Rituximab induces remission in refractory HCV associated cryoglobulinaemic vasculitis

Abstract

Objectives: To report the successful induction of remission with the monoclonal anti-CD20 antibody rituximab in a patient with hepatitis C virus (HCV) associated cryoglobulinaemic vasculitis and a non-Hodgkin's lymphoma (NHL) resistant to previously advocated conventional treatments.

Case report: The patient was a 45 year old woman with HCV associated cryoglobulinaemic vasculitis, with purpura, arthralgia, constitutional symptoms, and a polyneuropathy. A malignant NHL was found as underlying lymphoproliferative disease. At this stage the disease was refractory to interferon alpha2b and ribavirin and to subsequent immunosuppressive treatment with cyclophosphamide. Six rituximab infusions targeting the CD20 antigen on cells of the B cell lineage induced remission of the vasculitis. Bone marrow biopsy disclosed absence of the NHL. Remission has subsequently been maintained and HCV eliminated with the new pegylated interferon alpha2b and ribavirin for nearly one year.

Conclusions: Transition of the underlying "benign" lymphoproliferative disease to a malignant lymphoma may result in difficult to treat HCV associated cryoglobulinaemic vasculitis. Rituximab offers a new possibility for inducing remission in refractory HCV associated cryoglobulinaemic vasculitis and the lymphoproliferative disorder. After remission, HCV may subsequently be eliminated with pegylated interferon alpha2b and ribavirin.

Figure 1

(A) Bone marrow trephine stained for NACE (x40). Two small lymphoid aggregates were found next to bone trabeculae (→). The lymphoid cells were mainly small lymphocytes with dense chromatin structure and small cytoplasm. Some lymphoplasmacytoid cells were intermingled as were rare blasts. (B) High power view of a Giemsa staining of these lymphoid aggregates. Note the small lymphocytes and lymphoplasmacytoid cells (→). Some of the nuclei show small indentations, rarely a small nucleolus can be found. (C) Bone marrow trephine after treatment with rituximab. NACE staining (x40). No lymphoid aggregates were visible, the haematopoiesis is regularly distributed and all three mature lineages are represented. (D) Immunohistochemical staining of the lymphoid aggregates from the bone marrow trephine before treatment using CD20 antibody, the ABC method DAB (x200). Note: ill defined B cell aggregates which slightly replace the regular haematopoietic cells. (E) CD20 staining of the bone marrow after treatment (x200). Rare CD20 positive B cells were scattered throughout the marrow. (F) Transverse section through the colon sigmoideum with an ulceration of the mucosa (upper right) and an increase in the number of inflammatory cells in the lamina propria and submucosa. There were irregularities of the glands at the margins of the ulcer. In the lower right of the figure a vascular occlusion is shown (x25). Masson trichrome staining. (G) Section of (F). Moderate vascular inflammation with fibrosis and central fibrinoid necrosis is demonstrated. Small to medium sized muscular arteries were involved, resembling cryoglobulinaemic vasculitis. Typically, the inflammatory infiltrate consists of lymphocytes, neutrophilic granulocytes, some eosinophils, and monocytes/histiocytes. Haematoxylin and eosin (H&E) staining (x100).

Figure 2

IgH-rearrangment study of DNA extracted from the bone marrow trephine (1A) before treatment. Lane 1: a clonal band (→) is visible in a polyclonal background ({}). Lane 2: a polyclonal control case. Lane 3: another positive case. Lane 4: a water control, negative control. Lane 5: a positive control with two strong signals (biclonal). Lane 6: the DNA length standard. DNA from the same patient, extracted from the bone marrow trephine (1C) after treatment, did not yield a monoclonal band (data not shown).

Figure 3

Patient's disease course. Cryoglobulin levels and HCV-RNA load are depicted as well as the Birmigham vasculitis activity score.¹¹ Abbreviations for organ involvement due to the cryoglobulinaemic vasculitis: S, skin; A, arthritis; P, polyneuropathy; B, constitutional symptoms/B symptoms; GI, gastrointestinal involvement—that is, vasculitis of the colon. NHL, non-Hodgkin's lymphoma; Cyc i.v., cyclophosphamide infusions; Pl, plasmapheresis; IFNα2b, interferon-α2b; PEG-IFN, pegylated IFNα2b; Riba, ribavirin. Corticosteroid (prednisolone) was given at 5 mg/day by mouth.