumatism patients affect the effect of the vaccine? Professor Winthrop enumerated some studies to help everyone understand this problem by explaining the existing clinical research data of different vaccines for patients with rheumatic immune diseases
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1TNF inhibitor In a cohort study, the investigator monitored the antibody titers of 3 groups of subjects vaccinated with different vaccines (including the use of non-steroidal anti-inflammatory drugs and prednisone in 2 test groups).
No difference), the results proved: Except for the A/H1N1 vaccine, the average geometric titers of antibodies in patients with tumor necrosis factor (TNF) inhibitors 4 weeks after vaccination with other vaccines were lower than those of the healthy control group and the non-TNF inhibitor group ( The difference is statistically significant), but there is no statistical difference in the protection rate of each group after 4 weeks of vaccination
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This shows that TNF inhibitors can indeed reduce the amount of antibodies produced after vaccination with related vaccines, but it does not affect the protective effects of related vaccines
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Figure 3: Comparison of antibody titers before and after vaccination in the TNF antagonist group, the TNF antagonist and the healthy control group before and after vaccination [2] In an experiment to observe the serum antibody level of patients with inflammatory bowel disease (IBD) infected with the new coronavirus , The researchers found that the level of antibodies to the new coronavirus in the infliximab treatment group was significantly lower than that in the vedolizumab treatment group, and the combined use of methotrexate and other immunosuppressive agents could further weaken the resistance of patients treated with infliximab to the new crown.
In the serological response of viral infection, only one-third of patients can detect antibodies to the new coronavirus
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Regardless of whether infliximab-treated IBD patients are vaccinated with mRNA vaccine or adenovirus vaccine, the antibody concentration and seroconversion rate are lower than those of vedolizumab [3]
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Figure 4: 4 weeks after the positive test of vedolizumab-treated patients, the antibody reactivity increased, while the same situation did not occur in patients treated with infliximab [4] 2 Methotrexate was published in an unpublished article In the trial, Professor Winthrop and his team found that when vaccines related to H1N1, H3N2 and other dominant strains were used as antigens, the test group with methotrexate stopped for 2 weeks at the time of vaccination was better than that without stopping the drug.
The immune response of the control group is dominant, which may provide inspiration for the management of therapeutic drugs when vaccinated patients with rheumatism
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Figure 5: The immune response of patients who stopped the drug for 2 weeks at the time of vaccination was better than that of the non-discontinued group, and both were statistically significant.
3JAK inhibitors were in a trial to observe the effect of JAK inhibitor tofacitinib on the immunogenicity of specific vaccines , The investigator randomly divided rheumatoid arthritis (RA) subjects who met the enrollment conditions into no DMARDs (n=50), methotrexate alone (n=50), and tofacitinib alone (N=50) and tofacitinib combined with methotrexate (n=50) group, received 23-valent influenza vaccine (PPSV-23: can prevent influenza B, H1N1 and H3N2 virus infection) after 28 days of treatment, and The antibody titer was measured by hemagglutination inhibition method 35 days after vaccination, and it was found that the use of tofacitinib or methotrexate did affect the immune response of RA subjects to PPSV-23
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Professor Winthrop said bluntly that he would prefer to see whether the test results of tofacitinib 5mg will be different
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Figure 6: The results of antibody titers 35 days after vaccination in patients under different conditions [5] and in another unpublished study, the results showed that in subjects taking tofacitinib, 13-valent pneumonia The immunogenicity of the vaccine (PCV-13) is better than that of PPSV-23, and the immune response of subjects 31 days after vaccination is more "fairly robust"
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Figure 7: PCV-13 and tofacitinib related trial data (not officially published) 4 Rituximab As early as 2010, a study conducted by a team at Johns Hopkins University in tetanus vaccine and PPSV A clue was found between -23: The study included 103 RA subjects, compared with rituximab combined with methotrexate treatment and methotrexate alone, and found that rituximab can reduce the number of subjects tested The patient is immune to the humoral immunity of PPSV-23, but does not have this negative effect on the tetanus vaccine
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Therefore, the researchers believe that a polysaccharide vaccine similar to PPSV-23 should be vaccinated before rituximab
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Professor Winthrop believes that the impact of rituximab on vaccination is especially significant within a few months of initial use of rituximab, so his experience is: try to use rituximab as much as possible.
Vaccination will be repeated for a while, the longer the better
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Figure 8: The use of rituximab can weaken the patient's humoral immunity [6] 5 tocilizumab interleukin (IL)-6 receptor inhibitor tocilizumab performs better, the study observed whether or not the combination of alpha Neither methotrexate nor tocilizumab will reduce the immune response of RA patients to PPSV-23.
Therefore, researchers believe that the use of tocilizumab in RA patients to inoculate PPSV-23 is effective [7]
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After briefly explaining the impact of DMARDs on the vaccination of patients with rheumatism, I believe you in front of the screen have already understood the opening questions
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So, can this patient be vaccinated against herpes zoster? A study by the Cleveland Medical Center found that after vaccinating patients with a variety of rheumatoid diseases including RA with recombinant shingles vaccine (RZV), the onset of disease within 12 weeks is not uncommon [8], so RZV is given to such patients Should give full consideration to medication and disease recurrence
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Figure 9: Overview of the recurrence of the disease in patients with rheumatism vaccinated with RZV at 12 weeks and other information.
According to a trial published by the American College of Rheumatology (ACR) in 2020, 40 RA patients (average age) who used JAK inhibitors 62.
3 years old, and nearly 80% of them were women) and 20 RA patients in the control group received Shingrix shingles vaccine, 75% of the test showed positive humoral immunity, while the control group saw 100% positive humoral immunity (p=0.
014)
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During the trial, most people who reported vaccine-related mild to moderate adverse reactions (redness and pain at the injection site, headache, fever) were relieved without intervention, and no subjects in the trial group experienced deterioration or outbreaks
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Therefore, not only the immune response of RA patients who use JAK inhibitors vaccinated with shingles vaccine is satisfactory, but also the tolerance of two doses is quite good [9]
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As for the relevant recommendations for patients with rheumatic immune diseases to vaccinate the new crown vaccine, Professor Winthrop recommends referring to the relevant ACR guidelines (see the table below)
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When facing clinical consultations with similar patients, all friends can also refer to my country's current "New Coronavirus Vaccination Technical Guidelines (First Edition)" for relevant vaccination suggestions for chronic diseases and immunocompromised people! Table 1: Medication and vaccination guidelines for the use of immunomodulators to treat rheumatism and musculoskeletal diseases for patients with new crown vaccine ** When the patient has stable disease control, the drug can be stopped for a short time; if this principle is not met, the decision will be made according to the specific situation ; **There is no consensus in patients receiving the equivalent dose of prednisone ≥20mg/day; IL-6R=sarilumab;tocilizumab;IL-1R=anakinra,canakinumab;IL-17=ixekizumab,secukinumab;IL-12/ 23=ustekinumab;IL-23=guselkumab,rizankizumab;JAKi=baricitinib,tofacitinib,upadacitinib The careful partner may have discovered that the ACR guidelines have not yet reached an agreement on the vaccination recommendations for prednisone equivalent doses ≥20mg/day.
Therefore, Professor Winthrop cited a recent study that has not been peer reviewed for reference
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The study observed 133 subjects with chronic inflammatory diseases and 53 healthy control subjects
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The serum samples were collected for analysis before and after the mRNA vaccine .

The study found that compared with the control group, the humoral immune response of the test group using glucocorticoids was reduced by 10 times (p<0.
0001)
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At the same time, it has been observed that the use of JAK inhibitors and methotrexate and other drugs can also reduce antibody titers (respectively p<0.
0001, p=0.
0023), while biological agents (such as TNF inhibitors, IL-12/23 inhibitors and Integrin inhibitors have little effect on the formation and neutralization of antibodies [10]
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The final decision: What should this patient do? After a thousand words of information, do you now know how to provide advice to this 50-year-old patient with psoriatic arthritis? Professor Winthrop believes that although the effectiveness of cholera vaccine can reach 80% within 3 months after vaccination, it is not necessary for patients to vaccinate.
The reasons are as follows: Cholera vaccine is a live vaccine, and there are many ways to prevent cholera.
Only rely on vaccines for protection
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As for the yellow fever vaccine, this patient cannot be vaccinated.
The reason is simple: patients in an immunosuppressed state cannot be vaccinated with live vaccines
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The two shingles vaccines mentioned in the sharing: Merck’s Zostavax and GlaxoSmithKline’s Shingrix, the professor recommends the latter, and try to vaccinate before using DMARDs
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The main reason for this recommendation is that the latter has better immunogenicity in clinical trials and is not a live vaccine, which is a perfect match for immunosuppressed patients, while the former is for patients who use TNF inhibitors.
May cause damage
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Regarding the methotrexate used by this patient, you can refer to the shared content and analyze the specific situation
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Regarding the use of prednisone, many studies have confirmed that the 5 mg dose will not affect the effect of vaccination
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Therefore, when facing such patients, low-dose glucocorticoids should not become a problem that bothers both doctors and patients
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Experts comment on whether patients with rheumatism can be vaccinated.
It requires a comprehensive range of factors including the risk of specific pathogen infection, the activity of rheumatism, the potential impact of immunosuppressive drugs on antibodies, and the characteristics of the vaccine itself
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In view of the decline in the body's ability to defend against infection in patients with rheumatism, it has become a consensus to vaccinate certain specific inactivated vaccines during the stable period of disease to reduce the risk of infection
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Data on the effects of immunosuppressive drugs, including biological agents, on the effectiveness of vaccination are also emerging, providing a certain reference for clinicians to make decisions
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At the EULAR meeting in 2021, Professor Winthrop shared some representative studies on the effects of immunosuppressive drugs on the body's immune response to vaccines.
Research data suggests that methotrexate, tofacitib, and rituximab can reduce the body For the immune response of certain vaccines, tumor necrosis factor inhibitors and IL-6 receptor antagonists have no significant effect on the protective effects of vaccines
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Regarding the vaccination of new crown vaccines for immunosuppressed people, ACR has published relevant guidelines for reference, but it is worth noting that the relative lack of new crown vaccination data for rheumatism patients, the level of evidence in the ACR guidelines is not high, and the ACR guidelines are for prednisone The vaccination recommendations for equivalent doses ≥20mg/day have not yet been agreed
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Therefore, in clinical practice, whether patients with rheumatism are suitable for vaccination of a particular vaccine, and whether the immunosuppressive drugs they use need to be adjusted, and individualized recommendations should be made after weighing the pros and cons of various factors
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 Expert profile Professor Yao Haihong, Department of Rheumatology and Immunology, Peking University People’s Hospital, Associate Chief Physician, Associate Professor, Associate Editor, 1 rheumatology book, participated in the compilation of 3 rheumatology books, and participated in the compilation of the "13th Five-Year Plan" National Higher Medical College Undergraduate Program Textbook 1 Department, participated in the translation of "Kelly's Rheumatology" published more than 20 academic papers in both Chinese and English, chaired the National Natural Science Foundation of China, Peking University Clinical + X Fund, Chinese Medical Doctor Association Rheumatology and Immunology Physician Committee, Beijing Rheumatology Professional Committee Youth Member of the Beijing Medical Education Association Rheumatology Specialty Committee Member of the University of Hong Kong Visiting Scholar Reference: [1]CAS.
2020.
Meet the mRNA vaccine rookies aiming to take down COVID-19.
[DB/OL]:https://www.
cas.
org/resource/blog/covid-mrna-vaccine,2020-12-04/2021-06-07.
[2]Gelinck LBS,Van Der Bijl AE,Beyer WEP,et al.
The effect of anti-tumour necrosis factorαtreatment on the antibody response to influenza vaccination[J].
Annals of the rheumatic diseases,2008,67(5):713-716.
[3]Kennedy NA,Lin S,Goodhand JR,et al.
Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD[J].
Gut,2021.
[4]Kennedy NA,Goodhand JR,Bewshea C,et al.
Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab[J].
Gut,2021,70(5):865-875.
[5]Winthrop KL,Silverfield J,Racewicz A,et al.
The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis[J].
Annals of the rheumatic diseases,2016,75(4):687-695.
[6]Bingham III CO,Looney RJ,Deodhar A,et al.
Immunization responses in rheumatoid arthritis patients treated with rituximab:results from a controlled clinical trial[J].
Arthritis&Rheumatism:Official Journal of the American College of Rheumatology,2010,62(1):64-74.
[7]Mori S,Ueki Y ,Hirakata N,et al.
Impact of tocilizumab therapy on antibody response to influenza vaccine in patients with rheumatoid arthritis[J].
Annals of the rheumatic diseases,2012,71(12):2006-2010.
[8]Lenfant T,Jin Y, Kirchner E, et al.
Safety of recombinant zoster vaccine:a retrospective study of 622 rheumatology patients[J].
Rheumatology,2021.
[9]Källmark H,Gullstrand B,Nagel J,et al.
Immunogenicity of Adjuvanted Herpes Zoster Subunit Vaccine in Rheumatoid Arthritis Patients Treated with Janus Kinase Inhibitors and Controls:Preliminary Results[abstract].
Arthritis Rheumatol.
2020;72(suppl 10).
https://acrabstracts.
org/abstract/immunogenicity-of-adjuvanted-herpes-zoster-subunit-vaccine-in-rheumatoid- arthritis-patients-treated-with-janus-kinase-inhibitors-and-controls-preliminary-results/.
Accessed June 9,2021.
[10]Deepak P,Kim W,Paley MA,et al.
Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2[J].
medRxiv,2021.
Immunogenicity of Adjuvanted Herpes Zoster Subunit Vaccine in Rheumatoid Arthritis Patients Treated with Janus Kinase Inhibitors and Controls:Preliminary Results[abstract].
Arthritis Rheumatol.
2020;72(suppl 10).
https://acrabstracts.
org/abstract/immunogenicity-of- adjuvanted-herpes-zoster-subunit-vaccine-in-rheumatoid-arthritis-patients-treated-with-janus-kinase-inhibitors-and-controls-preliminary-results/.
Accessed June 9,2021.
[10]Deepak P,Kim W,Paley MA,et al.
Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2[J].
medRxiv,2021.
Immunogenicity of Adjuvanted Herpes Zoster Subunit Vaccine in Rheumatoid Arthritis Patients Treated with Janus Kinase Inhibitors and Controls:Preliminary Results[abstract].
Arthritis Rheumatol.
2020;72(suppl 10).
https://acrabstracts.
org/abstract/immunogenicity-of- adjuvanted-herpes-zoster-subunit-vaccine-in-rheumatoid-arthritis-patients-treated-with-janus-kinase-inhibitors-and-controls-preliminary-results/.
Accessed June 9,2021.
[10]Deepak P,Kim W,Paley MA,et al.
Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2[J].
medRxiv,2021.
org/abstract/immunogenicity-of-adjuvanted-herpes-zoster-subunit-vaccine-in-rheumatoid-arthritis-patients-treated-with-janus-kinase-inhibitors-and-controls-preliminary-results/.
Accessed June 9,2021 .
[10]Deepak P,Kim W,Paley MA,et al.
Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2[J].
medRxiv,2021.
org/abstract/immunogenicity-of-adjuvanted-herpes-zoster-subunit-vaccine-in-rheumatoid-arthritis-patients-treated-with-janus-kinase-inhibitors-and-controls-preliminary-results/.
Accessed June 9,2021 .
[10]Deepak P,Kim W,Paley MA,et al.
Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2[J].
medRxiv,2021.