MUSCAT, Oman — A multicentre study led by researchers at Sultan Qaboos University has found that patients with a rare inherited form of lupus may continue to accumulate organ damage even when conventional measures indicate that their disease activity has declined. According to the research team, this represents the largest longitudinal cohort of DNASE1L3 deficiency reported to date.
The study examined DNASE1L3 deficiency, a rare genetic disorder that can cause systemic lupus erythematosus and hypocomplementaemic urticarial vasculitis syndrome at an early age.
The DNASE1L3 gene produces an enzyme that helps clear DNA released from dying cells. When this enzyme is deficient, genetic material may remain in the circulation and contribute to the formation of immune complexes that trigger chronic inflammation and damage the body’s tissues.
Researchers followed 57 genetically confirmed patients from 22 families receiving care at pediatric rheumatology centers in Oman and the United Arab Emirates. The cohort showed a striking geographic clustering, with 79% of patients originating from Al Sharqiyah Governorate in Oman and a second cluster identified in Al Ain, UAE. Most Omani patients shared the same homozygous DNASE1L3 variant, while the UAE cluster carried a different recurrent variant, highlighting the strong familial and regional pattern of this rare inherited condition
The group included 32 males and 25 females, with a median age at diagnosis of just five years, which is an unusually early age for SLE. The near-equal sex distribution was also striking, contrasting with the strong female predominance typically seen in more common forms of lupus.
The researchers compared disease activity and long-term health outcomes during pediatric care and subsequent follow-up as adults. They assessed organ damage, disease flares, hospital admissions, serious infections and mortality.
Disease activity scores declined significantly during follow-up, falling from a median score of nine to four. However, this apparent improvement was not accompanied by a clear improvement in long-term outcomes.
Several indicators of organ involvement increased numerically over time. The proportion of patients with lupus nephritis, a serious form of kidney inflammation, rose from 34% to 46%, while pulmonary involvement increased from 3.7% to 11%. The recorded mortality rate also rose from 8.8% during paediatric care to 13.5% at later follow-up.
The individual increases in these outcomes were not statistically significant, and the researchers cautioned that the small number of patients due to disease rarity, limits the statistical power of the study. Nevertheless, the overall pattern suggests that lower clinical disease activity may not fully reflect the biological processes continuing beneath the surface.
The researchers propose that this mismatch may arise because standard lupus activity scores primarily capture visible symptoms and active inflammation. They may not fully detect the persistent immune-complex activity caused by the underlying genetic deficiency.
Unlike more common forms of lupus, DNASE1L3 deficiency causes a continuous, genetically determined failure to clear cell-free DNA. This could allow immune complexes to continue accumulating in organs such as the kidneys, lungs and blood vessels even when patients experience fewer obvious disease flares.
The findings highlight the importance of maintaining long-term clinical and laboratory surveillance rather than relying solely on improvements in symptoms or standard disease activity scores. The authors recommend continued monitoring of kidney, lung and vascular health, alongside the development of more sensitive biomarkers that can detect ongoing subclinical inflammation and organ injury.
They also underline the need for carefully coordinated transition from paediatric to adult healthcare services. Patients with childhood-onset inherited autoimmune conditions may remain at risk of progressive complications as they enter adulthood, even when their condition appears clinically stable.
Because the study was retrospective, the researchers could not establish that reduced disease activity directly caused or failed to prevent particular outcomes. Follow-up duration also varied among patients, and the study did not include a matched comparison group with non-inherited childhood-onset lupus.
Further prospective studies are therefore needed to confirm the findings and determine whether different monitoring or treatment strategies could reduce long-term organ damage in patients with DNASE1L3 deficiency.
The study was led by Professor Reem Abdwani of the Department of Child Health, College of Medicine and Health Sciences, Sultan Qaboos University. The researchers represented academic and clinical institutions in Oman and the United Arab Emirates, including Sultan Qaboos University, University Medical City, the Royal Hospital, the Oman Medical Specialty Board and United Arab Emirates University.
The study, “Discordance between disease activity and long-term outcomes in DNASE1L3 deficiency: a multicentre longitudinal cohort study,” was published in Lupus Science & Medicine .
Lupus Science & Medicine
Observational study
People
Discordance between disease activity and long-term outcomes in DNASE1L3 deficiency: a multicentre longitudinal cohort study
9-Sep-2026