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PUVA for Psoriasis
PUVA for Psoriasis Safety Worries Cloud an Effective New Treatment
•The ultraviolet spectrum is divided into three parts. UV-A, commonly called blacklight, contains the longest wavelengths (320-400 nanometers); UV-B covers the midrange (290-320 nm); and UV-C contains the shortest wavelengths (200-290 nm) and is referred to as germicidal radiation because it kills numerous microorganisms.
34
P
so ria sis does not kill. But as many as 6 million Americans who suffer from psoriasis know first hand how it can stand in the way of a normal life. Creating inflamed, scaly patches on the skin, often on visible areas, psoriasis can be disfiguring to the point where its victims no longer participate in the normal work and play activities of everyday life. In recent years, increasing attention has been paid to a new therapy for the most severe forms of psoriasis, a therapy that offers dramatic results in previously untreatable cases but which may, in the process, be exposing as many as 100,000 people to a heightened long-term risk of skin cancer. The therapy is called PUVA, a combination of oral psoralen medication (the "P" in the acronym) and long-wavelength ultraviolet light exposures (UVA)*. The Food and Drug Administration says PUVA isn't yet shown to be safe and hasn't approved it. Many medical authorities, including the American Academy of Dermatology's Task Force on Psoriasis and Photobiology and FDA's Dermatology Advisory Committee, think FDA's stand is the right one for the foreseeable future. But many physicians are using it under investigational (IND) protocols. An estimated 30,000 patients are in these IND studies and probably another 70,000 are being treated in uncontrolled circumstances. Both the drug involved and the ultraviolet light apparatus are easily available and a substantial number of physicians, including some members of the AAD Task Force, think PUVA should receive limited approval for use in cases where no good alternative treatment is available.
Psoriasis Therapies PUVA therapy, as a result, poses a classic question of risks vs. benefits. Since psoriasis is rarely, if ever, fatal, both the physician and the patient must consider the degree of hardship imposed on the patient in a particular case, and the level of long-range risk a properly informed patient is willing to accept as the price for what may be the only relief available. The financial impact of psoriasis is great. A study funded by the National Institutes of Health estimated the total expenditure on psoriasis remedies in 1979 at $248 million and calculated the total direct and indirect costs of psoriasis to each patient at $5,800 per year. 1 Traditional therapies for psoriasis, effective in the large majority of cases, have relied on topical steroid creams applied to the skin to ease inflammation and reduce the size of affected areas. These medications are minimally absorbed and unwanted side effects occur infrequently. More radical therapies can involve the use of methotrexate, a potent drug sometimes used in cancer therapy, and coal tar regimens. Coal tar treatment requires hospitalization, often several weeks in duration, and at considerable expense. And there are patients for whom these therapies are ineffective and whose psoriasis remains intractable. In 1974, a team of physicians at the Massachusetts General Hospital published a report that ushered in the debate that continues to this day. They found that patients with severe psoriasis could be successfully treated by ultraviolet light if they presensitized the skin to UV radiation by administering oral methoxsalen.
American Pharmacy Vol. NS21, No.9, September 1981/530 I
PUVA Treatment Methoxsalen, a naturally occurring member of the psoralen family, was first isolated in 1947 from Ammi majus Linn, a plant with a long history of medical use, found primarily in the Middle East. In the mid-1950s it was approved by FDA for the treatment of vitiligo. The sensitivity-enhancing effect of methoxsalen peaks about two hours after ingestion, then gradually declines until the drug is fully eliminated from the body, generally after about 24 hours, depending on the dosage . In PUVA treatment, the dosage ranges from 20-70 mg depending on the patient's weight. The drug is taken orally about two hours before each scheduled UV treatment session. Since the skin is more sensitive to all wavelengths of UV light, not merely the UV -A spectrum used in treatment, patients should be cautioned to minimize exposure to sunlight, sunlamps and fluorescent light while the drug is active in the system, or at least for 24 hours. Protective clothing should be worn and special precautions taken, including sunglasses to protect the eyes. Taking methoxsalen with meals is recommended to avoid nausea. After taking the medication the patient goes to the treatment site-a hospital, clinic or a physician's office-and receives the UV expos·ure. The supervising physician controls the intensity and duration of the exposures to eliminate such unwanted immediate side effects as burning and inflam·m a tion of the skin. Parts of the body can be screened, either to protect them from the UV l~ght completely or to vary exposure hme for different areas. In this way
American Pharmacy Vol. NS21, No. 9, September 1981/531
an arm or leg, for example, can be given treatment without exposing the entire body to more UV light than is necessary. PUVA treatments are repeated no more frequently than every other day and typically continue for 6-8 weeks. The mean response time of severe psoriasis cases is five weeks, although there is wide individual variation and some cases do not respond at all.
Efficacy of PUVA Since the Massachusetts General study in 1974, clinical tests of PUVA have been underway at medical centers throughout the country, medical and popular interest in the therapy have increased, and concern for the long-term dangers posed by PUVA has grown a pace. Th~re is little disagreement about its efficacy:
''The combination of irradiation of long ultraviolet wavelength and psoralens is a highly effective treatment for psoriasis," says Dr. Eugene Farber of Stanford University in a 1980 report. 2 Farber is chairman of the AAD Task Force on Psoriasis. "Nonetheless," Farber continued, "PUVA is not a cure for psoriasis, as patients require continued therapy. The Stanford studies, as well as those at other university centers, have confirmed the efficacy of PUVA throughout this country and abroad. For example, follow-up studies of 130 patients have shown that 87% of the patients 'cleared' within three months." PUVA treatment is relatively free of acute immediate side effects and is well tolerated by patients. Those immediate side effects that do occur-nausea, for example-can be eliminated by moderating the
35
treatment regimen. As Farber pointed out, the PUVA treatment doesn't cure psoriasis since the patient will suffer a relapse unless maintenance treatments continue over a long period of time. Although the need to return for periodic retreatment for many years may be quite acceptable to the patient, it is this long-term treatment that generates medical concern about skin cancer and other problems, including cataracts, and damage to the skin that leads to premature aging. Farber noted that in a study of 104 PUVA patients at Stanford followed for five years, 18% of the patients developed precancerous skin lesions. Similar studies from other sources have also reported an association between PUVA treatments and a variety of skin conditions that often presage development of skin cancer. While these studies don't firmly establish that PUVA causes skin cancer, they do create concern. A confounding problem in the debate is that the patients best suited to PUVA treatment-those with severe and extensive psoriasislhave often had X-ray, coal tar or other radical therapies, some of which lh ave also been associated with canper. Finding a population of patients who have received only PUVA, p1aking clearer conclusions possible, has proved quite difficult.
Fontrols on Use? ~ One investigator who supports a cautious approval of PUVA is Dr. 1fhomas Nigra of the Washington 1 Hospital Center, Washington, DC. W shington Hospital Center is one of 16 centers around the country that undertook the first wave of clinical trials of PUVA. Extensive clinical testing, with voluminous follow-up, is going on there now. To Nigra, limited approval could improve a potentially dangerous situation that exists now. ul'm not at all in favor of a blanket approval," Nigra said, ubecause I'd fear it could result in overutilization of PUVA and the potential risks are not yet clearly understood." Under a blanket approval, Nigra noted, it would also be difficult, if
36
opment of the adverse effects, if any; use of PUVA in those younger than 18 should be very strongly discouraged . • All conventional therapies must have failed. • The patient's psoriasis must be life-ruining emotionally or economically, and involve at least 30% of the patient's body, although severe involvement of limited areas .such as the palms and soles may justify PUVA even if 30% of the total skin area is not involved. "The nature and location of the . affected areas are more important It will take years than the extent," Nigra said. "For to determine , example, a surgeon who has psoriasis on his palms is out of business whether PUVA's unless he can get his psoriasis benefits outweigh cleared up." FDA's Dermatology Advisory its risks. Committee hasn't discussed PUVA since its December 1979 meeting. Dr. C. Carnot Evans, group leader of PUVA to use in hospitals, group of the Dermatology Section at FDA, health practices and other settings, says the subject will come before the "where some sort of peer review committee when it meets again, could exist" as a control on indisprobably this month. criminate use. "The committee's recommenHowever, FDA cannot approve dation was that it remain inany drug for "limited use." The vestigational until we know more agency has tried to restrict drug use about its long-term toxicity," Evans in the past, but successful lawsuits said. ''Since the committee met last, brought against the agency have hasn't been anything outthere made this approach infeasible. standing that would change a perThe agency can, however, write son's view.'' the labeling in a way that would PUVA may offer a new hope for a make it difficult to use the drug for significant number of patients sufPUVA therapy outside a controlled fering from severe psoriasis. It environment. According to an FDA might provide a means, when other spokesman, the agency can specify, methods have failed, of bringing a for example, that the equipment measure of normalcy to a life used in PUVA therapy meet strict crippled by intractable psoriasis. standards likely to be met only by But there are clouds in the PUVA hospitals and other special settings. picture that can't be dispelled today or tomorrow . The most crucial eleIND Guidelines ment in a final evaluation of PUVA Criteria have been adopted as part is one that nobody in the governof the IND protocol to guide the sement, the medical profession or the lection of patients for PUVA, and pharmaceutical industry can prowhat they amount to is a strong arvide-time . It will be 5, 10 or 15 gument for limiting the therapy to years before any relatively firm conthose for whom no other choice is clusions can be made about whether adequate and whose disease absoPUVA's benefits outweigh its risks. lutely demands successful treat-fohn f . McKeon ment, in cases where, as Farber put American Pharmacy correspondent it, "the duress is intolerable." In general, the guidelines are: References • PUVA should be limited to 1. joumal of illves tixative Dermatology, 73, part 2, 395 (1979). older patients because of the long 2. E. Farber, Jou rnal of tire American Academy of Oermntolo8fi· 2, 342 (1980). time period involved in develnot impossible, to limit PUVA to use by experienced and competent dermatologists. "At the moment, FDA's h~nds are strapped," Nigra said. "There are people out there now using PUVA and there are no controls over it. If we had some kind of approval, then FDA would have some regulations they could work with." Among those restrictions Nigra would like to see accompany an FDA approval would be a limitation
American Pharmacy Vol. NS21, No. 9, September 1981/
•The ultraviolet spectrum is divided into three parts. UV-A, commonly called blacklight, contains the longest wavelengths (320-400 nanometers); UV-B covers the midrange (290-320 nm); and UV-C contains the shortest wavelengths (200-290 nm) and is referred to as germicidal radiation because it kills numerous microorganisms.
34
P
so ria sis does not kill. But as many as 6 million Americans who suffer from psoriasis know first hand how it can stand in the way of a normal life. Creating inflamed, scaly patches on the skin, often on visible areas, psoriasis can be disfiguring to the point where its victims no longer participate in the normal work and play activities of everyday life. In recent years, increasing attention has been paid to a new therapy for the most severe forms of psoriasis, a therapy that offers dramatic results in previously untreatable cases but which may, in the process, be exposing as many as 100,000 people to a heightened long-term risk of skin cancer. The therapy is called PUVA, a combination of oral psoralen medication (the "P" in the acronym) and long-wavelength ultraviolet light exposures (UVA)*. The Food and Drug Administration says PUVA isn't yet shown to be safe and hasn't approved it. Many medical authorities, including the American Academy of Dermatology's Task Force on Psoriasis and Photobiology and FDA's Dermatology Advisory Committee, think FDA's stand is the right one for the foreseeable future. But many physicians are using it under investigational (IND) protocols. An estimated 30,000 patients are in these IND studies and probably another 70,000 are being treated in uncontrolled circumstances. Both the drug involved and the ultraviolet light apparatus are easily available and a substantial number of physicians, including some members of the AAD Task Force, think PUVA should receive limited approval for use in cases where no good alternative treatment is available.
Psoriasis Therapies PUVA therapy, as a result, poses a classic question of risks vs. benefits. Since psoriasis is rarely, if ever, fatal, both the physician and the patient must consider the degree of hardship imposed on the patient in a particular case, and the level of long-range risk a properly informed patient is willing to accept as the price for what may be the only relief available. The financial impact of psoriasis is great. A study funded by the National Institutes of Health estimated the total expenditure on psoriasis remedies in 1979 at $248 million and calculated the total direct and indirect costs of psoriasis to each patient at $5,800 per year. 1 Traditional therapies for psoriasis, effective in the large majority of cases, have relied on topical steroid creams applied to the skin to ease inflammation and reduce the size of affected areas. These medications are minimally absorbed and unwanted side effects occur infrequently. More radical therapies can involve the use of methotrexate, a potent drug sometimes used in cancer therapy, and coal tar regimens. Coal tar treatment requires hospitalization, often several weeks in duration, and at considerable expense. And there are patients for whom these therapies are ineffective and whose psoriasis remains intractable. In 1974, a team of physicians at the Massachusetts General Hospital published a report that ushered in the debate that continues to this day. They found that patients with severe psoriasis could be successfully treated by ultraviolet light if they presensitized the skin to UV radiation by administering oral methoxsalen.
American Pharmacy Vol. NS21, No.9, September 1981/530 I
PUVA Treatment Methoxsalen, a naturally occurring member of the psoralen family, was first isolated in 1947 from Ammi majus Linn, a plant with a long history of medical use, found primarily in the Middle East. In the mid-1950s it was approved by FDA for the treatment of vitiligo. The sensitivity-enhancing effect of methoxsalen peaks about two hours after ingestion, then gradually declines until the drug is fully eliminated from the body, generally after about 24 hours, depending on the dosage . In PUVA treatment, the dosage ranges from 20-70 mg depending on the patient's weight. The drug is taken orally about two hours before each scheduled UV treatment session. Since the skin is more sensitive to all wavelengths of UV light, not merely the UV -A spectrum used in treatment, patients should be cautioned to minimize exposure to sunlight, sunlamps and fluorescent light while the drug is active in the system, or at least for 24 hours. Protective clothing should be worn and special precautions taken, including sunglasses to protect the eyes. Taking methoxsalen with meals is recommended to avoid nausea. After taking the medication the patient goes to the treatment site-a hospital, clinic or a physician's office-and receives the UV expos·ure. The supervising physician controls the intensity and duration of the exposures to eliminate such unwanted immediate side effects as burning and inflam·m a tion of the skin. Parts of the body can be screened, either to protect them from the UV l~ght completely or to vary exposure hme for different areas. In this way
American Pharmacy Vol. NS21, No. 9, September 1981/531
an arm or leg, for example, can be given treatment without exposing the entire body to more UV light than is necessary. PUVA treatments are repeated no more frequently than every other day and typically continue for 6-8 weeks. The mean response time of severe psoriasis cases is five weeks, although there is wide individual variation and some cases do not respond at all.
Efficacy of PUVA Since the Massachusetts General study in 1974, clinical tests of PUVA have been underway at medical centers throughout the country, medical and popular interest in the therapy have increased, and concern for the long-term dangers posed by PUVA has grown a pace. Th~re is little disagreement about its efficacy:
''The combination of irradiation of long ultraviolet wavelength and psoralens is a highly effective treatment for psoriasis," says Dr. Eugene Farber of Stanford University in a 1980 report. 2 Farber is chairman of the AAD Task Force on Psoriasis. "Nonetheless," Farber continued, "PUVA is not a cure for psoriasis, as patients require continued therapy. The Stanford studies, as well as those at other university centers, have confirmed the efficacy of PUVA throughout this country and abroad. For example, follow-up studies of 130 patients have shown that 87% of the patients 'cleared' within three months." PUVA treatment is relatively free of acute immediate side effects and is well tolerated by patients. Those immediate side effects that do occur-nausea, for example-can be eliminated by moderating the
35
treatment regimen. As Farber pointed out, the PUVA treatment doesn't cure psoriasis since the patient will suffer a relapse unless maintenance treatments continue over a long period of time. Although the need to return for periodic retreatment for many years may be quite acceptable to the patient, it is this long-term treatment that generates medical concern about skin cancer and other problems, including cataracts, and damage to the skin that leads to premature aging. Farber noted that in a study of 104 PUVA patients at Stanford followed for five years, 18% of the patients developed precancerous skin lesions. Similar studies from other sources have also reported an association between PUVA treatments and a variety of skin conditions that often presage development of skin cancer. While these studies don't firmly establish that PUVA causes skin cancer, they do create concern. A confounding problem in the debate is that the patients best suited to PUVA treatment-those with severe and extensive psoriasislhave often had X-ray, coal tar or other radical therapies, some of which lh ave also been associated with canper. Finding a population of patients who have received only PUVA, p1aking clearer conclusions possible, has proved quite difficult.
Fontrols on Use? ~ One investigator who supports a cautious approval of PUVA is Dr. 1fhomas Nigra of the Washington 1 Hospital Center, Washington, DC. W shington Hospital Center is one of 16 centers around the country that undertook the first wave of clinical trials of PUVA. Extensive clinical testing, with voluminous follow-up, is going on there now. To Nigra, limited approval could improve a potentially dangerous situation that exists now. ul'm not at all in favor of a blanket approval," Nigra said, ubecause I'd fear it could result in overutilization of PUVA and the potential risks are not yet clearly understood." Under a blanket approval, Nigra noted, it would also be difficult, if
36
opment of the adverse effects, if any; use of PUVA in those younger than 18 should be very strongly discouraged . • All conventional therapies must have failed. • The patient's psoriasis must be life-ruining emotionally or economically, and involve at least 30% of the patient's body, although severe involvement of limited areas .such as the palms and soles may justify PUVA even if 30% of the total skin area is not involved. "The nature and location of the . affected areas are more important It will take years than the extent," Nigra said. "For to determine , example, a surgeon who has psoriasis on his palms is out of business whether PUVA's unless he can get his psoriasis benefits outweigh cleared up." FDA's Dermatology Advisory its risks. Committee hasn't discussed PUVA since its December 1979 meeting. Dr. C. Carnot Evans, group leader of PUVA to use in hospitals, group of the Dermatology Section at FDA, health practices and other settings, says the subject will come before the "where some sort of peer review committee when it meets again, could exist" as a control on indisprobably this month. criminate use. "The committee's recommenHowever, FDA cannot approve dation was that it remain inany drug for "limited use." The vestigational until we know more agency has tried to restrict drug use about its long-term toxicity," Evans in the past, but successful lawsuits said. ''Since the committee met last, brought against the agency have hasn't been anything outthere made this approach infeasible. standing that would change a perThe agency can, however, write son's view.'' the labeling in a way that would PUVA may offer a new hope for a make it difficult to use the drug for significant number of patients sufPUVA therapy outside a controlled fering from severe psoriasis. It environment. According to an FDA might provide a means, when other spokesman, the agency can specify, methods have failed, of bringing a for example, that the equipment measure of normalcy to a life used in PUVA therapy meet strict crippled by intractable psoriasis. standards likely to be met only by But there are clouds in the PUVA hospitals and other special settings. picture that can't be dispelled today or tomorrow . The most crucial eleIND Guidelines ment in a final evaluation of PUVA Criteria have been adopted as part is one that nobody in the governof the IND protocol to guide the sement, the medical profession or the lection of patients for PUVA, and pharmaceutical industry can prowhat they amount to is a strong arvide-time . It will be 5, 10 or 15 gument for limiting the therapy to years before any relatively firm conthose for whom no other choice is clusions can be made about whether adequate and whose disease absoPUVA's benefits outweigh its risks. lutely demands successful treat-fohn f . McKeon ment, in cases where, as Farber put American Pharmacy correspondent it, "the duress is intolerable." In general, the guidelines are: References • PUVA should be limited to 1. joumal of illves tixative Dermatology, 73, part 2, 395 (1979). older patients because of the long 2. E. Farber, Jou rnal of tire American Academy of Oermntolo8fi· 2, 342 (1980). time period involved in develnot impossible, to limit PUVA to use by experienced and competent dermatologists. "At the moment, FDA's h~nds are strapped," Nigra said. "There are people out there now using PUVA and there are no controls over it. If we had some kind of approval, then FDA would have some regulations they could work with." Among those restrictions Nigra would like to see accompany an FDA approval would be a limitation
American Pharmacy Vol. NS21, No. 9, September 1981/