Rheumatology Advance Access originally published online on March 7, 2008
Rheumatology 2008 47(5):734-735; doi:10.1093/rheumatology/ken076
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Occurrence of cold agglutinin disease in RA patient during etanercept therapy successfully treated with rituximab
Rheumatology Unit of Second University of Naples, via Pansini 5, 80131, Napoli, Italy.
Correspondence to: D. Malesci, Rheumatology Unit of Second University of Naples, via Pansini 5, 80131, Napoli, Italy. E-mail: d.malesci{at}virgilio.it
SIR, Cold agglutinin disease (CAD) is characterized by the presence of cold agglutinins (CAs), directed against the I/i carbohydrate antigens on the surface of red blood cells (RBCs), causing haemagglutination and haemolysis [1]. Pathogenic CAs are generally of the IgM isotype and derive from monoclonal B-cell expansions [2], exclusively encoded by the VH4-34 segment of the rearranged heavy chain gene [3].
Chronic CAD is usually idiopathic, but it has been occasionally described in patients with autoimmune diseases such as SLE, RA, adult onset Still's disease, SS, SSc or lymphoproliferative disorders [4, 5]. It has been shown that the primary form frequently represents a lymphoproliferative bone marrow disorder characterized by clonal expansion of B cells [4, 5]. Conventional treatment with corticosteroids, alkylating agents, immunosuppressive drugs, IFN-
or cladribine are usually ineffective in CAD [6]. Conversely, the chimeric monoclonal anti-CD20 antibody rituximab, that is currently used for the treatment of non-Hodgkin lymphoma and refractory RA, has been shown to induce remission in >50% of CAD patients [7].
Here, we report a case of RA developing CAD during a course with an anti-TNF- agent successfully treated with rituximab.
The patient, a 52-yr-old woman, affected by RA (ACR 1987 criteria) since 1988, had been treated with both prednisolone 5–7.5 mg/day and low dose of MTX (7.5–15 mg/week) until 1996, and successively with both prednisolone 5–7.5 mg/day and LEF 20 mg/day until 1997, because of lack of efficacy. For the occurrence of gastrointestinal adverse events and inefficacy, the patient started etanercept 25 mg/twice a week, achieving a marked improvement of the arthritis with remission [28-joint disease activity score (DAS28) <2.6] at month 6. Nevertheless, during this course the patient showed laboratory abnormalities including mild leucopenia with neutropenia and anaemia, that worsened progressively causing the withdrawal of treatment at week 40 [white blood cells (WBCs) 4.0 x 103/µl, neutrophils 1.7 x 103/µl, RBCs 3.3 x 106/µl, Hb 11.0 g/dl]. At this time, laboratory data showed clumps of agglutinated red cells on blood smear taken at room temperature, positive direct Coombs test (DAT) using polyspecific anti-serum, high CA titre of 1:512 with no evidence of clonal lymphoproliferation as assessed by bone marrow histology. Finally, flow-cytometric analysis revealed IgM-class antibodies against antigen I on RBCs. The patient was treated with prednisolone (1 mg/kg/day then tapered to 0.25 mg/kg/day) and CSA (3 mg/kg/day). Both a worsening of anaemia and a relapse of polyarthritis were detected after 2 months of partial response defined according to Zaja et al. [8]. Rituximab was given at 1000 mg intravenously for two courses on days 1 and 14 according to the Reflex study protocol. The patient showed rapid improvement in arthritis achieving a good response according to EULAR criteria at day 14, and persistent remission between months 2 and 6. No infusion-related adverse events were pointed out. Complete recovery of haemoglobin level, reticulocyte count, leucocyte count, BUN, lactate dehydrogenase, bilirubin and haptoglobin level and reduction of CA titre at month 3 were recorded, without any new change 6 month after rituximab therapy (Table 1).
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The efficacy of rituximab in patients with CAD has also been recently reported by other groups [8], with response rates and response duration very similar to those reported in follicular lymphoma and other indolent CD20+ B-cell lymphomas [9, 10]. To our knowledge, our report documented for the first time the occurrence of CAD in a RA patient during treatment with etanercept, confirming the efficacy of rituximab when CAD is refractory to conventional treatment. Moreover, the occurrence of leucopenia and neutropenia, that have not been described in primary CAD [5, 6] may be considered independent adverse events during etanercept course successfully treated with rituximab as well.
The relation between CAs and lymphoproliferative disorders [4, 5], and the lack of consensus on the risk of lymphoma with anti-TNF- agents, may suggest CAs evaluation as an additional safety parameter in RA patients taking TNF- inhibitors.
Disclosure statement: The authors have declared no conflicts of interest.
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