Infliximab in the treatment of refractory vasculitis secondary to hepatitis C-associated mixed cryoglobulinaemia

M.-O. Chandesris, S. Gayet, N. Schleinitz, B. Doudier, J.-Robert Harlé and G. Kaplanski

Service de Médecine Interne, Hôpital de la Conception, 156, Boulevard Baille, 13005 Marseille, France

Correspondence to: G. Kaplanski. E-mail: gkaplanski{at}marseille.inserm.fr

SIR, Recently, P. Bartolucci et al. [1] reported promising data on the efficacy of the anti-TNF-{alpha} antibody infliximab in the treatment of 10 patients with refractory systemic vasculitis, including Wegener's granulomatosis and rheumatoid arthritis-associated vasculitis. The authors observed a good but incomplete and transitory response while treating a patient with hepatitis C-associated mixed cryoglobulinaemia (MC). We had the opportunity to treat two such patients with infliximab and did not obtain comparable promising responses.

Case 1 was a 46-yr-old-man who had a first episode of cutaneous purpura affecting both legs, arthralgia and mild renal insufficiency in 1995, when a diagnosis of MC associated with post-transfusion hepatitis C was made. Symptoms resolved under low-dose corticosteroids, but because of a history of dilated cardiomyopathy interferon was not introduced. This patient was seen for the first time in our institution in December 2000, because of recurrent episodes of cutaneous purpura associated with peripheral sensitive polyneuropathy. Liver tests were moderately elevated; genotype 1a and a Knodell score of 9 on liver biopsy were found. A type III MC and low levels of C4 (0.08, N: 0.1–0.35) and CH50 (45%) were present, but no anti-nuclear or anti-neutrophil cytoplasmic antibodies. Biopsy of the purpura disclosed a small-artery leucocytoclastic vasculitis. Treatment associating low doses of interferon (106 U three times a week), oral corticosteroids (30 mg/day) and plasma exchange was started, but because of venous access limitations, only three exchanges could be performed. In March 2001, the patient presented with a flare of the disease associated with a 10 kg weight loss, cutaneous purpura, toe ulcers and increasing neuropathic leg pains. A muscle biopsy showed mononuclear cells vasculitis affecting the capillaries. An abdominal CT scan and a bone marrow biopsy were normal. With the patient's approval, three injections (5 mg/kg) of infliximab were given on days 1, 14 and 40 with no side-effects. His condition deteriorated severely after the third injection, with extensive purpura affecting both legs, trunk and nose, painful fingers and toe ulcers, worsening of peripheral neuropathy and the appearance of central nervous symptoms with coma. The patient condition worsened despite an intravenous bolus of cyclophosphamide (800 mg) and he died with global polyvisceral insufficiency. A post-mortem examination showed severe small and medium-size vessel necrotic vasculitis.

Case 2 was a 60-yr-old woman who had a blood transfusion in 1962 and had a diagnosis of hepatitis C-associated MC in 1992 after she presented with cutaneous purpura of both legs and arthralgia. Slightly elevated liver enzymes, type 1 genotype and a Knodell score of 7 on liver biopsy were present. A type II MC with low C4 (0.03 g/l) and CH50 (45%) levels were found. During the subsequent years, the patient received several treatments, including interferon (three courses), low doses of steroids, plasma exchanges, ribavirin. In July 2000, however, her physical condition worsened, with recurrent purpura, severe leg ulcers, sensitive motor neuropathy, and increased creatininaemia with persistent proteinuria (1 g/24 h). Since plasma exchanges were impossible at that time, and interferon unusable because of severe side-effects, cyclophosphamide was introduced but with no benefit. She then received, after informed consent, two injections (5 mg/kg) of infliximab at J1 and J15. No improvement was observed and this treatment was discontinued. Subsequently, despite corticosteroids and cyclophosphamide reintroduction, her condition deteriorated and she died a year later with severe renal insufficiency and cutaneous symptoms of vasculitis.

MC is the most frequent immune disorder associated with hepatitis C virus (HCV) infection [2], and may present in two clinical forms. The more common is a chronic vasculitis, affecting the skin, joints, peripheral nerves and kidneys, and is characterized by a mononuclear cell perivascular infiltrate [3]. The other type, reminiscent of hepatitis B virus-associated periarteritis nodosa, is an acute, life-threatening polyvisceral vasculitis with both mononuclear cell and neutrophil infiltrates, inducing vessel fibrinoid necrosis. Although both types of vasculitis are generally successfully treated with a combination of interferon, ribavirin, corticosteroids and plasma exchange [3], in some patients this treatment may be insufficient or cannot be fully conducted, thus other therapeutic strategies may be needed. Since we previously observed increase soluble TNF-{alpha} receptor concentrations in HCV-associated MC-related vasculitis, suggesting a role for this cytokine in the pathogenesis of this disease [4], we decided to use infliximab. Unfortunately, unlike in the case reported by Bartolucci et al., this treatment appears at least inefficient. Although pathological data are not available, the patient reported by these authors, like our second patient, belongs to the first type of HCV-associated MC vasculitis; after a long-lasting hepatitis C, she had a chronic cutaneous and renal form of the disease and could not be given the classical treatment, but experienced a rapid but transient skin improvement 2 weeks after the first infliximab infusion. We did not observe such a response in our second patient, nor did we observe a favourable response in our first patient, who presented a severe form of HCV MC vasculitis. Noteworthy is the fact that, in this patient, severe periarteritis nodosa followed a chronic form of MC-induced vasculitis, a very uncommon and intriguing finding that led us to question the role of infliximab in such an event. Although infliximab may be efficient in certain types of vasculitis, we think our two observations suggest that caution is needed in using this treatment in hepatitis C-associated vasculitis, and suggest that other therapeutics such as anti-CD20 antibody may be more promising, as recently reported [5].

The authors have declared no conflicts of interest.

References

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  2. Cacoub P, Renou C, Rosenthal E et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. Medicine 2000;79:47–56.[CrossRef][ISI][Medline]
  3. Cacoub P, Costedoat-Chalumeau, Lidove O, Alric L. Cryoglobulinemia vasculitis. Curr Opin Rheumatol 2002;14:29–35.[CrossRef][ISI][Medline]
  4. Kaplanski G, Marin V, Maisonobe T et al. Increased soluble p55 and p75 tumour necrosis factor-{alpha} receptors in patients with hepatitis C-associated mixed cryoglobulinaemia. Clin Exp Immunol 2002;127:123–30.[CrossRef][ISI][Medline]
  5. Zaja F, De Vita S, Mazzaro C et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 2003;101:3827–34.[Abstract/Free Full Text]
Accepted 22 October 2003