Department of Medicine, University College London, Centre for Rheumatology, Arthur Stanley House, 4050 Tottenham Street, London W1T 4NJ, UK and 1 Immunomedics, Inc., 300 American Road, Morris Plains, New Jersey, USA
Correspondence to: D. A. Isenberg, Department of Medicine, University College London, Centre for Rheumatology, Arthur Stanley House, 4050 Tottenham Street, London W1T 4NJ, UK. E-mail: d.isenberg{at}ucl.ac.uk
SIR, We present, to the best of our knowledge, the first case of a patient with severe resistant systemic lupus erythematosus (SLE) including the development of human antichimeric antibodies (HACA) after rituximab, who responded both clinically and serologically to an investigational humanized anti-CD20 monoclonal antibody (hA20) provided on a compassionate use basis by Immunomedics, Inc. (Morris Plains, NJ, USA).
A 20-yr-old Afro-Caribbean female was diagnosed with SLE in October 1997. She first presented with a vasculitic rash, polyarthritis, serositis, mild glomerulonephritis (WHO grade 2) and a haemolytic anaemia (Coombs test positive). She developed severe pneumococcal septicaemia and adult respiratory distress syndrome requiring intensive care (ICU) admission.
Her SLE was initially managed with i.v. methylprednisolone (MP) (3 g in total), oral prednisolone (PDN) (60 mg/day tapering to 7.5 mg/day) and hydroxychloroquine (HCQ) (200 mg/day). Over the ensuing 2 yr, her immunosuppression was changed initially to azathioprine (AZA) (100 mg/day) and then mycophenolate mofetil (MMF) (2 g/day) followed by i.v. CYC (6 monthly 1.2 g pulses) due to persistent disease activity. During this period she also required intermittent pulses of i.v. MP on five separate occasions (3 g in total on each occasion) for flares of her SLE.
In December 1999, she developed proteinuria (5.2 g/24 h) for which she was retreated with i.v. CYC (6 monthly 1.2 g pulses) and thereafter maintained on oral AZA (175 mg/day). Her disease continued to be active and a renal biopsy was obtained in October 2000, which showed a WHO grade 4 lupus nephritis, prompting the use of further i.v. CYC (single 1.2 g dose).
In March 2001, her disease remained persistently active and unresponsive to conventional immunosuppressive therapy. She was enrolled after informed consent into a phase 1 trial of B-cell depletion [1, 2]. She was treated with two doses of rituximab (Mabthera®, Roche, Herts, UK) (1 g on each occasion) 2 weeks apart in combination with i.v. MP and i.v. CYC (750 mg). She depleted her B cells [CD19 = 0% (normal range 520%)] and her disease improved clinically and serologically (Table 1), but she relapsed a year later requiring a further two doses of rituximab (1 g on each occasion) with i.v. MP. She made no clinical response to the latter treatment and did not deplete her B cells (CD19 = 5%) as she developed a HACA response (43,500 ng/ml, normal range <5 ng/ml), measured by a rituximab HACA ELISA bridging assay. Consequently, she was pulsed with i.v. MP (3 g in total) and i.v. CYC (750 mg), and maintained on oral AZA (100 mg/day).
|
Rituximab could not be used as she had developed an HACA response. However, on a compassionate use basis, we were able to obtain humanized anti-CD20 monoclonal antibody (hA20), which was being used in a phase 1 trial as a humanized anti-CD20 monoclonal antibody for patients with non-Hodgkin's lymphoma [3]. Having obtained full consent, our patient was treated initially with a single dose of hA20 (375 mg/m2) in combination with i.v. MP. Within a week a dramatic response in her clinical symptoms was noted (Table 1) and her haemoglobin count had increased to 8.8 g/dl; however, her platelet count remained low at 8 x 109/l. Our patient's course was complicated with thoracic shingles, which was treated with i.v. aciclovir. Following the resolution of her shingles, a second dose of hA20 (375 mg/m2) was administered with i.v. MP and i.v. CYC (500 mg). Nine days later her haemoglobin improved further to 11.5 g/dl and her platelet count a little to 9 x 109/l. Remarkably 2 weeks later her haemoglobin was 12.4 g/dl and her platelet count 177 x 109/l. She received a third dose of the hA20 (375 mg/m2) a week later, but unfortunately towards the end of this infusion developed a mild hypersensitivity reaction, namely mild facial swelling and arthralgia. No further therapy was administered. Her B cells had depleted (CD19 = 1.4%).
Three months later, our patient continues to improve; her haemoglobin is 11.8 g/dl and platelet count 275 x 109/l. This is mirrored by an improvement in some of her SLE markers, namely double-stranded DNA of 300 IU/ml and C3 of 0.44 g/l. However, on this occasion her albumin and urine protein/creatinine ratio has not changed. We surmise that her renal disease has now progressed to the stage of damage rather than just activity.
This case report not only demonstrates that B-cell depletion is effective in the management of patients with severe resistant SLE, but that in the presence of host antibody against the chimeric anti-CD20 monoclonal antibody rituximab, the humanized anti-CD20 antibody hA20 appeared to be effective. This response may be due to the fact that the antibody hA20 has fewer murine amino acid sequences in the variable region. The variable clinical response to the different anti-CD20 antibodies may thus be analogous to the different responses to TNF-alpha blocking agents used in patients with rheumatoid arthritis. However, it is also plausible the response is due to an unknown mechanism that is independent of the chimeric variable region.
The authors would like to thank Professor Andrew Lister, Professor of medical oncology at St Bartholomew's Hospital, London for providing us with the humanized monoclonal antibody.
W. A. Wegener is an employee of Immunomedics Inc. The other authors have declared no conflicts of interest.
References