Retinoids in ANCA Small Vessel Vasculitis: Silencing Autoantigens

Inclusion Criteria:

• Patients with ANCA disease and no more than mild activity as determined by a BVAS score of 1 to 4. These are patients who will have undergone induction with cyclophosphamide and corticosteroids in the past, and will be in partial remission on maintenance therapy with azathioprine or mycophenolate mofetil with or without small dose prednisone. We anticipated that most patients enrolled in the study will have low grade persistent ("grumbling") disease on stable immunosuppressants.
• Documented 6-fold or greater elevation in PR3 and/or MPO gene expression by the RT-PCR technique. We estimate that approximately 25% of patients with a BVAS <5 will have an elevation in PR3 and/or MPO gene expression based on our previous studies. 2 Patients must be on stable maintenance therapy with prednisone (<10 mg/day or equivalent), cyclosporine A, mycophenolate mofetil or azathioprine for at least 8 weeks.

Exclusion Criteria:

• Patients with severe, active vasculitis requiring institution or an increase in dose of corticosteroids, cyclophosphamide, azathioprine, mycophenolate mofetil or any new immunosuppressive medication within the previous 8 weeks or at the time of enrollment.
• Pregnancy, breastfeeding, or unwillingness to use at least two contraceptive methods (at least one of which must be primary, including tubal ligation, partner vasectomy, oral contraceptives, implanted contraceptives, and intrauterine device). The rationale is that retinoids are teratogenic and are excreted in breast milk. Contraceptive methods must be instituted at least 1 month before starting tretinoin and continued at least 1 month after stopping the medication.
• History of hepatitis, cirrhosis or abnormal liver tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), Alkaline phosphatase, Gamma-glutamyl transpeptidase (GGT), total bilirubin, or prothrombin time; unless the abnormality is due to a specific hepatotoxic medication, AND the liver test levels are l< 2 times the upper limit of the normal AND normalize upon holding the offending drug.
• Hypertriglyceridemia (>500 mg/dL) despite statin/fibrate therapy.
• Any medical conditions requiring concurrent use of tetracycline, minocycline, or doxycycline, due to enhanced risk of increased intracranial pressure.
• Any medical conditions requiring concurrent use of rifampin, phenobarbital, pentobarbital, ketoconazole, cimetidine, erythromycin, verapamil, diltiazem, vitamin A and antithrombotic agents (Tranexamic Acid, Aminocaproic Acid or Aprotinin)due to the potential for interactions with tretinoin therapy.
• Presence of unstable cardiovascular disease, uncontrolled diabetes with hemoglobin A1c > 8% g/dL, or chronic inflammatory or infectious conditions.
• Glomerular Filtration Rate (GFR) <25 ml/min/1.73m^2 as estimated by the MDRD equation, as the metabolites of retinoids are excreted in part in urine, and there is a concern for increased toxicity.
• Untreated depression, as retinoids have been associated with depression, suicidal ideation, and aggressive behavior.
• Neutropenia (neutrophil count < 1000 cell/mm^3).
• Known osteoporosis.