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Photoallergic skin reaction to ribavirin
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 1999 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 94, No. 6, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00220-8
Photoallergic Skin Reaction to Ribavirin Danuta Stryjek-Kaminska, M.D., Falk Ochsendorf, M.D., Claudia Ro¨der, M.D., Manfred Wolter, M.D., and Stefan Zeuzem, M.D. Medizinische Klinik II and Klinik fu¨r Dermatologie, Universita¨tsklinikum, Frankfurt, Germany
ABSTRACT A 65-yr-old woman with chronic hepatitis C was treated with three million units interferon-a t.i.w. and 1000 mg ribavirin daily. At wk 16 of combination therapy the patient developed an itchy eczematous erythema, partly of urticarial character, which was almost confined to ultraviolet (UV)exposed sites. Histopathological examination of the skin lesions was consistent with a photoallergic reaction. The minimal erythematous dose for UVA and UVB was assessed on healthy skin. After 24 h, a distinct erythema at the UVB irradiated site was found, whereas no reaction was seen with UVA provocation up to a dose of 10 J/cm2. Correspondingly, determination of the absorption spectrum of ribavirin revealed maximum absorption within UVB at 282.5 nm. Ribavirin was stopped, and the cutaneous lesions and pruritus completely disappeared without subsequent hyperpigmentation. This case indicates that ribavirin is a potential photosensitizer for UVB, which may become increasingly relevant in patients with chronic hepatitis C undergoing combination therapy for 6 –12 months with interferon-a and ribavirin. (Am J Gastroenterol 1999;94: 1686 –1688. © 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION Hepatitis C virus infection often progresses to chronic hepatitis, cirrhosis, and sometimes hepatocellular carcinoma (1). Interferon-a is an approved treatment for chronic hepatitis C; however, the sustained virological response rate is ,20% (2). Additional clinical trials have been conducted to evaluate alternative treatment modalities in chronic hepatitis C, including therapy with the synthetic purine nucleoside ribavirin (1-b-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide). Although ribavirin monotherapy revealed no consistent effect on HCV-RNA relative to that of placebo (3–5), results of combination therapy with subcutaneously administered interferon-a and orally administered ribavirin indicate a potential synergistic effect, particularly in terms of maintenance of long term response (6 –10). Ribavirin is generally well tolerated. The most common side effect is hemolytic anemia, which is reversible after dose reduction or discontinuation of drug treatment. Other adverse reactions are less common and include mild to moderate fatigue, headache, myalgia, dyspnea, nausea, anorexia, dizziness, nervousness, depression, insomnia, and
paraesthesia. Skin disorders such as rash, pruritus, urticaria, and eczema are reported in #14% of patients under ribavirin treatment (4, 9 –11). The possibility that such skin reactions could be due to a drug-induced photoallergy has not yet been considered.
CASE REPORT A 65-yr-old woman with chronic hepatitis C was referred to our hepatology outpatient clinic in March 1996. Physical examination was unremarkable, without peripheral signs of chronic liver disease. The patient had no history of atopy or allergies. Liver histology revealed a moderate degree of portal and lobular inflammation with focal and piecemeal necrosis, bridging fibrosis, and septa formation. Molecular genotyping identified HCV-1b, and virus quantification revealed 4,800,000 genome equivalents per milliliter. Treatment was initiated with 3 MU recombinant interferon-a2b (Intron A, Schering-Plough, Kenilworth, NJ) t.i.w. subcutaneously in combination with 1000 mg ribavirin in two divided doses per day p.o. After initiation of therapy, serum aminotransferase levels gradually normalized and HCV-RNA was undetectable already after 4 wk of treatment. Because of a ribavirin-induced osmotic hemolysis, a gradual decline of hemoglobin from 13.5 g/dl to 9.2 g/dl (wk 4) was observed. The ribavirin dose was reduced to 600 mg daily, whereas the interferon-a dose was kept constant. The hemoglobin levels recovered within 8 wk after dose reduction (12.0 g/dl). At wk 16 of combination therapy, the patient developed an itchy eczematous erythema, partly with urticarial character, which was confined to ultraviolet (UV)-exposed sites but tended to progress to areas not exposed to UV radiation (Fig. 1). Systemic reactions were not observed. Histopathological examination revealed epidermal parahyperkeratosis and spongiosis, partly with vesicle formation, and in the upper dermis a perivascular infiltrate of lymphocytes, macrophages, some plasma cells, eosinophils, and mucinous infiltrates consistent with a drug and/or light-induced subacute eczema (Fig. 2). The minimal erythematous dose for UVA and UVB was assessed on healthy skin. After 24 h a distinct erythema at the UVB irradiated site was found at #18 mJ/cm2 (normal range 38 –53 mJ/cm2), whereas no reaction was seen with UVA provocation at a dose of #10 J/cm2, confirming the
AJG – June, 1999
Photoallergy to Ribavirin
1687
diagnosis of photosensitivity. Ribavirin was stopped and the dermatitis treated topically with a mild corticosteroid ointment. Within 6 days, the cutaneous lesions and the pruritus completely disappeared. The patient was started again 2 wk later on 600 mg ribavirin per day. However, after readministration of a single dose of ribavirin, pruritus and new eczematous eruptions on the areas of the original lesions recurred after 1 day, leading to the definite discontinuation of ribavirin therapy. The dermatitis disappeared within 2 days without persisting hyperpigmentation. Interferon-a was continued for 12 months and no other skin reactions appeared. After termination of therapy, the patient was asymptomatic, aminotransferase levels were within the normal range, and HCV-RNA remained undetectable.
DISCUSSION
Figure 1. Infiltrated eczematous, partly urticarial erythema of the neck and the anterior V of the chest. Note the sparings of the submental skin and of areas below the mandibles.
Drug-induced photosensitivity reactions are triggered by usually harmless doses of sunlight and can be categorized as either phototoxic or photoallergic (12). Phototoxicity is characterized by a rapid onset within minutes to hours, and resembles an exaggerated sunburn with erythema and edema. The reaction is confined to the exposed skin and is frequently associated with persistent hyperpigmentation (13). Photoallergic reactions to drugs are almost always of the delayed hypersensitivity or the cell-mediated type, and occur weeks and even months after initiation of the medication. The clinical spectrum of photoallergic reactions may range from a simple erythema to a severe vesiculobullous dermatitis. Lesions are distributed on the light-exposed skin, but may spread also to unexposed areas. Subsequent hyper-
Figure 2. Epidermal parahyperkeratosis and spongiosis, partly with vesicle formation, and in the upper dermis a perivascular infiltrate of lymphocytes, macrophages, some plasma cells, eosinophils, and mucinous infiltrates (subacute eczema).
1688
Stryjek-Kaminska et al.
AJG – Vol. 94, No. 6, 1999
cations ribavirin was given as a short term treatment, and clinical experience with long term therapy is limited. In patients with chronic hepatitis C undergoing combination therapy, immunomodulatory effects of interferon-a may precipitate the development of photoallergic reactions. Because of the improvement in sustained virological response rates, an increasing number of HCV-infected patients will be treated with interferon-a and ribavirin for 6 –12 months. In patients developing a rash, photoallergic skin reactions to ribavirin must be considered. Reprint requests and correspondence: Prof. Dr. med. Stefan Zeuzem, Medizinische Klinik II, Zentrum der Inneren Medizin, Klinikum der Johann Wolfgang Goethe-Universita¨t, TheodorStern-Kai 7, 60590 Frankfurt a.M., Germany. Received May 21, 1998; accepted Aug. 21, 1998.
REFERENCES
Figure 3. Absorption spectrum of ribavirin (1-b-D-ribofuranosyl1H-1,2,4-triazole-3-carboxamide). The chemical structure is shown in the insert.
pigmentation is unusual. The wavelength of light implicated in photoallergic reactions is mainly within UVA (320 – 400 nm) and less frequently within UVB (280 –320 nm). Generally, the action spectrum required by photosensitizing drugs to induce disease is similar to the absorption spectrum of the photosensitizer (14). The patient fulfilled the criteria for a photoallergic reaction to ribavirin: 1) the skin reaction occurred 4 months after initiation of ribavirin therapy; 2) the lesions spread to unexposed skin, resembled subacute eczema both clinically and histologically, and healed without hyperpigmentation; and 3) recurrence of the erythema occurred .24 h after re-exposure to ribavirin. Furthermore, determination of the absorption spectrum of ribavirin revealed maximum absorption within UVB at 282.5 nm (Fig. 3) corresponding well to the reduced minimal erythematous dose for UVB in our patient. Like many other UVB photosensitizing drugs ribavirin contains ring structures (see insert in Fig. 3); however, an aromatic ring like that in tricyclic antidepressants, thiazides, nifedipine, or diphenhydramine is not present. Ribavirin has previously not been indicated as an agent of UVB-inducible systemic photosensitization. For many indi-
1. Seeff LB. Natural history of hepatitis C. Hepatology 1997; 26(suppl 1):21S– 8S. 2. Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: Effects of dose and duration. Hepatology 1996;24:778 –9. 3. Di Bisceglie AM, Conjeevaram HS, Fried MW, et al. Ribavirin as therapy for chronic hepatitis C. A randomized, doubleblind, placebo-controlled trial. Ann Intern Med 1995;123:897– 903. 4. Dusheiko G, Main J, Thomas H, et al. Ribavirin treatment for patients with chronic hepatitis C: Results of a placebo-controlled study. J Hepatol 1996;25:591– 8. 5. Bodenheimer HC, Lindsay KL, Davis GL, et al. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: A multicenter trial. Hepatology 1997;26:473–7. 6. Brillanti S, Garson J, Foli M, et al. A pilot study of combination therapy with ribavirin plus interferon alfa for interferon alfa-resistant chronic hepatitis C. Gastroenterology 1994;107: 812–7. 7. Lai MY, Kao JH, Yang PM, et al. Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. Gastroenterology 1996;111:1307–12. 8. Reichard O, Norkrans G, Fryde´n A, et al. Randomised, doubleblind, placebo-controlled trial of interferon a-2b with and without ribavirin for chronic hepatitis C. Lancet 1998;351:83–7. 9. Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998;339:1493–9. 10. Schalm S, Hansen B, Chemello L, et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C: A meta-analysis of individual patient data from European centers. J Hepatol 1997;26:961– 6. 11. de Ledinghen V, Brudieux E, Beylot-Barry M, et al. Severe local cutaneous necrosis during treatment with interferonalpha and ribavirin for chronic viral hepatitis C. Gastroenterol Clin Biol 1997;21:523– 4 (letter). 12. Allen JE. Drug-induced photosensitivity. Clin Pharm 1994;12: 580 –7. 13. Gonzalez E, Gonzalez S. Drug photosensitivity, idiopathic photodermatosis, and sunscreens. J Am Acad Dermatol 1996; 35:871– 85. 14. Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. J Am Acad Dermatol 1995;33:551–73.
Vol. 94, No. 6, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00220-8
Photoallergic Skin Reaction to Ribavirin Danuta Stryjek-Kaminska, M.D., Falk Ochsendorf, M.D., Claudia Ro¨der, M.D., Manfred Wolter, M.D., and Stefan Zeuzem, M.D. Medizinische Klinik II and Klinik fu¨r Dermatologie, Universita¨tsklinikum, Frankfurt, Germany
ABSTRACT A 65-yr-old woman with chronic hepatitis C was treated with three million units interferon-a t.i.w. and 1000 mg ribavirin daily. At wk 16 of combination therapy the patient developed an itchy eczematous erythema, partly of urticarial character, which was almost confined to ultraviolet (UV)exposed sites. Histopathological examination of the skin lesions was consistent with a photoallergic reaction. The minimal erythematous dose for UVA and UVB was assessed on healthy skin. After 24 h, a distinct erythema at the UVB irradiated site was found, whereas no reaction was seen with UVA provocation up to a dose of 10 J/cm2. Correspondingly, determination of the absorption spectrum of ribavirin revealed maximum absorption within UVB at 282.5 nm. Ribavirin was stopped, and the cutaneous lesions and pruritus completely disappeared without subsequent hyperpigmentation. This case indicates that ribavirin is a potential photosensitizer for UVB, which may become increasingly relevant in patients with chronic hepatitis C undergoing combination therapy for 6 –12 months with interferon-a and ribavirin. (Am J Gastroenterol 1999;94: 1686 –1688. © 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION Hepatitis C virus infection often progresses to chronic hepatitis, cirrhosis, and sometimes hepatocellular carcinoma (1). Interferon-a is an approved treatment for chronic hepatitis C; however, the sustained virological response rate is ,20% (2). Additional clinical trials have been conducted to evaluate alternative treatment modalities in chronic hepatitis C, including therapy with the synthetic purine nucleoside ribavirin (1-b-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide). Although ribavirin monotherapy revealed no consistent effect on HCV-RNA relative to that of placebo (3–5), results of combination therapy with subcutaneously administered interferon-a and orally administered ribavirin indicate a potential synergistic effect, particularly in terms of maintenance of long term response (6 –10). Ribavirin is generally well tolerated. The most common side effect is hemolytic anemia, which is reversible after dose reduction or discontinuation of drug treatment. Other adverse reactions are less common and include mild to moderate fatigue, headache, myalgia, dyspnea, nausea, anorexia, dizziness, nervousness, depression, insomnia, and
paraesthesia. Skin disorders such as rash, pruritus, urticaria, and eczema are reported in #14% of patients under ribavirin treatment (4, 9 –11). The possibility that such skin reactions could be due to a drug-induced photoallergy has not yet been considered.
CASE REPORT A 65-yr-old woman with chronic hepatitis C was referred to our hepatology outpatient clinic in March 1996. Physical examination was unremarkable, without peripheral signs of chronic liver disease. The patient had no history of atopy or allergies. Liver histology revealed a moderate degree of portal and lobular inflammation with focal and piecemeal necrosis, bridging fibrosis, and septa formation. Molecular genotyping identified HCV-1b, and virus quantification revealed 4,800,000 genome equivalents per milliliter. Treatment was initiated with 3 MU recombinant interferon-a2b (Intron A, Schering-Plough, Kenilworth, NJ) t.i.w. subcutaneously in combination with 1000 mg ribavirin in two divided doses per day p.o. After initiation of therapy, serum aminotransferase levels gradually normalized and HCV-RNA was undetectable already after 4 wk of treatment. Because of a ribavirin-induced osmotic hemolysis, a gradual decline of hemoglobin from 13.5 g/dl to 9.2 g/dl (wk 4) was observed. The ribavirin dose was reduced to 600 mg daily, whereas the interferon-a dose was kept constant. The hemoglobin levels recovered within 8 wk after dose reduction (12.0 g/dl). At wk 16 of combination therapy, the patient developed an itchy eczematous erythema, partly with urticarial character, which was confined to ultraviolet (UV)-exposed sites but tended to progress to areas not exposed to UV radiation (Fig. 1). Systemic reactions were not observed. Histopathological examination revealed epidermal parahyperkeratosis and spongiosis, partly with vesicle formation, and in the upper dermis a perivascular infiltrate of lymphocytes, macrophages, some plasma cells, eosinophils, and mucinous infiltrates consistent with a drug and/or light-induced subacute eczema (Fig. 2). The minimal erythematous dose for UVA and UVB was assessed on healthy skin. After 24 h a distinct erythema at the UVB irradiated site was found at #18 mJ/cm2 (normal range 38 –53 mJ/cm2), whereas no reaction was seen with UVA provocation at a dose of #10 J/cm2, confirming the
AJG – June, 1999
Photoallergy to Ribavirin
1687
diagnosis of photosensitivity. Ribavirin was stopped and the dermatitis treated topically with a mild corticosteroid ointment. Within 6 days, the cutaneous lesions and the pruritus completely disappeared. The patient was started again 2 wk later on 600 mg ribavirin per day. However, after readministration of a single dose of ribavirin, pruritus and new eczematous eruptions on the areas of the original lesions recurred after 1 day, leading to the definite discontinuation of ribavirin therapy. The dermatitis disappeared within 2 days without persisting hyperpigmentation. Interferon-a was continued for 12 months and no other skin reactions appeared. After termination of therapy, the patient was asymptomatic, aminotransferase levels were within the normal range, and HCV-RNA remained undetectable.
DISCUSSION
Figure 1. Infiltrated eczematous, partly urticarial erythema of the neck and the anterior V of the chest. Note the sparings of the submental skin and of areas below the mandibles.
Drug-induced photosensitivity reactions are triggered by usually harmless doses of sunlight and can be categorized as either phototoxic or photoallergic (12). Phototoxicity is characterized by a rapid onset within minutes to hours, and resembles an exaggerated sunburn with erythema and edema. The reaction is confined to the exposed skin and is frequently associated with persistent hyperpigmentation (13). Photoallergic reactions to drugs are almost always of the delayed hypersensitivity or the cell-mediated type, and occur weeks and even months after initiation of the medication. The clinical spectrum of photoallergic reactions may range from a simple erythema to a severe vesiculobullous dermatitis. Lesions are distributed on the light-exposed skin, but may spread also to unexposed areas. Subsequent hyper-
Figure 2. Epidermal parahyperkeratosis and spongiosis, partly with vesicle formation, and in the upper dermis a perivascular infiltrate of lymphocytes, macrophages, some plasma cells, eosinophils, and mucinous infiltrates (subacute eczema).
1688
Stryjek-Kaminska et al.
AJG – Vol. 94, No. 6, 1999
cations ribavirin was given as a short term treatment, and clinical experience with long term therapy is limited. In patients with chronic hepatitis C undergoing combination therapy, immunomodulatory effects of interferon-a may precipitate the development of photoallergic reactions. Because of the improvement in sustained virological response rates, an increasing number of HCV-infected patients will be treated with interferon-a and ribavirin for 6 –12 months. In patients developing a rash, photoallergic skin reactions to ribavirin must be considered. Reprint requests and correspondence: Prof. Dr. med. Stefan Zeuzem, Medizinische Klinik II, Zentrum der Inneren Medizin, Klinikum der Johann Wolfgang Goethe-Universita¨t, TheodorStern-Kai 7, 60590 Frankfurt a.M., Germany. Received May 21, 1998; accepted Aug. 21, 1998.
REFERENCES
Figure 3. Absorption spectrum of ribavirin (1-b-D-ribofuranosyl1H-1,2,4-triazole-3-carboxamide). The chemical structure is shown in the insert.
pigmentation is unusual. The wavelength of light implicated in photoallergic reactions is mainly within UVA (320 – 400 nm) and less frequently within UVB (280 –320 nm). Generally, the action spectrum required by photosensitizing drugs to induce disease is similar to the absorption spectrum of the photosensitizer (14). The patient fulfilled the criteria for a photoallergic reaction to ribavirin: 1) the skin reaction occurred 4 months after initiation of ribavirin therapy; 2) the lesions spread to unexposed skin, resembled subacute eczema both clinically and histologically, and healed without hyperpigmentation; and 3) recurrence of the erythema occurred .24 h after re-exposure to ribavirin. Furthermore, determination of the absorption spectrum of ribavirin revealed maximum absorption within UVB at 282.5 nm (Fig. 3) corresponding well to the reduced minimal erythematous dose for UVB in our patient. Like many other UVB photosensitizing drugs ribavirin contains ring structures (see insert in Fig. 3); however, an aromatic ring like that in tricyclic antidepressants, thiazides, nifedipine, or diphenhydramine is not present. Ribavirin has previously not been indicated as an agent of UVB-inducible systemic photosensitization. For many indi-
1. Seeff LB. Natural history of hepatitis C. Hepatology 1997; 26(suppl 1):21S– 8S. 2. Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: Effects of dose and duration. Hepatology 1996;24:778 –9. 3. Di Bisceglie AM, Conjeevaram HS, Fried MW, et al. Ribavirin as therapy for chronic hepatitis C. A randomized, doubleblind, placebo-controlled trial. Ann Intern Med 1995;123:897– 903. 4. Dusheiko G, Main J, Thomas H, et al. Ribavirin treatment for patients with chronic hepatitis C: Results of a placebo-controlled study. J Hepatol 1996;25:591– 8. 5. Bodenheimer HC, Lindsay KL, Davis GL, et al. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: A multicenter trial. Hepatology 1997;26:473–7. 6. Brillanti S, Garson J, Foli M, et al. A pilot study of combination therapy with ribavirin plus interferon alfa for interferon alfa-resistant chronic hepatitis C. Gastroenterology 1994;107: 812–7. 7. Lai MY, Kao JH, Yang PM, et al. Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. Gastroenterology 1996;111:1307–12. 8. Reichard O, Norkrans G, Fryde´n A, et al. Randomised, doubleblind, placebo-controlled trial of interferon a-2b with and without ribavirin for chronic hepatitis C. Lancet 1998;351:83–7. 9. Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998;339:1493–9. 10. Schalm S, Hansen B, Chemello L, et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C: A meta-analysis of individual patient data from European centers. J Hepatol 1997;26:961– 6. 11. de Ledinghen V, Brudieux E, Beylot-Barry M, et al. Severe local cutaneous necrosis during treatment with interferonalpha and ribavirin for chronic viral hepatitis C. Gastroenterol Clin Biol 1997;21:523– 4 (letter). 12. Allen JE. Drug-induced photosensitivity. Clin Pharm 1994;12: 580 –7. 13. Gonzalez E, Gonzalez S. Drug photosensitivity, idiopathic photodermatosis, and sunscreens. J Am Acad Dermatol 1996; 35:871– 85. 14. Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. J Am Acad Dermatol 1995;33:551–73.