Next Article in Journal
COVID-19 Vaccination in Pregnancy: Pilot Study for Maternal and Neonatal MicroRNA Profiles
Next Article in Special Issue
RBD-Protein/Peptide Vaccine UB-612 Elicits Mucosal and Fc-Mediated Antibody Responses against SARS-CoV-2 in Cynomolgus Macaques
Previous Article in Journal
Global Analysis of Tracking the Evolution of SARS-CoV-2 Variants
Previous Article in Special Issue
A Phase I/II Clinical Trial of Intradermal, Controllable Self-Replicating Ribonucleic Acid Vaccine EXG-5003 against SARS-CoV-2
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

COVID-19 Vaccination and Immunosuppressive Therapy in Immune-Mediated Inflammatory Diseases

by
José M. Serra López-Matencio
1,*,
Esther F. Vicente-Rabaneda
2,
Estefanía Alañón
1,
Ainhoa Aranguren Oyarzabal
1,
Pedro Martínez Fleta
3 and
Santos Castañeda
2,*
1
Hospital Pharmacy Service, Hospital Universitario de La Princesa, IIS-Princesa, 28006 Madrid, Spain
2
Rheumatology Service, Hospital Universitario de La Princesa, IIS-Princesa, 28006 Madrid, Spain
3
Immunology Service, Hospital Universitario de La Princesa, IIS-Princesa, 28006 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Submission received: 16 October 2023 / Revised: 25 November 2023 / Accepted: 30 November 2023 / Published: 4 December 2023
(This article belongs to the Special Issue COVID Vaccines: Design, Development, and Immune Response Studies)

Abstract

:
The COVID-19 vaccination program has probably been the most complex and extensive project in history until now, which has been a challenge for all the people involved in the planning and management of this program. Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapy have required special attention, not only because of the particular haste in carrying out the process but also because of the uncertainty regarding their response to the vaccines. We now have strong scientific evidence that supports the hypothesis that immunosuppressive therapy inhibits the humoral response to vaccines against other infectious agents, such as influenza, pneumococcus and hepatitis B. This has led to the hypothesis that the same could happen with the COVID-19 vaccine. Several studies have therefore already been carried out in this area, suggesting that temporarily discontinuing the administration of methotrexate for 2 weeks post-vaccination could improve the vaccine response, and other studies with various immunosuppressive drugs are in the same line. However, the fact of withholding or interrupting immunosuppressive therapy when dealing with COVID-19 vaccination remains unclear. On this basis, our article tries to compile the information available on the effect of immunosuppressant agents on COVID-19 vaccine responses in patients with IMIDs and proposes an algorithm for the management of these patients.

1. Introduction

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has recently caused a global pandemic with devastating consequences. Fortunately, after a period of uncertainty, several vaccines against SARS-CoV-2 have been developed. The purpose of these vaccines is to reduce the incidence of new infections and to minimize the morbidity, mortality and sequelae of the infection. By inducing an effective and long-lasting immune response, SARS-CoV-2 raised special concerns in physicians attending to patients with immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Ps), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) or multiple sclerosis (MS), as it might represent an important health challenge in this population. First, at the beginning of the SARS-CoV-2 pandemic, these patients were thought to be more susceptible to contracting the infection and developing worse clinical consequences; however, the importance of other factors, such as age or comorbidities, was identified later on. Additionally, the immune dysfunction related to this disease might be associated with a reduced immune response to COVID-19 vaccines, as well as to an increased risk of flares. Finally, the disease-modifying antirheumatic drugs (DMARDs) needed to control the activity of this disease might have a negative effect on the immune response (both cellular and humoral) to these vaccines, based on previous knowledge about other vaccines [1,2]. Furthermore, the initial lack of data on the efficacy and safety of the COVID-19 vaccine in immunosuppressed subjects due to their exclusion from clinical trials added uncertainty about whether to continue or temporarily withhold the DMARDs after a COVID-19 vaccination in an attempt to maximize its efficacy against SARS-CoV-2. In addition, this uncertainty was amplified by the novel mechanism of action of the mRNA vaccines and thus the scarce evidence of their long-term clinical activity [1]. In this context, the possibility that the immune response to the COVID-19 vaccine in patients with IMIDs could be altered and that DMARDs, such as methotrexate, among others, could exert a negative effect on its efficacy was more than plausible; this hypothesis was supported by several studies [3].
The purpose of this review is to analyze and discuss the current evidence on the COVID-19 vaccine immune response, both humoral and cellular, in patients with IMIDs receiving immunosuppressive medication, with a special emphasis on RA. Additionally, we searched for evidence of the efficacy of the vaccine in terms of reducing the incidence of severe COVID-19, hospitalizations and mortality.

2. Methods

A literature review from the PubMed database was performed by the authors between 1 August 2022 and 29 August 2023. The following terms were combined in the search strategy: COVID-19 vaccine, immunogenicity, efficacy, IMIDs, rheumatoid arthritis, immunosuppressants, glucocorticoids, DMARDs and their specific groups (methotrexate, biologics, tumor necrosis factorα inhibitors, anti-CD20, Janus kinase inhibitors, abatacept, interleukin-6 receptor inhibitors). The studies had to meet the following inclusion criteria to be selected: (a) be original articles (such as clinical trials, observational studies and case series) and (b) evaluate the immunogenicity and efficacy of the COVID-19 vaccine in patients with IMIDs being treated with DMARDs. Reviews, systematic reviews or recommendations lacking original data as well as case reports or studies that focused exclusively on safety were excluded. After a review of the abstract, articles that did not meet the inclusion criteria were excluded. Afterward, the complete reading of the works was carried out, with the selection of the articles finally being included in this narrative review. This review study did not require ethical approval.

3. Results

3.1. Disease-Modifying Antirheumatic Drugs (DMARDs)

There is currently little information in the literature regarding the effect of conventional synthetic (cs)DMARDs on patients’ immune responses to the COVID-19 vaccine. Previous evidence with other vaccines in this regard suggests the existence of a different impact is dependent on the DMARD used. Azathioprine (antimetabolite), sulfasalazine, hydroxychloroquine or leflunomide seem to reduce the antibody titers generated upon the administration of the influenza vaccine, but without affecting the seroprotection conferred by the vaccine [4,5]. Mycophenolate mofetil, an inhibitor of DNA synthesis and thus of the proliferation of T and B-lymphocytes, was shown to be associated with a reduction in antibody titers generated by the influenza vaccine in a trial, although below the limit necessary to have a significant impact on the immune response [4].
MTX—which inhibits dihydrofolate reductase, prevents the reduction of dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4) and increases the sensitivity of T cells to apoptosis (diminishing immune responses)—is the drug that has been most extensively studied in the literature and it has been associated with a reduction in the humoral response generated by influenza and pneumococcal vaccines [6]. In fact, MTX is used in clinical practice to reduce the formation of human anti-chimeric antibodies (HACA) [7]. The randomized studies that have investigated the effect of temporarily withdrawing MTX after the influenza vaccination are of special interest. They suggest that the critical period in the generation of the humoral response is 2 weeks after vaccination. Of the strategies investigated, the interruption of MTX 2 weeks after vaccination is the one that obtains the best results, enhancing the humoral response to the vaccine, without having a clinically relevant impact on the activity of the disease; longer treatment breaks (4 weeks) do not seem to increase this benefit and are associated with a greater risk of a flare [8].
Based on these data, some researchers have investigated the impact of MTX on the COVID-19 vaccine, finding similar results that support the possibility of establishing strategies to enhance the response to the COVID-19 vaccine in patients with IMIDs who receive MTX and open the door to investigate the impact of analogous strategies with other csDMARDs and other vaccines. One randomized clinical trial including 138 patients with RA showed that a 2-week MTX withdrawal after each dose of the COVID-19 vaccine improves the anti-SARS-CoV-2 IgG response when compared to maintaining MTX unchanged [9]. In another open label, a superiority clinical trial including 254 patients, which were randomized 1:1 to continue MTX or discontinue it for two weeks at the time of vaccination, with RA and psoriasis on MTX treatment found an enhanced boosting of antibody responses in the second group [10]. Two additional trials assessing the effect of withholding methotrexate for 2 weeks after the first and second doses (MIVAC I) or after the second dose (MIVAC II) of the COVID-19 vaccine in patients with RA or psoriatic arthritis (PsA) resulted in a higher humoral response measured 4 weeks after vaccination in the withdrawal arm than in the group that maintained MTX unchanged [11].
Observational studies have also studied the impact of MTX on the immune response to the COVID-19 vaccine and identified additional factors involved. One retrospective study concluded that MTX reduces the humoral response after the COVID-19 vaccination in an age-dependent manner [12]. In the same line, Haberman et al. showed that MTX hindered the immune response in adults with autoimmune diseases [13]. Recently, the same group has carried out a study that indicates that this reduction in the humoral response can be avoided with a week of rest from MTX [14], with similar findings documented by other authors in an observational study including 136 patients with RA [15]. Furthermore, Frommert et al. have reported additional factors to MTX with a negative impact on the humoral immune response to the COVID-19 vaccine, such as the type of vaccine, the dosage interval or age [16].
Regarding the cellular response, data are scarcer than for humoral immunogenicity. Schmiedeberg et al. found a similar T cell response in a treated RA population and healthy controls after the COVID-19 vaccine, although it declined earlier in patients with RA [17]. The preservation of the cellular response reaffirms the positive role of the COVID-19 vaccine even in patients in whom the humoral response may foreseeably be more affected due to the disease or its treatments, although it would be of great interest to know if temporary DMARD rest strategies also enhance cellular immunity in these patients.
A summary of the main studies on COVID-19 vaccine immunogenicity in patients with IMIDs undergoing chronic DMARDs therapy is shown in Table 1 [10,13,18,19,20,21,22,23,24,25,26,27,28,29].

3.2. Glucocorticoids

Glucocorticoids have several immunomodulatory effects, such as the inhibition of the synthesis of pro-inflammatory cytokines, reduction of leucocyte trafficking and induction of the apoptosis of T-lymphocytes. Concerning the modification of the immune response to vaccines in patients undergoing chronic treatment with GCs, it should be remembered that it is dose-dependent. In fact, doses of prednisolone ≥ 10 mg/d have been associated with a decrease in the patient’s humoral response to the 23-valent pneumococcal polysaccharide vaccine and a higher rate of infections [30]. It is also noteworthy that prednisolone doses higher than 10 mg/d have been associated with worse disease progression in patients with COVID-19, indicating that cellular immunity could also be affected [31], although the use of GCs can improve the patient’s prognosis, especially in severe pneumonia caused by COVID-19 [32]. Interestingly, several mechanisms underlying the beneficial effects of dexamethasone during severe COVID-19 have been postulated: it affects circulating neutrophils, alters IFN active neutrophils, downregulates interferon-stimulated genes and activates IL-1R2+ neutrophils in severe COVID-19 patients [33].
Humoral and cellular immune responses to COVID-19 in patients undergoing GC therapy show contradictory results. A recent study on patients with SLE concludes that the medium-term response of these patients to the SARS-CoV-2 vaccination may be compromised by GC use and by other prescribed treatments aimed to control the severity of the disease, such as rituximab, identifying the GC therapy as the factor most associated with declining levels of neutralizing antibodies induced by the vaccine [34]. On the contrary, another study concludes that COVID-19 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, despite the response being impaired compared to healthy individuals [35].

3.3. Tumor Necrosis Factor-α Inhibitors

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine that recruits neutrophils and monocytes to the inflammation areas and activates intracellular signaling in several cells of the immune system. There are numerous studies on the immune response to different types of vaccines when administered concomitantly with TNF inhibitors. Most of these studies did not find a significant decrease in the immune response to pneumococcal, influenza and varicella vaccines [3,4,36,37]. Regarding the impact of TNF inhibitors on the immune response to the COVID-19 vaccine, the quality of the evidence is low and does not allow for firm conclusions to be drawn since some authors have described diminished serological and cellular responses in these patients, and others have reported that immunogenicity is not hampered.
Table 2 shows a summary of the main studies on the immune response to the COVID-19 vaccine in patients with biological treatments [18,19,20,21,22,23,25,26,27,28,29,38,39,40,41,42,43,44,45,46,47].

3.4. ANTI-CD20

B-cells are an essential component of the adaptive immune system. In fact, CD-20 depletion produces a clear decrease in the immune response to certain vaccines, such as influenza or pneumococcal [4,24], as it is to be expected given the key role of B cells in humoral immunity.
Evidence from the literature indicates that RTX is associated with a worse evolution of COVID-19 and an increased risk of hospitalization [48,49]. Nevertheless, it is worth noting that RTX-treated patients may have additional risk factors contributing to these worse outcomes. In this context, the data on the cellular response to the COVID-19 vaccine in patients with IMIDs treated with rituximab are especially relevant, given the foreseeable negative effect on the humoral response due to its mechanism of action. As expected, a negative association between seroconversion rates to the COVID-19 vaccine and rituximab has been confirmed, identifying the interval between the last RTX infusion and the first vaccination, the number of peripheral B-cells and the immunoglobulin quantity among the related factors [50,51], while the cellular response seems to be preserved [52]. Intervals of 6 to 9 months between the last rituximab administration and COVID-19 vaccination appear to improve the humoral response, although pharmacokinetic studies suggest that the presence of B cells and/or rituximab in the blood predict seroconversion better than time since last infusion [50,51,53]. The evidence points to the special need to individualize the COVID-19 vaccination strategy in patients with IMIDs being treated with rituximab, although it does not seem advisable to delay primary immunization in cases in which it is not advisable to delay treatment due to the activity of the disease [54].

3.5. Janus Kinase Inhibitors

The Janus kinase (JAK)/signal transduction and activators of transcription (STAT) pathway is responsible for signal transductions triggered by a number of cytokines and growth factors. Thus, theoretically, this family of drugs may be problematic in the case of the COVID-19 infection, given its mechanism of action. Previous evidence shows that the effect of a pneumococcal conjugate and a tetanus toxoid vaccine in baricitinib-treated patients results in lower and less durable immune responses [55]. However, there is no clear evidence in the case of tofacitinib.
Data about the influence of JAK inhibitors on COVID-19 vaccine are scarce and focused on the humoral response. A retrospective French registry found an overall serological response rate of 88%, which was negatively affected by older age and a relatively higher rate of non-responders among upadacitinib users in comparison with baricitinib or tofacitinib [56]. However, other studies have found a lower humoral response in patients undergoing treatment with JAK inhibitors than in patients treated with csDMARDs or healthy controls, with a deeper reduction in neutralizing antibody titers when administered in combination with methotrexate, suggesting the potential beneficial role of a temporary discontinuation of the JAK inhibitors after vaccination [57,58].

3.6. Interleukin-6 Receptor Inhibitors

Interleukin-6 (IL-6) is a very important pro-inflammatory cytokine, and is involved in the acute phase response and in the differentiation and function of B and T cells. The response to pneumoccocal and influenza vaccines in anti-interleukin-6 receptor (anti-IL-6R)-treated patients, with or without MTX, has been assessed and showed no differences with the control group when anti-IL-6 receptor inhibitors were used in monotherapy, while presenting an impairment of the immune responses if combined with MTX [59].
Regarding the COVID-19 vaccine, SARS-CoV-2-specific IgG1 titers seem to depend on disease severity and not on tocilizumab treatment [60]. If we extrapolate these results to the vaccination response, we could hypothesize that humoral immunogenicity may not be affected by IL-6 receptor inhibitors, though this would be a mere assumption. In this line, a recent retrospective cross-sectional multicenter study in neuromyelitis optica spectrum disorder (NMOSD)/myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) patients treated with anti-IL-6 receptor therapy found a 100% seroconversion rate after a COVID-19 vaccination, despite titers being lower than in healthy controls, although comparable to csDMARDs and higher than B-cell depleting agents [61].

3.7. Abatacept

Abatacept is a fusion protein of the cytotoxic T lymphocyte-associated antigen-4 that selectively modulates the CD80/CD86:CD28 costimulatory signal required for full T-cell activation. Data existing so far regarding the efficacy of the vaccination in patients undergoing abatacept therapy have shown an impaired humoral response to both the influenza [62] and pneumococcal vaccines [63]. However, these results should be considered with caution due to the small sample size and the absence of a control group.
Patients with IMIDs treated with abatacept have shown to display a reduced humoral and cellular response to the COVID-19 vaccine, in contrast with rituximab and belimumab, which only affect the seroconversion and reduce the titers of neutralizing antibodies regarding the T cell response, or mycophenolate and azathioprine which impair antibody production, while leflunomide and anti-cytokine therapies seem to minimally hamper immunogenicity [64,65,66,67]. Notably, the administration of second or third doses of the COVID-19 vaccine to non-responders induced a more robust antibody response and an increased T cell response [64,65,67].

4. Discussion

Concerns about how to manage vaccination in patients with IMIDs have long existed [68]. Regarding the COVID-19 vaccine, preliminary progress has been made with the development of guidelines by several scientific societies [69,70,71,72]. However, a universally accepted consensus still needs to be reached, requiring a standardization of the proposed protocols (Table 3).
Current evidence indicates that seroconversion rates after vaccination against COVID-19 are lower in patients with IMIDs on immunosuppressive therapy than in healthy subjects despite the administration of a second dose. Thus, COVID-19 booster vaccines after a primary series have been used, and some evidence on their efficacy elicited seroconversion in non-responders without major adverse events to date [73].
Most of the patients with IMIDs are undergoing treatment with DMARDs, even in combination, and we have previously reviewed that some DMARDs have been associated with a reduced response to the COVID-19 vaccine, especially when used in combination. Accordingly, the type of DMARD received has to be taken into consideration because a different immune response profile to the COVID-19 vaccine has been found for each family of drugs. Anti-CD20 drugs have the lowest seroconversion rate, followed by abatacept and JAK inhibitors, and their impact seems to be deepened by the combination of methotrexate [74].
Therefore, the most coherent approach seems to act according to the type of DMARD and the patient’s situation at the time of vaccination to maintain a balance between enhancing the protection against the SARS-CoV-2 infection and not compromising the evolution/activity of the disease. Considering MTX, a temporal withdrawal of 2 weeks after the administration of the vaccine could help improve the immune system response to the COVID-19 vaccine. This strategy could be considered safe in patients in remission or with a low disease activity, as the risk of flares may be low. However, if the patient is active, the approach might be completely different in the following way: priority could be placed on the control of the disease and, therefore, DMARDs would maintain unchanged or a reduction in the interval of methotrexate interruption to one week would be applied, according to the clinical situation. In fact, we cannot forget that the mere fact of having previously suffered from the COVID-19 infection can worsen the course of several autoimmune diseases [75]. Therefore, in certain patients, it would not be indicated to interrupt the administration of the immunomodulatory agent. Nevertheless, patients infected by SARS-CoV-2 previously to being administer a vaccination have been described to develop higher response rates and titers of induced antibodies, making it less necessary to temporarily interrupt their DMARDs.
The GC dose should be as low as possible to improve the immune response to the vaccine, ideally <10 mg/d; however, the activity and course of the disease must be considered.
Evidence about other DMARDs is scarcer but points towards the same direction, finding a better response to the vaccine after withholding the administration of JAK inhibitors for only one week post-vaccination, and the same could be applied to abatacept given the evidence previously mentioned in the corresponding section. Anti-cytokine drugs, such asIL-6 receptor inhibitors and TNF-α inhibitors, require more in-depth research to reach a consensus about the best timing of these therapies when administering the COVID-19 vaccine, although preliminary data suggest they minimally hamper vaccine-induced immunogenicity.
However, there are clinical efficacy parameters that we can consider to be of greater weight than the immunogenicity response to the vaccine, such as the efficacy against symptomatic COVID (especially severe COVID), ICU, hospital and emergency admissions and mortality. We have less information in this regard, although reviews are beginning to be published showing substantial reductions in all of them, in the following order: 50%–87%, 55%–100% and 82%–87%, respectively [76,77,78,79]. In patients with IMIDs, a 0% incidence of post-vaccination COVID-19 has been described in a study that included 158 cases [80]; however, studies with larger sample sizes and longer follow-ups are needed to draw conclusions about the true impact of DMARDs and the temporary rest strategies from these treatments on relevant clinical outcomes, such as hospitalizations and mortality.

Limitations

There is insufficient evidence to generate robust recommendations for most of the drugs involved due to the scarcity of the data and the low quality of the evidence that comes from uncontrolled retrospective observational studies, with the exception of the randomized studies about methotrexate. Additionally, the immune response to COVID-19 vaccines is affected by many factors, not only the immunosuppressive therapy, such as the type of immune disease, demographic factors, comorbidities, other therapies or the event of a prior COVID-19 infection (among others), making the interpretation of the results more complex. Furthermore, many patients receive a combination of therapies that include glucocorticoids and more than one immunosuppressive drug, adding extra difficulties to the analysis of the results. The activity of the rheumatic disease at vaccination is another key factor that can have an impact on the immune response to vaccines and was not clearly described in some of the studies. Given the limitation of the data, caution and an individualized approach to immunosuppressive therapy management during COVID-19 vaccination should be advised.
Figure 1 shows the main factors that may influence the management of these patients when designing a COVID-19 vaccination strategy based on the currently available knowledge [81].

5. Summary

Vaccination is one of the most important strategies that have been used to mitigate the damage of the global COVID-19 pandemic. In fact, it has been decisive in overcoming the worst pandemic that humanity has suffered in recent history. Moreover, all this has been thanks to, on the one hand, its great effectiveness and, on the other, to the great coordination of the parties involved. Patients with IMIDs may be especially prone to a more severe COVID-19 infection due to their disease and therapies and the associated comorbidities. Therefore, the COVID-19 vaccination should be prioritized in these patients. It has been documented that the use of DMARDs, especially MTX and drugs that suppress the CD-20-positive lymphocyte population, may decrease the humoral and cellular response rate of the COVID-19 vaccine. The potential efficacy of the strategies that temporarily withdraw these DMARDs for a short period of time after COVID-19 vaccination deserves to be highlighted in patients with IMIDs under control, as it seems not be associated with relevant safety issues. Therefore, vaccination timing and DMARD administration adjustments should be planned in order to optimize the immune response to the COVID-19 vaccine in patients with IMIDs, whenever possible.
The potential clinical efficacy of strategies based on the adjustment of the administration of DMARDs during vaccination, the relevance of the cellular response in patients with IMIDs, the duration of the humoral and cellular responses or the need of periodic boosters of the COVID-19 vaccine in these patients are issues that still need to be clarified. Therefore, it is important to continue working on the generation of evidence on whether or not to delay DMARD administration at the time of vaccination. Although, at present, the COVID-19 infection seems to have been overcome, we are never exempt from the appearance of another similar pandemic wave. Thus, it is essential to be prepared by having clear, efficient and standardized vaccination strategies.
Overall, any vaccination needs to be individualized to each patient, weighing the benefits of transiently stopping DMARDs against the risks of potential flares of the disease. The evidence available in the literature is in favor of this strategy as it has been associated with enhanced humoral and cellular responses to the COVID-19 vaccine, with a scarce incidence of flares, which were mostly mild in intensity. However, more research is needed on the clinical relevance of these findings in terms of decreasing the incidence and severity of subsequent COVID infections, although preliminary data suggest a trend towards a beneficial effect.

Author Contributions

Conceptualization, J.M.S.L.-M., E.F.V.-R. and S.C.; methodology, J.M.S.L.-M. and E.F.V.-R.; resources, S.C.; writing—original draft preparation, J.M.S.L.-M. and E.F.V.-R.; writing—review and editing, J.M.S.L.-M., E.F.V.-R., E.A., A.A.O., P.M.F. and S.C.; supervision, E.F.V.-R. and S.C.; funding acquisition, S.C. All authors have read and agreed to the published version of the manuscript.

Funding

This study has not received support from any institutional or private organization. S. Castañeda was supported with a grant from Ministerio de Economía y Competitividad (Instituto de Salud Carlos III) (grant no. PI21/01474) and co-funded by the European Regional Development Fund (ERDF) “A way to make Europe”.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We appreciate the support of all members of the Hospital Pharmacy Department at Hospital de La Princesa, Madrid, Spain.

Conflicts of Interest

S. Castañeda received grants/research support from MSD, Pfizer and UCB, and consultation fees in company-sponsored speaker’s bureau from Amgen, BMS, Gedeon Richter, Lilly, MSD, Roche, Sanofi and UCB. S. Castañeda is an assistant professor at Cátedra UAM-Roche, EPID-Future, Universidad Autónoma de Madrid (UAM), Madrid, Spain.

References

  1. Pollard, A.J.; Bijker, E.M. A guide to vaccinology: From basic principles to new developments. Nat. Rev. Immunol. 2021, 21, 83–100. [Google Scholar] [CrossRef] [PubMed]
  2. Elkayam, O.; Bashkin, A.; Mandelboim, M.; Litinsky, I.; Comaheshter, D.; Levartovsky, D.; Mendelson, E.; Wigler, I.; Caspi, D.; Paran, D. The effect of infliximab and timing of vaccination on the humoral response to influenza vaccination in patients with rheumatoid arthritis and ankylosing spondylitis. Semin. Arthritis Rheum. 2010, 39, 442–447. [Google Scholar] [CrossRef] [PubMed]
  3. Andreica, I.; Blazquez-Navarro, A.; Sokolar, J.; Anft, M.; Kiltz, U.; Pfaender, S.; Blanco, E.V.; Westhoff, T.; Babel, N.; Stervbo, U.; et al. Different humoral but similar cellular responses of patients with autoimmune inflammatory rheumatic diseases under disease-modifying antirheumatic drugs after COVID-19 vaccination. RMD Open 2022, 8, e002293. [Google Scholar] [CrossRef] [PubMed]
  4. Keshtkar-Jahromi, M.; Argani, H.; Rahnavardi, M.; Mirchi, E.; Atabak, S.; Tara, S.A.; Gachkar, L.; Noori-Froothghe, A.; Mokhtari-Azad, T. Antibody response to influenza immunization in kidney transplant recipients receiving either azathioprine or mycophenolate: A controlled trial. Am. J. Nephrol. 2008, 28, 654–660. [Google Scholar] [CrossRef] [PubMed]
  5. Fomin, I.; Caspi, D.; Levy, V.; Varsano, N.; Shalev, Y.; Paran, D.; Levartovsky, D.; Litinsky, I.; Kaufman, I.; Wigler, I.; et al. Vaccination against influenza in rheumatoid arthritis: The effect of disease modifying drugs, including TNFa blockers. Ann. Rheum. Dis. 2006, 65, 191–194. [Google Scholar] [CrossRef] [PubMed]
  6. Hua, C.; Barnetche, T.; Combe, B.; Morel, J. Effect of methotrexate, anti-tumor necrosis factor a, and rituximab on the immune response to influenza and pneumococcal vaccines in patients with rheumatoid arthritis: A systematic review and meta-analysis. Arthritis Care Res. 2014, 66, 1016–1026. [Google Scholar] [CrossRef]
  7. Farhangian, M.E.; Feldman, S.R. Immunogenicity of biologic treatments for psoriasis: Therapeutic consequences and the potential value of concomitant methotrexate. Am. J. Clin. Dermatol. 2015, 16, 285–294. [Google Scholar] [CrossRef]
  8. Park, J.K.; Lee, Y.J.; Shin, K.; Ha, Y.-J.; Lee, E.Y.; Song, Y.W.; Choi, Y.; Winthrop, K.L.; Lee, E.B. Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: A randomised clinical trial. Ann. Rheum. Dis. 2018, 77, 898–904. [Google Scholar] [CrossRef]
  9. Araujo, C.S.R.; Medeiros-Ribeiro, A.C.; Saad, C.G.S.; Bonfiglioli, K.R.; Domiciano, D.S.; Shimabuco, A.Y.; Silva, M.S.R.; Yuki, E.F.N.; Pasoto, S.G.; Pedrosa, T.; et al. Two-week methotrexate discontinuation in patients with rheumatoid arthritis vaccinated with inactivated SARS-CoV-2 vaccine: A randomised clinical trial. Ann. Rheum. Dis. 2022, 81, 889–897. [Google Scholar] [CrossRef]
  10. Abhishek, A.; Boyton, R.J.; Peckham, N.; McKnight, Á.; Coates, L.C.; Bluett, J.; Barber, V.; Cureton, L.; Francis, A.; Appelbe, D.; et al. Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): A randomised, open label, superiority trial. Lancet Respir. Med. 2022, 10, 840–850. [Google Scholar] [CrossRef]
  11. McHugh, J. Optimizing methotrexate withdrawal during COVID vaccination. Nat. Rev. Rheumatol. 2022, 18, 613. [Google Scholar] [CrossRef] [PubMed]
  12. Arumahandi de Silva, A.N.; Frommert, L.M.; Albach, F.N.; Klotsche, J.; Scholz, V.; Jeworowski, L.M.; Schwarz, T.; Hagen, A.T.; Zernicke, J.; Corman, V.M.; et al. Pausing methotrexate improves immunogenicity of COVID-19 vaccination in elderly patients with rheumatic diseases. Ann. Rheum. Dis. 2022, 81, 881–888. [Google Scholar] [CrossRef]
  13. Haberman, R.H.; Herati, R.; Simon, D.; Samanovic, M.; Blank, R.B.; Tuen, M.; Koralov, S.B.; Atreya, R.; Tascilar, K.; Allen, J.R.; et al. Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease. Ann. Rheum. Dis. 2021, 80, 1339–1344. [Google Scholar] [CrossRef] [PubMed]
  14. Habermann, E.; Gieselmann, L.; Tober-Lau, P.; Klotsche, J.; Albach, F.N.; Hagen, A.T.; Zernicke, J.; Ahmadov, E.; de Silva, A.N.A.; Frommert, L.M.; et al. Pausing methotrexate prevents impairment of omicron BA.1 and BA.2 neutralisation after COVID-19 booster vaccination. RMD Open 2022, 8, e002639. [Google Scholar] [CrossRef] [PubMed]
  15. Stahl, D.; Tho Pesch, C.; Brück, C.; Esser, R.L.; Thiele, J.; Di Cristanziano, V.; Kofler, D.M. Reduced humoral response to a third dose (booster) of SARS-CoV-2 mRNA vaccines by concomitant methotrexate therapy in elderly patients with rheumatoid arthritis. RMD Open 2022, 8, e002632. [Google Scholar] [CrossRef] [PubMed]
  16. Frommert, L.M.; Arumahandi de Silva, A.N.; Zernicke, J.; Scholz, V.; Braun, T.; Jeworowski, L.M.; Schwarz, T.; Tober-Lau, P.; Hagen, A.T.; Habermann, E.; et al. Type of vaccine and immunosuppressive therapy but not diagnosis critically influence antibody response after COVID-19 vaccination in patients with rheumatic disease. RMD Open 2022, 8, e002650. [Google Scholar] [CrossRef] [PubMed]
  17. Schmiedeberg, K.; Abela, I.A.; Pikor, N.B.; Vuilleumier, N.; Schwarzmueller, M.; Epp, S.; Pagano, S.; Grabherr, S.; Patterson, A.B.; Nussberger, M.; et al. Postvaccination anti-S IgG levels predict anti-SARS-CoV-2 neutralising activity over 24 weeks in patients with RA. RMD Open 2022, 8, e002575. [Google Scholar] [CrossRef] [PubMed]
  18. Ammitzbøll, C.; Bartels, L.E.; Bøgh Andersen, J.; Vils, S.R.; Mistegård, C.E.; Johannsen, A.D.; Hermansen, M.-L.F.; Thomsen, M.K.; Erikstrup, C.; Hauge, E.-M.; et al. Impaired Antibody Response to the BNT162b2 Messenger RNA Coronavirus Disease 2019 Vaccine in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis. ACR Open Rheumatol. 2021, 3, 622–628. [Google Scholar] [CrossRef]
  19. Boyarsky, B.J.; Ruddy, J.A.; Connolly, C.M.; Ou, M.T.; Werbel, W.A.; Garonzik-Wang, J.M.; Segev, D.L.; Paik, J.J. Antibody response to a single dose of SARS-CoV-2 mRNA vaccine in patients with rheumatic and musculoskeletal diseases. Ann Rheum Dis. 2021, 80, 1098–1099. [Google Scholar] [CrossRef]
  20. Braun-Moscovici, Y.; Kaplan, M.; Braun, M.; Markovits, D.; Giryes, S.; Toledano, K.; Tavor, Y.; Dolnikov, K.; Balbir-Gurman, A. Disease activity and humoral response in patients with inflammatory rheumatic diseases after two doses of the Pfizer mRNA vaccine against SARS-CoV-2. Ann. Rheum. Dis. 2021, 80, 1317–1321. [Google Scholar] [CrossRef]
  21. Bugatti, S.; De Stefano, L.; Balduzzi, S.; Greco, M.I.; Luvaro, T.; Cassaniti, I.; Bogliolo, L.; Mazzucchelli, I.; D’Onofrio, B.; di Lernia, M.; et al. Methotrexate and glucocorticoids, but not anticytokine therapy, impair the immunogenicity of a single dose of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic inflammatory arthritis. Ann. Rheum. Dis. 2021, 80, 1635–1638. [Google Scholar] [CrossRef] [PubMed]
  22. Furer, V.; Eviatar, T.; Zisman, D.; Peleg, H.; Paran, D.; Levartovsky, D.; Zisapel, M.; Elalouf, O.; Kaufman, I.; Meidan, R.; et al. Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: A multicentre study. Ann. Rheum. Dis. 2021, 80, 1330–1338. [Google Scholar] [CrossRef] [PubMed]
  23. Kappelman, M.D.; Weaver, K.N.; Boccieri, M.E.; Firestine, A.; Zhang, X.; Long, M.D.; Chun, K.; Fernando, M.; Zikry, M.; Dai, X.; et al. Humoral Immune Response to Messenger RNA COVID-19 Vaccines Among Patients With Inflammatory Bowel Disease. Gastroenterology 2021, 161, 1340–1343.e2. [Google Scholar] [CrossRef] [PubMed]
  24. Mrak, D.; Tobudic, S.; Koblischke, M.; Graninger, M.; Radner, H.; Sieghart, D.; Hofer, P.; Perkmann, T.; Haslacher, H.; Thalhammer, R.; et al. SARS-CoV-2 vaccination in rituximab-treated patients: B cells promote humoral immune responses in the presence of T-cell-mediated immunity. Ann Rheum Dis. 2021, 80, 1345–1350. [Google Scholar] [CrossRef]
  25. Deepak, P.; Kim, W.; Paley, M.A.; Yang, M.; Carvidi, A.B.; El-Qunni, A.A.; Haile, A.; Huang, K.; Kinnett, B.; Liebeskind, M.J.; et al. Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2. medRxiv 2021. [Google Scholar] [CrossRef]
  26. Ruddy, J.A.; Connolly, C.M.; Boyarsky, B.J.; Werbel, W.A.; Christopher-Stine, L.; Garonzik-Wang, J.M.; Segev, D.L.; Paik, J.J. High antibody response to two-dose SARS-CoV-2 messenger RNA vaccination in patients with rheumatic and musculoskeletal diseases. Ann. Rheum. Dis. 2021, 80, 1351–1352. [Google Scholar] [CrossRef]
  27. Shenoy, P.; Ahmed, S.; Cherian, S.; Paul, A.; Shenoy, V.; Vijayan, A.; Reji, R.; Thampi, A.; Babu, A.S.S.; Mohan, M. Immunogenicity of the ChAdOx1 nCoV-19 and the BBV152 vaccines in patients with autoinmune rheumatic diseases. medRxiv 2021. [Google Scholar] [CrossRef]
  28. Simon, D.; Tascilar, K.; Fagni, F.; Krönke, G.; Kleyer, A.; Meder, C.; Atreya, R.; Leppkes, M.; Kremer, A.E.; Ramming, A.; et al. SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases. Ann. Rheum. Dis. 2021, 80, 1312–1316. [Google Scholar] [CrossRef]
  29. Veenstra, J.; Wang, J.; McKinnon-Maksimowicz, K.; Liu, T.; Zuniga, B.; Hamzavi, I.; Zhou, L.; Mi, Q.-S. Correspondence on ‘Immunogenicity and safety of anti-SARS-CoV-2 mRNA vaccines in patients with chronic inflammatory conditions and immunosuppressive therapy in a monocentric cohort’. Ann. Rheum. Dis. 2021, 80, e160. [Google Scholar] [CrossRef]
  30. Fischer, L.; Gerstel, P.F.; Poncet, A.; Siegrist, C.-A.; Laffitte, E.; Gabay, C.; Seebach, J.D.; Ribi, C. Pneumococcal polysaccharide vaccination in adults undergoing immunosuppressive treatment for inflammatory diseases a longitudinal study. Arthritis Res. Ther. 2015, 17, 151. [Google Scholar] [CrossRef]
  31. Gianfrancesco, M.; Hyrich, K.L.; Al-Adely, S.; Carmona, L.; I Danila, M.; Gossec, L.; Izadi, Z.; Jacobsohn, L.; Katz, P.; Lawson-Tovey, S.; et al. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: Data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann. Rheum. Dis. 2020, 79, 859–866. [Google Scholar] [CrossRef] [PubMed]
  32. RECOVERY Collaborative Group; Horby, P.; Lim, W.S.; Emberson, J.R.; Mafham, M.; Bell, J.L.; Linsell, L.; Staplin, N.; Brightling, C.; Ustianowski, A.; et al. Dexamethasone in Hospitalized Patients with COVID-19. N. Engl. J. Med. 2021, 384, 693–704. [Google Scholar]
  33. Sinha, S.; Rosin, N.L.; Arora, R.; Labit, E.; Jaffer, A.; Cao, L.; Farias, R.; Nguyen, A.P.; de Almeida, L.G.N.; Dufour, A.; et al. Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19. Nat. Med. 2022, 28, 201–211. [Google Scholar] [CrossRef] [PubMed]
  34. Garcia-Cirera, S.; Calvet, J.; Berenguer-Llergo, A.; Pradenas, E.; Marfil, S.; Massanella, M.; Mateu, L.; Trinité, B.; Llop, M.; Arévalo, M.; et al. Glucocorticoids’ treatment impairs the medium-term immunogenic response to SARS-CoV-2 mRNA vaccines in Systemic Lupus Erythematosus patients. Sci Rep. 2022, 12, 14772. [Google Scholar] [CrossRef] [PubMed]
  35. Galmiche, S.; Luong Nguyen, L.B.; Tartour, E.; de Lamballerie, X.; Wittkop, L.; Loubet, P.; Launay, O. Immunological and clinical efficacy of COVID-19 vaccines in immunocompromised populations: A systematic review. Clin. Microbiol. Infect. 2022, 28, 163–177. [Google Scholar] [CrossRef]
  36. Kivitz, A.J.; Schechtman, J.; Texter, M.; Fichtner, A.; de Longueville, M.; Chartash, E.K. Vaccine responses in patients with rheumatoid arthritis treated with certolizumab pegol: Results from a single-blind randomized phase IV trial. J. Rheumatol. 2014, 41, 648–657. [Google Scholar] [CrossRef]
  37. Curtis, J.; Bridges, S.L.; Cofield, S.S.; Bassler, J.; Ford, T.; Lindsey, S.; Kivitz, A.; Messaoudi, I.; Michaud, K.; Huffstter, J.; et al. Results from a randomized controlled trial of the safety of the live varicella vaccine in TNF-treated patients. Arthritis Rheumatol. 2019, 71 (Suppl. 10), 1417–1418. [Google Scholar]
  38. Mahil, S.K.; Bechman, K.; Raharja, A.; Domingo-Vila, C.; Baudry, D.; A Brown, M.; Cope, A.P.; Dasandi, T.; Graham, C.; Khan, H.; et al. Humoral and cellular immunogenicity to a second dose of COVID-19 vaccine BNT162b2 in people receiving methotrexate or targeted immunosuppression: A longitudinal cohort study. Lancet Rheumatol. 2022, 4, e42–e52. [Google Scholar] [CrossRef]
  39. Al-Janabi, A.; Littlewood, Z.; Griffiths, C.E.M.; Hunter, H.J.A.; Chinoy, H.; Moriarty, C.; Yiu, Z.Z.N.; Warren, R.B. Antibody responses to single-dose SARS-CoV-2 vaccination in patients receiving immunomodulators for immune-mediated inflammatory disease. Br. J. Dermatol. 2021, 185, 646–648. [Google Scholar] [CrossRef]
  40. Dailey, J.; Kozhaya, L.; Dogan, M.; Hopkins, D.; Lapin, B.; Herbst, K.; Brimacombe, M.; Grandonico, K.; Karabacak, F.; Schreiber, J.; et al. Antibody Responses to SARS-CoV-2 after Infection or Vaccination in Children and Young Adults with Inflammatory Bowel Disease. medRxiv 2021. [Google Scholar] [CrossRef] [PubMed]
  41. Geisen, U.M.; Berner, D.K.; Tran, F.; Sümbül, M.; Vullriede, L.; Ciripoi, M.; Reid, H.M.; Schaffarzyk, A.; Longardt, A.C.; Franzenburg, J.; et al. Immunogenicity and safety of anti-SARS-CoV-2 mRNA vaccines in patients with chronic inflammatory conditions and immunosuppressive therapy in a monocentric cohort. Ann. Rheum. Dis. 2021, 80, 1306–1311. [Google Scholar] [CrossRef] [PubMed]
  42. Kennedy, N.A.; Lin, S.; Goodhand, J.R.; Chanchlani, N.; Hamilton, B.; Bewshea, C.; Nice, R.; Chee, D.; Cummings, J.F.; Fraser, A.; et al. Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD. Gut 2021, 70, 1884–1893. [Google Scholar] [CrossRef] [PubMed]
  43. Rubbert-Roth, A.; Vuilleumier, N.; Ludewig, B.; Schmiedeberg, K.; Haller, C.; von Kempis, J. Anti-SARS-CoV-2 mRNA vaccine in patients with rheumatoid arthritis. Lancet Rheumatol. 2021, 3, e470–e472. [Google Scholar] [CrossRef] [PubMed]
  44. Seyahi, E.; Bakhdiyarli, G.; Oztas, M.; Kuskucu, M.A.; Tok, Y.; Sut, N.; Ozcifci, G.; Ozcaglayan, A.; Balkan, I.I.; Saltoglu, N.; et al. Antibody response to inactivated COVID-19 vaccine (CoronaVac) in immune-mediated diseases: A controlled study among hospital workers and elderly. Rheumatol. Int. 2021, 41, 1429–1440. [Google Scholar] [CrossRef] [PubMed]
  45. Spiera, R.; Jinich, S.; Jannat-Khah, D. Rituximab, but not other antirheumatic therapies, is associated with impaired serological response to SARS- CoV-2 vaccination in patients with rheumatic diseases. Ann. Rheum. Dis. 2021, 80, 1357–1359. [Google Scholar] [CrossRef] [PubMed]
  46. Westhoff, T.H.; Seibert, F.S.; Anft, M.; Blazquez-Navarro, A.; Skrzypczyk, S.; Doevelaar, A.; Hölzer, B.; Paniskaki, K.; Dolff, S.; Wilde, B.; et al. Correspondence on ‘SARS-CoV-2 vaccination in rituximab-treated patients: Evidence for impaired humoral but inducible cellular immune response’. Ann. Rheum. Dis. 2021, 80, e162. [Google Scholar] [CrossRef] [PubMed]
  47. Wong, S.Y.; Dixon, R.; Martinez Pazos, V.; Gnjatic, S.; Colombel, J.F.; Cadwell, K.; ICARUS-IBD Working Group. Serologic response to messenger RNA coronavirus disease 2019 vaccines in inflammatory bowel disease patients receiving biologic therapies. Gastroenterology 2021, 161, 715–718.e4. [Google Scholar] [CrossRef]
  48. Nuño, L.; Novella Navarro, M.; Bonilla, G.; Franco-Gómez, K.; Aguado, P.; Peiteado, D.; Monjo, I.; Tornero, C.; Villalba, A.; Miranda-Carus, M.-E.; et al. Clinical course, severity and mortality in a cohort of patients with COVID-19 with rheumatic diseases. Ann. Rheum. Dis. 2020, 79, 1659–1661. [Google Scholar] [CrossRef]
  49. Schulze-Koops, H.; Krueger, K.; Vallbracht, I.; Hasseli, R.; Skapenko, A. Increased risk for severe COVID-19 in patients with inflammatory rheumatic diseases treated with rituximab. Ann. Rheum. Dis. 2021, 80, e67. [Google Scholar] [CrossRef]
  50. Seree-Aphinan, C.; Ratanapokasatit, Y.; Suchonwanit, P.; Rattanakaemakorn, P.; O-Charoen, P.; Pisitkun, P.; Suangtamai, T.; Setthaudom, C.; Chirasuthat, S.; Chanprapaph, K. Optimal time for COVID-19 vaccination in rituximab-treated dermatologic patients. Front. Immunol. 2023, 14, 1138765. [Google Scholar] [CrossRef]
  51. Schumacher, F.; Mrdenovic, N.; Scheicht, D.; Pons-Kühnemann, J.; Scheibelhut, C.; Strunk, J. Humoral immunogenicity of COVID-19 vaccines in patients with inflammatory rheumatic diseases under treatment with Rituximab: A case-control study (COVID-19VacRTX). Rheumatology 2022, 61, 3912–3918. [Google Scholar] [CrossRef] [PubMed]
  52. Egri, N.; Calderón, H.; Martinez, R.; Vazquez, M.; Gómez-Caverzaschi, V.; Pascal, M.; Araújo, O.; Juan, M.; González-Navarro, E.A.; Hernández-Rodríguez, J. Cellular and humoral responses after second and third SARS-CoV-2 vaccinations in patients with autoimmune diseases treated with rituximab: Specific T cell immunity remains longer and plays a protective role against SARS-CoV-2 reinfections. Front. Immunol. 2023, 14, 1146841. [Google Scholar] [CrossRef] [PubMed]
  53. Asplund Högelin, K.; Ruffin, N.; Pin, E.; Hober, S.; Nilsson, P.; Starvaggi Cucuzza, C.; Khademi, M.; Olsson, T.; Piehl, F.; Al Nimer, F. B-cell repopulation dynamics and drug pharmacokinetics impact SARS-CoV-2 vaccine efficacy in anti-CD20-treated multiple sclerosis patients. Eur. J. Neurol. 2022, 29, 3317–3328. [Google Scholar] [CrossRef] [PubMed]
  54. Bennett, B.; Tahir, H.; Ganguly, S.; Moorthy, A. An update on the considerations for patients with rheumatic disease being treated with rituximab during the COVID-19 pandemic and the potential drug treatment strategies. Expert Opin. Pharmacother. 2022, 23, 1695–1700. [Google Scholar] [CrossRef] [PubMed]
  55. Winthrop, K.L.; Bingham, C.O., III; Komocsar, W.J.; Bradley, J.; Issa, M.; Klar, R.; Kartman, C.E. Evaluation of pneumococcal and tetanus vaccine responses in patients with rheumatoid arthritis receiving baricitinib: Results from a long-term extension trial substudy. Arthritis Res. Ther. 2019, 21, 102. [Google Scholar] [CrossRef] [PubMed]
  56. Seror, R.; Camus, M.; Salmon, J.-H.; Roux, C.; Dernis, E.; Basch, A.; Germain, V.; Leske, C.; Brousseau, S.; Truchetet, M.-E.; et al. Do JAK inhibitors affect immune response to COVID-19 vaccination? Data from the MAJIK-SFR Registry. Lancet Rheumatol. 2022, 4, e8–e11. [Google Scholar] [CrossRef]
  57. Schäfer, A.; Kovacs, M.S.; Eder, A.; Nigg, A.; Feuchtenberger, M. Janus kinase (JAK) inhibitors significantly reduce the humoral vaccination response against SARS-CoV-2 in patients with rheumatoid arthritis. Clin. Rheumatol. 2022, 41, 3707–3714. [Google Scholar] [CrossRef]
  58. Iancovici, L.; Khateeb, D.; Harel, O.; Peri, R.; Slobodin, G.; Hazan, Y.; Melamed, D.; Kessel, A.; Bar-On, Y. Rheumatoid arthritis patients treated with Janus kinase inhibitors show reduced humoral immune responses following BNT162b2 vaccination. Rheumatology 2022, 61, 3439–3447. [Google Scholar] [CrossRef]
  59. Mori, S.; Ueki, Y.; Hirakata, N.; Oribe, M.; Hidaka, T.; Oishi, K. Impact of tocilizumab therapy on antibody response to influenza vaccine in patients with rheumatoid arthritis. Ann. Rheum. Dis. 2012, 71, 2006–2010. [Google Scholar] [CrossRef]
  60. Chauvin, C.; Levillayer, L.; Roumier, M.; Nielly, H.; Roth, C.; Karnam, A.; Bonam, S.R.; Bourgarit, A.; Dubost, C.; Bousquet, A.; et al. Tocilizumab-treated convalescent COVID-19 patients retain the cross-neutralization potential against SARS-CoV-2 variants. iScience 2023, 26, 106124. [Google Scholar] [CrossRef]
  61. Schwake, C.; Pakeerathan, T.; Kleiter, I.; Ringelstein, M.; Aktas, O.; Korporal-Kuhnke, M.; Wildemann, B.; Jarius, S.; Bayas, A.; Pul, R.; et al. Humoral COVID-19 vaccine response in patients with NMOSD/MOGAD during anti-IL-6 receptor therapy compared to other immunotherapies. Mult. Scler. J. 2023, 29, 757–761. [Google Scholar] [CrossRef] [PubMed]
  62. Ribeiro, A.C.; Laurindo, I.M.; Guedes, L.K.; Saad, C.G.; Moraes, J.C.; Silva, C.A.; Bonfa, E. Abatacept and reduced immune response to pandemic 2009 influenza A/H1N1 vaccination in patients with rheumatoid arthritis. Arthritis Care Res. 2013, 65, 476–480. [Google Scholar] [CrossRef] [PubMed]
  63. Kapetanovic, M.C.; Saxne, T.; Jönsson, G.; Truedsson, L.; Geborek, P. Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis. Arthritis Res. Ther. 2013, 15, R171. [Google Scholar] [CrossRef] [PubMed]
  64. Isnardi, C.A.; Cerda, O.L.; Landi, M.; Cruces, L.; Schneeberger, E.E.; Montoro, C.C.; Alfaro, M.A.; Roldán, B.M.; Gómez Vara, A.B.; Giorgis, P.; et al. Immune Response to SARS-CoV-2 Third Vaccine in Patients With Rheumatoid Arthritis Who Had No Seroconversion After Primary 2-Dose Regimen With Inactivated or Vector-Based Vaccines. J. Rheumatol. 2022, 49, 1385–1389. [Google Scholar] [CrossRef] [PubMed]
  65. Filippini, F.; Giacomelli, M.; Bazzani, C.; Fredi, M.; Semeraro, P.; Tomasi, C.; Franceschini, F.; Caruso, A.; Cavazzana, I.; Giagulli, C. Efficacy of COVID-19 mRNA vaccination in patients with autoimmune disorders: Humoral and cellular immune response. BMC Med. 2023, 21, 210. [Google Scholar] [CrossRef] [PubMed]
  66. Sieiro Santos, C.; Calleja Antolin, S.; Moriano Morales, C.; Garcia Herrero, J.; Diez Alvarez, E.; Ramos Ortega, F.; Ruiz de Morales, J.G. Immune responses to mRNA vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory rheumatic diseases. RMD Open 2022, 8, e001898. [Google Scholar] [CrossRef] [PubMed]
  67. Saleem, B.; Ross, R.L.; Bissell, L.A.; Aslam, A.; Mankia, K.; Duquenne, L.; Corsadden, D.; Carter, C.; Hughes, P.; Nadat, F.A.; et al. Effectiveness of SARS-CoV-2 vaccination in patients with rheumatoid arthritis (RA) on DMARDs: As determined by antibody and T cell responses. RMD Open 2022, 8, e002050. [Google Scholar] [CrossRef] [PubMed]
  68. Van Assen, S.; Agmon-Levin, N.; Elkayam, O.; Cervera, R.; Doran, M.F.; Dougados, M.; Emery, P.; Geborek, P.; Ioannidis, J.P.; Jayne, D.R.; et al. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann. Rheum. Dis. 2011, 70, 414–422. [Google Scholar] [CrossRef]
  69. Landewé, R.B.M.; Kroon, F.P.B.; Alunno, A.; Najm, A.; Bijlsma, J.W.; Burmester, G.R.; Caporali, R.; Combe, B.; Conway, R.; Curtis, J.R.; et al. EULAR recommendations for the management and vaccination of people with rheumatic and musculoskeletal diseases in the context of SARS-CoV-2: The November 2021 update. Ann. Rheum. Dis. 2022, 81, 1628–1639. [Google Scholar] [CrossRef]
  70. Tam, L.S.; Tanaka, Y.; Handa, R.; Li, Z.; Lorenzo, J.P.; Louthrenoo, W.; Hill, C.; Pile, K.; Robinson, P.C.; Dans, L.F.; et al. Updated APLAR consensus statements on care for patients with rheumatic diseases during the COVID-19 pandemic. Int. J. Rheum. Dis. 2021, 24, 733–745. [Google Scholar] [CrossRef]
  71. Curtis, J.R.; Johnson, S.R.; Anthony, D.D.; Arasaratnam, R.J.; Baden, L.R.; Bass, A.R.; Calabrese, C.; Gravallese, E.M.; Harpaz, R.; Kroger, A.; et al. American College of Rheumatology Guidance for COVID-19 Vaccination in Patients with Rheumatic and Musculoskeletal Diseases: Version 5. Arthritis Rheumatol. 2023, 75, E1–E16. [Google Scholar] [CrossRef] [PubMed]
  72. Harris, E. Updated WHO Guidance for Prioritizing COVID-19 Vaccines. JAMA 2023, 329, 144. [Google Scholar] [CrossRef] [PubMed]
  73. Mallory, R.M.; Formica, N.; Pfeiffer, S.; Wilkinson, B.; Marcheschi, A.; Albert, G.; McFall, H.; Robinson, M.; Plested, J.S.; Zhu, M.; et al. Safety and immunogenicity following a homologous booster dose of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373): A secondary analysis of a randomised, placebo-controlled, phase 2 trial. Lancet Infect. Dis. 2022, 22, 1565–1576. [Google Scholar] [CrossRef] [PubMed]
  74. Ehrenfeld, M.; Tincani, A.; Andreoli, L.; Cattalini, M.; Greenbaum, A.; Kanduc, D.; Alijotas-Reig, J.; Zinserling, V.; Semenova, N.; Amital, H.; et al. COVID-19 and autoimmunity. Autoimmun Rev. 2020, 19, 102597. [Google Scholar] [CrossRef] [PubMed]
  75. Valero, C.; Baldivieso-Achá, J.P.; Uriarte, M.; Vicente-Rabaneda, E.F.; Castañeda, S.; García-Vicuña, R. Vasculitis flare after COVID-19: Report of two cases in patients with preexistent controlled IgA vasculitis and review of the literature. Rheumatol. Int. 2022, 42, 1643–1652. [Google Scholar] [CrossRef] [PubMed]
  76. Meo, S.A.; Aftab, S.; Bayoumy, N.M.; Meo, A.S. Efficacy of Oxford-AstraZeneca (ChAdOx1 CoV-19) vaccine against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) cases, hospital admissions, type of variants, and deaths. Eur. Rev. Med. Pharmacol. Sci. 2023, 27, 10133–10143. [Google Scholar] [PubMed]
  77. Zhang, X.; Xia, J.; Jin, L.; Wu, Y.; Zheng, X.; Cao, X.; Meng, X.; Li, J.; Zhu, F. Effectiveness of homologous or heterologous immunization regimens against SARS-CoV-2 after two doses of inactivated COVID-19 vaccine: A systematic review and meta-analysis. Hum. Vaccin. Immunother. 2023, 19, 2221146. [Google Scholar] [CrossRef]
  78. Monteiro, H.S.; Lima Neto, A.S.; Kahn, R.; Sousa, G.S.; Carmona, H.A.; Andrade, J.S., Jr.; Castro, M.C. Impact of CoronaVac on COVID-19 outcomes of elderly adults in a large and socially unequal Brazilian city: A target trial emulation study. Vaccine 2023, 41, 5742–5751. [Google Scholar] [CrossRef]
  79. Marchese, A.M.; Zhou, X.; Kinol, J.; Underwood, E.; Woo, W.; McGarry, A.; Beyhaghi, H.; Áñez, G.; Toback, S.; Dunkle, L.M. NVX-CoV2373 vaccine efficacy against hospitalization: A post hoc analysis of the PREVENT-19 phase 3, randomized, placebo-controlled trial. Vaccine 2023, 41, 3461–3466. [Google Scholar] [CrossRef]
  80. Yanfang, W.; Jianfeng, C.; Changlian, L.; Yan, W. COVID-19 vaccination of patients with chronic immune-mediated inflammatory disease. Adv. Rheumatol. 2023, 63, 54. [Google Scholar] [CrossRef]
  81. COVID-19 Vaccination and Prioritisation Strategies in the EU/EEA. European Center for Disease Prevention and Control. December 2020. Available online: https://www.ecdc.europa.eu/sites/default/files/documents/COVID-19vaccination-and-prioritisation-strategies.pdf (accessed on 10 October 2023).
  82. Lista de Actividades Esenciales. Gobierno de España. March 2020. Available online: https://www.mites.gob.es/ficheros/ministerio/contacto_ministerio/lista_actividades_esenciales.pdf (accessed on 10 October 2023).
Figure 1. Main factors that may influence the management of immunosuppressed a patient when designing a vaccination strategy for COVID-19. Footnotes: (cs)DMARDs: (conventional synthetic) disease-modifying antirheumatic drugs; IL: interleukin; JAK: Janus kinase; mo: month; MTX: methotrexate; TNF: tumor necrosis factor; wks: weeks. * Proposal of the authors considering the available bibliography. ** According to the ECDC (European Centre for Disease Prevention and Control) Technical Report: https://www.ecdc.europa.eu/sites/default/files/documents/COVID-19-vaccination-and-prioritisation-strategies.pdf (accessed on 10 October 2023). *** According to the Spanish government: https://www.mites.gob.es/ficheros/ministerio/contacto_ministerio/lista_actividades_esenciales.pdf (accessed on 10 October 2023) [82].
Figure 1. Main factors that may influence the management of immunosuppressed a patient when designing a vaccination strategy for COVID-19. Footnotes: (cs)DMARDs: (conventional synthetic) disease-modifying antirheumatic drugs; IL: interleukin; JAK: Janus kinase; mo: month; MTX: methotrexate; TNF: tumor necrosis factor; wks: weeks. * Proposal of the authors considering the available bibliography. ** According to the ECDC (European Centre for Disease Prevention and Control) Technical Report: https://www.ecdc.europa.eu/sites/default/files/documents/COVID-19-vaccination-and-prioritisation-strategies.pdf (accessed on 10 October 2023). *** According to the Spanish government: https://www.mites.gob.es/ficheros/ministerio/contacto_ministerio/lista_actividades_esenciales.pdf (accessed on 10 October 2023) [82].
Vaccines 11 01813 g001
Table 1. Main studies on the COVID-19 vaccine immunogenicity in patients with IMIDs receiving DMARDs.
Table 1. Main studies on the COVID-19 vaccine immunogenicity in patients with IMIDs receiving DMARDs.
First Author and
Reference Number
Pts (N)Age
(Median)
DiseaseDMARDs
Abhishek A et al. [10]34059RA, PsAMTX
Ammitzbøll C et al. [18]13470 SLE, RA MTX
Boyarsky BJ et al. [19]12350 IJDs, SLE, SS,
myositis,
vasculitis
AZA, HCQ,
MMF, SSZ,
TAC, MTX,
leflunomide
Braun-Moscovici Y et al. [20]26450IJDs, CTDs,
vasculitis
MTX, MMF, GC
Bugatti S et al. [21]14055.7RA, PsA, SpAMTX, SSZ,
leflunomide,
cyclosporine A
Furer V et al. [22]68659RA, PsA, SpA,
SLE, vasculitis,
LVV, AAV
GC, MTX,
HCQ, MMF,
leflunomide
Haberman RH et al. [13]7736LymphomaMTX
Kappelman MD et al. [23]31750.9IBDGC, 5-ASA, SSZ,
thiopurines
Mrak D et al. [24]7461.7IgG4-related,
CTDs, RA, vasculitis
MTX, MMF, HCQ, AZA, SSZ, GC
leflunomide
Deepak P et al. [25]13345.5IBD, IJDs, RA, SpA, SLE,
SS, psoriasis, PsA
AZA, MMF,
MTX, GC,
leflunomide
Ruddy JA et al. [26]404384MyositisMMF, GC
Shenoy P et al. [27]44952RA, IJDs, SpA, SLE,
PR, scleroderma
vasculitis, myositis
MTX, SSZ, leflunomide, HCQ, MMF, GC, TAC, AZA
Simon D et al. [28]8453.1IBD, RA, SpA,
psoriasis
5-ASA, HCQ,
MTX, GC
Veenstra J et al. [29]7455.9IBD, RA, SLE,
psoriasis, PsA
HCQ, AZA,
MMF, GC
Abbreviations: AAV: anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis; 5-ASA: 5 amino salicylates; AZA: azathioprine; CTDs: connective tissue diseases; GC: gucocorticoids; HCQ: hydroxychloroquine; IBD: inflammatory bowel disease; IMIDs: immune-mediated inflammatory diseases; IJDs: inflammatory joint diseases; LVV: large vessel vasculitis; MMF: mycophenolate mofetil; MTX: methotrexate; PR: palindromic rheumatism; PsA: psoriatic arthritis; Pts: patients; RA: rheumatoid arthritis; SSZ: sulfasalazine; SLE: systemic lupus erythematosus; SpA: spondyloarthritis; SS: Sjogren’s syndrome; TAC: tacrolimus.
Table 2. Main studies on the management of COVID-19 vaccine in patients receiving biological DMARDs.
Table 2. Main studies on the management of COVID-19 vaccine in patients receiving biological DMARDs.
First Author and
Reference Number
Pts (N)Age
(Median)
DiseasebDMARDs/Targeted Therapies
Al-Janabi A et al. [39]12053Psoriasis, PsA, RA,
SLE, Cröhn’s
Abatacept, adalimumab, brodalumab, certolizumab,
etanercept, guselkumab, ixekizumab, risankizumab,
secukinumab, tildrakizumab, ustekinumab
Ammitzbøll C et al. [18]13470SLE, RA Infliximab, adalimumab, JAKi, rituximab, tocilizumab,
abatacept, belimumab
Boyarsky BJ et al. [19]12350IJDs, SLE, SS,
myositis, vasculitis
Abatacept, belimumab, rituximab, infliximab,
adalimumab, tofacitinib
Braun-Moscovici Y et al. [20]26450IJDs, CTDs, vasculitisRituximab, belimumab,
infliximab, adalimumab,
abatacept, JAKi
Bugatti S et al. [21]14056RA, PsA, SpAInfliximab, adalimumab, tocilizumab, guselkumab,
secukinumab, JAKi, CTLA4-Ig
Dailey J et al. [40]33-IBDVedolizumab, infliximab
Furer V et al. [22]68659 RA, PsA, SpA,
SLE, IIM, vasculitis, LVV, AAV vasculitis
Infliximab, adalimumab, tocilizumab, rituximab,
guselkumab, abatacept, JAKi, belimumab
Geisen UM et al. [41]2651PsA, RA, MCTD, SpA, SLE, IBD, psoriasis,
myositis, vasculitis,
sarcoidosis
Infliximab, adalimumab, golimumab, certolizumab,
etanercept, tocilizumab, vedolizumab, secukinumab,
ustekinumab, ixekizumab, belimumab
Kappelman MD et al. [23]31751IBDVedolizumab, ustekinumab
Kennedy NA et al. [42]129344IBDInfliximab, vedolizumab
Mahil SK et al. [38]8443 Infliximab, adalimumab, guselkumab
Deepak P et al. [25]13346IBD, IJDs, RA, SpA, SLE, SS, psoriasis, PsAInfliximab, adalimumab,
golimumab, abatacept,
vedolizumab, ustekinumab, tofacitinib,
rituximab, tocilizumab
Rubbert-Roth A et al. [43]5164RAAbatacept, JAKi
Ruddy JA et al. [26]40444MyositisInfliximab, adalimumab, rituximab
Seyahi E et al. [44]10442RA, SpA/IBD,
vasculitis, CTDs
Rituximab and various biological agents
Shenoy P et al. [27]44952RA, PR, IJDs, SpA, SLE, vasculitis, scleroderma,
myositis
Tofacitinib, apremilast, rituximab, adalimumab
Simon D et al. [28]8453IBD, RA, SpA, psoriasisInfliximab, adalimumab, guselkumab,
secukinumab, JAKi, tocilizumab
Spiera R et al. [45]8961RA, SLE, SS, PsA,
vasculitis, myositis, MCTD, scleroderma
Adalimumab, etanercept, abatacept, secukinumab,
JAKi, rituximab, tocilizumab, belimumab, anakinra
Veenstra J et al. [29]7456IBD, RA, SLE,
psoriasis, PsA
Infliximab, tofacitinib, ixekizumab
Westhoff TH et al. [46]964Rituximab-treated ptsRituximab
Wong SY et al. [47]26-IBDInfliximab, adalimumab, vedolizumab, ustekinumab
Abbreviations: AAV: anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis; bDMARDs: biological disease-modifying antirheumatic drugs; CTLA4-Ig: cytotoxic T lymphocyte-associated protein-4 immunoglobulin; IBD: inflammatory bowel disease; IJDs: inflammatory joint diseases; MCTD: mixed connective tissue disease; JAKi: Janus kinase inhibitors; LVV: large vessel vasculitis; PR: palindromic rheumatism; PsA: psoriatic arthritis; Pts: patients; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; SpA: spondyloarthritis; SS: Sjogren’s syndrome.
Table 3. Main COVID-19 vaccination guidelines in rheumatic patients with inflammatory immune-mediated and joint diseases.
Table 3. Main COVID-19 vaccination guidelines in rheumatic patients with inflammatory immune-mediated and joint diseases.
Year Author/Institution
[Reference Number]
Title
2021European League Against Rheumatism (EULAR) [69]EULAR recommendations for the management and vaccination of people with rheumatic and musculoskeletal diseases in the context of SARS-CoV-2: the November 2021 update
2021Asia Pacific League of Associations for Rheumatology (APLAR) [70]Updated APLAR consensus statements on care for patients with rheumatic diseases
during the COVID-19 pandemic
2023American College of Rheumatology (ACR) [71]American College of Rheumatology Guidance for COVID-19 Vaccination in Patients With
Rheumatic and Musculoskeletal Diseases: Version 5
2023World Health Organization (WHO) [72]Updated WHO Guidance for Prioritizing COVID-19 Vaccines
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Serra López-Matencio, J.M.; Vicente-Rabaneda, E.F.; Alañón, E.; Aranguren Oyarzabal, A.; Martínez Fleta, P.; Castañeda, S. COVID-19 Vaccination and Immunosuppressive Therapy in Immune-Mediated Inflammatory Diseases. Vaccines 2023, 11, 1813. https://doi.org/10.3390/vaccines11121813

AMA Style

Serra López-Matencio JM, Vicente-Rabaneda EF, Alañón E, Aranguren Oyarzabal A, Martínez Fleta P, Castañeda S. COVID-19 Vaccination and Immunosuppressive Therapy in Immune-Mediated Inflammatory Diseases. Vaccines. 2023; 11(12):1813. https://doi.org/10.3390/vaccines11121813

Chicago/Turabian Style

Serra López-Matencio, José M., Esther F. Vicente-Rabaneda, Estefanía Alañón, Ainhoa Aranguren Oyarzabal, Pedro Martínez Fleta, and Santos Castañeda. 2023. "COVID-19 Vaccination and Immunosuppressive Therapy in Immune-Mediated Inflammatory Diseases" Vaccines 11, no. 12: 1813. https://doi.org/10.3390/vaccines11121813

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop