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Pruritus
Pruritus Timothy G. Waodall, MD, and Gary R. Kantor, MD
Pruritus is the most common symptom in dermatology. The cause is obvious when the pruritus is accompanied by a cutaneous eruption. In the absence of a skin eruption, however, determination of the cause requires a meticulous history, physical examination, and occasionally laboratory studies. Treatment of pruritus is most rewarding when it is directed to the underlying cause. This article focuses on some of the current issues in pruritus--associated conditions and treatments--from a clinical perspective.
by the presence of sterile papules and pustules of the face, trunk, and extremities. The condition occurs in patients whose CD4 count is less than 250/mL. The pruritic papular eruption of HIV is manifested as skincolored papules on the face, extremities, and trunk. The papules resemble those seen in eosinophilic folliculitis but they lack the eosinophils. Patients with both types of eruptions respond inconsistently to treatment with corticosteroids, emollients, and antihistamines; ultraviolet light seems to offer the most benefit. 46
Hepatitis and Pruritus
Evaluation of Patients for Pruritus
It is well established that obstructive hepatobiliary disease from internal or external sources is an important systemic cause for generalized pruritus. Hepatitis C was first recognized in 1975.1 However, hepatitis C as a cause for pruritus was not recognized until 1994 when it was reported that generalized pruritus that had developed in 4 patients was attributed to hepatitis C. 2 Subsequently it has been shown that 4% of patients with an initial complaint of pruritus may have hepatitis C, and that in another 14%, hepatitis C is diagnosed later in the course of the infection. In some cases, pruritus associated with hepatitis C is so severe and its effects on the patient's quality of life are so profound that liver transplantation may be considered. 3 It has also been found that chronic pruritus was 3 times more prevalent in patients with hepatitis C than in a control group of patients with other liver diseases. Considering that a screening test for hepatitis C is available, that the prevalence of hepatitis C in the patient population-at-large is increasing, and that evidence has emerged that hepatitis C causes pruritus more often than other hepatic disorders, patients with pruritus should be evaluated for possible hepatitis C as part of their work-up. 4
As with any medical condition, the history and physical examination are the starting points in the evaluation of a patient for possible pruritus; in many cases, they are also the most revealing. The history should include the nature, onset, and duration of pruritus as well as its association with medications, cosmetic products, and exogenous substances. When pruritus is generalized, physicians should consider a systemic cause, whereas localization points to another cause] In some cases, differentiating organic pruritus from psychogenic pruritus is difficult. One useful clue, however, is that psychogenic pruritus, in contrast to organic pruritus, does not awaken patients from their sleepf Inquiry into routine skin care is also important because irritants used on the skin such as isopropyl alcohol or witch hazel might be contributing to the problem. A positive review of systems, especially in relation to general health, should alert the physician to search for an underlying systemic disease. A thorough cutaneous examination should be done with particular attention to the middle part of the upper back. This area is unaffected in pruritus that is unrelated to dermatologic disease. If lymphadenopathy or organomegaly of the liver and spleen is present, the patient should be evaluated immediately for the cause. When a definitive diagnosis cannot be made, laboratory tests to disclose relevant diseases should be ordered (Table 1). Radiographic studies of the chest and skin biopsy should also be considered. The upper back is a good area for skin biopsy because it is likely to be free from secondary changes caused by scratching. If screening studies reveal abnormalities,
HIV and Pruritus Pruritus occurs frequently in HIV patients, and its causes are even more varied than in non-HIV-infected patients. It is a presenting symptom of HIV/AIDS 4 and may be accompanied by a rash. However, several skin eruptions accompanied by severe pruritus have been linked to HIV. Eosinophilic folliculitis is characterized 14
Curr Probl Dermatol, January/February 2000
TABLE 1. Laboratory tests to screen for pruritus Complete blood cell count with differential white blood cell count Chemistry profile that includes tests for liver and renal function Hepatitis C profile Thyroid function tests (thyroxine and thyroid-stimulating hormone) Urinalysis Occult blood in stool (if patient aged >40 years)
additional studies or tests (Table 2) are recommended. The presence of risk factors for HIV may necessitate screening for HIV as part of the initial evaluation. If pruritus persists, these studies may need to be repeated at 6-month intervals.
New Treatments of Pruritus Danazol, a synthetic androgen, has been used for treatment of pruritus associated with myeloproliferative disorders (polycythemia vera and myelofibrosis) as well as systemic lupus erythematosus, primary biliary cirrhosis, chronic urticaria, lichen planus, erythema multiforme, and several idiopathic causes of pruritus. It was found that when patients were treated with danazol, 54% (who were refractory to other forms of therapy) experienced control of their pruritus. Although the exact mechanism is unclear, it was proposed that danazol is inserted into the red cell membrane, resulting in greater membrane stability and a decrease in the concentration of pruritus-associated mediators from mast cells and platelets. 1° Although ultraviolet B phototherapy has been useful in treatment of pruritus associated with chronic renal failure, thalidomide has been shown to be strikingly effective in treating refractory uremic pruritus 11 and prurigo nodularis. 12 The mechanism by which thalidomide acts is unknown, but the drug is believed to affect inflammatory mediators. A derivative of the pepper plant, capsaicin is believed to act against pruritus by depleting substance P in peripheral neurons, thereby blocking the transmission of pruritic stimuli. Topical capsaicin cream (0.025%) has been used successfully to treat localized areas associated with uremic pruritus 13 but was unsuccessful in treating lichen simplex chronicus. 14 Polycythemia vera-related pruritus improved with interferon-od 5 and psoralen plus ultraviolet A. 16 Both ultraviolet B and psoralen plus ultraviolet A 17 have been used successfully in treating pruritus of the papular eruption of HIV. Recently, pentoxifylline 18 has shown promise in treating this eruption as well. Interferon substantially improves life expectancy and the quality of life for patients with hepatitis C. HowCurr Probl Dermatol, January/February 2000
TABLE 2. Tests to use when screening reveals abnormalities Serum iron, ferritin ~ serum protein electrophoresis and immunoelectrophoresis Skin biopsy for special stains (to exclude mastocytosis) Skin biopsy for direct immunofluorescence (to exclude dermatitis, herpetiformis, and bullous pemphigoid) Ova and parasites in stool 5-Hydroxyindoleacetic acid and mast cell metabolites in urine Additional radiologic studies
ever, its efficacy on the relief of associated pruritus has varied. ~9 Topical doxepin cream was found to be effective in the treatment of pruritus associated with lichen simplex chronicus, eczematous dermatitis, nummular eczema, and contact dermatitis. Treatment efficacy of doxepin for pruritus associated with hepatitis C and HIV has not been established. 2° High-dose intravenous immunoglobulin was used successfully to treat the recurrence of malignancy-associated pruritus of dermatomyositis in a Japanese woman 5 years after removal of her gastric malignancy. 21 Various modes of electrical-stimulation treatment of pruritus have been investigated, including transcutaneous electronic nerve stimulation (TENS) and cutaneous field stimulation (CFS). The latter uses a flexible plate with needle electrodes as opposed to separate electrodes used in TENS. In one study, CFS was found to be more effective in controlling generalized pruritus than TENS. 22,23 Long-term studies of the efficacy of TENS and CFS have not been established. Pruritus is a known adverse effect of opiates. Naltrexone, an opiate antagonist, has been found to relieve pruritus associated with hemodialysisy suggesting that central opioid receptors are in some way responsible for the pruritus.
Conclusion The millennium holds much promise for patients suffering from pruritus. Treatments have vastly improved in the last 50 years, and as more research is invested into mechanisms and causes, our ability to relieve pruritus will be even further enhanced.
REFERENCES 1. Feinstone SM, Kapikian AL, Purcell RH. Transfusion associated hepatitis not due to hepatitis A or B. N Engl J Med 1975;292:767-70. 2. Chia SC, Bergasa NV, Kleiner DE, et al. Pruritus as a presenting symptom of chronic hepatitis C. Dig Dis Sci 1998; 43:2177-83. 15
3. Cribier B, Samien F. Systematic cutaneous examination in hepatitis C virus infected patients. Acta Derm Venereol 1998; 78:355-7. 4. Shapiro RS, Samarodin C, Hood AF. Pruritus as a presenting symptom of acquired immunodeficiency syndrome. J Am Acad Dermatol 1987; 16:1115-7. 5. Hoover WD, Lang PG. Pruritus in HIV infection. J Am Acad Dermatol 1991;24:1020-1. 6. Kantor GR, Bernhard JD. Investigation of the pruritic patient in daily practice. Semin Dermatol 1995;14:290-6. 7. Buchness MR, Lim HW, Hatcher VA. Eosinophilic pustular folliculitis in AIDS. N Engl J Med 1988;318:1183. 8. Bernard JD. Nocturnal wakening caused by pruritus: organic or psychogenic. J Am Acad Dermatol 1990;23:767. 9. Adams SJ. Iron deficiency and other hematologic causes of generalized pruritus. In: Bernhard JD, editor. Itch: mechanisms and management of pruritus. New York: McGrawHill; 1994. p 243-50. 10. Kolodny L Horstman LL, Bernd-Uwe S, et al. Danazol relieves refractory pruritus associated with myeloproliferative disorders and other diseases. Am J Hematol 1996;51:112-6. 11. Silva S, Viana PC, Lugon NV, et al. Thalidomide for treatment of uremic pruritus: a crossover randomized doubleblind trial. Nephron 1994;67:270-3. 12. Berger TM, Hoffman C, Thieberg MD. Prurigo nodularis and photosensitivity in AIDS: treatment with thalidomide. J Am Acad Dermatol 1995;33:837-8. 13. Tarng DC, Cho YL, Lui H, et al. Hemodialysis related prutitus: a double-blind, placebo controlled, crossover study of capsaicin 0.025%. Nephron 1996;72:617-22. 14. Kantor GR, Resnik KS. Treatment of lichen simplex chroni-
16
15.
16.
17.
18.
19. 20.
21.
22.
23.
24.
cus with topical capsaicin cream. Acta Derm Venereol 1997; 77:158-9. Muller EW, Dewolf JT, Wijermans PW, et al. Long-term treatment with interferon alpha-2b for severe pruritus in patients with polycythemia vera. Br J Hematol 1995;89:313-8. Jeamougin M, Rain JD, Najean Y. Efficacy of photochemotherapy on severe pruritus in patients with polycythemia vera. Ann Hematol 1996;73:91-3. Pardo RJ, Bogaert MA, Penneys NS, et al. UVB phototherapy of the pruritic papular eruption of the acquired immunodeficiency syndrome. J Am Acad Dermatol 1992;26:423-8. Berman B, Flores F, Burke G. Efficacy of pentoxyfylline in the treatment of pruritic papular eruption of HIV-infected persons. J Am Acad Dermatol 1998;38:955-9. Hadziyannis SJ. Skin diseases associated with hepatitis C virus infection. J Eur Acad Dermatol Venereol 1998; 10:12-21. Drake LA, Millikan LE. The antipruritic effect of 5% doxepin cream in patients with eczematous dermatitis. Arch Dermatol 1995;131:1403-8. Kikuchi-Numagami K, Sato M, Tagami H. Successful treatment of a therapy-resistant severely pruritic skin eruption of malignancy-associated dermatomyositis with high-dose intravenous immunoglobulin. J Dermatol 1996;23:340-3. Monk BE. Transcutaneous electronic nerve stimulation in the treatment of generalized pruritus. Clin Exp Dermatol 1993;18:67-8. Nilsson H, Levinsson A, Schovenberg J. Cutaneous field stimulation (CFS): a powerful new method to combat itch. Pain 1997;71:49-55. Peer G, Kivity S, Agami O, et al. Randomized crossover trial of naltrexone in uraemic pruritus. Lancet 1996;348:1552-4.
Curr Probl Dermatol, January/February 2000
Pruritus is the most common symptom in dermatology. The cause is obvious when the pruritus is accompanied by a cutaneous eruption. In the absence of a skin eruption, however, determination of the cause requires a meticulous history, physical examination, and occasionally laboratory studies. Treatment of pruritus is most rewarding when it is directed to the underlying cause. This article focuses on some of the current issues in pruritus--associated conditions and treatments--from a clinical perspective.
by the presence of sterile papules and pustules of the face, trunk, and extremities. The condition occurs in patients whose CD4 count is less than 250/mL. The pruritic papular eruption of HIV is manifested as skincolored papules on the face, extremities, and trunk. The papules resemble those seen in eosinophilic folliculitis but they lack the eosinophils. Patients with both types of eruptions respond inconsistently to treatment with corticosteroids, emollients, and antihistamines; ultraviolet light seems to offer the most benefit. 46
Hepatitis and Pruritus
Evaluation of Patients for Pruritus
It is well established that obstructive hepatobiliary disease from internal or external sources is an important systemic cause for generalized pruritus. Hepatitis C was first recognized in 1975.1 However, hepatitis C as a cause for pruritus was not recognized until 1994 when it was reported that generalized pruritus that had developed in 4 patients was attributed to hepatitis C. 2 Subsequently it has been shown that 4% of patients with an initial complaint of pruritus may have hepatitis C, and that in another 14%, hepatitis C is diagnosed later in the course of the infection. In some cases, pruritus associated with hepatitis C is so severe and its effects on the patient's quality of life are so profound that liver transplantation may be considered. 3 It has also been found that chronic pruritus was 3 times more prevalent in patients with hepatitis C than in a control group of patients with other liver diseases. Considering that a screening test for hepatitis C is available, that the prevalence of hepatitis C in the patient population-at-large is increasing, and that evidence has emerged that hepatitis C causes pruritus more often than other hepatic disorders, patients with pruritus should be evaluated for possible hepatitis C as part of their work-up. 4
As with any medical condition, the history and physical examination are the starting points in the evaluation of a patient for possible pruritus; in many cases, they are also the most revealing. The history should include the nature, onset, and duration of pruritus as well as its association with medications, cosmetic products, and exogenous substances. When pruritus is generalized, physicians should consider a systemic cause, whereas localization points to another cause] In some cases, differentiating organic pruritus from psychogenic pruritus is difficult. One useful clue, however, is that psychogenic pruritus, in contrast to organic pruritus, does not awaken patients from their sleepf Inquiry into routine skin care is also important because irritants used on the skin such as isopropyl alcohol or witch hazel might be contributing to the problem. A positive review of systems, especially in relation to general health, should alert the physician to search for an underlying systemic disease. A thorough cutaneous examination should be done with particular attention to the middle part of the upper back. This area is unaffected in pruritus that is unrelated to dermatologic disease. If lymphadenopathy or organomegaly of the liver and spleen is present, the patient should be evaluated immediately for the cause. When a definitive diagnosis cannot be made, laboratory tests to disclose relevant diseases should be ordered (Table 1). Radiographic studies of the chest and skin biopsy should also be considered. The upper back is a good area for skin biopsy because it is likely to be free from secondary changes caused by scratching. If screening studies reveal abnormalities,
HIV and Pruritus Pruritus occurs frequently in HIV patients, and its causes are even more varied than in non-HIV-infected patients. It is a presenting symptom of HIV/AIDS 4 and may be accompanied by a rash. However, several skin eruptions accompanied by severe pruritus have been linked to HIV. Eosinophilic folliculitis is characterized 14
Curr Probl Dermatol, January/February 2000
TABLE 1. Laboratory tests to screen for pruritus Complete blood cell count with differential white blood cell count Chemistry profile that includes tests for liver and renal function Hepatitis C profile Thyroid function tests (thyroxine and thyroid-stimulating hormone) Urinalysis Occult blood in stool (if patient aged >40 years)
additional studies or tests (Table 2) are recommended. The presence of risk factors for HIV may necessitate screening for HIV as part of the initial evaluation. If pruritus persists, these studies may need to be repeated at 6-month intervals.
New Treatments of Pruritus Danazol, a synthetic androgen, has been used for treatment of pruritus associated with myeloproliferative disorders (polycythemia vera and myelofibrosis) as well as systemic lupus erythematosus, primary biliary cirrhosis, chronic urticaria, lichen planus, erythema multiforme, and several idiopathic causes of pruritus. It was found that when patients were treated with danazol, 54% (who were refractory to other forms of therapy) experienced control of their pruritus. Although the exact mechanism is unclear, it was proposed that danazol is inserted into the red cell membrane, resulting in greater membrane stability and a decrease in the concentration of pruritus-associated mediators from mast cells and platelets. 1° Although ultraviolet B phototherapy has been useful in treatment of pruritus associated with chronic renal failure, thalidomide has been shown to be strikingly effective in treating refractory uremic pruritus 11 and prurigo nodularis. 12 The mechanism by which thalidomide acts is unknown, but the drug is believed to affect inflammatory mediators. A derivative of the pepper plant, capsaicin is believed to act against pruritus by depleting substance P in peripheral neurons, thereby blocking the transmission of pruritic stimuli. Topical capsaicin cream (0.025%) has been used successfully to treat localized areas associated with uremic pruritus 13 but was unsuccessful in treating lichen simplex chronicus. 14 Polycythemia vera-related pruritus improved with interferon-od 5 and psoralen plus ultraviolet A. 16 Both ultraviolet B and psoralen plus ultraviolet A 17 have been used successfully in treating pruritus of the papular eruption of HIV. Recently, pentoxifylline 18 has shown promise in treating this eruption as well. Interferon substantially improves life expectancy and the quality of life for patients with hepatitis C. HowCurr Probl Dermatol, January/February 2000
TABLE 2. Tests to use when screening reveals abnormalities Serum iron, ferritin ~ serum protein electrophoresis and immunoelectrophoresis Skin biopsy for special stains (to exclude mastocytosis) Skin biopsy for direct immunofluorescence (to exclude dermatitis, herpetiformis, and bullous pemphigoid) Ova and parasites in stool 5-Hydroxyindoleacetic acid and mast cell metabolites in urine Additional radiologic studies
ever, its efficacy on the relief of associated pruritus has varied. ~9 Topical doxepin cream was found to be effective in the treatment of pruritus associated with lichen simplex chronicus, eczematous dermatitis, nummular eczema, and contact dermatitis. Treatment efficacy of doxepin for pruritus associated with hepatitis C and HIV has not been established. 2° High-dose intravenous immunoglobulin was used successfully to treat the recurrence of malignancy-associated pruritus of dermatomyositis in a Japanese woman 5 years after removal of her gastric malignancy. 21 Various modes of electrical-stimulation treatment of pruritus have been investigated, including transcutaneous electronic nerve stimulation (TENS) and cutaneous field stimulation (CFS). The latter uses a flexible plate with needle electrodes as opposed to separate electrodes used in TENS. In one study, CFS was found to be more effective in controlling generalized pruritus than TENS. 22,23 Long-term studies of the efficacy of TENS and CFS have not been established. Pruritus is a known adverse effect of opiates. Naltrexone, an opiate antagonist, has been found to relieve pruritus associated with hemodialysisy suggesting that central opioid receptors are in some way responsible for the pruritus.
Conclusion The millennium holds much promise for patients suffering from pruritus. Treatments have vastly improved in the last 50 years, and as more research is invested into mechanisms and causes, our ability to relieve pruritus will be even further enhanced.
REFERENCES 1. Feinstone SM, Kapikian AL, Purcell RH. Transfusion associated hepatitis not due to hepatitis A or B. N Engl J Med 1975;292:767-70. 2. Chia SC, Bergasa NV, Kleiner DE, et al. Pruritus as a presenting symptom of chronic hepatitis C. Dig Dis Sci 1998; 43:2177-83. 15
3. Cribier B, Samien F. Systematic cutaneous examination in hepatitis C virus infected patients. Acta Derm Venereol 1998; 78:355-7. 4. Shapiro RS, Samarodin C, Hood AF. Pruritus as a presenting symptom of acquired immunodeficiency syndrome. J Am Acad Dermatol 1987; 16:1115-7. 5. Hoover WD, Lang PG. Pruritus in HIV infection. J Am Acad Dermatol 1991;24:1020-1. 6. Kantor GR, Bernhard JD. Investigation of the pruritic patient in daily practice. Semin Dermatol 1995;14:290-6. 7. Buchness MR, Lim HW, Hatcher VA. Eosinophilic pustular folliculitis in AIDS. N Engl J Med 1988;318:1183. 8. Bernard JD. Nocturnal wakening caused by pruritus: organic or psychogenic. J Am Acad Dermatol 1990;23:767. 9. Adams SJ. Iron deficiency and other hematologic causes of generalized pruritus. In: Bernhard JD, editor. Itch: mechanisms and management of pruritus. New York: McGrawHill; 1994. p 243-50. 10. Kolodny L Horstman LL, Bernd-Uwe S, et al. Danazol relieves refractory pruritus associated with myeloproliferative disorders and other diseases. Am J Hematol 1996;51:112-6. 11. Silva S, Viana PC, Lugon NV, et al. Thalidomide for treatment of uremic pruritus: a crossover randomized doubleblind trial. Nephron 1994;67:270-3. 12. Berger TM, Hoffman C, Thieberg MD. Prurigo nodularis and photosensitivity in AIDS: treatment with thalidomide. J Am Acad Dermatol 1995;33:837-8. 13. Tarng DC, Cho YL, Lui H, et al. Hemodialysis related prutitus: a double-blind, placebo controlled, crossover study of capsaicin 0.025%. Nephron 1996;72:617-22. 14. Kantor GR, Resnik KS. Treatment of lichen simplex chroni-
16
15.
16.
17.
18.
19. 20.
21.
22.
23.
24.
cus with topical capsaicin cream. Acta Derm Venereol 1997; 77:158-9. Muller EW, Dewolf JT, Wijermans PW, et al. Long-term treatment with interferon alpha-2b for severe pruritus in patients with polycythemia vera. Br J Hematol 1995;89:313-8. Jeamougin M, Rain JD, Najean Y. Efficacy of photochemotherapy on severe pruritus in patients with polycythemia vera. Ann Hematol 1996;73:91-3. Pardo RJ, Bogaert MA, Penneys NS, et al. UVB phototherapy of the pruritic papular eruption of the acquired immunodeficiency syndrome. J Am Acad Dermatol 1992;26:423-8. Berman B, Flores F, Burke G. Efficacy of pentoxyfylline in the treatment of pruritic papular eruption of HIV-infected persons. J Am Acad Dermatol 1998;38:955-9. Hadziyannis SJ. Skin diseases associated with hepatitis C virus infection. J Eur Acad Dermatol Venereol 1998; 10:12-21. Drake LA, Millikan LE. The antipruritic effect of 5% doxepin cream in patients with eczematous dermatitis. Arch Dermatol 1995;131:1403-8. Kikuchi-Numagami K, Sato M, Tagami H. Successful treatment of a therapy-resistant severely pruritic skin eruption of malignancy-associated dermatomyositis with high-dose intravenous immunoglobulin. J Dermatol 1996;23:340-3. Monk BE. Transcutaneous electronic nerve stimulation in the treatment of generalized pruritus. Clin Exp Dermatol 1993;18:67-8. Nilsson H, Levinsson A, Schovenberg J. Cutaneous field stimulation (CFS): a powerful new method to combat itch. Pain 1997;71:49-55. Peer G, Kivity S, Agami O, et al. Randomized crossover trial of naltrexone in uraemic pruritus. Lancet 1996;348:1552-4.
Curr Probl Dermatol, January/February 2000