Clinical Toxicity of the Interferons
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Since their initial description in 1957, the interferons (IFNs) have been increasingly used to treat a wide array of diseases. Acute adverse effects, i.e. ‘flu-like’ syndromes, hypo- or hypertension, tachycardia, headache, myalgias and gastrointestinal disorders, occur within the first hour or day after starting treatment. They are seldom treatment-limiting and are easily manageable.
Sub-acute and chronic effects develop after several days, usually within 2 and 4 weeks of therapy. The most typical is neurological toxicity, including fatigue/asthenia, and behavioural and cognitive changes. Such symptoms may seriously impair quality of life and result in treatment discontinuation. Seizures have seldom been described. Other infrequent central nervous system adverse effects include vertigo, cramp and oculomotor nerve paralysis. Distal paraesthesias and peripheral neuropathy have been reported.
IFN-associated autoimmunity is quite rare but a matter of concern. Biological or clinical manifestations usually require several months to become apparent. Autoantibodies have been shown to develop in most patients but have been inconsistently associated with clinical symptoms of systemic lupus erythematosus, rheumatoid-like arthritis and thyroiditis. Both hypo-and hyperthyroidism have been described but are usually reversible. Other infrequent autoimmune reactions include diabetes, pemphigus and worsening of multiple sclerosis. Although several patients present with a pre-existing autoimmune disorder, no predisposing factor has been clearly established.
While hypotension and tachycardia are the most frequent acute cardiovascular complications, a few additional cases of cardiac arrhythmias and myocardial ischaemia have been reported after a short course or several weeks of treatment. These latter complications do not appear to be dose-dependent or age-related. Isolated cases of congestive heart failure have also been described.
Mild proteinuria has been observed in 15 to 25% of patients, but acute renal toxicity is uncommon. A transient rise in serum aminotransferase levels is frequently noted during the first stage of therapy, especially in patients receiving the highest dosages. Direct hepatotoxicity is extremely rare. Autoimmune hepatitis, which is ill-diagnosed as chronic viral hepatitis, and de novo induction of autoimmune hepatitis, account for the majority of liver diseases.
Haematotoxicity is relatively common but mild to moderate, and develops gradually during the first weeks of treatment. Neutropenia is the most common haematological toxicity, but is usually not dose-limiting and resolves rapidly upon drug discontinuation. Myelosuppression, autoimmune and immune allergic haemolytic anaemias and thrombocytopenias have seldom been described.
Cutaneous adverse effects comprised nonspecific erythema and hair loss and, less frequently, vasculitis, local ulcerations at the site of injection and exacerbation of psoriasis.
Anti-IFN antibodies have been found with greatly varying incidence. The clinical consequences, e.g. loss of therapeutic activity, need to be further clarified. The appearance of anti-IFN antibodies should not lead to discontinuing treatment, but the use of another IFN preparation is required in patients with resistance.
Mild hormonal and metabolic disorders have been documented of which hypertriglyceridaemia is the more common. Clinically significant drug interactions have rarely been reported despite the potential inhibition of hepatic drug metabolism by IFN. The safety of IFN in pregnant women remains to be established.
Due to the more extensive use of IFNα, most adverse effects have been reported with IFNα preparations. Overall, the mechanisms underlying toxic effects are not well understood, and the incidence of adverse effects is usually dose- and duration-dependent.
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- Alvarez JS, Sacristan JA, Alsar MJ. Interferon alpha-2a-induced impotence. Annals of Pharmacotherapy 25: 1397, 1991Google Scholar
- Ayub A, Zafar M, Al-Harbi A, Ellis M, Qunibi W. Acute renal failure with α-interferon therapy: a case report. Medical Science Research 21: 123–124, 1993Google Scholar
- Chazerain P, Meyer O, Ribard P, de Bandt M, Mechelany, et al. Trois cas de polyarthrite survenant au cours d’un traitement par interféron-alpha recombinant. Revue du Rhumatisme et des Maladies Ostéoarticulaires 59: 303–309, 1992Google Scholar
- Crockett DM, Lusk RP, McCabe BF, Mixon JH. Side effects and toxicity of interferon in the treatment of recurrent respiratory papillomatosis. Annals of Otology, Rhinology and Laryngology 96: 601–607, 1987Google Scholar
- Dianzani F. Interferon treatments: how to use an endogenous system as a therapeutic agents. Journal of Interferon Research (special issue, May 1992): 109–118, 1992Google Scholar
- Echizen H, Ohta Y, Shirataki H, Tsukamoto K, Umeda N, et al. Effects of subchronic treatment with natural interferons on antipyrine clearance and liver function in patients with chronic hepatitis. Gastroenterology 30: 562–567, 1990Google Scholar
- Färkkilä M, Iivanainen M, Roine R, Bergström L, Laaksonen R, et al. Neurotoxic and other side effects of high-dose interferon in amyotrophic lateral sclerosis. Acta Neurologica Scandinavica 69: 42–46, 1984Google Scholar
- Gauci L. Management of cancer patients receving interferon alfa-2a. International Journal of Cancer (Suppl. 1): 21–30, 1987Google Scholar
- Harousseau JL, Milpied N, Bourhis JH, Guimbretiere L, Talmant P. Aplasie fatale après traitement par interféron alpha d’une leucémie myéloïde chronique en rechute après greffe de moelle osseuse allogénique. Presse Medicale 17: 80–81, 1988Google Scholar
- Herrman J, Gabriel F. Membranoproliferative glomerulonephritis in a patient with hairy-cell leukemia treated with alpha-II interferon. Lancet 316: 112–113, 1987Google Scholar
- Iaffaioli RV, Fiorenza L, D’Avino M, Frasci G, La Mura G, et al. Neurotoxic effects of long-term treatment with low-dose alpha 2B interferon. Current Therapeutic Research 48: 403–408, 1990Google Scholar
- Janssen HLA, Brouwer JT, Nevens F, Sanchez-Tapias JM, Craxi A, et al. Fatal hepatic decompensation associated with interferon alfa. Lancet 306: 107–108, 1993Google Scholar
- Jaubert D, Hauteville D, Pelissier JF, Muzellec Y. Neuropathie périphérique au cours d’un traitement par interféron alpha. Presse Médicale 20: 221–222, 1991Google Scholar
- Javier RM, Sibilia J, Kuntz JL, Schlienger JL, Asch L. Interféron alpha-2b et hypothyroïdie. Revue du Rhumatisme et des Maladies Ostéoarticulaires 59: 501, 1992Google Scholar
- Mattson K, Niiranen A, Iivanainen M, Färkkilä M, Bergström L, et al. Neurotoxicity of interferon. Cancer Treatment Report 67: 958–961, 1983Google Scholar
- McNair ANB, Jacyna MR, Thomas HC. Severe haemolytic transfusion reaction occurring during alpha-interferon therapy for chronic hepatitis. European Journal of Gastroenterology and Hepatology 3: 193–194, 1991Google Scholar
- Mirro J, Kalwinsky D, Whisnant J, Weck P, Chesney C, et al. Coagulopathy induced by continuous infusion of high doses of human lymphoblastoid interferon. Cancer Treatment Report 69: 315–317, 1985Google Scholar
- Oberg KE. Development of an SLE syndrome in a patient with malignant carcinoid tumor after treatment with alpha interferon. Interferons and Cytokines 12: 30–32, 1989Google Scholar
- Oberg KE, Alm G, Magnusson A, Lundqvist G, Theodorsson E, et al. Treatment of malignant carcinoid tumors with recombinant interferon alpha-2b: development of neutralizing interferon antibodies and possible loss of antitumor activity. Journal of the National Cancer Institute 81: 531–535, 1989PubMedCrossRefGoogle Scholar
- Ornellas de Souza MH, Abdelhay E, Silva MLM, Diamond HR, Valente AN, et al. Late marrow allograft rejection following alpha-interferon therapy for hepatitis in a patient with paroxysmal nocturnal hemoglobinuria. Bone Marrow Transplantation 9: 495–497, 1992Google Scholar
- Pecorari P. Colite ulcerosa in corso di leucemia a cellule capellute. Descrizione di un caso. Recenti Progressi in Medicina 82: 269–271, 1991Google Scholar
- Prasad S, Waters B, Hill PB, Portera FA, Riely CA. Psychiatric side effects of interferon alpha-2b in patients treated for hepatitis C. Abstract. Clinical Research 40: 840A, 1992Google Scholar
- Schilsky RL, Davidson HS, Magid D, Daiter S, Golomb HM. Gonadal and sexual function in male patients with hairy cell leukemia: lack of adverse effects of recombinant alpha 2-interferon treatment. Cancer Treatment Report 71: 179–181, 1987Google Scholar
- Simone G, Iaffaioli VR, La Mura G, D’Avino M, Costantino G, et al. Reversible heart failure in a non-Hodgkin lymphoma patient being treated with alpha-interferon. Current Therapeutic Research 44: 78–85, 1988Google Scholar
- Sonnenblick M, Rosin A. Cardiotoxicity of interferon. A review of 44 cases. Chest 99: 557–561, 1991Google Scholar
- Von Wussow P, Jakschies D, Freund M, Deicher H. Humoral response to recombinant interferon-α2b in patients receiving recombinant interferon-α2b therapy. Journal of Interferon Research 9 (suppl. 1): s25–S31, 1989Google Scholar