Rituximab as a Therapeutic Tool in Severe Mixed Cryoglobulinemia

Abstract

Type II mixed cryoglobulinemia (MC) is a systemic vasculitis, associated in most cases with hepatitis C virus (HCV) infection, sustained by proliferation of oligoclonal cells. Systemic B cell depletion and clinical remission can be achieved in non-Hodgkin lymphoma by human/mouse chimeric monoclonal antibody that specifically reacts with the CD20 antigen (rituximab). Similar effects could be expected in type II MC. Twelve patients, mean age 61.9 years (range 37-76), 11 with HCV infection genotype 2a2c (4 cases) or 1b (6 cases) and 3 (1 case) and symptomatic type II MC with systemic manifestations, including renal involvement, marrow clonal restriction, large necrotizing ulcers, and polyneuropathy, were considered eligible for rituximab therapy because of resistance or intolerance to conventional therapy or important bone marrow infiltration. Rituximab was administered intravenously at a dose of 375 mg/m2 on days 1, 8, 15, and 22. Two more doses were administered 1 and 2 months later. No other immunosuppressive drugs were added. Response was evaluated by assessing the changes in clinical signs, symptoms, and laboratory parameters. Levels of proteinuria, hematuria, erythrocyte sedimentation rate, cryocrit, rheumatoid factor, and IgM decreased while C4 values increased and HCV viral load remained stable during short- and medium-term observation. Bone marrow abnormalities were found to reverse to normal. Constitutional symptoms disappeared or ameliorated. No acute or delayed side effects were seen. Based on this experience and a number of reports published in the last 5 years, Rituximab appears to be a safe and effective therapeutic option in symptomatic patients with HCV-associated MC with signs of systemic vasculitis.

Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: Results of multicenter cohort study and review of the literature

“…This multicenter, retrospective study including a large patients' series further supports and expands the results of previous reports showing the usefulness of rituximab in active MCs [9][10][11][12][24][25][26][27][28][29][30][31]. The positive effects of this treatment were particularly evident for the most frequent disease manifestations such cutaneous vasculitic lesions, i.e.…”

“…Review papers were excluded. A total of 39 manuscripts that reported on at least one case of cryoglobulinemic vasculitis treated with rituximab were included in the present analysis [9][10][11][12][24][25][26][27][28][29][30][31]. Three manuscripts were excluded because they included patients that had already been described in other publications [9,11,37].…”

“…The safety and efficacy of this drug have been reported in various vasculitides and other systemic autoimmune diseases [13][14][15][16][17][18][19][20][21][22][23]. The usefulness of monoclonal antibodies directed to CD20 antigen, a trans membrane protein expressed on pre-B lymphocytes and mature B lymphocytes, on both cutaneous and visceral organ involvement of MCs, including low grade B-cell lymphoma, has been reported by various Authors, generally referred to small patients' series [24][25][26][27][28][29][30][31]. These are often characterized by a heterogeneous composition of clinical manifestations that does not permit an accurate evaluation of the effect of rituximab on single organ involvement.…”

Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases

“…While antiviral drugs administered with RTX may possibly be synergic [44], [56], [57], [58] and [59], they multiply the adverse effects thereby making treatment poorly tolerated. Until recently, it was believed that staggered administration after a critical phase of vasculitis was mandatory in order to avoid the risk of exacerbating HCV infection, but in most cases it is probably unnecessary [60].…”

Novel diagnostic approaches and cost–benefit balance of treatment of immune-mediated and rare disease in the era of biologic drugs: Lessons from the 15th Turin Congress on Immune Pathology and Orphan Disease

“…Given the understanding that in several renal diseases, such as ANCA-associated vasculitis, mixed cryoglobulinemia, membranous nephropathy and lupus nephritis, auto-antibodies have been implicated either in direct glomerular injury or as correlates with disease activity, rituximab has emerged as a potent option for many immune-mediated glomerulopathies. Based on recent large clinical trials, it has been FDA-approved for the treatment of ANCA-associated vasculitis and continues to be studied in off-label usage for many glomerular diseases, including membranous nephropathy, lupus nephritis, and mixed cryoglobulinemia [31], [32], [33], [34], [35], [36], [37], [38], [39], [40] and [41]. It has been used as a treatment in nephrotic syndrome in children and adults, including both minimal change disease and focal segmental glomerulosclerosis.…”