Many clinicians have had experiences with using imiquimod since its arrival on the dermatology formularies. However, many questions still remain among dermatologists and physician extenders about how to obtain the results expected as well as how to minimize potential hurdles to compliance.
Several issues that still linger can be resolved by applying the science of the mechanisms of action of the drug to the science of the disease process being approached. This requires taking the cookbook and throwing it away, because the reality is that this class of drugs works outside of recipes.
MECHANISM OF ACTION
Imiquimod is a member of the imidazoquinolinamine family. Its mechanism of action classifies it as an immune response modifier, based on the augmentation of cellular immune responses and recruitment of cytokines and natural killer cell activity. The main impact is up regulation of the primary Th-1 cytokines IL-1, IL-6, IL-8, IL-12, IFNa, and TNF-a. However, there are no effects on IL-2, which signifies that imiquimod does not create a new immune process; rather it augments a response that is already active to make it more effective. In addition, there is inhibition of the Th-2 response, resulting in diminished levels of IL-4, IL-5.1,2 Therefore, imiquimod is useful in disease states requiring cellular immunity such as tumors and viral infections, as well as conditions of Th-2 over-expression like atopic or autoimmune states. 1,2,3,4
In essence, this means that imiquimod is not creating a new immune response against a target antigen; rather it is taking the process that is already in motion and making it work harder. For example, when we see a biopsy specimen of a basal cell carcinoma (BCC), more often than not there is an infiltrate surrounding the tumor. The BCC has developed ways to render that infiltrate useless as well as fight off the mechanisms of apoptosis by the host. However, when imiquimod is introduced, the host immune machinery is restored.
MODIFYING DISEASE PROCESS
The concept of augmenting an immune response and promoting cellular immunity is the basis for modifying the process of the disease, not just alleviating symptoms. For example, this is important for preventing long-term outcomes such as invasive squamous cell carcinoma occurring in skin that has heavy photodamage or multiple actinic keratoses.
This is based on the idea that antigen processing leads to inflammation that is focused against that target, whether it is inflammatory, infectious, or neoplastic. When inflammation is created with a purpose in this fashion, it can be considered to be a primary component of the process to modify the disease.
The opposite effect occurs when inflammation is recruited as an after-effect of the disease or treatment but has no impact on the progression or future of the disease; in this case, the inflammation is a secondary phenomenon. 3,4
DOES MECHANISM OF ACTION MATTER?
When choosing therapies, one of the first questions asked is, “What is the likelihood of improvement?” This is where we have to step back and be cognizant of what is truly the disease and what are symptoms of the disease. For example, while actinic keratosis is considered a disease, the lesions are also a symptom of photodamage, which is the true disease process that creates AKs. As a result, we must consider the recurrence potential of the disease in addition to the clearance potential of the treatment.5
An ability to differentiate between recurrence and relapse are important in understanding the impact of therapy on the disease process and determining if it is in fact working.
For example, if a treated AK on the nose resolves but recurs in 6 months, then this is a recurrence of that original symptom.
However, if the AK on the nose clears and a new one appears on the forehead, that is a relapse of the disease of photodamage with a new symptom.5,6
WHY SOME PATIENTS HAVE MINIMAL REACTIONS
The clinical signs of immune stimulation can vary among patients in that responses may range from minimal erythema to aggressive crusted plaques around the applications sites.
Some patients do not have erythema or induration at the site of action, yet when assessed at the endpoint of treatment there is clinical evidence of efficacy, for example, with reduction in size of tumors or warts or numbers of actinic keratoses.
This may be explained by a study done by Li et al,7 where a randomized group of patients was treated with different dosage protocols up to the point of erythema but did not actually become red. However, there was improvement overall in the conditions treated.
The message to consider is that the subtherapeutic effects correlate to recruitment of cytokines, not to clinical inflammation.7
Therefore, patients may not have a clinical inflammatory sign even though their immune system has processed the antigens involved and the response is augmented. Clinically, it is clear that patients need to continue the course to the endpoint of treatment, even if there is no evidence of erythema.7
WHY SOME PEOPLE HAVE BRISK REACTIONS
On the other hand, the patients who experience vigorous reactions often have concomitant superinfections in the treatment sites. This is often due to photodamaged skin’s having lost its baseline immune surveillance, resulting in colonization of gram-positive and anaerobic skin organisms such as Staphylococcus aureus or epidermidis species. Isolation of S. aureus can result in aggressive reactions in eroded lesions resulting in heavy crust and erosions. Whether it is a function of infection vs. colonization is often secondary to the augmented immune response. One possibility is a result of the activity of protein A superantigen from S. aureus.8
Another possible explanation is enhanced CD8 recruitment to the site of application because more than one toll-like receptor has been stimulated to recognize bacterial antigens, such as TLR-2 (bacterial peptidoglycan) or TLR-4 (bacterial lipopolysaccharide).9
HOW CAN YOU GET PATIENTS TO STICK WITH IT?
Compliance problems develop from the persistence of reactions as well as reactions between lesions that patients may not expect or fully understand. This is where dermatologists or staff members should take time to explain these concepts as well as other measures when giving the first prescriptions.
Many patients will need significant hand-holding working with the packets, understanding the risks of over-application and being aware of “interferon”-type reactions such as myalgias, flu-like symptoms, and nausea.
In addition, patients can be encouraged to continue when seen back in 10 to 14 days, at which point they can be reassured that reactions they may have thought were adverse or possibly allergic are actually the desired ones.
Another consideration is that if patients are “not reacting,” they can be told to watch more for the endpoint rather than the erythematous reaction, because they may be having subclinical responses.
From this step, the patient’s treatment regimen can be altered because he or she will have a better understanding of the unique class of drug being used.
The main thing to remember is that, unlike the old regimen of steroids after a course of topical 5-FU, with imiquimod, steroids are never used to calm a response, because it would be counterproductive to the mechanism of processing antigen, thereby negating the gains of using imiquimod. Patients would benefit more from control of the symptoms with topical anesthetics, topical anti-itch lotions, and bacteriostatic ointments and emollients while continuing the treatment with the IRM so that the overall process is not disrupted and compliance is not sacrificed.
But for many, the question of “why add a topical when freezing does just fine?” has to be answered. When a patient has an endless supply of actinic keratoses, poor wound healing, an intolerance to liquid nitrogen after countless appointments, minimal prescription coverage and a history of poor compliance — what do you do?
The simplest approach is to bargain with the patient about distributing the drug on different days but still maximizing the full treatment course to the endpoint. In addition, with a few samples and rebates for the prescription, the patient can afford the complete course.
From here, the treatment plan involves rotation of sites to minimize side effects so that he does not give up in the middle of the course.
By treating his temples and cheeks on Monday and Thursday, his dorsal hands on Tuesday and Friday, and his scalp and forehead on Wednesday and Saturday, this accomplishes several goals:
1. He is still treating himself with the protocol from the package insert with 2x/week for 16 weeks in each treatment area.
2. He is able to maximize a packet to last 3 days and thereby make the packets last up to 6 weeks by using two packets per week on all the treatment areas.
3. He can apply moisturizer over the face and limbs to maximize distribution, which will not impair absorption, thus achieving a better a spread of the drug.
CAN THE PATIENT STILL USE SUNSCREENS, RETINOIDS AND KERATOLYTICS?
Patients with photodamage and solid tumors commonly treated with imiquimod can still benefit from other therapies. Hats and sunscreens do not interfere with the mechanism of the drug or outcomes.
The use of retinoids will enhance the overall control of photodamage and wound healing repair, although the minimal anti-inflammatory effect of retinoids will not impact imiquimod.
Finally, other keratolytics and even topical antimetabolites such as topical 5-FU can be used at the same time because they affect epidermal turnover and keratolytic effects, which are not part of the impact that imiquimod has on the process.
Topical preparations that include hyaluronic acid such as Bionect 0.2% cream have healing properties beneficial to the photodamaged skin treated with imiquimod.
This concept began with studies done on patients receiving radiation therapy where they were randomized between vehicle and active drug. The patients treated with active drug experienced less erythema, less tissue breakdown, and accelerated wound healing. These would be beneficial to the imiquimod patient who is experiencing vigorous responses or may not wish to look very red and therefore limit their compliance.10
Download Table 1
Many clinicians have had experiences with using imiquimod since its arrival on the dermatology formularies. However, many questions still remain among dermatologists and physician extenders about how to obtain the results expected as well as how to minimize potential hurdles to compliance.
Several issues that still linger can be resolved by applying the science of the mechanisms of action of the drug to the science of the disease process being approached. This requires taking the cookbook and throwing it away, because the reality is that this class of drugs works outside of recipes.
MECHANISM OF ACTION
Imiquimod is a member of the imidazoquinolinamine family. Its mechanism of action classifies it as an immune response modifier, based on the augmentation of cellular immune responses and recruitment of cytokines and natural killer cell activity. The main impact is up regulation of the primary Th-1 cytokines IL-1, IL-6, IL-8, IL-12, IFNa, and TNF-a. However, there are no effects on IL-2, which signifies that imiquimod does not create a new immune process; rather it augments a response that is already active to make it more effective. In addition, there is inhibition of the Th-2 response, resulting in diminished levels of IL-4, IL-5.1,2 Therefore, imiquimod is useful in disease states requiring cellular immunity such as tumors and viral infections, as well as conditions of Th-2 over-expression like atopic or autoimmune states. 1,2,3,4
In essence, this means that imiquimod is not creating a new immune response against a target antigen; rather it is taking the process that is already in motion and making it work harder. For example, when we see a biopsy specimen of a basal cell carcinoma (BCC), more often than not there is an infiltrate surrounding the tumor. The BCC has developed ways to render that infiltrate useless as well as fight off the mechanisms of apoptosis by the host. However, when imiquimod is introduced, the host immune machinery is restored.
MODIFYING DISEASE PROCESS
The concept of augmenting an immune response and promoting cellular immunity is the basis for modifying the process of the disease, not just alleviating symptoms. For example, this is important for preventing long-term outcomes such as invasive squamous cell carcinoma occurring in skin that has heavy photodamage or multiple actinic keratoses.
This is based on the idea that antigen processing leads to inflammation that is focused against that target, whether it is inflammatory, infectious, or neoplastic. When inflammation is created with a purpose in this fashion, it can be considered to be a primary component of the process to modify the disease.
The opposite effect occurs when inflammation is recruited as an after-effect of the disease or treatment but has no impact on the progression or future of the disease; in this case, the inflammation is a secondary phenomenon. 3,4
DOES MECHANISM OF ACTION MATTER?
When choosing therapies, one of the first questions asked is, “What is the likelihood of improvement?” This is where we have to step back and be cognizant of what is truly the disease and what are symptoms of the disease. For example, while actinic keratosis is considered a disease, the lesions are also a symptom of photodamage, which is the true disease process that creates AKs. As a result, we must consider the recurrence potential of the disease in addition to the clearance potential of the treatment.5
An ability to differentiate between recurrence and relapse are important in understanding the impact of therapy on the disease process and determining if it is in fact working.
For example, if a treated AK on the nose resolves but recurs in 6 months, then this is a recurrence of that original symptom.
However, if the AK on the nose clears and a new one appears on the forehead, that is a relapse of the disease of photodamage with a new symptom.5,6
WHY SOME PATIENTS HAVE MINIMAL REACTIONS
The clinical signs of immune stimulation can vary among patients in that responses may range from minimal erythema to aggressive crusted plaques around the applications sites.
Some patients do not have erythema or induration at the site of action, yet when assessed at the endpoint of treatment there is clinical evidence of efficacy, for example, with reduction in size of tumors or warts or numbers of actinic keratoses.
This may be explained by a study done by Li et al,7 where a randomized group of patients was treated with different dosage protocols up to the point of erythema but did not actually become red. However, there was improvement overall in the conditions treated.
The message to consider is that the subtherapeutic effects correlate to recruitment of cytokines, not to clinical inflammation.7
Therefore, patients may not have a clinical inflammatory sign even though their immune system has processed the antigens involved and the response is augmented. Clinically, it is clear that patients need to continue the course to the endpoint of treatment, even if there is no evidence of erythema.7
WHY SOME PEOPLE HAVE BRISK REACTIONS
On the other hand, the patients who experience vigorous reactions often have concomitant superinfections in the treatment sites. This is often due to photodamaged skin’s having lost its baseline immune surveillance, resulting in colonization of gram-positive and anaerobic skin organisms such as Staphylococcus aureus or epidermidis species. Isolation of S. aureus can result in aggressive reactions in eroded lesions resulting in heavy crust and erosions. Whether it is a function of infection vs. colonization is often secondary to the augmented immune response. One possibility is a result of the activity of protein A superantigen from S. aureus.8
Another possible explanation is enhanced CD8 recruitment to the site of application because more than one toll-like receptor has been stimulated to recognize bacterial antigens, such as TLR-2 (bacterial peptidoglycan) or TLR-4 (bacterial lipopolysaccharide).9
HOW CAN YOU GET PATIENTS TO STICK WITH IT?
Compliance problems develop from the persistence of reactions as well as reactions between lesions that patients may not expect or fully understand. This is where dermatologists or staff members should take time to explain these concepts as well as other measures when giving the first prescriptions.
Many patients will need significant hand-holding working with the packets, understanding the risks of over-application and being aware of “interferon”-type reactions such as myalgias, flu-like symptoms, and nausea.
In addition, patients can be encouraged to continue when seen back in 10 to 14 days, at which point they can be reassured that reactions they may have thought were adverse or possibly allergic are actually the desired ones.
Another consideration is that if patients are “not reacting,” they can be told to watch more for the endpoint rather than the erythematous reaction, because they may be having subclinical responses.
From this step, the patient’s treatment regimen can be altered because he or she will have a better understanding of the unique class of drug being used.
The main thing to remember is that, unlike the old regimen of steroids after a course of topical 5-FU, with imiquimod, steroids are never used to calm a response, because it would be counterproductive to the mechanism of processing antigen, thereby negating the gains of using imiquimod. Patients would benefit more from control of the symptoms with topical anesthetics, topical anti-itch lotions, and bacteriostatic ointments and emollients while continuing the treatment with the IRM so that the overall process is not disrupted and compliance is not sacrificed.
But for many, the question of “why add a topical when freezing does just fine?” has to be answered. When a patient has an endless supply of actinic keratoses, poor wound healing, an intolerance to liquid nitrogen after countless appointments, minimal prescription coverage and a history of poor compliance — what do you do?
The simplest approach is to bargain with the patient about distributing the drug on different days but still maximizing the full treatment course to the endpoint. In addition, with a few samples and rebates for the prescription, the patient can afford the complete course.
From here, the treatment plan involves rotation of sites to minimize side effects so that he does not give up in the middle of the course.
By treating his temples and cheeks on Monday and Thursday, his dorsal hands on Tuesday and Friday, and his scalp and forehead on Wednesday and Saturday, this accomplishes several goals:
1. He is still treating himself with the protocol from the package insert with 2x/week for 16 weeks in each treatment area.
2. He is able to maximize a packet to last 3 days and thereby make the packets last up to 6 weeks by using two packets per week on all the treatment areas.
3. He can apply moisturizer over the face and limbs to maximize distribution, which will not impair absorption, thus achieving a better a spread of the drug.
CAN THE PATIENT STILL USE SUNSCREENS, RETINOIDS AND KERATOLYTICS?
Patients with photodamage and solid tumors commonly treated with imiquimod can still benefit from other therapies. Hats and sunscreens do not interfere with the mechanism of the drug or outcomes.
The use of retinoids will enhance the overall control of photodamage and wound healing repair, although the minimal anti-inflammatory effect of retinoids will not impact imiquimod.
Finally, other keratolytics and even topical antimetabolites such as topical 5-FU can be used at the same time because they affect epidermal turnover and keratolytic effects, which are not part of the impact that imiquimod has on the process.
Topical preparations that include hyaluronic acid such as Bionect 0.2% cream have healing properties beneficial to the photodamaged skin treated with imiquimod.
This concept began with studies done on patients receiving radiation therapy where they were randomized between vehicle and active drug. The patients treated with active drug experienced less erythema, less tissue breakdown, and accelerated wound healing. These would be beneficial to the imiquimod patient who is experiencing vigorous responses or may not wish to look very red and therefore limit their compliance.10
Download Table 1
Many clinicians have had experiences with using imiquimod since its arrival on the dermatology formularies. However, many questions still remain among dermatologists and physician extenders about how to obtain the results expected as well as how to minimize potential hurdles to compliance.
Several issues that still linger can be resolved by applying the science of the mechanisms of action of the drug to the science of the disease process being approached. This requires taking the cookbook and throwing it away, because the reality is that this class of drugs works outside of recipes.
MECHANISM OF ACTION
Imiquimod is a member of the imidazoquinolinamine family. Its mechanism of action classifies it as an immune response modifier, based on the augmentation of cellular immune responses and recruitment of cytokines and natural killer cell activity. The main impact is up regulation of the primary Th-1 cytokines IL-1, IL-6, IL-8, IL-12, IFNa, and TNF-a. However, there are no effects on IL-2, which signifies that imiquimod does not create a new immune process; rather it augments a response that is already active to make it more effective. In addition, there is inhibition of the Th-2 response, resulting in diminished levels of IL-4, IL-5.1,2 Therefore, imiquimod is useful in disease states requiring cellular immunity such as tumors and viral infections, as well as conditions of Th-2 over-expression like atopic or autoimmune states. 1,2,3,4
In essence, this means that imiquimod is not creating a new immune response against a target antigen; rather it is taking the process that is already in motion and making it work harder. For example, when we see a biopsy specimen of a basal cell carcinoma (BCC), more often than not there is an infiltrate surrounding the tumor. The BCC has developed ways to render that infiltrate useless as well as fight off the mechanisms of apoptosis by the host. However, when imiquimod is introduced, the host immune machinery is restored.
MODIFYING DISEASE PROCESS
The concept of augmenting an immune response and promoting cellular immunity is the basis for modifying the process of the disease, not just alleviating symptoms. For example, this is important for preventing long-term outcomes such as invasive squamous cell carcinoma occurring in skin that has heavy photodamage or multiple actinic keratoses.
This is based on the idea that antigen processing leads to inflammation that is focused against that target, whether it is inflammatory, infectious, or neoplastic. When inflammation is created with a purpose in this fashion, it can be considered to be a primary component of the process to modify the disease.
The opposite effect occurs when inflammation is recruited as an after-effect of the disease or treatment but has no impact on the progression or future of the disease; in this case, the inflammation is a secondary phenomenon. 3,4
DOES MECHANISM OF ACTION MATTER?
When choosing therapies, one of the first questions asked is, “What is the likelihood of improvement?” This is where we have to step back and be cognizant of what is truly the disease and what are symptoms of the disease. For example, while actinic keratosis is considered a disease, the lesions are also a symptom of photodamage, which is the true disease process that creates AKs. As a result, we must consider the recurrence potential of the disease in addition to the clearance potential of the treatment.5
An ability to differentiate between recurrence and relapse are important in understanding the impact of therapy on the disease process and determining if it is in fact working.
For example, if a treated AK on the nose resolves but recurs in 6 months, then this is a recurrence of that original symptom.
However, if the AK on the nose clears and a new one appears on the forehead, that is a relapse of the disease of photodamage with a new symptom.5,6
WHY SOME PATIENTS HAVE MINIMAL REACTIONS
The clinical signs of immune stimulation can vary among patients in that responses may range from minimal erythema to aggressive crusted plaques around the applications sites.
Some patients do not have erythema or induration at the site of action, yet when assessed at the endpoint of treatment there is clinical evidence of efficacy, for example, with reduction in size of tumors or warts or numbers of actinic keratoses.
This may be explained by a study done by Li et al,7 where a randomized group of patients was treated with different dosage protocols up to the point of erythema but did not actually become red. However, there was improvement overall in the conditions treated.
The message to consider is that the subtherapeutic effects correlate to recruitment of cytokines, not to clinical inflammation.7
Therefore, patients may not have a clinical inflammatory sign even though their immune system has processed the antigens involved and the response is augmented. Clinically, it is clear that patients need to continue the course to the endpoint of treatment, even if there is no evidence of erythema.7
WHY SOME PEOPLE HAVE BRISK REACTIONS
On the other hand, the patients who experience vigorous reactions often have concomitant superinfections in the treatment sites. This is often due to photodamaged skin’s having lost its baseline immune surveillance, resulting in colonization of gram-positive and anaerobic skin organisms such as Staphylococcus aureus or epidermidis species. Isolation of S. aureus can result in aggressive reactions in eroded lesions resulting in heavy crust and erosions. Whether it is a function of infection vs. colonization is often secondary to the augmented immune response. One possibility is a result of the activity of protein A superantigen from S. aureus.8
Another possible explanation is enhanced CD8 recruitment to the site of application because more than one toll-like receptor has been stimulated to recognize bacterial antigens, such as TLR-2 (bacterial peptidoglycan) or TLR-4 (bacterial lipopolysaccharide).9
HOW CAN YOU GET PATIENTS TO STICK WITH IT?
Compliance problems develop from the persistence of reactions as well as reactions between lesions that patients may not expect or fully understand. This is where dermatologists or staff members should take time to explain these concepts as well as other measures when giving the first prescriptions.
Many patients will need significant hand-holding working with the packets, understanding the risks of over-application and being aware of “interferon”-type reactions such as myalgias, flu-like symptoms, and nausea.
In addition, patients can be encouraged to continue when seen back in 10 to 14 days, at which point they can be reassured that reactions they may have thought were adverse or possibly allergic are actually the desired ones.
Another consideration is that if patients are “not reacting,” they can be told to watch more for the endpoint rather than the erythematous reaction, because they may be having subclinical responses.
From this step, the patient’s treatment regimen can be altered because he or she will have a better understanding of the unique class of drug being used.
The main thing to remember is that, unlike the old regimen of steroids after a course of topical 5-FU, with imiquimod, steroids are never used to calm a response, because it would be counterproductive to the mechanism of processing antigen, thereby negating the gains of using imiquimod. Patients would benefit more from control of the symptoms with topical anesthetics, topical anti-itch lotions, and bacteriostatic ointments and emollients while continuing the treatment with the IRM so that the overall process is not disrupted and compliance is not sacrificed.
But for many, the question of “why add a topical when freezing does just fine?” has to be answered. When a patient has an endless supply of actinic keratoses, poor wound healing, an intolerance to liquid nitrogen after countless appointments, minimal prescription coverage and a history of poor compliance — what do you do?
The simplest approach is to bargain with the patient about distributing the drug on different days but still maximizing the full treatment course to the endpoint. In addition, with a few samples and rebates for the prescription, the patient can afford the complete course.
From here, the treatment plan involves rotation of sites to minimize side effects so that he does not give up in the middle of the course.
By treating his temples and cheeks on Monday and Thursday, his dorsal hands on Tuesday and Friday, and his scalp and forehead on Wednesday and Saturday, this accomplishes several goals:
1. He is still treating himself with the protocol from the package insert with 2x/week for 16 weeks in each treatment area.
2. He is able to maximize a packet to last 3 days and thereby make the packets last up to 6 weeks by using two packets per week on all the treatment areas.
3. He can apply moisturizer over the face and limbs to maximize distribution, which will not impair absorption, thus achieving a better a spread of the drug.
CAN THE PATIENT STILL USE SUNSCREENS, RETINOIDS AND KERATOLYTICS?
Patients with photodamage and solid tumors commonly treated with imiquimod can still benefit from other therapies. Hats and sunscreens do not interfere with the mechanism of the drug or outcomes.
The use of retinoids will enhance the overall control of photodamage and wound healing repair, although the minimal anti-inflammatory effect of retinoids will not impact imiquimod.
Finally, other keratolytics and even topical antimetabolites such as topical 5-FU can be used at the same time because they affect epidermal turnover and keratolytic effects, which are not part of the impact that imiquimod has on the process.
Topical preparations that include hyaluronic acid such as Bionect 0.2% cream have healing properties beneficial to the photodamaged skin treated with imiquimod.
This concept began with studies done on patients receiving radiation therapy where they were randomized between vehicle and active drug. The patients treated with active drug experienced less erythema, less tissue breakdown, and accelerated wound healing. These would be beneficial to the imiquimod patient who is experiencing vigorous responses or may not wish to look very red and therefore limit their compliance.10
Download Table 1
