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Keywords:

  • C1-INH;
  • C3;
  • C4;
  • danazole;
  • hereditary angioedema

Patients with hereditary angioedema are rare in clinical practice and thus therapeutical experience is rather based on individual cases. A 46-year old man was first diagnosed to have hereditary angioedema type-1 (HAE-1) on the basis of clinical history and serological findings in March 2002. He presented in casualty with a recent onset of spontaneously evolving, angioedema at various sites, triggered sometimes by manual labor such as gardening work. Complement C4 and C1-esterase inhibitor (C1-INH) levels were found to be far below the normal baseline. A functional assay of C1-INH came back as normal and thus the diagnosis HAE-1 was confirmed.

As attack frequency was high, continuous therapy was needed. In absence of any contraindications, and facing a male patient, we decided to start danazole 200 mg/day according to the Budapest protocol, as the second drug of choice Tranexamic acid is regarded as less effective and the patient was worried about the particular side effects (1). As expected, the attacks ceased within a few days. The dosage was reduced step-by step over time as shown in Fig. 1A, based on absence of clinical symptoms. The patient's compliance was high, follow-up was every 3–4 months until today. Monitoring included routine biochemistry, yearly abdominal ultrasound, full blood count and control of serum levels for C3, C4 and C1-INH. Up to today no side effects of danazole became evident. In April 2004, the patient ran out of medication for 2 weeks and suddenly HAE attacks relapsed, but stopped again within 2 weeks of restarting danazole 50 mg/day. In January 2005 the minimum maintenance dose of 50 mg/d 5 days a week was reached (1). As evident from our time course analysis of serum C3, C4 and C1-INH levels shown in Fig. 1B there was no evident correlation between the values of these three parameters and the clinical success of therapy in our patient. The serum C4 gradually went back to normal, C3 was always normal and C1-INH stayed below the normal range for the whole monitored time of 3 years. This observation is in accordance with the small study (n = 8) by Zimmermann (2), who found similar long-term patterns for C4 and C1-INH. Gelfand described in the first danazole study in 1976 an initial increase of C1-INH and C4 within the first days of starting the drug, but did not perform a long-term survey (3). The mechanism of action for the attenuated steroid danazole is not known but it seems to depend on its 17α alkylation (4). In summary neither of the three monitored values could be regarded as valuable for clinical decisions about dosage reduction of danazole in our patient, these relied purely on the clinical history obtained at each follow-up visit. Long-term low dose danazole therapy, as expected (3), proved to be very effective for disease control and a maintenance dose of 50 mg 5×/week was enough to suppress the HAE attacks completely. For dosage determination there is still no biochemical marker available, as the diagnostically relevant C3, C4 and C1-INH levels did neither in the previously published eight patients (2) nor in our case provide any valuable clinical information for follow-up and C1–C1–INH complexes monitored by Cicardi did also not prove to be useful for this purpose (5). At present only studies with a few patients looking at long-term effects of danazole, such as liver neoplams and androgenetic effects, exist (6). However, despite the concern of side effects, which are serious for women because of the endocrinological interference, experience with low dose treatment for more than 15 years supports the status of danazole as a first line therapy for HAE-1 (2).

image

Figure 1. (A) Danazole dose over the last 3 years since starting the medication. The arrow points the only medication gap of 2 weeks in 3 years during which HAE attacks relapsed. (B) Time course of C1-INH, C4 and C4 levels in serum (laboratory: clinical chemistry, University of Ulm).

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References

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  2. References
  • 1
    Bowen T, Cicardi M, Farkas H, Bork K, Kreuz W, Zingale L et al. Canadian 2003 International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema. J Allergy Clin Immunol 2004;114: 629637.
  • 2
    Zimmermann HP, Wuthrich B, Spath P. [Hereditary angioedema. A clinical and immunologic contribution based on our 8 clinical cases under long-term treatment with androgens]. Schweiz Med Wochenschr 1983;113: 876884.
  • 3
    Gelfand JA, Sherins RJ, Alling DW, Frank MM. Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Engl J Med 1976;295: 14441448.
  • 4
    Agostoni A, Cicardi M, Martignoni GC, Bergamaschini L, Marasini B. Danazol and stanozolol in long-term prophylactic treatment of hereditary angioedema. J Allergy Clin Immunol 1980;65: 7579.
  • 5
    Cicardi M, Bergamaschini L, Cugno M, Hack E, Agostoni G, Agostoni A. Long-term treatment of hereditary angioedema with attenuated androgens: a survey of a 13-year experience. J Allergy Clin Immunol 1991;87: 768773.
  • 6
    Fabiani JE, Avigliano A, Dupont JC. Hereditary angioedema. Long-term follow-up of 88 patients. Experience of the Argentine Allergy and Immunology Institute. Allergol Immunopathol (Madr) 2000;28: 267271.