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Cutis is a peer-reviewed clinical journal for the dermatologist, allergist, and general practitioner published monthly since 1965. Concise clinical articles present the practical side of dermatology, helping physicians to improve patient care. Cutis is referenced in Index Medicus/MEDLINE and is written and edited by industry leaders.
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A peer-reviewed, indexed journal for dermatologists with original research, image quizzes, cases and reviews, and columns.
Pemphigus, Pregnancy, and Plasmapheresis
Recurrent, Localized Urticaria and Erythema Multiforme: A Review and Management of Cutaneous Anthrax Vaccine–Related Events
The October 2001 domestic anthrax attacks affected 22 people, resulting in 5 fatalities. The added global terrorist threats have created an increasing need for homeland protection, as well as protection of our widely deployed forces battling terrorism. It is now relevant for physicians to be familiar with both clinical anthrax and adverse vaccine-related events associated with the resumption of the anthrax vaccine program. Dermatologists played a lead role in the initial response to the anthrax attack. We must be the lead providers most familiar with the cutaneous reactions that may be seen with the preventive vaccination. This article reviews the latest recommended evaluation and management of anthrax vaccine adverse events.
Case Reports Patient 1—A 36-year-old white male active duty military fighter pilot developed recurrent, localized urticaria after receiving his sixth anthrax vaccination (Figure 1). Results of a skin biopsy showed a superficial perivascular dermatitis with eosinophils consistent with urticaria. The urticaria continues to recur 21/2 years after his last vaccination and remains localized to the vaccinated arm.
Patient 2—A 33-year-old black male military member developed erythema multiforme one day after receiving his fifth anthrax vaccination. He had been treated for pharyngitis with a 10-day course of oral penicillin, which had been completed 2 days prior to receiving the vaccination. Target lesions were present on both arms and hands but were more prominent on the arm that received the vaccination (Figure 2). Results of a skin biopsy revealed a superficial perivascular and interface lymphocytic dermatitis, with vacuolar changes along the dermoepidermal junction compatible with erythema multiforme.
Patient 3—A 28-year-old white male military member presented with a pruritic rash that had developed on his face approximately 12 hours after receiving his fifth anthrax vaccination. The rash had spread to his torso (Figure 3) and lower extremities. Results of a punch biopsy revealed a superficial and deep lymphocytic infiltrate with interface changes and some extravasated red blood cells, findings felt to be consistent with an erythema multiforme reaction (Figure 4). The patient was treated with a 2-week course of prednisone and intramuscular diphenhydramine (Benadryl®), and clearing of symptoms was noted within 10 days.
Comment
The threat of anthrax is deadly and real, as shown by the domestic attacks via the US Postal Service in October 2001. In all, there were 11 confirmed cases of inhalation anthrax, resulting in 5 fatalities. In addition, there were 7 confirmed cases and 4 suspected cases of cutaneous anthrax. Twenty of the 22 cases were unquestionably linked to mail contaminated with a single strain of Bacillus anthracis.1 Anthrax is easy and cheap to produce and can be stored for prolonged periods, with spores survivable for decades in ambient conditions.2 The spores are resistant to dryness, heat, UV light, gamma radiation, and many disinfectants.3 In addition, anthrax is odorless, colorless, tasteless, and difficult to detect, thus making it a likely choice for future biological attacks. After the first gulf war, Iraq admitted to producing and deploying weaponized anthrax in missiles.4 The Sverdlovsk anthrax outbreak in the former Soviet Union occurred after the accidental release of aerosolized anthrax spores from a bioweapons facility and resulted in as many as 250 cases with 100 deaths.2 Fortunately, we have a vaccine that has been judged safe and effective by the US Food and Drug Administration (FDA), Centers for Disease Control and Prevention, and National Academy of Sciences. Protecting the health of US military forces who defend our vital interests is a national obligation.5 The trade-off for force protection of our military personnel involves a small incidence of vaccine-related adverse events (AEs), the most common being local type injection site reactions or skin reactions.
Natural cutaneous anthrax manifests within a few days as a painless, pruritic papule that progresses to a blister and evolves to a painless ulcer, with a black central eschar and surrounding local edema. In contrast, vaccine-related events manifest differently, and the vaccine cannot cause clinical anthrax infections. An algorithm for the evaluation of suspected cutaneous anthrax has been published by the American Academy of Dermatology Ad Hoc Task Force on Bioterrorism.6 Additional guidelines for clinical and laboratory diagnoses, specimen handling, and postexposure prophylaxis are available from the US Centers for Disease Control and Prevention.7
The vaccine itself is made from a noninfectious, cell-free sterile filtrate of an attenuated, nonencapsulated, nonproteolytic strain of B anthracis.8 It is considered an inactivated vaccine and is unable to cause infection. The anthrax vaccine has been approved by the FDA since 1970 and is safely administered to veterinarians, laboratory workers, woolen mill workers, and livestock handlers.8 In 1997, it was mandated that all US military personnel receive it. Full protection requires a schedule of 6 injections over 18 months (specifically, at 0, 2, and 4 weeks and 6, 12, and 18 months), with an annual booster thereafter. In the event of anthrax exposure, the vaccine also can be offered as postexposure prophylaxis with 3 doses at 2-week intervals, along with postexposure antibiotics.2 Contraindications to the anthrax vaccine include hypersensitivity reaction to a prior dose or vaccine component, human immunodeficiency virus positivity or immune suppression (active corticosteroid or other immunosuppressive treatment), any active infection or acute illness, pregnancy (confirmed or suspected), and age younger than 18 years or older than 65 years.
Efficacy and Safety
The vaccine's efficacy against aerosolized anthrax was shown in studies on nonhuman primates. Sixty-two (95%) of the 65 primates vaccinated with the anthrax vaccine adsorbed (AVA) survived a lethal aerosol challenge, whereas all 18 unvaccinated controls died.8 In actively monitored studies on the safety of AVA, mild local reactions occurred in 3% to 20% of doses, moderate reactions in 1% to 3% of doses, and severe reactions in less than 1% of doses.8 Acute systemic reactions were reported in 0.06% of doses and consisted of transient symptoms of fever, chills, nausea, and general body aches.8
The current system for reporting AEs is the Vaccine Adverse Event Reporting System (VAERS), and the FDA reviews 100% of these reports. In addition, a US Department of Defense directive requires its military providers to initiate a report for any event following AVA that results in hospitalization, any loss of duty of more than 24 hours, or for suspected vaccine contamination.9 Reporting of other reactions suspected because of vaccination is encouraged, especially those that are clinically significant or unusual. The form can be obtained on the Web at http://www.vaers.org or via telephone at 800-822-7967. Electronic reporting is available on the Web at http://secure.vaers.org/VaersDataEntryintro.htm. The VAERS is a passive surveillance system, and determining causal associations between vaccines and AEs is not always possible.10 Other concurrent infections or exposures may precipitate a given symptom that may simply coincide with the receipt of a vaccine.11 For example, patient 2 may have had vaccine-associated erythema multiforme but because he had recently completed a course of penicillin, we cannot exclude the possibility of a concurrent antibiotic association.
The Anthrax Vaccine Expert Committee reviewed 602 VAERS reports filed from 1998 through 1999.12 Nearly one half of reports noted a local injection site AE, 33% of which were noted to be moderate to large. A subcutaneous nodule was cited in 5.3% of reports. Although three fourths of reports noted a "systemic" AE, these covered a broad spectrum, with 34 types cited at a frequency of more than 1%. The most common AEs, in declining order of incidence, were flulike symptoms, 20.8%; malaise, 13.3%; rash, 14.2%; arthralgia, 12%; headache, 10.1%; with the remainder of AEs all affecting fewer than 10% of patients. Among the reported 45 total "serious or medically important AEs," one report of each of the following was noted: systemic lupus erythematosus, angioedema, anaphylactoid reaction, and toxic epidermal necrolysis. None of these AEs were judged to be causally (defined as likely, certain, or probable) related to the vaccine itself.12 According to Friedlander et al,8 the "FDA continues to view the anthrax vaccine as safe and effective for individuals at risk of exposure to anthrax."
Management of Adverse Events
Adverse reactions after vaccination can be divided into local and systemic.
Cutaneous Reactions—The cutaneous manifestations and the latest recommendations from the Walter Reed National Vaccine healthcare center network9 are summarized partially in Tables 1 and 2.
Local reactions involve the injection site or have contiguous spread and are graded based on the measured size of the local redness or swelling (Table 1). Most local anthrax vaccine reactions require no treatment and resolve within 72 hours, though topical or oral steroids and oral antihistamines can be used to help manage symptoms. Unless the local reaction is very large or complicated, the patient can usually proceed with subsequent doses. Although some of these reactions may mimic cellulitis, antibiotic therapy for postvaccination inflammation is not warranted. Allergy consultation is recommended for a large or complicated reaction, especially if this occurs after the second dose. In this instance, the patient may be immune (a hyperresponder) and may not require further series (with the exception of the yearly booster).9 When a significant local type reaction has occurred, pretreatment to help prevent future large local reactions is indicated.
Systemic Reactions—These commonly include flulike symptoms, such as fever, anorexia, nausea, arthralgia, myalgia, or malaise. Treatment of mild to moderate systemic events is symptomatic (Table 2). Pretreatment also may be given with the next vaccine in patients who have had these symptoms on prior AVA vaccinations. If symptoms are clinically consistent with serum sickness or are severe and prolonged, the patient may benefit from a short course of oral prednisone. Vaccine-related AEs may warrant temporary delay from the schedule. When resumed, this does not require starting over but rather simply continuing from the last dose.9
For a generalized maculopapular rash or target lesions, a skin biopsy should be performed, especially if the rash is suggestive of early erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. In these cases, temporary exemption from further vaccinations and VAERS reporting are indicated. The possibility exists that additional doses may result in a more serious skin reaction and should be given with caution only after expert evaluation and consideration of the risk:benefit ratio. The dermatologist should provide a clinical histopathologic diagnosis to help the allergist or expert in the vaccination program decide the best course for continuation or exemption from the full anthrax series. These cases may warrant permanent exemption from further vaccination series. No apparent safety data for challenge dosing or desensitization in these potentially life-threatening skin reactions exist. In patient 2 with erythema multiforme, further vaccinations for anthrax were waived permanently. Similarly, deferral from further anthrax vaccinations was recommended in patient 3.
In those cases of severe urticaria or angioedema, temporary exemption may be granted while requesting allergy consultation. Additional doses should be given with caution only after expert evaluation and consideration of the risk:benefit ratio. Permanent exemption may be required for those with anaphylaxis or sudden onset angioedema. In patient 1 with recurrent localized urticaria, the allergist recommended that a formal skin-prick test to future vaccine lots be performed before he received any further vaccine in the series. Although this local allergic-type reaction may be due to some component of the vaccine, we are unable to define the specific cause at this time. This is a rather unusual manifestation, with recurrence of the urticaria still persisting 21/2 years later and restricted only to the vaccinated arm.
Conclusion
There are ongoing studies to evaluate whether a reduced number of anthrax vaccinations will provide the same immunity. In addition, other ongoing studies are comparing intramuscular administration versus the current usual subcutaneous route. Preliminary reports have shown that local reactions are less common in patients who received the vaccine via the intramuscular route than in those who received the vaccine via the subcutaneous route.13 This change in route of administration could reduce the number of adverse cutaneous reactions in the future. For further expert advice or clinical consultations, contact the Walter Reed National Vaccine Healthcare Center via telephone: 202-782-0411; fax: 202-782-4658; or e-mail: [email protected].
Since the domestic anthrax attacks in October 2001 and in the presence of continued worldwide threats to our armed forces, force protection remains a top priority. As dermatologists, we should be familiar with the current anthrax vaccine
program and be able to recognize and treat anthrax vaccine–related AEs.
- Bartlett JG, Inglesby TV, Borio L. Management of anthrax. Clin Infect Dis. 2002;35:851-858.
- Inglesby TV, O'Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA. 2002;287:2236-2252.
- Dixon TC, Meselson M, Guillemin J, et al. Anthrax. N Engl J Med. 1999;341:815-826.
- Swartz MN. Recognition and management of anthrax—an update. N Engl J Med. 2001;345:1621-1626.
- Mazzuchi JF, Claypool RG, Hyams KC, et al. Protecting the health of U.S. military forces: a national obligation. Aviat Space Environ Med. 2000;71:260-265.
- Carucci JA, McGovern TW, Norton SA, et al. Cutaneous anthrax management algorithm. J Am Acad Dermatol. 2002;47:766-769.
- Centers for Disease Control and Prevention. Guidelines for comprehensive procedures for collecting environmental samples for culturing Bacillus anthracis (revised April 2002) and anthrax: exposure management/prophylaxis (preventing transmission). Atlanta, Ga: Centers for Disease Control and Prevention Web sites. Available at: http://www.bt.cdc.gov. Accessed August 18, 2003.
- Friedlander AM, Pittman PR, Parker GW. Anthrax vaccine: evidence for safety and efficacy against inhalational anthrax. JAMA. 1999;282:2104-2106.
- Clinical guidelines for the management of adverse events after vaccination (official AVIP version). August 2002 Web site. Available at: http://www.deploymenthealth.mil/VHC/providers_management.htm. Accessed August 18, 2003.
- Centers for Disease Control and Prevention. Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS)—United States, 1991-2000. MMWR Morb Mortal Wkly Rep. 2003;52:1-19.
- Halsey NA. Anthrax vaccine and causality assessment from individual case reports. Pharmacoepidemiol Drug Saf. 2002;11:185-187.
- Sever JL, Brenner AI, Gale AD, et al. Safety of anthrax vaccine: a review by the Anthrax Vaccine Expert Committee (AVEC) of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS). Pharmacoepidemiol Drug Saf. 2002;11:189-202.
- Use of anthrax vaccine in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2000;49:1-20.
The October 2001 domestic anthrax attacks affected 22 people, resulting in 5 fatalities. The added global terrorist threats have created an increasing need for homeland protection, as well as protection of our widely deployed forces battling terrorism. It is now relevant for physicians to be familiar with both clinical anthrax and adverse vaccine-related events associated with the resumption of the anthrax vaccine program. Dermatologists played a lead role in the initial response to the anthrax attack. We must be the lead providers most familiar with the cutaneous reactions that may be seen with the preventive vaccination. This article reviews the latest recommended evaluation and management of anthrax vaccine adverse events.
Case Reports Patient 1—A 36-year-old white male active duty military fighter pilot developed recurrent, localized urticaria after receiving his sixth anthrax vaccination (Figure 1). Results of a skin biopsy showed a superficial perivascular dermatitis with eosinophils consistent with urticaria. The urticaria continues to recur 21/2 years after his last vaccination and remains localized to the vaccinated arm.
Patient 2—A 33-year-old black male military member developed erythema multiforme one day after receiving his fifth anthrax vaccination. He had been treated for pharyngitis with a 10-day course of oral penicillin, which had been completed 2 days prior to receiving the vaccination. Target lesions were present on both arms and hands but were more prominent on the arm that received the vaccination (Figure 2). Results of a skin biopsy revealed a superficial perivascular and interface lymphocytic dermatitis, with vacuolar changes along the dermoepidermal junction compatible with erythema multiforme.
Patient 3—A 28-year-old white male military member presented with a pruritic rash that had developed on his face approximately 12 hours after receiving his fifth anthrax vaccination. The rash had spread to his torso (Figure 3) and lower extremities. Results of a punch biopsy revealed a superficial and deep lymphocytic infiltrate with interface changes and some extravasated red blood cells, findings felt to be consistent with an erythema multiforme reaction (Figure 4). The patient was treated with a 2-week course of prednisone and intramuscular diphenhydramine (Benadryl®), and clearing of symptoms was noted within 10 days.
Comment
The threat of anthrax is deadly and real, as shown by the domestic attacks via the US Postal Service in October 2001. In all, there were 11 confirmed cases of inhalation anthrax, resulting in 5 fatalities. In addition, there were 7 confirmed cases and 4 suspected cases of cutaneous anthrax. Twenty of the 22 cases were unquestionably linked to mail contaminated with a single strain of Bacillus anthracis.1 Anthrax is easy and cheap to produce and can be stored for prolonged periods, with spores survivable for decades in ambient conditions.2 The spores are resistant to dryness, heat, UV light, gamma radiation, and many disinfectants.3 In addition, anthrax is odorless, colorless, tasteless, and difficult to detect, thus making it a likely choice for future biological attacks. After the first gulf war, Iraq admitted to producing and deploying weaponized anthrax in missiles.4 The Sverdlovsk anthrax outbreak in the former Soviet Union occurred after the accidental release of aerosolized anthrax spores from a bioweapons facility and resulted in as many as 250 cases with 100 deaths.2 Fortunately, we have a vaccine that has been judged safe and effective by the US Food and Drug Administration (FDA), Centers for Disease Control and Prevention, and National Academy of Sciences. Protecting the health of US military forces who defend our vital interests is a national obligation.5 The trade-off for force protection of our military personnel involves a small incidence of vaccine-related adverse events (AEs), the most common being local type injection site reactions or skin reactions.
Natural cutaneous anthrax manifests within a few days as a painless, pruritic papule that progresses to a blister and evolves to a painless ulcer, with a black central eschar and surrounding local edema. In contrast, vaccine-related events manifest differently, and the vaccine cannot cause clinical anthrax infections. An algorithm for the evaluation of suspected cutaneous anthrax has been published by the American Academy of Dermatology Ad Hoc Task Force on Bioterrorism.6 Additional guidelines for clinical and laboratory diagnoses, specimen handling, and postexposure prophylaxis are available from the US Centers for Disease Control and Prevention.7
The vaccine itself is made from a noninfectious, cell-free sterile filtrate of an attenuated, nonencapsulated, nonproteolytic strain of B anthracis.8 It is considered an inactivated vaccine and is unable to cause infection. The anthrax vaccine has been approved by the FDA since 1970 and is safely administered to veterinarians, laboratory workers, woolen mill workers, and livestock handlers.8 In 1997, it was mandated that all US military personnel receive it. Full protection requires a schedule of 6 injections over 18 months (specifically, at 0, 2, and 4 weeks and 6, 12, and 18 months), with an annual booster thereafter. In the event of anthrax exposure, the vaccine also can be offered as postexposure prophylaxis with 3 doses at 2-week intervals, along with postexposure antibiotics.2 Contraindications to the anthrax vaccine include hypersensitivity reaction to a prior dose or vaccine component, human immunodeficiency virus positivity or immune suppression (active corticosteroid or other immunosuppressive treatment), any active infection or acute illness, pregnancy (confirmed or suspected), and age younger than 18 years or older than 65 years.
Efficacy and Safety
The vaccine's efficacy against aerosolized anthrax was shown in studies on nonhuman primates. Sixty-two (95%) of the 65 primates vaccinated with the anthrax vaccine adsorbed (AVA) survived a lethal aerosol challenge, whereas all 18 unvaccinated controls died.8 In actively monitored studies on the safety of AVA, mild local reactions occurred in 3% to 20% of doses, moderate reactions in 1% to 3% of doses, and severe reactions in less than 1% of doses.8 Acute systemic reactions were reported in 0.06% of doses and consisted of transient symptoms of fever, chills, nausea, and general body aches.8
The current system for reporting AEs is the Vaccine Adverse Event Reporting System (VAERS), and the FDA reviews 100% of these reports. In addition, a US Department of Defense directive requires its military providers to initiate a report for any event following AVA that results in hospitalization, any loss of duty of more than 24 hours, or for suspected vaccine contamination.9 Reporting of other reactions suspected because of vaccination is encouraged, especially those that are clinically significant or unusual. The form can be obtained on the Web at http://www.vaers.org or via telephone at 800-822-7967. Electronic reporting is available on the Web at http://secure.vaers.org/VaersDataEntryintro.htm. The VAERS is a passive surveillance system, and determining causal associations between vaccines and AEs is not always possible.10 Other concurrent infections or exposures may precipitate a given symptom that may simply coincide with the receipt of a vaccine.11 For example, patient 2 may have had vaccine-associated erythema multiforme but because he had recently completed a course of penicillin, we cannot exclude the possibility of a concurrent antibiotic association.
The Anthrax Vaccine Expert Committee reviewed 602 VAERS reports filed from 1998 through 1999.12 Nearly one half of reports noted a local injection site AE, 33% of which were noted to be moderate to large. A subcutaneous nodule was cited in 5.3% of reports. Although three fourths of reports noted a "systemic" AE, these covered a broad spectrum, with 34 types cited at a frequency of more than 1%. The most common AEs, in declining order of incidence, were flulike symptoms, 20.8%; malaise, 13.3%; rash, 14.2%; arthralgia, 12%; headache, 10.1%; with the remainder of AEs all affecting fewer than 10% of patients. Among the reported 45 total "serious or medically important AEs," one report of each of the following was noted: systemic lupus erythematosus, angioedema, anaphylactoid reaction, and toxic epidermal necrolysis. None of these AEs were judged to be causally (defined as likely, certain, or probable) related to the vaccine itself.12 According to Friedlander et al,8 the "FDA continues to view the anthrax vaccine as safe and effective for individuals at risk of exposure to anthrax."
Management of Adverse Events
Adverse reactions after vaccination can be divided into local and systemic.
Cutaneous Reactions—The cutaneous manifestations and the latest recommendations from the Walter Reed National Vaccine healthcare center network9 are summarized partially in Tables 1 and 2.
Local reactions involve the injection site or have contiguous spread and are graded based on the measured size of the local redness or swelling (Table 1). Most local anthrax vaccine reactions require no treatment and resolve within 72 hours, though topical or oral steroids and oral antihistamines can be used to help manage symptoms. Unless the local reaction is very large or complicated, the patient can usually proceed with subsequent doses. Although some of these reactions may mimic cellulitis, antibiotic therapy for postvaccination inflammation is not warranted. Allergy consultation is recommended for a large or complicated reaction, especially if this occurs after the second dose. In this instance, the patient may be immune (a hyperresponder) and may not require further series (with the exception of the yearly booster).9 When a significant local type reaction has occurred, pretreatment to help prevent future large local reactions is indicated.
Systemic Reactions—These commonly include flulike symptoms, such as fever, anorexia, nausea, arthralgia, myalgia, or malaise. Treatment of mild to moderate systemic events is symptomatic (Table 2). Pretreatment also may be given with the next vaccine in patients who have had these symptoms on prior AVA vaccinations. If symptoms are clinically consistent with serum sickness or are severe and prolonged, the patient may benefit from a short course of oral prednisone. Vaccine-related AEs may warrant temporary delay from the schedule. When resumed, this does not require starting over but rather simply continuing from the last dose.9
For a generalized maculopapular rash or target lesions, a skin biopsy should be performed, especially if the rash is suggestive of early erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. In these cases, temporary exemption from further vaccinations and VAERS reporting are indicated. The possibility exists that additional doses may result in a more serious skin reaction and should be given with caution only after expert evaluation and consideration of the risk:benefit ratio. The dermatologist should provide a clinical histopathologic diagnosis to help the allergist or expert in the vaccination program decide the best course for continuation or exemption from the full anthrax series. These cases may warrant permanent exemption from further vaccination series. No apparent safety data for challenge dosing or desensitization in these potentially life-threatening skin reactions exist. In patient 2 with erythema multiforme, further vaccinations for anthrax were waived permanently. Similarly, deferral from further anthrax vaccinations was recommended in patient 3.
In those cases of severe urticaria or angioedema, temporary exemption may be granted while requesting allergy consultation. Additional doses should be given with caution only after expert evaluation and consideration of the risk:benefit ratio. Permanent exemption may be required for those with anaphylaxis or sudden onset angioedema. In patient 1 with recurrent localized urticaria, the allergist recommended that a formal skin-prick test to future vaccine lots be performed before he received any further vaccine in the series. Although this local allergic-type reaction may be due to some component of the vaccine, we are unable to define the specific cause at this time. This is a rather unusual manifestation, with recurrence of the urticaria still persisting 21/2 years later and restricted only to the vaccinated arm.
Conclusion
There are ongoing studies to evaluate whether a reduced number of anthrax vaccinations will provide the same immunity. In addition, other ongoing studies are comparing intramuscular administration versus the current usual subcutaneous route. Preliminary reports have shown that local reactions are less common in patients who received the vaccine via the intramuscular route than in those who received the vaccine via the subcutaneous route.13 This change in route of administration could reduce the number of adverse cutaneous reactions in the future. For further expert advice or clinical consultations, contact the Walter Reed National Vaccine Healthcare Center via telephone: 202-782-0411; fax: 202-782-4658; or e-mail: [email protected].
Since the domestic anthrax attacks in October 2001 and in the presence of continued worldwide threats to our armed forces, force protection remains a top priority. As dermatologists, we should be familiar with the current anthrax vaccine
program and be able to recognize and treat anthrax vaccine–related AEs.
The October 2001 domestic anthrax attacks affected 22 people, resulting in 5 fatalities. The added global terrorist threats have created an increasing need for homeland protection, as well as protection of our widely deployed forces battling terrorism. It is now relevant for physicians to be familiar with both clinical anthrax and adverse vaccine-related events associated with the resumption of the anthrax vaccine program. Dermatologists played a lead role in the initial response to the anthrax attack. We must be the lead providers most familiar with the cutaneous reactions that may be seen with the preventive vaccination. This article reviews the latest recommended evaluation and management of anthrax vaccine adverse events.
Case Reports Patient 1—A 36-year-old white male active duty military fighter pilot developed recurrent, localized urticaria after receiving his sixth anthrax vaccination (Figure 1). Results of a skin biopsy showed a superficial perivascular dermatitis with eosinophils consistent with urticaria. The urticaria continues to recur 21/2 years after his last vaccination and remains localized to the vaccinated arm.
Patient 2—A 33-year-old black male military member developed erythema multiforme one day after receiving his fifth anthrax vaccination. He had been treated for pharyngitis with a 10-day course of oral penicillin, which had been completed 2 days prior to receiving the vaccination. Target lesions were present on both arms and hands but were more prominent on the arm that received the vaccination (Figure 2). Results of a skin biopsy revealed a superficial perivascular and interface lymphocytic dermatitis, with vacuolar changes along the dermoepidermal junction compatible with erythema multiforme.
Patient 3—A 28-year-old white male military member presented with a pruritic rash that had developed on his face approximately 12 hours after receiving his fifth anthrax vaccination. The rash had spread to his torso (Figure 3) and lower extremities. Results of a punch biopsy revealed a superficial and deep lymphocytic infiltrate with interface changes and some extravasated red blood cells, findings felt to be consistent with an erythema multiforme reaction (Figure 4). The patient was treated with a 2-week course of prednisone and intramuscular diphenhydramine (Benadryl®), and clearing of symptoms was noted within 10 days.
Comment
The threat of anthrax is deadly and real, as shown by the domestic attacks via the US Postal Service in October 2001. In all, there were 11 confirmed cases of inhalation anthrax, resulting in 5 fatalities. In addition, there were 7 confirmed cases and 4 suspected cases of cutaneous anthrax. Twenty of the 22 cases were unquestionably linked to mail contaminated with a single strain of Bacillus anthracis.1 Anthrax is easy and cheap to produce and can be stored for prolonged periods, with spores survivable for decades in ambient conditions.2 The spores are resistant to dryness, heat, UV light, gamma radiation, and many disinfectants.3 In addition, anthrax is odorless, colorless, tasteless, and difficult to detect, thus making it a likely choice for future biological attacks. After the first gulf war, Iraq admitted to producing and deploying weaponized anthrax in missiles.4 The Sverdlovsk anthrax outbreak in the former Soviet Union occurred after the accidental release of aerosolized anthrax spores from a bioweapons facility and resulted in as many as 250 cases with 100 deaths.2 Fortunately, we have a vaccine that has been judged safe and effective by the US Food and Drug Administration (FDA), Centers for Disease Control and Prevention, and National Academy of Sciences. Protecting the health of US military forces who defend our vital interests is a national obligation.5 The trade-off for force protection of our military personnel involves a small incidence of vaccine-related adverse events (AEs), the most common being local type injection site reactions or skin reactions.
Natural cutaneous anthrax manifests within a few days as a painless, pruritic papule that progresses to a blister and evolves to a painless ulcer, with a black central eschar and surrounding local edema. In contrast, vaccine-related events manifest differently, and the vaccine cannot cause clinical anthrax infections. An algorithm for the evaluation of suspected cutaneous anthrax has been published by the American Academy of Dermatology Ad Hoc Task Force on Bioterrorism.6 Additional guidelines for clinical and laboratory diagnoses, specimen handling, and postexposure prophylaxis are available from the US Centers for Disease Control and Prevention.7
The vaccine itself is made from a noninfectious, cell-free sterile filtrate of an attenuated, nonencapsulated, nonproteolytic strain of B anthracis.8 It is considered an inactivated vaccine and is unable to cause infection. The anthrax vaccine has been approved by the FDA since 1970 and is safely administered to veterinarians, laboratory workers, woolen mill workers, and livestock handlers.8 In 1997, it was mandated that all US military personnel receive it. Full protection requires a schedule of 6 injections over 18 months (specifically, at 0, 2, and 4 weeks and 6, 12, and 18 months), with an annual booster thereafter. In the event of anthrax exposure, the vaccine also can be offered as postexposure prophylaxis with 3 doses at 2-week intervals, along with postexposure antibiotics.2 Contraindications to the anthrax vaccine include hypersensitivity reaction to a prior dose or vaccine component, human immunodeficiency virus positivity or immune suppression (active corticosteroid or other immunosuppressive treatment), any active infection or acute illness, pregnancy (confirmed or suspected), and age younger than 18 years or older than 65 years.
Efficacy and Safety
The vaccine's efficacy against aerosolized anthrax was shown in studies on nonhuman primates. Sixty-two (95%) of the 65 primates vaccinated with the anthrax vaccine adsorbed (AVA) survived a lethal aerosol challenge, whereas all 18 unvaccinated controls died.8 In actively monitored studies on the safety of AVA, mild local reactions occurred in 3% to 20% of doses, moderate reactions in 1% to 3% of doses, and severe reactions in less than 1% of doses.8 Acute systemic reactions were reported in 0.06% of doses and consisted of transient symptoms of fever, chills, nausea, and general body aches.8
The current system for reporting AEs is the Vaccine Adverse Event Reporting System (VAERS), and the FDA reviews 100% of these reports. In addition, a US Department of Defense directive requires its military providers to initiate a report for any event following AVA that results in hospitalization, any loss of duty of more than 24 hours, or for suspected vaccine contamination.9 Reporting of other reactions suspected because of vaccination is encouraged, especially those that are clinically significant or unusual. The form can be obtained on the Web at http://www.vaers.org or via telephone at 800-822-7967. Electronic reporting is available on the Web at http://secure.vaers.org/VaersDataEntryintro.htm. The VAERS is a passive surveillance system, and determining causal associations between vaccines and AEs is not always possible.10 Other concurrent infections or exposures may precipitate a given symptom that may simply coincide with the receipt of a vaccine.11 For example, patient 2 may have had vaccine-associated erythema multiforme but because he had recently completed a course of penicillin, we cannot exclude the possibility of a concurrent antibiotic association.
The Anthrax Vaccine Expert Committee reviewed 602 VAERS reports filed from 1998 through 1999.12 Nearly one half of reports noted a local injection site AE, 33% of which were noted to be moderate to large. A subcutaneous nodule was cited in 5.3% of reports. Although three fourths of reports noted a "systemic" AE, these covered a broad spectrum, with 34 types cited at a frequency of more than 1%. The most common AEs, in declining order of incidence, were flulike symptoms, 20.8%; malaise, 13.3%; rash, 14.2%; arthralgia, 12%; headache, 10.1%; with the remainder of AEs all affecting fewer than 10% of patients. Among the reported 45 total "serious or medically important AEs," one report of each of the following was noted: systemic lupus erythematosus, angioedema, anaphylactoid reaction, and toxic epidermal necrolysis. None of these AEs were judged to be causally (defined as likely, certain, or probable) related to the vaccine itself.12 According to Friedlander et al,8 the "FDA continues to view the anthrax vaccine as safe and effective for individuals at risk of exposure to anthrax."
Management of Adverse Events
Adverse reactions after vaccination can be divided into local and systemic.
Cutaneous Reactions—The cutaneous manifestations and the latest recommendations from the Walter Reed National Vaccine healthcare center network9 are summarized partially in Tables 1 and 2.
Local reactions involve the injection site or have contiguous spread and are graded based on the measured size of the local redness or swelling (Table 1). Most local anthrax vaccine reactions require no treatment and resolve within 72 hours, though topical or oral steroids and oral antihistamines can be used to help manage symptoms. Unless the local reaction is very large or complicated, the patient can usually proceed with subsequent doses. Although some of these reactions may mimic cellulitis, antibiotic therapy for postvaccination inflammation is not warranted. Allergy consultation is recommended for a large or complicated reaction, especially if this occurs after the second dose. In this instance, the patient may be immune (a hyperresponder) and may not require further series (with the exception of the yearly booster).9 When a significant local type reaction has occurred, pretreatment to help prevent future large local reactions is indicated.
Systemic Reactions—These commonly include flulike symptoms, such as fever, anorexia, nausea, arthralgia, myalgia, or malaise. Treatment of mild to moderate systemic events is symptomatic (Table 2). Pretreatment also may be given with the next vaccine in patients who have had these symptoms on prior AVA vaccinations. If symptoms are clinically consistent with serum sickness or are severe and prolonged, the patient may benefit from a short course of oral prednisone. Vaccine-related AEs may warrant temporary delay from the schedule. When resumed, this does not require starting over but rather simply continuing from the last dose.9
For a generalized maculopapular rash or target lesions, a skin biopsy should be performed, especially if the rash is suggestive of early erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. In these cases, temporary exemption from further vaccinations and VAERS reporting are indicated. The possibility exists that additional doses may result in a more serious skin reaction and should be given with caution only after expert evaluation and consideration of the risk:benefit ratio. The dermatologist should provide a clinical histopathologic diagnosis to help the allergist or expert in the vaccination program decide the best course for continuation or exemption from the full anthrax series. These cases may warrant permanent exemption from further vaccination series. No apparent safety data for challenge dosing or desensitization in these potentially life-threatening skin reactions exist. In patient 2 with erythema multiforme, further vaccinations for anthrax were waived permanently. Similarly, deferral from further anthrax vaccinations was recommended in patient 3.
In those cases of severe urticaria or angioedema, temporary exemption may be granted while requesting allergy consultation. Additional doses should be given with caution only after expert evaluation and consideration of the risk:benefit ratio. Permanent exemption may be required for those with anaphylaxis or sudden onset angioedema. In patient 1 with recurrent localized urticaria, the allergist recommended that a formal skin-prick test to future vaccine lots be performed before he received any further vaccine in the series. Although this local allergic-type reaction may be due to some component of the vaccine, we are unable to define the specific cause at this time. This is a rather unusual manifestation, with recurrence of the urticaria still persisting 21/2 years later and restricted only to the vaccinated arm.
Conclusion
There are ongoing studies to evaluate whether a reduced number of anthrax vaccinations will provide the same immunity. In addition, other ongoing studies are comparing intramuscular administration versus the current usual subcutaneous route. Preliminary reports have shown that local reactions are less common in patients who received the vaccine via the intramuscular route than in those who received the vaccine via the subcutaneous route.13 This change in route of administration could reduce the number of adverse cutaneous reactions in the future. For further expert advice or clinical consultations, contact the Walter Reed National Vaccine Healthcare Center via telephone: 202-782-0411; fax: 202-782-4658; or e-mail: [email protected].
Since the domestic anthrax attacks in October 2001 and in the presence of continued worldwide threats to our armed forces, force protection remains a top priority. As dermatologists, we should be familiar with the current anthrax vaccine
program and be able to recognize and treat anthrax vaccine–related AEs.
- Bartlett JG, Inglesby TV, Borio L. Management of anthrax. Clin Infect Dis. 2002;35:851-858.
- Inglesby TV, O'Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA. 2002;287:2236-2252.
- Dixon TC, Meselson M, Guillemin J, et al. Anthrax. N Engl J Med. 1999;341:815-826.
- Swartz MN. Recognition and management of anthrax—an update. N Engl J Med. 2001;345:1621-1626.
- Mazzuchi JF, Claypool RG, Hyams KC, et al. Protecting the health of U.S. military forces: a national obligation. Aviat Space Environ Med. 2000;71:260-265.
- Carucci JA, McGovern TW, Norton SA, et al. Cutaneous anthrax management algorithm. J Am Acad Dermatol. 2002;47:766-769.
- Centers for Disease Control and Prevention. Guidelines for comprehensive procedures for collecting environmental samples for culturing Bacillus anthracis (revised April 2002) and anthrax: exposure management/prophylaxis (preventing transmission). Atlanta, Ga: Centers for Disease Control and Prevention Web sites. Available at: http://www.bt.cdc.gov. Accessed August 18, 2003.
- Friedlander AM, Pittman PR, Parker GW. Anthrax vaccine: evidence for safety and efficacy against inhalational anthrax. JAMA. 1999;282:2104-2106.
- Clinical guidelines for the management of adverse events after vaccination (official AVIP version). August 2002 Web site. Available at: http://www.deploymenthealth.mil/VHC/providers_management.htm. Accessed August 18, 2003.
- Centers for Disease Control and Prevention. Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS)—United States, 1991-2000. MMWR Morb Mortal Wkly Rep. 2003;52:1-19.
- Halsey NA. Anthrax vaccine and causality assessment from individual case reports. Pharmacoepidemiol Drug Saf. 2002;11:185-187.
- Sever JL, Brenner AI, Gale AD, et al. Safety of anthrax vaccine: a review by the Anthrax Vaccine Expert Committee (AVEC) of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS). Pharmacoepidemiol Drug Saf. 2002;11:189-202.
- Use of anthrax vaccine in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2000;49:1-20.
- Bartlett JG, Inglesby TV, Borio L. Management of anthrax. Clin Infect Dis. 2002;35:851-858.
- Inglesby TV, O'Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA. 2002;287:2236-2252.
- Dixon TC, Meselson M, Guillemin J, et al. Anthrax. N Engl J Med. 1999;341:815-826.
- Swartz MN. Recognition and management of anthrax—an update. N Engl J Med. 2001;345:1621-1626.
- Mazzuchi JF, Claypool RG, Hyams KC, et al. Protecting the health of U.S. military forces: a national obligation. Aviat Space Environ Med. 2000;71:260-265.
- Carucci JA, McGovern TW, Norton SA, et al. Cutaneous anthrax management algorithm. J Am Acad Dermatol. 2002;47:766-769.
- Centers for Disease Control and Prevention. Guidelines for comprehensive procedures for collecting environmental samples for culturing Bacillus anthracis (revised April 2002) and anthrax: exposure management/prophylaxis (preventing transmission). Atlanta, Ga: Centers for Disease Control and Prevention Web sites. Available at: http://www.bt.cdc.gov. Accessed August 18, 2003.
- Friedlander AM, Pittman PR, Parker GW. Anthrax vaccine: evidence for safety and efficacy against inhalational anthrax. JAMA. 1999;282:2104-2106.
- Clinical guidelines for the management of adverse events after vaccination (official AVIP version). August 2002 Web site. Available at: http://www.deploymenthealth.mil/VHC/providers_management.htm. Accessed August 18, 2003.
- Centers for Disease Control and Prevention. Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS)—United States, 1991-2000. MMWR Morb Mortal Wkly Rep. 2003;52:1-19.
- Halsey NA. Anthrax vaccine and causality assessment from individual case reports. Pharmacoepidemiol Drug Saf. 2002;11:185-187.
- Sever JL, Brenner AI, Gale AD, et al. Safety of anthrax vaccine: a review by the Anthrax Vaccine Expert Committee (AVEC) of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS). Pharmacoepidemiol Drug Saf. 2002;11:189-202.
- Use of anthrax vaccine in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2000;49:1-20.
Large Solitary Café au Lait Spots: A Report of 5 Cases and Review of the Literature
Dermatology, Volumes 1 and 2 [book review]
Treatment of Palmoplantar Keratoderma With Continuous Infusion 5-Fluorouracil
Although, to our knowledge, there has been no literature that associates systemic 5-fluorouracil (5-FU) with the treatment of palmoplantar keratoderma (PPK), we are convinced that systemic 5-FU was responsible for clearing the lesions in a patient—possibly due to the epidermal changes in the palms and soles secondary to hand-foot syndrome induced by 5-FU.
An objective assessment of our patient suggested that systemic 5-FU most likely was the reason for the apparent clearing of his keratoses; however, a randomized controlled trial is needed to determine if systemic 5-FU is applicable in the treatment of PPK. This case brings new light to a disease for which treatment options are limited and no cure exists.
PPK represent a heterogeneous group of disorders most often characterized by a hyperkeratosis of the palms and soles.1,2 PPK may be hereditary, acquired, or an associated feature that is part of a syndrome. Clinically, inherited PPK can be divided into 3 forms: diffuse, striated, and punctate.3
The pathogenesis of PPK remains unknown, and the treatment is purely symptomatic; there is no definitive treatment or cure.4 Treatment modalities have consisted of topical and systemic therapy as well as surgical excision. The literature has indicated no major benefits with the use of topical therapy, including topical retinoids, corticosteroids, calcipotriol, or topical keratolytics such as 5% to 10% salicylic acid ointment, 30% propylene glycol, 20% to 30% lactic acid, and 10% to 12% urea ointment.1,5-7 Keratolytic agents may be useful in reducing the thickness of the keratoderma, but the lesions recur when treatment is stopped.6 Overall, the outcomes of treatment of PPK have been rather disappointing. Superior results from systemic treatment with oral retinoids, specifically isotretinoin, have been reported in some cases of PPK. However, there are significant risks and toxicities associated with long-term oral retinoid therapy; and like keratolytic agents, discontinuance of therapy causes the lesions to recur to their initial severity.1,7
We report a case of inherited punctate PPK treated successfully with systemic 5-FU. Prior to this, the patient had tried treatment with many topical keratolytic agents, including salicylic acid, urea, and topical 5-FU, from which he attained only minimal benefit. The option of therapy with oral isotretinoin was discussed with the patient; however, he did not choose this option because it is not a cure and lifelong treatment would be required for long-term benefits.
Case Report
A 49-year-old man electively chose to undergo a trial of intravenous chemotherapy with 5-FU for his punctate PPK. He had had this dermatologic disorder since he was a teenager. The patient reported that the calluses on his feet were painful and that those on his hands were embarrassing. Differential diagnosis ruled out toxin-induced PPK (ie, arsenic) because of the lack of chemical exposure; he was diagnosed with hereditary punctate PPK, of which his family history is significant (his father also had the disorder). In 1987, his father was diagnosed with lung cancer and received chemotherapy consisting of continuous infusion (CI) 5-FU and cisplatin. Coincidentally, his lesions cleared after 2 treatments and never recurred, though he died of lung cancer 2 years later.
The patient's dermatologist noted that treatments had been unsuccessful thus far and that therapeutic options had been exhausted. The dermatologist was unaware of alternative treatments and thoroughly reinforced to the patient that other than his father's case, there was no evidence to suggest that treatment with 5-FU was effective. The patient was aware that systemic 5-FU was not the standard of care for PPK; however, he was willing to accept all risks associated with treatment.
Prior to initiating therapy, the patient weighed 81 kg and was not taking any medications including topical creams and over-the-counter products. His medical history was significant for back problems and a herniorrhaphy. He smoked three quarters of a pack of cigarettes a day. His mother died of heart disease. His siblings were alive and well.
The patient's laboratory results were acceptable to start treatment. A peripherally inserted central catheter line was placed. Pictures were taken of the lesions before treatment to document possible response. A single course of CI 5-FU was instituted: 1000 mg/m2 per day for 5 days via an infusion pump connected to his catheter line. The patient was instructed to gargle daily with 0.5% hydrogen peroxide solution.
The patient tolerated the first course of 5-FU without incidence. Other than minor fatigue and slight mucositis, he experienced no particular side effects, though he noticed his feet were more painful than usual. Physical examination revealed mild erythema over his hands, and some of the lesions that used to be skin colored were now purplish and erythematous.
At his 1-month follow-up, the patient was pleased that the lesions over his hands and feet had regressed remarkably after only one treatment. The oncologist and patient agreed that the lesions had been reduced by approximately 80%. Laboratory tests disclosed the following values: a white blood cell count of 5400/mm3, a hemoglobin level of 15.5 g/dL, and a platelet count of 194,000/mm3. It was clearly reiterated to the patient again that there was no evidence to suggest that treatment with intravenous 5-FU was effective, despite encouraging results.
After 2 courses of CI 5-FU at 1000 mg/m2 per day for 5 days, the patient desired to pursue further treatment because after each course the lesions seemed to grow back to some degree, though they remained about 75% improved. Because the patient was adamant about pursuing further therapy, CI 5-FU was dosed at 250 mg/m2 per day in the hope that he might develop some hand-foot syndrome, which may lead to long-term benefits. The full course of treatment would require several weeks; thus, a port-a-cath was surgically placed and connected to an infusion pump that administered 5-FU continuously.
After a 12-week therapeutic regimen of 250 mg/m2 per day of CI 5-FU, the patient's lesions were approximately 95% cleared and, for the most part, were unapparent. He had no significant side effects from the 5-FU other than mild cheilosis. Two months later, the lesions had not returned. At follow-up nearly 4 years later, the dermatologist rated the lesions as being 90% cleared; however, the patient believes that the lesions are 100% cleared with only scar tissue remaining. The Figure demonstrates the effectiveness of treatment.
Please refer to the PDF to view the figure.
The patient has experienced one adverse effect since the time 5-FU was initiated, ie, an increased dermatologic sensitivity to non–glycerin-based soaps and shampoos. However, by switching to glycerin-based products, the problem disappeared. Although it is not known whether treatment with 5-FU was the sole culprit of this problem, the timing of treatment and onset of the sensitivity suggest an association.
Comment
In 1879, Davies-Colley described punctate PPK as "disseminated clavis of the hands and feet."3,8 Punctate PPK also is referred to as keratosis punctata palmaris et plantaris or Buschke-Fischer-Brauer disease.6,9 Although the incidence in the United States is unknown, the reported incidence for this rare genodermatosis is 1.17 per 100,000 people in Croatia.10 Hereditary PPK is autosomal dominant and usually develops when a patient is between 12 and 30 years of age.3,11 Punctate PPK presents with abundant hyperkeratotic papules on the palms and soles that are irregularly distributed. The papules tend to be asymmetric, vary greatly in size, and occur more frequently over pressure points, causing pain in many cases.3,6,9 To our knowledge, there have been no cases of spontaneous remission in patients with inherited PPK.
For years, retinoid therapy has represented the treatment of choice for severe inherited keratodermas.12 Treatment of punctate PPK, specifically, usually consists of topical retinoids or calcipotriol to soften the keratoses, and systemic retinoid therapy, if warranted. Although topical tretinoin (vitamin A acid) has been proven to be effective in many keratinizing dermatoses, Muller et al13 revealed that topical tretinoin 0.1% cream was not effective in palmar-plantar hyperkeratosis. In the early 1980s, Bergfeld et al1 demonstrated that oral isotretinoin, a vitamin A analogue, was effective in treating a variety of keratinizing disorders, including one case of punctate keratoderma. Despite the "antikeratolytic" effects of isotretinoin, disease relapse occurred with a reduced retinoid dose and symptoms fully recurred after therapy was discontinued. Oral retinoid therapy is not a cure; therefore, treatment must be continued indefinitely to maintain results.
Topical 5-FU has been used to treat actinic keratoses and basal cell carcinomas.14,15 Osman et al5 reported a case of "spiny keratoderma of the palms and soles" that responded well to 5-FU 5% cream. Recently, a study performed by Levy et al16 suggested that 5-FU 0.5% cream compared with 5-FU 5% cream is equally effective, is associated with less toxicity and may actually be more specific to the affected area of skin in which the cream is applied. These conclusions, though counterintuitive, stem from higher concentrations of 5-FU found in the skin following application of the 0.5% cream compared with the 5% cream. This data is applicable for actinic keratoses; however, it is not clear whether PPK would require higher concentrations of topical 5-FU. The patient in our case, as previously mentioned, experienced only minimal response with topical 5-FU 5% cream. To our knowledge, there has been no evidence that associates systemic 5-FU therapy for treatment of PPK.
In vivo, the mechanism of 5-FU is quite complex. Depending on whether the tissue type is normal or a tumor, the compound will exert a different action.17 Cells proliferating at a rapid rate, especially solid tumors, are more of a target for the toxic effects from 5-FU than are nonproliferating cells.15 Systemic therapy with 5-FU can cause a variety of dermatologic manifestations, such as maculopapular eruption, hyperpigmentation, nail changes, lupuslike butterfly rash, inflammation of actinic keratoses, and palmar-plantar erythrodysesthesia syndrome (PPES), also known as hand-foot syndrome.18 Clinically, these changes can be categorized into 3 subsets: rashes and eruptions, cytotoxic changes, and alterations in pigmentation.18,19
Hand-foot syndrome is characterized by a "tingling sensation" of the palms and soles. It starts out as dysesthesia, and after a few days, there is a burning pain associated with swollen palms and soles that are erythematous, cracked, and eruptive. In severe cases, ulceration and blistering can occur followed by desquamation.18-20 Treatment with pyridoxine (100–150 mg/d) has been proven to be effective in preventing PPES or in making the symptoms less severe without having to discontinue 5-FU therapy.18,21 Therefore, pyridoxine should be avoided if hand-foot syndrome is a desired outcome, such as in our case.
The specific mechanism by which 5-FU causes PPES remains unknown, and the specific distribution on the palms and soles also is poorly understood. However, it has been hypothesized that PPES is a "direct toxic effect of the chemotherapeutic drug against epidermal cells" and, thus, PPES is the result of a cytotoxic reaction that mainly affects keratinocytes.22 The epidermis of the palms and soles are highly proliferative, making it a target for 5-FU to induce changes within the epidermis—making it more susceptible to PPES.15 Histologic findings in the basal cell layer of the skin include a variable degree of epidermal necrosis and poor cell infiltrate. Changes in the epidermis consist of vasodilation of the blood vessels and papillary edema from the mechanical and thermal trauma.22,23
Two meta-analyses of frontline trials for advanced colorectal cancer compared and evaluated the efficacy and toxicities of intravenous CI 5-FU versus bolus administration. With the exception of hand-foot syndrome, the meta-analysis revealed that CI 5-FU was associated with a significant reduction in grade 3 or 4 hematologic and nonhematologic toxicities (4% vs 31%), but there was an increased incidence of hand-foot syndrome with CI 5-FU compared with bolus administration (34% vs 13%).24,25
There is little, if any, data to support or guide therapy duration; therefore, the basis for treatment length was determined by oncologist and dermatologist observations of drug effect, lack of adverse effect, and willingness of the patient to continue therapy. Treatment was discontinued when it appeared that it had been fully successful, which was approximately 12 weeks for our patient.
Although our patient experienced only mild side effects, 5-FU has the potential to cause serious adverse effects. The earliest of milder untoward effects include anorexia and nausea followed by stomatitis and diarrhea. Mucosal ulcerations may occur throughout the gastrointestinal tract, particularly in patients receiving continuous infusions of 5-FU; these ulcerations can lead to fulminant diarrhea and hypovolemic shock.26 Myelosuppressive effects are more common with bolus administration of 5-FU than with CI and include leukopenia, thrombocytopenia, and anemia.26 Neurologic manifestations, including acute cerebellar syndrome, have been reported, as have reports of cardiac toxicity, particularly acute chest pain with ischemia.26
Cisplatin was ruled out as being a contributory factor in the clearing of the patient's father's keratoses. Other than alopecia, cisplatin is known to have minimal dermatologic effects. However, Lee et al27 reported a case of cisplatin-induced severe allergic exfoliative dermatitis associated with ischemia and necrosis of the hands. The adverse effects and toxicities associated with cisplatin are well recognized and include immunosuppression, neurotoxicity, nausea and vomiting, ototoxicity, and hypomagnesemia.27
Conclusion
An objective assessment of our patient suggested that systemic 5-FU was the most likely reason for the apparent clearing of this patient's keratoses. However, a randomized controlled trial is needed to determine if systemic 5-FU is applicable in the treatment of PPK. This case brings new light to a disease for which treatment options are limited and no cure exists.
- Bergfeld WF, Derbes VJ, Elias PM, et al. The treatment of keratosis palmaris et plantaris with isotretinoin. a multicenter study. J Am Acad Dermatol. 1982;6:727-731.
- Rivers JK, Duke EE, Justus DW. Etretinate: management of keratoderma hereditaria mutilans in four family members. J Am Acad Dermatol. 1985;13:43-49.
- Schnyder UW. Inherited keratodermas of palms and soles. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedburg IM, Austen KF, eds. Dermatology in General Medicine. Vol 1. 4th ed. New York, NY: McGraw-Hill; 1993:557-564.
- Engin H, Akdogan A, Altundag O, et al. Non–small-cell lung cancer with nonfamilial diffuse palmoplantar keratoderma. J Exp Clin Cancer Res. 2002;21:45-47.
- Osman Y, Daly TJ, Don PC. Spiny keratoderma of the palms and soles. J Am Acad Dermatol. 1992;26:879-881.
- Kanitakis J, Tsoitis G, Kanitakis C. Hereditary epidermolytic palmoplantar keratoderma (Vorner type). report of a familial case and review of the literature. J Am Acad Dermatol. 1987;17:414-422.
- Emmert S, Kuster W, Hennies HC, et al. 47 patients in 14 families with the rare genodermatosis keratosis punctata palmoplantaris Buschke-Fischer-Brauer. Eur J Dermatol. 2003;13:16-20.
- Lokich JJ, Ahlgren JD, Gullo JJ, et al. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol. 1989;7:425-432.
- Salamon T, Stolic V, Lazovic-Tepavac O, et al. Peculiar findings in a family with keratodermia palmo-plantaris papulosa Buschke-Fischer-Brauer. Hum Genet. 1982;60:314-319.
- Stanimirovic A, Kansky A, Basta-Juzbasic A, et al. Hereditary palmoplantar keratoderma, type papulosa, in Croatia. J Am Acad Dermatol. 1993;29:435-437.
- Wachters DH, Frensdorf EL, Hallsman R, et al. Keratosis palmoplantaris nummularis ("hereditary painful callosities"). clinical and histopathological aspects. J Am Acad Dermatol. 1983;9:204-209.
- Lacour M, Menta-Nikhar B, Atherton DJ, et al. An appraisal of acitretin therapy in children with inherited disorders of keratinization. Br J Dermatol. 1996;134:1023-1029.
- Muller SA, Belcher RW, Esterly NB, et al. Keratinizing dermatoses. combined data from four centers on short-term topical treatment with tretinoin. Arch Dermatol. 1977;113:1052-1054.
- Sander CA, Pfeiffer C, Kligman AM, et al. Chemotherapy for disseminated actinic keratoses with 5-fluorouracil and isotretinoin. J Am Acad Dermatol. 1997;36:236-238.
- Antineoplastic agents: antimetabolites. In: Drug Evaluations. 7th ed. Chicago, Ill: American Medical Association; 1994:2033-2052.
- Levy S, Furst K, Chern W. A novel 0.5% fluorouracil cream is minimally absorbed into the systemic circulation yet is as effective as 5% fluorouracil cream. Cutis. 2002;70:14-21.
- Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology. J Clin Oncol. 1988;6:1653-1664.
Although, to our knowledge, there has been no literature that associates systemic 5-fluorouracil (5-FU) with the treatment of palmoplantar keratoderma (PPK), we are convinced that systemic 5-FU was responsible for clearing the lesions in a patient—possibly due to the epidermal changes in the palms and soles secondary to hand-foot syndrome induced by 5-FU.
An objective assessment of our patient suggested that systemic 5-FU most likely was the reason for the apparent clearing of his keratoses; however, a randomized controlled trial is needed to determine if systemic 5-FU is applicable in the treatment of PPK. This case brings new light to a disease for which treatment options are limited and no cure exists.
PPK represent a heterogeneous group of disorders most often characterized by a hyperkeratosis of the palms and soles.1,2 PPK may be hereditary, acquired, or an associated feature that is part of a syndrome. Clinically, inherited PPK can be divided into 3 forms: diffuse, striated, and punctate.3
The pathogenesis of PPK remains unknown, and the treatment is purely symptomatic; there is no definitive treatment or cure.4 Treatment modalities have consisted of topical and systemic therapy as well as surgical excision. The literature has indicated no major benefits with the use of topical therapy, including topical retinoids, corticosteroids, calcipotriol, or topical keratolytics such as 5% to 10% salicylic acid ointment, 30% propylene glycol, 20% to 30% lactic acid, and 10% to 12% urea ointment.1,5-7 Keratolytic agents may be useful in reducing the thickness of the keratoderma, but the lesions recur when treatment is stopped.6 Overall, the outcomes of treatment of PPK have been rather disappointing. Superior results from systemic treatment with oral retinoids, specifically isotretinoin, have been reported in some cases of PPK. However, there are significant risks and toxicities associated with long-term oral retinoid therapy; and like keratolytic agents, discontinuance of therapy causes the lesions to recur to their initial severity.1,7
We report a case of inherited punctate PPK treated successfully with systemic 5-FU. Prior to this, the patient had tried treatment with many topical keratolytic agents, including salicylic acid, urea, and topical 5-FU, from which he attained only minimal benefit. The option of therapy with oral isotretinoin was discussed with the patient; however, he did not choose this option because it is not a cure and lifelong treatment would be required for long-term benefits.
Case Report
A 49-year-old man electively chose to undergo a trial of intravenous chemotherapy with 5-FU for his punctate PPK. He had had this dermatologic disorder since he was a teenager. The patient reported that the calluses on his feet were painful and that those on his hands were embarrassing. Differential diagnosis ruled out toxin-induced PPK (ie, arsenic) because of the lack of chemical exposure; he was diagnosed with hereditary punctate PPK, of which his family history is significant (his father also had the disorder). In 1987, his father was diagnosed with lung cancer and received chemotherapy consisting of continuous infusion (CI) 5-FU and cisplatin. Coincidentally, his lesions cleared after 2 treatments and never recurred, though he died of lung cancer 2 years later.
The patient's dermatologist noted that treatments had been unsuccessful thus far and that therapeutic options had been exhausted. The dermatologist was unaware of alternative treatments and thoroughly reinforced to the patient that other than his father's case, there was no evidence to suggest that treatment with 5-FU was effective. The patient was aware that systemic 5-FU was not the standard of care for PPK; however, he was willing to accept all risks associated with treatment.
Prior to initiating therapy, the patient weighed 81 kg and was not taking any medications including topical creams and over-the-counter products. His medical history was significant for back problems and a herniorrhaphy. He smoked three quarters of a pack of cigarettes a day. His mother died of heart disease. His siblings were alive and well.
The patient's laboratory results were acceptable to start treatment. A peripherally inserted central catheter line was placed. Pictures were taken of the lesions before treatment to document possible response. A single course of CI 5-FU was instituted: 1000 mg/m2 per day for 5 days via an infusion pump connected to his catheter line. The patient was instructed to gargle daily with 0.5% hydrogen peroxide solution.
The patient tolerated the first course of 5-FU without incidence. Other than minor fatigue and slight mucositis, he experienced no particular side effects, though he noticed his feet were more painful than usual. Physical examination revealed mild erythema over his hands, and some of the lesions that used to be skin colored were now purplish and erythematous.
At his 1-month follow-up, the patient was pleased that the lesions over his hands and feet had regressed remarkably after only one treatment. The oncologist and patient agreed that the lesions had been reduced by approximately 80%. Laboratory tests disclosed the following values: a white blood cell count of 5400/mm3, a hemoglobin level of 15.5 g/dL, and a platelet count of 194,000/mm3. It was clearly reiterated to the patient again that there was no evidence to suggest that treatment with intravenous 5-FU was effective, despite encouraging results.
After 2 courses of CI 5-FU at 1000 mg/m2 per day for 5 days, the patient desired to pursue further treatment because after each course the lesions seemed to grow back to some degree, though they remained about 75% improved. Because the patient was adamant about pursuing further therapy, CI 5-FU was dosed at 250 mg/m2 per day in the hope that he might develop some hand-foot syndrome, which may lead to long-term benefits. The full course of treatment would require several weeks; thus, a port-a-cath was surgically placed and connected to an infusion pump that administered 5-FU continuously.
After a 12-week therapeutic regimen of 250 mg/m2 per day of CI 5-FU, the patient's lesions were approximately 95% cleared and, for the most part, were unapparent. He had no significant side effects from the 5-FU other than mild cheilosis. Two months later, the lesions had not returned. At follow-up nearly 4 years later, the dermatologist rated the lesions as being 90% cleared; however, the patient believes that the lesions are 100% cleared with only scar tissue remaining. The Figure demonstrates the effectiveness of treatment.
Please refer to the PDF to view the figure.
The patient has experienced one adverse effect since the time 5-FU was initiated, ie, an increased dermatologic sensitivity to non–glycerin-based soaps and shampoos. However, by switching to glycerin-based products, the problem disappeared. Although it is not known whether treatment with 5-FU was the sole culprit of this problem, the timing of treatment and onset of the sensitivity suggest an association.
Comment
In 1879, Davies-Colley described punctate PPK as "disseminated clavis of the hands and feet."3,8 Punctate PPK also is referred to as keratosis punctata palmaris et plantaris or Buschke-Fischer-Brauer disease.6,9 Although the incidence in the United States is unknown, the reported incidence for this rare genodermatosis is 1.17 per 100,000 people in Croatia.10 Hereditary PPK is autosomal dominant and usually develops when a patient is between 12 and 30 years of age.3,11 Punctate PPK presents with abundant hyperkeratotic papules on the palms and soles that are irregularly distributed. The papules tend to be asymmetric, vary greatly in size, and occur more frequently over pressure points, causing pain in many cases.3,6,9 To our knowledge, there have been no cases of spontaneous remission in patients with inherited PPK.
For years, retinoid therapy has represented the treatment of choice for severe inherited keratodermas.12 Treatment of punctate PPK, specifically, usually consists of topical retinoids or calcipotriol to soften the keratoses, and systemic retinoid therapy, if warranted. Although topical tretinoin (vitamin A acid) has been proven to be effective in many keratinizing dermatoses, Muller et al13 revealed that topical tretinoin 0.1% cream was not effective in palmar-plantar hyperkeratosis. In the early 1980s, Bergfeld et al1 demonstrated that oral isotretinoin, a vitamin A analogue, was effective in treating a variety of keratinizing disorders, including one case of punctate keratoderma. Despite the "antikeratolytic" effects of isotretinoin, disease relapse occurred with a reduced retinoid dose and symptoms fully recurred after therapy was discontinued. Oral retinoid therapy is not a cure; therefore, treatment must be continued indefinitely to maintain results.
Topical 5-FU has been used to treat actinic keratoses and basal cell carcinomas.14,15 Osman et al5 reported a case of "spiny keratoderma of the palms and soles" that responded well to 5-FU 5% cream. Recently, a study performed by Levy et al16 suggested that 5-FU 0.5% cream compared with 5-FU 5% cream is equally effective, is associated with less toxicity and may actually be more specific to the affected area of skin in which the cream is applied. These conclusions, though counterintuitive, stem from higher concentrations of 5-FU found in the skin following application of the 0.5% cream compared with the 5% cream. This data is applicable for actinic keratoses; however, it is not clear whether PPK would require higher concentrations of topical 5-FU. The patient in our case, as previously mentioned, experienced only minimal response with topical 5-FU 5% cream. To our knowledge, there has been no evidence that associates systemic 5-FU therapy for treatment of PPK.
In vivo, the mechanism of 5-FU is quite complex. Depending on whether the tissue type is normal or a tumor, the compound will exert a different action.17 Cells proliferating at a rapid rate, especially solid tumors, are more of a target for the toxic effects from 5-FU than are nonproliferating cells.15 Systemic therapy with 5-FU can cause a variety of dermatologic manifestations, such as maculopapular eruption, hyperpigmentation, nail changes, lupuslike butterfly rash, inflammation of actinic keratoses, and palmar-plantar erythrodysesthesia syndrome (PPES), also known as hand-foot syndrome.18 Clinically, these changes can be categorized into 3 subsets: rashes and eruptions, cytotoxic changes, and alterations in pigmentation.18,19
Hand-foot syndrome is characterized by a "tingling sensation" of the palms and soles. It starts out as dysesthesia, and after a few days, there is a burning pain associated with swollen palms and soles that are erythematous, cracked, and eruptive. In severe cases, ulceration and blistering can occur followed by desquamation.18-20 Treatment with pyridoxine (100–150 mg/d) has been proven to be effective in preventing PPES or in making the symptoms less severe without having to discontinue 5-FU therapy.18,21 Therefore, pyridoxine should be avoided if hand-foot syndrome is a desired outcome, such as in our case.
The specific mechanism by which 5-FU causes PPES remains unknown, and the specific distribution on the palms and soles also is poorly understood. However, it has been hypothesized that PPES is a "direct toxic effect of the chemotherapeutic drug against epidermal cells" and, thus, PPES is the result of a cytotoxic reaction that mainly affects keratinocytes.22 The epidermis of the palms and soles are highly proliferative, making it a target for 5-FU to induce changes within the epidermis—making it more susceptible to PPES.15 Histologic findings in the basal cell layer of the skin include a variable degree of epidermal necrosis and poor cell infiltrate. Changes in the epidermis consist of vasodilation of the blood vessels and papillary edema from the mechanical and thermal trauma.22,23
Two meta-analyses of frontline trials for advanced colorectal cancer compared and evaluated the efficacy and toxicities of intravenous CI 5-FU versus bolus administration. With the exception of hand-foot syndrome, the meta-analysis revealed that CI 5-FU was associated with a significant reduction in grade 3 or 4 hematologic and nonhematologic toxicities (4% vs 31%), but there was an increased incidence of hand-foot syndrome with CI 5-FU compared with bolus administration (34% vs 13%).24,25
There is little, if any, data to support or guide therapy duration; therefore, the basis for treatment length was determined by oncologist and dermatologist observations of drug effect, lack of adverse effect, and willingness of the patient to continue therapy. Treatment was discontinued when it appeared that it had been fully successful, which was approximately 12 weeks for our patient.
Although our patient experienced only mild side effects, 5-FU has the potential to cause serious adverse effects. The earliest of milder untoward effects include anorexia and nausea followed by stomatitis and diarrhea. Mucosal ulcerations may occur throughout the gastrointestinal tract, particularly in patients receiving continuous infusions of 5-FU; these ulcerations can lead to fulminant diarrhea and hypovolemic shock.26 Myelosuppressive effects are more common with bolus administration of 5-FU than with CI and include leukopenia, thrombocytopenia, and anemia.26 Neurologic manifestations, including acute cerebellar syndrome, have been reported, as have reports of cardiac toxicity, particularly acute chest pain with ischemia.26
Cisplatin was ruled out as being a contributory factor in the clearing of the patient's father's keratoses. Other than alopecia, cisplatin is known to have minimal dermatologic effects. However, Lee et al27 reported a case of cisplatin-induced severe allergic exfoliative dermatitis associated with ischemia and necrosis of the hands. The adverse effects and toxicities associated with cisplatin are well recognized and include immunosuppression, neurotoxicity, nausea and vomiting, ototoxicity, and hypomagnesemia.27
Conclusion
An objective assessment of our patient suggested that systemic 5-FU was the most likely reason for the apparent clearing of this patient's keratoses. However, a randomized controlled trial is needed to determine if systemic 5-FU is applicable in the treatment of PPK. This case brings new light to a disease for which treatment options are limited and no cure exists.
Although, to our knowledge, there has been no literature that associates systemic 5-fluorouracil (5-FU) with the treatment of palmoplantar keratoderma (PPK), we are convinced that systemic 5-FU was responsible for clearing the lesions in a patient—possibly due to the epidermal changes in the palms and soles secondary to hand-foot syndrome induced by 5-FU.
An objective assessment of our patient suggested that systemic 5-FU most likely was the reason for the apparent clearing of his keratoses; however, a randomized controlled trial is needed to determine if systemic 5-FU is applicable in the treatment of PPK. This case brings new light to a disease for which treatment options are limited and no cure exists.
PPK represent a heterogeneous group of disorders most often characterized by a hyperkeratosis of the palms and soles.1,2 PPK may be hereditary, acquired, or an associated feature that is part of a syndrome. Clinically, inherited PPK can be divided into 3 forms: diffuse, striated, and punctate.3
The pathogenesis of PPK remains unknown, and the treatment is purely symptomatic; there is no definitive treatment or cure.4 Treatment modalities have consisted of topical and systemic therapy as well as surgical excision. The literature has indicated no major benefits with the use of topical therapy, including topical retinoids, corticosteroids, calcipotriol, or topical keratolytics such as 5% to 10% salicylic acid ointment, 30% propylene glycol, 20% to 30% lactic acid, and 10% to 12% urea ointment.1,5-7 Keratolytic agents may be useful in reducing the thickness of the keratoderma, but the lesions recur when treatment is stopped.6 Overall, the outcomes of treatment of PPK have been rather disappointing. Superior results from systemic treatment with oral retinoids, specifically isotretinoin, have been reported in some cases of PPK. However, there are significant risks and toxicities associated with long-term oral retinoid therapy; and like keratolytic agents, discontinuance of therapy causes the lesions to recur to their initial severity.1,7
We report a case of inherited punctate PPK treated successfully with systemic 5-FU. Prior to this, the patient had tried treatment with many topical keratolytic agents, including salicylic acid, urea, and topical 5-FU, from which he attained only minimal benefit. The option of therapy with oral isotretinoin was discussed with the patient; however, he did not choose this option because it is not a cure and lifelong treatment would be required for long-term benefits.
Case Report
A 49-year-old man electively chose to undergo a trial of intravenous chemotherapy with 5-FU for his punctate PPK. He had had this dermatologic disorder since he was a teenager. The patient reported that the calluses on his feet were painful and that those on his hands were embarrassing. Differential diagnosis ruled out toxin-induced PPK (ie, arsenic) because of the lack of chemical exposure; he was diagnosed with hereditary punctate PPK, of which his family history is significant (his father also had the disorder). In 1987, his father was diagnosed with lung cancer and received chemotherapy consisting of continuous infusion (CI) 5-FU and cisplatin. Coincidentally, his lesions cleared after 2 treatments and never recurred, though he died of lung cancer 2 years later.
The patient's dermatologist noted that treatments had been unsuccessful thus far and that therapeutic options had been exhausted. The dermatologist was unaware of alternative treatments and thoroughly reinforced to the patient that other than his father's case, there was no evidence to suggest that treatment with 5-FU was effective. The patient was aware that systemic 5-FU was not the standard of care for PPK; however, he was willing to accept all risks associated with treatment.
Prior to initiating therapy, the patient weighed 81 kg and was not taking any medications including topical creams and over-the-counter products. His medical history was significant for back problems and a herniorrhaphy. He smoked three quarters of a pack of cigarettes a day. His mother died of heart disease. His siblings were alive and well.
The patient's laboratory results were acceptable to start treatment. A peripherally inserted central catheter line was placed. Pictures were taken of the lesions before treatment to document possible response. A single course of CI 5-FU was instituted: 1000 mg/m2 per day for 5 days via an infusion pump connected to his catheter line. The patient was instructed to gargle daily with 0.5% hydrogen peroxide solution.
The patient tolerated the first course of 5-FU without incidence. Other than minor fatigue and slight mucositis, he experienced no particular side effects, though he noticed his feet were more painful than usual. Physical examination revealed mild erythema over his hands, and some of the lesions that used to be skin colored were now purplish and erythematous.
At his 1-month follow-up, the patient was pleased that the lesions over his hands and feet had regressed remarkably after only one treatment. The oncologist and patient agreed that the lesions had been reduced by approximately 80%. Laboratory tests disclosed the following values: a white blood cell count of 5400/mm3, a hemoglobin level of 15.5 g/dL, and a platelet count of 194,000/mm3. It was clearly reiterated to the patient again that there was no evidence to suggest that treatment with intravenous 5-FU was effective, despite encouraging results.
After 2 courses of CI 5-FU at 1000 mg/m2 per day for 5 days, the patient desired to pursue further treatment because after each course the lesions seemed to grow back to some degree, though they remained about 75% improved. Because the patient was adamant about pursuing further therapy, CI 5-FU was dosed at 250 mg/m2 per day in the hope that he might develop some hand-foot syndrome, which may lead to long-term benefits. The full course of treatment would require several weeks; thus, a port-a-cath was surgically placed and connected to an infusion pump that administered 5-FU continuously.
After a 12-week therapeutic regimen of 250 mg/m2 per day of CI 5-FU, the patient's lesions were approximately 95% cleared and, for the most part, were unapparent. He had no significant side effects from the 5-FU other than mild cheilosis. Two months later, the lesions had not returned. At follow-up nearly 4 years later, the dermatologist rated the lesions as being 90% cleared; however, the patient believes that the lesions are 100% cleared with only scar tissue remaining. The Figure demonstrates the effectiveness of treatment.
Please refer to the PDF to view the figure.
The patient has experienced one adverse effect since the time 5-FU was initiated, ie, an increased dermatologic sensitivity to non–glycerin-based soaps and shampoos. However, by switching to glycerin-based products, the problem disappeared. Although it is not known whether treatment with 5-FU was the sole culprit of this problem, the timing of treatment and onset of the sensitivity suggest an association.
Comment
In 1879, Davies-Colley described punctate PPK as "disseminated clavis of the hands and feet."3,8 Punctate PPK also is referred to as keratosis punctata palmaris et plantaris or Buschke-Fischer-Brauer disease.6,9 Although the incidence in the United States is unknown, the reported incidence for this rare genodermatosis is 1.17 per 100,000 people in Croatia.10 Hereditary PPK is autosomal dominant and usually develops when a patient is between 12 and 30 years of age.3,11 Punctate PPK presents with abundant hyperkeratotic papules on the palms and soles that are irregularly distributed. The papules tend to be asymmetric, vary greatly in size, and occur more frequently over pressure points, causing pain in many cases.3,6,9 To our knowledge, there have been no cases of spontaneous remission in patients with inherited PPK.
For years, retinoid therapy has represented the treatment of choice for severe inherited keratodermas.12 Treatment of punctate PPK, specifically, usually consists of topical retinoids or calcipotriol to soften the keratoses, and systemic retinoid therapy, if warranted. Although topical tretinoin (vitamin A acid) has been proven to be effective in many keratinizing dermatoses, Muller et al13 revealed that topical tretinoin 0.1% cream was not effective in palmar-plantar hyperkeratosis. In the early 1980s, Bergfeld et al1 demonstrated that oral isotretinoin, a vitamin A analogue, was effective in treating a variety of keratinizing disorders, including one case of punctate keratoderma. Despite the "antikeratolytic" effects of isotretinoin, disease relapse occurred with a reduced retinoid dose and symptoms fully recurred after therapy was discontinued. Oral retinoid therapy is not a cure; therefore, treatment must be continued indefinitely to maintain results.
Topical 5-FU has been used to treat actinic keratoses and basal cell carcinomas.14,15 Osman et al5 reported a case of "spiny keratoderma of the palms and soles" that responded well to 5-FU 5% cream. Recently, a study performed by Levy et al16 suggested that 5-FU 0.5% cream compared with 5-FU 5% cream is equally effective, is associated with less toxicity and may actually be more specific to the affected area of skin in which the cream is applied. These conclusions, though counterintuitive, stem from higher concentrations of 5-FU found in the skin following application of the 0.5% cream compared with the 5% cream. This data is applicable for actinic keratoses; however, it is not clear whether PPK would require higher concentrations of topical 5-FU. The patient in our case, as previously mentioned, experienced only minimal response with topical 5-FU 5% cream. To our knowledge, there has been no evidence that associates systemic 5-FU therapy for treatment of PPK.
In vivo, the mechanism of 5-FU is quite complex. Depending on whether the tissue type is normal or a tumor, the compound will exert a different action.17 Cells proliferating at a rapid rate, especially solid tumors, are more of a target for the toxic effects from 5-FU than are nonproliferating cells.15 Systemic therapy with 5-FU can cause a variety of dermatologic manifestations, such as maculopapular eruption, hyperpigmentation, nail changes, lupuslike butterfly rash, inflammation of actinic keratoses, and palmar-plantar erythrodysesthesia syndrome (PPES), also known as hand-foot syndrome.18 Clinically, these changes can be categorized into 3 subsets: rashes and eruptions, cytotoxic changes, and alterations in pigmentation.18,19
Hand-foot syndrome is characterized by a "tingling sensation" of the palms and soles. It starts out as dysesthesia, and after a few days, there is a burning pain associated with swollen palms and soles that are erythematous, cracked, and eruptive. In severe cases, ulceration and blistering can occur followed by desquamation.18-20 Treatment with pyridoxine (100–150 mg/d) has been proven to be effective in preventing PPES or in making the symptoms less severe without having to discontinue 5-FU therapy.18,21 Therefore, pyridoxine should be avoided if hand-foot syndrome is a desired outcome, such as in our case.
The specific mechanism by which 5-FU causes PPES remains unknown, and the specific distribution on the palms and soles also is poorly understood. However, it has been hypothesized that PPES is a "direct toxic effect of the chemotherapeutic drug against epidermal cells" and, thus, PPES is the result of a cytotoxic reaction that mainly affects keratinocytes.22 The epidermis of the palms and soles are highly proliferative, making it a target for 5-FU to induce changes within the epidermis—making it more susceptible to PPES.15 Histologic findings in the basal cell layer of the skin include a variable degree of epidermal necrosis and poor cell infiltrate. Changes in the epidermis consist of vasodilation of the blood vessels and papillary edema from the mechanical and thermal trauma.22,23
Two meta-analyses of frontline trials for advanced colorectal cancer compared and evaluated the efficacy and toxicities of intravenous CI 5-FU versus bolus administration. With the exception of hand-foot syndrome, the meta-analysis revealed that CI 5-FU was associated with a significant reduction in grade 3 or 4 hematologic and nonhematologic toxicities (4% vs 31%), but there was an increased incidence of hand-foot syndrome with CI 5-FU compared with bolus administration (34% vs 13%).24,25
There is little, if any, data to support or guide therapy duration; therefore, the basis for treatment length was determined by oncologist and dermatologist observations of drug effect, lack of adverse effect, and willingness of the patient to continue therapy. Treatment was discontinued when it appeared that it had been fully successful, which was approximately 12 weeks for our patient.
Although our patient experienced only mild side effects, 5-FU has the potential to cause serious adverse effects. The earliest of milder untoward effects include anorexia and nausea followed by stomatitis and diarrhea. Mucosal ulcerations may occur throughout the gastrointestinal tract, particularly in patients receiving continuous infusions of 5-FU; these ulcerations can lead to fulminant diarrhea and hypovolemic shock.26 Myelosuppressive effects are more common with bolus administration of 5-FU than with CI and include leukopenia, thrombocytopenia, and anemia.26 Neurologic manifestations, including acute cerebellar syndrome, have been reported, as have reports of cardiac toxicity, particularly acute chest pain with ischemia.26
Cisplatin was ruled out as being a contributory factor in the clearing of the patient's father's keratoses. Other than alopecia, cisplatin is known to have minimal dermatologic effects. However, Lee et al27 reported a case of cisplatin-induced severe allergic exfoliative dermatitis associated with ischemia and necrosis of the hands. The adverse effects and toxicities associated with cisplatin are well recognized and include immunosuppression, neurotoxicity, nausea and vomiting, ototoxicity, and hypomagnesemia.27
Conclusion
An objective assessment of our patient suggested that systemic 5-FU was the most likely reason for the apparent clearing of this patient's keratoses. However, a randomized controlled trial is needed to determine if systemic 5-FU is applicable in the treatment of PPK. This case brings new light to a disease for which treatment options are limited and no cure exists.
- Bergfeld WF, Derbes VJ, Elias PM, et al. The treatment of keratosis palmaris et plantaris with isotretinoin. a multicenter study. J Am Acad Dermatol. 1982;6:727-731.
- Rivers JK, Duke EE, Justus DW. Etretinate: management of keratoderma hereditaria mutilans in four family members. J Am Acad Dermatol. 1985;13:43-49.
- Schnyder UW. Inherited keratodermas of palms and soles. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedburg IM, Austen KF, eds. Dermatology in General Medicine. Vol 1. 4th ed. New York, NY: McGraw-Hill; 1993:557-564.
- Engin H, Akdogan A, Altundag O, et al. Non–small-cell lung cancer with nonfamilial diffuse palmoplantar keratoderma. J Exp Clin Cancer Res. 2002;21:45-47.
- Osman Y, Daly TJ, Don PC. Spiny keratoderma of the palms and soles. J Am Acad Dermatol. 1992;26:879-881.
- Kanitakis J, Tsoitis G, Kanitakis C. Hereditary epidermolytic palmoplantar keratoderma (Vorner type). report of a familial case and review of the literature. J Am Acad Dermatol. 1987;17:414-422.
- Emmert S, Kuster W, Hennies HC, et al. 47 patients in 14 families with the rare genodermatosis keratosis punctata palmoplantaris Buschke-Fischer-Brauer. Eur J Dermatol. 2003;13:16-20.
- Lokich JJ, Ahlgren JD, Gullo JJ, et al. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol. 1989;7:425-432.
- Salamon T, Stolic V, Lazovic-Tepavac O, et al. Peculiar findings in a family with keratodermia palmo-plantaris papulosa Buschke-Fischer-Brauer. Hum Genet. 1982;60:314-319.
- Stanimirovic A, Kansky A, Basta-Juzbasic A, et al. Hereditary palmoplantar keratoderma, type papulosa, in Croatia. J Am Acad Dermatol. 1993;29:435-437.
- Wachters DH, Frensdorf EL, Hallsman R, et al. Keratosis palmoplantaris nummularis ("hereditary painful callosities"). clinical and histopathological aspects. J Am Acad Dermatol. 1983;9:204-209.
- Lacour M, Menta-Nikhar B, Atherton DJ, et al. An appraisal of acitretin therapy in children with inherited disorders of keratinization. Br J Dermatol. 1996;134:1023-1029.
- Muller SA, Belcher RW, Esterly NB, et al. Keratinizing dermatoses. combined data from four centers on short-term topical treatment with tretinoin. Arch Dermatol. 1977;113:1052-1054.
- Sander CA, Pfeiffer C, Kligman AM, et al. Chemotherapy for disseminated actinic keratoses with 5-fluorouracil and isotretinoin. J Am Acad Dermatol. 1997;36:236-238.
- Antineoplastic agents: antimetabolites. In: Drug Evaluations. 7th ed. Chicago, Ill: American Medical Association; 1994:2033-2052.
- Levy S, Furst K, Chern W. A novel 0.5% fluorouracil cream is minimally absorbed into the systemic circulation yet is as effective as 5% fluorouracil cream. Cutis. 2002;70:14-21.
- Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology. J Clin Oncol. 1988;6:1653-1664.
- Bergfeld WF, Derbes VJ, Elias PM, et al. The treatment of keratosis palmaris et plantaris with isotretinoin. a multicenter study. J Am Acad Dermatol. 1982;6:727-731.
- Rivers JK, Duke EE, Justus DW. Etretinate: management of keratoderma hereditaria mutilans in four family members. J Am Acad Dermatol. 1985;13:43-49.
- Schnyder UW. Inherited keratodermas of palms and soles. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedburg IM, Austen KF, eds. Dermatology in General Medicine. Vol 1. 4th ed. New York, NY: McGraw-Hill; 1993:557-564.
- Engin H, Akdogan A, Altundag O, et al. Non–small-cell lung cancer with nonfamilial diffuse palmoplantar keratoderma. J Exp Clin Cancer Res. 2002;21:45-47.
- Osman Y, Daly TJ, Don PC. Spiny keratoderma of the palms and soles. J Am Acad Dermatol. 1992;26:879-881.
- Kanitakis J, Tsoitis G, Kanitakis C. Hereditary epidermolytic palmoplantar keratoderma (Vorner type). report of a familial case and review of the literature. J Am Acad Dermatol. 1987;17:414-422.
- Emmert S, Kuster W, Hennies HC, et al. 47 patients in 14 families with the rare genodermatosis keratosis punctata palmoplantaris Buschke-Fischer-Brauer. Eur J Dermatol. 2003;13:16-20.
- Lokich JJ, Ahlgren JD, Gullo JJ, et al. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol. 1989;7:425-432.
- Salamon T, Stolic V, Lazovic-Tepavac O, et al. Peculiar findings in a family with keratodermia palmo-plantaris papulosa Buschke-Fischer-Brauer. Hum Genet. 1982;60:314-319.
- Stanimirovic A, Kansky A, Basta-Juzbasic A, et al. Hereditary palmoplantar keratoderma, type papulosa, in Croatia. J Am Acad Dermatol. 1993;29:435-437.
- Wachters DH, Frensdorf EL, Hallsman R, et al. Keratosis palmoplantaris nummularis ("hereditary painful callosities"). clinical and histopathological aspects. J Am Acad Dermatol. 1983;9:204-209.
- Lacour M, Menta-Nikhar B, Atherton DJ, et al. An appraisal of acitretin therapy in children with inherited disorders of keratinization. Br J Dermatol. 1996;134:1023-1029.
- Muller SA, Belcher RW, Esterly NB, et al. Keratinizing dermatoses. combined data from four centers on short-term topical treatment with tretinoin. Arch Dermatol. 1977;113:1052-1054.
- Sander CA, Pfeiffer C, Kligman AM, et al. Chemotherapy for disseminated actinic keratoses with 5-fluorouracil and isotretinoin. J Am Acad Dermatol. 1997;36:236-238.
- Antineoplastic agents: antimetabolites. In: Drug Evaluations. 7th ed. Chicago, Ill: American Medical Association; 1994:2033-2052.
- Levy S, Furst K, Chern W. A novel 0.5% fluorouracil cream is minimally absorbed into the systemic circulation yet is as effective as 5% fluorouracil cream. Cutis. 2002;70:14-21.
- Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology. J Clin Oncol. 1988;6:1653-1664.
