Seasonal Variation in Antineutrophil Cytoplasmic Antibody (ANCA)‐Associated Vasculitis Onset Before and During the Coronavirus Disease 2019 (COVID‐19) Pandemic: Findings From the Multicenter J‐CANVAS Registry

1. Introduction

Antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV) comprises a group of systemic small‐vessel diseases including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA) [1]. AAV is characterized by the presence of autoantibodies directed against proteinase 3 (PR3‐ANCA) or myeloperoxidase (MPO‐ANCA), which can lead to severe inflammation and organ damage [2]. Environmental exposure to specific infectious agents or allergens is considered a trigger for ANCA production and AAV development [3, 4].

The coronavirus disease 2019 (COVID‐19) pandemic, which began in late 2019, drastically altered infectious disease transmission patterns and environmental exposure through widespread public health measures, including lockdowns and universal mask use. Although cases of vasculitis following COVID‐19 infection have been reported [5], a large single‐center study failed to demonstrate a clear association [6]. Therefore, evidence for a causal relationship remains inconclusive.

We previously reported seasonal variation in AAV onset, including a consistent reduction in autumn among patients with MPA and MPO‐ANCA [7]. However, the overall effect of the COVID‐19 pandemic on the epidemiology and seasonality of AAV has not been established. Therefore, in this study, we aimed to investigate whether seasonal patterns of AAV onset differed between the pre‐COVID‐19 and COVID‐19 periods using data from a nationwide, multicenter registry in Japan (J‐CANVAS) and to compare seasonal patterns across AAV subtypes and ANCA serotypes.

2. Materials and Methods

3. Results

4. Discussion

In this large multicenter study, we demonstrated that AAV exhibits a clear seasonal pattern, with higher incidence in spring and summer and lower incidence in autumn during the pre‐COVID‐19 period. Importantly, this seasonal pattern differed between the pre‐COVID‐19 and COVID‐19 periods, as evidenced by a relative increase in spring‐onset cases and attenuation of the summer peak in the whole AAV cohort.

However, these changes were not consistently observed across individual disease subtypes or ANCA serotypes. While seasonal variation was evident in MPA and MPO‐ANCA‐positive AAV, no significant overall seasonality or interaction with the COVID‐19 period was detected in GPA, EGPA, or other serotype‐defined subgroups. Collectively, these findings suggest heterogeneity in seasonal patterns among AAV disease subtypes.

Studies during the COVID‐19 pandemic suggested an increased incidence of various autoimmune diseases, including vasculitides [13, 14]. In Japan, administrative data showed an increase in the number of new applicants to designated intractable disease programs, suggesting a broader rise in newly diagnosed immune‐mediated disorders [15]. However, in the present study, the number of registered patients decreased during the COVID‐19 period (Figure S2). This discrepancy may partly reflect pandemic‐related restrictions on healthcare access, delayed referral to specialized institutions, altered referral patterns, and variability in case capture inherent to voluntary registries, rather than necessarily indicating a true decline in AAV incidence. Additionally, the exact latency period from exposure to an infectious trigger to the clinical onset of vasculitis has not been defined. Therefore, the direct temporal relationship between infection waves and AAV onset should be interpreted with caution. Accordingly, we focused on differences in the seasonal patterns rather than absolute case numbers. This study did not track individual infections or behaviors; instead, it examined the relationship between AAV onset and the COVID‐19 pandemic as a macro‐level environmental factor.

We consistently observed decreased frequency of AAV onset in autumn throughout 2017–2022. Environmental factors have been considered contributors to seasonal variations in AAV onset, potentially through infections, allergens, or other external exposures [16, 17]. Vitamin D may be a potential seasonal factor, as serum 25‐hydroxyvitamin D levels reportedly peak toward the end of summer in the Japanese population [18], potentially contributing to the decreased frequency of AAV onset observed in autumn [19, 20]. However, as serum vitamin D levels were not measured in our cohort, this hypothesis remains speculative. In contrast to the consistently decreased frequency of autumn onset, the seasonal pattern differed between the pre‐COVID‐19 and COVID‐19 periods, with a relative increase in spring‐onset cases and a reduced relative frequency of the summer‐onset cases during the COVID‐19 period. These changes may have been associated with changes in environmental exposures, infection patterns, healthcare‐seeking behavior, and public health measures during the pandemic. The reduction in summer onset occurred during a period when Japan experienced major COVID‐19 waves accompanied by substantial changes in mobility and social activity [12, 21]. However, such temporal overlap cannot distinguish the potential effects of SARS‐CoV‐2 infection or its variants from those of behavioral changes, public health measures, or altered healthcare access. Moreover, we identified no clear temporal explanation for the relative increase in spring‐onset cases, which may partly reflect a relative redistribution of cases across seasons. Therefore, these interpretations remain speculative.

The epidemiological context also varied substantially throughout the COVID‐19 period. In particular, 2022 was characterized by widespread circulation of Omicron variants in Japan [22]. In that year, the infection patterns, disease severity, public health measures, and population behavior differed from those during the earlier pandemic period. However, the additional phase‐stratified analysis did not indicate a clear difference in seasonal patterns between the early COVID‐19 period (2020–2021) and 2022. Nevertheless, pandemic‐related changes in healthcare access, delayed referral, and altered referral patterns may have influenced the observed temporal distribution of AAV onset.

The lack of consistent seasonal patterns and period‐related differences across individual disease subtypes highlights the heterogeneity of AAV and suggests that the factors driving disease onset may differ by subtype. Although seasonal variation was prominent in MPA and MPO‐ANCA‐positive AAV, no clear seasonal variation was observed in GPA or EGPA. This discrepancy may reflect fundamentally different pathogenetic mechanisms, such as the involvement of upper respiratory tract infections, which are frequently implicated in GPA and EGPA [23, 24], or simply reflect a lack of statistical power due to limited sample sizes.

This study had certain limitations. As data on ANCA levels were unavailable, we could not assess their potential correlations with seasonality. Additionally, data on prior COVID‐19 infections and patients' vaccination status were not collected, thereby preventing assessment of their influence on disease onset. Accordingly, future studies incorporating detailed data on prior infection, vaccination status, and behavioral changes during the pandemic may provide additional insights. Furthermore, the sample sizes of the GPA, EGPA, and PR3‐ANCA‐positive subgroups were relatively small, which may have reduced the statistical power of the subgroup analyses. Finally, as the analysis was restricted to data through 2022, we could not assess whether the seasonal pattern of AAV onset subsequently returned to the pre‐COVID‐19 pattern.

This study has several strengths. First, it includes the largest number of cases to date among studies investigating environmental factors and AAV onset. Second, the use of a nationwide multicenter registry (J‐CANVAS) involving 29 institutions enhances the generalizability of our findings. Third, the use of the exact date of symptom onset, based on BVAS, enabled a more precise temporal analysis compared with studies relying on the date of diagnosis.

In conclusion, AAV exhibited a clear seasonal pattern during the pre‐COVID‐19 period, with higher incidence in spring and summer and lower incidence in autumn. The seasonal distribution differed during the COVID‐19 period, although these differences were not consistently observed across disease subtypes or ANCA serotypes. However, the factors underlying these differences remain uncertain and warrant further investigation.

Author Contributions

N.O. contributed to formal analysis and writing – original draft. Y.Y. contributed to conceptualization, formal analysis, methodology, and writing – review and editing. T.K., N.Y., T.I.‐I., T.K., and Y.K. contributed to project administration and supervision. All authors contributed to investigation, critically revised the manuscript for important intellectual content, approved the final version of the manuscript, and agreed to be accountable for all aspects of the work.

Funding

This study was partially supported by the JSPS Program for Forming Japan's Peaks Research Universities (J‐PEAKS) (grant number JPJS00420230011). This work was supported in part by JSPS KAKENHI (grant number 24K18642 to Y. Yoshida) and the Tsuchiya Memorial Medical Foundation (to Y. Yoshida).

Ethics Statement

This study was approved by the Ethical Committee for Epidemiology at Hiroshima University on June 2, 2021 (approval number: E‐2021‐2465) and by the Institutional Review Board or Ethics Committee of each participating institution and was conducted in accordance with the principles of the Declaration of Helsinki.

Consent

Informed consent was obtained from patients via an online opt‐out form. Patients who did not provide consent were excluded from the study.

Conflicts of Interest

Hirosuke Takagi has received speaker honoraria from Asahi Kasei Pharma, Astellas Pharma, and Kissei Pharmaceutical, and travel/accommodation support from Asahi Kasei Pharma, Chugai Pharmaceutical, and Kissei Pharmaceutical. Naoto Azuma has received speaker honoraria from Eli Lilly Japan and a research grant from Asahi Kasei Pharma. Hiroaki Dobashi has received speaker honoraria from Kissei Pharmaceutical, AbbVie, Asahi Kasei Pharma, UCB, Ayumi Pharmaceutical, GlaxoSmithKline, Novartis Pharma, Eli Lilly Japan, AstraZeneca, and has received research funding from AbbVie and Chugai Pharmaceutical. Isao Matsumoto has received speaker's fees, consultancy fees or honoraria from Chugai Pharmaceutical, Eisai, Glaxo SmithKline, Eli Lilly Japan, Boehringer Ingelheim and UCB. Toshiko Ito‐Ihara has received speaker honoraria from Kissei Pharmaceutical. Takashi Kawaguchi has received honoraria and speaker's fees from Chugai Pharmaceutical. Yutaka Kawahito has received research grants from Asahi Kasei and Chugai Pharmaceutical, and speaker's fees from Asahi Kasei Pharma, Chugai Pharmaceutical, Pfizer, Novartis Pharma, Kissei Pharmaceutical, AstraZeneca, Ayumi Pharmaceutical and Viatris. Shintaro Hirata has received speaker's fees, consultancy fees, or research grants from AbbVie, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Ayumi Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Chugai Pharmaceutical, Daiichi‐Sankyo, Eisai, Eli Lilly Japan, Gilead Sciences, Glaxo SmithKline, Janssen, Nihon‐Shinyaku, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, Sandoz, Taisho Pharmaceutical, Mitsubishi Tanabe Pharma, and UCB. The remaining authors declare no conflicts of interest.

Supporting information

Data Availability Statement

The datasets generated and analyzed in the current study are not publicly available but are available from the corresponding author upon reasonable request.