Flare and change in disease activity among patients with stable rheumatoid arthritis following coronavirus disease 2019 vaccination: a prospective Chinese cohort study : Chinese Medical Journal

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Original Article

Flare and change in disease activity among patients with stable rheumatoid arthritis following coronavirus disease 2019 vaccination: a prospective Chinese cohort study

Geng, Yan; Fan, Yong; Wang, Yu; Deng, Xuerong; Ji, Lanlan; Zhang, Xiaohui; Song, Zhibo; Huang, Hong; Gui, Yanni; Zhang, Haoze; Sun, Xiaoying; Li, Guangtao; Zhao, Juan; Zhang, Zhuoli

Editor(s): Guo, Lishao

Author Information
Chinese Medical Journal ():10.1097/CM9.0000000000002562, March 15, 2023. | DOI: 10.1097/CM9.0000000000002562
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Abstract

Introduction

Vaccination has been shown effective in controlling the global coronavirus disease 2019 (COVID-19) pandemic and reducing severe cases. Considering the benefits outweighing the risks, vaccination has been strongly recommended by the guidance of both European League Against Rheumatism (EULAR)[1] and American College of rheumatology (ACR)[2] for patients with stable rheumatoid arthritis (RA). But the impact of COVID-19 vaccination on disease activity has been a concern. A couple of previous studies found that RA flare requiring treatment adjustment following COVID-19 vaccination was uncommon.[3,4] A cohort study showed no evidence of increased risk of possible arthritis flare among COVID-19-vaccinated RA patients compared with non-vaccinated individuals.[5] Importantly, in all these studies, the adjudication of disease activity and RA flare was mainly based on the information obtained via online survey or telephone interview. So far, there is no study trying to definitely answer the questions via hospital site visit and assessment.

Based on a well-established prospective RA cohort in our center, we enrolled those RA patients in remission or with low disease activity. Their disease activity before and after two-dose vaccination was evaluated. The flare rate of vaccinated RA patients was also compared with that of non-vaccinated RA patients during the same period. The aim of the study was to exactly evaluate the change of disease activity as well as RA flare associated with COVID-19 vaccination.

Methods

Ethical approval

The study was approved by the Ethics Committee of the Peking University First Hospital (No. 2021-037), and informed consent was obtained from each patient.

Study design and participants

The Collaboratively intENsive Treat-to-target in RA (CENTRA) cohort patients who achieved remission or low disease activity between January 1, 2021 and January 31, 2022 were enrolled. The CENTRA cohort is a prospective RA cohort, which has been established since 2015 in Peking University First Hospital, China. All patients were at least 18 years old and fulfilled the 2010 ACR classification criteria for RA. More details of the cohort have been described in our previous published study.[6] The enrolled RA patients were divided into a vaccination group and a non-vaccination group based on their COVID-19 vaccination status. Each of them was pre-scheduled for examination every 3 to 6 months via hospital-based face-to-face consultation. Additional visit can be arranged when the patients were likely to experience a disease flare unexpectedly. There are no specifications in the protocol regarding choice of treatments, but clinicians follow the EULAR recommendations for use of synthetic and biological disease-modified antirheumatic drugs (DMARDs).

Data collection

Demographics, comorbidities, smoking history, physical examinations, laboratory tests, and disease activity assessments including tender joint count, swollen joint count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), patient global assessment, and evaluator global assessment were recorded at each visit. Disease activity scores based on 28-joint count using either ESR (DAS28-ESR) or CRP (DAS28-CRP) as well as clinical disease activity index (CDAI) and simplified disease activity index (SDAI) were calculated.

Ultrasonography was performed by an experienced rheumatologist who was blinded to all clinical data. Next, 22 joints (bilateral wrists, metacarpophalangeal joints, and proximal interphalangeal joints) were scanned from a dorsal aspect on transverse and longitudinal planes. Ultrasound was performed using a ML6-15 scanner (GE, Wauwatosa, Milwaukee, USA). Synovitis was measured and semi-quantitatively graded with the 2001 Sukudlarek method. Gray Scale (GS) and Power Doppler (PD) synovitis scores were graded on a scale of 0 to 3 for each joint. GS total score (0–66) and PD total score (0–66) were defined as the sum of GS scores and PD scores at each joint, respectively.

The medications used during the whole follow-up period were recorded. The safety profile related to the COVID-19 vaccination was also collected at the post-vaccination visit, including vaccination time, brand of vaccine, and any adverse events (AEs).

Study outcomes

The primary outcome was the rate of flare defined as DAS28-ESR > 3.2 with ΔDAS28-ESR ≥ 0.6 at the post-vaccination visit compared to pre-vaccination visit. The secondary outcome was the variations of disease activity scores and the synovitis scores on ultrasound on post-vaccination assessment compared to pre-vaccination assessment.

Statistical analysis

Quantitative data were presented as mean ± standard deviation or median with interquartile range (IQR) as appropriate. Categorical variables are described as number (percentage). In addition, quantitative data were analyzed using independent t-tests (for parametric data) or Mann-Whitney U-tests (for non-parametric data). Categorical data were compared using chi-squared tests or Fisher's exact tests. Univariable and Multivariable logistic regression analyses were performed to explore risk factors associated with disease flare or AEs. For all statistical analyses, P < 0.05 was considered as being statistically significant. Data analyses and graphing were conducted by SPSS 20.0 (SPSS Inc., Chicago, IL, USA) and Prism software 8 (GraphPad Software, San Diego, CA, USA).

Results

Patient characteristics and baseline variables

Among a total of 369 RA patients in the CENTRA cohort, 223 patients in remission or with low disease activity were followed up between January 1, 2021 and January 31, 2022. Except for four who only received one dose of vaccine and 17 who were lost to follow-up, 202 patients were finally enrolled in this study, including 98 patients who received no vaccine shot (called non-vaccination group hereafter) and 104 patients who received two doses of vaccine (called vaccination group hereafter). Flow of enrollment was shown in Figure 1.

F1
Figure 1:
Flow diagram of enrollment in this study. CENTRA: Collaboratively intENsive Treat-to-target in RA; RA: Rheumatoid arthritis.

After excluding 17 patients who were lost to follow-up, vaccination status of 206 eligible patients was recorded. Then, 104 out of 206 patients (50.5%) received two-dose COVID-19 vaccine. In the vaccination group, the median time interval between the pre-vaccination visit and the first immunization dose was 67 days (IQR: 22–115). Between the second shot of vaccine and the post-vaccination visit, the median interval was 83 days (IQR: 45–134). Most of them received inactivated COVID-19 vaccines, including Sinovac (70, 67.3%) and Sinopharm (27, 26.0%), followed by recombinant subunit vaccine from Zhifei Longcom (7, 6.7%). Compared with the non-vaccination group, the vaccination group patients were younger (51.6 ± 14.0 vs. 55.5 ± 13.0 years, P = 0.041). Other demographics and clinical characteristics, such as gender, disease course, seropositivity, disease activity scores, ultrasound synovitis scores, and DMARD usage, were comparable at enrollment between two groups [Table 1].

Table 1 - Comparisons of the demographics and clinical features at enrollment between COVID-19 vaccination and non-vaccination RA cohorts.
Items Vaccination RA (n = 104) Non-vaccination RA (n = 98) Statistical value P values
Demographics characteristics
 Female 85 (81.7) 81 (82.7) 0.029 0.864
 Age (years) 51.6 ± 14.0 55.5 ± 13.0 −2.055 0.041
 Disease duration (years) 9.2 ± 7.4 9.7 ± 8.8 −0.493 0.623
 Body mass index (kg/m2) 23.3 ± 4.0 22.7 ± 3.8 1.074 0.284
 Smoking history 12 (11.5) 16 (16.3) 0.969 0.325
 Comorbidities 49 (47.1) 45 (45.9) 0.029 0.865
Clinical characteristics at baseline
 TJC28 0 (0, 1) 0 (0, 1) −1.405 0.160
 SJC28 0 (0, 1) 0 (0, 1) 0.440 0.660
 PGA (0–100) 10 (1, 15) 10 (5, 20) −1.808 0.071
 EGA (0–100) 5 (0, 10) 5 (0, 10) 0.456 0.649
 HAQ (0–60) 0 (0, 2) 0 (0, 3) −1.925 0.054
 ESR (mm/1h) 11 (6, 20) 14 (8, 24) −1.792 0.073
 CRP (mg/L) 3 (2, 4) 3 (2, 6) −1.464 0.143
 DAS28-ESR 2.13 ± 0.79 2.35 ± 0.87 −1.901 0.059
 DAS28-CRP 1.88 ± 0.61 2.04 ± 0.64 −1.864 0.064
 CDAI 2 (1, 4) 2 (1, 5) −1.434 0.152
 SDAI 2 (1, 5) 3 (1, 5) −1.614 0.107
 Boolean remission 64 (61.5) 47 (48.0) 3.758 0.053
 Positive RF 72 (69.2) 75 (76.5) 1.357 0.244
 Positive anti-CCP 88 (84.6) 83 (85.6) 0.036 0.850
Ultrasound characteristics at baseline
 GS total score 2 (0, 4) 1 (0, 3) 1.906 0.053
 PD total score 0 (0, 1) 0 (0, 0) 0.961 0.320
Medications at baseline
 Methotraxate 83 (79.8) 73 (74.4) 0.811 0.368
 Leflunomide 11 (10.6) 12 (12.2) 0.139 0.709
 Hydroxycloroquine 35 (33.7) 34 (34.7) 0.024 0.876
 Salphasalazine 3 (2.9) 2 (2.0) 0.149 0.700
 Azathioprine 1 (1.0) 3 (3.1) 1.146 0.357
 Iguratimod 2 (1.9) 6 (6.1) 1.366 0.243
 Glucocoriticoid 5 (4.8) 10 (10.2) 2.137 0.144
 TNFi 6 (5.8) 4 (4.1) 0.052 0.820
 JAKi 18 (17.3) 24 (24.3) 1.580 0.209
Follow-up data
 Flare rate 5 (4.8) 9 (9.2) 1.498 0.221
 DAS28-ESR at the time of flare 4.47 ± 0.65 4.07 ± 0.57 1.208 0.250
 DAS28-CRP at the time of flare 3.90 ± 0.91 3.23 ± 0.52 1.778 0.101
 CDAI at the time of flare 14.0 ± 8.6 9.9 ± 4.0 1.224 0.244
 SDAI at the time of flare 15.5 ± 9.3 10.5 ± 4.1 1.416 0.182
 Follow-up duration (days) 188.3 ± 65.5 183.4 ± 52.9 0.576 0.565
Values are presented as mean ± SD, median (Q1, Q3) or n (%), as applicable. anti-CCP: Anti-cycliccitrullinated peptide; CDAI: Clinical disease activity index; COVID-19: Coronavirus disease 2019; CRP: C-reactive protein; DAS28: Disease activity score based on 28 joints; EGA: Evaluator's global assessment; ESR: Erythrocyte sedimentation rate; GS: Gray score synovial hypertrophy; HAQ: Health Assessment Questionnaire; JAKi: Janus kinase inhibitor; PD: Power Doppler synovitis; PGA: Patient's global assessment; RA: Rheumatoid arthritis; RF: Rheumatoid factor; SD: Standard deviation; SDAI: Simplified disease activity index; SJC: Swollen joint count; TJC: Tender joint count; TNFi: Tumor necrosis factor inhibitor.

Change in disease activity and flare rate following COVID-19 vaccination

In the vaccination group, there were no significant differences in DAS28-ESR (2.13 ± 0.79 vs. 2.19 ± 0.89), DAS28-CRP (1.88 ± 0.61 vs. 1.86 ± 0.81), CDAI (2 (1, 4) vs. 2 (1, 5)), and SDAI (2 (1, 5) vs. 3 (1, 5)) between pre-vaccination and post-vaccination visits (P > 0.05) [Figure 2]. The synovitis ultrasound scores were also similar between pre-vaccination and post-vaccination visits (P > 0.05). Flares occurred in five (4.8%) of vaccination group patients at the post-vaccination visit. While during the same observation period, the disease activity scores and synovitis ultrasound scores of those non-vaccination group patients were also overall stable with nine (9.2%) patients who flared.

F2
Figure 2:
Flare and disease activity assessment in this study. (A) Flare rates in vaccination group and non-vaccination group (P = 0.221). (B) Comparisons of disease activity scores (DAS28-ESR, DAS28-CRP, CDAI and SDAI) between pre-vaccination and post-vaccination visits in the vaccination group. Violin plots: green violin represents pre-vaccination visit, and orange violin stands for post-vaccination visit. Blue dashed lines represent median value; blue dotted lines stand for IQR. (P > 0.05). CDAI: Clinical disease activity index; CRP: C-reactive protein; DAS28: Disease activity score based on 28 joints; ESR: Erythrocyte sedimentation rate; IQR: Interquartile range; SDAI: Simplified disease activity index.

The flare rates were comparable between the vaccination group and non-vaccination group (4.8% vs. 9.2%, P = 0.221, Figure 2). The DAS28-ESR at the time of flare was also comparable between two groups (4.47 ± 0.65 vs. 4.07 ± 0.57, P = 0.250) [Table 1]. Similar results were found with other composite disease activity scores, including DAS28-CRP, CDAI, and SDAI.

There were 14 patients who experienced flare in two groups. All these were minor flares and well controlled after escalating treatment. Flare more commonly occurred in those patients with higher DAS28-ESR at enrollment (OR: 2.03, 95% CI: 1.11–3.70). The frequency of flare appeared to be unassociated with age, gender, disease course, and COVID-19 vaccination (P > 0.05). A multivariable logistic regression model examining risk factors for RA flare revealed that only patients with higher DAS28-ESR at enrollment had greater risk of experiencing flare in our cohort [Table 2].

Table 2 - Univariable and multivariable logistic analyses for predicting RA flare in 202 enrolled patients.
Univariable analysis Multivariable analysis


Items OR (95% CI) P value OR (95% CI) P value
Gender (female vs. male) 2.974 (0.376–23.493) 0.301 / /
Age (per 1 year) 1.029 (0.985–1.074) 0.882 / /
Disease duration (per 1 year) 1.023 (0.964–1.085) 0.149 / /
COVID-19 vaccination (yes vs. no) 0.499 (0.161–1.546) 0.229 / /
DAS28-ESR at baseline 2.028 (1.111–3.704) 0.021 1.041 (1.008–1.074) 0.013
Boolean remission at baseline (yes vs. no) 0.303 (0.092–1.000) 0.050 / /
GS total score at baseline (per 1 score) 1.018 (0.900–1.153) 0.773 / /
PD total score at baseline (per 1 score) 1.155 (0.959–1.300) 0.155 / /
COVID-19: Coronavirus disease 2019; DAS28: Disease activity score based on 28 joints; ESR: Erythrocyte sedimentation rate; GS: Gray score synovial hypertrophy; PD: Power Doppler synovitis; RA: Rheumatoid arthritis; /: Not applicable.

Safety profiles of COVID-19 vaccination in RA patients with stable disease

Among 104 vaccination group patients, 29 (27.9%) experienced AEs after vaccination [Table 3]. Localized AEs, such as pain or swelling, at the injection site occurred in 28 (26.9%) patients and systemic AEs in 11 (10.6%) patients. Fatigue and sleepless (6, 5.8%) was the most reported systemic AE, followed by skin rash (3, 2.9%) and headache (3, 2.9%). The median time from vaccination shot to onset of AEs was 1 to 2 days. All AEs were mild and self-limiting. No severe AEs happened.

Table 3 - Safety data of COVID-19 vaccination in RA patients.
Items Vaccination RA
Paticipants (n) 104
Female, n (%) 85 (81.7)
Age (years), mean ± SD 51.6 ± 14.0
Allergic history, n (%) 8 (7.7)
Vaccine band, n (%)
 Sinovac 70 (67.3)
 Sinopharm 27 (26.0)
 Zhifei Longcom 7 (6.7)
 AEs (n, %) 29 (27.9)
 Local (n, %) 28 (26.9)
 Systemic (n, %) 11 (10.6)
 Rash (n) 3
 Fever/chills (n) 2
 Headache (n) 3
 Fatigue/sleepless (n) 6
 Nausea/vomiting (n) 1
 Diarrhea (n) 0
 Others (n) 1
 Side effects after first vaccine, n (%) 17 (16.3)
 Timing of onset (days), median (Q1, Q3) 1 (0, 3)
 Side effects after second vaccine, n (%) 12 (11.5)
 Timing of onset (days), median (Q1, Q3) 2 (1, 3)
 Severe AE, n (%) 0
 Fatal AE of interest, n (%) 0
Means anaphylactic shock, myocarditis, idiopathic thrombocytopenic purpura and death.AEs: Adverse events; COVID-19: Coronavirus disease 2019; RA: Rheumatoid arthritis; SD: Standard deviation.

Discussion

Among our RA patients in remission or with low disease activity from a prospective cohort, the COVID-19 vaccination rate of 50.5% is much lower than 85.1% in the Chinese national population[7] but comparable with the average vaccination rate of 54.7% globally in 2021.[7] Focusing on the patients with chronic rheumatic diseases, we notice that the vaccination rate of 50.5% in our cohort is even higher than that reported (30.2% and 29.0%).[8,9] Although the novel guidelines recommend that vaccination should be a privilege for patients with well-controlled inflammatory rheumatic disease, many of them remain hesitant due to the concern of disease flare or side effects.[10]

The RA disease activity before and after COVID-19 vaccination was comparable in our cohort patients with stable RA. Similar results in the Systemic Lupus Erythematosus Disease Activity Index between pre-vaccination and post-vaccination assessment were also observed in SLE patients.[11] These indicated that COVID-19 vaccinations had no significant effect on disease activity of rheumatic diseases, especially among RA patients in remission or with low disease activity. An Israel team assessed the SDAI of 263 RA patients during 2 to 6 weeks after two doses of mRNA vaccine and found RA remained stable in 80% of patients.[12] But in the study, the correlation of worsened SDAI occurring (in 20% of patients) with COVID-19 vaccination cannot be determined without the data of non-vaccinated RA patients in the same period as control.

In our prospective cohort, the flare rate was 4.8% assessed at a median of 83 days after vaccination. More importantly, we demonstrated the comparable flare rates between the vaccination and non-vaccination group patients during the same observation period. A cohort study also showed that COVID vaccination did not increase the risk of flare in RA patients,[5] but the counting of flare was based on territory-wide electronic medical records in which disease activity assessment is generally not available. By the way of survey, we reported that the flare rate was 9.4%.[3] Only RA patients in remission or with low disease activity were included and may account for the low flare rate in this study. Besides, hospital-based face-to-face assessment on disease activity adopted in this study is more accurate and reliable than the patient self-reported flare via survey in previous studies.

Numerous factors may trigger RA flare, such as infection and poor medication adherence. In our study, the flare rate following COVID-19 vaccination was not associated with age, gender, and vaccination. Multivariable logistic analyses demonstrated that only DAS28-ESR at enrollment was the risk factor for disease flare in all enrolled patients with stable RA. Our previous study also supported that the stable status of autoimmune inflammatory rheumatic diseases was the negative predictor for disease flare.[3] It is commonly accepted that high baseline disease activity is associated with subsequent RA relapse even in patients in clinical remission. The deeper the remission, the lower the risk to relapse.[13] In this study, vaccinated RA patients were with lower disease activity at enrollment than non-vaccinated patients, which may explain the numerically lower flare rate in the vaccinated group. Moreover, in line with previous literature, inactivated COVID-19 vaccine has been proved to have no effect on flare of rheumatic diseases.[14] Regarding ultrasonic subclinical synovitis, its value in predicting flare in RA patients with clinical remission has been confirmed by previous studies.[15] But unfortunately, neither GS nor PD synovitis score was identified as a risk factor of flare, probably because of low frequency of flare in this study.

Overall, 27.9% of RA patients exhibited AEs, with 10.6% of systemic but non-lethal AEs, indicating the good tolerability of COVID-19 vaccination in patients with stable RA. Our results aligned with two large real-world studies based on EULAR COVID-19 database, showing 31% to 37% vaccine-related AEs in rheumatic and musculoskeletal disease patients.[16,17]

This prospective cohort study focused on the change of RA disease activity and flare following COVID-19 vaccination. Most importantly, the determination of disease activity and flare in the study was based on hospital site assessment, which is much more reliable than telephone interview or online survey. In addition, we only included RA patients in remission or with low disease activity in this study. This is compliant with currently available expert recommendations on COVID-19 vaccination in patients with rheumatic diseases but may limit the generalization of the study conclusions to patients with active RA. COVID-19 vaccination is currently not strongly recommended for patients with active RA due to lack of evidence.

Conclusions

The prospective cohort study confirmed that COVID-19 vaccinations had no significant effect on disease activity or risk of flare in RA patients in remission or with low disease activity. The COVID-19 vaccination rate among patients with stable RA is currently low and insufficient. It is hypothesized that a similar phenomenon might exist in other immunocompromised diseases. Perhaps physicians should encourage RA patients as well as other immunocompromised patients with stable disease to receive COVID-19 vaccination.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81771740, 81901646), Interdisciplinary Clinical Research Project of Peking University First Hospital (No. 2021CR30), and Peking University Medicine Seed Fund for Interdisciplinary Research supported by the Fundamental Research Funds for the Central Universities (No. BMU2022MX003).

Conflicts of interest

None.

References

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Keywords:

COVID-19 vaccination; Rheumatoid arthritis; Disease activity; Flare; Adverse events

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