GRAPHICAL ABSTRACT

Key Message

Despite being at high risk for infection, most adult patients with non-rheumatoid arthritis rheumatic diseases (NRRDs) did not complete the recommended adult vaccinations. Vaccination rates, including those for the influenza, pneumococcal, and herpes zoster vaccines, were significantly lower in the high-level immunosuppression (HLI) group than in the non-HLI group. Overall, these findings reveal a critical gap in the preventive care of immunocompromised patients with NRRDs and underscore the need for systematic vaccination strategies in this vulnerable population.

INTRODUCTION

Vaccination is one of the greatest achievements in the history of public health. In the United States, immunization programs have substantially reduced the incidence and mortality of many vaccine-preventable diseases (VPDs) [1]. Patients with autoimmune inflammatory rheumatic diseases (AIIRDs) are more vulnerable to infectious diseases, including VPDs, than the general population due to the underlying disease and immunosuppressive medications, such as glucocorticoids, disease-modifying antirheumatic drugs (DMARDs), conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs), and targeted synthetic DMARDs [2-5]. Several studies have estimated that the incidence of severe infections in these patients is approximately twice as high as that in the general population [6,7].

To mitigate this risk, major international societies, including the European Alliance of Associations for Rheumatology, the American College of Rheumatology, the Korean College of Rheumatology, and the Korean Society of Infectious Diseases (KSID), strongly recommend appropriate vaccinations for patients with AIIRDs [2,3,8,9]. Vaccination is one of the most cost-effective and clinically effective strategies for reducing the incidence and severity of infectious diseases in immunocompromised patients [3,10]. Despite these clear recommendations, several studies have shown that vaccination rates in patients with AIIRDs remain very low, often lower than those in the general population [10,11].

Most previous studies have focused on relatively common rheumatic diseases, such as rheumatoid arthritis, while few have examined real-world vaccination status in patients with non-rheumatoid arthritis rheumatic diseases (NRRDs), a diverse and understudied subset of AIIRDs. Additionally, the degree of immunosuppression is a key determinant of both infection risk and vaccine-related decision-making in clinical practice. However, it remains unclear whether real-world vaccination coverage differs according to the degree of immunosuppression in patients with NRRDs.

For these reasons, this study aimed to evaluate vaccination status among patients with NRRDs according to the degree of immunosuppression by comparing high-level immunosuppression (HLI) and non-HLI groups.

MATERIALS AND METHODS

Data source

This retrospective single-center study was conducted at a tertiary care hospital, the largest independent rheumatology center in Korea, from January 2023 to March 2023. We analyzed all adult patients (aged ≥19 years) with NRRDs, as defined according to the Copayment Decreasing Policy of Korea’s National Health Insurance System, who received DMARDs in the rheumatology outpatient department during the study period. Patients diagnosed with NRRDs after January 1, 2022, were excluded because there was insufficient time to assess their vaccination history. A flowchart of the patient selection process is shown in Figure 1, and the types of NRRDs included in this study are detailed in Supplementary Material 1.

Vaccination information about the enrolled patients was collected by reviewing both electronic health records (EHRs) and the vaccination management system of the Korea Disease Control and Prevention Agency.

Study groups and definitions

Patients were classified into the HLI and non-HLI groups based on the degree of immunosuppression. The HLI group was defined as including: (1) patients who were prescribed biologics, (2) patients who were prescribed prednisolone or an equivalent at a dose of ≥20 mg/day for more than 14 days, (3) patients who had undergone solid organ transplantation within 2 months, and (4) patients who had undergone hematopoietic stem cell transplantation within 2 years [6,12,13]. A list of the VPDs was obtained from the 2019 KSID Vaccination Guidelines for Adults [8,14] (Supplementary Material 2). The types of DMARDs used by patients in this study are listed in Supplementary Material 3 [2,15].

The category “not indicated” includes patients for whom vaccination was not indicated or could not be classified due to insufficient information. More specifically, “not indicated” was defined as follows: for hepatitis A virus (HAV), individuals who were anti-HAV antibody-positive with no history of HAV vaccination, or individuals aged ≥40 years with no history of HAV vaccination and no available laboratory results for anti-HAV antibodies; for hepatitis B virus (HBV), individuals who were HBV carriers; for herpes zoster, individuals aged <50 years who had received a live zoster vaccine; and for human papillomavirus (HPV), individuals aged >26 years.

For HAV, because a substantial proportion of patients were categorized as “not indicated,” statistical comparisons were performed in the population with known status after excluding the remaining patients from the denominator. Supplementary age-stratified analyses were also conducted to explore the potential influence of age-related HAV seropositivity and unavailable antibody results.

Statistical analysis

All statistical analyses were performed using SPSS version 21 (IBM Corp., Armonk, NY, USA). Continuous variables were compared using the independent t-test, and categorical variables were compared using the chi-square test.

For each vaccination, we compared the combined proportion of patients who were completely or partially vaccinated between the HLI and non-HLI groups. In addition, to determine whether the level of immunosuppression independently predicted low vaccination coverage, we performed multivariable logistic regression analysis after adjustment for age and sex.

A two-tailed p-value <0.05 was considered to indicate statistical significance.

Ethics statement

The study protocol was approved by the Institutional Review Board of Hanyang University Seoul Hospital (approval No. 2023-09-11).

RESULTS

Demographic characteristics of the high-level immunosuppression (HLI) and non-HLI groups

A total of 4,070 patients with NRRDs were included in the study, of whom 1,522 (37.4%) were classified in the HLI group. The mean age was 42.6±12.4 years in the HLI group and 47.0±14.2 years in the non-HLI group, a statistically significant difference (p<0.001). The proportion of female patients also differed significantly between the groups (p<0.001): 27.5% in the HLI group and 86.1% in the non-HLI group. Ankylosing spondylitis (87.6 vs. 9.3%, p<0.001) and systemic lupus erythematosus (5.3 vs. 59.2%, p<0.001) were the most common rheumatic diseases in the HLI and non-HLI groups, respectively, with both differing significantly in frequency between the groups (Table 1).

Types of medications in the high-level immunosuppression (HLI) and non-HLI groups

Adalimumab (32.0%) was the most frequently used medication in the HLI group, followed by etanercept (30.2%), infliximab (17.7%), and golimumab (12.0%). In contrast, hydroxychloroquine (71.6%) was the most commonly used medication in the non-HLI group, followed by low-dose corticosteroids (65.9%), methotrexate (21.9%), and sulfasalazine (10.2%) (Table 2).

Vaccination status of the high-level immunosuppression (HLI) and non-HLI groups

Regarding the recommended adult vaccines, 27.0% of patients had completed influenza vaccination, and this proportion was significantly lower in the HLI group than in the non-HLI group (20.2 vs. 31.0%, p<0.001). For hepatitis A vaccination, 10.9% of patients had received at least 1 dose, with no significant difference between groups (11.3 vs. 10.5%, p=0.535). For hepatitis B vaccination, 65.3% of patients had received at least 1 dose, and the proportion was significantly lower in the HLI group than in the non-HLI group (59.5 vs. 68.8%, p<0.001). In addition, 21.6% of patients had received pneumococcal vaccination (13-valent pneumococcal conjugate vaccine [PCV13] or 23-valent pneumococcal polysaccharide vaccine [PPSV23]), and this proportion was significantly lower in the HLI group than in the non-HLI group (12.9 vs. 26.9%, p<0.001). Furthermore, 8.3% of patients had received herpes zoster vaccination (live or inactivated vaccine), with this proportion significantly lower in the HLI group (4.3 vs. 10.8%, p<0.001). Regarding HPV vaccination, 1.5% of patients had received at least 1 dose, and this proportion was also significantly lower in the HLI group (0.4 vs. 2.2%, p<0.001) (Table 3).

Because the sex distribution differed substantially between the HLI and non-HLI groups, additional sex-stratified analyses were performed separately for male and female patients (Supplementary Materials 4 and 5). Even after stratification by sex, differences in vaccination rates for the major VPDs remained significant between the 2 groups, except for HPV.

In addition, for certain VPDs for which recommended vaccination schedules may differ by age group (HAV, pneumococcal disease, and herpes zoster), we stratified patients according to the relevant age cutoffs and reanalyzed the data accordingly (Supplementary Materials 6-8).

Multivariable logistic regression of factors associated with vaccination coverage

After adjustment for age and sex, multivariable analysis showed that HLI was independently associated with lower vaccination coverage for HBV (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.65 to 0.91; p=0.002), tetanus/diphtheria/acellular pertussis (Tdap)/tetanus/diphtheria (Td) (OR, 0.76; 95% CI, 0.60 to 0.96; p=0.019), and pneumococcal vaccination (OR, 0.71; 95% CI, 0.57 to 0.89; p=0.003) (Table 4).

DISCUSSION

To our knowledge, this is the first real-world study in Korea to investigate vaccination status in patients with NRRDs according to the degree of immunosuppression. Patients in the HLI group were younger and more likely to be male, which may reflect the high prevalence of ankylosing spondylitis, a male-predominant condition, in this group [16,17]. In contrast, diseases such as systemic lupus erythematosus and systemic sclerosis, which are more prevalent in women, were more common in the non-HLI group [18,19]. These disease distributions likely reflect real-world treatment patterns in which bDMARDs are prescribed more frequently for certain inflammatory conditions, resulting in a higher proportion of patients with HLI. In fact, bDMARDs exert stronger immunosuppressive effects than csDMARDs because they directly inhibit specific immune pathways. Several studies have reported higher rates of infection and hospitalization among patients treated with bDMARDs than among those receiving csDMARDs [20-22].

Our findings suggest a substantial gap between clinical guidelines and real-world practice. This highlights a notable paradox in the care of patients with NRRDs: despite their increased vulnerability to infectious diseases due to immunosuppressive therapy, vaccination uptake in this population, particularly among those in the HLI group, remained low across nearly all recommended vaccines, including influenza, pneumococcal, and herpes zoster vaccination. These findings may be explained by factors at both the patient and healthcare provider levels, including limited patient awareness, concerns about vaccination, and insufficient clinician recognition of the importance of vaccination [10,23]. In a single-center survey-based study, 14.7% of patients with rheumatic diseases reported that they had never been advised to receive pneumococcal vaccination, while 8.2% indicated that influenza vaccination had never been recommended [23]. Additionally, concerns about potential disease flare-ups or vaccine safety may contribute to low vaccination rates [24,25]. However, multiple large-scale studies have found no significant increase in disease activity following most recommended vaccines [26,27].

Several strategies have been proposed to improve vaccination rates in this population, including computerized alert systems, financial support for vaccination, patient education, and standardized vaccination policies [11]. In a study in the United States, strategies such as reminders and recalls, onsite vaccination, and behaviorally targeted incentives were effective in increasing vaccination uptake [25]. Extending these strategies to adult populations, particularly immunocompromised patients such as those with AIIRDs, may improve vaccination uptake in these high-risk groups.

This study had several limitations. First, because this was a single-center study, its findings may not be fully generalizable to the national population. Second, the accuracy and completeness of data extracted from EHRs may have been limited because retrospective chart reviews are inherently subject to documentation errors and missing information. In addition, some patients may have received vaccinations at other institutions without those data being entered into the national vaccine registry. Third, although we performed adjusted analyses controlling for age and sex, this study remained primarily descriptive, and residual confounding due to underlying disease categories, treatment heterogeneity, and other unmeasured factors could not be excluded. Finally, although the coronavirus disease 2019 (COVID-19) pandemic had effectively ended and influenza activity had largely returned to patterns similar to those of the pre-pandemic period at the time of the survey, there was minimal influenza circulation during the 2020–2022 seasons [28]. Therefore, awareness of influenza vaccination may have declined substantially among both the public and healthcare professionals. This decline may have contributed to the low influenza vaccination rate. Nevertheless, a major strength of this study is that it was conducted at the largest rheumatology center in Korea, which enabled the inclusion of many patients with NRRDs, a sample size that would have been difficult to achieve at other institutions. This strengthens the robustness of the findings, despite the aforementioned limitations.

In conclusion, vaccination coverage among adults with NRRDs was low, particularly among those in the HLI group. Systematic vaccination strategies are needed to improve protection against VPDs in this high-risk population.

Supplementary materials

NOTES

Conflict of interest

The authors have no conflicts of interest to declare for this study.

Funding

None.

Acknowledgements

Kiho Jeong was a trainee in the Medical Scientist Training Program at Hanyang University College of Medicine. The abstract of this article was presented as a poster at ISAAR & KSAT 2024 in Seoul, Korea.

The authors thank Dr. Jiyeong Kim (Department of Pre-Medicine, College of Medicine, and Biostatistics Laboratory, Medical Research Collaborating Center, Hanyang University, Seoul, Korea) for providing statistical advice.

Author contributions

Conceptualization: Kim B. Data curation: Yoon C, Jeong K. Formal analysis: Yoon C, Jeong K. Funding acquisition: None. Methodology: Kim B. Project administration: Kim B. Visualization: Yoon C, Jeong K. Writing – original draft: Yoon C, Jeong K. Writing – review & editing: Jang W, Kim J, Park SY, Kim B.

Figure 1.

Flowchart of the patient selection process. This figure presents the patient selection process for the HLI and non-HLI groups. NRRDs, non-rheumatoid arthritis rheumatic diseases; DMARDs, disease-modifying antirheumatic drugs; HLI, high-level immunosuppression.

REFERENCES

• 1. Roush SW, Murphy TV; Vaccine-Preventable Disease Table Working Group. Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States. JAMA 2007;298:2155-2163. https://doi.org/10.1001/jama.298.18.2155ArticlePubMed
• 2. Bass AR, Chakravarty E, Akl EA, Bingham CO, Calabrese L, Cappelli LC, et al. 2022 American College of Rheumatology guideline for vaccinations in patients with rheumatic and musculoskeletal diseases. Arthritis Care Res (Hoboken) 2023;75:449-464. https://doi.org/10.1002/acr.25045ArticlePubMedPMC
• 3. Furer V, Rondaan C, Heijstek MW, Agmon-Levin N, van Assen S, Bijl M, et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis 2020;79:39-52. https://doi.org/10.1136/annrheumdis-2019-215882ArticlePubMedPMC
• 4. Calabrese C. Vaccinations in patients with rheumatic disease: consider disease and therapy. Med Clin North Am 2021;105:213-225. https://doi.org/10.1016/j.mcna.2020.09.008ArticlePubMed
• 5. Ranjan P, Chakrawarty A, Kumari A, Kumar J. Immunization in patients with rheumatic diseases: a practical guide for general practitioners. J Clin Diagn Res 2015;9:OE01-OE04. https://doi.org/10.7860/JCDR/2015/14147.5972ArticlePubMedPMC
• 6. Rákóczi É, Szekanecz Z. Pneumococcal vaccination in autoimmune rheumatic diseases. RMD Open 2017;3:e000484. https://doi.org/10.1136/rmdopen-2017-000484ArticlePubMedPMC
• 7. Glück T, Müller-Ladner U. Vaccination in patients with chronic rheumatic or autoimmune diseases. Clin Infect Dis 2008;46:1459-1465. https://doi.org/10.1086/587063ArticlePubMed
• 8. Seo YB, Moon SJ, Jeon CH, Song JY, Sung YK, Jeong SJ, et al. The practice guideline for vaccinating Korean patients with autoimmune inflammatory rheumatic disease. Infect Chemother 2020;52:252-280. https://doi.org/10.3947/ic.2020.52.2.252ArticlePubMedPMC
• 9. Papadopoulou D, Sipsas NV. Comparison of national clinical practice guidelines and recommendations on vaccination of adult patients with autoimmune rheumatic diseases. Rheumatol Int 2014;34:151-163. https://doi.org/10.1007/s00296-013-2907-9ArticlePubMed
• 10. Neusser S, Neumann A, Zur Nieden P, Speckemeier C, Schlierenkamp S, Walendzik A, et al. Facilitators and barriers of vaccine uptake in patients with autoimune inflammatory rheumatic disease: a scoping review. RMD Open 2022;8:e002562. https://doi.org/10.1136/rmdopen-2022-002562ArticlePubMedPMC
• 11. Hmamouchi I, Winthrop K, Launay O, Dougados M. Low rate of influenza and pneumococcal vaccine coverage in rheumatoid arthritis: data from the international COMORA cohort. Vaccine 2015;33:1446-1452. https://doi.org/10.1016/j.vaccine.2015.01.065ArticlePubMed
• 12. Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014;58:e44-e100. https://doi.org/10.1093/cid/cit684ArticlePubMed
• 13. Eibl MM, Wolf HM. Vaccination in patients with primary immune deficiency, secondary immune deficiency and autoimmunity with immune regulatory abnormalities. Immunotherapy 2015;7:1273-1292. https://doi.org/10.2217/IMT.15.74ArticlePubMed
• 14. Korean Society of Infectious Diseases. 2019 vaccination guideline information [cited 2026 Mar 20]. Available from: https://www.ksid.or.kr/content/info/vaccine_info.php (Korean)
• 15. Nimmana BK, Patel P. Disease-modifying antirheumatic drugs (DMARDs). In: StatPearls [Internet]. . Treasure Island: StatPearls Publishing; 2025, PMID: 29939640.
• 16. Kwon SR, Kim TH, Kim TJ, Park W, Shim SC. The epidemiology and treatment of ankylosing spondylitis in Korea. J Rheum Dis 2022;29:193-199. https://doi.org/10.4078/jrd.22.0023ArticlePubMedPMC
• 17. Kim TJ, Kim TH. Clinical spectrum of ankylosing spondylitis in Korea. Joint Bone Spine 2010;77:235-240. https://doi.org/10.1016/j.jbspin.2009.11.015ArticlePubMed
• 18. Tsokos GC. Systemic lupus erythematosus. N Engl J Med 2011;365:2110-2121. https://doi.org/10.1056/NEJMra1100359ArticlePubMedPMC
• 19. Peoples C, Medsger TA Jr, Lucas M, Rosario BL, Feghali-Bostwick CA. Gender differences in systemic sclerosis: relationship to clinical features, serologic status and outcomes. J Scleroderma Relat Disord 2016;1:177-240. https://doi.org/10.5301/jsrd.5000209ArticlePubMedPMC
• 20. Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA, et al. The risk of hospitalized infection in patients with rheumatoid arthritis. J Rheumatol 2008;35:387-393.PubMed
• 21. Ozen G, Pedro S, England BR, Mehta B, Wolfe F, Michaud K. Risk of serious infection in patients with rheumatoid arthritis treated with biologic versus nonbiologic disease-modifying antirheumatic drugs. ACR Open Rheumatol 2019;1:424-432. https://doi.org/10.1002/acr2.11064ArticlePubMedPMC
• 22. Riley TR, George MD. Risk for infections with glucocorticoids and DMARDs in patients with rheumatoid arthritis. RMD Open 2021;7:e001235. https://doi.org/10.1136/rmdopen-2020-001235ArticlePubMedPMC
• 23. Andreica I, Roman I, Redeker I, Baraliakos X, Braun J, Kiltz U. Facilitators and barriers for vaccination in patients with inflammatory rheumatic musculoskeletal diseases: a prospective cohort study. RMD Open 2023;9:e002875. https://doi.org/10.1136/rmdopen-2022-002875ArticlePubMedPMC
• 24. Papadopoulou D, Tsoulas C, Tragiannidis A, Sipsas NV. Role of vaccinations and prophylaxis in rheumatic diseases. Best Pract Res Clin Rheumatol 2015;29:306-318. https://doi.org/10.1016/j.berh.2015.02.001ArticlePubMed
• 25. Brewer NT. What works to increase vaccination uptake. Acad Pediatr 2021;21:S9-S16. https://doi.org/10.1016/j.acap.2021.01.017ArticlePubMed
• 26. Rondaan C, Furer V, Heijstek MW, Agmon-Levin N, Bijl M, Breedveld FC, et al. Efficacy, immunogenicity and safety of vaccination in adult patients with autoimmune inflammatory rheumatic diseases: a systematic literature review for the 2019 update of EULAR recommendations. RMD Open 2019;5:e001035. https://doi.org/10.1136/rmdopen-2019-001035ArticlePubMedPMC
• 27. Sim JJ, Lim CC. Influenza vaccination in systemic lupus erythematosus: efficacy, effectiveness, safety, utilization, and barriers. Am J Med 2022;135:286-296. https://doi.org/10.1016/j.amjmed.2021.08.038ArticlePubMed
• 28. Kim H, Son HS. Analysis of the incidence of influenza before and after the COVID-19 pandemic in South Korea. Trop Med Int Health 2024;29:1018-1025. https://doi.org/10.1111/tmi.14055ArticlePubMedPMC

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