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Prolonged B-cell depletion following rituximab therapy in systemic lupus erythematosus: a report of two cases
  1. T Y-T Lu1,
  2. T Jonsdottir2,
  3. R F van Vollenhoven2,
  4. D A Isenberg1
  1. 1
    Centre for Rheumatology Research, University College of London, London, UK
  2. 2
    Department of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
  1. Professor D A Isenberg, Centre for Rheumatology, Room 331, 3rd floor, Windeyer Building, University College London, 46 Cleveland Street, London W1T 4JF, UK; d.isenberg{at}ucl.ac.uk

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Rituximab, a chimeric monoclonal antibody against the B-lymphocyte marker CD 20, has been previously used in open studies in the treatment of patients with systemic lupus erythematosus (SLE), with some success.1 2 Its therapeutic effect is attributed to the profound depletion of native and autoimmune B cells. The initial period of depletion has been reported to last for about 6 months, followed by a repopulation of peripheral B cells 9–12 months after treatment in most cases. We report two cases of prolonged B-cell depletion of 7 and 5 years’ duration, respectively, after a single course of rituximab treatment in two patients with SLE.

A 42-year-old woman with anti-SSA and anti-RNP positive SLE was initially referred to the Centre for Rheumatology Research, University College of London in 1995 for management of persistent fatigue, polyarthritis, Raynaud’s phenomenon and pleurisy. Despite treatment with various immunosuppressive agents, her disease remained clinically and serologically active (table 1). In September 2000 the patient underwent treatment with a single course of rituximab (500 mg) in conjunction with cyclophosphamide (750 mg) on two occasions 2 weeks apart. In the months after treatment the patient experienced a significant improvement in her clinical symptoms. The disease remained suppressed on 400 mg hydroxychloroquine and 5 mg prednisolone from 2002 onwards. There were no major septic complications during the years of follow-up, although in early 2005 the patient developed recurrent sinusitis, requiring treatment with oral antibiotics. She remained anti-SSA and anti-RNP positive after B-cell depletion therapy, and her IgM and IgG levels were 0.16 g/l and 10.4 g/l, respectively. This patient continued to be B-cell depleted 7.5 years after the initial treatment with rituximab. In February 2008, the absolute CD19 count was <0.001×109/l.

Table 1 Clinical characteristics of patients A and B, respectively

A 37-year-old woman with anti-SSA and anti-SSB positive SLE was referred to the Department of Rheumatology, Karolinska University Hospital, Stockholm in 1995 with fever, myalgia, arthritis, serositis and haematological manifestations, including leucopenia, anaemia and thrombocytopenia. A diagnosis of antiphospholipid syndrome was also made on the basis of thrombocytopenia, positivity for anticardiolipin antibodies and episodes of thrombosis and lung emboli. During the following years her disease remained clinically active mainly with haematological manifestations and a difficult to treat Quincke’s oedema, despite treatment with various immunosuppressive agents (table 1). In February 2003 she was treated with rituximab 375 mg/m2 once a week for 4 weeks; the first and fourth infusions were combined with intravenous cyclophosphamide 500 mg. During the following months the patient recovered completely from her attacks, with Quincke’s oedema and the haematological aberration normalised. Her disease has since remained quiescent with only low-dose prednisolone (5–10 mg). She remained anti-SSA, anti-SSB and anticardiolipin antibody (IgM and IgG) positive after B-cell depletion therapy, and her IgM and IgG levels were 3.1 g/l and 10.2 g/l, respectively. This patient continued to be B-cell depleted 5 years after the treatment with rituximab. In February 2008, the absolute CD19 count was <0.01×109/l.

Treatment with rituximab induces a rapid depletion of CD20-expressing B cells in the peripheral blood with levels remaining low or undetectable for 2–6 months, followed by return to pretreatment levels generally occurring within 12 months.3 Although B-cell depletion beyond 12 months of initial treatment does occur infrequently, our patients are particularly unusual with respect to the extent and duration of B-cell depletion after a single course of rituximab treatment. This has not been previously reported in rheumatological publications. There are reports of patients with follicular lymphoma on rituximab maintenance therapy, receiving regular doses of rituximab for periods of up to 2 years after the initial induction treatment. These patients are completely depleted of B cells throughout this time, although B cells eventually recover when maintenance treatment is stopped.4

The observation of prolonged B-cell depletion after a single course of rituximab in our patients cannot be adequately explained by the current understanding of B-cell development or the pharmacodynamic effects of rituximab on CD20-expressing B cells. It is notable that a bone marrow trephine biopsy performed on patient A in July 2004 showed a normocellular marrow with trilineage maturing haematopoiesis and normal percentage of plasma cells, although B cells were not identified by immunostaining with anti-CD20 or anti-Pax5. There is some evidence to suggest that in a subset of patients with SLE treated with rituximab with prolonged clinical responses, reconstitution of peripheral blood memory B cells is delayed for several years after B-cell depletion therapy.5 These two cases may represent an extreme example of this observation. Serum B-cell activation factor was measured serially in patient B and was found to be raised after B-cell depletion therapy with levels ranging from 3604 to 7717 pg/ml.

In our two centres combined, there are a total of 57 patients with SLE for whom more than 2 years of clinical data exist after B-cell depletion therapy. The cases described are the only two patients who have experienced such a prolonged B-cell lymphopenia after a single course of B-cell depletion therapy.

REFERENCES

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Footnotes

  • Competing interests: None.

  • Ethics approval: Ethics committee approval obtained.

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