The purpose of this study is to assess the efficacy of Rituximab (anti-CD20) in the treatment of patients with hepatitis C associated cryoglobulinemic vasculitis (HCV-CV) who have failed or are intolerant to interferon-alpha/ribavirin therapy. Up to 75 patients may be screened to enroll 34 adult patients with active HCV-CV in this randomized, non-blinded phase I/II trial. Patients will be randomized to receive either Rituximab 375 mg/M(2) on days 1, 8, 15 and 22 beginning at the time of enrollment or standard therapy. Patients in both groups will be maintained on stable doses of any immunosuppressive therapies that they were receiving at the time of enrollment. Response to Rituximab will be assessed by clinical and laboratory parameters.

Although the cause of cryoglobulinemic vasculitis is not known, a critical component is the presence of cryoglobulins-abnormal proteins that white blood cells called B lymphocytes produce in response to the chronic hepatitis C infection. Rituximab decreases the number of B cells. The Food and Drug Administration approved Rituximab in 1997 for the treatment of B-cell non-Hodgkin's lymphoma.

Patients between 18 and 75 years of age with hepatitis C and signs and symptoms of cryoglobulinemic vasculitis may be eligible for this study. They must have failed, or been unable to tolerate, treatment with IFN-a and ribavirin. Candidates will be screened with a history and physical examination, electrocardiogram (ECG), blood and urine tests, 24-hour urine collection and chest X-ray, if clinically indicated.

Participants will be randomly assigned to receive Rituximab upon entering the study or 6 months after entering the study. Those whose treatment is delayed 6 months will be followed once a month at NIH for disease evaluation and blood tests during that time.

Patients will be given Rituximab intravenously (through a vein) once a week for 4 weeks. For the first dose, patients will be admitted to the hospital for at least 24 hours after the infusion for monitoring. Subsequent infusions will be given on an inpatient or outpatient basis, depending on how the infusion is tolerated. The day before each infusion they will have a history and physical examination, blood work, and other tests, such as X-rays, as clinically indicated.

After the four infusions, patients will be followed for drug side effects and response to treatment. They will have blood tests every week for 4 weeks and will then return to NIH for 1 day every month for 12 months for a physical examination, blood tests, and X-rays, if medically indicated. Visits may be more frequent, if necessary, and patients may be asked to stay longer than a day if test findings requ...

Although the cause of cryoglobulinemic vasculitis is not known, a critical component is the presence of cryoglobulins-abnormal proteins that white blood cells called B lymphocytes produce in response to the chronic hepatitis C infection. Rituximab decreases the number of B cells. The Food and Drug Administration approved Rituximab in 1997 for the treatment of B-cell non-Hodgkin's lymphoma.

Patients between 18 and 75 years of age with hepatitis C and signs and symptoms of cryoglobulinemic vasculitis may be eligible for this study. They must have failed, or been unable to tolerate, treatment with IFN-a and ribavirin. Candidates will be screened with a history and physical examination, electrocardiogram (ECG), blood and urine tests, 24-hour urine collection and chest X-ray, if clinically indicated.

Participants will be randomly assigned to receive Rituximab or standard therapy for 6 months after entering the study. All patients will be followed once a month at NIH for disease evaluation and blood tests during that time.

Patients will be given Rituximab 375 mg/m2intravenously once a week for 4 weeks. The day before each infusion they will have a history and physical examination, blood work, and other tests, such as X-rays, as clinically indicated.

After the four infusions, patients will be followed for drug side effects and response to treatment. They will have blood tests every week for 4 weeks and will then return to NIH for 1 day every month for 12 months for a physical examination, blood tests, and X-rays, if medically indicated. Visits may be more frequent, if necessary.

• INCLUSION CRITERIA:

Diagnosis of HCV-CV: must have all of the following

HCV infection documented by serology and/or plasma HCV RNA.

One or more organ system with objective evidence of active vasculitis such as:

Palpable purpura;

Glomerulonephritis (defined by the presence of glomerular hematuria and/or new or worsening proteinuria);

Acute peripheral neuropathy.

Detectable cryoglobulins and/or RF.

Failure of treatment with IFN-alpha and ribavirin to control manifestations of HCV-CV OR intolerance to IFN-alpha/ribavirin regimen.

Patients must have a personal physician responsible for the care of their HCV.

Ages of 18 and 75 years

Willingness to use effective contraception during and for 12 months following Rituximab treatment. Effective contraception methods include abstinence, surgical sterilization of either partner, barrier methods such as diaphragm, condom, cap or sponge, or hormonal contraception.

EXCLUSION CRITERIA:

Recent (within 4 weeks) initiation of or increase in immunosuppressive therapy.

Active systemic infection (other than hepatitis C).

Pregnancy or breast feeding.

Prior treatment with Rituximab.

Known allergy to murine proteins.

Significant renal insufficiency (creatinine clearance less than 30 ml/min).

Presence of life-threatening HCV-CV; defined as rapidly progressive glomerulonephritis (defined as a doubling of the serum creatinine over a 3 month period), CNS vasculitis, cardiac disease due to active vasculitis, or GI vasculitis (defined by ischemic bowel, perforation, or infarction).

Significant hepatic insufficiency as manifested by Child-Pugh classification of B or C.

History of variceal bleeding, encephalopathy.

History of liver transplantation.

Co-infection with either HBV or HIV.

Any underlying medical condition that in the judgment of the investigator would put the patient at increased risk for serious infusion-related adverse events.

6 months

Only adverse events that were grade 3 or greater and were possibly or probably related to the study drug were collected and analyzed for the purposes of this study

The study was not blinded. In addition, the study was limited to patients who had failed antiviral therapy.