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Leukocytoclastic vasculitis secondary to trazodone treatment
CorFes
oHdeNce
Leukocytoclastic vasculitis secondary to trazodone t r e a t m e n t To the Editor: Trazodone, a triazole pyridine derivative, is a recently introduced effective antidepressant differing structurally and pharmacologically from the tricyclics, tetracyclics, and monoamine oxidase inhibitors, t It displays a favorable side effect profile, including low anticholinergic activity, and may have a reduced potential for both cardiotoxicity and lethal overdose? ,3 Previously, trazodone has been associated only with mild dermatologic reactions? We are reporting the development of leukocytoclastic vasculitis, a more serious skin disorder, during trazodone treatment. Leukocytoclastic vasculitis is characterized by inflammation and destruction of small blood vessels. 4''~ The cutaneous vessels of the lower extremities represent the major site of involvement, and lesions may range from classical palpable purpura to severe ulcerations. This disorder may extend to the renal, pulmonary, cardiovascular, hepatic, and central nervous systems and thus lead to further serious complications. While most cases are idiopathic, drugs are the most common known cause of leukocytoelastic vasculitis. Agents most frequently implicated include barbiturates, phenothiazines, aspirin, sulfonamides, and iodides. 4 Leukocytoclastic vasculitis may also develop in association with collagen vascular diseases, neoplasia, and mixed cryoglobulinemia. Case report. The patient was a 62-year-old white man with bipolar affective disorder. His history was positive for osteoarthritis, asthma, multiple allergies, and a previous episode of hypersensitivity vasculitis 10 years previously while taking Equagesic (meprobamate, ethoheptazine, and aspirin). For the preceding 2 years he had attended our lithium clinic and had taken lithium, 300 mg twice daily, theophylline, 300 mg twice daily, temazepam, 30 mg at bedtime, multivitamins, and aspirin, 650 mg four times daily. He was taking no other over-the-counter medications. Six months previously, the patient became depressed and started trazodone, which was increased to 350 mg daily. His mood improved rapidly and he experienced fewer side effects than with previous antidepressants. Within several days he developed a skin rash that progressively worsened but that he failed to bring to our attention until 3 months later. His reluctance to infoma us stemmed from his suspicion that the rash represented an allergic reaction and that discontinuation of the drug
Fig. 1. Biopsy-proved leukocytoclastic vasculitis secondary to trazodone treatment.
might be indicated. The consulting dermatologist found scattered 8-14 mm erythematous macular-papular lesions, with eroded necrotic centers, on the extensor aspect of the thighs and anterior portion of the trunk. Biopsy of a typical lesion indicated leukocytoclastic vasculitis consisting of reactive endothelium of the vessels in the superficial portion of the dermis, with extravasated red blood cells, fibrinoid deposition around the blood vessels, and nuclear dust (Fig. 1). The overlying epidermis was necrotic. History and presentation suggested a drug reaction. Other causes of leukoeytoclastic vasculitis were ruled out by physical examination and laboratory studies. We stopped all medications except lithium and trazodone. While on this regimen for 3 weeks, there was no change in the rash. Next, we withheld lithium for 8 days, again with no change. Finally, we discontinued trazodone and reinstated lithium. After 5 days, no new lesions had occurred, and within 10 days all lesions were resolving. We then restarted his temazepam and multivitamins but continued withholding aspirin, as this has been as-
669
670
Journal of the American Academy of Dermatology
Correspondence
sociated frequently with leukocytoclastic vasculitis. ~ He remained clear of rash. Three months later he complained of depression and asked to resume trazodone. We restarted trazodone, and 5 days later the rash reappeared. We again discontinued trazodone and all lesions quickly resolved. At no time was there evidence of the vasculitis extending to other organ systems. This pattern of clinical presentation--appearance of leukocytoclastic vasculitis shortly after the introduction of the new drug, resolution with cessation of the drug, and re-emergence upon challenge--indicates that leukocytoclastic vasculitis was precipitated by trazodone.
Stephan C. Mann, M.D. Veterans Administration Medical Center Mental Hygiene Clinic 1421 Cherry St. Philadelphia, PA 19102 Mary M. Walker, R.Ph., B.S. Veterans Administration Medical Center Department of Pharmacy 1421 Cherry St. Philadelphia, PA 19102 Gregory G. Messenger, M.D. University of Pennsylvania Department of Dermatology Philadelphia, PA 19104 Robert A. Greenstein, M.D. University of Pennsylvania Department of Psychiatry Philadelphia, PA 19104
immunohistochernical Study With an Antibody to S-100 Protein" (J AM ACAD DERMATOL 9:360-362, 1983). On the basis of their study, these authors concluded, "It therefore seems unlikely that fibrous papule represents a form of degenerative nevus as some investigators have proposed." I am gratified that Spiegel et al came to the very same conclusion as did A. Bernard Ackerman and I in 1979 in an article about fibrous papule that appeared in the A merican Journal of Der-
matopatholo gy. 1 We concluded that, "We do not believe that the multinueleated cells are melanocytes, nor do we share the view o f Graham, Sanders, Johnson, and Helwig or Sayland, Marks, and Jones that fibrous papules of the face represent resolving melanocytic nevi." Adding another reference to their paper might have enriched the bibliography of Spiegel et al, and it is to that end that this letter is written.
Prof. Dr. Wilhelm Meigel Chefarzt der Dermatologischen Abteilung, Allg. Krankenhaus St. Georg Lohmi'thlenstr. 5, D-2000 Hamburg 1, West Germany REFERENCE 1. Meigel WN, Ackerman AB: Fibrous papule of the face. Am J Dermatopathol 1:329-340, 1979.
Reply
To the Editor: REFERENCES 1. Kellams LI, Klapper MH, Small JG: Trazodone, a new antidepressant: Efficacy and safety in endogenous depression. J Ctin Psychiatry 40:390-395, 1979. 2. Himmelhoch JM: Cardiovascular effects of trazodone in humans. J Clin Psychopharmacol 1:76S-81S, 1981. 3. Rawls WN: Trazodone. Drug Intell Clin Pharm 16:7-13, 1982. 4. Domonkos AN, Arnold HL, Odom RB, editors: Andrews' Diseases of the skin, ed. 7. Philadelphia, 1982, W. B. Saunders Co. 5. Lever WF, Schaumburg-Lever G, editors: Histopathology of the skin, ed. 6. Philadelphia, 1983, J. B. Lippincott Co.
F i b r o u s p a p u l e s a n d n e v o c e l l u l a r nevi
To the Editor: I read with interest the paper by J. Spiegel, M. Nadji, and N. S. Penneys entitled "Fibrous Papule: An
In their article (J AM ACAD DERMATOL 9:360-362, 1983), Spiegel, Nadji, and Penneys conclude that the absence of C-100 protein in stellate cells of fibrous papule makes it unlikely that this lesion represents a form of degenerated nevus. Although they acknowledge that absence of this protein may represent a result of the degenerative process, they indicate that this finding is more likely an indicator that there is no pathogenetic relationship between fibrous papule and nevocellular nevus. No convincing data are offered to support this view. It is hazardous to draw conclusions about dynamic processes from static evidence. A previous paper from this group (Cancer 50:2203-2206, 1982) concluded that the presence of carcinoembryonic antigen (CEA) in Paget's cells confirmed that these cells were of glandular origin, disregarding the possibility that the glandular characteristics of Paget's cells are the result of metaplasia of keratinocytes. Theories concerning histogenesis and pathogenesis
oHdeNce
Leukocytoclastic vasculitis secondary to trazodone t r e a t m e n t To the Editor: Trazodone, a triazole pyridine derivative, is a recently introduced effective antidepressant differing structurally and pharmacologically from the tricyclics, tetracyclics, and monoamine oxidase inhibitors, t It displays a favorable side effect profile, including low anticholinergic activity, and may have a reduced potential for both cardiotoxicity and lethal overdose? ,3 Previously, trazodone has been associated only with mild dermatologic reactions? We are reporting the development of leukocytoclastic vasculitis, a more serious skin disorder, during trazodone treatment. Leukocytoclastic vasculitis is characterized by inflammation and destruction of small blood vessels. 4''~ The cutaneous vessels of the lower extremities represent the major site of involvement, and lesions may range from classical palpable purpura to severe ulcerations. This disorder may extend to the renal, pulmonary, cardiovascular, hepatic, and central nervous systems and thus lead to further serious complications. While most cases are idiopathic, drugs are the most common known cause of leukocytoelastic vasculitis. Agents most frequently implicated include barbiturates, phenothiazines, aspirin, sulfonamides, and iodides. 4 Leukocytoclastic vasculitis may also develop in association with collagen vascular diseases, neoplasia, and mixed cryoglobulinemia. Case report. The patient was a 62-year-old white man with bipolar affective disorder. His history was positive for osteoarthritis, asthma, multiple allergies, and a previous episode of hypersensitivity vasculitis 10 years previously while taking Equagesic (meprobamate, ethoheptazine, and aspirin). For the preceding 2 years he had attended our lithium clinic and had taken lithium, 300 mg twice daily, theophylline, 300 mg twice daily, temazepam, 30 mg at bedtime, multivitamins, and aspirin, 650 mg four times daily. He was taking no other over-the-counter medications. Six months previously, the patient became depressed and started trazodone, which was increased to 350 mg daily. His mood improved rapidly and he experienced fewer side effects than with previous antidepressants. Within several days he developed a skin rash that progressively worsened but that he failed to bring to our attention until 3 months later. His reluctance to infoma us stemmed from his suspicion that the rash represented an allergic reaction and that discontinuation of the drug
Fig. 1. Biopsy-proved leukocytoclastic vasculitis secondary to trazodone treatment.
might be indicated. The consulting dermatologist found scattered 8-14 mm erythematous macular-papular lesions, with eroded necrotic centers, on the extensor aspect of the thighs and anterior portion of the trunk. Biopsy of a typical lesion indicated leukocytoclastic vasculitis consisting of reactive endothelium of the vessels in the superficial portion of the dermis, with extravasated red blood cells, fibrinoid deposition around the blood vessels, and nuclear dust (Fig. 1). The overlying epidermis was necrotic. History and presentation suggested a drug reaction. Other causes of leukoeytoclastic vasculitis were ruled out by physical examination and laboratory studies. We stopped all medications except lithium and trazodone. While on this regimen for 3 weeks, there was no change in the rash. Next, we withheld lithium for 8 days, again with no change. Finally, we discontinued trazodone and reinstated lithium. After 5 days, no new lesions had occurred, and within 10 days all lesions were resolving. We then restarted his temazepam and multivitamins but continued withholding aspirin, as this has been as-
669
670
Journal of the American Academy of Dermatology
Correspondence
sociated frequently with leukocytoclastic vasculitis. ~ He remained clear of rash. Three months later he complained of depression and asked to resume trazodone. We restarted trazodone, and 5 days later the rash reappeared. We again discontinued trazodone and all lesions quickly resolved. At no time was there evidence of the vasculitis extending to other organ systems. This pattern of clinical presentation--appearance of leukocytoclastic vasculitis shortly after the introduction of the new drug, resolution with cessation of the drug, and re-emergence upon challenge--indicates that leukocytoclastic vasculitis was precipitated by trazodone.
Stephan C. Mann, M.D. Veterans Administration Medical Center Mental Hygiene Clinic 1421 Cherry St. Philadelphia, PA 19102 Mary M. Walker, R.Ph., B.S. Veterans Administration Medical Center Department of Pharmacy 1421 Cherry St. Philadelphia, PA 19102 Gregory G. Messenger, M.D. University of Pennsylvania Department of Dermatology Philadelphia, PA 19104 Robert A. Greenstein, M.D. University of Pennsylvania Department of Psychiatry Philadelphia, PA 19104
immunohistochernical Study With an Antibody to S-100 Protein" (J AM ACAD DERMATOL 9:360-362, 1983). On the basis of their study, these authors concluded, "It therefore seems unlikely that fibrous papule represents a form of degenerative nevus as some investigators have proposed." I am gratified that Spiegel et al came to the very same conclusion as did A. Bernard Ackerman and I in 1979 in an article about fibrous papule that appeared in the A merican Journal of Der-
matopatholo gy. 1 We concluded that, "We do not believe that the multinueleated cells are melanocytes, nor do we share the view o f Graham, Sanders, Johnson, and Helwig or Sayland, Marks, and Jones that fibrous papules of the face represent resolving melanocytic nevi." Adding another reference to their paper might have enriched the bibliography of Spiegel et al, and it is to that end that this letter is written.
Prof. Dr. Wilhelm Meigel Chefarzt der Dermatologischen Abteilung, Allg. Krankenhaus St. Georg Lohmi'thlenstr. 5, D-2000 Hamburg 1, West Germany REFERENCE 1. Meigel WN, Ackerman AB: Fibrous papule of the face. Am J Dermatopathol 1:329-340, 1979.
Reply
To the Editor: REFERENCES 1. Kellams LI, Klapper MH, Small JG: Trazodone, a new antidepressant: Efficacy and safety in endogenous depression. J Ctin Psychiatry 40:390-395, 1979. 2. Himmelhoch JM: Cardiovascular effects of trazodone in humans. J Clin Psychopharmacol 1:76S-81S, 1981. 3. Rawls WN: Trazodone. Drug Intell Clin Pharm 16:7-13, 1982. 4. Domonkos AN, Arnold HL, Odom RB, editors: Andrews' Diseases of the skin, ed. 7. Philadelphia, 1982, W. B. Saunders Co. 5. Lever WF, Schaumburg-Lever G, editors: Histopathology of the skin, ed. 6. Philadelphia, 1983, J. B. Lippincott Co.
F i b r o u s p a p u l e s a n d n e v o c e l l u l a r nevi
To the Editor: I read with interest the paper by J. Spiegel, M. Nadji, and N. S. Penneys entitled "Fibrous Papule: An
In their article (J AM ACAD DERMATOL 9:360-362, 1983), Spiegel, Nadji, and Penneys conclude that the absence of C-100 protein in stellate cells of fibrous papule makes it unlikely that this lesion represents a form of degenerated nevus. Although they acknowledge that absence of this protein may represent a result of the degenerative process, they indicate that this finding is more likely an indicator that there is no pathogenetic relationship between fibrous papule and nevocellular nevus. No convincing data are offered to support this view. It is hazardous to draw conclusions about dynamic processes from static evidence. A previous paper from this group (Cancer 50:2203-2206, 1982) concluded that the presence of carcinoembryonic antigen (CEA) in Paget's cells confirmed that these cells were of glandular origin, disregarding the possibility that the glandular characteristics of Paget's cells are the result of metaplasia of keratinocytes. Theories concerning histogenesis and pathogenesis