#760 Monogenic lupus with ANCA associated vasculitis-phenotype and ANCA positivity due to DNASE1L3 mutations: case report and review of the literature

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Abstract Background and Aims Monogenic systemic lupus erythematosus (SLE) accounts for 7-10% of cases of early-onset SLE. DNASE1L3 is an extracellular nuclease that digests chromatin released from apoptotic cells and its deficiency, enhance autoantibody production and type I interferon responses and cause different autosomal recessive phenotypes including SLE and hypocomplementemic urticarial vasculitis syndrome (HUVS) [1]. In some cases patients can have a mixed SLE-AAV phenotype. Kidney involvement in patients with DNASE1L3 mutations is poorly characterised. Method We present the case report of a 7-years-old boy with monogenic SLE due to DNASE1L3 mutations who developed severe glomerulonephritis leading to kidney failure. Results The patient had a history of urticaria and arthralgia and presented with fever, haemolytic anaemia, lymphadenopathy, hepato-splenomegaly, erythematous- macular and necrotic skin lesions, and interstitial lung disease. He also had acute kidney injury (serum creatinine 5.4 mg/dL), nephrotic- range proteinuria (3.9 g/24 h) and microhaematuria. Immunological tests revealed low C3 and C4, positive anti-nuclear antibody (ANA) and myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCA), with negativity of anti-extractable nuclear antigen antibodies (anti-ENA) and anti-double stranded DNA (anti-dsDNA). Kidney biopsy showed pauci-immune (mesangial C3+ and IgG+) necrotising crescentic glomerulonephritis. The patient proved refractory to standard immunosuppression with cyclophosphamide and steroids. Two years later, due to renal function decline, a new kidney biopsy was performed and showed diffuse necrotising glomerulonephritis with endo- and extra-capillary proliferation; intense mesangial and subendothelial full-house deposits were evident on immunofluorescence. The patient did not respond to other lines of immunosuppression (mycophenolate mofetil, tacrolimus, azathioprine, rituximab), including the JAK inhibitor ruxolitinib. Kidney failure progressed to end stage at the age of 15 years, when the patient began haemodialysis. The kidney presentation, immunological profile and the first kidney biopsy led to diagnosis of AAV. However, the diagnosis was questioned due to the refractory course, the systemic clinical presentation and the second kidney histology (consistent with lupus nephritis). High interferon signature was detected and in the suspicion of a monogenic lupus nephritis Whole Exome Sequencing was performed and revealed homozygous DNASE1L3 variants (c.290_291delCA p.T97Ifs*2); thus, a final diagnosis of DNASE1L3 monogenic SLE was made. DNASE1L3 serum levels were normal but the DNAse enzymatic activity was low. Conclusion Renal involvement is one of the most frequent manifestations of DNASE1L3-related lupus; in the literature 32 cases of DNASE1L3-associated lupus nephritis are described. ANCA are positive in about 55% of these cases and are associated with a mixed lupus-AAV phenotype. All cases are characterized by resistance to common immunosuppressors and poor renal prognosis [2]. DNASE1L3 regulates neutrophil extracellular trap (NET) clearance and when this function is reduced the permanence of NETs induces endothelial damage and autoantibody formation. This pathogenic pathway is shared both by SLE and by AAV. There is no association between specific mutations and antibody positivity or clinical manifestations.