• Sjogren's Syndrome
• Autoimmune Diseases
• Biological Therapy

Sjögren disease (SjD) is complicated by systemic manifestations in 30%–40% of the patients. B cells targeted therapies including rituximab (RTX) can be proposed to treat some of these systemic manifestations but is not always successful. Since plasmablasts and plasma cells are recognised as essential drivers of disease activity in SjD, present in the salivary glands and part of the cell signature of the disease,1 they could be a promising therapeutic target. Daratumumab is a monoclonal antibody targeting CD38, leading to plasma cell depletion and approved in multiple myeloma. Here, we report the first two cases of patients with severe complications of SjD, refractory to RTX and successfully treated with daratumumab.

Patient 1, a 18-year-old woman, had an SjD diagnosed when she was 13 years old. She presented with positive anti-SSA and anti-SSB antibodies, positive rheumatoid factor (RF), hypergammaglobulinaemia at 24 g/L and an OMERACT score at 2 at ultrasound examination of the salivary glands. She had almost no symptom due to SjD, except very mild dryness, but she presented with hypertriglyceridaemia at 52 g/L. The search for antiglycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) was positive at high titre (6121 U/mL, threshold of positivity=57 U/mL) leading to the diagnosis of autoimmune hyperchylomicronemia complicating SjD.2 Hyperchylomicronaemia is characterised by marked accumulation of chylomicrons in the plasma, and elevated triglyceride (TG) levels exceeding 10 g/L with high risk of acute pancreatitis. A treatment with RTX 1 g day 1 and 15 had no effect on the TG levels, which remained unchanged at 6 months. Thus, it has been decided to treat the patient with daratumumab 1800 mg subcutaneously once a week for 4 weeks. Daratumumab produced no adverse effects and was not associated with injection-site reactions. Three months after daratumumab, TG level normalised at 1.24 g/L and anti-GPIHBP1 decreased to 272 U/mL. Six months after daratumumab, TG level still normalised at 0.67 g/L and anti-GPIHBP1 decreased to 234 U/mL (figure 1A). Anti-nuclear antibodies (ANA) remained positive at high titre (>1/1280). Gamma globulins decreased at 9.2 g/L but stayed in a normal range of values. ESSDAI was at 2 before daratumumab (biological domain only) and decreased to 0 after since gamma globulins normalised. ESSPRI remained stable at 1. No adverse event and notably no infection occurred.

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Figure 1

Effect of daratumumab on the pathogenic autoantibodies in the two SjD patients. (A) Follow-up of anti- GPIHBP1 antibodies (Ab) titre and triglycerides (TG) levels. (B) Follow-up of RF titre. Red dotted line represents the TG normality threshold. Blue dotted line represents anti-GPIHBP1 threshold. Green arrows represent daratumumab infusion. Purple arrows represent RTX infusion. RF, rheumatoid factor; RTX, rituximab; SjD, Sjögren disease.

Patient 2, a 68-year-old woman, presented with SjD with positive anti-SSA and anti-SSB antibodies and type II cryoglobulinaemia that was complicated by flare of vascular purpura, axonal symmetric polyneuropathy and glomerulonephritis. The patient first received RTX in monotherapy, then RTX and cyclophosphamide (600 mg/m²) 4 months later, then, because of recurrent relapses, RTX followed by belimumab with RTX maintenance every 6 months. Vasculitis relapsed with flare of purpura and reappearance of proteinuria with a protein/creatinine ratio at 650 mg/g and of cryoglobulin despite these different lines of treatment. ESSDAI score was at 20. There was no immunisation against RTX, thus we did not propose using another anti-CD20 antibody. Thus, we decided to treat the patient with daratumumab with the same protocol as for patient 1. Four and 6 months after daratumumab, there was no flare of purpura, proteinuria was negative, cryoglobulinaemia was negative and titre of RF dramatically decreased from 339 u/mL before daratumumab to 48 U/mL (figure 1B). ANA decreased from 1/320 to 1/160. ESSDAI decreased from 20 to 2. ESSPRI remained stable under treatment at 3.6.

There are few case reports of treatment with daratumumab for refractory autoimmune diseases. Ostendorf et al reported efficacy of daratumumab in two severe cases of lupus.3 More recently, it has been shown that daratumumab could be an efficient strategy in multirefractory autoimmune cytopenia,4 MDA5 positive dermatomyositis5 and refractory ANCA-associated vasculitis.6

These two observations suggest that targeting plasmablasts and plasma cells could be an effective strategy in severe and refractory SjD especially when systemic manifestations are due to pathogenic autoantibodies. Daratumumab was safe in these two patients without any infusion reaction and without infection events. Gamma globulins level decreased in patient 1 but remained in the normal range and was relatively stable in patient 2 at a low level. Decreased of IgG level could be an issue if daratumumab needed to be repeated mainly in patients with normal or only mild hypergammaglobulinaemia. Interestingly, the two patients remained in remission 6 months after one cycle. In lupus, it has been very recently reported that two patients treated with daratumumab remained in remission after only one cycle with a long-term follow-up 3 years.7 Daratumumab could deplete autoantibodies producing cells in tissue, which is not the case of RTX.8 Beyond direct effect on plasma cells/plasmablasts, daratumumab may have an immunomodulatory action through targets other than plasma cells including NK or effector T cells.3 6 Further studies are mandatory to study the impact of daratumumab on autoreactive B cell repertoire and to assess the possible long-term efficacy of the drug.