Discordance between disease activity and long-term outcomes in DNASE1L3 deficiency: a multicentre longitudinal cohort study.

OBJECTIVES: DNASE1L3 deficiency is a rare monogenic cause of early-onset SLE and hypocomplementaemic urticarial vasculitis syndrome (HUVS). While early disease manifestations are increasingly recognised, longitudinal data extending into adulthood remain scarce. In this study, we described the long-term disease trajectory, damage accrual and mortality across the largest DNASE1L3 deficiency cohort reported to date. METHODS: We conducted a multicentre retrospective longitudinal cohort study of patients with genetically confirmed DNASE1L3 deficiency followed at paediatric rheumatology tertiary centres in Oman and the UAE. Primary outcomes included damage accrual, flare rates, hospitalisation frequency, serious infections and mortality. Longitudinal comparisons were made between the last paediatric assessment and most recent adult follow-up. RESULTS: 57 patients from 22 families were enrolled, most carrying the homozygous DNASE1L3 c.643delT loss of function variant. Median age at diagnosis was 5 (1.75-13) years and median disease duration was 9 (1-22) years. Initial phenotypes comprised of SLE in 36 patients (63%) and HUVS in 21 (37%). Despite a significant reduction in disease activity (SLE Disease Activity Index scores) over the follow-up period (9 vs 4; p<0.001), this was not accompanied by clear improvement in long-term outcomes. Mean Systemic Lupus Interntational Collaborating Clinics (SLICC)/American College of Rheumatology Damage Index increased numerically from 0.37±0.85 to 0.72±1.17; p=0.295. The proportion with lupus nephritis increased from 34% to 46% (p=0.07) and pulmonary involvement from 3.7% versus 11% at follow-up (p=0.289), osteoporosis increased from 23% to 41% (p=0.065) and mortality was numerically higher following transition, increasing from 8.8% to 13.5% (p=0.125). CONCLUSIONS: In the largest DNASE1L3 deficiency cohort, reduction in clinical disease activity does not prevent progressive organ damage. These findings suggest that apparent disease quiescence may mask ongoing subclinical injury, underscoring the need for sustained long-term surveillance and optimised transitional care strategies. However, the findings should be interpreted with caution in light of the small sample size in this ultra-rare disease.