Ofatumumab: a novel treatment for severe systemic lupus erythematosus

S ir , Randomized controlled trials have not demonstrated a clear benefit of rituximab in refractory SLE, likely due to study design problems [ 1 , 2 ]. However, numerous other studies have demonstrated efficacy, and B cell depletion with rituximab is now regarded as established treatment for SLE [ 3 ]. Unfortunately, infusion reactions may occur, hence alternative B cell-depleting agents need to be defined for patients with a previous clear response in whom further treatment is precluded due to a severe adverse reaction. Here we describe such a patient, the first report to our knowledge of a patient with SLE successfully treated with the anti-CD20 mAb ofatumumab. Alternative anti-CD20 mAbs to rituximab include ocrelizumab and ofatumumab. While rituximab is chimeric and ocrelizumab is a humanized mAb, ofatumumab is a human IgG1κ mAb that binds CD20 on B cells at a unique epitope. All are type I anti-CD20 mAbs, capable of B cell lysis through both complement-dependent and antibody-dependent cell-mediated cytotoxicity, but differences in structure and binding epitopes lead to differences in immunogenicity and intensity of B cell depletion. Ocrelizumab, while unlicensed, has been used to treat SLE, but has not been found to be significantly more efficacious than placebo, with an increased risk of infection [ 4 ]. Ofatumumab is approved for the treatment of chronic lymphocytic leukaemia and has shown efficacy in treating in RA [ 5 ]. There are no reports of its use in SLE. Our patient is a 22-year-old woman of Nigerian descent who developed SLE at 11 years of age, when she presented with fever, arthritis, pericarditis and positive ANA, anti-dsDNA and anti-Sm antibodies with hypocomplementaemia. After AZA, mycophenolate and high-dose steroids failed to control her illness, she was treated with rituximab on two occasions 6 months apart in 2006–7 with good response, although she suffered anaphylaxis requiring adrenaline resuscitation on the second cycle. She remained well until 2011, when she developed a severe flare with rash, arthritis, pericarditis and proteinuria. Despite treatment with pulsed i.v. and high-dose oral steroids, CYC (cumulative dose 6 g), MTX, ciclosporin, belimumab for 5 months and IVIG, her disease remained persistently active over the next 2 years with recurrent fever, weight loss, rash, arthritis, an episode of pancreatitis, two episodes of macrophage activation syndrome (associated with infection), hypocomplementaemia and persistently high anti-dsDNA titres. In December 2013, the decision was made to treat her with ofatumumab off-licence, given her previous good response to rituximab. Ofatumumab was administered intravenously using the following regimen: 300 mg on day 0, 700 mg on day 7 and 700 mg on day 21. Each infusion was preceded by i.v. methylprednisolone 250 mg; no infusion reaction was noted. Following ofatumumab, B cells were fully depleted and our patient responded extremely well: her pre-treatment SLEDAI score was 15 (December 2013), while 5 months after ofatumumab her SLEDAI score had fallen to 2 (May 2014). Her anti-dsDNA titre fell by >90% and C3 normalized ( Fig. 1 ). Her oral prednisolone decreased from 30 mg/day pre-ofatumumab to 10 mg/day 5 months post-infusion. Six months later she has no symptoms of active SLE, has gained weight and has re-entered education. Her B cells remain depleted and there have been no infections or changes in serum immunoglobulins. Variation of anti-dsDNA titres and complement C3 levels with time Time 0 represents the first dose of ofatumumab. Normal ranges: anti-dsDNA <50 IU/ml; C3 >0.9 g/l. Although our patient was treated with both methylprednisolone and ofatumumab, previous i.v. steroid pulses did not achieve lasting disease control, so it is unlikely that these were responsible for her sustained improvement on this occasion. This report suggests that ofatumumab may be efficacious for severe SLE in patients who have responded to rituximab but in whom further treatment is precluded due to anaphylaxis. Randomized controlled trials of ofatumumab to treat SLE may be warranted. Our patient provided written informed consent to have her case published, in accordance with the Declaration of Helsinki. Ofatumumab may be an effective alternative B cell-depleting agent in patients with SLE intolerant to rituximab. Disclosure statement : The authors have declared no conflicts of interest.