To the Editor:

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a type of systemic vasculitis characterized by autoantibody development against the neutrophil proteins leukocyte proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA. We previously reported that newly developed AAV in Japan was influenced by seasonal variations and that AAV was less frequently observed in autumn.1 However, because the study focused on new-onset AAV, the environmental effects on AAV recurrence remain unclear. Therefore, this present study aimed to clarify seasonal and other environmental effects on AAV relapse.

Patients who were registered in the Japan Collaborative Registry of ANCA-Associated Vasculitis (J-CANVAS) study, conducted at 24 institutions, and diagnosed with a major relapse between January 2017 and December 2019 were enrolled. All patients were aged ≥ 20 years, and AAV was classified into eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA), and granulomatosis with polyangiitis (GPA) based on established definitions.2 A major relapse was defined as organ and/or life-threatening conditions due to AAV relapse.3,4 Details of the definitions of seasons and rural areas are described previously.1

This study was approved by the Ethical Committee for Epidemiology of Hiroshima University (approval number: E-2021-2465) and was performed in accordance with the ethical standards of the Helsinki Declaration. The requirement for written consent was waived according to local regulations.

Overall, 101 patients with AAV relapse were enrolled. Among these, 43, 39, and 19 patients were classified as having MPA, GPA, and EGPA, respectively, with the corresponding mean ages of 73.0 (SD 12.1) years, 64.0 (SD 13.6) years, and 60.7 (SD 16.0) years. The proportions of female patients were 53.5%, 59%, and 73.7%, respectively, and MPO-ANCA positivity was found in 97.7%, 30.8%, and 42.1% of patients with MPA, GPA, and EGPA, respectively. The corresponding percentages for PR3-ANCA positivity were 2.3%, 64.1%, and 5.3%, respectively.

Spring, summer, autumn, and winter relapses were observed in 21.8%, 41.6%, 17.8%, and 18.8% of the patients, respectively. The seasonality of relapse significantly deviated (P = 0.002) from the expected 25% for each season (Figure 1A and Table). The trend of increased relapses in summer was observed every year from 2017 to 2019, although the seasonal effects on relapse were weak in 2018 compared with 2017 or 2019 (Figure 1B). Subsequently, we analyzed the seasonality in terms of disease type (Figures 1C,D). In patients with GPA, spring, summer, autumn, and winter relapses were observed in 30.8%, 46.2%, 10.3%, and 12.8% of the patients, respectively, and marked seasonality was observed (P = 0.004). Among those with MPA, the corresponding percentages were 14%, 34.9%, 27.9%, and 23.3% (P = 0.26), and in those with EGPA, they were 21.1%, 47.4%, 10.5%, and 21.1% (P = 0.13).

(A) Seasonal variations at the time of AAV recurrence. (B) Seasonal distribution of patients with AAV in 2017, 2018, and 2019. (C) Distribution of the seasons of MPA, GPA, and EGPA relapses. (D) Distribution of the months of MPA, GPA, and EGPA relapses. AAV: antineutrophil cytoplasmic antibody–associated vasculitis; EGPA: eosinophilic granulomatosis with polyangiitis; GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis.

Association between ANCA serotypes and environmental factors.

Seasonal analysis showed that 33.3%, 44.4%, 3.7%, and 18.5% of the patients with PR3-ANCA had AAV recurrence in spring, summer, autumn, and winter, respectively (Table), and the seasonal difference was significant (P = 0.02). However, no significant differences were observed in patients with MPO-ANCA (spring, summer, autumn, and winter recurrence: 19.4%, 35.5%, 19.4%, and 21%, respectively; P = 0.27). Next, we investigated the triggering factors for AAV relapse, including smoking habits and rurality (Table). The proportion of ANCA serotypes did not differ between smokers and nonsmokers (P = 0.64) or between patients living in rural and urban areas (P = 0.97).

We conducted this study to identify environmental factors influencing the relapse of AAV, focusing on seasonal variations in Japan. Our results suggest that AAV relapse is influenced by seasonal variations and was frequently observed in the summer, particularly in patients with GPA or PR3-ANCA. Kemna et al reported that a vitamin D deficiency–related increase in ANCA titers in autumn and winter resulted in relapse within 6 months, mainly in patients positive for PR3-ANCA.5 Although data regarding when ANCA elevation occurred in our patients were unavailable, higher relapse rates in the spring or summer in our patients with PR3-ANCA seem consistent with the results reported by Kemna et al.5

Stegeman et al described the association between nasal carriage of Staphylococcus aureus and GPA relapse.6 Nasal carriage of S. aureus proved to be a strong risk factor for recurrence (relative risk 9.0). Because S. aureus infection can elicit the activation of the innate immune system through the inflammatory pathways,7 its colonization may trigger GPA relapse. Previous research investigating the seasonality of S. aureus colonization suggested a higher colonization prevalence during the hot season in Japan.8 Thus, the reason AAV relapse is more frequently observed in summer may be related to the nasal carriage of the microorganism.9,10

Our study has some limitations. We could not obtain information regarding ANCA titers, and the date of AAV relapse was analyzed according to the time of diagnosis because it was difficult to ascertain the date of recurrence. In addition, subanalyses for patients with EGPA and MPO-ANCA also showed a tendency for more frequent relapses in the summer; however, they were not significant owing to insufficient power. Thus, large-scale studies are needed to validate these findings.

In conclusion, AAV relapse was influenced by seasonal variations and was frequently observed in summer.

We thank all staff who treated the enrolled patients at the collaborating institutions.

List of study collaborators. Japan Collaborative Registry of ANCA–Associated Vasculitis study group: Dr. Satoshi Omura, Dr. Daiki Nakagomi, Dr. Yoshiyuki Abe, Dr. Masatoshi Kadoya, Dr. Naoho Takizawa, Dr. Atsushi Nomura, Dr. Yuji Kukida, Dr. Naoya Kondo, Dr. Yasuhiko Yamano, Dr. Takuya Yanagida, Dr. Koji Endo, Dr. Kiyoshi Matsui, Dr. Tohru Takeuchi, Dr. Kunihiro Ichinose, Dr. Masaru Kato, Dr. Ryo Yanai, Dr. Yusuke Matsuo, Dr. Yasuhiro Shimojima, Dr. Ryo Nishioka, Dr. Ryota Okazaki, Dr. Tomoaki Takata, Dr. Takafumi Ito, Dr. Mayuko Moriyama, Dr. Ayuko Takatani, and Dr. Yoshia Miyawaki.

SH received speaker fees, consultancy fees, research grants, and honoraria from AbbVie, Asahi-Kasei, Astellas, AstraZeneca, Ayumi, BMS, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Gilead Sciences, GSK, Eli Lilly, Janssen, Nippon Shinyaku, Novartis, Otsuka, Pfizer, Taisho, Tanabe-Mitsubishi, and UCB. The remaining authors declare no conflicts of interest relevant to this article.