Daratumumab for the treatment of refractory ANCA-associated vasculitis

Abstract

Objective Treatment-refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a life-threatening condition without evidence-based treatment options. One emerging treatment option for several antibody-mediated autoimmune diseases is the anti-CD38 antibody daratumumab, which depletes autoantibody-secreting plasma cells.Methods We treated two patients with severe life-threatening AAV with renal and pulmonary manifestation despite induction therapy with rituximab and cyclophosphamide with four to eight doses of 1800 mg daratumumab. We followed clinical and immunological responses.Results The first patient with myeloperoxidase-ANCA-positive microscopic polyangiitis had resolution of pneumonitis and pleuritis and stabilisation of kidney function after daratumumab. The second patient with proteinase 3-ANCA-positive granulomatosis with polyangiitis, diffuse alveolar haemorrhage necessitating extracorporeal membrane oxygenation (ECMO) and acute kidney failure, requiring kidney replacement therapy, was weaned off ECMO, mechanical ventilation and dialysis and discharged home after daratumumab. Clinical improvement was paralleled by a strong reduction in serum ANCA levels as well as total IgG, indicating depletion of plasma cells. Apart from the depletion of CD38⁺ natural killer cells, blood leucocyte levels were not notably influenced by daratumumab. Only mild adverse events, such as hypogammaglobulinaemia and an upper respiratory tract infection occurred.Conclusion Daratumumab was safe and effective in inducing remission in two patients with severe treatment-refractory AAV, warranting prospective clinical trials to establish safety and efficacy.

Keywords: Autoimmune Diseases; Systemic vasculitis; Treatment.

Figure 1

Improvement of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) disease activity after daratumumab treatment. (A) Serum creatinine levels before and after daratumumab treatment. Previous induction therapies with cyclophosphamide (CYC), rituximab (RTX) and plasma exchange (PEX) did not lead to clinical remission or stabilisation of kidney function. Arrows indicate daratumumab doses, the dotted line indicates the upper normal limit for serum creatinine. Patient 2 underwent renal replacement therapy with continuous veno-venous haemodialysis (CVVHD) and intermittent haemodialysis (iHD). (B) CT of lung sections showing pleural effusion and alveolitis (patient 1) and AAV-induced acute respiratory distress syndrome and ventilator-associated soft tissue emphysema (patient 2). Only some fibrotic changes remain after daratumumab treatment. (C) Birmingham Vasculitis Activity Score (BVAS) shows clinical remission after daratumumab treatment. (D) C reactive protein (CRP) levels in both patients decline to normal levels after daratumumab treatment, the dotted line indicates the upper normal limit.

Figure 2

CD20-negative antibody-secreting cells are present in the kidney after rituximab treatment. Tissue sections of a kidney biopsy from patient 1 24 days before the initiation of daratumumab show ongoing crescentic glomerulonephritis (PAS, periodic acid–Schiff staining (×10)). No CD20-positive cells were detected in the kidney (10×, 20×), consistent with previous rituximab treatment. However, antibody-secreting cells, indicated by their expression of the kappa or lambda immunoglobulin light chains and CD138 (×20), are still found in the kidney.

Figure 3

Immunological effects of daratumumab treatment. (A) Antibody levels of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and proteinase-3 (PR3)-ANCA after daratumumab treatment. Arrows indicate daratumumab doses, the dotted line indicates the upper normal limit for ANCA. (B) Total serum IgG levels decline under daratumumab treatment. The dotted line indicates the lower limit of normal IgG levels, red x indicates intravenous IgG (IVIG) supplementation. (C) Relative levels of major leucocyte subsets in the peripheral blood remain stable under daratumumab treatment of patient 1. (D) Mean signal intensity of surface CD38 expression of major leucocyte subsets in the peripheral blood of patient 1 as measured with a polyclonal antibody that binds independent of daratumumab presence. NK, natural killer.