title: Cyclophosphamide: As bad as its reputation? Long-term single centre experience of cyclophosphamide side effects in the treatment of systemic autoimmune diseases.
abstract: OBJECTIVE
  Despite new treatment modalities, cyclophosphamide (CYC) remains a cornerstone in the treatment of organ or life-threatening vasculitides and connective tissue disorders. We aimed at analysing the short- and long-term side-effects of CYC treatment in patients with systemic autoimmune diseases.
  
  
  METHODS
  Chart review and phone interviews regarding side effects of CYC in patients with systemic autoimmune diseases treated between 1984 and 2011 in a single university centre. Adverse events were stratified according to the "Common Terminology Criteria for Adverse Events" version 4.
  
  
  RESULTS
  A total of 168 patients were included. Cumulative CYC dose was 7.45 g (range 0.5-205 g). Gastro-intestinal side effects were seen in 68 events, hair loss occurred in 38 events. A total of 58 infections were diagnosed in 44/168 patients (26.2%) with 9/44 suffering multiple infections. Severity grading of infections was low in 37/58 cases (63.8%). One CYC-related infection-induced death (0.6%) was registered. Amenorrhoea occurred in 7/92 females (7.6%) with 5/7 remaining irreversible. In females with reversible amenorrhoea, prophylaxis with nafarelin had been administered. Malignancy was registered in 19 patients after 4.7 years (median, range 0.25-22.25) presenting as 4 premalignancies and 18 malignancies, 3 patients suffered 2 premalignancies/malignancies each. Patients with malignancies were older with a higher cumulative CYC dose. Death was registered in 28 patients (16.6%) with 2/28 probably related to CYC.
  
  
  CONCLUSIONS
  Considering the organ or life-threatening conditions which indicate the use of CYC, severe drug-induced health problems were rare. Our data confirm the necessity to follow-up patients long-term for timely diagnosis of malignancies. CYC side-effects do not per se justify prescription of newer drugs or biologic agents in the treatment of autoimmune diseases.
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Dan
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Rahel
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Adler
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Frauke
authors.initials: F
authors.lastname: Förger
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Villiger
mesh_terms: D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D003520:Cyclophosphamide