Rheumatology Advance Access originally published online on November 24, 2006
Rheumatology 2007 46(2):366-367; doi:10.1093/rheumatology/kel387
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Lack of efficacy of Rituximab in a patient with essential mixed cryoglobulinaemia
Department of Rheumatology, Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath, BA1 1RL, 1Department of Rheumatology, Ysbyty Gwynedd, Bangor, Gwynedd, LL57 2PW and 2Department of Rheumatology, University Hospital of Wales, Heath Park, Cardiff, Wales, CF14 4XW
Correspondence to: Dr Helen Cohen, Department of Rheumatology, Royal National Hospital for Rheumatic Diseases, Bath, BA1 1RL. E-mail: Helen.cohen{at}rnhrd-tr.swest.nhs.uk
SIR, Whilst it is encouraging to read the increasing body of literature reporting positive results using Rituximab in hepatitis C-associated mixed cryoglobulinaemia (MC) such as the recent article by Quartuccio et al. [1], we feel that it is equally important to record treatment failures in this area where the evidence is not yet clear. We describe the case of a woman with essential mixed cryoglobulinaemic (EMC) vasculitis, who failed to respond to treatment with rituximab.
A 57-yr-old woman presented with a 19-yr history of arthralgia, and new symptoms of night sweats, rash and a sudden onset of pain, tingling and weakness in the left hand. Physical examination revealed a purpuric rash on the trunk and limbs, weakness of the intrinsic muscle weakness of the left hand and sensory loss in the ulnar nerve distribution. Nerve conduction studies confirmed a left ulnar neuropathy and background sensory neuropathy in the legs. Investigations showed rheumatoid factor (RF) 179 iU/ml, low complement especially C4 (7 mg/dl) (14–54 mg/dl) compared with C3 (62 mg/dl) (75–165 mg/dl) and cryoglobulins of 67 mg/dl. Bone marrow biopsy demonstrated no evidence of lymphoma, and a weakly CD20 positive, IgM staining 
clone. She was hepatitis B and hepatitis C virus (HCV) negative to both enzyme-linked immunoabsorbant assay (ELISA) and HCV–RNA detection by polymerase chain reaction testing, and was diagnosed with essential mixed cryoglobulinaemia (ECM), type II.
Initially she was treated with intravenous methyl prednisolone and cyclophosphamide 750 mg/m2. She responded well with improvement in her symptoms and a decrease in her cryoglobulins (Fig. 1). Subsequently, she deteriorated with recurrence of painful neuropathy affecting the hands and feet, purpuric rash, and developed severe cardiac failure, renal impairment (creatinine 180 µmol/l, creatinine clearance 34 ml/min) and anaemia together with rising cryoglobulins. Serial blood cultures were negative. Echocardiography excluded vegetations and confirmed severe left ventricular dysfunction with an ejection fraction of 10–15%. Plasma exchange was performed to which she responded clinically, and for the next 11 months she received three weekly exchanges and oral prednisolone. During this time, she proved intolerant to oral cyclophosphamide deveolping leucopenia and recurrent infections. She was readmitted with weakness, recurrence of her previous symptoms and rising cryoglobulins. At this point she was commenced on Rituximab therapy, and given four infusions of 375 mg/m2 at weekly intervals. After two infusions, there did appear to be a brief, slight improvement in the peripheral neuropathy and purpuric rash with a fall in cryoglobulin levels (Table. 1). Unfortunately this was not sustained. There was an acute rise in cryoglobulins and a disease flare. She continued to deteriorate with worsening renal and cardiac failure requiring maintenance ultrafiltration, and died 4 months later.
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MC has strong aetiological links with the HCV. Recent trials and some case reports demonstrate a beneficial role for rituximab in HCV related MC [2, 3].
However, there remains a small group of cryoglobulinaemic patients who do not have HCV infection and for whom the term ‘essential’ MC is appropriate. The published evidence for treatment of EMC with rituximab is restricted to case reports, which have shown positive results. Zaja et al. [2] treated four patients with type II MC with rituximab, one of whom was a 68-yr-old woman with EMC. This patient reported improvement in neuropathic and skin manifestations, and demonstrated a fall in IgM and cryoglobulin levels following rituximab treatment. Arzoo et al. [4] report a 71-yr-old lady with EMC treated with rituximab. Her neuropathy and skin lesions improved, repeat cryoglobulins were negative and she remained in remission 8 months after treatment. Nehme-Schuster et al. [5] reported a lack of effect of rituximab in two patients with type 1 cryoglobulinaemia, and noted in one patient a transient flare induced by rituximab administration. They postulated that this could be through mechanisms of CD20 cross linking provoked cryoglobulin release through B-cell apoptosis or activation. We also noted a flare and rise in cryoglobulins after rituximab administration (Fig. 1, Table. 1).
Once rituximab has bound to CD20, its lymphotoxic mechanisms include complement dependent cytotoxicity, antibody dependent cellular cytotoxicity and induction of apoptosis [6]. Fc
RIIIa polymorphisms might influence the degree of B-cell depletion by antibody-dependent cellular toxicity [7].
In our patient, it appears that the particular B-cell clone producing the monoclonal IgM was little affected by rituximab administration, perhaps because it was only weakly CD20 positive, or that IgM was being produced by CD20-negative plasma cells. Other possibilities include that although it might have bound CD20 effectively, it could not mount a sufficient cytotoxic response (due to hypocomplementaemia) or induce apoptosis. The FcRIIIa genotype of our patient was not known. Additional stimulatory and prosurvival B-cell signals could also have been present, which would diminish the effect of rituximab.
Whilst rituximab may offer some benefit in HCV-related MC, its role in EMC is less clear, and further clinical trials are needed.
The authors have declared no conflicts of interest.
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- Quartuccio L, Soardo G, Romano G, et al. (2006) Rituximab treatment for glomerulonephritis in HCV-associated mixed cryoglobulinaemia:efficacy and safety in the absence of steroids. Rheumatology 45:842–46.
[Abstract/Free Full Text] - Zaja F, DeVita S, Russo D, et al. (2002) Rituximab for the treatment of type II mixed cryoglobulinemia. Arthritis Rheum 46:2252–64.[CrossRef][Web of Science][Medline]
- Sansonno D, DeRe V, Lauletta G, Tucci FA, Boiocchi M, Dammaco F. (2002) Treatment of mixed cryoglobulinemia resistant to interferon-
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[Abstract/Free Full Text] - Nehme-Schuster H, Korganow AS, Pasquali JL, Martin T. (2005) Rituximab inefficiency during type 1 cryoglobulinaemia. Rheumatology 44:410–1.
[Free Full Text] - Shan D, Ledbetter JA, Press OW. (1998) Apoptosi of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood 91:1644–52.
[Abstract/Free Full Text] - Anolik JH, Campbell D, Felger RE, et al. (2003) The relationship of FcRIIIa genotype to the degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum 48:455–9.[CrossRef][Web of Science][Medline]
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