Effectiveness and cost of hepatitis C virus cryoglobulinaemia vasculitis treatment: From interferon-based to direct-acting antivirals era.

BACKGROUND: The net benefits of new hepatitis C virus (HCV) direct-acting antiviral drugs (DAA) in patients with cryoglobulinaemia vasculitis (CryoVas) are unknown. OBJECTIVE: To analyse the effectiveness and cost of all treatments used for HCV-CryoVas in the DAA vs pre-DAA era. METHODS: A chart review of all HCV-CryoVas patients who received antivirals from 1993 to 2016 in a tertiary centre was performed. Treatment effectiveness was analysed for clinical, immunological and virological responses. Cost analyses included anti-HCV treatments, non-antiviral drugs, plasmapheresis, dialysis and hospitalizations. We compared main data in the pre-DAA vs DAA period. RESULTS: About 201 HCV-CryoVas patients were included (women, 53.2%; mean age, 59.2 years; Metavir score F3-F4, 36.7%; genotype 1, 64.2%). Patients in the DAA era (n=27) compared to those in the pre-DAA era (n=174) showed higher rates of clinical (96.3% vs. 78.6%), immunological (89.5% vs. 77.1%), and sustained virological response (75.0% vs. 42.8%). Death rate was 14.8% vs. 24.4% respectively. In the DAA compared to pre-DAA era, mean cost of anti-HCV drugs increased from 11 855 to 57 632 € while mean CryoVas-related cost decreased for both hospitalizations (from 33 510 to 21 347€) and non-antiviral treatments (from 17 347 to 11 397€). CONCLUSION: Improved antiviral efficacy of HCV drugs in the DAA era led to increased clinical and immunological efficacy and a lower death rate. Use of DAAs was associated to higher costs for HCV drugs while costs related to both hospitalizations and non-antiviral treatments decreased.

It's not what it looks like: atypical rash in cryoglobulinaemic vasculitis.

A 48-year-old man with a history of intravenous drug use and chronic, untreated hepatitis C presented to the emergency room with acute bilateral lower extremity swelling, erythema and maculopapular rash. Serum C4 levels were low, but dermatology felt the rash was due to venous stasis dermatitis. The patient was discharged with compression stockings, but returned to the hospital 5 days later with no improvement in his symptoms. A more extensive laboratory workup revealed hepatitis C viral load of 4 million, elevated serum cryoglobulins, and skin biopsy showing leucocytoclastic vasculitis. He was treated with oral prednisone, with complete resolution of his symptoms after 2 weeks. He was scheduled for follow-up in gastroenterology clinic for treatment of his hepatitis C for definitive cure of his mixed cryoglobulinaemia, but failed to get insurance authorisation to begin treatment with Harvoni. He presented to the hospital 4 months later with diffuse alveolar haemorrhage.

Elevated serum osteopontin levels in chronic hepatitis C virus infection: association with autoimmune rheumatologic manifestations.

Owing to the suggested role of osteopontin (OPN) in inflammation, autoimmunity and fibrosis, we investigated their serum concentrations in chronic hepatitis C virus (HCV) infected patients with and without autoimmune manifestations and correlated those levels to clinical manifestations and the histological severity of hepatic fibrosis. A total of 70 chronic HCV-infected patients (35 with and 35 without autoimmune rheumatic manifestations ) were compared with 35 healthy volunteers matched for age and gender. Epidemiological, clinical, immunochemical and virological data were prospectively collected. OPN serum levels were assessed by an Enzyme Linked Immunosorbant Assay. The mean serum OPN levels were higher in HCV patients with autoimmune rheumatologic manifestations and in patients without; than that for the normal controls (p = 0.000). The mean OPN values progressively increased by increasing severity of liver fibrosis (p = 0.009). Multivariate analysis revealed that the presence of rheumatologic manifestations had the highest predictive value (b = 7.141, Beta = 0.414, p = 0.000) followed by liver fibrosis (b = 4.522, Beta = 0.444, p = 0.000) on the variation of OPN levels in our HCV patients. Among the group of patients with HCV and rheumatologic involvement, OPN serum levels were higher in patients with positive cryoglobulin and rheumatoid factor than in those without, and with systemic vasculitis than in those without. Correlation analysis didn't reveal any statistical significance of OPN with age, serum albumin, aminotransferases and viral load. Our data suggests OPN as a promising marker for HCV associated autoimmune rheumatologic involvement, particularly with regard to development of vasculitis and cryoglobinemia. In addition, it could serve as a biomarker to evaluate the severity of liver damages in HCV infected subjects.

Performance of the preliminary classification criteria for cryoglobulinaemic vasculitis and clinical manifestations in hepatitis C virus-unrelated cryoglobulinaemic vasculitis.

BACKGROUND: Cryoglobulinaemic vasculitis (CV) is often related to hepatitis C virus (HCV) infection, but it can develop in other diseases (e.g. other infections, connective tissue diseases, malignancies) in the absence of HCV infection. A comparison of the performance of the recently published classification criteria for the CV was made between HCV-positive and HCV negative patients with serum cryoglobulins. METHODS: 500 patients with serum cryoglobulins were studied. Their mean age was 60.77±13.75 years, they were 356 females (71.2%) and 144 males (28.8%). CV was diagnosed in 272 patients (54.4%), while other diseases associated with serum cryoglobulins without CV (CwV) were diagnosed in 228 patients (45.6%). RESULTS: 117 HCV negative patients were collected (23.4%) and they were 42/272 (15.4%) among the CV group, while they were 75/228 (32.9%) among the CwV. In HCV negative patients the sensitivity and specificity of the classification criteria of CV were 89.5% CI 95% [79.5-99.5] and 90.3% CI 95% [82.8-97.8], respectively, while in HCV positive patients they were 88.3% CI 95% [83.6%-93.1%] and 96.1% CI 95% [91.8-100], respectively. The most frequent disease recognised among the HCV negative patients was Sjögren's syndrome (SS) (55/117, 47.0%), and the sensitivity and the specificity of the CV classification criteria were 88.9% CI 95% [76.5-100] and 91.3% CI 95% [79.2-100], respectively. CONCLUSIONS: The classification criteria for CV showed a good performance even in HCV-unrelated patients. A slightly lower specificity was observed for the classification of HCV-unrelated CV, since some clinical manifestations included in the clinical item for the classification criteria occurred more frequently in HCV-negative rather than HCV-positive controls with CWV.

HIV infection and clinical spectrum of associated vasculitides.

Various infections have been causative in the pathogenesis of systemic vasculitides, and HIV infection is not spared. In an immunocompromised host, cytomegalovirus, Epstein-Barr virus, varicella zoster virus, herpes simplex virus, hepatitis B and hepatitis C virus, and mycobacteria, along with HIV infection can cause vasculitis. Herein we emphasize the spectrum of vasculitides, their pathogenesis, presentation, course, and therapy in the HIV-infected population. Every spectrum and size of the blood vessel involvement have been seen in HIV-associated vasculitides. We review each spectrum in detail and describe our experience with polyarteritis nodosa, the most common presentation occurring in HIV-infected patients. We also discuss the differences in HIV, hepatitis B, and hepatitis C- related polyarteritis nodosa in detail.

Prognostic factors in patients with hepatitis C virus infection and systemic vasculitis.

OBJECTIVE: Hepatitis C virus (HCV)-related systemic vasculitis can cause significant morbidity and mortality. Most studies of the prognosis of patients with HCV-related systemic vasculitis are based on heterogeneous studies performed before the era of antiviral therapy. The aim of this study was to analyze the clinical, biologic, and therapeutic factors associated with prognosis in a homogeneous series of patients with HCV-related systemic vasculitis who were followed up during the era of antiviral therapy. METHODS: One hundred fifty-one consecutive HCV RNA-positive patients with vasculitis were prospectively followed up between 1993 and 2009 and were analyzed for clinical, biologic, and therapeutic factors associated with survival. RESULTS: After a median followup period of 54 months, 32 patients (21%) had died, mainly of infection and end-stage liver disease. The 1-year, 3-year, 5-year, and 10-year survival rates were 96%, 86%, 75%, and 63%, respectively. Baseline factors associated with a poor prognosis were the presence of severe liver fibrosis (hazard ratio [HR] 5.31), central nervous system involvement (HR 2.74), kidney involvement (HR 1.91), and heart involvement (HR 4.2). The Five-Factors Score (FFS), a vasculitis scoring system, was significantly associated with outcome. In multivariate analysis, severe fibrosis (HR 10.8) and the FFS (HR 2.49) were significantly associated with a poor prognosis. Treatment with the combination of PEGylated interferon plus ribavirin was associated with a good prognosis (HR 0.34), whereas treatment with immunosuppressive agents was associated with a poor outcome, after adjustment for the severity of vasculitis (HR 4.05). Among patients without severe fibrosis, the FFS was a good predictor of outcome, while among those with severe fibrosis, the severity of vasculitis had no prognostic value. CONCLUSION: At the time of the diagnosis of HCV-related systemic vasculitis, severe liver fibrosis and the severity of vasculitis were the main prognostic factors. Use of antiviral agents was associated with a good prognosis, whereas treatment with immunosuppressant agents had a negative impact.

A retrospective analysis of treatment outcomes in patients with hepatitis C related systemic vasculitis receiving intravenous methylprednisolone and cyclophosphamide.

The aim of this work is to describe the outcome of a series of patients with hepatitis C virus (HCV)-related vasculitis who were treated with corticosteroids and I.V. cyclophosphamide without receiving any antiviral therapy. The data of 16 patients with HCV infection and vasculitis were retrospectively analyzed for the treatment outcome in the present study. Eleven patients were females (68.8%) with a mean age of 49.6 ± 10.0 years. Nine patients (56.2%) had medium-sized vessel vasculitis (group A) and seven patients (43.8%) had small vessel vasculitis (group B). Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS 2003) and organ damage was assessed by the Vasculitis Damage Index (VDI). HCV infection was confirmed in all patients by the detection of antibodies to HCV in serum by ELISA and HCV RNA using qualitative PCR. Quantitative PCR was done using the branched DNA technique. None of our study patients had received antiviral therapy, but they all received I.V.-pulsed cyclophosphamide monthly for 6 months, then every 3 months for six times if needed, preceded by I.V. methylprednisolone. Twelve patients (75%) had undetectable viral load by the quantitative technique. The drop in mean BVAS recorded at different intervals was highly significant. Although there was a drop in the VDI mean between the first and second reading, it was not statistically significant. All patients responded to treatment. Seven patients (43.8%) had relapse. Two patients died (12.5%). One patient died from renal failure (group B) and another died from sepsis (group A). The treatment outcomes were not statistically significant between the two vasculitis groups. A subset of patients with HCV-related vasculitis and with low levels of viremia can be safely treated with corticosteroids and cyclophosphamide alone. Despite successful treatment, a significant proportion of patients relapse and some develop severe complications and death.

Systemic vasculitis in patients with hepatitis C virus infection with and without detectable mixed cryoglobulinemia.

OBJECTIVE: to describe hepatitis C virus (HCV)-related systemic vasculitis in patients without detectable mixed cryoglobulinemia (MC) and to compare them to typical cases of HCV-MC vasculitis. METHODS: twelve HCV RNA+ patients with histologically proven vasculitis in the absence of detectable MC (cases) were retrospectively compared with 48 HCV RNA+ patients with MC vasculitis (controls). Each case was matched with 4 controls for age and sex. RESULTS: the main epidemiological and virologic features were similar between cases and controls. No clinical difference was found, except for lower rates of arthralgias (33% vs 71%; p = 0.02) and purpura (50% vs 83%; p = 0.03) in cases. Cases showed higher mean serum C3 (1.17 ± 0.21 vs 0.93 ± 0.23 g/l; p = 0.01) and median C4 levels (0.25 vs 0.04 g/l; p < 0.001), lower median serum IgM levels (0.6 vs 1.9 g/l; p < 0.001), and lower rates of rheumatoid factor positivity (8% vs 82%; p < 0.001) than controls. The main histologic features were similar between cases and controls. Immunofluorescence analysis of skin biopsy from 1 case revealed perivascular deposits of C3 and IgA. After treatment, overall clinical response of vasculitis (75% vs 83%) and sustained virological response (40% vs 64%; p = 0.3) were similar between cases and controls, except for higher complete clinical response (42% vs 73%; p = 0.05) in controls. CONCLUSION: HCV-related systemic vasculitis may occur in the absence of detectable MC. Our findings suggest that such vasculitis probably results from immune complex-mediated mechanisms, and that the therapeutic management of such vasculitis should be similar to that of HCV-MC vasculitis.

Presentation and outcome of gastrointestinal involvement in hepatitis C virus-related systemic vasculitis: a case-control study from a single-centre cohort of 163 patients.

BACKGROUND: During primary systemic vasculitides gastrointestinal (GI) involvement is associated with a poor outcome, leading to the use of immunosuppressive therapy. The significance of GI involvement during hepatitis C virus (HCV)-related systemic vasculitis has never been evaluated. OBJECTIVE: To evaluate the significance of GI involvement during HCV-related systemic vasculitis in the antiviral therapy era. METHODS: Data from 163 patients were retrospectively reviewed to describe the presentation and outcome of patients with HCV-related systemic vasculitis with GI involvement (GI+), and to compare them with patients without GI involvement (GI-). RESULTS: GI manifestations were present in 12 (7.4%) patients. Abdominal pain was consistently present in GI+ patients, and half of patients presented with surgical abdomen and/or intestinal bleeding. GI+ compared to GI- patients had more frequent renal (75% vs 30%; p=0.003) and cardiac involvement (25% vs 2%; p=0.006), medium-vessel vasculitis (67% vs 22%; p=0.003) and higher mixed cryoglobulinaemia levels (2.2 g/l vs 1.2 g/l; p=0.07). After treatment, GI+ and GI- patients had similar rates of overall clinical response of the vasculitis and immunological and virological responses. HCV-MC vasculitis patients with GI involvement did not have poorer overall survival than those without. CONCLUSION: GI involvement is a rare manifestation of HCV-related vasculitis, associated with acute-onset and life-threatening manifestations. In contrast with primary vasculitides, GI+ patients do not seem to have poorer overall survival than GI- patients.

Clinical trials on systemic necrotizing vasculitides.

Treatments of systemic necrotizing vasculitides have progressed markedly over the past few decades. The first attempts to obtain better-adapted therapeutic strategies evaluated the indications of conventional drugs, and their abilities to prolong survival and prevent relapses, while decreasing the severity and number of side effects. Most of the prospective clinical trials were organized by the French Vasculitis Study Group and the European Vasculitis Study Group, and have contributed to optimizing targeted treatment strategies. Recent therapeutic strategies include immunomodulating methods, like plasma exchanges, or products, like intravenous immunoglobulins, or, more recently, new agents called biotherapies. Some of the latter have achieved promising effects, for example, anti-tumor necrosis factor-alpha and anti-CD20 monoclonal antibodies, and are now being evaluated in prospective trials.

Rituximab may form a complex with IgMkappa mixed cryoglobulin and induce severe systemic reactions in patients with hepatitis C virus-induced vasculitis.

OBJECTIVE: To report on 6 cases of hepatitis C virus (HCV)-induced mixed cryoglobulinemia (MC) vasculitis in patients who developed severe systemic reactions after rituximab infusion, and to report the results of the in vitro analysis of the underlying immunologic mechanisms. METHODS: Twenty-two HCV-infected patients with MC vasculitis received rituximab infusions (a low-dose protocol cycle with 375 mg/m2/week for 4 consecutive weeks in 18 patients and a high-dose protocol cycle with 1,000 mg on days 1 and 15 in 4 patients). Systemic drug reactions following rituximab infusion were recorded and analyzed clinically and immunochemically. RESULTS: Six of 22 patients (27.3%) experienced systemic drug reactions after rituximab infusion. Four patients developed a severe flare of MC vasculitis 1 or 2 days after rituximab infusion. Two patients developed serum sickness syndrome 7 and 9 days after the first 1,000 mg rituximab infusion. Compared with patients without drug reactions, those with drug reactions had higher mixed cryoglobulin levels (mean+/-SD 1.4+/-0.82 gm/liter versus 0.71+/-0.77 gm/liter; P=0.0475) and lower C4 levels (mean+/-SD 0.02+/-0.006 gm/liter versus 0.07+/-0.07 gm/liter; P=0.02), and more of them received 1,000 mg high-dose rituximab protocol (50% versus 6.25%; P=0.046). In vitro immunochemical assays showed that rituximab formed a complex with the cryoprecipitating IgMkappa that had rheumatoid factor (RF) activity. Moreover, the in vitro addition of rituximab to serum containing an RF-positive IgMkappa type II mixed cryoglobulin was associated with visibly accelerated cryoprecipitation. CONCLUSION: In HCV-associated MC vasculitis, rituximab may form a complex with RF-positive IgMkappa, leading to accelerated cryoprecipitation and to severe systemic reactions. Rituximab should be administered with caution in MC vasculitis, with use of the 375 mg protocol and plasma exchanges prior to rituximab infusion in patients with high baseline levels of mixed cryoglobulin.