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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Objective

To perform a randomized controlled trial of rituximab in patients with hepatitis C virus (HCV)–associated mixed cryoglobulinemic vasculitis.

Methods

We conducted a single-center, open-label, randomized controlled trial of rituximab (375 mg/ m2/week for 4 weeks) compared to the best available therapy (maintenance or increase in immunosuppressive therapy) for HCV-associated cryoglobulinemic vasculitis in patients in whom antiviral therapy had failed to induce remission. The primary end point was disease remission at 6 months from study entry.

Results

A total of 24 patients were enrolled (12 in each treatment group). Baseline disease activity and organ involvement were similar in the two groups. Ten patients in the rituximab group (83%) were in remission at study month 6, as compared with 1 patient in the control group (8%), a result that met the criterion for stopping the study (P < 0.001). The median duration of remission for rituximab-treated patients who reached the primary end point was 7 months. No adverse effects of rituximab on HCV plasma viremia or on hepatic transaminase levels were observed.

Conclusion

Rituximab was a well-tolerated and effective treatment in patients with HCV-associated cryoglobulinemic vasculitis in whom antiviral therapy failed to induce remission.

Chronic infection with hepatitis C virus (HCV) is a worldwide health problem, affecting an estimated 130 million people (1). As many as 20% of individuals with chronic HCV infection will develop potentially fatal complications, such as cirrhosis, liver failure, or hepatocellular carcinoma. Extrahepatic manifestations of HCV infection are also common, occurring in up to 40% of patients, and contributing to the morbidity and mortality associated with this chronic infection (2). One such extrahepatic manifestation is a form of small-vessel vasculitis associated with mixed cryoglobulinemia. HCV-associated cryoglobulinemic vasculitis is an uncommon complication of chronic HCV infection, characterized by the clonal expansion of B cells that produce IgM rheumatoid factor (RF) (3, 4). The RF produced by the expanded population of B cells plays a central role in the development of vasculitis by promoting the formation of immune complexes, consisting of RF, HCV, and polyclonal HCV-specific IgG. This cryoglobulin complex is deposited in blood vessel walls or in glomerular capillaries, triggering an inflammatory cascade that results in the syndrome of cryoglobulinemic vasculitis (5). A spectrum of disease manifestations and severity can occur in HCV-associated cryoglobulinemic vasculitis, with the primary clinical features being cutaneous vasculitis, arthralgia/arthritis, peripheral neuropathy, and membranoproliferative glomerulonephritis (6).

This lymphoproliferative disorder is driven by chronic HCV infection. Antiviral therapy with PEGylated interferon-α and ribavirin results in sustained remission of cryoglobulinemic vasculitis in nearly all cases in which a sustained virologic response is achieved (7). However, the effectiveness of current antiviral therapy is limited by toxicity and the failure to achieve a sustained virologic response in more than 50% of patients infected with HCV genotype 1, the most prevalent genotype in the Americas and Europe (8). For patients who do not respond to antiviral therapy, conventional immunosuppressive therapy with glucocorticoids or cytotoxic agents is ineffective at producing sustained remissions in the vast majority of cases (9–11). In addition, immunosuppressive therapy may accelerate progression of the underlying HCV liver disease. Thus, there is an important unmet need for safer and more effective treatment for patients with HCV-associated cryoglobulinemic vasculitis who do not respond to antiviral therapy.

Rituximab is a chimeric monoclonal antibody directed against CD20, which results in rapid depletion of circulating and tissue B cells. Based on this mechanism of action, rituximab has the potential to deplete the expanded population of B cells that develop in HCV-associated vasculitis, thereby reducing the production of pathogenic RF and the formation of cryoglobulin immune complexes. A number of published cases and cohort studies not using controls have reported encouraging results with the use of rituximab in patients with mixed cryoglobulinemic vasculitis (12–17). However, these reports included some patients with non–HCV-associated cryoglobulinemic vasculitis and used varying dosing regimens, often in combination with other immunosuppressive or antiviral agents. In addition, concern has been raised that treatment with rituximab may increase the replication of HCV (12). To address these issues, we conducted a prospective randomized controlled trial to examine the safety and efficacy of rituximab for the treatment of patients with HCV-associated cryoglobulinemic vasculitis in whom prior antiviral therapy failed to induce disease remission.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Study design and patient population.

The study was an open-label, randomized controlled trial conducted at a single center that involved 24 patients who were treated at the National Institutes of Health Clinical Center in Bethesda, MD. Inclusion in the study required the presence of active manifestations of HCV-associated cryoglobulinemic vasculitis, as evidenced by one or more of the following: cutaneous vasculitis, peripheral neuropathy, or glomerulonephritis. Only patients in whom treatment with interferon-α and ribavirin failed to induce a response or who could not tolerate this therapy were eligible for the study. Exclusion criteria included change in immunosuppressive therapy within 4 weeks of study entry, prior use of rituximab, diagnosis of lymphoma, severe renal insufficiency (creatinine clearance <30 ml/minute), severe hepatic insufficiency (Childs-Pugh class B or C), coinfection with human immunodeficiency virus or hepatitis B virus, liver transplantation, pregnancy, active systemic infection, or presence of potentially life-threatening vasculitis involving the central nervous system, heart, or gastrointestinal tract.

A total of 47 patients were screened for randomization into this study. Eighteen patients did not meet one or more of the above eligibility criteria. Three eligible patients elected not to enroll in the study because of concerns about potential rituximab toxicity. One patient experienced a myocardial infarction prior to randomization and was lost to followup; one additional patient did not return for randomization and was lost to followup. The remaining 24 patients were enrolled in the study and underwent randomization.

Patients were randomly assigned in a 1:1 ratio to receive investigational therapy (rituximab) or to continue to receive the best available therapy (control group). The NIH Clinical Center Pharmacy performed the randomizations.

The trial was sponsored by the National Institute of Allergy and Infectious Disease (NIAID) and approved by the Institutional Review Board of the NIAID. All patients provided written informed consent. The Regulatory Compliance and Human Subjects Protection Branch, Division of Clinical Research, NIAID monitored the study. The study drug (rituximab) was purchased by the NIH Clinical Center Pharmacy on the open market.

Treatment protocol.

Patients randomized to the investigational therapy group received rituximab at a dosage of 375 mg/m2 on days 1, 8, 15, and 22 beginning at the time of randomization (day 0). Patients were allowed to continue any immunosuppressive medications they were receiving at randomization, but could not increase the dosages of these medications or institute new immunosuppressive agents or plasma exchange therapy. All patients were premedicated with acetaminophen (650 mg) and diphenhydramine (50 mg) prior to each rituximab infusion. Premedication with glucocorticoids was not given to any patient.

Patients in the control group continued to take any immunosuppressive agents they had been receiving at the time of enrollment and were allowed to increase or initiate new immunosuppressive agents as needed to manage worsening disease activity. After study month 6, patients randomized to the control group were offered treatment with rituximab if they continued to have active manifestations of vasculitis.

Assessments and end points.

Following an initial screening visit to determine eligibility, patients returned to the NIH Clinical Center for randomization and then monthly thereafter for 12 months. Patients randomized to the rituximab group were also seen weekly during the first month at the time of rituximab administration. All patients underwent comprehensive clinical and laboratory evaluations at each monthly study visit. Laboratory evaluations included routine blood chemistries, urinalysis, complete blood cell counts, cryoglobulin levels, peripheral blood flow cytometry, and HCV plasma RNA levels.

Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0, indicating no new or worsened disease activity or no persistently active disease manifestations within the previous month (18, 19). Relapse was defined as the recurrence of disease activity after a period of remission, as indicated by a BVAS score >0. The primary end point of the study was remission at study month 6. Patients who withdrew from the study prior to month 6 were considered to have active disease regardless of their clinical status at the time of withdrawal. Secondary end points were the duration of remission and the occurrence of severe adverse events.

Serial HCV RNA levels in plasma were measured with the Versant HCV RNA 3.0 Assay (Bayer Diagnostics).

Statistical analysis.

Sample size estimation was based on the primary end point (i.e., remission at 6 months from study entry). The only previous standardized therapeutic study indicated a remission rate of <5% at 6 months while receiving either no treatment or treatment with glucocorticoids (11). Assuming a remission rate of 5% in the control group and 50% in the rituximab group, a sample size of 15 patients per group was needed to attain 90% power at nominal level of 2-sided alpha of 0.05. In September of 2010, an interim analysis was requested by the NIAID Institutional Review Board. Because there was no prespecified interim analysis plan for this study, a conservative efficacy boundary requiring strong evidence for early stopping was used. A modified Haybittle-Peto (20) analysis was carried out in which the declaration of efficacy at an interim analysis required the 2-tailed P value to be 0.001 or less. This interim analysis, which was done with 12 subjects in each group, showed a higher than anticipated remission rate with rituximab therapy and indicated efficacy of rituximab at P < 0.001. The study was thus stopped with 12 patients per group because of early evidence of benefit according to the modified rule of Haybittle-Peto (20).

Analyses were performed on an intent-to-treat basis except where indicated otherwise. As the primary analysis, we reported the remission rate at month 6 in each group and compared the data by Fisher's exact test. Among those attaining remission while receiving rituximab therapy, the duration of remission was summarized with Kaplan-Meier survival curves. Box plots were provided for the distribution of the BVAS and cryoglobulin levels, and data between the two groups were compared by Wilcoxon's rank sum test. Median plasma HCV levels and mean peripheral blood B cell counts with 95% confidence intervals (95% CIs) from lognormal distribution were plotted to depict the respective time trends.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Features of the study patients.

Between June 2002 and April 2010, a total of 24 patients were enrolled in the study. Twelve patients were randomized to the rituximab group and 12 patients to the control group. Nine of the patients in the rituximab group and 10 of the patients in the control group were infected with HCV genotype 1. The remaining patients in both groups were infected with HCV genotype 2. One patient in the rituximab group and 2 in the control group had not been able to complete a full course of antiviral therapy because of toxicity. In the remaining patients, antiviral therapy had failed to induce a sustained virologic response. The baseline characteristics of the study patients are listed in Table 1. The two groups were balanced with respect to clinical manifestations, disease activity, laboratory values, and exposure to glucocorticoids and other immunosuppressive agents (Table 1). All 12 patients in the rituximab group and 11 patients in the control group had involvement of >1 organ system at study entry.

Table 1. Baseline clinical and demographic characteristics of the study patients, by treatment group*
VariableRituximab group (n = 12)Control group (n = 12)
  • *

    HCV = hepatitis C virus; BVAS = Birmingham Vasculitis Activity Score.

  • Normal <3%; all patients had mixed cryoglobulins by immunofixation electrophoresis, with monoclonal IgMκ and polyclonal IgG.

  • Normal range 55–145 complement activity enzyme (CAE) units.

Age, median years5351
% male8367
Cryoglobulin level, % cryoprecipitate  
 Median5.56
 Interquartile range3–153–19
Total complement, CAE units  
 Median933
 Interquartile range9–5515–89
Median HCV level, log10 copies/ml6.045.50
 Genotype 1910
 Genotype 232
BVAS  
 Median88.5
 Interquartile range3–184–14
Clinical manifestations, no. (%) of patients  
 Arthritis/arthralgias7 (58)6 (50)
 Cutaneous vasculitis  
  Purpura12 (100)11 (92)
  Ulcers4 (33)2 (17)
 Peripheral neuropathy  
  Sensory polyneuropathy7 (58)3 (25)
  Mononeuritis2 (17)0
 Glomerulonephritis4 (33)4 (33)
Glucocorticoid therapy, no. (%) of patients  
 Past therapy10 (83)7 (58)
 At study entry6 (50)3 (25)
  Mean daily dose, mg of prednisone2610
Other therapy, no. (%) of patients  
 Cyclophosphamide2 (16)1 (8)
  Past therapy1 (8)1 (8)
  At study entry1 (8)0
 Plasma exchange2 (16)3 (25)
  Past therapy2 (16)3 (25)
  At study entry2 (16)0
 Methotrexate1 (8)1 (8)
  Past therapy1 (8)1 (8)
  At study entry00

Efficacy assessments.

Primary end point.

The primary end point of the study was the number of patients whose disease was in remission at study month 6. Ten of the 12 patients in the rituximab group (83.3% [95% CI 51.6–97.9]) reached the primary end point, as compared with 1 of the 12 patients in the control group (8.3% [95% CI 2.0–38.6]), indicating significantly higher remission with rituximab treatment (P < 0.001). Disease was not in remission at month 6 in 2 patients in the rituximab group. One patient had to discontinue rituximab after 2 infusions because of a severe febrile infusion reaction and withdrew from the study at month 5. The second patient achieved remission at study month 4, but subsequently experienced a relapse of cutaneous vasculitis at study month 6.

Disease activity, relapse, and laboratory data.

At baseline, BVAS scores were comparable between the 2 groups (P = 0.977), but became significantly lower in the rituximab group starting at month 4 with P values less than 0.02 (Figure 1A). The duration of remission for all patients in the rituximab group is illustrated in Figure 1B. Of the 10 rituximab-treated patients whose disease was in remission at 6 months, 6 remained in remission until the end of study participation. Three patients experienced a relapse after month 6, and 1 patient was lost to followup while in remission at study month 7. The median duration of remission for the 10 patients who met the primary end point was 7 months (interquartile range [IQR] 4.5–10). The 3 patients who experienced relapse after month 6 were treated with a second course of rituximab in an extension phase of the study. Remission was achieved in all 3 patients, and the disease remained in remission for more than 6 months following the second rituximab treatment.

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Figure 1. Birmingham Vasculitis Activity Score (BVAS) scores and duration of remission in patients with hepatitis C virus–associated mixed cryoglobulinemic vasculitis randomized to receive rituximab or control therapy (maintenance or increase in immunosuppressive therapy) (n = 12 per group). A, BVAS scores in the two treatment groups during the 6-month study period. Data are shown as box plots. The horizontal line within each box indicates the median, the bottom and top lines of the box indicate the 25th and 75th quartiles, respectively, the whiskers show the maximum and minimum values within 1.5 interquartile ranges from the 25th and 75th quartiles, respectively, and the circles represent values outside the range and are considered outliers. B, Kaplan-Meier curve for the duration of remission among patients in whom remission was achieved with rituximab therapy. Solid line indicates the percentage of patients whose disease remained in remission; broken lines indicate the 95% confidence intervals. Only a single patient in the control group achieved remission (data not plotted).

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No patient in the rituximab group needed a dosage increase or initiation of immunosuppressive therapy following study entry. Of the 6 patients in the rituximab group who were receiving prednisone at study entry, the dosage was tapered and discontinued in 5 patients during the study; 1 patient who had been receiving long-term therapy with glucocorticoids continued to take 5 mg of prednisone per day because of concerns about secondary adrenal insufficiency. Two patients in the rituximab group were being treated with plasma exchange at study entry but discontinued this treatment by study month 2. No patient in the control group discontinued prednisone treatment. One patient in the control group initiated plasma exchange at study month 5 because of worsening cutaneous vasculitis. This treatment did not result in disease remission.

Peripheral blood B cell depletion (defined as <0.5% CD19+ cells) occurred in the 11 rituximab-treated patients who received all 4 infusions. Return of B cells in the peripheral blood was detected between months 4 and 6 in most patients, with pretreatment levels being reached by months 8–12. The 3 patients who received a second course of rituximab showed similar depletion and recovery kinetics following the second treatment (data not shown). Cryoglobulin levels were similar at baseline between the 2 groups (P = 0.684), but became significantly lower in the rituximab group starting at month 2 (with P values less than 0.05) (Figure 2). Return of cryoglobulin levels did not correlate with relapses. All 3 patients in the rituximab group who experienced a relapse after month 6 had a return of cryoglobulin levels prior to the relapse, as did 4 of the 6 patients whose disease remained in remission. Total complement levels increased in the rituximab group over the course of treatment, from a median of 9 CAE units (IQR 9–55) pretreatment, to a median of 74 CAE units (IQR 36–129) at month 6. In contrast, total complement levels in the control group remained depressed (median month 6 value 15 CAE units [IQR 9–56]). The 3 patients in the rituximab group who experienced relapse after month 6 had a fall in complement levels prior to relapse, as did 1 of the 6 patients whose disease remained in remission.

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Figure 2. Cryoglobulin levels in patients with hepatitis C virus–associated mixed cryoglobulinemic vasculitis randomized to receive rituximab or control therapy (maintenance or increase in immunosuppressive therapy) (n = 12 per group). Cryoglobulin levels are expressed as a percentage of cryoprecipitate during the 6-month study period (normal <3%). Data are shown as box plots. The horizontal line within each box indicates the median, the bottom and top lines of the box indicate the 25th and 75th quartiles, respectively, the whiskers show the maximum and minimum values within 1.5 interquartile ranges from the 25th and 75th quartiles, respectively, and the circles represent values outside the range and are considered outliers.

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Rituximab treatment did not appear to affect HCV replication as measured by plasma HCV RNA levels. The median plasma HCV RNA level was higher at baseline in the rituximab group, but the difference did not reach statistical significance (Table 1). No statistically significant difference was observed in the change from baseline in the plasma HCV RNA levels between the rituximab group and the control group over the followup evaluations (Figure 3).

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Figure 3. Median change from baseline in plasma levels of hepatitis C virus (HCV) in patients with HCV-associated mixed cryoglobulinemic vasculitis randomized to receive rituximab or control therapy (maintenance or increase in immunosuppressive therapy) (n = 12 per group). Only data through month 6 are shown for the control group, since 9 of these patients subsequently received rituximab after month 6 during the extension phase of the study.

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Adverse events.

Table 2 summarizes selected adverse events seen during the first 6 months of the study. Only 1 patient experienced a severe adverse event related to the rituximab infusion; this was a grade 4 fever. This patient developed rigors, followed by a fever to 40.5°C, during his third rituximab infusion. The infusion was stopped and ibuprofen administered. The fever and rigors resolved within 1 hour. No patient in either group developed serious infection or required hospitalization for treatment of infection during the first 6 months of the study. One patient in the rituximab group developed probable viral bronchitis that resolved without antimicrobial therapy; 2 patients in the control group developed what was presumed to be bacterial sinusitis and were treated with oral antibiotics. Elevations in hepatic transaminase levels were generally mild, consistent with the underlying HCV infection, and were similar in the two study groups. No patient in either group developed clinical or laboratory evidence of worsening hepatic function.

Table 2. Selected adverse events at 6 months*
Specific adverse eventsRituximab group (n = 12)Control group (n = 12)
  • *

    Adverse events were categorized according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004; Clarification August 2009 (online at http://rsc.tech-res.com). AST = aspartate aminotransferase.

Leukopenia grade ≥212
Thrombocytopenia11
AST grade ≥243
Total bilirubin grade ≥200
Infection  
 Grade ≥212
 Grade ≥300
Infusion reaction grade ≥21

No patient in the rituximab group developed hypogammaglobulinemia during the study. Two patients in the rituximab group had significant hypogammaglobulinemia (IgG <200 mg/dl) at study entry that was thought to be secondary to nephrotic syndrome. Both patients experienced a >2-fold increase in serum IgG levels following rituximab treatment.

Of the 4 patients with glomerulonephritis in the control group, all experienced a decline in the estimated glomerular filtration rate (GFR) over the 6-month study period. In contrast, all 4 patients in the rituximab group either maintained stable renal function or had improvement in the estimated GFR.

Nine patients randomized to the control group elected to receive rituximab treatment after month 6 during the extension phase of the study. Two of these patients withdrew from the study after completing their course of infusions and were lost to followup. Of the remaining 7 patients, 4 achieved remission following rituximab treatment. The median duration of remission in these 4 patients was 6 months (IQR 5–9).

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Rituximab has been considered as a possible therapy for HCV-associated cryoglobulinemic vasculitis, based on retrospective, uncontrolled studies of cohorts that included some patients with non–HCV-associated cryoglobulinemic vasculitis. In contrast to previous reports, our study was a prospective randomized controlled trial that enrolled only patients with HCV-associated cryoglobulinemic vasculitis in whom antiviral therapy had failed. Furthermore, standard forms of immunosuppressive therapy had also failed to induce remission in 75% of the patients in our study. Thus, patients in this trial were highly representative of the patients with HCV-associated cryoglobulinemic vasculitis for whom effective therapy is lacking.

The trial was originally designed to enroll 30 patients but was halted at a total enrollment of 24 patients when an interim analysis revealed that there was sufficient difference between groups to warrant stopping the trial. Eighty-three percent of patients randomized to receive rituximab met the primary end point of remission at study month 6, as compared to 8% of patients in the control group. The median duration of remission in the 10 rituximab-treated patients who reached the primary end point was 7 months. The 3 patients who experienced relapse after month 6 were given a second course of rituximab, which led to sustained remission that lasted more than 6 months in all 3 of them. These data indicate that therapy with rituximab is able to induce remission in a high percentage of patients and that remission can be sustained beyond 6 months despite the presence of continuing HCV infection.

The current investigation was based upon the hypothesis that rituximab-induced depletion of the expanded population of autoreactive B cells would decrease pathogenic cryoglobulin formation and result in clinical improvement in the vasculitis. Depletion of peripheral blood B cells was observed in all patients who received 4 infusions of rituximab. B cell depletion was associated with a decrease in cryoglobulin levels and improvement in vasculitis activity. A return of B cells to pretreatment levels occurred within 6–8 months, but this did not correlate with a relapse of disease activity. Although in most patients, the disease remained in remission for months after the return of peripheral B cells, the persistence of low-level cryoglobulinemia and ongoing HCV infection suggest that rituximab treatment did not eradicate the pathogenic B cell population, and these patients remain at risk for future relapse.

Immunosuppression is known to increase viremia due to HCV and accelerate the progression of chronic HCV-related liver disease (21–23), and a previous uncontrolled study suggested that rituximab treatment was associated with a similar risk (12). In our controlled trial, we found no evidence of worsening of the HCV infection. No significant change in plasma viral levels over time was detected in the rituximab group as compared with the control group, and there was no biochemical evidence of worsening hepatitis. Rituximab treatment was well tolerated, the frequency of adverse events was not significantly different from that in the control group, and no serious infections were seen.

A significant strength of this study is that the primary outcome measure of remission was determined prior to study initiation and was based upon the BVAS, a validated instrument previously used to assess vasculitis disease activity (18, 19). In addition, patients in this trial received standardized clinical and laboratory evaluations each month, which allowed for accurate determination of time to remission, time to relapse, and potential adverse effects of rituximab on the underlying HCV infection.

This trial does have limitations that must be weighed. Accrual into the study was slow for several reasons, including the low incidence of HCV-associated vasculitis in the US (24), the restriction of enrollment to patients in whom antiviral therapy had failed, and the availability of rituximab for off-label use in the US. However, the slow accrual rate should not have had a major effect on study outcomes, since no new treatments for either HCV infection or HCV-associated vasculitis became available during the period in which the study was conducted. Although the study was randomized, it was not blinded. This design was chosen because the study end points were all based on objective measures of improvement in manifestations of vasculitis. Although BVAS has potential limitations with assignment of disease activity to subjective symptoms, particularly in open-label studies, it remains the most recognized validated instrument for standardized assessment of disease activity in vasculitis clinical trials. The sample size of the study was small, due to the efficacy of rituximab as well as the lack of efficacy of standard forms of immunosuppressive therapy in this patient population. No patients with immediately life-threatening manifestations of vasculitis involving the central nervous system, heart, or gastrointestinal tract were enrolled in our trial. Hence, the results of this trial may not be applicable to patients with these rare manifestations of HCV-associated cryoglobulinemic vasculitis. However, patients in our study did have significant disease activity as evidenced by the distribution of organ involvement and the BVAS scores. Finally, our study was limited to patients with HCV-associated cryoglobulinemic vasculitis, and the results cannot be extrapolated to patients with cryoglobulin disease not associated with chronic HCV infection.

It is important to emphasize that the first-line treatment for HCV-associated vasculitis should be antiviral therapy. Our study enrolled only patients in whom antiviral therapy had failed to induce remission, either because of a lack of sustained virologic response or regimen-related toxicity. Limiting our study to such patients made it possible to assess the efficacy, toxicity, and effect of rituximab on the underlying HCV infection without the confounders of concomitant antiviral therapy. Recent studies suggest that combining rituximab with interferon-based antiviral therapy results in improved response rates compared to antiviral therapy alone (17, 25), a hypothesis which cannot be directly addressed by our trial.

In conclusion, our data suggest that rituximab can induce sustained remissions in patients with HCV-associated cryoglobulinemic vasculitis following failure of antiviral therapy. Rituximab treatment was well tolerated and did not appear to increase HCV replication or to worsen the underlying hepatitis.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Sneller had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Sneller, Langford.

Acquisition of data. Sneller, Langford.

Analysis and interpretation of data. Sneller, Hu, Langford.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

We thank William Sachau, Rose McConnell, and Laura Heytens for coordinating the patient recruitment and study visits, Richard Kwan for coordinating the medical care of the patients, the staff and patients of Outpatient Clinic 8 at the NIH Clinical Center, and Dr. Anthony S. Fauci for his work in establishing the Vasculitis Research Program at the National Institute of Allergy and Infectious Diseases.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES