- Email: [email protected]
Panel discussions
PRESENTED AT THE SYMPOSIUM, "RETINOIDS: PRESENT AND FUTURE," AT THE 18TH WORLD CONGRESS OF DERMATOLOGY, SUPPORTED BY EDUCATIONAL GRANTS FROM F. HOFFMANN-LA ROCHE LTD AND ROCHE DERMATOLOGICS II
IIIII
I
III I
Panel discussions I: CLINICAL USE
Discussants: W. J. Cunliffe, MD; P. Fritsch, MD; J.-H. Saurat, MD," E. Sendagorta, MD; A. R. Shalita, MD; and J. Voorhees, MD Hidradenitis suppurativa Dr. J.-H. Saurat~ Do you have any experience with etretinate in the treatment of hidradenitis suppurativa? I believe there are reports that isotretinoin does not work well and etretinate appears to be effective. Dr. W. J. Cunliffe. Yes, we have treated about nine patients with isotretinoin and three or four with etretinate, but without too much success. For very severe disease, I tend to give oral steroids to reduce the inflammation and then refer the patient to a plastic surgeon. Dr. A. R. Shalita. Stu Madden has treated a fairly large group of patients with hidradenitis suppurativa with etretinate and reports that it requires very long treatment. One year is minimum. I think we have not seen some of those results because physicians tend to stop the drug too soon. Dr. Cunliffe. Yes, we stopped after about 6 or 8 months.
Topical medication after isotretinoin Question. After a patient has completed a regimen of isotretinoin, do you routinely use any topical medication afterward to decrease the chances of having to repeat isotretinoin? Dr. Cunliffe. Yes, but not routinely. I simply tell them to buy an over-the-counter preparation containing benzoyl peroxide.
Dermabrasion Question. How long should you wait after the use of isotretinoin to perform dermabrasion? Dr. Cunlitfe. A recent article in the Journal of 16/0/42340
Plastic and Reconstructive Surgery suggests that scarring is a problem when dermabrasion was performed up to 9 or 12 months after isotretinoin, However, there is a need for much more wellcontrolled study on this issue. We perform many biopsies as part of a research protocol, and we have looked at the type of scarring found in patients who had received isotretinoin and in patients who never received that drug. Measurement of the scarring revealed no difference between the two types of patients, but the results are those associated with biopsy and not dermabrasion. Dr. Shalita. That is an interesting and still somewhat controversial subject. John Strauss has pointed out that there is a highly variable response by the sebaceous gland. The sebaceous glands must return almost to normal before wound healing will occur after dermabrasion. The sebaceous glands participate in the healing phenomenon by dedifferentiating and providing an epithelium. In addition, investigators who use wire brush surgery, such as John Yarborough and Norman Orentreich, do not experience problems after isotretinoin therapy. The diamond fraise is much more common but causes friction and heat. Clearly, we need more research in this type of wound healing. Of course, retinoids also have a marked effect on collagenase. Disorders of keratinization Question. Are there disorders of keratinization in which you would use isotretinoin in preference to one of the aromatic retinoids? Dr. P. Fritsch. Actually, we have never done this. In Europe, etretinate was approved early, and we prescribed it for our patients who are hyperkeratotic. We never had to switch to isotretinoin, although I am aware that it has been done in the United States. Dr. Cunliffe. Have you seen patients with disorders of keratinization who respond to etretinate and not to etretin (acitretin) or vice versa? Dr. Fritseh. No, never. I believe that the two drugs are equal in their effects and the dosages required. $43
$44
Panel discussions
Question. How would you treat a 12-year-old girl with severe Darier's disease? Dr. Fritsch. I would start with the usual dose of t m g / k g of acitretin and tell her to take contraceptives. Dr. Sara'at. I disagree with the starting dose for Darier's disease. In our experience Darier's disease is often exacerbated by 1.0 mg/kg; thus we start with a very low dose of acitretin. At times we do not have to go as high as 0.5 mg/kg. Dr. Fritseh. In my experience the dosage requirements may differ with any type of ichthyosis. I agree that in Darier's disease, as in other situations, very low doses may be effective.
Photodamage studies Dr. Cunliffe. Have you looked at the relapse rate after the discontinuation of topical therapy for photodamage? Also, have you studied the type of acne the patients had? Dr. E, Sendagorta. No, we have not looked at relapse rates in these patients. Graham Bryce examined this question in his animal model and found that wrinkle effacement seems to be a long-lasting effect in the UVB-irradiated hairless mice. We are currently conducting a large-scale, multicenter clinical study that will hopefully answer this question. To answer your second question, we had reports that all patients had mild inflammatory ache. We may have to look at this more carefully. Dr. Fritsch. Don't you think that the erythema seen in almost every patient you showed us influenced the people who did the comparison? The slight erythema gives the patients a more juvenile appearance, perhaps clouding the objectivity of the comparison. Also, can you provide histopathologic data? Dr. Sendagorta. In response to your first question, of course there is a possibility. However, although some of the slides showed patients with a rosy glow or an erythematous appearance, the actual analysis of the erythema response showed that few patients had irritation at the end of treatment. Therefore I believe this might have influenced some of the panelists but not the global picture of the effect. I did not present histopathologic data because of time constraints, but basically we see the same histopathologic results as have been described by all investigators studying topical retinoids, including Drs. Voorhees and Bhawan. We have seen the same reported epidermal changes but no dermal changes. Dr. Saurat. You are saying that topical isotretinoin does not induce irritation but does induce skin
Journal of the American Academy of Dermatology
repair, in contrast to topical tretinoin, which induces both irritation and skin repair. Can you elaborate on this difference? Is it a question of dose or a characteristic of the active ligand or something different? Dr. Sendagorta. First, I am not sure that the term "dermal repair" is an accurate one. I prefer to say that it improves some of the manifestations associated with photodamaged skin. Nevertheless, I do not know what the exact mechanism might be. The reality is that we see efficacy associated with isotretinoin, and we do not believe that this efficacy is related to irritation because the drug is fairly well tolerated. Further studies may help us to better answer your difficult question. Question. The literature suggests that the histologic correlate of photodamaged skin, as opposed to intrinsic aging, is varying degrees of anomalies of the melanocytes and keratinocytes as well as the deposition of abnormal elastotic material. Did you find any such changes? Also, I understand that there are a few reports in the literature comparing tretinoin with benzoyl peroxide as well as lauryl sulfate in the treatment of photodamaged skin. The results suggest that those products show clinical and possibly histologic changes that correlate with those seen with tretinoin. Can you comment? Dr. Sendagorta. We have not seen a clear correlation between histologic and clinical changes in our studies. To the best of my knowledge, melanin content correlates very well with pigmentary changes, but it is unclear whether the other histologic changes correlate well with clinical changes. With respect to your second question, I am not familiar with clinical reports other than the study reported by Professor R. Marks and his group in Cardiff in the British Journal of Dermatology (1990;123:457-66). Dr. J. Voorhees. The paper by Dr. Marks and associates used histologic and bioengineering techniques but no clinical evaluations. The results suggested that some of the changes produced in the skin by tretinoin were similar to those induced by abrasive cleansers, but no clinical analysis was attempted. We have published studies that found that sodium lauryl sulfate (SLS) causes epidermal changes that are very similar to those of tretinoin. However, a clinical trial with SLS has never been performed, probably because it is extremely difficult to determine a dose that is sufficiently uniform from person to person. Our experience is that one would have to have a battery of different SLS concentrations to
Volume 27 Number 6, Part 2 December 1992 approximate the retinoic acid reaction to perform a clinical trial that would not be a nightmare. I believe that it will be quite some time before such a study is done. My last point concerns what appears to be happening at the dermoepidermal junction. I agree with Dr. Sendagorta that very little happens in the dermis at the level of light microscopic examination, even in patients who have responded dramatically after as much as 11/2years of therapy. It appears that some fairly dramatic but invisible changes occur in the grenz zone area of the dermis, which may be responsible for what is seen clinically, but the nature of that has not yet been worked out. II: PHARMACOLOGY AND SIDE EFFECTS OF RETINOID THERAPY
Discussants: R. Armstrong, MD," W. J. Cunliffe, MD," P. Fritsch, MD; W. E. Lambert, PhD," W. Zouboulis, MD,"J.-H. Saurat, MD,"A. R. Shalita, MD," A. Vahlquist, MD; and J. Voorhees, MD Alcohol-related risks Dr. A. Vahlquist. It seems that the patients at greatest risk of an acitretin-to-etretinate conversion are women in their childbearing years who use alcohol. Do you think it is feasible to monitor the plasma drug concentration in these patients after cessation of acitretin therapy to determine whether etretinate has actually been formed, and if etretinate is not present, inform the patient that there is no risk of delayed elimination and associated terategenicity? Dr. W. E. Lambert. No. I think even if people are not drinking at the time they start therapy with acitretin, they will form etretinate if they start to drink later. So we cannot use the terms "former" or "nonformer"; as soon as a person drinks while acitretin is present in the body, the compound will be formed, even after treatment is stopped. Ester conversion Question. Another point concerns the theoretic possibility that retinoids other than acitretin could also be converted to some esterified compounds. I wonder if there may be formation of such compounds in an isotretinoin-treated patient. Dr. Lambert. We did not look for it. Question. I would like to ask about other esters of the free acid. It is known, for example, that pyridoxal, a vitamin component, is converted to an ester under the influence of hydrolytic enzymes. If other esters may be stored in the adipose tissue, the high-
Panel discussions $45 performance liquid chromatographic system would not detect them. Dr. Lambert. We looked for other esters but found only ethyl ester. Therefore we found only etretinate, and no other compound, in that chromatographic region under these conditions. Dro R. Armstrong. We do not have any data at this time that would enlighten us regarding whether this esterification can occur with isotretinoin or other retinoids, but it clearly can happen with acitretin. Dr. J. Voorhees. What class of enzyme would you suspect is involved in the conversion? Dr. Lambert. I do not know. It is a very strange biochemical reaction that we never would have expected. Patient monitoring Dr. W. J. CunlNe. Regarding short-term isotretinoin therapy, we have now reviewed several hundred patients treated as long as 4 months. We know the short-term side effects are reversible, and we calculated savings of $25,000 a year by not doing long-term testing. Once risk factors are excluded, do you think that there is any justification for further measurements of lipid or liver function after a baseline test and a second one at 4 or 6 weeks? Dr. J.-H. Saul'at. No, I do not. I do only one baseline test and one at 4 weeks; if all results are normal, I do not pursue. Skeletal effects Dr. W. Zoubodis. Does retinoid-induced abnormal calcification correlate with changes in calcium phosphate product or calcitonin levels in serum or urine? Dr. Vahlquist. As far as I know no close correlation exists between these parameters. A poster presentation at this World Congress of Dermatology reported that isotretinoin was associated with a change in vitamin D metabolites, but this can be the result of the reformation of the skeleton. Dr. P. Fritsch. Could you address the possible correlation between the duration of retinoid administration and the DISH (diffuse idiopathic skeletal hyperostosis)-like syndrome? Did you find a correlation? Dr. Vahlquist. This is a very confusing issue because some patients develop these skeletal side effects within a couple of months and others develop them after many years of treatment. Clearly, there are individual differences in susceptibility to these
$46
Journal of the American Academy of Dermatology
Panel discussions
side effects; they are not just a reflection of cumulative toxicity. Dr. Fritsch. If you had a patient with a fairly severe condition who required retinoids and also had D I S H changes, would you recommend administration or discontinuation of the drug? Dr. Vahlquist. Provided you monitor these patients very carefully, I do not think there is any absolute contraindieation to continued therapy. We know of several patients in whom treatment was continued, and no additional formation of DISH or hyperostosis occurred.
Differing side effect profiles? Dr. Saurat. Do you have any evidence that changing from one retinoid to another reduces side effects? Dr. Vahlquist. We know, for example, that different retinoids induce different degrees of hyperlipidemia, and switching from one retinoid to another may dramatically improve retinoid-induced hyperlipidemia (Br J Dermato11985;112-59). Also, some of the newer synthetic retinoids have a totally different spectrum of side effects. For example, some retinoids lack skeletal toxicity, at least when tested in an animal system. This is an area of future research.
Mucocutaneous side effects Dr. A. R. Shalita. Most of what we have discussed are what I call the silent side effects because patients are not aware of them. However, some patients have persistent visible side effects, such as dry skin, hair loss, skin fragility, and so on. How common are these long-term, persistent, mucocutaneous side effects? Dr. Saurat. I have not seen these to be persistent. However, there are occasional reports.
Nonsteroidal antiinflarnmatory drng-retinoid interactions Dr. Fritsch, There is a report that retinoids interact with nonsteroidal antiinflammatory drugs. This is a common situation because patients who have psoriatic arthropathy are often given both drugs. What is your personal experience? Dr. Saul-at. I have seen no such side effect in our patients who are treated with both retinoids and nonsteroidal antiinflammatory agents.
III: RETINOID TREATMENT--THE FUTURE Discussants: W. J. Cunliffe, AID, and J. DiGiovanna, MD
Cancer studies Question. Are there any prospective or retrospective trials on retinoid use during the early stages of malignancies? Dr. J. DiGiovalma. There may be trials of combination treatments, but I am unaware of any that have been published. Question. Studies have shown that some doses of 13-cis retinoic acid and etretinate are helpful in patients who have multiple basal or squamous cell carcinomas. If you had a patient with coronary artery disease and severe multiple recurrences of skin carcinomas who said, "Is there an alternative to having you cut them out all the time?," which drug would you propose and at what dose? Dr. DiGiovanna. We have followed several patients who had multiple skin cancers. My opinion is that if a tumor is present, retinoids are not very effective therapy. In patients with multiple tumors who are treated with high-dose isotretinoin, only a small percentage of exist~g tumors undergo complete remission. However, if the patient is develophag multiple new lesions, some good documented studies show that retinoids can provide effective chemoprevention. You must choose patients care-
fully. Question. What minimal dose would you use for chemopreventionwnot for treatment, but chemoprevention? Dr. DiGiovanna. In our experience the chemoprevention dose varies tremendously. Some patients have done well on as low as 0.5 mg/kg/day; other patients have no benefit from doses as high as 1.75 or 2 mg/kg/day. The response is extremely variable between patients. A patient who can be cleared of existing tumors but is still developing many new tumors could be started on 0.5 mg/kg/day. If adequate chemoprevention does not occur by 6 to 12 months, the dose can be increased in increments of 0.5 mg/kg/day. Dr. W. J. Cunliffe. At this Congress we have heard about the interaction between vitamins D and A. There is an article in the Lancet on the use of calcipotriol in breast cancer. Do you know of any work that has used vitamin A and calcipotriol synergistically on skin malignancies? Dr. DiGiovanna. I do not know of any work that has been published, but I believe that we are going to see more studies of these combinations.
IIIII
I
III I
Panel discussions I: CLINICAL USE
Discussants: W. J. Cunliffe, MD; P. Fritsch, MD; J.-H. Saurat, MD," E. Sendagorta, MD; A. R. Shalita, MD; and J. Voorhees, MD Hidradenitis suppurativa Dr. J.-H. Saurat~ Do you have any experience with etretinate in the treatment of hidradenitis suppurativa? I believe there are reports that isotretinoin does not work well and etretinate appears to be effective. Dr. W. J. Cunliffe. Yes, we have treated about nine patients with isotretinoin and three or four with etretinate, but without too much success. For very severe disease, I tend to give oral steroids to reduce the inflammation and then refer the patient to a plastic surgeon. Dr. A. R. Shalita. Stu Madden has treated a fairly large group of patients with hidradenitis suppurativa with etretinate and reports that it requires very long treatment. One year is minimum. I think we have not seen some of those results because physicians tend to stop the drug too soon. Dr. Cunliffe. Yes, we stopped after about 6 or 8 months.
Topical medication after isotretinoin Question. After a patient has completed a regimen of isotretinoin, do you routinely use any topical medication afterward to decrease the chances of having to repeat isotretinoin? Dr. Cunliffe. Yes, but not routinely. I simply tell them to buy an over-the-counter preparation containing benzoyl peroxide.
Dermabrasion Question. How long should you wait after the use of isotretinoin to perform dermabrasion? Dr. Cunlitfe. A recent article in the Journal of 16/0/42340
Plastic and Reconstructive Surgery suggests that scarring is a problem when dermabrasion was performed up to 9 or 12 months after isotretinoin, However, there is a need for much more wellcontrolled study on this issue. We perform many biopsies as part of a research protocol, and we have looked at the type of scarring found in patients who had received isotretinoin and in patients who never received that drug. Measurement of the scarring revealed no difference between the two types of patients, but the results are those associated with biopsy and not dermabrasion. Dr. Shalita. That is an interesting and still somewhat controversial subject. John Strauss has pointed out that there is a highly variable response by the sebaceous gland. The sebaceous glands must return almost to normal before wound healing will occur after dermabrasion. The sebaceous glands participate in the healing phenomenon by dedifferentiating and providing an epithelium. In addition, investigators who use wire brush surgery, such as John Yarborough and Norman Orentreich, do not experience problems after isotretinoin therapy. The diamond fraise is much more common but causes friction and heat. Clearly, we need more research in this type of wound healing. Of course, retinoids also have a marked effect on collagenase. Disorders of keratinization Question. Are there disorders of keratinization in which you would use isotretinoin in preference to one of the aromatic retinoids? Dr. P. Fritsch. Actually, we have never done this. In Europe, etretinate was approved early, and we prescribed it for our patients who are hyperkeratotic. We never had to switch to isotretinoin, although I am aware that it has been done in the United States. Dr. Cunliffe. Have you seen patients with disorders of keratinization who respond to etretinate and not to etretin (acitretin) or vice versa? Dr. Fritseh. No, never. I believe that the two drugs are equal in their effects and the dosages required. $43
$44
Panel discussions
Question. How would you treat a 12-year-old girl with severe Darier's disease? Dr. Fritsch. I would start with the usual dose of t m g / k g of acitretin and tell her to take contraceptives. Dr. Sara'at. I disagree with the starting dose for Darier's disease. In our experience Darier's disease is often exacerbated by 1.0 mg/kg; thus we start with a very low dose of acitretin. At times we do not have to go as high as 0.5 mg/kg. Dr. Fritseh. In my experience the dosage requirements may differ with any type of ichthyosis. I agree that in Darier's disease, as in other situations, very low doses may be effective.
Photodamage studies Dr. Cunliffe. Have you looked at the relapse rate after the discontinuation of topical therapy for photodamage? Also, have you studied the type of acne the patients had? Dr. E, Sendagorta. No, we have not looked at relapse rates in these patients. Graham Bryce examined this question in his animal model and found that wrinkle effacement seems to be a long-lasting effect in the UVB-irradiated hairless mice. We are currently conducting a large-scale, multicenter clinical study that will hopefully answer this question. To answer your second question, we had reports that all patients had mild inflammatory ache. We may have to look at this more carefully. Dr. Fritsch. Don't you think that the erythema seen in almost every patient you showed us influenced the people who did the comparison? The slight erythema gives the patients a more juvenile appearance, perhaps clouding the objectivity of the comparison. Also, can you provide histopathologic data? Dr. Sendagorta. In response to your first question, of course there is a possibility. However, although some of the slides showed patients with a rosy glow or an erythematous appearance, the actual analysis of the erythema response showed that few patients had irritation at the end of treatment. Therefore I believe this might have influenced some of the panelists but not the global picture of the effect. I did not present histopathologic data because of time constraints, but basically we see the same histopathologic results as have been described by all investigators studying topical retinoids, including Drs. Voorhees and Bhawan. We have seen the same reported epidermal changes but no dermal changes. Dr. Saurat. You are saying that topical isotretinoin does not induce irritation but does induce skin
Journal of the American Academy of Dermatology
repair, in contrast to topical tretinoin, which induces both irritation and skin repair. Can you elaborate on this difference? Is it a question of dose or a characteristic of the active ligand or something different? Dr. Sendagorta. First, I am not sure that the term "dermal repair" is an accurate one. I prefer to say that it improves some of the manifestations associated with photodamaged skin. Nevertheless, I do not know what the exact mechanism might be. The reality is that we see efficacy associated with isotretinoin, and we do not believe that this efficacy is related to irritation because the drug is fairly well tolerated. Further studies may help us to better answer your difficult question. Question. The literature suggests that the histologic correlate of photodamaged skin, as opposed to intrinsic aging, is varying degrees of anomalies of the melanocytes and keratinocytes as well as the deposition of abnormal elastotic material. Did you find any such changes? Also, I understand that there are a few reports in the literature comparing tretinoin with benzoyl peroxide as well as lauryl sulfate in the treatment of photodamaged skin. The results suggest that those products show clinical and possibly histologic changes that correlate with those seen with tretinoin. Can you comment? Dr. Sendagorta. We have not seen a clear correlation between histologic and clinical changes in our studies. To the best of my knowledge, melanin content correlates very well with pigmentary changes, but it is unclear whether the other histologic changes correlate well with clinical changes. With respect to your second question, I am not familiar with clinical reports other than the study reported by Professor R. Marks and his group in Cardiff in the British Journal of Dermatology (1990;123:457-66). Dr. J. Voorhees. The paper by Dr. Marks and associates used histologic and bioengineering techniques but no clinical evaluations. The results suggested that some of the changes produced in the skin by tretinoin were similar to those induced by abrasive cleansers, but no clinical analysis was attempted. We have published studies that found that sodium lauryl sulfate (SLS) causes epidermal changes that are very similar to those of tretinoin. However, a clinical trial with SLS has never been performed, probably because it is extremely difficult to determine a dose that is sufficiently uniform from person to person. Our experience is that one would have to have a battery of different SLS concentrations to
Volume 27 Number 6, Part 2 December 1992 approximate the retinoic acid reaction to perform a clinical trial that would not be a nightmare. I believe that it will be quite some time before such a study is done. My last point concerns what appears to be happening at the dermoepidermal junction. I agree with Dr. Sendagorta that very little happens in the dermis at the level of light microscopic examination, even in patients who have responded dramatically after as much as 11/2years of therapy. It appears that some fairly dramatic but invisible changes occur in the grenz zone area of the dermis, which may be responsible for what is seen clinically, but the nature of that has not yet been worked out. II: PHARMACOLOGY AND SIDE EFFECTS OF RETINOID THERAPY
Discussants: R. Armstrong, MD," W. J. Cunliffe, MD," P. Fritsch, MD; W. E. Lambert, PhD," W. Zouboulis, MD,"J.-H. Saurat, MD,"A. R. Shalita, MD," A. Vahlquist, MD; and J. Voorhees, MD Alcohol-related risks Dr. A. Vahlquist. It seems that the patients at greatest risk of an acitretin-to-etretinate conversion are women in their childbearing years who use alcohol. Do you think it is feasible to monitor the plasma drug concentration in these patients after cessation of acitretin therapy to determine whether etretinate has actually been formed, and if etretinate is not present, inform the patient that there is no risk of delayed elimination and associated terategenicity? Dr. W. E. Lambert. No. I think even if people are not drinking at the time they start therapy with acitretin, they will form etretinate if they start to drink later. So we cannot use the terms "former" or "nonformer"; as soon as a person drinks while acitretin is present in the body, the compound will be formed, even after treatment is stopped. Ester conversion Question. Another point concerns the theoretic possibility that retinoids other than acitretin could also be converted to some esterified compounds. I wonder if there may be formation of such compounds in an isotretinoin-treated patient. Dr. Lambert. We did not look for it. Question. I would like to ask about other esters of the free acid. It is known, for example, that pyridoxal, a vitamin component, is converted to an ester under the influence of hydrolytic enzymes. If other esters may be stored in the adipose tissue, the high-
Panel discussions $45 performance liquid chromatographic system would not detect them. Dr. Lambert. We looked for other esters but found only ethyl ester. Therefore we found only etretinate, and no other compound, in that chromatographic region under these conditions. Dro R. Armstrong. We do not have any data at this time that would enlighten us regarding whether this esterification can occur with isotretinoin or other retinoids, but it clearly can happen with acitretin. Dr. J. Voorhees. What class of enzyme would you suspect is involved in the conversion? Dr. Lambert. I do not know. It is a very strange biochemical reaction that we never would have expected. Patient monitoring Dr. W. J. CunlNe. Regarding short-term isotretinoin therapy, we have now reviewed several hundred patients treated as long as 4 months. We know the short-term side effects are reversible, and we calculated savings of $25,000 a year by not doing long-term testing. Once risk factors are excluded, do you think that there is any justification for further measurements of lipid or liver function after a baseline test and a second one at 4 or 6 weeks? Dr. J.-H. Saul'at. No, I do not. I do only one baseline test and one at 4 weeks; if all results are normal, I do not pursue. Skeletal effects Dr. W. Zoubodis. Does retinoid-induced abnormal calcification correlate with changes in calcium phosphate product or calcitonin levels in serum or urine? Dr. Vahlquist. As far as I know no close correlation exists between these parameters. A poster presentation at this World Congress of Dermatology reported that isotretinoin was associated with a change in vitamin D metabolites, but this can be the result of the reformation of the skeleton. Dr. P. Fritsch. Could you address the possible correlation between the duration of retinoid administration and the DISH (diffuse idiopathic skeletal hyperostosis)-like syndrome? Did you find a correlation? Dr. Vahlquist. This is a very confusing issue because some patients develop these skeletal side effects within a couple of months and others develop them after many years of treatment. Clearly, there are individual differences in susceptibility to these
$46
Journal of the American Academy of Dermatology
Panel discussions
side effects; they are not just a reflection of cumulative toxicity. Dr. Fritsch. If you had a patient with a fairly severe condition who required retinoids and also had D I S H changes, would you recommend administration or discontinuation of the drug? Dr. Vahlquist. Provided you monitor these patients very carefully, I do not think there is any absolute contraindieation to continued therapy. We know of several patients in whom treatment was continued, and no additional formation of DISH or hyperostosis occurred.
Differing side effect profiles? Dr. Saurat. Do you have any evidence that changing from one retinoid to another reduces side effects? Dr. Vahlquist. We know, for example, that different retinoids induce different degrees of hyperlipidemia, and switching from one retinoid to another may dramatically improve retinoid-induced hyperlipidemia (Br J Dermato11985;112-59). Also, some of the newer synthetic retinoids have a totally different spectrum of side effects. For example, some retinoids lack skeletal toxicity, at least when tested in an animal system. This is an area of future research.
Mucocutaneous side effects Dr. A. R. Shalita. Most of what we have discussed are what I call the silent side effects because patients are not aware of them. However, some patients have persistent visible side effects, such as dry skin, hair loss, skin fragility, and so on. How common are these long-term, persistent, mucocutaneous side effects? Dr. Saurat. I have not seen these to be persistent. However, there are occasional reports.
Nonsteroidal antiinflarnmatory drng-retinoid interactions Dr. Fritsch, There is a report that retinoids interact with nonsteroidal antiinflammatory drugs. This is a common situation because patients who have psoriatic arthropathy are often given both drugs. What is your personal experience? Dr. Saul-at. I have seen no such side effect in our patients who are treated with both retinoids and nonsteroidal antiinflammatory agents.
III: RETINOID TREATMENT--THE FUTURE Discussants: W. J. Cunliffe, AID, and J. DiGiovanna, MD
Cancer studies Question. Are there any prospective or retrospective trials on retinoid use during the early stages of malignancies? Dr. J. DiGiovalma. There may be trials of combination treatments, but I am unaware of any that have been published. Question. Studies have shown that some doses of 13-cis retinoic acid and etretinate are helpful in patients who have multiple basal or squamous cell carcinomas. If you had a patient with coronary artery disease and severe multiple recurrences of skin carcinomas who said, "Is there an alternative to having you cut them out all the time?," which drug would you propose and at what dose? Dr. DiGiovanna. We have followed several patients who had multiple skin cancers. My opinion is that if a tumor is present, retinoids are not very effective therapy. In patients with multiple tumors who are treated with high-dose isotretinoin, only a small percentage of exist~g tumors undergo complete remission. However, if the patient is develophag multiple new lesions, some good documented studies show that retinoids can provide effective chemoprevention. You must choose patients care-
fully. Question. What minimal dose would you use for chemopreventionwnot for treatment, but chemoprevention? Dr. DiGiovanna. In our experience the chemoprevention dose varies tremendously. Some patients have done well on as low as 0.5 mg/kg/day; other patients have no benefit from doses as high as 1.75 or 2 mg/kg/day. The response is extremely variable between patients. A patient who can be cleared of existing tumors but is still developing many new tumors could be started on 0.5 mg/kg/day. If adequate chemoprevention does not occur by 6 to 12 months, the dose can be increased in increments of 0.5 mg/kg/day. Dr. W. J. Cunliffe. At this Congress we have heard about the interaction between vitamins D and A. There is an article in the Lancet on the use of calcipotriol in breast cancer. Do you know of any work that has used vitamin A and calcipotriol synergistically on skin malignancies? Dr. DiGiovanna. I do not know of any work that has been published, but I believe that we are going to see more studies of these combinations.