Rheumatoid Arthritis:Tolerance Induction by Mixed Chimerism
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Intervention: Hematopoietic Stem Cell Transplantation; Fludarabine; Cyclophosphamide; Campath 1H; GCSF; Cyclosporins; Mycophenolate Mofetil
Intervention description: Allogeneic Hematopoietic Stem Cell Transplantation; inhibits DNA synthesis or repair; Causes prevention of cell division by forming adducts with DNA; humanized monoclonal antibody against CD52 antigen; Hematopoietic growth factor; immune suppressive drug; immune suppressive drug
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Cyclophosphamide; Fludarabine; Alemtuzumab; Cyclosporins
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No

Summary:

      Rheumatoid arthritis disease is believed to be due to immune cells, cells that normally
      protect the body and are now causing damage to the body. Risk of death is highest in people
      with twenty or more joints actively involved with disease, positive rheumatoid factor, an
      elevated sedimentation rate (laboratory measures of active inflammation), and patients with
      limitation of daily activities (trouble doing simple things like opening a carton of milk).
      In these high risk patients, life is significantly shortened. Death is usually from heart
      disease, kidney failure, neck dislocation, broken hip bones, or blood clots to the lung. In
      this study we use moderate dose chemotherapy (cyclophosphamide and fludarabine) and
      CAMPATH-1H (a protein that kills the immune cells that are thought to be causing the
      disease), followed by infusion of blood stem cells that have been collected from the
      patient's brother or sister (allogeneic stem cell transplant). The purpose of the moderate
      dose chemotherapy and CAMPATH-1H is to destroy the cells in the immune system and to allow
      the cells from the patient's brother or sister to grow. The purpose of the stem cell infusion
      is to restore blood cell production, which will be severely impaired by the moderate dose
      chemotherapy and CAMPATH-1H, and to produce a normal immune system that will no longer attack
      the body.
    

Eligibility criteria:

        Participant Inclusion Criteria:

          -  Age > 18 and < 60 years at time of pre-transplant evaluation.

          -  An established clinical diagnosis of rheumatoid arthritis by American College of
             Rheumatology criteria.

          -  Patients must have failed an autologous hematopoietic transplant or have failed to
             respond to either methotrexate or leflunomide in combination with a TNF inhibitor.
             Failure is defined as an inability to tolerate treatment with at least 6 swollen
             joints and 20 involved joints or inability to answer at least 70% of HAQ questions
             with "no difficulty" despite 2 or more months of treatment.

               -  Ability to give informed consent.

               -  Patient must have a HLA matched sibling donor at the A, B, C, and DR loci to
                  proceed or HLA matched cord blood donor.

               -  If donor is HLA matched cord blood, cord blood stem cells will be obtained from
                  the NMDP (1-800-548-1375) and one or two units of HLA matched cord blood will be
                  infused on day zero.

        Participant Exclusion Criteria

          -  History of coronary artery disease, or documented congestive heart failure.

          -  HIV positive.

          -  Uncontrolled diabetes mellitus, or any other illness that in the opinion of the
             investigators would jeopardize the ability of the patient to tolerate aggressive
             chemoradiotherapy.

          -  Prior history of malignancy except localized basal cell or squamous skin cancer. Other
             malignancies for which the patient is judged to be cured by local surgical therapy,
             such as head and neck cancer, or stage I breast cancer will be considered on an
             individual basis.

          -  Positive pregnancy test, inability or unwillingness to pursue effective means of birth
             control, failure to willingly accept or comprehend irreversible sterility as a side
             effect of therapy.

          -  Psychiatric illness or mental deficiency making compliance with treatment or informed
             consent impossible.

          -  FEV1/FVC < 70% of predicted, DLCO < 40% of predicted.

          -  Resting LVEF < 45 %.

          -  Bilirubin > 2.0 mg/dl (unless due to Gilberts), transferase (AST) > 2.5 x upper limit
             of normal.

          -  Serum creatinine > 2.0 mg/dl.

        Donor Exclusion Criteria

          -  Age < 18 years.

          -  Positive for HIV-1, HIV-2, HTLV-I, HTLV-II.

          -  Active hepatitis B or C.

          -  History of a malignancy except for a localized cancer such as skin cancer that is
             deemed cured.

          -  History of myocardial infarction or congestive heart failure.

          -  Inability to give informed consent.

          -  Current pregnancy.