The association between ambient UVB dose and ANCA-associated vasculitis relapse and onset

Abstract

Background: The aetiology of ANCA-associated vasculitis (AAV) and triggers of relapse are poorly understood. Vitamin D (vitD) is an important immunomodulator, potentially responsible for the observed latitudinal differences between granulomatous and non-granulomatous AAV phenotypes. A narrow ultraviolet B spectrum induces vitD synthesis (vitD-UVB) via the skin. We hypothesised that prolonged periods of low ambient UVB (and by extension vitD deficiency) are associated with the granulomatous form of the disease and an increased risk of AAV relapse.

Methods: Patients with AAV recruited to the Irish Rare Kidney Disease (RKD) (n = 439) and UKIVAS (n = 1961) registries were studied. Exposure variables comprised latitude and measures of ambient vitD-UVB, including cumulative weighted UVB dose (CW-D-UVB), a well-validated vitD proxy. An n-of-1 study design was used to examine the relapse risk using only the RKD dataset. Multi-level models and logistic regression were used to examine the effect of predictors on AAV relapse risk, phenotype and serotype.

Results: Residential latitude was positively correlated (OR 1.41, 95% CI 1.14-1.74, p = 0.002) and average vitD-UVB negatively correlated (0.82, 0.70-0.99, p = 0.04) with relapse risk, with a stronger effect when restricting to winter measurements (0.71, 0.57-0.89, p = 0.002). However, these associations were not restricted to granulomatous phenotypes. We observed no clear relationship between latitude, vitD-UVB or CW-D-UVB and AAV phenotype or serotype.

Conclusion: Our findings suggest that low winter ambient UVB and prolonged vitD status contribute to AAV relapse risk across all phenotypes. However, the development of a granulomatous phenotype does not appear to be directly vitD-mediated. Further research is needed to determine whether sufficient vitD status would reduce relapse propensity in AAV.

Keywords: ANCA-associated vasculitis; Environment; Geoepidemiology; Ultraviolet B (UVB) radiation; Vitamin D.

Fig. 1

Annual distribution of average daily CW-D-UVB (dashed line) relative to the average daily vitD-UVB (solid line). Values in Dublin (red) and Cork (pink), averaged over 2004–2019, are displayed. The annual peak and nadir of CW-D-UVB were observed in August and February, respectively, lagging behind those of vitD-UVB by 2 months, thus mimicking 25OHD seasonal fluctuations

Fig. 2

Study design. i AAV diagnosis (cohorts 1 and 2). ii AAV relapse (cohort 2). i CW-D-UVB at diagnosis was calculated using the participant’s location and date of symptom onset if known, or the date of diagnosis minus 77 days. Seventy-seven days represents the undefined prodromal period [36] informed by the RKD registry analysis (see supplementary material). ii In this prospective n-of-1 component, each participant was a ‘case’ during period(s) of disease relapse and a ‘control’ during period(s) of remission [37]. The case window started at the date of relapse diagnosis minus 30 days (to account for the diagnostic delay) and ended 135 days later (see Additional file 1: Supplementary Methods). To improve the statistical power, 5 control dates were identified per patient, where possible

Fig. 3

AAV relapse. a Latitude (degrees), b average winter vitD-UVB (kJ/m²), c average winter CW-D-UVB (kJ/m²) and d average annual vitD-UVB (kJ/m²) stratified by disease activity (active vs. remission) in the entire cohort 2

Fig. 4

Effects plot demonstrating the marginal effect of average winter vitD-UVB (kJ/m2) on relapse risk. This is a graphical representation of the multi-level model reported in Table 2 (model 2), controlling for age at diagnosis, gender, AAV phenotype, ANCA serotype and treatment status. The average value for continuous covariates and the baseline value for categorical covariates are depicted. Ticks at the top and bottom of the graph refer to the relapse and remission events, respectively. The predictorEffect function from the effects R package [40, 41] was adapted to create this graphic