Cryoglobulinemia is defined as the presence of circulating immunoglobulins that precipitate with cold temperature and dissolve with rewarming. Mixed cryoglobulinemia (MC) are associated with auto-immune diseases, lymphoproliferative malignancies and chronic infections, mainly hepatitis C virus (HCV).1 When MC is found in the absence of well-defined disease, the syndrome is designated as essential MC. It may be responsible for a systemic vasculitis with purpura, skin ulcer, arthralgia, neuropathy and renal involvement.1, 2 Patients with essential MC vasculitis have a poor long-term outcome, and serious infections represent the main cause of death.2 Rituximab, a chimeric IgG1κ immunoglobulin that targets CD20 molecules on B cells, has recently demonstrated efficacy in MC vasculitis, due to HCV or not.1-4 The overall clinical and biologic tolerance is usually good.3 However, systemic drug reactions, such as serum sickness syndrome, have been reported. Recently, Sène et al.5 have reported patients with HCV-induced MC vasculitis who developed severe flares of vasculitis after rituximab infusion. We report here a patient with essential MC vasculitis who developed hemorrhagic bullous purpura considered as a flare of vasculitis after rituximab infusion. An 83-year-old man was hospitalized because of purpura and painful necrotizing skin ulcers (Fig. 1) associated with peripheral neuropathy. C-reactive protein (CRP) was 97 mg/L. Serum creatinine was 66 μmol/L (glomerular filtration rate [GFR] 100 mL/min using the Modified Diet in Renal Disease [MDRD] equation) without hematuria or proteinuria. Serum cryoglobulin was detected (1.2 g/L). Immunochemical typing disclosed type II cryoglobulinemia according to Brouet classification (monoclonal IgMκ and polyclonal IgG). Rheumatoid factor (RF) was 412 IU/mL (normal < 15). C3 fraction of complement level was 1.3 g/L (0.75–1.4) and C4 was 0.05 g/L (0.1–0.34). Serologies for human immunodeficiency virus, HCV and HBV infections were negative. There was no argument in favor of a B-cell non-Hodgkin lymphoma. Cutaneous biopsy of a purpuric lesion disclosed leucocytoclasic vasculitis. A diagnosis of essential MC vasculitis was made. The patient was treated with prednisone (1 mg/kg/day) without improvement. A treatment with rituximab was added (low-dose protocol cycle with 375 mg/m2/week for four consecutive weeks associated with premedication: 40 mg methylprednisolone, 8 mg dexchlorpheniramine, 1 g acetamenophen). Four days, after the second rituximab infusion, the patient presented a flare of vasculitis with hemorrhagic bullous purpura (Fig. 2) and renal failure (GFR 33 mL/min). He subsequently developed severe infections (Serratia marcescens septicemia due to cutaneous infection, Escherichia coli urinary tract infection) and died 3 months later (due to Pneumocystis jirovecii). Autopsy was not performed. Recently, rituximab plus corticosteroids showed the greater therapeutic efficacy compared to corticosteroids alone and alkylating agents plus corticosteroids to achieve complete response in non-infectious MC vasculitis.1 In a recent report, four patients developed acute flare of HCV-associated MC vasculitis 1 day or 2 days after rituximab infusion and two patients developed serum sickness syndrome 7 and 9 days after infusion.5 Serum sickness syndrome is defined as the occurrence of fever, arthralgia, rash, lymphadenopathy and elevation of acute phase reactants occurring 7–14 days after drug administration.6 This second hypothesis was excluded in our case because of clinical presentation and delay. The main features of the patients with HCV-induced MC vasculitis who developed rituximab-related MC vasculitis flare are indicated in Table 1. The four patients mentioned in the study by Sène et al.5 had similar features as this case. In their study, Sène et al.5 demonstrated that in vitro rituximab formed immune complexes with the cryoprecipitating IgMκ that had RF activity. Moreover, in vitro addition of rituximab to serum containing an RF-positive IgMκ type II MC was associated with visibly accelerated cryoprecipitation. We can evoke a similar mechanism in our case of RF-positive IgMκ type II MC without HCV infection. Accelerated cryoprecipitation lead to severe systemic reactions, including hemorrhagic bullous purpura. Major factors associated with the occurrence of severe rituximab-related drug reactions are high baseline levels of cryoglobulin (> 1 g/L), infusion of 1 g rituximab, high levels of complement activation (C4 < 0.03 g/L).5 So, careful use of rituximab is necessary when MC serum levels are high and C4 serum levels are low. High-dose rituximab protocol (1 g) should be avoided. Rituximab at a lower dose (250 mg/m2/week for two consecutive weeks) may be as effective as at 375 mg/m2/week for four consecutive weeks.7 Plasma exchanges to lower MC serum levels prior to rituximab treatment should be considered in patients with high serum level of MC.5 The role of each of these strategies remains to be defined in randomized controlled trials. The author declares no conflict of interest and no sources of financial support.
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Dec 1, 2013
A Omenetti + 9
Open Access
