NDT Advance Access originally published online on June 27, 2008
Nephrology Dialysis Transplantation 2008 23(9):3030-3032; doi:10.1093/ndt/gfn318
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Relapsed Wegener's granulomatosis after rituximab therapy—B cells are present in new pathological lesions despite persistent ‘depletion’ of peripheral blood
1 Division of Infection and Immunity, Institute of Biomedical Research, Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT 2 Department of Pathology, University Hospital Birmingham NHS Trust, Queen Elizabeth Hospital, Birmingham, B15 2TH, UK
Correspondence and offprint requests to: Caroline O. S. Savage, Division of Infection and Immunity, Institute of Biomedical Research, Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. Tel: +44 (0)121 414 6841; Fax: +44 (0)121 414 3599; E-mail: c.o.s.savage{at}bham.ac.uk
* Joint first authors.
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Abstract |
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Wegener's granulomatosis (WG) is a chronic, relapsing, systemic autoimmune disease. Rituximab, a monoclonal antibody against human CD20, has shown promise as a novel treatment for WG. The monitoring of therapeutic B-cell ‘depletion’ by peripheral blood flow cytometry has been proposed to help monitor rituximab therapy.
We report the case of a patient with known WG and granulomatous disease, successfully treated with rituximab, who relapsed whilst peripheral blood monitoring apparently indicated persistent B-cell depletion. Further investigations demonstrated CD20+ B cells in tissue at sites of active disease. The implications for disease pathogenesis and clinical monitoring of disease are discussed.
Keywords: B-cell depletion; monitoring; rituximab; vasculitis
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Background |
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Wegener's granulomatosis (WG) is a chronic, relapsing, systemic autoimmune disease, characterized by granulomatous inflammation, necrotising vasculitis and pauci-immune focal glomerulonephritis. Standard remission-induction therapy, with high-dose corticosteroids and cyclophosphamide, has significantly reduced morbidity and mortality. However, cyclophosphamide therapy is associated with substantial risks of acute and chronic toxicity including infections, infertility and malignancies. Consequently, attention has focused on identifying alternative treatment regimes.
Rituximab is a chimeric monoclonal antibody against human CD20. It results in profound depletion of B cells from the peripheral blood [1]. Case series have suggested that rituximab is an effective treatment for WG [2–4]. Formal European and American randomized controlled trials are currently in progress.
Whilst the targeting of B cells in WG may appear a logical conclusion from studies demonstrating the importance of anti-neutrophil cytoplasm antibodies (ANCA) in disease pathogenesis [5], direct depletion of antibody-producing plasma cells, which are likely to be CD20 negative, is unlikely.
We report the case of a patient with known WG and granulomatous disease, successfully treated with rituximab, who relapsed whilst peripheral blood monitoring apparently indicated persistent B-cell depletion. Further investigations demonstrated CD20+ B cells in tissue at sites of active disease. The implications for disease pathogenesis and clinical monitoring of disease are discussed.
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Case report |
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A 65-year-old Caucasian farmer had been diagnosed with WG in 2003 after developing dyspnoea, haemoptysis and a pustular rash affecting the dorsum of his hands. He did not smoke tobacco or drink alcohol. There was no significant previous personal or family medical history. Investigations revealed extensive pulmonary pathology with bilateral lung nodules and cavitations. There was no evidence of renal disease. Serological tests detected cANCA by immunofluoresence and anti-proteinase 3 Abs by antigen-specific ELISA (PR3-ANCA; 11.6 EU/ml; normal range <3). Skin biopsy demonstrated a leucocytoclastic vasculitis. Remission was induced with high-dose corticosteroids, pulsed intravenous cyclophosphamide and infliximab.
In 2005, he developed further haemoptysis and epistaxis. Radiological investigations identified multiple pulmonary nodules and new cavitating lung lesions. Bronchoalveolar lavage grew Candidia albicans and Aspergillus fumigatus. Maxillary sinus biopsy demonstrated ongoing necrotising vasculitis. Serum PR3-ANCA was undetectable (<3 EU/ml), but it was felt that the patient had active WG and an opportunistic aspergillus infection. The patient received 500 mg of intravenous methylprednisolone, 1.1 g of intravenous cyclophosphamide and two 1 g doses of rituximab 2 weeks apart. He also received 4 weeks of intravenous voriconazole and subsequent oral antifungal therapy. B cells (CD19+ cells) became undetectable in peripheral blood. He developed hypogammaglobulinaemia and received 30 mg of Vigam immunoglobulins. Clinical remission was achieved, with partial resolution of his cavitating lung lesions.
Thirteen months later the patient's exercise tolerance rapidly diminished to 50 yards, and haemoptysis reoccurred. He also complained of progressive hearing loss affecting his left ear and loss of sensation in his hands and feet. His immunosuppressive medication was prednisolone 15 mg and MMF 2 g daily. Salient clinical findings included a widespread expiratory wheeze and a peripheral sensory neuropathy in a glove and stocking distribution. Urinalysis was unremarkable. Blood tests showed a modest eosinophilia (0.7 x 109/L) and elevated CRP (21 mg/L). ANCA was positive (1:25) with a cytoplasmic pattern. Serum PR3-ANCA was 8 EU/ml.
Thoracic radiology demonstrated a new cavitating mass in the left upper lobe (Figure 1). Bronchial washings showed no evidence of infection. Lung biopsy of this new lesion demonstrated fibrotic lung tissue with active necrotising granulomatous inflammation consistent with active WG (Figure 2a). Immunohistochemistry demonstrated staining for CD20 (B cells) within the lesion (Figure 2b). Peripheral blood B cells were still undetectable by flow cytometry.
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He was diagnosed with a second relapse of WG. His prednisolone was increased to 40 mg, he received two intravenous doses of 1.1 g of cyclophosphamide and two 1 g doses of rituximab, and again went into clinical remission.
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Discussion |
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This case reports a man with recurrent granulomatous pathology due to WG, twice treated successfully for relapse with rituximab-based regimens. This contrasts with previous reports of granulomatous WG being refractory to rituximab-based therapy [6,7]. Unlike most reported disease relapses after rituximab [2,4], in the case reported here disease reoccurred before peripheral B cell recovery. Furthermore, despite the absence of peripheral B cells, CD20+ cells were demonstrable within the pathological lesion.
B cells have previously been reported in disease-related granulomata [8], and B-cell depletion appears therapeutic—both indicative of a role for B cells in disease, but the nature of the effective therapeutic mechanism of rituximab in AAV is not known.
The efficacy of peripheral B-cell depletion by rituximab is clear. The evidence for such efficacy within tissues is less so [9]. It may be that local resistance to B-cell depletion reflects limitations of effector mechanisms [9], or the local presence of B cell survival factors; indeed increased levels of BAFF due to systemic B-cell depletion may even enhance B cell survival at ‘sanctuary sites’ [10]. Localized resistance to B-cell depletion by rituximab may also account for the treatment failures previously reported in granulomatous WG [6,7].
We cannot know if B cells persisted in our patient's lung throughout the first rituximab-induced remission or whether newly emergent B cells survived recirculation once rituximab levels had fallen significantly. However, the co-localization of B cells with new autoimmune pathology, in a patient still predominantly B-cell deplete, provides further circumstantial evidence of the direct role of B cells in the local pathogenesis of AAV. This case also serves to highlight that vigilance for relapses in AAV must be maintained even during the period of ‘successful’ therapeutic B-cell depletion following administration of rituximab.
Conflict of interest statement. None to declare. The results presented in this paper have not been published previously in whole or part, except in abstract form.
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References |
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- Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood (1994) 83:435–445.
[Abstract/Free Full Text] - Keogh KA, Wylam ME, Stone JH, et al. Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum (2005) 52:262–268.[CrossRef][Web of Science][Medline]
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[Abstract/Free Full Text] - Smith KG, Jones RB, Burns SM, et al. Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: remission, relapse, and re-treatment. Arthritis Rheum (2006) 54:2970–2782.[CrossRef][Web of Science][Medline]
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[Abstract/Free Full Text] - Gong Q, Ou Q, Ye S, et al. Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J Immun (2005) 174:817–826.
[Abstract/Free Full Text] - Cambridge G, Stohl W, Leandro MJ, et al. Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: relationships with B-cell depletion, circulating antibodies, and clinical relapse. Arthritis Rheum (2006) 54:723–732.[CrossRef][Web of Science][Medline]
Accepted in revised form: 16. 5.08
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