Non|[ndash]|hepatitis virus associated mixed essential cryoglobulinemia

On direct questioning, she had noted nasal congestion in addition to epistaxis, but no symptoms of sinusitis or asthma. She had previously suffered from pulmonary tuberculosis as a teenager, for which she had been fully treated with appropriate antituberculous therapy, and had also undergone a hysterectomy 3 years previously for menorrhagia. Her medications included ferrous sulfate for iron deficiency and hormone replacement therapy. There was no history of nonsteroidal antiinflammatory use or of herbal medication intake. She had no history of tobacco or alcohol use. There was a positive family history of renal disease, with the patient's mother having developed end-stage renal failure of unknown etiology, successfully treated by renal transplantation. The patient was married with three children. On examination, she was hypertensive with a BP of 151/91 mm Hg and a pulse rate of 98 beats per minute with a regular rhythm. There was ankle edema, but the jugular venous pressure was not raised. There was a non-blanching purpuric rash over the medial aspect of both lower legs and ankles. The rest of the examination was unremarkable. Urinalysis revealed leukocytes 3+, protein 3+, and blood 3+. The presenting laboratory investigations are summarized in Table 1. The chest and sinus radiographs were normal. An ultrasound scan of the abdomen showed normal sized kidneys bilaterally, with no evidence of scarring or hydronephrosis, and a normal liver and spleen. Her lung function tests were within normal limits. The patient became pyrexial with a temperature of 38 °C. Her mid-stream urine specimen grew multi-resistant Klebsiella species and a lactose-fermenting coliform, for which treatment with intravenous imipenem was initiated. She subsequently developed Clostridium difficile-positive diarrhea, which was successfully treated with oral metronidazole and led to the resolution of her fever. As renal function did not improve and she still had an active urinary sediment, she proceeded to renal biopsy (Figure 1). Renal Biopsy showed by light microscopy that almost all of the glomeruli showed marked hypercellularity, with both mesangial hypercellularity and mononuclear cells in the capillary lumens (Figure 1a, b). In addition, occasional capillary loops contained eosinophilic thrombi. There was focal tubular atrophy and mild interstitial edema. The arterioles and veins appeared normal, but one interlobular artery contained eosinophilic periodic acid Schiff-positive material in the lumen, with necrosis in the walls (Figure 1c). Immunoperoxidase staining showed mesangial and capillary wall IgM and C1q deposition. On electron microscopy, the capillary loops examined were patent, whereas the mesangial cells and matrix were increased. No electron-dense deposits were seen. Overall, the renal biopsy showed a diffuse endocapillary proliferative glomerulonephritis with vasculitis. The eosinophilic thrombi in the glomeruli, with eosinophilic material in an inflamed artery suggested the possibility of a cryoglobulinemia. The circulating cryoglobulin titer subsequently returned with a value of 3200 mg/l (NR <20), and was typed as a type II or mixed cryoglobulin with a monoclonal IgM kappa component. Repeat serology and quantitative PCR for hepatitis B and C were entirely negative in the serum and within the cryoprecipitate. In addition, as her serology showed an acute parvovirus infection, we tested the cryoprecipitate and found no increased antiparvovirus activity in the cryoglobulinemic precipitant compared with serum, showing that this cryoglobulin was not directed against this particular virus. A reduction in the serum creatinine to 124 μmol/l without further active treatment led to her discharge. However, she returned 1 week later with symptoms of chest pain, cough, and hemoptysis. Her hemoglobin had dropped to 7.8 g/dl and serum creatinine was 134 μmol/l. A chest radiograph showed cardiomegaly and her electrocardiogram showed low-voltage complexes. An echocardiogram revealed a nondilated left ventricle with moderate to severe impairment, global hypokinesis, and a moderate pericardial effusion. Bone marrow examination revealed no evidence of lymphoproliferative abnormality or other secondary cause of cryoglobulinemia (Table 2). She was transfused with 2 U of blood, and was treated with immunosuppression, consisting of daily oral steroids starting at 1 mg/kg, which subsequently tapered, and two doses of rituximab (1 g), 14 days apart. After treatment, she made a significant improvement, with resolution of her pleural and pericardial effusions, and a fall in serum creatinine to 79 μmol/l (Figure 2). Her cryoglobulin levels fell to within normal limits over the course of 4 months, and there was a corresponding normalization of her complement C4 levels (Figure 2). She is currently in full remission, 18 months after presentation, off all oral steroids and maintained only on angiotensin receptor blockade for mild hypertension. Interestingly, she has maintained this remission despite reconstitution of her circulating B cells. We describe a patient with type II, mixed essential cryoglobulinemia (MEC) presenting with cryoglobulinemic glomerulonephritis, accompanied by myocardial dysfunction, and pericardial and pleural effusions. The illness developed coincidentally with an acute parvovirus infection, and was complicated by concomitant urinary tract and gastrointestinal infections. The renal impairment due to cryoglobulinemic glomerulonephritis was treated successfully with oral steroids and anti-CD20 antibody. Mixed (type II) cryoglobulinemia is characterized by the formation of immune complexes (polyclonal IgG and monoclonal IgM) that precipitate when the temperature decreases below 37 °F and redissolve on warming. The monoclonal IgM autoantibody is a rheumatoid factor, with activity against the Fc portion of other immunoglobulins. Other causes and features of cryoglobulinemia are summarized in Table 2. Deposition of immune complexes leads to small-vessel vasculitis with complement activation through the classical pathway, reflected by low serum C4 and CH50 levels, and usually a normal C3 level. The resulting syndrome most frequently involves the skin, joints, nerves, and kidney. Renal involvement is common with a prevalence of up to almost 50%, presenting with non-nephrotic proteinuria, hematuria, and variable renal impairment. Identification of the etiology in mixed cryoglobulinemia is important as it may significantly alter both prognosis and management (Table 2). An association between hepatitis C and cryoglobulinemia was first made in 1992 through quantitative assays of hepatitis C virus (HCV) antibody in whole serum, cryoprecipitates, and supernatants.1 Although other cases may be related to other viral infections or autoimmune disease (Table 2), recent data have consistently indicated that the majority of cases are associated with HCV infection, with up to 88% of cases in one study.2 In contrast to the experience in Southern Europe, our current cohort of 14 patients with biopsy-proven cryoglobulinemic glomerulonephritis, followed in a large urban UK teaching hospital, has showed that only 7.1% associated with hepatitis C, 14.2% with hepatitis B, and the rest classified as MEC. The majority of patients were Caucasians (64.3%), with the rest being Indo-Asians (21.4%) and Afro-Caribbeans (14.3%). A separate historical cohort, previously reported from our institution, also showed a low level of hepatitis B virus-related disease (8%) and a high incidence (31%) of subsequent lymphoma, which is typical of MEC.3 Similar trends in MEC have been noted in other Northern European cohorts, in which none of the 22 patients with MEC were found to be HCV positive.4 The discrepancy with the published literature, mostly from Southern Europe, may simply relate to the incidence of hepatitis C in the two populations. This is particularly important as patients with MEC vasculitis have a poorer outcome and a fourfold increased risk of developing B-cell non-Hodgkins lymphoma compared with HCV-related cryoglobulinemic patients.3, 5 In addition to excluding hepatitis C as a cause of cryoglobulinemia in this case, we also excluded parvovirus as a cause, as the cryoglobulins revealed no concentration of either IgM or IgG antiparvovirus activity compared with the serum. However, we cannot exclude a post-infection induction of cryoglobulins following acute parvovirus exposure. Treatment of mixed cryoglobulinemia is aimed at limiting the pathogenic antibody load by limiting B-cell proliferation and removing circulating cryoglobulins. Immunosuppression has been reserved for patients with severe disease manifestations, including membranoproliferative glomerulonephritis, severe neuropathy, and life-threatening complications.5 Traditionally, a combination of corticosteroids and agents such as cyclophosphamide or azathioprine have been used, as well as plasmapheresis. The cases in which HCV is implicated, antiviral therapy is used first, combined with immunosuppression in severe disease.6 Importantly, in a large retrospective study of 105 patients with cryoglobulinemic vasculitis and renal disease, in which 80% were given corticosteroids and/or cytotoxic agents and 67% underwent plasmapheresis, only 14% had a long-lasting remission, and the 10-year survival rate was just 49%.7 With a relatively low rate of remission and a high incidence of severe complications, the development and refinement of safer, more effective treatment regimes remains the primary goal. Rituximab, a chimeric monoclonal antibody that binds the B-cell CD20 antigen, has been widely used in the treatment of immune-mediated renal disease.8 CD20 appears at the late pre-B stage of development and is lost during the terminal differentiation into plasma cells. Therefore, rituximab may be expected to interfere with monoclonal IgM production, cryoglobulin synthesis, and renal deposition of immune complexes. A recent review of rituximab treatment in cryoglobulinemic vasculitis included 57 patients, in which the cause was non-hepatitis C-related in just 25% of cases.6 Of 57 patients, 18 (32%) had cryoglobulinemic glomerulonephritis, of whom 70% had a complete clinical response after rituximab therapy.6 However, in these studies, rituximab has been predominantly used as a second-line treatment because of nonresponse or intolerance of other treatments, and was used as first-line therapy in just 2 of 57 cases, both of which were associated with HCV infection. In addition, relapses were reported in 39% of cases, although the majority responded to further anti-CD20 therapy. No differences were noted in efficacy whether the disease was HCV related or not. Successful treatment of de novo type III cryoglobulinemic graft dysfunction with rituximab in renal transplant patients (non-HCV related in 2 of 7 cases) and in type I cryoglobulinemia has also been reported.9, 10 Overall, the anecdotal reports suggest that rituximab has a good safety profile and results in amelioration of constitutional symptoms, an increase in C4, decrease in proteinuria, and improvement in renal function.6 There have been no reports of primary treatment of MEC glomerulonephritis with rituximab in the literature to date. However, a well-designed randomized clinical trial is required to confirm the long-term efficacy of rituximab in comparison with current standard of care, before it should be considered a suitable first-line therapy. A phase II trial of rituximab in HCV-associated cryoglobulinemia is underway, whereas a similar study in non-viral MEC is yet to be undertaken. We have described a case of MEC, which developed in the context of an acute parvovirus infection, successfully treated with steroids and rituximab as primary immunosuppressive therapy. Given the significant morbidity associated with standard immunosuppressant therapies, and the number of small cohort studies already reported using salvage rituximab therapy, primary treatment of MEC glomerulonephritis with rituximab appears to offer a safe, effective treatment for this condition. However, randomized studies are required to fully evaluate the benefits. We are grateful for support from the NIHR Biomedical Research Centre funding scheme. ADS was supported by the NIHR.