- Email: [email protected]
Thalidomide and oxygen intermediates
304
Correspondence
two tablets of minocycline, 50 mg, 6 hours apart. Again there was no reaction and I must conclude that my allergy does not cross-react with this drug. It is not too surprising that one of Chan's patients' allergies did cross-react because it is well known that some patients show polysensitivities. I did not rechallenge myself to lower doses of tetracycline because I did not want to tempt fate and leave myself with the possibility of permanent hyperpigmentation. Although the etiology of FDE is unknown, it would seem to be a hypersensitivity phenomenon. I am surprised that all patients did not respond to the lower dose because the amount of drug ingested should not really matter. I wonder if the test doses were given on an empty stomach, since various foods and medicines will interfere with the absorption of tetracycline.
Howard Bargman, M.D., FR.C.P. University of Toronto, Sunnybrook Medical Center Toronto, Ontario, Canada REFERENCE 1. Chan HL: Fixed drug eruptions-a study oflO occurrences in Singapore. Int J Dennato1 23:607-609, 1984.
Thalidomide and oxygen intermediates To the Editor: We have read with great interest the paper, "Studies on the Anti-inflammatory Properties of Thalidomide: Effects on Polymorphonuclear Leukocytes and Monocytes," by Barnhill et al (J AM ACAD DERMATOL 11:814-819, 1984). The authors investigated the effects of thalidomide on phagocytosis by both polymorphonuclear leukocytes and monocytes as well as chemiluminescence. They found that phagocytosis was significantly depressed by 10 IJ-g/ml of thalidomide and that incubation of monocytes with 10 f..~g/ml resulted in a significant reduction of chemiluminescence, but no significant action on polymorphonuclear leukocyte chemiluminescence was observed at this concentration. We have reported that thalidomide (4, 40, 400 J-Lg/ml) had suppressive effects on the polymorphonuclear leukocyte-dependent generation of superoxide and hydroxyl radical, which is one of the most potent oxidants, without affecting chemiluminescence.' Thus, the lack of effect of thalidomide on chemiluminescence the authors found does not necessarily mean that oxygen intermediates are not involved in anti-inflammatory action mechanism of thalidomide. We have also pointed out
Journal of the American Academy of Dennato!ogy
the dissociation of the inhibitory effect of dapsone on the generation of oxygen intermediates. 2 •3 Taking these observations into consideration, we would like to stress that it is required to assess all possible oxygen intermediates before drawing conclusions because they do not always behave in an identical manner. As the authors mentioned, thalidomide has been used successfully in the treatment of various inflammatory conditions characterized by tissue infiltration with polymorphonuclear leukocytes, such as erythema nodosum leprosum which is considered to be an Arthus-type immune complex vasculitis. If thalidomide is effective in this disease by affecting polymorphonuclear leukocyte functions, it is required to suppress polymorphonuclear leukocyte chemotaxis to the inflammatory lesions and/ or the generation of inflammatory mediators in order to avoid blood vessel wall damage. We have recently found that vascular injury in cutaneous vasculitis 4 and Beh~et's diseaseS may be mediated in part by enhanced production of oxygen intermediates from polymorphonuclear leukocytes, especially hydroxyl radicals that are capable of causing tissue damages. In this context, hydroxyI radical is a much better indicator of inflammation than chemiluminescence as far as auto-oxidative tissue injuries are concerned. Our studies l •2 indicate that thalidomide and dapsone exert their anti-inflammatory effects on polymorphonuclear leukocyte-mediated dermatoses by interfering with the polymorphonuclear leukocyte-dependent oxygen intermediate generation, which may consequently protect from auto-oxidative tissue injury, and that colchicine is effective in the treatment of Beh~et's disease 6 mainly by suppressing polymorphonuclear leukocyte chemotaxis. 7.8 Thalidomide also has inhibitory effects on monocytes, as the authors reported, which may explain the effectiveness in other inflammatory processes with predominantly mononuclear cell accumulation. Both mechanisms are not mutually exclusive; however, we would like to add that favorable effects on several polymorphonuclear leukocyte-mediated dennatoses by thalidomide may be partly attributable to its reduction of oxygen intermediate generation by polymorphonuclear leukocytes, with resultant protection from oxygen intermediate-induced cytotoxic effects.
Yoshiki Miyachi, M.D. Department of Dermatology, Faculty of Medicine Kyoto University, Sakyo-ku, Kyoto 606, Japan Yukie Niwa, M.D. Niwa Institute for Immunology Tosashimizu, Kochi 787-03, Japan
Volume 13 Number 2, Part 1 August, 1985
REFERENCES 1. Miyachi Y, Ozaki M, Uchida K, Niwa Y: Effects of thalidomide on the generation of oxygen intermediates by zymosan-stimulated normal polymorphonuclear leukocytes. Arch Dermatol Res 274:363-367, 1982. 2. Miyachi Y, Niwa Y: Effects of potassium iodide, colchicine and dapsone on the generation of polymorphonuclear leukocyte-derived oxygen intermediates. Br J Dermatol 107:209-214, 1982. 3. Niwa Y, Sakane T, Miyachi Y: Dissociation of the inhibitory effect of dapsone on the generation of oxygen intermediates-in comparison with that of colchicine and various scavcngers. Biochem Pharmacol 33:2355-2360, 1984. 4. Miyachi Y, Yanase K, Imamura S, Niwa Y: Increased hydroxyl radical generation by normal polymorphonuclear leukocytes incubated in sera from patients with leukocytoclastic vasculitis. Arch Dermatol Res 274:65-71,1982. 5. Niwa Y, Miyake S, Ishimoto K, et al: Auto-oxiclative damage in Beh~et' s disease-cndothelial cell damage following the elevatecl oxygen radicals generated by stimulated neutrophils. Clin Exp Immunol 49:247-255, 1982. 6. Miyachi Y, Taniguchi S, Ozaki M, et al: Colchicine in the treatment of cutaneous manifestations of Beh~et's disease. Br J Dermatol 104:67-69, 1981. 7. Miyachi Y, Danno K, Imamura S: Suppression of active Arthus reaction by colchicine. Br J Dermatol 105:279283, 1981. 8. Miyachi Y, Takigawa M, Imamura 5: Suppression of DNCB-induced irritant dermatitis by colchicine. Acta Derm Venereol (Stockh) 61 :307-311, 1981.
Correspondence
305
thalidomide, we still do not believe that we understand how thalidomide works in the various inflammatory conditions in which it has been used. There may certainly be more than one level of action. An effect on polymorphonuclear leukocyte function would seem reasonable in view of the considerable benefit obtained in erythema nodosum leprosum and other neutrophilic dermatoses. Of particular significance would be an action on the control of polymorphonuclear leukocyte tissue influx. Since it is unsettled whether thalidomide affects polymorphonuclear leukocyte chemotaxis per se, perhaps it might be relevant to consider modulation of polymorphonuclear leukocyte influx via macrophage and/or lymphocyte regulation. 2 ,3 An action or actions on either or both of these cell types could also be germane to the clinical efficacy noted in processes such as cutaneous lupus erythematosus. We may conclude that a number of studies have suggested a variety of possible actions of thalidomide in inflammatory processes, but it is evident that only additional work will enable us to judge the significance of these and other data.
Raymond L. Barnhill, M.D. Department of Dermatology Yale University School of Medicine P.O. Box 3333, New Haven, CT 06510
Reply
REFERENCES
To the Editor:
I. Miyachi Y, Ozaki M, Uchida K, Niwa Y: Effects of thalidomide on the generation of oxygen intermediates by zymosan-stimulated normal polymorphonuclear leukocytes. Arch Demlatol Res 274:363-367, 1982. 2. Goihman-Yahr M, Convit J, Rodriguez-Ochoa G, et al: Significance of neutrophil activation in reactional lepromatous leprosy: Effects of thalidomide in vivo and in vitro. Activation in adjuvant disease. lnt Arch Allergy Appl Immunol 57:317-332, 1978. 3. Mshana RN: Hypothesis: Erythema nodosum leprosum is precipitated by an imbalance of T lymphocytes. Lepr Rev
The comments of Drs. Miyachi and Niwa are much appreciated. We would agree completely with their viewpoint that thalidomide's failure to suppress polymorphonuclear leukocyte chemiluminescence does not necessarily mean that thalidomide has no effect on the generation of all oxygen intermediates. Our conclusions did not exclude a role of thalidomide on this system or in fact on any other aspect of cellular function. Moreover, we have also considered a possible effect on oxygen intermediates in previous work. In carefully controlled experiments we found that thalidomide had only a small effect as a "scavenger" of oxygen-derived free radicals.* We nevertheless cannot dismiss the studies of Miyachi et all for various reasons. At the same time, we would advise caution in the comparison of our results with their results in view of the different methodologies used. While there have been significant investigative efforts in recent years on the mechanism(s) of action of *Barnhill RL, McDougall AC: Unpublished observations, 1982.
53:1-7, 1982,
Drug-induced pancreatitis presenting as subcutaneous fat necrosis* To the Editor: Subcutaneous fat necrosis is a rare dermatologic manifestation of underlying pancreatic disease. The Ie*The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Anny or the Department of Defense.
Correspondence
two tablets of minocycline, 50 mg, 6 hours apart. Again there was no reaction and I must conclude that my allergy does not cross-react with this drug. It is not too surprising that one of Chan's patients' allergies did cross-react because it is well known that some patients show polysensitivities. I did not rechallenge myself to lower doses of tetracycline because I did not want to tempt fate and leave myself with the possibility of permanent hyperpigmentation. Although the etiology of FDE is unknown, it would seem to be a hypersensitivity phenomenon. I am surprised that all patients did not respond to the lower dose because the amount of drug ingested should not really matter. I wonder if the test doses were given on an empty stomach, since various foods and medicines will interfere with the absorption of tetracycline.
Howard Bargman, M.D., FR.C.P. University of Toronto, Sunnybrook Medical Center Toronto, Ontario, Canada REFERENCE 1. Chan HL: Fixed drug eruptions-a study oflO occurrences in Singapore. Int J Dennato1 23:607-609, 1984.
Thalidomide and oxygen intermediates To the Editor: We have read with great interest the paper, "Studies on the Anti-inflammatory Properties of Thalidomide: Effects on Polymorphonuclear Leukocytes and Monocytes," by Barnhill et al (J AM ACAD DERMATOL 11:814-819, 1984). The authors investigated the effects of thalidomide on phagocytosis by both polymorphonuclear leukocytes and monocytes as well as chemiluminescence. They found that phagocytosis was significantly depressed by 10 IJ-g/ml of thalidomide and that incubation of monocytes with 10 f..~g/ml resulted in a significant reduction of chemiluminescence, but no significant action on polymorphonuclear leukocyte chemiluminescence was observed at this concentration. We have reported that thalidomide (4, 40, 400 J-Lg/ml) had suppressive effects on the polymorphonuclear leukocyte-dependent generation of superoxide and hydroxyl radical, which is one of the most potent oxidants, without affecting chemiluminescence.' Thus, the lack of effect of thalidomide on chemiluminescence the authors found does not necessarily mean that oxygen intermediates are not involved in anti-inflammatory action mechanism of thalidomide. We have also pointed out
Journal of the American Academy of Dennato!ogy
the dissociation of the inhibitory effect of dapsone on the generation of oxygen intermediates. 2 •3 Taking these observations into consideration, we would like to stress that it is required to assess all possible oxygen intermediates before drawing conclusions because they do not always behave in an identical manner. As the authors mentioned, thalidomide has been used successfully in the treatment of various inflammatory conditions characterized by tissue infiltration with polymorphonuclear leukocytes, such as erythema nodosum leprosum which is considered to be an Arthus-type immune complex vasculitis. If thalidomide is effective in this disease by affecting polymorphonuclear leukocyte functions, it is required to suppress polymorphonuclear leukocyte chemotaxis to the inflammatory lesions and/ or the generation of inflammatory mediators in order to avoid blood vessel wall damage. We have recently found that vascular injury in cutaneous vasculitis 4 and Beh~et's diseaseS may be mediated in part by enhanced production of oxygen intermediates from polymorphonuclear leukocytes, especially hydroxyl radicals that are capable of causing tissue damages. In this context, hydroxyI radical is a much better indicator of inflammation than chemiluminescence as far as auto-oxidative tissue injuries are concerned. Our studies l •2 indicate that thalidomide and dapsone exert their anti-inflammatory effects on polymorphonuclear leukocyte-mediated dermatoses by interfering with the polymorphonuclear leukocyte-dependent oxygen intermediate generation, which may consequently protect from auto-oxidative tissue injury, and that colchicine is effective in the treatment of Beh~et's disease 6 mainly by suppressing polymorphonuclear leukocyte chemotaxis. 7.8 Thalidomide also has inhibitory effects on monocytes, as the authors reported, which may explain the effectiveness in other inflammatory processes with predominantly mononuclear cell accumulation. Both mechanisms are not mutually exclusive; however, we would like to add that favorable effects on several polymorphonuclear leukocyte-mediated dennatoses by thalidomide may be partly attributable to its reduction of oxygen intermediate generation by polymorphonuclear leukocytes, with resultant protection from oxygen intermediate-induced cytotoxic effects.
Yoshiki Miyachi, M.D. Department of Dermatology, Faculty of Medicine Kyoto University, Sakyo-ku, Kyoto 606, Japan Yukie Niwa, M.D. Niwa Institute for Immunology Tosashimizu, Kochi 787-03, Japan
Volume 13 Number 2, Part 1 August, 1985
REFERENCES 1. Miyachi Y, Ozaki M, Uchida K, Niwa Y: Effects of thalidomide on the generation of oxygen intermediates by zymosan-stimulated normal polymorphonuclear leukocytes. Arch Dermatol Res 274:363-367, 1982. 2. Miyachi Y, Niwa Y: Effects of potassium iodide, colchicine and dapsone on the generation of polymorphonuclear leukocyte-derived oxygen intermediates. Br J Dermatol 107:209-214, 1982. 3. Niwa Y, Sakane T, Miyachi Y: Dissociation of the inhibitory effect of dapsone on the generation of oxygen intermediates-in comparison with that of colchicine and various scavcngers. Biochem Pharmacol 33:2355-2360, 1984. 4. Miyachi Y, Yanase K, Imamura S, Niwa Y: Increased hydroxyl radical generation by normal polymorphonuclear leukocytes incubated in sera from patients with leukocytoclastic vasculitis. Arch Dermatol Res 274:65-71,1982. 5. Niwa Y, Miyake S, Ishimoto K, et al: Auto-oxiclative damage in Beh~et' s disease-cndothelial cell damage following the elevatecl oxygen radicals generated by stimulated neutrophils. Clin Exp Immunol 49:247-255, 1982. 6. Miyachi Y, Taniguchi S, Ozaki M, et al: Colchicine in the treatment of cutaneous manifestations of Beh~et's disease. Br J Dermatol 104:67-69, 1981. 7. Miyachi Y, Danno K, Imamura S: Suppression of active Arthus reaction by colchicine. Br J Dermatol 105:279283, 1981. 8. Miyachi Y, Takigawa M, Imamura 5: Suppression of DNCB-induced irritant dermatitis by colchicine. Acta Derm Venereol (Stockh) 61 :307-311, 1981.
Correspondence
305
thalidomide, we still do not believe that we understand how thalidomide works in the various inflammatory conditions in which it has been used. There may certainly be more than one level of action. An effect on polymorphonuclear leukocyte function would seem reasonable in view of the considerable benefit obtained in erythema nodosum leprosum and other neutrophilic dermatoses. Of particular significance would be an action on the control of polymorphonuclear leukocyte tissue influx. Since it is unsettled whether thalidomide affects polymorphonuclear leukocyte chemotaxis per se, perhaps it might be relevant to consider modulation of polymorphonuclear leukocyte influx via macrophage and/or lymphocyte regulation. 2 ,3 An action or actions on either or both of these cell types could also be germane to the clinical efficacy noted in processes such as cutaneous lupus erythematosus. We may conclude that a number of studies have suggested a variety of possible actions of thalidomide in inflammatory processes, but it is evident that only additional work will enable us to judge the significance of these and other data.
Raymond L. Barnhill, M.D. Department of Dermatology Yale University School of Medicine P.O. Box 3333, New Haven, CT 06510
Reply
REFERENCES
To the Editor:
I. Miyachi Y, Ozaki M, Uchida K, Niwa Y: Effects of thalidomide on the generation of oxygen intermediates by zymosan-stimulated normal polymorphonuclear leukocytes. Arch Demlatol Res 274:363-367, 1982. 2. Goihman-Yahr M, Convit J, Rodriguez-Ochoa G, et al: Significance of neutrophil activation in reactional lepromatous leprosy: Effects of thalidomide in vivo and in vitro. Activation in adjuvant disease. lnt Arch Allergy Appl Immunol 57:317-332, 1978. 3. Mshana RN: Hypothesis: Erythema nodosum leprosum is precipitated by an imbalance of T lymphocytes. Lepr Rev
The comments of Drs. Miyachi and Niwa are much appreciated. We would agree completely with their viewpoint that thalidomide's failure to suppress polymorphonuclear leukocyte chemiluminescence does not necessarily mean that thalidomide has no effect on the generation of all oxygen intermediates. Our conclusions did not exclude a role of thalidomide on this system or in fact on any other aspect of cellular function. Moreover, we have also considered a possible effect on oxygen intermediates in previous work. In carefully controlled experiments we found that thalidomide had only a small effect as a "scavenger" of oxygen-derived free radicals.* We nevertheless cannot dismiss the studies of Miyachi et all for various reasons. At the same time, we would advise caution in the comparison of our results with their results in view of the different methodologies used. While there have been significant investigative efforts in recent years on the mechanism(s) of action of *Barnhill RL, McDougall AC: Unpublished observations, 1982.
53:1-7, 1982,
Drug-induced pancreatitis presenting as subcutaneous fat necrosis* To the Editor: Subcutaneous fat necrosis is a rare dermatologic manifestation of underlying pancreatic disease. The Ie*The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Anny or the Department of Defense.