title: Granulocytopenia after combined therapy with interferon and angiotensin-converting enzyme inhibitors: evidence for a synergistic hematologic toxicity.
abstract: OBJECTIVE
  The purpose of this study was to assess whether granulocytopenia observed in 3 of 38 patients with essential mixed cryoglobulinemia who were treated with low-dose interferon was due to the underlying disease or to synergistic toxicity of interferon with other drugs.
  
  
  METHODS
  Adverse effects of interferon therapy were monitored in 38 patients affected with type II essential mixed cryoglobulinemia. Patients were treated with 3 million units (MU), daily or on alternate days, of recombinant interferon-alpha 2a (35 patients) or with natural interferon-beta (3 patients). The duration of treatment ranged between 6 and 15 months; the total duration of follow-up, including after therapy, ranged between 8 and 93 months.
  
  
  RESULTS
  None of 35 patients treated with interferon alone developed significant hematologic alterations. In addition, none of 7 patients treated with angiotensin-converting enzyme (ACE) inhibitors alone showed hematologic toxicity. Three patients who were treated with a combination of interferon and ACE inhibitors developed severe granulocytopenia a few days after starting treatment. Granulocytopenia subsided within 1 to 2 weeks after suspending therapy. Resumption of treatment with this drug combination produced a granulocytopenia relapse in 1 patient. In these 3 patients, interferon treatment alone, or ACE inhibitor monotherapy, was not followed by granulocytopenia.
  
  
  CONCLUSIONS
  Although severe hematologic toxicity rarely develops in patients treated with low-dose interferon, granulocytopenia occurred in all 3 of our patients with mixed cryoglobulinemia who were treated with a combination of low-dose interferon-alpha 2a and ACE inhibitors. Neither drug alone was toxic in any of our cryoglobulinemic patients, indicating a high risk of severe hematologic toxicity for this drug combination, at least in patients with this disease. Physicians should be aware of this danger when using interferon treatment in patients with this, or possibly other, disorder(s) that also require antihypertensive therapy.
authors.affiliation: Department of Clinical Medicine, University of Rome La Sapienza, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Casato
authors.forename: L P
authors.initials: LP
authors.lastname: Pucillo
authors.forename: M
authors.initials: M
authors.lastname: Leoni
authors.forename: L
authors.initials: L
authors.lastname: di Lullo
authors.forename: A
authors.initials: A
authors.lastname: Gabrielli
authors.forename: D
authors.initials: D
authors.lastname: Sansonno
authors.forename: F
authors.initials: F
authors.lastname: Dammacco
authors.forename: G
authors.initials: G
authors.lastname: Danieli
authors.forename: L
authors.initials: L
authors.lastname: Bonomo
mesh_terms: D000328:Adult; D000368:Aged; D000380:Agranulocytosis / Q000139:chemically induced*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D003449:Cryoglobulinemia / Q000188:drug therapy* / Q000821:virology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D011994:Recombinant Proteins
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins